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1. E S r 2 ent i CA ES A 10 Elution Tine Minutes VAVOI30 1 3 Lniecr time 10 26 57 37 12 01 Scratch method Instrument 102 vial 6 Figure 4 Chromatogram of captopril Control No 197214 monitored at 200 nm WHO PHARM 97 595 page 54 The following conditions were used Eluent Methanol 0 1 concentrated phosphoric acid in water pH 2 1 44 56 mixed by hand Column Kromasil C8 4 6 x 250 mm 5 um particles Column temperature 40 C Detector Varian Polychrom 9065 operated at 200 nm Pump Varian 9012 operated at a flow rate of 1 0 ml min Injector Camegie Med CMA 200 operated at 8 C Integrator PeakPro Beckman Sample Captopril was dissolved in the eluent at a concentration of 1 0 mg ml 20 ul corresponding to 20 ue were injected dr Stability in the eluent When a sample was stored for 24 hours in the dark at 8 C a degradation of 1 3 was observed The solutions should be analyzed within two hours when stored at 8 C Limit of detection 5 ng 0 03 at 200 nm Limit of quantification 17 ng 0 09 at 200 nm Diode array detection The chromatographic system described above was used to record UV spectra for the detected peaks The spectra of the impurity peaks as well as the main peak were similar with UV maxima at about 200 nm The wavelength of 200 nm was chosen since in the purity method it gave the best sensitivity for all peaks The main peak was investigated by the peak purity
2. Le Centre collaborateur OMS pour les substances chimiques de r f rence fournit galement 69 spectres infrarouges internationaux de r f rence Les prix sont actuellement de US 5 par spectre et US 200 par s rie de 50 spectres au choix voir liste ci dessous sous classeur cartonn Le classeur peut tre command s par ment pour US 10 Des frais administratifs de US 10 couvrant la manutention et l exp dition par avion lettre ou paquet poste sont ajout s chaque commande Les commandes doivent tre envoy es Centre collaborateur OMS pour les substances chimiques de r f rence Apoteket AB Produktion amp Laboratorier Centrallaboratoriet ACL Prismavagen 2 5 14175 Kungens Kurva Suede T lex 11553 APOBOL S amp T l copie 46 8 740 6040 o Le paiement doit tre effectu dans le d lai indiqu sur la facture Veuillez effectuer le palement en indiquant le num ro de facture aupr s de Postgirot Utland 10506 Stockholrn Su de a c N 29840 6 Apoteksbolaget AB ACL SWIFT PGS SE S WHO PHARM 97 595 Page 18 Appendice 5 Les spectres infrarouges internationaux de r f rence suivants sont actuellement disponibles aupr s du Centre ac clidine salicylate ac tazolamide allopurinol amiloride chlorhydrate amitriptyline chlorhydrate ampicilline trihydrate b clom tasone dipropionate benzylp nicilline potassique biperid ne bip rid ne chlorhydrate b
3. WHO PHARM 97 595 page 92 Piperazine adipate ICRS 197212 El 250 PIPERAA1 EA 4 615 Cm 52 57 48 50463 54 d Ge AC 100 44 2 Ke 46 2 pi 551 42 3 57 2 85 1 86 1 45 2 51 7 we 80 1 84 1 Wh ar Sech 87 2 100 1 105 1 192 1 Qa a 4 Eege a Sal P zg Jai Lasel phase pe Hr gr ES EI a 3 Er Ose An TT de 60 55 I 80 v e oe 108 ie ds we ie n Figure 2 Positive ion electron ionization mass spectrum of piperazine adipate Control No 197212 ect Piperazine adipate has practically no UV absorbance except at wavelengths below 210 nm A UV spectrurn in water was recorded on a Varian Cary 5 spectrophotometer A UV maximum was observed at 195 nm A was about 46 n 1 d Thin laver chromatography For the identity of piperazine adipate see results under Purity Thin layer chromatography Assay See results from collaborating laboratories e vi When the substance was heated to 105 C a loss of lt 0 1 w w was observed n 6 Instrument Perkin Elmer TGA 7 Thermogravimetric analyzer Sample weight 10 mg Heating program 5 C min from 20 105 C and then holding 105 C for 360 minutes Melting point 250 C with decomposition WHO FHARM 97 595 page 93 0 1 n 2 determined by Karl Fischer titration rganic volatile com lt 0 1 The test included methanol ethanol acetone acetonitrile dichloromethane pyridine chloroform benzene trichloroethylene and dioxan Eac
4. 0 02 The detection limit of the system was about 1 25 ug 0 25 when examined visually The spot of piperazine citrate corresponds in position and appearance with that of the USPRS lot F of piperazine citrate C The ICRS was screened for the following anions chlorides bromides nitrates phosphates and sulfates lt 200 ppm of chlorides lt 10 ppm of bromides lt 30 ppm of nitrates lt 500 ppm of sulfates and lt 600 ppm of one unknown ion were found The following conditions were used Eluent 1 Sodium carbonate sodium bicarbonate 1 8 mM 1 7 mM Eluent 2 Sodium bicarbonate for the determination of chloride 2 5 mM Column Dionex HPIC AS4A SUPTessor ASRS I Detector Dionex 20001 conductivity Range 3 us Pump Dionex 20001 Injector Beckman System Gold Autoinjector 307 Integrator PeakPro Beckman Sample Piperazine citrate was dissolved in the eluent at a concentration of 1 0 mg ml in water 50 ul corresponding to 50 ug were injected et ns 1 1 LEE ET TY CERT a LL in Breet Ap TETE rer eue PPT TORE mr rm er ET ea rem mr CARTE CEE CAL rammed rere e ge EEE Lee WHO PHARM 97 595 page 101 Jon Chlorides Bromides Nitrates Phosphates Sulfates Limit of detection ppmin 10 10 30 100 30 the sample Limit of quantification 50 50 100 500 100 pprn in the sample Data given by collaborating laboratories European Pharmacopoeia lab EPCRS batch 1 is from the same batch as ICRS 197213
5. 2 1 p p TGA 0 2 Eau KF 0 2 Titrage potentiom trique 992 Nouvelle m thode plus s lective Optimisation de Ja longueur d onde de 254 nm 263 nm Par rapport un talon externe Dapsone N de contr le 183115 Premier rapport d analyse WHO PHARM 85 513 appendice 10 Ann e d examen 1983 1988 1997 IR conforme TLC 2 4 taches HPLC 1 2 1 9 0 7 ke LC MS identification de l impuret identifi e comme principale 4 aminodiph nyl sulfone PSA 1 0 TGA lt 0 1 0 1 LOD 0 1 e Titrage potentiom trique 99 9 100 0 Nouvelle m thode HPLC L ancienne n tait pas lin aire TEINT SPY CIE ECC TC TOC TT TT LT TH TELE om E ra rem mn ar SS _ die i E MICE SOR HTEO OO WHO PHARM 97 595 Page 29 Appendice 6 D soxycortone ac tate N de contr le 167007 Premier rapport d analyse WHO PHARM 66 431 appendice 1 a i i o o Ann e d examen 1965 1975 1980 1984 1997 IR conforme conforme TLC aucune aucune 2 taches impuret impuret d tect es d tect e d tect e HPLC 0 2 0 7 TGA lt 0 1 LOD lt Q 1 0 1 lt Q 1 9 DTA 0 7 j PSA lt Titrage spectrophotom trique 100 Nouveau syst me de chromatographie en phase liquide ayant une meilleure efficacit de s paration Dexam thasone acide phosphorique N de contr le 192161 Premier rapp
6. ALLO ll L E a NEA SSSR 4000 0 3500 3000 25300 2000 0 1800 4609 4400 4200 4000 B00 600 AB 8 bel 80 VW 40 Figure 1 Zk spectrum of 1 0 mg of ciprofloxacin hydrochloride Control No 197210 in 300 mg of potassium bromide recorded against a potassium bromide disc Instrument Perkin Elmer 1600 FTIR High performance liquid chromatography with mass nectrometric detectic A spectrum of ciprofloxacin was recorded by electrospray ESI in the positive ion mode The spectrum shows an M H ion of 332 0 which supports the identity of ciprofloxacin The spectrum given in Figure 2 is concordant with the spectrum of the European Pharmacopoeia Chemical Reference Substance EPCRS lot 1 of ciprofloxacin hydrochloride Eluent Acetonitrile 1 glacial acetic acid in water 50 50 Column Direct inlet Pump Hewlett Packard 1050 operated at a flow rate of 0 2 ml min Detector Fisons Platform II quadrupole mass spectrometer Operating conditions Cone voltage 65 V Source temperature 140 C Sample Ciprofloxacin hydrochloride was dissolved in the eluent at a concentration of 0 01 mg ml 20 ul corresponding to 200 ng were injected e ZA wn ee ee Meel Te EEN PAT COP Hien arin n PTT eT TT eT T TTY PT L A ara pre TT LHL UR PET mL eT ee sem d TS minaret WHO PHARM 97 595 page 59 Ciprofloxacin HCIICRS 197210 ESI 140 er ET CIPROFL2 46 3 935 Gm 40 54 25 31 t3 20 GV6S AC
7. Hanau Allemagne WHO PHARM 97 595 Page 4 APPENDICE 1 DISTRIBUTION DE SUBSTANCES CHIMIQUES DE REFERENCE EN 1997 SCIR Echantillons vendus Ac clidine salicylate p Ac tamidobenzalazine Ac tazolamide Allopurinol Amidotrizofque acide 2 Amino 5 nitrothiazole 3 Aminopyrazole 4 carboxamide h misulfate 3 Amino 2 4 6 triiodobenzoique acide Amitriptyline chlorhydrate Amodiaquine chlorhydrate Amphot ricine B Ampicilline anhydre 10 Ampicilline sodique 13 Ampiciuline trihydrate 24 Anhydrot tracycline chlorhydrate 16 Atropine sulfate 4 Azathioprine Bacitracine zinc B clom tasone dipropionate Bendazol chlorhydrate Benzobarbital Benzylamine sulfate Benzylp nicilline potassique Benzylp nicilline sodique B ph nium hydroxynaphtoate B tam thasone B tam thasone phosphate sodique B tam thasone val rate B tanidine sulfate NN bis 2 3 xylyDanthranilamide Bupivacaine chlorhydrate Caf ine Calcium folinate Leucovorine calcique Carbamaz pine Carb nicilline monosodique Chloramph nicol Chloramphenicol palmitate Chloramph nicol palmitate forme A 4 Chloro 2 m thy laminobenzoph none Chloroquine sulfate 2 4 Chioro 3 sulfamoyibenzoyl benzo que acide Chlorph namine hydrog nomal ate Chlorpromazine chlorhydrate Chlortalidone Chiort tracycline chlorhydrate LEO Oo Le kA L Lu res P Lu Ch EA n b Gah A ah Lo A BH oo ra ON SF FA le kA ZS A Ara Aa ka
8. LR LEP PME TE A ute Al 2 ga ue D D e Mell Athlet qua MAIS LCA AL KD dl An AELK L DES Ku ETAT ELITE PM PA elt KA AR Err re ee are ir A jure ere rar RTE AT PT HR LL EEN be Ht WHO PHARM 97 595 page 41 N297171T 5P LITI T h wt Neel ie i ae Figure 1 JR spectrum of 1 0 mg of acetanilide Control No 297171 in 300 mg of potassium bromide recorded against a potassium bromide disc Instrument Perkin Elmer 1600 FTIR Purity Assigned melting point 116 C Based on results from a collaborative study See under Collaborative study at the end of this Appendix Thermogravimetric analysis The substance is already volatile at 90 C therefore thermogravimetric analysis is not a suitable method Water lt 0 1 n 2 determined by Karl Fischer titration High performance liquid chromatography No impurities above the limit of quantification 0 08 were found A chromatogram is given in Figure 2 WHO PHARM 97 595 page 42 297171 Sug 13 46 12 97 02 18 u Kai E g B e P D vw S z 5 Ei d ai a OD 19 26 Elution Time Minutes VHPO240 Inject tite 14 38 18 97 02 12 GC1062 Tostrument 104 Vials Q Figure 2 Chromatogram of acetanilide Control No 297171 monitored at 240 nm The folowing conditions were used Fluent Acetonitrile 0 05 M phosphate buffer pH 3 0 15 85 Column Genesis C18 4 um 4 6 x150 mm Detector Gynkotek UVD 340 operated at 240 nm Pump Gynkotek M480 op
9. C Detector temperature 290 C Temperature program 40 C for 10 minutes 40 C min and holding 240 C for 5 minutes Sample 20 mg were shaken with 1 ml of benzyl alcohol and another 20 mg were shaken with 1 ml of Milli Q purified water each for about five minutes If undissolved particles were found filtration was performed Purity Thin o craph One secondary spot probably the ethylenediamine compound was detected but estimated to be lt limit of quantification 0 1 No detectable amounts of fluoroquinolonic acid were found not even when scanning at 254 nm where a higher UV absorbance was obtained The following thin layer chromatographic system according to The International Pharmacopoeia Third Edition Volume 5 was used WHO PHARM 97 595 page 62 Thin layer Silica gel 60 F 254 Merck TLC Eluent Acetonitrile ammonia 260 1 methanol dichloromethane 1 2 4 4 Sample 100 and 50 ug of ciprofloxacin hydrochloride dissolved in acetic acid were applied Visualization Scanning at 278 nm with a CAMAG TLC Scanner 3 was performed as well as visualization in UV light of 254 nm Ry ciprofloxacin hydrochloride 0 54 Rr fluoroquinolonic acid 0 68 Ky desfluoro compound 0 47 R ethylenediamine compound 0 43 R by compound A 0 49 The spot of ciprofloxacin hydrochloride corresponds in position and appearance with that of the EPCRS lot 1 of ciprofloxacin hydrochloride No secondary spots were detected in
10. Gynkotek 480 operated at a flow rate of 1 0 ml min Gynkotek Gina 50 operated at 8 C PeakPro Beckman Streptomycin sulfate was dissolved in water at a concentration of 2 0 mg ml 20 ul corresponding to 40 ug were injected A sample was stored for 1 week at room temperature No signs of degradation were observed 50 ng 0 1 at 200 nm 100 ng 0 25 at 200 am WHO PHARM 97 595 page 108 Diode array detection The chromatographic system described above was used to record UV spectra for the detected peaks The spectra of the impurity peaks as well as the main peak were similar None of them had a distinct maximum but they all showed a slope increasing towards lower wavelengths The wavelensth of 200 nm was chosen giving the best sensitivity for all peaks The main peak was investigated by the peak purity program and showed no signs of co eluting impurities Capillary Electrophoresis Three impurities above the limit of quantification were found Their total amount was estimated to be 5 2 by peak area normalization n 13 RSD 0 5 for the main peak RSD 13 6 at the 2 impurity level Dihydrostreptomycin does not separate from streptomycin in this method it is determined by liquid chromatography see Purity High performance liquid chromatography An electropherogram is given in Figure 4 streptomycin suifate Figure 4 Electropherogram of streptomycin sulfate Control No I 97215 monitored at 200 nm H a DE
11. The following conditions were used j Eluent 100 mM boric acid 50 mM phosphoric acid in water pH adjusted to 7 0 with 2 M sodium hydroxide Capillary Fused silica total length 60 cm length to detector 50 cm ID 50 um Detector P ACE System MDQ operated at 210 nm CE Instrument P ACE System MDQ operated with an applied voltage of 20 kV for 60 minutes Run temperature DC Sample temperature 15 C nhbesdudi cmd sl be A A hee AE a OC CN REP EE CPC aa LICE TL af diate bP AP Tet MLL A Puree gra Daag En ur A e AA Nik pl Krea mn Injection Integrator Sample Stability in 0 5 NaCl Limit of detection Limit of quantification Silver content WHO PHARM 97 595 page 71 20 seconds pressure injection at a pressure of 0 5 psi which corresponds to about 24 nl PeakPro Beckman Cisplatin was dissolved in 0 5 NaC at a concentration of 1 0 mg ml A sample was stored for 4 h at 15 C No signs of degradation were observed After 24 h a degradation of about 0 5 was observed 0 4 at 210 nm Cisplatin 1 3 at 210 nm Transplatin 0 8 at 210 nm Potassium trichloroaminoplatinate 1 3 at 210 nm Cisplatin 4 3 at 210 nm Transplatin 2 5 at 210 nm Potassium trichloroaminoplatinate See results from the manufacturer Platinum content See results from the manufacturer Data given by the manufacturer Pt content 65 14 limit 64 9 65 2 Characterization according
12. ZA Le oh Fesch eh D VUN MA AC SE EEE AE OS TOC POUR vunn s i RTC Ae EA T SCIR Cim tidine Clomif ne citrate Clomif ne citrate isom re Z voir Zuclomif ne Cloxacilline sodique Col calcif rol Cortisone ac tate Dapsone D soxycortone ac tate Dexam thasone Dexarn thasone ac tate Dex m thasone acide phosphorique D xam thasone phosphate sodique Diaz pam Diazoxide Dicloxaciiline sodique Dicolinium iodure Dicoumarol Di thylcarbamazine dihydrog nocitrate Digitoxine Digoxine Dopamine chlorhydrate Doxorubicine chlorhydrate Em tin chlorhydrate 4 Fpianhydrot tracycline chlorhydrate 4 Epit tracycline chlorhydrate Ergocalcif rol Ergome trine hydrog nomal ate Frgotamine tartrate Erythromycine Erythromycine B Erythromycine C Estradiol benzoate Estrone Etacrynique acide Ethambutol chlorhydrate Ethinylestradio Ethist rone Ethosuximide Etocarlide Flucloxacilline sodique Flucytosine Fludrocortisone ac tate Fluorouracil Fluph nazine d canoate dichlorhydrate Fluph nazine nantate dichiorhydrate Fluph n zine chlorhydrate Folique acide 3 Pormylrifamycine SE rT A ri ARIA ere rea er r ry manuel ann ar une me LUE TE ame ven ques eine ve Del WHO PHARM 97 595 Page 5 Appendice 1 Echantillons vendus ro oo NON CMON NNN KH BA Nw A W oe mu P 40 EJ ke L OF OO E Gi I aka kA D CA AA ND oh P Li MM
