Ewa Pruszkowski

This article focuses on the use of a cell-based inductively coupled plasma–mass spectrometry (ICP-MS) approach that utilizes ion–molecule chemistry to reduce many of the traditional spectral interferences seen in the analysis of high-purity hydrochloric acid used in manufacturing integrated circuits and semiconductor devices. In addition, a solid-state radio frequency (RF) generator allows the use of lower powers to reduce formation of argon-based polyatomic interferences while still maintaining strong ionization conditions. The combination of controlled gas-phase reaction chemistry with the unique RF generator results in the elimination or significant reduction of many of the problematic chloride-, water-, and argon-based polyatomic spectral interferences, allowing the determination of a suite of 43 ultratrace elements in semiconductor-grade hydrochloric acid by following the validated analytical protocols described in the Semiconductor Equipment Manufacturers International (SEMI) Tier C guidelines.

	The semiconductor industry provides one of the most demanding application areas for inductively coupled plasma–mass spectrometry (ICP-MS) with regard to the detection capability requirements. Consumer demand for smaller electronic devices and more compact integrated circuits has resulted not only in the need for lower trace metal contamination levels on the surface of silicon wafers, but also in the high-purity chemicals and gases used in various stages of the semiconductor manufacturing process. To reduce costs and increase yield, chip manufacturers are making larger diameter wafers with ever smaller chip components. This trend, which is being driven by initiatives like the International Technology Roadmap for Semiconductors (ITRS) (1), is setting the course for the next generation of semiconductor devices and has resulted in requirements for lower and lower trace-element contamination levels in all semiconductor-related materials. Whereas 20 years ago the Semiconductor Equipment Manufacturers International (SEMI) organization deemed that 10-ppb (µg/L) purity levels were adequate for many of the process chemicals, today Tier C levels of 100 ppt (ng/L) are typical-and for some of the more critical chemicals, 10-ppt (ng/L) levels are required (2).

	Tier C refers to third-generation guidelines generated by the SEMI North American Process Chemicals Committee and published in its 

) (3). The guidelines are intended to describe the quality required to produce integrated circuits whose critical dimensions lie in the range of 0.09–0.2 µm. Hydrochloric acid (HCl) is currently in the 

 at the Tier C guideline level, meaning that the maximum contaminant level of 18 elemental impurities should each be less than 100 ppt (ng/L) in the process chemical. On completion and approval of the validated analytical method described in the guideline, it will meet the SEMI Grade 4 Standard (4).

	Traditionally, ICP-MS has been the technique of choice for ultratrace-element determinations in many of the high-purity chemicals used in the semiconductor and electronics industries. However, to get to the next required purity level of 10 ppt (ng/L) and beyond, conventional ICP-MS has shown that it does not have the detection capability for the full suite of trace metals-even with the use of spectral background reduction techniques like cool or cold plasma conditions and collision-cell technology. To achieve the next required analytical levels, a cell-based ICP-MS approach capable of using pure, highly reactive gases to produce targeted, controlled reactions to eliminate argon-, matrix-, and solvent-based spectral interferences is required. When combined with optimized plasma conditions, detection limits can be dramatically lowered for many of the semiconductor elements. 

	It is well-recognized that the ability to control ion-molecule chemistry in cell-based ICP-MS is essential when using the highly reactive gases required for maximum removal of atomic and polyatomic spectral interferences to meet the SEMI Tier C levels and beyond (5,6). For example, consider the analysis of hydrochloric acid, which requires the removal of the chloride-based interferences such as oxygen-chloride (

) on arsenic at mass 75. In addition, other prominent interferences include argon-oxide (

) on iron at mass 56 and chlorine-hydroxide (

 52. Pure ammonia is the most effective gas for removing 

 while allowing for low-parts-per-trillion (nanograms-per-liter) determinations of vanadium, iron, and chromium (7), limited only by levels of contamination. Oxygen has proven most effective for the determination of arsenic in hydrochloric acid by reacting with 

 91, where it is measured interference-free, away from the 

	In addition, the use of cold plasma conditions has been very effective at reducing the number of argon ions formed in the plasma, which minimizes the formation of argon-based species such as 

 and facilitates the determination of elements like 

 (8). Even though cold plasma has been used for many years, it has several limitations, including the ability to deal with real-world matrices such as concentrated mineral acids, susceptibility to matrix suppression effects, and the inability to switch rapidly between cold and normal plasma conditions during a multielement analysis. 

	However, advances in solid-state free-running radio frequency (RF) generators have enhanced the capability of ICP-MS to analyze real-world samples using cold and normal plasma conditions (9). The combination of pure, highly reactive gases in a controlled reaction environment with cold plasma conditions provides the most efficient reduction of polyatomic interferences, allowing ultratrace levels to be accurately measured. Table I shows chloride-, water-, and argon-based spectral interferences, which can potentially interfere with a suite of analyte masses during the analysis of hydrochloric acid, together with the optimum reaction gas and plasma conditions. 

