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A study of sponge as a disintegrating agent in compressed tablets

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Title:
A study of sponge as a disintegrating agent in compressed tablets
Creator:
Crisafi, Robert Carl, 1931-
Publication Date:
Language:
English
Physical Description:
viii, 106 leaves : ill. ; 29 cm.

Subjects

Subjects / Keywords:
Corn starch ( jstor )
Hardness ( jstor )
Lubricants ( jstor )
Magnesium ( jstor )
Relative humidity ( jstor )
Sodium ( jstor )
Starches ( jstor )
Storage conditions ( jstor )
Storage time ( jstor )
Writing tablets ( jstor )
Dissertations, Academic -- pharmacy -- UF ( mesh )
Pharmacy Thesis Ph.D ( mesh )
Porifera ( mesh )
Tablets ( mesh )
Genre:
bibliography ( marcgt )
non-fiction ( marcgt )

Notes

Thesis:
Thesis (Ph.D.)--University of Florida, 1956.
Bibliography:
Bibliography: leaves 102-105.
General Note:
Typescript.
General Note:
Vita.
Statement of Responsibility:
by Robert Carl Crisafi.

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University of Florida
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University of Florida
Rights Management:
Copyright [name of dissertation author]. Permission granted to the University of Florida to digitize, archive and distribute this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Resource Identifier:
000892231 ( ALEPH )
25174131 ( OCLC )
AEK0708 ( NOTIS )

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A STUDY OF SPONGE

AS A DISINTEGRATING AGENT

IN COMPRESSED TABLETS









By
ROBERT CARL CRISAFI


A DISSERTATION PRESENTED TO THE GRADUATE COUNCIL OF
THE UNIVERSITY OF FLORIDA
IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE
DEGREE OF DOCTOR OF PHILOSOPHY









UNIVERSITY OF FLORIDA
August, 1956















ACKNOWLEDGMEN TS


The writer wishes to express his sincere appreciation and thanks

to Dr. Charles H. Becker, Chairman of the Supervisory Committee, under

whose guidance this work was undertaken. It was through his advice and

understanding that the completion of this investigation was made possible.

The assistance and friendship of Dr. William J. Husa throughout

the writer's graduate work are also gratefully acknowledged.

Suggestions generously offered by the other members of the

Supervisory Committee, Drs. W. M. Later, M. Herzberg, and C. H. Johnson

are greatly appreciated.

As a Fellow of the American Foundation for Pharmaceutical Edu-

cation, the writer wishes to acknowledge its invaluable support.

To his parents, Mr. and Mrs. Joseph Crisafi, he will be eternally

indebted for their love and encouragement.

Sincere and deepest appreciation is expressed to the writer's

wife, Barbara, for her encouragement, love and understanding, as well as

her help in the preparation of this manuscript. Without her assistance

and moral support this work would not have been accomplished.












TABLE OF CONTENTS


Page
ACKNOWLEDGMENTS iS

LIST OF TABLES v

LIST OF FIGURES viii

INTRODUCTION 1

REVIEW OF THE LITERATURE 3

Methods of Preparing Tablets 3

Disintegrating Agents 7

Methods of Testing Disintegration 15

Factors Influencing Tablet Disintegration 19

Sponge 23

EXPERIMENTAL PROCEDURE 26

Materials and Equipment Used 26

Description of Sponges Used 28

Natural Sponge 28

Synthetic Sponge 28

Treatment of Spongin Before Use 29

Cleansing Procedure 29

Bleaching Procedure 30

Grinding Procedure 32

Treatment of Synthetic Sponge Before Use '33

Tablet Constituents 34

Active Ingredients 34


lii








Page

Diluent 34
Disintegrating Agents 34
Binding Agents 36
Lubricating Agents 37

Tablet Formulation 38

Preparing the Tablet Granulation 39
Compressing the Granulation 47

Equipment and Procedure 47

Test Methods 50
-Hardness Test 50
Disintegration Test 50
Friability Test 5$1
Storage Test 52
Absorption Study 54

EXPERIMENTAL RESULTS 55
DISCUSSION OF RESULTS 85
Bleaching of Sponge 85
Tablet Preparation 86
Disintegration Studies 88
Friability Studies P2
Binding and Lubrication Studies 94
Storage Studies 97
SUMMKAR 100
BIBLIOGRAPHY 102
BIOGRAPHICAL ITEMS 106
COMMITTEE REPORT 107









-LIST OF TABLES


Table Page

1. Materials Used 26
2. Equipment Used 27

3. Drugs Compressed into Tablets 34

4. Tablet Formulas for Preliminary Study 40
5. Tablet Formulas 41

6. Tablet Formulas 43

7. Description of Sized Granulations 16
8. Moisture Absorbed by Powdered Spongin and Corn Starch
at Various Relative Humidities 55

9. A Comparison of the Disintegration Times of Tablets
Immediately After Compression 57

10. Relationship Between Tablet Hardness, Friability and
Disintegration Time 59

11. Friability Values After Two Shaking Periods 65

12. Friability Values of Tablets Protected with a Cotton
Filler in Vials 66

13. Comparison of Disintegration Rates of Tablets Prepared
with Different Binding Agents 66

14. Comparison of Disintegration Rates of Tablets Prepared
with Different Lubricating Agents 67

15. Tablet Disintegration Times After Storage for Intervals
of 250, 500 and 750 Hours in Open Vials at Various
Temperature Conditions 69

16. Tablet Disintegration Times After Storage for Intervals
of 250, 500 and 750 Hours in Closed Vials at Various
Temperature Conditions 69

17. Tablet Disintegration Times After Storage for Intervals
of 250, 500 and 750 Hours in Open Vials at Various
Relative Humidities 70









Page


Table


18. Tablet Disintegration Times After Storage for Intervals
of 250, 500 and 750 Hours in Closed Vials at Various
Relative Humidities 71

'19. Changes in Tablet Hardness After Storage for Intervals
of 250, 500 and 750 Hours at Various Relative Humidities 72

20. Changes in Tablet Weight After Storage at Various
Relative Humidities 73

21. Changes in Tablet Weight, Hardness and Disintegration
Time After Storage for Intervals of 500 and 1000 Hours
in Open Vials at Various Temperature Conditions 74

22. Changes in Tablet Weight, Hardness and Disintegration
Time After Storage for Intervals of 500 and 1000 Hours
in Closed Vials at Various Temperature Conditions 75

23. Changes in Tablet Weight, Hardness and Disintegration
Time After Storage for 1000 Hours in Open Vials at
Various Relative Humidities 76

24. Changes in Tablet Weight, Hardness and Disintegration Time
After Storage for 1000 Hours in Closed Vials at Various
Relative Humidities 77

25. Changes in Tablet Weight, Hardness and Disintegration Time
After Storage for Intervals of 500 and 1000 Hours in Open
Vials at Various Temperature Conditions 78

26. Changes in Tablet Weight, Hardness and Disintegration Time
After Storage for Intervals of 500 and 1000 Hours in Closed
Vials at Various Temperature Conditions 79

27. Changes in Tablet Weight, Hardness and Disintegration Time
After Storage for 1000 Hours in Open Vials at Various
Relative Humidities 80

28. Changes in Tablet Weight, Hardness and Disintegration Time
After Storage for 1000 Hours in Closed Vials at Various
Relative Humidities g

29. Changes in Tablet Weight, Hardness and Disintegration Time
After Storage for 1000 Hours in Open Vials at Various
Relative Humidities 81









Table


Page


30. Changes in Tablet Weight, Hardness and Disintegration
Time After Storage for 1000 Hours in Closed Vials at
Various Relative Humidities 82

31. Changes in Tablet Weight of Differently Lubricated Tablets
After Storage for 500 Hours in Open Vials at Various
Temperature Conditions 83

32. Changes in Tablet Weight of Differently Lubricated Tablets
After Storage for 500 Hours in Open Vials at Various
Relative Humidities 84











LIST OF FIGURES


Figure Page

1. Sponge Clippings Before Cleansing and Bleaching 31

2. Sponge Clippings After Cleansing and Bleaching 31

3. Absorption of Moisture by Powdered Spongin and
Corn Starch $6

4. Relationship Between Disintagration Time and Tablet
Hardness for Tablets Prepared with Spongin as the
Disintegrant Showing a Minimum Point in the Curve 62

5. Tablets Prepared with Corn Starch as the Disintegrant
Showing a Linear Relationship Between Disintegration
Time and Tablet Hardness 63

6. Relationship Between Tablet Friability and Tablet
Hardness 64

7. Relationship Between Tablet Friability and Tablet
Hardness 64

8. Comparative Disintegration Rates for Differently
Lubricated Tablets of Formula BSN-AT-5-a 68

9.' Comparative Disintegration Rates for Differently
Lubricated Tablets of Formula BSN-AS-1O-c 68

10. Comparative Disintegration Rates for Differently
Lubricated Tablets of Formula SB-B-10 68


viii












INTRODUCTION


Tablets, as a means of administering medicine, have been in ex-

istance for over one hundred years. Today, compressed tablets are the

most popular form of medication. Americans consume about forty-two

million tablets daily (1). Whether or not these forty-two million tab-

lets exert the intended therapeutic action depends to a great extent

on one essential property of the tablets, namely disintegration. Despite

the importance of this property, it took eighty years from the time tab-

lets were first manufactured in the United States, in 1870, and thirty-

four years after the first tablet appeared in the U. S. P. IX, until

official requirements for disintegration were established. During the

interim, great objection was made'to tablets due to the fact that many

tablets, as described by one observer, would pass through the human

system showing as much change as a glass marble (2).

In order to accomplish tablet disintegration, at least in the

case of insoluble materials, it is necessary to add a substance to the

tablet formula which has the capacity to break the tablet apart. This

agent is called a disintegrator. While there are many conditions which

influence the rate of disintegration, the proportions and types of

binding and disintegrating agents in the tablet formula are, in many cases,

the most important factors controlling the disintegration of this form of

medication.

On the basis of a study by Gross and Becker (3), powdered sponge










2

was found to be the beet disintegrating agent among the twenty-two dif-

ferent materials "tried. Since their work was limited to lactose tablets

and a single percentage of sponge, it was the purpose of this investi-

gation to make a more detailed study of this agent.

Sponges, both natural an^ synthetic, in varying concentrations

were evaluated as disintegrants for compressed tablets. These tablets

were compared for disintegration time against tablets containing corn

starch as the disintegrator. In addition, the effects of various lubri-

cants and binding agents on disintegration time of the tablets were

studied.













REVIEW OF THE LITERATURE


Methods of Preparing Tablets

Tablets are unit dosage forms of medication in the form of a

granular powder, with or without diluents, compressed into a suitable

shape (h).

The general method of preparing compressed tablets encompasses

one of three specific procedures.

a. Direct compression

b. Slugging process

c. Wet granulation process

If the material to be compressed is free-flowing and cohesive

without the addition of binders or lubricants, then the first of the

above methods, direct compression, is utilized. In this method the

material need only be reduced to the proper particle size, which is de-

pendent upon the size of the tablet to be made, and is run directly into

the tablet press without any further preparation or special handling.

Some materials, on the other hand, do not possess either co-

hesiveness or lubricity and these properties must be given to the

materials by either one or the other methods of granulation.

The basic objective in granulation is the conversion of the

powdered ingredients into a free-flowing, uniformly compressible material.

Such a granular material is essential since the compression machines

rely on volumetric gravity fill to achieve uniformity in dosage. Upon












completion of the granulation process, the granules must be self binding

and non-sticking to the punches and dies (5).

The choice of the granulation method to be used is dependent upon

the properties of the materials to be compressed. If the powders are

either heat or moisture labile, then the precompression or "slugging"

method is used which excludes these two factors from the process. If,

on the other hand, these factors are of no concern to the particular

formulation in question, one may use the wet granulation process, cur-

rently the most widely used method for the preparation of granules for

tablet compression.

The process of precompression involves the production of "slugs"

or large tablets which are subsequently screened and recompressed into

finished tablets. In this method, the ingredients in the formula, which

are usually in powder form, are weighed out, mixed, and then sifted

through a No. 30 or h0 sieve. The resultant mixture is compressed in

heavy duty machines into over-sized tablets called "slugs" which are

3/h 7/8" in diameter. These "slugs" are then broken down into ap-

propriate particle size by passing through mechanical granulators with

the desired sieves attached (6).

Although the precompression process completely eliminates many

steps, which are essential in the wet granulation method, it also pos-

sesses several drawbacks. First, the tablets produced are not as hard

as those prepared by wet granulation. Secondly, in order to accomplish

this method satisfactorily, a slow, heavy duty tablet press is required

so that extremely high pressures may be obtained, since such pressures










5

are necessary for the production of "slugs". A third and most important

drawback is the fact that few materials lend themselves to tableting by

this method (10).

For materials that cannot be directly compressed, or are not

heat or moisture labile, the wet granulation method is perhaps the most

generally employed. Here, the material is first converted into a doughy

mass through the use of a granulating agent which is capable of aggre-

gating the powders through either a bonding or solvent action on the

components of the tablets. This doughy mass is broken up into coarse

granules which are subjected to uniform drying. These primary granules

are obtained by forcing the aggregated mass through a No. 6 or No. 8

sieve. After these coarse granules have been sufficiently dried, they

are further broken down to appropriate dimensions. The size of these

final granules has a direct relationship to the appearance and properties

of the finished tablet. Malpass (7) stipulated that the mesh size must

be governed by the size of the tablet and the hardness desired. In 1947,

Silver and Clarkson (11) presented the following schedule of sieve sizes

through which the material should be passed for granulation:

Tablet Size Size Sieve

up to 3/16" No. 20

7/32" 5/16" No. 16

11/32" 13/32" No. 14

7/16" and over No. 12

It is necessary when preparing these final granules, that they










6

be free from excessive "fines" (8). Little and Mitchell (5) state that

fine powders are apt to pack or "bridge" in the hopper, feed shoe, or

die; and thus tablets of uniform weight and uniform compression are not

obtainable. Nevertheless, it should be kept in mind, that in order to

obtain a good tablet a certain percentage of "fines" are necessary.

Silver and Clarkson (11) state that 10 20 per cent of "fines" based on

total granulation are necessary to fill the void space between granules

in order to produce a tablet of smooth appearance. Caspari and Kelly (4)

advocate the use of 10 15 per cent "fines" for optimum tablet appear-

ance. Villacorta (9), working on granulation of acetylsalicylic acid,

recommends that "fines", designated as particles less than 125 microns,

should not exceed 20 per cent in the granulation mixture.

Contrary to all the above findings, Chavkin (10) states that.up

to 80 per cent of material finer than 80 mesh (177 microns) can be in-

corporated into a tablet granulation without adverse effect upon the

hardness of the resulting tablet.

The final step in the wet granulation process, before feeding

the hopper with the granulation, is lubrication of the granules. Lubri-

cation is accomplished by adding a substance to the dry granulation that

will facilitate ejection of the finished tablet from the die after com-

pression.

The disintegrating agent, in some cases, is completely added

with the lubricant during addition of the latter to the granules, but

in most cases it is mixed with the active ingredient and filler, and

an additional amount is very often added to the lubricant.










7

After addition of these latter agents and proper mixing of the

granulation, the material is then ready for compressing.

Disintegrating Agents

An examination of the literature to determine previous research

accomplished on disintegrating agents revealed very little published

information in this field. Undoubtedly, a great deal of work has been

done, especially by pharmaceutical companies, however, since the manu-

facture of tablets is an art and the uniqueness of many commercial

tablets depends upon the type of disintegrating agent used as well as

several.other factors, much of this knowledge has been carefully guarded

by the industry itself and thus remains unpublished. The information

found has been seriously considered in the study of this problem.

A disintegrating agent is a substance which is added to the

tablet to help break it apart after administration or to hasten dis-

persion in water (11).

Disintegrators fall into two main classes. They are: (a) sub-

stances which will swell in the presence of sufficient moisture or other

suitable medial and (b) the addition of chemically reactive ingredients

which when wetted will produce a gas upon reaction and break the tablet.

The former of these two classes, that is, those substances that swell in

the presence of moisture are, by far, the most widely used agents in

tablet manufacture.

Corn starch is one of the oldest and still most cauommonly used

disintegrators in tableting. Starches have a great affinity for water








.8

and through rapid absorption the starch grains swell to many times their

normal size. This expansion causes the tablet to disintegrate or break

apart quite rapidly. This valuable use of starch was first observed by

Charles Killgore, an American, who in 1887 applied for a process patent

which was denied on the basis that starches had previously occurred in

tablets though their value was not recognized (12).

Killgore's patent application, No. 238,375, which was filed May

16, 1887, was in part as follows:

It is well known that the administration of medicines in the
form of'compressed tablets or pills, while having many advantages,
has been open to disadvantage arising from the slowness with which
the same dissolve in the stomach.
The object of my present invention is to form tablets or pills
which, while possessing all the advantages of those heretofore em-
ployed, are not attended by the disadvantage above referred to; in
that when subjected to moisture they rapidly disintegrate. This
result I accomplish by mixing with the ordinary ingredients con-
stituting a compressed tablet or pill a percentage of starch which
will so change the character of the compressed tablet or pill that
the same will not be open to the objection heretofore existing.
The tablet or pill resulting from my invention possesses, as
far as I know, all of the qualities of those heretofore made ex-
cepting when taken into the stomach it immediately disintegrates.
I claim a compressed tablet or pill containing a substantial
percentage of starch, for the purpose of facilitating disintegration,
as set forth.

The following notation was made by the Patent Examiner in re-

jecting the patent application:

Starch is the most commonly used dividing agent. It enters
into pills, tooth powders, baking powders, and toilet powders
generally. Such having been compressed, there is neither novelty
nor invention in applicant's procedure. The application is rejected.
That Killgore's discovery wap quickly used, in secret and without

credit to him, is indicated by an interesting controversy between two

English manufacturers concerning their newly improved tablets (13).

Dieterich (14) wrote, in 1890, that a simple means for









9
obtaining disintegration of tablets was merely to add some powdered

sugar with the active ingredient. Since this method did not accom-

plish its purpose in all tablets, he advised the introduction of a

substance that swells up in water and gave tragacanth powder as an ex-

ample. He noted the use of 10 25 per cent tragacanth as being suf-

ficient.

Blaschnek (15), in 1909, investigated potato, wheat, corn, rice

and maranta starches as disintegrating agents. The results clearly

showed a distinct advantage for maranta and potato starches. A point

brought out by this investigator was that starch must be nearly anhy-

drous if the best results are desired.

In 1914, Kebler (16) stated that mixtures of a bicarbonate and

an acid when incorporated in a tablet and immersed in water react and

give off carbon dioxide, thus mechanically breaking up the tablet. In

the same paper he mentioned that although powdered agar-agar and Irish

moss had been advocated as disintegrators for compressed tablets they

had not been used to any extent.

White (2), in a summary on tablet manufacture, wrote that potato

starch was far superior to all other disintegrating agents used up to

that time. He stated that the potato starch should be adried to the dry

granulation immediately before compressing and not during the granu-

lation process. When prepared in this manner the tablets were found to

swell and rapture when immersed in water.

American and foreign literature on the subject of tablet dis-

integration is very scanty from 1923 to 1946, the majority of the reports

being focused on the application of starch as a means of facilitating








10
tablet disintegration (17 31). Most of this research, however, is

repetitious or contradictory and in many cases hinders rather than

helps the inexperienced tablet maker.

Husa (23), in 1928, suggested the classification of tablets into

different groups according to the type of disintegration they undergo.

He roted that certain tablets dissolve without the aid of a disintegrator

and that these tablets were made from soluble chemicals. He proposed

that tablets of this nature should be classified as a tablet not re-

quiring the aid of a disintegrating agent.

A review on tablet making (24), in 1931, mentioned the use of

pectin as a disintegrant for preparing tablets on a large scale. The

experiments carried out with the addition of one per cent pectin to the

granulation along with a little rice starch proved to give satisfactory

tablets with rapid disintegration rates. It was noted that the addition

of pectin to tablet masses in quantities of ten per cent or more is not

advisable because a thick layer of mucilage forms around the tablet

during the process of disintegration or solution, which, unless vigorous

shaking is resorted to, prevents the water from coming into contact with

the nucleus of the tablet and retards disintegration.

Potato starch, gelonide, and magnesium peroxide have been com-

pared as disintegrants for tablets (27). Oelonide was prepared by

treating a ten per cent aqueous solution of gelatin with a few drops of

formaldehyde solution until a glue-like consistency was obtained. It

was then forced through a No. 22 screen, dried for several hours at 900

C., and powdered. The disintegrants were added to an acetanilid granu-

lation prepared with ten per cent gelatin solution. Potato starch was

found to be superior to the other two disintegrants for acetanilid










tablets.

Milne (32) postulated that methylcellulose would be of value as

a binding agent and compared it to other granulating agents by the dis-

integration time of the resulting tablets. He used the following granu-

lating agents: (a) 10 per cent gelatin solution, (b) 50 per cent alcohol,

(c) 10 per cent starch paste, (d) equal parts of mucilage of acacia and

syrup, and (e) 3 per cent methylcellulose solution. In all cases, the

tablets made were Compound Aspirin Tablets, B. P. C., and all conditions

were kept as constant as possible. Milne found that methylcellulose

compared favorably with starch paste and gelatin solution, the disinte-

gration in these three cases being of the explosive type. He also in-

dicated that tablets made with alcohol or the acacia mucilage-syrup

mixture as a binding agent disintegrated very slowly. Because methyl-

cellulose is stable to heat and is not subject to attack by micro-

organisms and molds, he suggested its use as a binding and disintegrating

agent for compressed tablets.

In 1949s Granberg and Benton (33), working on tablet formulations,

stated that bentonite serves both as a filler and disintegrating agent

when added to thyroid tablets. Because the color of bentonite is ap-

proximately the same as that of powdered thyroid, they suggested its use

as being advantageous over starch, since the latter has a tendency to

discolor the tablet.

Studying alginic acid as a disintegrating agent, Berry and iidout

(30), found that when ten per cent was added in phenobarbital tablets, it

gave a much better disintegration time than 15 per cent of potato starch,

and in the case of barbital tablets the time of disintegration was









12

approximately the same. They stated that alginic acid can be granulated

with the medicaments in a tablet which has the following advantages:

a. The addition of a very fine powder, such as starch to the
granules before tableting, means that there is a considerable
risk of separation of powder and granules during the transfer
of the bulk material to the tablet machine and also, whilst
the material is in the hopper, due to the vibration of the
hopper or of the machine itself. This separation of fine
powder will cause variation in weight of the tablets and also
variation in the amount of active ingredient in each tablet.
There is also the difficulty- by no means inconsiderable- of
ensuring an even distribution of a large quantity of starch
in a bulk of granules.

b. Since the alginic acid in these experiments is an integral
part of the granules, when the tablet breaks up it will do
so to give material which is smaller than the original gran-
ule. The active constituents thus being presented in a finer
form will be more quickly absorbed and give a more rapid
therapeutic action.

c. The process of tableting will be simplified.

Gross ind Becker (3) discovered two new substances and claired

them to be more effective disintegrating agents than many of those

-commonly used. These new agents were powdered sponge and dried citrus

pulp, both prepared in the laboratory from natural Florida products.

These were tested along with 20 other substances on a comparative basis.

The agents'used were corn starch, bentonite, and tragacanth, all of

U. S. P. XIV grade; pectin, karaya gum, sodium alginate, and methyl-

cellulose (100 and h000 cps.) all of N. F. IX grade; also Gelloid 50,

locust bean gum, algin, Veegum H7, Aveeno, and QGC 70. In a separate

category were magnesium peroxide, and, combinations of calcium carbonate

with either citric acid, pectin, or urea monophosphate, in addition to

sodium carbonate peroxide and sodium pyrophosphate peroxide. For the

investigation, tablets were prepared without medicament, lactose being

used as the inert filler and two per cent leucine as the lubricant.









13
Two granulating solutions were employed. One contained five per cent

Zein (corn protein) in isopropyl alcohol and the other had five per cent

zein in a mixture of syrup, water and alcohol. Alternative methods were

employed fof incorporating the disintegrating agents (a) the whole of

the agent was mixed with the lactose before moistening with the granu-

lating solution; (b) five per cent of the agent was reserved for ad-

mixture with the lubricant after granulation. For each test the same

amount of disintegrating agent was used, namely, 17 per cent. In order

to obtain results of a -.comparative nature, the disintegration times

were extrapolated from individual hardnesses to a hardness of seven
kilograms. All hardness tests were determined with a Monsanto Hardness

Tester. The authors concluded from this study that powdered sponge not

only was the most effective disintegrating agent of the 22 studied but

also that tablets prepared with it as the disintegrant remained stable

after being aged at room, elevated, and reduced temperatures. No changes

in either hardness or disintegration time were noted after 500 hours of

aging.

In 1953, Swintosky and Kennon (34) prepared two powdered acid

gums, namely, carboxymethylcellulose (CMC acid) and linseed acid. They

described a new procedure for the preparation of these acids in a pow-

dered, water dispersible form. A preliminary study using these agents

in compressed tablets indicated that carboxymethylcellulose possesses

tablet disintegrating properties analogous to those of powdered alginic

acidj however, it was suggested that further work be carried out in order

to make a true evaluation of these substances for that purpose.

Firoutabadian and Huyck (35), in 1954, compared four substances










with corn starch as disintegrating agents for tablets of both soluble

and insoluble medicaments.' These substances used in ten per cent con-

centrations included alginic acid, Veegum HV, methylcellulose, and a

starch-agar mixture. Sodium bicarbonate was selected as the soluble

medicinal ingredient while aluminum hydroxide served as the ingredient

for the insoluble tablets. Of these four agents tested, alginic acid

and Veegum HV compared favorably as disintegrants for the particular

formula of sodium bicarbonate tablets while the starch-agsr mixture and

Veegum HV were the best for those tablets containing aluminum hydroxide.

Although these latter two substances gave satisfactory disintegration

rates when used in the aluminum hydroxide formula, they'could not be re-

commended since in ten per cent quantities they discolored the tablets

slightly. The authors, however, did suggest their use as disintegrating

agents for colored or coated tablets.

Eatherton, et.al., (36) tested three grades of guar gum as dis-

integrating agents for tablets of.digitalis, lactose, sulfathiazole and

thyroid with corn starch being used as a control in the disintegration

tests. Although one and one-half per cent of each of the three grades

of guar gum produced effective disintegration times for the sulfa-

thiasole and lactose tablets, this same concentration of gum had no

advantage over corn Starch when used in digitalis and thyroid tablets.

Following storage tests of increased temperature and humidity, the

hardness values of the tablets prepared in this study were found to have

decreased from their original values.

In 1955, Swintosky, et alo. (37), tested several new powdered

polyaaccharide acids for their effects on the hardness and disintegration









15

time of sulfathiazole tablets. Several of these new polysaccharide type

acids were shown to hasten disintegration whereas others retarded dis-

integration. It was found that alginic acid, carboxymethylcellulose in

powdered acid form (HCMC), elm acid and starch served to facilitate

tablet disintegration, whereas linseed acid, quince acid, arabic acid

and plantago acid served as disintegration retarders. The authors, in

summarizing, stated that since delayed or sustained drug release have

become so popular in recent years, disintegration retarders or in-

hibitors such as arabic acid, linseed acid and quince acid may possibly

be employed when these actions are desired.

The'mechanism through which starch serves as a disintegrating

agent, from the discovery of its use in 1887 up until recent times,

has not been disputed. However, Gurlin, in 1955 (38), stated that the

disintegration action of starch was not due to its swelling property

but instead due to its capillary action in the tablet. This action, he

noted, may be due to the spherical shape of the starch which increases

the porosity of the tablets. When placing a drop of dye solution on a

tablet and then cutting it in two, he found the color had penetrated

the tablet as though it were a blotter. To substantiate his claims, he

stated that, upon examination of the slurry obtained from disintegrated

tablets, the starch granules were not swollen.


Methods of Testing Disintegration

Although the need of a substance to facilitate the breaking up

of a compressed tablet had been realized since 1900, it was not until 25

years later that studies were undertaken to find a method which would









16

give reproducible disintegration rates of tablets. Before this time the

disintegration rate of a tablet was noted by dropping it in a glass of

water and observing its breakdown.

The methods of determining the disintegration time of tablets

fall under two main classes. The first class includes those methods

which test for hardness and resistance to breakage and the second in-

cludes those methods which test for speed at which the tablet will dis-

solve or break up into its original granules when placed in a liquid at

a specified temperature. Research has thus far produced 27 disintegration

methods, of which two fall under the first class and 25 under the second

class (39). It is easily realized, after a careful review of these

methods, that there is a great amount of confusion as to the value of

these disintegration studies and that the many variables arising from

them show a definite need for standardization.

Probably the first attempt to study disintegration testing in a

systematic manner was carried out in 1930 (40). This was the earliest

comprehensive investigation of tablet disintegration and was conducted

by a subcommittee of the Research Board of the APMA, under the chairman-

ship of George Ewve. fwe described a method for determining disintegration

of tablets based on a classification as to where and how the tablet dis-

integrated or dissolved. Nine classes of tablets were designated as

follows:

a. Uncoated tablets intended to disintegrate
or dissolve rapidly in the stomach.

b. Uncoated tablets intended to disintegrate
or dissolve in the stomach.

c. Hypodermic tablets.








17

d. Uncoated tablets intended to dissolve or
disintegrate in water at room temperature.

e. Uncoated tablets intended to dissolve or
disintegrate in water at elevated tem-
peratures..

f. Uncoated tablets intended to pass into the
intestines and be disintegrated there.

g. Coated tablets intended to disintegrate
rapidly in the stomach.

h. Coated tablets intended to disintegrate
in the stomach.

i. Coated tablets intended to pass into the
intestines and be disintegrated there.

In addition, Ewe recommended a method of determining the disin-

tegration time of tablets and suggested maximum rates of disintegration

for certain classes of tablets.

In 1934, the Swiss Pharmacopoeia gave the first official method

for testing disintegration and in 1936 the subject was discussed at the

British Pharmaceutical Conference (41).

Brown, in 1939 (27), devised his own method for determining

tablet disintegration. He determined the force (weight) required to

break tablets when dry and again when wet. The ratio of these two

breaking points was taken as the significant measure since it would con-

trol the degree of attrition during transport and storage as well as the

clinical effectiveness of the tablets.

