FARMAKOPEJA

Farmakopeja je skup propisa koji utvruju zahtjeve i

postupke za izradu i provjeru kakvoe lijekova

Sve farmaceutske sirovine, koje se rabe u proizvodnji

gotovog lijeka ili izradi magistralnih i galenskih
pripravaka, moraju odgovarati zahtjevima
farmakopejskih monografija s obzirom na njihov
kvalitativan i kvantitativan sastav.

EUROPSKA FARMAKOPEJA
European Pharmacopoeia
(Ph. Eur.)

1. izdanje 1964.
2. izdanje 1986.
3. izdanje 1997. i dopuna 1999.
4. izdanje 2002.
5. izdanje 2005.
6. izdanje na snazi je od 1.1.2008.

http://www.pheur.org/

 Europsku farmakopeju objavljuje

Europsko ravnateljstvo za kakvou lijekova pri Vijeu Europe
(European Directorate for the Quality of Medicines (EDQM) of the Council of Europe)

 Europska farmakopeja postavlja zajednike i obvezatne standarde

kojima jami kvalitetu lijekova u svim zemljama potpisnicima
Konvencije o izradi Europske farmakopeje

 svi sastojci koje ulaze u sastav lijekova za ljude ili ivotinje

standardizirani su, jednako kao i metode analize, s ciljem
osiguranja kvalitete optimalne za zdravlje potroaa.

 usklaivanje kontrole kakvoe lijekova na europskom tritu

~ 2000 obvezatnih standarda
za lijekove (monografije)

~ 300 opih metoda za ispitivanje identiteta,

istoe i odreivanje sadraja

 objavljene monografije podlijeu reviziji

proizvodi na tritu
znanstveni napredak
razvoj zakonske regulative

 farmaceutska tvar nema kakvou koja zadovoljava farmakopeju

ako ne udovoljava svim zahtjevima navedenim u monografiji

 mrea europskih laboratorija za provjeru kakvoe lijekova

Official Medicine Control Laboratories (OMCL)

HRVATSKA FARMAKOPEJA
 1994. potpisnica Konvencije o izradi europske farmakopeje
i lanica Europske farmakopeje

 norme kakvoe za tvari iz monografijskog fonda Ph.Eur.

postale su obvezne za sve lijekove proizvedene u Hrvatskoj ili
uvezene u Hrvatsku
2007.

Hrvatska farmakopeja jest propis koji utvruje zahtjeve

izrade, kakvoe i postupke za provjeru kakvoe lijekova i
homeopatskih proizvoda, koji je odgovarajue povezan i usklaen
s Europskom farmakopejom.

Zakon o lijekovima i medicinskim proizvodima

(Narodne novine broj 121/03)

1. Kakvoa lijeka i sirovina za proizvodnju lijeka, ukljuujui

materijale za unutarnje pakovanje lijeka, mora biti u skladu s
Hrvatskom farmakopejom, odnosno ako nije obuhvaena
farmakopejom, drugim meunarodnim priznatim normama.
2. Hrvatsku farmakopeju na prijedlog Agencije donosi ministar
nadlean za zdravstvo.
3. Agencija za lijekove i medicinske proizvode izrauje monografije
za Hrvatsku farmakopeju
Odsjek za farmakopeju i meunarodnu suradnju

 1888. Pharmacopea Croatico-Slavonica

 1901. Hrvatsko-slavonski ljekopis
 1933. Pharmacopoea Jugoslavica, izd. I
 1984. Ph. Jug. IV
 1994. potpisnica Konvencije o izradi europske farmakopeje
 2007. Hrvatska farmakopeja

Nacionalne farmakopeje
United States Pharmacopeia (USP)

http://www.usp.org/

Deutsches Arzneibuch (DAB)

British Pharmacopoeia (BP)
Japanese Pharmacopoeia (JP)

http://jpdb.nihs.go.jp/jp14e/

Nacionalne farmakopeje

International Pharmacopoeia
ope metode analize, zahtjeve kakvoe
za ljekovite i pomone tvari,
gotove ljekovite oblike
nije prireena kao regulatorni akt
namijenjena kao izvor podataka ili za prilagodbu bilo koje zemlje
lanice Svjetske zdravstvene organizacije koja eli
uspostaviti vlastite farmakopejske zahtjeve

