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Cambridge Crystallographic Data Centre
The CSD Solid Form Suite provides knowledge-based informatics tools for improving effectiveness, quality and risk assessment in the development of solid formulations of drugs, agrochemicals and molecular materials.
Solid Form Suite
The CambridgeStructural Database
www.ccdc .cam.ac .uk
Polymorphism Risk Assessment
Polymorphism risk assessment based on a statistical analysis of hydrogen bondingpatterns.
• Quantifying the risk of polymorphism: The Hydrogen Bond Propensity tool helpsscientists to quantify the risk of polymorphism allowing them to make informeddecisions on which crystalline form to develop. The tool, applied to known crystalstructures and even 2D renditions of a molecular structure, can advance theexperimental screening and selection of drug crystal forms, the first step towardsensuring Quality by Design.
• H-bond propensity: Probabilities for hydrogen bond pairings to form in the targetsystem are calculated from a statistical model built from relevant structures in theCSD. The model [6-8] encapsulates information regarding the environment of thefunctional groups, ensuring the prediction is specific to the target molecule.Combining these propensities for hydrogen bond formation with information abouthow often a functional group participates in an H-bond allows the in-silicogeneration of chemically reasonable alternative crystal forms. The resultant view ofthe solid state landscape addresses questions such as: how likely is polymorphism,and is there the possibility of a more stable form?
Solid Form Informatics
Enabling the rational design of solid forms based on the knowledge containedwithin more than 600,000 crystal structures.
• Solid Form Informatics: Solid Form Informatics supports key decisions [1] aboutdevelopment routes of solid formulations of drugs, agrochemicals and molecularmaterials. It provides knowledge-based assessment of potential polymorphism andassociated manufacturing risks, as well as information vital to reformulation and thetuning of property profiles [2]. Solid Form Informatics distils the vast amount ofstructural data available today into targeted and actionable information [3]. It ispoised to become a powerful new asset supporting a Quality by Design approach [4]and its adoption can help significantly reduce the risk of late stage failure that hasbeen so costly to the industry.
• Addressing development needs: Developed with a consortium of majorpharmaceutical and agrochemical companies, the CSD Solid Form Suite includespredictive analytics methods that exploit the vast wealth of structural knowledge inthe Cambridge Structural Database (CSD) [5]. The CSD Solid Form Suite is designedto integrate neatly into a lab chemist's workflow and presents results in a form thatsupports form screening, selection and polymorphism risk assessment.
• Predictive analytics: Given the millions of intermolecular interactions containedwithin the CSD and broad coverage of relevant pharmaceutical structures, it hasbecome possible to derive quantitative and actionable information for substancedevelopment and risk assessment [3]. This advance is based on the combination oflarge datasets and predictive analytics methods i.e. the likelihood of a certainbehaviour predicted from an analysis of recorded behaviour. The technique puts keyfigures of merit regarding development risks into the hands of scientists and projectmanagers and is qualitatively different to pure database searches, which provideinteresting insights but lack the statistical rigour required for risk assessment.
• The Cambridge Structural Database: Established in 1965, the CSD [5] is the world’srepository for small-molecule organic and metal-organic crystal structures.Containing the results of over 600,000 X-ray and neutron diffraction experiments thisunique database of accurate 3D structures has become an essential resource toscientists around the world.
The CCDC archived the 600,000th crystal structure to the CSD in
January 2012. The histogram shows the growth of the CSD from
1970 to present. Each crystal structure undergoes extensive
validation ensuring that the CSD is maintained to the highest
possible standards.
H-bond propensity output chart for omeprazole. The observed
structure (shown in pink) is found to be the best in terms of
both propensity and participation. It is also well separated from
other possible structures, indicating that it is unlikely that
competitive polymorphs exist.
White papers introducing the benefits of adopting an informatics approach to solid formdesign are available from the CCDC website. A range of case studies and recordedwebinars illustrating how the CSD Solid Form Suite can be applied to a diverse range ofdevelopment problems, including analysis of polymorphism, co-crystallisation and hydrateformation, are also available.
References[1] M. Ticehurst and R. Docherty, From Molecules to Pharmaceutical Products – The Drug Substance/Drug
Product Interface, Am. Pharm. Rev., 2007, 9 (7), 32-36.
