Crystal Growth & Design最新文献

{"title":"A Novel Solid Form of Erlotinib: Synthesis by Heterogeneous Complexation and Characterization by NMR Crystallography.","authors":"Sean T Holmes, Ren A Wiscons, Kerrigan Parks, Sarah Nickel, Halie S Ankeny, Aaron M Viggiano, Derek Bedillion, Deben Shoup, Robbie J Iuliucci, Qiang Wang, Robert W Schurko, Rosalynn Quiñones","doi":"10.1021/acs.cgd.5c00268","DOIUrl":"https://doi.org/10.1021/acs.cgd.5c00268","url":null,"abstract":"<p><p>We describe the synthesis of a novel complex of the anticancer \"active pharmaceutical ingredient erlotinib (<b>ERL</b>) via heterogeneous nucleation on polished zinc tiles. The resulting product, <b>ERL</b> _<b>2</b> <b>·ZnCl</b> _<b>2</b> , is characterized by single-crystal X-ray diffraction, multinuclear solid-state NMR (ssNMR) spectroscopy, and density functional theory (DFT) calculations. Also characterized are the hydrochloride salt (<b>ERL·HCl</b>) and monohydrate free base (<b>ERL·H</b> _<b>2</b> <b>O</b>) forms of erlotinib. ¹³C ssNMR spectroscopy is useful for site-by-site assignment and rapid fingerprinting, while also providing preliminary structural interpretations, such as the number of molecules in the asymmetric unit. ³⁵Cl ssNMR can readily differentiate between the chloride ions in <b>ERL·HCl</b> and the covalently bonded chlorine in <b>ERL</b> _<b>2</b> <b>·ZnCl</b> _<b>2</b> . ¹⁵N ssNMR proves to be critical here because of the large isotropic chemical shift differences between <b>ERL·H</b> _<b>2</b> <b>O</b>, <b>ERL·HCl</b>, and <b>ERL</b> _<b>2</b> <b>·ZnCl</b> _<b>2</b> . The ¹⁵N chemical shift tensors are linked directly to differences in structure and bonding with the aid of DFT calculations. Together, these results demonstrate the utility of multinuclear NMR crystallography for the characterization of solid forms of APIs, especially when other analytical techniques face significant challenges.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 9","pages":"3219-3228"},"PeriodicalIF":3.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063053/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nonequilibrium Crystal Growth Model for Organic Molecules of Real API Complexity","authors":"Neha A. Padwal,&nbsp; and ,&nbsp;Michael F. Doherty*,&nbsp;","doi":"10.1021/acs.cgd.4c0129910.1021/acs.cgd.4c01299","DOIUrl":"https://doi.org/10.1021/acs.cgd.4c01299https://doi.org/10.1021/acs.cgd.4c01299","url":null,"abstract":"<p >Steps play a crucial role in growth of crystal faces. The step velocity is a critical parameter within the growth models and is a function of the density of <i>kinks</i>, which are the most favorable sites of attachment along crystal steps. In this article, we introduce a symbolic-numerical computational tool to generalize the Simplified Steady–State Framework (SSSF), introduced in our earlier articles, to nonequilibrium kink density calculations for crystals with any number of molecules in the unit cell. The tool employs a graph theoretic approach for representation of the crystal surface kinetics, which allows digital implementation of the method for molecules of API complexity. The SSSF is based on identifying a small subset of most-probable surface events which dominate the surface kinetics. Our new model replaces Boltzmann statistics for kink density modeling with a fully nonequilibrium model that captures both the surface correlations between sites (via the use of conditional probabilities) as well as their dependence on supersaturation. The digital tool demonstrates the versatility of the theory for providing key growth parameters within crystal growth models for a wide range of crystals. The tool was successfully used to predict the crystal morphology for three organic compounds with four molecules in the unit cell, one forming platelets and the other two needle-like crystals.