TUCr MONOGRAPHS ON €
`
`TALLOGRAPHY- 14
`
`JOEL BERNSTEIN
`
`INTERNATION
`
`-1-
`
`Gilead 2007
`I-MAK v. Gilead
`IPR2018-00126
`
`Gilead 2007
`I-MAK v. Gilead
`IPR2018-00126
`
`

`

`I N T E R NAT I O NAL U N I O N O F C RYS TALLO G RAPHY
`B O O K S E R I E S
`
`I U C r B O O K S E R I E S C O M M I TT E E
`
`E. N. Baker, New Zealand
`J. Bernstein, Israel
`G. R. Desiraju, India
`A. M. Glazer, UK
`J. R. Helliwell, UK
`P. Paufler, Germany
`H. Schenk, (Chairman), The Netherlands
`
`Page 2 of 81
`
`

`

`6
`
`13
`
`IUCr Monographs on Crystallography
`1 Accurate molecular structures
`A. Domenicano, I. Hargittai, editors
`2 P. P. Ewald and his dynamical theory of X-ray diffraction
`D. W. J. Cruickshank, H. J. Juretschke, N. Kato, editors
`3 Electron diffraction techniques, Vol. 1
`J. M. Cowley, editor
`4 Electron diffraction techniques, Vol. 2
`J. M. Cowley, editor
`5 The Rietveld method
`R. A. Young, editor
`Introduction to crystallographic statistics
`U. Shmueli, G. H. Weiss
`7 Crystallographic instrumentation
`L. A. Aslanov, G. V. Fetisov, G. A. K. Howard
`8 Direct phasing in crystallography
`C. Giacovazzo
`9 The weak hydrogen bond
`G. R. Desiraju, T. Steiner
`10 Defect and microstructure analysis by diffraction
`R. L. Snyder, J. Fiala and H. J. Bunge
`11 Dynamical theory of X-ray diffraction
`A. Authier
`12 The chemical bond in inorganic chemistry
`I. D. Brown
`Structure determination from power diffraction data
`W. I. F. David, K. Shankland, L. B. McCusker, and Ch. Baerlocher, editors
`14 Polymorphism in molecular crystals
`J. Bernstein
`15 Crystallography of modular materials
`G. Ferraris, E. Makovicky, S. Merlino
`16 Diffuse x-ray scattering and models of disorder
`T. R. Welberry
`17 Crystallography of the polymethylene chain: an inquiry into the structure of waxes
`D. L. Dorset
`18 Crystalline molecular complexes and compounds: structure and principles
`F. H. Herbstein
`19 Molecular aggregation: structure analysis and molecular simulation of crystals and liquids
`A. Gavezzotti
`20 Aperiodic crystals: from modulated phases to quasicrystals
`T. Janssen, G. Chapuis, M. de Boissieu
`Incommensurate crystallography
`S. van Smaalen
`
`21
`
`IUCr Texts on Crystallography
`1 The solid state
`A. Guinier, R. Julien
`4 X-Ray charges densities and chemical bonding
`P. Coppens
`5 The basics of crystallography and diffraction, second edition
`C. Hammond
`6 Crystal structure analysis: principles and practice
`W. Clegg, editor
`7 Fundamentals of crystallography, second edition
`C. Giacovazzo, editor
`8 Crystal structure refinement: a crystallographer’s guide to SHELXL
`P. Müller, editor
`9 Theories and techniques of crystal structure determination
`U. Shmueli
`10 Advanced structural inorganic chemistry
`Wai-Kee Li, Gong-Du Zhou, Thomas Mak
`
`Page 3 of 81
`
`

`

`Polymorphism in
`Molecular Crystals
`
`J O E L B E R N S T E I N
`
`Department of Chemistry
`Ben-Gurion University of the Negev
`
`C L A R E N D O N P R E S S • O X F O R D
`2002
`
`Page 4 of 81
`
`

