Heike Lorenz

Coupling of simulated moving bed chromatography and fractional crystallisation for efficient enantioseparation

An optimised coupling of liquid chromatography and fractional crystallisation is suggested for efficient enantioseparation. As a first stage, a chromatographic separation, preferably simulated moving bed (SMB) chromatography, is applied to achieve an enantiomeric enrichment sufficient for a subsequent crystallisation. First results of the experimental and modelling work for the model system (+)-/(-)-mandelic acid in an aqueous solution are described. Chromatographic investigations involve the estimation of adsorption isotherms on a suitable chiral stationary phase and the simulation and optimisation of a corresponding SMB process. From the ternary phase diagram measured for the (+)-/(-)-enantiomer/ solvent system, the conditions required to crystallise a pure enantiomer from an asymmetric mixture can be derived. The productivity gains achievable from the combined process compared to the application of chromatography alone are discussed.

Binary and ternary phase diagrams of two enantiomers in solvent systems

Abstract The binary phase diagram of the mandelic acid enantiomers and the binary and ternary phase diagrams of the same enantiomer(s) and water are studied as a typical enantiomeric system. The results of the experimental work performed are presented in detail and discussed both with regard to the applicability of different methods for solubility measurement and their importance for crystallization based enantioseparation. It will be shown that, in addition to classical methods differential scanning calorimetry (DSC) can be applied successfully for solubility determination. From the obtained phase diagrams various possibilities of gaining pure mandelic acid enantiomers from aqueous solutions are derived. The particular role of the eutectic composition in the enantiomeric system is emphasized.

Potential of different techniques of preferential crystallization for enantioseparation of racemic compound forming systems

Recently the feasibility of preferential crystallization for enantioseparation of racemic compound forming systems has been demonstrated (Lorenz et al., Application of preferential crystallization to resolve racemic compounds in a hybrid process. Chirality 2006;18:828-840; Polenske et al., Separation of the propranolol hydrochloride enantiomers by preferential crystallization: thermodynamic basis and experimental verification. Cryst Growth Des 2007;7:1628-1634). Here, the development and the potential of an efficient separation process operated via two different techniques of preferential crystallization are studied: (1) seeded isothermal preferential crystallization and (2) auto-seeded polythermal preferential crystallization. Both techniques were investigated in the batch and in the cyclic operation mode. On the example of mandelic acid as a typical racemic compound forming system, it is demonstrated that a cyclic auto-seeded polythermal process is feasible and significantly more efficient than the seeded isothermal one.

Enantiomeric 3-Chloromandelic Acid System: Binary Melting Point Phase Diagram, Ternary Solubility Phase Diagrams and Polymorphism

A systematic study of binary melting point and ternary solubility phase diagrams of the enantiomeric 3-chloromandelic acid (3-ClMA) system was performed under consideration of polymorphism. The melting point phase diagram was measured by means of thermal analysis, that is, using heat-flux differential scanning calorimetry (DSC). The results reveal that 3-ClMA belongs to the racemic compound-forming systems. Polymorphism was found for both the enantiomer and the racemate as confirmed by X-ray powder diffraction analysis. The ternary solubility phase diagram of 3-ClMA in water was determined between 5 and 50 degrees C by the classical isothermal technique. The solubilities of the pure enantiomers are extremely temperature-dependent. The solid-liquid equilibria of racemic 3-ClMA are not trivial due to the existence of polymorphism. The eutectic composition in the chiral system changes as a function of temperature. Further, solubility data in the alternative solvent toluene are also presented.

A hybrid process for chiral separation of compound-forming systems

The resolution of chiral compound-forming systems using hybrid processes was discussed recently. The concept is of large relevance as these systems form the majority of chiral substances. In this study, a novel hybrid process is presented, which combines pertraction and subsequent preferential crystallization and is applicable for the resolution of such systems. A supported liquid membrane applied in a pertraction process provides enantiomeric enrichment. This membrane contains a solution of a chiral compound acting as a selective carrier for one of the enantiomers. Screening of a large number of liquid membranes and potential carriers using the conductor-like screening model for realistic solvation method led to the identification of several promising carriers, which were tested experimentally in several pertraction runs aiming to yield enriched (+)-(S)-mandelic acid (MA) solutions from racemic feed solutions. The most promising system consisted of tetrahydronaphthalene as liquid membrane and hydroquinine-4-methyl-2-quinolylether (HMQ) as chiral carrier achieving enantiomeric excesses of 15% in average. The successful production of (+)-(S)-MA with a purity above 96% from enriched solutions by subsequent preferential crystallization proved the applicability of the hybrid process.

