1 Department 2 Department of Chemistry, King Faisal University, P.O. Box 400, Hofuf 31982, Saudi Arabia of Chemistry, King Fahd University for Petroleum and Minerals, P.O. Box 2026, Dhahran 31261, Saudi Arabia Received 8 May 2007; Accepted 7 June 2007 Experimental design optimization approach was utilized to develop a sequential injection analysis (SIA) method for promazine assay in bulk and pharmaceutical formulations. The method was based on the oxidation of promazine by Ce(IV) in sulfuric acidic media resulting in a spectrophotometrically detectable species at 512 nm. A 33 full factorial design and response surface methods were applied to optimize experimental conditions potentially controlling the analysis. The optimum conditions obtained were 1.0 Ã 10â4 M sulphuric acid, 0.01 M Ce(IV), and 10 Î¼L/s ï¬ow rate. Good analytical parameters were obtained including range of linearity 1â150 Î¼g/mL, linearity with correlation coeï¬cient 0.9997, accuracy with mean recovery 98.2%, repeatability with RSD 1.4% (n = 7 consequent injections), intermediate precision with RSD 2.1% (n = 5 runs over a week), limits of detection 0.34 Î¼g/mL, limits of quantiï¬cation 0.93 Î¼g/mL, and sampling frequency 23 samples/h. The obtained results were realized by the British Pharmacopoeia method and comparable results were obtained. The provided SIA method enjoys the advantages of the technique with respect to rapidity, reagent/sample saving, and safety in solution handling and to the environment. Copyright Â© 2007 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. INTRODUCTION Experimental conditions including chemical and instrumental eï¬ect dependently and/or independently on the eï¬ciency of analytical methods in diï¬erent levels. Therefore, the optimization of these conditions potentially develops analytical methods. Despite its limitation, the univariate method has still been applied for the optimization of analytical methods. This may be due to its simplicity and familiarity. The univariate method optimizes conditions one-by-one by varying levels of one condition while keeping others constant at unspeciï¬ed levels. Experimental design, including factorial design and response surface, is a multivariate approach recommended for the development of analytical methods. This approach is applied to (a) reduce large amount of data that could be easily interpreted, (b) examine main and interaction eï¬ects of experimental conditions on the eï¬ciency of methods, and (c) optimize simultaneously experimental conditions regarding their interaction with each other by a minimum number of experiments . Furthermore, the response surface method is a powerful tool for ruggedness testing . Rugged- ness evaluates the eï¬ciency of analytical methods under the variation of experimental conditions . In 1990, sequential injection analysis (SIA) technique was introduced as the second generation following ï¬ow injection analysis (FIA) technique with dramatic modiï¬cations and developments . The versatility of SIA enables the technique to hyphen with diï¬erent types of detection including spectrophotometry, ï¬uorescence, chemiluminescence, electrochemical, mass spectrometry, and so forth. In addition, as SIA is a fully automated technique, more accurate, precise and safer analytical methods could be adopted; rather than safety in solution handling and reduction of manpower in analytical laboratories. Furthermore, the miniaturization of the technique drastically reduces volumes of reagents/samples from the scale of milliliters to microliters. This does not only oï¬er reagent/sample saving but also offers rapidity and safety to the environment. Due to these advantages, SIA has been extensively applied to pharmaceutical analysis [4, 5]. Promazine is chemically known as 3-(10H-phenothiazin-10-yl)-N, N-dimethylpropan-1-amine hydrochloride (Figure 2). It is a phenothiazine neuroleptic agent with strong anticholinergic, hypotensive, and sedative eï¬ects and 2 moderate antiemetic eï¬ects. Promazine is additionally used as an adjunct