[2] P. A. Wood, M. A. Oliveira, A. Zink, and M. B. Hickey, CrystEngComm (2012) 14. In Press.
[3] P. T. A. Galek, E. Pidcock, P. A. Wood, I. J. Bruno, C. R. Groom, CrystEngComm (2012) 14. In Press
[4] R. Docherty, T. Kougoulos and K. Horspool, Materials Science and Crystallization: The Interface of DrugSubstance and Drug Product, Am. Pharm. Rev., 2009, Sept-Oct, 34-43.
[5] F. H. Allen, Acta Cryst., B58, 380-388, 2002.
[6] P. T. A. Galek, L. Fabian,W. D. S. Motherwell, F. H. Allen and N. Feeder, Acta Cryst., Sect. B, 2007, 63, 768-782.
[7] P. T. A. Galek, F. H. Allen, L. Fabian and N. Feeder, CrystEngComm, 2009, 11, 2634-2639.
[8] P. T. A. Galek, L. Fabian and F. H. Allen, CrystEngComm, 2010, 12, 2091-2099.
[9] I. J. Bruno, J. C. Cole, M. Kessler, Jie Luo, W. D. S. Motherwell, L. H. Purkis, B. R. Smith, R. Taylor, R. I. Cooper, S.E. Harris and A. G. Orpen, J. Chem. Inf. Comput. Sci., 44, 2133-2144, 2004
[10] C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington, P. McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J.van de Streek, J. Appl. Cryst., 41, 466-470, 2008.
[11] S. L. Childs, P. A. Wood, N. Rodriguez-Hornedo, L. S. Reddy and K. I. Hardcastle, Cryst. Growth Des., 9, 1869-1888, 2009.
White Papers, Case Studies & Further Information
www.ccdc .cam.ac .uk
Stability
Better understand the stability of your active ingredient by analysing CSDinformation.
• Find similar structures: By interrogating the world’s repository of crystal structuredata, you can find and compare other known structures containing the compound(s)in your crystal form such as polymorphs, hydrates, solvates, salts and co-crystals. Thestructures of closely related chemical analogues can also be easily located viasubstructure-based and chemical similarity searching.
• Understand molecular geometry: Pre-computed knowledge-based libraries ofstructural information [9] can be used to rapidly validate the complete geometry ofyour structure and identify any unusual or strained features without the need toconstruct complex search queries, or carry out detailed data analyses. Anappreciation of the conformational preferences of your compound will aid theunderstanding and control of its solid-state behaviour.
• Explore interaction patterns: By identifying and exploring networks ofintermolecular contacts you will gain an understanding of the key interactions thatdrive crystal packing in your structure. The strengths and weaknesses of structurescan be assessed by searching for extended functional group interaction motifsquickly and easily [10]. Determine which functional groups in your molecule aremost likely to pair up based on frequency of occurrence of motifs in the CSD.Investigate alternative interaction patterns that might be available in other crystalforms (e.g. polymorphs, hydrates and co-crystals).
• Compare packing patterns: The CSD Solid Form Suite enables you to quantifysimilarity and differences between polymorphs, hydrates and solvates. You can easilyfind groups of similar structures amongst families of polymorphs and multi-component systems [11]. Regions of structural similarity can be identified by flexiblysearching for any arrangement of atoms or functional groups in 3D space using acrystal structure as a template and finding the most closely matched structures.
Results of a crystal packing similarity search on the
carbamazepine family. Only 2 molecules in CBMZPN01
(P21/c polymorph) overlay with CBMZPN03 (R-3 polymorph),
illustrating that the crystal structures are very different.
Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK
www.ccdc.cam.ac.uk • Email: [email protected] • Tel: +44 1223 336408
Registered in England No. 2155347 • Registered Charity No. 800579
Evaluations
To request an evaluation of the CSD Solid Form Suite, please [email protected]
Supported platforms
The CSD Solid Form Suite is supported on Windows, Mac and Linux platforms.For a full list of supported operating systems visit the CCDC website.
The CSD Solid Form Suite
The CSD Solid Form Suite is an integrated suite of tools comprising the followingsoftware components:
