pharmaceutics Article Continuous Manufacture and Scale-Up of Theophylline- Nicotinamide Cocrystals Steven A. Ross 1 , Andrew P. Hurt 1 , Milan Antonijevic 1 , Nicolaos Bouropoulos 2,3 , Adam Ward 4 , Pat Basford 5 , Mark McAllister 5 and Dennis Douroumis 1, *   Citation: Ross, S.A.; Hurt, A.P.; Antonijevic, M.; Bouropoulos, N.; Ward, A.; Basford, P.; McAllister, M.; Douroumis, D. Continuous Manufacture and Scale-Up of Theophylline-Nicotinamide Cocrystals. Pharmaceutics 2021, 13, 419. https://doi.org/10.3390/ pharmaceutics13030419 Academic Editor: Saeed Shirazian and Rahamatullah Shaikh Received: 25 February 2021 Accepted: 14 March 2021 Published: 20 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Faculty of Engineering and Science, University of Greenwich, Medway Campus, Chatham Maritime, Kent ME4 4TB, UK; S.A.Ross@greenwich.ac.uk (S.A.R.); A.Hurt@greenwich.ac.uk (A.P.H.); M.Antonijevic@greenwich.ac.uk (M.A.) 2 Department of Materials Science, University of Patras, Rio, 26504 Patras, Greece; nbouro@upatras.gr 3 Foundation for Research and Technology Hellas, Institute of Chemical Engineering and High Temperature, Chemical Processes, 26504 Patras, Greece 4 Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, West Yorkshire HD1 3DH, UK; Adam.Ward@pfizer.com 5 Pfizer Global Research & Development, Ramsgate Road, Sandwich CT13 9NJ, UK; pat.basford@pfizer.com (P.B.); Mark.McAllister@pfizer.com (M.M.) * Correspondence: D.Douroumis@gre.ac.uk; Tel.: +44-(0)-208-331-8440; Fax: +44-(0)-208-331-9805 Abstract: The aim of the study was the manufacturing and scale-up of theophylline-nicotinamide (THL-NIC) pharmaceutical cocrystals processed by hot-melt extrusion (HME). The barrel temperature profile, feed rate and screw speed were found to be the critical processing parameters with a residence time of approximately 47 s for the scaled-up batches. Physicochemical characterization using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffraction of bulk and extruded materials revealed the formation of high purity cocrystals (98.6%). The quality of THL-NIC remained unchanged under accelerated stability conditions. Keywords: cocrystals; hot-melt extrusion; scale-up; continuous manufacturing; X-ray; Rietveld refinement; solubility; surface dissolution imaging; stability 1. Introduction Oral drug administration has proven to be the most preferred delivery option in modern medicine with studies showing it to have high patient compliance rates, as well as being more convenient and relatively inexpensive [1]. However, over the past two decades, there has been a substantial increase in the complexity and specificity of drugs. The increased complexity has been accompanied by a decrease in the solubility of the active pharmaceutical ingredient (API) [2]. Approximately 60% of drugs screened in industrial research have poor water solubility, and the traditional formulation of these drugs can lead to poor bioavailability. For a drug to be effective it must be readily available at the target site after administration, bioavailability describes the degree to which a drug can achieve this. After oral delivery, the drug must dissolve in the gastro-intestinal fluid before being absorbed into systemic circulation. Poor solubility can limit drug absorption, thus decreasing its effectiveness. As a result, there has been increased importance in industry and research placed on formulation strategies to enhance the solubility of poorly water-soluble drugs [3]. One such strategy to improve the solubility of poorly soluble APIs is through cocrystal- lization. Although the exact definition of what constitutes a cocrystal is still being debated this day, a recent perspective authored by 46 specialists defined cocrystals as "solids that are crystalline single-phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio which are neither solvates nor simple salts” [4]. Cocrystallization allows for the modification of components and the chemical Pharmaceutics 2021, 13, 419. https://doi.org/10.3390/pharmaceutics13030419 https://www.mdpi.com/journal/pharmaceutics