agent in the management of severe pain [6â8]. The increasing use of promazine in medicine has prompted the development of several methods for its quantitative determination in bulk form and pharmaceutical preparations. For this purpose, a wide variety of analytical techniques were utilized including titrimetry [9, 10], spectrophotometry [7, 8, 11], chemiluminescence [12, 13], electrophoresis [14, 15], conductimetry , polarography , and FIA [18, 19]. In general, most of the previous spectrophotometric methods for phenothiazines assay are unsatisfactory for different reasons, for example, some of them lacked sensitivity or speciï¬city [20â23]. Some others required long time of heating or lengthy procedure or were conducted in nonaqueous media . Moreover, these methods are not straightforward since they did not base on the detection of one of promazine derivatives. In the present study, SIA technique was utilized to adopt a new method for the assay of promazine hydrochloride in bulk and pharmaceutical preparations. The method was based on the oxidation of promazine by Ce(IV) in sulphuric acid media resulting in a spectrophotometrically detectable species. Experimental conditions potentially controlling the method including Ce(IV) concentration, sulfuric acid concentration, and ï¬ow rate were optimized using experimental design-based methods. 2. EXPERIMENTAL Journal of Automated Methods and Management in Chemistry motor, which drives the piston at rates from 1.5 seconds to 10.0 min per stroke. It is >99% accuracy at full stroke. The syringe has a volume of 2.5 mL. The MPV is chemically inert and has eight ports with a standard pressure of 250 psi (gas)/600 psi (liquid); zero dead volume. The Z is 10 mm path-length Plexiglass compatible with ï¬ber optic connectors. Pump tubing of â0.03 inchâ ID Teï¬on type supplied from Upchurch Scientiï¬c, Inc. (Oak Harbor, WA, USA) was used to connect SIA units and to make HC with a long of 200 cm. The optical devices were composed of radiation source, spectrometer, and ï¬ber optic connectors. They were fabricated by Ocean Optics (Dunedin Florida, USA). The radiation source is an LS-1 Tungsten Halogen lamb optimized for VIS-NIR (360 nmâ2 Î¼m wavelength range). The detector is a USB2000 Spectrometer adapted to 200â1100 nm wavelength range. The ï¬ber optic connectors are 200 micron Sub Miniature version A (SMA). FIALab for Windows version 5.0 supplied from FIAlab (Medina, WA, USA) was used for programming and controlling SIA manifold. SigmaPlot for Windows version 9.01 supplied from Systat Software, Inc. (Point Richmond, CA, USA) was used for data interpolation and constructing surface plots. 2.3. Preparation of standard solutions and samples 2.1. Chemicals and reagents All chemicals and reagents used in this study were of analytical reagent grade; and the quality of water was distilled deionized. Promazine hydrochloride was supplied from Sigma (Taufkirchen, Germany). Ammonium cerium sulphate dihydrate (Ce(NH4 )4 (SO4 )4 Â· 2H2 O), hydrochloric acid, sulphuric acid, and sodium hydroxide were supplied from Fluka (Buchs, Switzerland). Promazine hydrochloride in bulk form as well as inactive ingredients possibly found in pharmaceutical formulations were a generous gift from Samf (Khartoum North, Sudan). These ingredients included sodium citrate, citric acid, sodium formaldehyde sulphoxylate, microcrystalline cellulose, magnesium stearate, maize starch, titanium dioxide, carnauba wax, propylene glycol, povidone, and talc. 2.2. Instrumentation and software packages The manifold used in this method is composed of sequential injection analyzer combined with miniaturized ï¬ber optic spectrometer. Full components of the manifold are diagrammed in Figure 1. SIA manifold used in this study is a FIALab 3500 (Medina, WA USA). It is composed of a syringe pump (SP), multiposition valve (MPV), holding coil (HC), and Z-ï¬ow cell (Z) as well as pump tubing and personal computer (PC). The SP includes 24,000 increments with high-resolution stepper A 3.516Ã10â3 M promazine