Marc-Antoine Perrin

Revisiting the blind tests in crystal structure prediction: accurate energy ranking of molecular crystals.

In the 2007 blind test of crystal structure prediction hosted by the Cambridge Crystallographic Data Centre (CCDC), a hybrid DFT/MM method correctly ranked each of the four experimental structures as having the lowest lattice energy of all the crystal structures predicted for each molecule. The work presented here further validates this hybrid method by optimizing the crystal structures (experimental and submitted) of the first three CCDC blind tests held in 1999, 2001, and 2004. Except for the crystal structures of compound IX, all structures were reminimized and ranked according to their lattice energies. The hybrid method computes the lattice energy of a crystal structure as the sum of the DFT total energy and a van der Waals (dispersion) energy correction. Considering all four blind tests, the crystal structure with the lowest lattice energy corresponds to the experimentally observed structure for 12 out of 14 molecules. Moreover, good geometrical agreement is observed between the structures determined by the hybrid method and those measured experimentally. In comparison with the correct submissions made by the blind test participants, all hybrid optimized crystal structures (apart from compound II) have the smallest calculated root mean squared deviations from the experimentally observed structures. It is predicted that a new polymorph of compound V exists under pressure.

Polymorphism of progesterone: Relative stabilities of the orthorhombic phases I and II inferred from topological and experimental pressure‐temperature phase diagrams

Temperatures and melting enthalpies of orthorhombic Phases I and II of natural progesterone, together with the temperature dependence of their lattice parameters and the specific volume of the melt at ordinary pressure, have been determined. With these results, a topological pressure-temperature (P-T) phase diagram accounting for the thermodynamic relationships between these phases has been constructed by way of the Clapeyron equation. The dependence of the melting temperature on the pressure has also been determined for each phase by high-pressure differential thermal analysis. It was found that, upon increasing the pressure, the melting curves converge to the I-II-liquid triple point (T(I-II-liquid) = 459.4 K, P(I-II-liquid) = 149.0 MPa), in close agreement with its topological location. This entails that Phase II should exhibit a stable phase region at higher pressure.

Overall Monotropic Behavior of a Metastable Phase of Biclotymol, 2,2′-Methylenebis(4-Chloro-3-Methyl-Isopropylphenol), Inferred From Experimental and Topological Construction of the Related P-T State Diagram

The melt from the usual monoclinic phase (Phase I) of biclotymol (T(fusI) = 400.5 +/- 1.0 K, Delta(fus)H(I) = 36.6 +/- 0.9 kJ mol(-1)) recrystallizes into another phase, Phase II, that melts at T(fusII) = 373.8 +/- 0.2 K (Delta(fus)H(II) = 28.8 +/- 1.0 kJ mol(-1)). The transformation of Phase II into Phase I is found to be exothermic upon heating either as a direct process at 363 K or through a melting-recrystallization process (II --> liquid --> I). The melting curves, obtained from differential thermal analyses at various pressures ranging from 0 to 85 MPa, diverge as the pressure increases ((dP/dT)(fusI) = 2.54 +/- 0.07 MPa K(-1), (dP/dT)(fusII) = 5.14 +/- 0.85 MPa K(-1)). A topological P-T diagram with no stable phase region for Phase II, and similar to the 4th case of the P-T state diagrams formerly published by Bakhuis Roozeboom, is drawn, thus illustrating the overall monotropic behavior of Phase II.

Can crystal structure prediction guide experimentalists to a new polymorph of paracetamol

The results of an extensive in silico polymorph screen with the program GRACE of paracetamol in all 230 space groups with one and two molecules in the asymmetric unit are presented. The three experimentally known forms I, II and III are found in the list of predicted crystal structures in the correct stability order with rank 1, 3 and 6, respectively. Structures with ranks 3 to 8 exhibit the same motif of 2-D hydrogen-bonded sheets. The hydrogen-bonding scheme of the rank 2 structure is markedly different from the known forms, consisting of two interpenetrating 3-D hydrogen-bonded networks. The excellent agreement with experiment and the prediction of one and only one new packing motif within the lattice energy window delimited by the known forms confirms the fitness for crystal structure prediction of the employed methodology. Analysis of the structure at rank 2 is used to propose experimental strategies that may lead to a new form IV of paracetamol.

Rimonabant Dimorphism and Its Pressure–Temperature Phase Diagram: A Delicate Case of Overall Monotropic Behavior

Crystalline polymorphism occurs frequently in the solid state of active pharmaceutical ingredients, and this is problematic for the development of a suitable dose form. Rimonabant, an active pharmaceutical ingredient developed by Sanofi and discontinued because of side effects, exhibits dimorphism; both solid forms have nearly the same melting temperatures, melting enthalpies, and specific volumes. Although the problem may well be academic from an industrial point of view, the present case demonstrates the usefulness of constructing pressure-temperature phase diagrams by direct measurement as well as by topological approach. The system is overall monotropic and form II is the more stable solid form. Interestingly, the more stable form does not possess any hydrogen bonds, whereas the less stable one does.