13. with the same Ry as captopril disulfide was detected When determined against an external standard its amount was roughly estimated to 0 7 The following thin layer chromatographic system according to The International Pharmacopoeia Third Edition Volume 5 was used Thin layer Silica gel 60 F 254 Merck TLC and HPTLC Eluent Toluene glacial acetic acid methanol 75 25 1 Sample 100 ug of captopril dissolved in methanol were applied Visualization Scanning at 200 nm with Camag TLC scanner 3 was performed as well as visualization in day light after spraying with 2 2 dinitro 5 5 dithiodibenzoic acid methanol nvolte A4 Petector Response d IENNI D E E ITT vans Wes mule A NATL CTT TOPE ERPS PNEU PSE IDN ETEA TES MP MK ae d laaa ba rara Al SEAN AA ii ECTS WHO PHARM 97 595 page 53 Ry captopril 0 3 TLCV0 4 HPTLC Ry captopril disulfide 0 1 TLC HPTLC The limit of detection of the impurity captopril disulfide was about 0 1 HS 0 1 when scanning at 200 nm The spot of captopril corresponds in position and appearance with that of the USPRS lot H of captopril High ormance liquid chroma h One impurity above the limit of quantification was found It was identified by LC MS as captopril disulfide and estimated to be 0 5 n 6 RSD 10 8 against an external standard A chromatogram is shown in Figure 4 ape il TORS 10 ptepri ug 13 42 58 97 12 18 captopril GA T S S 7 P V e
14. 3 7 a 35 0 30 0 25 0 20 0 15 0 16 0 5 0 0 0 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 Time hours Galn of welght Figure 5 Kanamycin monosulfate Control No 19721 stored at 98 relative humidity As the substance 1s extremely hygroscopic it is advisable ke let it equilibrate with the surrounding atmosphere before weighing it Conclusion Kanamycin monosulfate Control No 197211 can be considered suitable as International Chemical Reference Substance for the intended purpose As this is a biological substance it is difficult to obtain a better quality This ICRS is purer than other official reference materials WHO PHARM 97 595 page 82 APPENDIX 14 Phenacetin WHO Melting Point Reference Substance Melting temperature 136 C Control No 297172 Analytical Report Intended use The stock of the current batch of the WHO Melting Point Reference Substance for phenacetin ki Control No 192572 is depleted and has to be replaced The WHO Melting Point Reference Substance for phenacetin is supplied primarily for calibration of different instruments and methods used for determination of melting temperatures against the method of The International Pharmacopoeia Third Edition Volume 1 Material About 4000 g of the sample manufacturers batch no 207372 were received at the WHO Centre in April 1997 The material is being stored in tightly closed containers at 20 C protected from light Analytical data A white
15. A UV spectrum of the main peak recorded in the eluent is given in Figure 3 E Cumkaoune 247 0 nm 1000 60 0 247 nm MT 0 2 1 i i 1 l La 220 240 260 280 300 320 340 360 380 Ch Figure 3 UV spectrum of phenacetin recorded in the eluent WHO PHARM 97 595 page 86 Capillary l ctrophoresis No impurities above the limit of quantification 0 1 were found An electropherogram 1s given in Figure 4 Chreimh Tritan nhim100S Char A phan OTt han aas OO 0 9 CE phenacetin M n teg Figure 4 Electropherogram of phenacetin Control No 297172 monitored at 247 nm WHO PHARM 97 595 page 87 Eluent 11 7 mM borate 8 3 mM phosphate and 50 mM SDS at pH 9 20 Capillary Fused silica total length 67 cm length to detector 60 cm ID 75 um Detector Beckman P ACE Diode Array Detector operated at 247 nm and 200 nm CE Instrument Beckman P ACE system 5510 operated with an applied voltage of 30 kV for 20 minutes Run temperature 50 C Injection 10 seconds pressure injection Integrator Beckman P ACE Station Software amp Sample Phenacetin was dissolved in water at a concentration of 20 0 mg ml in methanol and then diluted with water to a concentration of 2 0 mg ml fresh solutions 10 seconds high pressure injection corresponds to 118 ng injected sample Limit of detection 0 03 at 247 nm Limit of quantification 0 10 at 247 nm The purity was estimated to about 99 99 mo
16. EE A T ar rm ra PTT OT TT T Fa Aden Er Ww ar a PP mme HEaA RAUEN AHE ARAN TRAE Hemel tel ral WHO PHARM 97 595 Page 15 Appendice 4 Substances de r f rence Conditionnement N de contr le Pip razine adipate 100 mg 197212 Pip razine citrate 100 mg 197213 Praziquantel 100 mg 19419 Prednisolone 100 mg 389029 Prednisolone ac tate 100 mg 289030 Prednisolone h rnisuccinate 200 mg 195196 Prednisolone phosphate sodique 200 mg 194190 Prednisone 100 mg 16703 Prednisone ac tate 100 mg 169032 Prob n cide 100 mg 192156 Proca ne chlorhydrate 100 mg 183119 Procarbazine chlorhydrate 100 mg 184120 Progest rone 100 mg 167033 Propicilline potassique 200 mg 274034 Propranolol chlorhydrate 100 mg 187139 Propylthiouracile 100 mg 185126 Pyrantel ermbonate 500 mg 192157 Pyridostigmine bromure 100 mg 182110 R serpine 100 mg 186133 R tinol ac tate solution 5 capsules 791038 Riboflavine 250 mg 382035 Rifampicine 200 mg 191151 Rifampicine quinone 200 mg 190148 Sodium cromoglicate 100 mg 188140 Spectinomycine chlorhydrate 200 mg 193176 Streptomycine sulfate 100 mg 197215 Substances de r f rence pour le point de fusion Azobenzene 69 C 4g 192168 Vanilline 83 C 4g 192169 Benzile 96 C 4g 294170 Ac tanilide 116 C 4g 297171 Ph nac tine 136 C 4g 297172 Benzanilide 165 C 4g 192173 Sulfaniiamide 166 C 4g 192162 Sulfapyridine 193 C 4g 192163 Dicyandiarnide 210 C dp 192164 Saccharine 229 C 4 192165 Ca
17. OG td p WHO PHARM 97 595 Page 6 Appendice 1 SCIR Framyc tine sulfate N omycine B sulfate Furos mide Gentamicine sulfate Gris ofulvine Halope ridol Hydrochlorothiazide Hydrocortisone Hydrocortisone ac tate Hydrocortisone succinate sodique 3 4 Hydroxy 3 m thoxyph nyl 2 hydrazino 2 me thylalanine 3 4 Hydroxy 3 m thoxyph ny 2 m thylalanine Ibuprofene Imipramine chlorhydrate Indom tacine o lodohippurique acide Isoniazide Lanatoside C L vodopa L vonorgestre L vothyroxine sodique Thyroxine sodique Lidocaine Lidocaine chlorhydrate Liothyronine sodique Lop ramide chlorhydrate M bendazole M f namique acide M tazide M thaqualone M thotrexate M thyldopa M thyltestost rone M ticilline sodique M tronidazole Nafcilline sodique N amine chlorhydrate N omycine B sulfate voir Framyc tine sulfate N ostigmine m tilsulfate Nicotinamide Nicotinique acide Nifurtimox Niridazole Niridazole chlor thylcarboxamide Nor thist rone Norethist rone ac tate Nystatine Quabaine Oxacilline sodique Oxyt tracycline chlorhydrate Echantillons vendus pol kee LA LA ER O k kA D Lo Oo ra kal L LA Une P KN F5 WN PU GG AAA kA MO L b La A G OH WW Mid ba Bho BR O Loi P R a ent D eh UL a SNS SEVEN TENTE ENTREE VTT SEH PLO ST TT ATP LP TA ll ts OL ed iad A PT hh dard ie Pee ee BETEN TTT ie da uadi
18. PeakPro Beckman Sample Kanamycin sulfate was dissolved in the eluent at a concentration of 1 0 mg ml in water 50 ul corresponding to 50 ug were injected Jon Chlorides Bromides Nitrates Phosphates Sulfates Limit of detection ppm in 10 10 30 100 30 the sample Limit of quantification 50 50 100 500 100 ppin in the sample Data given by collaborating laboratories 8 NIBSC Description The first International Standard for Microbiological assay determined in a collaborative study Moisture content Stability Hy eroscopicity Kanamycin Established in 1986 10345 International Units per ampoule lt 0 2 in the closed ampoule Accelerated degradation studies on the sealed ampoules at 56 C for 20 months showed no loss in potency The ampoule contents are extremely hygroscopic AL A ALT ALT TNT NE AA PL LE lb LL arth a are aura re ua PET RT WHO PHARM 97 595 page 81 Stability Stability studies were not performed as this substance was not suspected to degrade easily when stored at 20 C Regular re examinations of the JCRS when stored in the dry state will be performed Hygroscopicity The ampoule contents are extremely hygroscopic When stored for 7 hours at 98 relative humidity the substance gained 30 in weight Results are given in Figure 5 After 30 minutes it gained 16 in weight At continued storage for 24 hours to one week at 98 relative humidity the content of water decreases to
19. Sodium bicarbonate for the determination of chloride 2 5 mM Column Dionex HPIC AS4A Supressor ASRS Detector Dionex 20001 conductivity Range 3 US Pump Dionex 2000 Injector Beckman System Gold Autoinjector 507 Integrator PeakPro Beckman Sample Captopril was dissolved in the eluent at a concentration of 1 0 mg ml in water 50 ul corresponding to 50 pg were injected Jon Chlorides Bromides Nitrates Phosphates Sulfates Limit of detection ppmin 10 10 30 100 30 the sample DM 49 Limit of quantification 50 50 100 500 100 ppm In the sample Data given by the manufacturer Identification IR Spectrum is consistent with structure Assay HPLC 99 5 as is lodometric titration 99 5 dried basis 99 4 as is Chromatographic purity HPLC Captopril disulfide 0 4 Individual impurities Complies Unknown Complies Total other impurities Complies WHO PHARM 97 595 page 56 Chromatographic impurities TLC Captopril disulfide lt 0 5 L Proline Q24836 ND SO 14224 ND SQ 25487 2 methyl 3 ND acetyithiopropionic acid 3 Mercapto 2 i Acid 0 001 Loss on drying 0 06 Melting point 108 C Specific optical rotation 129 Heavy metals lt 30 ppm Residue on ignition 0 0 Appearance Crystalline powder practically free from visible impurities Color White to off white Odor Characteristic sulfide odor Stability Regular re examinations of the ICRS w
20. WHO PHARM 97 595 page 65 Jon Chlorides Bromides Nitrates Phosphates Sulfates Limit of detection Gomm 10 10 30 100 30 the sample Limit of quantification 50 50 100 500 100 ppm in the sample Data given by the manufacturer Appearance Complies Identity IR Complies Identity TLC Complies Identity chloride Complies d Clarity of solution Complies Colour of solution Complies pH value 3 8 limits 3 0 4 5 Sulfate lt 200 ppm limit max 400 ppm Heavy metals lt 10 ppm limit max 20 ppm Water 6 03 limits 4 7 6 7 Sulfated ash lt 0 05 limit max 0 1 By products HPLC Fluoroguinolonic acid z 0 05 mut max 0 2 By product A lt 0 1 Y iimit max 0 2 Desfluoro compound lt 0 05 limit max 0 2 Ethylenediamine compound lt 0 05 limit max 0 2 Other by products individual 0 05 limit max 0 2 A Sum of by products 0 1 imit max 0 5 Assay calculated on the dried 99 9 limit 98 0 102 0 substance Stability Stability studies were not performed as this substance was not suspected to degrade easily according to WHO PHARM 86 529 Regular re examinations of the ICRS when stored in the dry state will be performed Conclusion Ciprofloxacin hydrochloride Control No 197210 can be considered suitable as International Chemical Reference Substance for the intended purpose When used in the liquid chromatographic assay according to The International Pharmacopoeia Third Edition Volu
21. allowed to equilibrate with the atmosphere for 24 hours at a relative humidity of 22 27 a loss of 8 1 w w was observed n 2 RSD 18 8 Instrument Perkin Elmer TGA 7 Thermogravimetric analyzer Sample weight 3 5 mg Heating program gt C min from 20 105 C and then holding 105 C for 240 minutes Melting point Indefinite melting range Streptomycin sulfate becomes slightly discoloured already when heating to 105 C Water 8 5 n 2 RSD 7 7 determined by Karl Fischer titration The determination was performed on samples that had equilibrated for 24 hours with the atmosphere at a relative humidity of 22 27 Organic volatile compounds lt 0 1 The test included methanol ethanol acetone acetonitrile dichloromethane pyridine chloroform benzene trichloroethylene and dioxan Each of them were estimated to be lt 100 ppm The content of organic solvents was tested by gas chromatography with the following conditions Instrument Hewlett Packard 6890 Column HP 5 30 m x 0 53 mm 2 65 om film Camier gas Helium 8 ml min Detector FID Injection volume 2 Hl Injector temperature 200 C Detector temperature 250 C Temperature program 40 C for 10 minutes 40 C min and holding 240 C for 5 minutes Sarnple 20 mg were shaken with ml of benzyl alcohol and another 20 mg were shaken with 1 ml of Milli Q purified water each for about five minutes The sample shaken with benzyl alcohol was filt
22. de contr le des lots actuels Cette liste comprend galement neuf substances mentionn es ci dessous dont on peut pr voir qu elles seront officiellement adopt es par te Comit d experts sa prochaine r union Etablissement de spectres de r f rence en 1997 On trouvera l appendice 5 une liste compl te de tous les spectres infrarouges internationaux de r f rence avec indication des nouveaux spectres tablis depuis 1993 Aucun nouveau spectre n a t tabli en 1997 Travaux effectu s en 1997 sur de nouvelles substances de reference Le Centre a poursuivi ses travaux en vue de fournir de nouvelles substances de r f rence qui seront n cessaires pour accompagner les sp cifications de la troisi me dition de la Pharmacop e internationale En 1997 sept nouvelles substances de r f rence destin es accompagner les volumes 3 4 et 5 ont t examin es captopril chlorhydrate de ciprofloxacine cisplatine monosulfate de kanamycine adipate de pip razme citrate de pip razine et sulfate de streptomycine Les rapports d analyse pour ces substances figurent aux appendices 10 13 et 14 17 Ces substances sont jug es satisfaisantes en vue de leur adoption comme substances chimiques internationales de r f rence Les stocks N 192171 d ac tanilide et N 192172 de ph nac tine taient en cours d puisement et ont t remplac s par les stocks N 297171 d ac tanilide et N 297172 de ph nac tine On trouve
23. e par un r examen p riodique des substances d tenues par le C ntre Les r sultats obtenus pour les substances r examin es en 1997 sont r sum s ci apr s A titre comparatif on a aussi indique les r sultats obtenus lors des r examens pr c dents Les substances ont t conserv es dans des r cipients tanches a 5 C et sous une humidit relative inf rieure 30 Dans les tableaux on adopt les abr viations suivantes CE Electrophor se en tube capillaire DSC Calorim trie diff rentielle DTA Analyse thermique diff rentielle GC Chromatographie en phase gazeuse HPLC Chromatographie liquide haute performance IR Spectrophotom trie infrarouge KF M thode de Karl Fischer pour la d termination de la teneur en eau LC MS Chromatographie en phase liquide spectrom trie de masse LOD Perte la dessiccation RMN R sonance magn tique nucl aire PSA Analyse de solubilit par phases TLC Chromatographie en couche mince TOA Analyse thermogravimetrique La valeur estim e des impuret s solides totales obtenue par HPLC CE et TLC est exprim e en aire sauf indication contraire lorsqu elle est obtenue par DSC et par DTA elle est exprim e en mole et par PSA en poids Les pertes de poids mesur es par LOD et TGA sont exprim es en poids Da Les valeurs obtenues par titrage sont calcul es par rapport la substance dess ch e ou anhydre sauf indication contraire Pour plus de d tails sur les m thod
24. le 189143 Premier rapport d analyse WHO PHARM 90 547 appendice 7 mamii _ oO Ann e d examen 1989 1997 TLC lt 0 01 _ HPLC lt 0 005 0 06 A TGA lt 0 1 0 1 Titrage spectrophotome trique 100 2 S Nouveau syst me chromatographique ayant une meilleure efficacit de s paration WHO PRARM 97 595 Page 24 Appendice 6 Chloramph nicol N de contr le 486004 Premier rapport d analyse WHO PHARM 87 532 appendice amp Ann e d examen 1986 1992 1997 IR conforme conforme TLC 0 2 tache tr s faible HPLC 0 2 0 3 0 2 0 3 TGA lt 0 1 lt 0 1 LOD 0 05 A Titrage spectrophotom trique 99 8 100 0 99 6 Le r examen de cette substance a t en partie r alis par le Department of Scientific Services Institute of Science and Forensic Medicine Singapour Chloramph nicol palmitate N de contr le 286072 Premier rapport d analyse WHO PHARM 87 532 appendice 9 Ann e d examen 1986 1992 1997 IR conforme pas de conforme pasde forme A forme A DSC Set 2 2 TLC environ 2 7 HPLC Ca 3 1 29 TGA 0 1 lt 0 lt 0 1 Eau KF 0 2 lt 0 1 LOD 0 1 7 Titrage spectrophotom trique 100 2 100 0 RPT IUT LP a LL ib rer eme PTE TTT apen Chloramphenicol palmitate forme A N de contr le 175073 Premier rapport d analyse WHO PHARM 75 485 appendice 10 tar pp OUUU Ann d exame
25. let it equilibrate with the surrounding atmosphere overnight if accurate weighing is requested Conclusion Streptomycin sulfate Control No 197215 can be considered suitable as International Chemical Reference Substance for the intended purpose As this is a biological substance it is not possible to obtain a better quality Kak
26. of Science and Forensic Medicine Singapour WHO PHARNM 97 5985 Page 22 Appendice 6 Azathioprine N de contr le 172060 Premier rapport d analyse WHO PHARM 72 471 appendice 11 WHO PHARM 73 473 appendice 3 Ann e d examen 1973 1979 1981 1997 IR conforme conforme TLC environ 0 5 tache l tache HPLC 0 5 TGA 0 6 LOD 0 7 0 7 S PSA environ l Benzobarbital N de controle 172051 Premier rapport d analyse WHO PHARM 72 471 appendice 13 Ann e d examen 1972 1977 1981 1987 1997 IR conforme conforme TLC tache 1 tache 2 taches environ 0 5 secondaire secondaire secondaires HPLC 0 3 0 7 TGA 0 1 Eau KF EN 0 1 LOD 0 4 0 1 0 1 DTA environ 1 Titrage titrim trique 100 0 100 2 100 3 Di 1 PORTO TOPOL SPP arr eT ee Sn ES Pe AT PET LOT UE LL Li IHH DAHA Li OELLE D L GAN NICE r Lain ere erra D CPAM PTT A TEL CAL a dre rare re pre deelt age ll ri lle kde VU hedi on 1 ete WHO PHARM 97 595 Page 25 Appendice 6 Benzylamine sulfate N de contr le 172052 Premier rapport d analyse WHO PHARM 72 471 appendice 14 EE Ann e d examen 1972 1977 1979 1997 E ee O IR conforme conforme TELE 1 tache l tache secondaire secondaire HPLC lt 0 05 TGA lt 0 LOD lt 0 1 2 A amp LC MS confirme l identit a a Carbamaz pine N de contr
