Quantitative determination of polymorphic impurity by X-ray powder diffractometry in an OROS® formulation

An ALZA OROS (R) drug delivery system was evaluated for its potential to increase drug load and reduce side effects when used with RWJ-333369 (S-2-O-carbamoyl-1-o-chlorophenyl-ethanol), a novel neuromodulatory agent initially developed by SK Bio-Pharmaceuticals and licensed by Johnson & Johnson. RWJ-333369 was found to have two crystalline polymorphs (A and B) that are enantiotropically related. Polymorph A, used in the formulation, was thermodynamically stable at room temperature. A partial polymorphic conversion in the solid state was observed at an elevated temperature of 60 degrees C during a two-week stability test. The OROS (R) RWJ-333369 manufacturing process included milling, granulation, compression, subcoating, membrane coating, drilling, and drying to produce a capsule-shaped OROS (R) tablet. The potential for polymorphic conversion during manufacturing and stability testing was evaluated using Fourier Transform Infrared Spectroscopy (FTIR), Raman Spectroscopy (Raman), and X-ray Powder Diffractometry (XRD) to detect impurities; the latter was determined to be preferred method. Pure polymorph A and polymorph B reference materials were used for method development. Mixtures with different ratios of polymorph A and polymorph B were scanned using XRD, and the peak heights and areas were used to generate a calibration curve. OROS (R) RWJ-333369 formulations were spiked with polymorph B reference, and the detection limit was about 2% using the 22 degrees 2 theta diffraction angle relative peak area. Samples from different OROS (R) manufacturing process and stability tests were analyzed. The results indicated that polymorph A was not converted to polymorph B during manufacturing process. Polymorph B impurity was, however, detected in stability samples. (C) 2008 Published by Elsevier B.V.