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  3. Pre-concentration of aripiprazole drug by liquid phase and hollow fiber microextraction method and measurement of drug amount in plasma and urine by HPLC method in trace amounts

Pre-concentration of aripiprazole drug by liquid phase and hollow fiber microextraction method and measurement of drug amount in plasma and urine by HPLC method in trace amounts

Number of pages: 106 File Format: word File Code: 32086
Year: 2013 University Degree: Master's degree Category: Paramedical
Tags/Keywords: Aripiperazole drug - Aripiprazole - Biological fluids - Halofiber - Hollow fiber - HPLC - Liquid phase extraction - Measure the drug - Micro extraction - Trace
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  • Summary of Pre-concentration of aripiprazole drug by liquid phase and hollow fiber microextraction method and measurement of drug amount in plasma and urine by HPLC method in trace amounts

    Dissertation

    To receive the degree of Doctor of Pharmacy

    Persian summary                                                

    Aripiprazole is an atypical antipsychotic drug with a combination of 5-HT2A receptor antagonist and partial agonist activity. 5-HT1A and D2 dopamine receptors show their therapeutic effect. This drug is used in the treatment of schizophrenia, type I bipolar disorders and as an adjunctive treatment in major depression.

    In cases where the appropriate response from the drug is not seen, it is necessary to measure the plasma levels in order to bring it to the necessary values ??before stopping the drug and replacing other antipsychotic drugs. Considering that the plasma level of aripiprazole reaches nanograms per milliliter, it is necessary to use a method that has the ability to identify and separate this drug at this low concentration.

    In this study, a liquid phase microextraction method using hollow fiber along with high performance liquid chromatography (HPLC) and UV detector to preconcentrate and identify aripiprazole in plasma and urine was used Aripiprazole was extracted from 15 ml of sample alkaline solution with pH 8.8 into an organic solvent (octanol) which was located in the pores of the fiber wall. After that, this drug was introduced from the organic solvent into the water-receptive phase with an acidic nature inside the fiber. In this study, the effective factors in microextraction including the pH of donor phase and receptor phase, type of organic solvent, ionic strength of donor phase, temperature of donor phase, extraction time and stirring speed were investigated and optimized. After drug extraction with optimal conditions of donor phase with pH 8.8 and receptor phase with pH 2.4, organic solvent, ethanol, extraction time 45 minutes, temperature of donor phase 40 degrees Celsius, stirring speed 625 and Without adding salt, the pre-concentration factor was 127 and the detection limit was 3.9 ng/ml and the standard deviation was 2.4% in one working day and the relative standard deviation was 3.9% in several consecutive working days. gives Nowadays, the separation methods have made it possible to separate species in complex tissues with a very low detection limit (femtogram). In addition to the separation methods, the sample preparation stage is also one of the most important stages in the analysis process. This step involves converting the texture of a real sample into a state suitable for analysis by a separation technique or other methods. It can be said that the sample preparation stage is designed for the following purposes:

    1- Removing disturbances from the sample in order to increase the selectivity of the method

    2- Preconcentrating the desired analyte and increasing its concentration so that it can be measured with analytical devices.

    3- Converting the analytes into A form that is suitable for identification with an analytical device.

    The most basic method of sample preparation is the extraction method. The efforts of analytical chemists to invent and develop measurement methods with high precision and accuracy, as well as to eliminate manual steps that cause low reproducibility in analytical methods, have led to the invention of new extraction methods. Figure (A) categorizes different extraction and microextraction methods, which are detailed in the references (1).

    In general, liquid-liquid microextraction with drops and extraction methods based on the use of porous hollow fibers will be briefly discussed.

