2020 Abstracts Archives - Pharma Crystallization Summit

Particle Surface Engineering for Predictive Enhancement of API Properties

wpadm — Tue, 16 Jun 2020 15:43:37 +0000

Rajesh Dave, New Jersey Center for Engineered Particulates, New Jersey Institute of Technology Newark, NJ, USA dave@njit.edu Particle surface engineering is a cost-effective, promising route to achieve enhancements in the flowability, bulk density and other properties of a variety of cohesive active pharmaceutical ingredients (APIs). This presentation will discuss predictive enhancements after dry coating based particle surface engineering and discuss models and guidelines for the selection of flow aid type and amount, as well as predicting powder bulk properties from their particle-scale properties such as the particle size and distribution, materials density, surface energy, and surface roughness. The use of dry coating in developing direct compression ready blends will be also presented. through dry coating of either API or excipients. Towards those goals, industrially relevant and scalable dry coating devices are used and compared against a material sparing benchmarking device. Mechanistic particle contact models are employed for examining the causes of cohesion reduction and subsequent property enhancements. The bulk property based 2-D processability maps are introduced and used to assess the extent of enhancements in flow and packing as well as the possibility of avoiding wet and/or dry granulation, as well as for moving towards direct compression at high drug loadings. Results are presented to demonstrat that dry coating for particle surface engineering is a powerful technique. Along with our predictive, model-based approach, it can help mitigate problems posed by fine powders, with positive outcomes in flow, and bulk density improvements. Such enhancements enable high drug loaded fine and cohesive API blends through particle engineering. Overall, the bulk property based 2-D processability maps along with dry coating based property enhancements can help make manufacturing decisions regarding the formulation strategy for solid pharmaceutical dosages, presenting a promising platform for commercial applications and cost reduction. Key Words: Cohesive powders, dry coating, flowability, bulk density, predictive models

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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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Locality, Strength, and Hierarchy of Intermolecular Interactions in Crystallization

wpadm — Tue, 16 Jun 2020 02:32:49 +0000

Tonglei Li, Ph.D. Department of Industrial and Physical Pharmacy, Purdue University 575 Stadium Mall Drive, West Lafayette, Indiana 47907 tonglei@purdue.edu Abstract. Self-assembling of molecules in crystallization is collectively driven by intermolecular interactions among the solute and solvent. Better understanding of nucleation mechanism may be perceived in light of the locality, strength, and hierarchy of intermolecular interactions. Primary interactions such as hydrogen bonding decide pre-nucleation dynamics and the secondary such as aromatic stacking and close contacts may effect complementing and competing functions while primary assemblies develop. Additionally, molecular conformation and local preference of a particular interaction can mutually influence the kinetics and structure of self-associates. To demonstrate these principles, several of our recent studies focus on solution chemistry and the interplay between conformation and intermolecular interaction of a series of structurally similar diarylamine compounds.

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Partnering for Addressing API Crystallization Engineering Challenges of Today and the Future

wpadm — Mon, 15 Jun 2020 22:03:26 +0000

Dr. Fang Wang Global Blood Therapeutics, USA Abstract: In light of the balancing act among quality, speed, and cost, collaborative partnering between pharmaceutical companies and contract research/manufacturing organizations is becoming increasingly important in meeting our goals of delivering high quality APIs and drug products to patients. This talk will summarize the challenges the pharmaceutical industry is facing today and will continue to face in the future in the area of API crystallization engineering and manufacturing. In addition, various strategies will be discussed to overcome the challenges in order to deliver high quality therapies to patients quickly and cost effectively. Case studies will be provided to illustrate the strategies. Ultimately an effective model of partnering to meet patient’s needs will be presented.

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Integrative Approaches to Addressing Canonical Problems in Pharmaceutical Crystallization

wpadm — Mon, 15 Jun 2020 22:02:53 +0000

William Glauser XtalPi, Inc., USA Problems associated with polymorphic instability and increasingly insoluble drug candidates represent white space to innovate novel forms and processing methods with better properties in the drug product. But the journey from identifying new solid forms to creating engineered particles with optimal formulation properties has often been too inefficient to realize this goal. Industry-wide voice of customer studies have revealed several bottlenecks along the critical pathway and a multicriteria optimization problem similar to that in earlier discovery phases. These studies suggest solutions that enhance the integration of experiment and computation, which itself integrates both physics-based and AI-based approaches. It also requires integrating mechanical and processing considerations earlier into the form discovery/selection stage. This desiloization of effort will require—in many instances—creative partnerships among biopharma, commercial technology providers, and academia to achieve.

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Addressing Bottleneck Problems in Crystallization R&D for New Drug Development

wpadm — Mon, 15 Jun 2020 22:02:23 +0000

Jian Wang Center for Pharma Crystallization, J-Star Research Inc 6 Cedar Drive, Cranbury, New Jersey 08512 Diverse crystallization challenges encountered by CfPC (Center for Pharma Crystallization) and our clients will be analyzed systematically to provide insights into main bottleneck problems in today’s drug development programs. The general approaches taken at CfPC to address such problems as well as opportunities for improvement will be discussed. Examples will be given to highlight how enabling technologies and synergetic partnerships played a critical role in providing timely solutions to great challenges.

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Co-processing: An Effective Particle Engineering Approach for Drug Substances

wpadm — Mon, 15 Jun 2020 15:44:44 +0000

Dr. Deniz Erdemir, Principal Scientist Bristol Myers Squibb, New Brunswick/New Jersey Abstract coming soon

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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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Pharmaceutical Crystallization Support by Computational Approaches

wpadm — Mon, 15 Jun 2020 15:14:30 +0000

Yuriy A. Abramov yuriy.abramov@xtalpi.com XtalPi Inc, Cambridge MA, USA. Given challenges facing the pharmaceutical industry, an accelerated Drug Development greatly benefits from guidance provided by computational methods.¹ This presentation will focus on computational support of the following important tasks related to the pharmaceutical crystallization. That includes derisking of the stable solid form selection of pharmaceutical API; in silico coformer screening for an API or intermediate cocrystallization; rational solvent selection for solid solvate desolvation; and in silico solvent screening for impurity purge via recrystallization.

Abramov, Y.A., Ed. Computational Pharmaceutical Solid State Chemistry, John Wiley & Sons, 2016.

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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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