Lisinopril USP – Specification & STP / ATP

Raw Material Specification & Method of Analysis (MOA) / Standard Testing Procedure (STP) for Lisinopril USP and per USP Volume No. PF 41(4).

RM Specification of Lisinopril USP

Sr. No. Test Parameter Specification
01 Description White crystalline powder.
02 Solubility Soluble in water; sparingly soluble in methanol; practically insoluble in alcohol, in acetone; in acetonitrile and in chloroform.
03 Identification – A By IR;  The infra-red absorption spectrum should be concordant with reference spectrum of that standard.
Identification – B By HPLC;  The retention time of the major peak in the  chromatogram of the Assay preparation corresponds to that of the standard preparation as directed in the Assay.
04 Melting Point About 160°.
05 Optical Rotation, Specific Rotation Between  – 115.3°  and  – 122.5°.
06 Water Between 8.0  and  9.5%.
07 Residue on Ignition Not more than 0.1%.
08 Organic Impurities By HPLC.
N-Alkyl-L-Iysinea Not more than 0.3%.
Lisinopril epimerc Not more than 0.3%.
Lisinopril cyclohexylanalogd Not more than 0.3%.
R,S,S-Diketopiperazinee Not more than 0.3%.
S,S,S-Diketopiperazine (lisinopril relatedcompound A)f Not more than 0.3%.
N-Alkyl lisinoprilg Not more than 0.15%
Any individualunspecified impurity Not more than 0.1%
Total impuritiesh Not more than 0.5%
09 Assay By HPLC;  Not less than 98.0% and not more than  102.0% on anhydrous basis.

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MOA/STP of Lisinopril USP

1.0     Description

2.0     Solubility of Lisinopril

    • Procedure : Soluble in water; sparingly soluble in methanol; practically insoluble in alcohol, in acetone; in acetonitrile and in chloroform.  Carry out the test as per procedure of solubility check.

Solubility Table

Descriptive Term Parts of Solvent Required for 1 Part of Solute
Very soluble Less than 1
Freely soluble From 1 to 10
Soluble From 10 to 30
Sparingly soluble From 30 to 100
Slightly soluble From 100 to 1,000
Very slightly soluble From 1,000 to 10,000
Practically insoluble, or Insoluble Greater than or equal to 10,000

3.0     Identification

    • Test A  :  By IR
    • The infra-red absorption spectrum of lisinopril is concordant with the reference spectrum of lisinopril or with the spectrum obtained from USP lisinopril RS.  Carry out the test as per procedure.
    • Test B  :  By HPLC
    • The retention time of the major peak of the sample solution corresponds to that of the standard solution, as obtained  in  the  Assay.

4.0     Melting Point

5.0     Optical Rotation

    • Specific Rotation 
    • It is determined in the test solution containing 10 mg per ml of lisinopril, in  0.25 M  zinc  acetate solution.  (At l = 405 nm).
    • Preparation of 0.25 M Zinc Acetate Solution  : 
    • Mix  600 ml of water with 150 ml of  glacial acetic acid and  54.9 gm of zinc acetate and  stir to dissolve the zinc acetate.
    • While stirring, add 150 ml of ammonium hydroxide, cool to room temperature and adjust with ammonium hydroxide to a pH of 6.4.
    • Transfer the solution to a 1000 ml volumetric flask,  dilute with water to volume, and mix.

6.0     Water Content of Lisinopril USP

7.0     Residue on Ignition

    • Carry out the test on 1 gm sample powder as per procedure.

8.0     Organic Impurities Test of Lisinopril USP

  • Procedure  :    

    • Buffer  : 3.53 g/L of monobasic sodium phosphate dehydrate in water adjusted with phosphoric acid to a pH of 4.1.
    • Solution A : Acetonitrile and Buffer  (7 : 193)
    • Solution B : Acetonitrile and Buffer  (20 : 80)
    • Mobile phase : See Table 1.

Table 1

Time  (min.) Solution A  (%) Solution B  (%)
0 100 0
35 60 40
55 60 40
60 100 0
    • Standard solution : 0.006 mg/ml of USP Lisinopril RS in solution A

(Dilution: about 6 mg  USP Lisinopril RS→ 10 ml→ take 1 ml →100 ml)

    • Sensitivity solution : 1µg/ml of USP Lisinopril RS in Solution A from Standard solution.

