Working document QAS/17.716/Rev.2

December 2018

Revised document for comments

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POLYMORPHISM 3

Draft chapter for The International Pharmacopoeia 4

(December 2018) 5

DRAFT FOR COMMENTS 6

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DRAFT FOR COMMENTS 9

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© World Health Organization 2018 15 16 All rights reserved. 17 18 This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 19 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 20 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 21 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 22 website. 23 24 Please send any request for permission to: 25 26 Dr Sabine Kopp, Manager, Medicines Quality Assurance Programme, Technologies Standards and Norms, Department of 27 Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland, fax: +41 22 791 28 4856; email: kopps@who.int. 29 30 The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 31 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 32 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 33 border lines for which there may not yet be full agreement. 34 35 The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 36 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 37 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 38 39 All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 40 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 41 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 42 Organization be liable for damages arising from its use. 43 44 This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 45

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Please send any comments you may have on this draft to Dr Herbert Schmidt, Medicines

Quality Assurance Programme, Technologies Standards and Norms, Department of

Essential Medicines and Health Products, World Health Organization, 1211 Geneva 27,

Switzerland; email: schmidth@who.int, with a copy to Ms Sinéad Jones (email:

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Working document QAS/17.716/Rev.2

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SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/17.716: 47

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DRAFT CHAPTER FOR THE INTERNATIONAL PHARMACOPOEIA 49

POLYMORPHISM 50

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Drafting of the text by a WHO Expert. March 2017

Discussion at the informal consultation on quality control

laboratory tools and specifications for medicines. 2–4 May 2017

Draft text sent out for public consultation. July–September 2017

Presentation to the Fifty-second WHO Expert Committee on

Specifications for Pharmaceutical Preparations. October 2017

First revision drafted based on the comments received

during the public consultation. March 2018

Discussion at the consultation on screening technology,

sampling and specifications for medicines. 2–4 May 2018

Revision 1 sent out for public consultation. June – July 2018

Second revision drafted based on the comments received

during the public consultation. October 2018

Presentation to the Fifty-third WHO Expert Committee on

Specifications for Pharmaceutical Preparations. October 2018

Revision 2 sent out for public consultation. December 2018 –

February 2019

Further follow-up action as required.

Working document QAS/17.716/Rev.2

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[Note from the Secretariat. It is proposed to publish the following chapter on Polymorphism 59

in the Supplementary Information section under “Notes for guidance”. 60

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The text was revised based on the comments received during the last public consultation in 62

June – July 2018 (see history).] 63

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POLYMORPHISM 65

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1. INTRODUCTION AND TERMINOLOGY 67

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The aim of this chapter is to provide a brief overview of: 69

70

the terminology associated with crystal polymorphism; 71

some analytical techniques commonly used to characterise polymorphs; 72

the relevance of polymorphism for active pharmaceutical ingredients (APIs) and 73

finished pharmaceutical products (FPPs); and 74

the control strategies for polymorphism employed by The International 75

Pharmacopoeia. 76

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APIs and excipients, in the solid phase, can be classified as either crystalline or non-78

crystalline solids. A crystalline structure implies that the structural units (i.e. the unit cells) 79

are repeated in a long range order (i.e. three dimensional crystal lattice). The arrangement of 80

atoms and/or molecules in an amorphous solid is non-ordered (i.e. does not have a long range 81

order), or random system, analogous to the liquid state, and does not possess a 82

distinguishable crystal lattice. Amorphous solids are classified as non-crystalline solids. 83

84

Variation in the crystallization conditions (temperature, pressure, solvent composition, 85

concentration, rate of crystallization, seeding of the crystallization medium, presence and 86

concentration of impurities, etc.) may cause the formation of different crystalline forms. 87

88

When a chemical element (e.g. sulfur) exists in different crystalline forms, it is referred to as 89

allotropy, not polymorphism (1). When a chemical compound with a given chemical 90

structure crystallizes in more than one crystalline lattice with different unit cells, these 91

