Evaluation of drug physical form during granulation, tabletting and storage
Williams, A. C., Cooper, V. B., Thomas, L., Griffith, L. J., Petts, C. R. and Booth, S. W. (2004) Evaluation of drug physical form during granulation, tabletting and storage. International Journal of Pharmaceutics, 275 (1-2). pp. 29-39. ISSN 0378-5173
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To link to this article DOI: 10.1016/j.ijpharm.2004.01.042
An active pharmaceutical ingredient (API) was found to dissociate from the highly crystalline hydrochloride form to the amorphous free base form, with consequent alterations to tablet properties. Here, a wet granulation manufacturing process has been investigated using in situ Fourier transform (FT)-Raman spectroscopic analyses of granules and tablets prepared with different granulating ﬂuids and under different manufacturing conditions. Dosage form stability under a range of storage stresses was also investigated. Despite the spectral similarities between the two drug forms, low levels of API dissociation could be quantiﬁed in the tablets; the technique allowed discrimination of around 4% of the API content as the amorphous free base (i.e. less than 1% of the tablet compression weight). API dissociation was shown to be promoted by extended exposure to moisture. Aqueous granulating ﬂuids and manufacturing delays between granulation and drying stages and storage of the tablets in open conditions at 40◦C/75% relative humidity (RH) led to dissociation. In contrast, non-aqueous granulating ﬂuids, with no delay in processing and storage of the tablets in either sealed containers or at lower temperature/humidity prevented detectable dissociation. It is concluded that appropriate manufacturing process and storage conditions for the ﬁnished product involved minimising exposure to moisture of the API. Analysis of the drug using FT-Raman spectroscopy allowed rapid optimisation of the process whilst offering quantitative molecular information concerning the dissociation of the drug salt to the amorphous free base form.