Domperidone Maleate

Summary Validation Report

June 29, 2012
________________

1. Executive Summary
a. Goals: The reference procedure described herein was developed for the MC monograph for Domperidone
Maleate.
b. Background
i. Domperidone Maleate is a specific blocker of dopamine receptors, used as antiemetic drug and also as tool
in the study of dopaminergic mechanisms.
ii. The active moiety of the medicine is Domperidone Maleate, and all dosing information is based on the
Domperidone Maleate.
iii. The drug is available as tablets and oral suspension.
iv. Quality monographs in BP and EP are available.
v. The molecular formula C22H24ClN5O2.C4H4O4 and the molecular weight is 541.98.

c. The Reference procedure is based upon the literature, Indian Journal of Pharmaceutical Sciences (2007),
69(5), 674-676.

2. Reference Procedures
a. Assay Procedure: LC-PDA (Both Waters (primary) and Agilent (secondary)
i. Solution A: 10 mM ammonium acetate in water. Adjust with ammonium hydroxide to pH 7.0.
ii. Solution B: Methanol and acetonitrile (1:1)
iii. System suitability Solution: 0.5 µg/mL of USP Domperidone Maleate CRM, USP Domperidone Impurity B
RS and USP Domperidone Impurity C RS in methanol.
iv. Standard Solution: 0.2 mg/mL of USP Domperidone Maleate CRM in methanol.
v. Sample Solution: 0.2 mg/mL of Domperidone Maleate in methanol.
vi. Chromotographic System (See Chromatography <621>, System Suitability.)
1. Mode: LC
2. Detector: PDA (Scan 200-700 nm) [Note: Calculations are based on the chromatograms collected at
285 nm]
3. Column: 4.6-mm x 25-cm; 5-µm L1 packing, similar to Thermo Hypersil BDS
4. Flow rate: 1.0 mL/min
5. Column Oven Temperature: 30°
6. Auto sampler Temperature: 5°
7. Injection volume: 20 µL
 vii. Gradient Program:

Time Solution A Solution B

(min) (%) (%)
0.01 60 40
30 45 55
35 30 70
45 30 70
47 60 40
50 60 40

b. Organic Impurities Procedure: LC-PDA (Both Waters (primary) and Agilent (secondary)) and MS
i. Solution A: 10 mM ammonium acetate in water. Adjust with ammonium hydroxide to pH 7.0.
ii. Solution B: Methanol and acetonitrile (1:1)
iii. System suitability Solution: 0.5 µg/mL of USP Domperidone Maleate CRM, USP Domperidone Impurity A
RS, USP Domperidone Impurity B RS, USP Domperidone Impurity C RS, USP Domperidone Impurity D
RS, USP Domperidone Impurity F RS and USP Domperidone Impurity G RS in methanol.
iv. Sample Solution: 0.5 mg/mL Domperidone Maleate in methanol.
v. Chromotographic System (See Chromatography <621>, System Suitability.)
1. Mode: LC
2. Detector: PDA (Scan 200-700 nm) [Note: Calculations are based on the chromatograms collected at
285 nm]
3. Column: 4.6-mm x 25-cm; 5-µm L1 packing, similar to Thermo Hypersil BDS
4. Flow rate: 1.0 mL/min
5. Column Oven Temperature: 30°
6. Auto sampler Temperature: 5°
7. Injection volume: 20 µL
vi. Gradient Program:
Time Solution A Solution
(min) (%) B (%)
0 60 40
30 45 55
35 30 70
45 30 70
47 60 40
50 60 40

vii. Chromotographic System (See Chromatography <621>, System Suitability.)

