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Temperature cycling induced deracemization (TCID) is an attractive method to provide a pure enantiomer from a racemic solid phase. In this work, we performed deracemization of the nonessential amin...

The stereoisomeric system of rac-2-phenylglycinamide (PGA) and rac-N-acetyl tryptophan (NAT) is significant in the application of chiral resolution because it has been shown that this system can be used for enantioseparation of PGA and/or NAT using a novel deracemization route of the conglomerate salt formed. However, it was also found that the conglomerate salt eventually converted into different crystal forms that limited the time available for the separation. Herein, we try to understand the phase conversion occurring in this system using DSC, PXRD, and SC-XRD. The related structures of the salt (two polymorphs of the more stable homochiral (dd- and ll-) salts and one polymorph of the less stable heterochiral (dl- and ld-) monohydrate salts) are demonstrated and discussed relating to their relative stabilities. The successful deracemization was demonstrated using the heterochiral (dl- or ld-) monohydrate salts. However, following Ostwald’s rule of stages, only limited time is available for the deracemization before the metastable compound converts into the more stable homochiral (dd- and ll-) pair. Moreover, the occurrence of the (dd- and ll-) phase always coincides with the formation of yet another phase of the racemic compound containing four components in a crystal. Ostwald’s rule of stages here thus involves three steps and phases and is highly significant during the deracemization of the homochiral species., The evolution of the stereoisomeric system of rac-2-phenylglycinamide (PGA) and rac-N-acetyl tryptophan (NAT) follows a complex route involving three steps in Ostwald’s rule of stages. Deracemization requires termination of the process at the correct time, before more stable crystal forms develop.

It is known that the antisolvents used for crystallization can affect the crystallization outcome and may promote the crystallization of a specific polymorph. In this study L-histidine (L-his) is used as a model substance, and ethanol was selected to be an antisolvent. The formation of the polymorphs of L-his in antisolvent crystallization as a function of supersaturation, ethanol volume fraction, and temperature was studied. The induction time for the antisolvent crystallization was also measured. The results showed that the induction time decreases with higher supersaturation and ethanol volume fraction, indicating that the nucleation rate of L-his from antisolvent crystallization (where water was used as the solvent and ethanol as the antisolvent) increases with higher supersaturation, as expected, and ethanol fraction. At all temperatures studied, the pure metastable polymorph B of L-his was obtained initially at higher ethanol volume fraction and supersaturation, while a mixture of the polymorphs A and B was obtained at lower ethanol volume fraction and supersaturation.

Lysozyme was successfully separated from mixtures of lysozyme and ovalbumin by crystallization. The purity of the lysozyme product is more than 98%, the remaining activity is greater than 97%, and the yields of the crystal products were greater than 80%. The experimental conditions used were varied to study the effect of the operating parameters on the growth kinetics of lysozyme crystal and the separation ability of the process. The growth rates of lysozyme are second order with respect to the relative supersaturation. Therefore the growth kinetics of the crystallization process is controlled by the surface integration mechanism. The calculated growth rate constants were 5.4×10 −6 cm/h and 2.5×10 −6 cm/h for the crystallization process at 20 °C and 10 °C, respectively. There is no significant effect of the ovalbumin impurity up to the concentration of 67.5% ovalbumin (based on total protein) on the growth kinetics of lysozyme. Changing the NaCl concentration from 4% to 3% had no effect on the growth kinetics of lysozyme, although this does change the solubility and therefore the yield. The calculated activation energy was 53.08 kJ/mol which supports the hypothesis that the crystallization process is controlled by the surface integration mechanism.

We describe a facile strategy to synthesize hybrid nanocapsules with an oil core for hindering interactions between payloads and silica shell. Polycaprolactone/silica nanocapsules are synthesized by an interfacial sol-gel process occurring simultaneously with internal phase separation of the polymer produced by a miniemulsion-solvent evaporation technique. The localization of the polycaprolactone in the nanocapsules is depending on the ratio between polymer and silica. Formation of hybrid nanocapsules is found to significantly hinder interactions of drugs such as ibuprofen and carbamazepine with the silica surface.

