Meeting the USP and Guidelines with ICP-OES

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Special Issues

Special Issues-09-01-2018, Volume 33, Issue 9
Pages: 8–15

With its advantages-compared to ICP-MS-in matrix tolerance, robustness, simplicity, and cost, ICP-OES may be the technique of choice for the analysis of medications with low daily doses. For such analyses, the use of high-pressure, high-temperature microwave digestion in sealed containers simplifies sample preparation and prevents the loss of volatile elements.

With the implementation of USP <232> and <233> for the determination of metals in pharmaceutical products, the need has arisen for analysis of a wide variety of sample types, ranging from raw materials to final medications. Depending on how the medication is administered (oral, inhalation, or parenteral) and its daily dose, the maximum permissible exposure of the various elements changes. Although inductively coupled plasma–mass spectrometry (ICP-MS) is generally thought of as the preferred analytical method because of its ability to measure extremely low levels, ICP-optical emission spectroscopy (OES) can easily meet the requirements for many medications with low daily doses. With its advantages (compared to ICP-MS) in matrix tolerance, robustness, simplicity, and cost, ICP-OES is the technique of choice for the analysis of medications with low daily doses. This article will focus on sample preparation considerations and the analysis of a variety of medications with ICP-OES to meet the USP <233> criteria.

With the implementation of USP <232> and <233> for the analysis of elemental impurities in finished drug products (1,2), it is important for manufacturers to monitor the metal content of the final products to be in compliance. The maximum permitted daily exposure (PDE) of different target elements is primarily defined in ICH Q3D <232>, and is based on the route of administration of the medications (1).

USP <233> defines the analytical requirements, which are all based on the J values for each element. The J values are a function of the PDE, the maximum daily dose of the medication, and the dilution factor used in sample preparation. The four analytical criteria specified in the quantitative procedures for USP <233> are accuracy, repeatability, ruggedness, and system suitability.

Pharmaceutical tablets are complex mixtures that can contain a wide variety of excipients. Because of the variation and complexity, closed-vessel microwave digestion is the most efficient technique to get the tablets into solution without losing volatile elements, such as mercury (Hg). However, when tablets contain silica (SiO2) and titanium dioxide (TiO2) as excipients, digestion becomes more complex as hydrofluoric acid (HF) must be used. The presence of HF also requires the use of non-glass sample introduction components, unless the HF is dealt with during the digestion process.

Inductively coupled plasma–optical emission spectroscopy (ICP-OES) can easily meet the requirements for many medications with daily doses of 1 g or less. With its advantages (compared to ICP-mass spectrometry [MS]) in matrix tolerance, robustness, simplicity, and cost, ICP-OES is the technique of choice for the analysis of medications with low daily doses.

This article focuses on sample preparation considerations, and the analysis of a variety of medications with ICP-OES to meet the USP <233> criteria.


Samples and Sample Preparation

A variety of medicines were purchased locally, as summarized in Table I. These samples represent common, over-the-counter medications that are popular among consumers, and include both tablets and nasal sprays. In addition, the acid reducers contained titanium dioxide, while the sleep aid and motion sickness medications had silica dioxide as an inactive ingredients. As a result, these medications required special treatment during sample preparation.

Because of the variety of sample types and analytes, closed-vessel microwave digestion with a Titan MPS microwave preparation system was used for sample preparation. The high temperature and pressures easily broke down the medications while using a minimum amount of acid (1.5–3 mL HNO3 + 0.5–1.5 mL HCl, depending on the analytes), while the sealed vessels facilitated the recovery of volatile elements, such as mercury and selenium. Table II shows the microwave digestion program used. For each digestion, one tablet was used. For tablets containing SiO2 and TiO2, hydrofluoric acid was required, followed by a HF-complexation step (3 mL of saturated boric acid solution), which allowed a standard glass sample introduction system to be used for all medications.


Instrumental Conditions

All analyses were performed on a PerkinElmer Avio ICP-OES system, using standard sample introduction components and plasma conditions. All measurements were made against external calibration curves prepared in a mixture of nitric and hydrochloric acids to match the acid composition of the samples after digestion. Yttrium (Y) and scandium (Sc) were added to all blanks, standards, and samples as internal standards.

Results and Discussion

Microwave Digestion

The digestion procedure was designed to minimize acid use and time. While most elements require nitric acid to be stable in solution, the platinum group elements (PGEs: Au, Ir, Pd, Pt, Rh, Ru) are only stable in hydrochloric acid. However, silver (Ag) precipitates in the presence of low HCl concentration, but remains stable at large excess HCl levels. Therefore, when measuring Group 2B elements, the challenge was to find appropriate HNO3 and HCl concentrations to maintain the stability of all elements in solution, which turned out to be 3% HNO3 + 3% HCl (v/v).

