Aqueous solution and solid-state behaviour of l-homophenylalanine: experiment, modelling, and DFT calculations.

In the present study, the solid-state and aqueous solubility behaviour of l-homophenylalanine (l-Hpa) is explored. Different characterization techniques such as TG, DSC, temperature-resolved PXRD, and hot-stage microscopy were used to investigate basic thermal solid-state characteristics. Solubilities of l-Hpa in water were determined as a function of temperature and pH. Moreover, a thermodynamic model based on perturbation theory (PC-SAFT) is applied to represent the data. In addition, aqueous density data of l-Hpa were measured in a broader temperature range. To model the solubility data as a function of pH, pKa values are needed, which were accessed by employing density functional theory (DFT) calculations. The solid-state investigation did not show a simple melting process of l-Hpa, but a complete decomposition of the prevalent initial solid phase at elevated temperatures approximately above 520 K. This system exhibited extraordinarily low solubilities for an amino acid at all investigated temperatures. While the solubility does not differ from its isoelectric-point value over a wide pH range, it dramatically increases as the pH falls below 2.5 and rises above 9.5. The PC-SAFT model was able to calculate the solubilities as a function of pH and predict the density values.

Real-Time Crystal Growth Monitoring of Boric Acid from Sodium or Lithium Sulfate Containing Aqueous Solutions by Atomic Force Microscopy.

The crystal growth of boric acid from an aqueous solution in the absence and presence of sodium and lithium sulfate was studied by real-time monitoring. For this purpose, atomic force microscopy in situ has been used. The results show that the growth mechanism of boric acid from its pure and impure solutions is spiral growth driven by screw dislocation and that the velocity of advancement of steps on the crystal surface, and the relative growth rate (ratio of the growth rate in presence and absence of a salt) is reduced in the presence of salts. The reduction of the relative growth rate could be explained by the inhibition of advancement of steps of the (001) face mainly in the growth direction [100] caused by the adsorption of salts on the actives sites and the inhibition of the formation of sources of steps such as dislocations. The adsorption of the salts on the crystal surface is anisotropic and independent of the supersaturation and preferentially on the active sites of the (100) edge. Moreover, this information is of significance for the improvement of the quality of boric acid recovered from brines and minerals and the synthesis of nanostructures and microstructures of boron-based materials.

Shortcut Model for Batch Preferential Crystallization Coupled with Racemization for Conglomerate-Forming Chiral Systems.

Kinetically controlled preferential crystallization (PC) is a well-established elegant concept to separate mixtures of enantiomers of conglomerate-forming systems. Based on a smaller number of laboratory investigations, the key parameters of an available shortcut model (SCM) can be estimated, allowing for a rapid and reliable process design. This paper addresses a severe limitation of the method, namely, the limitation of the yield to 50%. In order to exploit the valuable counter enantiomer, the crystallization process is studied, coupled with a racemization reaction and a recycling step. It will be shown that the process integration can be performed in various ways. To quantify the different options in a unified manner and to provide a more general design concept, the SCM of PC is extended to include a kinetic model for the enzymatically catalyzed reaction. For illustration, model parameters are used, which characterize the resolution of the enantiomers of asparagine monohydrate and the racemization rate using an amino acid racemase. The theoretical study highlights the importance of exploiting the best stop time for batch operations in order to achieve the highest process productivity.

A Contribution to the Solid State Forms of Bis(demethoxy)curcumin: Co-Crystal Screening and Characterization.

Bis(demethoxy)curcumin (BDMC) is one of the main active components found in turmeric. Major drawbacks for its usage are its low aqueous solubility, and the challenging separation from other curcuminoids present in turmeric. Co-crystallization can be applied to alter the physicochemical properties of BDMC in a desired manner. A co-crystal screening of BDMC with four hydroxybenzenes was carried out using four different methods of co-crystal production: crystallization from solution by slow solvent evaporation (SSE), and rapid solvent removal (RSR), liquid-assisted grinding (LAG), and crystallization from the melt phase. Two co-crystal phases of BDMC were obtained with pyrogallol (PYR), and hydroxyquinol (HYQ). PYR-BDMC co-crystals can be obtained only from the melt, while HYQ-BDMC co-crystals could also be produced by LAG. Both co-crystals possess an equimolar composition and reveal an incongruent melting behavior. Infrared spectroscopy demonstrated the presence of BDMC in the diketo form in the PYR co-crystals, while it is in a more stable keto-enol form in the HYQ co-crystals. Solubility measurements in ethanol and an ethanol-water mixture revealed an increase of solubility in the latter, but a slightly negative effect on ethanol solubility. These results are useful for a prospective development of crystallization-based separation processes of chemical similar substances through co-crystallization.

