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E-grāmata: Control and Prediction of Solid-State of Pharmaceuticals: Experimental and Computational Approaches

  • Formāts: PDF+DRM
  • Sērija : Springer Theses
  • Izdošanas datums: 02-Feb-2016
  • Izdevniecība: Springer International Publishing AG
  • Valoda: eng
  • ISBN-13: 9783319275550
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Control and Prediction of Solid-State of Pharmaceuticals: Experimental and Computational ApproachesPalielināt
  • Formāts: PDF+DRM
  • Sērija : Springer Theses
  • Izdošanas datums: 02-Feb-2016
  • Izdevniecība: Springer International Publishing AG
  • Valoda: eng
  • ISBN-13: 9783319275550
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This thesis investigates a range of experimental and computational approaches for the discovery of solid forms. Furthermore, we gain, as readers, a better understanding of the key factors underpinning solid-structure and diversity. A major part of this thesis highlights experimental work carried out on two structurally very similar compounds. Another important section involves looking at the influence of small changes in structure and substituents on solid-structure and diversity using computational tools including crystal structure prediction, PIXEL calculations, Xpac, Mercury and statistical modeling tools. In addition, the author presents a fast validated method for solid-state form screening using Raman microscopy on multi-well plates to explore the experimental crystallization space. This thesis illustrates an inexpensive, practical and accurate way to predict the crystallizability of organic compounds based on molecular structure alone, and additionally highlights the molecu

lar factors that inhibit or promote crystallization.

