A combined experimental and computational study on the solubility and biological activity of carbamazepine (CBZ), three co-crystals (COCs), and their parent physical mixtures (MIXs) is carried out to shed light onto the possible modulation of the drug properties. Two of the considered co-crystals, CBZ with vanillic acid (VAN) and CBZ with 4-nitropyridine N-oxide (NPO), are newly synthesized, while the third, CBZ with succinic acid (SUC), is already known. While COC CBZ-VAN and MIX CBZ-NPO did not alter the CBZ dissolution profile, MIX CBZ-SUC and COCs CBZ-SUC and CBZ-NPO inhibit straightaway its solubility. On the other hand, MIX CBZ-VAN induced a remarkable increase of the drug solubility. Analogously, different CBZ permeability values were registered following its dissolution from MIXs and COCs: CBZ and MIXs CBZ-SUC and CBZ-VAN slightly reduce the integrity of intestinal cell monolayers, whereas MIX CBZ-NPO and COCs CBZ-SUC, CBZ-VAN, and CBZ-NPO maintain the monolayer integrity. The molecular aggregates formed in solution were found to be the key to interpret these different behaviors, opening new possibilities in the pharmaceutical utilization and definition of drug co-crystals.

From Physical Mixtures to Co-Crystals: How the Coformers Can Modify Solubility and Biological Activity of Carbamazepine

Dalpiaz, Alessandro
Primo
Membro del Collaboration Group
;
Ferretti, Valeria
Secondo
Membro del Collaboration Group
;
Bertolasi, Valerio
Membro del Collaboration Group
;
Pavan, Barbara
Membro del Collaboration Group
;
2018

Abstract

A combined experimental and computational study on the solubility and biological activity of carbamazepine (CBZ), three co-crystals (COCs), and their parent physical mixtures (MIXs) is carried out to shed light onto the possible modulation of the drug properties. Two of the considered co-crystals, CBZ with vanillic acid (VAN) and CBZ with 4-nitropyridine N-oxide (NPO), are newly synthesized, while the third, CBZ with succinic acid (SUC), is already known. While COC CBZ-VAN and MIX CBZ-NPO did not alter the CBZ dissolution profile, MIX CBZ-SUC and COCs CBZ-SUC and CBZ-NPO inhibit straightaway its solubility. On the other hand, MIX CBZ-VAN induced a remarkable increase of the drug solubility. Analogously, different CBZ permeability values were registered following its dissolution from MIXs and COCs: CBZ and MIXs CBZ-SUC and CBZ-VAN slightly reduce the integrity of intestinal cell monolayers, whereas MIX CBZ-NPO and COCs CBZ-SUC, CBZ-VAN, and CBZ-NPO maintain the monolayer integrity. The molecular aggregates formed in solution were found to be the key to interpret these different behaviors, opening new possibilities in the pharmaceutical utilization and definition of drug co-crystals.
2018
Dalpiaz, Alessandro; Ferretti, Valeria; Bertolasi, Valerio; Pavan, Barbara; Monari, Antonio; Pastore, Mariachiara
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