X ray techniques for Pharma: is it just X ray diffraction? 2012/PDF/Casini.pdf · XRD – XRF…complementary techniques E. Casini 21.01.2012 2 Ron Jenkins, Encyclopedia of Analytical

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

2 21.01.2012 E. Casini

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