Stoichiometric and Nonstoichiometric Hydrates of Brucine

The complex interplay of temperature and water activity (<i>a</i>_w)/relative humidity (RH) on the solid form stability and transformation pathways of three hydrates (<b>HyA</b>, <b>HyB</b>, and <b>HyC</b>), an isostructural dehydrate (<b>HyA</b>_<b>dehy</b>), an anhydrate (<b>AH</b>), and amorphous brucine has been elucidated and the transformation enthalpies quantified. The dihydrate (<b>HyA</b>) 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 <b>AH</b> upon storage at the driest conditions or to <b>HyA</b> if exposed to moisture. <b>HyB</b> is a stoichiometric tetrahydrate. The loss of the water molecules causes <b>HyB</b> to collapse to an amorphous phase. Amorphous brucine transforms to <b>AH</b> at RH < 40% RH and a mixture of hydrated phases at higher RH values. The third hydrate (<b>HyC</b>) is only stable at RH ≥ 55% at 25 °C and contains 3.65–3.85 mol equiv of water. Dehydration of <b>HyC</b> occurs in one step at RH < 55% at 25 °C or upon heating, and <b>AH</b> is obtained. The <b>AH</b> is the thermodynamically most stable phase of brucine at RH < 40% at 25 °C. Depending on the conditions, temperature, and <i>a</i>_w, 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

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<p>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.</p

Why Do Hydrates (Solvates) Form in Small Neutral Organic Molecules? Exploring the Crystal Form Landscapes of the Alkaloids Brucine and Strychnine

Computational methods were used to generate and explore the crystal structure landscapes of the 2 alkaloids strychnine and brucine. The computed structures were analyzed and rationalized by correlating the modeling results to a rich pool of available experimental data. Despite their structural similarity, the 2 compounds show marked differences in the formation of solid forms. For strychnine, only 1 anhydrous form is reported in the literature and 2 new solvates from 1,4-dioxane were detected in the course of this work. In contrast, 22 solid forms are known so far to exist for brucine, comprising 2 anhydrates, 4 hydrates (<b>HyA</b> – <b>HyC</b> and a 5.25-hydrate), 12 solvates (alcohols and acetone), and 4 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 challenge 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 2 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

Dapsone Form V: A Late Appearing Thermodynamic Polymorph of a Pharmaceutical

Five anhydrate polymorphs (forms I–V) and the isomorphic dehydrate (Hydehy) of dapsone (4,4′-diaminodiphenyl sulfone or DDS) were prepared and characterized in an interdisciplinary experimental and computational study, elucidating the kinetic and thermodynamic stabilities, solid form interrelationships, and structural features of the known forms I–IV, the novel polymorph form V, and Hydehy. Calorimetric measurements, solubility experiments, and lattice energy calculations revealed that form V is the thermodynamically stable polymorph from absolute zero to at least 90 °C. At higher temperatures, form II, and then form I, becomes the most stable DDS solid form. The computed 0 K stability order (lattice energy calculations) was confirmed with calorimetric measurements as follows, V (most stable) > III > Hydehy > II > I > IV (least stable). The discovery of form V was complicated by the fact that the metastable but kinetically stabilized form III shows a higher nucleation and growth rate. By combining laboratory powder X-ray diffraction data and ab initio calculations, the crystal structure of form V (P21/c, Z′ = 4) was solved, with a high energy DDS conformation allowing a denser packing and more stable intermolecular interactions, rationalizing the formation of a high Z′ structure. The structures of the forms I and IV, only observed from the melt and showing distinct packing features compared to the forms II, III, and V, were derived from the computed crystal energy landscapes. Dehydration modeling of the DDS hydrate led to the Hydehy structure. This study expands our understanding about the complex crystallization behavior of pharmaceuticals and highlights the big challenge in solid form screening, especially that there is no clear end point

Exploring the Supramolecular Interactions and Thermal Stability of Dapsone:Bipyridine Cocrystals by Combining Computational Chemistry with Experimentation

