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Crystallinity changes and phase transitions of selected pharmaceutical solids with processing Wong, Marion W. Y. 1994

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CRYSTALLINITY CHANGES AND PHASE TRANSITIONS OF SELECTEDPHARMACEUTICAL SOLIDS WITH PROCESSINGbyMARION W.Y. WONGB.Sc. (Pharm), The University of British Columbia, 1988A THESIS SUBMITTED IN PARTIAL FULFILLMENT OFTHE REQUIREMENTS FOR THE DEGREE OFDOCTOR OF’ PHILOSOPHYinTHE FACULTY OF GRADUATE STUDIESFaàulty of Pharmaceutical SciencesDivision of Pharmaceutics and BiopharmaceuticsWe accept this thesis as conformingto the required standardTHE UNIVERSITY OF BRITISH COLUMBIANovember 1993© Marion W.Y. Wong, 1993In presenting this thesis in partial fulfilment of the requirements for an advanceddegree at the University of British Columbia, I agree that the Library shall make itfreely available for reference and study. I further agree that permission for extensivecopying of this thesis for scholarly purposes may be granted by the head of mydepartment or by his or her representatives, It is understood that copying orpublication of this thesis for financial gain shall not be allowed without my writtenpermission.Department of_______________________The University of British ColumbiaVancouver, CanadaDate jt7’ /(Signature)DE-6 (2/88)11ABSTRACTThe solid state properties of drugs and pharmaceutical excipients canbe significantly affected by processing (e.g. grinding, tabletting, heating andadditive incorporation) and reflect structural changes within a solid. Suchchanges may involve alterations in both the chemical and physical nature ofthe crystal structure (e.g. hydrates), complete rearrangements of the samechemical components in three-dimensional space (e.g. polymorphs), or moresubtle changes which involve neither the chemical composition nor the spacelattice. These more subtle changes do not involve phase changes and arereferred to as changes in the degree of crystallinity, X. Metronidazole(MTZ), acetylsalicylic acid (ASA), diphenylhydantoin (DPH) andchiorpromazine hydrochloride (CPZ) were selected to illustrate these variouschanges.Many of the empirical methods which have been proposed for studyingcrystallinity were initially used to assess the X ofMTZ before and afterprocessing. Although a reduction and subsequent increase in X wasindicated, the observed changes could not be adequately explained. Theresults were inconclusive and a more direct measure ofX was necessary.X-ray powder diffractograms reflect the crystal structure, and when used inconjunction with the Rietveld structure refinement method, the processeswhich cause changes in X (i.e. crystallite size and lattice distortion) can bedirectly quantified.Tabletting reduced the peak intensities of ground MTZ and this wasaccompanied by an increase in the full width at halfmaximum height(FWHM). Since the unit cell dimensions were not significantly altered,reductions in crystallite size were thought to be primarily responsible for the111reduction in the X ofMTZ. This was confirmed using the Voigt profilefunction. Though the Gaussian component was slightly affected (indicatingsome lattice strain), it was the FWHM of the Lorentzian component of thediffractograms which showed dramatic increases with processing andsubsequent reductions with time at 25°, 54°, 700 and 10000. From theLorentzian profile, a mean crystallite size for MTZ can be obtained.Tabletting the mechanically ground MTZ further reduced the meancrystallite size. With storage at elevated temperatures, a subsequentincrease in crystallite size was observed, where the rate and extent ofrecovery was dependent on the storage temperature (i.e. recovery at 100°Cwas greater than recovery at 700, 54° or 25°C). Complete recovery was notobserved.The extent to which the peak intensities of ASA were reduced withprocessing was similar to MTZ, but the underlying structural changes weredifferent. Significant lattice distortion was observed with a 0.5% reduction inthe b dimension on tabletting. No significant recovery was found on storageat elevated temperatures.Contrary to previous workers who suggested that the incorporation ofDPH with 3-propanoyloxymethyl-5,5-diphenylhydantoin (PMDPH) causedsignificant “lattice disorder or disruption”, no significant changes in thelattice dimensions were detected. Analysis of bond lengths suggested thatthe incorporation of PMDPH into the crystal lattice was unlikely.CPZ illustrated a complete change in both the chemical and physicalnature of the crystal lattice with processing. Wet granulation completelyconverted CPZ from a room temperature metastable form to a hemihydrate ofthe room temperature stable polymorph. Significant differences in thetablettability of each form were shown.ivTABLE OF CONTENTSPageAbstractTable of Contents ivList ofTables viiiList of Figures xList of Abbreviations and Symbols xivAcknowledgements xixI. INTRODUCTION 1A. Solids 3B. Crystallinity 6C. Methods of Quantitating Crystallinity and Their Limitations 101. Density 102. Calorimetry 123. Nuclear Magnetic Resonance 144. Infrared Spectroscopy 155. Counting of Dislocation Etch Pits 156. Polarized-Light Microscopy 167. Water Adsorption 168. Kinetics 179. Powder X-ray Diffraction 17VPage9.1. The Rietveld Structure Refinement Method 209.2. Application of the Rietveld Method to XRPD 219.2.1. The Structure Model 219.2.2. Data Collection 229.2.3. Profile Functions 249.3. Determination of Crystallite Size and Lattice Strain 32D. Effect of Pharmaceutical Processing on Crystallinity 35E. Trace Additives 40F. Phase Changes of Pharmaceutical Solids 401. Polymorphism 411.1. Methods of Characterizing Polymorphs 411.2. Polymorphism and Pharmaceutical Processing 432. Solvation 43II. EXPERIMENTAL 44A. Materials 441. Chemicals 442. Solvents 453. Gases 45B. Equipment 46C. Methods 491. Suspension Density 492. Gas (Helium) Displacement Pycnometry 493. Specific Surface Area Measurements 494. Scanning Electron Microscopy 505. Solid-State Nuclear Magnetic Resonance 506. Differential Scanning Calorimetry 51viPage7. Thermal Microscopy 518. Relative Humidity-Composition Diagram 529. Solution Calorimetry 5310. Solubility and Dissolution Rates 5311. Gas Chromatography 5512. Grinding 5613. Tabletting 5614. Tablet Strength Testing 5615. X-ray Powder Diffraction 59III. RESULTS AND DISCUSSION 63A. Changes in Crystallinity with Pharmaceutical Processing 631. Determination of Crystallinity using traditional Methods 632. The Rietveld Structure Refinement Method 702.1. X-ray Powder Data and the Structural Model 722.2. Assessment of Crystallinity Changes 792.2.1. Grinding and Tabletting 792.2.2. Storage at Elevated Temperatures 862.2.3. Incorporation of Additives 96B. Phase Transitions with Pharmaceutical Processing 1001. Physical Characterization of Chiorpromazine HC1 and its 101Granules1.1. Scanning Electron Microscopy 1011.2. Powder X-ray Diffraction 1011.3. Thermal Analysis 1051.4. Heat of Solution and True Density 1081.5. Solubility and Dissolution Rate 111viiPage1.6. Relative Humidity-Composition Studies 1112. Tabletting 1163. Tablet Strength Testing 122IV. SUMMARY 126V. REFERENCES 129APPENDIXA 148APPENDIX B 160APPENDIX C 166v-IllLIST OF TABLESPage1. Data collection and details of structure refinement for MTZ, ASA, 62DPH and PMDPH doped DPH.2. Comparison of refined cell dimensions ofMTZ to literature values. 763. Comparison of refined cell dimensions ofASA to literature values. 774. Comparison of refined cell dimensions of DPH and DPH doped 78with PMDPH to literature values for DPH.5. Changes in the cell dimensions of ASA with processing. 836. Indexed X-ray diffraction pattern of DPH. 977. Thermal analysis of CPZ(II) and CPZ(I)-H. 1078. A comparison of the heats of solution and true densities of CPZ(II), 110CPZ(I), CPZ(I)-H’ and CPZ(I)-H.9a. Analytical functions used to represent the diffraction profile. 1529b. Variables used in profile functions. 15310. Agreement indices for the Rietveld refinement. 15611. Chemical structure, crystal system, space lattice, and space group 160ofMTZ.12. Chemical structure, crystal system, space lattice, and space group 161of ASA.13. Chemical structure, crystal system, space lattice, and space group 162of DPH.Page14. Chemical structure, crystal system, space lattice, and space group 163of CPZ(I)-H.15. Chemical structure, crystal system, space lattice, and space group 164of CPZ(II).ixxLIST OF FIGURESPRg1. Schematic representation in two dimensions of the structural 4differences between a crystalline solid and a noncrystalline solid.2. The relationship between crystalline and noncrystalline solids, 5and liquids and gases.3. The arrangement of crystallites within a mosaic crystal. 94. Deviation of the peak shape ofXRPD from Gaussian behaviour. 265. Variations of peak width with Bragg angle. 296. Comparison of an asymmetric diffraction peak with a symmetric 31and asymmetric corrected calculated profile.7. Schematic diagram of the CT4O mechanical strength tester with 57modifications.8. Heat of solution ofMTZ: (a) as received, (b) hand ground, and 65stored at 54°C for (c) 90 and (d) 162 hours.9. Changes in the intrinsic dissolution rate ofMTZ tablets (270 MPa) 67with storage at 25°C.10. Heat of fusion ofMTZ with grinding using a mechanical ball and 69mill.11. Diffractograms ofMTZ (a) hand ground and (b) tabletted. 7112. Diffractogram ofMTZ shown with the calculated and difference 73patterns.xiPage13. Diffractogram ofASA shown with the calculated and difference 74patterns.14. Diffractogram of DPH shown with the calculated and difference 75patterns.15. FWHM ofMTZ (a) ground and (b) tabletted shown as a function of 8020. Barium fluoride was used as the peak width standard.16. Diffractograms ofASA (a) as received, (b) hand ground, and hand 82ground and tabletted at (c) 270 and (d) 408 MPa.17. FWHM ofASA (a) as received, (b) hand ground, and hand ground 84and tabletted at (c) 270 and (d) 408 MPa shown as a function of 20.18. FWHM of the Lorentzian component (FL) ofMTZ hand ground and 87tabletted.19. FWHM of the Gaussian component (FG) ofMTZ hand ground and 88tabletted.20. FWHM of the Lorentzian component (FL) ofMTZ hand ground 89with storage at 25°C.21. FWHM of the Lorentzian component (FL) of MTZ hand ground 90with storage at 54°C.22. FWHM of the Lorentzian component (FL) ofMTZ hand ground 91with storage at 70°C.23. FWHM of the Lorentzian component (FL) ofMTZ hand ground 92with storage at 100°C.24. Changes in the crystallite size of ground MTZ with storage at 25°, 9454°, 70° and 100°C.xiiPage25. Changes in the b ofASA as received, hand ground, and tabletted 95at 270 MPa. Changes in b with storage at 54°C are also shownafter 3, 7, and 14 days.26. Diffractogram of DPH, and DPH with fluorophiogopite. 9827a. Scanning electron image of CPZ(II). 10227b. Scanning electron image of CPZ(I)-H’. 10328. X-ray diffractograms of(a) CPZ(II) and (b) CPZ(I)-H’. The 104diffractograms of CPZ(I)-H and CPZ(I) are qualitatively the sameas CPZ(I)-H’.29. DSC thermograms of(a) CPZ(II), (b) CPZ(I)-H’ and (c) CPZ(I) 106using hermetically sealed pans with pinhole.30. Interconversions of CPZ. 10931. Comparison of the dissolution rates of CPZ(I) and CPZ(II). 11232. Relative humidity-composition profile of CPZ(I). 11333. Changes in the lattice dimensions of CPZ(I) with the incorporation 115ofwater.34. X-ray diifractograms of CPZ(I)-H’ treated as follows: (a) dried 117under vacuum with silica gel at 70°C; (b) hand ground and driedas in (a); (c) compressed under 210 MPa (the top face of a tabletwas scanned and the appearance of two new peaks at 5.3 and 9.520 are due to magnesium stearate and talc, respectively); and (d)heated under vacuum with silica gel at 100°C.35. Peak offset times of CPZ(II) and CPZ(I)-H’ with increasing 118compression pressure.XIIIPage36. Peak offset times of CPZ(I)-H’, CPZ(I)-H and CPZ(I) with 120increasing compression pressure.37. Elastic recoveries of CPZ(I), CPZ(II), CPZ(I)-H’ and CPZ(I)-H. 12138. Force of failure of tablets of CPZ(I)-H’, CPZ(I)-H and CPZ(I). 12339. Deformation of tablets of CPZ(I)-H’, CPZ(I)-H and CPZ(I). 12440. Simple monocinic lattice. 16541. Rectangular (orthorhombic) lattice. 16542. 400 MHz13C-NMR spectrum of CPZ(II). 16743. 400 MHz 13C-NMR spectrum of CPZ(I)-H’. 168xivLIST OF ABBREVIATIONS AND SYMBOLSa dimension of the crystallographic unit cell along the x-axisA ampereA angstromASA 0-acetylsalicylic acidb dimension of the crystallographic unit cell along the y-axisBKPOS background positionc dimension of the crystallographic unit cell along the z-axisdegrees CelsiusC equilibrium solubilityheat capacityCPZ chiorpromazine hydrochlorideCPZ(I) chiorpromazine hydrochloride, form ICPZ(I)-H’ partially hydrated chiorpromazine hydrochloride, form ICPZ(I)-H fully hydrated chiorpromazine hydrochloride, form ICPZ(II) chiorpromazine hydrochloride, form IICu copperdegreed Durbin-Watson d statisticDBW D.B.WilesDSC differential scanning calorimetryesd estimated standard deviationxvF Young’s modulusproportionality constant of Hooke’s Law at a given porosityFWHM full width at half height, Hkg grampg microgramG GaussianFWHM of the Gaussian peakF’WHM of the Lorentzian peakAG Gibbs free energyGC gas chromatographyGofF Goodness-of-FitGSAS Generalized Crystal Structure Analysis Systemmixing parameterh Planck constantH enthalpyAHf enthalpy of fusionElk full width at half maximum (height), FWHMAH enthalpy of solutionHz hertzIL Intermediate LorentzianJ joulek Boltzmann constantK kelvinkg kilogramkob observed rate constantmicrolitremL milliliterxviL LorentzianLVDT linear variable differential transducerm metrem2 square metreurn micrometremA milliamperemg milligramMHZ megahertzmm minuteml millilitreML Modified LorentzianMPa megapascalMod-TCH Modified Thompson-Cox-Hastings pseudo-VoigtpVmol moleMTZ metronidazoleN newtonN’ number of stepsNBS National Bureau of StandardsNi nickelNMR nuclear magnetic resonancePa pascalPoly Edgeworth seriesppm parts per millionpV Pseudo-VoigtPVII Pearson VIIR gas constantxviiRB Bragg intensity R-factorRexp expected R-factorRF structure amplitudes R-factorR pattern R-factorweighted R-patternRH relative humidityrpm revolutions per minute0 thetatris tris(hydroxymethyl)-aminomethanes secondmicrosecondS entropyASf entropy of fusionentropy of solutionSA specific surface areaSC solution calorimetrySEM scanning electron microscopySRM standard reference materialT counting timeUSGS United States Geological SocietyUSP United States PharmacopoeiaUV ultravioletV voltkV kilovoltVIS visibleV VoigtX degree of crystallinityXRPD X-ray powder diffractionYib background intensity at step iYic calculated intensity at step iyj0 observed intensity at step iZ number of molecules in a crystallographic unit cellxviiixixACKNOWLEDGMENTSIt gives me great pleasure to acknowledge the guidance and support ofmy supervisor, Dr. Alan Mitchell. I am also very grateful to the members ofmy research committee, Dr. Frank Abbott, Dr. Helen Burt, Dr. Lee Groat andDr. Mati Raudsepp, for their invaluable insight. Special thanks is extendedto Dr. C. Fyfe for the solid-state NMR analysis of chiorpromazinehydrochloride and its granules, Dr. L. Groat for his assistance in therefinement of the unit-cell dimensions of chlorpromazine hydrochloride, Dr.M. Raudsepp for his assistance in the Rietveld analysis, and Dr. W. Riggs andDr. A. Szeitz for the gas chromatographic analysis of ethanol. The technicalassistance of Randall Oates and Sarvajna Dwivedi during the tablettingstudies are gratefully acknowledged.I am also very grateful to my ‘extended family’, Ron Aoyama, IbrahimEl-bagory, John Jackson, Eva Law, and Chuck Winternitz, and mycolleagues, Anthony Borel, Ahmad Doroudian, John Gordon, John Kim, JuditOrbay, Sue Panesar, George Tonn, Jing Wang and Matthew Wright, for theirencouragement and helpful discussions.The financial support of the Medical Research Council of Canada,Merck Frosst Canada Inc., Stanley Pharmaceuticals and the University ofBritish Columbia is gratefully acknowledged.Finally, I gratefully acknowledge my family and friends for their neverfailing love and continual prayers.1INTRODUCTIONPharmaceutical processing can lead to marked changes in the solidstate properties of drugs and excipients. These changes can include theformation of hydrates, which involve dramatic alterations in both thechemical and physical nature of the crystal structure, polymorphicchanges, in which the chemical composition is the same but where themolecules occupy a different space lattice, and lastly, more subtle changes,which involve neither chemical changes nor changes in the space lattice.These latter changes, unlike the formation of hydrates and polymorphs, donot involve phase changes but can still have significant effects on solidstate properties and will be referred to as changes in the degree ofcrystallinity. This thesis presents examples of pharmaceutical compoundswhich illustrate each of these changes. Particular emphasis is placed onthe use of X-ray powder diffraction data to estimate crystallite size and thedegree of lattice distortion as measures of structural order.HYPOTHESES:1. That pharmaceutical processing can lead to crystal disorder andto phase changes;2. That, on storage, the crystal structure recovers to a more stablestate.2OBJECTIVES:1. To assess changes in the crystallinity and/or solid-solid phasechanges of selected pharmaceutical solids as a result ofprocessing;2. To develop a direct quantitative method of assessing changes incrystal structure.APPROACH: Phase changes which may arise as a result ofpharmaceutical processing are readily identified by differential scanningcalorimetry (DSC), solution calorimetry (SC) and X-ray powder diffraction(XRPD), but the quantitation of crystallinity remains a challenge inpharmaceutics. Most of the existing methods are indirect and inferchanges in crystallinity from an empirical measurement. To understandchanges in the structural order of the crystalline state, the effects ofcrystallite size were separated from the effects of lattice distortion byapplying the Rietveld structure refinement method to XRPD data.RESEARCHPLAN: The effects of grinding, tabletting and heating on thecrystallinity of acetylsalicylic acid (ASA) and metronidazole (MTZ) werestudied. Both solids exhibited extensive crystal growth post-compression,which suggested that they may be suitable model compounds for studyinga decrease in crystallinity during processing, and a return to order duringstorage. The effect of additive incorporation on the crystallinity ofphenytoin was studied since previous authors have suggested thatsignificant lattice distortion occurs when additives are incorporated.Since pharmaceutical processing can also lead to phase changes, it wasnecessary to differentiate between changes in crystallinity and phase3changes. Chiorpromazine hydrochloride (CPZ) was studied as a modelcompound showing both polymorphism and solvation on processing.A. SolidsSolids, by definition, can transmit shear waves or have a minimumviscosity of 1014 poise (1013 Nm2s) (Roy, 1970) and are crystalline ornoncrystalline. The crystalline solid is demonstrated by long range three-dimensional order which occurs over a minimum distance of 30-50 A or sixunit cells (Kiug and Alexander, 1974a); in a perfect crystal, atoms, ions ormolecules are positioned accurately at points throughout an undistortedspace lattice (Darwin, 1922; Ewald, 1958). All remaining solids arenoncrystalline. Noncrystalline solids obtained from crystalline solids areamorphous, while noncrystalline solids obtained from liquids are glasses.The structural difference between a crystalline solid and a noncrystallinesolid is illustrated in Figure 1. The transition from crystalline tononcrystalline occurs when free energy, in excess of that required tomaintain a stable arrangement, is incorporated. This may result from asudden change in a thermodynamic variable such as temperature orpressure. The relationship between crystalline and noncrystalline solidsis illustrated in Figure 2 (Roy, 1970).4Figure 1. Schematic representation in two dimensions of the structuraldifferences between a crystalline solid (left) and anoncrystalline solid (right). The composition of lattice isA2X3where the solid circles are the atoms ofA and the open circlesare the atoms ofX.(Reproduced from Zachariasen, W.H., The atomic arrangement in glass. J.Am. Chem. Soc., 54 (1932) 3845-3846.)5Metastable Non—crystallinesolidsphases2iiuorphized solidsGlasses1 +Energy Energy EnergyEnergyadded added left infrozenby by byin fromExcess shear radi— reac— melt offree ation tion sameenergy cmposi—tion bycoolingStable Crystalline solids Liquidsphases_______________________________________________Figure 2. The relationship between crystalline and noncrystallinesolids, and liquids and gases are shown (after Roy, 1970).