An improved process for the deracemization of a racemic conglomerate suspension of enantiomorphs has been created based on principles developed in an earlier method using temperature fluctuations. The method consists of circulating the suspension between two vessels, each controlled at a specific temperature in order to make the process more effective and faster to achieve a homochiral solid state. Crystals in the suspension were partially dissolved in the hot vessel, and the remaining crystals were regrown in the cold vessel. The crystals in the cold vessel have a longer residence time than those in the hot vessel to allow more time for the crystal growth process. The results show that complete deracemization can be achieved via this process far more rapidly than by using the previous temperature cycling (one-vessel) process. Moreover, the new process could easily be scaled up to an industrial scale. The current process can be an effective alternative to currently used enantiopurification methods, with s...

This research aims to investigate the nucleation kinetics of the metastable polymorph B of L -histidine ( L -his). The nucleation rate of the metastable polymorph B of L -his was studied using water as a solvent and using various antisolvents to reduce the solubility and increase the supersaturation of L -his. Various methods can be used to determine the nucleation rate, e.g., induction time, metastable zone width, and direct measurement. However, direct measurement of the time evolution of the crystal size distribution by in-situ measurement is more suitable for scale-up purposes. The time evolution of the number of crystals was measured online via Focused Beam Reflectance measurement (FBRM). To investigate the nucleation rate, the antisolvent was added to the saturated solutions of L -his, then the crystals were allowed to nucleate under conditions of differing antisolvent type (methanol, ethanol, acetone, and acetonitrile), volume fraction of antisolvent to saturated solution (0.7 to 0.8), and the crystallization temperature (10, 25, and 40 °C). The nucleation rate increases with increasing volume fraction of antisolvent and supersaturation. The nucleation rate increases with higher temperature. The nucleation rates with acetonitrile and acetone antisolvents are very high whereas the nucleation rate with methanol is lowest because of the relatively high solubility of L -his in methanol at the same volume fraction. The interfacial energy of primary nucleation of the metastable polymorph B of L -his are different when using various antisolvents.

Crystal growth rate dispersion (GRD) and size-dependent crystal growth (SDG) models are models to extend McCabe’s ΔL Law to more accurately account for variation in the crystal growth rates within a population of crystals. GRD is a phenomenon where the crystal growth rate either fluctuates randomly over time or varies over a population of crystals. SDG is where the growth rate of a crystal depends on its size, typically with growth rates assumed to increase monotonically with crystal size. Although it has been recognized for more than 30 years that, except for extremely small crystals, SDG is an artifact of GRD, it is still common in the literature for GRD in experimental results to be modeled using SDG models. This discussion will present some background and new experiments on the mechanism and extent of GRD to demonstrate that GRD is a real phenomenon, whereas SDG is largely an artifact, and some modeling work to demonstrate that SDG models cannot successfully replicate crystal size distribution data th...

A deracemization technique using periodic temperature fluctuations on a conglomerate forming system undergoing a swift racemization in solution is demonstrated. The method uses heating and cooling periods of the suspension in order to create cycles of partial dissolution of the crystal phase followed by crystal regrowth: this enables symmetry breaking in the solid phase. The technique is an effective, simple, and cheap operation, and can promote understanding of the effects of dissolution and recrystallization on chiral symmetry breaking in the solid phase. The heating period leads to the decrease of the size of crystals and the destruction of small crystals; the surviving crystals can then grow during the cooling period. A succession of such cycles allows the autocatalytic transformation from a racemic suspension into pure enantiomer, with an enantiomeric excess (ee) > 99% within a few days. The results demonstrate a possible mechanism for the emergence of homochirality of molecules of biological signifi...

