Determination of tetramethylammonium hydroxide in air using ion ...

Tetramethylammonium hydroxide (TMAH) is extensively utilized in the semiconductor and optoelectronic industries, serving as either a developer or an etchant. TMAH possesses acute toxicity and alkaline corrosiveness, having caused several fatal and injurious accidents in Taiwan. However, there is currently a lack of methods available for assessing TMAH exposure. This study developed a method involving sampling with quartz fiber filters followed by ultrasonic agitation in 10 mL mobile phase, filtering, and analysis using either ion chromatography (IC) or ultra-performance liquid chromatography - high-resolution mass spectrometry (UPLC-HRMS). Utilizing the characteristics of HRMS, the compound analyzed was identified as tetramethylammonium ion (TMA+) through mass spectrometry analysis. The method exhibits excellent trapping capacity and recovery rate. The linear range of TMA+ for IC is 0.3 to 100 μg/mL, with a correlation coefficient of R = 0.. The linear range of TMA+ for UPLC-HRMS is 0.002 to 1 μg/mL, with a correlation coefficient of R = 0.996. The recovery rates for IC and HRMS were 116.6% and 90.6%, with corresponding coefficient of variation (CV) of 2.25% and 3.53%, respectively. Samples can be stored at room temperature for 28 days. Verification of this method was conducted at the TMAH factory, and the air concentrations measured in the TMAH filling area were 3.29 and 4.75 μg/m3 from IC and UPLC-HRMS, respectively. This method will be applied in the on-site analysis of occupational hazards for operators in chemical plants, technology factories, and recycling plants, aiming to evaluate risk values to protect the safety and health of workers and prevent occupational diseases.

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INTRODUCTION

The tetramethylammonium ion (TMA+, C4H13N+), a basic quaternary ammonium compound, was first isolated from a sea anemone in [1]. The hydroxide salt, tetramethylammonium hydroxide [TMAH; (CH3)4NOH, CAS No. 75-59-2], functions as an etchant or developer commonly used in the optoelectronic and semiconductor industries[2]. According to a survey by Taiwan’s Industrial Technology Research Institute, approximately 2,000,000 tons of TMAH are used in Taiwan each year[3]. Numerous semiconductor facilities in mainland China, Japan, South Korea, and the USA also use TMAH. TMAH is known as an alkaline corrosive and cholinergic agonist, capable of causing chemical skin burns and systemic toxicity[4]. Dermal exposure to TMAH can result in fatal intoxication, and it is increasingly becoming a serious concern in Taiwan[5,6,7]. The structure of the TMA+ resembles the cationic component of acetylcholine. TMA+ can stimulate muscarinic or nicotinic autonomic ganglia, potentially leading to a depolarization blockade[2]. The neurological effects of TMA+ intoxication include respiratory muscle paralysis caused by ganglionic blockade. Cholinergic symptoms resulting from acetylcholine accumulation were first reported in Taiwanese patients in [7]. There have also been cases in South Korea where workers died from splashing TMAH[8].

Currently, the detection methods for TMAH mainly focus on testing TMAH in sewage or solutions, which can be divided into acid titration, conductivity measurement, ion chromatography (IC), and liquid chromatography-mass spectrometry (LC-MS/MS). Wang et al. targeted the OH- group in the structure of TMAH compounds, using phenolphthalein as an indicator and titrating with standard hydrochloric acid solution to determine the concentration of TMAH, achieving a measurement accuracy of up to 0.005 wt%[9]. Because in aqueous solution, TMAH completely dissociates into (CH3)4N+ and OH-. Its conductivity is directly proportional to the concentration of TMAH. Jie et al. used real-time conductivity measurement technology to measure the changes in electrical charge caused by different concentrations of TMAH solution online; TMAH concentrations within the range of 0 to 3 wt% can be detected using this method[10]. IC is widely used in TMAH-related research. Urakami et al. used an ion chromatograph to measure the concentrations of TMAH, Trimethylamine (TriMA), dimethylamine (DMA) and monomethylamine (MMA), and NH4[11]. Chang et al. used IC to analyze the concentrations of TMAH and ammonium ions in sewage to investigate the anaerobic treatment of TMAH-containing sewage. The samples were eluted with 11 mM H2SO4 at a flow rate of 1 mL/min. When the TMAH concentration was 1.0, 2.0, 5.0, and 10.0 mg/L, the R-square of the calibration curve between TMAH concentration and IC peak area was all above 0.999. The detection limit (MDL) was 0.45 mg/L, and the analytical recovery rate was 92%[12]. Koga et al. used LC-MS/MS to analyze the concentration of TMAH in wastewater. They used weak cation exchange resin (Oasis WCX) for solid-phase extraction (SPE). The quantitative limit for TMA+ analysis was 0. mg/L[13]. Acid titration and conductivity measurements are more susceptible to interference from OH- in the environment, and their detection limits are also higher. Therefore, IC and LC-MS/MS will be selected as measuring instruments.

