Development and Characterization of Dapsone Cocrystal Prepared by Scalable Production Methods


In this study, the formation of caffeine/dapsone (CAF/DAP) cocrystals by scalable production methods, such as liquid-assisted grinding (LAG) and spray drying, was investigated in the context of the potential use of processed cocrystal powder for pulmonary delivery. A CAF/DAP cocrystal (1:1 M ratio) was successfully prepared by slow evaporation from both acetone and ethyl acetate. Acetone, ethyl acetate, and ethanol were all successfully used to prepare cocrystals by LAG and spray drying. The powders obtained were characterized by X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravimetry (TGA), and Fourier transform infrared spectroscopy (FTIR). Laser diffraction analysis indicated a median particle size (D50) for spray-dried powders prepared from acetone, ethanol, and ethyl acetate of 5.4 ± 0.7, 5.2 ± 0.1, and 5.1 ± 0.0 μm respectively, which are appropriate sizes for pulmonary delivery by means of a dry powder inhaler. The solubility of the CAF/DAP cocrystal in phosphate buffer pH 7.4, prepared by spray drying using acetone, was 506.5 ± 31.5 μg/mL, while pure crystalline DAP had a measured solubility of 217.1 ± 7.8 μg/mL. In vitro cytotoxicity studies using Calu-3 cells indicated that the cocrystals were not toxic at concentrations of 0.1 and of 1 mM of DAP, while an in vitro permeability study suggested caffeine may contribute to the permeation of DAP by hindering the efflux effect. The results obtained indicate that the CAF/DAP cocrystal, particularly when prepared by the spray drying method, represents a possible suitable approach for inhalation formulations with applications in pulmonary pathologies.

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The authors acknowledge the assistance of Dr. Helge Müller-Bunz, School of Chemistry and Chemical Biology, University College Dublin, Ireland, in undertaking the SC-XRD analysis.


This material is based upon works supported by FAPERJ (Rio de Janeiro, Brazil), CAPES (Brasília, Brazil) under Grant No. 3372/13-8 and the Science Foundation Ireland under Grant No. 12/RC/2275.

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Correspondence to Lucio Mendes Cabral.

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Fig. S1 TGA of physical mixture CAF:DAP(1:1) (A); cocrystal obtained by LAG CAF:DAP(1:1) using acetone (B), using ethanol (C) and using ethyl acetate(D); cocrystal obtained by spray drying CAF:DAP(1:1) using acetone (E), using ethanol (F) and using ethyl acetate (G) (PNG 54.7 kb)


Fig. S2 FTIR spectra of physical mixture CAF:DAP(1:1) (A), cocrystal obtained by milling LAG CAF:DAP(1:1) using acetone (B), using ethanol (C) and using ethyl acetate(D). Cocrystal obtained spray drying CAF:DAP(1:1) using acetone (E), using ethanol (F) and using ethyl acetate (G) (PNG 56.1 kb)


Fig. S3 SEM of physical mixture CAF:DAP(1:1) (A1 and A2); cocrystal obtained by LAG CAF:DAP(1:1) using acetone (B1 and B2), using ethanol (C1 and C2) and using ethyl acetate(D1 and D2); cocrystal obtained by spray drying CAF:DAP(1:1) using acetone (E1 and E2), using ethanol (F1 and F2) and using ethyl acetate (G1 and G2). Magnification 1 = 100 X and 2 = 5000 X (PNG 454 kb)


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do Amaral, L.H., do Carmo, F.A., Amaro, M.I. et al. Development and Characterization of Dapsone Cocrystal Prepared by Scalable Production Methods. AAPS PharmSciTech 19, 2687–2699 (2018).

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  • dapsone
  • cocrystal
  • liquid-assisted grinding
  • spray drying
  • dry powder inhaler