Many of the chemical species prepared or purified using crystallization from solution exist in a number of polymorphic forms, and this can create challenges in the design and operation of industrial crystallizers, particularly where a polymorphically pure product is required. Where two or more polymorphs may crystallize from a solution simultaneously, the metastable polymorph may nucleate first, and will undergo a transformation to the stable polymorph over time. In a solution-based crystallizer the transformation between the metastable polymorph and the stable polymorph will usually occur via a solution mediated transformation (SMT) rather than a solid state transformation. Solution mediated transformation occurs via dissolution of the metastable polymorph crystals simultaneously with the nucleation and growth of the crystals of the stable polymorph. Theoretical models for these mechanisms (dissolution, nucleation, and growth) are all well known, and it is simple to measure the kinetic rates for fitting the models. An essentially exact model for the SMT can thus be created using a population balance model for each of the crystalline phases in the system, and this model can be parameterized based on models fitted using experimental data for the basic mechanisms. However to have a fully a priori model of the SMT is rarely attempted, and when it is it tends to be unsuccessful. More common is to use the nucleation or growth kinetics as fitted parameters in a model fitting the SMT data. This tends to fit the experimental data successfully but there is no guarantee that the model is fundamentally correct rather than simply a good fit to a set of data. Better a priori population balance models of the SMT should be achievable, however mechanisms which need to be better treated in the simulations include the induction time, crystal growth rate and dissolution rate dispersion, null supersaturation for crystal growth and null undersaturation for dissolution, the effect of crystal size and perfection on dissolution kinetics, and variations in crystal shape factors during the growth which may modify the mass balance terms in the model.

Attrition of crystals in industrial crystallization is the major source of secondary nucleation and has strong effects on product quality. This work describes attrition in industrial crystallizers using an empirical engineering model based on dimensionless groups describing crystal properties, suspension properties, and crystallizer geometry and operating conditions. Here the attrition rate of sodium chloride crystals in a small scale mixed-suspension crystallizer is studied, varying the following parameters: impeller speed, parent crystal size, suspension density, draft-tube impeller clearance, off-bottom impeller clearance, impeller type, and impeller material. It was found that the attrition rate depends on most of the variables investigated. The direction of the dependence is predictable based on intuitive modeling. An empirical power law model based on dimensionless groups predicted by Buckingham-Pi theory (using variables mentioned above) gives a good fit to the data.

Growth kinetics of the two common polymorphs of dl -methionine ( dl -met), α- dl -met and γ- dl -met, and dissolution kinetics of γ- dl -met, were studied in aqueous solution as part of an attempt to complete an a-priori model of the solution-mediated transformation (SMT) of polymorphs in this system, which will then be compared to measured rates of polymorph transformation. The growth rates of α- dl -met and γ- dl -met were found to be linearly dependent on the relative supersaturation of dl -met in the system. The dissolution rate of γ- dl -met was found to linearly depend on the relative undersaturation of dl -met in the system. Both the growth and dissolution rate constants are temperature dependent and follow an Arrhenius relationship. At all temperatures studied, both the growth rate of α- dl -met and the dissolution rate of γ- dl -met are faster than the growth rate of γ- dl -met, indicating that if the dissolution is a diffusion controlled process, then the SMT of the polymorphs of dl -met is likely to be controlled by the growth rate of γ- dl -met.

Optical resolution of dl -methionine hydrochloride ( dl -met·HCl) by preferential crystallization was studied for the purification of l -met·HCl (the desired enantiomer) from supersaturated solutions of dl -met·HCl. The nucleation thresholds (NT) of dl -met·HCl affect the maximum resolution time suitable for preferential crystallization and also the percentage purity of the product crystals. Crystal growth rates of l -met·HCl single crystals both in supersaturated solutions of dl -met·HCl and in supersaturated solutions of pure l -met·HCl were measured in order to model the preferential crystallization more effectively. Results showed that the growth rate depends strongly on the relative supersaturation (especially from pure l -met·HCl solutions), that there is a wide crystal growth rate distribution in growth from both types of solution, and that the growth is faster from pure l -met·HCl solutions, as expected. A batch crystallizer seeded with l -met·HCl crystals was used to study the preferential crystallization, and to study the behavior of purity decrease of the product crystals during the crystallization process. The purity of the l -met·HCl product decreased to the equilibrium value over time, with almost no plateau at 100% purity (as is hoped for in preferential crystallizations). This is explainable by the very short induction times for nucleation in these solutions, and also that the l -met·HCl seed crystals may act as a template for the nucleation of the counter-enantiomer.

