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Two bipyridine isomers (2,2′- and 4,4′-), used as coformers and ligands in coordination chemistry, were subjected to solid form screening and crystal structure prediction. One anhydrate and a formic acid disolvate were crystallized for 2,2′-bipyridine, whereas multiple solid-state forms, anhydrate, dihydrate, and eight solvates with carboxylic acids, including a polymorphic acetic acid disolvate, were found for the 4,4′-isomer. Seven of the solvates are reported for the first time, and structural information is provided for six of the new solvates. All twelve solid-state forms were investigated comprehensively using experimental [thermal analysis, isothermal calorimetry, X-ray diffraction, gravimetric moisture (de)sorption, and IR spectroscopy] and computational approaches. Lattice and interaction energy calculations confirmed the thermodynamic driving force for disolvate formation, mediated by the absence of H-bond donor groups of the host molecules. The exposed location of the N atoms in 4,4′-bipyridine facilitates the accommodation of bigger carboxylic acids and leads to higher conformational flexibility compared to 2,2′-bipyridine. For the 4,4′-bipyridine anhydrate ↔ hydrate interconversion hardly any hysteresis and a fast transformation kinetics are observed, with the critical relative humidity being at 35% at room temperature. The computed anhydrate crystal energy landscapes have the 2,2′-bipyridine as the lowest energy structure and the 4,4′-bipyridine among the low-energy structures and suggest a different crystallization behavior of the two compounds., The solid form landscapes of 2,2′- and 4,4′-bipyridine were explored experimentally and computationally. The position of the nitrogen atoms defines not only the conformational flexibility of the molecule but also the crystallization behavior. 4.4′-Bipyridine was found to be more prone to solvate (including hydrate) formation than its 2,2′-isomer.

Controlling the physical properties of solid forms for active pharmaceutical ingredients (APIs) through cocrystallization is an important part of drug product development. However, it is difficult to know

Following the computational prediction that 3-hydroxybenzoic acid (3HBA) could exist in more than the two literature polymorphs, an experimental investigation targeting computationally generated structures was performed. The third polymorph III, solved from powder X-ray diffraction data, and the literature form II share a common hydrogen-bonded ladder motif in contrast to the carboxylic acid dimer based form I. The two metastable polymorphs (II and III) are storage stable if phase pure and monotropically related to form I. Calorimetric measurements and (lattice) energy minimisations revealed that the three polymorphs are close in energy.

Commercial samples of strychnine sulfate were used as the starting material in crystallization experiments accompanied by stability studies. Eight hydrate forms (HyA–HyG), including five novel hydrates, were verified. The crystal structures of HyA (“pentahydrate”) and HyF (“hexahydrate”) were determined from single-crystal X-ray diffraction data. HyF was identified as the most stable hydrate at high water activities at room temperature (RT), and HyA and HyC were also found to be stable at ambient conditions. Long-time storage experiments over nearly two decades confirm that these three hydrates are stable at ambient conditions (20–60% relative humidity). The other five hydrates, HyB (“dihydrate”), HyD, HyE, HyG, and HyH, are only observable at the low(est) relative humidity (RH) levels at RT. Some of these latter forms can only exist within a very narrow RH range and are therefore intermediate phases. By applying a range of complementary experimental techniques such as gravimetric moisture sorption analysis, thermal analysis, moisture controlled PXRD measurements, and variable temperature IR spectroscopy in combination with principal component analysis, it was possible to identify the distinct hydrate phases and elucidate their stability and dehydration pathways. The observed (de)hydration routes, HyA ↔ HyB, HyC ↔ HyD ↔ HyE, HyF ↔ HyG ↔ HyH and HyF → HyA ↔ HyB, depended on the initial hydrate form, particle size, and atmospheric conditions. In addition, a transformation from HyC/HyA to HyF occurs at high RH values at RT. The specific moisture and temperature conditions of none of the applied drying regimes yielded a crystalline water-free form, which highlights the essential role of water molecules for the formation and stability of the crystalline strychnine sulfate phases., The complex moisture- and temperature-dependent interconversion pathways and the stability of eight hydrate forms of strychnine sulfate were unraveled by a complementary approach comprising gravimetric moisture (de)sorption analysis, moisture controlled powder X-ray diffraction measurements, thermal analysis, and variable temperature infrared spectroscopy combined with multivariate data treatment. The study highlights the importance of high-resolution, moisture-dependent investigations for gaining insight into the structural reorganization and transient states of hydrates.