`

`3
`
`Great Clarendon Street, Oxford OX2 6DP
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`
`Published in the United States
`by Oxford University Press Inc., New York
`© Oxford University Press, 2002
`The moral rights of the author have been asserted
`Database right Oxford University Press (maker)
`First published 2002
`First published in paperback 2008
`All rights reserved. No part of this publication may be reproduced,
`stored in a retrieval system, or transmitted, in any form or by any means,
`without the prior permission in writing of Oxford University Press,
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`outside the scope of the above should be sent to the Rights Department,
`Oxford University Press, at the address above
`You must not circulate this book in any other binding or cover
`and you must impose this same condition on any acquirer
`British Library Cataloguing in Publication Data
`Data available
`Library of Congress Cataloging in Publication Data
`Bernstein, Joel.
`Polymorphism in molecular crystals / Joel Bernstein.
`(IUCr monographs on crystallography; 14)
`Includes index.
`1. Polymorphism (Crystallography) 2. Molecular crystals. I. Title. II. International
`Union of Crystallography monographs on crystallography; 14.
`(cid:2)
`QD951 .B57 2002
`548
`.3—dc21
`2001047556
`Typeset by
`Newgen Imaging Systems (P) Ltd., Chennai, India
`Printed in Great Britain
`on acid-free paper by
`Biddles Ltd., King’s Lynn, Norfolk
`
`ISBN 978–0–19–850605–8 (Hbk.)
`ISBN 978–0–19–923656–5 (Pbk.)
`
`10 9 8 7 6 5 4 3 2 1
`
`Page 5 of 81
`
`

`

`1
`
`2
`
`Contents
`
`Colour plates can be found between pp. 114 and 115
`
`1.3
`
`Introduction and historical background
`1.1
`Introduction
`1.2
`Definitions
`1.2.1
`Polymorphism
`1.2.2
`Pseudopolymorphism, solvates, and hydrates
`1.2.3
`Conventions for naming polymorphs
`Is this material polymorphic?
`1.3.1
`Occurrence of polymorphism
`1.3.2
`Literature sources of polymorphic compounds
`1.3.3
`Polymorphic compounds in the Cambridge
`Structural Database
`Powder Diffraction File
`1.3.4
`Patent literature
`1.3.5
`Polymorphism of elements and inorganic compounds
`1.3.6
`Polymorphism in macromolecular crystals
`1.3.7
`Historical perspective
`Commercial/industrial importance of polymorphism—some
`additional comments
`
`1.4
`1.5
`
`Fundamentals
`2.1
`Introduction
`2.2
`Thermodynamics of polymorphic molecular crystals
`2.2.1
`The Phase Rule
`2.2.2
`Thermodynamic relations in polymorphs
`2.2.3
`Energy vs temperature diagrams—the Gibbs free energy
`2.2.4
`Enantiotropism and monotropism
`2.2.5
`Phase diagrams in terms of pressure and temperature
`2.2.6
`Heat-of-transition rule
`2.2.7
`Heat-of-fusion rule
`2.2.8
`Entropy-of-fusion rule
`2.2.9
`Heat-capacity rule
`2.2.10 Density rule
`2.2.11
`Infrared rule
`Kinetic factors determining the formation of
`polymorphic modifications
`Structural fundamentals
`2.4.1
`Form vs habit
`
`2.3
`
`2.4
`
`Page 6 of 81
`
`1
`1
`2
`2
`4
`8
`9
`9
`10
`
`15
`17
`17
`17
`18
`19
`
`27
`
`29
`29
`29
`29
`31
`32
`34
`35
`38
`38
`40
`40
`40
`41
`
`42
`45
`46
`
`

