Amino Acids as Co-amorphous Excipients for Simvastatin and Glibenclamide: Physical Properties and Stability

Abstract

Co-amorphous drug mixtures with low-molecular-weight excipients have recently been shown to be a promising approach for stabilization of amorphous drugs and thus to be an alternative to the traditional amorphous solid dispersion approach using polymers. However, the previous studies are limited to a few drugs and amino acids. To facilitate the rational selection of amino acids, the practical importance of the amino acid coming from the biological target site of the drug (and associated intermolecular interactions) needs to be established. In the present study, the formation of co-amorphous systems using cryomilling and combinations of two poorly water-soluble drugs (simvastatin and glibenclamide) with the amino acids aspartic acid, lysine, serine, and threonine was investigated. Solid-state characterization with X-ray powder diffraction, differential scanning calorimetry, and Fourier-transform infrared spectroscopy revealed that the 1:1 molar combinations simvastatin-lysine, glibenclamide-serine, and glibenclamide-threonine and the 1:1:1 molar combination glibenclamide-serine-threonine formed co-amorphous mixtures. These were homogeneous single-phase blends with weak intermolecular interactions in the mixtures. Interestingly, a favorable effect by the excipients on the tautomerism of amorphous glibenclamide in the co-amorphous blends was seen, as the formation of the thermodynamically less stable imidic acid tautomer of glibenclamide was suppressed compared to that of the pure amorphous drug. Furthermore, the co-amorphous mixtures provided a physical stability advantage over the amorphous drugs alone.

Co-amorphous palbociclib–organic acid systems with increased dissolution rate, enhanced physical stability and equivalent biosafety

“…The co-amorphous systems had an equivalent inhibition rate for cancer cells compared with that of the drug substance. PAL formed three hydrogen bonds between 8 N, 16 N with CDK6cyclin V101 and 31 C]O with DFG-D163 N-H to inhibit cancer cell growth, 25 the co-amorphous forms displayed an ionic bond between 26 N on the piperazine ring with a carboxyl group in acid. The action sites of the pharmacophore and the coamorphous binding are inconsistent, thereby the formation of the co-amorphous salt did not affect the drug effect, which was also proved by cell experiments.…”

“…[13][14][15] An active drug and a ligand may interact via ionic bonds, hydrogen bonds, or other noncovalent bonds, which overcomes the disadvantages of amorphous drugs that it easily crystallizes, thereby improving the physical properties of drugs. [16][17][18] For example, ionic interactions in indomethacinarginine co-amorphous system remarkably enhanced the intrinsic dissolution rate and physical stability relative to amorphous indomethacin. 19 Tryptophan bound to carbamazepine via hydrogen bonding and p-p interaction.…”

Physico-Chemical Properties, Aerosolization and Dissolution of Co-Spray Dried Azithromycin Particles with L-Leucine for Inhalation

“…Amino acids have been investigated for improving the dissolution of poorly soluble drugs by forming co-amorphous dispersions (38–42). It is noted that the weak basic azithromycin exhibits a pH dependent solubility profile (43).…”

Dissolution behavior of co-amorphous amino acid-indomethacin mixtures: The ability of amino acids to stabilize the supersaturated state of indomethacin

“…By the definition of Dengale et al, these systems contain two or more small molecular weight compounds that are homogenously mixed to form an amorphous single phase system [19]. For example, two active compounds have been combined to produce co-amorphous mixtures [20,21], but finding compatible drug-drug pairs may, however, be challenging, which has increased the interest in combining a pharmacologically active molecule with an inactive low molecular weight excipient, such as an amino acid (AA) [22][23][24].…”