Hydrogen-bond motifs in the crystals of hydrophobic amino acids.

A computer program has been developed to survey a set of crystal structures for hydrogen-bond motifs. Possible ring and chain motifs are generated automatically from a user-defined list of interacting molecular fragments and intermolecular interactions. The new program was used to analyse the hydrogen-bond networks in the crystals of 52 zwitterionic alpha-amino acids. All the possible chain motifs (repeating 1-4 molecules) are frequent, while the frequency of ring motifs (2-6 molecules) ranges from 0 to 85% of the structures. The list of motifs displayed by each structure reveals structural similarities and it can be used to compare polymorphs. The motifs formed in cocrystals of alpha-amino acids and in crystals of beta- and gamma-amino acids are similar to those of alpha-amino acids.

Dipolar C[triple-bond]N...C[triple-bond]N interactions in organic crystal structures: database analysis and calculation of interaction energies.

The Cambridge Structural Database (CSD) has been used to study nonbonded interactions between dipolar cyano groups. The analysis shows that C[triple-bond]N...C[triple-bond]N interactions form in an analogous manner to those involving carbonyl groups, and with the same interaction motifs: a dominant antiparallel dimer (57.5%) together with smaller populations of perpendicular (19.4%) and sheared parallel (23.0%) motifs. Ab initio calculations using intermolecular perturbation theory (IMPT) show an attractive C[triple-bond]N...C[triple-bond]N interaction in the dominant antiparallel dimer, with E(t) = -20.0 kJ mol(-1) at d(C...N) = 3.30 A and with the motif having a shear angle close to 102 degrees . The antiparallel C[triple-bond]N...C[triple-bond]N interaction is therefore slightly weaker than the analogous C=O...C=O dimer (-23.5 kJ mol(-1)), but both interactions have attractive energies similar to that of a medium-strength hydrogen bond and, where sterically favoured, they are important in the stabilization of extended crystal structures.

Knowledge-based model of hydrogen-bonding propensity in organic crystals.

A new method is presented to predict which donors and acceptors form hydrogen bonds in a crystal structure, based on the statistical analysis of hydrogen bonds in the Cambridge Structural Database (CSD). The method is named the logit hydrogen-bonding propensity (LHP) model. The approach has a potential application in identifying both likely and unusual hydrogen bonding, which can help to rationalize stable and metastable crystalline forms, of relevance to drug development in the pharmaceutical industry. Whilst polymorph prediction techniques are widely used, the LHP model is knowledge-based and is not restricted by the computational issues of polymorph prediction, and as such may form a valuable precursor to polymorph screening. Model construction applies logistic regression, using training data obtained with a new survey method based on the CSD system. The survey categorizes the hydrogen bonds and extracts model parameter values using descriptive structural and chemical properties from three-dimensional organic crystal structures. LHP predictions from a fitted model are made using two-dimensional observables alone. In the initial cases analysed, the model is highly accurate, achieving approximately 90% correct classification of both observed hydrogen bonds and non-interacting donor-acceptor pairs. Extensive statistical validation shows the LHP model to be robust across a range of small-molecule organic crystal structures.

Lactonisation--a degradation pathway for active pharmaceutical compounds: an in silico study in amorphous trehalose.

The lactonisation of a CCR1 inhibitor (CC chemokine receptor 1, involved in autoimmune diseases) featuring a hydroxyl group in a gamma-position (gamma-OH) with respect to an amide group has been investigated in silico. The two key steps of the lactonisation reaction are (i) rearrangement to an optimal conformation and (ii) the formation of the lactone (ring closure) and expulsion of NH3. Quantum chemical calculations in the gas phase were employed to identify conformers of the molecule with favorable starting geometries for a lactonisation reaction. In total, calculations of 1296 conformers revealed that it is energetically feasible for an inhibitor molecule to adopt a conformation where the carbon atom of the amide group (C(amide)) is suitably close to the oxygen atom of the gamma-OH (O(gamma)) to facilitate a successful lactonisation reaction. Additionally, molecular dynamics methods were used to show that rearrangement to a suitable conformer for lactonisation to occur happens to a lesser extent when the CCR1 inhibitor was embedded in an amorphous trehalose matrix (a model carbohydrate excipient). The mechanism of the actual lactonisation was investigated using the complete Linear Synchronous Transit/Quadratic Synchronous Transit (LST/QST) method. This was performed in both the gas phase and in water and was found to be a concerted reaction.

Screening for pharmaceutical cocrystal hydrates via neat and liquid-assisted grinding.

