Method of Analysis for Dibutyl Phthalate : Pharmaguideline
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  • Jun 13, 2008

    Method of Analysis for Dibutyl Phthalate

    Procedure to analyze Dibutyl Phthalate in quality control in pharmaceutical laboratory.

    1. Description

    Clear, colorless or very slightly yellow, oily liquid.

    2. Solubility

    Miscible with ethanol (95%) and with ether; practically insoluble in water.

    3. Identification

    Test A may be omitted if tests B, C, D and E are carried out. Tests B, C and D may be omitted if tests A and E are carried out.

    A) By IR

    The infrared absorption spectrum is concordant with the reference spectrum of dibutyl phthalate or with the spectrum obtained from dibutyl phthalate WRS.

    B) By TLC

    Stationary Phase: Silica gel GF 254
    Mobile phase: 70 volumes of ether and 30 volumes of n-heptane.
    Apply separately to the plate 10 ml of each of two solutions.
    Solution (1): Dissolve 50 mg of the substance being examined in sufficient ether to produce 10 ml.
    Solution (2): Dissolve 50 mg of dibutyl phthalate WRS in sufficient ether to produce 10 ml
    After removal of the plate, allow it to dry in air and examine under ultra-violet light (254 nm). The principal spot in the chromatogram obtained with solution (1) corresponds to that in the chromatogram obtained with solution (2).

    C) Color Reaction

    To about 0.1 ml of sample add 0.25 ml of sulphuric acid and 50 mg of resorcinol, heat in a water-bath for 5 minutes, allow to cool and add 10 ml of water and 1 ml of 10M sodium hydroxide; the solution becomes yellow or brownish yellow and shows a green fluorescence.

    D) Relative Density

    Between 1.043 to 1.048

    E) Refractive Index

    Between 1.490 and 1.495, determined at 20°C.

    4. Clarity of solution

    Reference suspension: Dissolve 1.0 gm of hydrazine sulfate with 100ml water and allow standing for 4 to 6 hours. Add 25 ml of this solution to 25 ml of 10% w/v solution of hexamine mix well and allow standing for 24 hours. Dilute well and mix 15ml of the suspension to 1000 ml with water.
    Sample preparation: Take 10 ml of the sample in a Nessler cylinder.
    Procedure: Into separate Nessler cylinders Place sufficient of the sample solution, water and of the reference suspension, freshly prepared, such that the test tubes are filled to a depth of 40 mm. Five minutes after preparation of the reference suspension, compare the contents of the test tubes against a black background by viewing in diffused daylight down the vertical axes of the tubes. The clarity of the sample preparation is greater than water or reference suspension

    5. Color of solution

    Limit: The color intensity of the sample is same as that of water or is not greater than that of reference solution YS6.
    Reference solution: Transfer 1.6ml of Ferric chloride colorimetric solution, 0.4ml of Cobaltous chloride colorimetric solution. Make up the volume to 100 ml with 1% w/v HCl.
    Sample preparation: Take 10ml of the sample in the Nesseler’s cylinder.
    Procedure: Transfer to a flat-bottomed test tube of neutral glass, 15 to 25 mm in diameter, a suitable volume of the liquid being examined such that the test tube is filled to a depth of 40 mm. Into another matched test tube add the same volume of water and of the reference solution prepared. Examine the columns of liquid in diffused light by viewing down the vertical axis of the tubes against a white background.
    The color intensity of the sample is same as that of water or is not greater than that of reference solution YS6.

    6. Acidity

    Limit: NMT 0.5 ml of 0.1 M NaOH is required to change the color of the solution.
    Procedure: Dissolve 20 g in 50 ml of ethanol (95%) previously neutralized to phenolphthalein solution and add 0.2 ml of phenolphthalein solution. Not more than 0.50 ml of 0.1M sodium hydroxide is required to change the color of the solution.