`

`xii
`
`3
`
`C O N T E N T S
`
`2.4.2
`
`2.4.3
`
`Structural characterization and comparison of
`polymorphic systems
`Presentation of polymorphic structures for comparison
`
`Controlling the polymorphic form obtained
`3.1
`General considerations
`3.2
`Aggregation and nucleation
`3.3
`Thermodynamic vs kinetic crystallization conditions
`3.4
`Monotropism, enantiotropism, and
`crystallization strategy
`Concomitant polymorphs
`3.5.1
`Crystallization methods and conditions
`3.5.2
`Examples of different classes of compounds
`3.5.3
`The structural approach
`Disappearing polymorphs
`Control of polymorphic crystallization by design
`
`3.6
`3.7
`
`3.5
`
`4 Analytical techniques for studying and
`characterizing polymorphs
`4.1
`Introduction
`4.2
`Optical/hot stage microscopy
`4.3
`Thermal methods
`4.4
`X-ray crystallography
`4.5
`Infrared spectroscopy
`4.6
`Raman spectroscopy
`4.7
`Solid state nuclear magnetic resonance (SSNMR)
`spectroscopy
`Scanning electron microscopy
`Atomic force microscopy (AFM) and
`scanning tunnelling microscopy (STM)
`4.10 Density measurements
`4.11 New technologies and ‘hyphenated techniques’
`4.12 Are two samples polymorphs of the same compound?
`4.13
`Concluding remarks
`
`4.8
`4.9
`
`5
`
`Conformational polymorphism: intra- and
`intermolecular energetics
`5.1
`Introduction
`5.2
`Molecular shape and energetics
`5.3
`Intermolecular interactions and energetics
`5.4
`The search for examples of conformational polymorphism
`5.5
`Presenting and comparing conformational polymorphs
`5.6
`Some examples of conformational polymorphism
`5.7 What are conformational polymorphs good for?
`
`Page 7 of 81
`
`49
`49
`
`66
`66
`67
`72
`
`74
`75
`76
`80
`86
`89
`92
`
`94
`94
`94
`104
`111
`125
`131
`
`133
`144
`
`146
`147
`147
`148
`149
`
`151
`151
`152
`152
`156
`157
`157
`164
`
`

`

`C O N T E N T S
`
`5.8
`
`5.9
`5.10
`
`Computational studies of the energetics of
`polymorphic systems
`Some exemplary studies of conformational polymorphism
`The computational prediction of polymorphs
`
`6.2.5
`
`6.2.6
`
`Polymorphism and structure–property relations
`6.1
`Introduction
`6.2
`Bulk properties
`6.2.1
`Electrical conductivity
`6.2.2
`Organic magnetic materials
`6.2.3
`Photovoltaicity and photoconductivity
`6.2.4
`Nonlinear optical activity and
`second harmonic generation
`Chromoisomerism, photochromism, thermochromism,
`mechanochromism, etc.
`Thermal phase changes and the thermosalient effect—
`‘hopping’ or ‘jumping’ crystals
`Molecular properties
`6.3.1
`Infrared and Raman spectroscopy
`6.3.2
`UV/Vis absorption spectroscopy
`6.3.3
`Excimer emission
`6.3.4
`Excited state diffraction studies
`Photochemical reactions
`Thermal reactions and gas–solid reactions
`Pressure studies
`Concluding remarks
`
`6.3
`
`6.4
`6.5
`6.6
`6.7
`
`7.3
`
`Polymorphism of pharmaceuticals
`7.1
`Introduction
`7.2
`Occurrence of polymorphism in pharmaceuticals
`7.2.1
`Drug substances
`7.2.2
`Excipients
`Importance of polymorphism in pharmaceuticals
`7.3.1
`Dissolution rate and solubility
`7.3.2
`Bioavailability
`Microscopy and thermomicroscopy of pharmaceuticals
`Thermal analysis of pharmaceuticals
`The importance of metastable forms
`The importance of amorphous forms
`Concluding remarks
`
`7.4
`7.5
`7.6
`7.7
`7.8
`
`Polymorphism of dyes and pigments
`8.1
`Introduction
`8.2
`Occurrence of polymorphism among pigments
`8.3
`Polymorphism in some specific groups of pigments
`
`Page 8 of 81
`
`6
`
`7
`
`8
`
`xiii
`
`165
`169
`182
`
`188
`188
`189
`189
`197
`204
`
`207
`
`213
`
`223
`223
`224
`225
`231
`234
`234
`237
`238
`239
`
`240
`240
`241
`241
`242
`243
`243
`244
`249
`250
`251
`253
`255
`
`257
`257
`259
`259
`
`

`

`xiv
`
`9
`
`C O N T E N T S
`
`Quinacridones
`8.3.1
`Perylenes
`8.3.2
`Phthalocyanines
`8.3.3
`Some other pigments—old and new
`8.3.4
`Isomorphism of pigments
`
`8.4
`
`Polymorphism of high energy materials
`9.1
`Introduction
`9.2
`The ‘alphabet’ of high energy molecular materials
`9.3
`Individual systems
`9.3.1
`Aliphatic materials
`9.3.2
`Aromatic materials
`
`10 Polymorphism and patents
`10.1
`Introduction
`10.2
`Ranitidine hydrochloride
`10.3
`Cefadroxil
`10.4
`Terazosin hydrochloride
`10.5 Aspartame
`10.6
`Concluding remarks
`
`References
`
`Index
`
`259
`263
`264
`270
`271
`
`275
`275
`276
`278
`278
`287
`
`297
`297
`298
`301
`304
`305
`307
`
`308
`
`401
`
`Page 9 of 81
`
`

