Polymorphs Of L-histidine Research Articles

Thermodynamic characteristics of L-histidine polymorphs and effect of ethanol on the crystallization

L-Histidine(L-His) has two polymorphs of FormA and FormB. It is known that the crystallization of polymorphs is influenced by antisolvents. In this study, crystal morphology of polymorph was considered from prediction of crystal structures. Next, the effects of ethanol on polymorphs and morphology of L-His were studied by evaluating crystals obtained from saturated aqueous solutions by cooling or adding of ethanol. From the prediction of crystal structures, It is suggested that FormA crystal tend to grow in the long side direction. Experiments show that FormA tends to be obtained from aqueous solvent, on the other hands, FormB tends to be obtained from ethanol existing solution. However, FormB were found to dissolve gradually and transited to FormA. Furthermore, results show high concentration of ethanol change the morphology along its thickness direction, so it suggests that the effect of antisolvents has a big influence on crystallization. Moreover, the results of Thermogravimeter-Differential Thermal Analyzer (TG-DTA) and Differential Scanning Calorimetry (DSC) analysis demonstrate that FormB, which is thought as a metastable form, is possibly favorable in term of thermal stability and suggests the behavior of melting and decomposition of L-His.

Effect of ethanol on crystallization of the polymorphs of L-histidine

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.

14 N Solid-State NMR Spectroscopy of Amino Acids.

14 N ultra-wideline solid-state NMR (SSNMR) spectra were obtained for 16 naturally occurring amino acids and four related derivatives by using the WURST-CPMG (wideband, uniform rate, and smooth truncation Carr-Purcell-Meiboom-Gill) pulse sequence and frequency-stepped techniques. The 14 N quadrupolar parameters were measured for the sp3 nitrogen moieties (quadrupolar coupling constant, CQ , values ranged from 0.8 to 1.5 MHz). With the aid of plane-wave DFT calculations of the 14 N electric-field gradient tensor parameters and orientations, the moieties were grouped into three categories according to the values of the quadrupolar asymmetry parameter, ηQ : low (≤0.3), intermediate (0.31-0.7), and high (≥0.71). For RNH3+ moieties, greater variation in N-H bond lengths was observed for systems with intermediate ηQ values than for those with low ηQ values (this variation arose from different intermolecular hydrogen-bonding arrangements). Strategies for increasing the efficiency of 14 N SSNMR spectroscopy experiments were discussed, including the use of sample deuteration, high-power 1 H decoupling, processing strategies, high magnetic fields, and broadband cross-polarization (BRAIN-CP). The temperature-dependent rotations of the NH3 groups and their influence on 14 N transverse relaxation rates were examined. Finally, 14 N SSNMR spectroscopy was used to differentiate two polymorphs of l-histidine through their quadrupolar parameters and transverse relaxation time constants. The strategies outlined herein permitted the rapid acquisition of directly detected 14 N SSNMR spectra that to date was not matched by other proposed methods.