	The goal of this investigation was to meet or exceed the SEMI Tier C guideline levels for the analysis of semiconductor-grade hydrochloric acid. This guideline states that spike additions made at 50% of the proposed specification level (100 ppt in 37% HCl) must have recoveries within 75–125% of the expected value. To evaluate the long-term stability, a 10-h run was performed monitoring a solution of 20% HCl spiked with 50 ppt of all elements.

	In semiconductor plants, high-purity HCl (35–38%) is most commonly used as an etchant in the chip fabrication process. One of the main requirements is that it must contain extremely low levels of elemental impurities so the etching process does not deposit elemental contaminants on the surface of the wafer or chip. To analyze high-purity HCl by ICP-MS, it is typically diluted twofold with ultrapure deionized water before aspiration into the instrument. To eliminate potential contamination from dilution, ultrapure 20% HCl (Tamapure-AA-10, Moses Lake Industries) was used in this work and analyzed directly without dilution. Calibration standards (10, 20, and 40 ng/L) were made from 10-mg/L multielement stock solutions via serial dilution, with the final standards being prepared in 20% HCl. Spikes of 10 and 25 ppt in the 20% HCl were used to evaluate recovery. Although the 25-ppt spike meets the SEMI Tier C guidelines, the 10-ppt spike was also measured to evaluate the analytical methodology with an eye toward future SEMI requirements.

	All analyses were performed on a NexION 2000 S ICP-MS system (10) (PerkinElmer, Inc.) using the instrumental parameters shown in Table II.

	Analyses were accomplished with a combination of reaction (with NH

) and standard modes (no cell gas), using either normal plasma (1600 W) or cold plasma (600 W) conditions for the 43-analyte multielement method. To maximize the effectiveness of reaction mode, 100% ammonia and 100% oxygen were used in two different ways: Ammonia effectively removed interferences at the analytical mass, and oxygen was used to shift the analyte to a new analytical mass. The latter approach was found to be most effective for the measurement of arsenic and selenium. Table sI (

) displays the method parameters for all 43 analytes.

Interference Reduction Strategies Using Reaction Mode

	It is important to emphasize that the effects of interferences were removed in reaction mode in two different ways:

		removing the interference at the analytical mass, and 

		shifting the analyte to a new mass away from the interference. 

	An example of removing the interference at the analytical mass is the removal of the 

 at mass 51. Although ammonia reacts rapidly with 

 to remove it, the reaction is driven to completion by using 100% ammonia in the cell. In addition, because the reaction cell incorporates a quadrupole, the RF-only parameter (RPq) acts as a low mass filter to control the chemistry and prevent the formation of new interferences, which is critical when using highly reactive gases. This is particularly important in removing the 

 interference since one of the intermediate products is 

 at mass 51. However, because the RPq parameter serves as a low mass filter, it can be set to make 

 unstable in the cell, which prevents the formation of 

	This functionality is demonstrated in Figure 1, which shows the optimization of the RPq parameter for 1 μg/L V in 10% HCl. As the RPq parameter increases to 0.7, the background decreases sharply, which represents where 

Cl+ is no longer stable in the cell (blue plot). As a result, 

 is ejected from the cell, meaning that the reaction to 

can no longer occur, resulting in interference-free analysis of V

	The second method of dealing with interferences is using reaction chemistry in mass-shift mode where the analyte reacts with the reaction gas moving it to a new analytical mass. An example of this approach is the analysis of arsenic (As), which reacts rapidly with oxygen to form 

 is measured free of interferences. Figure 2 shows the conversion of 

 decreases (blue plot), while the signal for 

 increases (red plot), demonstrating complete conversion. 

 at mass 91 is that the presence of zirconium (

) in a sample may produce a false positive reading. However, because 

 reacts rapidly with oxygen (rate constant ≈ 10

 forms, allowing for interference-free measurement of 

 even if Zr is present at the same concentration as As, as shown in Figure 3. In this figure, mass 91 is monitored as a function of oxygen flow for a 1-μg/L Zr standard (blue) and a mixed standard containing 1 μg/L Zr + 1 μg/L As.

	To assess the effectiveness of interference removal, method detection limits (MDLs) and background equivalent concentrations (BECs) were determined in 20% HCl using a 1-s integration time. The MDLs (analyte signal and background noise) were calculated by multiplying the standard deviation of the blank (10 analyses) by three, and the BECs (analyte signal and background signal) were determined by measuring the background concentrations of the blank at each analyte mass. A spike recovery test was carried out based on SEMI Tier C guidelines, but using a lower spike level of 10 ppt (ng/L), Table sII (

) shows both the MDLs and BECs for all elements, as well as the 10-ppt (ng/L) spike recoveries. The majority of MDLs and BECs are less than 1 ng/L, demonstrating the effectiveness of using both controlled reaction chemistry and cold plasma conditions. All spike recoveries fall within 10% of the true values, showing the accuracy of low-level measurements.

