Loxapine Succinate
(lox' a peen sux' i nate).

C18H18ClN3O·C4H6O4 445.90
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Butanedioic acid, compd. with 2-chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][1,4]oxazepine (1:1);    
2-Chloro-11-(4-methyl-1-piperazinyl)dibenz[b,f][1,4] oxazepine succinate (1:1)     [27833-64-3].
Loxapine Succinate contains NLT 98.5% and NMT 101.0% of C18H18ClN3O·C4H6O4, calculated on the dried basis.
•  B. Ultraviolet Absorption 197U
Sample solution:  20 µg/mL in 0.01 N hydrochloric acid
•  Procedure
Sample:  400 mg of Loxapine Succinate
Analysis:  Dissolve in 80 mL of glacial acetic acid, and titrate with 0.1 N perchloric acid VS, determining the endpoint potentiometrically. Perform a blank determination, and make any necessary correction (see Titrimetry 541).
Calculate the percentage of C18H18ClN3O·C4H6O4 in the portion of Loxapine Succinate taken:
Result = [(V B) × N × F × 100]/W
V== sample titrant volume (mL)
B== blank titrant volume (mL)
N== normality of titrant (mEq/mL)
F== equivalence factor, 22.29 mg/mEq
W== sample weight (mg)
Acceptance criteria:  98.5%–101.0% on the dried basis
Inorganic Impurities 
•  Residue on Ignition 281: NMT 0.1%
•  Heavy Metals, Method II 231: NMT 20 ppm
Organic Impurities 
•  Procedure
Buffer:  3.9 g/L of ammonium acetate in water. Adjust with 20% acetic acid in water or 6 N ammonium hydroxide to a pH of 7.3.
Mobile phase:  Acetonitrile and Buffer (3:7)
Diluent:  Acetonitrile and Buffer (7:3)
Standard solution:  10 µg/mL of USP Loxapine Succinate RS and 1.5 µg/mL each of USP Amoxapine RS and USP Loxapine Related Compound A RS in Diluent. [Note—Amoxapine has been included in the Standard solution for peak identification purposes only. ]
Sample solution:  1 mg/mL of Loxapine Succinate in Diluent
Chromatographic system 
Mode:  LC
Detector:  UV 254 nm
Column:  4.6-mm × 5-cm; 2.7-µm packing L1
Column temperature:  35
Flow rate:  1.5 mL/min
Injection size:  10 µL
Run time:  2 times the retention time of loxapine succinate
System suitability 
Sample:  Standard solution
Suitability requirements 
Resolution:  NLT 2.0 between loxapine succinate and loxapine related compound A
Relative standard deviation:  NMT 5.0%
Samples:  Standard solution and Sample solution
Calculate the percentage of any individual impurity in the portion of Loxapine Succinate taken:
Result = (rU/rS) × (CS/CU) × (1/F) × 100
rU== peak response of each impurity from the Sample solution
rS== peak response of loxapine succinate from the Standard solution
CS== concentration of USP Loxapine Succinate RS in the Standard solution (mg/mL)
CU== concentration of Loxapine Succinate in the Sample solution (mg/mL)
Acceptance criteria 
Individual impurities:  See Impurity Table 1.
Total impurities:  NMT 0.5%
Impurity Table 1
Name Relative
NMT (%)
Amoxapinea 0.19 1.3 0.15
Chlorodibenzoxazepinoneb 0.45 0.70 0.15
Loxapine succinate 1.0
Loxapine related compound Ac 1.2 1.2 0.15
Any unspecified individual impurity 1.0 0.10
a  2-Chloro-11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazepine.
b  2-Chlorodibenzo[b,f]-1,4-oxazepin-11-one.
c  3-Chloro-11-(4-methylpiperazin-1-yl)dibenzo[b,f][1,4]oxazepine.
•  Loss on Drying 731: Dry a sample at 105 for 4 h: it loses NMT 0.5% of its weight.
•  Packaging and Storage: Preserve in tight containers.
•  USP Reference Standards 11
USP Amoxapine RS Click to View Structure
USP Loxapine Related Compound A RS
    C18H18ClN3O          327.81
USP Loxapine Succinate RS Click to View Structure
Auxiliary Information— Please check for your question in the FAQs before contacting USP.
Topic/Question Contact Expert Committee
Monograph Hariram Ramanathan, M.S.
Associate Scientific Liaison
(SM42010) Monographs - Small Molecules 4
Reference Standards RS Technical Services
USP35–NF30 Page 3730
Pharmacopeial Forum: Volume No. 36(4) Page 924