chemical process engineers

Abstract: Real materials consist of multiple stable or metastable states under real-world conditions, existing as statistical ergodic ensembles of configurations rather than ideal crystals. Yet, data-driven computational materials discovery increasingly biases itself toward finding "new stable structures" from ground-state DFT calculations alone. This limits our long-term ability to discover materials whose properties emerge from metastable phases, to explain experimental observations, or to model thermodynamic behavior comprehensively. Predicting ergodic sets of atomic configurations of known and hypothetical solids is a fundamental challenge in theoretical crystallography, approached via many complementary methods. We discuss this conceptually and introduce crystALL, a pragmatic and powerful data-driven approach to discovering ensembles beyond the convex hull, embracing structural diversity over stability alone, enabling robust experiment matching in cases evading traditional methods. crystALL leverages 5 million relaxed structures from OPTIMADE and MPDD to rapidly generate a comprehensive candidate set by: (1) species substitutions; (2) ML feature-space analysis with pySIPFENN; (3) representative structure selection via clustering and energy-minimization or property matching; and (4) construction of the final candidate ensemble for experimental or ab initio validation. We also uniquely address the common challenge of experimental composition uncertainties spanning many integer stoichiometries by new efficient searches across anonymized compositional ranges rather than fixed formulas. Overall, crystALL's ensemble-focused philosophy provides critical advantages over the prevailing convex-hull-searching paradigm, which often fails to account for key experimental observations and increases AI/ML discovery bias over time - akin to model collapse in LLMs retrained on iteratively generated content.

Abstract: Predictive models for activity coefficients, which describe the non-ideality of liquid mixtures, are foundational for process design and optimization. Group-contribution methods, such as UNIFAC, are computationally cheap and well established in process simulators. Modern machine learning models, such as HANNA, offer higher accuracy and broader applicability, but their integration into process simulation is expensive or even infeasible. In this work, we introduce COGNAC, a graph neural network that learns atom-level geometry and interaction parameters that depend on the molecular neighborhood and evaluates them in the UNIFAC framework. Trained on about 820,000 experimental data points, COGNAC achieves significantly higher accuracy than UNIFAC and HANNA for binary and multi-component mixtures, reduces error relative to HANNA by 13-63%, reliably predicts multi-phase equilibria and identifies azeotropes, yields interpretable parameters, and is strictly thermodynamically consistent. COGNAC evaluations run at a cost comparable to UNIFAC, thereby unlocking the potential of machine-learning models for process simulations.

Abstract: We give a self-contained proof that, for a finite detailed balanced mass-action system with positive rate constants, each positive stoichiometric compatibility class contains exactly one positive equilibrium and every positive trajectory converges to it, together with a Lean 4 formalization of the complete argument from persistence to convergence. Boundedness and persistence come from the barrier argument of OpenAI (2026) for weakly reversible systems: an arbitrary-tolerance affine approximation yields a finite-minimum barrier whose superlevel sets confine trajectories and give one logarithmic bound for all solutions from a given initial state. The Horn-Jackson dissipation identity identifies the positive equilibria as an exponential family with parameters in the orthogonal complement of the stoichiometric subspace, which gives uniqueness in each class. A bounded-speed descent argument replaces LaSalle's invariance principle; it uses neither uniqueness of solutions nor continuous dependence on initial data, and it places every cluster point in that family. The route given here is direct and elementary, and its main theorem is checked by the Lean kernel against explicit definitions. The proofs, the Lean development, and the manuscript were produced in ClawsGO Science, an agent harness that packages a complete research environment: Claude Opus 5.5 made the research decisions, GPT 6 Astra carried them out, and the Lean kernel checked every formal step.

