Excipientfest 2014 (5)
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Francine WalkerTechnical Director
Chemical Solutions Ltd.
Acid Leaching MethodsBioaccessibility Bioavailability Exposure
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Preparation Types
Digestions ….• Total Impurities• Strong acids
HNO3, HCl, HF, H2SO4, HClO4 , H3PO4
• Other Oxiders H2O2
• Heating Open Vessel vs. Microwave assistedTemps from 95 to 260 deg. C
Extractions….• Bioavailable Impurities• Weaker acids
HNO3, HCl
• Enzymes Pepsin
• Heating Body Temp. 37 deg. C
• Agitation Shaker, Rotator
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Toxicity(Oral Exposure)
Total Impurities – Present in any Form
Bioaccessible - Soluble in Digestive Juices
Bioavailable - Reaches Systemic Circulation
Total Impurities ≥
Bioaccessible Bioavailable
≥
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Bioaccessibility(Digestive Solubility)
Physical and Chemical Properties Element and Material of interest
For easily solubilized compounds in simple matrices: Pb(NO3)2 in water Total Pb = Bioaccessible Pb
For hard to solubilized compounds in complex matrices: Aluminum in clay Total Al ≥ Bioaccessible Al
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Bioaccessibility(Digestive Solubility)
Extraction of trace elements from natural sourced materials can be very dependent on extraction variables – especially strength and type of acid
• minerals (clays and talcs) • mineral derivatives (titanium compounds)
Elemental impurities may be bound within the structure of the compound, in complexes adhered to their surface or as cations that balance negative charges.
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Gastric Fluid Analogues have been used since the 1960s to study the bioaccessibility of nutritional elements, particularly iron……
• 0.07 – 1.0 N HCl• Pepsin (digestive protease)
• NaCl, KCl, phosphate buffers, NaHCO3, glycine
• pH 1.4 – 2.8 (can be stepped to/from pH 5 - 6)
• Temperature – 37deg. C • Time – 1 to 6 hours
Simulated Gastric Fluid
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EN 71-3 European Standard for Safety of Toys• Measures 17 Elements• Single Step: 1 N HCl at 37 deg. C for 2 hours
ASTM D5517 Extractability from Art Materials• Measures 20 Elements• Single step 0.07 N HCl at 37 deg. C for 1 hour / sit 1 hour• 45 micron filtration post extraction
EPA 9200.2-86 InVitro Bioaccessible Pb in Soil• Validated for Pb but has been used for others• 0.4 M glycine adjusted to pH 1.5 with HCl• Rotation end over end in large water bath• Bioavailability expressed as fraction
Bioaccessibility
References
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Sample Digestion Techniques
Open VesselBlock Digestion
Microwave Digestion(closed vessel)
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ExtractionTechniques
Incubator Shaker Rotator Shaker
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Extraction Apparatus
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ExtractionFluid Comparisons
Shaker Methods – Mod. EPA 9200.2-86 500 RPM at 37+/- 2o C for 1 hr Separate/Centrifuge 90 mins 1gram /100ml
1) Water – Deionized (ASTM Type 1)2) Glycine/HCl
0.4 M Glycine adjusted to a pH of 1.5 +/- 0.05 using conc. HCl3) 0.5 N HCl4) 1.0 N HNO3
Microwave Methods – Mod. EPA 3051A 175o C Final Temp. Ramp 5 mins Hold 5mins 0.5 gram / 10ml
5) 1.0 N HNO3
6) Conc. HNO3
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0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
Smectite Clay
Glycine/HCL Shaker
0.5N HCl Shaker
1N HNO3 Shaker
1N HNO3 µwave
Conc. HNO3 µwave
Note: Smooth transition with acid strength and temperature
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Complicating Issues
Hydrofluoric Acid Usage• Essential for dissolution of siliceous materials
- Minerals/Ores/Soils/Vegetables/Plants• Creates insoluble fluorides (CaF2 MgF2)
Unfiltered Particles• Picked up by autosampler
- Falsely Elevates Results
Internal Standards • Several common I.S. compounds found in minerals
- Indium Germanium Tellurium - Falsely Elevated I.S. = Falsely Lower Result
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0
10,000
20,000
30,000
40,000
50,000
60,000
70,000
Smectite Clay
Water
Glycine/HCL Shaker
0.5N HCl Shaker
1N HNO3 Shaker
1N HNO3 µwave
Conc. HNO3 µwave
Note: Aluminum anomaly due to unfiltered particulate
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0
2
4
6
8
10
12
Smectite Clay
Water
Glycine/HCL Shaker
0.5N HCl Shaker
1N HNO3 Shaker
1N HNO3 µwave
Conc. HNO3 µwave
Note: Lead anomaly due to unfiltered particulate or Internal Standard
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7.9 8.2 8.8
1112.4
0
2
4
6
8
10
12
14
Tellurium Germanium Indium Holmium Gallium
Lead Concentration in ppmmicrowave conc. HNO3
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“Quality is never an accident; it is always
the result of intelligent effort”
John Ruskin
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Chemical Solutions Ltd.
273 Mulberry Dr. , #9Mechanicsburg, PA 17050
717-697-7536717-697-4800 (fax)