Harmonizacija
 meunarodno usklaivanje propisa na podruju lijekova
 usklaivanje nacionalnih zakonodavstava o lijekovima s
farmaceutskim europskim zahtjevima
 usklaivanje Europske farmakopeje s USP i JP

 Meunarodna konferencija o harmonizaciji (ICH)

zajednika incijativa regulatornih tijela i proizvoaa lijekova s
podruja Europe, Japana i SAD-a radi breg stavljanja lijekova u
promet uz ouvanje dobrobiti pacijenta
 globalna harmonizacija tehnikih zahtjeva za registraciju lijekova
u EU, SAD, Japanu poznata kao Zajedniki tehniki dokument
(Common Technical Document, CTD)

PHARMEUROPA
PHARMEUROPA BIO

 objavljuju pripremne materijale novih i revidiranih monografija

koje se predlau za Ph.Eur.
 prua mogunost davanja komentara prije objave monografije u
Ph.Eur.
 izlaze etiri puta godinje

Europska farmakopeja
1. Ope napomene
2. Metode analize
2.1.
2.2.
2.3.
2.4.
2.5.
2.6.
2.7.
2.8.
2.9.

Aparature
Fizikalne i fizikalno-kemijske metode
Identifikacija
Ispitivanja graninih vrijednosti oneienja
Kemijske analize
Bioloka ispitivanja
Bioloke analize
Farmakognoke metode
Farmaceutsko-tehnoloki postupci

3. Materijali za proizvodnju spremnika lijekova

4. Reagensi, poredbene otopine i puferi
5. Opi tekstovi
Ope monografije
Dozirni oblici
MONOGRAFIJE LJEKOVITIH I POMONIH TVARI

Fizikalne i fizikalno-kemijske metode

2.2. Physical and physicochemical methods.............................
2.2.1. Clarity and degree of opalescence of liquids....................
2.2.2. Degree of coloration of liquids...........................................
2.2.3. Potentiometric determination of pH.. ................................
2.2.4. Relationship between reaction of solution, approximate
pH and colour of certain indicators.. ..............................
2.2.5. Relative density...................................................................
2.2.6. Refractive index.. ...............................................................
2.2.7. Optical rotation....................................................................
2.2.8. Viscosity..............................................................................
2.2.9. Capillary viscometer method.. ...........................................
2.2.10. Rotating viscometer method.. ..........................................
2.2.11. Distillation range...............................................................
2.2.12. Boiling point.. .....................................................................
2.2.13. Determination of water by distillation...............................
2.2.14. Melting point - capillary method.........................................
2.2.15. Melting point - open capillary method.. ...........................
2.2.16. Melting point - instantaneous method.. ...........................
2.2.17. Drop point............................................................................
2.2.18. Freezing point.....................................................................
2.2.19. Amperometric titration.. .....................................................
2.2.20. Potentiometric titration.. .....................................................
2.2.21. Fluorimetry.. .........................................................................
2.2.22. Atomic emission spectrometry.. .......................................
2.2.23. Atomic absorption spectrometry.. ...................................

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2.2.24. Absorption spectrophotometry, infrared.. ................ 34

2.2.25. Absorption spectrophotometry, ultraviolet and visible 36
2.2.26. Paper chromatography.. .............................................. 37
2.2.27. Thin-layer chromatography......................................... 38
2.2.28. Gas chromatography.. .................................................. 39
2.2.29. Liquid chromatography.. ............................................. 40
2.2.30. Size-exclusion chromatography.. .............................. 42
2.2.31. Electrophoresis............................................................. 43
2.2.32. Loss on drying.. ............................................................ 48
2.2.33. Nuclear magnetic resonance spectrometry.. ...........
48
2.2.34. Thermogravimetry.. ..................................................... 49
2.2.35. Osmolality.. .................................................................... 49
2.2.36. Potentiometric determination of ionic concentration
using ion-selective electrodes.. ..............................
50
2.2.37. X-ray fluorescence spectrometry ...........................
51
2.2.38. Conductivity.. ................................................................. 52
2.2.39. Molecular mass distribution in dextrans.. ...............
53
2.2.40. Near-infrared spectrophotometry.. ............................ 55
2.2.41. Circular dichroism.. ...................................................... 56
2.2.42. Density of solids.. .......................................................... 57
2.2.43. Mass spectrometry.. ...................................................... 58
2.2.44. Total organic carbon in water for pharmaceutical use 60
2.2.45. Supercritical fluid chromatography.............................. 61
2.2.46. Chromatographic separation techniques.................... 61
2.2.47. Capillary electrophoresis.............................................. 66
2.2.48. Raman spectrometry.. ................................................... 71
2.2.49. Falling ball viscometer method................................... 73
2.2.54. Isoelectric focusing........................................................ 73

