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HPLC determination of ziprasidone in urine
Davydovych S.
LNMU
Abstract
A simple, sensitive and rapid high performance liquid chromatography method with ultraviolete detection (210 nm) was developed and validated for the quantification of Ziprasidone in rat urine. Following a single-step solid phase extraction on Strata X 1 mg, ziprasidone and internal standard (vardenafil) were separated using an isocratic mobile phase of acetonitrile : 0,5 % triethylamine (30: 70) and 0.1 M phosphoric acid (pH: 2.5) on reverse phase LUNA” C18(2) 100A 250 mm ” 4.6 mm ” 5 ”m. The lower limit of ziprasidone quantitation in urine was 0.125 ”g/mL, with a relative standard deviation of less than 20%. A linear range of 1 ”g/mL to 200 ”g/mL was established. Procedure of SPE allowed obtaining good results for ziprasidone, with recovery about 95 %. This HPLC method was validated with between and within-batch precision of 9.1-12.1 % and 7.32-11.3% respectively. The between and within batch accuracy was 96.34-99.04 % and 97.75-99.5 %, respectively. Stability of Ziprasidone in urine was >90%, with no evidence of degradation during sample processing (autosampler) and 60 days storage in a freezer (-60 ” 5 ‘). This validated method is sensitive, simple and repeatable enough to be used in pharmacokinetic studies.
Key words: ziprasidone, HPLC, urine, SPE.
Introduction
Ziprasidone, (5-[2-[4-(1.2-benzisothiazol-3-yl)-1-piperazinyl] ethyl]-6-chloro-1.3-dihydro-2H-indol-2-one, is widely used for the treatment of both positive and negative symptoms of schizophrenia [15, 18]. In pharmacological respect it is a representative of atypical antipsychotic drugs with a unique receptor profile and ability to inhibit the reuptake of serotonin and norepinephrine [24]. The interaction with the 5-HT2A and 5-HT1A, 5-HT2S, 5 NT1D 5-NT7 receptors and type 2(D2) dopamine receptors ziprasidone has antipsychotic, antidepressant and anxiolytic effects [25]. The recommended dose for the treatment of acute conditions is 40-80 mg twice daily [26]. In case of overdose or combining it with drugs, which cause prolongation of the QT interval, the cardiotoxic effect of the drug is observed [10, 12, 14]. Cardiovascular disorders arising in this case often cause deaths (specified or sudden cardiac death) [3, 5, 9, 11, 12, 17, 18].
Ziprasidone is intensively metabolized by CYP3A4 and aldehyde oxidase ‘ about 5% of the dose of the drug is excreted in the urine (”1%) and faeces (”4%) unchanged. The major circulating metabolites of ziprasidone are S-methyl-dihydroziprasidone, ziprasidone sulfoxide, benzisothiazole piperazine (BITP) sulfoxide and BITP sulfone. S-methyl-dihydroziprasidone and ziprasidone sulfoxide in tests in vitro reveal properties that may indicate the action that extends the QT interval, so determining their content in biomaterial has toxicological significance as well [24].
Several authors describe techniques for determining the presence of ziprasidone in biological fluids (plasma and serum) and organs (rats’ brain) using LC/MS, HPLC/MS, HPLC/UV, HPLC with fluorescence detector and UPLC/UV [1, 4, 13, 16, 21, 22, 23, 19, 2]. Preparation and analysis of samples in the described techniques were carried out in several steps and were generally time-consuming. Moreover, in the literature there is no description of the pattern of isolation and identification of ziprasidone from samples of urine that would be suitable for the purpose of chemical-toxicological analysis. Summing up these factors, the relevance of this study is due to the need to develop a simple, rapid, accurate, and sensitive technique of sample preparation to detect ziprasidone in urine using the HPLC/UV.
The objective of our study is elaborating conditions for identification and quantification of ziprasidone by HPLC with UV detection in samples obtained during purification of extracts from urine by solid phase extraction.