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 9","pages":"2814–2829 2814–2829"},"PeriodicalIF":3.2,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the Coformer Carbon-Chain Length on the Properties of Haloperidol Pharmaceutical Salts.","authors":"Francisco J Acebedo-Martínez, Carolina Alarcón-Payer, Alicia Domínguez-Martín, Antonio Frontera, Cristóbal Verdugo-Escamilla, Duane Choquesillo-Lazarte","doi":"10.1021/acs.cgd.5c00251","DOIUrl":"https://doi.org/10.1021/acs.cgd.5c00251","url":null,"abstract":"<p><p>Haloperidol (HAL) is a conventional antipsychotic drug with poor aqueous solubility, which is associated with a major risk of side effects. In this context, crystal engineering has provided an efficient approach for tuning the physicochemical properties of active pharmaceutical ingredients (APIs). However, there is a huge lack of knowledge about how coformer molecules impact the pharmaceutical properties of the multicomponent materials, with special attention to solubility and stability. To this purpose, five novel salts and three ionic cocrystals were synthesized using HAL and a series of closely related dicarboxylic acid counterions. Mechanochemical strategies were applied for synthesis, while thermal, spectroscopic, and X-ray diffraction techniques were used for a complete characterization of the materials. By understanding the relationships between the crystal structures and the final properties, this research seeks to inform the rational design of HAL multicomponent drugs, providing a framework for improving the performance of not only HAL but also other APIs with similar challenges.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 9","pages":"3169-3185"},"PeriodicalIF":3.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of the Coformer Carbon-Chain Length on the Properties of Haloperidol Pharmaceutical Salts","authors":"Francisco J. Acebedo-Martínez,&nbsp;Carolina Alarcón-Payer,&nbsp;Alicia Domínguez-Martín,&nbsp;Antonio Frontera,&nbsp;Cristóbal Verdugo-Escamilla and Duane Choquesillo-Lazarte*,&nbsp;","doi":"10.1021/acs.cgd.5c0025110.1021/acs.cgd.5c00251","DOIUrl":"https://doi.org/10.1021/acs.cgd.5c00251https://doi.org/10.1021/acs.cgd.5c00251","url":null,"abstract":"<p >Haloperidol (HAL) is a conventional antipsychotic drug with poor aqueous solubility, which is associated with a major risk of side effects. In this context, crystal engineering has provided an efficient approach for tuning the physicochemical properties of active pharmaceutical ingredients (APIs). However, there is a huge lack of knowledge about how coformer molecules impact the pharmaceutical properties of the multicomponent materials, with special attention to solubility and stability. To this purpose, five novel salts and three ionic cocrystals were synthesized using HAL and a series of closely related dicarboxylic acid counterions. Mechanochemical strategies were applied for synthesis, while thermal, spectroscopic, and X-ray diffraction techniques were used for a complete characterization of the materials. By understanding the relationships between the crystal structures and the final properties, this research seeks to inform the rational design of HAL multicomponent drugs, providing a framework for improving the performance of not only HAL but also other APIs with similar challenges.</p><p >This study explores the impact of carbon-chain length in dicarboxylic acid coformers on the structure and properties of haloperidol salts and ionic cocrystals. Evidence from X-ray diffraction, DFT calculations, and thermal analysis supports a rational coformer selection strategy to enhance solubility and stability in haloperidol multicomponent materials.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 9","pages":"3169–3185 3169–3185"},"PeriodicalIF":3.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.cgd.5c00251","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combination of Nitropyrazole and Nitroaminotriazole: A Novel High-Energy Insensitive Energetic Material","authors":"Luyao Chen,&nbsp;Jie Tang,&nbsp;Teng Zhu,&nbsp;Chengchuang Li,&nbsp;Wei Hu,&nbsp;Chuan Xiao,&nbsp;Guangbin Cheng* and Hongwei Yang*,&nbsp;","doi":"10.1021/acs.cgd.5c0023110.1021/acs.cgd.5c00231","DOIUrl":"https://doi.org/10.1021/acs.cgd.5c00231https://doi.org/10.1021/acs.cgd.5c00231","url":null,"abstract":"<p >Currently, within the realm of high-energy material research, the foremost priority lies in harmonizing detonation performance and mechanical sensitivity. In this study, a high-energy insensitive tetracyclic energetic material N, N’-((4,4′-dinitro-1H,2′<i>H</i>-[3,3′-bipyrazole]-5,5′-diyl)bis(1<i>H</i>-1,2,4-triazole-3,5-diyl)) dinitramide (<b>4</b>) was designed by combining the high stability portion of bis(4-nitropyrazole) with the high energy portion of Nitroaminotriazole through ester cyclization reaction. Further combination with energetic bases forms energetic salts <b>5–9</b> with good detonation performance, high stability, and insensitivity. All newly synthesized compounds exhibit positive enthalpy of formation (Δ<i>H</i>_f: 978.3 to 1434.8 kJ/mol), outstanding detonation performance (<i>D</i>_v: 8125 to 9030 m/s; <i>P</i>: 26.05 to 34.6 GPa), and low mechanical sensitivity (IS ≥ 24 J, FS ≥ 360 N). Notably, the neutral tetracyclic energetic compound <b>4</b> (<i>D</i>_v = 9030 m/s, <i>P</i> = 34.6 GPa, IS = 24 J, FS = 360 N) demonstrates superior detonation performance and satisfactory mechanical sensitivity when compared to 1,3,5-trinitroperhydro-1,3,5-triazine (<b>RDX</b>, <i>D</i>_v = 8785 m/s, <i>P</i> = 34.7 GPa, IS = 7.4 J, FS = 120 N).