SPS-XRPD Workshop

6 May 2018, 08:30 → 8 May 2018, 16:30 US/East-Indiana

The Spring Synchrotron-XRPD workshop is jointly organized by the Purdue University in West Lafayette, Indiana, USA and Excelsus Structural Solutions, a spin-off company of the Paul Scherrer Institute in Switzerland. Scope of the workshop is to bring together experts from Pharma Industry and Synchrotron X-Ray Powder Diffraction community to discuss both current challenges in Pharma Research & Development and latest opportunities offered by Synchrotron-XRPD instruments and methods with the purpose of openly debating open questions and foster fruitful exchanges of ideas. SPS-XRPD 2018 workshop is the first of a series of meetings that will be held twice a year aiming at regularly informing pharma industry on new advanced available analytical tools and methodology involving synchrotron radiation and related techniques to address problems that conventional laboratory instrumentation cannot address. The Fall Pharmaceutical Synchrotron X-Ray Powder Diffraction(FSF-XRPD-2018)workshop will be held in Switzerland in fall 2018. X-Ray Powder Diffraction using synchrotron radiation has an enormous potential for applications in Pharma Research & Development as well as Quality Control and the workshop aims at promoting awareness of such a powerful analytical tool by the pharmaceutical industrial community. Phase identification of complex compounds, stability, structural characterization, and accurate quantification of crystalline phases below 0.05 wt% in drug substances and products will be extensively discussed, also in connection with intellectual property issues. A special session will be entirely dedicated to the application of the emerging Pair Distribution Function method applied to the structural characterization and quantification of amorphous and nano-crystalline solid formulations, a field of increasing interest over the past few years. On May 6th afternoon, a complimentary "XRPD refreshers" session on X-Ray Powder Diffraction and advantages of using synchrotron radiation will be offered to industrial participants who might not be familiar with the technique so to make the 2-days workshop more fruitful. Furthermore, on May 7th evening, a special "meet-the-experts" session will be organized, during which potential industrial customers are given the opportunity to discuss specific problems of interest with synchrotron XRPD experts. You will be requested to reserve in advance your own spot. A CDA can be worked out before the workshop.

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Sunday 6 May

Special session: 'XRPD Refreshers: an informal tutorial on X-Ray Powder Diffraction (XRPD) and Synchrotron X-Ray Powder Diffraction (SR-XRPD)'

Welcome and Networking Apero

Monday 7 May

Mission and Structure of the Spring and Autumn PS-XRPD workshops: S. Byrn & F. Gozzo

Pharmaceutical applications: an overview: S. Byrn

1 Pharmaceutical applications: An overview

Speaker: Prof. Stephen Byrn (Purdue University)

Synchrotron-XRPD applied to pharmaceutical compounds: F. Gozzo

2 S-XRPD applied to pharmaceutical compounds

Speaker: Dr Fabia Gozzo (Excelsus Structural Solutions (Swiss) AG)

09:35 Coffee break

Total Scattering and Pair Distribution Function: an Overview: Ch. Benmore & P. Whitfield

3 PDF intro

Introduction of PDF for molecular systems + underline the difficulties of PDF

Speaker: Dr Pamela Whitfield (Excelsus Structural Solutions (Swiss) AG)

4 PDF

Speaker: Dr Chris Benmore (Advanced Photon Source)

PDF & Industry

5 Pair Distribution Function

10 ' tutorial inside the allocated total of 35 minutes

Speaker: Prof. Simon Billinge (Columbia University)

6 PDF talk (xINTERPDF software)

Structures of organic compounds are more complex than their inorganic counterparts, which have usually a network structure, representing a giant “molecule”. Organics, on the other hand, have strong intramolecular bonds but much weaker intermolecular interactions, making them prone to structural disorders. Another complexity comes from the weak X-ray scattering of light elements (C, H, O, N etc) which are the building blocks of organic compounds. The atomic pair distribution function (PDF) calculated from synchrotron X-ray total scattering has been demonstrated to be a valuable tool for investigating structures of disordered and amorphous organics compounds (Shi et al., 2017; Prill et al., 2015; Prill et al., 2016). Although existing tools such as DiffPy-CMI (Juhás et al., 2016) and XISF (Mou et al., 2015) can be used for solving this problem, a new software program is still of great value that provides a user-friendly graphical user interface (GUI, as opposed to command-driven in DiffPy-CMI) and analyzes the data in real-space (as opposed to reciprocal space in XISF). In my talk I will introduce xINTERPDF, a GUI program for analyzing intermolecular pair distribution functions in organic compounds from X-ray total scattering data. I will briefly discuss its design, distribution and application examples. The program is freely available at https://github.com/curieshicy/xINTERPDF. References: Shi, C., Teerakapibal, R., Yu, L. & Zhang, G. G. Z. (2017). IUCrJ 4, 555-559. Prill, D., Juhás, P., Schmidt, M. U. & Billinge, S. J. L. (2015). J. Appl. Cryst. 48, 171-178. Prill, D., Juhás, P., Billinge, S. J. L. & Schmidt, M. U. (2016). Acta Crystallogr. A 72, 62-72. Juhás, P., Farrow, C. L., Yang, X., Knox, K. R. & Billinge, S. J. L. (2015). Acta Crystallogr. A 71, 562-568. Mou, Q., Benmore, C. J. & Yarger J. L. (2015). J. Appl. Cryst. 48, 950-952.