(Reproduced from Suryanarayanan, R., Studies on the Crystallinity andPhase Transitions of Calcium Gluceptate. Ph.D. Thesis, the University ofBritish Columbia, 1985, p. 2.)6B. CrystallinityExperimentally, the division between crystalline and noncrystallinesolids is not clear; the term degree of crystallinity (Xe.) is used to describe astate of order intermediate between perfect crystals and noncrystallinesolids. Crystallinity has been extensively studied in polymers which inmany cases have been shown to exhibit crystalline and noncrystallineproperties (Miller, 1966a). Two models have been used to relate theobserved physicochemical properties of polymers to their structure: thefringed-micelle model and the folded-chain model (Chung and Scott, 1973).The common premise in both models is that two distinct states coexist -namely, small perfectly crystalline regions embedded within anamorphous matrix, where the amorphous material is regarded as adistinct ‘state’. The degree of crystallinity is expressed as the weightfraction of crystalline component in a sample (Chung and Scott, 1973;Smith, 1989).The two-state model was adopted by the USP XIX (1975) and is stillused to define the crystallinity of pharmaceutical solids (USPXXII/NFXVII, 1990). Solids are classified as either crystalline, noncrystalline or amixture of the two forms. This definition implies that solids are eitherperfectly ordered (100% crystalline) or completely disordered (0%crystalline). Most solids, however, lie between these extremes.An alternative concept, the one-state model, was proposed bySuryanarayanan and Mitchell (1985). Unlike the two-state model, theone-state model does not assume a clear distinction between thecrystalline and amorphous states. Rather, it gives X a value between 0%(amorphous) and 100% (perfectly crystalline) based upon the state of7structural order. An increasing concentration of structural imperfectionsincreases the disorder and causes a decrease in X.Although the one-state model has improved our understanding ofthe crystallinity of pharmaceutical solids, few methods are available todistinguish between these two concepts. Most X calculations implicitlyassume the two-state model (Suryanarayanan and Mitchell, 1985). Thecomplex transition from crystalline to amorphous is also highly simplifiedand the structural changes which are responsible for this transitionremain poorly understood.Solids contain different types and numbers of imperfections whichcause regions of misfit and disorder (Boldyrev et al., 1979a). Most obviousis the interruption of periodicity at a crystal face. Other imperfectionsinclude surface irregularities and cracks. With respect to the properties ofpharmaceutical solids, significant imperfections within the crystalinclude point defects (due to impurities and additives), dislocations, andgrain boundaries.A direct correlation between the concentration of structural defectsand X has not been established. Furthermore, even when present atmaximum concentrations, crystal defects cannot be solely responsible forremoving all long range order and causing a solid to become amorphous(Suryanarayanan, 1985). Crystallite size and lattice strain must also beconsidered when studying the crystallinity of a solid (Smith, 1989).The terms crystallite size and particle size are sometimesinterchanged in the literature but they are not synonymous. A particlecan be either a single crystal or an aggregate of crystals, while acrystallite is a single diffracting domain. Atomic planes within a crystalrarely traverse the entire crystal without appreciable distortion or8discontinuity. Most crystals are mosaic crystals composed of relativelyperfect regions (mosaic blocks) separated by subgrain boundaries (arraysof dislocations) (Figure 3). These small-angle boundaries slightly misalignthe mosaic blocks from the neighboring regions. Since the angularmisalignment between blocks is only between 2’ to 30’ of arc (0.03° to 0.5°)(Ladd and Palmer, 1977), an aggregate of mosaic blocks can contribute to asingle reflection and form a crystallite (refer also to Section I.C.9.).The periodicity within crystals is usually assessed using X-raydiffraction which measures crystallite size and not particle size.Crystalline solids are differentiated from noncrystalline solids by the sizeof their crystallites and the size limit used is dictated by the practicallimits of this method (30-50 A). According to Roy (1970), noncrystallinesolids contain crystallites of 10 to 100 A. Crystallites in this size rangeproduce very broad X-ray diffraction peaks and are considered X-rayamorphous.In the present work, both crystallite size and lattice distortion wereused to measure changes in X, where crystallite size has been discussedabove and lattice distortion refers to changes in the dimensions of the unitcell within the mosaic domains. A decrease in crystallite size and/or anincrease in lattice distortion as a result of pharmaceutical processing willlead to a decrease in X.9Figure 3. The mosaic structure of a crystal; the angular misalignmentbetween blocks may vary from 2’ to about 30’ of arc (i.e. 0.03°to 0.5°).(Reproduced from Ladd, M.F.C. and Palmer, R.A., Structure Determinationby X-ray Crystallography, Plenum Press, New York, 1977, p. 347.)10C. Methods of Quantitating Crystallinity and TheirLimitationsThe quantitation ofX is an ongoing challenge in pharmaceutics.Many of the methods used originated from crystallinity studies withpolymers. The principle methods include density, calorimetry, nuclearmagnetic resonance (NMR), infrared spectrometry (IR), and X-ray powderdiffraction (XRPD) (Chung and Scott, 1973).In most cases, an indirect measure ofX is obtained by monitoringchanges in specific properties affected by changes in X. Values ofXc arefrequently based on regression analysis and rely heavily upon accuratemeasurements of perfectly crystalline and amorphous standards (Nakai etal., 1982) - neither ofwhich exists. Therefore, absolute X values varydepending upon the choice of standards (Pikal et al., 1978). The definitionoforder or crystallinity also differs depending on the method. Hence, theX values obtained using different methods have only empirical value andrarely agree.A number of other methods are used, including polarized lightmicroscopy, counting dislocation etch pits, water adsorption and kineticstudies. These techniques and their limitations will also be discussed.1. DensityDensity measurements are an alternative to estimating the state oforder within a solid. The density of a crystalline solid is usually higherthan its amorphous counterpart since interatomic distances are at theirminimum (Suryanarayanan and Mitchell, 1985; Brown et al., 1990). A11decrease in lattice order or X increases the volume of a crystal which inturn decreases its density.Several techniques are available for determining the density ofsolids (Bauer and Lewin, 1972). Most recently, helium pycnometry hasbecome popular in measuring the true density of pharmaceutical solids(with the purpose of assessing X) because it is simple to use, rapid, andnondestructive. Brown et al. (1990) used helium pycnometry to studychanges in the X of ibuprofen when crystallized from acetonitrile atdifferent cooling rates and Saleki-Gerhardt et al. (1992) used the samemethod to assess disorder in sucrose with mechanical milling.Measurement of true density using the suspension density (flotation)method, however, is unique in that samples having very small differencesin density can be differentiated (Johnston and Hutchison, 1940), and thetwo models of crystallinity can be distinguished (Suryanarayanan andMitchell, 1985). If the simple two-state model is valid, a partial crystallinesample would separate into two fractions when dispersed in thesuspending liquid, due to the different densities of the crystalline andamorphous fractions. On the other hand, if the one-state model is valid,progressive changes in X will be accompanied by a gradual change indensity.The effect of temperature on the density of a solid is usuallyneglected when interpreting suspension density data and this is oftenunacceptable. Duncan-Hewitt and Grant (1986) found that as theincorporation of oleic acid into adipic acid or p-acetoxyacetanilide intoacetaminophen increased, depending on the temperature used, thermalexpansivity:(a) decreased with an accompanying increase in crystal density;12(b) simply decreased; or(c) was unaffected.The use of thermal expansivity as a more reliable indicator ofX wasproposed.2. CalorimetryA thermodynamic definition of order is provided by calorimetricmethods. The use of solution calorimetry (SC) is based on the observationthat, for many solids, the energy of the amorphous form is higher than theenergy of the crystalline form (Pikal et at., 1978; Vanderzee et at., 1981). Ifthe energy difference between the amorphous and crystalline states islarge, this method can provide a very accurate assessment of Xc. Caremust be taken, though, in the interpretation of these data. Two processesare involved in the dissolution of a solid: the interaction between thesolute and the solvent, and bond breaking. The heat measured is the sumof the heat of solvation (exothermic) and the heat absorbed to break up thecrystal lattice (endothermic). Only the heat involved in the breaking ofbonds is thought to reflect X, but separation of this process from theoverall heat measured is difficult. The adsorption of atmospheric moisture(exothermic) during sample preparation presents another serious problem.With pharmaceutical processing (e.g. grinding and tabletting), the abilityof solids to adsorb water increases as clean surfaces are created andexisting crystal faces are activated. This, in turn, causes the heatinvolved in bond breaking to be underestimated. Differential scanningcalorimetry (DSC) has also been used (York and Grant, 1985; SalekiGerhardt et at., 1992). The heat of fusion is measured and non-crystalline(amorphous) compounds are characterized by the absence of a sharp13melting endotherm. A major disadvantage of this method is that heatingcan alter the concentration of defects by the process of annealing and maycause decomposition. Therefore, during DSC, the parameters beingmeasured may be constantly changing.Thermodynamics is a powerful quantitative tool in the study ofsolids (Swalin, 1972). Specific models of a crystal need not be postulatedand atomic details of the structure of a material are not necessary. Simplyby applying the three laws of thermodynamics with standardmathematical techniques, many macroscopic properties can be obtained.Grant and coworkers extended the principles of thermodynamics tostudy the X of pharmaceutical solids and developed a number ofapproaches based on entropy (York and Grant, 1985; Grant and York,1986a and 1986b; Vachon and Grant, 1987). The problems inherent incrystallinity scales were avoided. The first method quantified latticedisorder resulting from the incorporation of additives or impurities byusing a dimensionless disruption index (d.i.). D.i. was defined as the rateof change of the difference between the entropy of the solid and the entropyof the liquid with respect to the ideal entropy of mixing of the componentsof the solid (York and Grant, 1985; Grant and York, 1986a). A morerigorous treatment of d.i. was presented later by Pikal and Grant (1987).The second more generally applicable method was the ‘entropy ofprocessing (or imperfection)’, ASP, which assesses the contribution oflattice imperfections to the disorder of a solid by measuring the differencebetween the entropy of the sample and the entropy of the same amount of areference material (Grant and York, 1986b). Measurements of either theheat of fusion and melting point or the heat of solution and dissolution ratewere used to derive d.i., while determinations of the heat of fusion or heat14of solution with studies of solubility were used to calculate ASP. In a thirdapproach, Vachon and Grant (1987) formulated the enthalpy-entropycompensation model to describe the complex interplay betweenpharmaceutical processing and inherent particle parameters. Theconcomitant energizing and disordering which occur imply an increase inenthalpy (AH) and entropy (AS) with the extent of such increasesdependent on the nature and intensity of the treatment. The small change(ö) in AH and AS can be related by the compensation principle,o(AH)=f3.o(AS), where I is the proportionality constant and is termed the‘compensation temperature’.Although these approaches are sound in theory, the power ofthermodynamics becomes its disadvantage. Experimentally, theapplication of thermodynamics by itself is too general and simplistic(Swalin, 1972). No information is obtained about the detailed relationshipamong atoms or defects in crystals, and no mechanistic explanation isprovided for the observed changes in X.3. Nuclear Magnetic ResonanceNuclear magnetic resonance (NMR) has also been used to assess Xbut it measures motion rather than order. Slower-moving protons areused to represent the ‘rigid’ crystalline fraction while the faster-movingprotons represent the ‘mobile’ amorphous fraction. Factors such astemperature, molecular weight, and the extent of molecular bonding insolids affect the amount of motion measured (Miller, 1966b).154. Infrared SpectrosconyAccording to Kossler (1967), some JR absorption bands of polymersmay appear only when the materials exist in a crystalline state. However,there does not seem to be a predictable relationship between the X of acompound and its JR absorption behavior. Grant and Auburn (1965)observed sharp JR bands with anhydrous ampicillin while ampicillinmonohydrate exhibited diffuse bands which were indicative of a low degreeof order. Even when a relationship is established (Black and Lovering,1977; Kamat et at., 1988), changes in X cannot be explainedmechanistically.5. Counting of Dislocation Etch PitsTo gain insight into the crystal structure of single crystals, aphysical measure of dislocation density was proposed (Burt and Mitchell(1981); Friesen et at. (1981)). Dislocations are sites of localized energy andtwo-dimensional nucleation is known to occur more rapidly at dislocationsthan anywhere else on the crystal surface. Treating a cleaved surfacewith etching solution reveals the sites of emergent dislocations andenables one to count them under a microscope. A direct estimate of thenumber of dislocations per unit area is obtained. Unfortunately, thismethod is restricted to large, well-formed crystals with a maximum ofabout 108 dislocations/cm2.Although the extent ofX is dependent on thenumber and type of lattice imperfections, only dislocations can bequantified using this method. Furthermore, only dislocations on thecleaved surface are measured and a relationship between dislocationdensity and X has yet to be determined (discussed above).166. Polarized-Light MicroscopyPolarized-light microscopy is a qualitative method recognized by theUSPXXII/NFXVII (1990) for determining whether or not apharmaceutical solid is crystalline. Non-cubic crystalline solids areoptically anisotropic and will exhibit birefringence (interference colors)and extinction when rotated between crossed-polarizers (Bunn, 1946; USPXXIIINFXVII, 1990). Unstrained amorphous solids, on the other hand,are optically isotropic and are extinct at all orientations between crossed-polarizers.Pikal et al. (1978), Oberholtzer and Brenner (1979), and Osawa et al.(1988) used this method in combination with X-ray powder diffraction todefine whether a sample was crystalline or amorphous. Solids which didnot show distinct peaks in the XRPD pattern nor birefringence whenplaced between crossed-polarizers were classified as amorphous.7. Water AdsorptionHuttenrauch (1978) proposed that solids of higher states of disorderpossess higher free energies which in turn enhance vapor adsorption. Thewater adsorption isotherm of sodium chloride (Kontny et al., 1987), forexample, confirmed that the extent of adsorption per unit area could beenhanced by hand-grinding. For cephalothin sodium (Pikal et al., 1978,Otsuka and Kaneniwa, 1990) and indomethacin (Imaizumi et aL, 1980),the amount of water adsorbed was linearly related to X. The hygroscopicbehavior of cefazolin sodium was used by Osawa et al. (1988) to quantitatethe crystallinity of their freeze-dried products. Saleki-Gerhardt et al.(1992) found that for sucrose, water vapor uptake measurements wereeffective in quantitating even low degrees of disorder.178. KineticsChanges in X are sometimes reflected in changes in chemicalreactivity. Pikal et at. (1978) and Otsuka and Kaneniwa (1990) showedthat the chemical stability of cephalothin sodium in the solid state wasclosely related to X; stability data were used successfully to evaluate X(Pikal et at., 1978). Since the crystalline sample remained stable at 50°C,only the solid-state decomposition of the amorphous counterpart wasmeasured, thereby making this method particularly useful inquantitating crystallinity when a perfectly crystalline standard is notavailable. Decomposition kinetics was also used by Kitamura et at. (1989)to quantitate reductions in X with grinding when studying its effect onthe chemical and color stability of cefixime trihydrate. The crystallinityvalues obtained were in agreement with values calculated using theinternal standard method of XRPD (Otsuka and Kaneniwa, 1983).9. X-ray Powder DiffractionX-ray powder diffraction (XRPD) is the method most widely used todetermine the X of pharmaceutical solids (e.g. Black and Lovering, 1977;Nakai et at., 1977; Imaizumi et at., 1980; Morita and Hirota, 1982; Nakai etat., 1982; Suryanarayanan and Mitchell, 1985; Ryan, 1986; Kitamura etat., 1989; Ashizawa et at., 1990; Egawa et at., 1992; Saleki-Gerhardt et at.,1992) and provides a physical definition of order (Chung and Scott, 1973).The assessment of this structural order is one of the primary objectives ofthis study.Most of our understanding of the structure of crystalline materialshas originated from single crystal X-ray and neutron diffraction studies18Most of our understanding of the structure of crystalline materialshas originated from single crystal X-ray and neutron diffraction studies(Post and Bish, 1989). In many situations, however, the synthesis ofcrystals suitable for single-crystal studies is difficult (Stout and Jensen,1989b) and, more importantly, in pharmaceutics, the analysis of finelycrystalline or poorly ordered solids is required (e.g. the analysis ofmaterials as received or after processing).Traditionally, X-ray powder diffraction (XRPD) has been animportant standard tool for the identification and characterization ofpharmaceutical solids. Structural information can also be obtained fromthe position, intensity, and shape of the peaks in the diffractogram(Cullity, 1956a). Peak position provides information about the size andshape of the unit cell, peak intensity provides information about the typeand position of the atoms within the unit cell, and peak shape and breadthprovide information about the mean crystallite size or the crystallite sizedistribution, and the nature and extent of lattice imperfections (Kiug andAlexander, 1974c). Until recently, XRPD data were considered to beunsuitable for serious crystal structure studies, primarily because of theproblems of peak overlap and the difficulties in measuring accurate Braggintensities.A basic requirement of XRPD is a clear separation between theamorphous halo and the crystalline pattern. According to Bragg’s law, thecrystalline regions diffract X-rays to give sharp peaks while theamorphous regions scatter X-rays to produce a diffuse halo. The X-raydiffraction pattern of a poorly crystalline solid is a combination of both.Crystallinity indices are based on the ratio of the crystalline diffractionpattern to the amorphous scattering intensity and use either area19measurements or some function of peak heights and valleys (Smith, 1989).Absolute values are questionable but relative values of a series of relatedsamples can be used to examine the progression of a reaction. However,little information is provided on the reason for the X changes observed(i.e. crystallite size and lattice distortion).As a solid becomes increasingly more crystalline, an increase inpeak height is inherently assumed. However, the peak intensity of nearperfect crystals may be less than expected because ofprimary extinction(Woolfson, 1970). When atoms in the crystal lattice diffract, there is nophase difference introduced by path differences from surrounding atoms.The diffracted wave at any point is it radians behind the unscatteredincident ray. Some rays of the incident beam are doubly diffracted whenpassing through the crystal. The unscattered radiation may be joined byradiation which has been doubly scattered and is out of phase, resulting indestructive interference. The intensity of the primary and diffracted beamis reduced and the total energy of diffraction is less than anticipated.Therefore, mosaic crystals are preferred for X-ray diffraction studies (referto Section I.B.). Slight misalignments of the mosaic blocks reduce primaryextinction, and as a crystal becomes increasingly imperfect, destructiveinterference becomes negligible. In an ideally imperfect crystal, anotherextinction process occurs and the intensity of the X-ray beam isattenuated while passing through amorphous material. This is known assecondary extinction. Some of the X-ray energy from the incident beam isremoved and converted to thermal energy which contributes to thediffracted beam.Various methods for measuring crystallinity have been proposed(Matthews, Peiser & Richards, 1949; Ruland, 1961; Weidinger and20Hermans, 1961; Challa et at., 1962). Many empirical rules, correctionfactors, and/or abstract functions are required, making these methodsinconvenient for routine analysis. Development of these methods wasbased on the two-state model of crystallinity, the application of which topharmaceutical solids is questionable.9.1. The Rietueld Structure Refinement MethodThe two methods most widely used to extract structural informationfrom powder