The solid form landscape of brucine sulphate (BS) was elucidated, resulting in three hydrate forms (HyA–C) and amorphous BS. Interconversion of the hydrates of BS with small changes in the relative humidity complicated identifying and characterising the solid forms. The hydrate obtained from crystallisation experiments (from water), HyA, is the only solid form described in the literature. The other two hydrates were produced by dehydration starting from the known hydrate. HyA contains 6.5 to 7.4 molecules of water per BS and is only stable in the relative humidity (RH) range ≥26% at room temperature (RT). HyB is only observable in a very narrow RH window (22–25%) at RT and shows a hexahydrate stoichiometry. At RH values ≤20%, the third hydrate, HyC, forms. Similar to HyA, the latter hydrate shows a variable water content of five or less water molecules per BS. Removal of the essential water molecules stabilising the hydrate structures causes the collapse to the amorphous state, a process which was not completed within 3.5 years of storing HyC under driest conditions (approx. 0%) at room temperature. Only the combination of intermolecular interaction and electronic structure calculations with thermal analytical techniques, X-ray diffraction, IR spectroscopy and gravimetric moisture (de)sorption studies and careful control of the external conditions allowed the discovery and rationalisation of the three hydrates of BS. The investigations on BS were complemented with an exploitation of the Cambridge Structural Database (CSD) to unravel the incidence of hydrates of sulphate salts. The analysis indicates that 56.5% of the sulphate salts (C, H, N, O, and S atoms only) are hydrate structures, with higher hydrates being more commonly present amongst sulphate salts than amongst all organic hydrates.

Experimental and theoretical characterisation and studies of the stability of heterobicyclic thiazinium salts (bicyclic 2-mercaptoimidazolium chlorides and bromides) were performed to rationalise and understand the influence of the counterion (Cl−↔ Br−) and the replacement of CH by N on crystal packing, the influence of the anion on the moisture and temperature dependent stability, and the racemisation behaviour of the imidazo-thiazinium chloride. Six compounds were synthesised and for five of the compounds the structures were solved from single-crystal X-ray diffraction data. The structural features of the sixth compound could be derived from powder X-ray diffraction data comparisons. An exchange of the Cl−anion by Br−does not influence the crystal packing of the racemic thiazinium salt but increases its moisture dependent stability. In contrast, replacing the imidazole moiety of the cation by a triazole or tetrazole moiety results in distinct packing arrangements of the investigated bromide salts, although,substitution calculations suggest that isostructural packing arrangements might exist. The binary melting point phase diagram was constructed to confirm the nature of the racemic species of the thiazinium chloride, and differential scanning calorimetry and lattice energy minimisations were used to estimate the enthalpy difference between the racemic and enantiopure crystals, rationalising the high tendency of racemisation of the enantiopure compound.

Circularity of cellulose-based pre- and post-consumer wastes requires an integrated approach which has to consider the characteristics of the fibre polymer and the presence of dyes and additives from textile chemical processing as well. Fibre-to-fibre recycling is a condition to avoid downcycling of recycled material. For cellulose fibres regeneration via production of regenerated cellulose fibres is the most promising approach. Textile wastes contain dyes and additives, thus a recycling technique has to be robust enough to process such material. In an ideal case the reuse of colorants can be achieved as well. At present nearly 80% of the regenerated cellulose fibre production utilises the viscose process, therefore this technique was chosen to investigate the recycling of dyed material including the reuse of the colorant. In this work, for the first time, a compilation of all required process steps to a complete circular concept is presented and discussed as a model. Indigo-dyed viscose fibres were used as a model to study cellulose recycling via production of regenerated cellulose fibres to avoid downcycling. Indigo was found compatible to the alkalisation and xanthogenation steps in the viscose process and blue coloured cellulose regenerates were recovered from indigo-dyed cellulose. A supplemental addition of reduced indigo to the cellulose solution was also found feasible to adjust colour depth in the regenerated cellulose to the level required for use as warp material in denim production. By combination of fibre recycling and indigo dyeing the conventional yarn dyeing in denim production can be omitted. Model calculations for the savings in water and chemical consumption demonstrate the potential of the process. The proportion of the substitution will depend on the collection rate of denim wastes and on the efficiency of the fibre regeneration process. Estimates indicate that a substitution of more than 70% of the cotton fibres by regenerated cellulose fibres could be achieved when 80% of the pre- and post-consumer denim wastes are collected. Therefore, the introduction of fibre recycling via regenerated cellulose fibres will also make a substantial impact on the cotton consumption for jeans production.

A method for structure solution in thin films that combines grazing incidence X-ray diffraction data analysis and crystal structure prediction was presented in a recent work (Braun et al. Cryst. Growth Des.2019, DOI: 10.1021/acs.cgd.9b00857). Applied to phenytoin form II, which is only detected in films, the approach gave a very reasonable, but not fully confirmed, candidate structure with Z = 4 and Z′ = 2. In the present work, we demonstrate how, by calculating and measuring the crystal Raman spectrum in the low wavenumber energy region with the aim of validating the candidate structure, this can be further refined. In fact, we find it to correspond to a saddle point of the energy landscape of the system, from which a minimum of lower symmetry may be reached. With the new structure, with Z = 4 and Z′ = 2, we finally obtain an excellent agreement between experimental and calculated Raman spectra., Experimental low wavenumber Raman spectroscopy validates the presence of a non-centrosymmetric packing arrangement that is energetically very close to a centrosymmetric saddle point structure.