Ispitivanja graninih vrijednosti oneienja

2.4. Limit tests.. ............................................................................
2.4.1. Ammonium.. ......................................................................
2.4.2. Arsenic.. ..............................................................................
2.4.3. Calcium...............................................................................
2.4.4. Chlorides.. ..........................................................................
2.4.5. Fluorides.. ..........................................................................
2.4.6. Magnesium.........................................................................
2.4.7. Magnesium and alkaline-earth metals.. .......................
2.4.8. Heavy metals.. ...................................................................
2.4.9. Iron.. ....................................................................................
2.4.10. Lead in sugars.................................................................
2.4.11. Phosphates.. ....................................................................
2.4.12. Potassium.. ......................................................................
2.4.13. Sulphates.. .......................................................................
2.4.14. Sulphated ash.. ...............................................................
2.4.15. Nickel in polyols.. ...........................................................
2.4.16. Total ash...........................................................................
2.4.17. Aluminium.. .....................................................................
2.4.18. Free formaldehyde.. .......................................................
2.4.19. Alkaline impurities in fatty oils.. .................................
2.4.21. Foreign oils in fatty oils by thin-layer chromatography..
2.4.22. Composition of fatty acids by gas chromatography..
2.4.23. Sterols in fatty oils.. .......................................................
2.4.24. Identification and control of residual solvents.. ......
2.4.25. Ethylene oxide and dioxan.........................................
2.4.26. N,N-Dimethylaniline.. ..................................................
2.4.27. Nickel in hydrogenated vegetable oils.....................
2.4.28. 2-Ethylhexanoic acid.. .................................................

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100
101
102
102

Kemijske analize
2.5. Assays.. ............................................................................. 105
2.5.1. Acid value........................................................................ 105
2.5.2. Ester value.. ................................................................... 105
2.5.3. Hydroxyl value.. ............................................................ 105
2.5.4. Iodine value.. ................................................................. 105
2.5.5. Peroxide value.. ............................................................. 106
2.5.6. Saponification value.. .................................................. 106
2.5.7. Unsaponifiable matter.. ............................................... 106
2.5.8. Determination of primary aromatic amino-nitrogen.. .. 107
2.5.9. Determination of nitrogen by sulphuric acid digestion. 107
2.5.10. Oxygen-flask method................................................... 107
2.5.11. Complexometric titrations.......................................... 107
2.5.12. Water: semi-micro determination.. ........................... 108
2.5.13. Aluminium in adsorbed vaccines.............................. 108
2.5.14. Calcium in adsorbed vaccines.. ................................. 108
2.5.15. Phenol in immunosera and vaccines.. ..................... 109
2.5.16. Protein in polysaccharide vaccines.. ........................ 109
2.5.17. Nucleic acids in polysaccharide vaccines................ 109
2.5.18. Phosphorus in polysaccharide vaccines.. ............... 109
2.5.19. O-Acetyl in polysaccharide vaccines......................... 109
2.5.20. Hexosamines in polysaccharide vaccines................ 110
2.5.21. Methylpentoses in polysaccharide vaccines.. ......... 110
2.5.22. Uronic acids in polysaccharide vaccines.. ............... 110
2.5.23. Sialic acid in polysaccharide vaccines.. ................... 111
2.5.24. Carbon dioxide in gases.............................................. 111
2.5.25. Carbon monoxide in gases......................................... 111
2.5.26. Nitrogen monoxide and nitrogen dioxide in gases.... 112
2.5.27. Oxygen in gases............................................................ 113
2.5.28. Water in gases............................................................... 114
2.5.29. Sulphur dioxide.. .......................................................... 114
2.5.30. Oxidising substances................................................... 114
2.5.31. Ribose in polysaccharide vaccines.. ......................... 114
2.5.32. Water: micro determination.. ....................................
115
2.5.33. Total protein.................................................................. 115
2.5.34. Acetic acid in synthetic peptides.. ............................ 118

