Influence of solvent on crystal nucleation of risperidone.

Donal Mealey,Åke C Rasmuson,Jacek Zeglinski,Dikshitkumar Khamar

doi:10.1039/c4fd00223g

Abstract

Over 2100 induction time experiments were carried out for the medium-sized, antipsychotic drug molecule, risperidone in seven different organic solvents. To reach the same induction time the required driving force increases in the order: cumene, toluene, acetone, ethyl acetate, methanol, propanol, and butanol, which reasonably well correlates to the interfacial energies as determined within classical nucleation theory. FTIR spectroscopy has been used to investigate any shifts in the spectra and to estimate the interaction of solute and solvent at the corresponding site. The solution condition has also been investigated by Density Functional Theory (DFT) calculations over (1 : 1) solvent-solute binding interactions at 8 different sites on the risperidone molecule. The DFT computational results agree with the spectroscopic data suggesting that these methods do capture the binding strength of solvent molecules to the risperidone molecule. The difficulty of nucleation correlates reasonably to the DFT computations and the spectroscopic measurements. The results of the different measurements suggest that the stronger the solvent binds to the risperidone molecule in solution, the slower the nucleation becomes.

Highlights

Crystal nucleation from solution is a key step in crystallization processes and solution crystallization is widely used in the pharmaceutical, food, chemical and agrochemical industries
Crystal nucleation is in uenced by the solvent and within the Classical Nucleation Theory (CNT) framework this is captured in the interfacial energy[1,2] and in the pre-exponential factor.[3]
The induction time experiments reveal that in order to reach the same induction time the required driving force increases in the order: cumene < toluene < acetone < ethyl acetate < methanol < propanol < butanol

Summary

Introduction

Crystal nucleation from solution is a key step in crystallization processes and solution crystallization is widely used in the pharmaceutical, food, chemical and agrochemical industries. Paper methods (IR,[4] Raman,[5] NMR,[6] UV-visible7) to establish a link with the crystal structure of the nucleating solid phase. In some cases such a link could be established and in others cases not.[8,9] In addition to the type of aggregates[6,10] in the solutions, the type of solvent–solute interaction can dictate the morphology[11] as well as the kinetics of nucleation.[12] Lohani et al.[13] showed the type of solvent–solute interaction affecting the diffusion coefficient, resulting in the preferential crystallization of one form over another. The hydrogen bonding capabilities of a solvent and the nature of interaction prevailing between solute and solvent resulting in the nucleation of a particular form has been a subject of a number of studies.[5,14]

Methods

Results

Discussion

Conclusion