Evgeniy A. Losev

The effect of carboxylic acids on glycine polymorphism, salt and co-crystal formation. A comparison of different crystallisation techniques

The effect of carboxylic acids on glycine polymorphism, salt and co-crystal formation was compared for slow evaporation of solutions at ambient conditions, spray drying, “fast” and “slow” anti-solvent crystallisation and dry co-grinding. Different phases were found to crystallise from the same starting components, depending on the preparative technique. Small amounts of most carboxylic acids (glutaric acid being the only exception) promoted crystallisation of the γ-polymorph in solution and as a result of co-grinding. When added in equimolar quantities, the same carboxylic acids formed salts with glycine (addition of glutaric acid resulted in co-crystal formation) on slow evaporation of solutions and on co-grinding. Neither succinic nor L-malic acids produced glycine salts, but instead promoted formation of γ-glycine when present in any amount. Anti-solvent crystallisation and spray drying of solutions containing small or large amounts of carboxylic acids produced a variety of glycine polymorphs as both pure phases and their mixtures, whereas only oxalic acid yielded salts. The ability to synthesise glycinium semi-oxalate form II by spray drying was demonstrated.

The role of a liquid in “dry” co-grinding: a case study of the effect of water on mechanochemical synthesis in a “L-serine–oxalic acid” system

The results of the synthesis in the “L-serine–oxalic acid–water” system were compared for co-grinding of powder samples with water added in four different ways: as crystal water to either or both of the reactants or as a drop of water in the liquid phase. The products formed on co-grinding were compared with each other and with those that crystallised from solutions on slow evaporation under ambient conditions, on spray drying and on antisolvent crystallisation. Co-grinding of dry anhydrous reagents gave only trace amounts of the product phase (anhydrous 1 : 1 serinium oxalate) apparently due to the interaction with trace amounts of water in the air. In the presence of crystal water or water added in the liquid phase, the polymorphs of [L-serH]2[ox]·2H2O (as pure forms or in a mixture) were formed. Neat co-grinding of anhydrous oxalic acid with L-serine monohydrate or of anhydrous L-serine with oxalic acid dihydrate gave polymorph II (kinetic form). Co-grinding of L-serine monohydrate with oxalic acid dihydrate as well as liquid-assisted grinding with a sufficient amount of liquid water added gave polymorph I (thermodynamic form) and polymorph 2 (with a very low transformation degree) if too little water was added. The seemingly solid-state reaction proceeded in fact in the liquid phase at a contact between the solid particles and did not depend on the crystal structures of the initial components. The role of mechanical treatment in inducing the synthesis is merely bringing the reacting species into contact, improving their mixing, and facilitating the dehydration of crystal hydrates. The reaction could be observed also on storage of mixtures, via the intermediate aqueous solution formed at the contacts between particles, resulting in the same intermediate product as obtained by spray drying, whereas antisolvent crystallisation and slow evaporation gave the same polymorph as was eventually observed on LAG or on prolonged storage of a solid mixture.

Low-temperature phase transition in glycine-glutaric acid co-crystals studied by single-crystal X-ray diffraction, Raman spectroscopy and differential scanning calorimetry.

The occurrence of a first-order reversible phase transition in glycine-glutaric acid co-crystals at 220-230 K has been confirmed by three different techniques - single-crystal X-ray diffraction, polarized Raman spectroscopy and differential scanning calorimetry. The most interesting feature of this phase transition is that every second glutaric acid molecule changes its conformation, and this fact results in the space-group symmetry change from P2(1)/c to P1. The topology of the hydrogen-bonded motifs remains almost the same and hydrogen bonds do not switch to other atoms, although the hydrogen bond lengths do change and some of the bonds become inequivalent.

Polymorphism of “glycine–glutaric acid” co-crystals: the same phase at low temperatures and high pressures

Glycine–glutaric acid co-crystals undergo a first-order reversible phase transition at a very low pressure (0.1 GPa) to give the low-temperature phase described recently. This fact was confirmed by single crystal X-ray diffraction and Raman spectroscopy.

Glycinium semi-malonate and a glutaric acid–glycine cocrystal: new structures with short O—H...O hydrogen bonds

Glycinium semi-malonate, C(2)H(6)NO(2)(+)·C(3)H(3)O(4)(-), (I), and glutaric acid-glycine (1/1), C(2)H(5)NO(2)·C(5)H(8)O(4), (II), are new examples of two-component crystal structures containing glycine and carboxylic acids. (II) is the first example of a glycine cocrystal which cannot be classified as a salt, as glutaric acid remains completely protonated. In the structure of (I), there are chains formed exclusively by glycinium cations, or exclusively by malonate anions, and these chains are linked with each other. Two types of very short O-H...O hydrogen bonds are present in the structure of (I), one linking glycinium cations with malonate anions, and the other linking malonate anions with each other. In contrast to (I), no direct linkages between molecules of the same type can be found in (II); all the hydrogen-bonded chains are heteromolecular, with molecules of neutral glutaric acid alternating with glycine zwitterions, linked by two types of short O-H...O hydrogen bonds.

Crystallographic education in the 21st century

Methods and outcomes for teaching crystallography in graduate, post-graduate and secondary school environments are presented. This is an extended report based on the ideas presented in the MS92 Microsymposium at the IUCr 23rd Congress and General Assembly in Montreal.

Polymorphic transformations in glycine co-crystals at low temperature and high pressure: two new examples as a follow-up to a glycine–glutaric acid study

The effects of temperature and pressure on the co-crystals of glycine with DL-tartaric and phthalic acids (GTa and GPh, respectively) have been studied by X-ray diffraction and Raman spectroscopy in comparison with those on glycine–glutaric acid (GGa). On cooling, no phase transitions were observed in GTa or GPh, in contrast to the situation with GGa. On hydrostatic compression, both GTa and GPh underwent reversible phase transformations, accompanied by fracture. In the high-pressure phases, the main structural framework was preserved, and the number of crystallographically independent molecules in the unit cell increased. In GTa, dimers are squeezed together so that some hydrogen bonds get a three-centered character, and the interactions of one of the two glycine molecules change dramatically.