	Calibration curves were established with 10-, 20-, and 40-ng/L (ppt) standards using the method of standard additions. All curves had regression values of >0.999, demonstrating both the linearity of the analysis and the ability to accurately measure at low concentrations. Figure s1 (

) shows three calibration curves, which highlight the effectiveness of the interference reduction: calibration curves for 

 were acquired using ammonia as the reaction gas and cold plasma conditions, demonstrating the ability to remove significant plasma-based interferences (

 was acquired with ammonia and normal plasma conditions, exemplifying how effectively a significant chloride interference (

) can be removed. The accuracy of low-level measurements was then verified by measuring the recoveries of 10-ng/L (ppt) spiked additions in 20% HCl, which are all within 10% of the true value.

	With the ability to remove interferences and quantitative accuracy established, the stability of the methodology was evaluated by measuring a 50-ng/L (ppt) spike in 20% HCl over 10 h of continuous aspiration. The results shown in Figure 4 demonstrate the stability for all 43 elements when using a mixed-mode method consisting of standard (no cell gas) and reaction (NH

) modes with both normal and cold plasma conditions. These data show that for every element the drift of the signal is less than 10% from the initial reading, while the RSDs over the 10 h are less than 3% for all elements.

	Tables sI and sII as well as Figure s1 are available online in a supplementary information section. Please visit 

www.spectroscopyonline.com/supplementary-information-optimized-icp-ms-analysis-elemental-impurities-semiconductor-grade-hydroch

	This study has demonstrated the ability of the methodology used in this investigation to perform the elemental analysis of 20% HCl at SEMI Tier C guideline levels and beyond, without the need for dilution. The combination of fast switching between hot and cold plasma together with reaction cell technology using 100% ammonia and oxygen led to the elimination of spectral interferences on many of these elements. This capability allows for sub-part-per-trillion detection limits, excellent spike recoveries and accurate quantitation at the 100-ppt Tier C guideline level while offering the kind of long-term stability required by a high-throughput semiconductor production laboratory. In addition, the data show that quantitation at the SEMI Tier D guideline level (proposed Grade 5) of 10 ppt can be achieved.

		International Technology Roadmap for Semiconductors (ITRS 2.0), Semiconductor Industry Association (2015), 

http://www.semiconductors.org/main/2015_international_technology_roadmap_for_semiconductors_itrs/

		Semiconductor Equipment and Materials International (SEMI) (Organization, Milpitas, California, 

SEMI Book of Standards (BOSS): Process Chemica

http://ams.semi.org/ebusiness/standards/semistandard.aspx?volumeid=13)

		SEMI C27-0708 - Specifications and Guidelines for Hydrochloric Acid, 

http://ams.semi.org/ebusiness/standards/SEMIStandardDetail.aspx?ProductID=211&DownloadID=30

		T.S. Cheung, C. Wong, and H.R. Badiei, Technical Note, PerkinElmer Inc., Woodbridge, Ontario, Canada.

		NexION 2000 ICP-MS System: Product Description, 

http://www.perkinelmer.com/lab-solutions/resources/docs/BRO-NexION-2000-ICP-MS-012730_01.pdf

 are with PerkinElmer, Inc., in Shelton, Connecticut. Direct correspondence to: 

Articles

A closer look at the use of a cell-based ICP-MS approach that utilizes ion–molecule chemistry to reduce many of the traditional spectral interferences seen in the analysis of high-purity hydrochloric acid used in manufacturing integrated circuits and semiconductor devices

Optimized ICP-MS Analysis of Elemental Impurities in Semiconductor-Grade Hydrochloric Acid

This study focuses on an inductively coupled plasma–mass spectrometry (ICP-MS) sample preparation procedure and analytical methodology optimized for both toxic and nutritional elements in dried hops, a surrogate for the cannabis family of flowering plants. It shows that the wide dynamic range of the technique allows it to be used for the simultaneous determination of parts-per-billion levels of heavy metals including Pb, As, Cd, and Hg, together with high parts-per-million levels of nutritional elements, such as P, Ca, K, and Mg.

	More than half of the states in the United States now allow for some form of legal use of cannabis in its various forms, including marijuana products and hemp. Its use as a medicine has been allowed in Colorado, Washington, California, Maine, Massachusetts, and Nevada for a number of years, and even traditionally conservative states like Arkansas, Florida, Montana, and North Dakota have recently enacted policy, enabling it be used for medical purposes. As a result of the widespread use of cannabis, there is not only a growing need for high-quality analytical testing of its potency, but also to assess its purity and level of contaminants (1).

	One of the main areas of concern is the level of heavy metals and other elemental impurities in the cannabis plant. Metals such as arsenic, lead, cadmium, mercury, nickel, copper chromium, and aluminum can all be present in the cannabis plant because of uptake from the soil, from the use of fertilizers or hydroponic media used to enhance the growth of the plant, or possibly due to environmental pollution from industrial fallout. In addition, cannabis plants are also very efficient at extracting and accumulating metals from their environment and as a result have historically been used to clean up contaminants from toxic waste sites (2).

