Chromatographic study of sitagliptin and ertugliflozin under quality-by-design paradigm

Abstract The present study entails the systematic development and validation of a stability-indicating RP-HPLC method for the analysis of sitagliptin and ertugliflozin in a fixed-dose combination. Analytical quality by design (AQbD) concepts were used to define critical method variables, employing Pareto risk assessment and a Placket-Burman screening design, preceded by a Box-Behnken design with response surface analysis to optimise critical method parameters such as % acetonitrile (X1), buffer pH (X2) and column oven temperature (X3). Multiple response optimisation (Derringer's desirability) of variables was accomplished by studying critical analytical attributes, such as resolution, retention time and theoretical plates. The title analytes were separated effectively on a PRONTOSIL C18 column at 37 °C using a mobile phase of acetonitrile:acetate buffer, pH 4.4 (36:64 percent v/v), pumped at a flow rate of 1 mL/min, and UV detection at 225 nm. Linearity was observed over a concentration range of 25-150 µg/mL and 3.75-22.5 µg/mL at retention times of 2.82 and 3.92 min for sitagliptin and ertugliflozin, respectively. The method obeyed all validation parameters of the ICH Q2(R1) guidelines. The proposed robust method allows the study of the selected drugs in pharmaceutical dosage forms as well as in drug stability studies under various stress conditions.

Separation and determination of D-malic acid enantiomer by reversed-phase liquid chromatography after derivatization with (R)-1-(1-naphthyl) ethylamine

Abstract L-Malic acid is the Active Pharmaceutical Ingredient of the latest generation of compound electrolyte injection (STEROFUNDIN ISO, Germany) and plays a very important role in the rescue of critically ill patients. The optical purity of L-malic acid is a Critical Quality Attributes. A new reversed-phase high performance liquid chromatography (RP-HPLC) method for pre-column derivatization of D-malic acid enantiomer impurity in L-malic acid bulk drug was established. The derivatization reaction was carried out using (R)-1-(1-naphthyl)ethylamine ((R)-NEA) as a chiral derivatization reagent. The Kromasil C18 column was used with a detection wavelength of 225 nm, a flow rate of 1.0 mL·min-1, and a column temperature of 30 °C. The mobile phase was acetonitrile-0.01 mol·L-1 potassium dihydrogen phosphate solution (containing 20 mmol·L-1 sodium heptanesulfonate, adjusted to pH 2.80 with phosphoric acid) (at a ratio of 45:55) and the resolution of D-malic acid and L-malic acid derivatization products reached 1.7. The proposed method possesses the advantages of simple operation, mild conditions, stable derivatization products and low cost. Also it gave better separation and was more accurate than previous methods

Extração de recomendações farmacológicas para subsidiar o processo de adaptação de guias de prática clínica utilizados no tratamento da fibrilação atrial não valvar - uma revisão sistemática de guias de prática clínica / Extraction of pharmacological recommendations to support the process of adaptation of clinical practice guides used in the treatment of non-valvular atrial fibrillation a systematic review of clinical practice guidelines

A fibrilação atrial (FA) não valvar é a arritmia cardíaca mais comum em adultos, principalmente na população idosa. Para o tratamento da FA, recomenda-se a utilização de guias de prática clínica (GPCs), que são documentos que apresentam as melhores e mais atualizadas evidências para o tratamento dos pacientes acometidos por essa arritmia. Todavia, o processo de desenvolvimento dos GPCs requer recursos humanos, financeiros e tempo. Assim, a adaptação dos referidos documentos é uma opção para reduzir a duplicação de esforços e possibilitar sua adequação para uso local. O objetivo deste trabalho foi elaborar uma matriz de recomendações farmacológicas para subsidiar o processo de adaptação de GPCs utilizados no tratamento da fibrilação atrial não valvar. Para tanto, aplicou-se o método ADAPTE: revisão sistematizada de GPCs, avaliação e seleção dos GPCs de qualidade e elaboração da matriz. Foram considerados elegíveis 26 GPCs com recomendações farmacológicas para assistência primária da fibrilação atrial não valvar em adultos, publicados em inglês, espanhol ou português no período de abril de 2014 a abril de 2019 e indexados às bases de referência: MEDLINE, Embase, Cochrane Library e em 12 bases de dados específicas. A qualidade dos GPCs, foi avaliada pela aplicação do instrumento Appraisal of Guidelines for Research & Evaluarion II (AGREE II), sendo considerados de alta qualidade aqueles que apresentaram nota igual ou superior a 60 % no domínio Rigor de desenvolvimento. Todas as etapas foram realizadas por, pelo menos, 2 avaliadores e em caso de discrepância, um terceiro avaliador participou do processo. Dos 26 GPCs avaliados apenas 7 (26,9%) foram considerados de alta qualidade. A maioria dos GPCs utiliza o escore CHA2DS2-VASc, que indica a profilaxia tromboembólica em pacientes com FA não valvar a partir da pontuação 1 (fator de risco não sexual) e sugere a anticoagulação com anticoagulantes de ação direta. Houve pouca ênfase à complexidade da profilaxia de eventos tromboembólicos em idosos. Esta matriz visa contribuir para que sejam realizadas discussões e adaptações de GPCs destinado ao tratamento da FA não valvar com ênfase nas demandas e necessidades locais

