Suspension polymerization for preparation of prolonged release dosage forms

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Suspension polymerization for preparation of prolonged release dosage forms
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xi, 128 leaves : ill. ; 29 cm.
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Croswell, Roger W
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Subjects / Keywords:
Delayed-Action Preparations   ( mesh )
Suspensions   ( mesh )
Pharmacy Thesis Ph.D   ( mesh )
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Thesis:
Thesis (Ph.D.)--University of Florida, 1972.
Bibliography:
Bibliography: leaves 123-127.
Statement of Responsibility:
by Roger Wayne Croswell.
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Typescript.
General Note:
Vita.

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SUSPENSION POLYMERIZATION FOR
PREPARATION OF PROLONGED RELEASE
DOSAGE FORMS




By





ROGER WAYNE CROSWELL


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








UNIVERSITY OF FLORIDA
1972













DEDICATION

The devotion, respect and encouragement of my parents,

Mr. and Mrs. Richard 0. Croswell, in large measure, account

for this moment in my professional life. It is to them that

I proudly dedicate this dissertation.














ACKNOWLEDGMENTS


Sincere appreciation is expressed to the Chairman of

the Supervisory Committee, Dr. Charles H. Becker, for the

enthusiasm, interest and concern exhibited throughout the

duration of this investigation. His interest in the progress

of the work has been very encouraging.

The comments and advice of other members of the

committee, Dr. Oscar E. Araujo, Dr. Henry C. Brown and

Dr. Richard H. Hammer, have been valued.

The assistance of the Instrument Shop, J. Hillis Miller

Health Center, which constructed the polytetrafluoroethylene

bushing and stainless steel shaft used in this investigation,

is greatly appreciated.

The many hours spent by my aunt, Miss Dorothy M. Croswell,

in checking this manuscript for acceptable format and general

mechanics is also appreciated.


iii















TABLE OF CONTENTS


ACKNOWLEDGMENTS .

LIST OF TABLES .

LIST OF FIGURES. .

ABSTRACT ,

INTRODUCTION *

REVIEW OF LITERATURE .

Spherical Bead Preparations *

Suspension Polymerization *

Characteristics *
History .
Difficulties encountered *
Aqueous phase and suspending agents
Monomeric phase *
Mechanism of action *
Polymerization conditions *
Expandable polystyrene beads *

Evaluation and Control *

Dissolution methods and kinetics
In vitro evaluation methods *

EXPERIMENTAL PROCEDURE *

Materials and Chemicals *

Equipment *

Suspension polymerization apparatus
Filter
Oven *
Balances *
pH meter *
Microscope
Sieves *
Tablet press


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TABLE OF CONTENTS Continued


Dissolution apparatus *
Spectrophotometer *

Production Procedures *

Formulations .
Preparation of expandable beads
Preparation of tablets from expanded

Test Methods *

Particle size classification .
Assay procedure *. *
Visual characteristics *
Density determinations
Porosity *
Dissolution studies .

EXPERIMENTAL DATA .

DISCUSSION OF RESULTS .

Preliminary Research *

Manufacture of Expanded Beads *

Assay for Acetaminophen Content .

Physical Characteristics .

Density and Porosity Data .

True density *
Bulk density e *
Porosity *

Dissolution Studies *

Dissolution testing *
Model prediction *
Assessment of beaded products *

SUMMARY AND CONCLUSIONS *

LIST OF REFERENCES .

BIOGRAPHICAL SKETCH .


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LIST OF TABLES


Table


MATERIALS AND CHEMICALS USED .


0 0


II FORMULATIONS OF NONEXPANDED POLYSTYRENE BEADS

III ACETAMINOPHEN CONTENT OF NONEXPANDED POLY-
STYRENE BEADS .

IV BULK DENSITY, TRUE DENSITY AND PERCENT POROSITY
OF NONEXPANDED POLYSTYRENE BEADS .


V DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 400 R.P.M.
IN THE PRESENCE OF 0.5% SODIUM SULFATE

VI DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 400 R.P.M.
IN THE PRESENCE OF 1.0% SODIUM SULFATE

VII DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 400 R.P.M.
IN THE PRESENCE OF 1.5% SODIUM SULFATE

VIII DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 450 R.P.M.
IN THE PRESENCE OF 0.5% SODIUM SULFATE

IX DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 450 R.P.M.
IN THE PRESENCE OF 1.0% SODIUM SULFATE

X DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 450 R.P.M.
IN THE PRESENCE OF 1.5% SODIUM SULFATE

XI DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 500 R.P.M.
IN THE PRESENCE OF 0.5% SODIUM SULFATE


XII


S 54



S 58



62



S 66



S 70



S 74



S 78


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 500 R.P.M.
IN THE PRESENCE OF 1.0% SODIUM SULFATE 82


Page








LIST OF TABLES Continued


Table Page

XIII DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 500 R.P.M.
IN THE PRESENCE OF 1.5% SODIUM SULFATE 86

XIV ACETAMINOPHEN CONTENT OF EXPANDED POLYSTYRENE
BEADS 90

XV BULK DENSITY, TRUE DENSITY AND PERCENT
POROSITY OF EXPANDED POLYSTYRENE BEADS 91

XVI DISSOLUTION DATA OF ACETAMINOPHEN FROM
EXPANDED POLYSTYRENE BEADS FORMULATION I 92

XVII DISSOLUTION DATA OF ACETAMINOPHEN FROM
EXPANDED.POLYSTYRENE BEADS FORMULATION II 93

XVIII DISSOLUTION DATA OF ACETAMINOPHEN FROM
EXPANDED POLYSTYRENE BEADS FORMULATION III 94

XIX DISSOLUTION DATA OF ACETAMINOPHEN FROM
EXPANDED POLYSTYRENE BEADS FORMULATION IV 95

XX DISSOLUTION DATA OF ACETAMINOPHEN FROM TABLETS
COMPRESSED OUT OF EXPANDED POLYSTYRENE BEADS
AT 3000 P.S.I. AND CONTAINING 40% POTASSIUM
CHLORIDE 97

XXI DISSOLUTION DATA OF ACETAMINOPHEN FROM TABLETS
COMPRESSED OUT OF EXPANDED POLYSTYRENE BEADS
AT 6000 P.S.I. AND CONTAINING 40% POTASSIUM
CHLORIDE 98

XXII DISSOLUTION DATA OF ACETAMINOPHEN FROM TABLETS
COMPRESSED OUT OF EXPANDED POLYSTYRENE BEADS
AT 3000 P.S.I. AND CONTAINING 20% POTASSIUM
CHLORIDE 99

XXIII DISSOLUTION DATA OF ACETAMINOPHEN FROM TABLETS
COMPRESSED OUT OF EXPANDED POLYSTYRENE BEADS
AT 6000 P.S.I. AND CONTAINING 20% POTASSIUM
CHLORIDE 100

XXIV DISSOLUTION DATA OF ACETAMINOPHEN FROM TABLETS
COMPRESSED OUT OF EXPANDED POLYSTYRENE BEADS
AT 3000 P.S.I. IN THE ABSENCE OF POTASSIUM
CHLORIDE 101

XXV DISSOLUTION DATA OF ACETAMINOPHEN FROM TABLETS
COMPRESSED OUT OF EXPANDED POLYSTYRENE BEADS
AT 6000 P.S.I. IN THE ABSENCE OF POTASSIUM
CHLORIDE 102
vii














LIST OF FIGURES

Figure Page

1 SUSPENSION POLYMERIZATION APPARATUS 33

2 DISSOLUTION APPARATUS 37

3 STANDARD CURVE FOR ACETAMINOPHEN 53

4 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 400 R.P.M. IN THE PRESENCE OF 0.5% SODIUM
SULFATE. 57

5 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 400 R.P.M. IN THE PRESENCE OF 1.0% SODIUM
SULFATE. 61

6 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 400 R.P.M. IN THE PRESENCE OF 1.5% SODIUM
SULFATE. 65

7 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 450 R.P.M. IN THE PRESENCE OF 0.5% SODIUM
SULFATE. 69

8 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 450 R.P.M. IN THE PRESENCE OF 1.0% SODIUM
SULFATE. 73

9 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 450 R.P.M. IN THE PRESENCE OF 1.5% SODIUM
SULFATE. 77

10 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 500 R.P.M. IN THE PRESENCE OF 0.5% SODIUM
SULFATE 81

11 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 500 R.P.M. IN THE PRESENCE OF 1.0% SODIUM
SULFATE. 85
viii







LIST OF FIGURES Continued


Figure Page

12 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED
AT 500 R.P.M. IN THE PRESENCE OF 1.5% SODIUM
SULFATE 89

13 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
EXPANDED POLYSTYRENE BEAD FORMULATIONS I,
II, III and IV 96

14 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
TABLETS COMPRESSED OUT OF EXPANDED POLYSTYRENE
BEADS 103

15 DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
EXPANDED POLYSTYRENE BEAD FORMULATIONS I,
II, III AND IV 105

16 30-MESH NONEXPANDED POLYSTYRENE BEADS 111

17 CROSS SECTION OF NONEXPANDED POLYSTYRENE BEAD 111

18 CROSS SECTION OF TABLET COMPRESSED FROM
EXPANDED POLYSTYRENE BEADS 113

19 30-MESH EXPANDED POLYSTYRENE BEADS 113







Abstract of Dissertation Presented to the
Graduate Council of the University of Florida in Partial
Fulfillment of the Requirements for the Degree of Doctor of Philosophy



SUSPENSION POLYMERIZATION FOR
PREPARATION OF PROLONGED RELEASE
DOSAGE FORMS


By


Roger Wayne Croswell

December, 1972


Chairman Dr. Charles H. Becker
Major Departments Pharmacy

An investigation was undertaken to develop a process,

utilizing suspension polymerization, for the production of

prolonged release medicated dosage forms. The effects of

production variables upon dissolution of acetaminophen from

these dosage forms were studied, 4he results of each manu-

facturing process are presented ir both tabular and graphical

form and where possible are explained.

Sodium polyacrylate and sodium sulfate were used as

suspension stabilizers. These were employed in concentrations

of 0.05%, 0.10%, 0.15%, and 0.50%, 1.00% and 1.50% respec-

tively. Three different speeds of agitation, 400 r.p.m.,

450 r.p.m. and 500 r.p.m., were used to maintain dispersion

of the monomeric phase. A total of 27 nonexpanded polysty-

rene bead formulations were developed.

