Development of dosage form composition using response surface methodology

Introduction. Matrix tablets have great potential as an oral drug delivery system due to their simplicity, reduced risk of systemic toxicity and minimal likelihood of dose splitting effects. Based on the DoE design of experiments, the response surface methodology involves generating polynomial equations and response in the experimental domain to determine the optimal formulation of a dosage form. Traditionally, developers select optimal formulations by changing one variable at a time, a time-consuming method. However, many experiments fail to achieve their goal because they are not thought out and designed properly, and even the best data analysis cannot compensate for the lack of planning. Therefore, it is important to understand the impact of variables in a pharmaceutical product formulation on quality using a minimum number of experimental trials and variables to develop an optimized formulation using established statistical tools.

Aim. Development of a modified release matrix tablet formulation based on 3,6,9-triazatricyclotetradecane derivative using response surface methodology.

Materials and methods. The object of the study is the drug candidate compound QM-25, a derivative of 3,6,9-triazatricyclotetradecane. A 2³ full factorial experiment was used to develop the composition of the matrix tablet based on QM-25. The matrix tablets were obtained by direct compression on a rotary press after proper mixing of suitable ratios of various hydrophilic polymers as release modifiers with other excipients. A tablet hardness tester was used to calculate the crushing strength of the prepared matrix tablets. The in vitro release studies were carried out on a dissolution apparatus II "Bladder mixer", at 50 rpm and a temperature of 37 ± 0.5 °C in two stages for drugs of group 2 in accordance with OFS.1.4.2.0014. The completeness of the formulation release after 2 hours 45 minutes in % and the tablet crushing hardness in N were selected as the responses of the factorial design system. To select the optimal formulation and to evaluate the influence of the effects of different variables on the measured responses, a mathematical model equation was used, including independent variables and their interactions for the different measured responses generated by the design 2³. Data approximation and regression parameters were calculated using the built-in Data Analysis module of Microsoft Excel. To construct the regression equation in Microsoft Excel, a matrix was constructed using the correlation function.

Results and discussion. The algorithm of the response surface methodology based on the regression model is presented. Each response coefficient of the design parameter space was studied for its statistical significance. Factors with values in the interval p < 0.05 were identified. Using the regression model, regression coefficients of the main factors affecting release and crushing strength were established in the model equation, equations for the dependence of factors on responses, and the paired effect of the amount of sodium alginate and carbomer 940 per unit of the dosage form were derived. The influence of the main effects (factors) on the studied formulations was analyzed using the design parameter space with visualization in three-dimensional space. To select the optimal composition with the desired responses, a numerical optimization method was used based on the approach to obtaining the desired values, which made it possible to select the optimal values of the content of excipients per unit of the model composition of the dosage form.

Conclusion. Using the design method – construction of the design parameter space, the influence of many parameters of the matrix tablet composition was studied using a small number of experiments. The mathematical relationship between the X factors and the Y response indices was established using the calculated regression model for the solid dosage form based on the 3,6,9-triazatricyclotetradecane derivative. The calculated factor dependencies using the regression model allowed us to establish the optimal model composition of the solid dosage form with modified release for further experimental studies, the crushing strength values of which were in the confidence interval acceptable for tablets with the used punch diameter, and the dissolution kinetics results demonstrated the nature of the modified release behavior.

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