USP Method 233 -Microwave Sample Preparation of Pharmaceutical Samples

Jason D. Keith, Tina Restivo, Elaine Hasty, Ivana Mrvalj, Daniel Iverson: CEM Corporation, Matthews, NC

The current USP Method 231 – Heavy Metals, has many issues that have prompted its replacement. USP Method 231 is to be replaced in May 2014 with USP Methods 232 and 233. USP Method 233 – Elemental Impurities Procedures, is the proposed laboratory procedures for sample preparation and analysis of pharmaceutical drug products. USP Method 233 requires that drug product samples are prepared for ICP-OES or ICP-MS analysis by closed vessel microwave digestion if the sample does not dissolve in water or solvent.

The development and validation of sample preparation and analysis procedures for all of a pharmaceutical manufacturer’s drug products can seem overwhelming. The method development and validation of microwave closed vessel digestion procedures will be challenging and time consuming. These procedures are difficult to develop and validate because there are many factors that can affect the quality of the digestion such as sample type and size, acid selection, and digestion temperature and time. The closed vessel microwave digestion method development and validation process can be made more manageable by understanding each of these factors. Closed vessel digestion method development discussion will include each of these factors, as well as results from a spike recovery study of finished products and raw materials.

The MARS 6 with EasyPrep vessels allow for the processing of up to 12 samples simultaneously. The EasyPrep vessel is the fastest, simplest to assemble high pressure, high temperature vessel available. The control vessel has an integrated thermowell. All wetted vessel parts are made of TFM. Each digestion is controlled via a dual IR and fiber optic temperature measurement systems ensuring complete and reproducible reactions. Additionally the digestion is also pressure controlled.

The acetylsalicylic acid and loratadine pseudoephedrine tablets were ground into a powder in triplicate

The folic acid and zinc sulfate were used without preparation in triplicate

A 0.50 gram sample was weighed and 5 mL of concentrated nitric acid and 5 mL DI water was added to a CEM EasyPrep vessel. The tablets and ingredients were prepared in a single run. The MARS 6 system for each run was ramped to 200 °C in 25 minutes and

held for 15 minutes. Vessels were allowed to cool for 15 minutes prior to uncapping and dilution. All

samples and blanks were diluted to 25 mL for ICP-OES analysis.

A 0.50 gram sample was weighed and 5 mL of concentrated nitric acid and 5 mL of DI water was added to a CEM 35 mL Discover SP-D vessel. The Discover SP-D system was programmed for 300 watts. The temperature was ramped to 200 °C in 5 minutes and held for 3 minutes. All samples and blanks were diluted to 25 mL for ICP-OES analysis.

Pass the proposed accuracy and precision requirements for the proposed USP Method 233

Can be used for the digestion of pharmaceutical finished products and ingredients in both R&D and QC laboratories

Are very simple systems to use with the easiest to assemble vessels on the market

Include an optional IQ/OQ/PQ

Include developed SOPs for maintenance and software

The Discover SP-D and MARS 6 with EasyPrep vessels both:

USP Method 233 proposed accuracy is 70 – 150% and proposed precision is less than 20% for each element.

The Big Four elements of As, Cd, Pb, and Hg had passing accuracy and precision with the Discover SP-D and MARS 6 with EasyPrep vessels for the pharmaceutical finished products and ingredients

The volatile Big Four elements, arsenic and mercury, recoveries and RSD were:

Discover SP-D recoveries were 72 – 102% with RSD less than 7.5%

EasyPrep vessel recoveries were 81 – 108% with RSD less than 12.2%

The non-volatile Big Four elements, cadmium and lead, recoveries and RSD were:

Discover SP-D recoveries were 79 – 100% with RSD less than 6.8%

EasyPrep vessel recoveries were 84 – 106% with RSD less than 6.5%

The Metal Catalyst elements of Cr, Mn, Ni, Pd, Rh, and V had passing accuracy and precision with the Discover SP-D and MARS 6 with EasyPrep vessels for the pharmaceutical finished products and ingredients.

The Metal Catalyst elements recoveries and RSD were:

Discover SP-D recoveries were 75 – 109% with RSD less than 7.1%

EasyPrep vessel recoveries were 81 – 119% with RSD less than 16.7%

The Discover SP-D system allows for the processing of up to 48 different sample types sequentially when equipped with an optional Explorer automation deck. The system features a simple, two-part vessel with snap-on caps. Each sample can be processed using a pre-programmed application specific for that sample, including programmed temperature and pressure controlled parameters. Once started, the operation of the system requires no operator attention. Samples are processed at a rate of 5/hour, or 40 per day. Because the system operates unattended, it can be run overnight. The system is compatible with hydrofluoric acid.

EasyPrep Spike Recovery Results of 125 ppb Metal ImpuritiesAs Cd Pb Hg Cr Mn Ni Pd Rh V

Acetylsalicylic AcidTabletAverage 135.5 115.0 121.3 112.5 121.2 124.0 123.2 95.2 148.2 124.2% Recovery 108 92 97 90 97 99 99 76 119 99RSD 6.84 4.72 6.44 4.99 6.22 4.47 12.57 16.62 6.92 5.36

LoratadinePseudoephedrine TabletAverage 101.0 109.5 132.2 109.5 116.7 117.7 112.8 106.7 144.7 117.8% Recovery 81 88 106 88 93 94 90 85 116 94RSD 4.94 0.79 4.69 0.92 2.75 1.82 5.84 5.12 6.85 1.31

Folic AcidAverage 128.0 117.5 128.2 113.5 124.3 123.5 117.3 103.3 101.5 123.2% Recovery 102 94 103 91 99 99 94 83 81 99RSD 12.18 1.98 5.08 1.74 2.56 2.33 2.65 4.30 13.52 2.05

Zinc SulfateAverage 115.7 113.2 105.0 110.2 135.8 124.5 118.2 106.0 140.3 122.8% Recovery 93 91 84 88 109 100 95 85 112 98RSD 8.13 4.63 5.23 0.92 14.29 5.77 10.27 4.03 8.77 4.58

Note: Average is from 3 independent digestion and ICP-OES analyses.

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

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

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

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

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

Note: Average is from 3 independent digestion and ICP-OES analyses.

Abstract Discussion

Conclusions

Instrumentation

Analytical Procedure

Sample Preparation

A 0.50 gram sample was weighed and 5 mL of concentrated nitric acid and 5 mL DI water was added to a CEM EasyPrep vessel. The tablets and ingredients were prepared in a single run. The MARS 6system for each run was ramped to 200 °C in 25 minutes and

held for 15 minutes. Vessels were allowed to cool for 15 minutes prior to uncapping and dilution. All

samples and blanks were diluted to 25 mL for