a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Department of Pharmacy, University of Copenhagen, Universitetsparken 2, Copenhagen 2100, Denmark
In the recently published paper Symmetry and chirality in crystals [Nespolo, M.; Benahsene, A. H. (2021). J. Appl. Cryst. 54, 1594-1599.], the authors state that `chiral crystal structures from achiral molecules can occur in 28 types of space group having screw axes n(p), with p =/= n/2, not in any Sohncke type of space group'. We argue that this is not true and demonstrate counter-examples of chiral structures from achiral molecules crystallizing in other Sohncke space groups apart from the proposed list of 28.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
c. Institute of Chemical Sciences, Faculty of Chemistry, Maria Curie-Skłodowska University, Maria Curie-Skłodowska Square 2, 20-031 Lublin, Poland
d. Polish Academy of Sciences, Centre of Molecular and Macromolecular Studies, 90-363 Lodz, Poland
e. ICGM, Univ Montpellier, CNRS, ENSCM, Montpellier 34296, France
We present a crystallographic and computational study of three hydantoin-based active pharmaceutical ingredients─nitrofurantoin, furazidin, and dantrolene─aimed at identifying factors resulting in different propensities of these compounds to form polymorphs, hydrates, solvates, and solvate-hydrates. This study is a continuation of our research toward understanding how small structural differences in closely related compounds affect their propensity to form different crystal phases, as all three compounds contain an imidazolidine-2,4-dione scaffold and a N-acyl hydrazone moiety and all form multiple crystalline phases. Crystallographic and computational analysis of the already known and newly obtained nitrofurantoin, furazidin, and dantrolene crystal structures was performed by dissecting the properties of individual molecules and searching for differences in the tendency to form hydrogen bonding patterns and characteristic packing features. The propensity to form solvates was found to correlate with the relative packing efficiency of neat polymorphs and solvates and the ability of molecules to pack efficiently in several different ways. Additionally, the differences in the propensity to form solvate-hydrates were attributed to the different stability of the hydrate phases.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
We present an experimental and computational study of solid solution formation between structurally highly similar active pharmaceutical ingredients droperidol and benperidol in nonsolvates, dihydrates, and several solvates formed by these compounds. We demonstrate that the formation of solid solutions strongly depends on the crystal structure of the phase. In some of the structures, almost complete replacement of benperidol with droperidol can be achieved, whereas in other structures, the replacement is possible only up to a limited molar ratio. However, only limited replacement of droperidol with benperidol can be achieved and only in some of the structures. The solid solution formation is primarily determined by the change in intermolecular interaction energy resulting from the molecule replacement. Only structures where molecule replacement allows the formation of efficient intermolecular interactions can be obtained experimentally. The results indicate that the energy requirements of intermolecular interaction changes to obtain solid solutions in the nonsolvated phase are less strict than those for solvates.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
In this study, we present a detailed crystallographic analysis of multiple solvates of an antibacterial furazidin. Solvate formation of furazidin was investigated by crystallizing it from pure solvents and solvent–water mixtures. Crystal structure analysis of the obtained solvates and computational calculations were used to identify the main factors leading to the intermolecular interactions present in the solvate crystal structures and resulting in the formation of the observed solvates and solvate hydrates. Furazidin forms pure solvates and solvate hydrates with solvents having large hydrogen bond acceptor propensity and with a hydrogen bond donor and acceptor formic acid. In solvate hydrates, the incorporation of water allows the formation of additional hydrogen bonds and results in more efficient hydrogen bond networks in which water is “hooking” the organic solvent molecule, and this slightly reduces the cut-off of solvent hydrogen bond acceptor propensity required for obtaining a solvate. The crystal structures of all pure solvates are formed from molecule layers, and in almost all structures, the solvent is hydrogen-bonded to furazidin, but the packing in each solvate is unique. In contrast, the hydrogen bonding and packing in most solvate hydrates are nearly identical.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
2,6-Dimethoxyphenylboronic acid was used as a model substance to investigate the additive crystallization approach for polymorph control in phenylboronic acids. It was crystallized under different conditions by performing evaporation and cooling crystallization from different solvents. Most of the crystallizations from pure solvents produced the thermodynamically stable Form I, but in evaporation crystallization from alcohols, Form II or even a new polymorph, Form III, could be obtained. Structurally related substances, polymers, and surfactants with diverse intermolecular interaction possibilities were tested as additives. Surfactants were found to facilitate the crystallization of the metastable forms and therefore were investigated more extensively. The surfactants Span 20 and n–octyl-β-D-glucopyranoside provided crystallization of the metastable forms in the evaporation crystallization and notably stabilized Form II. The lattice energy, energy frameworks, Hirshfeld surface analysis, full interaction maps, and morphology prediction were used to identify the structural differences between Forms I and II and rationalize the ability of the additives to provide formation of Form II in the crystallization and to stabilize it.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
In this study, 2,6-dimethoxybenzoic acid (2,6MeOBA) was used as a model substance to investigate the use of additives to control the polymorphic outcome of crystallization. 2,6MeOBA exists as three polymorphs. Two of the 2,6MeOBA polymorphs, I and III, obtained in most of the crystallization experiments, were characterized by thermal analysis, and their relative thermodynamic stability was determined. Forms I and III are enantiotropically related, where form III is the high-temperature form. Pure form II was very difficult to obtain. Crystallization of 2,6MeOBA was explored under different conditions by performing evaporation and cooling crystallization from different solvents. Surfactants, polymers, and different molecular compounds with diverse possibilities for the formation of intermolecular interactions were tested as additives. The additives facilitating the crystallization of the metastable forms were additionally studied under different crystallization conditions. The effect of additives polyethylene glycol (PEG) and hydroxypropyl cellulose (HPC) on the thermodynamic stability and solvent-mediated phase transition (SMPT) kinetics was evaluated. HPC and PEG showed the potential to favor the formation of form III in crystallization from water.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Institute of Solid State Physics, University of Latvia, Ķengaraga iela 8, LV1063 Riga, Latvia
Solid solutions with fine-tunable photoluminescence have been obtained in a 4-iodothioxanthone–4-chlorothioxanthone system. Both pure components are room-temperature luminophors demonstrating different luminescence properties. It was discovered that in the 4-chlorothioxanthone structure, up to half of the molecules can be replaced by the iodo analogue obtaining solid solutions in the respective composition range. Despite this solid solution existing in such a large composition range, the variation of the luminescence spectra is not substantial. In the 4-iodothioxanthone structure, only up to ∼20% of the molecules can be replaced by the chloro analogue before the composition limit of this solid solution is reached. In contrast, there is a strong composition-dependent response of the luminescence. A considerable change in luminescence spectra is observed even if only a few mol % of the opposite component is added. The spectra of mechanical mixtures of pure components are different from those of the solid solutions, which demonstrates the unique behavior of the newly obtained solid phases. This study shows great potential to use solid solution engineering in the organic solid state to tune material properties in a continuum as opposed to other crystal engineering approaches, leading to property tunability in a stepwise fashion.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Thomas Young Centre and Department of Chemical Engineering, University College London, Torrington Place, London WC1E 7JE, U.K.
