Controlled Release: A Quantitative Treatment

241 Pages·1989·5.686 MB·English

by  Professor Liang-tseng Fan, Dr. Satish Kumar Singh (auth.)

Polymers 13
Properties and Applications
Editorial Board:
Prof. Hans-Joachim Cantow
Institut fUr Makromolekulare Chemie der Universitiit
Stefan-Meier-StraBe 31,
7800 Freiburg/Federal Republic of Germany
Prof. H. James Harwood
Institute of Polymer Science, The University of Akron
Akron, OH 44325/USA
Prof. Joseph P. Kennedy
Institute of Polymer Science, The University of Akron
Akron, OH 44325/USA
Prof. Anthony Ledwith
Pilkington Brothers pic., R&D Laboratories
Lathom Ormskirk
Lancashire UO 5UF/UK
Prof. Joachim MeifJner
Eidgentissische Technische Hochschule Zurich
Institut fUr Polymere, ETH-Zentrum
CH-8092 Zurich
Prof. Seizo Okamura
No. 24 Minami-Goshomachi
Okazaki
Sakyo-ku, 606 Kyoto, Japan
Dr. G. Henrici-Olivet Prof. S. OIM
1332 Neal Road
Cantonment, FL 32533/USA
L. T. Fan, S. K. Singh
Controlled Release
A Quantitative Treatment
With 81 Figures
Springer-Verlag
Berlin Heidelberg NewY ork
London Paris Tokyo Hong Kong
Professor Liang-tseng Fan
Department of Chemical Engineering
Kansas State University
Durland Hall
Manhattan, KS 66506jUSA
Dr. Sat ish Kumar Singh
Kabi Pharma
Giirdsvagen 6
Box 1828
S-171 26 Solna, Sweden
ISBN-13: 978-3-642-74509-6 e-ISBN-13: 978-3-642-74507-2
DOl: 10.1007/978-3-642-74507-2
Library of Congress Cataloging-in-Publication Data
Fan, L. T. (Liang-tseng), 1929
Controlled release: a quantitative treatment 1 L. T. Fan, S. K. Singh, p. cm. -
(Polymers, properties and applications; 13) Includes index.
1. Controlled release technology. 1. Singh, S. K. II. Title. III. Series.
TP 156.C64F36 1989 660.2 -dc 19 89-4323
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© Springer-Verlag, Berlin Heidelberg 1989
Solkover reprint of the hardcover 1st edition 1989
The use of registered names, trademarks, etc. in this publication does not imply, even in tbe absence of a specific state
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2152/3020-543210
To the Memory of
Professor Takeru Higuchi
Father of
Modem Controlled-Release Technology
Preface
The concept of controlled release has attracted increasing attention over the last two
decades, with the applications of this technology proliferating in diverse fields in
cluding medicine, agriculture and biotechnology. Research and developmental
efforts related to controlled release are multiplying in both industry and academia.
The reason for this phenomenal growth is obvious. The use of a variety of
biologically active agents, such as drugs, fertilizers and pesticides, has become an
integral part of modern society. Along with the use of these reagents has evolved an
awareness that their uncontrolled application almost inevitably induces harmful
effects on the health of humans and their surrounding environments. To eliminate
or minimize these harmful effects necessitates the controlled release of these
chemicals. Moreover, the controlled release of substances, not usually considered
toxic or hazardous, e.g., some catalysts and nutrients, can enhance their effectiveness.
The number and variety of controlled release systems, differing in their physical
and chemical makeup, are increasing rapidly. Proliferation almost always demands
correlation, generalization and unification; it requires both the development of
underlying theories of their behavior and the mechanistic interpretation of their
performance. This, in turn, requires a statistical and mathematical (quantitative)
treatment of the scientific information and technical data pertaining to them.
A quantitative treatment can also facilitate the formulation of procedures for
computer-aided design of these systems through a priori prediction of their per
formance for a variety of design parameters.
Various controlled release systems are treated in this monograph; these systems
are classified on the basis of the release mechanisms. A discussion is given of the
release mechanisms and of the factors governing the release profile. This is followed
by a review of major mathematical models that are .applicable to the systems.
