Kinetics Estimation and Polymorphic Transformation Modeling of Buspirone Hydrochloride

Abstract

In this work, solvent-mediated polymorphic transformation of metastable Form II to stable Form I of Buspirone Hydrochloride (BUS-HCl) was studied. The polymorphic transformation was monitored using in-situ Raman spectroscopy. The solvent-mediated transformation process is governed by the dissolution of Form II and the nucleation and subsequent growth of Form I. The model parameters for each of these sub-processes were determined with the aid of experimental data including polymorphic fraction in solid phase, solute concentration, and the crystal size distribution. In order to estimate the kinetic parameters, independent seeded batch sets of experiments were conducted, first to estimate the growth rate of Form I, and consequently to estimate the secondary nucleation of Form I and dissolution rate of Form II. The experimental data showed that the secondary nucleation of Form I occurred slightly after the dissolution of Form II was initiated. The estimated parameters for growth, nucleation and dissolution rates were successfully implemented in the population model and validated with the experiments.

A population balance model for solvent-mediated polymorphic transformation in unseeded solutions

“…In an investigation of the mechanism for solvent-mediated polymorphic transformation, numerical simulation is a powerful tool, as it provides useful information that cannot be obtained in actual experiments. However, the reported simulation studies 2,11,13,15,17,20,23 are not satisfactory. One reason for this may be that crystallization of a polymorphic compound is very complicated, with many rate processes.…”

“…It depends on the operating conditions such as seeding, agitation rate, [2][3][4][5][6][7] reactor size, 3,4 temperature, 8 concentration, the presence of impurities 9,10 and seeding. 2,7,8,[10][11][12][13][14][15][16][17][18] Polymorphism sometimes shows an unexpected behaviour in an industrial crystallizer. 19 A metastable polymorph (high solubility) transforms into a lower solubility polymorph during crystallization through a solventmediated 2,5,6,8,[13][14][15]17,20,21 (or solution-mediated 1,3,4,7,9,12,16,[22][23][24][25][26] ) mechanism, where the unstable polymorph crystals dissolve and the stable polymorph crystallizes.…”

“…2,7,8,[10][11][12][13][14][15][16][17][18] Polymorphism sometimes shows an unexpected behaviour in an industrial crystallizer. 19 A metastable polymorph (high solubility) transforms into a lower solubility polymorph during crystallization through a solventmediated 2,5,6,8,[13][14][15]17,20,21 (or solution-mediated 1,3,4,7,9,12,16,[22][23][24][25][26] ) mechanism, where the unstable polymorph crystals dissolve and the stable polymorph crystallizes. In an investigation of the mechanism for solvent-mediated polymorphic transformation, numerical simulation is a powerful tool, as it provides useful information that cannot be obtained in actual experiments.…”

Process Analytical Technology for Crystallization of Active Pharmaceutical Ingredients

“…Table 3. [107] Progesterone in wateracetone mixture Raman spectroscopy, multivariate MLR calibration [108] Flufenamic acid in water-ethanol mixture Raman spectroscopy, FBRM, univariate calibration [109] Carbamazepine in ethanol-water mixture Raman spectroscopy, univariate calibration [110] MK-A in isopropyl acetate Raman spectroscopy, multivariate PLS calibration [111] Piroxicam in acetone Raman spectroscopy, PVM, FBRM, ATR-UV/Vis, multivariate calibration [68] Buspirone in isopropyl alcohol Raman spectroscopy, univariate calibration [112] Isonicotinamide in five organic solvents…”

Systematic model identification and optimization-based active polymorphic control of crystallization processes

“…The functions used to express the nucleation rates for both the stable and metastable forms of L-glutamic acid were different in the mentioned studies: Cornel at al. (2009) and Sheikoleslamzadeh and Rohani The solution-mediated transformation of DL-methionine polymorphs was modelled by Wantha and Flood (2013) (Trifkovic et al 2012). Such model was solved using the methods of moments.…”