Elucidating the structure relationships and transformation pathways of the solid forms of gandotinib was an enormous challenge. Only seven of the eleven experimentally observed forms crystallized directly from solution: a neat form (I), a tetrahydrate (Hy4), a 3.0–3.7-hydrate (HyY), and four solvates (methanol, n-propanol, n-butanol, and N-methyl-2-pyrrolidone). The four remaining forms (II, Hy2.2, Hy1.3, and HyX) were produced by dehydration and/or rehydration processes. Interconversion of the anhydrates and hydrates of gandotinib with small changes in the relative humidity complicated identifying and characterizing the crystalline forms to such an extent that some experiments conducted in the humidity of summer could not be reproduced in the winter, and vice versa. Thus, with solid-state transformations being the only route to four of the solid forms, elucidating the crystal structural relationships underpinning the dehydration–rehydration pathways as a function of temperature and humidity required not ...

Dapsone (DDS) shows a rich solid form landscape, comprising five anhydrates, one hydrate and 15 solvates. The four isostructural DDS hemisolvates, with dichloromethane, acetonitrile, nitromethane and dimethyl sulfoxide as guest molecules, obtained by cooling crystallisation, slurry or solvent vapour diffusion experiments were investigated in this study. Experimental (thermal analysis and X-ray diffraction) and computational studies (lattice, intermolecular and stability energy calculations) were undertaken to rationalise and understand (hemi)solvate formation, stability and phase transitions occurring during the desolvation of the solvates. It was found that DDS⋯solvent interactions and the shape/size of the solvent molecules are critical for solvate formation. Careful control of the experimental crystallisation and storage conditions were required for identifying and characterising solvates that are unstable at ambient conditions. The solvent molecules of the hemisolvates are located at isolated-sites and form strong hydrogen bonds and/or interactions involving dispersion forces. The isostructurality of the four hemisolvates was confirmed by single crystal X-ray diffraction determinations and modelling, i.e. solvent exchange calculations. Furthermore, the formation of either the hemi- or monosolvate stoichiometry was rationalised on the basis of lattice energy calculations.

3-(3-Methylimidazolium-1-yl)propanoate (OOCEMIM), the related zwitterion of the parent ionic liquid [HOOCEMIM] [Cl], crystallises in two hydrated and one neat (AH) solid-state forms. All three forms can be produced directly in solution crystallisation experiments and their single crystal structures as well as the temperature- and moisture dependent interconversion pathways between the forms were unravelled. The OOCEMIM molecule adopts an elongated high energy conformation in both the mono- (Hy1) and dihydrates (Hy2), with water⋯OOCEMIM interactions contributing significantly to the lattice energy. A substantial conformational rearrangement of OOCEMIM is observed upon dehydration, resulting in a bent low energy conformation in the anhydrous form. Each of the three OOCEMIM solid-state forms shows a limited existence range. The anhydrous form AH can only be preserved at very dry atmospheric conditions (at 25 °C). The exposure of AH to elevated water vapour conditions results in a fast transformation to Hy1, which then transforms to Hy2 at relative humidities (RH) above 18%. Increasing the RH above 40% leads to deliquescence of the zwitterion. Hy1 and Hy2 melt at 90 °C and 61 °C (peritectic dissociation temperature), respectively, whereas AH melts and decomposes at 172 °C. The measured transformation enthalpies between the three solid-state forms, derived from differential scanning and isothermal calorimetry experiments, are in excellent agreement with the 0 K PBE-TS and PBE-D2 lattice energy differences. Knowledge about the interconversion pathways and stability ranges of the OOCEMIM solid-state forms is essential for handling the compound.

The reversible solid-state phase transformation between the neat forms II and III of dapsone (DDS) was studied using thermal analytical methods, variable temperature X-ray diffraction and solid-state modeling at the electronic level. The first order III ↔ II phase transformation occurs at 78 ± 4 °C with a heat of transition of 2 kJ mol–1 and a small hysteresis. The two isosymmetric polymorphs (both P212121) differ only in movement of layers of molecules and show a small variation in conformation. The combination of variable-temperature single-crystal structure determinations and pair-wise intermolecular energy calculations allowed us to unravel the single-to-single crystal transformation at a molecular level, to estimate the molecular contributions to the heat of transformation and to rationalize why the room and low temperature form III is the less dense polymorphic form, which is a rare phenomenon in enantiotropically related pairs of polymorphs in molecular crystals.

