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Manufacturing and Analytical Characterization - Chemical

Category: Poster Abstract

(T1430-08-52) Application of Twin-Screw Extrusion for Generating Polymorphs to Support Phase Mapping and Scale Up Crystallization of the Desired Form

Tuesday, October 24, 2023
2:30 PM – 3:30 PM ET


Purpose: Twin screw extrusion (TSE) is an efficient, scalable, and environmentally friendly process for the manufacture of polymorphs/co-crystals/salts with little to no solvent requirements.1,2 TSE was utilized to apply mechanochemistry to support process investigations for scaling API unsolvated polymorphs to map their thermodynamic stability.

Methods: In an attempt to make unsolvated Form A, a methanol solvate of the API was run through the Leistritz ZSE-12-40D utilizing a screw temperature of 80 °C and a screw speed of 10 rpm, while attempts to make unsolvated Form B were conducted when the methanol and ethyl acetate solvates were run separately through the extruder utilizing a screw temperature of 190 °C and a screw speed of 300 rpm. Unsolvated Form C was made by reverse addition of an acetone solution into water, while unsolvated Form D was made via desolvation of a liable toluene solvate via suction filtration at ambient conditions. Solubility as a function of temperature was measured on the various polymorphs via a Pion Rainbow Fiber Optic UV micro-dissolution 6 channel profiler with magnetic stirring. It was performed using six channels in 0.5% triton X in water for 2-4 hours at 30, 40 and 50 °C for all forms.

Results: TSE was used to successfully scale up 15 grams of Form A and 8 grams of Form B of the API, while solubility measurements as a function of temperature identified Form C as the thermodynamic stable room temperature form. Crystallization conditions were then identified to successfully scale Form C at approximately 120 grams in 1:1 MtBE:heptane at 50 °C.

Conclusion: The ZSE-12-40D extruder was successfully used to scale up several unsolvated polymorphs of the API, thus again demonstrating the utility of these machines to support process investigations via mechanochemistry.

References: 1: Org. Process Res. Dev. 2018, 22, 10, 1432–1440
2: Org. Process Res. Dev. 2013, 17, 3, 533–539