The formation of cocrystal hydrates represents a potential route to achieve molecular materials with improved properties, particularly stability under conditions of high relative humidity. We describe the use of neat and liquid-assisted grinding for screening for hydrated forms of pharmaceutical cocrystals. In the case of liquid-assisted grinding, water is present in the reaction mixture as a liquid, whereas in the case of neat grinding, it is introduced by employing crystalline hydrates as reactants. The ability to form a cocrystal hydrate by either of the two methods appears to be variable, depending on the choice of cocrystal components. Theophylline readily forms a cocrystal hydrate with citric acid. This contrasts with the behavior of caffeine, which provides only an anhydrous cocrystal ("caffeine citrate") even when both reactants are crystalline hydrates. The preference of theophylline to form a cocrystal hydrate is qualitatively explained by similarity between crystal structures of the products and reactant hydrates. Overall, liquid-assisted grinding is less sensitive to the form of the reactant (i.e., hydrate or anhydrate) than neat grinding. For that reason liquid-assisted grinding appears to be a more efficient method of screening for cocrystal hydrates, and it is also applicable to screening for hydrates of APIs.

Solvent inclusion in form II carbamazepine.

We report on experimental and theoretical evidence for solvent inclusion in form II carbamazepine (R3) and discuss the implications for the formation and stability of this form.

The glass transition temperatures of amorphous trehalose-water mixtures and the mobility of water: an experimental and in silico study.

Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of models of trehalose and three amorphous trehalose-water mixtures (2.9%, 4.5% and 5.3% (w/w) water, respectively) as a function of temperature. Plots of specific volume versus temperature exhibit a characteristic change in slope when the amorphous systems change from the glassy to the rubbery state and the intersection of the two regression lines provides an estimate of the glass transition temperature T(g). A comparison of the calculated and experimental T(g) values, as obtained from differential scanning calorimetry, shows that despite the predicted values being systematically higher (about 21-26K), the trend and the incremental differences between the T(g) values have been computed correctly: T(g)(5.3%(w/w))

Search for a predicted hydrogen bonding motif--a multidisciplinary investigation into the polymorphism of 3-azabicyclo[3.3.1]nonane-2,4-dione.

The predictions of the crystal structure of 3-azabicyclo[3.3.1]nonane-2,4-dione submitted in the 2001 international blind test of crystal structure prediction (CSP2001) led to the conclusion that crystal structures containing an alternative hydrogen bonded dimer motif were energetically competitive with the known catemer-based structure. Here we report an extensive search for a dimer-based crystal structure. Using an automated polymorph screen a new catemer-based metastable polymorph (form 2) and two new catemer-based solvates were found, and concurrent thermal studies reproduced form 2 and identified a plastic phase (form 3), whose powder X-ray diffraction pattern was consistent with the cubic space group I23 (a = 7.5856(1) A). Computational studies on the monomer showed that the imide N-H was a weak hydrogen bond donor, rationalizing the occurrence of the plastic phase which involved the breaking of all hydrogen bonds, and modeling of small clusters showed that dimers could easily reorganize to give the catemer. FTIR spectra confirmed the weakness of the hydrogen bond, with the solute showing no self-assembly in solution. It is concluded that the weakness of the N-H donor, coupled with the globular shape of the molecule, allows unusually facile transformation between alternative hydrogen bonding motifs during aggregation and nucleation.

Exploring cocrystal-cocrystal reactivity via liquid-assisted grinding: the assembling of racemic and dismantling of enantiomeric cocrystals.

The reaction between pairs of enantiomeric cocrystals involving caffeine or theophylline and a chiral cocrystal former has been investigated by liquid-assisted grinding: we demonstrate two different outcomes for such cocrystal-cocrystal reactions.

Prediction and observation of isostructurality induced by solvent incorporation in multicomponent crystals.

The crystal structures of two pharmaceutical molecules-carbamazepine and its 10,11-dihydro derivative-with acetic acid have been successfully predicted by computational methods. While the crystalline structure of the former was known a priori, no structural information was available for the latter. Possible crystal structures were generated in silico before any experimental work was performed. Although the crystal structures of the pure drug molecules are very different, incorporation of acetic acid in their crystal lattices results in isomorphic products.

Glass transition temperature of glucose, sucrose, and trehalose: an experimental and in silico study.

Isothermal-isobaric molecular dynamics simulations are used to calculate the specific volume of models of different amorphous carbohydrates (glucose, sucrose, and trehalose) as a function of temperature. Plots of specific volume vs temperature exhibit a characteristic change in slope when the amorphous systems change from the glassy to the rubbery state. The intersection of the regression lines of data below (glassy state) and above (rubbery state) the change in slope provides the glass transition temperature (T(g)). These predicted glass transition temperatures are compared to experimental T(g) values as obtained from differential scanning calorimetry measurements. As expected, the predicted values are systematically higher than the experimental ones (about 12-34 K) as the cooling rates of the modeling methods are about a factor of 10(12) faster. Nevertheless, the calculated trend of T(g) values agrees exactly with the experimental trend: T(g)(glucose) < T(g)(sucrose) < T(g)(trehalose). Furthermore, the relative differences between the glass transition temperatures were also computed precisely, implying that atomistic molecular dynamics simulations can reproduce trends of T(g) values in amorphous carbohydrates with high quality.

Screening for crystalline salts via mechanochemistry.

