Solid-State Pharmaceutical Development, Characterization, and Intellectual Property - Novel Insight to Old problems

Different solid forms of an active pharmaceutical ingredient (API) can have very different properties. Those differences can impact bioavailability, solubility, dissolution rate, first pass metabolism, side effect incidence, stability, API and drug product manufacturability, and other important parameters. The vast majority of APIs can exist in multiple solid forms, including polymorphs, hydrates, solvates, salts, cocrystals, and non-crystalline forms. Part of pharmaceutical preformulation is selection of the optimal solid form of the API. That includes salt or cocrystal screening as well as polymorph screening.  While the existence of crystalline forms remains unpredictable, rational approaches to screening can be applied to increase the likelihood of hits.  The various solid forms found among organic compounds used as APIs will be discussed using examples. Both qualitative and quantitative methods for analysis of solid mixtures will be discussed. Various techniques can be used, including x-ray diffraction, vibrational spectroscopy, NMR spectroscopy, differential scanning calorimetry, and moisture sorption. However, solid mixtures pose unique validation issues that are not currently addressed in ICH guidelines. Those issues, and approaches for dealing with them, will be presented. Spectroscopic mapping and imaging are relatively new techniques that are useful for a variety of tasks.  They are particularly valuable for analysis of finished products containing multiple components.  For example, drug products such as tablets, caplets, microspheres, etc. can be analyzed with little or no sample preparation.  Applications for such analyses include detection of minute amounts of a specific component of interest (such as a potentially patent-infringing solid form), determination of the spatial locations of components, identification of component interactions leading to changed product performance, and verification of content uniformity. Examples will be presented. This presentation is intended as a tutorial for scientists who are unfamiliar with Intellectual Property aspects of solid forms (polymorphs, salts, cocrystals). Special attention will be placed on recent case law, claim construction strategies past and present, and insight into the US Patent & Trademark Office's recent views of solid-forms. Can one expect to obtain patents on new solid forms (polymorphs, salts, cocrystals, non-crystals)- If so, will the patents be listable in the FDA's Orange Book and, more importantly, will they survive a court challenge- Historical perspective and recent court decisions will be used to illustrate the complexity of such questions, as well as to provide some insight into current trends.

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