Bioloka ispitivanja
2.6. Biological tests.. .................................................................
2.6.1. Sterility.. ...........................................................................
2.6.2. Mycobacteria.. .................................................................
2.6.3. Tests for extraneous viruses using fertilised eggs..
2.6.4. Test for leucosis viruses.. ..............................................
2.6.5. Test for extraneous viruses using cell cultures.. .....
2.6.6. Test for extraneous agents using chicks.. .................
2.6.7. Mycoplasmas....................................................................
2.6.8. Pyrogens...........................................................................
2.6.9. Abnormal toxicity.. .........................................................
2.6.10. Histamine.......................................................................
2.6.11. Depressor substances..................................................
2.6.12. Microbiological examination of non-sterile products
(total viable aerobic count).. .................................
2.6.13. Microbiological examination of non-sterile products
(test for specified micro-organisms).. ..................
2.6.14. Bacterial endotoxins....................................................
2.6.15. Prekallikrein activator.. ..............................................
2.6.16. Tests for extraneous agents in viral vaccines for
human use.. ..............................................................
2.6.17. Test for anticomplementary activity of
immunoglobulin.. ....................................................
2.6.18. Test for neurovirulence of live virus vaccines.. .....
2.6.19. Test for neurovirulence of poliomyelitis vaccine
(oral).. .........................................................................
2.6.20. Anti-A and anti-B haemagglutinins (indirect method).. ..
2.6.21. Nucleic acid amplification techniques.. ...................
2.6.22. Activated coagulation factors.. ..................................

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140
147
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152
153
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156

Bioloke analize
2.7. Biological assays.. ..............................................................
2.7.1. Immunochemical methods.. .........................................
2.7.2. Microbiological assay of antibiotics............................
2.7.3. Assay of corticotropin....................................................
2.7.4. Assay of blood coagulation factor VIII.. ....................
2.7.5. Assay of heparin.. ...........................................................
2.7.6. Assay of diphtheria vaccine (adsorbed).. ...................
2.7.7. Assay of pertussis vaccine.. ..........................................
2.7.8. Assay of tetanus vaccine (adsorbed).. ........................
2.7.9. Test for Fc function of immunoglobulin.. .................
2.7.10. Assay of human coagulation factor VII...................
2.7.11. Assay of human coagulation factor IX.. ..................
2.7.12. Assay of heparin in coagulation factor concentrates..
2.7.13. Assay of human anti-D immunoglobulin.. ..............
2.7.14. Assay of hepatitis A vaccine.......................................
2.7.15. Assay of hepatitis B vaccine (rDNA).. ......................
2.7.16. Assay of pertussis vaccine (acellular).. ....................
2.7.17. Assay of human antithrombin III.. ...........................
2.7.18. Assay of human coagulation factor II......................
2.7.19. Assay of human coagulation factor X.. ....................
2.7.20. In vivo assay of poliomyelitis vaccine (inactivated)..

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Opi tekstovi
General texts on sterility
General texts on vaccines
Statistical analysis of results of biological assays and tests
Residual solvents
Alcoholimetric tables
Assay of interferons
Table of physical characteristics of radionuclides mentioned
in the European Pharmacopoeia..
Pharmacopoeial harmonisation
Polymorphism
Control of impurities in substances for pharmaceutical use

Standardi Europske farmakopeje

Ope monografije

Pojedinane monografije

skupina ljekovitih pripravaka

ljekovite tvari

vrsta dozirnih oblika

pomone tvari

 ope monografije definiraju propise za cijelu grupu proizvoda

 farmaceutske tvari s pojedinanom monografijom moraju
odgovarati i zahtjevima opih monografija

Ope monografije
Allergen products.............................................................. 507
Extracts.. ............................................................................ 508
Herbal drug preparations................................................... 510
Herbal drugs.. .....................................................................510
Herbal teas.......................................................................... 510
Immunosera for human use .. ........................................... 511
Immunosera for veterinary use .. ......................................511
Products of fermentation.. ................................................ 512
Products with risk of transmitting agents of animal
spongiform encephalopathies...............................
514
Radiopharmaceutical preparations.. ............................. 514
Recombinant DNA technology, products of................... 520
Substances for pharmaceutical use.. .............................. 522
Tinctures.. .......................................................................... 524
Vaccines for human use.................................................. 524
Vaccines for veterinary use.............................................. 526
Vegetable fatty oils............................................................ 530

