BIORELEVANT DISSOLUTION TEST METHODS TO ASSES BIOEQUIVALENCE OF DRUG PRODUCTS

Transcription

1 BIORELEVANT DISSOLUTION TEST METHODS TO ASSES BIOEQUIVALENCE OF DRUG PRODUCTS Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften vorgelegt beim Fachbereich Chemische und Pharmazeutische Wissenschaften der Johann Wolfgang Goethe-Universitat Frankfurt am Main von Erika Simona Stippler (Arad, Rumanien) Frankfurt am Main 2003

2 TABLE OF CONTENTS 1 INTRODUCTION In vitro dissolution testing Applications of in vitro dissolution testing In vitro dissolution testing as a quality control tool Dissolution testing devices Factors that influence dissolution testing Factors related to the physicochemical properties of the drug Factors'related to drug product formulation Factors related to dosage form manufacture Factors related to dissolution test parameters Dissolution medium Hydrodynamics Test duration The Biopharmaceutics Classification System Outline and goal of this study 18 2 DRUGS SELECTED Highly soluble drugs Chloroquine diphosphate Metronidazole Doxycycline hyclate Poorly soluble drugs Weakly acidic drugs Potassium phenoxymethylpenicillin Ibuprofen : Indomethacin Phenytoin sodium Nonionizable drugs Carbamazepine 32 I

3 Griseofulvin Weakly basic drugs Mebendazole Erythromycin stearate Erythromycin Ethylsuccinate 38 3 MATERIALS AND METHODS Pharmaceutical Preparations Reagents Media used for solubility investigations Media used for in vitro dissolution testing Mobile phaseforthe HPLC analyses Phenytoin sodium Mebendazole, Erythromycin stearate Erythromycin ethylsuccinate Analytical Instruments Methods of Investigations Methods for solubility investigations Methods for in vitro dissolution testing Methods described in the USP Methods for the in vitro dissolution testing of drug products containing highly soluble drugs Methods for in vitro dissolution testing of drug products containing poorly soluble drugs BCS-conform in vitro dissolution testing methods Methods for in vitro dissolution testing of drug products containing highly soluble drugs Methods for the in vitro dissolution testing of drug products containing poorly soluble drugs Methods of Chemical Analysis UV-Analyses HPLC-Analyses Phenytoin sodium Mebendazole Erythromycin stearate Erythromycin ethylsuccinate Evaluation and In-Study Validation 90

4 4 SOLUBILITY INVESTIGATIONS Highly soluble drug substances Poorly soluble drug substances Influence of the ph value on the solubility Weakly acidic drugs Nonionizable drugs Weakly basic drugs Influence of the type of surfactant on the solubility of poorly soluble drug substances Solubility investigations in aqueous solutions containing surface active agents at double the CMC Solubility investigations in aqueous solutions containing surface active agents at tenfold higher than the CMC Influence of the SLS concentration on the solubility of poorly soluble drug substances Influence of SLS concentration in SGFsp ph Influence of SLS concentration in Na-SIFsp ph DISSOLUTION BEHAVIOUR OF THE PURE DRUG SUBSTANCE Comparison of dissolution behaviour of highly soluble drug substances Comparison of dissolution behaviour of poorly soluble drug substances Weakly acidic drugs Nonionizable drugs Weakly basic drugs ; COMPARISON OF DISSOLUTION BEHAVIOUR OF THE PHARMACEUTICAL PREPARATIONS Pharmaceutical Preparations of Highly Soluble Drugs Drug products containing chloroquine diphosphate Drug products containing metronidazole Drug products containing doxycycline hyclate Recommendations for dissolution testing conditions for drug products containing highly soluble drugs Pharmaceutical Preparations of Poorly soluble Drugs 181

5 6.3.1 Weakly acidic drugs Drug products containing potassium phenoxymethylpenicillin Drug products containing ibuprofen Drug products containing indomethacin Drug products containing phenytoin sodium Nonionizable drugs Drug products containing carbamazepine Drug products containing griseofulvin Weakly basic drugs Drug products containing mebendazole Drug products containing erythromycin stearate Drug products containing erythromycin ethylsuccinate Recommendations for dissolution testing conditions for drug products containing poorly soluble drugs Poorly soluble nonionizable drugs Poorly soluble weakly acidic drugs Poorly soluble weakly basic drugs DISCUSSION SUMMARY ZUSAMMENFASSUNG LITERATURE APPENDIX, Surface active agents Bile salts.: Synthetic surfactants Anionic surfactants Cationic surfactants Ampholytic surfactants Nonionic surfactants.' Physico-chemical properties of surfactants Selected surfactants for surface tension measurements Surface tension measurements Surface tension of solutions containing various bile salts 324 IV

6 Surface tension of solutions containing cationic surfactants Surface tension of solutions containing anionic surfactants Surface tension of solutions containing nonionic surfactants Fazit Influence of formulation on the in vitro dissolution behaviour Highly soluble drugs Chloroquine diphosphate Metronidazole Doxycycline hyclate Poorly soluble drugs Weakly acidic drugs Potassium phenoxymethylpenicillin (borderline BCS Class I) Ibuprofen Mdomethacin Phenytoin sodium Nonionizable drugs Carbamazepine Griseofulvin Weakly basic drug Mebendazole Erythromycin stearate Erythromycin ethylsuccinate Analytical Determination of Dissolved Drug Substances UV Analyses HPLC Analyses ABBREVIATIONS 377 V