Study of structural response of chlorpropamide polymorphs to external stress

Polymorphism in molecular crystals is a remarkable property of Nature to create a wide range of various combinations of limited amount of components. Studies of the polymorphic crystals upon different types of external influence could be very useful in terms of analysis of molecular packing, nature and dynamics of the intermolecular interactions. When applied to pharmaceuticals, crystal structure may noticeably affect on stability, solubility, bioavailability, etc. which are essential for drug development. Sulfonyl urea derivatives represent a great example of compounds which are potentially inclined to conformational polymorphism. In particular generation drug chlorpropamide could be crystallized in a five different polymorphs. Chlorpropamide molecule is highly flexible in the crystal structure whereby we obtain various types of molecular conformations and their relative arrangements within the main structural forming motif - directed hydrogen bonded chains. Although polymorphic properties of chlorpropamide have been well-known for a decade there are still a lot of open questions regarding relative stability and crystallization conditions of the polymorphs as well as their behavior under extreme conditions such as cryogenic temperatures, hydrostatic pressure and mechanical stress. In order to follow dynamics of molecular fragments and to observe possible phase transitions on cooling and compression polarized Raman spectroscopy was used. Low temperature spectra were recorded in a wide temperature (5-300 K) range. The effect of hydrostatic pressure was studied using diamond anvil cell up to 5 - 5.5 GPa. Nanoindentation was applied to five polymorphs of chlorpropamide to examine and compare their mechanical properties. Experimental results were also supported by quantum-mechanical calculations. The research was supported by a grant for Russia-Slovenia collaboration BI-RU-12-13-038, a grant from RFBR and the Integration project 108 of the SB RAS.

The effects of pressure on structural strain in crystals with acetamide groups

Polymorphism is an ever growing area of interest in chemistry. Many active pharmaceutical ingredients (APIs) have the potential to have polymorphic forms, which can subsequently be used to the advantage of the pharmaceutical industry. There are a variety of conditions in which polymorphism can be examined; one way which has sparked interest in recent years is the influence of pressure and its effect on the behaviour of intermolecular bonds. The polymorphs of paracetamol were the first solid drugs for which the properties were compared at different pressures [1-2]. Another interesting research direction involves the comparison of the structural response to pressure of a series of chemically different compounds with similar molecular fragments, but possessing different molecular packing and intermolecular interactions. This is important for crystal engineering and for understanding structure-properties relationships. In the present study, we compare the response to pressure of a series of organic compounds with a common acetamide fragment: two polymorphs of paracetamol, two polymorphs of acetotoluidine, polymorphs and a hydrate of metacetamol, methacetin, and phenacetin. Both single-crystal Raman spectroscopy and X-ray diffraction were used. The effects of various pressure media have also undergone examination. The study was supported by the Year Abroad Programme of the University of Edinburgh (LM, CB), Russian Ministry of Science and Education and Russian Academy of Sciences (BAZ, SVG, EVB).

Effect of high pressure on the crystal structures of sarcosine and betaine

It is well known that infinite head to tail chains built of zwitterions linked to each other by N-H...O hydrogen bonds are common structural motifs in crystals of amino acids. These chains coincide with directions of the smallest compressibility of a crystal structure on cooling and increasing pressure and can even remain after structural phase transitions. However one should take into account the dual nature of these chains. From the one hand zwitterions of amino acids are linked by N-H...O hydrogen bonds formed from the head, amino group, and the tail, carboxylate group. From the other hand besides hydrogen bonding there is electrostatic interactions which occur between positively charged amino group and negatively charged carboxylate group. Being guided by an idea to distinguish electrostatic contribution from the charge assisted N-H...O hydrogen bonds and to understand their role in the crystal structure distortion on increasing pressure, two crystal structures of N-methyl derivatives of the simplest amino acid glycine are considered as a case study. N-methylglycine or sarcosine has two donors for hydrogen bonding and so forms two infinite head to tail chains in the structure whereas N,N,N-trimethylglycine or betaine has no hydrogen bonds at all, but its zwitterions are lined up resembling head to tail chains. The effect of increasing hydrostatic pressure is different for two crystals. The structure of betaine compresses anisotropically, but sarcosine undergoes a phase transition accompanying crystal fragmentation and changes in N-H...O hydrogen bonds. The phase transition is kinetically controlled and strongly depends on the rate of variation of pressure. Of special interest is distortion of head to tail chains on increasing pressure comparing with those observed in polymorphic modifications of glycine.