The induction time for precipitation of pure sodium dodecylsulfate (NaDS) solutions by CaCl2 both below and above the cmc at a specific temperature depends only on the supersaturation ratio of the precipitating species in the bulk solution, rather than the means of achieving the supersaturation (changes in calcium ion concentration or in surfactant concentration). For mixed NaDS/sodium decylsulfate (NaDeS) systems precipitated by CaCl2, the induction time is only a function of the supersaturation ratio calculated based on Ca(DS)2, which is formed from these solutions, since its solubility product is orders of magnitude less than that of Ca(DeS)2. The increase in induction time in mixtures of these surfactants, compared to pure systems of the same total surfactant content, is only due to the change in the concentration of the precipitating species (DS) because of changes in the molar ratio of the surfactants present and thermodynamic changes due to mixed micellization. For mixed NaDS/sodium octylbenzenesul...

The Secondary Nucleation Threshold (SNT) of γ- dl -methionine ( dl -met) in aqueous solution was measured for the temperature range 10–61 °C. The width of the SNT is weakly temperature dependent with slightly smaller induction times at higher temperatures. Seeded batch crystallizations of γ- dl -met were performed isothermally at 10, 25, and 40 °C in an agitated batch crystallizer, and within the SNT region to avoid nucleation. The effect of the initial supersaturation and seed mass on crystal growth were also studied at 25 °C. The initial growth rate (during the first 20 min of the batch) is significantly higher than subsequent crystal growth, a phenomenon previously seen with other species. The measured growth rates are independent of seed mass, as expected, for the usable portion of the growth rate data. The growth rates were found to linearly depend on the relative supersaturation of the total dl -met in the system. The growth rate constants increase with increasing temperature and follow an Arrhenius relationship. The growth kinetics of the γ- dl -met will be used to study in order to begin characterization of the polymorphic transformations and the overall crystallization rate of dl -met.

This article analyzes a collection of recent research on a recently discovered feedback mechanism between the crystal growth rate and the surface features of the crystal, and the ramifications the mechanism has on crystallization in general and also on the design and analysis of industrial crystallizers. It has been found that growth under high supersaturations degrades the crystal surface, causing a roughening that is probably due to imperfect incorporation of growth clusters into the surface of the crystal. The effect becomes more pronounced under higher growth rate conditions, and for higher residence times under such conditions. The mechanism only occurs if the supersaturation is increased above a critical level known as the macroscopic roughening transition, although this level is typically quite low; for sucrose it has been measured as a relative supersaturation between 2.5 and 3.9% which is in the range used in many industrial crystallizations. The mechanism appears to be associated with the surface energy of the crystal, with the surface of high surface energy crystals being degraded at lower values of the supersaturation, and such crystals also have larger reductions in growth rate after the roughening has occurred. The mechanism also appears related to growth rate dispersion (GRD), since it gives a mechanism for variation in growth rates in batches of crystals, and also because GRD also appears to be more significant in species having a higher value of the surface energy. The mechanism also causes an increase in the impurity incorporation in the crystal, thus leading to reduced product crystal purities. The mechanism for the impurity incorporation is probably due to enhanced adsorption of impurity molecules due to large crystal surface areas (due to the roughening) and also larger numbers of adsorption sites. The mechanism also complicates measurement of crystal growth kinetics, and thus makes efficient design of industrial crystallization units more difficult.

The effect of crystallization conditions on the dextran partition coefficient between impure syrup and sugar crystal has been investigated in a batch crystallizer. The crystallizer is operated isothermally at temperatures of 30, 40, and 50 °C, at constant relative supersaturations of 0.05, 0.07, and 0.09, and with mother liquor dextran concentrations of 1000 and 2000 ppm/Brix. The dextran content has been determined by the CSR method. A 1:1 mass ratio of high-fraction dextran (approximately 250,000 Da) and low-fraction dextran (60,000–90,000 Da) is used to represent a wide range of dextran contamination. It is seen that the dextran partition coefficient in sucrose crystallization increases with both increasing supersaturation and increasing crystallization temperature. However it appears that these are secondary effects, with the partition coefficient strongly correlating with crystal growth rate alone, despite the regressed data having large variations in temperature, mother liquor dextran content, and supersaturation. Dextran incorporation into the sugar crystal results from both dextran adsorption onto the crystal surface and mother liquor inclusions. The explanation for the variation in the dextran content in sugar crystal with respect to the growth rate is due to increased adsorption due to the higher surface roughness of crystals grown at high growth rates. Although the dextran concentration in the solution affects the dextran content in the crystal, it does not strongly affect the dextran partition coefficient.

