Differential Pulse Voltammetric Determination of Clozapine in Drug

Hittite Journal of Science and Engineering, 2021, 8 (1) 71–77 ISSN NUMBER: 2148–4171 DOI: 10.17350/HJSE19030000215

Differential Pulse Voltammetric Determination of Clozapine in Drug Dosage Forms at Bismuth Film Electrode Ozlem Kurtoglu Yigit Ebru Gokmese Faruk Gokmese Hitit University, Department of Chemistry, Corum, Turkey Article History: ABSTRACT Received: 2021/01/20 Accepted: 2021/03/06 Online: 2021/03/31 new differential pulse voltammetric method for the determination of clozapine in drug dosage forms has been described. In this study, the amount of clozapine in com- Correspondence to: Ebru Gokmese, Hitit A University, Department of Chemistry, mercial forms has been determined at bismuth modified glassy carbon electrode by taking 19030, Corum, Turkey advantage of the electrochemical oxidation of it. The glassy carbon electrode was modified E-Mail: [email protected] Phone: +90 364 227 7000 with BiCl3 to prepare the bismuth film electrode. The acetate buffer solution at pH = 5.00 Fax: +90 364 227 7005 was selected as the supporting electrolyte in where the maximum current was observed for clozapine at the bismuth film electrode. The effect of pH on peak current and peak potential of clozapine was investigated by differential pulse voltammetry (DPV), and the effect of scan rate on the peak current was examined by cyclic voltammetry (CV). With this developed voltammetric method, the detection limit for clozapine in the working range of 1 µM and 10 µM was found to be 6.112×10-9. The amount of clozapine in the drug tablets was stated after the determination of analytical parameters. The recovery study was executed to check the accuracy and precision of the applied method. Keywords: Clozapine; bismuth film; drug analysis; modified electrode; differential pulse voltammetry