`

`IS THIS MATERIAL POLYMORPHIC?
`
`9
`
`encouraged. For those studying (and naming) polymorphic systems it is important to
`be fully aware of previous work, to try to identify the correspondence between their
`own polymorphic discoveries and those of earlier workers, and to avoid flippancy in
`the use of nomenclature in the naming of truly new polymorphs.
`
`1.3 Is this material polymorphic?
`
`1.3.1 Occurrence of polymorphism
`Perhaps the most well-known statement about the occurrence of polymorphism is
`that of McCrone (1965): ‘It is at least this author’s opinion that every compound has
`different polymorphic forms and that, in general, the number of forms known for a
`given compound is proportional to the time and money spent in research on that com-
`pound.’ As a corollary to this rather sweeping, even provocative, statement, McCrone
`noted that ‘all the common compounds (and elements) show polymorphism’, and he
`cited many common organic and inorganic examples.
`These echo similar statements by Findlay (1951) p. 35, ‘[polymorphism] is now
`recognized as a very frequent occurrence indeed’, Buerger and Bloom (1937), ‘poly-
`morphism is an inherent property of the solid state and that it fails to appear only
`under special conditions’, and Sirota (1982), ‘[polymorphism] is now believed to be
`characteristic of all substances, its actual non-occurrence arising from the fact that a
`polymorphic transition lies above the melting point of the substance or in the area of
`yet unattainable values of external equilibrium factors or other conditions providing
`for the transition.’
`Such statements tend to give the impression that polymorphism is the rule rather
`than the exception. The body of literature in fact indicates that caution should be
`exercised in making them. It appears to be true that instances of polymorphism are
`not uncommon in those industries where the preparation and characterization of solid
`materials are integral aspects of the development and manufacturing of products (i.e.
`those on which a great deal of time and money is spent): silica, iron, calcium sili-
`cate, sulphur, soap, pharmaceutical products, dyes, and explosives. Such materials,
`unlike the vast majority of compounds that are isolated, are prepared not just once, but
`repeatedly, under conditions that may vary slightly (even unintentionally) from time to
`time. Similarly, in the attempt to grow crystals of biomolecular compounds, much time
`and effort is invested in attempts to crystallize proteins under carefully controlled and
`slightly varying conditions, and polymorphism is frequently observed (Bernstein et al.
`1977; McPherson 1982). Even with the growing awareness and economic importance
`of polymorphism, most documented cases have been discovered by serendipity rather
`than through systematic searches. Some very common materials, such as sucrose and
`naphthalene, which certainly have been crystallized innumerable times, have not been
`reported to be polymorphic. The possibility of polymorphism may exist for any par-
`ticular compound, but the conditions required to prepare as yet unknown polymorphs
`are by no means obvious. There are as yet no comprehensive systematic methods
`for feasibly determining those conditions. Moreover, we are almost totally ignorant
`about the properties to be expected from any new polymorphs that might be obtained.
`
`Page 10 of 81
`
`

