In vitro monitoring of dissolution of an immediate release tablet by focused beam reflectance measurement.

Changes in in vitro drug release profiles of oral dosage forms are commonly observed due to storage of drug product at elevated temperature and humidity. An example is presented of an immediate release drug product which underwent changes to both release profile and crystal form on storage at elevated humidity. The dissolution rate for unstressed tablets was comparable regardless of the crystal form present. Decreased release rate was only observed for stressed tablets that exhibited crystal form conversion. The cause of the dissolution change was determined by evaluating tablets manufactured with three drug substance crystal forms by fiber optic ultraviolet detection and focused beam reflectance measurement (FBRM). Tablets were also analyzed by near-infrared spectroscopy for crystal form determination. The observed change in dissolution rate correlated with detection of a greater number of larger particles by FBRM. FBRM results indicate increased aggregation of the tablet material due to crystal form conversion, resulting in the presence of slowly disintegrating and dissolving granules during the dissolution process. The improved understanding of the dissolution process allows evaluation of the potential in vivo impact of the stability changes.

Evaluating the performances of quantitative structure-retention relationship models with different sets of molecular descriptors and databases for high-performance liquid chromatography predictions.

Quantitative structure-retention relationship (QSRR) models were studied for two databases: one with 151 compounds and the other with 1719 compounds. In both cases, the three modeling methods employed (multiple linear regression, partial least squares, and random forests) provided similar prediction results with regard to root-mean-square error of prediction. The reversed-phase retention related seven molecular descriptors provided better models for the smaller dataset, while the use of over 2000 molecular descriptors generated better models for the larger dataset. The QSRR models were then validated with a mixture of an active pharmaceutical ingredient and its four process/degradation impurities. Finally, classification of compounds based on similar logD profiles before QSRR modeling improved chromatographic predictability for the models used. The results showed that database composition had a desirable effect on prediction accuracy for certain input molecules.

A simple and efficient approach to reversed-phase HPLC method screening.

The development and utility of an efficient HPLC method screening strategy using only four columns for the separation of pharmaceutical compounds and related impurities is presented. The strategy established a two-column approach to enable rapid early method development, along with a four-column approach for commercial method development of the analytical methods utilized to verify the quality of drug substance or drug product. Mobile phases consisted of acetonitrile or methanol with aqueous trifluoroacetic acid for low pH screening, and ammonium hydroxide for high pH screening. Examples are provided to demonstrate the practicality and orthogonality of the method screening process. A unique system suitability check, using commercially available compounds, was incorporated as a tool for troubleshooting and for ensuring adequate system performance prior to screening. Initial testing of the strategy revealed that the columns chosen were successful in leading to assay and impurity methods for 40 pharmaceutical compounds.