Farmaceutski oblici
Glossary..................................................................................... 535
Capsules.. .................................................................................. 536
Chewing gums, medicated.. .................................................... 537
Ear preparations...................................................................... 538
Eye preparations.. ................................................................... 539
Foams, medicated.. ................................................................. 541
Granules.................................................................................... 542
Intramammary preparations for veterinary use.. ..............
543
Intraruminal devices.. ............................................................. 544
Liquid preparations for cutaneous application.. ................ 544
Liquid preparations for oral use.. ......................................... 545
Nasal preparations.. ................................................................ 547
Parenteral preparations.......................................................... 548
Patches, transdermal............................................................... 550
Powders for cutaneous application....................................... 551
Powders, oral.. ........................................................................ 551
Premixes for medicated feeding stuffs for veterinary use.. 552
Preparations for inhalation...................................................... 552
Preparations for irrigation.. ..................................................... 556
Pressurised pharmaceutical preparations.. .......................... 556
Rectal preparations................................................................. 557
Semi-solid preparations for cutaneous application.. .......... 559
Sticks.. ..................................................................................... 560
Tablets.. .................................................................................... 561
Tampons, medicated .............................................................. 563
Vaginal preparations.. ............................................................ 563
Veterinary liquid preparations for cutaneous application.. 565

SASTAV MONOGRAFIJE
Naslov i podnaslov monografije
 naslov: naziv farmaceutske tvari
meunarodno nezatieno ime preporueno od WHO
(International Nonproprietary Name, INN)
 podnaslov: latinski

Relativna atomska i molekulska masa

Empirijska i strukturna formula

Definicija
 kemijsko ime farmaceutske tvari (IUPAC)
 granice sadraja
utvrene metodama u Odreivanju sadraja
 monografije kiralnih spojeva

apsolutna konfiguracija

 monografije hidrata ili solvata

udio vode ili otapala

 tvari dobivene iz prirodnih izvora ili fermentacijom

 terapeutici kombinacije kemijskih tvari

podrijetlo

udio svakog sastojka

01/2002:0049

PARACETAMOL
Paracetamolum

C8H9NO2

Mr 151.2

DEFINITION
Paracetamol contains not less than 99.0 per cent and
not more than the equivalent of 101.0 per cent of
N-(4-hydroxyphenyl)acetamide, calculated with reference to
the dried substance.
CHARACTERS
A white, crystalline powder, sparingly soluble in water,
freely soluble in alcohol, very slightly soluble in ether and
in methylene chloride.

Znaajke
 izgled (boja i fizikalni oblik) i miris
 topljivost
 stabilnost, higroskopnost, kristalininost, polimorfizam
Izraz

Vrlo lako topljiv

Lako topljiv
Topljiv
Umjereno topljiv
Teko topljiv
Vrlo teko topljiv
Gotovo netopljiv

Priblian volumen otapala u mililitrima

po gramu tvari
manje od 1
od 1 do 10
od 10 do 30
od 30 do 100
od 100 do 1000
od 1000 do 10 000
vie od 10 000

Proizvodnja
 podaci o proizvodnji djelatne tvari prirodnog podrijetla
INSULIN, HUMAN
PRODUCTION
Human insulin is produced in conditions designed to
minimise the degree of microbial contamination.
For human insulin produced by enzymatic modification of
insulin obtained from the pancreas of the pig, the
manufacturing process is validated to demonstrate removal of
any residual proteolytic activity. The competent authority
may require additional tests.
For human insulin produced by a method based on rDNA
technology, prior to release the following test is carried out
on each batch of the final bulk product unless exemption has
been granted by the competent authority.
Host-cell-derived proteins. Not more than 10 ppm
determined as described in the general monograph on
Products of recombinant DNA technology (0784).