These mathematical models are classified on the basis of the assumptions involved.
The majority of the models are of the deterministic type; however, the hetero
geneous or meso scopic nature of some of the systems requires that a stochastic
approach be employed. Thus a fairly extensive treatment of this approach to
the modeling of diffusion is included at the end.
Acknowledgement
The authors' research, supported for several years by the Kansas Agricultural
Experiment Station, Kansas State University, has culminated in the present mono-
VII
Preface
graph. The manuscript was ably typed mainly by Janet Vinduska and Peggy Hanes.
The first author (LTF) also wishes to acknowledge the aid of his wife, Eva, in
preparing the manuscript.
March 1989 L. T. Fan
S. K. Singh
VIII
Table of Contents
1 Introduction . . . . . . . . . . I
1.1 Diffusion-Controlled Systems . 3
1.1.1 Reservoir Devices . . . 3
1.1.2 Monolithic Devices. . . 4
1.2 Erosion or Chemical Reaction Controlled Systems 5
1.2.1 Erosion-Controlled Devices . . . . . 5
1.2.2 Chemical Reaction Controlled Devices 6
1.3 Swelling-Controlled Release Systems. 6
1.4 Osmotic Pumping Systems 6
References. . . . . . . . 7
2 Diffusion-Controlled Release 9
2.1 Diffusion in Polymers . II
2.1.1 Estimation of Diffusion Coefficients 14
2.1.2 Factors Influencing Diffusional Release. 20
2.2 Models for Diffusion-Controlled Release Systems . 44
2.2.1 Reservoir Devices . 49
2.2.2 Monolithic Devices. 61
2.2.3 Porous Devices 79
References. . . . . . . 83
3 Chemical Reaction Controlled Release . . . . . . 89
3.1 Physically Immobilized Active Agent Systems . 90
3.2 Chemically Immobilized Active Agent Systems 94
3.3 Models for Physically Immobilized Erosion-Activated Systems 102
References. . . . . . . . 107
4 Swelling-Controlled Release . 110
4.1 Penetrant Transport and the Polymer Relaxation Phenomena 111
4.1.1 Transport of Penetrants in Polymers . . . . . . . . . 112
4.1.2 Models for Transport of Penetrants in Glassy Polymers . 120
IX
Table of Contents
4.2 Active Agent Release from Swell able Polymers 125
4.3 Models for Swelling-Controlled Release Systems. 130
4.3.1 One-Region Models 131
4.3.2 Two-Region Models 136
References. . . . . . . . . 152
5 Special Controlled-Release Systems 157
5.1 Osmotic Pumping Devices . . 157
5.2 Osmotically Activated Monolithic Devices 162
5.3 Externally Modulated Devices 164
References. . . . . . . . . . . 166
6 Stochastic Model for Diffusion in Porous
or Heterogeneous Polymer Matrix. . . 167
6.1 Derivation . . . . . . . . . . . . . 170
6.1.1 Statistical Model for the Porous!
Heterogeneous-Polymer Matrix. . 170
6.1.2 State of the Diffusing Molecule and State Transitions. 172
6.1.3 Derivation of the Master Equation . . . . . 175
6.1.4 Recovery of the Diffusion Equation 177
6.2 Transport Coefficients from the Diffusion Equation 184
6.2.1 Mean or Effective Diffusion Coefficient . 185
6.2.2 Drift or Convective Velocity. . . . 187
6.3 Transport Coefficients in Specific Systems . . 188
6.3.1 Mean or Effective Diffusion Coefficient. 188
6.3.2 Drift or Convective Velocity. . . . . . 191
6.4 Monte Carlo Simulations of Transport in Porous Media 192
6.4.1 Procedure. . . 193
6.4.2 Results . . . . 195
6.5 Concluding Remarks. 197
References. . . . . . . 200
Appendix 6A. Conversion of Probability to Number Concentration 202
Appendix 6B. Derivation of Equation (6.39) from Equation (6.37). 204
Appendix 6C. Algorithm and FORTRAN Code for Monte Carlo
Simulation of Transport in Porous Networks 206
7 Epilogue. . 225
References . 226
Author Index . 227
Subject Index . 231
x
1. Introduction
In the search for safe, economical, and efficient means of providing for the
health and well-being of mankind, modern science has produced numerous active
agents that manipulate the biological environment around and within us. Never
theless, the use of these active agents is fraught with inefficiencies stemming from
an inability to deliver these agents to their targets at the right time and in
the right amounts. This results in their loss and in undesirable side effects and
leads to a regimen requiring repeated treatment to produce and sustain the desired
