Ziprasidone Hydrochloride

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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C₂₁H₂₁ClN₄OS · HCl 449.39

C₂₁H₂₁ClN₄OS · HCl · H2O 467.41

2H-Indol-2-one, 5-{2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-1,3-dihydro-, monohydrochloride;

5-{2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl}-6-chloro-2-indolinone monohydrochloride.

Monohydrate CAS RN®: 138982-67-9; UNII: 216X081ORU.

Anhydrous CAS RN®: 122883-93-6; UNII: JAL53626GG.

1 DEFINITION

Ziprasidone Hydrochloride contains NLT 97.5% and NMT 102.0% of ziprasidone hydrochloride (C₂₁H₂₁ClN₄OS · HCl), calculated on the anhydrous and solvent-free basis.

2 IDENTIFICATION

A. Spectroscopic Identification Tests 〈197〉, Infrared Spectroscopy: 197A or 197K. If a difference appears in the spectra of the analyte and the Reference Standard, dissolve equal portions of the analyte and the Reference Standard in equal volumes of methanol separately, evaporate to dryness, and record new spectra using the residues.

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

C. Identification Tests - General 〈191〉, Chemical Identification Tests, Chloride

Sample solution: Suspend 30 mg of the analyte in 2 mL of water, acidify with 0.15 mL of 2 N nitric acid TS, and filter. Use the filtrate.

Acceptance criteria: Meets the requirements

3 ASSAY

Procedure

Buffer: 6.8 g/L of monobasic potassium phosphate in water. Adjust with phosphoric acid to a pH of 3.0.

Mobile phase: Methanol and Buffer (40:60)

Diluent: Methanol and water (60:40)

Standard solution: 0.23 mg/mL of USP Ziprasidone Hydrochloride RS in Diluent

Sample solution: 0.23 mg/mL of Ziprasidone Hydrochloride in Diluent. [Note—Because of its hygroscopic nature, the anhydrous form may be dried at 70° under vacuum for 2 h prior to the preparation of the Sample solution.]

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: 40°

Flow rate: 1.5 mL/min

Injection volume: 20 μL

Run time: NLT 2 times the retention time of ziprasidone

System suitability

Sample: Standard solution

Suitability requirements

Tailing factor: NMT 2.0

Relative standard deviation: NMT 0.73%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ziprasidone hydrochloride (C₂₁H₂₁ClN₄OS · HCl) in the portion of Ziprasidone Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 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 = concentration of Ziprasidone Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: 97.5%–102.0% on the anhydrous and solvent-free basis

4 IMPURITIES

Residue on Ignition 〈281〉: NMT 0.2%

Limit of Tetrahydrofuran

[Note - Perform this test only if tetrahydrofuran is likely to be present as the result of the manufacturing process.]

Standard solution: 0.05 mg/mL of tetrahydrofuran in dimethyl sulfoxide. Transfer 4 mL of this solution to a 20-mL headspace vial, and seal.

Sample solution: Transfer 40 mg of Ziprasidone Hydrochloride and 4.0 mL of Dimethyl sulfoxide to a 20-mL headspace vial, seal, and mix.

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: GC with headspace injector

Detector: Flame ionization

Column: 30-m × 0.32-mm fused silica; coated with a 1.8-μm film of phase G43

Temperatures

Injection port: 180°

Detector: 260°

Column: See Table 1.

Table 1

Carrier gas: Helium

Flow rate: 1.6 mL/min

Injection volume: 2 mL

Injection type: Headspace; split ratio, 30:1

Vial treatment: Maintain at 105° for 60 min prior to injection

System suitability

Sample: Standard solution

Suitability requirements

Relative standard deviation: NMT 5%

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of tetrahydrofuran in the portion of Ziprasidone Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × 100

r_U = peak response of tetrahydrofuran from the Sample solution

r_S = peak response of tetrahydrofuran from the Standard solution

C_S = concentration of tetrahydrofuran in the Standard solution (mg/mL)

C_U = concentration of Ziprasidone Hydrochloride in the Sample solution (mg/mL)

Acceptance criteria: NMT 0.4% of tetrahydrofuran

Change to read:

Organic Impurities

Buffer: 6.8 g/L of monobasic potassium phosphate in water

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 A RS, USP Ziprasidone Related Compound B RS, USP Ziprasidone Related Compound C RS, USP Ziprasidone Related Compound D RS, and USP Ziprasidone Related Compound F RS in Diluent. [Note - Ziprasidone related compound F is stable for 6 h at 10° in this solution.]

