SOLVENT SCREENING STUDY OF CARBAMAZEPINE CRYSTAL POLYMORPH MUHAMAD HADI BIN SULAIMAN A thesis submitted in fulfillment of the requirements for the award of the degree of Bachelor of Chemical Engineering Faculty of Chemical & Natural Resources Engineering Universiti Malaysia Pahang FEBRUARY 2013
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SOLVENT SCREENING STUDY OF CARBAMAZEPINE CRYSTAL POLYMORPH
MUHAMAD HADI BIN SULAIMAN
A thesis submitted in fulfillment
of the requirements for the award of the degree of
Bachelor of Chemical Engineering
Faculty of Chemical & Natural Resources Engineering
Universiti Malaysia Pahang
FEBRUARY 2013
vi
SOLVENT SCREENING STUDY OF CARBAMAZEPINE CRYSTAL
POLYMORPH
ABSTRACT
Realizing solvents can be paramount critical and important in crystallizing specific
polymorphs, complete manual, references, method and approach in predicting the
polymorph formed from the specific parameter need to be developed. Solvent screening
is the process of determining the relation between solvent choose and respective crystal
form mainly focused on the solubility and its related properties. For this particular
research, the approaches is by choosing specific properties of solvent used to find the
relationship between them to relate with the crystallize structure formed. Polarity,
hydrogen-donor-acceptor, and dipole moment is known to give much effect on the
polymorph formation. By selecting the solvent with distinct properties considering its
polarity, hydrogen-donor-acceptor, and dipole moment, the carbamazepine will be
dissolve and recrystallize. Gravimetric method was used to determine the solubility of
carbamazepine. DSC and optical microscopes was used to characterize the polymorph.
Van `t Hoff plot was constructed from the solubility data and the stability prediction was
made based on the free energy value calculated. It is found that weak interaction of
solvent-solute will result in more stable polymorph but not necessarily correct because
other factor such as temperature need to be consider during dissolution and
crystallization process. One solvent having a tendency to produce more than one type of
polymorph depend on the temperature of dissolution. Morphology of carbamazepine
polymorph inconsistent for several trials and can be change easily through the process.
This result will be potential additional reference for more perfect approaches in the
future especially for molecular dynamic simulation.
vii
KAJIAN PENYARINGAN PELARUT PADA POLIMORF HABLUR
KARBAMAZEPIN
ABSTRAK
Menyedari kepentingan pelarut dalam penghabluran polimorf tertentu, manual lengkap,
rujukan, kaedah dan pendekatan dalam meramalkan polimorf yang terbentuk daripada
parameter tertentu perlu dibangunkan. Penyaringan pelarut adalah proses menetukan
kaitan antara pelarut yang dipilih dan hablur yang terhasil terutamanya tertumpu kepada
kelarutan dan ciri-ciri yang berkaitan. Bagi tujuan penyelidikan ini, pendekatan yang
diambil adalah memilih sifat tertentu pelarut yang digunakan dan dikaitkan dengan
struktur hablur yang terbentuk. Kekutuban, penerima-penderma ikatan hidrogen, dan
momen dwikutub adalah diketahui sangat memberi kesan kepada pembentukan polimorf.
Dengan memilih pelarut dengan sifat-sifat yang berbeza seperti kekutuban, penderma-
penerima ikatan hidrogen, dan momen dwikutub, carbamazepine akan dilarutkan dan
dihablurkan semuala. Kaedah gravimetrik telah digunakan untuk menentukan kelarutan
carbamazepine. DSC dan mikroskop optik telah digunakan untuk menentubeza polimorf.
Graf Van `Hoff telah dilukis daripada data kelarutan dan ramalan kestabilan telah dibuat
berdasarkan nilai tenaga bebas yang dikira. Didapati bahawa interaksi yang lemah antra
pelarut bahan larut akan menghasilkan polimorf lebih stabil namun tidak keseluruhanya
diterima kerana faktor lain seperti ganguan suhu semasa pelarutan dan proses
penghabluran perlu dipertimbangkan. Satu pelarut mempunyai kecenderungan untuk
menghasilkan lebih daripada satu jenis polimorf bergantung kepada suhu pelarutan.
