Swelling of hydroxypropyl methylcellulose matrix tablets. 2. Mechanistic study of the influence of formulation variables on matrix performance and drug release.

We characterized the effect of hydroxypropyl methylcellulose (HPMC)/lactose ratio and HPMC viscosity grade (molecular weight) on solute release and swelling of matrix tablets. We used a semiquantitative optical imaging method to monitor the swelling of matrices with HPMC content from 20% to 80% (w/w) and four viscosity grades. Several aspects of the swelling process common to all formulations were revealed: (i) swelling is anisotropic with a preferential expansion in the axial direction, (ii) swelling is isotropic with respect to the gel layer thickness and composition in both axial and radial directions, (iii) the gel layer develops in three stages, and (iv) water penetration is Fickian in nature and essentially constant for all formulations. We monitored simultaneously drug, lactose, and HPMC release. Lactose and drug release rates were superimposed, indicating a similar diffusional release mechanism and no interaction with HPMC. The strong dependence of HPMC release on viscosity grade is explained on the basis of the concept of polymer disentanglement concentration. We analyzed drug release rates using a model for a reservoir-type release system that incorporates swelling kinetics. HPMC/lactose ratio modulates drug release rate by altering drug diffusivity, a function of gel composition. In contrast, HPMC viscosity grade impacts matrix dissolution and gel layer thickness development below a critical molecular weight. For slowly dissolving matrices containing high viscosity grade (> 4000 cps) HPMC, similar drug release rates are observed mainly due to the same drug diffusivity as a result of the identical gel composition and thickness. For fast dissolving matrices (< or = 100 cps) swelling inhomogeneity is proposed as being responsible for a higher apparent drug diffusivity and release rate.

Gradient high performance liquid chromatographic assay for degradation products of adinazolam mesylate in a sustained release tablet formulation.

A gradient high performance liquid chromatographic method was developed to determine degradation products of adinazolam mesylate in a sustained release tablet formulation. Sample preparations were chromatographed on a YMC-Basic column using a formate buffer/acetonitrile gradient with absorbance detection at 254 nm. Adinazolam mesylate was found to degrade at high relative humidity and temperature to form a major product, the 6-aminoquinoline analog, plus numerous other compounds. Five of these compounds were identified and their structures indicate that the solid-state degradation of adinazolam, in the presence of sufficient moisture, involves not only a hydrolytic mechanism, but also an oxidative mechanism. Potential process impurities were resolved from the drug and degradation products. Recovery was near 100% over the 0.5 to 10% range for the major degradate (6-aminoquinoline) and over the 0.5 to 1% range for the other analytes. The method was applied to tablet samples stressed at high relative humidity and temperature. The relative standard deviation of the assay for the 6-aminoquinoline was less than 2% and less than 13% for the minor components. Calculated mass balances (sum of adinazolam plus degradation products in the degraded tablet divided by the same sum in the undegraded tablet) were less than 100% and were dependent on the extent of degradation in the tablet. The average mass balance result obtained for samples that were an average of 9.5% degraded was 95.0 +/- 1.5%. It is possible that the decrease in mass balance with increase in percent degradation may be explained by the formation of many components at trace levels due to degradation by various permutations of hydrolytic and oxidative reaction pathways.

Determination of the antileukemia agents cytarabine and azacitidine and their respective degradation products by high-performance liquid chromatography.

A reversed-phase high-performance liquid chromatography (HPLC) system was developed for the determination of the antineoplastic agents cytarabine and azacitidine. Separations were performed on an octadecylsilane column with a mobile phase of methanol-phosphate buffer pH 7.0 (5:95). The assay methods are suitable for bulk drugs and sterile powder formulations of the agents. Specificity in the presence of analogues and decomposition products was demonstrated. UV spectra of the components of interest were obtained in the HPLC effluent, and appropriate wavelengths were employed for the various analytes. Samples of azacitidine in various solutions were analyzed as a function of time by HPLC to determine the three first-order constants associated with its decomposition.

Determination of the fatty-acid composition of soybean oil by high-pressure liquid chromatography.

A method for determining the fatty-acid composition of soybean oil by using high-pressure liquid chromatography (HPLC) is discussed and compared with the determination using gas chromatography. The oil is saponified and an aliquot is treated directly to form the p-bromophenacyl esters of the fatty acids, which are separated by gradient-elution HPLC. It is shown that glycerol does not interfere with the esterification, thus obviating the solvent extraction previously used to isolate fatty acids from biological samples.