Self-association of four benzoic acid derivatives 2-chloro-4-nitrobenzoic acid, 2-methyl-4-nitrobenzoic acid, 3-hydroxybenzoic acid, and 2,6-dimethoxybenzoic acid in solution was investigated using spectroscopic measurements (Fourier transform infrared and 1H and 13C NMR spectroscopy) and molecular simulation methods. Based on the formation of hydrogen bonds, solvents can be divided into two groups: apolar solvents or solvents with a low hydrogen bond acceptor propensity, in which the benzoic acid derivatives form hydrogen-bonded dimers, and solvents with hydrogen bond acceptor propensity β > 0.3, interacting with the carboxylic group of benzoic acid, thus screening its interaction in the formation of self-associates. The formation propensity and structure of self-associates stabilized by weak interactions, such as π···π stacking and CH3···π interactions, however, are determined by the substituents in the benzene ring. Despite all the studied compounds being polymorphic, in none of the cases, an unequivocal structural link between self-associates present in the solution and the crystal form was observed.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
The arrangement of hydroxyl groups in the benzene ring has a significant effect on the propensity of dihydroxybenzoic acids (diOHBAs) to form different solid phases when crystallized from solution. All six diOHBAs were categorized into distinctive groups according to the solid phases obtained when crystallized from selected solvents. A combined study using crystal structure and molecule electrostatic potential surface analysis, as well as an exploration of molecular association in solution using spectroscopic methods and molecular dynamics simulations were used to determine the possible mechanism of how the location of the phenolic hydroxyl groups affect the diversity of solid phases formed by the diOHBAs. The crystal structure analysis showed that classical carboxylic acid homodimers and ring-like hydrogen bond motifs consisting of six diOHBA molecules are prominently present in almost all analyzed crystal structures. Both experimental spectroscopic investigations and molecular dynamics simulations indicated that the extent of intramolecular bonding between carboxyl and hydroxyl groups in solution has the most significant impact on the solid phases formed by the diOHBAs. Additionally, the extent of hydrogen bonding with solvent molecules and the mean lifetime of solute–solvent associates formed by diOHBAs and 2-propanol were also investigated.
a. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
b. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
New pseudopolymorphs of ivermectin (IVM), a potential anti-COVID-19 drug, were prepared. The crystal structure for three pseudopolymorphic crystalline forms of IVM has been determined using single-crystal X-ray crystallographic analysis. The molecular conformation of IVM in crystals has been compared with the conformation of isolated molecules modeled by DFT calculations. In a solvent with relatively small molecules (ethanol), IVM forms monoclinic crystal structure (space group I2), which contains two types of voids. When crystallized from solvents with larger molecules, like γ-valerolactone (GVL) and methyl tert-butyl ether (MTBE), IVM forms orthorhombic crystal structure (space group P212121). Calculations of the lattice energy indicate that interactions between IVM and solvents play a minor role; the main contribution to energy is made by the interactions between the molecules of IVM itself, which form a framework in the crystal structure. Interactions between IVM and molecules of solvents were evaluated using Hirshfeld surface analysis. Thermal analysis of the new pseudopolymorphs of IVM was performed by differential scanning calorimetry and thermogravimetric analysis.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
c. Department of Physical Chemistry, Kazan Federal University, Kremlevskaya str. 18, 420008 Kazan, Russia
Dantrolene represents yet another interesting example of abundant molecular crystal polymorphism existing in at least six different neat polymorphs, three of which can be obtained via crystallization (I–III) and an additional three (IV– VI) via solid-state dehydration from three different monohydrates (MH-I–MH-III). The reasons for polymorph formation were rationalized by analyzing the crystal structures of the polymorphs and hydrates used in their preparation. The thermodynamic relations among the polymorphs were established from calorimetric data, solubility measurements, and lattice energy calculations.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
The binary system of xanthone–thioxanthone has been explored, showing that two solid solutions (formed based on xanthone and thioxanthone parent structures, respectively) exist for this system. One of the solid solutions shows miscibility of both molecules in a large composition range (>0–80 mol % of xanthone). The structure of thioxanthone has been redetermined to reveal a special case of nonmerohedral twinning in the crystals. Such a twinning feature has apparently been the reason for incorrect crystal structure determination previously. A structure of thioxanthone:xanthone (75:25 mol %) solid solution is also presented. Several similar molecules to the title compounds have been found in the Cambridge Structural Database and shown to crystallize in structures isostructural to that of thioxanthone. The different packing of pure xanthone is thus an exception among the explored compounds.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
Analysis of crystal structures, molecular properties, interaction strength in solution, and computationally generated nonsolvated form crystal structure landscapes of five chloronitrobenzoic acid isomers and two additional 2-substituted 4-nitrobenzoic acids were used to rationalize the obtained solvate landscape of these compounds. Screening of the solid forms was performed for each of the compounds, and crystal structures of the obtained nonsolvated forms and selected solvates were determined. Molecular conformation, intermolecular interactions, and packing efficiency of nonsolvated forms and solvates were analyzed to understand factors contributing to structure stabilization and determining the formation of the observed crystal structures. Computationally generated crystal structure landscapes of nonsolvated forms were tested for the possibility to predict the propensity to form solvates and identify polymorphic compounds. It was observed that most of the solvates were obtained with solvents acting as strong hydrogen bond acceptors and/or able to form aromatic interactions. Solute–solvent association Gibbs energy representing interaction strength was found to be the most apparent identifiable factor explaining the solvate formation of the studied compounds, and using this tool, the existence of 3 new multicomponent phases was successfully predicted.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
Already validated methodology for self-association in solutions were used to evaluate if this method could also be used in other studies regarding association in solution. Three isomeric dihydroxybenzoic acids were used to calculate Gibbs free energies of association for homodimers, heterotetramers and associates with solvent molecules by using DFT calculations in multiple environments and having different conformations.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
Several 2-substituted 4-nitrobenzoic acid (NBA) derivatives such as 2-chloro-4-nitrobenzoic acid (2C4NBA), 2-methyl-4-nitrobenzoic acid (2CH34NBA) and 2-hydroxy-4-nitrobenzoic acid (2OH4NBA) were selected as model compounds because of their availability and chemically similar structures, in which the different group/atom (R) does not significantly affect the dominant intermolecular interactions – hydrogen bonds formed by the carboxylic group [1]. Quantum chemical calculations of lattice and intermolecular interaction energy were carried out to identify possible factors, which could be, used in prediction of the formation of solid solutions (SS) in binary systems of chemically similar molecules, in this case - various nitrobenzoic acid derivatives. Meanwhile, crystallization experiments were used to determine the experimental information about formation of solid solutions. The obtained crystalline phases were characterized by combined use of powder X-ray diffraction (XRPD) and differential scanning calorimetry/thermogravimetry (DSC/TG) [2].
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
A detailed study on chiral compound structures found in the Cambridge Structural Database (CSD) is presented. Solvates, salts and co-crystals have intentionally been excluded, in order to focus on the most basic structures of single enantiomers, scalemates and racemates. Similarity between the latter and structures of achiral monomolecular compounds has been established and utilized to arrive at important conclusions about crystallization of chiral compounds. For example, the fundamental phenomenon of conglomerate formation and, in particular, their frequency of occurrence is addressed. In addition, rarely occurring kryptoracemates and scalemic compounds (anomalous racemates) are discussed. Finally, an extended search of enantiomer solid solutions in the CSD is performed to show that there are up to 1800 instances most probably hiding among the deposited crystal structures, while only a couple of dozen have been previously known and studied.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
An elegant statistical mechanics approach has been exploited in combination with accurate quantum chemical calculations to justify the disorder in two previously reported racemic solids. Generated canonical ensembles and performed lattice energy calculations show that the disorder in the studied systems of small organic enantiomer molecules can be modelled with great accuracy. Ensemble averages fully correspond to the disordered structure models repeatedly obtained in X-ray diffraction studies. The present work not only demonstrates that disorder and its extent in molecular crystals can be theoretically calculated, but also explains from a thermodynamic point of view the origins of the rarely encountered phenomenon of enantiomer solid solutions. Such phases are promising in materials science as their properties can be finely tuned depending on the composition. The lack of complete enantiomer discrimination in the studied examples is evident and it is related to the absence of any donor–acceptor groups providing highly directional interactions, as well as to conformational flexibility in one case and a specific inner symmetry of the molecule in the other one.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
