Polymorphs Of Glycine Research Articles

Natural-Abundance Solid-State 2H NMR Spectroscopy at High Magnetic Field

High-resolution solid-state (2)H NMR spectroscopy provides a method for measuring (1)H NMR chemical shifts in solids and is advantageous over the direct measurement of high-resolution solid-state (1)H NMR spectra, as it requires only the application of routine magic angle sample spinning (MAS) and routine (1)H decoupling methods, in contrast to the requirement for complex pulse sequences for homonuclear (1)H decoupling and ultrafast MAS in the case of high-resolution solid-state (1)H NMR. However, a significant obstacle to the routine application of high-resolution solid-state (2)H NMR is the very low natural abundance of (2)H, with the consequent problem of inherently low sensitivity. Here, we explore the feasibility of measuring (2)H MAS NMR spectra of various solids with natural isotopic abundances at high magnetic field (850 MHz), focusing on samples of amino acids, peptides, collagen, and various organic solids. The results show that high-resolution solid-state (2)H NMR can be used successfully to measure isotropic (1)H chemical shifts in favorable cases, particularly for mobile functional groups, such as methyl and -N(+)H(3) groups, and in some cases phenyl groups. Furthermore, we demonstrate that routine (2)H MAS NMR measurements can be exploited for assessing the relative dynamics of different functional groups in a molecule and for assessing whole-molecule motions in the solid state. The magnitude and field-dependence of second-order shifts due to the (2)H quadrupole interaction are also investigated, on the basis of analysis of simulated and experimental (1)H and (2)H MAS NMR spectra of fully deuterated and selectively deuterated samples of the α polymorph of glycine at two different magnetic field strengths.

Characterization of α and γ polymorphs of glycine crystallized from water‐ammonia solution

AbstractCrystallization of metastable α and stable γ polymorphs of glycine was carried out from aqueous solution in the presence of ammonia. Pure aqueous solution and solution with lower concentration of ammonia yield α nucleation and solution with a critical concentration of ammonia yield γ nucleation. Variation in the solubility of glycine in double distilled water and pH of the resulting solution due to the ammonia incorporation was studied in a range of temperatures. The induction period for the α and γ nucleation in the solution was determined and its variation due to the ammonia incorporation was also studied. Single crystals of both the polymorphs were grown by slow evaporation method. Effect of ammonia concentration and the resultant pH of the solution on the nucleation, growth and morphology of the grown polymorphs were investigated. The unidirectional growth of the γ polymorph along the polar axis was revealed. X‐ray powder diffraction method was employed to distinguish both the polymorphs structurally. Their thermal stability above room temperature was studied by differential scanning calorimetry which revealed that the as‐grown γ polymorph transforms to α at 179.6 °C while the as‐grown α retains its phase until melting. The optical transmittance of the grown γ polymorph was studied in the UV‐Vis‐Near IR region. The second harmonic generation (SHG) efficiency of the grown γ polymorph was studied with a Nd:YAG laser source and is about 6.8% higher than that of the inorganic standard KDP. (© 2011 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)

Raman study of low-frequency modes in three glycine polymorphs

The temperature dependence of selected low-wavenumber (< 200 cm(-1)) Raman bands was studied for the different crystalline phases (α-, β-, γ-) of glycine--the simplest possible "building block" of a biomolecule. The temperature dependence of the frequencies of vibrational modes deviates from the theoretical expectation based on the assumption of cubic anharmonicity. Although relatively small, this deviation was observed above 250 K for all the three polymorphs. This finding was discussed in relation to the "dynamical transition" phenomenon, observed in variety of biomolecules in the range 200-250 K. The similarity of the temperatures suggests, that the origin of the dynamical transition phenomenon can be related to intrinsic conformational states of biomolecules, while water serves rather as a plasticizer or a structure organizer.