Also in 1939 Berry (42), upon request of the British Pharmacopoeia

Committee, investigated and reported on a new method for determining tablet

disintegration. For this method he used a specially constructed wire

device, which, when weighted, cut through the tablet. Later this device








18

was modified by Berry and Smith (43), but it was admitted that while the

method contributed to research in the field, it was actually a measure of

the rate of softening rather than disintegration. Finally, in 1945, the

7th Addendum to the British Pharmacopoeia was published, introducing a

standard test for the disintegration of tablets.

Several articles were published from 1942 to 1945 1by both Ameri-

can and British authors containing descriptions and results of tablet

disintegration tests (44 48).

In 1946, Gershberg and Stoll (49) described the apparatus that

has been in use in chemical inspection laboratories of the U. S. Army

Medical Department since 1940. This apparatus was noted as having several

advantages over other disintegration methods and also as being capable of

testing enteric coated tablets, since they could first be immersed in an

acid-pepsin solution for a specified period and then transferred to an

artificial intestinal fluid without taking the tablets out of the ap-

paratus.

During the year of 19648, the Stoll-Gershberg apparatus was studied

by a subcommittee of twelve members. The subcommittee generally agreed,

a&ter intense investigation, that it fulfilled the requirements as well

as any simple, mechanical apparatus could be expected to do, and recom-

mended its use for a disintegration test to be included in the forth-

coming revisions of the U. S. P. and N. F. The recommended test and time

limits of official tablets appeared in the U. S. P. XIV and N. F. IX with

only slight modifications. However, additional experience on the dis-

integration of compressed tablets has caused the end-point definition of

the official test to be revised in the current U. S. P. and N. F. The








19
former end-point definition read (50): "the tablets are completely dis-

integrated when substantially no residue remains on the screen." Sinde

it was found that certain tablets do not break down during this test but

instead form soft residues that will easily break down with the slightest

touch of a finger or stirring rod, the following new clause was added to

the original end-point definition. It now reads (51): "the tablets are

disintegrated if substantially no residue remains on the screen or if

any residue that remains is a soft mass having no palpably firm core."


Factors Influencing Tablet Disintegration

Since most compressed tablets are composed of more than one in-

gredient and require several steps in manufacture, it is possible that

these factors greatly affect disintegration rates for any given tablet.

There is much evidence to show that the following are contributory fac-

tors affecting the rate of disintegration:

a. The nature of the active and other
constituents used.

b. The type and quantities of binding
agents used.

c. The disintegrator used.

d. The lubricant used.

e. The size and weight of the finished
tablet.

f. The hardness of the finished tablet.

g. The degree of compression.

h. The speed of compression.

i. The type of hopper feed in the machine,
particularly if the disintegrant is added
to the finished granules.








20

J. The age of the tablets.

k. The means of testing disintegration.

Among the substances that will influence the disintegration of

the finished tablet are: the active medicament, e. g., which may be or-

ganic or inorganic, a salt or an acid, an ester or an alcohol, all of

which nay have.different crystal structure and properties that will in-

fluence the compression characteristics of a formula; the binding agent

which is usually carbohydrate or proteinaceous in character; the fillers,

which, depending on their nature and content have a great influence on

the final tablet; the disintegrant; and the lubricant. Combinations of

these many substances when compressed will yield a certain structure

which may be varied according to the physical properties and particle

sizes of the ingredients (52). It is obvious that, as the structure of

the tablet it changed, the disintegration rate will be affected.

Several independent studies have indicated the existing re-

lationship between the active ingredient of the tablet and the rate at

which the tablet disintegrates (35, 36, 53, 54). Firouzabadian and

Huyck (35) have shown that in order to control disintegration, the se-

lection and quantity of disintegrant used in the formula must be made

according to the nature of the active ingredient. They reported that

the solubility of the finished tablet has a marked effect on the time at

which it disintegrates.

Indications of the inhibitory action of binding agents on the

disintegration of tablets have been reported by numerous workers (29, 32,

36, 55, 56, 57). Chavkin (10) in discussing problems of producing com-

pressed tablets, indicated the indiscriminate use of binding agents during









21

the process of granulation as being the cause of excessively hard granules,

which invariably, when compressed, result in the production of tablets with

prolonged disintegration rates.

According to Strickland, et al. (58) the addition of excessive

proportions of lubricant to the granules produces softer tablets with a

severalfold increase in disintegration time. The best lubricants were

found to be impervious to water (59). making it evident that an excess of

such a lubricant will have a waterproofing effect on the finished tablet,

thus hindering its disintegration rate. Other recent reports have also

described this effect of lubricants on disintegration (60, 61).

Higuchi, et al., (54), in a report on the physics of tablet com-

pression, stated that hardness varied directly with the logarithm of

compressional force, leveling off at high forces. It also was found to

vary directly with the apparent density of tablets. Using varying pro-

portions of disintegrant in the same basic formula, they found that the

logarithm of the disintegration time also varied directly with compres-

sional force, and that higher rates of disintegration were produced by

increasing the proportion.Qf disintegrant. In sane instances, however,

when a high percentage of disintegrating agent was present, faster rates

of tablet disintegration were obtained as the maximal compressional force

was increased. This continued up to an optimum compression after which

the ordinary relationship of disintegration time with compressional

force was manifested. These results are in general agreement with those

observed by Berry and Ridout (30) who had determined the disintegration

times of the different tablets as a function of the ratio of the weight

to height of the tablets which they called "compression ratio", and is
I*








22

obviously the same as maximal force applied during the compression of the

tablets.

Statements have been made that the uniformity of tablet mixtures

could be modified during compression due to mechanical vibration of the

tablet press (30, 62). In general, the disintegrating agent is added in

the form of a very fine powder to the granules just previous to tableting;

therefore, any separation of powder and granules before or during com-

pression would undoubtedly result in uneven distribution of the disinte-

grant which would in turn influence disintegration of the finished tab-

lets. Raff (63) described a method of following this separation of fine

material by means of statistically recording resultant tablet weights,

compressional pressures, hardness, and changes in color, supplemented by

a test utilizing sieving at an intermediate point. He reported this

separation to be enhanced by starting with a full hopper and operating

until the supply of granulation was exhausted he suggested that the

hopper be kept filled to a reasonable level during tableting if this is

to be avoided.

The effect of aging on disintegration times of tablets has been

the subject of many investigations (1, 29, 30, 36, 64, 65, 66). Because

these investigations have been carried out on an independent basis, the

data collected is very broad and seems to indicate that the effect of age

on tablets cannot be generalized but instead must be determined for the

particular tablets in question. However, the reports cited do agree that

the factors influencing the effect of age on tablet disintegration are as

follows; the conditions of storage, the length of time stored, the con-

tainers used for storage, and the nature of the tablets stored.









23

DeKay and Holstius (31) stated in a recent paper that of all the

variables investigated, such as active ingredient, binding agent, dis-

integrating agent, hardness of tablet, etc., no one variable was solely

responsible for influencing the disintegration rate of the finished

tablet. They postulated that disintegration is probably due to the

interaction of all these factors combined.

Sponge

Tschirch (67) believes the medicinal use o~ sponges dated back

to the Salernian School (13th century). Sponge ash was official in the

pharmacopoeias of the 18th and 19th centuries, appearing last in Pharm.

Helv. I (1865). As late as 1899, the United States Dispensatory, 18th

edition, set up standards and methods of preparation for Spongia

officinalis (68).

Besides the specific use for goiter, due to their iodine content,

sponges have also been used for surgical procedures, where their great

absorptive power is utilized.

Unfortunately, early investigation and classification of sponge

was hindered and confused by the fact that it was believed to be plant

rather than animal. As late as the middle of the 19th century it was

often classified in the plant kingdom, and the animal character of the

sponge was definitely established only in the last few years of the cen-

tury (69).

Due to a lack of broad knowledge of the sponge, the few.studies

that have been undertaken on it often disagree on many points. For ex-

ample, even now there is no universally accepted system of naming and








2h

classifying sponges. One of the best documented systems of classifi-

cation now in use is that of M. W. deLaubenfels (70). This system is

comparatively new, but is becoming very popular and widespread.

Sponge in its natural state, when alive, is covered and permeated

throughout with a gelatinous substance known as "gurry". Soon after the

sponge is collected this "gurry" is removed by washing and expressing.

This process of washin' and expressing, when finished, leaves but the

fibrous skeleton of the animal, and it is in this condition that the

sponge is sold on the Market.

Stadeler (71), in 1859, was first to give the fibrous skeleton of

the sponge a name; he called it "Spongin". Spongin is classified under

scleroproteins albuminoidss), which include all proteins having a sup-

porting or protective function in aniral organisms (72). More specif-

ically, it belongs to the class of scleroproteins known as keratins.

The keratins have been defined as insoluble proteins which are extra-

ordinarily resistant to digestion with the usual proteolytic enzymes.

Spongin, according to Block (73), is classified still further as a

pseudokeratin, thus being less resistant toward enzymatic hydrolysis than

the eukeratins.

The most recent and by far the most complete elemental anal.

ysis of spongin was performed by Ramsey in 1948 (74). Three species of

Florida salt water sponges furnished the spongin for the analysis. The

results of Ramsey's analysis of the sheep's-wool sponge, the same species

used in the present investigation, are summarized as follows:










Nitrogen ------ 14,.68 per cent Bromine ------ 0.53 per cent

Carbon -------- l6.04 per cent Potassium ---- 0.36 per cent

Hydrogen ...------ 6.06 per cent Iron --------- 0.27 per cent

Oxygen -------- 29.71 per cent Calcium ----- 0.52 per cent

Sulphur -----. 0.08 per cent Barium ------- 0.14 per cent

Phosphorus ---- Trace Sodium ----.14 per cent

Iodine ----- 0.74 per cent Copper ------ 0.05 per cent

Chlorine ------ 0.32 per cent Ash ---------- 3.90 per cent

Trace Elements --- Aluminum, Boron, Chromium, Lead, Manganese,
Nickel, Silver, Strontium, Vanadium and
Titanium.

The organic nature of spongin from a chemical standpoint has

been ascertained as beine protein by several workers (73, 75, 76).

Studies on the amino acid content of these proteins, however, have been

few, and most of those undertaken have neglected to mention the exact

specie of sponge used in the analysis. Sheep's-wool sponge obtained

from Florida's west coast has been reported by Wintter (77) as being

made up of the following amino acids: aspartic acid, glycine, alanine,

lysine, arginine, proline, glutamic acid, threonine, tyrosine, hydroxy-

proline, phenylalanine and leucines (mixture of isomers).

Although no specific studies have been reported on the toxi-

cology of sponge on human subjects, experiments on animals have indi-

cated it to be non-toxic to the species of animals used (78).












EXPERIMENTAL PROCEDURE


Materials and Equipment Used


The materials and equipment used in this investigation are listed

in Tables 1 and 2.


TABLE 1

MATERIALS USED


Material Quality


Sponge
Sponge-
Corn Starch
Calcium Gluconate
Sulfadiasine
Dried Aluminum Hydroxide Gel
Bismuth Subnitrate
Magnesium Hydroxide
Bismuth Subcarbonate
Lactose
Sodium Bicarbonate
Syrup
Zein
PVP (Plasdone)
Locust Bean Gua
Magnesium Stearate
Taleum
Boric Acid
Isopropyl Alcohol
Potassium Permanganate
Sodium Bisulfite
Hydrochloric Acid
Glycerin
Sucrose
Sulfurous Acid
Hydrogen Peroxide Solution
Sodium Perborate
Oxalic Acid
Sodium Thiosulfate


Natural
Synthetic
U. S. P.
U. S. P.
U. S. P.
U. S. P.
N. ?.
N. F.
U. S. P.
U. S. P.
U. S. P.
U. S. P.
Food
Commercial
Food
U. S. P.
U. S. p.
U. S. P.
N. F.
U. S. P.
U. S. P.
U. S. P.
U. S. P.
U. S. P.
Reagent
U. S. P.
N. F.
Reagent
N. F.













I Itaa I iic ~j a u"~sSS.^rafn""0

..CI H ..BO OOP O .. ..! d .8 .6
< M 1MM ,A< $a Si a.






N 0 EG
0. a --04 Si 0 "*.? u-E4CJ o MoI..s-i
5 2 Sas ma> S<& gg2|










0*.%I H9 I S .2






SWSp
r.t

a~ ~ ~ Is Ii 4 1 ^ ^ agg a










28

Description of Sponges Used

Natural Sponge

Sheep's-wool sponge was chosen as the source of the spongin because

of its availability and commercial importance. The Sheep's-wool sponge, in

the form of clippings, was obtained from the commercial sponge markets of

Tarpon Springs, Florida..

The classification set forth by M. W. deLaubenfels (70) was fol-

lowed for the identification of the material used in this study. For

Sheep's-wool sponge it is as follows


Phylum: Porifera

Class: Demospongia

Orders Keratosa

Family: Spongiidae

Genus: Hippiospongia

Species: Hippiospongia lachne

For the sake of convenience, the name, spongin, was frequently

used in place of the common name, wool-sponge, or the species name,

Hippiospongia lachne.


Synthetic Sponge
The synthetic cellulose sponge was obtained locally in block form

and had the dimensions of 4i" x 3" x 1" in length, width, and thickness,

respectively. This synthetic sponge was manufactured by E. I. DuPont de

Nemours Company, Incorporated.









29
TreatAent of Spongin Before Use

The spongin used in this study was in the form of clippings which

were trimmed from sponges in the process of preparing them for market.

These clippings, in the state obtained, contained large proportions of

sand, shell, and other foreign material. The inclusion of these

particles in the organism is a mechanical process which takes place

during the growth of the sponge. The particles are not part of the

spongin composition since the sponge is non-calcareous and non-

siliceous (70). Because of the large amount of foreign material and the

dark yellowish-brown color of the sponge, it appeared that a thorough

cleaning and decolorization was necessary before it could be used in a

tablet formula.


Cleansing Procedure
A batch of about three to four hundred grams of sponge was

taken by selecting the cleaner and more perfectly formed pieces. These

pieces were inspected and any large foreign particles present were re-

moved by hand picking. The sponge was then placed in a stainless steel

tank containing tap water and soaked for a period of twelve hours.

During this soaking period the sponge was kneaded and churned by hand

periodically. This operation was repeated four or five times depending

on the need of the particular batch, each time using a fresh bath of

water. After each wash, the spongin was skimed from the sand and other

foreign material which had settled to the bottom of the tank. Fragments

that were still heavily contaminated were found on the bottom of the

tank with the residual matter. These fragments were discarded along with








30

the foreign material since they were unsuitable for use. After the last

washing period the spongin was pressed to remove the water. Upon ex-

amination of this washed sponge, it was found that several minute pieces

of calcareous matter still remained embedded. In order to remove these

particles a further wash was given using a cold bath of two per cent

hydrochloric acid instead of the tap water used in the previous washings.

The spongin was allowed to remain in this acidulated bath for twelve hours,

after which, upon removal, it no longer showed any traces of calcareous

material. The spongin was then thoroughly rinsed in several baths of

cold water, pressed by hand to remove excess water, and oven-dried at

1400 F. for five hours. Representative samples of the dried sponge were

selected, and inspected for foreign matter with a hand magnifying glass.

This inspection revealed no sand, shell, or other foreign bodies present

in or on the cleansed sponge. The next step, before the grinding process,

was to remove the dark yellowish-brown color by a bleaching treatment.


Bleaching Procedure

In search of a method to bleach natural sponge, several bleaching

agents were tried with little or no success. The agents tried were

aqueous solutions of sodium thiosulfate, sodium hypochlorite, oxalic acid,

hydrogen peroxide, and sodium perborate.

Although sulfurous acid showed some promise of good bleaching

action on the sponge, the best results were obtained through the use of

potassium permanganate followed by a sodium bisulfite treatment,

To decolorise the spongin, the cleansed dried material was

placed in a one per cent solution of potassium permanganate for one-half










31
hour. This procedure was repeated five times, using a fresh solution of

potassium permanganate each time. When the sponge was removed from the

permanganate bath it was dark brown in color due to a deposit of an

oxide of manganese. This colored compound was removed by washing the

sponge in a twenty per cent cold solution of sodium bisulfite. The sponge

was then placed in a ten per cent sodium bisulfite solution, which had

been acidified with hydrochloric acid, for thirty minutes. This last

steeping was repeated, using fresh acidified solutions, until the color

had been sufficiently bleached. The bleached spongin was then rinsed in

several changes of fresh water to remove all residues of chemicals and

dried at 1450 F. Sponge clippings before and after cleansing and

bleaching are shown in Figures 1 and 2.


Figure 1

Sponge clippings before
cleansing and bleaching.


Figure 2

Sponge clippings after
cleansing and bleaching.








32

Grinding Procedure

Before the spongin could be incorporated into a tablet formula,

it had to be ground to a suitable fineness so that it could be uniformly

mixed with the other materials.

Because of the physical nature of the sponge, several experi-

mental runs were undertaken before a suitable method of grinding could

be obtained. The use of a Fitspatrick Comminuter was found to be of

little value in grinding the sponge because of its large grinding chamber

and also because of the fibrous "bouncy" properties of the sponge. The

revolving blades, upon striking the sponge, would cause it to be thrown

out of the grinding chamber and back into the feed throat, and as a

result, the sponge was ground at a very slow rate. The use of this

machine made it necessary to regrind the material several times, each

time passing it through a smaller screen, before it was suitable for use.

Since this procedure was not feasible, other types of grinders were

tried.

*It was found that by using a Wiley Mill grinding of the sponge

became relatively easy. The Wiley Mill is an attrition type mill having

four knives on a revolving shaft that work with a shearing action against

six knives which are set in the frame. The shearing action of the cut-

ting edges, between which there is always a clearance, powdered the

spongin without difficulty. Two screens, 2-am. and 1-em., respectively,

were used. These screens dovetail into the frame of the mill so that

none of the material comes out of the grinding chamber until it is fine

enough to pass through. To facilitate grinding, the bleached sponge was

cut up into fragments of about four to eight centimeters in length









33

before being fed into the hopper of the mill. The second milling was

collected and stored in screw-capped, brown bottles at 145 C. for future

use in tablet formulas.

Attempts made to size the powdered spongin using standard mesh

sieves were unsuccessful. When screening for sizing, portions of the

powder would pass through a No. 200 mesh screen, however, when it was

collected and resieved through the same screen, all of the same powder

would not pass through as it did previously. This was accounted for by

the fact that, after the first screening some of the powder would "mat",

and upon subsequent sieving through the same screen only that powder

which had not matted would go through. Although this powder could not

be sized accurately, it was required to pass through a No. 40 mesh

screen before being used in a tablet formula.


Treatment of Synthetic Sponge Before Use

The same procedure used for grinding the natural sponge was used

for powdering the synthetic sponge. The synthetic sponge required no

special treatment before grinding with the exception of cutting the

blocks into fragments of about three centimeters in length. Like natural

sponge, this also was ground first through the 2-ma. mesh screen and then

through the smaller 1-um. mesh screen. The powder produced after mil-

ling through the smaller screen had the appearance of dry sawdust. The

powdered synthetic sponge was collected and stored in brown bottles at

450 C. Before using this powder in tablet mixtures it was passed through

a No. h0 mesh screen.









34

Tablet Constituents


Active Ingredients

The medicinal ingredients selected as the active components of

the tablets prepared in this study were represented by drugs of variable

solubilities. As a control, lactose replaced all of the active medicinal

agent'in the tablet. The drugs used as active ingredients are described

in Table 3.

TABLE 3

DRUGS COMPRESSED INTO TABLETS



Solubility Mesh
Drug in Water Size

Calcium Gluconate Sparingly Soluble 20/AO
Sulfadiasine Insoluble 40/60
Dried Aluminum Hydroxide Gel Insoluble 80/100
Bismuth Subcarbonate Insoluble 40/60
Bismuth Subnitrate Practically Insoluble h0/60
Magnesium Hydroxide Practically Insoluble 100/200
Sodium Bicarbonate Freely Soluble 40/60
Lactose Freely Soluble hO/60


Diluent

For those formulas requiring a diluent, Lactose, U. S. P., was

used.


Disintegrating Agents

Sponges, both natural and synthetic, were compared with corn

starch for their effectiveness as disintegrating agents when used in

compressed tablets.









35

It should be noted here that the addition of disintegrating agent

to the formula varied depending on the properties of the agent used and

also on the formula being prepared. Husa (79) indicates that some of the

disintegrating agent may be mixed with the medicaments prior to granu-

lation while an additional amount may be added to the dry granules before

compression. The portion added to the dry granulation before compression

serves to disintegrate the tablet into its original granules while that

which is mixed with the medicaments prior to granulation serves,to break

apart the individual granules.

In this investigation some formulas required the disintegrants to

be added either before granulation with the active ingredient and filler

or to the dry granules prior to compression while in other formulas a

combination of both methods was used.

In the case of powdered spongin, its addition to the dry granules

Just previous to compression had several disadvantages. The chief disad-

vantage was the inability of the powdered spongin to flow freely with the

granulation from the hopper into the die. Instead, it had a tendency to

mat up and become unevenly distributed throughout the granulation thus

affecting uniform concentration in the finished tablets. Another disad-

vantage of powdered spongin, when added to the granulation in this manner,

was 'that at times it "bridged" the bore of the die which in turn prevented

further filling of the die with granulation. This resulted in tablets

having extreme weight variations. Although the spongin could not be added

to the granulation prior to compression, it was very easily incorporated

and granulated with the active ingredient and filler. When incorporated

in this manner, the spongin did not hinder the free flowing characteristic








36

of the granulation, and distribution throughout the granulation was uni-

form. It was necessary, therefore, in those formulas containing powdered

spongin, to add this agent during the process of granulation.

Since powdered synthetic sponge does not possess the same natty

character as the powdered spongin, it could be added in reasonable pro-

portions to the finished granules prior to compression. However, it was

discovered that, by granulating the powdered synthetic sponge alone with

a ten per cent starch paste solution using the same procedure as was used

for tablet granulation, uniform sized granules were produced which could

be added to the finished granulation in all proportions. Whether the

powdered synthetic sponge was added in this manner or mixed with the

active ingredient prior to granulation depended on the formula being

prepared.

Dried corn starch when used as a disintegrant was either incorpo-

rated during granulation, after granulation, or both, again depending on

the formulation in question.

Binding Agents

Four different binding agents were used in this investigation.

The formulas and methods of preparing these binding agents are as follows:

I. Syrup U. S. P. 8% (/v)

Sucrose 85 parts
Distilled Water, a sufficient amount
to make 100 parts

The syrup was prepared in accordance with the
procedure given for the hot process on page 601 of
the U. S. P. 11V (50).









37
II.. Starch Paste 10% (w/w)

Corn Starch 10 parts
Distilled Water, a sufficient amount
to make .. 100 parts

The starch was placed in a suitable container and
a sufficient quantity of cold water was slowly added.
This mixture was heated slowly, with continued stirring
to avoid the formation of lumps, until the solution
just boiled and a translucent paste resulted. This
paste was removed from the heat and allowed to cool to
about $0 C., at which temperature it was used. This
binding agent was freshly prepared just previous to its
need.

III. Zein Solution 5% (w/v)

Zein (corn protein) 5 parts
Isopropyl Alcohol 95%, a sufficient
amount to make 00 parts

The Zein was dissolved in the isopropyl alcohol
with agitation.

IV. PVP Solution 15% (w/v)

Polyvinylpyrrolidone 15 parts
Distilled Water, a sufficient amount
to make 100 parts

The PVP was added to a small amount of water and
agitated until the powder was completely wetted. The
remainder of water was slowly added and the mixture
stirred with an electric stirrer until solution was
e6mplete.


Lubricating Agents

Two per cent magnesium stearate was selected as the lubricant in

all formulations with the exception of those formulas in which the effect

of lubricants on the disintegration time was being determined. For

studying .this property, the lubricants used in addition to magnesium

stearate were talc and boric acid.









38

Tablet Formulation

A typical formula for compressed tablets consists of the following:

Medicinal Agent
Diluent, q. a.
Binding Agent, q. a.
Disintegrating Agent, q. a.
Lubricating Agent, q. s.

In order that a sufficient amount of information could be col-

lected and evaluated for this investigation, it was necessary to prepare

and study several different formulas. The formulas studied are found in

Tables 4, $ and 6. The letters and symbols used to describe the tablet

formulas are as follows:

The letter P is used to indicate tablet
formulas prepared for preliminary inves-
tigation.

The following capital letters indicate
the active ingredients used in the
formulas.

L Lactose

BS Bismuth Subcarbonate

S Sulfadiazine

MH Magnesium Hydroxide

CG Calcium Gluconate

AH Dried Aluminum Hydroxide Gel

BSN Bismuth Subnitrate

SB Sodium Bicarbonate

The disintegrants are represented by the
following abbreviations:

A Spongin that has been cleansed
and ground.











AT Spongin that has been cleansed,
bleached and ground.

AS Powdered synthetic sponge.

B Dried corn starch.

Arabic numbers indicate the percentage of
disintegrant used in the formula.

Small letters are used in those formulas where
a different binding agent was used for the
same active ingredient.

a Syrup

b Zein Solution

c Starch Paste

d PVP Solution

The symbol / is used for those formulas in
which the disintegrant was added to the fin-
ished granulation prior to compression. The
capital letters and arabic numbers following
this symbol indicate which agent was used and
how much was added. If the disintegrant was
also added to the active ingredient, it is
indicated by the abbreviations preceding this
symbol.

The symbol /gAS represents those formulas
having granulated synthetic sponge added to
the finished granulation prior to com-
pression.


Preparing the Tablet Granulation

All tablets were made from granulations prepared by the wet pro-

cese. The general procedure used for preparing a granulation was as

follows:

Mixing the Dry Ingredients. -- The powdered ingredients which

entered into the formula were first carefully weighed out and then put

through a No. 40 mesh screen to eliminate any foreign materials and









ho




S *** ** f .* fo *
19; C; 0i 0c (a^3 C; -c c v; a (3tr- a;C ;




W4-

U3
*-4 000 00 000 00 00 I



95 S SS
P-i1




HH
0


St-4 N NW N NW N3N N



O99 004 06 00N 0 0 C
4>
(XJ V OOH l 0 .c





0


1114-
33 as24Wo

^ ~ ~* *** ***i 'i 5 **ss *p






0o 0 0 3
4A Ooo







ca to Aq 7 a
S ^m 94S 4S 0 41-4 cr o w














SAll 9A AAA A A 0A Q
Go- Coc w ,-r C ^ w



Q-i ^1 -i

a. A. A.P4 4 4











0
co

r- b(5 **** **t
00000000 0000 0000 0000









00000000 0000 00O 0000

C C S C C S a C C S C
& *** ** ****H-i ****43 Ti 'I' "^1' *** olt
01 14CY (-4 A 4 9 A rAc;4 s43 AAA c AIA;


s0
6* > C5JC8Jf8rv 0 iC C 53 0 5 5





0 0 P 4 0 C A
UU
0 2*0t- os mUNmr wwwXm NO m 0 t-Ul\

ar4 r4l tM -4 1^ r-4K C H0 4 AO Xr CY0 c l *\'U^K lr-









In
8- .- 0^(11-








E 000)
sow~~~s 'CCOC P4)7 .E












00000OO0 w-I E-.
*~~- 0040> 42)
~~o.











00000000 0000 emm 0000
S0 C -0 4 O CA C4 r 0 C S S C C S C i0

S r1
PQ4 434



0 0 CDO

44 4g g Hl l qE 3





U 410,g C4 1 1 111


00 00 0 0 0 en -- 0004
(; c; UU O (3c ;4 ** 0 0 #O *O << 0 aZ 0 0








fin~~ IO Ul* t04 Ho .I
C13~i wv
""^ \ 00 I Im










0
4

C; 4* o o 0; 0 C 8 0' C 0
S 0000 0000 000




col
4., .cjrij2rI


*- 0000 0000 000
04W **** 0*** **. 5



4 A
A ko
o Wo a N
4 too


N N N p -JCN Sig
0 0


S4) O 4) 'D
*0 4j 0co 4- 1





41414
44 4> oct 43~tr 4a oc









00


:9 eM V.0a 0
~. 4.4 1 r43r'-

0000 0000 000 04S
5~ 8














Vic

CIO0 1 1 1H 0V
P4E-4 L-1
114 111 "a~ ..4.00
*g ~ ~ SI Er4f 5& &
^ ~~ aE TC3C f~ L TMC t'













.Qtr '0 '0 & &4
43

*p~ +2
< o 0 0 0 0 0-0 0 0 o a
0 0*


*04 000
0 0 .0 .0.0 .0 .0 .0 .0. .0 0-





a ooooooooooooooo~,~coo S

-H -r4



as 0


0 V) V) to
*IJco \ V\ \0 cmj cyj -~- --jS

00 0 0 0 0

010
*?




90. o6)
40 0 .4V
"S E S S & S S E E iS









434

H O )
S50 0 0 0 0 0
4 0 o
14 140
0 0 0 0 0 0 0 0 *h



0~~~4 0m S

H, P. C,
44 q 1 | I

0 ll 21 ghaings .e hA
4-1 0H 0

A 0
to c o v




3 ~ ~ ~ ~ ~~- r ^"w^f i l
I i
5 'i' S @ 8 @ 8 S S .t0u









44

reduce any lumps of powder. The powders were then combined, placed in a

Stokes Granulating Mixer, and allowed to mix for one hour. The resulting

mixture was next sieved through a No. 40 mesh screen to further mix and

aid in proper distribution of the ingredients. The mixture of powdered

ingredients was now ready for granulation.

Granulating the Dry Mixture. -- In order that the percentage of

active ingredient and disintegrator remained constant for each series of

formulas, it was necessary to predetermine the proportions of binding

agent needed for each granulation. 'This was accomplished through a pre-

liminary experiment on a small amount of each formula. With the pro-

portion of granulating agent determined for the actual granulation process,

the adjustment of diluent to obtain a specific tablet weight was calcu-

lated.