Differential Water Thermodynamics Determine PI3K-Beta/Delta Selectivity for Solvent-Exposed Ligand Modifications

Phosphoinositide 3-kinases (PI3Ks) are involved in important cellular functions and represent desirable targets for drug discovery efforts, especially related to oncology; however, the four PI3K subtypes (α, β, γ, and δ) have highly similar binding sites, making the design of selective inhibitors challenging. A series of inhibitors with selectivity toward the β subtype over δ resulted in compound 3(S), which has entered a phase I/Ib clinical trial for patients with advanced PTEN-deficient cancer. Interestingly, X-ray crystallography revealed that the modifications making inhibitor 3(S) and related compounds selective toward the β-isoform do not interact directly with either PI3Kβ or PI3Kδ, thereby confounding rationalization of the SAR. Here, we apply explicit solvent molecular dynamics and solvent thermodynamic analysis using WaterMap in an effort to understand the unusual affinity and selectivity trends. We find that differences in solvent energetics and water networks, which are modulated upon binding of different ligands, explain the experimental affinity and selectivity trends. This study highlights the critical role of water molecules in molecular recognition and the importance of considering water networks in drug discovery efforts to rationalize and improve selectivity.

Liquid–liquid miscibility gaps and hydrate formation in drug–water binary systems: Pressure–temperature phase diagram of lidocaine and pressure–temperature–composition phase diagram of the lidocaine–water system

The pressure-temperature (P-T) melting curve of lidocaine was determined (dP/dT = 3.56 MPa K(-1)), and the lidocaine-water system was investigated as a function of temperature and pressure. The lidocaine-water system exhibits a monotectic equilibrium at 321 K (ordinary pressure) whose temperature increases as the pressure increases until the two liquids become miscible. A hydrate, unstable at ordinary pressure, was shown to form, on increasing the pressure, from about 70 MPa at low temperatures (200-300 K). The thermodynamic conditions of its stability were inferred from the location of the three-phase equilibria involving the hydrate in the lidocaine-water pressure-temperature-mole fraction (P-T-x) diagram.

Validation of dispersion-corrected density functional theory calculations for the crystal structure prediction of molecular salts: a crystal structure prediction study of pyridinium chloride

A crystal structure prediction study for the molecular salt pyridinium chloride was carried out with Z′ = 1 and Z′ = 2 in all 230 space groups. The predicted crystal structures were ranked by energy using dispersion-corrected density functional theory calculations, with the dispersion-correction parameterised against uncharged systems only. The experimental structures are ranked 1st and shared 2nd, which suggests that the dispersion-correction parameters are likely to be at least partially transferable to charged systems. For the structure generation step, a high-accuracy tailor-made force field was prepared for pyridinium chloride. The accuracy of the tailor-made force field is comparable to those for neutral molecules. A problem caused by spurious pseudo-symmetry due to the use of a cascade of energy potentials of different accuracies is described, as is its solution. Our calculations confirm that a previously reported P21/m structure for pyridinium chloride should have been reported in P, our calculations suggest the existence of a high-pressure polymorph in Pnma, and our calculations suggest that the high-temperature phase of pyridinium chloride might be subtly different from the high-temperature phase of pyridinium iodide.

Crystal Structures and Phase Relationships of 2 Polymorphs of 1,4-Diazabicyclo[3.2.2]nonane-4-Carboxylic Acid 4-Bromophenyl Ester Fumarate, A Selective α-7 Nicotinic Receptor Partial Agonist

Two polymorphs of the 1:1 fumarate salt of 1,4-diazabicyclo[3.2.2]nonane-4-carboxylic acid 4-bromophenyl ester, developed for the treatment of cognitive symptoms of schizophrenia and Alzheimer disease, have been characterized. The 2 crystal structures have been solved, and their phase relationships have been established. The space group of form I is P2₁/c with a unit-cell volume of 1811.6 (5) Å(3) with Z = 4. The crystals of form I were 2-component nonmerohedral twins. The space group of form II is P2₁/n with a unit-cell volume of 1818.6 (3) Å(3) with Z = 4. Relative stabilities have been inferred from experimental and topological P-T diagrams exhibiting an overall enantiotropic relationship between forms I and II although the solid-solid transition has never been observed. The slope of the I-II equilibrium in the P-T diagram is negative, form II is the stable phase below the solid-solid transition temperature of 371 K, and form I exhibits a stable melting equilibrium. The I-II transition temperature has been obtained from the intersection of the sublimation curves of the 2 solid forms.

Differentiating amorphous mixtures of cefuroxime axetil and copovidone by X-ray diffraction and differential scanning calorimetry.

The amorphous, molecular solid dispersion of cefuroxime axetil and copovidone with the mass ratio 71/29 is compared to its pure components in the amorphous state and to an amorphous mechanical mixture with the same mass ratio. Calorimetric studies demonstrate that all these materials are vitreous. By using X-ray diffraction profiles, a clear difference can be observed between the local order of the solid dispersion and that of the mechanical mixture. More generally, it is shown how the presence or absence of additivity in the diffraction data can be used to distinguish between different amorphous mixtures.