Sample preparation time was further reduced by incorporating a cooling step in the microwave program. This step allowed the vessels to be handled 15 min after the digestion was complete, as opposed to 1–2 h if the cooling step were not used.

Although a single tablet of each medication is required to meet the USP requirements, the digestion methodology was tested with multiple tablets of each medication in a single digestion vessel. It was found that the methodology could completely digest two of the SiO2- and TiO2-containing tablets (total mass = 0.86 g) and five of the allergy tablets (total mass = 0.5 g). Higher levels were not evaluated.



One of the concerns with the analysis is that some analytes can interfere with other analytes. Consequently, it is possible to obtain results that meet the criteria of USP <233> while actually measuring an interference on an analyte instead of the analyte itself. To address this situation, all analytes were run individually as single-element solutions at their 1.5J concentrations, and their spectra compared. Where interferences were observed, alternate interference-free wavelengths were chosen when available. For elements where they were not, the effects of the interferences were removed using the system's multicomponent spectral fitting (MSF) feature. Although interelement corrections (IECs) could also be used, MSF was found to be simpler to implement and more robust.

Sample Analysis

The concentrations of all elements in each tablet analyzed were less than 0.3J, signifying that these medications do not pose a health risk.

Meeting the USP <233> Criteria

USP <233> defines four validation criteria that must be met when performing an analysis: suitability, accuracy, repeatability, and ruggedness. Each medication that was analyzed was subjected to these validation criteria.

To meet the system suitability criterion, a 1.5J standard must be run at the beginning and end of each batch run, and the difference between the results must be less than 20%. Figure 1 demonstrates that each type of medication easily meets this criteria, with the largest variance being less than 6%.

Figure 1: System suitability plot showing the drift over a batch analysis from 1.5J standards measured at the beginning and end of batch analyses for allergy tablets and TiO2- and SiO2-containing medications (2).

With the suitability of the system established, the accuracy of the methodology was evaluated. The accuracy criteria requires that spikes of 0.5J, 1J, and 1.5J be added to the microwave vessels before digestion and carried through the complete sample preparation scheme to determine if analytes are lost during sample preparation. The results are shown in Figure 2, indicating that all spike recoveries are less than 10% for all elements in all medications, significantly less than the method acceptance criteria of 70–150%.


With the accuracy proven, the repeatability of the methodology was assessed. According to USP <233>, the repeatability is evaluated through the preparation and analysis of six individual samples of the same medicine spiked at the J values. The RSD of the analysis of these six samples must be less than 20%. As shown in Figure 3, the RSDs are all less than 6%, easily surpassing the USP criterion.

Figure 2: Accuracy plot showing 0.5J, 1J, and 1.5J predigestion spikes in allergy (green), TiO2-containing (blue), and SiO2-containing (pink) tablets. The black lines define the USP <233> limits.

With the repeatability of the methodology demonstrated, the ruggedness was evaluated by analyzing the tablets in Figure 3 on a second day. According to USP <233>, the RSDs of the 12 measurements over two days must be less than 25%, which is easily met, as shown in Figure 4.

Figure 3: Repeatability plot showing RSDs of six predigestion spikes of individual tablets containing TiO2 and SiO2, along with allergy tablets.


This article has demonstrated the ability of ICP-OES, in combination with closed-vessel microwave digestion, to meet the requirements of USP <232> and <233> for allergy tablets and medicines containing TiO2 or SiO2 as excipients. With the inclusion of volatile elements and difficult matrices, high-pressure, high-temperature microwave digestion in sealed containers simplifies and speeds up sample preparation while preventing the loss of volatile elements. Although ICP-MS can also be used for these analyses, ICP-OES has the advantages of lower cost, higher matrix robustness, and ease of use for medicines with a daily dose of less than 1 g per day.

Figure 4: Ruggedness plot showing RSDs of 12 measurements over 2 days of allergy medications and tablets containing TiO2 or SiO2, spiked at the J level for all analytes.


(1) General Chapter <232> Elemental Impurities – Limits: Second Supplement of USP 35-NF 30.

(2) General Chapter <233> Elemental Impurities – Procedures: Second Supplement of USP 35-NF 30.

Aaron Hineman is a Product Line Leader at PerkinElmer in Seattle, Washington. Direct correspondence to:

Ken Neubauer is a Senior Application Specialist at PerkinElmer in Shelton, Connecticut. Direct correspondence to: