Evaluation Of Dissolution/Release Kinetics Of Instable Drugs From Dosage Forms Based On Determination Of The Stable Degradation Products

Purpose: To develop a rapid, sensitive and accurate method for the determination ofroxithromycin and roxithromycin impurity B in dissolution/release medium by liquidchromatography-mass spectrometry (LC-MS/MS), the assay was successfully appliedto determine the content of stable degradation product: roxithromycin impurity B, andthe dissolution/release kinetics of roxithromycin dosage forms was evaluated in asimulated human physiological pH environment. At the same time, the concept ofstable degradation products of instable drug was proposed in order to apply it to theevaluation. The acidic degradation product, roxithromycin impurity B ofroxithromycin, has been prepared and its structure and purity were accuratelyidentified. The dissolution/release kinetics of roxithromycin dosage forms has beenevaluated through the stable degradation product: roxithromycin impurity B toprovide the evaluation of control of the quality and the dissolution and release kineticsof the dosage forms of the instable drugs with a new method.Methods: According to the state regulations and published papers concerned, a rapidand sensitive method has been developed and validated for determination ofroxithromycin, the degradation kinetics of roxithromycin was explored under thecondition of the simulated human physiological pH environment, different buffers,various temperatures and three-level concentrations of roxithromycin.The concept of stable degradation product was proposed for a method for thedermenation of prototype drug. The acidic degradation product, roxithromycinimpurity B of roxithromycin, has been prepared and its structure and purity have beenidentified by LC-MS, NMR and HPLC. Meanwhile, roxithromycin impurity B wasproved as main degradation product of roxithromycin in acidic solution. A rapid andsensitive method for the determination of roxithromycin impurity B by LC-MS/MSwas developed and validated, and the assay was successfully applied to evaluate thestability of roxithromycin impurity B in artificial gastric fluid in2hours and thestability during12hours in its artificial intestinal fluid as well as in the dissolutionmedium of roxithromycin preparation prescribed in present China Pharmacopeia. To develop a rapid, sensitive and accurate method for the determination ofroxithromycin and roxithromycin impurity B in dissolution/release medium byLC-MS/MS, the assay was successfully applied to determine the concentration ofstable degradation product, namely, roxithromycin impurity B, and through which thedissolution/release kinetics of roxithromycin preparations was evaluated in asimulated human physiological pH environment according to present ChinaPharmacopeia for the dissoulution/release of roxithromycin preparations. The assaywas validated systematically.Results: According to the regulations and published papers concerned, the kinetics ofroxithromycin was explored under the condition of physiological pH value in human,different buffers, various temperatures and three-level concentrations ofroxithromycin. The results indicated that the degradation of roxithromycin follows thefirst-order reaction kinectics.The concept of stable degradation product of instable drugs was proposed toevaluate the dissolution/release kinetics of instable drug from the dosage forms. Theacidic degradation product, roxithromycin impurity B, has been prepared andidentified with a purity of96.1%and used as reference substance in the research.Roxithromycin impurity B was proved as main degradation product of roxithromycinin acidic solution. The stability of roxithromycin impurity B in artificial gastric fluidin2hours and the stability during12hours in its artificial intestinal fluid as well as inthe dissolution medium of roxithromycin dosage forms in China Pharmacopeia hadbeen explored, and proved to be stable.A rapid, sensitive and synchronous method for the determination ofroxithromycin and roxithromycin impurity B in dissolution/release medium byLC-MS/MS was developed and validated, and was successfully applied to determinethe concentrations of the stable degradation product, roxithromycin impurity B,through which, the overall dissolution/release kinetics of roxithromycin preparationswas evaluated in a simulated human gastric fluid and the medium listed in presentChina Pharmacopeia for the test of the dissolution/release of roxithromycin dosageforms. The result indicated that roxithromycin mostly degraded into roxithromycin impurity B during the process of dissolution and release in pH1.0medium, whileroxithromycin extended release tablet was degradated by67.8%during2hours inartificial gastric fluid. The overall characteristic of dissolution/release kinetics ofroxithromycin dosage form was determinated accurately through the concentration ofthe stable degradation product, roxithromycin impurity B, in the above-mentionedcondition. After fitting into zero-order, first-order and Higuchi kinetics equation, thedissolution of roxithromycin dispersible tablets was well fitted with Higuchi equationin pH1.0hydrochloric acid solution and roxithromycin capsules and extended releasetablets followed the first-order kinetics equations.Conclusion: The degradation kinetics of roxithromycin is first-order in the differentmedia prescribed in the research. The concept of stable degradation products wasproposed to develop a method for determing the concentration of the stabledegradation product of the instable drug. Roxithromycin impurity B, acid degradationproduct of roxithromycin, was successfully prepared and identified. Stability ofroxithromycin impurity B was investigated in artificial gastric fluid in2hours andstability during12hours of the artificial intestinal fluid as well as in the dissolutionmedium of roxithromycin dosage forms in the present China Pharmacopeia. Methodfor determination of roxithromycin and roxithromycin impurity B by LC-MS/MS hasbeen successfully established, validated and applied to test the dissolution/releasekinetics of instable drug dosage forms through the stable degradation product toprovide a new method for evaluating dissolution/release kinetics of the dosage formsof instable drugs and quality control.