Ziprasidone Capsules

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

Ziprasidone Capsules contain an amount of ziprasidone hydrochloride equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS).

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

Change to read:

Procedure

Buffer: 0.3% (v/v) of triethylamine in water

Mobile phase: Acetonitrile and Buffer (35:65). Adjust with glacial acetic acid to a pH of 6.0.

Diluent: Acetonitrile, water, and glacial acetic acid (70:30:5)

Standard stock solution: 1.0 mg/mL of USP Ziprasidone Hydrochloride RS in Diluent

Standard solution: 0.2 mg/mL of USP Ziprasidone Hydrochloride RS from the Standard stock solution in Mobile phase

Sample stock solution: Nominally 1 mg/mL of ziprasidone prepared as follows. Empty the contents of NLT 20 Capsules into a container.

Blend the contents. Transfer an amount of the contents, equivalent to NLT 50 mg of ziprasidone, to a suitable volumetric flask. Dissolve the contents in 60% of the flask volume of Diluent. Sonicate for NLT 5 min. Dilute with Diluent to volume. Pass a portion of the solution through a suitable filter of 0.45-μm pore size and use the filtrate to prepare the Sample solution.

Sample solution: Nominally 0.2 mg/mL of ziprasidone prepared from the filtered Sample stock solution and Mobile phase

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm. For Identification B, a diode array detector may be used in the wavelength range of 200–300 nm.

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

Flow rate: 2.0 mL/min

Injection volume: 20 μL

Run time: 1.5 times the retention time of ziprasidone

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS) in the portion of Capsules taken:

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

r_U = peak response of ziprasidone from the Sample solution

r_S = peak response of ziprasidone from the Standard solution

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

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

M_r1 = molecular weight of ziprasidone free base, 412.94

M_r2 = molecular weight of ziprasidone hydrochloride; 467.41 for the monohydrate, 449.39 (ERR 1-Sep-2023) for the anhydrous form

Acceptance criteria: 90.0%–110.0%

4 PERFORMANCE TESTS

Change to read:

Dissolution 〈711〉

4.1 Test 1

Tier 1

Phosphate buffer, pH 7.5: Dissolve 7.8 g of monobasic sodium phosphate dihydrate and 20 g of sodium dodecyl sulfate in 1 L water.

Sonicate to dissolve and adjust with phosphoric acid or sodium hydroxide solution (ERR 1-Sep-2023) to a pH of 7.5.

Medium: Phosphate buffer, pH 7.5; 900 mL

Apparatus 2: 75 rpm. Use a suitable sinker, if necessary.

Time: 45 min

Buffer: 0.3% (v/v) of triethylamine in water. Adjust with glacial acetic acid to a pH of 6.0.

Mobile phase: Acetonitrile and Buffer (45:55)

Diluent: Acetonitrile, water, and glacial acetic acid (70:30:5)

Standard stock solution: 0.24 mg/mL of USP Ziprasidone Hydrochloride RS prepared as follows. Dissolve a suitable amount of USP Ziprasidone Hydrochloride RS in a suitable volumetric flask first in 60% of the flask volume of Diluent, and then dilute with Diluent to volume.

Standard solution: 0.024 mg/mL of USP Ziprasidone Hydrochloride RS in Medium from the Standard stock solution

Sample solution: Pass a portion of the solution through a suitable filter of 0.45-μm pore size. Dilute with Medium to a concentration similar to that of the Standard solution.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

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

Flow rate: 1.5 mL/min

Injection volume: 10 μL

Run time: 1.5 times the retention time of ziprasidone

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 1.5

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS) dissolved:

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

r_U = peak response of ziprasidone from the Sample solution

r_S = peak response of ziprasidone from the Standard solution

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

L = label claim (mg/Capsule)

V = volume of Medium, 900 mL

M_r1 = molecular weight of ziprasidone free base, 412.94

M_r2 = molecular weight of ziprasidone hydrochloride; 467.41 for the monohydrate, 449.39 (ERR 1-Sep-2023) for the anhydrous form

Tolerances: NLT 75% (Q) of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS) is dissolved.

