Design of Biorelevant Test Setups for the Prediction of Diclofenac In Vivo Features After Oral Administration

• Published in: Pharmaceutical research Vol. 30; no. 6; pp. 1483 - 1501
• Main Authors: Guhmann, Marie, Thommes, Markus, Gerber, Frédéric, Pöllinger, Norbert, Klein, Sandra, Breitkreutz, Jörg, Weitschies, Werner
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.06.2013; Springer; Springer Nature B.V
• Subjects: Administration, Oral; Biochemistry; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering and Bioengineering; Biomedicine; Body fluids; Chemistry, Pharmaceutical - methods; Diclofenac - administration & dosage; Diclofenac - chemistry; Diclofenac - metabolism; Dissolution; Drug delivery systems; Gastric Emptying - physiology; Hydrogen-Ion Concentration; Intestinal Absorption - physiology; Medical Law; Medical sciences; Models, Biological; Mouth; Particle Size; Pharmaceutical sciences; Pharmaceutical Solutions - administration & dosage; Pharmaceutical Solutions - chemistry; Pharmaceutical Solutions - metabolism; Pharmacology. Drug treatments; Pharmacology/Toxicology; Pharmacy; Research Paper; Saliva - metabolism; Saliva - physiology; Solubility; Stomach - metabolism; Stomach - physiology; Suspensions - administration & dosage; Suspensions - chemistry; Suspensions - metabolism; orodispersible tablets; biorelevant test setups; diclofenac; multiple absorption peaks; mouth exposure; Prostaglandin-endoperoxide synthase; Enzyme; Orodispersible form; Prediction; Oral administration; Enzyme inhibitor; Diclofenac; Non steroidal antiinflammatory agent; Design; In vivo; Arylacetic acid derivatives; Absorption; Analgesic; Dosage form; Antipyretic; Tablet; Oxidoreductases; Pharmacokinetics
• ISSN: 0724-8741; 1573-904X
• DOI: 10.1007/s11095-013-0974-y

ABSTRACT Purpose Design of biorelevant test setups mimicking the physiological conditions experienced by drugs after oral administration along the passage through the mouth and the GI tract for the in vitro evaluation of diclofenac exhibiting multiple-peak phenomenon during absorption. Methods The biorelevant models simulated successively saliva (SSF, pH 6.2–6.75–7.4, 5 mL, 3 min), gastric (SGF-FaSSGF, pH 1.2–1.6, 50–250 mL, 30 min) and intestinal (FaSSIF, pH 6.8, 250 mL, 60 min) fluids. Applying these models, diclofenac free acid and its sodium/potassium salt were comparatively evaluated for dissolution and further characterized by HPLC, optical morphogranulometry, DSC and PXRD to elucidate peculiar behaviors. Results Diclofenac salts almost completely dissolved in SSF and showed a transitional dissolution pattern before complete precipitation in SGF/FaSSGF. This peculiar pattern correlated with simultaneous chemical modification and formation of agglomerates. With low dissolution in SSF and almost immediately complete precipitation, these behaviors were not observed with diclofenac free acid. Distinct diclofenac features were strongly determined by pH-modifications after oral administration. Conclusions The multiple-peak phenomenon observed after administrating a solution, suspension or dispersible formulation of diclofenac salts are likely caused by drug precipitation and agglomeration in the stomach leading to irregular gastric-emptying. Diclofenac free acid may provide more reliable in vivo features.