Feature

API Scale-Up During Research and Development (continued)

Other important challenges. In recent years, API process development has become more challenging because of the need for making APIs with a desired enantiomeric purity and a desired polymorphic form. The following examples justify the need for the stringent regulatory requirements in these areas. Enantioselective synthesis. More than half of the drugs used in clinical medicine are chiral compounds (4). Yet, the majority of these drugs are still prescribed as racemates. There is a need to make enantiomerically pure APIs when one enantiomer does not contribute to efficacy but may contribute to toxicity. Some interesting examples of isomers with various activities are shown in Figure 2 (5). The data in Figure 2 indicate a need for enantioselective synthesis in many racemic APIs. In such cases, one must validate the process carefully to ensure the formation of only the desired isomer. The other isomers should be considered impurities. In addition, it must be ensured that there is no chiral inversion during formulation, storage, or in the human body to avoid adverse side effects. Synthesis of the desired polymorph. Polymorphism is the ability of a substance to exist in two or more crystalline phases that have different arrangements and/or conformations of molecules in a crystal lattice.Many APIs exist in several polymorphic forms with various properties such as crystallinity, bulk density, solubility, and bioavailability. Two interesting cases of product recalls that were a result of drug polymorphism follow (6). Abbot Laboratories had to withdraw its HIV protease inhibitory drug Norvir (Ritonavir) from the market because an unwanted polymorph of the drug was produced (Form II) during shelf life. This form has a different dissolution rate to the known polymorph (Form I), thereby affecting the drug’s bioavailability. Chloramphenicol-3-palmitate of Form B is a metastable form having eightfold higher bioavailability than the other polymorph, Form A, thereby creating a danger of fatal dosages when the unwanted polymorph is unwittingly administered as a result of alterations in process and storage conditions. These examples demonstrate the need to identify all polymorphs of an API at the R&D stage. One can establish the polymorphs by determining physicochemical properties, by conducting thermodynamic stabilities, and by studying conditions of interconversions. Useful tools for such determinations include Fourier transform infrared spectroscopy, X-ray powder diffraction, and differential scanning calorimetry. The formation of a specific polymorph can depend on the type and composition of the solvents, temperature, synthetic route, storage conditions, and so forth. An interesting example of solvent composition giving various polymorphs is cholamide (7),which exhibits needle-like crystals (Form I) by recrystallization from a solution of 1:1 acetonitrile:water and platelet-like crystals (Form II) by recrystallization from a solution of 25:1 acetonitrile:water (see Figure 3). Once the desired polymorph has been identified, the process must be validated to obtain the desired polymorph consistently. Further, the stability protocol of the formulated drug must include some suitable tests to ensure that there is no change in the polymorphic form under these conditions. Conclusion The various process considerations described in this article can help chemists understand and adopt a systematic and prospective approach in research and development to have documented and controlled synthetic processes. This approach will help manufacturers meet product-quality objectives consistently and build a good basis for achieving the goals of prospective validation and scale-up activities. References Impurities: Guidelines for Residual Solvents, Q3C, recommended by ICH on July 17, 1997. Process Chemistry in the Pharmaceutical Industry, K.G. Gadamasetti, Ed. (Marcell Dekker, Inc., New York, NY, 1999), p. 389. Internet databases such as Cole-Palmer Chemical compatibility database, ARO chemical compatibility, eFunda O ring material compatibility with chemicals, Varidisk chemical compatibility information, Flowline Chemical compatibility database and DMRTM fluid compatibility table by Daemar Inc. Physician’s Desk Reference (Thomson PDR,Montvale, NJ, 1997). S. Ahuja, Chiral Separations: Applications and Technology (ACS Publications, Washington, DC, 1996), p. 4. G. Chawla and A. Bansal, “Challenges in Polymorphism of Pharmaceuticals,” Scrip 5 (1), 9 (Jan.–Mar. 2004). N. Yoswathananont et al., “A Novel Three-Component Pseudo-Polymorphism in the Cholamide Inclusion Crystals Promoted by the Combination of Organic Guest and Water,” Chem. Lett. 12, 1234 (2002). PT