PCA-CR analysis of dissolution profiles. A chemometric approach to probe the polymorphic form of the active pharmaceutical ingredient in a drug product.

A simple chemometric approach to differentiate among the three crystalline polymorphs of the model drug Furosemide (FUR) in a pharmaceutical dosage form is presented. The proposed method is based on the principal component analysis with confidence regions (PCA-CR) comparison of the dissolution profiles of the test pharmaceutical formulation, and formulations containing the different polymorphs, employed as the corresponding references. For the elaboration of the references, FUR polymorphs I, II and III were prepared, characterized and compounded with the excipients found in the test commercial formulation. The dissolutions were carried out in a discriminating HCl-KCl dissolution medium (pH 2.2), and the corresponding profiles were constructed from the absorbances (274 nm) of the dissolution samples. PCA-CR was able to differentiate among the three crystalline polymorphs of FUR and to confirm the presence of polymorph I in the test sample, with 99% statistical confidence. The PCA-CR results were compared with those obtained by a bootstrap-mediated implementation of Moore and Flanner's difference factor (f(2)). The same conclusion was reached employing an f(2)-based comparison, despite its inability to differentiate between polymorphs II and III. Therefore, PCA-CR may be considered a complementary and useful tool for probing the polymorphic form present in a pharmaceutical formulation.