L-Histidine polymorphs

For this, we describe two different stages of crystals such as glycine polymorphs [a-form (a-glycine)" and 7-form (7-glycine) ] and L-histidine polymorphs [A-form (A-histidine) and B-form (B-histidine) ]. 

Fig. 18, 67.80 MHz C CP-MAS NMR spectra of L-histidine polymorphs (A) A-histidine and (B) B-histidine. Numbering of side-chain structure is done by the systematic lUPAC nomenclature (see ref. 25). Reproduced with permission from Elsevier Science.

C and N CP-MAS NMR spectra of A-histidine and B-histidine Figures 18 and 19 show the 67.80 MHz CP-MAS and 27.25 MHz N CP-MAS NMR spectra respectively of L-histidine polymorphic crystals, A-histidine and B-histidine. The C CP-MAS NMR spectra show solid high-resolution signals separated into six regions. Their assignment and chemical shifts are shown in Table 2. It can be easily admitted that the polymorphic forms of L-histidine can not be distinguished from C CP-MAS NMR spectra, because the C chemical shifts are nearly the same in these crystals. 

Next, CP-MAS NMR spectra shows high-resolution N signals separated into three regions for the L-histidine polymorphs. It is impossible to distinguish between A-histidine and B-histidine from N CP-MAS NMR at the present stage, because the three N chemical shifts are the same, as shown in Table 2. 

Kitamura, M., Furukawa, H. and Asaeda, M. (1994) Solvent effect of ethanol on crystallization and growth of L-histidine polymorphs. Journal of Crystal Growth, 141, 193-199. 

A popular method is antisolvent crystallization in which very high supersaturation is achieved by the addition of a second solvent, that is, an antisolvent, which decreases the solubility of the solutes. Supersaturation levels can be controlled by varying the amount of antisolvent added. For example, nucleation and growth rates of L-histidine polymorphs are influenced by the composition of the solvent (mixture of water and ethanol). Various other factors such as antisolvent addition rate and initial concentrations of the solution also control crystallization behavior. Supercritical CO2 can also be used as an antisolvent. ... 

Polymorphs and solvated crystals is generally observed in pharmacentical indnstry [1], The bioavailability, stability, solnbility, and morphology of the pharmacentical products are very influenced by polymorphs [2-7], therefore the control of the polymorphic crystallization is very important. The crystallization process of polymorphs and solvated crystals is composed of competitive nucleation, growth, and transformation from a meta-stable form to a stable form [4], Furthermore, the crystallization behavior is influenced by various controlling factors such as temperature, supersaturation, additives and solvents [8], In order to perform the selective crystallization of the polymorphs, the mechanism of each elementary step in the crystallization process and the key controlling factor needs to be elucidated [8], On the other hand, we reported for L-Glutamic acid and L-Histidine system previously [4] that the nucleation and transformation behaviors of polymorphs depend on the molecular stractures. If the relationship between molecular stmcture and polymorphic crystallization behavior is known, the prediction of the polymorphism may become to be possible for the related compound. However, detail in such relationship is not clearly understood. 

The polymorphic forms of L-histidine are known as A-histidine and B-histidine. The crystal structures of both A-histidine (orthorhombic P2 2 2i space group and four molecules per cell) and B-histidine (monoclinic P2i space group and... 

From these results, it was concluded that the polymorphic forms of L-histidine can be readily distinguished by H CRAMPS NMR spectra, even when it is quite difficult to distinguish using the C and N CP-MAS NMR spectra. From the H CRAMPS NMR measurement, it is concluded that the H chemical shifts of a-amino acid crystals are very sensitive to a small difference in the magnetic surroundings of protons as well as that in the hydrogen-bond network. Accordingly, the solid H CRAMPS NMR is a very useful means for structural analysis of L-histidine crystals. 

In conclusion, the polymorphic forms of some a-amino acid crystals such as a glycine and L-histidine have been successfully studied by H CRAMPS NMR spectra. For glycine crystals, the H" signals of a-glycine splits into two peaks... 

Tenkanen H, Lukka M, Jauhiainen M, Metso J, Baumann M, Peltonen L, Ehnholm C. The mutation causing the common apolipoprotein A-IV polymorphism is a glutamine to histidine substitution of amino acid 360. Arterioscler Thromb. 1991, 11 851-856. 

Weissbuch, 1. Zbaida, D. Addadi, L. Leiserowitz, L. Lahav, M. Design of polymeric inhibitors for the control of crystal polymorphism - induced enantiomeric resolution of racemic histidine by crystallization at 25 degrees. J. Am. Chem. Soc. 1987,109 (6), 1869-1871. 

Weissbuch I Leisorowitz L, Lahav M (1994) Tailor-made and chtiige-transfer auxiliaries for the control of the crystal polymorphism of glycine. Adv Mater 6 952—956 Weissbuch I, Zbaida D, Addadi L, Leiserowitz L, Lahav M (1987) Design of polymeric inhibitors for the control of crystal polymorphism— induced enantiomeric resolution of racemic histidine by crystallization at 25-Degrees-C. 1 Am Chem Soc 109 1869—1871 Yamashita K, Nakate T, Okimoto K, Ohike A, Tokunaga Y, Ibuki R, Higaki K, Kimura T (2003) Estabhshment of new preparation method for soUd dispersion formulation of tacrolimus. Int J Pharm 267 79-91... 

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