Cocrystals by Design: A Rational Coformer Selection Approach for Tackling the API Problems

Pharmaceutics, Год журнала: 2023, Номер 15(4), С. 1161 - 1161

Опубликована: Апрель 6, 2023

Active pharmaceutical ingredients (API) with unfavorable physicochemical properties and stability present a significant challenge during their processing into final dosage forms. Cocrystallization of such APIs suitable coformers is an efficient approach to mitigate the solubility concerns. A considerable number cocrystal-based products are currently being marketed show upward trend. However, improve API by cocrystallization, coformer selection plays paramount role. Selection not only improves drug's but also therapeutic effectiveness reduces side effects. Numerous have been used till date prepare pharmaceutically acceptable cocrystals. The carboxylic acid-based coformers, as fumaric acid, oxalic succinic citric most commonly in products. Carboxylic capable forming hydrogen bond contain smaller carbon chain APIs. This review summarizes role improving APIs, deeply explains utility afore-mentioned cocrystal formation. concludes brief discussion on patentability regulatory issues related

Язык: Английский

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Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals

Pharmaceutics, Год журнала: 2023, Номер 15(3), С. 836 - 836

Опубликована: Март 3, 2023

In this study, the existing set of carbamazepine (CBZ) cocrystals was extended through successful combination drug with positional isomers acetamidobenzoic acid. The structural and energetic features CBZ 3- 4-acetamidobenzoic acids were elucidated via single-crystal X-ray diffraction followed by QTAIMC analysis. ability three fundamentally different virtual screening methods to predict correct cocrystallization outcome for assessed based on new experimental results obtained in study data available literature. It found that hydrogen bond propensity model performed worst distinguishing positive negative experiments 87 coformers, attaining an accuracy value lower than random guessing. method utilizes molecular electrostatic potential maps machine learning approach named CCGNet exhibited comparable terms prediction metrics, albeit latter resulted superior specificity overall while requiring no time-consuming DFT computations. addition, formation thermodynamic parameters newly evaluated using temperature dependences Gibbs energy. reactions between selected coformers be enthalpy-driven, entropy being statistically from zero. observed difference dissolution behavior aqueous media thought caused variations their stability.

Язык: Английский

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Recent Advances in Co-Former Screening and Formation Prediction of Multicomponent Solid Forms of Low Molecular Weight Drugs

Pharmaceutics, Год журнала: 2023, Номер 15(9), С. 2174 - 2174

Опубликована: Авг. 22, 2023

Multicomponent solid forms of low molecular weight drugs, such as co-crystals, salts, and co-amorphous systems, are a result the combination an active pharmaceutical ingredient (API) with pharmaceutically acceptable co-former. These can enhance physicochemical pharmacokinetic properties APIs, making them increasingly interesting important in recent decades. Nevertheless, predicting formation API multicomponent early stages formulation development be challenging, it often requires significant time resources. To address this, empirical computational methods have been developed to help screen for potential co-formers more efficiently accurately, thus reducing number laboratory experiments needed. This review provides comprehensive overview current screening prediction forms, covering both crystalline states (co-crystals salts) amorphous (co-amorphous). Furthermore, discusses advances emerging trends methods, particular focus on artificial intelligence.

Язык: Английский

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Machine Learning-Guided Prediction of Cocrystals Using Point Cloud-Based Molecular Representation

Chemistry of Materials, Год журнала: 2024, Номер 36(3), С. 1153 - 1161

Опубликована: Фев. 2, 2024

The design and synthesis of cocrystals have emerged as promising crystal engineering strategies for enhancing the physicochemical properties a diverse range target molecules. A prediction strategy to identify whether pair auxiliary molecules would form cocrystal can greatly accelerate process discovery. In this study, we compiled performed DFT calculations 12,776 (6,388 cocrystals). All entries in database were obtained from experimental attempts reported literature. Electrostatic potential (ESP) surfaces then extracted results used development four machine learning models (PointNet, ANN, RF, Ensemble). Ensemble model, leveraging complementary strengths PointNet, RF models, demonstrated superior discriminatory performance with BACC (0.942) an AUC (0.986) on unseen test data subset. To assess individual molecules, separated caffeine, fumaric acid, salicylic acid overall database. model exhibited remarkable robustness, classifying 312 subset into their respective classes, average 98%. Furthermore, through conducting analysis, 132 batches instances gathered. After three excluded, our proposed tested these previously both before after implementation batchwise retraining method.

