In a seminal review paper published in the journal Molecular Pharmaceutics published by the American Chemical Society (ACS), Prof. Ashwini Kumar Nangia from the School of Chemistry at University of Hyderabad (UoH) and his post-doctoral research associates Chaitanya Mannava and Abhijit Garai put forward novel mechanisms for the enhancement of drug permeability in low solubility and low permeability drugs as pharmaceutical cocrystals and salts.
Mechanism 1: The acid-pyridine hydrogen-bonded heterosynthon is the most popular design strategy for drug cocrystals to improve solubility and permeability
Over a decade ago, Prof. Nangia had postulated the Spring and Parachute model for solubility and dissolution improvement in pharmaceutical cocrystals, published in ACS Crystal Growth & Design journal. In the present publication, they reviewed the 50 or so papers published within the last 6-7 years on improving drug permeability as hydrogen-bonded complexes of drugs with additives known as cocrystal formers (CCFs) which can enhance solubility and/ or permeability of known drugs. Their paper is published in the May issue of Molecular Pharmaceutics highlighting Advances in Molecular Pharmaceutical Research from Asia.
Mechanism 2: The tight junctions in the lipid bilayer are loosened by the drug cocrystal and coformer chemicals which increases transport across the membrane
The researchers classified the known examples of drug diffusion and permeability improvement in two categories depending on the reported and possible reasons from the data presented and postulate the reasons for permeability enhancement as: the hydrogen-bonded drug-coformer aggregates (defined as heterosynthons) survive long enough in the experimental media such that the drug, which is present in high concentration due to supersaturation, exhibits higher flux across the semipermeable membrane; the coformer or cocrystal is able to reduce the transepithelial electrical resistance values of lipid monolayers, which impairs their tight junctions, and facilitates drug passage to improve its diffusion/ permeability. The identification of these mechanisms in diffusion/ flux/ permeability enhancement will allow drug researchers to improve the solubility and permeability of novel drugs in the R&D pipeline. Poor solubility and low permeability affect over 90% drugs currently in drug discovery and clinical trials. High solubility and high permeability are opposite in nature physicochemical properties, like water and oil, which must be simultaneously optimized to formulate drugs of high bioavailability and improved therapeutic efficacy. The review article is truly an Asia contribution since several of the reviewed papers on permeability were published from India and China, said Prof. Nangia. In addition to modulating drug properties, pharmaceutical cocrystals and salts provide a novel platform for the discovery and development of new supramolecular-complex drugs in an accelerated time frame with less investment of money compared to new molecular entity medicines, and hence could be of potential utility for the Indian generic pharma companies.
Prof. B J Rao, Vice Chancellor, UoH said, “I congratulate Prof. Ashwini Nangia and his team for proposing new models for enhanced drug solubility and permeability. This will help drug researchers to identify novel drugs which will benefit mankind.”
Link for the publication: https://doi.org/10.1021/acs.molpharmaceut.3c00159