Practical Implications and Ramifications of Multiple Crystal Forms Pharmaceuticals

Practical Implications and Ramifications of Multiple Crystal Forms - Pharmaceuticals 

A dramatic example of the impact of crystal polymorphism on a drug formulation is that of ritonavir (Norvir ), used for the treatment of HIV patients. The problem arose in May of 1998, approximately two years after the launch of the drug, when researchers at the Abbott Laboratories became aware that after 240 production batches it was no longer possible to obtain ritonavir in the crystal form (Form I) approved by the FDA and required for the formulation of Norvir because of the sudden and unexpected appearance of a more stable and much less soluble crystal form (Form II, Fig. 3.3.17). The loss of control over the production process forced Abbott to withdraw the drug from the market for approximately one year until they learned how to replace the solid formulation with a gel capsule suspension with greater problems of stability and bioavailability. Subsequent investigations have led to the discovery of four other crystalline forms of ritonavir [33]. 

Other well-known authors have made similar statements, a. F. Findlay, who authored the classic book The Phase Rule noted in that [polymorphism] is now recognized as a very frequent occurrence indeed. [34] Buerger and Bloom stated, ... polymorphism is an inherent property of the solid state and it fails to appear only under special conditions. [35] Similarly, Sirota in 1982 [Polymorphism is now believed to be characteristic of all substances, its actual non-occurrence arising from the fact that a polymorphic transition lies above the melting point of the substance or in the area of as yet unattainable values of external equilibrium factors or other conditions providing for the transition. [36] 

These generalizations are often supported, especially in the field of pharmaceuticals, by citing Kuhnert-Brandstatter s 1965 statistics [37], expanded upon in her 1971 book [38] on three common classes of drugs 70% of the barbiturates, 60% of sulfonamides and 23% of steroids exist in various polymorphic or solvate forms. These statistics were based on HSM studies that Kuhnert-Brandstatter herself performed. Due to the inherent microscopic nature of this technique and the metastable nature of many observed phases it is often difficult to translate HMS observations into fully characterized crystal forms. In fact, as Kuhnert-Brandstatter noted in her 1965 paper, ...optical crystallographic methods require a more 

A number of statistical analyses of the literature have been carried out in an attempt to estimate the extent of polymorphism. A search of the Cambridge Structural Database on the keywords polymorph , form , modification and phase indicates that about 3.5% of the -350 000 entries fall into this category. Approximately 25 % of the entries are either solvates or hydrates. At the other end of the spectrum, Byrn has reported that of the 150 compounds submitted for crystal form screening and analysis to SSCI, Inc. 85 % exhibit more than one crystal form, 37% are solvates and 31 % are hydrates [40]. Other studies based on different selection criteria reveal results falling somewhere between these two extremes [41]. For instance, Griesser and Burger have collected information on about 600 polymorphic forms and solvates (including hydrates) pharmaceutical compounds that are solid at 25 °C [41c], 

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