`

`10
`
`I N T R O D U C T I O N A N D H I S T O R I C A L B A C K G R O U N D
`
`With the growing awareness among chemists of the phenomenon of polymorphism
`its actual occurrence in any particular system may not be as great a surprise as a
`generation or two ago. The predicted existence of any particular polymorphic structure
`for a single compound, the conditions and methods required to obtain it, and the
`properties it will exhibit are still problems that will challenge researchers for many
`years to come.2
`
`1.3.2 Literature sources of polymorphic compounds
`As noted in the previous section, the phenomenon of polymorphism is not new
`to chemistry. Nineteenth century chemists were very much aware of the prop-
`erties of solids, and in the decades preceding the development of spectroscopic
`and X-ray crystallographic methods, the characterization of solids was a crucial
`aspect of the identification of materials. Chemists grew crystals carefully in order
`to obtain characteristic morphologies and then determined physical properties such
`as colour, interfacial angle, indices of refraction, melting point, and even taste
`(e.g. Schorlemmer 1874; Senechal 1990; Kahr and McBride 1992). Being critically
`observant was essential, for there was little other information to rely on.
`A great deal of information on crystalline properties, including polymorphism
`was summarized in the five-volume compendium covering over 10 000 compounds
`by Groth, published between 1906 and 1919. The first two of these volumes (Groth
`1906b, 1908) deal with elements and inorganic compounds, while the last three (Groth
`1910, 1917, 1919) are concerned with organic materials. The genesis of this opus is
`vividly described by Ewald (1962):
`‘Groth’s most stupendous work was the Chemische Kristallographie, five volumes which
`appeared between 1906 and 1919, comprising in toto 4208 pages and 3342 drawings and
`diagrams of crystals. The manuscript was written entirely by Groth in his fine hand and corrected
`over and over again by him until there was hardly a white spot left on the manuscript and again
`on the galley proofs. Oh for the admirable compositors in the Leipzig printing centres in the
`days before the general use of typewriters! The volumes contain a review of all crystallographic
`measurements . . . Each section is preceded by a survey of the crystal–chemical relations and
`includes many hints of gaps which should be filled by further work. In many instances Groth
`doubted the correctness of the work reported in the literature, and wherever possible, he got
`his pupils, assistants, or visiting colleagues to prepare the same substances again, and to
`recrystallize and remeasure them . . . Altogether measurements on between 9000 and 10 000
`
`2 While perhaps anecdotal, the following appears to be a good measure of the state of our knowledge
`about the ‘pervasiveness’ of polymorphism. In assigning a research project to a graduate student, a research
`advisor assumes a certain risk that the project will not succeed. One could imagine as a perfectly reasonable
`project the assignment to prepare and characterize the polymorphic forms of a single compound of interest,
`which is, of course, the practical manifestation of all four quotations at the start of this section. Unexpected
`results can constitute the basis for a Ph.D. thesis, but the absence of results, that is the inability to obtain
`any polymorphs, would constitute a total failure of project. This author has yet to encounter an academic
`research advisor who would be prepared to take the responsibility of assigning such a research project to a
`Ph.D. student. That is, in spite of the hyperbole of McCrone’s statement and the notoriety it has received,
`and the increasing importance of polymorphism in the market place, there is not sufficient confidence in
`its veracity to risk the career of a student on any single particular compound.
`
`Page 11 of 81
`
`

`

`IS THIS MATERIAL POLYMORPHIC?
`
`11
`
`are critically discussed in Chemische Kristallographie, an astounding feat considering the small
`number of the team . . .’
`
`The work thus contains a thorough, checked survey of the physical properties of
`many of the crystals that had been studied up to its publication. Typical pages of the
`‘crystal–chemical relations’ for dimorphic diphenyl malonic anhydride are shown in
`Fig. 1.1, in which the methods for obtaining both structures are described. A few
`pages on appear the entries for the description of crystal habit, melting point, solvent,
`appropriate reference(s), interfacial angles, and indices of refraction, if reported in
`the literature. Many of the substances had been reported to be polymorphic, and
`Groth recorded those facts, along with methods for preparing the polymorphs and
`the original literature references. It is a remarkable work, and one which should be
`consulted to check for the existence of polymorphism in a specific material, as well
`as for the source of physical phenomena, once observed, but since forgotten.
`A second rich collection of references on the polymorphic behaviour of organic
`materials is the compilation by Deffet (1942). This contains information and
`references to primary sources on 1188 substances that exhibit polymorphism at
`atmospheric pressure and another 32 that exhibit polymorphic behaviour at elevated
`pressures. A typical entry contains the number of reported polymorphic forms, their
`melting points, temperature(s) of transition, crystal system, some physical properties,
`and literature references, of which there are nearly 1000. Substances are organized
`by empirical formula with an index organized by compound name (in French).
`A third compilation intended to be devoted to polymorphic materials is that of
`Kuhnert-Brandst¨atter (1971). The body of this book is an identification table for
`hot stage studies of pharmaceutical materials (see Sections 4.2 and 7.2), in which
`materials are arranged by increasing melting point, with eutectic data for mixtures
`with azobenzene and benzil. There is considerable descriptive detail on the melt-
`ing behaviour and identification and description of polymorphic forms, albeit only
`microscopic determinations, for approximately 1000 pharmaceutically important
`
`Fig. 1a
`
`Page 12 of 81
`
`

