Crystallinity Changes and Phase Transitions of Selected Pharmaceutical Solids with Processing
Total Page：16
File Type：pdf, Size：1020Kb
CRYSTALLINITY CHANGES AND PHASE TRANSITIONS OF SELECTED PHARMACEUTICAL SOLIDS WITH PROCESSING by MARION W.Y. WONG B.Sc. (Pharm), The University of British Columbia, 1988 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF’ PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES Faàulty of Pharmaceutical Sciences Division of Pharmaceutics and Biopharmaceutics We accept this thesis as conforming to the required standard THE UNIVERSITY OF BRITISH COLUMBIA November 1993 © Marion W.Y. Wong, 1993 _______________________ In presenting this thesis in partial fulfilment of the requirements for an advanced degree at the University of British Columbia, I agree that the Library shall make it freely available for reference and study. I further agree that permission for extensive copying of this thesis for scholarly purposes may be granted by the head of my department or by his or her representatives, It is understood that copying or publication of this thesis for financial gain shall not be allowed without my written permission. (Signature) Department of The University of British Columbia Vancouver, Canada Date jt7’ / DE-6 (2/88) 11 ABSTRACT The solid state properties of drugs and pharmaceutical excipients can be significantly affected by processing (e.g. grinding, tabletting, heating and additive incorporation) and reflect structural changes within a solid. Such changes may involve alterations in both the chemical and physical nature of the crystal structure (e.g. hydrates), complete rearrangements of the same chemical components in three-dimensional space (e.g. polymorphs), or more subtle changes which involve neither the chemical composition nor the space lattice. These more subtle changes do not involve phase changes and are referred to as changes in the degree of crystallinity, X. Metronidazole (MTZ), acetylsalicylic acid (ASA), diphenylhydantoin (DPH) and chiorpromazine hydrochloride (CPZ) were selected to illustrate these various changes. Many of the empirical methods which have been proposed for studying crystallinity were initially used to assess the X of MTZ before and after processing. Although a reduction and subsequent increase in X was indicated, the observed changes could not be adequately explained. The results were inconclusive and a more direct measure of X was necessary. X-ray powder diffractograms reflect the crystal structure, and when used in conjunction with the Rietveld structure refinement method, the processes which cause changes in X (i.e. crystallite size and lattice distortion) can be directly quantified. Tabletting reduced the peak intensities of ground MTZ and this was accompanied by an increase in the full width at half maximum height (FWHM). Since the unit cell dimensions were not significantly altered, reductions in crystallite size were thought to be primarily responsible for the 111 reduction in the X of MTZ. This was confirmed using the Voigt profile function. Though the Gaussian component was slightly affected (indicating some lattice strain), it was the FWHM of the Lorentzian component of the diffractograms which showed dramatic increases with processing and subsequent reductions with time at 25°, 54°, 700 and 10000. From the Lorentzian profile, a mean crystallite size for MTZ can be obtained. Tabletting the mechanically ground MTZ further reduced the mean crystallite size. With storage at elevated temperatures, a subsequent increase in crystallite size was observed, where the rate and extent of recovery was dependent on the storage temperature (i.e. recovery at 100°C was greater than recovery at 700, 54° or 25°C). Complete recovery was not observed. The extent to which the peak intensities of ASA were reduced with processing was similar to MTZ, but the underlying structural changes were different. Significant lattice distortion was observed with a 0.5% reduction in the b dimension on tabletting. No significant recovery was found on storage at elevated temperatures. Contrary to previous workers who suggested that the incorporation of DPH with 3-propanoyloxymethyl-5,5-diphenylhydantoin (PMDPH) caused significant “lattice disorder or disruption”, no significant changes in the lattice dimensions were detected. Analysis of bond lengths suggested that the incorporation of PMDPH into the crystal lattice was unlikely. CPZ illustrated a complete change in both the chemical and physical nature of the crystal lattice with processing. Wet granulation completely converted CPZ from a room temperature metastable form to a hemihydrate of the room temperature stable polymorph. Significant differences in the tablettability of each form were shown. iv TABLE OF CONTENTS Page Abstract Table of Contents iv List of Tables viii List of Figures x List of Abbreviations and Symbols xiv Acknowledgements xix I. INTRODUCTION 1 A. Solids 3 B. Crystallinity 6 C. Methods of Quantitating Crystallinity and Their Limitations 10 1. Density 10 2. Calorimetry 