An apparatus consisting of a constant temperature water

bath, a reaction chamber and a variable speed stirrer was








constructed for the suspension polymerization reaction,and
the rotating bottle apparatus proposed by Souder and

Ellenbogen was used for dissolution studies.

The suspension polymerized beads were filtered, dried

and assayed for total drug content. The average acetaminophen

content of the nonexpanded polystyrene bead formulations

was always less than 2% while that of the expanded polysty-

rene bead formulations was about 20%.

Dissolution studies were conducted in USP Simulated

Gastric and Intestinal Fluids. Results indicated that the

27 formulations of nonexpanded beads possessed no prolonged

release action. Only 64% of the available drug was released

from these formulations, most of which released this amount

within the first hour of dissolution. The expanded bead

formulations also released about 64% of the available

acetaminophen within the first 30 min.; however, an

additional 29% was released by the conclusion (24 hr.) of

dissolution testing.

A dissolution model was proposed to describe the release

of drug from the expanded polystyrene bead formulations.

Drug release was found to possess a log-log relationship.













INTRODUCTION


The pharmaceutical industry has, for many years, employed

small spherical pellets, in one form or another, for use in

sustained release medicated dosage forms. These pellets may

either be coated with different waxes and plastics or the

drug may be granulated with various resins to produce spheri-

cally shaped pellets. The rate of the release of the medica-
ment from the coated pellets is usually controlled by varying

the thickness or the composition of the coats on the pellets.

Those drugs which are granulated with resinous compounds

accomplish their sustained action by a three-step process

involving (1) absorption and solution of a solvent through

the polymeric matrix; (2) diffusion of the solute through the

polymeric barrier under a concentration potential; and

(3) desorption of the solute from the polymer surface. This

leaching and diffusion process may be facilitated by the use

of channeling agents.

Until recently, there have not been any significant

advances in sustained release technology. The use of

suspension polymerization has opened many areas of experi-

mentation in the preparation of sustained release products (1).

Suspension polymerization has been used for a long time
in the plastic industry as a step in the development of both

cationic and anionic exchange resins, in the formation of

1






2

beads which are easily filtered, washed and dried to form

molding powders and as an easy, efficient and relatively

inexpensive way to produce spherical pellets of controlled

diameter.

Suspension polymerization is synonymous with bead or

pearl polymerization. In this process, a monomer or mixture

of monomers is dispersed by strong mechanical agitation into

droplets. These droplets are suspended in a second liquid

phase in which both monomer and polymer are essentially

insoluble. The droplets of monomer are polymerized while

dispersion is maintained. Agents which hinder the coales-

*cence of these droplets during polymerization are added to

the suspending liquid which is almost always water.

Polymerization initiators or catalysts, soluble in the

monomeric phase, are also used. Depending upon the particu-

lar monomer treated, hard or soft spheres, beads, pearls or,

less often,irregularly shaped granules (which separate easily

from the aqueous phase when agitation is discontinued) are

formed.

The intense heat of polymerization, common to most

monomers, is dissipated rapidly, and granular, easily filtered

products which may then be dried, can be obtained from many

types of monomers.
It is the purpose of this investigation to utilize the

process of suspension polymerization as a means of manufac-

ture of a prolonged release product, containing a medicament,

followed by the evaluation of manufacturing parameters






3
(i.e., initiators, stabilizing agents, monomers, speed of

agitation and length of polymerization) on the effect of

incorporation and dissolution of the medicament from the

plastic matrix.

Monomers to be studied include styrene, divinylbenzene,

ethylvinylbenzene and methylmethacrylate.

The experimental section of this investigation includes

several distinct phases as follows

(A) Manufacture of a suitable dosage form

(B) Evaluation of production and formulation

variables on bead characteristics

(C) In vitro dissolution studies of the

spherical pellets and tablets compressed

from these pellets in a simulated gastric

and simulated intestinal fluid.













REVIEW OF LITERATURE


Spherical Bead Preparations

In the pharmaceutical industry, there are a great number

of methods and processes used to produce a prolonged release

medicated dosage form. Numerous processes (2-14) involve the

use of spherical pellets (12-40 mesh nonpareils coated with

drug) coated with various amounts of glyceryl monostearate

and beeswax dissolved in chloroform (14) or synthetic polymers.

To obtain an initial dosage level, several uncoated pellets,

containing drug, are employed.

The disintegration of the Spansule (SK&F) is indepen-

dent of pH and is based upon the vapor pressure permeability

of the lipid film which is determined by the composition and

thickness of the coat.

Medules (Upjohn) function in a manner similar to the

Spansule. However, the coating material (styrene-maleic

acid copolymer) is pH sensitive,thereby preventing dissolution
of the drug in the stomach.

The "Trickle System" (15) is uniquely representative of

other processes which employ a similar system of coating. In

this process, the release of the drug from the bead is a

function not of pH or mechanical agitation, but of porosity

of the coating materials. This process uses a "liquid"





5
dusting powder (i.e,, freely flowing) which, when it is

exposed to water, produces a porosity, thereby permitting the

passage of water, in, and the drug in solution, out. It is

then obvious that the rate is controlled by proportioning the

powder to film forming liquid, by the number of such propor-

tioned layers, by selection of compounds used to form the film

and by the regulation of densification.

With some of these methods, the coatings may shrink and

crack upon aging and thereby release a major portion of the

medication more quickly than originally intended. Aging may

also produce the opposite effect of preventing the beads from

releasing their medication to any significant degree.

Leaching is a process by which there is a steady dissolu-

tion and removal of a medicament from an intact, insoluble

matrix. The Gradumet (Abbott) is a well-known example of

this type of dosage form. It consists of a copolymer of

methylmethacrylate and methylacrylate. The Gradumet is

produced by compressing the granulated drug with the insoluble

plastic matrix. The release of drug is independent of pH of

the surroundings and is entirely dependent upon the drug

leaching from the matrix. If the drug is one which is slowly

soluble, a channeling agent (a highly soluble substance) may

be added.

Goodman and Banker (16) investigated a system of drug

entrapment in which a highly concentrated colloidal polymeric

dispersion in the presence of the drug in solution provides

the entrapment. Methapyrilene hydrochloride and an acrylic





6

copolymer were prepared by Goodman and Banker and then

evaluated for sustained action characteristics. The entrap-

ment procedure consisted of slowly adding the acrylic

copolymer emulsion to a constantly agitated solution of

methapyrilene hydrochloride in water resulting in immediate

flocculation and precipitation. The precipitate was then

filtered, dried and comminuted so that it would pass through

a 60-mesh screen.

In a later study, Rhodes et al. (17) showed that by

incorporating an organic acid, both drug interaction with the

polymer and subsequent release rates could be controlled.

The use of ion exchange resins has also been suggested

(18-19) for use in sustained release preparations.

Small spherical beads containing one or more active

ingredients (20) may be formed by dropping a suitable volatile

solvent into a bed of finely divided particles of polymer or

copolymer and by separating that powder by screening and

drying. Thus a mixture of ethylene chloride and methyl

alcohol may be dropped into a bed of cellulose acetate

phthalate producing beads 1.4 mm. in diameter and weighing

1.2 mg. A similar process was utilized by Gerhard Ross (21).

Suspension Polymerization

One of the more recent methods of producing sustained

release spherical beads is the process of suspension poly-

merization (22-24). Because of the considerable importance
of suspension polymerization to industry, a great number of





7
publications can be found in patent literature. One method

employed in suspension polymerization is the mechanical

agitation of a mixture of epoxy compound, curing agent and

drug until it is polymerized to the form of droplets insoluble

in the continuous phase (25-26).

In their first article on epoxy resin beads, Khanna and

Speiser (26) prepared beads by first heating the continuous

phase and then either dissolved or suspended the drug in the

melted resin. This melt was then poured over the continuous

phase while stirring. After polymerization was complete, the

suspension was cooled and the beads were separated by filtra-

tion. Silicone oil was used for the continuous phase because

it was found to prevent agglomeration of the beads due to the

formation of a layer of polymethylsiloxane on the beads. The

beads were soluble in buffer pH 1.2 to 7.5 and were spheri-

cally shaped with a diameter of 0.5 to 1.0 mm. It was found

that longer polymerization time periods at higher temperatures

produced more uniform beads with no air bubbles incorporated

in the final product.

In a later report (27) Khanna used suspension polymeri-

zation of monomers as methylmethacrylate, vinylacetate and

divinylbenzene to produce spherical prolonged release dosage

forms. The continuous outer phase (water and suspension

stabilizer) was heated in a three-necked flask to the desired

reaction temperature. The monomer, either with or without

added medicament, was then added to the continuous phase which
was stirring at the desired speed. A catalyst was then added






8

and the whole system was placed under an inert nitrogen

atmosphere. When polymerization was complete the beads were

removed, washed and then dried,

Yu (28) prepared polystyrene beads by suspension poly-

merization of styrene in the presence of a surfactant, free

radical catalyst and calcium oxalate as stabilizer. The pH

of the suspension was 7.7. Thus, 18.9 g. of sodium oxalate

in 100 ml. of water was agitated at 600 r.p.m. and heated to

820 before treating with 11.5 g. of calcium chloride for

10 min. After the addition of 0.4 parts sodium beta-

naphthalene sulfonate anionic surfactant, the suspension was

treated with 1,250 g. of styrene, 2.5 g. of
azobisisobutyronitrile, 0.625 g. of benzoyl peroxide and

1.125 g. of tertiary butylbenzoate. The mixture was then

allowed to polymerize for 6 hr. at 80, 5 hr. at 870 and 3 hr.

at 950 before cooling. This mixture was then acidified to

pH 1.0 with dilute hydrochloric acid and the polystyrene

beads were then removed by filtration. More than 54% of

the particles so obtained were retained on a 20-mesh screen.

Slightly crosslinked smooth polymers of spherical shape

and of uniform size were obtained by Wolfen (29). These were

prepared by the aqueous suspension polymerization of a mixture

of divinylbenzene, a suspension stabilizer, a polymerization

initiator and a monomer. The reaction was held at a con-

stant temperature of 75 until the spherical pellets were

formed. The temperature was then increased to 1000 to termi-

nate the polymerization and to harden the spheres. The






9

suspension was then cooled and the products were separated by

filtration.

Wolf (30) prepared styrene-divinylbenzene copolymer

particles with a narrow particle size distribution using lig-

nin sulfonic acid as a dispersant. The reaction mixture

consisted of 0.5 g. of lignin sulfonic acid dissolved in

250 ml. of water which was then added to a mixture of

92 mole-% styrene, 8 mole-% divinylbenzene and 0.5 weight-%

catalyst. The mixture was then heated to 90* for 4 hr. to

give a product which had a particle range of 0.3 to 0.8 mm.


