Cetirizine HCL BP - TP

Common Technical Document
Cetirizine HCl BP
PRMF/CZ5/BP/12/06
April- 2022
TABLE OF CONTENT: MODULE - 3.2
3.2.S DRUG SUBSTANCE 1-254

3.2.S.1 General Information 2-18
3.2.S.1.1 Nomenclature 3-4
3.2.S.1.2 Structure 5-6
3.2.S.1.3 General properties 7-18
3.2.S.2 Manufacture 19-28

3.2.S.2.1 Manufacture (s) 20-21
3.2.S.2.2 Description of manufacturing process and process 22-28
control
3.2.S.3 Characterization 29-50

3.2.S.3.1 Elucidation of structure and other characteristics 30-44
3.2.S.3.2 Impurities 45-50
3.2.S.4 Control of Drug Substance 51-215

3.2.S.4.1 Specification 52-53
3.2.S.4.2 Analytical procedures 54-71
3.2.S.4.3 Validation of Analytical Procedures 72-209
3.2.S.4.4 Batch analysis 210-213
3.2.S.4.5 Justification of specification 214-215
3.2.S.4.5 Reference standards or materials 216-223
3.2.S.6 Container closure system 224-237
3.2.S.7 Stability 238-251

3.2.S.7.1 Stability summary and conclusions 239-242
3.2.S.7.2 Post Approval Stability Protocol and Stability 243-244
Commitment
3.2.S.7.3 Stability data 245-254
3.2.S
DRUG SUBSTANCE
1
3.2.8.1
GENERAL INFORMATION
2
3.2.8.1.1
NOMENCLATURE
3
NOMENCLATURE
BAN Cetirizine Hydrochloride
rINN Cetirizine Hydrochloride
USAN Cetirizine Hydrochloride
Ph. Eur. Cetirizine Di Hydrochloride
(Cetirizini Di Hydrochloridum)
Chemical Name (RS)-2-[2-[ 4-[(4-Chlorophenyl) phenyl methyl] piperazin-1-

yl]ethoxy] acetic acid dihydrochloride
CAS Number 83881-52-1
4
3.2.S.1.2
STRUCTURE
5
STRUCTURE
Ci
1 2 Hel
H
and enantiomer
CETIRIZINE DIHYDROCHLORIDE
Molecular Formula <=2IfI27<=13~2()3

Molecular Weight 461.8
6
3.2.S.1.3
. GENERAL PROPERTIES
7
GENERAL PROPERTIES
Characters A white or almost white powder, freely soluble in water, practically

insoluble in acetone and in methylene chloride.
Identification 1) The infrared absorption spectrum of sample and standard are

concordant.
2) It gives reaction (a) of chlorides.
pH 1.2 to 1.8
Hygroscopicity Non - Hygroscopic
Therapeutic function Histamine HI-receptor antagonist (Antihistaminic)
Polymorphism Ipca has done polymorphic study on three consecutive batches namely
200 I CZ5RII, 2002CZ5RII & 2003CZ5RII. As per the results of
XRPD, FTIR analysis, all the three samples are consistent.
8
DATE-25-08-20J I
HYGROSCOPICITY-DATA
Name of the Product
Batch No.
Test Hygroscopicity
Conditions Temperature 25°C.:t IOC Relative humidity 80%
.:t2% for 24hrs as per Ep.5.0
Weight of empty vessel == 14.8780 gm
Weight of sample = I.OO73gm
Weighed of vessel + sample == 15.8853 gIn
Weight of vessel + sample = 15.8855gm

(After 24hrs)
Weight of incr~ed mass = O,OO02gm
% of Increased Mass == O.0002x 100

1.0073
= O.02%w/w
Result: - The above prod~ct is Non Hygroscopic
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"Date: 6/412012 Time: 5:23:07 PM File: celirizine Hydrochlorlde-2001 CZ5RU_20120404 [IPCA]
Peak List
Pos. [o2Th.] d-spacinq[A) Rel.Int. ['II Area[cts*o2Th.)
6.8786 12.84019 23.23 27.46
7.5359 11.72171 2.75 5.13
8.2693 10.68369 77.19 108.30
11.8875 7.43876 5.90 7.38
13.2226 6.69053 10.92 19.70
14.2334 6.21757 13.49 15.18
14.5800 6.07052 17.06 18.90
14.9586 5.91"773 14.53 18.55
15.1735 5.83439 8.52 12.95
16.6626 5.31618 3.48 18.07
17.2393 5.13963 20.29 23.42
17.7280 4.99903 1.12 21.19
18.2002 4.87038 77.97 97.37
18.7608 4.72610 91.33 131.33
19.0224 4.66168 17.62 22.65
20.8013 4.26687 27.08 60.81
21.8890 4.05724 11.34 23.39
22.2612 3.99023 9.39 26.61
23.1612 3.83718 53.31 81.88
23.9058 3.71931 78.14 135.99
24.5305 3.62600 52.43 150.44
25.0442 3.55278 100.00 247.53
25.5688 3.48106 19.95 39.40
26.0162 3.42220 21. 74 29.05
26.4222 3.37053 15.75 12.25
26.4408 3.36819 15.19 47.13
26.6467 3.34263 29.21 39.42
28.1084 3.17205 5.79 46.82
29.0161 3.07485 28.07 55.96
29.3773 3.03786 4.64 24.64
30.5830 2.92079 10.95 51. i3
30.9702 2.88514 15.11 34.68
31. 4732 2.84017 5.83 8.12
31.9232 2.80116 6.44 10.01
33.1385 2.70115 28.54 136.00
33.7097 2.65668 8.19 10.03
34.5309 2.59535 13.31 32.20
34.9127 2.56784 3.34 14.05
36.0763 2.48765 5.61 27.78
36.9925 2.42811 13.47 55.24
38.6017 2.33051 3.21 11. 49
40.3763 2.23208 2.43 46.71
42.3551 2.13226 7.83 36.14
43.1338 2,09555 3.18 8.63
45.0578 2.01044 2.79 42.77
~ __ ~~ __ ~~ __ ~_~=-~----~==~====~=='":i'1"'Of~1
11
Date: 4/4/2012 Time: 5:26:17 PM File: Cetirizine Hydrochloride-2002 CZ5RII 20120404 [IPCA]
Counts
Cetirizine Hydrochloride-2002 CZ5RII20 0404
- qj
":
1000
500
o
10 20 30 40
Position [02Theta]
Page: 1 of 1
12
Date: 4/4/2012 Time: 5:26:22 PM File: Cl:.tirizine Hydrochloride-2002 CZ5RII_20120404 [IPCA]
~ak'tAt
Pas. (°2Th .I d-spacing[AI Rel.Int. [tl Area [cttl*o2Th.]
6.6812 12.83531 29.49 32.64
7.5492 11.70099 3.32 5.36
8.2626 10.69233 88.18 116.88
11.8844 7.44067 7.57 'j.44
12.9842 6.81280 2.45 6.28
13.2245 6.68957 14 .22 17 .51
14.2288 6.21959 11.37 11.63
14.5752 6.07253 14.91 13.93
14.9556 5.91891 12.91 111.21
15.1809 5.83155 10.03 13.20
16.6179 5.33038 3.47 1.7.55
17.2372 5.14024 16.30 19.79
18.1961 4.87147 76.71 92.65
16.7610 4.72604 100.00 143.20
19.0222 4.66173 17.26 20.06
20.7953 4.26808 27.83 62.03
21.9097 4.05346 9.51 20.73
22.2375 3.99444 9.92 24.66
23.1603 3.83732 53.30 77.62
23.9121 3.71836 86.38 147.76
24.5430 3.62418 64.01 169.02
25.0294 3.55484 99.96 230.71
25.5167 3.48805 13.75 114. 07
26.0186 3.42189 18.57 13.81
26.4144 3.37150 13.71 8.99
26.6493 3.34232 32.04 55.53
27.9897 3.18523 5.55 6.69
28.2533 3.15610 3.89 51.21
29.0214 3.07430 28.89 59.52
29.5033 3.02517 !i.50 7.38
30.f.i3f.iJ 2.92526 '11.f.ifl 48.76
30.9590 2.88616 13.14 32.51
]1.4649 2.84091 4.69 5.11
31.8871 2.80425 5.07 6.97
33.107~, /.70358 32.22 130.89
33.5681 2.667% 9.21 25.74
34.5395 2.59473 14.05 40.80
]6.0521 2.40926 5.65 23.05
36.9695 2.12957 11.15 59.18
38.6184 ~.32954 ::.11 10.81
40.1674 2.24320 2.17 5~.~€
"2.3434 2.13283 7.93 ;/.58
13.0860 2.09777 3. ::'0 6.10
4". fJ791 ~.Q09!:;4 .3.~;8 .~a_~;~
1 Of 1
13
Date: 4/4/2012 Time: 5:48:49 PM File: Cetirizine Hydrochloride-2003 CZ5RlI 20120404 [iPeAl
Counts
Celirizine Hydrochloride-2003 CZ5RIL20 0404
I
1000 E:-- !
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Position [02Theta]
Pagl~: 1 of 1
14
Da~: 4f4~2012Time: 5:48:57 PM File: 'Celirizine Hydrochloride.2003 CZ5RIC20120404 [IPCA)
Peak List
Pos. [02Th.) d-spacing[AJ Rel.Int.[t-J AT.e~[cts*o2Th.J .
6.6970 1Z.8050~ 29.66 35.75
7.5447 11.70803 3.50 5.20
0 ..2574 10.69902 02 ..99 117.30
11. 9003 7.13080 7. g.l 10.02
U.:':>41i f..foR"!iO 1~.;:;q '1 . .:1 F.
14.2330 6.21773 11. 05 13. '18
14.5743 6.07290 13.89 15.43
14.9~,81 5.917,.1 12.72 17 ..
39
15.1587 ~ ..
81006 9 .. 12 11.59
H ..f.?F.O :•.::;?7Rl :i. /.~l 17. R{l
17.2520 5.13588 15.75 20.10
18.2011 4.87014 56.90 8'}.90
10.7631 4.72552 100.00 156.79
19.0103 1.66'16'i 16.8:- Hl.02
'0.7(:1::\ 4.:'f.R'W ~4_ 79 ~:1.qJl
21.9151 1.05216 10.71 2iJ.::i6
22.1986 4.00134 11.30 26.63
23.1733 3.03520 40.73 76.0?
23.9286 :;.71582 83.68 119.00
7.4.:,1lP.4 .~.F.17IiO F.4.r;q lW;.!i9
25.0169 3.55658 93.27 208.09
25.4526 3.49669 13.40 146.62
26.0247 3.42110 20.17 1..
;'':3
26.6122 3.31320 29.i/i 59.50
?7 .'14.17 3 ..1 Qn'i1 ~.74 n.~
;:f..
;:;6.6947 3.06750 10.69 38.21
29.0380 3.07250 35.59 38.44
~9.5040 3.02510 4.95 ;.34
30.16H 2.93156 9.87 1/~. 2.3
::lO.CJ4n ?.RR70F. 11.7F. 1:: .:)4
31. 4836 2.83926 5.06 5.46
31.9086 2.80241 4.62 7.32
3J .1404 2.70100 30.72 14].58
31.3375 2.60953 1.£2 22.18
14.r,701 ;>. :,QF.14 "I:; .sa 79.7.:'1
34.n22 2.56788 ';.38 ].05
35.9860 2.49368 5.61 27.24
36.9053 2.43365 10.2(l 67.19
39.5995 2.33063 1.12 16.91
40.;>:~4) ,. ,.')Qf11 ).01 r:;O.n::
12.3783 2.13115 8 . 9f~ 39.79
4.r"J. :1"' fi.1 i . qg9:11 :~ . /..'i 4<).91
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15
Date: 4/17/2012
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REF4000 80.162000 66.09 600

3918.66 80.98 3854.55 84.59 3787.30 84.66 3705.40 84.42 3645.23 83.23
3459.42 76.40 3043.78 20.68 2985.57 17.63 2950.07 18.31 2628.80 22.36
2362.58 8.56 1956.44 59.51 1907.76 61.07 1774.02 36.28 1740.99 7.59
1598.6444.82 1574.81 48.38 1495.99 20.98 1456.58 17.56 1434.90 17.02
1383.56 14.80 1357.07 13.52 1320.05 10.52 1284.91 27.67 1274.61 27.49
1263.53 22.41 1242.5635.58 1186.55 19.52 1137.52 11.06 1114.5630.71
1092.36 18.17 1076.8628.95 1055.5022.22 1030.8024.83 1018.87 19.90
961.47 31.78 946.79 36.07 921.14 17.56 887.95 48.00 867.21 37.29
845.91 19.85 808.85 18.86 782.51 38.04 758.46 18.21 720.06 26.01
699.16 19.26 648.82 30.64 620.80 27.37 611.20 37.73 592.88 41.87
557.5I 39.00 535.82 23.87 503.08 32.59 484.71 42.40 454.39 57.25
16
Date: 4/17/2012
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170420-3.SP 3551 4000.00 450.00 8.76 85.42 4.00 %R 8 2.00
REF4000 78.572000 66.65 600

3918.57 79.56 3798.98 82.29 3646.95 79.93 3567.90 81.11 3537.51 80.11
3460.21 72.54 3044.87 22.04 3024.33 22.46 2985.45 18.13 2951.56 19.08
2626.70 23.73 2361.99 10.50 1956.37 60.90 1909.11 62.21 1773.70 38.17
1741.10 8.75 1599.31 47.75 1574.61 51.47 1496.13 23.33 1456.90 19.01
1434.86 19.28 1383.66 17.01 1357.01 15.77 1319.79 11.69 1284.91 30.66
1274.4530.47 1263.5425.17 1242.46 39.34 1186.0721.88 1137.40 13.38
1114.09 34.46 1092.20 21.64 1077.10 31.91 J055.50 25.70 1030.73 27.88
1018.89 22.74 961.65 35.58 946.52 39.39 920.88 20.11 888.00 51.38
867.33 41.36 845.9J 22.85 808.83 21.08 782.45 42.58 758.50 21.98
720.14 30.80699.42 23.70648.71 37.36620.89 31.60611.10 42.88
592.76 46.74 557.10 44.47 535.56 28.50 503.27 39.55 484.67 48.83
17
Date: 4/17/2012
87.4
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75
70
65
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170420-I.SP 3551 4000.00 450.00 7.04 87.43 4.00 %R 8 2.00
REF400080.342000 65.17600
3918.34 80.00 3853.92 82.66 3802.13 82.78 3741.07 83.75 3679.23 85.06
3644.72 81.89 3566.82 84.20 3460,62 74.86 3043.37 19.19 2984.12 16.35
2952.88 16.57 2630.72 2J.27 2381.77 9.26 1956.05 58.89 1907.40 60.45
1773.46 34.56 1741.17 7,03 1599.04 42.90 1574.31 47.79 1496.13 20.37
1456.44 16.44 1435.07 15.90 1383.65 14.17 1357.26 13.14 1320.16 9.63
1284,7426.66 1274.18 25.12 1263,69 21.30 1242.13 34.01 1185.67 18.30
1137.459,75 II 14.76 29.92 1092.07 17.99 1077.07 27.57 1055.31 22.12
1030.7123.80 1018.97 19.27 961.50 31.77 946.55 35.26 921.06 17.40
887.62 45.83 867.25 37.10 845.97 19.58 808.74 18.01 782.49 36.oJ
758.46 18.17 730.73 46.26 720.17 26.51 699.25 18.26649.03 31.71
620.86 27.36 611.15 35.57 591.76 41.45 557.67 38.01 535.70 23.27
503.32 30.26 484.41 42.06 462.77 60.63
18
3.2.S.2
MANUFACTURE
19
3.2.S.2.1
MANUFACTURE(S)
20
NAME & ADDRESS OF MANUFACTURER AND MANUFACTURING SITE
Manufacturing Facility
Ipca Laboratories Limited
Sejavta, District Ratlam (Madhya Pradesh)
Pin: 457 002, India.
Phone Nos : +91-7412-278259
Fax Nos : +91-7412-279083
Headquarters & Registered Office

48, Kandivli Industrial Estate,
Kandivli (West), Mumbai 400 067,
Maharashtra India
Phone: +91 22 – 6210 5047
Email: prema.vinodkumar@ipca.com
Name & address of DMF holder

48, Kandivli Industrial Estate,
Kandivli (West), Mumbai 400 067,
Maharashtra India
Phone: +91 22 – 6210 5047
Email: prema.vinodkumar@ipca.com
21
3.2.S.2.2
DESCRIPTIONOFMANUFACTURING
PROCESS
ANDPROCESSCONTROL
S
22
CHEMICAL REACTION
SEQUENCE
23
24
25
MATERIAL FLOW CHART
26
27
28
3.2.8.3
CHARACTERIZATION
29
3.2.S.3.1
ELUCIDATION OF
STRUCTURE AND OTHER CHARACTERISTICS
30
ELUCIDATION OF STRUCTURE AND OTHER CHARACTERISTICS
Structure elucidation studies have been performed on Batch No. 2001CZ5RII of Cetirizine
Dihydrochloride for IR, NMR and Mass. A summary of the analysis undertaken to confirm the structure
is provided below:
Infrared absorption
The Infrared spectrum of the sample i.e. Cetirizine Dihydrochloride Batch No. 2001CZ5RII and
corresponding Working Standard Batch No. 1023CZRII which was compared with USP Reference
Standard NO.FOG124 over a range from about 4000cm-l. The Infrared spectrum of the sample
concordant to that of working standard and reference standard.
NMRSpectra
The Proton spectrum of Cetirizine Dihydrochloride Batch No. 2001CZ5RII was recorded on Bruker
400MHz in DMSO-d6 solvent. The Proton spectral assignment is concordant to structure of Cetirizine
Hydrochloride
Mass Spectra
Mass spectra of Cetirizine Dihydrochloride Batch No. 2001CZ5RIII were performed. Mass spectra of
above batches were recorded on Micro mass instrument. Mass value is expressed as rnlz. Cetirizine
Hydrochloride give molecular ion peak at rnlz 388.9.
Conclusion
The results from the various physicochemical techniques used, confirmed the structure of Cetirizine
Dihydrochloride.
31
I.R. ABSORPTION
32
INFRARED ABSORPTION
The Infrared spectrum of the sample i.e. Cetirizine Dihydrochloride Batch No. 200lCZ5RII and
corresponding Working Standard Batch No. 1023CZRII which was compared with USP Reference
Standard NO.FOG124 over a range from about 4000cm-1• The Infrared spectrum of the sample
concordant to that of working standard and reference standard.
The Infrared spectra of Cetirizine Dihydrochloride Batch No. 2001CZ5RII, Working Standard
I023CZRII are enclosed herewith.
33
QUALITY CONTROL DEPARTMENT date: 26//0212012
Ipca Laboratories Limited,Ratlam. time: IS:l91ndiaStandard Time

66.3
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2001 CZ5RII.U.sp - 26/02/2012 - CETIZINE DI HCL USP # 2001 CZ5RII :724/02
2001 CZ5RII.U.pk
2001 CZSRII.U.sp 3601 4000.00 400.00 15.24 61.85 4.00 %T 5 2.00

CETIZINEDI HCL USP # 2001 CZ5RII :724/02
REF 4000 22.46 2000 29.30 600
2948.23 17.75 2378.38 15.24 1740.41 15.27 1495.95 26.00 1435.02 24.21
1383.17 23.37 1356.29 22.43 1319.18 20.24 1263.08 28.41 1185.53 27.33
1136.83 22.81 1092.01 28.54 1055.06 31.10 1018.73 30.7~ 961.06 36.13
920.54 30.69 845.80 33.97 808.33 34.09 758.30 36.66 719.68 40.41
698.13 37.53 648.41 45.06 620.53 44.75 535.48 45.22 502.62 51.31
434.61 52.53
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-- 2001 CZSRII.U.sp - 26/02/2012 - CETIZINE DI HCL USP # 2001 CZSRII :724/02

. CETRIUSPWS.sp - 21/10/2011 - CETIRlZINE HYDROCHLORIDE USP WS # 1023CZRII : S~/lO
~~ fl2
AJ.tLYST r~D BY
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34
QUALITY CONTROL DEPARTMENT date: 21//1012011
Ipca Laboratories Limited,Ratlam. time: 12:28 India Standard Time

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CETRIUSPWS.sp 3601 4000.00 400.00 17.37 66.31 4.00 %T 1 2.00

CETIRIZINE HYDROCHLORIDE USP WS # 1023CZRII : 529/1 0
REF 4000 24.23200033.15600
2924.15 18.36 2383.50 18.01 1740.52 17.32 1495.82 30.52 1435.28 28.10
1383.05 28.26 1356.28 26.97 1319.26 24.79 1263.16 33.79 1185.31 32.73
1136.91 27.75 1092.00 33.93 1055.12 36.88 1018.71 35.88 961.11 42.60
920.58 37.34 845.87 41.27 808.42 41.15 758.39 43.16 719.91 46.63
698.45 44.61 648.67 51.33 620.67 51.20 535.56 51.48 434.90 58.40
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----:"'---'"
.-_"_'"
~ ~-.I/
'-~./ C-
_..--. - ; r-"v- .
"a. .
• ,'1
8.8
4000,0 3000 2000 1500 1000 400.0
em-l
-- CETRIUSPWS.sp - 21/10/2011 - CETIRlZINE HYDROCHLORIDE USP WS # 1023CZRII : 529110
CETRIUSPRS.sp - 21/10/201 I - CETIRIZINE HYDROCHLORIDE USP RS LOT-FOG124.:5}8~10lt'
ANALYST . ~\.
cr=... C!0'f-J CHECKED BY
ePl})O)1I
35
QUALITY CONTROL DEPARTMENT date: 21//10/2011
Ipea Laboratories Limited,Ratlam. time: 12:18 India Standard Time

60.0_
I
- 50
1,
40 i
%T" ,oJ
I
20r-'~~£
8.8_, - .. -.---. I ----..,..., ------.-, ------,.-------r----"
4000.0 3000 2000 1500 1000 400.0
em-}
- -. CETRIUSPRS.sp - 21/10/2011 - CETIRIZINE HYDROCHLORIDE USP RS LOT-FOG124:S28/

CETRIUSPRS.pk
CETRIUSPRS.sp 3601 4000.00 400.00 8.75 60.03 4.00 %T 1 2.00

CETIRIZINE HYDROCHLORIDE USP RS LOT-FOGI24:528/10
REF 400017.77200027.83600
2922.87 8.75 2365.04 13.54 1740.03 12.88 1495.84 24.86 1456.95 21.48
1382.70 22.60 1355.80 21.08 1318.95 19.59 1262.97 28.45 1185.45 26.89
1137.15 22.51 1091.66 28.00 1054.91 31.07 1018.40 29.46 961.12 37.58
920.34 30.63 866.96 40.81 845.63 35.08 808.10 34.89 758.18 37.11
719.77 40.84 698.12 38.27 648.17 46.50 620.24 45.79 535.52 45.31
502.82 51.40 434.60 53.41
.,pI /0 ~\"
~
ANALYST '1 CHECKED BY
36
NMRSPECTRA
37
NMRSPECTRA
The Proton spectrum ofCetirizine Hydrochloride Batch No. 2001CZ5RII was recorded on BRUKER
400MHz in DMSO-d6 solvent. The Proton spectral assignment is concordant to structure of
Cetirizine Hydrochloride.
The NMR spectra is enclosed which clearly confirms the sample namely Batch No. 2001CZ5RII is
38
IPCA LABORATORIES LIMITED
CRD, ANALYTICAL DIVISION
(NMR INTERPRETATION DATA)
Date: 24/0412012
Sample : Cetirizine HCI

Instrument : BRUKER 400MHz
Batch. No. : 2001CZSRII
Solvent : DMSO-d6
Experiment : 1H NMR
Structure.
c
CI 2HCI
Inter retation:
Chemical shift value (li/ppm)
3.344.08
5.52
7.32-7.90
11.62
# m- multiplet, s-singlet, Ar- Aromatic.
By the above data, it is confirmed to the structure ofCetirizme ReI.
Performed by: Approved bY~ V

Signature: ~ Signature: W/'
Name: Mr. Brajesh Sharma Name: Mr. Mukesh Gupta
39
CetlrlZlne HC) # 2001CZ5RII lH
:urrent Oata Parameters

'lAME Allrl0-2012
~~PNO 6
....•
e
n
n
LO
C>
C1l
co co
C> CO
Lf1 ..,.
I.'")
'Or ru C>
LO
'Or 'Or 'Or

co ~
LO
(T)
LO
'Or ru
l"1
co
l"1
C1l
CO
C>
OJ
CO
CO
,....
CO - -
co I""l
,.... ~
f"'l
0
Lf1
LO C\l
C> 0
Lf1 Ul
;)ROCNO 1
"' •....•.,.....T"""-,...." •.••••.•.••••.••••.. ,....., q I""l C"': rr"l (TI ru OJ C\l

=" - AOulSlllon Parameters
~\V~ \~// \V )ate_

TIme
INS'RIP..I
;)ROBHD 5 mm 6BD BB-1H
20120410
15.29
:,".4(-0
;)ULPROG Z9~0
10 65536
SOlvENl OMSO
NS 6
OS 4
SWH 99aO.040 Hz
FlORES O. 1522B3 HZ
A(l 3. 2B34036 sec
RG 143.7
OW 50 .100 usee
DE 6.00 usee
TE 300.0 I(
01 3.00000000sec
••••••• = CHANNF.l fj ===_11===

NUCI IH
PI l2 .15 usee
Pll 0.00 dB
5F01 400.1324710MHz
F2 - Processing parameters
Sl 32768
SF 400.1300000MHz
WOW EM
SSB 0
LB 0.30 Hz
GB 0
PC 1.00
lD NMR plot parameters

CX 20.00 em
CY B.OO em
FjP 15.509 ppm
.1 6205.77 Hz
F2P -0.654 pom
F2 -265.83 Hz
PPHCM 0.80669 ppm/em
HZCM 323.57965 Hz/em
I I . t I !r I I I I • '111''11 1 I 1I •.r', • I • I I • II I ~: , •• I rill' •I rI I I I f I " 1 I 11 I ii, f • I , I I • 1 I I II ,. 1 f I 1 I •• I I • I I I I : I r I tit I It' j , I 1 I I r! 1I , ttl I • I I : • I I • I I I I I • I 1 r I r I : I I I I I 1"1I I I I I I , . II I ~I I .
rmm tIl 1; 10 B f; .} 2 Q
40
MASS SPECTRA
41
MASS SPECTRA
Mass spectra of Cetirizine Hydrochloride Batch No. 2001CZ5RJII were performed. Mass spectra of
above batches were recorded on Micro mass Q-T of instrument. Mass value is expressed as m/z.
Cetirizine Hydrochloride give molecular ion peak at m/z 388.9.
The Mass spectra is enclosed which clearly confirms the sample namely Batch No. 2001CZ5RII is
42
CRD ANALYTICAL DIVISION
RATLAM
Interpretation of Mass Spectrum CETIRIZINE _DI_ HCL
Batch No. : 2001 CZ5RII
Instrument : Micro mass

Type : Q-Tof
Ionization : ESI +ve Mode
----
m/z Assignment
388.9 (M+Ht Ion For 2001 CZ5RIJ
Structure of CETIRIZINE 01 HCL
CI
Monoisotopic Mass = 388.155371 Os
perf°711Y Approved By
GoJ~
Reasearch Associate
R&D (Analytical)
Pankaj Harnol
Asst. Manager
R&D (Analytical)
Date: 30/04/12
43
.27~Apr~20t'
t'1:34:2
27-04-2012 CETRIZINE_DCHCL_2001 CZ5RII7 (0.121) em (1:55)
TOFMS ES+
100 388.9623
4.83e5
.
I
I
1389.9739
'/
*'1 V.
b
j1391.0060
~/
I .1
,.
I .:.
il
I .1
I
I
i
~I
I! 1!
'I
j'
;201.3146 ~
, 'i3~2.0203
1 ..
0-._ _._ . - .. -. ----. _...:.w._--: __ .__ .__ -.--.- ....---. -.. ,---'_ ._.. ----m/z
200 225 250 275 300 325 350 37 400 425 450 475 500 525 550 575 600 625 6S0 675 700
44
3.2.S.3.2
IMPURITIES
45
IMPURITY PROFILE
46
IMPURITY PROFILE
I mpurity specifications are as per BP monograph and inhouse Validated method as follows:
Related substance by HPLC
Impurity A : NMT 0.15%

Impurity B : NMT 0.15%
Impurity C : NMT 0.15%
Impurity D : NMT 0.15%
Impurity E : NMT 0.15%
Impurity F : NMT 0.15%
Any unspecified impurity : NMT 0.10%
Total Impurities :NMTO.30%
Inorganic Impurity
Inorganic impurities are controlled as per BP monograph as follows:
Sulphated Ash : NMT 0.2% w/w
47
RESIDUAL SOLVENT
48
RESIDUAL SOL VENTS
The Solvents used in the manufacturing process of Cetirizine Hydrochloride are Methanol, n-Hexane,
Toluene, Chloroform, Dimethyl Formamide, Ethyl Acetate, Methylene Dichloride & Acetone.
Methanol, n-Hexane, Toluene, Chloroform, Dimethyl Formamide, Ethyl Acetate & Methylene
Dichloride are found to be less than 10% of the ICH limit hence routine testing is not required. Solvent
Ethyl Acetate and Acetone being class III solvent is controlled by the test of Loss on Drying. Three
batch data is represented below.
Solvents ICH limit Batch No.
2001CZ5RII 2002CZ5RII 2003CZ5RII
NMT 3000 ppm ND ND 34 ppm

Methanol
NMT 290 ppm < 5 ppm ND ND

n-Hexane
NMT 890 ppm < 17.98 ppm ND < 45 ppm

toluene
NMT60ppm ND ND ND
Chloroform
NMT880ppm < 88.07 ppm ND ND

Dimethyl
Formamide
Ethyl Acetate NMT 5000 ppm ND ND ND
Methylene NMT600ppm < 65 ppm ND ND

Dichloride
NMT 5000 ppm 102 ppm 115 ppm 173 ppm

Acetone
Above data demonstrates that content of Class II solvents in final API is less than 10% specified limit,
hence routine testing of these solvents are not required. This is in line with CPMP/QWP/450/03 dated
10/2/05 titled Annex to CPMP/ICH/283/95 Impurities: Guidelines for Residual Solvents &
CVMP/VICH/502/99 Guideline on Impurities Residual solvent Annex I: Specifications for Class 1 &
Class 2 residual solvents in Active Substances. And Class III solvent Ethyl Acetate and Acetone
controlled by Loss on drying with limit NMT 0.5% w/w.
Analytical Method Validation report is provided in DMF Section 3.2.S.4.3. Validation of Analytical
Procedures.
49
RESIDUAL SOLVENTS
Benzene content
Benzene is not used in the manufacturing process of Cetirizine Dihydrochloride; however it may be a
possible impurity in other solvent used. An in house GC method is developed and validated to detect
Benzene content in final API. Results of the same are tabulated below:
Batch Number Benzene Content
200lCZ5RII Not Detected
2002CZ5RII Not Detected
2003CZ5RII Not Detected
Limit of Detection O.lOppm
Limit of Quantitation 0.20ppm
In line with CPMP/QWP/450/03 dated 10.02.2005 titled Annex to CPMP/ICH/283/95 Impurities:

guideline for residual solvents and CVMPNICH/502/99 Guideline on Impurities: Residual Solvents
Annex I: Specifications for Class I and Class 2 Residual Solvents in active Substances, the data on three
batches indicates that benzene is not detected hence routine testing is not required as it has been
demonstrated that this solvent is less than 30% ofICH limit in the final Drug Substance.
Analytical method validation report for the same is provided in DMF Section 3.2.S.4.3 Validation of
Analytical Method.
50
3.2.8.4
CONTROL OF DRUG SUBSTANCE
51
3.2.8.4.1
SPECIFICATIONS
52
53
3.2.S.4.2
ANALYTICAL PROCEDURES
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
3.2.S.4.3
VALIDATION
OF
ANALYTICAL PROCEDURES
72
VALIDATION REPORT FOR
DETERMINATION OF RESIDUAL
SOLVENT
(METHANOL, METHYLENE CHLORIDE,
N- HEXANE, ETHYL ACETATE,
TOLUENE, ACETONE)
73
(lvea)
REPORT ON ANALYTICAL DEVELOPMENT AND VALIDATION FOR
RESIDUAL SOLVENT IN CETIRIZINE DIHYDROCHLORIDE (METHOD-1)
1. OBJECTIVE
To provide documented evidence of the suitability of the analytical method-1 for its
intended purpose of establishing the quality of Cetirizine Dihydrochloride with respect to
Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene.
2. SCOPE
This scope shall evaluate the acceptability of analytical method used for determination of
Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene in Cetirizine
Dihydrochloride by Gas chromatography analysis.
Following solvents are used:
Methanol
Acetone
Dichloromethane
n-Hexane
Ethyl acetate
Toluene
Chloroform
Ethylene Dichloride
Benzene
N,N-Dimethylformamide
Ethylene dichloride is used in raw material and Benzene is hidden solvent.