Identifikacija
 ispitivanja navedena u poglavlju identifikacije nisu predviena za
potpunu potvrdu kemijske strukture, ve daju potvrdu da ispitivana
tvari odgovara opisu na certifikatu analize proizvoaa

 u veini monografija postoji podjela na prvu (First identification) i

drugu identifikaciju (Second identification)

 mogunost izbora postupaka prve ili

druge potvrde identiteta
 nije potrebno izvesti obje

 metode koje zahtijevaju sloenu

instrumentalnu tehniku
spektrofotometrijske analize
IR, NMR
kromatografsko istraivanje
HPLC, GC
 druge jednostavne metode
odreivanje fizikih konstanti
talite, krutite, vrelite, specifino optiko zakretanje,
UV spektar, specifina apsorbancija, relativna gustoa,
indeks loma, viskoznost
tankoslojna kromatografija
kemijske reakcije identifikacije
odreivanje kemijskih veliina
saponifikacijski, esterifikacijski, hidroksilni i jodni broj

 ispitivanja koja su ukljuena u drugu identifikaciju mogu se izvesti

umjesto ispitivanja u prvoj identifikaciji

ispitivana tvar potpuno odgovara seriji s izdanim

certifikatom analize udovoljavajui svim propisanim
zahtjevima monografije
 neka ispitivanja istoe u monografiji mogu biti namijenjena za
potvrdu identiteta
sadraj vode u razliitim hidratima, optika rotacija razliitih izomera,
viskoznost homologa polimera

 najee reakcije identifikacije opisane su u poglavlju

Identifikacija u metodama analize

Identifikacija paracetamola prema Europskoj farmakopeji

First identification: A, C.
Second identification: A, B, D, E.
A. Melting point (2.2.14) : 168 C to 172 C.
B. Dissolve 50 mg in methanol R and dilute to 100.0 ml with the same solvent.
To 1.0 ml of the solution add 0.5 ml of 0.1 M hydrochloric acid and dilute to
100.0 ml with methanol R. Protect the solution from bright light and
immediately measure the absorbance (2.2.25) at the absorption maximum at
249 nm. The specific absorbance at the maximum is 860 to 980.
C. Examine by infrared absorption spectrophotometry (2.2.24), comparing
with the spectrum obtained with paracetamol CRS. Examine the substances
prepared as discs.
D. To 0.1 g add 1 ml of hydrochloric acid R, heat to boiling for 3min, add 10 ml
of water R and cool. No precipitate is formed. Add 0.05 ml of 0.0167 M
potassium dichromate. A violet colour develops which does not change to red.
E. It gives the reaction of acetyl (2.3.1). Heat over a naked flame.

Zastupljenost metoda potvrde identiteta

d2020 nt

LC

[]D20
UV-Vis
TLC
Tt

IR

Ispitivanja
 ispitivanje istoe (Tests)
ograniavanja oneienja koja mogu nastati
tijekom proizvodnje ili uvanja

 ispitivanja istoe provode se kao:

ispitivanja graninih vrijednosti pri emu se zahtjevi povezuju
s rezultatima dobivenim analizom odgovarajuih poredbenih
otopina te iz fizikalno-kemijskih mjerenja
kvantitativna odreivanja oneienja

 izgled otopine
bistrina i stupanj zamuenja
stupanj obojenosti otopine
 kiselost/lunatost otopine ili mjerenje pH vrijednosti
 specifino optiko zakretanje
 ispitivanja graninih vrijednosti oneienja (Limit tests)
strani anioni i kationi
teki metali

 odreivanje udjela vode

 gubitak suenjem, gubitak arenjem, ostatak nakon isparavanja,
ostatak nakon arenja, sulfatni ostatak
 ostatna otapala

 srodne tvari
oneienja srodne strukture
meuprodukti i nusprodukti proizvodnog postupka
razgradni produkti
usput ekstrahirane tvari iz prirodnih produkata
kontroliraju se razliitim metodama
kromatografskim (TLC, HPLC, GC)
spektroskopskim (UV)
elektroforeza
ogranienje razine pojedinog oneienja i sume oneienja
postavljene granice za kontrolu oneienja ovise o nizu faktora
ukljuujui toksinost oneienja, nain i duinu primjene lijeka

