Influence of solvent on crystal nucleation of risperidone

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.

Crystal Nucleation of Tolbutamide in Solution: Relationship to Solvent, Solute Conformation, and Solution Structure

“…The solute–solvent interaction enthalpies range from −188 kJ mol −1 in toluene to −272 kJ mol −1 in n ‐propanol, and increases in the order: toluene<ethyl acetate<acetonitrile< n ‐propanol, This order deviates from the nucleation order reported above, especially with respect to toluene but also with respect to ethyl acetate versus acetonitrile, and accordingly deviates from our previous findings for salicylic acid and risperidone where the difficulty of nucleation increases with increasing solvent‐solute binding. However, like in those previous studies the binding to specific domains of the solute molecule needs to be analysed.…”

“…Six new conformers (local energy minima) are found to be distinguished from the initial crystal‐like F II conformation, by energy barriers (energy maxima) of 21–72 kJ mol −1 (Figure ). These barriers are substantially larger than those for risperidone (10–26 kJ mol −1 ) . A full (360°) scan over the rotational centre R1 yields an energy barrier of 22.5 kJ mol −1 and results in the same conformation as the starting tolbutamide geometry (Figure a).…”

“…As determined by adoption of the classical nucleation theory, the interfacial energy has been found to in some cases be inversely related to macroscopic properties like the solubility, and the solvent boiling point . The nucleation behaviour has also been correlated to solvation and deformation energies as well as strength of solvent‐solute binding and successive desolvation …”

“…A strong positive correlation is shown between the interfacial energy calculated from induction times and several experimental and modelled variables describing solvent‐solute bonding at SA′s carboxyl group: the carbonyl peak shift in the Raman spectrum for the salicylic acid monomer, the DFT‐derived (1:1) binding energy to the carbonyl group, the calorimetrically‐derived enthalpy of solvent–solute interaction, and the DFT‐derived solvation energy. In a similar study on risperidone, a larger and flexible molecule, we also found evidence suggesting that the difficulty of nucleation of this compound depends on the strength by which the solvent binds the risperidone molecules in solution …”

Does the γ Polymorph of Glycine Nucleate Faster? A Quantitative Study of Nucleation from Aqueous Solution

“…Many samples are needed to get statistics on the random process of nucleation. Previous researchers have used microfluidics 22,23 or other techniques [24][25][26][27][28] to achieve the same goal. Quantitative analysis of these data requires statistical tools.…”