	Cannabis growers with laboratory capabilities, who are authorized to analyze cannabinoids, can easily gain access to samples for testing purposes. However, other researchers who want to carry out scientific studies on the level of contaminants in cannabis cannot legally obtain these types of samples. Fortunately, cannabis, and humulus (hops used to make beer) belong to the same small family of flowering plants called 

. For that reason, hops are a generally accepted surrogate for cannabis because of its similar chemical and physical properties (3).

	Therefore, this study focuses on a sample preparation procedure and analytical methodology optimized for both toxic elements at low parts-per-billion (ppb) levels and high concentrations of macro elements at parts-per-million (ppm) levels in dried hop samples by inductively coupled plasma–mass spectrometry (ICP-MS).

	The working range of ICP-MS makes it ideally suited for the analysis of plant materials. The ultratrace detection limits of ICP-MS permit the determination of low-level contaminants such as Pb, As, Se, and Hg, while the macro-level nutritional elements such as Ca, Mg, K, and Na can be quantified using the extended dynamic range capability of the technique, which provides up to 10–11 orders of magnitude. However, there are still a number of challenges to overcome, which makes the routine analysis of plant matrices difficult unless the sample dissolution procedure is well thought out and instrumental conditions are optimized for complex sample matrices. For example, plant matrices contain high levels of organic components which when digested can pose major problems for any ICP-MS because of the potential for blocking of the interface cones or deposition on the ion optics. For this reason, if the instrument design is not optimized for high-matrix samples, long-term stability can be severely compromised.

	In addition to signal drift, the sample’s organic components, together with macro minerals, can combine with elements present in the digestion acid or the plasma argon to form polyatomic interferences. For example, chloride ions (at mass 35) combine with the major argon isotope (mass 40) to produce the argon chloride interference 

, which interferes with arsenic at mass 75. Another example is the argon dimer (

), which forms from the plasma gas and exists at the same masses as the major selenium isotopes. In addition, the major isotope of chromium at mass 52 is overlapped by 

 interferences generated by the sample matrix and the plasma gas. As a result, these kinds of spectral interferences have made the determination of both trace and macro elements in plant digest samples extremely challenging, unless the system is fitted with collision-reaction cell capability, which can reduce the impact of these interferences.

	Hops were purchased from a commercial store and chopped into small pieces, both to homogenize the sample and expose more surface area for increased digestion efficiency. A microwave sample preparation system (Titan MPS, PerkinElmer Inc.) using standard 75 mL polytetrafluoroethylene (PTFE) vessels was used for digestion, following the program shown in Table I.

	Each vessel contained 0.25 g of plant material, 5.0 mL of concentrated nitric acid, 5.0 mL water, and 3.0 mL of 30% hydrogen peroxide. After digestion, the samples were diluted to 50 mL with deionized water, along with the addition of gold (Au) equivalent to 200 μg/L Au in the final solution, to stabilize the mercury.

	All analyses were performed on a NexION 300/350 ICP-MS system (Perkin-Elmer Inc.) with the standard sample introduction system of a concentric nebulizer and a cyclonic spray chamber. The full instrumental operating conditions for this investigation are shown in Table II.

	The elements chosen for the investigation, analytical masses, and universal cell conditions used are shown in Table II. It should be emphasized that the benefits of collision–reaction cell technology are well documented (4). However, the capability to switch between collision, reaction, and standard modes is critically important for a large suite of elements, particularly when spectral complexity varies based on the analyte mass used and different combinations of matrix, solvent, and argon ions encountered. For this suite of 30 elements, the method development process identified a group that required collision mode (kinetic energy discrimination [KED] mode using helium gas) and a group that required standard mode conditions. Table III identifies the analyte masses, together with the choice of collision-reaction cell modes used.

	Multielement calibration standards, representing all of the analytes of interest, were made up from PerkinElmer Pure single and multielement standards and diluted into 10% HNO

. As with the samples, gold was added to all solutions at a final concentration of 200 μg/L to stabilize mercury. Calibration standard ranges were based on whether the analyte was expected to be a high-level, nutritional element like potassium (K), a low-level essential element like iron (Fe), or an ultratrace contaminant such as arsenic (As). As a result, three different calibration ranges were made up to cover the complete suite of elements being determined:

		High-level nutritional analytes: 0–300 ppm

		Low-level essential analytes: 0–2 ppm

		Ultratrace-level contaminants: 0–20 ppb

	It should also be noted that these are concentrations introduced into the instrument, but represented a 200-fold dilution based on the sample preparation procedure of 0.25 g in 50 mL. Additionally, the following internal standards were used to cover the full suite of analyte masses: 10 mg/L 

Tb in 10% methanol and 1% nitric acid, which were added on-line via a mixing tee to all blanks, standards, and samples.