</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 10","pages":"3414–3424 3414–3424"},"PeriodicalIF":3.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"New Hydroxybenzoic Acid Salts of Nintedanib with Improved Aqueous Solubilities","authors":"Avinash Madhesiya,&nbsp;Saroj Maji,&nbsp;Gautam Panda and Tejender S. Thakur*,&nbsp;","doi":"10.1021/acs.cgd.5c0021910.1021/acs.cgd.5c00219","DOIUrl":"https://doi.org/10.1021/acs.cgd.5c00219https://doi.org/10.1021/acs.cgd.5c00219","url":null,"abstract":"<p >Nintedanib is a kinase inhibitor used primarily for the treatment of idiopathic pulmonary fibrosis and nonsmall cell lung cancer. It exhibits poor aqueous solubility and low oral bioavailability (∼4.7%). To address the poor aqueous solubility, we have prepared several new crystalline salts of the drug with hydroxybenzoic acid coformers. We have also prepared new crystalline salts with compounds nicotinic acid, vanillic acid, <i>p</i>-fluorobenzoic acid, <i>p</i>-aminobenzoic acid, and 2-chloro-4-nitrobenzoic acid with reported anticancer activities for exploring new anticancer combinations of nintedanib. All crystalline salts were thoroughly characterized, and their aqueous solubility was determined in the study. The physical stability of the anhydrous nintedanib salts was studied under ambient and accelerated conditions. The amorphous phases of some of these crystalline Nin salts were also prepared by milling, and their kinetic solubilities were compared. Further, the amorphous solid dispersions of the amorphous 2,6-dihydroxybenzoate salt (showing the highest kinetic solubility) were prepared with polymers PVP-K-30 and Eudragit-L-100 in different w/w ratios, and the physical stability and <i>in vitro</i> powder dissolution profile were studied.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 10","pages":"3394–3403 3394–3403"},"PeriodicalIF":3.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144098209","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toward the Identification of Point Defects Formation and Solution Growth Mechanisms of Herbertsmithite ZnxCu4–x(OH)6Cl2 Crystals","authors":"Vijaya Shanthi Paul Raj,&nbsp;Alexandra Peña-Revellez,&nbsp;Jean-Sébastien Micha,&nbsp;Ravi Raj Purohit Purushottam Raj Purohit,&nbsp;Didier Chaussende,&nbsp;Marc Verdier,&nbsp;Vincent Motto-Ros,&nbsp;Fabrice Bert,&nbsp;Philippe Mendels,&nbsp;German Montes-Hernandez and Matias Velazquez*,&nbsp;","doi":"10.1021/acs.cgd.4c0148310.1021/acs.cgd.4c01483","DOIUrl":"https://doi.org/10.1021/acs.cgd.4c01483https://doi.org/10.1021/acs.cgd.4c01483","url":null,"abstract":"<p >Zn_<i>x</i>Cu_4–<i>x</i>(OH)₆Cl₂ single crystals were grown under varying experimental conditions such as dissolution and growth temperatures, pH, and initial ZnCl₂ concentration of the solution. The crystals were characterized to determine their crystallographic phase purity and lattice parameters, chemical composition, and surface morphology. Two spatially resolved mapping techniques, laser-induced breakdown spectroscopy (LIBS) and micro-X-ray fluorescence spectroscopy (μ-XRF), were used to firmly establish the Cu and Zn concentrations of the crystals obtained in different growth conditions. Once correctly calibrated, LIBS allowed for mapping of Cu and Zn contents with very good statistics and at various depths from the crystal surface. An interesting correlation between the <i>c</i>-lattice parameter and the <i>x</i>-value was observed in the range of <i>x</i> = 0.75–1.04. Using the microdiffraction multimodal station (μ-Laue, μ-XRF) at the BM32 beamline of the European Synchrotron Radiation Facility (ESRF), we were able to orient the most salient features of the (101) facets’ morphology, including the ubiquitous macrosteps. Combining these data with an exhaustive thermochemical investigation of the growth solutions, aimed at identifying the most concentrated Cu- and Zn-based species as a function of the growth conditions (T, pH, Zn, Cu, Cl, and O concentrations), we proposed plausible growth and point defect disorder formation reactions. This analysis was partially supported for Zn-based species by <i>in situ</i> Raman spectroscopy. Further, through a systematic analysis of the height-difference correlation function obtained by atomic force microscopy (AFM) images of large terraces and macrosteps, we concluded that surface diffusion and related thermal noise are the kinetically limiting mechanisms in the growth process.