Nitrofurantoin was crystallized from multiple mixtures of water and organic solvents with and without additives to try to find and identify factors affecting phase obtained in crystallization and provide possible information on crystallization control. Obtained crystals were identified with powder X-ray diffractometry. Crystallization control possibilities were evaluated by using polymer additives and crystallization additives, by also using quantum chemical calculations to investigate the association of nitrofurantoin and additive molecules and calculate Gibbs energy of association.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Laboratory of Crystallography, University of Bayreuth, Universitaetsstrasse 30, Bayreuth 95440, Germany
c. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
In a study of the solid form landscape of R-encenicline hydrochloride (Enc-HCl), it was found that this compound is dodecamorphic and presents the first published example of polymorphism with a record-breaking 10 solved crystal structures. In addition to the four known polymorphs, eighth new polymorphs and their precursor solvates as well as several new hydrates have been characterized. The polymorph formation behavior is investigated by analyzing crystal structures of polymorphs and solvates used in their preparation. Molecular packing in crystal structures of the polymorphs is highly similar to that in the precursor solvates, whereas conformations in all structures are nearly identical and correspond to the same energy minimum.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
Structural aspects of solid solutions of enantiomers have been considered and the corresponding definitions of type 1 and type 2 solid solutions have been revised based on the available structures reported in the literature. Examples of both types are presented indicating that (e.g., type 1 solid solutions) there is a straightforward relationship between the particular structural aspects and the enantiomer miscibility limits in the solid state. Furthermore, enantiomer recognition in a type 2 solid solution formed by the enantiomers of a pharmaceutically active ingredient, pimobendan, has been studied in more detail. It was found that upon rapid crystallization from a solution a structure possessing a fully disordered enantiomer layout forms. By suspending such a crystalline phase in a solvent over time it tends to form an ordered (racemic compound) state. The study demonstrates that a non-equilibrium crystalline phase reaches the equilibrium state structure, very similar to that determined by an SCXRD study of a slowly grown single crystal. The study also proves that the degree of enantiomer recognition in type 2 solid solutions has a profound thermodynamic origin, unlike that indirectly claimed in some literature sources to be arising from kinetic aspects during the crystal growth.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
Encenicline hydrochloride (Enc-HCl) crystallizes in four different monohydrate phases, but at the same time crystallization in a nonsolvated phase is not observed, indicating that water plays a crucial role in guiding the crystallization process and ensuring structure stability. All monohydrate phases show exceptionally high stability, and the main structural motif stays intact even after dehydration, leading to isostructural (for I and II) or isomorphic (for III) desolvates. Three monohydrate phases with determined crystal structure information consists of Enc-HCl-water hexamers that are stacked into similar slabs, that are further packed identically in monohydrates I, II, and III. The features of these hexamer slabs determine the properties of the Enc-HCl monohydrates and dehydrates, the dehydration mechanism, and stability of each phase. It was justified that in the Enc-HCl system efficient intermolecular interactions provided by the incorporation of water in the crystal structure play a crucial role in stabilization of the structures.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
In structural study of seven bile acids it was identified that their propensity for solvate formation is directly related to the packing efficiency of the unsolvated phases: low packing index, voids, and unsatisfied hydrogen bonding lead to extensive solvate formation, whereas efficient packing leads to the opposite. This was determined to be caused by the presence of OH group attached to carbon C12. Solvate formation was determined to provide a noticeable improvement in the packing efficiency for compounds having ansolvates with inefficient packing.
a. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany
c. Ecole polytechnique fédérale de Lausanne, Route Cantonale, 1015 Lausanne, Switzerland
Over ten polymorphs and solvatomorphs of chiral pharmaceutically active ingredient pimobendan were found to lack enantioselectivity in the solid state, accordingly, forming solid solutions of enantiomers, which is reported to be a rare phenomenon. Solid form screening was performed on different enantiomeric composition samples to analyse obtained phases with PXRD and TG/DSC. For non-solvated forms a melt phase diagram has been constructed convincingly showing existence of stable and metastable solid solutions near the pure enantiomer and around the racemic composition regions. A crystal structure study combined with solid-state NMR experiments was performed to analyse and explain structural aspects of pimobendan solid solutions. Furthermore, driving force for existence of such a surprisingly large amount of different solid state phases lacking enantioselectivity for a single compound is elucidated tracking down the origin of their formation to the molecular level.
a. Department of Chemistry, University of Bologna, Via Zamboni 33, Bologna 40126, Italy
b. Department of Physical Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
The enantiomers of a previously reported naphthalimide derivative are shown in this study to form a solid solution; furthermore, on the basis of the knowledge of solid solution structural aspects other naphthalimide derivatives have been synthesized and shown to lack the enantioselectivity in the solid state. The structural origin of solid solution formation is the same as observed in most of the cases in the literature—quasi-centrosymmetric structures form at nonracemic compositions where the most abundant enantiomer adjusts its conformation to mimic the absent one. Such solid solutions belong to the type showing some enantioselectivity. An extended single crystal X-ray diffraction study of the crystals of different enantiomeric compositions reveals the nature of the disorder in studied solid solutions. Intermolecular interactions are analyzed in terms of Hirshfeld surfaces and by means of density functional theory calculations to explore the differences of isostructural quasi-centrosymmetric (enantiopure) and genuine centrosymmetric (racemic) packings to shed light on the energetic aspects of solid solution formation as well as to explain the origin of partial enantioselectivity. Furthermore, lattice energy calculations explain why two structurally distinct solid solutions (around the racemic and near the pure enantiomer regions) form as found for one of the studied compounds.
a. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
Solvate formation and the desolvation mechanism of 25 obtained methyl cholate solvates were rationalized using crystal structure analysis and study of the phase transformations. The facile solvate formation was determined to be associated with the possibility for more efficient packing in structures containing solvent molecules. Most of the obtained solvates crystallized in one of the six isostructural solvate groups, with solvent selection based on the solvent capability to provide particular intermolecular interactions along with appropriate size and shape. In crystal structures several different methyl cholate conformers were observed, as apparently more efficient packing could be achieved by diversifying the molecule conformation and even adopting energetically quite unfavorable conformations. Nevertheless, the packing was generally controlled by the steroid ring system, particularly employing hydrogen bonding of the attached hydroxyl groups. Study of the desolvation mechanism showed that the primary desolvation product is determined by the structure similarity with the solvate, with thermodynamic stability of the desolvate having no directly identifiable effect. In the case of the absence of an acceptable structurally similar desolvate, desolvation produced an amorphous phase.
a. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
Study of structures and physicochemical properties of racemic (rac-H) and enantiopure (enant-H) hydrates of the active pharmaceutical ingredient pimobendan revealed that both hydrates have highly similar crystal structures and exhibit unusually high stability. Both structures contain identical two-dimensional layers and very similar conformations. The most significant difference is the stacking of these layers. The high stability of both hydrates appeared as extremely low solubility over a wide temperature range as well as an exceptionally high dehydration temperature and melting point. Study of the dehydration process showed that both hydrates have different activation energies of dehydration and kinetic model. Intermolecular interaction energy calculations showed that the dispersion interactions provide a highly significant stabilizing force in both pimobendan hydrates, while their exceptionally high stability can be associated with an efficient interplay between the hydrogen bonding and the dispersion interactions.
a. Max Planck Institute for Dynamics of Complex Technical Systems, Sandtorstraße 1, 39106 Magdeburg, Germany
b. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
c. Institute of Organic Chemistry, Hungarian Academy of Sciences, Magyar tudósok körútja 2, 1117 Budapest 1004, Hungary
A detailed thermochemical and structural study of the phenylpiracetam enantiomer system was performed by characterizing the solid solutions, rationalizing the structural driving force for their formation as well as identifying a common structural origin responsible for the formation of solid solutions of enantiomers. Enantiomerically pure phenylpiracetam forms two enantiotropically related polymorphs (enant–A and enant–B). Transition point (70(7) °C) was determined based on isobaric heat capacity measurements. Structural studies revealed that enant–A and enant–B crystallize in space groups P1 (Z'=4) and P212121 (Z'=2), respectively. However, pseudoinversion centres were present resulting in apparent centrosymmetric structures. The quasi–centrosymmetry was achieved by a large variety of phenylpiracetam conformations in the solid state (6 in total). As a result, miscibility of the phenylpiracetam enantiomers in the solid state is present for scalemic and racemic samples, which was confirmed by the melt phase diagram. Racemic phenylpiracetam (rac–A) was determined to crystallize in P–1 space group being isostructural to enant–A, furthermore, disorder is present showing that enantiomers are distributed in a random manner. The lack of enantioselectivity in the solid state is explained. Furthermore, structural aspects of phenylpiracetam solid solutions are discussed in the scope of other cases reported in the literature.
a. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
In this study, detailed analysis of crystal structures was used to rationalize the observed stability and phase transformations of sequifenadine hydrochloride polymorphs and hydrates, as well as to understand the observed structural diversity. The performed polymorph and hydrate screening revealed the existence of six polymorphs and four hydrates. Crystal structures of these phases were determined either from single crystal or from powder diffraction data. The different possibilities for packing of sequifenadine cations were found to be the main reason for the observed structural diversity of polymorphs. The hydrate structures were found to be structurally similar and related to those of particular polymorphs, which was consistent with the observed easy phase transitions amongst the related pairs.
a. Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, Poznań, Poland
b. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
High pressure strongly favors the highest-density polymorph Z of active pharmaceutical ingredient 2-(2,6-xylidino)-5,6-dihydro-4H-1,3-thiazine hydrochloride (xylazine hydrochloride, XylHCl) up to about 0.1 GPa only, but still higher pressure destabilizes this structure. Above 0.1 GPa, XylHCl preferentially crystallizes as solvates with CH2Cl2, CHCl3, or (CH3)2CHOH depending on the solvent used. However, when XylHCl·H2O is dissolved in any of these solvents, the high-pressure crystallizations yield the hydrate XylHCl·H2O only. The single crystals of the CH2Cl2, CHCl3, and (CH3)2CHOH solvates could be grown in situ in a diamond anvil cell, which allowed their structure determination from the single-crystal diffraction data. At 0.4 GPa the XylHCl·H2O hydrate undergoes a pressure-induced phase transition doubling the unit cell dimensions.
a. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Department of Pharmaceutics, College of Pharmacy, University of Minnesota, 308 Harvard Street S.E., Minneapolis, MN, United States
Degradation of drug furazidin was studied under different conditions of environmental pH (11–13) and temperature (30–60 °C). The novel approach of hybrid hard- and soft-multivariate curve resolution-alternating least squares (HS-MCR-ALS) method was applied to UV–vis spectral data to determine a valid kinetic model and kinetic parameters of the degradation process. The system was found to be comprised of three main species and best characterized by two consecutive first-order reactions. Furazidin degradation rate was found to be highly dependent on the applied environmental conditions, showing more prominent differences between both degradation steps towards higher pH and temperature. Complimentary qualitative analysis of the degradation process was carried out using HPLC-DAD-TOF-MS. Based on the obtained chromatographic and mass spectrometric results, as well as additional computational analysis of the species (theoretical UV–vis spectra calculations utilizing TD-DFT methodology), the operating degradation mechanism was proposed to include formation of a 5-hydroxyfuran derivative, followed by complete hydrolysis of furazidin hydantoin ring.
a. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
A series of dasatinib crystalline forms were obtained, and a hierarchical cluster analysis of their powder X-ray diffraction patterns was performed. The resulting dendrogram implies 3 structural groups. The crystal structures of several solvates representing 2 of these groups were determined. The crystal structure analysis confirms the isostructurality of solvates within structural group I and suggests a correlation between solvent molecule size and trends in crystal structures within this group. In addition, the formation relationships in 2-solvent media between different dasatinib solvate groups were determined. The formation preference of solvates was found to follow the ranking group I > group III > group II.
a. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
Cocrystallisation with a series of related compounds allows for the exploration of trends and limitations set by structural differences between these compounds. In this work, we investigate how the length of a dicarboxylic acid influences the outcome of cocrystallisation with isoniazid. We have performed a systematic study on the mechanochemical, thermal and solvent vapour-assisted cocrystallisation of aliphatic dicarboxylic acids (C3-C10) with isoniazid. Our results demonstrate that the rate of mechanochemical and vapour-assisted cocrystallisation depends on the acid chain length and shows alternation between odd- and even-chain acids. The results of thermal cocrystallisation showed that the eutectic melting temperatures of isoniazid-dicarboxylic acid mixtures follow the same trend as the melting points of dicarboxylic acids.
a. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
A detailed study of molecular conformation and intermolecular interactions in the experimental crystal structures and general trends observed in the Cambridge Structural Database as well as theoretical calculations were performed to identify the reason for the formation of different crystal structures of two chemically very similar pharmaceutical molecules benperidol and droperidol. The most important difference between both molecules was the weak intermolecular interactions formed by the central ring which therefore was responsible for the formation of different crystal structures. Cross-seeding experiments were performed to check the possibility for the formation of mutually isostructural phases, and theoretical calculations were performed to compare the stability of experimentally observed phases and theoretical isostructural phases by therefore rationalizing the results of the cross-seeding experiments. In cross-seeding crystallizations, three new droperidol phases—an ethanol monosolvate, a dihydrate and a new polymorph, all three isostructural to already known phases of benperidol—were obtained.
a. Drug Delivery and Materials Science Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom
b. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
Little is known concerning the pathway of the crystallization of the thermodynamically stable polymorph of theophylline, form IV. Here we study the reasons why the thermodynamically stable theophylline form IV can be obtained only by slow, solvent mediated phase transformation (SMPT) in specific solvents, and whether the presence of prenucleation aggregates affect the polymorphic outcome. Solution concentration, polymorphic composition and morphology were monitored over time during the transformation from form II to form IV in several solvents. NMR and FTIR spectroscopy were used to detect prenucleation molecular aggregates present in the solutions. It was determined that theophylline self-associates in solvents which are good H-bond donors and the presence of these aggregates hinder the nucleation and phase transformation. SMPT from form II to form IV is a nucleation-growth controlled polymorphic transformation, nucleation is most likely homogenous, and form IV crystals grow along the (001) plane, forming plate-like crystals.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Department of Chemistry, Durham University, South Road, Durham, United Kingdom
13C, 15N and 2H solid-state NMR spectroscopy have been used to rationalize arrangement and dynamics of solvent molecules in a set of isostructural solvates of droperidol. The solvent molecules are determined to be dynamically disordered in the methanol and ethanol solvates, while they are ordered in the acetonitrile and nitromethane solvates. 2H NMR spectra of deuterium-labelled samples allowed the characterization of the solvent molecule dynamics in the alcohol solvates and the non-stoichiometric hydrate. The likely motion of the alcohol molecules is rapid libration within a site, plus occasional exchange into an equivalent site related by the inversion symmetry, while the water molecules are more strongly disordered. DFT calculations strongly suggest that the differences in dynamics between the solvates are related to differences in the energetic penalty for reversing the orientation of a solvent molecule.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Formulation and Drug Delivery Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom
Degradation of the drug antazoline was studied in aqueous solutions by means of pH-rate profiling (pH 0-7.4). The novel approach of Runge-Kutta numerical integration in combination with multi-parameter optimisation was applied to UV-Vis spectral data to determine a valid kinetic model and kinetic parameters of the degradation process. The overall degradation mechanism was found to be dependent on the environmental pH. In the pH range of 3.0-7.4, the formation of the antazoline hydrolysis product (N-(2-aminoethyl)-2-(N-benzylanilino)acetamide) through three different pathways (acidic, non-catalysed, and semi-alkaline hydrolysis) was observed. In highly acidic media (pH 0-2), the degradation mechanism was found to be more complex. Although the same primary degradation product formed, a colourful (dark blue/violet) intermediate was also observed and further investigated by HPLC/TOF-MS.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Formulation and Drug Delivery Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom
Crystal structures of dihydrate (DH) and three anhydrous forms (A, B and C) of quifenadine (1-azabicyclo[2.2.2]oct-8-yl-diphenyl-methanol) hydrochloride are presented, and crystal structure information is used to explain and rationalize the relative stability of polymorphs and observed phase transformations. The dehydration mechanism of the hydrate is provided by interpreting the results obtained in studies of crystal structures, dehydration kinetics and thermal analysis. Structural analysis is used to explain the observed relative stability of the anhydrous phases and the hydrate. The crystal structures have been determined either from single crystal (form DH) or from powder diffraction data (forms A, B and C). All three polymorphs consist of similar hydrogen bonded tetramers, and the structural differences arise due to differences in conformation or/and molecular packing.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Department of Chemistry, Durham University, South Road, Durham, United Kingdom
