Structural Chemistry

, Volume 25, Issue 3, pp 707–714 | Cite as

Transforming aspirin into novel molecular salts of salicylic acid

  • Vânia André
  • Inês Martins
  • Sílvia Quaresma
  • Marta Martins
  • M. Teresa Duarte
Original Research


Aspirin is one of the most widely used analgesic, antipyretic, and anti-inflammatory drugs. Herein we disclose a way to transform aspirin into novel multicomponent crystal forms of salicylic acid, also a long-known analgesic with anti-inflammatory properties, among others, covering a broad spectrum of applications, including skin care products. A salicylic acid:salicylate ammonium salt and a salicylate:2-methyl-4-oxopentan-2-aminium molecular salt are concomitantly formed in acetone/ammonia solutions, resulting from aspirin decomposition. Furthermore the 2-methyl-4-oxopentan-2-aminium cation results from a sequence of in situ reactions: (i) imine formation, in which acetone is known to undergo under basic pH conditions; (ii) nucleophilic attack of α-carbon of the deprotonated acetone to the imine yielding 4-amino-4-methylpentan-2-one; and (iii) protonation of 4-amino-4-methylpentan-2-one. In the structures obtained for the novel multicomponent crystal forms, the strong charge-assisted N+–H···O/O hydrogen bonds between the drug molecule and the co-former play a key function in the supramolecular arrangement. The typical \({\mathbf{R}}_{{\mathbf{2}}}^{{\mathbf{2}}} ({\mathbf{8}})\) carboxylic···carboxylic homosynthon observed in salicylic acid was inhibited by the salt formation. These results are in agreement with the results of a careful survey on the Cambridge Structural Database.

Graphical abstract


Aspirin Salicylic acid Molecular salts Acetone reactions Supramolecular anion 

Supplementary material

11224_2013_326_MOESM1_ESM.doc (780 kb)
Supplementary material 1 (DOC 779 kb)


