In Situ Cocrystallization of Dapsone and Caffeine during Fluidized Bed Granulation Processing


Different pharmaceutical manufacturing processes have been demonstrated to represent feasible platforms for the production of pharmaceutical cocrystals. However, new methods are needed for the manufacture of cocrystals on a large scale. In this work, the suitability of the use of a fluidized bed system for granulation and concomitant cocrystallization was investigated. Dapsone (DAP) and caffeine (CAF) have been shown to form a stable cocrystal by simple solvent evaporation. DAP is the active pharmaceutical ingredient (API) and CAF is the coformer. In the present study, DAP-CAF cocrystals were produced through liquid-assisted milling and the product obtained was used as a cocrystal reference. The granulation of DAP and CAF was carried out using four different experimental conditions. The solid-state properties of the constituents of the granules were characterised by differential scanning calorimetry (DSC) and x-ray powder diffraction (PXRD) analysis while the granule size distribution and morphology were investigated using laser diffraction and scanning electron microscopy (SEM), respectively. DAP-CAF cocrystal granules were successfully produced during fluidized bed granulation. The formation of cocrystals was possible only when the DAP and CAF were dissolved in the liquid phase and sprayed over the fluidized solid particles. Furthermore, the presence of polymers in solution interferes with the cocrystallization, resulting in the amorphization of the DAP and CAF. Cocrystallization via fluidized bed granulation represents a useful tool and a feasible alternative technique for the large scale manufacture of pharmaceutical cocrystals for solid dosage forms.

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Active pharmaceutical ingredient


Differential scanning calorimetry


Powder x-ray diffraction


Scanning electron microscopy


Biopharmaceutics Classification System


Fluidized bed granulation


Microcrystalline cellulose




Hydroxypropyl methylcellulose


Experimental conditions


Stability index


Flow rate index


Angle of internal friction


Flow function coefficient


Conditioned bulk density


  1. 1.

    Otsuka M, Hasegawa H, Matsuda Y. Effect of polymorphic forms of bulk powders on pharmaceutical properties of carbamazepine granules. Chem Pharm Bull. 1999;47(6):852–6.

    CAS  Article  Google Scholar 

  2. 2.

    Airaksinen S, Karjalainen M, Räsänen E, Rantanen J, Yliruusi J. Comparison of the effects of two drying methods on polymorphism of theophylline. Int J Pharm. 2004;276(1–2):129–41.

    CAS  Article  Google Scholar 

  3. 3.

    Panchagnula R, Sundaramurthy P, Pillai O, Agrawal S, Raj YA. Solid-state characterization of mefenamic acid. J Pharm Sci. 2004;93(4):1019–29.

    CAS  Article  Google Scholar 

  4. 4.

    Chieng N, Zujovic Z, Bowmaker G, Rades T, Saville D. Effect of milling conditions on the solid-state conversion of ranitidine hydrochloride form 1. Int J Pharm. 2006;327(1–2):36–44.

    CAS  Article  Google Scholar 

  5. 5.

    Liu X, Lu M, Guo Z, Huang L, Feng X, Wu C. Improving the chemical stability of amorphous solid dispersion with cocrystal technique by hot melt extrusion. Pharm Res. 2012;29(3):806–17.

    CAS  Article  Google Scholar 

  6. 6.

    Food and Drug Administration. Guidance for industry: waiver of in vivo bioavailability and bioequivalence studies for immediate-release solid oral dosage forms based on a biopharmaceutics classification system. Rockville: Food and Drug Administration; 2000.

    Google Scholar 

  7. 7.

    Aguiar AJ, Krc J, Kinkel AW, Samyn JC. Effect of polymorphism on the absorption of chloramphenicol from chloramphenicol palmitate. J Pharm Sci. 1967;56(7):847–53.

    CAS  Article  Google Scholar 

  8. 8.

    Bauer J, Spanton S, Henry R, Quick J, Dziki W, Porter W, et al. Ritonavir: an extraordinary example of conformational polymorphism. Pharm Res. 2001;18(6):859–66.

    CAS  Article  Google Scholar 

  9. 9.

    Sun C, Grant DJ. Influence of crystal structure on the tableting properties of sulfamerazine polymorphs. Pharm Res. 2001;18(3):274–80.

    CAS  Article  Google Scholar 

  10. 10.

    Amidon GL, Lennernäs 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(3):413–20.

    CAS  Article  Google Scholar 

  11. 11.

    Kalepu S, Nekkanti V. Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharm Sin B. 2015;5(5):442–53.

    Article  Google Scholar 

  12. 12.

    Leuner C, Dressman J. Improving drug solubility for oral delivery using solid dispersions. Eur J Pharm Biopharm. 2000;50(1):47–60.

