Optimization of Monolayer Hydrophilic Matrix Tablets Containing Nisoldipine Solid Dispersion Using D-optimal Design

Abstract

Abstract: Background: Nisoldipine (NIS) is a BCS-class II drug with a low oral bioavailability (~5%). The popular marketed product is a trilayer Geomatrix® system. Although it provides for drug release control of NIS, a trilayer matrix system is a complex design, which is difficult to manufacture on an industrial scale using conventional press. The present study discusses an alternate approach to improve drug dissolution using solid dispersion (SD) method followed by design of a simple monolayer controlled release (CR) matrix system. Methods: Aqueous drug solubility study was carried out at various copovidone levels. NIS-copovidone SD was prepared by hot-melt extrusion and was characterized by infrared spectroscopy (FTIR) and scanning electron microscopy (SEM). A risk assessment based approach was used to select the factors and levels affecting the design of a monolayer matrix tablet. A custom screening design of experiments was used to screen the type and level of excipients followed by a D-optimal mixture design and the dissolution profile was selected as the main response to statistically analyze the data to optimize the final formula. Results: A solvent free approach by hot-melt extrusion was used to prepare NIS-copovidone solid dispersion at 20% drug load, which lead to a significant improvement in dissolution (T90 = 30 min). An interaction between the drug and polymer was revealed in FTIR studies. No drug crystals were seen in SEM studies indicating its presence in a substantially amorphous state in the SD. The statistical analysis of in vitro dissolution data of screening study revealed that high viscosity hypromellose and diluent type had significant effect (p<0.05) on dissolution while the hardness of the tablet had no significant effect (p>0.05). The mixture design thereafter predicted the optimum formula through a significant model. High and low viscosity hypromellose (66:44) at ~17% w/w of matrix provided the desired drug release control. Conclusion: Dissolution enhancement could be attained by SD prepared using solvent free process. D-optimal mixture design approach, where the unit weight remains constant in spite of controlled variation in level of factors studied, was found to be a promising approach in pharmaceutical formulation optimization. A combined approach of SD and CR was found to be a promising strategy for better control of the drug release in a relatively simple monolayer matrix compared to a complex trilayer design. Key words: Nisoldipine, Solid Dispersion, Design of Experiments, Screening, Mixture Design