Hence the method-1 shall be designed to detect and quantify Methanol, Acetone,
Dichloromethane, n-Hexane, Ethyl acetate and Toluene in Cetirizine Dihydrochloride.
As per ICH guideline the classification of the above residual solvents and their
acceptable concentration in ppm are as below: -
Sr. No. Name of solvent Classification Specification Limit

1 Methanol Class-II NMT3000 m
2 Acetone Class-III NMT5000 m
3 Dichloromethane Class-II NMT600p m
4 n-Hexane Class-II NMT290 m
5 Eth I acetate Class-III NMT5000 m
6 Toluene Class-II NMT890 m
The protocol shall define the procedure, documentation, references and acceptance
criteria to be used in method of Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl
acetate and Toluene in Cetirizine Dihydrochloride by Gas chromatography analysis.
74
(Ipc~
RESIDUAL SOLVENT IN CETIRIZINE DIHYDROCHLORIDE (METHOD-i)
3. PROCEDURE
3.1 SELECTION OF ANALYTICAL PERFORMANCE PARAMETER
As per the cGMP regulation guidelines, the test method, which is used for assessing the
quality of pharmaceutical product with established specification, must be validated for
analytical performance parameters described in the USP 29 under section 1225" (i.e.
llvalidation of compendial method") and! or ICH (028) guideline for "Validation of
analytical procedure: methodology"
The method for detection of Residual Solvents in Cetirizine Dihydrochloride is by Gas

chromatographic method hence it's validation is carried out for Precision, Accuracy,
Specificity, limit of detection, Limit of quantitation, Linearity & Range, Robustness and
Ruggedness.
3.2 REVALIDATION CRITERIA
The analytical method shall be revalidated for the following changes.
1. Change in the analytical procedure.
2. Change in the synthesis of the drug substance.
3. Change in the guidance documents.
75
REPORT ON ANAL vrlCAL DEVELOPMENT AND VALIDATION FO
'~pca)
4. PLAN OF STUDY
The validation of Residual Solvent (Methanol, Acetone, Dichloromethane, n-Hexane,
Ethyl acetate and Toluene) method of Cetirizine Dihydrochloride shall be carried out as
per the plan given below:
1. Identification of Residual solvents shall be carried out by injecting Diluent,

Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene.
2. System suitability shall be assessed by injecting six replicate injections of

Standard solution and calculating RT, RRT, Plate count, Tailing Factor,
Resolution and % RSD of replicate injection.
3. Specificity/selectivity of the method shall be established with respect to

interference study.
4. The Precision study of the analytical method shall be established by injecting six
replicate injections of Standard solution for injection precision and six replicate
injections of Test solution for result precision. (Acceptance criteria: % RSD NMT
10.00%)
5. Limit of Detection and Limit of Quantitation of Residual solvents (i.e. Methanol,

Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene) for the method
shall be established by injecting series of concentration up to lowest detectable
concentration. (Acceptance criteria: to detect minimum concentration of the
compounds for LOD and % RSD for LOa should not be more than 15.00%)
6. Precision, Accuracy and linearity curve of Residual solvent at LOQ level shall
be established.
7. Linearity and Range study shall be done at various concentration levels of

individual Residual solvent (i.e. Methanol, Acetone, Dichloromethane, n-Hexane,
Ethyl acetate and Toluene) using the proposed method. Linearity curve shall be
plotted for peak area response against concentration and correlation coefficient
shall be calculated using above data
(Acceptance criteria: correlation coefficient NLT 0.9800)
76
(Ipea)
8. Accuracy study of the method shall be done by spiking of the various

concentrations (i.e. 80%, 100%, 120% of the targeted concentration and LOQ
concentration) of Residual solvent (i.e. Methanol, Acetone, Dichloromethane. n-
Hexane, Ethyl acetate and Toluene) (Acceptance criteria: % Recovery should
be between 80% to 120%)
9. Ruggedness study shall be carried out in similar manner as described in precision

study, by different analyst, on different date, with different instrument, in different
laboratory w.r.t. Precision of injection repeatability and test results reproducibility.
10. Robustness study shall be carried out by deliberately change in flow and
temperature method parameter.
Three production batches of Cetirizine Dihydrochloride shall be studied for

Residual Solvent analysis of Cetirizine Dihydrochloride for data accumulation. by
using the given method.
The conclusion shall be drawn, after assessing the validation data of the above
studies, whether this method can be used for analysis of Residual Solvent for its
intended purpose of establishing the quality of Cetirizine Dihydrochloride.
CHM
(Officer -ARDL)
DATE: oq I Oi/ t"6
APPROVED BY
(Manager-ARDL)
DATE: M I Drlc5t.
77
(Ipea)
REPORT ON ANAL VTICAl DEVELOPMENT AND VALIDATION FOR
RESIDUAL SOLVENT IN CETIRIZINE DIHYDROCHlORIDE (METHOO-1)
5. ABSTRACT AND APPROVAL
Analytical method validation study was carried out for Residual solvents method-1
(Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene) by GC.
Identification of individual Residual Solvent was done with respect to RT by separately

analyzing Diluent, Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and
Toluene. RT was found 2.67 min. for Methanol, 4.20 min for Acetone, 4.93 min for
Dichloromethane, 5.70 min. for n-Hexane, 7.71 min. for Ethyl acetate and 12.65 min. for
Toluene. RRT was 0.16 for Methanol, 0.25 for Acetone, 0.29 for Dichloromethane, 0.34
for n-Hexane, 0.46 for Ethyl acetate and 0.75 for Toluene w.r.t. N,N-Dimethylacetamide.
System suitability was carried out by injecting six injections of Standard solution and
following system suitability parameters were observed.
Observed
Dichlor n- Specificati
Sr. System suitability Aceton Ethyl
Methan ometh Hexan Toluene on limit
No. parameter e acetate
01 ane e
RT (Retention 2.70 4.23 4.97 5.77 7.77 12.68 Infonnative
1
Time)
RRT (Relative 0.16 0.25 0.29 0.34 0.46 0.75 Infonnative
2 Retention Time)
20120.81 23027.61 15052.65 40348.19 163286.05 Infonnative
3 Plate count 22929.23
1.037 0.971 1.008 1.005 1.003 Infonnative

4 Tailing Factor 1.043
Between Acetone & Dichloromethane is 5.93 MLT2.0

5 Resolution
NMT
0.96 0.88 1.29 1.59 1.07 1.30
6 % RSD [n=6] 10.00%
Injection Precision study (Injection repeatability) for Residual Solvent i.e. Methanol,
Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene was carried out by
replicate analysis of six consecutive injections of Standard solution of Residual Solvent
(i.e. concentration of Methanol 300 ppm. Acetone 500 ppm, Dichloromethane 60 ppm, n-
Hexane 29 ppm, Ethyl acetate 500 ppm and Toluene 89 ppm). % RSD was calculated
and found 0.96% for Methanol, 0.88% for Acetone, 1.29% for Dichloromethane, 1.59%
for n-Hexane, 1.07% for Ethyl acetate and 1.30% for Toluene. This indicates that the
precision of the method is well within the limit of RSD NMT 10.00%.
Test precision study was also carried out for Residual Solvent of one the batch B. No.
PP5012CZRI of Cetirizine Dihydrochloride. % RSD of result of ppm content of Acetone
was found 6.11 %. Methanol, Dichloromethane. n-Hexane, Ethyl acetate and Toluene is
not detected. This is well within the acceptance limit of 15.00% RSD.
78
(Ipea)
Specificity/selectivity of the method was established by analyzing Diluent, Methanol,

Acetone, Dichloromethane, n-Hexane, Ethyl acetate, Toluene and Standard solution i.e.
mixture of Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene
was injected and all the solvents were found well separated from each other.
The Limit of detection values for Residual solvents, for above method were found to be
0.75 ppm for Methanol, 2.52 ppm for Acetone, 0.65 ppm for Dichloromethane, 0.03 ppm
for n-Hexane, 5.03 ppm for Ethyl acetate and 1.80 ppm for Toluene w.r.t. target
concentration (i.e. 7.52 ppm for Methanol, 25.19 ppm for Acetone, 6.48 ppm for
Dichloromethane, 0.29 ppm for n-Hexane, 50.28 ppm for Ethyl acetate and 17.98 ppm
for Toluene w.r.t. Test).
The limits of quantitation values for Residual solvents were found to be 3.01 ppm for
Methanol, 5.04 ppm for Acetone, 6.48 ppm for Dichloromethane, 0.58 ppm for n-Hexane,
10.06 ppm for Ethyl acetate and 4.50 ppm for Toluene w.r.t. target concentration (i.e.
30.09 ppm for Methanol, 50.37 ppm for Acetone, 64.80 ppm for Dichloromethane, 5.82
ppm for n-Hexane, 100.56 ppm for Ethyl acetate and 44.95 ppm for Toluene w.r,t. Test).
Linearity and Range study was conducted by analyzing the various concentration levels
of Residual Solvent i.e. Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate
and Toluene in the synthetic mixture solutions for the concentration range LOa to 150%
of the targeted concentrations (3.01 ppm to 451.35 ppm for Methanol, 5.04 ppm to
755.55 ppm for Acetone, 6.48 ppm to 77.76 ppm for Dichloromethane, 0.58 ppm to 43.65
ppm for n-Hexane, 10.06 ppm to 754.20 ppm for Ethyl acetate and 4.50 ppm to 134.85
ppm for Toluene). The Linearity curves were plotted for peak area responses of Methanol,
Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene against concentrations
of Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene and
correlation coefficient was found 0.9999 for Methanol, 0.9985 for Acetone, 0.9980 for
Dichloromethane, 0.9998 for n-Hexane, 0.9999 for Ethyl acetate and 0.9998 for Toluene.
(Acceptance criteria: correlation coefficient NL T 0.9800)
Accuracy study was carried out by spiking various known concentrations of Methanol,
Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene in Cetirizine
Dihydrochloride test sample and calculating the % Recovery of the same. Accuracy was
determined over the range of 80% to 120% cone. The results of accuracy study, in terms
of % Recovery, were found in the range of 98.74% to 100.63% for Methanol, 97.96% to
99.59% for Acetone, 99.05% to 102.72% for Dichloromethane, 97.21% to 99.57% for n-
Hexane, 98.25% to 100.18%for Ethyl acetate and 97.79% to 99.95% for Toluene. Result
were well within the acceptable limits 80% to 120%.
79
(Ipea)
Accuracy study at LOa level was carried out by spiking lowest quantiable concentration
of Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene in
Cetirizine Dihydrochloride test sample w.r.t. target concentration. The % Recovery was
found 100.66% for Methanol, 98.67% for Acetone, 106.94% for Dichloromethane,
102.87% for n-Hexane, 97.98% for Ethyl acetate and 102.69% for Toluene.
Precision at LOa level were carried out by replicate analysis of six consecutive injections
(i.e. 3.01 ppm for Methanol, 5.03 ppm for Acetone, 6.39 ppm for Dichloromethane, 0.58
ppm for n-Hexane, 10.05 ppm for Ethyl acetate and 4.46 ppm for Toluene w.r.t. target
concentration). The % RSD was found 9.83% for Methanol, 3.26% for Acetone, 11.28%
for Dichloromethane, 1.98% for n-Hexane, 6.24% for Ethyl acetate and 9.05% for
Toluene at above concentration (Acceptance criteria: % RSD is NMT 15.00%)
The Ruggedness of the method was established by analyzing Cetirizine Dihydrochloride

for Residual Solvents in similar manner as precision study, by different analysts, on
different dates, on different instruments in different laboratories W.r.t. Precision of
injection repeatability and test results reproducibility. The method was found to be
enough rugged under the acceptable limit.
The results of three consecutive batches of Cetirizine Dihydrochloride were studied for
Residual solvent analysis of Cetirizine Dihydrochloride for data accumulation by using
the same method.
The results are in excellent agreement within the acceptance criteria for Precision,
Linearity and Range, Accuracy study, Specificity, Limit of Detection and Limit of
Quantitation, Robustness and Ruggedness etc. Thus this analytical method is
considered as validated for its intended use to establish the method of a Residual
Solvent of Cetirizine Dihydrochloride with consistent results.
c1
CHECKED BY APP~
(Officer -ARDL) (Manager -ARDL)
DATE: ~31031 trb DATE: 0 If - 03- 0-6
80
Upca)
6. DETAIL METHOD AND PREPARATIONS FOR

DETERMINATION OF RESIDUAL SOLVENT IN CETIRIZINE
DIHYDROCHLORIDE
[Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene]
(i) Working standards/Reference samples used in the study
The following samples were used for the study as Standards.
Sr.
Name of Component Grade Make % Purity
No.
1 Methanol HPLC grade Merck 100%
2 Acetone GR grade Merck 100%
3 Dichloromethane Extra pure Merck 100%
4 n-Hexane HPLC grade Merck 99.2%
5 Ethyl acetate GR grade Merck 99.9%
6 Toluene GR grade Merck 100%
(ii) Regular production. batches of Cetirizine Dihydrochloride for data

accumulation study
Sr. No. Batch No.

1. PPOS011CZRI
2. PPOS012CZRI
3. PP05013CZRI
a) INSTRUMENT (USED FOR VALIDATION STUDY):
I GAS CHROMATOGRAPH Perkin Elmer Clarus 500

II AUTO SAMPLER TURBOMATRIX HS - 40
III INTEGRATOR TotalChrom Navigator
IV COLUMN RTX-624 Capillary column 30m x 0.53mm x 3.0Jjm
V DETECTOR Flame Ionization Detector
b) INSTRUMENT (USED FOR RUGGEDNESS STUDY):

IV COLUMN RTX-624 Capillary column 30m x 0.53mm x 3.0J,Lm
'.
81
(lpca)
c) CHROMATOGRAPHIC PARAMETERS:
Oven Temperature
RATE (OC/MIN) TEMPERATURE (OC) HOLD (MIN)

0.0 42 6
10 220 2
INJECTOR TEMPERA lURE 180°C

DETECTOR TEMPERATURE 240°C
CARRIER GAS Nitrogen
SPLIT RATIO 7:1
CARRIER GAS FLOW 3.0 psi
ATIENUATION -5 (2)
RANGE 1
Headspace Parameter
VIAL OVEN TEMPERATURE 100°C

NEEDLE TEMPERATURE 110°C
TRANSFERLINE TEMPERATURE 130°C
HEADSPACE CARRIER PRESSURE 15 psi
THERMOSTATING TIME 20 min.
PRESSURIZE TIME 2.5 min.
NEEDLE WITHDRAW TIME 0.2 min.
INJECTION VOLUME 0.22 ml (0.05 min.)
GC CYCLE TIME 40 min.
INJECTION MODE Volume
OPERATING MODE Constant
d) PREPARATION OF SOLUTIONS:
I) Preparation of Standard Stock solution

Weigh accurately about 300mg of Methanol, 500mg of Acetone, 60 mg of
Dichloromethane, 29 mg of n-Hexane, 500 mg of Ethyl acetate and 89 mg of
Toluene in 100 ml of volumetric flask containing about 50 ml of N,N-
Dimethylacetamide as diluent, mix and dilute up to mark with diluent. (i.e.
concentration of Methanol is 3000 ppm, Acetone is 5000 ppm, Dichloromethane
is 600 ppm, n-Hexane is 290 ppm Ethyl acetate is 5000 ppm and Toluene is
I
890 ppm)
II) Preparation of Standard solution

Take 10 ml of Standard stock solution in 100 ml volumetric flask and dilute with
diluent. {i.e. concentration of Methanol is 300 ppm, Acetone is 500 ppm,
82
(lpca)
REPORT ON ANALYTICAL DEVELOPMENTAND VALIDATION FOR
RESIDUAL SOLVENT IN CETIRIZINEDIHYDROCHLORIDE (METHOD-1)
Dichloromethane is 60 ppm, n-Hexane is 29 ppm , Ethyl acetate is 500 ppm and

Toluene is 89 ppm)
Transfer 5.0 ml of Standard solution in dry headspace vial and seal it properly.
III) System suitability

Same solution as described in Standard solution.
IV) Test solution

Weigh accurately about 0.5 g of sample in dry headspace vial and add 5 ml of
diluent
V) Diluent
N,N-Dimethylacetamide.
VII) System suitability parameter

1. Resolution between Acetone and Dichloromethane is not less than 2.0
2. % RSD of each solvent peak area in six replicate of Standard solution is not
more than 10.00%
Remark
1. Subtract the peak response corresponding to diluent peaks from the Standard
and Test solution.
e) SOLUTION PREPARATION FOR VALIDATION STUDY:
i) Preparation for Identification study
Further dilution Final conc. of

Name of components Wt. of solvent with diluent Solvent in ppm
(mI7ml)
300 mg-7100 ml 10-7100 300

Methanol
500 mg-7100 ml 10-7100 500
Acetone
60 mg-7100 ml 10-7100 60
Dichloromethane
29 mg-7100 ml 10-7100 29
n-Hexane
500 mg-71 00 ml 1007100 500
Ethyl acetate
89 mg7100 ml 1007100 89
Toluene
ii) Preparation for Injection precision [Injection Precision]

iii) Preparation for Test precision [Result Precision]

Same solution as described in Test solu
83
(Ipea)
REPORT ON ANALYTICAL DEVELOPMENTAND VALIDATION FOR
iv) Preparation for Accuracy study
a) Standard Solution-I:
Pipette out 8.0 ml of Standard Stock solution in 100 ml volumetric flask and make
up the volume with diluent. (for 80% Recovery)
b) Standard Solution-II:
Pipette out 10 ml of Standard Stock solution in 100 ml volumetric flask and make
c) Standard Solution-III:
Pipette out 12 ml of Standard Stock solution in 100 ml volumetric flask and make
Spiked cone. in ppm

Wt.of
Sr. Spike in HS vial Diehl
Levels sampl n- Ethyl
No. Meth Acet orom Tolue
e (g) Hexa aceta
anol one ethan ne
ne te
e
01 Parent sample 0.5 - - - - - - -

240 400 48 23.2 400 71.2
02 Test-1 (80% spiked) 0.5 5ml of Std. sol.-I
240 400 48 23.2 400 71.2

Test-2 (80% spiked) 0.5 5ml of Std 501.-1
240 400 48 23.2 400 71.2

Test-3 (80% spiked) 0.5 5ml of Std sol.-I
Test-1 (100% spiked) 0.5 5ml of Std soL-III 300 500 60 29 500 89
03
5ml of Std soL-III 300 SOD 60 29 500 89

Test-2 (100% spiked) 0.5
300 500 60 29 500 89

Test-3 (100% spiked) 0.5 5ml of Std soL-III
5ml of Std soL-III 360 600 72 34.8 600 106.8

04 Test-1 (120% spiked) 0.5
360 600 72 34.8 600 106.8

360 600 72 34.8 600 106.8

84
Opca)
RESIDUAL SOLVENT IN CETIRIZINE DIHYDROCHlORIDE (METHOD-1)
v) Preparation for Linearity, laD and LOQ study

Table -1 Dilutions preparation for LaD and LOQ (from std stock solution)
Concentration in ppm
Dilution No. Dilute from stock solution
DichIara n- Ethyl
Methanol Acetone Toluene
methane Hexane acetate
Dilution-1 (0.05%) 1ml ~100mI/0.5ml ~100ml 0.15 0.25 0.03 0.015 0.25 0.045
Dilution-2 (0.1%) 1ml ~100ml/1ml ~100ml 0.30 0.50 0.60 0.029 0.50 0.089
Dilution-3 (0.3%) 1ml 7100ml/3ml 7100ml 0.90 1.50 0.18 0.087 1.50 0.267
Dilution4 (0.5%) 1ml 7100ml/5ml 7100ml 1.50 2.50 0.30 0.15 2.50 0.45
Difution-5 (1.0%) 1ml 7100ml/10ml 7100ml 3.00 5.00 0.60 0.29 5.00 0.90
Dilution-6 (5.0%) 0.5m17100ml 15.00 25.00 3.00 1.45 25.00 4.45
Dilution-7 (10%) 1ml7100ml 30.00 50.00 6.00 2.90 50.00 8.90
Dilution-8 (30%) 3ml7100ml 90.00 150.00 18.00 8.70 150.00 26.70
Conc. =Concentration
Table -2 Dilutions preparation for Linearity (from std stock solution)
Dilution No. Dilute from Stock Concentration in ppm

solution
Methano DichIara n- Ethyl
Acetone Toluene
I methane Hexane acetate
Dilution-9 (50%) 5ml ~100ml 150.00 250.00 30.00 14.50 250.00 44.50
Dilution-10 (80%) 8ml7100ml 240.00 400.00 48.00 23.20 400.00 71.20
Dilution-11 (100%) 10ml ~100ml 300.00 500.00 60.00 29.00 500.00 89.00
DiJution-12 (120%) 12ml7100ml 360.00 600.00 72.00 34.80 600.00 106.80
DiJution-13 (150%) 15ml7100ml 450.00 750.00 90.00 43.50 750.00 133.50
Cone. = Concentration
VI) Preparation for Data Accumulation study

Same as described in Precision study
VII) Preparation for Ruggedness study
85
REPORT ON ANALYTICAL DEVELOPMENT AND VALIDATION FO
'HpcaJ
Calculation formula:
AT WS 10 5
% of Residual solvents = --x x-- x
AS 100 100 WT
= Weight of Test Solution in mg.

AT = Peak area response obtained from the Test solution WT
= Weight of Standard in mg.
AS = Mean peak area response obtained from the Standard WS
Solution
la)% Methanol= xl-

~oo
3 X
100S
X 5 X 10' = _ppm
Results: Methanol in ppm = ppm [Limit: NMT 3000ppm]
(b) % of Acetone = -- xL 3
~OO
X
-100f
X 5 XiII' = -ppm
Results: Acetone in ppm = ppm [Limit: NMT 5000ppm]
Ie) % of Diehloromethane= xL 3
~OO
X
100f
X 5 X 10' = -ppm
Results: Dichloromethane in ppm = ppm [Limit: NMT 600ppm]
(d) % n-Hexane =
Results: n-Hexane in ppm =
--xioo x ~x
-100f
ppm [Limit: NMT 290ppm]

5 X106 =-ppm
(e) % of Ethyl acetate = xL

~oo
X ~x
- .•oof
5 X 106 =-ppm
Results: Ethyl acetate in ppm:= -ppm [Limit: NMT 5000ppm]
(f)% of Toluene = _-xL x ~X 5 X 106 =-ppm

~oo 100f
Results: Toluene in ppm := - ppm [Limit: NMT 890ppm]
86
(lpeaJ
Specification Limit:
Methanol Not more than 3000 ppm
Acetone Not more than 5000 ppm
Dichloromethane Not more than 600 ppm
n-Hexane Not more than 290 ppm
Ethyl acetate Not more than 5000 ppm
Toluene Not more than 890 ppm
87
(Ipea)
7. IDENTIFICATION
Solutions were separately prepared, containing known concentrations of Methanol 300

ppm, Acetone 500 ppm, Dichloromethane 60 ppm, n-Hexane 29 ppm, Ethyl acetate 500
ppm and Toluene 89 ppm.
Table No. 7.1 represents data of Retention Times/Relative Retention Times of solvents.
The respective chromatograms of above study are enclosed herewith.
TABLE NO-7.1
IDENTIFICATION OF RESIDUAL SOLVENTS
Sr. Retention Time (RT) RRT

Name of Solvents Mean
No. 01 of 02 02 of 02
1. Methanol 2.67 2.66 2.67 0.16
2. Acetone 4.20 4.19 4.20 0.25
3. Dichloromethane 4.91 4.94 4.93 0.29
4. n-Hexane 5.71 5.68 5.70 0.34
5. Ethyl acetate 7.70 7.71 7.71 0.46
6. Toluene 12.64 12.65 12.65 0.75
7. N,N-Dimethylacetamide 16.91 16.91 16.91 1.00
REMARKS:
Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate, Toluene and N,N-
Dimethylacetamide peaks are well separated from each other.
~
PERFORMED BY
(Q1ficer- ARDL)
CHMBY
(Officer -ARDL)
DATE: \ l.-\ \ 0'1 o~ DATE: 11/tllo-G
88
(DpcaJ
8. STANDARD METHOD AND PREPARATIONS FOR

DETERMINATION OF RESIDUAL SOLVENTS IN
[METHANOL, ACETONE, DICHLOROMETHANE, N-HEXANE, ETHYL ACETATE
AND TOLUENE]
All the detected Residual solvents were found well separated by the above GC method.
(From six consecutive injections of Stand.ard solution)
Table No. 8.1 represents data of RT and RRT of Methanol, Acetone, Dichloromethane, n-
Hexane, Ethyl acetate, Toluene.
The respective chromatograms attached with precision study (Standard solution n = 6)
89
(Ipea)
8.1 SEPARATION OF METHANOL, ACETONE,

DICHLOROMETHANE, N-HEXANE, ETHYL ACETATE AND
TOLUENE BY RT/RRT W.R.T. N,N-DIMETHYLACETAMIDE
[Standard solution of Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and
Toluene in diluent]
TABLE NO - 8.1
Name of compound: Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate
and Toluene
DICHLORO ETHYL
INJ. METHANOL ACETONE METHANE N-HEXANE ACETATE TOLUENE
NO.
RT RRT RT RRT RT RRT RT RRT RT RRT RT RRT
10t6 2.73 0.16 4.26 0.25 5.01 0.29 5.82 0.34 7.81 0.46 12.71 0.75
20f6 2.71 0.16 4.24 0.25 4.98 0.29 5.79 0.34 7.78 0.46 12.70 0.75
30f6 2.70 0.16 4.23 0.25 4.97 0.29 5.77 0.34 7.77 0.46 12.69 0.75
4 ot6 2.70 0.16 4.23 0.25 4.97 0.29 5.77 0.34 7.77 0.46 12.69 0.75
50f6 2.70 0.16 4.23 0.25 4.97 0.29 5.77 0.34 7.77 0.46 12.68 0.75
60f6 2.69 0.16 4.22 0.25 4.96 0.29 5.76 0.34 7.76 0.46 12.67 0.75
Mean 2.10 0.16 4.23 0.25 4.91 0.29 5.11 0.34 7.11 0.46 12.68 0.75
SO :t 0.007 0.000 0.007 0.000 0.007 0.000 0.007 0.000 0,007 0.000 0.007 0.000
%RSD 0.26 0.00 0.17 0.00 0.14 0.00 0.12 0.00 0.09 0.00 0.06 0.00
This data taken from six consecutive injections of Standard solution from Precision study.
4~
PERFORMED BY
~
CHECKED BY
(Officer-ARbL) (Officer -ARDL)
DATE: \\.\\Q\\~~ DATE: Itt 1~ {bt:,
90
REPORT ON ANAL vrlCAL DEVELOPMENT AND VALIDATION FOR
UpcaJ
8.2 SYSTEM SUITABiliTY
The System suitability of above method was carried out by calculating RRT, Plate count,
Tailing Factor and Resolution between Acetone & Dichloromethane and selecting the
acceptance limits.
Inject the Standard solution to check the system suitability parameters of

components.
The following system suitability requirements were assessed.
System suitability parameters:

Specification
Observed limit
System
Sr. Dichlor n-
suitability Ethyl
No. Methan Aceton Hexan Toluene Informative
parameter ometh acetate
01 e e
ane
RT (Retention 2.70 4.23 4.97 5.77 7.77 12.68 Informative
1
Time)
RRT (Relative
0.25 0.29 0.34 0.46 0.75 Informative
2 Retention 0.16
Time)
Plate count 22929.23 20120.81 23027.61 15052.65 40348.19 163286.05 Informative

3
Tailing Factor 1.043 1.037 0.971 1.ooB 1.005 1.003 Informative

4
5 Resolution Between Acetone & Dichloromethane is 5.93 NLT2.00
6 % RSD [n=6} 0.96 O.BB 1.29 1.59 1.07 1.30 NMT 10.00%
Table No. 8.2.1 to 8.2.5 represents data on system suitability parameter for six replicate
injections of Standard solution.
The respective chromatograms taken from Standard solution of Precision study are
enclosed herewith.
91
Table No. 8.2.1

SYSTEM SUITABILITY STUDY
(A) *RETENTION TIME [Rl] (in min)

Standard solution (Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene)
NUMBER OF INJECTION STATISTICAL ANAL YSIS

Name of components
I II III IV V VI MEAN SDt %RSD MIN. MAX.
Methanol 2.73 2.71 2.70 2.70 2.70 2.69 2.70 0.007 0.26 2.69 2.73
Acetone 4.26 4.24 4.23 4.23 4.23 4.22 4.23 0.007 0.17 4.22 4.26
Dichloromethane 5.01 4.98 4.97 4.97 4.97 4.96 4.97 0.007 0.14 4.96 5.01
n-Hexane 5.82 5.79 5.77 5.77 5.77 5.76 5.77 0.007 0.12 5.76 5.82
Ethyl acetate 7.81 7.78 7.77 7.77 7.77 7.76 7.77 0.007 0.09 7.76 7.81
Toluene 12.71 12.70 12.69 12.69 12.68 12.67 12.68 0.007 0.06 12.67 12.71
Six replicate injection data for system suitability taken from standard solution of Precision study.
*System suitability parameters by using software TotaiChrom.
REMARKS: The above results of system suitability parameters were found satisfactory and well within acceptable
range of system suitability requirements.
~
PERFORMED BY C~-Y-
(Officer ARDL) (Officer -ARDL)
DATE: \'-1\0\' bb DATE: l~I~I~
92
Table No. 8.2.2
SYSTEM SUITABiliTY STUDY
(B) *RELATIVE RETENTION TIME [RRT] (w.r.t. N, N-Dimethylacetamide)