Immobilization of an amino acid racemase for application in crystallization-based chiral resolutions of asparagine monohydrate.

Integration of racemization and a resolution process is an attractive way to overcome yield limitations in the production of pure chiral molecules. Preferential crystallization and other crystallization-based techniques usually produce low enantiomeric excess in solution, which is a constraint for coupling with racemization. We developed an enzymatic fixed bed reactor that can potentially overcome these unfavorable conditions and improve the overall yield of preferential crystallization. Enzyme immobilization strategies were investigated on covalent-binding supports. The amino acid racemase immobilized in Purolite ECR 8309F with a load of 35 mg-enzyme/g-support showed highest specific activity (approx. 500 U/g-support) and no loss in activity in reusability tests. Effects of substrate inhibition observed for the free enzyme were overcome after immobilization. A packed bed reactor with the immobilized racemase showed good performance in steady state operation processing low enantiomeric excess inlet. Kinetic parameters from batch reactor experiments can be successfully used for prediction of packed bed reactor performance. Full conversions could be achieved for residence times above 1.1 min. The results suggest the potential of the prepared racemase reactor to be combined with preferential crystallization to improve resolution of asparagine enantiomers.

Speeding up Viedma Deracemization through Water-catalyzed and Reactant Self-catalyzed Racemization.

Viedma deracemization is based on solution phase racemization, dissolution of racemic or scalemic conglomerates and crystal growth through autocatalytic cluster formation. With rate limiting racemization, its acceleration by appropriate catalysts may result in speeding up deracemization. A conglomerate-forming chiral compound may principally racemize directly, or via reverse of its formation reaction. For a hydrazine derivative, we investigated available racemization pathways in presence of pyrrolidine or thiourea amine as base catalysts: via Mannich or aza-Michael reaction steps and their reverse, or by enolization. Racemization by enolization was computationally found to dominate, both under water-free conditions and in presence of water, involving a multitude of different pathways. Faster racemization in presence of water resulted indeed in more rapid deracemization, when the base was pyrrolidine. Under water-free conditions, the role of water as enolization catalyst is assumed by chiral hydrazine itself - in autocatalytic racemization and in which both reactant and product are catalysts.

Separation Processes to Provide Pure Enantiomers and Plant Ingredients.

Enantiomer separation and the isolation of natural products from plants pose challenging separation problems resulting from the similarity of molecules and the number of compounds present in synthesis or extract mixtures. Furthermore, limited theory is available to predict productivities for possible alternative separation techniques. The application and performance of chromatography- and crystallization-based processes are demonstrated for various case studies devoted to isolating valuable target compounds from complex initial mixtures. In all cases, the first emphasis is set to determine the process-specific phase equilibria to identify feasible process options. For all examples considered, yields and productivities are evaluated and compared for different scenarios. Guidelines to approach and solve similar separation tasks are given.

Resolution of Racemic Guaifenesin Applying a Coupled Preferential Crystallization-Selective Dissolution Process: Rational Process Development.

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.

Shortcut Model for Describing Isothermal Batch Preferential Crystallization of Conglomerates and Estimating the Productivity.

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.

Solid-Phase and Oscillating Solution Crystallization Behavior of (+)- and (-)-N-Methylephedrine.

This work involves the study of the solid-phase and solution crystallization behavior of the N-methylephedrine enantiomers. A systematic investigation of the melt phase diagram of the enantiomeric N-methylephedrine system was performed considering polymorphism. Two monotropically related modifications of the enantiomer were found. Solubilities and the ternary solubility phase diagrams of N-methylephedrine enantiomers in 2 solvents [isopropanol:water, 1:3 (Vol) and (2R, 3R)-diethyl tartrate] were determined in the temperature ranges between 15°C and 25°C, and 25°C and 40°C, respectively. Preferential nucleation and crystallization experiments at higher supersaturation leading to an unusual oscillatory crystallization behavior as well as a successful preferential crystallization experiment at lower supersaturation are presented and discussed.

Physical-Chemical Properties of the Chiral Fungicide Fenamidone and Strategies for Enantioselective Crystallization.

