This manuscript describes comprehensive approach for assessment of degradation behavior of simvastatin employing experimental design methodology as scientific multifactorial strategy. Experimental design methodology was used for sample preparation and UHPLC method development and optimization. Simvastatin was subjected to stress conditions of oxidative, acid, base, hydrolytic, thermal, and photolytic degradation. Using 2n full factorial design degradation conditions were optimized to obtain targeted level of degradation. Screening for optimal chromatographic condition was made by Plackett–Burman design and optimization chromatographic experiments were conducted according to Box-Behnken design. Successful separation of simvastatin from the impurities and degradation products was achieved on Poroshell 120 EC C18 50 × 3.0 mm 2.7 μm, using solutions of 20 mM ammonium formate pH 4.0 and acetonitrile as the mobile phase in gradient mode. The proposed method was validated according to International Conference on Harmonization (ICH) guidelines. Validation results have shown that the proposed method is selective, linear, sensitive, accurate, and robust and it is suitable for quantitative determination of simvastatin and its impurities. Afterwards, the degradation products were confirmed by a direct hyphenation of liquid chromatograph to ion-trap mass spectrometer with heated electrospray ionization interface. This study highlights the multiple benefits of implementing experimental design, which provides a better understanding of significant factors responsible for degradation and ensures successful way to achieve degradation and can replace the trial and error approach used in conventional forced degradation studies.

This study involved the optimization of experimental conditions for the forced degradation of atorvastatin employing the experimental design (DoE) approach, as a scientific multifactorial strategy. Using 2n full factorial design, stress conditions of oxidative, hydrolytic and thermal degradation were optimized to obtain a targeted level of atorvastatin degradation. Atorvastatin and all related and degradation products were separated on Poroshell 120 EC C18 50 ´ 3.0 mm 2.7 μm, using 10 mM ammonium formate and acetonitrile as mobile phases in the gradient mode. The impurity structures were confirmed by the direct hyphenation of a liquid chromatograph to an ion trap mass spectrometer with a heated electrospray ionization interface.This study highlights the multifold benefits of implementing the DoE concept, which provides a better understanding of the significant factors responsible for degradation and ensures a successful way to achieve degradation, thereby replacing the trial and error approach used in conventional forced degradation studies.

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In vitro dissolution profiles are increasingly used to evaluate drug release characteristics of pharmaceutical products. The dissolution methods is expected to be an appropriate tool for checking consistency of the pharmaceutical attributes by discriminating similarities and dissimilarities between different drug formulations. Expansion in development of novel “special” dosage forms, due to the manner in which these dosage forms release the active pharmaceutical ingredient, usually requires applying non-compendial dissolution strategy that differs from the traditional compendial recommendations. For demonstrating sameness in the dissolution profile, in vitro drug release comparison between test and reference product of highly viscous oral suspension by applying non-compendial peak vessel against conventional hemispheric vessel was demonstrated in this study. All reference batches exhibited high variability in dissolution data when using hemispheric vessel due to forming mound compact mass at the bottom of the vessel. Different strategies for samples manipulation, before and during dissolution period, were performed in order to eliminate additional variabilities. Modifications of conventional USP 2 apparatus such as using peak vessel provided with more reproducible and reliable result for distinguishing in vitro similarities between different formulations of oral suspensions. Misinterpretation of dissolution data can lead to negative impact on product development. Taking time to observe and evaluate what is happening to the product in the vessel during dissolution is of curtail consideration for proper selection of the dissolution strategy. Keywords: oral suspensions; in-vitro release; hydrodynamic variability; USP apparatus 2/ Paddle apparatus; peak vessel

This manuscript presents chemometrically assisted optimization and validation of UPLC method intended for the quantitative analysis of simvastatin in pharmaceutical preparations. To achieve the desired chromatographic response and to simultaneously optimize the most important chromatographic parameters with a limited number of experiments in a minimum amount of time, Box-Behnken design was used. The separation was performed on Poroshell 120 EC C18 50 x 3.0 mm 2.7 μm, using 10 mM ammonium formate pH 4.0 and acetonitrile as the mobile phase. To obtain complete information about method performance and robustness, seven factors (column type, acetonitrile content, temperature, pH of mobile phase, molarities of ammonium formate, flow rate and wavelength) were assessed in twelve experiments according to Plackett–Burman design. The proposed method was validated according to International Conference on Harmonization (ICH) guidelines to confirm specificity, linearity, precision, detection and quantification limits. Validation results have shown that the proposed method is selective, linear, accurate, sensitive (LOD 0.06 μg/mL and LOQ 0.18 μg/mL), and robust and it is suitable for quantitative determination of simvastatin in pharmaceutical preparations. The optimized and validated method gives rapid and efficient separation and represents an improvement over the existing methods especially in the terms of sensitivity, low cost of analysis per sample and the environmental impact of the method. Keywords: chemometry, design of experiments, UPLC/DAD, simvastatin