Dissolution MarketVinod Mehta• Objective◆ Dissolution - What is it?
◆ Market and Product Situation◆ Carl Zeiss Offering◆ System Packages◆ Competition• What is Dissolution◆ Solid dosage form assays in thepharmaceutical industry◆ Release profiles of tablets or capsules in an invitro system◆ Test for measuring uniformity both within andbetween batches◆ Correlation between the in-vitro and in-vivo
for assessment of product performance• USP 1 and 11 Methods◆ Method 1 - Apparatus 1 using baskets◆ Method 11 -Apparatus 11 using paddles◆ Typically 3 to 4 time points for 1 hour test
◆ Analysis by manual, flow through to UV

spectrometer or HPLC• Market Review◆ Many dissolution bath companies ie– Vankel, Pharmatest, Hanson, Distek, Logon◆ Nearly all major spectrophotometercompanies offer systems and software tolink up to a bath
– HP, PE, Varian, Beckman, Shimadzu, Hitachi,
Unicam etc◆ Same applies for HPLC suppliers• Manual Methods◆ Time consuming and tedious– Targeted for laboratory automation long time ago– Automated off-line chemical analysis systems
available:◆ Automated dissolution baths– Zymark Multidose, Pharmatest Auto Dis✦ samples then presented to spec via autosampler

•Automated spectrometer
method◆ Samples extracted by pump throughtubing(1-2m)◆ Filters used to remove particulates◆ 8 cell programmmer with flow cells◆ Calibration of flow and recovery needs tobe checked regularly✦ These have inherent weakness:

• Disadvantages– Blockage of tubing, wear and tear - cost andtime– Filters need to be regularly changed - cost andtime– Cell transport systems never the most reliable– Calibration is a time consuming function•Zymark - Zeiss System◆ Automated filling of vessels with media◆ Automated tablet dropping◆ USP 1 and 11 apparatus◆ Control of MCS Spectrometer◆ Ability to do queued runs
◆ Automated cleaning of probe◆ Automated cleaning of vessels

•Fibre optic probe method◆ Readings directly in vessel with single

probe - no extractive problems as withtubing and filters etc◆ All readings receive same probe error iepathlength, unspecified contamination◆ Probe can be cleaned between
measurements◆ Carry over is greatly reduced

System Software◆ NT operating system◆ Security Level Access◆ User friendly◆ Secure◆ Data written to NT server◆ Automated Report Geberation

Business Advantages◆ 293 dissolutions in 31 robot days
◆ Manual@4/day = 73 days. 15 working weeks◆ 3 fold increase in productivity◆ Payback for system < 2 years

Advantages with MCS
500◆ Optimised fibre optic based system◆ PDA detection for full spectrum analysis -robust calibration methods◆ Modular units ie CLD cassette design◆ Stable - MCS patented design◆ Sensitivity

The Z-Dis-Mux SystemA Multi-Channel Dissolution MonitoringSystem

Application◆ Dissolution profiling of extended releaseformulations over 24-48 hours◆ Fast release products also possible as time
point intervals of 2 minutes can be achieved◆ Aimed at Analytical and Pharm R&D
groups involved in product enhancement
and new formulation development

Advantages◆ In-situ analysis via fibre optic probes -avoids problems related to extractive
sampling i.e. filters and tubing◆ Blank and standard readings taken during
every cycle for higher accuracy◆ All measurements and report generation areautomatic freeing operator for other tasks

System Configuration◆ VanKel 8 vessel bath with autotemp

controller and manifold for USP 1 or 2methods◆ Dicon Multiplexer◆ 1/4 in diameter probes with 2 m fibres fromHellma or CST◆ MCS 551 UV Spectrometer◆ Zeiss labView Z-Dis-Mux softwareMCS 551 UV Spectrometer with Dicon
Multiplexer

Vankel Bath with manifold

Side view of Vankel with manifold andattached F/O probes with temperaturesensors

Front view of Vankel, 6 vessel positions
and two for blank and standard on
extreme rightPaddle shaft, F/O probe andtemperature sensor

Operation◆ Vankel bath prepared for paddles or baskets◆ Vessels manually filled with media◆ All probes lowered for Interchannel Calibration◆ 2 standards placed in vessels 4 and 8 for system

suitability check◆ Standard in vessel 4 replaced with blank solution◆ System ready for run

Z-Dis-Mux Software - mainfeatures◆ LabView programme under NT linked to client

network for data storage and printout of reports◆ Security access and password protected◆ Validation screen for testing and checking status ofVankel, Dicon and MCS hardware◆ Automatic and manual operation◆ Automatic Interchannel Calibration with bubbledetection◆ Absorbance data can be viewed in Aspect software

Automatic Dissolution Run ScreenManual ScreenSample Points

Interchannel Calibration(ICC)- Why◆ 8 probes via 8 different channels of multiplexer will havedifferent transmission characteristics i.e. level of counts
will vary for a fixed integration time
◆ Multichannel system must be normalized before any
measurements otherwise false absorbance readings will be
generated as we are comparing difference in energy ofmeasurement channels with a reference channel◆ A pathlength correction factors also need to be applied for
accurate quantitative measurements as required fordissolution

ICC - How◆All vessels positions, including blank and standard are filled withmedia solution. The ICC runs automatically through the following
steps:– Acquires energy curve set to 80% of the ADC for each channeland storing the given integration times– The lowest integration time found is then used to set identicalconditions for each channel(avoids any saturation) and each energy
curve is reacquired– The channel with highest number of counts is then selected as thereference to which all energies are corrected. ICC curves computed
are a function of wavelength– ICC can be tested by running all channels again and the resulting
energy curves should be identical– Bubble detection warning is raised if the determined integration istoo high

ICC Curves

Selling Strategy◆ System uses standard, off the shelf, hardware

components◆ Proven , stable, reliable spectrometer designed for
fibre optics◆ State of art software and easy to use◆ Pfizer reference(undergoing validation)◆ Potential clients only to be handled on a projectbasis until a demo plan can be addressed