Protein-based therapeutics are becoming increasingly important in the treatment of human diseases. The primary reason for their popularity is their high target specificity and broad applicability. A significant fraction of the protein formulations on the market are lyophilized. Such protein formulations are generally multicomponent systems, providing numerous opportunities for excipient-excipient and protein-excipient interactions. Such interactions can influence the physical form of some excipients during the different stages of the freeze-drying process, as well as in the final drug product. The physical form can influence the excipient functionality, and thereby the stability of the active compound. Because in this case the active ingredient is a protein, it is likely to remain amorphous in the final product. We are actively conducting research to understand such interactions and their impact on product performance, with a view to improving the existing knowledge space for the development of such formulations. We make use of multiple complimentary techniques to conduct intensive characterization of frozen and freeze-dried systems. These include, but are not limited to: sub-ambient differential scanning calorimetry, low temperature X-ray diffractometry (both laboratory and synchrotron), low temperature pH measurement, low temperature small angle neutron scattering, dynamic light scattering, microflow imaging, and size exclusion chromatography.
Representative Publications
- Thakral, Seema, et al. "Stabilizers and their interaction with formulation components in frozen and freeze-dried protein formulations." Advanced Drug Delivery Reviews 173 (2021): 1-19.
- Thorat, Alpana A., et al. "Freezing-induced protein aggregation - Role of pH shift and potential mitigation strategies." Journal of Controlled Release 323 (2020): 591-599.
- Sonje, Jayesh, Seema Thakral, and Raj Suryanarayanan. "t-Butanol enables dual functionality of mannitol: A cryoprotectant in frozen systems and bulking agent in freeze-dried formulations." Molecular Pharmaceutics 17.8 (2020): 3075-3086.
- Snell, Jared R., et al. "Nanobubbles in Reconstituted Lyophilized Formulations: Interaction With Proteins and Mechanism of Formation." Journal of Pharmaceutical Sciences 109.1 (2020): 284-292.
- Jena, Sampreeti, et al. "Stability of lyophilized albumin formulations: Role of excipient crystallinity and molecular mobility." International Journal of Pharmaceutics 569 (2019): 118568.
- Kulkarni, Shreya S., et al. "Mechanisms by which crystalline mannitol improves the reconstitution time of high concentration lyophilized protein formulations." European Journal of Pharmaceutics and Biopharmaceutics 131 (2018): 70-81.
- Sundaramurthi, Prakash, and Raj Suryanarayanan. "Trehalose crystallization during freeze-drying: Implications on lyoprotection." The Journal of Physical Chemistry Letters 1.2 (2010): 510-514.