Name of components
I II III IV V VI MEAN SD:t %RSD MIN. MAX.
Methanol 0.16 0.16 0.16 0.16 0.16 0.16 0.16 0.000 0.00 0.16 0.16
Acetone 0.25 0.25 0.25 0.25 0.25 0.25 0.25 0.000 0.00 0.25 0.25
n-Hexane 0.34 0.34 0.34 0.34 0.34 0.34 0.34 0.000 0.00 0.34 0.34
Ethyl acetate 0.46 0.46 0.46 0.46 0.46 0.46 0.46 0.000 0.00 0.46 0.46
Toluene 0.75 0.75 0.75 0.75 0.75 0.75 0.75 0.000 0.00 0.75 0.75
I
*Systemsuitability parameters by using software TotafChrom.
REMARKS: The above results of system suitability parameters of Residual Solvent were found satisfactory and
well within acceptable range of system suitability requirements.
~~
~
PERFORMEDBY CHECKED BY
(Officer ARDL) (Officer -ARDL)
DATE: \'-\\~\ \I:lG DATE: 1~llH'~
93
Table No. 8.2.3
(C) *PLATE COUNT

Name of NUMBER OF INJECTION STATISTICAL ANAL YSIS

components
I II III IV V VI MEAN SO:t %RSD MIN. MAX.
Methanol 23280.86 22822.23 22890.54 22545.32 23100.24 22936.19 22929.23 250.308 1.09 22545.32 23280.86
Acetone 20267.53 20194.80 20167.39 20203.60 20032.41 19859.11 20120.81 149.884 0.74 19859.11 20267.53
n-Hexane 15095.78 14930.50 14879.12 15231.15 15213.16 14966.17 15052.65 149.665 0.99 14879.12 15231.15
Ethyl acetate 42520.62 40919.49 39931.65 39943.78 39531.33 39242.28 40348.19 1206.083 2.99 39242.28 42520.62
Toluene 166975.06 165719.79 162668.75 164740.80 164033.27 155578.64 163286.05 4049.488
.. .. . .
2.48 155578.64 166975.06
SIXreplicate injection data for system sUitability taken from standard solution of PrecISion study .
"Systemsuitability parameters by using software TotalChrom.
REMARKS:The above results of system suitability parameters of Residual Solvent were found satisfactory and
~
PERFORMEDBY ~B-Y--
(Officer ARDL)
(Officer -ARDL)
DATE: \V\ 'ol\t> 6 DATE: 1-4Ib-f I~
94
Table No. 8.2.4
(D) *TAILING FACTOR

Standard solution (Methanol, Acetone. Dichloromethane, n-Hexane. Ethyl acetate and Toluene)

Name of components
I II III IV V VI MEAN SOt %RSD MIN. MAX.
Methanol 1.041 1.044 1.041 1.043 1.048 1.040 1.043 0.003 0.28 1.040 1.048
Acetone 1.041 1.032 1.033 1.036 1.039 1.040 1.037 0.004 0.36 1.032 1.041
n-Hexane 1.008 1.000 1.004 1.019 1.007 1.011 1.008 0.006 0.64 1.000 1.019
Ethyl acetate 1.000 1.011 1.008 1.006 1.005 0.998 1.005 0.005 0.49 0.998 1.011
Toluene 1.020 1.012 0.997 0.996 0.988 1.005 1.003 0.012 1.17
. . 0.988 1.020
. .
SIXreplicate Injection data for system suitability taken from standard solution of PrecIsIon study .
.System suitability parameters by using software TotalChrom.
~
PERFORMED BY
(Officer ARDL)
M
CHECKED BY
(Officer -ARDL)
DATE: \'1\0\\06 DATE: 14'61 I~
95
Table No. 8.2.5
(E) *RESOLUTION

Name of components
I III
Resolution between
" IV V VI MEAN SOt %RSD MIN. MAX.
Acetone and 5.94 5.93 5.96 5.94 5.88 5.92 5.93 0.026 0.44 5.88 5.96
Dichloromethane
*Systemsuitability parameters by using software TotalChrom.
~ ~
PERFORMED BY
CHECKED BY
(Officer ARDL)
(Officer -ARDL)
DATE: \'1 l()ll ~G
DATE: 1.it'~ I~
96
(lpcaJ
Table No. 8.2.6
SYSTEM SUITABILITY DATA AT A GLANCE
Mean Mean *Tailing %RSD

* Plate *Resolution
Components *RT *RRT factor (n=6)
counts
(Min)
Methanol 2.70 0.16 22929.23 1.043 0.96
4.23 0.25 20120.81 1.037 0.88

Acetone
Resolution
4.97 0.29 23027.61 0.971 Between 1.29
Dichloromethane
Acetone &
0.34 15052.65 1.008 Dichlorometh 1.59
n-Hexane 5.77
ane is 5.93
0.46 40348.19 1.005 1.07
Ethyl acetate 7.77
0.75 163286.05 1.003 1.30

Toluene 12.68
*Mean of six replicate injections. [RRTw.r.t. N,N-Dimethylacetamide]
Remarks: The above results of system suitability parameters was found satisfactory
and well within acceptable range of system suitability requirements.
C~BY
PERFORMEDBY
(Officer -ARDL)
(Officer-ARDL)
DATE: \\\\ ~\' 0 b DATE: r'-i I bit ot
97
(Ipea)
9. METHOD VALIDATION
"Validation of a method is the process by which a

method is tested by the developer or user for
reliability, accuracy and preciseness for its intended
purpose".
As per the cGMP regulation guidelines the test method, which are used for assessing
the quality of pharmaceutical products with established specifications, must be validated
for analytical performance parameters described in the USP28 under section 1225
"Validation of compendial method"
Typical analytical parameters used for method validation
9.1 Precision
9.2 Specificity
9.3 Limit of Detection
9.4 Limit of Quantitation
9.5 Linearity and range
9.6 Accuracy
9.7 Ruggedness
9.8 Robustness
98
(Ipc~
9.1 PRECISION STUDY

Precision study was carried out by injection precision and result precision, performing
the six consecutive injections of Standard solution and calculating % RSD of the peak
area response obtained due to Residual solvent i.e. Methanol, Acetone,
Dichloromethane, n-Hexane, Ethyl acetate and Toluene. Residual Solvent analysis of
Cetirizine Dihydrochloride was carried out to establish the result reproducibility by
replicate injections of the Test sample against the same Standard solution and
calculating %RSD of the peak response of the Residual solvent from replicate
injections.
From the above injection precision study it is evident that %RSD of peak areas for
Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene (for six
consecutive injections) was found 0.96%, 0.88%, 1.29%, 1.59%, 1.07% and 1.30%
respectively. This is well within the acceptance limit NMT 10.00% RSD.
From the Result precision study it is evident that Methanol, Dichloromethane, n-Hexane,
Ethyl acetate and Toluene was not detected but Acetone was detected in low level. This
is well within the acceptance limit NMT 15.00% RSD of result.
Table No. 9.1.1 represents the precision study data (injection precision) for peak areas
of Residual Solvent (i.e. Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate
and Toluene) in Standard solution.
Table No. 9.1.2 represents the precision study data of results of Residual solvent (i.e.
Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene) in
Cetirizine Dihydrochloride Test solution (result reproducibility).
The respective chromatograms of above studies are enclosed herewith.
PREPARATION OF SOLUTIONS FOR PRECISION STUDY:

Weigh accurately about 300mg (weighed 300.9 mg) of Methanol, 500mg (weighed
500.01 mg) of Acetone, 60 mg (weighed 64.4 mg) of Dichloromethane, 29 mg (weighed
29.1 mg) of n-Hexane, 500 mg (weighed 502.8 mg) of Ethyl acetate and 89 mg
(weighed 89.9 mg) of Toluene in 100 ml of volumetric flask containing about 50 ml of
N,N-Dimethylacetamide as diluent, mix and dilute up to mark with diluent.

Take 10 ml of Standard stock solution in 100 ml volumetric flask and dilute with diluent.

IV) Test solution

Weigh ac;curFJtely about 0.5 9 of sample in dry headspace vial ~nd add 5 ml of diluent
and seal it properly.
99
(Bpc~
TABLE NO- 9.1.1

PRECISION STUDY
(Injection Reproducibility)
Name of compounds: Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl

acetate and Toluene
INJ.NO. METHANOL ACETONE DICHLORO n-HEXANE ETHYL TOLUENE

METHANE ACETATE
1of6 533705 3135609 84930 1238562 1867281 328448
2 of6 524722 3104409 84132 1229462 1840550 325265
30f6 528734 3126375 85095 1236298 1859932 329501
4of6 536013 3162663 86567 1248980 1881403 331444
50f6 538649 3178843 87124 1281462 1898141 338133
6of6 534811 3120468 85708 1265239 1857922 331631
Mean 532772 3138061 85593 1250001 1867538 330737
SD :!: 5122.09 27759.60 1107.06 19816.70 20037.56 4306.04
%RSD 0.96 0.88 1.29 1.59 1.07 1.30
REMARKS: From the above injection precision study, it is evident that Relative
Standard Deviation of Peak area response of six consecutive injections for Methanol,
Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene were found 0.96%,
0.88%, 1.29%, 1.59%, 1.07% and 1.30% respectively. This is well within the acceptance
limit of % RSD NMT 10.00%.
~
PERFORMED BY
-%¥'f
CHECKED BY
(Officer-ARDL) (Officer -ARDL)
DATE: \'1\ O\'~b DATE: 14101)1)(.
100
(lpcaJ
TABLE NO- 9.1.2

PRECISION STUDY
(RESULTS PRECISION STUDY)
Standard solution containing Mean Area %RSD

Methanol 532772 0.96
Acetone 3138061 0.88
Dichloromethane 85593 1.29
n-Hexane 1250001 1.59
Ethyl acetate 1867538 1.07
Toluene 330737 1.30
Batch used for study PP5012CZRI
Area ppm Area Area ppm Area ppm
Weight of ppm Area ppm Area
Sr. of of of of of of of
sample of ofn- of of Tarue
No. Metha Metha Aceto Dichlo Dichlo Ethyl Ethyl
(mg) Aceto Hexan Hexan Tolue ne
nol nol ne romet romet acetat acetat
ne e e ne
hane hane e e
1 500.09 - NO 22601 36.27 - NO - NO - NO - NO
2 500.12 - NO 23204 37.24 - NO - NO -- NO - NO
3 500.02 - NO 22592 36.26 - NO - NO - NO - NO
4 500.26 - NO 26107 41.88 - NO - NO - NO - NO
5 500.23 - NO 25305 40.60 - NO - NO - NO - NO
6 500.13 - NO 23755 38.12 - NO - -
NO NO - NO
STATISTICAL ANAL YSIS

Mean - --- - 38.40 - - - - - - - -
SD - - - 2.34 - - - - -- - - -
%RSD - - - - - - -
6.11 - - - -
REMARKS:
The ppm content of Methanol, Dichloromethane, n-Hexane, Ethyl acetate and Toluene
was found not detected. % RSD of ppm content of Acetone is 6.11%. This is well within
the acceptance limit of 15.00% RSD.
s~
PERFORMED BY
(Officer-ARDL)
C:£OBY
(Officer -ARDL)
DATE: \ l-\ \ 0\ \ ob DATE: ll1Hrlf 8t
101
(Ipea)
9.2 SPECIFICITY STUDY
Specificity/selectivity of the method was established by analyzing Diluent, Methanol,

Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene separately. Standard
solution i.e. mixture of Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate
and Toluene was injected and all the solvents were found well separated from each
other.
Table 9.2.1 represent specificity/selectivity of the method for analysis of Residual

solvent in Cetirizine Dihydrochloride.
The respective chromatograms with Identification study are enclosed .
TABLE NO- 9.2.1
SPECIFICITY

Name of Solvents 02 of 02 Mean
No. 01 of 02
Methanol 2.67 2.66 2.67 0.16
1.
Acetone 4.20 4.19 4.20 0.25
2.
Dichloromethane 4.91 4.94 4.93 0.29
3.
4. n-Hexane 5.71 5.68 5.70 0.34
5. Ethyl acetate 7.70 7.71 7.71 0.46
6. Toluene 12.64 12.65 12.65 0.75
7. N,N-Dimethylacetamide 16.91 16.91 16.91 1.00
REMARKS:
Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene peaks

are well separated from each other and also from N,N-Dimethylacetamide peak.
~~ C~B-Y--
PERFORMED BY
(Officer -ARDL)
(Officer-ARDL)
DATE: \L1\\o\\{)O ATE: 1'-1I&! I~
102
(Ipea)
9.3 LIMIT OF DETECTION

The above study was conducted for establishing the limit of detection of Methanol,
Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene. LOD of the given
Residual solvents was determined by injecting replicates of synthetic mixture of
Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene having
different serial concentration levels.
The lowest detection response for Methanol, Acetone, Dichloromethane, n-Hexane,

Ethyl acetate and Toluene was established w.r.t. target concentration.
Table No. 9.3.1 to 9.3.6 represent the minimum detector response of Methanol,
Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene.
PREPARATION OF SOLUTIONS FOR LODI LOa STUDY:
Standard Stock solution:

Weigh accurately about 300 mg (weighed 300.9 mg) of Methanol, 500 mg (weighed
503.7 mg) of Acetone, 60 mg (weighed 64.8 mg) of Dichloromethane, 29 mg (weighed
29.1 mg) of n-Hexane, 500 mg (weighed 502.8 mg) of Ethyl acetate and 89 mg
(weighed 89.9 mg) of Toluene in 100 ml of volumetric flasks containing diluent, and
dissolve and dilute up to mark with diluent.
LOD/Loa solutions are prepared as follows:
150%Standard solution:
Pipette out 15 ml Standard stock solution into 100 ml volumetric flask dilute up to mark
with diluent.
with diluent.
with diluent.
80% Standard solution:

with diluent.

[@.ipette out 5 ml Standard stock solution into 100 ml volumetric flask dilute up to mark
.'with diluent.
103
(Hpca)

with diluent.

with diluent.
Pipette out 10 ml of 50% Standard solution into 100 ml volumetric flask dilute up to mark
with diluent.
with diluent.
with diluent.
0.5% Standard solution:

with diluent.

Pipette out 0.5 ml of 50% Standard solution into 100 ml volumetric flask dilute up to
mark with diluent.
Pipette out 10 ml of 0.5% Standard solution into 100 ml volumetric flask dilute up to
mark with diluent.

Pipette out 2 ml of 0.5% Standard solution into 100 ml volumetric flask dilute up to mark
with diluent.
104
(Ipea)
TABLE NO-9.3.1
LIMIT OF DETECTION STUDY

Limit of detection data for Methanol
Conc. of component
Sr. No. w.r.t. target conc. w.r.t. test sample REMARKS
ppm ppm
Dilution-1 (0.01%) 0.03 0.30 Not Detected
Dilution-3 (0.1%) 0.75 7.52 ~
Dilution-4 (0.5%) 1.50 15.05 ~
Dilution-5 (1.0%) 3.01 30.09 ~
Dilution-6 (2.0%) 6.02 60.18 ~
Dilution-7 (5.0%) 15.05 150.45 ~
Dilution-8 (10%) 30.09 300.90 ~
Dilution-9 (20%) 60.18 601.80 ~
Dilution-10 (50%) 150.45 1504.50 ~

Dilution-11 (80%) 240.72 2407.20 ~
Dilution-12 (100%) 300.90 3009.00 ~
Dilution-13 (120%) 361.08 3610.80 ~
Dilution-14 (150%) 451.35 4513.50 ~
~ = Detected
REMARKS: On the basis of above data the Limit of Detection for Methanol was found
0.75 ppm w.r.t. target concentration and 7.52 ppm w.r.t. Test solution. (Preliminary
observation)
~
p~y CHECKED BY
DATE: U5 to\ \.::>l:. DATE: f" 6 f1 tTl
105
(Ipca)
TABLE NO.9.3.2

Limit of detection data for Acetone
Conc. of component
Sf. No. REMARKS
W.f.t. target conc. w.r.t. test sample
ppm ppm
Dilution-4 (0.5%) 2.52 25.19 ~
Dilution-5 (1.0%) 5.04 50.37 ~
Dilution-6 (2.0%) 10.07 100.74 ~
Dilution-7 (5.0%) 25.19 251.85 ~
Dilution-8 (10%) 50.37 503.70 ~
Dilution-9 (20%) 100.74 1007.40 ~
Dilution-10 (50%) 251.85 2518.50 ~
Dilution-11 (80%) 402.96 4029.60 ~
Dilution-12 (100%) 503.70 5037.00 ~
Dilution-13 (120%) 604.44 6044.40 ~
Dilution-14 (150%) 755.55 7555.50 ~
v = Detected
REMARKS: On the basis of above data the Limit of Detection for Acetone was found
observation)
:2?~
PERFORMED BY
~
CHECKED BY
(Officer -ARDL)
(Officer-ARDL)
DATE: \6 \0\ \.~
DATE: t G \ &i l b-e
106
(Ipea)
TABLE NO-9.3.3

Limit of detection data for Dichloromethane
Conc. of component
Sr. No. REMARKS
w.r.t. target conc. w.r.t. test sample
ppm ppm

0.32 3.24 Not Detected
Dilution-4 (0.5%)
Dilution-5 (1.0%) 0.65 6.48 ~
Dilution-6 (2.0%) 1.30 12.96 ~
Dilution-7 (5.0%) 3.24 32.40 ~
Dilution-8 (10%) 6.48 64.80 ~
Dilution-9 (20%) 12.96 129.60 ~
Dilution-10 (50%) 32.40 324.00 ~
Dilution-11 (80%) 51.84 518.40 ~
Dilution-12 (100%) 64.80 648.00 ~
Dilution-13 (120%) 77.76 777.60 ~
Dilution-14 (150%) 97.20 972.00 ~
~ = Detected
REMARKS: On the basis of above data the Limit of Detection for Dichloromethane was
found 0.65 ppm w.r.t. target concentration and 6.48 ppm w.r.t. Test solution.
(Preliminary observation)
~
f'~ CHECKED BY
PERFORMED BY
(Officer -ARDL)
(Officer-ARDL)
DATE: \ bl e-t l frl,
DATE:\.6~0\ \0(,
107
(Ipea)
TABLE NO-9.3.4

Limit of detection data for n-Hexane
Cone. of component
Sr. No. REMARKS
w.r.t. target cone. w.r.t. test sample
ppm ppm
Dilution-1 (0.01 %)
Dilution-2 (0.05%)
Dilution-3 (0.1%) 0.03 0.29 ~
Dilution-4 (0.5%) 0.15 1.46 ~
Dilution-5 (1.0%) 0.29 2.91 ~
Dilution-6 (2.0%) 0.58 5.82 ~
Dilution-? (5.0%) 1.46 14.55 ~
Dilution-8 (10%) 2.91 29.10 ~
Dilution-9 (20%) 5.82 58.20 ~
Dilution-10 (50%) 14.55 145.50 ~
Dilution-11 (80%) 23.28 232.80 ~
Dilution-12 (100%) 29.10 291.00 ~
Dilution-13 (120%) 34.92 349.20 ~
Dilution-14 (150%) 43.65 436.50 ~
~ = Detected
REMARKS: On the basis of above data the Limit of Detection for n-Hexane was found
observation)
~~
CH~Y
PERFORMED BY
(Officer -ARDL)
(Officer-ARDL) DATE: l b I tJt , t(
DATE: \6 \0\' ob
108
Opca)
TABLE NO..9.3.5

Limit of detection data for Ethyl acetate
Conc. of component
Sr. No. w.r.t. target conc. w.r.t. test sample REMARKS
ppm ppm
Dilution-5 (1.0%) 5.03 50.28 ..J
Dilution-6 (2.0%) 10.06 100.56 ~
Dilution-? (5.0%) 25.14 251.40 ~
Dilution-8 (10%) 50.28 502.80 ~
Dilution-9 (20%) 100.56 1005.60 ..J

Dilution-10 (50%) 251.40 2514.00 ..J
Dilution-11 (80%) 402.24 4022.40 ~
Dilution-12 (100%) 502.80 5028.00 ..J

Dilution-13 (120%) 603.36 6033.60 ~
Dilution-14 (150%) 754.20 7542.00 ~

...j = Detected
REMARKS: On the basis of above data the Limit of Detection for Ethyl acetate was
found 5.03 ppm w.r.t. target concentration and 50.28 ppm w.r.t. Test solution.
~
PERFORMED BY C~BY
DATE: \5\'0"0& DATE: 'C I b-'\. ! Ii-€.
109
(~pca)
TABLE NO-9.3.6

Limit of detection data for Toluene
Conc. of component
Sr. No. w.r.t target conc. w.r.t test sample REMARKS
ppm ppm
Dilution-6 (2.0%) 1.80 17.98 ~
Dilution-7 (5.0%) 4.50 44.95 ~
Dilution-8 (10%) 8.99 89.90 ~
Dilution-9 (20%) 17.98 179.80 ~
Dilution-10 (50%) 44.95 449.50 ~
Dilution-11 (80%) 71.92 719.20 ~
Dilution-12 (100%) 89.90 899.00 ~
Dilution-13 (120%) 107.88 1078.80 ~
Dilution-14 (150%) 134.85 1348.50 ~

=
...j Detected
REMARKS: On the basis of above data the Limit of Detection for Toluene was found
observation)
~~
PERFORMED BY CHECKEDB
~
DATE: \ 6 \ 0 \ \ () b DATE: tblo'U~
110
(Ipea)
9.4 LIMIT OF QUANTITATION
The Limit of Ouantitation was established by analyzing for acceptable precision of

syntheticmixture of Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and
Toluene having the concentration as below. (Acceptance criteria: % RSD NMT
15.00%)
Table No. 9.4.1 represent the limit of quantitation and detection data for Methanol.
Acetone, Dichloromethane. n-Hexane, Ethyl acetate and Toluene.
Table No. 9.4.2 represents the Precision at LOa Level of Methanol, Acetone,
Dichloromethane, n-Hexane, Ethyl acetate and Toluene.
111
(Ipca)
TABLE NO.9.4.1
LIMIT OF DETECTION AND QUANTITATION

[For Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene]
Sr. LIMIT OF DETECTION LIMIT OF QUANTITATION

NAME OF
No. w.r.t. Target w.r.t. Test w.r.t. Target w.r.t. Test
COMPONENT
cone. (ppm) solution (ppm) cone. (ppm) solution (ppm)
1 Methanol 0.75 7.52 3.01 30.09
2 Acetone 2.52 25.19 5.04 50.37
3 Dichloromethane 0.65 6.48 6.48 64.80
4 n-Hexane 0.03 0.29 0.58 5.82
5 Ethyl acetate 5.03 50.28 10.06 100.56
6 Toluene 1.80 17.98 4.50 44.95
4~
PERFORMED BY CH~-Y---
(Officer-ARDL) (Officer -ARDl)
DATE: I (, I~I J ~ DATE: l' J rr-( I rr€
•
112
_ (Ipea)
PRECISION AT LOQ LEVEL
PREPARATION OF LOa STANDARD SOLUTION:
Standard stock solution of Methanol:

Weigh accurately about 300 mg (weighed 300.9 mg) of Methanol in 100 ml of volumetric
flasks containing diluent, and dissolve and dilute up to mark with diluent.
with diluent.
Standard stock solution of Acetone:

Weigh accurately about 500 mg (weighed 503.7 mg) of Acetone in 100 ml of volumetric
with diluent.
Standard stock solution of Dichloromethane:

Weigh accurately about 60 mg (weighed 64.8 mg) of Dichloromethane in 100 ml of
volumetric flasks containing diluent, and dissolve and dilute up to mark with diluent.
Standard stock solution of n-Hexane:

Weigh accurately about 29 mg (weighed 29.1 mg) of n-Hexane in 100 ml of volumetric
with diluent.
Standard stock solution of Ethyl acetate:

Weigh accurately about 500 mg (weighed 502.8 mg) of Ethyl acetate in 100 ml of
with diluent.
Standard stock solution of Toluene:

Weigh accurately about 89 mg (weighed 89.9 mg) of Toluene in 100 ml of volumetric
with diluent.
Loa standard solution:

Pipette out 2 ml of Standard stock solution of Methanol, 2 ml of Standard stock solution
of Acetone, 1 ml of Standard stock solution of Dichloromethane, 4 ml of Standard stock
solution of n-Hexane, 4 ml of Standard stock solution of Ethyl acetate and 10 ml of
Standard stock solution of Toluene into 100 ml volumetric flask, dilute upto the mark.
113
(~pcaJ
TABLE NO.9.4.2
(Synthetic mixture solution containing 3.01 ppm of Methanol, 5.03 ppm of Acetone,
6.39 ppm of Dichloromethane, 0.58 ppm of n-Hexane, 10.05 ppm of Ethyl
acetate and 4.46 ppm of Toluene w.r.t. target concentration)
AREA RESPONSE
Sr. No. DICHLORO ETHYL
METHANOL ACETONE N-HEXANE TOLUENE
METHANE ACETATE
1. 12493 38056 11055 71680 42844 20839
2. 12096 39525. 9897 71444 43070 20071
3. 10124 36524 9200 71041 42446 19828
4. 12206 37047 11977 72772 45428 20772
5. 12646 37109 12415 74410 44012 24583
6. 10234 39212 11547 74161 49864 19328
MEAN 11633 37912 11015 72585 44611 20904
SO:!: 1143.92 1235.48 1242.11 1439.04 2785.84 1891.67
%RSD 9.83 3.26 11.28 1.98 6.24 9.05
REMARKS: The % RSD were found 9.83 % for Methanol, 3.26 % for Acetone, 11.28 %
for Dichloromethane, 1.98 % for n-Hexane, 6.24 % for Ethyl acetate and
9.05 % for Toluene at above concentration (Acceptance criteria: % RSD NMT15.00 %)
4~
PERFORMED BY CH~Y
DATE: \1"-\0\\06 DATE: 11-1 lJi (cr(,
114
(Ipea)
9.5 LINEARITY AND RANGE
Linearity and Range for determination of Residual solvent of Cetirizine Dihydrochloride

were studied by measuring the peak area responses of residual solvent i.e. Methanol,
Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene at different serial
concentration levels as below.
(LOa to 150% targeted analyzing concentration). By using stock solution of Methanol,

Linearity curves were plotted for peak area responses against concentrations for given
compounds and correlation coefficients were calculated for the same using linearity data
and were found as 0.9999 for Methanol, 0.9985 for Acetone, 0.9980 for
Dichloromethane, 0.9998 for n-Hexane, 0.9999 for Ethyl acetate and 0.9998 for
Toluene. (Acceptance criteria: Correlation coefficient NLT 0.9800)
Table 9.5.1 Represents Linearity and range data of Residual solvent i.e. Methanol,
The respective chromatograms and linearity curve of above study are enclosed
herewith.
PREPARATION OF SOLUTIONS FOR LINEARITY STUDY:
Use LOD/LOa solutions for this study.
115
TABLE NO-9.5.1
LINEARITY AND RANGE STUDY
Cone. Cone. Cone. Cone. Cone.

*Area *Area *Area *Area Cone.
Level (ppm) (ppm) (ppm) (ppm) (ppm)
*Area *Area
(ppm)
Methanol Acetone Diehloromethane n-Hexane Ethyl acetate Toluene
LOa 3.01 13001 5.04 39734 6.48 14452 0.56 69681 10.06 49367 4.50 22912
50% 150.45 323747 251.85 1837548 12.96 27817 14.55 736002 251.40 1109515 44.95 192584
80% 240.72 515057 402.96 2916842 32.40 46807 23.26 1185831 402.24 1753022 71.92 300872
100% 300.90 634826 503.70 3639191 51.84 74690 29.10 1439003 502.80 2191783 89.90 375705
_ 120% 361.08 752380 604.44 4371700 64.80 94289 34.92 1728021 603.36 2640141 107.88 451121
150% 451.35 953481 755.55 5146267 77.76 116104 43.65 2183443 754.20 3345119 134.85 574553
~Correlation
o coefficient
0.9999 0.9985 0.9980 0.9998 0.9999 0.9998
"Slope 2084.84 6919.23 1399.01 48871.64 4406.20 4199.53
Intercept 8261.93 81723.28 5218.88 33785.73 -5423.77 1863.81
* Mean area of Standard [n=3] .
REMARKS:
The Linearity curve was plotted for peak area responses against concentration. The correlation coefficient was calculated
using the linearity data. The correlation coefficients were found 0.9999 for Methanol, 0.9985 for Acetone, 0.9980 for
Dichloromethane, 0.9998 for n-Hexane, 0.9999 for Ethyl acetate and 0.9998 for Toluene, which is within the limit.
(Acceptance criteria: Correlation coefficient NL T 0.9800)
PERFORMEDBY CH~-Y--
DATE: \ 6( ()\ 1<:)6 DATE: 'l:,I51 (rrc
116
Linearity of Methanol
Level Conc.(ppml Area Regg area

LOQ-1% 3.01 13001 14535
50% 150.45 323747 321927
80% 240.72 515057 510126
100%. 300.90 634826 635591
120% 361.08 752380 761057
150% 451.35 953481 949256
Corrcoeff 0.9999
Sipoe 2084.84
Intercept 8261.93
1200000 Linearity of Methanol
1000000
800000 /
M /
~ 600000 /
400000 /
roooooj/
0, i
I
I -Reggarea
Area
0.00 100.00 200.00 300.00

Concentration (ppm)
400.00 500.00 I
I
~~
PERFORMED BY
CH~-Y---
(Officer-ARDL) (Officer-ARDL)
DATE: \(,\0\ \06 DATE: l (; I o-f I ~
117
Linearity of Acetone
Level ConcJliPm) Area Recut area

LOQ-1% 5.04 39734 116596
50% 251.85 1837548 1824330
80% 402.96 2916842 2869894
100%. 503.70 3639191 3566937
120% 604.44 4371700 4263980
150% 755.55 5146267 5309544
Corr coeff 0.9985

Sipoe 6919.23
Intercept 81723.28
6000000 1 Lin,,<Ity of Aoetone
e
::::i
3000000 ~ /'
/
~ 2000000~ /
I Area I
1000000 , /
1-Regg area J
0-, I I
0,00 100.00 200.00 300.00 400.00 500.00 600.00 700.00 800.00

Concentration (ppm)
~~ CH~BY
PERFORMED BY
(Officer-AROL) .
(Officer-AROL) I
DATE: I~' trl. / ~
DATE: \ (, \ 0 \ \ 01;:)
118
Linearity of Dichloromethane
Conc.(ppm) Area 'Regg area

Level
LOQ-10% 6.48 14452 14284
20% 12.96 27817 23350
32.40 46807 50547
50%
51.84 74690 77744
80%
100%. 64.80 94289 95875
120% 77.76 116104 114006
97.20 142851 141203
150%
Corr coeff 0.9980

Slpoe 1399.01
Intercept 5218.88
DATE:14012006
160000 linearity of Dichloromethane
140000
120000
100000
1lI
e
c(
80000
60000 ~
40000 ~
Area
20000 ~ -Reggarea
a 4-~ -----~---~--...----~-~
100.00 120.00
0.00 20.00 40.00 60.00 80.00
Concentration (ppm)
~~ CH~-Y---
PERFORMED BY
(Officer-ARDL)
(Officer-ARDL) ,
DATE: \ b \ 0 \, b 'a
DATE: t'
IOj { ~
119
Linearity of n-Hexane
Level Conc.(ppm) Area Regg area

LOQ-2% 0.58 69681 62229
50% 14.55 736002 744868
80% 23.28 1185831 1171517
100% 29.10 1439003 1455950
120% 34.92 1728021 1740383
150% 43.65 2183443 2167033
Corr coeff 0.9998

Sipoe 48871.64
Intercept 33785.73
25000001 Linearity of n.Hexane

I
2000000; /
III 1500000 ~ /
e I /
< 1000000~ /
~oooj/ Area
-Reggarea
o +-! ----.-.--
I
I
0.00 10.00 20.00 30.00 40.00 50.00

Concentration (ppm)
~ ~
PERFORMED BY CHECKED BY
(Offlcer-ARDL) (Officer-ARDL)
DATE: \ 6 \0\ \.06 DATE: t l: I tr( I ~
120
Linearity of Ethyl acetate
Conc"JiiPm) Area Regg area

Level
10.06 49367 38885
LOQ-2%
251.40 1109515 1102294
50%
402.24 1753022 1766925
80%
502.80 2191783 2210013
100%
603.36 2640141 2653100
120%
754.20 3345119 3317731
150%
Corr coeff 0.9999

Slpoe 4406.20
Intercept -5423.77
4000000 Linearity of Ethyl acetae
3500000
3000000 /
~ 2500000 ~
~ 2000000 ~
1500000 I ~
1000000.. ./
500000 ~ ./_ I_~~egag area]
0- i (----- "~I-------
0.00 100.00 200.00 300.00 400.00 500.00 600.00 700.00 800.00 I
Concentration (ppm) I
~ C~-Y---
pERFORMED BY
(Officer-ARDL)
(Officer-ARDL) DATE: ICltrlf~
DATE: \ (, ~ 0\ \ ()b
121
Linearity of Toluene
Level Conc.(ppm) Area Regg area

LOQ-5% 4.50 22912 20741
50% 44.95 192584 190633
80% 71.92 300872 303894
100% 89.90 375705 379402
120% 107.88 451121 454909
150% 134.85 574553 568170
Corr coeff 0.9998

Sipoe 4199.53
Intercept 1863.81
700000 ] Linearity of Toluene
600000
500000 ~ /
It 400000 ~ /'
f I /'
c( 3000001 /'
200000 1/
100000 ~ Area
I -Reggarea
o +I--~-~----~---~-~~~
0.00 20.00 40.00 60.00 80.00 100.00 120.00 140,00 160.00
Concentration (ppm) II
~
PERFORMED BY CAitt
(Officer-ARDL)
(Officer-ARDL)
DATE: \ b '0\\
~C:::. DATE: I 6 I ~ I 0-(,
122
9.6 ACCURACY STUDY
Accuracy study was carried out by spiking various known concentrations of Methanol,
Acetone and Toluene in Cetirizine Dihydrochloride Test sample and calculating the %
Recovery. Accuracy was determined over a range of concentrations from 80% to 120%.
The result of accuracy study in term of %recovery were found in the range of 98.74% to
100.63% for Methanol, 97.96% to 99.59% for Acetone, 99.05% to 102.72% for
Dichloromethane, 97.21% to 99.57% for n-Hexane, 98.25% to 100.18%for Ethyl acetate
and 97.79% to 99.95% for Toluene. The results were found well within the acceptable
limits i.e. between 80% to 120%.
% Recovery of LOa Level was found 100.66% for Methanol, 98.67% for Acetone.
106.94% for Dichloromethane, 102.87% for n-Hexane, 97.98% for Ethyl acetate and
102.69% for Toluene.
Table 9.6.1 to 9.6.6 represents recovery data of Methanol, Acetone, Dichloromethane,

n-Hexane, Ethyl acetate and Toluene for 80% to 120% and LOa level concentration.
PREPARATION OF SOLUTIONS:

Use LOa standard solution from LOa precision study.

