Polymorphism
`
`in the Pharmaceutical Industry
`
`Edited by
`RolfHilfiker
`
`WILEY-
`VCH
`WILEY-VCH Verlag GmbH & Co. KGaA
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`Contents
`
`Preface XV
`
`List of Contributors
`
`XVII
`
`1
`
`1.1
`1.2
`1.3
`1.4
`1.4.1
`1.4.2
`1.4.3
`1.4.4
`1.4.5
`1.5
`1.6
`
`2
`
`2.1
`2.2
`2.3
`2.4
`
`2.4.1
`2.4.2
`2.4.3
`
`Relevance of Solid-state Properties for Pharmaceutical Products 1
`Rolf Hilfker, Fritz Blatter, and Markus von Raumer
`
`Introduction 1
`Drug Discovery and Development 4
`Bioavailability of Solids 6
`Phases of Development and Solid-state Research 7
`Salt Selection 8
`Polymorph Screening 9
`Crystallization Process Development 12
`Formulation 13
`Method Development 14
`Solid-state and Life Cycle Management 15
`Conclusions 15
`References
`17
`
`Thermodynamics of Polymorphs 21
`Sachin Lohani and David J. W. Crant
`
`Introduction 21
`Structural Origin of Polymorphism 22
`Thermodynamic Theory of Polymorphism 22
`Thermodynamic Relationship Between Polymorphs:
`Enantiotropy and Monotropy 24
`Energy-Temperature Diagrams 24
`Pressure-Temperature Diagrams 28
`Inversion of Polymorphic Behavior 30
`
`Polymorphism: in the Pharmaceutical Industry. Edited by Rolf Hilfiker
`Copyright © 2006 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
`ISBN: 3-527-31146-7
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`VI Contents
`
`2.5
`
`2.5.1
`2.5.2
`2.5.3
`2.5.4
`2.5.5
`2.5.6
`2.6
`2.7
`2.7.1
`2.8
`2.8.1
`2.9
`
`3
`
`3.1
`3.2
`
`3.2.1
`3.2.2
`
`3.2.3
`3.3
`3.3.1
`3.3.2
`3.3.3
`3.4
`3.4.1
`3.4.2
`3.4.3
`3.4.4
`3.4.5
`3.4.6
`3.4.7
`3.5
`
`Rules to Predict Thermodynamic Relationships Between
`Polymorphs 31
`Heat of Transition Rule 31
`Heat of Fusion Rule 31
`Entropy of Fusion Rule 32
`Heat Capacity Rule 32
`Density Rule 33
`Infrared Rule 33
`Relative Thermodynamic Stabilities of Polymorphs 33
`Crystallization of Polymorphs 34
`Nucleation of Polymorphs 34
`Introduction to Solvates and Hydrates 37
`Thermodynamics of Hydrates 37
`Summary 40
`References
`41
`
`Characterization of Polymorphic Systems
`Using Thermal Analysis 43
`Duncan Q. M. Craig
`
`Introduction - Scope of the Chapter 43
`Use of Differential Scanning Calorimetry for the Characterization
`of Polymorphs 44
`Principles of DSC in the Context of Polymorphism 44
`Examples of the Uses of DSC: Characterization of Drugs,
`Excipients and Dosage Forms 49
`Further Uses of DSC 54
`Combined Approaches 58
`Multi-instrument Approaches 58
`Thermal and Crystallographic Studies 63
`Interfaced Techniques 65
`Additional Thermal Methods for the Study of Polymorphism 67
`Thermogravimetric Analysis 67
`Thermal Microscopy 68
`Heat of Solution Studies 69
`Modulated Temperature DSC 70
`High-speed DSC 72
`Microthermal Analysis 73
`Thermally Stimulated Current 74
`Conclusions 76
`References
`77
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`Contents VII
`
`4.1
`4.1.1
`4.2
`4.2.1
`4.2.2
`4.2.3
`4.2.4
`4.3
`
`5
`
`Solid-state NMR Spectroscopy 81
`Joseph W. Lubach and Eric]. Munson
`
`82
`
`Introduction 81
`Basics of Solid-state NMR
`Applications 82
`Identification 82
`Selectivity 84
`Mobility and Dynamics 85
`Quantitation of Forms 86
`Conclusions 92
`References
`92
`
`Vibrational Spectroscopic Methods in Pharmaceutical
`Solid-state Characterization 95
`John M. Chalmers and Geoffrey Dent
`
`5.1
`5.2
`
`Introduction 95
`Mid-infrared, Raman and THz Spectroscopy:
`Basic Comparison of Theory, Instrumentation and Sampling 97
`Basic Theory 97
`5.2.1
`Instrumentation Brief 100
`5.2.2
`Sampling 104
`5.2.3
`Raman Sampling 104
`5.2.3.1
`5.2.3.2 Mid-infrared Sampling 105
`5.2.3.3
`THz Spectroscopy Sample Presentation 109
`5.3
`Changes of State and Solid-state Effects on Infrared and
`Raman Spectra 110