Abstract: Solubility depends on intermolecular interactions between solutes and solvents, and is central to drug discovery, chemical and materials process engineering. Its prediction requires out-of-distribution (OOD) generalization to unseen solutes, solvents, and solvent mixtures, where supervised methods suffer from data scarcity, and existing self-supervised methods do not explicitly learn chemically meaningful relations. Learning chemically meaningful relational information without labels can alleviate data scarcity and improve OOD generalization, but remains challenging. We introduce Prior Relational Information for Self-supervised Modeling (PRISM) and apply it to solubility OOD generalization. PRISM is a label-free pretraining framework that converts expert-defined chemical priors into relational teachers. For solubility prediction, it trains four encoders to preserve the population-level relational information from priors capturing hydrophobic, electrostatic, polarizability, and substructural effects, using Kullback-Leibler (KL) divergence to match distance-based neighborhood distributions during pretraining. Across scaffold, solute, and solvent OOD settings, PRISM matches or surpasses supervised and self-supervised baselines. Under mixed-solvent OOD, freezing the four PRISM encoders and training a lightweight fusion-and-composition head outperforms strong baselines and substantially reduces run-to-run variation. Ablations and control studies confirm that gains stem from chemically meaningful relational structures baked into the encoders by PRISM. We expect this strategy of turning relational priors into self-supervision signals to extend beyond solubility prediction to domains where chemically or biologically meaningful relational priors are available.

Abstract: Computer-aided retrosynthesis has advanced through single-step prediction, tree search and route scoring, but complex targets still require judgement over the whole route, where stereochemistry, functional-group compatibility, cost and greenness interact. Here we present \textbf{\mbox{ReTRACE}} (\textbf{RE}trosynthesis with \textbf{T}ool-orchestrated \textbf{R}easoning \textbf{A}nd \textbf{C}ontext-aware \textbf{E}vidence), an agent that places a large language model (LLM) in a chemistry harness that integrates molecular tools, complementary single-step prediction engines, a purchasable starting-material library, a route memory and a multi-criterion route evaluator. Routes are judged by a new metric that combines programmatic checks with adversarial LLM review, and its verdicts are compared with a synthetic chemist's. The agent learns continually from evaluator feedback during search, diagnosing weak routes and backtracking to revise them. With Claude Opus 4.8, at least one of the top 10 routes proposed by ReTRACE passed the audit for 87.4\%, 95.0\% and 86.7\% of targets on the three benchmarks. Two prospective wet-lab syntheses show that ReTRACE route proposals can be converted into executable procedures after expert revision.

Abstract: Designing synthesizable materials with targeted properties remains one of the central objectives in materials sciences. Ionic liquids (ILs) are well suited to this goal due to their "tunability", where physical and chemical properties can be precisely customized by modifying their molecular structure, specifically by varying the combination of cations and anions. At the same time, current data-driven property models for ionic liquids often degrade in scarce, noisy, and uneven data regimes, where measurements cover only a small fraction of chemical space and a limited range of thermodynamic conditions. This makes out-of-distribution screening brittle: even when point predictions look plausible, it is difficult to compare candidates consistently, quantify downstream implications, or trust rankings enough to guide molecular discovery. We present a property-prediction and optimal candidate selection workflow that treats data processing, deep learning modeling, and physics-based calculations as a coupled system, linking property prediction with uncertainty estimation and physics-based filtering. By tightening the link between predicted properties and the criteria used for down-selection, the workflow supports reliable out-of-distribution ranking and enables prioritization of previously untested ionic liquid candidates with favorable predicted trade-offs. We demonstrate the application of our workflow by designing novel ionic liquids for CO2 capture from flue gas, predicting their properties and selecting Pareto-optimal candidates based on CO2 solubility, IL viscosity and working capacity.