    CAS  Article  Google Scholar 

  13. 13.

    Babu NJ, Nangia A. Solubility advantage of amorphous drugs and pharmaceutical cocrystals. Cryst Growth Des. 2011;11(7):2662–79.

    CAS  Article  Google Scholar 

  14. 14.

    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.

    CAS  Article  Google Scholar 

  15. 15.

    Lee KS, Kim KJ, Ulrich J. In situ monitoring of cocrystallization of salicylic acid–4, 4′-dipyridyl in solution using Raman spectroscopy. Cryst Growth Des. 2014;14(6):2893–9.

    CAS  Article  Google Scholar 

  16. 16.

    Liu M, Hong C, Yao Y, Shen H, Ji G, Li G, et al. Development of a pharmaceutical cocrystal with solution crystallization technology: preparation, characterization, and evaluation of myricetin-proline cocrystals. Eur J Pharm Biopharm. 2016;107:151–9.

    CAS  Article  Google Scholar 

  17. 17.

    Chieng N, Hubert M, Saville D, Rades T, Aaltonen J. Formation kinetics and stability of carbamazepine−nicotinamide cocrystals prepared by mechanical activation. Cryst Growth Des. 2009;9(5):2377–86.

    CAS  Article  Google Scholar 

  18. 18.

    Bysouth SR, Bis JA, Igo D. Cocrystallization via planetary milling: enhancing throughput of solid-state screening methods. Int J Pharm. 2011;411(1–2):169–71.

    CAS  Article  Google Scholar 

  19. 19.

    Dhumal RS, Kelly AL, York P, Coates PD, Paradkar A. Cocrystalization and simultaneous agglomeration using hot melt extrusion. Pharm Res. 2010;27(12):2725–33.

    CAS  Article  Google Scholar 

  20. 20.

    Moradiya HG, Islam MT, Halsey S, Maniruzzaman M, Chowdhry BZ, Snowden MJ, et al. Continuous cocrystallisation of carbamazepine and trans-cinnamic acid via melt extrusion processing. Cryst Eng Comm. 2014;16(17):3573–83.

    CAS  Article  Google Scholar 

  21. 21.

    Alhalaweh A, Velaga SP. Formation of cocrystals from stoichiometric solutions of incongruently saturating systems by spray drying. Cryst Growth Des. 2010;10(8):3302–5.

    CAS  Article  Google Scholar 

  22. 22.

    Serrano DR, O’Connell P, Paluch KJ, Walsh D, Healy AM. Cocrystal habit engineering to improve drug dissolution and alter derived powder properties. J Pharm Pharmacol. 2016;68(5):665–77.

    CAS  Article  Google Scholar 

  23. 23.

    Waldie B. Growth mechanism and the dependence of granule size on drop size in fluidized-bed granulation. Chem Eng Sci. 1991;46(11):2781–5.

    CAS  Article  Google Scholar 

  24. 24.

    Davis TD, Morris KR, Huang H, Peck GE, Stowell JG, Eisenhauer BJ, et al. In situ monitoring of wet granulation using online x-ray powder diffraction. Pharm Res. 2003;20(11):1851–7.

    CAS  Article  Google Scholar 

  25. 25.

    Potter CB, Kollamaram G, Zeglinski J, Whitaker DA, Croker DM, Walker GM. Investigation of polymorphic transitions of piracetam induced during wet granulation. Eur J Pharm Biopharm. 2017;119:36–46.

    CAS  Article  Google Scholar 

  26. 26.

    Davis TD, Peck GE, Stowell JG, Morris KR, Byrn SR. Modeling and monitoring of polymorphic transformations during the drying phase of wet granulation. Pharm Res. 2004;21(5):860–6.

    CAS  Article  Google Scholar 

  27. 27.

    do Amaral LH, do Carmo FA, Amaro MI, de Sousa VP, da Silva LC, de Almeida GS, et al. Development and characterization of dapsone cocrystal prepared by scalable production methods. AAPS PharmSciTech. 2018;19(6):2687–99.

  28. 28.

    Jiang L, Huang Y, Zhang Q, He H, Xu Y, Mei X. Preparation and solid-state characterization of dapsone drug–drug co-crystals. Cryst Growth Des. 2014;14(9):4562–73.

    CAS  Article  Google Scholar 

  29. 29.

    Freeman R. Measuring the flow properties of consolidated, conditioned and aerated powders—a comparative study using a powder rheometer and a rotational shear cell. Powder Technol. 2007;174(1–2):25–33.

    CAS  Article  Google Scholar 

  30. 30.

    Newman A, Zografi G. Critical considerations for the qualitative and quantitative determination of process-induced disorder in crystalline solids. J Pharm Sci. 2014;103(9):2595–604.