`Introduction 110
`Spectra of Gases, Liquids and Solutions 110
`Hydrogen Bonding 111
`Amine Salts (including Amino Acids) 114
`Solids 115
`Polymorphism 117
`Enantiomers and Racemates 118
`Tautomerism 119
`Summary 119
`Examples and Applications 119
`Polymorphism 120
`Hydration/Drying 126
`Quantitative Analysis and Process Monitoring 128
`Tablets 230
`Closing Remarks 135
`References
`136
`
`5.3.1
`5.3.2
`5.3.3
`5.3.4
`5.3.5
`5.3.6
`5.3.7
`5.3.8
`5.3.9
`5.4
`5.4.1
`5.4.2
`5.4.3
`5.4.4
`5.5
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`VIII Contents
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`6
`
`6.1
`6.2
`6.3
`6.4
`6.5
`6.6
`6.7
`6.8
`6.9
`6.10
`
`7
`
`7.1
`7.2
`7.3
`7.4
`7.5
`7.5.1
`7.5.1.1
`7.5.1.2
`7.5.2
`7.5.3
`7.6
`7.6.1
`7.6.2
`7.6.3
`7.6.3.1
`7.6.3.2
`7.6.3.3
`7.6.3.4
`7.6.3.5
`7.6.4
`7.7
`7.7.1
`7.7.2
`7.7.3
`7.8
`7.9
`7.10
`7.11
`
`Crystallography for Polymorphs 139
`Philippe Ochsenbein and KurtJ. Schenk
`
`Introduction 139
`Solving Difficult Crystal Structures with Parallel Experiments 140
`Atropisomers and Desmotropes 144
`Salts 148
`Influence of Solvents 149
`Isolation of a Furtive Species 153
`Mizolastine Polymorphs 154
`Solid Solutions 157
`Structures from Powder Data 160
`"Behind Every Structure There is a Crystal" 164
`References
`165
`
`Light Microscopy 167
`Gary Nichols
`
`Introduction 167
`Why Use a Light Microscope to Study Solid-state Properties? 168
`Polarizing Light Microscope 169
`Photomicrography 170
`Specimen Preparation 171
`Permanent and Temporary Mounts 172
`Permanent Mounts 172
`Temporary Mounts
`173
`Preparation of Temporary Mounts 173
`Examination of Tablets 173
`Observations Using Polarized Light Microscopy 174
`Polarized Light 174
`Crystal Studies with Plane Polarized Light 175
`Crystal Studies with Crossed Polarizers 177
`Interference Colors 177
`Extinction 179
`Interference Figures 181
`Compensator Plates 183
`Use of Circularly Polarized Light 183
`Crystallinity 184
`Refractive Index 186
`Measuring Refractive Indices 187
`The Becke Test 188
`Dispersion Staining 188
`Particle Size 189
`Particle Shape 290
`Comparing Powder Samples 294
`Thermomicroscopy 295
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`Contents
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`IX
`
`7.12
`7.13
`7.14
`7.15
`7.16
`7.17
`7.18
`7.19
`7.20
`
`8
`
`8.1
`8.2
`8.2.1
`8.2.2
`8.2.2.1
`8.2.2.2
`8.2.3
`8.3
`8.4
`8.5
`8.6
`8.7
`8.8
`8.9
`
`9
`
`9.1
`9.1.1
`9.1.2
`9.2
`9.3
`9.3.1
`9.3.2
`9.3.3
`9.3.3.1
`9.3.3.2
`9.3.3.3
`
`The Microscope as a Micro-scale Laboratory 196
`Twinning 297
`Color and Pleochroism 199
`Fluid Inclusions 202
`Mechanical Properties of Crystals 203
`Pseudomorphs 204
`Mesomorphism 205
`Identification of Contaminants and Foreign Matter 206
`Conclusion 207
`References 207
`
`The Importance of Solvates 211
`Ulrich J. Griesser
`
`Introduction 211
`Terminology and Classification of Solvates 213
`General Terms and Definitions 213
`Types of Solvates 225
`Stoichiometric Solvates 215
`Non-stoichiometric Solvates 226
`Classification Models of Hydrates 218
`Statistical Aspects and Frequency of Solvates 229
`Generation and Characterization of Solvates 222
`Stability and Solubility of Solvates 224
`Processing of Solvates 227
`Relevance, Problems and Potential Benefits 228
`Patents 229
`Conclusions 230
`References
`230
`
`Physical Characterization of Hygroscopicity in Pharmaceutical
`Solids 235
`Susan M. Reutzel-Edens and Ann W. Newman
`
`Introduction 235
`Definition of Hygroscopicity 235
`Classification of Hygroscopic Behavior 236
`Water-Solid Interactions 238
`Characterizing Water-Solid Interactions 239
`Moisture Sorption Analysis 239
`Surface Energy Approaches 243
`Molecular Level Approaches 244
`Stoichiometric Hydrates 244
