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Simultaneously Improving the Mechanical Properties, Dissolution Performance, and Hygroscopicity of Ibuprofen and Flurbiprofen by Cocrystallization with Nicotinamide

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ABSTRACT

Purpose

To be fully exploitable in both formulation and manufacturing, a drug cocrystal needs to demonstrate simultaneous improvement of multiple key pharmaceutical properties over the pure drug crystal. The present work was aimed at investigating such feasibility with two model profen-nicotinamide cocrystals.

Methods

Phase pure 1:1 ibuprofen-nicotinamide and flurbiprofen-nicotinamide cocrystals were prepared from solutions through rapid solvent removal using rotary evaporation,and characterized by DSC, PXRD, FTIR, phase solubility measurements, equilibrium moisture sorption analysis, dissolution testing and tabletability analysis.

Results

Temperature-composition phase diagrams constructed from DSC data for each profen and nicotinamide crystal revealed the characteristic melting point of the 1:1 cocrystal as well as the eutectic temperatures and compositions. Both cocrystals exhibited higher intrinsic dissolution rates than the corresponding profens. The cocrystals also sorbed less moisture and displayed considerably better tabletability than the individual profens and nicotinamide.

Conclusions

Phase behaviors of 1:1 profen-nicotinamide cocrystal systems were delineated by constructing their temperature-composition phase diagrams. Cocrystallization with nicotinamide can simultaneously improve tableting behavior, hygroscopicity, and dissolution performance of ibuprofen and flurbiprofen. This could pave the way for further development of such cocrystal systems into consistent, stable, efficacious and readily manufacturable drug products.

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REFERENCES

  1. Ku MS. Preformulation consideration for drugs in oral CR formulation. In: Wen H, Park K, editors. Oral controlled release formulation design and drug delivery: Theory to practice. New Jersey: John Wiley & Sons; 2010. p. 47–70.

  2. Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev. 2007;59(7):617–30.

    Article  PubMed  CAS  Google Scholar 

  3. Desiraju GR. Crystal engineering: The design of organic solids. Amsterdam: Elsevier; 1989.

  4. Tong HHY, Chow ASF, Chan HM, Chow AHL, Wan YKY, Williams ID, Shek FLY, Chan CK. Process-induced phase transformation of berberine chloride hydrates. J Pharm Sci. 2010;99(4):1942–54.

    PubMed  CAS  Google Scholar 

  5. Khankari RK, Grant DJW. Pharmaceutical hydrates. Thermochim Acta. 1995;248:61–79.

    Article  CAS  Google Scholar 

  6. Giron D, Grant DJW. Evaluation of solid-state properties of salts. In: Stahl PH, Wermuth CG, editors. Handbook of pharmaceutical salts: Properties, selection, and use. Weinheim: Wiley-VCH; 2008. p. 41–82.

  7. Basavoju S, Bostroem D, Velaga SP. Indomethacin-Saccharin cocrystal: design, synthesis and preliminary pharmaceutical characterization. Pharm Res. 2008;25(3):530–41.

    Article  PubMed  CAS  Google Scholar 

  8. Shiraki K, Takata N, Takano R, Hayashi Y, Terada K. Dissolution improvement and the mechanism of the improvement from cocrystallization of poorly water-soluble compounds. Pharm Res. 2008;25(11):2581–92.

    Article  PubMed  CAS  Google Scholar 

  9. Trask AV, Motherwell WDS, Jones W. Physical stability enhancement of theophylline via cocrystallization. Int J Pharm. 2006;320(1–2):114–23.

    Article  PubMed  CAS  Google Scholar 

  10. McNamara DP, Childs SL, Giordano J, Iarriccio A, Cassidy J, Shet MS, et al. Use of a glutaric acid cocrystal to improve oral bioavailability of a low solubility API. Pharm Res. 2006;23(8):1888–97.

