Tolterodine Tartrate

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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C₂₂H₃₁NO · C₄H₆O₆          475.57

(R)-2-[3-[Bis(1-methylethyl)amino]-1-phenylpropyl]-4-methylphenol (2R,3R)-2,3-dihydroxybutanedioate (1:1) (salt);

(+)-(R)-2-[α-[2-(Diisopropylamino)ethyl]benzyl]-p-cresol l-tartrate (1:1) (salt);

(R)-2-[3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol tartrate CAS RN: 124937-52-6; UNII: 5T619TQR3R.

1 DEFINITION

Tolterodine Tartrate contains NLT 97.0% and NMT 103.0% of tolterodine tartrate (C₂₂H₃₁NO · C₄H₆O₆), calculated on the as-is basis.

2 IDENTIFICATION

Change to read:

A. SPECTROSCOPIC IDENTIFICATION TESTS (197), Infrared Spectroscopy: 197K _{(CN 1-MAY-2020)}

B. 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

PROCEDURE

Mobile phase: Acetonitrile, water, and phosphoric acid (330:670:1)

Standard solution: 0.35 mg/mL of USP Tolterodine Tartrate RS in Mobile phase

Sample solution: 0.35 mg/mL of Tolterodine Tartrate in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 285 nm

Column: 4.6-mm x 6-mm x 25-cm; 5-µm packing 11

Flow rate: 1.0 mL/min

Injection volume: 5 µL

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 1.0% from six replicate injections

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of tolterodine tartrate (C₂₂H₃₁NO · C₄H₆O₆) in the portion of Tolterodine Tartrate 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 Tolterodine Tartrate RS in the Standard solution (mg/mL)

C_u = concentration of Tolterodine Tartrate in the Sample solution (mg/mL)

Acceptance criteria: 97.0%–103.0% on the as-is basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.1%

Organic Impurities

Solution A: Acetonitrile, water, and perchloric acid (100:900:1.5)

Solution B: Acetonitrile, water, and perchloric acid (500:500:1.5)

Solution C: Acetonitrile

Mobile phase: See Table 1. Return to original conditions, and re-equilibrate the system.

Table 1

Diluent: Acetonitrile and water (50:50)

System suitability solution: 10 mg/mL of USP Tolterodine System Suitability Mixture RS in Diluent. See Table 2 for relative retention times of the main components of the mixture.

Table 2

   ^a Undened stereochemistry.

Standard solution: 0.01 mg/mL of USP Tolterodine Tartrate RS in Diluent

Sensitivity solution: 0.005 mg/mL of USP Tolterodine Tartrate RS in Diluent from the Standard solution

Sample solution: 10 mg/mL of Tolterodine Tartrate in Diluent

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 25-cm; 5-µm packing L1

Column temperature: 65°

Flow rate: 1.0 mL/min

Injection volume: 10 µL

System suitability

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

Suitability requirements

Resolution: NLT 1.5 between diol acetate impurity and 6-methyl-4-phenylchroman-2-one, System suitability solution

Relative standard deviation: NMT 3.0%, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of each impurity in the portion of Tolterodine Tartrate taken:

Result = (r_u /r_s ) × (C_s /C_u ) × (1/F) × 100

r_u = peak response for each impurity from the Sample solution

r_s = peak response of tolterodine from the Standard solution

C_s = concentration of USP Tolterodine Tartrate RS in the Standard solution (mg/mL)

C_u = concentration of Tolterodine Tartrate in the Sample solution (mg/mL)

F = relative response factor (see Table 3)

Acceptance criteria: See Table 3. Disregard any peak below 0.05% and any peak eluting at retention times of less than 4 min.

Table 3

ENANTIOMERIC PURITY

Buffer: Prepare pH 7.1 buffer as follows. Transfer 21.0 mL of 1 M solution of monobasic sodium phosphate and 53.3 mL of 0.5 M solution of dibasic sodium phosphate dihydrate to a 1000-mL volumetric flask, and dilute with water to volume. Dilute 100.0 mL of this solution with water to 1000.0 mL

Mobile phase: Add 0.97 g of tetrabutylammonium bromide to a mixture of 930 mL of Buffer and 70 mL of isobutyl alcohol.

System suitability solution: 0.02 mg/mL each of USP Tolterodine Tartrate RS and USP Tolterodine S-Enantiomer RS in Mobile phase

Standard solution: 0.0004 mg/mL of USP Tolterodine S-Enantiomer RS in Mobile phase

Sample solution: 0.04 mg/mL of Tolterodine Tartrate in Mobile phase

Chromatographic system

(See Chromatography (621), System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 2-mm x 10-cm; 5-um packing L41

Flow rate: 0.2 mL/min

Injection volume: 20 µL

System suitability

Sample: System suitability solution

[NOTE-The relative retention times for tolterodine S-enantiomer and tolterodine are 0.9 and 1.0, respectively.]

Suitability requirements

Resolution: NLT 1.4 between tolterodine S-enantiomer and tolterodine

Column efficiency: NLT 1500 theoretical plates for tolterodine

Relative standard deviation: NMT 3% for each of tolterodine S-enantiomer and tolterodine

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of tolterodine S-enantiomer in the portion of Tolterodine Tartrate taken:

Result = (r_u /r_s ) × (C_s /C_u ) × 100

r_u = peak response of tolterodine S-enantiomer from the Sample solution

r_s = peak response of tolterodine S-enantiomer from the Standard solution

C_s = concentration of USP Tolterodine S-Enantiomer RS in the Standard solution (mg/mL)

C_u = concentration of Tolterodine Tartrate in the Sample solution (mg/mL)

Acceptance criteria: NMT 1.0%

5 SPECIFIC TESTS

Loss on Drying 〈731〉

Analysis: Dry under vacuum at 100° for 2 h.

Acceptance criteria: NMT 0.5%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers. Store at room temperature.

USP Reference Standards 〈11〉

USP Tolterodine S-Enantiomer RS

(S)-2-[3-(Diisopropylamino)-1-phenylpropyl]-4-methylphenol tartrate.

C₂₂H₃₁NO · C₄H₆O₆               475.57

USP Tolterodine System Suitability Mixture RS

The mixture contains tolterodine tartrate and the following impurities (other impurities may also be present):

p-Cresol.

C₇H₈O                                              108.14

trans-Cinnamic acid. C₉H₈O₂          148.16

Monoisopropyl tolterodine;

(R)-2-[3-(Isopropylamino)-1-phenylpropyl]-4-methylphenol. C₁₉H₂₅NO            283.41

Diol impurity;

2-(3-Hydroxy-1-phenylpropyl)-4-methylphenol. C₁₆H₁₈O₂                                242.32

Tolterodine dimer;

N,N-Bis[3-(2-hydroxy-5-methylphenyl)-3-phenylpropyl]-N-isopropylamine. C₃₅H₄₁NO₂   507.72

6-Methyl-4-phenylchroman-2-ol. C₁₆H₁₆O₂                 240.30

Diol acetate impurity;

3-(2-Hydroxy-5-methylphenyl)-3-phenylpropyl acetate. C₁₈H₂₂O₃         284.35

6-Methyl-4-phenylchroman-2-one. C₁₆H₁₄O₂       238.29

USP Tolterodine Tartrate RS