Challenges and opportunities for computer-aided molecular and process design approaches in advancing sustainable pharmaceutical manufacturing

Current Opinion in Chemical Engineering, Год журнала: 2025, Номер 47, С. 101073 - 101073

Опубликована: Янв. 11, 2025

Язык: Английский

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Accurate Lattice Free Energies of Packing Polymorphs from Probabilistic Generative Models

Journal of Chemical Theory and Computation, Год журнала: 2025, Номер unknown

Опубликована: Фев. 21, 2025

Finite-temperature lattice free energy differences between polymorphs of molecular crystals are fundamental to understanding and predicting the relative stability relationships underpinning polymorphism, yet computationally expensive obtain. Here, we implement critically assess machine-learning-enabled targeted calculations derived from flow-based generative models compute difference two ice crystal (Ice XI Ic), modeled with a fully flexible empirical classical force field. We demonstrate that even when remapping an analytical reference distribution, such methods enable cost-effective accurate calculation disconnected metastable ensembles trained on locally ergodic data sampled exclusively interest. Unlike perturbation methods, as Einstein method, approach analyzed in this work requires no additional sampling intermediate perturbed Hamiltonians, offering significant computational savings. To systematically accuracy monitored convergence estimates during training by implementing overfitting-aware weighted averaging strategy. By comparing our results ground-truth computed efficiency different model architectures, employing representations supercell degrees freedom (Cartesian vs quaternion-based). conduct assessment supercells sizes temperatures assessing extrapolating energies thermodynamic limit. While at low small system sizes, perform similar accuracy. note for larger systems high temperatures, choice representation is key obtaining generalizable quality comparable obtained method. believe be stepping stone toward efficient larger, more complex crystals.

Язык: Английский

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Falsifiability Test for Classical Nucleation Theory

Physical Review Letters, Год журнала: 2025, Номер 134(14)

Опубликована: Апрель 7, 2025

Classical nucleation theory (CNT) is built upon the capillarity approximation, i.e., assumption that properties can be inferred from bulk of melt and crystal. Although simplicity usefulness CNT cannot overstated, experiments simulations regularly uncover significant deviations its predictions, which are often reconciled through phenomenological extensions CNT, fueling debate over general validity theory. In this Letter, we present a falsifiability test for any grounded in approximation. We focus on cases where predicts no differences rates between different crystal polymorphs. then introduce system all polymorphs have same free energy (both interfacial) across state points. Through extensive molecular simulations, show exhibit remarkably properties, directly contradicting predictions CNT. argue CNT's primary limitation lies neglect structural fluctuations within liquid phase.

Язык: Английский

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Solution Thermodynamics of l-Glutamic Acid Polymorphs from Finite-Sized Molecular Dynamics Simulations

Industrial & Engineering Chemistry Research, Год журнала: 2025, Номер 64(2), С. 1309 - 1318

Опубликована: Янв. 7, 2025

Efficiently obtaining atomic-scale thermodynamic parameters characterizing crystallization from solution is key to developing the modeling strategies needed in quest for digital design industrial processes. Based on thermodynamics of crystal nucleation confined solutions, we develop a simulation framework efficiently estimate solubility and surface tension organic crystals few unbiased molecular dynamics simulations at reference temperature. We then show that such result can be extended with minimal computational overhead capture curve. This enables an efficient self-consistent limit stability associated systems equilibrium without need sophisticated free energy calculations. apply our analysis investigate relative aqueous α β polymorphs l-glutamic acid. Our appraisal emergent ensemble properties solutions against experimental data, demonstrating while absolute still far being quantitatively captured by off-the-shelf point charge transferable force field, polymorphic obtained finite temperature are consistent experimentally available information glutamic foresee ability obtain limited number experiments as critical component high-throughput polymorph screenings.