The compatibility of thermodynamically unstable polymorph of two active pharmaceutical compounds (xylazine hydrochloride form X and zopiclone form C) with different excipients was investigated. The effects of the excipient and its amount in the sample on the thermal properties and possible chemical interactions were studied. The most commonly used excipients in the pharmaceutical industry - calcium carbonate, lactose hydrate, cellulose, magnesium stearate hydrate and calcium stearate hydrate were selected for this study. The dependence of the phase transition rate from an unstable to a more stable polymorph on the excipients and their amounts in the initial sample was analysed at 80. °C, and the corresponding phase transition rate constants were calculated.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
The compatibility of thermodynamically unstable polymorph of two active pharmaceutical compounds (xylazine hydrochloride form X and zopiclone form C) with different excipients was investigated. The effects of the excipient and its amount in the sample on the thermal properties and possible chemical interactions were studied. The most commonly used excipients in the pharmaceutical industry - calcium carbonate, lactose hydrate, cellulose, magnesium stearate hydrate and calcium stearate hydrate were selected for this study. The dependence of the phase transition rate from an unstable to a more stable polymorph on the excipients and their amounts in the initial sample was analysed at 80. °C, and the corresponding phase transition rate constants were calculated.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, Norfolk, United Kingdom
Solid-state cocrystallization is of contemporary interest because it offers an easy and efficient way to produce cocrystals, which are recognized as prospective pharmaceutical materials. Research explaining solid-state cocrystallization mechanisms is important but still too scarce to give a broad understanding of factors governing and limiting these reactions. Here we report an investigation of the mechanism and kinetics of isoniazid cocrystallization with benzoic acid. This reaction is spontaneous; however, its rate is greatly influenced by environmental conditions (humidity and temperature) and pretreatment (milling) of the sample. The acceleration of cocrystallization in the presence of moisture is demonstrated by kinetic studies at elevated humidity. The rate dependence on humidity stems from moisture facilitated rearrangements on the surface of isoniazid crystallites, which lead to cocrystallization in the presence of benzoic acid vapor. Furthermore, premilling the mixture of the cocrystal ingredients eliminated the induction time of the reaction and considerably increased its rate.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
New antazoline salts with organic acids (fumaric acid, oxalic acid, and maleic acid) were prepared. The effect of the crystallization solvent and mechanochemical treatment on the crystalline forms of these salts was studied. Two polymorphs of antazoline hydrogen maleate were identified and their relative stability was determined. The molecular structures of antazoline hydrogen oxalate and antazoline hydrogen maleate showed differences in antazoline cation conformation. In crystal structures of all salts both imidazoline nitrogens of antazoline cation are involved in hydrogen bond formation with carboxyl groups of the acid.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Formulation and Drug Delivery Research Group, School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, United Kingdom
This paper describes a study of the solvent-mediated polymorphic transformation (SMPT) of the metastable α tegafur to the thermodynamically stable β tegafur in several solvents. Phase transformation in acetone, ethanol, i-propanol, toluene, and water at 22 °C was described using the solid-state kinetic model P2; the rate constants for this process were in the range from 0.028 min-1 to 0.0056 min-1. In all of the employed solvents, an induction time was observed. Kinetic, solubility and scanning electron microscopy data indicated that nucleation kinetics corresponded to a second-order power function and according to the kinetic model, the nuclei growth rate was constant in the examined SMPT. Surface nucleation was observed, and the possible nucleation mechanism was given. The phase transition rate depended linearly on the difference between the equilibrium solubilities of α and β tegafur in the respective solvent, i.e. supersaturation.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
An experimental and theoretical investigation of protonation effects on the UV/Vis absorption spectra of imatinib showed systematic changes of absorption depending on the pH, and a new absorption band appeared below pH 2. These changes in the UV/Vis absorption spectra were interpreted using quantum chemical calculations. The geometry of various imatinib cations in the gas phase and in ethanol solution was optimized with the DFT/B3LYP method. The resultant geometries were compared to the experimentally determined crystal structures of imatinib salts. The semi-empirical ZINDO-CI method was employed to calculate the absorption lines and electronic transitions. Our study suggests that the formation of the extra near-UV absorption band resulted from an increase of imatinib trication concentration in the solution, while the rapid increase of the first absorption maximum could be attributed to both the formation of imatinib trication and tetracation.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
This paper reports an investigation of a complex solid state phase transition where two inter-converting polymorphs (X and A) of the pharmaceutical molecule xylazine hydrochloride formed and transformed during and after the dehydration of its monohydrate (H). The crystal structures of all three forms were compared. During the investigation of this solid state phase transition it was determined that the dehydration of H produced either a pure X form, or a mixture of the X and A forms. The phase composition depended on the sample preparation procedure and the experimental conditions. It was found that grinding of the hydrate enhanced the formation of polymorph X as a product of dehydration, whereas higher humidity, temperature, or mechanical compression enhanced the formation of polymorph A. The transition mechanism of this complex process was analysed and explained by taking into account the crystal structures of these three forms.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
In order to find a tool for comparison of solvate stability and to rationalize their relative stability, droperidol nonstoichiometric isostructural solvates were characterized experimentally and computationally. For the experimental evaluation of stability, three comparison tools were considered: thermal stability characterized by the desolvation rate, desolvation activation energy, and solvent sorption-desorption isotherms. It was found that the desolvation process was limited by diffusion, and the same activation energy values were obtained for all of the characterized solvates, while the solvent content in the sorption isotherm was determined by the steric factors. Therefore, the only criterion characterizing the solvate stability in this particular system was the thermal stability. It was found that computationally obtained solvent-droperidol and solvent-solvent interaction energies could be used for the rationalization of the isostructural solvate stability in this system and that the solvent-solvent interaction energy has a crucial role in determining the stability of solvates.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
The dehydration of mildronate dihydrate (3-(1,1,1-trimethylhydrazin-1-ium- 2-yl)propionate dihydrate) was investigated by powder X-ray diffraction, thermal analysis, hot-stage microscopy, water sorption-desorption studies and dehydration kinetic studies. It was determined that mildronate dihydrate dehydrated in a single step, directly transforming into the anhydrous form. In order to understand the reasons for a one step dehydration mechanism, crystal structures of dihydrate, monohydrate and anhydrous forms were compared, proving the similarity of the dihydrate and anhydrous forms. In order to understand the reasons for molecule reorganization during dehydration, the energy of the anhydrous form was compared with that of a theoretical dihydrate structure without water molecules. It was proven that the experimentally observed anhydrous phase AP was thermodynamically more stable. By analyzing the effect of the particle size and sample weight on the dehydration kinetic parameters it was determined that besides the main rate limiting step, phase boundary advancement, contribution from the water diffusion outside the crystal and the water diffusion outside the powdered sample also appeared to affect the dehydration kinetics and contribution from these processes could be changed by changing the aforementioned factors.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
A solvate screening and characterization of the obtained solvates was performed to rationalize and understand the solvate formation of active pharamaceutical ingredient droperidol. The solvate screening revealed that droperidol can form 11 different solvates. The analysis of the crystal structures and molecular properties revealed that droperidol solvate formation is mainly driven by the inability of droperidol molecules to pack efficiently. The obtained droperidol solvates were characterized by X-ray diffraction and thermal analysis. It was found that droperidol forms seven nonstoichiometric isostructural solvates, and the crystal structures were determined for five of these solvates. To better understand the structure of these five solvates, their solvent sorption-desorption isotherms were recorded, and lattice parameter dependence on the solvent content was determined. This revealed a different behavior of the nonstoichiometic hydrate, which was explained by the simultaneous insertion of two hydrogen-bonded water molecules. Isostructural solvates were formed with sufficiently small solvent molecules providing effective intermolecular interactions, and solvate formation was rationalized based on already presented solvent classification. The lack of solvent specificity in isostructural solvates was explained by the very effective interactions between droperidol molecules. Desolvation of stoichiometric droperidol solvates produced one of the four droperidol polymorphs, whereas that of nonstoichiometic solvates produced an isostructural desolvate.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