Speaker: Dr Chenyang Shi (AbbVie Inc)

7 Characterization of Mesomorphous Pharmaceuticals Using Pair Distribution Function.

Crystalline pharmaceuticals have long and short range three dimensional and translational symmetry order. However, these crystalline materials may lose one or even two-dimensional order to become mesophases (or commonly referred to as liquid crystals). Characterizing pharmaceutical mesophases using Bragg based X-ray powder diffraction has its limitation and generally is not enough to understand the molecular based structure of these unique phases. In this presentation a case study of using pair distribution function (a total scattering technique) calculated using Synchrotron X-ray powder diffraction to characterize lab generated thermotropic mesomorphous materials will be presented. The process used to analyze the synchrotron diffractogram and the techniques used to analyze the calculated pair distribution function and improve its resolution are outlined and discussed. The results of this work illustrate the power of pair distribution function in analyzing disordered pharmaceuticals in order to explore the molecular structures of these materials.

Speaker: Dr Faraj Atassi (Pulmatrix Inc)

12:25 Lunch, coffee and networking

In-situ S-XRPD

8 Monitoring phase transformations in formulations

The disproportionation of pioglitazone hydrochloride in intact tablets was mapped by transmission-mode synchrotron X-ray diffractometry (SXRD; Argonne National Laboratories). Tablet mapping was performed in situ at the beamline using a custom-built temperature and humidity controlled setup. Presence of basic excipients (magnesium stearate or croscarmellose sodium) caused disproportionation, yielding the crystalline free base. The disproportionation reaction, influenced by sorbed water and microenvironmental acidity, was initiated at the tablet surface and progressed toward the core. The transformation was solution-mediated, and the spatial heterogeneity in disproportionation could be explained by the migration of sorbed water. SXRD also revealed spatial heterogeneity in mannitol phase composition in intact ‘unperturbed’ lyophilized cakes. When lyophilized alone, mannitol appeared to crystallize completely, predominantly as the delta anhydrous polymorph. On the other hand, a second non-crystallizing component influenced the crystallization behavior of mannitol and there was pronounced intra vial heterogeneity in mannitol phase composition. Vertical mapping of ‘as is’ lyophiles using SXRD revealed the formation of mannitol hemihydrate and spatial heterogeneity in its distribution across the depth of the lyophile. Such intra vial heterogeneity can have a pronounced “local” effect and hence serious implications on the stability of lyophilized formulations. Processing conditions for lyophilization (annealing at different temperatures) and formulation composition influenced the formation and distribution of mannitol hemihydrate in the final lyophile.

Speaker: Prof. Raj Suryanarayanan (College of Pharmacy, University of Minnesota)

9 Using Containerless Methods to Synthesize and Characterize Amorphous Pharmaceuticals

This talk will focus on the application of non-contact (containerless) methods, such as acoustic levitation, to access metastable and amorphous forms of organic compounds. The complete absence of extrinsic nucleation sites in containerless conditions enables deep supercooling and/or extreme supersaturation to be achieved for a wide variety of compositions. The ability to extend the glass forming range in metal oxides by using containerless methods is well established; a similar capability to make amorphous and non-equilibrium forms of organic compounds is a relatively recent innovation. The presentation will be illustrated with details of instruments, examples of using containleress methods to synthesize new materials and to make in-situ measurements on materials during processing. The potential for using the tools to investigate and characterize large scale processing methods such as spray drying will be outlined. Ongoing experiments and plans for expansion of the current capabilities will be described and discussed in the context of developing pipeline drugs that require delivery in special dosage forms.

