Picking out polymorphs: H-bond prediction and crystal structure stability

A methodology has been developed to predict the propensity for hydrogen bonds to form in crystal structures, treating each potential H-bond as a binary response variable, and modelling its likelihood using a set of relevant chemical descriptors [1]. Modelling is tailored to a target using chemically similar known structures, from e.g. the Cambridge Structural Database [2], making it accessible to the complete spectrum of organic structures, including solvates, hydrates and cocrystals. Recent work has developed the approach to predicting interand intramolecular H-bonds when either type can occur. By way of a comparison between possible and observed H-bonds, the method has been applied to assess structural stability, which shows much promise in the domain of polymorph screening in the pharmaceutical industry. We will introduce the methodology and illustrate its application using a selection of pharmaceutical compounds, one of which will be Abbott’s wellpublicised anti-HIV medication ritonavir (Norvir™). Owing to a hidden, more stable form II with much lower bioavailability, ritonavir was temporarily withdrawn from the market with significant financial impact [3]. Our method quickly suggests a real threat of polymorphism in this compound, and strongly supports the relative stability of form II over form I. For all examples, the high predictivity of the method is emphasised

Evaluation of spring rye forms similarity on the basis of selected technological traits

Celem pracy była ocena podobieństwa 20 kolekcyjnych form żyta jarego pochodzących z różnych stref klimatycznych na podstawie kilku cech technologicznych z wykorzystaniem analizy skupień Warda. Doświadczenia polowe zakładano metodą losowanych bloków w czterech powtórzeniach w dwóch miejscowościach przez trzy lata. Analizowano masę 1000 ziaren (g), masę hektolitra (kg) oraz zawartość białka ogólnego (%), lizyny (mg·g⁻¹ ziarniaków) i włókna (mg·g⁻¹ ziarniaków). Analiza wariancji wykazała istotne zróżnicowanie środowisk dla wszystkich badanych cech. Stwierdzono również istotne zróżnicowanie badanych genotypów żyta jarego dla wszystkich badanych cech, za wyjątkiem zawartości włókna w ziarnie. Dla analizowanych cech technologicznych ziarna, oprócz zawartości włókna w ziarnie, wystąpiła również istotna interakcja genotypowo-środowiskowa. Wykreślony dendrogram według metody najdalszego sąsiedztwa Warda pozwolił na podział badanych obiektów na grupy i określenie odległości między nimi. Otrzymano jedenaście grup jednorodnych, z czego aż osiem (SMH-01, 'Gotav', 'Sorom', 'Petka', 'Żyto jare P Grandosa', 'Zenit', 'Wrens Abruzzi', Tiroler') stanowią pojedyncze genotypy. Najbardziej podobne do siebie, pod względem badanych cech jakościowych, okazało się 7 populacji żyta jarego: DL 67/176, DL 67/190, Tiroler Smolicki', Tosevschi', 'Priaborschi', 'Gazelle', 'Bred Bosch'. Następne 2 oddzielne grupy utworzyły również: 'Somro', 'Strzekęcińskie' i SMH-02 oraz 'Ludowe' i 'Karlshulder'.The aim of study was to evaluate the similarity of 20 spring rye forms originating from different climatic zones for several technological characters with the use of Ward's cluster analysis. Field experiments were conducted for three years using a randomised complete block design with four replications at two sites. 1000 grain weight, a hectolitre weight, protein, lysine and fiber contents in grain were analysed. Variance analyses showed significant differentiation of environments for investigated traits. Significant differentiation of genotypes and genotype × environment interaction for all traits, except of the fiber content, followed the cluster analysis to divide the genotypes into groups and to determine distances between them. Out of eleven homogeneous groups, eight were of single geno types (SMH-01, 'Gotav', 'Sorom', 'Petka', 'Żyto jare P. Grandosa', 'Zenit', 'Wrens Abruzzi', Tiroler'). Very similar to each other were 7 populations of spring rye: DL 67/176, DL 67/190, 'Tiroler Smolicki', Tosevschi', 'Priaborschi', 'Gazelle', 'Bred Bosch'. The populations 'Somro', 'Strzekęcińskie', SMH-02, 'Ludowe' and 'Karlshulder' formed another 2 separate groups

