Analysis of Pharmaceuticals by ICP-MS and WDXRF

Transcription

1 Analysis of Pharmaceuticals by ICP-MS and WDXRF Frank X. Weber, James M. Harrington, Andrea McWilliams, James Medlin, Keith E. Levine Trace Inorganics Department, RTI International, Research Triangle Park, NC RTI International is a trade name of Research Triangle Institute.

2 New United States Pharmacopeia (USP) Methods ICP-MS <232> <233> WDXRF <735>

3 New United States Pharmacopeia Methods <232> Elemental Impurities - Limits 15 elements

4 <232> Elemental Impurities - Limits J = the w/w concentration of the analyte at the target limit, calculated using per day exposure limit and maximum daily dose of product Levels vary with administration route Spike samples at: 50% J 100% J 150% J

5 Example J Calculation - Product Arsenic PDE: 1.5 µg/day Maximum dose: 0.65 g/day Sample size: 150 mg Final volume: L J = 1.5 µg/day / 0.65 g/day = 2.31 µg/g solution calculation: (2.31µg/g * g) / 0.05 L J = 6.92 µg/l

6 Example J Calculation - API Arsenic PDE: 1.5 µg/day Maximum dose: 0.1 g/day Sample size: 150 mg Final volume: L J = 1.5 µg/day / 0.1 g/day = 15 µg/g solution calculation: (15 µg/g * g) / 0.05 L J = 45 µg/l

7 <232> Elemental Impurities - Limits Active Pharmaceutical Ingredient Small amount Ratio to maximum dose, higher impurity limits Excipient Higher weight Ratio to maximum dose, lower impurity limits

8 Challenges Multiple matrices <233> Elemental Impurities - Procedures Method validation Element retention

9 <233> Elemental Impurities - Procedures Method validation Linearity Precision and accuracy Robustness Selectivity Stock solution stability

10 <233> Elemental Impurities - Procedures Example Compound Naproxen sodium Widely used Easily available Clean surrogate for spiking

11 <233> Elemental Impurities - Procedures Sample Preparation Microwave acid digestion

12 <233> Elemental Impurities - Procedures Closed vessel HNO 3 and HCl acids H 2 O 2

13 <233> Elemental Impurities - Procedures Accuracy Results Accuracy a Concentration 51V 60Ni 63Cu 65Cu 75As 95Mo 98Mo 101Ru 102Ru 50%J %J %J Concentration 103Rh 104Ru 105Pd 106Pd 108Pd 111Cd 114Cd 191Ir 50%J %J %J Concentration 193Ir 194Pt 195Pt 200Hg 202Hg 206Pb 207Pb 208Pb 50%J %J %J a Accuracy was measured as % recovery against nominal concentrations.

14 <233> Elemental Impurities - Procedures Precision Results Precision b Concentration 51V 60Ni 63Cu 65Cu 75As 95Mo 98Mo 101Ru 102Ru 50%J %J %J Concentration 103Rh 104Ru 105Pd 106Pd 108Pd 111Cd 114Cd 191Ir 50%J %J %J Concentration 193Ir 194Pt 195Pt 200Hg 202Hg 206Pb 207Pb 208Pb 50%J %J %J b Precision is measured as the % CV of six replicate sample preparations.

15 <233> Precision and Accuracy P&A by element

16 WDXRF <735> Wavelength dispersive X-ray fluorescence (WDXRF) is a sensitive, selective technique to meet specifications expected in final implementation of <735>. Non-destructive analysis. Less extensive sample preparation Fusion, pellet, powder, or liquid Chapter <735> is in-process, implementation date has not been determined.

17 <735> X-Ray Fluorescence Spectrometry WDXRF OQ Chapter recommends Inconel 625 alloy standard

18 <735> X-Ray Fluorescence Spectrometry Challenges with WDXRF instrument calibration and sample preparation: Calibration and quality control check standards difficult to obtain Uniform thickness Homogeneity

19 Example Compound <735> X-Ray Fluorescence Spectrometry Non-coated aspirin Widely used Easily available Clean surrogate for spiking

20 <735> Pb Tablet preparation for Pb Tablets were reduced to a fine powder Spiked with a NIST-traceable Pb standard solution Dried in an oven (99 C) Mixed Pressed into a pellet ~ 25,000 psi

21 <735> Pb Pb Measurement WDXRF Conditions: 60 kv and 50 ma = 3.0 kw LiF200 crystal Scintillation detector Solids analyzed under vacuum environment Considerations Lα and Lβ lines Lβ used in event of arsenic (negates the use of Pb Lα)

22 <735> Pb Results Pb Results Pb dosed in aspirin demonstrated linearity and precision over the range of 0-40 ppm for both the Lα and Lβ lines

23 <735> Osmium Os calibration analysis: 40 mm liquid cell XRF sample cups Prepared by spiking 2% HCl solution with a NIST-traceable Os standard solution Analysis done under helium purge

24 <735> Os Osmium Results

25 <735> Summary WDXRF P&A

26 Summary New methods will have to be used for testing. <232> <233> likely issued first (2015) Excipient testing API testing Wide range <735> is a viable method Fast preparation Ideal for higher J values API dependent on the dosage limit

27 ICH and USP Different elements Different limits for now Possible agreement?

28 More Information Frank X. Weber Laboratory Manager James Harrington, Ph.D. Research Chemist