Journal of Thermal Analysis and Calorimetry

, Volume 123, Issue 3, pp 2345–2356 | Cite as

Spectroscopic and thermal approaches to investigate the formation mechanism of piroxicam–saccharin co-crystal induced by liquid-assisted grinding or thermal stress

  • Hong-Liang Lin
  • Yu-Ting Huang
  • Shan-Yang Lin


The use of co-crystal technology applied to pharmaceutical industry has recently attracted considerable interest. It is important to better understand the mechanism of co-crystal formation via specific intermolecular interactions. The objective of the present study was to evaluate a stepwise mechanism of a co-crystal formation between piroxicam (PIR) and saccharin (SAC) after different grinding and thermal treatments by using spectroscopic and thermal analyses. The physical and ground mixtures of PIR–SAC (molar ratio = 1:1) and their preheated mixtures were analyzed using FTIR, DSC and DSC-FTIR techniques. Typical PIR–SAC co-crystal was prepared by solvent evaporation method. Various PIR–SAC ground mixtures after neat grinding process showed the same FTIR spectra as their physical mixtures, but these ground mixtures might be changed to co-crystals after further thermal treatment. By adding two drops of chloroform into PIR–SAC physical mixture, however, the PIR–SAC co-crystal was gradually formed with the increase in grinding time (>57 min) via inter-/intramolecular N–H···O and C–H···O hydrogen bonding between PIR and SAC. By preheating the PIR–SAC physical mixture over 170 °C, it was also gradually transformed into a co-crystal with temperature. The PIR–SAC co-crystal formation might be possibly attributed to a mobile phase formed between PIR and SAC, leading to a co-crystal formation. This mobile phase could be formed by either solution through a lubricating liquid added during grinding process or eutectic melt via thermal stress. A simultaneous DSC-FTIR technique also directly evidenced the PIR–SAC co-crystal formation via a one-step process. The present study concludes that the chloroform-assisted grinding process or thermal stress easily enhanced a PIR–SAC co-crystal formation via gradual induction of inter-/intramolecular hydrogen bonding between PIR and SAC.


Piroxicam Saccharin Liquid-assisted grinding Thermal stress DSC-FTIR Co-crystal formation 



This work was supported by National Science Council, Taipei, Taiwan, ROC (NSC 100-2320-B-264-001-MY3).

