List of most important methods of analysis performed at Solvias, with amounts of substance required Typical elements/tests C, H, N, S Total contents, individually or combined Quantitation range in each case 0.3 to 100% m/m Organic solid and liquid samples TOC (total content of organic carbon) In water/aqueous samples and in water-soluble solids and liquids Quantitation range ppb to %
Method/description
Amount of substance required
Reference
Classical combustion analysis with physical detection
4-10 mg (duplicate determination) Always carried out as duplicate determination
Confirmation with more than one reference material
Catalytic combustion in an oven after separation of inorganic carbon - IR detection
50-100 mL (ppb range) Other ranges on request
All official methods can be performed, e.g. Ph. Eur. 2.2.44 Total Organic Carbon in Water for Pharmaceutical Use USP/NF Total Organic Carbon Ph. Eur. 2.2.44 Total Organic Carbon in Water for Pharmaceutical Use, adaptation to determination of TIC USP/NF Total Organic Carbon
TIC (total content of inorganic carbon) In water/aqueous samples and in water-soluble solids and liquids Quantitation range ppb to %
Conversion (acidification) of 50-100 mL (ppb range) inorganic carbon (carbonate, Other ranges on request hydrogen carbonate) to CO2 - IR detection
N (total content) Solid, liquid, and aqueous samples
Kjeldahl method
10 mg/10 μl: LOQ = 2% 100 mg/100 μl: LOQ = 0.2% 1 g/1 mL: LOQ = 0.02% (200 ppm) 10 g/10 mL: LOQ = 0.002% (20 ppm)
Ph. Eur. 2.5.9 Determination of Nitrogen by Sulphuric Acid Digestion USP/NF Nitrogen Determination
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Typical elements/tests TNb (Total bound nitrogen: all bound forms taken together) Quantitation range approx. 1 ppm to % Additional application: Total protein as total bound nitrogen In water/aqueous samples and in water-soluble solids and liquids Nitrogen species Nitrite, nitrate, ammonium, amines, aminoalcohols, hydroxylamines, hydrazines, amino acids In water/aqueous samples and in water-soluble/extractable solids and liquids O Total content Quantitation range in each case 0.3 to 100% m/m Organic solid and liquid samples Halogens (total) (Cl, Br, I) Total contents, individually or combined Quantitation range in each case approx. 100 mg/kg to 100% m/m Organic solid and liquid samples
Method/description
Amount of substance required
Reference
Catalytic combustion in an oven - IR detection Alternative method to Kjeldahl (dramatically reduced amount of test material due to higher sensitivity)
≤ 10 mg/L TNb: min. 10 mL 10 -100 mg/L TNb: min. 2 mL > 100 mg/L TNb: min. 1 mL
European Standard EN 12260 Method is generically validated
Ion chromatography
On request
See ion chromatography
Pyrolysis - IR detection
4-10 mg (duplicate determination) Always carried out as duplicate determination
Confirmation with more than one reference material
Combustion - Titration
4-10 mg (% content, as duplicate determination) 50-200 mg (trace amounts, as duplicate determination) Always carried out as duplicate determination
Ph. Eur. 2.5.10 Oxygen Flask Combustion in combination with Ph. Eur. 2.2.20 Potentiometric Titration. Equivalent to USP/NF Oxygen Flask Combustion in combination with USP-NF Titrimetry
Alternative method for trace contents ≥ approx. 3 mg/kg: XRF
2/7