Charge density analysis of paracetamol, acetotoluidine and methacetin

Paracetamol (p-hydroxyacetanilide, Pbca), acetotoluidine (p-methylacetanilide, P21/c) and methacetin (p-methoxyacetanilide, Pbca) contain acetamide group included in molecular fragments, which play an important role in many drugs and proteins. As all of them are derivatives of acetanilide used in medicine, and due to the presence of the amide bond, their charge density analysis is important for better understanding amide infinite peptide chains. Thus, comparing the data obtained for paracetamol with acetotoluidine and with methacetin charge density data can provide deeper insight into NH···O bonding. Another point of interest is the possibility of methyl group rotation that remains to be ambiguous in these acetanilide molecule based compounds. In the present study we have attempted to elucidate these problems using precise X-ray diffraction at 100K with subsequent charge density topological analysis. All charge density refinements were based on the Hansen and Coppens multipolar atom model. The topologies of the inter- and intramolecular interactions are carefully analyzed for compounds. The atomic charges, bond orders, and the electrostatic energy in molecules are discussed. The topological characteristics in the critical point of the NH···O bond of paracetamol, acetotoluidine and methacetin are shown in the table below. In contrast to similarity in NH···O bonds for all studied compounds, intermolecular interactions between the double bonded oxygen atom and the hydrogen of dimer's methyl group are different. In acetotoluidine and methacetin the (3, -1) critical points with the same topological characteristics were detected between these atoms. In comparison to them, paracetamol with disordered methyl group [1, 2] has no such point. That can be related to the absence of the methyl group disorder in acetotoluidine and methacetin.

The Only N-H...O Hydrogen Bond - Two Ways to Build a Structure of Dimethylglycine

Crystalline amino acids are considered to mimic important interactions in peptides, therefore the studies of the structure-forming factors in these systems attract much attention. N,N-dimethylglycine is an interesting model compound that was used to test the role of the N-H...O H-bonds in forming the head-to-tail chains - the main structural unit in the crystals of amino acids. It was hypothesized previously that additional side N-H...O H-bonds play an important role in forming the head-to-tail chains of amino acid zwitterions linked via N-H...O H-bonds between the charged -NH3 and -COO terminal groups. Twice methylated amino group of N,N-dimethylglycine is able to form only one N-H...O H-bond in the crystal structure, so that this hypothesis could be tested. There are two polymorphs of N,N-dimethylglycine, in which the zwitterions are packed in two different ways. In one polymorph (orthorhombic, Pbca) they form finite four member ring motifs not linked to each other via any H-bonds, but only by weak van der Waals interactions. However, in the second polymorph (monoclinic, P21/n) the zwitterions do form infinite head-to-tail chains though the N-H...O H-bond is the only one and is not assisted via any additional H-bonds. The effect of cooling on the two crystal structures was followed by single-crystal X-ray diffraction combined with polarized Raman spectroscopy of oriented single crystals, in order to compare the response of the N-H...O H-bonds to temperature variations. The crystal structure of the monoclinic polymorph compresses anisotropically on cooling, whereas that of the orthorhombic polymorph undergoes a reversible single-crystal to single-crystal phase transition at ~200 K accompanied by non-merohedral twinning, reducing the space symmetry to monoclinic (P21/b), and doubling the asymmetric unit from 2 to 4 molecules. This phase transition could not be detected by Raman spectroscopy and DSC because of the subtle related changes in intermolecular energies.