Strategy for control of crystallization of polymorphs

The controlling factor and mechanism of the crystallization of polymorphs were investigated in various systems; i.e. amino acids, inorganic compounds (calcium carbonate), pharmaceuticals and inclusion compounds. The controlling factor depends on the systems (compounds and solvents and additives) and the crystallization methods (cooling crystallization, reactive crystallization and anti-solvent crystallization). The controlling factors for each system were found and a schematic diagram was shown. The mechanism of each controlling factor was investigated and some rules were found. It appears that the establishment of “Ostwald's step rule” depends on the systems. In the cooling crystallization of amino acids (L-glutamic acid and L-histidine), the “Ostwald's step rule” cannot be observed; however, in the crystallization of BPT esters, it is clearly established. The difference of the temperature effect between L-glutamic acid and L-histidine polymorphs may be related to the difference of the molecular conformation between the polymorphs. In the reactive crystallization of calcium carbonate polymorphs, the concentration (supersaturation) of reactant solutions, the mixing rate of the solutions, pH, stirring rate and temperature were found to be the controlling factors for the morphology and the crystallization behavior of polymorphs. As for the effect of additives it should be noted that the additive affects not only one polymorph, but on each polymorph. Then, knowing the relative effect of additives on each polymorph is important for the control. The growth kinetics of polymorphs of L-glutamic acid and the mechanism of morphology change of each polymorph were examined in the presence of L-phenylalanine (as an additive) with batch crystallization and the single crystal method. The growth rate model including the additive concentration was proposed for each polymorph and the method of the selective crystallization of the polymorphs by controlling the supersaturation and the additive concentration was also indicated. In anti-solvent crystallization of pharmaceuticals (BPT) it was shown that the addition rate of anti-solvent, initial concentration of solute and temperature are the controlling factors. With the increase of the addition rate the water composition in the nucleation zone increases, resulting in the preferential crystallization of the hydrate crystals. The transformation from BH to A form was observed, however, the transformation rate increased with a decrease in the water addition rate. It is that even when none of the A form was detected by XRD a small amount of fine crystals (A form) is included within the BH crystals and act as seed crystals for the transformation. Furthermore, the change in the molecular structure is related with a dynamic change of the polymorphic crystallization behavior as observed in L-Glu and L-His systems. The dependence of the polymorphic crystallization behavior on the molecular structure was systematically investigated using the newly synthesized BPT esters. It appeared that the conformational flexibility, the size of alkyl group of the esters and the presence of functional group influences the formation of hydrogen bond and the polymorphism. The solvent effect on the polymorphism was also examined in relation to the molecular structure. The functionality of clathrate crystals and the separation efficiency of isomers by clathrate crystals depend on their polymorphic crystallization behavior. The mechanism of the molecular recognition for the guest isomers by the host molecule is clarified. It was also elucidated that the release process of a guest biocide molecule from clathrate crystals includes polymorphic transformation.

Polarization Switching of Crystal Structure in the Nonphotochemical Laser-Induced Nucleation of Supersaturated Aqueous l-Histidine

Polarization switching of polymorphs has been observed in the nonphotochemical laser-induced nucleation of aqueous l-histidine in the supersaturation range 1.40–1.60. Exposure of solutions to 0.24 GW/cm2, 7 ns pulses of 532 nm light induced the nucleation of different polymorphs of l-histidine depending on polarization state of the light. Circularly polarized laser pulses tended to nucleate the orthorhombic A polymorph, whereas linearly polarized pulses tended to nucleate a mixture of the orthorhombic A and monoclinic B polymorphs. Higher supersaturation also favors the formation of mixed polymorphs. These observations support the hypothesis that the laser is organizing hydrogen-bonded groups of histidine molecules through an optical Kerr alignment.

Antisolvent Crystallization of the Polymorphs of l-Histidine as a Function of Supersaturation Ratio and of Solvent Composition

During the antisolvent crystallization of l-histidine from aqueous solution with the antisolvent ethanol, the polymorphic fraction of the metastable polymorph B increased with increasing supersaturation ratio. For supersaturation ratio SA ≤ 2.0, a mixture of the stable polymorph A and the metastable polymorph B was obtained, while for high supersaturation, SA ≥ 2.3, only form B was observed. The supersaturation ratio was increased either by increasing the l-histidine concentration in the aqueous solution or by increasing the ethanol volume fraction. The induction time for the antisolvent crystallization was one to several orders of magnitude smaller than the time to transform the metastable polymorph B into stable polymorph A in solution, indicating that both polymorphs formed simultaneously. Process simulation of the batch antisolvent crystallization of the polymorphs of l-histidine was applied to predict the outcome of the competition between heterogeneous nucleation and polynuclear growth rates for both polymorphs. When the interfacial energy was calculated as a function of the solubility, only the formation of the stable polymorph A was erroneously predicted. By modification of the relative interfacial energy and the relative step free energy, the predicted polymorphic fraction could be directed toward the observed polymorphic fraction.

