Determination of the Optimal Molar Ratio in Amino Acid-Based Coamorphous Systems

Abstract

Coamorphous drug formulations are a promising approach to improve solubility and bioavailability of poorly watersoluble drugs. On the basis of theoretical assumptions involving molecular interactions, the 1:1 molar ratio of drug and coformer is frequently used as "the optimal ratio" for a homogeneous coamorphous system (i.e., the coamorphous system with the highest physical stability and, if strong interaction is possible between two molecules, the highest glass transition temperature (T g )). In order to more closely investigate this assumption, L-aspartic acid (ASP) and L-glutamic acid (GLU) were investigated as coformers for the basic drug carvedilol (CAR) at varying molar ratios. Salt formation between CAR with ASP or GLU was expected to occur at the molar 1:1 ratio based on their chemical structures. Interestingly, the largest deviation between the experimental T g and the theoretical T g based on the Gordon−Taylor equation was observed at a molar ratio of around 1:1.5 in CAR−ASP and CAR−GLU systems. In order to determine the exact value of the ratio with the highest T g , a data fitting approach was established on thermometric data of various CAR−ASP and CAR−GLU systems. The highest T g was found to be at CAR−ASP 1:1.46 and CAR− GLU 1:1.43 mathematically. Spectroscopic investigations and physical stability measurements further confirmed that the optimal molar ratio for obtaining a homogeneous system and the highest stability can be found at a molar ratio around 1:1.5. Overall, this study developed a novel approach to determine the optimal ratio between drug and coformers and revealed the influence of varying molar ratios on molecular interactions and physical stability in coamorphous systems.

Co-Amorphous Drug Formulations in Numbers: Recent Advances in Co-Amorphous Drug Formulations with Focus on Co-Formability, Molar Ratio, Preparation Methods, Physical Stability, In Vitro and In Vivo Performance, and New Formulation Strategies

“…Similarly, a PCA was performed on the FTIR spectra of freshly prepared carvedilolaspartic acid and carvedilol-glutamic acid CAMS to investigate the spectral differences among CAMS at different molar ratios [72]. Similar-shaped distribution patterns of CAMS were obtained at different molar ratios in the PCA score plots, as those seen in the T g α deviations at different molar ratios (see Section 6.1.2.).…”

“…In approximately half of the cases, where the molar ratio was optimized, it was shown that the ideal molar ratio (with respect to physical stability or/and dissolution performance of CAMS) between drug and co-former was not at the equimolar ratio. For example, for the carvedilol and aspartic acid CAMS, it was shown that the 1:1 molar ratio was not the ideal molar ratio for physical stability, even though salt formation between carvedilol and aspartic acid was expected to occur at the equimolar ratio based on the chemical nature of the drug and co-former [72].…”

“…It was confirmed that carvedilol-aspartic acid and carvedilol-glutamic acid CAMS (at a molar ratio of 1:1.5), which showed the largest positive deviation between the theoretical and experimental T g α, indeed were the most physically stable CAMS. When applying a fitting model on the theoretical and experimental T g α to determine the exact optimal molar ratio value, the highest T g α was found to be at a molar ratio of 1:1.46 for carvedilol-aspartic acid CAMS and at a molar ratio of 1:1.43 for carvedilol-glutamic acid CAMS [72].…”

“…Application of multivariate analysis on different spectra of CAMS can visualize minor changes during storage and the underlying interaction differences among samples at different molar ratios. To date, multivariate analysis has been used to trace changes during storage, to explain the interaction mechanism, and to further confirm the found optimal molar ratio [72,74,[88][89][90]. More research focusing on multivariate analysis on CAMS needs to be done to investigate the predictability of physical stability of CAMS.…”

A Multivariate Approach for the Determination of the Optimal Mixing Ratio of the Non-Strong Interacting Co-Amorphous System Carvedilol-Tryptophan

“…The co-former can interact with the drug through different kinds of molecular interactions which can be divided into non-strong interactions (such as hydrogen bond formation and π-π interactions) and strong interactions (such as ionic interactions) [11][12][13][14]. A method of detecting the optimal mixing ratio of strongly interacting co-amorphous systems was suggested by Liu et al and a method for non-strongly interacting co-amorphous systems was investigated by Kissi et al, but the latter method was experimentally demanding and not widely accessible [6,15]. Therefore, it would be beneficial if another, less complex, method could be developed.…”