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Understanding Microwave Sample Preparation for USP Methods 232,233 and 2232

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Understanding Microwave

Sample Preparation for USP

Methods 232,233 and 2232

USP Method 231

Current Methodology

• USP Method 231 – introduced in 1905

– 3 different sample preparation methods can be used

dependent on sample type

– Metal impurities: Ag, As, Bi, Cd, Cu, Mo, Hg, Pb, Sb,

Sn are precipitated with sulfide and compared to lead

standards

• Qualitative (semi-quantitative at best) test to

determine metal impurities

Limitations of USP Method 231

Methodology

• Difficult to reproduce results

– Solutions and standards change with time

• Nondiscriminatory test – Individual metals not reported separately, reported as group

• Low spike recoveries – Aggressive sample preparation techniques result in low

recovery of volatile metals

• Large sample size of 2 grams is required to

achieve the MDL of 10 ppm

New USP Chapters Will Replace Method 231

In May 2014

• Chapter 232 - Elements of Interest and Limits

• Chapter 233 – Procedures

• Chapter 2232 – Dietary Supplements Speciation*

* Implementation of 2232 may be delayed

USP 232 Elements of Interest

• The Big Four Toxic Elements:

– Always must be analyzed – As, Cd, Pb, Hg

• Environmental and Catalyst Impurities:

– Must be analyzed if added during the process either

intentionally or unintentionally

– Cr, Cu, Mn, Mb, Ni, Pd, Pt,V, Os, Rh, Ru, In

USP 233 Sample Preparation Options

• Sample preparation procedures include:

– Direct aqueous solution – if the sample dissolves in DI water,

then acidify samples per instrument manufacturer specifications

and perform analytical measurement

– Direct organic solution – if the samples dissolves in organic

solvent, perform analytical measurement (if instrument is

organic solvent compatible)

– Indirect solution (closed vessel digestion) – if sample will not

dissolve in DI water or organic solvent, then closed vessel

digestion is required

USP Method 233

Sample Preparation – Closed Vessel Digestion

• Choice of strong acid (HNO3, H2SO4, HCl, HF, Aqua

Regia) is dependent on the sample matrix

• Sample weights and acid volumes can be adjusted for the

sample type and digestion apparatus

• Closed vessel digestion procedure parameters to be

determined by user

Why Do We Digest Samples?

• Measurements take time

• Signal must stay constant during measurement

• Analyzer needs homogeneity

• The solution is a solution…..

Why Pressurized Digestion?

• Temperatures above boiling point

• Oxidative potential of reagents is higher at

elevated temperatures

• Digestion is faster and more complete

Why the USP Pursued a

Microwave Method?

• Rapid Heat Up Time

• Instantaneous on:off = control

• Reproducibility of conditions

• Only the sample and reagent is heated

• Rapid cool down

• High Throughput

CEM’s Solutions to Sample Preparation for

USP Method 233

• Applications Support

– Free phone support for applications issues and method development

– Applications notes, reference papers and sample preparation advice available

24-7 on the CEM website.

– ICP-OES and ICP-MS capabilities for analytical measurement

– IQ/OQ/PQ Documentation

– CEM has been attending USP meetings regarding method 232, 233 for three

years in order to provide our customers the best and latest advice regarding

the changes being made

CEM IQ/OQ/PQ and Service Capabilities • CEM service offers IQ/OQ/PQ for SP–D and Mars

• CEM service offers service contracts for SP–D and Mars that

include recertification of the instrument Discover SP-D

Microwave Accelerated Reaction System

IQ, OQ and PQ

Instrument Qualification

Operation Qualification

Performance Qualification

Installation Procedures

CEM Corporation

P.O. Box 200 3100 Smith Farm Road

Matthews, NC 28106-0200 704.821.7015 ▪ 800.726.3331

www.cem.com [email protected]