Non-valvular atrial fibrillation (AF) is the most common cardiac arrhythmia in adults, especially in the elderly population. For the treatment of AF, the use of clinical practice guidelines (CPGs) is recommended, which are documents that present the best and most up-to-date evidence for the treatment of patients who are affected by this arrhythmia. However, the CPGs development process requires human, financial and time resources. However, the adaptation of documents is an option to reduce the duplication of efforts and make it possible to adapt them for any local use. The objective of this work was to elaborate a matrix of pharmacological treatment to support the process of adaptation of CPGs used in the treatment of non-valvular atrial fibrillation. Therefore, the ADAPTE method was applied: systematic review of CPGs, evaluation and selection of quality CPGs and matrix definition. Twenty-six CPGs were considered eligible with pharmacological recommendations for primary care of non-valvular atrial fibrillation valid in adults, published in English, Spanish or Portuguese from April 2014 to April 2019 and indexed to the following reference databases: MEDLINE, Embase, Cochrane Library and in 12 specific databases. The quality of the CPGs was assessed by applying the Assessment of Guidelines for Research and Assessment II (AGREE II) instrument, being considered of high those who had a grade equal to or greater than 60% in the domain Rigour of development. All steps were performed by a least 2 evaluators and in case of discrepancy, a third evaluator participated in the process. Of the 26 CPGs evaluated, only 7 (26.9%) were considered to be of high quality. Most CPGs use the CHA2DS2-VASc score, which indicates thromboembolic prophylaxis in patients with non-valvular AF from score 1 (non-sexual risk factor), and suggest anticoagulation with direct-acting anticoagulants. There was little emphasis on the complexity of prophylaxis for thromboembolic events in the elderly. This matrix aims to contribute to discussion and adaptations of CPGs for the treatment of non-valvar AF with the emphasis on local demands and needs

Optimization of HPLC method using central composite design for estimation of Torsemide and Eplerenone in tablet dosage form

Abstract A simple, precise, accurate and robust high performance liquid chromatographic method has been developed for simultaneous estimation of Torsemide and Eplerenone in tablet dosage form. Design of experiment was applied for multivariate optimization of the experimental conditions of RP-HPLC method. A Central composite design was used to study the response surface methodology and to analyse in detail the effects of these independent factors on responses. Total eleven experiments along with 3 center points were performed. Two factors were selected to design the matrix, one factor is variation in ratio of Acetonitrile and the second factor is flow rate (mL/min). Optimization in chromatographic conditions was achieved by applying Central composite design. The optimized and predicted data from contour diagram comprised mobile phase (acetonitrile, water and methanol in the ratio of 50: 30: 20 v/v/v respectively), at a flow rate of 1.0 ml/min and at ambient column temperature. Using these optimum conditions baseline separation of both drugs with good resolution and run time of less than 5 minutes were achieved. The optimized assay conditions were validated as per the ICH guidelines (2005). Hence, the results showed that the Quality by design approach could successfully optimize RP-HPLC method for simultaneous estimation of Torsemide and Eplerenone.

Optimization of Diltiazem hydrochloride osmotic formulation using QBD approach

Abstract Diltiazem hydrochloride (DLH) is a calcium channel blocker useful for the treatment of angina pectoris, arrhythmia, and hypertension. DLH having a short half-life needs frequent administration for successful treatment but this poses a problem of poor patient compliance. These requirements are served by elementary osmotic pump tablets (EOP) based controlled-release (CR) systems. Quality by design (QbD) approach assists in screening various factors with subsequent assessment of critical parameters that can have a major impact on the scalability of EOP. Tablets were formulated using wet granulation method followed by osmotic coating. Factorial design based QbD strategy aided in defining the risk assessment of influential variables such as hydrophilic polymers and osmotic coat component on the in-vitro release kinetics of the designed EOP tablets. These formulated EOP systems followed zero-order kinetics, a characteristic feature of EOPs. EOP tablets were formulated applying a systematic QbD statistical approach. The formulated DLH EOP systems with improved concentration-independent behavior helped to address the challenges of IR formulation. Application of QbD strategy in ascertaining the scalability of DLH EOP formulation would help pharmaceutical industries in the translation of EOP based drug delivery systems from R&D to market.

Curso de gestión de la calidad para laboratorios / Course of management of the quality for laboratories Module 6. Equipment and materials

Medicina & Laboratorio ha recibido los derechos de publicación de la Organización Panamericana de la Salud, para reproducir en su totalidad el ®Curso de Gestión de Calidad para laboratorios¼, una excelente herramienta para el mejoramiento continuo del desempeño de los laboratorios. La vigilancia de la salud tanto individual como de la población general, el desarrollo de un número creciente de técnicas de laboratorio y la mejora continua de los métodos diagnósticos requieren la adopción de herramientas de gestión para su óptima implementación en los sistemas y laboratorios de salud. Por estas razones, entre otras, el concepto universal de calidad y el estudio de sus procesos se han extendido de la industria de la manufactura a las ciencias médicas. No sólo lo anteriormente mencionado, sino también el buen servicio y la satisfacción del cliente -o de los usuarios- son objetivos primordiales para los hospitales y laboratorios que tratan de establecer un sistema de gestión de la calidad que se adapte tanto a las necesidades operativas y fiduciarias de su organización, como a los requisitos prácticos de los usuarios: pacientes, médicos, epidemiólogos, autoridades sanitarias y comunidad entre otros.El objetivo de este curso es brindar capacitación en los principios básicos necesarios para la gestión de la calidad en los laboratorios. El contenido de los módulos incluye una información apropiada que, junto a la terminología descrita, permite la familiarización del participante con los conceptos básicos sobre las principales áreas de un sistema de gestión de la calidad.