The solid forms emerging from an experimental screening programme of 1,10-phenanthroline (o-phen), a heavily used bidentate ligand, and interconversion pathways of its two neat forms, the monohdyrate (Hy1) and four solvates with acetone, chloroform, dichloromethane and 1,2-dichloroethane are described. The solvates, identified and characterised with thermoanalyical methods, are unstable when removed from the mother liquor and desolvate at room temperature depending on the relative humidity (RH) to anhydrate I° (AH I°) or transform to Hy1. At ambient conditions Hy1, a stoichiometric channel hydrate, is the thermodynaically most stable o-phen solid form. The enthalpically stabilised Hy1 melts at 102 °C or dehydrates to AH I° at RH < 10% at 25 °C. The potential energy difference between Hy1 and AH I° was calculated to be approx. 15 kJ mol–1. The second anhydrate polymorph (AH II) can be obatined from the quench cooled melt of o-phen, but is unstable at ambient conditions and transforms wihtin minutes to either AH I° or Hy1. The two neat polymorphs are enantiotropically related and water-free o-phen transforms to Hy1 at RH > 16%. The structural and stablity features of the solid forms, in paricular Hy1, are unravelled by a combination of experimental (thermal analysis, moisture sorption/desorption and storage experiments, infrared spectroscopy and powder X-ray diffraction) and computational modelling (crystal structure prediction and lattice energy calculations), providing a consistent picture why o-phen forms a very stable Z’ = 3 channel hydrate.

A computational search for polymorphs of cytosine, 5-flucytosine and a 1 : 1 mixture of the two substances not only rationalised the preferred packing arrangements but also enabled the finding and characterisation of cytosine/5-flucytosine solid solutions. The structures of the new solid forms were determined by combining laboratory powder X-ray diffraction data and computational modelling.

New polymorphs of thymine emerged in an experimental search for solid forms, which was guided by the computationally generated crystal energy landscape. Three of the four anhydrates (AH) are homeoenergetic (A° – C) and their packing modes differ only in the location of oxygen and hydrogen atoms. AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Anhydrates AHs A° and B are ordered phases, whereas AH C shows disorder (X-ray diffuse scattering). Analysis of the crystal energy landscape for alternative AH C hydrogen bonded ribbon motifs identified a number of different packing modes, whose 3D structures were calculated to deviate by less than 0.24 kJ mol–1 in lattice energy. These structures provide models for stacking faults. The three anhydrates A° – C show strong similarity in their powder X-ray diffraction, thermoanalytical and spectroscopic (IR and Raman) characteristics. The already known anhydrate AH A° was identified as the thermodynamically most stable form at ambient conditions; AH B and AH C are metastable but show high kinetic stability. The hydrate of thymine is stable only at water activities (aw) > 0.95 at temperatures ≤ 25 °C. It was found to be a stoichiometric hydrate despite being a channel hydrate with an unusual water:thymine ratio of 0.8:1. Depending on the dehydration conditions, either AH C or AH D is obtained. The hydrate is the only known precursor to AH D. This study highlights the value and complementarity of simultaneous explorations of computationally and experimentally generated solid form landscapes of a small molecule anhydrate ↔ hydrate system.

Crystal structure prediction studies indicated the existence of an unknown high density monohydrate structure (Hy1B°) as the global energy minimum for 4-aminoquinaldine (4-AQ). We thus performed an interdisciplinary experimental and computational study elucidating the crystal structures, solid form inter-relationships, and kinetic and thermodynamic stabilities of the stable anhydrate (AH I°), the kinetic monohydrate (Hy1A) and this novel monohydrate polymorph (Hy1B°) of 4-AQ. The crystal structure of Hy1B° was determined by combining laboratory powder X-ray diffraction data and ab initio calculations. Dehydration studies with differential scanning calorimetry and solubility measurements confirmed the result of the lattice energy calculations, which identified Hy1B° as the thermodynamically most stable hydrate form. At 25 °C the equilibrium of the 4-AQ hydrate/anhydrate system was observed at an aw (water activity) of 0.14. The finding of Hy1B° was complicated by the fact that the metastable but kinetically stable Hy1A shows a higher nucleation and growth rate. The presence of an impurity in an available 4-AQ sample facilitated the nucleation of Hy1B°, whose crystallisation is favored under hydrothermal conditions. The value of combining experimental with theoretical studies in hydrate screening and characterisation, as well as the reasons for hydrate formation in 4-AQ, are discussed.

