Skip to main content
SpringerLink
Log in

Salts and Co-crystals of Theobromine and their phase transformations in water

  • Published:
Journal of Chemical Sciences Aims and scope Submit manuscript

Abstract

Theobromine, a xanthine derivative analogous to caffeine and theophylline, is an effective central nervous system stimulant. It has lower aqueous solubility than caffeine and theophylline. Salts of theobromine with hydrochloric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid were prepared using liquid-assisted grinding (LAG). Proton transfer from the strong acid to the weak base imidazole N resulted in N+–H ⋯O− hydrogen-bonded supramolecular assemblies of theobromine salts. The mesylate salt is polymorphic with amide N–H ⋯O dimer and catemer synthons for the theobromine cations. A variable stoichiometry for phosphate salts (1:3 and 1:2.5) were observed with the latter being more stable. All new salts were characterized by FT-IR, PXRD, DSC and finally single crystal X-ray diffraction. In terms of stability, these salts transformed to theobromine within 1 h of dissolution in water. Remarkably, the besylate and tosylate salts are 88 and 58 times more soluble than theobromine, but they dissociated within 1 h. In contrast, theobromine co-crystals with gallic acid, anthranilic acid and 5-chlorosalicylic acid were found to be stable for more than 24 h in the aqueous slurry conditions, except malonic co-crystal which transformed to theobromine within 1 h. Water mediated phase transformation of theobromine salts and co-crystal may be due to the incongruency (high solubility difference) between the components. These results suggest that even though traditional salts are highly soluble compared to co-crystals, co-crystals can be superior in terms of stability.

Mesylate salt polymorphs of theobromine containing amide dimer and catemer synthons of TBRH+ represent a rare category of synthon polymorphs for salts. TBR salts are shown to be more soluble than the corresponding cocrystals, but in terms of stability the salts dissociated within 1 h in aqueous medium.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Scheme 1
Scheme 2
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Scheme 3
Figure 8
Figure 9

Similar content being viewed by others

References

  1. (a) Byrn S R, Pfeiffer R R and Stowell J G 1999 In Solid-State Chemistry of Drugs 2nd ed. (Indiana: SSCI Inc.); (b) Lipinski C 2002 Am. Pharm. Rev. 5 82; (c) Vippagunta S R, Brittain H G and Grant D J W 2001 Adv. Drug Delivery Rev. 48 3; (d) Babu N J and Nangia A 2011 Cryst. Growth Des. 11 2662

  2. (a) Yalkowsky S 1999 In Solubility and Solubilization in Aqueous Media (Washington DC: American Chemical Society); (b) Chemburkar S R, Bauer J, Deming K, Spiwek H, Patel K, Morris J, Henry R, Spanton S, Dziki W, Porter W, Quick J, Bauer P, Donaubauer J, Narayanan B A, Soldani M, McFarland D and McFarland K 2000 Org. Process Res. Dev. 4 413; (c) Saharan V A, Kukkar V, Kataria M, Gera M and Choudhury P K 1999 Int. J. Health Res 2 107; (d) Sanphui P, Bolla G, Nangia A and Chernyshev V V 2014 IUCRJ 1 136

  3. (a) Berge S M, Bighley L D and Monkhouse D C 1977 J. Pharm. Sci. 66 1; (b) Prohotsky D L and Zhao F 2012 J. Pharm. Sci. 101 1

  4. (a) Stahl P H and Wermuth C G 2002 In Handbook of pharmaceutical salts: Properties, selection and use (Weinheim: Wiley-VCH); (b) Serajuddin A T M 2007 Adv. Drug Del. (Rev.) 59 603; (b) Sarveya V, Templeton J F and Benson H A E 2004 J. Pharm. Pharmacol. 56 717; (c) Kim S, Lee H and Kwan E 2008 Clin. Pharmacol. Therap. 83 S59; (d) Davies G 2001 Pharm. J. 266 322; (e) Sarma B, Thakuria R, Nath K and Nangia A 2011 Cryst. Eng. Comm. 13 3232; (f) Bolla G and Nangia A 2012 Cryst. Growth Des. 12 6250

  5. (a) Cardew P T and Davey R J 1985 Proc. R. Soc. Lond. A 398 415; (b) Greco K and Bogner R 2012 J. Pharm Sci. 101 2996