27. to EP H Identification IR Identification TLC Appearance of solution 1 pH of solution 1 Related substances Ag content Assay cisplatin Meets requirements Meets requirements Meets requirements 5 88 limits 4 5 6 0 Meets requirements 18 ppm based on cisplatin limit lt 250 ppm 100 12 limit 97 0 102 0 Characterization according to USP XXI Identification HPLC Identification IR Identification TLC Crystallinity Meets requirements Meets requirements Meets requirements Crystalline WHO PHARM 97 595 page 72 Water content 0 1 limit 1 UV Purity E 301 E 246 5 12 limit gt 4 5 Potassium 0 1 limit lt 1 trichloroarminoplatinate Transplatin 0 06 limit lt 2 Assay cisplatin 100 77 limit gt 98 Stability Regular re examinations of the ICRS when stored in the dry state will be performed For stability in solution please see under capillary electrophoresis Conclusion Cisplatin Control No 197207 can be considered suitable as International Chemical Reference Substance for the intended purpose When used in the spectrophotometric assay according to The International Pharmacopoeia Third dition Volume 4 the content of cisplatin is taken to be 100 calculated with reference to the dried substance which corresponds to 100 on the as is basis htm ht dom sh Ahoy LU paved ro ea hr lh TI TT NIE D ahir eet am an en erin en rare reng PT
28. vitamine A ac tate de r tinol la ph nac tine P F la vanilline P F la caf ine P F et l acide folique On trouvera l appendice 1 le d tail de la distribution des diverses substances En 1997 les substances ont t distribu es dans 38 pays On trouvera a l appendic 2 le d tail de la distribution par pays En ce qui concerne la distribution par R gion de l OMS on constate qu environ 14 3 des substances ont t fournies la R gion africaine 3 7 la R gion des Am riques 14 4 la R gion de la M diterran e orientale 60 4 Ja R gion europ enne 2 9 a la R gion de l Asie du Sud Est et 4 4 la R gion du Pacifique occidental Distribution de spectres de r f rence en 1997 Aucun spectre de r f rence n a t distribu en 1997 Etablissement de substances de r f rence en 1997 Conform ment la proc dure recommand e par l Comit OMS d experts des Sp cifications relatives aux Pr parations pharmaceutiques dans son trente deuxi me rapport S rie de Rapports techniques N 823 huit substances chimiques internationales de r f rence ont t tablies en 1997 On trouvera la liste de ces substances l appendice 3 On trouvera l appendice 4 une liste compl te de toutes les substances chimiques internationales de r f rence d tenues par le Centre en janvier 1998 avec indication de la quantit de substance contenue dans chaque unit de conditionnement et du num ro
29. 0 Buffer Phosphoric acid 2 45 g 1 mixed with triethylamine to get a pH of 3 0 Genesis C18 4 um 4 6 x 150 mm 40 C Gynkotek UVD 340 operated at 278 nm Gynkotek M480 operated at a flow rate of 1 5 ml min Gynkotek Gina 30 operated at 8 C PeakPro Beckman Ciprofloxacin hydrochloride was dissolved in the eluent ata concentration of 0 5 mg ml 10 ul corresponding to 5 ug were injected A sample was stored for about 15 hours No signs of degradation were observed 2 ng 0 04 at 278 nm 5 ng 0 1 at 278 nm WHO PHARM 97 595 page 64 In this system fluoroquinolonic acid elutes late In order to elute it within 30 minutes a gradient was used The amount of fluoroquinolonic acid was determined by another liquid chromatographic method optimized for fluoroquinolonic acid The same result lt 0 1 impurities was observed for EPCRS lot 1 Diode The chromatographic system described above was used to record UV spectra for the main peak of ciprofloxacin and for the potential impurities Ciprofloxacin showed UV maxima at 205 and 278 nm Fluoroquinolonic acid showed main maxima at 255 and 262 nm by compound A at 255 and 270 nm desfluoro compound at 283 nm and the ethylenediamine compound at 276 nm The wavelength of 278 nm was chosen in the purity method The main peak was investigated by the peak purity program and showed no signs of co eluting impurities The impurities mentioned will be available as se
30. 0 RSD 0 09 Perkin Elmer DSC7 Differential Scanning Calorimeter No signs of polymorphic forms were found when the substance was heated from 40 C to 200 C The previous batch CRS 192171 showed a purity of 99 95 mol WHO PHARM 97 595 page 46 Data given by the manufacturer Identification IR Conforms Assay 98 5 101 0 Anilin lt 0 01 Phenol z 0 002 Sulphated ash lt 0 1 Water lt 0 2 Collaborative study The melting point was assigned after a collaborative study including four laboratories The melting point was determined according to The International Pharmacopoeia Third Edition Volume 1 as a capillary melting point determination Participating laboratories Lab 1 Bj rm Egil Olsen Norsk Medicinaldepot AS Sven Oftedalsvej 10 PO Box 100 N 0518 OSLO NORWAY Lab 2 Camilla Alvesson Mettler Toledo AB Hangpilsgatan 56 42677 Vastra Fr lunda GOTEBORG SWEDEN Lab 3 Dr Ulrich Rose service de la Qualite du Medicament European Pharmacopoeia Laboratory B P 907 F 67029 Strasbourg Cedex 1 FRANCE Lab 4 WHO Collaborating Centre for Chemical Reference Substances STOCKHOLM SWEDEN le bad 1 sm ck mm mono eS do o mb mem d eh que cab LAN L sall 1 d Pl ES A WHO PHARM 97 595 page 47 Lab 1 Mean Capillary melting point C 115 7 115 5 116 0 115 5 115 7 Assigned melting point 116 C Stability No special stability studies were performed as it was
31. 0 ppm of phosphates were found Chlorides were found and estimated to 300 ppm Sulfates were found and roughly estimated to be 21 9 theoretical value 19 8 The following conditions were used Eluent 1 Eluent 2 Column SUPTESSOF Detector Range Pump Injector Integrator Sodium carbonate sodium bicarbonate 1 8 mM 1 7 mM Sodium bicarbonate for the determination of chloride 2 5 mM Dionex HPIC AS4A ASRS 1 Dionex 20001 conductivity 3 LS for determination of sulfate 300 uS Dionex 20001 Beckman System Gold Autoinjector 507 PeakPro Beckman WHO PHARM 97 595 page 110 Sample Streptomycin sulfate was dissolved in the eluent at a concentration of 1 0 mg ml in water 50 ul corresponding to 50 ug were injected Ton Chlorides Bromides Nitrates Phosphates Sulfates Limit of detection ppmin 10 10 30 100 30 the sample Limit of quantification 50 50 100 500 100 ppm in the sample Data given by collaborating laboratories NIBSC Description 7 The third International standard for Streptomycin established 1979 Microbiological assay 78500 International Units per ampoule determined in a collaborative study Stability Stability studies were not performed as this substance was not suspected to degrade easily when stored at 20 C Regular re examinations of the ICRS when stored in the dry state will be performed Hygroscopicity d As the substance is very hygroscopic it is advisable to
32. 00 2 l 1143 1174 103 3 4 naa BG 4 1133 1702 173 2 4882 201 2 DE I d I al op ans 130 3126 152 3 454 3 Wei A i DA Gre AR dy get SE EE s ch be teilen hell Wer ere zech ger C lak every ss Dale Figure 2 Positive ion atmospheric pressure chemical ionization mass spectrum of captopril Control No 197214 V spect A UV spectrum in 0 1 M NaOH was recorded on a Varian Cary 5 spectrophotometer The spectrum is given in Figure 3 A shoulder was observed around 235 nm A eel 259 at 235 nm n 6 RSD 0 6 calculated with reference to the dried substance te hese ha mm LA fl pe pr pd md Sc nd ride dla Stet Hi IS ACL EMO MR DA TITRE TT NT PE MCR er LA MTN A TY dth dur WA ET ENTREE LL all GITTAREN ets Pak lh rhan ung mmm WHO PHARM 97 595 page 51 ABS 1 0000 0 3000 0 0000 250 00 350 00 450 00 NH Captopril 1 Figure 3 UV spectrum of captopril Control No 197214 11 ng ml in 0 1 M NaOH Thin laver chromatography Por the identity of captopril see results under Purity Thin layer chromatography d Assay spectrophotometric assay 99 8 n 6 RSD 0 6 The determination was performed according to the method described above under Evidence of chemical structure UV spectrum The USPRS lot H of Captopril was used as standard and regarded as 100 The difference between the proposed ICRS and the USPRS lot H is statistically not significant at the 95 confidence level using unpaired t test
33. 286072 175073 172061 195201 181106 182109 178080 183114 187138 190150 197210 197207 187136 274005 I CAE hr a mt 4 re Lun D A A ENG TO dar AT TT PTIT PT IL ANAL rm rm mr WHO PHARM 87 595 Page 13 Appendice 4 Substances de r f rence Conditionnement N de contr le Col calcif rol Vitamine D 500 mg 190146 Cortisone acetate 100 mg 167006 Dapsone 100 mg 183115 D soxycortone ac tate 100 mg 167007 Dexam thasone 100 mg 388008 Dexam thasone ac tate 100 mg 288009 Dexam thasone acide phosphorique 100 mg 192161 Dexam thasone phosphate sodique 100 mg 192158 Diaz pam 100 mg 172062 Diazoxide 100 mg 181103 Dicloxacilline sodique 200 mg 174071 Dicolimum iodure 100 mg 172055 Dicoumarol 100 mg 178077 Di thyicarbamazine dihydrog nocitrate 100 mg 181100 Digitoxine 100 mg 277010 Digoxine 100 mg 587011 Dopamine chlorhydrate 100 mg 192159 Doxorubicine chlorhydrate 100 mg 196202 Em tine chlorhydrate 100 mg 187134 4 Eptanhydrot tracycline chlorhydrate 25 mg 288097 4 Epit tracycline chlorhydrate 25 mg 293098 Ergocalcif rol Vitamine D 500 mg 190147 rgom trine hydrog nomal ate 50 mg 277012 Ergotamine tartrate 50 mg 385013 Erythromycine 250 mg 191154 Erythromycine B 150 mg 194186 Erythromycine C 25 mg 194187 Estradiol benzoate 100 mg 167014 Estrone 100 mg 279015 Etacrynique acide 100 mg 281056 Ethambutol chlorhydrate 100 mg 179081 Ethinylestradiol 100 mg 291016 Ethist rone 100 mg 167017
34. 4 dinitrofluorobenzene reagent and 7 ml of the tris hydroxymethy aminomethane reagent were added The solution was heated for 60 minutes in a water bath at 60 C The flask was left at room temperature for 10 minutes to cool before dilution to volume with acetonitrile N B As cooling occurs on mixing with acetonitrile it is advisable to add the acetonitrile slowly permitting the mixture to reach room temperature before the final dilution Stability in the eluent A sample was stored for 24 hours at 8 C in the dark No signs of change in the derivatized sample were observed 0 5 ng 0 02 at 365 nm 2 ng 0 06 at 365 nm Lirrut of detection Limit of quantification lon chromatog raphy The ICRS was screened for the following anions chlorides bromides nitrates phosphates and sulfates Less than 10 ppm of bromides less than 100 ppm of nitrates and less than 500 ppm of phosphates were found Chlorides were found and estimated at 500 ppm Sulfates were found and roughly estimated to be 16 2 theoretical value 16 0 WHO PHARM 97 595 page 80 The following conditions were used Eluent 1 Sodium carbonate sodium bicarbonate 1 8 mM 1 7 mM Eluent 2 Sodium bicarbonate for the determination of chloride 2 5 mM i Column Dionex HPIC AS4A Supressor ASRS 1 Detector Dionex 20001 conductivity Range 3 uS for determination of sulfate 300 pS Pump Dionex 20001 Injector Beckman System Gold Autoinjector 507 Integrator
35. 690 ae Le 2 talon biologique OMS dont la teneur d clar e est de 4855 Ulme a t utilis comme talon pn Nouvelle colonne HPLC 1997 8 2 mars 11 2 octobre 7 octobre 5 1 mars 5 0 octobre 4 586 mars 4 622 octobre Ces valeurs lev es sont dues un nouveau syst me chromatographique ayant une meilleure efficacit de s paration L RPCRS dont la teneur figurant sur l tiquette est fausse a t utilis e comme talon Remarques concernant le r examen d octobre 1997 une nouvelle m thode HPLC valid e donnant une meilleure s lectivit a t adopt e La tendance observ e au niveau des impuret s d tect es par HPLC ne traduit pas une d gradation mais l utilisation de m thodes d analyse de plus en plus s lectives L intention tait de changer de lot de nystatine mais les autres substances examin es contenaient davantage d impuret s Par exemple le 2 talon biologique OMS contient 16 8 d impuret s La SCIR actuelle est done la plus pure chimiquement Le Centre continuera rechercher des lots encore plus purs Une m thode de CE a galement t d velopp e mais la m thode HPLC une sensibilit et une s lectivit sup rieures En ce qui concerne le titrage microbiologique un calcul a montr que lorsqu on comparait la valeur obtenue en 1995 4728 Ul mg celles de 1996 et 1997 la diff rence n tait pas statistiquement signif
36. 7 in 300 mg of potassium bromide recorded against a potassium bromide dise Instrument Perkin Elmer 1600 FTIR A spectrum of the main peak cisplatin was mem zm gege ESD in the positive ion mode The spectrum shows an M HT ion of 300 9 which supports the identity of cisplatin The spectrum is given in Figure 2 The EPCRS lot 1 of cisplatin shows a similar mass spectrum as the ICRS 197207 Eluent Water 100 Column Hypercarb 100 mm Shandon Pump Hewlett Packard 1050 operated at a flow rate of 1 ml min After splitting the flow rate into the mass spectrometer was about 0 07 ml min Detector Fisons Platform I quadrupole mass spectrometer Operating conditions Cone voltage 35 V Source temperature 150 C Sample Cisplatin was dissolved in the eluent at a concentration of mg ml After splitting about 1 Lg was injected into the mass spectrometer WHO PHARM 97 595 page 68 Clapladn ICRS ESl Hypercarb 100 H20 Geh er 170 63 143 Em 148 180 141 187 2283202 Sean ESe TE 264 9 FETA i 792 9 EIER 790 9 STE A CN z 417 9 264 5 eg A HA os M gj Ra SAT af 224 223 9 yaa pe 280 Serie 1 9 a 1 74 d 233 0 zapa 260 9 E EINE ET ee E AC OL H an Eet Zrtennein W e ge SEL EE DEER eee ee TEE TEE peseeyp ay BE l D i at Ose 100 t 40 160 180 300 zn 749 in app 300 T Figure 2 Positive ion electrospray mass spectrum of cisplatin Control No 197207 Identific
37. Appearance Satisfactory Identity IR Conforms Water content 11 3 Identity melting point 191 C TLC Complies Stability Stability studies were not performed as this substance was not suspected to degrade easily according to WHO PHARM 86 529 Regular re examinations of the ICRS when stored in the dry state will be performed Conclusion Piperazine citrate Control No 197213 can be considered suitable as International Chemical Reference Substance for the intended purpose WHO PHARM 97 595 page 102 Streptomycin sulfate Control No 197215 Analytical Report Intended use The monograph for Streptomycin sulfate powder for injections in The International Pharmacopoeia Third Edition Volume 4 requires a reference substance of streptomycin sulfate to be used in the thin layer chromatographic test for identity Material About 21 g of the sample were received at the WHO Centre in January 1998 The material is being stored in sealed ampoules at 20 C protected from light This ICRS is of the same origin as that of the 3rd International Biological Standard for streptomycin sulfate Analytical data A white fluffy freeze dried sample Evidence of chemical structure Infrared spectrum An infrared spectrum is given in Figure 1 No W197215T The spectrum is concordant with the spectrum of the European Pharmacopoeia Chemical Reference Substance EPCRS lot 1 of streptomycin sulfate as well as with the spectrum of the
38. CE 3 SUBSTANCES CHIMIQUES INTERNATIONALES DE REFERENCE ETABLIES EN 1997 Substance de r f rence Amidotrizoique acide 3 Amino 2 4 6 triiodobenzoique acide B tam thasone phosphate sodique Doxorubicine chlorhydrate Sulfac tamide Tamoxifene citrate Tamoxif ne citrate isom re E Tolu ne 2 sulfonamide N de controle 196205 196206 196205 136202 196200 196208 196209 196204 Rapport d analyse WHO FHARM 86 587 Appendice 9 WHO PHARM 96 587 Appendice 10 WHO PHARM 96 587 Appendice 11 WHO PHARM 86 587 Appendice 12 WHO PHARM 66 587 Appendice 13 WHO PHARM 96 587 Appendice 14 WHO PHARM 96 587 Appendice 15 WHO PHARM 66 587 Appendice 16 Remarques A Je An Jk AR Lt Wien W Den D ee ereechen ses po pee Mr d n a ua ak AAA CN AA LL TTL hn aue Merry ATP TT LT or QC Tee rem ABER VE UN ET ART AS VTA A Lo TE a Meter Mile od hima a H emmer ce WHO PHARM 97 595 Page 11 APPENDICE 4 LISTE DES SUBSTANCES CHIMIQUES INTERNATIONALES DE REFERENCE DISPONIBLES 1998 Informations g n rales Les substances chimiques internationales de r f rence sont tablies conform ment lavis du Comit OMS d experts des Sp cifications relatives aux Pr parations pharmaceutiques Elles sont fournies principalement pour tre utilis es dans des preuves physiques t chimiques ainsi que dans des dosages d crits dans les sp cifications pour le contr le de la qualit
