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A stability-indicating high-performance liquid chromatography (HPLC) procedure was developed for the determination of metformin HCl (MTH), atorvastatin calcium (AC) and glimepiride (GP) in combination and their main degradation products. The separation and quantization were achieved on a 5-µm Qualisil gold, C18 column (4.6 mm × 250 mm). The mobile phase selected was phosphate buffer ( pH 2.9)-organic phase in proportion of 70:30. Organic phase consisted of methanol-acetonitrile (90:10) at a flow rate of 1 mL/min and detection of analytes was carried out at 230 nm. The method exhibited good linearity over the range of 10-60 µg/mL for MTH, 2-20 µg/mL for AC and 5-30 µg/mL for GP. Square of the correlation coefficients was found to be >0.999. Various stress degradation studies were carried out in combination as per International Conference of Harmonization (ICH) guidelines for 4 h. The recovery and precision were determined in terms of intraday and interday precisions and expressed as relative standard deviations. These were <1 and <2%, respectively. Finally, the applicability of the method was evaluated in nanoparticle analysis of MTH, AC and GP as well as in stability studies of nanoformulation.

Atorvastatin, an HMG CoA reductase inhibitor, is widely used for the treatment of dyslipidemia and prevention of cardiovascular disease. It belongs to Class 2 of the Biopharmaceutics Classification System owing to its low solubility and high permeability. In vitro dissolution testing is an essential tool for the design of a dosage form. Appropriate selection of dissolution test conditions is essential since it will help establish an appropriate in vitro-in vivo correlation (IVIVC), which is imperative for a waiver of costly bioequivalence studies. Compounds belonging to BCS Class 2 are suitable for establishing a significant IVIVC. USP Apparatus 4 (flow-through cell) is an attractive alternative to conventional dissolution methods like Apparatus 1 and 2. The ability of the apparatus to maintain sink conditions over a longer period of time has proved useful in the development of dissolution methods for poorly soluble drugs, making the development of IVIVCs easier for such drugs. Nanoparticles of atorvastatin were formulated by an emulsion-solvent evaporation method to overcome its bioavailability problems. Development of a discriminatory dissolution method for the same was attempted using a flow-through cell (Apparatus 4) because dissolution performed using Apparatus 1 did not provide complete release of the drug within 60 min. Phosphate buffer pH 6.8 with 1.5% SLS was selected as the dissolution medium based on the results of the solubility studies. Various parameters such as flow rate and sample-loading method were optimized. The dissolution method was validated with respect to various parameters as per ICH guidelines.

Introduction: Surface engineering of nanocrystals for improving the biopharmaceutical features is a multivariate process involving numerous formulation and process variables, thus making it a complicated process to get the desired biopharmaceutical quality profile. Nano-by-design is hereby proposed as an approach to nanonize an orally active, lipid lowering fenofibrate, to improve feasibility in product development. Methodology: Top-down wet ball milling (media milling) in zirconia planetary chamber was methodically explored for improving the solubility and bioavailability of fenofibrate by formulating a nanosuspension using polyvinyl alcohol as a stabilizer. Several influencing variables were screened using a systematic one-factor-at-a-time approach. DSC, SEM, XRD, and FTIR were utilized for physical characterization of the product during the development stage and study the effect of milling time, milling speed, fenofibrate: stabilizer ratio, premilling time and stabilizer concentration. Potential risk factors affecting critical quality biopharmaceutical attributes of fenofibrate nanocrystals like size, zeta potential, in vitro release, crystallinity and intrinsic solubility were optimized to improve pharmacokinetic performance. Result: Formulated nanosized fenofibrate exhibited a crystalize nature as evident from XRD and DSC, 411 nm size, and a rapid but complete dissolution (~99% in 30 min). This resulted into quick onset of action and improved bioavailability as observed from 51.46% shorter Tmax, 82.63% higher Cmax, and 69.34% higher AUC0–24h, respectively.

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