In granulating, the thoroughly mixed powdered ingredients were

put in a Readco Dough Type Mixer and the granulating solution was slowly

added with constant mixing. Sufficient time was allowed for the granu-

lating solution to work in well before the next addition was made. When

the mass had attained a "ball" consistency and seemed to have the proper

"feel", it was considered ready for screening.

Screening the Wet Mass. -- The moistened mass was removed from

the mixer, placed on a No. 8 mesh screen, and by hand, using a hard rubber

spatula, forced through the screen.

Drying the Granulation. -- The coarse granules obtained from

screeftg the wet mass were spread in thin layers on trays upon which had

been laid heavy brown wrapping paper. The trays were placed in a circu-

latory hot air oven set at a drying temperature of 1400 F. The time











required for drying varied with the nature of the granulation being dried,

however, as a rule the time ranged between eight and twelve hours. During

the drying period the granulation was periodically turned to assure uni-

form drying.

Screening the Dry Granulation. Following the drying period,

the granulation was again hand screened, this time through a No. 14 mesh

sieve. For those granulations that had a tendency to produce excessive

"fines" when completely dried, it was necessary to screen the coarse granu-

lation when it was about 3/4 or 2/3 dry. After screening a partially dried

granulation it was placed back into the oven and allowed to completely dry

with a minimum of fines. The granules obtained from this second screening

were gently mixed by tumbling in a large jar.

81sing the Finished Granules. The granulation resulting from

the final screening was sized using a series of sieves. The sieves used

were Nos. 20, 40, 60, 80, and 100 mesh. The sizing was accomplished by

determining the percentage of the total granulation that passed through

one size screen but not through the next smallest screen. For example,

those granules that would not pass through a No. 40 mesh screen were re-

corded as 20/A0 mesh granules since they passed through a No. 20 and were

retained on a No. 40 mesh screen. This sizing procedure was performed on

all formulas. It was noted that the size range for optimal tableting

varied depending on the formulation involved. Information pertaining to

the sized granulations is found in Table 7. Following the sizing of the

granulation, the granules were put in a large, wide-mouth, screw-capped,

brown bottle, and stored until needed at a temperature of 00 C.

Lubricating the Granulation. Lubrication of the granulation










TABLE 7


DESCRIPTION OF SIZED GRANULATIONS


Granulation Weight, Percentage of Granules
Formula in Grams, Previous within Mesh Range of
to Sizing 14/20 20140 40/60 60/80 0/100


P-L
P-L.A-7
P-L-A-14
P-BS
P-BS-A-7
P-BS-A-14
P-S
P-S-A-7
P.S.A-14h
P.M4..A
P-MN
P-MH-A-7
P-MH -A -lh
P-CO
P..CG
P-CG-A-7
CG-A-1
CG.A-2
CO-A-3
OG-A-4
CG-A-5
CO-A-7
CG-a-15
S.A-5
S-A-10
S-AT-5
S-B-10
AH.L-5
AH-AT-5
AR-B-10
AH.-B-10/B-10
BSN.AT-5-a
BSN-AT-5-b
BSN-AT-5-c
BSN.AT-5-d
BSN-AS-10.a
BSN-AS-10-b
BS..AS-10-c
BSN.AS-10-d
BSN-B-10-a
BSN-B-10-b
BSN-B-iO-c
BSN-B-10-d


108
113
423
307
317
341
350
352
358
358
361
305
411
418
392
423
1451
472
323
366
259
305
285
139
452
428
377
476
429
372
1411
465
372
132
187
161
388
4100
417
364
355
397
289


70.2
73.1
60.14
65.3
62.8
60.3
66.1
70.14
71.1
50.0
43.0
32.6
50.7
51.7
57.4
59.3
58.6
53.0
62.5
62.9
68.14
51.5
53.3
60.1
58.14
70.5
62.9
60.2
56.0
63.14
51.8
73.7
51.5
60.6
75.2
70.14
56.0
66.9
* 73.14
68.3
60.5
62.7
71.6


13.5
12.8
23.8
20.8
24.2
18.9
11.6
13.9
20.3
13.3
17.7
19.14
31,1
27.3
28.1
31.8
22.0
25.9
15.7
24.6
20.2
29.0
28.3
18.5
18.9
12.1
16.2
18.8
20.1
22.14
31.5
8.14
13.7
20.3
11.6
11.9
7.5
12.8
9.2
17.8
22.14
20.7
13.9


4.1
5.0
8.8
6.7
7.7
9.4
6.3
7.5
2.6
14.9
18.41
20.3
9.9
6.1
5.0
3.4
9.9
11.7
8.3
5.2
6.8
9.6
10.1
8.5
13.2
5.4
10.3
10.8
12.1
7.5
4.9
4.3
12.1
9.6
8.0
9.4
14.7
8.6
9.7
6.3
8.7


2.0
4.6
1.2
2.9
3.6
5.3
8.7
2.2
1.5
12.2
10.5
4.3
4.8
8.6
4.0
2.1
4.6
$.14
4.2
3.7
2.9
8.3
1.7
5.5
'7.4
1.3
6.5
4.6
7.2
3.8
7.3
6.7
11.4
5.6
1.8
3.8
12.3
5.5
3.2
1.9
2.7
5.1
7.5


1.8
3.9
1.0
1.3
1.0
2.2
4.3
3.4
3.7
8.6
3.0
1.5
3.3
l.h
2.7
0.3
2.5
2.0
3.1
2.2
0.7
0.4
2.6
3.4
2.0
5.1
2.8
2.7
4.h
1.2
2.6
4.1
9.3
2.h
1.7
3.9
9.2
5.6
1.8
5.1

3.7









47

was carried out immediately prior to compression. For adding the lubri-

cant, the granulation was spread on a large sheet of heavy brown paper,

the lubricant was dusted on the granules by.sifting it through an 80 mesh

sieve, and the entire formula was mixed well by grasping each end of the

paper and gently tumbling the mixture until the granules were thoroughly

covered with the lubricant. The use of an 80 mesh sieve for dusting the

lubricant on the granulation not only insured the removal of any lumps

that may have been present but also increased the covering power of the

lubricant. Subsequent to lubrication the granulation was ready for

tableting.


Compression of the Granulation


Equipment and Procedure

Description of Tablet Machines Used. -- A single punch, Eureka

Hand Model, tablet machine and a rotary, Model B-2, tablet machine were

used to compress the completed granulations into tablets. Both these

machines are manufactured by F. J. Stokes Machine Company.

The Eureka hand operated machine had a production rate of up

to 70 tablets per minute using standard concave 3/8" or 13/32" punches

and dies. This machine has a maximum depth of fill of 7/16" and it can

attain pressures up to one ton.

This hAnd operated machine was used mostly to determine the

characteristics of the finished granulation before compressing it on the

rotary machine. It was also useful in preparing individual tablets by

hand filling the die for experimental work on formulas. This eliminated

the need of filling and emptying the hopper each time a change was made











in the granulation.

The rotary, Model B-2, tablet machine produces from 350 to 500

tablets per minute and has a depth of fill up to 11/16". All tablets

produced using this machine were prepared with standard concave 3/8"

punches and dies. Although this machine ordinarily requires 16 sets of

punches and dies, the machine can and was run with eight pairs of punches.

Corks were driven into the other eight dies to prevent the granulation

from falling through them. This rotary tablet machine is capable of

attaining pressures of more than two tons.

Operating Adjustments Required for the Eureka Machine. Weight

and pressure adjustments, which varied according to the particular granu-

lation being compressed, were made by raising or lowering the punches.

The speed of the machine was governed by the rate at which the hand wheel

was turned and thus could be controlled as desired.

Operating Adjustments Required for the Model B-2 Machine. -

Prior to the initial use of the rotary machine, it was disassembled,

cleaned, and thoroughly lubricated. From then on it was cleaned following

each tablet run and lubricated according to its need.

The feed frame was set about 1/64" away from the moving die plate,

while the take-off plate at the front of the feed frame was raised suf-

ficiently to allow any granulation to pass back into the feed frame, and

the scrapper at the back of the feed frame was pressed down against the

table by means of a spring to keep the granulation inside the feed frame.

The hopper was set so that the gap between the funnel opening and

the die plate was just large enough to allow sufficient material to flow

from the hopper into the feed frame and partially fill its various











openings.


Adjustments for weight and pressure were made as follows. The -

exact amount of granulation needed to make one tablet was weighed and

poured into the die cavity at the last opening of the feed frame just in

front of the scrape-off plate. The weight adjuster was either raised or

lowered until the material just filled the die cavity and was flush with

the top of the die plate. The flywheel was then turned by hand until

the filled die came between the compression rolls. At this point the

lower roll carriage was raised by means of a pressure regulator until a

tablet of proper hardness was formed.

Effects of Operating Speed on Tablets. In determining whether

the operating speed of the rotary tablet machine manifests itself as a

critical variable in the compression of certain granulations, studies

were made using three different speeds. These speeds, regulated by ad-

justing the variable speed drive, were arbitrarily set as slow, medium,

and fast, depending on the number of tablets compressed in a minute.

The slow speed represented 100 tablets per minute, the medium speed 200

tablets per minute, and the fast speed 250 tablets per minute using eight

sets of punches.

In this experiment, the various speeds of the rotary machine did

not show any difference in the tablets produced. The weight and hardness

of the tablets remained constant; the surfaces' smoothness was not af-

fected, and the disintegration time was unaltered. Since the speed of

the machine did not influence the properties of the tablets, the slow

speed was selected for regular tablet runs.

Batch Uniformity. -- At frequent intervals during compression,









50

weight and hardness checks were made to ascertain tablet uniformity. If

the weight or hardness showed a deviation from the original standards, the

machine was stopped and further adjustments made until this deviation was

alleviated.

Test Methods


Hardness Test

Hardness of tablets is considered to be a measure of resistance

to capping, chipping or breakage under conditions of storage, packaging,

and handling before actual use. A practical rule for judging proper

tablet hardness is that the tablet should be readily broken when pressed

between the thumb and forefinger but should not break when dropped on

the floor.

In order to measure the comparative hardness of the tablets pre-

pared in this investigation, the Monsanto Hardness Tester was used. This

device is calibrated in terms of kilograms of compressional force. To

determine its hardness, the tablet was centered on its vertical plane

between the anvil and spring spindle. The zero reading Was noted.

Pressure was applied until the tablet broke. The difference between the

zero and the final reading was the pressure in kilograms required to

fracture the tablet. Reported values are averages of five determinations

and are stated to the nearest 0.5 kilogram.

Disintegration Test

The disintegration tests were conducted in accordance with the

U. S. P. XIV directions (50). The test apparatus used consists of a








51

basket-rack assembly which moves up and down at a rate of 31 complete

cycles per minute through a distance of 5 cm. For .the test, the basket

assembly is immersed in a constant temperature water bath. The bath

used in this investigation was maintained at 370 C. The electrically

heated water bath was equipped with a mechanical stirrer and a Cenco

DeKhotinsky Thermo-Regulator. Six compressed tablets were chosen at ran-

dom and placed in the tubes of the basket-rack assembly. The basket was

set in motion, and the time required for the tablets to completely pass

through the No. 10 mesh screen was the disintegration time. Three de-

terminations were made on all tablets tested and the average time was

calculated and recorded in minutes and seconds.

The end-point for tablet disintegration has been revised in the

U. S. P. XV (51) to read as follows: "the tablets are disintegrated if

substantially no residue remains on the screen or if any residue that

remains on the screen is a soft mass having no palpably firm core". It

was obvious that this new end-point required judgment to determine what

is "substantially no residue" and when a soft mass has "no palpably firm

core." Since this Judgment would most likely vary somewhat for each

individual, it was decided to signify a tablet as being disintegrated when

the tablet had completely passed through the screen. In the case of those

tablets where the end-point was thought to be substantially different from

that of the official end-point, a footnote was made indicating this.

Friability Test

An automatic shaking machine, simulating the most extreme handling

practices, demonstrated comparative resistance ability of the tablets to











chipping and breaking.

The shaking machine completed 200 forward and backward movements

per minute as it shook the tablet vials through a distance of four inches.

For the test, ten tablets were placed in a five dram vial and

stoppered securely. The vial was put into the shaking compartment and

the machine wps operated for two 15-minute periods. After each shaking

period, the tablets were sifted and blown with compressed air to remove

the pulverized material. Following this treatment the tablets were

weighed. The difference in weight expressed as a per cent of the original

weight was designated as the friability value.

Another short series of tests were also made to determine the in-

fluence of well filled vials protected with cotton on the friability

value. In this test the vial was filled to the neck with tablets and

protected with a cotton filling.


Storage Test

Pharmaceutical products mast be stable over extended periods of

time and under varying storage conditions. To gain insight into the

stability of the tablets prepared, storage studies were conducted.

.The tablets tested were subjected to the following storage con-

ditions:

a. Room temperature

b. Increased temperature

c. Decreased temperature

d. Various relative humidities

For storage tests, ten tablets were placed in an open five dram









53
vial and ten tablets from the same series were placed in a capped five

dram vial. By storing the tablets in this manner the effect of the con-

tainer on storage could be determined.

All samples stored at room temperature were placed on laboratory

shelves for a specific time interval. The average room temperature during

the storage period was 26.90 C. and the average relative humidity was

61.2 per cent.

In order to calculate the average room temperature and relative

humidity, daily determinations of each were made for a two week period

followed by semiweekly determinations for the duration of the storage

studies. All relative humidity determinations were made with a sling

psychrometer.

Those samples stored at elevated temperature were placed in vials

and put in an electric oven at h45 C. while those stored at decreased

temperature were placed in a refrigerator at hO C. t 10 C.

Individual desiccators were set up containing aqueous glycerin

solutions (80) in varying proportions to provide relative humidities of

30, 40, 50, 80, and 95 per cent in one series of tests and 30, 45, 60,

70, 80, and 95 per cent in another series of-tests. The samples, in

vials, were placed in these desiccators, the desiccator covers were se-

curely replaced, and the desiccators were placed on a shelf at room temp-

erature.

Time intervals that the samples were stored depended on the de-

terminations being made and are reported in the storage tables.

After specific storage intervals, the following determinations were











conducted:


A, Moisture gain or loss

b. Disintegration time

o. Hardness

To determine moisture gain or loss, each of the samples was weighed

prior to storage and at subsequent intervals. The increase or decrease in

weight denotes moisture gain or loss. Moisture loss is represented in the

tables by a negative sign preceding the per cent weight change in tablets.


Absorption Study

The mechanism through which powdered spongin and corn starch ac.

complish their disintegrating action is basically the same. Both agents

swell if in contact with water and as a result, when incorporated into

tablets, are capable of rupturing the tablet. In order for this swelling

to take place the materials must be able to absorb the water, and for this

reason tests were conducted to determine the rate at which this absorption

took place for each of the substances. To control the moisture conditions

for the tests, several constant humidity chambers were prepared in the

same manner as described earlier.

The tests were carried out by first drying the materials to con-

stant weight at 1100 C. and then placing them in each humidity chamber

for 24 hours. The weight gain was calculated by reweighing the sample

following this 24 hour period and was recorded as per cent of sample

weight.












EXPERIMENTAL RESULTS


TABLE 8

MOISTURE ABSORBED BY POWDERED SPONGIN AND CORN STARCH
AT VARIOUS RELATIVE HUMIDITIES


Relative Humidities
at 270 C.

30

45%
60

70
80

95


Water Absorbed After 2h hours
Powdered Spongin Corn Starch

9.22 8.13

12.21 10.33

15.43 12.69
17.65 14.1
21.36 16.12

29.51 20.61


The results listed in Table 8 and illustrated in Figure 3 show

that the moisture absorbed by powdered spongin and corn starch increased
with increased relative humidities. The increase in moisture content is
indicated by an S-shaped curve which is more pronounced for powdered

spongin. The moisture content of the corn starch and powdered spongin
before drying to constant weight was calculated as 9.76 per cent and 11.2
per cent, respectively.









Figure 3. Absorption of Moisture by Powdered Spongin
and Corn Starch


30 ho
Per Cent Moisture Absorbed


0 Powdered Spongin


Corn Starch


100




80




60




o


0











TABLE 9


A COMPARISON OF THE DISINTDERATION TIMES OF TABLETS
IMMEDIATELY AFTER COMPRESSION



Disintegration
Formula Hardness Time
Kg. min.:aec.
P.L 7.0 2l423
P-L.A-7 7.0 2135
P-L.A-14 5.0 0:48

P.as 6.5 180,00a
P.-BS-A-7 7,$ 19,44
P.BS.A-14 7.0 8,02

P-S 7.0 180:00a
P-S.A-7 7.5 7tl717
P-S.A-14 7.0 21:21
P.MH 6.0 180 0a
P'.M.A.7 6.0 2111
P.-MH.A-4 5.0 0o58
P.0( 7.0 180300a
P-.C.A-7 6.0 19:23
P.CG-A-1l4 6.5 -10:02
CG.A-1 7.0 29:20
CG-A-2 6.0 22:58
C0-A-3 6.5 17:33
CG.A-4 7.0 16:59
0C-A-5 6.5 15.26
CG-A.6 8.0 18t05
CG0.-7 7.5 13:31
CG-B-15 7.0 h7:22
S.A-$ 7.0 58:45
S-A-10 6.0 49:37
S-AT-5 8.0 116121
S-B-10 7.5 98138


(Table continued on following page)











TABLE 9 (continued)


Formula Hardness Disintegration
Time
Kg. min.:sec.


AH-A-5
AH.-AT.-5
AH-B-10
AH.IB.1/B-10

BSN-AT-5-a
BSN-AT-5-b
BSN.AT-5-c
BSN-AT-5-d

BSN-AS-10-a
BSN.AS-10-b
BSN.AS-10-c
BSN-AS-10-d

BSN-B-10-a
BSN-B-10-b
BSN-B-10-c
BSN-B-10-d


SB.B-10
SB-AT-5
SB.AS-5


S-A-5/gAS-5
S-A-5/gAS-10


BSN-AT-5-a/gAS-5
BSN-.AT-5-a/gAS-10
BSN.AT-5-b/gAS-10

BSN.AS-10-a/gAS-5
BSN-AS-10-a/gAS-10
BSN-AS-10-b/gAS-10
BSN-B-10-a/gAS-0
BSN-B-10-a/gAS-10


6.0
7.0
7.0
5.5

6.5
6.$
7.5
7.0

6.5
6.0
7.0
6.5

6.0
6.5
5.5
6.5

8.5
8.0
7.5

7.0
7.0

6.5
7.5
6.0

8.0
7.0
6.5


35:37
8:53
68:0h
15:02


35: i
180:00a
i4:21
12:39

52:11
33:05
31:i7
20:22.
73:51
180:00o .
75:35
72:09


11,11
9:07
10:35

21:44
9:08

10,58
6:27
9:33

9:56
7:55
10,03

6:04


did not dis-


aThe disintegration test was discontinued if the tablets
integrate within three hours.











TABLE 10


RELATIONSHIP BETWEEN TABLET HARDNESS,
AND DISINTEGRATION TIME


FRIABILITY


Friability Disintegration
Formula Hardness Value- Time
Kg. min.:sec.


1.5
2.5
1.0
5.5
7.0
9.0
10.0
11.0

0.5
1.5
2.0
2.5
41.0
$.5
7.0
9.0


AH-B-10


BSN-AT-5.a


BSN-B-10-a


0.5
1.0
1.5
2.5
4.0
5.0
6.5
8.0
10.0
12.0
0.5
1.0
2.0
3.5
1.5
6.0
8.0
12.0
(Table


continued on


71.989
9.808
2.929
0.913
0.255
0.096
0.080
0.077
78.967
25.861
10.817
1.829
0.834
0.626
0.492
0.325


99.210
96.189
91.344
87.273
9.608
1.980
0.502
0.260
0.130
0.078
85.935
57.275
16:9142
1.765
0.998
0.288
0.150
0.135
following page)


6:10
4133
3:01
:4h9
8:53
14:34
18:27
18:58
29:40
36:00
41851
49155
53:55
63:27
68:35
75,:1

l305
3:32
10:27
12:08
22:08
27:21
135:1
60:38
62:03
109:00
96:46
65t02
56:21
66:t1
73:51
88:09
95:39











TABLE 10 (continued)


Friability Disintegration
Formula Hardnesa Value Time
g. in.sseec.


BSN-AT-5-b


BSN-B-10-b






BSN.AT-5-c








BSN-B-10-c


0.5
1.5
3.0
5.0
6.5
7.5
10.0
11.0

0.5
1.5
2.5
5.0
6.5
7.5
10.0

0.5
1.0
2.5
3.5
5.0
6.5
7.5
9.0
10.5
1.0
1.5
2.5
3.5
5.5
6.5
8.0
10.5


100.000
63.541
2.381
0.349
0.205
0.131
0.127
0.1014

100.000
75.2149
1.223
0.192
0.130
0.095
0.043
100.000
92:137
80.016
3.763
1.254
0.997
0.275
0.196
0.188

93.476
86.006
69.072
3.555
0.964
0.231
0.1914
0.088


180:00a
180:00a
18o0: 0a
180,00a
180:00o
180, 00a
180:00a
180:00a


180:00O
180o00a
180,00a
180:00a
180:00a
180:00*
.180:00'


9:35
8:52
9:27
6:01
-9:48
12253
14:21
18:16
22,49

72:00
74:12
79:47
83-24
90:35
98:37
103:22
119:17


(Table continued on following page)


















TABLE 10 (continued)


Friability Disintegration
Formula Hardness Value Time
Kg. .min.,sec.

BSN-AT-5-d 0.5 100.000 10:47
1.5 91.583 9:01
3.0 68.502 8:58
4.5 5.229 7:36
7.0 1.257 11:1l
8.0 o0.67 1545
10.0 0.179 22:30

BSN-B-10-d 1.0 96.068 66 09
3.0 80.003 73:17
4.5 37.852 77:10
6.5 2.207 72:09
7.5 1.111 87:25
8.5 0.480 94:38
10.0 0.221 97*07
11.0 0.099 107:03


athe disintegration test was
integrate within three hours.


discontinued if the tablets did not dis-







Figure I, -


Relationship Between Disintegration Time
and Tablet Hardness for Tablets Prepared
with Spongin as the Disintegrant Showing
a Minimum Point in the Curve.


7 9 11
Hardness in Kilogrami


0 BSK-AT--d


AH-AT-5
BSNMAT-5*


A BSNATT-.-a


B
I
V


ii
'f-I*1
V

I









Figure 5. -


63
Tablets Prepared with Corn Starch as the
Disintegrant showing a Linear Relationship
Between Disintegration Time and Tablet
Hardness


120 -


90.


30 -


1 3


7
Hardness


9 11
in Kilograms


0 BSN-B-10-c


BSN-B-10-d
AH.-B-10


| I I


I I I


i I I











Figure 6. Relationship
Between Tablet Friability
and Tablet Hardness


Figure 7. Relationship
Between Tablet Friability
and Tablet Hardness


2 h 6 6 10
Hardness in Kilograms


* AH..B-10
0 AH..AT.


* BSN-AT-..-a
0 BSN-B-10-b


I

4100

80
f5


h0

20

10

1
0.5
0.1















TABLE 11
FRIABILITY VALUES AFTER TWO SHAKING PERIODS


Friability Value
Formula Hardness After After
15 Minutes 30 Minutes
Kg.
S-A-5 5.0 0.038 0.178
S-B-1o 5.0 0.115 0.21L
AH~.T-5 7.0 0.255 0.501
AH-B-10 7.0 0.493 0.739
BSK-AS-10-a 8.0 0.1438 0.742
BSN. S-10-b 7.5 0.183 0.351
BSN-.S-10-c 7.5 0.679 1.099
BSN.AS-10-d 7.0 0.214 0.367
BSN AT-5-a 6.5 0.502 1.218
BSN-AT-$5.b 6.5 0.205 0.351
BSN-AT-5.- 6.5 0.997 .2.093
BSN-AT-5-d 7.0 0.301 0.521
BS--B-IO-a 6.0 0.288 0.492
BSN-B-10-b 6.5 0.130 0.217
BSN-B-10-c 6.5 0.231 0.488
BSN-B-10-d 6.0 0.194 0.316












TABLE 12

FRIABILITY VALUES OF TABLETS PROTECTED WITH
A COTTON FILLER IN VIALS


Friability Value
Formula Hardness After 15 Minutes
Kg.
S.A-5 5.0 0.002
S-B-10 5.0 0.000
AHJAT-5 7.0 0.000
AH.B.10 7.0 0.000
BSN-AS-10-a 8.0 0.000
BSN-AT-5-a 6.5 0.006
BSN-B-0l-a 6.0 0.003


TABLE 13

COMPARISON OF DISINTEGRATION RATES OF TABLETS
PREPARED WITH DIFFERENT BINDING AGENTS


Disintegration
Formula Hardness Binder Time
rg min.sec.
BSN-T-5-a 6.5 Syrup 35:l1
BSN-AT-5-b 6.5 Zein Solution 1800o0a
BSN-AT-5-c 6.5 Starch Paste 12:53
BSN-AT-5-d 7.0 PVP Solution 12:39

BSN-B-.0-a 6.0 Syrup 73:51
BSN-B-10-b 6.5 Zein Solution 180400a
BSN-B-10-c 6.5 Starch Paste 89:37
BSN-B-10-d 6.5 PVP Solution 72:09

BSN.AS-10-a 6.5 Syrup '52 1i
BSN-AS-10-b 6.0 Zein Solution 33,05
BSN.AS-10-c 7.0 Starch Paste 31:47
BSN-AS-10-d 6.5 PVP Solution 20:22


aThe disintegration test was
integrate within three hours.


discontinued if the tablets did not'dis-











TABLE 14
CCRPARISON OF DISINTEGRATION RATES OF TABLETS
PREPARED WITH DIFFERENT LUBRICATING AGENTS


Lubricating Disintegration
Formula Hardness Agent Time
Kg. min. ec.


AH.AT-5


BSN-AT-5-a



BSN.AS-10-c



BSN-B-10-a



SB-B-10



SB-AT-.


7.5
7.0
7.0
7.0
6.5
6.5
7.0
6.0

7.0
6.5
7.5
8.0
6.0
6.5
6.5
7.0
8.5
7.0
6.5
6.5
8.0
7.5
7.0
7.5


Magnesium Stearate
Talc
Boric Acid
None

-Magnesium Stearate
Talc
Boric Acid
None
Magnesium Stearate
Talc
Boric Acid
None
Magnesium Stearate
Talc
Boric Acid
None

Magnesium Stearate
Talc
Boric Acid
None

Magnesium Stearate
Tale
Boric Acid
None


8t53
6:23
2:30
io02

32 li
9:2h
8:53
6:59
23:01
9t44
5:57
5:00
46: 19

$508

11ll1
8:33
4:07
3125


9:07
6055
3s00
3:21










Figures 8, 9 and 10. Coparative
Differently


Disintegration Rates for
Lubricated Tablets


1 2 3 k 1 2 3 u
Lubricant Lubricant
Fig. 8. Formula BSN-AT-5-a Fig. 9. Formula BSN.AS-10-c


Fig. 10. -


KEY TO LUBRICANTS USED

1 No lubricant

2 Boric Acid

3 21ac

4 Magnesium Stearate


2 3
Lubricant
Formula SB-B-10











TABLE 15
TABLET DISINTEGRATION TIMES AFTER STORAGE FOR INTERVALS OF
250, 500 AND 750 HOURS IN OPEN VIALS AT
VARIOUS TEMPERATURE CONDITIONS


Disintegration Time
Formula Hard- Storage After Storage at
ness Time Originally 270 C. 45 C. 5o C.
Kg. hrs. min.:sec. min.:sec. mintsec. min.:sec.
CG-A-2 10.0 250 25t23 31'56 26337 26:09
500 25t23 26.18 27:20 26t52
790 25:23 30:42 27:37 27:08
CG-A-4 9.5 250 22:58 29:59 23:10 23:01
500 22:58 24t41 2h,07 22t52
790 221:8 27,*8 24h:0 23v05


TABLE 16
TABLET DISINTEGRATION TIMES AFTER STORAGE FOR INTERVALS OF
250, 500 AND 750 HOUBS IN CLOSED VIALS AT
VARIOUS TEMPERATURE CONDITIONS


Disintegration Time
Formula Hard- Storage Atter Storage at
ness Time Originally 27 C. 5go C. 0O C.
Kg. hra. min.:sec. min.2sec. min.:sec. min.:sec.
CO-A.2 10.0 250 25s23 29: 4 27:18 27l11
500 25:23 25:12 27:42 27:00
S 750 25:23 27:53 28:33 28:lh
00-3A-4 9.5 250 22:58 28:46 23:18 23:01
500 22:58 25:01 23:h6 23:04
750 22t58 26:01 22434 23t42















































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DISCUSSICK OF RESULTS


Bleaching of Sponge

Although an acidified solution of sodium bisulfite was found to

satisfactorily bleach the cleansed sponge without any further treatment,

it was noted that on standing for three to five days the bleached sponge

acquired a yellowish color.

The following reaction took place when a sodium bisulfite solu-

tion was treated with hydrochloric acid:

NaHSO3 + HC1 NaCI + S02 + H20


It was the sulfurous acid formed that served as the bleaching agent.

Since exposure of the sponge to air, after being bleached with this agent,

resulted in the gradual return of the yellowish color, it was assumed that

the pigment was not destroyed, but instead, reduced or converted into a

colorless compound. It is probably through a reoxidation process that

this colorless compound is restored to its original pigment state. If

such is the case, this would account for the return of the yellowish

color when the bleached sponge was exposed to air.

When a potassium permanganate solution was used for bleaching,

the sponge remained in an almost white condition indefinitely. Potas-

sium permanganate, contrary to sulfurous acid, produces its bleaching

effect through an oxidation process. The action of potassium perman-

ganate is through the liberation of nascent oxygen which takes place as
follows:










86

2KMnO4 + 3H20 -- 2KO + 2Mn02.H20 + 30


The brown deposit that remained on the sponge following the per-

manganate treatment was due to the precipitation of hydrated manganese

dioxide. In order to remove this brown deposit it was necessary to sub-

sequently place the sponge in a sodium bisulfite bath. This reduced the

manganese compound to a colorless soluble salt which was removed by solu-

tion, leaving the sponge in an almost white condition.

