Pharmaceutisch weekblad

, Volume 1, Issue 1, pp 1171–1204 | Cite as

Joint international quality control programme on the determination of antiepileptic drugs

  • I. C. Dijkhuis
  • H. J. De Jong
  • A. Richens
  • C. E. Pippenger
  • E. E. A. Leskinen
  • A. P. W. Nyberg
Original Articles Related to the Theme


In a joint effort, 4 existing Quality Control programmes organized in September 1978 a test on the determination of antiepileptic drugs and made an inventory of the various methods of analysis used.

To approx. 700 laboratories 3 lyophilized calf s serum specimens, each of them spiked with 8Ae drugs, were distributed together with an extensive questionnaire. The number of laboratories reporting results, were: phenobarbital 601, phenytoin 624, carbamazepine 398, 10, 11- epoxide-Cbz 15, primidone 434, ethosuximide 302, valproic acid 167 and clonazepam 26; approx. 95% of them also completed the questionnaire.

As to themethods per Q.C. programme,Emit was mainly used in USA,Glc in Europe,Hplc in USA (Rp systems) and in The Netherlands (sp systems),Ria in USA and Scandinavia.

As to theresults per method,Emit, Glc andHplc produced similar results in therapeutic and sub-toxic concentrations ofPb, Dph andPri; in the sub-therapeutic range of these drugs,Glc andHplc gave better results thanEmit (which produced values 10–20% higher than the theoretical ones).

InEsm andVal, Glc-methods are preferred while inCbz, Hplc is the method of choice, followed byEmit. InClona, severalGlc andHplc methods are still under investigation. Spectrophotometric determinations (mainly used inPb, Dph andCbz) proved to be not reliable.

In tables, results per technique are subdivided into approx. 5 methods. This enables to distinguish betweene.g.Glc-derivatization with and without previous clean up or betweenEmit-automatic < 10Μl and 50Μl samples. Per drug, the various methods of assay are discussed; also, methods and results are given when drugs were determined simultaneously. Bovine serum (calfs serum) proved to be a suitable matrix in all methods used.


Carbamazepine Valproic Acid Phenobarbital Clonazepam Primidone 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations and symbols

Apparatus and analytical techniques


alkaliflame ionization detection or nitrogen detection,used in GLC


electron capture detection,used in GLC


enzyme multiplied immunoassay technique


flame ionization detection,used in GLC


gas liquid chromatography


high pressure liquid chromatography


reversed phase,used in HPLC




straight (or normal) phase,used in HPLC


thin layer chromatography

Drugs, internal standards, reagents


(D) antiepileptic (drugs)








α,α-dimethyl-Β-methylsuccinimide,int. stand. for ESM


phenytoin, 5,5-diphenylhydantoin

ep. CBZ

10,11-epoxide-carbamazepine,metabolite of CBZ



int. stand.

internal standard


5-methylphenobarbital, 5-ethyl-5(p.methylphenyl) barbituric acid,int. stand, for PB


-5-(p.methylphenyl)5-phenylhydantoin,int. stand, for DPH


4-methylprimidone,int. stand, for PRI


α-methyl-α-propylsuccinimide,int. stand, for ESM


naphthenic acid, cyclohexane carboxylic acid,int. stand, for VAL






tetramethylammonium hydroxide


trimethylphenylammonium hydroxide


valproic acid, dipropylacetic acid



Bartholomew's Hospital, Quality Control


(1973) British Pharmacopoeia (1973)

cl. up

clean up






number of results, tests, laboratories etc.


total number of N


number of rejected N (deviation from ¯x is > 3 sd)


quality control


retention time


standard deviation


temperature (in ‡C)


coefficient of variation


mean value

¯x, (%)

mean value in percentages relative to the weighed-in value


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Copyright information

© Bohn, Scheltema & Holkema 1979

Authors and Affiliations

  • I. C. Dijkhuis
    • 1
  • H. J. De Jong
    • 2
  • A. Richens
    • 3
  • C. E. Pippenger
    • 4
  • E. E. A. Leskinen
    • 5
  • A. P. W. Nyberg
    • 5
  1. 1.Department of Clinical Pharmacy and ToxicologyThe Hague Hospitals Central PharmacyThe HagueThe Netherlands
  2. 2.Department of Analytical Chemistry and Pharmaceutical Analysis, Gorlaeus LaboratoriesState University of LeidenLeidenThe Netherlands
  3. 3.Institute of NeurologyLondonEngland
  4. 4.Columbia University,College of Physicians & SurgeonsDepartment of NeurologyNew York
  5. 5.Department of Clinical LaboratoryKivelä HospitalHelsinkiFinland

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