effect. With drugs, periodic dosage produces peaks and valleys in the concentration
of the drug in the blood stream, possibly between harmful and ineffective levels
(see Fig. 1.1). Agricultural chemicals such as pesticides, fertilizers, herbicides,
and fumigants create the same problems when applied directly. To counter these
problems, scientists have conventionally looked to altering the persistency and
effectiveness of the reagents through modification of the reagents themselves.
However, this approach tends to be difficult, time consuming, and expensive.
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c:
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c:
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Fig. 1.1. Typical drug level in blood vs. time profiles for various modes of delivery.
a standard oral dose, b oral overdose, c intraveneous injection, d controlled release dose
1 Introduction
In recent years, increasing attention has been given to methods by which active
reagents or chemicals are administered, giving rise to the field of controlled release.
Controlled release may be defined as a technique by which active chemicals are
made available to a target at a rate and duration so as to produce a desired effect.
The objective of the technique is the maintenance of this desired rate or concentration
level (Kydonieus, 1980). Among the advantages of this technique are more efficient
utilization of the active agent, possibility of targeting, less frequent administration,
and reduction in side effects. These advantages can sometimes make an otherwise
unsuitable active agent attractive. This is especially true in pharmaceutics. New
and powerful macromolecular drugs are being discovered or "engineered" at
a rapid rate. Nevertheless, these drugs can be cumbersome to administer and
often produce side effects. Controlled release can alleviate these difficulties.
In medicine, the approach of sustained-release has been utilized for a long
time. This approach comprises the formulation of drug complexes, enteric formula
tions, suspensions, emulsions, and compressed tablets, to retard the drug's rate of
availability to the body. The formulations, however, are strongly influenced by
the environmental conditions and are not true controlled-release systems. Controlled
release implies a predictible and reproducible release profile relatively independent
of environment; this gives rise to a higher degree of control than achieved in
sustained release formulations.
The basic controlled-release formulation consists of an active agent (the drug,
fertilizer etc.) and a carrier (commonly a polymeric material) arranged so as to
allow the active agent to be released at the target over a period of time at
a controlled rate. Numerous design variations towards this objective have been
proposed. Some of the common ones are (see, e.g., Cowsar, 1974; Kydonieus,
1980) :
1. A capsule of polymeric material filled with the active agent in either the
solid, liquid or solution form, release being controlled by diffusion through the
capsule wall (reservoir deviCes).
2. A heterogeneous dispersion or homogeneous solution of the active agent in
a polymeric matrix, release being controlled by diffusion through and/or erosion
of the polymer (monolithic devices).
3. A laminate of the active agent and polymer forming a "sandwich", release being
controlled by diffusion, erosion or both.
4. A swellable polymeric matrix with the active agent dispersed and/or dissolved in
the polymer, release occurring as a result of swelling (or gelatinization) of the
polymer in the environmental fluid and the consequent diffusion of the active
agent.
5. Liquid-liquid encapsulation of the active agent in a viscous solution, release
being controlled by diffusion or dilution.
6. Chemical bonding of the active agent to a polymeric backbone and subsequent
release by controlled bond cleavage in the target environment.
7. Macromolecular structures of the active agent formed via ionic or covalent
linkages with release controlled by hydrolysis, thermodynamic dissociation,
or microbial or enzymatic degradation.
8. A capsule of active agent-impermeable polymer membrane, with release occurring
2