Язык: Английский

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Cocrystals and Drug–Drug Cocrystals of Anticancer Drugs: A Perception towards Screening Techniques, Preparation, and Enhancement of Drug Properties

Crystals, Год журнала: 2022, Номер 12(10), С. 1337 - 1337

Опубликована: Сен. 21, 2022

The most favored approach for drug administration is the oral route. Several anticancer drugs come under this category and mostly lack solubility bioavailability, which are common causes of inadequate clinical efficiency. Enhancing absorption with low aqueous impermeability currently an effective area research. Many scientists have looked into pharmaceutical cocrystals as a way to improve physicochemical properties several drugs. Benefits over other solid forms may include improved solubility, reduced susceptibility phase transition. Cocrystal strategy also stands green synthesis tool by using very limited organic solvents during its formulation. Having so many advantages, date, reported drug–drug limited. Here we review in last decade their future imaging, shed light on opportunities challenges development cocrystals.

Язык: Английский

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Salt Cocrystal and Salt of Marbofloxacin with Butenedioic Acid: Impact of cis–trans Isomerism of Coformer on the Conformation and Properties of Marbofloxacin

Crystal Growth & Design, Год журнала: 2024, Номер 24(3), С. 1339 - 1349

Опубликована: Янв. 10, 2024

Based on the study of effect positional isomerism coformer functional groups cocrystallization and physicochemical properties active pharmaceutical ingredients, impact cis–trans isomeric butenedioic acid as coformers conformation, crystal structure, its marbofloxacin was further explored. In this work, fumaric (FA) maleic (MA) with different configurations were chosen to synthesize salt cocrystal (MBF-FA-H2FA) (MBF-MA) (MBF), their structures fully characterized. Significant differences between conformations in found. cocrystal, N atom piperazine group from is coplanar pyridone ring, whole straight like acid, whereas bent configuration. Furthermore, conformational variability resulted opposite properties. Notably, both multicomponent crystals have a surface hydrophilic intercalation structure. However, exhibited solubility permeability. Specifically, MBF-MA showed improved permeability, while MBF-FA-H2FA decreased permeation rate compared MBF. addition, vitro bacterial inhibitory activity assays indicated that has stronger against Gram-negative Gram-positive strains than pure

Язык: Английский

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Solvent Replacement Strategies for Processing Pharmaceuticals and Bio-Related Compounds—A Review

Liquids, Год журнала: 2024, Номер 4(2), С. 352 - 381

Опубликована: Апрель 9, 2024

An overview of solvent replacement strategies shows that there is great progress in green chemistry for replacing hazardous di-polar aprotic solvents, such as N,N-dimethylformamide (DMF), 1-methyl-2-pyrrolidinone (NMP), and 1,4-dioxane (DI), used processing active industrial ingredients (APIs). In synthetic chemistry, alcohols, carbonates, ethers, eucalyptol, glycols, furans, ketones, cycloalkanones, lactones, pyrrolidinone or mixtures, 2-methyl tetrahydrofuran methanol, HCl cyclopentyl methyl ether, trifluoroacetic acid propylene carbonate surfactant water (no organic solvents) are suggested solvents. For the dichloromethane (DCM) chromatography, ethyl acetate ethanol 2-propanol heptanes, with without acetic ammonium hydroxide additives, suggested, along methanol tert-butyl cyclohexane, CO2-ethyl acetate, CO2-methanol, CO2-acetone, CO2-isopropanol. Supercritical CO2 (scCO2) can be to replace many solvents materials from natural sources. Vegetable, drupe, legume, seed oils co-extractants (mixed substrate before extraction) typical co-solvents (ethanol, acetone) scCO2 extraction. Mixed consisting a hydrogen bond donor (HBD) acceptor (HBA) not addressed GSK CHEM21 guides. Published data 100 water-soluble water-insoluble APIs mono-solvents show polarity ranges appropriate mixed When used, possible HBA candidate acetone, acid, acetonitrile, ethanol, tetrahydrofuran, 2,2,5,5-tetramethyloxolane, dimethylisosorbide, Cyrene, Cygnet 0.0, diformylxylose. alcohol candidates cyclopentanone, esters, lactone, eucalytol, MeSesamol, HBA—HBA Cyrene—Cygnet could provide interesting new combinations. Solubility parameters, Reichardt polarity, Kamlet—Taft linear solvation energy relationships practical ways identifying applicable API systems.