1. Mode: LC
2. Detector: MS Source: ES Scan (+ and -)
3. MS Conditions:
a. Capillary (kv): 4.00
b. Cone (v): 20.0
c. Extractor (v): 2.0
d. Rf lense (v): 0.1
e. Source temperature: 80°
f. Desolvation temperature: 450°

c. HPTLC was used to demonstrate the interference of the impurities

Chromatographic System (See Chromatography <621>, Thin-Layer Chromatography.)
1. Solvent A: 10 mM ammonium acetate in water. Adjust with ammonium hydroxide to pH 7.0.
2. Solvent B: Acetonitrile and methanol (1:1)
Domperidone Maleate Summary Validation Report—Page 2 of 19
 3. Developing solvent system: Solvent A and Solvent B (3:2).
4. Standard solution 1: 0.2 mg/mL of USP Domperidone Maleate CRM in methanol.
5. Standard solution 2: 0.5 mg/mL of USP Domperidone Maleate CRM in methanol.
6. Standard solution 3: 1 mg/mL of USP Domperidone Maleate CRM in methanol.
7. Sample solution: 0.5 mg/mL of Domperidone Maleate in methanol.
8. Mode: HPTLC
9. Adsorbent: TLC Silica gel 60 F254 Aluminum sheet 20 х 20 cm
10. Application volume:
a. Standard solution: 20 µL
b. Sample solution: 20 µL
11. Visualization: Short wavelength UV – 254 nm and exposure to iodine chamber
12. Analysis: Proceed as directed for Chromatography <621>, Thin-Layer Chromatography. Allow the
spots to dry, and develop the chromatogram in a Developing solvent system until the solvent front
has moved three-fourths of the length of the plate. Remove the plate from the developing chamber,
mark the solvent front, and allow the solvent to evaporate. Locate the spots on the plate.
13. Results:
Principle Spot Secondary Spots Spots at origin
(Rf) (Rf) or solvent front
Lane 1: Standard
0.30 None None
solution 1
Lane 2: Standard
0.30 None None
solution 2
Lane 3: Standard
0.30 None None
solution 3

3. Validation Results
a. Assay
i. Precision and Accuracy
1. 7 independent solutions 6 compared to first
2. Acceptable Criteria: NLT 0.95 (Probability)
3. Calculated probability: 1.00 (Passes)
a. Mean = 100.06
b. Standard Deviation = 0.13
c. % RSD = 0.13
d. Lower = 98.0, Upper =102.0%

Table 1: Precision and Accuracy

Weight of the
Solution Area Area Average % Assay (or)
sample taken
name Response Response Area % Recovery
(mg)
1 20.21 5466888 5475977 5471433 100.00
2 20.22 5484102 5462881 5473492 99.99
3 20.23 5480265 5481213 5480739 100.07
4 20.2 5480803 5481057 5480930 100.22
5 20.23 5479536 5476963 5478250 100.03
6 20.22 5483460 5491669 5487565 100.25
7 20.23 5498282 5443809 5471046 99.89

Domperidone Maleate Summary Validation Report—Page 3 of 19

ii. Intermediate Precision

Table 2 – Assay Ruggedness – Data Summary

Standard
Mean (%) % RSD Probability
deviation
Day 1 100.06 0.13 0.13 1.00
Day 2 100.31 0.19 0.19 1.00
Day 3 100.71 0.38 0.38 1.00
Combined 100.36 0.37 0.37 1.00

4. Day 2 & 3 – Assay Intermediate Precision

Table 3 - Ruggedness (Day 2)

Solution Weight of the Response Response Average

% Assay
name sample (mg) Inj. 1 Inj. 2 response

1 20.42 5552069 5511222 5531646 100.00

2 20.10 5410441 5496114 5453278 100.15

3 20.23 5506069 5501629 5503849 100.43

4 20.20 5494575 5499950 5497263 100.46

5 20.23 5491797 5491658 5491728 100.21

6 20.21 5498922 5505727 5502325 100.50

7 20.21 5488186 5509719 5498953 100.44

Table 4 - Ruggedness (Day 3)