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 9","pages":"2857–2873 2857–2873"},"PeriodicalIF":3.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911335","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthesis of Redox-Active Terbium(III)-Based Metal–Organic Framework Crystals and Visual Fluorescence Sensing for Vanillylmandelic Acid","authors":"Miao-Miao Wang,&nbsp;Huan Zhang,&nbsp;Jun-Jie Hu,&nbsp;Yan Peng,&nbsp;Sui-Jun Liu and He-Rui Wen*,&nbsp;","doi":"10.1021/acs.cgd.5c0009810.1021/acs.cgd.5c00098","DOIUrl":"https://doi.org/10.1021/acs.cgd.5c00098https://doi.org/10.1021/acs.cgd.5c00098","url":null,"abstract":"<p >Fluorescent sensing metal–organic framework crystalline materials have potential applications in the detection of biomarkers for disease. Two highly thermally and chemically stable redox-active <b>Tb-MOF</b> and <b>Tb-MOF-Ox</b> crystalline materials based on the tetracarboxylic acid ligand were successfully synthesized and characterized, and the <b>Tb-MOF</b> nanocrystals also were prepared, which can quantitatively identify vanillylmandelic acid (VMA), an early pathological feature of pheochromocytoma (PCh). <b>Tb-MOF</b> shows high sensitivity and high selectivity with a low detection limit of 0.044 μM for VMA. <b>Tb-MOF-Ox</b> was obtained through the oxidation of <b>Tb-MOF</b>, which has better fluorescence performance and lower detection limit of 0.025 μM. Further, synthesized <b>Tb-MOF</b> nanocrystals also have better fluorescence properties and a lower detection limit of 0.026 μM. <b>Tb-MOF</b> and <b>Tb-MOF-Ox</b> can be fabricated into portable test strips and LED light beads or doped into sodium alginate to prepare hybrid sensing membranes (Tb@SA), which exhibit excellent VMA sensing ability. Moreover, <b>Tb-MOF</b> exhibits an exceptionally high proton transport capacity with a value of 1.20 × 10^–3 S·cm^–1 at 60 °C and 98% RH. Therefore, <b>Tb-MOF</b> is a bifunctional material for fluorescence sensing and proton conduction.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 9","pages":"3037–3047 3037–3047"},"PeriodicalIF":3.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One Size Fits All? Development of the CPOSS209 Data Set of Experimental and Hypothetical Polymorphs for Testing Computational Modeling Methods.","authors":"Louise S Price, Matteo Paloni, Matteo Salvalaglio, Sarah L Price","doi":"10.1021/acs.cgd.5c00255","DOIUrl":"https://doi.org/10.1021/acs.cgd.5c00255","url":null,"abstract":"<p><p>Organic crystal structure prediction (CSP) studies have led to the rapid development of methods for predicting the relative energies of known and computer-generated crystal structures. There is a compromise between the level of theoretical treatment, its reliability across different types of organic systems, how its accuracy depends on the size and shape of the unit cell, and the size and the number of structures that can be modeled at an affordable computational cost. We have used our database of crystal structure prediction studies, often performed as a complement to experimental screening, to produce sets comprising 6 to 15 crystal structures, covering known polymorphs, observed packings of closely related molecules, and CSP-generated energetically competitive but distinct structures, for 20 organic molecules. These have been chosen to illustrate some of the issues that need consideration in any lattice energy method, seeking to be generally applicable to moderate-sized organic molecules, including small drug molecules. We included the methods of crystallization reported for the experimental polymorphs. In all of the examples, the original CSP used electronic structure calculations on the molecule to give the conformational energy and an anisotropic atom-atom model for the electrostatic intermolecular energy, combined with an empirical \"exp-6\" repulsion dispersion model to give the intermolecular lattice energy. The lattice energies and structures are compared with those obtained by reoptimizing with periodic, plane-wave, dispersion-corrected