Compliance with ethical standards

Conflict of interest



  1. 1.
    Vishweshwar P, McMahon JA, Bis JA, Zaworotko MJ. Pharmaceutical co-crystals. J Pharm Sci. 2007;95:499–516.CrossRefGoogle Scholar
  2. 2.
    Schultheiss N, Newman A. Pharmaceutical co-crystals and their physicochemical properties. Cryst Growth Des. 2009;9:2950–67.CrossRefGoogle Scholar
  3. 3.
    Miroshnyk I, Mirza S, Sandler N. Pharmaceutical co-crystals: an opportunity for drug product enhancement. Expert Opin Drug Deliv. 2009;6:333–41.CrossRefGoogle Scholar
  4. 4.
    Steed JW. The role of co-crystals in pharmaceutical design. Trends Pharmacol Sci. 2013;34:185–93.CrossRefGoogle Scholar
  5. 5.
    Shan N, Perry ML, Weyna DR, Zaworotko MJ. Impact of pharmaceutical cocrystals: the effects on drug pharmacokinetics. Expert Opin Drug Metab Toxicol. 2014;10:1255–71.CrossRefGoogle Scholar
  6. 6.
    Shiraki K, Takata N, Takano R, Hayashi Y, Terada K. Dissolution improvement and the mechanism of the improvement from co-crystallization of poorly water soluble compounds. Pharm Res. 2008;25:2581–92.CrossRefGoogle Scholar
  7. 7.
    Chadha R, Saini A, Arora P, Bhandari S. Pharmaceutical cocrystals: a novel approach for oral bioavailability enhancement of drugs. Crit Rev Ther Drug Carrier Syst. 2012;29:183–218.CrossRefGoogle Scholar
  8. 8.
    FDA. Guidance for Industry: Regulatory Classification of Pharmaceutical Co-Crystals. April, 2013.Google Scholar
  9. 9.
    Thakuria R, Delori A, Jones W, Lipert MP, Roy L, Rodríguez-Hornedo N. Pharmaceutical cocrystals and poorly soluble drugs. Int J Pharm. 2013;453:101–25.CrossRefGoogle Scholar
  10. 10.
    Brittain HG. Pharmaceutical co-crystals: the coming wave of new drug substances. J Pharm Sci. 2013;102:311–7.CrossRefGoogle Scholar
  11. 11.
    Friscic T, Jones W. Benefits of co-crystallization in pharmaceutical materials science: an update. J Pharm Pharmacol. 2010;62:1547–59.CrossRefGoogle Scholar
  12. 12.
    Qiao N, Li M, Schlindwein W, Malek N, Davies A, Trappitt G. Pharmaceutical co-crystals: an overview. Int J Pharm. 2011;419:1–11.CrossRefGoogle Scholar
  13. 13.
    Sun CC. Co-crystallization for successful drug delivery. Expert Opin Drug Deliv. 2013;10:201–13.CrossRefGoogle Scholar
  14. 14.
    Rodríguez-Spong B, Price CP, Jayasankar A, Matzger AJ, Rodríguez-Hornedo N. General principles of pharmaceutical solid polymorphism: a supramolecular perspective. Adv Drug Deliv Rev. 2004;56:241–74.CrossRefGoogle Scholar
  15. 15.
    Trask AV. An overview of pharmaceutical co-crystals as intellectual property. Mol Pharm. 2007;4:301–9.CrossRefGoogle Scholar
  16. 16.
    Hasa D, Rauber GS, Voinovich D, Jones W. Cocrystal formation through mechanochemistry: from neat and liquid-assisted grinding to polymer-assisted grinding. Angew Chem Int Ed Engl. 2015;54:7371–5.CrossRefGoogle Scholar
  17. 17.
    Bysouth SR, Bis JA, Igo D. Co-crystallization via planetary milling: enhancing throughput of solid-state screening methods. Int J Pharm. 2011;411:169–71.CrossRefGoogle Scholar
  18. 18.
    Braga D, Maini L, Grepioni F. Mechanochemical preparation of co-crystals. Chem Soc Rev. 2013;42:7638–48.CrossRefGoogle Scholar
  19. 19.
    Zhang GC, Lin HL, Lin SY. Thermal analysis and FTIR spectral curve-fitting investigation of formation mechanism and stability of indomethacin-saccharin co-crystals via solid-state grinding process. J Pharm Biomed Anal. 2012;66:162–9.CrossRefGoogle Scholar
  20. 20.
    Hsu PC, Lin HL, Wang SL, Lin SY. Solid-state thermal behavior and stability studies of theophylline–citric acid co-crystals prepared by neat cogrinding or thermal treatment. J Solid State Chem. 2012;192:238–45.CrossRefGoogle Scholar
  21. 21.
    Lin HL, Zhang GC, Hsu PC, Lin SY. A portable fiber-optic Raman analyzer for fast real-time screening and identifying co-crystal formation of drug-coformer via grinding process. Microchem J. 2013;110:15–20.CrossRefGoogle Scholar
  22. 22.
    Lin HL, Wu TK, Lin SY. Screening and characterization of co-crystal formation of metaxalone with short-chain dicarboxylic acids induced by liquid-assisted grinding approach. Thermochim Acta. 2014;575:313–21.CrossRefGoogle Scholar