Abstract: Materials synthesis planning (MSP) connects AI-driven materials discovery to experimental realization by proposing precursors, synthesis operations, and processing conditions for a target material. Existing approaches predict these components separately or in pairs and treat conditions only as a prediction target. Consequently, MSP remains centered on recipe prediction: it leaves unexplored how conditions can serve as process context for constructing synthesis routes, and it does not address which candidate routes should be executed under limited experimental resources. We propose CondMSP, which extends MSP from recipe prediction to execution-aware planning. CondMSP predicts temperature, time, and atmosphere by combining a joint predictor with variable-specific experts, and then uses these predictions both as process context, grounding the generation and retrieval of operation sequences, and as execution requirements, specifying which thermal stages can share a furnace run and at what cost. This specification is held fixed across all compared methods; within it, CondMSP ranks routes across precursor sets by a common utility and, under furnace budgets, jointly selects routes and allocates their thermal stages by constrained optimization. CondMSP improves condition and operation prediction and, under this shared constraint, raises reference-recipe recovery from 27.9% to 32.9% at three simulated furnace runs per target and from 34.7% to 40.0% at 30 trials, while a new evaluation set of 2,344 targets supports generalization beyond oxide-dominated training chemistry.

Abstract: Mixed-variable optimization in scientific discovery often requires exploring large combinatorial spaces under costly experimental evaluations, making sample?efficient Bayesian optimization (BO) essential. However, existing BO methods typ?ically rely on structural descriptors to define similarity among categorical variables, implicitly assuming that structural similarity reflects similarity in task performance. In scientific optimization, this assumption is often violated, leading to surrogate representations that are poorly aligned with the optimization objective. To address this limitation, we propose TagBO (Task-aware Graph Bayesian Optimization), a method that integrates LLM-derived relational priors with descriptor-based struc?tural information for mixed-variable Bayesian optimization. Rather than directly using LLM outputs as predictive scores, TagBO treats LLM outputs as a potentially noisy source of task-aware relational priors and extracts coarse ordinal relational signals from LLM reasoning to construct task-aware similarity structures for scien?tific optimization. TagBO then performs constrained Gaussian process Bayesian optimization over the resulting joint discrete-continuous representation space. Ex?periments on diverse chemistry and materials formulation tasks demonstrate that TagBO consistently improves sample efficiency under fixed evaluation budgets across LLMs of varying capabilities.

Abstract: Sampling transitions between metastable states is a central problem in dynamical systems theory and molecular dynamics in particular. A key challenge is the existence of high free-energy barriers that separate the states, making transitions extremely rare. Recent machine learning-based methods cast transition path sampling (TPS) as an optimal stochastic control (OSC) problem over a fixed time horizon, and parameterize the drift bias via a neural network trained by simulation-in-the-loop, requiring repeated biased rollouts. To address computational and performance guarantee issues of these models, we propose a new approach for the problem based on Koopman operators. Because Koopman operators are linear, their leading eigenfunctions reveal the metastable sets and provide an estimate of the committor function with no transition path information required. Furthermore, we formulate TPS as an OSC problem up to an exit time. Our time horizon is the first hitting time of the target set, and our running cost penalizes time spent in nonreactive regions by encoding the estimated committor function. We derive the optimal controller in closed form and approximate it in a reproducing kernel Hilbert space (RKHS). This reduces the problem of constructing the optimal controller to solving a single equality-constrained quadratic program, whose solution can be characterized by a linear Karush-Kuhn-Tucker (KKT) system. On the two-channel double well and alanine dipeptide, our controller increases the fraction of trajectories reaching the target from 0% to 99.8% within 1000 steps, and from 0% to 93% within 1ps, respectively.

Abstract: Recovering complete phase sets from powder X-ray diffraction (PXRD) is challenging when weak-phase peaks overlap stronger signals. A natural strategy is to identify phases iteratively, removing the contribution of each identified phase from the observed pattern before predicting the next. However, even after a phase is correctly identified, misestimating its contribution can distort the residual and cause subsequent errors. We introduce PhaseMatcher, an autoregressive framework for complete phase-set identification with physics-guided spectral decomposition. After each phase prediction, PhaseMatcher re-estimates the contributions of all selected phases and the residual from the original observation and all selected reference patterns, accounting for physically plausible variation between reference patterns and the corresponding phase contributions in the observation. The resulting residual guides subsequent phase identification, while a separate stopping module determines when the phase set is complete. On synthetic mixtures and controlled mixtures constructed from measured single-phase patterns, PhaseMatcher improves complete-set identification over the evaluated baselines. On PhaseMix-135K, it also estimates contributions and residuals more accurately than scalar subtraction.