Use 50% Standard solution from LOD/LOa study.


Use 120% Standard solution.from LOD/LOa study.
Formulae used to calculate accuracy:
Recovery in ppm _ Corrected area of solvent X Concentration of Standard solution in ppm

Area of Standard solution
Recovery in ppm X 100

% Recovery -.",----------
Added concentration in ppm
123
--------

RESIDUAL SOLVENT IN CETRIZINE DIHYDROCHLORIDE (METHOD-1)
TABLE NO- 9.6.1
ACCURACY STUDY
RECOVERY STUDY OF METHANOL IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
%Recovery calculated by mean area of Methanol from Standard solution [n=6] METHANOL
Mean Area 633220
%RSD 0.70
Mean area of Methanol in Parent sample [n=3] Not detected
Corrected area counts

only for added Mean 0/0 RSD
Cone. of Methanol Area counts for Test Recovered against added
Test Level Methanol (After 0/0 Recovery
added (ppm) + Added Methanol amount in ppm (n=3) (n=3)
subtracting the parent
area)
Test-1 6111 6111 2.90 96.35
LOa Test-2 3.01 6293 6293 2.99 99.34 100.66 5.08
Test-3 6742 6742 3.20 106.31
Test-1 496293 496293 235.83 97.97
80% Test.2 240.72 494345 494345 234.91 97.59 98.74 1.70
Test-3 509925 509925 242.31 100.66
Test-1 630476 6304764 299.60 99.57
100% Test-2 300.90 644195 644195 306.12 101.73 100.63 1.08
Test-3 636993 636993 302.69 100.59
Test-1 753374 753374 358.00 99.15
120% Test-2 361.08 752839 752839 357.74 99.07 98.86 0.43
Test-3 747486 747486 355.20 98.37
REMARKS:
The resultsof accuracystudy in terms of % Recovery were found in the range of 98.74% to 100.63% for Methanol and recovery at LOa level was found
100.66%.These are well within the acceptance range of 80% to 120%.
4~
PERFORMEDBY
(Officer-ARDL)
DATE:\ ~ \ 19\\ r.> b
c~~t--
(Officer -ARDL)
DATE: ,~ tri 1t><
124
TABLE NO- 9.6.2
ACCURACY STUDY
RECOVERY STUDY OF ACETONE IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
%Recovery calculated by mean area of Acetone from Standard solution [n=6] ACETONE
Mean Area 3630110
%RSD 0.56
Mean area of Acetone in Parent sample [n=3] 18688

Test Level Cone, of Acetone Area counts for Test only for added Acetone
added (ppm) Recovered against added Mean %RSD
+ Added Acetone (After subtracting the % Recovery
amount in ppm (n=3) (n=3)
parent area)
Test-1 53232
LOa 34544 4.79 95.23
Test-2 5.03 56155 37467 5.20 103.38 98.67
Test-3 53967 4.28
35279 4.90 97.42
Test-1 2849863
80% 2831175 392.84 97.49
Test-2 402.96 2851334 2832646 393.05 97.54 97.96
Test-3 2889423 0.79
2870735 398.33 98.85
Test.1 3587132
100% Test-2 3568444 495.14 98.30
503.70 3678024 3659336 507.76 100.81 99.59
Test-3 3636177 1.26
3617489 501.95 99.65
Test-1 4299629
120% Test.2 4280941 594.01 98.27
604.44 4308546 4289858 595.24 98.48 98.56
Test-3 4327445 0.33
REMARKS: 4308757 597.87 98.91
The resultsof accuracystudy in terms of % Recovery were found in the range of 97.96% to 99.59% for Acetone and recovery at LOa level was found
98.67%.These are well withinthe acceptance range of 80% to 120%.
~~
PERFORMEDBY
(Officer-ARDL) C~-y--
DATE: \-:\ \0\ \Ob (Officer -ARDL)
DATE: 19-1 rtfl tJt
125
TABLE NO- 9.6.3
ACCURACY STUDY
RECOVERY STUDY OF DICHLOROMETHANE IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
DICHLOROMETHANE
%Reeovery calculated by mean area of Dichloromethane from Standard solution [n=6]
Mean Area 94816
%RSD 0.65
Mean area of Dichloromethane in Parent sample [n=3] Not detected

Cone. of Area counts for Test only for added Mean %RSD
Recovered against added % Recovery
Diehloromethane + Added Dichloromethane (After (n=3) (n=3)
Test Level amount in ppm
added (ppm) Dichloromethane subtracting the parent
area)
9592 6.56 102.66
Test-1 9592 3.66
6.89 107.82 106.94
LOa Te5t-2 6.39 10082 10082
10312 7.05 110.33
Te5t-3 10312
76359 52.19 100.68
Test-1 76359 102.72 2.29
79865 54.58 105.29
80% Test-2 51.84 79865
77522 52.98 102.20
Test-3 77522
96507 65.96 101.79
Test-1 96507 1.93
67.60 104.32 102.18
100% Test-2 64.80 98914 98914
95223 65.08 100.43
Te5t-3 95223
111014 75.87 97.57
Test-1 111014 1.66
76.79 98.75 99.05
120% Test-2 77.76 112356 112356
114717 78.40 100.82
Te5t-3 114717
REMARKS:
The results of accuracystudy in terms of % Recovery were found in the range of 99.05% to 102.72% for Dichloromethane and recovery at LOa level was
found 106.94%.These are well within the acceptance range of 80% to 120%.
:=;~
PERFORMEDBY
C~y
(Officer -ARDL)
(Officer-ARDL) DATE: tq-( ot I ~
DATE: \-=\- \0' \()b
126
TABLE NO- 9.6.4
ACCURACY STUDY
RECOVERY STUDY OF n-HEXANE IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
%Recovery calculated by mean area of n-Hexane from Standard solution [n=6] n-HEXANE
Mean Area 1432225
%RSD 1.21
Mean area of n-Hexane in Parent sample [n=3] Not detected

only for added n- Mean % RSD
Cone. of n-Hexane Area counts for Test Recovered against added
Test Level Hexane (After % Recovery (n=3) (n=3)
added (ppm) + Added n-Hexane amount in ppm
area)
Test-1 27798 27798 0.56 96.55
LOQ Test-2 0.58 30835 30835 0.63 108.62 102.87 5.89
Test-3 29763 29763 0.60 103.45
Test. 1 1134307 1134307 23.05 99.01
80% Test-2 23.28 1135510 1135510 23.07 99.10 99.57 0.90
Test-3 1152690 1152690 23.42 100.60
Test-1 1410720 1410720 28.66 98.49
100% Test.2 29.10 1401566 1401566 28.48 97.87 97.92 0.56
Test-3 1394795 1394795 28.34 97.39
Test. 1 1662078 1662078 33.77 96.71
120% Test-2 34.92 1665258 1665258 33.83 96.88 97.21 0.75
Test.3 1685260 1685260 34.24 98.05
REMARKS:
The results of accuracy study in terms of % Recovery were found in the range of 97.21 % to 99.57% for n-Hexane and recovery at LOa level was found
102.87%. These are well within the acceptance range of 80% to 120%.
~~
PERFORMED BY
~-B-Y--
DATE:\1-t0\lo~ DATE: ltH b"( I ~
127
TABLE NO- 9.6.5
ACCURACY STUDY
RECOVERY STUDY OF ETHYL ACETATE IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
%Recovery calculated by mean area of Ethyl acetate from Standard solution [n=6] ETHYL ACETATE
Mean Area 2195192
%RSD 0.74
Mean area of Ethyl acetate in Parent sample [n=3] Not detected

Cone. of Ethyl only for added Ethyl Recovered against added Mean %RSD
Area counts for Test % Recovery
Test Level acetate added acetate (After amount in ppm (n=3) (n=3)
+ Added Ethyl acetate subtracting the parent
(ppm)
area)
Test-1 43078 43078 9.87 98.21
42609 9.76 97.11 97.98 0.79
LOa Test-2 10.05 42609
Test-3 43260 43260 9.91 98.61
Test-1 1719527 1719527 393.85 97.91
1719350 1719350 393.81 97.90 98.25 0.60
80% Test-2 402.24
Test.3 1737410 1737410 397.95 98.93
Test-1 2168264 2168264 496.63 98.77
2228380 2228380 510.40 101.51 100.18 1.37
100% Test-2 502.80
Test.3 2200648 2200648 504.05 100.25
Test-1 2596588 2596588 594.74 98.57
2604370 596.52 98.87 98.92 0.38
120% Test-2 603.36 2604370
Test.3 2616297 2616297 599.25 99.32
REMARKS:
The resultsof accuracystudy in terms of % Recovery were found in the range of 98.25% to 100.18% for Ethyl acetate and recovery at LOa level was found
97.98%.These are?wilhin the acceptance range of 80% to 120%.
.
~
PERFORMEDBY
(Offieer-ARDL)
C&fBY
(Officer -ARDL)
DATE: \ 'r-\0\ \ ~ DATE: l7'-l1:tf I ~
128
TABLE NO- 9.6.6
ACCURACY STUDY
RECOVERY STUDY OF TOLUENE IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
%Recovery calculated by mean area of Toluene from Standard solution [n=6] TOLUENE
Mean Area 377019
%RSD 0.89
Mean area of Toluene in Parent sample [n=3] Not detected

Cone. of Toluene Area counts for Test only for added Toluene Recovered against added Mean % RSD
Test Level % Recovery
added (ppm) + Added Toluene (After subtracting the amount in ppm (n=3) (n=3)
parent area)
Te5t-1 20149 20149 4.80 107.62
LOa Test-2 4.46 18782 18782 4.48 100.45 102.69 4.17
Test.3 18725 18725 4.46 100.00
Te5t-1 293180 293180 69.91 97.21
80% Te5t-2 71.92 292400 292400 69.72 96.94 97.79 1.28
Te5t-3 299327 299327 71.37 99.24
Te5t-1 370710 370710 88.40 98.33
100% Te5t-2 89.90 383790 383790 91.51 101.79 99.95 1.74
Te5t-3 375980 375980 89.65 99.72
Te5t-1 445178 445178 106.15 98.40
120% Te5t-2 107.88 445804 445804 106.30 98.54 98.67 0.36
Te5t-3 448230 448230 106.88 99.07
REMARKS:
The results of accuracystudy in terms of % Recovery were found in the range of 97.79% to 99.95% for Toluene and recovery at LOa level was found
102.69%.These are well within the acceptance range of 80% to 120%.
4~
PERFORMED BY C~BY
(Officer-ARDL) (Officer -ARDL) •
DATE: 1'\\0\ \()b DATE: I ~ ot I I)'t;
129
(~ca)
REPORT ON ANALYTICAL DEVELOPMENT AND VALIDATION FO
9.7 RUGGEDNESS STUDY
Two different analytical persons carried out the ruggedness of the method on different
dates to establish the degree of reproducibility of the results obtained by the analysis of
the same sample.
Ms. Suman Lata had carried out the first study on 13/01/2006 using Perkin-Elmer
Clarus-SOOsystems at R&D Ratlam, while Mr. Prakash Sangale has conducted the
second study on Perkin-Elmer Clarus-SOOsystems on 23/0212006 at CRD Mumbai.
The ruggedness studies were carried out as described in the precision study by
injection repeatability and result reproducibility. Results reproducibility was carried out,
by replicate analysis of the sample for Residual solvent against the same Standard
solution and by calculating %RSD of the replicate injection data.
The results of both the analysis for Methanol, Acetone, Dichloromethane, n-Hexane,
Ethyl acetate and Toluene were comparable (Limit of acceptance NMT 1S.00 %RSD).
Hence it is concluded that the method is rugged enough for the determination of
Residual solvent in Cetirizine Dihydrochloride.
Table 9.7.1 to 9.7.6 represents the data of Ruggedness study of Cetirizine

Dihydrochloride by GC method.
Respective chromatograms of the above study are enclosed herewith.
130
(Ipc~
TABLE NO-9.7.1
TABLE FOR RUGGEDNESS STUDY [METHANOL]
[A] [B)
Perkin-Elmer Clarus-500 Perkin-Elmer Clarus-500
INSTRUMENT
Ms. Suman Lata Mr. Prakash Sangale
ANALYSt
13/01/2006 23/02/2006
DATE
R&D-RA TALAM CRD-MUMBAI
LOCATION
of Methanol: 532772 Methanol: 546320

Mean Area
Standard solution
[%RSD]: 0.96% r/oRSD]: 0.38%
Amount of Test sample Peak Area of Test Results in ppm

Sr.
No. B# PP5012CZRI in mg sample
[A] [B) [AJ [BJ
[A] [B]
Not detected
1 500.09 500.19 -- --- Not detected
--- Not detected
2 500.12 500.23 -- Not detected
Not detected
3 500.02 500.06 --- --- Not detected
--- Not detected
4. 500.26 500.26 -- Not detected
Not detected
5 500.23 500.27 -- -- Not detected
--- Not detected
6 500.13 500.32 --- Not
Not
detected
detected Not detected
Mean
SO :t --- --
%RSO --- ---
Mean of above 12 results of two sets of analyst A+B --
SOt --
%RSD -
REMARKS: In both the set of analysis, the results of Methanol in Cetirizine
Dihydrochloride were found not detected. On the basis of the above data it is
concluded that, the method is rugged enough for the determination of Residual solvent
in Cetirizine Dihydrochloride
~
~ CH~-Y--
PERFORMED BY (Officer -ARDL)
(Officer-ARDL) DATE: ~, 62-1&-€
DATE: o.Ji I0 2.-l ab
131
REPORT-oN-AN-ALYTICAL DEVELOPMENT AND VALIDATION FOR
RESIDUAL SOLVENT IN CETIRIZINE DlHYDROCHLORIDE (METHOD-i.)
TABLE NO ..9. 7.2
TABLE FOR RUGGEDNESS STUDY [ACETONE]
[A] [B]
INSTRUMENT Perkin-Elmer Clarus-500 Perkin-Elmer Clarus-500
ANALYST Ms. Suman Lata Mr. Prakash Sangale
DATE 13/0112006 23/0212006
LOCATION R&D-RATALAM CRD-MUMBAI
Mean Area of Acetone: 3138061 Acetone: 3063982

Standard solution
[%RSD]: 0.88% [%RSD): 0.63%
Sr. Amount of Test sample Results In ppm

Peak Area of Test sample
No. B# PP5012CZRI in mg
fA] [B] -fA] [B] [A] [8]
1 500.09 500.19 2260113521 36.27 22.12
2 500.12 500.23 2320413213 37.24 21.62
3 500.02 500.06 2259210866 36.26 17.78
4 500.26 500.26 2610714013 41.88 22.92
5 500.23 500.27 2530514684 40.60 24.02
6 500.13 500.32 2375515015 38.12 24.56
Mean 38.40 22.17
SDt 2.34 2.42
%RSD 6.11 10.91
Mean of above 12 results of two sets of analyst A+B 30.28
SOt 8.77
%RSD 28.97
REMARKS: In both the set of analysis, the results of Acetone in Cetirizine

Dihydrochloride were found % RSD 28.97% (n=12). Since results are below
quantitation limit, % RSD found on higher side. On the basis of the above data it is
concluded that, the method is rugged enough for the determination of residual solvent
~ .~
DATE: 2.t-t 10'2-1 lJb DATE: .U."D~tn
132
TABLE NO-9.7 .3
TABLE FOR RUGGEDNESS STUDY [DICHLOROMETHANE]
[A] [B]
Perkin-Elmer Glarus-500 Perkin-Elmer Glarus-500
INSTRUMENT
ANALYST
13/01/2006 23/02/2006
DATE
R&D-RA TALAM GRD-MUMBAI
LOCATION
Dichloromethane: 85593 Dichloromethane: 93560

Mean Area of
Standard solution
rkRSDJ: 1.29% rkRSD]: 0.51%
Sr. Amount of Test sample Peak Area of Test Results in ppm)

[B] [A] [B] [A] [8]
[A] Not detected
1 500.09 500.19 --- -- Not detected
2 500.12 500.23 -- -- Not detected Not detected

Not detected
3 500.02 500.06 -- -- Not detected
Not detected Not detected
4 500.26 500.26 --- ---
Not detected
500.27 --- --- Not detected
5 500.23
--- Not detected Not detected
6 500.13 500.32 -- Not detected
Mean Not detected
SO :t --- --
%RSD --- --
Mean of above 12 results of two sets of analyst A+B -
SO:!: ---
%RSD --
REMARKS: In both the set of analysis, the results of Dichloromethane in Cetirizine
~
C~-B-Y---
PERFORMED BY (Officer -ARDL)
(Officer-ARDL) DATE: a.1f 10 f2.l.~
DATE: 2li \02-1 0(;
133
REPORT ON ANALYTICAL DEVELOPMENT AND VALIDATION F
TABLE NO-9.7.4
TABLE FOR RUGGEDNESS STUDY [n-HEXANE]
[A] [B]
INSTRUMENT Perkin-Elmer Clarus-SOO Perkin-Elmer Clarus-500
ANALYST Ms. Suman Lata Mr. Prakash Sangale
DATE 13/01/2006 23/02/2006
LOCATION R&D-RA TALAM CRD-MUMBAI
Perkin-Elmer Clarus-SOO
Mean Area of n-Hexane: 1250001 n-Hexane: 1135256
Standard solution
[%RSD]: 1.59% [%RS 0]: 1.38%
Sr. Amount of Test sample Peak Area of Test

Results in ppm)
[A] [B] [A] [B] [A] [B]
1 500,09 500.19 --- --- Not detected Not detected
2 500.12 500.23 -- --- Not detected Not detected
4 500.26 500,26 --- -- Not detected Not detected
5 500.23 500.27 --- --- Not detected Not detected
6 500.13 500.32 -- - Not detected Not detected
Mean Not detected Not detected
SDt --- --
%RSD --- ---
SO:!: ---
%RSD --
REMARKS: In both the set of analysis, the results of n-Hexane in Cetirizine
~
PERFORMED BY
(Officer-ARDL)
CitfB-Y---
(Officer -ARDL)
DATE: a..l.tlo2-l~ DATE: QA.f' 00.-{ ~
134
TABLE NO-9.7.5
TABLE FOR RUGGEDNESS STUDY [ETHYL ACETATE]
[A] [B]
INSTRUMENT Perkin-Elmer Clarus-500 Perkin-Elmer Clarus-500
ANALYST Ms. Suman lata Mr. Prakash Sangale
DATE 13/01/2006 23/02/2006
lOCATION R&D-RA TAlAM CRD-MUMBAI
Mean Area of Ethyl acetate: 1867538 Ethyl acetate: 1889047

Standard solution
[%RSO]: 1.07% rkRSD]: 0.56%

No. B# PP5012CZRI in mg Results in ppm)
sample
[A] [B] [A) [B] [A] [B)
1 500.09 500.19 --- -- Not detected Not detected
6 500.13 500.32 --- -- Not detected Not detected
SOt -- -
Mean of above 12 results
%RSD
of two sets of analyst A+B
--- ---
-
SOt ---
%RSD ---
REMARKS: In both the set of analysis, the results of Ethyl acetate in Cetirizine
~
PERFORMED BY CH~-Y---
(Offic~r-ARDL) (Officer -ARDL)
DATE: 1.'-/ 1'{).2..{~ DATE: ~ ItYU irC
135
TABLE NO-9.7.6
TABLE FOR RUGGEDNESS STUDY [TOLUENE]
[A] [B]
Perkin-Elmer Clarus-500 Perkin-Elmer Clarus-500
INSTRUMENT
ANALYST
13/01/2006 23/02/2006
DATE
R&D-RA TALAM CRD-MUMBAI
LOCATION
Toluene: 330737 Toluene: 362000

Mean Area of
Standard solution
[%RSD): 1.30% [%RSD]: 0.43%
Amount of Test sample Peak Area of Test Results in ppm)

Sr.
B# PP5012CZRI in mg sample
No. [B]
[A] [B] [A] [B] [A]
Not detected
1 500.09 500.19 --- --- Not detected
.- Not detected Not detected
2 500.12 500.23 ---
Not detected
3 500.02 500.06 - ---
---
Not detected
Not detected Not detected
4 500.26 500.26 --- Not detected
5 500.23 500.27 --- --- Not detected
-- Not detected Not detected
6 500.13 500.32 ---
Mean Not detected Not detected I
SOt --- -
%RSD --- ---
Mean of above 12 results of two sets of analvst A+B ---
SDt .--
%RSD ---
REMARKS: In both the set of analysis, the results of Toluene in Cetirizine
~
PERFORMED BY
:::-:-:::
(Officer-ARDL)
CH*BY
(Officer -ARDL)
DATE: 52~ 1~2-l 0'(
DATE: Q.4 /02../0b
136
TABLE NO-9.7.7
TABLE FOR RUGGEDNESS STUDY [SYSTEM SUITABILITY]
Comparative System suitability data of both analysts

Name of Analyst A Analyst B
Component
RT RT
RRT Resolution RRT Resolution
(min) (min)
Methanol 2.70 0.16 2.56 0.15
Acetone 4.23 0.25 3.89 0.24

Resolution Resolution
Dichloromethane 4.97 0.29 between 4.57 0.28 between
Acetone & Acetone &
n-Hexane 5.77 0.34 Dichloromet 5.34 0.32 Dichloromet
hane is 5.93 hane is 5.26
Ethyl acetate 7.77 0.46 7.27 0.44
Toluene 12.68 0.75 12.18 0.74
~
(Officer -ARDL)
(Officer-ARDL)
DATE: 2.1; lot.--! iJ{ DATE: ~t~CI
137
RESIDUAL SOLVENT IN CETIRIZINE DlHYDROCHLORIDE (METHOD-i)
9.8 ROBUSTNESS
"The robustness of an analytical method is measure of its capacity to remain
.unaffected by small but deliberate variations in method parameters and provides an
indication of its 'reliability during normal usage"
To check the robustness of the method the following parameters were deliberately
changed.
1. Change in column oven temperature [+ 3°C]

Change in column oven temperature i.e. 42°C + 3°C. No significant change was
observe d' In S)yS tem SUI'ta bTt
I Ity parame ter.
Change in column oven temperature [+ JOC]
Name of *42°C 45°C
Component
RT RT
RRT Resolution RRT Resolution
(min) (min)
Methanol 2.74 0.16 2.72 0.16
Acetone 4.29 0.25 4.15 0.25

Resolution Resolution
Dichloromethane 5.04 0.29 between 4.85 0.29 between
Acetone and Acetone and
n-Hexane 5.85 0.34 Dichloromet 5.58 0.33 Dichlorometh
hane is 5.89 ane is 5.62
Ethyl acetate 7.85 0.46 7.50 0.45
Toluene 12.77 0.75 12.46 0.74
Change in column oven temperature r+ 3°Cl

Name of *42°C 45°C
Component ppm ppm
1!it Injection 2nd Injection 1st Injection 2na Injection
Methanol NO NO NO NO
Acetone 36.27 37.24 53.47 56.41
Dichloromethane NO NO NO NO
n-Hexane NO NO NO ND
Ethyl acetate ND NO ND NO
Toluene ND NO NO ND
ND = Not Detected
*Data taken from precision study Chromatogram.
Respective Chromatograms of the above study are enclosed herewith,
~~
PER ORMEDBY CH~BY
(Officer-ARDl) (Officer -ARDL)
DATE: t ~ \ 0\ \ 00 DATE: 19/1!l1 (~
138
2. Change in column pressure

With change in the column pressure i.e. 3.0 psi:!: 0.2 psi. No significant change was
observed in System suitability parameter.
Change in column pressure [:t 0.2 psi]

Name of 2.8 psi *3.0 psi 3.2 psi
Component
RT Resol RT Resol RT Resol
RRT RRT RRT
(min) ution (min) ution* (min) ution
Methanol 2.94 0.17 2.74 0.16 Resol 2.58 0.15
Resol Resolu
ution ution
Acetone 4.60 0.26 tion
betwe 4.29 0.25 betwe 4.04 0.24
betwe
en en
Dichloromethane 5.41 0.31 5.04 en
0.29 Metha 4.75 0.28
Aceto Aceton
ne and nol
n-Hexane 6.27 eand
0.36 5.85 0.34 and 5.51 0.33
Dichlo Dichlor
ramet Aceto
Ethyl acetate 8.22 0.47 ometh
7.85 0.46 neis 7.51 0.45
hane aneis
i56.09 5.89
Toluene 13.11 0.75 12.77 5.55
0.75 12.44 0.74
Change in column pressure [:t 0.2 ~sD_

Component ppm pJrn ppm
f51 2"11 1Sl 2"g 1Sl 200
Injection Injection Injection Injection Injection Injection
Methanol NO NO NO NO NO NO
Acetone 22.78 19.41 53.47 56.41 21.71 24.15
Oichloromethane NO NO ND NO NO NO
n-Hexane NO NO ND NO NO ND
Ethyl acetate ND NO NO NO NO NO
Toluene NO NO NO NO NO ND
NO = Not Detected

Respective Chromatograms of the above study are enclosed herewith.
~-2::
PEORMEDBY
~
CHECKED BY
DATE: 2.0\ ()\.\ob DATE: a-ol frl/~
139
RESIDUAL SOLVENT IN CETIRIZINE DIHYDROCHLORIDE (METHOD 1) a
3. Change in vial oven temperature [:t 20°CJ

Change in vial oven temperature i.e. 100°C :t 20°C. No significant change was
observed in System suitability parameter.
Change in vial oven temperature [:f: 20°C]

.
Name of 80°C *100°C 120°C
Component
RT Resolu RT Resol RT Resol
RRT RRT RRT
(min) tion (min) ution (min) ution
Methanol 2.86 0.17 2.74 0.16 Resol 2.60 0.16
Resolu Resol
tion ution
Acetone 4.47 0.26 4.29 ution
0.25 betwe 4.05 0.24
betwee betwe
Oichloromethane n en en
5.26 0.31 5.04 0.29 4.77 0.28
Aceton Meth Aceton
n-Hexane 6.11 0.36 e and anal eand
5.85 0.34 5.54 0.33
Dichlor and Oichlor
Ethyl acetate 8.08 0.47 ometha 7.85 Aceto ometh
0.46 7.54 0.45
neis neis aneis
Toluene 12.88 0.75 5.96 12.77 0.75 5.89 12.47 0.74 5.43
Change in vial oven temperature r:f: 20°C]

Name of 80°c *100°C 120°C
Component ppm ppm ppm
1st 2na 1st 2 nd
1 st
2na
Methanol NO NO NO NO NO NO
Acetone 23.94 22.18 53.47 56.41 24.75 26.62
Oichloromethane ND ND ND ND ND NO
n-Hexane ND ND ND NO ND NO
Ethyl acetate ND ND ND ND NO NO
Toluene ND NO ND NO ND NO
=
ND Not Detected

.-
5?--
PERFORMED BY CH~Y
(Officer-ARDl) (Officer -ARDL)
DATE: '2..\' 0 \ \ o~ DATE: Q-ll 011 a-(
140
10. DATA ACCUMULATION STUDY
Analysis of the manufactured batches of Cetirizine Dihydrochloride, Batch No.