`Non-Stoichiometric/Channel Hydrates 245
`Isomorphic Desolvates 250
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`X I Contents
`
`9.4
`
`9.4.1
`9.4.2
`9.4.3
`9.5
`9.6
`
`10
`
`10.1
`10.2
`10.2.1
`10.2.2
`10.3
`10.3.1
`10.3.2
`10.3.3
`10.3.4
`10.3.5
`10.3.6
`10.3.7
`10.4
`10.4.1
`10.4.2
`10.4.3
`10.4.4
`10.4.5
`
`10.4.6
`10.5
`10.5.1
`10.5.2
`10.6
`10.6.1
`10.6.2
`10.6.3
`
`Significance of Water-Solid Interactions in Pharmaceutical
`Systems 251
`Physicochemical Stability 251
`Dissolution 252
`Physical-mechanical Characteristics 253
`Strategies for Dealing with Hygroscopic Systems 254
`Conclusions 256
`References
`256
`
`The Amorphous State 259
`Samuel Petit and Gerard Coquerel
`
`Introduction 259
`Definition of the Amorphous State 260
`Order, Disorder and Structural Aspects 260
`Energetic Aspects: Thermodynamics and Kinetics 262
`Preparation of Amorphous Solids 263
`Preparation from a Liquid Phase: Quench-cooling 264
`From a Solution: Rapid Precipitation 265
`From a Frozen Solution: Freeze-drying (Lyophilization) 265
`From an Atomized Solution: Spray-drying 266
`From a Crystalline Phase: Grinding and Milling 266
`From a Crystalline Solvate: Desolvation/Dehydration 268
`Physical Mixture with Amorphous Excipients 269
`Properties and Reactivity 269
`The Glass Transition 270
`Molecular Mobility and Structural Relaxation 272
`Strong/Fragile Classification of Angell 272
`Mixing with Solvents/"Dissolution" Behavior 273
`Influence of Water Content: Plasticization and Chemical
`Degradation 274
`Polyamorphism 275
`276
`Characterization and Quantification
`Thermal Analysis and Spectroscopic Methods 277
`Detection and Quantification of Small Amorphous Contents 277
`Crystallization of Amorphous Solids 278
`"Difficult-to-crystallize" Compounds 279
`Inadvertent Crystallization 280
`Crystallization as a Tool for Insight into the Amorphous State 280
`References
`282
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`Contents XI
`
`11
`
`11.1
`11.2
`11.3
`11.4
`11.5
`11.6
`11.6.1
`11.6.2
`11.6.3
`11.6.4
`11.6.5
`11.7
`11.8
`11.9
`
`12
`
`Approaches to Polymorphism Screening 287
`Rolf Hilfiker, Susan M. De Paul, and Martin Szelagiewicz
`
`Introduction 287
`Crystallization Methods 289
`Solvent Parameters 290
`Systematic Polymorphism Screening 291
`High-throughput Methods 294
`An Example of a High-throughput Screening Approach 296
`Model Substance 296
`Solubility 296
`Crystallization Experiments 297
`Data Acquisition 297
`Data Analysis 298
`Theoretical Methods 300
`Characterization 302
`Conclusions 303
`References
`305
`
`Salt Selection 309
`Peter Heinrich Stahl and Bertrand Sutter
`
`Introduction 309
`12.1
`Salt Formation and Polymorphism 309
`12.2
`Target Properties of Active Substances for Drug Products 311
`12.3
`Injectables 322
`12.3.1
`Solid Dosage Forms 312
`12.3.2
`Dosage Forms for Other Routes of Application 312
`12.3.3
`Inhalation 312
`12.3.3.1
`12.3.3.2 Topical Products and the Transdermal Route 313
`12.4
`Basics of Salt Formation 314
`12.4.1
`Ionization Constant 314
`12.4.2
`Ionization and pH 315
`12.4.3
`Solubility 326
`12.5
`Approaches to Salt Screening 319
`12.5.1
`Initial Data 329
`12.5.2
`Selection of Salt Formers 329
`12.5.3
`Automated Salt Screening 320
`12.6
`Selection Procedures and Strategies 322
`12.6.1
`Points to be Considered 322
`12.6.2
`Final Decision 323
`12.6.3
`Salt Form and Life Cycle Management of Drug Products 325
`12.7
`Case Reports 325
`12.7.1
`Overview of Salt Forms Selected 325
`12.7.2
`Salt Selection Process 325
`12.7.3
`Case 1: NVP-BS001 326
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`XII Contents
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`Case 2: NVP-BS002 327
`12.7.4
`12.7.4.1 Discussion and Decision 329
