Frontiers of molecular crystal structure prediction for pharmaceuticals and functional organic materials

Chemical Science, Journal Year: 2023, Volume and Issue: 14(46), P. 13290 - 13312

Published: Jan. 1, 2023

Molecular crystal structure prediction has matured to the point where it can routinely facilitate discovery and design of new organic materials.

Language: Английский

---

Is It Salt, Cocrystal, or Continuum? Successes and Limitations of Computationally Efficient Periodic System Calculations

Crystal Growth & Design, Journal Year: 2024, Volume and Issue: 24(10), P. 4017 - 4024

Published: April 26, 2024

Definitive characterization of pharmaceutical salt and cocrystal solid forms is crucial from regulatory intellectual property perspectives. Consequently, predicting acid–base solid-state configurations along the salt–cocrystal spectrum has become a quest for modern computational methods. The successes limitations two computationally efficient GGA m-GGA periodic system density functional (DFT) methods were benchmarked against data set 19 organic crystals displaying 24 N···H···O intermolecular hydrogen bonds, with proton positions assigned by NMR or single-crystal neutron diffraction experiments. revTPSS method demonstrated accurate reliable performance in configurations, while PBE-MBD* calculations yielded somewhat less results. However, at both levels failed to describe continuum characterized short (below ∼2.57 Å 100–120 K) N···O bonds. A practical workflow support conjunction routine single crystal X-ray measurements was proposed.

Language: Английский

---

Thermodynamic Stability Is a Poor Indicator of Cocrystallization in Models of Organic Molecules

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(4), P. 2805 - 2815

Published: Jan. 19, 2024

Cocrystallizing a given molecule with another can be useful for adjusting the physical properties of molecules in solid state. However, most combinations do not readily cocrystallize but form either one-component crystals or amorphous solids. Computational methods crystal structure prediction can, principle, identify thermodynamically stable cocrystal and thus predict if will not. pronounced polymorphism tendency many organic to disordered solids suggest that kinetic factors play an important role cocrystallization. The question remains: binary system has cocrystal, it indeed cocrystallize? To address this question, we simulate crystallization more than 2600 distinct pairs chiral model similar size 2D calculate accurate energy landscapes all them. Our analysis shows thermodynamic criteria alone are unreliable While vast majority cocrystals our simulations favorable, coformer systems have cocrystallize. We furthermore show cocrystallization rates increase 3-fold when coformers used well-ordered single-component crystals. results decisive cases.

Language: Английский

---

On the Road to Cocrystal Prediction: A Screening Study for the Validation of In Silico Methods

Crystal Growth & Design, Journal Year: 2024, Volume and Issue: 24(13), P. 5486 - 5493

Published: June 20, 2024

The pharmaceutical industry is increasingly exploring cocrystals as a solution to provide improved material properties for otherwise intractable active ingredients (APIs). Researchers have attempted streamline the experimental process of screening by developing in silico predictive tools. These tools use intermolecular interactions, primarily hydrogen bonding, well other molecular descriptors quickly assess likelihood cocrystal formation between an API and set small-molecule coformers. We developed web-based application using three such help us prioritize against library nearly 300 individual In order validate our algorithms, molecules from compound were screened, experimentally with application, subset 40 Here, we present design app, work used its predictions, relative success techniques.

Language: Английский

---

Prioritizing Computational Cocrystal Prediction Methods for Experimental Researchers: A Review to Find Efficient, Cost-Effective, and User-Friendly Approaches

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(22), P. 12045 - 12045

Published: Nov. 9, 2024

Pharmaceutical cocrystals offer a versatile approach to enhancing the properties of drug compounds, making them an important tool in formulation and development by improving therapeutic performance patient experience pharmaceutical products. The prediction involves using computational theoretical methods identify potential cocrystal formers understand interactions between active ingredient coformers. This process aims predict whether two or more molecules can form stable structure before performing experimental synthesis, thus saving time resources. In this review, commonly used are first overviewed then evaluated based on three criteria: efficiency, cost-effectiveness, user-friendliness. Based these considerations, we suggest researchers without strong experiences which tools should be tested as step workflow rational design cocrystals. However, optimal choice depends specific needs resources, combining from different categories powerful approach.