Typical elements/tests F Fluorine, total content Quantitation range approx. 10 mg/kg to 100% m/m (special cases < 1 mg/kg) Organic solid and liquid samples Halides (Cl-, Br-, I-) Ionic content, individually or combined In water/aqueous samples and in water-soluble/extractable solids and liquids
F- (fluoride) Ionic content In water/aqueous samples and in water-soluble/extractable solids and liquids
Method/description Oxidative digestion/combustion - ISE (ion selective electrode)
Titration
ISE (ion selective electrode) or ion chromatography (see therein)
Amount of substance required 4-10 mg (% content, as duplicate determination) 50-200 mg (trace amounts, as duplicate determination) Always carried out as duplicate determination 4-10 mg (% content, as duplicate determination) 50-200 mg (trace amounts, as duplicate determination) Always carried out as duplicate determination Alternative method for trace contents if not much substance available: ion chromatography 4-10 mg (% content, as duplicate determination) 50-200 mg (trace amounts, as duplicate determination) Always carried out as duplicate determination
Reference ISE detection: Ph. Eur. 2.2.36. Potentiometric Determination of Ionic Concentration Using Ion-Selective Electrodes
Ph. Eur. 2.2.20 Potentiometric Titration USP/NF Titrimetry
Ph. Eur. 2.2.36. Potentiometric Determination of Ionic Concentration Using Ion-Selective Electrodes
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Typical elements/tests
Method/description
Water content (moisture) Karl Fischer method (volumetric/titrimetric) Traces and % contents Organic solid and liquid samples Available variants: - Direct method (classical) - Direct method (microgram scale) - Gas extraction method = oven method (KF method with initial heating step) - Various methods for determination of the water content in vials and ampoules (avoids inaccuracies due to contact of the contents with air) Ash (loss on ignition), micro method Composite parameter inorganic residue (as oxides) Ash (loss on ignition), standard method Composite parameter inorganic residue (as oxides) Sulfated ash (USP residue on ignition) Composite parameter inorganic residue (as sulfates) Loss on drying/dry residue
Combustion in oxygen atmosphere at 1000°C, gravimetric determination of the residue Ignition in muffle furnace
Amount of substance required 2 mg (LOQ approx. 1% m/m) - 5 mg (LOQ approx. 0.5% m/m) - 10 mg (LOQ approx. 0.3% m/m) - 20 mg (LOQ approx. 0.1% m/m) - 100 mg (LOQ approx. 0.02% m/m) For GMP analyses, product-specific confirmation as per Ph. Eur. 2.5.12 is carried out in all cases. -
-
1 mg (LOQ 1% m/m) 10 mg (LOQ 0.1% m/m)
Reference Direct method: Ph. Eur. 2.5.12 Water: SemiMicro Determination Equivalent to USP/NF Water Determination, method Ia, b
Solvias method without direct reference to official method
1g Micro method: 100 mg
Ph. Eur. 2.4.16. USP/NF
Ashing with sulfuric acid, 1g followed by ignition at 600°C Micro method: 100 mg
Ph. Eur. 2.4.14 USP/NF
Oven drying, where appropriate under vacuum
Ph. Eur. 2.2.32, methods a) e) USP/NF
1g Micro method: ≥ 100 mg
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Typical elements/tests Heavy metals limit test (sulfide precipitation)
Method/description Heavy metals (pharmacopeial methods)
e.g. Na, K, Li, Ca, Mg, Cu, Cr, Al Flame AAS (FAAS)
Amount of substance required Depending on the specification: 2-4 g
Reference Ph. Eur. 2.4.8 USP/NF Ph. Eur. 2.2.23 USP/NF
Impurities of heavy metals (As, Cd, Ni, Pb, etc. LOQs: approx. each 0.1 mg/kg) Impurities of Mercury, LOQ: 0.05 mg/kg Hg
Graphite furnace AAS (ETAAS)
