Method of Analysis for Hypromellose Phthalate

1. Description

White granular powder.

2. Solubility

Practically insoluble in water, in dehydrated alcohol and in hexane. Dissolves in 1 N sodium hydroxide.

3. Identification

By IR:

Procedure: Record IR absorption spectrum of the sample as KBr pellet, by taking 2-3 mg of sample in 150-200 mg of KBr, and compare it with similarly recorded the spectrum of Bupropion Hydrochloride reference standard.

4. Viscosity

Limit: Not less than 80% and not more than 120% of the label claim.
Procedure: Dissolve 10 g, previously dried sample at 105° for 1 hour, in 90 g of a mixture of equal weights of methanol and methylene chloride by mixing and shaking: the viscosity, determined at 20 ± 0.1°, is not less than 80% and not more than 120% of that indicated by the label.

5. Water

Limit: Not more than 5.0%
Procedure: Transfer 35 to 40 ml of methanol 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 100 mg substance, mix, and again titrate with the reagent to the electrometric end-point. Calculate the % of water using the formula:
Calculation
                                 V x F x 100
Water (% w/w) = -----------------
                                        W
Where,
V= Volume of K.F. reagent consumed (ml)
F= Water equivalence factor of reagent in mg/ml.
W= Weight of substances in mg.

6. Residue on Ignition

Limit: Not more than 0.2%
Procedure: Heat a silica crucible to redness for 10 min., allow to cool in a desiccator and weigh. Place about 1 g of accurately weighed substance (the residue obtained in the test for loss on drying) in the silica crucible, moisten with sulphuric acid, ignite gently, again moisten with sulphuric acid and ignite at about 800°, 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)

7. Chloride

Limit: Not more than 0.07%
Procedure: Dissolve 1.0 g sample in 40 ml of 0.2 N sodium hydroxide, add 1 drop of phenolphthalein, and add 2 N nitric acid dropwise, with stirring, until the red color is discharged. Add an additional 20 ml of 2 N nitric acid with stirring. Heat on a water bath, with stirring, until the gel-like precipitate formed becomes granular. Cool the mixture and centrifuge. Separate the liquid phase, and wash the residue with three successive 20-ml portions of water, separating the washings by centrifuging. Dilute the combined liquids with water to 200 ml, mix, and filter. A 50-ml portion of the filtrate so obtained shows no more chloride than a control solution made by treating 0.50 ml of 0.01 N hydrochloric acid with 10 ml of 0.2 N sodium hydroxide, adding 7 ml of 2 N nitric acid, and diluting with water to 50 ml.

8. Heavy metals

Limit: Not more than 0.001%.
Reagent required
Lead standard solution (20 ppm Pb)
6N ammonium Hydroxide
1N acetic acid
Sulphuric acid
Nitric acid
6N Hydrochloric acid
Acetate Buffer pH 3.5
Thiacetamide-Glycerine base
Standard Solution: Into a 50 ml Nessler cylinder pipette 2.0 ml of lead standard solution (20 ppm Pb) and dilute with water to 25 ml. Adjust with 1N acetic acid or 6N ammonium Hydroxide to a pH between 3.0 and 4.0, dilute with water to about 40 ml and mix.
Test Solution: Weigh accurately about 2 gm of sample in a silica crucible, add sufficient sulphuric acid to wet the sample, ignite carefully at a low temperature until thoroughly charred. Add to the charred mass 2 ml of nitric acid and 5 drops of sulphuric acid and heat cautiously until white fumes are no longer evolved. Ignite, preferably in a muffle furnace, at 500° to 600°, until the carbon is completely burnt off. Cool, add 4 ml of 6N hydrochloric acid, cover, digest on a water bath for 15 minutes, uncover and slowly evaporate to dryness on a water bath. Moisten the residue with 1 drop of hydrochloric acid; add 10 ml of hot water and digest for 2 minutes. Add 6N ammonium hydroxide solution drop-wise until the solution is just alkaline to litmus paper, dilute to 25 ml with water and adjust with 1N acetic acid to a pH between 3.0 and 4.0. Filter, if necessary, rinse the crucible and the filter with 10 ml of water, combine the filtrate and washings in a 50 ml Nessler cylinder, dilute with water to about 40 ml and mix.
Procedure: To each of the tubes containing the standard preparation and the test preparation, add 2 ml of pH 3.5 acetate buffer, then add 1.2 ml of thioacetamide-glycerin base TS, dilute with water to 50 ml, mix, allow to stand for 2 minutes, and view downward over a white surface the color of the solution from the test preparation is not darker than that of the solution from the standard preparation.

