FloVitro™

FloVitro™ provides a three-cell system to simulatehuman physiology. Samples (tablets, capsules etc.) aredropped into the Gastric Cell, where they disintegrateand start dissolving in stirred simulated gastric fluid(SGF). Pressure from the gastric fluid pump forcesliquid and small particles through the sieve, and theymove into the Intestinal Cell, just as they would movefrom the human stomach to the intestine.

Sodium hydroxide is added to raise the pH in theIntestinal Cell to 6.8, where the drug continuesdissolving in simulated intestinal fluid (SIF). Liquid ispumped from the base of the Intestinal Cell, butparticles remain because they can’t pass through thefilter (typically 3 micron). The liquid flows via UV

Analyzer 1 into the Systemic Cell, which representsthe rest of the blood plasma system. Solution fromthe Systemic Cell passes though UV Analyzer 2 beforeflowing to waste.

Absorbance is measured every 30 seconds by UVAnalyzer 2, and concentration of drug is calculated. Ifthe method is correctly designed, the concentration-time profile from FloVitro™ will have the same shapeand tmax as the in vivo profile.

Typical analytical projects have three stages –obtaining in vivo data, designing a method andrunning FloVitro™ experiments using the “originatordrug” to simulate the in vivo profile, and then usingthe same method to evaluate new formulations,generic drugs or other versions of the drug.

Application note 412/16

Comparing behaviour of ibuprofen tablets from different manufacturers with in vivo plasmaconcentration vs. time data

Sirius Analytical e sirius@sirius-analytical.com w www.sirius-analytical.com

Generating in vivo plasma concentration vs. time data is an important part of drugdevelopment – but experiments with human subjects are hard to organise and timeconsuming to perform. FloVitro™ provides biorelevant experiments in vitro that convey thesame information. This Application Note explains the FloVitro™ method, and then showshow it can be used to compare the behaviour of Advil® (the “originator drug”) and ibuprofentablets from several different manufacturers.

The FloVitro™ systemFloVitro™ technology is owned by The Dow Chemical Company. Thissystem is used to provide analyticalservices for our customers.

One API – One method

Biorelevant Dissolution TechnologyR

Application note 412/16

Sirius Analytical e sirius@sirius-analytical.com w www.sirius-analytical.com

References[1] Schettler, T. Comparative Pharmacokinetics of Two Fast-Dissolving Oral Ibuprofen Formulations and a Regular-Release Ibuprofen Tablet inHealthy Volunteers. Clin Drug Invest 2001, 21 (1), 73-78.

Biorelevant Dissolution TechnologyR

Step 1Obtain in vivo data

Schettler et al [1] ran a nonblind, randomised, three-waycrossover study in which a single oral dose of ibuprofen400mg was administered to 26 healthy malevolunteers, with a 6-day washout interval between eachdrug administration period. Their mean results forsugar-coated tablets (Advil®, the originator drug*) aresummarised here.

* Advil® is a brand of ibuprofen

Step 2Develop in vitro method using originator drug

We designed a FloVitro™ experiment that wouldgenerate a concentration-time profile similar to the in vivo profile. FloVitro™ uses a program called the“Starting point Algorithm” that calculates volumes ofliquid media to be placed in the three cells at the startof the experiment, and flow rates for the SGF and SIF.For Advil® 400 mg the starting point algorithmrecommended values listed below.

Step 3Compare other drugs

The FloVitro™ method used in step 2 was appliedwithout modification to analyse generic ibuprofentablets (2 x 200mg). The shape of the profile wassimilar to the in vivo and Advil data, and the values oftmax were similar for all experiments. However, thevalue of cmax for the generic ibuprofen was about 15%lower. Experiments like these are called “innovatorEquivalence Studies”, and can help when preparingbioequivalence studies of new formulations.

Initial cell volumes (mL)Gastric Intestinal Systemic

Flow rates (mL/min)SGF SIF

50 150 700 2.5 7.4

Scaling factor: 4.0

FloVitro™ Fasted state media

Simulated Gastric Fluid (SGF): 0.1M HCl, 2g/L NaCl, pH 1.2

Simulated Intestinal Fluid (SIF): 6.8g/L KH2PO4 at pH 6.8