Salsalate

This article is compiled based on the United States Pharmacopeia (USP) – 2025 Edition

Issued and maintained by the United States Pharmacopeial Convention (USP)

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» Salsalate contains not less than 98.0 percent and not more than 102.0 percent of total salicylates, expressed as the sum of the percentages of salsalate, salicylic acid, and trisalicylic acid, calculated on the dried basis.

Packaging and storage— Preserve in tight containers.

USP Reference standards 〈11〉—

USP Salsalate RS

USP Salicylic Acid RS

USP Trisalicylic Acid RS C₂₁H₁₄O₇ 378.34

1 Identification

▲Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197M▲ (CN 1-May-2020)

Loss on drying 〈731〉—

Dry it in vacuum at 60° for 3 hours: it loses not more than 0.5% of its weight.

Residue on ignition 〈281〉:

Not more than 0.10%.

Chloride 〈221〉—

Dissolve 1.4 g in 6 mL of methanol, warming if necessary to effect solution.

Dilute with water to 50 mL to precipitate the salsalate, allow to stand for 5 minutes, and filter.

A 25-mL portion of the filtrate shows no more chloride than corresponds to 0.20 mL of 0.010 N hydrochloric acid (0.01%).

Sulfate 〈221〉—

A 17-mL portion of the filtrate prepared for the test for Chloride shows no more sulfate than corresponds to 0.50 mL of 0.010 N sulfuric acid (0.05%).

Limit of dimethylaniline—

Internal standard solution—

Prepare a solution in methylene chloride containing 0.4 mg of indene per mL.

Standard preparation—

Transfer about 50 mg of N,N-dimethylaniline, accurately weighed, to a 100-mL volumetric flask, dilute with Internal standard solution to volume, insert the stopper securely, and mix.

Test preparation—

Transfer about 5 g of Salsalate, accurately weighed, to a 125-mL separator fitted with a cotton pledget in its stem.

Add 50 mL of water and 6 mL of 6 N ammonium hydroxide, and swirl until dissolved.

Add 5.0 mL of Internal standard solution, insert stopper, shake 1 minute, allow layers to separate.

Drain lower phase into a screw-capped test tube — use as Test preparation.

Chromatographic system

Gas chromatograph with flame-ionization detector, 10:1 split injector, 30-m × 0.53-mm capillary column, 1.0-µm G42 phase film.

Column 105°, injector 250°, detector 250°.

Helium carrier gas, 13 mL/min.

Relative retention times: 0.75 (indene), 1.0 (N,N-dimethylaniline).

R ≥ 2.0.

RSD ≤ 3%.

Procedure—

Inject equal volumes (about 1 µL) of Standard preparation and Test preparation.

Use peak areas.

Indene elutes before N,N-dimethylaniline.

Calculate percentage of N,N-dimethylaniline:

0.5(C/W)(Rᵤ/Rₛ)

C = concentration of N,N-dimethylaniline in Standard preparation (mg/mL)

W = weight of Salsalate taken (g)

Rᵤ, Rₛ = peak ratios (N,N-dimethylaniline/indene) of Test and Standard preparations

Limit: 0.05%.

Isopropyl, ethyl, and methyl salicylates—

Standard stock solution—

Solution in n-heptane containing:

• 0.20 mg/mL isopropyl salicylate
• 0.50 mg/mL ethyl salicylate
• 0.50 mg/mL methyl salicylate

Standard preparation—

2.0 g Salsalate + 10 mL 1 N NaOH + 2 mL n-heptane → shake, separate layers.

Discard upper layer.

Add 2.0 mL Standard stock solution → shake, separate.

Use upper layer as Standard preparation.

Test preparation—

Identical to Standard preparation but without added Standard stock solution.

Chromatographic system—

Same GC system; column 120°, injector & detector 250°; helium 13 mL/min.

Procedure—

Inject equal volumes (about 1 µL).

Relative retention times:

• 0.65 methyl salicylate
• 0.9 ethyl salicylate
• 1.0 isopropyl salicylate

Limits:

• Isopropyl salicylate ≤ Standard (0.02%)
• Ethyl salicylate ≤ Standard (0.05%)
• Methyl Salicylate ≤ Standard (0.05%)

Chromatographic purity—

Calculate each impurity:

10,000(C/W)(rᵢ/rₛ)

C = concentration of USP Salsalate RS in Salsalate standard preparation (mg/mL)

W = weight of Salsalate in Assay stock (mg)

rᵢ = impurity peak response

rₛ = salsalate peak response

Limit: ≤ 0.2% for each impurity (except salicylic & trisalicylic acids).

Related compounds—

Salicylic acid ≤ 0.5%

Trisalicylic acid ≤ 2.5%

2 Assay—

Mobile phase:

Filtered/degassed methanol : water : phosphoric acid (650 : 350 : 1), pH 3.1.

Diluent:

Water : acetonitrile : phosphoric acid (540 : 460 : 1).

Standards

Salsalate standard preparation:

1 mg/mL → dilute to 0.02 mg/mL.

Salicylic acid standard preparation:

0.5 mg/mL → dilute to 0.005 mg/mL.

Trisalicylic acid standard preparation:

0.5 mg/mL → dilute to 0.025 mg/mL.

Resolution solution:

Diluent containing:

0.02 mg/mL Salsalate RS

0.02 mg/mL Salicylic Acid RS

0.04 mg/mL Trisalicylic Acid RS

Assay stock solution:

100 mg Salsalate → 100-mL Diluent → mix, sonicate.

Assay preparation:

2.0 mL stock → 100 mL Diluent.

Chromatographic system—

LC with 236-nm detector

Column 4-mm × 15-cm, 5-µm packing L7

Flow 1.5 mL/min

Relative retention times:

• 0.55 salicylic acid
• 1.0 salsalate
• 1.5 trisalicylic acid

Resolution: R ≥ 2.0

Salicylic acid standard: RSD ≤ 2.0%

Procedure—

Inject equal volumes (about 10 µL) of:

Salsalate standard

Salicylic acid standard

 Trisalicylic acid standard

Assay stock

Assay preparation

Continue chromatography ≥ retention time of trisalicylic acid.

Calculate salicylic acid % (C₇H₆O₃):

10,000(C/W)(rᵤ/rₛ)

Calculate trisalicylic acid % (C₂₁H₁₄O₇):

10,000(C/W)(rᵤ/rₛ)

Calculate salsalate % (C₁₄H₁₀O₅):

500,000(C/W)(rᵤ/rₛ)