Abstract
Introduction: Oral drug delivery is the most
favored route of drug administration. However,
poor oral bioavailability is one of the leading
reasons for insufficient clinical efficacy. Improving
oral absorption of drugs with low water solubility
and/or low intestinal membrane permeability is
an active field of research. Cocrystallization of
drugs with appropriate coformers is a promising
approach for enhancing oral bioavailability.
Methods: In the present review, we have focused on recent advances that have been made in
improving oral absorption through cocrystallization. The covered areas include supersaturation
and its importance on oral absorption of cocrystals, permeability of cocrystals through membranes,
drug-coformer pharmacokinetic (PK) interactions, conducting in vivo-in vitro correlations for
cocrystals. Additionally, a discussion has been made on the integration of nanocrystal technology
with supramolecular design. Marketed cocrystal products and PK studies in human subjects are
also reported.
Results: Considering supersaturation and consequent precipitation properties is necessary when
evaluating dissolution and bioavailability of cocrystals. Appropriate excipients should be included
to control precipitation kinetics and to capture solubility advantage of cocrystals. Beside to
solubility, cocrystals may modify membrane permeability of drugs. Therefore, cocrystals can find
applications in improving oral bioavailability of poorly permeable drugs. It has been shown that
cocrystals may interrupt cellular integrity of cellular monolayers which can raise toxicity concerns.
Some of coformers may interact with intestinal absorption of drugs through changing intestinal
blood flow, metabolism and inhibiting efflux pumps. Therefore, caution should be taken into
account when conducting bioavailability studies. Nanosized cocrystals have shown a high potential
towards improving absorption of poorly soluble drugs.
Conclusions: Cocrystals have found their way from the proof-of-principle stage to the clinic. Up
to now, at least two cocrystal products have gained approval from regulatory bodies. However,
there are remaining challenges on safety, predicting in vivo behavior and revealing real potential of
cocrystals in the human.