Characteristics


A. MONOMER SOLUBILITY slightly soluble, e.g., styrene,

acrylic and methacrylic esters, vinyl chloride

and vinyl acetate


B. AQUEOUS PHASE low concentration of suspension

stabilizers


C. INITIATOR soluble in monomer, e.g., benzoyl perox-

ide in styrene


D. LOCATION OF POLYMERIZATION INITIATION in monomer

droplets


E. POLYMER PRODUCT spheres suspended in the aqueous

phase








History


Suspension polymerization was first carried out in 1931
with acrylic esters. Bauer and Lauth (31) found that when

these easily polymerized monomers are suspended in an aqueous

medium or salt solution with the application of strong

mechanical agitation upon warming of the mixture with the

addition of benzoyl peroxide, pearls are formed and their

size is dependent upon the intensity of agitation.

The first commercial use of suspension polymerization

was the preparation of polyvinylchloroacetate (32). It was

polymerized in an aqueous salt solution in the presence of

a soap-like emulsifier. The products formed were clear

beads 0.5 to 1.0 mm. in diameter.

Difficulties encountered

There are many variables in suspension polymerization

which will affect the outcome of the final product. Too much

agitation will incorporate air bubbles and yield beads which

are deformed.

Studies have been completed by Hohenstein (33) about

the effect of air on the percent conversion of monomer in

suspension polymerization. It was found with styrene that,

by performing the polymerization in an air-free environment,

monomer conversion of almost 100% could be obtained.

During the process of suspension polymerization, there

is a tendency for the viscous adhesive pearls to agglomerate

leading to a high heat buildup and formation of large





11

polymer masses. This may be prevented by the addition of

certain additives to the aqueous phase. These additives are

classified under titles as suspending agents, granulating

agents or suspension stabilizers. Crawford (34) used water

soluble high polymers (protective colloids) as granulating

agents. These include gelatin, gum tragacanth, methylcellu-

lose, polymethacrylamide, polyvinylalcohol as well as salts

of the polymeric carboxylic acids, e.g., polyacrylic acid and

polymethacrylic acid. Rohm and Trommsdorff obtained similar

dispersing effects by the addition to the aqueous phase of

water insoluble, finely divided, inorganic substances such

as talc, barium sulfate, magnesium carbonate and aluminum

hydroxide.


Aqueous phase and suspending agents

The aqueous phase maintains the monomer in the form of

droplets and serves as a heat exchange medium. It is the

vehicle for the monomer and for the polymer.

The aqueous medium is usually modified by the addition

of various suspending agents. The more protective suspending

agents are classified as water soluble organic polymers (pro-

tective colloids) and inorganic compounds in the form of

water insoluble powders or precipitates. Surfactants may be

added in small concentrations.

The lower the interfacial tension, the more easily are

the monomer droplets deformed under the influence of the
moving water as judged by the intensity of agitation required






12

for forming the elongated droplets (35). On the other hand,

a high surface tension has the effect of greatly increasing

the stability of the large spherical drops. In this case,

upon collision with another drop a deformation of the

spherical drop can hardly occur. Instead, there is an

elastic reaction which leads to rebound. When the surface

tension is low, there is a comparatively low tendency to

maintain spherical form. Thus, low values of surface ten-

sion leads, with agitation, to breaking up the monomer into

very small droplets followed by the formation of an emulsion.

Among good suspending agents are found polymeric sub-

stances as starch, proteinaceous materials and polyvinyl-

alcohol, which are only very weak surfactants.

Pronounced surfactants, e.g., wetting agents and soaps

when used alone, generally give true emulsions which polymer-

ize to latex. However, when used in combination with other

agents, e.g., strongly dissociated inorganic salts which

raise the surface tension of the aqueous phase and thereby

compensate to some extent for the wetting action, they may

be helpful in reducing bead size.

It is easy to understand how the increase in viscosity,

in the aqueous phase, by dissolved organic polymers has a

stabilizing action in suspension polymerization. The mole-

cules of the aqueous layer which exist between two colliding

droplets are easily pushed aside. However, if the thin

layer of water contains dissolved polymer, as polyvinylalcohol

or protein, an increased viscosity and greater resistance to





13

droplet coalescence is possible. It is for this reason that

these polymers, serving as suspension stabilizers, be soluble

in water but completely insoluble in the monomeric phase.

In the case of inorganic materials, used in finely

powdered form, there is no change in the viscosity of the

aqueous phase. However, their action follows a similar

process. The powders, suspended in water, are wetted by the

aqueous phase. As two monomer droplets approach one another,

their union may be prevented by the powder particles which

are located between them. If the powder is not finely

divided, larger monomer droplets can slip through, thereby

leading to coalescence of the monomer.

The grain size of suspension produced polymers shows

quite a narrow range of cross section (36). Beads of fairly

uniform size are formed and, as the dispersing powder is

reduced in particle size, the bead size is generally reduced

also.

This mechanism also makes it clear as to why no powder

particles are lodged within the beads. Rather, after sus-

pension polymerization, the suspension stabilizer can be

easily washed away as a slurry or can be separated by other

means.

The shearing force in the agitated liquid elongates

the monomer droplets and eventually breaks them into smaller

droplets. However, the force of agitation also thrusts these

droplets into numerous violent collisions causing the coales-

cence of the individual droplets followed by the formation of






14

large monomer globules. The function of many of the stabili-

zers is to prevent the droplets from coalescing when they are

in contact.

Surfactants have had a great influence, along with

powders, as suspending agents. Their importance is due to

the decrease that they produce in surface tension. Very

small additions of surfactants produce fine dispersions of

the insoluble powder without changing the surface tension

of the aqueous phase to any great extent. If these surfac-

tants are only used in extremely small concentrations, they

are adsorbed almost completely upon the powder surface.

Essentially, they are present as diffusing wetting molecules

in the aqueous phase.

These suspension stabilizers must perform their action

throughout the whole course of the polymerization reaction.

During the induction period, there is little tendency for

the liquid monomer droplets to coalesce. The most critical

phase of the suspension polymerization is when the monomer

droplets become sticky and, because of their higher viscosity,

they can no longer be broken up readily by mechanical agita-

tion (33). It is at this point that suspension stabilizers

are necessary. As more polymer is formed, this sticky phase

disappears and the droplets harden into their final form.

When the polymer is insoluble in the monomer, as with vinyl

chloride, no coalescence is observed.

Occasionally, with water soluble polymeric suspending

agents, a small proportion of monomer dissolved in the water







is polymerized as an emulsion. This is highly undesirable

and may be prevented by dissolving inorganic salts in the

water* This reduces the solubility of the monomer in the

aqueous phase and increases the interfacial tension between

the phases. There are two types of substances that may be

incorporated in the aqueous phase. Water soluble inhibitors

as ammonium thiocyanate or copper salts may be employed (37).

However, the use of this method leads to contamination of the

bead products. It is best to use water soluble polymers, such

as the salts of acrylic acid polymers, as well as some of the

inorganic suspending agents as calcium phosphate or magnesium

carbonate. The latter are effective in extremely low concen-

trations (0.005%-based on aqueous phase water soluble polymer

as polyvinylalcohol and 0.0001% inorganic powder as trical-

cium phosphate).

Winslow and Matreyek of Bell Telephone Laboratories (38)

studied the effects of various grades of polyvinylalcohol

upon the suspension polymerization of divinylbenzene. They

found that an increase in the concentration of polyvinyl-

alcohol produced a decrease in the size of the granule. The

use of 80% hydrolyzed polyvinylacetate gave smaller beads

than polyvinylalcohol free of acetate groups. Higher viscos-

ity, partially saponified polyvinylacetate gave granules of

even smaller cross section. Lower viscosity grades of poly-

vinylalcohol in concentrations as low as 0.005% (based on

divinylbenzene) were found to hinder agglomeration of the

granules. The high viscosity grades, having a smaller number






16
of individual molecules present, showed less action in this

respect.

Numerous suspension stabilizers have been used in past

years with the results showing the following to be most

beneficial polymethacrylic acid, gelatin, citrus pectin,

apple pectin and polyvinylalcohol.

A partially saponified polyvinylacetate at 0.02%

concentration in the aqueous phase was used by Kaghan and

Shreve (36) for the suspension polymerization of styrene

with benzoyl peroxide as catalyst. The bead size was little

affected by pH which is in direct contrast to polymerization

usingcalcium phosphate as dispersant. The use of 80% to

86% polyvinylacetate gave favorable performance in the sus-

pension polymerization of vinyl chloride at 50 using lauroyl

peroxide as catalyst (39). The system composed of methanol,

water, methylcellulose and lauroyl peroxide gave a fine poly-

mer of vinyl chloride having good chemical stability. It

was found that with inorganic suspending agents the polymer

granule size decreased with the use of agents of smaller

particle size.


Monomeric phase

Suspension polymerization is used primarily for water

insoluble or water slightly soluble monomers. If the solu-

bility of monomers or products is too great, the addition of

electrolytes as the alkali salts of strong acids, which have

a salting out effect, may be used to facilitate suspension





17

polymerization with such compounds as acrylic acid, meth-

acrylic acid or acrylonitrile.

Some of the more important monomers in use today include

acrylic esters, methacrylic esters, styrene, vinylacetate,

vinyl chloride and vinylidene chloride.

Initially, plasticizers may be added to the monomeric

phase to facilitate uniform pearl formation.

Partially polymerized materials may be used in place of

the monomer in suspension polymerization. The use of a

solution of polymer in monomer is advantageous when the pre-

paration of larger sized pearls is desired. This prepoly-

merization to a syrup may reduce the time required for the

suspension polymerization of certain monomers. This method

has been used to a large extent in the preparation of poly-

vinylacetate beads.

The monomeric phase usually contains the dissolved

polymer initiator or catalyst. It is usually advantageous

to select especially active initiators which permit rapid

passage through the critical phase of suspension polymeriza-

tion. This phase may last up to 80% completion of polymeri-

zation. These active initiators are represented by such

compounds as tolyl peroxides and orthochlorobenzoyl peroxide.
The use of azo compounds as initiators has been consid-

ered for suspension polymerization. This group includes

azobisisobutyronitrile, o<, o'-azodicyclohexanecarbonitrile,

azobis-o(,Y -dimethylvaleronitrile and dimethyl-C (, '-
azodiisobutyrate. Some of these azo compounds tend to give






18

clustering or particle agglomeration. This may be prevented

by the addition of potassium or sodium hypophosphite to the

aqueous phase (40).

