Green in-Line Ion Selective Electrode Potentiometric Method for

Research Article pubs.acs.org/journal/ascecg

Green in-Line Ion Selective Electrode Potentiometric Method for Determination of Amantadine in Dissolution Media and in Pharmaceutical Formulations Eman S. Elzanfaly and Ahmed S. Saad* Faculty of Pharmacy, Cairo University, Analytical Chemistry Department, Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt ABSTRACT: Amantadine HCl (AMN) is a well-known antiviral agent. Chemically, AMN chromophore privation leads to the absence of UV-absorbance, a condition that hinders direct spectrophotometric or simple chromatographic determination using common detectors without prior derivatization steps. In this work, an environmentally friendly ion selective electrode (ISE) method was developed for the determination of AMN, and measurements were carried out directly in the aqueous solution of the sample without pretreatment or derivatization steps. PVC-membranes were fabricated using nitrophenyl octyl ether as a plasticizer along with different cation exchangers, responses were compared, and that containing phosphomolybdic acid proved to have the best near-Nernstian slope through a wide linear range (4.57 × 10−7)−(1.0 × 10−2) M. The ion pair was obtained by soaking the membrane sensor in a 1 × 10−2 M solution of AMN. The sensor was able to determine AMN in colored and turbid solutions of its tablets and capsules without prior extraction, pretreatment, filtration, or derivatization steps. Additionally, the sensor was successfully applied as a benchtop real-time inline analyzer in dissolution monitoring experiments from its capsules and tablets formulations as per the recommended USP and FDA regulations, respectively, where no sample withdrawal, pretreatment, or filtration was required. Sensor response was validated as per IUPAC recommendations. The proposed technique provided a green eco-friendly method that saves cost, time, and effort and consumes the least amount of chemicals. KEYWORDS: Green analytical method, ISE-potentiometry, Amantadine, Dissolution experiment

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INTRODUCTION Dissolution testing is a mandatory requirement throughout product development and release procedures. Officially, in vitro

samples one at a time. A very arduous task is to undergo a prederivatization procedure for the sample to be determined using the applied technique. Several trials have been carried out to cut short the effort and time for the analysis by including an online procedure. The trend was followed in the past decade by several scientists in both ultraviolet (UV)2−4 and high-pressure liquid chromatography (HPLC)-UV5,6 techniques. However, the developed automated systems still have to carry the major drawbacks of UV detection especially in the presence of insoluble matter, pigments, air bubbles, and vast dilution commonly encountered in dissolution experiments. In addition to being an environmentally friendly technique, electrochemical methods of analysis on the contrary have the potential to solve many of the encountered drawbacks. Electrochemical detection produces a fast and sensitive response for the analyte regardless of the solution color or turbidity found in it. Recently, the ion selective electrode analytical technique has been employed for the in-line analysis

Figure 1. Structural formula of amantadine.

dissolution testing has been a key analytical test in quality control laboratories for in vitro and in vivo correlation studies and for the detection of manufacturing variables.1 UV/visible spectrophotometry and HPLC techniques represent the largest portion of pharmaceutical analysis in research and development as well as quality control laboratories. In dissolution experiments, samples are frequently withdrawn at different time intervals, although the two techniques are widely employed in most pharmaceutical laboratories to assess the extent of dissolution, it really seems a laborious task to carry out the analysis of the collected © 2017 American Chemical Society

Received: February 10, 2017 Revised: April 9, 2017 Published: April 11, 2017 4381

DOI: 10.1021/acssuschemeng.7b00421 ACS Sustainable Chem. Eng. 2017, 5, 4381−4387

Research Article

ACS Sustainable Chemistry & Engineering in the dissolution experiments.7,8 The technique seems rewarding, being green and offering prompt and sensitive response selective for the analyte as a function of time in the dissolution media with no need for sample withdrawal or costly devices, supplies, chemicals, and solvents.9 Amantadine (AMN), chemically known as adamantan-1amine, is an antiviral agent used in the management of herpes zoster and also to ameliorate symptoms when administered during the early stages of influenza type A viral infections.10 Additionally, it has mild antiparkinsonism activity; therefore, it has been used in the management of the mild symptoms in the early stages. Usually, AMN is given by mouth as the hydrochloride salt.11 The chemical structure of AMN, Figure 1, shows that it lacks the minimal double bond conjugation necessary for adequate UV/visible absorbance above 200 nm, which was the main reason behind the absence of a direct spectrophotometric methods or HPLC methods coupled to the commonly used spectrophotometric detectors; therefore, derivatization procedures were mandatory for its spectrophotometric determination,12−18 HPLC-fluorescence19−22 and HPLC-UV23 detection. Amantadine was also determined in plasma using liquid chromatography−mass spectrometry24,25 and by gas chromatography.26 Ion selective electrodes were also suggested for the determination of amantadine in its dosage form by flow injection analysis27 or by direct potentiometry using a modified carbon paste electrode.28 The USP pharmacopeia describes a GC method for monitoring AMN concentration during dissolution testing after extraction with an organic solvent.11 Eventually, most of these methods can be described as timeconsuming and noneconomical and require a derivatization step. The aim of the work in this study was to develop and validate a green inline cost-effective analytical method for inprocess tracking of the concentration of amantadine during its dissolution from tablets and capsules and for its assay without any sample extraction, pretreatment filtration, or derivatization steps and without the need of sample withdrawal at each time interval.

