Kinetic and Thermodynamic Spectrophotometric Technique to Estimate Gabapentin in Pharmaceutical Formulations using Ninhydrin
© Siddiqui et al.; licensee Springer. 2013
Received: 11 June 2013
Accepted: 26 September 2013
Published: 31 October 2013
Simple and sensitive spectrophotometric method is described based on the reaction of drug (gabapentin) with ninhydrin in pure form and in pharmaceutical preparations.
Complex formed during this reaction is measured at 575 nm as a function of time. Kinetic study involve initial-rate, rate-constant and fixed-time (80 minutes) procedures to determine the concentration of the drug.
Drug was studied in the concentration range of 10-30 ?gmL-1 showing correlation coefficient 0.9997, 0.9970 and 0.9990 for initial rate, rate constant and fixed time respectively. Limit of detection (LOD) and limit of quantification (LOQ) was found to be 0.13 and 0.04 nana grams respectively. The variables affecting the reactions were optimized and the developed method was validated according to ICH guidelines.
The proposed method has been efficiently applied to the estimation of gabapentin in pharmaceutical formulation with first-class recovery (98.3-101.4%). Thermodynamic parameters were studied i.e., association constants and standard free energy changes were determined by Benesi?Hildebrand equation while, Gibbs free energy change for the complex was also estimated.
The new anti-convulsant drug gabapentin (1-(aminomethyl)cyclo-hexaneacetic acid) is a GABA analogue. It was originally developed for the treatment of epilepsy, and currently, gabapentin is widely used to relieve pain, especially neuropathic pain, it is indicated in the treatment of epilepsy and neuropathic pain, also in the treatment of bipolar disorder and may be effective in reducing pain and spasticity in multiple sclerosis. Gabapentin is a ?-aminobutyric acid (GABA) analogue that does not bind to GABA receptors or alter GABA metabolism in the brain (Goldlust et al. 1995). Its action is attributed to the irreversible inhibition of the enzyme GABA-transaminase, thus preventing the physiological degradation of GABA in the brain (Ouellet et al. 2001). Analytical methods reported for its determination consist of high-performance liquid chromatography (HPLC) (Jiang & Li 1999; Tang et al. 1999; Chollet et al. 2000; Ifa et al. 2001; Ratnaraj & Patsalos 1998; Wad & Kramer 1998), spectrofluorimetry (Belal et al. 2002; Hassan et al. 2001), gas chromatography?mass spectrometry (GC?MS) (Kushnir et al. 1999; Van Lentea & Gatautis 1998), capillary electrophoresis (Rada et al. 1998) and spectrophotometry applying Hantzsch reaction (al-Zehouri et al. 2001). So far, no traces of any attempts have been found for determination of gabapentin by colorimetric method and the literature is still starving for such analytical procedures. There are number of methods for determination of gabapentin in literature (Manera et al. 2009; Lin et al. 2004; Jia et al. 2012; Ribeiro et al. 2007; Abdulrahman & Basavaiah 2011; Abdulrahman & Basavaiah 2012; Jalali et al. 2007; Hegde et al. 2009; Patel et al. 2011; Siddiqui et al. 2010).
Reactions with ninhydrin (NIN) has been widely used to analyze and characterize amino acids, thiophen and proteins as well as numerous other NIN positive compounds in biomedical, clinical, food, forensic, histochemical, microbiological, nutritional and plant studies (Friedman 2004). It has been extensively used in the determination of the compounds of pharmaceutical importance applied to their kinetic studies (Rahman & Azmi 2001a; Campins-Falco et al. 1996; Arayne et al. 2008). Present study describes a direct, sensitive and precise spectrophotometric method simpler than the existing UV and HPLC methods that is free from such experimental variables as extraction step for the determination of gabapentin in reference material and pharmaceutical formulations by means of developing charge transfer complex with NIN.