Abstract: Modeling the temporal evolution of macroscopic properties of complex systems is an important scientific task. To predict this evolution without full microscopic simulation, a common approach encodes microstates into compact latent states, learns their evolution, and reads out macroscopic predictions from the latent trajectory. These latent states are often learned through microstate reconstruction. However, with limited latent capacity, reconstruction can favor high-variance microscopic details over information needed for macroscopic prediction. Yet jointly learning latent states and their transition without reconstruction often fails to obtain latent dynamics that support accurate macroscopic prediction. We show that this failure can arise from latent scale collapse: shrinking the latent state scale reduces training loss while macroscopic evolution error remains large. Here, we propose a reconstruction-free framework to learn latent states with their dynamics for prescribed macroscopic prediction. Training alternates between updating the latent representation with the transition and next-state latent targets fixed, and updating the transition with the latent representation fixed. At inference, the trained model predicts macroscopic states recursively from an initial microstate. Our theoretical analysis characterizes reconstruction misalignment and scale collapse under joint training, and gives a sufficient condition for local convergence to correct latent dynamics for our method. Experiments on epidemic spreading on a lattice, mixing of two particle species, and polymer stretching demonstrate that the proposed method achieves substantially better macroscopic prediction over baselines.

Abstract: Molecular solubility directly affects key aspects of molecular development such as reaction feasibility, formulation performance, separation efficiency, and solvent selection. However, experimental measurement across solutes, solvents, and temperatures remains costly and sparsely sampled. Existing computational models often rely on fixed-solvent assumptions, deterministic formulations, or simplified representations of solute-solvent interactions, limiting their ability to capture complex molecular interactions, continuous temperature effects, and experimental uncertainty. Here, we introduce EnSol, an environment-aware probabilistic framework for molecular solubility prediction. EnSol represents the solute and solvent as molecular graphs and learns separate representations for each before bringing them together through cross-attention to capture solute-solvent interactions. Temperature is incorporated directly into the solvent environment through feature-wise modulation, and a mixture density network predicts full solubility distributions to capture both temperature-dependent behavior and experimental uncertainty. On the independent SolProp and Leeds benchmark datasets, EnSol achieved Spearman correlations of 0.876 and 0.601, respectively, outperforming state-of-the-art solubility prediction models across both benchmarks. Beyond computational benchmarking, experimental validation across chemically diverse solute-solvent pairs showed that EnSol maintained strong predictive performance and supported reliable solvent ranking, achieving a Spearman correlation of 0.715. These results show that EnSol can support reliable solubility prediction and solvent selection across diverse chemical systems while accounting for predictive uncertainty.

Abstract: Foundational machine-learning interatomic potentials (MLIPs) are transforming atomistic simulations by achieving near-ab initio accuracy across large chemical spaces at a fraction of the computational cost. A central challenge in using these tools for high-throughput property calculations is translating high-level scientific intent into adaptive simulation campaigns without compromising workflow rigour. We introduce El Agente Potente, an agentic system that combines typed execution graphs with a complementary coding mode for MLIPs-driven atomistic simulations. Typed execution graphs provide structured and provenance-aware execution for standardized workflows, with large language models (LLMs) restricted to planning and routing while deterministic Python components perform scientific computation and validation. Complementing this structured execution, a coding agent constructs customized workflows for tasks requiring greater procedural flexibility while invoking existing Potente functions for supported calculations. We demonstrate El Agente Potente across computational materials discovery, molecular energy-landscape exploration, adsorption, and catalytic reaction workflows, together with systematic benchmarks of reproducibility and LLM token cost. These results establish typed execution graphs and code-based workflow construction as complementary mechanisms for agentic scientific computing, combining controlled, auditable execution with the flexibility required for customized atomistic simulations