600099S Rev. 1

CEM Solutions for

USP Method 233- Documentation

CEM Synergy–D Software

Operating Procedures Page 1 – Instrument and Software Start-up Page 3 – Set-up New User Accounts Page 4 – Copy Applications (CEM) Methods to a User Page 4 – Create New Methods Page 6 – Set-up and Start a Sample Queue with the Explorer Page 7 – Set-up and Start a Sample Queue without the Explorer Page 8 – Add a Priority Sample to a Sample Queue Page 9 – Save Explorer Rack Sequences Page 9 – View Data and Generate Reports Page 12 – Automatic Save of Data After Each Run Page 13 – Save Data to a File Instrument and Software Start-up

1. Turn on the Discover SP–D.

2. Double click on the SynergyD icon on your computer desktop.

3. The software will load and a CEM Discover Logon screen will prompt you to select the User and type the

Password.

4. The software will open. Note the difference between the screen with and without the Explorer autosampler.

Make sure the Discover (and Explorer) are connected– see highlighted area.

CEM SP–D Maintenance Procedures Page 1 – Instrument Adjustment – Explorer Attenuator Set-up Page 4 – Instrument Adjustment – Explorer Rack Set-up Page 7 – Instrument Adjustment – Load/Return Vessels, Adjust Vessel Pickup Height, Home Explorer Page 9 – Instrument Repair – Vessel Failure Clean-up Page 13 – Instrument Test – IR Temperature Verification with Water Page 14 – Instrument Maintenance – Spray Grippers and Rails with Teflon Page 15 – Instrument Maintenance – Grease ActiVent Drive Gear Page 17 – Instrument Maintenance – Checking the ActiVent for Corrosion Instrument Adjustment – Explorer Attenuator Set-up

1. Install 35 mL attenuator

2. In CEM SynergyD software, go to top menu bar → Explorer → Explorer Attenuator Calibration. The Explorer Attenuator Setup box will open.

3. Click Calibrate Attenuator Position – see highlighted area.

CEM’s Solutions to Sample Preparation for

USP Method 233

• Customized Training Available on Site or at CEM

CEM’s Sample Preparation

Instrumentation Line-up

CEM SP-D with Explorer

(Sequential Sample Preparation)

CEM Mars6

(Batch Sample Preparation)

SP–D Pharmaceutical Applications

• CEM has created nearly 100

pharmaceutical application notes

so far – constantly adding more

• Samples include raw materials,

stabilizers, excipients, fillers and

finished products

CEM’s Sample Preparation Considerations

For USP 233

• Nitric acid alone will not work for all sample types, even at high

temperatures

• Nitric acid uses: – ~ 200oC will digest most organic samples

– ~ 210oC - 220oC will work for samples with more difficult matrices

• Acid mixtures will be required for most inorganic samples – HCl required for recovery of most metal catalysts as well as Sn and Sb

– HF needed for silicates – silicates can be found in tablet coatings, fillers, etc.

– Boric acid – dissolve insoluble fluoride due to HF and neutralize HF

• Sample size & Elements of Interest – Will dictate the requirements of ICP-OES or ICP-MS for your laboratory

CEM’s Sample Preparation Considerations

For USP 233

However…

A mixture of 9 ml of HNO3 and 1 ml of HCl will digest and stabilize the

majority of samples and elements for analysis that don’t require HF

Examples of Samples Digested in Nitric Acid and HCl

Antioxidant Tablets Ascorbic Acid Aspirin Beta Carotene Calcium Carbonate

Calpan Chromium Chelate Claritin Cold/Flu Relief Cupric Sulfate

d-Biotin Folic Acid Herbal Supplement Hydrocodone Kelp

Magnesium Oxide Manganese Carbonate Niacinamide Non-Drowsy Allergy Relief Potassium Chelate

Protopic Ointment Pyridoxine Riboflavin Selenium Chelate Thiamine

Valsartan Vitamin B12

Vitamin D3 Vitamin E Zinc Sulfate

Sample Weight: 0.1 - 0.3g

Reagents: 9 ml HNO3 and 1 ml HCl

Sample Preparation Procedure

Microwave Heating Program

Control Style: Ramp To Temperature Pressure Mode: Organic

Stage Temp(C) Ramp

Time

Hold

Time

Pressure

(PSI)