Following this permanganate treatment, a final bleaching with an

acidified sodium bisulfite solution left the spongin in a permanently

bleached state. Therefore, it was concluded that the oxidative perman-

ganate treatment chemically decomposed the coloring matter in such a

manner that it was incapable of being subsequently reformed.


Tablet Preparation

It was found that most of the materials making up the tablet for-

mulas behaved in a very similar manner in that they offered no major com-

pression problems. Special attention was required only when the spongin

was added in excessive proportions and when it was added to the granu-

lation just before compression.

When the spongin was added to the granulation prior to compres-

sion it would not flow uniformly with the granulation, but instead, it

matted and bridged the die bore. Attempts to remedy this situation were

unsuccessful. Lubrication with magnesium stearate was increased up to

five per cent but did not alleviate the condition. Other lubricants,

namely, boric acid, high molecular weight Carbowaxes and talc were also












tried with no success.

In the case of those tablets prepared containing spongin in pro-

portions greater than ten per cent, satisfactory tablets were produced

only when special handling of the formula was carried out. When preparing

formulas containing 14 per cent spongin for preliminary study, great care

was required in adding the binding agent during the granulation process.

If an insufficient quantity was added, the resulting granulation had

"spongy" characteristics. A granulation of this nature would not flow

smoothly or uniformly into the dies regardless of the proportion of lubri-

cant used; thus the final weight of the finished tablet was affected. On

the other hand, if too great a quantity of binder was added, the granules

resulting from the first screening would be excessively hard and resistant

to further screening. It was necessary, therefore, to use the method of

trial and error when determining the proportion of granulating agent re-

quired for optimum granulation. Since this proved to be impractical,

this agent did not exceed a ten per cent concentration in any subsequent

formula.

Table 7 summarizes the individual size characteristics of the

tablet granulations prepared. It should be noted that with certain for-

mulas comparatively large variations occurred in the granulationsj however,

in most cases this had no noticeable influence on tablet compression.

The granulatiomhaving magnesium hydroxide as the active ingredient

were excessively soft and could be powdered when rubbed between the fin-

gers. When compressing these magnesium hydroxide granulations high pres-

sures were required in order to produce satisfactory tablets. If high










88

pressures were not used, capping of the tablets would result. When the

tablets capped immediately following compression, the upper punch faces

were observed to have the capped portion of the tablet adhered to' them.

However, some tablets were obtained in a whole state following compres-

sion and capped only when pressure was applied to the upper portion of

the finished tablet with the thumb nail. This latter type of capping was

most probably due to entrapped air in the tablet resulting from an exces-

sive amount of fine powder in the granulation.

All other formulas prepared produced excellent, well defined,

Smooth tablets.


Disintegration Studies

The data listed in Table 9 indicate that the tablets prepared

from formulas having powdered spongin as the disintegrating agent, dis-

integrated in all cases more quickly than the corresponding formulas

having corn starch as the disintegrator. It should be noted that powdered

spongin did not exceed five per cent of the tablet weight with the ex-

ception of those formulas prepared for preliminary study and two additional

formulas used for purposes of comparison. On the other hand, corn starch

was used in either 10 or 15 per cent concentrations.

All tablets containing powdered spongin disintegrated within the

official requirements provided by the U. S. P. or N. F. Although tablets

prepared from formula BSN-AT-5-b remained undisintegrated following three

hours of testing, they offered no resistance to the gentle touch of a

stirring rod following only five minutes of testing. When touched, the

tablets readily broke into several small pieces which passed through the










89

No. 10 mesh screen of the basket-rack assembly in two or three minutes.

Upon removal of these undisintegrated tablets from the disintegration

apparatus after five minutes of testing, they were found to be extremely

soft and easily crushed when squeezed between the fingers. Obviously,

such a tablet when subjected to the peristaltic action of the G. I. tract

would deliver the medication just as readily as one that would have fal-

len apart and passed through the screen. This tablet, therefore, would

have been considered disintegrated in accordance with the new U. S. P. XV

disintegration end-point.

In the preliminary studies conducted, all control tablets (those

having no disintegrating agent added), with the exception of the soluble

lactose tablets, showed no signs of disintegration subsequent to three

hours testing. However, upon the addition of powdered spongin to the

formulas, the same tablet formulas revealed no resistance to disinte-

gration whatsoever. The data compiled also show that tablets prepared

with 14 per cent spongin did not exhibit a substantial decrease in dis-

integration time over those tablets prepared with 7 per cent spongin.

This indicates that large proportions of spongin are not required in order

to accomplish satisfactory disintegration.

In general, synthetic sponge, when incorporated during the granu-

lation process with the active ingredient and filler, possessed no advan-

tage over lower concentrations of powdered spongin, but did surpass the

disintegrating action of corn starch. However, when the synthetic sponge

was granulated and added to the finished granulation prior to compression,

it swelled within seconds and broke the tablet down into its original










90

granules very rapidly. Well defined, smooth tablets were obtained when

adding the granulated synthetic sponge to the granulation prior to com-

pression,

Since tablet hardness has an influence on the rate of disinte-

gration, an attempt was made to maintain the tablet hardness within a range

of 6.0 to 8.0 Kg. Four formulas, however, fell out of these limits. This

was found to be caused either by the nature of the granulation being com-

pressed or by difficulty encountered in adjusting the pressures to this

hardness range.

The data listed in Table 10 and illustrated in Figures 4 and 5

indicate that the relationship which exists between the rate of tablet

disintegration and tablet hardness depends on the tablet formula being

tested. The results illustrated in Figure 4 show a minimum in the time-

hardness curves for four tablet formulas containing powdered spongin as

the disintegrant. In Figure 5, which represents the time-hardness re-

lationship of three tablet formulas containing corn starch as the dis-

integrant, this minimum in the curve is completely absent. Instead, the

disintegration rate varies directly with changes in hardness.

In general, a direct relationship manifests between disintegration

time and tablet hardness; however, before assuming this to be true in any

one case, a time-hardness curve should be plotted since in some instances

faster rates of disintegration are obtained as the tablet hardness is in-

creased. This continues up to an optimum hardness after which the ordinary

relationship holds true.

Higuchi, Elowe, and Busse .(5) have indicated a direct linear










91

dependency of hardness of tablets on the logarithm of the maximal compres-

ional force. Since this is the case, curves similar those found in Figure

4 and Figure 5 would be obtained if compressional force was substituted

for tablet hardness.

Berry and Ridout (30) determined the disintegration times of

different tablets as a function of the ratio of the weight to height of

the tablets which they called "compression ratio." Compression ratio

is actually a measure of the maximal force applied during the compression

of the tablets. They found that for some tablets there is a critical

compression which will give a minimum time of disintegration.

The minima in curves representing a time-hardness relationship

for the formulas (four) containing spongin are similar to those obtained

by Berry and Ridout (30). Observations as to why this minima occurred

with tablets containing spongin are also in correlation with those made

by Berry and Ridout. It was found that the tablets showing this phenom-

enon disintegrated from the outside, that is, small pieces flaked off

until the tablet was completely disintegrated. The disintegration of these

tablets depends on the swelling of the sponge particles. Under a very

light compression the tablets formed would be very soft and as a conse-

quence have large intergranular spaces. Although the spongin swelled in

these tablets, due to the large void spaces there was a certain lag period

before the swelled particles began to exert pressure on the surrounding

granules. This resulted in an inhibited disintegration rate. At the

optimum hardness, however, as soon as the spongin particles swelled, they

exerted sufficient pressure on the surrounding granules causing the tablets












to break apart more rapidly. When harder tablets were produced under

heavier compression, more time was required for the water to seep through

the outer layers of the tablets and, as a result, slower disintegration

rates -were obtained.

It should be indicated that the minimum point on a time-hardness

curve should not be used in determining the tablet hardness in actual pro-

duction. It is necessary to run, in conjunction with these tests, fria-

bility tests. In many cases it will be found that this optimum hardness

is merely a theoretical value and has no use in tablet manufacture since

the tablets are far too friable at this point. On the other hand, if

friability experiments show the tablets to be quite firm at this optimum

hardness, it is obvious that this hardness should be utilized.


Friability Studies

The data compiled in Table 10 and illustrated in Figure 6 and

Figure 7 indicate the relationship of tablet friability to tablet hard-

ness. Although the friability values are pronounced for extremely soft

tablets, they drop sharply as small changes in tablet hardness take place.

Following the sudden drop in the friability value, little change is noted

with progressively harder tablets.

In this investigation tablets having a friability value of 3.000

or less were considered as having a high degree of resistance to chipping

or breaking.

As previously stated, in order to determine the optimum hardness

for a particular tablet formula, it was necessary to conduct friability

values on several series of tablets. This data was correlated with




Full Text

PAGE 1

A STUDY OF SPONGE AS A DISINTEGRATING AGENT IN COMPRESSED TABLETS By ROBERT CARL CRISAFI A DISSERTATION PRESENTED TO THE GRADUATE COUNOL OF THE UNNERSITY OF FLORIDA IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY UNIVERSITY OF FLORID.A .August 1956

PAGE 2

1 .. ACKNOWLEDGMENTS The writer wishes to express his sincere appreciation and thanks to Dr. Charles H. Becker, Chainnan of the Supervisory Committee, under whose guidance this wor k was undertaken. It was through his advice and understanding that the completion of this investigation was made possible. The assistance and friendship of Dr. William J. Husa throughout the writer's graduate work are also gratefully acknowledged. Suggestions generously offered by the other members of the Supervisory Committee, Drs. W. M Lauter, M Herzber g and c. H. Johnson are greatly appreciated. As a Fellow of the American Foundation for Pharmaceutical Edu cation, the writer wishes to acknowled g e its invaluable support. To his parents, Mr. and Mrs. joseph Crisafi, he will be eternally indebted for their love and encouragement. S1ncere and deepest appreciation is expressed to the -writer's wife, Barbara, for her encouragement, love and understanding, as well as her help in the preparation of this manuscript. Without her assistance and moral sup port this work would not have been accomplished. 11

PAGE 3

TABLE OF CONTENTS ACKNOWLEOOtffiNT S LIST OF TABLES LIST OF FIGURES INTRODUCTION REVIEW OF THE LITERATURE Methods of Preparing Tablets Disintegrating Agents Methods of Testing Disintegration Factors Influencing Tablet Disintegration Sponge EXPERIMENTAL PROCEDURE Materials and Equipment Used Description of Sponges Used Natural Sponge Synthetic Sponge Treatment of Spongin Before Use Cleansing Procedure Bleaching Procedure Grinding Procedure Treatment of Synthetic Sponge Before Use Tablet Constituents Active Ingredients iii Page ii V viii 1 3 3 7 15 19 23 26 26 28 28 28 29 29 30 32 33 34 34

PAGE 4

Diluent Disintegrating Agents Binding Agents Lubricating Agents Tablet Formulation Preparing the Tablet Granulation Compressing the Granulation Equipnent and Procedure Test Methods Hardness Test Disintegration Test Friabili ty Test Storage Test Absorption Study EXPERIMENTAL RESULTS DISCUSSION OF RESULT$ Bleaching of Sponge Tablet Preparation Disintegration Studies Friabi1ity Studies Binding and Lubrication Studies Storage Studies SUMMARY BIBLIOGRAPHY BIOGRAPHICAL ITD15 COMMITTEE REPORT iv Page 34 34 36 37 38 39 47 47 50 50 50 51 52 54 55 85 85 86 88 ~2 94 97 100 102 106 107

PAGE 5

Table 1. 2. 3. 4. 5. 6. 1. 8. 9. 10. ll. 12. 13. 14. 15. 16. 17. Materials Used Equipment Used LIST OF TABLES Drugs Compressed into Tablets Tablet Fonnulas for Preliminary Study Tablet Fonnulas Tablet Fonnulas Description of Sized Granulations Moisture Absorbed by Powdered Spongin and corn Starch at Various Relative Humidities A Comparison of the Disintegration Times of Tablets Immediately After Compression Relationship Between Tablet Hardness, Friability and Disintegration Time Friability Values After Two Shaking Periods Friability Values of Tablets Protected with a Cotton Filler in Vials Comparison of Disintegration Rates of Tablets Prepared with Different Binding A gents Comparison of Disintegration Rates of Tablets Prepared with Different Lubricating Agents Tablet Disintegration Times After Storage for Intervals o f 250, 500 and 750 Hours in Open Vials at Various Temperature Conditions Tablet Disintegration Times After Storage for Intervals of 250, 500 and 750 Hours in Closed Vials at Various Temperature Conditions Tablet Disintegration Times After Storage for Intervals of 250, 500 and 750 Hours in Open Vials at Various Relative Humidities V Page 26 27 34 40 41 43 46 55 57 59 65' 66 66 67 69 69 70

PAGE 6

Table 18. Tablet Disintegration Times After Storage for Intervals of 250, 500 and 750 Hours in Closed Vials at Various Page Relative Humidities 71 19: Changes in Tablet Hardness After Storage for Intervals of 250., .500 and 750 Hours at Various Relative Humidities 72 20. Changes in Tablet Weight After Storage at Various Relative Humidities 73 21. Changes in Tablet Weight, Hardness and Disintegration Time After Storage for Intervals of 500 and 1000 Hours in Open Vials at Various Temperature Conditions 74 22. Changes in Tablet Weight., Hardness and Disintegration Time After Storage for Intervals of 500 and 1000 Hours in Closed Vials at Various Temperature Conditions 75 23. Changes in Tablet Weight., Hardness and Disintegration Time After Storage for 1000 Hours in Open Vials at Various Relative Humidities 76 24. Changes in Tablet Weight, Hardness and Disintegration Time After Storage for 1000 Hours in Closed Vials at Various Relative Humidities 77 25. Changes in Tablet Weight, Hardness and Disintegration Time After Storage for Intervals of 500 and 1000 Hours in Open Vials at Various Temperature Conditions 78 26. Changes in Tablet Weight, Hardness and Disintegration Tll?le After Storage for Intervals of 500 and 1000 Hours in Closed Vials at Various Temperature Cond;itions 79 27. Changes in Tablet Weight., Hardness and Disintegration Time After Storage for 1000 Hours in Open Vials at Various Relative Humidities 80 28. Changes in Tablet Weight, Hardness and Disintegration Time After Storage for 1000 Hours in Closed Vials at Various Relative Humidities 80 29. Changes in Tablet Weight, Hardness and Disintegration Time After Storage for 1000 Hours in Open Vials at Various Relative Humidities 81 vi

PAGE 7

Table 30. Changes in Tablet Weight, Hardness and Disintegration Time After Storage for 1000 Hours in Closed Vials at Page Various Relative Humidities 82 31. Changes in Tablet Weight of Differently Lubricated Tablets After Storage for 500 Hours in Open Vials at Various 32. Temperature Condit~ons 83 Changes in Tablet Weight of Differently Lubricated Tablets After Storage for 500 Hours in Open Vials at Various Relative Humidities 84 i vii ... (:

PAGE 8

LIST OF FIGURES Figure Page 1. Sponge Clippings Before Cleansing and Bleaching 31 2. Sponge Clippings After Cleansing and Bleaching 31 3. Absorption of Moisture by Powdered Spongin and Corn Starch 56 u. Relationship Between Disin t egration Time and Tablet Hardness for Tablets Prepared with Spongin as the Disintegrant Showin g a Minimum Point in the Curve 62 5. Tablets Prepared with Corn Starch as the Disintegrant Sh9Wing a Linear Relationship Between Disintegration Time and Tablet Hardness 63 6. Relationship Between Tablet Friability and Tablet Hardness 7. Relationship B etwee n Tablet Friability and Tablet Hardness 8. Comparative Disintegration Rates for Differently Lubricated Tablets of Formula BSN-AT-5-a 68 9. Comparative Disintegration Rates for Differently Lubricated Tablets of Fonnula BSN -AS-10-c 68 10. Comparative Disintegration Rates for Differently Lubricated Tablets of Formula S B B-10 68 viii

PAGE 9

INTIDDUCTION Tablets, as a means of administering medicine, have been in existence for over one hundred years. Today, compressed tablets are the_ most popular fonn of medication. Americans consume about forty-two million tablets daily (1). Whether or not these forty-two million tablets exert the intended therapeutic action depends to a great extent on one essential property of the tablets, namely disintegration. Despite the importance of this property, it took eighty years from the time tablets were first manufactured in the United States, in 18701 and thirtyfour years after the first tablet appeared in the u. s. P. IX, until official requirements for disintegrJ:Ltion were established. During the interim, great objection was made.to tablets due to the fact that many tablets, as described by one observer, would pass through the hmnan system showing as much chan ge as a glass marble (2). In order to accomplish tablet disintegration, at least in the case of insoluble materials, it is necessar y to add a sub stance to the tablet formula which has the capacity to break the tablet apart. This agent is called a disintegrator. While there are many conditions which influence the rate of disintegration, the proportions and types of binding and disintegrating agents in the tablet fonnula are, in many cases, the most important factors controlling the disintegration of this fonn of medication. On the basis o f a s t udy by Gross and Becker (3), powdered sponge 1

PAGE 10

2 was found to be the best disintegrating agent among the twenty-two different materials lried. Since their work was limited to lactose tablets and a single percentage of sponge, it was the purpose of this investigation to make a more detailed study of this agent. Spon ges, both natur.al an n synthetic, in varying concentrations were evaluate as disintegrants for compressed tablets. 'Ihese tablets were compared for disintegration time against tablets containing corn starch as the disintegrator. In addition, the effects of various lubricants an d binding a gents on disintegration time of the tablets were studied.

PAGE 11

REVIEW OF THE LITERATURE Methods of Preparing Tablets Tablets are unit dosage forms of medication in the form of a granular powder, with or without diluents, compressed into a suitable shape (h). The general method of preparing compressed tablets encompasses one of three specific procedures. a. Direct compression b. Slugging process c. Wet granulation process If the material to b'e compt:E-ssed is free-flowing and cohesive without the addition of binders or lubricants, then the first of the above methods, direct compression, is utilized. In this method the material need only be reduced to the proper particle size, which is dependent upon the size of the t ablet to be made and is run directly into the tablet press 'Without any further preparation or special handling. Some materials, on the other hand, do not possess either c-0hesiveness or lubricity and these pro~erties must be given to the materials by either one or the other methods of granulation. The basic objective in granulation is the conversion of the powdered ingredients into a free-flowing unifonnly compressible material. Such a granular material is essential since the compression machines rely on volumetric gravi t y fill to achieve uniformity in dosage. Upon 3

PAGE 12

4 completion of the granulation process, the granules must be self binding and non-sticking to the punches and dies (5). The choice of the granulation method to be used is dependent upon the properties o f the materials to be compr essed If the powders are either heat or moisture labile, then the precompression or "slugging met h o d is used which excludes these two factors from the process. I~, on the other hand, these factors are of no concern to the p~rticular fonnulation in question, one may use the wet granulation process, currently the most widely used method for the preparation of granules for tablet compression. 'Ihe process of precompressio~ involves the production of 11slugs" or larg e tablets which are subsequently screened and recompressed into finished tablets. In this metho d the ingredients in the formula, which are usually in powder form, are wei g hed out, mixed, and then sifted throug h a No. 30 or 40 sieve. The resuitant mixture is compressed in he avy duty machines into over-sized tablets c alled "slugs" which are 3/4" 7/8" in diameter. 'Ihese 11slugs11 are then broken down into appropriate p article size by passing throug h mechanical granulators with the desired sieves attached ( 6). Although the precompression process completely eliminates many steps, which are essential in.the wet granulation m e t hod, it also possesses s everal drawbacks. First the tablets produced are not as hard as t h ose prepare d b y wet granulation Secondly, in order to accomplish t his met h od satisfactorily, a slow, heavy duty tablet press is required so tha t extremely hig h pressures may be obtained since such pressure s

PAGE 13

5 are necessary for the production of "slugs". A third and most important dra wback is the fact that few materials lend themselves to tableting b y this method (10). For materials that cannot be directly compressed, or are not heat or moisture labile, the wet granulation method is perhaps the most generally employed. Here the material is first converted into a doughy mass through the use o f a granulating agent which is capable of aggregating the powders through either a bondin g or solvent action on the components of the t blets. This doughy mass is broken up into coarse granules w h i ch are subjected to uniform drying. These prim a r y granules are obtained by forcing the aggregated mass throu h a No. 6 or No. 8 sieve. After t hese coars e granules have been sufficiently dried they are further broken down to ap propriate dimensions. The size o f these final granules has a direct relationship to the appearance and properties .. of t he finished t ab let. Malpass (7) stipulated that the mesh size must be g overned by the size o f the tablet and the hardness desired. In 19u7, Silver. and Clarkson {11) presented the followi~ schedule of sieve sizes through which the material should be passed for granulation: Tablet Size Size Sieve up to 3/16 No. 20 7/3211 5/16" No. 16 11/32" 13/32" No. 1h 7/1 6 and over No. 12 I t is necessary when prepa ring these f inal gran ules that they

PAGE 14

6 be free from excessive "fines" (8). Little and Mitchell (5) state that fine powders are apt _to pack or "bridge" in the hopper, feed shoe, or die; and thus tablets of uniform weight and uniform compression are not obtainable. Nevertheless, it should be kept in mind, that in order to obtain a good tablet a certain percentage of "fines" are necessary. Silver anr Clarkson (11) state that 10 -20 per cent of "fines" based on total granulatiO'Il are necessary to fill the void space between granules in order to produce a tablet of smooth appearance. Caspari and Kelly (4) advocate the use of 10 15 per cent 11fines11 for optimum tablet appearance. Villacorta (9), working on granulation of acetylsalicylic acid, recommends that "fines", designated as particles less than 125 microns, should not exceed 20 pe~ cent in the granulation mixture. Contrary to all the above findings, Chavkin (10) states that. up to 80 per cent of material finer than 80 mesh (177 microns) can be incorporated into a tablet granulation wi.t~out adverse effect upon the hardness of the resulting tablet. The final step in the wet granulation process, before fee ding the hopper with the gra nulation, is lubrication of the granules. Lubri-. cation is accomplished by adding a substance to the dry granulation that will facilitate ejection of the finished tablet from the die after com-pression. The disintegrating a gent, in some cases, is comple~ely added with the lubricant durin g addition of the latter to the granules, but in most cases it is mixed with the active ingredient and filler, and an additional amount is very often added to the lubricant.

PAGE 15

7 After addition of these latter agents and proper mixing of the granulation, the material is then ready for compressing. Disintegrating Agents An examination of the literature ~o determine previous research accomplished on disintegrating agents revealed very little published infonnation in this field. Undoubtedly, a grea t deal of work has been done, especially by pharmaceutical companies, however, since the manufacture of tablets is an art and the urtj..queness of many commercial tablets depends upon_the type. o f disintegrating a gent used as well as several.other factors, much ~f this knowledge has been carefully guarded by the industry itself and thus remains unpublished. The infonnation found has been seriously considered in the study of this problem. A disintegrating agent is a substance which is added to the tablet to help break it apart after administration or to hasten dispersion in water (11). Disintegrators fall into two main classes. They are: (a) substances which will swell in the presence of sufficient moisture or other suitable media; and (b) the addition of chemically reactive ingredients which when wetted will produce a gas upon reaction and break the tablet. The forme r of these two classes, that is, those substances that swell in the presence of moisture are, by far, the most widely used agents in tablet manufacture. Corn starch is one of the oldest and still most commonly used disintegrators in tableting. Starches have a great affinity for water

PAGE 16

' 8 and through rapid absorption the starch grains swell to many times their normal size. This expansion causes the tablet to disintegrate or break apart quite rapidly. This valuable use of starch was first observed by Charles Killgore, an American, who in 1887 applied for a process patent which was denied on the basis that starches had previously occured in tablets though their value was not recognized (12). Killgore's patent application, No. 238,375, which was filed May 16, 1887, was in part as follows: It is well known that the administration of medicines in the form ofcompressed tablets or pills, while having many advantages, has been open to disadvantage arising from the slowness with which the same dissolve in the stomach. The object of my present invention is to fonn tablets or pills which, while possessing all the advantages of those heretofore em ployed, are not attended by the disadvantage above refeITed to; in that when subjected to moisture they rapidly disintegrate. This result I accomplish by mixing with the ordinary ingredients constituting a compressed tablet or pill a percentage of starch which will so change the character of the compressed tablet or pill that the same will not be open to the objection heretofore existing. The tablet or pill resulting from my invention possesses, as far as I know, all of the qualities of those heretofore made excepting when taken into the stomach it imnediately disinte,grates. I claim a compressed tablet or pill containing a substantial percentage of starch, for the purpose of facilitating disintegration, as set forth. Th.e following notation was made by the Patent Examiner in rejecting the patent application: Starch is the most commonly used dividing a gent. It enters into pills, tooth powders, baking powders, and toilet powders generally. Such having been compressed, there is neither novelty nor invention in applicant's procedure. The application is rejected. That Killgore's discovery wa~ quickly used, in secret and without credit to him, is indicated by an interesting controversy between two English manufacturers conc erning their newly improve tablets (lJ). Dieterich (14) wrote, in 1890, that a simple means for

PAGE 17

9 obtaining disintegration of tablets was merely to add some powdered sugar ~rith the active ingredient. Since this method did not accomplish its purpose in all tablets, he advised the introduction of a substance that swells up in water and gave tragacanth powder as an example. He noted the use of 10 25 per cent tragacanth as being sufficient. Blaschnek (15), in 1909, investigated potato, wheat, corn, rice and m.aranta starches as disintegrating agents. The results clearly showed a distinct advantage for maranta and potato starches. A point brought out by this inv.estigator was that starch must be nearly anhy drous if the best results are desired. In 191.L, Kebler (16) stated that mixture. a of a bicarbonate and an acid when incorporated in a tablet and immersed in water react and give off carbon dioxide, thus mechanically breaking up the tablet. In the same paper he mentione d that although powdered agar-agar and Irish moss had been advocated as disintegrators for compressed tablets they had not been used to any extent. White (2), in a SUll'll'llary on tablet manufacture, wrote that potato starch was far superior to all other disintegrating a gents used up to that time. He stated that the potato starch should be a d ed to the dry granulation immediately before compressin g and not during the granulation process. When prepared in this manner the tablets were found to swell and rupture when immersed in water. American and foreign literature on the subject of tablet disintegration is very scanty from 1923 to 1946, the majority of the reports being focused on the application o f starch as a means of facilitating

PAGE 18

10 tablet disintegration (17 31). Most of this research, however, is repetitious or contradictory and in many cases hinders rather than helps the inexperienced tablet maker. Husa (23), in 1928, sug gested the classification of tablets into different g roups according to the t yp e of disintegration they undergo. He rioted that certain tablets dissolve without t he aid of a disintegrator and that t hese tablet s were made from soluble chanicals. He proposed that tablets of this nature should be classified as a tablet not re quiring the aid of a disintegrating agent. A review on tablet making (24), in 1931, mentioned the use of pectin as a disintegrant for p reparing tablets on a large scale. The experim ents carried out w'ith the addition of one per cent pectin to the granulation along with a _little rice starch proved to give satisfactory tablets with rapid d isintegration rates. It was noted that the addition of pectin to tablet masses in quantities of ~en per cent or more is not advisable because a thick layer of mucilag e fonns aroun d the tablet during the process of disintegration or solution, which, unless vigorous, shaking is resorted to, prevents the wat e r from comin g into contact with the nucleus of the t able t and retards disintegration. Potato starch, gelonide, and magnesium peroxi_de have been compared as disintegrants for tablets (27). Oelonide was prepared by treating a ten per cent aqueous solution of gelatin with a few drops of formaldehyde solutio n until a glue-like consistency was obtained. It was then forced through a No. 22 screen, dried for several hours at 900 c., and powdered. The diaintegrants were added to an acetanilid granulation prepared with ten per cent gelatin solution. Potato s tarch was found to be superior to the other two disintegrants for acetanilid

PAGE 19

11 tablets. Milne (32) postulated that methylcellulose would be of value as a binding agent and comp,2red it to other granulating agents by the dis integration time of the resulting tablets. He used the following granulating agents: (a) 10 per cent gelatin solution, (b) 50 per cent alcohol, (c) 10 per cent starch paste, (d) equal parts of mucilage of acacia and syrup, and (e) 3 per cent methylcellulose solution. In all cases, the tablets made were Compound Aspirin Tablets, B. P. c., and all conditions were kept as constant as possible. Milne found that methylcellulose compared favorably with starch paste and gelatin solution, the disintegration in these three cases being of.the explosive type. He also indicated that tablets made with alcohol or the acacia mucilage-syrup mixture as a binding a gent disintegrated very slowly. Because .methylcellulose is stable to heat and is not subject to attack by microorganisms and molds, he suggested its use as a binding and disintegrating agent for compressed tablets. In 1949, Granberg and Benton (33), workin g on tablet fonnulations, stated that bentonite serves both as a filler and disintegrating agent when added to thyroid tablets. Because the color of bentonite is approximately the seme as tnat of powdered thyroid, they suggested its use as being advantageous over starch, since the latter has a tendency to discolor the tablet. Studying alginic acid as a disintegrating agent, Berry and Ridout (30), found that when ten per cent was added in phenobarbital tablets, it gave a much better disintegration time than 15 p e r cent of potato starch, and in the case of barbital tablets the tillle of disintegration was

PAGE 20

12 approximately the same. They stated that alginic acid can be granulated with the medicaments in a tablet which has the following advantages: a. The addition o f a very fine powder, such as starch to the granules before tableting, means that there is a considerable risk of separation of J>Owder and granules during the transfer of the bulk material to the tablet machine and also, whilst the material is in the hopper, due to the vibration of the hopper or of the machine itself. This separation of fine powder will cause variation in weight of the tablets and also variation in the amount of active ingredient in each tablet. There is also the difficulty-by no means inconsiderable-of ensuring an even distribution of a large quantity of starch in a bulk of granules. b. Since the a1ginic acid in these experiments is an integral part of the granules, when the tablet breaks up it will do so to give material which is smaller than the original granule. The active constituents thus being presented in a finer form will be more quickly absorbed and give a more rapid therapeutic action. c. The process of tableting will be simplified. Gross an Becker (3) discovered two new s ubstances and claired them to be more effective disintegrating agents than many of those commonly used. These new agents were powdered sponge and dried citrus pulp, both prepared in the laboratory from natural Florida products. These were tested along with 20 other substances on a comparative basis. The agents used were: corn starch, bentonite, and tragacanth, all of u. s. P. XIV grade; pectin, karaya gum, sodium alginate., and methylcellulose (100 and LOOO cps.) all of N. F. IX grade; also Gelloid .50, locust bean gum, algin, Veegum HV., Aveeno., and CMC 70. In a separate category were magnesium peroxide., and combinations of calcium carbonate with eithe r citric acid, pectin, or urea monophosphate, in addition to sodium carbonate peroxide and sodium pyrophosphate peroxide. For the investigation, tablets were prepared without medicament., lactose being used as the inert filler and two per cent leucine as the lubricant.

