Ziprasidone Hydrochloride
(zi pras' i done hye'' droe klor' ide).
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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, monohydrate;    
5-[2-[4-(1,2-Benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-2-indolinone monohydrochloride, monohydrate      [138982-67-9].
DEFINITION
Ziprasidone Hydrochloride contains NLT 98.0% and NMT 102.0% of C21H21ClN4OS·HCl, calculated on the anhydrous and solvent-free basis.
IDENTIFICATION
•  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, Chloride 191: Meets the requirements
ASSAY
•  Procedure
Buffer:  6.8 g/L of monobasic potassium phosphate in water. Adjust with 85% phosphoric acid to a pH of 3.0.
Mobile phase:  Methanol and Buffer (2:3)
Diluent:  Methanol and water (3:2)
Standard solution:  0.23 mg/mL of USP Ziprasidone Hydrochloride RS in Diluent
Sample solution:  0.23 mg/mL of Ziprasidone Hydrochloride in Diluent
Chromatographic system 
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 size:  20 µL
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 C21H21ClN4OS·HCl in the portion of Ziprasidone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response from the Sample solution
rS== peak response from the Standard solution
CS== concentration of USP Ziprasidone Hydrochloride RS in the Standard solution (mg/mL)
CU== nominal concentration of Ziprasidone Hydrochloride in the Sample solution (mg/mL)
Acceptance criteria:  98.0%–102.0% on the anhydrous and solvent-free basis
IMPURITIES
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.1%
•  Heavy Metals, Method II 231: NMT 20 ppm
Organic Impurities 
•  Procedure 1: Limit of Tetrahydrofuran
Standard solution:  0.05 mg/mL 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 
Mode:  GC with headspace injector
Detector:  Flame ionization
Column:  30-m × 0.32-mm fused silica column coated with a 1.8-µm film of phase G43
Temperature 
Injection port:  180
Detector:  260
Column:  See the temperature program table below.
Initial
Temperature ()
Temperature
Ramp
(/min)
Final
Temperature
()
Hold Time
at Final
Temperature
(min)
40 0 40 5
40 2 90 0
90 30 225 2
Injector split ratio:  30:1
Carrier gas:  Helium
Flow rate:  1.6 mL/min
Injection size:  2 mL
System suitability 
Sample:  Standard solution
Suitability requirements 
Relative standard deviation:  NMT 5%
Analysis:  [Note—The headspace vials are maintained at 105 for 60 min prior to headspace injection. ]
Samples:  Standard solution and Sample solution
Calculate the percentage of tetrahydrofuran in the portion of Ziprasidone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × 100
rU== peak response of tetrahydrofuran from the Sample solution
rS== peak response of tetrahydrofuran from the Standard solution
CS== concentration of tetrahydrofuran in the Standard solution (mg/mL)
CU== nominal concentration of Ziprasidone Hydrochloride in the Sample solution (mg/mL)
Acceptance criteria 
Tetrahydrofuran:  NMT 0.4%
•  Procedure 2: Limit of Early-Eluting Impurities
Mobile phase and Chromatographic system:  Proceed as directed in the Assay.
Diluent A:  Methanol, water, and hydrochloric acid (20:5:0.01)
Diluent B:  Methanol and water (3:2)
Standard solution A:  0.5 µg/mL of USP Ziprasidone Related Compound A RS and 0.8 µg/mL of USP Ziprasidone Related Compound B RS in Diluent A
Standard solution B:  0.4 µg/mL of USP Ziprasidone Related Compound B RS in Diluent A
System suitability solution:  0.24 mg/mL of USP Ziprasidone Hydrochloride RS in Standard solution A
Sample solution A:  0.4 mg/mL of Ziprasidone Hydrochloride in Diluent A
Sample solution B:  0.2 mg/mL of Ziprasidone Hydrochloride in Diluent B
System suitability 
Sample:  System suitability solution
Suitability requirements 
Resolution:  NLT 1.5 between the ziprasidone related compound B and ziprasidone peaks
Relative standard deviation:  NMT 10% for the ziprasidone related compound B peak
Analysis:  [Note—Run the Sample solution NLT 7 times the ziprasidone retention time in Sample solution A. ]
Samples:  Standard solution A and Sample solution A
Calculate the percentages of ziprasidone related compounds A and B relative to the content of ziprasidone free base in the portion of Ziprasidone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (Mr2/Mr1) × 100
rU== peak response of the ziprasidone related compound from Sample solution A
rS== peak response of the ziprasidone related compound from Standard solution A
CS== concentration of the ziprasidone related compound in Standard solution A (mg/mL)
CU== nominal concentration of Ziprasidone Hydrochloride in Sample solution A (mg/mL)
Mr1== molecular weight of ziprasidone free base, 412.94
Mr2== molecular weight of ziprasidone hydrochloride, 467.41
Samples:  Standard solution B and Sample solution B
Calculate the percentage of ziprasidone open ring relative to the content of ziprasidone free base in the portion of Ziprasidone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (Mr2/Mr1) × 100
rU== peak response of ziprasidone open ring from Sample solution B
rS== peak response of ziprasidone related compound B from Standard solution B
CS== concentration of ziprasidone related compound B in Standard solution B (mg/mL)
CU== nominal concentration of Ziprasidone Hydrochloride in Sample solution B (mg/mL)
Mr1== molecular weight of ziprasidone free base, 412.94
Mr2== molecular weight of ziprasidone hydrochloride, 467.41
Samples:  Diluent A, Diluent B, Standard solution B, and Sample solution A
Calculate the percentage of unspecified impurity eluting before ziprasidone relative to the content of ziprasidone free base in the portion of Ziprasidone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (Mr2/Mr1) × 100
rU== peak response of each unspecified impurity from Sample solution A
rS== peak response of ziprasidone related compound B from Standard solution B
CS== concentration of ziprasidone related compound B in Standard solution B (mg/mL)
CU== nominal concentration of Ziprasidone Hydrochloride in Sample solution A (mg/mL)
Mr1== molecular weight of ziprasidone free base, 412.94
Mr2== molecular weight of ziprasidone hydrochloride, 467.41
[Note—Disregard the peaks in the injections of Diluent A and Diluent B. ]
Acceptance criteria 
Individual impurities:  See Impurity Table 1.
