Solid-State NMR Investigation of Compaction Induced Amorphization of Crystalline Pharmaceuticals

Solid-state NMR (ssNMR) spectroscopy has shown its indispensable capability of elucidating atomic level structures and interactions in pharmaceutical studies [1-3]. In the past one decade, it has been utilized to investigate polymorphism of pharmaceutical crystalline compounds and the phase transformations during manufactural processing. These thermodynamic transitions of active pharmaceutical ingredients (APIs), including polymorph transition, hydration and dehydration, crystalline to amorphous or amorphous to crystalline, can have major impact on the chemical stability and bioavailability of drug products. Among these undesired phase conversions, the transformations of polymorph transition and hydration and dehydration have been extensively studies by ssNMR and other solid-state characterization techniques [4,5]. However, the compaction inducted API amorphization has been rarely reported and investigated. In this study, we have utilized 19 F CP/MAS method to quantify the amorphous content of model APIs to investigate the crystalline amorphization upon compaction. An API database has been firstly established as the screening methodology to evaluate phase change in the tablet compression process. The ssNMR quantification results indicate that posaconazole, the active ingredient in the commercially available product NOXAFIL ® , produces ~ 20% (w/w) amorphous content in the tablet compressed at 400 MPa (Fig. 1), showing sensitive response to pressure. Taking posaconazole as a model API, we aim to investigate the impact of axial and shear stress induced in tablet compression to understand the compaction-induced amorphization. Tablets composed of crystalline posaconazole with or without excipients are compressed for this research. The results have successfully established the correlation between amorphous contents and various compression pressures. Moreover, excipients in the formulation including weight concentration, type of diluent and lubrication are known to alter the force distribution and fraction in the compaction process. In order to investigate the impact of excipients, the API-diluent binary system has been established (Fig. 2). The results suggest the dependence of both pressure and weight concentration in binary formulation. Percolation theory model has been applied to rationalize the relationship between solid fraction and the observed amorphization. Our experimental investigations have given quantitative results on amorphization of crystalline compounds, providing understanding of the underlying mechanism of the undesired phase conversion upon compression. The study has provided an example of utilizing ssNMR to investigate the structural properties of crystalline API in the formulation process. Further investigations of a large category of APIs are undergoing to understand how and why the amorphization is happening to a certain class of compounds, and be able to predict the tendency, and finally mitigate the process induced amorphization of drug substances. Reference: 1. Berendt R, Sperger D, Isbster P, Munson E, Trends Anal. Chem., 2006, 25 (10) 977 2. Skotnicki M.; Apperley D.; Aguilar J.; Milanowski B.; Pyda M.; Hodgkinson P., Mol. Pharmaceutics, 2016, 13, 211 3. Hong, M and Su, Y, Protein Sciences, 2011, 20 (4), 641 4. Leung S.; Padden B.; Munson E.; Grant D., J. Pharm. Sci., 1998, 87, 501 5. Pyszczynski S.; Munson E., Mol. Pharmaceutics, 2013, 10, 3323 Figure 1. Left: 19 F ssNMR spectra of neat crystalline posaconazole and tablets compressed at 50Mpa, 100Mpa, 200Mpa and 400Mpa. Right: Amorphous content of compressed tablets at 50Mpa, 100Mpa, 200Mpa and 400Mpa from ssNMR quantification.