The document provides an overview of inductively coupled plasma mass spectrometry (ICP-MS), including its instrumentation, principle of operation, applications in pharmaceutical analysis, and next generation developments. ICP-MS allows for simultaneous multi-element analysis with very low detection limits. It has various applications in drug development, quality control, clinical trials, and analysis of drug impurities and packaging leachables. The next generation NexION 300 ICP-MS offers improved stability, flexibility, and performance for pharmaceutical analysis.

1. INDUCTIVELY COUPLED PLASMA MASS
SPECTROMETER
(ICP-MS)
Prepared By :
Mahendra G S
M-Pharm,
Pharmaceutical Chemistry
JSSCP, MYSURU

2. OVERVIEW
• INTRODUCTION
• INSTRUMENTATION
• PRINCIPLE
 Sample introduction
 Ion source
 Mass analysers
 Detection unit
 Peak measurement
 Methods of quantitation
 Interferences
• PHARMACEUTICAL APPLICATIONS
• NEXT GENERATION OF ICP-MS
• CONCLUSIONS

3. INTRODUCTION
What is ICP-MS?
Inductively Coupled Plasma Mass Spectrometry
Elemental analysis with:
• Wide elemental coverage
• Very low detection limits(ppt /ppm)
• Fast analysis times (all elements at once)
• Simple spectra
• Isotopic information

4. LIMITS OF DETECTION : IN COMPARISION

5. • TIMS: Thermal ionisation mass spectrometry
• ICP-AES :Inductively coupled plasma atomic
emission spectroscopy
• NEE: Neutron Activation Analysis
• XRF: X-ray fluorescence spectrometer
• EMP: empirical formula

6. Why is ICP-MS unique?
ICP-MS can:
• measure almost any element at ppt to ppm levels in almost any material.
• measure all elements in a single analysis.
• distinguish different element species (speciation).
Main requirements in pharmaceutical analysis are:
• high sensitivity
• good matrix tolerance
• low levels of interferences
• ease of coupling to speciation techniques ( LA, LC and maybe GC)

7. INSTRUMENTATION
USING PERISTALTIC
PUMP(1ml/min)
TO SEPARATE FINE DROPLETS
(1-2%)FROM LARGER ONES
2 METALLIC CONES (SAMPLER AND
SKIMMER CONE ( 0.6-1.2mm ORIFICE, AT
760 TORR)
750-1500W

9. PRINCIPLE
• Liquid samples to form aerosol in nebulizer.
• Introduction of Argon to the ICP torch, which is located in center of a radio
frequency (RF) coil for energy supply.
• RF field causes collisions of Ar atoms, generating a high-energy plasma.
• Sample aerosol decomposed in plasma (6000 - 10000 K) to form analyte atoms
which are simultaneously ionized.
• Ions extracted from the plasma into mass spectrometer region.

12. SAMPLE INTRODUCTION

13. SAMPLE INTRODUCTION DATA ANALYSIS

15. 1.QUADRUPOLE MASS SPECTROMETER
• dc field on one pair of opposite rods and RF field on the
other pair.
• Ions of a selected m/z ratio are allowed to pass through
the rods of the detector.
MASS
ANALYSERS

16. 2.MAGNETIC SECTOR FIELD

17. 3.DOBLE FOCUSSING SECTOR MS
• ESA- kinetic energy focusing
• Magnet : ions travel in a curved path and are
separated according to their m/z.

19. 1.SECONDARY ELECTRON MULTIPLIER
• Incoming ion creates an electron.
• Acceleration of electron towards the second dynode.
• Electron cascade is analysed as pulse or current.
DETECTION
UNIT

20. 2.FARADAY CUP
• Incoming ion draw an electron from the ground to neutralize the positive
charge of the incoming ion.
• A voltage is measured.

21. 3.MULTIPLE COLLECTOR DEVICES
• Multiple detectors are aligned parallel.
• Nuclides are measured simultaneously.
• Prerequisite for precise isotopic ratio measurement.

22. MULTI COLLECTOR ICP-MS

23. PEAK MEASUREMENT
MEASUREMENT VARIABLES:
• Whether it is a continuous or transient signal.
• The temporal length of the sampling event.
• Volume of sample available.
• Number of samples being analyzed.
• Number of replicates per sample.
• Number of elements being determined.
• Detection limits required.
• Precision/accuracy expected.
• Dynamic range needed.
• Integration time used.