Varying experimental conditions to study interactions in the solid state

Supramolecular interactions in the solid state attract much attention. Different experimental and computational approaches are used, to predict and to design crystal structures, to predict the properties based on molecular and crystal structures, to range different types of intermolecular interactions. Analysis of the crystal structures at fixed (e.g. ambient) temperature and pressure conditions is most common for experiments, whereas most DFT calculations are limited to 0 K, to minimize computational costs. At the same time, evolution of a crystal structure as a function of experimental conditions can contribute significantly to understanding the structure-forming role and relative energies of different types of intermolecular interactions in the same crystal structure and of similar interactions in a series of different but structurally or chemically related compounds. In the present invited contribution I attempt to illustrate this using several selected examples from my own practice and from the papers published by other research groups. I consider, in particular, the results of variable-temperature and variable-pressure studies of continuous lattice strain and phase transitions in small-molecule organic compounds, the results of variable-temperature and variable-pressure crystallization, the results of comparing the dissolution profiles of mono- and multi-component small-molecule organic crystals. I shall also discuss how variable-temperature and variable-pressure experimental diffraction data can assist in optimizing the calculations aimed at comparing the relative stability of polymorphs and predicting polymorph transitions. The study was supported by Russian Ministry of Science and Education and Russian Academy of Sciences.

Serotonin in different compounds: crystallographic and computational insight

Biologically active substances are in the focus of pharmaceutical and chemical research. Serotonin, one of the most common neurotransmitters, is widely studied in relation to its effect on humans from cellular to neurological levels. Although serotonin plays a key role in some biological processes, its chemistry and crystallography are not sufficiently understood. The aim of the present study was to crystallize serotonin adipate and creatinine sulfate monohydrate, determine their crystal structures, and analyze them in a comparison with other previously known serotonin crystal structures. Special attention was paid to the interrelation between the molecular conformation and crystalline environment. This issue was addressed using crystallographic and computational chemistry (DFT-D, MD) approaches. In our research was shown that the crystal structure of the creatinine sulfate complex significantly differs from what was previously determined. The conformation of serotonin in the new structure differs from serotonin conformations in all other known complexes, as well as from the most stable conformation, predicted by the adiabatic conformational analysis using quantum chemical calculations (DFT, MP) in different phases. This work has explicitly shown the influence of different interactions on serotonin molecular conformation in the crystalline state, described from a crystallographic and theoretical point of view. It has been previously demonstrated that salt formation in the presence of different anions produces variation in pharmacological, therapeutic and physic-chemical properties. This study has shown that alterations of the anion affects the molecular geometry of the bioactive substance and invite further investigation to rationalize the geometry changes. The work was supported by the RFBR Grants No.14-03-31866, 13-03-92704, Russian Ministry of Science and Education and RAS, Siberian Supercomputer Center SB RAS Integration Grant No.130, Edinburgh Compute and Data Facility

High pressure studies of L-Serine-L-Ascorbic acid co-crystal

"Experiments for studying crystalline materials under extreme conditions are a powerful tool for investigating ""structure-property"" relationships. They also give information on the behavior of hydrogen bonds and are important both for materials science and crystal engineering. In addition, many processes in the living organisms are also related to mechanical stress. One of the most interesting tasks is to identify factors which influence the stability of a structure, or a part of the structure, at high pressure. Experiments on the systematic study of compounds in a wide range of pressures allow us to accumulate data that can be used to solve this problem. For a more complete picture, the mixed crystals of the selected compound are studied. Investigation of mixed crystals and cocrystals of interest can be compared with the crystals of individual compounds. We have chosen the structure of L-serine - L-ascorbic acid to be compared with those of L-serine and L-ascorbic acids for such a study. Phase transitions were previously reported to be induced by increasing pressure in both L-serine [1] and L-ascorbic acid [2]; moreover, the structure of L-serine was followed at multiple pressures by single-crystal and powder X-ray diffraction[3]. L-serine - L-ascorbic acid co-crystal was studied in the pressure range 0-5.4 GPa (at multiple points at every 0.5-0.7 GPa) by single-crystal X-ray diffraction and Raman spectroscopy. A phase transition has been detected and some rearrangement in the network of hydrogen bonds was observed. The high pressure data were compared with those for the individual structures of the L-serine and L-ascorbic acid. This work was supported by RFBR (grants 12-03-31541, 14-03-31866, 13-03-92704, 14-03-00902 ), Ministry of Science and Education of Russia and Russian Academy of Sciences."

