(T1130-02-10) Enhancing Aqueous Solubility of BCS Class II Drugs Through a Dual Approach of Salt Formation and Amorphous Solid Dispersion

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. Around 60-70% of new molecular entities (NMEs) belong to the BCS Class II with low solubility and high permeability. Various amorphous solid dispersion formulations (ASDs) by Hot Melt Extrusion (HME) have been developed to overcome this problem of poor aqueous solubility. However, impaired drug release and poor physical stability have been significant challenges with these formulations. Since most currently marketed drug products contain either weak bases or weak acids, salt production is the most frequently employed method for increasing their solubility. Combining salt formation and amorphous solid dispersions is an emerging strategy that unifies the benefits of both amorphization and salt formation. This technique increases aqueous solubility by taking advantage of the effects 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. The salt formation has also led to an elevation in Glass Transition temperature (T_g) which helps to make the ASDs more stable and prevents the drug from recrystallization. This study aims to optimize this dual approach for BCS Class II weakly acidic drugs and potentially create formulations with enhanced aqueous solubility, dissolution, and physical stability.

Methods: Indomethacin and Gliclazide belonging to BCS Class II were used as model drugs. Salts were formed using multiple basic counterions, which were selected based on their pK_a values making sure that difference in the pK_a of the drug and the counterions is > 3. The model drugs and the counterions (sodium hydroxide, L-arginine, piperazine, diethanolamine, meglumine, and potassium hydroxide) were each dissolved in a suitable organic solvent (Methanol or ethanol) and mixed in a 1:1 molar ratio. The resulting mixture was subjected to solvent evaporation using rotary evaporator. The pressure was decreased stepwise from 500 mbar to 150 mbar at 60°C or 80°C based upon the solvent used (methanol or ethanol, respectively) with a rotational speed of 100 rotations per minute (rpm). Upon complete evaporation of the solvent, the salts were air-dried and stored in a desiccator for 24 hours. The prepared salts were characterized by thermal analyses (differential scanning calorimetry (DSC) and thermogravimetric analysis) and structurally by using Infrared spectroscopy (FTIR). Equilibrium solubility for all the formed salts was determined in 1 mL of deionized water. An excess quantity of salts and pure model drugs were added to the water and kept for 24 hours in an incubator shaker following the WHO's protocol for equilibrium solubility. The samples were centrifuged for 15 mins, diluted with the mobile phase, and analyzed using UV-visible Spectrophotometer at each drug's ƛ_max. The Drug-counterion pair with the highest solubility was selected for ASD preparation using HME. The polymer used to disperse the drug was Soluplus, a commercially available polymer proven effective in improving solubility and dissolution of poorly soluble drugs. The drug, counterion, and Soluplus were all added simultaneously (in situ salt formation) through the feeder of the extruder. The temperature was adjusted to 110°C, and the twin screw speed was maintained at 50 rpm. Kolliphor P188 plasticizer was added for better HME processability.

Results: Solvent evaporation by rotary evaporator proved effective in preparing crystalline and stable salt forms of both drugs. Most of the salts had sharp endothermic peak, which shifted from the pure drug suggesting possible salt formation. Diethanolamine and Meglumine pairs led to the formation of a thin film instead of solid salts. TGA showed negligible weight loss in most salts before reaching their degradation temperature. IR spectra indicated the shift of carbonyl group from 1705-1720 cm^-1 of Indomethacin to a shorter wavelength in its sodium, arginine, and piperazine salts because of its ionization due to salt formation. The Gliclazide salts also showed similar results, with carbonyl groups shifting to a smaller wavelength for the same three counterions. All the salts had greater solubility after 24 hours compared to pure drugs, with sodium salt of both drugs showing maximum improvement. Indomethacin sodium had almost 200 folds increase in aqueous solubility and hence was chosen for preparing ASD. The prepared Indomethacin ASD and sodium salt ASD showed no sharp endothermic peak suggesting amorphization with a slight shift in baseline (T_g). Sodium salt ASD had a higher T_g than Indomethacin, had negligible weight loss, and increased solubility by 225 folds

Conclusion: The dual approach of salt formation and amorphous solid dispersions resulted in higher solubility when compared with the individual approaches alone, suggesting synergetic action between the two techniques. Salt ASD had a higher T_g, implying low recrystallization tendency of the drug with better physical stability.

References: 1. Mesallati H, Tajber L. Polymer/Amorphous Salt Solid Dispersions of Ciprofloxacin. Pharm Res. 2017 Nov 1;34(11):2425–39.

Acknowledgements:Acknowledgment: Grateful to the School of Pharmacy and Health Professions for funding the project.