CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 1 2-4
PerspectiVe Pseudopolymorph: Retain This Widely Accepted Term Ashwini Nangia* School of Chemistry, UniVersity of Hyderabad, Hyderabad 500 046, India ReceiVed July 19, 2005; ReVised Manuscript ReceiVed October 25, 2005
Continuing the ongoing debate and discussion in Crystal Growth & Design1-3 on the use of the word pseudopolymorph, I argue in favor of retaining this term in the chemical literature. To summarize the debate thus far, Kenneth Seddon and Joel Bernstein feel that the words pseudopolymorph and pseudopolymorphism are incorrect and should not be used. Gautam Desiraju says that pseudopolymorphism still is the best of all possible names. My stand is that the meaning of these words are clear enough to a room full of researchers from several related fieldss crystal engineering, chemistry, pharmaceutical R&D, crystallography, materials science and biochemistry. Even if a different name is agreed upon (say solvate) through some consensus there is no guarantee that chemists will switch to that name because they are by now very familiar with the terms pseudopolymorph and pseudopolymorphism. The most important reason though for retaining the status quo is that polymorphs and pseudopolymorphs are now more than mere scientific terms: they have entered the legal lexicon in recent court battles involving major pharmaceutical companies. There is no shying away from the fact that the twin phenomena of polymorphism and pseudopolymorphism have gained in importance largely due to their impact in the development and patenting of drug substances4 (commonly called active pharmaceutical ingredients or APIs). I reproduce here my definitions5 of the above terms, which are a restatement of available definitions from the works of McCrone,6 Threlfall,7 and Bernstein.8 “Polymorph is a solid crystalline phase of a compound resulting from the possibility of at least two different arrangements of the molecules of that compound in the solid state....Pseudopolymorphs are crystals formed by the same substance crystallized with different amounts or types of solvent molecules.” Notwithstanding occasional scientific debates about exact definitions in a particular system of conformational, configurational, and/or concomitant polymorphs,9 these terms are by and large easily understood even by laypersons.10 Polymorphs and pseudopolymorphs have been central to a number of legal cases between innovator and generic drug companies. Take for example the blockbuster anti-depressant Paxil (paroxetine hydrochloride) with worldwide sales of US * To whom correspondence should be addressed. Tel.: +91 40 23011338. Fax: +91 40 23011338. E-mail:
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$4-5 billion per annum in 2003. Efforts by the innovator company GlaxoSmithKline to protect Paxil from generic competition were based on separate patents claiming anhydrous and hemihydrate forms of the same drug substance. What do these terms mean in the eyes of the law? The stand taken by one of the judges in SmithKline Beecham vs Apotex11 is reproduced here: “Polymorphs are distinct crystalline structures containing the same molecules. These structural differences can affect various properties of the crystals. The two forms of paroxetine hydrochloride were technically pseudopolymorphs, though pseudopolymorphs are often loosely called polymorphs (an apparently common looseness that the district court adopted and that I haVe retained in this opinion). Pseudopolymorphs not only have their molecules arranged differently but also have a slightly different molecular composition. A common type of pseudopolymorph is a solvate (emphasis added).” The issue of molecular composition has come up in scientific debate. Desiraju2 stated, “In multicomponent crystals, there are too many structural variations and the term polymorphism seems to be unnecessarily restrictive with regard to identity of chemical composition. It is in this context that the virtues of the term pseudopolymorphism need to be considered. This term brings to attention the fact that certain related multicomponent crystals, with slightly different chemical compositions or stoichiometries, have slightly different crystal structures in a manner reminiscent of polymorphism.” The above case is perhaps the first of many related patent litigations involving polymorphs and pseudopolymorphs. Bristol-Myers Squibb’s attempts to protect the antibiotic cefadroxil was based on whether its patented monohydrate is a transient intermediate in drug action on the way from the generic hemihydrate form. What does all this signify? The SmithKline Beecham vs Apotex judgment11 brings polymorphs and pseudopolymorphs closer together and suggests that pseudopolymorphs are a “kind of polymorph.” There are similar echoes in Desiraju’s perspective2 in which he says that solVate “does not show the resemblance of this situation to true polymorphism.” The same meaning given to polymorphs and pseudopolymorphs in patent litigation (within the loose definition) is corroborated by scientific results from leading research groups. Pseudopolymorphs behave like polymorphs in many wayssthey may be conformational, they appear concomitantly, they are grown
