Guanfacine Extended-Release Tablets

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

Guanfacine Extended-Release Tablets contain an amount of guanfacine hydrochloride equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of guanfacine (C₉H₉Cl₂N₃O).

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.

B. The UV spectrum of the major peak of the Sample solution corresponds to that of the Standard solution, as obtained in the Assay.

3 ASSAY

3.1 Procedure

Buffer: 20 mM sodium bicarbonate and 10 mM tetrabutylammonium phosphate prepared as follows. For each liter, dissolve 1.68 g of sodium bicarbonate and 3.39 g of tetrabutylammonium phosphate in 970 mL of water. Adjust with 5 N sodium hydroxide to a pH of 10.0. Dilute with water to volume.

Mobile phase: Acetonitrile and Buffer (17:83)

Standard solution: 0.023 mg/mL of USP Guanfacine Hydrochloride RS in Mobile phase

Sample solution: Nominally 0.02 mg/mL of guanfacine prepared as follows. Transfer a portion of coarsely powdered Tablets (NLT 20) to an appropriate volumetric flask as directed in Table 1. Add 50% of the flask volume of Mobile phase, sonicate for 10 min, and shake mechanically for 1 h. [Note T- he sonicator should be kept cold with ice to maintain a temperature below 25°.] Repeat the steps of the sonication/shaking sequence two additional times with an additional sonication of 10 min at the end. [Note - An additional 1 h of shaking and 10 min of sonication may be needed if the sample is not fully dissolved.] Dilute with Mobile phase to volume. Centrifuge a portion of this solution for 10 min and use the supernatant. [Note - The use of a centrifuge speed of NLT 2500 rpm may be suitable.]

Table 1

3.2 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm. For Identification B, use a diode array detector in the range of 200–400 nm.

Column: 4.6-mm × 15-cm; 5-μm packing L1

3.3 Temperatures

Autosampler: 4°

Column: 27°

Flow rate: 1 mL/min

Injection volume: 100 μL

Run time: NLT 1.8 times the retention time of guanfacine

3.4 System suitability

Sample: Standard solution

3.5 Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

3.6 Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of guanfacine (C₉H₉Cl₂N₃O) in the portion of Tablets taken:

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

r_U = peak response of guanfacine from the Sample solution

r_S = peak response of guanfacine from the Standard solution

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

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

M_r1 = molecular weight of guanfacine, 246.09

M_r2 = molecular weight of guanfacine hydrochloride, 282.55

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

4.1 Test 1

Medium: Hydrochloric acid buffer, pH 2.2; 900 mL prepared as follows. For each liter, mix 250 mL of 0.2 M potassium chloride with 39 mL of 0.2 N hydrochloric acid. Dilute with water to volume.

Apparatus 2: 75 rpm with suitable sinkers

Times: 1, 4, 8, and 20 h

Buffer: 20 mM sodium bicarbonate, prepared as follows. For each liter, dissolve 1.68 g of sodium bicarbonate in 970 mL of water, and adjust with 5 N sodium hydroxide to a pH of 10.0. Dilute with water to volume.

Mobile phase: Acetonitrile and Buffer (25:75)

Standard stock solution: 0.23 mg/mL of USP Guanfacine Hydrochloride RS in Mobile phase

Standard solution: 0.0023 mg/mL of USP Guanfacine Hydrochloride RS in Medium from Standard stock solution

Sample solution: Pass a portion of the solution under test through a suitable filter at the time points specified.

4.1.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 15-cm; 5-μm packing L1

Flow rate: 1.2 mL/min

Injection volume: 20 μL

Run time: NLT 1.4 times the retention time of guanfacine

4.1.2 System suitability

Sample: Standard solution

4.1.3 Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

4.1.4 Analysis

Samples: Standard solution and Sample solution

Calculate the concentration of guanfacine (C₉H₉Cl₂N₃O) in the sample withdrawn from the vessel at each time point (i):

Result = (r_U/r_S) × C_S × (M_r1/M_r2)

r_U = peak response of guanfacine from the Sample solution

r_S = peak response of guanfacine from the Standard solution

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

M_r1 = molecular weight of guanfacine, 246.09

M_r2 = molecular weight of guanfacine hydrochloride, 282.55

Calculate the percentage of the labeled amount of guanfacine (C₉H₉Cl₂N₃O) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_S)] + (C₁ × V_S)} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 x V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) × 100

Result₄ = ({C₄ × [V − (3 x V_S)]} + [(C₃ + C₂ + C₁) × V_S]) × (1/L) × 100

C_i = concentration of guanfacine in the portion of the sample withdrawn at the specified time point (i) (mg/mL)

V_S = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point (i) (mL)

Tolerances: See Table 2.

