draft chapter for the international pharmacopoeia · as allotropy,74 not polymorphism (1). the...

Working document QAS/17.716

July 2017

Draft document for comment

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POLYMORPHISM 3

Draft chapter for The International Pharmacopoeia 4

(July 2017) 5

DRAFT FOR COMMENT 6

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DRAFT FOR COMMENTS 9

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© World Health Organization 2017 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: [email protected]. 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

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Working document QAS/17.716 page 2

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 61

in the Supplementary Information section under “Notes for guidance”.] 62

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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 WHO Expert Committee on

Specifications for Pharmaceutical

Preparations

October 2017

Further follow-up action as required


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Polymorphism 64

Active pharmaceutical ingredients (APIs) and excipients, in the solid phase, can be classified 65

as either crystalline or amorphous solids or a mixture thereof. A crystalline structure implies 66

that the structural units (i.e. unit cells) are repeated regularly, indefinitely and three-67

dimensionally in space. The unit cells of an amorphous solid, however, are arranged in a non-68

ordered, random system, related to the liquid state. 69

Polymorphism is the phenomenon where crystalline forms of the same chemical compound 70

exist in different crystalline phases. The difference in internal crystal structure could be 71

attributed to differences in crystal packing arrangements and/or different molecular 72

conformations. When a chemical element exists in different crystalline forms, it is referred to 73

as allotropy, not polymorphism (1). The phenomenon where crystals with the same internal 74

structure exhibit different external shapes is referred to as differences in crystal habit. 75

Other variations in the crystal structures of the same chemical compound are encountered 76

where these unit cells differ in elemental composition through the inclusion of one or more 77

solvent molecules, known as solvates. Solvent inclusion can be in stoichiometric or non-78

stoichiometric order. In the past solvent inclusion has been considered to be a mechanism of 79

polymorphism (due to changes/differences in the unit cell of a solid) but was dubbed 80

pseudopolymorphism, due to the fact that the composition of the pseudopolymorph differs 81

chemically (due to the presence of solvent molecules) from the unsolvated form. The terms 82

solvatomorphs and solvatomorphism are also used to avoid issues associated with 83

inconsistent nomenclature (2). 84

When water is incorporated in stoichiometric proportions into the crystal lattice of the 85

compound, the molecular adduct(s) formed is referred to as a hydrate. 86

Occasionally a compound of a given hydration/solvation state may crystallize into more than 87

one crystalline form, thus producing hydrates/solvates that exhibit polymorphism themselves, 88

which is known as polymorphic pseudopolymorphs. An example of this phenomenon is 89

Nitrofurantoin (3). Nitrofurantoin can be crystallized as two monohydrous forms (Forms I 90

and II) and two anhydrous species (designated polymorphs and ) (3). Solvated forms 91

(from different solvents) that do not exhibit significant differences in XRPD patterns and 92

crystal packing (i.e. hydrate and isopropanolate of hexakis(2,3,6-tri-O-acetyl)-α-cyclodextrin 93

are called isostructural pseudopolymorphs (4). 94


The term desolvated solvates has been used to classify a compound that was originally 95

crystallized as a solvate but when the incorporated solvent is removed the crystal lattice of 96

the solvated and desolvated crystal lattices do not show any or relatively small differences, 97

for example, desolvated monohydrate of terazosin HCl (5). 98

Amorphous forms of APIs and excipients are of substantial interest because they are usually 99

more soluble than their crystalline counterparts but are usually considered to be 100

thermodynamically less stable.6 Solid-state properties of amorphous forms of the same 101

chemical compound (i.e. melting behaviour, solubility profile, etc.) may differ; this 102

phenomenon is referred to as polyamorphism (6). 103

Another phenomenon of crystal engineering is that of pharmaceutical co-crystals. 104

Pharmaceutical co-crystals can be defined as crystalline materials comprised of an API and 105

one or more unique co-crystal formers (e.g. Fluoxetine HCl/succinic acid co-crystal), which 106

are solids at room temperature (7), thus it is suggested that co-crystal formation could be 107

considered a subdivision of pseudopolymorphism. 108

Variation in the crystallization conditions (temperature, pressure, solvent, concentration, rate 109

of crystallization, seeding of the crystallization medium, presence and concentration of 110

impurities, etc.) may cause the formation of different crystalline forms and/or solvates. 111

In general, the more stable the form (including polymorphs, amorphous forms, etc.), the less 112

soluble the form is in water. 113

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Figure 1 provides a summary of the groups wherein solids can be classified. 115

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Figure 1. Summary of the groups wherein solids can be classified (8). 120