	In a separate study, to show how the potential problem areas previously outlined could be minimized, six National Institute of Standards and Technology (NIST) food or plant-based standard reference materials (SRMs) (corn bran, bovine muscle, mussel tissue, milk powder, wheat flour, and spinach leaves) were analyzed using similar sample preparation and analytical conditions to assess the accuracy of this methodology (5). These data are exemplified in Table IV, which shows the determination of a large suite of elements in one of the certified reference materials (CRMs), “NIST 1570a Spinach Leaves.” The experimental data show very good agreement with the certified values, especially for the elements that suffer from known spectral interferences. The elements that are outside the specified limits are mostly the ones that are well recognized as environmental contami-nants, which were most likely impacted by the sample preparation procedure. Note: The figures in parentheses in the reference value column are not certified values, but are included for information purposes only.

	To emphasize the long-term drift capability of the instrument, the six NIST SRM samples were run for 6 h continuously, while a quality control (QC) standard was read every five samples. Figure 1 shows the long-term stability of a selected group of high-level, low-level, and ultratrace-level analytes in the QC standard. On further examination, the data shows recoveries of 91–103% over the 6 h.

	Once the method had been validated with the NIST SRMs, the analysis of two separate digestions of the hop samples were carried out. The average results are shown in Table V. In addition, to evaluate the accuracy, predigestion samples were spiked for those elements present at less than 50 mg/kg. The spike levels were 20 mg/L for all elements, except Hg, which was spiked at 2 mg/L. All spike recoveries were within 15% of the added amounts, further validating the methodology.

	This work has demonstrated the ability of ICP-MS, combined with microwave sample digestion to effectively analyze hop samples (as a surrogate for cannabis) for both nutritional elements at high milligram-per-kilogram (ppm) levels and trace elemental contaminants at microgram-per-kilogram (ppb) levels in the original matrix, without having to carry out further sample dilutions. Analyses were optimized using a combination of collision cell and standard modes, which required only 100 s per sample total analysis time. The drift characteristics of the applied method was further assessed by running QC check standards and plant or food-based materials over 6 h. The accuracy was validated by analyzing a NIST spinach leaf CRM. 

http://cen.acs.org/cannabis-analysis-takes-off.html

		“Heavy Metals and Cannabis: What You Don’t See Can Hurt You,” United Patients Group, April 6, 2015, 

https://unitedpatientsgroup.com/blog/2015/04/06/heavy-metals-and-cannabis-what-you-dont-see-can-hurt-you

		C. Borbone, J. Yu, and N. Zabe, “Cannabis, Hemp, and Hops: Sample Comparative Results with Qualitative Strip Test Analysis for the Determination of Total Aflatoxin,” presented at the Cannabis Extraction and Analytics Poster Session at the 107th AOCS Annual Meeting & Expo, Salt Lake City, Utah, 2016.

		C. Bosnak and E. Pruszkowski, “The Determination of Toxic, Essential, and Nutritional Elements in Food Matrices Using ICP-MS,” PerkinElmer Application Note, 2015, 

https://www.perkinelmer.com/pdfs/downloads/APP_FoodAnalysisbyNexIONICPMS.pdf

 are with PerkinElmer Inc., in Shelton, Connecticut. Direct correspondence to: 

The wide dynamic range of ICP-MS allows it to be used for the simultaneous determination of parts-per-billion levels of heavy metals including lead, arsenic, cadmium, and mercury, together with high parts-per-million levels of nutritional elements, such as phosphorus, calcium, potassium, and magnesium.

The Benefits of ICP-MS for the Determination of Toxic and Nutritional Elements in the Cannabis Family of Flowering Plants

This article describes the use of an in-line, autodilution, and autocalibration sample delivery system coupled to an inductively coupled plasma–mass spectrometry system to analyze a group of over-the-counter pharmaceutical products. The study will follow the method protocol outlined in the recently approved 

 Chapters <232> and <233> on the determination of elemental impurities in the major four drug delivery systems.

The standard method for measuring elemental impurities in pharmaceutical products has been based on a 100-year-old "Heavy Metals Test," described in Chapter <231> of the 

) (1). This test involves precipitation of the metal sulfide in the sample, and compares the intensity and color of the precipitate to a lead standard. Even though this test has been used for more than 100 years, it is well-accepted that it is prone to error because it is not specific to any particular heavy metal, it suffers from quite severe matrix interferences, it is prone to very low recoveries, and it requires a skilled analyst to interpret the color correctly. For this reason, four years ago the USP organization set up an expert committee to investigate the viability of alternative analytical approaches to get around all these problems and replace Chapter <231> with a more robust and reliable instrumental technique.  

In April 2012, USP came out with a brand new inductively coupled plasma–optical emission spectrometry (ICP-OES) and inductively coupled plasma–mass spectrometry (ICP-MS) method to determine a group of metallic contaminants in pharmaceutical products. This method was summarized in General Chapter <232> entitled "Elemental Impurities – Limits" and Chapter <233> entitled "Elemental Impurities – Analytical Procedures,", which will be published in the 

 on December 1, 2012 (2). Pharmaceutical stakeholders will then have until May 2014 to implement these changes and be consistent with the new method described in Chapters <232> and <233>. 