Table 2

The percentages of the labeled amount of guanfacine (C₉H₉Cl₂N₃O) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

4.2 Test 2

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 2.

Medium: Hydrochloric acid buffer, pH 2.2 (3.73 g/L of potassium chloride in water. Adjust with hydrochloric acid to a pH of 2.2.); 900 mL,deaerated

Apparatus 2: 75 rpm with wire helix sinker

Times: 1, 4, 9, and 15 h

Solution A: 1 g/L of sodium dodecyl sulfate and 0.1% of phosphoric acid in water prepared as follows. Dissolve 1 g of sodium dodecyl sulfate in 1000 mL of water. Add 1 mL of phosphoric acid to the resulting solution.

Mobile phase: Acetonitrile and Solution A (50:50)

Standard stock solution: 0.2525 mg/mL of USP Guanfacine Hydrochloride RS in methanol

Standard solution: (L/900 × 1.15) mg/mL of USP Guanfacine Hydrochloride RS prepared by diluting Standard stock solution with Medium, where L is the label claim in mg/Tablet.

Sample solution: At the times specified, withdraw a known volume of the solution under test. Pass through a suitable filter.

4.2.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

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

Flow rate: 1 mL/min

Injection volume: 50 μL

Run time: NLT 1.5 times the retention time of guanfacine

4.2.2 System suitability

Sample: Standard solution

4.2.3 Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

4.2.4 Analysis

Samples: Standard solution and Sample solution

Calculate the concentration of guanfacine (C₉H₉Cl₂N₃O) in the sample withdrawn from the vessel at each time point (i):

Result = (r_U/r_S) × C_S × (M_r1/M_r2)

r_U = peak response of guanfacine from the Sample solution

r_S = peak response of guanfacine from the Standard solution

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

M_r1 = molecular weight of guanfacine, 246.09

M_r2 = molecular weight of guanfacine hydrochloride, 282.55

Calculate the percentage of the labeled amount of guanfacine (C₉H₉Cl₂N₃O) dissolved at each time point (i):

Result₁ = C₁ × V × (1/L) × 100

Result₂ = {[C₂ × (V − V_S)] + (C₁ × V_S)} × (1/L) × 100

Result₃ = ({C₃ × [V − (2 x V_S)]} + [(C₂ + C₁) × V_S]) × (1/L) × 100

Result₄ = ({C₄ × [V − (3 x V_S)]} + [(C₃ + C₂ + C₁) × V_S]) × (1/L) × 100

C_i = concentration of guanfacine in the portion of the sample withdrawn at the specified time point (i) (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point (i) (mL)

Tolerances: See Table 3 and Table 4.

Table 3. For Tablets Labeled to Contain 1 mg

Table 4. For Tablets Labeled to Contain 2, 3, and 4 mg

The percentages of the labeled amount of guanfacine (C₉H₉Cl₂N₃O) dissolved at the times specified conform to Dissolution 〈711〉, Acceptance Table 2.

4.3 Test 3

If the product complies with this test, the labeling indicates that it meets USP Dissolution Test 3.

Medium: Hydrochloric acid buffer, pH 2.2 prepared as follows. Dissolve 3.72 g of potassium chloride and 0.66 mL of hydrochloric acid in 1000 mL of water. Adjust with 1 N hydrochloric acid or 1 N potassium hydroxide to a pH of 2.2, if necessary; 900 mL.

Apparatus 2: 75 rpm with sinker (see Dissolution 〈711〉, Figure 2a)

Times: 1, 4, 8, and 20 h

Buffer: 6.8 g/L of potassium phosphate monobasic in water prepared as follows. Dissolve 6.8 g of potassium phosphate monobasic in 1000 mL of water and add 5 mL of triethylamine. Adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile and Buffer (17:83)

Standard stock solution: 0.05 mg/mL of USP Guanfacine Hydrochloride RS in methanol. Sonicate to dissolve, if necessary.