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crystalline phases are called polymorphs and the phenomena is referred to as polymorphism. 92

The difference in internal crystal structure could be attributed to differences in molecule 93

packing arrangements and/or different molecular conformations. Polymorphic substances, 94

having identical chemical composition, will on dissolution exhibit the same chemical 95

behaviour in solution. 96

97

Crystals of a given chemical compound with the same internal structure may exhibit different 98

external shapes or crystal habits. In addition, variations in crystal habit may indicate the 99

presence of polymorphism but is not necessarily indicative of polymorphic forms (12). 100

101

Solvates are crystal forms containing stoichiometric or non-stoichiometric quantities of a 102

solvent. When the solvent incorporated into the crystal structure of the compound is water, 103

the molecular adduct formed is referred to as a hydrate. Hydrates can be classified as three 104

categories based on different structural aspects: Class I represents hydrates where the water 105

molecules exist at isolated sites; Class II hydrates are generally referred to as channel 106

hydrates; and Class III hydrates are generally referred to as ion-coordinated site hydrates. In 107

such systems, water molecules form ion-water bonds that are usually much stronger than 108

hydrogen bonds (13). Solvation and hydration products are also sometimes referred to as 109

pseudopolymorphs (2, 3, 4). However, the term “pseudopolymorphism” is ambiguous 110

because of its use in different circumstances. It is therefore preferable to use only the terms 111

“solvates” and “hydrates”. 112

113

Occasionally, a compound of a given hydration/solvation composition may crystallize into 114

more than one crystalline form; an example of such a compound is nitrofurantoin (5). 115

Nitrofurantoin can be crystallized as two monohydrate forms (Forms I and II) and two 116

anhydrous forms (designated polymorphs and ) (5). 117

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Crystal forms are said to be isostructural (also referred to as isomorphous) when they have 119

the same overall crystal packing. Solvates, which have the same overall crystal packing, but 120

differ only in the solvents included in their crystal structures, are termed isostructural or 121

isomorphous solvates, e.g. hydrate and isopropanolate of hexakis(2,3,6-tri-O-acetyl)-α-122

cyclodextrin (6). 123

124

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The term desolvated solvate (or desolvated hydrates), also referred to as isomorphous 125

desolvates, has been used to describe a solid form obtained by removing solvent from the 126

solvate crystal structure (or water from a hydrate) without significantly changing the crystal 127

structure (4), as in the desolvated monohydrate of terazosin HCl (7). 128

129

Amorphous forms of APIs and excipients are of substantial interest because they are usually 130

more soluble (also having a faster kinetic solubility) than their crystalline counterparts but are 131

thermodynamically less stable. Solid-state properties of amorphous forms of the same 132

chemical compound (i.e. thermal behaviour, solubility profile, density, etc.) may differ; 133

134

Co-crystals are crystalline materials composed of two or more different molecules, typically 135

an API and co-crystal formers (“coformers”) within the same crystal lattice that are 136

associated by nonionic and noncovalent bonds. An example of a co-crystal is the succinic 137

acid co-crystal of fluoxetine HCl (8). Co-crystals are thus more similar to solvates, in that 138

both contain more than one component in the lattice. However, for co-crystals the coformer 139

is non-volatile (i.e. exists as solid material at ambient conditions) (3). 140

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Pharmaceutical co-crystals have gained considerable attention as alternative forms in an 142

attempt to enhance the bioavailability, stability and processability of the API in the 143

manufacturing process. Another advantage of co-crystals is that they generate a diverse array 144

of solid state forms for APIs that lack ionisable functional groups, which is a prerequisite for 145

salt formation (3). Guidance and reflection papers on the use and classification of 146

pharmaceutical co-crystals have been published (3, 9). 147

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2. CHARACTERIZATION AND THERMODYNAMIC STABILITY OF SOLID 149

FORMS 150

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Crystalline and amorphous forms are characterized based on their physicochemical 152

properties. Table 1 lists some examples of the properties that may differ among different 153

forms (9). 154

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Table 1. Examples of physicochemical properties that may differ among different forms 158