`12.7.5
`Case 3: NVP-BS003 329
`References
`332
`
`13
`
`Processing-induced Phase Transformations and
`Their Implications on Pharmaceutical Product Quality 333
`Ramprakash Govindarajan and Raj Suryanarayanan
`
`Introduction 333
`13.1
`Processing-related Stress 336
`13.2
`Mechanical Stress 337
`13.2.1
`13.2.1.1 Milling 337
`13.2.1.2 Compression 337
`13.2.2
`Thermal and Pressure Stresses 338
`13.2.2.1
`Freezing 338
`13.2.2.2 Drying 339
`13.2.2.3 Melting 340
`13.2.3
`Interaction with Other Components 341
`13.2.3.1 Hydrate Formation 341
`13.2.3.2 Complexation 342
`13.2.3.3
`Salt-Free-acid/Base Conversions 342
`13.2.3.4 Metastable Phase Formation 342
`13.2.3.5 Multiple Interactions 343
`13.3
`Detection and Quantification of Phase Transformations 343
`13.3.1
`Generation (Creation) of Lattice Disorder 343
`13.3.2
`Crystallization - Anhydrous Phase 347
`13.3.3
`Hydrates - Formation and Dehydration 349
`13.3.4
`Salt-Free-acid/Base Transformations 351
`13.4
`Implications of Phase Changes 352
`13.4.1
`Amorphization 352
`13.4.2
`Crystallization 356
`13.4.3
`Polymorphic Transitions 357
`13.4.4
`Hydration/Dehydration 358
`13.4.5
`Salt-Free-acid/Base Conversion 360
`13.5
`Summary 360
`References
`361
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`Contents XIII
`
`14
`
`14.1
`14.2
`
`14.3
`14.4
`14.5
`14.6
`14.7
`
`15
`
`15.1
`15.2
`15.3
`
`15.3.1
`15.3.2
`15.3.3
`15.4
`15.4.1
`15.4.2
`15.4.3
`
`15.5
`15.5.1
`15.5.2
`15.6
`15.6.1
`
`15.6.2
`
`15.7
`
`Polymorphism and Patents from a Chemist's Point of View 365
`Joel Bernstein
`
`Introduction 365
`Some Fundamentals of Patents Related to Polymorphism
`and Some Historical Notes 366
`Ranitidine Hydrochloride (RHC1) 369
`Cefadroxil 372
`Paroxetine Hydrochloride 375
`The Importance of Seeding 379
`Concluding Remarks 381
`References
`382
`
`Scientific Considerations of Pharmaceutical Solid Polymorphism
`in Regulatory Applications 385
`Stephen P. F. Miller, Andre S. Raw, and Lawrence X. Yu
`
`Introduction 385
`General Principles of Pharmaceutical Solid Polymorphs 385
`Influence of Polymorphism on Product Quality
`and Performance 386
`Effect on Bioavailability (BA)/Bioequivalence (BE) 386
`Effect on Stability 387
`Effect on Manufacturability 388
`Pharmaceutical Solid Polymorphism in Drug Substance 389
`Polymorph Screening 390
`Control of Polymorphism in Drug Substance 391
`Acceptance Criterion for Polymorph Content
`in Drug Substance 394
`Pharmaceutical Solid Polymorphism in Drug Product 395
`Polymorphism Issues in Drug Product Manufacturing 395
`Control of Polymorphism in Drug Product 396
`Process Analytical Technology 399
`Process Analytical Technology and the Crystallization of
`Polymorphic Forms 399
`Process Analytical Technology and Polymorphs
`in Drug Products 400
`Summary 402
`References
`402
`
`Subject Index 405
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`9
`Physical Characterization of Hygroscopicity
`in Pharmaceutical Solids
`
`Susan M. Reutzel-Edens and Ann W. Newman
`
`9.1
`Introduction
`
`The terms hygroscopic and hygroscopicity are widely used in the pharmaceuti·
`cal literature to describe the moisture uptake of materials. Water vapor. an ever
`present component of the environment. can have profound, and often detrimen·
`tal, effects on physicochemical processes of interest to the pharmaceutical and
`fine chemical industries, such as crystallization of lyophilized cakes, direct com·
`paction, powder caking. coating and packaging material permeability, and solid(cid:173)
`state stability. In terms of solid dosage forms and excipients, knowledge of
`moisture adsorption phenomena will give useful information for selecting exci·
`pients, such as disintegrating agents, direct compression carriers and binders.