  1. 1.
    Nordstrom FL, Rasmuson AC (2006) Solubility and melting properties of salicylic acid. J Chem Eng Data 51(5):1668–1671CrossRefGoogle Scholar
  2. 2.
    Mackowiak PA (2000) Brief history of antipyretic therapy. Clin Infect Dis 31:S154–S156CrossRefGoogle Scholar
  3. 3.
    Fonari, Ganin EV, Basok SS, Lyssenko KA, Zaworotko MJ, Kravtsov VC (2010) Structural study of salicylic acid salts of a series of azacycles and azacrown ethers. Cryst Growth Des 10(12):5210–5220CrossRefGoogle Scholar
  4. 4.
    Mehta A (2005) Aspirin. Chem Eng News 83(25):46–47Google Scholar
  5. 5.
    Moore N, Van Ganse E, Le Parc JM, Wall R, Schneid H, Farhan M, Verriere F, Pelen F (1999) The PAIN study: paracetamol, aspirin and ibuprofen new tolerability study—a large-scale, randomised clinical trial comparing the tolerability of aspirin, ibuprofen and paracetamol for short-term analgesia. Clin Drug Investig 18(2):89–98CrossRefGoogle Scholar
  6. 6.
    Wan A, Sun Y, Gao L, Li HL (2009) Preparation of aspirin and probucol in combination loaded chitosan nanoparticles and in vitro release study. Carbohydr Polym 75(4):566–574CrossRefGoogle Scholar
  7. 7.
    Mitchell AG, Saville DJ (1967) Dissolution of aspirin and aspirin tablets. J Pharm Pharmacol 19(11):729CrossRefGoogle Scholar
  8. 8.
    Bond AD, Boese R, Desiraju GR (2007) On the polymorphism of aspirin. Angew Chem Int Ed 46(4):615–617CrossRefGoogle Scholar
  9. 9.
    Kildsig DO, Denbo R, Peck GE (1971) Structural differences in solution derived from polymorphic modifications of aspirin. J Pharm Pharmacol 23(5):374–376CrossRefGoogle Scholar
  10. 10.
    Mitchell AG, Saville DJ (1969) Dissolution of commercial aspirin. J Pharm Pharmacol 21(1):28CrossRefGoogle Scholar
  11. 11.
    Tawashi R (1968) Aspirin—dissolution rates of two polymorphic forms. Science 160(3823):76CrossRefGoogle Scholar
  12. 12.
    Tawashi R (1969) Gastrointestinal absorption of two polymorphic forms of aspirin. J Pharm Pharmacol 21(10):701CrossRefGoogle Scholar
  13. 13.
    De Bisschop M (1970) Melting points of acetylsalicylic acid. J Pharm Belg 25(4):330–334Google Scholar
  14. 14.
    Bettinetti GP, Giordano F, Giuseppetti G (1975) Polymorphism of acetylsalicylic acid. Farmaco Prat 30(5):244–251Google Scholar
  15. 15.
    Chang CJ, Diaz LE, Morin F, Grant DM (1986) Solid-state C-13 NMR study of drugs: aspirin. Magn Reson Chem 24(9):768–771CrossRefGoogle Scholar
  16. 16.
    Pfeiffer RR (1971) Aspirin polymorphism questioned. J Pharm Pharmacol 23(1):75CrossRefGoogle Scholar
  17. 17.
    Mitchell AG, Milaire BL, Saville DJ, Griffith Rv (1971) Aspirin dissolution: polymorphism, crystal habit or crystal defects. J Pharm Pharmacol 23(7):534CrossRefGoogle Scholar
  18. 18.
    Mulley BA, Rye RM, Shaw P (1971) Further evidence on question of polymorphism in aspirin. J Pharm Pharmacol 23(11):902–904CrossRefGoogle Scholar
  19. 19.
    Schwartz G (1972) Does aspirin exist in polymorphic states. J Pharm Pharmacol 24(2):169CrossRefGoogle Scholar
  20. 20.
    Glaser R (2001) Aspirin. An ab initio quantum-mechanical study of conformational preferences and of neighboring group interactions. J Org Chem 66(3):771–779CrossRefGoogle Scholar
  21. 21.
    Ouvrard C, Price SL (2004) Toward crystal structure prediction for conformationally flexible molecules: the headaches illustrated by aspirin. Cryst Growth Des 4(6):1119–1127CrossRefGoogle Scholar
  22. 22.
    Payne RS, Rowe RC, Roberts RJ, Charlton MH, Docherty R (1999) Potential polymorphs of aspirin. J Comput Chem 20(2):262–273CrossRefGoogle Scholar
  23. 23.
    Wilson CC (2002) Interesting proton behaviour in molecular structures. Variable temperature neutron diffraction and ab initio study of acetylsalicylic acid: characterising librational motions and comparing protons in different hydrogen bonding potentials. New J Chem 26(12):1733–1739CrossRefGoogle Scholar
  24. 24.
    Vishweshwar P, McMahon JA, Oliveira M, Peterson ML, Zaworotko MJ (2005) The predictably elusive form II of aspirin. J Am Chem Soc 127(48):16802–16803CrossRefGoogle Scholar
  25. 25.
    Bond AD, Boese R, Desiraju GR (2007) On the polymorphism of aspirin: crystalline aspirin as intergrowths of two “polymorphic” domains”. Angew Chem Int Ed 46(4):618–622CrossRefGoogle Scholar
  26. 26.
    Wheatley PJ (1964) Crystal and molecular structure of aspirin. J Chem Soc 1964:6036CrossRefGoogle Scholar
  27. 27.