`

`
`C.C.H;.
`Diphenylmaleinséureanhydrid = (,H;.¢
`co.0.co
`
`Stabile Modification.
`
`Fig. 2576,
`
`Fig. 2575.
`
`
`
`Schmelzpunkt 155°.
`Spec. Gew. 1,340 Drugman*).
`Rhombisch bipyramidal.
`@ib:¢ = 0,8476 24: 6,7094 Drugman44),
`Aus Aceton entsteht die Combination (Fig. 2878): m{4410}, of444}, 7 {014},
`ebenso aus Benzol, Chloroform, Ather und Alkohol, aus letzterem nach der
`c-Axe diinn nadelférmig. Einmal wurden
`aus Aceton kleine oktaéderahnliche Kry-
`stalle
`erhalten,
`die nur m{440} und
`g{014} zeigten;
`aus etwas harzhaltiger
`Lésung wurden Combinationen mit unter-
`geordneten Flachen von «{412}, {122},
`c{o01} und
`4{040} beobachtet.
`Die
`Krystalle aus Toluol zeigen die Formen
`(Fig. 2876): m{110}, {oat}, S{oroh,
`untergeordnet: g{014}, c{001}, seltener
`o{144}; die hier vorhandene Verlangerung
`nach der a-Axe tritt noch mehr hervor
`an den Krystallen aus Xylol, welche die-
`selben Formen, aber mit besser ausgebil-
`detem o{111}, zeigen. Eine solche nach der @-Axe prismatische Combination
`mit untergeordnetem @{100} hatte frither bereits Jenssen‘) (1. c. 64) an den
`von Anschiitz und Bendix aus Ather erhaltenen Krystallen beobachtet,
`ihr
`aber eine andere Aufstellung gegeben.
`Berechnet:
`
`mim=(A10): (110) = —
`gig =(041):(011} = —
`oro == (Alt): TA) = 45°14
`org = (441): (041) = 48
`0
`orm == (141): (110) = 33 12
`ovma=(iti): (410) — 61
`64
`gim == (0141): (440) = 74 41
`ki b = (024): (010) = 35 27
`kim ==({021):(410) = 68
`of
`wro == (442): (441) = 19 28
`wig == (142): (011) = 37 23
`yig == (122):(044) == 29
`2h
`
`Beobachtet:
`Drugman:
`Jenssen:
`54° Rd!
`34° 49"
`*70 40
`—
`45 13
`—
`48
`—
`33 415
`—
`61
`7
`—
`Th 42
`—
`35
`5 ca.
`34 43
`67 BB
`>
`67 49
`49 13
`_
`37 24
`—
`a9
`94
`_
`
`Keine deutliche Spaltbarkeit.
`Doppelbrechung positiv; Axenebene a{100},
`winkel klein.
`
`1. Mittellinie Axe ¢; Axen-
`
`Lz,
`a= 1,508
`B= 1,B0Bca.>
`y= 4,841
`>
`
`1,541 Ma,
`41,5145 >
`1,836
`»
`
`77 (alle optischen Angaben von
`1,517
` 1,B18ca. »
`Drugman).
`1,865
`»
`
`44: Drugman, Zeitschr.
`
`f. Krystall. 1912, 560, 576.
`
`Fig. 1b
`Fig. 1b
`
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`Page 13 of 81
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`Fig. 1c
`Fig. 1.1 A typical entry from Groth’s Chemische Kristallographie. (a) Textual description of
`the dimorphic diphenyl maleic anhydride. (b) Physical data for the stable modification melting
`C. (c) Physical data for the metastable modification melting at 146 ◦
`at 155 ◦
`C.
`
`compounds. There is no formula index, and the subject index contains only a par-
`tial listing of the compounds included. Nevertheless, the book contains some very
`useful information about the existence of polymorphism and the characterization of
`its behaviour in many of these commercially important materials. In this context, it
`is perhaps noteworthy that the 1997 edition of the Merck Index describes polymor-
`phic behaviour for only 140 of over 10 000 entries, many of which appear in the
`Kuhnert-Brandst¨atter compilation.
`There are a number of additional sources for consultation on information on poly-
`morphism of particular compounds. From 1948 to 1961, McCrone edited a regular
`column in Analytical Chemistry entitled ‘Crystallographic Data’, in which were pub-
`lished the details on crystal growth, physical properties, and polymorphic behaviour
`of approximately 200 compounds. The series was undertaken at the time ‘because
`optical crystallography is neglected as an analytical tool because too few compounds
`have been described’, and with the desire to ‘. . .initiate a process which [would]
`enable a group of crystallographers to complete the tabulation of crystal data for most
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`I N T R O D U C T I O N A N D H I S T O R I C A L B A C K G R O U N D
`
`of the common everyday compounds.’ (Grabar and McCrone 1950). About 140 of
`these were organic compounds, and 25 per cent of these exhibited polymorphism.
`Even in the cases where there is no evidence of polymorphism, these reports contain
`detailed descriptions of conditions for growth of crystals with well-defined faces,
`and the characterization of crystal habit very much in the tradition of Groth. It is
`information that future investigators will be able to utilize for a variety of studies.
