(T1130-08-53) Miniaturized Screening Tool for Evaluating Solubility Enhancement Across Multiple Active Pharmaceutical Ingredients

Purpose: Spray Drying (SD) and Hot Melt Extrusion (HME) enhance drug solubility but require large Active Pharmaceutical Ingredient (API) quantities, are time-consuming, and need extensive efforts during development. To make this process easier, our study presents a miniaturized screening tool (MST) that allows researchers to quickly test different combinations of the API and polymers. The study involves preparation of amorphous solid dispersion using smaller quantities of API and polymer, providing information on the amorphous or crystalline nature of solid dispersion along with solubility data. This tool accelerates the testing phase and lays the basis for subsequent laboratory work, enhancing the efficiency and effectiveness of the solubility improvement process.

Methods: Part I- Methodology for SD-MST technology: For SD-MST, experiments were conducted using flat, non-treated 12-well and 24-well polystyrene cell culture plates. The instrument used was a Nitrogen evaporator that purges heated nitrogen through jets into the solutions, resulting in the evaporation of solvents in the wells of the well plate, leaving a residue. In the current study, celecoxib (anionic), fenofibrate (neutral) and ritonavir (cationic) representing three different classes of drugs, were selected as model drugs. They were screened with EUDRAGIT^® L 100-55 as carrier polymer at various ratios of drug to polymer. A 24- well plate was used for preparation of solid dispersion, where sample was scrapped for DSC experimentation. A 12-well plate was used for solubility determination. The polymer solutions (10% for DSC study & 1% for solubility study) and API solutions (2% for DSC study & 0.2% for solubility study) were prepared separately in ethanol. A known amount of drug and polymer solution were added to each well of the well plate, to get required ratio of drug to polymer. The volume of the API-polymer solution would range from 1.2-2.8 mL per well for DSC plate & 0.12 to 0.28 mL per well for solubility plate based on the ratio. The solution in the well plate was mixed using a vortex mixer and then placed in a nitrogen evaporator. Here the solvent was evaporated by continuous nitrogen flow to obtain solid dispersions. After evaporation, the plate was equilibrated for 24 hours at room temperature. For DSC study, residue from 24-well plate was scrapped, and DSC was performed to determine crystalline or amorphous nature of the solid dispersion. For solubility determination, 2 mL solubility media was added to each well of 12-well plate, and the plate was stirred for 2 hours using a vortex mixer. Filtered solution was then analyzed by HPLC. Part II- Methodology for HME-MST technology For HME-MST, experiments were conducted using a 5 mL glass beaker kept in a perforated stand in an oil bath. The API and polymer of interest were mixed well in a polybag to obtain 1 to 1.5 g of mixture in different ratios. A sample quantity of 100 mg was weighed in a 5 mL beaker and melted using an oil bath. In the current study, celecoxib (anionic), fenofibrate (neutral) and clotrimazole (cationic), representing three different classes of drugs, were selected as model drugs. They were screened with the carrier polymers EUDRAGIT^® E PO (for celecoxib and fenofibrate) and EUDRAGIT^® L 100-55 (for clotrimazole) at various ratios of drug to polymer. After melting, the beaker was equilibrated for 24 hours at room temperature. For DSC study, residue from the beaker was scrapped, and DSC was performed to determine crystalline or amorphous nature of the solid dispersion. For solubility determination, 5 mg of scraped material was stirred in solubility media at 37°C and 360 RPM for 2 hours using magnetic stirrer. Filtered solution was then analyzed by HPLC. Part III- Verification of tool The results from MST were verified against the solubility of actual R&D batches. The ratio showing improved solubility was selected for R&D-scale experiments using SD and HME. Actual dissolution of these batches was conducted, and the results were then compared to verify the performance of the tool.

Results: As shown in Tables 1 and 2, suitable combinations were identified during the screening study. Lab experiments confirmed their similarity, supporting tool verification

Conclusion: In a single study, 24 different combinations were screened using the SD technique, and another 12 combinations were evaluated in a HME technique utilizing the miniaturized screening tool. The solubility method was found to identify optimal API: polymer ratio for the preparation of solid dispersions through spray drying or hot melt extrusion. The developed screening methods for SD and HME techniques provide results comparable to actual lab dissolution studies, reinforcing the reliability of the screening. The miniaturized tool can be very useful in accelerating the identification of promising prototype compositions and pre-selection of appropriate polymers for solid dispersions for solubility enhancement.

Table-1: Spray Drying Screening Tool for Solubility Enhancement

Table-2: HME Screening Tool for Solubility Enhancement