The observed moisture- and temperature dependent transformations of the dapsone (4,4′-diaminodiphenyl sulfone, DDS) 0. 33-hydrate were correlated to its structure and the number and strength of the water-DDS intermolecular interactions. A combination of characterization techniques was used, including thermal analysis (hot-stage microscopy, differential scanning calorimetry and thermogravimetric analysis), gravimetric moisture sorption/desorption studies and variable humidity powder X-ray diffraction, along with computational modeling (crystal structure prediction and pair-wise intermolecular energy calculations). Depending on the relative humidity the hydrate contains between 0 and 0.33 molecules of water per molecule DDS. The crystal structure is retained upon dehydration indicating that DDS hydrate shows a non-stoichiometric (de)hydration behavior. Unexpectedly, the water molecules are not located in structural channels but at isolated-sites of the host framework, which is counterintuitively for a hydrate with non-stoichiometric behavior. The water-DDS interactions were estimated to be weaker than water-host interactions that are commonly observed in stoichiometric hydrates and the lattice energies of the isomorphic dehydration product (hydrate structure without water molecules) and (form III) differ only by ~1 kJ mol−1. The computational generation of hypothetical monohydrates confirms that the hydrate with the unusual DDS:water ratio of 3:1 is more stable than a feasible monohydrate structure. Overall, this study highlights that a deeper understanding of the formation of hydrates with non-stoichiometric behavior requires a multidisciplinary approach including suitable experimental and computational methods providing a firm basis for the development and manufacturing of high quality drug products.

The preparation of six new 5,5′-azotetrazolates with organic cations is reported. Differential scanning calorimetry of all compounds showed exothermic decompositions. The crystal structures of the six 5,5′-azotetrazolates were determined by single-crystal X-ray diffraction analyses. The phase purities of the bulk samples were confirmed by Pawley fits of the experimental and calculated powder X-ray diffraction patterns.

Computational methods were used to generate and explore the crystal structure landscapes of the two alkaloids strychnine and brucine. The computed structures were analyzed and rationalized by correlating the modelling results to a rich pool of available experimental data. Despite their structural similarity, the two compounds show marked differences in the formation of solid forms. For strychnine only one anhydrous form is reported in the literature and two new solvates from 1,4-dioxane were detected in the course of this work. In contrast, 22 solid forms are so far known to exist for brucine, comprising two anhydrates, four hydrates (HyA – HyC and a 5.25-hydrate), twelve solvates (alcohols and acetone) and four heterosolvates (mixed solvates with water and alcohols). For strychnine it is hard to produce any solid form other than the stable anhydrate while the formation of specific solid state forms of brucine is governed by a complex interplay between temperature and relative humidity/water activity and it is rather a challenging to avoid hydrate formation. Differences in crystal packing and the high tendency for brucine to form hydrates are not intuitive from the molecular structure alone, as both molecules have hydrogen bond acceptor groups but lack hydrogen bond donor groups. Only the evaluation of the crystal energy landscapes, in particular the close-packed crystal structures and high-energy open frameworks containing voids of molecular (water) dimensions, allowed us to unravel the diverse solid state behavior of the two alkaloids at a molecular level. In this study we demonstrate that expanding the analysis of anhydrate crystal energy landscapes to higher energy structures and calculating the solvent-accessible volume can be used to estimate non-stoichiometric or channel hydrate (solvate) formation, without explicitly computing the hydrate/solvate crystal energy landscapes.

The complex interplay of temperature and water activity (aw)/relative humidity (RH) on the solid form stability and transformation pathways of three hydrates (HyA, HyB, and HyC), an isostructural dehydrate (HyAdehy), an anhydrate (AH), and amorphous brucine has been elucidated and the transformation enthalpies quantified. The dihydrate (HyA) shows a nonstoichiometric (de)hydration behavior at RH < 40% at 25 °C, and the removal of the water molecules results in an isomorphic dehydrate structure. The metastable dehydration product converts to AH upon storage at the driest conditions or to HyA if exposed to moisture. HyB is a stoichiometric tetrahydrate. The loss of the water molecules causes HyB to collapse to an amorphous phase. Amorphous brucine transforms to AH at RH < 40% RH and a mixture of hydrated phases at higher RH values. The third hydrate (HyC) is only stable at RH ≥ 55% at 25 °C and contains 3.65–3.85 mol equiv of water. Dehydration of HyC occurs in one step at RH < 55% at 25 °C or upon heating, and AH is obtained. The AH is the thermodynamically most stable phase of brucine at RH < 40% at 25 °C. Depending on the conditions, temperature, and aw, each of the three hydrates becomes the thermodynamically most stable form. This study demonstrates the importance of applying complementary analytical techniques and appropriate approaches for understanding the stability ranges and transition behavior between the solid forms of compounds with multiple hydrates., Complementary analytical techniques were applied to unravel the complex interplay of temperature and water activity/relative humidity on the solid form stability and transformation pathways of practically relevant forms of brucine. Depending on the environmental conditions, three hydrates (stoichiometric and nonstoichiometric) or anhydrous brucine may become the thermodynamically most stable form. The transformation enthalpies between the solid forms were determined.