Truly prospective prediction: inter- and intramolecular hydrogen bonding

Accurately predicting which H-bonds might form in an organic crystal structure is demonstrated in a prospective, chronological setting using our recently developed method. The extent of correct classification for present and absent H-bonds is assessed whereby training and trial data are separated on the basis of age; the choice of cut-off is termed the model date. An encouragingly high predictivity is maintained for H-bonds in target structures published over the last 7–8 years, indicating promising future application toward novel structures. Predictions are computed using probability models trained for chosen target compounds using existing crystal structures in the public domain. An extension to the prediction of intramolecular H-bonds is also applied and is seen to be significant when considering the combination of possible H-bonds for target structures. Two target systems are selected for illustration: an amino-chloride salt hydrate and an amido-carboxylic acid

Persistent hydrogen bonding in polymorphic crystal structures

The significance of hydrogen bonding and its variability in polymorphic crystal structures is explored using new automated structural analysis methods. The concept of a chemically equivalent hydrogen bond is defined, which may be identified in pairs of structures, revealing those types of bonds that may persist, or not, in moving from one polymorphic form to another. Their frequency and nature are investigated in 882 polymorphic structures from the Cambridge Structural Database. A new method to compare conformations of equivalent molecules is introduced and applied to derive distinct subsets of conformational and packing polymorphs. The roles of chemical functionality and hydrogen-bond geometry in persistent interactions are systematically explored. Detailed structural comparisons reveal a large majority of persistent hydrogen bonds that are energetically crucial to structural stability

Analysis of xenia in F1 seeds of yellow-grain winter-rye lines.

The object of research were F1 hybrid grains of winter rye resulting from the topcross of 90 yellow-seed inbred lines with the green-seed tester SMH-108. The degree of crossing ability and the effect of xenia on 1000-grain weight were confirmed. In the present investigation quantitative xenia was analysed with regard to the green colour of grain. In the collection of 90 inbred lines of yellow grain differences in% of crossing were ascertained and in 26.7% of the analysed lines a significant quantitative xenia (1000-grain weight) was found. Among the 90 lines as much as 28.9% gave, in conditions of open pollination, from 66 to 85% of hybrid grain. Four lines were selected, which gave a quantitative xenia in 38, 25, 20 and 12% and crossing of 57, 84, 58 and 74%. These lines may be of practical use in producing heterosis hybrids

Knowledge-based H-bond prediction to aid experimental polymorph screening

With an ever increasing regulatory and financial emphasis on solid form screening in the pharmaceutical industry, a knowledge-based method has been developed to assess crystal stability based on hydrogen bonding. An application is illustrated for the polymorphic drug ritonavir (Norvir™). The method quickly suggests a real threat of polymorphism in this compound by quantifying the likelihood of competing H-bonds, and strongly supports the relative stability of form II over form I. For the first time, H-bond geometry data are also reported following structure redeterminations deposited recently in the Cambridge Structural Database. The method's speed and versatility are emphasized, facilitating future application in assisting solid form selection of a diverse range of compounds

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 ~ 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

Universal prediction of intramolecular hydrogen bonds in organic crystals

A complete exploration of intramolecular hydrogen bonds (IHBs) has been undertaken using a combination of statistical analyses of the Cambridge Structural Database and computation of ab initio interaction energies for prototypical hydrogen-bonded fragments. Notable correlations have been revealed between computed energies, hydrogen-bond geometries, donor and acceptor chemistry, and frequencies of occurrence. Significantly, we find that 95% of all observed IHBs correspond to the five-, six- or seven-membered rings. Our method to predict a propensity for hydrogen-bond occurrence in a crystal has been adapted for such IHBs, applying topological and chemical descriptors derived from our findings. In contrast to intermolecular hydrogen bonding, it is found that IHBs can be predicted across the complete chemical landscape from a single optimized probability model, which is presented. Predictivity of 85% has been obtained for generic organic structures, which can exceed 90% for discrete classes of IHB