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Amantadine hydrochloride working standard was kindly supplied by Pharco Pharmaceuticals, Alexandria, Egypt, and its purity was certified to be 99.78%. Adamine capsules, batch number 141216, labeled to contain 100 mg of amantadine hydrochloride, manufactured by Rameda Pharmaceuticals Co. 6th October Egypt and PK-Merz tablets, batch number 149, labeled to contain 100 mg of amantadine sulfate, manufactured by Pharco Pharmaceuticals, Alexandria, Egypt under license from Merz +Co. GmbH & Co. Germany. Standard Solutions. AMN stock standard solution (1.0 × 10−2 mol/L) was prepared using bidistilled water as a solvent. A serial dilution of the stock solution was carried out to prepare AMN working solutions (10−7 to 10−2 mol/L) using bidistilled water as a solvent. Procedures. Construction of the Membrane Sensors. Into a 5 cm glass Petri dish, 10 mg of the ion exchanger was mixed with 0.19 g of PVC and 0.35 mL of NPOE; then, the mixture was dissolved in 5 mL of THF. The Petri dish was covered with filter paper and left to stand overnight at room temperature (25 °C ± 5 °C). After solvent evaporation, a master membrane of thickness 0.1 mm was obtained. The master membrane was used for membrane construction. Sensor Assembly. A 5 mm diameter circular disk was cut from the prepared master membrane and adhered using THF to an elastic PVC tip attached to the hard electrode body. The internal compartment of the electrode consisted of a 1 mm Ag/AgCl wire immersed into an internal reference solution consisting of equal volumes of 10−2 mol/L AMN and 10−2 mol/L KCl. Conditioning was carried out by soaking the electrode for 1 day in a 1 × 10−2 mol/L AMN solution. For long period storage, the electrode was kept in distilled water. Calibration. Calibration of the conditioned electrode was carried out in a series of 50 mL beakers containing 25 mL aliquots of AMN working standard solutions (10−7 to 10−2 mol L−1). At controlled temperature (37 °C ± 0.5 °C), both the reference and working electrodes were dipped into each beaker and the potentials in millivolts were recorded separately for each concentration of the working solutions. The electrodes were washed with distilled water and dried with a clean tissue in between measurement. The measured potentials were plotted against the logarithm of their molar concentrations and regression equation was computed for the straight part of the curve. pH Effect. Effect of pH on the response of the electrode in the range 2.0 to 10.0 was investigated. At controlled temperature (37 °C ± 0.5 °C), a 2.0 N solutions of NaOH and HCl were used to increase and decrease the pH of a 10−3 and 10−4 mol/L AMN solution, respectively. Sensors Selectivity. The separate solution method was used to pot ) of the study the potentiometric selectivity coefficients (KA.B developed sensor toward commonly present interfering ions by applying the following equation:30

EXPERIMENTAL SECTION

Apparatus. Potential measurements were carried out using a digital potentiometer, Jenway model 3330 (Essex, U.K.) with double junction Ag/AgCl reference electrode, Orion, ThermoScientific no. 900200. Dissolution Apparatus. A USP 2 (paddle) apparatus, VanKel VK 7000, equipped with standard USP paddles was used to carry out the dissolution tests. Dissolution Conditions. Dissolution was carried out as per the USP and FDA for capsules and tablets containing AMN, respectively.11,29 The apparatus consisted of six 900 mL vessels containing deaerated water in case of AMN capsules and 500 mL in the case of AMN tablets thermostatically adjusted at 37 ± 0.5 °C, and the dosage form was agitated at a rotation rate of 50 rpm for the AMN capsules and 100 ppm for AMN tablets. Chemicals and Reagents. Analytical grade reagents were used all over the experiment. Water used was bidistilled. Nitrophenyl octyl ether (NPOE), sodium tetraphenylborate (TPB), sodium phosphotungstate tribasic (PT), sodium phosphomolybdate (PM) were purchased from Aldrich (Steinheim, Germany). Ammonium reineckate (RN), tetrahydrofuran (THF) and high molecular weight poly(vinyl chloride) (PVC) were purchased from BDH (Poole, England). Poly(vinyl chloride) carboxylated (PVC-COOH) labeled to contain 1.8% as carboxyl was purchased from Selectophore, Fluka.