MATERIALS AND METHODS
Chemicals and Reagents
A standard sample of ziprasidone (‘98.0% Sigma-Aldrich, USA) was used to produce a series of stock solutions, as internal standard ‘ Vardenafil (‘98.0% Sigma-Aldrich, USA). Methanol, acetonitrile and phosphoric acid, all ‘HPLC’ grade (‘ 99.9%, Sigma-Aldrich, USA) were used to prepare mobile phase, and triethylamine (for HPLC, ‘99.5%, Fluka). All other chemicals were of analytical grade. Bidistilled water obtained in Milli-Q purification system (Millipore; Vienna, Austria) was used to prepare triethylamine and calcium chloride solutions. Test animals were injected with the content of Zeldox capsules (Pfizer Laboratories pvt. ltd.) containing 40 mg of ziprasidone.
Instrumentation and Chromatographic conditions
Preparation of urine samples for the analysis was performed using Strata X 30 mg cartridges (Phenomenex).
Identification and quantification of ziprasidone were performed with liquid chromatograph Thermo Dionex ultimate 3000 UHPLC. The system consists of an UltiMate 3000 RS pump, an UltiMate 3000 RS autosampler and an UltiMate 3000 RS column compartment (Dionex, Olten/Switzerland).
Chromatographic separation of analyte was performed with a reverse phase column LUNA” C18(2) 100 ” 250 mm ” 4.6 mm ” 5 ”m , at 25’C. The composition of the mobile phase: acetonitrile-0.5% triethylamine (30:70), pH 3.0. The acidic pH was adjusted 0.1 M phosphoric acid. The isocratic flow rate of the mobile phase was 1 ml/min. The volume of injected sample was 10 ‘l. Spectrum of ziprasidone was recorded in range 190 ‘ 350 nm. Detection was performed with LED UV detector (UV-VIS-DAD, FLD) at 210 nm.
The results were processed with Chromeleon” Chromatography Data System software (Version 7.2.0.3765, Thermo Fisher Scientific).
Organic solvents were evaporated with A TurboVap evaporator (Zymark; Hopkinton, MA). Urine samples were centrifuged in Sigma 3-16 KL centrifuge with cooling. Filtration of the mobile phase and samples before the injection into chromatograph was performed using PTFE membrane syringe filters with diameter of 13 mm and a pore size of 0.2 microns by STL-labortechnics (Czech Republic).
Preparations of standard and sample solutions
Stock solutions of ziprasidone and vardenafil were prepared by dissolving an accurately weighed amount of stock substances in methanol with a final concentration of 1 mg/ml. All stock solutions were stored at 4’C in the dark place for 30 days. To make working solutions of ziprasidone and vardenafil the stock solutions of these compounds were diluted with methanol. Concentration of working ziprasidone solution was 200 ”g/ml and internal standard ‘ 50 ”g/ml.
Three parallel series of model samples of urine with ziprasidone concentration of 1.0 to 200.0 ”g/ml (1.0; 5.0; 10.0; 20.0; 30.0, 100.0, 150.0 and 200.0 ”g/ml) were prepared for the analysis. 2 ml of pure rats’ urine were introduced with 100 ”l of internal standard working solution and with 10.0, 50.0, 100.0, 200.0, 300.0 ”l of working solutions of ziprasidone; 200.0, 300.0, 400.0 ”l of stock solutions. Samples were kept for 3 minutes in orbital mixer of "Vortex" type, and then incubated at 37’C for 60 minutes. The resulting solutions were used to construct the calibration curve by the method of internal standard in the concentration range of 1-30 ”g/ml and 30-200 ”g/ml. Similarly quality control samples were prepared for method validation (QC) ‘ pure rats’ urine was introduced with ziprasidone to obtain concentrations of 5, 100 and 200 ”g/ml. Model samples and quality control samples were subject further sample preparation by the approach described below.
