Keynote Presentations Archives - Pharma Crystallization Summit

Dr. Jian Wang, J-Star Research

wpadm — Mon, 26 Sep 2022 22:43:49 +0000

Dr. Jian Wang is an expert in API crystallization, with comprehensive knowledge of the science and technologies required to meet the needs of small molecule drug development. She has over 30 years of R&D experience in API crystallization and reaction engineering, and has been providing R&D services since 2005 to pharmaceutical clients around the globe.

Dr. Wang received her Ph.D. degree in Chemical Engineering in 1994, from the University of Pittsburg with Prof. Donna Blackmond and Prof. Irving Winder. She published 20 peer-reviewed articles and 6 patents (5 related to API crystallization) before getting into technical services.

During her 11-year tenure at Merck since 1994, Jian became an expert in API process R&D and a champion in implementing science-based and technology-enabled approaches. She promoted the application of PAT tools in process R&D serving as a consultant at Mettler Toledo AutoChem during 2005-2010. In 2011-2013, Jian took the responsibility as VP of Crystallization Development at Crystal Pharmatech, helping a diverse client base in solving API crystallization problems. To better assist new drug development programs, Jian started up a state-of-the-art crystallization center at J-Star Research in the beginning of 2014 complementing its strong API Process Research. She now leads the Center for Pharma Crystallization at J-STAR as Senior Vice President, addressing a wide range of challenges associated with API isolation from early to late developmental stages. Working closely with drug formulation experts, Jian also has been driving the establishment of drug formulation services at J-Star that are well integrated with API crystallization R&D.

Session 2: Physical Property Based Crystallization Process Development

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Spherical Cocrystallization of Pharmaceuticals

wpadm — Wed, 07 Sep 2022 00:05:18 +0000

By Prof. Changquan Calvin Sun, Pharmaceutical Materials Science and Engineering Laboratory, University of Minnesota

The development of a quality tablet product requires overcoming deficiencies in pharmaceutical properties of an active pharmaceutical ingredient (API) to meet several performance standards. APIs with poor aqueous solubility present a challenge in tablet development for meeting the desired dissolution performance to assure adequate bioavailability. If it can be adequately controlled for robust manufacturing performance, direct compression is preferred among common manufacturing processes, because of its economy. Cocrystallization is an effective crystal engineering approach for overcoming deficiencies of APIs, e.g., solubility, tabletability, and stability. Spherical crystallization is an established particle engineering technique for improving powder properties to enable direct compression. Spherical cocrystallization holds the potential to simultaneously improve both key pharmaceutical properties and powder properties to enable direction compression of tablets with both robust manufacturability and superior in vivo performance. In this talk, examples of spherical cocrystallization of APIs and their use in developing direct compression tablet formulations will be presented.

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Five Degrees of Separation: Characterization and Temperature Stability Profiles for the Polymorphs of PD-0118057 (Molecule XXIII)

wpadm — Wed, 20 Jul 2022 01:13:38 +0000

By Mr. Brian Samas, Pfizer

Molecule XXIII is the most experimentally characterized crystal structure prediction (CSP) blind test molecule to date. Crystal structures of five polymorphs are presented with corresponding stability data based on solvent-mediated phase transformation studies. In our phase transformation studies, we show that solubility is a crucial parameter. Computations reveal there is no strong dependence on the conformer distribution as a function of the solvent system. Position in the polymorph cascade is an important factor in predicting which form will be obtained in phase transformation experiments. Molecule XXIII remains the most important CSP example, and this work adds experimental backing and more precise transition temperatures between the forms.

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Amorphous or Crystalline? Using Next Generation PAT to Track API Particle Attributes for Enhanced Downstream Processability

wpadm — Mon, 18 Jul 2022 02:26:34 +0000

By Richard Becker, BlazeMetrics

Process Analytical Technology (PAT) has dramatically expanded its capabilities over the last decade. Today’s PAT enables an in-depth understanding of process behavior on both macroscopic and molecular levels, allowing users to accurately track the impact of process variables on system behavior. Whether in a reactor, a continuous flow line, or a filter/dryer, kinetic mechanisms such as nucleation, growth, breakage, agglomeration, and “oiling out” play a major role in downstream drug product manufacturing. Using next generation PAT, these mechanisms are understood in real-time such that they can be related to final crystal morphology, surface, size, and structure, which ultimately drive downstream processability.

In this talk, I will review the enabling improvements to the PAT landscape as they relate to crystal manufacturing and provide examples of how those improvements deepen process understanding, speed process development and in some cases enable new paths to process optimization.

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Particle engineering by spray drying: process dev., scale-up, and technology transfer

wpadm — Mon, 18 Jul 2022 02:14:11 +0000

By Dr. Nima Yazdanpanah, Procegence

Drug substance isolation by crystallization and filtration and spray drying are last stages of the drug substance manufacturing process, where critical quality attributes (CQAs) and powder properties (such as flowability, stability, particle size distribution, and purity) were defined. These unit operations are scale depended and mixing and heat and mass transfer (scale dependent phenomena) could have significant impact on the CQA of product, performance of equipment, and also impact on downstream (drug product) and bioavailability. The manufacturing scale process development, technology transfer, and scale-up are challenging steps at the interface of R&D and manufacturing. The dynamic correlation of critical process parameters (CPPs) and CQAs should be defined for the design space development, control strategy, and CMC. Some notable examples for spray drying would be atomizer selection, flowrate and drying temperature optimization. However, developing the manufacturing scale process by just utilizing lab scale data could be misleading, or running DoE at that large scale is not efficient, especially when small amount of material available or time to the market is short.