diffraction data are: the integrated-peak-intensity fittingmethod (Young et at., 1977) and the whole-pattern least-squares fitting orRietveld structure refinement method (Rietveld, 1967 and 1969). In theintegrated-peak-intensity method, the integrated intensities of individualBragg reflections are measured, converted to structure factors, and usedto solve or refine structures. This approach readily decomposes diffractionpatterns with minimal peak overlap (i.e. relatively simple structures withhigh symmetry) into their constituent Bragg reflections. However, itquickly becomes inadequate for the patterns from more complexstructures of lower symmetry or poorly crystalline materials because ofthe many Bragg reflections with severe peak overlap (Post and Bish, 1989).The Rietveld method (Rietveld, 1967 and 1969) does not useintegrated peak intensities but takes each data point (20 step) as anobservation. Thus, it is the preferred method for structural refinement.Structural parameters, background coefficients, and profile parametersare varied in a least-squares procedure to minimize differences betweenthe calculated and observed patterns. Complex overlapping patternsproduced by poorly crystalline and/or low symmetry materials can bestudied (Post and Bish, 1989; Raudsepp et al., 1990). The amount of21information that is extracted from the pattern is also optimized. Veryprecise and accurate structure determinations are possible for crystals toosmall for single crystal studies (Post and Bish, 1989; Raudsepp et al.,1990). Twinning (regions where the lattice orientation is changed along acomposite plane by homogeneous shear) is a serious problem with singlecrystal work but only promotes the random orientation of crystallites inthe powder (Post and Bish, 1989).9.2. Application of the Rietueld method to XRPDThere are three basic requirements for Rietveld refinements:9.2.1. a model that closely approximates the actualstructure of the material studied;9.2.2. accurate intensity data collected in a step-scanmanner; and,9.2.3. a model that accurately characterizes peak shape,peak width, and any systematic errors in peakposition.9.2.1. The Structure ModelThe requirement of the Rietveld method for a starting model thatclosely approximates the actual crystal structure is also its limitation(Post and Bish, 1989). In principle, structures can on1y be refined and notsolved.Ideally, a powder pattern is calculated based upon the single crystaldata of the material to be studied. In situations where single crystalinformation is not available, a partial model can be formulated from theknown crystal structure or from a previous refinement of an isomorph or a22solid with structural similarities (McCusker et al., 1985; Post and Bish,1989). Other alternatives include computer modeling procedures (e.g.distance-least-squares method (Meier and Villiger, 1969) or electrostaticenergy minimization (e.g. Busing, 1981; Post and Burnham, 1986)) andhigh-resolution transmission electron microscopy (Bish and Post, 1988).9.2.2. Data CollectionAccurate step-scan intensities are essential for Rietveld refinement.Powder samples which contain randomly oriented crystallites arerequired so proper sample preparation is critical. Although bothinstrumental and sample effects influence the quality of the diffractionintensities obtained, preferred orientation is the most important factor toconsider (Hubbard and Smith, 1976). Many crystals encountered inpharmaceutics are nonisometric (e.g. needles or plates) and preferredorientation is a serious problem. Inaccurate peak intensities result andthe refined structures become inaccurate.Proper sample mounting techniques greatly reduce preferredorientation (Smith and Barrett, 1979). Grinding to very small particlesizes (<15 tm (Kiug and Alexander, 1974d); 0.1-10 tm (Cullity, 1956b) andloosely packing powders into a sample cavity (Kiug and Alexander, 1974e)have been recommended. Several other methods have been described inthe literature and include side- or back-loading (Kiug and Alexander,1974f), dilution with a second phase which is preferably non-diffracting(Otsuka and Kaneniwa, 1983), dusting onto glass fiber-filters (Davis,1986), and forming spherulites by spray drying (Smith et al., 1979) orliquid phase agglomeration (spherical agglomeration) using smallamounts of binder (Calvert and Sirianni, 1980). These techniques do not23always ensure random samples so data from several samples prepared bydifferent methods must be compared. In all cases, the mounted sampleshould be ‘infinitely’ thick to X-rays and large enough to fully contain theX-ray beam at the lowest diffraction angle of interest. Mountingtechniques which use grinding and spray-drying to reduce preferredorientation are not suitable for the present work since the method itselfwill reduce X.A wide range of step intervals and counting times have been usedfor data collection. Increasing the number of steps and the counting timeimproves data precisiOn but the experiment becomes time consuming.Since Bragg intensities and not step intensities are fundamental tostructure analysis, long counting times are not always necessary forsuccessful refinements. Decreasing the step interval is more efficientthan increasing the counting time in improving precision. Hill andMadsen (1984 and 1986) recommend using counting times which producea few thousand counts for the strongest peaks and step intervals 115-1/2that of the minimum full-width at half maximum (FWHM).The reduction in peak intensities with increasing 20 should also beconsidered when formulating a strategy for data collection. Thisphenomenon is primarily due to the decrease in atomic scattering factors(Kiug and Alexander, 1974h) so longer counting times might be needed incollecting high-angle data.Data should be collected to the highest 20 angle possible. Highangle data are especially important in facilitating the refinement ofdisplacement factors. However, the overlap of reflections becomesincreasingly more severe with increasing 20, and data collection at higherBragg angles becomes limited by the practical number of reflections that24can be handled and/or resolved. The time required for data analysisincreases substantially with the number of reflections and the amount ofinformation that can be extracted decreases with peak overlap.9.2.3. Profile FunctionsAccurate modeling of the diffraction profile (i.e. peak shape, peakwidth, and systematic errors in peak position) is essential. Profileparameters describing peak widths and shape are varied in a least-squares procedure with structure parameters (atom positions,displacement and occupancy factors), scale factor, unit-cell parameters,and background coefficients, until the calculated pattern approximatesthe observed pattern (Post and Bish, 1989).The observed intensity at a given step is the sum of thecontributions from neighboring Bragg reflections and the background.Therefore, an accurate background description is also necessary. Thebackground can arise from several factors including fluorescence andthermal diffuse scattering from the sample, detector noise, disordered andamorphous phases in the sample, incoherent scattering, and scattering ofX-rays by air, diffractometer slits, and the sample holder. The moststraightforward approach of background modeling is the linearinterpolation between selected points which are removed from the Braggpeaks. While this method is adequate for relatively simple patterns withseveral well-spaced intervals, the inclusion of background coefficients asvariables in the refinement is preferred for more complex patterns. Properpeak shape characterization facilitates background fit. The backgroundcan be fitted for even complex patterns when the peak shape is known,However, if a pattern is poorly resolved, systematic underestimations of25the standard deviations of other parameters occur, particularly withdisplacement factors. The background function used in this study isdiscussed in detail in Appendix A.The peaks in a powder diffraction pattern are the integratedintensities distributed by a peak shape function (Post and Bish, 1989).Accurate representation of the peak shape is important in extractinginformation about crystallite size and lattice distortion. Any inaccuraciesin the fit of the profile shape also introduce large errors in the occupancyfactors and displacement parameters. Peak intensities are determined byatomic positions and other structure parameters but can be affected bysample effects such as absorption, extinction, and preferred orientation.Kiug and Alexander (1974g) further identified six instrumental effectswhich are a function of: the geometry of the X-ray source, varyingdisplacements of different portions of the flat specimen surface, axialdivergence of the X-ray beam, specimen transparency, effects of receivingslits, and misalignment of the diffractometer. Consequently the peakshape becomes a complex convolution of sample and instrumental effectswhich vary depending upon the conditions of data collection and thecharacteristics of the sample. The peak shapes obtained with XRPDdeviate from the near Gaussian peaks obtained using powder neutrondiffraction (Figure 4) (Rietveld 1967 and 1969) thereby making the choiceof profiles a problem. As a result, application of the Rietveld method toXRPD data was seriously delayed (Malmros and Thomas, 1977; Young etaL, 1977; Young, 1980).Complex functions are required to describe peak shape and severaloptions are now available. In the DBW-9006PC, the Gaussian, Lorentzian(Cauchy) , modified 1 Lorentzian, modified 2 Lorentzian, Edgeworth Series,26Figure 4. Deviation of the peak shape ofXRPD from Gaussian behavioris illustrated by comparing a measured diffraction peak (•) toa calculated Gaussian peak profile (—).(Reproduced from Rietveld, H.M., A profile refinement method for nuclearand magnetic structures. J. Appi. Cryst., 2 (1969) 66.)U,4—CD --0U0123 124 125 126 12727Voigt, pseudo-Voigt, modified Thompson-Cox-Hastings pseudo-Voigt, orPearson VII can be used. Details are provided in Table 9a in Appendix A.The intermediate Lorentzian, modified Lorentzian, pseudo-Voigt andPearson VII are most commonly used. Young and Wiles (1982) reportedthat the combined Gaussian and Lorentzian functions of the pseudo-Voigtand the Pearson VII performed consistently better. Of the two, the pseudoVoigt was recommended because of the simpler calculations and therefineable constants which can be used to interpret the degree ofLorentzian versus Gaussian component. Instrumental effects aredescribed by the Gaussian function (David and Matthewman, 1985) andthe sample related effects by the Lorentzian function. The pure Voigt isalso a convolution of Gaussian and Lorentzian functions and is themathematically correct way to combine the various phenomena to formthe final peak shape (David, 1986). However, due primarily to its relativecomplexity, the Voigt function is commonly substituted by the pseudoVoigt. David (1986) developed a method of parameterizing the pseudoVoigt to allow for refinement of separate half-width functions for theLorentzian and Gaussian components. This improved its functionalsimilarity to that of the Voigt.Once the angular dependencies of the Lorentzian and Gaussiancontributions are independently modeled, information on crystallite sizeand lattice strain can be extracted (Keisser et al., 1983; David andMatthewman, 1985; and Larson and Von Dreele, 1988). Madsen and Hill(1988) determined the crystallite size and strain properties for CaF2 usingSi for instrument profile with the Rietveld refinement method and a Voigtprofile function. The determination of crystallite size and lattice distortionis discussed below.28XRPD profiles can also be modeled by the learned peak-shapefunction developed by Baerlocher (1986). In this approach, anonanalytical function, containing symmetric and asymmetric partsdetermined in numerical form (“learned”) from a single resolved peak inthe pattern, is used (Hepp, 1981). The advantages of Baerlocker’sapproach are that it is easily calculated, accounts for peak asymmetry,and describes virtually any peak shape (Baerlocher, 1986). Thedisadvantage is that a completely resolved reflection is the minimumrequirement - a condition that is rarely met.Improvements in the fit between the observed and calculateddiffraction profiles occur when the pseudo-Voigt coefficient is allowed tovary as a function of 20 (Hill, 1984). If the angular dependence of peakshape is neglected, overestimation of the displacement factors can result.With the Rietveld refinement method, peak widths are typicallymodeled as a quadratic function in tan 0 and describe the full-width athalf maximum height (FWHM), Hk, as a function of the diffraction angle(Caglioti et al., 1958):H=Utan2O÷VtanO÷W (1)where U, V, and W are refineable parameters dependenton the instrumental configuration and the profileshape function chosen.The variation of peak width with Bragg angle is illustrated in Figure 5.However, the peak broadening which results from structural disordercannot be explained using the peak-width expression of Caglioti et al.(1958). Thompson et at. (1987) modified the pseudo-Voigt profile function29I50•10050(‘4‘a4 4 4 4 4 4 I 4 4 4 4 I I0 10 20 30 40 50 60 70 80 90 100 110 120 130 140Figure 5. Variations of peak width with Bragg angle. The measuredhalfwidths (•) are shown with the calculated curve of Cagliotiet at. (1958) (—).(Reproduced from Rietveld, H.M., A profile refinement method for nuclearand magnetic structures. J. AppL Cryst., 2 (1969) 67.)scattedcig angie (2w)30so that information on Lorentzian strain and crystallite-size broadeningcould be extracted.Finally, any asymmetry in the profile shape should be corrected.Most of the commonly used profile shape functions are symmetrical aboutthe peak and do not account for the significant asymmetry which canoccur as a result of instrumental and sample effects. A comparison of anasymmetric diffraction peak with a symmetric- and asymmetric- correctedcalculated profile is shown (Figure 6). The use of the semi-empiricalasymmetry correction term primarily compensates for the asymmetry atlow angles that is caused by the axial divergence of the X-ray beam.Integrated intensities are unaffected but the apparent peak positions areshifted. Using incident- and diffracted-beam Soller slits during datacollection significantly reduces asymmetry on the low-angle side of peaksand improves resolution. Results might be improved if only the higherangle data are used in the refinement.In this work, the Rietveld structural refinement method was used toextract structural information from the powder diffraction data of selectedpharmaceutical solids. Each data point was used as an observation andstructural parameters (atomic positions, site occupancies, displacementparameters), background coefficients, and profile parameters were variedin a least-squares procedure. This minimized the difference between thecomplete observed and calculated diffraction patterns. Unit-cellparameters were refined, and Lorentzian strain and crystallite-sizebroadening were studied.31scatteriiig angle (209Figure 6. Comparison of an asymmetric diffraction peak with asymmetric and asymmetric corrected calculated profile.Measured intensities (•) are shown with a symmetricGaussian curve (---) and an asymmetric curve (—).(Reproduced from Rietveld, H.M., A profile refinement method for nuclearand magnetic structures. J. Appi. Cryst., 2 (1969) 67.)(I,C0C)10 12329.3. Determination of Crystallite Size and Lattice StrainThe determination of crystallite size has been of great interest tomaterials science and has occupied the attention of crystallographers formany years (Howard and Snyder, 1985; Bonetto et al., 1990). A rapidapproximation can be obtained using the width of a single diffraction line(Howard and Preston, 1989). The Scherrer equation is a well knownexample (Cullity, 1956c):0.9?.(2)BcosOBwhere B is the peak width.The peak width is measured in radians at an intensity equal to half themaximum intensity. This method assumes that the diffraction peaks aretriangular in shape, that peak broadening is solely a function of crystallitesize (i.e., the sample is strain-free and instrumental effects have beendeconvoluted), and that the crystals (e.g. 500 A thick) are sufficientlysmall such that peak broadening can be easily measured. Theseconditions are rarely met and other methods were developed for lessideally behaving materials. Rather than using just peak breadth, theinterpretation of Warren and Averbach (1950) is based on peak shapeanalysis in attempts to obtain more information without making any apriori assumptions. The corrected shape is expressed as a cosine Fourierseries where a set ofA coefficients is determined (Warren-Averbachmethod):P20 =KN(Acos22rnh3+Bsin2rnh), (3)33where: A =(cos22thaZfl)AV, andB,L = —(sin2th3Z,L)AV.No appreciable shift in peak position is assumed, the sine terms arenegligible, and the final equation becomes:P20 =KNAcos2inh3, (4)where: h3 =2a(sinO)/A, andA =(cos2niZfl)AV.A plot of the A coefficients versus n distinguishes between distortion andcrystallite size broadening. Information on distortion is provided by theA coefficients and for both distortion and crystallite-size broadening, A0is unity:dA=_J1p(i)dt. (5)The initial slope ofA versus n is:(ct4 /dn),0 = —N IN = —1/ N3, (6)where N3a is the average length.The second derivative gives the length distribution. The crystallite size indirection a becomes:(d2A,1)I(dn=(1/N)p(n). (7)34A rapid assessment of the effects of crystallite size and lattice strainis provided by the Williamson-Hall method (Williamson and Hall, 1953):fl•cosQl4AasinO(8)A A a Awhere: A=mean crystallite size normal to diffraction planesAa . .— =average lattice distortion normal to diffractionaplanesf3=true breadth of the crystalline sample?=X-ray wavelengthO=diffraction angle.cosO . sinO .A plot ofAagainstAis linear, and the average strain valuenormal to the diffraction planes and the mean crystallite size normal tothe diffraction planes are given by the slope and the reciprocal value of thefJ•coso . . .Aintercept, respectively. Though originally introduced as a meansof separating size effects from strain broadening, this method has beensuperseded by other methods and is now used only as the first step in theana1ysis of peak breadths (Ziegler, 1978; Langford and Louër, 1986).The inherent asymmetry of XRPD profiles has been one of theprinciple difficulties limiting this work. The development of the Rietveldrefinement method enabled the angular dependencies of the Lorentzianand Gaussian contributions to be independently modeled. This allowedboth crystallite size and lattice distortion information to be extractedsimultaneously (de Keisser etal., 1983; David and Matthewman, 1985; andLarson and Von Dreele, 1988; Lutterotti and Scardi, 1990). Enzo et at.35(1988) and Benedetti et at. (1988) used a truncated exponential convolvedwith a pseudo-Voigt to model the instrumental function and a secondpseudo-Voigt to model the specimen function. De Keijser et at. (1983)proposed two methods to measure size and strain simultaneously with theprofile refinement method: direct analysis of breath parameters of theprofile shape function, and analysis of the breath parameters of thepseudo-Voigt and the Pearson VII profile shape functions in terms ofbreath parameters of the Voigt function. The Voigt profile shape function(Table 9a of Appendix A) was preferred. Madsen and Hill (1988)determined the crystallite size and strain properties for CaF2 using Si forinstrument profile with the Rietveld refinement method and a Voigt profilefunction. Modifications of this approach were used to obtain crystallitesize and lattice distortion information from pharmaceutical solids.D. Effect of Pharmaceutical Processing on CrystallinityDuring the processing of pharmaceutical solids (such ascrystallization, drying, milling, compression, heating and irradiation),defects within the crystal lattice may develop, migrate or disappear (Grantand York, 1986). XRPD, SC, and suspension density were used bySuryanarayanan and Mitchell (1985) to measure the reduction in Xwhich resulted from grinding anhydrous calcium gluceptate. This markedreduction in X was accompanied by an increase in apparent watersolubility. Significant changes in the thermal behavior of metoclopramidehydrochloride monohydrate resulted from grinding and compaction(Mitchell, 1985). It was suggested that the increased crystal disorder36induced by mechanical stress accelerated dehydration during differentialscanning calorimetry and promoted the recrystallization of an anhydrouspolymorph.The effect of processing on the X of cephalosporins has beenextensively studied using XRPD. Otsuka and Kaneniwa (1983a) followedthe reduction in X of cephalexin with grinding and examined theresulting increases in hygroscopicity, dehydration and decomposition(Otsuka and Kaneniwa, 1984). Egawa et at. (1992) found that withgrinding, the apparent solubility and dissolution behavior increased as Xwas reduced. Amorphous cephalexin prepared by freeze-drying showedenhanced hygroscopicity and solubility (Otsuka and Kaneniwa, 1983b),more rapid dehydration (Otsuka and Kaneniwa, 1983c), and a reducedbinding energy for water (Kaneniwa and Otsuka, 1984). On tabletting,cephalexin was converted to a less crystalline state; this conversion wasaccompanied by an increase in the rate of dehydration and decomposition(Kaneniwa et