    7. Sulphated Ash

    Limit: Not more than 0.1%
    Procedure: Heat a silica crucible to redness for 10 min., allow cooling in a desiccator and weighing. Place about 1 g of accurately weighed substance being examined in the silica crucible, moisten with sulphuric acid, ignite gently, again moisten with sulphuric acid and ignite at about 800o, cool, weigh again, ignite for 15 min. and repeat this procedure until two successive weighing do not differ by more than 0.5 mg.
    Calculation
                                        W3 – W1
    % Sulphated Ash = ---------------- x 100
                                        W2 – W1
    Where:
    W1 = Weight of empty platinum crucible.
    W2 = Weight of crucible + sample.
    W3 = Weight of crucible + residue. (After ignition)

    8. Related Substances (By GC)

    Limit: Not more than 1.0%
    Internal standard solution: Dissolve 60 mg of bibenzyl in methylene chloride and dilute to 20 ml with the same solvent.
    Test solution (a): Dissolve 1 gm of the sample in methylene chloride and dilute to 20 ml with the same solvent.
    Test solution (b): Dissolve 1gm of the sample in methylene chloride, add 2 ml of the internal standard solution and dilute to 20 ml with methylene chloride.
    Reference solution: To 1 ml of test solution (a) add 10 ml of the internal standard solution and dilute to 100 ml with methylene chloride.
    Chromatographic Conditions
    Column: A glass column 1.5 m long and 4 mm in internal diameter, packed with silanized diatomaceous earth for gas chromatography R (150 µm to 180 µm) impregnated with 3 percent m/m of polymethylphenylsiloxane R.
    Column Temperature
    Initial temperature
    Initial hold
    Heating rate
    Final temperature
    Final hold
    Injection Port Temperature
    Detector temperature (FID)
    Carrier gas
    Head pressure
    Split ratio
    Stop time
    Flow rate
    Injection volume



    190°C

    225°C
    225°C
    Nitrogen


    12 minute
    30ml/ minute
    1ml
    Procedure: Inject 1 µl of the reference solution. The substances elute in the following order: bibenzyl and dibutyl phthalate. Adjust the sensitivity of the detector so that the height of the bibenzyl peak is not less than 70 percent of the full scale of the recorder. The test is not valid unless the resolution between the peaks corresponding to bibenzyl and dibutyl phthalate is at least 12.
    Inject 1 µl of test solution (a). In the chromatogram obtained, verify that there is no peak with the same retention time as the internal standard.
    Inject separately 1 µl of test solution (b) and the reference solution. Continue the chromatography 3 times the retention time of dibutyl phthalate, which is about 12 min. From the chromatogram obtained with the reference solution, calculate the ratio (R) of the area of the peak due to dibutyl phthalate to the area of the peak due to the internal standard. From the chromatogram obtained with test solution (b), calculate the ratio of the sum of the areas of any peaks, apart from the principal peak, the peak due to the internal standard and the peak due to the solvent, to the area of the peak due to the internal standard: this ratio is not greater than R (1.0 percent).

    9. Water content

    Limit: Not more than 0.2%
    Procedure: Transfer 20 ml of anhydrous pyridine to the titration vessel, and titrate with K.F. reagent, standardized earlier, to the electrometric endpoint to consume any moisture that may be present. Quickly and accurately add 10gm substance mix and again titrate with the reagent to the electrometric endpoint. Calculate the % of water using formula
    Calculation
                                     V x F x 100
    Water (% w/w) = --------------------
                                            A

    10. Assay

    Limit: Not less than 99.0% and Not more than 101.0% Calculated on the anhydrous basis.
    Procedure: Boil a convenient quantity of ethanol (95 %) thoroughly to expel carbon dioxide and neutralize it to phenolphthalein solution. Weigh accurately about 1.5 g of the substance being examined dissolve it in 5 ml of the neutralized ethanol contained in a hard-glass flask and neutralize the free acid in the solution with 0.1M ethanolic potassium hydroxide using 0.2 ml of phenolphthalein solution as indicator. Add 25.0 ml of 0.5 M ethanolic potassium hydroxide and boil under a reflux condenser on a water-bath for 1 hour. Add 20 ml of water and titrate the excess of alkali with 0.5 M hydrochloric acid using a further 0.2 ml of phenolphthalein solution as indicator. Repeat the operation without the substance being examined. The difference between the titrations represents the alkali required to saponify esters.
    Each ml of 0.5M ethanolic potassium hydroxide is equivalent to 0.06959 g of C16H22O4
    Calculation
                             (B – T) x M x F x100
    % Assay = -------------------------------
                               0.1 x Wt. of sample
    Where,
    B = Blank reading
    T = Test Reading
    M = Molarity of 0.1 M Zinc Sulphate
    F = Factor

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