TY - JOUR

T1 - Influence of variation in molar ratio on co-amorphous drug-amino acid systems

AU - Jensen, Katrine Birgitte Tarp

AU - Larsen, Flemming Hofmann

AU - Löbmann, Korbinian

AU - Rades, Thomas

AU - Grohganz, Holger

N1 - Copyright © 2016 Elsevier B.V. All rights reserved.

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1016/j.ejpb.2016.06.020

DO - 10.1016/j.ejpb.2016.06.020

M3 - Journal article

C2 - 27368747

VL - 107

SP - 32

EP - 39

JO - European Journal of Pharmaceutics and Biopharmaceutics

JF - European Journal of Pharmaceutics and Biopharmaceutics

SN - 0939-6411

ER -