Sample collections
To conduct the experimental study a group of twelve laboratory rats (230-240 g) aged 2-3 months was used. Half of them was the study group, the other half was the control one. In case of animal experiments or clinical trials authors must give the details of ethical approval. The animals were kept with free access to food. Animals in the study group received ziprasidone in a dose of 174 mg/kg in three divided doses during the day. The drug was administered intragastricly in the form of an aqueous suspension with the addition of Tween-80 as stabilizing agent. The choice of dose to model acute poisoning was resulting from the literature data [7, 10, 14]. Control animals received the same amount of solvent (water). The collection of daily urine for the analysis was performed from the first injection. The biological material was stored at -20’C.
Sample preparation
2 ml of rats’ urine were introduced with 100 ”l of internal standard solution (50 ”g/ml) and 0.2 ml of 20% solution of calcium chloride to precipitate of uric acid salts, and centrifuged for 15 min (5000 ” g). Supernatant was quantitatively selected and passed through a solid phase extraction cartridges Strata X (30 mg; Phenomenex, UK). Previously the cartridges were treated in 1 ml of methanol and 1 ml of distilled water. After the introduction of the sample, the columns were washed with 1 ml of phosphate buffer with pH 7.8 and 1 ml of distilled water. The flow rate of all liquids through the cartridge was 1 ml/min. Sorbent was dried in a stream of nitrogen for 5 minutes, and then eluted ziprasidone with 2 ml of methanol. The volume of the solution was adjusted to 5 ml of methanol. 1 ml of methanol eluate was evaporated to dryness in a stream of nitrogen and dissolved in 500 ”l of methanol. Samples were mixed using a shaker of "Vortex" type for 2 minutes and filtered through membrane filters PTFE 0.2 ”m. 10 ”l of the resulting solution was injected into the chromatograph. Control urine samples were studied in parallel by the same scheme. Extraction recovery was evaluated by performing SPE in triplicate on urine samples containing ziprasidone at three concentration levels of the analyte and IS.
Method validation was performed by such characteristics as specificity, accuracy and precision, linearity, repeatability, and matrix effects according to International Conference on Harmonization (ICH) Guidelines [6, 8].
An important part of method validation is to determine the indicators of the suitability of the system. To this end, the following parameters were calculated: a number of theoretical plates, peak asymmetry, and repeatability of retention times and peak areas.
To prove the specificity of the technique chromatograms of a stock, tested, and placebo solution were compared. Selectivity was studied by analyzing urine samples from several different laboratory rats.
The lower limit of quantitation (LLOQ) was defined as the minimal concentration of ziprasidone that can be precisely measured (coefficient of variation (CV) of less than 20%) and is determined by 5 samples of model tests independent of this curve. Limit of detection (LOD) was determined by 5 samples of model tests with signal to noise ratio of at least 3:1.
The efficacy of extraction and matrix effects were studied by model samples with three levels of concentrations (low, medium, high). Accuracy and precision of the method was determined by analyzing a series of three solutions with concentrations of 5, 100, 200 ”g/ml (n=6). Samples were analyzed on the day of preparation and 24 hours after preparation (samples were stored at 4’C).
Short-term and long-term stability of ziprasidone was studied by model urine samples containing 1 ”g/ml and 200 ”g/ml of a drug. Ziprasidone stability during three freeze-thaw cycles were determined as well. 10% degradation criterion was used to confirm the stability.
RESULTS AND DISCUSSION
Ziprasidone identification was performed by retention time, which was 9.573 ” 0.075 min. and by UV spectrum under described analysis conditions (Figure 1). Retention time of internal standard (vardenafil) was 7.613 ” 0.06 min.
Fig. 1: UV spectrum of ziprasidone.
The proposed method of extraction and detection of ziprasidone was used to analyze urine samples of laboratory rats that were given the drug under study. Concurrently the results were compared that were obtained after the analysis of model samples of urine containing ziprasidone (Figure 2) and samples of biological fluid of test animals (Figure 3) with blank samples.
