Synchrotron X-ray Analysis of Amorphous Drugs and Drug/Polymer - - PowerPoint PPT Presentation

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Synchrotron X-ray Analysis of Amorphous Drugs and Drug/Polymer - - PowerPoint PPT Presentation

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Synchrotron X-ray Analysis of Amorphous Drugs and Drug/Polymer Dispersions Tuesday, November 5, 2019 Pamela Smith, PhD #PharmSci360 Slide 1 Session Description and Objectives Synchrotron X-ray Pair Distribution What is PDF? Function

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Synchrotron X-ray Analysis of Amorphous Drugs and Drug/Polymer Dispersions

Tuesday, November 5, 2019

Pamela Smith, PhD

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#PharmSci360

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Session Description and Objectives

  • Synchrotron X-ray Pair Distribution

Function (SXPDF) techniques provide valuable information about amorphous materials and dispersions.

  • What is PDF?
  • Why is a synchrotron needed?
  • Domains of drug molecules in a

dispersion

  • Stability
  • Latest advances
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Biography and Contact Information

  • Contact information:
  • At the show: booth 551
  • After the show: pam.smith@improvedpharma.com
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XRD vs. PDF … global view vs. local view

XRD (Bragg diffraction)

  • Average structure, or global view
  • f the structure
  • Peaks in the pattern represent

periodic occurrences of an atomic plane in a crystal

  • There is also information between

and underneath the Bragg peaks

  • We can extract this additional

information by mathematical methods and the right experimental techniques PDF (atomic pair distribution function)

  • Fourier transform of XRD
  • Yields local structure, environment of

the atom

  • How many neighbors are there and

how far away are they?

  • Determines the distribution of

distances between pairs of atoms

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Distribution Functions

σ

First Coordination shell Second Coordination shell

g(r) 1.0 σ 2σ 3σ

Flaw of Averages

PDF measures the AVERAGE structure i.e. coordination number

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Different Types of Interactions: Total = Intra + Inter

NN NNN NNNN

Intramolecular PDF: Distances between atoms within a molecule Intermolecular PDF: Distances between atoms of neighboring molecules

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Synchrotron XRPD is required

Qmax affects SNR and resolution

  • Data quality at large Q-values

reflects the importance of using a high-energy X-ray beam

  • More Q-space provides more

data for the Fourier transform; leads to better quality data

  • If Qmax is too low, resolution

suffers keV 114.76 61.62 17 19.6

Germanium Dioxide

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PDF of Drug/Polymer Dispersion

  • Industry need
  • Amorphous forms have better solubility, but can be difficult to keep

amorphous

  • Drug/polymer dispersions are one solution
  • How to know which dispersions will successfully inhibit crystallization?
  • PDF
  • API molecules in close contact with each other increase the likelihood
  • f crystallization
  • Can differentiate PDF of drug from PDF of polymer
  • PDF can determine if API domains exist
  • Lack of API domains are desired
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Lapatinib Drug/Polymer Dispersion Study

Comparison of measurement X-ray factors

Pure polymer 1:3 API/Polymer 1:1 API/Polymer 3:1 API/Polymer Pure amorphous API Pure crystalline API

  • Residual crystallinity of lapatinib can be seen in several samples, including the “pure” amorphous API
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Lapatinib Drug/Polymer Dispersion Study

Total PDF curves and intra/inter PDF curves

  • Separate the total PDF curve into separate components
  • Subtract components to reveal differences
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Lapatinib Drug/Polymer Dispersion Study

Differential PDF curves

HPMCP dispersions HPMC-E3 dispersions

  • The only dispersion lacking intermolecular API interactions (no NN API domains)
  • The only dispersion that remained amorphous after stress testing at 40 ˚C/75% RH
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Latest Advances

Collaboration with Materials Development Inc. through Phase 2 SBIR

  • Lab on a drop with acoustic levitation
  • Lab model for spray drying
  • Suspend a droplet in the sample beam and
  • btain patterns as the drop evaporates,

leaving amorphous material behind

  • Vitrification by container-less melting
  • Obtain hard-to-get amorphous materials
  • Drug/polymer dispersion screen
  • Quickly screen several different formulations
  • n an extremely small scale
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References

  • Egami, T. and Billinge, S. J. L. 2003. Underneath the Bragg peaks:

Structural Analysis of Complex Materials. Pergamon Press, Elsevier Ltd. New York

  • Benchmark oxygen-oxygen pair-distribution function of ambient water from

x-ray diffraction measurements with a wide Q-range, L.B. Skinner, C. Huang, D. Schlesinger, L.G.M. Pettersson, A. Nilsson, C.J. Benmore. J.

  • Chem. Phys. 138, 074506 (2013).
  • Local Structure of Drug Interactions in Amorphous Solid Dispersions

characterized by Synchrotron X-Ray diffraction and Pair Distribution Function Analysis. G. Lima Barros de Araujo, C.J. Benmore and S.R. Byrn, Scientific Reports 7 (2017) 46367.

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Acknowledgments

  • Stephen R. Byrn, Improved Pharma
  • Gabriel L.B. de Araujo, Department of Pharmacy, University of Sao Paulo
  • Chris J. Benmore, X-ray Science Division, Advanced Photon Source,

Argonne National Laboratory

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Questions

Pamela A. Smith Booth Number 551 pam.smith@improvedpharma.com www.improvedpharma.com Stephen R. Byrn Booth Number 551 steve.byrn@improvedpharma.com www.improvedpharma.com