Local structural dynamics and vibrational energy transfer in an angiotensin receptor-neprilysin inhibitor by ultrafast 2D IR spectroscopy

As a novel drug-drug cocrystal, sacubitril allisartan calcium (S086) has demonstrated significant efficacy in the treatment of hypertension and heart failure. S086 has two crystalline forms (alpha and xi) with the same molecular composition, but only the crystal structure of the latter has been disclosed. Using the carboxylic group (COO-) and the amide group (CONH) as structural probes, the core structures and local dynamics of the Ca2+ coordination complex in the unit cell of the two cocrystals were examined by ultrafast two-dimensional infrared (2D IR) spectroscopy. A notable variation in the molar ratio of bidentate to bridging binding types of COO- groups that bind to Ca2+ was first identified between the two crystal forms by linear IR spectroscopy. This variation is accompanied by greater local structural rigidity of the alpha-crystal compared to that of the xi-crystal, as evidenced by a greater residual amplitude in the spectral diffusion dynamics extracted from the time-dependent 2D IR spectroscopy. Vibrational energy transfer between the bidentate and tridentate COO- groups in the alpha-crystal was found to be faster than that in the xi-crystal, suggesting shorter intermolecular distances between EXP3174 and sacubitril in the former. These findings provide dynamical structural parameters that help to understand the stability and releasing mechanisms of the drug molecules.