Development and characterization of poly(vinyl acetate) based oral dosage forms [Elektronische Ressource] / von Sandra Strübing

Ingo Schulze

Sujets

• Gesundheit

Informations

• Publié par: martin-luther-universitat_halle-wittenberg
• Publié le: 01 janvier 2008
• Nombre de lectures: 32
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

Development and characterization
of poly(vinyl acetate) based oral dosage forms



Dissertation
zur Erlangung des akademischen Grades
doctor rerum naturalium (Dr. rer. nat.)



vorgelegt der
Naturwissenschaftlichen Fakultät I
der Martin-Luther-Universität Halle-Wittenberg


von
Sandra Strübing
geboren am 20.10.1977 in Waren (Müritz)





Gutachter:
1. Prof. Dr. Karsten Mäder
2. Prof. Dr. Dr. h.c. Reinhard Neubert
3. Prof. Dr. Jürgen Siepmann


urn:nbn:de:gbv:3-000014858
[http://nbn-resolving.de/urn/resolver.pl?urn=nbn%3Ade%3Agbv%3A3-000014858]

Halle, den 02. Oktober 2008
Contents

1 Introduction 1
2 Thermal analysis of polymer films 11
2.1 Introduction 11

2.2 Materials 13

2.3 Methods 13

2.3.1 Preparation of free films 13

2.3.2 Thermal mechanical analysis experiments 14

2.3.3 Differential scanning calorimetry experiments 14

2.4 Results and discussion 15

2.4.1 Thermal mechanical analysis experiments 15

2.4.2 Differential scanning calorimetry experiments 15

2.5 Conclusion 18
3 Mechanistic analysis of drug release 19
3.1 Introduction 19

3.2 Materials 21

3.3 Methods 21

3.3.1 Preparation of tablet cores 21

3.3.2 Film Coating of tablet cores 22

3.3.3 Determination of dissolution characteristics 23

3.3.4 Comparison of lag times before drug release 23

3.3.5 Determination of water uptake behaviour 23

3.3.6 Monitoring of water diffusion characteristics by means

of EPR spectroscopy 24

3.4 Results and discussion 24

3.4.1 Determination of dissolution characteristics 24

3.4.2 Comparison of lag times before drug release 26

3.4.3 Determination of water uptake behaviour 27

3.4.4 Monitoring of water diffusion characteristics by means

of EPR spectroscopy 28

3.5 Conclusion 32
4 Monitoring of dissolution induced changes in coat composition 33
4.1 Introduction 33
I

4.2 Materials 35

4.3 Methods 35

4.3.1 Monitoring of dissolution induced changes in film coat

1composition by means of H NMR spectroscopy 35

4.3.2 Monitoring of dissolution induced changes in film coat

composition by means of SEM 37

4.4 Results and discussion 37

4.4.1 Monitoring of dissolution induced changes in film coat

1composition by means of H NMR spectroscopy 37

4.4.2 Monitoring of dissolution induced changes in film coat

composition by means of SEM 44

4.5 Conclusion 47
5 Development and characterization of poly(vinyl acetate) coated
floating tablets 48
5.1 Introduction 48

5.2 Materials 54

5.3 Methods 54

5.3.1 Tablet core preparation for preliminary trials 54

5.3.1.1 Optimization of excipient composition 54

5.3.1.2 Optimization of drug content and crushing forces 55

5.3.2 Preparation of optimized tablet cores 56

5.3.3 Coating of tablet cores 56

5.3.4 Monitoring of the floating strength 57

5.3.5 Determination of dissolved drug amount 59

5.3.6 Monitoring of hydration and gas development

1characteristics by means of H NMR benchtop imaging 59

5.3.7 Impinging light microscopy 60

5.4 Results and discussion 60

5.4.1 Preliminary trials regarding the composition of

the tablet core 60

5.4.1.1 Optimization of excipient composition 60

5.4.1.2 Optimization of drug content and crushing forces 61

5.4.2 Monitoring of floating characteristics 63

5.4.3 Characterization of Propranolol HCl release behaviour 69

II
5.4.4 Determination of lag times prior to drug release 70

5.4.5 Monitoring of hydration and gas development

1characteristics by means of H NMR benchtop imaging 72

5.4.6 Impinging light microscopy 76

5.5 Conclusion 78
6 Development and characterization of poly(vinyl acetate) floating
matrix tablets 79
6.1 Introduction 79

