Category: Formulation and Quality
Purpose: Molecular behaviors of organic solids, typically categorized as crystalline or amorphous materials, have significant impact on material functions. In recent years, amorphous solid dispersion (ASD) is one of the major platforms to deliver poorly water-soluble drugs. Molecular interactions in ASDs have been proposed to impact the physical stability and dissolution profile. However, structural details of amorphous pharmaceutical materials remain unclear mainly due to the lack of resolution in the solid-state analysis. We aim to utilize solid-state NMR to probe molecular structure and interactions in amorphous drug substances and products by taking posaconazole (POSA) as an example.
Methods: Solid-state NMR experiments at magic angle spinning (MAS) frequency of 12 kHz were carried out on a Bruker AVANCE III 400 spectrometer. 19F spectra were obtained with a Bruker 4 mm triple resonance HFX MAS probe tuned to 1H and 19F frequencies, while 13C and 1H spectra were obtained with the HXY MAS probe in double-resonance mode, respectively. Ultrafast MAS experiments at 60 kHz and 110 kHz were performed on a Bruker 400 spectrometer using a 1.3 mm HFX probe and a Bruker 800 spectrometer using an HXY probe.
Results: Full chemical shift assignments (13C, 1H, 15N and 19F) were accomplished for both crystalline and amorphous POSA using one-dimensional (1D) and two-dimensional (2D) homo- and heteronuclear correlation experiments. With these resonance assignments, intramolecular and intermolecular contacts in crystalline POSA were explored by identifying 13C-1H, 19F-1H and 19F-13C proximities. These results support "head-to-head" and "head-to-tail" intermolecular packings in crystalline posaconazole, which agrees well with single crystal XRD results. Ultrafast MAS (60-110 kHz) averages the proton dipolar couplings and thus provides narrower 1H and 19F linewidth for probing structural details at a higher resolution. A series of 2D heteronuclear (1H-19F and 1H-13C) and homonuclear (1H-1H and 19F-19F) correlation experiments have been developed and utilized to probe the molecular packing of crystalline and amorphous posaconazole. Interestingly, the "head-to-head" molecular packing no longer exists in amorphous POSA while the "head-to-tail" contact remains. To quantify the intermolecular drug-polymer distance in the POSA-HPMCAS ASD, the atomic distance is experimentally measured and uncovers the nature and strength of the hydrogen bond.
Conclusion: Conclusion: Our studies have probed molecular packing changes from the crystalline-to-amorphous conversion of posaconazole. Very interestingly, intermolecular "head-to-tail" packing has been identified in amorphous POSA. Quantitative experiments have identified the atomic distance of a hydrogen-bond between POSA and HPMCAS in the amorphous dispersion, for the first time. These molecular findings provide a structural basis to further evaluate the correlation between intermolecular interactions and material properties of amorphous dispersions in terms of physical stability and dissolution rate, and also demonstrate solid-state NMR as a high-resolution spectroscopic tool for probing structures of amorphous materials.