Introduction.- Aims and Objectives.- Materials and Methods.- Development and Validation of High_Throughput Crystallization and Analysis (HTCAA) Methodology for Physical Form Screening.- Predicting Crystallizability of Organic Molecules using Statistical Modelling Techniques.- Exploring Crystal Structure Landscape of Olanzapine.- Exploring the Physical Form Landscape of Clozapine, Amoxapine and Loxapine.- Conclusions and Further Work.
1 Introduction
1(28)
1.1 Background
1(2)
1.2 Polymorphism
3(1)
1.3 Multi-component Crystalline Systems: Solvates, Salts and Co-crystals
4(2)
1.4 Amorphous Solids
6(1)
1.5 Importance of Solid-State Form for Pharmaceutical Industry
6(1)
1.6 Crystallisation
7(1)
1.7 Crystallisation Techniques
8(2)
1.8 Control of Solid Form
10(3)
1.9 Computational Methods
13(5)
1.9.1 Crystal Structure Prediction
13(3)
1.9.2 Energetics of Non-bonded Interactions: The PIXEL/Semi-classical Density Sums Methods
16(2)
1.10 Experimental and Computational Studies on Structurally Related Compounds
18(11)
References
23(6)
2 Aims and Objectives
29(2)
2.1 Aims
29(1)
2.2 Objectives
30(1)
3 Materials and Methods
31(8)
3.1 Material
31(1)
3.2 Methods
31(8)
3.2.1 Crystallisation Techniques
31(2)
3.2.2 X-Ray Crystallography
33(2)
3.2.3 Thermal Analysis
35(1)
3.2.4 Raman and Infrared Spectroscopy
35(1)
3.2.5 PIXEL Calculations
35(1)
3.2.6 Crystal Packing Analysis
36(1)
References
36(3)
4 Development and Validation of High-Throughput Crystallisation and Analysis (HTCAA) Methodology for Physical Form Screening
39(38)
4.1 Introduction
39(6)
4.2 Sample Preparation and Methodology Development
45(7)
4.2.1 96/48 Quartz Multi-well Plate
45(1)
4.2.2 Preparation of 96-Well Plate for Salt Screening of Amoxapine
46(1)
4.2.3 Preparation of 48-Well Plate for Physical Form Screening of Clozapine
47(1)
4.2.4 Preparation of 96-Well Plate for Physical Form Screening of Olanzapine
47(2)
4.2.5 Raman Microscopy
49(1)
4.2.6 Chemometric Analysis
50(1)
4.2.7 Scale-up and Characterisation of Novel Forms
51(1)
4.3 Results and Discussion
52(18)
4.3.1 Salt Screening of Amoxapine
52(8)
4.3.2 Physical Form Screening of Clozapine
60(5)
4.3.3 Physical Form Screening of Olanzapine
65(5)
4.4 Key Findings of the Developed HTCAA Methodology
70(3)
4.5 Summary
73(4)
References
74(3)
5 Predicting Crystallisability of Organic Molecules Using Statistical Modelling Techniques
77(22)
5.1 Statistical Modelling Techniques
77(9)
5.1.1 Introduction
77(1)
5.1.2 Principal Component Analysis
78(1)
5.1.3 Criteria for Deciding the Number of Principal Components
79(1)
5.1.4 Random Forests Classification Method
80(2)
5.1.5 Applications of Statistical Modelling Techniques in Pharmaceutical Industry
82(4)
5.2 Descriptor Calculations, Model Building and Validation
86(2)
5.2.1 Training Dataset and 2- and 3-Dimensional Descriptors Calculations
86(2)
5.2.2 Training the Statistical Model
88(1)
5.3 Results and Discussion
88(7)
5.3.1 Principal Component Analysis
88(1)
5.3.2 Random Forests Classification Model
89(2)
5.3.3 Model Optimisation Attempts
91(2)
5.3.4 Important Descriptors Assessment
93(1)
5.3.5 Limitations of Random Forests Classification Model
94(1)
5.4 Summary
95(4)
References
95(4)
6 Exploring the Crystal Structure Landscape of Olanzapine
99(54)
6.1 Introduction
99(3)
6.2 Experimental Procedures
102(4)
6.2.1 Crystallisation
102(3)
6.2.2 Variable Temperature-X-Ray Powder Diffraction
105(1)
6.2.3 XPac Analysis of Crystal Structures of Olanzapine
105(1)
6.2.4 Random Forests Classification Model of Olanzapine Solvates
106(1)
6.3 Calculation and Analysis of the Crystal Energy Landscape (Crystal Structure Prediction) of Olanzapine
106(3)
6.4 Results and Discussion
109(14)
6.4.1 Forms I, II and III of Olanzapine
109(3)
6.4.2 Solution Crystallisation of Olanzapine
112(6)
6.4.3 Neat and Liquid-Assisted Grinding of Olanzapine
118(2)
6.4.4 Desolvation of Olanzapine Solvates
120(1)
6.4.5 Melt Quenching and Recrystallisation of Amorphous Olanzapine
120(3)
6.4.6 Spray Drying and Freeze Drying of Olanzapine
123(1)
6.5 Molecular Packing Analysis of Olanzapine Crystal Structures Using XPac
123(4)
6.6 Hydrogen-Bonding Analysis of Olanzapine Crystal Structures
127(5)
6.6.1 Hydrogen Bonding in Olanzapine Solvates Based on Packing Type SC31
129(1)
6.6.2 Hydrogen Bonding in Olanzapine Solvates Based on Packing Type SC32
129(1)
6.6.3 Hydrogen Bonding in Olanzapine Solvates Based on Packing Type, SC33
130(1)
6.6.4 Hydrogen Bonding in Other Olanzapine Solvates Based on SC0, SC11 and SC22
131(1)
6.7 Prediction of Olanzapine Solvate Formation Using Random Forests Classification Model
132(6)
6.7.1 Random Forests Classification Model -- Prediction Results
132(4)
6.7.2 Important Solvent Physicochemical Descriptors for Random Forests Classification Model of Olanzapine Solvates
136(2)
6.8 Crystal Energy Landscape of Olanzapine
138(3)
6.9 PIXEL Calculations on Olanzapine
141(3)
6.10 Concomitant Appearance of Form III with Other Polymorphs of Olanzapine
144(1)
6.11 Prolific Solvate Formation of Olanzapine
145(1)
6.12 Challenges with Crystal Structure Prediction of Olanzapine and Unobserved Calculated Structures
146(1)
6.13 Summary
147(6)
References
148(5)
7 Exploring the Physical Form Landscape of Clozapine, Amoxapine and Loxapine
153(42)
7.1 Introduction
153(2)
7.1.1 Background of Molecule in Group 1-Clozapine
154(1)
7.1.2 Background of Molecules in Group 2-Amoxapine and Loxapine
154(1)
7.2 Experimental Details
155(4)
7.2.1 Principal Component Analysis of Solvent Properties
155(1)
7.2.2 Crystallisation Experiments of Clozapine
155(1)
7.2.3 Crystallisation Experiments of Amoxapine
155(1)
7.2.4 Crystallisation Experiments of Loxapine
156(2)
7.2.5 Preliminary Crystal Structure Prediction Studies for Clozapine, Amoxapine and Loxapine
158(1)
7.2.6 Solid-State Calculations Using CASTEP
158(1)
7.2.7 Structure Analysis
159(1)
7.3 Results and Discussion
159(31)
7.3.1 Physical Form Screening of Clozapine
159(14)
7.3.2 Physical Form Screening Results of Amoxapine
173(5)
7.3.3 Physical Form Screening Results of Loxapine
178(12)
7.4 Summary
190(5)
References
191(4)
8 Conclusions and Further Work
195(12)
8.1 Conclusions and Further Work
195(6)
8.1.1 Development and Validation of High Throughput Crystallisation and Analysis Methodology for Physical Form Screening
198(1)
8.1.2 Predicting Crystallisability of Organic Molecules Using Statistical Modelling Techniques
198(1)
8.1.3 Exploring the Physical Form Landscape of Structurally Related Pharmaceutical Molecules in Group 1 (Olanzapine and Clozapine) and 2 (Amoxapine and Loxapine)
199(2)
8.2 Further Work
201(6)
8.2.1 Development and Validation of High Throughput Crystallisation and Analysis Methodology for Physical Form Screening
201(1)
8.2.2 Predicting Crystallisability of Organic Molecules Using Statistical Modelling Techniques
202(1)
8.2.3 Exploring the Physical Form Landscape of Structurally Related Pharmaceutical Molecules in Group 1 (Olanzapine and Clozapine) and 2 (Amoxapine and Loxapine)
203(1)
References
204(3)
Appendix 207
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