`as well as humidity control during production and storage. The objectives of
`this chapter are to review basic concepts of water-solid interactions, to present
`approaches taken to characterize such interactions. on empirical, surface energy.
`and molecular structural levels, and to identify risksJsolid-state issues encoun(cid:173)
`tered in the pharmaceutical industry that arise from these interactions.
`
`9.1.1
`Definition of Hygroscopicity
`
`Finding a workable definition of hygroscopicity applicable to pharmaceutical
`systems is not straightforward. Definitions from common sources are given in
`Table 9.1 to demonstrate the variability of the term. A common theme is the
`sorption and retention of moisture. One definition requires that deliquescence
`not occur [lj, while others do not mention a change in physical form . This as(cid:173)
`pect can be an important consideration during the development of a pharma(cid:173)
`ceutical material.
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`2361 9 Phystcal Charactenzation of Hygroscop:aty m Pharmaceutical Solids
`
`Table 9.1 Definitions of hygroscopic from common sources
`
`Definition
`
`1. Readily taking up and retaining motsture.
`2. Motsture taken up and retained under some condtltons of humtdtty and tempera·
`ture.
`
`Readily absorbmg, becoming coated with, and retaining moisture. but not enough
`to make a liquid.
`
`A solid that can adsorb atmospheric motsture. There is both a kinetic and a thermo·
`d)·namic component to this process. The kinetic component determines the rate of
`water uptake. while the thermodynamic component determines the energy of this
`process.
`
`A substance that can remove moisture from the air.
`
`Descriptive of a substance that has the property of adsorbmg moisture from the air.
`
`Ref.
`
`[2)
`
`(l]
`
`[3]
`
`:•1
`fS]
`
`9.1.2
`Classification of Hygroscopic Behavior
`
`Attempts have been made to classify hygroscopic behaviors based on data ob(cid:173)
`tained from adsorption isotherms, i.e., the curves obtained by plotting the
`weight change of a sample versus the relative humidity (RH) or water vapor
`pressure. The shape of the isotherm is determined by the specific conditions
`for adsorption onto a surface, such as pore size and heats of adsorption. The
`common isotherm classification types (I-V) are relevant to any adsorbate, in·
`eluding water, and are summarized in Fig. 9.1. It has been theorized that the
`isotherm of a uhygroscopic solid" should resemble a Type II isotherm where
`multilayer adsorption occurs (6). Giles [7) proposes class H. L, C, and S curves
`for adsorption based on the slope of the initial portion of the isotherm, with L
`curves indicative of Langmuir isotherms.
`Adsorption isotherms may be classified; however, there remains no universally
`accepted definition for hygroscopicity. This is because there are both thermody(cid:173)
`namic driving forces and kinetic rate components to the term. Hygroscopicity
`can describe both the amount of moisture in a substance and the rate of mois(cid:173)
`ture uptake when a sample is placed in a known RH. An excellent review by
`Umprayn and Mendes [8] discusses the hygroscopicity of pharmaceutical solids,
`as well as the thermodynamic and kinetic aspects of moisture sorption. Meth(cid:173)
`ods to measure and describe hygroscopicity in various organic and inorganic
`systems have been reviewed by Van Campen et al. (9]. Parameters used to evalu(cid:173)
`ate the hygroscopicity of various systems include the critical RH (CRH) (8, 9).
`the hygroscopicity potential (HP) (10), the hygroscopicity coefficient [11), and
`heats of absorption [12]. Griffin [13) has introduced the terms "equilibrium
`hygroscopicity'' and "dynamic hygroscopicity" to describe the amount and rate of
`uptake, respectively. The classification scheme for hygroscopicity proposed by
`Callahan (14, IS] (Table 9.2) is used for pharmaceutical excipients.
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`9.1 lmrQduwon 1237
`
`Typel EJ
`Typell [2]
`Typelll l2l
`
`occurs in chemisorption, limited to a few
`monolayers of absorbate, at high pressures,
`the pores are filled and the isotherm plateaus
`
`physical adsorption on nonporous or
`microporous adsorbent, inflection indicates first
`monolayer formation
`
`additional adsorption occurs as the adsorbate
`preferentially interacts with the monolayer than
`with the adsorbent surface, i.e., heat of
`adsorption < heat of liquification
`
`TypeiV ~
`TypeV [2J
`
`porous surfaces, infection indicates monolayer
`formation
`
`small adsorbate-adsorbant interaction. capillary
`condensation in porous surfaces
`
`Fig. 9.1 Types of isotherms.
`
`Table 9.2 Hygroscopicity classification scheme.
