In this paper, we present the application of four different in situ analytical techniques to monitor the solvent-mediated polymorphic transformation of L-glutamic acid. Focused beam reflectance measurement (FBRM) and particle vision and measurement (PVM) have been used to track the chord length and morphology of the crystals over the course of the transformation. The polymorphic forms present have been monitored using Raman spectroscopy, while attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy has been used to measure the liquid-phase concentration profile. The combination of the different in situ data was used to identify the fundamental phenomena of nucleation and growth that govern the process. Moreover, the measurement data were combined with a mathematical model based on population balance equations and the fundamental equations describing the kinetics of nucleation and growth of both polymorphs. This combination allowed for the estimation of the characteristic nucleation and growth rates of the two polymorphic forms, while the dissolution process of the metastable polymorph was estimated using a Sherwood correlation. Finally, the experimental results obtained with different initial conditions and their simulation allowed for the validation of the population balance model and for a deeper understanding of the transformation process.

This work presents a new procedure to determine the nucleation kinetics during the reactive precipitation of an organic substance. The new method has been applied to the pH-shift precipitation of L-glutamic acid upon mixing of an aqueous monosodium glutamate solution with hydrochloric acid. The induction time has been measured precisely in a stirred batch reactor by the combination of two in-situ measurement techniques, namely ATR-FTIR spectroscopy (attenuated total reflection Fourier Transform technique) and Focused Beam Reflectance Measurement (FBRM). It is shown that ATR-FTIR is a suitable tool to measure the concentrations of the different L-glutamic acid ions, and can be used to determine the starting time of the process when the desired supersaturation is established in the reactor. The onset of particle formation is detected through FBRM. The precipitated polymorph is identified using in-situ Raman spectroscopy and Particle Vision & Measurement (PVM). Finally, the induction time is used together with the independently measured growth kinetics to determine the nucleation rate.

In this work, the effect of agglomeration on the final particle size distribution is investigated for batch precipitation processes carried out in stirred tank reactors. Agglomeration kinetics of R L-glutamic acid was determined based on seeded batch experiments by a combination with a population balance model and an integral parameter estimation technique. Different modeling approaches for the description of agglomeration are applied and assessed. The empirical model only takes into account the influence of supersaturation and stirring rate on the agglomeration process, while it neglects size dependencies. In the more rigorous modeling approaches, the agglomeration kernel is decomposed into a size-dependent collision frequency and an agglomeration probability. Computational fluid dynamics (CFD) is used to model the turbulent flow in the stirred reactor and to extract information about the shear rate distribution, which in turn can be used to incorporate the dependence of the agglomeration kernel on the local shear rate. The population balance model accounting for nucleation, growth, and agglomeration is used to predict the particle size distribution in precipitation experiments.

--solutions are compared in their accuracy to predict ion activities in saturated and supersaturated solutions. The Pitzer and the Bromley model are employed, taking into account ion pair formation of barium sulfate. Such models are then used to describe particle nucleation and growth, and finally they are imbedded in a mechanistic mixing-precipitation model for a single feed semibatch process. The effect of the key operating parameters on the mean particle size is analyzed through simulations. The results are compared with previous experimental data, thus highlighting the significance of a proper choice of the thermodynamic model.

Growth kinetics of alpha L-glutamic acid was determined based on seeded batch desupersaturation experiments. The growth rate correlation applied in this study accurately describes the growth process in a temperature range of 25-45 degrees C and in a supersaturation range of 1-3. The newly developed approach for the growth rate characterization has the advantage of a high robustness especially with respect to the influence of competing particle formation mechanisms as nucleation or agglomeration. The efficient technique employs in situ process analytical technologies, e.g. attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR) and focused beam reflectance measurement (FBRM), different ex situ analytical tools and population balance modeling combined with a non-linear least squares optimization algorithm to determine the growth kinetics. The growth mechanism was identified to be integration controlled and of birth and spread (B + S) type. The quality of the determined growth rate correlation was assessed by comparison with the experimental data and with literature data.

No abstract

No abstract

The application of two recently developed protocols for the fast and robust determination of nucleation and growth kinetics to the antisolvent precipitation of PDI 747 is presented in this work. Both characterization methods are based on two in situ process analytical technologies, i.e., attentuated total reflection-Fourier transform infrared spectroscopy and focused beam reflectance measurement, to monitor the liquid and the solid phase during the characterization experiments. The method to determine growth rate kinetics is based on seeded batch desupersaturation experiments. It combines the accurate characterization of seed particle size distributions and the measurement of desupersaturation profiles for different experimental conditions with population balance modeling and an optimization routine to determine the growth mechanism and the kinetic parameters. In a second step, the growth kinetics are combined with induction time experiments to calculate the nucleation rate. Earlier, these protocols were successfully applied to α-l-glutamic acid, consisting of prismatic crystals. In the case of PDI 747, their application is a challenge due to the needle-like shape of the crystals. The benefits and the limitations of the proposed method are thoroughly assessed.