INTRODUCTION

lozapine, which has a heterocyclic structu- methods such as chromatography [6,7] and spectrop- re is 8-chloro-11-(4-methyl-1-piperazinyl)- hotometry [8] have been used to determine dosage C5H-dibenzo-diazepine and Fig. 1 shows the chemical forms. Studies on the therapeutic and toxic effects of structure of this compound [1,2]. Clozapine, which drugs have shown that sensitive methods are required is a strong antipsychotic agent from the dibenzodi- to obtain results at the trace level. The sensitivity of the azepine group, is called a typical antipsychotic since studies with spectroscopic methods is not sufficient. it has typical pharmacological and clinical features. Voltammetric and polarographic studies of the elect- Many studies comparing clozapine with traditional rochemical behavior of clozapine are available in the antipsychotics have shown that clozapine is at least as literature [9,10]. To date, techniques for the detection effective as traditional antipsychotics, even in some of clozapine, including high-performance liquid chro- cases, this effect has increased [3]. matography, spectrophotometry, chemiluminescence, capillary electrophoresis, and titrimetry, are available Clozapine has been used in the treatment of pa- [11, 12]. These methods, however, are exhausting, costly, tients with schizophrenic resistant to treatment who and require the pretreatment of samples. On the other are caused by neuroleptic drugs that block the typical hand, electrochemical techniques such as voltammetry D2 receptor and develop unsuccessful physiological supply a wide linear working range as well as high preci- conditions. Also, clozapine treatment as in conventi- sion, low cost, and high accuracy. Therefore, studies on onal antipsychotics stops the abnormal movements of the electrochemistry of drugs have increased in recent Tardive dyskinesia and clozapine can additionally cure years [13, 14]. Since clozapine is a good electroactive the defect of movement. On the other hand, clozapine substance, electroanalytical results of oxidation beha- is partially active in the treatment of tardivdistonia [4, vior in different electrodes have been described [15,16]. 5]. Clozapine is also used to treat some schizophrenic patients cannot be treated by traditional neuroleptic Electrochemical techniques are strong and mul- drugs. Since the analysis of clozapine in pharmaceutical tipurpose analytical techniques that can easily solve and chemical liquids is important, different analytical many pharmaceutical-related problems. Especially vol- E. Gokmese at al. / Hittite J Sci Eng, 2021,8 (1) 71–77 Apparatus and Instrumentation and Apparatus A 1×10 A Voltammetric studies were performed with CH Instru CH with were performed studies Voltammetric (pH 3.50 - 8.00) as supporting electrolyte was investiga was electrolyte supporting as - 8.00) (pH 3.50 MATERIAL AND METHODS AND MATERIAL Reagents Clozapine and drug tablets are commercially available. available. commercially are tablets drug and Clozapine NaOH (Reidel de Haen). Glassy carbon electrode was po was electrode carbon NaOH (Reidel Haen). de Glassy electrode as a working electrode, Ag/AgCl electrode as as electrode Ag/AgCl electrode, aworking as electrode carbon glassy coated bismuth formed system electrode Britton-Robinson (pH 3.50-8.00) and 0.2 M acetate buffer buffer Macetate 0.2 and (pH 3.50-8.00) Britton-Robinson cloth. Also, argon gas (99% purity), methanol, and deioni and methanol, (99% purity), gas argon Also, cloth. de Haen, 100%), Haen, de H que with high sensitivity, selectivity, large linear range, and and range, linear large selectivity, sensitivity, high with que was prepared in 0.2 MKCl 0.2 solution. in prepared was ments 660C Model Potentiostat/Galvanostat. A triple Atriple Potentiostat/Galvanostat. Model 660C ments develop a sensitive electrochemical methodology for direct for direct methodology electrochemical asensitive develop to and of clozapine properties electrochemical the examine clozapine, of determination properties, on electrochemical methanol and stored in the fridge. In all voltammetric voltammetric all In fridge. the in stored and methanol a bismuth-coated glassy carbon electrode, 100 ppm BiCl 100 electrode, carbon glassy a bismuth-coated performed on bismuth film electrode. This study aims to to aims study This electrode. film on bismuth performed formulations on bismuth film electrode using voltammetric voltammetric using electrode film on bismuth formulations stock solutions with methanol. The suitability of 0.04 M of 0.04 suitability The methanol. with solutions stock the bydiluting were prepared solutions standard studies, size alumina powders and deionized water on the Buehler Buehler on the water deionized and powders alumina size and rapid determination of clozapine from pharmaceutical pharmaceutical from clozapine of determination rapid and were techniques voltammetric of applied validation and ting electrolytes were prepared with CH with prepared were electrolytes ting suppor and Buffers selected. was buffer acetate and ted lished with slurries prepared from 1, 0.3 and, 0.05-micron 0.05-micron and, 1, 0.3 from prepared slurries with lished zed water were used without any purification. To prepare purification. any without were used water zed tammetry is an effective electrochemical analytical techni analytical electrochemical effective an is tammetry techniques. have