Johnston, Blair

Litster, James D.

Maclean, Natalie

Markl, Daniel

University of Strathclyde Institutional Repository

7 5WWW.CMAC.AC.UKCMAC POSTER COLLECTION7 4Multi-modal Dissolution Testing System for Pharmaceutical TabletsH. Jesney , I. Khadra , J. Mann  , R. Barker   and D. MarklIntroduction and AimsThe fundamental processes that underpin disintegration and dissolution arehighly complex and poorly understood [1]. As disintegration and dissolution play keyroles in drug release, it is essential to gain a better understanding of:Results and DiscussionFuture WorkConclusionAcknowledgementsThis work is funded by EPSRC with AstraZeneca sponsorship. John Nevin carried out the electricalengineering on the direct heating vessel.Optical coherence tomography (OCT) has been integratedwith a bathless direct heating vessel and stirrer to create asystem that mimics a standard USPII dissolution system. Off-line UV-Vis is used to analyse dissolution samples.• High resolution imaging technique that captures 2D and 3D cross-sectional images at high speed (up to 200 2D images per second)• Image contrast results from variations in the refractive index at the interface of different materialsWhat is Optical Coherence Tomography?MethodsFigure 1 – A simplified diagram of the experimental set-up and areas of interest. A is an OCT B-scanof a tablet undergoing dissolution testing in the novel set-up. A1 is interface between the tablet surfaceand the dissolution medium. A2 is a disintegrating particle falling to the bottom of the vessel. A3 is asection of the tablet that A2 is blocking the light to, leading to an incomplete image of the surface.Manual sampling cannula• Stop sample movement under stirring conditions• Accurate and consistent sample placementIntegration of other analytical probes including FBRM,pH monitoring, UV-Vis auto-sampling and in-situ                Raman spectroscopy.,   Analysis of a variety of formulations, with a focus onthose that have issues relating to disintegration and dissolution.12Optical coherence tomography has been successfullyintegrated with a bathless direct heating vessel as the firststep in the development of a unique analytical system.Integration of additional analytical probes will enable greaterinformation to be gained and will aid in the overall goal offurthering the understanding disintegration and dissolution.1 Centre for Continuous Manufacturing & Advanced Crystallisation, University of Strathclyde, Glasgow, UK.         2 Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glasgow, UK.3 Oral Product Development, Pharmaceutical Technology & Development, Operations, AstraZeneca, Macclesfield, UK.1,2                         2                        3                           3                                 1,2Figure 3 – System validation data. Percent drug release for 200 mg (20 % w/wparacetamol) tablets in pH 5.8 phosphate buffered saline, in threeexperimental set-ups. 𝑁𝑁 = 3. Error bars represent standard deviation.A1A2A3Dissolution mediumTablet bulk100 µmAWhat is being measured and why?• Hold the tablet off the bottom of the vessel Figure 2 – A 3D rendering of the sample holder that is held in place at the bottom of the vessel by magnets (see Figure 1).Why is a Sample Holder Needed?Liquid penetration and tablet swelling to establish the relationship between drug release and these mechanisms for any formulation undergoing testing.Figure 4 - Time series OCT images of 200 mg tablet (20 %Paracetamol, 79 % MCC and 1 % MgSt). OCT/Dissolutionsystem with tablet in holder. pH 5.8 phosphate buffer. Scalebar in first image (2 s) true for all images• how they relate to each other• the factors that influence themThis project aims to develop a novel multimodal sensor system that is capable ofresolving the key processes, as well as how these processes are linked tomicrostructure, formulation and raw material attributes.References[1] Markl, D., & Zeitler, J. A. (2017). A Review of Disintegration Mechanisms and MeasurementTechniques. Pharmaceutical research, 34(5), 890–917. https://doi.org/10.1007/s11095-017-2129-z• these processes• the synergistic mechanismsthat contribute to themPaddle/stirrer Direct heating vesselOCT probeSample holder0 20 40 60 80 100 120 140050100Time (min)DrugRelease(%)ALS ADT8automateddissolutionsystemOCT/dissolutionsystemOCT/dissolutionwith sampleholder 1020204060708090 Tablet bulkDissolution MediumThe particle (A2) in Figure 1 is actually an image artefact but presents an interesting opportunity