pot log(KAMN.Interferent )=

E Interferent − EAMN 2.303RT /ZAMNF ⎛ ZAMN ⎞ + ⎜1 − ⎟log a Z Interferent ⎠ ⎝

(1)

Kpot AMN.Interferent

where is the potentiometric selectivity coefficient, E is the potential measured in millivolts, Z is the carried charge a is the activity of the drug, and 2.303 RT/ZAMNF represents the sensor’s slope (mV/decade). Potentiometric Determination of AMN in Its Pharmaceutical Formulations. Ten capsules were evacuated and mixed well. In the case of the tablets, ten tablets were weighed then finely powdered. An accurately weighed portion of the powder claimed to contain 5 × 10−5 moles of AMN base was transferred to a 50 mL volumetric flask to prepare 1.0 × 10−3 mol/L AMN and completed to the mark with water. The potential was recorded using the proposed sensor coupled to the reference electrode, and the concentration of AMN was calculated using the corresponding regression equation. Dissolution Curves by Potentiometric Method. Both the sensor and the reference electrode were immersed into the dissolution vessel, and the potential was recorded at time intervals specified by the official methods. Using the computed regression equation, the concentration of AMN and the percentage dissolution was calculated. 4382


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sensor 5

RESULTS AND DISCUSSION ISE Characteristics. Usually, during dissolution experiments, samples are withdrawn at time intervals specified by the

Table 1. Composition in g % w/w of the Fabricated Sensors composition (% w/w)

sensor 1

sensor 2

sensor 3

sensor 4

PVC PVC-COOH NPOE TPB PT PM RK

31%

31%

31%

31%

67% 2%

67%

67%

67%

sensor 5 33% 67%

45.98 252.76 0.9991 10 4.0−9.0 (1.23 × 10−5)−(1.0 × 10−2) 30

ACS Sustainable Chemistry & Engineering

4383

58.56 318.31 0.9996 4 4.0−9.0 (4.57 × 10−7)−(1.0 × 10−2) 30 a

Average of three determinations.

58.05 438.75 0.9995 4 4.0−9.0 (1.23 × 10−5)−(1.0 × 10−2) 30

sensor 2 sensor 1

a

parameter

Table 2. Electrochemical Response Characteristics of the Fabricated Sensors

sensor 3

official method. The collected samples are collected for the analysis; the preparation may include filtration or sometimes an additional derivatization procedure is mandatory. Afterward, determination of the analyte is carried out using a proper analytical technique. Most of the laboratories rely on UV/ visible spectrophotometry or HPLC-UV for the analysis of the samples. Ion selective electrode potentiometric determination has recently been introduced for dissolution testing. In addition to being an environmentally friendly technique, electrochemical methods have the advantages of rapid response, which is mandatory to construct a dissolution profile as a function of time, with no need for sample withdrawal, and the whole procedure can be automated. For drugs lacking chromophore group such as AMN, the dissolution experiment is an arduous and time-consuming task, where a derivatization step should be carried out prior to detection. The possibility of the applying ion selective membrane electrode technique as a green inline tool for AMN concentration monitoring in its dissolution media and in its pharmaceutical dosage forms. According to its chemical structure, AMN behaves as a monovalent cation owing to the presence of a single basic functional group; therefore, a cation exchanger should be used for membrane construction. Five sensors were fabricated with different composition. Four membranes contained high molecular weight PVC as the matrix along with a suitable solvent mediator and different cation exchangers, namely, sodium tetraphenylborate, sodium phosphotungstate tribasic (PT), sodium phosphomolybdate (PM), and ammonium reineckate (RN) and a fifth membrane consisting of plasticized PVC-COOH, which serves as matrix and sensing material through its carboxyl content.31 Plasticizers complement the characters of PVC required for a membrane sensor through its dual role, they permit the mobility of the ions inside the membrane and acts as solvents for membrane components.32 Moreover, the plasticizer facilitates mobility of AMN form the aqueous phase into the organic membrane and therefore ion exchange. A polar plasticizer, NPOE, was selected for membrane construction to act as a solvent mediator for AMN,8 and the composition of the fabricated membranes is illustrated in Table 1. In situ complex formation was carried out by soaking the fabricated membranes into 10−2 M solutions of AMN, while the reported sensors were prepared by incorporating the prepared ion pair association complex during the preparation of the membrane.27,28 Separation of the complex formation and membrane fabrication steps was found to be more economical