no studies literature, the in of clozapine behavior tion oxida on the studies are there Although devices. low-cost been found with bismuth film electrode. Therefore, a study astudy Therefore, electrode. film bismuth with found been Figure 1. -2 The chemical structure of Clozapine Clozapine of structure chemical The M stock solution of clozapine was prepared in in prepared was of clozapine solution Mstock 3 PO (Carlo Erba, 35%), Erba, 4 (Carlo H 3 COOH (ReidelCOOH 3 B0 (Merck), 3 (Merck), 3 ------72 The stock solution of 1×10 solution stock The Therefore, the GC (CHI 104, 0.071 cm 0.071 104, (CHI GC the Therefore, The Procedure of Pharmaceutical Preparations of Pharmaceutical Procedure The Measurements executed at ambient laboratory tempera laboratory at ambient executed Measurements RESULTS AND DISCUSSION AND RESULTS volumes of these stock solutions. The measurements for measurements The solutions. stock of these volumes versus the Ag/AgCl electrode. pH measurements were pH measurements electrode. Ag/AgCl the versus containing 1×10 containing clozapine. Ten drug tablets (each tablet conta (each tablet Ten tablets clozapine. drug containing tablet drug the from started was process determination daily in methanol. The standard solutions for the calib for the solutions standard The methanol. in daily Bismuth-coated glassy carbon electrode is used as awor as used is electrode carbon glassy Bismuth-coated Preparation of Working Electrode Working of Preparation cal characterization of the bismuth coated GC electrode electrode GC coated bismuth of the characterization cal cene were demonstrated in Fig. 2 and Fig. 3, respectively. 3, Fig. 2and Fig. in were demonstrated cene water used in the preparation of the solutions was obta was solutions of the preparation the in used water aPL-700PV deionized pH meter. The model with made was achieved by using 1 mM dopamine and ferrocene ferrocene and dopamine 1mM byusing achieved was ration study were prepared by diluting the appropriate appropriate the bydiluting were prepared study ration rode was used. All voltammetric responses were taken were taken responses voltammetric All used. was rode r rometric technique at -1 V potential. The electrochemi The at -1 Vpotential. technique rometric us medium was buffered with acetic acid/sodium acetate acetate acid/sodium acetic with buffered was medium us previously [17]. ppm 100 BiCl was solution previously coating The amplitude, 50 mV; pulse width 50 ms; scan rate, 20 mV 20 rate, s scan mV; ms; 50 50 width amplitude, pulse peaks belong to electrochemical oxidation and reduction of of reduction and oxidation electrochemical to belong peaks king electrode. The first step of the modification process process modification of the step first The electrode. king and 0.05 µm alumina particles, respectively, as described described as respectively, particles, alumina µm 0.05 and solution in 0.5 M KCl supporting electrolyte. The aqueo The electrolyte. MKCl supporting 0.5 in solution ture. solutions. The voltammograms for dopamine and ferro and for dopamine voltammograms The solutions. ter preparing the calibration graph (10 graph calibration the preparing ter lished successively in alumina slurries in which 1-, which in 0.3-, slurries alumina in successively lished the GC in the coating solution and then apply the ampe the apply then and solution coating the in GC the ining 25 mg clozapine according to the label) were weig label) the to according clozapine mg 25 ining the electrode was successfully coated with bismuth. At the At the bismuth. with coated successfully was electrode the that distinguished it is GC, coated bismuth and GC bare the buffer solution. The coating step was performed to dip dip to performed was step coating The solution. buffer ined from the Zeneer Power-Water Purification System. Power-Water System. Zeneer the from ined Purification in a 100 mL volumetric flask. volumetric mL a100 in individual concentration was repeated three times. Af times. three repeated was concentration individual bare GC, there is only one anodic peak observed at about at about observed peak one anodic only is there GC, bare is polishing a commercial glassy carbon electrode (GC). electrode carbon glassy acommercial polishing is hed and well ground to a fine powder. The stock solution solution powder. stock The afine to ground well and hed 0.5 V potential with an accompanying cathodic peak. These These peak. cathodic accompanying an with Vpotential 0.5 eference electrode and platinum wire as a counter elect acounter as wire platinum and electrode eference When we compare the voltammetric results from both both from results voltammetric the we compare When Differential pulse voltammetry conditions were: Pulse Pulse were: conditions voltammetry pulse Differential -2 M clozapine in methanol was prepared prepared was methanol in Mclozapine -2 M clozapine was prepared prepared was Mclozapine -5 µM - 1 µM), the the -1µM), µM area) was po was 2 area) -1 . 3 ------Figure 4. Figure 2. The cyclic voltammograms for 1 mM dopamine solution in The cyclic voltammograms for 2 µM clozapine solution in 0.5 M NaCl supporting electrolyte at a) the bare GC electrode and b) the 0.2 M acetate buffer (pH=5.00) solution at a) the bare GC electrode and -1 bismuth coated GC (bismuth film) electrode (scan rate: 0.1 Vs-1). b) the bismuth coated GC (bismuth film) electrode (scan rate: 0.1 Vs ).

