Jason D. Keith

Pharmaceutical samples spiked with several heavy metals were prepared for ICP-MS analysis using microwave digestion following the protocols in proposed USP chapters <232> and <233>. The results of the spike recovery study are discussed.

The current United States Pharmacopeia (USP) chapter <231> Heavy Metals will be replaced in 2014 by USP chapter <232> Elemental Impurities – Limits and USP chapter <233> Elemental Impurities – Procedures. These new methods will provide a more accurate analysis by identifying specific elements of interest and will enable the detection of additional elements, such as chromium and catalyst metals, which may be introduced during the manufacturing process. Additionally, the new methods require closed vessel microwave digestion for samples that cannot be successfully dissolved in an aqueous solution or an organic solvent, preventing the loss of volatile analytes from the open flask heating technique used in Method <231>. The digested materials can then be analyzed by ICP-OES or ICP-MS, depending upon the detection limits required. 

CEM's MARS 6 and Discover SP-D microwave sample preparation systems were used to prepare several finished pharmaceutical products. The MARS system has the ability to prepare up to 40 samples simultaneously, while the Discover SP-D with an autosampler can prepare a sample every 10 min completely unattended. The accuracy and precision of the spiked recovery results for each system are discussed.

In our study, pharmaceutical finished products including a tablet with the active ingredient acetylsalicylic acid, a tablet with the active ingredient loratadine, and liquid gel capsule with the active ingredient diphenhydramine HCl were digested and analyzed with an ICP-MS. A tablet or liquid gel capsule was added to a MARS EasyPrep Plus vessel or a Discover SP-D 35-mL vessel along with 9 mL of concentrated nitric acid and 1 mL of spiked DI water containing 50 ppb of arsenic, mercury, and cadmium. The liquid gel capsule also required hydrogen peroxide in order to fully oxidize the sample – 1 mL in the EasyPrep Plus vessel and 0.5 mL in the 35-mL vessel. Each of the samples and blanks was prepared in triplicate using the digestion parameters shown in Table I. 	

Table I:  Digestion parameters for MARS 6 and Discover SP-D			

The digested samples were then diluted with DI water to a volume of 50 mL and analyzed with an ICP-MS. 

The accuracy of proposed USP Method <233> is 70–150% with a relative standard deviation of not more than 20%. The results of the digestions performed with the MARS 6 and Discover SP-D are shown in Table II. The volatile elements, arsenic and mercury, achieved percent recoveries of 101–136% and an RSD of less than 15.1%. The non-volatile element, cadmium, showed percent recoveries from 94–111% and an RSD of less than 9.1%. The percent recovery and RSD for each element is within the proposed requirements of USP Method <233>. 

Table II: Recovery results of 50 ppb spike of As, Hg, Cd in finished pharmaceutical products			

The CEM MARS 6 and the Discover SP-D provide a fast, accurate means to prepare pharmaceutical ingredients and finished products to meet the requirements of the upcoming USP Method <233>.

Articles

Microwave Digestion of Pharmaceutical Samples for USP Method

Current USP Method 231 "Heavy Metals" was introduced in 1905 for determining heavy metal impurities in pharmaceutical drug products. The procedures of the method have several limitations, which produce results that are nondiscriminatory, difficult to reproduce, and qualitative, or at best, semi-quantitative. For these reasons, the United States Pharmacopeia will be replacing USP Method 231 with USP Method 232 "Elemental Impurities Limits" and USP Method 233 "Elemental Impurities Procedures" in September 2013. USP Method 233 requires the use of current analytical instrumentation including a closed vessel microwave digestion system for sample preparation and an ICP-OES or ICP-MS for analysis. The CEM MARS™ 6 microwave digestion system with EasyPrep

  vessels was used to prepare samples for analysis by ICP-OES. The results were compared to allowable limits stated in USP Method 232.  

 Figure 1: Running at full vessel turntable capacity, the MARS 6 completely digested acetylsalicyclic acid samples (shown above) compared to the partial digestion accomplished in a traditional microwave laboratory digestion system operating under the same parameters.			

Two pharmaceutical samples were prepared, digested, and analyzed with an ICP-OES. A finished product, acetylsalicylic acid tablets, was ground into a powder prior to use and an ingredient, folic acid, was used without preparation. A 0.50 g sample, 5 mL of concentrated nitric acid, and 5 mL of spiked DI water containing 125 ppb of arsenic, cadmium, lead, and mercury were added to an EasyPrep vessel. Each of the samples and blanks were prepared in triplicate and digested in a single run in a CEM MARS 6 with EasyPrep vessels. The samples were ramped to 200 °C in 25 min and held at this temperature for 15 min. The digested samples were diluted with DI water to a volume of 25 mL. The samples and three blanks containing 20 mL of DI water and 5 mL of HNO

 with no concentration of arsenic, cadmium, lead, or mercury were analyzed with an ICP-OES.  

The average, percent recovery, and RSD for each of the samples are shown in Table I.  

Table I: MARS 6 EasyPrep spike recovery results of 125 ppb As, Cd, Pb, and Hg			

The USP Method 233 proposed accuracy is 70–150% and the proposed precision is no more than 20%. The results from the digestion and analysis of acetylsalicylic acid tablets and folic acid show that the volatile elements, arsenic and mercury, had percent recoveries from 90–108% and an RSD of less than 12.2%. The results from the digestion and analysis of the nonvolatile elements, cadmium and lead, had percent recoveries from 92–103% and an RSD of less than 6.5%. The percent recovery and RSD for each element is well within the proposed requirements of USP Method 233. 

Microwave digestion provides a fast, accurate, and reliable method for sample preparation prior to elemental analysis. The CEM MARS 6 microwave digestion system with the high-temperature, high-pressure EasyPrep vessels with proprietary vent and reseal technology provide the necessary temperatures and pressures for a complete digestion of pharmaceutical finished products and ingredients without the loss of volatile analytes because of uncontrolled venting, ensuring the accuracy and precision needed to meet the requirements of proposed USP Method 233.  

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Current USP Method 231 "Heavy Metals" was introduced in 1905 for determining heavy metal impurities in pharmaceutical drug products. The procedures of the method have several limitations, which produce results that are nondiscriminatory, difficult to reproduce, and qualitative, or at best, semi-quantitative.

Jason D. Keith

Articles

Microwave Digestion of Pharmaceutical Samples for USP Method

Microwave Digestion of Pharmaceutical Finished Products and Ingredients for Upcoming USP Method 233