24. METHODS OF QUANTITATION
• Quantitative analysis
• Semiquantitative routine
• Isotope dilution
• Isotope ratio
• Internal standardization

25. INTERFERENCES
• Polyatomic Interferences
Minimized by:
1. Optimization of nebulizer gas flow (1.5-1.8ml/min).
2. RF power adjustment (500-800W).
3. Sampling position within plasma.
• Isobaric Interferences
Minimized by:
1. cold plasma technique
2. collision/reaction cell
3. High resolution mass analysers as double focussing magnetic field sector.
• Matrix Interferences
Minimized by: use internal standardization

26. ICP-MS : FIELDS OF APPLICATIONS

27. FIELDS OF APPLICATIONS
• Qualitative and Quantitative (simultaneous multi element
analysis).
• Isotope ratio measurement
• Coupling techniques:
 Chromatographic system
 Laser ablation

28. LC-ICP-MS
Advantages of HPLC
• Wide applicability
• High resolution
• Rapid analysis
• High sensitivity
• High reproducibility
• Quantitative
• Easily automated
ICP-MS as detector
• Selective for the element
• Provide isotopic information
• Determination of multiple
elements simultaneously
• Universal ,regardless the mode of
chromatography
• Extremely sensitive
• Detection limits in ppt range

29. ABLATION ICP-MS
Analysis of solid sample surfaces
Procedure:
• Laser beam focused onto sample surface in ablation
chamber or cell.
• Miniature plasma above sample ablates material from
surface.
• Resultant particulate material is transported to ICP-MS
with carrier gas stream (e.g. Ar)
• Sample is decomposed, atomised and ionized in ICP
plasma and analyzed in mass spectrometer.
Applications for LA-ICP-MS:
• Monitor distribution of administered drugs among different tissues and body
compartments.
• In-situ analysis of metals and other elements in samples separated using PAGE,
e.g.:
– Au and Pt drug metabolite identification.
– Determine degree of phosphorylation of different separated proteins.

30. PHARMACEUTICAL APPLICATIONS
• Pharmaceutical waste water
• Drug discovery / drug development:
 Analysis of individual forms of drug compounds using target element
analysis
 Simple metal analysis during development of metal-based drugs
• QA/QC and process development:
National Pharmacopeia (e.g. USP, EP, JP) Testing
 Impurity limit tests
 Metals in active pharmaceutical ingredients (API)
 QC of natural products – toxic impurities
 Toxic element impurities (e.g. heavy metals)
• Clinical trials:
 Simple metal analysis for active component confirmation
 Monitoring of the metabolites of an administered drug

31. • Metal impurities – Leachables from pharmaceutical packaging materials
1. Interaction between formulation and packaging material results in
components migrating into the drug product.
2. These components may be toxic or affect the stability of the drug product
3. Storage conditions impact leaching (heat, UV radiation, storage time)
Typical leachables are:
• Small organic molecules [monomers, excipients, reaction by-products],
• Metal ions and trace elements (e.g. aluminum, cadmium, chromium, copper, lead,
manganese, and zinc)
• Metal ions can affect the stability of the formulation, catalyze the degradation
of the active pharmaceutical ingredient (API) and cause unqualified degrades to
form, or pose a toxicity threat on their own.

32. NEXT GENERATION OF ICP-MS
(NexION 300 ICP-MS Instruments)
• Engineered to deliver a level of stability, flexibility and performance never
before seen in an ICP-MS instrument, PerkinElmer's NexION® 300 is the
first truly significant and revolutionary industry advancement in recent
years.

33. The NexION 300 offers:
• 3 modes of operation (Standard, Collision and Reaction) and can be quickly
switched from 1 mode to another.
• So, every analysis can be performed on the same instrument.
• It's the only ICP-MS that lets you maximize productivity without compromising
sensitivity or performance.
• A single ICP-MS instrument offers both the simplicity and convenience of a
collision cell and the exceptional detection limits of a true reaction cell.
• Stability is optimized by incorporating a unique Triple Cone Interface and
Quadrupole Ion Deflector. Designed to remove an unprecedented level of un-
ionized material (and preventing it from entering the Universal Cell), this
innovative ion path keeps the instrument clean, minimizing drift and eliminating
the need for cell cleanings.

34. Features/Benefits
• Large, accessible sample introduction system
• Low liquid uptake nebulizer
• Free-running RF plasma generator
• Automated X, Y, Z torch positioning
• Patented PlasmaLok® technology
• Fastest scanning quadrupole in the industry
• Quadrupole Ion Deflector
• Triple Cone Interface
• Plasma View window
• Four-stage vacuum system
• Benchtop design

35. APPLICATIONS
• Gold Nanoparticles Reference Materials Using the NexION 300 ICP-MS in
Single Particle Mode.
• Coupling Flow Field Flow Fractionation to ICP-MS for the Detection and
Characterization of Silver Nanoparticles.
• The Determination of Lead in Calcium-Based Antacid and Dietary
Supplements.
• The Determination of Metals in Cosmetics.
• Assuring safety of traditional Chinese herbal medicines by monitoring
inorganic impurities using ICP-MS.

36. CONCLUSIONS
• ICP-MS is excellent detector for HPLC in bioanalysis.
• Orthogonal to other detectors.
• Rapid and efficient method for metabolism studies
/speciation.
• Polyatomic interferences from high matrix samples are a
major challenge.
• Room for instruments improvements.