Galantamine Oral Solution

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

Galantamine Oral Solution contains an amount of galantamine hydrobromide (C₁₇H₂₁NO₃·HBr) equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of galantamine (C₁₇H₂₁NO₃). Galantamine Oral Solution also contains one or more suitable preservatives.

2 IDENTIFICATION

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

3 ASSAY

Change to read:

3.1 PROCEDURE

(USP 1-Aug-2020)

Solution A: Acetonitrile and water (1:99)

Solution B: 5 mg/mL of ammonium acetate in Solution A

Solution C: Acetonitrile

Solution D: Water

Mobile phase: See Table 1.

Table 1

Diluent: 5 mg/mL of ammonium acetate in water

System suitability solution: 0.26 mg/mL of USP Galantamine Hydrobromide Related Compounds Mixture RS prepared as follows. Transfer a suitable quantity of USP Galantamine Hydrobromide Related Compounds Mixture RS to a suitable flask, and dissolve in 3% of the flask volume of methanol. Dilute with Diluent to volume.

Standard solution: 0.26 mg/mL of USP Galantamine Hydrobromide RS (equivalent to 0.2 mg/mL of galantamine) prepared as follows.

Transfer a suitable quantity of USP Galantamine Hydrobromide RS to an appropriate flask, and dissolve in 3% of the flask volume of methanol. Dilute with Diluent to volume.

Sample solution: Nominally 0.2 mg/mL of galantamine from Oral Solution prepared as follows. Transfer a suitable volume of Oral Solution to an appropriate volumetric flask. Add 3% of the flask volume of methanol, and dilute with Diluent to volume.

3.2 Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 230 nm

Column: 4.6-mm × 10-cm; 3-µm packing L1

Flow rate: 1.5 mL/min

Injection volume: 10 µL

(USP 1-Aug-2020)

3.3 System suitability

Samples: System suitability solution and Standard solution

[NOTE-See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 5 between galantamine and 6S-galantamine, (USP 1-Aug-2020) System suitability solution

Tailing factor: NMT 1.3, Standard solution

Relative standard deviation: NMT 1.0% (USP 1-Aug-2020) Standard solution

3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of galantamine (C₁₇H₂₁NO₃) in the portion of Oral Solution taken:

Result = (r_U/r_S) x (C_S/C_U) x (M_r1/M_r2) x 100

r_U = peak response of galantamine (USP 1-Aug-2020) from the Sample solution

r_S = peak response of galantamine (USP 1-Aug-2020) from the Standard solution

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

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

M_r1 = molecular weight of galantamine, 287.35

M_r2 = molecular weight of galantamine hydrobromide, 368.27

Acceptance criteria: 90.0%-110.0%

4 PERFORMANCE TESTS

DELIVERABLE VOLUME (698): Meets the requirements

5 IMPURITIES

Change to read:

5.1 ORGANIC IMPURITIES

(USP 1-Aug-2020)

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

Sensitivity solution: 0.5 µg/mL of USP Galantamine Hydrobromide RS prepared as follows. Transfer a suitable quantity of USP Galantamine Hydrobromide RS to an appropriate flask, and dissolve in 3% of the flask volume of methanol. Dilute with Diluent to volume.

5.2 System suitability

Samples: System suitability solution, Standard solution, and Sensitivity solution

[NOTE-See Table 2 for relative retention times.]

Suitability requirements

Resolution: NLT 5 between galantamine and 6S-galantamine, (USP 1-Aug-2020) System suitability solution

Tailing factor: NMT 1.3, Standard solution

Relative standard deviation: NMT 2.0%, Standard solution

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

5.3 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each degradation product in the portion of Oral Solution taken:

Result = (r_U/r_S) x (C_S/C_U) x (M_r1/M_r2) x 100

r_U = peak response of each degradation product from the Sample solution

r_S = peak response of galantamine from the Standard solution

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

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

M_r1 = molecular weight of galantamine, 287.35

M_r2 = molecular weight of galantamine hydrobromide, 368.27

Acceptance criteria: See Table 2. The reporting threshold is 0.10% (USP 1-Aug-2020)

Table 2

^a(4aS,6R,8aS)-3-Methoxy-4a,5,9,10,11,12-hexahydro-6H-benzo[2,3]benzofuro [4,3-cd]azepin-6-ol. (USP 1-Aug-2020)

^b This degradation product may be found if the drug substance is isolated from a natural source.

^c (4aS,6R,8aS)-6-Hydroxy-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepine 11-oxide. (USP 1-Aug-2020)

^d (4aS,6R,8aS)-3-Methoxy-11-methyl-4a,5,7,8,9,10,11,12-octahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepin-6-ol. (USP 1-Aug-2020)

^e This is a process impurity and is listed for information only. It is controlled in the drug substance. It is not to be reported and is not to be included in the total degradation products.

^f (4aS,6S,8aS)-3-Methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepin-6-ol. (USP 1-Aug-2020)

^g (4aS, 8aS)-3-Methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzo[2,3]benzofuro[4,3-cd]azepin-6-one. (USP 1-Aug-2020)

^h (4aS,8aS)-3-Methoxy-11-methyl-9,10,11,12-tetrahydro-4aH-benzo[2,3]benzofuro [4,3-cd]azepine. (USP 1-Aug-2020)

6 SPECIFIC TESTS

6.1 MICROBIAL ENUMERATION TESTS (61) and TESTS FOR SPECIFIED MICROORGANISMS (62)

The total aerobic microbial count does not exceed 10² cfu/mL. The total yeasts and molds count does not exceed 5 x 10¹ cfu/mL. It meets the requirements of the test for absence of Escherichia coli.

6.2 PH (791)

3.9-6.2

7 ADDITIONAL REQUIREMENTS

7.1 PACKAGING AND STORAGE

Preserve in tight, light-resistant containers, and store at controlled room temperature. Protect from freezing.

Change to read:

7.2 USP REFERENCE STANDARDS (11)

USP Galantamine Hydrobromide RS

USP Galantamine Hydrobromide Related Compounds Mixture RS

Contains a mixture of the following 5 compounds:

Galantamine hydrobromide;

Galantamine N-oxide;

(4aS,6R,8aS)-6-Hydroxy-3-methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzo[2,3]benzofuro [4,3-cd]azepine 11-oxide.

C₁₇H₂₁NO₄ 303.35

Dihydrogalantamine;

(4aS,6R,8aS)-3-Methoxy-11-methyl-4a,5,7,8,9,10,11,12-octahydro-6H-benzo[2,3]benzofuro [4,3-cd]azepin-6-ol. C₁₇H₂₃NO₃17 289.37

6S-Galantamine;

(4aS,6S,8aS)-3-Methoxy-11-methyl-4a,5,9,10,11,12-hexahydro-6H-benzo[2,3]benzofuro[4,3-ca]azepin-6-ol. C₁₇H₂₁NO₃ 287.35

Anhydrogalantamine;

(4aS,8aS)-3-Methoxy-11-methyl-9,10,11,12-tetrahydro-4aH-benzo[2,3]benzofuro [4,3-cd]azepine. C₁₇H₁₉NO₂ 269.34

[NOTE-The contents have previously been referred to as galantamine hydrobromide, 6β-hexahydrogalantamine, 6β-octahydrogalantamine, 6α-hexahydrogalantamine, and tetrahydrogalantamine, respectively.] (USP 1-AUG-2020)