Track: Manufacturing and Analytical Characterization - Chemical - Integrated and Continuous Processing and Manufacturing - For Use in Drug Substance Manufacture
Category: Poster Abstract
Polymorphic Discrimination via Powder Brillouin Light Scattering
Purpose: Over 50% of all small molecule, active pharmaceutical ingredients are estimated to have more than one polymorphic form. This phenomenon is responsible for differences in many physical and chemical properties, resulting in changes to drug performance and processability. Detecting polymorphs in formulation and manufacturing is consequently very important for quality control and assurance. Conventional polymorphic characterization techniques are time consuming, offline and require grams of materials. As the industry shifts further towards continuous manufacturing interest has surged in alternative methods, which are faster, more reliable, and suitable for process analytical technology (PAT). In this work, we demonstrate the use of powder Brillouin light scattering (p-BLS) for a rapid material sparing discrimination technique for polymorphic solids. Our working hypothesis is that the anisotropic sound velocities of a material are a quantitative gauge of the strength and distribution of its intermolecular forces. This intermolecular interaction topology is re-distributed under polymorphic conversion, and we anticipate the sound velocity distributions obtained through p-BLS to sensitively reflect this phase transition. Methods: Three polymorphic pharmaceuticals (resorcinol, sulfamerazine and furosemide) were selected to perform a proof-of-concept study that demonstrates the utility of p-BLS for discriminating polymorphs. Each polymorphic system was analyzed using p-BLS and compared against their energy frameworks using CrystalExplorer, a computation tool recently developed to illustrate a material's intermolecular interaction topology. Results: Distinct polymorph specific acoustic frequency distributions were observed, and corresponding aggregate elastic moduli determined. The p-BLS spectra for β-resorcinol, sulfamerazine Form II, furosemide Form I, and furosemide Form II displays a higher longitudinal cutoff frequency, indicating at least one direction of stronger intermolecular interactions. These interactions are consistently observed through energy frameworks and fully supported by hydrogen-bond analysis. Additionally, sulfamerazine Form II and furosemide Form I display a population of low-velocity shear modes, indicating a direction of facilitated shear. Slip plane determination via energy framework diagrams support this facile slip indication. Conclusion: Calculated energy frameworks complement the experimental p-BLS results and support our working hypothesis that p-BLS is a novel spectroscopic technique capable of easily and rapidly discriminating different polymorphs.