A B
Fig. 2: Chromatograms of blank and model urine samples
(A) Placebo urine.
(B) Model sample: 1 ‘ internal standard, 2 ‘ ziprasidone
(content of ziprasidone is 30 ”g/ml, and vardenafil ‘ 10 ”g/ml. Sample volume is 500 ”l.)
Most of urine components were eluted from the chromatographic column long before the time of ziprasidone release because no interaction between them was observed. The suggested technique of the extraction of the drug enabled to achieve high efficiency in isolation and purity of samples obtained, as evidenced by minor variations in the zero line in the chromatograms. It was experimentally determined that the ziprasidone recovery from an aqueous solution after solid phase extraction was 97.5-98.2% [S.I. Davydovych, I.Y. Halkevych. Study of conditions of ziprasidone isolation from biological objects].
The efficiency of extraction of ziprasidone from urine was determined by analyzing model urine samples (n=9) with three levels of drug concentrations (low, medium, high). The overall recovery of ziprasidone in the assay was above 95%. Validation parameters of ziprasidone isolation from model urine samples by SPE are presented in Table 1.
Table 1: The extent and efficacy of extraction and matrix effects in the preparation of samples.
Concentration added (”g/ml) Extraction recovery
(%) ” SD Process efficiency
(%) ” SD % CV (RSD) Matrix effect (%)
5 95.58 ” 0.12545 95.25 12.55 100.8
100 95.15 ” 0.19592 95.15 9.54 100.11
200 95.08 ” 0.78776 95.05 7.5 100.17
There is a clear separation of ziprasidone peaks with its metabolites in the chromatograms obtained from urine samples of laboratory rats (Figure 3). Conclusions about the ziprasidone metabolites presence in extracts from the urine of test animals were made comparing the chromatograms of pure urine samples, urine with standard solution of ziprasidone addition, and urine of animals treated with the drug. We have identified four metabolites observed in all urine samples of the animals treated with ziprasidone and were absent in chromatograms of control urine samples. Their retention time was 9.083, 10.2, 10.75 and 13.43 min. The proposed method enabled to identify mean 46.2 ”g of ziprasidone in 1 ml of daily urine of animals. The total content of metabolites constituted about 28% of drug concentration level. The minimum concentration that can be determined in biomaterial is 0.125”g/ml.
Fig. 3: A representative chromatogram of urine samples of rats treated with ziprasidone.
(Peak area of ziprasidone corresponds to 37”g/ml, and peak area of vardenafil – 10”g/ml. Volume of alcohol sample is 0.5ml)
System suitability
To study system suitability 10 ”l of stock solution of ziprasidone was injected into the chromatograph (n=6) and determined the following parameters: the number of theoretical plates, the number of theoretical plates per meter, coefficient of asymmetry and height equivalent to theoretical plate. Measurement results are presented in Table 2.
Table 2: System suitability parameters for ziprasidone.
Parameters Values
Theoretical Plates (n) 17,112
Theoretical plates per meter (N) 68,448
Height equivalent to theoretical plates [HETP] (mm) 0.01
Tailing factor 1.06
The figures in Table 2 confirm high efficacy and selectivity of the proposed system compared to the described before.
The specificity of the proposed method is confirmed by the absence of peaks in the retention time of ziprasidone and its metabolites in chromatograms of control samples of urine.
Linearity and range.
Area ratio of ziprasidone peaks to the internal standard in urine samples was linear in relation to the concentration of ziprasidone within 1-30 ”g/ml and 30-200 ”g/ml. In the concentration range of 1-30 ”g/ml the calibration graph is described as Y=0.252”X-0.0158 (R”=0.9992), and in the range of 30 to 200 ”g/ml, this dependence is Y=0.1566”X + 2.3932 (R”=0.9988), where Y is the area ratio of ziprasidone peaks to the internal standard and X is the ziprasidone concentration, ”g/ml. Results obtained using the calibration graph for model samples of urine are presented in Table 3.