The Electrooxidation of Clozapine at Bismuth Modified GC Electrode

The electrooxidation of clozapine was investigated using two different electrodes. When the peak currents of clozapine at bare GC and bismuth coated GC electrodes were compared, the calculation showed that the peak current for the modified electrode (bismuth coated GC) is approximately 75 times higher than that of bare GC electrode. This result demonstrated that the new modified electrode was more sensitive than the commercial GC electrode (Fig. 4).

Figure 3. The cyclic voltammograms for 1 mM ferrocene solution in 0.1 M TBATFB supporting electrolyte in acetonitrile at a) the bare GC Determination of Optimum Conditions for electrode and b) the bismuth coated GC (bismuth film) electrode (scan Oxidation of Clozapine rate: 0.1 Vs-1). The effects of pH and supporting electrolyte on the oxi- dopamine. On the other hand, one different anodic peak ad- dation potential and peak current were monitoring vario- ditionally shows up at about -0.1 V potential, which is more us conditions. First, the conditions for which the highest negative than that of dopamine. This new narrow peak was current was observed for the oxidation of clozapine were attributed to the oxidation of bismuth on the GC surface determined. Using differential pulse voltammetry (DPV) (Fig. 2). technique, the dependence of peak current and potential on pH was investigated in both acetic acid/acetate and In addition to the dopamine test, the electrochemical Britton Robinson buffer solutions as a supporting elect- behavior of ferrocene also supported the coating of GC with rolyte. The results are tabulated in Table 1 for acetate and bismuth. Fig. 3 shows the cyclic voltammograms of 1 mM BR buffer solutions. ferrocene solutions. The first one belongs to the electrochemical oxidation of ferrocene at bare GC electrode. On the The change in the peak current with pH was also plot- other hand, the second one represents the same reaction ted (Fig. 5) as well as peak potential (Fig. 6). but at the bismuth coated GC electrode. As shown from the results, there are some differences between the two According to the results given in Table 1 and the be- voltammograms. The oxidation potential shifted to a more haviors observed in Fig. 5 and Fig. 6, the maximum peak negative value because of the surface change. This behavior current was 0.5958 µA and obtained in an acetate buffer gave a hint about the potential catalytic effect of bismuth. solution with a pH of 5. Fig. 5 shows the effect of pH on the Besides, a new oxidation peak showed up at around -0.2 V in oxidation of clozapine. As seen from the figure, anodic peak the case of bismuth coated GC electrode. This potential is potentials away from positive values as the pH values incre- very near to the oxidation of bismuth on the surface. These ase. This change occurred as the potential value decreased results confirmed the modification of the GC electrode with GokmeseE. at al. / Hittite J Sci Eng, 2021,8 (1) 71–77 from 384 mV to 216 mV as the pH increased from 3 to pH 8. bismuth and preparation of bismuth coated GC electrode. This behavior shows that protons are involved in the electrode process.

73 E. Gokmese at al. / Hittite J Sci Eng, 2021,8 (1) 71–77 Table 1. Table on the electrochemical oxidation of clozapine (2 µM clozapine, 0.2 M 0.2 clozapine, (2 µM clozapine of oxidation electrochemical the on of 2 µM clozapine solution. clozapine of 2 µM acetate buffer, 0.04 M BR buffer) MBR 0.04 buffer, acetate scan rates from 10 mVs from rates scan 2 µM clozapine solution. clozapine 2 µM acetate buffer solution (pH=5.00). solution buffer acetate Figure 5. Figure 7. Figure 6. 5. 3. 8. 6. pH pH 5 0 5 0 0. 0. 0. 0. Current(µA) Voltammetric results for the study of pH and buffer type effect effect type buffer and pH of study the for results Voltammetric 357 583 596 032

The effect of pH from different buffers on the peak current of of current peak the on buffers different from pH of effect The The effect of pH from different buffers on the peak potential potential peak the on buffers different from pH of effect The The cyclic voltammograms of 2 µM clozapine for different different for clozapine 2 µM of voltammograms cyclic The Acetate Buffer -1 to 450 mVs 450 to 0. 0. 0. 0. Potential (V) 320 204 080 444 -1 at bismuth film electrode in 0.2 M 0.2 in electrode film bismuth at 0. 0. 0. 0. Current(µA) 380 540 171 489 BR Buffer BR 0. 0. 0. 0. Potential (V) 328 384 216 264 74 The analytical working range was determined according according determined was range working analytical The investiga been has (2 µM) of clozapine oxidation The The Variation of Current with The Scan Rate Scan The with of Current Variation The electrode in 0.2 M acetate buffer solution (pH=5.00). solution buffer Macetate 0.2 in electrode root of scan rate (v rate scan of root Determination of Analytical Working Range of Analytical Determination voltammetry (CV). The voltammograms obtained from from obtained voltammograms The (CV). voltammetry of the peak current and the scan rate is examined (Fig. 8), (Fig. examined is rate scan the and current peak of the logarithm the when Furthermore, current. on controlled adsorpti an is this that shows 8and Fig. from seen be can were given in Fig. 7. In this range of scan rate values, there there values, rate of scan range 7. Fig. in were given this In nine different scan rates between 50 mVs 50 between rates scan different nine range of 1 µM–10 µM (Fig. 10). Voltammograms at dif of 1µM–10 10). (Fig. range µM Voltammograms rate (v rate ferent concentrations for clozapine were recorded under under were recorded for clozapine ferent concentrations acetate (pH = 5.00) buffer solution in the concentration concentration the in solution buffer (pH =5.00) acetate to the measurements obtained by the DPV technique in in DPV technique by the obtained measurements the to that the current is adsorption controlled [18]. controlled adsorption is current the that criterion another is 1.1834, which be to found is slope the ted in acetate buffer solution (pH=5.0) by using cyclic cyclic (pH=5.0) byusing solution buffer acetate in ted Figure 8. is a linear relationship between the square root of scan of scan root square the between relationship a linear is Figure 9. bismuth film electrode in 0.2 M acetate buffer solution (pH=5.00). solution buffer Macetate 0.2 in electrode film bismuth 1/2

