Session 2: Physical Property Based Crystallization Process Development Archives - Pharma Crystallization Summit

The Crystallisation Structural Pathway of Para Amino Benzoic acid: From Solvated Molecule through Solute Clustering and Nucleation to the Growth of Facetted Crystals

wpadm — Tue, 16 Jun 2020 15:16:14 +0000

Kevin Roberts School of Chemical & Process Engineering, University of Leeds LS2 9JT, UK email: k.j.roberts@leeds.ac.uk In solution phase crystallisation processes, understanding and controlling the transition pathway associated with the assembly of molecules from their solvated state, into three-dimensional, ordered crystalline-solids, represents a significant grand challenge for the physical-chemical sciences. Crystallisation can be sub-divided into three-dimensional nucleation and two-dimensional, surface-mediated, crystal growth stages. Understanding and controlling the various physico-chemical aspects associated with these two stages is important mindful of their impact upon the critical quality attributes of the resulting product crystals. In particular, the nucleation stage directs the crystal size distribution, crystallinity and polymorphic form whilst the crystal growth stage directs crystal purity, morphology, surface properties and inter-particle properties. This paper presents an integrated multi-technique examination of the crystallisation behaviour of the two polymorphic forms of para amino benzoic acid (PABA) encompassing both computational modelling and experimental studies comprising:

Examination of the molecular conformational stability and energetics using DFT QM modelling.
Determination of the bulk crystal chemistry and lattice energies using inter-molecular (intrinsic synthons) crystallographic modelling.
Modelling solution state molecular cluster energetics and propensities using synthonic, DFT/statistical mechanics and molecular dynamics techniques.
Studies of solubility, crystallisability, nucleation kinetics and mechanism as a function of solvent using gravimetric, optical turbidimetric and SAXS methods.
Characterisation of crystal morphology and surface chemistry using inter-molecular (extrinsic synthons) modelling in relation to observed crystal habits.
Assessment of surface-specific single crystal growth kinetics, growth mechanism and interfacial stability.

The industrial relevance of the research in terms of the evolving Industry 4.0 agenda for the digital design of drug products and the processes for their manufacture will be highlighted. Acknowledgements: The talk presents a summary of a wide ranging collaborative research project with: Robert Hammond, Xiaojun Lai, Caiyun Ma, Jonathan Pickering, Ian Rosbottom, Tom Turner and Guangyi Xi at the University of Leeds. I also gratefully acknowledge them and also the associated funding support from UK Research and Innovation through Molecules, clusters and crystals: A multi-scale approach to understanding kinetic pathways in crystal nucleation from solution (EPSRC Critical Mass Grant EP/I014446/1) and ADDoPT: Advanced digital design of pharmaceutical therapeutics” (Advanced Manufacturing Supply Chain Initiative Grant No. 14060).

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Facilitating DS/DP development through integrated solid-state and crystallization development

wpadm — Mon, 15 Jun 2020 15:17:33 +0000

Bing-Shiou Yang Boehringer Ingelheim, Ridgefield, CT Abstract Crystallization is an important and economic unit operation for the purification of pharmaceutical API. It also serves as the key step to define the required quality attribute of the API (e.g. solid form, particle size distribution) that would impact the subsequent processing (e.g. filtration, drying, milling) and drug product performance (e.g. dissolution, content uniformity). To successfully bring a compound into the market, an integrated approach to link the development of API solid form, isolation and dosage form is essential to ensure the robust delivery of the desired drug product quality, throughout the scale. Thorough understanding of the solid form of a compound would significant facilitate the design of proper crystallization, resolve process challenges, and enhance the control of the API quality attributes. This presentation will use several examples in development or manufacturing to illustrate the concepts, including producing small particle size of API for enhance dissolution, producing the desired form for a compound with complex solid form landscape and identifying root-case of out-of-specification via solid form understanding, etc.

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A Challenging Path to Controlled Nano-API Crystallization and Isolation

wpadm — Sun, 14 Jun 2020 22:04:22 +0000

Don Kientzler Center for Pharma Crystallization, J-Star Research Inc 6 Cedar Drive, Cranbury, New Jersey 08512 Controlled crystallization of an API in submicron size was enabled based on an accurate solubility profile and a growth inhibition property via semi-continuous processing, to meet special formulation requirements. This process was also challenged by isolation of nano-API crystals to meet the low specification of residual salt content. When residual salt becomes too low, crystal growth accelerates. Diafiltration using membranes was applied for salt removal in connection to outstream of a flow-through CSTR for generation of submicron crystals, to deliver product meeting the specifications of both crystal size and the residual salt content.

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