at., 1985). Similar results were obtained upon grindingcefazolin sodium (Osawa et at., 1988), cefixime trihydrate (Kitamura etal.,1989), and cephalothin sodium (Otsuka and Kaneniwa, 1990).Disordering within a solid can be reversed. Using SC, Vanderzee etat. (1981) demonstrated that perturbations in an organic system,tris(hydroxymethyl)-aminomethane (tris), resulting from milling can besubsequently removed upon storage at elevated temperatures. Significantamounts of energy (40 to 90 J/mol) were stored in the solid as a result ofgrinding in an agate mortar. Thermal annealing at 3500 to 360°K for 18hours relieved the strains and returned the solid to its original energystate.37Mechanical stress due to milling and compression can be followed bysubsequent recrystallization. The recrystallization of X-ray amorphouscellulose following grinding was reported by Hermans and Weidinger(1946a and b). Recent studies report a nucleation phenomena inamorphous sucrose following lyophilization (Scoik and Carstensen, 1990).Post-compressional recrystallization was first reported by Hess (1978) andestablished as a general phenomenon by Mitchell and Down (1984).Crystal growth on the surface and in the void spaces of compacts wasobserved with aspirin (ASA), anhydrous calcium gluceptate, ferroussulfate monohydrate, metoclopramide hydrochloride monohydrate,methenamine, and sucrose after compaction on a single-punch tablet pressusing both unlubricated and lubricated dies. The materials examinedwere directly compressible and included examples of solids which undergoplastic deformation (aspirin and methenamine) and brittle fracture(metoclopramide hydrochloride and sucrose) upon consolidation. Surfacerecrystallization and alterations within the tablet matrix were observedfollowing storage at both 0 and 43%RH (25°C). Crystal growth wasobserved both on the edge and faces of the compact, but was morepronounced on the edges where a greater frictional contact between thecrystals and the die wall exists.The growth rate of aspirin crystals was particularly dramatic(Mitchell and Down, 1984). Crystals were seen within 15 minutes aftercompression and increased in size and definition with time. The natureand extent of crystal growth was independent of whether lubricant wasused and exhibited a solid state Ostwald ripening effect where thedevelopment of larger crystals was accompanied by the disappearance ofsmaller ones. Miller et al. (1986) conducted a more extensive study to38examine the nature of crystals growing on the surface of ASA tablets.Crystalline acetylsalicylic acid was compressed using a hand-operatedinstrumented rotary tablet press. Compressional force, dwell time andcompact weight were held constant and no excipients were used. After 5hours at 30°C and 32%RH, the beginnings of step-like ridges wereobserved on the surface of aspirin tablets. These ridges grew morepronounced on storage and appeared to result from crystal growth alongdisplaced slip planes. Hexagonal-, prism- and plate-shaped crystals alsoevolved. The undifferentiated mass of plates and discrete hexagons wassimilar to those obtained by Jamali and Mitchell (1973) afterrecrystallization from ethanol under unstirred conditions. Miller et al.(1986) postulated that prisms and plates were the result of differences inthe development of the various crystal faces, and that post-compressionalgrowth of these habits may depend on which faces of the original crystalswere stressed during compaction. However, the habit obtained uponcrystal growth following compaction was later found to be independent ofthe habit of the starting material (Mitchell, unpublished data).These findings coupled with observations that milling causesperturbations in tris (a reduction in X) and that storage at elevatedtemperatures results in a subsequent removal of the stored energy ofcrystal deformation (increase in X) (Vanderzee etal., 1981) suggestedthere was a link between the disordering of the lattice duringpharmaceutical processing and the later restoration of order. The returnof the solid back to a more ordered state following processing is one of thehypotheses of this research project.It is important to differentiate the post-compressionalrecrystallization discussed above, from crystal growth involving phase39changes (such as changes in the state of hydration or polymorphicchanges). For example, carbamazepine exhibits crystal growth followingtabletting but this was said to involve phase changes associated withhydration (Stahl, 1980), or polymorphism (DeCrosta and Eckhart, 1989),or recrystallization from solution in molten stearic acid, the tablettinglubricant (Matthews et at., 1989). At high humidities, Otsuka et at. (1978)measured the moisture sorption and volume expansion of amorphous f3-anhydrous lactose tablets and found that this was accompanied by anautocatalytic crystallization to form a-monohydrate lactose. The crystalgrowth of theophylline monohydrate from tablets containing anhydroustheophylline was shown to be mediated by the presence of water. Thisgrowth occurred when hygroscopic materials such as magnesium chlorideor potassium acetate were placed in the formulation and the tablets werestored at high relative humidities (Ando et at., 1986). The recrystallizationof amorphous penicillin (Matthews et al., 1966) and digoxin (Black andLovering, 1978) were also mediated by water.Ando et at. (1985) observed needle-shaped crystals on the surface ofa-lactose monohydrate and mannitol tablets when hygroscopic materialssuch as docusate sodium, magnesium chloride, and potassium acetatewere added to the formulation. Tablets were stored at high relativehumidities (59, 75 and 90%RH) and the extent of recrystallization wasfound to depend only on the hygroscopicity of the additive and the relativehumidity of storage. Using scanning electron microscopy (SEM), Downand McMullen (1985) observed both interparticulate and surfacerecrystallization in sodium chloride compacts after storage at relativehumidities (RH) of 33 to 94% (ambient temperatures). The observedgrowth appeared to depend upon atmospheric vapor pressure and the40crushing strength of these compacts was found to increase from 33%RH tothe critical point of deliquescence (76%RH). This was correlated with therecrystallization observed.E. Trace AdditivesThe incorporation of trace amounts of intermediates or degradationproducts during the chemical synthesis of drugs can affect the surface andbulk properties of the solids produced (York, 1983). A number of importantpharmaceutical properties were reproducibly altered by incorporatingtraces of additives (0.45 mol%), with the observed changes attributed tothe disordering and disruption of the lattice (Chow et at., 1984; Chow et al.,1985; Chow etaL, 1985a; Go and Grant, 1987; Chow and Hsia, 1991; andGordon and Chow, 1992). The disordering was indirectly measured usingDSC (Gordon and Chow, 1992), and in this study, a more direct methodwas used to assess the effect of the incorporation of 3-propanoyloxymethyl-5 ,5-diphenylhydantoin (PMDPH) into 5 ,5-diphenylhydantoin (DPH)crystals.F. Phase Changes of Pharmaceutical SolidsIn the present study, changes in crystallinity are differentiatedfrom phase changes due to polymorphism and solvation (or desolvation).-D-uring—phaimaceutica-I—processing, reductions in X only involvereductions in the periodic arrangement within a crystal, while phase41changes involve a complete rearrangement of the constituent atoms, ionsor molecules (polymorphism), andlor a change in chemical composition(solvation).1. PolymornhismPolymorphism is the ability of a given compound to exist in morethan one crystalline form, each chemically identical to the other andwhich differ only in their three-dimensional arrangement in space(Glasstone, 1946; Findlay, 1951; Leigh, 1990). At a given temperature andpressure (apart from triple points), there is only one stable form. All otherforms are metastable.Polymorphism is prevalent in pharmaceutical solids, particularlywith steroids, sulfonamides, barbiturates, and antibiotics, but it is difficultto predict whether a compound will exhibit polymorphism (KuhnertBrandstatter, 1971). Extensive literature reviews on the polymorphism ofpharmaceutical compounds have been provided by Kuhnert-Brandstatter(1971), Haleblian and McCrone (1975), Borka and Haleblian (1990) andBorka (1991).1.1. Methods of Characterizing FolymorphsThe significant lattice differences among the polymorphs of a givencompound are manifested in the very different physical propertiesobserved. Properties such as true density, chemical and physical stability,nuclear magnetic resonance, electrical and thermal conductivity, meltingpoint and heat of fusion, heat of solution, solubility, dissolution rate, JRspectroscopy, and X-ray diffraction are affected (Carstensen, 1973c; Byrn,1982a; Lindenbaum and McGraw, 1985). Several techniques are available42for characterizing the polymorphic behavior of pharmaceutical solids andthese include X-ray powder diffraction (XRPD), JR spectroscopy, thermalanalysis (thermal microscopy, differential thermal analysis (DTA),differential scanning calorimetry (DSC)), polarized-light (optical)microscopy, electron microscopy, densitometry, and the measurement ofsolubility and dissolution rate.XRPD and measurements of solubility are particularly important.Information about the crystal structure can be obtained from X-raypowder diffractograms. Since the three-dimensional arrangement ofpolymorphs differ, their diffractograms are significantly different.Solubility measurements, on the other hand, differentiate the stable formfrom the metastable forms. At a given temperature, the stablepolymorphic form will have a lower solubility. When these two methodsare used with thermal analysis, polymorphic systems can be fullycharacterized.Polymorphs can be either enantiotropic or monotropic and these twosystems are differentiated by the position of the transition point relative tothe melting point of the solid. For enantiotropic polymorphs, thetransition point lies below the melting point. Each polymorph has a rangeof stability and is capable of undergoing reversible solid-solidtransformation to the other form. At this transition point, the vaporpressure of the two forms is identical. Monotropic polymorphs, on theother hand, have their transition point above the melting point of thestable form. At all temperatures up to the melting point of the stable form,only one form is stable and all other forms are metastable. Thetransformation from the metastable form to the stable form is irreversible.431.2 Polymorphism and Pharmaceutical ProcessingPolymorphic transformations have been reported to occur ininorganic and organic substances under pressure (Bridgeman, 1956;Drickamer, 1967). Examples of pharmaceutical solids which undergopolymorphic transformations during grinding and/or tabletting includebarbitone (Nogami et al., 1969; Summers et at., 1976), carbamazepine(Lefebvre and Guyot-Hermann, 1986), chioramphenicol (Kaneniwa andOtsuka, 1985; Otsuka and Kaneniwa, 1986 and 1989), chiorpropamide(Otsuka etal., 1989; Matsumoto etal., 1991), indomethacin (Otsuka etal.,1986), phenylbutazone (Ibrahim et at., 1977), and suiphathiazole(Summers et at., 1976).2. SolvationSolvates are crystals that contain the solvent of crystallization instoichiometric or nonstoichiometric amounts. When water is the solvent,these solvates are termed hydrates, and when lattice water issubsequently removed, an anhydrate is formed.One of three events can occur when the water of crystallization isremoved from an hydrate:1. the lattice collapses and recrystallizes to a lower hydrate oranhydrate;2. the lattice collapses without recrystallization; or,3. the lattice remains structurally identical to that of the hydratebut chemically different.Lattice collapse followed by recrystallization is the most common, whilethe maintenance of lattice integrity throughout the desolvation process israre.44EXPERIMENTALA. Materials1. Chemicals0-Acetylsalicylic acid, BDH Chemicals Inc. (Lot 10927115851)Barium fluoride, high purity, BDH.Calcium sulphate (Drierite®), Aldrich Chemical Company Inc.Chiorpromazine hydrochloride, Rhone Poulenc Pharma Inc.(Lot M-21673)Chiorpromazine hydrochloride granules, Rhone Poulenc PharmaInc. (Lot AM97)5,5-Diphenyihydantoin, synthesized by Gordon and Chow (1992)5 ,5-Diphenylhydantoin doped with 3-propanoyloxymethyl-5 ,5-diphenyihydantoin, synthesized by Gordon and Chow (1992)Fluorophiogopite mica (synthetic), NBS (SRM 675)Hydraulic oil, Shell Canada Products Ltd. (Tellus Oil 68)Hydrochloric acid, reagent grade, Caledon LaboratoriesLithium fluoride extra pure, BDH Chemicals Inc.Magnesium stearate, Mallinckrodt Inc.Metronidazole, Rhone Poulenc Pharma Inc. (Lot M-2 16 15)Nail polishclear base coat, Cutex45clear top coat, Max FactorOil, certified index of refraction of 1.532, Cargille Laboratory Inc.Potassium chloride, analytical reagent, BDH Chemicals Inc.Silicon, NBS (SRM 640b)Stearic acid, BDH Chemicals Inc.Talc, CyprusTris(hydroxymethyl)-aminomethane, Parr Instrument Co.2. SolventsAbsolute ethanol, StanChemAcetone, BDH Chemicals1-Bromobutane, BDH Chemicals1-Butanol, analytical grade, BDH ChemicalsCarbon tetrachloride, BDH ChemicalsChloroform, GC grade, BDH ChemicalsDibromomethane, Aldrich ChemicalsEthanol, StanChemEthylbromide, J.T. Baker ChemicalsMethanol, GC grade, BDH Chemicals2-Methylpropan-2-ol, analytical grade, BDH Chemicals1-Octanol, analytical grade, BDH ChemicalsWater, deionized via a Milli-RO Water System, Millipore Corp.Water, glass distilled3. GasesHelium, Matheson Gas Products Canada0.0322 and 0.1380% Krypton in helium, Matheson Gas Products0.075% Krypton in helium, Linde Union Carbide46Nitrogen, ultra pure, Linde Union CarbideB. EquipmentApple II Plus personal computer with ADALAB analog-to-digitalconverterBalances, Mettler (Model AE 163) and Sartorius, and thermalcontrolled infrared moisture balance, SartoriusBorosilicate glass tubes, Kimax, with polytetrafluoroethylene-linedscrew capsCaliper (electronic), NSK Corp.Centrifuge, Damon/IEC Division (Model HN-SII)CT4O tablet strength tester, Engineering Systemslinear variable differential transducer, Sangamo DG5Circulating water bath, Forma Scientific (Model 2376)Densitometer (digital), Paar (Model DMA 45)Differential interference contrast microscope, Nikon (Model R)Differential scanning calorimetryaluminum sample pans (standard and closed), PL ThermalSciencesdifferential scanning calorimeter, Du Pont Instruments (Model910)thermal analyzer, Du Pont Instruments (Series 99)Dissolution-testing apparatusfraction collector, Vanderkamp (Model 10)programmable dissolution sequencer, VanKel Corp. (EDS-lO)47six-spindle dissolution tester, Vanderkamp (Series 600)temperature regulators for water baths, Julabo Co. (Model P) andHaake (E8)variable speed paddle stirrers, Heidolph Co. (Model RZR-2000)Fisher-Kendall mixer, Fisher Scientific Co.Gas chromatographygas chromatograph, Hewlett-Packard (Model 5840), with a flameionization detectorgas chromatograph terminal, Hewlett-Packard (Model 18850A)25 m x 0.31 mm Tjltra-2 fused silica column with a bonded phaseof 0.52 pm 5% phenyl-methylsilicone0.1 mL Gastight syringe, Hamilton Co.Helium multipycnometer, Quantachrome Co.Hot plate/stirrer, Corning (Model PC-35 1) and Fisher (Thermomix)Hydraulic press (instrumented)hydraulic press, Fleck Brothers Ltd.(except for the hydraulic pump, J.S. Burns Corp.)linear variable differential transducer, Sangamo DG5load cell, SensotecRIIC D-01 0.5-inch flat-faced punch and die assembly ofhardened steel (upper punch and adjustable arm, Tool Tech.)Incubator, FisherInstrumented rotary tablet press, Manesty (Betapress) with IPTpunches (0.5-inch flat-faced punches)Isoperibol solution calorimeter, Tronac (Model 458)Mechanical agate ball and mill, Fritsch (Pulverisette)48Ovens, Chicago Surgical and Electrical Co. and Fischer (IsotempModel 350 and Model 500 series)Rotary stirrer, FischerScanning electron microscope, Hitachi, Model F-570400 MHz MSL Solid-state NMR spectrophotometer, BrukerSonicating water bath, Branson (Model 2200)Surface area analyzer, Quantachrome Corp. (Quantasorb SorptionSystem)Thermal microscopycamera, Nikon AFX-IIAgas-flow heating/freezing system, Fluid Inc.polarized light cross-nicols microscope, Nikontrendicator and thermocouple (calibrated), U.S.G.S., Fluid Inc.,and monitored using a Doric 410A trendicatorThermometer (digital platinum resistance), Guildline (Model 9540)Ultraviolet/visible diode-array spectrophotometer, Hewlett Packard(Model 8452A), with Hewlett Packard 89530 MS-DOS UV/VIScomputer software programVacuum oven, National Appliance Co.WA measuring stationtemperature-controlled chamber, Rotronic Hygroskop BTtemperature-humidity probe, RotronicHigh resolution wide angle X-ray diffractometer, Rigaku (D/MAX2MBX), with scintillation counter49C. Methods1. Suspension DensityMixtures of carbon tetrachloride with benzene (Blaton et at., 1979)or 1-bromobutane were used as suspending vehicles for determining thetrue density of MTZ. MTZ, as received, was dispersed in the varioussuspending mixtures and tightly sealed in borosilicate glass tubes withpolytetrafluoroethylene-lined screwcaps. The tubes were thenequilibrated in a jacketted beaker containing water. A mixture of 60%ethylene glycol in water was continually circulated from an externalthermostatic water bath (± 0.01 °C) to the double-wall of the cell and thenthrough the outer jacket surrounding the oscillating tube of a digitaldensity meter. The temperature was gradually increased or decreaseduntil the dispersed sample was suspended. A detailed description of theapparatus used, the equilibration process, the determination of densityand the calibration procedure is given by Suryanarayanan and Mitchell(1985).2. Gas (Helium) Displacement PycnometryTrue densities were determined using a helium multipycnometer.40-60g of MTZ and CPZ were accurately weighed directly into the largesample cell (149.59 cm3)with tapping. The reference cell (70.95 cm3) waspressurized to 15-17 psi with predried purified helium.3. Specific Surface Area MeasurementsA surface area analyzer (Quantachrome Corporation, NY)interfaced to a strip chart recorder was used to determine the specific50surface area of CPZ by the multipoint BET method (Lowell, 1973). Gasconcentrations of 0.0322%, 0.0750% and 0.1380% krypton (adsorbate) inhelium (carrier) were used. Nitrogen was used as the calibration gas. 100mg samples were accurately weighed in glass capillary sample cells. Theheights of the desorption peaks were measured. Measurements werecalibrated by injecting a volume (2-30 jiL) of nitrogen into the Kr/Hestream with a gas-tight syringe equivalent to within ± 10% of the volumeof krypton adsorbed. The peak heights and corresponding volumes ofnitrogen were entered into a computer program (Orr, 1983) along with theambient temperature and atmospheric pressure, allowing the surface areato be calculated by using the BET equation. Each measurement wasperformed in triplicate.4. Scanning Electron Microscopy (SEM)The shape of solids was studied visually using scanning electronmicroscopy (SEM). Samples were sputter-coated with gold under vacuumin an argon atmosphere and examined in a scanning electron microscopeusing secondary electron imaging with an accelerating velocity of 20 kV.5. Solid-State Nuclear Magnetic Resonance (NMR)solid-state NMR was performed using a 400 MHz MSLsolid-state NMR spectrophotometer with 90° pulses on the proton of 7.5 ps.A contact time of 80 ps was used and up to 3728 scans were performed persample at a recycle time of 20 seconds. Spectra were processed with a linebroadening of 100 Hz.516. Differential Scanning Calorimetry (DSC)Changes in the thermal behavior of selected solids with processingwere studied using a 910 Differential Scanning Calorimeter moduleinterfaced to a Du Pont Series 99 Thermal Analyzer, with thethermograms recorded on a chart recorder. 