Effect of pressure on two polymorphs of tolazamide: why no interconversion?

Two polymorphs of tolazamide, N-[(azepan-1-ylamino)carbonyl]-4-methylbenzenesulfonamide, a sulfonylurea anti-diabetic drug, have different densities and molecular packings. Polymorph II converts into polymorph I in the solid state on heating or via recrystallization if solvent-assisted. The effect of pressure on the two forms and the possibility of a transformation to a denser form on compression have been studied. No phase transitions have been observed in either of the forms in a pentane–isopentane mixture (when no recrystallization is possible). Polymorph II recrystallized partly into a denser polymorph I in methanol at 0.1 GPa, but the transformation stopped at an early stage. Solid state DFT calculations of the two forms as well as conformational landscape investigation in the gas phase were used to rationalize this result. The anisotropic pressure-induced strain of the two polymorphs has been compared in relation to changes in the hydrogen bond geometry and the behavior of stacking interactions.

A salt or a co-crystal – when crystallization protocol matters

The problem of obtaining multi-component crystals as co-crystals (with neutral molecules) rather than as salts (with charged cations and anions) attracts much attention. This is not merely a scientific challenge, but is often important for issues related to intellectual property in the pharmaceutical industry. Until now, examples have been documented where control over co-crystal–salt state has been achieved by modifying either the chemical components (co-formers) or temperature. Serendipitously we recently obtained, for the first time, a co-crystal and a salt of the same chemical composition – β-alanine and DL-tartaric acid – crystallizing stochastically at the same temperature from the same solution (E. A. Losev and E. V. Boldyreva, Acta Crystallogr., Sect. C: Struct. Chem., 2018, 74, 177–185, 10.1107/S2053229617017909). Here we report the possibility of obtaining reproducibly crystals of either of the two forms, the stable co-crystal (II) or a metastable salt (III), depending on the crystallization protocol. These observations are rationalized in terms of control over nucleation and the nuclei growth of the two phases, Ostwalds rule of stages and “disappearing polymorphs”. We report the results of using slow evaporation, fast and slow anti-solvent crystallization, and co-grinding with a variable amount of added water, as well as of “slurry experiments”. The thermodynamically stable co-crystal (II) can be obtained as a pure phase through liquid-assisted grinding, and upon crystallization from solution if seeds of it are already present in solution. The metastable molecular salt (III) is formed as a pure phase upon “dry” co-grinding without any water added specially (although in a humid atmosphere), upon fast anti-solvent crystallization, or during slow anti-solvent crystallization experiments before any seeds of the co-crystal (II) become available. After the co-crystal (II) has been formed once, even introducing a seed of the molecular salt (III) does not help to crystallize the salt from solution. The salt (III) is thus a typical “disappearing polymorph”. For comparison, we describe the co-crystallization of DL-tartaric acid with other amino acids of the same homological series. This gives the same products under all of the tested crystallization conditions – salts for the larger γ- and α-aminobutyric acids (GABA (IV) and AABA (V), respectively), and a co-crystal for the smaller glycine (I). The findings shed light on the mechanism of the alternative precipitation of co-crystals or salts of zwitterionic compounds from their aqueous solutions.

The effect of amino acid backbone length on molecular packing: crystalline tartrates of glycine, β-alanine, γ-aminobutyric acid (GABA) and DL-α-aminobutyric acid (AABA)

We report a novel 1:1 cocrystal of β-alanine with DL-tartaric acid, C3H7NO2·C4H6O6, (II), and three new molecular salts of DL-tartaric acid with β-alanine {3-azaniumylpropanoic acid-3-azaniumylpropanoate DL-tartaric acid-DL-tartrate, [H(C3H7NO2)2]+·[H(C4H5O6)2]-, (III)}, γ-aminobutyric acid [3-carboxypropanaminium DL-tartrate, C4H10NO2+·C4H5O6-, (IV)] and DL-α-aminobutyric acid {DL-2-azaniumylbutanoic acid-DL-2-azaniumylbutanoate DL-tartaric acid-DL-tartrate, [H(C4H9NO2)2]+·[H(C4H5O6)2]-, (V)}. The crystal structures of binary crystals of DL-tartaric acid with glycine, (I), β-alanine, (II) and (III), GABA, (IV), and DL-AABA, (V), have similar molecular packing and crystallographic motifs. The shortest amino acid (i.e. glycine) forms a cocrystal, (I), with DL-tartaric acid, whereas the larger amino acids form molecular salts, viz. (IV) and (V). β-Alanine is the only amino acid capable of forming both a cocrystal [i.e. (II)] and a molecular salt [i.e. (III)] with DL-tartaric acid. The cocrystals of glycine and β-alanine with DL-tartaric acid, i.e. (I) and (II), respectively, contain chains of amino acid zwitterions, similar to the structure of pure glycine. In the structures of the molecular salts of amino acids, the amino acid cations form isolated dimers [of β-alanine in (III), GABA in (IV) and DL-AABA in (V)], which are linked by strong O-H...O hydrogen bonds. Moreover, the three crystal structures comprise different types of dimeric cations, i.e. (A...A)+ in (III) and (V), and A+...A+ in (IV). Molecular salts (IV) and (V) are the first examples of molecular salts of GABA and DL-AABA that contain dimers of amino acid cations. The geometry of each investigated amino acid (except DL-AABA) correlates with the melting point of its mixed crystal.