Conclusions and Further Work

  • Rajni M. BhardwajEmail author
Part of the Springer Theses book series (Springer Theses)


The complementary application of experimental and computational approaches has helped in improving methods for discovery of solid forms and providing a more complete and accurate interpretation of the solid-state structure and diversity. By combining multi-well plate for high throughput crystallisation, Raman spectroscopy for data collection and chemometric approach for data analysis, an efficient methodology for solid form screening was developed. The developed methodology has proved to be an effective tool for discovering solid forms by utilizing only mgs of material. Future work would include further refinement of the methodology by incorporating stirring element and temperature control unit to have better control over crystallisation conditions, by combining Raman with another analytical techniques and applying this methodology under variety of crystallization conditions. A random forest model has for the first time enabled the prediction of the crystallisability (crystals vs. no crystals) of organic molecules with ~70 % accuracy. Future work would include incorporating information about crystallisation conditions (solvent, rate of solvent evaporation, RH, and temperature) and extending this technique to multi-component systems such as salts and co-crystals. Complementary application of experimental and computational tools has provided a better understanding of the factors underpinning the solid-state structure and diversity in two groups each comprising of two structurally related molecules. Future work include to investigate if any of the experimentally observed crystal structure of these molecules can act as a template for the predicted structure of structurally related molecules on the crystal energy landscape. Other computational tools such as electrostatic potential surfaces calculations and Hirshfeld surface analysis can be tested to study the influence of overall molecular shape on distinct solid-state behaviour.


Solid Form Crystallisation Condition Centrosymmetric Dimer Packing Motif Statistical Modelling Technique 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Arlin J-B, Price LS, Price SL, Florence AJ (2011) A strategy for producing predicted polymorphs: Catemeric carbamazepine form V. Chem Commun 47:7074–7076CrossRefGoogle Scholar
  2. Billinge SJL, Dykhne T, Juhas P, Bozin E, Taylor R, Florence AJ, Shankland K (2010) Characterisation of amorphous and nanocrystalline molecular materials by total scattering. CrystEngComm 12:1366–1368CrossRefGoogle Scholar
  3. Gelbrich T, Hursthouse MB (2005) A versatile procedure for the identification, description and quantification of structural similarity in molecular crystals. CrystEngComm 7:324–336CrossRefGoogle Scholar
  4. Gracin S, Uusi-Penttilä M, Rasmuson ÅC (2005) Influence of ultrasound on the nucleation of polymorphs of p-aminobenzoic acid. Cryst Growth Des 5:1787–1794CrossRefGoogle Scholar
  5. Grzesiak AL, Uribe FJ, Ockwig NW, Yaghi OM, Matzger AJ (2006) Polymer-induced heteronucleation for the discovery of new extended solids. Angew Chem Int Ed 45:2553–2556CrossRefGoogle Scholar
  6. Hiremath R, Basile JA, Varney SW, Swift JA (2005) Controlling molecular crystal polymorphism with self-assembled monolayer templates. J Am Chem Soc 127:18321–18327CrossRefGoogle Scholar
  7. Hursthouse M (2004) High-throughput chemical crystallography (HTCC): meeting and greeting the combichem challenge. Crystallogr Rev 10:85–96CrossRefGoogle Scholar
  8. Hursthouse MB, Huth LS, Threlfall TL (2009) Why do organic compounds crystallise well or badly or ever so slowly? Why is crystallisation nevertheless such a good purification technique? Org Process Res Dev 13:1231–1240CrossRefGoogle Scholar
  9. Johnston A, Johnston BF, Kennedy AR, Florence AJ (2008) Targeted crystallisation of novel carbamazepine solvates based on a retrospective Random Forest classification. CrystEngComm 10:23–25CrossRefGoogle Scholar
  10. Johnston A, Bardin J, Johnston BF, Fernandes P, Kennedy AR, Price SL, Florence AJ (2011) Experimental and predicted crystal energy landscapes of chlorothiazide. Cryst Growth Des 11:405–413CrossRefGoogle Scholar
  11. Llinàs A, Goodman JM (2008) Polymorph control: Past, present and future. Drug Discovery Today 13:198–210CrossRefGoogle Scholar
  12. McCabe JF (2010) Application of design of experiment (DOE) to polymorph screening and subsequent data analysis. CrystEngComm 12:1110–1119CrossRefGoogle Scholar
  13. McKellar SC, Urquhart AJ, Lamprou DA, Florence AJ (2012) Polymer templating of supercooled indomethacin for polymorph selection. ACS Combinatorial Science 14:155–159CrossRefGoogle Scholar
  14. McKinnon JJ, Spackman MA, Mitchell AS (2004) Novel tools for visualizing and exploring intermolecular interactions in molecular crystals. Acta Crystallogr B 60:627–668CrossRefGoogle Scholar
  15. Morissette SL, Soukasene S, Levinson D, Cima MJ, Almarsson Ö (2003) Elucidation of crystal form diversity of the HIV protease inhibitor ritonavir by high-throughput crystallization. Proc Natl Acad Sci 100:2180–2184CrossRefGoogle Scholar
  16. Parveen S, Davey RJ, Dent G, Pritchard RG (2005) Linking solution chemistry to crystal nucleation: the case of tetrolic acid. Chem Commun 12:1531–1533Google Scholar
  17. Remenar JF, MacPhee JM, Larson BK, Tyagi VA, Ho JH, McIlroy DA, Hickey MB, Shaw PB, Almarsson Ö (2003) Salt selection and simultaneous polymorphism assessment via high-throughput crystallization: The case of sertraline. Org Process Res Dev 7:990–996CrossRefGoogle Scholar
  18. Sarma JARP, Desiraju GR (2002) The supramolecular synthon approach to crystal structure prediction. Cryst Growth Des 2:93–100CrossRefGoogle Scholar
  19. Stahly GP (2007) Diversity in single- and multiple-component crystals. The search for and prevalence of polymorphs and cocrystals. Cryst Growth Des 7:1007–1026CrossRefGoogle Scholar
  20. Storey R, Docherty R, Higginson P, Dallman C, Gilmore C, Barr G, Dong W (2004) Automation of solid form screening procedures in the pharmaceutical industry—How to avoid the bottlenecks. Crystallogr Rev 10:45–56CrossRefGoogle Scholar
  21. Sun X, Garetz BA, Myerson AS (2008) Polarization switching of crystal structure in the nonphotochemical laser-induced nucleation of supersaturated aqueous l-histidine. Cryst Growth Des 8:1720–1722CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  1. 1.Lilly Corporate CenterEli Lilly and CompanyIndianapolisUSA

Personalised recommendations