PPS01.1CZRI,PPS012CZRI and PP5013CZRI was carried out as a data accumulation
study to assess the content of Residual solvent.
Table No. 10.1 represents the result of Methanol, Acetone, Dichloromethane,

n-Hexane, Ethyl acetate and Toluene found in Cetirizine Dihydrochloride samples.
Respective'chromatograms of the above study are enclosed herewith.
141
TABLE NO-10.1
DATA ACCUMULATION STUDY

Mean areas df Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate
and Toluene obtained from replicate injections of Standard solution.
Mean Area %RSD
Methanol 532772 0.96
Acetone 3138061 0.88
Dichloromethane 85593 1.29
n-Hexane 1250001 1.59
Ethyl acetate 1867538 1.07
Toluene 330737 1.30
RESIDUAL SOLVENT (IN PPM)

Sr.
No. B.No. Inj. No. Dich'oro n- Ethyl
Methanol Acetone Toluene
methane Hexane acetate
1 NO 42.86 NO NO NO NO
1 PP5011CZRI
2 PP5012CZRI
1 ND 45.36 NO NO NO NO
3
PP5013CZRI
2 NO 39.45 ND NO NO NO
NO = Not detected
Data accumulation study was done in continuation with Precision study
Remarks: Results are well within the specified limits of Residual solvent
(i.e. Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and
Toluene)
~ J?1Q
CHECKED BY
PERFORMED BY
(Officer-ARDL) (Officer -ARDLl.
DATE: f~'ol(tTO
DATE: It.{ \D\ \Ob
142
11. SUMMARY REPORT AND APPROVAL
Sr. RESULTS
No. PERFORMANCE PARAMETER Dichiara ACCEPATANCE
Methanol Acetone Ethyl
n-Hexane Toluene CRITERIA
methane acetate
1.0 Identification
Well resolved
RT (Retention Time) 2.67 4.20 4.93 5.70 7.71 12.65 with adjacent
RRT (Relative Retention Time) 0.16 0.25 0.29 0.34 peak
0.46 0.75
2.0 System suitability
RT (Retention Time) 2.70 4.23 4.97 5.77 7.77 12.98 Informative
RRT (Relative Retention Time) 0.16 0.25 0.29 0.34 0.46 0.75 Informative
Plate count 22929.23 20120.81 23027.61 15052.65 40348.19 163286.05 Informative
Tailing Factor 1.043 1.037 0.971 1.008 1.005 1.003 Informative .
Resolution
Resolution between Acetone & Dichloromethane is 5.93 NLT 2.0
% RSD [n=6] 0.96 0.88 1.29 1.59 1.07 1.30 NMT 10.00%
3.0 Precision (Injection)
%RSD of replicate injection (n=6) 0.96 0.88 1.29 1.59 1.07 1.30 NMT 10.00%
Precision (Result)
%RSD of replicate result (n=6) _.- 6.11 --- --- --- --- NMT 15.00%
4.0 Accuracy (80% to 120%)
% Recovery 98.74% to 97.96% to 99.05% to 97.21 % to 98.25% to 97.79% to % Recovery

100.63% 99.59% 102.72% 99.57% 100.18% 99.95% should be
Accuracy at LOQ Level between 80% to
% Recovery 120%
100.66% 98.67% 106.94% 102.87% 97.98% 102.69%
143
RESIDUAL SOLVENT IN CETIRIZINE ~I,HYDROCHLORIDE (METHOD-1)
Sr. RESULTS
PERFORMANCE PARAMETER ACCEPATANCE
No. Methanol Dichloro Ethyl
Acetone n-Hexane Toluene CRITERIA
methane acetate
5.0 Specificity/Selectivity
Well resolved
All peaks are well resolved with adjacent peak, so method is Specific. with adjacent
peak
6.0 Linearity and Range Correlation
LOQto 150% coefficient NLT
0.9999 0.9985 0.9980 0.9998 0.9999 0.9998 0.9800
w.r.t Target in ppm 0.75 2.52 0.65 0.03 5.03 1.80
.. w.r.t Test in ppm 7.52 25.19 6.48 0.29 50.28 17.98
Positive
Response
8.0
Limit of Quantitation (LOQ)
w.r.t Target in ppm 3.01 5.04 6.48 0.58 10.06 4.50

w.r.t Test in ppm Informative
30.09 50.37 64.80 5.82 100.56 44.95
Precision at LOQ level
%RSD of replicate of LOQ cone.
(n=6) 9.83% 3.26% 11.28% 1.98% 6.24% 9.05% NMT 15.00%
9.0
Ruggedness
%RSD of replicate injection (n=6) 0.38 0.53 0.51 1.38 0.56 0.43 NMT 10.00%
%RSD of cumulative results
(n=12) --- 10.91 -- --- --- --- NMT 15.00%
144
REMARKS:
On the basis of above results the analytical method for Residual solvent (Methanol,
Acetone, Dichloromethane, n-Hexane, Ethyl acetate and Toluene) in Cetirizine
Dihydrochloride is found well within the acceptance limit. Therefore, the analytical
method for analysis of Residual solvent in Cetirizine Dihydrochloride is to be considered
as a VALIDATED method for its intended purpose to establish the quality of Cetirizine
Dihydrochloride.
CH!:t
(Officer -ARDl)
DATE: 02>109>Ie1-6
APPROVED BY
(Manager -ARDL)
DATEo~3~a~
145
12. CONCLUSION
The analytical method validation study for the determination of a Residual solvent
method-1 i.e. Methanol, Acetone, Dichloromethane, n-Hexane, Ethyl acetate and
Toluene in Cetirizine Dihydrochloride by Gas Chromatographic (Capillary) method is
considered to be validated for its intended use.
CHZi
(Officer -ARDL)
DATE: D!3!631 ~
~
APPROVED BY
(Manager -ARDL)
DATE: 04-- 03 .06 ,
146
VALIDATION REPORT FOR
DETERMINATION OF RESIDUAL
SOLVENT (CHLOROFORM, N, N-
DIMETHYFORMAMIDE, BENZENE)
147
1. OBJECTIVE
To provide documented evidence of the suitability of the analytical method-2 for its
intended purpose of establishing the quality of Cetirizine Dihydrochloride with respect to
Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide.
2. SCOPE
This scope shall evaluate the acceptability of analytical method used for determination of
Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide in Cetirizine
Dihydrochloride by Gas chromatography analysis.
Following solvents are used:
Chloroform
1,2-Dichloroethane
Dichloromethane
n-Hexane
Ethyl acetate
Toluene
Chloroform
1,2-Dichloroethane
Benzene
N,N-Dimethylformamide
1,2-Dichloroethane is used in raw material and Benzene is hidden solvent, hence the
method-2 shall be designed to detect and quantify Chloroform, 1,2-Dichtoroethane,
Benzene and N,N-Dimethylformamide in Cetirizine Dihydrochtoride.
As per ICH guideline the classification of the above residual solvents and their
acceptable concentration in ppm are as below: -
Name of solvent Classification Specification Limit

Sr. No.
1 Chloroform Class-II NMT60 m
2 1,2-Dichloroethane Class-I NMT5 m
Benzene Class-I NMT2 m
3
N,N-Dimeth lformamide Class-II NMT880 m
4
The protocol shall define the procedure, documentation, references and acceptance
criteria to be used in method of Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide in Cetirizine Dihydrochloride by Gas chromatography analysis.
148
3. PROCEDURE
3.1 SELECTION OF ANALYTICAL PERFORMANCE PARAMETER
As per the cGMP regulation guidelines, the test method, which is used for assessing the
quality of pharmaceutical product with established specification, must be validated for
analytical performance parameters described in the USP 29 under section 1225" (i.e.
"validation of compendial method") andl or ICH (028) guideline for "Validation of
analytical procedure: methodology"
The method for detection of Residual Solvents in Cetirizine Dihydrochloride is by Gas

chromatographic method hence it's validation is carried out for Precision, Accuracy,
Specificity, Limit of detection, Limit of quantitation, Linearity & Range, Robustness and
Ruggedness.
3.2 REVALIDATION CRITERIA
The analytical method shall be revalidated for the following changes.
1. Change in the analytical procedure.

\
2. Change in the synthesis of the drug substance.
3. Change in the guidance documents.
149
4. PLAN OF STUDY
The validation of Residual Solvent (Chloroform, 1,2-Dichloroethane, Benzene and N,N-

Dimethylformamide) method of Cetirizine Dihydrochloride shall be carried out as per the
plan given below:
1. Identification of Residual solvents shall be carried out by injecting Diluent, 1,2-

Dichloroethane, Dichloromethane, Chloroform, 1,2-Dichloroethane, Benzene and
N,N-Dimethylformamide.
2. System suitability shall be assessed by injecting six replicate injections of

Standard solution and calculating RT, RRT, Plate count, Tailing Factor,
Resolution and % RSD of replicate injection.
3. Specificity of the method shall be established with respect to interference study.
4. The Precision study of the analytical method shall be established by injecting six
replicate injections of Standard solution for injection precision and six replicate
injections of Test solution for result precision. (Acceptance criteria: ok RSD NMT
10.00%)
5. Limit of Detection and Limit of Quantitation of residual solvents (i.e. Chloroform,

1,2-Dichloroethane, Benzene and N,N-Dimethylformamide) for the method shall
be established by injecting series of concentration up to lowest detectable
concentration. (Acceptance criteria: to detect minimum concentration of the
compounds for LOD and % RSD for LOQ should not be more than 15.00%)
6. Precision, Accuracy and Linearity curve of residual solvent at LOa level shall
be established.
7. linearity and Range study shall be done at various concentration levels of

individual residual solvent (i.e. Chloroform, 1,2-Dichloroethane, Benzene and
N,N-Dimethylformamide) using the proposed method. Linearity graph shall be
plotted for peak area response against concentration and correlation coefficient
shall be calculated using above data.
150
8. Accuracy study of the method shall be done by spiking of the various

concentrations (i.e.80%, 100%, 120% of the targeted concentration and LOQ
concentration) of residual solvent (i.e. Chloroform, 1,2-Dichloroethane,
Benzene and N,N-Dimethylformamide) (Acceptance criteria: % Recovery
should be between 80.00% to 120.00%)
9. Ruggedness study shall be carried out in similar manner as described in

precision study, by different analyst, on different date, with different instrument
w.r.t. Precision of injection repeatability and test results reproducibility.
10.Robustness study shall be carried out by deliberate change in method

parameter like change in carrier pressure.
Three production batches of Cetirizine Dihydrochloride shall be studied for

residual solvent analysis of Cetirizine Dihydrochloride for data accumulation, by
using the given method.
The conclusion shall be drawn, after assessing the validation data of the above
studies, whether this method can be used for analysis of residual solvent for its
intended purpose of establishing the quality of Cetirizine Dihydrochloride.
~
CHECKED BY APPROVED BY
(Sr. Executive -ARDL) (Manager-ARDL)
DATE: ,.~, 02.1 0' DATE: 2. 4l D'l-io ~
151
5. ABSTRACT AND APPROVAL
Analytical method validation study was carried out for Residual solvents method-2
(Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide) by GC.
Identification of individual residual solvent was done with respect to RT by separately

analyzing Diluent, Acetone, Dichloromethane, Chloroform, 1,2-Dichloroethane, Benzene
and N,N-Dimethylformamide. RT was found 3.74 min. for Acetone, 4.85 min for
Dichloromethane, 8.41 min for Chloroform, 9.99 min. for 1,2-Dichloroethane, 10.73 min.
for Benzene and 15.00 min. for N,N-Dimethylformamide. RRT was 0.16 for Acetone,
0.21 for Dichloromethane, 0.36 for Chloroform, 0.42 for 1,2-Dichloroethane, 0.45 for
Benzene and 0.63 for N,N-Dimethylformamide w.r.t. N,N-Dimethyllmidazolidinone.
System suitability was carried out by injecting six injections of Standard solution and
following system suitability parameters were observed.
Observed
System N,N- Specification
Sr.
suitability 1,2- Benzene Dimethylform limit
No. Chloroform
parameter Dichloroethane
amide
RT (Retention 9.99 10.72 15.00 Informative
1 8.41
Time)
RRT (Relative 0.45 0.63 Informative
2 0.36 0.42
Retention Time)
3 Plate count 15799 29911 34821 194047 Informative
4 Tailing Factor 1.01 0.98 1.02 1.15 Informative
5 Resolution Between 1,2-Dichloroethane & Benzene is 3.19 NLT2.00
6 % RSD [n=6] 0.57 1.32 1.23 0.70 NMT 10.00%
Injection precision study (Injection repeatability) for residual solvent i.e. Chloroform, 1,2-
Dichloroethane, Benzene and N,N-Dimethylformamide was carried out by replicate
analysis of six consecutive injections of Standard solution of residual solvent (i.e.
concentration of Chloroform 60 ppm, 1,2-Dichloroethane 5 ppm, Benzene 2 ppm and
N,N-Dimethylformamide 880 ppm). % RSD was calculated and found 0.57% for
Chloroform, 1.32% for 1,2-Dichloroethane, 1.23% for Benzene and 0.70% for N,N-
Dimethylformamide. This indicates that the precision of the method is well within the limit
of % RSD NMT 10.00%.
Test precision study was also carried out for residual solvent of one the batch B. No.
PP5012CZRI of Cetirizine Dihydrochloride. Chloroform, 1,2-Dichloroethane, Benzene
and N,N-Dimethylformamide is not detected. This is well within the acceptance limit of
15.00% RSD.
152
Specificity of the method was established by analyzing Diluent, Chloroform, 1,2-

Dichloroethane, Benzene, N,N-Dimethylformamide and Standard solution i.e. mixture of
Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide was injected and
all the solvents were found well separated from each other.
The Limit of detection values for residual solvents, for above method were found to be
0.60 ppm for Chloroform, 0.10 ppm for 1,2-Dichloroethane, 0.10 ppm for Benzene, and
88.07 ppm for N,N-Dimethylformamide w.r.t. target concentration (i.e. 0.60 ppm for
Chloroform, 0.10 ppm for 1,2-Dichloroethane, 0.10 ppm for Benzene and 88.07 ppm for
N,N-Dimethylformamide w.r.t. Test).
The Limits of quantitation values for residual solvents were found to be 3.00 ppm for
Chloroform, 0.25 ppm for 1,2-Dichloroethane, 0.20 ppm for Benzene and 176.14 ppm for
N,N-Dimethylformamide w.r.t. target concentration (i.e. 3.00 ppm for Chloroform, 0.25
ppm for 1,2-Dichloroethane, 0.20 ppm for Benzene and 176.14 ppm for N,N-
Dimethylformamide w.r.t. Test).
Linearity and Range study was conducted by analyzing the various concentration levels
of residual solvent i.e. Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide in the synthetic mixture solutions for the concentration range LOa to
150% of the targeted concentrations (3.00 ppm to 90.02 ppm for Chloroform, 0.25 ppm to
7.51 ppm for 1,2-Dichloroethane, 0.20 ppm to 3.00 ppm for Benzene, and 176.14 ppm to
1321.07 ppm for N,N-Dimethylformamide). The Linearity curves were plotted for peak
area responses of Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide
against concentrations of Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide and correlation coefficient was found 0.9981 for Chloroform, 0.9989
for 1,2-Dichloroethane, 0.9961 for Benzene and 0.9992 for N,N-Dimethylformamide.
Accuracy study was carried out by spiking various known concentrations of Chloroform,
1,2-Dichloroethane, Benzene and N,N-Dimethylformamide in Cetirizine Dihydrochloride
test sample and calculating the % Recovery of the same. Accuracy was determined over
the range of 80% to 120% conc. The results of accuracy study, in terms of % recovery
were found in the range of 100.55% to 106.92% for Chloroform, 97.78% to 100.92% for
1,2-Dichloroethane, 103.67% to 106.11% for Benzene and 99.02% to 101.26% for N,N-
Dimethylformamide. Result were well within the acceptable limits 80% to 120%.
153
Accuracy study at LOa level was carried out by spiking lowest quantiable concentration
of Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide in Cetirizine
Dihydrochloride test sample w.r.t. target concentration. The % recovery was found
99.56% for Chloroform, 102.67% for 1,2-Dichloroethane, 101.67% for Benzene and
97.02% for N,N-Dimethylformamide.
Precision at LOa level were carried out by replicate analysis of six consecutive injections
(i.e. 3.00 ppm for Chloroform, 0.25 ppm for 1,2-Dichloroethane, 0.20 ppm for Benzene
and 176.13 ppm for N,N-Dimethylformamide W.r.t. target concentration). The % RSD
was found 1.04 % for Chloroform, 1.00 % for 1,2-Dichloroethane, 1.25 % for Benzene
and 3.29 % for N,N-Dimethylformamide at above concentration (Acceptance criteria: %
RSD is NMT 15.00%)
The Ruggedness of the method was established by analyzing Cetirizine Dihydrochloride

for Residual Solvents in similar manner as precision study, by different analysts, on
different dates, on different instruments w.r.t. Precision of injection repeatability and test
results reproducibility. The method was found to be enough rugged under the acceptable
limit.
Robustness study shall be carried out by deliberately change in carrier gas pressure
method parameter.
The results of three consecutive batches of Cetirizine Dihydrochloride were studied for
residual solvent analysis of Cetirizine Dihydrochloride for data accumulation by using the
same method.
The results are in excellent agreement within the acceptance criteria for Precision,
Linearity and Range, Accuracy study, Specificity, Limit of Detection and Limit of
auantitation, Robustness and Ruggedness etc. Thus this analytical method is
considered as validated for its intended use to establish the method of a Residual
Solvent of Cetirizine Dihydrochloride with consistent results.
&fr
CHECKED BY
APPROVED BY
(Manager -ARDL)
(Officer -ARDL)
DATE: o4/~ ltrC
DATE: O~ \ 04 f 0 6
154
6. DETAIL METHOD AND PREPARATIONS FOR

DETERMINATION OF RESIDUAL SOLVENT IN CETIRIZINE
DIHYDROCHLORIDE
[Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide)
(i) Working standards/Reference samples used in the study
The following samples were used for the study as Standards.
Sr.
Nameof Component Grade Make % Purity
No.
1 Chloroform HPLC arade Merck 99.1%
2 1,2-Dichloroethane Merck
3 Benzene Synthesis grade Merck 100%
4 N,N-Dimethylformamide GR grade Merck 99.8%
(ii) Regular production batches of Cetirizine Dihydrochloride for data

accumulation study
Sr. No. Batch No.

1. PP05011 CZRI
2. PP05012CZRI
3. PP05013CZRI
a) INSTRUMENT (USED FOR VALIDATION STUDY):

IV COLUMN DB-5 Caoillarv column 30m x O.53mm x 5.0um
b) INSTRUMENT (USED FOR RUGGEDNESS STUDY):
I GAS CHROMATOGRAPH Agilent 6890N

II AUTO SAMPLER GERSTEL MPS2
III INTEGRATOR Chemstation
IV COLUMN DB-~ CaDillarv column 30m x O.53mm x 5.0lJ.m
155
c) CHROMATOGRAPHIC CONDITIONS:
Oven Temperature
RATE (OC/MIN TEMPERATURE °C HOLD MIN

0.0 50 8
10 220 5
INJECTOR TEMPERATURE 180°C

DETECTOR TEMPERATURE 220°C
CARRIER GAS Nitroaen
SPLIT FLOW 20 ml/min
CARRIER GAS FLOW 3.0 psi
ATIENUATION -6 (1)
RANGE 1
Headspace Parameter
VIAL OVEN TEMPERATURE 95°C

NEEDLE TEMPERATURE 105°C
TRANSFERLINE TEMPERATURE 115°C
HEADSPACE CARRIER PRESSURE 15 psi
THERMOSTATING TIME 20 min.
PRESSURIZE TIME 2.5 min.
NEEDLE WITHDRAW TIME 0.2 min.
INJECTION VOLUME 0.10 "min.
GC CYCLE TIME 35 min.
INJECTION MODE Time
OPERATING MODE Constant
d) PREPARATION OF SOLUTIONS:

Weigh accurately about 600 mg of Chloroform, 50 mg of 1,2-Dichloroethane, 20
mg of Benzene and 8800 mg of N,N-Dimethylformamide in 100 ml of volumetric
flask containing about 50 ml of diluent, mix and dilute up to mark with diluent. (i.e.
concentration of Chloroform is 6000 ppm, 1,2-Dichloroethane is 500 ppm,
Benzene is 200 ppm and N,N-Dimethylformamide is 88000 ppm)

Take 1 ml of Standard stock solution in 100 ml volumetric flask and dilute with
diluent. (i.e. concentration of Chloroform is 60 ppm, 1,2-Dichloroethane is 5 ppm,
Benzene is 2 ppm and N,N-Dimethylformamide is 880 ppm)
156
RESIDUAL SOLVENT IN CETIRIZINE DlHYDROCHLORIDE (METHOD-2)
III) System suitability solution

IV) Test solution

Weigh accurately about 1.0 g of sample in dry headspace vial and add 1 ml of
diluent
V) Diluent
N,N-Dimethyllmidazolidinone: Water (1:1)
VII) System suitability parameter

1. Resolution between 1,2-Dichloroethane and Benzene is not less than 2.0
2. % RSD of each solvent peak area in six replicate of Standard solution is not
more than 10.00%
Remark
1. Subtract the peak response corresponding to diluent peaks from the Standard
and Test solution.
e) SOLUTION PREPARATION FOR VALIDATION STUDY:
i) Preparation for Identification study
Further dilution
Final conc. of
Name of components Wt. of solvent with diluent
solvent in ppm
(ml~ml)
Acetone 100 mg-7100 ml 107100 100

Dichloromethane 100 mg-7100 ml 107100 100
Chloroform 600 mg-7100 ml 17100 60
1,2-Dichloroethane 50 mg7100 ml 17100 5
Benzene 20 mg-7100 ml 17100 2
N N-Dimethylformamide
I 8800 mg -7 100 ml 17100 880
ii) Preparation for Injection precision [Injection Precision]

iii) Preparation for Test precision [Result Precision]

Same solution as described in Test solution.
157
(Ipea)
iv) Preparation for Accuracy study
a) Standard Solution-I:
b) Standard Solution-II:
c) Standard Solution-III:
Spiked cone. in ppm

Wlof N,N-
Sr. sam pi Spike in HS vial 1,2-
Levels Dimethyl
No. Chlorofo
e (9) Dichlora Benzene
rm formam!
ethane de
01 Parent sample 1.0 -- - - - --

1.0 1ml of Std. 501.-1 48.00 4.00 1.60 704.00
02 Test-1 (80% spiked)
1.0 1ml of Std soL-I 48.00 4.00 1.60 704.00

Test-2 (80% spiked)
1.0 1ml of Std 501.-1 48.00 4.00 1.60 704.00

Test-3 (80% spiked)
Test-1 (100% spiked) 1.0 1ml of Std 501.-111 60.0 5.00 2.00 880.00
03
Test-2 (100% spiked) 1.0 1mJof Std 501.-111 60.0 5.00 2.00 880.00
Test-3 (100% spiked) 1.0 1ml of Std soL-III 60.0 5.00 2.00 8BO.00
Test-1 (120% spiked) 1.0 1ml of Std soL-III 72.00 6.00 2.40 1056.00
04
Test-2 (120% spiked) 1.0 1ml of Std soL-III 72.00 6.00 2.40 1056.00
Test-3 (120% spiked) 1.0 1ml of Std 501.-111 72.00 6.00 2.40 1056.00
158
v) Preparation for Linearity, LOD and LOQ study

Table -1 Dilutions preparation for LOD and LOQ (from std stock solution)
Concentration in ppm
Dilution No. Dilute from stock solution 1,2- N,N-

Chlorofonn Dichloroet Benzene Dimethylfo
hane nnamide
Dilution-11 (0.5%) 1ml 7100m1l0.5ml 7100ml 0.30 0.03 0.01 4.40
Dilution-10 (1.0%) 1ml7100ml/1ml7100ml 0.60 0.05 0.02 8.80
1ml 7100mll2ml 7100ml 1.20 0.10 0.04 17.60

Dilution-9 (2.0%)
1ml 7100mll5ml 7100ml 3.00 0.25 0.10 44.00
Dilution-8 (5.0%)
1ml7100ml/10ml7100ml 6.00 0.50 0.20 88.00
Dilution-7 (10%)
12.00 1.00 0.40 176.00
Dilution-6 (20%) 0.2mI7100ml
Cone. =Coneentration
Table -2 Dilutions preparation for Linearity (from std stock solution)
Dilution No. Dilute from Stock solution Concentration in ppm
1,2. N,N.
Chlorofonn Dichloroet Benzene Dimethylfo
hane nnamide
30.00 2.50 1.00 440.00

Dilution-5 (50%) 0.5m17100ml
48.00 4.00 1.60 704.00
Dilution-4 (80%) 0.8ml 7100ml
60.00 5.00 2.00 880.00
Dilution-3 (100%) 1.0m17100ml
1.2mI7100ml 72.00 6.00 2.40 1056.00

Dilution-2 (120%)
1.5m17100ml 90.00 7.50 3.00 1320.00

Dilution-1 (150%)
ConcA = Concentration
VI) Preparation for Data Accumulation study
VII) Preparation for Ruggedness study
159
Calculation formula:
AT WS 1 1
% of Residual solvents = --x --X--X
AS 100 100 WT
,
AT = Peak area response obtained from the Test solution WT = Weight of Test Solution in mg.
AS = Mean peak area response obtained from the Standard WS = Weight of Standard in mg.
Solution
1 1
(b) ppm of Chloroform = X X X X 106 = ppm
100 100
r
Results: Chloroform in ppm :: ppm [Limit: NMT 60 ppm]
1 1
(b) ppm of 1,2-Dichloroethane = X X X X 106 =_ppm
100 100
Results: 1,2-Dichloroethane in ppm :: ppm [Limit: NMT 5 ppm]
1 1
(c) ppm of Benzene = X X X X 106 =_ppm
100 100
Results: Benzene in ppm = ppm [Limit: NMT 2 ppm]
(d) ppm of N,N-

1 1
X X X X 106 =_ppm
Dimethylformamide = 100 100
Results: N,N-Dimethylformamide in ppm = ppm [Limit: NMT 880 ppm]
Specification Limit:
Chloroform Not more than 60 ppm
1,2-Dichloroethane Not more than 5 ppm
Benzene Not more than 2 ppm
N,N-Dimethylformamide Not more than 880 ppm
160
.
7. IDENTIFICATION
Solutions were separately prepared, containing known concentrations of Acetone 100

ppm, Dichloromethane 100 ppm, Chloroform 60 ppm, 1,2-Dichloroethane 5 ppm,
Benzene 2 ppm and N,N-Dimethylformamide 880 ppm.
Table No. 7.1 represents data of Retention Times/Relative Retention Times of solvents.
TABLE NO-7.1
IDENTIFICATION OF RESIDUAL SOLVENTS

Name of Solvents 01 of 02 02 of 02 Mean
No.
Acetone 3.74 3.74 3.74 0.16
1.
Dichloromethane 4.84 4.85 4.85 0.21
2.
Chloroform 8.41 8.41 8.41 0.36
3.
1,2-Dichloroethane 9.99 9.99 9.99 0.42
4.
Benzene 10.72 10.73 10.73 0.45
5.
6. N,N-Dimethylformamide 15.00 14.99 15.00 0.63
REMARKS:
Acetone, Dichloromethane, Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide peaks are well separated from each other.
~
PE;KBV
(Officer- ARDL)
CHECKED BY
(Sr. Executive -ARDL)
DATE: O:tI03 ftr6 DATE: C)')..lo~lob
161
8. STANDARD METHOD AND PREPARATIONS FOR

DETERMINATION OF RESIDUAL SOLVENTS IN
[CHLOROFORM, 1,2-DICHLOROETHANE, BENZENE AND N,N..
DIMETHYLFORMAMIDE]
All the detected residual solvents were found well separated by the above GC method.
(From six consecutive injections of Standard solution)
Table No. 8.1 represents data of RT and RRT of Chloroform, 1,2-Dichloroethane,

Benzene and N,N-Dimethylformamide.
The respective chromatograms attached with precision study (Standard solution n = 6)
162
8.1 SEPARATION OF CHLOROFORM, 1,2-DICHLOROETHANE,

BENZENE AND N,N-DIMETHYLFORMAMIDE BY RT/RRT
W.R.T. N,N-DIMETHYL IMIDAZOLIDINONE
[Standard solution of Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimelhylformamide in diluent]
TABLE NO - 8.1
Name of compound: Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide
N,N-
1,2- DIMETHYLFORMA
CHLOROFORM BENZENE
INJ. DICHLOROETHANE MIDE
NO.
RT RRT RT RRT RT RRT RT RRT
10f6 8.40 0.36 9.99 0.42 10.72 0.45 15.00 0.63
20f6 8.44 0.36 10.02 0.42 10.75 0.45 15.02 0.64
30f6 8.40 0.36 9.99 0.42 10.72 0.45 15.00 0.63
40f6 8.40 0.36 9.98 0.42 10.72 0.45 15.00 0.63
50f6 8.41 0.36 9.98 0.42 10.72 0.45 15.00 0.63
60f6 8.40 0.36 9.98 0.42 10.71 0.45 15.00 0.63
Mean 8.41 0.36 9.99 0.42 10.72 0.45 15.00 0.63
so:!: 0.016 0.000 0.015 0.000 0.014 0.000 0.006 0.004
%RSD 0.19 0.00 0.16 0.00 0.13 0.00 0.05 0.65
This data taken from six consecutive injections of Standard solution from Precision study.
~
PERF!£OBV
(Officer-ARDL)
CHECKED BY
DATE: {)~10BIlrb DATE: rollS3l ($ f,
163
8.2 SYSTEM SUITABiliTY
The System suitability of above method was carried out by calculating RRT, Plate count,
Tailing Factor and Resolution between 1,2-Dichloroethane & Benzene and selecting the
acceptance limits.
Inject the Standard solution to check the system suitability parameters of components.
The following system suitability requirements were assessed.
System suitability parameters:

Specification
Observed limit
System
Sr. N,N-
suitability 1,2-
No. Benzene Dimethylfor Informative
parameter Chlorofonn Dichloroeth
ane mamide
RT (Retention 10.72 15.00 Informative

1 8.41 9.99
Time)
RRT (Relative
2 Retention 0.36 0.42 0.45 0.63 Informative
Time)
3 Plate count 15799 29911 34821 194047 Informative
4 Tailing Factor 1.01 0.98 1.02 1.15 Informative
5 Resolution Between 1,2-Dichloroethane & Benzene is 3.19 NLT2.00
6 % RSD (n=6J 0.57 1.32 1.23 0.70 NMT 10.00%
Table No. 8.2.1 to 8.2.5 represents data on system suitability parameter for six replicate
injections of Standard solution.
The respective chromatograms taken from Standard solution of Precision study are
enclosed herewith.
164
RESIDUAL SOLVENT IN CETIRIZINE DIHYDROCHLORIDE (METHOO-2)
Table No. 8.2.1
(A) *RETENTION TIME [RT] (In min)

Standard solution (Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide)
NUMBER OF INJECTION STATISTICAL ANALYSIS

Name of components
I III
Chloroform 8.40 "
8.44 8.40
IV
8.40
V
8.41 8.40
VI MEAN
8.41
SO:!:
0.016
%RSD
0.19
MIN.
8.40
MAX.
8.44
1,2.Dichloroethane 9.99 10.02 9.99 9.98 9.98 9.98 9.99 0.015 0.16 9.98 10.02
Benzene 10.72 10.75 10.72 10.72 10.72 10.71 10.72 0.014 0.13 10.71 10.75
N,N.Dimethylformamide 15.00 15.02 15.00 15.00 15.00 15.00 15.00 0.008 0.05 15.00 15.02
SIXreplicate Injection data for system suitability taken from standard solution of Precision study.
*System suitability parameters by using software TotalChrom.
REMARKS: The above results of system suitability parameters were found satisfactory and well within acceptable
range of system suitability requirements.
PE~EDBY CHECKED BY
(Officer AROL)
DATE: OS/!l~I~
DATE: V~IO'bl0-6
165
Table No. 8.2.2

(B) *RELATIVE RETENTION TIME [RRT] (w.r.t. N, N-Dimethyllmidazolidinone)