Speaker: Dr Richard Weber (Materials Development, Inc. and Argonne National Laboratory)

GSAS

10 GSAS presentation

Speakers: Dr Brian Toby (Advanced Photon Source), Prof. Robert Von Dreele (Argonne National Laboratory)

14:40 Coffee break

Lab. vs S-XRPD

11 Applications of XRPD for Phase Identification throughout Pharmaceutical Product Development

Small molecule APIs can exist in a variety of distinct solid-state forms with drastically different physicochemical properties. During development of these APIs, many factors are considered during form selection, such as stability, manufacturability, bioavailability, and intellectual property. If solid-state changes are observed during development, these selection factors can be negatively impacted, which can have detrimental effects to the development process and timeline. The “gold standard” tool to characterize solid-state forms is XRPD, which is used to ensure product quality from the late stages of Discovery as well as throughout Product Development, Commercialization, and Life Cycle Management. We will discuss several case studies in order to illustrate the use of XRPD in screening of solid forms of APIs and in determining the impact of DS and DP unit operations on the solid-state form of APIs. We will further discuss the use of XRPD to troubleshoot processing or stability failures due to contamination or raw material variability. Throughout the presentation, comparisons to other solid-state characterization techniques, such as Raman, NIR, IR, and ssNMR, will be discussed to illustrate gaps in areas of implementation of XRPD.

Speaker: Dr Anisha Patel (Bristol-Myers Squibb)

12 Synchrotron studies on amorphous pharmaceuticals

Speaker: Prof. Lynne Taylor (Purdue University)

13 In house and synchrotron based atomic PDF studies on non-crystalline drugs: is there room for both ?

Pharmaceutical industry is entering a new era in drugs development involving a transformation from crystalline to non-crystalline drug formulations. The driving force of the transformation is the largely improved bioavailability of the latter in comparison to the former. Non-crystalline drugs, however, are both an opportunity and challenge for pharmaceutical research and development (R&D). In particular, assessing the quality of a non-crystalline drug requires precise information about its 3D structure type, phase content, amount of different non-crystalline ingredients eventually present, stability, and others. With crystalline drugs, such information is almost straightforward to obtain by traditional powder x-ray diffraction (XRD). A non-traditional “powder XRD-type” technique using x-rays of higher (> 15 keV) than usual (Cu Kα ~ 8 keV) energy, often referred to as total x-ray scattering coupled to atomic pair distribution function (PDF) analysis, is emerging as a powerful analytical tool for structural characterization of non-crystalline drugs [1]. We will present results from recent total x-ray scattering studies utilizing in house equipment (Panalytical XRD instrument) and state-of-the-art synchrotron x-ray sources. Examples will include indomethacin, aspirin and ingredients used in non-crystalline drugs, such as starch, trehalose, polyvinylpolypyrrolidone, and others. Special attention will be given to demonstrating the viability of in house PDF studies on non-crystalline drugs since experiments at National Synchrotron Radiation Facilities are not necessarily an affordable (e.g. proprietary issues) and/or time-efficient pharmaceutical R&D option. Figure 1. Comparison between atomic PDFs for indomethacin and Polyvinylpyrrolidone (PVP) obtained on an in-house XRD instrument (Ag Kα) and using high-energy x-rays (115 keV) at the 11-ID-C beamline, Argonne. 1. Petkov, V., Ren, Y., Kabekkodu, S., Murphy, D., PhysChemChemPhys 15, 8544-8554 (2013).

Speaker: Dr Valeri Petkov (Dept. Physics, Central Michigan university)

Flash presentation + Poster session

17:45 Standing dinner

Special session: 'Guidelines for total scattering experts'

Tuesday 8 May

IP & Industry

14 Current treatment of crystalline forms under US and EP patent law

Patent law pertaining to prosecution and litigation of patents claiming crystalline forms continues to develop in view of scientific advances in the ability to detect, analyze, characterize, and distinguish crystalline forms. General principles of patent law particularly relevant to claims to crystalline forms in each of the United States and Europe will be discussed, followed by a focused discussion of the current treatment of such claims by courts and patent offices in each of the United States and Europe. Scientific concepts and technical information deemed useful under current patent laws for showing patentability and validity of claims to crystalline forms will be reviewed. Case studies and examples based on publically available patents, prosecution histories of patent applications, and documents from litigations will be used throughout to highlight issues, considerations, and potential strategies and pitfalls under current patent laws for protecting crystalline forms.

