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Title: | Exploring the influence of hydrogen bond donor groups on the microstructure and intermolecular interactions of amorphous solid dispersions containing diflunisal structural analogues | Authors: | COOLS, Lennert DERVEAUX, Elien Reniers, Felien Dehaen, Wim ADRIAENSENS, Peter van den Mooter, Guy |
Issue Date: | 2024 | Publisher: | ELSEVIER | Source: | International journal of pharmaceutics (Print), 661 (Art N° 124438) | Abstract: | Drug-polymer intermolecular interactions, and H-bonds specifically, play an important role in the stabilization process of a compound in an amorphous solid dispersion (ASD). However, it is still difficult to predict whether or not interactions will form and what the strength of those interactions would be, based on the structure of drug and polymer. Therefore, in this study, structural analogues of diflunisal (DIF) were synthesized and incorporated in ASDs with poly(vinylpyrrolidone-co-vinyl acetate) (PVPVA) as a stabilizing polymer. The respective DIF derivatives contained different types and numbers of H-bond donor groups, which allowed to assess the influence of these structural differences on the phase behavior and the actual interactions formed in the ASDs. The highest possible drug loading of these derivatives in PVPVA were evaluated through film casting. Subsequently, a lower drug loading of each compound was spray dried. These spray dried ASDs were subjected to an in-depth solidstate nuclear magnetic resonance (ssNMR) study, including 1D spectroscopy and relaxometry, as well as 2D dipolar HETCOR experiments. The drug loading study revealed the highest possible loading of 50 wt% for the native DIF in PVPVA. The methoxy DIF derivative reached the second highest drug loading of 35 wt%, while methylation of the carboxyl group of DIF led to a sharp decrease in the maximum loading, to around 10 wt% only. Unexpectedly, the maximum loading increased again when both the COOH and OH groups of diflunisal were methylated in the dimethyl DIF derivative, to around 30 wt%. The ssNMR study on the spray dried ASD samples confirmed intermolecular H-bonding with PVPVA for native DIF and methoxy DIF. Studies of the proton relaxation decay times and 2D 1H-13C dipolar HETCOR experiments indicated that the ASDs with native DIF and methoxy DIF were homogenously mixed, while the ASDs containing DIF methyl ester and dimethyl DIF were phase separated at the nm level. It was established that, for these systems, the availability of the carboxyl group was imperative in the formation of intermolecular H-bonds with PVPVA and in the generation of homogenously mixed ASDs. | Notes: | van den Mooter, G (corresponding author), Katholieke Univ Leuven, Dept Pharmaceut & Pharmacol Sci, Drug Delivery & Disposit, Campus Gasthuisberg ON2,Herestr 49 B921, B-3000 Leuven, Belgium. guy.vandenmooter@kuleuven.be |
Keywords: | Amorphous solid dispersion;Abbreviations: AAPS, Amorphous-amorphous phase separation;API, Active pharmaceutical ingredient;sInteractions;ASD, Amorphous solid dispersion;Hydrogen bonds;CPMAS, Cross polari- zation magic angle spinning;Solid -state NMR;DIF, Diflunisal;Diflunisal;Structural analogues;FT-IR, Fourier transform -infrared spectroscopy;HETCOR, Heteronuclear correlation;Heteronuclear correlation;mDSC, Modulated differential scanning calorimetry;PVP, Poly(vinylpyrrolidone);PVPVA, Poly(vinylpyrrolidone-co-vinylacetate);ssNMR, Solid-state nuclear magnetic resonance;T g , Glass transition temperature;wPMLG, Windowed Phase-modulated Lee-Goldburg;XRPD, X-ray powder diffraction | Document URI: | http://hdl.handle.net/1942/43449 | ISSN: | 0378-5173 | e-ISSN: | 1873-3476 | DOI: | 10.1016/j.ijpharm.2024.124438 | ISI #: | 001269515700001 | Rights: | 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies | Category: | A1 | Type: | Journal Contribution |
Appears in Collections: | Research publications |
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