LOD and LOQ were determined by the ratio of signal intensity of analyte to noise signal. Limit of quantitation was set as the lowest concentration that provides the signal/noise ratio above 3:1 for the detection and 5:1 for quantitation. Their values were 0.2 ”g/ml and 0.5 ”g/ml in methanol solution, respectively.
Accuracy and precision.
Results to determine the accuracy and precision of the HPLC method were within acceptable limits. The results presented in Table 2 show that the method is correct and reproducible for repeated tests of ziprasidone in urine within one day and on different days.
Table 3: Accuracy and precision of the method for determining the concentration of ziprasidone in model urine samples.
ziprasidone inserted in sample, ”g/ml Intra-day (n=6) Inter-day (n=6)
found ”g/ml ” SD (mean value) Accuracy (%) Precision (% CV) found ”g/ml ” SD (mean value) Accuracy (%) Precision (% CV)
1 0.995 ” 0.004 99.5 11.3 0.985 ” 0.054 98.56 12.1
5 4.956 ” 0.009 99.25 11.25 4.948 ” 0.0059 98.96 12.01
10 9.912 ”0.014 99.12 10.9 9.904 ” 0.063 99.04 11.35
20 19.808 ”0.025 99.04 10.75 19.778 ” 0.076 98.89 11.22
30 29.67 ”0.030 98.9 10.2 29.589 ” 0.081 98.63 10.9
100 98.6 ” 0.085 98.6 9.8 98.42 ” 0.105 98.42 10.7
150 147.3 ”0.096 98.2 8.45 146.295 ” 0.129 97.53 9.1
200 195.5 ” 0.122 97.75 7.32 192.8 ” 0.145 96.34 7.41
Stability.
Stock solutions of ziprasidone maintained stability for at least 1 month when stored at 4’C. Model urine samples with ziprasidone maintained stability at -60”5’C. Three freeze-thaw cycles of model urine samples and storage at room temperature for 18 hours demonstrated stability of ziprasidone in urine. When testing ziprasidone stability the loss of the drug does not exceed acceptable limits when stored in autosampler for 72 hours. The research results are summarized in Table 4.
Table 4. Stability of ziprasidone in urine.
Storage conditions of samples Concentration of ziprasidone in the sample (”g/ml) Found concentration
(”g/ml) % changes
Three freeze-thaw cycles cycles (-20 ‘ / room temperature) 1
200 0.982
197.2 -1.8
– 1.4
Storage at room temperature for 18 hours 1
200 0.955
191.8 -4.5
-4.1
Stability when stored in autosampler for 72 hours 1
200 0.957
193.76 -4.3
-3.12
Prolonged storage of urine samples with ziprasidone for 60 days 1
200 0.922
187.6 -7.8
-6.2
CONCLUSIONS
1. The simple and quick method to determine ziprasidone in urine of laboratory rats by HPLC/UV in reverse phase column LUNA” C18(2) was described. The suggested conditions of chromatographic analysis provide rapid extraction of ziprasidone with the matrix components and metabolites, as well as high selectivity, reproducibility and asymmetry of peaks.
2. The suggested analysis technique enables to determine both therapeutic and toxic doses of ziprasidone providing accurate determination of concentrations of the drug in urine sample to determine the cause of the poisoning or fatality. When administering the ziprasidone dose of equal LD50, its content in daily urine of test animals was about 0.67%; the total percentage of identified metabolites in relation to ziprasidone concentration was approximately 28%.
3. The use of TFE allowed to eliminate the influence of endogenous contaminants from biological fluids and to concentrate the sample, which in turn provided the limit to determine ziprasidone in biological material at the level of 0.125 ”g in 1 ml of urine.
4. The results of method validation showed good precision, accuracy and reproducibility. The method maintains linearity in a much larger concentration range than is usually described in the studies making it suitable for chemical and toxicological analysis.
Financial support and sponsorship:
Conflict of Interests: There are no conflict of interest.
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