The structural, temperature- and moisture dependent stability features of cytosine and 5-flucytosine monohydrates, two pharmaceutically important compounds, were rationalized using complementary experimental and computational approaches. Moisture sorption/desorption, water activity, thermal analysis and calorimetry were applied to determine the stability ranges of hydrate ↔ anhydrate systems, while X-ray diffraction, IR spectroscopy and crystal structure prediction provided the molecular level understanding. At 25 °C, the critical water activity for the cytosine hydrate ↔ anhydrate system is ~0.43 and for 5-flucytosine ~0.41. In 5-flucytosine the water molecules are arranged in open channels, therefore the kinetic desorption data, dehydration < 40% relative humidity (RH), conform with the thermodynamic data, whereas for the cytosine isolated site hydrate dehydration was observed at RH < 15%. Peritectic dissociation temperatures of the hydrates were measured to be 97 °C and 84.2 °C for cytosine and 5-flucytosine, respectively, and the monohydrate to anhydrate transition enthalpies to be around 10 kJ mol–1. Computed crystal energy landscapes not only revealed that the substitution of C5 (H or F) controls the packing and properties of cytosine/5-flucytosine solid forms, but also have enabled the finding of a monohydrate solid solution of the two substances which shows increased thermal- and moisture-dependent stability compared to 5-flucytosine monohydrate.

Hydrate and anhydrate crystal structure prediction (CSP) of creatine (CTN), a heavily used, poorly water-soluble, zwitterionic compound, has enabled the finding and characterization of its anhydrate polymorphs, including the thermodynamic room temperature form. Crystal structures of the novel forms were determined by combining laboratory powder X-ray diffraction data and ab initio generated structures. The computational method not only revealed all experimental forms but also predicted the correct stability order, which was experimentally confirmed by measurements of the heat of hydration., A computationally driven experimental search for anhydrate and hydrate solid forms of creatine enabled the finding and characterization (structure and stability) of its three polymorphs and the monohydrate. The computational method not only found the experimental forms but also correctly predicted the stability order, which was experimentally confirmed by measurements of the heat of hydration.

Polymorphs of 4-aminoquinaldine (4-AQ) have been predicted in silico and experimentally identified and characterised. The two metastable forms, AH (anhydrate) II and AH III, crystallise in the trigonal space group [Formula: see text] and are less densely packed than the thermodynamically most stable phase AH I° (P21/c ). AH II can crystallise and exist both, as a solvent inclusion compound and as an unsolvated phase. The third polymorph, AH III, is exclusively obtained by desolvation of a carbon tetrachloride solvate. Theoretical calculations correctly estimated the experimental 0K stability order, confirmed that AH II can exist without solvents, gave access to the AH III structure, and identified that there exists a subtle balance between close packing and number of hydrogen bonding interactions in the solid state of anhydrous 4-AQ. Furthermore, the prevalence of void space and solvent inclusion in [Formula: see text] structures is discussed.

Following the computational prediction that (RS)-naproxen would be more stable than the therapeutically used and more studied homochiral (S)-naproxen, we performed an interdisciplinary study contrasting the two compounds. The crystal structure of the racemic compound was solved from powder X-ray diffraction data (Pbca) and showed no packing similarity with the homochiral structure (P21). The binary melting point phase diagram was constructed to confirm the nature of the racemic species, and differential scanning calorimetric and solubility measurements were used to estimate the enthalpy difference between the crystals (ΔHR+S→RScry) to be −1.5 ± 0.3 kJ·mol–1 at T ∼ 156 °C and −2.4 ± 1.0 kJ·mol–1 in the range 10–40 °C. A comparison of the different approximations involved in estimating ΔHR+S→RScry implied that the difference in the lattice energies overestimated the stability of the (RS) crystal. The naproxen lattice energy landscape confirmed that all the practically important crystal structures have been ...

A combined experimental and computational study was undertaken to establish the solid-state forms of β-resorcylic acid (2,4-dihydroxybenzoic acid). The experimental search resulted in nine crystalline forms: two concomitantly crystallizing polymorphs, five novel solvates (with acetic acid, dimethyl sulfoxide, 1,4-dioxane, and two with N,N-dimethyl formamide), in addition to the known hemihydrate and a new monohydrate. Form II°, the thermodynamically stable polymorph at room temperature, was found to be the dominant crystallization product. A new, enantiotropically related polymorph (form I) was obtained by desolvation of certain solvates, sublimation experiments, and via a thermally induced solid−solid transformation of form II° above 150 °C. To establish their structural features, interconversions, and relative stability, all solid-state forms were characterized with thermal, spectroscopic, X-ray crystallographic methods, and moisture-sorption analysis. The hemihydrate is very stable, while the five solvates and the monohydrate are rather unstable phases that occur as crystallization intermediates. Complementary computational work confirmed that the two experimentally observed β-resorcylic acid forms I and II° are the most probable polymorphs and supported the experimental evidence for form I being disordered in the p-OH proton position. These consistent outcomes suggest that the most practically important features of β-resorcylic acid crystallization under ambient conditions have been established; however, it appears impractical to guarantee that no additional metastable solid-state form could be found., An extensive experimental screen, coupled with a computational study, revealed seven new solid-state forms of β-resorcylic acid. The known, stable polymorph II° shows a reversible phase transformation to the new, kinetically stable, probably disordered high temperature form I. The study provides a consistent picture of the solid-state of β-resorcylic acid.

