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In general,many pharmaceuticals contain moisture in them. so,determination of moisture content is very important. Determination of moisture content can be done by 3 methods. They are: 1.Titrimetric method(method 1) 2.Azeotropic method(method 2) 3.Gravimetric method(method 3)

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TITRIMETRIC METHOD: This can be performed by 2 methods. 1.Volumetric method a.Direct titration b.Residual titration 2.Coulumetric method. Titrimetric methods are known as Karl- F ischer titrations. The fundamental principle behind the Karl Fischer Titration is based on the reaction between iodine and sulfur dioxide in an aqueous medium shown below: I2+ SO2+2H2O → 2HI+ H2SO4

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Karl Fischer Reagent Sulphur dioxide + iodine dissolved in pyridine and methanol . 1.VOLUMETRIC METHOD DIRECT TITRATION Principle— The titrimetric determination of water is based upon the quantitative reaction of water with an anhydrous solution of sulfur dioxide and iodine in the presence of a buffer that reacts with hydrogen ions . Reagent— Prepare the Karl Fischer Reagent as follows. Add 125 g of iodine to a solution containing 670 mL of methanol and 170 mL of pyridine, and cool. Place 100 mL of pyridine in a 250-mL graduated cylinder, and, keeping the pyridine cold in an ice bath, pass in dry sulfur dioxide until the volume reaches 200 mL. Slowly add this solution, with shaking, to the cooled iodine mixture .

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Standardization of the Reagent :- Place enough methanol or other suitable solvent in the titration vessel to cover the electrodes, and add sufficient Reagent to give the characteristic endpoint color, or 100 ± 50 microamperes of direct current at about 200 mV of applied potential. S odium tartrate may be used as a convenient water reference substance. Add 150 to 350 mg of sodium tartrate (C 4 H 4 Na 2 O 6 ·2H 2 O), accurately weighed, and titrate to the endpoint. The water equivalence factor F, in mg of water per mL of reagent, is given by the formula: F=2(18.02/230.08)( W / V ) Test Preparation — Unless otherwise specified in the individual monograph, use an accurately weighed or measured amount of the specimen under test estimated to contain 10 to 250 mg of water . Procedure :- Transfer 35 to 40 mL of methanol or other suitable solvent to the titration vessel, and titrate with the Reagent to the electrometric or visual endpoint to consume any moisture that may be present. Add the test preparation, mix, and again titrate with the reagent to the electrometric or visual endpoint.

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The water content of the specimen, W=SF. Reaction involved is: py ·I2+ py ·SO2+H2O+ py → 2py ·HI+ py ·SO3 b. Residual Titration Principle:- . In the residual titration, excess Reagent is added to the test specimen, sufficient time is allowed for the reaction to reach completion, and the unconsumed Reagent is titrated with a standard solution of water in a solvent such as methanol. Standardization of Water Solution for Residual Titration :- Prepare a Water Solution by diluting 2 mL of water with methanol or other suitable solvent to 1000 mL. Standardize this solution by titrating 25.0 mL with the Reagent, previously standardized as directed under Standardization of the Reagent. Calculate the water content, in mg per mL, of the Water Solution taken by the formula W`= V′F /25

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Procedure :- Transfer 35 to 40 ml of methanol or other suitable solvent to the titration vessel, and titrate with the reagent to the electrometric or visual endpoint. Add the test preparation, mix, and add an accurately measured excess of the reagent. Allow sufficient time for the reaction to reach completion, and titrate the unconsumed reagent with standardized water solution to the electrometric or visual endpoint. Calculate the water content of the specimen, in mg, taken by the formula: W=FX`XR F-water equivalence factor. X`-volume of reagent X-volume of standardized water solution R-V`/25

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2.COULOMETRIC TITRATION Principle— The Karl Fischer reaction is used in the coulometric determination of water. Iodine,however , is not added in the form of a volumetric solution but is produced in an iodide-containing solution by anodic oxidation. The reaction cell usually consists of a large anode compartment and a small cathode compartment that are separated by a diaphragm. Other suitable types of reaction cells (e.g., without diaphragms) may also be used. Each compartment has a platinum electrode that conducts current through the cell. Iodine, which is produced at the anode electrode, immediately reacts with water present in the compartment. Coulometry is best suited for determination of water content in the range of 1 ppm to 5ppm. There are two main types of coulometric KFT reagent systems. Conventional, or fritted-cell Fritless -cell