This study focuses on the practical benefits of an ICP-MS system coupled to an in-line, autodilution, and autocalibration sample delivery system to determine a group of toxicologically relevant elements in various pharmaceutical products. It provides an overview of the 

 methodology with particular emphasis on the impurity levels and the recommended analytical procedure. It also analyzes some common pharmaceutical products covering the major drug delivery systems of oral, intravenous, and inhalational, and presents performance figures of merit for the system based on the 

Elemental Impurities in Pharmaceutical Products

Chapter <232> specifies the list of elements and their toxicity limits, defined as maximum daily doses of the different drug categories — oral, parenteral (intravenous injection), inhalation, and large-volume parenteral, whereas Chapter <233> deals with the sample preparation, analytical procedure, and quality control (QC) validation protocol for measuring the elements, including the choice of either inductively coupled plasma–atomic emission spectroscopy (ICP-AES), ICP-MS, or the use of an alternative technique as long as it is fully validated to be acceptable and equivalent to the plasma-based procedures described in the method.  

Chapter <232> Elemental Impurities — Limits

Table I shows the maximum permissible daily exposure (PDE) values (in micrograms per day) for the administration of drug products based on an "average" 50-kg person (3). The toxicity of an elemental impurity is related to its bioavailability. The extent of "chronic" exposure has been determined for each of the elemental impurities of interest for three routes of administration: oral, intravenous (parenteral), and inhalational. When the daily dose of an injection is >100 mL, the amount of element must be controlled through the individual components used to produce the drug product. This is known as the large-volume parenteral (LVP) component limit (in micrograms per gram) and is shown in the last column of Table I.  

Table I: Maximum permissible daily exposure (PDE) values (in Î¼g/day) for the administration of drug products based on an "average" 50-kg person 

This chapter also defines the maximum limit of the elemental impurities based on the material's final use and dosage. This is to ensure the drug manufacturers determine an acceptable level of impurity in the drug based on a typical maximum daily dosage of ≤10 g/day. These values are also used to take into account the sum of all the individual chemicals, active ingredients, and excipient compounds (fillers) used to produce the final drug product, which is intended to be the basis of discussions between the drug manufacturer and the suppliers of the raw materials.  

Chapter <233> Elemental Impurities — Analytical Procedure

This chapter describes the ICP-OES and ICP-MS analytical procedures (including sample preparation), together with the validation protocol for the determination of the elemental impurities in the drug products described earlier (4,5). 

To ensure the method is working correctly, a summary of the QC/QA validation protocols is given below. 

Target (element) limits (known as "J" values) defined as the acceptance value for the elemental impurity being evaluated, based on the weight, number of doses, and frequency of taking or administering the drug.

Calibration using two matrix-matched calibration standards and a matrix-matched blank. For each element, the high standard is twice (2J) the target limit and the low standard is half (0.5J) the target limit.

Samples are diluted so the concentration does not exceed 2× (2J) the target limits.

Samples are analyzed according to the manufacturer's suggestions for instrumental conditions and analyte masses, taking appropriate measures to correct for matrix-induced polyatomic interferences. 

A collision–reaction cell may be used to reduce the polyatomic spectral interferences.

A series of QC validation protocols, including spike recovery, accuracy, precision, and stability tests are followed to ensure the method is generating credible data. 

Sample preparation can be approached in four different ways. However, careful consideration should be given to the choice of acids because of the potential for matrix-induced spectral interferences generated in the ICP. 

Analyze neat, undiluted sample, if the sample is in suitable liquid form.

Dilute the sample in an acidified aqueous solution if the sample is soluble in water.

If the sample is not soluble in water, dilute it in an appropriate organic solvent. 

Use closed-vessel microwave acid digestion for insoluble samples. 

This study was performed using a NexION 300X ICP–MS system (PerkinElmer, Inc.) coupled with a prepFAST (Elemental Scientific Inc.) automated in-line autodilution and autocalibration system. The ICP-MS system has been described in the literature but is basically a single-channel version of PerkinElmer's Universal Cell Technology, which enables the instrument to be used in either the collision (KED) mode or the reaction (DRC) mode using one cell gas, in addition to the standard or normal ICP-MS mode (6).  

Figure 1: Schematic of the sample delivery system (prepFAST) illustrating a two-step process of loading sample into a loop and in-line dilution. During syringe reset in step 1, the loop is rapidly (vacuum) rinsed and loaded with the sample while the nebulizer and spray chamber are rinsed with carrier. In step 2, the sample is injected into the ICP-MS system along a flow path where in-valve addition and mixing of diluent (port 3) and internal standard (port 7) occurs.  