Язык: Английский

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COSMOPharm: Drug–Polymer Compatibility of Pharmaceutical Amorphous Solid Dispersions from COSMO-SAC

Molecular Pharmaceutics, Год журнала: 2024, Номер 21(9), С. 4395 - 4415

Опубликована: Июль 30, 2024

The quantum mechanics-aided COSMO-SAC activity coefficient model is applied and systematically examined for predicting the thermodynamic compatibility of drugs polymers. drug–polymer a key aspect in rational selection optimal polymeric carriers pharmaceutical amorphous solid dispersions (ASD) that enhance drug bioavailability. evaluated terms both solubility miscibility, calculated using standard equilibrium relations based on coefficients predicted by COSMO-SAC. As inherent to COSMO-SAC, our approach relies only quantum-mechanically derived σ-profiles considered molecular species involves no parameter fitting experimental data. All used were determined this work, with those polymers being from their shorter oligomers replicating properties central monomer unit(s). Quantitatively, achieved an overall average absolute deviation 13% weight fraction predictions compared Qualitatively, correctly categorized different polymer types provided meaningful estimations amorphous–amorphous phase separation. Furthermore, we analyzed sensitivity results ASD configurations In general, while free volume dispersion exerted limited effect predictions, structures produce appeared be more important, especially case strongly interacting Explanations these observations are provided. proved efficient method prediction screening ASD, particularly its performance–cost ratio, as it first-principles calculations species. open-source nature Python-based tool COSMOPharm, developed work API–polymer compatibility, invites interested readers explore utilize further research or assistance design formulations.

Язык: Английский

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Cocrystals of tuberculosis antibiotics: Challenges and missed opportunities

International Journal of Pharmaceutics, Год журнала: 2022, Номер 623, С. 121924 - 121924

Опубликована: Июнь 21, 2022

Cocrystals have been extensively used to improve the physicochemical properties and bioavailability of active pharmaceutical ingredients. anti-tuberculosis medications are among those commonly reported. This review provides a summary tuberculosis antibiotic cocrystals reported in literature, providing main results on current utilized cocrystals. Moreover, limitations advantages described, including evidence for enhanced solubility, stability effect. Opportunities enhance fixed dose combinations using given. Several cocrystal pairs suggested effectiveness drugs.

Язык: Английский

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Exploring the Cocrystal Landscape of Posaconazole by Combining High-Throughput Screening Experimentation with Computational Chemistry

Crystal Growth & Design, Год журнала: 2022, Номер 23(2), С. 842 - 852

Опубликована: Дек. 23, 2022

The development of multicomponent crystal forms, such as cocrystals, represents a means to enhance the dissolution and absorption properties poorly water-soluble drug compounds. However, successful discovery new pharmaceutical cocrystals remains time- resource-consuming process. This study proposes use combined computational-experimental high-throughput approach tool accelerate improve efficiency cocrystal screening exemplified by posaconazole. First, we employed COSMOquick software preselect rank candidates (coformers). Second, crystallization experiments (HTCS) were conducted on selected coformers. HTCS results successfully reproduced liquid-assisted grinding reaction crystallization, ultimately leading synthesis thirteen posaconazole (7 anhydrous, 5 hydrates, 1 solvate). characterized PXRD, 1H NMR, Fourier transform-Raman, thermogravimetry-Fourier transform infrared spectroscopy, differential scanning calorimetry. In addition, prediction performance was compared that two alternative knowledge-based methods: molecular complementarity (MC) hydrogen bond propensity (HBP). Although HBP does not perform better than random guessing for this case study, both MC show good discriminatory ability, suggesting their potential virtual screening.

Язык: Английский

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