to measure the size of disintegrating particles.Interesting fact!POSTER 73POSTER 72 -.. ~CMAC ' Developing Framework for Flexible and Robust Real-Time Release Testing Natalie Maclean1·2, Blair Johnston1·2, James D. Litster3 & Daniel Mark11·2 1 Strathclyde Institute of Pharmacy & Biomedical Sciences, University of Strathclyde, Glas3ow, UK 2 Centre for Continuous Manufacturing and Advanced Crystallisation (CMAC), University of Strathclyde, Glasgow, UK. 3 Department of Chemical and Biological Ensineering, University of Sheffie ld, Sheffield, UK. Right First-Time Manufacturing of Pharmaceuticals (RiFTMaP) Pilot plant campaign 2 Cha llenging specifications Process parameter Quolityottribute Robust operating space Robust and Hexible real-lime release testing Increased opportunity to implement RTRT in manufacturing lines due to advances in process analytical technology and digital manufacturing. fl/ A three-year, £1.Sm EPSRC collaboration between the University of Sheffield, University College London, University of Strathclyde and Purdue University. Developing right-first-time smart manufacturing systems incorporating Industry 4 .0 concepts within a systematic framework for smart continuous manufacturing. Development of a framework and computational tools for optimal design of pharmaceutical processes with real-time process management system and a flexible real-time release framework, all verified at pilot scale. ·-IMHM■l-m;;.: .. rnu:.~ -- _ _ _ Review and adjust sensors os needed - - - - 1 wiHmWiii .wa■ & manufacturing properties .• ,. = = Historical data Q. Raw Material Properties J' Hybrid Models Sensor sensitivity index Predict content uniformity & dissolution performance Fig 2 R1FTMaP WP4 Developmg flexible and robust RTRT framework Performance-Controlling Mechanisms of Tablets 01smtegrat1onM,x:hani sm Mechanisms determined by raw material properties and the process conditions Allows the identification of critical farmulatian and manufacturing parameters which influence the performance of a specific formulation ♦°"'"'~· Ol : A.relhemljor tabletcomponentSsoluble? 02:0oit-..m,jortablel componeni.<:1'9~,.pidly? 03: 111he wettabllity high (low con1aCt angle & high porosity)? Use this knowledge to identify the appropriate sensors for RTRT Identifying the Critical Formulation & Manufacturing Properties Ml 1.00 0.75 0.50 i i 0.25 § i • ! ~ -0.25 1 i· .Q.50 j' -0.75 -1 .00 • W ettability controlled Dismtegrat1on time sensitive to changes m ~& ~ ;~~ •· 11 Dissolution controlled D1smtegration time sensitive to changes m contact ang~ (wettability) * Swelling controlled Disintegration time 1s not strongly affected by tensi le strength, porosity or contact angle Predicting Performance ~ Raw Material Properties Surface energy Particfe size & shape Moisture sorption Solubility & intrinsic dissofution rate True density & intra-particfe porosity Surface area ! Performance of Tablets Compare and mode( dissolution profiles for a range of different AP/, formulations & manufacturing settings Development of data driven models to predict product performance Acknowledgements This work is part of a collaborative EPSRC-funded project which focuses on the Right-First Time Manufacturing of Pharmaceuticals (RiFTMaP). The authors would like to thank Dr James Mann, Mr Alexander Abbott, Ms Helen W illiams, Ms Heather Mead and Dr Ibrahim Khadra for their contributions. The work depicted in Figures 3 and 4 was funded by EPSRC and AstraZeneca. References 1. Mark(, D. et al. (2020) Review of rea(-time release testing of pharmaceutical tablets: State-of-the-art, cha/fenges, and future perspective. (n t J Pharm, 582, 119353. 2. Madean, N. et af. (202 1) Expforing the performance-controffing tab(et disintegration mechanisms for direct compression formulations. (nt J Pharm, 599, 120221. 3. Macfean, N. et af. (2022) Investigating the role of excipients on the physicaf stability of directly campressed tablets. In t J Pharm: X, 4, 100106. MCC - microcrystalline cellulose; DCPA - dibasic calcium phosphate anhydrous; CCS - croscarmellose sodium; XPVP - crospovidone; L-HPC - /ow-substituted hydroxypropyl cellulose; SSG - sodium starch glycolate; 9c,o - initial contact angle. Engineering and Physical Sciences Research Council 

Developing framework for flexible and robust real-time release testing

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Developing framework for flexible and robust real-time release testing

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