If the above tolerance cannot be met, proceed to Tier 2.

Tier 2

Solution A: Dissolve 7.8 g of monobasic sodium phosphate dihydrate in 1 L of water. Sonicate to dissolve and adjust with phosphoric acid or sodium hydroxide solution (ERR 1-Sep-2023) to a pH of 7.5. Dissolve 10 g of pancreatin in the resulting solution.

Solution B: Dissolve 7.8 g of monobasic sodium phosphate dihydrate in 1 L of water. Adjust with phosphoric acid or sodium hydroxide solution (ERR 1-Sep-2023) to a pH of 7.5. Dissolve 90 g of sodium dodecyl sulfate in the resulting solution. Sonicate to dissolve.

Medium: Transfer 700 mL of Solution A to the dissolution vessel and equilibrate at 37° for 15 min. Add 200 mL of Solution B; 900 mL.

Apparatus 2: 75 rpm. Use a suitable sinker, if necessary.

Time: 45 min

Analyze the Sample solution using the liquid chromatographic procedure described in Tier 1.

Tolerances: NLT 75% (Q) of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS) is dissolved.

4.2 Test 2

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

Tier 1

Medium: 2% sodium lauryl sulfate in pH 7.5 phosphate buffer (dissolve 6.9 g of monobasic sodium phosphate monohydrate and 1.6 g of sodium hydroxide in 900 mL of water, adjust with 1 N sodium hydroxide to a pH of 7.5 and dilute with water to 1000 mL); 900 mL

Apparatus 2: 75 rpm. Use a suitable sinker, if necessary.

Time: 60 min

Tier 2

Medium A: pH 7.5 phosphate buffer (dissolve 6.9 g of monobasic sodium phosphate monohydrate and 1.6 g of sodium hydroxide in 900 mL of water, adjust with 1 N sodium hydroxide to a pH of 7.5 and dilute with water to 1000 mL) with 1% pancreatin; 700 mL

Medium B: pH 7.5 phosphate buffer with 9% of sodium lauryl sulfate; 200 mL

Apparatus 2: 75 rpm. Use a suitable sinker, if necessary.

Time: 15 min for Medium A; 45 min for Medium A with the addition of Medium B

Solution A: Dissolve 2.7 g of monobasic sodium phosphate monohydrate in 1 L of water. Adjust with 1 N sodium hydroxide to a pH of 6.0.

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

Diluent: Acetonitrile and water (50:50)

Standard stock solution: 0.48 mg/mL of USP Ziprasidone Hydrochloride RS in Diluent

Standard solution: (L/900) mg/mL of USP Ziprasidone Hydrochloride RS in Medium from Standard stock solution, where L is the label claim of ziprasidone in mg/Capsules

Sample solution: Pass a portion of the solution through a suitable filter of 0.45-μm pore size.

Procedure: Perform the test using the conditions in Tier 1. In the presence of cross-linking repeat the test with new Capsules using the conditions in Tier 2 as follows. After 15 min with 700 mL of Medium A, stop the dissolution bath and timer and add 200 mL of Medium B pre-equilibrated at 37 ± 0.5°. Restart the bath and timer, and continue the dissolution for an additional 45 min.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 254 nm

Column: 3.9-mm × 15-cm; 5-μm packing L1

Column temperature: 40°

Flow rate: 1.5 mL/min

Injection volume: 20 μL

Run time: 1.8 times the retention time of ziprasidone

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 2.0%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS) dissolved:

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

r_U = peak response of ziprasidone from the Sample solution

r_S = peak response of ziprasidone from the Standard solution

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

L = label claim (mg/Capsule)

V = volume of Medium, 900 mL

M_r1 = molecular weight of ziprasidone, 412.94

M_r2 = molecular weight of ziprasidone hydrochloride; 467.41 for the monohydrate form, 449.39 (ERR 1-Sep-2023) for the anhydrous form

Tolerances: NLT 75% (Q) of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS) is dissolved.