No interference was observed in the assay of gabapentin from common excipients in levels found in pharmaceutical formulations. The method rely on the use of simple and inexpensive technique but give out sensitivity analogous to that procured by sophisticated and expensive techniques such as HPLC, and are validated as per ICH recommendations (ICH Topic Q2(R1) 2005). The kinetic approach for determining gabapentin in commercial dosage form, using NIN as a reagent, confer simplicity and rapidity as the procedure simply require heating and cooling of the reaction mixture. During this study the reaction conditions and application of the methods for determination of gabapentin in pharmaceutical formulations have been established, in addition, the association constant, stoichiometric ratio of reactants and the standard free energy changes (?G?) were determined.
Our present study suggests kinetic and thermodynamic spectrophotometric procedure for the determination of gabapentin in pharmaceutical formulations. The methods are based on the reaction of primary amino group of gabapentin with NIN.
Shimadzu 1601 double beam UV?visible spectrophotometer possessing a fixed slit width (2?nm) with quartz cells of 10?mm path length connected to a PIV computer loaded with Shimadzu UVPC version 3.9 software were used to record the absorption spectra.
Materials and reagents
All reagents were of analytical grade. Gabapentin pure drug was obtained from Godecke AG, Darmstadt, Germany under license of Park-Davis (Pvt.) Ltd. Karachi, Pakistan. Gabin? capsules 200?mg (PharmEvo Pharmaceutical Company (Pvt.) Ltd., Karachi, Pakistan), Gaba? capsules 100?mg (Nabi Qasim Pharmaceuticals (Pvt) Ltd., Karachi, Pakistan), Gabaplus? capsules 100?mg (Platinum Pharma (Pvt.) Ltd., Karachi, Pakistan) and Neupentin? capsules 400?mg (Highnoon Pharma (Pvt.) Ltd., Karachi, Pakistan) were purchased from the market. Ninhydrin was purchased from Merck Schuchardt OHG, Darmstadt, Germany. HPLC grade methanol was from fisher scientific UK.
Preparation of standard stock solutions
Solution of 0.1 mgmL?1 gabapentin was prepared in water by dissolving 10?mg of gabapentin in 100?mL of purified water and stored in a cool (<25?C) and dark place. Ninhydrin reagent was 2 mgmL?1 in methanol and was prepared fresh daily.
Aliquots of 1?mL of stock solution corresponding to 100 ?gmL-1 of gabapentin were transferred into heating tubes. 2?mL of 1% NIN solution was added and heated on boiling water bath for 2?hours, after cooling the mixture was transferred into 25?mL volumetric flask and diluted to volume with distilled water. Increase in absorbance at 575?nm was recorded as a function of time against the reagent blank at room temperature (spectra 1). The initial rate of reaction at different concentrations was calculated from the initial slope of absorbance time curve. The calibration curves were constructed by plotting logarithm of initial-rate of reaction versus logarithm of molar concentration, rate-constant versus final concentration and absorbance measured at a fixed-time versus final concentration of gabapentin.
Procedures for pharmaceuticals formulation
Twenty capsules of each formulation were weighed and powdered. The powder equivalent to 10?mg of gabapentin was dissolved in 100?mL of water to give 0.1?mg?mL-1 of gabapentin. The procedure was continued as described under general procedures.
Job?s method of continuous variation (Rose 1964) was employed. Master equimolar solution of gabapentin was prepared in water whereas NIN was prepared in methanol and made up to volume with the same solvent. A series of 10?mL portions of master solution of gabapentin with NIN was made up comprising different complementary proportions (0:10, 1:9, 2:8??9:1) in 10-mL calibrated flasks. The absorbance of the resulting solutions were measured at the wavelength of maximum absorption after the appropriate time against reagent blanks treated similarly.
Interference from excipients
Samples were prepared by mixing 50?mg of gabapentin with various amounts of common excipients such as glucose, lactose, talc powder, magnesium stearate, pyrrolidone, HPMC (hydroxypropylmethylcellulose) and starch. The procedure was continued as described under general procedures.
Results and discussion
Gabapentin exhibits a very low UV absorption, with A1% 1cm at 276?nm?=?6.5 (Abdellatef & Khalil 2003) and as a result poor sensitivity will be achieved by conventional UV spectrophotometric methods. There was a critical need to develop a spectrophotometric method that could quantitate gabapentin in pharmaceutical formulations.
