PubMed · 12944095
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Andrew Bradbury. 2003-08-15. scFvs and beyond.. https://doi.org/10.1016/s1359-6446(03)02786-7
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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 degrees 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.
In this study, the potential of micro-focus X-ray (MFX) imaging as a tool in the design and quality control of drug delivery systems has been demonstrated. MFX imaging has been used to map the spatial distribution of a drug down to length-scales of approximately 10-100 microm and has shown that the spatial distribution of the drug amiodarone within a hydroxypropylmethylcellulose (HPMC) controlled release tablet (diameter 10 mm) is not homogeneous. MFX imaging allows an assessment to be made of the degree of mixing of the original powders. Despite vigorous mixing during the manufacture of the tablets, the drug particles, originally of size 180-420 microm, were found to be concentrated within isolated but spatially extended patches of sizes up to 1 mm that were scattered across the tablet.
The slurry equilibration method used to determine the relative physical stability of polymorphs is extended to a crystal system of an anhydrate and hydrate. The method involves preparation of organic/aqueous slurries of known water activity containing mixtures of the anhydrate and hydrate forms. The slurries equilibrate to the lowest free energy form, from which the relative physical stability is determined as a function of relative humidity. The method is particularly valuable when one or more of the crystal forms is kinetically stable, since solvent-mediated transformation accelerates the conversion process. Results are provided for GW2016 anhydrate and monohydrate crystal forms, for which it was determined that interconversion occurs between 7 and 15% relative humidity.