Development of Delayed Release Oral Formulation Comprising Esomeprazole Spray Dried Dispersion Utilizing Design of Experiment As An Optimization Strategy.

Abstract

Solid dispersion (SD) technology is one of the most widely preferred solubility enhancement methods, especially for Biopharmaceutics classification system class II and IV drugs. Since the last decade, its application for the dual purpose of solubility hike and modified release using novel carriers has been in demand for its added advantages. Spray drying is a commercially accepted technique with high aspects of scalability and product characteristics. The current study used spray-dried dispersion to design delayed release capsule for the proton pump inhibitor esomeprazole. The SD carrier hydroxypropyl methylcellulose acetate succinate-medium grade (HPMCAS-MF) enhanced solubility, inhibited precipitation of saturated drug solutions, and allowed enteric release owing to its solubility above pH 6. The proposed approach avoided compression, coating with enteric polymers, and the development of multi-particulate pellet-based formulations, improving manufacturing feasibility. The formulation was optimized using Box-Behnken design, considering significant formulation variables like HPMCAS-MF proportion and critical process parameters like feed flow rate and inlet temperature. The optimized spray-dried dispersion were characterized based on Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM) and also evaluated for solubility, in vitro drug release, residual solvent content, and stability testing. Response surface methodology optimization anticipated that formulation variables affected solubility and release profile, whereas CPPs affected yield. The design space was developed via overlay plot based on constraints specified to attain the desired response and validated using three checkpoint batches with desirability 1. FTIR showed active pharmaceutical ingredient-polymer compatibility. Particle size and SEM studies showed spherical particles with an average Z-value of 1.8 µ. DSC and PXRD confirmed SD's amorphous nature. The drug release investigation and release kinetics prediction utilizing DD-solver software showed a 2-h lag time with > 90% cumulative drug release up to 4h for the DR formulation. ESM SDD were prepared by spray drying technique using the novel solid dispersion carrier HPMCAS-MF to serve the dual purpose of solubility enhancement and delayed release. The ratio of API:carrier and process variables like feed flow rate and inlet temperature were varied using the Box-Behnken Design to determine the design space of optimized product to procure the desired characteristics of solubility improvement compared to crystalline API and delayed release of PPI to avoid the degradation in the gastric environment. The developed formulation represents several benefits over the already existing marketed products.