Citric Acid Monohydrate
C6H8O7·H2O 210.14
1,2,3-Propanetricarboxylic acid, 2-hydroxy-, monohydrate
[5949-29-1].
Heavy Metals 
231
:
(sit' rik as' id mon'' oh hye' drate).
Portions of the monograph text that are national USP text, and are not part of the harmonized text, are marked with symbols () to specify this fact.
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C6H8O7·H2O 210.14
1,2,3-Propanetricarboxylic acid, 2-hydroxy-, monohydrate
[5949-29-1].DEFINITION
Citric Acid Monohydrate contains one molecule of water of hydration. It contains NLT 99.5% and NMT 100.5% of C6H8O7, calculated on the anhydrous basis.
IDENTIFICATION
• A. Infrared Absorption 197K:
Dry the substance to be examined at 105
for 2 h.
197K:
Dry the substance to be examined at 105 for 2 h.
ASSAY
• Procedure
Sample:
0.550 g of Citric Acid Monohydrate. Record the weight accurately.
Analysis:
Dissolve the Sample in 50 mL of water, and add 0.5 mL of phenolphthalein TS. Titrate with 1 N sodium hydroxide VS. Each mL of 1 N sodium hydroxide is equivalent to 64.03 mg of C6H8O7.
Acceptance criteria:
99.5%–100.5% on the anhydrous basis
IMPURITIES
• Residue on Ignition 281:
NMT 0.1%, determined on 1.0 g
281:
NMT 0.1%, determined on 1.0 g
Delete the following:
Heavy Metals 231:
(Official 1-Dec-2015)
• Sulfate
Standard sulfate solution A:
1.81 mg/mL of potassium sulfate in 30% alcohol. Immediately before use, transfer 10.0 mL of this solution to a 1000-mL volumetric flask, dilute with 30% alcohol to volume, and mix. This solution contains 10 µg/mL of sulfate.
Standard sulfate solution B:
1.81 mg/mL of potassium sulfate. Immediately before use, transfer 10.0 mL of this solution to a 1000-mL volumetric flask, dilute with water to volume, and mix. This solution contains 10 µg/mL of sulfate.
Sample stock solution:
66.7 mg/mL of Citric Acid Monohydrate
Sample solution:
To 4.5 mL of Standard sulfate solution A, add 3 mL of a barium chloride solution (1 in 4), shake, and allow to stand for 1 min. To 2.5 mL of the resulting suspension add 15 mL of the Sample stock solution and 0.5 mL of 5 N acetic acid, and mix.
Standard solution:
Prepare as directed in the Sample solution, except use 15 mL of Standard sulfate solution B instead of the Sample stock solution.
Analysis
Samples:
Sample solution and Standard solution
Acceptance criteria:
Any turbidity produced in the Sample solution after 5 min standing is not greater than that produced in the Standard solution (0.015%).
• Limit of Aluminum (where it is labeled as intended for use in dialysis)
Standard aluminum solution:
To 352 mg of aluminum potassium sulfate in a 100-mL volumetric flask, add a few mL of water, swirl to dissolve, add 10 mL of diluted sulfuric acid, and dilute with water to volume. Immediately before use, dilute 1.0 mL of this solution with water to 100.0 mL.
pH 6.0 acetate buffer:
Dissolve 50 g of ammonium acetate in 150 mL of water, adjust with glacial acetic acid to a pH of 6.0, dilute with water to 250 mL, and mix.
Sample solution:
Dissolve 20.0 g of Citric Acid Monohydrate in 100 mL of water, and add 10 mL of pH 6.0 acetate buffer. Extract this solution with successive portions of 20, 20, and 10 mL of a 0.5% solution of 8-hydroxyquinoline in chloroform, combining the chloroform extracts in a 50-mL volumetric flask. Dilute the combined extracts with chloroform to volume, and mix.
Standard solution:
Prepare a mixture of 2.0 mL of Standard aluminum solution, 10 mL of pH 6.0 acetate buffer, and 98 mL of water. Extract this mixture as described for the Sample solution, dilute the combined extracts with chloroform to volume, and mix.
Blank solution:
Prepare a mixture of 10 mL of pH 6.0 acetate buffer and 100 mL of water. Extract this mixture as described for the Sample solution, dilute the combined extracts with chloroform to volume, and mix.
Fluorometric conditions
Excitation wavelength:
392 nm
Emission wavelength:
518 nm
Analysis
Samples:
Sample solution and Standard solution
Determine the fluorescence intensities of the Samples in a fluorometer set as directed under Fluorometric conditions, using the Blank solution to set the instrument to zero.
Acceptance criteria:
The fluorescence of the Sample solution does not exceed that of the Standard solution (0.2 ppm).