density functional theory, specifically PBE with the TS dispersion correction, and with single point energies where the many body dispersion (MBD) dispersion correction is applied, as an example of a widely used \"workhorse\" method. The use of this data set for a preliminary test of modeling methods is illustrated for two Machine Learned Foundation Models, MACE-MP-0 and MACE-OFF23. The challenges in modeling the putative and observed polymorphs for a range of molecules, their energies, and the possible level of agreement with experimental data are illustrated. Very similar molecules can differ significantly in the polymorphs observed, only partially reflecting the range of polymorph screening experiments used and the energetically competitive structures produced by CSP approaches based on a purely thermodynamic paradigm.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 9","pages":"3186-3209"},"PeriodicalIF":3.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12063060/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"One Size Fits All? Development of the CPOSS209 Data Set of Experimental and Hypothetical Polymorphs for Testing Computational Modeling Methods","authors":"Louise S. Price,&nbsp;Matteo Paloni,&nbsp;Matteo Salvalaglio and Sarah L. Price*,&nbsp;","doi":"10.1021/acs.cgd.5c0025510.1021/acs.cgd.5c00255","DOIUrl":"https://doi.org/10.1021/acs.cgd.5c00255https://doi.org/10.1021/acs.cgd.5c00255","url":null,"abstract":"<p >Organic crystal structure prediction (CSP) studies have led to the rapid development of methods for predicting the relative energies of known and computer-generated crystal structures. There is a compromise between the level of theoretical treatment, its reliability across different types of organic systems, how its accuracy depends on the size and shape of the unit cell, and the size and the number of structures that can be modeled at an affordable computational cost. We have used our database of crystal structure prediction studies, often performed as a complement to experimental screening, to produce sets comprising 6 to 15 crystal structures, covering known polymorphs, observed packings of closely related molecules, and CSP-generated energetically competitive but distinct structures, for 20 organic molecules. These have been chosen to illustrate some of the issues that need consideration in any lattice energy method, seeking to be generally applicable to moderate-sized organic molecules, including small drug molecules. We included the methods of crystallization reported for the experimental polymorphs. In all of the examples, the original CSP used electronic structure calculations on the molecule to give the conformational energy and an anisotropic atom–atom model for the electrostatic intermolecular energy, combined with an empirical “exp-6” repulsion dispersion model to give the intermolecular lattice energy. The lattice energies and structures are compared with those obtained by reoptimizing with periodic, plane-wave, dispersion-corrected density functional theory, specifically PBE with the TS dispersion correction, and with single point energies where the many body dispersion (MBD) dispersion correction is applied, as an example of a widely used “workhorse” method. The use of this data set for a preliminary test of modeling methods is illustrated for two Machine Learned Foundation Models, MACE-MP-0 and MACE-OFF23. The challenges in modeling the putative and observed polymorphs for a range of molecules, their energies, and the possible level of agreement with experimental data are illustrated. Very similar molecules can differ significantly in the polymorphs observed, only partially reflecting the range of polymorph screening experiments used and the energetically competitive structures produced by CSP approaches based on a purely thermodynamic paradigm.</p><p >Derivation and illustrative use of the CPOSS209 dataset of 209 experimental and hypothetical crystal structures of 20 small pharmaceutical molecules and precursors, as optimized by two well-established lattice energy models used in CSP, discussed in the context of current experimental knowledge.</p>","PeriodicalId":34,"journal":{"name":"Crystal Growth & Design","volume":"25 9","pages":"3186–3209 3186–3209"},"PeriodicalIF":3.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.cgd.5c00255","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143911435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}