Quantitative determination of residual 2-( 2-chloroethoxy ) ethanol ( CEE ) in quetiapine fumarate by gas chromatogaraphy

A simple and specific gas chromatographic method developed and validated for the determination of 2-(2-chloroethoxy) ethanol in Quetiapine Fumarate. The method is carried out with a flame ionization detector and DB-FFAP capillary column. The linearity was established over a range of 40-150 μg ml and correlation coefficient is more than 0.999.


INTRODUCTION
Quetiapine is an antipsychotic drug belonging to the group of the dibenzothiazepines and used for the treatment of schizophrenia and other psychotic syndromes [1,2].Quetiapine is used in a form of tablets containing 50, 100, 200 and 300 mg of the active substance.The starting material which is used in the synthesis of Quetiapine fumarate is 2-(2-chloroethoxy) ethanol.2-(2-chloroethoxy)-ethanol: CEE, structural formula C4H9ClO2; CAS number 628-89-7, boiling point 200℃ at 101.3 kPa.The starting material are often not totally removed by practical manufacturing techniques, and consequently low levels are present in most pharmaceuticals.An acceptable level of CEE is unclassified but it is known impurity so was specified with acceptance criterion of 0.01% [3].{Based on NOEL and PDE Value of CEE and Quetiapine}The European Pharmacopoeia (Eur.Ph.) included this guideline in the chapter Residual Solvents [4,5] and described a general procedure for identification and control of residual solvents in drug substances.Some problems have been overcome, for instance quantitative determination of non-volatile solvents such as 2-(2-chloroethoxy)-ethanol (CEE).In the literature there is no information about the methods for determination of CEE in the Quetiapine.In the present study, a gas chromatographic method with direct injection for the determination of CEE in the active substance has been developed.

EXPERIMENTAL
The active substance was synthesized by Precise pharmaceutical Ltd (Pharmaceutical Research Centre, Mumbai, India).Acetonitrile was purchased by J.T baker (USA), Hydrochloride was purchased by S.D. Fine chem.(India), Water was purchased by Lab chem.(India), and 2-(2-chloroethoxy) ethanol was purchased by Sigma Aldrich, (Germany).

Preparation of Solution
Quantitative standard solution of CEE Standard solutions was prepared from standard stock solutions.Standard stock solutions were prepared in Diluent {0.2N Hydrochloride in Acetonitrile: Water (70:30 v/v)}.Standard stock solution A: containing 1mg ml -1 of CEE; Standard solution: containing 0.01mg ml -1 of CEE which corresponds to 0.1mg ml -1 of CEE in the tested substance.Qualitative standard solution of CEE for system suitability: Selectivity solution was prepared to check Eur.Ph. system suitability requirements.A total of 7 solvents were included in this standard solution.Selectivity solution contained 300 ppm of methanol, 500ppm of Ethanol, 500ppm of Acetone, 500 ppm of Isopropyl alcohol, 89 ppm of Toluene, 88 ppm of N, N-dimethyl formamide, 60 ppm of Dichloromethane and 10 ppm of CEE [6].Test solution was prepared solution 1 containing 100mg ml -1 .A blank was prepared using the diluent, but without sample or standard solution.

Instrumentation and Operating Condition
The experiments were performed on an Agilent 7890A gas chromatograph (GC) equipped with a CTC combipal autosampler and a flame ionization detector.A DB-FFAP column (phase composition: Nitroterepthalic acid modi-fied polyethylene Glycol) film thickness 1.0 µm, 30 m long, 0.32 mm ID was used.GC conditions: Inlet heater 200℃, detector 280℃, Oven initial temperature 100℃ for 5 minutes, then raised at a rate of 15℃/min to 180℃ and hold for 2 minutes, then raised at a rate of 35℃/min to 230℃ and hold for 2 minutes.Helium gas was used as a carrier gas at 3.0ml min -1 and a split flow of 1:1.FID air flow was 400 ml min -1 and FID hydrogen flow was 40 ml min -1 . 1 µl was injected.

Procedure
Separately inject 1 µl of standard solution and test solution into gas chromatograph.Record chromatograms and compare peak areas of analytes from the test and standard solution.Under described conditions the retention time of CEE is 10.7 minutes.The area of the peak of CEE in the chromatogram from the test solution must not be greater than the mean area of the peak from the standard solution (0.1 mg ml -1 corresponds to the substance).

System Suitability Test (SST)
The selectivity of the method was evaluated by injecting the selectivity solution to ensure the separation of all  .Good separation was obtained between CEE and other solvents used in the synthetic route of the active substance.For the drug substance excellent recoveries of 92-95% were obtained at 0.1 mg ml -1 corresponds to the substance.

Validation of Method for CEE in API
Full validation data was required for API as it was in last stage development.

Limit of detection and limit of Quantification for CEE
The LOD and LOQ were calculated form S/N data generated from six injection of CEE (with API) containing

Linearity of the CEE on Gas Chromatography
The linearity of CEE was satisfactorily demonstrated with six point calibration graph between LOQ to 150% of analyte concentrations (LOQ, 50, 75,100,125 & 150).
The peak area versus concentration data was performed by least-squares linear regression analysis.The calibration curve was produced by plotting the average of triplicate CEE injections against the concentration expressed in percentage.Correlation coefficient for CEE was 0.99.Linearity of the CEE chromatogram was shown in the

DISCUSSION AND CONCLUSION
In this study, a GC analytical method was developed for control of residual 2-(2-chloroethoxy)ethanol (CEE) in the active substance.Sample solvent diluent was selected to obtain good selectivity and sensitivity for CEE.The sample dilution factor was adapted to detect unclassified solvent CEE at known impurity levels (100 ppm) by FID.This GC method is suitable for its intended purpose.

Figure 2 .
Figure 2. Limit of Detection of CEE.

Figure 3 .
Figure 3. Limit of Quantification of CEE.