Language: Английский

---

Conformational polymorphism in a mononuclear phosphanegold(I) thiocarbamato species, Cy₃PAu[SC(OEt)=N(C₆H₄Cl-3)]

Zeitschrift für Kristallographie - Crystalline Materials, Journal Year: 2025, Volume and Issue: unknown

Published: March 28, 2025

Abstract Two polymorphs of Cy 3 PAu[SC(OEt)=N(C 6 H 4 Cl-3)], that is a triclinic form ( P 1 ‾ $\overline{1}$ with Z ′ = 1; the α -form) and monoclinic 2 1 / c ; β have been characterised. The molecular structures feature linear P–Au–S coordination geometries close intramolecular Au⋯O(ethoxy) contacts 3.1552(17) 3.097(2) Å for - -forms, respectively. major conformational differences between relates to relative orientations thiocarbamato anions cyclohexylphosphane ligands. Computational chemistry shows be isoenergetic (single-point calculations) practically zero barrier interconversion. An analysis packing highlights importance cyclohexyl-C–H···S(thiolate) methyl-C–H···π(chlorophenyl) in crystal -form, π(chlorophenyl)···π(chlorophenyl) -form. While similarities are apparent solid-state luminescence spectra, different electronic transitions responsible spectroscopic observations.

Language: Английский

---

Caprolactam Cocrystals: Bridging Virtual Screening to Experimental Solid-State Forms and Stability

Crystal Growth & Design, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

This study revisits and expands the field of lactam cocrystals to include additional structural analogues sulfonamides evaluates potential virtual screening methods. Cocrystallization lactams is driven by both lactam–lactam lactam–API interactions. Four cocrystals, SA/CLCC, SG/CLCC, DDS/CLCC-I, DDS/CLCC-II, were experimentally produced, including two novel ones, SG/CLCC DDS/CLCC-II. The structures new multicomponent phases successfully solved using powder X-ray diffraction data complemented DFT-d calculations. Calorimetric analysis confirmed that DDS/CLCC-II high-temperature polymorph enantiotropically related DDS/CLCC-I. Virtual methods, molecular complementarity, hydrogen-bond propensity, electrostatic maps, demonstrated utility but limited properties chosen coformer class. Crystal structure prediction on other hand proved be most reliable computational approach, identifying cocrystallization outcomes in all three systems matching experimental 1:1 cocrystal with computationally generated ones. investigations revealed could reduce, not completely prevent, sublimation tendency ε-caprolactam. Solubility tests showed no improvement API solubility, as disintegrated into their individual components within shortest time contact water. Thus, this work sheds light cocrystallization, highlighting strengths limitations current predictive approaches, well challenges need addressed work.

Language: Английский

---

High-Throughput Encapsulated Nanodroplet Screening for Accelerated Co-Crystal Discovery

Chemical Science, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

A high-throughput nanoscale co-crystallisation approach is presented, that combines automation and small scale to enable the exploration of conditions, resulting in 30 new binary, ternary quaternary co-crystals.

Language: Английский

---

Discovery of Cilnidipine Cocrystals with Enhanced Dissolution by the Use of Computational Tools and Semiautomatic High-Throughput Screening

Crystal Growth & Design, Journal Year: 2025, Volume and Issue: 25(10), P. 3374 - 3385

Published: April 29, 2025

Cocrystals are an attractive option for overcoming drug limitations, such as a low dissolution rate and absorption of poorly water-soluble compounds. Nevertheless, the discovery new cocrystals remains trial-and-error approach in which hundreds coformers several experimental methods often tested. To streamline cocrystal screening, computational can be used to select most likely form cocrystal, while high-throughput screening (HTS) approaches rapidly screen them experimentally. In this manuscript, extremely soluble cilnidipine (solubility ≈30 ng/mL, 0.06 μM) was successfully discovered by applying HTS approaches. Only one resulted from with total 52 coformers, whereby molecular complementarity ranked coformer (p-toluenesulfonamide) at third position list. Dissolution studies conducted on blank FaSSIF (fasted-state simulated intestinal fluid) pH 6.5 revealed enhanced maximum achieved supersaturation equal seven times solubility crystalline drug. rates were compared better mechanistic understanding dissolution-supersaturation-precipitation behavior. The case rare occurrence emphasized importance using joint enable successful identification pharmaceutical development.

Language: Английский

---

Resources for Accelerating Medicine Discovery

Burger's Medicinal Chemistry and Drug Discovery, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 57

Published: May 26, 2025

Abstract Using artificial intelligence and machine learning, computational tools are increasingly accelerating new medicine discovery. Applications to the stages of drug discovery, including target identification, hit lead optimization, developability assessment, described. This chapter provides a compilation databases, software packages, web‐based applications for evaluation, optimization molecules.

Language: Английский

---