`
`Class I
`
`Non-hygroscopic
`
`Class II
`
`Slightly hygroscopic
`
`Class Ill
`
`Moderately
`hygroscopic
`
`Class IV
`
`Very hygroscopic
`
`Essentially no moisture increase below 90% RH;
`less than 20% increase in moisture content above
`90% RH in one week
`
`Essentially no moisture increase below 80% RH;
`less than 40% increase in moisture content above
`80% RH in one week
`
`Moisture content does not increase > 5% below 60%
`RH; less than 50% increase in moisture content
`above 80% RH in one week
`
`Moisture content will increase as low as 40-500..6 RH;
`greater than 20% increase in moisture content above
`90% RH in one week
`
`Current approaches to classifying hygroscopic behaviors provide a limited
`view of water sorption in pharmaceutical solids. The absolute level of water up·
`take is an important consideration and certainly needs to be obtained. However,
`the rate of uptake as well as the RH and temperature also need to be considered
`{16). How the water sorbs and the location of the water on a molecular level will
`be specific for a system and is useful information to have during development.
`
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`2381 9 Phys1co/ Characterization of Hygroscopicity in Pharmaceuticol Solids
`
`9.2
`Water-Solid Interactions
`
`When a solid is exposed to water vapor, the water molecules may attach to the
`surface of the solid via van der Waals. ion-dipole, or specific hydrogen-bonding
`interactions with the functional groups on the surface of the solid. Experimental
`studies [17) of adsorbed species on well-defined crystalline surfaces, using vibra(cid:173)
`tional spectroscopy. NMR spectroscopy. and dielectric relaxation, have shown an
`especially strong tendency of water to form hydrogen bonds. Indeed, the ability
`of water to act as both a Lewis acid and Lewis base accounts for the wide range
`of interactions with pharmaceutical compounds. The Cambridge Structural
`Database has been used to closely examine the diverse solid-state environments
`of water molecules in crystalline hydrates of organic compounds. Desiraju [18)
`has suggested that the incorporation of water into crystal structures helps to bal(cid:173)
`ance the mismatch between the number of hydrogen bond donors and accep(cid:173)
`tors in the host molecules. Ferraris and Franchini-Angela [19). in analyzing the
`geometry and environments of water molecules in crystalline hydrate structures
`determined by neutron diffraction, attributed the "quasi-normal" distribution of
`H-bond lengths and angles to the "strain-absorbing" ability of water. Jeffrey and
`Maluszynska {20) reported that three-coordinate water molecules were more
`common than four-coordinate ones. Gillon et al. [21), in drawing the same con(cid:173)
`clusion, suggested that while water prefers to maximize its hydrogen-bonding
`interactions within a hydrate structure. severe steric interactions often preclude
`two H-bond donors and two acceptors from forming a four-coordinate, i.e.,
`tetrahedral. geometry. The states of water associated with solids have been
`reviewed in detail by Zografi [16. 22, 23).
`Water can interact with crystalline solids by sorption at the solid surface, in(cid:173)
`corporation into the lattice, deliquescence, and captllary condensation (in sam(cid:173)
`ples with micropores). This is shown schematically in Fig. 9.2. Deliquescence
`and capillary condensation will lead to condensed (bulk) water that may dissolve
`water-soluble compounds. Water sorption on surfaces can be in the form of
`individual molecules, clusters. monolayers, and multimolecular layers. which
`will eventually lead to condensed water [22]. In sohd-state systems, water is not
`
`..
`
`Hydrate formation
`·Stoichiometric
`1 -Non-stoichiometric
`
`Adsorption
`Cllpill#ry condenSlltion
`Dellque.scence
`
`Absorption
`Crystallization
`
`Fig. 9.2 Water-solid Interactions.
`
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`

`9.3 Characterizing Water-Solid Interactions 1239
`
`static. Even when hydrogen bonding is present, water can move along the sur-
`face or within the crystal lattice over a period of time [22, 24).
`In amorphous solids, various physical changes can occur during water sorp(cid:173)
`tion. Water can dissolve in the solid due to the disordered state of the system,
`where it can act as a plasticizer and significantly lower the glass transition (Tg)
`temperature of the material. A lower T~ can result in greater mobility and crys(cid:173)
`tallization of the amorphous material. The effect of water (or other additives)
`can be described by the Gordon-Taylor equation [25]. Crystalline materials can
`change form . convert into crystalline hydrates, or deliquesce. Approaches to
`determine the changes that occur and examples of these changes are presented
`to illustrate the utility of understanding water uptake at a molecular level.
`
`9.3
`Characterizing Water-Solid Interactions
`
`A thorough evaluation of hygroscopicity is routinely performed for drug sub(cid:173)
`stances and excipients during the early stages of pharmaceutical development.
`This entails determining both the equilibrium moisture content as a function of
`RH and the rate at which equilibrium is attained. To fully appreciate the impact
`that water-solid interactions can have on physical and chemical properties, the
`underlying mechanisms by which moisture is sorbed {or desorbed) must be un(cid:173)
`derstood. For this purpose, several methodologies have been used to character(cid:173)
`ize water-solid interactions at empirical. energetic, and molecular levels.