The use of calcium phosphate, as a suspending agent, has

been suggested along with the use of a water soluble initia-

tor (0.01% of a soluble persulfate) to obtain beads which are

essentially free of monomer (41).

Hill (42) obtained polyvinylchloride granules by using

potassium chlorate activated by a bisulfite as an initiator

in water.

For controlling the degree of polymerization, regulators

which are soluble in the monomeric phase may be added, e.g.,

aliphatic mercaptans (37).

Highly water soluble retarders, or regulators, may be

added to the suspension polymerization reaction mixture to

prevent any undesirable solution or emulsion polymerizations

from occurring as side reactions. Small amounts of copper

salts, methylene blue or phenols have been suggested for

this purpose.


Mechanism of action

Peroxides are commonly used as initiators in the manu-

facture of vinyl plastics which are formed by the polymeri-

zation of their respective monomers.

The two primary initiators used are benzoyl peroxide

and azobisisobutyronitrile. These initiators, upon decom-
position, form free radicals which, being extremely reactive,





19

can activate the double bond of the monomers, react with the

monomer, form another free radical and cause polymerization

to proceed until growth ceases by chain termination.

The basic mechanism of action can be divided into four

distinct phases#

(1) Free radical formation

(2) Polymerization initiation

(3) Polymerization propagation

(4) Polymerization termination.
Free radical formation is accomplished by the decom-

position of the initiators

(1) Benzoyl peroxide

(C6H5COO)2 --- 2C6H5COO- -2 CO2 --2 C6H5


(2) Azobisisobutyronitrile

(CH3)2-CH-N=N-CH-(CH3)2 -- 2(CH3)-(H'
CEN

Polymerization initiation then proceeds according tot

H
R" + CH2=CHX --I)R-CH2-"
X

Polymerization initiation is immediately followed by

polymerization propagation or growth of the polymer chains

R-CH *
2-9* + CH2=CHX--)- R-(CH2-CHX)n-CH2-9
X X

In order for the reaction to stop it must be terminated
by the use of a coupling or disproportionation process.





20
Styrene polymerization is usually terminated by coupling in

which the following is observed


R-(CH2-CHX)n-CH2-q9 + 'Q-CH2-(CHX-CH2)-R ---
x x

R-(CH2-CHX) n-CH ---CH2- (CHX-CH )n-R
XX

Disproportionation is exhibited in the termination of the

polymerization of methylmethacrylate and may be represented bys


R-(CH2-CHX)n-CH2-9 + *C-CH2-(CHX-CH2)n-R -
X x

R-(CH2-CHX)n-CH2-CH2-X + CHX=CH-(CHX-CH2)n-R


Polymerization conditions


The ratio of continuous phase to dispersed monomeric
phase usually ranges from 2:1 to 41s by volume. In laboratory

experimentation, where much heat must be removed in a short

time, ratios up to 81s may be used (produces rapid polymeri-

zations as with divinylbenzene).

Vigorous stirring results in finer granules. The use

of highly effective suspending agents produces very fine

granules even with low rates of mechanical agitation.

Granule size may also be reduced by using a higher

temperature and a higher catalyst concentration.

To obtain well-formed spherical beads, polymerization

must be carried out at temperatures below the boiling point

of water and of the monomer.





21

Several methods and formulae have been devised for the

preparation of beads using suspension polymerization.

Hiltner (43) suggests the following recipes


Aqueous phase Monomeric phase

Water 4700.0 Methylmethacrylate 1400.0
Sod. Lauryl Sulfate 1.0 Stearic Acid 15.0
Sod. Polyacrylate 12.5 Benzoyl peroxide 7.5
Sod. Sulfate 38.0


Using styrene, particle sizes of 0.5 to 5.0 mm. diameter

may be obtained (44).

Stearic acid is employed as a plasticizer. After pearl

polymerization, the beads must be separated from the aqueous

phase by the use of a filter.

The purity of the polymer depends, to some extent, upon

the nature of the suspending agent used. An insoluble

inorganic agent such as barium sulfate, is removed by

washing. In some cases, flotation can facilitate separation

of insoluble suspending agents. Aluminum hydroxide, magnesium

carbonate, zinc oxide and other acid soluble agents may be

removed by acidification of the slurry with sulfuric acid.

The resulting soluble salts may then easily be washed away

with water.

Turnbull (45) recommends the use of a thin coat of

resin, such as some grades of polyvinylacetate, for use on

polymer beads which have a tendency to stick together during

storage.







Expandable polystyrene beads


In order to manufacture polystyrene beads which possess
a cellular structure it is necessary to incorporate a blow-

ing agent into the preformed polymeric bead or to polymerize

the styrene in the presence of a blowing agent. After

incorporation of the blowing agent the beads are heated for

several minutes either in boiling water or hot air to soften

the plastic matrix and to volatilize the blowing agent.

Several patents (46-50) describe these processes in detail.

Roth (51) prepared a styrene polymer which contained

8% pentane by suspension polymerization in the presence of

pentane and polyvinylalcohol. These beads were cooled to

-40 F for 24 hr. and then foamed by heating for 5 min. in

boiling water.

The use of low boiling nonsolvent paraffins which may be

boiled off to produce a porous structure was demonstrated

by Cleland (52).

Mueller-Tamm (53) also prepared suspension polymerized

beads in the presence of 4 parts of pentane for each 35

parts' styrene. The average diameter of the beads produced

was 0.6 mm.

The crystalline structure of expanded polystyrene beads

has been studied by Giuffria (54). It was demonstrated that

there was considerable variation in cell size from bead to

bead and the amount of expansion among the various.beads was

not constant. After sectioning several beads with a microtome

it was obvious that the cells at the bead surface were smaller






23
than those in the center. The absence of a discrete cell

wall was also very apparent.


Evaluation and Control

Dissolution methods and kinetics


According to Wiegand and Taylor (55), sustained release

products of the leaching and ion exchange type release their

drug in accordance with

-kt
ar = aofl + aofs(-e-kt Eq. 1


where a is the amount of drug released at any time t, f is

the fraction of the dose released immediately and f is the
s
fraction released experimentally. It is further stated that

this equation should approximate the process of release from

an inert matrix and ion exchange mechanism which are both

first order processes* fl should be sufficiently large to

produce a rapid effect if the drug is administered occasional-

ly. However, if it is designed for repeated administration,

fl should be as close to zero as possible since the drug level

is not starting from zero after the first administration.

Higuchi (56) related the rate of drug release, from

sustained action solid matrices, to physical constants based

on simple laws of diffusion. He obtained the following

mathematical relation for the case where the drug particles

are incorporated into a granular matrix which is inert,

insoluble, remains intact and from which release is by a

leaching action of the penetrating solvent









Q = (2A- Cs)Cst Eq. 2


In Eq. 2, Q is the amount of drug released after time t, per
unit exposed area, is the tortuosity factor, A is the total

amount of drug in the permeating fluid and E is the porosity

of the matrix. This equation predicts a linear relationship

if the amount of drug released per unit area is plotted against

the square root of time.

Higuchi (57) also states that drug release from inert

plastic matrices initially saturated with a drug solution of
concentration C may follows
o


0 =2 C i Eq. 3


Desai (58) has extended Eq. 2 to take into account the
hydrodynamic flow of the solvent in the pores of the matrix.

This was necessary to adequately explain the behavior of

moderately soluble solutes.

Goyan (59) describes the dissolution of small spherical

particles by the equations

G = + SD) (Cs-C) Eq. 4

where G is the dissolution rate per unit area, D is the
solute molecule diffusion coefficient, S is the mean rate of

fresh surface production, A is the particle radius, Cs is the

solubility coefficient and C is the solute concentration.





25
In studying the release of a drug from a silicone polymer,
Roseman (60) presented two different geometric cases in which

the rate-limiting step was the diffusion of the drug from

the matrix (matrix controlled release). The first case was

that of a planar surface where the amount of drug released

from the matrix per unit time per unit area may be expressed

bys
D
d = -G = e (C -C') Eq. 5
dt 1 s


in which De is the effective diffusion coefficient, 1 is the

diffusional distance and CL is the concentration in the

matrix at the surface. In the cylindrical case it was found

that

9 = -2 hD a- Eq. 6
dt e da


where h is the height of the cylinder and a is the radius of

the area under consideration.

A pharmacokinetic model, involving first order processes

for drug release, absorption and elimination for sustained

release preparations has been described by Kruger-Thiemer and

Eriksen (61). Also published (62-63) were several review

articles describing drug release from fatty matrices and its

influence on the rectal absorption of drugs.

In a series of articles, Garrett and Chemburkar (64-66)

evaluated the effect of temperature, pH and solvent on the

diffusion of drugs through silastic membranes.

Equations for the kinetics of sustained release tablets





26

were developed by Bonciocat (67). These equations consisted

mainly in simplification of Higuchi's equation for the case

where a solid drug is incorporated into a solid matrix.

Further discussion on dissolution rates and rate laws

as well as numerous dissolution rate equations are presented

by Higuchi (57), Desai (68) and Schwartz (69).

In vitro evaluation methods

There does not exist a single in vitro test which will

accurately reflect the availability of a drug from a sustained

release dosage form. The primary use of in vitro testing is

to show that there exists or does not exist uniformity from

batch to batch. The values obtained from these tests are

meaningless beyond this unless it is possible to correlate

them with bioavailability in the human.

Numerous types of dissolution apparatus exist. Baun (70)

classifies these various types in essentially the following

manners

(A) USP XVIII Dissolution Test and Modifications

of the Tablet Disintegration Test

(B) NF XII Tablet Disintegration Apparatus

(C) NF XIII Dissolution Apparatus

(D) USFDA Apparatus (Wiley Apparatus)
The USP dissolution apparatus (71) provides a satisfac-

tory means for the determination of the dissolution charac-

teristics of a solid dosage form. This apparatus consists of
four main sections a suitable water bath used to maintain





27
the temperature at 37 0.50 a 1000-ml. covered glass vessel;

a variable speed motor which is inserted in the center of the

vessel and is capable of obtaining speeds between 25 and 150

r.p.m.; and a 40-mesh woven wire cloth basket in which the

dosage form under investigation is placed.

