P harmaceutical during crystal form selection. Important design strategies for making cocrystals are described, along with some recent examples of using cocrystals to enhance specific physical properties. Cocrystal screening and synthesis are also covered, particu- Cocrystals: An larly using solid-state grinding and solvent-drop selective cocrystal synthesis. Solid-State Modifications of APIs Emerging Approach Polymorphs Apolymorph is “a solid crystalline phase of a given compound resulting from the possibility of at least two different arrange- to Physical Property ments of the molecules of that compound in the solid state.” 2 Different polymorphs of a given compound each possess a Enhancement unique set of physicochemical properties, and many, if not most, compounds exhibit polymorphism to some extent. 1,3,4 Some compounds exist in more than ten crystal form modifications. 5 At present, it is not William Jones, W.D. Samuel Motherwell, and generally possible to computationally pre- Andrew V . Trask dict the number of observable polymorphs of even the simplest molecules, 6 and as a result, the use of high-throughput screen- ing methods to search for new polymor- Abstract phic forms has become an important tool Pharmaceutical cocrystals are crystalline molecular complexes containing in form screening. 5 therapeutic molecules. They represent an emerging class of pharmaceutical materials offering the prospect of optimized physical properties. This article highlights important Hydrates and Solvates Frequently during crystallization, sol- opportunities and challenges associated with the design and synthesis of vent may be taken up and incorporated as pharmaceutical cocrystals. Cocrystallization is first placed into context with the more part of the crystal structure. Most solvents, established approaches to physical property optimization of polymorph, hydrate, and however, are biologically toxic; as a re- salt selection. A directed, intermolecular-interaction-based approach to cocrystal sult, most solvate-containing crystals are design is described. The enhancement of specific physical properties, such as avoided in the development of the solid dissolution rate and physical stability, is illustrated by summarizing several recent form of an API. reports. Synthetic approaches to cocrystallization are considered; in particular, the An important exception is the subclass selectivity and screening-related opportunities afforded by solid-state grinding and of API hydrates, which are well known in solvent-drop grinding methods are discussed. Finally, an outlook on future pharmaceutical products. 7,8 It has been es- developments summarizes the growth potential in this field, especially with regard to timated that one-third of pharmaceutical targeted, informatics-driven cocrystal screening approaches. molecules are capable of forming hy- drates. 9,10 As a result of process-induced Keywords: biomedical, crystal growth, crystalline. stresses, such as changes in temperature, pressure, or relative humidity, hydrates often convert into anhydrous crystal Introduction forms. This conversion from hydrate to On average, about a decade of research Frequently, however, the API does not anhydrate can result in significant changes and development is expended in the dis- crystallize on its own or it crystallizes into in physical properties and can present covery and commercialization of a new one or more crystal forms that possess un- major issues, for example, during storage, pharmaceutical product. Initial R&D ef- desirable physical properties. In either case, where hydrate conversion can compromise forts center on the identification of a suit- an alternative crystal form is typically dosage form appearance and integrity. able molecular structure, physical form, sought. Various options include single- and formulation. Whereas the molecular component and multiple-component mod- Pharmaceutical Salts structure of the active pharmaceutical in- ifications of an API, including polymorphs, Salt formation is a common approach to gredient (API) of a drug substance is se- salts, solvates, and hydrates. In addition to modifying the properties of an API. 11–13 lected to optimize therapeutic properties, these established crystalline API modifica- Salt formation is an acid–base reaction be- selecting the physical form of an API rep- tions, pharmaceutical cocrystals, or crys- tween the API and an acidic or basic resents a strategic opportunity for opti- talline molecular complexes involving an substance. It is an attractive strategy, be- mizing such physical properties as API, have recently attracted interest as cause most pharmaceutical compounds solubility, dissolution rate, hygroscopicity, an alternative approach. possess either acidic or basic functionality, physical stability, and chemical stability. 1 This article outlines how pharmaceuti- and the widespread use of salt formation Most APIs are dosed as solids, and most cal cocrystals offer an alternative ap- is evidenced by the large number of mar- solid APIs exist in the crystalline form. proach to physical property optimization keted crystalline salts of APIs. 14 MRS BULLETIN • VOLUME 31 • NOVEMBER 2006 875
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