    CAS  Article  Google Scholar 

  31. 31.

    Morris KR, Griesser UJ, Eckhardt CJ, Stowell JG. Theoretical approaches to physical transformations of active pharmaceutical ingredients during manufacturing processes. Adv Drug Deliv Rev. 2001;48(1):91–114.

    CAS  Article  Google Scholar 

  32. 32.

    Zhang GG, Law D, Schmitt EA, Qiu Y. Phase transformation considerations during process development and manufacture of solid oral dosage forms. Adv Drug Deliv Rev. 2004;56(3):371–90.

    CAS  Article  Google Scholar 

  33. 33.

    Seefeldt K, Miller J, Alvarez-Nunez F, Rodriguez-Hornedo N. Crystallization pathways and kinetics of carbamazepine–nicotinamide cocrystals from the amorphous state by in situ thermomicroscopy, spectroscopy, and calorimetry studies. J Pharm Sci. 2007;96(5):1147–58.

    CAS  Article  Google Scholar 

  34. 34.

    Friščić T. Supramolecular concepts and new techniques in mechanochemistry: cocrystals, cages, rotaxanes, open metal–organic frameworks. Chem Soc Rev. 2012;41(9):3493–510.

    Article  Google Scholar 

  35. 35.

    Davies WL, Gloor WT. Batch production of pharmaceutical granulations in a fluidized bed I: effects of process variables on physical properties of final granulation. J Pharm Sci. 1971;60(12):1869–74.

    CAS  Article  Google Scholar 

  36. 36.

    Schaefer T, Worts O. Control of fluidized bed granulation. I. Effects of spray angle, nozzle height and starting materials on granule size and size distribution. Arch Pharm Chem Sci. 1977;5:51–60.

    CAS  Google Scholar 

  37. 37.

    Schaafsma SH, Vonk P, Segers P, Kossen NW. Description of agglomerate growth. Powder Technol. 1998;97(3):183–90.

    CAS  Article  Google Scholar 

  38. 38.

    Schaafsma SH, Vonk P, Kossen NW. Fluid bed agglomeration with a narrow droplet size distribution. Int J Pharm. 2000;193(2):175–87.

    CAS  Article  Google Scholar 

  39. 39.

    Alkan H, Ulusoy A. Granulation in a fluidized bed. I. Effect of addition of the binder in solution or in dry form. DOGA TU J Med Pharm. 1987;11(1):1–7.

    CAS  Google Scholar 

  40. 40.

    D'alonzo GD, O'connor RE, Schwartz JB. Effect of binder concentration and method of addition on granule growth in a high intensity mixer. Drug Dev Ind Pharm. 1990;16(12):1931–44.

    CAS  Article  Google Scholar 

  41. 41.

    Wells JI, Walker CV. The influence of granulating fluids upon granule and tablet properties: the role of secondary binding. Int J Pharm. 1983;15(1):97–111.

    CAS  Article  Google Scholar 

  42. 42.

    Dias VH, Pinto JF. Identification of the most relevant factors that affect and reflect the quality of granules by application of canonical and cluster analysis. J Pharm Sci. 2002;91(1):273–81.

    CAS  Article  Google Scholar 

  43. 43.

    Sastry KV, Fuerstenau DW. Mechanisms of agglomerate growth in green pelletization. Powder Technol. 1973;7(2):97–105.

    Article  Google Scholar 

  44. 44.

    Vora C, Patadia R, Mittal K, Mashru R. Preparation and characterization of dipyridamole solid dispersions for stabilization of supersaturation: effect of precipitation inhibitors type and molecular weight. Pharm Dev Technol. 2016;21(7):847–55.

    CAS  Article  Google Scholar 

  45. 45.

    Ho HO, Su HL, Tsai T, Sheu MT. The preparation and characterization of solid dispersions on pellets using a fluidized-bed system. Int J Pharm. 1996;139(1–2):223–9.

    CAS  Article  Google Scholar 

  46. 46.

    Zhou Q, Armstrong B, Larson I, Stewart PJ, Morton DA. Improving powder flow properties of a cohesive lactose monohydrate powder by intensive mechanical dry coating. J Pharm Sci. 2010;99(2):969–81.

    CAS  Article  Google Scholar 

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This publication has emanated from research supported in part by a research grant from Science Foundation Ireland (SFI) and is co-funded under the European Regional Development Fund under Grant Number 12/RC/2275.

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Correspondence to Valerio Todaro.

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Todaro, V., Worku, Z.A., Cabral, L.M. et al. In Situ Cocrystallization of Dapsone and Caffeine during Fluidized Bed Granulation Processing. AAPS PharmSciTech 20, 28 (2019).

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  • cocrystals
  • fluidized bed granulation
  • ball milling
  • pharmaceutical processing