Intellectual Property Battles in Solid-State Chemistry - Pharmaceutical Technology

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Intellectual Property Battles in Solid-State Chemistry
The rejection by India's Supreme Court on Novartis' Glivec/Gleevec (imatinib mesylate) and other recent case law raise important issues on patent strategies for solid forms.


Pharmaceutical Technology
Volume 37, Issue 5, pp. 54-58

Technical considerations

Although intellectual property concerns play a role in the development of pharmaceutical solid forms, the rationale to use a particular solid form (e.g., salt, polymorph, or cocrystal) of an API is dictated by the target product profile and encompasses various factors, such as bioavailability, physical and chemical stability, desired dissolution properties, the impurity profile of the API, drug-substance hygroscopicity, morphology, size distribution, compaction properties, and the ability to formulate the drug (6).

In the case of polymorphs, for example, screening for and identifying polymorphs when developing and manufacturing APIs is an ongoing challenge for pharmaceutical manufacturers. Polymorphism is the ability of a compound to exist in more than one crystalline structure. Polymorphs or other solid forms are identified using a polymorph study or screen (6). Different solid forms can possess different properties, including solubility, which, in turn, can affect the bioavailability of the drug.

One of the more well-chronicled examples of polymorphism occurred in ritonavir, the API in Norvir, a protease inhibitor developed by Abbott Laboratories (now AbbVie), The drug was approved in 1996, and in mid-1998, Abbott encountered manufacturing difficulties with the capsule formulation (5). Ritonavir exhibited conformational polymorphism of two unique crystal lattices that had significantly different solubility properties (6, 7). The formation of the polymorph caused Abbott to pull the drug from the market and reformulate.

Polymorph stability is evaluated experimentally by monitoring the phase transition of the different polymorphs in different crystallization media and at different temperatures by using in-situ monitoring probes and analytical solid-state methods (6). These data are used to manufacture the desired polymorph and to control it through the various manufacturing steps. Polymorphs can undergo phase transitions when exposed to a range of manufacturing processes, such as drying, milling, micronization, wet granulation, spray drying and compaction. Exposure to environmental conditions, such as humidity and temperature, also can induce polymorph transition. The extent of transition depends on the relative stability of the polymorphs, kinetic barriers to phase transition, and applied stress (6). Moreover, the physical stability of polymorphs may be monotropic or enantiotropic, where the relative thermodynamic stability between the two forms can be inverted with temperature (6). Additional considerations are made when the physical form of the drug-substance may be modified in the formulation process, such as in hot-melt, lyophilization, solubilization or suspension in a semisolid matrix. Drug substance–excipient interactions also are considered when stabilizing particular physical and other process parameters that may affect the performance or quality of the product.

References

1. Indian Supreme Court, Civil Appeal No. 2728 Novartis AG vs. Union of India and Others (Mumbai, 2013).

2. J. Zimmerman, "Pyrimidine Derivatives and Processes for the Preparation Thereof (US Patent No,521,184), 28, May, 1996.

3. R. Ahmed, "India Revokes Roche Patent," Wall Street Journal, Nov. 3, 2012.

4. J.F. Tremblay, C&E News, 90 (38), 9 (2012).

5. S. Houlton, "India Rejects Novartis Patent Appeal," Chemistry World Apr. 8, 2013.

6. P. Van Arnum, Pharm. Technol. 35 (7), 44-48 (2011).

7. SEC, Abbott 10-K Annual Report (Washington, DC, 1998).

Patricia Van Arnum is a executive editor of Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072,
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