Hundreds of thousands of workers in Taiwan who are engaged in manufacturing, transportation, storage, or waste reduction face the risk of exposure to TMAH[14]. TMAH has been reported to cause severe burning sensations in the eyes, nose, throat, lungs, and skin[15]. However, there is currently a lack of analytical methods that can assess the TMAH exposure concentrations in labor working environments. Therefore, the goal of this study is to develop a sampling and IC or ultra-performance liquid chromatography - high-resolution mass spectrometry (UPLC-HRMS) analysis method for TMAH in the working environment, and to use UPLC-HRMS to verify the accuracy of the method. This method can be used not only to assess workers’ exposure to TMAH in the workplace environment but also to evaluate environmental hazardous substance exposure and health risk assessment.

RESULTS AND DISCUSSION

Sampling materials

TMAH solution, which is released into the air as water vapor, becomes an aerosol particulate pollutant. Therefore, the “filter collection method” was chosen. However, with many types of filter papers available, it is necessary to determine which type is most suitable. Six different types of filters commonly used for air sampling in occupational hygiene were tested to evaluate their efficiency in collecting TMAH: Quartz Fiber, PTFE, PVC, Glass Fiber, and MCE. On the day before the analysis, 40 μL of 1 mg/mL TMA+ was added to each type of filter paper, resulting in a total of 30 samples (6 samples per filter type). The filters were placed in 15 mL plastic centrifuge tubes. The filters were placed in 15 mL plastic centrifuge tubes, and 10 mL of 5 mM sulfuric acid solution was added. After standing for 30 min, the sample solution was filtered through a 0.22 μm filter membrane, and the TMA+ concentration was analyzed using IC to calculate the recovery rate. The results are shown in Table 1. The results indicate that, except for the MCE filter, the average recovery rates for all other filters are above 95%. Quartz fiber filters, which are commonly used for sampling alkaline aerosols in workplace environmental monitoring, were therefore chosen as the sampling medium for subsequent testing.

Table 1

Extraction recoveries of five sampling materials (n = 6)

FilterRecovery (%)Precision (%)Quartz fiber100.50.63PTFE101.90.68PVC100.90.98Glass fiber96.51.22MCE72.92.31

Retention efficiency

This test aimed to determine whether TMAH captured by the sampling medium would be washed away during sampling, potentially leading to an underestimation of the measurement results. Forty microliters (40 μL) of 1 mg/mL TMA+ were added to six quartz fiber filters one day before sample preparation. After allowing TMA+ to be fully absorbed, the next day, a sampling pump was set to a flow rate of 4 L/min, and air was passed through the quartz fiber filters containing TMA+ for 6 h. The filters were then placed in 15 mL plastic centrifuge tubes, 10 mL of 5 mM sulfuric acid solution was added, and after standing for 30 min, the sample was filtered and analyzed using IC. The results showed a recovery rate of 97.5% with a coefficient of variation (CV) of 1.84%. This indicates that TMA+ on the quartz fiber filter was not significantly lost after being subjected to a gas flow of 4 L/min for 6 h.

Effect of desorption solvent

The test aimed to determine which solvent would be more effective in desorbing TMA+ from the quartz fiber filters. The day before the analysis, 40 μg of 1 mg/mL TMA+ was added to each quartz fiber filter. Two desorption agents were tested, with a total of 12 samples (6 for each desorption agent). After allowing TMA+ to be fully absorbed, the next day, DI water and 5 mM sulfuric acid solution (mobile phase) were used as desorption solvents. The quartz fiber filters were placed in 15 mL plastic centrifuge tubes. Next, 10 mL of 5 mM sulfuric acid solution or water was added, and after 30 min of standing, the sample solution was filtered and analyzed using an IC. The results showed a recovery rate of 101.1% with a CV of 0.79% for water, and a recovery rate of 96.1% with a CV of 0.77% for the mobile phase. Both desorption agents achieved a recovery rate of over 95%. While water had a slightly better desorption efficiency than the flushing solution, it was prone to interference during analysis. Therefore, the mobile phase was chosen as the desorption agent.