Reaction with Ninhydrin (NIN)
Ninhydrin reagent is used for the determination of an aliphatic primary amine or an amino acid group (Friedman 2004; Rahman & Azmi 2001a; Campins-Falco et al. 1996; Arayne et al. 2008; Rahman & Azmi 2001b; Nobrega Jde et al. 1994; Molnar-Perl & Pinter-Szakacs 1989). The presence of an aromatic ring exhibits the response; the exhibition increases if the amino group is nearer to the ring. The end product of NIN reaction with amino acid (Ruhemanns purple) give best color in methanol, however water can be used as good option in case when extraction of the active molecule is compromised. The reaction mixture is heated for a short while and is measured at maximum wavelength 568?nm which is dependent on solvent system and reaction condition (G?r?g 1995).
Gabapentin was found to be competent of reacting with NIN only at higher temperatures. Maximum color was obtained by heating on a water bath at 70???5?C for 80?minutes. Prolonged heating decreased the chromogenic intensity, so the reaction time should be controlled. Different solvents such as water, ethanol, methanol, isopropanol, and acetonitrile have been tried, but the best results were obtained with methanol.
Optimization of reaction
The reaction between gabapentin and ninhydrin in methanol resulted in the formation of blue colored complex. At 70?C, the intensity of color increased with time and became stable after 80?minutes.
Initial rate method
In order to study the kinetic parameters of the proposed reactions, the initial rate of the reaction was determined by using time curve (from the measurement of the slope of the initial tangent to the absorbance). Concentration of NIN was kept constant and the reaction was studied at different concentrations of gabapentin to establish the order of reaction with respect to gabapentin. For each run, a plot of log A?/A??At versus time was a straight line indicating a first order reaction. The first order rate constant was also estimated from the slopes of the above plot.
Statistical and regression data of proposed method
Correlation coefficient (r)
The value of ?n? in the regression equation also indicated the first order reaction with respect to gabapentin concentration. The calibration curve constructed in the range of 10-30 ?gmL-1 (absorbance of different concentrations of gabapentin versus time) showed a linear relationship.
Method of rate constant
Concentration ?gmL -1
Calculated Value of Rate Const
(slope) Min -1
Fixed time method
Regression characteristics of gabapentin concentration at different time interval
Correlation coefficient (r)
Accuracy and precision of proposed method
Determination of gabapentin in pharmaceuticals formulations by proposed
Gabaplus 100?mg cap (Platanium)
Gabin 200?mg cap (PharmEvo)
Neupentin 400?mg cap (Highnoon)
Gaba 100?mg cap (NabiQasim)
Stoichiometry of the reaction
On observing the molar ratio of the gabapentin with NIN using Job?s method of continuous variation (Rose 1964), it was found to be 1:2 for NIN.
Association constants and standard free energy changes
where Ca and Cb are the concentrations of the acceptor and donor respectively, A is the absorbance of the complex, ? is the molar absorptivity of the complex and K c is the association constant of the complex.
Where ?G? is the free energy change of the complex (kJ?mol?1), R the gas constant (1.987?cal?mol?1?deg?1), T the temperature in Kelvin (273?+?C) and K c is the association constant of drug-acceptor complexes (1?mol?1).
Linearity, accuracy and precision
Linearity, accuracy and precision were assessed for the method in the range of 10 to 30 ?gmL-1. Regression statistics were calculated for the colorimetric procedures and linear regression plots showed the directly proportional relationship of absorbance over Beer?s law range given in Tables?1 and 4. The table also shows the results of the statistical analysis of the experimental data, such as the slopes, the intercepts, the Square of correlation coefficients obtained by the linear least-squares treatment of the results.
Five different concentrations of gabapentin were prepared, each solution was analyzed in five replicate to evaluate the accuracy and precision of the methods.. The mean Standard Deviation and% relative standard deviation (%RSD) as depicted in Table?4 were found to be in the acceptable range of (0.0793 ? 0.8376) and (0.494 ? 0.8317) respectively.
It was observed that at specific wavelength the absorption intensity was dependent upon the concentration of gabapentin. It was observed that Beer?s law was followed in all cases with very small range of intercept values (-0.0028 to 0.0021) and slopes ranged from (0.01018 to 0.0146) for the concentration ranges as described in Table?1. The correlation coefficient values were found to be in the range of 0.9970 ? 0.9997 using the least-square method.