) and current function (Ip/Cv function current and )

The log Ip–log v curve from CV study of 2 µM clozapine at at clozapine 2µM of study CV from vcurve Ip–log log The The dependence of current function (Ip/Cv function of current dependence The 1/2 ) from CV study of 2 µM clozapine at bismuth film film bismuth at clozapine 2µM of study CV ) from 1/2 ). This behavior behavior ). This -1 and 450 mVs 450 and 1/2 ) to the square square the ) to -1 - - -

Table 2. Analytical parameters of the calibration graph for differential pulse voltammetric determination of clozapine at bismuth film electrode in 0.2 M acetate buffer solution (pH=5.00)

Parameters Results

Linear concentration range, mol/L from 1×10-6 to 10×10-6

Slope, μA M-1 0.10274

SD of slope 0.00314

The correlation coefficient, r 0.9963

Regression standard deviation, sr 2.850×10-8

Number of measurements 3 Figure 10. The differential pulse voltammograms of clozapine for diffe- LOD, mol L-1 6.112×10-9 rent concentrations from 1 µM to 10 µM at bismuth film electrode in 0.2 M acetate buffer solution (pH=5.00). LOQ, mol L-1 2.0373×10-8

Table 3. The comparison of different studies in the literature with the present study for voltammetric determination of CLZ

WE Technique Linear Range LOD

HMDE SWAdCS 1.0 – 3.3 nM 0.45 nM

TiO2NP/MCPE AD-DPV 0.5 – 45 µM 61.00 nM

PPY/CNT/GCE LSV 0.01 – 5.00 µM 3.00 nM

EPGCE AdSV 0.1 – 1 µM 8.00 nM

F3O4/Ala/Pd/GCE DPV 3 – 70 nM 1.53 nM

Ru/TiO2/CPE SWV 0.9 – 40 µM 0.43 nM

Bi/GCE DPV 1 – 10 µM 6.11 nM

Figure 11. The calibration graph for determination of clozapine at bis- WE: Working Electrode, HMDE: hanging Mercury Drop Electrode NP: Nanoparticles, MCPE: Modified Carbon Paste muth film electrode in 0.2 M acetate buffer solution (pH=5.00). Electrode, PPY: PolyPyrrole, CNT: Carbon Nanotube, GCE: Glassy Carbon Electrode, EP: Electrochemically Pretreated, SWAdCS: Square Wave Adsorptive Cathodic Stripping, AD-DPV: Adsorptive Differential Voltammetry, LSV: Linear Sweep Voltammetry. optimal analytical conditions. For clozapine, a calibration curve with high linearity was obtained in this medium powder. A stock solution of concentration 1×10-2 mol/L in the range of 1 µM-10 µM (Fig. 11). was prepared by weighing the appropriate amount of the powdered solid and dissolving it in methanol. Appropri- According to the equations, LOD=3 s/m and LOQ=10 ate solutions were prepared by taking proper volumes of s/m, the limit of detection and the limit of quantitation the stock solution and diluting with 0.2 mol/L acetic acid/ were calculated using measured peak currents, respectively. sodium acetate buffer solution used as supporting elect- Where “s” is the standard deviation of peak currents (for rolyte. The quantity of clozapine in the trading tablet was three measurements) and “m” is the slope of the calibrati- calculated as 25.3 ± 2.2 mg using the calibration equation. on curve [19]. LOD and LOQ were calculated as 6.112×10-9 -8 mol/L and 2.0373×10 mol/L for bismuth-modified glassy Besides, a recovery test was performed for the develo- carbon electrodes, respectively (Table 2). ped method, and the results are given in Table 5. According to the results, the new analytical method has shown that On the other hand, there are several references in the tablets can be applied successfully without any interventi- literature about the determination of CLZ. The results of on in the determination of clozapine. When the amount of these methods as well as that of the present study are gi- clozapine was added, and the amount of clozapine detected ven in Table 3. Table 3 contains the information about these was compared, recovery from the commercial tablets was studies such as working electrodes, the techniques used, the found to be 97.00%. linear ranges, and LOD. CONCLUSION Analytical Application and Recovery Study E. GokmeseE. at al. / Hittite J Sci Eng, 2021,8 (1) 71–77 In this study, the electrochemical oxidation property of Commercial drug tablets containing 25 mg of clozapi- clozapine on the bismuth coated glassy carbon electro- ne per tablet were exactly weighed and ground to a fine