PAGE 21

13 Two granulating solutione were employed. One contained five per cent Zein (corn protein) in isopropyl alcohol and the othe r had five per cent zein in a mixture o f syrup, water and alcohol. Alternative methods were employed for incorporating the disintegrating agents: (a) the whole of the agent ~ras mixed with the lactose before moistening with the granulating solution; (b) five per cent of the a gent was reserved for admixture ..,._ri_ th the l ubricant after granulation. For each test the same amount of disintegrating agent we. s used, namel y 17 p e r c ent. In order to obtain results of a.comparative nature, the disintegration times were extrapolated from individual hardnesses to a hardness of seven kilograms. All hardness tests were determined with a Monsant o Hardness Tester. The authors concluded from this study that powdered spon ge not only was the most effective disintegrating agent of the 22 studied but also that tablets prepared with it as the disintegrant remained stable after being aged at room, elevated, and reduced temp eratures. No changes in either hardness or disintegration time were noted after 500 hours of aging. In 1953, Swintosky and Kennon (34) prepared two powdered acid gums, namely, carboxymethylcellulose (CMC acid) and linseed acid. They described a new procedure for the preparation of these acids in a powdered, water dispersible form. A preliminary study using these agents in compresse d tablets indicated ~h a t c arboxymethylcellulose possesses tablet disintegrating properties analogous to those o f powdered alginic ( acidJ however, it was s ug ested that further work b e carrie out in order to make a true evaluation o f these substances for that purpose. Firouzabadian and Huyck (35), in 1954, compared four substances

PAGE 22

w1 th corn starch as disintegrating agents for tablets of both soluble and insoluble medicaments. These subs~ances used in ten per cent concentrations included alginic acid, Veegum HV, methylcellulose, and a starch-agar mixture. Sodium bicarbonate was selected as the soluble medicinal ingredient while aluminum hydroxide served as the ingredient for the insoluble tablets. Of these four a gents tested, alginicacid an d Veegum HV compare d favorably as disintegrants for the particular formula of sodium bicarbonate tablets while the starch-agar mixture and Veegum HV were the best for those tablets containing aluminum hydroxide. Although t~ese latter two substances gave satisfactory disintegration rates when used in the alumi num hydroxide formula, they-could not be recommended since in ten per cent quantities they discolored the tablets slightly. The authors, however, did sug ~est their use as disintegrating agents for colored or coated tablets. Eatherton, et.al., (36) tested three grades of guar gum as disintegrating agents for tablets of.digitalis, lactose, sulfathiazole and thyroid with corn starch being used as a control in the disintegration tests. Although one and one-half per cent of each of the three grades of guar gum produced effective disintegration times for the sulfa thiazole and lactose t ablets, this same conce ntration of gum had no advantag e ove r oorn starch when used in digitalis an d thyroid tablets. Following storage tests of increased temper ature and humidity, the hardness values of the tablets prepared in this study were found to have decreased from their original values. In 1955 Swintosky, et al., (3 7), tested several new powdered polysaccharide acids for their effects on the hardness and disintegration

PAGE 23

15 time of sulfathiazole tablets. Several of these new polysaccharide type acids were shown to hasten isintegration whereas others retarded disintegration. It was found that alginic acid, carboxymethylcellulose in powdered acid fonn (HCMC), elm acid and starch served to facilitate tablet disintegration, whereas linseed acid, quince acid, arabic acid and plantago acid served as disintegration retarders. The authors, in sunnnarizing, stated that since delayed or sustained drug release have become so p-opular in recent years, disintegration retarders or inhibitors such as arabic acid, linseed acid and quince acid may possibly be employed when these actions are desired. The-mechanism through which starch serves as a disintegrating agent, from the discovery of its use in 1887 up until recent times, has not been dispute. However Curlin, in 1955 (38), stated that the disintegration action of starch was not due to its swelling property but instead due to is capillary acti on in the tablet. 'Ihis action, he noted, may be due to the spherical shape of the starch which increases the porosity of the tablets. When placing a drop of dye solution on a tablet an then cutting it in two, he f~und the color had penetrated the tablet as though it were a blotter. To s ubstantiate his claims, he stated that, u~on examination of the slurry obtained from disintegrated table~s, the starch granules were not swollen. Methods of Testing Disintegration Although the need of a substance to facilitate the breaking up of a compressed tablet had been realized since 1900, it was not until 25 years later that studies were undertaken to find a method which would

PAGE 24

16 give reproducible disintegration rates of tablets. Before this time the disintegration rate of a tablet was noted by dropping it in a glass of water and observing its breakdown. The methods of determining the disintegration time of tablets fall under two main classes. The first class includes those methods which test for hardness and resistance to breakage and the second includes those methods which test for speed at which the tablet will dissolve or break up into its original granules when placed in a liquid at a specified temperature. Research has thus far prod uced 27 disintegration methods, o f which two fall under the first class and 25 under the second class (39). It is easily realized, after a care f u l review o f these methods, that ther e is a great amount of confusion as to the value of these disintegration studies and that the many variables arising from them show a definite need for standardization. Probably the first attempt to study disintegration testing in a systematic manner was carried out in 1930 (40). This was the earliest comprehensive investigation of table t disintegration and was conducted .. by a subcommittee o f the Research Board o f the AP?-l A, under t h e chairmanship of Geor g e Ewe. Ewe described a method for determining disintegration of tablets based on a classification as to where and how the tablet disintegrated or dissolved. Nine classes of tablets were designate d as .follows: a. Uncoated tablets intended to disintegrate or dissolve rapidly in the stom~ch. b. Uncoat e d tablets inte nded to disintegrate o r dissolve in the stomach. c. Hypodermic tablets.

PAGE 25

17 d. Uncoated tablets intended to dissolve or disintegrate in water at room temperature. e. Uncoated tablets intended to d issolve or disintegrate in water at elevated temperatures. f. Uncoated tablets intended to pass into the intestines and be disintegrated there. g. Coated tablets intended to disintegrate rapidly in the stomach. h. Coated tablets intended to disintegrate in the stomach. i. Coated tablets intended to pass into the intestines and be disintegrated there. In addition, Ewe recoJIU'llended a method of detennining the disintegration time of tablets and suggested maximum rates of disintegration for certain classes of tablets. In 1934, the Swiss Phannacopoeia gave the first official method fortesting disintegration and in 1936 the subject was discussed at the British Phannaceutical Conference (41). Brown, in 1939 (27), devised his own method for determining tablet disintegration. He determined the force (weight) required to break tablets when dry and again when wet. The ratio of these two breaking point s w e s taken as the significant measure since it would con-. trol the degree of attrition during transport and storage as well as the clinical effectiveness of the tablets. Also in 1939 Berry (h2), upon request of the British Phannacopoeia Committee, investigated an reported on a new method for determining tablet disintegration. For this m ethod he used a specially constructed wire device, which, when weighted, cut through the tablet. Later this device

PAGE 26

18 was modified by Berry and Smith ( 43), but it was admitted that while the method con tributed to research in the field, it was actually a measure of the rat e of softening rather than disinte ration. Finally, in 1945, the 7th Addendum to t he B~itish Pharmacopoeia was published, intro ucing a standard test for the disintegration of tablets. S everal articles were published fro. 1942 to 1945 b y both American and British authors co~taining descriptions an d results of tablet disinte ration tes s (44 -48). In 1946, Gersh berg and Stoll (49) described the apparatus that has been in use in chemical inspection laboratories of the u. s. Army Medical Department since 1940. This apparatus was noted as having several advanta ges over other disintegration methods and also as being capable of testi n g enteric coate d tablets, since they could first be immersed in an acid-pepsin solution for a specified period and then transferred to an artificial intestinal fluid without taking the tablets out of the apparatus. Dup..ng the year of 1948 the Stoll-Gershberg a pparatus w a s studied by a subcommittee of twelve members. The subcommittee g en erally agreed, atter intense investigation, that it fulfilled the requirements as well as any simple, mechanical apparatus co u l d be expected to do, and recommended its use for a d isintegration test to b e includ ed in the forthcomin g revisi9ns of the U. s. P. and N F. The recommended test and time limits of official tablets appeared in the U. s. P._XIV and N F. IX with only slight modifications. How eve r additional experience on the disintegration of co mpressed tablets ha s caused the end-point definition of the official test to be revised in the current U s. P. and N F 'lb.e

PAGE 27

19 former end~point definition read (50): "the tablets are completely dis i ntegrated when substantially no residue remains on the screen." Sinte it w s found that certain t ablets do no t bre ak down durinu thi s test but instead form soft resinues that will easily break down with the slightest touch o f a finger or stirring rod, the following new clause was added to the original end-point definition. It now reads (51): "the tablets are disintegrated if substantially no residue remains on the screen or if any residue that remains is a soft mass having no palpably firm core. 11 Factors Influencing Tablet Disintegration Since most compressed tablets are composed of more than one ingredient and require several steps in manufacture, it is possible that these factors greatly affect disint~gration rates for any given tablet. There is much evidence to show that the following are contributory factors af_ecting the rate of disintegration: a. The nature of the active and othe r co nstituents used. b. The type and quantities of binding agents used. c. The disintegrator used. d. The lubricant used. e. The size ~d weight of the finished tablet. f. The hardness of the finished tablet. g. The degree of compression. h. The speed of compress ion. i. The type of hopper feed in the machine, particularly if the disintegrant is added to the finished granules.

PAGE 28

' 20 j. The age of the tablets. k. The means of testing disintegration. Among the s ubstances that will influence the disintegration of the finished table are: the active medicament, e.g., which may be org anic or i norganic, a salt or an acid, an ester or an alcohol, all of whic h m a y have i :ferent crystal structure and properties that will innuence the compress i on characteristics of a formula; the binding agent which is usually carbohydrate or proteinaceous in character; the fillers, which, depending on their nature and content have a great influence on the final tablet; the disintegrant; and the lubricant. Combinations of these many substances w hen compressed will yield a certain structure which may be varied according to the physical properties and particle sizes o f the i ngredients (52). It is obvious that, as the structure of the tablet i t changed, the disintegration rate will be affected. Several independent studies have indicate d the existing relationship between the active ingredient of the tablet and the rate at which the tablet disintegrate s (35, 36, 53, 54). Firouzabadian an Huyck (35) have shown tha t in order to control disintegration, theselection and quantity of disintegrant used i n the fonnula must be made according to the nature of t h e active ingredient. They reported that the solubility of the finished tablet has a marked effect on the time at which it disintegrates. Indications of the inhibitory action of binding agents on the disintegration of tablets have been reported by numerous workers (29, 321 3 6 55, 5 6 57). Chavkin (10) in discussing problems o f producing compressed tablets, indicate d t h e indiscriminate use of binding agents during

PAGE 29

21 the process of granulation as being the cause of excessively hard granules, which invariably, when compressed, result in the production of tablets with prolonged disintegration rates. Accordin g to Strickland, et al., (58) the addition of excessive proportions of lubricant to the granules produces softer tablets with a severalfold increase in disintegration time. The best lubricants were found to be impervio u s to water (S9), making it evident that an excess of such a lubricant will have a waterproofing effect on the finished tablet, thus hindering its disintegration rate. Other recent reports have also described this effect of lubricants on disintegration (6o, 61). Higuchi, et ai., (54), in a report on the physics of ~ablet compression, stated that hardness varied directly with the logarithm of compressional force, leveling off at hig h forces. It also was found to vary directly with the apparent density of tablets. Using varying proportions o f disintegrant i n the same basic fomula., they found that the logarithm of the disintegration time also varied directly with compres sional force, a n d that higher ra:tes of disintegration were produced by increasing the proportionQf disintegrant. In sane instances, however, when a high percentage of disintegrating agent was present, faster rates of tablet disintegration were obtained as the maxi.1nal compressional force was increased. This contin~ ed up to an optimum compression after which the ordinary relationship of disintegration time with compressional force was manifested. Thes e results are in general agreement with those observed by Be?Ty and Ridout (30) who had determined the disintegration times of the different tablets as a func tion o f the ratio of the wei ght to height of the tablets which they called "compress i on ratio", and is

PAGE 30

22 obviously the same as maximal force applied during the compression of the tablets. Statements have been made that the unifonnity of tablet mixtures could be modified during compression due to mechanical vibration of the tablet press (30, 62). In general, the disintegrating agent is added in the fom of a very fine powder to the granules just previous to tableting; therefore, any separation of powder and granules before or during compression would undoubtedl y result in uneven distribution of the disintegrant which would in turn influence disintegration of the finished tablets. Raff (63) described a method o f following this separation of fine m aterial by means of statistically recording resultant tablet weights, compressional pressures, hardness, an d changes in color, supplemented by a test utilizing sieving at an intemediate point. He reported this separation to be enhanced by starting with a full hopper and operating until t he supply of granulation was exhausted ; he sugg .este d that the hopper be kept filled to a reasonable leve l during tableting if this is to be avoided. The effect of aging on disintegration times of tablets has been the subject of many investigations (1, 29, 30, 36, Cl4, 65, 66). Because these investigations have been carried out on an independent basis, the data collected is very broad an d seems to indicate that the ef:ect of age on tablets cannot be generalized but inste ad must be detenr~ned for the particular tablets in question. However, the reports cited do agree that the factors influencing the effect of age on tablet disintegration are as follows; the conditions of storage, the length of time stored, t he containers u sed for storag~, and the nature of the tablets stored.

PAGE 31

23 DeKay and Holstius (31) stated in a recent paper that of all the variables invest.igated, such as active ingredient, binding agent,. disintegrating a gent, hardness of tablet, etc., no one variable was solely \ responsible for influencing the disintegration rate of the finished tablet They postulated that disintegration is probably due t o the interaction of all these factors c o mbined. Sponge Tschirch (67) believes the medicinal use of sponges dated back to the Salernian School .(13th century). Sponge ash was official in the phamacopoeias of the 18th and 19th centuries, appearing last in Pham. Helv. I (186 5) As late as 1899, the United States Dispensatory, 18th edition, set up standards and methods of preparation for Spongia officinalis (68). Besides the specific use for goiter, due to their iodine content, sponges have also bee n used for surgical procedures, where their great absorptive power is utilized. Unfortunately, early investigation and classification of sponge was hindered and confused by the fact that it was believed to be plant rather than animal. As late as the mirldle of the 19th century it was I often classified in the plant kingdom anrl the animal character of the spon g e was definitely established only in the last few years of the century (69). Due to a lack of broad knowled g e of the sponge, the few studies that have been undertaken on it often disagree on m a ny points. For example, even now there is no universally accepted system of naming and

PAGE 32

24 classifying sponges. One of the best documented systems of classification now in use is that o f M w deLaubenfels (70). This system is comparatively new, bu t is becomin g very popular an d widespread Sponge in its natural state, when alive, is covered and pemeated throughout with a gelatinous substance known as "guITyl'. Soon after the sponge is collected this 11gurry" is removed by washing and expressing. This process of washin ~ and expr,essing, when inished, leaves but the fibrous ~keleton o f the animal, and it is in this con dition that the sponge is sold on the market. St~deler (71), in 1859, was first to give the fibrous skeleton of the sponge a name; he called it "Spongin.11 Spongin is classified under scleroproteins (albininoids), which include all proteins having a supportin or protective function in aniFal organisms (72). More specifically it belong s to the class of scleroproteins known as keratins. The keratins have be en defined as insoluble proteins which are extraordinarily resistant to digestion with the usual proteolytic enzymes. Spon gin, accordin to Block (73), is classified still further as a pseudokera tin, t hus being less resistant toward enzymatic hydrolysis than the eu.trnratins. The most recent and by far the most comple t e elemental anal. ysis of spongin was perfomed by Ramsey in 1948 (74). Three species of Florida salt water ~pon g e s furnished the spongin for the analysis. The results of R amsey's analysis of the sheep's-wool sponge, the same specie, used in the present investigation, are summari zed as follows:

PAGE 33

Nitrogen-----J.4.68 per Carbon-------46.04 per Hydrogen------6.06 per Oxygen--------29.71 per Sulphur------0.08 per Phosphorus----Trace Iodine-------0.74 per Chlorine------0.32 per cent cent cent cent cent cent cent 25 Bromine-----o.53 per cent Potassium---0.36 per cent Iron---------0.27 per cent Calcium-----o.52 per cent Barium------0.14 per cent Sodium------0.14 per cent Copper------0.05 per cent Ash---------3.90 per cent Trace Elements---Aluminum, Boron, Chromium, Lead, Manganese, Nickel, Silver, Strontium, Vanadium and Titanium. The organic nature of spongin from a chemical standpoint has been ascertained as be i n g protein by several workers (73, 75, 76). Studies o n the amino acid content of these proteins howeve r have been few, and most o f those un certaken have ne glected to mention the exact specie of sponge used in the analysis. Sheep's-wool sponge obtained from Florida's west coast has been reported byWintter (77) a s being made up o f the following amino acids: aspartic acid, glycine, alanine, lysine, arginine, prol~e, glutamic acid, threonine, tyrosine, hydroxyproline, phenylalanine and leucines (mixture of isomers). Althoug h no specific studies have been reported on the toxicolog y of spo n g e on human subjects, exp eriments on animals ha v e indicated it to be non-toxic to the specie s of animals used (78).

PAGE 34

EXPERIMENTAL PROCEDURE Materials and Equipment Used The materials and equipment used in this investigation are listed in Tables 1 and 2. TABLE 1 MA TERIAL.S USED Material Sponge Sponge Corn Starch Calcium Gluconate Sulfadiazine Dried Aluminlllll Hydroxide Gel Bismuth Subnitrate Magnesium Hydroxide Bismuth Subcarbonate Lactose Sodium Bicarbonate Syrup Zein PVP (Plasdone) Locust Bean Oum Magnesium Stearate Talcum Boric Acid Isopropyl Alcohol Potassium Penuanganate Sodium Bisulfite Hydrochloric Acid Glycerin Sucrose "' Sulfurous Acid Hydrogen Peroxide Solution Sodium Perborate Oxalic Acid Sodium 'l'hiosulfate 26 Quality Natural Synthetic u. s. p. U. s. P. U. S. P. U.S. P. N. F. N. F. U. s. P. U. S. P. U. s. P. U. S. P. Food Commercial Food u. s. p. U.S. P. U. s. P. N. F. u. s. P. U. S. P. U. s. P. o. S. P. u. s. p. Reagent U. S. P. N. F. Reagent N. F.

PAGE 35

F;quipment Tablet press Tablet press Mikro~verizer Conun.inuting mill Wiley mill Sifter (electric) Sieves a, 14, 40 mesh 10, 20, 40 mesh &:J, 80, 100 mesh 200, 350 mesh Dough Mixer Ribbon blender Air circulating oven Oven (electric) Analytical balance Prescription balance Platfonn scale Refrigerator Disintegration apparatus Hardness tester Shaking machine Cenco DeKhotinsky thermostat Lightnin' mixer Stainless steel tanks Pony mixer Sling psychrometer TABLE 2 ~UIPMmT USED Description Rotary B-2 Eureka Bantam Model D Model No. 2 Model P-S Stainless steel Brass Wire cloth Stainless steel Model K-20 Model 21...AA Model J8-B Storage Chainomatic Class A Model 4021-Y Frigidaire, 22 .ft. 3 Model 8918 Model F San-I-Tanks Model 13111 ML-24 Source F. J. Stokes Machine Company F. J. Stokes Machine Company Pulverizing Machinery Company w. J. Fitzpatrick Company A. H Thomas Company Read Standard Corporation Newark Wire Cloth Company E. H. Sargent Company E. H. Sargent Company Read Standard Corporation Read Standard Corporation F. J. Stokes Machine Company F. J. Stokes Machine Company Precision Scientific Company A. S. Aloe Company Torsion Balance Company Toledo Scale Company General Motors Corporation J. Vanderl{amp Instrument Company Monsanto Chemical CamP.anY Fisher Scientific Company Central Scientific Company Mixing F,quipment Company, Inc. Metal Glass Products Company J. H. Day COMpany, Inc. Signal Corps, U. S. Army N -.J

PAGE 36

28 Description of Sponges Used Natural Sponge Sheep's-wool sponge was chosen as the source of the spongin because of its availability and commercial importance. The Sheep I a-wool sponge, in the form of clippings, was obtained from the commercial sponge markets of Tarpon Springs, Florida. The classification set forth by M. W. deLaubenfels (70) was followed for the identification of the material used in this study. For Sheep's-wool sponge it is as follows: Phylum: Porifera Class: Demospongia Order: Keratosa Family: Spongiidae Genus: Hippiospongia Species: Hippiospongia lachne For the sake of convenience, the name, spongin, was frequently used in place of the common name, wool-sponge, or the species name, Hippiospongia lachne. Synthetic Sponge The synthetic cellulose sponge was obtained locally in block fonn and had the dimensions of 4" x 3" x 1" in length, width, and thickness, respectively. This synthetic sponge was manufactured by E. I. Du.Pont de Nemours Company, Incorporated.

PAGE 37

29 Treat.ment of Spongin Before Use The spongin used in this study was in the form of clippings which were trimmed from sponges in the process of preparing them for market. These clippings, in the state obtained, contained large proportions of sand, shell, and other foreign material. '!he inclusion of these particles in the organism is a mechanical process which takes place during the growth of the sponge. The particles are not part of the spongin composition since the sponge is non-calc~eous and non-siliceous (70). Because of the large amount of foreign material and the dark yellowish-brown color of the sponge, it appeared that a thorough cleaning and decolorization was necessary before it could be used in a tablet formula. Cleansing Procedure A batch of about three to four hundred grams of sponge was taken by selecting the cleaner and more perfectly formed pieces. These pieces were inspected and any large foreign particles present were removed by hand picking. The sponge was then placed in a stainless steel tank containing tap water and soaked for a period. of twelve h _ours. During this soaking period the sponge was kneaded and churned by hand periodically. This operation was repeated four or five times depending on the need of the particular batch, each time using a fresh bath of water. After each wash, the spongin was skimmed from the sand and other foreign material which had settled to the bottom of the tank. Fragments that were still heavily contaminated were found on the bottom of the tank 'With the residual matter. These fragments were discarded along 'With

PAGE 38

30 the foreign material since they were unsuitable for use. After the last washing peripd the spongin was pressed to remove the water. Upon ex amination of this washed sponge, it was r'ound that several minute pieces of calcareous matter still remained embedded. In order to remove these particles a further wash was given using a cold bath of two per cent hydrochlori c acid instead of t~e tap w ater used in the prenous washings. 'Ihe spongin was allowed to remain in this acidulated bath for twelve hours, after which, upon removal, it no longer showed any traces of c alcareous material. The spon gin w a s then thoroughly rinsed in several baths of cold water, pressed by hand to remove excess water~ and oven-dried at 140 F. for five hours. Representative samples of the dried sponge were selected, and inspected for foreign matter with a hand magnifying glass. ' 'Ihis inspectiQn revealed no sand, shell, or other foreign bodies present in or on the cleansed sponge. The next step, before the grinding process, was to remove the dark yellowish-brown color by a bleaching treatment. Bleaching Procedure In search of a method to bleach natural sponge, several bleaching agents were tried with little or no success. The agents tried were aqueous solutions of sodium thiosulfate, sodium hypochlorite, oxalic acid, hydrogen peroxide, and sodium perborate. Although sulfurous acid showed some promise of good bleaching action on the sponge, the best results were ob tained through the use of potassium permanganate followed by a sodium bisulfite treatment. To decolorize the spongin, the cleansed dried material was placed in a one per cent solution of potassium permanganate for one-half

PAGE 39

31 hour. This procedure was repeated five times, using a fresh solution of potassium pennanganate each t:ill!e. When the sponge was removed from the pennanganate bath it was dark brown in color due to a deposit of an oxide of manganese. This colored compound was. removed by washing the sponge in a twenty per cent cold solution of sodium bisulfite. The sponge was then placed in a ten per cent sodium bisulfite solution, which had been acidified with hydrochloric acid, for thirty minutes. This last steeping was repeated, using fresh acidified solutions, until the color had been sufficiently bleached. The bleached spongin was then rinsed in several changes of fresh water to remove .all residues of chemicals and dried at 145 F. Sponge clippings before and after cleansing and bleaching are shown in Figures 1 and 2. Figure 1 Sponge clippings before cleansing and bleaching. Figure 2 Sponge clippings after cleansing and bleaching.

PAGE 40

32 Grinding Procedure Before the spongin could be incorporated into a tablet fomula, it had to be ground to a suitable fineness so that it could be unifonnly mixed with the other materials. Because of the physical nature of the sponge, several experimental runs were undertaken before a s~itable method of grinding could be obtained. The use of a Fitzpatrick Comminuter was f ound to be of little value in grinding the sponge because of its large grinding chamber and also because of the fibrous "bouncy" properties of the sponge. '!he revolving blades, upon striking the sponge, would cause it to be thrown out of the grinding chamber and back into the feed throat, and as a result, the sponge was ground at a very slow rate. The use of this machine made it necessary to regrind the material several times, each time passing it through a smaller screen, before it was suitable for use. Since this procedure was not feasible, other types of grinders were tried. It was found that by using a Wiley Mill grinding of the sponge became relatively easy. The 'Wiley Mill is an attrition type mill having four knives on a revolving shaft that work with a shearing action against six knives which are set in the frame '!he shearing action of the cutting edge~, between which there is always a clearance, powdered the spongin without difficulty. Two screens, 2-mm. and 1-mm., respectively, were used. These screens dovetail into the frame of the mill so that none of the material comes out of the grinding chamber until it is fine enough to pass through. To faciiitate grinding, the bleached sponge was cut up into fragments of about four to eight centimeters in length

PAGE 41

33 before being fed into the hopper of the mill. The second milling was collected and stored in screw-capped, brown bottles at 45 C. for future use in tablet fornm].as. Attempts made to size the powdered spongin using standard mesh sieves were unsuccessful. When screening for sizing, portions of the powder would pass through a No. 200 mesh screen, however, when it was collected and resieved through the same screen, all of the same powder would not pass through as it did previously. ~s was accounted for by the fact that, after the first screening some of the powder would "mat", and upon subsequent sieving through the same screen only that powder which had not matted would go through. Although this powder could not be sized accurately, it was required to pass through a No. 40 mesh screen before being used in a tablet formula. Treatment of Synthetic Sponge Before Use The same procedure used for grinding the natural sponge was used for powdering the synthetic sponge. The synthetic sponge required no special treatment before grinding with the exception of cutting the blocks into fragments of about three centimeters in length. Like natural sponge, this also w a s ground first through the 2-mm. mesh screen and then through the smaller 1-mm. mesh screen. '!he powder produced after milling through the smaller screen had the appearance of dry sawdust. The powdered synthetic sponge was collected and stored in brown bottles at 45 C. Before using this powder in tablet mixtures it was passed through a No. 40 mesh screen.

PAGE 42

34 Tablet Constituents Active Ingredients The medicinal ingredients selected as the active components of the tablets prepared in this study were represented by drugs of variable solubilities. As a control, lactose replaced all of the active medicinal agent'in the tablet. The drugs used as active ingredients are described in Table 3. TABLE 3 DRUGS COMPRESSED INTO TABLETS Drug Calcium Gluconate Sulfadiazine Dried Aluminum Hydroxide Gel Bismuth Subcarbonate Bismuth Subnitrate Magnesium Hydroxide Sodium Bicarbonate Lactose Solubility in Water Sparingly Soluble Insoluble Insoluble Insoluble Practically Insoluble Practically Insoluble Freely Soluble Freely Soluble Diluent Mesh Size 20/40 40/60 80/100 40/60 40/60 100/200 40/60 40/60 For those formulas requiring a diluent, Lactose, U. s. P., was used. Disintegrating Agents Sponges, both natural and synthetic, were compared with corn starch for their effectiveness as disintegrating agents when used in compressed tablets.

PAGE 43

35 It should be noted here that the ~ddition of disintegrating agent to the formula varied depending on the properties of the agent used and also on the fonnula being prepared. Husa (79) indicates that some of the disintegrating agent may be mixed with the medicaments prior to granulation while an additional amount may be added to the dry granules before compression. The portion added to the dry granulation before compression serves to disintegrate the tablet into its original granules while that which is mixed with the me
PAGE 44

36 of the granulation, and distribution throughout the granulation was uni "' form. It was necessary, therefore, in those formulas containing powdered spon gin, to ad d this agent during t he process of granulation. Since powdered synthetic sponge does not possess the same matty character as the powdered spongin, it could be added in reasonable proportions to the finished granules prior to compression. However, it was discovered that, by granulating the powdered synthetic sponge alone with a ten per cent starch paste solution using the same procedure as was used for tablet granulation, unifonn sized granules were produced llhich could be added to the finished granulation in all proportions. Whether the powdered synthetic sponge was added in this manner or mixed with the active ingredient prior to granulation depended on the formula being prepared. Dried corn s tarch when used as a disintegrant was either incorporated during granulation, after granulation, or both, again depending on the formulation in questi on. Binding Agents Four different binding agents were used in this investigation. The fonnulas and methods of preparing these binding agents are as follows: I Syrup U.S. P. 85% (v/v) Sucrose. 85 parts Distilled Water, a sufficient amount to m ak e 100 parts The syrup was prepared in accorda nce with the procedur e given for the hot process on page 601 of the U.S. P. XIV (50).

