Determination of acetaminophen by flow injection with on-line chemical derivatization: Investigations using visible and FTIR spectrophotometry

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Abstract

A new FI/FTIR method for the determination of acetaminophen (paracetamol, N-acetyl-p-aminophenol) involving on-line reaction is described. The proposed method is based on the alkaline hydrolysis of the analyte to produce p-aminophenol and its oxidation reaction with potassium ferricyanide to produce p-benzoquinone-monoimine which eventually oxidizes to form p-benzoquinone. The chemistry of the reaction was studied both, in the visible and IR regions of the spectrum and the method has been developed by the application of flow-injection methodology. The reaction was carried out in aqueous media and at room temperature. The micro-flow version of the CIRCLE® IR accessory, which is compatible with aqueous solutions, was used. Measurements were carried out at the OH-phenolic deformation (1274.1 cm−1) and the aromatic ring mode (1498.2 cm−1) infrared vibrations for the hydrolysis product, p-aminophenol. The method was applied to the determination of acetaminophen in commercial tablets, and mean detection values of 512 and 491 mg were found at 1274.1 and 1498.2 cm−1, respectively.

Introduction

There is a sustained interest in the development of simple and reliable methods for the determination of the active ingredients in pharmaceutical preparations. Not only are analyses performed in support of the production of such preparations but large numbers of dissolution studies are routinely performed to evaluate the kinetics of release of the drug species.

Although direct UV absorption spectrometry is a frequent choice for the instrumental technique in such methods, there are some analyses, such as acetaminophen, for which methodology is still being developed. A survey of the literature indicates that over the past 20 years in excess of 20 papers have been published describing the determination of acetaminophen by a variety of methods, none of which included direct UV absorption. Several analytical procedures for its determination have been reported, including its assay in drug formulations. These include titrimetry [1], fluorimetry [2], colorimetry based upon nitration 3, 4, oxidation 5, 6and diazo coupling 7, 8, chromatography 9, 10, 11, 12, 13, and spectrophotometry 14, 15, 16, 17, 18, 19. In addition, electrochemical detection with liquid chromatography 20, 21, 22, 23, 24and flow injection (FI) 25, 26, 27has been applied for the determination of acetaminophen in both, pharmaceutical preparations and in body fluids.

As direct UV absorption is subject to interference from scatter from insoluble excipient particles and, together with visible absorption, is susceptible to spectral interference from unresolved, overlapping features in the spectra of other sample components or reagents, we wished to investigate the possible role for FTIR absorption spectrometry in such analyses.

The starting point for the investigations was the development of a flow-injection method for the determination of acetaminophen in which (a) direct UV absorption was used or (b) an on-line reaction product was monitored. Flow-injection (FI) methodology for systems involving on-line chemical reactions has been applied using UV-visible spectrophotometry 28, 29, 30. An FI method was described by Stewart et al. [28]for the determination of acetaminophen based on its oxidation with 2-iodylbenzoate in acid medium to produce a colored product, N-acetyl-p-benzoquinonimine, which was monitored at 445 nm. Other FI spectrophotometric methods 29, 30were based on the oxidation of acetaminophen with potassium ferricyanide and subsequent reaction with phenol at elevated temperatures in aqueous ammoniacal solution. In the second of these two reports [30], a method which used an ionic-exchange column to retain the potassium ferricyanide as an immobilized reagent was described. The reaction with phenol occurred at 80°C. The oxidation product was thought to be N-acetyl-p-benzoquinonimine, which reacted with phenol to produce a blue compound, N-(p-hydroxyphenyl)-p-benzoquinonimine which was monitored at 630 nm. Martı́nez Calatayud et al. [29]reported that no reaction occurred when the ammonia used was replaced by sodium hydroxide.

Work coupling FI methodology and Fourier transform infrared (FTIR) spectrometry first appeared about a decade ago. The earliest publication reported the determination of aqueous solutions of dioctyl sulfosuccinate using the cylindrical internal reflectance cell for liquid evaluation (CIRCLE®) as the detector cell [31]. Subsequent papers have reported on both aqueous 32, 33, 34, 35and organic based systems 36, 37, 38, 39, 40, 41, 42, 43.

The application of the combined technique for quantitative determinations with the use of suitable flow cells to obtain information from transient IR signals has demonstrated its capability for the following:

  • 1.

    the accurate measurement of the baseline and the exact determination of the absorbance maximum [44];

  • 2.

    the simultaneous determination of various compounds in the same sample 38, 43;

  • 3.

    pharmaceutical analysis 31, 32, 39;

  • 4.

    determination of organic compounds by the use of FTIR derivative spectrometry 41, 43, 44, 45; and

  • 5.

    the quantitative determination of glucose and urea in complex matrices 33, 34, 35.

The analysis of aqueous solutions by IR spectrometry is usually accomplished by attenuated total reflectance (ATR). The mode of operation of the CIRCLE® accessory is based on the ATR technique. The FI/FTIR technique coupled with the CIRCLE® accessory provides a potential combination for rapidly analyzing and quantifying pharmaceutical samples in aqueous solution. The use of the micro-version CIRCLE® for aqueous FI with FTIR detection has been reported 31, 32. Optimization of a basic FI-FTIR system using the CIRCLE® has been reported for the determination of acetaminophen in aqueous solutions [46]. The accessory has also been applied as a flow detector for chromatographic systems with FTIR detection [47]. An ultramicro cylindrical internal-reflectance cell was designed to fit on the stage of an IR-PLAN infrared microscope [48]. All of these papers have reported on the use of infrared (IR) spectrometry for monitoring FI transients, however none of these describe applications involving on-line chemical derivatization.

In our studies of the UV and visible spectrophotometric determination of acetaminophen, positive interferences were encountered which were overcome by using the chemistry of the visible absorption method and adapting it for monitoring in the IR region. This paper, therefore, presents an FI procedure using FTIR of aqueous solutions in which an on-line reaction product is monitored. Using an attenuated total-internal reflectance flow cell the new FI/FTIR method was developed to follow the alkaline hydrolysis of acetamineophen with sodium hydroxide followed by the oxidation reaction of the hydrolysis product with potassium ferricyanide in aqueous media. This oxidation reaction was carried out at room temperature. There was no need for the oxidative coupling reaction with phenol at elevated temperature. The FI method is fast and simple, and was evaluated by application to the determination of acetaminophen in a commercial formulation.

Section snippets

Apparatus

Infrared spectra were obtained with a Mattson Cygnus 100 Fourier Transform Infrared (FTIR) spectrometer (ATI Instruments, Madison, WI) equipped with a photoconductive narrow-band mercury–cadmium-telluride detector (700 cm−1 cutoff). The spectrometer was controlled by a Dell Model 486D/33 computer which was interfaced with the Mattson Galaxy 7020A on-board electronics. The software package time-evolved kinetics operations (ATI, Madison, WI) was used for data collection, processing and analysis.

Results and discussion

The chemical reaction is seen as consisting of two steps. The first step is based on the basic hydrolysis of acetaminophen to produce p-aminophenol, and the second one involves the oxidation reaction with potassium ferricyanide to produce p-benzoquinonemonoimine, an intermediate product of acetaminophen oxidation. The orange-red species which had a wavelength of maximum absorbance of 476 nm was believed to be the imine intermediate. The reaction scheme is shown in Fig. 2. It is believed that the

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    Present address: Department of Physics and Chemistry, University of Puerto Rico-Arecibo, PO Box 4010, Arecibo P.R. 00613-4010.

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