39. Cm 173 184 184 171 161 167 l Ver 100 300 7 160 3 82 9 ees M H 70 9 582 0 3301 123 6 176 1 1485 0 241 9 Lo 271 7 349 4 LU Ch T3 aaay 428 6 454 3 488149145288 eS D An L AN Au PAR PA AU hi o ae Wed ia Gul UE cf 4 christine fl heal UA nul Mi Dave Figure 2 Positive ion electrospray mass spectrum of streptomycin sulfate Control No 197215 UV spectrum A UV spectrum in water was recorded on a Vaden Cary 5 spectrophotometer Streptomycin sulfate has no distinct maximum but a slope increasing towards lower wavelengths was observed A 160 at 200 nm n 1 The calculation was performed on the as is basis in laver chromatogra For the identity of streptomycin sulfate see results under Purity Thin layer chromatography Sulfate For the identity and estimation of sulfate see results under Purity lon Chromatography Assay IC See results under collaborating laboratories A Hr pope ata et Abee H T DFT A LEE PC H OOF FFI iets roma e 5 oo sun oe nn sen ne oe et b d i hame Arr ml Rd Aach Ar rl br Ls e eet at per LL Tr bMS Nd narra a anr liran E E PTEE A TEHEL Ciel ra Cause anus Lan Leit haaa WHO PHARM 97 595 page 105 Thermogravimetric analysis When the substance was heated to 105 C a loss of 1 8 w w was observed n 2 RSD 28 3 The substance is hygroscopic and picks up moisture immediately This determination was performed on freshly opened ampoules If the sample was
40. D 0 1 lt 0 1 DTA 0 37 0 33 e PSA environ 0 7 a i S klen mme e muer ee eS a on md comm mm ne at Di Ki A 9 me ERNEST TEE ree ee EST AAA LL nev vane Lia aaa iT AN a Dd T ali bee Kin OO CRT hialin anneer Pre ama aaen d PA TE TEA AATE e IST BESTEET IT A ur WHO PHARM 97 595 Page 27 Appendice 6 Chlortalidone N de contr le 183114 Premier rapport d analyse WHO PHARM 84 513 appendice 9 EE Ann e d examen 1983 1997 IR conforme TLE 0 3 HPLC 0 5 0 8 HPLC acide 2 4 chloro 3 sulfamoy 0 1 0 1 benzoyl benzoique LOD 0 1 TGA zl PSA 0 9 Titrage potentiom trique 99 5 ry a ak Clomif ne citrate N de contr le 187136 Premier rapport d analyse WHO PHARM 88 537 appendice 8 i te en Ann e d examen 1987 1997 IR conforme TLC Q tache secondaire HPLC 0 3 0 9 Isom re Z HPLC environ 35 aire 32 6 p p Isom re Z RMN 33 S TGA 0 3 Eau KF 0 7 Titrage potentiom trique 97 6 nr Nouvelle m thode plus s lective Optimisation de la longueur d onde de 254 nm 263 nm Avec la SCIR 187137 comme talon ext rne WHO PHARM 97 595 Page 28 Appendice 6 Clomif ne citrate isom re Z N de contr le 187137 Premier rapport d analyse WHO PHARM 88 537 appendice 9 Ann e d examen 1987 1997 IR conforme TLC lt 0 1 HPLC 0 3 0 3 Isom re E HPLC environ 2 aire
41. EE D PEN OA ZT Tr PC PC NC EELER A 9476 amp x D EYE aR Here rl LD LL A TPE LE EL DUT D CR Anker Agape OO Ce RAN EL SO EPS OP PE maga p p men ee Wale AAA FETE SEE ONE ES A A A ONE CNE RER AN CARRE NT sg Ki TT Au Lulu J wT AT fr daten ir CH 1 1 1 OD 37 DISTR LIMITED DISTR LIMITEE WHO PHARM 97 595 ORIGINAL ANGLAIS WORLD HEALTH ORGANIZATION ORGANISATION MONDIALE DE LA SANTE CENTRE COLLABORATEUR OMS POUR LES SUBSTANCES CHIMIQUES DE REFERENCE Rapport d activit pour 1997 par M Westermark Les substances chimiques internationales d r f rence nouvellement tablies propos es par l Centre collaborateur OMS pour les substances chimiques de r f rence sur la base d essais et d une caract risation appropri s figurent dans le rapport annuel du Centre Ce rapport est communiqu entre autres aux membres du Tableau consultatit d experts de la Pharmacop e internationale et des Pr parations pharmaceutiques auxquels il est demand d examiner soigneusement les propositions ainsi que la documentation jointe concernant les analyses effectu es et de faire part au Centre de toute r serve ou critique avant la fin septembre 1998 En de tels cas le Centre proc dera toutes consultations ou analyses compl mentaires n cessaires pour la validation de la substance gt i aucun commentaire n gatif mest re u dans jes trois mois l s nouvelles substances chimiques intemationales de r f r
42. EPCRS lot 1 ce liquid atogra No impurities above the limit of quantification were found which means lt 0 1 when determined by peak area normalization External reference substances of four possible impurities were injected They were all estimated to be below the limit of detection or quantification which means for fluoroquinolonic acid lt 0 04 limit of detection for the desfluoro compound lt 0 02 limit of detection for the ethylenediamine compound lt 0 06 limit of quantification and for by compound A lt 0 06 limit of detection A chromatogram is shown in Figure 4 P myopia Cetsctor Redponaa Lon Lag d 134 d 1 ZO 70 BD SL so j af 1p 79 Ciereti MCL Sug desfiu ra compourd gt lt et yelenediamine compound Hlution Tine VHHO LSD Seratch method enden deer ET EE regen CDTI ET PAL i RAAT ete Aare FY mr TI TO D unknown lt LOQ WHO PHARM 97 595 page 63 15 31115 37 04 02 ciprofloxacin kydrochlortde by compound A Minuces inject tine 23 95 10 37 03 14 Inatriment 103 Vial ba Figure 4 Chromatogram of ciprofloxacin hydrochloride Control No 197210 monitored at 278 nm The following conditions were used Bluent Column Column temperature Detector Pump Injector Integrator Sample Stability in the eluent Limit of detection Limit of quantification Acetonitrile Phosphate buffer with triethylamine 10 9
43. Ethosuximide 100 mg 179088 Etocarlide 100 mg 172037 Flucloxacilline sodique 200 mg 195194 Flucytosine 100 mg 184121 Fludrocortisone ac tate 200 mg 195199 Fluorouracil 100 mg 184122 Fiuph nazine chlorhydrate 100 mg 176076 Fluph nazine d canoate dichlorhydrate 100 mg 182107 Fluph nazine nantate dichlorhydrate 100 mg 182108 Folique acide 100 mg 388019 3 Formylrifamycine 200 mg 190149 Framyc tine sulfate N omycine B sulfate 200 mg 193178 Furos mide 100 mg 171044 Gentamicine sulfate 100 mg 194183 Gris ofulvine 200 mg 280040 Halop rido 100 me 172063 Hydrochlorothiazide 100 mg 179087 Hydrocortisone 100 mg 283020 Hydrocortisone ac tate 100 mg 280021 WHO PHARM 97 595 Page 14 Appendice 4 Substances de r f rence Hydrocortisone succinate sodiqu 3 4 Hydroxy 3 m thoxyph nyl 2 hydrazino 2 m thylalanine 3 O M thylcarbidopa 3 4 Hydroxy 3 m thoxyph nyl 2 m thylalanine 3 0 M thylm thyldopa Ibuprofene Imipramine chlorhydrate Indom tacine o lodohippurique acide Isoniazide Kanamycine monosulfate Lanatoside C L vodopa L vonorgestrel L vothyroxine sodique Lidoca ne Lidoca ne chlorhydrate Liothyronine sodique Lop ramide chlorhydrate M bendazole M f namuque acide M tazide M thaqualone M thotrexate M thyidopa M thyltestost rone M ticilline sodique M tronidazole Nafcilline sodique N amine chlorhydrate N omycine A chlorhydrate
44. Instrutwae 143 Vial Figure 2 Chromatogram of phenacetin Control No 297172 monitored at 247 nm The following conditions were used Eluent Acetonitrile 0 05 M phosphate buffer pH 3 0 23 77 Column Kromasil C18 5 um 4 6 x150 mm Detector Gynkotek UVD 3405 operated at 247 nn Pump Gynkotek M480 operated at a flow rate of 1 0 ml min Injector Gynkotek Gina 50 operated at 8 C Integrator PeakPro Beckman Sample Phenacetin was dissolved in the eluent at a concentration of 1 0 mg ml 5 ul corresponding to 5 pg were injected Stability in the eluent A sample was stored in the eluent for about ten hours in the dark at 8 C No signs of degradation were observed When the sample was stored in daylight for one week at 20 C a degradation of less than 0 06 was observed Limit of detection 1 ng 0 02 at 247 nm Limit of quantification 3 ng 0 06 at 247 nm In the previous batch ICRS 192172 two impurities were found and estimated to be about 020 SAL EE TR n E TS ld nu PR FO a ot OT EENEG HE at D E niert E wie Drees LA AL TS und dev eme eek dde dl deht mme E aen le WHO PHARM 97 595 page 85 Diode CH The chromatographic system described above was used to record UV spectra for the detected peaks The spectra of the main peak and the peak of impurity were similar with UV maxima at 247 nm The main peak was investigated by the peak purity program and showed no signs of co eluting impurities
45. Lab3__ Lab4 Mean Capillary melting point C 136 1 135 7 135 9 136 2 136 0 Assigned melting point 136 C ot LCR DES PES PRE OO ET TC PCT AE TEE PCM ET da mm na ha DTA Akc th Le ET CT OCEAN aia s oe TANNE NE h d wei ET EE kA 4 TETAP TETTO a ET LT OMT TITE tt sall raan r eruera re nr CAP iriiri br a AHH H hrer EE e e 1 dites i Geen hd Meesch shee ee eee SUR WHO PHARM 97 595 page 89 Stability No special stability studies were performed as it was considered that this substance based on the experience of the stability of the previous lot was stable and showed no signs of degradation when stored for 34 years at 20 C Regular re examinations of this ICRS when stored in the dry state will be performed Conclusion Phenacetin Control No 297172 can be considered suitable as WHO Melting Point Reference Substance for the intended purpose with the melting point set to 136 C WHO PHARM 97 595 page 90 APPENDIX 15 Piperazine adipate Control No 197212 Analytical Report Intended use The monograph for Piperazine adipate tablets in The International Pharmacopoeia Third Edition Volume 4 requires a reference substance of piperazine adipate to be used in the thin layer chromatographic test for identity Material About 10 g of the sample manufacturers batch NOENR4786 were received at the WHO Centre in June 1996 The material is being stored in tightly closed containers at 5 C p
46. N omycine B sulfate voir Framyc tine sulfate N ostigmine m tilsulfate Nicotinamide Nicotinique acide Nifurtimox Ninidazole Niridazole chlor thyicarboxamide Nor thist rone Nor thist rone ac tate Nystatine Quabaine Oxacilline sodique Oxyt tracycline chlorhydrate Oxyt tracycline dihydrate Papav rine chlorhydrate Parac tamo Paromomycine sulfate Ph n ticilline potassique Ph noxym thylp nicilline Ph noxyme thylp nicilline calcique Ph noxym thylp nicilline potassique Ph nytoine Conditionnement 200 mg 25 mg 25 mg 100 mg 100 mg 100 mg 100 mg 100 mg 12 mg 100 mg 100 mg 200 mg 100 mg 100 mg 100 mg 50 mg 100 mg 200 mg 100 mg 100 mg 100 mg 100 mg 100 mg 100 mg 200 mg 100 mg 200 mg 0 5 mg 00 mg 100 mg 100 mg 100 mg 200 mg 25 mg 100 mg 100 mg 200 mg 100 mg 200 mg 200 mg 200 mg 100 mg 100 mg 75 mg 200 mg 200 mg 200 mg 200 mg 100 mg N de contr le 194184 193180 179085 183117 172064 178078 171045 185124 197211 281022 295065 194182 189144 181104 181105 193179 194185 195195 173068 172058 173069 194193 179084 167023 274024 183118 272025 193177 187135 179090 179091 194189 186129 186130 186132 185123 191152 283026 382027 189141 189142 185127 195198 195197 167028 179082 179083 176075 179089 delid dIe MII Ima ha d Gei 7 WA die ee ee ee T EA PP PP r r a A TT AEE EATE TEAT TAT AEAT TTT CNP PC
47. N 1 HAc 50 50 100 314 0 ui 246 0 288 0 G d 332 0 g S 231 0 l GE 289 0 318 0 202 9 204 St 333 0 69 9 Ek 268 0 SE 447 9 162 5 4749 Ta 286 0 80 8 be me 249 0 294 0 LE 127 5 D Er SE ST 330 0 334 0 On ce tere Le do Ge di hs 130 Si He Wee V alk ths a 4 ive A ui Ss CG E Ai eg My ez BH EE e Dain 120 260 280 300 320 340 ae Figure 2 Positive ion electrospray mass spectrum of ciprofloxacin hydrochloride Control No 197210 ect A Vania In water was recorded on a Varian Cary 5 spectrophotometer The spectrum is given in Figure 3 A UV maximum was observed at 275 nm A jm 1079 at 275 nm n 6 RSD 0 4 Calculations were performed with reference to the dried substance WHO PHARM 97 595 page 60 ABS 1 0000 0 5000 0 0000 200 00 300 00 400 00 500 00 NM Ciprofiexacin HCl 2 Figure 3 UV spectrum of ciprofloxacin hydrochloride Control No 197210 4 6 ug ml in water Thin lav aph For the identity of ciprofloxacin hydrochloride see results under Purity Thin layer chromatography d Chloride For the identity and estimation of chloride see under Purity Ion Chromatography Assay igui tographic a 100 5 n 6 RSD 0 5 The determination was performed at 278 nm according to the method described below under Purity High performance liquid chromatography The EPCRS lot 1 of ciprofloxacin hydrochloride was used as standard and regarded as 100 The result was calculated on t
48. O PHARM 97 595 Page 33 Appendice 6 M ticilline sodique N de contr le 274024 Premier rapport d analyse WHO PHARM 74 478 appendice 9 Ann e d examen 1974 1978 1984 1997 IR conforme S HPLC lt 0 1 0 2 0 2 TGA 4 5 Eau KF 4 7 4 6 3 Titrage alcalim trique 999 2 A Titrage mercurim trique 99 5 Nafcilline sodique N de contr le 272025 Premier rapport d analyse WHO PHARM 72 471 appendice 6 EE Ann e d examen 1972 1978 1984 1997 IR conforme HPLC lt 0 1 0 1 0 6 TGA 4 7 Eau KF 4 0 4 2 d Compos s organiques volatils 0 6 d GC Titrage mercurim trique 99 1 Titrage alcalim trique 99 9 e e emie EE Nouveau syst me chromatographique avec d tection 225 nm WHO PHARM S7 595 Page 34 Appendice 6 Nystatine N de contr le 191152 Premier rapport d analyse WHO PHARM 92 558 appendice 10 Ann e d examen IR HPLC impuret s 304 nm CE impuret s 304 nm HPLC titrage TGA Eau KF Titrage microbiologique Umg TLC UV titrage 304 nm W W 1991 conforme K 100 0 5 0 4 8 6 382 4 1 3 taches secondaires 100 6 1992 we 5 205 1993 7 9 100 0 4962 3 taches secondaires 100 0 1994 8 7 100 5 5 3 4 868 1995 9 1 5 3 4 728 1996 8 8 E ds 5 1 4
49. T A A HAL MM of mr rrara Fee STE A Adare ha urar errre arrera oz ii RTS tee WHO PHARM 97 595 page 73 APPENDIX 13 Kanamycin monosulfate anhydrous Control No 197211 Analytical Report Intended use The monograph for Streptomycin sulfate powder for injections in The International Pharmacopoeia Third Edition Volume 4 requires a reference substance of kanamycin monosulfate to be used in the thin layer chromatographic test for identity Material About 3 6 g of the sample dispensed in ampoules of about 12 mg ampoule were received from the National Institute for Biological Standards and Control in January 1998 The material is being stored at 20 C protected from light This ICRS is of the same origin as that of the Ist International Biological Standard for Kanamycin Analytical data Description A white and very fluffy powder Evidence of chemical structure Infrared spectrum An infrared spectrum of the untreated substance is given in Figure 1 No W960042T WHO PHARM 97 595 page 74 EC LEE CITT eT TTT EM Ye 4900 0 3500 3000 2300 2000 0 1460 12 800 GH enn Figure 1 R spectrum of 1 5 mg of untreated kanamycin monosulfate Control No 197211 in 300 mg of potassium bromide recorded against a potassium bromide disc Instrument Perkin Elmer 1600 FTIR The spectrum in Figure 1 is concordant with the spectra of the United States Pharmacopeia Reference Standard USPRS lot I and of the Eu
50. United States Pharmacopeia Reference Standard USPRS lot H of streptomycin sulfate k ek gell ET DEET EECH E ERR dr 9 OK bold ddd akoka L D sata Lab La LANTA nn PTT re a mmer PT SOTTO EARN UAE Se il AA da rt Sora v ASA eT TT ih raven ru er RSC WHO PHARM 97 595 page 103 Bares 4000 0 3500 3000 909 oun nu 1800 1600 1400 200 000 800 600 50 0 CH 1 Figure 1 R spectrum of 1 1 mg of streptomycin sulfate Control No 197215 in 300 me Of potassium bromide recorded against a potassium bromide disc Instrument Perkin Elmer 1600 FTIR High pe ance liquid chromatography with mass spect Lc detecti A spectrum of streptomycin was recorded by electrospray ESI in the positive ion mode The spectrum shows an M H ion of 582 0 which supports the identity of streptomycin The spectrum which is given in Figure 2 is concordant with the spectrum of the European Pharmacopoeia Chemical Reference Substance EPCRS lot 1 Eluent Acetonitrile 1 glacial acetic acid 50 50 Column Direct inlet Pump Hewlett Packard 1050 operated at a flow rate of 0 2 ml min Detector Fisons Platform II quadrupole mass spectrometer Operating conditions Cone voltage 65 V Source temperature 140 C Sample Streptomycin sulfate was dissolved in the eluent at a concentration of 0 01 mg ml 20 ul corresponding to 200 ng were injected WHO PHARM 97 595 page 104 Streptomycin sulfate ICAS 197215 ESi 140 Direct inlet THEN TO E Gei Ce
51. aaka da rT te re WHO PHARM 97 595 Page 7 Appendice 1 SCIR Echantillons vendus Oxyt tracycline dihydrate il Papav rine chlorhydrate 2 Parac tamol 13 Paromomycine sulfate 0 Ph n ticilline potassique 2 Ph noxym thylp nicilline 2 Ph noxym thylp nicilline calcique Ph noxym thylp nicilline potassique 11 Ph nyto ne 3 Praziquantel Prednisolone 14 Prednisolone ac tate Prednisolone h misuccinate Prednisolone phosphate sodique d Prednisone Prednisone ac tate Prob n cide Procaine chlorhydrate Procarbazine chlorhydrate Progest rone Propicilline potassique Propranolol chlorhydrate Propylthiouracile Pyrantel embonate Pyridostigmine bromure R serpine R tinol ac tate solution 25 000 UD Riboflavine Rifampicine Rifampicine quinone Sodium cromoglicate Spectinomycine chlorhydrate ei hela SSNS PA Ca F9 AAA F9 GE HA L Lo R bi Vi a Substances de r f rence pour le point de fusion Azobenz ne 26 Vanilline 70 Benzile 20 Ac tanilide 30 Ph nac tine 71 Benzanilide 26 Sulfanilamide 19 Sulfapyridine 17 Dicyandiamide 15 Saccharine 14 Caf ine 70 Ph nolphtal ine 27 Sulfac tarmde 0 Sulfam thoxazole 10 Sulfam thoxypyridazine 4 WHO PHARM S7 595 Page 8 Appendice 1 SCIR Sulfanulamide Sulfasalazine Tamoxif ne citrate Tamoxif ne citrate isomere E Testost rone nantate Testost rone propionate T tracycline chlorhydrate Thioac ta