`
`9.3.1
`Moisture Sorption Analysis
`
`Moisture sorption isotherms, which are plots of the equilibrium water content
`of a solid as a function of RH at constant temperature, are commonly used to
`assess the hygroscopicity of pharmaceutical solids. Sorption-desorption iso(cid:173)
`therms can be obtained gravimetrically by measuring the mass change of a
`sample with changes in RH. A pre-weighed sample is placed in a constant RH
`environment, e.g .. a closed desiccator containing a saturated solution of an elec(cid:173)
`trolyte, then periodically removed and weighed [26). This process is repeated un(cid:173)
`til the sample has reached equilibrium. The conventional desiccator method as
`described here has to a certain extent given way to automated techniques; how(cid:173)
`ever, it is still widely used to equilibrate samples when in situ analysis at speci(cid:173)
`fied humidities is not possible.
`The development of dynamic vapor sorption instruments, which operate in a
`closed system at controlled temperature and either ambient or controlled pres(cid:173)
`sure, has significantly automated moisture sorption analysis. In dynamic vapor
`sorption, a sample is placed on a microbalance and exposed to a continuous
`flow of air or N2 of a predetermined RH [27, 28]. An isotherm is then calculated
`from the equilibrium moisture uptake at each partial pressure or RH. Because
`the mass must stabilize at each RH increment for an isotherm to be accurate
`
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`

`2..0 I 9 Physir::ol Characlerizalion of Hygroscopicity in Pharmaceulical Solids
`
`14,-------------------------------------------~ 100
`
`12
`
`l 10 -c::
`~ 6
`8
`~ -.,
`!
`i 4
`
`6
`
`2
`
`80
`
`60
`
`40
`
`20
`
`;1.
`:D
`CD
`§"
`< CD
`::1:
`c::
`3
`ii
`~
`
`0
`
`500
`
`1000
`
`1500
`
`2000
`
`0
`2500
`
`Time (minutes)
`
`Fig. 9.3 Sorption kinetics of microcrystalline cellulose, showing the extent
`and rate of water uptake.
`
`(Fig. 9.3), the duration of the experiment will depend in part on the nature of
`the moisture uptake. Whereas surface adsorption is typically relatively fast, bulk
`absorption via vapor diffusion is frequently quite slow.
`Figure 9.4 shows several moisture sorption isotherms that are characteristic
`of many different types of pharmaceutical solids. Whereas substantial water up(cid:173)
`take, particularly at high RHs, is commonly observed for amorphous (Fig. 9.4a)
`and deliquescent materials (Fig. 9.4 b). highly crystalline solids {Fig. 9.4c) can
`have very low (less than 0.1%) reversible affinities for moisture sorption. In
`cases of moderate water uptake. the equilibrium water content may experience
`stepwise jumps when stoichiometric hydrates form (Fig. 9.4d- g) andfor gradual
`increases as water is continuously incorporated into non-stoichiometric or chan·
`nel hydrates (Fig. 9.4f and h). The overall percent weight change observed dur(cid:173)
`ing hydrate formation will. of course, depend on the molecular weight of the
`compound. That is, a monohydrate formed by a low molecular weight com·
`pound will produce a larger percent weight increase than a monohydrate
`formed by a higher molecular weight compound. The percent weight change
`will also depend on the extent to which solvent (water) is lost from the sample
`during the initial equilibration at low RH. Because samples can partially or
`completely desolvate under these conditions, the water that is not lost during
`initial drying needs to be added to the sorbed water for the determination of ab(cid:173)
`solute stoichiometry. Weight corrections for the initial water content may be ac(cid:173)
`complished using equilibrium moisture content (EMC) or relative to dry weight
`{RTDW) calculations p4, 29). Quite often, the moisture sorption analysis of sol·
`vated materials is initiated at ambient RH, so as to avoid initial drying, which
`can change the crystal form or crystallinity of the sample.
`
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`

`

`a
`
`20
`
`0
`"E
`-!r
`~
`
`.,
`
`10
`
`9.3 Charaeferizing Water-Solid Interactions 1241
`
`b
`
`u
`!!
`~JO
`
`..
`
`~
`#
`
`..... _
`10 ---
`...... __
`.. ---
`..
`t 1~ _/ f •O
`
`:!0
`
`10
`
`c
`
`0
`
`0
`
`1.0
`
`01
`
`~
`.!! 0.1
`0
`t
`
`J; a ...
`#
`
`u
`
`G.o
`
`0
`
`..
`
`..
`
`110
`'IC.R<IIa_t<....,o.y
`
`..
`
`100
`
`..............
