1) Smarter Solid Form & Pre-formulation Studies Archives - Pharma Crystallization Summit

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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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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Dr. Bob Docherty, Pfizer

wpadm — Sat, 16 Jul 2022 18:08:31 +0000

Dr. Robert Docherty did his degree and PhD. at Strathclyde University and joined ICI/Zeneca in 1988 where he worked on the solid-state structure and crystallization of dyes, pigments, biocides, electrophotographic agents, agrochemicals, and pharmaceuticals. He joined Pfizer in 1999 as Head of Material Sciences. He retired from his role as Strategic Lead for Digital Design at Pfizer in December 2020. He is now Director of West View House Consulting Limited. He holds a visiting professorship at Leeds University and is a Fellow of the Royal Society of Chemistry. His research interests have focused on the structural and simulation aspects of the assembly of molecules to crystals, crystals to particles and particles to products. He has through various activities continued to support a community vision towards an unprecedented digital perspective of the journey from molecule to medicine.

Throughout his career he has been fortunate to work at the industrial/academic interface with numerous partners to help create and guide a range of research projects and has published over 75 journal papers and book chapters

Keynote presentation: Digitally Enabled Workflows: Accelerating the Molecule to Medicine Journey

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Digitally Enabled Workflows: Accelerating the Molecule to Medicine Journey

wpadm — Sat, 16 Jul 2022 18:07:53 +0000

By Dr. Bob Docherty, Pfizer

The focus would be on solid form screen & selection, crystallization process development, pre-formulation evaluations, particle engineering and projecting the API attributes to drug product but with the challenges and opportunities of embracing digital tools and methods woven throughout the presentation.

Talk Outline:

Importance of Digital Design to our vision.
Reflections on how our vision is being shaped by the ecosystem
- Industry 4.0 – Made Smarter
- NASA 2040
- European Materials Modelling Council (EMMC)
- Material Genome Initiative (MGI)
Short vignettes to exemplify
- Properties – Solubility
- Solid Form Informatics
- Digital Definition of a Crystal
- Solid State Stability
- Particle Passport
- Particle Informatics
- Sticking Propensity
ISCF Wave 3 Engagement and Digital Design Roadmap.
Future Perspective and Acknowledgements.

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Reducing or Managing Complexity- New realities with emerging chemical space for small molecule developability

wpadm — Sat, 16 Jul 2022 18:00:14 +0000

By Dr. Ahmad Sheikh, AbbVie

While new chemical entities represent majority of the drugs approved in the last five years, the diversity and complexity of these molecules continue to increase and cover chemically labile structures such as pro-drugs, large, small molecules specifically designed to disrupt protein-protein interactions, and heterobifunctional molecules called PROTACs. These complex molecules are better suited for modulation of large, flat, and groove-shaped binding sites representing half of druggable targets. The structural complexity and diversity make overall pharmaceutical development challenging and developability indicating properties need to be assessed early in the Medical Chemistry Design Cycle with sufficient accuracy. Assessment of thermodynamic crystalline solubility in lead optimization is one such property. Our physics-based ensemble approach which uses predicted crystal structures and modified FEP protocols results in very close match (< 1 log unit) to experimental data for structurally related molecules. We demonstrate the importance of such predictions by observing upto 4 log unit differentiation not captured by HT solubility screening assays or classic amorphous solubility FEP+ predictions. Similarly, molecular conformations in polar (aqueous) and non-polar (membrane) media and calculation of their Boltzmann Weighted 3D-Polar Surface Area can provide information on shielding of polarity, which can be used to design molecules with improved passive permeability. When molecular complexity becomes unavoidable as in the case of disease eliminating direct activity antivirals for Hepatitis C, a robust and toolkit of advanced computational and experimental approaches is key to make a difference in patient’s lives.

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