52. and dioxan Each of them were estimated to be lt 100 ppm The content of organic solvents was tested by gas chromatography with the following conditions Instrument Hewlett Packard 6890 Column HF 5 30 m x 0 53 mm 2 65 um film Carrier gas Helium 8 ml min Detector FID Injection volume 2 pl Injector temperature 200 C Detector temperature 250 C Temperature program 40 C for 10 minutes 40 C min and holding 240 C for 5 minutes Sample 20 mg were shaken with 1 ml of benzyl alcohol and another 20 mg were shaken with 1 mi of Milli Q purified water each for about five minutes The sample shaken with benzyl alcohol was filtered Purity in la atograph No secondary spots were detected which means lt 0 25 The following thin layer chromatographic system according to The International Pharmacopoei Third Edition Volume 4 was used Thin layer Silica gel G Merck TLC Eluent Ammonia conc acetone 20 80 Sample 500 ug of piperazine citrate dissolved in ethanol ammonia conc 2 3 were applied WHO PHARM 97 595 page 100 Visualization Visualization in day light after spraying with triketohydrindenehydrate 3 mg ml in glacial acetic acid 1 butanol 3 100 and then with triketohydnndenehydrate 1 5 mg ml in ethanol and drying at 105 C Thereafter spraying with 16dine 0 05 mol l Ry piperazine citrate 0 06 Re ethylenediamine 0 18 Re triethylenediamine 0 08 Ry piperazine 0 06 Re citrate
53. ation of a degradation product in solution The chromatographic system described above was used to check the identity of a peak appearing when cisplatin was stored in an aqueous solution A peak eluting at about 2 minutes was identified as the monohydrated complex with an M H ion of 284 Cisplatin elutes at about 2 9 minutes One potential impurity transplatin was also injected and found to elute at about 5 6 minutes It showed an M HI ion of 300 9 Mass spectrometry of the monohydrated complex has been reported by H Ehrsson I Wallin A Andersson and P O Edlund Cisplatin transplatin and their hydrated complexes Separation and identification using porous graphitic carbon and electrospray ionization mass spectrometry Anal Chem 67 1995 3608 361 1 Assay See results from the manufacturer Assay performed according to the European Pharmacopoeia and the United States Pharmacopeia When the substance was heated to 100 C a loss of lt 0 1 w w was observed n 3 Instrument Perkin Elmer TGA 7 Thermogravimetric analyzer Sample weight 2 mg 5 C min from 20 100 C and then holding 100 C for 70 minutes 270 C with decomposition Heating program Melting point Water See results from the manufacturer WHO PHARM 97 595 page 69 Purity in lave a ograph See results from the manufacturer apillary e esi Capulary electrophoresis was chosen for the purity determination as cisplatin and the two po
54. ckard 1050 operated at a flow rate of 0 2 ml min Detector Fisons Platform II quadrupole mass spectrometer Operating conditions Cone voltage 25 V Source temperature 140 C Sample Kanamycin sulfate was dissolved in the eluent ata concentration of 0 01 mg ml 20 ul corresponding to 200 ng were injected Kanamycin sulfate ICRS 197211 ESi 149 C CV25 ACN 1 HAc 50 50 100 KAMAMYCS 26 2 235 Gm 21 35 14 47 30 Scan ES 217 1 1 06e4 104 8 H 161 9 230 8 53 9 203 5 143 0 179 9 i 143 9 SE 162 9 145 8 Pf art re M H 119 9 243 Sa 324 1 i sc SR 330 1 Ke TUM K 87 9 Zb ee EREM 12442 292 0 d d S a7 ill ku i HMD 1 7 i oi 126 3330 Je a E til wel tad tj r ai 2 Lu A dr HUT e A wd LL Kleer E E H E EE ETTE TELIT Wana baje 60 109 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440 460 ab Figure 3 Positive ion electrospray mass spectrum of kanamycin sulfate Control No 197211 WHO PHARM 97 595 page 76 V A UV spectrum in water was recorded on a Varian Cary 5 spectrophotometer No maximum above 190 nm was observed the absorbance was calculated on the slope at 200 nm A ia 12 at 200 nm n 1 The calculation was performed on the as is basis in la a Por the identity of kanamycin monosulfate see results under Purity Thin layer chromatography Sulfa
55. considered that this substance based on the e experience of the stability of the previous lot was stable and showed no signs of degradation when stored for 34 years at 20 C Regular re examinations of this ICRS when stored in the dry state will be performed Conclusion Acetanilide Control No 297171 can be considered suitable as WHO Melting Point Reference Substance for the intended purpose with the melting point set to 116 C WHO PHARM 97 595 page 48 Captopril Control No 197214 Analytical Report Intended use The monograph for Captopril in The International Pharmacopoeia Third Edition Volume 5 requires a reference substance of captopril to be used in the infrared spectrophotometric and thin layer chromatographic tests for identity as well as in the liquid chromatographic system suitability test under related substances Material About 100 g of the sample manufacturers batch no SO 14225 Capto 1 Re were received at the WHO Centre in November 1997 The material is being stored in tightly closed containers at 5 C protected from light Analytical data Description A white powder with characteristic sulfide odour Evidence of chemical structure An infrared spectrum is given in Figure 1 No W970028T The spectrum is concordant with the spectrum of the United States Pharmacopeia Reference Standard USPRS lot H of captopril Dat en lk a dh A Lt Man el Roe oe nt een me ne de ee cee keelen nd md del
56. des produits pharmaceutiques publi es dans la Pharmacop e internationale o propos es sous forme de projets de monographies Les substances chimiques internationales de reference sont principalement destin es servir d talons primaires pour l talonnage d talons secondaires Le mode d emploi et les donn es analytiques pour usage auquel elles sont destin es dans la sp cification correspondante de la Pharmacop e internationale sont fournis dans les certificats Joints aux substances distribu es Les substances chimiques internationales de r f rence peuvent tre utilis es galement dans des preuves et des dosages qui ne sont pas d crits dans la Pharmacop e internationale Cependant dans ce cas il incombe l utilisateur ou la Commission de la Pharmacop e ou toute autre autorit qui a prescrit l utilisation de ces substances de v rifier qu elles conviennent l usage qui en est fait Il est en g n ral recommand de conserver les substances l abri de la lumi re et de l humidit et de pr f rence une temp rature voisine de 5 C Lorsque d s conditions sp ciales de stockage sont n cessaires l indication en est port e sur l tiquette ou figure dans la notice jointe aux substances Il est recommand l utilisateur de n acheter que la quantit suffisante pour l usage imm diat La stabilit des substances chimiques internationales de r f rence conserv es au Centre est surveill e par des e
57. e Figure 2 Positive ion atmospheric pressure chemical ionization mass spectrum of piperazine citrate Control No 197213 ect e Piperazine citrate has practically no UV absorbance except at wavelengths below 210 nm A UV spectrurn in Water was recorded on a Varian Cary 5 spectrophotometer A UV maximum was observed at 191 nm AS en was about 30 n 1 Thin laver chromatography For the identity of piperazine citrate see results under Purity Thin layer chromatography Citrate The identity of citrate was confirmed according to The International Pharmacopoeia Third Edition Volume 1 by the general identification test for citrate Assay See results from collaborating laboratories e vimetn alvsi When the substance was heated to 105 C a loss of 11 1 w w was observed n 6 RSD 0 35 CL LL LL LL Lo om a ka Ate RUE mm TV TT ep PA i E SES aa is em P LA ER ee me Ml ds i pl ey ysl Lee Urner NE waan daaa on tal kad TT sdb kacht een sim U I WHO PHARM 97 595 p ge 99 Instrument Perkin Elmer TGA 7 Thermogravimetric analyzer Sample weight 10 mg Heating program 5 C mun from 20 105 C and then holding 105 C for 360 minutes Melting point 183 187 C with decomposition Water 11 3 n 2 determined by Karl Fischer titration Orsanic volatile compounds lt 0 1 The test included methanol ethanol acetone acetonitrile dichloromethane pyridine chloroform benzene trichloroethylene
58. en in Figure 1 W197213 The spectrum is concordant with the spectrum of the United States Pharmacopeia Reference Standard USPRS lot F of piperazine citrate WHO PHARM 97 595 page 97 200 000 800 4000 0 2500 zen e 1800 1500 1400 600 90 Figure 1 R spectrum of 1 1 mg of piperazine citrate Control No 197213 in 300 me of potassium bromide recorded against a potassium bromide dise Instrument Perkin Elmer 1600 FTTR igh performance liquid e atography with mass spectrometric tion A spectrum of piperazine given in Figure 2 was recorded by atmospheric pressure chemical ionization APcl in the positive ion mode The spectrum shows an M HI ion of 87 2 which supports the identity of piperazine Eluent Methanol Water 50 50 Column Direct inlet Pump Hewlett Packard 1050 operated at a flow rate of 0 3 ml min Detector Fisons Platform ff quadrupole mass spectrometer Operating conditions Cone voltage 30 V Source temperature 180 C sample Piperazine citrate was dissolved in water at a concentration of 0 01 mg ml 20 uI corresponding to 200 ng were injected WHO PHARM 97 595 page 98 S M H Piperazine citrate ICRS 197213 APci 180 Direct inlat PIPERACS 86 7 335 Cm 84 97 106 143 71 78 a Scan APs j a i 44 3 70 2 aso 882 45 3 ep ee e E Ek Ven T a ba es yim PR oe Tant me fg fe pemr he pee DAVE 40 42 EW WEE e2 e 6 70 72 14 76 18 60 42 24 Es 2190
59. ence propos es peuvent tre consid r es comme provisoirement adopt es Leur adaption d finitive fera l objet d un examen au Cours de la r union suivante du Comit d experts Pri re d adresser vos remarques Mme M Westermark Centre collaborateur OMS pour les substances chimiques de r f rence Apoteket AB Produktion amp Laboratorier Gentrallaboratoriet ACL Prismavagen 2 S 14175 Kungens Kurva Su de TABLE DES MATIERES Pages Distribution de substances de r f rence en 1997 1 0 cee cece eect ccccccecce ccc 2 Distribution de spectres de r f rence en 1997 4 cece eee ee eo 2 Etablissement de substances de r f rence en 1997 cece eee ee 2 Etablissement de spectres de r f rence en 1997 cece 2 Travaux effectu s en 1997 sur de nouvelles substances de r f rence eat H eebe eg EES 2 Travaux en cours et travaux futurs 44 cuee TT 3 Questions administratives et financi res 3 Remerciements dais ln basant ne vad io sus nine tags dE sh ele net 3 Appendice 1 Distribution de substances chimiques de r f rence en 1997 4 Appendice 2 Distribution de substances chimiques internationales de r f rence dans les diff rentes R gions de l OMS en 1997 0 00 ccs cece cece sueur 9 Appendice 3 Substances chimiques internationales de
60. endice 13 Ann e d examen 1979 1985 1992 1997 IR conforme conforme HPLC environ 0 02 environ 0 02 lt 0 04 0 02 TGA 0 1 0 1 Eau KP x i 0 1 S LOD lt 0 1 0 17 DSC lt 0 1 Titrage potentiom trique 100 1 Titrage chromatographie en phase 100 0 liquide Le r examen de cette substance a t en partie r alis par le Department of Scientific Services Institute of Science and Forensic Medicine Singapour KRAUT Select 1 ue ene bee eae ee E is ell A HGS AAP aident MELEN CHA OL o Cr aura ar POLA VS FA rare Reg deem RTT BL ALL TL enkt EU AAG 1d HHE 8 gett ed mak ene vu wn HE WHO PHARM 97 595 Page 37 Appendice 6 Propicilline potassique N de contr le 274034 Premier rapport d analyse WHO PHARM 75 485 appendice _ _ _apapaL de 2 r y Ann e d examen 1974 1984 1987 1990 1997 IR conforme HPLC isom re L environ 60 environ 60 HPLC 0 8 0 5 0 7 0 7 TGA 0 3 0 3 0 4 Eau KF 0 3 0 4 0 2 0 3 PSA 37 u d isom re L Titrage mercurim trique 98 2 98 3 97 9 Produits de d gradation 0 8 0 8 mercurim trie Titrage alcalim trique 99 5 Titrage iodometrique 98 3 e Titrage potentiom trique 98 3 WHO PHARM 97 595 Page 38 APPENDICE 7 SUBSTANCES CHIMIQUES INTERNATIONALES DE REFERENCE Liste pr visionnelle pour 1998 Les sub
61. erated at a flow rate of 1 0 ml min Injector Gynkotek Gina 50 operated at 8 C Integrator PeakPro Beckman Sample _ Acetanilide was dissolved in the eluent at a concentration of 1 0 mg ml 5 ul corresponding to 5 pg were injected Stability in the eluent A sample was stored in daylight for one week in the eluent No signs of degradation were observed Limit of detection 1 ng 0 02 at 240 nm Limit of quantification 4 ng 0 08 at 240 nm The same result lt 0 08 impurities was observed for ICRS 192171 FP UN 55 AL a an dut haalia ah hss hd male Hl Alen ed kl hs pd yy Sh Lol Ly La TIETE OT PCPA CL on ALL La Fr beet my Ar ALL CL LL Lo LL mL To td Lt dubai Li AAA pe ln ru hy a ALR itera reel deg enr WHO PHARM 97 595 page 43 Diode array detection The chromatographic system described above was used to record UV spectra for the detected peaks The spectrum of the main peak given in Figure 3 showed a UV maximum at 240 nm The main peak was investigated by the peak purity program and showed no signs of co eluting impurities 113 l Acerontlide 239 7 nm 1000 110 100 30 80 70 60 240 nm so 40 30 20 10 rm CA a E i a A S Ab 198 220 ran 260 280 ana 320 340 360 Me Figure 3 UV spectrum of acetanilide recorded in the eluent WHO PHARM 97 595 page 44 Capillary electrophoresis No impurities above the limit of quantification 0 15 were found An electropherogram 1s given in Fi
62. ered WHO PHARM 97 595 page 106 Purity Thin layer chromatography One secondary unknown spot was detected it was roughly estimated to 2 The following thin layer chromatographic system according to The International Pharmacopoeia Third Edition Volume 4 was used Thin layer Silica gel Merck HPTLC 60 F254 Eluent 7 potassium dihydrogen phosphate Sample 100 ug of streptomycin sulfate dissolved in water were applied Visualization Visualization in day light after spraying with naphthalene 1 3 dioVethanol and sulfuric acid Rp streptomycin sulfate 0 60 Re unknown 0 14 Ry kanamycin sulfate 0 2 Ke neomycin sulfate 0 09 The detection limit of the system was about 0 5 ug 0 5 when examined visually after spraying The spot of streptomycin sulfate ICRS Control No 197215 corresponds in position and appearance with that of the EPCRS iot 1 of streptomycin sulfate ig ance liquid c atogra The total amount of impurities estimated by peak area normalization was about 6 0 n 5 RSD 0 08 for the main peak RSD 0 8 calculated on the 2 6 impurity level A chromatogram is shown in Figure 3 Five impurities above the limit of quantification were found One of them was identified as dihydrostreptomycih eluting at 20 5 minutes by means of an external standard from National Institute for Biological Standards and Control NIBSC 62 013 and estimated to 1 2 n 5 RSD 5 4 The main impurity was unk
63. es 40 C min and holding 240 C for 5 minutes Sample 20 mg were shaken with 1 ml of benzylalcohol and another 20 mg were shaken with 1 ml of Milli Q purified water each for about five minutes The sample shaken with benzylalcoho was filtered Purity Thin laver chromatography Two secondary spots were detected Their total amount was estimated to be about 2 1 One of the spots was identified as kanamycin B sulfate and roughly estimated to be 0 1 The following thin Si layer chromatographic system according to The International Pharmacopoeia Third Edition Volume 4 was used Thin layer Silica gel Merck TLC Eluent 7 potassium dihydrogen phosphate Sample 100 ug of kanamycin monosulfate dissolved in water were applied Visualization Visualization in day light after spraying with naphthalene 1 3 diol ethanol and sulfuric acid as well as scanning at 400 nm with a CAMAG TLC Scanner 3 R Kkanamycin sulfate 0 2 Ky kanamycin B sulfate 0 1 The detection limit of the system was about 0 1 ug 0 1 both after visual Inspection and when amp scanning at 400 nm The spot of kanamycin monosulfate ICRS Control No 197211 corresponds in position and appearance with that of the EPCRS batch 2 and USPRS lot I of kanamycin sulfate The EPCRS contained two secondary spots Their total amount was estimated to about 5 7 One of the spots was identified as kanamycin B sulfate and roughly estimated to be 0 5 The USPRS con