Morfologi polimorf carbamazepine adalah tidak konsisten untuk beberapa cubaan
penghabluran dan mudah sepanjang proses penghabluran. Dapatan kajian ini berpotensi
sebagai rujukan tambahan untuk pendekatan yang lebih sempurna di masa hadapan
terutamanya bagi simulasi dinamik molekul.
viii
TABLE OF CONTENTS
Page
SUPERVISOR’S DECLARATION i
STUDENT’S DECLARATION ii
TITLE PAGE iii
ACKNOWLEDGEMENT v
ABSTRACT vi
ABSTRAK vii
LIST OF TABLES xi
LIST OF FIGURES xii
LIST OF SYMBOLS xiv
LIST OF ABBREVIATIONS xv
CONTENT
CHAPTER 1 INTRODUCTION
1.1 Background of Proposed Study 1
1.2 Problem Statements 2
1.3 Research Objectives 2
1.4 Research Questions/Hypothesis 3
1.5 Scope of Proposed Study 3
1.6 Expected outcome 4
1.7 Significance of Proposed Study 5
1.8 Conclusion 5
CHAPTER 2 REVIEW OF LITERATURE
2.0 Introduction 6
2.1 Polymorphism 7
2.1.1 Polymorphism of API 8
ix
2.2 Carbamazepine 9
2.3 Carbamazepine Polymorph 11
2.4 Solvent 16
2.4.1 Solvent Role in Polymorphism of Crystal Solid 18
2.5 Solubility of Active Pharmaceutical Ingredient 18
2.5.1 Carbamazepine Solubility 19
2.6 Crystal Characterization Technique 20
CHAPTER 3 METHODOLOGY
3.1 Materials 22
3.2 Methodology
3.2.1 Common Method in Solvent Screening 24
3.2.2 Screening Method 24
3.2.3 Crystal Characterization Method
3.2.3.2 DSC 27
3.2.3.3 Microscopy 28
CAPTER 4 RESULT AND DISCUSSION
4.1 Solubility of Carbamazepine 30
4.2 Van `t Hoff Plot 34
4.3 Crystal Morphology 36
4.4 Differential Scanning Calorimetry 39
4.4.1 DSC thermogram of Crystal Form from Dissolution in Methanol 40
4.4.2 DSC thermogram of Crystal Form from Dissolution in Acetone 42
4.5 Relation of Stability with Polymorph and Solvent used 44
x
CHAPTER 5 CONCLUSION AND RECOMMENDATION
45
5.1 Conclusion
5.2 Recommendation and Future Works 46
REFERENCES 48
APPENDICES
Appendix A DSC Thermogram Results 52
xi
LIST OF TABLES
Page
Table 2.1 Table of summarized properties of carbamazepine polymorph 12
Table 2.2 Temperature dependence of carbamazepine form III solubility in 20
various high boiling solvents
Table 3.1 Table of selected solvents and its properties 23
Table 3.2 Table of selected solvent and its’ molecular structure 23
Table 4.1 Solubility of carbamazepine in various solvent at three different
temperature. 31
Table 4.2 Table of calculated ΔHdiss, ΔSdiss, and ΔGsol for all solvent 35
Table 6.1 Heat flow data of DSC thermogram for polymorph form from 52
dissolution in methanol
Table 6.2 Heat flow data of DSC thermogram for polymorph form from 53
dissolution in acetone
xii
LIST OF FIGURES
Page
Figure 2.1 Chemical structure of carbamazepine 10
Figure 2.2 More well illustrated chemical structure of carbamazepine 10
Figure 2.3 Form I carbamazepine showing its hydrogen bond 13
Figure 2.4 Form II carbamazepine showing its hydrogen bond 14
Figure 2.5 Form III carbamazepine showing its hydrogen bond 14
Figure 2.6 Form IV carbamazepine showing its hydrogen bond 15
Figure 2.7 PXRD patterns of all four anhydrous polymorphs of CBZ 16