4.3 Test 3

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

Tier 1

Medium: 2% sodium lauryl sulfate in pH 7.5 phosphate buffer (6.9 g/L of monobasic sodium phosphate pH adjusted with 5 N sodium hydroxide ); 900 mL

Apparatus 2: 75 rpm. Use a suitable sinker.

Time: 60 min

Tier 2

Medium A: pH 7.5 phosphate buffer (6.9 g/L of monobasic sodium phosphate pH adjusted with 5 N sodium hydroxide ) with 1% pancreatin; 700 mL

Medium B: pH 7.5 phosphate buffer (6.9 g/L of monobasic sodium phosphate pH adjusted with 5 N sodium hydroxide ) with 9% sodium lauryl sulfate; 200 mL

Apparatus 2: 75 rpm. Use a suitable sinker.

Time: 15 min for Medium A; 45 min for Medium A with the addition of Medium B

Buffer: 6.8 g/L of monobasic potassium phosphate. To each liter of this solution, add 1 mL of triethylamine and adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Acetonitrile and Buffer (30:70)

Diluent

Diluent 1: Acetonitrile and methanol (35:65)

Diluent 2

Tier 1: Medium

Tier 2: Medium A and Medium B (70:20)

Standard stock solution 1: 0.5 mg/mL of USP Ziprasidone Hydrochloride RS in Diluent 1

Standard stock solution 2: Prepare solutions of USP Ziprasidone Hydrochloride RS in Diluent 2 at concentrations given in Table 1 as follows. Transfer a suitable volume of Standard stock solution 1 into a suitable volumetric flask and dilute with Diluent 2 to volume.

Table 1

Standard solution: Transfer 5 mL of Standard stock solution 2 to a 25-mL volumetric flask and dilute with Mobile phase to volume.

Sample solution: Centrifuge a portion of the solution under test. Dilute the supernatant with Mobile phase to volume to obtain nominal concentration of ziprasidone similar to that of the Standard solution. Pass through a suitable filter of 0.45-μm pore size. [Note - A centrifuge speed of 4000 rpm for 10 min may be suitable.]

Procedure: Perform the test using the conditions in Tier 1. In the presence of cross-linking repeat the test with new Capsules using the conditions in Tier 2 as follows. After 15 min with 700 mL of Medium A, stop the dissolution bath and timer and add 200 mL of Medium B pre-equilibrated at 37 ± 0.5°. Restart the bath and timer, and continue the dissolution for an additional 45 min.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 230 nm

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

Flow rate: 1.3 mL/min

Injection volume: 10 μL

Run time: 1.3 times the retention time of ziprasidone

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 1.5%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS) dissolved:

Result = (r_U/r_S) × C_S × V × D × (1/L) × (M_r1/M_r2) × 100

r_U = peak response of ziprasidone from the Sample solution

r_S = peak response of ziprasidone from the Standard solution

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

V = volume of Medium (Tier 1 or Tier 2), 900 mL

D = dilution factor for the Sample solution, 5

L = label claim (mg/Capsule)

M_r1 = molecular weight of ziprasidone, 412.94

M_r2 = molecular weight of ziprasidone hydrochloride; 467.41 for the monohydrate form, 449.39 (ERR 1-Sep-2023) for the anhydrous form

Tolerances: NLT 70% (Q) of the labeled amount of ziprasidone (C₂₁H₂₁ClN₄OS) is dissolved.

Uniformity of Dosage Units 〈905〉: Meet the requirements

5 IMPURITIES

Change to read:

Organic Impurities

Buffer: 0.05 M monobasic potassium phosphate

Solution A: Methanol and Buffer (33:67). Adjust with phosphoric acid to a pH of 3.0.

Solution B: Acetonitrile, methanol, and Buffer (55:5:40). Adjust with potassium hydroxide solution (ERR 1-Sep-2023) to a pH of 6.0.

Mobile phase: See Table 2.

Table 2

Diluent: Acetonitrile, methanol, and water (40:10:50). Adjust with phosphoric acid to a pH of 2.5.

