Exploring molecular reorientations in amorphous and recrystallized felodipine at the microscopic level.

A Pajzderska,J Wąsicki,J P Embs,J Jenczyk

doi:10.1039/d0ra07266d

Abstract

Molecular reorientations were studied in amorphous, partially and fully recrystallized felodipine (calcium channel blocker, a drug from the family of 1′,4-dihydropyridine) using a set of experimental methods: high-resolution solid-state nuclear magnetic resonance (NMR), relaxometry NMR and quasielastic neutron scattering (QENS). The results were compared with molecular dynamics in crystalline felodipine previously investigated [A. Pajzderska, K. Drużbicki, M. A. Gonzalez, J. Jenczyk, J. Mielcarek, J. Wąsicki, Diversity of Methyl Group Dynamics in Felodipine: a DFT Supported NMR and Neutron Scattering Study, CrystEngComm, 2018, 20, 7371–7385]. The kinetics of the recrystallization was also studied. The most stable sample was the sample stored in a closed ampoule (at room temperature, in 0% RH) and its complete recrystallization lasted 105 days. In the fully recrystallized sample, the same molecular reorientation identified in the crystalline form was detected, so reorientations of all methyl groups and the ethyl ester fragment. In the partially recrystallized sample, static disorder caused by the two positions of both side chains was revealed. In the amorphous sample the reorientation of all methyl groups was analyzed and the distribution of correlation times and energy barriers connected with the loss of long-range ordering and disorder of side chains were analyzed. Additionally, inhibition of reorientation in the ethyl ester fragment was observed.

Highlights

The bioavailability of active pharmaceutical ingredients, which determines the effectiveness of therapy, is directly related to both the solubility and dissolution rate
The physicochemical properties of organic systems, including amorphous ones are in uenced by molecular dynamics, and it is believed that mobility is one of the main factors that govern their physical stability,[1,2] analysing this seems to be an important factor of the characteristics of amorphous samples
It is widely believed that knowledge of the reorientation and mobility of molecular amorphous systems may be the key to understanding their physicochemical properties and an indication of effective methods of increasing physical stability

Summary

Introduction

The bioavailability of active pharmaceutical ingredients, which determines the effectiveness of therapy, is directly related to both the solubility and dissolution rate. The physicochemical properties of organic systems, including amorphous ones are in uenced by molecular dynamics, and it is believed that mobility is one of the main factors that govern their physical stability,[1,2] analysing this seems to be an important factor of the characteristics of amorphous samples. It is widely believed that knowledge of the reorientation and mobility of molecular amorphous systems may be the key to understanding their physicochemical properties and an indication of effective methods of increasing physical stability. The rate of structural relaxation (a relaxation) close to the glass transition correlates with a high tendency to crystallize pharmacologically active ingredients.[3,4,5] In addition, molecular reorientations described by b relaxation[3,5,6] can in uence the recrystallization of amorphous systems. Nuclear magnetic resonance[7,8,9,10] and quasielastic neutron scattering methods are used to analyse molecular reorientation in amorphous systems.[11,12]

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