Язык: Английский

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Navigating Solid-Form Screening Using In Silico Methods Validated with Experimental Data for a Drug-like Molecule

Crystal Growth & Design, Год журнала: 2025, Номер unknown

Опубликована: Апрель 23, 2025

Язык: Английский

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One Size Fits All? Development of the CPOSS209 Data Set of Experimental and Hypothetical Polymorphs for Testing Computational Modeling Methods

Crystal Growth & Design, Год журнала: 2025, Номер 25(9), С. 3186 - 3209

Опубликована: Апрель 28, 2025

Organic crystal structure prediction (CSP) studies have led to the rapid development of methods for predicting relative energies known and computer-generated structures. There is a compromise between level theoretical treatment, its reliability across different types organic systems, how accuracy depends on size shape unit cell, number structures that can be modeled at an affordable computational cost. We used our database studies, often performed as complement experimental screening, produce sets comprising 6 15 structures, covering polymorphs, observed packings closely related molecules, CSP-generated energetically competitive but distinct 20 molecules. These been chosen illustrate some issues need consideration in any lattice energy method, seeking generally applicable moderate-sized including small drug included crystallization reported polymorphs. In all examples, original CSP electronic calculations molecule give conformational anisotropic atom-atom model electrostatic intermolecular energy, combined with empirical "exp-6" repulsion dispersion energy. The are compared those obtained by reoptimizing periodic, plane-wave, dispersion-corrected density functional theory, specifically PBE TS correction, single point where many body (MBD) correction applied, example widely "workhorse" method. use this data set preliminary test modeling illustrated two Machine Learned Foundation Models, MACE-MP-0 MACE-OFF23. challenges putative polymorphs range their energies, possible agreement illustrated. Very similar molecules differ significantly observed, only partially reflecting polymorph screening experiments produced approaches based purely thermodynamic paradigm.

Язык: Английский

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Autonomous Control of the Crystal Size and Shape in Dense Suspensions via Imaging

Industrial & Engineering Chemistry Research, Год журнала: 2025, Номер unknown

Опубликована: Май 6, 2025

Язык: Английский

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Pharmaceutical Cocrystals for Drug Delivery

Burger's Medicinal Chemistry and Drug Discovery, Год журнала: 2025, Номер unknown, С. 1 - 62

Опубликована: Май 26, 2025

Abstract Pharmaceutical cocrystals offer the ability to tune solubility, permeability, tableting, and bioavailability of a solid, oral drug formulation without changing chemical structure molecule. Crystal engineering pharmaceutical salts via supramolecular heterosynthons with acceptable generally recognized as safe (GRAS) coformers provides platform technology for improving efficacy optimal delivery. With almost 90% drugs in Biopharmaceutics Classification System (BCS) class II IV suffering from low‐solubility and/or low‐permeability challenges, have provided an opportune intervention populating pipeline over past decade. From prototype cocrystal itraconazole‐succinic acid first salt‐cocrystal complex Entresto containing valsartan‐sacubitril, this review covers origins subject early 2000s peak growth curve model systems between 2005 2015, successful lab‐to‐market translation witnessed The combined application machine learning neural network tools is bringing speed accuracy research exercise designing drug–coformer therapeutic properties. This article snapshot summary latest trends leading discovery, development, continuous manufacturing.

Язык: Английский

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Crystallization of Small Molecules in Microgravity Using Pharmaceutical In-Space Laboratory–Biocrystal Optimization eXperiment (PIL-BOX)

Crystals, Год журнала: 2025, Номер 15(6), С. 527 - 527

Опубликована: Май 30, 2025

Crystallization in microgravity has measurable benefits, from molecules as simple sodium chloride to elaborate protein complexes. However, small organic have not been reported. The glycine, famoxadone, carbamazepine, and 5-methyl-2-((2-nitrophenyl)amino)thiophene-3-carbonitrile (ROY) were crystallized on Earth under conditions. When comparing these different gravity crystallization conditions, we found the formation of polymorphs and/or habits for ROY. famoxadone occurred more slowly microgravity. differences size, appearance, and, case ROY, color, are detailed this report.

Язык: Английский

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Depicting polymorphism in eutectic mixtures

Journal of the Indian Chemical Society, Год журнала: 2024, Номер unknown, С. 101489 - 101489

Опубликована: Дек. 1, 2024

Язык: Английский

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