PAGE 45

37 II Starch Paste 10% (w/w) Corn Starch Distilled Water, a sufficient amount to make . . . . . . 10 parts 100 parts The starch was placed in a suitable container and a sufficient quantity of cold water was slowly added. This mixture was heated slowly, with continued stirring to avoid the formation of lumps, until the solution just boiled and a translucent paste resulted. This paste was removed from the heat and allowed to cool to about 50 c., at which temperature it was used. This binding agent was freshly prepared just previous to its need. III. Zein Solution 5% (w/v) Zein (corn protein) Isopropyl Alcohol 95%, a sufficient amount to make 5 parts 100 parts The Zein was dissolved in the isopropyl alcohol with agitation. IV. PVP Solution 15% (w/v) Polyvinylpyrrolidone . Distilled Water, a sufficient amount to make 15 parts 100 parts The PVP was added to a small amount of water and agitated until the powder was completely wetted. The remainder of water was slowly added and the mixture stirred with an electric stirrer until solution was c~mplete. Lubricating Agents Two per cent magnesium stearate was selected as the lubricant in all formulations with the exception of tnose'formulas in which the effect of lubricants on the disintegration time was being determined. For studying.this property, the lubricants used in addition to magnesium stearate were talc and boric acid.

PAGE 46

38 Tablet Formulation A typical fonnula for compressed tablets consists of the following: Medicinal Agent Diluent, q. s. Binding Agent, q. s. Disintegrating Agent, q. s. Lubricating A gent, q. s. In order that a sufficient amount of infonnation could be col-lected and ev aluated for this investigation, it was necessary to prepare and study several different formulas. The fonnulas studied are found in Tables L, Sand 6. '!he letters and symbols used to describe the tablet fonn ulas are as follows: The letter Pis used to indicate tablet fonnulas prepared for preliminary investigation. The following capital letters indicate the active ingredients used in the formulas. L Lactose BS Bismuth Subcarbonate s Sulfadiazine MB Ma.gnesiwn Hydroxide 00 Calcium Gluconate AH Dried Aluminum Hydroxide Gel BSN Bismuth Subnitrate SB Sodium Bicarbonate The disintegrants are represented by the following abbreviations: A Spon gin that has been cleansed and ground.

PAGE 47

.39 AT Spongin that has been cleansed, bleached and ground. AS Powdered synthetic sponge. B Dried corn starch. Arabic numbers indicate the percentage of disintegrant used in the formula. Small letters are used in those formulas where a different binding age n t was used for the same active ingredient. a Syrup b Zein Solution c Starch Paste d PVP Solution The symbol/ is used for those formulas in which the disintegrant was added to the finished granulation prior to compression. The capital letters and arabic numbers following this symbol indicate which agent was used and how much was added. If the disintegrant was also added to the active ingredient, it is indicated by the abbreviations preceding this symbol. The symbol /gAS represents those fonnulas having granulated synthetic sponge added to the finished granulation prior to compression. Preparing the Tablet Granulation All tablets were made from granulations prepared b y the wet process. The general procedure used for preparing a granulation was as follows: Mixing the Dry Ingredients. The powdered ingredients which entered into the formula were f irst carefully weighed out and then p u t through a No. 40 mesh screen to eliminate any foreign materials and

PAGE 48

TABLE L TABLET FDRMULA.S FOR PRELIMINARY STUDY Tableta,b Formula Per Cent Active Per Cent Per Cent Weight Ingredient Binder Disintegrant in Gm. P-L 88.o Lactose 10.0 Zein --o.3L1 P-L-A-7 78.8 Lactose 12.2 Zein 7.0 Spongin 0.379 P-L-A-14 70.5 Lactose 13.5 Zein 14.o Spongin 0.423 P-BS 88.o Bismuth Subcarbonate 10.0 Zein --0.341 P-BS-A-7 80.0 Bismuth Subcarbonate ll.O Zein 7.0 Spongin 0.375 P-BS-A-14 68.9 Bismuth Subcarbonate 15.1 Zein 14.o Spongin o.435 P-S 88.o Sulfadiazine 10.0 Zein --o .341 P-S-A-7 79.0 Sulfadiazine 12.0 Zein 7.0 Spongin 0.379 P-S-A-14 70.5 Sulfadiazine 13.5 Zein 14.0 Spongin o.425 s::0 P-MH 70.0 Magnesium Hydroxide 28.o Zein --0.428 P-MH-A-7 68.2 Magnesium Hydroxide 22.2 Zein 7.0 Spongin o.44o P-MH-A-14 56.9 Magnesium Hydroxide 27.1 Zein 14.o Spongin o.5oo P-00 88.0 Calcium Gluconate 10.0 Zein ---0.341 P-CG..A-7 81.0 Calcium Gluconate 10.0 Zein 7. 0 Spong in 0.371 P-00..A-lu 71.8 Calcium Gluconate 12.2 Zein lu.O Spongin 0.418 aAll percentages are based on the dry weight of the finished tablet. bTwo per cent lubricant, based on the weight of the finished granulation, was used in all fonnulas.

PAGE 49

Fonnula 00-A-l CO-A-2 CG-A-3 CG-A-4 CG...A-S CG-A-6 00...A-7 CG-B-15 S-A-5 S-A-10 S-AT-S S-B-10 AH-A-5 AH-AT-5 AH-B-10 AH-B-10/B-10 BSN..AT-5-a BSN-AT-S-b BSN-AT-5-c BSN-AT-5-d Per Cent Active Ingredient 30.0 Calcium Gluconate 30.0 Calcium Gluconate 30.0 Calcium Gluconate 30.0 Calcium Gluconate 30.0 Calcium Gluconate JO.O Calcium Gluconate 30.0 Calcium Gluconate 30.0 Calcium Gluconate So.o Sulfadiazine 50.0 Sulfadiazine 50.0 Sulfadiazine SO.O Sulfadiazine 43.3 Aluminum ~ydroxide 43.J Aluminum Hydroxide 43.3 Aluminum Hydroxide 39.4 Aluminum Hydroxide 50.0 Bismuth Subnitrate 50.0 Bismuth Subnitrate 50.0 Bismu t h Subnitrate So.o Bismuth Subnitrate TABLE. S TABLEI' FORMULAS Per Cent Binder 12.0 Syrup 12.2 Syrup 12.9 Syrup 13.4 Syrup 13.6 Syrup 14.7 Syrup 14.8 Syrup 13.5 Syrup 19.8 Syrup 23.6 Syrup 18.0 Syrup 21.J Syrup 24.6 Syrup 24.3 Syrup 25.0 Syrup 22.7 Syrup 16.5 Syrup 27 .6 Zein 21.1 Starch Paste 18.3 PVP (Table continued on following page) Tableta,b,c Per Cent Weight Disintegrant in Gm. 1.0 Spongin o.soo 2.0 Spongin o.soo 3.0 Spongin o.soo 4.o Spongin o.soo S.o Spongin o.5oo 6.o Spongin o.5oo 7.0 Spongin o.5oo 15.o Starch o.soo 5.0 Spongin 0.600 .i::10.0 Spongin 0.600 ..... S.o Spongin o.600 10.0 Starch 0.600 S.o Spong"'in o.693 5.0 Spongin o.693 10.0 Starch o.693 18.2 Starch o. 762. 5.o Spongin 0.600 5.o Spongin o.600 5.0 Spongin 0.600 5.o Spongin o.600

PAGE 50

TABLE 5 ( continued) Fonnula Per Cent Active Per Cent Per Cent Ingredient Binder Disintegrant BSN-AS-10-a 50.0 Bismuth Subnitrate 17.2 Syrup 10.0 Pyn. Sponge BSN-AS-10-b So.o Bismuth Subnitrate 29.L Zein 10.0 Syn. Sponge BSN-AS-10-c 50.0 Bismuth Subnitrate 23.9 Starch Paste 10.0 Syn. Sponge BSN ...AS-10-d 50.0 Bismuth Subni trate 20.0 PVP 10.0 Syn. Sponge BSN-B-10-a ,o.o Bismuth Subnitrate 17.4 Syrup 10.0 Starc;:h BSN-B-10-b 50.0 Bismuth Subnitrate 26.6 Zein 10.0 Starch BSN-B-10-c 50.0 Bismuth Subnitrate 25.0 Starch Paste 10.0 Starch BSN-B-10-d 50.0 Bismuth _Subnitrate 20.7 PVP 10.0 Starch SB-B-10 45.0 Sodium Bicarbonate 13.7 Syrup 10. 0 Starch SB..AT-5 45.o Sodium Bicarbonate 12.1 Syrup 5.0 Spongin SB...AS-5 45.0 Sodium Bicarbonate 11.6 Syrup 5.o Syn. Sponge aAll percentages are based on the weight of the finished tablet. bThe remaining weight of the tablet was furnished by lactose. Tableta,b,c Weight in Gm. o.6oo o.6oo o.600 o.6oo o.6oo 0.600 o.600 o.600 o.5oo 0~500 o.5oo CTwo per cent lubricant, based 0n the weight. of the finished granulation, was used in all formulas. &:-N

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Fonnula $-A-5/gAS-5 S-A-S/ gAS-10 BSN..AT-5-a/gAS-S BSN-AT-5-a/gAS-10 BSN-AT-5-b/gAS~lO BSN-AS-10-a/gAS-5 BSN-AS-10-a/gAS-10 BSN-AS-10-b/gAS-10 BSN-B-10-a/gAS-S BSN-B-10-a/gAS-10 TABLE 6 TABLET FORMULAS Per Cent Activea Per Cent Ingredient Binder SO.O Sulfadiazine 19.8 Syrup SO.O Sulfadiazine 19.8. Syrup SO.O Bismuth Subnitrate 16.5 Syrup SO.O Bismuth Subnitrate 16.S Syrup SO.O Bismuth Subnitrate 27 .6 Zein 50.0 Bismuth Subnitrate 17.2 Syrup 50.0 Bismuth Subnitrate 17.2 Syrup SO.O Bismuth Subnitrate 29.4 Zein 5o.o Bismuth Subnitrate 17 .4 Syrup 50.0 Bismuth Subnitrate 17.4 Syrup Per Cent Disintegrant S.o ~pongin 5.0 Syn. Spongeb 5.0 Spongin 10.0 Syn. Spongeb 5.o Spongin 5.o Syn. Spongeb 5.0 Spongin 10.0 Syn. Spongeb S.O Spongin 10.0 Syn. Spongeb 10.0 Syn. Sponge 5.0 Syn. Spongeb 10.0 Syn. Sponge 10.0 Syn. Spongeb 10.0 Syn. Sponge 10.0 Syn. Spongeb 10.0 Starch 5.o Syn. Spon g eb 10.0 Starch 10.0 Syn. Spongeb The weight per cent of ingredients is based on a &Jo mg. tablet. bSynthetic sponge, in a granulated state, was ad d ed to the granulation prior to compr ession. CTablet weight in excess of 600 mg. was contributed b y the additional disintegrating agent. Tabletc Wei ght in Gm. 0.630 o.6&:J 0.630 o.660 0.660 e; 0.630 o.6&:J o.6&J 0.630 o.660

PAGE 52

44 reduce any lumps of powder. 'Ille powders were then combined, placed in a Stokes Granulating Mixer, and allowed to mix for one hour. The resulting mixture was next sieved through a No. LO mesh screen to further mix and aid in proper distribution of the ingredients. The mixture of powdered ingredients was now ready for granulation. Granulating the Dry Mixture. --In order that the percentage of active ingredient and disintegrator remained constant for each series of' fonnulas, it was necessary to predetennine the proportions of binding agent needed for each granulation. This wa; accomplished through a preliminary experiment on a small amount of each fonnula. With the proportion of granulating agent determined for the actual granulation process, the adjustment of diluent to obtain a specific tablet weight was calculated. In granulating, the thoroughly mixed powdered ingredients were put in a Readco Dough Type Mixer and the granulating solution was slowly added with constant mixing. Sufficient time was allowed for the granulating solution to work in well before the next addition was made. When the mass had attained a "ball" consistency and seemed to have the proper "feel", it was considered ready for screening Screening the Wet Mass. -The moistened mass was removed from the mixer, placed on a No~ 8 mesh screen, and by hand, using a hud rubber spatula, forced through the screen. Drying the Granulation. -The coarse granules obtained from screeaing the wet mass were spread in thin layers on trays upon which had been laid heavy brown wrapping paper. The trays were placed in a circulatory hot air oven set at a drying temperature of 140 F. The time

PAGE 53

45 required for drying varied with the nature of the granulation being dried, however, as a rule the time ranged between eight and twelve hours. During the drying period the granulation was periodically turned to assure uniform drying. Screening the Dry Granulation. --Following the drying period, the granulation was again hand screened, this time through a No. 14 mesh sieve. For those granulations that had a ~endency to produce excessive "fines" when completely dried, it was necessary to screen the coarse gramilation when it was about 3/4 or 2/3 dry. _After screening a partially dried granulation it was placed back into the oven and allowed to completely dry with a minimum of fines. The granules obtained from this second screening were gently mixed by tumbling in a large jar. Sj.ting the Finished Granules. -The granulation resulting from the final ~creening was si, zed using a series of sieves. The sieves used were Nos. 20, 40, clJ, Bo, and 100 mesh. The sizing was accomplished by determining the percentag e of the total granulation that passed through one size screen but not throug h the next smallest screen. For example, those granules that would not pass throug h a No. 40 mesh screen were recorded as 20/40 mesh granules since they passed through a No. 20 and were retained on a No. 40 mesh screen. This sizing procedure was perforn.ed on all forn.u.las. It was noted that the size rang e for optimal tableting varied depending on the formulation involved. Information pertaining to I the sized granulations is found in T~ble 7. Following the sizing of the granulation, the grarrules were put in a large, wide-mouth, screw-capped, brown bottle, and stored until needed at a temperature of 40 c. Lubricating the Granulation. --Lubrication of th~ granulation

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Fonnula P-L P..L-A-7 P-L-A-14 P-BS P-BS..A-7 P-BS...A-J.4 P-S P-S...A-7 P-S...A-14 P-MH P-MH-A-7 P-MH...A-J.4 P-CG P-CG...A-7 P-CG...A-14 CG-A-1 CG-A-2 CG-A-3 CG..A-4 CG...A-5 CG...A-6 CG-A-7 CG-B-15 S...A-5 S..A-10 S..AT-5 S-B-10 AH...A-5 AH..AT-5 AH-B. -10 AH-B-10/B-10 BSN...AT-5-a BSN-AT-5-b BSN..AT-5-c BSN..AT-5-d BSN-AS-10-a BSN...AS-10-b BSN ...AS-10-c BSN-AS-10-d BSN-B-10-a BSN-B-10-b BSN-B-io-c BSN-B-10-d 46 TABLE 7 DESCRIPTION OF SIZED GRANULATIONS Granulation Weight, Percentage of Granules in Grams, Previous within Mesh Range of to Sizing 14/20 20740 40760 60780 408 70.2 13.5 4.1 2.0 413 73.1 12.8 5.o 4.6 423 60.4 23.8 8.8 1.2 307 65.J 20.8 6.7 2.9 317 62.8 24.2 7.7 J.6 341 &>.3 18.9 9.4 5.J 350 66.1 11.6 6.3 8.7 352 70.4 13 .9 7.5 2.2 358 71.1 20.3 2.6 1.5 358 50.0 13.3 14.9 12.2 361 43.0 17.7 18.4 10.5 305 32.6 19.4 20.3 4.3 411 50.7 31. 1 9.9 4.8 418 51.7 27.3 6.1 8.6 392 57.4 28.1 5.0 4.o 423 59.3 31.8 3.4 2.1 451 58.6 22.0 9.9 4.6 472 53.0 25.9 11.7 5.4 323 62.5 15.7 8.3 4.2 366 62.9 24.6 5.2 3. 7 259 68.4 20.2 6.8 2.9 305 51.5 29.0 9.6 8.3 285 53 .3 28.3 10.1 4.7 439 &>.l 18.5 8.5 5.5 452 58.4 18.9 13.2 7 .4 428 70.5 12.1 5.4 1.3 377 62.9 16.2 10.3 6.5 476 60.2 18.8 10.8 4.6 429 56.o 20.1 12.1 7.2 372 63.4 22.4 7.5 3.8 411 51.8 31.5 4.9 7.3 465 73.7 8.4 4.3 6.7 372 51 .5 13.7 12.1 11.4 432 &>.6 20.3 9.6 5.6 487 75.2 11.6 8.o 1.8 461 70.4 11.9 9.4 3.8 388 56.o 7.5 14.7 12.3 400 66.9 12.8 8.6 5.5 417 73.4 9.2 9.7 3.2 36u 68.3 17.8 6.3 1.9 355 60.5 22.4 8.7 2.7 397 62.7 20.7 5.7 5.1 289 71.6 13.9 2.8 7.5 807100 1.8 3.9 1.0 1.3 1.0 2.2 4.3 3,.4 J.7 8.6 3.0 1.5 3.3 4.4 2.7 0.3 2.5 2.0 3.1 2.2 0.7 0.4 2.6 3.4 2.0 5.1 2.8 2.7 4.4 1.2 2.6 4.1 9.3 2.4 1.7 3.9 9.2 5.6 1.8 5.1 1.3 4.4 3.7

PAGE 55

47 was carried out immediately prior to compression. For adding the lubricant, the granulation was spread on a large sheet of heavy brown paper, the lubricant was dusted on the granules by.sifting it through an 80 mesh sieve, and the entire formula was mixed well by grasping each end of the paper and gently tumbling the mixture until the granules were thoroughly covered with the lubri.cant. The use of an 80 mesh sieve for dusting the lubricant on the granulation not only insured the removal of any lumps that may have been present but also increased the covering power of the lubricant. Subsequent to lubrication the granulation was ready for tableting. Compression of the Granulation Equipment and Procedure Description of Tablet Machines Used. --A single punch, Eureka Hand Model, tablet machine and a rotary, Model B-2, tablet machine were use d to compress the completed granulations into tablets. Both these machines are manufactured by F. J. Stokes Machine Company. The Eureka hand operated machine had a prod~ction rate of up to 70 tablets per minute using standard concave 3/811 or 13/32" punches and dies. This machine has a maximum depth of fill of 7/16" and it can attain pressures up to one ton. 'lhis hand operated machine was used mostly to detennine the chara~teristics of the finished granulation before compressing it on the rotary machine. It was also useful in preparing individual tablets by hand filling the die for experimental work on formulas. This eliminated the need of filling and emptying the hopper each tillle a change was made

PAGE 56

48 in the granulation. The rotary, Model B-2, tablet machine produces from 350 to 500 tablets per minute and has a depth of fill up to 11/16". All tablets produced using this 'machine were prepared with standard concave 3/8" punches and dies. Although this machine ordinarily requires 16 sets of punches and dies, the machine can and was run with eight pairs of punches. Corks were driven into the other eight dies to prevent the granulation from falling through them. This rotary t _ablet machine is capable of attaining pressures of more than two tons. Operating Adjustments Required for the Eureka Machine. -Weight and pressure adjustments, which varied according to the particular granulation being compressed, were made by raising or lowering the punches. '!he speed of the machine was governed by the rate at which the hand wheel was turned and thus could be controlled as desired. Operating Adjustments Required for the Model B-2 Machine. Prior to the initial use of the rotary machine, it was disassembled, cleaned, and thoroughly lubricated. From then on it was cleaned following each tablet run and lubricated according to its need. 'nle feed frame was set about 1/~" away from the movin g die plate, while the take-off plate at the front of the feed frame was raised sufficiently to allow any granulation to pass back into the feed frame, and the scrapper at the back of the feed frame w a s pressed down against the table by means of a spring to keep the granulation inside the feed frame. The hopper was set so that the gap bet ween the funnel opening and the die plate was just large enough to allow sufficient material to flow from the hopper into the feed frame and partially fill its various

PAGE 57

49 openings. Adjustments for weight and pressure were made as follows. 'lbe exact amount of granulation needed to make one tablet was weighed and poured into the die cavity at the last opening of the feed frame just in front of the scrape-off plate. The weight adjuster was either raised or lowered until the material just filled the die cavity and was flush with the top of the die plate. The flywheel was then turned by hand until the filled die came between the compression rolls. At this point the low e r roll carriage w a s raised by means of a pressure regulator until a tablet of proper hardness was fomed. Effects of Operating Speed on Tablets. --In detennining whether the operating speed of the rot~ tablet machine manifests itself as a critical variable in the canpression of certain granulations, studies were made using three different speeds. These speeds, regulated by adjusting the variable speed drive, were arbitrarily set as slow, medium, and fast, dependin g on the number of tablets compressed in a minute. The slow speed represented 100 tablets per minute, the medium speed 200 tablets per minute, and the f ast speed 250 tablets per minute using eight sets of punches. In this experiment, the various speeds of the rotary machine did not show any difference in the tablets produced. The weight and hardness of the tablets remained constant; the ~urface~ smoothness was not affected, and the disintegration time was unaltered. Since the speed of the machin~ did not influence the properties of the tablets, the slow speed was selet:ted for regular tablet runs. Batch Uniformity. --At frequent intervals during compressi on, .

PAGE 58

50 weight and hardness checks were made to ascertain tablet unifonnity Ir the wei ght or hardness showed a deviation from the original standards, the machine was stopped and further adjustments made until this deviation was alleviated. Test Methods Hardness Test Hardness of tablets is considered to be a measure of resistance to cappin g chipping or breakage under conditions of storage, packaging, and handling before actual use. A practical rule for judging proper tablet hardness is that the tablet should be readily broken when pressed between t h e thumb and forefinger but should not break when dropped on the floor. In order to m easure the compara.tive h ardness of the tablets prepared in thi s investigation, the Monsanto Hardness Tester was used. This device is calibrated in terms o f kilograms of compressional force. To determine its hardness, the tablet was centered on its vertical plane between the anvil and spring spindle. The zero reading va.s noted. Pressure w ~ s applied until the tablet broke. The difference between the zero and the final reading was the pressure in kilograms required to fracture the tablet. Reported values are averages of five determinations and are stated to the nearest 0.5 kilogram. Disintegration Test The disintegration tests were conducted in accordance with the U. s. P. XIV directions (50). The test apparatus used consists of a

PAGE 59

51 basket-rack assembly which moves up and down at a rate of 31 complete cycles per minute through a distance of .5 cm. For.the test, the basket assembly is immersed in a constant t anperature water bath. The bath used in this investigation w ~ s maintained at 37 C. The electrically heated water bath was equipped with a mechanical stiITer and a Cenco DeKhotinsky Thermo-Regulator. Six compressed tablets were chosen at random and placed in the tubes of the basket-rack assembly. The basket was set in motion, and the time required for the tablets to completely pass through the No. 10 mesh screen was the ~isintegration time. Three determinations were made on all tablets tested and the average time was calculated and recorded in minutes and seconds. The end-point for tablet disintegration has been revised in the U.S. P. XV (.51) to read as follows: "the tablets are disintegrated if substantially no residue remains on the screen or if any residue that remains on the screen is a soft mass having no palpably finn core". It was obviou s that this new end-point required judgment to detennine what is "substantially no residue" and when a soft mass has "no palpably finn core.11 Since this judgment would most 1,ikely vary. somewhat for each individual, it was decided to signify a tablet as being disintegrated when the tablet had completel~ passed through the screen. In the case of those tablets where the end-point was thought to be substantially different from that of the official end-point, a footnote was mar.e indicating this. Fri.ability Test An automatic shaking m achine, simulating the most extreme handling practices, demonstrated comparative resistance ability of the tablets to ~------~---------~~---------------~-----------~---

PAGE 60

52 chipping and breaking. The shaking machine completed 200 forward and backward movements per minute as it shook the tablet vials through a distance of four inches. For the test, ten tablets were placed in a five dram vial and stoppered securely The vial was put into the shaking compartment and the machine w e s operated for two 15-minute periods. After eaqh shaking period, the tablets were sifted and blown with compressed air to remove the pulverized material. Following this treatment the tablets were weighed. The difference in weight expressed as a per cent of the original weight was designated as the friability value. Another short. series of tests were also made to determine the influence of well filled vials protected with cotton on the friability value. In this test the vial was filled to the neck with tablets and protect~d with a cotton filling. Storage Test Pharmaceutical products must be stable over extended periods of time and under varying storage conditions. To gain insight into the stability of the tablets prepa r ed, storage studies were conducted. The tablets tested were subjected to the following storage conditions: a. Room temperature b. Increaeed temperature c. Decreased temperature d. Various relative humidities For storage tests, ten tablets were placed in an open five dram

PAGE 61

53 vial and ten tablets from the same series were placed in a capped five dram vial. By storing the tablets in thi s manner the effect of the container on storage could be determined. All samples stored at room temperature were placed on laboratory shelves for a specific time interval. The average room temperature during the storage period was 26.9 C. and the average relative humidity was 61.2 per cent. In order to calculate the average room temperature and relative humidity, daily detenninations of each were made for a two week period followed by semiweekly deterninations for the duration of the storage studies. All relative humidity determinations were made with a sling psychrometer. Those samples stored at elevated temperature were placed in vials and put in an electric oven at 45 C. 'While those stored at decreased temperature were placed in a refrigerator at 4 c. 1 c. Individual desiccators were set up containing aqueous glycerin solutions ( 8 0) in varying proportions to provide relative humidities of 30, 40, 50, 80, and 95 per cent in one series of tests and 30, 45, ciJ, 70, 80, and 95 per cent in another series of-tests. The samples, in vials, were placed in these desiccators, the desiccator covers were securely replaced, and the desi9cators were placed on a shelf at room temp e rature. Time intervals that the samples were stored depen?ed on the determinations being made and are reported in the storage tables. After specific storage intervals, the following detenninations were

PAGE 62

54 conducted: a. Moisture gain or loss b. Disintegration time c. Hardness To detemine moisture gain or loss, each of the ~amples was wei g hed prior to storage and at subsequent intervals. The increase or decrease in weight denotes moisture gain or loss. Moisture loss is represented in the tables by a negative sign preceding the per cent weight change in tablets. Absorption Study The mechanism through which powdered spongin and corn starch accomplish thetr disintegrating action is basically the same. Both agents swell if in contact with water and as a result, when incorporated into tabl~ts, are capable of rupturi ng the tablet. In order for t his swelling to take place the materials must be able to absorb the w ater, and for thi~ reason tests were conducted to detennine the rate at which this absorption took place for each of the substances. To control the moisture conditions for the tests, several constant humidity chambers were prepared in the same manner as described earlier. The tests were carried out by first drying the materials to constant weig h t at 110 C. and then placing them in each humidity chamber for 24 hours. The weight gain was calculated by reweighing the sample following this 24 hour period and was recorded as per cent of sample weight.

PAGE 63

EXPERIMENTAL RESULTS TABLE 8 MOISTURE ABSORBED BY POWDERED SPONGrn AND CO'RN STARCH AT VARIOUS RELATIVE HUMID I TIES Relative H'lllllidities Water Absorbed After 24 hours at 27 C. Powdered Spongin Corn Starch % 30 9.22 8.13 4, 12.21 10.33 60 15.43 12.69 70 17.65 14.14 80 21.36 16.12 95 29.51 20.61 The results listed in Table 8 and illustrated in Figure 3 show that the moisture absorbed by powdered spongin and corn starch increased with increased relative humidities. '!he increase in moisture content is indicated by an S-shaped curve which is more pronounced for powdered spongin. The moisture content of the corn starch and powdered spongin before drying to constant weight wa~ calculated as 9.76 per cent and 11.2 per cent, respectively. 55

PAGE 64

u 0 r-(\J +) al l>) +) :a :::i:: ~ +) "' r-1 +) u J.t Q) 100 Bo 00 4 0 20 56 Figure .3. -Absorption of Moisture by Powdered Spongin and Corn Starch / o -; 1 ;/ .o. I 0 oe o------------------------0 10 30 Per Cent Moisture Absorbed e Powdered Spongin 0 Corn Starch

PAGE 65

57 TABLE 9 A COMPARISON OF THE DISINTIDRATION TIMES OF TABLETS IMMEDIATELY AFTER COMPRESSION Disintegration Formula Hardness Time Kg. min. :sec. P-L 1.0 24123 P-L..A-7 1.0 2,35 P-1..A-J.4 5.o 0:48 P...BS 6.5 180:oo& P...BS..A-7 1.5 19:44 p -BS ..A-14 1.0 8,02 P-S 1.0 180:QO& P-S-A-7 7.5 47:17 P-S..A .. J.4 1.0 21:21 P..MI! 6.0 180:ooa P:..Mli..A-7 6.o 2:11 P..Mll..A-14 5.o 0:58 P..CO 1.0 180:0()8. P-CG-A.-7 6.0 19:23 P..CG..A-14 6.~ 10:02 CG-A-1 1.0 29:20 CG..A-2 6.o 22:58 CG-A-J 6.5 17:JJ CG..A-4 1.0 16:59 CG-A-5 6.5 15.26 CG..A-6 8.o 18:05 CG..A-7 7.5 13:31 CG-B-15 1.0 47:22 S..A.-5 7.0 58:45 S..A-10 6.o 49:37 S..AT-5 a.o 116,21 S-B-10 7.5 98:)8 (Table continued on following page)

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Forrrru.la AH...A-.5 AH-AT-.5 AH-B-10 AH-B-10/B-10 BSN ...A T-.5-a BSN-AT-.5-b BSN-A T-.5-c BSN..AT-.5-d BSN..AS-10-a BSN~-10-b BSN-AS-10-c BSN-AS-10-d BSN-B-10-a BSN-B-10-b BSN-B-10-c BSN..B-10-d SB-B-10 SB...AT-5 SB-AS-5 S...A-5/gAS-.5 S-A-5/gAS-10 BSN-AT-5-a/gAS-5 BSN-AT-5-a/gAS-10 BSN-AT-5-b/gAS-10 BSN-AS-10-a/gAS-5 B S N-AS-10-a/gAS-10 BSN-AS-10-b/gAS-10 BSN-B-10-a/gAS-5 BSN-B-10-a/gAS-10 .58 TABLE 9 (continued) Hardness Kg. 6.o 1.0 1.0 5.5 6.5 6 .5 7.5 1.0 6.5 6.o 1.0 6 .5 6.0 6.5 5.5 6.5 8.5 a.o 1 .5 1.0 1.0 6.5 7.5 6.o a.o 1.0 6.5 7.5 6.5 Disintegration Time min. :sec. 35:37 8:.53 68 :04 15:02 J.5:Ll 180:ooa 11:21 12:39 52:11 33:05 31:L7 20:22 13: .51 180:ooa 15:35 12:09 11111 9:01 10:35 21:LL 9:08 10158 6:27 9:33 9:.56 7:.5.510:03 8:49 6:oL aThe disintegration test was discontinued if the tablets did not disintegrate within three hours.