The control of inorganic contaminants in active pharmaceutical ingredients has a significant role in the quality control of drug products. The concentration limits for metal residues in drug products have been defined by various regulatory guidelines. Laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) is a powerful and fast analytical technique for multi-elemental analysis. A disadvantage in using LA-ICP-MS method is the lack of matrix reference materials for validation and calibration purposes. This article focuses on the handling strategy of laboratory-made matrix calibration standards for the quantification of elemental impurities in an active pharmaceutical ingredient by LA-ICP-MS.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
The kinetics of the solid-state phase transformation of xylazine hydrochloride form X to A has been investigated using powder X-ray diffraction and differential thermal analysis. Three different kinetic models have been used to describe transition kinetics: the Avrami-Erofeev equation, the Cardew equation, and the methodology for simulation of solid-state phase transition kinetics by the combination of nucleation and nuclei growth processes. The latter has been recently developed and has been tested in this paper for the case of a real solid-state transition. The relative humidity, mechanical pressure, temperature, and sample-preparation effect on phase-transition kinetics have been investigated, and rate constant changes have been analyzed.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
Flecainide base is pharmaceutically active substance used for production of flecainide acetate which is known in market as Tambacor, Almarytm, Apocard, Ecrinal or Flecaine. It is determined that flecainide base forms four polymorphic forms abbreviated as Ib, IIb, IIIb and IVb. Flecainide base form Ib is thermodynamically stable form at laboratory temperature while form IIIb is stable at higher temperatures. Flecainide form Ib absorbs water in its structure between layers and forms non-stoichiometric hydrate. Flecainide base binds with organic solvents and form monosolvates. Flecainide base form Ib crystallizes in orthorhombic crystals with lattice parameters a=27.88Å, b=13.78Å, c=9.98Å and two independent molecules in unit cell (Z =2; Z=8). Molecule arrangement in flecainide base form Ib structure is not dense and it forms a channel-type structure, where molecules of water and alcohols are placed.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Faculty of Natural Sciences and Mathematics, Daugavpils University, Daugavpils, Latvia
Flecainide base is pharmaceutically active substance used for production of flecainide acetate which is known in market as Tambacor, Almarytm, Apocard, Ecrinal or Flecaine. It is determined that flecainide base forms four polymorphic forms abbreviated as Ib, IIb, IIIb and IVb. Flecainide base form Ib is thermodynamically stable form at laboratory temperature while form IIIb is stable at higher temperatures. Flecainide form Ib absorbs water in its structure between layers and forms non-stoichiometric hydrate. Flecainide base binds with organic solvents and form monosolvates. Flecainide base form Ib crystallizes in orthorhombic crystals with lattice parameters a=27.88Å, b=13.78Å, c=9.98Å and two independent molecules in unit cell (Z =2; Z=8). Molecule arrangement in flecainide base form Ib structure is not dense and it forms a channel-type structure, where molecules of water and alcohols are placed.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
The umifenovir salts of maleic, salicylic, glutaric, and gentisic acid as well as the chloroform solvate of the salicylate were prepared. Single crystals of the five compounds were obtained and their molecular and crystal structures determined by X-ray diffraction. In each structure the conformation of phenyl ring with respect to the indole group of the umifenovir moiety is different. The water solubility and melting points of the studied umifenovir salts have been determined.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
A new polymorph of the cinnamic acid-isoniazid cocrystal has been prepared by slow evaporation, namely cinnamic acid-pyridine-4-carbohydrazide (1/1), C9H8O2•C6H7N 3O. The crystal structure is characterized by a hydrogen-bonded tetrameric arrangement of two molecules of isoniazid and two of cinnamic acid. Possible modification of the hydrogen bonding was investigated by changing the hydrazide group of isoniazid via an in situ reaction with acetone and cocrystallization with cinnamic acid. In the structure of cinnamic acid-N'-(propan-2-ylidene)isonicotinohydrazide (1/1), C9H 8O2•C9H11N3O, carboxylic acid-pyridine O - H⋯N and hydrazide-hydrazide N - H⋯O hydrogen bonds are formed.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
The dehydration kinetics of mildronate dihydrate [3-(1,1,1- trimethylhydrazin-1-ium-2-yl)propionate dihydrate] was analyzed in isothermal and nonisothermal modes. The particle size, sample preparation and storage, sample weight, nitrogen flow rate, relative humidity, and sample history were varied in order to evaluate the effect of these factors and to more accurately interpret the data obtained from such analysis. It was determined that comparable kinetic parameters can be obtained in both isothermal and nonisothermal mode. However, dehydration activation energy values obtained in nonisothermal mode showed variation with conversion degree because of different rate-limiting step energy at higher temperature. Moreover, carrying out experiments in this mode required consideration of additional experimental complications. Our study of the different sample and experimental factor effect revealed information about changes of the dehydration rate-limiting step energy, variable contribution from different rate limiting steps, as well as clarified the dehydration mechanism. Procedures for convenient and fast determination of dehydration kinetic parameters were offered.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
Desorption behavior of 8 different solvents from α and β tegafur (5-fluoro-1-(tetrahydro-2-furyl)uracil) has been studied in this work. Solvent desorption from samples stored at 95% and 50% relative solvent vapor pressure was studied in isothermal conditions at 30 C. The results of this study demonstrated that: solvent desorption rate did not differ significantly for both phases; solvent desorption in all cases occurred faster from samples with the largest particle size; and solvent desorption in most cases occurred in two steps. Structure differences and their surface properties were not of great importance on the solvent desorption rates because the main factor affecting desorption rate was sample particle size and sample morphology. Inspection of the structure packing showed that solvent desorption rate and amount of solvent adsorbed were mainly affected by surface molecule arrangement and ability to form short contacts between solvent molecule electron donor groups and freely accessible tegafur tetrahydrofuran group hydrogens, as well as between solvents molecule proton donor groups and fluorouracil ring carbonyl and fluoro groups. Solvent desorption rates of acetone, acetonitrile, ethyl acetate and tetrahydrofuran multilayers from α and β tegafur were approximately 30 times higher than those of solvent monolayers. Scanning electron micrographs showed that sample storage in solvent vapor atmosphere promotes small tegafur particles recrystallization to larger particles.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
Desorption behavior of 8 different solvents from α and β tegafur (5-fluoro-1-(tetrahydro-2-furyl)uracil) has been studied in this work. Solvent desorption from samples stored at 95% and 50% relative solvent vapor pressure was studied in isothermal conditions at 30 C. The results of this study demonstrated that: solvent desorption rate did not differ significantly for both phases; solvent desorption in all cases occurred faster from samples with the largest particle size; and solvent desorption in most cases occurred in two steps. Structure differences and their surface properties were not of great importance on the solvent desorption rates because the main factor affecting desorption rate was sample particle size and sample morphology. Inspection of the structure packing showed that solvent desorption rate and amount of solvent adsorbed were mainly affected by surface molecule arrangement and ability to form short contacts between solvent molecule electron donor groups and freely accessible tegafur tetrahydrofuran group hydrogens, as well as between solvents molecule proton donor groups and fluorouracil ring carbonyl and fluoro groups. Solvent desorption rates of acetone, acetonitrile, ethyl acetate and tetrahydrofuran multilayers from α and β tegafur were approximately 30 times higher than those of solvent monolayers. Scanning electron micrographs showed that sample storage in solvent vapor atmosphere promotes small tegafur particles recrystallization to larger particles.
a. Department of Chemistry, M. V. Lomonosov Moscow State University, Moscow 119991, Russian Federation
b. A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky Prospect 31, Moscow 119071, Russian Federation
c. Department of Chemistry, University of Latvia, Kr. Valdemara Street 48, Riga LV-1013, Latvia
d. JSC Grindeks, Krustpils Street 53, Riga LV-1057, Latvia
e. JSC Pharmstandard, 141700 Likhachevsky Drive 5b, Dolgoprudny, Moscow Region 141700, Russian Federation
Afobazole {systematic name: 2-[2-(morpholin-4-yl)ethylsulfanyl]-1H- benzimidazole} is a new anxiolytic drug and Actins, Auzins and Petkune [(2012). Eur. Patent EP10163962] described four polymorphic modifications. In the present study, the crystal structures of two monoclinic polymorphs, 5-ethoxy-2-[2-(morpholin-4-ium-4-yl)ethylsulfanyl]-1H-benzimidazol-3-ium dichloride, C15H23N3O2S 2+·2Cl-, (II) and (IV), have been established from laboratory powder diffraction data. The crystal packing and conformation of the dications in (II) and (IV) are different. In (II), there are channels in the [001] direction, which offer atmospheric water molecules an easy way of penetrating into the crystal structure, thus explaining the higher hygroscopicity of (II) compared with (IV).