Desorption condition

The effects of different sample pretreatment methods - stand, agitation, and ultrasonic agitation - on the recovery rate of TMA+ were evaluated. On the day before analysis, 40 μg of 1 mg/mL TMA+ was added to each quartz fiber filter. With three desorption conditions tested, a total of 18 samples were prepared. After allowing TMA+ to fully absorb overnight, the filters were transferred to 15 mL plastic centrifuge tubes the next day and 10 mL of 5 mM sulfuric acid solution was added. Desorption was performed by standing for 30 min, agitation for 30 min, and ultrasonic for 30 min. The samples were filtered and analyzed using IC. The results are shown in Table 2. The recovery rates for stand, agitation, and ultrasonic agitation for 30 min were 95.4%, 100.2%, and 100.0%, respectively, with a CV of 0.59%, 0.86%, and 1.17%, respectively. All three desorption methods achieved recovery rates of over 95%. Considering the effectiveness of desorption, ultrasonic treatment was selected as the preferred method.

Table 2

Extraction recoveries of stand, agitation, and ultrasonic sample pretreatment methods and ultrasonic times (n = 6)

ExtractionRecovery (%)Precision (%)Stand 30 min95.40.59Agitation 30 min100.20.86Ultrasonic 30 min100.01.17Ultrasonic 5 min98.82.24Ultrasonic 15 min99.61.56Ultrasonic 30 min100.42.16

Effect of desorption time

Based on the previous test results, ultrasonic was identified as the optimal desorption method. However, how long does ultrasonic agitation need to effectively desorb TMA+ from the quartz fiber filter? In this study, three different durations of ultrasonic agitation were tested. A total of 18 samples were prepared by adding 40 μL of 1 mg/mL TMA+ to each quartz fiber filter and allowing them to absorb the TMA+ overnight. The next day, the filter papers were placed in 15 mL plastic centrifuge tubes, and 10 mL of 5 mM sulfuric acid solution was added. Ultrasonic was performed for 5, 15, and 30 min, respectively. The results are shown in Table 2. The recovery rates after ultrasonic agitation for 5, 15, and 30 min were 98.8%, 99.6%, and 100.4%, respectively, with CV values of 2.24%, 1.56%, and 2.16%, respectively. The best desorption effect was achieved with 30 min of ultrasonic.

Extraction recovery

Using the optimal pretreatment conditions determined from previous tests (10 mL elution with rinsing solution, followed by 30 min of ultrasonic agitation), the desorption efficiency of low, medium, and high concentrations was tested. Add 25, 50, and 100 μL of 10 mg/mL TMA+ to each quartz fiber filter one day before analysis, including one blank sample for each concentration, resulting in a total of 21 samples. The results are shown in Table 3. The average recovery rate was 116.6% with a CV of 2.25%, and the maximum difference in recovery rates among the concentrations was 1.55%. The sample preparation steps for UPLC-HRMS are the same as those for IC, except that the desorption solution is replaced with an aqueous solution. The average desorption efficiency for UPLC-HRMS is 90.6% and the CV value is 3.53%.

Table 3

Extraction recoveries of the proposed method at low, medium and high concentration levels (n = 6)

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InstrumentConcentration (μg/mL)Extraction recovery (%)Average recovery (%)Precision (%)Total precision (%)IC..61.982..42..62.40UPLC-HRMS.090.63.763..54..42.56

Storage

The accuracy of measurements can be significantly affected by the storage environment of samples collected for TMAH aerosol capture. To assess whether the samples deteriorate during transportation or storage and whether there is any diffusion effect leading to sample loss, storage period tests were conducted under both room temperature and refrigeration conditions. Add 40 μL of 1 mg/mL TMA+ to each quartz fiber filter, with 7 samples needed for each storage condition (6 with added TMA+ and 1 blank sample) to be tested on days 1, 7, 14, 21, and 28, resulting in a total of 70 samples. The results are shown in Table 4. The recovery rates after 28 days of storage at room temperature (20 to 25 °C) and under refrigeration (< 4 °C) were comparable, with no significant difference. Therefore, samples collected for TMAH analysis can be stored at room temperature for at least 28 days.

Table 4

The sample recoveries of storage in refrigeration and room temperature (n = 6)

DayRefrigerationRoom temperatureRecovery (%)Precision (%)Recovery (%)Precision (%)..72..34..64..40..70..71..92..52..71.99

Air sampling

To verify the capability of the method developed in this study to effectively capture TMAH in the air, we employed a mist generator (JSQ-C) to simulate TMA+ aerosols present in workplace air. Sampling was conducted for 2 h using an impinger containing 10 mL of deionized water and quartz fiber filters, respectively, with a sampling pump (Gilian GilAir Plus) set at a flow rate of 1 L/min. Given the high water solubility of TMAH, the TMA+ signal intensity in deionized water was established as the reference (100%). The analysis of the quartz fiber filters yielded 137% of the reference value, indicating potential sources of error, such as the positioning of the sampler or losses in the absorbing liquid. Nonetheless, these results confirm that quartz filters can indeed effectively capture TMAH aerosols in the air.