Traces (10 mg/kg to 0.1%): 200 mg Contents in the % range: 1050 mg 200 mg Ph. Eur. 2.2.23 USP/NF
Cold-vapour AAS (CVAAS)
200 mg
B, P (%), Si (%), noble metals (%)
ICP-OES
5-30 mg
Impurities of heavy metals (Cd, Cr, Co, Cu, Fe, Mn, Mo, Ni, Pb, Pd, V, Zn, etc., LOQs: each 1 mg/kg) Impurities of precious metals (Pd, Ru, Rh, Pt, Ir, Au, LOQs: each 0.1 mg/kg) Impurities of metals (As, Cd, Co, Hg, Mn, Pb, Sb, Sn, etc., LOQs: each 0.1 mg/kg) Impurities Osmium, LOQ: 0.1 mg/kg
ICP-OES
200 mg
ICP-MS
50 mg
USP/NF Ph. Eur. 2.2.58
ICP-MS
200 mg
USP/NF Ph. Eur. 2.2.58
ICP-MS
40 mg
Traces of P, Si, S, halogens (except F), metals
X-ray fluorescence spectrometry (XRF)
2.5 g/2.5 mL
USP/NF Ph. Eur. 2.2.58 Ph. Eur. 2.2.37
Ph. Eur. 2.2.23 USP/NF Ph. Eur. 2.2.57 USP/NF Ph. Eur. 2.2.57 USP/NF
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Typical elements/tests
Method/description
Amount of substance required
Reference
Anions (inorganic, organic), cations (inorganic, organic) In water/aqueous samples and in water-soluble/extractable solids and liquids Entire concentration range. LOQs (strongly matrix-dependent) approx. 10-100 mg/kg (solids, liquids) or 10-1000 μg/l (aqueous solutions) Miscellaneous species such as cyanide, azide, hydrazine, formaldehyde, acetaldehyde, Fe(II), Fe(III), free Cu, free Cr etc. In aqueous samples and in water-soluble/extractable solids and liquids (including organics) Concentration range and LOQs are strongly matrix-dependent (feasibility study): approx. 0.11000 mg/kg (solids, liquids) Refractive index
Ion chromatography (IC) 5-50 mg All current separation techniques and elution/detection methods Carbonate, hydrogen carbonate as CO2: see "TIC" (determination by IC not feasible)
USP/NF Ion Chromatography
Voltammetry/polarography
50-500 mg
USP/NF Polarography
Refractometric
1 mL*
Density of solids
Exclusively by helium pycnometry
1g
Density of liquids
Exclusively by oscillation measurement
10 mL*
Infrared absorption spectroscopy
FTIR as ATR, KBr disk or cell
10 mg
Surface tension
Tensiometer
≥ 0.1 g
Ph. Eur. 2.2.06 USP/NF Ph. Eur. 2.2.42 Ph. Eur. 2.9.23 USP/NF Ph. Eur. 2.2.05 USP/NF Ph. Eur. 2.2.24 USP/NF 6/7
Typical elements/tests
Method/description
Osmolality
Osmometer
Particle size distribution/ wet dispersion
Laser diffraction, GMP only after validation or transfer
Particle size distribution/ dry dispersion
Laser diffraction, GMP only after validation or transfer
Particle size distribution Optical rotation
Disk centrifuge Polarimetry
Melting point
Exclusively by heating block with automatic detection
Sieving
Air-jet sieving
Specific surface area (BET)
BET
UV/Vis spectroscopy
Twin-beam photometer
Partition coefficient, log P Viscosity
Shake flask method Ubbelohde capillary viscometer
Viscosity
Rheometer
Amount of substance required 0.5 mL*
Reference
Ph. Eur. 2.2.35 USP/NF 3g Ph. Eur. 2.9.31 USP/NF 10 g Ph. Eur. 2.9.31 USP/NF 2 mL* 20 mL*, approx. 100 mg Ph. Eur. 2.2.07 USP/NF 10 mg Ph. Eur. 2.2.60 USP/NF 15 g Ph. Eur. 2.9.12 Ph. Eur. 2.9.38 USP/NF dependent on expected Ph. Eur. 2.9.26 surface area, sample should USP/NF give approx. 1 m2 total surface area 5 mL* Ph. Eur. 2.2.25 USP/NF Substance-dependent 10 mL* Ph. Eur. 2.2.08 Ph. Eur. 2.2.09 USP/NF ≥ 0.5 mL* Ph. Eur. 2.2.08 Ph. Eur. 2.2.10 USP/NF
*Solutions: In the case of solid samples, the mass must be sufficient to prepare the specified volume at the required concentration. Information status: November 2009 Version: 10.09 7/7