Controlling Factors and Mechanism of Polymorphic Crystallization

The mechanism and controlling factors of polymorphic crystallization were investigated using amino acids and a thiazole derivative (BPT) (pharmaceutical). The controlling factors depend on the system and crystallization method. In the cooling crystallization of amino acids, supersaturation hardly influenced the crystallization behavior of either l-glutamic acid or l-histidine polymorphs. On the other hand, the effects of temperature and polymorphous seeds were remarkable in the polymorphic crystallization of l-glutamic acid, whereas no effect appeared in the crystallization of l-histidine polymorphs. Such a difference between the amino acids may be due to the conformational difference and/or the exchange rate between the conformers (or embryos) corresponding to each polymorph. The controlling factor in antisolvent crystallization of 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5- thiazolecarboxylic acid (BPT) was also examined in water−methanol mixture solvents. The thermodynamic stability of each polymorph a...

Controlling factor of polymorphism in crystallization process

The controlling factor and mechanism of the crystallization of polymorphs were investigated in the various systems. The effect of supersaturation was hardly observed in the polymorphic crystallization of both L-glutamic ( α, β) and L-histidine (A,B). The temperature effect appeared intensively in the case of L-glutamic acid polymorphs, however, no effect of temperature was observed for L-histidine polymorphs. Such difference of the temperature effect may be related with the difference of the molecular conformation between the polymorphs. In the reactive crystallization of calcium carbonate polymorphs between the calcium chloride and the sodium carbonate solutions, the effect of the concentration (supersaturation) of reactant solutions, the mixing rate of the solutions and temperature on the morphology and the crystallization of polymorphs (calcite, vaterite and aragonite) was observed. The complicated precipitation behavior and the morphological change may be related with the formation of the precursors. The effect of L-phenylalanine on the growth rate and morphology of L-glutamic acid polymorphs was also investigated by the single crystal method. The relationship between the additive concentration and the growth rate of each polymorphs was presented by the equation of the proposed model. The method of the selective crystallization of the polymorphs by controlling the supersaturation degree and the additive concentration was also indicated.

Solvent effect of ethanol on crystallization and growth process of L-histidine polymorphs

The solvent effect of ethanol on precipitation behavior and crystal growth rates of the A and B polymorphs of L-histidine were investigated in aqueous solutions. The fraction of A in precipitates decreases quickly when the volume fraction of ethanol in solvent (VOL) increases above 0.2, and finally pure B is obtained at 0.4 VOL. The transformation rate from B to A decreases with ethanol concentration. The growth rate of B was larger than that of A at the same supersaturation degree in both aqueous and ethanol solutions. However, the growth rates of both polymorphs are almost the same at the same concentration in aqueous solution, corresponding to the precipitation behaviors. In ethanol solutions, the growth rate of B is slightly larger than that of A at the same concentration of 0.2 VOL. However, the growth rate of B is much larger than A at 0.4 VOL. The results indicate that the precipitation behavior is controlled mainly by the relative growth rates of the polymorphs. The change of the growth mechanism with increasing VOL is suggested. The concentration decrease of the conformer which corresponds to A is suggested as responsible for the solvent effect.

Crystallization behavior and transformation kinetics of L-histidine polymorphs.

The crystallization and transformation behavior of the polymorphs of L-histidine (A, B) and the transformation kinetics were investigated in aqueous solutions. Both polymorphs precipitate in almost the same ratio from solutions in a wide concentration range. The ratio of the polymorphs. in the precipitate was scarcely influenced by temperature, unlike the behavior of L-glutamic acid. Transformation from B to A with a solution-mediated transformation mechanism occurred. The activation energy for the overall transformation was estimated as about 38 kJ/mol. From measurements of the solubilities at temperatures between 283 and 333 K, it was confirmed that A is a stable and B a metastable form. From a van’t Hoff plot the heat of fusion of L-histidine polymorphs was obtained as 15 kJ/mol, which is about half that of L-glutamic acid. No seed effect of either A or B crystals on the precipitation behavior was observed. A kinetic study of the transformation process was carried out and both the rate constants of growth of A(kG) and dissolution of B crystals(kD) were estimated simultaneously. At 313 K kD was nearly six times larger than kG, indicating that the transformation process is growth-controlled.