Comprehensive Assessment of Degradation Behavior of Simvastatin by UHPLC/MS Method, Employing Experimental Design Methodology

Abstract

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.

Mass spectrometry-based structure elucidation of small molecule impurities and degradation products in pharmaceutical development

“…Although a one-parameter-at-a-time experimental setup is common practice in forced degradation studies and following method development, also multivariate and DoE approaches have been described [31][32][33]. For drug combinations consisting of multiple APIs, the drug-drug compatibility must be shown and the development of stability indicating methods can sometimes be challenging in terms of the selection of the most appropriate wavelength for UPLC-MS analysis [23,34].…”

Quality-by-Design Based Development and Validation of Stability Indicating Method by UPLC Method for Impurities of Simvastatin from Drug and Pharmaceutical Dosage Form

“…The OFAT is very time consuming and lengthy process which generates voluminous data, resulting in a tedious approach. Also, once the method is developed, the method still may need additional efforts when validated [1] . The modern pharmaceutical analysis and regulatory scenario, demands to use novel chemometric tools which control many variables simultaneously and helps to provide desired results with minimum experimental trials.…”

“…This can be achieved by implementing Quality-by-Design (QbD) approach in analytical method development. In International Conference on Harmonization (ICH) guideline Q8(R2) for Pharmaceutical development, QbD is defined as "A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management" [1,2] . The elements of QbD can be extended for analytical method development.…”

“…The literature shows few methods for estimation of SMV along with its impurities are reported in the literature such as HPLC with Ultra-Violet detection [8][9][10][11][12] . The degradation behavior studies using ultra-high performance liquid chromatography (UHPLC)/Mass spectrometry (MS) is reported [1] . There are various stability indicating methods available for determination of SMV along with the other drugs and its degradation products [13][14][15][16][17] .…”