Progesterone Compounded Vaginal Inserts

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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1 DEFINITION 

Progesterone Compounded Vaginal Inserts contain NLT 90.0% and NMT 110.0% of the labeled amount of progesterone (C₂₁H₃₀O₂)

Prepare Compounded Progesterone Vaginal Inserts in Fatty Acid Base or Polyethylene Glycol Base as follows (see Pharmaceutical Compounding—Nonsterile Preparations 〈795〉). 

Calibrate the actual molds with the Base that is used for preparing the Inserts, and adjust the formula accordingly. Heat the Base slowly and evenly until melted. Slowly add the Progesterone powder to the melted base, with stirring. Mix thoroughly, and pour into molds. If preparing Inserts in Fatty Acid Base, cool in a refrigerator until solidified, trim, and wrap. If preparing Inserts in Polyethylene Glycol Base, cool, trim, and wrap. 

2 ASSAY 

Inserts in Fatty Acid Base 

Solution A: Dehydrated alcohol, isopropyl alcohol, and methanol (90:5:5) 

Mobile phase: Solution A and water (55:45). Filter, and degas. 

Diluent: Solution A and water (70:30) 

System suitability stock solution A: 0.4 mg/mL of USP Methyltestosterone RS in Mobile phase 

System suitability stock solution B: 0.4 mg/mL of USP Progesterone RS in Mobile phase 

System suitability solution: Transfer 2.0 mL each of System suitability stock solution A and System suitability stock solution B to a 10-mL volumetric flask, and dilute with Mobile phase to volume. 

Standard solution A: Prepare 0.25 mg/mL of USP Progesterone RS in n-propyl alcohol. Mix 5.0 mL of the solution with 10.0 mL of Diluent. Standard solution B: Prepare 3 mg/mL of USP Progesterone RS in n-propyl alcohol. Transfer 3.0 mL of the solution to a 100-mL volumetric flask, and dilute with Diluent to volume. 

Sample solution A: Transfer 1 Insert, containing NMT 100 mg of progesterone, to a 100-mL volumetric flask. Dissolve in 90 mL of n-propyl alcohol, heat at 45° for 4 min, and sonicate for 10 min. Cool, and dilute with n-propyl alcohol to volume. Dilute quantitatively, and stepwise if necessary, with n-propyl alcohol, sonicating if necessary, to obtain a solution containing a nominal concentration of 0.25 mg/mL of progesterone. Transfer 5.0 mL of this solution to a 50-mL centrifuge tube, add 10.0 mL of Diluent, sonicate for 1 min, and centrifuge for 10 min at 2000 rpm. Pass the supernatant through a filter of 0.45-µm or finer pore size, discarding the first 4 mL of the filtrate. 

Sample solution B: Transfer 1 Insert, containing more than 100 mg of progesterone, to a 200-mL volumetric flask. Dissolve in 180 mL of n propyl alcohol, heat at 45° for 8 min, and sonicate for 5 min. Cool, and dilute with n-propyl alcohol to volume. Dilute quantitatively, and stepwise if necessary, with n-propyl alcohol, sonicating each dilution for 1 min, to obtain a solution with a nominal concentration of 0.09 mg/mL of progesterone. Transfer 15 mL of this solution to a 50-mL centrifuge tube, and centrifuge for 10 min at 2000 rpm. Pass the supernatant through a filter of 0.45-µm or finer pore size, discarding the first 4 mL of the filtrate. 

Chromatographic system 

(See Chromatography 〈621〉, System Suitability.) 

Mode: LC 

Detector: UV 245 nm 

Column: 3.9-mm × 30-cm; packing L1 

Column temperature: 40° 

Flow rate: 1.0 mL/min 

Injection volume: 10 µL 

System suitability 

Sample: System suitability solution 

[Note—The relative retention times for methyltestosterone and progesterone are about 0.8 and 1.0, respectively.] Suitability requirements 

Resolution: NLT 2.0 between methyltestosterone and progesterone 

Tailing factor: NMT 2.0 for the progesterone peak 

Relative standard deviation: NMT 2.0% for replicate injections for progesterone 

Analysis 

Samples: Standard solution A and Sample solution A or Standard solution B and Sample solution B 

Calculate the percentage of the labeled amount of progesterone (C₂₁H₃₀O₂) in the Insert taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response from the Sample solution 

r_S = peak response from the Standard solution 

C_S = concentration of USP Progesterone RS in the Standard solution (mg/mL)

C_U = nominal concentration of progesterone in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0% 

Inserts in Polyethylene Glycol Base 

Solution A, Mobile phase, System suitability stock solution A, System suitability stock solution B, System suitability solution, Chromatographic system, and System suitability: Proceed as directed in the Assay for Inserts in Fatty Acid Base. 

Standard solution: 0.1 mg/mL of USP Progesterone RS in Mobile phase 

Sample solution: Dissolve 1 Insert in 200 mL of Mobile phase, and dilute quantitatively, and stepwise if necessary, with Mobile phase to obtain a solution with a nominal concentration of 0.1 mg/mL of progesterone. Pass a 10-mL portion of the mixture through a filter of 0.45-µm or finer pore size, discarding the first 4 mL of the filtrate. 

Analysis 

Samples: Standard solution and Sample solution 

Calculate the percentage of the labeled amount of progesterone (C₂₁H₃₀O₂) in the Insert taken: 

Result = (r_U/r_S) × (C_S/C_U) × 100 

r_U = peak response from the Sample solution 

r_S = peak response from the Standard solution 

C_S = concentration of USP Progesterone RS in the Standard solution (mg/mL)

C_U = nominal concentration of progesterone in the Sample solution (mg/mL)

Acceptance criteria: 90.0%–110.0% 

3 PERFORMANCE TESTS 

Uniformity of Dosage Units 〈905〉: Meet the requirements for Weight Variation 

4 ADDITIONAL REQUIREMENTS 

Packaging and Storage: Package in light-resistant containers, and store in a refrigerator. Store Inserts in Fatty Acid Base in well-closed containers. Store Inserts in Polyethylene Glycol Base in tight containers, and do not dispense or store in polystyrene containers. Beyond-Use Date: NMT 90 days after the date on which they were compounded when stored in a refrigerator 

Labeling: Label Inserts to state whether they are Progesterone Vaginal Inserts in a Fatty Acid Base or in a Polyethylene Glycol Base. Label to state the amount of progesterone, in mg, in each Insert. Label to state that they are to be stored in a refrigerator. Label to state that wrappers are to be removed before use. If necessary, Inserts in Polyethylene Glycol Base may be moistened before insertion. USP Reference Standards 〈11〉 

USP Methyltestosterone RS 

USP Progesterone RS