58.05 417.15 0.9990 4 4.0−9.0 (3.70 × 10−5)−(1.0 × 10−2) 30

sensor 4

2%

slope (mV/decade) intercept (mV) correlation coefficient response time (s) working pH range concentration range (mol/L) stability (days)

2%

55.00 291.37 0.9992 4 4.0−9.0 (4.12 × 10−6)−(1.0 × 10−2) 30

2%


Research Article


Figure 2. Profile of the potential in mV versus log the molar concentrations of AM obtained for the five fabricated sensors.

Table 3. Potentiometric Selectivity Coefficients (Kpot AMN,Interferent) of Sensor 3 Using the Separate Solutions Method (SSM) interferent 2+

Co Mg2+ K+ Na+ Ca2+ Ni2+ Mn2+ NH4+ Pb2+ Zn2+ Fe2+

log Kpot AMN,Interferent −2.612 −2.783 −2.714 −2.317 −3.551 −4.473 −2.988 −3.039 −3.175 −3.688 −4.114

Figure 3. Effect of pH on sensor 3 performance.

sensor. Table 2 shows the results obtained for each sensor. Typical calibration plots are shown in Figure 2. The sensors showed stable calibration slopes, within ±1 mV/decade, over a period of 21 days. The near Nernstian slope approaching 60

and enabled versatility in applications since a single membrane can be used for several analytes. The IUPAC recommendations30 was followed to address the electrochemical performance characteristics of the proposed 4384


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The effect of temperature on the response of PM sensor was evaluated. A slight increase in the response was detected as temperature increases in the range of 26−40 °C; however, parallel calibration plots of relatively similar slopes at different temperatures, which indicates relatively stable response at the specified temperature range, Figure 4. Potentiometric Determination of AMN in Pharmaceutical Formulations. The proposed PM sensor was applied for the assay of AMN in tablets and capsules in aqueous solutions without preliminary drug extraction or derivatization, Table 4. Standard addition technique was applied to assess the accuracy of the method, and results are presented in Table 5.

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Figure 4. Effect of temperature on sensor 3 performance.

DISSOLUTION METHOD VALIDATION The third sensor containing PM as ion exchanger was used for dissolution experiment and the method was validated as per the USP guidelines,11 results are illustrated in Table 6.

Table 4. Determination of AM in Pharmaceutical Formulations Using Sensor 3 and Application of Standard Addition Technique

a

pharmaceutical formulations

recovery ± SD%a

Adamine capsule PK Merz tab

98.28 ± 1.27 99.09 ± 1.47

Table 6. Assay Validation Sheet of the Developed Dissolution Method parameter


accuracya precision repeatabilityb intermediate precisionc robustnessd LODe (mol/L) linearity slope intercept correlation coefficient (r) range (mol/L)

mV suggested that the reaction between AMN and the ion exchangers occurred in the ratio of 1:1. The concentration of AMN was increased by 10-fold, and the time required to reach a stable response within ±1 known as the dynamic response time was recorded. It was found to be 4 s for all sensors except for sensor 5 where the response time reached 10 s. Results suggest better performance characteristics for the first four membranes. Table 2 shows that sensor 3 containing PM as ion exchanger has the highest sensitivity and can detect AMN in very dilute solutions reaching 4.57 × 10−7 mol/L. This concentration enables monitoring AMN concentration in the specified volume of the dissolution medium down to less than 1% of its labeled amount. Sensor 3 was used for all subsequent measurements. The mentioned electrode expressed good selectivity for the drug when tested in the presence of common interfering ions, Table 3. The pH effect on the response of the electrode was studied in different pH values ranging from 2.0 to 10.0, as shown in Figure 3. The potential was almost pH-independent in the range from 3 to 9, which could be attributed to the high pKa of AMN (pKa = 10.7), (Figure 3).