At this presentation, some scale-up issues for spray drying will be discussed. Applications of in-silico tools (mathematical simulation) for rapid scale-up and process development and optimization, and challenges and benefits will be demonstrated with case studies.

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Intelligent Cloud-Based Algorithms for Reducing Risk in Crystallization Process Development

wpadm — Sun, 17 Jul 2022 02:49:58 +0000

By Dr. Mike Bellucci, XtalPi Inc

Crystallization is the most widely used separation and purification process in the pharmaceutical industry. The resulting crystal structure and corresponding crystal morphology isolated from this process can have a profound influence on the physical properties and manufacturability of drug product APIs. Consequently, the ability to characterize the crystal polymorph landscape and control the crystal morphology are two fundamental aspects of pharmaceutical manufacturing. At XtalPi, we have developed a cloud-based computational platform that combines advanced physics-based algorithms with A.I/machine learning algorithms in order to mitigate polymorph risk and support rational design of crystallization experiments for improved morphological control. We highlight various applications from our Crystal Structure Prediction and Morphology platforms and discuss our recent investigation of the effect of polymer additives on the crystal growth of metformin HCl. This study was performed both with experiments and computational methods with the aim of developing a combined screening approach for crystal shape engineering. Additionally, we have developed analysis methods to characterize the morphology “landscape” and quantify the overall effect of solvent and additives on the predicted crystal habits. Further analysis of our molecular dynamics simulations was used to rationalize the effect of additives on the growth rate of specific crystal faces.

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A Digital Mechanistic Workflow for Predicting Solvent-Mediated Crystal Morphology

wpadm — Sun, 17 Jul 2022 02:44:40 +0000

By Prof. Kevin Roberts, University Of Leeds

The crystallization of organic materials provides a common, energy efficient methodology for the purification and isolation of high value compounds such as pharmaceuticals. The inherent anisotropic molecular and morphological properties of these materials can affect downstream ingredient processing such as powder flow, blending and compaction as well as impact upon product quality associated with stability and bioavailability. Hence, the ability to control the morphological characteristics of crystals through the rational design of the crystallization process can be important to reduce bottlenecks in both R&D and manufacturing associated with the production of new drug products.

In this presentation a digital mechanistically-based workflow, encompassing a combination of attachment energy and grid-based systematic search methods, is applied to predict the solvent-dependent morphologies of the monotropically related α and β polymorphic forms of L-glutamic acid. This work encompasses calculation of the crystal lattice energy and its constituent intermolecular synthons, their interaction energies, and their key role in understanding and predicting crystal morphology. It also assesses the surface chemistry, topology, and solvent binding on crystal habit growth surfaces. Through a comparison between the contrasting morphologies of the conformational polymorphs of L-glutamic acid, the overall approach highlights how the interfacial chemistry of organic crystalline materials and their inherent anisotropic interactions with their solvation environments direct their crystal habit with potential impact on their further downstream processing behaviour.

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Simulation aided solvent selection for robust impurity rejection by crystallization

wpadm — Sun, 17 Jul 2022 02:24:22 +0000

By Dr. Yuriy Abramov, Exe. Director of CC&DS, J-Star Research

Regulatory expectations for control of impurities in new drugs have been established through ICH guidelines. The most efficient approach to impurity rejection is provided by API crystallization. Computational applications are highly desirable to guide crystallization design for fast-paced projects.1 Novel impurity uptake computational model is proposed, which considers solvent, lattice-substitution and doping level contributions to impurity incorporation into crystal structure during crystallization. Application of the model for impurities rejection from various APIs, including investigational oncology drug candidate MRTX849, is presented.

1. Abramov, Y.A. Cryst. Growth Des. 2018, 18, 1208−1214.

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A new approach to stere-opure atropisomeric molecules enabled by continuous flow-crystallization

wpadm — Sun, 17 Jul 2022 02:17:21 +0000

By Dr. Michal Achmatowicz, Mirati Therapeutics

Abstract: A new approach to stereopure atropisomeric molecules is enabled by a continuous flow-crystallization process. Continuous accumulation of the product under its optimal crystallization conditions is combined with a parallel synthetic process occurring within its own optimal regime. Therefore, in a holistic sense, this approach constitutes an asymmetric synthesis via dynamic kinetic resolution (DKR). The application of Simultaneous Processing of Antagonistic Chemical Events methodology (SPACE-DKR) will be showcased on a densely functionalized active pharmaceutical ingredient (MRTX1719) for which significant yield improvement (from 37% to 87%) was realized.

This protocol provides a complementary means to atroposelectivity for substrates which challenge current asymmetric methodologies, and greatly improves sustainability by decreasing consumption of solvent and advanced synthetic intermediates

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Novel analytical methods and insights into Amorphous Solid Dispersions

wpadm — Sat, 16 Jul 2022 18:31:49 +0000

By Dr. Simon Bates, Rigaku Americas Corp

X-ray powder diffraction has been the gold standard for solid state pharmaceutical analysis for quite some time. However, when it comes to amorphous solid dispersions, the reliance on traditional peak based peak analysis is not sufficient to glean a complete structural understanding of the system. Total diffraction methods, on the other hand, contain a wealth f information on local structure and molecular packing within the amorphous state. But, structural information alone is not sufficient to fully characterize amorphous systems. The total diffraction characterization should be combined with dynamic thermal measurements for a more complete materials characterization. In this presentation, I will discuss total diffraction methods for amorphous materials and the combination with simultaneous in situ DSC measurements for a more enhanced materials characterization.

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