Crystallization of β‐glycine by spray drying

AbstractGlycine crystallization during spray drying has been investigated on a laboratory scale. In order to obtain different polymorphs the experiments have been performed at different hot air temperatures, concentrations, different flow of the solution and spraying air. The obtained crystals were analyzed by means of X‐ray powder diffractometry, differential scanning calorimetry and the Fourier transform infrared spectrometry. Crystallization mostly resulted with a mixture of α‐ and β‐glycine with a small amount of γ‐glycine. The glycine polymorphism is affected by the drying air temperature, concentration and the flow of the solution, as well as the spraying air flow. Decrease of the drying air temperature and increase of the solution flow rate causes the increase of the quantity of β‐glycine. At room conditions, β‐glycine spontaneously transforms into thermodynamically more stable α‐glycine. (© 2011 WILEY‐VCH Verlag GmbH &amp; Co. KGaA, Weinheim)

Effects of the alpha- and gamma-polymorphs of glycine on the behavior of catalepsy prone rats

Glycine is used to treat various health problems and is efficient in the treatment of the negative symptoms of schizophrenia. Since glycine exists as a few polymorphs, the aim of this work is to compare the effects of the alpha- and gamma-forms of glycine on the behavior of the genetic catalepsy (GC) strain of rats. Both polymorphs of glycine have been administered to rats orally as pure solid chemicals, and cataleptic behavior and behaviors in the open-field, elevated plus-maze, and light–dark box tests were studied. Both the alpha- and gamma-polymorphs of glycine increased exploratory activity in the open-field test, but only the gamma-polymorph had beneficial effects on catalepsy and exploratory activity in the light–dark box and reduced anxiety in the elevated plus-maze.

Different effects of α- and γ-polymorphs of glycine on behavior of GC rats predisposed to catalepsy

1 The amino acid glycine is currently widely used in medicine. Medicines containing glycine can reduce the psychoemotional stress and aggression, raise social adaptation, normalize sleep and enhance mental per� formance, reduce the severity of brain disorders in ischemic stroke, and reduce the toxic effect of alcohol [1–3]. In the United States, drugs containing glycine have been approved for the treatment of negative symptoms in patients with schizophrenia [4]. Usually glycine is administrated as sublingual pills. It was found that the solution of glycine is less effective than the dry form [5]. Hence we can assume that the biolog� ical activity of glycine is associated not only with its chemical formula per se, but with the characteristics of the solid, such as its crystal structure (polymorphs). When glycine is used in formulations, its activity may also depend on the structure and properties of supramolecular complexes with excipients. Despite the fact that glycine can exist as several polymorphs [6], the influence of the crystal structure on the biolog� ical activity was not investigated. Neither catalogs nor packages of reagents and drugs containing glycine (as a pure substance or as a part of multicomponent pills) provide information on which polymorph(s) of glycine are present in the sample. In the publications devoted to the therapeutic use of glycine, there is no informa� 1 The article was translated by the authors. tion on which polymorph(s) of glycine have been used. 2 The aim of this work was to compare the effect of α and γ polymorphs of glycine on behavior of GK rats with a genetic predisposition to catalepsy. As a result, it was shown that γ�polymorph of glycine has a higher biological activity than the α�form. This effect was very unusual because both forms of glycine have almost the same kinetics of dissolution and their mol� ecules have the same conformation. An interpretation of the difference in the biological activity of two poly� morphs of glycine can be sought in the different struc� tures of molecular associates that enter the body when the two forms of drug have been taken orally. Glycine bought from Soyuzkhimreaktiv (Russia) contained a mixture of α and γ polymorphs; it was recrystallized to obtain pure α and γ polymorphs. The

Preparation of glycine polymorphs crystallized in water and physicochemical characterizations

This study shows that it is possible to obtain pure α-glycine or a mixture of glycine polymorphs (α and γ) in aqueous solution, depending on the mode of preparation, either continuous or semi-continuous. The differences between the two samples of glycine in solid state and in aqueous solution have been studied, using the following techniques: X-ray analysis, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), thermal microscopy, calorimetric analysis, thermally stimulated current (TSC) analysis and electrochemical impedance analysis. These analyses show that the presence of γ-glycine significantly modifies the physico-chemical properties of these two samples.

