edti/'ff• *..

WropeanOiredorilttlDman~for theQ.. litJ de ~ qwlitl

ofMedidnes ctImt!di(iKl'lMt&"'~tl>""& ""nsde ... ,.

COUNCIL OF EUROPE

CONSEll DE [EUROPE

Certificate of suitabilityNo. Rl-CEP 2008-316-Rev 00

12

3456

7 Site(s) of production:8 SEE ANNEX 1

910

11 After examination of the manufacturing method and subsequent12 processes(including purification) for the site(s) of production listed in annex,we

13 certify that the quality of the ri~~11~~I~II~~'I~,:\;controlledby the current version of the14 monograph IBUPROFEN no. 721 of t current edition including15 supplements,only if it is supplementedby below, basedon the analytical16 procedure(s)given in annex.

Address:7 AlleeKastner,CS30026F-67081Strasbourg(France)

Tel: +33 (0) 3 88413030 - Fax: +33 (0) 3 88 41 27 71 - e-mail: cep@edqm.euInternet: http://www.edqm.eu

(Annex2)17 - Test for residualsolventsby gas rhr·n....'::118 Acetone19 n-Hexane

20 In the last stepsof the synthesiswater is usedas

21 The substanceis packedin double polyethylenebags22 carton box or flexible intermediatebulk container.

23 The holder of the certificate has declared the absenceof use of24 origin in the manufactureof the substance.

25 The submitted dossier must be updated after any significant change that26 safetyor efficacyof the substance.

27 Manufactureof the substanceshall take place in accordancewith the Good28 and in accordancewith the dossiersubmitted.

to comply with these provisions will render this certificate void.

333435

< 0ll;g:jsice:[t!f:Jt;a.tehas two annexes, the first of 1 page and the second of 3 pages.Tlli!l~···.~~ftif1li~~has:

Director of EDQM

IOL CHEMICALS LTD, as holder of the certificate of suitability

00 for Ibuprofen

hereby authorises

to use the above-mentioned certificate ofMarketing Authorisation(s): (name of product(s)

Date and Signature (of the CEPho/def):

Address:7 AlleeKastner,CS30026F-67081Strasbourg(France)

Tel: +33 (0) 3 88 413030 - Fax: +33 (0) 3 88 41 27 71 - e-mail: cep@edqm.euInternet: http://www.edam.eu

effll'"*European Oirtdoratt I Oirtdion tlI'DpI!en!'lt

rortheOuoIit) do~qualiIiofM_ ct>_amont&lI<alth( are & .... d.....

COUNCIL OF EUROPE

CONSEll DE [EUROPE

of Substances Division

EDQMCertificate of SuitabilityCEPNo Rl-CEP 2008-316-Rev 00Annex 1 Page 1/1

IO~

12.3

Iv 50 mL of N, N-Dimethylformamide into 100 mL volumetric flask.):li;i;iiI to zero, Add 200 mg of Benzene and record the weight. Dilute to volumeiii'}"'{) ~'- .1C. .3. d I h t

III ~ UUl/l1Ul an c ose t e s opper.I [1. tiS, LJ~kSolution-B:

a hi, ;'.'.:..:i'.1 ~l 50 mL of N, N-Dimethylformamide into 100 mL volumetric flask.Weigh it ~;;> au. Add 80 mg of Trichloroethylene. Record the weight and tare to zero.Repeat thi )T 100 mg of Isopropyl Alcohol, 100mg of Acetone, and 100 mg of n-Hexane. ~\ solution A into it and dilute to volume with N, N-

.LLLi ? :I' the stopper.. .Jiilb&.u:}: I.:]

Preparation of .::lSt~i,i~l!rl~!~~!~ltioTransfer 5 mL of31;""1, .;i< B into 100 mL volumetric flask. Dilute to volume with N, N-Dimethylformamide. rl. of this solution separately into 6 different 20 mL headspace vials and close rubber septum and seal with aluminum crimp caps. Thissolution contains 2 ppm ppm of Trichloroethylene, 100 ppm each of IsopropylAlcohol, Acetone, and -r ~'.. g spect to sample for a sample concentration of 500 mgper mL. I.?,;, ,'.}'

'<, }}"",., ... }'Preparation of Sample Solutia,~· .'.Weigh accurately about 500Dimethylformamide. Close the ill!The concentration of this solution is

12.4

12.520 mL headspace vial. Add 1 mL of N, N­

septum and seal with aluminum crimp caps.

