466532 Continuous Co-Crystallization of Novel Theophylline and 4-Aminobenzoic Acid Co-Crystals from Twin Screw Extrusion

Tuesday, November 15, 2016: 10:20 AM
Continental 4 (Hilton San Francisco Union Square)
Rahamatullah Shaikh1, Shaza Darwish1, Manuel Kuhs1, Ahmad B. Albadarin2, Denise Croker1 and Gavin Walker1, (1)Bernal Institute, University of Limerick, Limerick City, Ireland, (2)Synthesis and Solid State Pharmaceuticals Centre (SSPC), Bernal Institute, University of Limerick, Limerick, Ireland

Recently, increased demand for greener and more environmentally sustainable processes has focused the attention on mechano-chemical process. Mechano-chemical synthesis is one in which solid reactants are vigorously ground (milling or grinding) together with minimal or even no solvent [1]. Mechano-chemical synthesis is environmentally friendly, easy, cheap, fast reaction rates and high yields; these advantageous properties made mechano-chemical synthesis a method of choice for co-crystal formation [2 & 3]. Pharmaceutical co-crystals are solids that are crystalline materials comprise of two or more components held together by non-covalent forces [4]. In recent years co-crystals are being studied intensively due to the potential for improved pharmaceutical properties such as increased solubility, bioavailability, chemical stability and hygroscopicity of active pharmaceutical ingredients [1].

High-shear granulation and twin screw extrusion, have recently been used for co-crystal preparation. These methods are environmentally friendly as they avoid, or minimise, the use of organic solvents [2 & 5]. Twin screw extruder mediated co-crystallisation is a promising processing technique for continuous co-crystallisation. Although twin screw extruder mediated co-crystallisation has been reported with various primary experimental parameters (screw geometry, temperature, feed rate and the RPM of the screws) that can affect co-crystal conversion, information on the impact of processing parameters processing temperature (eg. at eutectic temperature and room temperature), shear dependent crystallization, residence time and addition of organic solvents is less available. Therefore to enhance understanding of continuous co-crystallisation process in the present study the effect of key extrusion processing parameters that influence extent of conversion to the co-crystals has been studied. A Theophylline-4-Aminobenzoic acid novel co-crystal forming system was selected for the study. Appropriate stoichiometric ratios of Theophylline-4-Aminobenzoic acid were prepared. Co-crystallization of novel co-crystal system was carried out in a co-rotating 12 mm Hybrid Mini-Extruder (Three-Tec GmbH, Switzerland) with a length-to-diameter ratio of 40:1. The extrudates were mainly characterised by powder X-ray diffraction (PXRPD), differential scanning calorimetry (DSC), and in vitro drug release studies. As shown parameters had a significant influence on co-crystallization process, consequently they are important to consider in co-crystallization process. Finally twin screw extruder mediated co-crystallisation can be considered easy, cheap, scalable, and environmentally friendly for continues co-crystallization.

Key words: continuous co-crystallisation, twin screw extrusion, Theophylline-4-Aminobenzoic acid.


1. S.F. Chow, M. Chen, L. Shi, A.H.L. Chow, C.C. Sun, Simultaneously improving the mechanical properties, dissolution performance, and hygroscopicity of ibuprofen and flurbiprofen by cocrystallization with nicotinamide, Pharm. Res. 29 (2012) 1854–1865.

2. D. Daurio, C. Medina, R. Saw, K. Nagapudi, F. Alvarez-Nunez, Application of twin screw extrusion in the manufacture of cocrystals, Part I: four case studies, Pharmaceutics 3 (2011) 582–600.

3. James, S.L., Adams, C.J., Bolm, C., Braga, D., Collier, P., Friˇsˇci ´ c, T., Grepioni, F., Harris, K.D.M., Hyett, G., Jones, W., Krebs, A., Mack, J., Maini, L., Orpen, A.G., Parkin, I.P., Shearouse, W.C., Steed, J.W., Waddell, D.C., 2012. Mechanochemistry: opportunities for new and cleaner synthesis. Chem. Soc. Rev. 41, 413–447.

4. FDA Guidance (draft), December 2011: Regulatory Classification of Pharmaceutical Co-Crystals.

5. R.S. Dhumal, A.L. Kelly, P. York, P.D. Coates, A. Paradkar, Cocrystallization and simultaneous agglomeration using hot melt extrusion, Pharm. Res. 27 (2010) 2725–2733.

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