Three polymorphs of the calcimimetic cinacalcet hydrochloride were characterized by a variety of methods including thermal analysis (hot-stage microscopy and differential scanning calorimetry), vibrational spectroscopy (FT-IR and FT-Raman spectroscopy), and X-ray diffractometry (powder and single crystal). The crystal structures of all polymorphs have been determined either from single crystals (form III°) or from powder data (forms I and II). Forms III° and I both exhibit an orthorhombic cell with space group P212121, whereas form II crystallizes in the triclinic space group P1. All three polymorphs show basically the same hydrogen-bond synthon, and the structural differences are associated with conformational changes. In contrast to form III°, form II shows two conformationally different molecules, and in the high temperature form I the phenyl moiety is dynamically disordered. Among the three enantiotropically related polymorphs, form III° (Tfus: 165 °C) is the thermodynamically stable modification belo...

An intriguing example of conformational and color polymorphism is observed in p-tolyl-(2,4,6-trinitrophenyl)-amine (picryltoluidine, PT), which forms two crystalline modifications, the red form I R and the orange form II O . Solvated crystals with a PT/solvate ratio of 1:1 (pyridine) or 2:1 (benzene, chlorobenzene, toluene, or xylene) were obtained only from aromatic solvents, albeit with some difficulty, from aromatic solvents. The crystallization from all other tested solvents produced either a highly pure phase or a mixture of the two anhydrous forms. Single crystal structure determinations were carried out on the seven solid forms, along with a characterization by thermal analysis (hot stage microscopy, DSC, TGA), vibrational spectroscopy (IR, Raman) and X-ray powder diffraction. The PT molecules in all structures exhibit intramolecular N−H···O bonds. The different colors are attributed to intramolecular electronic effects due to an increased delocalization of the secondary amino nitrogen lone-pair el...

A study of two dihydroxybenzoic acid isomers shows that computational methods can be used to predict hydrate formation, the compound : water ratio and hydrate crystal structures. The calculations also help identify a novel hydrate found in the solid form screening that validates this study.

Attempts to co-crystallise 3-arylbutanoic acid derivatives with isonicotinamide have led to co-crystals and novel polymorphs of the isonicotinamide co-former appearing under similar crystallisation conditions.

The ability of the pharmaceutically acceptable cocrystallising agents, succinic acid and 4-aminobenzoic acid, to form cocrystals with ten small organic molecules with hydrogen bonding acceptors but no donors, was investigated by grinding, hot-stage microscopy and solution based crystallisation experiments. The reproducible results obtained by different methods showed that only six cocrystals formed. The crystal structures of the four novel cocrystals, succinic acid·2,2′-bipyridine (1 : 1, P21/c, I), succinic acid·diphenylcyclopropenone (1 : 2, P21/c, II), 4-aminobenzoic acid·antipyrine (1 : 1, P21, III) and 4-aminobenzoic acid·phenazine (1 : 2, P, IV), are reported. The computed crystal energy landscapes of the cocrystals and their components show why succinic acid·1,4-dicyanobenzene did not form a cocrystal as well as predicting the observed structure of succinic acid·2,2′-bipyridine as the most stable. The most stable hypothetical structures of a 1 : 1 succinic acid·1,4-dicyanobenzene cocrystal are closely related to those of the components. The results demonstrate that cocrystal formation requires both hydrogen bonding and close packing, and so markedly non-planar pharmaceuticals will be quite specific in the steric and hydrogen bonding disposition requirement of coformers.

The study describes the solid state behaviour, and the thermal and structural features of four monosolvates of cinacalcet hydrochloride with acetic acid, chloroform, 1,4-dioxane, and tetrachloromethane, and summarises the transformation and production pathways of the seven crystal forms of this promising drug compound (calcimimetic). The solvates were identified and characterised by hot-stage microscopy, differential scanning calorimetry, thermogravimetric analysis, FT-infrared and Raman spectroscopy, powder diffractometry, and the structure of the acetic acid solvate was determined by single crystal X-ray diffraction. All solvates are unstable when removed from the mother liquor and desolvate to form II. To our knowledge, phase pure samples of this metastable but kinetically stable form are only obtainable via desolvation of one of the solvates.Thermoanalytical data and a conformation and packing analysis of the acetic acid solvate and the polymorphs indicate that the desolvation is a destructive process forming an isotropic intermediate state with high molecular mobility. Therefore the desolvation process results in the kinetic form II, which is structurally less similar to the solvate than the thermodynamically stable form III°. The study demonstrates that in spite of strong structural similarities between a solvate and a polymorph we can obtain a polymorph with less structural resemblance to the solvent adduct if the structure collapses during the desolvation process.