Solution Weight of the Response Response Average

% Assay
name sample (mg) Inj. 1 Inj. 2 response

1 20.24 5530207 5462234 5496221 100.00

2 20.23 5511622 5529038 5520330 100.49

3 20.25 5527492 5538262 5532877 100.62

4 20.25 5536127 5564331 5550229 100.93

5 20.23 5541531 5551289 5546410 100.96

6 20.23 5544385 5547115 5545750 100.95

7 20.24 5553720 5554408 5554064 101.05

Domperidone Maleate Summary Validation Report—Page 4 of 19

iii. Specificity
1. Acceptable criteria: resolution of NLT 1.5 from primary peak
2. The degradation conditions applied:
a. Acid: 1 N HCl, reflux at 80°C for 15 min
b. Base: 1 N NaOH, reflux at 80°C for 30 min
c. Peroxide: 3% peroxide, reflux at 80°C for 15 min
d. Thermal: At 105°C for 65 hr
e. UV degradation: Solid and solution were exposed for 65 hr
f. Fluorescent: Solid and solution were exposed for 65 hr
g. Ultrasonic: At 25°C for 1 hr

Table 5 - Specificity – Impurities

Relative
Impurity Peak Area (%
Retention Time Degradation Route/Source
Descriptor TDA)
(UV)
Unknown 0.14 3.33 Acid
Unknown 0.21 0.18 UV solid
Unknown 0.23 0.85 UV solid
0.07, 0.13, 0.05,
Acid, Base, Thermal, UV solid, UV
Impurity A 0.26 0.04, 0.46, 0.05,
solution, Fluorescent solid, Sample
0.01
Unknown 0.30 0.04 Sample
0.77, 70.65, 0.06, UV solution, Peroxide, Fluorescent
Impurity C 0.33
0.01 solution, Sample
Unknown 0.36 0.13 UV solution
0.06, 8.13, 0.13, Fluorescent solution, Peroxide, UV
Impurity B 0.38
0.01 solution, Sample
Unknown 0.44 0.18 UV solution
UV solid, UV solution, Fluorescent
Unknown 0.54 0.09, 8.03, 0.96
solution
Unknown 0.83 0.15 UV solution
Unknown 0.88 0.03 Sample
Unknown 1.09 0.01 Sample
Unknown 1.35 0.01 Sample
Unknown 1.49 0.09 Fluorescent solution
Unknown 1.50 1.12 UV solution
Unknown 1.68 0.19 UV solution
Unknown 1.84 0.06 Ultrasonication
Unknown 1.85 0.01 Sample
0.07, 0.08, 0.06, Acid, Base, Thermal, UV solid,
Impurity D 1.87
0.06, 0.06 Fluorescent solid
Unknown 1.93 0.19 UV solution
Unknown 2.02 0.17 UV solution
Unknown 2.09 0.12 UV solution
Impurity F 2.22 - -
Unknown 2.39 0.04 Sample
Unknown 2.42 0.02 Sample

Domperidone Maleate Summary Validation Report—Page 5 of 19

 iv. Range
1. Acceptable criteria: NLT 0.95 (Probabiliy over 80-120%)
a. 80% - 1.00 (Pass)
b. 90% - 1.00 (Pass)
c. 100% - 1.00 (Pass)
d. 110% - 1.00 (Pass)
e. 120% - 1.00 (Pass)

Table 6 – Assay Range

Linearit Weight of Mean
So Injection Injection %
y level sample Average Recovery % Assay
l’n 1 2 RSD
(%) (mg) (%)
1 16.19 4453072 4446918 4449995 100.53
2 16.21 4438986 4438832 4438909 100.15
3 16.21 4494537 4511120 4502829 101.59
80 100.36 0.70
4 16.22 4390196 4432165 4411181 99.47
5 16.20 4436860 4440633 4438747 100.21
6 16.21 4445964 4435194 4440579 100.19
1 18.24 4972924 4981767 4977346 99.74
2 18.23 4972631 5006571 4989601 100.04
3 18.22 4955286 4942984 4949135 99.29
90 99.64 0.35
4 18.22 4962325 4996161 4979243 99.89
5 18.21 4967272 4969117 4968195 99.72
6 18.21 4962181 4914641 4938411 99.13
1 20.24 5530207 5462234 5496221 99.21
2 20.23 5511622 5529038 5520330 99.69
3 20.25 5527492 5538262 5532877 99.82
100 99.86 0.37
4 20.25 5536127 5564331 5550229 100.13
5 20.23 5541531 5551289 5546410 100.16
6 20.23 5544385 5547115 5545750 100.15
1 22.27 6052756 6117822 6085289 99.79
2 22.25 6102427 6105344 6103886 100.18
3 22.24 6096125 6099628 6097877 100.13
110 100.11 0.66
4 22.26 6132360 6129157 6130759 100.57
5 22.27 6041655 6038104 6039880 99.04
6 22.26 6151991 6154770 6153381 100.94
1 24.27 6667853 6680848 6674351 100.39
2 24.29 6654507 6569726 6612117 99.38
3 24.28 6656247 6663601 6659924 100.13
120 100.05 0.36
4 24.28 6646852 6653283 6650068 99.98
5 24.28 6651454 6667282 6659368 100.12
6 24.31 6688471 6671462 6679967 100.31

