The number of drug candidates with poor solubility (according to the Biopharmaceutical Classification System) has been steadily rising in the past years. One of the prevailing technologies to address this problem is the formulation of Amorphous Solid Dispersions (ASDs), in which an Active Pharmaceutical Ingredient (API) is stabilized in its amorphous form by dispersion in polymers. Spray dry methods are among the most popular used to generate amorphous dispersions of the drug with the goal to have little-to-no crystalline API in the matrix. Any presence of crystalline material can directly impact bioavailability and hence efficacy and dosage of the final drug.
The relatively high LODs for routine quantitation of crystalline material in amorphous formulations is problematic both in the manufacturing process and stability testing which. The inability to detect less than 10% of the API being crystalline means dosing of the drug can easily vary +/-10% which begs the question of whether or not that would affect treatments. The high LOD also makes it difficult to have rapid process control feedback when developing manufacturing processes for spray dried dispersions and other amorphous formulations. Lower sensitivity in detection would allow for processes to be adjusted on a faster time scale without the need to wait until 10% of the drug is crystallized. Shelf life stability studies could also be accelerated with more sensitive detection methods ensuring that the products on patients’ shelves remain stable and dosing in the tablet does not change over time.
Correa-Soto et al. recently demonstrated the use of Second Harmonic Generation utilizing a commercially available SONICC instrument from Formulatrix to detect crystalline ezetimibe and flutamide in amorphous spray dried dispersions. They report that SONICC is 10 times more sensitive than XRPD. In a side by side experiment of an environmentally stressed formulation, SONICC was able to detect the formation of crystalline material after 8 days of storage versus 26 days with XRPD for ezetimibe and 11 days versus 53 days of storage for flutamide. This 2.5 to 6 weeks time difference in detecting a physical change of a sample earlier, brings enormous cost savings to pharmaceutical companies. With the use of SONICC, scientists can get information on the kinetics of crystallization much earlier than what the currently available commercial practice allows.
Correa-Soto C, Trasi NS, Schmitt PD, Su Y, Liu Z, Miller E, Variankaval N, Marsac PJ, Simpson GJ, Taylor LS. “Second harmonic generation microscopy as a tool for the early detection of crystallization in spray dried dispersions”; J Pharm Biomed Anal. 2017 Nov 30; 146:86-95.