Several workers (72-79), prior to the development of the

USP XVIII dissolution test, utilized the USP XVII tablet

disintegration apparatus with some modifications for drug

dissolution studies. The main modification was the replace-

ment of the 10-mesh screen with a 40-mesh screen so that more

tablet particles would be retained.

The apparatus employed by the NF XII (80) is essentially

based on the rotating bottle method of Souder and Ellenbogen

(81) in which the samples to be tested are placed in containers

with the dissolution medium and then sealed. The bottles

are then rotated at a fixed rate, end over end, in a water

bath maintained at 37 0.5. Sample size may vary from 60-

100 ml. and rotation rates may range from 28-32 rotations per

minute. Goldman (82) noted that in the rotating bottle method

30 r.p.m. will usually give a maximum amount released.

The NF XIII dissolution apparatus (83) consists of a

1000-ml. resin flask in which is inserted a 40-mesh stainless

steel basket. The basket is in the form of a cylinder 3.6 cm.

in height and 2.5 cm. in diameter and is attached to a high

torque stirring motor by means of a stainless steel rod.

The beaker apparatus described by Levy and Hayes (84)
consists of a 400-ml. beaker into which the dissolution





28
medium is placed. The contents are agitated by a stirrer

which is coated with polyethylene. Stirring rates between

30 and 60 r.p.m. have been used.

The Buchner funnel apparatus was developed by Nash and

Marcus (85) for screening various formulations of sustained

action medications. In this procedure, the dissolution

medium, containing the sustained release dosage form,is added

to a Buchner funnel which is fitted with a fritted disk.

The contents are stirred and at various time intervals samples

are suctioned into the flask and then analyzed.

The development of an apparatus for testing sustained

release preparations by the FDA was accomplished by Wiley and

has been reviewed by Meyers (86). A modification of Wiley's

apparatus was used by Baun (70). Wiley's apparatus allows

the establishment of a close relationship with in vivo

conditions providing the drug concentration does not exceed

10% to 20% of solubility in the dissolution medium. In

Wiley's procedure, the dosage formulation was first eluted

with 100 ml. of Simulated Gastric Fluid USP for 1 hr. Each

hour thereafter, up to 8 hr. 50 ml. of the circulating fluid

was withdrawn and replaced with a modified simulated intes-

tinal medium adjusted to pH 7.9. The amount of drug eluted

each hour and the residue at the end of the dissolution period

was determined by assay of the aliquot removed (85).

Several other methods have been used in dissolution

studies.. One method developed by Marlowe and Shangraw (87)

and by Patel and Foss (88) uses an apparatus which consists of





29

a plastic cell which is divided into two compartments by a

semipermeable membrane. Samples to be tested are placed in

one chamber and dissolution medium is placed in both chambers.

The cell is then placed in a water bath at 37 0.5 and

rotated at 15 r.p.m. At periodic time intervals, samples are

withdrawn and analyzed.

In sustained release preparations, if the digestive media

are allowed to become saturated, diffusion will yield a low

rate of drug release.

One aspect common to almost all of the dissolution tests

reviewed. is some form of mechanical agitation. At the

moment of release of medicament from a dosage form, on the

outer surface of the pellet there is a region of high concen-

tration, the thickness of which is determined by how fast the

external medium sweeps it away. This now alters the concen-

tration gradient which spontaneous diffusion must work against.

It can be seen how the speed of rotation or flow of dissolution

medium is directly involved with the rate of dissolution.

Therefore, it is best that a series of determinations are

employed by utilizing increasing agitation rates until a

maximum rate of release is observed.













EXPERIMENTAL PROCEDURE


Materials and Chemicals


All materials, chemicals and drugs, used in this inves-

tigation were of a quality or purity in accordance with

their intended purposes. Reagent grade chemicals were used

for the assay procedures and monomers of high purity were

utilized in the suspension polymerization processes. Table I

provides a list of the name, manufacturer, and grade or

control numbers of the chemicals used in this investigation.


Equipment

Suspension polymerization apparatus

Principle of operation.--The ingredients for each formu-

lation were combined in a 1-1. three-necked round bottom

flask equipped with a variable speed motor, reflux condenser

and nitrogen inlet. The contents of the flask were then

brought to proper polymerization temperature by immersion into

a thermostatically regulated water bath. Nitrogen, continu-

ously supplied to the reaction vessel, was used to overcome

the inhibiting effect of oxygen upon the polymerization

reaction. Bead size was controlled by careful regulation of

the rate of agitation and by varying the concentration of

suspension stabilizers added to the aqueous phase. After

30






31

TABLE I


MATERIALS AND CHEMICALS USED


Manufacturer


Acetaminophen

Benzene

Benzoyl peroxide

Calcium phosphate

Carboxymethylcellulose,
sodium salt

Chloroform

Divinylbenzene

Ethylvinylbenzenea

Hydrochloric acid

Methanol

Methylmethacrylate

Pancreatin

Pentane

Pepsin

Polyvinylalcohol

Potassium phosphate,
monobasic

Sodium hydroxide

Sodium phosphate,
dibasic

Sodium polyacrylateb

Sodium sulfate

Styrene


Ruger

Mallinckrodt

MCB

Fisher


MCB

J.T. Baker

MCB

Foster Grant

Allied Chemical

MCB

MCB

MCB

Curtin

Fisher

MCB


Fisher

Mallinckrodt


MCB

Rohm and Haas

MCB

MCB


Grade or


Name


aMarketed as Evisol@
bMarketed as Acrysol@


_ _


Grade or
Control Number

L-03922

Analytical Reagent

BX-469

C-122


CX-441

715195

DX-2403

L-582

Reagent

Anhydrous Reagent

MX-1150

NF Powder

36375

NF Powder

99% Hydrolyzed


705674

Analytical Reagent


Reagent

44189-5

Anhydrous, granular

SX-1030






32
polymerization was complete, the beads were filtered, washed

with water and dried overnight in an oven. The assembled

apparatus is illustrated in Figure 1.

Flasks.--Three-necked round bottom glass distilling

flasks of 1-1. capacity were used to contain the formulations

during the suspension polymerization processes.

Water bath.--The water bath for polymerization reactions

was a "Magni Whirl" Blue M equipped with a memory ring for

accurate temperature control. It had a 5 gal, capacity and

was capable of maintaining temperature within 0.5 of the

desired temperature. A layer of mineral oil, approximately

1 cm. thick was placed over the top of the bath to reduce

evaporation of the water.

Motor.--A Fisher Stedi-Speed stirrer was utilized to

maintain the dispersion of the monomer-drug mixture in the

continuous aqueous phase. It was capable of regulating the

speed within 5% of that indicated on the speed control. For

agitation of the reaction mixture, a folding type impeller

(two blade) attached to a 16-in. stainless steel shaft was

used. To enable polymerization to occur in an inert atmo-

sphere, a 2-in. polytetrafluoroethylene bushing was designed

and manufactured by the J. Hillis Miller Health Center

Instrument Shop. This sleeve allowed rotation of the stain-

less steel shaft and yet provided isolation of the contents

from external oxygen.

Nitrogen inlet.--After initial purging of air, nitrogen

was allowed to slowly flow throughout the system during the






























F~3~.:;:;
^~ *'
~;















C'
I
i;
*";'
i : ;.I~~'
i ;.. ;ii:





--
;


'I.


33





















W.K













:i





































um
















i..ULUE -









Figure 1



SUSPENSION POLYMERIZATION APPARATUS







entire polymerization process. The relative rate of flow was

observed by bubbling the nitrogen stream through heavy mineral

oil.


Filter


When polymerization was complete, beads were collected

in a Buchner funnel which was connected to a filter flask.

The beads were washed with several 100-ml. portions of

distilled water.


Oven


A Thelco, model 14, convection type oven was used to dry

all bead formulations at 70%.


Balances


Balances of suitable sensitivity and capacity were

employed in all weighing operations. These are listed below

Mettler Top Loading Balance, model P1200
Capacity 1200 g.

Mettler Analytical Balance, type B-5
Capacity 200 g.


pH meter


The pH of the dissolution medium was determined on a

Corning expanded scale pH meter, model 12.


Microscope


Optical examination of the pellets was conducted with a





35

Bausch and Lomb microscope fitted with a movable stage and a

Bausch and Lomb dissecting scope.


Sieves


To perform particle size analysis on the suspension

polymerized beads, a W. S. Tyler Ro-Tap testing sieve shaker,

model 1525, and Tyler testing sieve screens were used. All

bead formulations were subjected to 1 min. of mechanical

agitation on the sieve shaker. Previous testing indicated

that shaking for longer periods of time did not produce a

significant change in the size distribution.

Tablet press


All tablet formulations were compressed on a Carver

laboratory press, model C, using a suitable test cylinder.


Dissolution apparatus

Dissolution was conducted in order to show relative rates

of release of medicament between the various samples of each

monomer. Due to time limitations, no attempt was made to

relate these rates to those which may be obtained in vivo.

A modification of the rotating bottle apparatus described by

Souder and Ellenbogen (81) was selected for dissolution test-

ing. The apparatus consisted, basically, of 16 spring clamps

mounted on a stainless steel shaft. The shaft was attached

to a variable speed motor which was used to rotate samples

in the spring clamps. Dissolution was conducted in a water






36

bath maintained at 370 employing 90-ml. glass screw cap vials.

Temperature was regulated by a Haake, model ED, constant

temperature circulator. The assembled apparatus is illus-

trated in Figure 2.

Spectrophotometer


Spectrophotometric analysis of all extraction media was

conducted on a Beckman, model DB-GT, grating spectrophotometer.


Production Procedures


Formulations


Initial polymerizations with styrene as the only monomer

were conducted in the presence of 0.4 g. of calcium phosphate

and 0.1 g. of polyvinylalcohol. Polymerization of styrene-

divinylbenzene-ethylvinylbenzene terpolymer was conducted in

the presence of 2.4 g. of sodium carboxymethylcellulose.

These compounds were incorporated into the polymerization

reactions to decrease the incidence of agglomeration. Three

monomers, styrene, divinylbenzene and ethylvinylbenzene were

chosen to form the various plastic matrices for use in initial

testing. Three different speeds of rotation to obtain dis-

persion of the monomer in the aqueous continuous phase were

used 400 r.p.m., 450 r.p.m. and 500 r.p.m. Two dispersion

stabilizers, sodium sulfate and sodium polyacrylate,were also

used. These dispersion stabilizers minimized solubility of

the acetaminophen in the aqueous phase and prevented coales-

cence of the partially polymerized droplets. All nonexpanded










UL


~1


qr
Ii


-:, ., :: .. ..: .. .., -






38

bead formulations were manufactured in the presence of 600 ml.

of water, 100 g. of styrene monomer, 1 g. of benzoyl peroxide,

0.4 g. of calcium phosphate and 0.1 g. of polyvinylalcohol.

