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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.

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Controlling the shape of crystals is of great practical relevance in fields like pharmacology and fine chemistry. Here we examine the paradigmatic case of urea which is known to crystallize from water with a needle-like morphology. To prevent this undesired effect, inhibitors that selectively favor or discourage the growth of specific crystal faces can be used. In urea the most relevant faces are the {001} and the {110} which are known to grow fast and slow, respectively. The relevant growth speed difference between these two crystal faces is responsible for the needle-like structure of crystals grown in water solution. To prevent this effect, additives are used to slow down the growth of one face relative to another, thus controlling the shape of the crystal. We study the growth of fast {001} and slow {110} faces in water solution and the effect of shape controlling inhibitors like biuret. Extensive sampling through molecular dynamics simulations provides a microscopic picture of the growth mechanism and of the role of the additives. We find a continuous growth mechanism on the {001} face, while the slow growing {110} face evolves through a birth and spread process, in which the rate-determining step is the formation on the surface of a two-dimensional crystalline nucleus. On the {001} face, growth inhibitors like biuret compete with urea for the adsorption on surface lattice sites; on the {110} face instead additives cannot interact specifically with surface sites and play a marginal sterical hindrance of the crystal growth. The free energies of adsorption of additives and urea are evaluated with advanced simulation methods (well-tempered metadynamics) allowing a microscopic understanding of the selective effect of additives. Based on this case study, general principles for the understanding of the anisotropic growth of molecular crystals from solutions are laid out. Our work is a step toward a rational development of novel shape-affecting additives.

The Focused Beam Reflectance Measurement (FBRM) technique provides on‐line and in‐situ information about the chord length distribution of a population of particles in dispersion. This is rather promising for applications such as crystal size distribution control in crystallization processes. The objective of this study is to deepen the understanding of the characteristics of the FBRM measurement. On the one hand, a model is presented, which allows in principle to transform particle size distributions (PSD) into chord length distributions (CLD). On the other hand, measurements with particles in suspension show the critical dependence of the measurement on the optical properties of the system. A special technique has been developed to measure CLDs of single particles. These measurements clarify some of the above effects, detect possible over‐ and underestimations of particle size and give indications about how to interpret and exploit on‐line CLD spectra.

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The control objectives of batch crystallization processes are often defined in terms of particle size distribution (PSD), or properties related to the PSD, viz. average particle size, product filterability, dry solids flow properties, etc. To achieve these control objectives, a constrained nonlinear model-based optimization strategy has been adopted. This involves the detailed modeling of batch crystallization including model validation and parameter estimation, on-line monitoring of supersaturation and PSD, and the application of optimization strategies. A deterministic population balance model accounting for solution thermodynamics, crystal growth, and nucleation has been developed. State estimation is achieved by the on-line monitoring of temperature, concentrations in the liquid phase, particle density, and PSD. For this purpose, the focused beam reflectance measurement (FBRM) provides an on-line, in-situ information of crystal size and particle concentration in the form of a chord length distribution (CLD). A method using a three-dimensional geometrical CLD model and an inverse technique based on projections onto convex sets (POCS) has been introduced to calculate PSDs from CLD raw data. These concepts are applied to the batch cooling crystallization of paracetamol in ethanol.