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Test preparation :- When the specimen is a soluble solid, dissolve an appropriate quantity, accurately weighed, in anhydrous methanol or other suitable solvents. Liquids may be used as such or as accurately prepared solutions in appropriate anhydrous solvents.When the specimen is an insoluble solid, the water may be extracted using a suitable anhydrous solvent from which an appropriate quantity, accurately weighed, may be injected into the anolyte solution. Alternatively an evaporation technique may be used in which water is released and evaporated by heating the specimen in a tube in a stream of dry inert gas, this gas being then passed into the cell. Procedure — Using a dry syringe, inject the Test Preparation, accurately measured and estimated to contain 0.5 to 5 mg of water, or as, mix, and perform the coulometric titration to the electrometric endpoint. Read the water content of the Test Preparation directly from the instrument's display, and calculate the percentage that is present in the substance. Perform a blank determination, and make any necessary corrections. Determine the quantity of electricity (C) required for the production of iodine during the titration.

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ADVANTAGES 1.High accuracy and precision 2.Selectivity for water 3.Small sample quantities required 4.Easy sample preparation 5.Short analysis duration 6.Nearly unlimited measuring range (1ppm to 100%) 7.Suitability for analyzing solids, liquids, and gases 8.Independence of presence of other volatiles 9.Suitability for automation.

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METHOD II –AZEOTROPIC(TOLUENE DISTILLATION) Toluene Moisture App Apparatus — Use a 500-mL glass flask A connected by means of a trap B to a reflux condenser C by ground glass joints. The connecting tube D is 9 to 11 mm in internal diameter. The trap is 235 to 240 mm in length. The condenser, if of the straight-tube type, is approximately 400 mm in length and not less than 8 mm in bore diameter. The receiving tube E has a 5-mL capacity, and its cylindrical portion, 146 to 156 mm in length, is graduated in 0.1-mL subdivisions, so that the error of reading is not greater than 0.05 mL for any indicated volume. The source of heat is an electric heater with rheostat control or an oil bath. The upper portion of the flask and the connecting tube may be insulated.

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Procedure — Place in the dry flask a quantity of the substance, weighed accurately to the nearest centigram, which is expected to yield 2 to 4 mL of water. Place about 200 mL of toluene in the flask, connect the apparatus, and fill the receiving tube E with toluene poured through the top of the condenser. Heat the flask gently for 15 minutes and, when the toluene begins to boil, distill at the rate of about 2 drops per second until most of the water has passed over, then increase the rate of distillation to about 4 drops per second. When the water has apparently all distilled over, rinse the inside of the condenser tube with toluene while brushing down the tube with a tube brush attached to a copper wire and saturated with toluene. Continue the distillation for 5 minutes, then remove the heat, and allow the receiving tube to cool to room temperature. If any droplets of water adhere to the walls of the receiving tube, scrub them down with a brush consisting of a rubber band wrapped around a copper wire and wetted with toluene. When the water and toluene have separated completely, read the volume of water, and calculate the percentage that was present in the substance.

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3.GRAVIMETRY Mix and accurately weigh the substance to be tested, and, unless otherwise directed in the individual monograph, conduct the determination on 1 to 2 g.. Tare a glass-stoppered, shallow weighing bottle that has been dried for 30 minutes under the same conditions to be employed in the determination. Put the test specimen in the bottle, replace the cover, and accurately weigh the bottle and the contents. By gentle, sidewise shaking, distribute the test specimen as evenly as practicable to a depth of about 5 mm generally, and not more than 10 mm in the case of bulky materials. Place the loaded bottle in the drying chamber, removing the stopper and leaving it also in the chamber. Dry the test specimen at the temperature and for the time specified in the monograph. [NOTE—The temperature specified in the monograph is to be regarded as being within the range of ±2 of the stated figure.] Upon opening the chamber, close the bottle promptly, and allow it to come to room temperature in a desiccator before weighing. Now,note down the difference in reading before drying and after drying.



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