Low temperature and high pressure study of three molecular glycine co-crystals

Only three glycine co-crystals with carboxylic acids were reported till now: those with glutaric[1a], DL-tartaric[1b] and phthalic acids[1c]. Co-crystallisation of glycine with some other carboxylic acids (oxalic, malonic, maleic) gives molecular salts. The reason why the three selected carboxylic acids form not salts, but co-crystals with glycine remains unclear. No obvious correlations with any physiochemical properties of acidic co-formers such as solubility, acidity, dissolution rate, geometry of molecule, etc. could be suggested. Intermolecular interactions in these crystals are of great interest and can be probed, in particular, by varying temperature and pressure in a wide range. The effect of pressure and temperature on a co-crystal of glycine with glutaric acid was investigated in our research group under low temperatures[2] and high pressure[3] and a first order phase transition giving the same new polymorph was observed (at 220 K and 1.75 GPa, respectively). No variable-temperature or variable-pressure studies of co-crystals of glycine with DL-tartaric and phthalic acids were reported. The aim of the present study was to compare the behavior of three glycinium co-crystals at low temperature and high pressure. The changes in the unit cell volumes and parameters, as well as in the geometry of the hydrogen bonds were analysed. The orientation of principal axes of strain ellipsoid with respect to the main structural motifs and relative linear strain values along these axes were calculated. The conformations and the local environment of glycine molecules, as well as the hydrogen-bonded motifs were compared for three co-crystals. The work was supported by the Russian Foundation for Basic Research (RFBR) (Grants No. 14-03-31866 mol_a, 13-03-92704 IND_a), Russian Ministry of Science and Education and Russian Academy of Sciences.

Furosemide solvates: can they serve as precursors to different polymorphs?

The importance of polymorphism of molecular crystals is hard to overestimate, especially when dealing with compounds used as materials or drugs. Different polymorphs of a drug substance may have different properties related to their manufacturing, therapeutic usage, or storage (density, hygroscopicity, melting points, thermal stability, solubility, rate of dissolution, surface free energy, toxicity, bioavailability, tabletting, etc.). Different polymorphs, solvates, and co-crystals can be patented, and this opens the way for a competition with brand drugs. Since the energies of different polymorphs are sometimes very close, producing desirable crystalline forms is quite a challenge and can also be complicated by the phenomena of concomitant polymorphism (when several polymorphs crystallize simultaneously from the same batch), or erratic and poorly reproducible (when crystallization gives different polymorphs even at seemingly identical experimental conditions). The aim of the present study was to crystallize various solvates of furosemide, to check whether these solvates can be used as precursors for producing different polymorphs of pure furosemide on their subsequent decomposition upon heating, and to search any correlation between the crystal structures of the solvates and on the furosemide polymorphs produced by desolvation. Four solvates of furosemide with tetrahydrofuran, dioxane, dimethylformamide, and dimethylsulfoxide were crystallized. The detailed structural analysis of furosemide-containing crystal structures showed that the molecule of furosemide has a high conformational lability because of the rotations of the sulfamoyl and furanylmethylamino fragments. Some of the furosemide conformations were shown to be stabilized by the intramolecular N-H···Cl H-bond. Desolvation of the four solvates was studied by TG and X-ray diffraction and was shown to give different products depending on the precursor and particle size.

Influence of high pressure on amino acids and their multicomponent crystals

The studies of molecular crystals at high pressures help to understand intermolecular interactions, their role in the formation of crystal structures and in crystal structure response to external actions. Multicomponent crystals are promising for high-pressure research since a large number of phenomena has been observed for them [1]. Crystals of amino acids, their salts and co-crystals are of special interest in this respect. They are promising as new materials and can serve as biomimetics since the structure forming units of these crystals are similar to those in biomolecules. The aim of this study was to follow the effect of increasing pressure on crystal structures of amino acid salts and co-crystals to compare the results with those obtained for individual amino acids. Glycine, alanine, serine and their corresponding salts with carboxylic acids were chosen as objects of the study. Single-crystal X-ray diffraction and Raman spectroscopy were used as main experimental techniques. Three different types of behavior of salts on increasing pressure as compared with individual crystals were observed. For some salts, adding the second component stabilized the crystal structure with respect to phase transitions [2]. In the second group, on the contrary, the salts underwent phase transitions at relatively low pressures, though individual components did not undergo phase transitions at least up to 8-10 GPa. The last, third group of salts showed phase transitions in a similar pressure range as the individual components, but the mechanism of the transition changed. The phase transitions were accompanied either by crystal structure disordering, or by switching-over hydrogen bonds [3]. This work was supported by a grant from RFBR (12-03-31541 mol_a), by the Ministry of Education and Science of Russia, Russian Academy of Sciences, and by a grant of President of Russia for State support of Russian leading Scientific Schools (project NSh-279.2014.3).