Neat grinding and solvent-drop grinding methods are found to be effective screening tools for indicating the potential for crystalline salt formation involving a given acid-base pair, as demonstrated with two model pharmaceuticals.

Investigating the latent polymorphism of maleic acid.

The unexpected appearance of a new polymorph of maleic acid is reported and a computational study addresses the predictability of this new polymorph and future potential polymorphism.

Selective polymorph transformation via solvent-drop grinding.

A method of inducing specific polymorph transformations is exemplified with two single-component systems, whereby a given crystal form undergoes conversion when subjected to solid state grinding in the presence of a minor quantity of a certain solvent.

Formation of quinol co-crystals with hydrogen-bond acceptors.

The crystal structures of eight new co-crystals of quinol with pyrazine, piperazine, morpholine, pyridine, piperidine, 4,4'-bipyridine, N-methylmorpholine and N,N'-dimethylpiperazine are reported. Quinol forms 1:1 co-crystals with pyrazine, piperazine and N,N'-dimethylpiperazine, but 1:2 co-crystals with morpholine, 4,4'-bipyridine, N-methylmorpholine, pyridine and piperidine. This difference can be rationalized in most cases by the presence of, respectively, two or one strong hydrogen-bond acceptor(s) in the guest molecule. The exception to this generalization is 4,4'-bipyridine, which forms a 1:2 co-crystal, possibly to optimize crystal packing. All structures are dominated by hydrogen bonding between quinol and the guest molecules. A doubly bridging motif, which connects pairs of quinol and guest molecules via NH...O or CH...O interactions, is present in all but the sterically hindered N,N'-dimethylpiperazine and N-methylmorpholine co-crystals.

Structures of the monofluoro- and monochlorophenols at low temperature and high pressure.

2-Fluorophenol, 3-fluorophenol and 3-chlorophenol were recrystallized from frozen solids at 260, 263 and 283 K. All compounds were also crystallized by the application of high pressure (0.36, 0.12 and 0.10 GPa). While 3-fluorophenol and 3-chlorophenol yielded the same phases under both conditions, different polymorphs were obtained for 2-fluorophenol. 4-Chlorophenol was crystallized both from the melt and from benzene to yield two different ambient-pressure polymorphs; crystallization from the melt at 0.02 GPa yielded the same phase as from benzene at ambient pressure. 3-Fluorophenol is unusual in forming a hydrogen-bonded chain along a 2(1) screw axis. Such behaviour is usually only observed for small alcohols, but here it appears to be stabilized by intermolecular C-H...F hydrogen-bond formation. 3-Chlorophenol is a more typical large alcohol and emulates a fourfold screw axis with two independent molecules positioned about a 2(1) axis, although there are significant distortions from this ideal geometry. The two phases of 4-chlorophenol consist of chains or rings connected by C-Cl...H interactions. The low-temperature and high-pressure polymorphs of 2-fluorophenol consist of chains of molecules connected through OH...OH hydrogen bonds; while inter-chain C-H...F interactions are significant at high pressure, there are none in the low-temperature form.

Solvent-drop grinding: green polymorph control of cocrystallisation.

By grinding with a minimal addition of a solvent of appropriate polarity, control over the polymorphic outcome of a novel cocrystallisation involving the model pharmaceutical compound caffeine may be achieved.

A database survey of molecular and crystallographic symmetry.

The point of contact between molecular and crystallographic symmetries is that of the Wyckoff position, the position at which a molecule resides in a crystal structure. These Wyckoff positions may have the same symmetry as the molecules, some symmetry in common with the molecules or no symmetry at all. Using CSDSymmetry [Yao et al. (2002). Acta Cryst. B58, 640-646], a relational database containing information pertaining to the symmetry of molecules and the crystal structures that play host to them, the distribution of molecules over Wyckoff positions and the occupancy of Wyckoff positions in crystal structures is presented. Analysis of these data has led to the characterization of some relationships between molecular and crystallographic symmetry.

The formation of paracetamol (acetaminophen) adducts with hydrogen-bond acceptors.

The crystal structures of five hemiadducts of paracetamol with 1,4-dioxane, N-methylmorpholine, morpholine, N,N-dimethylpiperazine and piperazine and a related 1:1 adduct of paracetamol with 4,4'-bipyridine are described. All structures are characterized by the formation of chains of paracetamol molecules, which are linked via either OHtriplebondO=C interactions [C(9) chains in graph-set notation] or NHtriplebondO=C interactions [C(4) chains], depending on the presence or absence of substituent groups on the guest molecule. In all cases except for the morpholine and bipyridine adducts these chains are connected by hydrogen-bond interactions with the guest molecules, which reside on crystallographic inversion centres. In the bipyridine adduct this linkage also involves a pi-stacking interaction; in the morpholine adduct it is formed between the OH groups of two opposed paracetamol molecules. Most adducts (that with 4,4'-bipyridine is an exception) decompose on heating to give monoclinic paracetamol. This is the first systematic study of a series of co-crystals containing paracetamol.