64. es d analyse utilis es on peut s adresser au Centre Amodiaquine chlorhydrate N de contr le 192160 Premier rapport d analyse WHO PHARM 93 564 appendice 7 Ann e d examen 1992 1997 IR conforme TLC environ 0 6 HPLC 0 3 0 4 TGA 7 9 7 8 Eau KF 8 0 Titrage spectrophotom trique 99 9 S RETTEN EEN EH Een EE EA A e e Mi DJ AT EE Kaka klen ere vu EAR ORT TTT DE LC eee erageet A mr Ire EU A PT DRM ETA rue rm vw che de don om et EOL matin ue Si WHO PHARM S7 595 Page 21 Appendice 6 Ampicilline trihydrate N de contr le 274003 Premier rapport d analyse WHO PHARM 75 485 appendice 6 tt y OOOOUSUULULULULU Ann e d examen 1974 1989 1992 1997 TR conforme conforme HPLC 0 3 0 3 0 5 TGA 13 9 13 8 13 7 Eau KF 13 9 e s Titrage alcalim trique 98 5 o Titrage mercurim trique 98 8 Nouvelle colonne ayant une meilleure efficacit de s paration Atropine sulfate N de contr le 183111 Premier rapport d analyse WHO PHARM 84 513 appendice 5 r e a a IOUO Ann e d examen 1983 1990 1997 IR conforme conforme TLC 3 taches secondaires lt 1 lt 0 1 faibles HPLC 0 6 0 5 0 5 a TGA 2 37 Eau KF 3 1 3 8 LOD scht 7 Titrage potentiom trique 100 4 eee Le r examen de cette substance a t en partie r alis par le Department of Scientific Services Institute
65. eted deich nn eq pe Le el rl 23 dr La ln Lal a PP A La OOFOT FLA d TPA Pe HEC VTT AMEL LA Lh nd ere urarea Arr a Aal Hd La at gt m FLAL had b tn de bled sm RT md ve 4 en WHO PHARM 97 595 page 49 i i aT in ete CET War COPA ee Figure 1 R spectrum of 1 1 mg of captopril Control No 197214 in 300 mg of potassium bromide recorded against a potassium bromide disc Instrument Perkin Elmer 1600 FTIR High pe ance liquid c atographv wi s spectrometric detecti A spectrum of the main peak captopril was recorded by atmospheric pressure chemical ionization APcD in the positive ion mode The spectrum given in Figure 2 shows an M ET ion of 218 2 which supports the identity of captopril Eluent Methanol 0 5 glacial acetic acid 44 56 Column Kromasil C18 4 6x150 mm 5 um particles Column temperature 40 C Pump Hewlett Packard 1050 operated at a flow rate of 1 ml min After splitting the flow rate into the mass spectrometer was 0 1 ml min Detector Fisons Platform I quadrupole mass spectrometer Operating conditions Cone voltage 20 V Source temperature 180 C Sample Captopril was dissolved in the eluent at a concentration of i mg ml After splitting about 2 tig reached the mass spectrometer WHO PHARM 97 595 page 50 Captopril ICRS 197214 CAPTOP20 34B 6 410 Crn 31 8 304 208 2464462 03 Scan AP CH t 13e4 un vu mm 70 5 a DE WE 172 2 M H 218 2 2
66. f ine 237 C 4g 192166 Ph nolphtal ine 263 C 4g 192167 Sulfac tamide 100 mg 196200 Sulfam thoxazole 100 mg 179092 Sulfam thoxypyridazine 100 mg 178079 Sulfanilamide 100 mg 179094 Sulfasalazine 100 mg 191155 Tamoxifene citrate 100 mg 196208 Tamoxif ne citrate isom re E 10 mg 196209 Testost rone nantate 200 mg 194192 Testost rone propionate 100 mg 167036 T tracycline chlorhydrate 200 mg 180095 Thioac tazone 100 mg 171046 4 4 Thiodianiline 50 mg 183116 Thyroxine sodique voir L vothyroxine sodique WHO PHARM 7 595 Page 16 Appendice 4 Substances de r f rence Tolbutamide Tolnaftate Tolu ne 2 sulfonamide Trim thadione Trim thoprime Trim thy guanidine sulfate Tubocurarine chlorure Vitamine A ac tate solution voir R tinol ac tate Vincristine sulfate Warfarine Zuclomif ne Par capsule environ 9 mg dans 250 mg d huile Conditionnement 100 mg 100 mg 100 mg 200 mg 100 mg 100 mg 100 mg 9 7 mg flacon 100 mg 50 mg N de controle 179086 176074 196204 185125 179093 172059 170037 193181 168041 187137 BAAM ob deu a Vo mm nn ppm gd vm pe AA a aa FRA Er mg re qq n A FT VAA ETETEA NT AP URR T rar armement area era ar bunak legen ra DCE ETUI TH re P dreet WHO PHARM 97 595 Page 17 APPENDICE 5 ON WORLD HEALTH ORGANIZATION Si ORGANISATION MONDIALE DE LA SANTE CES LISTE DES SPECTRES INFRAROUGES INTERNATIONAUX DE REFERENCE DISPONIBLES
67. gure A Cvertad Traces aen 3009 Ghal agyi i008 CranlA C 024 0 022 0 020 0 016 6 014 acetanilide GAME Cr Ch 6 010 0 08 S 0 008 0 004 9 007 blank D O G oo 0 002 ie Figure 4 Electropherogram of acetanilide Control No 297171 monitored at 240 nm Eluent Capillary _ Detector CE Instrument Run temperature Injection Integrator Sample stability m the eluent Limit of detection Limit of quantification WHO PHARM 97 595 page 45 11 7 mM borate 8 3 mM phosphate and 50 mM SDS at pH 9 20 Fused silica total length 67 cm length to detector 60 cm ID 75 um Beckman P ACE Diode Array Detector operated at 240 nm and 200 nm Beckman P ACE system 5510 operated with an applied voltage of 30 kV for 20 minutes 50 C 10 seconds pressure injection Beckman P ACE Station Software Acetanilide was dissolved in water at a concentration of 1 0 mg ml 10 seconds high pressure injection corresponds to 59 ng injected sample A sample was stored for 2 days No signs of degradation were observed 0 05 at 240 nm 0 15 at 240 nm Differential scanning calorimetry The purity was estimated to about 99 97 mol n 10 RSD 0 02 determined by differential scanning Calorimetry The determination was performed on 2 mg using a heating rate of 2 C per Tnute Melting temperature Tu Onset Instrument 113 9 C n 10 RSD 0 1 113 7 C n 1
68. h of them were estimated to be lt 100 ppm The content of organic solvents was tested by gas chromatography with the following conditions Instrument Hewlett Packard 6890 Column HP 5 30 m x 0 53 mm 2 65 um film Carrier gas Helium 8 ml min Detector FID Injection volume 2 g Injector temperature 200 C Detector temperature 230 C Temperature program 40 C for 10 minutes 40 C min and holding 240 C for 5 minutes Sample 20 mg were shaken with 1 ml of benzyl alcohol and another 20 mg were shaken with 1 ml of Milli Q purified water each for about five minutes The sample shaken with benzyl alcohol was filtered Purity hin laver chromatography No secondary spots were detected which means lt 0 25 The following thin layer chromatographic system according to The International Pharmacopoeia Third Edition Volume 4 was used Thin layer Silica gel G Merck TLC Bluent Ammonia conc acetone 20 80 Sample 300 ug of piperazine adipate dissolved in ethanol ammonia conc 2 3 were applied Visualization Visualization in day light after spraying with triketohydrindenehydrate 3 mg ml in glacial acetic acid 1 butanol 3 100 and then with triketohydrindenehydrate 1 5 mg ml in ethanol and drying at 105 C Thereafter spraying with iodine 0 05 mol l WHO PHARM 97 595 page 94 Rp piperazine adipate 0 Re ethylenediamine 0 4 Ry triethylenediamine 0 2 RF adipic acid 0 04 Ry piperazi
69. he dried substances The difference between the proposed ICRS and the EPCRS lot 1 is Statistically not significant at the 95 confidence level using unpaired t test Spectrophotometric assay 100 0 n 6 RSD 0 4 The determination was performed according to the method described above under Evidence of chemical structure UV spectrum The EPCRS lot 1 of ciprofloxacin hydrochloride was used as standard and regarded as 100 Calculations were performed with reference to the dried substances WEHO PHARM 97 595 page 61 When the substance was heated to 120 C a loss of 6 0 w w was observed n 6 RSD 2 2 Fe Instrument Perkin Elmer TGA 7 Sample weight 3 mg Heating program 5 C min from 20 120 C and then holding 120 C for 40 minutes Melting point 255 257 C decomposition for ciprofloxacin The corresponding result for the EPCRS lot 1 was 6 4 w w n 6 RSD 0 9 Fo Water 6 1 n 2 determined by Karl Fischer titration Organic volatile compounds lt 0 1 The test included methanol ethanol acetone acetonitrile dichloromethane pyridine chloroform benzene trichloroethylene and dioxan Each of them were estimated to be lt 100 ppm The content of organic solvents was tested by gas chromatography with the following conditions Instrument Hewlett Packard 6890 Column HP 5 30 m x 0 53 mm 2 65 um film Cartier gas Helium 8 mi min Detector FID Injection volume 2 ul Injector temperature 200
70. hen stored in the dry state will be performed Conclusion Captopril Control No 197214 can be considered suitable as International Chemical Reference Substance for the intended purpose ATAPI NY OORT AY OCRed ra arr WHO PHARM 97 595 page 57 TIX Ciprofloxacin hydrochloride Control No 197210 Analytical Report Intended use The monograph for Ciprofloxacin hydrochloride in The International Pharmacopoeia Third Edition Volume 5 requires a reference substance of ciprofloxacin hydrochloride to be used in the infrared spectrophotometric and thin layer chromatographic tests for identity as well as in the liquid chromatographic assay The monograph for Ciprofloxacin in The International Pharmacopoeia Third Edition Volume 5 requires a reference substance of ciprofloxacin hydrochloride to be used in the liquid chromatographic test for related substances Material About 66 g of the sample manufacturers batch no R 124 2 were received at the WHO Centre in July 1996 The material is being stored in tightly closed containers at 5 C protected from light Analytical data Description A pale yellow powder Evidence of chemical structure Infrared spectru An infrared spectrum is given in Figure 1 No W197210T The spectrum is concordant with the spectrum of the European Pharmacopoeia Chemical Reference Substance EPCRS lot 1 of ciprofloxacin hydrochloride WHO PHARM 97 595 page 36 emeng WiS7240T SP H
71. hermnoeravi ic analysi This technique was not suitable to use as stabilization of weight during the analysis never occured Captopril melts at 107 C Loss on drying was used instead WHO PHARM 97 595 page 52 Water It was not possible to use Karl Fischer titration as captopril reacted with the reagent resulting in values that are too high 0 1 determined at 60 C under reduced pressure over phosphorus pentoxide Organic volatile compounds lt 0 1 The test included methanol ethanol acetone acetonitrile dichloromethane pyridine chloroform benzene trichloroethylene and dioxan They were all estimated to be lt 100 ppm The content of organic solvents was tested by gas chromatography with the following conditions Instrument Hewlett Packard 6890 Column HP 5 30 m x 0 53 mm 2 65 um film Camer gas Helium 8 ml min Detector FID Injection volume 2 pl Injector temperature 200 C Detector temperature 250 C Ternp rature program 40 C for 10 minutes 40 C min and holding 240 C for 5 minutes Sample 20 mg were shaken with 1 ml of benzyl alcohol and another 20 mg were shaken with 1 ml of Milli Q purified water each for about five minutes The sample shaken with benzyl alcohol was filtered Purity 3 Mercapto 2 methylpropanoic acid lt 0 01 determined by gas chromatography according to The International Pharmacopoeia Third Edition Volume 5 tun layer chromatography One secondary spot
72. icative au niveau de confiance 95 avec un test z par s ries non appari es CATEATEI TA HH del dain ra era re eee eee re rare TT r TNE OAT P LA TTC TERU HA WHO PHARM 97 595 Page 35 Appendice 6 Quabaine N de contr le 283026 Premier rapport d analyse WHO PHARM 84 513 appendice 14 EE Ann e d examen 1983 1987 1997 IR conforme TLC 0 2 0 3 HPLC 0 4 0 7 0 6 TGA 19 9 LOD 20 0 19 9 Titrage colorim trique 100 1 100 0 Oxacilline sodique N de contr le 392027 Premier rapport d analyse WHO PHARM 85 510 appendice 8 e aaa a IOSU Ann e d examen 1982 1984 1987 1990 1997 EE IR conforme e z S HPLC 1 1 1 0 1 3 0 7 14 TGA S a 4 2 Eau KF 4 3 4 5 d 4 2 PSA 0 9 d S p Titrage mercurim trique 99 4 99 4 98 9 GC 1 1 s 1 1 Nouveau syst me de chromatographie en phase liquide ayant une meilleure efficacit de s paration WHO PHARM 97 595 Page 36 Appendice 6 Ph n ticilline potassique N de contr le 167028 Premier rapport d analyse WHO PHARM 68 448 appendice 7 Ann e d examen 1967 1978 1982 1984 1997 TR conforme conforme TLC 2 impuret s HPLC 0 4 0 5 0 6 0 7 TGA 0 2 Eau KF 0 5 0 3 0 4 PSA 56 5 isom re L Titrage mercurim trique 99 1 99 5 Ph nytoine N de contr le 179089 Premier rapport d analyse WHO PHARM 80 504 app
73. l n 10 RSD 0 007 determined by differentia scanning calorimetry The determination was performed on 2 mg using a heating rate of 2 C per minute Melting temperature Tu 134 4 C n 10 RSD 0 09 Onset 134 3 C n 10 RSD 0 07 AJ Instrument Perkin Elmer DSC7 Differential Scanning Calorimeter No signs of polymorphic forms were found when the substance was heated from 40 C to 200 C The previous batch ICRS 197172 showed the same result Data given by the manufacturer Identification Conforms Assay 99 3 Chloroacetanilide within limits p Phenetidine within limits Heavy metals within limits Sulphated ash 0 0 Loss on drying 0 0 WHO PHARM 97 595 page 88 Collaborative study The melting point was assigned after a collaborative study including four laboratories The melting point was determined according to The International Pharmacopoeia Third Edition Volume 1 as a capillary melting point determination Participating laboratories Lab 1 Bj rn Egil Olsen Norsk Medicinaldepot AS Sven Oftedalsvej 10 PO Box 100 N 0518 OSLO NORWAY Lab 2 Camilla Alvesson Mettler Toledo AB Hangpilsgatan 56 42677 Vastra Fr lunda GOTEBORG SWEDEN Lab 3 Dr Ulrich Rose Service de la Qualite du M dicament European Pharmacopoeia Laboratory B P 907 F 67029 Strasbourg Cedex 1 FRANCE Lab 4 WHO Collaborating Centre for Chemical Reference Substances STOCKHOLM SWEDEN RESULTS Lab2
74. l thylammonium 3 mercapto 2 m thylpropanoate Dithranol Doxyeyeline hyclate Econazole nitrate 6 Epidoxycycline chlorhydrate Erythromycine thylsuccinate Erythromycine st arate Etoposide d Fluoroquinolinique acide 1 Hydroxy 9 anthrone Idoxuridine K toconazole L vamisole chlorhydrate Lincomycine chlorhydrate M floquine chlorhydrate M tacycline chlorhydrate DL M thionine 2 M thyl 3 ac tylthiopropionique acide Metronidazole benzoate Nif dipine Nonoxino 9 Octoxinol 9 R tinol palmitate R tinol propionate Indique que des travaux sont en cours au Centre sur cette substance Hu M eg lees ate Malte CARRE CPE PP EP CT LEP IT m Dee TETE PASE AL LA en nm LL TT TTT LNT rr HEEN L CI UMA Pe ar are ha ee Pm TPR perma ET THE WHO PHARM 97 595 Page 39 APPENDICE 8 SPECTRES INFRAROUGES INTERNATIONAUX DE REFERENCE Liste pr visionnelle pour 1998 Les spectres infrarouges internationaux de r f rence ci apr s sont n cessaires pour accompagner les sp cifications qui figurent dans la troisi me dition de la Pharmacop e internationale Volume 3 Volume 4 Diloxanide furoate Disodiurn detate M toclopramide chlorhydrate Eph drine sulfate Naloxone chlorhydrate lopanoique acide Nitrofurantoine Jotroxique acide Pyrazinarnide K tamine chlorhydrate a Spironolactone Nor thist rone nantate Pentamidine is tionate Timolol mal ate Vo
75. laborating laboratories European Pharmacopoeia lab EPCRS batch 1 is from the same batch as ICRS 197212 Appearance Satisfactory Water content 0 1 To Identity IR Conforms Identity melting point 248 C Identity melting point 151 C as piperazine Related substances 0 3 Assay 100 22 Stability Stability studies were not performed as this substance was not suspected to degrade easily according to WHO PHARM 86 529 Regular re examinations of the CRS when stored in the dry state will be performed Conclusion Piperazine adipate Control No 197212 can be considered suitable as International Chemical Reference Substance for the intended purpose WHO PHARM 97 595 page 96 Piperazine citrate Control No 197213 Analytical R port Intended use The monograph for Piperazine citrate tablets in The International Pharmacopoeia Third Edition Volume 4 requires a reference substance of piperazine citrate to be used in the thin layer chromatographic test for identity Material About 10 g of the sample manufacturers batch NOENR4787 were received at the WHO Centre in June 1996 The material is being stored in tightly closed containers at 5 C protected from light This ICRS is of the same origin as that of the European Pharmacopoeia Chemical Reference Substance EPCRS lot 1 Analytical data Description A white granular powder Evidence of chemical structure a ect An infrared spectrum is giv
76. lume 5 Azote protoxyde Benzoyle peroxyde Ciprofloxacine Cod ine phosphate Colchicine Dh thyltoluamide Diloxanide furoate Erythromycine lactobionate Isosorbide dinitrate Morphine sulfate P thidine chlorhydrate Ph nobarbital Proguanil chlorhydrate g Sulfadiazine Tropicamide Travaux en cours WHO PHARM 97 595 page 40 APPENDIX 9 Acetanilide WHO Melting Point Reference Substance Melting temperature 116 C Control No 297171 Analytical Report Intended use The stock of the current batch of the WHO Melting Point Reference Substance for acetanilide Control No 192171 1s depleted and has to be replaced The WHO Melting Point Reference Substance for acetanilide is supplied primarily for calibration of different instruments and methods used for determination of melting temperatures against the method of The International Pharmacopoeia Third Edition Volume 1 Material About 1000 of the sample manufacturers batch no K22532110 were received at the WHO Centre in May 1997 The material is being stored in tightly closed containers at 20 C protected from light Analytical data Description A white crystalline powder Evidence of chemical structure Infrared spectrum The spectrum is concordant with the spectrum of the previous lot of the International Chemical Reference Substance ICRS of acetanilide with Control No 192171 An infrared spectrum is given in Figure No W297171T