6.2 Materials 82

6.3 Methods 82

6.3.1 Preparation of floating matrix tablets 82

6.3.2 Curing experiments 83

6.3.3 Determination of tablet density 83

6.3.4 Quantification of tablet erosion 83

6.3.5 Propranolol HCl release studies 83

6.3.6 Monitoring of floating behaviour 84

6.3.7 Determination ofswelling parameters 84

16.3.8 H NMR benchtop imaging experiments 84

6.4 Results and discussion 84

6.4.1 Determination of tablet density 84

6.4.2 Quantification of tablet erosion 86

6.4.3 Characterization of Propranolol HCl release 86

6.4.4 Monitoring of floating behaviour 93

6.4.5 Characterization of swelling behaviour 95

16.4.6 H NMR benchtop imaging experiments 97

6.5 Conclusion 100
7 Summary and perspectives 101
7.1 English version 101

7.2 German version 105

List of publications 110
Literature 112
Acknowledgements 135
Curriculum Vitae 136


III
Abbreviations

API Active pharmaceutical ingredient
BCS Biopharmaceutical classification system
CW Continuous wave
DDS Drug delivery system
DMSO Dimethyl sulfoxide
DSC Differential scanning calorimetry
EC Ethyl cellulose
EPR Electron paramagnetic resonance
ESR Electron spin resonance
FLT Floating lag time
GI Gastrointestinal
GRDF Gastro retentive dosage form
HBS Hydrodynamically balanced system
HCl Hydrochloric acid
HLB Hydrophilic lipophilic balance
HPC Hydroxypropyl cellulose
HPMC Hydroxypropyl methylcellulose
IMMC Interdigestive migration myoelectric complex
LOD Limit of detection
Log P Log octanol/water partition coefficient
MCC Microcrystalline cellulose
MRI Magnetic resonance imaging
NMR Nuclear magnetic resonance
NSAID Non steroidal antiinflammatory drugs
PCM N-3-carbamoyl-2,2,5,5-tetramethylpyrrolidin-1-yloxy
= 3-Carbamoyl-proxyl
PEG Poly(ethylene glycol)
Ph. Eur. Pharmacopoea Europaea
PVA Poly(vinyl alcohol)
PVAc Poly(vinyl acetate)
PVP Poly(vinyl pyrrolidone)
rpm rotations per minute
IV
SEM Scanning electron microscopy
TEC Triethyl citrate
TEM Transmission electron microscopy
TMA Thermal mechanical analysis
TMS Tetramethyl silane
TPI Terahertz pulsed imaging
USP United States Pharmacopeia
V Chapter 1 Introduction


1. Introduction

The peroral administration of drugs represents nowadays the most common way of
drug application not least due to its high patient acceptance. Applicable devices may
be classified into single unit dosage forms such as tablets, dragées and capsules as
well as multi particulate dosage forms like for example pellets, granulates and
powders [1]. In principle immediate release drug delivery systems have to be
distinguished from modified release dosage forms. Immediate release DDSs are,
particularly with regard to drugs with a short biological half-life, associated with a fast
increase and decrease and hence fluctuations of drug plasma levels. Therefore,
therapeutic drug plasma levels are under-run or exceeded, leading to a reduction or
loss in drug effectiveness or an increased incidence of side effects. Modified release
DDSs include systems with pH-dependent, extended, delayed or pulsed drug
release. Sustained, extended or prolonged release drug delivery systems are terms
used synonymously to describe this group of controlled drug delivery devices. By
contrast, delayed release dosage forms have to be distinguished from the ones
mentioned above as they exhibit a more or less pronounced lag time before drug
release.
Extended release oral DDSs offer the opportunity to provide constant or nearly
constant drug plasma levels over a certain time period after administration [2]. As
therapeutic drug plasma concentrations are maintained over prolonged periods by
applying extended release dosage forms, an attenuation of adverse effects, the
application frequency and thus improved patient compliance can be achieved,
especially when used in long-term treatment [3,4]. Sustained release drug delivery
systems include single-unit and multiple-unit dosage forms as well as coated and
matrix devices [5]. Sustained release oral dosage forms have to conform to the <