Name of components
I II III IV V VI MEAN SO:!:: %RSD MIN. MAX.
Chloroform 0.36 0.36 0.36 0.36 0.36 0.36 0.36 0.000 0.00 0.36 0.36
1,2-Dichloroethane 0.42 0.42 0.42 0.42 0.42 0.42 0.42 0.000 0,00 0.42 0.42
Benzene 0.45 0.45 0.45 0.45 0.45 0.45 0.45 0.000 0.00 0.45 0.45
N,N-Dimethylformamide 0.63 0.64 0.63 0.63 0.63 0.63 0.63 0.004 0.65 0.63 0.64
SIXreplicate injection data for system suitability taken from standard solution of Precision study .
•System suitability parameters by using software TotalChrom.
PE~EDBY CHECKED BY
(Officer ARDL) (Sr. Executive -ARDL)
DATE: o,glo!3' ~ DATE: o~I62>'ob
166
Table No. 8.2.3
(C) .PLATE COUNT
Name of NUMBER OF INJECTION STATISTICAL ANALYSIS

components
I II III IV V VI MEAN SD:t: %RSD MIN. MAX.
Chloroform 16008 13656 16406 16723 15829 16170 15799 1095.162 6.93 13656 16723
1,2-Dichloroethane 29644 31112 30700 29529 28631 29852 29911 885.891 2.96 28631 31112
Benzene 34588 36186 33997 34686 34888 34582 34821 731.618 2.10 33997 36186
N,N-
189671 171961 223711 196126 189807 193006 194047 16794.506 8.65 171961 223711
Dimethylformamide
Six replicate injection data for system suitability taken from standard solution of Precision study .
~
pEifMEDBY
(Officer ARDL)
CHECKED BY
DATE: o,g(oglltC DATE: ~16?>lo.(,.
167
Table No. 8.2.4
(D) *TAILING FACTOR

Standard solution (Chloroform. 1,2-Dichloroethane, Benzene and N, N-Dimethylformamide)

Name of components
I II III IV V VI MEAN SD:t %RSD MIN. MAX.
Chloroform 1.01 1.00 1.02 1.03 1.00 1.00 1.01 0.013 1.25 1.00 1.03
1,2-Dichloroethane 0.96 0.97 0.97 0.97 0.96 0.98 0.98 0.005 0.56 0.97 0.98
Benzene 1.02 1.03 1.03 1.00 1.01 1.03 1.02 0.013 1.24 1.00 1.03
N,N-Dimethylformamide 1.21 1.18 1.12 1.10 1.13 1.14 1.15 .(l041 3.56 1.10 1.21
SIXreplicate injection data for system suitability taken from standard solution of Precision study .
~
P&EDBY CHECKED BY
(Officer ARDL)
(Sr. Executivp- -ARDL)
DATE: 0..5)1l31lft' DATE: ~2p.lo~
168
Table No. 8.2.5

(E) *RESOLUTION
Standard solution (Chloroform, 1,2-Dichloroethane. Benzene and N,N-Dimethylformamide)

Name of components
I II III IV V VI MEAN SD:!: %RSD MIN. MAX.
Resolutionbetween 1,2-
Dichloroethaneand 3.19 3.23 3.19 3.19 3.17 3.19 3.19 0.020 0.64 3.17 3.23
Benzene
"System suitability parameters by using software TotalChrom.
~-
PERFORMEDBY
~
CHECKED BY
(Officer ARDL) (Sr. Executive -ARDL)
DATE: O.sIO~I~ DATE: 0!:>(o3Iok,
169
Table No. 8.2.6
SYSTEM SUITABiliTY DATA AT A GLANCE
Mean Mean
Components *RT *RRT *Plate *Tailing %RSD
counts factor *Resolution
(Min) (n=6)
Chloroform 8.41 0.36 15799 1.01 0.57

Resolution
1,2.;Dich/oroethane 9.99 0.42 29911 0.98 between 1,2- 1.32
Dichloroethane
Benzene 10.72 0.45 34821 1.02 and benzene is 1.23
3.19
N N-
I
Dimethylformamide 15.00 0.63 194047 1.15 0.70
*Mean of six replicate injections. [RRTw.r.t. N,N-Dimethyllmidazolidinone]
Remarks: The above results of system suitability parameters was found satisfactory
and well within acceptable range of system suitability requirements.
PER!£EDBY
(Officer-ARDL)
~
CHECKED BY
DATE: oglo,;;et(; DATE: C'b( o;'{C6
170
9. METHOD VALIDATION
"Validation of a method is the process by which a

method is tested by the developer or user for
reliability, accuracy and preciseness for its intended
purpose",
As per the cGMP regulation guidelines the test method, which are used for assessing
the quality of pharmaceutical products with established specifications, must be validated
for analytical performance parameters described in the USP29 under section 1225
"Validation of compendial method"
Typical analytical parameters used for method validation
9.1 Precision
9.2 Specificity
9.4 Limit of Quantitation
9.5 Linearity and range
9.6 Accuracy
9.7 Ruggedness
9.8 Robustness
171
9.1 PRECISION STUDY

Precision study was carried out by injection precision and result precision, performing
the six consecutive injections of Standard solution and calculating % RSD of the peak
area response obtained due to residual solvent i.e. Chloroform, 1,2-Dichloroethane,
Benzene and N,N-Dimethylformamide. Residual solvent analysis of Cetirizine
Dihydrochloride was carried out to establish the result reproducibility by replicate
injections of the Test sample against the same Standard solution and calculating %RSD
of the peak response of the Residual solvent from replicate injections.
From the above injection precision study it is evident that %RSD of peak areas for
Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide (for six
consecutive injections) was found 0.57%, 1.32%, 1.23% and 0.70% respectively. This is
well within the acceptance limit NMT 10.00% RSD.
From the result precision study it is evident that Chloroform, 1,2-Dichloroethane,

Benzene and N,N-Dimethylformamide was not detected. This is well within the
acceptance limit NMT 15.00% RSD of result.
Table No. 9.1.1 represents the precision study data (injection precision) for peak areas
of residual solvent (i.e. Chloroform, 1,2-Dichloroethane, . Benzene and N,N-
Dimethylformamide) in Standard solution.
Table No. 9.1.2 represents the precision study data of results of residual solvent (i.e.
Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide) in Cetirizine
Dihydrochloride Test solution (result reproducibility).
The respective chromatograms of above studies are enclosed herewith.
PREPARATION OF SOLUTIONS FOR PRECISION STUDY:

Weigh accurately about 600 mg (weighed 600.10 mg) of Chloroform, 50 mg (weighed
50.06 mg) of 1,2-Dichloroethane, 20 mg (weighed 20.03 mg) of Benzene and 8800 mg
(weighed 8807.1 mg) of N,N-Dimethylformamide in 100 ml of volumetric flask containing
about 50 ml of N,N-Dimethyllmidazolidinone as diluent, mix and dilute up to mark with
diluent.

Take 1.0 ml of Standard stock solution in 100 ml volumetric flask and dilute with diluent.

IV) Test solution. .

Weigh accurately about 1.0 g of sample in dry headspace vial and add 1 ml of diluent
and seal it properly.
172
TABLE NO- 9.1.1
PRECISION STUDY
(Injection Reproducibility)
Name of compounds: Chloroform, 1,2-Dichloroethane, Benzene and N,N-

Dimethylformamide
INJ. NO. CHLOROFORM

1,2- BENZENE
N,N-
OICHLOROETHANE OIMETHYLFORMAMIOE
10f6 716543 151788 196898 60896
20f6 722919 156080 203265 61592
30f6 724292 156166 201496 61280
40f6 719092 155412 201347 62094
50f6 722502 151813 198005 61599
60f6 728333 153649 198685 61893
Mean 722280 154151 199949 61559
SOt 4104.17 2033.39 2450.67 428.46
%RSD 0.57 1.32 1.23 0.70
REMARKS: From the above injection precIsIon study. it is evident that Relative
Standard Deviation of peak area response of six consecutive injections for Chloroform,
1,2-Dichloroethane, Benzene and N,N-Dimethylformamide were found 0.57%, 1.32%,
1.23%, and 0.70% respectively. This is well within the acceptance limit of % RSD NMT
10.00%.
; ".,'
~
~
(Officer-ARDL) (Sr. Executive -ARDL)
DATE: ~, a~ l 6b DATE: (j3)~J 06
173
TABLE NO- 9.1.2

PRECISION STUDY
(RESULTS PRECISION STUDY)
Standard solution containing Mean Area %RSD

Chloroform 722280 0.57
1,2-Dichloroethane 154151 1.32
Benzene 199949 1.23
N,N-Dimethylformamide 61559 0.70
Batch used for study PP5012CZRI
Weight Area of ppm of Area of ppm of
Sr. of Area of ppm of 1,2- 1,2- Area of ppm of N,N- N,N-
No. sample Chloroform Chloroform Dichloro Dichloroe Benzene Benzene Dimethylf Dimethylfo
(mg) ethane thane ormamide nnamide
I
1 1030.1 - NO -- NO -- NO - NO
2 1056.2 -- NO --- NO --- NO - NO
3 1023.9 -- NO - NO -- NO - NO
4 1009.7 - NO - NO - NO -- NO
5 1040.3 -- NO - NO -- NO -- NO
6 I 1019.5 - NO - NO -- NO - NO
STATISTICAL ANAL YSIS

Mean - -- - - .- - -- -
SO - - - -- - - - -
%RSD - - -- - - - - -
REMARKS:
The ppm content of Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide
was found not detected. This is well within the acceptance limit of 15.00% RSD.
PE.EDBY CHECKED BY
(Officer-ARDl) (Sr. Executive -ARDl)
DATE: O~lo~l 0'( DATE: 03>1 Cl~lob
174
9.2 SPECIFICITY STUDY
Specificity/selectivity of the method was established by analyzing Diluent. Acetone,

Dichloromethane, Chloroform. 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide separately. Standard solution i.e. mixture of Chloroform, 1,2-
Dichloroethane. Benzene and N,N-Dimethylformamide was injected and all the solvents
were found well separated from each other.
Table 9.2.1 represent specificity/selectivity of the method for analysis of residual solvent
in Cetirizine Dihydrochloride.
The respective chromatograms with Identification study are enclosed.
TABLE NO- 9.2.1
SPECIFICITY
Sr. Retention Time 'Rn

Name of Solvents RRT
No. 01 of 02 02 of 02 Mean
1. Acetone 3.74 3.74 3.74 0.16
2. Dichloromethane 4.84 4.85 4.85 0.21
3. Chloroform 8.41 8.41 8.41 0.36
4. 1,2-Dichloroethane 9.99 9.99 9.99 0.42
5. Benzene 10.72 10.73 10.73 0.45
6. N,N-Dimethylformamide 15.00 14.99 15.00 0.63
REMARKS:
Acetone, Dichloromethane, Chloroform, 1,2-Dichloroethane, Benzene and N,N-

Dimethylformamide peaks are well separated from each other and also from N,N-
Dimethyl Imidazolidinone peak.
~
P~MEDBY CHECKED BY
DATE: 0"'03/ bb DATE: 02lt"3)O~
175
9.3 LIMIT OF DETECTION

The above study was conducted for establishing the limit of detection of Chloroform,
1,2-Dichloroethane, Benzene and N,N-Dimethylformamide. LOD of the given residual
solvents was determined by injecting replicates of synthetic mixture of Chloroform, 1,2-
Dichloroethane, Benzene and N,N-Dimethylformamide having different serial
concentration levels.
The lowest detection response for Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide was established w.r.t. target concentration.
Table No. 9.3.1 to 9.3.4 represent the minimum detector response of Chloroform. 1.2-
Dichloroethane, Benzene and N,N-Dimethylformamide.
PREPARATION OF SOLUTIONS FOR LODI LOa STUDY:
Standard Stock solution:

Weigh accurately about 600 mg (weighed 600.10 mg) of Chloroform, 50 mg (weighed
50.06 mg) of 1,2-Dichloroethane, 20 mg (weighed 20.03 mg) of Benzene and 8800 mg
(weighed 8807.1 mg) of N,N-Dimethylformamide in 100 ml of volumetric flask containing
about 50 ml of N,N-Dimethyllmidazolidinone as diluent, mix and dilute up to mark with
diluent.
LOD/Loa solutions are prepared as follows:

Pipette out 1.5 ml Standard stock solution into 100 ml volumetric flask dilute up to mark
with diluent.

with diluent.

with diluent.

Pipette out 0.8"11 Standard stock solution into 100 ml volumetric flask dilute up to mark
with diluent.

with diluent.
176

with diluent.

Pipette out 10.0 m1100% Standard solution into 100 ml volumetric flask dilute up to
mark with diluent.
Pipette out 5.0 m1100% Standard solution into 100 ml volumetric flask dilute up to mark
with diluent.
Pipette out 2.0 m1100% Standard solution into 100 ml volumetric flask dilute up to mark
with diluent.
Pipette out 1.0 ml1 00% Standard solution into 100 ml volumetric flask dilute up to mark
with diluent.

Pipette out 0.5 ml 100% Standard solution into 100 ml volumetric flask dilute up to mark
with diluent.
177
TABLE NO-9.3.1

Limit of detection data for Chloroform
Conc. of component
Sr. No. w.r.l test sample REMARKS
w.r.t. target cone.
ppm ppm
Dilution-10 (1.0%) 0.60 0.60 -V
Dilution-9 (2.0%) 1.20 1.20 -V
Dilution-8 (5.0%) 3.00 3.00 -V
Dilution-7 (10%) 6.00 6.00 -V
Dilution-6 (20%) 12.00 12.00 -V
Dilution-5 (50%) 30.01 30.01 ~
Dilution-4 (80%) 48.01 48.01 ~
Dilution-3 (100%) 60.01 60.01 -V

Dilution-2 (120%) 72.01 72.01 ~
Dilution-1 (150%) 90.02 90.02 -V
-v = Detected
REMARKS: On the basis of above data the Limit of Detection for Chloroform was found
0.60 ppm w.r.t. target concentration and 0.60 ppm W.r.t. Test solution. (Preliminary
observation)
CHECKED BY
DATE: 06(03'0(',
178
TABLE NO-9.3.2

Limit of detection data for 1,2-Dichloroethane
Cone. of component
Sr. No. w.r.t. target cone. w.r.l test sample REMARKS
ppm ppm
Di/ution-9 (2.0%) 0.10 0.10 ""
Di/ution-8 (5.0%) 0.25 0.25 ""
Dilution-7 (10%) 0.50 0.50 ""
Dilution-6 (20%) 1.00 1.00 ""
Di/ution-5 (50%) 2.50 2.50 ""
Di/ution-4 (80%) 4.00 4.00 ~
Dilution-3 (100%) 5.01 5.01 ""
Di/ution-2 (120%) 6.01 6.01 ~
Dilution-1 (150%) 7.51 7.51 ""
...J = Detected
REMARKS: On the basis of above data the Limit of Detection for 1,2-Dichloroethane
was found 0.10 ppm w.r.t. target concentration and 0.10 ppm w.r.t. Test solution.
~
PE~EDBY CHECKED BY
DATE: ~[D31~ DATE: 06[o8[ok
179
TABLE NO.9.3.3

Limit of detection data for Benzene
Conca of component
Sr. No. w.r.t. target conca W.f.t. test sample REMARKS
ppm ppm
Dilution-8 (5.0%) 0.10 0.10 V
Dilution-? (10%) 0.20 0.20 V
Dilution-6 (20%) 0.40 0.40 V
Dilution-5 (50%) 1.00 1.00 V
Dilution-4 (80%) 1.60 1.60 -J
Dilution-3 (100%) 2.00 2.00 -J
Dilution-2 (120%) 2.40 2.40 -J
Dilution-1 (150%) 3.00 3.00 -J
-J = Detected
REMARKS: On the basis of above data the Limit of Detection for Benzene was found
0.10 ppm w,r.t. target concentration and 0.10 ppm w.r.t. Test solution. (Preliminary
observation)
~
PE~DBY CHECKED BY
DATE: 061 0;) ~ DATE: 0 6\ o~1 Ob
180
TABLE NO-9.3.4

Limit of detection data for N,N-Dimethylformamide
Cone. of component
Sr. No.
w.r.t. target cone. w.r.t. test sample REMARKS
j)pm ppm
Dilution-7 (10%) 88.07 88.07
Dilution-6 (20%)
Dilution-5 (50%)
176.14
440.36
176.14
""
Dilution-4 (80%)
Dilution-3 (100%)
704.57
880.71
440.36
704.57
880.71
""
""
Dilution-2 (120%) 1056.85 1056.85
Dilution-1 (150%) 1321.07 1321.07
"
" = Detected
REMARKS: On the basis of above data the Limit of Detection for N,N-
Dimethylformamide was found 88.07 ppm w.r.t. target concentration and 88.07 ppm
w.r.t. Test solution. (Preliminary observation)
~~
P~EDBY CHECKED BY
DATE: ~,'O~
(Officer-ARDL)
\<%
DATE:06101(0'
181
9.4 LIMIT OF QUANTITATION
The Limit of Quantitation was established by analyzing for acceptable precision of

synthetic mixture of Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide having the concentration as below. (Acceptance criteria: % RSD
NMT 15.00%)
Table No. 9.4.1 represent the limit of quantitation and detection data for Chloroform,
1,2-Dichloroethane, Benzene and N,N-Dimethylformamide.
Table No. 9.4.2 represents the Precision at LOQ Level of Chloroform, 1,2-
182
TABLE NO-9.4.1
LIMIT OF DETECTION AND QUANTITATION
[For Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide)
LIMIT OF DETECTION LIMIT OF QUANTITATION

Sr. NAME OF w.r.l Test w.r.l Test
w.r.t. Target w.r.t. Target
No. COMPONENT solution solution
conc. (ppm) conc. (ppm) (ppm)
(DDm)
1 Chloroform 0.60 0.60 3.00 3.00
2 1,2-Dichloroethane 0.10 0.10 0.25 0.25
3 Benzene 0.10 0.10 0.20 0.20
N ,N- 88.07 176.14 176.14

4 88.07
Dimethylformamide
PEaEDBY CHECKED BY
DATE: ~ 1'03) fi(, I
DATE: of, 'l)~{o-6
183
PREPARATION OF LOQ STANDARD SOLUTION:
Standard stock solution of Chloroform:

Weigh accurately about 600 mg (weighed 600.03 mg) of Chloroform in 100 ml of
with diluent.
Standard stock solution of 1,2-Dichloroethane:

Weigh accurately about 50 mg (weighed 50,09 mg) of 1,2-Dichloroethane in 100 ml of
with diluent.
Standard stock solution of Benzene:

Weigh accurately about 20 mg (weighed 20.06 mg) of Benzene in 100 ml of volumetric
with diluent.
Standard stock solution of N,N-Dimethylformamide:

Weigh accurately about 8800 mg (weighed 8806.3 mg) of N,N-Dimethylformamide in
100 ml of volumetric flasks containing diluent, and dissolve and dilute up to mark with
diluent.
LOQ standard solution:

Pipette out 5 ml of Standard stock solution of Chloroform, 5 ml of Standard stock
solution of 1,2-Dichloroethane, 10 ml of Standard stock solution of Benzene and 0.2 ml
of Standard stock solution of N,N-Dimethylformamide into 100 ml volumetric flask, dilute
upto the mark.
184
TABLE NO-9.4.2
(Synthetic mixture solution containing 3.00 ppm of Chloroform, 0.25 ppm of 1,2-
Dichloroethane, 0.20 ppm of Benzene and 176.01 ppm of N,N-
Dimethylformamide w,r.t. target concentration)
AREA RESPONSE
Sr. No. 1,2- N,N-
CHLOROFORM OICHLOROETH BENZENE DIMETHYLFOR
ANE MAMIOE
1. 44222 9504 23935 10458
2. 43984 9438 23745 10256
3. 43985 9570 23468 10970
4. 44517 9310 23823 10052
5. 43711 9532 23509 10705
6. 44989 9409 24272 10791
MEAN 44235 9461 23792 10539
SO:!: 457.88 94.66 296.34 346.59
%RSD 1.04 1.00 1.25 3.29
REMARKS: The % RSD were found 1.04 % for Chloroform, 1.00 % for 1,2-
Dichloroethane, 1.25 % for Benzene and 3.29 % for N,N-Dimethylformamide at above
concentration (Acceptance criteria: % RSD NMT15.00 %)
PE~EDBY CHECKED BY
DATE: O~\o81~ DATE: 08\ ~lo.6
185
9.5 LINEARITY AND RANGE
Linearity and Range for determination of residual solvent of Cetirizine Dihydrochloride

were studied by measuring the peak area responses of residual solvent i.e. Chloroform,
1,2-Dichloroethane, Benzene and N,N-Dimethylformamide at different serial
concentration levels as below.
(LOa to 150% targeted analyzing concentration). By using stock solution of Chloroform,

1,2-Dichloroethane, Benzene and N,N-Dimethylformamide.
Linearity curves were plotted for peak area responses against concentrations for given
compounds and correlation coefficients were calculated for the same using linearity data
and were found as 0.9981 for Chloroform, 0.9989 for 1,2-Dichloroethane, 0.9961 for
Benzene and 0.9992 for N,N-Dimethylformamide. (Acceptance criteria: Correlation
coefficient NLT 0.9800)
Table 9.5.1 represents Linearity and range data of Residual solvent i.e. Chloroform, 1,2-
The respective chromatograms and linearity curve of above study are enclosed
herewith.
PREPARATION OF SOLUTIONS FOR LINEARITY STUDY:
Use LaD/LaO solutions for this study.
186
TABLE NO-9.5.1
LINEARITY AND RANGE STUDY
Cone. (DDm) *Area Cone. (DPm) *Area Cone. (ppm) *Area Cone. (DPm) *Area
Level N,N-Dimeth Iformamide
Chloroform 1,2-Diehloroethane Benzene
LOa 3.00 40136 0.25 9273 0.20 19323 176.14 11239
50% 30.01 361186 2.50 74526 1.00 88753 440.36 31067
80% 48.01 647818 4.00 127447 1.60 166486 704.57 52929
100% 60.01 808940 5.01 162314 2.00 218389 880.71 66816
120% 72.01 980513 6.01 188492 2.40 256666 1056.85 81629
150% 90.02 1287100 7.51 246382 3.00 347746 1321.07 106594
Correlation 0.9961 0.9992

0.9981 0.9989
, coefficient
Slope 14318.35 32591.000 117252.89 82.83
Intercept -35604.33 -2579.544 -16735.01 -4842.44
••Mean area of Standard [n=3]
REMARKS:
The Linearity curve was plotted for peak area responses against concentration. The correlation coefficient was calculated
usingthe linearitydata. The correlation coefficients were found 0.9981 for Chloroform, 0.9989 for 1,2-Dichloroethane, 0.9961
for Benzene and 0.9992 for N,N-Dimethylformamide, which is within the limit. (Acceptance criteria: Correlation coefficient
NLT 0.9800)
~
~
DATE: ~loS}j;(. DATE: 061'C>310b
187
Linearity of Chloroform
Conc.(ppm) Area Regg area

5%(LOQ) 3.00 40136 7351
50% 30.01 361186 394089
80% 48.01 647818 651820
100% 60.01 808940 823640
120% 72.01 980513 995460
150% 90.02 1287100 1253333
Corrcoeff 0.9981
Slope 14318.35
Intercept -35604.33
1400000 Linearity of Chlorofonn

o
1200000
1000000
800000
ca
~
e
600000 .
400000
o Area
200000
-Reggarea
o
10.00 20.00 30.00 40.00 50.00 60.00 70.00 80.00 90.00 100.00
0.00
Concentration (ppm)
~
CHECKED BY
P~DBY (Sr. Executive -ARDL)
(Officer-ARDL) DATE: ob\~I()b
DATE: lJ'G1051 ~
188
Linearity of 1,2-Dichloroethane

5%(LOQ) 0.25 9273 5578
50% 2.50 74526 78996
80% 4.00 127447 127941
100% 5.01 162314 160571
120% 6.01 188492 193201
150% 7.51 246382 242146
Corr coeff 0.9989

Slope 32591.00
Intercept -2579.54
300000
Linearity of 1,2-Dichloroethane
250000
200000
ClI
f150000
«
100000
50000
o Area
-Reggarea
a --.----.---.--------,--- i
0.00 1.00 2.00 3.00 4.00 5.00 6.00 7.00 8.00

Concentration (ppm)
M
PERFORMEDBY CHECKED BY
(Officer-ARDL)
DATE: ~Io~l~ DATE: 0.6102;.1 00k.
189
Linearity of Benzene

10%(LOQ) 0.20 19323 6751
50% 1.00 88753 100694
80% 1.60 166486 171151
100% 2.00 218389 218123
120% 2.40 256666 265094
150% 3.00 347746 335551
Corrcoeff 0.9961
Slope 117252.89
Intercept -16735.01
400000
Linearity of Benzene
350000 o
300000
250000
ClI
e
c(
200000
150000
100000
50000 CI Area
-Reggarea
0
0.00 0.50 1.00 1.50 2.00 2.50 3.00 3.50
Concenbation(ppm)
CHECKED BY
0"
DATE: t)6/ o.b'
190
Linearity of N,N-Dimethylformamide

20%(LOQ) 176.14 11239 9747
50% 440.36 31067 31631
80% 704.57 52929 53516
100% 880.71 66816 68105
120% 1056.85 81629 82695
150% 1321.07 106594 104579
Corr coeff 0.9992

Slope 82.83
Intercept -4842.44
120000 Linearity of N,N~Dimethylformamide
100000
80000
III
e 60000
c(
40000
20000 o Area
-Reggarea
o 800.00 1000.00 1200.00 1400.00

0.00 200.00 400.00 600.00
Concentration (ppm)
PER~-B-Y--- CHECKED BY
(Officer-ARDL) DATE: 06/ a31~b
DATE: mlo ,3",r
191
9.6 ACCURACY STUDY
Accuracy study was carried out by spiking various known concentrations of Chloroform,
1,2-Dichloroethane, Benzene and N,N-Dimethylformamide in Cetirizine Dihydrochloride
Test sample and calculating the % recovery. Accuracy was determined over a range of
concentrations from 80% to 120%. The result of accuracy study in term of %recovery
were found in the range of 100.55% to 106.92% for Chloroform, 97.78% to 100.92% for
1,2-Dichloroethane, 103.67% to 106.11% for Benzene and 99.02% to 101.26% for N,N-
Dimethylformamide. The results were found well within the acceptable limits i.e.
between 80% to 120%.
% recovery of LOa Level was found 99.56% for Chloroform, 102.67% for 1,2-
Dichloroethane, 101.67% for Benzene and 97.02% for N,N-Dimethylformamide.
Table 9.6.1 to 9.6.4 represents recovery data of Chloroform, 1,2-Dichloroethane,

Benzene and N,N-Dimethylformamide for 80% to 120% and LOa level concentration.
PREPARATION OF SOLUTIONS:

Use LOa standard solution from LOa precision study.



