School of Pharmacy, University of Otago, Dunedin, New Zealand; Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
Eur J Pharm Biopharm. 2013 Nov;85(3 Pt B):882-8. doi: 10.1016/j.ejpb.2013.03.026. Epub 2013 Apr 6.
The formation of co-amorphous drug-drug mixtures has proved to be a powerful approach to stabilize the amorphous form and at the same time increase the dissolution of poorly water-soluble drugs. Molecular interactions in these co-amorphous formulations can play a crucial role in stabilization and dissolution enhancement. In this regard, Fourier-transform infrared spectroscopy (FTIR) is a valuable tool to analyze the molecular near range order of the compounds in the co-amorphous mixtures. In this study, several co-amorphous drugs--low molecular weight excipient blends--have been analyzed with FTIR spectroscopy. Molecular interactions of the drugs carbamazepine and indomethacin with the amino acids arginine, phenylalanine, and tryptophan were investigated. The amino acids were chosen from the biological target site of both drugs and prepared as co-amorphous formulations together with the drugs by vibrational ball milling. A detailed analysis of the FTIR spectra of these formulations revealed specific peak shifts in the vibrational modes of functional groups of drug and amino acid, as long as one amino acid from the biological target site was present in the blends. These peak shifts indicate that the drugs formed specific molecular interactions (hydrogen bonding and π-π interactions) with the amino acids. In the drug-amino acid mixtures that contained amino acids which were not present at the biological target site, no such interactions were identified. This study shows the potential of amino acids as small molecular weight excipients in co-amorphous formulations to stabilize the amorphous form of a poorly water-soluble drug through strong and specific molecular interactions with the drug.
共无定形药物混合物的形成已被证明是一种稳定无定形形式并同时提高难溶性药物溶解度的有力方法。这些共无定形制剂中的分子相互作用在稳定和溶解增强方面可以发挥关键作用。在这方面，傅里叶变换红外光谱（FTIR）是分析共无定形混合物中化合物分子近程有序的有价值的工具。在这项研究中，使用 FTIR 光谱分析了几种共无定形药物 - 低分子量赋形剂混合物。研究了药物卡马西平和吲哚美辛与氨基酸精氨酸、苯丙氨酸和色氨酸的分子相互作用。选择了这两种药物的生物靶位的氨基酸，并通过振动球磨与药物一起制备成共无定形制剂。对这些制剂的 FTIR 光谱的详细分析表明，只要混合物中存在生物靶位的一种氨基酸，药物和氨基酸的官能团振动模式就会出现特定的峰位移。这些峰位移表明药物与氨基酸形成了特定的分子相互作用（氢键和π-π相互作用）。在含有生物靶位不存在的氨基酸的药物-氨基酸混合物中，没有鉴定出这种相互作用。这项研究表明，氨基酸作为共无定形制剂中的小分子赋形剂具有潜力，通过与药物的强特异性分子相互作用稳定难溶性药物的无定形形式。
