Working document QAS/17.716/Rev.1

May 2018

Revised document for comment

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POLYMORPHISM 3

Draft chapter for The International Pharmacopoeia 4

(May 2018) 5

DRAFT FOR COMMENT 6

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DRAFT FOR COMMENTS 9

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© World Health Organization 2018 15

All rights reserved. 16

This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The 17 draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, 18 in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and 19 member organizations) without the permission of the World Health Organization. The draft should not be displayed on any 20 website. 21

Please send any request for permission to: 22

Dr Sabine Kopp, Manager, Medicines Quality Assurance Programme, Technologies Standards and Norms, Department of 23 Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. 24 Fax: (41-22) 791 4730; email: kopps@who.int. 25

The designations employed and the presentation of the material in this draft do not imply the expression of any opinion 26 whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or 27 of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate 28 border lines for which there may not yet be full agreement. 29

The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or 30 recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors 31 and omissions excepted, the names of proprietary products are distinguished by initial capital letters. 32

All reasonable precautions have been taken by the World Health Organization to verify the information contained in this 33 draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The 34 responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health 35 Organization be liable for damages arising from its use. 36

This draft does not necessarily represent the decisions or the stated policy of the World Health Organization. 37

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Should you have any comments on this draft, please send these 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,

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Working document QAS/17.716/Rev.1

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SCHEDULE FOR THE ADOPTION PROCESS OF DOCUMENT QAS/17.716: 39

Draft chapter for The International Pharmacopoeia 40

Polymorphism 41

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[Note from the Secretariat. It is proposed to publish the following chapter on Polymorphism 64

in the Supplementary Information section under “Notes for guidance”.] 65

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Date

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 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

Presentation to the WHO Expert

Committee on Specifications for

Pharmaceutical Preparations

October 2018

Further follow-up action as required

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Polymorphism 67

Introduction and terminology 68

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The aim of this chapter is to provide a brief overview of 70

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the terminology associated with crystal polymorphism; 72

some analytical techniques commonly used to characterise polymorphs; 73

the relevance of polymorphism for active pharmaceutical ingredients (APIs) and 74

finished pharmaceutical products (FPPs); 75

the control strategies for polymorphism employed by The International 76

Pharmacopoeia. 77

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APIs and excipients, in the solid phase, can be classified as either crystalline or non-79

crystalline solids or a mixture thereof. A crystalline structure implies that the structural units 80

(i.e. the unit cells) are repeated in a long range order. The atoms and/or molecules of an 81

amorphous solid, however, are arranged in a non-ordered, random system, such as in the 82

liquid state, and do not possess a distinguishable crystal lattice. Amorphous solids are 83

classified as non-crystalline solids. 84

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Variation in the crystallization conditions (temperature, pressure, solvent, concentration, rate 86

of crystallization, seeding of the crystallization medium, presence and concentration of 87

impurities, etc.) may cause the formation of different forms. 88

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When the crystalline structure of the same chemical compound (and atomic formula) 90

exhibitstwo or more patterns of the repeated unit cells, these crystalline structures are called 91

polymorphs and the phenomena is referred to as polymorphism. The difference in internal 92

crystal structure could be attributed to differences in molecule packing arrangements and/or 93

different molecular conformations. When a chemical element (e.g. sulfur) exists in different 94

crystalline forms, it is referred to as allotropy, not polymorphism (1). Due to the identical 95

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chemical composition of the polymorphic substance it will have the same chemical behaviour 96

in solution, irrespective in the form in which it is presented. 97

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Crystals of the same chemical compound with the same internal structure may exhibit 99

different external shapes or crystal habits. 100

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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. Solvation and hydration products are 104

also sometimes referred to as pseudopolymorphs (2, 3, 4). However, the term 105

“pseudopolymorphism” is ambiguous because of its use in different circumstances. It is 106

therefore preferable to use only the terms “solvates” and “hydrates”. 107

108

Occasionally a compound of a given hydration/solvation state may crystallize into more than 109

one crystalline form; an example of such a compound is nitrofurantoin (5). Nitrofurantoin can 110

be crystallized as two monohydrate forms (Forms I and II) and two anhydrous forms 111

(designated polymorphs and ) (5). 112

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Crystal forms are said to be isostructural when they have the same overall crystal packing. 114

Solvates, which have the same overall crystal packing, but differ only in the solvents included 115

in their crystal structures, are termed isostructural solvates ,e.g. hydrate and isopropanolate of 116

hexakis(2,3,6-tri-O-acetyl)-α-cyclodextrin (6). 117

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The term desolvated solvate (which includes hydrates) has been used to classify a compound 119

that was originally crystallized as a solvate but when the incorporated solvent is removed the 120

crystal lattice of the solvated and desolvated crystal lattices show no or only relatively small 121

differences (4), for example, desolvated monohydrate of terazosin HCl (7). 122

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Amorphous forms of APIs and excipients are of substantial interest because they are usually 124

more soluble than their crystalline counterparts but are usually considered to be 125

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thermodynamically less stable. Solid-state properties of amorphous forms of the same 126

chemical compound (i.e. thermal behaviour, solubility profile, etc.) may differ; this 127

phenomenon is referred to as polyamorphism (6). 128

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Traditionally polymorphic forms of an API are classified as either crystalline, amorphous or 130

solvate and hydrate forms. Co-crystals are crystalline materials composed of two or more 131

different molecules, typically an API and co-crystal formers (“conformers”) within the same 132

crystal lattice that are associated by nonionic and noncovalent bonds. An example of a co-133

crystal is fluoxetine HCl/succinic acid co-crystal (8). Co-crystals are thus more similar to 134

solvates, in that both contain more than one component in the lattice. However, for co-135

crystals the conformer is non-volatile (3). 136

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Pharmaceutical co-crystals have gained considerable attention as alternative forms in an 138

attempt to enhance the bioavailability, stability and processability of the API in the 139

manufacturing process. Another advantage of co-crystals is that they generate a diverse array 140

of solid state forms for APIs that lack ionisable functional groups, which is a prerequisite for 141

salt formation (3). Guidance and reflection papers on the use and classification of pharmaceutical co-142

crystals have been published (3, 9). 143

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Characterization and thermodynamic stability of solid forms 145

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Crystalline forms are characterized based on the differences of their physical properties. 147

Table 1 lists some examples of the properties that may differ among different forms (9). 148

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Table 1. Examples of physical properties that may differ among different forms 150

1. Packing properties 151

a. Molar volume and density 152

b. Refractive index 153

c. Conductivity (electrical and thermal) 154

d. Hygroscopicity 155

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2. Thermodynamic properties 157

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a. Melting and sublimation temperatures 158

b. Internal energy (i.e. structural energy) 159

c. Enthalpy (i.e. heat content) 160

d. Heat capacity 161

e. Entropy 162

f. Free energy and chemical potential 163

g. Thermodynamic activity 164

h. Vapour pressure 165

i. Solubility 166

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3. Spectroscopic properties 168

a. Electronic state transitions 169

b. Vibrational state transitions 170

c. Nuclear spin state transitions 171

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4. Kinetic properties 173

a. Dissolution rate 174

b. Rates of solid state reactions 175

c. Stability 176

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5. Surface properties 178

a. Surface-free energy 179

b. Interfacial tensions 180

c. Habit (i.e. shape) 181

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6. Mechanical properties 183

a. Hardness 184

b. Tensile strength 185

c. Compactibility, tableting 186

d. Handling and flow 187

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Table 2 summarizes some of the most commonly used techniques to study and/or classify 189

different forms. These techniques are often complementary and it is indispensable to use 190

several of them. Demonstration of a non-equivalent structure by single crystal X-ray 191

diffraction is currently regarded as the definitive evidence of polymorphism. X-ray powder 192

diffraction can also be used to provide unequivocal proof of polymorphism (10). 193

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Any technique(s) chosen to confirm the identity of the specific form(s) must be proven to be 195

suitably specific for the identification of the desired form(s). Care must be taken in choosing 196

the appropriate sample preparation technique, as heat generation or exposure to elevated 197

pressure may trigger conversion between different forms. 198

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Table 2. Examples of some techniques that may be used to study and/or classify different 200