  6. (a) http://www.xocoatl.org/science.htm (accessed on 2 August, 2014); (b) Usmani O S, Belvisi M G, Patel H J, Crispino N, Birrell M A, Korbonits M, Korbonits D and Barnes P J 2005 The FASEB Journal 19 231; (c) Scheindlin S 2007 Mol. Interv. 7 236; (d) Lee H J, Lee K W, Kang K S, Kim D Y, Park H H, Lee M J, Kim H S and Kwon I B US patent 2003/0099686A1 May 2003; (e) Griesser U J and Burger A 1995 Int. J. Pharm. 120 83; (f) de Smidt J H, Fokkens J G, Grijseels H and Crommelin D J 1986 J Pharm Sci. 75 497

  7. (a) Shefter E, Brennan T F and Sackman P 1971 Chem. Pharm. Bull. 19 746; (b) Karki S, Fábián L, Friščić T and Jones 2007 W. Org. lett. 9 3133; (c) Cruz-Cabeza A J, Karki S, Fábián L, Friščić T, Day G M and Jones W 2010 Chem. Commun. 46 2224; (d) Clarke H D, Arora K K, Bass H, Kavuru P, Ong T T, Pujari T, Wojtas L and Zaworotko M J 2010 Cryst. Growth Des. 10 2152; (e) Biradha K, Samai S, Maity A C and Goswami S 2010 Cryst. Growth Des. 10 937; (f) Madusanka N, Eddleston M D, Arhangelskis M and Jones W 2014 Acta Crystallogr. B Struct. Sci. Cryst. Eng. Mater. 70 72

  8. (a) Rajput L, Sanphui P and Desiraju G R 2013 Cryst. Growth Des. 13 3681; (b) Goud N R, Suresh K and Nangia A 2013 Cryst. Growth Des 13 1590

  9. Ford K A, Ebisuzaki Y and Boyle P D 1998 Acta Crystallogr., Sect. C. 54 1980

  10. (a) Derollez P, Correia N T, Danede F, Capet F, Affouard F, Lefebvre J and Descamps M 2005 Acta Cryst. C. 61 329; (b) Lehmann C W and Stowasser F 2007 Chem. Eur. J. 13 2908; (c) Enright G D, Terskikh V V, Brouwer D H and Ripmeester J A 2007 Cryst.Growth Des. 7 1406; (d) Ebisuzaki Y, Boyle P D and Smith J A 1997 Acta Cryst. C. 53 777; (e) Zhang S and Fischer A 2011 Acta Cryst. E. 67 o3357; (f) Khamar D, Pritchard R G, Bradshaw I J, Hutcheon G A and Seton L 2011 Acta Cryst. C. 67 o496; (g) Fucke K, McIntyre G J, Wilkinson C, Henry M, Howard J A K and Steed J W 2012 Cryst. Growth Des. 12 1395

  11. (a) Steed J W 2003 CrystEngComm. 5 169; (b) Desiraju G R 2007 CrystEngComm. 9 91; (c) Roy S, Banerjee R, Nangia A and Kruger G J 2006 Chem. Eur. J. 12 3777; (d) Babu N J, Reddy L S, Aitipamula S and Nangia A 2008 Chem. Asian J. 3 1122

  12. Dunitz J D and Bernstein J. 1995 Acc. Chem. Res. 28 193

  13. (a) Ostwald W 1879 Z. physik. Chem. 22 289; (b) Nývlt J 1995 Cryst. Res. Technol. 30 443

  14. (a) Ma L Y Y, Camerman N, Swartzendruber J K, Jones N D and Camerman A 1987 Can. J. Chem. 65 256; (b) Jegorov A, Horak Z, Cejka J, Kratochvil B and Cisarova I 2003 Acta Crystallogr. 59 o575; (c) Zhu N, Johnson L, White J and Klein-Stevens C L 2002 Struct. Chem. 13 491; (d) Gratz S R, Zeller M, Mincey D W and Flurer C L 2009 J. Pharm. Biomed. Anal. 50 228; (e) Grillo D, Polla G and Vega D 2012 J. Pharm. Sci. 101 541