`The need for recording the detailed description of crystal growth, crystal habit, and
`crystal properties was recently echoed in an appeal by Dunitz (1995) to authors of
`crystallographic structure analyses:
`. . . please give the color (easy to observe) and melting point of crystals studied (easy to mea-
`sure); if possible, also the heat of fusion and of any observed phase transitions (only slightly
`more difficult to measure): report also any ‘unusual’ behavior, any observed change of physical
`properties or of the diffraction pattern.
`
`The short reports solicited and edited by McCrone are models of the kind of data
`which should be required and included in descriptions of crystals and crystal structure
`reports, even if only in deposited form (Section 1.3.3).
`Some additional literature sources should also be consulted to check for earlier
`reports of polymorphism. The Barker Index (Porter and Spiller 1951, 1956; Porter
`and Codd 1963) made use of the characteristic interfacial angles for purposes of iden-
`tification of crystals. The Index is based on Groth’s earlier compilation (which is
`organized by chemical composition) and is arranged by increasing interfacial angle
`within a crystal system. There are some additional compounds, with totals of 2991
`in tetragonal, trigonal, and orthorhombic space groups (Volume I) (Porter and Spiller
`1951), 3572 in monoclinic (Volume II) (Porter and Spiller 1956), and 871 in tri-
`clinic (Volume III) (Porter and Codd 1963), space groups. However, the method of
`arrangement means that polymorphs of a compound crystallizing, say, in monoclinic
`and orthorhombic space groups, requires that the compound be checked in all three
`volumes.
`Another approach was taken by Winchell (1943, 1987), who prepared a com-
`pilation of ‘all organic compounds whose optical properties are sufficiently well
`known to permit identification by optical methods’. The compilation is arranged
`in the same fashion as the fourth edition of Beilstein’s Handbuch der organischen
`Chemie (Beilstein 1978), and at the time of its first publication was meant to include
`all organic compounds whose indices of refraction had been measured. Since indices
`of refraction differ among them, polymorphs could be easily recognized by different
`optical properties. The book does contain references to primary sources and drawings
`of crystals, as illustrated in a typical entry Fig. 1.2.
`Another useful compilation of crystallographic data as a source of examples of poly-
`morphic systems, NIST Crystal Data (NIST 2001; Mighell and Stalick 1983), which
`contains the principal crystallographic data on over 237 000 organic and organometal-
`lic entries. Each entry contains cell constants, space group, and other crystallographic
`information and bibliographic citations. In some cases the fact that a crystalline
`compound is one of a polymorphic system is specifically noted. In other cases the
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`Fig. 1.2 Typical entry from Winchell’s Optical Properties of Organic Crystals for dimorphic
`p-methylbenzophenone (reproduced, with permission).
`
`polymorphism may be recognized by the fact that a compound has more than one
`entry either in the formula index or the compound name index.
`In addition to these compilations of crystal data in which instances of polymorphism
`may be recorded, a number of texts on the subject of the solid state properties of
`organic compounds contain many examples of polymorphism. Since these books are
`based in part, at least, on work by the authors not published elsewhere, they may be
`considered as primary literature sources. Particularly noteworthy in this regard are
`the books by Pfeiffer (1922), Kofler and Kofler (1954), and McCrone (1957).
`The usual search strategies for information on the preparation and properties, such
`as Chemical Abstracts and Beilstein can also be useful for determining if a particular
`compound has been reported to be polymorphic. However, reference to the primary
`sources on the preparation and the characterization of the compound may reveal
`unusual behaviour (e.g. melting points or colours which differed from one crystal-
`lization to the next) which testifies to the possible existence of polymorphic forms,
`behaviour that is not specifically noted in the abstracted material.