Zastupljenost metoda ispitivanja oneienja

odreivanje udjela
vode

TLC

mjerenje optike
rotacije
HPLC
AAS
UV-Vis
GC
spektroskopske
metode
elektroforeza

kromatografske
metode

Odreivanje sadraja
 propisane granice sadraja djelatne tvari
(analitike pogreke, prihvatljiva odstupanja u proizvodnji)

 titracijske metode analize

nepecifina, ali precizna odreivanja
potenciometrijsko odreivanje zavrne toke titracije (49 %)

titracija u nevodenom mediju (50 %)

neutralimetrijska titracija
redoks titracija
kompleksometrijska titracija
talone titracije
titracija s natrij-nitritom

 instrumentalne metode analize

UV/Vis spektrofotometrija
kromatografija (HPLC i GC)

PARACETAMOL
ASSAY
Dissolve 0.300 g in a mixture of 10 ml of water R and 30 ml of
dilute sulphuric acid R. Boil under a reflux condenser for 1 h,
cool and dilute to 100.0 ml with water R. To 20.0 ml of the
solution add 40 ml of water R, 40 g of ice, 15 ml of dilute
hydrochloric acid R and 0.1 ml of ferroin R. Titrate with 0.1 M
ammonium and cerium sulphate until a yellow colour is
obtained. Carry out a blank titration.
1 ml of 0.1 M ammonium and cerium sulphate is equivalent
to 7.56 mg of C8H9NO2.

Bioloka odreivanja
 rezultati kvantitativnih ispitivanja pokazuju terapijsku aktivnost
 bioloke metode varijabilnije su od fizikalno-kemijskih;
ispitivanja se provode paralelno s odgovarajuim poredbenim
materijalom
 ispitivanje bioloke aktivnosti lijeka (potency) - IU/ml; IU/mg

mikrobioloka analiza
imunokemijske metode

HUMAN HEPATITIS A
IMMUNOGLOBULIN
POTENCY
The potency is determined by comparing the antibody
titre of the immunoglobulin to be examined with that of a
reference preparation calibrated in International Units, using
an immunoassay of suitable sensitivity and specificity (2.7.1).
The International Unit is the activity contained in a stated
amount of the International Standard for anti-hepatitis A
immunoglobulin. The equivalence in International Units of
the International Standard is stated by the World Health
Organisation.
Human hepatitis A immunoglobulin BRP is calibrated in
International Units by comparison with the International
Standard.
The stated potency is not less than 600 IU/ml. The estimated
potency is not less than the stated potency. The fiducial
limits of error (P = 0.95) of the estimated potency are not
less than 80 per cent and not more than 125 per cent.

Zastupljenost metoda odreivanja sadraja

mikrobioloka analiza
GC
LC

UV
titracijske metode
analize

Metode odreivanja sadraja u Ph. Eur. i USP

uvanje
 navedeni su uvjeti uvanja kako bi se zatitila kakvoa
 ponaanje materijala s obzirom na izlaganje atmosferskom zraku
i dnevnom svjetlu, razliitoj vlanosti i temperaturi
 vrsta spremnika i temperaturne granice pohranjivanja

STORAGE
- Store protected from light, at a temperature not exceeding 30C.
- Store in an airtight container, protected from light.
- Unless otherwise prescribed, store in a sterile, airtight, tamper-proof
container, protected from light, at a temperature of 2C to 8C. Insulin
preparations are not to be frozen.

Oznaavanja
 predmet nacionalne regulative i meunarodnih dogovora
 sadre ovlateni izvjetaj i druge postavke kao preporuke
 primjerice: sterilnost, dodani stabilizatori, aditivi
BENZYLPENICILLIN, PROCAINE
LABELLING
The label states :
where applicable, the name and quantity of any added
dispersing or suspending agents,
where applicable, that the substance is sterile,
where applicable, that the substance is free from bacterial
endotoxins.