Speaker: Dr Jill MacAlpine (Finnegan, Henderson, Farabow, Garrett & Dunner LLP)

Beamline Overview

15 PDF-beamline overview DLS

Speaker: Dr Philip Chater

16 X-ray Powder Diffraction Facilities Available at the Advanced Photon Source

The facilities at the APS for powder diffraction includes the very high resolution 12-crystal analyzer/detector diffractometer (11-BM-B) which operates at medium energy (20-33keV) and a high throughput 2D imaging detector instrument (17-BM-B) that operates also at somewhat higher energy (27-51keV). Canonical measurement times on 11-BM are circa 1 hour/scan, while 17-BM can collect a dataset in seconds. The APS also has other diffraction beamlines optimized for PDF measurements, surface scattering, small-angle scattering and engineering studies. 11-BM operates ~50% of the time via a mail-in system that allows rapid turnaround (2-6 weeks) producing data often suitable for structure solution and Rietveld refinement for complex materials, with the balance used for on-site users. The 17-BM instrument, coupled with Argonne’s data processing/analysis software (GSAS-II) allows tracking of experiments in real time with both powder patterns and pair distribution function (PDF) data produced from image integrations done as in situ experimental or operando conditions (temperature, gas atmosphere, humidity, etc.) are varied. The GSAS-II software package is a fully developed, open source, crystallographic data analysis system written almost entirely in Python. For powder diffraction, it encompasses the entire data analysis process beginning with 2D image integration, peak selection, fitting and indexing, followed by intensity extraction, structure solution and ultimately Rietveld refinement, all driven by an intuitive graphical interface. Significant functionality of GSAS-II also can be scripted to allow it to be integrated into workflows or other software. This talk will cover these capabilities with some examples.

Speakers: Dr Brian Toby (Advanced Photon Source), Prof. Robert Von Dreele (Advanced Photon Source)

17 Instrumentation ESRF

Speaker: Dr Andy Fitch (ESRF)

18 SLS instrumentation

09:55 Coffee break

Examples from service providers

19 The role of intermediate companies

Speaker: Dr Mathilde L. Reinle-Schmitt (Excelsus Structural Solutions (Swiss) AG)

20 Crystal Structures of Large-Volume Commercial Pharmaceuticals

As part of a continuing project, the room-temperature crystal structures of several commercial pharmaceutical APIs have been solved using synchrotron X-ray powder diffraction data (11-BM at APS), and optimized using density functional techniques. The molecules to be discussed include: 1. terazosin hydrochloride dihydrate (Hytrin), which was originally solved (but only approximately) using data contained in the Powder Diffraction File database. 2. bretylium tosylate (Bretylol and others), which exhibited significant decomposition in the beam. 3. oxybutynin hydrochloride hemihydrate (Dytropan and Lyrinel XL), which has not been described as a hemihydrate, and which exhibits X-ray induced photoreduction of a triple bond. 4. levocetirizine dihydrochloride (Xyzal), which solves and refines better in P21/n rather than the true space group P21. 5. methylpednisolone acetate (Medrol). The presentation may also include progress (or lack thereof) on februxostat Form G (Uloric and Adenuric), as well as other new structures as they are solved.

Speaker: Dr James A. Kaduk (North Central College - Poly Crystallography Inc. - Illinois Institute of Technology)

21 Powder Diffraction File™ Coverage of Polymers used in Pharmaceutical and Biomedical Applications

Polymers show a range of order from amorphous to semi-crystalline. Traditional organic analytical techniques, such as infrared spectroscopy (IR), differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA), and nuclear magnetic resonance (NMR), are typically used for polymer analysis. Though X-ray diffraction (XRD) is not commonly used as the primary technique for polymer characterization, XRD does provide unique information about a polymer particularly when assessing crystallinity and crystallite size. In medical applications, polymers are often used as excipients in pharmaceuticals, and the base material for delivery devices used in biomedical applications. ICDD has been adding polymer diffraction data to the Powder Diffraction File (PDF®) with the focus on adding raw data diffraction patterns (1D and 2D) as part of the PDF entry. The inclusion of the raw data diffraction pattern is important in correctly identifying the polymer contribution to a composite material diffraction pattern. A traditional d-spacing/intensity stick pattern or simulated diffraction pattern is not capable of accounting for the full-pattern diffraction profile of polymers since all polymers have some amorphous component. The ICDD polymer project focuses on industrially important polymers with an added emphasis on polymers used in medical and biomedical applications. New entries resulting from this project will be presented along with phase identification analysis results for pharmaceutical formulations including an interesting finding for a change in the polymers used in the formulation of opioid based oxycodone pain medication.

Speaker: Dr Thomas Blanton (International Centre for Diffraction Data)

12:05 Lunch, coffee and networking

Additional contributions

Meet the experts - alt. Panel discussion: What pharma industry needs? what can we provide?

Wrap up of the workshop