Advanced process for precipitation of lignin from ethanol organosolv spent liquors

An advanced process for lignin precipitation from organosolv spent liquors based on ethanol evaporation was developed. The process avoids lignin incrustations in the reactor, enhances filterability of the precipitated lignin particles and significantly reduces the liquor mass in downstream processes. Initially, lignin solubility and softening properties were understood, quantified and exploited to design an improved precipitation process. Lignin incrustations were avoided by targeted precipitation of solid lignin at specific conditions (e.g. 100 mbar evaporation pressure, 43°C and 10%wt. of ethanol in lignin dispersion) in fed-batch operation at lab and pilot scale. As result of evaporation the mass of spent liquor was reduced by about 50%wt., thus avoiding large process streams. By controlled droplet coalescence the mean lignin particle size increased from below 10 μm to sizes larger than 10 μm improving the significantly filterability.

Solubility and Some Crystallization Properties of Conglomerate Forming Chiral Drug Guaifenesin in Water

The solubility of 3-(2-methoxyphenoxy)-propane-1,2-diol, the well-known chiral drug guaifenesin 1, in water has been investigated by means of polythermal and isothermal approaches. It was found that the solubilities of racemic and enantiomeric diols rac- and (R)-1 depend strongly on temperature. The ternary phase diagram of the guaifenesin enantiomers in water in the temperature range between 10°C and 40°C was constructed. Clear evidence was obtained that rac-1 crystallizes as a stable conglomerate. The Meyerhoffer coefficient for the guaifenesin-water system is more than two and strongly depends on temperature. Neither crystalline hydrates nor polymorphs were detected within the range of conditions covered. Metastable zone width data with regard to primary nucleation were also collected for rac-1 and (R)-1. On the basis of the knowledge acquired, the resolution of racemic guaifenesin by preferential crystallization from solution could be realized successfully.

The binary phase diagram of propranolol hydrochloride and crystallization-based enantioseparation

Inconsistent results were reported for the solid-state nature of the racemic species of the pharmaceutical relevant compound propranolol hydrochloride. In this work the binary phase diagram of the propranolol hydrochloride enantiomers is studied. Differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and high performance liquid chromatography (HPLC) were used as analytical methods. The type of the racemic species, the presence and extent of partial solid solutions and the stability regions of polymorphic forms in the system were investigated. The identified binary phase diagram is sketched. Finally, the feasibility of crystallization-based resolution is discussed.

A new method for investigating the combustion behaviour of solid fuels in FBC

A new method for the estimation of fuel specific parameters is introduced to characterize the burn-up behaviour of solid fuels, biomass and waste materials under fluidized bed conditions. For this purpose a specially designed gaspotentiometric oxygen sensor probe is used to detect the oxygen consumption during the batchwise fuel combustion directly in the combustion zone of a fluidized bed reactor. As a result of the in situ measurement and the fast response time of the sensor, the combustion behaviour of the fuel can be immediately described by its typical burn-out curve and, moreover, by the burn-out time, the effective reaction rate constant and a relative reactivity value as fuel specific parameters.

Non-equimolar discrete compounds in binary chiral systems of organic substances

Since knowledge on the occurrence of non-equimolar discrete compounds in binary systems containing chiral molecules is very limited, this study reviews and systematizes the current state of investigating such systems and summarizes the results on two example systems studied in detail by the authors. In particular, the identification and verification of the non-equimolar discrete compounds compared to other discrete solid phases occurring in the two systems are discussed by presenting the results of related SCXRD, PXRD, TRPXRD, DSC, IR, and HSM studies. The (S)-malic acid–(R)-malic acid system has been found to contain non-equimolar 1 : 3 and 3 : 1 stable (S3R and SR3) and metastable (3S1R and 1S3R) discrete compounds, along with the equimolar compounds RSI and RSII (known monoclinic modifications) and the recently discovered RSIII modification. Polymorphic transformations of the discrete phases are debated, and the crystal structure of the stable compound S3R is identified (S. G. P1). The L-valine–L-isoleucine system has been stated to contain a non-equimolar 2 : 1 discrete compound, V2I, that could independently be proven by the ternary solubility diagram in water and its crystal structure solved (S. G. C2). The results obtained are discussed in conjunction with the findings reported in the literature. In order to systematize the variety of terms used for the description of discrete phases in binary chiral systems of organic substances, a systematization of equimolar and non-equimolar compounds based on chemical and crystallographic characteristics is proposed.