Session 3: Physical Property Based Crystallization Process Development Archives - Pharma Crystallization Summit

The Importance of Understanding and Characterising the Physical & Chemical Properties of APIs in the Digital Design of Drug Products

wpadm — Tue, 16 Jun 2020 02:27:04 +0000

Kevin J Roberts Brotherton Professor of Chemical Engineering University of Leeds There is a growing interest in the prediction of the surface properties of active pharmaceutical ingredients in relation to their formulation downstream into practical dosage forms. In particular, it is well known [1, 2] that crystal surface properties of pharmaceutical ingredients can significantly impact on the physical chemical properties of these materials, and hence upon the critical quality attributes that impact on product performance, for both drug substance and drug product. This talk will overview the application of synthonic modelling techniques [3, 4] using inter-molecular energy calculations with the atom-atom method. It will highlight how synthonic analysis can be applied to reveal the balance of intermolecular interactions between those of an intrinsic nature which stabilise the bulk structure and those of an extrinsic nature which, being surface-terminated, contribute to the surface energetic properties of the crystal particle. The utility of these techniques will be illustrated through case studies based on recent research involving:

Understanding and optimising the particle morphology of lovastatin through a predictive solvent selection approach [5];
Characterising differences in the flow and compaction behaviour of two polymorphic forms of L-glutamic acid using X-ray computed tomography [6].
Predicting the surface properties of terbutalene sulphate and its adhesive/cohesive balance when formulated with excipients [7,8].

The integration of synthonic engineering tools within pharmaceutical R&D workflows will be highlighted and the potential extension of these techniques to the de novo design of drug products and the processes needed to manufacture them will be briefly overviewed and discussed. Acknowledgements I would like to gratefully acknowledge

INFORM2020 project supported by EPSRC (EP/N025075/1) in collaboration with: AstraZeneca, DFE Pharma, GSK, Intertec, Kindeva, Malvern Pananalytical, Nanopharm, Neutec and Zeiss together with the Universities of Hertfordshire, Cambridge & Manchester.
ADDoPT Digital Design project supported by Advanced Manufacturing Supply Chain Initiative (AMSCI 14060) in collaboration with: AstraZeneca, Britest, BMS, CCDC, GSK, Perceptive Engineering, Pfizer, PSE and STFC together with Cambridge & Strathclyde Universities.
Henry Moseley X-ray Imaging Facility at University of Manchester who provided X-CT beam time (EPSRC grants EP/F007906/1, EP/I02249X/1, EP/F028431/1 & EP/T02593X/1)

References [1] Material science: solid form design and crystallisation process development, K J Roberts, R Docherty and S Taylor in Pharmaceutical Process Development: Current Chemical and Engineering Challenges, RSC Drug Discovery Series No. 9 ( ISBN978-1-84973—146-1), (Edited by J Blacker and M T Williams), The Royal Society of Chemistry, Cambridge, 2011, 286-313 [2] Engineering crystallography: from molecule to crystal to functional form, K J Roberts, R Docherty and R Tamura (Editors), Springer Advanced Study Institute (ASI) Series, ISBN 878-94-024-1118-8/1115-7/1117-1, 2017 [3] Synthonic engineering: from molecular and crystallographic structure to the rational design of pharmaceutical solid dosage forms, K J Roberts, R B Hammond, V Ramachandran and R Docherty, Chapter 7 in Computational Approaches in Pharmaceutical Solid State Chemistry (Edited by Y.A. Abramov), 2015 Wiley, Inc. [4] “Particle Informatics”: advancing our understanding of particle properties through digital design, Mathew J. Bryant, Ian Rosbottom, Ian J Bruno, Robert Docherty, Colin M Edge, Robert B Hammond, Robert Peeling, Jonathan Pickering, Kevin J Roberts and Andrew G P Maloney, Crystal Growth and Design 19 (2019) 5258-5266 [5] Habit modification of the API lovastatin through a predictive solvent selection approach, T. D. Turner, L. E. Hatcher, C. C. Wilson, K. J. Roberts, Journal of Pharmaceutical Sciences 108 (2019) 1637-1922 [6] Measuring particle packing of glutamic acid through x-ray computed tomography to understand powder flow and consolidation behaviour, Thomas Turner, Parmesh Gajjar, Ioannis Fragkopoulos, James Carr, Thai Thu Hien Nguyen, Debbie Hooper, Fiona Clarke, Neil Dawson, Philip Withers and Kevin Roberts, Crystal Growth & Design 20 (2020) 4252–4263 [7] A Digital Workflow from Crystallographic Structure to Single Crystal Particle Attributes for Predicting the Formulation Properties of Terbutaline Sulphate, Thai T. H. Nguyen, Robert B. Hammond, Ioanna D. Styliari, Darragh Murnane and Kevin J. Roberts, CrystEngComm 22 (2020) 3347-3360 [8] From Particles to Powders: Digital Approaches to Understand Structure and Powder Flow of Inhaled Formulations, Parmesh Gajjar, Thai T. H. Nguyen, Ioanna Danai Styliari, Vivian W. Barron, Timothy L. Burnett, Xizhong Chen, Simon D. Connell, James A. Elliott, Robert Hammond, Faiz M. Mahdi, Kevin Roberts, Philip J. Withers and Darragh Murnane, Respiratory Drug Delivery (2021) in press