Thermodynamic and kinetic parameters are of prime importance for designing crystallization processes. In this article, Preferential Crystallization, as a special approach to carry out enantioselective crystallization, is described to resolve the enantiomers of the chiral fungicide fenamidone. In preliminary investigations the melting behavior and solid-liquid equilibria in the presence of solvents were quantified. The analyses revealed a stable solid phase behavior of fenamidone in the applied solvents. Based on the results obtained, a two-step crystallization route was designed and realized capable of providing highly pure enantiomers. An initial Preferential Crystallization of the racemate was performed prior to crystallizing the target enantiomer preferentially out of the enriched mother liquor. Chirality 28:514-520, 2016. © 2016 Wiley Periodicals, Inc.

An Examination of the Phase Transition Thermodynamics of (S)- and (RS)-Naproxen as a Basis for the Design of Enantioselective Crystallization Processes.

A detailed experimental analysis of the phase transition thermodynamics of (S)-naproxen and (RS)-naproxen is reported. Vapor pressures were determined experimentally via the transpiration method. Sublimation enthalpies were obtained from the vapor pressures and from independent TGA measurements. Thermodynamics of fusion which have been well-studied in the literature were systematically remeasured by DSC. Both sublimation and fusion enthalpies were adjusted to one reference temperature, T = 298 K, using measured heat capacities of the solid and the melt phase by DSC. Average values from the measurements and from literature data were suggested for the sublimation and fusion enthalpies. In order to prove consistency of the proposed values the vaporization enthalpies obtained by combination of both were compared to vaporization enthalpies obtained by the group-additivity method and the correlation-gas chromatography method. The importance of reliable and precise phase transition data for thermochemical calculations such as the prediction of solid/liquid phase behaviour of chiral compounds is highlighted.

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.

Are the Crystal Structures of Enantiopure and Racemic Mandelic Acids Determined by Kinetics or Thermodynamics?

Mandelic acids are prototypic chiral molecules where the sensitivity of crystallized forms (enantiopure/racemic compound/polymorphs) to both conditions and substituents provides a new insight into the factors that may allow chiral separation by crystallization. The determination of a significant number of single crystal structures allows the analysis of 13 enantiopure and 30 racemic crystal structures of 21 (F/Cl/Br/CH3/CH3O) substituted mandelic acid derivatives. There are some common phenyl packing motifs between some groups of racemic and enantiopure structures, although they show very different hydrogen-bonding motifs. The computed crystal energy landscape of 3-chloromandelic acid, which has at least two enantiopure and three racemic crystal polymorphs, reveals that there are many more possible structures, some of which are predicted to be thermodynamically more favorable as well as slightly denser than the known forms. Simulations of mandelic acid dimers in isolation, water, and toluene do not differentiate between racemic and enantiopure dimers and also suggest that the phenyl ring interactions play a major role in the crystallization mechanism. The observed crystallization behavior of mandelic acids does not correspond to any simple "crystal engineering rules" as there is a range of thermodynamically feasible structures with no distinction between the enantiopure and racemic forms. Nucleation and crystallization appear to be determined by the kinetics of crystal growth with a statistical bias, but the diversity of the mandelic acid crystallization behavior demonstrates that the factors that influence the kinetics of crystal nucleation and growth are not yet adequately understood.

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.

Processes to separate enantiomers.

The provision of pure enantiomers is of increasing importance not only for the pharmaceutical industry but also for agrochemistry and biotechnology. In general, there are two rival approaches to provide pure enantiomers. The "chiral" approach is based on developing an asymmetric synthesis of just one of the enantiomers, while the "racemic" approach is based on separating mixtures of the two enantiomers. In the last few years remarkable progress has been achieved in the latter area. This Review focuses in particular on enantioselective crystallization processes and preparative chromatography, including hybrid processes and the incorporation of racemization steps. Several examples from our research are used for illustration purposes.

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.

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.

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.

(3R*,5'S*)-6,7-Dimeth-oxy-3-(4'-meth-oxy-6'-methyl-5',6',7',8'-tetra-hydro-1,3-dioxolo[4,5-g]isoquinolin-5'-yl)isobenzofuran-1(3H)-one (racemic α-noscapine).

In the racemic title compound, C(22)H(23)NO(7), the dihedral angle between the fused ring systems is 51.87 (6)°. Two of the meth-oxy groups are disordered over two orientations in 0.688 (5):0.312 (5) and 0.672 (15):0.328 (15) ratios. In the crystal, weak C-H⋯O inter-actions link the mol-ecules.