Abstract
Crystal polymorphism has a major impact on material properties such as thermal stability, bioavailability, and solubility. The application of co-crystals in the pharmaceutical industry requires polymorph screening to avoid unwanted phase transitions, which can cause property reduction. In this work, three polymorphs of urea–barbituric acid (1:1) co-crystals were investigated to describe the dynamic character of their H-bond networks and to explain the disappearance of the polar polymorph. For the studied polymorphs, Born–Oppenheimer molecular dynamics simulations were performed. Detailed analysis of hydrogen bonds and power spectra calculations were conducted using the obtained trajectories. The relative stability of each polymorph has been considered in terms of NVT and NVE ensembles. The results of computations were discussed in light of the analysis of H-bond propensities, coordination scores, and the obtained experimental data. To our knowledge, the polar form of urea–barbituric acid co-crystal can be called one of the first known examples of co-crystal disappearing polymorph.
Highlights
Polymorphism in co-crystal solids has been extensively studied in recent years, mainly because of its pivotal role in the understanding of self-assembly phenomena in molecular crystals.[1,2] The possibility to predict and control the production of stable and functional co-crystal materials and pharmaceuticals is the Holy Grail of crystal engineering.[1,3,4] The recently performed analysis of the Cambridge Structural Database[5] has indicated 600 entries of co-crystal polymorphs with 184 distinct chemical compositions.[6]
Crystal structure prediction (CSP) methods are most useful in foreseeing new polymorphs and in providing clues to their experimental realization.[33−36] as most density-functional theory (DFT) calculations performed for molecular organic crystals, those methods are based not on free energies but on “static lattice energies”
Anhydrous barbituric acid (BA, Sigma-Aldrich, 99.5%; the anhydrous state of BA was verified using PXRD); urea (U, Sigma-Aldrich, ≥99%); solvents purchased from Sigma-Aldrich: methanol, 2-propanol (≥99.8%), ethane-1,2diol (≥98%), glycerol (≥99%), 1-butanol (≥98%), ethyl acetate (≥99.5%), tetrahydrofurane (≥99.8%), acetonitrile (≥99.8%), and 1,4-dioxane (≥99%); solvents purchased from Avantor: ethanol (96%, pure p.a.), nitromethane (≥98%), petroleum ether, 2-butanol (≥99%), and 1-propanol (≥99.5%); and other used solvents: toluene (Lach-ner, ≥99%), n-hexane (Chempur, ≥99%), dimethyl sulfoxide (DMSO) (Fisher BioReagents, ≥99.7%), dimethylformamide (DMF) (Acros Organics, ≥99%), and acetone (Acros Organics, ≥99.8%)
Summary
Polymorphism in co-crystal solids has been extensively studied in recent years, mainly because of its pivotal role in the understanding of self-assembly phenomena in molecular crystals.[1,2] The possibility to predict and control the production of stable and functional co-crystal materials and pharmaceuticals is the Holy Grail of crystal engineering.[1,3,4] The recently performed analysis of the Cambridge Structural Database[5] has indicated 600 entries of co-crystal polymorphs with 184 distinct chemical compositions.[6]. Crystal structure prediction (CSP) methods are most useful in foreseeing new polymorphs and in providing clues to their experimental realization.[33−36] as most density-functional theory (DFT) calculations performed for molecular organic crystals, those methods are based not on free energies but on “static lattice energies” (energies at 0 K, neglecting zero-point motions).[34] As a result, the thermal effects are neglected in energy landscape assessment, which can cause the creation of many additional energy minima To overcome these limitations, molecular dynamics methods were introduced to the studies of polymorphism.[37,38] Recently, metadynamics simulations[39,40] were used to analyze the disappearing conformational polymorph of succinic acid.[41] In our studies, Born−Oppenheimer molecular dynamics (BOMD) calculations[42] were used to investigate the selfassembly and stability of three urea−barbituric acid (UBA) polymorphs.[43,44] The BOMD results were compared with the analysis of H-bond propensities,[45] coordination scores (CS),[46] and the previous experimental data in the context of known thermodynamic stability rules.[47,48] Despite numerous experimental and theoretical trials, the “metastability” of the polar UBA polymorph is still unclear.[49−54] To our knowledge, UBA form (II) can be called one of the first known examples of disappearing co-crystal polymorphs
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