Power (W) Stirring

1 200 5:00 3:00 400 300 Med

Samples Digested in Nitric Acid and HF

Allergy Relief Dicloflenac Potassium Glipizid/Metformin HCL Losartan Potassium Multivitamin

Naproxen Sodium Sleep Aid Sodium Aluminum Silicate Talc

Vitamin C

Sample Weight: 0.1 - 0.3g

Reagents: 9 ml HNO3 , 1 ml HF

Sample Preparation Procedure

Microwave Heating Program

Control Style: Ramp To Temperature Pressure Mode: Organic

Stage Temp(C) Ramp

Time

Hold

Time

Pressure

(PSI)

Power (W) Stirring

1 200 5:00 3:00 400 300 Med

SP–D Blank and Spike Recovery Studies

• Blank and cleaning

studies – extensive

testing at ppb/ppt

levels with ICP-MS

underway

• Recovery studies –

ppm studies

completed and

ppb/ppt studies

underway

• Results available

during next webinar

Multi-Vitamin

(250 mg) Ca Fe Mg Zn Cu Mn

#1 489.3 70.67 181.50 74.500 7.285 7.754

#2 493.2 70.47 175.9 76.31 7.664 8.024

#3 458.1 68.09 178.2 71.74 7.07 7.593

#4 471.7 64.04 182.6 72.41 7.05 7.386

#5 482.6 64.99 173.4 73.35 7.039 7.351

AVG (ppm) 478.98 67.652 178.32 73.662 7.2216 7.6216

True Value

(ppm) 370 66.2 184 55.8 7.360 7.360

% Recovery 128% 100% 96% 131% 96% 101%

Std Dev 14.24 3.06 3.82 1.808 0.267 0.278

%RSD 2.97 4.52 2.14 2.45 3.70 3.65

SP-D Spike Recovery Results of 125 ppb Metal Impurities As Hg Cd Pb Cr Mn Ni Pd Rh V

Acetylsalicylic Acid

Tablet Average 127.5 114.7 118.7 121.3 123.2 120.5 121.5 107.0 132.2 123.8 % Recovery 102 92 95 97 99 96 97 86 106 99 RSD 7.45 1.04 1.21 1.44 0.80 2.62 4.82 3.25 0.81 1.01

Loratadine

Pseudoephedrine

Tablet

Average 90.5 98.2 103.3 98.8 104.2 103.8 99.8 93.7 108.5 100.8 % Recovery 72 79 83 79 83 83 80 75 87 81 RSD 5.88 1.23 1.72 6.72 0.50 3.71 3.16 1.12 5.63 0.29

USP Method 233 Proposed accuracy is 70-150% with

precision < 20%

SP-D Spike Recovery Results of 125 ppb Metal Impurities As Hg Cd Pb Cr Mn Ni Pd Rh V

Folic Acid Average 114.8 118.3 119.3 120.2 122.3 120.7 120.0 119.8 128.3 123.8 % Recovery 92 95 95 96 98 97 96 96 103 99 RSD 4.96 0.86 1.05 5.57 1.76 1.93 1.79 2.45 2.85 0.84

Zinc Sulfate Average 124.7 116.5 121.3 125.3 126.0 113.3 121.5 123.7 136.7 126.3 % Recovery 100 93 97 100 101 91 97 99 109 101 RSD 3.50 1.27 1.61 3.27 3.24 7.02 1.21 1.55 2.13 1.15

USP Method 233 Proposed accuracy is 70-150% with

precision < 20%

Conclusions – CEM SP–D • Fast sample digestions

• Digest real sample sizes – ICP-OES and ICP-MS have plenty of

sensitivity

• Digest a mix of sample types with different acids and temperatures,

ALL during a single run

• Automated, unattended operation

• Several safety features

– Temperature and pressure control

– ActiVent pressure management

– Safety interlocks

• IQ/OQ/PQ and service contracts available

• USP has already purchased the SP-D and Explorer