Investigation of the secondary nucleation threshold (SNT) of alpha-glucose monohydrate was conducted in aqueous solutions in agitated batch systems for the temperature range 10 to 40 degrees C. The width of the SNT decreased as the induction time increased and was found to be temperature independent when supersaturation was based on the absolute concentration driving force. Nonnucleating seeded batch bulk crystallizations of this sugar were performed isothermally in the same temperature range as the SNT experiments, and within the SNT region to avoid nucleation. The growth kinetics were found to be linearly dependent on the supersaturation of total glucose in the system when the mutarotation reaction is not rate limiting. The growth rate constant increases with increasing temperature and follows an Arrhenius relationship with an activation energy of 50 +/- 2 kJ/mol. alpha-Glucose monohydrate shows significant crystal growth rate dispersion (GRD). For the seeds used, the 95% range of growth rates was within a factor of 6 for seeds with a narrow particle size distribution, and 8 for seeds with a wider distribution that was used at 25 degrees C. The results will be used to model the significance of the mutarotation reaction on the overall crystallization rate of D-glucose in industrial crystallization.

The effect of a crystal's growth rate history on the current growth behavior was investigated as a cause of crystal growth rate dispersion (GRD), which is a significant problem in crystallizer design and modeling. The solute used in the experiments was sucrose, a high production commodity still crystallized mainly in batch crystallizers, where GRD is most significant. The results show that the growth history of a crystal has a significant effect on the crystal growth rate of that crystal. In particular, a history of rapid crystal growth under high supersaturation causes a roughening of the crystal surface, apparently due to poor surface integration, and subsequent growth occurs at lower rates than would be expected without this growth history. The process of crystal surface healing occurs at low levels of supersaturation over periods of several hours of growth and results in the crystals again reaching their normal growth rate levels. The growth layer formed to heal the surface of the crystal is greater t...

The current study investigated a potential mechanism of growth rate dispersion (GRD) by determining the effect of a crystal’s “growth rate history” on its current crystal growth, for sucrose, potash alum, potassium dihydrogen phosphate (KDP), and potassium sulfate crystals, using a combination of growth kinetic analysis and surface analysis via atomic force microscopy (AFM) and scanning electron microscopy (SEM). The growth history of a crystal had a significant effect on the future crystal growth rate: if a crystal had a period of high growth in a high supersaturation environment, the subsequent growth of the crystal in a lower supersaturation had a lower rate than a crystal that had been kept in the lower supersaturation environment. These results can be explained by the effect of high growth rates on the growing surface of a crystal: crystals grown in high supersaturation solutions had a rougher surface (on a macroscopic rather than molecular scale) than those grown in low supersaturation solutions. Th...

International audience; The occurrence of concentration and temperature gradients in saline microdroplets evaporating directly in air makes them unsuitable for nucleation studies where homogeneous composition is required. This can be addressed by immersing the droplet in oil under regulated humidity and reducing the volume to the picoliter range. However, the evaporation dynamics of such a system is not well understood. In this work, we present evaporation models applicable for arrays of sessile microdroplets with dissolved solute submerged in a thin layer of oil. Our model accounts for the variable diffusion distance due to the presence of the oil film separating the droplet and air, the diffusive interaction of neighboring droplets, as well as the variation of the solution density and water activity due to the evolving solute concentration. Our model shows excellent agreement with experimental data for both pure water and NaCl solution. With this model, we demonstrate that assuming a constant evaporation rate and neglecting the diffusive interactions can lead to severe inaccuracies in the measurement of droplet concentration particularly during nucleation experiments. Given the significance of droplet evaporation in a wide array of scientific and industrial applications, the models and insights presented herein would be of great value to many fields of interest.