Amorphous solid dispersion formulations are utilized for poorly water soluble active pharmaceutical ingredients (APIs) in an attempt to increase bioavailability and dissolution kinetics. Spray dry methods are used to generate amorphous dispersions of the drug with the goal to have little-to-no crystalline API in the matrix. Efficacy and dosage of the final drug is greatly related to whether or not the API is crystalline with the desired form being amorphous. Any presence of crystalline material can directly impact efficacy and dosage of the final drug. X-Ray Powder Diffraction (XRPD), which is routinely used for characterizing crystallization within amorphous solid dispersions, can only detect down to 1% crystallinity of an API which is not sensitive enough when drug loadings in final formulation can be on the order of 10%. Second Harmonic Generation (SHG) has been shown to have 10-fold improved sensitivity over XRPD and should be considered as an important tool in ensuring the delivery of safe and effective drugs.
XRPD is most often used in the characterization of amorphous versus crystalline forms with a limit of detection (LOD) generally around 1%. The problem arises though when trying to characterize a final formulated tablet or capsule where drug loading may be around 15%. An LOD of 1% for a product with 15% drug loading means that 10% of the drug must be crystallized before XRPD can detect it. This is quite a large amount of drug that must be crystallized for it to be detected, which raises questions over the true composition, and therefore dosage, of drugs on the market.
The relatively high LODs for routine quantitation of crystalline material in amorphous formulations is problematic both in the manufacturing process and the stability testing which, in turn, may adversely affect patients. 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.
Taylor 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.