Sensitivity solution: 0.5 μg/mL of USP Ziprasidone Hydrochloride RS in Diluent

Standard solution: 0.001 mg/mL of USP Ziprasidone Hydrochloride RS and 0.002 mg/mL each of USP Ziprasidone Related Compound A RS, USP Ziprasidone Related Compound B RS, USP Ziprasidone Related Compound C RS, and USP Ziprasidone Related Compound D RS in Diluent

Sample solution: 1.0 mg/mL of Ziprasidone Hydrochloride in Diluent. [Note—Because ziprasidone related compound F is stable only for 6 h at 10°, it is recommended that the freshly prepared Sample solution be analyzed.]

Chromatographic system

(See Chromatography 〈621〉, System Suitability.)

Mode: LC

Detector: UV 229 nm

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

Temperatures

Autosampler: 10°

Column: 30°

Flow rate: 1.5 mL/min

Injection volume: 10 μL

System suitability

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

[Note - The relative retention times in Table 3 are provided as information that could aid to peak assignment.]

Table 3

^a 6-Chloroindolin-2-one.

Suitability requirements

Resolution: NLT 1.5 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 ziprasidone, ziprasidone related compound B, ziprasidone related compound C, and ziprasidone related compound D, Standard solution

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

Analysis

Samples: Standard solution and Sample solution

Calculate the percentage of ziprasidone related compounds A, B, C, and D, relative to the content of ziprasidone free base, in the portion of Ziprasidone Hydrochloride taken:

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

r_U = peak response of ziprasidone related compounds A, B, C, and D from the Sample solution

r_S = peak response of the corresponding USP Reference Standard from the Standard solution

C_S = concentration of the corresponding USP Reference Standard in the Standard solution (mg/mL)

C_U = concentration of Ziprasidone Hydrochloride in the Sample solution (mg/mL)

M_r1 = molecular weight of ziprasidone hydrochloride in the sample taken, 467.41 for the monohydrate, 449.39 (ERR 1-Sep-2023) for the anhydrous form

M_r2 = molecular weight of ziprasidone free base, 412.94

Calculate the percentage of chloroindolinone, ziprasidone related compound F, and any unspecified impurity, relative to the content of ziprasidone free base, in the portion of Ziprasidone Hydrochloride taken:

Result = (r_U/r_S) × (C_S/C_U) × (1/F) × (M_r1/M_r2) × (M_r3/M_r1) × 100

r_U = peak response of chloroindolinone, ziprasidone related compound F, or any unspecified impurity 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 = concentration of Ziprasidone Hydrochloride in the Sample solution (mg/mL)

F = relative response factor (see Table 4)

M_r1 = molecular weight of ziprasidone free base, 412.94

M_r2 = molecular weight of ziprasidone hydrochloride anhydrous form, 449.39 (ERR 1-Sep-2023)

M_r3 = molecular weight of ziprasidone hydrochloride in the sample taken, 467.41 for the monohydrate, 449.39 (ERR 1-Sep-2023) for the anhydrous form

Acceptance criteria: See Table 4. The reporting threshold is 0.05%.

Table 4

^a A process impurity specific to a manufacturing process; may not be present in all manufacturing processes.

5 SPECIFIC TESTS

Water Determination 〈921〉, Method I

Monohydrate: 3.7%–5.0%

Anhydrous: NMT 2.0%

6 ADDITIONAL REQUIREMENTS

Packaging and Storage: Preserve in tight, light-resistant containers, and store at room temperature.

Labeling: If this is an anhydrous form, it is so labeled.

USP Reference Standards 〈11〉

USP Ziprasidone Hydrochloride RS

USP Ziprasidone Related Compound A RS

3-(Piperazin-1-yl)benzoisothiazole monohydrochloride;

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

C₁₁H₁₃N₃S · HCl 255.77

USP Ziprasidone Related Compound B RS

5-{2-[4-(Benzoisothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloroindoline-2,3-dione;

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

C₂₁H₁₉ClN₄O₂S 426.92

USP Ziprasidone Related Compound C RS

5,5′-Bis{2-[4-(benzoisothiazol-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-(benzo[d]isothiazol-3-yl)piperazin-1-yl]ethyl}-6,6′-dichloro-3-hydroxy-3,3′-biindoline-2,2′-dione.

C₄₂H₄₀Cl₂N₈O₃S₂ 839.85

USP Ziprasidone Related Compound D RS

3-(Benzoisothiazol-3-yl)-5-{2-[4-(benzoisothiazol-3-yl)piperazin-1-yl]ethyl}-6-chloroindolin-2-one;

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

C₂₁H₂₁ClN₄OS 546.11

USP Ziprasidone Related Compound F RS

Sodium 2-(2-amino-5-{2-[4-(benzisothiazol-3-yl)piperazin-1-yl]ethyl}-4-chlorophenyl)acetate monohydrate;

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

C₂₁H₂₂ClN₄NaO₂S · H₂O 470.95