77. me 5 the content of ciprofloxacin hydrochloride is taken to be 100 0 calculated with reference to the dried substance which corresponds to 94 0 on the as 18 basis WHO PHARM 97 595 page 66 APPENDIX 12 Cisplatin Control No 197207 Analytical Report Intended use The monograph for Cisplatin in The International Pharmacopoeia Third Edition Volume 4 requires a reference substance of cisplatin to be used in the infrared spectrophotometric and thin layer chromatographic tests for identity as well as in the spectrophotometric assay Material About 10 g of the sample manufacturers batch no 89 730 02 1 33 94 were received at the WHO Centre in June 1995 The material is being stored in tightly closed containers at 5 C protected from light CAUTION As cisplatin is a cytotoxic drug it should be handled with care Avoid contact with the skin and inhalation of airborne particles Analytical data Description A yellow crystalline powder ro Evidence of chemical structure e I An infrared spectrum is given in Figure 1 No W197207 The spectrum is concordant with the spectrum of the European Pharmacopoeia Chemical Reference Substance EPCRS lot 1 of cisplatin WA en homme eue ve os LL LL mn awe LI AL IN em OL AALLLLL LL TETE aD Lid TRE FED EHA nr ra ee ren re T WHO PHARM 97 595 page 67 N147207 5P TLE ALE A ADA AAT w UT AOT Hi Figure 1 IR spectrum of mg of cisplatin Control No 19720
78. ments Tunisie et Vasenta Perera du National Drug Quality Assurance Laboratory Sri Lanka Ces boursiers ont tudi les aspects administratifs de la manutention des substances de r f rence ainsi que diff rentes techniques d analyse utilis es dans l essai des substances chimiques internationales de r f rence Questions administratives et financi res Le co t de fonctionnement total du Centre en 1997 a t estim US 574 447 Le revenu de la vente de substances de r f rence a t d environ US 95 990 Le Si ge de l OMS a apport une contribution de US 16 000 Cela laisse un d ficit de US 462 457 couvert gr ce au soutien d Apoteket AB En 1997 le prix des substances a t maintenu US 60 par paquet et les frais d exp dition et de manutention ajoutant chaque commande ont t maintenus US 10 Remerciements Le Centre remercie les laboratoires qui ont contribu ses travaux en 1997 notamment le Laboratoire de la Pharmacop e europ enne Strasbourg France I Institute of Science and Forensic Medicine Singapour et le National Institute for Biological Standards and Control Londres Le Centre d sire galement remercier les laboratoires pharmaceutiques qui lui ont fourni des substances pour examen et ont particip aux travaux d analyse Cette ann e ses remerciements vont en particulier Bayer Leverkusen Allemagne Bristol Myers Squibb New Brunnswick Etats Unis d Am rique et Heraeus GmbH
79. mt om nm ti SEO HH a a Lu K i te a PFT AT A da river i j Md NaM er Lan Ca LEE y TROTTED LY PM a ru d 4 sid Wun E N s OF S W ll etats E AE n EU OS j RE Clare plots ShP M MAVIN eo en am she ma i da Uant WHO PHARM 97 595 page 109 The following conditions were used Fluent Rinsing of capillary Capillary CE instrument Detector Run temperature Sample temperature Injection i Integrator Sample Stability in the eluent Limit of detection Limit of quantification lon chromatography 100 mM phosphoric acid and 50 mM triethylamine pH adjusted to 3 00 with 2 M sodium hydroxide 3 0 minutes with 0 1 M sodium hydroxide 3 0 minutes with water 3 0 minutes with running buffer Fused silica total length 100 cm length to detector 90 em ID 75 um Beckman P ACE System MDQ operated with an applied voltage of 20 kV for 45 minutes Beckman P ACE System MDQ Diode Array Detector operated at 200 nm bandwidth 10 nm 50 C 8 C 20 seconds pressure injection at a pressure of 0 5 psi Beckman P ACE System MDQ soft ware Streptomycin sulfate was dissolved in water at a concentration of 3 mg ml A sample was stored for one week at 8 C in darkness No signs of degradation were observed 0 1 at 200 nm 0 25 at 200 nm The ICRS was screened for the following anions chlorides bromides nitrates phosphates and sulfates Less than 10 ppm of bromides less than 100 ppm of nitrates and less than 50
80. n IR DSC TLC HPLC TGA Eau KF LOD Titrage titrim trique CC ER Geier An AA TT Ls La an LL WHO PHARM 97 595 Page 25 Appendice 6 1974 1992 1997 conforme Conforme 0 6 0 7 2 taches environ 2 1 6 lt 0 1 0 1 lt 0 1 0 26 e 100 9 100 0 Titrage spectrophotom trique 3 Chloro 2 m thylaminobenzoph none N de contr le 172061 Premier rapport d analyse WHO PHARM 73 475 appendice 4 r raaa r e I U Ann d examen IR TLC HPLC TGA LOD Eau KF DTA 1972 1985 1991 1997 Conforme conforme Q tache 0 tache 0 tache secondaire secondaire secondaire 0 8 1 0 lt Q 1 AN 0 3 0 4 0 5 g 0 5 P DSC i es WHO PHARM 97 595 Page 26 Appendice 6 2 4 Chioro 3 sulfamoylbenzoylbenzoique acide N de contr le 181106 Premier rapport d analyse WHO PHARM 82 509 appendice 8 Ann e d examen 1981 1997 IR conforme conforme TLC 2 taches secondaires 2 taches secondaires HPLC 0 4 0 2 gt limite de dosage TGA lt 0 1 LOD 0 2 Titrage potentiom trique 98 9 d Chlorpromazine chlorhydrate N de contr le 178080 Premier rapport d analyse WHO PHARM 79 499 appendice 4 Ann e d examen 1978 1984 1990 1997 IR conforme P TLC lt 0 5 lt 0 5 environ 0 2 HPLC 8 0 06 TGA lt 0 1 lt 0 1 LO
81. ne 0 08 The detection limit of the system was about 1 25 pg 0 25 when examined visually The spot of piperazine adipate corresponds in position and appearance with that of the USPRS lot F of piperazine adipate fon chromatography The ICRS was screened for the following anions chlorides bromides nitrates phosphates and sulfates Less than 300 ppm of chlorides less than 10 ppm of bromides less than 100 ppm of phosphates and less than 30 ppm of nitrates were found Sulfates co eluted with adipate and could not be determined The following conditions were used Eluent I Eluent 2 Column Supressor Detector Range Pump Injector Integrator Sample jon Limit of detection ppm in the sample Limit of quantification ppm in the sample Sodium carbonate sodium bicarbonate 1 8 mM 1 7 mM Sodium bicarbonate for the determination of chloride 2 5 mM Dionex HPIC AS4A ASRS 1 Dionex 2000i conductivity 3 ps Dionex 20001 Beckman System Gold Autoinjector 507 s PeakPro Beckman Piperazine adipate was dissolved in the eluent at a concentration of 1 0 mg ml in water 50 ul corresponding to 50 g were injected Chlorides Bromides Nitrates Phosphates Sulfates 10 10 30 100 30 50 50 100 500 100 AM ETUIS ee ee SR ee ee ee FEES UC EU PO ER SES ve GL DEE GEIER Lo E i TEER PARC Cr Lah LL PH DEU TP TT YN Ad er mu Lu tds 14 a ee TT ed rin en WHO FHARM 97 595 page 95 Data siven by col
82. nown 4 estimated to 2 6 by peak area normalization According to results from the validation of the method unknown 2 increased when stored in solution It is here estimated to 1 3 and might be stability indicating Cren 7601941 71 4854873 T g a 3 a a ix i bel a EA z a molta Lat 176 L 119 unknown 2 Ip ap 1 40 R Tiveion Tine BAAIIS4 Serateh method unknown 3 TETE RTA a al LA LELLA SAA CU e rar ware PTR lus fd Me OL LE ngemeeg are Al ME D HU ien WHO PHARM 97 595 page 107 14 06 02 98 02 26 e Ka E g S 3 F Val o Fa P y AE mt E n S E SIS E Is S G a z Bal 2 19 19 Minutes Inject Elmer 9114 01 38 02 06 Inn Eitenss 103 Vial a Figure 3 Chromatogram of streptomycin sulfate Control No 197215 monitored at 200 nm The following conditions were used Fluent Column Detector Pump Injector Integrator Sarnple Stability in the eluent Limit of detection Limit of quantification 0 1 M phosphate buffer at pH 3 8 was prepared Then hexanesulfonic acid sodium salt was added to a concentration of 0 015 M 100 ml acetonitrile were mixed manually with 200 mi buffer The low wavelength gives noise if the eluent is not properly mixed The amount of organic solvent has strong effect on the retention time and resolution Kromasil C18 4 6 x 250 mm 5 pm particles Gynkotek DAD340 operated at 200 nm
83. ort d analyse WHO PHARM 93 564 appendice 10 rr a r a yO Ann e d examen 1992 1997 go IR conforme TLC 0 1 HPLC O 0 1 0 2 TGA l enviton Eau KF 0 7 0 7 LOD 1 0 Titrage spectrophotom trique 100 2 WHO PHARN 97 5985 Page 30 Appendice 6 Diazepam N de contr le 172062 Premier rapport d analyse WHO PHARM 73 475 appendice 5 Ann e d examen 1972 1982 199 1997 IR conforme conforme TLC tache l tache 2 taches secondaire secondaire secondaires tr s faibles HPLC lt 0 05 lt 0 1 DTA 0 05 0 04 i DSC 0 05 TGA D I LOD lt 0 1 lt 0 1 Eau KF 0 1 Titrage potentiometrique 100 0 100 0 a Dicloxacilline sodique N de contr le 174071 Premier rapport d analyse WHO PHARM 74 478 appendice 5 Ann e d examen 1974 1982 1984 1989 1995 1997 IR conforme conforme N TLC 5 taches e secondaires HPLC 0 3 0 4 0 3 0 5 0 4 TGA 3 9 3 9 3 9 Eau KF 3 8 3 9 3 8 i Produits de d gradation 0 6 mercurim trie Titrage alealim trique 99 5 99 4 r Titrage mercurim trique 99 5 CERN PTT EN ETS ES TT REQUEST LPC ETES POP RAA A D DROE HIERT PALETTE AT mT FAR r TL iita a TET TTOTTE TETTEK T K CH ul rer See E un mere Dh oh m ee er n all lie A P AN ee WHO PHARM 97 595 Page 31 Appendice 6 Dicoumarol N de contr le 178077 Premie
84. parate impurity reference substances Differential scanning calorimetry The thenmogram of ciprofloxacin hydrochloride showed a small exotherm at about 160 C which indicates the presence of another polymorphic form The melting temperature peak maximum is about 325 C for ciprofloxacin hydrochloride Similar results were obtained for the EPCRS lot 1 The ICRS was screened for the following anions chlorides bromides nitrates phosphates and sulfates Less than 10 ppm of bromides 100 ppm of nitrates and less than 500 ppm of phosphates were found Sulfates were found and estimated to 350 ppm Chlorides were found and roughly estimated to be 9 7 theoretical value 9 2 The following conditions were used Eluent 1 Sodium carbonate sodium bicarbonate 1 8 mM 1 7 mM Fluent 2 Sodium bicarbonate for the determination of chlonde d 2 5 mM Column i Dionex HPIC AS4A Supressor ASRS 1 Detector Dionex 2000i conductivity Range 3 uS for determination of chloride 300 us Pump Dionex 2000 Injector Beckman System Gold Autoinjector 507 Integrator PeakPro Beckman Sample Ciprofloxacin hydrochloride was dissolved in the eluent at a concentration of 1 0 mg ml in water 50 pl corresponding to 50 ug were injected mm diis oa mmlm ma m da s ee dense des ae eeben de des dans ens Lk wpm buh ub ws dd WA L H TROT TT UT EAU OLA CEET TECH HCH CDR ALTER Mila ele reene er AP EEN mere 4 APEM AT LE HR AT ALL eed
85. powder Evidence of chemical structure Infrared spectrum The spectrum is concordant with the spectrum of the previous lot of the International Chemical Reference Substance ICRS of phenacetin with Control No 192172 An infrared spectrum is given in Figure 1 No W297172T DDT or derre rare 0 MATHIS a e me e H J ua ME RETTEN d dee eer eng el le mme khan den mn a J ve Gang 3 3 wert d ven A av dh va ven seg re WIHO PHARM 97 595 page 83 42971721 SP Lay a A r MEL LAY 80 nn I BA go um n 3500 3000 2500 enn 4800 4600 1400 4200 1000 800 600 450 0 CH 1 Figure 1 ZR spectrum of 1 0 mg of phenacetin Control No 297172 in 300 mg of potassium bromide recorded against a potassium bromide disc Instrument Perkin Elmer 1600 FTIR Purity Assigned melting point 136 C Based on results from a collaborative study See under Collaborative study at the end of this Appendix Water lt 0 1 n 2 determined by Karl Fischer titration igh oe ance liquid ograph One impurity was found It was estimated to be 0 06 n 6 RSD 2 6 when calculated on the 0 06 impurity level RSD lt 0 01 for the main peak A chromatogram is given in Figure 2 WHO PHARM 97 595 page 84 henaei97172 Sug 1335122 97 06 06 yo ts 194 4a 20 10 EG unknown 1 phenacetin Tetector Kesponse Blucion Time THIGLTIS Soratch mathe Minutes Inject cite 19 20 06 g a 29
86. program and showed no signs of co eluting impurities One possible impurity 2 methyl 3 acetylthiopropionic acid has another UV spectrum with a maximum around 230 nm This impurity was however not found in this ICRS AUT UE IEN OV Jee CAN The method described under Evidence of chemical structure High performance liquid chromatography with mass spectrometric detection was used to identify the impurity eluting at 15 minutes in Figure 4 The impurity was identified as captopril disulfide which was also verified by an external standard Differential scanning calorimet The purity was estimated to about 99 5 mol n 6 RSD 0 04 The determination was performed on 2 mg using a heating rate of 2 C per minute Melting temperature TM 106 7 C n 6 RSD 0 05 Onset 105 6 C n 6 RSD 0 06 Instrument Perkin Elmer DSC7 Differential Scanning Calorimeter No polymorphism was found when measuring between 40 and 125 C lbs mens ee et LUE RES LE Me Mear MA e T AER ua EH F TH Atar bebe Jon WHO PHARM 97 595 page 55 The ICRS was screened for the following anions chlorides bromides nitrates phosphates and sulfates lt 10 ppm of bromides lt 30 ppm of nitrates and lt 100 ppm of sulfates were found Chlorides and phosphates were not possible to determine as they co elute with captopril The following conditions were used Eluent 1 Sodium carbonate sodium bicarbonate 1 8 mM 1 7 mM Fluent 2
87. r f rence tablies en 1997 10 Appendice 4 Liste des substances chimiques internationales de r f rence disponibles 11 Appendice 5 Liste des spectres infrarouges intemationaux de r f rence disponibles 17 amp Appendice 6 e de SAR ea faa aide re be Are ae ae da Leck do ne ce 20 Appendice 7 Substances chimiques internationales de r f rence Liste pr visionnelle pour 1998 38 Appendice Spectres infrarouges internationaux de r f rence Liste pr visionnelle pour 1998 39 Appendice 9 Ac tanilide N de contr le 297171 40 Appendice 10 Captopril N de contr le 197214 eee ell 48 Appendice 11 Chlorhydrate de ciprofloxacine N de contr le 197210 57 Appendice 12 Cisplatine N de contr le 197207 ace 66 Appendice 172 Monosulfate de kanamycine N de contr le 197211 000 73 Appendice l4 Ph nac tine N de contr le 20711 cece cee eee 82 Appendice 15 Adipate de pip razine N de contr le 197212 IE 90 Appendice 16 Citrate de pip razine N de contr le 197213 e 96 Appendice 17 Sulfate de streptomycine N de contr le 197215 lle 102 Note Pour des raisons techniques les appendices 9 17 n ont t tablis Ou en anglais This document is not issued to the general public and all rights ara reserved by the Wo
88. r rapport d analyse WHO PHARM 79 499 appendice 5 ENEE Ann e d examen 1978 1997 IR conforme TLC 0 tache secondaire HPLC lt 0 05 lt 0 04 limite de d tection lt 0 1 limute de dosage TGA ZU LOD lt 0 1 Titrage potentiom trique 100 0 PSA 0 3 PS Nouvelle m thode de chromatographie en phase liquide passage des phases normales aux phases invers es Limite de dosage 0 1 limite de d tection 0 04 Erythromycine N de contr le 191154 Premjer rapport d analyse WHO PHARM 92 558 appendice 8 EE Ann e d examen 1991 1997 IR conforme TLC environ HPLC environ 1 6 1 5 TGA 2 2 2 6 Eau KF 1 4 Titrage titrim trique 97 6 Activit HPLC 962 ug mg Titrage microbiologique 915 Ul mg rR yu pu WHO PHARM 97 595 Page 32 Appendice 6 Hydrochlorothiazide N d contr le 179087 Premier rapport d analyse WHO PHARM 80 504 appendice 8 Ann e d examen 1979 1987 1997 IR conforme conforme DTA 0 4 0 7 HPLC 0 4 0 4 0 5 TGA gt 0 2 LOD ch 0 2 Titrage titrim trique 100 0 M thyldopa N de contr le 179084 Premier rapport d analyse WHO PHARM 80 504 appendice 10 Ann e d examen 1979 1954 1992 1997 IR conforme TLC 0 2 0 1 HPLC lt 0 2 0 2 0 1 0 1 TGA 11 7 11 4 Eau KF 11 5 11 5 11 3 Titrage potentiom trique 99 7 e S WH
89. ra aux appendices 9 et 14 les rapports d analyse de ces substances Essais de stabilit Le Centre a poursuivi ses examens p riodiques de la stabilit des substances chimiques internationales de r f rence existantes En 1997 33 substances ont t r examin es On trouvera les r sultats de ce r examen a l appendice 6 On peut obtenir aupr s du Centre des d tails concernant les m thodes utilis es Loti enh ts mahi vide ege d Al yea AA ton bb a Dehati LE cht tt d C War CA AU LIOLL Bas PUSH LU Ka a LA LE a TTL LETTRE UE vr AN TETT PS TAN EL a BELA APH ea eae LU ML nt pi LE TO LR Sen Liesen re ar rana Ce re TT A aii EE pire WHO PHARM 97 595 Page 3 Travaux en cours et travaux futurs Les travaux sur les substances n cessaires pour accompagner les monographies des volumes 3 4 et 5 de la Pharmacop e internationale se poursuivent Actuellement le Centre proc de tude de 14 des 59 substances num r es l appendice 7 En 1997 le Centre a poursuivi ses activit s de contr le de a qualit Un contr le des modifications par exemple t mis en place Des modifications ont t apport es la documentation qui accompagne les envois de substances de r f rence Par exemple depuis juillet 1997 tous les nouveaux certificats sont sign s Trois boursiers sont venus au Centre en janvier et octobre le Professeur Kamel Bouzouita et Hassen Trabelsi du Laboratoire national de Contr le des M dica
