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ELEMENTAL ANALYSIS AND
TRACE METALS BY ICP-MS
K.LOHITHA
PA2016106 (Department of Pharmaceutical Analysis)
1/3/2017
1
INTRODUCTION
REGULATORY COMPLIANCE
ICP-MS
INSTRUMENTATION &WORKING
ASSETS & LIMITATIONS
APPLICATIONS & REFERENCES
1/3/2017...
Elemental impurities are
 Elements found in environment
 Introduced in manufacturing of drug and excipients
 They have ...
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.)
1/3/2017
4
REGULATORY COMPLIANCE
1/3/2017
5
ICH Q3D-Guideline for elemental impurity
Development of
design for control
Establishment ...
CLASSIFICATIONOF ELEMENTAL IMPURITIES
1/3/2017
6
1/3/20177
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
...
DIFFERENT ANALYTICAL TECHNIQUES FOR
ELEMENTAL ANALYSIS
1/3/2017
8
ELEMENT
AL
TECHNIQ
UES
ATOMIC
ABSORPTION
SPECTROSCO
PY
I...
WHAT IS ICP-MS ???
1/3/2017
9
 Inductively coupled plasma mass spectrometry (ICP-MS) is a type
of mass spectrometry which...
PRINCIPLE
1/3/2017
10
 Liquid sample is introduced into an argon plasma as aerosol
droplets.
 The plasma dries the aeros...
ICP-MS INSTRUMENTATION AND
WORKING
1/3/2017
11
SAMPLE PREPARATION TECHNIQUES
1/3/2017
12
• By HNO3, HF, HCl, HClO4
ACID DIGESTION
• Rare earth elements are made soluble ...
Laser ablation
1/3/2017
13
 Useful for surface analysis of solid
samples
ICP TORCH – making ions
1/3/2017
14
 Argon gas flows through a series of concentric quartz tubes (ICP
torch) that are wra...
1/3/2017
15
+
++
N
Vaporized
sample
Ionization chamber Sample cone
M
+
Ar
+
M
Ar
THE INTERFACE – sampling ions
16
 The interface region in the ICP-MS transmits the ions travelling in
the argon sample st...
TWO-CONE DESIGN
1/3/2017
17
The ions from the ICP source are then focussed by the electrostatic lenses in the
system.
Th...
MASS ANALYZER
1/3/2017
18
 Heart of MS
 Mass analyzers separate the ions according to their mass-to-charge
ratio.
 The ...
QUADRUPOLE ANALYZER
1/3/2017
19
+
+ ++ m/z
RA
OTHER MASS ANALYZERS
1/3/2017
20
 Time-of-flight ( rare)
 High resolution (HR) – Uses magnetic sector analyzer
High sens...
INTERFERENCES
 Polyatomic interference
40 Ar & 35 Cl for 75As
 Isobaric interference
Fe and Ni
 Matrix interference
 O...
DETECTOR
1/3/2017
22
 Fundamental purpose of the detector is to translate the number of
ions striking the detector into a...
ICP-MS AND HYPHENATION
1/3/2017
23
 ICP-MS can be coupled with various separation techniques :
Liquid chromatography HPLC...
ELEMENTAL COVERAGE OF ICP-MS
1/3/2017
24
TECHNIQUE DECISION MATRIX
1/3/2017
25
DETECTION LIMIT RANGES & WORKING
RANGES
1/3/2017
26
COST
1/3/2017
27
COMPARISON BETWEEN DIFFERENT
INORGANIC TECHNIQUES
1/3/2017
28
ADVANTAGES
1/3/2017
29
 Multi Element Analysis (consistent conditions for most/all
elements)
 Wide elemental coverage (a...
LIMITATIONS
1/3/2017
30
 Difficult to determine negative species (Cl,Br)
 Dissolved solids/matrix effects –need to dilut...
APPLICATIONS
1/3/2017
31
PHARMACEUTICAL
FOOD ANALYSIS
ENVIRONMENTAL
GEOLOGICAL
ARCHAELOGICAL
FORENSIC
CASE STUDY
1/3/2017
32
RESULT AND DISCUSSION
1/3/2017
33
Comparison of analytical values is done for discrimination of pellets with
possession of...
1/3/2017
34
ICP-MS is an ideal choice for the laboratory that is
seeking the lowest possible detection limits and the
highest level of...
REFERENCES
1/3/2017
36
[1] V. Balaram ; Recent advances in the determination of elemental
impurities in pharmaceuticals – ...
1/3/201737
1/3/2017
T
H
N
K
Y
O
UA
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Elemental analysis & Trace metals by ICP-MS

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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.