Recovery of Gabapentin in presence of different excipient
Limit of detection (LOD) and limit of quantification (LOQ)
The theoretically determined values of LOD and LOQ for gabapentin with NIN were cross checked by actual analysis of these concentrations using proposed methods. LOD of gabapentin with NIN 0.04??g?mL?1 while LOQ were 0.13??g?mL?1.
Analysis of pharmaceutical dosage forms
The determination of gabapentin in formulation was carried out using the proposed charge transfer spectrophometric method along with the reference method (Abdellatef & Khalil 2003) using the same samples. Similar accuracy and precision were observed for the calculated and theoretical values (95% confidence) of the proposed and official methods as no remarkable difference was observed for the t and F tests. From Table?5 it is apparent that the present method can be followed for the analysis of these drugs in their single dosage forms. The recoveries in the range from 98.3 to 101.4% clearly showed no interference of any excipients of formulation.
The IR spectra of gabapentin+Nin Complex showed neither the expected doublet of primary NH2 in the region 3200 ? 3400?cm-1 nor the usual carbonyl stretch of COOH near 1710?cm-1. Instead multiple peaks were observed in the region 2500 ? 3000?cm-1 that can be attributed to ammonium ion (NH3 +), the asymmetric and symmetric peaks of carboxylate ion were observed at 1600 and 1400?cm-1 coincide with the one observed in amino acids (Wright & Vanderkooi 1997) and NH3 + bending at 1550?cm-1 conclude that the gabapentin exists in zwitterionic form. Our studies match up to the already reported infrared absorptions of gabapentin (Chimatadar et al. 2007).
NIN produced two broad bands at 3300 and 3250?cm-1 and a C-O stretching at 1061?cm?1 signify the presence of two OH groups. The carbonyl gave two peaks in the region 1660 to 1760?cm?1. Aromatic resonance appeared at 750?cm?1 (Arayne et al. 2008; Charles & Pouchert 1989; Charles & Pouchert 1981).
Primary amines to give Ruhemann?s Purple complex with NIN (Arayne et al. 2008). The formation of the complex was evidenced by comparing the spectra of complex with parent reactant. Many of the functionalities of NIN and gabapentin were found absent which confirms the formation of complex. The doublet of carbonyl in NIN changed significantly into one single sharp peak at 1680?cm-1 and the broad band of O-H shifted to 3400?cm-1.
Nuclear magnetic resonance spectra
The 1H NMR spectra of gabapentin showed two ?CH2 peaks at ? 2.443 and ? 2.873?ppm and the cyclohexyl protons appeared in the region of ? 1.365?1.585?ppm. The likely peak of NH2 near ? 2?ppm and that of carboxylic OH near ? 11?ppm were not observed but one peak of NH3+ at 4.849 ? ppm was observed, may be as suggested earlier, due to zwitterion formation. Same is also reported in literature (Chimatadar et al. 2007). NIN exhibited two singlets at ? 7.240 and ? 7.446?ppm for the four protons of the aromatic group and a singlet at ? 1.52?ppm for two protons of the OH group. This coincides with the reported studies (Arayne et al. 2008; Charles & Pouchert 1981). By studying the 1H-NMR spectrum of the gaba-NIN complex it was found that the NH2 protons completely diminished and the broad multiplet appearing between ? 7.42 and ? 8.163?ppm showing eight aromatic CH protons. A singlet at ? 4.803?ppm represents the enolic OH proton. The above results were found in accord with UV and IR spectra, confirming the proposed structure.
The data given above divulge that the proposed methods are easy, accurate and sensitive with good precision and accuracy. With these methods, one can do the analysis with pace at low cost without losing accuracy. The proposed methods can be used as alternative methods to the reported ones for the routine determination of gabapentin in pharmaceutical formulations. This encourages their successful use in routine analysis of these drugs in quality control laboratories.
FAS designed, coordinated and carried out experiments the study. NS, NS and HS carried out experiments, FAS, NS, NS, HS and AZ drafted the manuscript. All authors read and approved the final manuscript.
Valuable comments of two anonymous reviewers are acknowledged.
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