1. Packing properties 159

a. Molar volume and density 160

b. Refractive index 161

c. Conductivity (electrical and thermal) 162

d. Hygroscopicity 163

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2. Thermodynamic properties 165

a. Melting and sublimation temperatures 166

b. Internal energy (i.e. structural energy) 167

c. Enthalpy (i.e. heat content) 168

d. Heat capacity 169

e. Entropy 170

f. Free energy and chemical potential 171

g. Thermodynamic activity 172

h. Vapour pressure 173

i. Solubility 174

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3. Spectroscopic properties 176

a. Electronic state transitions 177

b. Vibrational state transitions 178

c. Nuclear spin state transitions 179

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4. Kinetic properties 181

a. Dissolution rate 182

b. Rates of solid state reactions 183

c. Stability 184

d. Solid state 185

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5. Surface properties 187

a. Surface-free energy 188

b. Interfacial tensions 189

c. Habit (i.e. shape) 190

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6. Mechanical properties 192

a. Hardness 193

b. Tensile strength 194

c. Compactibility 195

d. Flow 196

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Table 2 summarizes some of the most commonly used techniques to study and/or classify 197

different amorphous or crystalline forms. These techniques are often complementary and it is 198

indispensable to use several of them. Demonstration of a non-equivalent structure by single 199

crystal X-ray diffraction is currently regarded as the definitive evidence of polymorphism. 200

X-ray powder diffraction and/or solid state NMR can also be used, as bulk techniques, to 201

provide unequivocal proof of polymorphism (10). 202

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Any technique(s) chosen to confirm the identity of the specific form(s) must be proven to be 204

suitably specific for the identification of the desired form(s). Care must be taken in choosing 205

the appropriate sample preparation technique, as heat generation, mechanical stress or 206

exposure to elevated pressure and other environmental conditions (humidity) may trigger 207

conversion between different forms. 208

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Table 2. Examples of some techniques that may be used to study and/or classify different 210

crystalline forms 211

1. X-ray powder diffraction*

& Single crystal X-ray diffraction 212

2. Microcalorimetry 213

3. Thermal analysis (1.2.1 Melting point,* differential scanning calorimetry, thermogravimetry, 214

thermomicroscopy) 215

4. Moisture sorption analysis 216

5. Polarized optical microscopy and electronic microscopy with diffraction capability (ex. Transmission 217

Electron Microscopy) 218

6. Solid-state nuclear magnetic resonance; 219

7. Solubility studies 220

8. Spectrophotometry in the infrared region (1.7)* and Raman spectrophotometry 221

9. Intrinsic dissolution rate 222

10. Density measurement 223

* Methods currently employed by The International Pharmacopoeia 224

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Using suitable analytical techniques, the thermodynamic stability of the forms should be 226

investigated. The form with the lowest free energy is the most thermodynamically stable at a 227

given temperature and pressure. All other forms of the given system are in a metastable state. 228

At standard temperature and pressure, a metastable form may remain unchanged or may 229

change to a thermodynamically more stable form. In general, the more stable the form the 230

less soluble it is. Conversion to a thermodynamically more stable form, may cause changes 231

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in some of the physicochemical properties (see Table 1) of the compound that may result in 232

changes to other critical properties such as bioavailability, manufacturability (also referred to 233

as processability), etc. 234

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If there are several crystalline forms one form is thermodynamically more stable at a given 236

temperature and pressure. A given crystalline form may constitute a phase that can reach 237

equilibrium with other solid phases and with the liquid and gas phases. 238

239

If each crystalline form is stable within a given temperature range the change from one form 240

to another is reversible and is said to be enantiotropic. The change from one phase to another 241

is a univariate equilibrium so that at a given pressure this state is characterized by a transition 242

temperature. However, if only one of the forms is stable over the entire temperature range, 243

the change is irreversible or monotropic (11). 244

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3. RELEVANCE OF POLYMORPHISM FOR APIs AND FPPs 246