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Chemical compounds

Crystalline solids Amorphous solids

Amorphous forms withdifferent physico-chemical

properties

Poly-amorphism

Single entities Molecular adducts

Polymorphs

Packing polymorphism

Conformationalpolymorphism

Polymorph A

Polymorph B

Polymorph C

SolvateHydrate Hydrated solvate Co-crystals

Hydrate D1

Hydrate D2

* PolymorphicPsudopolymorps

*

Iso-structuralpseudopolymorphs

*


Desolvation**

** Desolvated Solvate

Solvent moleculeWater molecule

Chemical compounds

Crystalline solids Amorphous solids

Amorphous forms withdifferent physico-chemical

properties

Poly-amorphism

Single entities Molecular adducts

Polymorphs

Packing polymorphism

Conformationalpolymorphism

Polymorph A

Polymorph B

Polymorph C

SolvateHydrate Hydrated solvate Co-crystals

Hydrate D1

Hydrate D2

* PolymorphicPsudopolymorps

*


*


Desolvation**

** Desolvated Solvate

Solvent moleculeWater molecule


Crystalline forms are characterized based on the differences of their physical properties. 122

Table 1 lists some examples of the properties that may differ among different morphic forms 123

(9). 124

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Table 1. Examples of physical properties that may differ among different morphic forms (9) 126

1. Packing properties 127

a. Molar volume and density 128

b. Refractive index 129

c. Conductivity (electrical and thermal) 130

d. Hygroscopicity 131

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2. Thermodynamic properties 133

a. Melting and sublimation temperatures 134

b. Internal energy (i.e. structural energy) 135

c. Enthalpy (i.e. heat content) 136

d. Heat capacity 137

e. Entropy 138

f. Free energy and chemical potential 139

g. Thermodynamic activity 140

h. Vapour pressure 141

i. Solubility 142

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3. Spectroscopic properties 144

a. Vibrational transitions (i.e. infrared absorption spectra and Raman spectra) 145

b. Rotational transitions (i.e. far infrared or microwave absorption spectra) 146

c. Nuclear spin transitions (i.e. solid state nuclear magnetic resonance spectra) 147

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4. Kinetic properties 149

a. Dissolution rate 150

b. Rates of solid state reactions 151

c. Stability 152

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5. Surface properties 154

a. Surface-free energy 155

b. Interfacial tensions 156

c. Habit (i.e. shape) 157

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6. Mechanical properties 159

a. Hardness 160


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b. Tensile strength 161

c. Compatibility, tableting 162

d. Handling, flow, and blending 163

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Table 2 summarizes some of the most commonly used techniques to study and/or classify 165

different morphic forms of substances. These techniques are often complementary and it is 166

indispensable to use several of them. 167

Any method(s) chosen to confirm the identity of the specific form(s) must be validated to 168

show the method is suitably specific for the identification of the desired form(s). 169

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Table 2. Examples of some techniques that may be used to study and/or classify different 171

crystalline forms of substances 172

1. X-ray powder diffraction 173

2. Single crystal X-ray diffraction 174

3. Microcalorimetry 175

4. Thermal analysis (1.2.1 Melting point,* differential scanning calorimetry, 176

thermogravimetry, thermomicroscopy) 177

5. Moisture sorption analysis 178

6. Microscopy (electronic and optical) 179

7. Solid-state nuclear magnetic resonance; 180

8. Solubility studies 181

9. Spectrophotometry in the infrared region (1.7)* 182

10. Intrinsic dissolution rate 183

11. Density measurement 184

* Methods employed by The International Pharmacopoeia 185

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When a substance shows polymorphism the form with the lowest enthalpy at a given 187

temperature and pressure is the most thermodynamically stable. The other forms are said to 188

be in a metastable state. At normal temperature and pressure a metastable form may remain 189

unchanged or may change to a thermodynamically more stable form. 190

Polymorphism, amorphism and pseudopolymorphism (or solvatomorphism) of APIs and 191

excipients are of interest, as they may affect the bioavailability, suitability for manufacturing 192

of solid dosage forms and thermodynamic stability of the polymorphic form included in the 193

solid dosage form. Control of the morphic form by the manufacturer is necessary during the 194

processing of APIs and excipients and during the manufacturing of a dosage form to ensure 195

the correct physical characteristics thereof. The control of a specific morph is especially 196

critical in the areas where the bioavailability and stability are directly impacted. 197

The morphic form of a readily soluble starting material that is incorporated into a solution, 198

for example, an injection, an oral solution or eye drops, is normally non-critical (an exception 199

to this statement might be if the concentration of the solution is such that it is close to the 200

limit of solubility of one of the possible polymorphs). Similarly, if the API is processed 201

during the manufacturing process to obtain an amorphous form (e.g. hot melt extrusion), the 202

original form is considered non-critical. 203

The morphic form may be critical when the material is included in a solid dosage form or as a 204

suspension in a liquid dosage form when the characteristics of the different polymorphs are 205

such as to affect the bioavailability or dissolution of the material (10). The polymorphic form 206

of a biopharmaceutical classification system (BCS) class I or III API in a solid oral dosage 207

form is normally non-critical in terms of dissolution rate or bioavailability. 208