9. Limit of Free Phthalic acid

Limit: Not more than 1.0% found.
Procedure: Mobile phase: Prepare a filtered and degassed mixture of 0.1 M cyanoacetic acid and acetonitrile (85:15). Make adjustments if necessary.
Standard solution: Transfer about 12.5 mg of phthalic acid, accurately weighed, to a 250-ml volumetric flask, add about 125 ml of acetonitrile, and mix to dissolve. Add 25 ml of water, dilute with acetonitrile to volume, and mix.
Test solution: Transfer about 200 mg of Hypromellose Phthalate, accurately weighed, to a 100-ml volumetric flask, add about 50 ml of acetonitrile, and sonicate to dissolve partially. Add 10 ml of water, and sonicate to dissolve. Cool to room temperature, diluted with acetonitrile to volume and mix.

Column	A 4.6-mm × 25-cm column that contains packing L1 with a high carbon load.
Detector	UV, 235 nm.
Flow rate	2.0 ml/min.
Injection volume	10 ml

Chromatograph the Standard solution, and record the peak responses as directed under Procedure: the relative standard deviation for replicate injections is not more than 1.0%.
Procedure: Separately inject equal volumes (about 10 µl) of the Standard solution and the Test solution into the chromatograph, record the chromatograms, and measure the peak responses. Calculate the percentage of phthalic acid in the portion of Hypromellose Phthalate taken by the formula:
10(C / W)(r U / r S),
In which C is the concentration, in µg per ml, of phthalic acid in the Standard solution,
W is the weight, in mg, on the anhydrous basis, of Hypromellose Phthalate taken to prepare the test solution, r U and r S are the phthalic acid peak responses obtained from the Test solution and the Standard solution, respectively: not more than 1.0% is found.

10. Organic Volatile Impurities

Limit:
Chloroform: Not more than 60 ppm
1,4-Dioxane: Not more than 380 ppm
Methylene chloride: Not more than 600 ppm
Trichloroethylene: Not more than 80 ppm
Standard solution preparation: Prepare a solution in organic free water containing in each ml, 12mg of Methylene chloride, 7.6mg of 1,4-dioxane, 1.6mg of Trichloroethylene, and 1.2mg of chloroform. Pipette 5ml of this solution into a vial fitted with a septum and crimp-cap, containing 1g of anhydrous sodium sulfate, and seal. Heat a sealed vial at 80°C for 60 minutes.
Test Solution: Transfer 100mg, accurately weighed sample to a vial, add 5.0ml of water, and 1gm of anhydrous sodium sulfate, and seal with a septum and crimp cap. Heat the sealed vial at 80°C for 60 minutes.
Chromatographic conditions: Column: 0.53mm X 30m fused silica analytical column coated with a 3.0 mm G43 stationary phase, and a 0.53mm X 5m silica guard column deactivated with phenyl methyl siloxane.

Detector Carrier gas Carrier flow Column Int. Temp Column Pro. Rate Column Pro. Rate Injector temp. Injection volume Detector temp

Flame ionization detector Nitrogen 40°C for 20 minutes 140C 1ml 260°C

Procedure: Separately inject equal volumes (about 1ml) of the standard solution and the test solution into the chromatograph, record the chromatograms, and measure the peak responses. Identify based on retention time, any peaks present in the chromatogram of the test solution. The identity and the peak response in the chromatogram may be established as being from any of the organic volatile impurities that are mentioned in the limit.
Calculation

                                                                   Rt        WS        P
Content of each components (ppm) = --------x ------ x ------- x D x 10⁶
                                                                   RS      Wt      100
Where,
Rt = Ratio of the detector response of the component to IS in test preparation.
RS = Ratio of the detector response of the component to IS in std. preparation.
WS = weight of a component in standard in gms.
Wt = weight samples taken in gms
P = % purity of component.
D = Dilution factor 0.01 for methanol and THF, 0.001 for n-hexane and toluene).

11. Phthalyl Content

Limit: It contains not less than 21.0 percent and not more than 35.0 percent of phthalyl groups, calculated on the anhydrous basis.
Procedure: Transfer about 1 g sample, accurately weighed, to a conical flask, dissolve in 50 ml of a mixture of alcohol, acetone, and water (2:2:1), add phenolphthalein, and titrate with 0.1 N sodium hydroxide. Perform a blank determination, and make any necessary correction. Calculate the percentage of phthalyl taken by the formula:
0.01(149.1)(V / W) - 2(149.1 / 166.1)(P),
In which 149.1 and 166.1 are the molecular weights of the phthalyl group and phthalic acid, respectively,
V is the volume, in ml, of 0.1 N sodium hydroxide consumed after correction for the blank,
W is the weight, in g, calculated on the anhydrous basis, of Hypromellose Phthalate taken,
P is the percentage of free phthalic acid found as directed in the test for Limit of free phthalic acid.