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Continuous Crystallization and Purification: The Role of Impurity Incorporation Mechanism in Non-Equilibrium Processes

wpadm — Tue, 16 Jun 2020 02:24:53 +0000

Allan S. Myerson Professor of the Practice Massachusetts Institute of Technology Key Words: Continuous crystallization, impurity incorporation, crystal growth, purification, MSMPR Purpose Crystallization plays a critical role in the isolation of Active Pharmaceutical Ingredients (APIs), defining several of the drug substance’s critical quality attributes for formulation. As a rate-based purification process, rejection of critical impurities requires a deep knowledge of the mechanisms that affect impurity incorporation and crystal growth. In this work, we will discuss the interplay between crystal growth and impurity incorporation in organic molecular materials, particularly at non-equilbrium conditions found in continuous MSMPR crystallizers. Crystals grown in a steady-state MSMPR crystallizer have experienced constant conditions of supersaturation, temperature, and mixing through their entire growth.1 Using this type of system, accurate estimations of crystal growth rates can be directly related to observed non-equilibrium distribution coefficients for impurities present. Methods Paracetamol Form I was crystallized from ethanol solutions with the presence of two relevant impurities: 4’-chloroacetanilide, and 4’-hydroxyacetophenone. The crystallization system was a single stage MSMPR crystallizer equipped with a Blaze 900 probe for the in situ assessment of crystal growth rates via image analysis. Parallel to the continuous crystallization experiments, suspension aging experiments were conducted to determine the API solubility and the equilibrium distribution coefficients for each impurity. The measured values were related to empirical and mechanistic models for crystal growth and impurity incorporation. Results As previously seen for multiple systems, the presence and type of impurities had a significant effect on the observed crystal growth rates.2–4 At the same time, crystal growth had a significant impact on impurity incorporation. For both impurities, the effective distribution coefficients had a thermodynamic component and a kinetic component. The first was isolated from equilibrium distribution coefficients as a main function of temperature. The kinetic component was a direct function of the crystal growth rate, by which faster growth lead to increased impurity incorporation. These results are expected and coincide with prior observations in similar studies.5 A large number of steady state MSMPR experiments was conducted to isolate the contributions of temperature and growth on nonequilibrium impurity incorporation. Based on these results, a set of mechanistic and empirical models were modified to find a generalizable expression that captures the behavior for both impurities. For both systems, the effective distribution coefficients could be calculated from the same semi-empirical function of temperature and crystal growth rate. Conclusions Understanding the interplay between crystal growth and impurity incorporation is a critical step for the effective purification of APIs during crystallization. Taking advantage of the stable growth conditions provided in MSMPR crystallizers, we have isolated the contributions of temperature and crystal growth on nonequilibrium impurity incorporation for two relevant impurities in the acetaminophen-ethanol system. The behavior of both impurities could be well predicted by a semi-empirical function of temperature and crystal growth. References (1) Randolph, A. D.; Larson, M. A. Theory of Particulate Processes – Analysis and Techniques of Continuous Crystallization; Academic Press, Inc., 1971. (2) Black, S. N.; Davey, R. J.; Halcrow, M. The Kinetics of Crystal Growth in the Presence of Tailor-Made Additives. J. Cryst. Growth 1986, 79, 765–774. (3) Kubota, N. Effect of Impurities on the Growth Kinetics of Crystals. Cryst. Res. Technol. 2001, 36 (8–10), 749–769. (4) Davey, R.; Fila, W.; Garside, J. The Influence of Biuret on the Growth Kinetics of Urea Crystals from Aqueous Solutions. J. Cryst. Growth 1986, 79, 607–613. (5) Capellades, G.; Wiemeyer, H.; Myerson, A. S. Mixed-Suspension, Mixed-Product Removal Studies of Ciprofloxacin from Pure and Crude Active Pharmaceutical Ingredients: The Role of Impurities on Solubility and Kinetics. Cryst. Growth Des. 2019, 19 (7), 4008–4018.

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Co-Crystals Platform to Improve Physical Properties of Early Intermediates during API Manufacturing Process

wpadm — Tue, 16 Jun 2020 02:23:23 +0000

Dr. Samir Kulkarni Principal Scientist Pfizer Co-crystal development is important to the pharmaceutical industry because it offers the opportunity to modify the physiochemical properties of crystalline API and intermediates without altering its covalent structure. While there are many computational assays that promise to rationally predict co-crystals, including: hydrogen bonding propensities, solubility parameters, crystal database screening, thermodynamic characteristics, etc., in reality the most reliable method to discover and prepare new co-crystals is still based on empirical screening. In the current work, we describe a systematic and effective method to discover new co-crystals. The method consists of comparison of different in silico methods to find the list of co-formers suitable to form co-crystal with the given target compound. The experimental techniques for synthesizing co-crystals are time consuming and expensive, our goal is to develop an in silico method to rationalize co-crystal formation.

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Correlation of Solubility with the Metastable Limit

wpadm — Tue, 16 Jun 2020 02:22:26 +0000

Prof. Ken Morris University Professor, Director of the Lachman Institute for Pharmaceutical Analysis Long Island University The similarity in functionality between the solubility-temperature and the MSL-temperature curve is well documented (Mullin, Myerson, others). However, since the MSL is considered a kinetic limit while the solubility is an equilibrium property, it is not intuitive that the MSL should be correlated to the solubility much less predictively related. The initial hypothesis in the work to be presented relied on collision theory to make the case for a common root for the two phenomena and supporting data are shown. Ultimately gauge-cell Monte Carlo simulations to target spontaneous nucleation and measure thermodynamic properties of the system at nucleation reveal a widespread correlation over 5 orders of magnitude of solubilities, in which the metastable limit depends exclusively on solubility and the number density of generated nuclei. The result support a strong link between solubility and the meta-stable limit, and highlight an inverse relationship between MSZW and normalized solubility. Clark et al., Langmuir 2017, 33, 9081−9090

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