hydrochloride (1000 Î¼g/mL promazine) as a primary standard solution was prepared in aqueous media and stored protected from light. A 0.10 M Ce(IV) as a primary standard solution was prepared in 0.01 M sulphuric acid media. Secondary standard solutions of promazine, Ce(IV), and sulphuric acid were prepared by dilution in the appropriate way. Promazine is taken by patients in injection or tablets formulations [7, 8]. These formulations with the appropriate inactive ingredients were prepared at our laboratory. Ampoules were synthesized by mixing 50 mg of promazine hydrochloride with other inactive ingredients including sodium citrate, citric acid, and sodium formaldehyde sulphoxylate in a total quantity of 5 mg. Tablets were synthesized by mixing 50 mg of promazine hydrochloride and excipients including microcrystalline cellulose, magnesium stearate, maize starch, titanium dioxide, carnauba wax, propylene glycol, povidone, and talc in a total quantity of 10 mg. Ingredients of both injection and tablets formulations were dissolved in water to give a ï¬nal volume of 10 mL. Placebo injection and tablets samples were prepared by mixing the appropriate excipients. All solutions were ï¬ltered and the ï¬ltrates were used for further analysis. 2.4. SIA procedure A suitable SIA manifold was constructed. As shown in Figure 1, water was linked to the inposition in the SP and to port-1 in the MPV. Sulphuric acid, Ce(IV), and placebo sample were linked to port 2, 3, and 4, respectively. Standards/samples were linked to port 5 to 7. Z was linked to port 8. An appropriate protocol controlling the SIA procedure was Multiport valve Syringe pump Holding coil H2 SO4 1 2 Water Ce (IV) 3 4 Placebo solution Standard/ sample 5 6 8 7 Radiation source Standard/ sample Standard/ sample Waste Water Z-ï¬ow cell Detector Figure 1: Schematic diagram of a SIA manifold constructed for promazine assay. programmed using FiaLab software. It is brieï¬y described as follows. (i) At a ï¬ow rate of 150 Î¼L/s, the syringe was ï¬lled with 1000 Î¼L of water. (ii) Tubes were loaded by aspirating 100 Î¼L of each of sulphuric acid, Ce(IV), placebo, and standards/samples, and then the syringe was emptied. (iii) 30 Î¼L of each of sulphuric acid, Ce(IV), and blank solutions and 10 Î¼L of water as a spacer solution were sequentially aspirated into the HC. The solutions were mixed by short reverse strokes. (iv) At the required ï¬ow rate, a volume of 1000 Î¼L was dispensed to the Z; and the reference and absorbance scan were carried out at wavelength 512 nm. (v) To measure the absorbance of promazine derivative, steps (iii) and (iv) were repeated with replacing standard/sample solutions instead of placebo solution. (vi) Values of peak height of absorbance of both placebo and standards/samples were recorded. The diï¬erence was calculated and the obtained values are termed as âresponseâ in the following sections. 3. RESULTS AND DISCUSSION Promazine structure S N C3 H6 N(CH3 )2 Ce(IV) H+ Ce(IV) H+ â¢+ N C3 H6 N(CH3 )2 â¢ â¢ + + N C3 H6 N(CH3 )2 Figure 2: Proposed reaction scheme of promazine oxidation by Ce(IV) in sulphuric acid media. 3.1. Preliminary investigation A preliminary investigation on a possible oxidation of promazine indicated that promazine is oxidized by the means of Ce(IV) in sulphuric acid media at room temperature in a fast reaction. The scheme of the reaction is depicted in Figure 2. Similar to what has been earlier proposed to another member of phenothiazines , promazine is oxidized to form mono- and dication radicals in two steps. The free radical recorded maximum absorbance at 512 nm, and no spectrum interference was recorded from other species in the matrix of the adopted reaction. 