From crystal to solution and across the membranes: the case of carbamazepine co-crystals

Combining a pharmaceutical active ingredient (API) with a pharmaceutically acceptable agent, to obtain the so-called ‘pharmaceutical co-crystal’, has become an increasingly attractive route for developing new products with enhanced physico-chemical properties. Since the co-crystal coformers are assembled through intermolecular interactions which are different from those found in the crystals of the pure components, these new solid forms can exhibit improved solubility, dissolution rate, bioavailability, permeability and stabiity properties retaining at the same time the unaltered chemical structure of the APIs. Very recently, however, we have shown for the first time [1,2] that a drug dissolved from its co-crystals or from a API/coformer physical mixture can have greatly different effects both on the integrity of cell monolayers and on API permeability. Our analysis has brought to light an intriguing aspect of the biological properties of pharmaceutical co-crystals which can be drastically different from those of their parent physical mixtures. As a further development of this type of investigation, the present communication deals with the evaluation of the dissolution properties and permeation ability across human intestinal cell monolayers of (i) carbamazepine (CBZ), a poorly water soluble anti-epileptic drug,; (ii) two new CBZ co-crystals with vanillic acid and 4-nitropyridine-N-oxyde and (iii) a published CBZ co-crystal with succinic acid. Overall, the results confirm our previous findings. The crystal structure of the CBZ-vanillic acid and the dissolution profiles of the physical mixtures considered in this work are reported in Fig. 1 Moreover, in order to elucidate at a molecular level the dissolution processes in water, we have implemented our investigation with DFT and molecular dynamics studies.