Download Solid Form Suite Data Sheet - The Cambridge Crystallographic Data

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The Cambridge
Structural Database
Solid Form Suite
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.
Cambridge Crystallographic Data Centre
Solid Form Informatics
Enabling the rational design of solid forms based on the knowledge contained
within more than 600,000 crystal structures.
•
Solid Form Informatics: Solid Form Informatics supports key decisions [1] about
development routes of solid formulations of drugs, agrochemicals and molecular
materials. It provides knowledge-based assessment of potential polymorphism and
associated manufacturing risks, as well as information vital to reformulation and the
tuning of property profiles [2]. Solid Form Informatics distils the vast amount of
structural data available today into targeted and actionable information [3]. It is
poised 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 has
been so costly to the industry.
•
Addressing development needs: Developed with a consortium of major
pharmaceutical and agrochemical companies, the CSD Solid Form Suite includes
predictive analytics methods that exploit the vast wealth of structural knowledge in
the Cambridge Structural Database (CSD) [5]. The CSD Solid Form Suite is designed
to integrate neatly into a lab chemist's workflow and presents results in a form that
supports form screening, selection and polymorphism risk assessment.
•
Predictive analytics: Given the millions of intermolecular interactions contained
within the CSD and broad coverage of relevant pharmaceutical structures, it has
become possible to derive quantitative and actionable information for substance
development and risk assessment [3]. This advance is based on the combination of
large datasets and predictive analytics methods i.e. the likelihood of a certain
behaviour predicted from an analysis of recorded behaviour. The technique puts key
figures of merit regarding development risks into the hands of scientists and project
managers and is qualitatively different to pure database searches, which provide
interesting insights but lack the statistical rigour required for risk assessment.
•
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.
The Cambridge Structural Database: Established in 1965, the CSD [5] is the world’s
repository for small-molecule organic and metal-organic crystal structures.
Containing the results of over 600,000 X-ray and neutron diffraction experiments this
unique database of accurate 3D structures has become an essential resource to
scientists around the world.
Polymorphism Risk Assessment
Polymorphism risk assessment based on a statistical analysis of hydrogen bonding
patterns.
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.
•
Quantifying the risk of polymorphism: The Hydrogen Bond Propensity tool helps
scientists to quantify the risk of polymorphism allowing them to make informed
decisions on which crystalline form to develop. The tool, applied to known crystal
structures and even 2D renditions of a molecular structure, can advance the
experimental screening and selection of drug crystal forms, the first step towards
ensuring Quality by Design.
•
H-bond propensity: Probabilities for hydrogen bond pairings to form in the target
system are calculated from a statistical model built from relevant structures in the
CSD. The model [6-8] encapsulates information regarding the environment of the
functional groups, ensuring the prediction is specific to the target molecule.
Combining these propensities for hydrogen bond formation with information about
how often a functional group participates in an H-bond allows the in-silico
generation of chemically reasonable alternative crystal forms. The resultant view of
the solid state landscape addresses questions such as: how likely is polymorphism,
and is there the possibility of a more stable form?
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Stability
Better understand the stability of your active ingredient by analysing CSD
information.
Results of a crystal packing similarity search on the
carbamazepine family. Only 2 molecules in CBMZPN01
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Find similar structures: By interrogating the world’s repository of crystal structure
data, 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. The
structures of closely related chemical analogues can also be easily located via
substructure-based and chemical similarity searching.
•
Understand molecular geometry: Pre-computed knowledge-based libraries of
structural information [9] can be used to rapidly validate the complete geometry of
your structure and identify any unusual or strained features without the need to
construct complex search queries, or carry out detailed data analyses. An
appreciation of the conformational preferences of your compound will aid the
understanding and control of its solid-state behaviour.
•
Explore interaction patterns: By identifying and exploring networks of
intermolecular contacts you will gain an understanding of the key interactions that
drive crystal packing in your structure. The strengths and weaknesses of structures
can be assessed by searching for extended functional group interaction motifs
quickly and easily [10]. Determine which functional groups in your molecule are
most likely to pair up based on frequency of occurrence of motifs in the CSD.
Investigate alternative interaction patterns that might be available in other crystal
forms (e.g. polymorphs, hydrates and co-crystals).
•
Compare packing patterns: The CSD Solid Form Suite enables you to quantify
similarity and differences between polymorphs, hydrates and solvates. You can easily
find groups of similar structures amongst families of polymorphs and multicomponent systems [11]. Regions of structural similarity can be identified by flexibly
searching for any arrangement of atoms or functional groups in 3D space using a
crystal structure as a template and finding the most closely matched structures.
(P21/c polymorph) overlay with CBMZPN03 (R-3 polymorph),
illustrating that the crystal structures are very different.
White Papers, Case Studies & Further Information
White papers introducing the benefits of adopting an informatics approach to solid form
design are available from the CCDC website. A range of case studies and recorded
webinars illustrating how the CSD Solid Form Suite can be applied to a diverse range of
development problems, including analysis of polymorphism, co-crystallisation and hydrate
formation, 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 Drug
Substance 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, 18691888, 2009.
The CSD Solid Form Suite
The CSD Solid Form Suite is an integrated suite of tools comprising the following
software components:
Evaluations
To request an evaluation of the CSD Solid Form Suite, please contact
[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.
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