crystalline forms 201

1. X-ray powder diffraction* 202

2. Single crystal X-ray diffraction 203

3. Microcalorimetry 204

4. Thermal analysis (1.2.1 Melting point,* differential scanning calorimetry, 205

thermogravimetry, thermomicroscopy) 206

5. Moisture sorption analysis 207

6. Microscopy (electronic and optical) 208

7. Solid-state nuclear magnetic resonance; 209

8. Solubility studies 210

9. Spectrophometry: Spectrophotometry in the infrared region (1.7)*

and Raman 211

spectrophotometry 212

10. Intrinsic dissolution rate 213

11. Density measurement 214

* Methods currently employed by The International Pharmacopoeia 215

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Using suitable analytical techniques, the thermodynamic stability of the forms should be 217

investigated. The form with the lowest free energy is the most thermodynamically stable at a 218

given temperature and pressure. The other forms are said to be in a metastable state. At 219

normal temperature and pressure, a metastable form may remain unchanged or may change to 220

a thermodynamically more stable form. In general the more stable the form the less soluble it 221

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is. Conversion to a thermodynamically more stable form, may cause changes in some of the 222

physical properties (see Table 1) of the compound that may result in changes to other critical 223

properties such as bioavailability, manufacturability (also referred to as processability), etc. 224

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If there are several crystalline forms one form is thermodynamically more stable at a given 226

temperature and pressure. A given crystalline form may constitute a phase that can reach 227

equilibrium with other solid phases and with the liquid and gas phases. 228

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If each crystalline form is the more stable within a given temperature range the change from 230

one form to another is reversible and is said to be enantiotropic. The change from one phase 231

to another is a univariate equilibrium so that at a given pressure this state is characterized by 232

a transition temperature. However, if only one of the forms is stable over the entire 233

temperature range, the change is irreversible or monotropic (11). 234

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Relevance of polymorphism for APIs and FPPs 236

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Polymorphism of APIs and excipients are of interest as they may affect bioavailability, 238

toxicity and processability. Also the thermodynamic stability of the form included in the FPP 239

is considered important as environmental conditions may compromise the stability thereof. 240

For formulations where the API is dissolved, attention has to be paid to supersaturation with 241

regards to different forms. A formulation might not be supersaturated regarding a metastable 242

polymorph but supersaturated with regards to the thermodynamically stable polymorph. 243

Control of the form by the manufacturer may be required during the processing of APIs and 244

excipients and during the manufacturing of a dosage form to ensure the correct physical 245

characteristics thereof. The control of a specific form is especially critical in the areas where 246

the bioavailability, stability or processability are directly impacted (4). 247

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The form of a readily soluble API that is incorporated into a solution, for example, an 249

injection, an oral solution or eye drops, is normally non-critical (an exception to this 250

statement might be if the concentration of the solution is such that it is close to the limit of 251

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solubility of one of the possible polymorphs – as mentioned above). Similarly, if an API is 252

processed during the manufacturing process to obtain an amorphous form (e.g. hot melt 253

extrusion, spray-dried dispersion, etc.), the original form is considered non-critical, as long as 254

the processability is not influenced. 255

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The form may be critical when the material is included in a solid dosage form or as a 257

suspension in a liquid dosage form. In such cases the characteristics of the different 258

polymorphs may affect the bioavailability or dissolution of the material. The polymorphic 259

form of a biopharmaceutical classification system (BCS) class I or III API in a solid oral 260

dosage form is normally non-critical in terms of dissolution rate or bioavailability as by 261

definition it would be readily soluble, but confirmation thereof by the manufacturer, is 262

recommended. The ICH Harmonised Tripartite Guideline on Specifications: Test procedures 263

and acceptance criteria for new drug substances and new drug products: Chemical substances 264

Q6A, provides guidance on when and how polymorphic forms should be monitored (4). 265

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The inclusion of potentially harmful solvents in the crystal lattice, which may render APIs or 267

excipients to be toxic or harmful to patients (i.e. solvates), should also be suitably regulated 268

and monitored by the manufacturer. 269

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Polymorphism in The International Pharmacopoeia 271

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Where a monograph indicates that a compound shows polymorphism this may be true crystal 273

polymorphism, occurrence of solvates or occurrence of the amorphous form. 274

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The International Pharmacopoeia controls the forms of a limited number of substances by 276

restricting it to either: 277

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a single form, for example, carbamazepine API (Anhydrous Form III), 279

mebendazole API (Form C); or 280

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by limiting the presence of unwanted forms, for example, chloramphenicol 281

palmitate API (should contain at least 90% of polymorph B). 282

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The control of forms specified in The International Pharmacopoeia may be achieved by: 284