In addition to these compounds, the following ingredients

were used sodium sulfate in concentrations of 0.5%, 1.0%,

and 1.5% by weight, and sodium polyacrylate in concentrations

of 0.05%, 0.10%, and 0.15% by weight. Table II lists the

various formulations of nonexpanded beads. This design of

experimental variables provided 27 samples for initial product

development. After evaluation of each of the 27 samples it

was decided to use the formulation which produced the smallest

size distribution and yielded particles with a mean diameter

of approximately 0.3 mm. to manufacture the expanded beads.

This formulation was produced using 0.5% sodium sulfate, 0.15%

sodium polyacrylate and an agitation rate of 450 r.p.m. and

is represented by the code MIN4SIP3.


Preparation of expandable beads

The first step in the manufacture of expandable beads is

the formation, by suspension polymerization, of the appropriate

size beads. To produce these beads, 600 ml. of water was added

to a 1000-ml. three-necked round bottom flask which was then

placed into a water bath maintained at 840. A water cooled

condenser was inserted into one of the side necks and a

stainless steel shaft with a two-blade folding impeller was

inserted into the other neck. While stirring, 15 ml. of a

6.0% solution of sodium polyacrylate, 0.4 g. of calcium





.39

TABLE II


FORMULATIONS OF

Sample d a Speed
Number Code r.p.m.

1 M1N3S1P1 400

2 M1N3S1P2 400
3 M1N3S1P3 400

4 MIN3S2P1 400

5 M1N3S2P2 400

6 M1N3S2P3 400

7 M1N3S3P1 400

8 M N3S3P2 400

9 MIN3S3P3 400

10 M1N4S1P1 450

11 M1N4S1P2 450

12 M1N4S1P3 450

13 MIN4S2P1 450

14 MIN4S2P2 450

15 M N4S2P3 450

16 M1N4S3P1 450

17 MIN4S3P2 450

18 MN4SP3 450

19 MIN5S1P1 500

20 M1N5S1P2 500

21 M N5S1P3 500

22 M1N5S2P1 500

23 M N5S2P2 500


NONEXPANDED POLYSTYRENE

Sodium Sulfate Sodium
grams
3.0

3.0

3.0

6.0

6.0

6.0

9.0

9.0

9.0

3.0

3.0

3.0

6.0

6.0

6.0

9.0

9.0

9.0

3.0

3.0

3.0

6.0

6.0


BEADS

Polyacrylate
grams

0.3

0.6

0.9

0.3

0.6

0.9

0.3

0.6

0.9

0.3

0.6

0.9

0.3

0.6

0.9

0.3

0.6

0.9

0.3

0.6

0.9

0.3

0.6






40

TABLE II Continued


Sample Speed Sodium Sulfate


Sample Codea
Number

24 M N5S2P

25 MIN5S3P

26 M N5S3P

27 MIN5S3P


3

1

2

3


Speed Sodium Sulfate
r.p.m. grams

500 6.0

500 9.0

500 9.0

500 9.0


Sodium Polyacrylate
_grams

0.9

0.3

0.6

0.9


a1 denotes type of monomer, N refers to speed of agitation,
S represents concentration of sodium sulfate and P the
concentration of sodium polyacrylate.


II I





41

phosphate, 0.1 g. of polyvinylalcohol and 3.0 g. of sodium

sulfate were added to the flask through the center neck and

the flask was flushed with nitrogen. While the contents of

the flask were being dispersed and solution effected, 100 g.

of styrene was washed with two 50-ml. portions of 1 N sodium

hydroxide and then two 50-ml. portions of distilled water.

Benzoyl peroxide, 1.0 g., was mixed with the styrene monomer

and this mixture was then added through the center neck of

the flask. The polymerization was allowed to continue for

24 hr. at 450 r.p.m. to produce the desired size polystyrene

beads. Following polymerization, the beads were filtered,

washed with several 100-ml. portions of water and then allowed

to dry overnight at 70 in a convection type oven. The

dry beads were then sized on a set of sieves using a Ro-Tap

mechanical shaker and 6 different mesh screens. Four 40 g.

samples of the beads retained on the 30-mesh screen were then

placed in 500-ml. erlenmeyer flasks, containing n-pentane,

and stirred. After 12 hr. one sample was removed from the

n-pentane and at the end of 24 hr. the remaining three samples

were removed. The purpose of these treatments was to produce

beads of varying porosity. These beads were slowly added,

with rapid stirring, to 1000-ml. beakers containing boiling

water. The beads were allowed to remain in the boiling water

for 5 min. and were then cooled, filtered and allowed to

dry at 70. When completely dry, the expanded beads were

placed in 1000-ml. erlenmeyer flasks containing concentrated

alcoholic solutions of acetaminophen (1 g. of acetaminophen






42

per 10 ml. alcohol). These mixtures were then stirred for

24 hr. after which time the contents were filtered and allowed

to dry. Formulations I, II and III are represented by those

beads which were exposed to n-pentane for 24 hr. Formulation

IV is represented by the sample of beads removed at the end

of 12 hr.


Preparation of tablets from expanded beads


Preliminary investigations showed that nonexpanded poly-

styrene beads alone could not be compressed into tablets

utilizing compression pressures up to 20,000 p.s.i. However,

the expanded beads were compressible.

Several samples of the dried expanded polystyrene beads,

containing acetaminophen, were accurately weighed. Accurately

weighed portions of potassium chloride were then added in

specific proportions so that a mixture weighing exactly 0.5000

g. would be obtained. Potassium chloride was added to

demonstrate the effect of a channeling agent upon dissolution

of acetaminophen from the compressed tablet. These mixtures

were then compressed at each of two different pressures

(3000 p.s.i. and 6000 p.s.i.) using a Carver laboratory press

and test cylinder. The finished tablets were found to weigh

0.5000 0.005 g. Tablets were made to contain 0%, 20% or

40% potassium chloride with the remainder of the tablet

consisting only of expanded polystyrene beads containing

acetaminophen. No binders or lubricants were used.






43

Test Methods


Particle size classification


Particle size classification of the bead formulations

was performed on a Ro-Tap mechanical sifter so that beads of

the desired size could be obtained for further study. Each

bead formulation was subjected to 1 min. of mechanical agi-

tation in a series of sieves varying in size from 8-50-mesh.

Those beads which were retained on a 30-mesh screen were

separated and retained.


Assay procedure


A spectrophotometric assay using a Beckman, model DB-GT,

grating spectrophotometer was used to determine acetaminophen

content of the various formulations.

A standard curve was constructed using five different

concentrations of acetaminophen in absolute methanol.

Absorbances of these solutions were determined at 250 mp. A

plot of concentration versus absorbance was made to establish

a linear relationship which agreed with Beer's Law.

To assay for the amount of drug in each bead formulation

and to determine the amount of drug remaining in the formu-

lations after dissolution, the following procedure was used

the beads were ground using a wedgewood mortar and pestle to

a fine (50-mesh) powder and accurately weighed portions were

placed into 100-ml. volumetric flasks which contained 1.0 ml.

of 0.1 N hydrochloric acid and made to volume with absolute






44
methanol. The absorbances of these solutions were then

determined using a blank which consisted of 1.0 ml. of 0.1

N hydrochloric acid in enough absolute methanol to make 100 ml.


Visual characteristics


All suspension polymerized bead formulations were examined

macroscopically and microscopically for color, external pore

openings and entrapped air bubbles.


Density determinations


Bulk density of the various bead formulations was

determined by placing a known quantity of the suspension

polymerized beads into a 100-ml. cylindrical graduate. The

graduate was then dropped five times from a height of 2 in.

onto a desk top. The bulk density was then calculated by

dividing the weight of beads added to the graduate by the

volume occupied by the beads after tamping.

True density of the bead formulations was determined

using a pycnometer by adding a known weight of the powdered

plastic beads to the pycnometer and then filling it with

95% ethanol. The amount of alcohol displaced by the powdered

beads could then be calculated by weighing the pycnometer

before and after the addition of the powdered beads.

Subsequent calculations provided the true density.


Porosity


The percent porosity for each bead formulation was





45
calculated from the following equations


% 1 100 Eq. 7


where C is the porosity, PB is the bulk density and T is

the true density (89).

Dissolution studies

Approximately 2-g. samples of beads accurately weighed,
containing drug, and accurately weighed samples of tablets

compressed from the expanded beads were placed in 90-ml. glass

screw cap vials to which was added 60 ml. of prewarmed Simu-

lated Gastric Fluid USP. The glass vials were then clamped

in place and allowed to rotate, end over end, at 40 r.p.m.,
in a water bath maintained at 370. Samples were removed at
0.25 hr., 0.50 hr., 1.50 hr., 2.33 hr., 4.50 hr., 7.00 hr.,

12.00 hr. and 24 hr. At the end of the 1.5 hr. dissolution

period the remaining vials were also removed and the gastric

fluid was removed by filtration and replaced with prewarmed

Simulated Intestinal Fluid USP. These samples were then

returned to the dissolution apparatus and removed at the

appropriate time. After each of the samples was removed from
the dissolution apparatus it was filtered, washed with a
small quantity of water and then dried at 700.














EXPERIMENTAL DATA


The experimental results are presented in tabular and

graphical form. Graphs are placed immediately after the data

to which they correspond. Those results which were not able

to be placed in tabular form are reviewed in the Discussion

of Results section.

For the purpose of designating individual samples the

following system of nomenclature is used for the nonexpanded

polystyrene beads:

Speed of Sodium Polyacrylate Sodium Sulfate
Aqitation Concentration Concentration

N3 = 400 r.p.m. P1 = 0.05% S = 0.50%

N4 = 450 r.p.m. P2 = 0.10% S2 = 1.00%

N5 = 500 r.p.m. P3 = 0.15% S3 = 1.50%

Acetaminophen content of nonexpanded polystyrene beads

(Table III) was determined by assaying 2 samples of each of

the 27 different formulations. The percent acetaminophen

listed is the average of the 2 samples.

Acetaminophen content of the expanded polystyrene beads

(Table XIV) was determined by assaying 4 samples of each of

the different formulations and then calculating the average

percent acetaminophen in these 4 samples.

