Probing intermolecular crystal packing in γ-indomethacin by high-resolution (1)H solid-state NMR spectroscopy

An NMR crystallography approach that combines experimental solid-state magic-angle-spinning (MAS) NMR with calculation is applied to the gamma polymorph of the pharmaceutical molecule, indomethacin. First-principles calculations (GIPAW) for the full crystal structure and an isolated molecule show changes in the (1)H chemical shift for specific aliphatic and aromatic protons of over -1 ppm that are due to intermolecular CH-pi interactions. For the OH proton, (1)H double-quantum (DQ) CRAMPS (combined rotation and multiple-pulse spectroscopy) spectra reveal intermolecular H-H proximities to the OH proton of the carboxylic acid dimer as well as to specific aromatic CH protons. The enhanced resolution in (1)H DQ-(13)C spectra, recorded at 850 MHz, enables separate (1)H DQ build-up curves (as a function of the DQ recoupling time) to be extracted for the aromatic CH protons. Supported by eight-spin density-matrix simulations, it is shown how the relative maximum intensities and rates of build-up provide quantitative insight into intramolecular and intermolecular H-H proximities that characterize the crystal packing

New forms of old drugs: improving without changing

ObjectivesIn a short approach, we want to present the improvements that have recently been done in the world of new solid forms of known active pharmaceutical ingredients (APIs). The different strategies will be addressed, and successful examples will be given. Key findingsThis overview presents a possible step to overcome the 10-15 years of hard work involved in launching a new drug in the market: the use of new forms of well-known APIs, and improve their efficiency by enhancing their bioavailability and pharmacokinetics. It discusses some of the latest progresses. SummaryWe want to present, in a brief overview, what recently has been done to improve the discovery of innovative methods of using well-known APIs, and improve their efficiency. Multicomponent crystal forms have shown to be the most promising achievements to accomplish these aims, by altering API physico-chemical properties, such as solubility, thermal stability, shelf life, dissolution rate and compressibility. API-ionic liquids (ILs) and their advantages will be briefly referred. An outline of what has recently been achieved in metal drug coordination and in drug storage and delivery using bio-inspired metal-organic frameworks (BioMOFs) will also be addressed