Add the following:

Misoprostol Dispersion

DEFINITION

Misoprostol Dispersion is a mixture of Misoprostol and Hypromellose. It contains NLT 95.0% and NMT 104.0% of the labeled amount of misoprostol (C22H38O5).

IDENTIFICATION

• A. Ultraviolet Absorption

Perform both Procedure 1 and Procedure 2.

Procedure 1

Medium: Methanol and water (4:1)

Sample solution: Nominally 16 µg/mL of misoprostol in Medium prepared as follows. Dissolve the amount of Misoprostol Dispersion, equivalent to 400 µg of misoprostol, in 25 mL of Medium.

Blank: Prepare a solution of hypromellose in Medium having the same concentration as in the Sample solution.

Analysis: Determine UV absorption spectrum of Sample solution against the Blank from 330–230 nm.

Acceptance criteria 1: It exhibits no maximum near 280 nm.

Procedure 2

Medium: Methanol and 1 N potassium hydroxide (4:1)

Sample solution: Add 10 mL of Medium to 10 mL of the Sample solution prepared from Procedure 1. Allow to stand for 30 min at room temperature.

Blank: Add 10 mL of Medium to 10 mL of the Blank prepared from Procedure 1. Allow to stand for 30 min at room temperature.

Analysis: Determine UV absorption spectrum of Sample solution against the Blank from 330–230 nm.

Acceptance criteria 2: It exhibits a maximum near 280 nm.

• B. The retention time of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

ASSAY

• Procedure

[Note—During addition of water to a solution of misoprostol in isopropyl alcohol, an exothermic reaction takes place. After each addition of water, invert the flask to mix isopropyl alcohol and water. Allow the solution to cool to room temperature before the final dilution.

]

Buffer: 1.36 g/L of monobasic potassium phosphate in water, adjusted with phosphoric acid to a pH of 3.0 ± 0.1

Mobile phase: Isopropyl alcohol and Buffer (27:73)

Standard stock solution: 0.5 mg/mL of USP Misoprostol RS in isopropyl alcohol. [Note—This solution is stable up to 28 days when stored at 5 ± 3

]

Standard solution: 0.1 mg/mL of USP Misoprostol RS in water from Standard stock solution. [Note—This solution is stable up to 7 days when stored at 5 ± 3

]

Sample solution: Nominally 0.1 mg/mL of misoprostol prepared as follows. Place an amount of Misoprostol Dispersion, equivalent to about 10 mg of misoprostol, into a 100-mL volumetric flask, and add 25 mL of isopropyl alcohol. Shake to disperse the solid, place the solution in an ice bath, swirl, and allow to cool for 10 min. Carefully add about 70 mL of water, previously chilled in a refrigerator, remove from the ice bath, and shake. Sonicate as necessary at a temperature not exceeding 20

. Equilibrate to room temperature, dilute with water to volume, and immediately cool the solution to 5

. [Note—This solution is stable up to 7 days when stored at 5 ± 3

]

Chromatographic system

(See Chromatography

621

, System Suitability.)

Mode: LC

Detector: UV 205 nm

Column: 4.6-mm × 15-cm; 5-µm packing L7

Temperatures

Column: 50 ± 2

; the Mobile phase must be preheated prior to introduction on the column.

Autosampler: 5 ± 3

Flow rate: 1.5 mL/min

Injection volume: 100 µL

System suitability

Sample: Standard solution

[Note—USP Misoprostol RS contains 12-epimisoprostol as a minor component. The relative retention times for 12-epimisoprostol and misoprostol are 0.84 and 1.0, respectively.

]

Suitability requirements

Resolution: NLT 2.7 between 12-epimisoprostol and misoprostol

Relative standard deviation: NMT 1.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of misoprostol (C22H38O5) in the portion of Misoprostol Dispersion taken:

Result = (rU/rS) × (CS/CU) × 100

rU	=	= peak response from the Sample solution
rS	=	= peak response from the Standard solution
CS	=	= concentration of USP Misoprostol RS in the Standard solution (mg/mL)
CU	=	= nominal concentration of misoprostol in the Sample solution (mg/mL)

Acceptance criteria: 95.0%–104.0%

IMPURITIES

• Organic Impurities

[Note—During the addition of water to a solution of misoprostol in isopropyl alcohol, an exothermic reaction takes place. After each addition of water, invert the flask to mix isopropyl alcohol and water. Allow the solution to cool to room temperature before the final dilution.