As previously explained, Formulations I, II and III of

the expanded beads differ only from Formulation IV of the

46






47

expanded beads by the length of time each formulation was

exposed to n-pentane. Formulations I, II and III were exposed

for 24 hr. and Formulation IV was exposed for 12 hr.






48

TABLE III


ACETAMINOPHEN CONTENT OF NONEXPANDED POLYSTYRENE BEADS


Sample
Summer Absorbance
Number


1-A

1-B


2-A

2-B


3-A

3-B


4-A

4-B


5-A

5-B


6-A

6-B


7-A

7-B


8-A

8-B


9-A

9-B


0.33

0,49


0.30

0.58


0.27

0.54


0.19

0.38


0.19

0.36


0.20

0.39


0.23

0.45


0.23

0.45


0.20

0.40


Concentration
moles/liter
xl105

2.25

3.50


2.15

4.20


1.90

3.90


1.35

2.72


Average
Percent
Acetaminophen


1.72




1.58




1.44




1.01


1.35

2.60


1.40

2.80


1.65

3.25


1.65

3.25


1.40

2.90


0.98


1.05


1.23


1.23


1.06






49

TABLE III Continued


Sample
ample Absorbance
Number


10-A

10-B


11-A

11-B


12-A

12-B


13-A

13-B


14-A

14-B


15-A

15-B


16-A

16-B


17-A

17-B


18-A

18-B


0.30

0.49


0.27

0.54


0.21

0.43


0,34

0.68


0.22

0.45


0.31

0.62


0.18

0.37


0.25

0.51


0.21

0.42


Concentration
moles/liter
xl0-5

2.20

3.50


2.00

3.90


1.50

3.10


2.50

4.80


1.60

3.20


2.20

4.50


1.30

2.70


1.75

3.70


1.50

3.00


Average
Percent
Acetaminophen


1.48




1.48




1.15




1.83


1.20


1.68


1.01


1.35


1.13






50

TABLE III Continued


Absorbance


Sample
Number

19-A

19-B


0.27

0.55


0.23

0.47


0.27

0.55


0.15

0.31


0.22

0.46


0.25

0.50


0.29

0.58


0.20

0.40


0.25

0.51


20-A

20-B


21-A

21-B


22-A

22-B


23-A

23-B


24-A

24-B


25-A

25-B


26-A

26-B


27-A

27-B


Average
Percent
Acetaminophen


1.58


1.04


1.34


Concentration
moles/1 ter
x10"-

1.90

3.95


1.65

3.40


1.90

3.95


1.10

2.20


1.60

3.30


1.75

3.55


2.10

4.20


1.35

2.90


1.80

3.70


- ----


1.46




0.81




1.22




1.33


- -


1.45




1.26


- I -- --






51

TABLE IV


BULK DENSITY, TRUE DENSITY AND PERCENT POROSITY
OF NONEXPANDED POLYSTYRENE BEADS


Sample
Number

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22


Bulk
Density

0.873

0.918

0.924

0.921

0.964

0.974

0.939

0.947

0.960

0.871

0.862

0.863

0.857

0.912

0.891

0.905

0.950

0.859

0.819

0.841

0.881

0.825


---~


True
Density

1.166

1.049

1.048

1.109

1.086

1.086

1.099

1.094

1.085

1.020

1.000

1.010

0.980

1.000

1.010

1.040

1.000

0.988

1.046

0.955

0.992

1.006


Percent
Porosity

25.2

12.5

12.0

17.0

11.3

10.4

14.6

13.5

11.5

14.6

13.8

14.5

13.2

8.8

12.1

12.8

5.2

13.1

21.7

12.0

11.2

18.0





52

TABLE IV Continued


Sii le Percenti


Percent
Porosity

16.9

12,0

10.9

11.9

12.4


Sample
Number

23

24

25

26

27


Bulk
Density

0.818

0.867

0.889

0.885

0.895


True
Density

0.984

0.985

0.998

1.004

1.022


_ __ _~_~


-











1.8-




to





CQ )
0.6 2-



0.2-
I I I I I I I
/ 3 5 7 9 /I 13
CONCENTRA TION
MOLES/L ITER
Figure 3
Figure 3


STANDARD CURVE FOR ACETAMINOPHEN








TABLE V


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 400 R.P.M. IN THE
PRESENCE OF 0.5% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/1 ter Percent
Hours x10- Extracted


M1N3S 1P


0.5


1.5


2.3


0.435

0.660


0.455

0.710


0.465

0.722


0.620

0.930


0.545

0.840


0.500


4.5


7.0


24.0


3.38

5.09


3.47

5.45


3.55

5.57


4.78

7.18


4.15

6.43


3.82


53.9


54.9


57.7


58.0


59.0


0.840 6.43


59.0








TABLE V Continued


Time Concentration Cumulative
Removed Absorbance moles/i ter Percent
Hours x10" Extracted


M1N3SP 2


0.5


1.5


2.3


0.395

0.628


0.375

0.552


0.502

0.791


0.500

0.788


0.450

0.702


0.228


4.5


7.0


24.0


3.02

4.80


2.85

4.27


3.83

6.05


3.82

6.02


3.45

5.37


1.71


50.8


53.5


56.3


59.0


59.2


0.545 4.15


59.0








TABLE V Continued


Time Concentration Cumulative
Removed Absorbance moles/lIter Percent
Hours xl10- Extracted


MIN3S1P3


0.5


1.5


2.3


0.465

0.690


0.421

0.635


0.488

0.762


0.468

0.700


0.465

0.694


0.412


4.5


7.0


24.0


3.56

5.31


3.24

4.85


3.75

5.83


3.57

5.35


3.55

5.34


3.15


55.9


57.5


59.6


61.2


62.0


0.640 4.90


61.9











Q
S -80




Qj


Lt 40-



20



/ 2 3 4 5 6
TIME HR.
Figure 4
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
400 R.P.M. IN THE PRESENCE OF 0.5% SODIUM SULFATE

M1N3S1P1
O) M1N3SP2








TABLE VI


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 400 R.P.M. IN THE
PRESENCE OF 1.0% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10-5 Extracted


M1N3S2P1


0.5


1.5


2.3


0.324

0.520


0.273

0.453


0.315

0.470


0.243

0.400


0.315

0.471


0.315


4.5


7.0


2.48

4.00


2.08

3.47


2.39

3.60


1.87

3.05


2.39

3.61


2.39


58.1


60.1


60.3


60.5


60.6


0.471 3.61


24.0


60.6







TABLE VI Continued


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10-5 Extracted


M N3S2P2


0.5


1.5


2.3


0.231

0.380


0.269

0.409


0.298

0.445


0.285

0.430


0.269

0.403


0.382

0.400


4.5


7.0


24.0


1.76

2.90


2.05

3.12


2.27

3.40


2.20

3.30


2.06

3.08


2.92

3.05


49.4


52.6


53.8


54.7


54.8


54.5





60

TABLE VI Continued


Time Concentration Cumulative
Removed Absorbance moles/l ter Percent
Hours x10" Extracted


M N3S2P3


0.5


1.5


2.3


0.276

0.413


0.229

0.375


0.186

0.315


0.289

0.470


0.322

0.483

0.249

0.249


4.5


7.0


24,0


2.12

3.16


1.75

2.85


1.43

2.40


2.20

3.60


2.46

3.69


1.70

1.70


51.9


53.0


53.6


55.7


56.4


56.9









O/lO


S80


60


I--
LU
J40

Lj
Q.
20


/O)


I


I


- -O- 0 .. .
__________ C








I I I
1 2 3 4 5 6
TIME HR.

Figure 5
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
400 R.P.M. IN THE PRESENCE OF 1.0% SODIUM SULFATE

M1N3S2P1
SM1N3S2P2
0 M1N3S2P3







TABLE VII


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 400 R.P.M. IN THE
PRESENCE OF 1.5% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10-5 Extracted


M 1N3S3P1


0.5


1.5


2.3


0.414

0.620


0.502

0.753


0.382

0.598


0.322

0.483


0.360

0.544


0.412


4.5


7.0


24.0


3.17

4.78


3.83

5.77


2.93

4.58


2.46

3.69


2.79

4.19


3.15


56.5


58.6


59.5


60.4


61.0


0.255 1.95


61.7






63

TABLE VII Continued


Time Concentration Cumulative
Removed Absorbance moles/1 ter Percent
Hours xl105 Extracted


M1N3S3P2


0.5


1.5


- 2.3


0.382

0.588


0.330

0.492


0.418

0.645


0.340

0.525


0.354

0.530


0.378

0.379


4.5


7.0


24.0


2.92

4.50


2.54

3.80


3.20

4.95


2.60

4,00


2.74

4.08


2.89

2.89


54.1


56.9


58.6


62.4


63.1


63.1





64

TABLE VII Continued


Time Concentration Cumulative
Removed Absorbance moles/1 ter Percent
Hours xl0"- Extracted


1N3S3P 3


0.5


1.5


2.3




4.5



7.0


0.409

0.630


0.439

0.670


0.310

0.489


0.355

0.535


0.280

0.423


0.296

0.438


24.0


3.12

4.82


3.35

5.14


2.35

3.75


2.74

4.11


2.18

3.27


2,25

3.38


64.4


64.1


64.9


65.0


65.1


65.2








Q100
Q
U4

80

0-.


Q.



C)


TIME HR.