Kinetics of solid-state polymorphic transition of glycine in mechano-chemical processing

The kinetics of solid-state polymorphic transition of the stable polymorph of glycine (Form γ) to an unstable Form α were studied using a planetary ball mill to demonstrate the effect of mechano-chemical processing. The kinetics were analyzed in terms of operating variables, i.e. revolution speeds, the number of balls, mass of sample, materials of jar and balls, and grinding time. The rate of the transition was well correlated with the two-dimensional Avrami equation, and the apparent rate constants empirically determined were correlated with the above-mentioned variables. For the transition in a stainless steel jar and balls, the changes of polymorphic compositions were successfully correlated over the ranges of experimental conditions examined.

Control of Crystal Polymorph of Glycine by Photon Pressure of a Focused Continuous Wave Near-Infrared Laser Beam

Crystal polymorph of glycine is controlled by tuning the power of a linearly polarized continuous wave 1064-nm laser beam. Upon focusing the beam to the air/solution interface of a supersaturated glycine/D2O solution, its single crystal is spatiotemporally formed at a focal spot within a few seconds to a few tens of seconds. Fourier transform infrared measurement and single-crystal X-ray crystallographic analysis of the fabricated single crystal reveal that two polymorphs of α- and γ-forms are prepared depending on the laser power. The probability of γ-form preparation, which is not available under ambient conditions, arises up to 50% at 1.3 W laser power after an objective lens. The mechanism of the polymorph control is discussed in view of both photon pressure and local temperature elevation due to laser irradiation at the focal spot.

Self‐trapped NH vibrational states in the polymorphs of glycine, L‐ and DL‐alanine

AbstractThe polarized Raman spectra of the oriented single crystals of L‐ and DL‐alanine, α‐, β‐ and γ‐polymorphs of glycine have been studied at 3–300 K. Regularly spaced band packets have been observed in the spectral range of 2500–3000 cm−1, with intensity decreasing noticeably on heating. These band packets were interpreted as the manifestations of the existence of NH self‐trapped states in these systems at low temperatures. The analysis of the polarized spectra has shown that the self‐trapping is observed exclusively for the NH stretching vibration of the amino groups, which is related to the NH···O hydrogen bonds along the head‐to‐tail chains of zwitterions in the crystal structures. The wavenumber of this NH stretching vibration, however, was proposed to depend not solely on the length of this NH···O hydrogen bond, but also on the lengths of all the other NH···O hydrogen bonds formed by the NH3+ and the COO− groups in the structure linking the head‐to‐tail chains with each other. The arguments in favor of the hypothesis that the self‐trapping in these systems can be mediated by zero‐point quantum motions, and not by lattice phonons, are considered. The unusually low wavenumber (2500 cm−1) observed for the NH stretching vibration and indicating at the formation of a very strong NH···O bond is interpreted based on considering the effect of the crystalline environment on the formation and properties of the NH···O bonds in the head‐to‐tail chains of amino acid zwitterions. The results are interesting for understanding the factors determining the dynamics and structural instability of crystalline amino acids and also for biophysical chemistry, as the hydrogen bonded chains formed by amino acid zwitterions in the crystals can mimic the peptide chains. Copyright © 2009 John Wiley &amp; Sons, Ltd.

The Effect of Temperature and Solvent Composition on Transformation of β- to α-Glycine As Monitored in Situ by FBRM and PVM

The application of in situ focused beam reflectance measurement (FBRM) and particle vision measurement (PVM) in monitoring transformation of glycine polymorphs is introduced. The effect of solvent composition and temperature on the transformation from β- to α-glycine was investigated. It is noted that the transformation kinetics are highly sensitive to both the solvent composition and temperature and the transformation rate is a function of ethanol content in aqueous ethanol mixtures. At 303 K, high initial ethanol concentration accounts for a steady transformation. At the same ethanol content, the transformation rate decreases with decrease in temperature. A smoother transformation was observed at 293 K. The results are consistent with the solvent-mediated transformation mechanism in which β-glycine dissolves and α-glycine nucleates and grows. The thermodynamically stable γ-glycine was not observed. Understanding these effects can aid optimization and improve process control.