12 3. Nuclear Magnetic Resonance 14 4. Infrared Spectroscopy 15 5. Counting of Dislocation Etch Pits 15 6. Polarized-Light Microscopy 16 7. Water Adsorption 16 8. Kinetics 17 9. Powder X-ray Diffraction 17 V Page 9.1. The Rietveld Structure Refinement Method 20 9.2. Application of the Rietveld Method to XRPD 21 9.2.1. The Structure Model 21 9.2.2. Data Collection 22 9.2.3. Profile Functions 24 9.3. Determination of Crystallite Size and Lattice Strain 32 D. Effect of Pharmaceutical Processing on Crystallinity 35 E. Trace Additives 40 F. Phase Changes of Pharmaceutical Solids 40 1. Polymorphism 41 1.1. Methods of Characterizing Polymorphs 41 1.2. Polymorphism and Pharmaceutical Processing 43 2. Solvation 43 II. EXPERIMENTAL 44 A. Materials 44 1. Chemicals 44 2. Solvents 45 3. Gases 45 B. Equipment 46 C. Methods 49 1. Suspension Density 49 2. Gas (Helium) Displacement Pycnometry 49 3. Specific Surface Area Measurements 49 4. Scanning Electron Microscopy 50 5. Solid-State Nuclear Magnetic Resonance 50 6. Differential Scanning Calorimetry 51 vi Page 7. Thermal Microscopy 51 8. Relative Humidity-Composition Diagram 52 9. Solution Calorimetry 53 10. Solubility and Dissolution Rates 53 11. Gas Chromatography 55 12. Grinding 56 13. Tabletting 56 14. Tablet Strength Testing 56 15. X-ray Powder Diffraction 59 III. RESULTS AND DISCUSSION 63 A. Changes in Crystallinity with Pharmaceutical Processing 63 1. Determination of Crystallinity using traditional Methods 63 2. The Rietveld Structure Refinement Method 70 2.1. X-ray Powder Data and the Structural Model 72 2.2. Assessment of Crystallinity Changes 79 2.2.1. Grinding and Tabletting 79 2.2.2. Storage at Elevated Temperatures 86 2.2.3. Incorporation of Additives 96 B. Phase Transitions with Pharmaceutical Processing 100 1. Physical Characterization of Chiorpromazine HC1 and its 101 Granules 1.1. Scanning Electron Microscopy 101 1.2. Powder X-ray Diffraction 101 1.3. Thermal Analysis 105 1.4. Heat of Solution and True Density 108 1.5. Solubility and Dissolution Rate 111 vii Page 1.6. Relative Humidity-Composition Studies 111 2. Tabletting 116 3. Tablet Strength Testing 122 IV. SUMMARY 126 V. REFERENCES 129 APPENDIX A 148 APPENDIX B 160 APPENDIX C 166 v-Ill LIST OF TABLES Page 1. Data collection and details of structure refinement for MTZ, ASA, 62 DPH and PMDPH doped DPH. 2. Comparison of refined cell dimensions of MTZ to literature values. 76 3. Comparison of refined cell dimensions of ASA to literature values. 77 4. Comparison of refined cell dimensions of DPH and DPH doped 78 with PMDPH to literature values for DPH. 5. Changes in the cell dimensions of ASA with processing. 83 6. Indexed X-ray diffraction pattern of DPH. 97 7. Thermal analysis of CPZ(II) and CPZ(I)-H. 107 8. A comparison of the heats of solution and true densities of CPZ(II), 110 CPZ(I), CPZ(I)-H’ and CPZ(I)-H. 9a. Analytical functions used to represent the diffraction profile. 152 9b. Variables used in profile functions. 153 10. Agreement indices for the Rietveld refinement. 156 11. Chemical structure, crystal system, space lattice, and space group 160 of MTZ. 12. Chemical structure, crystal system, space lattice, and space group 161 of ASA. 13. Chemical structure, crystal system, space lattice, and space group 162 of DPH. ix Page 14. Chemical structure, crystal system, space lattice, and space group 163 of CPZ(I)-H. 15. Chemical structure, crystal system, space lattice, and space group 164 of CPZ(II). x LIST OF FIGURES PRg 1. Schematic representation in two dimensions of the structural 4 differences between a crystalline solid and a noncrystalline solid. 2. The relationship between crystalline and noncrystalline solids, 5 and liquids and gases. 3. The arrangement of crystallites within a mosaic crystal. 9 4. Deviation of the peak shape of XRPD from Gaussian behaviour. 26 5. Variations of peak width with Bragg angle. 29 6. Comparison of an asymmetric diffraction peak with a symmetric 31 and asymmetric corrected calculated profile. 7. Schematic diagram of the CT4O mechanical strength tester with 57 modifications. 8. Heat of solution of MTZ: (a) as received, (b) hand ground, and 65 stored at 54°C for (c) 90 and (d) 162 hours. 9. Changes in the intrinsic dissolution rate of MTZ tablets (270 MPa) 67 with storage at 25°C. 10. Heat of fusion of MTZ with grinding using a mechanical ball and 69 mill. 11. Diffractograms of MTZ (a) hand ground and (b) tabletted. 71 12. Diffractogram of MTZ shown with the calculated and difference 73 patterns. xi Page 13. Diffractogram of ASA shown with the calculated and difference 74 patterns. 14. Diffractogram of DPH shown with the calculated and difference 75 patterns. 15. FWHM of MTZ (a) ground and (b) tabletted shown as a function of 80 20. Barium fluoride was used as the peak width standard. 16. Diffractograms of ASA (a) as received, (b) hand ground, and hand 82 ground and tabletted at (c) 270 and (d) 408 MPa. 17. FWHM of ASA (a) as received, (b) hand ground, and hand ground 84 and tabletted at (c) 270 and (d) 408 MPa shown as a function of 20.