Abstract: Optimising chemical reactions across multiple objectives, such as yield, selectivity, and safety, is central to chemical synthesis, and model-driven approaches depend critically on how reaction components are represented. Established featurisations are either chemically uninformative, as with one-hot encodings, or, as with molecular descriptors, do not readily extend across chemically distinct components. For structurally and functionally diverse components, it is therefore unclear what a shared representation should contain. Constructing such a representation is itself a challenging research undertaking that must be revisited for each new reaction system. Here we bypass this step by learning the reaction representation dynamically from text. Textual descriptions of reaction conditions are encoded by a fine-tuned language model trained jointly with Gaussian process surrogates, yielding task-adaptive representations within a multi-objective Bayesian optimisation loop. Across nickel- and palladium-catalysed cross-couplings in both sequential and parallel experimentation regimes, this approach reaches optimisation convergence in fewer experiments than descriptor libraries or one-hot encoding. Applied prospectively to a palladium-catalysed cyanation spanning mixed ligand denticity and heterogeneous additives, and to a three-objective asymmetric hydrogenation across chiral iridium and ruthenium catalyst families, two rounds of high-throughput experimentation (192 reactions, under 3% of each design space) delivered conditions translating directly to gram scale in 94% and 84% isolated yield, the latter at 99.6% enantiomeric excess.

Abstract: Agitated filter dryers (AFDs) are a crucial unit operation in small molecule manufacturing that enables simultaneous filtration, washing, and drying of active pharmaceutical ingredients. One of the key challenges in AFDs is associated with undesired agglomeration, where the presence of hard agglomerates results in off-spec products, equipment damage, and additional downstream processing. This article presents a novel mechanistic model that describes the formation of soft and hard agglomerates during agitated filter drying. By integrating population balance and multiphysics modeling, the model can accurately predict the evolution of the product temperature, moisture content, and particle size distribution, and hence quantify the extend and impact of undesired agglomeration across various operating conditions. Our proposed model-based framework enables the rational design and operation of AFDs for improving the product quality and process reliability.

Abstract: Choosing a recovery process for scale-up requires connecting laboratory results with product requirements, process costs, and scale effects. We analyze records from Pacific Northwest National Laboratory's Computer Intelligence for Critical Element Recovery and Optimization (CICERO) workflow for autonomous selective precipitation. Active learning uses prior results to choose experiments. In a conditional retrospective benchmark with fitted models and recycled neodymium-iron-boron (NdFeB) magnet records, active learning finds the best recorded result with fewer experiments than nonadaptive space filling. Enrichment is the selected rare-earth-to-iron ratio relative to that in the feed. Adaptive policies reach the recorded enrichment maximum by 16 to 24 wells (individual experiments), versus 48. Our two-stage reconstruction ties two adaptive alternatives at 16 wells. Conditional analyses of recycled samarium-cobalt (SmCo) magnets show a Round 2 tradeoff between purity and nominal yield, the recovery fraction calculated from an assumed starting amount - NdFeB Round 1 routes differ in enrichment. Rankings for produced water from oil and gas extraction depend on phase and dilution assumptions requiring confirmation. We propose choosing batches by their expected reduction in downstream Bayes risk: the minimum expected loss among available process decisions under current beliefs. In exploratory simulations, a hybrid that filters candidates has lower estimated loss than the implemented joint search across routes and conditions. Differences involving the synthetic two-stage policy are small relative to estimation uncertainty. We outline a pre-registered prospective test under a shared loss and logging standard, requiring clarified measurements and records, a defined process decision and relevant outputs, credible economic inputs, and validation at the intended scale.