  23. 23.
    Lipinski CA. Poor aqueous solubility: an industry-wide problem in drug discovery. Am Pharm Rev. 2002;5(1):82–5.Google Scholar
  24. 24.
    Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement techniques. ISRN Pharm. 2012; Article ID 195727.Google Scholar
  25. 25.
    Kawakami K. Modification of physicochemical characteristics of active pharmaceutical ingredients and application of supersaturatable dosage forms for improving bioavailability of poorly absorbed drugs. Adv Drug Deliv Rev. 2012;64:480–95.CrossRefGoogle Scholar
  26. 26.
    Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability. Pharm Res. 1995;12:413–20.CrossRefGoogle Scholar
  27. 27.
    Javadzadeh Y, Siahi MR, Asnaashari S, Nokhodchi A. An investigation of physicochemical properties of piroxicam liquisolid compacts. Pharm Dev Technol. 2007;12:337–43.CrossRefGoogle Scholar
  28. 28.
    Löbenberg R, Amidon GL. Modern bioavailability, bioequivalence and biopharmaceutics classification system. New scientific approaches to international regulatory standards. Eur J Pharm Biopharm. 2000;50:3–12.CrossRefGoogle Scholar
  29. 29.
    Verma MM, Kumar MT, Balasubramaniam J, Pandit JK. Dissolution, bioavailability and ulcerogenic studies on piroxicam-nicotinamide solid dispersion formulations. Boll Chim Farm. 2003;142:119–24.Google Scholar
  30. 30.
    Prabhu S, Ortega M, Ma C. Novel lipid-based formulations enhancing the in vitro dissolution and permeability characteristics of a poorly water-soluble model drug, piroxicam. Int J Pharm. 2005;301:209–16.CrossRefGoogle Scholar
  31. 31.
    Jug M, Bećirević-Laćan M, Cetina-Cizmek B, Horvat M. Hydroxypropyl methylcellulose microspheres with piroxicam and piroxicam-hydroxypropyl-beta-cyclodextrin inclusion complex. Pharmazie. 2004;59:686–91.Google Scholar
  32. 32.
    Vrecer F, SrciE S, Smid-Korbar J. Investigation of piroxicam polymorphism. Int J Pharm. 1991;68:35–41.CrossRefGoogle Scholar
  33. 33.
    Vrecer F, Vrbinc M, Meden A. Characterization of piroxicam crystal modifications. Int J Pharm. 2003;256:3–15.CrossRefGoogle Scholar
  34. 34.
    Naelapää K, Boetker JP, Veski P, Rantanen J, Rades T, Kogermann K. Polymorphic form of piroxicam influences the performance of amorphous material prepared by ball-milling. Int J Pharm. 2012;429:69–77.CrossRefGoogle Scholar
  35. 35.
    Lyn LY, Sze HW, Rajendran A, Adinarayana G, Dua K, Garg S. Crystal modifications and dissolution rate of piroxicam. Acta Pharm. 2011;61(4):391–402.CrossRefGoogle Scholar
  36. 36.
    Good DJ, Rodríguez-Hornedo N. Solubility advantage of pharmaceutical cocrystals. Cryst Growth Des. 2009;9:2252–64.CrossRefGoogle Scholar
  37. 37.
    Fucke K, Myz SA, Shakhtshneider TP, Boldyreva EV, Griesser UJ. How good are the crystallisation methods for co-crystals? A comparative study of piroxicam. New J Chem. 2012;36:1969–77.CrossRefGoogle Scholar
  38. 38.
    Childs SL, Hardcastle KI. Co-crystals of piroxicam with carboxylic acids. Cryst Growth Des. 2007;7:1291–304.CrossRefGoogle Scholar
  39. 39.
    Wu TK, Lin SY, Lin HL, Huang YT. Simultaneous DSC-FTIR microspectroscopy used to screen and detect the co-crystal formation in real time. Bioorg Med Chem Lett. 2011;21:3148–51.CrossRefGoogle Scholar
  40. 40.
    Banerjee R, Bhatt PM, Ravindra NV, Desiraju GR. Saccharin salts of active pharmaceutical ingredients, their crystal structures, and increased water solubilities. Cryst Growth Des. 2005;5:2299–309.CrossRefGoogle Scholar
  41. 41.
    Lin HL, Zhang GC, Lin SY. Real-time co-crystal screening and formation between indomethacin and saccharin via DSC analytical technique or DSC-FTIR microspectroscopy. J Thermal Anal Calorim. 2015;120:679–87.CrossRefGoogle Scholar
  42. 42.
    Lin HL, Hsu PC, Lin SY. Theophylline-citric acid co-crystals easily induced by DSC-FTIR microspectroscopy or different storage conditions. Asian J Pharm Sci. 2013;8:19–27.CrossRefGoogle Scholar
  43. 43.
    Padrela L, de Azevedo EG, Velaga SP. Powder X-ray diffraction method for the quantification of cocrystals in the crystallization mixture. Drug Dev Ind Pharm. 2012;38:923–9.CrossRefGoogle Scholar