3-5 mg samples wereaccurately weighed directly into standard aluminum open pans,hermetically sealed pans, and sealed pans with 0.1-0.2 mm pinholes. Theencapsulated sample was heated at rates varying between 2° and 20°C perminute under a purified nitrogen atmosphere. Immediately after eachendotherm or exotherm, the temperature was held and the sample wasreweighed before resuming the scan. The leading edge of each peak wasused to determine the transition temperature. Hydrated samples werealso cooled to below the freezing point of water using a cooling accessorywith liquid nitrogen, and scanned under the conditions described above todifferentiate between liquid water and molecular water. Weight loss ondrying was confirmed using a thermal controlled infrared moisturebalance. Samples were ground manually using an agate mortar andpestle. A minimum of three trials was performed for each set ofexperimental conditions.7. Thermal MicroscopyThe thermal behavior exhibited during DSC analysis was confirmedvisually using thermal microscopy. Samples were mounted in an oil-basedliquid of a certified index of refraction and centered in the central chamberof a gas-flow heating/freezing system designed by the U.S. GeologicalSociety (U.S.G.S.). Preheated atmospheric air was circulated uniformlyand continuously above and beneath the sample. Vertical gradients were52negligible and horizontal gradients were low and easily calibrated.Heating was controlled using a calibrated trendicator and thermocoupleand monitored with a Doric 410A trendicator. Samples were viewed at480-fold magnification using a polarized light cross-nicols microscope(Nikon) with camera accessory.8. Relative Humidity-Composition DiaramThe relative humidity-composition phase diagram was constructedfor the room temperature stable polymorph of chiorpromazinehydrochloride, CPZ(I). CPZ(I) was obtained by drying CPZ(I)-H’ at 70°Cunder vacuum, in the presence of silica gel, and stored at 25°C indesiccators over saturated salt solutions selected to give relativehumidities (RH) of 15%, 31%, 43%, 52%, 66%, 76% and 90% (NationalPhysical Laboratory, 1958). Once constant weight was established, thepowders were sealed in the temperature-controlled chamber of a WAmeasuring station with a combined temperature-humidity probe(Mitchell, 1984). The %RH of the powders was measured at 25°C.Immediately after a constant humidity reading was recorded, the samplewas removed from the chamber and a portion of the bulk was accuratelyweighed into a sealed pan with pin hole and scanned using DSC. Theweight loss after the dehydration endotherm corresponds to the watercontent of the powder. After equilibration at the various RHs, samples ofthe CPZ(I) crystals were also subjected to XRPD. The room temperaturemetastable form, CPZ(II), did not exhibit significant weight changes whenstored at the above humidities. No dehydration endotherm or weight losswas observed when scanned using DSC. Both Form I and Form II53deliquesced when stored under the ethanol-water saturated atmosphere ofthe granulation mixture.9. Solution CalorimetryHeats of solution of MTZ and CPZ were measured using anisoperibol calorimeter. The bath temperature was maintained at 25.000 ±.0.005°C. 50 mg samples were accurately weighed and encapsulated insample cells designed by Winnike et at. (1988). All reactions weremeasured in a calibrated 50 mL capacity fully silvered vacuum flask at25°C and a stirrer rotating at 600 rpm. Dissolution was rapid andcomplete with either glass distilled water or an aqueous solution of 0.1 Mhydrochloric acid with 0.1% w/v sodium dodecyl sulphate as the solvent.Any temperature changes during the reaction were monitored by athermistor bridge system. The calorimeter was interfaced to an Apple IIPlus computer through an ADALAB analog-digital converter andaccompanying signal amplifier to facilitate data collection and analysis.The chart recorder was calibrated with tris(hydroxymethyl)aminomethane and checked using potassium chloride. Heats of solutionfor potassium chloride were 17.00 ± 0.34 kJ/mol compared with a reportedvalue of 17.22 kJ/mol (Lide, 1991). A minimum of five repetitions wereperformed.10. Solubility and Dissolution RatesEquilibrium solubility and dissolution rates of CPZ were measured.Excess amounts of sample were placed in tightly closed glass containerscontaining various solvents (e.g. 1-octanol, 1-butanol, tertiary butanol,and a mixture of water in tertiary butanol (1:19)) and rotated continuously54while submersed in a water bath maintained at 25°C protected from light.Samples were drawn until equilibrium solubility was reached. Eachextract was immediately centrifuged and the supernatant removed,diluted, and analyzed using a diode-array UV spectrophotometer. Eachexperiment was performed with a blank and standard curve (coefficient ofdetermination between 0.97 and 0.99). Each run was done in triplicate.The dissolution behavior of intact flat-faced tablets of MTZ wasdetermined using an automated six-spindle dissolution tester. A paddlestirring rate of 50 rpm was used and temperature regulators maintainedthe water bath at 25°C. Tablet sides were coated with clear top coat nailpolish, and tablet bottoms were blanked off and fixed to the base of thedissolution flasks with clear base coat nail polish. 2.4 mL samples werewithdrawn using an automated fraction collector at 0, 10, 15, 20, 25, 30,45, 60, 90, and 120 minutes immediately following the addition of 900 mLof the dissolution medium (e.g. 0.1 M hydrochloric acid and 0.1% w/vsodium dodecyl sulphate solution). As above, these samples were analyzedusing UV spectroscopy. A calibration curve was prepared for eachexperiment and typical r2 values of 0.9995 were obtained. Six replicateswere performed for each sample. The mass dissolved was calculated fromthe concentration after correcting for the change in volume of thedissolution medium. Freshly degassed glass distilled water was usedthroughout.For CPZ which severely laminated and capped on compression,dissolution rates were examined using the compression die apparatus ofWoodet at. (1965). The threaded inner die wall prevented layers of thelaminated andlor capped tablet from flaking during the dissolution study.A constant surface area was maintained, the hydrodynamic conditions55were reproducible, and wetting problems due to adsorbed air and/orelectrostatic charges on small particles were minimized. In eachexperiment, 250 mg of solid was accurately weighed into the die cavity andcompressed using a manual hydraulic press at 113 MPa with a dwell timeof 60 s. The assembly was then mounted vertically in a Fisher motorassembly and rotated at 100 rpm in a jacketed glass beaker containing 250mL of either distilled water or a mixture of water and tertiary butanol. Instudying phase changes of CPZ, aqueous buffered solutions were also usedto decrease the dissolution rate and to differentiate between differentforms. Experiments were performed at 25°C and 2 mL samples were takenat 0, 5, 10, 15, 20, 25, 30, 40, 50, and 60 s. Appropriate dilutions were madeof the collected aliquots to yield a final absorbance reading between 0.2and 0.8 absorbance units. Each sample was analyzed using TJVspectroscopy as above.11. Gas ChromatographyThe ethanol content of chlorpromazine hydrochloride granules asreceived (CPZ-H’) was measured using a Hewlett-Packard 5840 gaschromatograph (GO) with a flame ionization detector (FID) interfaced to aHewlett-Packard 18850A GO terminal. A 25 m x 0.31 mm Ultra-2 fusedsilica colunm was used with 0.52 iim 5% phenylmethylsilicone as thebonded phase. CPZ(I)-H’ was dissolved in chloroform and 2 pL wereinjected in the split mode using a split ratio of 3:1. The temperatures of theinjection port, FID, and oven were 160°C, 250°C and 60°C respectively.Helium was used as the carrier gas and a constant flow rate of 1.0 mL/minwas maintained.5612. GrindingThe grinding of small amounts of powder was performed manuallyusing an agate mortar and pestle while larger samples were ground in amechanical ball and mill under controlled conditions.13. TablettingFor studies of crystallinity, tablets of MTZ and ASA werecompressed in a 1.29 cm die using an instrumented hydraulic press. Aslow ramp rate was used to reach 270 and 408 MPa, with the pressuremaintained for 10 s before decompression. Details of the instrumentationand analysis were given by Doroudian (1991).The effects of a phase change of CPZ on tablettability were studiedunder rurming conditions using an instrumented rotary tablet press. Adetailed description of the tablet press is given elsewhere (Oates andMitchell, 1989, 1990; Dwivedi etal., 1991, 1992). Compression profiles ofthe various forms of CPZ were obtained with 1.27 cm flat faced IPTpunches and a turret time of 1.00 s. 0.5% w/w magnesium stearate(lubricant) and 0.5% w/w talc (glidant) were added to the samples tofacilitate tabletting.14. Tablet Strength TestingThe diametral compression test was used to evaluate themechanical strength of CPZ tablets stored for 24 hours at ambientconditions (23°C and 34%RH). A commercial tablet strength tester (CT4O)was modified to permit accurate measurements of tablet deformationsimultaneously with measurements of force (Figure 7). A linear variable57force(N)tabletdeformationmovement ofupper platenFigure 7. Schematic diagram of the CT4O mechanical strength testercrossbarlinearvoltagedisplacementtransducer(LVDT)referencesurface“fixecr platendeflectionunder loadwith modifications.58displacement transducer (LVDT) was added to measure displacement. Thecrosshead was replaced by a crosshead designed to carry both the upperplaten and the LVDT. During the test, the crosshead descended andapplied a load to a tablet placed on the lower platen. The LVDT measuredthe vertical distance travelled by the crosshead from zero force (the top ofthe tablet) to the force of failure (Ff), the maximum force applied to thetablet immediately prior to diametral failure. The top surface of the CT4Oserved as the fixed reference point. The force applied to the tablet wasmeasured up to tablet failure by means of the load cell, whose analogoutput was calibrated against known weights placed on the lower platen.Lower platen deflection was determined by placing a steel ‘tablet’ betweenthe upper and lower platens and then measuring the crossheaddisplacement as a function of applied force. Since steel was incompressibleunder the test conditions, the measured displacement was due entirely todeflection of the lower platen. The relationship between applied force anddeflection was linear with a value of 1.05 x io cmJN. The force anddisplacement signals were collected on the computer using the analog-to-.digital converter. Software was written to correct the crossheaddisplacement for the load cell deflection and to analyze the data for tensilestress and the work of failure.Downward crosshead movement was set at 3.0 x 10 cm/s. The truespeed was less than this since the lower platen deflection depended on theapplied load. The average speed was calculated from the true change indistance between the upper and lower platens divided by the time tofailure. No padding was used on the platens since this increased theerrors in the measurement of diametral deformation.5915. X-ray Powder Diffraction (XRPD)XRPD was the primary tool in studying the X changes and phasetransitions which occurred with MTZ, ASA, DPH and CPZ during andafter processing. A high resolution wide-angle X-ray diffractometer wasused with a scintillation counter. The D/max-B Bragg-Brentanogoniometer was equipped with incident- and diffracted-beam Soller slits,1/2° divergence and anti-scatter slits, and a 0.15 mm receiving slit. It wasoperated at a radius of 285 mm. For rapid qualitative analysis,diffractograms were obtained using the continuous scan mode at ascanning rate of 3.00-5.00°28 per minute; for elucidating structuralinformation, a step scan mode was used with a step interval of 0.02 to0.05°2 8 from 6.00 to 60.00°20 with a counting time at each step of 5 s.Samples which had been received with manufacturer’s certificationor processed (i.e. ground, tabletted, heat-treated andlor doped) were back-loaded against a frosted glass slide into standard aluminum sampleholders and irradiated with Ni-filtered CuK X-radiation (40 kV, 30 mA)using a take-off angle of 6°. Tabletted material was first scraped from thesurface and edges of the tablet using a sieve of 420 i.m mesh size prior toloading.Scans were performed in triplicate and a variety of preparationtechniques were compared to ensure that preferred orientation was not aproblem. The frosted glass slide helped to promote a more random sample,ensured that a flat surface was obtained level with the top of the holder,and enabled consistent packing from sample to sample. Thus, specimendisplacement and transparency errors were also minimized. Occasionallydilution of the sample with a second phase (e.g. lithium fluoride) and/orgentle hand-grinding was also necessary. To obtain accurate intensity60data for structure refinement, the already textured surface was finelyserrated with a razor blade in a direction parallel to the path of the X-raybeam. This randomized the orientation of anisotropic crystals which willalign during filling, while maintaining a relatively flat surface flush withthe top of the sample holder.The Rietveld method (Rietveld, 1967 and 1969) was used to extractstructural information from the diffraction pattern by implementing theDBW 3.2S program, version 9006PC (Wiles et al., 1988; Sakthivel andYoung, 1991). Details of this package are summarized in Appendix A.Peaks were defined as pseudo-Voigts(8)where L is the Lorentzian component and G is theGaussian component.The percentage of Lorentzian contribution varies linearly as a function of20 and is described by i’, the mixing parameter, which is refined usingvariables NA and NBij=NA+NB(20) (9)A polynomial function was used to fit the background and the equationderived by Caglioti et al. (1958) was used to define the angular dependenceof the full-width at half-maximum (F’WHM), Hk (Equation 1).Reported single-crystal data for MTZ, ASA, DPH and CPZ were usedto provide the starting model. From there, the structures were refined in aleast-squares method using the Newton-Raphson algorithm. Refinements61were performed in three stages. First, the scale factor, cell parameters,and zero-point were refined while atomic positions, site-occupancies, andisotropic temperature factors for individual atoms were fixed at valuespreviously reported (or estimated based on knowledge of similar organicmaterials). A background model was selected based on inspection. Second,the cell dimensions were refined. The half-width parameters, W, U, and Vwere added to the refinement in that order and once convergence wasobtained, parameters for peak shape (NA), peak asymmetry, peak shape(NB) and preferred orientation were included. The polynomial function inthe background model was re-evaluated. Third, the remaining structuralparameters (e.g. atomic positions, site occupancies, and isotropicdisplacement factors) were added and the background model wasreadjusted. Refinement of the preferred orientation parameters using theMarch-Dollase function had no effect on the final results. Finalconvergence was assumed when the shifts in the parameter refinementwere less than 30% of their standard deviations. Information pertinent todata collection MTZ, ASA, DPH and PMDPH doped DPH is provided inTable 1.In addition to the Rietveld structure refinement method (withoutinternal standard), cell dimensions of DPH and CPZ were refined withreference to SRM 675 (synthetic fluorophiogopite mica) and SRM 640b(silicon) using the method of Appleman and Evans (1973).62Table 1. Data Collection and Details of Structure Refinement for MTZ,ASA, DPH and PMDPH doped DPH.MTZ1 ASA DPH PMDPH-DPH20 scan range (°) 6-60 6-60 6-60 6-60Step interval (°20) 0.05 0.05 0.05 0.05Integration time/step (s) 5 5 5 5Maximum step intensity 12288 11028 4394 4777(counts)No. of unique reflections 256 270 199 199No. of structure parameters 41 44 61 61No. of experimental 11 10 11 11parametersScale factor x103 1.380 0.832 0.477 0.414N-P2 1028 1026 1008 1008R 11.10 10.20 11.69 8.48R 14.36 13.22 14.93 11.10RB 4.84 4.07 3.96 3.57Durbin-Watson d-statistic 1.14 1.01 1.50 1.43U 0.119 2.072 0.072 0.418V 0.135 -0.331 0.114 0.316W -0.006 0.021 0.027 0.027fixed fixed fixed fixedY2 fixed fixed fixed fixed1 MTZ crystals were too large and acicular. A random sample was notpossible. Refinements could only be performed on ground and tablettedsamples. The refinement of ground MTZ is reported here.2 N-P is the no. of observations (steps) - no. of least-squares parameters63RESULTS AND DISCUSSIONA. Changes in Crystallinity due to Pharmaceutical Processing1. Determination of Crystallinity Changes using traditional MethodsThe X of MTZ was studied before and after processing usingsuspension density, SC, DSC and XRPD.The density of metronidazole was measured by Blaton et al. (1979)using the suspension density method with carbon tetrachioride andbenzene as the flotation vehicle. A density of 1.44 g/cm3 was reported.Attempts to reproduce their experiments in order to measure changes inX with processing were unsuccessful. Dissolution and recrystallizationof MTZ was observed and the density values were not reliable beyond thesecond decimal place. Using varying mixtures of carbon tetrachloride in1-bromobutane failed to eliminate recrystallization. The closest value tothat reported by Blaton et al. (1979) was 1.45 ± 0.01 g/cm3 (n=5). However,because of recrystallization, the suspension density method isquestionable for assessing changes in X. Helium pycnometry gave avalue of 1.4441 ± 0.0003 g/cm3 (n=10) but the large sample requirementsmade this method unsuitable for our crystallinity determinations.The heat of solution obtained using SC is the sum of the heat ofsolvation (exothermic) and the heat absorbed to break up the crystallattice (endothermic) (refer to Section I.C.2.). Changes in the heat required64to break bonds reflect changes in X. For many organic solids, the energyof the amorphous form is higher than that of the crystalline form (Pikal etat., 1978; Vanderzee et at., 1981), and therefore, less additional heat isrequired for bond breaking. With pharmaceutical processing, the samplebecomes less crystalline (reduction in X) and a decrease in the overallheat of solution is anticipated.A reduction in the heat of solution was observed when MTZ wasground or tabletted and this was followed by a subsequent increase onstorage (Figure 8). The heat of solution ofMTZ as received was 10.5 ± 0.2kJ/mol (n=5), and when ground by hand with an agate mortar and pestlefor 15 minutes, the heat of solution decreased to 9.7 ± 0.1 kJ/mol (n=5). Theheat of solution of tabletted MTZ (compressed to 217 MPa) was identical tothat of the hand ground material (9.7 ± 0.1 kJ/mol, n=5). Changes in theheat of solution of ground MTZ with time was studied at 54°C. After 90hours, the heat of solution increased from 9.7 ± 0.1 kJ/mol to 10.1 ± 0.1kJ/mol (n=5), and to 10.5 ± 0.2 kJ/mol (n=5) after storage for 162 hours. Nofurther change in the heat of solution was observed after storage for 500hours. A portion of the ground MTZ was also stored at room temperaturein a dessicator containing calcium sulphate (Drierite®). After 500 hoursof storage, the heat of solution ofMTZ recovered to 10.3 ± 0.1 kJ/mol. Thevarious treated samples were tested using single factor ANOVA at cz=0.05and statistical significance was found (Fo.051),3,6=27.41, P<0.0005). Themost significant difference was observed between MTZ as received andground.Vanderzee et at. (1981) reported differences of 40 to 90 J/mol intris(hydroxymethyl)-aminomethane (tris) and suggested that thesedifferences were indicative of the significant amount of energy and65H (kJ/mol)Figure 8. Heat of solution ofMTZ: (a) as received, (b) hand ground, andstored at 54°C for (c) 90 and (d) 162 hours. The mean isprovided with standard deviations (n=5). Statisticallysignificant differences were shown using single factorANOVA at a=O.05 (Fo.05l),3,16=27.41, P<0.0005).66mechanical strain stored as the result of grinding. The energy differencebetween the native and ground sample was 800 JImol (i.e. 10 times that oftris) which suggests that substantial structural disordering had occurred(i.e., reductions in crystallite size, increases in the number of crystaldefects (e.g. dislocations), andlor increases in lattice strain).Figure 8 also shows that the increase in energy due to processingwas removed on storage. This can be attributed to the process ofannealing. Annealing is a means by which mechanical strain is removedfrom processed solids; numerous dislocations are eliminated and othersare rearranged into lower-energy configurations (Hayden et al., 1965;Vernon, 1975). This reduction in dislocation density occurs by the mutualannihilation of moving dislocations, and by the running out of dislocationsinto surfaces, grain boundaries and voids. Dislocations which cannot beremoved tend to change their configuration; jogs may disappear anddislocation lines shorten, or similar dislocations may be arranged intosubgrain boundaries. The reduction in dislocation density reducesmisalignments between mosaic blocks and increases the number of mosaicblocks which contribute to a single reflection. An increase in thecrystallite size (an increase in X) results (refer to Section I.B.). The moreendothermic heat of solution observed with MTZ on storage indicated anoverall increase in X, where the rate and extent of recovery wasfacilitated by temperature. Complete recovery was achieved after 162hours at 54°, but 500 hours was required at room temperature.The dissolution rate of MTZ tablets was monitored with time toshow whether or not mechanical energy stored within a crystal as aconsequence of the compression process can affect this important physicalproperty of a solid. Figure 9 shows the intrinsic dissolution rate of MTZ671.91.8-Intrinsic dC/dt(gcm2min1)1.7-1.6-0 10 20 30Time (days)Figure 9. Changes in the intrinsic dissolution rate of MTZ tablets (270MPa) with storage at 25°C. Mean is shown with standarddeviations (n=5). Differences were not statisticallysignificant at a=0.05 using single factor ANOVA(Fo.05l),5,24=L70, 0. 