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.. 59 TABLE 10 RELATIONSHIP BE'IWEEN TABLET HARDNESS, FRIABILITY AND DISINTIDRATION TIME Friability Disintegration Fo:nnula Hardness Value Time Kg. min.: sec. AH-AT-5 1.5 71.989 6:10 2.5 9.808 4:.3.3 4.o 2.929 ):01 5.5 0.913 4:49 7.0 0.255 8:53 9.0 0.096 14:34 10.0 0.080 18:27 11.0 0.077 18:58 AH-B-10 o.5 78.967 29:40 1.5 25.861 36:00 2.0 10.817 LJ.i51 2.5 1.829 49:55 4.0 o.834 53:55 5.5 0.626 63:27 1.0 o.492 68:35 9.0 0.325 75:14 BSN~T-5-a o.5 99.210 4105 1.0 96.189 3:32 1.5 91.344 10:27 2.5 87.273 12:08 4.0 9.648 22:08 5.o 1.980 27:21 6.5 0.,02 35:41 8.o 0.260 41:14 10.0 0.130 60:38 12.0 0.078 62:0J BSN-B-10-a o.5 85.935 109:00 1.0 51.215 96:46 2.0 16:942 6 5 :02 3.5 1.765 56:21 4.5 0.998 66:14 6.o 0.288 73: 51. 8.o 0.150 88:09 12.0 0.135 95~39 (Table continued on following page)

PAGE 68

60 TABLE 10 (continued) Friability Disintegration Fonnula Hardness Value Time Kg. min.:sec. BSN.J.T-5-b o.5 100.000 180:oo& 1.5 63 .541 180:QO& 3.0 2.381 180:ooa 5.o 0.349 180:ooa 6.5 0.205 180:008 7.5 0.131 180:008 10.0 0.127 180:ooa 11.0 0.104 180:ooa BSN -B-10-b o.5 100.000 180:ooa 1.5 75.249 180:ooa 2.5 1.223 180:ooa 5.o 0.192 180:ooa 6.5 0.130 180:008 7.5 0.095 180:ooa 10.0 0~043 180:ooa BSN~T-5-c o.5 100.000 9:35 1.0 92:137 8:52 2.5 80.016 9:27 3.5 J. 763 6:01 5.o 1.254 9:48 6.5 0.997 12: 53 7.5 0.275 14:21 9.0 0.196 18:16 10.5 0.188 22:49 BSN-B-10-c 1.0 93.476 72:00 1.5 86.006 74:12 2.5 69.072 79:47 3.5 3.555 83:24 5.5 0.9(:u 90:35 6.5 0.231 98:37 8.o 0.194 103;22 10.5 o.088 119:17 (Table continued on following page)

PAGE 69

Formula BSN -AT-5-d BSN-B-10-d 61 TABLE 10 (continued) Hardness Kg. o.5 1.5 3.0 4.5 7.0 8.0 10.0 1.0 3.0 4.5 6.5 7.5 8.5 10.0 11.0 Friability Value 100.000 91.583 68.502 5.229 1.257 o.467 0.179 96.068 80.003 .37 .852 2.207 1.lll o.48o 0.221 0.099 Disintegration Time min.:sec. 10:47 9:01 8:58 7:36 11:14 15:45 22:.30 66:09 73:17 77:10 72:09 87:25 94:38 97,07 107:0.3 &.rhe disintegration test was discontinued if the tablets did not disintegrate within'three hours.

PAGE 70

cu r 20 10 62 '' Figure 4. -Relationship Between Disintegration Time and Tablet Hardness for Tablets Prepared with Spongin as the Disintegrant Showing a Minimum Point in the Curve. l J 7 9 11 Hardness in Kilograms Q BSN..AT-5-d e AH..A.T-5 BSN..AT-5 ... c 6 BSN..AT-5-a

PAGE 71

63 Figure 5. -Tablets Prepared with Corn Starch as the Disintegrant showing a Linear Relationship Between Disintegration Time and Tablet Hardness 1 .3 7 9 11 Hardness in Kilograms Q BSN-B-10-c BSN..B-10-d I) AH-B-10

PAGE 72

Q) l> t-100 'M r-1 r-i 80 'fj r.:. 40 20 10 1 o.5 0.1 Figure 6. -Relationship Between Tablet Fri.ability and Tablet Hardness \ \0 \ t\ ---. 0 "' ...._0-0-o2 4 6 8 10 Hardness in Kilograms 0 AH-B-10 AH...AT-5 64 Q) :::s l> >-+> '" it Figure 7. -Relationship Between Tablet Fri.ability and Tablet Hardness 100 80 40 20 10 1 o.5 0.1 t 0 \ \_ ~ 0--......st. o_O-o 2 4 6 8 10 Hardness in Kilograms 0 BSN...AT-.5-a BSN..B-10-b

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65 TABLE 11 FRIABILITY VALUES AFTER 'IWO SHAKING PERIODS Fonnula Hardness Friabiliti Value Af'ter After 1.5 Minutes 30 Minutes Kg .. S..A-5 5.0 0.038 0.178 S-B-10 5.o 0.115 0.214 AH...AT-5 1.0 0.255 o.so1 AH...B-10 1.0 0.493 o. 739 BSN-AS-10-a 8.o o.438 0.742 BSN-AS-10-b 7.S 0.183 0.354 BSN...AS-10-c 1.5 o.679 1.099 BSN ...AS-10-d 7.0 0.244 0.367 \ BSN-AT-5-a 6.5 o.502 1.218 BSN-AT-5-b 6.5 0.205 0.351 BSN-AT-5-c 6.S 0.997 2.093 BSN-AT-5-d 1.0 0.301 o.521 BSN-B-10-a 6.o 0.288 o.492 BSN-B-10-b 6.5 0.130 0.217 BSN-B-10-c 6.5 0.231 o.488 BSN-B-10-d 6.0 0.194 0.316

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Fomula S-A-5 S-B-10 AH-AT-5 AH-B-10 BSN-AS-10-a BSN-AT-5-a BSN-B-10-a Formula BSN-AT-5-a BSN-AT-5-b BSN-AT-5-c BSN-AT-5-d BSN..B-10-a BSN-B-10-b BSN-B-10-c BSN-B -10-d BSN-AS-10-a BSN-AS-10-b BSN -AS -1 0 c BSN-AS-10-d 66 TABLE 12 FRIABILITY VALUES OF TABLETS .PROTECTED WITH A COTTON FILLE R IN VIALS Hardness g. 5.o 5.o 1.0 1.0 B.o 6.5 6.o TABLE 13 Friability Value After 15 Minutes 0.002 0.000 0.000 0.000 0.000 o.oo6 0.003 COMPA.RISO,N OF DISI NTIDRATION RATES. OF TABLETS PREPARED WITH DIFFERENT BINDING AGENTS Disintegration Hardness .Binder Time Kg. min.: sec. 6.5 Syrup 35:41 6.5 Zein Solution 180:ooa 6.5 Starch Paste 12:53 7.0 PVP Solution 12:39 6.0 Syrup 13 :51 6.5 Zein Solution 180-:ooa 6.5 Starch Paste 89:37 6.5 PVP Solution 12:09 6.5 Syrup 52:11 6.0 Zein Solution 33:05 1.0 Starch Paste Jl:47 6.5 PVP Solution 20:22 nie disintegration test was discontinued if the tablets did not'disintegrate withi n three hours.

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Formula AH-AT-5 BSN-AT-5-a BSN~S-10-c BSN-B-10-a SB-B-10 SB .. AT-5 67 TABLE 14 CCJ.1PARISON OF DISINTEGRATION RATES OF TABLETS PREPARED WI'lll DIFFERENT LUBRICATING AGEN'IS Lubricating Hardness Agent Kg. 7.5 Magnesium Stearate 1.0 Talc 7.0 Boric Acid 1.0 None 6.5 Magnesium Stearate 6.5 Talc 7 .o Boric Acid 6.o None 1.0 Magnesium Stearate 6.5 Talc 7.5 Boric Acid 8.o None 6.o Magnesium Stearate 6.5 Talc 6.5 Boric Acid 1.0 None 8.5 Magnesium Stearate 1.0 Talc 6.5 Boric Acid 6.5 None 8.o Magnesium Stearate 1.5 Talc 7.0 Boric Acid 1.5 None Disintegration Time min. :sec. 8: 53 6:23 2:J0 4:02 32:J.4 9:24 8:5J 6:59 2.3:01 9:44 5:57 5:00 46:19 9:46 7:45 5:08 11:ll 8:.33 4:07 .3:25 9:07 6:55 .3 :00 .3:21

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68 Figures B, 9 and 10. Comparative Disintegration Rates for Differently Lubricated Tablets ----------T-----,,..._ U) 25 1 2 J L Lubrica n t Fig. 8. -Formula BSN-AT-5-a Q) i::: it 2 0 i::: ..-1 Q) 15 s:: 0 r-1 +> 10 5 A 0 25 U) Q) 1 20 s:: "r1 Q) 15 s:: 0 r-1 -+> io Q) -+> Cl) 5 ,---r-t A 7 I ---1 2 3 L Lubricant 0 Fig 10. Fonnula SB-B 10 1 2 3 4 Lubricant Fig 9 Formula BSN-AS-10-c KEY TO LUBRICANT S USED 1 -No lubricant 2 Boric Acid 3 Talc L -Magnesium Stearate

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69 TABLE 15 TABLET DISINTIDRATION TIMES AFTER STORAGE FCR INTERVALS OF 250, 500 AND 750 HOURS IN OPEN VIALS AT VARIOUS TEMPERATURE CONDITIONS Disintegration Time Fonnula HardStorage After Storage at CG-A-2 CG-A-L ness Time Originally 21 c. 45 c. 5 c. Kg. hrs. min.:sec. min.:sec. min:sec. min.: sec. 10.0 2.50 25:23 31:56 26:37 500 25:23 26:18 27:20 750 2.5: 23 30:L2 27:37 9.5 250 22:58 29:59 23:10 500 22 :56 24:Ll 2L:07 750 22:58 27:58 24:40 TABLE 16 TABLET DISINTEDRATION TIMES AFTER STORAGE FOR INTERVALS OF 250, 500 AND 750 HOURS IN CLOSED VIALS AT VARIOUS TEMPERATURE C ONDITIONS 26:09 26r 52 27:08 23:01 22:52 23:05 Formula Hard-Storag e Disint,ration Time fter Storage at ness Time Originallr 27~ c. fi~o c. ~o c. Kg. hrs. min.: sec. min.: sec. min.: sec. min.:sec. 00-A-2 10.0 2.50 25:23 29:44 27:18 27:11 500 2,:23 2.5:12 27:42 27:00 150 25:23 27:.53 28:33 28:J.h 00-A-4 9.5 2.50 22:.58 28:46 23:18 2):01 500 22:.58 25 :01 2):46 23:oL 7.50 22:58 26:01 24:JL 23:L2

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Formula Hard-ness Kg. 00-A-2 10.0 CG-A-3 8.5 -CG-A-4 9.5 TABLE 17 TABLET DISINTEGRATION TIMES AFTER STORAGE FOR INTER\TAIS OF 2.50, 500 AND 750 HOURS IN OPEN VIAU, AT VARIOUS RELATIVE HUMIDITIES Original Disintigration Times After Storage Storage Disintegration Relative Humidities at 270 ~. Time Time Jct' 4(1, 93% 80% hrs. min.:sec. min. :sec min.ssec. min. isec. min.:sec. 250 25:23 25:27 30:56 29:48 31:43 500 25:23 25:49 31:28 31:31 32:08 750 25:23 25:53 32:39 31:59 33:47 250 23:39 23:21 25:10 25:23 28:40 500 23:39 25:52 26:08 27:31 28:21 750 23:39 27:21 28:29 27:58 28:Lo 250 22:58 26:21 26:00 23:06 30:08 500 22:58 26:32 28:17 28:11 JL:51 750 22:58 27:05 30:06 28:41 38:23 9.$1, min. :sec. L6:o6 57:51 180:ooa 30:05 55:44 180:00S-L9:ll 58:26 180:ooa The disintegration test was discontinued if the tablets did not disintegrate within three hours. -4 0

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Formula Hard-ness Kg. CG-A-2 10.0 CG..A-3 8.5 00-A-4 9.5 TABLE 18 TABLET DISINTIDRATION TIMFS AFTER STORAGE FOR INTERVALS OF 250: 500 AND 750 HOURS IN CLOSED VIALS AT VARIOUS RELATIVE HUMIDITIES C Original Disintegration Times After Storage Storage Disintegration Relative Humidities at 27 C. Time Time JO% 40% 50% 8o% hrs. min.: sec. min.: sec. min.: sec. min.: sec. min.: sec. 250 25:23 25:29 J0:24 25:57 30:22 500 25:23 25:52 31:15 28:00 .33:01 750 25:23 28:10 .32:22 28:20 33:56 250 2.3:39 22: .51 23:16 24:59 24:31 500 23:39 25:30 26:19 25:0l 25:11 750 2.3:39 29:05 27:.39 26:00 26:05 250 22: 58 24:36 2u.:58 24:12 23:33 500 22:58 25:07 25:09 24:18 25:2.3 750 22:58 26:25 25:28 24:47 25:54 95% min .: sec. 30:00 30:01 -.J ..... 31:10 23:13 23:33 24:01 '24:21 27:39 26:20

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Formula Storage Time hrs. CG-A-2 2.50 500 150 CG-A-3 250 500 750 CG-A-4 250 500 750 TABLEl9 CHANGES IN TABLET HAROO'ESS AF'IER S'IDRAGE FOR INTERVALS OF 2 -.50, 500 AND 750 HOURS AT VARIOUS RELATIVE HUMIDITIES Tablet Hardness After Storage (Kilograms) Original Relative Humidities at 27 C. Hardness Jo% 40% so% 8o% 9% 3o% 4o% SO% 8(lf; Kg. Open Vials Closed Vials 10.0 9.0 10.0 4.0 5.5 2.5 10.0 10.5 10.5 10.0 10.0 9.0 8.5 3.0 4.0 1.0 10.0 11.0 12.0 10.0 10.0 6.5 8.0 3.0 1.0 ___ a 1 _1.0 12.5 12.0 10.5 8.o B.5 8.o 9.0 6.5 5.o B.o B.o 9.5 9.0 8.o 8.5 8.0 9.5 4.0 2.0 9.0 9.0 n.o 9.5 8.0 9.0 7.0 13.5 2.0 a 10.0 10.0 11.5 10.5 -..--7.5 7.5 1.5 5.5 2.5 2.0 7.5 8.0 7.5 7.5 7.5 7.0 6.5 4.5 1.5 ___ a 1.5 8.5 7.5 7.5 7.5 6.5 L.S 2.0 1.5 ___ a 7.5 8.5 7.5 8.o a Tablets had a soft soggy consistency and could not be tested. 95% 10.0 10.s 10.5 B.o -.) I\) B.o 8.o 7.5 7.5 1.0

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Fonnula Storage Time hrs. S-A-5 24 96 25'0 500 S..B-10 24 72 96 250 500 1000 AH-A-5 24 48 72 96 250 500 750 1000 3~ TABLE 20 CHANGES IN TABLET WEIGHT AFTER S'IDRAGE AT VARIO US RELATIVE HUMIDITIES Per Cent Change in WeiBht After Storage Relative Humidities at 27~ C. 40% 50% Bat 9rJI, Jo% 4o% 50% Bo% Open Vials Closed Vials o.oo o.oo o.oo 0.21 J.07 o.oo o.oo o.oo o.oo o.oo o.oo o.oo 1.04 7.58 o.oo o.oo o.oo o.oo o.oo o.oo o.oo 1.09 12.66 o.oo. o.oo o.oo o.oo o.oo o.oo o.oo 2.03 25. 74 o.oo o.oo o.oo o.oo -1.73 -1.38 -0.92 -0.50 3. 73 o.oo o.oo o.oo o.oo -1.74 -1.71 -0.99 -0.50 4.43 o.oo o.oo o.oo o.oo -1.74 -1.71 -0.98 -0.97 4.49 o.oo o.oo o.oo o.oo -1.74 -1.71 -0.87 -1.28 ll.06 -0.42 -0.17 -0.16 -0.13 -1.74 -1.71 -1.72 -1.28 ----a -0.50 -0.24 -0.24 -0.22 -1.74 -1.71 -1.72 -1.28 _____ a -0.50 -0.24 -0.24 -0.22 0.08 o.59 0.78 1.66 2.18 o.oo o.oo o.oo o.oo 0.28 o.59 0.78 1.78 3.10 o.oo o.oo o.oo o.oo 0.28 o.59 0.78 1.78 5.17 o.oo o.oo o.oo o.oo 0.28 o.59 0.78 1.87 8.23 o.oo o.oo o.oo o.oo 0.28 o.59 0.78 2.07 17.86' o.oo o.oo o.oo o.oo 0.28 o.59 0.78 2.07 23.55 o.oo o.oo o.oo o.oo 0.28 o.59 0.78 2.07 _____ a o.oo o.oo o.oo o.oo 0.28 o.59 0.78 2.07 _____ a o.oo 0.00 o.oo o.oo aTablets were soggy and moldy and adhered within the container. 95% o.oo o.oo o.oo 0.61 o.oo o.oo -J o.oo w o.oo 0.29 0.29 o.oo o.oo o.o o 0.90 o.oo o.oo o.oo o.oo

PAGE 82

Storage Fonnula Time hrs. S-A-5 500 1000 S-B-10 500. 1000 8Room Temperature. TABLE 21 CHANGES IN TABLET WEIGHT, HARmESS AND DISINTIDRATION TIME AFTER STORAGE FOR INTERVALS OF 500 AND 1000 HOURS IN OPEN VIALS AT VARIOUS 'l'El-1PERATURE CONDITIONS Storage Weight Hardness Temperature Change Original Resultant % Kg. Kg. R. T. a o .. oo 5.o 5.0 45 c -0.29 5.o 1.0 5 c. o.oo 5.0 5.o R. T.a o.oo 5.o 4.5 45 c. -0.12:t> 5.0 1.0 5 c. o.oo 5.o 5.o R. T.a -2.23 5.o 11.0 45 c. -2.49 5.o 12.5 5 c. -1.69 5.0 10.5 R., T.a -2.23 5.o 11.0 45 C. -2.49 5.o 12.5 5 c. -1.69 5.o 10.0 Disint~ration Time Original Resultant min.:sec. min.:sec. 66:42 10:56 66:42 5h:32 66:L2 110:43 66:42 60:08 66:42 62:28 66:42 115:11 80:54 122:.36 80:54 J.48:29 80:54 143:53 80:5h 123:05 80:5h 1.49:48 80:54 128:32 bin general the tablets were removed from the oven and allowed to cool to room temperature before weighing; however, these tablets remained at room temperature for over an hour before weighing. :=-

PAGE 83

Fonnu.la Storage Time hrs. S-A-5 500 1000 S-B-10 500 1000 8Room Temperature. TABLE 22 CHANGES IN TABLE!' WEIGHT, HARDNESS AND DISINTIDRA TION TIME AFTER STORAGE FOR INTERVALS OF 500 AND 1000 HOURS IN CLOSED VIALS AT VARIOUS TEMPERATURE CONDITIONS Storage Weight Hardness Temperature Change Original Resultant % Kg. Kg. R. T.a o.oo 5.o 5.o 45 C. o.oo 5.0 5.o 50 c. o.oo 5.0 5.o R. T.a o.oo 5.o 5.o 45 c. o.oo 5.o 5.o 5 c. o.oo 5.o s.o R. T.a -0.25 5.o 5.5 45 c. -0.49 5.o 5.5 5 c. -0.24 5.o 5.5 R. T.8 -0.25 s.o 5.5 45 c. -0.74 5.o 6.5 5 c. -0.24 5.0 5.5 Disintegration Time Original !Resultant min.:sec. min.:sec. 66:42 59:43 66:42 65:22 66:42 40:35 66:42 58:58 V\ 66:42 69:33 66:42 70:06 80:54 106:15 80:54 lh-9:01 80:54 120:50 80:54 121:48 80:54 165:SJ 80:54 135:58

PAGE 84

Fonnula S-.A.-5 S~-10 TABLE 23 CHANGES IN TABLET WEIGHT, HARDNESS AND DISIN'l'EGRA TION TIME AFTER S'IDRAGE FOR 1000 HOURS IN OPEN VIALS AT VARIOUS RELATIVE HUMIDITIES = Relative Humidity Weight Hardness at 27 C. Change Original Resultant % % Kg. Kg. 30 o.oo 5.o 5.5 40 o.oo 5.o 5.o 50 o.oo 5.o 5.o 80 2.30 5.o 2.5 95 ____ a 5.o ___ a 30 -1.74 5.o 10.5 40 -1.n 5.o 9.5 50 -1.72 5.0 10.5 80 -1.28 5.o 5.5 95 a 5.o ---a ---8Tablets were soggy and moldy and adhered within the container. Disintegration Time Original Resultant min.:sec. min.:sec. 66:42 55:32 66s42 62:18 66:42 10:50 66:42 80:4h 66:42 a ----80:54 188:28 80:54 1.40:33 80:54 180:16 80s54 135:52 80:54 ______ a

PAGE 85

Formula S-A-5 S...B-10 TABLE 24 CHANGES IN TABLET WEIGHT, HARDNESS AND DISINTffiRATION TIME AFTER STORAGE FOR 1000 HOURS IN CLQSED VIALS AT VARIOUS REI.A TIVE HUMIDITIF.S Relative Humidity Weight Hardness at 27 c. Change Original Resultant % 'I, Kg. Kg. 30 o.oo 5.o 6.o 40 o.oo 5.o 5.5 50 o.oo 5.o 5.5 80 o.oo 5.o 6.5 95 o.62 5.o 4.o 30 -0.50 5.0 5.o 40 -0.24 5.o 4.5 50 -0.24 s.o 4.o 80 -0.22 5.o li.5 95 0.29 5.o 3.5 Disinte~ation Time Original Resultant min.ssec. min.:sec. 66:42 49:58 66:42 59:01 66:42 58:46 -.J 66:42 63:23 -.J 66:42 95:16 80:5L 105:36 80:54 140:)5 80:54 142:14 80:54 120:59 80:54 165:22

PAGE 86

TABLE 25 CHANGES IN TABLET WEIGHT HARDNESS AND DISINTIDRATION TIME AFTER STORAGE FOR INTERVALS OF 500 AND 1000 HOURS IN OPEN VIALS AT VARIOUS TEMPERATURE CCM)ITIONS Storage Storage Weight Hardness Disintegration Time Formula Time Temperature Change Original Resultant Original ~esultant hrs. % Kg. Kg. ndn.:sec. min.:sec. AH...AT-5 500 R. T.a -o.45 1.0 B.5 B:53 11:47 4_50 C. -0.69 1.0 9.5 B:53 10:o6 _50 c. o.84 1.0 6.5 B:53 22:15 1000 R. T.a -0.13 7.0 B.o 8:53 9:11 45 c. -0.16 1.0 10.0 8153 18:29 -.J co 5 c. 0.91 1.0 6.5 8:53 25:37 AH-B-10 500 R. T. a 0.18 1.0 1.0 68:04 69:)6 h5 c. -0.36 1.0 6.o 68:04 72:55 50 c. 0.18 1.0 1.0 68:04 69:43 1000 R. T.a -0.16 1.0 6.0 68:04 17:15 45 c. -0.54 1.0 1.0 68:0h 79:02 5 c. 0.11 1.0 5.5 68:04 69:59 8Room Temperature.

PAGE 87

Storage Formula Time hrs. AH-AT-5 500 1000 AH-B-10 500 1000 aRoom Temperature. TABLE 26 CHANGES IN TABLET WEIGHT, HARDNESS AND DISINTEnRATION TIME AFTER STORAGE FOR INTERVALS O:f 500 AND 1000 HOURS IN CWSED VIALS AT VARIOUS TEMPERATURE CONDITIONS Storage Weight Hardness Temperature Change crri ginal Resultant % Kg. Kg. R. T.8 o.oo 1.0 1.5 4.5 C. -0.25 1.0 B.o 50 c. o.oo 1.0 7.5 R. T.8 o.oo 7.0 1.0 45 c. -0.51 1.0 7.5 .50 C o.oo 1.0 6.5 R. T.a o.oo 1.0 1.0 4.50 c. -0.11 1.0 1.0 5 c. o.oo 1.0 1.0 R. T.a o.oo 1.0 7.0 4.50 C. -0.18 1.0 7.0 5 c. o.oo 1.0 7.0 Disintegration Time Original Resultant min.:sec. min.:sec. B:53 10:46 B:53 10:Jl 6:53 14:08 B:53 11:5) -.J 'O B:53 9:54 8: .53 16:25 68:04 69:05 68:04 74:54 68:04 68:09 68:04 69:11 68:04 76:49 68:04 70:.56

PAGE 88

Fonnu.la AH...AT-5 TABLE 27 CHANGES IN TABLET WEIGHT HARDNESS AND DISINTIDRA'l'ION TIME AFTER STOliAGE FOR 1000 HO'QRS IN OPEN VIALS 1Relati ve Humid.i ty at 27 C. % 30 45 f:IJ Bo 95 AT VAfilOUS RELATIVE HUMIDITIES Weight Change % -0.26 -0.06 0.19 0.78 ----a Hardness Original Resultant Kg. 1.0 1.0 7.0 7.0 7.0 Kg. 6.5 1.0 1.0 6.0 ___ a aTablets were soggy and moldy and adhered within the container. Fo:nnula AH...AT-5 TABLE 28 CHANGES Ilf TABLET WEIGHT, HARDNESS AND msINTF.GRATION TIME AFTER STORAGE IN CIDSED VIALS FOR 1000 HOURS AT VARIOUS RELATIVE HUMIDITIES Relative Humidity Weight Hardness at 27 C. Change Original Resultant % % Kg. Kg. 30 -0.03 1.0 1.0 45 o.oo 1.0 1.0 c:IJ o.oo 1.0 6.5 80 o.oo 1.0 6.5 95 0.73 1.0 6.o Disintegration Time Original Resultant min.:sec. min.:sec. 8:53 15:26 8:53 12: 55 8:53 14:04 8 :5J 16:08 8:53 _____ a Disin~ration Time Origi ~esultant min.:sec. min.:sec. 8:53 9:24 8:5J 12:09 8:53 13:00 8:53 l.4:33 8:53 16:27 CD 0

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Fonnula AH-A-5 AH...B-10 TABLE 29 CHANGES IN TABLET WEIGHT, HARDNESS AND DISINTEGRATION TIME AFTER S'IDRAGE FOR 1000 HOURS IN OPEN VIALS AT VARIOUS RELATIVE HUMIDITIES Relative Humidity Weight Hardness at 27 c. Change Original Iiesultant % % Kg. Kg. .30 0.28 13 .5 12.5 40 o.59 13.5 12.0 50 0.78 13.5 11.0 80 2.01 13.5 4.o 95 a 13.5 a ------30 0.10 1.0 7.0 40 0.18 1.0 7.0 50 0.19 7.0 7.0 80 0.74 7.0 4.o 95 ____ a 1.0 ..,, a a Tablets were soggy and moldy and adhered within the container. Disintegration Time Original Resultant min.:sec. min.:sec. L2:17 L1:02 L2:17 49:20 L2:17 52:33 CD 42:17 8.3:32 I-' 42:17 _____ a 68:04 68: 51 68:04 69:02 68:04 70:00 68:04 101:-35 68:04 _____ a

PAGE 90

Fonnula AH..\-5 AH-B-10 TABLE JO CHANGES IN TABLET WEIGHT, HARDNESS AND DISINTEGRATION TIME AFTER S'IORAGE FOR 1000 HOURS IN CLOSED VIALS AT VARIOUS RELATIVE HUMIDITIES Relative Htunidity Weight Hardness at 27 C. Change Original Resultant 'I, % Kg. Kg. 30 o.oo 13 .5 12.5 40 o.oo 13 .5 13.0 50 o.oo 13.5 13.0 80 o.oo 13.5 13.0 9.5 0.36 13 .5 10.0 30 o.oo 1.0 1.0 40 o.oo 1.0 7.0 50 o.oo 7.0 7.5 80 o.oo 1.0 1.0 95 0.19 7.0 6.o Disinte~ration Ti.me Resultant Original min.:sec. min.:sec. 42:17 hl:56 42:17 hl:39 42:17 41:22 co I\) 42:17 41:40 42:17 44:08 68:04 70:11 68:04 68:01 68:04 68:47 68:04 69t01 68:04 70:02

PAGE 91

TABLE 31 CHANGES IN TABLET WEIGHT OF DIFFERENTLY LUBRICATED TABLETS AFTER S'IDRAGE FOR 500 HOURS IN OPEN VIALS AT VARIOU S TEMPERATURE CONDITIONS Weight Change in Tabletsa Storage Formula Temperature Unlubricated % BSN~T-S-a R. T. b 0.21 45 c. -0.22 5 c. o.59 BSN~S-10-a R. T. b o.46 45 c. -0.48 5 c. 0.34 BSN-B-10-a R. T. b 0.11 45 c. -0.39 50 c. 0.39 a'l'he tablets tested were within a hardness range of 6.0 and 7.5 Kg. bRoom Temperature. Lubricated with Magnesium Boric Stearate Acid % % 0.11 1.40 o.oo -0.26 o.69 o.69 0.78 0.12 -0.59 -1.28 o.58 0.31 0.30 0.10 -0.19 -0.39 0.29 0.31 CD v.,

