Abstract
The main aim of this work is the biopharmaceutical characterization of a new hybrid benzodiazepine-dihydropyridine derivative, JM-20, derived with potent anti-ischemic and neuroprotective effects. In this study, the pKa and the pH-solubility profile were experimentally determined. Additionally, effective intestinal permeability was measured using three in vitro epithelial cell lines (MDCK, MDCK-MDR1 and Caco-2) and an in situ closed-loop intestinal perfusion technique. The results indicate that JM-20 is more soluble at acidic pH (9.18 ± 0.16); however, the Dose number (Do) was greater than 1, suggesting that it is a low-solubility compound. The permeability values obtained with in vitro cell lines as well as with the in situ perfusion method show that JM-20 is a highly permeable compound (Caco-2 value 3.8 × 10−5). The presence of an absorption carrier-mediated transport mechanism was also demonstrated, as well as the efflux effect of P-glycoprotein on the permeability values. Finally, JM-20 was provisionally classified as class 2 according to the biopharmaceutical classification system (BCS) due to its high intestinal permeability and low solubility. The potential good oral absorption of this compound could be limited by its solubility.
Highlights
Drug discovery and development processes are extremely costly in both time and money
The pKa and solubility values confirm that this weakly basic compound has a low pH-dependent solubility; in the physiological pH range, the dose is not expected to dissolve completely, and dissolution is likely to be the rate-limiting process of its absorption
In vitro permeability assays suggest that an absorption transport mechanism exists in the permeation of JM-20 across the membrane and that this compound is a substrate of P-glycoprotein
Summary
Drug discovery and development processes are extremely costly in both time and money. BCS has proven to be a very important tool for the identification of compounds whose solubility and absorption characteristics may be sensitive to physiological and formulation variables, allowing early optimization in the preformulation stages from the knowledge of the physicochemical properties of the active pharmaceutical ingredient (API) [3]. In this sense, it is evident that new compounds with low permeability and solubility/dissolution will have low and highly variable oral bioavailability, which may limit the chances of developing a clinically useful product
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