    Article  PubMed  CAS  Google Scholar 

  11. Sun CC, Hou H. Improving mechanical properties of caffeine and methyl gallate crystals by cocrystallization. Cryst Growth Des. 2008;8(5):1575–9.

    Article  CAS  Google Scholar 

  12. Lancaster RW, Karamertzanis PG, Hulme AT, Tocher DA, Lewis TC, Price SL. The polymorphism of progesterone: stabilization of a ‘disappearing’ polymorph by co-crystallization. J Pharm Sci. 2007;96(12):3419–31.

    Article  PubMed  CAS  Google Scholar 

  13. Lou B, Bostroem D, Velaga SP. Polymorph control of felodipine form II in an attempted cocrystallization. Cryst Growth Des. 2009;9(3):1254–7.

    Article  CAS  Google Scholar 

  14. Yip AG, Green RC, Huyck M, Cupples LA, Farrer LA. Nonsteroidal anti-inflammatory drug use and Alzheimer’s disease risk: the MIRAGE Study. BMC Geriatr. 2005;5:2.

    Article  PubMed  Google Scholar 

  15. Prasad KN, Cole WC, Prasad KC. Risk factors for Alzheimer’s disease: Role of multiple antioxidants, non-steroidal anti-inflammatory and cholinergic agents alone or in combination in prevention and treatment. J Am Coll Nutr. 2002;21(6):506–22.

    PubMed  CAS  Google Scholar 

  16. Babiloni C, Frisoni GB, Del Percio C, Zanetti O, Bonomini C, Cassetta E, et al. Ibuprofen treatment modifies cortical sources of EEG rhythms in mild Alzheimer’s disease. Clin Neurophysiol. 2009;120(4):709–18.

    Article  PubMed  CAS  Google Scholar 

  17. Berry DJ, Seaton CC, Clegg W, Harrington RW, Coles SJ, Horton PN, et al. Applying hot-stage microscopy to Co-crystal screening: a study of nicotinamide with seven active pharmaceutical ingredients. Cryst Growth Des. 2008;8(5):1697–712.

    Article  CAS  Google Scholar 

  18. Green KN, Steffan JS, Martinez-Coria H, Sun X, Schreiber SS, Thompson LM, et al. Nicotinamide restores cognition in Alzheimer’s disease transgenic mice via a mechanism involving sirtuin inhibition and selective reduction of Thr231-phosphotau. J Neurosci. 2008;28(45):11500–10.

    Article  PubMed  CAS  Google Scholar 

  19. Higuchi T, Connors KA. Phase-solubility techniques. Advan Anal Chem Instr. 1965;4:117–212.

    CAS  Google Scholar 

  20. Tong HHY, Wong SYS, Law MWL, Chu KKW, Chow AHL. Anti-hygroscopic effect of dextrans in herbal formulations. Int J Pharm. 2008;363(1–2):99–105.

    Article  PubMed  CAS  Google Scholar 

  21. Zhang J, Zografi G. The relationship between “BET” - and “free volume” - derived parameters for water vapor absorption into amorphous solids. J Pharm Sci. 2000;89(8):1063–72.

    Article  PubMed  CAS  Google Scholar 

  22. Sun C, Grant DJW. Influence of crystal shape on the tableting performance of L-lysine monohydrochloride dihydrate. J Pharm Sci. 2001;90(5):569–79.

    Article  PubMed  CAS  Google Scholar 

  23. Sun C, Grant DJW. Effects of initial particle size on the tableting properties of L-lysine monohydrochloride dihydrate powder. Int J Pharm. 2001;215(1–2):221–8.

    Article  PubMed  CAS  Google Scholar 

  24. Friscic T, Jones W. Cocrystal architecture and properties: design and building of chiral and racemic structures by solid-solid reactions. Faraday Discuss. 2007;136:167–78.

    Article  PubMed  CAS  Google Scholar 

  25. Henck J, Kuhnert-Brandstaetter M. Demonstration of the terms enantiotropy and monotropy in polymorphism research exemplified by Flurbiprofen. J Pharm Sci. 1999;88(1):103–8.