b. Impurity Procedures:
On hold until Impurity A-F are available

Domperidone Maleate Summary Validation Report—Page 6 of 19

 c. Reference Procedure Characterization
i. Domperidone Maleate – Diluent

ii. Domperidone Maleate – Total Ion Count

Domperidone Maleate Summary Validation Report—Page 7 of 19

iii. Domperidone Maleate – MS Spectra (At RT 18.67)

iv. Domperidone Maleate – MS Spectra (At RT 2.48)

Domperidone Maleate Summary Validation Report—Page 8 of 19

v. Domperidon Maleate – Peak Identification solution

vi. Domperidone Maleate – Sample Solution (1.0 mg/mL)

Domperidone Maleate Summary Validation Report—Page 9 of 19

vii. Domperidone Maleate – Total Ion Count

viii. Domperidone Maleate – System suitability solution MS Spectra (Impurity A – RT 4.94 )

Domperidone Maleate Summary Validation Report—Page 10 of 19

 ix. Domperidone Maleate – System suitability solution MS Spectra (Impurity C - RT 6.31)

x. Domperidone Maleate – System suitability solution MS Spectra (Impurity B – RT 7.23)

Domperidone Maleate Summary Validation Report—Page 11 of 19

xi. Domperidone Maleate – System suitability solution MS Spectra (Droperidol – RT 26.10)

xii. Domperidone Maleate – System suitability solution MS Spectra (Impurity D – RT 35.02)

Domperidone Maleate Summary Validation Report—Page 12 of 19

xiii. Domperidone Maleate – System suitability solution MS Spectra (Impurity F – RT 40.46)

xiv. Peroxide degradation – Total Ion Count

Domperidone Maleate Summary Validation Report—Page 13 of 19

xv. Peroxide degradation – MS Spectra (Impurity C – RT 6.27)

xvi. Peroxide degradation – MS Spectra (At RT 7.20)

Domperidone Maleate Summary Validation Report—Page 14 of 19

xvii. Peroxide degradation – MS Spectra (Domperidone – RT 18.44)

xviii. Peroxide degradation – PDA Spectra

Domperidone Maleate Summary Validation Report—Page 15 of 19

xix. Photolytic degradation (UV Exposed Solution) – Total Ion Count

xx. Photolytic degradation (UV Exposed Solution) – MS Spectra (At RT 10.16)

Domperidone Maleate Summary Validation Report—Page 16 of 19

xxi. Photolytic degradation (UV Exposed Solution)– MS Spectra (At RT 18.67)

xxii. Photolytic degradation (UV Exposed Solution)– PDA Spectra

Domperidone Maleate Summary Validation Report—Page 17 of 19

xxiii. HPTLC at 254 nm (on TLC Silica gel 60 F254S Aluminum sheet):

xxiv. HPTLC exposed to iodine chamber (on TLC Silica gel 60 F254S Aluminum sheet):

Domperidone Maleate Summary Validation Report—Page 18 of 19

c. Reference Material—Preliminary Characterization

i. IR Spectra

Domperidone Maleate Summary Validation Report—Page 19 of 19