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Method of Analysis for Cross Carmelose Sodium

Learn the procedure for analysis of the Cross Carmelose Sodium in pharmaceutical quality control laboratory.
1. Description
White free flowing powder.

2. Solubility
Partially soluble in water, insoluble in alcohol, in ether and in other organic solvents.

3. Identification
A. By color test
Reagent required
Methylene blue solution (1g in 250,000ml water)
Mix 1g of the sample with 100ml of methylene blue solution. Stir the mixture and allow it to settle. 
The substance absorbs methylene blue and settles as a blue fibrous mass.
B. By color test
Reagent required
1-naphthol TS
Sulfuric acid AR
Mix 100 mg of sample with 5.0 ml of water.  Transfer 1ml of the mixture to a small test tube, and add 1ml of water and 5 drops of 1-naphthol TS.  Incline the test tube and carefully add 2 ml of sulphuric acid down the side so that it forms a lower layer. A red purple color develops at the interface.
C. Responds to the test for sodium
Reagent required
15% potassium carbonate
Potassium pyroantimonate TS
Take 2 ml of solution (prepared for identification test (b)) in a clean test tube; add 2ml of 15% potassium carbonate and heat to boiling. No precipitate is formed. Add 4 ml of potassium pyroantimonate TS and heat to boiling. Allow to cool in ice water and if necessary, rub the inside of the test tube with a glass rod. A dense precipitate is formed.

4. pH
Limit: Between 5.0 and 7.0
Mix 250 mg of substance with 24.5 ml of water in a clean beaker, for 1 hour.  Measure the pH of the dispersion using a suitably calibrated pH meter.

5. Loss on drying
Limit: Not more than 10.0%
Weigh 1.000 g of substance in a clean and dried pre-weighed LOD Bottle. Cover the stopper and gently shake to distribute material to not more than 10 MM height. Place the LOD Bottle in an oven and remove the cover and leave it also inside the oven. Dry the sample at 105o for 2hours On opening the chamber, immediately close the LOD Bottle, transfer it to desiccators and bring it to room temperature. Weigh up to constant weight.
                       W2 – W3
% LOD  =   --------------- X 100
                       W2 – W1
W1 = Weight of empty clean and dried LOD Bottle.
W2 = Weight of LOD Bottle + sample.
W3 = Weight of LOD Bottle + sample.  (After drying)

6. Sodium chloride and Sodium Glycolate
Limit: The sum of the percentage of sodium chloride and sodium glycolate is not more than 0.5%
(A) Sodium chloride
Reagent required
30% hydrogen peroxide
Nitric acid
0.05N Silver nitrate VS
Weigh accurately about 5 g of substance into a clean & dried beaker; add 50ml of water and 5ml of 30 % hydrogen peroxide and heat in the water bath for 20 minutes.  Cool, add 100ml of water and 10ml of nitric acid and titrate with 0.05N silver nitrate VS determining the endpoint potentiometrically, and stirring constantly. Calculate the percentage of the sodium chloride by the following formula

                                          584.4 x V x N
% Sodium Chloride  = ----------------------
                                          W x  (100-b)

584.4 = Equivalence factor for sodium chloride
V = volume of silver nitrate VS
N = Normality of silver nitrate VS
b = % of loss on drying
W = Weight of the sample in ‘g’

(B) Sodium Glycolate
Reagent required
Glacial acetic acid AR
Acetone AR
Sodium chloride AR
Glycolic acid
2,7 Dihydroxynaphthalene TS
Preparation of test solution: Weigh about 500 mg sample into a 100 ml beaker; moisten with a 5 ml of glacial acetic acid, followed by 5 ml of water, and stir with a glass rod to ensure proper hydration (usually about 15 min.).  Slowly add 50 ml of acetone, with stirring then add 1 g of sodium chloride and stir for several minutes to ensure complete precipitation of the carboxymethylcellulose. Filter through a soft, open textured paper, previously wetted with a small amount of acetone and collect the filtrate in a 100 ml volumetric flask. Use an additional 30 ml of acetone to facilitate the transfer of the solids and to wash the filter cake, then dilute to volume with acetone and mix.
Preparation of standard solution: Prepare a series of standard solutions as follows. Weigh about 100mg of glycolic acid, previously dried in desiccators at room temperature, overnight and dilute with 100 ml water and mix. Transfer 1.0, 2.0, 3.0 and 4.0 ml portions of the solution respectively to separate 100ml volumetric flask, add water to each flask to make 5 ml (i.e. in the flask containing 1.0 ml, add 4 ml water and in the flask containing 2.0 ml, add 3.0 ml of water vice versa) then add 5.0 ml of glacial acetic acid, dilute with acetone to volume and mix.
Transfer 2.0 ml of the test solution and 2.0 ml of each standard solution to separate 25 ml volumetric flask and prepare a blank flask containing 2.0 ml of a solution containing 5% each of glacial acetic acid and water in acetone. Place uncovered flasks in a boiling water bath for 20 minutes, accurately timed to remove  the acetone, remove from the water-bath and cool.
Add to each flask 5.0 ml of 2,7-dihydroxynaphthalene TS, mix add an additional 15ml and again mix.  Cover the month of each flask with a small piece of aluminum foil. Place the flask upright in a boiling water-bath for 20 minutes, then remove from the bath, cool, dilute with sulphuric acid to volume and mix.
Determine the absorbance of each solution at 540 nm, with a suitable spectrophotometer, against the blank and prepare a standard curve using the absorbance obtained from the standard solutions. From the standard curve and the absorbance of the test specimen, determine the (w) in mg, of glycolic acid in the specimen, and calculate the percentage of sodium glycolate in the specimen taken by the formula:

                                     12.9  x  w
%Glycolic acid =  -----------------
                                  W x  (100-b)
12.9 = factor converting glycolic acid to sodium glycolate
b = % of loss on drying
W = Weight of sample in G

7. Heavy metals
Limit: Not more than 0.001%
Reagent required
Nitric acid AR
Sulphuric acid AR
6N Hydrochloric acid AR
Hydrochloric acid
6N Ammonium hydroxide AR
1N Acetic acid
Acetate buffer pH 3.5
Thioacetamide – glycerin base TS
Standard lead solution (10 ppm)
Standard Preparation: Into a clean color comparison tube pipette out 2 ml of standard lead solution (20 ppm) 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 using short-range pH indicator paper as the external indicator, dilute with water to 40 ml, and mix.
Test Preparation: Transfer accurately weighed 2 gm of substance to a suitable crucible, add sufficient sulphuric acid to wet the substance and carefully ignite at a low temperature until thoroughly charred.  Add 2 ml of nitric acid and 5 drops of sulphuric acid and heat cautiously until white fumes no longer evolve.  Ignite preferably in a muffle furnace at 500 to 600° until the carbon is completely burned off. Cool, add 4 ml of 6N hydrochloric acid, cover, digest on a water bath for 15 minutes, uncover and slowly evaporate on a water bath to dryness. Moisten the residue with one drop of HCl; add 10ml of hot water and digest for 2 minutes. Add 6N ammonium hydroxide dropwise until the solution is just alkaline to litmus paper, dilute with water to 25 ml and adjust with 1N acetic acid to a pH between 3.0 and 4.0, using short-range pH indicator paper as the external indicator.  Filter rinse the crucible and filter with 10 ml of water, combine the filtrate and rinsing in a 50 ml color comparison tube, dilute with water to 40 ml and mix.
To each of the tube containing standard preparation and test preparation add 2 ml of pH 3.5 acetic buffer, then add 1.2 ml 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 solution from the standard preparation.

8. Degree of substitution
Limit: Between 0.60 and 0.85 calculated on the dried basis.
Reagent required
Sodium chloride solution (1 gm in 10 ml water)
0.1N sodium hydroxide VS
M-cresol purple TS
0.1N Hydrochloric acid.
Weigh about 1g of the sample in a glass-stoppered, 500 ml conical flask, add 300 ml of sodium chloride (1 in 10), then add 25ml 0.1N sodium hydroxide VS. Insert the stopper and allow standing for 5 minutes with intermittent shaking. Add 5 drops of m-cresol purple TS and from a burette add about 15 ml of 0.1N Hydrochloric acid VS. Insert the stopper in the flask and shake.  If the solution is purple, add 0.1N hydrochloric acid VS in 1 ml portions until the solution become yellow, shaking after each addition. Titrate with 0.1N sodium hydroxide VS to a purple end point.  Note down the 0.1N sodium hydroxide consumed (Y). Calculate the net number of milli equivalence (M) by the following for mark
                                               (4 x Y x N)
Degree of substitution =  ------------------
Y = Titer value of 0.1 sodium hydroxide consumed.
4 = Milliqeuivalence for 1 ml of 0.1Sodium hydroxide
N = Normality of 0.1N NaOH
W = Weight of sample in mg

9. Residue on ignition
Reagent required
Concentrated Sulphuric acid AR
Weigh a silica crucible, previously heated at about 800°C and cooled in a desiccator. Weigh 1gm of the sample in the crucible and ignite on a flame until the substance is thoroughly charred, cool the crucible and moisten the residue with 1ml of sulphuric acid. Heat the crucible gently over a flame until the white fumes are no longer evolved. Keep the crucible for ignition at about 800°C in muffle furnace until all the black particles have been disappeared. Cool the crucible in a desiccator, weigh the crucible. Repeat the procedure until two successive weights do not differ by more than 0.5mg of the substance.