Figure 6
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
400 R.P.M. IN THE PRESENCE OF 1.5% SODIUM SULFATE

M N3S3P1


M1N3S3P2
M1NsP


O








TABLE VIII


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 450 R.P.M. IN THE
PRESENCE OF 0.5% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10" Extracted


M1N4S1P1


0.5


1.5


2.3


0.428

0.655


0.590

0.901


0.520

0.770


0.455

0.684


0.460

0.688


0.460


4.5


7.0


24.0


3.28

5.00


4.50

6.85


3.99

5.90


3.48

5.29


3.52

5.29


3.52


63.4


65.0


65.2


65.4


65.8


0.572 4.38


65.8






67

TABLE VIII Continued


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10- Extracted


M1N4S1P2


0.5


1.5


_ 2.3


0.382

0.590


0.588

0,850


0.572

0.878


0.480

0.730


0.515

0.793


0.688

0.642


4.5


7.0


24.0


2.92

4.50


4.28

6.52


4.38

6.70


3.68

5.60


3.95

6.08


5.29

4.92


64.3


65.0


67.8


69.7


72.8


72.6






68

TABLE VIII Continued


Absorbance


Concentration
moles/liter
xl0-5


Cumulative
Percent
Extracted


M1 N4SP3


0.418

0.629


0.491

0.740


0.561

0.860


0.483

0.720


0.550

0.848


0.552

0.845


3.20

4.82


3.75

5.65


4.30

6.60


3.69

5.51


4.20

6.50


4.21

6.48


70.3


73.4


73.9


73.7


74.1


74.0


Time
Removed
Hours


0.5


1.5


_ 2.3


4.5


7.0


24.0


___~_~









Q'z
Lu

80-

U 60 -






S20




/ 2 3 4 5 6
TIME HR.
Figure 7
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
450 R.P.Mo IN THE PRESENCE OF 0.5% SODIUM SULFATE

M1N4SlPI
M N4SIP2
O M1N4S P3
40



.20



/ 2 3 4 5 6
TIME HR.
Figure 7
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
450 R.P.M. IN THE PRESENCE OF 0.5% SODIUM SULFATE



0 M1N4S1P3








TABLE IX


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 450 R.P.M. IN THE
PRESENCE OF 1.0% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10-5 Extracted


M1N4S P1


0.5


S1.5


2.3


0.590

0.920


0.692

1.060


0.800

1.225


0.640

0.980


0.588

0.901


1.225


4.5


7.0


24.0


4.50

7.00


5.30

8.10


6.12

9.40


4.90

7.45


4.50

6.90


9.40


66.9


71.7


76.3


71.4


77.5


1.225 9.40


77.8





71

TABLE IX Continued


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10-5 Extracted


M1N4S2P2


0.5


1.5


2.3


0.438

0.676


0.512

0.788


0.382

0.598


0.510

0.790


0.524

0.810


0.439

0.670


4.5


7.0


24.0


3.35

5.17


3.92

6.02


2.93

4.58


3.90

6.05


4.00

6.20


3.35

5.14


76.3


75,5


82.5


82.6


82.8


82.2








TABLE IX Continued


Time Concentration Cumulative
Removed Absorbance moles/I ter Percent
Hours x10" Extracted


MIN4S2P3


0.5


1.5


2.3


0.680

1.040


0.688

1.035


0.678

1.042


0.642

0.988


0.525

0,790


0.280


4.5


7.0


5.20

7.95


5.29

7.95


5.18

7.98


4.92

7,55


4,05

6.10


2.18


68.6


71.8


73.3


73.5


73.5


0.670 5.14


24.0


72,9








o/ OO
Lu


< 80- _



L60


40o

Lu

020

%C)
I I I I
/ 2 3 4 5 6
TIME HR.
Figure 8
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
450 R.P.M. IN THE PRESENCE OF 1.0% SODIUM SULFATE

M N4S2P1
q M N4S2P2
0 M1N4S2P3







TABLE X


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 450 R.P.M. IN THE
PRESENCE OF 1.5% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10-5 Extracted


M1N4S3P1


0.5


1.5


2.3


0.200

0.320


0.282

0.443


0.274

0.430


0.250

0.383


0.339

0.520


0.340


4.5


7.0


1.53

2.45


2.15

3.38


2.10

3.30


1.93

2.92


2.58

3.98


2.58


58.0


66.8


68.0


68.2


68.5


0.520 3.98


24.0


68.5












Absorbar


75

TABLE X Continued


Concentration
ice moles/liter
xl10-


Cumulative
Percent
Extracted


M1N4S3P2


Time
Removed
Hours


0.5




1.5




S2.3


61.9




62.9




64.7


4.5


0,412

0.640


0.378

0.589


0.371

0.583


0.296

0.438


0.342

0.540


0,590

0.980


3.15

4.90


2.89

4.50


2.82

4.47


2.25

3.38


2.62

4.13


4.50

7.45


7.0


24.0


65.2




68.6




69.0


-- -






76

TABLE X Continued


Time Concentration Cumulative
Removed Absorbance moles/i ter Percent
Hours x10-i Extracted


M1N4S3P3


0.5


1.5


2.3


0.253

0.400


0.215

0.343


0.331

0.510


0.281

0.438


0.324

0.485


0.400

0.790


4.5


7.0


24.0


1.94

3.05


1.65

2.62


2.53

3.90


2.15

3.35


2.49

3.74


3.05

6.10


54.9


52.8


65.0


67.2


67.5


67,6


--




























/ 2 3 4 5 6
TIME HR.

Figure 9
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
450 R.P.M. IN THE PRESENCE OF 1.5% SODIUM SULFATE

M1N4S3P1

0 M1N4S3P3


1Q00
Lu
ki


F-
ro
LU ^n


ki
Ct
cr
Lu
Q.

Q)








TABLE XI


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 500 R.P.M. IN THE
PRESENCE OF 0.5% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10-5 Extracted


MIN5S1P1


0.5


- 1.5


2.3


0.203

0.206


0.294

0.296


0.259

0.255


0.248

0.248


0.273

0.273


0.296


4.5


7.0


24.0


1.59

1.60


2.23

2.25


1.99

1.95


1.90

1.90


2.07

2.07


2.25


60.4


61.4


61.9


62.0


62.5


0.280 2.18


62.4








TABLE XI Continued


Time Concentration Cumulative
Removed Absorbance moles/l ter Percent
Hours xl 0-- Extracted


M1N5S1P2


0.5




1.5


2.3


0.206

0.206


0.202

0.202


0.202

0.201


0.241

0.241


0.230

0.231


0.248

0.255


4.5


7.0


24.0


1.60

1.60


1.58

1.58


1.58

1.57


1.85

1.85


1.74

1.75


1.90

1.95


60.1


63,8


66.5


65.8


65.6


65.8






80

TABLE XI Continued


Time Concentration Cumulative
Removed Absorbance moles/liter Percent
Hours x10-3 Extracted


MIN5S1P3


0.5


1.5


- 2.3


0.228

0.230


0.242

0.243


0.218

0.217


0.258

0.258


0.291

0.294


0.242

0.259


4.5


7.0


24.0


1.71

1.75


1.85

1.86


1.67

1.67


1.97

1.97


2.21

2.23


1.85

1.99


59.0


60.7


59.5


61.4


61.3


61.3


-- --~- --









Q/OO
li
C,

^80-






SluI


20-


,20


1 2 3 4 5 6
TIME HR.
Figure 10
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
500 R.P.M. IN THE PRESENCE OF 0.5% SODIUM SULFATE

M0 N5S1P1
4) M1N5S1P2
O M1N5S1P3







TABLE XII


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 500 R.P.M. IN THE
PRESENCE OF 1.0% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/1 ter Percent
Hours xl0- Extracted


M1N5S2P1


0.5


1.5


2.3


0.159

0.159


0.187

0.187


0.171

0.171


0.151

0.149

0.164

0.163


0.243


4.5


7.0


24.0


1.20

1.20


1.43

1.43


1.31

1.31


1.15

1.14


1.25

1.25


1.87


70,8


72.5


71.8


72.1


73.8


0.187 1.43


73.9







TABLE XII Continued


Time Concentration Cumulative
Removed Absorbance moles/l ter Percent
Hours x10" Extracted


M1N5S2P 2


0.5


1.5


2.3


0.218

0.215


0.232

0.232


0.244

0.244


0.193

0.198


0.228

0.228


0.232


4.5


7.0


24.0


1.67

1.65


1.77

1.77


1.89

1.89


1.47

1.52


1.72

1.72


1.77


64.4


64.5


65.1


66.3


67.8


0.187 1.43


66.9






84

TABLE XII Continued


Concentration
Lnce moles/liter
xl10-


Cumulative
Percent
Extracted


M1N5S2P3


Time
Removed
Hours


Absorb


0.5




1.5




2.3


52.9




56.9




61.2


4.5


0.221

0.221


0.249

0.249


0.247

0.247


0.209

0.208


0.199

0.199


0.171

0.228


1.70

1.70


1.90

1.90


1.90

1.90


1.60

1.59


1.52

1.52


1.31

1.72


7.0


24.0


58.0




58.8




59.0


- II II II II




































TIME HR.


Figure 11
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
500 R.P.M. IN THE PRESENCE OF 1.0% SODIUM SULFATE

M1N5S2P1
M1N5S2P
1 522








TABLE XIII


DISSOLUTION OF ACETAMINOPHEN FROM NONEXPANDED
POLYSTYRENE BEADS MANUFACTURED AT 500 R.P.M. IN THE
PRESENCE OF 1.5% SODIUM SULFATE


Time Concentration Cumulative
Removed Absorbance moles/i ter Percent
Hours xl0~ Extracted


MIN5S3P1


0.5


1.5


2.3


0.292

0.296


0.311

0.309


0.285

0.288


0.289

0.291


0.279

0.281


0.292


4.5


7.0


24.0


2.22

2.26


2.35

2.33


2.17

2.20


2.20

2.21


2.13

2.15


2.22

2.22


64.3


65.5


65.1


68.6


68.6


0.292


68.9







TABLE XIII Continued


Time Concentration Cumulative
Removed Absorbance moles/1 ter Percent
Hours xl0- Extracted


M1N5S3P2


0.5


1.5


2.3


0.193

0.189


0.186

0.186


0.199

0.200


0.197

0.195


0.188

0.189


0.199


4.5


7.0


1.48

1.44


1.42

1.42


1.52

1.53


1.51

1.50


1.45

1.45


1.52


64.8


65,7


66.4


65.8


67.0


0.200 1.53


24.0


67.1






88

TABLE XIII Continued


Time Concentration Cumulative
Removed Absorbance moles/i ter Percent
Hours x10 lExtracted


M N5S3P3


0.5


1.5


- 2.3


0.235

0.231


0.252

0.250


0.234

04234


0.204

0.200


0.208

0.205


0.203

0.201


4.5


7.0




24.0


1.80

1.76


1.93

1.91


1.79

1.79


1,57

1.54


1.60

1.58


1.59

1.57


59.2


59.6


60.8


58.8


58.8


58.5









C IUU


C 80
k .




60 )- o --0 o 0o


O40
1u6 o





Q.
S20


I I I (
/ 2 3 4 5 6
TIME HR.
Figure 12
DISSOLUTION PATTERNS OF ACETAMINOPHEN FROM
NONEXPANDED POLYSTYRENE BEADS MANUFACTURED AT
500 R.P.M. IN THE PRESENCE OF 1.5% SODIUM SULFATE

M N5S3P 1
O M1N5S3P2
O M1N5S3P3