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Perspective
selectively by seeding, and a metastable kinetic pseudopolymorph will transform to the stable thermodynamic form of different stoichiometry.12 The last of these four situations often occurs spontaneously in hydrates. In such a background, any change in the name for pseudopolymorph is more than just a scientific decision because the consequences are far-reaching and the implications could be worth billions of dollars. Seddon1 suggested that we use the word solvate instead of pseudopolymorph. Bernstein3 suggests polymorphs of a solvate for two structures with identical stoichiometry but different crystal structures. The prefix pseudo makes one think that pseudopolymorph is a false polymorph and so one should look for alternative names. But there is a caveat to all of this. New terms, even if they are more precise in definition, are often not adopted by chemists. Take for instance our frequent usage of common names such as acetic acid, acrylic acid, ethyl alcohol, ether, etc. instead of their systematic IUPAC names. My guess is that the word pseudopolymorph will continue to appear in papers because we all know what it stands for and means. Chemists are by now just too familiar with it. The focus so far has been on whether to call a solid a pseudopolymorph or solvate. But there are many other terms out there! Inclusion compound, clathrate, host-guest, cocrystal, co-crystal, molecular complex.5 Do we abandon all these as well in favor of solVate? The distinction between a pseudopolymorph and a cocrystal seems only to have to do with the physical state of the isolated component used in cocrystallization: if the pure compound is a solid under ambient conditions then the resulting product is a cocrystal,13 whereas if it is a liquid we get a pseudopolymorph. Bernstein3 refers to this point, “The discussion of definitions will almost always degenerate to a debate on how to pigeonhole a particular situation that does not quite correspond to the strict definition.” This, I believe, is the real issue not just with pseudopolymorphs but also with several other terms in crystal engineering. We will not resolve these issues by removing the word pseudopolymorph or by calling it by another name. Exact definitions are all but impossible in chemistry, and working definitions should not be taken too literally.5 To add further weight to my arguments, I show that the meaning of pseudopolymorph is clearly understood and also adaptive to new situations being discovered. These are good reasons for a terminology to stay, and they also address Robin Rogers’ justified concerns on nomenclature.14 Adam Matzger used the word pseudopolymorphism in the title of his paper on two-dimensional crystallography and justifies this term (footnote 57):15 “Although numerous definitions have been offered for the term pseudopolymorphism, as reviewed by Bernstein,8 we use the definition from Nangia and Desiraju16 that refers to crystalline forms that differ in the nature or stoichiometry of included solvent molecules. Applying this definition to twodimensions implies that monolayers of a given compound that differ in stoichiometry with the surface are pseudopolymorphs.” Let me say then that pseudopolymorphs are well entrenched in scientific thinking and removing this name is not a good idea. I conclude with a reinterpretation of pseudopolymorphs in the modern context of supramolecular chemistry. Dunitz’s17 description of a crystal as “the supermolecule par excellence” is apt and on that basis, “If a crystal is a supermolecule then polymorphic modifications are superisomers and polymorphism is a kind of superisomerism.” So what are pseudopolymorphs? Pseudopolymorphs may be viewed as derivatives of a supermolecule with the solvent being the substituent group. Just as
Crystal Growth & Design, Vol. 6, No. 1, 2006 3
