Sample Preparation for Quantitative Metal Impurity Testing - Pharmaceutical Technology

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Sample Preparation for Quantitative Metal Impurity Testing
The author examines sample-preparations methods used in inductively coupled plasma–optimal emission spectroscopy for four test metals.


Pharmaceutical Technology
Volume 35, pp. s31-s33

When analyzing for trace metals using inductively coupled plasma (ICP), sample preparation is crucial. For sample preparation in general, a key question is what is the best method to get the test article in solution. The ideal situation would be to dilute the test article in water or dilute acid. The time and effort are minimized, thereby allowing for quicker result generation. Using this simplistic approach, however, may not be appropriate for most test materials when using ICP methods.

Sample preparation methods


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The United States Pharmacopeia (USP) proposed General Chapter <233> Elemental Impurities—Procedures suggests four sample-preparation methods (1). These solutions may be analyzed using an inductively coupled plasma–optical emission spectrometer (ICP–OES) or an inductively coupled plasma–mass spectrometer (ICP–MS). Liquid samples may be analyzed neat, and solid or liquid samples may be analyzed in aqueous or organic solutions or digested in a closed-vessel apparatus. It is important to ensure the blank and standard solutions are prepared in the same matrix as the sample by using the same solvent, acid concentration, and stabilizers.

Neat . A few test articles can be analyzed without dilution or digestion. This technique is appropriate when the sample is not too viscous for aspiration into the ICP–OES or ICP-MS. An example would be water.

Direct aqueous solution . Test articles that are water-soluble can be prepared in a dilute acid and analyzed directly. It is important to ensure complete dissolution of the test article and that no precipitate or turbidity is present.

Direct organic solution . Test articles that are not water-soluble may be prepared in an organic solvent. To run organic solutions on the ICP–OES or ICP-MS, a cooled spray chamber, as well as a special torch, may be required. A separate oxygen hookup may be needed as well. The ICP parameters need to be optimized to run organic solutions and may differ significantly from parameters used for analyzing aqueous solutions.

Indirect solution . Test articles requiring concentrated acid for dissolution can be prepared using a closed-vessel microwave apparatus. This method minimizes the loss of volatiles but may require multiple microwave cycles and acid additions to complete the digestion. The analyst must consider the test articles being digested when using the microwave digestion vessels. The vessels are expensive, and contamination of the Teflon sleeves can occur from the test article. Additional precautions are needed when using hydrofluoric acid. In addition to the safety concerns of working with the acid, special microwave digestion vessels, a special ICP nebulizer, and torch are required when using hydrofluoric acid.

Other sample-preparation methods may be used that are not outlined in the USP proposed method. A few examples include refluxing with dilute acid and performing acid digestion according to EPA method 3050B (2).

Other considerations

Glassware used for trace-metal testing must be scrupulously clean before use. To prepare glassware for analysis, rinse the clean glassware with a dilute acid solution that is prepared from a trace-metal-grade acid and rinse with USP purified water (3). Glassware can be used immediately if being used for direct aqueous solution preparation. Let glassware dry for all other sample preparation methods.

Standards are prepared by diluting commercially available NIST traceable standard solutions. Precautions must be taken when making mixed standard preparations to ensure all of the elements are compatible in solution and that no precipitation occurs. It is important to prepare standards and blanks in the same matrix as that of the sample to eliminate interference.

Additionally, when screening for mercury, typically a stabilizer, such as gold (III) chloride (AuCl3), is added to maintain mercury as the mercuric ion and to prevent reduction to elemental mercury.


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