Crystallization of a polymorphic drug in a stirred tank
Advancing the chemical engineering fundamentals
Crystallization (T2-9P)
Keywords: crystallization, polymorphism, modelling, Computational Fluid Dynamics, mixing
Crystallization by cooling followed by separation of the crystals from the resulting suspension is the most frequent method of choice to achieve the required purity of active pharmaceutical ingredients. However, this method may generate several types of polymorphs if uncontrolled.
Hereafter, the crystallization behaviour of a drug presenting several polymorphic forms is investigated.
In this process, the crude product is initially dissolved in an alcohol at high temperature and stirred. The cooling of this solution in a controlled manner induces the crystallization of the drug, but in a non-desired crystallographic form (morph II). In order to obtain the desired crystallographic form (morph I), the temperature is further reduced under 0°C and the system is kept at this constant maturation temperature. After a latency period, the polymorphic transition from morph II to morph I is observed.
The objective of this work is, on the one hand, to identify the mechanism of the polymorphic transition, and, on the other hand, to model the influence of the operating parameters on the latency period, in order to reduce it.
In a first step, the two morphs are characterized by different techniques: XR diffraction, electronic microscope and Differential Scanning Calorimetry. Solubility curves of the two morphs are experimentally measured.
In a second step, the nature of the polymorphic transition is investigated. For this purpose, the industrial installation has been reproduced in the lab, on a small-scale pilot installation. Using it, and some other measurement apparatus, as FBRM, FTIR or Raman probes, it is shown that the polymorphic transition follows a mechanism of dissolution-recrystallization mediated by the solvent.
In a third step, the influence of two operating parameters on the latency period is modelled.
Firstly, a model of the influence of the temperature on the latency period is developed. For this purpose, thermodynamic calculations, fed by the data obtained in the first step, and latency period measurements on the small-scale installation, using different maturation temperatures, are performed.
Secondly, a model of the influence of mixing on the latency period is developed. For this purpose, Computational Fluid Dynamics simulations of the flow in the tank and latency period measurements on the small-scale installation, using several impellers and different rotation speeds, are performed. It appears that the latency period can be well correlated to local hydrodynamic characteristics such as the Kolmogorov micro-scale.
Based on the developed models, optimal operating conditions are derived, and validated against experimental data, for different reactor scales.
See the full pdf manuscript of the abstract.
Presented Wednesday 19, 13:30 to 15:00, in session Crystallization (T2-9P).
