Online microscopy has received much attention in the field of crystal shape control over recent years, since commonly used measurement techniques cannot provide enough information for this purpose. In this work, we present an estimation scheme that serves to reconstruct the 3D crystal shape from the measured 2D crystal projection. The boundary curves of the crystal projections are parametrized by Fourier descriptors, which are subsequently compared with a precomputed database. The procedure is evaluated in comparison with various effects that might impair the estimation. A good agreement between the true and estimated values is found in all cases. The presented methods are applied to batch cooling crystallizations of potassium dihydrogen phosphate (KDP) dissolved in water. As a result, the face specific growth rates are determined as a function of supersaturation. To validate the performance of this scheme, the calculated face specific growth rates are used in a model-based prediction of the supersaturation profiles, which agrees well with the experimental data.

An integrated process for the chiral separation of the industrially relevant substance 2′,6′-pipecoloxylidide (PPX), an intermediate in the manufacture of a number of anesthetics, was developed. By combining three different techniques, chromatography, crystallization, and racemization, high productivity was achieved. All unit operations were executed using a common solvent system, full recycling, and a minimum of solvent exchanges or removals. The target molecule was obtained with an enantiopurity of >99.5 wt %.

Growth kinetics of L-asparagine monohydrate in racemic aqueous solutions as well as nucleation, growth and dissolution kinetics of the same enantiomer crystallized from pure Lasparagine solutions are measured and the kinetic parameters are estimated applying a recently developed shortcut-method. The corresponding experimental procedure is based on a small number of preferential (seeded) cooling crystallizations where the crystal size distribution is monitored with an online microscope. Afterwards, image analysis yields the transient particle size evolution of initially provided crystals, from which the response of the solid phase to the liquid phase driving force can be extracted. Subsequently, parameter estimation is carried out applying this data together with the information of concentration and composition of the liquid phase, to discriminate between different model approaches. The kinetics are validated finally with independent experiments to evaluate their quality. It is proven that growth kinetics of L-and D-asparagine monohydrate from water are identical. In contrast, it can be shown and quantified, that growth kinetics from racemic and enantiopure solutions of asparagine differ significantly from each other. The corresponding calculation of the driving force of enantiomeric systems is discussed in detail by means of ternary phase diagrams.

Abstract

Preferential crystallization is a cost efficient method to provide pure enantiomers from a racemic mixture of a conglomerate forming system. Exploiting small amounts of pure crystals of both enantiomers, several batch or continuous processes were developed, capable of providing both species. However, an intermediate production step has to be used when pure enantiomers are not available. In such cases, partially selective synthesis, chromatography, or crystallization processes utilizing chiral auxiliaries have to be used to provide the initial seed material. Recently, it was shown that a coupled Preferential Crystallization-selective Dissolution process (CPCD) in two coupled crystallizers can be applied if at least one pure enantiomer is available to produce both antipodes within one batch. The corresponding process is carried out in one reactor (crystallization tank) by seeding a racemic supersaturated solution with the available enantiomer at a certain temperature. The second reactor (dissolution tank) contains a saturated racemic suspension at a higher temperature. Both reactors are coupled via the fluid phase, allowing for a selective dissolution of the preferentially crystallizing enantiomer from the solid racemic feed provided in the dissolution vessel. The dissolution and crystallization processes continue until the solid racemic material is completely resolved and becomes enantiopure. At this point, both enantiomers can be harvested in their pure crystalline form. For a specific pharmaceutically relevant case study, a rational process design and the applied empirical optimization procedure will be described. The achieved productivities after optimization show the great potential of this approach also for industrial applications. Also, a strategy to control this process based on inline turbidity measurement will be presented.

No abstract

Preferential crystallization (PC) is a powerful method to separate the enantiomers of chiral molecules that crystallize as conglomerates. The kinetically controlled separation method works in a typically narrow metastable zone. Currently, there are no simple models available that allow estimating the productivity of PC and, thus, the comparison with rivalling resolution techniques. In this Article, we suggest a simple shortcut model (SCM) capable of describing the main features of batch-wise operated PC using three ordinary differential equations originating from the mass balance of the target enantiomer and solvent in the liquid and solid phases. Compared to population balance models, the basis of the SCM is the assumption that the crystals for each enantiomer have the same size, which increases continuously from prespecified initial values. The goal of the model is to describe the initial period of the batch, during which the purity is within the specification required. It is accepted that after reaching this border, the precision of predictions can drop. This Article also illustrates a simple strategy how to parametrize the model based on a few experimental runs of PC. At first, for demonstration purposes, theoretical transients generated using the more rigorous PBE model is analyzed using SCM considering the separation of the enantiomers of dl -threonine. Subsequently, results of an experimental study with the enantiomers of asparagine monohydrate are presented to validate the shortcut model, which is seen as a new valuable tool to quantify more rapidly the productivity of PC and to further promote this elegant technique capable to resolve enantiomers of conglomerate forming chiral systems.

For the design of crystallization processes, the specific substances have to be characterized in terms of their thermodynamic properties but also with respect to the corresponding crystallization kinetics. In an accompanying theoretical study, a short-cut-method was suggested and demonstrated for the quantification of different kinetic mechanisms, i.e. growth, dissolution and nucleation. Here, this method will be utilized for the estimation of parameters comprised in kinetic sub-models for three different substances. The experimental procedures as well as the data analysis will be discussed and the quality of the parameter estimates will be evaluated by comparing predictions of a population balance model using the identified parameters with the results of corresponding validation experiments. AbstractFor the design of crystallization processes, the specific substances have to be characterized in terms of their thermodynamic properties but also with respect to the corresponding crystallization kinetics. In an accompanying theoretical study, a shortcut-method was suggested and demonstrated for the quantification of different kinetic mechanisms, i.e. growth, dissolution and nucleation. Here, this method will be utilized for the estimation of parameters comprised in kinetic sub-models for three different substances. The experimental procedures as well as the data analysis will be discussed and the quality of the parameter estimates will be evaluated by comparing predictions of a population balance model using the identified parameters with the results of corresponding validation experiments.