3.2. Experimental design optimization Before undertaking any optimization study, it is important to delineate clearly the boundaries of conditions controlling the analysis, namely, sulphuric acid concentration, Ce(IV) con- centration, and ï¬ow rate. Preliminary investigation revealed that acid concentration bellow 1.0 Ã 10â4 M, hydrolysis of Ce(IV), took place. Acid concentration above 0.10 M, dense yellow color, was produced in the mixture of Ce(IV) and the acid. This caused spectrum interference with the analyte. On the other hand, high acid concentration decreased the repeatability of SIA measurement. For Ce(IV) concentration, 0.01 M was considered at the maximum since beyond this level the solution is not stable. Below 1.0 Ã 10â4 M, the molar equivalency of Ce(IV) would not be enough to oxidize relatively high concentration of promazine in bulk and pharmaceutical formulations. A ï¬ow rate ranging from 10 to 60 Î¼L/s was found to be suitable for spectrophotometric measurement. When applying experimental design methodologies, it is advisable to keep the number of variables as low as possible in order to avoid very complex response models and large variability . 3.3. The main and interaction effect factors A 33 full factorial design was carried out; where the base 3 stands for variable levels considering the lowest, the medium, and the highest values; and the power 3 is the number of 4 parameters that would be optimized. The ranges obtained from the preliminary investigation were considered as minimum and maximum levels, while medium levels were mathematically calculated. 27 experiments, as the result of the adopted factorial design, were conducted and the results obtained are introduced in Table 1. The main and interaction eï¬ect factors were calculated and the results obtained are depicted in Figure 3. For the main factors, the level of the positive eï¬ect of Ce(IV) concentration was higher than the level of the negative eï¬ect of ï¬ow rate; and the latter was higher than the level of the negative eï¬ect of acid concentration. For the interaction eï¬ect factors, the level of the negative interaction eï¬ect of Ce(IV) concentration with ï¬ow rate was higher than other levels of interaction eï¬ect factors. The eï¬ect factor study concluded that Ce(IV) and ï¬ow rate were found to be critically controlling the adopted method. The negative interaction eï¬ect of Ce(IV) concentration with acid concentration may be attributed to the increase of the potential oxidation of Ce(IV) concentration with the decrease of acid concentration. On the other hand, higher acid concentration negatively eï¬ects the stability of the oxidized form of promazine leading to its disassociation. As proposed before, although the oxidation of promazine is fast, the negative eï¬ect of ï¬ow rate may be due to phenomena that low ï¬ow rate delays solution in tubings, and thus dispersion is increased. This enhanced the reaction, and thus the absorbance of the detectable species increased. 3.4. Response surface The coded levels of the adopted factorial design with their respective responses were interpolated; and the response surface plots were constructed. As examples, two ï¬gures are depicted. Figure 4 shows the response surface plot as a function of Ce(IV) concentration versus acid concentration. The highest response obtained was above 0.50. The general trend of the ï¬gure is that the eï¬ect of Ce(IV) concentration is higher than the eï¬ect of acid concentration. The bimodal shape appearing at the left side indicates that acid concentration interacts with higher Ce(IV) concentrations. The response of the surface plot of acid concentration versus ï¬ow rate reaches 0.75. The ï¬ow rate resembled a higher eï¬ect on the response value than that of acid concentration. Figure 5 shows the response surface plot as a function of Ce(IV) concentration versus ï¬ow rate. As shown in this ï¬gure, the highest response obtained was above 1.0 when Ce(IV) concentration was at the highest level and the ï¬ow rate was at the lowest. Therefore, it was decided to consider 0.01 M Ce(IV) and ï¬ow arte 10 Î¼L/s as the optimum. On the other hand, based on its negative eï¬ect on the response, 1.0 Ã 10â4 M was considered as the optimum acid concentration. 