]

Buffer, Mobile phase, Standard solution, Sample solution, and Chromatographic system: Proceed as directed in the Assay.

Diluent: Isopropyl alcohol and water (27:73)

Blank: Prepare a solution of hypromellose in the Diluent having the same concentration as in the Sample solution.

Diluted standard solution: 0.5 µg/mL of USP Misoprostol RS in Diluent from Standard solution

Sensitivity solution: 0.1 µg/mL of USP Misoprostol RS in Diluent from Diluted standard solution

System suitability

Samples: Standard solution and Sensitivity solution

Suitability requirements

Resolution: NLT 2.7 between 12-epimisoprostol and misoprostol, Standard solution

Signal-to-noise ratio: NLT 10, Sensitivity solution

Analysis

Samples: Sample solution, Blank, and Diluted standard solution

Calculate the percentage of any individual impurity in the portion of Misoprostol Dispersion taken:

Result = (rU/rS) × (CS/CU) × (1/F) × 100

rU	=	= peak response of any individual impurity from the Sample solution
rS	=	= peak response of misoprostol from the Diluted standard solution
CS	=	= concentration of USP Misoprostol RS in the Diluted standard solution (µg/mL)
CU	=	= nominal concentration of misoprostol in the Sample solution (µg/mL)
F	=	= relative response factor (see Table 1)

Acceptance criteria: See Table 1. Disregard a peak from the Diluent, eluting at about 4 min, and any other peak observed in the Blank.

Table 1

Name	Relative Retention Time	Relative Response Factor	Acceptance Criteria, NMT (%)
12-Epimisoprostol	0.84	—	—a
8-Epimisoprostolb	0.90	0.90	0.50
Misoprostol	1.0	—	—
B-Type misoprostolc	1.6	0.78	0.30
A-Type misoprostold	1.9	2.6	0.50
Any other individual impurity	—	1.0	0.1
Total impurities	—	—	1.8
a This is a process impurity in the manufacturing of misoprostol. It is controlled in the misoprostol, which is the starting material for the Misoprostol Dispersion. This impurity is included in the table for identification only, and it is not to be reported or included in the total impurities for the Misoprostol Dispersion. b Methyl (1S,2R,3R)-3-hydroxy-2-[(E)-4-hydroxy-4-methyl-1-octenyl]-5-oxocyclopentaneheptanoate. c (E)-Methyl 7-[2-(4-hydroxy-4-methyloct-1-enyl)-5-oxocyclopent-1-enyl]heptanoate. d Methyl 7-[(1R,2S*)-2-[(E)-4-hydroxy-4-methyloct-1-enyl]-5-oxocyclopent-3-enyl]heptanoate.

SPECIFIC TESTS

• Water Determination, Method Ic

921

Sample: 300 mg

Analysis: Perform the test immediately after opening the sample container. Use the evaporation technique in which water is released and evaporated from the Sample by heating it in an external oven at 105

and transferring it to the reaction cell with the aid of an inert gas.

Acceptance criteria: NMT 1.0%

ADDITIONAL REQUIREMENTS

• Packaging and Storage: Preserve in tight containers, protected from light, and store in a refrigerator.

• Labeling: The label states that this article is not intended for direct administration to humans or animals. Label it to indicate the nominal concentration or percentage of misoprostol in the Misoprostol Dispersion.

• USP Reference Standards

USP Misoprostol RS

USP38

Auxiliary Information— Please check for your question in the FAQs before contacting USP.

Topic/Question	Contact	Expert Committee
Monograph	Elena Gonikberg, Ph.D. Director - Chemical Medicines (301) 816-8251	(SM32010) Monographs - Small Molecules 3
Reference Standards	RS Technical Services 1-301-816-8129 rstech@usp.org

USP38–NF33 Page 4418

Pharmacopeial Forum: Volume No. 39(6)