Method validation

The linear range of quantification refers to the ability to obtain a measurement signal proportional to the concentration of TMA+ in the analysis of samples. Understanding the linear range of quantification of TMA+ can ensure the proper accuracy and precision of the measurement results. The calibration curve was constructed by plotting the peak areas against the concentrations of the TMA+ spiked in 5 mM H2SO4 (IC) or DIW (UPLC-HRMS). The limit of quantification (LOQ) is the lowest concentration on the calibration curve by the desorption volume, then by the conversion factor of TMA+ to TMAH (1.23), and dividing the result by the total sampling volume (sampling flow rate of 4 L/min multiplied by the sampling time of 8 h). The results are shown in Table 5. The linear range of TMA+ of IC is 0.3 to 100 μg/mL, with a correlation coefficient of R = 0.. The linear range of TMA+ of UPLC-HRMS is 0.002 to 1 μg/mL, with a correlation coefficient of R = 0.996. The collision energy was set at 35 for UPLC-HRMS analysis and the precursor ion m/z = 74.097 was used to obtain the TMA+ signals.

HRMS verification

Utilizing the characteristics of HRMS, the compound analyzed was identified as TMA+ through mass spectrometry analysis [Figure 1]. The molecular weight of TMA+ is 74.097, and the mass spectrometer indeed detected signals corresponding to the molecular weight of 74.097.

Figure 1. (A) The ion chromatogram of TMA+ in standard solution (B) HRMS product ion profile of the TMA+. TMA+: Tetramethylammonium ion; HRMS: high-resolution mass spectrometry.

Workplace environmental exposure assessment

To validate that the method we developed can be applied in the TMAH operational environment exposure assessment, we conducted operational environment sampling and analysis at a TMAH supply factory located in northern Taiwan. We carried out sampling in the TMAH Filling Area, Quality Control Laboratory, On-site Office, and Lounge. Sampling was conducted for 6.5 h using quartz fiber filters with a sampling pump set at a flow rate of 4 L/min. After pretreatment, the samples were analyzed using IC and UPLC- HRMS, with the results shown in Table 6. The highest air concentrations measured in the TMAH Filling Area were 3.29 and 4.75 μg/m³ from IC and UPLC-HRMS, respectively. The concentrations at the other sampling locations were below the quantitation limit of IC. However, due to the better quantitation limit of UPLC-HRMS, all samples could be measured. Because of the lower quantitation limit of UPLC-HRMS, the samples from the TMAH Filling Area needed to be diluted. This might be the reason for the discrepancy in measurements of the same sample using IC and UPLC-HRMS.

Table 6

The results of workplace environmental exposure assessment of the TMAH factory

IC (μg/m3)UPLC-HRMS (μg/m3)TMAH filling area3.294.75Quality control laboratory< 2.480.07On-site office< 2.460.15Lounge< 2.400.05

Most novolac-based photoresists are characterized by high etch stability in the presence of acids (except in highly concentrated oxidizing acids or in concentrated hydrofluoric acid), while resists are comparably sensitive in alkaline solutions. A developer composed of aqueous-alkaline components with a pH of 12 to 13 will dissolve exposed areas of positive-tone resists within seconds, but unexposed areas are likewise dissolved within 5 – 20 minutes.

It has now been possible to develop a novolac-based negative-tone resist with improved features in this respect. After an additional bake, resists structures are stable in the presence of 1 n NaOH for 4 hours without any measurable removal. A 2:1 dilution of TMAH-remover AR 300-73 was used as developer in these experiments. Surprisingly, the resist is highly sensitive despite the drastic development procedure and can be processed with generally used lithography equipment. Removal is also easily possible.

This negative resist is thus well suited for an application in strongly alkaline galvanic baths and for an etching of aluminium films with strong TMAH developers. Cross-linked resist films are furthermore remarkably solvent-resistant. If structures are baked at only 120°C, these are protected for hours against acetone, IPA, PMA and NEP. At higher bake temperatures, films are stabilized to such an extent that even commonly used removers are ineffective. In these cases, removal of the resist is only possible with plasma etching procedures or using piranha-solution.

The resistance in the presence of solvents can be adjusted by a thorough choice and combination of raw materials (see SX AR-N /7).

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