    . Necessity and importance of the topic

    Aripiprazole is an atypical antipsychotic drug that shows its therapeutic effect with a combination of antagonistic activity of 5-HT2A receptor and partial agonistic activity of 5-HT1A and D2 dopamine receptors. On the other hand, with its effects on these receptors, it causes unwanted side effects such as significant weight gain, akathisia, tremors, tardive dyskinesia, extrapyramidal side effects, postural hypotension, malignant neuroleptic syndrome, etc.The plasma level of this drug can be different among patients, and in cases where the appropriate response from the drug has not been seen, it is necessary to measure the plasma levels in order to bring it to the necessary levels before stopping the drug and replacing it with other antipsychotic drugs. Considering that its plasma level reaches nanograms per milliliter, it is necessary to use a method that has the ability to identify and separate this drug at this low concentration. One of these methods is the use of LC-MASS device, but this method is very expensive. Therefore, the aim of this thesis is to invent a new method using hollow fiber so that this drug can be concentrated in very small amounts and then measured with a simple HPLC device with a UV detector.

    1-2. Statement of the problem

    In order to measure the amount of aripiprazole in body fluids, a method should be used that helps the medical team in adjusting the dose of the drug without the need for blood sampling and through a non-invasive method, and has the power to identify and separate this drug. Using the drug pre-concentration method with the liquid phase microextraction with the help of halofiber, very small amounts of this drug can be concentrated and extracted in plasma and urine, then measured by HPLC. Since the elimination of this drug is mainly through feces and due to its half-life, it is possible to use the plasma sample of people for analysis. This method is very new and has not been used to preconcentrate and measure this drug.

    1-3. Objectives: To provide a simple and efficient extraction method with high precision. Performance liquid chromatography with UV detection methods was successfully developed for the determination of trace levels of Aripiperazole in biological fluids. The analyte was extracted into n-octanol that was immobilized in the wall pores of a porous hollow fiber from 15mL of aqueous sample (donor phase), and was back extracted into 20 µL of acceptor phase.

    Parameters effecting the extraction process such as type of extraction solvent, donor phase PH, acceptor phase PH, extraction time, stirring speed and salt addition were studied and optimized, under the optimized condition extraction solvent n-octanol, donor phase PH=8.8, acceptor phase PH=2.4, stirring speed 625 rpm, extraction time 45 min and without addition of salt, enrichment factor of 127 was obtained for the target drug. The percent relative intraday and interday standard deviations (RSD%) based on 3 replicate determinations were 2.4% and 3.9%. The developed method is simple, rapid, sensitive and is suitable for the determination of trace amounts of Aripiperazole in biological fluids.

  • Contents & References of Pre-concentration of aripiprazole drug by liquid phase and hollow fiber microextraction method and measurement of drug amount in plasma and urine by HPLC method in trace amounts

    List:

    Persian summary.. 1

    Introduction .. 2

     

    Chapter one: generalities

    1-1. The necessity and importance of the subject. 5

    1-2. Statement of the problem.. 5

    1-3. Objectives.. 6

    Chapter Two: Examining the texts and studies of others in this field

    2-1. An overview of liquid-liquid extraction and liquid-liquid microextraction methods. 8

