Trimebutine Maleate

The G protein‐coupled receptor (GPCR) pharmacology accounts for a significant field in research, clinical studies, and therapeutics. Computer‐aided drug discovery is an evolving suite of techniques and methodologies that facilitate accelerated progress in drug discovery and repositioning. However, the structure–activity relationships of molecules targeting GPCRs are highly challenging in many cases since slight structural modifications can lead to drastic changes in biological functionality. Numerous molecular descriptors have been described, many of which successfully characterize the structural and physicochemical features of drug sets. Nonetheless, elucidating the structure–functionality relationships over extensive sets of drugs with multiple structural variations and known biological activity remains challenging in various biological systems. This work presents novel topological descriptors using Laplacian matrices, weighted, and scaled by atomic mass and partial charges. We tested these descriptors on three sets of GPCR ligands: muscarinic, β‐adrenergic, and δ‐opioid receptor ligands, evaluating their potential as functional descriptors of these receptors.

The purpose of the present study was to compare the dissolution profiles of high-dose salt-form drugs in bicarbonate buffer (BCB) and phosphate buffer (PPB) focusing on the pH changes in the bulk phase. The pH titration curves of BCB and PPB (pH 6.5, buffer capacity (β) = 4.4 mmol/L/pH unit) were first theoretically calculated and experimentally validated. For dissolution tests, six drug salts with an acid counterion, one drug salt with a weak base counterion, and one free acid drug were employed (125-800 mg clinical dose). The dose/fluid volume ratio (Dose/FV) was aligned with the clinical condition. In the pH titration study, the pH value decreased below pH 6.0 by adding HCl > 2.8 mmol/L (BCB) or > 1.6 mmol/L (PPB) and increased above pH 7.0 by adding NaOH > 2.0 mmol/L (BCB) or > 2.4 mmol/L (PPB). In the dissolution test, even though the initial pH and β values were the same, the pH value at 4 h was lower in PPB than in BCB in all cases. For the drug salts with an acid counterion, the area under the dissolution curve was 1.2 to 2.6-fold lower in BCB than in PPB. A marked precipitation process was observed in BCB, but less pronounced or absent in PPB. The results of this study suggest the use of BCB and a clinically equivalent Dose/FV may be valuable in predicting the oral absorption of high-dose drug salts.