  15. Nath N K and Nangia A 2011 CrystEngComm. 13 47

  16. Nanubolu J B, Sridhar B, Ravikumar K, Sawant K D, Naik T A, Patkar L N, Cherukuvada S and Sreedhar B 2013 CrystEngComm 15 4448

  17. CSD version 5.35, November 2013, Feb 2014 update, www.ccdc.cam.ac.uk.

  18. (a) Etter C M 1990Acc. Chem. Res. 23 120 (b) Aakery C B, Epa K, Forbes S, Schultheiss N and Desper J 2013Chem. Eur. J. 19 14998

  19. (a) Stuart B H 2004 In Infrared Spectroscopy: Fundamentals and Applications (UK: John-Wiley); (b) Gunasekaran S, Sankari G and Ponnusamy S 2005 Spectrochimica Acta Part A 61 117

  20. (a) Friščić* T, Childs S L, Rizvi S A A and Jones W 2009 CrystEngComm. 11 418; (b) Alhalaweh A and Velaga S P 2010 Cryst. Growth Des. 10 3302; (c) Rodríguez-Hornedo N, Nehm S J, Seefeldt K F, Pagan-Torres Y and Falkiewicz C J 2006 Mol. Pharmaceutics 3 362; (d) Goud N R, Gangavaram S, Suresh K, Pal S, Manjunatha N G, Nambiar S and Nangia A 2012 J. Pharm. Sci. 101 664

  21. (a) Good D J and Rodríguez-Hornedo N 2009 Cryst. Growth Des. 9 2252; (b) Sanphui P, Tothadi S, Ganguly S and Desiraju G R 2013 Mol. Pharmaceutics 10 4687

  22. US-FDA guideline on pharmaceutical cocrystals (2013). http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm

  23. CrysAlis CCD and CrysAlis RED Ver. 1.171.33.55, Oxford Diffraction Ltd., Yarnton Oxfordshire UK 2008

  24. Dolomanov O V, Bourhis L J, Gildea R J, Howard J A K and Puschmann H 2009 J. Appl. Crystallogr. 42 339

  25. SMART, Ver. 5.625 and SHELX-TL, Ver. 6.12; Bruker-AXS Inc., Madison, Wisconsin, USA, 2000

  26. (a) Spek A L 2002 In PLATON: A Multipurpose Crystallographic Tool (;trecht University: Netherlands); (b) Spek A L 2003 J. Appl.Crystallogr. 36 7

  27. Barbour L J 1999 In X-Seed, Graphical Interface to SHELX-97 and POV-Ray, Program for Better Quality of Crystallographic Figures (University of Missouri-Columbia: USA)

  28. Fraus N and Nolze G 2000 Powder Cell, Ver. 2.3, A Program For Structure Visualization, Powder Pattern Calculation and Profile Fitting, ;ederal Institute for Materials Research and Testing. Berlin, Germany

Download references

Acknowledgements

PS thanks the UGC for a fellowship. We thank DST-SERB JC Bose fellowship (SR/S2/JCB-06/2009), SERB scheme Novel solid-state forms of APIs (SR/S1/OC-37/2011), and CSIR Project Pharmaceutical Cocrystals (01-2410/10/EMR-II). DST (IRPHA) and UGC (PURSE grant) are thanked for providing instrumentation and infrastructure facilities.

Author information

Authors and Affiliations

  1. School of Chemistry, University of Hyderabad, Prof. C. R. Rao Road, Gachibowli, Central University P.O., Hyderabad, 500 046, India

    PALASH SANPHUI & ASHWINI NANGIA

Authors
  1. PALASH SANPHUI
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. ASHWINI NANGIA
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to ASHWINI NANGIA.

Additional information

Supporting Information

Crystallographic .cif files (CCDC Nos. 1019198-1019204) are available at www.ccdc.cam.ac.uk/data_request/cif or as part of the Supporting Information. Normalized H bond table, IR and PXRD plots, and crystallographic .cif files are available http://www.ias.ac.in/chemsci/index.html.

Electronic supplementary material

Below is the link to the electronic supplementary material.

(DOC 586 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

SANPHUI, P., NANGIA, A. Salts and Co-crystals of Theobromine and their phase transformations in water. J Chem Sci 126, 1249–1264 (2014). https://doi.org/10.1007/s12039-014-0707-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12039-014-0707-8

Keywords

Search

Navigation