Amino acids as co-amorphous excipients for tackling the poor aqueous solubility of valsartan

Abstract

Co-amorphization has recently been shown to be a promising approach for stabilizing amorphous drugs and improving the dissolution rate of poorly water-soluble drugs. In this study, three basic amino acids were chosen as small molecular weight excipients to interact with the drug to form co-amorphous combinations. The co-amorphous combinations of valsartan (VAL) with l-histidine, l-arginine, and l-lysine were prepared by vibrational ball milling. Solid-state characterization with X-ray powder diffraction and differential scanning calorimetry (DSC) revealed that all of the co-amorphous mixtures were homogeneous. The molecular interactions of the co-amorphous mixtures were investigated through the glass transition temperature (T) in the DSC measurements and Fourier transform infrared spectroscopy. The drug remained chemically stable during the milling process, and the co-amorphous formulations were generally physically stable over at least 3 months at 40 °C under dry conditions. The dissolution rate of all of the co-amorphous mixtures was significantly increased over that of the amorphous VAL alone. The results of this study demonstrated the potential of amino acids as small molecular weight excipients in co-amorphous formulations to improve the drug solubility and dissolution rate.

The natural bile acid surfactant sodium taurocholate (NaTC) as a coformer in coamorphous systems: Enhanced physical stability and dissolution behavior of coamorphous drug-NaTc systems

“…Coformers that have been successfully applied to stabilize an amorphous drug include saccharin (Gao et al, 2013), nicotinamide (Shayanfar, 2013), carboxylic acids (Lu and Zografi, 1998;Masuda et al, 2012;Hoppu et al, 2007Hoppu et al, & 2009Ali et al, 2015;Han et al, 2016;Hu et al, 2014) and sugars (Descamps et al, 2007). In particular, amino acids capable of forming charge-assisted hydrogen bonds have been widely studied (Löbmann et al, 2013;Jensen et al, 2014Jensen et al, , 2015Jensen et al, & 2016Laitinen et al, 2014;Lenz et al, 2015;Huang et al, 2016;Craye et al, 2015). On the other hand, an increase in the physical stability was observed for coamorphous simvastatin-glipizide, even though there was no evidence for intermolecular interactions, suggesting that molecular level mixing may be sufficient to stabilize the amorphous phase (Löbmann et al, 2012).…”

Coamorphous Active Pharmaceutical Ingredient–Small Molecule Mixtures: Considerations in the Choice of Coformers for Enhancing Dissolution and Oral Bioavailability

“…Limited solubility studies have been reported for coamorphous systems, 7,80,102,103 and this is an area where more work is needed. Generally, coamorphous systems show a higher solubility when compared to crystalline materials, due to the amorphous nature of the API.…”

“…While binary coamorphous systems come with their challenges, several studies have reported ternary systems containing a third miscible component. The third component can be a second coformer 7,80,103,120 or another API. 121 In other cases, a polymer (such as Soluplus 122 or copovidone 20 ) or cyclodextrin [123][124][125][126] is added to the system.…”

Co-Amorphous Solid Dispersions for Solubility and Absorption Improvement of Drugs: Composition, Preparation, Characterization and Formulations for Oral Delivery

“…Huang et al [ 79 ] studied combinations of valsartan (VAL) with l -histidine, l -arginine, and l -lysine with XRPD and DSC. The Tg values of the co-amorphous mixtures were higher than those of the single components and the predicted Tg values of the combinations (Gordon Taylor equation) suggesting a strong interaction between VAL and the amino acids.…”

“…The reason for the remarkable IDR increase of VAL from the co-amorphous SD was the ionization and salt drug-amino acid formation, as well as the high-water solubility of AAs. The co-amorphous VAL-ARG and VAL-LYS SDs were stable for 3 months [ 79 ].…”