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.