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Polymorphism (and hydrate formation) of APIs and excipients are of interest as they may 248

affect bioavailability, toxicity and processability. Also, the thermodynamic stability of the 249

form included in the FPP is considered important as environmental conditions may 250

compromise the stability thereof. For formulations where the API is dissolved, attention has 251

to be paid to supersaturation with regards to different forms. A formulation might not be 252

supersaturated regarding a metastable polymorph but supersaturated with regards to the 253

thermodynamically stable polymorph. Control of the form by the manufacturer may be 254

required during the processing of APIs and excipients and during the manufacturing of a 255

dosage form to ensure the correct physicochemical characteristics thereof. The control of a 256

specific form is especially critical in the areas where the bioavailability, stability or 257

processability are directly impacted (4). 258

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The form of a readily soluble API that is incorporated into a solution, for example, an 260

injection, an oral solution or eye drops, is normally non-critical (exceptions to this statement 261

might be if the concentration of the solution is such that it is close to the limit of solubility of 262

one of the possible polymorphs – as mentioned above - or solvate formation is observed with 263

one of the excipients). Similarly, if an API is processed during the manufacturing process to 264

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obtain an amorphous form (e.g. hot melt extrusion, spray-dried dispersion, etc.), the original 265

form is considered non-critical, as long as the processability is not influenced. 266

267

The form may be critical when the material is included in a solid dosage form or as a 268

suspension in a liquid dosage form. In such cases, the characteristics of the different 269

polymorphs may affect the bioavailability or dissolution of the material. The polymorphic 270

form of a biopharmaceutics classification system (BCS) class I or III API in a solid oral 271

dosage form is normally non-critical in terms of dissolution rate or bioavailability as by 272

definition it would be readily soluble, but confirmation thereof by the manufacturer, is 273

recommended. The ICH Harmonised Tripartite Guideline on Specifications: Test procedures 274

and acceptance criteria for new drug substances and new drug products: Chemical substances 275

Q6A, provides guidance on when and how polymorphic forms should be controlled and 276

monitored (4). 277

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The inclusion of potentially harmful solvents in the crystal lattice, which may render APIs or 279

excipients to be toxic or harmful to patients (i.e. solvates), should also be suitably regulated 280

and monitored by the manufacturer. 281

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4. POLYMORPHISM IN THE INTERNATIONAL PHARMACOPOEIA 283

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Where a monograph indicates that a compound shows polymorphism this may be true crystal 285

polymorphism, occurrence of solvates/hydrates or occurrence of the amorphous form. 286

287

The International Pharmacopoeia controls the polymorphic or crystalline forms (hereafter 288

referred to as form) of a limited number of substances by restricting it to either: 289

290

a single form, for example, carbamazepine API (Anhydrous Form III), mebendazole 291

API (Form C); or 292

by limiting the presence of unwanted forms, for example, chloramphenicol palmitate 293

API (should contain at least 90% of polymorph B). 294

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The control of forms specified in The International Pharmacopoeia may be achieved by: 298

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permitting no deviation from the infrared absorption spectrum of the reference 300

substance prescribed (or reference spectrum supplied) – when the infrared absorption 301

spectrum has been proven to be specific to the preferred form and able to distinguish 302

the undesired form(s), for example, indomethacin API; 303

restricting the melting point range, when the melting properties of the forms are clearly 304

distinguishable, for example, phenobarbital API; 305

recommending the use of any other suitable methods such as X-ray powder 306

diffractometry, for example, carbamazepine tablets; and 307

limiting the incorporated solvent (in the case of solvates/hydrates) with a specific limit 308

test, for example, nevirapine hemihydrate API. 309

310

The specific control to be used will be indicated in the applicable monograph. 311

312

When the infrared identification test is able to detect differences in forms for a specific 313

compound (i.e. polymorphism may be present for this compound), but the control of a 314

specific form is not required by the monograph, the user may be instructed to: 315