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Elemental analysis & Trace metals by ICP-MS

  1. 1. ELEMENTAL ANALYSIS AND TRACE METALS BY ICP-MS K.LOHITHA PA2016106 (Department of Pharmaceutical Analysis) 1/3/2017 1
  2. 2. INTRODUCTION REGULATORY COMPLIANCE ICP-MS INSTRUMENTATION &WORKING ASSETS & LIMITATIONS APPLICATIONS & REFERENCES 1/3/2017 2
  3. 3. 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 1/3/2017 3
  4. 4. 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.) 1/3/2017 4
  5. 5. REGULATORY COMPLIANCE 1/3/2017 5 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
  6. 6. CLASSIFICATIONOF ELEMENTAL IMPURITIES 1/3/2017 6
  7. 7. 1/3/20177 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 elements na: Not included in EMA guidance nc: Not considered a safety concern except for drugs administered by inhalation Fe - - 1300
  8. 8. DIFFERENT ANALYTICAL TECHNIQUES FOR ELEMENTAL ANALYSIS 1/3/2017 8 ELEMENT AL TECHNIQ UES ATOMIC ABSORPTION SPECTROSCO PY INSTRUMENTAL NEUTRON ACTIVATION ANALYSIS ICP-MS ICP-AES/ ICP- OES/GFAAS X-RAY FLUORESCENCE SPECTROMETRY
  9. 9. WHAT IS ICP-MS ??? 1/3/2017 9  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.
  10. 10. PRINCIPLE 1/3/2017 10  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.
  11. 11. ICP-MS INSTRUMENTATION AND WORKING 1/3/2017 11
  12. 12. SAMPLE PREPARATION TECHNIQUES 1/3/2017 12 • 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
  13. 13. Laser ablation 1/3/2017 13  Useful for surface analysis of solid samples
  14. 14. ICP TORCH – making ions 1/3/2017 14  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.
  15. 15. 1/3/2017 15 + ++ N Vaporized sample Ionization chamber Sample cone M + Ar + M Ar
  16. 16. THE INTERFACE – sampling ions 16  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
  17. 17. TWO-CONE DESIGN 1/3/2017 17 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.
  18. 18. MASS ANALYZER 1/3/2017 18  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.
  19. 19. QUADRUPOLE ANALYZER 1/3/2017 19 + + ++ m/z RA
  20. 20. OTHER MASS ANALYZERS 1/3/2017 20  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.
  21. 21. INTERFERENCES  Polyatomic interference 40 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 1/3/2017 21 TYPES MINIMIZED BY
  22. 22. DETECTOR 1/3/2017 22  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 detector Electrons release Striking next surface of detector Amplification of signal
  23. 23. ICP-MS AND HYPHENATION 1/3/2017 23  ICP-MS can be coupled with various separation techniques : Liquid chromatography HPLC-ICP-MS Capillary electrophoresis CE-ICP-MS Laser 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
  24. 24. ELEMENTAL COVERAGE OF ICP-MS 1/3/2017 24
  25. 25. TECHNIQUE DECISION MATRIX 1/3/2017 25
  26. 26. DETECTION LIMIT RANGES & WORKING RANGES 1/3/2017 26
  27. 27. COST 1/3/2017 27
  28. 28. COMPARISON BETWEEN DIFFERENT INORGANIC TECHNIQUES 1/3/2017 28
  29. 29. ADVANTAGES 1/3/2017 29  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%)
  30. 30. LIMITATIONS 1/3/2017 30  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
  31. 31. APPLICATIONS 1/3/2017 31 PHARMACEUTICAL FOOD ANALYSIS ENVIRONMENTAL GEOLOGICAL ARCHAELOGICAL FORENSIC
  32. 32. CASE STUDY 1/3/2017 32
  33. 33. RESULT AND DISCUSSION 1/3/2017 33 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.
  34. 34. 1/3/2017 34
  35. 35. ICP-MS is an ideal choice for the laboratory that is seeking the lowest possible detection limits and the highest level of productivity. Conclusion 1/3/2017 35
  36. 36. REFERENCES 1/3/2017 36 [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
  37. 37. 1/3/201737
  38. 38. 1/3/2017 T H N K Y O UA

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