Asymmetric Membrane Tablet Coatings

95 Pages·2002·5.48 MB·English

Asymmetric Membrane Tablet Coatings
For
Controlled(cid:150)Release of Drugs

By
Hacer YENAL

A Dissertation Submitted to the
Graduate School in Partial Fulfillment of the
Requirements for the Degree of

MASTER OF SCIENCE

Department: Chemical Engineering
Major: Chemical Engineering

İzmir Institute of Technology
İzmir, Turkey
We approve the thesis of Hacer YENAL
Date of Signature

.................................................. 27.09.2002
Assoc. Prof. Dr. Sacide ALSOY ALTINKAYA
Supervisor
Department of Chemical Engineering

.................................................. 27.09.2002
Assist. Prof. Dr. Sedat AKKURT
Co-Supervisor
Department of Mechanical Engineering

.................................................. 27.09.2002
Prof. Dr. Semra (cid:220)LK(cid:220)
Department of Chemical Engineering

.................................................. 27.09.2002
Prof. Dr. Devrim BALK(cid:214)SE
Department of Chemical Engineering

.................................................. 27.09.2002
Assist. Prof. Dr. Oğuz BAYRAKTAR
Department of Chemical Engineering

.................................................. 27.09.2002
Prof. Dr. Devrim BALK(cid:214)SE
Head of Department
ACKNOWLEDGEMENTS
I would like to express my sincere gratitude to Associated Professor Sacide Alsoy
Altınkaya for her supervision, support, guidance and encouragement during this study
and in the preparation of this thesis.
I also would like to thank to Assistant Professor Sedat Akkurt for his guidance, help and
recommendations.
I am very grateful to Assistant Professor Yeşim Karasulu from Ege University, Faculty
of Pharmacy, for her help and valuable suggestions.
I also wish to thank to Associated Professor Ahmet Yemenicioğlu for his comments and
help for construction of experimental-set up.
Special thanks to B(cid:252)lent (cid:214)zbaş for his help and friendship.
I also present my deepest thanks to Deniz Şimşek because of not only his friendship but
also his kind efforts, helps and endless support.
I would like to appreciate deeply to my friends: Şule U(cid:231)ar, Berna Topuz, Sevdiye
Atakul, Mehmet G(cid:246)nen and G(cid:246)khan Erdoğan for their friendships and encouragements.
I would like to express my thanks to Murat Pakel for his help, support and
understanding during this study.
Finally, I could not be able to complete this thesis without encouragements and
understandings of my family.
ABSTRACT
Most of the controlled release systems developed for drug delivery applications depend
on membrane technology. The dense structure of the membrane in conventional
controlled release systems prolongs the release of drug. To eliminate this disadvantage
while maintaining the benefits of dense membrane systems, an asymmetric type of
coating was applied on tablets. Coatings were prepared from cellulose acetate, acetone,
water solution by phase inversion technique. To determine the release rate of drug,
dissolution studies on tablets were performed according to United States of
Pharmacopeia (USP). In these studies, the effects of composition of the
polymer/solvent/nonsolvent, coating time, number of coating layers, evaporation
conditions and the nonsolvent type on the release rate of the drug and the structure of
membrane were investigated. Experiments were designed using commercial software
package Design-Expert and a quadratic model equation was obtained to predict the
effect of composition of cellulose acetate, acetone and water on the release rate of drug.
The advantage of asymmetric type coating over the conventional dense type coating
was further demonstrated by measuring the permeabilities of both type of coatings. In
addition, the structures of membranes were analyzed using scanning electron
microscope (SEM) micrographs.
ÖZ
İlacın v(cid:252)cutta kontroll(cid:252) salımı i(cid:231)in geliştirilen sistemlerin bir(cid:231)oğu membran
teknolojisine dayalıdır.Geleneksel kontroll(cid:252) salım sistemlerinde kullanılan yoğun
yapıdaki membranlar ila(cid:231) salımını uzatmaktadır. Bu dezavantajı ortadan kaldırmak i(cid:231)in,
yoğun yapıdaki membran sistemlerinin yararları sabit tutularak tabletlere asimetrik
yapıdaki kaplamalar uygulanmıştır. Kaplamalar faz ayrımı y(cid:246)ntemi ile sel(cid:252)loz asetat,
aseton ve su (cid:231)(cid:246)zeltisi kullanılarak hazırlanmıştır. İlacın salım hızını belirlemek i(cid:231)in,
tabletlerin (cid:231)(cid:246)z(cid:252)nme (cid:231)alışmaları United States Pharmacopeia (USP) standartlarına g(cid:246)re
yapılmıştır. Bu (cid:231)alışmalarda, polimer/(cid:231)(cid:246)z(cid:252)c(cid:252)/(cid:231)(cid:246)z(cid:252)c(cid:252) olmayan kompozisyonlarının
etkileri, kaplama zamanı, kaplama sayısı, buharlaşma koşulları ve (cid:231)(cid:246)z(cid:252)c(cid:252) olmayan
malzemenin ila(cid:231) salım oranına ve membran yapısına etkisi incelenmiştir. Deneyler ticari
bilgisayar yazılım programı Design-Expert kullanılarak tasarlanmış ve sel(cid:252)loz asetat,
aseton ve su kompozisyonunun ila(cid:231) salımına etkisini belirlemek i(cid:231)in kuadratik model
denklemi elde edilmiştir. Asimetrik yapıdaki kaplamaların geleneksel yoğun yapıdaki
membrana g(cid:246)re avantajı, her iki tipteki kaplamaların ge(cid:231)irgenlikleri (cid:246)l(cid:231)(cid:252)lerek de
kanıtlanmıştır. Buna ek olarak, taramalı elektron mikroskobu fotoğrafları incelenerek
membran yapıları analiz edilmiştir.
TABLE OF CONTENTS
LIST OF FIGURES............................................................................................ iv
LIST OF TABLES............................................................................................. viii
CHAPTER 1. INTRODUCTION...................................................................... 1
CHAPTER 2. CONTROLLED-RELEASE SYSTEMS.................................... 3
2.1. Advantages and Disadvantages of Controlled-Release
Systems.............................................................................. 4
2.2. Classification of Controlled-Release Systems.................... 5
2.2.1. Diffusion-Controlled Release Systems................. 5
2.2.1.1. Reservoir Systems................................. 5
2.2.1.2. Matrix Systems...................................... 8