Formulae used to calculate accuracy:
Corrected area of solvent

Recovery in ppm - X Concentration of Standard solution in ppm
Area of Standard solution
Recovery in ppm X 100

% Recovery -----------
Added concentration in ppm
192
TABLE NO- 9.6.1
ACCURACY STUDY
RECOVERY STUDY OF CHLOROFORM IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
%Recovery calculated by mean area of Chloroform from Standard solution [n=6] CHLOROFORM
Mean Area 696623
%RSD 1.35
Mean area of Chloroform in Parent sample [n=3] Not detected

Cone. of only for added
Area counts for Test Recovered against Mean %RSD
Test Level Chloroform added Chloroform (After % Recovery
+ Added Chloroform added amount In ppm (n=3) (n=3)
(ppm) subtracting the parent
area)
Test-1 34396 34396 2.96 98.67
LOa Test-2 3.00 35155 35155 3.03 101.00 99.56 1.27
Test-3 34534 34534 2.97 99.00
Test-1 568864 568864 49.00 102.06
80% Test-2 48.01 562125 562125 48.42 100.85 100.55 1.68
Test-3 550250 550250 47.40 98.73
Test-1 701636 701636 60.44 100.72
100% Test-2 60.01 696766 696766 60.02 100.02 101.24 1.53
Test-3 717392 717392 61.80 102.98
Test-1 892754 892754 76.91 106.80
120% Test-2 72.01 911331 911331 78.51 109.03 106.92 1.91
Test-3 877205. 877205 75.57 104.94
REMARKS:
The results of accuracy study in terms of % recovery were found in the range of 100.55% to 106.92% for Chloroform and recovery at LOa level was found
99.58%. These are well within the acceptance range of 80% to 120%.
P~EDBY CHECKED BY
DATE: OCJloSl~ I
DATE: oq a3106
193
TABLE NO- 9.6.2
ACCURACY STUDY
RECOVERY STUDY OF 1 ,2-DICHLOROETHANE IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
%Recoverv calculated by mean area of 1.2-Dichloroethane from Standard solution rn=61 1,2-DICHLOROETHANE
Mean Area 148436
%RSD 0.78
Mean area of 1 ,2-Dlchloroethane in Parent sample -[n=3] Not Detected

Cone. of 1,2. Area counts for Test only for added 1,2.
Test Level Dlchloroethane + Added 1,2- Recovered against added Mean %RSD
Dichloroethane (After % Recovery
added (ppm) Dichloroethane amount in ppm (n=3) (n=3)
area)
Test-1 7785 7785 0.26 104.00
LOO Test-2 0.25 7645 7645 0.26 104.00 102.67 2.25
Test-3 7472 7472 0.25 100.00
Test-1 123380 123380 4.16 104.00
80% Test.2 4.00 115479 115479 3.90 97.50 100.92 3.23
Test-3 120065 120065 4.05 101.25
Test-1 149012 149012 5.03 100.40
100% Test-2 5.01 147743 147743 4.99 99.60 100.53 1.00
Test.3 150717 150717 5.09 101.60
Test-1 171765 171765 5.80 96.51
120% Test-2 6.01 173395 173395 5.85 97.34 97.78 1.58
I Test-3 177126 177126 5.98 99.50
REMARKS:
The results of accuracy study in terms of % recovery were found in the range of 97.78% to 100.92% for 1,2-Dichloroethane and recovery at LOa level was
found 102.67%. These are well within the acceptance range of 80% to 120%.
JJ)J) ~
PERFORi-E-D-B-Y- CHECKED BY
DATE: 01 1'&.91~ DATE: oq ftf3lo.(;
194
TABLE NO- 9.&.3
ACCURACY STUDY
RECOVERY STUDY OF BENZENE IN CETIRIZINE DIHYDROCHLORIDE TEST SAMPLE
%Recovery calculated by mean area of Benzene from Standard solution In=61
BENZENE
Mean Area 184884
%RSD 6.64
Mean area of Benzene In Parent sample fn=31 Not detected

Test Level Cone.of Benzene Area counts for Test only for added Benzene
added (ppm) Recovered against added Mean %RSD
+ Added Benzene (After subtracting the % Recovery
amount In ppm (n=3) (n=3)
parent area)
Test-1 18084
LOQ 18084 0.20 100.00
Test-2 0.20 18956 18956 0.21 105.00 101.67
Test-3 18715 2.84
18715 0.20 100.00
Test-1 156283
80% 156283 1.69 105.63
Test-2 1.60 151901 151901 1.64 102.50 105.42
Test-3 159670 2.67
159670 1.73 108.13
Test-1 189888
100% 189888 2.05 102.50
Test-2 2.00 188905 188905 2.04 102.00 103.67
Test-3 196448 2.38
196448 2.13 106.50
Test-' 230797
120% 230797 2.50 104.17
Test-2 2.40 239663 239663 2.59 107.92 106.11
Test-3 235803 1.77
REMARKS: 235803 2.55 106.25
The resultsof accuracystudyin terms of % recovery were found in the range of 103.67% to 10&.11% for Benzene and recovery at LOQ level was found
101.67%.Thesearewellwithinthe acceptance range of 80% to 120%.
-~ ~
PE~ED BY CHECKED BY
(Offieer-ARDL) (Sr. Executive -ARDL)
DATE: OCfIO~If:6 DATE: oct I ~}'OG
195
TABLE NO- 9.6.4

ACCURACY STUDY
-
RECOVERY STUDY OF N N DIMETHYLFORMAMIDE IN CETIRIZINE DIHYDROCHLORIDE
%Recoverv calculated by mean area of N,N-Dimethylformamide from Standard solution m=6r
TEST SAMPLE
N,N-DIMETHYLFORMAMIDE
Mean Area 62725
%RSD 0.78
Mean area of N,N-Dimethylformamide in Parent samele In=31 Not detected

Area counts for Test
Conc. of N,N- only for added N,N-
Test Level + Added N,N- Recovered against added Mean %RSD
Dimethylformamide Dlmethylformamlde(Aft % Recovery
Dimethylformamide amount in ppm (n=3) (n=3)
added (ppm) er subtracting the
added
parent area)
Test-1 12017 12017 168.73 95.80
LOO Test-2 176.13 12212 12212 171.47 97.35 97.02 1.12
Test-3 12281 12281 172.43 97.90
Test-1 48910 48910 686.73 97.47
80% Test-2 704.57 50286 50286 706.05 100.21 99.02 1.42
Test-3 49865 49865 700.14 99.37
Test-1 63543 63543 892.19 101.30
100% Test-2 880.71 63143 63143 886.58 100.67 101.26 0.56
Test-3 63851 63851 896.52 101.80
Test-1 76620 76620 1075.80 101.79
120% Test-2 1056.85 74990 74990 1052.92 99.63 101.06 1.23
Test--3 76598 76598 1075.50 101.76
REMARKS:
The results of accuracy study in terms of % recovery were found in the range of 99.02% to 101.26% for N,N-Dimethylformamide and recovery at LOa level
was found 97.02%. These are well within the acceptance range of 80% to 120%.
~
PE~EDBY CHECKED BY
DATE: '9i1'.9/~ DATE: ~ )rJ:>1 00
196
9.7 RUGGEDNESS STUDY
Two different analytical persons carried out the ruggedness of the method on different
dates to establish the degree of reproducibility of the results obtained by the analysis of
the same sample.
Mr. Ashish Haldankar had carried out the first study on 02/03/2006 using Perkin-Elmer
Clarus-500 systems at CRD Mumbai, while Mr. Prashant Kulkarni has conducted the
second study on Agilent 6890N systems on 29/03/2006 at CRD Mumbai.
The ruggedness studies were carried out as described in the precision study by
injection repeatability and result reproducibility. Results reproducibility was carried out,
by replicate analysis of the sample for residual solvent against the same Standard
solution and by calculating %RSD of the replicate injection data.
The results of both the analysis for Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide were comparable (Limit of acceptance NMT 15.00 %RSD). Hence
it is concluded that the method is rugged enough for the determination of residual
solvent in Cetirizine Dihydrochloride.
Table 9.7.1 to 9.7.4 represents the data of ruggedness study of Cetirizine

Dihydrochloride by GC method.
197
~jo-~'+-~-.tl'~ '""~",,,,";", .•...oi••;~,
RESIDUAL SOLVENT IN CETIRIZINE OIHYDROCHLORIOE (METHOD-2)
TABLE NO-9. 7.1
TABLE FOR RUGGEDNESS STUDY [CHLOROFORM]
[A] [B]
INSTRUMENT Perkin-Elmer Clarus-500 Agilent 6890N
ANALYST Mr. Ashish Haldankar Mr. Prashant Kulkarni
DATE 02/03/2006 29/03/2006
LOCATION CRD-MUMBAI CRD-MUMBAI
Mean Area of Chloroform: 722280 Chloroform : 168.567

Standard solution
rkRSD]: 0.57% [%RSD1: 0.88% I
Results in ppm
[A] [8] [AJ [8] [AJ [8]
2 1056.2 1010.3 -- - Not detected Not detected J
3 1023.9 1003.6 - - Not detected Not detected

SO :!: --- -
%RSO - -
Mean of above 12 results of two sets of analvst A+B -
SO:!: --
%RSO -
REMARKS: In both the set of analysis, the results of Chloroform in Cetirizine
PE~EDBY CHECKED BY
(Officer-AROL) (Sr. Executive -ARDL)
DATE:.~'Io~ It( DATE: So 10'310"
198
TABLE NO-9.7.2
TABLE FOR RUGGEDNESS STUDY [1,2-DICHLOROETHANE]
[A] [B)
DATE 02/03/2006 29/03/2006
Mean Area of 1,2-Dichloroethane: 154151 1,2-Dichforoethane: 37.331

Standard solution
[%RSD]: 1.32% rkRSD]: 0.92%

No. B# PP5012CZRI in mg Results in ppm
sample
[A] [B] [A] [B] [A] [B]
j
3 1023.9 1003.6 - --- Not detected Not detected
j
4 1009.7 1001.2 - -- Not detected Not detected
j
5 1040.3 1005.7 -- --- Not detected Not detected j
6 1019.5 1003.3 - -- Not detected Not detected j
Mean Not detected Not detected j
SDf -- - t
%RSD --
SD:!: --
%RSD -
REMARKS: In both the set of analysis, the results of 1,2-Dichloroethane in Cetirizine
~
PE~EDBY CHECKED BY
DATE: 3'DltJ3/~ DATE: .3ale.:3rOb
199
TABLE NO-g. 7.3
TABLE FOR RUGGEDNESS STUDY [BENZENE]
[A] [B]
INSTRUMENT . Perkin-Elmer Clarus-500 Agilent 6890N
DATE 02/03/2006 29/03/2006
Mean Area of Benzene: 199949 Benzene: 52.397

Standard solution
rkRSD]: 1.23% [%RSO): 0.48%

No. B# PP5012CZRI in rna sample
[A] [B) [A) [B] [A] [B]
1 1030.1 1008.9 - -- Not detected Not detected
4 1009.7 1001.2 --- - Not detected Not detected i
5 1040.3 1005.7 -- -- Not detected Not detected I
6 1019.5 1003.3 --- - Not detected Not detected J
Mean Not detected Not detected i
SO :t: - --
%RSD --- --
Mean of above 12 results of two sets of analyst A+B -
SDf -
%RSD --
REMARKS: In both the set of analysis, the results of Benzene in Cetirizine
PE~EDBY CHECKED BY
DATE: 3111113/0b DATE: "60 ]0310~
200
TABLE NO-g. 7.4
TABLE FOR RUGGEDNESS STUDY [N,N-DIMETHYLFORMAMIDE]
rA] [B)
DATE 02/03/2006 29/03/2006
Mean Area of N,N-Dimethylformamide: 61559 N,N-Dimethylformamide: 8.485

Standard solution
[%RSD]: 0.70% rIoRSD]: 2.21%

[A] IB] [A] [B] [A] [B] I
1 1030.1 1008.9 -- -- Not detected Not detected :
2 1056.2 1010.3 -- -- Not detected Not detected j
1023.9 1003.6 - - Not detected Not detected i
j
3
4 1009.7 1001.2 -- -- Not detected Not detected j
5 1040.3 1005.7 -- -- Not detected Not detected .

~
6 1019.5 1003.3 - --- Not detected Not detected 'j
Mean Not detected Not detected j
SO :t - - j
%RSD - --
SO:!: --
%RSO -
REMARKS: In both the set of analysis, the results of N,N-Dimethylformamide in
Cetirizine Dihydrochloride were found not detected. On the basis of the above data it is
~
PE~EDBY CHECKED BY
DATE: 3e!t!>/ o-e DATE: 201031'06
201
TABLE NO-9. 7.7
TABLE FOR RUGGEDNESS STUDY [SYSTEM SUITABILITY]
Comparative System suitability data of both analysts

Name of Analyst A AnalystB
Component
RT RT Resolution
RRT Resolution RRT
(min) (min)
Chloroform 8.44 0.36 Resolution 9.14 0.38 Resolution

between between
1,2-Dichloroethane 10.01 0.42 1,2- 10.64 0.44 1,2-
Dichloroetha Dichloroeth
Benzene 10.75 0.45 ne& 11.36 0.47 ane&
Benzene is Benzene is
N N- 15.01 0.64 15.58 0.64 3.60
I
3.25
Dimethylformamide
~
CHECKED BY
PE~EDBY
(Officer-ARDL)
DATE: ga 102.106
DATE: "3D16~1 ~
202
9.8 ROBUSTNESS
'The robustness of an analytical method is measure of its capacity to remain
unaffected by small but deliberate variationsin method parameters and provides an
indication of its reliability during normal usage"
To check the robustness of the method the following parameters were deliberately
changed.
1. Change in column pressure

With change in the column pressure i.e. 3.0 psi :t 0.2 psi. No significant change w~s
o bserve d' In S)ys t em SUI't a bTt
I Ity parame ter.
Change in column pressure [:t 0.2 psi]

Component
RT Resol RT Resol RT Resol
RRT RRT RRT
(min) ution (min) ution* (min) ution
Resolut Resolut 8.09 0.35 Resolut

Chloroform 9.13 0.38 8.44 0.36
ion ion ion
betwee betwee betwee
1,2-Dichloroethane 10.60 0.44 n 1,2- 10.01 0.42 n 1,2- 9.70 0.42 n 1,2-
Dichlor Dichlor Dichlor
oethan oethan oethan
Benzene 11.31 0.47 e& 10.75 0.45 e& 10.44 0.45 e&
Benzen Benzen Banze"
N,N- eis eis eis
15.44 0.64 15.01 0.64 3.25 14.71 0.63 3.22
Dimethylformamide 3.28
Change in column Dressure [+ 0.2 Dsil

2.8 psi *3.0 psi 3.2 psi
Name of
ppm ppm Plm
Component 2"a
1st 2"a 1st 2"d 1st
Chloroform NO NO NO NO NO NO
1,2-0ichloroethane NO NO NO NO NO NO
Benzene NO NO NO NO NO NO
N,N- NO NO NO
NO NO NO
Oimethvlformamide
=
NO Not Detected
*Oata taken from precision study System suitability solution chromatogram.
~
PER~EDBY CHECKED BY
DATE: '" 031 trb DATE: ,,' as~
203
REPORT ON ANALYTICAL DEVELOPMENT AND VALIDA
10. DATA ACCUMULATION STUDY
Analysis of the manufactured batches of Cetirizine Dihydrochloride, Batch No.

PP5011CZRI, PP5012CZRI and PP5013CZRI was carried out as a data accumulation
study to assess the content of Residual solvent.
Table No. 10.1 represents the result of Chloroform, 1,2.Dichloroethane, Benzene and
N,N.Oimethylformamide found in Cetirizine Oihydrochloride samples.
204
TABLE NO-10.1
DATA ACCUMULATION STUDY

Mean areas of Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylfonnamide obtained from replicate injections of Standard solution.
Mean Area %RSD
Chloroform 722280 0.57
1,2-Dichloroethane 154151 1.32
Benzene 199949 1.23
N,N-Dimethylformamide 61559 0.70
RESIDUAL SOLVENT (IN PPM)

Sr.
No. B.No. Inj. No. 1,2- N,N-
Chlorofonn Benzene
Dichloroelhane Dimethylfonnamide
1 NO NO NO NO
1 PP5011CZRI
2 NO NO NO NO
1 NO NO NO NO
2
PP5012CZRI
2 NO NO NO NO
1 NO NO NO NO
3
PP5013CZRI
2 NO NO NO NO
NO = Not detected
Data accumulation study was done in continuation with Precision study
Remarks: Results are well within the specified limits of residual solvent
(i.e. Chloroform, 1,2-Dichloroethane, Benzene and N,N-
Dimethylformamide)
~~
PEaEDBY CHECKED BY
DATE: 6'2>/0'31 ot DATE: ~l~JOb
205
11. SUMMARY REPORT AND APPROVAL
RESULTS
Sr.
No. PERFORMANCE PARAMETER 1,2- N,N- ACCEPATANCE
Chloroform Benzene Dimethylforma
Dichloroethane CRITERIA
mlde
1.0 Identification
RT (Retention Time) 8.41 9.99 Well resolved with
10.73 15.00
RRT (Relative Retention Time) adjacent peak
0.36 0.42 0.45 0.63
2.0 System suitability
RT (Retention Time) 8.41 9.99 10.72 15.00 Informative
RRT (Relative Retention Time) 0.36 0.42 0.45 0.63 Informative
Plate count 15799 29911 34821 194047 Informative
Tailing Factor 1.01 0.98 1.02 1.15 Informative
Resolution
Resolution between 1,2-Dichloroethane & Benzene is 3.01 NLT 2.00
% RSD [n=6] 0.57 1.32 1.23 0.70 NMT 10.00%
3.0 Precision (Injection)
%RSD of replicate injection (n=6) 0.57 1.32 1.23 0.70 NMT 10.00%
Precision (Result)
%RSD of replicate result (n=6) --- -.- -. --- NMT 15.00%
4.0 Accuracy (80% to 120%)
% Recovery 100.55% to 97.78% to 103.67% to 99.02% to % Recovery should be

106.92% 100.92% 106.11% 101.26%
Accuracy at LOQ Level between 80.00% to
120.00%
% Recovery 99.56% 102.67% 101.67% 97.02%
206
RESULTS
Sr.
PERFORMANCE PARAMETER 1.2- N.N- ACCEPATANCE
No. Chloroform Benzene
Dichloroethane Dimethylform CRtTERIA
amide
5.0 Speclflclty/Selectivity
All peaks are well resolved with adjacent peak, so method is Specific. Well resolved with
adjacent oeak
6.0 Linearity and Range
Correlation coefficient
LOQ to 150% 0.9981 0.9989 0.9961 0.9992 NLT 0.9800
7.0. Limit of Detection
w.r.t Target in ppm 0.60 0.10 0.10 88.07
w.r,t Test in ppm 0.60 Positive Response
0.10 0.10 88.07
8.0
Limit of Quantitation (LOQ)
w.r.t Target in ppm 3.00 0.25 0.20 176.14

w.r.t Test in ppm Informative
3.00 0.25 0.20 176.14
Precision at LOQ level
%RSD of replicate of LOa cone.
(n=6) 1.04% 1.00% 1.25% 3.29% NMT 15.00%
9.0 Ruggedness
%RSD of replicate injection (n=6) 0.88 0.92 0.48 2.21 NMT 10.00%
%RSD of cumulative results
(n=12) --- -- --- --- NMT 15.00%
207
REMARKS:
On the basis of above results the analytical method for residual solvent (Chloroform, 1,2-
Dichloroethane, Benzene and N,N-Dimethylformamide) in Cetirizine Dihydrochloride is
found well within the acceptance limit. Therefore, the analytical method for analysis of
Residual solvent in Cetirizine Dihydrochloride is to be considered as a VALIDATED
method for its intended purpose to establish the quality of Cetirizine Dihydrochloride.
(Sr. Executive -ARDL) (Manager -ARDL)
DATE: {) '-1 f 0'41 ():(, DATE: ()t{ 1b41~
208
12. CONCLUSION
The analytical method validation study for the determination of a residual solvent
method-1 i.e. Chloroform, 1,2-Dichloroethane, Benzene and N,N-Dimethylformamide in
Cetirizine Dihydrochloride by Gas Chromatographic (Capillary) method is considered to
be validated for its intended use.
(Sr. Executive -ARDL) (Manager -ARDL)
DATE: oJ; I C)q I 06 DATE: ~J~ 1M.:.
209
3.2.S.4.4
BATCH ANALYSIS
210
TEL. : 07412 - 278649,278244, 278000 Ipca Laboratories Limited
TELEFAX: 07412-279083 P.0. SEJAVTA 457 002. DIST. RATLAM (M. P.)
QUALITY DIVISION
CERTIFICATE OF ANALYSIS
NAME OF THE PRODUCT : CETIRIZINE HYDROCHLORIDE BP
BATCH No. : 21013CZ6RII BATCH SIZE 232.00 Kgs
MFC. DATE : Apr. 2021 A.R. No. RA/2021/0333
EXP. DATE : Mar. 2026 DATE 24/06/2021
SPECIFICATION No. / REV. No. : TS/BPC/CZ6/PS/BP / 02
CUSTOMER NAME / ITEM CODE : NA
TESTS SPECIFICATIONS RESULTS

CHARACTERS A white or almost white powder. White powder
Freely soluble in water, practically insoluble in acetone and Conforms
in methylene chloride.
IDENTIFICATION 1) The infrared absorption spectrum of sample and Conforms
standard are concordant.
2) It gives reaction (a) of chlorides. Conforms
APPEARANCE OF Solution is clear and not more intensely coloured than Conforms
SOLUTION reference solution BY7.
pH 1.2 to1.8 1.53
RELATED Impurity A NMT 0.15% < 0.05%
SUBSTANCES Impurity B NMT 0.15% < 0.05%
(By HPLC) Impurity C NMT 0.15% < 0.05%
Impurity D NMT 0.15% Not Detected
Impurity E NMT 0.15% 0.06%
Impurity F NMT 0.15% < 0.05%
Any Unspecified Impurity NMT 0.10% < 0.05%
Total Impurities NMT 0.30% 0.11%
LOSS ON DRYING NMT 0.5% w/w 0.29% w/w
(at 105°C)
SULPHATED ASH NMT 0.2% w/w 0.05% w/w
ASSAY 99.0% -101.0% of C21H27CI3N2O3 (on dried basis) 99.9% (odb)
REMARKS: The above sample CONFORMS as per BP Specifications.
Reviewed By QA
PREPARED BY Sign/Date MANAGER QUALITY CONTROL

DATE : jLq |o(>)>-:L DATE
Regd. Off.: 48, Kandivli Industrial Estate, Kandivli (West), Mumbai-400 067. Phone: 6647 4444
Corporate Office: 142-AB, Kandivli Industrial Estate, Kandivli (West), Mumbai-400 067. Phone : 6647 4747
211
TEL, :07412 - 278649, 278244, 278000 Ipca Laboratories Limited
TELEFAX: 07412-279083 P.0. SEJAVTA 457 002, DIST, RATLAM (M. P.)
QUALITY DIVISION

BATCH No. 21014CZ6RII BATCH SIZE 225.00 Kgs
MFC. DATE Apr. 2021 A.R. No. RA/2021/0334
EXP. DATE Mar. 2026 DATE 24/06/2021
CUSTOMER NAME / ITEM CODE : NA

SOLUTION reference solution BY/.
pH 1.2 to1.8 1.37
RELATED Impurity A NMT 0.15% < 0.05%
SUBSTANCES Impurity B NMT 0.15% 0.05%
(By HPLC) Impurity C NMT 0.15% < 0.05%
(at 105°C)
[ Reviewed By QA
4
PREPARED BY Sign/Date MANAGER QUALITY CONTROL
DATE : w4|o4|to2-1_ DATE :
Regd. Off.: 48, Kandivli Industrial Estate, Kandivli (West), Mumbai-400 067, Phone : 6647 4444
Corporate Office : 142-AB, Kandivli Industrial Estate, Kandivli (West), Mumbai-400 067. Phone: 664 7 4747
212
TEL. : 07412 - 278649, 278244, 278000 Ipca Laboratories Limited
TELEFAX: 07412-279083 P.0. SEJAVTA 457 C02. DIST. RATLAM (M. P.)
QUALITY DIVISION
BATCH No. 21015CZ6RII BATCH SIZE 222.00 Kgs
MFG. DATE Apr. 2021 A.R. No. RA/2021/0335
EXP. DATE Mar. 2026 DATE 24/06/2021
CUSTOMER NAME/ITEM CODE : NA

SOLUTION reference solution BY/.
pH 1.2 to1.8 1.39
RELATED Impurity A NMT 0.15% Not Detected
SUBSTANCES Impurity B NMT 0.15% < 0.05%
(By HPLC) Impurity C NMT 0.15% Not Detected
(at 105°C)
j Reviewed By QA
PREPARED BY ateO\ MANAGER Q UALITY CONTROL

DATE DATE :
Regd. Off.: 48, Kandivli Industrial Estate, Kandivli (West), Mumbai-400 067. Phone: 6647 4444
Corporate Office : 142-AB, Kandivli Industrial Estate, Kandivli (West), Mumba-400 067. Phone : 6647 4747
213
3.2.S.4.5
JUSTIFICATION
OF
SPECIFICATIONS
214
JUSTIFICATION OF SPECIFICATION
TESTS SPECIFICATIONS JUSTIFICATIONS
Characters A white or almost white powder, freely soluble in Based on BP

water, practically insoluble in acetone and in Monograph.
methylene chloride.
Identification 1) The infrared absorption spectrum of sample and Based on BP
standard are concordant. Monograph.
2) It gives reaction (a) of chlorides.
Appearance of Solution is clear and not more intensely coloured Based on BP
solution than reference solution BY7. Monograph.
pH 1.2 to 1.8. Based on BP
Monograph.
Related Substances Impurity A :NMT 0.15% Base on BP Monograph
(By HPLC) Impurity B :NMT 0.15% and inhouse Validated
Impurity C :NMT 0.15% method
Impurity D :NMT 0.15%
Impurity E :NMT 0.15%
Impurity F :NMT 0.15%
Any Unspecified impurity :NMT 0.10%
Total Impurities :NMT 0.30%
Loss on Drying (at NMT 0.5% w/w Based on BP
105°C) Monograph.
Sulphated Ash NMT 0.2% w/w Based on BP
Monograph.
Assay 99.0%-101.0% of C21H27Cl3N2O3 (on dried basis) Based on BP
Monograph.
215
3.2.S.5
REFERENCE STANDARDS
OR
MATERIALS
216
REFERENCE OR WORKING STANDARD
One of the highest purity Batch No. 17028CZ6RII was selected and qualified as working
standard which has been evaluated against EP reference Standard batch no. 4.0.
Certificate of Analysis of Working Standard is enclosed in the following page.

Working Standard was compared with EP Reference standard. Comparison of IR Spectra
of EP reference standard with working standard is enclosed in the subsequent pages.
217
TEL. : 07412 -278244,278259, 278000
TELEFAX : 07412-278084, 279083
P.O. SEJAVTA 457 002. DIST. RATlAM (M.P.)
~~1pca
QUALITY DIVISION
WORKING STANDARD
CODE No. WS ID No. : WS/171/2018/02
EVALUATED AGAINST: EP REFERENCE STANDARD BATCH n°. 4.0
NAME OF THE PRODUCT : CETIRIZINE DIHYDROCHLORIDE Ph. Eur.
BATCH No. 17028CZ6RII DATE OF RELEASE 13/01/2018
MFG. DATE Aug. 2017 WS. A. R. No. ws -17053
EXP. DATE Jul. 2022 QUANTITY 1.00 Kgs.
MANUFACTURER IPCA LABORATORIES LTD., STORAGE CONDITION NMT 25°C
RATLAM
EFFECTIVE DATE 17/01/2018 VALID UP TO 12/01/2020
Freely soluble in water, practically insoluble in acetone and in Conforms
methylene chloride.
IDENTIFICATION 1) The infrared absorption spectrum of sample and standard are Conforms
concordant.
APPEARANCE OF Solution is clear and not more intensely coloured than reference Conforms
SOLUTION solution BY1.
pH 1.2to 1.8 1.72
RELATED SUBSTANCES Impurity A :NMT0.15% Not Detected
(By HPLC) Impurity B : NMT 0.15% <0.05%
Impurity C : NMT0.15% Not Detected
Impurity D :NMT0.15% Not Detected
Impurity E : NMT 0.15% 0.09%
Impurity F : NMT 0.15% < 0.05%
Impurity G : NMT 0.10% < 0.05%
Cetirizine methyl ester : NMT0.10% < 0.05%
3-Chlorocetirizine : NMT 0.10% <0.05%
Cetirizine N-Oxide : NMT 0.10% Not Detected
4-CBH : NMT 0.10% Not Detected
4-Chlorobenzophenone : NMT 0.10% < 0.05%
Any Unspecified Impurity : NMT 0.10% < 0.05%
Total Impurities : NMT 0.30% 0.09%
LOSS ON DRYING NMT 0.5% w/w 0.19%w/w
(at 105°C)
RESIDUAL SOLVENTS *Acetone : NMT 5000 ppm < 5000 ppm
*Acetone being Class Ill solvent, is limited by the Test for Loss on
Drying to a limit of NMT 0.5%.
ASSAY 99.0% -101.0% of C2,H21CI3N203(on dried basis) 99.48% (odb)
99.3% (aib)
REMARKS: The above sample CONFORMS as per above Specifications w.r.t. above test and is comparable
('\ to EP Reference Standard Batch n°. 4.0. /1 /
v
A
~
_A_N_A_L,.;;.
YS_T._ MANAGER QUALITY CONTROL
DATE : 15/03/2018 DATE OF PRINT : 15/03/2018
Regd. Off.: 48, Kandivli Industrial Estate, Kandivli (West), Mumbai-400 067. Phone : 6647 4444
Corporate Office : 142·AB. Kandivli Industrial Estate, Kandivli (West). Mumbai-400 067. Phone : 6647 4747
218
PerkinEimer Spectrum ES V ersion 10.4.3
Thursday, January 11 , 2018 16:46

FTIR218
Sample Details <'
Sample Name { CETIRIZINE Dl HCL EP WS 11.01.18 ,
Sample Description , CETIRIZINE Dl HCL EP WS #17028CZ6RII : 139/0~
Analyst ~eeta Gurbani ,.._/ ../
Creation Date 11/01/201816:44:52 <'
X-Axis Units c cm-1
Y-Axis Units %T
Instrument Detai ls
Instrument Model Spectrum 100
Instrument Serial Number 78476
Software Revision CPU32 Main 00.02.8200 12-December-2006 10:00:00
Number of Scans 20
Resolution 4
Spectrum Graph
80
70
f--
~
0
60
50
4
30
20
10
5
4000 3500 3000 2500 2000 1500 1000 500400
cm-1
Name Description
_ _ CETIRIZINE Dl HCL EP WS
CETIRIZINE Dl HCL EP WS #17028CZ6RII :139/01
11 .01 .18
Compare Result Graph
Page 1 I 3
219
PerkinEimer Spectrum ES Version 10.4.3

FTIR218
Sample Details
Sample Name CETIRIZINE Dl HCL EP CRS 11.01 .18 ~
Sample Description
(
'" CETIRIZINE Dl HCL EP CRS #4.0 :138/01 /
Analyst
Creation Date
Neeta Gurbani / /
( 11/01/2018 16:18:59
X-Axis Units / cm-1
Y-Axis Units %T
Instrument Details
Instrument Model Spectrum 100
Instrument Senal Number 78476
Software Revision CPU32 Main 00.02.8200 12-December-2006 10:00:00
Number of Scans 20
Resolution 4
Spectrum Graph
146
140..--- .........-~
130
12
11
9
f- 8
eft.
7
6
5
17
4000 3500 3000 2500 2000 1500 1000 500400
cm-1
Name Description
_ _ CETIRIZINE 01 HCL EP CRS
CETIRIZINE 01 HCL EP CRS #4.0 :138/01
11 .01 .18
Peak Table
Peak X (cm-1) Y(%D Peak X (cm-1) y (%T) Peak X (cm-1) Y(%T) Peak X (cm-1) Y(%T)
1 3044.03 73.01 2 3023.23 73.92 3 2984.71 62.52 4 2948.63 63.29
5 2628.04 76.82 6 2503.78 62.21 7 2378.86 36.47 8 2361 .73 37.08
9 2216.72 74. 1 10 1740.31 20.35 11 1600.78 91 .01 12 1495.83 61 .76
13 1456.91 54.51 14 1435.05 52.51 15 1383.34 50.51 16 1356.19 44
17 1319.22 35.79 18 1284.62 72.49 19 1274.14 71 .96 20 1263.03 65.07
21 1241 .88 80.32 22 1185.29 57.7 23 1154.06 70.6 24 1136.95 38.33
Page 1 / 2
220
Perkin Elmer Spectrum ES Version 10.4.3
Peak X (cm-1 ) Y(%T) Peak X (cm-1) Y(%T) Peak X (cm-11 Yl%TJ Peak Xlcm-1) Yl%TJ
25 1091.92 54.45 26 1076.73 72.18 27 1055.1 66.01 28 1030.29 69.38
29 1018.53 59.35 30 961 .11 78.11 31 946.39 82.93 32 920.62 54.05
33 867.07 83.83 34 845.74 61 .54 35 808.42 60.61 36 782.38 88.37
37 758.3 59.17 38 719.87 72.73 39 698.48 62.38 40 648.29 84.21
41 620.48 75.9 42 610.97 84.21 43 592.62 89.22 44 556.47 88.7
45 535.5 69.88 46 502.87 83.79 47 485 89.09 48 434.85 80.84
49 410.38 94.23
/
/
Page 2/2
221
cm-1
Name / Description /
CETIRIZINE Dl HCL EP WS 11 .01.18 CETIRIZINE Dl HCL EP WS #17028CZ6RII :139/01
CETIRIZINE Dl HCL EP CRS 11 .01 .18.sp CETIRIZINE Dl HCL EP CRS #4.0 :138/01
(
Compare Result
Best Hit Result
Best Hit Correlation Correlation Criteria Pass/Fail
D:\FTIR_DATA\Spectra\20 0.996212 0.95 Pass
18\JANUARY\CETIRIZINE /
Dl HCL EP CRS / /~ (
/
11 .01 .18.sp
Hit Details
Hit Name Hit Description Correlation Pass/Fail
D:\FTIR_DATA\Spectra\20 CETIRIZINE Dl HCL EP Wl.996212 Pass
18\JAN UARY\CETI RIZI NE
Dl HCL EP CRS
CRS #4.0 :138/01
/ ...,-
/ :7
11 .01 .18.sp
Peak Table
Peak X (cm-1) YC%n Peak X (cm-1) Y(o/oT) Peak X (cm-1) Y(%T) Peak X (cm-1) Y(o/oT)
1 3044.04 44.64 2 3023.26 46.74 3 2984.43 35.22 4 2948.74 36.13
5 2914.48 41 .3 6 2628.24 50.75 7 2503.85 35.97 8 2378.22 14.32
9 2216.63 42.7 10 1773.84 70.2 11 1740.26 7.87 12 1601.45 72.27
13 1574.82 80.82 14 1495.92 39.14 15 1456.83 31 .51 16 1435.14 30.39
17 1383.3 26.76 18 1356.24 22.26 19 1319.09 15.25 20 1284.61 49.71
21 1274.22 49.67 22 1263 40.93 23 1241 .93 60.19 24 1185.26 35.81
25 1154.36 51 .59 26 1136.78 18.36 27 1114.67 53.63 28 1091 .94 33.29
29 1076.85 52.77 30 1055:1 4•6 31 1030.39 49.05 32 1018.62 38.19
Page 2 / 3
222
Peak X (cm-1) y (%T) Peak X (cm-1) Y(%T) Peak X (cm-1) Y(%T) Peak X (cm-1) Y (%T)
33 961.16 59.52 34 946.47 66.19 35 920.58 31.99 36 888 02 76.7
37 867.08 66.7 38 845.73 39.76 39 808.43 38.27 40 782.38 70.24
41 758.2 36.8 42 719.79 52.23 43 698.5 39.2 44 648.25 63.92
45 620.41 55.07 46 610.94 66.26 47 592.67 74.08 48 556.45 73.32
49 535.42 49.08 50 502.87 68.1 51 484.79 75.5 52 434.72 60.49
53 410.18 82.27
I
/
/
Page 3/3
223
3.2.S.6
CONTAINERCLOSURESYSTEM
224
PACKINGINSTRUCTIONS
AND
SPECIFICATIONS
225
PACKING INSTRUCTION
Cetrizine Hydrochloride is packed in inner Clear LDPE Bag and outer Black LDPE bag then
packed in fibre / HMHDPE drum then sealed with metal locking system.
Primary Packaging Components:
Inner: 30” X 48”x 300 Clear LDPE bag

Outer: 30” X 48” x 300 Black LDPE bag
Secondary Packaging Components:
16”x 24”Fiber Drum / 80 Kg HMHDPE Drum
Certificate / Compliance Certificate:
The polythene bags used as primary packaging material are procured from approved vendor,
who in turn purchase the plastic granules from most reputed Manufacturers which certifies
that the plastic granules that are being supplied to approved vendor are certified according to
our National Standards “For Safe use in contact with foodstuffs, pharmaceutical, and drinking
water”. The grade also Complies with EU/US regulation.
The corresponding packaging material specification and LDPE granule certificate issued by
most reputed vendors are provided on following pages:
Sr. No. Components Specification reference no.