The autodilution system is fully integrated with the ICP-MS system for in-line autodilution of sample and stock standard solutions (7). Solutions are rapidly and reproducibly vacuum loaded from each autosampler location into a sample loop. This process is shown in Figure 1. Dilution, internal standard addition, and mixing all occur in line in the mixing valve. The system's high-resolution syringe-based delivery of all solution flow rates ensures precise and accurate dilution factors while maintaining a constant total sample flow rate. The system is used to autocalibrate the ICP-MS system and perform in-line dilutions of samples. Some of the benefits of this approach for the demands of a high-throughput pharmaceutical laboratory include  

Elimination of the errors associated with manual dilution steps

Reduction of reagent volumes required for high dilution factors

The samples investigated are shown in Table II, representing the three different categories of pharmaceutical products described earlier (oral, inhalation, and large volume parenteral).  

Table II: List of medications evaluated in this study 

For all medications, 1 g of sample was taken and brought into solution with an acid mixture of 2% HNO

 and 0.5% HCl. The arthritis pain medication was crushed into a powder and digested in a Multiwave 3000 microwave digestion system (PerkinElmer, Inc.) and made up to a final volume of 50 mL. The OTC cold and flu remedy was dissolved in the acid mixture, warmed on a hot plate, and made up to 50 mL. Both the allergy medication and the lactated Ringer's solution were already in liquid form, so they were prepared by diluting 1 g to a final volume of 50 mL. The oral medications were further diluted 10-fold in-line, using the autodilution system, to a final dilution factor of 500:1. It's worth emphasizing that if many different medications are being analyzed with large variations in daily dosage, the target values (J) change, requiring additional sample dilution or a new calibration graph. One of the major benefits of the in-line autodilution approach is that it can be done in a fully automated manner, without the need to make additional manual dilutions.  

Table III: ICP-MS instrumental conditions for the analysis of pharmaceutical compounds using USP methodology 

Depending on the target values (J) for the analyte of interest and the sample preparation technique used for the different drug compounds, 

defined calibration solutions at half (0.5J) and twice (2J) the target values are required. Table V (on-line) shows the PDE values (in micrograms per day) for the oral drugs and target concentration values (in micrograms per liter) calculated based on a daily dose of 10 g/day and a final sample dilution of 500:1 (10-fold in-line dilution of 1 g/50 mL). It can be seen that correlation coefficients for all calibration curves generated by in-line dilution (2% HNO

 and 0.5% HCl) of a single stock standard are 0.999 or better. 

Chapter <233> also defines a number of QC–QA protocols to validate the method, which include the following tests:  

Accuracy of the method by spiking the material under investigation at appropriate concentration levels related to the target limits and measuring the % recovery. 

Repeatability of the method by measuring six independent samples of the material under investigation, spiked at the target limits defined and measuring the recovery and precision of the measurements.

This article describes the use of an in-line, autodilution, and autocalibration sample delivery system coupled to an inductively coupled plasma–mass spectrometry system to analyze a group of over-the-counter pharmaceutical products.

ICP-MS with Autodilution and Autocalibration for Implementing the New USP Chapters on Elemental Impurities

Elemental analysis of food substances presents a challenge because of the wide variety of food types and range of concentrations that need to be analyzed. The complexity of food matrices requires digestion to both break down the matrix and to convert solids into liquids for analysis. ICP-MS has the ability to measure both trace and elevated analyte levels during the same analysis, while the use of cell-based ICP-MS systems can remove the effects of interferences, allowing lower levels to be determined. This article discusses the analysis of a variety of food matrices with a single digestion procedure and instrumental method. 

Food safety is an area of growing concern as a result of pollution, which can enter the food supply and be passed along to consumers, leading to health problems. Therefore, it is important that all food types are monitored for contaminants and toxic elements. It is also equally important to monitor levels of nutritionally significant elements, which are present at elevated levels. Much work has been done on the analysis of food substances with inductively coupled plasma–mass spectrometry (ICP-MS) (1–9). 

To establish analytical conditions for the determination of metals in a variety of food types, several food standard reference materials have been analyzed for both elevated and trace elemental content using ICP-MS. Emphasis was placed on finding a single set of sample preparation and analytical conditions that would be applicable to a number of different food matrices.  

Table I: Standard reference materials analyzed 

The samples analyzed in this study were all standard reference materials from NIST (Gaithersburg, Maryland) and represent a variety of food types. Table I shows the materials analyzed. Approximately 0.5 g of sample was digested in triplicate (along with a blank) with 4 mL of Optima-grade HNO

 (Fisher Scientific, Pittsburgh, Pennsylvania) and 2 mL of Optima-grade H

 (Fisher Scientific) in a Multiwave 3000 microwave digestion system (Anton Paar, Graz, Austria). Precleaned HF-100 vessels were used in a 16-position rotor. A pressure–temperature sensor was used to monitor the pressure and temperature of the sample in position 1 of the rotor. The external infrared sensor provided the temperatures for each individual sample in the rotor. The digestion program consisted of 30 min of heating and 15 min of cooling, as shown in Table II. The samples were dissolved completely, resulting in clear solutions that were diluted with 1% HNO

Mixed element calibration standards of appropriate concentrations were prepared from PerkinElmer Pure multielement and single element standards (PerkinElmer LAS, Shelton, Connecticut) in 1% HNO

. The following internal standard mix was spiked into each sample, blank, and standard: Sc, Ga, In, and Tm.  

