Stress testing polymorphism

If either the salt form or the physical characteristics (e.g., particle size, polymorphic form, surface area, etc.) change, all solid-state stress-testing studies should be repeated, since such changes could affect degradation rates and even degradation pathways. 

Accelerated stability studies are potentially problematic for at least three reasons. Stress testing conditions may exceed the temperature of a polymorphic phase transition or dehydration. The use of accelerated conditions may make a relaxation of a metastable phase more rapid due to the increased molecular mobility. Finally, the relative humidity of the station may be in the range sufficient to cause a pseudopolymorphic transition due to dehydration or hydration. It is sobering... 

Additional preformulation and physicochemical characterization of the candidate compound are performed and stress stability studies may be initiated. Ideally, the optimal solid state (polymorphic) and chemical (salt) form of the molecule are identified as part of clinical candidate selection. Selection of the most stable and bioavailable form will expedite subsequent development. The methods for testing the drug substance are refined and additional methods may be developed. 

A recent analytical study stresses the growing need, prompted partly by l islatory requirements, to differentiate polymorphs and to quantify polymorphic mixtures in pharmaceutical production [126]. The compounds benzil and benzoic add were chosen as a model system for the development of an XRD protocol which could be extended to the quantification of mixtures of drug polymorphs. The study involved the evaluation of sample thickness, the determination of preferred orientation effects, optimum milling conditions and the construction of diffraction intensity-composition calibration curves for mixtures of benzil and benzoic acid. Since the composition of such mixtures can be accurately determined by an independent method, namely HPLC, vaUdation of the quantification of mixtures by the XRD protocol was possible. It was concluded that the protocol is accurate for the model system to within a few percent. It is desirable that the general validity of the approach suggested be tested on a range of real polymorphic systems. 

From the phase diagram the regions of stabihty of the different polymorphic forms of iPP in oriented fibers are defined as a function of stereoregularity and degree of deformation e. The values of the critical strain at which the polymorphic transitions start and at which the transformation is complete depend on the stereoregnlarity. The critical values of the stress instead depend also on other parameters as, for instance, the degree of crystalhnity of the sample, the amonnt of strnctnral disorder present in the crystals and on the method of preparation of the test specimens. 

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