Purpose: Solubility enhancement by Spray Drying (SD) and Hot Melt Extrusion (HME) technique involves a wide choice of polymers and their ratios, which usually requires larger quantities of API, time and manual efforts for the experiments. In this study, a screening tool was developed to enable the formulator to screen a large number of polymers and formulations in a short time and with minimum API amounts. The results coming out of the screening will be the basis for following lab development.
Methods: Screening tool for Spray Drying technology: Instead of actual lab experiment, in the screening tool, miniaturized experiments were conducted using a 24 well plate and a nitrogen evaporator.
24-well plate: A 24 well plate is a set of small wells in a plate of 128 mm to 86 mm. The well plate is made of polystyrene. Each flat well has a capacity of 3.5 mL.
Nitrogen evaporator- Nitrogen evaporator is an instrument, which purges nitrogen through jets into the solutions, in the wells of the well plate. The nitrogen can be heated if required during purging. It also has an option of heating the solution in the wells during purging of nitrogen.
Procedure- In the current study, Felodipine (neutral), Celecoxib (anionic) and Ritonavir (cationic) representing three different classes of drugs were selected as model drugs. They were screened for carrier polymers EUDRAGIT® E PO, EUDRAGIT® RS PO, EUDRAGIT® RL PO, EUDRAGIT® L 100, EUDRAGIT® L 100-55, EUDRAGIT® S 100 and EUDRAGIT® FS 100 at different ratios (1:1 and 1:9). Ethanolic solutions of the three drugs were prepared. The polymers were dissolved separately in appropriate solvents as per their solubility. A known amount of drug solution and polymer solution were added to each well of the 24 well plate, in order to have ratios of 1:1 and 1:9 of drug to polymer. The volume of the API-polymer solution would range from 0.5 to 2.5 mL per well based on the ratio. The solution in the well plate was mixed well using mechanical shaker and then placed in the Nitrogen Evaporator. Here the solvent was evaporated by continuous nitrogen flow to obtain a solid dispersion. After evaporation, the plate was equilibrated for 24 hours at room temperature. The residue in each well was scraped and the powder was analyzed by Differential Scanning Calorimeter (DSC) to check amorphous or crystalline nature. The study was further confirmed for reproducibility and results were compared with actual R&D experiments, for the validation of the tool.
Screening tool for Hot Melt technology:
To miniaturize hot melt technology, 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 1-1.5 g of mixture in different ratios. Sample quantity of 100 mg was weighed in 5 mL beaker and melted using oil bath.
Procedure- In the current study, Fenofibrate (neutral), Celecoxib (anionic) and Ritonavir (cationic) representing three different classes of drugs were selected as model drugs. They were screened for carrier polymers EUDRAGIT® E PO, EUDRAGIT® RS PO, EUDRAGIT® RL PO, and EUDRAGIT® FS 100 at different ratios (1:1 and 1:9). After melting, the beaker was equilibrated for 24 hours at room temperature and then the residue was scraped and powder analyzed by DSC to check amorphous or crystalline nature. The study was further confirmed for reproducibility and results were compared with actual R&D experiments for the validation of the tool. Batches showing discriminatory results in terms of polymer and ratios were chosen for the confirmation with actual R&D experiments.
Results: Solid dispersions with different polymers and at different ratios could be obtained using above tools. The amorphous or crystalline nature could be identified using DSC. As shown in table 1, the reproducibility study and actual lab experiments confirm the similar nature by DSC, thereby assuring prediction of suitable combination
Conclusion: In a single study, 24 different combinations were screened for SD experiments and 12 combinations in hot melt study The screening tool developed was found to precisely identify the best EUDRAGIT® polymer and the best polymer: API ratio, for preparation of solid dispersions through spray drying or hot melt extrusion respectively. This pre-selection of appropriate polymers for solid dispersions can be very useful to accelerate the identification of promising prototype compositions for solubility enhancement.
Firouz Asgarzadeh– Director Formulation and Application Services, Evonik Corporation, New Jersey
Shraddha Joshi– Director, Formulation Development Orals, Evonik India Pvt Ltd, Mumbai, Maharashtra
Smitha Shetty– Head of Analytical Development, Evonik Industries
Preeti Patil– Evonik Industries
Anurag Salgaonkar– Evonik Industries, Mumbai
Priyanka Haksar– Evonik Industries
Viraj Kulthe– Evonik Industries
Anurag Salgaonkar– Evonik Industries, Mumbai