10<P<0 .25).68tablets as a function of storage time. The slight reduction in dissolutionrate with storage indicated an accompanying reduction in the apparentsolubility of MTZ with increasing X,. However, the differences were notstatistically significant using single factor ANOVA at a=0.05(Fo.051),5,24 = 1.70, 0. l0<P<0 .25).The heats of fusion were measured for MTZ as received and aftergrinding. MTZ was ground in a mechanical ball and mill for up to 12hours and samples were taken at regular intervals. There was nodifference between the heat of fusion of MTZ before (36.0 ± 0.9 kJ/mol, n=3)and after grinding (Figure 10). Even after 12 hours of grinding, the heat offusion of MTZ was still 34.7 ± 1.1 kJ/mol (n=3). Single factor ANOVAconfirmed that differences were not statistically significant at a=0.05(Fo.051),0,22=1.59, 0.10<P<0.25). This was contrary to the SC data(Figure 8) which indicated significant structural disordering withgrinding. However, Figure 8 also shows that, on storage, MTZ undergoesannealing and that this process is accelerated by heat. It is likely that theabsence of any decrease in the heat of fusion as a result of grinding is dueto annealing (refer to Section I.C.2.).The X-ray diffraction pattern reflects the structural order of a solid.Peak intensities indicate the atomic density at the different planes of thecrystal. As disorder is introduced, atomic densities are reduced andreductions in peak intensities are observed. Measurements of peakintensity can be used to give an indication of changes in X. Accuratemeasurements of peak intensity are very much dependent on obtaining acompletely randomly oriented sample. An accurate diffractogram of nativeMTZ could not be obtained because of the extensive preferred orientation69Heat of Fusion(lcJ/mol)Time (hours)Figure 10. Heat of fusion of MTZ with grinding. Even after 12 hours ofgrinding with a mechanical ball and mill, no differences in theheats of fusion of MTZ were observed. Heats of fusion areshown with their mean and standard deviation (n=3).Statistical significance was not found using single factorANOVA at cc=0.05 (Fo.05l),1o,22=1.59, 0.10<P<0.25).ITtJ TCJ0 5 1070of the large acicular crystals. The ability to pack MTZ significantlyimproved with grinding and tabletting. Typical diffractograms of MTZground and tabletted are given in Figure 11. Tabletting the groundmaterial reduced the intensity of the 12.25 20 peak (base peak) by 39-40%.Peak intensity ratios measured relative to an internal standard arecommonly used to quantitate X (Imaizumi et at., 1980; Otsuka andKaneniwa, 1983 and 1984; Kaneniwa et at., 1985; Suryanarayanan andMitchell, 1985; Ryan, 1986; Kamat et al., 1988; Kitamura et at., 1989; andAshizawa et at., 1990) (refer to Section I.C.9.). Only relative differencescan be examined and no explanation is given as to the type of structuralmodifications involved which are responsible for the X changes observed.2. The Rietveld Structure Refinement MethodThe Rietveld structure refinement method was originally developed torefine crystal structures from powder data when single-crystal work wasnot feasible, but a starting model which is based on published singlecrystal work is generally required (Rietveld, 1969). The high precision andaccuracy of the method lies in its ability to determine the peak positionsunambiguously, to correct peak intensities for preferred orientation, andto model peak shapes. This is exemplified by its use in mineralogy for thequantitation of individual components in a complex multiphase system(Raudsepp et at., 1990).Prior to the development of the Rietveld method, the ability to extractstructural information from XRPD data was limited by the ability toaccurately characterize the shape of the peaks. Although developmentsare still in progress, a large selection of profile shapes are now availablewhich closely approximate the peak shape. It is from the peak shape that71Figure 11. Diffractograms of MTZ (a) hand ground and (b) tabletted (270MPa). The cliffractogram ofMTZ as received could not beobtained since the large acicular crystals caused extensivepreferred orientation which made proper sample packingimpossible.2-THETA72information about crystallite size and lattice distortion can be obtained.To date, application of the Rietveld method has been limited toinorganic solids and the analysis of peak profiles has been restricted toideal inorganic materials (e.g. aluminum oxide (Hill and Madsen, 1986;Lutterotti and Scardi, 1990; Balasingh et al., 1991), calcium fluoride,lithium fluoride (Delhez et al., 1982), zinc oxide (Langford and Louër,1986)). Unique features of the present research have been to extend theRietveld method to organic crystals, and to adapt the analysis ofcrystallite size and lattice distortion of ideal inorganic solids to nonidealorganic crystals. Assessments of X using XRPD need no longer beempirical. The processes that cause changes in X (i.e. crystallite size andlattice distortion) can now be directly quantified.2.1. X-ray Powder Data and the Structural ModelThe Rietveld structure refinement method was .used to accuratelycharacterize the profiles of MTZ (hand ground), ASA (as received) andDPH (as received). Typical diffractograms of MTZ (Figure 12), ASA(Figure 13) and DPH (Figure 14) are shown with their calculated anddifference patterns. The difference patterns show that close agreementwas achieved between the calculated and observed patterns. Therefore,preferred orientation was negligible and the refined structural modelcould be used to accurately describe the structure of the solid. Calculatedcell parameters were in agreement with published single crystal work(Tables 2-4). Any minor discrepancies between the cell parametersobtained from single crystal studies and those calculated from powderdata can be attributed to systematic errors or instrumental effects such asI 16,-36 46 5673Figure 12. Observed, calculated and difference X-ray powder diffractionprofiles for MTZ (hand ground). The observed data areindicated by dots, and the calculated profile is the continuousline overlying them. The short vertical lines below thepattern represent the positions of all possible Braggreflections, and the lower curve is the value of sign (A)wA2ateach step, where A is the difference between the observed andcalculated intensity and w is the weight applied during least-squares refinement.10.0K-U)4JC:305.OK•O0K____1fL1i1II I I II III III 1111 111111 S 11111 II 11111111 RIIERSRTwo—Theta (degrees)74I-Figure 13. Observed, calculated and difference X-ray powder diffractionprofiles for ASA (as received). The observed data are indicatedby dots, and the calculated profile is the continuous lineoverlying them. The short vertical lines below the patternrepresent the positions of all possible Bragg reflections, andthe lower curve is the value of sign (A)wA2 at each step, whereA is the difference between the observed and calculatedintensity and w is the weight applied during least-squaresrefinement.6.0K-4-’CD00‘ 2.0K-O.OKZiI11 rut] lilt tltt-2.OK-I flU UI (U I III UI 11111 IRE (Elf IIfl UIE lITwo—Theta (degrees)75F’igure 14. Observed, calculated and difference X-ray powder diffractionprofiles for DPH (as received). The observed data areindicated by dots, and the calculated profile is the continuousline overlying them. The short vertical lines below thepattern represent the positions of all possible Braggreflections, and the lower curve is the value of sign (A)wA2 ateach step, where A is the difference between the observed andcalculated intensity and w is the weight applied during least-squares refinement.4.0KC’)4-,CD0U2.0K‘S4-,(aCa)0.0K—2.0K I I I I III I E III I RE I EERIE III lilt lIRE 1 lIE R ER 1Two—Theta (degrees)76Table 2. Cell dimensions of MTZ with processing.Cell Dimensions1a(A) b(A) c(A) 13(°) V(A3)MTZ2 7.034(2) 8.725(3) 12.818(3) 94.51(2) 784.2MTZ ground34 7.051(6) 8.738(1) 12.839(2) 94.56(8) 788.5MTZ tabletted3’5 7.055(6) 8.741(1) 12.841(2) 94.54(9) 789.81 cell dimensions are provided with their corresponding standarddeviations in parentheses2 from the single crystal work of Blaton et al. (1979)3 calculated using the Rietveld method4 ground for 30 minutes using a mechanical ball and mortar mill5 tabletted at 270 MPaNote: The cell dimensions ofMTZ as received could not be refined since thecrystals were large and acicular, making the preparation of a propersample impossible. Extensive preferred orientation could not beavoided.77Table 3. Cell dimensions of ASA refined using the Rietveld method.Cell Dimensions1a(A) b(A) c(A) B(°) V(A3)ASA(Wheatley, 1964) 11.446(13) 6.596(6) 11.388(9) 95.55(3) 855.7ASA(Kimetal., 1985) 11.430(1) 6.591(1) 11.395(2) 95.68(1) 854.2ASA(Masaki etaL, 1991) 10.8 6.0 N/A 90ASA as received2 11.449(3) 6.629(1) 11.429(2) 96.68(1) 861.51 cell dimensions are provided with their corresponding standarddeviations in parentheses2 cell dimensions refined using the Rietveld method78Table 4. Cell dimensions of DPH and DPH doped with PMDPH.Cell Dimensions1a(A) b(A) c(A) V(A3)DPH2 6.230(1) 13.581(1) 15.532(2) 1314.2DPH3 6.239(1) 13.608(2) 15.566(3) 1321.6DPH4 6.213(8) 13.559(12) 15.550(17) 1310.0DPH doped with 6.215(6) 13.537(10) 15.507(14) 1304.6PMDPH41 cell dimensions provided with their corresponding standard deviationsin parentheses2 cell dimensions obtained from the single crystal work of Camerman andCamerman (1971)3 cell dimensions calculated using the Rietveld methodcell dimensions corrected by the addition of an internal standard.(The Rietveld-derived cell dimensions (DPH3)were 0.5-1.0% larger andthis discrepancy is attributed to systematic errors which are usually ofthis magnitude (refer to Sections I.C.9.2.3. and III.A.2.1.). The celldimensions of DPH doped with PMDPH also exhibited thisdiscrepancy.)79the X-ray source geometry, displacement of the specimen surface, axialdivergence of the X-ray beam, specimen transparency, effects of receivingslits, and diffractometer misalignment (refer to Section I.C.9.2.3.).2.2. Assessment of Changes in CrystallinityThe effects of grinding, compaction and heating on X were studiedusing MTZ and ASA as model compounds which illustrate the importanceof examining both crystallite size and lattice distortion. The effect ofadditive incorporation on lattice distortion was studied using DPH.2.2.1. Grinding and TablettingChanges in the full-width at half-maximum (FWHM) of MTZ withprocessing is shown in Figure 15. Broadening of the peaks occur when theground MTZ was tabletted at 270 MPa, suggesting changes in order, andmore specifically, changes in crystallite size and/or lattice distortion. Asan accurate diffr•actogram of native MTZ could not be obtained, changes inFWHM are shown in comparison to barium fluoride as the peak widthstandard. The single crystal data of Blaton et at. (1979) was used to refinethe powder data of MTZ (Figure 12). Differences between the refined cellparameters of ground and tabletted MTZ (Table 2) were not statisticallysignificant (differences were less than 3 standard deviations) andindicated that distortions of the lattice had not been extensive. The unitcell volumes of ground and tabletted MTZ were virtually identical.Buckling of the atomic planes within the crystal structure or disruption ofstructural continuity could also cause peak broadening withoutsignificantly changing the size of the unit cell. The level of precision towhich cell parameters could be determined, however, would be affected800.40.3FWHM 0.20.10.0• I I I0 10 20 30 402-ThETAFigure 15. FWHM of ground (u) and tabletted (0) MTZ are shown as afunction of 20. Annealed barium fluoride (A) was used as thepeak width standard.81(larger standard deviations would be obtained). The standard deviationsof the cell dimensions of ground and tabletted MTZ were identical andindicated that these effects alone were not large enough to cause the peakbroadening observed (Figure 15). This suggested that crystallite size mayplay an important role (crystallite size is defined in Section I.B. anddiscussed in further detail below, Section III.A.2.2.2.).Slight differences were observed following the grinding of ASA, andtabletting to a peak pressure of 270 MPa reduced the intensity of the basepeak to the same extent as that observed with MTZ (i.e. 40%). Typicaldiffractograms for ASA as received, ground and tabletted are provided inFigure 16.Using the Rietveld method, diffractograms of ASA were fitted to acalculated diffractogram obtained from the single crystal data of Wheatley(1964) and Kim et al. (1985) (Figure 13). Structural parameters wererefined. The cell parameters of native and ground ASA were unchangedand no differences were observed between the 270 and 408 MPa tablets.However, there was a reduction in the unit cell volume when tabletted andthis was due to a 0.5% reduction in the b dimension of the unit cell, astatistically significant difference of over 3 standard deviations (Table 5).The larger standard deviations obtained for processed ASA compared tothose of ASA as received indicated that buckling of the atomic planesand/or degradation of structural order had also occurred.The FWHM of ASA was increased with pharmaceutical processing.Figure 17 shows the full width of the diffraction peaks at half maximum(FWHM) between 0 to 40°20. The diffraction peaks of the native samplewere narrow and following grinding, peak broadening was observed(FWHM increased). Tabletting further broadened all peaks and compared82Figure 16. Typical diffractograms of ASA (a) as received, (b) hand groundfor 15 minutes in an agate mortar and pestle, and handground (h) and tabletted at (c) 270 MPa and (d) 408 MPa.a2-ThETA83Table 5. Changes in the cell dimensions of ASA with processing.Cell Dimensions1a(A) b(A) c(A) B(°) V(A3)ASA (as received) 11.449(3) 6.629(1) 11.429(2) 96.68(1) 861.5Ground 11.449(3) 6.629(1) 11.406(2) 95.72(1) 861.4Tabletted (270 MPa) 11.436(3) 6.590(2) 11.407(3) 95.72(1) 855.4Tabletted (408 MPa) 11.444(3) 6.589(2) 11.417(3) 95.74(1) 856.61 cell dimensions were refined using the Rietveld method and are givenwith their standard deviations in parentheses.840.50.40.3FWfIM0.20.10.00 10 20 30 402-ThETAFigure 17. Changes in the FWHM ofASA as received (a), handground (a), and tabletted at 270 MPa (0) and408 MPa (.).85to the native sample, a two-fold increase in FWHM was observed. Nosignificant difference was seen between the peak intensities or F’WHM oftablets compressed at 270 and 408 MPa.Hence, even though the effect of pharmaceutical processing on thepeak intensity of MTZ and ASA was the same, the underlying reasons forthe reduction in X were very different. While crystallite size may beimportant for explaining the X changes of MTZ with processing, the peakbroadening of ASA after grinding suggested that the reduction in X maybe a result of a decrease in crystallite size and that further increases inFWHM with tabletting reflect both crystallite size reductions and latticedistortion. These observations are supported by the single crystal data ofMTZ (Blaton etal., 1979) (Appendix B - Table 11) and ASA (Wheatley, 1964;Kim etal., 1985) (Appendix B - Table 12). Within the unit cell of MTZ, eachmolecule forms a hydrogen bond with a symmetrically related neighbor[O(12)-H(12)”N(3)’: O(12)-N(3Y=2.816(2) A, H(12)N(3)’=1.98(2) A,andLO(l2)-H(12)•N(3)’=l69(2) A] with the formation of two additionalhydrogen bonds between the 0(8) atom of the nitro group and theneighboring H atoms {0(8)”H(10a)=2.47(2) A and O(8)”H(11a)=2.52(2) Al(Blaton et al., 1979) (Appendix B - Table 11). On the other hand, only twohydrogen bonds are formed between the molecules of ASA and involve thecarboxylic oxygens [O(1)”O(2)’=2.649(2) A and H0(1)O(2=1.67(3) A](Kimetal., 1985) (Appendix B - Table 12). The more extensive hydrogenbonding network of MTZ is exemplified by its higher melting point (159°Ccompared to the melting point of ASA, 135°C (Wheatley, 1964)) and sincetwo portions of the molecule are secured, sufficient molecular movement tocause a noticeable change in the unit cell dimensions is unlikely. Theenergy of processing is more likely to cause an increase in the86concentration of crystal defects, which in turn, reduces crystallite size (asseen above in Section III.A.2.2.1. and discussed in further detail below,Section III.A.2.2.2.). Only the carboxylic oxygens of ASA are involved inhydrogen bonding and the molecules of ASA are dimerized along a centerof symmetry. Shear along the ca and ab planes can occur during pressure,affecting crystallite size. The benzene rings are also planar and stackedflat one on top of the other along b axis (Wheatley, 1964). The length of theintermolecular van der Waal forces between the planes can be compressedand may explain the reduction in the b dimension with tabletting.The Voigt function was used to analyze the diffractograms of MTZand separate crystallite-size effects from strain-broadening. Theindividual peak full-width at half-maximum of the total peak, Fp, shownabove (Figure 15) can be separated into the Lorentzian component, FL, andthe Gaussian component, FG, where the reduction in crystallite size withtabletting is reflected in an increase in FL (Figure 18). A small degree oflattice distortion (strain) is also measured (Figure 19). The lack ofsignificant changes in the cell dimensions of MTZ with processingsuggests that, unlike ASA, a more detailed analysis of FL is warranted.2.2.2. Storage at Elevated TemperaturesWith pharmaceutical processing, the crystallite size of MTZ wasaffected, and on storage at elevated temperatures, an increase in L wasobserved (Figures 20-23). Figures 20-23 show a progressive reduction inFL, corresponding to the increase in crystallite size, at all storagetemperatures. From FL, a hypothetical value of crystallite size can becalculated. Very equant crystallites of highly idealized behavior areassumed, and therefore, the grain sizes reported in the present study87LorentzianFWHM0.075-0.07-0.065 -0.06-0.055-o-05 -I I I I I I I0 10 20 30 40 50 60 702-thetaFigure 18. FWHM of the Lorentzian component (EL) of MTZ mechanicallyground (D) and tabletted (<>).Gaussian FWHM0.2-I I20 40 60 802-theta88Figure 19. FWHM of the Gaussian component (FG) of MTZ mechanicallyground (<>) and tabletted (a).0.4-0.3 -0.1-0-0890.065-LorentzianFWHM0.06-o0o::: oe0 10 20 30 40 50 60 702-thetaFigure 20. FWHM of the Lorentzian component (rL) of MTZ hand groundwith storage at 25°C for 1(0), 2 (A), 7 (s), 10 (+)and 14(0)days.900.060LorentzianFWHM 000.055- 0 00000oJ 00.05- 00•0.045-0 10 20 30 40 50 60 702-thetaFigure 21. FWHM of the Lorentzian component (rL) of MTZ hand groundwith storage at 54°C for 1(o), 2 (ti), 3 (o), 4 (o), and 10 (,)days.910.055-LorentzianFWHM0.0525-0.05• o,o0,0.0475- 00000.045-0.0425- a i a a a0 10 20 30 40 50 60 702-thetaFigure 22. FWHM of the Lorentzian component (FL) of MTZ hand groundwith storage at 70°C for 1(0), 3 (o), 4(o), and 10(e) days.920.0525-LorentzianFWHM0.05- 00.0475- 000.045- 000QO0.0425-0.C)4—0 10 20 30 40 50 60 702-thetaFigure 23. FWHM of the Lorentzian component (FL) of MTZ hand groundwith storage at 100°C for 1(0), 2 (tI), 4 (), and 7 () days.Days 10 and 14 were not different from day 7 and are notshown this plot.93should not be considered absolute since the existence of these idealcrystallites within the acicular organic crystals studied is unlikely. Thesevalues, however, are of importance as relative values in studying changesin X. The FL profiles of Figures 20-23 were used to calculate crystallitesize, and to show changes in the crystallite size of MTZ with time (Figure24). This can be attributed to annealing (discussed in Section III.A.1.), andrecrystallization, which involves nucleation (the formation of stablestrain-free areas with high-angle boundaries suitable for rapid growth)and growth (the expansion and eventual impingement of the stablynucleated grains) (Vernon, 1975). It should be emphasized that Figure 24is provided for relative comparisons only. The increase in crystallite sizewas facilitated by elevated temperatures, but complete recovery of thetabletted material back to the ground starting material was neverachieved. This incomplete recovery of order was contrary to the resultsobtained using SC which indicated that complete recovery of MTZ could beachieved on storage (Figure 8). Since the definition of order varies withthe method (e.g. SC measures thermodynamic order while XRPD measuresstructural order), discrepancies among the X determined using differentmethods are not unusual (refer to Section 1.0.).The lattice distortion of ASA was monitored following tabletting(Figure 25). Complete recovery of the distortions in the lattice was notobserved, and in fact, very little recovery occurred even at elevatedtemperatures. Shear along atomic planes in addition to the movement ofmolecules closer to one another may account for the largely irreversibledistortion that occurred (refer to section III.A.2.2.1.).94Crystallite Size (A)Time (days)Figure 24. Changes in the crystallite size of ground MTZ with storage at25° (ti), 54° (0), 70° (<D>) and 100°C (c).2200210017000 5 10 1595b(A)Figure 25. Changes in the b ofASA (a) as received, (b) hand ground, and(c) tabletted at 270 MPa. Changes in b with storage at54°Care aiso shown after (d) 3, (e) 7, and (f) 14 days.6.666.646.62-1a ef962.2.3. Incorporation of AdditivesThe mechanism by which additives are incorporated intopharmaceutical solids is not clear. For DPH doped with PMDPH,significant “lattice disorder and disruption” (19-times that expected frompure random mixing alone) was suggested by the disruption index ofPMDPH (refer to Section I.C.2.) (Gordon and Chow, 1992).Very little X-ray work has been done on DPH and the first step was toaccurately index the powder pattern. Published powder diffractograms todate were poorly indexed and exhibited severe preferred orientation,particularly along the (002) plane (Chakrabarti et al., 1978; Gong, 1982;Gordon, 1991). The indexed X-ray diffraction pattern of DPH is provided inTable 6.The Rietveld structure refinement method (without internal standard)was used in conjunction with the method of Appleman and Evans (1973)(with internal standard) to investigate the incorporation of 3-propanoyloymethy1-5 ,5-diphenylhydantoin (PMDPH) into 5,5 -diphenyihydantoin (phenytoin, DPH) (Figure 26). The sample packingrequired to overcome the severe preferred orientation of the acicularcrystals compromised peak shape information and therefore accuratecrystallite size information could not be obtained.Contrary to the findings of other workers, the suggested “considerabledisorder and disruption” in the crystal lattice of DPH in the presence ofPMDPH was not substantiated. Changes in cell dimensions were notobserved suggesting that incorporation of PMDPH into the lattice of DPHwas unlikely. These dimensions are compared in Table 4. The Rietveld cellwas larger than the cell corrected by the addition of an internal standard,97Table 6 - Indexed X-ray powder pattern for DPH2Ocalc (°) dcalc (A) JJ’calc “Jobs hkl8.590 10.2855 12.8 17.7 01111.326 7.8063 66.7 84.1 00212.968 6.8213 28.4 33.7 02015.254 5.8038 1.2 2.3 10116.590 5.3393 100.0 100.0 11117.264 5.1323 27.1 29.9 02218.176 4.8768 36.2 42.4 102,01319.316 4.5915 15.2 26.1 11220.343 4.3620 55.0 42.7 121,03122.406 3.9648 78.8 76.3 103,12222.800 3.8971 13.5 20.7 00423.183 3.8336 1.7 3.2 11325.835 3.4458 20.4 10.8 12326.039 3.4193 11.0 27.4 03326.141 3.4061 19.8 28.9 04026.949 3.3058 10.7 10.3 132,10427.747 3.2125 18.4 20.4 11429.317 3.0440 1.6 2.7 210,01529.768 2.9989 5.7 5.9 13330.025 2.9738 1.6 2.7 12430.823 2.8986 3.1 2.8 20231.532 2.8350 2.8 4.1 220,21232.025 2.7925 1.3 1.7 221,142,10533.459 2.6760 10.5 8.7 203,051,13434.895 2.5691 1.7 3.5 035,04435.334 2.5382 2.4 3.3 23136.763 2.4427 0.9 1.8 23237.246 2.41 22 3.6 5.5 05337.482 2.3975 1.2 3.1 214,10638.081 2.3612 1.3 1.8 144,11639.679 2.2697 1.1 2.8 06039.832 2.2613 1.3 2.7 12641.405 2.1790 4.8 4.9 062,21542.066 2.1462 1.1 2.0 23442.755 2.1132 1.7 1.6 136,161,24343.084 2.0979 2.5 3.2 154,225,10743.819 2.0644 1.5 2.6 117,04644.093 2.0522 3.9 3.8 162,25045.402 1.9960 3.2 3.6 037,206,31245.915 1.9749 0.9 1.6 21646.266 1.9607 1.3 2.3 06447.095 1.9281 3.0 3.9 32247.612 1.9084 2.5 2.6 313,253,13749.453 1.8416 1.0 1.6 11849.874 1.8270 1.7 1.9 236,261,07350.217 1.8153 1.0 1.3 314,254,207980a2-thetaFigure 26. Diffractogram of (a) DPH and (b) DPH with fluorophiogopite,the internal standard used in the refinement of cellparameters using the method of Appleman and Evans(1973).The spikes below denote the peaks of the internal standard.b10 20 30I I I I I40 5099and any discrepancies were likely due to systematic errors, which aregenerally between 0.05 and 0.1% (refer to III.A.2.1.).Structural analysis indicated that the molecules of DPH wereextensively hydrogen bonded within the crystal structure, involving thehydrogens bonded to the nitrogen atoms and the two carbonyl oxygenatoms (Camerman and Camerman, 1971) (Appendix B - Table 13). Thestrength of this interaction is demonstrated by the short H” 0 hydrogenbond distances of 1.92 A (H(1)•”•O(7’)) and 1.98 A (H(3) “0(6’)). Thisextensive network of hydrogen bonds bestows upon DPH a strong crystalstructure which is reflected in its high melting point of 295°C (Philip et at.,1984).The absence of major structural changes suggest that the traceadditive may be present in the DPH crystals in the form of a substitutionalsolid solution. Two types of substitutional solid solutions are possible fororganic crystals, namely, true and interblock substitutional solidsolutions (Kitaigorodsky, 1984). For the formation of true substitutionalsolid solution, the additive must at least be able to partially maintain thehydrogen bonding network of DPH. This may be feasible for PMDPH sinceit retains all the hydrogen bond acceptor sites and one of the two donorsites of DPH. The formation of an interblock solid solution, on the otherhand, requires only that there be partial geometrical conformity betweenthe impurity and host molecules, and this may be more likely. In such asolid solution the additive molecules either occupy defect sites within thecrystals or the subgrain boundaries of mosaic blocks. Since theseoccupation sites are rarely the lattice positions, the presence of theadditive is unlikely to alter the unit cell parameters of the host crystal.100B. Phase Transitions during Pharmaceutical ProcessingChiorpromazine hydrochloride (CPZ( II)), a phenothiazineantipsychotic, makes poor tablets. Sticking to the die wall and picking bythe punch faces occurred during the compaction of the pure unlubricateddrug. Severe lamination and capping were observed at all compressionpressures.A nonconventional wet granulation method employed by RhonePoulenc significantly improves tablettability. In the granulationprocedure, CPZ(II) (Appendix B - Table 15) is wetted with an ethanol:watermixture (80.5:22.9 v/v) and dried at 50°C. No binding agent is used.Changes in the X of CPZ(II) during wet granulation were initiallythought to be responsible for the intact tablets formed, but Wong andMitchell (1992) showed that a phase change had occurred.During the wet granulation process, CPZ(II) is completely convertedto a stoichiometric hemihydrate, CPZ(I)-H (Appendix B - Table 14), andwhen dried at 50°C, some of the water of hydration is removed to form apartially dehydrated hydrate, CPZ(I)-H’. Complete dehydration produceda room temperature stable polymorph, CPZ(I). Polymorphs of CPZ havenot been reported in the pharmaceutical literature. Dorignac-Calas andMarsau (1972) isolated three different crystal forms of chiorpromazinehydrochloride but only documented the single crystal X-ray data of thehigh temperature stable form. In this work, the phase change of CPZ(II)during wet granulation was characterized, and differences in thecompaction properties of the various forms were assessed.1011. Physicochemical Characterization of Chlorpromazine HC1 and itsGranulesThe morphology, X-ray diffractograms, thermal behavior and truedensities of CPZ(II) and its granulated forms were significantly different.1.1. Scanning Electron MicroscopySEM images of CPZ(II) and its granules are provided in Figures 27aand b, respectively. After wet granulation, the aggregates of large needle-shaped CPZ(II) crystals are converted to smaller composite irregularlyshaped crystals. The step-like ridges on the crystal faces and the angularedges are replaced with an irregular pattern of indentations and roundedcorners.1.2. X-ray Powder DiffractionThe X-ray powder diffractograms of CPZ(II) exhibited major peaks at8.5, 15.7, 18.8, 22.3, 22.8 and 25.1 20, with minor peaks at 6.3, 10.0, 14.8,16.0, 16.9, 20.3, 25.7 and 28.1 20 (Figure 28a). The diffractogram of CPZ(I)H’ was completely different. Major peaks of CPZ(I)-H’ were observed at 5.6,11.3, 16.8, 19.2, 20.6, 22.6, 23.4, 27.1 and 28.2 20 (Figure 28b).Diffractograms of CPZ(I)-H, the fully hydrated granules, and CPZ(I), thedehydrated granules, were qualitatively the same as CPZ(I)-H’. It wasapparent that wet granulation with the ethanol-water mixture led to aphase change where the new crystal lattice, CPZ(I)-H’, could take up orlose water molecules without a marked change in the lattice structure.This is discussed in further detail in Section III.B.1.6. below.The peaks of CPZ(II) were narrower and of greater intensity thanthose of CPZ(I)-H’, CPZ(I)-H and CPZ(I), indicating that CPZ(II) was moreI 02Figure 27a. Scanning electron images of’ CPZ(II) (magnification, X2000).10:3Figure 27b. Scanning electron images of CPZ(I)-Ht (magnification, X2000).104obFigure 28. X-ray diffractograms of (a) CPZ(II) and (b) CPZ(I)-H’ (shownusing the same intensity scale for comparison). Thediffractograms of CPZ(I)-H and CPZ(I) are qualitatively thesame as CPZ(I)-H’.5 10 15 20 25 30 352 THETA105crystalline. This was confirmed by the sharper, more intense peaks ofCPZ(II) obtained from preliminary solid-state NMR studies (Appendix C).1.3. Thermal AnalysisThe DSC thermogram of CPZ(II) showed a single melting endothermat 188-189°C (Figure. 29a), while the thermograms of CPZ(I)-H’ andCPZ(I)-H exhibited two additional endotherms prior to melting - a broadpeak due to dehydration and vaporization, and a small endotherm at 132-134°C due to a solid (CPZ(I)) to solid (CPZ(II)) transition (Figure 29b).These findings are summarized in Table 7. All transitions were verifiedusing thermal microscopy.When heated at a temperature exceeding the dehydrationendotherm (70°C), the weight lost from CPZ(I)-H’ and CPZ(I)-Hcorresponded to 1.90% and 2.47% w/w water, respectively.. The ethanolcontent of CPZ(I)-H’ was negligible (0.0 144±0.0004% wlv).When CPZ(I)-H’ was completely dried at 70°C under vacuum in thepresence of silica gel, the dehydration endotherm disappeared but thesecond endotherm remained (Figure 29c). No further weight loss wasdetected after the second endotherm. Heating past the second endothermfollowed by immediate cooling to room temperature and reheatingproduced a thermogram identical to that of CPZ(II) (Figure 29a). Thephase change from CPZ(I) to CPZ(II) at elevated temperature wasconfirmed by XRPD. A diffractogram identical to that of CPZ(II) wasobtained when CPZ(I)-H’ was heated in an oven at 150°C for 15 minutes.The solid-solid transition was confirmed using thermal microscopyand suggested enantiotropic polymorphism. By definition, thecommercially available form, CPZ(II), is the high temperature stable form10650 100 150Temperature (°C)200Figure 29. DSC thermograms of (a) CPZ(II), (b) CPZ(I)-H’ and (c) CPZ(I)using hermetically sealed pans with pinhole.aendoI I I ITable 7. Thermal analysis of CPZ(II) and CPZ(I)-H.Pan Scan Rate Temperature’Type C/min Peak Proposed ReactionThermograms ofCPZ(7!)A,C2 10 1 CPZ(1I)(s) --> CPZ 188-189B2 10 1 CPZ(1I)(s) --> CPZ 184-185Thermograms ofCPZt’I)-HA 2-10 1 CPZ.H(s) > CPZ(1)(S) +l/2H2O(g)2 CPZ(1)(s) > CPZ(II)(s) 132-1343 CPZ(II)5—>i) 189B 10 1 CPZH()>CPZ(I)() +112°(g) 582 CPZ(1)(5--> CPZ(11)(5) 1293 CPZ(ll) --> CPZ0 187C 2-10 1 CPIH(s) .“> CPZ(I)( + ‘/2°(g) 50-552 CPZ(O(5)--> CPZ(U)(5) 134-1373 CPZ(fl) --> CPZ 187-190A,C 15,20 1 CPZ.H(s) > CPZ(I)(S) + ‘/2°(g) 582 CPZ(1)(s) --> CPZ(ll)(5) 134-1353 CPZ(II)5--> CPZ1 185-188Thermograms ofCPZ(1AC 10 2 CPZ(I)(5)--> CPZ(1I)(s) 135-1373 CPZ(II) --> CPZ1 187-189B 10 2 CPZ(I)(s) --> CPZ(II)(5) 1343 CPZ(I1) --> CPZ(j) 186‘Transition temperature measured from theleading edge2A=standard pan; B=sealed pan; C=sealed pan with pinhole107108which exists between 134° and 189°C, and is metastable at roomtemperature. A similar high temperature stable form was reported byDorignac-Calas and Marsau (1972), existing from 147° to 201°C (AppendixB - Table 15). No preparative details were given.The reverse transition, however, was not observed on cooling tobelow the transition temperature, and no evidence of conversion of CPZ(II)to CPZ(I) was found during storage under ambient conditions. When thegranulation procedure was simulated on a microscope slide and observedunder a light microscope, both the presence of liquid and CPZ(II) crystalswere found to be necessary for the formation of CPZ(I)-H. It is apparentthat while the conversion of CPZ(I) to CPZ(II) occurs at a specifictransition temperature on heating, the conversion of CPZ(II) to CPZ(I)only occurs through a hydrate intermediate and not through a solid-solidphase change. CPZ(I), the low temperature stable form, is a dehydratedhydrate in which the hydrate lattice structure does not collapse andrecrystallize when the water of crystallization is removed. This unusualphenomenon was also found with cephalexin and cephaloglycin (Pfeiffer etat., 1970), and calcium gluceptate (Suryanarayanan and Mitchell, 1986).Figure 30 summarizes the above.1.4. Heats of Solution and True DensityThe heats of solution support the hypothesis that CPZ(II) is ametastable form of chlorpromazine hydrochloride at room temperatureand that CPZ(I) is the stable form. The heat of solution for CPZ(I) is higher(more endothermic) than CPZ(II) (Table 8) . Their true densities alsodiffer. When CPZ(I)-H’ is fully hydrated (CPZ(I)-H), its heat of solution and109Conditions(20-26C,30-40%RH)(vacuum,silica gel)wet granulation withethanol :water80.5:22.9 (by volume)132-134C-K’RH>53%(25c)70 CCPZ(II) cpz(r)-Hb.C (vacuum,silica gel)C PZ (I)RH>53% (25C)Figure 30. Interconversions of CPZ.110A comparison of the heats of solution and true densities ofCPZ(II), CPZ(I), CPZ(I)-H’ and CPZ(I)-H.Heat of Solution True DensityMaterial (kJ mol) (g cm3)CPZ(lI) 28.80 (098)a 1.312 (0.001)CPZ(1) 29.49 (0.24) 1.285 (0.003)CPZ(I)-H’ 34.89 (0.28) 1.299 (0.001)CPZ(I—H 35.89 (0.22) 1.304 (0.004)a mean ± standard deviation(n=5 for solution calorimetry; and, n=6 for true densitymeasurements)Table 8.111true density increase; and, when fuiiy dehydrated CPZ(I), its heat ofsolution and true density decrease (Table 8).1.5. Solubility and Dissolution RateSolubility and dissolution studies were performed on CPZ(I) andCPZ(II) in both aqueous and nonaqueous media but no differences wereobserved in the apparent solubilities of these two forms due to the rapidconversion of CPZ(II) to CPZ(I)-H. Rapid conversion also occurred duringthe dissolution studies using both buffered and unbuffered aqueoussolutions, and a mixture of water and tertiary butanol. The dissolutionrates of CPZ(I) and CPZ(II) were virtually identical (Figure 31).1.6. Relative Humidity-Composition StudiesA relative humidity (RH)-composition phase diagram wasconstructed to describe the hydration/dehydration behavior of CPZ(I)(Figure 32). A typical adsorptionldesorption isotherm was obtained at RHsbetween 8 and 53%, and at higher RHs, CPZ(I)-H (a stoichiometrichemihydrate) was formed. CPZ(II) did not form hydrates at any of the RHvalues tested.The lattice expansion of CPZ(I) with water incorporation wasmeasured using XRPD. Cox et al. (1971) investigated a similar reversibleexpansion with cromolyn sodium when exposed to water vapor, but theirmethod required the preparation of single crystals for single crystaldiffractometry. Published single crystal data was used in this study.Klein and Conrad (1986) reported a detailed structural analysis of ahemihydrate of CPZ recrystallized from aqueous ethanol (Appendix B -1120.0030-Concentration 0.0025 -(mglmL) 0QD I]> C0.0020-C0.0015-0.0010•00.0005•0.0000-hid0 50 100 150Time (s)Figure 31. Dissolution rates of CPZ(I) (C) and CPZ(II) (c>) in aqueoussolution buffered at pH 11.113%RH100•806040200•0 0.5 1 1.5Water Composition (%)Figure 32. Relative humidity-composition profile of CPZ(I). (CPZ(I)-H’, asreceived, contained 1.90% w/wH20 and CPZ(I)-H contained2.47% w/wH20 (0.5 mol H20/mol CPZ)desorptionabsorption2 2.5114Table 14). The single crystal data was converted to a powder patternusing the LAZY PULVERIX program of Yvon et al. (1977).Information about the lattice parameters, the space-group symbol,and the coordinates and chemical symbols of atoms contained in oneasymmetric unit were required. The necessary constants from theInternational Tables for X-ray Crystallography were stored in the program(e.g. scattering factor tables, anomalous dispersion correction terms andX-ray wavelengths). All symmetry information was derived and themultiplicities of special positions were automatically calculated. Usingthis method, a tabular listing of hkl, d spacing, 20 values, structurefactors and intensities was obtained.The calculated powder pattern of Klein and Conrad (1986) was notonly identical with that of CPZ(I)-H, but also CPZ(I)-H’ and CPZ(I).Having established that our powder data and the published single crystaldata were in agreement, the published lattice parameters were used in theindexing and least-squares refinement method of Appleman et al. (1973).Slight shifts in the peak positions occurred when the amount of water inthe lattice was varied. Powder data was collected for a number of CPZ(I)samples whose lattices contained varying amounts of water, and thesediffractograms were indexed and refined to elucidate the correspondingchanges in the dimensions of the unit cell.The three-dimensional changes in the monoclinic lattice as afunction of water content are shown in Figure 33. While the unit cellgradually expands in the a and c direction as more water is incorporated,the longest length of the unit cell (i.e., along b) contracts. Upon formationof CPZ(I)-H (the hemihydrate) at 2.47%H20, expansion in all directions isobserved, with the most dramatic increase along b.115Change in Lattice Dimensions (Angstroms)0.200.1•cjJ0--0.3-0.5 1 1.5 22.5Water Content (%)FIgure 33. Changes in the lattice dimensions of CPZ(I) with theincorporation ofwater. CPZ(I).H is obtained at 2.47% wlwH20 (dotted line). Dimensions in the a (ti), b (0) and c ()directions are shown. Samples containing 1.85% w/w H20were analyzed in triplicate, and the mean and range areprovided.116Dorignac-Calas and Marsau (1972) isolated a form ofchiorpromazine hydrochloride which was metastable at ambienttemperatures (Appendix B - Table 15). The unit cell volume was one-half ofthat reported by Klein and Conrad (1986) for CPZ(I)-H. When the analysisofYvon et at. (1977) was used to convert the single crystal data ofDorignac-Calas and Marsau (1972) to a powder pattern, the calculateddiffractogram agreed with the powder pattern obtained for CPZ(II).XRPD studies also confirmed that the lattices of CPZ(I)-H’ andCPZ(I)-H remained intact after complete dehydration under vacuum in thepresence of silica gel at 70°C (Figure 34a). However, at 100°C undervacuum (as above) for prolonged periods of time (i.e., >3 days), completeconversion of CPZ(I)-H’ to CPZ(II) occurred (Figure 34d).Polymorphic transformations have been reported to occur withcertain organic substances and pharmaceutical solids when subjected tomechanical stress (Drickamer, 1967; Nogami et at., 1969; Summers et at.,1976; Ibrahim et at., 1977; Lefebvre and Guyot-Hermann, 1986; Otsukaand Kaneniwa, 1985, 1986 and 1989; Otsuka et at., 1986 and 1989;Matsumoto et at., 1991). However, hand grinding in an agate mortar(Figure 34b) or compression up to 210 MPa (Figure 34c) did not affect thecrystal lattice of CPZ(I)-W.2. TablettingMaterials which undergo extensive viscoplastic deformation duringcompression tend to form good tablets. In our Betapress analysis, peakoffset time can be used as an indication of the extent of viscoplasticdeformation (Oates and Mitchell, 1989; Dwivedi et at., 1991). The peakoffset times of CPZ(II) were slightly shorter than for CPZ(I)-H’ (Figure 35).1170bCd5Figure 34. X-ray difl±actograms of CPZ(I)-H’ treated as follows: (a)driedunder vacuum with silica gel at 70°C; (b) hand ground anddried as in (a); (c) compressed under 210 MPa (the top face of atablet was scanned and the appearance of two new peaks at5.3 and 9.5 20 are due to magnesium stearate and talc,respectively); and (d) heated under vacuum with silica gel at100°C. Diffractograms (a)-(d) are shown using the sameintensity scale for direct comparison.10 15 20 25 30 352 THETA118Peak Offset Time (ms)760003. 