Exploring the influence of hydrogen bond donor groups on the microstructure and intermolecular interactions of amorphous solid dispersions containing diflunisal structural analogues.

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 solid-state 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.

Three-Step Synthetic Pathway toward Fully Decorated [1,2,3]Triazolo[4,5-d]pyrimidine (8-Azapurine) Derivatives.

[1,2,3]Triazolo[4,5-d]pyrimidines (8-azapurines) are known bioisosteres of the purine nucleus. A step-efficient synthesis of 8-azapurines, in particular 6-alkyl derivatives, is currently unavailable. This work focuses on a three-step synthetic pathway for the synthesis of fully decorated 8-azapurines, with special attention on 6-alkyl-8-azapurines. A diverse library of 8-azapurines was obtained starting from various alkynes, azides, and amidines, involving interrupted CuAAC, oxidation, and cyclization reactions. Additionally, postfunctionalization reactions were demonstrated for a selected number of substrates.

The Value of Bead Coating in the Manufacturing of Amorphous Solid Dispersions: A Comparative Evaluation with Spray Drying.

Despite the fact that an amorphous solid dispersion (ASD)-coated pellet formulation offers potential advantages regarding the minimization of physical stability issues, there is still a lack of in-depth understanding of the bead coating process and its value in relation to spray drying. Therefore, bead coating and spray drying were both evaluated for their ability to manufacture high drug-loaded ASDs and for their ability to generate physically stable formulations. For this purpose, naproxen (NAP)-poly(vinyl-pyrrolidone-co-vinyl acetate) (PVP-VA) was selected as an interacting drug-polymer model system, whilst naproxen methyl ester (NAPME)-PVP-VA served as a non-interacting model system. The solvent employed in this study was methanol (MeOH). First, a crystallization tendency study revealed the rapid crystallization behavior of both model drugs. In the next step, ASDs were manufactured with bead coating as well as with spray drying and for each technique the highest possible drug load that still results in an amorphous system was defined via a drug loading screening approach. Bead coating showed greater ability to manufacture high drug-loaded ASDs as compared to spray drying, with a rather small difference for the interacting drug-polymer model system studied but with a remarkable difference for the non-interacting system. In addition, the importance of drug-polymer interactions in achieving high drug loadings is demonstrated. Finally, ASDs coated onto pellets were found to be more physically stable in comparison to the spray dried formulations, strengthening the value of bead coating for ASD manufacturing purposes.