Jensen Katrine Tarp, Larsen Flemming Hofmann, Löbmann Korbinian, Rades Thomas, Grohganz Holger
Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark.
Department of Food Science, University of Copenhagen, Copenhagen, Denmark.
Eur J Pharm Biopharm. 2016 Oct;107:32-9. doi: 10.1016/j.ejpb.2016.06.020. Epub 2016 Jun 28.
Molecular interactions were investigated within four different co-amorphous drug-amino acid systems, namely indomethacin-tryptophan (Ind-Trp), furosemide-tryptophan (Fur-Trp), indomethacin-arginine (Ind-Arg) and furosemide-arginine (Fur-Arg). The co-amorphous systems were prepared by ball milling for 90min at different molar ratios and analyzed by XRPD and DSC. Interactions within the co-amorphous samples were evaluated based on the deviation between the actual glass transition temperature (Tg) and the theoretical Tg calculated by the Gordon-Taylor equation. The strongest interactions were observed in the 50mol% drug (1:1M ratio) mixtures, with the exception of co-amorphous Ind-Arg where the interactions within the 40mol% drug samples appear equally strong. A particularly large deviation between the theoretical and actual Tgs was observed within co-amorphous Ind-Arg and Fur-Arg systems. Further analysis of these co-amorphous systems by (13)C solid-state NMR (ssNMR) and FTIR confirmed that Ind and Fur formed a co-amorphous salt together with Arg. A modified approach of using the Gordon-Taylor equation was applied, using the equimolar co-amorphous mixture as one component, to describe the evolution of the Tgs with varying molar ratio between the drug and the amino acid. The actual Tgs for co-amorphous Ind-Trp, Fur-Trp and Fur-Arg were correctly described by this equation, confirming the assumption that the excess component was amorphous forming a homogeneous single component within the co-amorphous mixture without additional interactions. The modified equation described the Tgs of the co-amorphous Ind-Arg with excess Arg less well indicating possible further interactions; however, the FTIR and ssNMR data did not support the presence of additional intermolecular drug-amino acid interactions.
在四种不同的共无定形药物 - 氨基酸体系中研究了分子间相互作用，即吲哚美辛 - 色氨酸（Ind-Trp）、呋塞米 - 色氨酸（Fur-Trp）、吲哚美辛 - 精氨酸（Ind-Arg）和呋塞米 - 精氨酸（Fur-Arg）。通过球磨在不同摩尔比下制备共无定形体系90分钟，并通过X射线粉末衍射（XRPD）和差示扫描量热法（DSC）进行分析。基于实际玻璃化转变温度（Tg）与通过戈登 - 泰勒方程计算的理论Tg之间的偏差，评估共无定形样品中的相互作用。在50mol%药物（1:1摩尔比）混合物中观察到最强的相互作用，但共无定形Ind-Arg除外，其中40mol%药物样品中的相互作用似乎同样强烈。在共无定形Ind-Arg和Fur-Arg体系中观察到理论和实际Tg之间存在特别大的偏差。通过（13）C固体核磁共振（ssNMR）和傅里叶变换红外光谱（FTIR）对这些共无定形体系进行的进一步分析证实，Ind和Fur与Arg一起形成了共无定形盐。应用了一种修改后的方法来使用戈登 - 泰勒方程，将等摩尔共无定形混合物作为一个组分，以描述Tg随药物和氨基酸之间摩尔比变化的演变。该方程正确地描述了共无定形Ind-Trp、Fur-Trp和Fur-Arg的实际Tg，证实了过量组分是无定形的这一假设，即在共无定形混合物中形成均匀的单一组分且无额外相互作用。修改后的方程对含有过量Arg的共无定形Ind-Arg的Tg描述得不太好，这表明可能存在进一步的相互作用；然而，FTIR和ssNMR数据并不支持存在额外的分子间药物 - 氨基酸相互作用。