(Dilution: about 5 mg USP Lisinopril RS→ 50 ml→ take 1 ml →100 ml)

    • Sample solution : 2 mg/ml of Lisinopril in Solution A
    • Chromatographic System  :
      • Mode             :       LC
      • Detector         :       UV 210 nm
      • Column          :       4.6-mm × 25-cm; 5µm packing L7 (Octylsilane (C8) bonded to porous silica)
      • Column temp. :      45°
      • Flow rate       :       1.8 ml/min
      • Inj. volume     :      20 µl
    • System Suitability
    • Samples  : Standard solution and Sensitivity solution
    • Suitability requirements
    • Relative standard deviation : NMT 10.0%, Standard solution
    • Signal-to-noise ratio: NLT 10, Sensitivity solution

  • Analysis

    • Samples : Standard solution and Sample solution.

Calculate the percentage of each impurity in the portion of Lisinopril taken:

Result          =       (ru/rs) × (Cs/Cu) × (1 /F) × 100

Where

ru        =       peak response of each impurity from the Sample solution

rs        =       peak response of lisinopril from the Standard solution

Cs       =       concentration of USP Lisinopril RS in the Standard solution (mg/ml)

Cu        =       concentration of Lisinopril in the Sample solution (mg/ml)

F           =       relative response factor (see Table 2)

Table 2

Name Retention Response Time Name Time Factor Acceptance Criteria  NMT (%)
N-Alkyl-L-Iysinea 0.57 0.35 Not more than 0.3%.
DL-Homophenylalanineb 0.72 1.08 Not more than 0.3%.
Lisinopril 1.00 1.00 –
Lisinopril epimerc 1.33 0.76 Not more than 0.3%.
Lisinopril cyclohexyl analogd 2.93 0.39 Not more than 0.30%.
R,S,S-Diketopiperazinee 3.88 0.79 Not more than 0.3%.
S,S,S-Diketopiperazine (lisinopril related compound A)f 4.04 0.76 Not more than 0.3%.
N-Alkyl lisinoprilg 4.60 0.86 Not more than 0.15%
Any individual unspecified impurity – 1.00 Not more than 0.1%
Total impuritiesh – – Not more than 0.5%

9.0     Assay of Lisinopril USP

  • Procedure : 

    • Solution A  :  Dissolve 2.76 gm of  monobasic sodium phosphate in about 900 ml of water in 1000 ml of  volumetric flask, and adjust its pH  to  5  with  1 N  sodium hydroxide.  Make up to the mark and mix.
    • Mobile phase :
    • Prepare a filtered and degassed mixture of Solution A and acetonitrile ( 4:96).  Make adjustment if necessary.  
    • Standard Preparation  : 
    • Dissolve  an  accurately  weighed  quantity  of  USP  lisinopril  RS  in water, and dilute quantitatively, and  step-wise if necessary, with water to obtain  a solution  having a known concentration of  about 0.3 mg/ml.
    • Assay Preparation :
    • Transfer about 30 mg of lisinopril, accurately weighed, to a 100 ml  volumetric flask, dissolve in water,  dilute with water to volume, and mix.
    • Chromatographic Conditions  :
    • Wave Length               :         210  nm.
    • Column Brief              :         4.6 mm x 25 cm column that contains 5 mm packing L7 and is maintained at a temperature of 50°.
    • Flow Rate                    :         1 ml / minute.
    • Tailing Factor             :         Not more than 1.7.
    • Relative standard deviation:      Not more than 0.73%
    • Volume Injected        :         20 ml.

Calculation  :  Calculate the quantity of lisinopril using the formula :

Result          =       (ru/rs) × (Cs/Cu)  × 100

ru        =       peak response of  Lisinopril  from the Sample solution

rs        =       peak response of lisinopril from the Standard solution

Cs       =       concentration of USP Lisinopril RS in the Standard solution (mg/ml)

Cu        =       concentration of Lisinopril in the Sample solution (mg/ml)

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