Advancement of Pharmaceutical Manufacturing through Selective Polymorph Control during Continuous Heterogenous Crystallization: A Case Study Using Indomethacin

For pharmaceutical manufacturing, transferring processes from batch to continuous has the potential to more rapidly provide patients with inexpensive and higher quality medicine. In this work, under NSF Award #1555647, Indomethacin (IMC), an anti-inflammatory small molecule drug, was used as a model active pharmaceutical ingredient to achieve continuous heterogeneous crystallization onto polymer beads. IMC has multiple polymorphs, and it was the goal of this work to selectively crystalize the stable γ form and the metastable α form onto Polyvinyl alcohol (PVA, MW 89000-98000). Commercially available IMC in the pure γ form was used as the starting material. Before continuous crystallization was achieved, batch experiments were performed to determine ideal operating conditions. The crystals from each experiment were filtered and dried under vacuum at room temperature for one hour and analyzed using XRD, DSC and optical microscope. The data was then compared against literature to determine the polymorph forms that were present in the sample. Initially, Ethanol was used as the solvent and work was focused on cooling the hot solution and varying the supersaturation value, the ratio of the initial concentration of IMC in Ethanol at the starting temperature to the solubility of IMC in Ethanol at the final temperature. However, it was found that a mixture of both γ and α forms would crystalize initially and pure γ was achieved after over 5 hours as the α form slowly stabilized into the γ form. As a solvent replacement, Acetonitrile was used which, after exploring multiple supersaturation values, allowed for pure γ form to be achieved after only 30 minutes, providing significantly shorter residence time. To achieve pure α form, Ethanol was used as the solvent and it was found that introducing water as an antisolvent created a more unstable crystallization environment thus favoring the metastable α form. Both γ and α process conditions were then successfully transferred to a small-scale continuous reaction setup, illustrating a successful proof of concept for larger processes.