2.2.2. Chemically-Controlled Systems........................... 8
2.2.2.1. Bioerodible Systems.............................. 8
2.2.2.2. Pendant Chain Systems......................... 9
2.2.3. Swelling – Controlled Systems............................ 10
2.2.4. Magnetically - Controlled Systems...................... 11
2.3. Polymers For Drug Release Formulations.......................... 11
2.4. Release Kinetics.................................................................. 12
CHAPTER 3. PREVIOUS STUDIES ON CONTROLLED-RELEASE
SYSTEMS.................................................................................. 14
3.1. Matrix Systems.................................................................... 14
3.2. Bioerodible Systems............................................................ 16
3.3. Swelling Systems................................................................ 16
3.4. Membrane Systems............................................................. 17
CHAPTER 4. DIFFUSION IN ASYMMETRIC MEMBRANES..................... 20
4.1. Diffusion in Dense Membranes........................................... 20
4.2. Diffusion in Asymmetric Membranes................................. 20
4.3. Diaphragm Cell Model........................................................ 22
CHAPTER 5. STATISTICAL DESIGN AND ANALYSIS OF
EXPERIMENTS........................................................................ 25
5.1. Experimental Designs for Fitting Response Surfaces......... 25
5.2. Mixture Design.................................................................... 27
5.3. Mixture Models................................................................... 28
CHAPTER 6. EXPERIMENTAL...................................................................... 30
6.1. Properties of Polymer and Model Drug.............................. 30
6.2. Tablet Preparation............................................................... 32
6.3. Tablet Coating..................................................................... 32
6.3.1. Preparation of Membrane Solution...................... 32
6.3.2. Dip-Coating.......................................................... 33
6.4. Dissolution Studies.............................................................. 33
6.5. Permeability Studies............................................................ 35
6.6. Characterization.................................................................. 36
CHAPTER 7. RESULTS AND DISCUSSION................................................. 37
7.1. Dissolution and Morphological Studies.............................. 37
7.1.1. Comparison of the Drug Release Rates of Dense
and Asymmetric Membrane Coated Tablets ....... 40
7.1.2. Effect of Polymer / Solvent (P/S) Ratio on
Release Rate......................................................... 42
7.1.3. Effect of Polymer / Nonsolvent (P/NS) Ratio on
Release Rate......................................................... 48
7.1.4. Effect of Solvent / Nonsolvent (S/NS) Ratio on
Release Rate......................................................... 49
7.1.5. Effect of Number of Coatings on Release Rate.... 51
7.1.6. Effect of Coating Time on Release Rate.............. 52
7.1.7. Effect of Evaporation Conditions on Release
Rate...................................................................... 52
7.1.8. Effect of Types of Nonsolvent on Release Rate... 54
7.2. Permeability Studies............................................................ 60
7.3. Statistical Analysis of Experiments..................................... 62
7.3.1. Determination of the Variables and Feasible
Region for the Design of Experiments................. 62
7.3.2. Mixture Design..................................................... 62
7.3.3. The Regression Model and Statistical Analysis... 65
7.3.4. The Response Surface Plot................................... 67
CONCLUSIONS................................................................................................ 70
REFERENCES.................................................................................................. 72
APPENDIX A
APPENDIX B
APPENDIX C
LIST OF FIGURES
Figure 2.1. Concentration profiles for (a) conventional (b) controlled-release
formulations..................................................................................... 3
Figure 2.2. Idealized diffusion-controlled reservoir release system.................. 6
Figure 2.3. Schematic diagram of the osmotic tablet system surrounded by
membrane drilled with two orifices................................................. 7
Figure 2.4. Idealized diffusion-controlled matrix tablets................................... 8
Figure 2.5. Idealized drug release from bioerodible systems (a) surface erodible
(b) bulk erodible............................................................................... 9
Figure 2.6. Idealized drug release from pendant chain systems......................... 10
Figure 2.7. Idealized swelling-controlled release system.................................. 10
Figure 2.8. Comparison of release kinetics from conventional (first-order) and
controlled-release formulations....................................................... 13
Figure 4.1. Schematic cross section of an asymmetric membrane and the mass
transport resistance configuration.................................................... 22
Figure 5.1. Simplex lattice design for a ternary mixture................................... 28
Figure 6.1. SEM micrograph of crystalline theophylline anhydrate.................. 30
Figure 6.2. Molecular structure of theophylline................................................. 31
Figure 6.3. Molecular structure of cellulose...................................................... 31
Figure 6.4. Dissolution test apparatus................................................................ 34
Figure 6.5. Schematic representation of diffusion cell...................................... 35
Figure 7.1. Release of theophylline from tablets coated with dense and
asymmetric-membrane coatings...................................................... 40
Figure 7.2. SEM micrograph of cross section of a membrane. Initial composition:
10% CA, 80% Acetone, 10% Water. Magnificationx5000............. 41