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
Kinetics of anhydrous cocrystal hydration and that of cocrystal monohydrate formation from starting compounds in the solid state are studied as a function of RH and time. The propensity of the anhydrate to hydration is related to the crystal structures of anhydrous and hydrated forms.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
Reaction of isoniazid with benzoic acid, sebacic acid, suberic acid, and cinnamic acid results in formation of cocrystals. Two polymorphs of isoniazid-suberic acid and two polymorphs of isoniazid-cinnamic acid cocrystals were isolated. Crystal structure analysis shows the presence of a pyridine-carboxylic acid synthon in the studied cocrystals. The hydrazide group of isoniazid participates in N-H···O and N-H···N hydrogen bond formation, producing different supramolecular synthons. The stability study of isoniazid cocrystals has been performed over a 22 week period. A comparison of melting points of isoniazid-dicarboxylic acid 2:1 cocrystals shows the decrease of melting point with an increasing length of the acid. Solubility of isoniazid-carboxylic acid cocrystals tends to increase with increasing solubility of the acid.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
Solvent effects on α tegafur (5-fluoro-1-(tetrahydro-2-furyl)uracil) phase transition to β tegafur during grinding with solvent additive, as well as phase transition in samples exposed to 95% relative solvent vapor pressure has been studied in this research. Samples containing 0.5% and 0.1% of β tegafur in α and β tegafur mixture, as well as samples of pure α tegafur were ground with different solvent additives, and conversion degrees depending on the solvent were determined using PXRD method. Samples with α and β tegafur weight fraction of 1:1 were exposed to 95% relative solvent vapor pressure, and phase transition rates were determined. Solubility of α tegafur, solvent sorption and desorption behavior on α and β tegafur have been examined. It was found that the conversion degree of α tegafur to β tegafur mainly depends on solubility of α tegafur in the relevant solvent, and the conversion degree to β tegafur is higher in such solvents, where solubility of α tegafur is higher. The samples ground in a ball mill with solvent additive had a trend of phase transition dynamics from α tegafur to β tegafur similar to the samples exposed to 95% relative solvent vapor pressure.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
We report a semiquantitative method for determining trace amounts (less than 1%) of thermodynamically stable forms in polymorphic mixtures, focusing on sample preparation effects on solid phase transitions. Tegafur [5-fluoro-1-(oxolan-2-yl)-1,2,3,4-tetrahydropyrimidine-2,4-dione] was used as a model material in this study. The amounts of the thermodynamically stable β tegafur were increased to levels detectable by powder X-ray diffractometry by grinding the samples in a ball mill in the presence of water. The limit of detection for this method was as low as 0.0005% of β tegafur in α and β tegafur mixtures. The amount of β tegafur after sample preparation was found to be proportional to the initial weight fraction of β tegafur. The sum of Langmuir and Cauchy-Lorentz equations was used to describe the change in conversion degree due to the added water volume, where Langmuir equation described water sorption during the sample preparation and Cauchy-Lorentz equation described the grinding efficiency.
a. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
b. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
In the title compound, C21H26ClN2O 4S.Cl, also known as tianeptine hydrochloride, the seven-membered ring adopts a boat conformation. The dihedral angle between the mean planes of the benzene rings is 44.44(7)°. There is an intramolecular hydrogen bond formed via S= O⋯H-N. In the crystal, molecules are connected via pairs of N-H.·O, N-H⋯Cl and O-H⋯Cl hydrogen bonds, forming inversion dimers, which are consolidated by C-H⋯O interactions. The dimers are linked by C-H⋯O and C-H⋯Cl interactions, forming a two-dimensional network lying parallel to (011).
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
The objective of this work was to investigate the relative humidity (RH) and solvent vapor pressure effects on the phase transition dynamics between tegafur polymorphic forms that do not form hydrates and solvates. The commercially available α and β modifications of 5-fluoro-1- (tetrahydro-2-furyl)-uracil, known as the antitumor agent tegafur, were used as model materials for this study. While investigating the phase transitions of α and β tegafur under various partial pressures of methanol, n-propanol, n-butanol, and water vapor, it was determined that the phase transition rate increased in the presence of solvent vapors, even though no solvates were formed. By increasing the relative air humidity from 20% to 80%, the phase transition rate constant of α and β tegafur was increased about 60 times. After increasing the partial pressure of methanol, n-propanol, or n-butanol vapor, the phase transition rate constant did not change, but the extent of phase transformation was increased. In the homologous row of n-alcohols, the phase transition rate constant decreased with increasing carbon chain length. The dependence of phase transformation extent versus the RH corresponded to the polymolecular adsorption isotherm with a possible capillary condensation effect.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
The anti-depressant pharmaceutical tianeptine has been investigated to determine the dynamics of polymorph formation under various pH conditions. By varying the pH two crystalline polymorphs were isolated. The molecular and crystal structures have been determined to identify the two polymorphs. One polymorph is an amino carboxylic acid and the other polymorph is a zwitterion. In the solid state the tianeptine moieties are bonded through hydrogen bonds. The zwitterion was found to be less stable and transformed to the acid form. During this investigation an amorphous form was identified.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Laboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, Helsinki 00014, Finland
c. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
Structural analysis of the supramolecular cocrystals formed by pyrogallol with acridine, 4,4′-bipyridine, and 1,10-phenanthroline shows that the studied cocrystals are assembled via the hydroxyl-pyridine heterosynthon. In the crystal and molecular structures of these cocrystals in order to form the maximum number of hydrogen bonds, taking into consideration steric effects, the pyrogallol moiety in the supramolecular arrangement has the following conformations: with acridine - syn1, 4,4′-bipyridine - anti, and 1,10-phenanthroline - syn2. Discrete supramolecular complexes are formed by acridine-pyrogallol and the 1,10-phenanthroline-pyrogallol polymorph I. The 1,10-phenanthroline-pyrogallol polymorph II and the 4,4′-bipyridine- pyrogallol trihydrate form extended hydrogen bonded chains.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
A new methodology for the simulation of solid state phase transition kinetics has been developed by combining the influence of nucleation rate, nuclei growth rate and the power p characterizing the contact area between the growing particles. The equations used in this methodology were well known, and have been used previously for creating some of the most popular solid-state kinetic equations. The developed methodology made possible calculations of separate rate constants for two processes affecting the rate of phase transition-nucleation (described with K 1) and nuclei growth (described with K 2). Similar phase transitions were also approximated with the well-known single constant Avrami-Erofeev equation, but we successfully calculated both constants according to the new methodology, which allowed a separate evaluation of these two processes and explained the different induction periods. The effects of empirically adjusted constants on theoretically calculated kinetic curves were thus determined.
