Abstract
In situ ATR-FTIR spectroscopy and imaging and image analysis were applied to the study of the multicomponent co-crystallization process involving S-valsartan and sacubitril in which LCZ696 crystals were formed. LCZ696 is a combination drug for use in heart failure that was approved by the FDA in 2015 following development by Novartis Pharmaceuticals. Though much work was reported on LCZ696 about its pharmacokinetic and pharmacodynamic effects in the evaluation and clinical testing, less attention was paid to study on the co-crystallization process. LCZ696 crystals have shown difficulties in filtration mainly due to the small particle size. In this work, LCZ696 crystals were prepared successfully by S-valsartan and sacubitril, and characterized by SEM, XRPD, TG-DSC and ATR-FTIR. ATR-FTIR and imaging and image analysis were used to monitoring solution concentration and investigating the co-crystallization mechanism. It revealed that the nucleation process was very slow compared with the transformation process, which is indication that the co-crystallization was controlled by nucleation. LCZ696 crystals are composed of very thin hexagonal plates, which seems indicating that LCZ696 crystals grow mainly in two size dimensions. Stirrer speed and crystal seeds were found to have noticeable effect on the induction time, transformation time and crystal size distribution. The Johnson-Mehl-Avrami equation was found to be able to describe the co-crystallization process.
Highlights
IntroductionValsartan (C24 H29 N5 O3 ; S-configure CAS No 137862-53-4; R-configure CAS No 137862-87-4; molar mass 957.99 g·mol−1 ; Figure 1), originally developed by Ciba-Geigy and later Novartis
Valsartan (C24 H29 N5 O3 ; S-configure CAS No 137862-53-4; R-configure CAS No 137862-87-4; molar mass 957.99 g·mol−1 ; Figure 1), originally developed by Ciba-Geigy and later NovartisPharmaceuticals is for hypertension and heart failure as an orally bioavailable and highly selective angiotensin receptor blocker (ARB) [1,2]
In order to control the co-crystallization of LCZ696, Johnson-Mehl-Avrami (JMA) equation was used to model the kinetics of the process as follows [44]: x(t) = 1 − exp( − (K(t − tind ))n where x(t) is the transformation fraction of valsartan and sacubitril at time t; K is nucleation and growth rate dependent constant; tind is the induction time; n is a parameter representing the nucleation mechanism and growth dimension
Summary
Valsartan (C24 H29 N5 O3 ; S-configure CAS No 137862-53-4; R-configure CAS No 137862-87-4; molar mass 957.99 g·mol−1 ; Figure 1), originally developed by Ciba-Geigy and later Novartis. Supramolecules have different structures and functions compared to the original self-assembly are formed by a combination of intermolecular weak interactions, including hydrogen bonds, coordinate bonds and π-π stacking [17,18,19]. 2020, 10, Supramolecules have different structures and functions compared to the original self-assembly molecules They are formed by a combination of intermolecular weak interactions, including hydrogen bonds, coordinate bonds and π-π stacking [17,18,19]. LCZ696 shows dual inhibition mechanisms of NEPi and ARB, the pentanoyl(2′-(tetrazol-5-ylate)biphenyl-4′-ylmethyl)amino)butyrate]. Previous literature about LCZ696 has focused on pharmacokinetic and pharmacodynamic effects in evaluation and clinical testing [21,27,28], but little attention was paid to the co-crystallization process of the complex. ATR-FTIR was used to monitor the supersaturation and the on-line imaging probe was utilized to detect the crystal shape and size as well as observing process phenomena
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