    Article  PubMed  CAS  Google Scholar 

  26. Nehm SJ, Rodriguez-Spong B, Rodriguez-Hornedo N. Phase solubility diagrams of cocrystals are explained by solubility product and solution complexation. Cryst Growth Des. 2006;6(2):592–600.

    Article  CAS  Google Scholar 

  27. Davis RE, Lorimer KA, Wilkowski MA, Rivers JH, Wheeler KA, Bowers J. Studies of phase relationships in cocrystal systems. ACA Trans. 2004;39:41–61.

    CAS  Google Scholar 

  28. Aakeroey CB, Salmon DJ, Smith MM, Desper J. Cyanophenyloximes: reliable and versatile tools for hydrogen-bond directed supramolecular synthesis of cocrystals. Cryst Growth Des. 2006;6(4):1033–42.

    Article  CAS  Google Scholar 

  29. Sanghvi R, Evans D, Yalkowsky SH. Stacking complexation by nicotinamide: a useful way of enhancing drug solubility. Int J Pharm. 2007;336(1):35–41.

    Article  PubMed  CAS  Google Scholar 

  30. Schultheiss N, Newman A. Pharmaceutical cocrystals and their physicochemical properties. Cryst Growth Des. 2009;9(6):2950–67.

    Article  PubMed  CAS  Google Scholar 

  31. Jayasankar A, Good DJ, Rodriguez-Hornedo N. Mechanisms by which moisture generates cocrystals. Mol Pharm. 2007;4(3):360–72.

    Article  PubMed  CAS  Google Scholar 

  32. Chattoraj S, Shi L, Sun CC. Understanding the relationship between crystal structure, plasticity and compaction behaviour of theophylline, methyl gallate, and their 1: 1 co-crystal. Cryst Eng Comm. 2010;12(8):2466–72.

    CAS  Google Scholar 

  33. Sun CC. Materials science tetrahedron-a useful tool for pharmaceutical research and development. J Pharm Sci. 2009;98(5):1671–87.

    Article  PubMed  CAS  Google Scholar 

  34. Sun CC. Decoding powder tabletability: roles of particle adhesion and plasticity. J Adhes Sci Technol. 2011;25(4–5):483–99.

    Article  CAS  Google Scholar 

  35. Sun C, Grant DJW. Compaction properties of L-lysine salts. Pharm Res. 2001;18(3):281–6.

    Article  PubMed  Google Scholar 

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ACKNOWLEDGMENTS & DISCLOSURES

Financial support from the Chinese University of Hong Kong (research postgraduate studentship and conference travel grant for SFC) is gratefully acknowledged.

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Authors and Affiliations

  1. School of Pharmacy, The Chinese University of Hong Kong, Rm 616, Basic Medical Sciences Building, Shatin, N.T., Hong Kong, SAR, China

    Shing Fung Chow & Albert H. L. Chow

  2. Department of Pharmaceutics Pharmaceutical Materials Science & Engineering Laboratory College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA

    Miles Chen, Limin Shi & Changquan Calvin Sun

  3. College of Pharmacy, University of Minnesota, 9-127B Weaver-Densford Hall, 308 Harvard street S.E., Minneapolis, Minnesota, 55455, USA

    Changquan Calvin Sun

Authors
  1. Shing Fung Chow
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  2. Miles Chen
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  3. Limin Shi
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  4. Albert H. L. Chow
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  5. Changquan Calvin Sun
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Correspondence to Albert H. L. Chow or Changquan Calvin Sun.

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Chow, S.F., Chen, M., Shi, L. et al. Simultaneously Improving the Mechanical Properties, Dissolution Performance, and Hygroscopicity of Ibuprofen and Flurbiprofen by Cocrystallization with Nicotinamide. Pharm Res 29, 1854–1865 (2012). https://doi.org/10.1007/s11095-012-0709-5

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