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Continuous Manufacturing of Cocrystals using Solid State Shear Milling Technology Sachin Korde, Sudhir K. Pagire, He Pan, Colin C. Seaton, Adrian L. Kelly, Yinghong Chen, Qi Wang, Phil D. Coates, and Anant Paradkar Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01733 • Publication Date (Web): 13 Mar 2018 Downloaded from http://pubs.acs.org on March 14, 2018
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Crystal Growth & Design
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Continuous Manufacturing of Cocrystals using Solid State Shear Milling
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Technology
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AUTHOR NAMES
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Korde, Sachin1,2; Pagire, Sudhir1,2; Pan, He5; Seaton, Colin4; Kelly, Adrian1,3; Chen,
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Yinghong5; Wang, Qi5; Coates, Phil3; Paradkar, Anant1,2*
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AUTHOR ADDRESS
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1. Centre for Pharmaceutical Engineering Science, University of Bradford, Bradford, UK.
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2. School of Pharmacy, University of Bradford, Bradford, UK
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3. Polymer IRC, Faculty of Engineering and Informatics, University of Bradford, UK
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4. School of Chemistry and Biosciences, University of Bradford, Bradford, BD7 1DP.
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5. The State Key Laboratory of Polymer Materials Engineering, Sichuan University,
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Chengdu, China
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ABSTRACT
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Solid State Shear Milling (S3M) is reported as a scalable, continuous, polymer-assisted
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cocrystallisation technique. A specially designed milling pan was employed to provide high
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levels of applied shear and the addition of polymeric processing aid enabled generation of
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high stress fields. Carbamazepine – salicylic acid cocrystals were produced with 5% - 25wt%
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of Polyethylene Oxide (PEO). A systematic study was carried out to understand the effect of
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process variables on properties and performance of the cocrystals. S3M offers an important
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new route for continuous manufacturing of pharmaceutical cocrystals.
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INTRODUCTION
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A pharmaceutical cocrystal is a multi-component crystalline system containing a drug with a
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hydrogen or halogen bond forming coformer1. Solution based cocrystallisation has several
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drawbacks including the high amount of solvent required, residual solvent in the product and
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low process yields2. In the last decade multidisciplinary teams have developed innovative
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technologies in the area of green and scalable technologies for cocrystal synthesis, including
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use of ultrasound3,4, microwaves5 and hot melt extrusion6-8. Investigations have also been
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carried out to understand challenges in formulation of cocrystals, which are summarised here.
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Jones, et al. made a major contribution to the application of mechanochemistry for cocrystal
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synthesis9-11. Mechanochemistry provides energy to enable the cocrystallisation reaction by
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subjecting reactants to forces between sliding/colliding surfaces12 for example grinding
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together a drug and coformer in a ball mill has been used to produce cocrystals9,10,13,14.
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Cocrystal synthesis using a ball mill can be performed either by neat grinding or in the
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presence of a small proportion of solvent or polymer. Although there have been significant
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investigations into cocrystal synthesis using ball mills, it is not easy to scale up the process.
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During ball milling, shearing of the two components occurs when balls impact each other and
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wall of the mill. Ball milling is a batch process, where the shear applied is relatively low and
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so it is generally used as a screening technique15,16. Andersen and Mack17 successfully
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applied Arrhenius equation to the ball milling process which will enable conversion of
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conventional solution based synthesis to ball milling process. This approach will address
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challenges in scale up and process control in ball milling. Recently, our group reported
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continuous thermo-mechanical synthesis of cocrystals using a hot melt extruder7. Significant
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advantages have been demonstrated for Solvent Free Continuous Cocrystallisation (SFCC)8
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using a hot melt extruder compared to solution cocrystallisation and grinding, including high
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yield and throughput18, control of stoichiometry, particle size control and suitability for real
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time monitoring19. However, as the material is exposed to shear and high temperature for
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relatively long periods of time its stability may be affected in some cases.
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Here we report for the first time a continuous milling technology for synthesis of cocrystals
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in the presence of small amounts of polymers. The Solid State Shear Mill (S3M) (Figure 1,
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drawn using solid modelling software SOLIDWORKS) is a pan mill designed by the polymer
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engineering group at Sichuan University, China for tribochemistry20. The unique design of
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the S3M provides extremely high frictional energy at the tribological interfaces. The high
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frictional forces cause a rise in temperature while subjecting the mixture to high shear
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stresses for a short duration.
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depolymerisation and compatibilisation applications for polymeric systems20-31. Here, S3M
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technology provides a continuous solvent free approach to the manufacture of cocrystals
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which may address issues associated with current technologies.
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S3M Design
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The S3M (SI 1, Figure 1) consists of two in-laid pans, a rotor and a stator made up of wear
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resistant materials with specially treated surfaces. The stator is fixed on the equipment case
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and a rotor pan is mounted on the axis attached to a motor. Engraved diametrical lines divide
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the pan surfaces into equal sectors. Within each sector a number of bevels are present with
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ridges parallel to the dividing diametrical lines. The ridges and the bevels of the pan surfaces
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are placed facing each other to form a unit cell CDEF-CHGB (Figure 2)20, ABCD represents
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its projection on the level surface. A 3D scissoring action is provided by the change in shape,
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volume and position of the unit cell when the moving pan surface runs over the stationary
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pan. The change in volume of the unit cell results in localised high pressure and shear forces.
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The movement of the unit cell in both circular and radial direction causes continuous
S3M has been successfully applied in nanocomposites,
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contraction and division of material from its entrance at the centre of the pan to its exit at the
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outer edge.
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Figure 1: Schematic of continuous cocrystallisation using S3M
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Figure 2: a) Pattern of moving pan on stationary pan, b) Three dimensional scheme for unit
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cell CDEF-CHGB20
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S3M, characterised by high shear, low residence time and the ability to operate without
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solvents is already proven in mechanochemical polymeric applications. The high level of
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shear at tribological interfaces coupled with the associated rise in temperature could also
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provide sufficient energy to synthesise cocrystals, with low residence times to minimise
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degradation. The objective of this work was to investigate the potential of S3M as a
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continuous technology for cocrystal manufacturing.
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EXPERIMENTAL SECTION
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Materials. Carbamazepine (CBZ, purity: 99.0%, Mol. Wt. 236.26 gram (g)/mol) was
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purchased from Taj pharmaceuticals, India (Lot no. TPL/CARB/002), salicylic acid (SAL,
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purity: 99.0%, Mol. Wt. 138.12 g/mol) was purchase from Sigma-Aldrich (UK), polyethylene
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oxide (PEO N80 grade, Mol. Wt. 200,000 g/mol) was purchased from Colorcon (UK). All the
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organic solvents used for UPLC analysis were purchased from Sigma-Aldrich (UK).
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S3M processing. Accurately weighed CBZ (236.26 g) and SAL (138.12 g) in 1:1 molar ratio
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were mixed well, to this PEO N80 was added in the concentration of 5%, 10% 15% and 25%
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w/w. This mixture was blended using a Turbula mixer for 15 mins. The resultant
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homogenous mixture was fed to the S3M through the hopper via central feeding port. The
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proof of concept mill does not have feed control so manual feeding was used. The motor
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speed was maintained at 500 rpm and the gap between stator and rotor was kept to the
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minimum setting (
