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

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Abstract

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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Abbreviations

DAP:

Dapsone

CAF:

Caffeine

API:

Active pharmaceutical ingredient

DSC:

Differential scanning calorimetry

PXRD:

Powder x-ray diffraction

SEM:

Scanning electron microscopy

BCS:

Biopharmaceutics Classification System

FBG:

Fluidized bed granulation

MCC:

Microcrystalline cellulose

PVP:

Polyvinylpyrrolidone

HPMC:

Hydroxypropyl methylcellulose

EXP:

Experimental conditions

SI:

Stability index

FRI:

Flow rate index

AIF:

Angle of internal friction

ffc:

Flow function coefficient

CBD:

Conditioned bulk density

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Funding

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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Authors and Affiliations

  1. Synthesis and Solid State Pharmaceutical Centre, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland

    Valerio Todaro, Zelalem Ayenew Worku & Anne Marie Healy

  2. Department of Drugs and Pharmaceutics, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil

    Lucio Mendes Cabral

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  1. Valerio Todaro
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  2. Zelalem Ayenew Worku
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  3. Lucio Mendes Cabral
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  4. Anne Marie Healy
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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). https://doi.org/10.1208/s12249-018-1228-4

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