This work highlights the structural and thermochemical differences of two modifications of the NK1receptor antagonist aprepitant. Form I° is the stable polymorph and crystallises in the orthorhombic space groupP212121 whereas the metastable form II is monoclinic (space groupP21). The monotropically related polymorphs show only minor differences in melting point and heat of fusion (Tfus,I = 253.6, ΔfusHI = 53.7 kJ mol−1, Tfus,II = 253.0 °C, ΔfusHII = 52.4 kJ mol−1) and often crystallise concomitantly. The forms exhibit a very close structural relationship based on a common 2D packing fragment, which is in fact a stack of 1D N–H⋯O hydrogen bonded ribbon chains. Forms I° and II may therefore be interpreted as two distinct stacking modes of this common 2D unit. The alternative modes are associated with slight differences in weaker intermolecular interactions. Somewhat surprisingly, the aprepitant molecule adopts almost the same conformation in the two crystal structures in spite of its potential conformational flexibility. Hirshfeld surface analysis was successfully deployed to visualise and elaborate the small differences in the molecular environments of the two polymorphs. The study emphasises the benefit of single-crystal structure data for the judgement of the phase purity and of polymorphs exhibiting only weak energetical and structural differences.

Background In solid state structures of organic molecules, identical sets of H-bond donor and acceptor functions can result in a range of distinct H-bond connectivity modes. Specifically, competing H-bond structures (HBSs) may differ in the quantitative proportion between one-point and multiple-point H-bond connections. For an assessment of such HBSs, the effects of their internal as well as external (packing) interactions need to be taken into consideration. The semi-classical density sums (SCDS-PIXEL) method, which enables the calculation of interaction energies for molecule–molecule pairs, was used to investigate six polymorphs of phenobarbital (Pbtl) with different quantitative proportions of one-point and two-point H-bond connections. Results The structures of polymorphs V and VI of Pbtl were determined from single crystal data. Two-point H-bond connections are inherently inflexible in their geometry and lie within a small PIXEL energy range (−45.7 to −49.7 kJ mol−1). One-point H-bond connections are geometrically less restricted and subsequently show large variations in their dispersion terms and total energies (−23.1 to −40.5 kJ mol−1). The comparison of sums of interaction energies in small clusters containing only the strongest intermolecular interactions showed an advantage for compact HBSs with multiple-point connections, whereas alternative HBSs based on one-point connections may enable more favourable overall packing interactions (i.e. V vs. III). Energy penalties associated with experimental intramolecular geometries relative to the global conformational energy minimum were calculated and used to correct total PIXEL energies. The estimated order of stabilities (based on PIXEL energies) is III > I > II > VI > X > V, with a difference of just 1.7 kJ mol−1 between the three most stable forms. Conclusions For an analysis of competing HBSs, one has to consider the contributions from internal H-bond and non-H-bond interactions, from the packing of multiple HBS instances and intramolecular energy penalties. A compact HBS based on multiple-point H-bond connections should typically lead to more packing alternatives and ultimately to a larger number of viable low-energy structures than a competing one-point HBS (i.e. dimer vs. catemer). Coulombic interaction energies associated with typical short intermolecular C–H···O contact geometries are small in comparison with dispersion effects associated with the packing complementary molecular shapes.Graphical abstractCompeting H-bond motifs can differ markedly in their energy contributions Electronic supplementary material The online version of this article (doi:10.1186/s13065-016-0152-5) contains supplementary material, which is available to authorized users.

A comprehensive characterization (thermal, spectroscopic, crystallographic, temperature- and moisture-dependent stability, and transition characteristics) of solvates of aripiprazole (APZ) with methanol (1:1), ethanol (2:1), dichloroethane (2:1), and a monohydrate is presented. To gain insight into packing similarities and differences, the four hydrate/solvate crystal structures and five APZ modifications were compared using the program XPac. It was found that all forms apart from the hydrate are based on either a common dimeric or catemeric motif of H-bonded APZ molecules, and this analysis confirmed also the isostructurality of the three solvates and pointed to possible mechanisms for the desolvation of the solvates and the transformation between forms X° and I. The fact that the intermolecular interactions in the monohydrate are completely different from those found in the isostructural solvates was further confirmed by analyzing the Hirshfeld fingerprint plots. The desolvation of all solvated forms re...