Standard solution: (L/900 × 1.15) mg/mL of USP Guanfacine Hydrochloride RS prepared by diluting Standard stock solution with Medium, where L is the label claim in mg/Tablet

Sample solution: At the times specified, withdraw a known volume of the solution under test and replace with an equal volume of Medium.

Pass the solution under test through a suitable filter of 0.45-μm pore size, discarding the first few milliliters of filtrate.

4.3.1 Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 220 nm

Column: 4.6-mm × 10-cm; 5 μm packing L1

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 100 μL

Run time: NLT 1.8 times the retention time of guanfacine

4.3.2 System suitability

Sample: Standard solution

4.3.3 Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

4.3.4 Analysis

Samples: Standard solution and Sample solution

Calculate the concentration (C_i) of guanfacine (C₉H₉Cl₂N₃O) in the sample withdrawn from the vessel at each time point (i):

Result_i = (r_U/r_S) × C_S × (M_r1/M_r2)

r_U = peak response of guanfacine from the Sample solution

r_S = peak response of guanfacine from the Standard solution

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

M_r1 = molecular weight of guanfacine, 246.09

M_r1 = molecular weight of guanfacine hydrochloride, 282.55

Calculate the percentage of the labeled amount of guanfacine (C₉H₉Cl₂N₃O) dissolved at each time point (i):

Result₁ = C ₁× V × (1/L) × 100

Result₂ = [(C₂ × V) + (C₁ × V_S)] × (1/L) × 100

Result₃ = {(C₃ × V) + [(C₂ + C₁ ) × V_S]} × (1/L) × 100

Result₄ = {(C₄ × V) + [(C₃ + C₂ + C₁ ) × V_S]} × (1/L) × 100

C_i = concentration of guanfacine in the portion of the sample withdrawn at time point i (mg/mL)

V = volume of Medium, 900 mL

L = label claim (mg/Tablet)

V_S = volume of the Sample solution withdrawn at each time point (i) and replaced with Medium (mL)

Tolerances: See Table 5.

Table 5

The percentages of the labeled amount of guanfacine (C₉H₉Cl₂N₃O) dissolved at the times specified conform to Dissolution 〈711〉,

Acceptance Table 2. (RB 1-Nov-2022)

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

5.1 Organic Impurities

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

Standard solution 1: Prepare as directed for the Standard solution in the Assay.

Standard solution 2: 0.023 mg/mL of 2,6-dichlorophenylacetic acid in Mobile phase

System suitability solution: 0.046 μg/mL each of USP Guanfacine Hydrochloride RS and 2,6-dichlorophenylacetic acid in Mobile phase from Standard solution 1 and Standard solution 2

5.2 System suitability

Samples: Standard solution 1 and System suitability solution

[Note - See Table 6(RB 1-Nov-2022) for the relative retention times.]

5.3 Suitability requirements

Resolution: NLT 4.0 between 2,6-dichlorophenylacetic acid and guanfacine, System suitability solution

Relative standard deviation: NMT 2.0%, Standard solution 1

5.4 Analysis

Samples: Standard solution 1 and Sample solution

Calculate the percentage of 2,6-dichlorophenylacetic acid or any unspeci

ed degradation product in the portion of Tablets taken:

Result = (r_U/r_S) × (C_S/C_U) × (M_r1/M_r2) × (1/F) × 100

r_U = peak response of 2,6-dichlorophenylacetic acid or any unspecified degradation product from the Sample solution

r_S = peak response of guanfacine from Standard solution 1

C_S = concentration of USP Guanfacine Hydrochloride RS in Standard solution 1 (mg/mL)

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

M_r1 = molecular weight of guanfacine, 246.09

M_r2 = molecular weight of guanfacine hydrochloride, 282.55

F = relative response factor (see Table 6 (RB 1-Nov-2022) )

Acceptance criteria: See Table 6. (RB 1-Nov-2022)

Table 6 (RB 1-Nov-2022)

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight containers and store at controlled room temperature.

Labeling: When more than one Dissolution test is given, the labeling states the test used only if Test 1 is not used.

USP Reference Standards 〈11〉

USP Guanfacine Hydrochloride RS