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ELEMENTAL ANALYSIS AND TRACE METALS BY ICP-MS

K.LOHITHA PA2016106 (Department of Pharmaceutical Analysis)

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FLOW OF PRESENTATION

INTRODUCTION

REGULATORY COMPLIANCE

ICP-MS

INSTRUMENTATION &WORKING

ASSETS & LIMITATIONS

APPLICATIONS & REFERENCES 05/03/2023

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INTRODUCTION

Elemental impurities are Elements found in environment Introduced in manufacturing of drug and excipients They have to be monitored for two reasons Enter the human body via food chain including medicines,

ambient air and drinking water leading to health problems Affect the stability of formulation and catalyze degradation

of drug substance

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POTENTIAL SOURCES OF ELEMENTAL IMPURITIES (As,Cd,Cu,Sn,Sb,Pb,Bi,Ag,Hg,Mo,In,Os,Pd,Pt,Rh,Ru,Cr,Ni,V,etc.)

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REGULATORY COMPLIANCE

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ICH Q3D-Guideline for elemental impurity

Development of design for control

Establishment of permitted daily exposure

(PDE)

Evaluation of toxicity data for potential source

Safety Toxicity Acceptance level

International Council for Harmonisation

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CLASSIFICATION OF ELEMENTAL IMPURITIES

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ICH Classl Element ICH Q3D**(µg/day)

USP<232>**(µg/day)

EMA/CHMP(µg/day)

Class 1 As 1.5 1.5 na

Cd 0.5 0.5 na

Hg 4 1.5 na

Pb 0.5 0.5 na

Class 2A Co 5

Mo 18 18 25

Se 17 - -

V 12 12 25

Class 2B Ag 17 - -

Au 13 - -

Ir 100* 10 10***

Os 100* 10 10***

Pd 10 10 10

Pt 100 10 10

Rh 100* 10 10***

Ru 100* 10 10***

Tl 0.8 - -

Class 3 Ba 1300 - -

Cr 1100 nc 25

Cu 130 130 250

Li 78 - -

Ni 60 60 25

Sb 120 - -

Su 640 - -

Class 4 Mn - - 250

Zn - - 1300

* PDE is based on Pt, due to insufficient data** Subclass limit - PDE is based on the sum of these elementsna: Not included in EMA guidancenc: Not considered a safety concern except for drugs administered by inhalation

Fe - - 1300

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DIFFERENT ANALYTICAL TECHNIQUES FOR ELEMENTAL ANALYSIS

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ELEMENTAL

TECHNIQUES

ATOMIC ABSORPTIO

N SPECTROSC

OPY

INSTRUMENTAL

NEUTRON ACTIVATION ANALYSIS

ICP-MSICP-AES/

ICP-OES/GFAAS

X-RAY FLUORESCE

NCE SPECTROME

TRY

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WHAT IS ICP-MS ???

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Inductively coupled plasma mass spectrometry (ICP-MS) is a type of mass spectrometry which is capable of detecting metals and non-metals at concentrations as low as one part in 1015 (ppq).

This is achieved by ionizing the sample with ICP and then using a MS to separate and quantify those ions.

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PRINCIPLE

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Liquid sample is introduced into an argon plasma as aerosol droplets.

The plasma dries the aerosol, dissociates the molecules, and then removes an electron from the components, forming singly-charged ions, which are directed into a mass filtering device known as mass spectrometer.

Once the ions enter MS (mostly quadrupole), they are separated by their mass-to-charge ratio and gets detected.

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ICP-MS INSTRUMENTATION AND WORKING

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SAMPLE PREPARATION TECHNIQUES

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• By HNO3, HF, HCl, HClO4

ACID DIGESTION

• Rare earth elements are made soluble in the sample material by sintering with Sod.peroxide, leaching with water and acidifying with HNO3

SODIUM PEROXIDE SINTERED DIGESTION

• For biological or organic samples.• Sample is digested with small amount of high

purity acid or peroxide in closed teflon vessel.

MICROWAVE DIGESTION

LASER ABLATION

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Laser ablation

Useful for surface analysis of solid samples

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ICP TORCH – making ions

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Argon gas flows through a series of concentric quartz tubes (ICP torch) that are wrapped at one end by a radio frequency (RF) coil.

Energy supplied to the coil by the RF generator couples with the argon to produce plasma.

As the sample travels through the different heating zones of plasma torch (6000-7000K)it is dried, vaporized, atomized, and ionized. The singly charged ions exit the plasma and enter the interface region.

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+++

N

Vaporizedsample

Ionization chamber

Sample cone

M+ Ar

+M

Ar

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THE INTERFACE – sampling ions

The interface region in the ICP-MS transmits the ions travelling in the argon sample stream at atmospheric pressure(1-2torr) into the low pressure region of the mass spectrophotometer(<1× 10-5 torr)

It consists of 2-3 inverted funnel-like devices called cones.