• Limit of Oxalic Acid
Sample stock solution:
0.80 g of Citric Acid Monohydrate in 4 mL of water
Sample solution:
To the Sample stock solution add 3 mL of hydrochloric acid and 1 g of granular zinc, boil for 1 min, and allow to stand for 2 min. Transfer the supernatant to a test tube containing 0.25 mL of a phenylhydrazine hydrochloride solution (1 in 100), and heat to boiling. Cool rapidly, transfer to a graduated cylinder, and add an equal volume of hydrochloric acid and 0.25 mL of a potassium ferricyanide solution (1 in 20). Shake and allow to stand for 30 min.
Standard solution:
Prepare as directed for the Sample solution, except use 4 mL of 0.10 mg/mL oxalic acid solution, equivalent to 0.0714 mg/mL of anhydrous oxalic acid, instead of the Sample stock solution. [Note—Prepare concomitantly with the Sample solution. ]
Analysis
Samples:
Sample solution and Standard solution
Acceptance criteria:
Any pink color produced in the Sample solution is not more intense than that produced in the Standard solution (0.036%).
SPECIFIC TESTS
• Bacterial Endotoxins Test 85:
The level of bacterial endotoxins is such that the requirement in the relevant dosage form monograph(s) in which Citric Acid Monohydrate is used can be met. Where the label states that Citric Acid Monohydrate must be subjected to further processing during the preparation of injectable dosage forms, the level of bacterial endotoxins is such that the requirement in the relevant dosage form monograph(s) in which Citric Acid Monohydrate is used can be met.
Bacterial Endotoxins Test 85:
The level of bacterial endotoxins is such that the requirement in the relevant dosage form monograph(s) in which Citric Acid Monohydrate is used can be met. Where the label states that Citric Acid Monohydrate must be subjected to further processing during the preparation of injectable dosage forms, the level of bacterial endotoxins is such that the requirement in the relevant dosage form monograph(s) in which Citric Acid Monohydrate is used can be met.
• Clarity of Solution
[Note—The Sample solution is to be compared to Standard suspension A in diffused daylight 5 min after preparation of Standard suspension A. ]
Hydrazine sulfate solution:
10 mg/mL of hydrazine sulfate in water. Allow to stand for 4–6 h before use.
Methenamine solution:
Transfer 2.5 g of methenamine to a 100-mL glass-stoppered flask, add 25.0 mL of water, insert the glass stopper, and mix to dissolve.
Primary opalescent suspension:
Transfer 25.0 mL of Hydrazine sulfate solution to the Methenamine solution in the 100-mL glass-stoppered flask. Mix, and allow to stand for 24 h. [Note—This suspension is stable for 2 months, provided it is stored in a glass container free from surface defects. The suspension must not adhere to the glass and must be well mixed before use. ]
Opalescence standard:
Dilute 15.0 mL of Primary opalescent suspension with water to 1000 mL. [Note—This suspension should not be used beyond 24 h after preparation. ]
Standard suspension A:
Dilute 5.0 mL of Opalescence standard with 95 mL of water.
Standard suspension B:
Dilute 10.0 mL of Opalescence standard with 90 mL of water.
Sample solution:
200 mg/mL of Citric Acid Monohydrate in water
Analysis
Samples:
Standard suspension A, Standard suspension B, water, and Sample solution
Transfer a sufficient portion of the Sample solution to a test tube of colorless, transparent, neutral glass with a flat base and an internal diameter of 15–25 mm to obtain a depth of 40 mm. Similarly transfer portions of Standard suspension A, Standard suspension B, and water to separate matching test tubes. Compare the Sample solution, Standard suspension A, Standard suspension B, and water in diffused daylight, viewing vertically against a black background (see Spectrophotometry and Light-Scattering 851, Visual Comparison). [Note—The diffusion of light must be such that Standard suspension A can readily be distinguished from water, and that Standard suspension B can readily be distinguished from Standard suspension A. ]
851, Visual Comparison). [Note—The diffusion of light must be such that Standard suspension A can readily be distinguished from water, and that Standard suspension B can readily be distinguished from Standard suspension A. ]
Acceptance criteria:
The Sample solution shows the same clarity as that of water or its opalescence is not more pronounced than Standard suspension A.
• Color of Solution
Standard stock solution A:
Ferric chloride CS, cobaltous chloride CS, cupric sulfate CS, and dilute hydrochloric acid (10 g/L) (2.4: 0.6: 0: 7.0)
Standard stock solution B:
Ferric chloride CS, cobaltous chloride CS, cupric sulfate CS, and dilute hydrochloric acid (10 g/L) (2.4: 1.0: 0.4: 6.2)
Standard stock solution C:
Ferric chloride CS, cobaltous chloride CS, cupric sulfate CS, and dilute hydrochloric acid (10 g/L) (9.6: 0.2: 0.2: 0)
[Note—Prepare the Standard solutions immediately before use. ]
Standard solution A:
Transfer 2.5 mL of Standard stock solution A, and dilute with dilute hydrochloric acid (10 g/L) to 100 mL.