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TABLE 32 CHANGES IN TABLET WEIGHT OF DIFFERENTLY LUBRICATED TABLETS AFTER S'IDRAGE FOR 500 HOUR3 IN OPEN VIALS AT V).RIOUS IlELATIVE HUMIDITIES Relative Humie.i ty at 27 c. Weight Change in Tabletsa Lubricated with Fonnula BSN-8. T-5-a BSN...AS-10-a BSN-B-10-a 30 L5 60 70 80 95 30 L5 60 70 Bo 95 30 45 60 10 Bo 95 Unlubricated % 0.22 o.58 0.77 0.9.3 1.62 ____ b o.oo O.JL 0.91 1.38 ::::b o.oo 0.16 o.L1 o.69 l.ll __ b aThe t~blets tested were within a hardness range or 6.0 and 7.5 Kg. bTablets were soggy and adhered within the container. Magnesium Boric Stearate Acid % 0.28 0.13 o.42 o.41 o.S6 o.55 0.98 o.67 1.85 ::~ lJ.22 o.oo 0.24 0.38 o.oo 0.96 o. 73 1.52 1.29 2.69 :::~b 9.34 o.oo o.oo 0.20 o.oo a.Lo Oa30 o.L9 0.39 1.22 1.09 9.55 ___ b ex, .i=-

PAGE 93

DISCUSSIOO OF RESUL'IS Bleaching of Sponge Although an acidified solution of sodium bisulfite was found to satisfactorily bleach the cleansed sponge without any further treatment, it was noted that on standing for three to five days the bleached sponge acquired a yellowish color. The following reaction took place when a sodium bisulfite solution was treated with hydrochloric acid: NaHS03 + HCl --+ NaCl + S02 + ~O It was the sulfurous acid fonned that served as the bleaching agent. Since exposure of the sponge to air, after being bleached with this agent, resulted in the gradual return of the yellowish color, it was assumed that the pigment was not destroyed, but instead, reduced or converted into a colorless compound. It is probably through a reoxidation process that this colorless compound is restored to its original pigment state. If such is the case, this would account for the return of the yellowish color when the bleached sponge was exposed to air. "When a potassium permanganate solution was used for bleaching, the sponge remained in an almost white CQnditj_on indefinately. Potas sium pennanganate, contrary to sulfurous acid, produces its bleaching effect through an oxidation process. The action of potassium permanganate is through the liberation of nascent oxygen which takes place as followsl 85

PAGE 94

86 'lhe brown deposit that remained on the sponge following the permanganate treatment was due to the precipitation of hydrated manganese dioxide. In order to remove this brown deposit it was necessary to subsequently place the sponge in a sodium bisulfite bath. 'Ibis reduced the manganese compound to a colorless soluble salt which was removed by solution, leaving the sponge in an almost white condition. Following thi s permanganate treatment, a final bleaching with an acidified sodium bisulfite solution left the spongin in a pennanently bleached state. Therefore, it w a s concluded that the oxidative perman ganate treatment chemically decomposed the coloring matter in such a manner that it was incapable of being subsequently reformed. Tablet Preparation It was found that most of the materials making up the tablet formulas behaved in a very similar manner in that they offered no major com' pression problems. Special attention was required only when the spongin was added in excessive proportions and when it was added to the granulation just before compression. When the spongin was added to the granulation prior to compression it would not flow uniformly with the granulation, but instead, it matted and bridged the die bore. Attempts to remedy this situation were unsuccessful. Lubrication with magnesium stearate was increased up to five per cent but did not alleviate the condition. Other lubricants, namely, boric acid, high mol ecular weight Carbowaxes and talc were also

PAGE 95

87 tried with no success. In the case of those tablets prepared containing spongin in proportions greater than ten per cent, satisfactory tablets were produced only when special handling of the fornru.la was carried out. When ~repari.ng fonnulas containing 14 per cent spongin for prelim.inary study., great care was required in adding the binding agent during the granulation process. If an insufficient quantity was added, the resulting granulation had 11 spongy!' characteristics~ A granulation of this nature would not flow smoothly or unifonnly into the dies regardless of the proportion of lubricant.used; thus the final weight of the finished tablet was affected. On the other hand, if too great a quantity of binder was added, the granules resulting from the first screening would be excessively hard and resistant to further screening. It was necessary, therefore, to use the method of trial and error when determining the proportion of granulating agent required for optimum granulation. Since this proved to be impractical, this agent did not exceed a ten per cent concentration in any subsequent fonnula. Table 7 summarizes the individual size characteristics of the tablet grarrulations prepared. It should be noted that with certain formulas comparatively large variations occurred in the gra.nulationsJ however., in most cases this had no noticeable influence on tablet compression. The granulatiom having magnesium hydroxide as the active ingredient were excessively so.rt and could be powdered when rubbed between the fingers. When compressin g these magnesium hydroxide granulations high pressures were required in order to produce satisfactory tablets. If high

PAGE 96

88 pressures were not used, capping of the tablets would result. When the tablets capped immediately following corn~ression, the upper punch faces were observed to have the capped portion of the tablet adhered to' them. However, some tablets were obtained in a whole state following compression and capped only when pressure was applied to the upper portion of the finished tablet with the thumb nail. 'Ihl.s latter type of capping was most probably due to entrapped air in the tablet resulting from an excessive amount of fine powder in the granulation. All other fonnulas prepared produced excellent, well defined, smooth tablets. Disintegration Studies The data listed in Table 9 indicate that the tablets prepared from formulas having powdered spongin as the disintegrating agent, disintegrated in all cases more quickly than the corresponding fonnulas having corn etarch as the disintegrator. It should be noted that powdered spongin did not exceed five per cent of the tablet weight with the exception of those formulas prepared for preliminary study and two additional formulas used for purposes of comparison. On the other hand, corn starch was used in eithe r 10 or 15 per cent concentrations. All t ablets containing powdered spongin disintegrated within the official requirements provided by the U. S~ P. or N. F. Although tablets prepared from fomula BSN-AT 5-b remained undisintegrated following three hours of testi~, they offered no resistance to the gentle touch of a stirring rod following only five minutes of testing. When touched, the tablets readily broke into several small pieces which passed through the

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89 No. 10 mesh screen of the basket-rack assembly in two or three minutes. Upon removal of these undisintegrated tablets from the disintegration apparatus after five minutes of testing, they were found to be extremely soft and easily crushed when squeezed between the fingers. Obviously, such a tablet when subjected to the perista;ttic action of the G. I. tract would deliver the medication just as readily as one that would have fallen apart and passed through the screen. This tablet, therefore, would have been considered disintegrated in accordance with the new U.S. P. IV disintegration end-point. In the preliminary studies conducted, all control tablets (those having no disintegrating agent added), with the exception of the soluble lactose tablets, showed no signs of disintegration subsequent to three hours testing. However, upon the addition of powdered spongin to the formulas, the same tablet fonnulas reve~ed no resistance to disintegration whatsoever. 'lhe data compiled also show that tablets prepared with 1h per cent spongin did not exhibit a substantial decrease in disintegration time over those tablets prepared with 7 per cent spongin. 'Ibis indicates that large proportions of spongin are not required in order to accomplish satisfactory disintegration. In general, synthetic sponge, when incorporated during the grarrulation process with the active ingredient and filler, possessed no advantage over lower concentrations of powdered spongin, but did surpass the disintegrating action of corn starch. However, when the synthetic sponge ( was granulated and added to the finished granulation prior to compression, it swelled within seconds and broke the tablet dow into its original

PAGE 98

90 granules very rapidly. Well defined, smooth tablets were obtained when adding the granulated synthetic sponge to the granulation prior to com-pression. Since tablet hardness has an influence on the rate of disintegration, an attempt was made to maintain the tablet hardness within a range of 6.o to B.o Kg. Four fonnulas, however, fell out of these limits. This was found to be caused either by the nature of the granulation being compressed or by difficulty encountered in adjusting the pressures to this hardness range. The data listed in Table 10 and illustrated in Figures 4 and 5 indicate that the relationship which exists between the rate of.tablet disintegration and tablet hardness depends on the tablet fonnula being tested. The results illustrated in Figure 4 show a minimum in the timehardness curves for four tablet fonnulas containing powdered spongin as the disintegrant. In Figure 5, which represents the time-hardness relationship of three tablet formulas containing corn starch as the disi -ntegrant, this minimum in the curve is completely .absent. Instead, the disintegration rate varies directly with changes in hardness. In general, a direct relationship manifests between disintegration time and tablet hardness; however, before assuming this to be true in any one case, a time-hardness curve should be plotted since in some instances faster rates of disintegration are obtained as the tablet hardness is increased. '.!his continues Up to an optimum hardness after which the ordinary relationship holds true. Higuchi, Elowe, and Busse (54) have indicated a direct linear

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91 dependency of hardness of tablets on the logarithm of the maximal compresion force. Since this is the case, curves similar those found in Figure 4 and Figure 5 would be obtained if compressional force was substituted for tablet hardness. Berry and Ridout (30) determined the disintegration times of different tablets as a function of the ratio of the weight to height of the tablets which they called "compression ratio.11 Compression ratio is actually a measure of the maximal force applied during the compression of the tablets. '!hey found that for some tablets there is a critical compression which wi.J.l give a minimum time of disintegration. 'Ihe minima in curves representing a time-hardness relationship for the formulas (four) containing spongin are similar to those obtained by Berry and Ridout (30). Observations as to why this minima occurred with tablets containing spongin are also in correlation with those made by Berry and Ridout. It was found tha t the tablets showing this phenom enon disintegrated from the outside, that is, small pieces flaked off until the tablet was completely disintegrated. The disintegration of these tablets depends on the swelling of the sponge particles. Under a very light compression the tablets formed would be very soft and as a conse quence have large intergranular spaces. Although the spongin swelled in these tablets, due to the large void spaces there was a certain lag period before the swelled particles began to exert pressure on the surrounding granules. Thi s resulted in an inhibited disintegration rate. At the optimum hardness, however, as soon as the spon gin particles swelled, they exerted sufficient pressure on the surrounding granules causing the tablets

PAGE 100

92 to bre~ apart more rapidly. When harder tablets were produced under heavier compressions, more time was required for the water to seep through the outer layers of the tablets and, as a result, slower disintegration rates were obtained. It should be indicated that the minimum point on a time-hardness curve should not be used in detennining_the tablet hardness in actual production. It is necessary to run, in conjunction with these tests, friability tests. In many cases it will be found that this optimum hardness is merely a theoretical value and has no use in tablet manufacture since the tablets are far too friable at this point. On the other han d if friability experiments show the tablets to be quite firm at this optimum hardness, it is obvious that this hardness should be utilized. Friability Studies 'lhe data compiled in Table 10 and illustrated in Figure 6 and Figure 7 indicate the relationship of tablet friability to tablet hardness. Although the friability values are pronounced for extremely soft tablets, they drop sharply as small changes in tablet hardness take place. Following the sudden drop in the friability value, little change is noted with progressively harde r t ablets. In this investigation tablets having a friability value of 3.000 or less were considered as having a high degree of resistance to chipping or breaking. As previously stated, in order to determ i ne the optimum hardness for a particular table t formula, it was necessary to cond uct friability values on several series of tablets. This data was correlated with

PAGE 101

93 disintegration time-hardness curves and the optimum tablet hardness for production was obtained. Table 11 shows that 1-lhen two 1 5-minute friabili ty runs were made on the same tablets, the friability values afte r the second run averaged approximately 1.7 times those of the first run. From this it may be concluded that during.the first shaking period, the tablet particles that were not firmly bonded were easily broken off. Therefore, upon being subjected to the second shaking period most of these loose particles were already removed leaving the more resistant structure of the tablet to be tested. Upon inspection of the tablets subsequent to friability shaking tests, it was observed that the tablets chipped or broke from the outside leaving intact a more or less finn core. This type of breakage was noted for all tablet hardnesses, with the exception of those tablets that had completely broken UP,and was most pronounced at hardnesses b e tween J.O and S.o Kg. This indicates that when tablet granulations are being compressed at high pressures, the individual granules making up the finished tablet are n o t unifonnly b o und throughout the tablet. Instead, the granules in the center of the tablet are more strongly bound to one another than those granules making up t he outer portiori o f the tablet. It h a s been stated (58) that the compression process does not cause the granules to break down and intennesh with one another but merely tends to bond the granules by flattening them within the tablets. The individual granules, therefore, retain their identity in the finished tablet. When tablets were cut in a vertical plane, and examined with a

PAGE 102

94 magni .fying glass, it was noted that flattening of the granules was more pronounced in the center of the tablet than it was at the outer portion of the tablet. '!his, in addition to the type of breakage that takes place during triability shaking tests, indicates that under compression pressure~, binding of the granules is greatest within the center of the tablet decreasing progressively in the outward direction. Tablet structure may also be the basis for certain types of tablet disintegration. $ome tablets p.re observed to disintegrate from the outside at a relatively fast rate, however, upon reaching a certain point this disintegration is slowed down considerably, and in some cases discontinued leaving a hard core in an undisintegrated condition. From the observations previously stated, it may be postulated that this type of disintegration in all probability is due to the varied degree of granule bonding through out the tablet. 'Ihe results of data compiled in Table 12 indicate that the tablets protected with a cotton filler are retained in excellent condition after 15 minutes of shaking Those tablets h aving friability values of 0.002, 0.003, and 0.006 showed no change in physical appearance when inspected by the naked eye. In general, the results show that those tablets containing sponge as a disintegrating a gent were no less friable than those containing corn starch as a disintegrator. Binding and Lubrication Studies Table 13 shows the comparative rate of disintegrati on of tablets prepared with different binding agents.Although insufficient data is

PAGE 103

95 available, the information obtained reveals that the rate of disintegration is definitely influenced by the binding agent used in preparing the granu lation. Starch paste and PVP solution were found to have approximately the same effect on disintegration. Zein solution was found to markedly inhibit the disintegration rate in two of the three formulas studied. '!his indicates that the influence of a binder on disintegration, besides being dependen on its adhesive properties, is also dependent on the materials being granulated. In general, syrup formed hard granules but had no adverse affect on disintegration. Table 11 reflects the degree of firmness of tablets prepared with each of the four binders used. 'Ihe results indicate that Zein solution formed the most resistant tablets while PVP solution, syrup, and starch paste in that order formed tablet s of decreasing resistance. The data listed in Table 14 and illustrated in Figure 8, Figure 9, and Figure 10 indicate that, with the exception of fonnu1a AH...AT-5, al1 unlubricated tablets tested disintegrated at a faster rate than those tablets that were lubricated. Two per cent lubricant based on the finished weight of the tablet was used in all formulas being compared. Boric acid, representing a soluble lubricant, had little influence on disintegration as compared with unlubricated tablets. It should be noted that boric acid was used for experimental purposes only and cannot be used in actual practice for tablets intended to be taken internally. Magnesium stearate, although a very efficient lubricant, produced a severalfold increase in disintegration time. Magnesium stearate, when used as a lubricant, adheres to the granules and forms a thin water-illlper vious sheath around the tablet. Through the waterproofing action of this

PAGE 104

96 sheath, the tablet is protected from the medium until this :impervious layer is penetrated. This delay in absorptio~ accounts for the several-fold increase in disintegration t:ime. tenfold increase was observed. In one case using this agent, a I Talc, although insoluble, does not exhibit this waterproofing action on the finished tablet. Disintegration rates for th& tablets lubricated with talc fell between those of boric acid and magnesium stearate. Talc possesses the disadvantage of giving the disintegration media a chalky white appearance. In gen eral, the results compiled indicate that the disintegration time of t hose fonnulas prepared with sponge as the disintegrating agent were not a fr'ected as greatly by changes in lubricating agent as were those formulas containing corn starch as the disintegrator. Tables 31 and 32 show that, when comparing differently lubricated tablets following 500 hours of storage at varying conditions, only slight variation in changes of tablet weight between the different formulas occurred. Actually the only significant difference in weight change of the differently lubricated tablets was with those lubricated with magnesium stearate These tablets appear~d to have absorbed less moisture than the other tablets when stored at humidities of 80 per cent and above. As reveal~d in Table 32, subsequent to storage at 95 per cent relative humidity for 500 hours, those tablets lubricated with magnesium stearate were found to retain their shape and were capable of being weighed. On the other hand, following these same storage conditions, the unlubricated tablets along with those lubricated with boric acid were found to be incapable

PAGE 105

97 of retaining their shape when touched, and in addition had adhered in the container. Actually, the tablets in these latter two cases had absorbed excessive amounts of moisture which caused them to become "soggy" and 11 sticky" which in turn caused them to adhere in the container. Storage Studies The data collected subsequent to the storage of tablets in open co ntainers at various temperature conditions are found in Tables 15, 21 and 25. The results indicate that disintegration time, hardness and weight changes following storage, vary considerably depending on the tablet fonnula in question. For example, formulas S-A-5, S-B-10 and AH-AT-5 all showed a significant increase in disintegration ti.me when they were stored at 5 c., whereas formula AH...B-10 showed a decrease in disintegration ti.me at the same temperature. It was found that room temperature affected the disfntegration time to some extent in all fonnulas. This was most likely due to the high relative humidities which prevailed during the storage period, at times being as high as 70 per cent. As stated previously, disintegration time is usually directly related to changes in table t hardness. Therefore, since increase in tablet hardness was shown to be generally dependent on the percentage of wei ht lost by the table t during storage, it may be concluded that delayed dis-integration times of tablets stored at h5 C. were caused by the pronounced moisture loss in the tablet. Th.e loss in weight revealed by formula S-B-10 was due to excessive moisture in the granulation. It should be noted that, as a result of this

PAGE 106

98 moisture loss upon storage, significant changes in the hardness and disintegration time of these tablets occurred. Tables 16, 22 and 26 show the effect of a closed container on tabl ets subjected to various temperature conditions. Little chan g e in tablets was found followin g storage in this manner. In general, the varied temperature conditions studied had a more pronounced influence on tablets containing spongin than they did on those tablets prepared with corn starch as the disintegrant. The results listed in Tables 23, 27 and 29 show that storage in open containers at variou s relative humidities is of significant interest. Again, as stated previously, the deviations talcing place in tablet hardness and disintegration tim~ _are shown to be closely related to the changes talcing place ln tablet wei ght. At low relative humidities of JO and 40 per cent little change is observed in tablet weight. Likewise, chang e s t alcin g place in tablet hardness and disintegration are also small. As the humidities begin to reach higher levels, however, changes in these three properties begin to become significant. At 50 per.cent relative humidity, increase in tablet weight, although slight, is definitely noticeable. At this same humidity tablet hardness b egan to sho w decreases of from 0.5 to 1.0 Kg. In addition, signs of increased disintegration time were n oted in all cases. Following storage at 80 per cent r elative humidity a much greater increase in tablet wei ght took place, and as would be expected the tablets . were much softer. The disintegratio n time also showed a marked increase for all tablet fonnulas.

PAGE 107

99 Relative humidities of 95 per cent caused the tablets to become soggy, swollen, and in many cases moldy. Attempts to test these tablets were unsuccessful ~ince the tablets would not retain their shape when touched. Tables 24, 28 and JO indicate that tablets stored in closed containers at various relative humidities show no significant changes in weight, hardness, or disintegration time following storage. In general, it may be stated that tablet formulas prepared using pO'wdered spongin as the disintegrating agent are more susceptible to increases in relative humidities than those tablets containing corn starch as the disintegrant. These results are in accord with those found in Table 8 and illustrated in Figure J. Here, the data compiled indicate that powdered spongin has a greater capacity for absorbing moisture than corn starch.

PAGE 108

SUMMARY The value of sponge, both natural and synthetic, as a disintegrating agent in compressed tablets was investigated. In addition, a method for cleansing, bleaching and grinding the natural sponge prior to its incorporation in tablet fonnulas has been devised. Tablets prepa:t>ed using sponge as the disintegrating agent proved to disintegrate more rapidly than those prepared with corn starch as the disintegrant. The disintegration time for tablets containing spongin, when related to tablet hardness, was characterized by a minimum in the curve which took place at an optimum hardness. Tablets prepared with corn starch, however, failed to show thia phenomenon. Instead, they usually revealed a linear relationship. Synthetic sponge, when granulated with starch paste and added to the fi.shed granulation prior to compression, was found to be very efficient as a disintegrant. This agent swelled immediately upon contact with water and broke down the tablet into its original_granules which in turn rapidly disintegrated. Shaking tests indicated that sponge had no adverse affect on the friability of the finished tablet. Using these friability tests as a basis, it was concluded that the degree of granule bonding throughout a tablet is varied. Apparently, the granules are bonded more finnly within the center of the tablet s with the magnitude of this bonding de~reasing 100

PAGE 109

101 in an outward direction. Lubrication studies revealed magnesium stearate to have a marked influence on the disintegration time of tablets. In most instances, when tablets were lubricated with magnesium stearate, a severalfold increase over unlubricated tablets was observed. This influence on disintegration was more pronounced in tablets prepared with corn starch as the disintegrant. Storage studies indicated that tablets prepared with sponge, and stored under specified conditions, were, in general, less stable in the properties studied than those tablets containing corn starch.

PAGE 110

BIBLIOORAPHY 1. Helenore, J. c., Chain Store Age, Drug Executives Edition,~, 93 {1953). 2. White, R. c., J. Am. Phann. Assoc., 2., 788 {1920). 3. Gross, H. G.~ and Becker C.H., J. Am. Phann. Assoc., Sci. Ed., !!1., 157 (1952). 4 Caspari, c., and Kelly, E F., "A Treatise on Pharmacy'' Lea and Febiger, Philadelphia, Pa., 1939, p. 408. 5. Little, A., and Mitchell, K. A., "Tablet Making", Northern Publishing Company, Ltd., Liverpool, England, 1949, p. 12. 6. Peck, W. c., Phann. J., fil, 171 {1939). 7. "Research in Tablet Making"., Phann. J ., 150, 184 (1943). 8. Burlinson, H ., J. Phann. and Phannacol. t ., 1055 {1954). 9. Villacorta., c. v ., Thesis, "Studies of Compressed Tablet Manufacture," University of Illinois., 1950. 10. Chavkin, L., Drug and Cosmetic Ind., 1.2, 466 {1954). 11. Silver, J. A., and Clarkson, R. "Manufacture of Compressed Tablets"., F. J. Stokes Machine Company, Philadelphia, Pa., 1947., p. 19. 12. Kebler, L. F., J. Am. Pharm. Assoc., J,; 820 (191.h). 13. Letters in Chemist and Druggist, ll., 5311 563, 603, 665, &J5 (1890). 14. Dieterich, E., Phann. Ztg., l2_, 400 (1890). 15. Blaschnek, R., Phann. Post, 42, 169 (1909)J through Pharm. Ztg., 54, 178 (1909). 16. Kabler, L. F., J. Am. Pharm. Assoc., l, 931 (1914). 17. Rusa, W J., Drug Markets, gQ., 317 (1927). 18. White, E., and Robinson, R A., Year-Book of Pham., p. 417 (1902). 19. White, E., and Rodwell, H., Ibid., p. 487 (1903). 102

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103 20. Lowry, W. J., Proc. Am. Phann. Assoc., 54, 663 (1906). 21. Dunnet, P., Chemist and Druggist, 78, 206 (1911). 22. White, R c., J. Am. Pharm. Assoc., 11, 345 (1922). 23. Husa, W. J., Ibid., ll, 38 (1928). 24. 11Tablet Making", Pharrn. J., 126, 233 (1931). 25. Davis, H~, and Gillett, F. H., Ibid., ill, 503 (1934). 26. Sprengler, H., and Schenker E., Phann. Acta Helv., g, 339 (1937). 27. Brown, c L. M., Quart. J. Pham. and Phamacol., g, 489 (1939). 28. Sprengler, H., and Jud, J., Pham. Acta Helv., 565 (1943). 29. Burlinson, H., and Pickering, c., J. Pha:nn. and Phannacol., g_, 63 (1950). JO. Berry, H., and Ridout, c. w., Ibid., p. 619. 31. Holstius, E. A., and DeKay, H G., J. Am. Phann. Assoc., Sci. Ed., Yl, sos (1952). 32. Milne G. R., Cherri.st and Druggist, 139, 276 (1943). -. 33. Granberg, C. B., an d Benton, B. E. J. Arn. Pharrn. Assoc., Sci. Ed., ~. 61.iB (1949). 34. Swintosky, J., and Kennon, L., Ibid., 42, 505 (1953). 35. Fir~uzabadian, H., and Huyck, L. c., Ibid., 43, 248 (1954). 36. Eatherton, L. E., et al., Drug Standards, gi, 42 (1955). 37. Swintosky, J., et al., J. Arn. Phann. Assoc., Sci. Ed., 44, 112 (1955). 38. Curlin, L., Ibid.,p. 16. 39. Evanson, R. V., and DeKay, G. H., Bull Natl. Formulary Comm., 18, 45 (1950). 40. Ewe, G. E., Proc. Am. Pham. Mfrs'. Assoc., p. 75 (1930). 41. Howard, B. F., Quart J. Pha:nn. and Phannacol., 2., 528 (1936). 42. Berry, H., Ibid., g, 501 (1939).

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104 43. Berry, H., and Smith, A. N., Ibid., !1, 248 (1944). 44. Malpass, G. N., Am. J. Phann., 114, 167 (1942). 45. Calamari, J. A., and Roth, P. B., Proc. Am. Phann. Mfrs'. Assoc., p. 75 (1942). 4.6. Hoehn, W. M., Bull. Natl. Formulary Cown., 11, 162 (1945). 4.7. Smith, A. N., Phann. J., 156, 317 (1946). 48. "Science Papers111 Pham. J., ill., 86 (1946). 49. Gershberg, s., and .Stoll, F., J. Am. Phann. Assoc., Sci. Ed., 35, 284. (1946). 50. "United States Pharmacopeia, Fourteenth Revision", Mack Publishing Company, Easton, Pa., 1950, p. 700. 51. Ibid., 11Fifteenth Revision" 1 19.55, p. 937. 52. Higuchi, T., et al., J, Am. Pharm. Assoc., Sci. F.d., 41, 93 (1952) .53. Holstius, E A., and DeKay, H. G., Ibid., p. 505. 54. Higuchi, T., et al., Ibid., 43, 685 (1954). 55. 56. Levi, R. s., 'lbesis, "A Comparative Study of Binding Agents for Compressed Tablets11, University of Florida, 1951. Sperandio, G. J.l and DeKay, H. G., J. Am. Phann. Assoc., Pract. Ed., 1-2., 512 (1949 J. 51. Griffin, J. c., and Huyck, C. L.,' Ibid., Sci. Ed., 44, 251 (1955). 58. Strickland, w A., et al., Ibid., !!z, 51 (1956). 59. Wolff, J. E., Ibid., l, 407 (l947). 60. Smilek, M., et al., Drug Standards, gi, 87 (1955). II II ) 61. Munzel, van K., and Kagi, w., P hann. Acta Helv., 29, 53 (1954 62. Beeler, E c., and Gathercoal, E. N., J. Am. Phann. Assoc., Sci. Ed., JQ, 56 (1941). 63. Raff, A. ., Ibid., hll_, 290 (1955). 64. Ewe, G. E., Ibid., 120.5 (1934).

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6 5 66. 67. 68. 69. 70. 71. 72. 10.5 Leonard, C. s., Proc. Am. Phann. Mfrs'. Assoc., p. 20 (1932). Silver, J. A., and Clarkson, R., Ibid., p. 10.5 (1933). Tschirch, A., Schweiz. Apoth. Ztg., 77, &5 (1939); through Chem. Abstracts, lk, 2S36 {19Lo). Wood H. c., et al., "The Dispensatory of the United States", J.B. Lippinco t t Co., Philadelphia, Pa., 18th edition, 1899, p. 1799. 0ficjalski, P., Phann. Zentralhalle, 78, 174 (1937). deLaubenfels, M W., "Papers from the Tortugas Laboratory", published by the Carnegie Institute of W ashing on, March, 1936. St~deler, G., Arm. Chem. u. Pharm., 11 1 12 (1859). Schmidt, C. L.A., "The Chemistry of Amino Acids and Proteins", Charles c Thomas, Springfield, Illinois, 2nd edition, 1944, p. 278. 73. Block, R. J., and Bolling, D., J. Biol. Chem., 127, 68.5 (1939). -74. Ramsey, J. c., Thesis, "An Elemental Analysis of Some Florida Salt Water Sponges", University of Florida, 1948, p. 18. 75~ Clanc y V. J., Biochem. J., gQ, ll86 (1926). 76. Smith, J. G., J. Ind. Eng. Chem., h 850 (1913). 77. Wintter, J. _.., Thesis, "Amino Acids From the Florida Wool Sponge", University of Florida, 1950, p. 6. 78. Gross, H. G., Thesis., "A Comparative Study of Tablet Disintegrating Agents", University of Florida, 19.51, p. 21. 79. Husa, W. J., "Pharmaceutical Dispensing", 4th edition, Husa Brothers:, Iowa City Iowa, 1951, p. 109. 80. "Why Glycerine for Drugs and Cosmetics?", Glycerine Producers' Assoc., New York, N Y., p. 13.

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BIOORAPHICAL ITEMS Robert C. Crisafi was born in Boston, Massachusetts, on May 13, 1931. He was educated in the schools of Revere, Massachusetts, and graduated from Revere Central High School in June, 1949. Following graduation from high school, he entered the New England College of Pharmacy. He received the degree of Bachelor of Science in Phannacy in June, 1953, the same year in which he enrolled in the Graduate School of the University of Florida. Du.ring his graduate s~udies at the University of Florida, he was a Graduate Teaching Assistant in Pharmacy for three years. He completed his graduate work as a Fellow of the American Foundation for Pharmaceutical Education. Mr. Crisafi is a registered phannacist in the states of Massachusetts and Florida and has had several years experience in retail phannacy. In addition, he is a member of the American Phannaceutical Association, Rho Chi, national honorary phannaceutical society, Gamma Sigma Epsilon, national honorary chemical fraternity, Phi Sigma, national biological society, and K appa Psi, national pha.nnaceutical fraternity. 106

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This dissertation was prepared under the direction of the chairman of the candidate's supervisory committee and has been approved by all members of the committee. It w a s submitted to the Dean of the College of Pharmacy and to the Graduate Council and was approved as partial fulfilment of the requirements for the degree of Doctor of Philosophy. August 11, 1956 Dean, Co11:ge of Pharmacy Dean, Gra duate School 107

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UNIVERSITY OF FLORIDA 1111111111111111111111111111 111111111111111111111111111111111111 3 1262 08554 3170


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