`
`1.3.3 Polymorphic compounds in the Cambridge Structural Database
`The Cambridge Structural Database (CSD) is the repository for the results obtained
`from the X-ray crystal structure analysis of organic and organometallic compounds
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`I N T R O D U C T I O N A N D H I S T O R I C A L B A C K G R O U N D
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`(Allen et al. 1991; Allen and Kennard 1993; Kennard 1993; Allen et al. 1994). The
`October 2000 release of the data base contains over 240 000 entries, and as of this
`date approximately 20 000 structures are added annually. It is now also serving as a
`depository for crystallographic data that may not be published elsewhere. In the past
`three decades the database has increasingly influenced the way structural chemists
`carry out their trade. An enormous amount of geometric and structural information
`is available in a very short time for searches, correlations, model compounds, pack-
`ing arrangements, reaction coordinates, hydrogen-bonding patterns, and a variety of
`studies. The rapid increase in the data availability which has been accompanied by
`increasingly sophisticated software has opened opportunities that could not have been
`imagined even a quarter of a century ago. Formerly accessible only on mainframes
`or work stations it has recently become available in a PC version on a CD-ROM.
`As the repository for all organic and organometallic crystal structures, the CSD
`naturally contains entries for polymorphic materials. As of the October 2000 release,
`approximately 5000–6000 compounds may possibly be classified as polymorphic (for
`details see Section 7.2.1). However, some words of caution are necessary in the use of
`these data. Each entry in the CSD contains 1D, 2D and 3D information. The 2D infor-
`mation is used to generate the structural formula and chemical connectivity, which
`clearly will be the same for polymorphs. The 3D information contains the results of
`the X-ray structure determination: cell constants, space group, atomic coordinates,
`and atomic attributes needed to generate the three-dimensional molecular and crystal
`structures. The 1D data contain bibliographical and chemical information (name and
`empirical formula), including qualifying phrase(s) such as ‘neutron study’, ‘absolute
`configuration’, etc. It is here that the CSD notes that the material is polymorphic
`with a qualifying phrase such as ‘red phase’, ‘metastable polymorph’, ‘Form II’ if the
`author of the primary publication noted this feature or if the abstractors recognized
`that the structure was one of a polymorphic system. In many cases note is taken of
`the fact that this is some special crystal form only when a second (or third, etc.)
`structure of a polymorphic series is being reported. The first report may not contain
`such a notation, since the author may not have been aware that the material is poly-
`morphic. (This may be the case for subsequent structure determinations as well. In
`the early days of the CSD some polymorphic structures were archived with different
`REFCODEs—the unique identifier for each chemical species. The more sophisticated
`archiving software used now prevents such duplication and has eliminated many of
`the older ‘orphans’, but some may still exist.) Once one member of a polymorphic
`set of structures has been identified care should be taken to extract all entries of that
`compound, including those not identified by appropriate descriptors. In short, the
`absence of a descriptor indicating that a material belongs to a polymorphic system
`is not a foolproof indication that the material is not polymorphic. Other literature
`sources should be consulted to make that determination.
`An example of the caution which must be exercised in performing such searches
`and the numbers obtained was given by Gavezzotti and Filippini (1995). The search
`was defined for organic compounds (containing only C, H, N, O, F, Cl, or S) and for
`which the crystal structures of more than one polymorphic form had been determined.
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`A total of 163 ‘clusters’ were obtained, where a cluster is a group of polymorphic
`crystal structures of the same compound. Of the 163 clusters, 147 contain