`
`0 _ . . ,
`
`..
`
`..
`
`100
`
`0
`
`0
`
`d
`20
`
`11
`
`11
`
`~ 14
`
`~ 1~
`t)
`-~ ID
`~ 01
`~
`# o•
`
`O•
`
`0~
`
`00
`
`0
`
`..
`
`...... _ ..
`---
`
`..
`
`..
`
`Ill'. Aet.tr¥e ~v"ftdtty
`
`..
`
`100
`
`/
`
`I
`I
`
`..
`
`II
`
`....
`
`% Roll'"" Hum:d~y
`
`..
`...,_ __
`---
`
`..
`
`(
`
`...0
`
`10
`
`..
`...,_ __
`---
`f .
`"6 .
`f.
`.,
`~
`
`0
`
`e
`
`10
`
`..
`t ..
`..
`t
`
`~
`
`~
`#
`
`~
`%Relr...,.Hu.,..lcfly
`
`~
`
`_ _._
`
`---
`..
`
`100
`
`20
`
`~
`
`%Rt18CftHumly
`
`....---·-·-----
`"'
`---
`..... __
`
`~
`
`/
`
`•
`
`0
`
`..
`
`..
`
`..
`
`% AN1-ve Hllr.IOA:'i
`
`00
`
`100
`
`0
`
`0
`
`"' Rela:M! tt.rnO!y
`
`100
`
`Fig. 9.4 Moisture sorption behaviors observed for pharmaceutical solids.
`
`~ :-=., _ ___.J
`..
`..
`
`20
`
`%Re18:MtH.uo:C!Iy
`
`..
`
`100
`
`•
`
`0
`
`h
`
`2.
`
`•"
`
`0
`
`I •
`
`g
`
`10• ---
`r--- :2
`..
`l
`i
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`
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`
`&
`
`u
`
`: 0
`t
`·- ~-/
`_....._.-
`..
`..
`..
`..
`
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`

`2421 9 Physu:al Characleflzalion of Hygroscopicity in Pharmaceutical Solids
`
`When the kinetics and for path of hydration and dehydration are different, the
`sorption and desorption isotherms will not coincide and hysteresis is observed.
`In Fig. 9.4(h), for example, absorbed water causes the material to crystallize
`(producing a spontaneous weight loss) in a different form, so the adsorption
`and desorption isotherms reflect the kinetic stability of different hydrates. It is
`good practice to use orthogonal techniques. e.g.. powder X-ray diffraction, to
`identify forms present at different regions of the moisture sorption isotherm to
`ensure that the sorption-desorption curves are interpreted correctly. Likewise,
`care should be exercised in interpreting moisture uptake curves on initial lots of
`materials that are of questionable crystallinity andfor purity. since the presence
`of phase impurities. crystalline defects and, especially, low levels of amorphous
`material can significantly alter the moisture sorption behavior.
`Moisture sorption isotherms can provide insights into the potential for phase
`transformations and, to a certain extent, the thermodynamic RH stability rela(cid:173)
`tionships between different crystal forms at a given temperature. One potential
`pitfall in using a moisture balance alone to determine critical moisture contents
`for physical transitions is the time-dependent nature of the measurement. In
`cases where conversion of an anhydrate to a hydrate (or of a lower hydrate to a
`higher hydrate) is observed and found to be reversible (no hysteresis on desorp·
`tion). the thermodynamic RH stability relationships will be readily apparent. If
`hysteresis is observed, however, then the water activity at which the relative ther(cid:173)
`modynamic stability of the forms reverses cannot be determined from the mois(cid:173)
`ture sorption-desorption isotherms alone. In these cases, a slurry equilibration,
`which accelerates the slow transformation kinetics of crystals surrounded by va(cid:173)
`por, can be used to determine the specific RH at which the hydrate (or higher
`hydrate) becomes thermodynamically more stable [30, 31).
`When crystal forms differing in hydration state show extreme kinetic stability,
`i.e., no conversions are apparent in the moisture sorption isotherms. the (high(cid:173)
`er) hydrate should not be assumed to be the more stable form at high RHs.
`Although hydrated crystal forms are generally more stable in water than anhy(cid:173)
`drates [32, 33], cases of the opposite stability relationship have been reported.
`The anhydrous form of LY334370 HCI. for example, is more stable than the
`dihydrate crystal form in water at ambient temperature [34). The moisture sorp(cid:173)
`tion isotherms, collected at ambient temperature, showed both of these crystal
`forms to be remarkably stable at all RHs (Fig. 9.4c and g). When suspended in
`water, however, the dihydrate immediately converted into the anhydrate, pre(cid:173)
`sumably by a solution-mediated process. In this case, the temperature at which
`the relative thermodynamic stability would be affected by water activity has
`most likely been exceed