Screening a trace amount of pharmaceutical cocrystals by using an enhanced nano-spot method.

Cocrystallization is an attractive and promising technology that can improve the physical properties of formulations of active pharmaceutical ingredients (APIs). We have developed a "nano-spot method" that can evaluate the crystalline form on the nanogram scale. In this study, the following studies were performed to obtain versatile and comprehensive improvements to the nano-spot method: modification of the sample solution, application of solvent vapor exposure to attempt the precipitation of various states of crystals, and adoption of low-frequency Raman spectroscopy. Carbamazepine was used as a model API and cocrystallization screening was examined with 12 cocrystal formers (coformers). In the case of combinations that are already known to form cocrystals, spectra similar to those of previously reported cocrystals or new spectra were obtained. It was considered that the reported cocrystals or new polymorphs were obtained. In contrast, in the case of the combination which has been reported not to form a cocrystal, the spectra were consistent with that for the physical mixture of API and coformer, suggesting that a cocrystal also did not form in this screening. In addition, the newly adopted low-frequency Raman spectroscopy enabled the high-sensitive detection of the crystalline form.

Solid dispersions of efonidipine hydrochloride ethanolate with improved physicochemical and pharmacokinetic properties prepared with microwave treatment.

Drug absorption into the body is known to be greatly affected by the solubility of the drug itself. The active pharmaceutical ingredient efonidipine hydrochloride ethanolate (NZ-105) is a novel 1,4-dihydropyridine calcium antagonist that has a very low solubility in water. It is classified as a poorly soluble drug, and improvements in its solubility and higher bioavailability with oral administration are needed. In this study, employing microwave technology as a new means to improve solubility, we established a method for preparing solid dispersions using hydroxypropyl methylcellulose acetate succinate as a polymeric carrier and urea as a third component. This effective method has a treatment time of several minutes (simple) and does not require the use of organic solvents (low environmental impact). The third component, urea, acts to lower the melting point of NZ-105, which promotes amorphization. This greatly improves the solubility compared with the microwave-treated product of NZ-105/HPMC-AS binary system. The solid dispersion prepared with this method, in addition to evaluation in vitro, was tested in vivo using beagle dogs and shown to be effective from the eightfold improvement in absorption compared with NZ-105 alone based on the area under the curve.

Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former.

Paracetamol (APAP), a frequently used antipyretic drug, has poor compression moldability. In this study, we identified a novel cocrystal consisting of APAP and trimethylglycine (TMG) that exhibits improved tabletability. TMG was used instead of oxalic acid (OXA), which is a coformer reported previously. The cocrystal (APAP-TMG at a molar ratio of 1:1) was characterized by X-ray analysis, infrared spectroscopy, and thermal analysis. The crystal structure of APAP-TMG revealed that it was a cocrystal, since no proton was transferred between the APAP and TMG molecules. The compression and dissolution properties of APAP-TMG were similar to that of the APAP-OXA cocrystal. In addition, taste sensing measurements suggested that TMG has a sweet and umami taste, indicating that TMG should suppress the bitterness of APAP. From these results, TMG could be a safe and promising cocrystal former that could replace OXA, which can irritate tissues.