0o °2 00000 00000 0o I I I I0 50 100 150 200 250Peak Pressure (MPa)Figure 35. Peak offset times ofCPZ(II) (0) and CPZ(I)41’ (0) withincreasing compression pressures.119This difference is unlikely to account for the poor tablettability of CPZ(II)since, compared with other materials, its peak offset times are stillrelatively long and on this basis alone, CPZ(II) might be expected to formgood tablets.Water has been shown to play a determinant role in thetablettability of pharmaceutical solids. Detailed investigations withdextrose (Armstrong and Patel, 1986), -cyc1odextrin (Giordano et al.,1990), maltodextrin (Li and Peck, 1990), and directly compressibledextrose-based diluents (Shukia and Price, 1991), for example, indicatethat the extent of particle deformation and interparticulate friction, thestrength of interparticulate bonds, and fragmentation during compressionmay be affected by water content. Crystal bridge formation as a result ofdissolution and subsequent recrystallization may also be responsible.The water of hydration of chlorpromazine hydrochloride appears toplay a role in the particle deformation mechanism during compression andin interparticulate bond formation. The length of the peak offset timesshow CPZ(I)-H deforming more during compression than CPZ(I). Nosignificant differences however were observed between CPZ(I)-H (2.47%w/wH20) and CPZ(I)-H’ (1.90% w/wH20) (Figure 36).Successful tabletting also depends on the ability of the bonds withinthe tablet to withstand elastic recovery during decompression. The in-dietablet recovery was calculated and Young’s modulus, E, was estimatedfrom recovery data (Dwivedi et at., 1992). Representative plots of theproportionality constant of Hooke’s Law at a given porosity, E (expressedin GPa), as a function of tablet porosity are shown in Figure 37. Nodifferences were observed in the elastic120Peak Offset Time (ms)250Figure 36. Peak offset times ofCPZ(I)-H’ (CD), CPZ(I)-H (0.) and CPZ(I)(cI)with increasing compression pressures.065400Do® 0®oc4]®o 030o0 0 000o0100aDo0 50 100 150 200Peak Pressure (MPa)121Ep (GPa)14120OD 010- 808.D0 08o6- 00 j004 020 I0 0.05 0.1 0.15 0.2 0.25 0.3Tablet PorosftyFigure 37. The proportionality constant of Hooke’s Law at a givenporosity, E, as a function of tablet porosity. CPZ(I) (ci);CPZ(II)(); CPZ(I)-H’ (0); and CPZ(I)-H (0).122recoveries of tablets of CPZ(I), CPZ(II), CPZ(I)-H’ and CPZ(I)-H duringdecompression.In previous work (Dwivedi et al., 1992), chlorpromazinehydrochloride lubricated with 0.5% magnesium stearate exhibitedextensive recovery during decompression. An E value of 5.5 GPa wasobtained, very similar to the microcrystalline celluloses (Avicel PH 102 andEmcocel, 5.8 and 6.1 GPa, respectively) which makes strong tablets, andibuprofen (5.9 GPa) which makes very weak tablets. Tablets made with0.5% magnesium stearate laminated and capped, but the addition of 0.5%w/w talc resulted in intact tablets. The E value was doubled and theextent of elastic recovery during decompression was reduced.3. Tablet Strength TestingTablet strength was measured using the diametral compressiontest. CPZ(II) did not form coherent tablets, and therefore, its force offailure, F and deformation could not be measured. The Ff values oftablets of CPZ(I)-H and CPZ(I)-H’ were similar to each other butconsistently higher than CPZ(I) (Figure 38). Tablet deformation, on theother hand, was not different among the various forms of CPZ(I) (Figure39).While the force of failure is indicative of the strength of theinterparticulate bonds within a tablet, the extent of tablet deformationbefore failure was characteristic of the material. Tablet deformation wasrelatively independent of compression pressure and relative densitydespite the fact that the tablets were porous anisotropic bodies in whichthe stress was not uniformly distributed during compaction. The absenceof differences in the deformation of CPZ(I), CPZ(I)..H’ and CPZ(I)-H was123200150100500Force of Failure (N)DFigure 38. Force offailure of tablets of (JPZ(fl-H’ (0), CPZ(I)-H () and0000000000000000.7 0.75 0.8 0.85 0.9Relative Density0.95CPZ(I)(o).124Deformation (1OE-03 cm)12D .. D•10 CDC DC08 0 0CLl064.2-0- I0 25 50 75100 125 150Force of Failure (N)Figure 39. Deformation of tablets of CPZ(I)-H’ (0), CPZ(I)-H () andCPZ(I) (C).supported by XRPD, which showed that their diffractograms werequalitatively the same. Since these forms shared structural similarities,tablet deformation was expected to be similar. Differences in the Ffindicated that the completely dehydrated lattice, CPZ(I), formed muchstronger interparticulate bonds on compression than CPZ(II), and duringdecompression, the tablets were able to withstand the stress of expansion.Water in the lattices of CPZ(I)-H’ and CPZ(I)-H led to a further increase intablet strength, but this increase appeared to be independent of the watercontent (Figure 38).125126SUMMARYA. Changes in Crystaffinity with Pharmaceutical ProcessingStandard methods used in quantitating crystallinity weremodified for following changes in the X of organic solids. Thesefindings suggested reductions in X with pharmaceuticalprocessing and subsequent increases with storage but resultswere inconclusive. The reasons for the changes in X could notbe explained.2. The Rietveld structure refinement method was used successfullyfor the first time in studying the XRPD data of organic solids.3. Modifications of the Rietveld method for the simultaneousmeasurement of crystallite size (relative) and lattice distortionwere adapted from work on ideal inorganic crystals to the studyof nonideal organic systems. MTZ and ASA were used as modelcompounds. Though the method was not definitive (e.g.crystallite size values were not absolute), the contribution ofeach phenomenon to the changes in X could be studied.1274. Both MTZ and ASA showed significant peak broadening andsimilar reductions in peak intensities with grinding andtabletting. Rietveld analysis revealed that while latticedistortion played an important role in the reduction of the X ofASA, the X changes ofMTZ were more dependent on changes incrystallite size.5. On storage, the b dimension of the unit cell ofASA remainedunchanged, while the crystallite size ofMTZ increased. The rateand extent of increase appeared dependent on the storagetemperature. At any given time, larger crystallites weremeasured at the higher temperatures, and the size of crystallitesstored at lower temperatures did not reach the sizes achieved forsamples stored at higher temperatures.6. The significant “lattice disruption or distortion” of doped DPHsuggested by other workers was investigated using XRPD.Indexed X-ray powder diffraction data derived from Rietveldcrystal structure refinements were reported. Using the Rietveldmethod (without internal standard) with the method ofAppleman and Evans (1973) (with internal standard), accuratecell dimensions were obtained to study the incorporationPMDPH into DPH. Changes in cell dimensions were notobserved suggesting that incorporation of PMDPH into thelattice of DPH was unlikely. Incorporation of PMDPH throughthe formation of a substitutional solid solution was proposed.128B. Phase Transitions with Pharmaceutical Processing(a) Differences in the tablettability of CPZ and its granuleswas found to result from a phase change rather thanchanges in X.(b) Detailed physicocheinical characterization revealed thatcomplete conversion to a stoichiometric hemihydrate hadoccurred during wet granulation.(c) The stoichiometric hemihydrate could be fully dehydratedto the room temperature stable polymorph without theloss of lattice integrity. Structural refinement ofX-raypowder diffraction data was used to measure theexpansion of the lattice with water uptake.2. (a) The improved tablettability of CPZ granules compared toCPZ could not be attributed to changes in viscoplasticdeformation or elastic recovery. 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Chem.Soc., suppl. 1163 (1964) 6036-6048.Weidinger, A. and Hermans, P.H., On the determination of the crystallinefraction of isotactic polypropylene from X-ray diffraction, Makromol.Chem., 50 (1961) 98-115.146Wiedemann, K.E., Unnam, J. and Clark, R.K., Computer program fordeconvoluting powder diffraction spectra. Powd. Diff, 2 (1987) 137-145.Wiles, D.B., Sakthivel, A. and Young, R.A., DBW 3.2S program for Rietveldanalysis ofX-ray and neutron powder diffraction patterns (version8804), 1988.Wiles, D.B. and Young, R.A., A new computer program for Rietveldanalysis of X-ray powder diffraction patterns. J. Appi. Cryst., 14 (1981)149-151Will, G., Parrish, W. and Huang, T.C., Crystal-structure refinement byprofile fitting and least-squares analysis of powder diffraction data. J.Appi. Cryst., 16 (1983) 611-622.Winnike, R.A., Wurster, D.E. and Guillory, J.K., A solid sampling device foruse in batch solution calorimetry. 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Definition andevaluation from heat of fusion. mt. J. Pharm., 25 (1985) 57-72.Young, R.A., Structural analysis from X-ray powder diffraction patternswith the Rietveld method. Symposium on Accuracy in PowderDiffraction, National Bureau of Standards, Gaithersburg, MD, (1980)143-163.147Young, R.A., Mackie, P.E. and von Dreele, R.B., Application of the pattern-fitting structure-refinement method to X-ray powder diffractometerpatterns. J. Appi. Cryst., 10 (1977) 262-269.Young, R.A., Prince, E. and Sparks, R.A., Suggested guidelines for thepublication of Rietveld analyses and pattern decomposition studies. J.Appl. Cryst., 15 (1982) 357-359.Young, R.A. and Wiles, D.B., Application of the Rietveld method forstructure refinement with powder diffraction data. Advances in X-rayAnalysis, 24 (1981) 1-23.Young, R.A. and Wiles, D.B., Profile shape functions Rietveld refinements.J. Appi. Cryst., 15 (1982) 430-438.Yvon, K., Jeitschko, W. and Parthe, E., LAZY PULVERIX, a computerprogram, for calculating X-ray and neutron diffraction powderpatterns. J. Appi. Cryst., 10 (1977) 73-74.Ziegler, G., Structural and morphological investigations of ceramic powdersand compacts. Pwdr. Met. mt., 10 (1978) 70-73.148APPENDIX ADESCRIPTION OF THE RIETVELD STRUCTURE ANALYSIS COMPUTERPROGRAMSThe original structure refinement program by Rietveld(1967, 1969)has been extensively modified. Several computer packages are now availablefor the analysis ofX-ray powder diffraction data (Young, 1980; Young andWiles, 1981; Bish and Post, 1989; and, Smith and Gorter, 1991). Amongthese versions, DBW (D.B. Wiles; Wiles and Young, 1981) and GSAS(Generalized Crystal Structure Analysis System; Larson and von Dreele,1987) are the most widely distributed (Bish and Post, 1989; Smith andGorter, 1991). DBW (9006 series) enables the simultaneous refinement of upto eight phases and runs on either a mainframe or a personal computer(Sakthivel and Young, 1991). GSAS automatically calculates bond anglesand distances but requires a VMS (Virtual rnemory System) operating systemon a VAX ( irtual ddress e)jtension) computer (Larson and von Dreele,1987; Bish and Post, 1989).In this project, the DBWS-9006PC program of Sakthivel and Young(1991) was used to perform Rietveld (1967 and 1969) analysis on X-raypowder diffraction data collected with a 0-20 diffractometer in the step-scanmode. No preparatory program is required (i.e. single-pass operation), and149direct applicability with all space groups and with all atoms is built-in byincorporating the required scattering factors listed in the InternationalTables for X-ray Crystallography (1974) as coefficients of an exponentialseries. This generates the X-ray scattering factors and necessary anomalousscattering corrections (Wiles and Young, 1981).A least-squares procedure is used to refine structure parameters(atomic positions, site occupancies, and displacement parameters) with thevarious instrumental parameters, in order to minimize differences betweenthe observed and calculated diffraction patterns (i.e. the residual, 91)= iv,— r (A-i)where: y is the observed intensity, andyj is the calculated intensity at step i.The weight assigned to each step, wt, is determined byWi=(A-2)yjo Yibwhere Yib is the background intensity at step iDuring the refinement, Yic is calculated as the sum of contributionsfrom neighboring Bragg reflections and the background150=ALkIF4(2Oj—2OK)FK+yth (A-3)where: A is a scale factor,LKincludes the Lorentz, polarization andmultiplicity factors for the Kth Braggreflection (K=h,k,l),FK is the structure factor,PK is the preferred orientation function, and• is the reflection profile function whichapproximates both instrumental and sampleeffects.The ratio of the intensities of the two a wavelengths is accounted for in thecalculation of F j. and therefore only one scale factor is required. Two optionsare available when refining PjToraya ‘s modification of the original Rietveld function:G2÷(1_G)e1 (A-4)and the March-Dollase function:3(A-5)G1) )where: G1 and G2 are refinable parameters, andcq(is the acute angle between the scatteringvector and the presumed cylindricalsymmetry axis normal to the crystallite.151As shown in equation 3, the calculation ofy1 is very dependent on thebackground and, therefore, an accurate description of Yib is essential. Thebackground intensity at each step is modelled from either the refinablebackground function:y11, = BmLBKPOS- lm(A-6)or an operator-supplied table of background intensities, or the linearinterpolation between operator-selected points in the diffiactogram.The accurate characterization of peak shape enables information aboutcrystallite size and heterogeneous strain to be extracted. Unfortunately, theX-ray powder diffraction pattern is a complex convolution of several sampleand instrumental effects. The peak shape deviates significantly fromGaussian and is very difficult to model mathematically. More complexfunctions are required. Several alternatives have been proposed and thoseavailable in the DBWS-9006PC package include the Lorentzian, Modified(mod 1) Lorentzian, Intermediate (mod 2) Lorentzian, Edgeworth Series,Voigt, pseudo-Voigt, modified Thompson-Cox-Hastings pseudo-Voigt, andPearson VII. Further details on these profile functions are provided in Table9aandb).The angle dependency of the peak shape is also modelled and enablesthe refinement to be valid over a wide range of diffraction angles. Profilebreath, expressed as the full-width at half-maximum height (FWHM) or Hjç152Table 9a - Analytical functions used to represent the diffraction profile1Name Symbol Function2C0(201—20K)Gaussian G - HeLorentzian L (20 — 20K)2 11.wHK [+Ti-2jKModified Lorentzian(Mod 1 Lorentzian) ML 2..j (20, — 20K)12XHK[+C2 H jIntermediate Lorentzian(Mod2Lorentzian) IL ‘/ 1i÷c(20,_20K){2HKL j‘“‘-KEdgeworth Series3 ( (2o — 20K )(Polynomial) Poly P, Q )Voigt3 V AfL(x)G((20—20K)—x)dxPseudo-Voigt pVModified Thompson-Cox- Mod-TCHHastings pseudo- pVVoigtPearsonVil p’\Tjj C4 F1 - (20._20K)21m________________ ______HK[(2m_1)1 References: Young and Wiles (1981); Smith (1989); and, Sakthivel andYoung (1991).2 detailed definitions of the function variables provided in Table 9b3 not available with the DBWS-9006PC package153Table 9b - Variables used in profile functions*Variable DefinitionA1A2 normalization factorsC0 41n2C1 4C2 4(J_iC3 4(2_i1 1Cd 2Y(2rn_1)2)(m-O.5)J(r +2. 69269TFL +2. 42843FI’ + 4.47 163rr0.2\+O.O7842I’Ij, + )(Utan2O+VtanO+W+cosO)X tan 0+cos 0H (u tan20K + V tan °K + w)NA+NB(2q)i.36603q-O.47719q+O.1116qNB NCm NA+j+()2P polynomial with even exponents onlyQ polynomial with even exponents only* References: Young and Wiles (1981); Smith (1989); and, Sakthivel andYoung (1991).t Gfu1l-width-at-half-maximum (FWHM)H=FWHM (Cagliotti et al., 1958)§ NA and NB are refinable§ NA, NB and NC are refinable154can be described as a function of the diffraction angle by the relationship(Cagliotti et al., 1958):14 =Utan2O÷VtanO+W (A-7)where U, V, and W are refinable constants for the X-ray pattern (dependenton the instrumental configuration and choice of profile shape function).The Newton-Raphson algorithm is the least-squares procedure usedand the normal matrix elements are formally given by:Mjk _2w{[Y0—Y]—(A-8)but can be approximated by omitting the term [y,-Theparameter is refinable.The standard deviation for thejth adjusted parameter, 5j, is calculatedas:1= °j (A-9)where: M is the diagonal element in the inverse of thenormal matrix,N is the number of observations,P is the number of parameters refined, andC is the number of constraints imposed.155During the refinement, agreement between the observed andcalculated pattern is constantly monitored by visual inspection and the use ofprofile agreement indices. Visual inspection of the intensity versus 20 plotsof the observed, calculated, and difference patterns is most informative inassessing goodness of fit (Young and Prince, 1982; Baerlocher, 1986) andprovides information about the source of discrepancies (e.g. an improperly fitbackground or peak shape irregularities). Profile agreement indices, on theother hand, supply a numerical measure of fit and enable quantitativecriteria of fit to be established (Hill and Fischer, 1990). These indices areusually defined in terms of R-factors (Table 10).The Bragg index (RB) provides a good measure of the validity of thecrystal structure model and uses the ‘observed’ Bragg intensity (‘Jobs’) whichis calculated by allocating the observed intensities, yj,3, to Bragg intensities,‘Jobs’, on the basis of the calculated intensities, ‘calc This procedure isdescribed by Rietveld (1969).Both the weighted profile residual (R) and the goodness-of-fit (GofF)indicate if the refinement is converging smoothly. Statistically, isconsidered the most important for following the progression of a refinementbecause its numerator is the quantity being minimized.Rexp, the expected R-factor, is the minimum value possible. As therefinement progresses, should approach Rexp and GofF should becomeunity. If the GofF is greater than unity, either the weights used areinappropriate, or the structural model or peak representation is incorrect.156.Table 10 - Agreement indices for the Rietveld refinement1Name Symbol EquationPattern R-factor2 R100— 31k IywWeighted Pattern R- 100 , (y —yfactor3w1(y,)2Bragg intensity R-factor4100 I 101,8 — ‘calcl‘obsExpected R-factor5 Rexp[(N - P + C)llootw(y)2 jStructure Amplitudes 100 2 II1obs’ I — Wcaic IIR-factor FGoodness-of Fit GofF Y — y)2 = (R2(N1’) kflexpDurbin-Watson statistic N ,‘ ( ‘ I 2(d-statistic)6 d ‘o — Yic) — Yio-i — Yk_1 j1 References: Post and Bish (1989); and, Sakthivel and Young (1991).2 y and Yic are the observed and calculated intensities, respectively, atstep i3 w is the weight assigned each step intensity.‘Jobs’ and ‘caic are the observed and calculated intensities, respectively, forBragg reflection K. “obs’ is not actually observed but determined byassuming that the ‘observed’ intensity is in the same proportion as itscalculated intensity.5 N is the number of data points, P is the number of parameters refined andC is the number of constraints.6 cs=(Hill and Flack, 1987)157Good agreement is assumed if is between 10%-20%. RB , on the otherhand, is biased towards the calculated model and a RB value greater than10% indicates large model fit errors.The reliability of the estimated standard deviations (esd, 2) calculatedby the Rietveld refinement model has been questioned. The esd erroneouslydecrease as the number of observations increase, thereby causing serialcorrelation and an increased GofF. The reliability of esd can be determined bythe Durbin-Watson d statistic (or d statistic), the numerical representation ofthe degree of serial correlation observed between points of the observed andcalculated profiles. The d statistic is a sensitive measure of the progress ofthe refinement and is the most reliable error because it remainsdiscriminating when other agreement indices fail (Hill and Flack, 1987). Thed statistic can be either weighted or unweighted. An unweighted d statisticbetween 1.5 and 2.5 is obtained when essentially no serial correlation exists.Positive serial correlation is indicated by an unweighted d statistic less than2.0; negative serial correlation occurs with an unweighted d statistic greaterthan 2.0. Limits for the weighted d statistic h.ave yet to be determined.In the least-squares refinement the following parameters can beadjusted simultaneously:1. Lattice;2. Atom position (x,y,z);3. Atom site occupancy;4. Atom thermal vibrational (isotropic or anisotropic);5. Profile (U,V,W, and asymmetry);6. Preferred orientation;1587. Background function;8. 20-zero correction;9. Overall scale (one for each phase);10. Overall isotropic thermal (B).The input information required is as follows:1. Initial values of all variable parameters;2. Step-scan data in equal increments in 20;3. 20 limits and excluded regions in the data;4. Wavelength data;5. Background specifications;6. Space-group symbol;7. Chemical symbol and valance of each atom;8. Number of phases;9. Profile function choice;10. Profile cut-off (in units of HK);11. Preferred orientation vector for each phase or preferredorientation function (i.e. Rietveld-Toraya or MarchDollase);12. Constraints;13. Termination control;14. Relaxation factors for the shifts (separately specified forfour different groups of parameters);15. Output control flags.The output includes:1591. The refinement conditions and subject so that a given runcan be reconstructed unambiguously;2. Adjustable-parameter final values, last shift and standarddeviations;3. R,, R, RB, R,, GofF and d-statistic values.And the following printouts are available:1. Observed and calculated intensities;2. Line-printer plot;3. IF2 and R-Bragg, with or without I FKI obs, I F I caic andR-F;4. Correlation matrix;5. Reflection list for each phase;6. Corrected data list, with w values;7. Merged relection list;8. Symmetry operators list;9. Off-line plot (e.g. Calcomp or Verastec);10. Stacked summary of cycle-by-cycle values or summary ofonly last-cycle parameters.160APPENDIX BCHEMICAL STRUCTURES AND SINGLE CRYSTAL INFORMATIONTable 11 - Chemical structure, crystal system, space lattice, and spacegroup ofMTZ (Blaton et al., 1979).Chemical StructureCH2OHCH33-D StructureSpace Lattice monoclinicSpace Group P2 1/c161Table 12 - Chemical structure, crystal system, space lattice, and spacegroup ofASA (Wheatley, 1964; Kim et al., 1985).Chemical StructureCOOHOCOCH33-D StructureSpace Lattice monoclinicSpace Group P2 i/c162Table 13 - Chemical structure, crystal system, space lattice, and spacegroup of DPH (Camerman and Camerman, 1971).Chemical Structure3-D Structurenot availableSpace Lattice orthorhombicSpace Group Pn2 ia163Table 14 - Chemical structure, crystal system, space lattice, and spacegroup of CPZ(I)-H (Klein and Conrad, 1986).( cr)2 •H20Chemical Structure3-D StructureSpace Lattice monoclinicSpace Group P2 i/cTable 15 - Chemical structure, crystal system, space lattice, and spacegroup of CPZ(II) (Dorignac-Calas and Marsau, 1972).164Chemical Structure3-D StructureLCI-Space Lattice monoclinicSpace Group P2 i/cC.165Figure 40. Simple monoclinic lattice.(Reproduced from Cullity, B.D., Elements ofX-ray Diffraction, SecondEdition, Addison-Wesley Publishing Company, Reading, MA, 1978, p. 36.)Figure 41. Rectangular (orthorhombic) lattice.(Reproduced from Cullity, B.D., Elements ofX-ray Diffraction, SecondEdition, Addison-Wesley Publishing Company, Reading, MA, 1978, p. 36.)APPENDIX CPRELIMINARY SOLID-STATE NMR SPECTRA FOR CHLORPROMAZINEHYDROCHLORIDE (CPZ(II)) AND ITS GRANULES (CPZ(I)-H)166167RUPIPPGCPCYCL. PCDOTE18-9-91SF 1BO.6l01 2924.SOSSt 4296TO 1224SW 58000.220HZ/PT 24.l4RD 30NE 1115 3228TO 27311W 111.8FW 6020002 8343.022tIP 6110000 20.000501 7.5201102 80.800U03 1.0001104 1.000ULB 120.800OB 0.11NC 1CX 20.02Cr 10.00SR -1768.27PPM120Figure 42. 400 MHz13C-NMRspectrum of CPZ(II).9999 99 199 91PHRRNC15. N&2Ru:RUE”PPQ:LPCEtL. PCORTE 21-Y-Y1Sr wu.Oi’l01 2924.8U5SI 4U96ro i124SW S2uu.Sc4Hz/Pr 24.414EECNE INS 2’i2rs V5OW 111.8FU 62281102 6547.11112OP 6H 0002 58.81111501 7.588U02 613.IE11EEU05 1.RIEEEU04 1.81311ULEE 1814.82858 2.14NC 14cx zurnCY U4.14258 —1768.2’168Ii__-213a 1148Figure 43. 400 MHz13C-NMR spectrum of CPZ(I)-H’.

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