    Caira MR (1994) Molecular complexes of sulfonamides. 3. Structure of 5-methoxysulfadiazine (form II) and its 1/1-complex with acetylsalicylic acid. J Chem Crystallogr 24(10):695–701CrossRefGoogle Scholar
  28. 28.
    Caira MR (1992) Molecular complexes of sulfonamides and sulfadimidine and.2. 1/1 complexes between drug molecules: sulfadimidine-acetylsalicylic acid and sulfadimidine-4-aminosalicylic acid. J Crystallogr Spectrosc Res 22(2):193–200CrossRefGoogle Scholar
  29. 29.
    Etter MC (1990) Encoding and decoding hydrogen-bond patterns of organic compounds. Acc Chem Res 23(4):120–126CrossRefGoogle Scholar
  30. 30.
    Bacon GE, Jude RJ (1973) Neutron diffration studies of salicylic acid and alpha-resorcinol. Z Fur Krist 138:19–40CrossRefGoogle Scholar
  31. 31.
    Cochran W (1953) The crystal and molecular structure of salicylic acid. Acta Crystallogr 6(3):260–268CrossRefGoogle Scholar
  32. 32.
    Sundaral M, Jensen LH (1965) Refinement of structure of salicylic acid. Acta Crystallogr 18:1053CrossRefGoogle Scholar
  33. 33.
    Nordstrom FL, Rasmuson AC (2006) Polymorphism and thermodynamics of m-hydroxybenzoic acid. Eur J Pharm Sci 28(5):377–384CrossRefGoogle Scholar
  34. 34.
    Downie TC, Speakman JC (1954) The crystal structures of the acid salts of some monobasic acids .4. Ammonium hydrogen disalicylate hydrate. J Chem Soc 787–793. doi:10.1039/JR9540000787
  35. 35.
    Klepeis J-HP, Evans WJ, Zaitseva N, Schwegler E, Teat SJ (2009) Ammonium salicylate: a synchrotron study. Acta Crystallogr Sect E 65:O2062–O02063CrossRefGoogle Scholar
  36. 36.
    Weyna DR, Shattock T, Vishweshwar P, Zaworotko MJ (2009) Synthesis and structural characterization of cocrystals and pharmaceutical cocrystals: mechanochemistry vs slow evaporation a from solution. Cryst Growth Des 9(2):1106–1123CrossRefGoogle Scholar
  37. 37.
    Skovsgaard S, Bond AD (2009) Co-crystallisation of benzoic acid derivatives with N-containing bases in solution and by mechanical grinding: stoichiometric variants, polymorphism and twinning. CrystEngComm 11(3):444–453CrossRefGoogle Scholar
  38. 38.
    Brittain HG, Felice PV (2010) Water-soluble aspirin-theanine cocrystal composition making method used for treating acute myocardial infarction, by adding theanine enantiomer to acetylsalicylic acid, wetting mixture, and grinding to produce dried crystalline mass. WO2010128977-A1; US2010286099-A1Google Scholar
  39. 39.
    Hathwar VR, Pal R, Row TNG (2010) Charge density analysis of crystals of nicotinamide with salicylic acid and oxalic acid: an insight into the salt to cocrystal continuum. Cryst Growth Des 10(8):3306–3310CrossRefGoogle Scholar
  40. 40.
    Berry DJ, Seaton CC, Clegg W, Harrington RW, Coles SJ, Horton PN, Hursthouse MB, Storey R, Jones W, Friscic T, Blagden N (2008) Applying hot-stage microscopy to co-crystal screening: a study of nicotinamide with seven active pharmaceutical ingredients. Cryst Growth Des 8(5):1697–1712CrossRefGoogle Scholar
  41. 41.
    Elbagerma MA, Edwards HGM, Munshi T, Scowen IJ (2010) Identification of a new co-crystal of salicylic acid and benzamide of pharmaceutical relevance. Anal Bioanal Chem 397(1):137–146CrossRefGoogle Scholar
  42. 42.
    Cheney ML, Weyna DR, Shan N, Hanna M, Wojtas L, Zaworotko MJ (2010) Supramolecular architectures of meloxicam carboxylic acid cocrystals, a crystal engineering case study. Cryst Growth Des 10(10):4401–4413CrossRefGoogle Scholar
  43. 43.
    Nangia A, Nanubolu JB, Sanphui P (2010) Stable cocrystals of temozolomide. IN200902303-I4Google Scholar
  44. 44.
    Elbagerma MA, Edwards HGM, Munshi T, Hargreaves MD, Matousek P, Scowen IJ (2010) Characterization of new cocrystals by Raman spectroscopy, powder X-ray diffraction, differential scanning calorimetry, and transmission Raman spectroscopy. Cryst Growth Des 10(5):2360–2371CrossRefGoogle Scholar
  45. 45.
    Huang N, Rodriguez-Hornedo N (2010) Effect of micelliar solubilization on cocrystal solubility and stability. Cryst Growth Des 10(5):2050–2053CrossRefGoogle Scholar
  46. 46.
    Childs SL, Wood PA, Rodriguez-Hornedo N, Reddy LS, Hardcastle KI (2009) Analysis of 50 crystal structures containing carbamazepine using the materials module of mercury CSD. Cryst Growth Des 9(4):1869–1888CrossRefGoogle Scholar
  47. 47.
    Childs SL, Stahly GP, Park A (2007) The salt-cocrystal continuum: the influence of crystal structure on ionization state. Mol Pharm 4(3):323–338CrossRefGoogle Scholar
  48. 48.
    Lu E, Rodriguez-Hornedo N, Suryanarayanan R (2008) A rapid thermal method for cocrystal screening. CrystEngComm 10(6):665–668CrossRefGoogle Scholar