The application of computational screening methodologies based on H-bond propensity scores, molecular complementarity, molecular electrostatic potentials, and crystal structure prediction has guided the discovery of novel cocrystals of dapsone and bipyridine (DDS:BIPY). The experimental screen, which included mechanochemical and slurry experiments as well as the contact preparation, resulted in four cocrystals, including the previously known DDS:4,4′-BIPY (2:1, CC44-B) cocrystal. To understand the factors governing the formation of the DDS:2,2′-BIPY polymorphs (1:1, CC22-A and CC22-B) and the two DDS:4,4′-BIPY cocrystal stoichiometries (1:1 and 2:1), different experimental conditions (such as the influence of solvent, grinding/stirring time, etc.) were tested and compared with the virtual screening results. The computationally generated (1:1) crystal energy landscapes had the experimental cocrystals as the lowest energy structures, although distinct cocrystal packings were observed for the similar coformers. H-bonding scores and molecular electrostatic potential maps correctly indicated cocrystallization of DDS and the BIPY isomers, with a higher likelihood for 4,4′-BIPY. The molecular conformation influenced the molecular complementarity results, predicting no cocrystallization for 2,2′-BIPY with DDS. The crystal structures of CC22-A and CC44-A were solved from powder X-ray diffraction data. All four cocrystals were fully characterized by a range of analytical techniques, including powder X-ray diffraction, infrared spectroscopy, hot-stage microscopy, thermogravimetric analysis, and differential scanning calorimetry. The two DDS:2,2′-BIPY polymorphs are enantiotropically related, with form B being the stable polymorph at room temperature (RT) and form A being the higher temperature form. Form B is metastable but kinetically stable at RT. The two DDS:4,4′-BIPY cocrystals are stable at room conditions; however, at higher temperatures, CC44-A transforms to CC44-B. The cocrystal formation enthalpy order, derived from the lattice energies, was calculated as follows: CC44-B > CC44-A > CC22-A

Comprehensive Insights into Sulfaguanidine in the Solid State: An Experimental and Computational Study

A thorough re-examination of sulfaguanidine’s (SGD) solid-state behavior was conducted, 65 years after the initial report on SGD polymorphism. This investigation focuses on the polymorphic nature of the compound, the formation of hydrates and solvates, and the pivotal role of experimental and computational methods in screening, assessing stability, and understanding transformation processes. The findings confirm the presence of five anhydrates (AH-I–V), two monohydrate polymorphs (Hy1-I and Hy1-II), and nine solvates (with tetrahydrofuran, methanol, ethanol, t-butanol, acetone, cyclohexanone, dimethyl sulfoxide, dimethyl formamide, and dimethyl acetamide). Notably, nine novel structures–two anhydrates and seven solvates–are reported, solved from powder X-ray diffraction data. Calorimetric measurements have revealed that AH-II is the thermodynamically stable polymorph at room and low temperatures. In contrast, AH-I emerges as the stable polymorph at higher temperatures, yet it exhibits remarkable kinetic stability at RT and demonstrates greater stability in terms of hydration. The anhydrate forms exhibit distinctive packing arrangements, while the two hydrates share a close structural resemblance. Among the seven structurally characterized solvates, only the tetrahydrofuran and dimethyl sulfoxide solvates are isostructural. Controlled desolvation experiments enabled the formation of AH-I, AH-II, and, notably, AH-V for the first time. The anhydrate and monohydrate crystal structure prediction studies reveal that the computed lowest-energy structures correspond to experimentally observed forms and propose models for the elusive AH-IV structure. Overall, the exploration of SGD’s solid-state landscape confirms a rich array of highly stable H-bonding motifs and packing arrangements, positioning this study as an ideal model for complex solid-state systems and shedding light on its intricate solid-state nature

Creatine: Polymorphs Predicted and Found

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

Creatine: Polymorphs Predicted and Found

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

Flavone Cocrystals: A Comprehensive Approach Integrating Experimental and Virtual Methods

The dapsone/flavone cocrystal system served as a benchmark for both experimental and virtual screening methods. Expanding beyond this, two additional active pharmaceutical ingredients (APIs), sulfanilamide and sulfaguanidine, structurally related to dapsone were chosen to investigate the impact of substituents on cocrystal formation. The experimental screening involved mechanochemical methods, slurry experiments, hot-melt extrusion, and the contact preparation method. The virtual screening focused on crystal structure prediction (CSP), molecular complementarity, hydrogen-bond propensity, and molecular electrostatic potentials. The CSP studies not only indicated that each of the three APIs should form cocrystals with flavone but also reproduced the known single- and multicomponent phases. Experimentally, dapsone/flavone cocrystals ACC, BCC, CCC, and DCC were reproduced, CCC was identified as a nonstoichiometric hydrate, and a fifth cocrystal (ECC), a t-butanol solvate, was discovered. The cocrystal polymorphs ACC and BCC are enantiotripically related, and DCC, exhibiting a different stoichiometric ratio, is enthalpically stabilized over the other cocrystals. For the sulfaguanidine/flavone system, two novel, enantiotripically related cocrystals were identified. The crystal structures of two cocrystals and a flavone polymorph were solved from powder X-ray diffraction data, and the stability of all cocrystals was assessed through differential scanning calorimetry and lattice energy calculations. Despite computational indications, a diverse array of cocrystallization techniques did not result in a sulfanilamide/flavone cocrystal. The driving force behind dapsone’s tendency to cocrystallize with flavone can be attributed to the overall strength of flavone interactions in the cocrystals. For sulfaguanidine, the potential to form strong API···API and API···coformer interactions in the cocrystal is a contributing factor. Furthermore, flavone was found to be trimorphic