Preparation of Multi Unit Rapid Disintegrating Controlled Release (RDCR) Granules by Wet Granulation Using Fluidized Bed Drying for Chronotherapeutic Drug Delivery System for Valsartan

Background

The Multi unit-controlled release dosage forms is a drug delivery system offering advantage over traditional monolithic controlled release system in achieving persistent and predictable drug delivery. Multiple unit dosage forms have advantages over single unit dosage form like more predictable gastric emptying, low intra or inter individual variability, lower risk of overdose and local irritation, gastric emptying less depend on nutritional status etc. Normally Multiple-Unit Dosage Forms (MUDF) are more complex technology requiring sophisticated manufacturing equipment like fluid bed processors, hot melt extruder, Extrusion and Spheronization etc. and capsule filling of Pellets. In this research work, a new Multi-Unit Rapid Disintegrating Controlled Release (RDCR) granules technology was manufactured using cost effective wet granulation technique producing controlled release granules for management of hypertension using model drug as Valsartan (VAL) is developed and compared against the conventional monolithic controlled release system of VAL.

Materials and Methods

Valsartan (VAL) is employed as the active pharmaceutical ingredient, lactose monohydrate as a diluent, hypromellose as a binder and pore former, ethyl cellulose as a release-regulating polymer, and Triethyl Citrate (TEC) as the plasticizer to increase the flexibility of the coat. Granules uniformity was controlled by granule size distribution by granulation, sizing and drying and release of VAL was controlled by ethyl cellulose coating as well as drying process parameter. The flexibility of the ethyl cellulose film and the strength of the RDCR granules were adjusted with TEC. The VAL RDCR was intended as a chronotherapeutic drug delivery system. This study did not involve any human participants, human biological samples, or animal subjects. All work was limited to pharmaceutical formulation development and in vitro evaluation.

Statistical Analysis

In vitro drug-release data were analysed using nonlinear regression analysis to elucidate the release kinetics and release mechanism of the developed RDCR tablets. Dissolution profiles were fitted to various kinetic models, including zero-order, first-order, Higuchi, Korsmeyer-Peppas, and Hixson-Crowell models. Release rate constants and kinetic parameters were calculated for each model. Model selection and goodness-of-fit were evaluated using statistical criteria such as adjusted coefficient of determination (Adjusted R²), Akaike Information Criterion (AIC), Model Selection Criterion (MSC), and Mean Square Error (MSE). The model exhibiting the highest Adjusted R² and MSC values along with the lowest AIC and MSE values was considered the best fit. All kinetic and statistical analyses were performed using DDSOLVER software.

Results and Discussion

The release of VAL derived from RDCR was evaluated by nonlinear regression analysis, release rate constant, and other kinetic parameters and compared against immediate release granules of valsartan. It was found that RDCR efficiently controls the release of VAL effectively over 18 hr. and act as a multi-unit modified release granules technology. The study results show granules can withstand tableting force for its integrity and can be a surrogate to currently available complex MUPS and Pelletization technology.

Conclusion

The RDCR offers advantages over other current technologies such as MUPS, Palletization, Extrusion Spheronization, and is more robust in terms of content uniformity, control over drug release and uniformity, tableting qualities, and production costs. The RDCR granules can be utilized for manufacturing different dosage forms like tablets, sachets, powder for oral suspension etc.