Detection of drug polymorphism

The majority of all APIs manufactured demonstrate structural polymorphism. In order to formulate a drug product that is physically and chemically stable, the formulation team must identify the most thermodynamically stable polymorph of the API. By identifying the proper polymorph, the patient s need for a drug product with reproducible bioavailability during the course of typical and atypical shelf-life conditions will be met. This section will review the use of spectroscopic techniques for identifying polymorphism of APIs during API crystallization and formulation. For a more comprehensive discussion of polymorphism the reader is directed to a work by Singhal85 and references cited therein. 

NIR spectroscopy was utilized by Aldridge and coworkers86 to determine, in a rapid manner, the polymorphic quality of a solid drug substance. Two computational methods, Mahalonobis distance and soft independent modeling of class analogy (SIMCA) residual variance, were used to distinguish between acceptable and unacceptable samples. The authors not only determined that the Mahalonobis distance classification yielded the best results, they addressed one of the key implementation issues regarding NIR as a PAT tool. 

Binary mixture diluted with 95% Sodium chloride 0.9998 0.54 1.0000 0.14 0.9999 0.52 

Terahertz pulse spectroscopy was used to observe the polymorphs of ranitidine hydrochloride.91 Sample preparation for this technique is the same as for Raman and FTIR spectroscopy and the data generated is complementary to Raman. Terahertz pulse spectroscopy provides information on the low-frequency intermolecular modes that are difficult to study with Raman due to the proximity of the laser excitation line. The authors concluded that this technique has many applications in pharmaceutical science including formulation, screening and stability studies. 

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