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- Title
Multi-dimensional population balance modeling of sonocrystallization of pyrazinamide with systematic estimation of kinetic parameters based on uncertainty and sensitivity analyses.
- Authors
Maharana, Abhishek; Sehrawat, Priyanka; Das, Ashok; Kumar, Jitendra; Sarkar, Debasis
- Abstract
Application of ultrasound has several beneficial effects on both crystallization process and product crystal properties. This work focuses on experimental study and population balance modeling of ultrasound-assisted unseeded batch cooling crystallization of an important polymorphic pharmaceutical. The δ -polymorph of pyrazinamide, a drug for mycobacterium tuberculosis, exhibits plate-like morphology, and such crystals are best described by atleast two dimensions: length and width. A multi-dimensional population balance model for batch cooling sonocrystallization of pyrazinamide from its 1,4-dioxane solution is developed and validated. A series of experiments are performed with different ultrasound amplitudes (silent, 10%, and 50%) to study the effect of ultrasound on nucleation rate, crystal size, and polymorphism. The ultrasound is applied till the point of nucleation and an enhanced nucleation rate is introduced in the model in the presence of ultrasound irradiation. The various kinetic parameters are estimated following a systematic methodology based on uncertainty quantification and sensitivity analysis using experimental observations related to solute concentration and crystal size distribution. The Polynomial Chaos Expansion (PCE) is used to quantify the uncertainties in model prediction due to kinetic parameter uncertainties and sensitivity analysis is performed using total order Sobol's sensitivity indices derived from PCE model. The kinetic parameters are estimated in two steps. First, a global search technique is used to simultaneously estimate all the kinetic parameters. Next, the less sensitive parameters are kept fixed and the more significant parameters are fine-tuned using a gradient-based local optimizer. Out of total nine kinetic parameters, only four parameters appeared to be significant for both silent and sonicated cases. The high-resolution finite volume scheme is used to solve the multi-dimensional population balance model and the simulation results agree very well with experimental data related to both concentration and crystal size distributions. The results revealed that compared to silent cases, sonication increased the nucleation rate by 102 times and 104 times for 10% and 50% amplitude, respectively. The growth rate was also enhanced significantly with increase in ultrasonic amplitude. All the experiments yielded the desired δ -polymorph of pyrazinamide. [Display omitted] • A multi-dimensional population balance model for sonocrystallization is developed. • The polymorphic pharmaceutical pyrazinamide is used as a model compound. • The effect of ultrasound on nucleation, crystal size and polymorphism is studied. • Kinetic parameters are estimated using uncertainty and sensitivity analysis. • Polynomial Chaos Expansion is used for uncertainty quantification.
- Subjects
SENSITIVITY analysis; PYRAZINAMIDE; POLYNOMIAL chaos; RATE of nucleation; PARAMETER estimation
- Publication
Chemical Engineering Research & Design: Transactions of the Institution of Chemical Engineers Part A, 2023, Vol 200, p356
- ISSN
0263-8762
- Publication type
Article
- DOI
10.1016/j.cherd.2023.10.049