A study of the process-property-performance relationship of a Bristol-Myers Squibb drug substance led to successful development of crystallization and drying processes that produce crystals with desired and consistent physical properties. A controlled crystallization technique was developed to obtain well-defined, large crystals with a narrow particle size distribution. This crystallization process provided a less compressible filter cake for effective cake washing and deliquoring and afforded an easily dried product with desired powder properties. To preserve the quality of the crystals during drying, a drying protocol using low shear agitation was developed. This protocol prevented crystal attrition during drying, which was shown to adversely affect the formulation process and, thus, drug product performance. API crystals prepared by this method consistently resulted in excellent formulation processing and drug product performance.

Structural characterization of the prion prone TAR DNA Binding protein (TDP)-43 has been challenging since its intrinsically disordered regions represents 15-30% of the total protein. TDP-43 is a nucleic acid binding protein with an N-terminal domain, two RNA Recognition Motifs (RRM1 and RRM2) and the C-terminal domain. In this study, we seek to define possible new targetable sites on the apo structure of TDP-43 RRM domains. To do so, we used molecular dynamic (MD) simulations on the NMR solved TDP-43RRM1-2 structure bound to RNA to predict the apo structure. Contact analysis of TDP-43 showed that while the integrity of the individual domains was maintained upon RNA removal, a decrease in interdomain contacts was observed. Moreover, we compared apo TDP-43 structures obtained from MD to AlphaFold 2 (AF2) predicted TDP-43 structures and found differences in loop regions. A Sitemap analysis identified five druggable sites for the RNA bound structure solved by NMR, while fewer sites were identified following MD simulations and AF2 predicted apo structures.