X ray techniques for Pharma: is it just X ray diffraction? 2012/PDF/Casini.pdf · XRD –...
Transcript of X ray techniques for Pharma: is it just X ray diffraction? 2012/PDF/Casini.pdf · XRD –...
X ray techniques for Pharma: is it just X ray diffraction?
A few examples of X-ray spectroscopy applications related to pharma
Casini Eugenio
XRD – XRF…complementary techniques
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Ron Jenkins, Encyclopedia of Analytical Chemistry, R.A. Meyer Ed., pg 13269 - 13288
About X-ray fluorescence spectroscopy (XRF)
• Advantages of XRF – Non-destructive – Suitable for solids, liquids and
powders – Simple, fast and safe sample
preparation – Accurate, highly reproducible data – Wide analytical concentration
range (ppm – 100 wt%)
• XRF is an atomic emission technique, like OES and ICP. Atoms in a sample energized by a primary X-ray source emit characteristic X-rays that enable identification and quantification of the elements present.
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XRD a versatile tool for problem – solving…(a)
• Physical characterization of pharmaceutical compounds – Structural investigation of compounds – Polymorph and salt screening – “Fingerprinting” of a crystalline drug – Stability and compatibility studies – Detection and quantification of polymorphic impurities – API and excipient control in final product
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XRD a versatile tool for problem – solving…(b)
• Physical characterization of pharmaceutical compounds – Optimization of process parameters – In situ crystallization and scale-up studies – Investigation of amorphous and nano-crystalline compounds
(SAXS and PDF) – Microstructure analysis of tablets by CT
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Therefore…when do I need XRF in pharma?
• However what about the chemical analysis? – Raw material analysis – Process optimization – Scale-up analysis – Final product testing
• Impurities: elemental analysis E.g. Heavy elements, stainless steel residues,
• Material identification: Fingerprinting
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US Pharmacopeia
• Heavy Metals chapter (231) is being replaced by a new chapter, Elemental Impurities (232)
• XRF will be a permissible technique
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Heavy metals and contaminants
• The new proposal (chapter 232) includes two distinctions; – The Big Four elements - As, Cd, Hg and Pb
– Additional process elements (e.g Ni, Pd, Pt, Rh, Ru …) • A related USP chapter (233 – detailing procedures) makes
provisions for alternative techniques for which XRF is permitted
• The European Pharmacopeia already recognize XRF
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Elemental impurities…limits
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• [1]: Pharmacopeial Forum, 36 (1) [Jan.-Feb. 2010], <232> Elemental impurities - Limits
• Class 1: Elements that should be absent
• Class 2: Elements in traces
Clear advantages of XRF
• XRF advantages – Easy and short sample preparation – No digestions required
• In most cast cases solids (loose powders) and liquids can be measured directly;
• Typical samples: liquids and slurries, loose powder, pressed pellets
– Recovery of samples for additional tests – Simplifying your analytical requirements
• Capable of mixed matrix methods* – No special facility requirements (No fume hoods) – Unattended operation (no flame/plasma safety risk) – Reduced waste stream
*European Pharmacopeia 5.0, section 2.2.37 – X-ray Fluorescence (2008) 21.01.2012 10 E. Casini
XRF – a highly robust alternative technique
• Robust and stable methods
– Single to multipoint external calibrations – No need for internal standards (no risk of contamination – further
use) – Improved accuracy and precision through the use of more
material
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XRF – a highly robust alternative technique
• Robust and stable methods – Single to multipoint external calibrations – No need for internal standards (no risk of contamination – further
use) – Improved accuracy and precision through the use of more
material
• Extended lifetime and reduced operational costs – Relative to destructive techniques such as AAS or ICP, XRF has
an extended life time – Minimal sample contact relates to cleaner measurement path and
operational costs
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Non destructive spectroscopic solutions
• Elemental analysis quantification (sub ppm to %) – Wavelength Dispersive (WD-XRF) – (C to U)
• Characterized by several optical components (goniometer, crystals, filters, etc…) and high power setting (1-4 kW)
– Energy Dispersive (ED-XRF) - (Na to U) • Simple optical configuration (benchtop and/or big systems); low
power setting; it works as a simultaneous system
Preferred solution for Pharma
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Some application: Elemental Impurities - USP
• Standards prepared using fine excipient grade cellulose and pure organic compounds (method validation by cross checking with ICP-MS)
• Specimens were prepared as loose powders (2.5g) load in a disposable cup
• The measurement conditions were optimized
Data collection conditions
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Some application: Elemental Impurities
• Standards were prepared using fine excipient grade cellulose and pure organic compounds (method validation by cross checking with ICP-MS)
• Specimens were prepared either as loose powders (using a disposable cup with prolene 4µm film) and as pressed pellet
Concentration range of the STDs prepared for this study
Spectra collected on Std5 21.1 µg/g Ru and 20.6 µg/g Pd
Measurement conditions
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Quantitative analysis with ED-XRF
• Find out the optimum conditions to measure a dedicated range of elements (simultaneous analysis)
• Find out which transition line should be monitored for the calibration
process and for the element content determination
• Take in account the matrix effect (i.e the contribution on the peak intensity due to the other elements in the sample under investigation – Compton correction[1])
[1]: European Pharmacopeia 5.0, section 2.2.37 – X-ray Fluorescence (2008)
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Some application: Elemental Impurities
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Some application: Elemental Impurities
Overview of the calibration parameters related to the measurements on the loose powders 21.01.2012 18 E. Casini
Repeatibility test
• Several measurements collected on the same specimen confirmed the stability of the proposed solution either for loose powder and pressed pellet specimens
Loose powder sample: Std 3
Pressed pellet sample: Std 3
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Examples of use
• Raw material analysis • Process optimization • Scale-up analysis • Final product testing
– Elemental analysis(impurities) • E.g. Heavy elements, stainless steel residues,
– Material identification (FingerPrinting) • Raw material and automatic encompassing
spectral comparison
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PANalytical hardware solutions
• A number of configurations are available • From benchtop portable units to full-scale
automatable
• Epsilon 3 and Epsilon 3 XL • Epsilon 5 • Axios 21.01.2012 21 E. Casini
Fingerprinting – general use material identification • FingerPrint uses all spectra features for statistical evaluation • Chi2 analysis automatically identifies unknowns • Advantage – no interpretation is required
XRD – XRF…complementary techniques
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Ron Jenkins, Encyclopedia of Analytical Chemistry, R.A. Meyer Ed., pg 13269 - 13288
Conclusions…X-ray solutions for the pharma
• Pre-Clinical Development
• Clinical Development Phase 1-3
• Manufacturing
• Pre-Formulation and Formulation • Quality control
• Solid form screening, selection and characterization • Stability and compatibility testing • Definition of process and quality control methods • Process chemistry and scale-up • Regulatory and legal documents
• Quality of incoming goods
• Product quality
• XRD is a versatile analysis tool for physical characterization of pharmaceutical compounds
• XRF allows the quantification of elemental impurities and rapid identification of materials
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Conclusions…X-ray solutions for the pharma
Thanks for your attention