316

recrystallize both the test substance and the specified reference substance, in the event 317

where the infrared spectra are found to be not concordant, for example, fluconazole 318

API; and/or 319

dry the API and/or specified reference substance to ensure that both forms are in the 320

anhydrous or dehydrated state, for example, nevirapine hemihydrate API. 321

322

Whenever the choice of a specific form is critical with regard to bioavailability and/or 323

stability, the method of the manufacturer of the product must be validated to consistently 324

yield the desired polymorph in the final product at release and over its shelf life. The 325

monograph will include a statement under the heading “Manufacturing” to draw attention to 326

the control of a specified form during manufacturing where control is known to be critical, 327

for example, carbamazepine oral suspension. 328

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It is the intention of The International Pharmacopoeia to extend the inclusion of explicit 331

statements in monographs, where appropriate, as information on the occurrence of 332

polymorphism becomes available. The Secretariat thus cordially invites the users of The 333

International Pharmacopoeia and manufacturers to share any relevant information that could 334

be included in the monographs. 335

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References 338

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1. Gaskell, DR. 2005. Allotropy and Polymorphism. Reference Module in Materials Science and 340

Materials Engineering. Encyclopedia of Condensed Matter Physics, 8–17. 341

2. Brittain, HG. 2007. Polymorphism and Solvatomorphism 2005. Journal of Pharmaceutical Sciences, 342

96(4):705–728. 343

3. US Department of Health and Human Services, Food and Drug Administration. Center for Drug 344

Evaluation and Research. 2013. Guidance to Industry: Regulatory Classification of Pharmaceutical 345

Co-crystals. 346

4. International Conference on Harmonisation of Technical Requirements for Registration of 347

Pharmaceuticals for Human Use. 1999. ICH Q6A – Specifications: The Procedures and Acceptance 348

Criteria for New Drug Substances and New Drug Products: Chemical Substances. 349

5. Caira, M, Pienaar, EW, Lötter, AP. 2006. Polymorphism and Pseudopolymorphism of the 350

Antibacterial Nitrofurantoin. Molecular Crystals and Liquid Crystals, 179(1):241-264. 351

6. Bettineti, G., Sorrenti, M., Catenacci, L., Ferrari, F. & Rossi, S. Bettinetti, G, et al. 2006. 352

Polymorphism, Pseudopolymorphism, and Amorphism of Peracetylated α-, β-, and γ-cyclodextrins. 353

Journal of Pharmaceutical and Biomedical Analysis, 41:1205-1211. 354

7. Bauer, J, et al. 2006. Identification, Preparation and Characterization of Several Polymorphs and 355

Solvates of Terazosin Hydrochloride. Journal of Pharmaceutical Sciences, 95(4):917-928. 356

8. Peterson, ML, et al. 2006. Expanding the Scope of Crystal Form Evaluation in Pharmaceutical 357

Science. Journal of Pharmaceutical Sciences, 9(3):317-326. 358

9. European Medicines Agency. 2015. Reflection Paper on the Use of Co-crystals of Active Substances 359

in Medicinal Products. 360

10. US Department of Health and Human Services, Food and Drug Administration. Center for Drug 361

Evaluation and Research. 2007. Guidance to Industry: ANDAs: Pharmaceutical Solid Polymorphism. 362

Chemistry, Manufacturing and Controls Information. 363

11. British Pharmacopoeia Commission. 2017. SC I B. Polymorphism. In: British Pharmacopoeia 364

Commission. British Pharmacopoeia 2017. Supplementary chapter. London: TSO. 365

12. J. Bernstein. 2002. Polymorphism in Molecular Crystals, Clarendon Press, Oxford, United Kingdom 366

volume. 367

13. Byrn, R.S, Zografi, G. & Chen, X. 2017. Solid state properties of pharmaceutical materials, John 368

Wiley & Sons. Inc. 369

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