Research Article In Situ Cocrystallization of Dapsone and Caffeine during Fluidized Bed Granulation Processing Valerio Todaro, 1,3 Zelalem Ayenew Worku, 1 Lucio Mendes Cabral, 2 and Anne Marie Healy 1 Received 20 August 2018; accepted 21 October 2018 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. KEY WORDS: cocrystals; fluidized bed granulation; ball milling; pharmaceutical processing. INTRODUCTION A variety of different manufacturing operations are commonly employed in the pharmaceutical industry, with most based on the application of mechanical and thermal energies and many also involving the use of different types of aqueous or non-aqueous solvents. The impact of process variables on the raw materials can significantly influence the quality of a final solid dosage form. Under stress conditions, many active pharmaceutical ingredients (APIs) have shown a tendency to change from the initial solid form to their related polymorphs. Process-related phase transformations have been reported for many of the most extensively used manufacturing processes such as compression, milling, hot melt extrusion, granulation and drying (1–5). Polymorphism constitutes the existence of different crystalline habits for the same compound and is a very commonly observed phenomenon for APIs. The disorganised arrangement of molecules without a defined crystal lattice (amorphous form) and the presence of solvent molecules in the crystal lattice (solvates and hydrates) may also be considered as polymorphic or pseudopolymorphic forms (6). However, different crystal structures of the same drug may present important differences in physiochemical properties, bioavailability and pharmacological activities (7–9). In this sense, understanding and controlling the process variables which can potentially induce changes in the solid state of the API during pharmaceutical manufacturing is critical to guaranteeing the quality and safety of the final medicinal product. APIs may be classified under the Biopharmaceutics Classification System (BCS) guidelines into four BCS classes, based on their ability to dissolve in water and permeate human tissues. The APIs that are classified as class II (high permeability and low solubility) and IV (low permeability and 1 Synthesis and Solid State Pharmaceutical Centre, School of Phar- macy and Pharmaceutical Sciences, Trinity College Dublin, Dublin, Ireland. 2 Department of Drugs and Pharmaceutics, Faculty of Pharmacy, Federal University of Rio de Janeiro, Rio de Janeiro, RJ, Brazil. 3 To whom correspondence should be addressed. (e–mail: todarov@tcd.ie) AAPS PharmSciTech (2019) 20:28 DOI: 10.1208/s12249-018-1228-4 1530-9932/19/0000-0001/0 # 2019 American Association of Pharmaceutical Scientists