Oneienja
 imena i kemijske strukture poznatih i moguih oneienja koja su
ograniena ispitivanjima u monografiji
ACETYLSALICYLIC ACID
IMPURITIES

A. R = H: 4-hydroxybenzoic acid,
B. R = CO2H: 4-hydroxybenzene-1,3-dicarboxylic acid
(4-hydroxyisophthalic acid),
C. salicylic acid,
F. 2-(acetyloxy)benzoic anhydride
(acetylsalicylic anhydride)

D. R = O-CO-CH3 : 2-[[2-(acetyloxy)benzoyl]oxy]
benzoic acid (acetylsalicylsalicylic acid),
E. R = OH: 2-[(2-hydroxybenzoyl)oxy]benzoic acid
(salicylsalicylic acid),

Hrvatska farmakopeja
 preuzimanje normi kakvoe Europske
farmakopeje u nacionalnu farmakopeju
 korisnici Farmakopeje: farmaceutska industrija,
regulatorna tijela, ljekarnika djelatnost
 Agencija je Hrvatsku farmakopeju dopunila objanjenjima i
komentarima te su uvrteni prijevodi odreenih monografija
 prilagoena potrebama ljekarnika i strunjaka ukljuenih u provjeru
kakvoe lijekova kojima e biti korisni hrvatski nazivi i rabljeni struni
izrazi
 Hrvatska farmakopeja moe normirati kakvou tvari koje nisu
obuhvaene Europskom farmakopejom

Sadraj Hrvatske farmakopeje

 DIO A. UVODNE ODREDBE

prijevod teksta OPE NAPOMENE iz Europske farmakopeje

poblia objanjenja i dopune (oznaena [HRFx])

objanjenja osnovnih farmakopejskih pojmova
npr. poredbena otopina, reagensi, iskazivanje sadraja,
stereokemijsko oznaavanje, suha tvar, bezvodna tvar,
topljivost, higroskopnost, identifikacija, ispitivanje istoe,
odreivanja, ...

 DIO B. NORME KAKVOE

popis monografija
naziv na hrvatskom, latinskom, engleskom i francuskom jeziku,
identifikacijski broj u Ph. Eur. 5, empirijska i strukturna formula,
molekulska masa

47 monografija s cjelovitim sadrajem izabranih prema

potrebama ljekarnika
npr. borna kiselina, glicerol, vazelin, rezorcinol, vitamin A, cinkov oksid,
salicilna kiselina, kalcijev glukonat, efedrin, etanol, metanol, kamfor,
bademovo ulje, talk, azitromicin, itd.

8 monografija farmaceutskih oblika s cjelovitim sadrajem

izabranih prema potrebama ljekarnika

3 ope monografije cjelovitog sadraja

 DIO C. POVEZNICE S EUROPSKOM FARMAKOPEJOM

trojezini popis opih propisa

izabrane analitike metode i postupci

izabrana poglavlja o spremnicima i materijalima za

spremnike

popis izabranih reagensa, standardnih otopina, puferskih

otopina, volumetrijskih otopina

alkoholometrijske tablice

popis izabranih poredbenih tvari

viejezini zbirni popis monografija

komentari i dopune jedinstvene za HRF2007

 DIO D. NORMIRANI IZRAZI

farmaceutski izrazi koje valja rabiti pri registraciji lijekova

 DIO E. OBAVIJESNA POGLAVLJA

tekstovi koji predstavljaju nacionalni dodatak bitan za

postavljanje normi i provjeru kakvoe lijekova
Uporaba poredbenih tvari i spektara
Osnova validacije farmakopejskih postupaka
Statistika kontrola kakvoe
Projekt HRF2007
Kako itati monografiju

FARMAKOPEJA U LJEKARNI
 za izradu magistralnih i galenskih pripravaka doputena je
uporaba sirovina koje odgovaraju farmakopejskim zahtjevima
 proizvoai definiraju kakvou sirovina prema farmakopeji i za
svaku proizvodnu seriju izdaju certifikat analize kojim
garantiraju deklariranu kakvou u roku valjanosti

 ljekarne su obvezne izvriti potvrdu identiteta

sirovina koje se rabe u izradi magistralnih i
galenskih pripravaka

Zakon o ljekarnitvu, 2003.

 U galenskom laboratoriju izrauju se galenski pripravci za
ljekarne i za zdravstvene ustanove, a prema postupcima izrade
propisanim vaeim farmakopejama ili magistralnim propisima.
 U laboratoriju za provjeru kakvoe galenskih pripravaka i
identifikaciju ljekovitih tvari obavlja se ispitivanje ljekovitih tvari i
provjera kakvoe galenskih pripravaka za ljekarne i za
zdravstvene ustanove, a prema vaeim farmakopejskim ili
magistralnim propisima.