In general, crystalline forms of drugs are preferred over amorphous forms of drugs, in part, because of their superior stability. For example, in many situations, an amorphous drug converts to a crystalline drug form upon storage. Because amorphous and crystalline forms of a drug typically have different physical/chemical properties, potencies and/or bioavailabilities, such interconversion is undesirable for safety reasons in pharmaceutical administration. A key characteristic of any crystalline drug substance is the polymorphism of such a material. Polymorphs are crystals of the same molecule which have different physical properties because the crystal lattice contains a different arrangement of molecules. The different physical properties exhibited by polymorphs can affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in formulation and product manufacturing) and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when the dosage form contains one polymorph rather than another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored crystalline form converts to a thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency and/or are toxic. In addition, the physical properties of the crystalline form may be important in pharmaceutical processing. For example, a particular crystalline form may form solvates more readily or may be more difficult to filter and wash free of impurities than other forms (e.g., particle shape and size distribution might be different between one crystalline form relative to other forms).
Agencies such as the United States Food and Drug Administration closely regulate the polymorphic content of the active component of a drug in solid dosage forms. In general, the regulatory agency requires batch-by-batch monitoring for polymorphic drugs if anything other than the pure, thermodynamically preferred polymorph is marketed. Accordingly, medical and commercial reasons favor synthesizing and marketing solid drugs as the thermodynamically stable polymorph, substantially free of kinetically favored polymorphs.
(3S)-{[1-Isobutanoyloxyethoxy]carbonylaminomethyl}-5-methyl-hexanoic acid (1) is a prodrug of the GABA analog pregabalin, (3S)-aminomethyl-5-methyl-hexanoic acid (2), which has high bioavailability as pregabalin when dosed either orally or directly into the colon of a mammal (Gallop et al., U.S. Pat. No. 6,972,341; and Gallop et al., U.S. Pat. No. 7,186,855, each of which is incorporated by reference in its entirety).

This high oral and/or colonic bioavailability makes this prodrug suitable for use in oral dosage forms (including sustained-release dosage forms) useful for treating diseases such as a movement disorder, a gastrointestinal disorder, a psychotic disorder, a mood disorder, an anxiety disorder, a sleep disorder, a pulmonary disorder, a neurodegenerative disorder, an inflammatory disease, neuropathic pain, musculoskeletal pain, chronic pain, migraine, hot flashes, faintness attacks, urinary incontinence, ethanol withdrawal syndrome, and premature ejaculation.
Compound (1), prepared as disclosed in Gallop et al., U.S. Pat. No. 6,972,341 and Gallop et al., U.S. Pat. No. 7,227,028, consists of a mixture of two diastereomers ((1S)/(1R)) and is isolated as a thick oil after concentration from solutions in organic solvents. The oily nature of the materials obtained by this process disclosed in Gallop et al. is undesirable from the perspective of formulating stable, pharmaceutically acceptable oral dosage forms. Moreover, it has been found that transformation of the diastereomeric compounds to certain alkali metal salt forms (e.g., sodium salts) affords solid materials that are distinctly hygroscopic. Hygroscopic solids are difficult to handle using typical pharmaceutical processing conditions because of low bulk densities and unsatisfactory flow properties. Moreover, handling of hygroscopic solids requires special techniques and equipment to obtain, for example, reproducible amounts of active compound or solid formulation stability. Furthermore, drugs that are hygroscopic must be packaged in special containers that are impervious to water vapor, thus substantially increasing the cost of such products.
USPTO Backgrounds
USPTO Backgrounds