Analytical Study on Certain Fluorinecontaining Drugs

Abstract

This thesis consisted of five parts: Part I: General introduction It explained the nature of fluorine-containing drugs, and their increased introduction into the pharmaceutical field. Part II: Literature review This part included a review of the physical and chemical properties of the studied fluorine-containing drugs, Rosuvastatin calcium, Fluticasone propionate, and Sodium fluoride. Also, it included different analytical methods reported in the literature that aimed for determination of the chosen drugs in pure form, mixtures, pharmaceutical formulations, and biological fluids. Part III: Spectrophotometric determination of fluorine-containing drugs This part involved the development of ratio derivative, ratio difference and mean centering procedures for analysis of Rosuvastatin calcium, as well as Area under curve and Savitsky-Golay filter procedures for analysis of Fluticasone propionate, with further application to mixtures, pharmaceutical formulations and urine samples. This part was divided into three sections: Section A: Ratio derivative and ratio difference methods for determination of Rosuvastatin in presence of Losartan The ratio derivative method was utilized to determine Rosuvastatin. The peak amplitude of Rosuvastatin at 237.00 nm from the ratio derivative spectrum (using Losartan 1 µg/ml as a divisor) was measured. In ratio difference method, the amplitude difference of the ratio spectra (RSV/LOS) at 215.30 and 309.50 nm (ΔP309.50-215.30) was utilized to determine Rosuvastatin without any interference from Losartan. The methods were applied for the determination of Rosuvastatin in its pure form, in presence of Losartan, and in their urine samples with good accuracy and recovery. Section B: Mean centering method for determination of Rosuvastatin in presence of Losartan and Metformin

The mean centering method was utilized to selectively quantify Rosuvastatin. Rosuvastatin was measured at 250.80 nm from the second-mean centered ratio spectrum (using Losartan and Metformin 1 µg/ml as a divisor). Rosuvastatin was determined in bulk powder, pharmaceutical formulation, and in presence of Losartan and Metformin in laboratory prepared mixtures and in urine samples. The proposed method was easily applicable for routine analysis. Section C: Area under curve and Savitsky-Golay Filter methods for simultaneous determination of Fluticasone and Salmeterol Area under curve method was utilized to simultaneously determine Fluticasone and Salmeterol. The values of Area under curve were measured in the range of 230.00-240.00 and 245.00-255.00 nm. In Savitsky-Golay Filter method, Peak amplitude of Fluticasone was measured at 226.80 nm (zero-crossing of Salmeterol). Fluticasone and Salmeterol were determined in bulk powder, laboratory prepared mixtures, and their pharmaceutical formulation. The proposed methods were used for routine analysis of the drugs. Part IV: HPLC-UV determination of fluorine-containing drugs High Performance Liquid Chromatographic techniques with UV detection were developed for simultaneous determination of Rosuvastatin, Losartan and Metformin as well as for simultaneous determination of Fluticasone and Salmeterol. The proposed methods were further applied to pharmaceutical formulation, spiked urine or plasma samples. A pre-column derivatization reaction was developed for selective determination of Sodium fluoride and was further applied to pharmaceutical formulations. This part involved three sections. Section A: Simultaneous determination of Rosuvastatin, Losartan and Metformin and application to urine This section was concerned with the application of HPLC method for the simultaneous determination of Rosuvastatin, Losartan and Metformin. The mobile phase of choice was acetonitrile: tri-fluoro acetic acid 0.1% (50:50, v/v). Diode array detector was set 252.00 nm for quantitative determination of Rosuvastatin and Losartan, and at 242.00 nm for quantitative determination of Metformin. The proposed HPLC method was successfully applied for determination of the mentioned drugs in pure form and laboratory prepared mixtures. The method was further applied to simultaneous determination of Rosuvastatin and Losartan in presence of Metformin in spiked urine samples. Section B: Determination of Sodium fluoride using pre-column derivatization reaction and application to pharmaceutical formulations

This section was concerned with the application of HPLC method for the selective determination of Sodium fluoride. A pre-column derivatization reaction, utilizing triphenyl silanol reagent, was developed. The reaction product, triphenyl silyl fluoride, was aspirated and subjected to HPLC measurement. The mobile phase of choice was acetonitrile: water (75:25, v/v). Diode array detector was set at 222.00 nm. The proposed HPLC method was successfully applied for determination of Sodium fluoride in pure form and pharmaceutical formulations.

Section C: Simultaneous determination of FP and SUB and application to plasma and pharmaceutical formulation This section was concerned with the application of HPLC method for the simultaneous determination of Fluticasone and Salbutamol. The mobile phase of choice was acetonitrile: phosphoric acid pH=3 (0.1% TEA) (80:20, v/v). Diode array detector was set 237.00 nm for quantitative determination of Fluticasone, and at 229.00 nm for quantitative determination of Salbutamol. The proposed HPLC method was successfully applied for determination of the mentioned drugs in pure form and laboratory prepared mixtures. The method was further applied to determination of Fluticasone in presence of Salbutamol in spiked plasma samples. Also, the method was applied to the determination of Fluticasone in its pharmaceutical formulation. Part V: UPLC-MS/MS determination of fluorine-containing drugs This part was concerned with the simultaneous determination of Fluticasone, Salmeterol and Salbutamol. The method was further applied to pharmaceutical formulation and plasma samples down to a concentration approaching their Cmax. It was divided into two sections. Section A: Simultaneous determination of Fluticasone, Salmeterol and Salbutamol in ternary mixture and application to pharmaceutical formulation

This section discussed the development of an UPLC-MS/MS method for the simultaneous determination of Fluticasone, Salmeterol and Salbutamol. The mobile phase of choice was methanol: 5 mM ammonium formate +0.1% formic acid (80:20, v/v). Electrospray ionization, in positive mode, and multiple reaction monitoring were used throughout the analysis. The proposed UPLC-MS/MS method was successfully applied for determination of the mentioned drugs in pure form and laboratory prepared mixtures. Very high sensitivity, down to 25 pg/ml, was achieved. The method was further applied to simultaneous determination of Fluticasone and Salmeterol in their pharmaceutical formulation. Section B: Simultaneous determination Fluticasone, Salmeterol and Salbutamol in plasma

This section discussed the development of an UPLC-MS/MS method for simultaneous determination of Fluticasone, Salmeterol and Salbutamol in spiked plasma samples. The use of an IS (Tolterodine) became very crucial to compensate for any errors during plasma samples analysis. The mobile phase of choice was methanol: 5 mM ammonium formate +0.1% formic acid (80:20, v/v). Electro spray ionization, in positive mode, and multiple reaction monitoring were used throughout the analysis. Very high sensitivity, downto100 pg/ml, was obtained. The proposed method was successfully applied for determination of the mentioned drugs in spiked plasma samples. References and Arabic summary This thesis contains 317 references, 53 tables and 63 figures and ended with an Arabic summary.