Two-cone design Three-cone design

Large pressure reduction-wide ion beam divergence

Small pressure reduction- small ion beam divergence

PURPOSE – to sample the center portion of the ion beam coming from ICP torch

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TWO-CONE DESIGN

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The ions from the ICP source are then focussed by the electrostatic lenses in the system.The ions coming from the system are positively charged, so the electrostatic lens which also has a positive charge serves to collimate the ion beam and focus into the entrance aperture or slit of MS.

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MASS ANALYZER

Heart of MS Mass analyzers separate the ions according to their mass-to-

charge ratio. The most commonly used type of mass analyzer is

Quadrupole mass filter. It consists of 4 cylindrical rods, set parallel to eachother. Alternating AC and DC voltages are applied to opposite pairs

of rods. The result is that an electrostatic filter is established that

only allows ions of a single mass-to-charge ratio (m/z) pass through the rods to the detector at a given instant in time.

So, quadrupole mass filter is really a sequential filter, with the settings being change for each specific m/z at a time.

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QUADRUPOLE ANALYZER

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DETECTOR

m/zRA

Parallel

rods

Bunch of ions

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OTHER MASS ANALYZERS

Time-of-flight ( rare) High resolution (HR) – Uses magnetic sector analyzer High sensitivity and resolution but slow, and requires stable working

environment Quite expensive Multi-collector (MD) – Also with magnetic sector, but

with detector array Good for accurate and precise

isotope ratios Isotope dilution measurements – eg.,

for accurate elemental ratios.

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INTERFERENCES

Polyatomic interference40 Ar & 35 Cl for 75As

Isobaric interference Fe and Ni

Matrix interference

Optimization of nebulizer gas flow (1.5-1.8ml/min)

RF Power adjustment (500-800watt)

Sampling position within plasma

Cold plasma technique Collision or reaction cell HR-mass analyzer as double

focusing magnetic field sector

Internal standard

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TYPES MINIMIZED BY

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DETECTOR

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Fundamental purpose of the detector is to translate the number of ions striking the detector into an electrical signal that can be measured and related to the number of atoms of that element in the sample via the use of calibration standards.

Uses a high negative voltage to attract positively charged ions

Most commonly used are discrete dynode detectors

Ion striking active surface

of detectorElectrons release

Striking next surface of detector

Amplification of signal

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ICP-MS AND HYPHENATION

ICP-MS can be coupled with various separation techniques :Liquid chromatography HPLC-ICP-MSCapillary electrophoresis CE-ICP-MSLaser ablation LA-ICP-MS

For surface analysis For materials that are

difficult to digest (eg., Alloys) ADVANTAGES OF HYPHENATED TECHNIQUES :

Better control over matrix Allows separation of different components : direct

access to speciation

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24 ELEMENTAL COVERAGE OF ICP-MS

Click icon to add picture

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TECHNIQUE DECISION MATRIX

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DETECTION LIMIT RANGES & WORKING RANGES

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COST

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COMPARISON BETWEEN DIFFERENT INORGANIC TECHNIQUES

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ADVANTAGES

Multi Element Analysis (consistent conditions for most/all elements)

Wide elemental coverage (almost all except H, noble gases and F)

Low detection limits for most elements (ppt or sub ppt in most cases)

Wide dynamic range (10-9 – 0.5 ppt-500 ppm) Short acquisition times (full mass acquisition in less than 5 mins) Good matrix tolerance (will handle acids, solvents, matrix up to

0.5%)

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LIMITATIONS

Difficult to determine negative species (Cl,Br) Dissolved solids/matrix effects –need to dilute samples

more than other techniques High capital cost Require skilled personnel

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APPLICATIONS

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PHARMACEUTICAL

FOOD ANALYSIS

ENVIRONMENTAL

GEOLOGICAL

ARCHAELOGICAL

FORENSIC

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CASE STUDY

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RESULT AND DISCUSSION

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Comparison of analytical values is done for discrimination of pellets with possession of a suspect in order to determine whether they are of common origin or not.

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ICP-MS is an ideal choice for the laboratory that is seeking the lowest possible detection limits and the highest level of productivity.

Conclusion

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REFERENCES

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[1] V. Balaram ; Recent advances in the determination of elemental impurities in pharmaceuticals – Status, challenges and moving frontiers ; Trends in Analytical Chemistry.

[2] R.N. Rao, M.K. Talluri, An overview of recent applications of inductively coupled plasma-mass spectrometry (ICP-MS) in determination of inorganic impurities in drugs and pharmaceuticals, J. Pharm. Biomed. Anal. 43 (2007) 1-13.

[3] ICH, Guideline for Elemental Impurities Q3D, in: International Council for Harmonisation, IFPMA, Geneva, Switzerland, 2014.

[4] Skoog, D. A., Holler, F. J., & Crouch, S. R.(2007).Principles of Instrumental Analysis.

[5] Available from: http://www.perkinelmer.com/icpmsthirtminuteguide.pdf

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