1 30”X 48”x 300 Clear LDPE bag TS/BPC/PKG/G99028
2 30” X 48” x 300 Black LDPE bag TS/BPC/PKG/G99036
3 14’’ X 24’’ Fibre Drum TS/BPC/PKG/D99005
4 80 Kg HMHDPE Drum TS/BPC/PKG/D99073
5 Plastic strip seal with metal locking TS/BPC/PKG/F99094
System
6 Plastic Coated Metal Locking Rope Seal TS/BPC/PKG/F99129
226
227
228
229
230
231
232
~J!1pca
Packaging Material Specification (pm api)
Document Number: TS PKG F99094 000001 10
Description: PLASTIC STRIP SEAL WITH METAL
LOCKING SYSTEM
Item Code: F99094
Version Number: 6.0
Document Status: Effective
Major Version change date: 17 Jan 2022 00:01:10 (GMT+05:30)
Signed By: Sharayu Lake (sharayu.loke)

Decision : Approved
Decision Date : 12 Jan 2022 18:05:45 (GMT +05:30)
Role: API Author
Purpose : Revision
Meaning Of Signature : I am the author of this document
Signed By : Megha Narkar (megha.narkar)

Decision : Approved
Decision Date : 12 Jan 2022 18:06:24 (GMT +05:30)
Role: API Reviewer
Purpose : Revision
Meaning Of Signature : I have reviewed and I do approve that this document is fit for use
Signed By : Catherine Raphael (catherine.raphael)

Decision : Approved
Decision Date: 13 Jan 2022 10:07:04 (GMT +05:30)
Role: API Approver
Purpose : Revision
Meaning Of Signature : I have checked this document/collection and approve it for use
Printed By: Garima Mehta (garima.mehta)

Reason for Print: Print to pdf
Print issue number: 1

Number of reprints for this user: 0
Print Information : A record has been made of this print in both the standard Audit trail
and in the Hardcopy log .
- End of Cover Page(s) -
Document Name : TS PKG F99094 000001 10 Printed By : Garima Mehta (garima.mehta)

Document Version : 6:0 - - Print Date : 17 Jan 2022 (GMT+05:30)
Cover Page 1 of 1 Print Time : 09:1 9:55 (GMT+05:30)
233
~~ 1pca
lpca Laboratories Limited, Mumbai
SPECIFICATIONS & ANALYTICAL PROCEDURES
SPECIFICATION OF
PACKAGING
PLASTIC STRIP SEAL WITH METAL LOCKING SYSTEM
MATERIAL I CRITICAL
CONSUMABLES
Specification Number TS/PKG/F99094
Version Number 6.0
Author Reviewer Approver
Name Sharayu Loke Megha Narkar Catherine Raphael
Department CQA CQA CQA
Effective date: 17.01.2022
TESTS LIMITS & METHODS GTP.REFE.NO.
Description Green coloured strip with metal locking system, made of --

polypropylene co-polymer. "lpca" logo is embossed on top of
carrier. "PAT - PEN" is embossed on one side of the strip
and "INSERT HERE" showing direction of insertion with
arrow mark is embossed on the other side of the strip
Total Length with flap 280 mm - 290 mm TS/GTP/PM/05
Length of Locking 225 mm - 235 mm TS/GTP/PM/05
Thickness of Strap 1.15 mm ± 0.20mm TS/GTP/PM/03
Size of the Box Length : 17mm ± 2mm TS/GTP/PM/05
Width : 17 mm ± 2mm TS/GTP/PM/06
Height : 8 mm ± 2mm TS/GTP/PM/02
Weight of Seal 3.40 ± 0.3 g TS/GTP/PM/04
Document Name : TS PKG F99094 000001 10 Printed By : Garima Mehta (garima.mehta)

Document Version : 6-:-o - - Print Date : 17 Jan 2022 (GMT+05:30)
Page 1 of 2 Print Time : 09:19:55 (GMT+05:30)
234
235
April 4, 2018
To whomsoever it may concern,
Dear Sir,
Polyethylene Relene 22FA002, F19010, F46003 and 24FS040 complies with the following
standards for food contact applications (based on recipe of production of grade):
 The grade and the additives incorporated in it comply with the FDA: CFR Title 21,
177.1520 olefin polymers.
 The grade complies with the requirement of Overall Migration Limit (OML) of
60mg/kg as mentioned in EU/10/2011.
 The product complies with the requirements of Regulation EU/10/2011 for plastics
intended to come to contact with foodstuff and its subsequent amendments applicable
to intermediate materials. (Amendments applicable are 2018/213, 2018/79, 2017/752,
2016/1416, 2015/174, 202/2014, 1183/2012, 1282/2011, 321/2011)
 The monomers and additives used to produce this product are listed in the Union List
of Authorized Substances of Regulation EU/10/2011.
 The grades conform to EU Directive 1935/2004 on materials and articles intended to
come into contact with food.
 The product complies with the requirements of Regulation 2023/2006/EC (GMP)
applicable to intermediate materials.
 The grades do not contain Bisphenol A.
This is applicable to the material as it leaves the production facilities and does not include any
substance subsequently added by the converter or any other agency.
Regards,
Yours sincerely,
(S V Raju)
For Reliance Industries Ltd
RIL - Baroda complex, P.O. Petrochemicals, Dist. Vadodara, 391346, Gujarat Tel : (0265) 6696000
Registered Office: 3rd Floor, Maker Chambers IV, 222, Nariman Point, Mumbai - 400 021, India.
236
STATEMENT OF COMPLIANCE
Haldia Petrochemicals Limited states that the High Molecular Weight High Density Polyethylene
grade Halene H F5400 complies with the requirements, recommendations or communications of
1. IS 10141:1982 on “Positive Lists of Constituents Of Polyethylene In Contact With

Foodstuffs, Pharmaceuticals And Drinking Water”.
2. IS 10146:1982 on “Specification of Polyethylene for its safe use in contact with Foodstuffs,
Pharmaceuticals and Drinking Water”.
3. 21CFR 177.1520 of US FDA. According to our information, all other additives and
constituents used in the grade meets the requirements of their respective FDA regulations
and 21 CFR 177.1520
4. Food Contact Regulation 2008/39/EC, the Amending Directive of 2007/19/EC &

2002/72/EC – Phthalates like BBP, DEHP, DBP, DINP & DIDP etc. are not used in
manufacturing & are not present in Halene H F5400.
5. Food Contact Regulation 2002/72/EC & Packaging & Packaging Waste Regulation
2004/12/EC, the Amending Directive of 94/62/EC - Lead (Pb), Hexavalent Chromium,
Mercury (Hg), Cadmium (Cd) & their compounds are not used in manufacturing & are not
present in Halene H F5400. It has the potentials to be recycled according to these
requirements.
Halene H F5400 may be used in articles that come in contact with food.
Raj. K. Datta
Head Customer Services and Sr General Manager
Application Research & Development Center
Haldia Petrochemicals Limited
Kolkata, India.
This is a computer generated statement and does not require signature.

CS/Certificate of Compliance/July 2010
237
3.2.S.7
STABILITY
238
3.2.S.7.1
STABILITY SUMMARY AND CONCLUSIONS
239
STABILITY SUMMARY & CONCLUSIONS
Accelerated and Long Term stability data are available for three batches of Cetirizine Hydrochloride as
follows:
Stability
Batch Stability Analysis
Batch Number Mfg. Date Study
Quantity conditions frequency
Initiated On
PP5017CZRI 17.0 Kg. Dec.2005 10-02-06 Accelerated: Accelerated :
40°C:l:: 2°C , RH Initial, 3, and
PP5018CZRI 20.0kgs Dec.2005 10-02-06 75%:l::5%

6 month
Long Term:
Long Term:
PP5019CZRI 20.60kgs Jan. 2006 10-02-06 30°C:l::2°C, RH .. I 3rd , 6th ,

Imba,
65%:l:: 5%.
9th , lih, 18th,
24th, 36th, 48th
and 60th month
6 months accelerated and 60 months long term stability studies have been completed. The stability data
shows that the product is stable at above storage conditions.
240
STABILITY PROTOCOL AND ANALYTICAL PROCEDURES
Initially Cetirizine Hydrochloride Batch Nos. PP5017CZRI, PP5018CZRI & PP5019CZRI were
subjected for stability study as per below specifications and test procedures.
Tests Limits
Characters A White or almost white powder, freely soluble in water.
Appearance of Solution is clear and not more intensely colored than reference solution
Solution BY?
pH 1.2 to 1.8
Related Substance Impurity A :NMTO.lO%
Individual Unknown Impurity :NMTO.lO%
Sum of All Impurities : NMT 0.30 %
Loss on Drying NMTO.5%w/w
Assay 99.0% - 100.5% C21H27C1]N203(on dried basis)
241
STABILITY PROTOCOL AND ANALYTICAL PROCEDURES
Subsequently stability specification has been revised from 9th & 48th month hence current specification
for Batch No. Batch Nos. PP50 17CZRI, PP50 18CZRI & PP5019CZRI is tabulated as follows:
Tests Limits
Characters A White or almost white powder, freely soluble in water.
Appearance of Solution is clear and not more intensely colored than reference solution
Solution BY7.
pH Between 1.2 and 1.8, in an aqueous solution 1 in 20
Loss on Drying NMT 0.5% w/w
Related Substance Impurity A : NMT 0.15%
(By HPLC) Impurity B :NMTO.15%
Impurity C :NMTO.15%
Impurity D : NMT 0.15%
Impurity E :NMTO.15%
Impurity F : NMT 0.15%
Any Unspecified Impurity : NMT 0.10%
Total Impurities :NMTO.30%
Assay (By HPLC) 99.0% -100.5% C21H27C1)N203(on dried basis)
Analytical procedures: All the tests shall be performed as detailed under section 3.2.S.4.2
Forced degradation studies: Forced degradation studies are performed and addressed under specificity
of the Impurity profile validation study under section 3.2.S.4.3.
242
3.2.S.7.2
POST APPROVAL STABILITY PROTOCOL AND
STABILITY COMMITMENT
243
244
3.2.S.7.3
STABILITY DATA
245
3.2.S.7.3.1
STABILITY STUDY DATA
246
ACCELERATED STABILITY
STUDY DATA
247
(Ipea)
, N8IDeof Company: Ipca Laboratl.lries Limited Location: Ratlam
ACCELERATED STABILITY STUDY DATA

PRODUCT NAME : CETlRIZINE DIHYDROCHLORIDE
SAMPLE STORED AT : 4O:l:rCI75:1:5%R.H. Start DIIte : .10102J2006
BATCH NO. : PP5017CZRJ REMARKS:

BATCH SIZE: 17.0 Kgs Accelerated StabIDty Study shows that prod~ II ltable at above-mlntloned cond1Uon.
MFa. DATE : Dec. 2005
CONTAINERI
CLOSURE SYSTEM: Doubt. black lOPE P«*f balllin FIBRE container
Sptdftcatfon initial 3 Months 'Montha

AnItp.ed for
A white or BImostVtflIlB powder. freely solutMl tonfonns Conforms Ccx1bms
Characters In waler.
SoIuIioh Is clear and not more i'l18nSely COnforms Conforms confonns
Appwance or Solution coloured \han referenQesoMIon BY,. • 1.59
pH 1.2bU. 1.50 1.56
N.D. ~.02%
ReIattd SUbstances !nllUrltyA
ro
:NMTO.10% 0.02%
0.04%
.
Indi'idJaIlIIlknoYm h1purlty :NMTO.10% O.04~ 0.03%
SUmof a'Ilmpu1ltes :NMTO.3O% 0.08% 0.08% 0.08%

0.32% ' 0.32% 0.34%
Loa on DryIng NMT 0.5% wJ.N
99.0% .100.5% C21H%1CbN~ (odb) 100.2% 100.2% 99.6'~
AJtri
04.01.06 10.05.06 10.08.06
DueDataot ana~ls
~.
z. -~
Q.A. MANAGEtt
Q.C. MANAGER
DATE: \~ tt-;1 - DATE: IBID'IO~
Data of prtnt:. August 18, 2007
248
[Ipeal
Name of Company: Ipc:aLa~oratories Limited Loc:ation~Ratlam
ACCELERATED STABILITY STUDY DATA

PRODUCT NAME.: CE1lRIZINE DIHYDROCHLORIDE
SAMPLESTOREDAT: 4O:t~CI75:t5'hR.H. Start Date : -10lO2l2OO6
SATCH NO. : PP5018Cl,Rl REMARKS:

SATCKSIZE: 2O.0Kga Ac=1ft'.8d ~ Study.howI that product lIstab'e at abovMlentlaned ccndIUon.
MFG. DATE : Dec.2005
CONt'AINERI
CLOSURE SYSTEM: Double black LOPE baalin F18RE container
AnaIyad for SpecIftcdon Initial 3Month1 'Montha

Chncterl A YtilII8 or &most VIt1IIe powder. fr8eIy soMlIe Conforml Conforms Ccnbms
inwa1Br.
SCkItiCln Is dear and not more Intensely
Appearance or Solution Conforms Conforms Confams
c:doured than referenoB &dutIon BY,.
pH 1.2101.8. 1.48 1.49 1.52
Related Substances impurityA :NMTO.1~ .0.08% N.D. 0.05%
r
II\rMMIIIlllkrtcMn hIpurtty :NMTO.10% 0.07% 0.08% .o.06t.
~ of an Impuri1es :NMTO.3O% 0.22% 0.28% 0.23OJi
Lon on DryIng NMT 0.5% wftI 0.30% 0.31% 0.36%
MvJ 99.0% -100.5% ez.~ (odb) 100.0% 100.0% 99.9%
Due Date of analysis 04.01.06 10.05.06 10.oa.06
.L
Q.C. MANAGER
~
Q.A.~GER
DATE: \ ~'8r.1- DATE: 'S/f1BIO~
Dateof prlnt- Augult 1~ 2001
249
(Ipeaj
Name of Company: Ipca Laboratories Limited Locadon: Ratlam
ACCELERATED STABilITY STUDY DATA

PRODUCT NAME : CET1R1Z1NEDIHYDROCHLORIDE
SAMPLE.STOREDAT : 4O:t2'CI75:t5% R.H. Start Date : .10lO2l2OO6
BATCH NO. : PP5019CZPJ REMARKS:

BATCH SIZE: 20.60 Kgs AcceIer$ld StabIlIty Study IhowI that product llltabteltabove-menUoned condltfon.
MFG. DATE : Jan. 2006
CONTAINERI
ClOSURE SYSTEM: Double black LOPE baas In FIBRE contat.,..
Anaryad for SpecIfication In1tIaJ

. /3Montha 6Monlhs
A Ylfl!lI «IlImostMtlta powder, t8ett sdubIe ConformI Confcrms Conbms
Clwlctn Inwatsr.
SClutionIs c:Iearmd not more kltensely Confonna Ccnforms Ccnbms
Appearance or Solution ooIoured "an refetence solutionBY,.
pH 1.210 1.8- 1.61 1.62 1.65
Related Substa.'K.8I ImpuItttA :1'4-MrO.10% 0.06% ND. 0.05%
-..;..- ,," 0.06% ...
IndMduai unkrlatmImpurlty :NMTO.10% 0.08% ~)'08" '.
Qm of all impurities :NMTO.30% om. 0.18% 0.21%
Loa on DryIng NMTO.5%wNi 0.- 0.34% 0.37%

MRf 99.0% -100.5% C21H27CbN2C>.J(odb) 99.7% 99.8% 99.7%
Due Date of analysis 18.01.06 10.05.06 10.08.06
~l- .
Q.c. MANAGER .
d--
Q.A. MANAGER
DATE: I Q'{ l1'r DATE: 1'10'1 'T
Dati of print:- August 18, ~
250
LONG TERM STABILITY
STUDY DATA
251
Name of Company: Ipca Laboratories Limited Location: Ratlam
LONG TERM STABILITY STUDY DATA
PRODUCT NAME: CETIRIZINE DIHYDROCHLORIDE

SAMPLE STORED AT: 30:t 2 C /65 :t 5% R.H. D
Start Date: .10/0212006
BATCH NO. : PP5017CZRI REMARKS: Long term Stability Study shows that product is stable at above-mentioned condition.
BATCH SIZE: 11.0 Kgs
MFG. DATE : Dec. 2005
CONTAINER!
CLOSURE SYSTEM: Double black LOPE poly bags in FIBRE container
Analyzed for Specification 3 6 *9 12 18 24 36 **48 60

Initial
Months Months Months Months Months Months Months Months Months
Description while or alrrost white powder. freely soluble in waler. Conforms .. Conforms Conforms Conforms Conforms Conforms Conforms Conforms Conforms Conforms
Appeal3l1ce or Solution is dear and not more intensely coloured !han
Solution refererll£solution BYr. Confonns Conforms- Confonns Conforms Conforms Conforms Conforms Conforms Conforms Conforms
pH • Beemeen 1.2 and 1.8 in an aaueous solution 1 in 20 1.50 1.55 1.57 1.59 1.56 1.57 1.45 1.63 1.67 1.68
Loss on Drvinll NMTO.5%wm 0.32"/. 0.30% 0.31% 0.32"10 0.33% 0.32"10 0.35% 0.36% 0.32% 0.38%
'Related ImOUriiVA :NMTO.15% 0.02% N.D. 0.02% <0.02% 0.03% N.D. N.D. 0.05% <O.OS%
0.02"-"
Substances hnourilv B ':NMTO.15% NA NA NA '. .:0.02% 0.05% <0.02% <0.02% N.D. <0.05% <0.05%
(By HPLC) Imouri~,C :NMTO.15% N.A. N.A. N.A. <0.02% 0.04% <0.02"1.1 <0.02% 0.03% <0.05% <0.05%
ImouriliD :NMTO.15% N.A. N.A. N.A. <0.02% N.D. N.D. N.D. N.D. N.D. <0.05%
Imouri liE :NMTO.15% NA- N.A. N.A. 0.04% 0.05% <0.02"/. 0.04% 0.02% N.D.' . <0.05%
l!l:P.uriliF :NMTO.15% N.A. N.A. N.A. 0'18% 0.06% N.D. 0.04% <O.02"k <0.05% N.D,
Anv Unsoecifl!!d Imouritv :NMTO.l0% 0.04% 0.07% 0.05% 0.04% 0.04% 0.03% 0.02"10 0,03% <0.05% <0.05%
Totallmpurities :NMTO.30% 0.08% 0.13% 0.11% 0.16% 0.28% 0.05% 0.10% 0.12% 0.05% <0.05%
Assay IBv HPLC) 99.0% • 100.5% C21HvChN2OJ(cxIb) 100.2"/0 100.1% 99.7% 99.8% 99.8% 100.0% 99.8% 99.7% 99.8% 99.9%
Due Date or analysis 04.01.06 10.05.06 10.08.06 10.11.06 10.0207 10.08.07 10.02.08 10.02.09 10.02.10 10.02.11
N.A..- Not Applicable. N.D.- Not Detec1ed •• Stability Specification Revised,
H Stability Specification Revised
Reporting threshold has been changed to 0.05% In accordance to Ph.Eur. 6.8
~
STABILITYIN~HARGE a.A. MANAGER
DATE: 13Joblll
DATE: tslG~f
Date or print:- Jb~t 13, 2011
252
Name of Com pan)' : Jpea Laboratories Limited Location: Ratlam
PRODUCT NAME: CETIRIZINE DIHYDROCHLORIDE

SAMPLE STORED AT: 3D:!: 2°C 165:!: 5% R.H. Start Date: -10/0212006
BATCH NO. :PP5018CZRI
REMARKS: Long term Stability Study shows that product is stable at above-mentioned condition.
BATCH SIZE: 20.0 Kgs
MFG. DATE : Dec. 2005
CONTAINERI
CLOSURE SYSTEM: Double black LOPE bags in FIBRE container
Analyzed for Specification 3 6 *9 12 18 24 36 **48 60

Initial
Months Months Months Months Months Months Months Months Months
DescriDtion while or almost while powder. freely soluble in waler. Conforms COnforms COnforms Conforms Conforms Conforms Conforms Conforms Conforms Confonns
Appearance or SoMon is clear and not more intensely coloured !han
Solution reference solution BYr. Conforms Conlonns Conforms Conforms Conforms Conforms Conforms Conforms Conforms Conforms
IlH 8eetween 1.2 and 1.8 in an aaueous solution 1 in 20 1.48 1.46 1.50 1.48 1.50 1.49 1.54 1.60 1.68 1.71
Loss on Drvino NMT 0.5% wilY 0.30% 0.29% 0.31% 0.32% 0.33% 0.34% 0.37% 0.38% 0.39% 0.41%
i 'Related Impurity A :NMTO.15% 0.06% N.D. 0.06% <0.02% 0.02% N.D. N.D. 0.05% 0.1l9% 0.09%
I Substances
Imouritv B :NMTO.15% NA N.A. N.A. < 0.02"10 0.04% 0.05%
(By HPlC} <0.02% N.D. 0.06% 0.08%
impurityC _____ --:..~MTO.15% __ NA:
NA N.A. <0.02% 0.04% 0.04% 0.04% 0.03% <0.05%
Impuri1yD --, <0.05%
:NMTO.15% NA. NA. N.A. <0.02% N.D. N.D. N.D. N.D. ND. N.D.
ImllurityE : NMTO.15% NA N.A. N.A. 0.04% 0.05% 0.05% 0.04% 0.06% 0.06% 0.06%
Impurity F : \IMTO.15% N.A. N.A. N.A. 0.08% 0.07% N.D. 0.05% N.D. N.D. N:O.
Arrt Unspecified Impurity :~'MTO.l0% 0.070/D 0.08% ('.06% 0.04% 0.04% 0.04%~ 0.02% 0.07% 0.05% '0.06%
Tolallmpurities :NMTO.30% 0.22% 0.28% 023% 0.16% 0.27% 0.23% 0.17% 0.27% 0.26% 0.29%
Assav 99.0% - 100.5% CllHnCbN20J (odb) 100.0% 99.9% 99.9% 99.9% 99.8% 100.0% 99.9% 99.8% 99.8% 99.5%
Due Date of analysis. 04.01.06 10.05.06 10.08.00 10.11.06 10.02.07 10.08.07 10.02.08 10.02.09 10.02.10 10.02.11
N.A. - Not Applicable, N.D.' Not Detected, • Stability Specification ••• Stability Specification Revised
Reporting threshold has been changed to 0.05% in accordance to Ph.Eur. 6.8
~--
5TABILlTY}INCHARGE Cl~G-E-R-
DATE: 13 obl"
DATE: IS1M:J"
Oale of print:. June 13, 2011
253
Name of Company : lpea Laboratories Limited
Location: Ratlam
PRODUCT NAME: CETIRIZINE D1HYDROCHLORIDE

SAMPLE STORED AT: 3D t 2°C 165 :!: 5% R.H.
BATCH NO. : PP5019CZRI . Start Date: . 10/0212006
BATCH SIZE: 20.60 Kgs REMARKS: Long lerm Stability Sludy shows thal product is stable at above-mentioned condition.
MFG. DATE : Jan. 2006
CONTAINER!
CLOSURE SYSTEM: Double black LOPE bags in FIBRE container
Analyzed for Specification 3 6 *9 12 18 24 36 **48

Initial 60
Months Months Months Months Months Months Months Months
Description whfte or almosl while powder. freely soluble in water. Confonns
Months
Conforms ConfOlmS Conforms COnforms Conforms Conforms
Appearance or SoluIKln is clear and not more intensely coloured than Conforms Confonns Conforms
Solution reference SOlution BY1. Confonns Conforms Conforms Conforms Conforms Conforms Conforms Confonns Conforms Conforms
pH Beetween 1.2 and 1.8 in an aQUeous solution 1 in 20 1.61 1.60 1.61 1.62 1.60
Loss on Drying NMTO.5%wAv 1.59 1.60 1.63 1.69 1.71
0.29% 0.32% 0.33% 0.34% 0.35%
I 'Related Impurity A 0.36% 0.35% 0.37% 0.38% 0.39%
:NMTO.15% 0.06% N.D. 0.06% <0.02%
Substances Impuri B 0.02% N.D. N.D. 0.03% 0.06% 0.06%
(By HPLC) : NMT 0.15% NA N.A. NA
Impuri LVe <0.02% O.04o/G 0.04% 0.02% N.D. 0.06%
:NMTO.15% N.A. 0.07'1'0
N.A. NA <0.02% 0.04% 0.02% 0.04%
Impur' vO :NMTO.15% 0.03% <0.05% <0.05%
N.A. N.A. N.A. < 0.02"10 N.D. N.D. N.D.
(mpun E - N.D. N.D. N.D.
:NMTO.15% N.A. r-J.A. NA 0.04% 0.05% 0.03% 0.04%
Impun ¥F 0.02% N.D. <(\.05% -:-
Any Unspecified IrnilUrity
: NMT O.lt~~:
: NMT 010"1
N.A.
0.08%
NA
0.08%
NA
0.06%
-
i
0.08%
0.04%
0.06%
0.03%
N.D.
0.05%
O.lJ4%
0.02%
I
<0.02% <0.05% N.D. -.
Tolallmpurilies 0.09% 0.05% 0.06%
:NMTO.30% 0.23% 0.18% 0.24%
Assay 0.16% 0.26% 0.17% 0.16% 0.23% 0.17%
99.0% • 100.5% CllHTtCbNlOJ (Odb) Q.19%
99.7% 99.7% 99.8% 99.8% 99.9%
Due Dale of analysis 100.1% 99.4% 100.00/. 99.8% 99.4%
18.01.06 10.05.05 10.08.00 10.11.06 10.02.07 10.08.07 10.02.08 10.02.09 I 10.02.10 10.02.11
N.A. - Not Applicable, N.D.- Not Detected, • Slabirity Specification, ••• Stability Specification Revised
Reporting thre5hold has been changed to 0.05% in accordance to Ph.Eur. 6.8
STABILITY INCJ'fARGE ~
DATE: \:l. J obl'f . a.A. MANAGER
DATE: '9-,\~\"
Date of print:- June 13, 2011
254

Cetirizine HCL BP - TP

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3.2.S DRUG SUBSTANCE 1-254

3.2.S.2 Manufacture 19-28

3.2.S.3 Characterization 29-50

3.2.S.4 Control of Drug Substance 51-215

3.2.S.4.5 Reference standards or materials 216-223

3.2.S.6 Container closure system 224-237

3.2.S.7 Stability 238-251

BAN Cetirizine Hydrochloride

rINN Cetirizine Hydrochloride

USAN Cetirizine Hydrochloride

Ph. Eur. Cetirizine Di Hydrochloride

Chemical Name (RS)-2-[2-[ 4-[(4-Chlorophenyl) phenyl methyl] piperazin-1-

CAS Number 83881-52-1

Molecular Formula <=2IfI27<=13~2()3

Characters A white or almost white powder, freely soluble in water, practically

Identification 1) The infrared absorption spectrum of sample and standard are

Hygroscopicity Non - Hygroscopic

Therapeutic function Histamine HI-receptor antagonist (Antihistaminic)

Name of the Product

Conditions Temperature 25°C.:t IOC Relative humidity 80%

.:t2% for 24hrs as per Ep.5.0

Weight of empty vessel == 14.8780 gm

Weight of sample = I.OO73gm

Weighed of vessel + sample == 15.8853 gIn

Weight of vessel + sample = 15.8855gm

Weight of incr~ed mass = O,OO02gm

% of Increased Mass == O.0002x 100

Result: - The above prod~ct is Non Hygroscopic

17042012_eTZ_ eTZ_200 1_eZ5RII.pk

17042D-2.sP3551 4000.00 450.00 7.59 88.92 4.00 %R 8 2.00

REF4000 80.162000 66.09 600

4000.0 3000 2000 1500 1000 450,0

17042012_ crz_ crz_2002_CZ5RlI.pk

REF4000 78.572000 66.65 600

170420-I.SP 3551 4000.00 450.00 7.04 87.43 4.00 %R 8 2.00

Headquarters & Registered Office

Name & address of DMF holder

Ipca Laboratories Limited,Ratlam. time: IS:l91ndiaStandard Time

2001 CZ5RII.U.sp - 26/02/2012 - CETIZINE DI HCL USP # 2001 CZ5RII :724/02

2001 CZSRII.U.sp 3601 4000.00 400.00 15.24 61.85 4.00 %T 5 2.00

-- 2001 CZSRII.U.sp - 26/02/2012 - CETIZINE DI HCL USP # 2001 CZSRII :724/02

Ipca Laboratories Limited,Ratlam. time: 12:28 India Standard Time

4000.0 3000 2000 ]500 1000 400.0

.. -'" CETRIUSPWS.sp - 21110/2011 - CETIRIZINE HYDROCHLORIDE USP WS # 1023CZRII : 52

CETRIUSPWS.sp 3601 4000.00 400.00 17.37 66.31 4.00 %T 1 2.00

Ipea Laboratories Limited,Ratlam. time: 12:18 India Standard Time

- -. CETRIUSPRS.sp - 21/10/2011 - CETIRIZINE HYDROCHLORIDE USP RS LOT-FOG124:S28/

CETRIUSPRS.sp 3601 4000.00 400.00 8.75 60.03 4.00 %T 1 2.00

Sample : Cetirizine HCI

Performed by: Approved bY~ V

:urrent Oata Parameters

'Or 'Or 'Or

"' •....•.,.....T"""-,...." •.••••.•.••••.••••.. ,....., q I""l C"': rr"l (TI ru OJ C\l

~\V~ \~// \V )ate_

••••••• = CHANNF.l fj ===_11===

lD NMR plot parameters

Interpretation of Mass Spectrum CETIRIZINE _DI_ HCL

Batch No. : 2001 CZ5RII

Instrument : Micro mass

388.9 (M+Ht Ion For 2001 CZ5RIJ

Structure of CETIRIZINE 01 HCL