3.5. Method validation A long series of standard solutions of promazine were subjected to the optimized SIA method for the purpose of calibration. Beerâs law was found to be obeyed in the concentration range of 1â150 Î¼g/mL with weighed regression âR = 0.0082C + 0.0956,â where R is the response, C is the concen- Journal of Automated Methods and Management in Chemistry Table 1: A 33 factorial design matrix with experimental results (responses). Experiment number 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 A1 â1 â1 â1 â1 â1 â1 â1 â1 â1 0 0 0 0 0 0 0 0 0 +1 +1 +1 +1 +1 +1 +1 +1 +1 Factor C2 â1 â1 â1 0 0 0 +1 +1 +1 â1 â1 â1 0 0 0 +1 +1 +1 â1 â1 â1 0 0 0 +1 +1 +1 F3 â1 0 +1 â1 0 +1 â1 0 +1 â1 0 +1 â1 0 +1 â1 0 +1 â1 0 +1 â1 0 +1 â1 0 +1 Response 0.149 0.116 0.081 0.267 0.117 0.103 2.013 0.669 0.641 0.237 0.204 0.12 0.165 0.104 0.108 1.100 0.273 0.173 0.257 0.187 0.114 0.251 0.100 0.090 1.334 0.321 0.203 (1) Sulphuric acid concentration (M); (2) Ce(IV) concentration (M); (3) ï¬ow rate (Î¼L/s). Table 2: Results obtained by the SIA and BP methods for promazine assay in pharmaceutical formulations. Sample type Bulk Injection Tablets (1) Mean recovery Â± RSD1 SIA method BP method 99.4 Â± 0.9 99.1 Â± 1.2 98.1 Â± 1.7 98.6 Â± 2.2 97.8 Â± 1.6 102.7 Â± 2.4 t-test value 1.4 1.7 2.1 Relative standard deviation for 10 consequent injections. tration of promazine in Î¼g/mL. The correlation coeï¬cient was 0.9997 indicating good linearity. Figure 6 shows a typical SIA calibration obtained under the optimum conditions by triplicate consequent injection of four standard solutions of promazine (1, 50, 100, and 150 Î¼g/mL). The accuracy was examined by analyzing bulk, tablets, and injection formulations. The obtained results were realized by the British Pharmacopoeia (BP) method. BP provided a classical potentiometric titration method by sodium hydroxide for promazine assay in bulk form ; and a [Ce(IV)] Flow rate [Ce(IV)]Ãï¬ow rate [Acid]Ã[Ce(IV)] [Acid] [Acid]Ã[Ce(IV)]Ãï¬ow rate [Acid]Ãï¬ow rate 0.2 Factor â0.2 â0.4 â0.6 â0.8 Figure 3: The main and interaction eï¬ect factors of Ce(IV) concentration (M), acid concentration (M), and ï¬ow rate (Î¼L/s) on the response of the proposed SIA method. Response Response â0.5 â1 â1 Eï¬ect factor 0 0 1 â1 [Ac id 0 0 1 â1 [Ce(I V)] Flow rate Figure 4: Response surface plot of Ce(IV) concentration (M) versus sulphuric acid concentration (M). Figure 5: Response surface plot of Ce(IV) concentration (M) versus ï¬ow rate (Î¼L/s). classical spectrophotometric method in hydrochloric acid media in tablets and injection formulations. Analysis for each sample was repeated seven times, and the relative standard deviation (RSD) was calculated. The t-test values were also calculated. The results obtained are introduced in Table 2. The obtained results indicating that the provided SIA method is accurate and repeatable. The intermediate precision of the SIA method was examined by analyzing the same solutions 5 times over a week. Relative standard deviation (RSD) of the mean recovery for samples under study was 2.1% indicating good intermediate precision. The limits of detection (LOD) and quantiï¬cation (LOQ) were also examined. LOD was calculated as 3.3( s/S) and LOQ as 10( s/S) where s is the standard deviation for seven replicates of the measurement of placebo solution, S is slope of the weighed regression of calibration equation. The LOD and LOQ obtained were 0.34 and 0.93 Î¼g/mL, respectively, indicating good detectability. 4. CONCLUSIONS The SIA technique was utilized to adopt a simple, accurate, precise, rapid, and reagent/sample saving method for [Ce (IV )] 1.2E + 00 1E + 00 8E â 01 Absorbance 6E â 01 4E â 01 2E â 01 0E + 00 â2E â 01 Journal of Automated Methods and Management in Chemistry  P. D. Tzanavaras and D. G. Themelis, âReview of recent applications of ï¬ow injection spectrophotometry to pharmaceutical analysis,â Analytica Chimica Acta, vol. 588, no. 1, pp. 1â9, 2007.  V. Larsimont, J. Meins, H. Fieger-BÂ¨ schges, and H. 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Journal of Automated Methods and Management in Chemistry – Hindawi Publishing Corporation
Published: Nov 20, 2007