Standard solution B:
Transfer 2.5 mL of Standard stock solution B, and dilute with dilute hydrochloric acid (10 g/L) to 100 mL.
Standard solution C:
Transfer 0.75 mL of Standard stock solution C, and dilute with dilute hydrochloric acid (10 g/L) to 100 mL.
Sample solution:
Prepare as directed in the test for Clarity of Solution.
Analysis 1
Samples:
Water and Sample solution
Transfer a sufficient portion of the Sample solution to a test tube of colorless, transparent, neutral glass with a flat base and an internal diameter of 15–25 mm to obtain a depth of 40 mm. Similarly transfer water to a separate matching test tube. Compare the Sample solution and water in diffused daylight, viewing vertically against a white background (see Spectrophotometry and Light-Scattering 851, Visual Comparison).
851, Visual Comparison).
Acceptance criteria 1:
The Sample solution is not more intensely colored than water. If more intensely colored, follow Analysis 2.
Analysis 2
Samples:
Standard solution A, Standard solution B, Standard solution C, and Sample solution
Transfer a sufficient portion of Standard solution A, Standard solution B, and Standard solution C to separate test tubes of colorless, transparent, neutral glass with a flat base and an internal diameter of 15–25 mm to obtain a depth of 40 mm. Compare the Sample solution from Analysis 1 to Standard solution A, Standard solution B, and Standard solution C in diffused daylight, viewing vertically against a white background (see Spectrophotometry and Light-Scattering 851, Visual Comparison).
851, Visual Comparison).
Acceptance criteria 2:
The Sample solution is not more intensely colored than Standard solutions A, B, and C.
• Readily Carbonizable Substances
Sample:
1.0 g powdered Citric Acid Monohydrate
Analysis:
Transfer the Sample to a 22-mm × 175-mm test tube previously rinsed with 10 mL of sulfuric acid and allowed to drain for 10 min. Add 10 mL of sulfuric acid, agitate until solution is complete, and immerse in a water bath at 90 ± 1 for 60 ± 0.5 min, keeping the level of the acid below the level of the water during the entire period. Cool the tube in running water, and transfer the acid to a color-comparison tube.
for 60 ± 0.5 min, keeping the level of the acid below the level of the water during the entire period. Cool the tube in running water, and transfer the acid to a color-comparison tube.
Acceptance criteria:
The color of the acid is not darker than that of a similar volume of Matching Fluid K (see Color and Achromicity 631) in a matching tube, the tubes being observed vertically against a white background.
631) in a matching tube, the tubes being observed vertically against a white background.
• Sterility Tests 71:
Where the label states that Citric Acid Monohydrate is sterile, it meets the requirements for Sterility Tests 71 in the relevant dosage form monograph(s) in which Citric Acid Monohydrate is used.
Sterility Tests 71:
Where the label states that Citric Acid Monohydrate is sterile, it meets the requirements for Sterility Tests 71 in the relevant dosage form monograph(s) in which Citric Acid Monohydrate is used.
• Water Determination, Method I 921
921
Sample:
0.5 g of Citric Acid Monohydrate
Acceptance criteria:
7.5%–9.0%
ADDITIONAL REQUIREMENTS
• Packaging and Storage:
Preserve in tight containers. No storage requirements specified.
Packaging and Storage:
Preserve in tight containers. No storage requirements specified.
• Labeling:
Where it is intended for use in dialysis solutions, it is so labeled. Where Citric Acid Monohydrate must be subjected to further processing during the preparation of injectable dosage forms to ensure acceptable levels of bacterial endotoxins, it is so labeled. Where Citric Acid Monohydrate is sterile, it is so labeled.
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Auxiliary Information—
Please check for your question in the FAQs before contacting USP.
| Topic/Question | Contact | Expert Committee |
|---|---|---|
| Monograph | Kevin T. Moore, Ph.D.
Manager, Pharmacopeial Harmonization (301) 816-8369 |
(EXC2010) Monographs - Excipients |
| 85 |
Radhakrishna S Tirumalai, Ph.D.
Principal Scientific Liaison (301) 816-8339 |
(GCM2010) General Chapters - Microbiology |
| 71 |
Radhakrishna S Tirumalai, Ph.D.
Principal Scientific Liaison (301) 816-8339 |
(GCM2010) General Chapters - Microbiology |
| Reference Standards | RS Technical Services 1-301-816-8129 rstech@usp.org |
USP38–NF33 Page 2842
Pharmacopeial Forum: Volume No. 34(5) Page 1151