All analyses were performed on an ELAN DRC II (PerkinElemerSciex, Concord, Ontario, Canada); instrumental parameters appear in Table III.  

Most elements were analyzed in standard mode (that is, no reaction gas in the cell). However, those elements that suffered from interferences were measured in dynamic reaction cell (DRC) mode using oxygen and ammonia as the reaction gases. Because no elements were certified in the sucrose sample, spike recoveries of common elements were measured.  

Table V: Analysis of NIST 8433: Corn Bran 

Sodium and potassium were measured in standard mode, but with a different Rpa (DC voltage) than other elements. Both of these elements were present at high concentrations in the final solution and are either monoisotopic (Na) or greater than 90% natural abundance at the primary isotope (

K). As a result, it could be difficult to measure these elements in the same sample along with elements present in the low microgram-per-liter range. If the sample is not diluted adequately, Na and K could saturate the detector. If the sample is diluted too much, the other trace elements cannot be measured.  

Table VI: Analysis of NIST 8436: Durum Wheat Flour 

To solve this problem, the signals from sodium and potassium were attenuated selectively without affecting the sensitivity of other elements (10). This was accomplished by increasing the RPa on the reaction cell quadrupole only for sodium and potassium. Varying the RPa value changes the amount of the attenuation, effectively extending the dynamic range. Table IV shows the reaction cell parameters for the analytes measured in DRC and extended dynamic range modes.  

Table VII: Analysis of NIST 8414: Bovine Muscle Powder 

All quantitative measurements were made against aqueous, external three- or five-point calibration curves.    

Table VIII: Analysis of NIST 2976: Mussel Tissue 

Tables V–X show results for the various food matrices analyzed. The majority of results are within the certified ranges, demonstrating the robustness and applicability of the methodology for various food types.  

Table IX: Analysis of NIST 1549: Nonfat Milk Powder 

This work has demonstrated the ability to analyze a variety of food samples accurately for elements present at both trace and nutritional levels. A single microwave digestion procedure and ICP-MS method were used for all samples, demonstrating their robustness and flexibility. The ability to attenuate the intensities of specific elements selectively without affecting other isotopes allows for the analysis of both trace and high-level analytes to be performed using a single dilution. The analytical results show that microwave digestion followed by ICP-MS analysis effectively measures both toxic and nutritional elements in a variety of food matrices.  

 are with PerkinElmer, Waltham, Massachusetts. 

(2)  M. Resano, E. Garcia-Ruiz, L. Moens, and F. Vanhaecke, 

(3)  R.B. Myors, R. Hearn, and L.G. Mackay, 

(4)  M. Shah, R.G. Wuilloud, S.S. Kannamkumarath, and J.A. Caruso, 

(5)  C. Fragniere, M. Haldimann, A. Eastgate, and U. Krahenbuhl, 

(6)  C.R. Quetel, J.P. Snell, Y. Aregbe, L. Abranko, Zs. Jokai, C. Brunori, R. Morabito, W. Hagan, S. Azemard, E. Wyse, V. Fajon, M. Horvat, M. Logar, O.F.X. Donard, E. Krupp, J. Entwisle, R. Hearn, M. Schantz, K. Inagaki, A. Takatsu,P. Grinberg, S. Willie, B. Dimock, H. Hintelmann, J. Zhu, E. Blanco Gonzalez, G. Centineo, J. Ignacio Garcia Alonso, A. Sanz-Medel, and E. Bjorn, 

(7)  D. Hammer, M. Nicolas, and D. Andrey, 

(8)  W. Dufalilly, L. Noel, and T. Guerin, 

(9)  M.A. Knopp, F. Chan, and K.R. Neubauer, Analysis of Food Substances with Dynamic Reaction Cell ICP-MS, PerkinElmer Field Application Report, 2004. 

(10) F. Abou-Shakra, "Extending the Dynamic Range of the ELAN DRC by Selective Attenuation of High Signal" PerkinElmer Field Application Report 007437_01 (2005). 

Elemental analysis of food substances presents a challenge because of the wide variety of food types and range of concentrations that need to be analyzed. This article discusses the analysis of a variety of food matrices with a single digestion procedure and instrumental method.

Ewa Pruszkowski

Articles

Optimized ICP-MS Analysis of Elemental Impurities in Semiconductor-Grade Hydrochloric Acid

The Benefits of ICP-MS for the Determination of Toxic and Nutritional Elements in the Cannabis Family of Flowering Plants

ICP-MS with Autodilution and Autocalibration for Implementing the New USP Chapters on Elemental Impurities

The Analysis of Food Substances by ICP-MS