12.6 Preparation of Blank solution: i;';t~:=~)<Transfer 1 mL of N, rlformam ~t;0~~;:;litrubber septum and seal with aluminum cC'll>"nii':""m'p}s;(;!,p;

i

:-'headspace vial. Close the vial with a

12.7 Chromatgraphic conditions:

Split ratio 1:10 •Initial 40°C, holdfor 3 minutes1--------------"4 ~..,.:} -----iIncrease @ 10°C per minute to 120°CHold at 120°C for 2 minutes

BJl ternal diameter, and 31lm film

r---------------~----------------------------~±±}%c~%c.kCarrier gas Nitrogen : e: ", ••

Flow rate 2.0 mL per minute (Linear velocity 15.4 emInjector temperature 230°CDetector temperature

Column DB-624, J&W Scientific, 30 m 1thickness

Oven temperatureprogram

Increase @ 18°C per minute to 230°CHold at 230°C for 5 minutes

EDQMCertificate of SuitabilityCEPNo Rl-CEP 2008-316-Rev 00Annex 2 Page 1/3

Ii.::::: 'i,"'"

....... i,; ::,: !\.,;: ." I?I I '

+r- c, Ph.Eur.

/O~,':,:,,':,I ':':'\.It , '.' { t, I

..'••::•.:.:••• I{····.,.,:·.··,· .:.•,•••..•.,".."':. I'r"•.:·,.,:".·.:••••••••;.·•.:·••:•."

R P. W.",;;;'Isopropyl alcohol, RRT about 1.03Acetone, RRT 1.00

n-Hexane, RRT about 1.19Benzene, RRT about 1.50

,',"""Trichloroethylene, RRT about 1.61

.8H~ rnld.:0;:" .. :0;:, "";;"''CC

TlV~fij ~1-;~~~ II"..VB temperature

12.9Injection Sequence:S.#

115°C35 minutes

0.2 minutes

T. iarur c

GC cyr' :,.•.•.".

CJl,t;,,/vial,··'..>~!!ir"" .'.A;' time 25 minutes

Loop fill time \ ( \iInjection time

0.3 minutes0.5 minutes

Loop equilibration ti

Vial shake0.3 minutesOff

34

11

1 Blank2 Standard solution

# of Injections

BlankSample solution

16

12.10GC analysis:12.10.1 Condition the column at 220°C for 60 minutes. I ,

least for 30 minutes).12.10.3 After the system has equilibrated, inject blank sohr all the six vials of the

standard solution. Ensure that system suitability P'.¥..~ cceptance criteria.12.10.4 Finally inject sample solution as per injection sequence.

12.11 Acceptance Criteria for System Suitability: < t}12.11.1%RSD: The percentage relative standard deviation of peak are ilicate injections

of standard solution for each solvent should not be more than 1.(12.11.2Resolution: The resolution between Acetone and Isopropyl A lcol del be more

than 1.0. "'{,'.,.,,},'•.},.,,},.,~.•@:;;.:':......'{•••••••••'.,.'.'.'.'

12.12Calculations and Results: t~~1~1llf!~~!!I~~i~1 ••••••.

Detection limit (DL) & quantitation limit (QL) are given in the following tab __

EDQMCertificate of Suitability q~i·I:;~I'I;I~~'~~~0~~~1CEPNo Rl-CEP 2008-316-Rev 00Annex 2 Page 2/3

Sr.# Name of Solvent DL (ppm) QL(ppm)

2. Acetone 2.0 6.0

3. n-Hexane 1.0 3.0Trichloroethy lene 2.0 6.0Isopropyl Alcohol 2.0 6.0Benzene 0.30 0.90

Call~IJ~I!~~;;!~I~'i,~~~~!,entof Benzene in the sample using the following formula:x WsllOOx 11100x 5/100 xllWt x P/100 x 106

Where,solvent in sample.standard replicates.

12.12.2 Calculate thesample using the

Cone. in ppm =AtlAs x

Isopropyl Alcohol, Acetone, and n-Hexane in the

Where,At - Area of individualAs - Mean Area of six "L'''.lYUl

Ws - Weight of standard inmg.Wt - Weight of sample in mg.P - Purity of standard solvent.

EDQMCertificate of SuitabilityCEPNo Rl-CEP 2008-316-Rev 00Annex 2 Page 3/3