    2-1-1. Liquid phase microextraction. 8

    2-1-1-1. Single-drop liquid phase microextraction. 8

    2-1-1-2. Hollow fiber liquid phase microextraction. 11

    2-1-1-2-1. Extraction principles and different systems using HF-LPME. 12

    2-1-1-2-2. Practical aspects and different configurations of HF-LPME. 15

    2-1-1-2-3. Hollow fiber headspace liquid phase microextraction. 18

    2-1-1-3. Liquid phase microextraction using extractant solvent freezing. 21

    2-1-1-4. Dispersive liquid-liquid phase microextraction (DLPME). 21

    2-1-2. Solid phase extraction.. 22

    2-2. Chromatography.. 22

    2-2-1. Classification of chromatography methods. 23

    2-2-1-1. High Performance Liquid Chromatography (HPLC). 23

    2-2-1-2. Liquid chromatography devices. 25

    2-2-1-2-1. Mobile phase tank. 26

    2-2-1-2-2. Pumping systems. 26

    2-2-1-2-3. Sample injection systems. 27

    2-2-1-2-4. Liquid chromatography columns. 28

    2-2-1-2-4-1. Types of column fillers. 29

    2-2-1-2-5. Piston temperature.. 29

    2-2-1-2-6. detectors.. 29

    2-2-1-2-6-1. Photometric detector. 30

    2-2-1-2-6-2. Ultraviolet (UV) absorption detector. 31

    2-3. Review of HF-HPME studies. 32

    2-4. Review of the study drug. 36

    2-4-1. Drug pharmacokinetics.. 36

    2-4-2. Mechanism of drug action.. 37

    2-4-3. Uses of medicine.. 37

    2-4-4. Dosage of medicine.. 38

    2-4-5. Contraindications and precautions. 39

    2-4-6. Side effects.. 39

    2-4-7. Interferences.. 40

    2-4-8. Medicinal forms.. 41

    2-4-9. Physical properties of the drug. 41

    2-5. The importance of measuring aripiprazole. 42

    2-6. Objectives.. 42

    Chapter Three: Materials and Methods

    3-1. Chemicals and equipment. 44

    3-1-1. Chemicals, standards and real samples. 44

    3-1-2. Device equipment.. 44

    3-2. Extraction method.. 45

    3-2-1. Briefly, the extraction was done in the following steps. 45

    3-2-2. Optimization steps.. 47

    3-2-2-1. Optimization of isolation conditions. 47

    3-2-2-2. Optimizing extraction conditions. 47

    3-2-2-2-1. Type of organic solvent.. 47

    3-2-2-2-2. Effect of pH of the donor phase. 47

    3-2-2-2-3. Effect of pH of the receptor phase. 47

    3-2-2-2-4. The effect of ionic strength of the phase donor. 48

    3-2-2-2-5. The effect of stirring the analyte solution. 48

    3-2-2-2-6. Effect of extraction time. 48

    3-2-2-2-7. Effect of temperature.. 48

    3-2-3. Evaluating the efficiency of the extraction method. 48

    3-2-3-1. Grading curve. 48

    3-2-3-2. Determination of preconcentration factor (PF). 49

    3-2-3-3. Repeatability determination (RSD). 49

    3-2-4. Real sample analysis.. 49

    Chapter Four: Results

    4-1. Three-phase microextraction based on the use of porous hollow fiber. 51

    4-1-1. Principles of theory.. 51

    4-2. Optimization steps.. 54

    4-2-1. Optimization of isolation conditions. 54

    4-2-2. Optimizing extraction conditions. 55

    4-2-2-1. Type of organic solvent.. 55

    4-2-2-2. Effect of pH of acceptor phase and donor phase. 56

    4-2-2-3. The effect of stirring speed of the analyte solution. 58

    4-2-2-4. The effect of ionic strength of the phase donor. 59

    4-2-2-5. The effect of extraction time.. 61

    4-2-2-6. Effect of temperature.. 61

    4-3. Determining the analytical parameters of the extraction method. 63

    4-3-1. Preparation of grading curve. 63

    4-3-2. Preconcentration factor (PF). 64

    4-3-3. Determination of the limit of detection (LOD). 65

    4-3-4. Repeatability of the method (RSD). 66

    4-4. Real sample analysis.. 66

    Chapter five: discussion and conclusion

    5-1. Comparison of the extraction method with the reported methods of other references. 71

    5-2. Conclusion.. 73

    English summary.. 76

    Resources..77

    Appendixes

    Source:

     

     

    Sources:

    Alders. L. Liquid-Liquid Extraction: Theory and Laboratory Experiments, 2nd ed. London: Elsevier Pub.Co; 1955. P.109-205.

     

    Dean. J. R. Extraction Techniques in Analytical Sciences, Boston: John Wiley and Sons; 2010. P. 55.

     

    Kokosa. J. M. A, Jeannot. M. A. Solvent Microextraction: Theory and practice. Boston: John Wiley and Sons; 2009. P. 17-35.