90. rld Health Organization WHO The document may not be reviewed abstracted quoted reproduced or translated in part or in whole without the prior written permission of WHO No part of this document may be stored in a retrieval system or transmitted in any form or by any maans lectronic mechanical ar other without the prior written permission of WHO The views expressed in documents hy named authors are solely the r sponsibihty of those authors Le document n est pas destin tre distribu au grand public et tout las droits y aff rents sont r serv s par l Organisation mondiale de la Sant OMS Il ne peut tre comment r sum cit reproduit ou traduit partiellement ou en totalit sans une autorisation pr alable crite de l OMS Aucune partie ne doit tre charg e dans un syst me de recherche documentaire ou diffus e sous quelque forme ou par queique moyen que c soit lectronique m canique ou autre sans une autorisation pr alable crite de l OMS Les opinions exprim es dans les documents par des auteurs cit s nommement n endgag nt que lesdits auteurs WHO PHARM 97 595 Page 2 Distribution de substances de r f rence en 1997 En 1997 le Centre a distribu 1559 substances chimiques internationales de r f rence Ce chiffre repr sente une augmentation d environ 34 par rapport celui de 1996 Les substances les plus fr quemment demand es ont t dans l ordre l ac tate de
91. ropean Pharmacopoeia Chemical Reference substance EPCRS batch 2 of kanamycin monosulfate when they are re crystallized in water The proposed ICRS was also stored for 24 hours in 98 relative humidity in order to pick up moisture to re crystallize Before preparing an IR disc the substance was dried An infrared spectrum of the substance after this re crystallization is given in Figure 2 960042RH Figure 2 R spectrum of 1 8 mg moisture treated kanamycin monosulfate Control No 197211 in 300 mg of potassium bromide recorded against a potassium bromide disc I e do dd dd Loge ng mb LL mb Ex Lu r ATIFA A O PAC TETI ia veer beer au W ren PT TT TD PT A RL mm bara mu AS ee d E RAP HN MIN WHO PHARM 97 595 page 75 The Spectrum in Figure 2 is concordant with the spectra of the United States Pharmacopeia Reference Standard USPRS lot I and of the European Pharmacopoeia Chemical Reference substance EPCRS batch 2 of kanamycin monosulfate igh performance liquid chromatography with mass spectrometric detection A spectrum of kanamycin was recorded by electrospray ESI in the positive ion mode The spectrum shows an M H ion of 485 1 which supports the identity of kanamycin The spectrum given in Figure 3 is concordant with the spectrum of the European Pharmacopoeia Chemical Reference Substance EPCRS batch 2 Eluent Acetonitrile 1 glacial acetic acid in water 50 50 Column Direct inlet Pump Hewlett Pa
92. rotected from light This ICRS is of the same origin as that of the European Pharmacopoeia Chemical Reference Substance EPCRS lot 1 Analytical data ti white powder Evidence of chemical structure Infrared spectrum An infrared spectrum is given in Figure 1 W197212 The spectrum is concordant with the spectrum of the United States Pharmacopeia Reference Standard USPRS lot F of piperazine achpate ACTH la BT TU NT CL PC CTP ENT EEE ES se s WHO PHARM 97 595 TT TI al hu AC Ai MUR TSC LL En Figure K spectrum of 0 3 mg of piperazine adipate Control No 197212 in 300 mg of potassium bromide recorded against a potassium bromide disc Instrument Perkin Elmer 1600 FTIR High performance liquid chromatosranhy wit pectrometric detecti A spectrum of piperazine adipate was recorded by particle beam electron ionization PB ED in the positive ion mode The spectrum which is given in Figure 2 is concordant with the spectrum of piperazine adipate published in the National Institute of Standards and Technology NIST library Eluent Methanol Water 50 50 Column Direct inlet Purp Hewlett Packard 1050 operated at a flow rate of 0 5 ml min Vi Detector Fisons Platform D quadrupole mass spectrometer Operating conditions Electron energy 70 V Source temperature 250 C Sample Piperazine adipate was dissolved in water at a concentration of 0 1 mg ml 10 ul corresponding to 1 ug were injected
93. s 2 4 dinitro fluorobenzenederivative monitored at 365 nm The following conditions were used luent A Acetonitnle B 2 0 g of tris hydroxymethyl aminomethane was dissolved in water then 10 0 mi 1 M sulfuric acid was added and diluted with water to 1000 ml Hdi dr Mann nan Hirt APR rare n D AM TE RAE hd md md do mm A p r pe leed mp tn AT WHO PHARM 97 595 page 79 Gradient A o B Time Type minutes 30 70 0 10 isocratic 3080 70 20 10 30 linear 80 930 20 70 30 31 linear 30 70 31 45 isocratic equilibration Column Brownlee Labs spheri 5 RP 18 at 40 C 4 6 x 250 mm 5 um particles Detector Waters Lambda Max model 481 operated at 365 nm Pump Waters 600E operated at a flow rate of 1 0 ml min Injector P Carnegie CMA 200 operated at 8 C Integrator PeakPro Beckman sample Kanamycin sulfate was derivatized see below Sample concentration was about 0 15 mg ml 20 ul corresponding to 3 ug Were Injected Derivatization 2 4 Dinitrofluorobenzene reagent 10 mg 2 4 dinitrofluorobenzene per ml of ethanol Tris hydroxymethyl aminomethane reagent 20 ml of a solution containing 15 mg tris hydroxymethylaminomethane per ml of water were transferred into a 100 m volumetric flask and diluted to volume with dimethylsulfoxide This reagent was used within 4 hours op Purity determination 1 50 ml of a sample solution containing 2 50 mg ml water were transferred into a Z5 m volumetric flask and 7 ml of the 2
94. stances chimiques internationales de r f rence ci apr s sont n cessaires pour accompagner Jes sp cifications qui figurent dans la troisi me dition de la Pharmacop e internationale Volume 3 Noroxymorphone chlorhydrate impuret du chlorhydrate de naloxone Volume 4 Dactinomycine lohexol M droxyprogest rone ac tate N omycine sulfate Volume 5 Albendazole Aleuronium chlorure Amoxicilline trihydrate Art ther Art m ther Art misinine Artesunate At nolol At nolol pour validation des colonnes Benznidazole 9 9 Bisanthracene 10 10 9H 9 dione Captopril disulfure C fadroxil monohydrate Chloramph nicol succinate sodique Ciclosporine Ciclosporme U Clindamycine chiorhydrate Clindamycine phosphate 1 Cyclopropyl 1 4 dihydro 4 0x0 6 fluoro 7 2 amino thyl amino 3 quinoline carboxylique acide d riv de l thyl n diamine 1 Cyclopropyl 1 4 dihydro 4 0x0 6 1 pip razinyl 7 chloro 3 quinoline carboxylique acide Cyclopropyl 1 4 dihydro 4 o0x0 7 1 pip razinyl 3 quinoline carboxylique acide Dacarbazine Dacarbazine substance apparent e A Dacarbazine substance apparent e B Sodium amidotrizoate Thiopental sodique Vinblastine sulfate Dibydroart misinine Dim thy 2 6 dim thyi 4 2 nitroph nyl pyridine 3 5 dicarboxylate Dim thy 2 6 dim thyi 4 2 nitrosoph nyl pyridine 3 5 dicarboxylate 1 2 Diph ny
95. tained two secondary spots Their total amount was estimated to about 5 2 One of the spots was identified as kanamycin B sulfate and roughly estimated to be 0 8 High performance liquid chromatography As kanamycin sulfate has practically no UV absorbance other detection principles had to be chosen Pre column derivatization using 2 4 dinitrofluorobenzene as denoted in the monograph for Tobramycin of the USP XXII was found satisfactory for the detection of kanamycin The total amount of impurities estimated by peak area normalization was about 6 7 n 24 RSD 0 15 for the main peak RSD 2 calculated on the 2 4 impurity level WHO PHARM 97 595 page 78 As can be seen in Figure 4 thirteen impurities above the limit of quantification were found One of them was identified as kanamycin B sulfate eluting at 30 minutes It was estimated to 0 4 against an external standard All peaks eluting before 23 minutes are blank peaks originating from the derivatization agents 8 47 06 97 11 19 o bolrte ren e a op 2 an ths fa mi Bi SS 33 g min E y TTE o EN F e ki o S g l E 5 S a S ge d z 4 S amp i a B E wl on O el g g i 3 D gt io ch S 5 a EH 8 AS A D 2 ao 21 ae 23 a4 25 d 2T 28 29 30 a1 a2 33 34 Elution Time Minutes BAAIH28 eanus25 0 Gc1131 GCLIIL A Figure 4 Chromatogram of kanamycin monosulfate Control No 197211 a
96. te For the identity and estimation of sulfate see under Purity lon Chromatography Assay see results from collaborating laboratories Thermosravimetric When the substance was heated to 105 C a loss of 4 1 w w was observed n 3 RSD 3 1 The substance was analyzed immediately after opening of the ampoule but as the substance 1s extremely hygroscopic it readily picks up moisture before the analysis starts The relative humudity at the analysis occasion was 25 Instrument Perkin Elmer TGA 7 Thermogravimetric analyzer sample weight 2 mg Heating program 5 C min from 20 105 C and then holding 105 C for 180 minutes Melting point About 270 C with decomposition It was not possible to determine the content of water by Karl Fischer titration due to the high hygroscopicity and the smali quantity of sample available Organic volatile compounds lt 0 1 The test included methanol ethanol acetone acetonitrile dichloromethane pyridine chloroform benzene trichloroethylene and dioxan Each of them were estimated to be lt 100 ppm The content of organic solvents was tested by gas chromatography with the following conditions Instrument Hewlett Packard 6890 Column HP 5 30 m x 0 53 mm 2 65 um film Carrier gas Helium 8 ml min Detector FID Injection volume 2 pl Injector temperature 200 C WHO PHARM 97 595 page 77 Detector temperature 250 C Temperature program 40 C for 10 minut
97. tential impurities transplatin and potassium trichloroaminoplatinate were possible to separate within reasonable time and to detect without derivatization Only one impurity was found namely the monohydrated complex which was estimated to 0 77 by peak area normalization n 9 RSD 0 14 for the main peak RSD 10 4 calculated on the 0 77 impurity level It was earlier identified by LC MS and found to increase rapidly in water solution After 24 hours only about 60 of intact cisplatin remains For stability reasons it is better to prepare the sample in 0 5 sodium chloride which is chosen in the method In this solution a degradation of about 0 5 was observed when stored at 15 C for 24 hours Electropherograms are given in Figure 3 full scale and Figure 4 details Ceri Treo Z HOT qe bh Can i 6 07 cisplatin KA gt a d Da Figure 3 Electropherogram of cisplatin Control No 197207 monitored at 210 nm WHO PHARM 97 595 pag 70 Dans Trans Ape H Es he g cisplatin 4 2 001 S wel M LE i a e LG z DOG qu A a s S m blank a at CH SS x Fad J bel i E Sam a 5 a 7 potassium trichiorouminoglatinate lt LOQ e p D KH Figure 4 Electropherogram details of cisplatin Control No 197207 monitored at 210 nm Transplatin limit of detection 1 3 and potassium trichloroaminoplatinate limit of detection 0 8 were not found in this ICRS
98. toate B tam th son B tam thasone phosphate sodique B tam thasone val rate B tanidine sulfate NN bis 2 3 xylylanthranilamide Bupivacaine chlorhydrate Caf ine Calcium folinate Leucovorine calcique Captopril Carbamaz pine Carb nicilline monosodique Chloramphenicol Chloramphenicol palmitate Chloramphenicol palmitate forme A 5 Chloro 2 me thylaminobenzoph none Chloroquine sulfate 2 4 Chloro 3 sulfamoylbenzoy benzoique acide Chlorphenamine hydrog nomal ate Chlorpromazine chlorhydrate Chlortalidone Chlort tracyeline chlorhydrate Cim tidine Ciprofloxacine chlorhydrate Cisplatine Clomif ne citrate Clomif ne citrate isom re Z voir Zuclomif ne Cloxacilline sodique Conditionnement 100 mg 100 mg 100 mg 100 mg 100 mg 25 mg 100 mg 100 mg 100 mg 200 mg 400 mg 200 mg 200 mg 200 mg 25 mg 100 mg 100 mg 200 me 200 mg 100 mg 100 mg 100 mg 200 mg 200 mg 100 mg 100 mg 100 mg 100 mg 100 mg 50 mg 100 mg 100 mg 100 mg 100 mg 100 mg 200 mg 200 mg lg 200 ms 100 mg 200 mg 50 mg 100 mg 100 mg 100 mg 200 mg 100 mg 400 mg 100 mg 100 mg 200 mg N de contr le 172048 290042 186128 287049 196205 186131 172050 196206 181101 192160 191153 390001 388002 274003 180096 183111 172060 192174 192175 175066 172051 172052 180099 280047 183112 183113 196203 190145 172053 173067 289054 181102 194188 197214 189143 383043 486004
99. upivacaine chlorhydrate caf ine anhvdre calcium folinate carbidopa chlorph namine hydrog nomal ate clofazimine cloxacilline sodique colchicine cytarabine dexamethasone dexam thasone ac tate monohydrate dextrom thorphane bromhydrate diaz pam dicolinium todure dicoumarol di thylcarbamazine dihydrog nocitrate diph noxylate chlorhydrate erythromycine thylsuccinate rythromycine st arate tacrynique acide thionamide thosuximide furosemide gallamine tri thiodure glibenclamide halop rido hydrochlorothiazide ibuprof ne imipramine chlorhydrate indom tacine isoniazide hdocaine lidocaine chlorhydrate lindane m tronidazole miconazole nitrate niclosamide nicotinamide noscapine oxammiquine papaverine chlorhydrate ph nobarbital ph noxyme thylp nicilline calcique ph nytoine primaquine phosphate propylthiouracile protionamide pyrim thamine salbutamol salbutamol sulfate sulfadimidine sulfadoxine sulfam thoxazole sulfam thoxypyridazine tlabendazo trihexyph nidyle chlorhydrate trim thoprime valpro que acide v raparnil chlorhydrate dt E PEPYS POA HD Jr mere rer H hr matali lh hee eA Ledesma 4 en WHO PHARM 97 595 Page 19 Appendice 5 WHO PHARM 97 595 Page 20 APPENDICE 6 ESSAIS DE STABILITE La stabilit des substances chimiques internationales de r f rence pendant leur stockage est surveill
100. xamens r guliers et lorsque cela est n cessaire les substances d t rior es sont remplac es par de nouveaux lots Des listes indiquant les num ros de contr le des lots en cours sont publi es dans les rapports annuels du Centre et peuvent tre obtenues sur demande Commandes de substances Les commandes de substances chimiques internationales de r f rence doivent tre envoy es Centre collaborateur OMS pour les substances chimiques de r f rence Apoteket AB Produktion amp Laboratorier Centrallaboratoriet ACL Prismavagen 2 14175 Kungens Kurva Su de T l copie 46 8 740 6040 Les substances chimiques internationales de r f rence sont exclusivement fournies par paquets standard contenant la quantit indiqu e sur la liste ci apr s WHO PHARM 97 595 Page 12 Appendice 4 Substances de reference Ac clidine salicylate p Ac tamidobenzalazine Ac tazolamide Alopurinol Anidotrizo qu acide 2 Amino 5 nitrothiazole 3 Aminopyrazole 4 carboxamide h misulfate 3 Amino 2 4 6 triodobenzoique acide Amitriptyline chlorhydrate Amodiaquine chlorhydrate Amphot ricine B Ampicilline anhydre Ampicilline sodique Ampicilline trihydrate Anhydrot tracycline chlorhydrate Atropine sulfate Azathioprine Bacitracine zinc B clom tasone dipropionate Bendazol chlorhydrate Benzobarbital Benzylamine sulfate Benzyipenicilline potassique Benzylp niciliine sodique B ph nium hydroxynaph
101. zone 4 4 Thiodianiline Thyroxine sodique voir L vothyroxine sodique Tolbutamide Tolnaftate Toluene 2 sulfonamide Trimethadione Trim thoprime Trim thylguanidine sulfate Tubocurarine chlorure Vincristine sulfate Vitamine A ac tate solution voir R tinol ac tate Warfarine Zuclomif ne Echantillons vendus En D E Gah Se H A INN bd H iw bo WHO PHARM 97 595 Page 9 APPENDICE 2 DISTRIBUTION DE SUBSTANCES CHIMIQUES INTERNATIONALES DE REFERENCE DANS LES DIFFERENTES REGIONS DE L OMS EN 1997 _ gt _ _ _ _ _ _ _ i UU R gions OMS Nombre de SCIR distribu es en 1997 R gion africaine AFRO Ethiopie 170 Ouganda 28 Sierra Leone 22 R gion des Am riques AMRO Argentine 10 Br sil 7 Cuba 8 Etats Unis d Am rique 29 Mexique 3 pp Tn Region de la M diterran e orientale EMRO Chypre 4 Libye 14 R publique arabe syrienne 20 R gion europ enne EURO Allemagne 266 Autriche 17 Belgique 16 Danemark 18 Espagne 12 Finlande 13 France 69 Hongrie 3 Irlande 6 Isra l 6 italie 5 Kirghizistan 181 Liechtenstein 3 Norv ge 17 Pays Bas 7 Pologne 15 Royaume Uni 92 Slovaquie 2 Suede 145 Suisse af Region de l Asie du Sud Est SEARO Cor e 3 Indon si 3 Sri Lanka 39 R gion du Pacifique occidental WPRO Laos Philippines 26 Singapour 35 Tawan 2 Age mm WHO PHARM 97 595 Page 10 APPENDI

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