a. Faculty of Chemistry, University of Latvia, Jelgavas 1, Riga 1004, Latvia
b. JSC Grindeks, Krustpils 53, Riga 1057, Latvia
The thermodynamic stability of detomidine hydrochloride monohydrate has been evaluated on the basis of phase transition kinetics in solid state. A method free of empirical models was used for the treatment of kinetic data, and compared to several known solid state kinetic data processing methods. Phase transitions were monitored by powder X-ray diffraction (PXRD) and thermal analysis. Full PXRD profiles were used for determining the phase content instead of single reflex intensity measurements, in order to minimize the influence of particle texture. We compared the applicability of isothermal and nonisothermal methods to our investigation of detomidine hydrochlorine monohydrate dehydration.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
Objectives The main objective of this work was to develop a suitable analytical technique for determining trace amounts of the thermodynamically stable solid form in bulk samples of metastable form, to a sensitivity of 0.005%-1.0%. Tegafur (5-fluoro-1-(tetrahydro-2-furyl)-uracil) α and β crystalline forms were used as a model for this problem. Methods The trace content of the thermodynamically stable β polymorphic form in tegafur samples was increased by promoting phase transition from the bulk of thermodynamically metastable α form to β form, and achieving sufficient β form content for a quantitative powder X-ray diffractometry (PXRD) analysis. The phase transition was stimulated by adding water to the samples and then grinding in controlled conditions (temperature, time, grinding speed). A calibration line was constructed using the least squares method. Key findings By using a solvent that does not form hydrates with the analysed polymorphs, it was possible to promote the phase transformation from metastable form to the thermodynamically stable form. After sample preparation, the thermodynamically stable solid form content in the analysed mixture had increased proportionally to the initial weight fraction (0.005%-1.0%) of the stable form seed crystals in the samples, and the coefficient of proportionality was 43.0 ± 0.9, with a standard deviation S n = 1.5%. Conclusions A simple, sensitive, semi-quantitative analytical method was developed for the low-level determination of the thermodynamically stable polymorphic form in mixtures of thermodynamically stable and metastable polymorphs.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Laboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, Helsinki 00014, Finland
Supramolecular complexes of phenanthridine have been prepared with various dicarboxylic acids. Cocrystallization of phenanthridine with fumaric acid, succinic acid, and isophthalic acid produced neutral cocrystals. Proton transfer from maleic acid and oxalic acid to the phenanthridine moiety results in salts of these two acids. It was found that neutral cocrystals are formed when the ΔpKa value of the complex is smaller than 2.56, whereas salts are formed when ΔpKa is greater than 3.66. The crystal structures of supramolecular complexes have been determined. The structure of each compound depends on acid geometry, and the compounds may be described as dimers, trimers, or chains. A comparison of the melting points, hydrogen bonds, and densities of each molecular complex and the corresponding dicarboxylic acid is presented. Utilizing the approximate relative bond strengths of hydrogen bonds, a comparison of the number of hydrogen bonds in the acid and the cocrystal is possible.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
Flecainide acetate forms acetic acid solvates with 0.5 and 2 acetic acid molecules. Powder X-ray diffraction, differential thermal analysis/thermogravimetric, infrared, and potentiometric titration were used to determine the composition of solvates. Flecainide acetate hemisolvate with acetic acid decomposes to form a new crystalline form of flecainide acetate. This form is less stable than the already known polymorphic form at all temperatures, and it is formed due to kinetic reasons. Both flecainide acetate nonsolvated and flecainide acetate hemisolvate forms crystallize in monoclinic crystals, but flecainide triacetate forms triclinic crystals. Solvate formation was not observed when flecainide base was treated with formic acid, propanoic acid, and butanoic acid. Only nonsolvated flecainide salts were obtained in these experiments.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
The phase transition kinetics of two chenodeoxycholic acid polymorphic modifications-. form I (stable at high temperature), form III (stable at low temperature) and the amorphous phase has been examined under various conditions of temperature and relative humidity. Form III conversion to form I was examined at high temperature conditions and was found to be non-spontaneous, requiring seed crystals for initiation. The formation kinetic model of form I was created incorporating the three-dimensional seed crystal growth, the phase transition rate proportion to the surface area of form I crystals, and the influence of the amorphous phase surface area changes with an empirical stage pointer q that contained the incomplete transition of the amorphous phase to form I with a residue ωA∞. The extent of transition and the phase transition rate constant depended on form I seed crystal amount in the raw mixture, and on the sample preparation. To describe phase transition kinetic curves, we employed the Runge-Kutta differential equation numeric solving method. By combining the Runge-Kutta method with the multi-point optimization method, the average quadratic deviation of the experimental results from one calculated series was under 2%.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
All four known xylazine hydrochloride polymorphous forms were obtained and their relative stabilities were compared directly at three different temperatures. At higher temperatures, it is possible to determine the relative stability of all forms directly by measuring the changes in the composition of the mixtures of two polymorphous forms using powder x-ray diffraction methods. At lower temperatures, a solvent was added to the mixture and the changes in composition were determined. Polymorph transition temperatures were determined directly. To predict the transition temperature which was not found using the direct method, the polymorph melting data and determined transition temperatures were used. A phase stability diagram was constructed from the acquired data. The stability of all anhydrous polymorphous forms was compared in the presence of water vapor pressure that was higher than the equilibrium pressure.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
The crystal structure of the title compound, 2C 19H17N2+·C4H 2O42-, consists of centrosymmetric trimers built up of two crystallographically independent N,N′-diphenyl-benzamid- in-ium cations and one fumarate dianion, which is located on a centre of inversion. The components of the trimers are linked by N-H⋯O hydrogen bonding. In the cation, the outer rings make dihedral angles of 53.66 (5) and 78.38 (5)° with the central ring. The two outer rings make a dihdral angle of 81.49 (5)°.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Laboratory of Inorganic Chemistry, Department of Chemistry, University of Helsinki, Helsinki 00014, Finland
Crystal structures of alpha2-adrenergic antagonist atipamezole base (1) and its hydrochloric acid salt (2) have been determined using X-ray diffraction methods. Atipamezole base crystallized in the monoclinic space group P21, with unit cell parameters a = 13.238(4), b = 9.747(4), c = 14.609(5) Å, β = 107.75(4)°, V = 1,795.3(12) Å3 and Z = 6 (three independent molecules of 1). Atipamezole hydrochloride crystallized in the monoclinic space group Cc, with unit cell parameters a = 12.052(1), b = 32.561(9), c = 13.668(5) Å, β = 102.64(1)°, V = 5,233(2) Å3 and Z = 16 (four independent molecules of 2). Each of the three atipamezole moieties in 1 has an intramolecular C-H⋯;N H-bond. In both structures the molecules are H-bonded to form extended chains.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
From the experiments where mixture of xylazine hydrochloride hydrate H and anhydrous X were held at constant conditions, the stable form of xylazine hydrochloride can be found out. To determine equilibrium relative humidity, the unstable form of xylazine hydrochloride was inserted in thermostated humidity chamber and its weight was recorded by weighing the sample outside the chamber. The kinetic model and the rate constant for each condition were determined. The rate constants give information regarding the speed of the process at every experimentally used relative humidity. Thus using the data in coordinates k p for each temperature it is possible to determine the water vapor pressure of the equilibrium. With this method the phase boundary for xylazine hydrochloride was determined and hydration enthalpy was calculated. The hydration rates of xylazine polymorphs A and X were investigated.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
Synthesis of nicotinamide and fumaric acid supramolecular cocrystals with 1 : 1 and 2 : 1 amide to acid stoichiometries results in the formation of an amide-acid heterosynthon (1 : 1 stoichiometry) and an amide-amide homosynthon (2 : 1 stoichiometry) and different conformations of the fumaric acid moieties.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
In the title compound, alternatively called xylazine hydro-chloride monohydrate, C12H17N2S+·Cl-·H2O, the six-membered thia-zine ring is in a half-chair conformation. In the crystal structure, six component centrosymmetric clusters are formed via inter-molecular O - H⋯Cl, N - H⋯O and N - H⋯Cl hydrogen bonds involving xylazine cations, chloride anions and water mol-ecules.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvia Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
The anion of the title compound, also called sygethin dihydrate, 2K +·C18H20O6S2 2-·2H2O, has crystallographic inversion symmetry. The K+ cation is surrounded by eight O atoms in a distorted cubic coordination geometry, forming extended K - O - S networks. There are also O - H...O hydrogen bonds.
a. Faculty of Chemistry, University of Latvia, Kr. Valdemara 48, Riga 1013, Latvia
b. Latvian Institute of Organic Synthesis, Aizkraukles 21, Riga 1006, Latvia
Crystals of two crystal modifications of droperidol: a hemihydrate (1) and the z polymorph (2), have been isolated and their structure determined using X-ray diffraction methods. Droperidol hemihydrate crystallized in the triclinic space group P - 1, with unit cell parameters a = 6.2842(15), b = 10.1473(8), c = 16.1850(2) Å; α = 102.554(9); β = 91.917(14); γ = 99.316(12)°; V = 991.6(3) Å3, and Z = 2. The droperidol z polymorph crystallized in the monoclinic space group P21/c, with unit cell parameters a = 20.0406(8), b = 7.4955(4), c = 12.9733(5) Å; β = 98.089(2)°; V = 1929.39(15) Å3, and Z = 4. In 1 and 2 two molecules of droperidol are joined by two N-H⋯O hydrogen bonds. The structure of 1 shows a possible additional hydrogen bond linking the two droperidol molecules via the water molecule.
University of Latvia, Faculty of Chemistry, Laboratory of Molecular Crystals. Address: Jelgavas iela 1, Riga, LV1004, Latvia
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