Combination Approach of Salt Formation and Amorphous Solid Dispersions for Enhancing Aqueous Solubility and Dissolution Profile of BCS Class II Drugs
Loading...
Authors
Pansare, Siddhesh Mohan
Issue Date
2024
Type
Thesis
Language
en_US
Keywords
Amorphous Solid Dispersions , Aqueous Solubility And Dissolution , BCS Class 2 Drugs , Drug Delivery , Enhancing Solubility , Salt Formation
Alternative Title
Abstract
Purpose: Numerous pharmaceutically active drug molecules have recently been discovered owing to molecular modeling and high-throughput screening. However, their formulation and commercialization have been a major challenge due to their poor aqueous solubility and low bioavailability. Combining salt formation and amorphous solid dispersions (ASDs) is an emerging strategy that utilizes the benefits of crystal lattice energy depletion (by the amorphous form) and enhanced solvation energy and pH buffering effect (by salt formation), leading to improved aqueous solubility and dissolution rate. This project aims to optimize this dual approach for Biopharmaceutical Classification System (BCS) Class II weakly acidic drugs and potentially create formulations with enhanced aqueous solubility and dissolution profile.Methods: Three model BCS Class II drugs- indomethacin, gliclazide, and celecoxib were combined with four basic counterions to form salts by crystallization and solvent evaporation process. The prepared salts were characterized by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and Infrared spectroscopy (IR). Equilibrium solubility studies were performed on the formed salts in deionized water following the WHO protocol. The drug-counterion pair with the highest solubility was further selected for ASD preparation using hot melt extrusion (HME). Intrinsic dissolution studies were performed using a modified Wood's apparatus on prepared salt solid dispersions (SSDs), their corresponding salts and compared.
Results: Elevation in melting point using DSC combined with IR peaks confirmed salt formation for all drug-counterion pairs. All the prepared salts had more aqueous solubility as compared to pure drugs, with indomethacin arginine, gliclazide sodium, and celecoxib sodium showing maximum enhancement of 3666, 189, and 372 times the pure free drug, respectively. These three counterions were further used to prepare SSDs. Intrinsic dissolution rate (IDR) was calculated for pure drugs and compared to individual approaches (Salt and ASD) and the combined approach (SSD). The SSDs of model drugs showed significant improvement in IDR compared to individual approaches.
Conclusion: The dual approach of salt formation and amorphous solid dispersions resulted in higher solubility and intrinsic dissolution rate than the individual approaches alone, suggesting that the combination approach was successful.
Description
2024
Citation
Publisher
Creighton University
License
Copyright is retained by the Author.
A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.