     

    Liu. H. H, Dasgupta. P. K. Analytical chemistry in a drop solvent extraction in a micro drop. Anal. Chem., 1996; 68:11817.

     

    Jeannot. M. A, Cantwell. F. F. Solvent microextraction in a single drop. J. Anal. Chem., 1996; 68:2236.

     

    Jeannot. M. A, Cantwell. F. F. Mass transfer characteristics of solvent extraction in a single drop at the tip of a syringe. Anal. Chem., 1997; 68: 4634.

     

    Shrivas. K, Wu. H.f. Single drop microextraction as a concentrating probe for rapid screening of low molecular weight drugs from human urine. J. Anal. Chem. Acta, 2007; 605:153.

     

    Ma. M. H, Cantwell. F. F. Solvent micro extraction with simultaneous back-extraction for sample clean up and preconcentration quantitative extraction.J. Anal Chem, 1999; 71:388.

     

    Theis. A. L, Waldack. A.J., Hansen. S. M, Jeannot. M. A. Headspace solvent microextraction. J. Anal. Chem., 2001; 73: 5651.

    Yu.Y. K [et al]. Multiple headspace single drop micro extraction coupled with gas chromatography for direct determination of residual solvents in solid drug product. J. Chromatographia. A. 2010; 1217:5158.

     

    Li. Y, Xiong.Y.Q, Liang.W.Y, Fang.C.C, Wang. C. J. Low density extraction solvent-based solvent terminated dispersive liquid-liquid microextraction combined with gas chromatography. J. Chromtographia. A, 2010; 1217:3561.

     

    Pedersen-Bjergaard.S, Rasmussen.K. E. Liquid-liquid-liquid microextraction for sample preparation of biological fluids prior to capillary electrophoresis. J. Anal. Chem., 1999; 71:2650.

     

    Rasmussen. K. E, Pedersen-Bjergaard. S, Krogh. M, Uganda. H. G. Gronhaug. T. Supported liquid membranes in hollow fiber liquid-phase microextraction (LPME) practical considerations in three phase mode. J. Chromatographia. A, 2000; 873:3.

     

    Rasmussen. K. E, Pedersen-Bjergaard. S. Developments in hollow fiber-based liquid-phase microextraction. J. Anal. Chem., 2004; 23:1.

     

    Zhao. L, Lee. H. K. Liquid phase microextraction combined with hollow fiber as a sample preparation technique prior to gas chrpmatography-MS. J. Anal. Chem., 2002; 74:2486.

     

    Hou. L, Shen. G, Lee. H, k. Automated hollow fiber-protected dynamic liquid-phase micro extraction of pesticides for GC-MS analysis. J. Chromatographia. A, 2003; 985:107.

     

    Hou. L, Lee. H. K. Dynamic three-phase microextraction as a sample preparation technique prior to capillary electrophoresis. J. Anal. Chem. 2003; 75:2784.

     

    Wu. H. F, Yen. J.h. Dynamic liquid phase nanoextraction coupled to GC/MS for rapid analysis of methoxyacetophenone and anisaldehyde isomer in urine. J. Sept. Sci., 2008; 31:2295.

     

     

    Jiang. X. M, Oh. S. Y, Lee. H. K. Dynamic liquid-liquid-liquid microextraction with automated movement of the acceptor phase. J. Anal. Chem., 2005; 77:1689.

     

    Xu. LK, Hauser. P. C, Lee. H. K. Electro membrane isolation of nerve agent degradation products across a supported liquid membrane followed by capillary electrophoresis with contactless conductivity detection. J. Chromatographia. A, 2008; 1214:17.

     

    Kramer. KE, Andrews. A. R. J. Screening method for 11-nor-?9-tetrahydrocannabinol-9-carboxylic acid in urine using hollow fiber membrane solvent microextraction with in-tube derivatization. J. Chromatographia. B, 2001; 760:27.

Pre-concentration of aripiprazole drug by liquid phase and hollow fiber microextraction method and measurement of drug amount in plasma and urine by HPLC method in trace amounts
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