AMN 99.89 0.87 1.25 1.70 × 10−7 58.56 318.31 0.9996 (4.57 × 10−7)−(1.0 × 10−2)

Average recovery percentage of three concentrations (10−5, 10−4, and 10−3 mol/L) of AMN. bThe RSD of three concentrations (10−5, 10−4, and 10−3 mol/L) of AMN repeated three times during the same day. c The RSD of three concentrations (10−5, 10−4, and 10−3 mol/L) of AMN repeated three times in three successive days. dThe RSD of determinations of three concentrations (10−5, 10−4, and 10−3 mol/L) of AMN in different dissolution conditions summarized in Table 7. e Limit of detection is the concentration at the point of intersection of the extrapolated arms of the potential versus logarithm of the concentration plot of AMN using sensor 3. a

Specificity. The effect of common tablet and capsule excipients was evaluated in water as the dissolution medium of

Table 5. Application of the Standard Addition Technique on the Dosage Forms pharmaceutical formulations

taken mol/L

recoverya %

added mol/L

found mol/L

recoverya %

Adamine capsule

1 × 10−3

98.28 ± 1.27

2 × 10−3 4 × 10−3 6 × 10−3

1.96 × 10−3 3.96 × 10−3 6.05 × 10−3

2 × 10−3 4 × 10−3 6 × 10−3

1.99 × 10−3 4.06 × 10−3 5.92 × 10−3

97.89 99.12 100.87 99.29 1.50 1.51 98.79 101.41 98.72 99.88 1.38 1.38

mean SD RSD % PK Merz tab

1 × 10−3

99.09 ± 1.47

mean SD RSD % a

Average of three determinations. 4385


Research Article


The obtained results ensure the robustness of the method, Table 7. Potentiometric Determination of AMN in Its Dissolution Medium. Dissolution profile can evaluate the capacity of the dosage form to release the active ingredient as a function of time. A sensitive analytical method is required to assess the dissolution profile since the concentration of the active ingredient is relatively small at the initial time intervals specified by the official methods. For AMN capsules, the USP dissolution medium is 900 mL of water while for the tablets the FDA dissolution medium is 500 mL of water and hence, the sensitivity of the suggested PM sensor enables the determination of AMN concentration down to about 0.08% of its labeled amount (100 mg/capsule) and up to 0.046% of its labeled amount (100 mg/tablet) in these dissolution volumes which is sufficient to monitor AMN during the whole dissolution profile. The concentration of AMN was obtained from the regression equation of the linear relationship between the potential in millivolts and the concentration of the drug. Percentage drug release was then calculated and plotted versus each time interval for adamine capsules, Figure 5, and PK-Merz tablets, Figure 6.8 Comparison between the Suggested Method of Analysis and the Official USP Method.11 The USP pharmacopeia describes a GC method of analysis for the assay and for monitoring the dissolution of amantadine hydrochloride from its capsule dosage form. This method involves the use of hazardous solvents and chemicals (naphthalene, hexane, hydrochloric acid, and sodium hydroxide), several steps of sample pretreatment before the final measurement, samples are frequently withdrawn at several time intervals, collected for subsequent assay. The developed inline method is simply carried out by dipping the sensor with and the reference electrodes into the dissolution vessel, measurements are recorded directly at the specified time intervals, with no sample withdrawal, collection, or subsequent derivatization or analysis procedures. A simple comparison between the proposed method and the USP official dissolution method can manifest that the proposed potentiometric method is a green environmentally friendly method that cut short time, effort, and money required for AMN dissolution experiment.

Table 7. Robustness of the Developed Method parameter pH (±0.3) temperature (±3 °C) agitation rate (±5 rpm) a

variation 6.8 6.2 34 °C 40 °C 70 rpm 80 rpm

RSD %a 0.160 0.354 0.081


Figure 5. Dissolution profile for Adamine capsules by in-line potentiometric procedure using sensor 3.

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Figure 6. Dissolution profile for PK-Merz tablet by in-line potentiometric procedure using sensor 3.

AUTHOR INFORMATION

Corresponding Author

AMN and the electrode represented a relatively high selectively for AMN, as shown in Table 3. Linearity and Range. Calibration graphs showed a linear relationship in the range of 4.57 × 10−7 to 1.0 × 10−2 mol/L, which covers the approximately 0.08−2000% of the labeled AMN dose according to the officially specified volume of dissolution medium, Table 6. Accuracy. The recovery percentage of three different concentrations (10−5, 10−4, and 10−3 mol/L) of AMN in the dissolution medium was determined to assess the accuracy of the method, Table 6. Precision. To assess the precision of the method, the potential and subsequent recovery of three concentrations (10−5, 10−4, and 10−3 mol/L) were determined three times within the same day (repeatability) and on three successive days (intermediate precision), and the results are shown in Table 6. Robustness. Robustness of the dissolution experiment was assessed for pH, temperature, and agitation rate parameters.

*E-mail: [email protected]. ORCID

Ahmed S. Saad: 0000-0002-9130-9083 Notes

The authors declare no competing financial interest.

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Green in-Line Ion Selective Electrode Potentiometric Method for

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