iv
Figure 7.3. SEM micrograph of cross section of a membrane. Initial composition:
10% CA, 90% Acetone. Magnificationx10000............................... 41
Figure 7.4. Release rate of theophylline as a function of P/S ratios for 5%, 10%
and 15% water content..................................................................... 43
Figure 7.5. SEM micrograph of cross section of a membrane. Initial composition:
15% CA, 80% Acetone, 5% Water. Magnificationx5000............... 43
Figure 7.6. SEM micrograph of cross section of a membrane. Initial composition:
10% CA, 85% Acetone, 5% Water. Magnificationx5000............... 44
Figure 7.7. SEM micrograph of cross section of a membrane. Initial composition:
5% CA, 90% Acetone, 5% Water. Magnificationx10000............... 44
Figure 7.8. SEM micrograph of cross section of a membrane. Initial composition:
5% CA, 85% Acetone, 10% Water. Magnificationx500................. 45
Figure 7.9. SEM micrograph of cross section of a membrane. Initial composition:
15% CA, 75% Acetone, 10% Water. Magnificationx4000............. 45
Figure 7.10. SEM micrograph of cross section of a membrane. Initial composition:
5% CA, 80% Acetone, 15% Water. Magnificationx10000............. 46
Figure 7.11. SEM micrograph of cross section of a membrane. Initial composition:
10% CA, 75% Acetone, 15% Water. Magnificationx10000........... 47
Figure 7.12. SEM micrograph of cross section of a membrane. Initial composition:
15% CA, 70% Acetone, 15% Water. Magnificationx10000........... 47
Figure 7.13. Release rate of theophylline as a function of P/NS ratio for 80%
acetone content............................................................................... 48
Figure 7.14. SEM micrograph of cross section of a membrane. Initial composition:
3% CA, 80% Acetone, 17% Water. Magnificationx5000............. 49
Figure 7.15. Release rate of theophylline as a function of S/NS ratio for 10%
and 15% polymer content.............................................................. 50
v