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permitting no deviation from the infrared absorption spectrum of the reference 286

substance prescribed (or reference spectrum supplied) – when the infrared 287

absorption spectrum has been proven to be specific to the preferred form and able 288

to distinguish the undesired form(s), for example, indomethacin API; 289

restricting the melting point range, for example, phenobarbital API; 290

recommending the use of any other suitable methods such as X-ray powder 291

diffractometry, for example, carbamazepine tablets; 292

limiting the incorporated solvent (in the case of solvates/hydrates) with a specific 293

limit test, for example, nevirapine hemihydrate API. 294

295

When the infrared identification test is able to detect differences in forms for a specific 296

compound (i.e. polymorphism may be present for this compound), but the control of a 297

specific form is not required by the monograph, the user may be instructed to: 298

299

recrystallize both the test substance and the specified reference substance, in the 300

event where the infrared spectra are found to be not concordant, for example, 301

fluconazole API; and/or 302

dry the API and/or specified reference substance to ensure that both forms are in 303

the anhydrous or dehydrated state, for example, nevirapine hemihydrate API. 304

305

Whenever the choice of a specific form is critical with regard to bioavailability and/or 306

stability, the method of the manufacturer of the product must be validated to consistently 307

yield the desired polymorph in the final product at release and over its shelf life. The 308

monograph will include a statement under the heading “Manufacturing” to draw attention to 309

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the control of a specified form during manufacturing where control is known to be critical, 310

for example, carbamazepine oral suspension. 311

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It is the intention of The International Pharmacopoeia to extend the inclusion of explicit 313

statements in monographs, where appropriate, as information on the occurrence of 314

polymorphism becomes available. The Secretariat thus cordially invites the users of The 315

International Pharmacopoeia and manufacturers to share any relevant information that could 316

be included in the monographs. 317

318

REFERENCES 319

1. Gaskell, DR. 2005. Allotropy and Polymorphism. Reference Module in Materials 320

Science and Materials Engineering. Encyclopedia of Condensed Matter Physics, 8–321

17. 322

323

2. Brittain, HG. 2007. Polymorphism and solvatomorphism 2005. Journal of 324

Pharmaceutical Sciences, 96(4):705–728. 325

326

3. US Department of Health and Human Services, Food and Drug Administration. 327

Center for Drug Evaluation and Research. 2013. Guidance to industry: Regulatory 328

classification of pharmaceutical co-crystals. 329

330

4. International Conference on Harmonisation of Technical Requirements for 331

Registration of Pharmaceuticals for Human Use. 1999. ICH Q6A – Specifications: 332

The procedures and acceptance criteria for new drug substances and new drug 333

products: Chemical substances. 334

5. Caira, M, Pienaar, EW, Lötter, AP. 2006. Polymorphism and pseudopolymorphism 335

of the antibacterial nitrofurantoin. Molecular Crystals and Liquid Crystals, 336

179(1):241-264. 337

338

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6. BETTINETTI, G., SORRENTI, M., CATENACCI, L., FERRARI, F. & ROSSI, S. 339

Bettinetti, G, et al. 2006. Polymorphism, pseudopolymorphism, and amorphism of 340

peracetylated α-, β-, and γ-cyclodextrins. Journal of Pharmaceutical and Biomedical 341

Analysis, 41:1205-1211. 342

343

7. Bauer, J, et al. 2006. Identification, preparation and characterization of several 344

polymorphs and solvates of terazosin hydrochloride. Journal of Pharmaceutical 345

Sciences, 95(4):917-928. 346

347

8. Peterson, ML, et al. 2006. Expanding the scope of crystal form evaluation in 348

pharmaceutical science. Journal of Pharmaceutical Sciences, 9(3):317-326. 349

350

9. European Medicines Agency. 2015. Reflection paper on the use of cocrystals of 351

active substances in medicinal products. 352

353

10. US Department of Health and Human Services, Food and Drug Administration. 354

Center for Drug Evaluation and Research. 2007. Guidance to industry: ANDAs: 355

Pharmaceutical Solid Polymorphism. Chemistry, Manufacturing and Controls 356

Information. 357

11. British Pharmacopoeia Commission. 2017. SC I B. Polymorphism. In: British 358

Pharmacopoeia Commission. British Pharmacopoeia 2017. Supplementary chapter. 359

London: TSO. 360

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