Impurity Table 1
Name Relative
Retention
Time
Acceptance
Criteria,
NMT (%)
Ziprasidone related compound A 0.4 0.1
Ziprasidone related compound B 0.8 0.2
Ziprasidone open ringa 0.9 0.2
Ziprasidone 1.0
Any individual unspecified impurity eluting before ziprasidone 0.1
a  2-(2-Amino-5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-4-chlorophenyl)acetic acid.

•  Procedure 3: Limit of Late-Eluting Impurities
Buffer:  6.8 g/L of monobasic potassium phosphate in water. Adjust with 5 N potassium hydroxide to a pH of 6.0.
Mobile phase:  Acetonitrile, methanol, and Buffer (11:1:8)
Diluent:  Methanol, water, and hydrochloric acid (20:5:0.01)
Standard solution:  0.8 µg/mL each of USP Ziprasidone Related Compound C RS and USP Ziprasidone Related Compound D RS in Diluent
System suitability solution:  0.24 mg/mL of USP Ziprasidone Hydrochloride RS in the Standard solution
Sample solution:  0.45 mg/mL of Ziprasidone Hydrochloride in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 229 nm
Column:  4.6-mm × 15-cm; 5-µm packing L7
Column temperature:  35
Flow rate:  1 mL/min
Injection size:  20 µL
System suitability 
Sample:  System suitability solution
Suitability requirements 
Resolution:  NLT 6.0 between the ziprasidone and ziprasidone related compound C peaks
Relative standard deviation:  NMT 10% for the ziprasidone related compound C peak
Analysis:  [Note—Run the Sample solution NLT 12 times the ziprasidone retention time in the Sample solution. ]
Samples:  Standard solution and Sample solution
Calculate the percentages of ziprasidone related compounds C and D relative to the content of ziprasidone free base in the portion of Ziprasidone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (Mr2/Mr1) × 100
rU== peak response of the ziprasidone related compound from the Sample solution
rS== peak response of the ziprasidone related compound from the Standard solution
CS== concentration of the ziprasidone related compound in the Standard solution (mg/mL)
CU== nominal concentration of Ziprasidone Hydrochloride in the Sample solution (mg/mL)
Mr1== molecular weight of ziprasidone hydrochloride free base, 412.94
Mr2== molecular weight of ziprasidone hydrochloride, 467.41
Samples:  Diluent, Standard solution, and Sample solution
Calculate the percentage of unspecified impurity eluting after ziprasidone relative to the content of ziprasidone free base in the portion of Ziprasidone Hydrochloride taken:
Result = (rU/rS) × (CS/CU) × (Mr2/Mr1) × 100
rU== peak response of each unspecified impurity from the Sample solution
rS== peak response of ziprasidone related compound D from the Standard solution
CS== concentration of ziprasidone related compound D in the Standard solution (mg/mL)
CU== nominal concentration of Ziprasidone Hydrochloride in the Sample solution (mg/mL)
Mr1== molecular weight of ziprasidone hydrochloride free base, 412.94
Mr2== molecular weight of ziprasidone hydrochloride, 467.41
[Note—Disregard the peaks in the injection of the Diluent. ]
Acceptance criteria 
Individual impurities:  See Impurity Table 2.
Total impurities:  NMT 0.5%. [Note—The total impurities are the sum of related compounds A, B, C, D, ziprasidone open ring, and all unspecified impurities found in Procedure 2: Limit of Early-Eluting Impurities and Procedure 3: Limit of Late-Eluting Impurities. ]
Impurity Table 2
Name Relative
Retention
Time
Acceptance
Criteria,
NMT (%)
Ziprasidone 1.0
Ziprasidone related compound C 2.0 0.2
Ziprasidone related compound D 3.0 0.2
Any individual unspecified impurity eluting after ziprasidone 0.1
SPECIFIC TESTS
•  Water Determination, Method I 921: Between 3.7% and 5.0%
ADDITIONAL REQUIREMENTS
•  Packaging and Storage: Preserve in tight, light-resistant containers, and store at room temperature.
•  USP Reference Standards 11
USP Ziprasidone Hydrochloride RS Click to View Structure
USP Ziprasidone Related Compound A RS
3-(Piperazin-1-yl)benzo[d]isothiazole monohydrochloride.
    C11H13N3S·HCl        255.77
USP Ziprasidone Related Compound B RS
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-(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-(Benzo[d]isothiazol-3-yl)-5-(2-(4-(benzo[d]isothiazol-3-yl)piperazin-1-yl)ethyl)-6-chloroindolin-2-one.
    C28H24ClN5OS2        546.11
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USP35–NF30 Page 5079
Pharmacopeial Forum: Volume No. 35(3) Page 592