Heat capacity of β-alanine in a temperature range between 6 and 300 K

Thermodynamic properties of β-alanine in the temperature range 6.3–301 K were studied. No phase transitions were observed for the sample specially prepared to contain no solvent inclusions. At 298.15 K the calorimetric entropy and the difference in the enthalpy values are equal, respectively, to 126.6 JK−1 mol−1 and 19.220 Jmol−1. The C p (T) in the temperature range 6–16 K can be well described by Debye equation C p = AT 3. A comparison of the data on the entropies of glycine polymorphs and of β-alanine was used to show, that the empirical Parks–Huffman rule holds in the case of these compounds.

Structure solution and refinement from powder or single-crystal diffraction data? Pros and cons: An example of the high-pressureβ′-polymorph of glycine

The structure of a high-pressure polymorph of glycine (theβ′-polymorph formed reversibly at 0.8 GPa from theβ-polymorph) was determined from high-resolution X-ray powder diffraction data collectedin situin a diamond anvil cell at nine pressure points up to 2.6 GPa. X-ray powder diffraction study gave a structural model of at least the same quality as that obtained from a single-crystal diffraction experiment. The difference between the powder-diffraction and the single-crystal models is related to the orientation of the NH3-tails and the structure of the hydrogen-bonds network. The phase transition between theβ- andβ′-polymorphs is reversible and preserves a single crystal intact. No transformations were observed between theβ-,α-, andβ′-polymorphs on compression and decompression, although theα- andβ′-polymorphs belong to the same space group (P21/c). The instability of theβ- andγ-forms with pressure can be predicted easily when considering the densities of their structures versus pressure. The direction of the transformation (i.e., which of the high-pressure polymorphs is formed) is determined by structural filiation between the parent and the high-pressure phases because of the kinetic control of the transformations.

Crystal growth of α and γ glycine polymorphs and their polymorphic phase transformations

The single crystals of α and γ polymorphs of glycine were grown from aqueous solutions at ambient conditions. The metastable α-form was crystallized from pure aqueous solution and the stable γ-form from aqueous solution in the presence of a critical concentration of a selective additive sodium chloride. Attempt to grow sizable β-form single crystals were not successful because of their high instability. In stability terms at ambient conditions these three glycine polymorphs are like this: β<α<γ. The form of crystallization was confirmed by X-ray powder diffraction (XRD). The α- and β-forms crystallize in the monoclinic system with centrosymmetric space groups P2 1/n and P2 1, respectively, and the γ-form crystallizes in trigonal–hexagonal system with non-centrosymmetric space group P3 2. At high-humidity conditions, the room temperature polymorphic phase transformations from α to γ and solution-mediated phase transformation from β to α were confirmed by XRD. The transformation from γ to α while heating well above the room temperature observed at around 179 °C was recorded by thermogravimetry (TG) and differential thermal analysis (DTA) and confirmed by differential scanning calorimetry (DSC). The morphology of the grown polymorphs were analysed by goniometry. CHN analysis shows the non-existance of sodium chloride species in the grown γ-glycine single crystals. The optical transparancy of the γ-form was recorded by UV–vis–Near IR spectroscopy.

Study of the temperature effect on IR spectra of crystalline amino acids, dipeptides, and polyamino acids. IV. L-cysteine and DL-cysteine

A study of the IR spectra of L- and DL-cysteine is carried out in a range of frequencies from 4000 cm−1 to 600 cm−1 and temperatures from 333 K to 83 K. Changes in the spectra of L- and DL-cysteine (NH 3 + CH(CH2SH)-COO−) on cooling are analyzed in comparison with the spectra of L- and DL-serine (NH 3 + CH(CH2OH)-COO−) and three polymorphs of glycine (NH 3 + CH2-COO−) previously studied under temperature variation. Changes in the IR spectra at variable temperatures are correlated with previously obtained diffraction data on anisotropic compression of the structure and changes in the geometric parameters of hydrogen bonds. Special attention is paid to temperature regions in which anomalies were detected by vibrational spectroscopy, X-ray diffraction, and calorimetry.