The inclusion of potentially harmful solvents in the crystal lattice which may render APIs or 209

excipients to be toxic or harmful to patients (i.e. solvates) should also be suitably regulated 210

and monitored by the manufacturer. 211

Where a monograph indicates that a substance shows polymorphism this may be true crystal 212

polymorphism, occurrence of solvates, allotropy or occurrence of the amorphous form. Due 213

to the identical chemical composition of the polymorphic substance it will have the same 214

chemical behaviour in solution, irrespective in the form in which it is presented. 215

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The International Pharmacopoeia controls the morphic forms of a limited number of 218

substances by restricting it to either: 219

i) a single form, for example, Carbamazepine API (Anhydrous Form III), 220

Mebendaozle API (Form C); or 221

ii) by limiting the presence of unwanted morphic forms, for example, 222

Chloramphenicol palmitate API (should contain at least 90% of polymorph B). 223

The control of morphic forms may be achieved by: 224

i) permitting no deviation from the infrared absorption spectrum of the reference 225

substance prescribed (or reference spectrum supplied) – when the infrared 226

absorption spectrum has been validated to be specific to the preferred form and 227

able to distinguish the undesired form(s), for example, Indomethacin API; 228

ii) restricting the melting point range, for example, Phenobarbital API; 229

iii) recommending the use of any other suitable methods such as X-ray powder 230

diffractometry, for example, Carbamazepine tablets; 231

iv) limiting the incorporated solvent (in the case of solvatomorphs) with a specific 232

limit test, for example, Nevirapine hemihydrate API. 233

In the instance where polymorphism may be present the user will be able to deduce this from 234

the infrared identification test (if infrared spectrophotometry is suitable for the detection of 235

differences in morphic forms of the specific compound) where the user may be instructed to: 236

i) recrystallize both the test substance and the specified reference substance, in the 237

event where the infrared spectra are found to be not concordant, for example, 238

Fluconazole API; and/or 239

ii) dry the API and/or specified reference substance to ensure that both forms are in 240

the anhydrous or dehydrated state, for example, Nevirapine hemihydrate API. 241

In the event where the choice of a specific morphic form is critical with regard to 242

bioavailability and/or stability, the method of the manufacture of the product should ensure 243

the presence of desired polymorph in the final product. The Secretariat will include a 244

statement under the heading “Manufacturing” to draw attention to the control of a specified 245


morphic form during manufacture where control is known to be critical, for example, 246

Carbamazepine oral suspension. 247

It is the intention of The International Pharmacopoeia to extend the inclusion of explicit 248

statements in monographs, where appropriate, as information on the occurrence of 249

polymorphism becomes available. The Secretariat thus cordially invites the users of The 250

International Pharmacopoeia and manufacturers to share such information that could be 251

included in the monographs if considered being appropriate. 252

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BIBLIOGRAPHY 254

1. Gaskell DR, 2005. Allotropy and Polymorphism. Reference Module in Materials 255

Science and Materials Engineering. Encyclopedia of Condensed Matter Physics, 8 – 256

17. 257

2. Brittain HG, 2007. Polymorphism and solvatomorphism 2005. Journal of 258

Pharmaceutical Sciences, 96(4):705-728. 259

3. Pienaar EW, 1994. Characterisation of anhydrous and monohydrous crystal forms of 260

nitrofurantoin. Potchefstroom: PU vir CHO. (Tesis – D.Sc.) 196p. 261

4. Bettinetti G, Sorrenti M, Catenacci L, Ferrari F and Rossi S, 2006. Polymorphism, 262

pseudopolymorphism, and amorphism of peracetylated α-, β-, and γ-cyclodextrins. 263

Journal of Pharmaceutical and Biomedical Analysis, 41:1205-1211. 264

5. Bauer J, Morley J, Spanton S, Leusen FJJ, Henry R, Hollis S, Heitmann W, Mannino 265

A, Quick J and Dziki W, 2006. Identification, preparation and characterization of 266

several polymorphs and solvates of terazosin hydrochloride. Journal of 267


6. Byrn S, Pfeifer M, Ganey M, Hoiberg C. and Poochikian G, 1995. Pharmaceutical 269

solids: a strategic approach to regulatory considerations. Pharmaceutical Research, 270

12(7):945-954. 271

7. Peterson ML, Hickey MB, Zaworotko MJ and Almarsson Ö, 2006. Expanding the 272

scope of crystal form evaluation in pharmaceutical science. Journal of 273


8. Brits M, 2008. Solid-state properties of pharmaceuticals. Potchefstroom: PU for 275

CHO (now known as North-West University). (Thesis – Ph.D.) 549p. 276

9. Grant DJW, 1999. Theory and Origin of Polymorphism. (In Brittain. H.G, ed. 277

Polymorphism in Pharmaceutical Solids). New York, Basel: Marcel Dekker Inc. 278

427p. 279

10. British Pharmacopoeia Commission, 2017. SC I B. Polymorphism. In: British 280

Pharmacopoeia Commission. British Pharmacopoeia 2017. Supplementary chapter. 281

London: TSO. 282

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