IYCr in Novosibirsk

The present contribution sums up the main activities related to celebrations of the IYCr in Novosibirsk (Russia). I give a general overview of crystallographic research and education in Novosibirsk at the Russian Academy of Sciences and at the Novosibirsk State University, to explain which basis we have for organizing various activities for children and for general public. I shall, in particular, describe the program of continuous crystallographic education starting from nursery to the university, including crystal growth courses and competitions, research projects involving children, festivals, public lectures, various competitions and exhibitions. A special attention will be paid to the activity of school-children from the French school, who have translated all the posters prepared by J.-L. Hodeau from French into Russian. The group has visited Grenoble and presented their work there, and participated also in the IYCr Opening Ceremony. Other activities include International Workshops and Conferences for students and young scientists, as well as an OpenLab in cooperation with STOE (Darmstadt).

Teaching in a Secondary School: Crystal Growth and Basics of Crystallography

Nowadays, secondary education provides a broad variety of different compulsory courses giving a solid basis for further student's progress at the university. However, there is an opinion that in this system we are losing the sense of adventures, discoveries and research. Now the main question is if we can efficiently combine compulsory subjects and open classrooms in order to support students in their self-realization needs and provoke interest in mundane school subjects. The educational course for pupils «Crystal Growth - from School Desk to Leading Scientific Research» began several years ago with close cooperation between Novosibirsk State University, the Institute of Solid State Chemistry and Mechanochemistry SB RAS and School #162 of Novosibirsk. The aim of the course is to provide further education in Chemistry and Crystallography via laboratory work and lectures, complementing the standard school program. We provide a targeted syllabus for students from 7 to 17 years old, covering related scientific topics starting from crystal symmetry to the basics of physical chemistry. Through close communication and interaction, pupils develop skills in growing crystals, paying particular attention to obtaining large single crystals of different substances. During the course, pupils crystallize more than 15 different substances using at least 5 different methods and their modifications. At the end of every year, the students are given the opportunity to carry out a personal project, calling on the new knowledge they have obtained from the course. Thus we can assume that an efficient program was developed and realized to support personal ideas and research for school students, based on compulsory subjects and modern experimental techniques. The work was supported by the grant of Dmitry Zimin Fund "Dynasty" "Entertaining Science for pupils" No.DP-55/13, Development Program of University Student Association, NSU, App. No.2012-PSO-225, City Hall grant for young scientists.

Difference of shear and impact treatment for mechanochemical co-cristallization.

Currently one of the most popular methods to obtain various molecular co-crystals is mechanochemical synthesis, i.e. mechanical treatment of a mixture of powder reactants. Traditional approach for mechanical treatment is milling in a ball mill or grinding in a mortar. However, using these methods causes a number of problems related to investigation of the reaction's mechanism. For instance, ball mill produces impact treatment and shear treatment simultaneously and it is almost impossible to separate these two types of mechanical treatment. So, if detailed analysis of reaction is required, alternative methods of mechanical treatment are necessary. This study describes how mechanochemical co-crystallization of piroxicam and succinic acid has been investigated by using special model devices constructed for separated impact and shear mechanical treatment. Such devices allowed us to perform controlled impact or shear mechanical treatment, what was necessary for detailed investigation of mechanochemical processes for molecular crystals, based on the X-ray powder diffraction analysis. We could change and control energy and frequency of mechanical pulses in the impact model device and average velocity and pressure in the shear model device. For some other systems applying controlled impact treatment allowed us to detect the intermediate products of the mechanochemical synthesis of molecular complexes [1-2]. As for `piroxicam - succinic acid" system, a comparison of impact and shear mechanical treatment had lead to opposite results for mechanochemical reactions - shear treatment appeared to disintegrate co-crystal obtained by impact mechanical treatment. Acknowledgements This work was supported by grants from RFBR (No. 11-03-00684, 12-03-31663, 13-03-00795, 13-03-92704) and Ministry of Education and Science Agreement (No. 14.B37.21.1093).