we have methyl, ethyl, i-propyl, t-butyl, nitro, ester, carboxylic acid, and hydroxyl derivatives of benzene, one has MeOH, EtOH, i-PrOH, t-BuOH, CH3NO2, EtOAc, AcOH, H2O pseudopolymorphs of a molecule or a drug substance. Applying this definition, the hundred or so pseudopolymorphs of sulfathiazole18 and its five polymorphs constitute a family of supermolecules. To use several names for the same phenomenon is not uncommon in nonscientific situations as well. ViVe la difference! What is a hurricane in America is a typhoon in China and a cyclone in India. References (1) Seddon, K. R. Pseudopolymorphism: A polemic. Cryst. Growth Des. 2004, 4, 1087. (2) Desiraju, G. R. Counterpoint: What’s in a name? Cryst. Growth Des. 2004, 4, 1089. (3) Bernstein, J. And another comment on pseudopolymorphism. Cryst. Growth Des. 2005, 5, 661. (4) Byrn, S. R.; Pfeiffer, R. R.; Stowell, J. G. Solid-state Chemistry of Drugs, 2nd ed.; SSCI Inc., West Lafayette, IN, 1999. (5) Nangia, A. Nomenclature in crystal engineering. In Encyclopedia of Supramolecular Chemistry; Atwood, J. L.; Steed, J. W., Eds.; Marcel Dekker: New York, 2004; Vol. 2, pp 967-972. (6) McCrone, W. C. Polymorphism. In Physics and Chemistry of the Organic Solid State; Fox, D.; Labes, M. M.; Weissberger, A., Eds.; Wiley-Interscience: New York, 1965; Vol. 2, pp 725-767. (7) Threlfall, T. Analysis of organic polymorphs. Analyst 1995, 120, 2435. (8) Bernstein, J. Polymorphism in Molecular Crystals; Oxford University Press: Oxford, 2002. (9) (a) Bilton, C.; Howard, J. A. K.; Madhavi, N. N. L.; Nangia, A.; Desiraju, G. R.; Allen, F. H.; Wilson, C. C. When is a polymorph not a polymorph? Helical trimer O-H‚‚‚O synthons in trans-1,4diethynylcyclohexane-1,4-diol. Chem. Commun. 1999, 1675. (b) Kumar, V. S. S.; Addlagatta, A.; Nangia, A.; Robinson, W. T.; Broder, C. K.; Mondal, R.; Evans, I. R.; Howard, J. A. K.; Allen, F. H. 4,4-Diphenyl-2,5-cyclohexadienone: Four polymorphs and nineteen crystallographically independent molecular conformations. Angew. Chem., Int. Ed. 2002, 41, 3848. (10) Rouhi, A. M. Crystallization: The right stuff. Chem. Eng. News, February 24, 2003, p 32. (11) Full text of the judgment in the United States Court of Appeals for the Federal Court may be downloaded from http://fedcir.gov/opinions/ 03-1285.pdf. (12) (a) Mondal, R.; Howard, J. A. K.; Banerjee, R.; Desiraju, G. R. Gauche and staggered forms of diethylamine in solvates of 1,5dichloro-cis-9,10-diethynyl-9,10-dihydroanthracene-9,10-diol. A case of conformational pseudopolymorphism? Chem. Commun. 2004, 644. (b) Ashmore, J.; Bishop, R.; Craig, D. C.; Scudder, M. L. Comparison of the X-ray crystal structures of concomitant pseudodimorphs formed between a diquinoline host and d-chloroform guest. MendeleeV Commun. 2003, 13, 144. (c) Yoshizawa, K.; Toyota, S.; Toda, F.; Chatziefthimiou, S.; Giastas, P.; Mavridis, I. M.; Kato, M. Control of differential inclusion complexation in the solid state by seed crystals. Angew. Chem., Int. Ed. 2005, 44, 5097. (d) Tanaka, K.; Wada, S.; Caira, M. R. Solvent-mediated transformation of a 1:1 2,3-bis-fluoren-9-ylidene succinic acid-ethanol solvate to the 1:2 solvate. CrystEngComm 2005, 7, 592. The idea that pseudopolymorphs are very much like polymorphs, expressed in these early papers, will hopefully get strengthened soon. (13) Almarsson, O ¨ .; Zaworotko, M. J. Crystal engineering of the composition of pharmaceutical phases. Do pharmaceutical co-crystals represent a new path to improved medicines? Chem. Commun. 2004, 1889. (14) Rogers, R. D. Introduction: Polymorphism in crystals. Cryst. Growth Des. 2003, 3, 867. “The most often used term for such compounds appears to be pseudopolymorphs, yet it is not clear if this conveys the scientific meaning it should. As the number of researchers increases in these important fields, care must be taken to provide the community with unambiguous directions on terminology that provides a ready understanding, but also scientific accuracy.” (15) Plass, K. E.; Kim, K.; Matzger, A. J. Two-dimensional crystallization: Self-assembly, pseudopolymorphism, and symmetry-independent molecules. J. Am. Chem. Soc. 2004, 126, 9042.
4 Crystal Growth & Design, Vol. 6, No. 1, 2006 (16) Nangia, A.; Desiraju, G. R. Pseudopolymorphism: Occurrences of hydrogen bonding organic solvents in molecular crystals. Chem. Commun. 1999, 605. (17) Dunitz, J. D. Thoughts on crystals as supermolecules. In The Crystal as a Supramolecular Entity. PerspectiVes in Supramolecular Chemistry; Desiraju, G. R., Ed.; Wiley: Chichester, 1996; Vol. 2, pp 1-30.
Perspective (18) Hughes, D. S.; Hursthouse, M. B.; Lancaster, R. W.; Tavener, S.; Threlfall, T. L. Over one hundred solvates of sulfathiazole. Chem. Commun. 2001, 603.
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