  49. 49.
    Bucar DK, Henry RF, Lou XC, Duerst RW, MacGillivray LR, Zhang GGZ (2009) Cocrystals of caffeine and hydroxybenzoic acids composed of multiple supramolecular heterosynthons: screening via solution-mediated phase transformation and structural characterization. Cryst Growth Des 9(4):1932–1943CrossRefGoogle Scholar
  50. 50.
    Goswami S, Jana S, Hazra A, Fun HK, Anjum S, Atta-ur R (2006) Recognition of creatinine by weak aromatic acids in solid phase along with their supramolecular network. CrystEngComm 8(9):712–718CrossRefGoogle Scholar
  51. 51.
    Limmatvapirat S, Yamaguchi K, Yonemochi E, Oguchi T, Yamamoto K (1997) A 1:1 deoxycholic acid salicylic acid complex. Acta Crystallogr Sect C 53:803–805CrossRefGoogle Scholar
  52. 52.
    Takata N, Shiraki K, Takano R, Hayashi Y, Terada K (2008) Cocrystal screening of stanolone and mestanolone using slurry crystallization. Cryst Growth Des 8(8):3032–3037CrossRefGoogle Scholar
  53. 53.
    Singh TP, Vijayan M (1974) Structural studies of analgesics and their interactions. 2. Crystal structure of a 1-1 complex between antipyrine and salicylic acid (saalipyrine). Acta Crystallogr Sect B 30:557–562CrossRefGoogle Scholar
  54. 54.
    Fan Z, Diao CH, Song HB, Jing ZL, Yu M, Chen X, Guo MJ (2007) Synthesis and structure of the inclusion complex of beta cyclodextrin and salicylic acid. Acta Chim Sin 65(15):1449–1453Google Scholar
  55. 55.
    Braga D, Grepioni F, Maini L, Polito M (2009) Crystal polymorphism and multiple crystal forms. Mol Netw 132:25–50CrossRefGoogle Scholar
  56. 56.
    Braga D, Chelazzi L, Grepioni F, Dichiarante E, Chierotti MR, Gobetto R (2013) Molecular salts of anesthetic lidocaine with dicarboxylic acids: solid-state properties and a combined structural and spectroscopic study. Cryst Growth Des 13(6):2564–2572CrossRefGoogle Scholar
  57. 57.
    Braga D, d’Agostino S, Grepioni F (2012) Shape takes the lead: templating organic 3D-frameworks around organometallic sandwich compounds. Organometallic 31(5):1688–1695CrossRefGoogle Scholar
  58. 58.
    Etter MC, Macdonald JC, Bernstein J (1990) Graph-set analysis of hydrogen-bon patterns in organic crystals. Acta Crystallogr Sect B 46:256–262CrossRefGoogle Scholar
  59. 59.
    Leiserowitz L (1976) Molecular packing modes: carboxylic acids. Acta Crystallogr Sect B 32:775–802CrossRefGoogle Scholar
  60. 60.
    Bruker AXS: SAINT+, release 6.22 (2005). Bruker Analytical Systems: Madison, WIGoogle Scholar
  61. 61.
    Bruker AXS:SADABS (2005). Bruker Analytical Systems: Madison, WIGoogle Scholar
  62. 62.
    Altomare A, Burla MC, Camalli M, Cascarano GL, Giacovazzo C, Guagliardi A, Moliterni AGG, Polidori G, Spagna R (1999) SIR97: a new tool for crystal structure determination and refinement. J Appl Crystallogr 32:115–119CrossRefGoogle Scholar
  63. 63.
    Sheldrick GM (2008) A short history of SHELX. Acta Crystallogr Sect A 64:112–122CrossRefGoogle Scholar
  64. 64.
    Farrugia LJ (1999) WinGX: Version 1.80.05. J Appl Cryst 32:837–838CrossRefGoogle Scholar
  65. 65.
    Macrae CF, Bruno IJ, Chisholm JA, Edgington PR, McCabe P, Pidcock E, Rodriguez-Monge L, Taylor R, van de Streek J, Wood PA (2008) Mercury CSD 2.0: new features for the visualization and investigation of crystal structures. J Appl Crystallogr 41:466–470CrossRefGoogle Scholar
  66. 66.
    Spek AL (2003) Single-crystal structure validation with the program PLATON. J Appl Crystallogr 36:7–13CrossRefGoogle Scholar
  67. 67.
    Hursthouse MB, Montis R, Tizzard GJ (2010) Intriguing relationships and associations in the crystal structures of a family of substituted aspirin molecules. CrystEngComm 12(3):953–959CrossRefGoogle Scholar
  68. 68.
    Lopez C, Claramunt RM, Garcia MA, Pinilla E, Torres MR, Alkorta I, Elguero J (2007) Cocrystals of 3,5-dimethyl-1H-pyrazole and salicylic acid: controlled formation of trimers via O–H···N hydrogen bonds. Cryst Growth Des 7(6):1176–1184CrossRefGoogle Scholar
  69. 69.
    Allen FH (2002) The Cambridge structural database: a quarter of a million crystal structures and rising. Acta Crystallogr Sect B 58:380–388CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Vânia André
    • 1
  • Inês Martins
    • 1
  • Sílvia Quaresma
    • 1
  • Marta Martins
    • 1
  • M. Teresa Duarte
    • 1
  1. 1.Departamento de Engenharia Química, Centro de Química Estrutural, Instituto Superior TécnicoUniversidade de LisboaLisbonPortugal

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