  44. 44.
    Taddei P, Torreggiani A, Simoni R. Influence of environment on piroxicam polymorphism: vibrational spectroscopic study. Biopolymers. 2001;62:68–78.CrossRefGoogle Scholar
  45. 45.
    Jovanovski G. The SO2 stretching vibrations in some metal saccharinates: spectra-structure correlations. Spectro Lett. 1995;28:1095–109.CrossRefGoogle Scholar
  46. 46.
    Binev IG, Stamboliyska BA, Velcheva EA. The infrared spectra and structure of o-sulfobenzimide (saccharin) and of its nitranion: an ab initio force field treatment. Spectrochim Acta A Mol Biomol Spectrosc. 1996;52:1135–43.CrossRefGoogle Scholar
  47. 47.
    Mohammad MA, Alhalaweh A, Velaga SP. Hansen solubility parameter as a tool to predict cocrystal formation. Int J Pharm. 2011;407:63–71.CrossRefGoogle Scholar
  48. 48.
    Lu E, Rodriguez-Hornedo N, Suryanarayanan R. A rapid thermal method for cocrystal screening. CrystEngComm. 2008;10:665–8.CrossRefGoogle Scholar
  49. 49.
    Yamashita H, Hirakura Y, Yuda M, Teramura T, Terada K. Detection of cocrystal formation based on binary phase diagrams using thermal analysis. Pharm Res. 2013;30:70–80.CrossRefGoogle Scholar
  50. 50.
    Bhatt PM, Ravindra NV, Banerjee R, Desiraju GR. Saccharin as a salt former Enhanced solubilities of saccharinates of active pharmaceutical ingredients. Chem Commun. 2005;28:1073–5.CrossRefGoogle Scholar
  51. 51.
    Mura P, Cirri M, Faucci MT, Ginès-Dorado JM, Bettinetti GP. Investigation of the effects of grinding and co-grinding on physicochemical properties of glisentide. J Pharm Biomed Anal. 2002;30:227–37.CrossRefGoogle Scholar
  52. 52.
    Colombo I, Grassi G, Grassi M. Drug mechanochemical activation. J Pharm Sci. 2009;98:3961–86.CrossRefGoogle Scholar
  53. 53.
    Bowmaker GA. Solvent-assisted mechanochemistry. Chem Commun. 2013;49:334–48.CrossRefGoogle Scholar
  54. 54.
    Trask V, Jones W. Crystal engineering of organic cocrystals by the solid-state grinding approach. Top Curr Chem. 2005;254:41–70.Google Scholar
  55. 55.
    Chattoraj S, Shi L, Chen M, Alhalaweh A, Velaga S, Sun CC. Origin of deteriorated crystal plasticity and compaction properties of a 1:1 cocrystal between piroxicam and saccharin. Cryst Growth Des. 2014;14:3864–74.CrossRefGoogle Scholar
  56. 56.
    Sun CC, Hou H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst Growth Des. 2008;8:1575–9.CrossRefGoogle Scholar
  57. 57.
    Maeno Y, Fukami T, Kawahata M, Yamaguchi K, Tagami T, Ozeki T, Suzuki T, Tomono K. Novel pharmaceutical cocrystal consisting of paracetamol and trimethylglycine, a new promising cocrystal former. Int J Pharm. 2014;473:179–86.CrossRefGoogle Scholar
  58. 58.
    Karki S, Frisic T, Fabian L, Laity PR, Day G, Jones W. Improving mechanical properties of crystalline solids by cocrystal formation: new compressible forms of paracetamol. Adv Mater. 2009;21:3905–9.CrossRefGoogle Scholar
  59. 59.
    Lin SY, Wang SL. Advances in simultaneous DSC-FTIR microspectroscopy for rapid solid-state chemical stability studies: some dipeptide drugs as examples. Adv Drug Deliv Rev. 2012;64:461–78.CrossRefGoogle Scholar
  60. 60.
    Hsu CH, Lin SY. Rapid examination of the kinetic process of intramolecular lactamization of gabapentin using DSC-FTIR. Thermochim Acta. 2009;486:5–10.CrossRefGoogle Scholar
  61. 61.
    Lin SY, Cheng WT, Wei YS, Lin HL. DSC-FTIR microspectroscopy used to investigate the thermal-induced intramolecular cyclic anhydride formation between Eudragit E and PVA copolymer. Polym J. 2011;43:577–80.CrossRefGoogle Scholar
  62. 62.
    Lin HL, Zhang GC, Huang YT, Lin SY. An investigation of indomethacin-nicotinamide cocrystal formation induced by thermal stress in the solid or liquid state. J Pharm Sci. 2014;103:2386–95.CrossRefGoogle Scholar

Copyright information

© Akadémiai Kiadó, Budapest, Hungary 2015

Authors and Affiliations

  1. 1.Department of Biotechnology and Pharmaceutical TechnologyYuanpei University of Medical TechnologyHsin ChuTaiwan, ROC

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