                                              W3  -  W1
% Residue on ignition = --------------- x 100
                                              W2  -  W1
W1 = Weight of empty crucible
W2 = Weight of crucible + sample
W3 = Weight of crucible + residue

Calculate degree of acid carboxymethyl substitution ‘A’ taken by the formula

= -------------------------
 (7102-412M – 80C)

M = Milliqeuivalence
C = Residue on ignition
Calculate the degree of sodium carboxy methyl substitution S taken by the formula:

        (162 + 58A) C
= ----------------------
        (7102 – 80 C)

A = Degree of acid carboxymethyl substitution
C = Residue on ignition
The degree of substitution   = A + S
A = Degree of acid carboxymethyl substitution
S = Degree of sodium carboxymethyl substitution

10. Content of water soluble material
Limit: Between 1.0% and 10.0 %
Disperse about 10 g of substance in 800ml of water and stir for 1 minute for every 10 minutes during the first 30 minutes. Allow standing for an additional one-hour, centrifuge if necessary.  Decant about 200 ml of the aqueous slurry into a rapid filtering filter paper in a vacuum filtration funnel, apply vacuum and collect about 150 ml of the filtrate. Pour the filtrate into previously weighed 250 ml beaker. Weigh and calculate the weight in ‘g’ of the filtrate. Keep the beaker on a hot plate and dry to small volume, but not to dryness, dry the beaker at 105°C for 4 hours again weigh, calculate the weight in ‘g’ of the residue by the difference. 
Calculate the percentage of water-soluble material, on the dried basis, taken by the formula.

                                                                     100 x W1x (800+W2)
Content of water soluble material = -----------------------------
                                                                     W2 x W3 x (1-0.01b)
W1 = Weight of the residue
W2 = Weight of the sample taken
W3 = Weight of the filtration taken in ‘g’
b = % of loss on drying

11. Setting volume
Limit: Between 10.0 ml and 30.0 ml
Take 75 ml of water in a 100 ml graduated cylinder; add 1.5 g of the substance of it in 0.5 g portions, shaking vigorously after each addition. Add water to make 100 ml, shake again until all the powder is homogeneously distributed and allow to stand for 4 hours. After 4 hours, note down the volume of the settled mass.

12. Organic volatile Impurity
Benzene: not more than 2.0 mg/g
Chloroform: not more than 60 mg/g
1,4-dioxane: not more than 380 mg/g
Methylene Chloride: not more than 600 mg/g
Trichloro ethylene: not more than 80 mg/g
Reagent required
Anhydrous Sodium Sulphate AR
Methylene Chloride AR
Chloroform AR
Benzene AR
1,4 – Dioxane AR
Trichloroethylene AR
Chromatographic conditions
Column: 30 m x 0.53 mm ID fused silica column deactivated with phenylmethyl siloxane.
Column Temperature program: Initially 35°C for 5 minutes. Then increase to 175°C at the rate of 8°C per minute followed by an increase to 260°C at a rate of 35°C per minute and held for at least 16 minutes
Carrier Gas: Nitrogen.
Injection volume: 1.0 ml
Standard Solution: Prepare a solution in organic – free water containing in each ml, 10.0 mg of Methylene Chloride, 1.0 mg of Chloroform and 2.0 mg each of benzene, 1,4 – Dioxane and Trichloroethylene. Pipette out 5.0 ml of this solution into a vial fitted with a septum and crimp-cap, containing 1.0 g of Anhydrous Sodium Sulphate and seal. Heat the sealed vial at 80°C for 60 minutes.
Sample Solution: Transfer accurately about 100 mg of the sample into a clean and dried vial. Add 5.0 ml of water and 1.0g of Anhydrous Sodium Sulphate and seal with a septum and crimp-cap. Heat the sealed vial at 80°C for 60 minutes.
Inject separately equal volumes (1.0ml each) of standard solution and sample solution into the chromatograph and record the chromatograms; measure the peak responses.
Identify any peaks present in the chromatogram in the sample solution based on the retention time. The impurity limit for benzene is 100 ppm; for chloroform 50 ppm; for 1,4 – Dioxane 100 ppm; for methylene chloride 500 ppm and for trichloroethylene 100 ppm.

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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