“Every compound has different polymorphic forms and the number offorms known for a given compound is proportional to the time and energy spentin research on that compound"
McCrone’s provocative comment1 is very well known within the crystal engineering community and it is fair to assert that it has inspired research into the phenomenon of polymorphism. However, one cannot accept it to be true since it is impractical to validate even in the era of robotic high throughput crystallization. Simply put, it would be practically impossible to conduct an infinite number of crystallization experiments on every compound that is not yet proven to exhibit polymorphism. Additionally, there are compounds that have been crystallized many times, as exemplified by naphthalene and sucrose, that are not yet known to exhibit polymorphism under ambient conditions.2,3Interestingly, aspirin used to be in this category but now there is a second polymorph of aspirin,4 although the nature of aspirin polymorphism remains a touchy subject.5,6 It would be nice to have the resources to go hunting for new crystal forms of naphthalene and sucrose but it would behard to justify funding for such a project.
Why does McCrone’s comment matter greatly? Much ofthe recent interest in polymorphism can be attributed to the legal implicationsof polymorphism in the context of the pharmaceutical industry. In particular,since a polymorph is not obvious until it has been made, new polymorphstypically meet the criteria of novelty, utility and lack of obviousness neededfor patentability in the United States. This issue was brought to the fore by thediscovery of form II of ranitidine hydrochloride or Zantac®, the #1 blockbusterdrug at the time of litigation (see SOTW 3). However, in Europe the equivalent criterion for issuing a patent is “inventiveness” rather than “obviousness” and this means that polymorphs discovered through high throughput screening might henceforth be difficult to patent because McCrone’s comment is regarded by some as scientifically accepted. Ironically, at least from the perspective of physicochemical properties, this is a “much ado about nothing”since polymorphs are often similar enough to each other in aqueous solubility (but not always) to make them bioequivalent.7 Therefore, this matter is primarily a legal and regulatory issue rather than a matter of whether thedrug works.
From my perspective it is not yet clear that polymorphism is a rule rather than an exception. What we do know is that of the 233,346 “organic only” crystal structures archived in the Cambridge Structural Database (see SOTW 1), there are only 9870 entries for polymorphs, .i.e. less than 9870/2 compounds out of (233,346-9870/2)or ca. 2.2% are presently known to be polymorphic. For a more in-depth perspective on polymorphism, including its legal implications, see JoelBernstein’s recent article on the subject of polymorphism.8
(1) W. C. McCrone, inPhysics and Chemistry of the Organic Solid State, eds. D. Fox, M. M. Labes andA. Weissberger, Interscience Publishers, London, 1965, vol. 2, pp. 725-767.
(3) T. Lee, G. D. Chang, “Sucrose Conformational Polymorphism: AJigsaw Puzzle with Multiple Routes to a Unique Solution”, 2009, Cryst. Growth Des., 9, 3551–3561
(4) P. Vishweshwar, J. A. McMahon, M.Oliveira, M.L. Peterson, M. J. Zaworotko, "The Predictably Elusive Form IIof Aspirin", 2005, J.Am. Chem. Soc. 127,16802–16803.
(6) E. J.Chan, T.R. Welberry, A.P.Heerdegen, D.J. Goossens, “Diffuse scattering study of aspirin forms (I)and (II)”, 2010, ActaCrystallographica, Section B: Structural Science, B66, 696-707.
(7) M. Pudipeddi, A.T.M.Serajuddin, “Trends in Solubility ofPolymorphs”, 2005, Journal of PharmaceuticalSciences, 94, 929-939.
(8) J. Bernstein, “Polymorphism - A Perspective, CrystalGrowth & Design”, 2011, 11,632-650.