System suitability solution: 0.5 mg/mL of USP Ziprasidone Hydrochloride RS and 0.05 mg/mL each of USP Ziprasidone Related Compound B RS and USP Ziprasidone Related Compound F RS in Diluent

Standard solution: 0.002 mg/mL each of USP Ziprasidone Hydrochloride RS and USP Ziprasidone Related Compound B RS in Diluent. Sonication may be used to aid in dissolution.

Sample solution: Nominally 1.0 mg/mL of ziprasidone in Diluent from a portion of contents of Capsules (NLT 20) prepared as follows.

Transfer a suitable amount of Capsule contents to a suitable volumetric flask. Add 60% of the flask volume of Diluent. Sonicate for 10 min.

Dilute with Diluent to volume. Pass through a suitable filter of 0.45-μm pore size.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 229 nm

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

Column temperature: 30°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

System suitability

Samples: System suitability solution and Standard solution

Suitability requirements

Resolution: NLT 2.0 between ziprasidone related compound B and related compound F; NLT 2.0 between ziprasidone related compound F and ziprasidone, System suitability solution

Tailing factor: NMT 1.5 for ziprasidone, Standard solution

Relative standard deviation: NMT 5.0% for both ziprasidone and ziprasidone related compound B, Standard solution

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ziprasidone related compound B in the portion of Capsules taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of ziprasidone related compound B from the Sample solution

r_S = peak response of ziprasidone related compound B from the Standard solution

C_S = concentration of USP Ziprasidone Related Compound B RS in the Standard solution (mg/mL)

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

Calculate the percentage of ziprasidone sulfoxide analog or any individual unspecified degradation product in the portion of Capsules taken:

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

r_U = peak response of ziprasidone sulfoxide analog or each unspecified degradation product from the Sample solution

r_S = peak response of ziprasidone from the Standard solution

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

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

F = relative response factor

M_r1 = molecular weight of ziprasidone free base, 412.94

M_r2 = molecular weight of ziprasidone hydrochloride; 467.41 for the monohydrate, 449.39 (ERR 1-Sep-2023) for the anhydrous form

Acceptance criteria: See Table 3. Disregard any peak with an area below 0.05% in the Sample solution.

Table 3

^a 6-Chloro-5-{2-[4-(1-oxidobenzisothiazol-3-yl)piperazin-1-yl]ethyl}indolin-2-one.

^b Process impurity included in the table for identification only; controlled in the drug substance. Process impurities are controlled in the drug substance and are not to be reported or included in the total impurities for the drug product.

^c 3-(Piperazin-1-yl)benzo[d]isothiazole; also known as 3-(Piperazin-1-yl)benzisothiazole monohydrochloride.

^d 6-Chloroindolin-2-one.

^e 5,5′-Bis{2-[4-(benzo[d]isothiazol-3-yl)piperazin-1-yl]ethyl}-6,6′-dichloro-3-hydroxy-3,3′-biindoline-2,2′-dione; also known as 5,5′-Bis{2-[4-(benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6,6′-dichloro-3-hydroxy-3,3′-biindoline-2,2′-dione.

^f 3-(Benzo[d]isothiazol-3-yl)-5-{2-[4-(benzo[d]isothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloroindolin-2-one; also known as 3-(Benzisothiazol-3-yl)-5-{2-[4-(benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloroindolin-2-one.

5.1 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in well-closed containers, and store at controlled room temperature.

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

USP Reference Standards 〈11〉

USP Ziprasidone Hydrochloride RS

USP Ziprasidone Related Compound B RS

5-{2-[4-(Benzo[d]isothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloroindoline-2,3-dione; also known as 5-{2-[4-(Benzisothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloroindoline-2,3-dione.

C₂₁H₁₉ClN₄O₂S 426.92

USP Ziprasidone Related Compound F RS

Sodium 2-(2-amino-5-{2-[4-(benzo[d]isothiazol-3-yl)piperazin-1-yl]ethyl}-4-chlorophenyl)acetate monohydrate; also known as Sodium 2-(2-amino-5-{2-[4-(benzisothiazol-3-yl)piperazin-1-yl]ethyl}-4-chlorophenyl)acetate monohydrate

C₂₁H₂₂ClN₄NaO₂S. H₂O 470.95