75 E. Gokmese at al. / Hittite J Sci Eng, 2021,8 (1) 71–77 ACKNOWLEDGEMENT The authors would like to express their gratitude to Se to gratitude their express to like would authors The 1. Table 4. Table 4. Ip change. Ip Oxidation peaks between 0.3 V and 0.6 Vwere determi 0.6 Vand 0.3 between peaks Oxidation CLZ. As seen from Table 3 some different methods and and methods Table from different seen 3some As CLZ. 2. obtained by using the DPV technique in different elect different in DPV technique the by using obtained were Voltammograms pH values. at different 3.50-8.00) techniques. CV DPV and byusing investigated was de electrode for this purpose. The linear range and LOD of this of this LOD and range linear The purpose. for this electrode of CLZ determination for the used been have electrodes aresult, As electrode. GC bare the than more sensitive is de medium was determined according to the obtained pH- obtained the to according determined was medium method are near the other methods. methods. other the near are method 3. ned on voltammograms taken with acetate buffers (pH buffers acetate with taken on voltammograms ned rolytes selected in acidic and basic regions. The working working The regions. basic and acidic in selected rolytes about 70 times higher, indicating that the modified electro modified the that indicating higher, 70about times is electrode modified at the current peak the compared, are 5. lehattin Yılmaz, who provided the drug active substance. active drug the provided who Yılmaz, lehattin this study suggests a new method for the determination of of determination for the method anew suggests study this bon electrode (0.330 µA) and modified electrode (21.69 µA) electrode modified and µA) (0.330 electrode bon but it is the first time to use the bismuth modified carbon carbon modified bismuth the use to time first the but it is t Table 5. ab Sample Drug tabletDrug Tablet Drug form a: Average of 3 different measurements. 3different of Average a: l et When the peak currents of clozapine in the glassy car glassy the in of clozapine currents peak the When clozapine based on its oxidation with bromate in a micellar medium. medium. amicellar in bromate with oxidation its on based clozapine clozapine: A double-blind, placebo-contolled trial. Schizophrenia trial. placebo-contolled A double-blind, clozapine: of Psychiatry 158 (1991) 158 10.1192/bjp.158.4.503. DOI: 503. Psychiatry of The effects of clozapine on tardive dyskinesia. The British Journal Journal British The dyskinesia. tardive on clozapine of effects The mercury electrode. Journal of Pharmaceutical Biomedical Analysis Analysis Biomedical Pharmaceutical of Journal electrode. mercury 36 (2004) 149. DOI: 10.1016/j.jpba.2004.04.012. DOI: 149. (2004) 36 voltammetric quantification of the antipsychotic drug clozapine drug antipsychotic the of quantification voltammetric Mohamed A, Sheikka MA. Spectrophotometric determination of determination Spectrophotometric MA. Sheikka A, Mohamed Güven FM, Birsöz S. Klozapin ve Şizofreni Sağaltımındaki Yeri. Sağaltımındaki Şizofreni ve Klozapin S. Birsöz FM, Güven Klinik Psikiyatri 4(2001) 124-128. Psikiyatri Klinik Freudenreich O, Henderson DC, Walsh JP, Culhane M.A., Goff DC. DC. Goff M.A., JP, Walsh Culhane DC, O, Henderson Freudenreich IL Farmaco, 59 (2004) 907. DOI: 10.1016/j.farmac.2004.07.008. 907. DOI: 59(2004) Farmaco, IL Hammam E, Tawfik A, Ghoneim AA. Adsorptive stripping Adsorptive AA. Ghoneim A, Tawfik E, Hammam Risperidone augmentation for schizophrenia partially responsive to to responsive partially schizophrenia for augmentation Risperidone Lieberman JA, Saltz BL, Johns CA, Pollack S, Borenstein M, Kane J. J. Kane M, Borenstein S, Pollack CA, Johns BL, Saltz JA, Lieberman in bulk form, pharmaceutical formulation and human serum at a at serum human and formulation pharmaceutical form, bulk in Result for the determination of clozapine in a drug dosage form dosage adrug in clozapine of determination the for Result Recovery study for thedetermination of clozapineinadrug Spiked 6. 536x10-3mg 25 mg per tablet per mg 25 Declared References Found 6. 363x10 25. Found -3 3 ±0.3 3 mg a /mg 97 % Recovery, 1. RSD, % RSD, 2 1. RSD, % RSD, 32 - - - - - 76 11. 10. 19. 18. 17. 16. 15. 14. 13. 12. 20. 7. 9. 6. 8.

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