Study of the temperature effect on IR spectra of crystalline amino acids, dipeptids, and polyamino acids. III. α-Glycylglycine

The IR spectra of α-glycylglycine (H3+N-CH2-CO-NH-CH2-COO−) are studied in the temperature range of 93 to 413 K. Changes in the spectra due to temperature variation are correlated with the previously obtained X-ray diffraction data on anisotropic compression of the structure and changes in the parameters of hydrogen bonding. Changes in the vibrational frequencies of NH3+ and COO groups in the IR spectrum of α-glycylglycine are compared to changes in the vibrational frequencies of the same groups in the IR spectra of polymorphs of glycine, L- and DL-serine.

Pressure-induced phase transitions in organic molecular crystals: a combination of x-ray single-crystal and powder diffraction, raman and IR-spectroscopy

The contribution summarizes the results of recent studies of phase transitions induced by high pressure in a number of molecular organic crystals, such as polymorphs of paracetamol, chlorpropamide, polymorphs of glycine, L- and DL-serine, β-alanine. The main attention is paid to the following topics: (1) Reversible / irreversible transformations; (2) Different behavior of single crystals / powders; (3) The role of pressure-transmitting liquid; (4) The role of the kinetic factors: phase transitions on decompression, or after a long storage at a selected pressure; (5) Isosymmetric phase transitions; (6) The role of the changes in the hydrogen bond networks / intramolecular conformational changes in the phase transitions; (7) Superstructures / nanostructures formed as a result of pressure-induced phase transitions.

Solubility of Form α and Form γ of Glycine in Aqueous Solutions

The solubilities of two polymorphs of glycine (α-form and γ-form) in different aqueous solvent mixtures were measured by using the analytical gravimetric method. Based on the measured solubility data in pure water, the relative stability and the enthalpy and entropy of dissolution of the two forms were determined using van’t Hoff plots. The solubilities of forms α and γ were also investigated in aqueous solutions containing methanol or polyethylene glycol (PEG200) at 20 °C. It was shown that the solubilities of both forms decreased with increasing concentration of methanol and PEG200. The pH dependence of solubility of the γ-form was measured in the pH range of (0.35 to 13.7) at temperatures of (20 and 25) °C. The solubility profiles show a U-shape with pronounced changes at pH below 3.0 or above 10.0.

Variable temperature NMR characterization of α-glycine

Proton NMR spin–lattice relaxation times in the laboratory frame ( T 1) and in the rotating frame ( T 1 ρ ) were measured as a function of temperature for a static sample of α-glycine. Both T 1 and T 1 ρ data can be fit quantitatively by a single thermally-activated motion (the modulation of the dipolar coupling by random hopping about the threefold axis of the –NH 3 group), with no addition of other mechanisms at any temperature between 173 and 415 K. An activation energy of 21.7 ± 1 kJ/mol was extracted and is compared with previously reported values for both α- and γ-glycine. Such comparisons allow the correction of glycine polymorphs misidentified in the literature. The minimum in T 1 at 325 K corresponds to a correlation time of 0.53 ns. Chemical shifts as a function of temperature were measured by 1H CRAMPS and by 13C and 15N CP/MAS experiments. These results are discussed relative to a previous report of anomalous electrical behavior in α-glycine within this temperature range.

Effect of sodium chloride on the nucleation and polymorphic transformation of glycine

The nucleation and transformation of two polymorphs of glycine (α- and γ-forms) have been investigated using sodium chloride (NaCl) as additive. The two polymorphs were unambiguously examined by using Powder XRD, FTIR, TGA and DSC. The polymorphic transition temperature was determined by both DSC and solubility measurements. The nucleation behavior of the two forms shows that the polymorph of initial nuclei strongly depends on the NaCl concentration and initial concentration of glycine. In aqueous solution without additive or at low concentration of NaCl, the α-form spontaneously nucleates, while at high concentration of NaCl and low initial concentration of glycine the γ-form crystallizes preferentially. Based on the above observations, it is proposed that the presence of NaCl could affect the packing arrangements of glycine molecules in aqueous solution through coulombic interactions, leading to the competitive nucleation of the two polymorphs. Furthermore, the solution-mediated polymorphic transformation experiments prove that the nucleation of γ-form could be significantly promoted in the presence of NaCl. This appears to be the first detailed experimental investigation of the occurrence domain as well as the polymorphic transformation of metastable form α and stable form γ of glycine crystallized from NaCl aqueous solution.