ToDo: Successful Dissolution Testing

ToDo: Successful Dissolution Testing

PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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+49 6182 9532-600 +49 6182 9532-650 [email protected] www.pharma-test.com

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Automation Techniques in Dissolution Testing ................................................................................ 4 A Guide to Successful Dissolution Testing ...................................................................................... 5 Introduction:...................................................................................................................................... 5 3.1 What do we need to do?............................................................................................................. 5 3.2 How can we measure what is in the sample? ............................................................................ 6 3.3 Off-line or On-line? ..................................................................................................................... 6 4 Elements of Automation…. .............................................................................................................. 6 4.1 Off-line Systems (DFC) .............................................................................................................. 6 4.2 Peristaltic or Piston Pump for sample transportation ................................................................. 7 4.3 DSR Sampling Robot - sampling, diluting, injecting................................................................... 8 4.4 ASP 2000 Auto Sampler - sampling from up to 16 vessels - dilution - injection ........................ 8 4.5 On-line HPLC Systems............................................................................................................... 9 4.6 On-line Systems ....................................................................................................................... 10 5 Keeping the cost sensible…........................................................................................................... 11 5.1 ADS-DT70 ................................................................................................................................ 12 5.2 ADS-PTWS100......................................................................................................................... 13 5.3 ADS-PTWS610......................................................................................................................... 14 5.4 ADS-PTWS1210....................................................................................................................... 14 5.5 ADS-PTWS310......................................................................................................................... 15 5.6 Spectrophotometers Drivers..................................................................................................... 16 6 On-line HPLC operation ................................................................................................................. 17 7 DTS 800 The “All-in-One” Compact Dissolution Analyser ............................................................. 19 8 IDS 1000 “In-Situ” Fibre Optic Dissolution Test System ................................................................ 20 9 The WinDiss32 Software Platform ................................................................................................. 21 10 Dissolution Automation: Key Points for Consideration .................................................................. 23 10.1 Which dosage forms can we characterise with a dissolution test?...................................... 25 10.2 The Dissolution test is made up of the following processes: ............................................... 25 10.3 We have looked at the various dissolution options.............................................................. 25 10.3.1 What about measurement techniques? Normal options: .............................................. 25 10.3.2 How do I know which technique should be used?........................................................... 25 10.3.3 Why can’t I always use a UV-VIS Spectrometer? ........................................................... 26 10.4 How should we take a sample for analysis? ........................................................................ 26 10.4.1 How can we take a sample for manual analysis?............................................................ 26 10.4.2 Why should I filter the sample?........................................................................................ 26 10.4.3 What size filter should I use?........................................................................................... 26 10.5 How can I use my UV Spectrometer to look at various materials with different absorbencies and different concentration levels? .................................................................................................... 27 10.6 How do I know that my response from the UV measurement is linear?.............................. 27 10.6.1 What are the steps or “Unit Processes” needed in a typical analysis? ........................... 27 10.7 Medium Preparation............................................................................................................. 27 10.8 Medium Degassing and Dosing ........................................................................................... 27 10.9 Standard Preparation ........................................................................................................... 28 10.10 Introduce the Sample ........................................................................................................... 28 10.11 Stirring the Sample Solution................................................................................................. 28 10.12 Sampling .............................................................................................................................. 28 10.13 Analyse the Sample ............................................................................................................. 28 10.14 Calculate the concentration.................................................................................................. 28 10.15 Print Out the Results ............................................................................................................ 29 11 Automation: What can I automate and what are the benefits? ..................................................... 29 11.1 Why Should I Automate? ..................................................................................................... 29 11.2 What Can I Automate?......................................................................................................... 29 11.3 Medium Preparation using the PHARMA TEST Media Prep and Dosing System .............. 29 11.4 Medium Dispensing.............................................................................................................. 29 11.5 Tablet Introduction ............................................................................................................... 29 PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing 11.6 Sampling .............................................................................................................................. 29 11.7 Analysis ................................................................................................................................ 30 12 Calculation of Results .................................................................................................................... 30 12.1 Documentation ..................................................................................................................... 30 13 Automated System Options ........................................................................................................... 30 14 Automation: Limitations and potential Problems............................................................................ 30 15 Know the Limits .............................................................................................................................. 31 16 Water Quality.................................................................................................................................. 31 17 Deaerated Medium......................................................................................................................... 31 18 Filtration of Medium and Samples.................................................................................................. 31 19 Absorption of Active Materials in Automated Systems .................................................................. 31 20 Concentration Differences.............................................................................................................. 31 21 Buffer Changes .............................................................................................................................. 31 22 Poor Absorption.............................................................................................................................. 31 23 What is impossible to Automate ?.................................................................................................. 31 24 What does PHARMA TEST offer ? ................................................................................................ 32 25 SOP : USP Dissolution Instrument Calibration or PQ.................................................................... 32 25.1 Introduction:.......................................................................................................................... 32 25.2 General Description: ............................................................................................................ 33 25.3 Details of the above: ............................................................................................................ 33 26 Differences between Automatic and Manual Measurements. ....................................................... 37 27 The Tablets .................................................................................................................................... 38 28 Medium Deaeration:....................................................................................................................... 40 29 Other Observations: ....................................................................................................................... 41 30 Vibration ......................................................................................................................................... 42 31 The Influence of Vibration on Dissolution Tests............................................................................. 43 31.1 What can go wrong? ............................................................................................................ 43 31.1.1 So this takes care of the De-aeration issue. What about Vibration? ............................... 43 31.1.2 Internal Sources............................................................................................................... 44 31.1.3 External Sources.............................................................................................................. 45 31.1.4 Intermittent and Operational Sources.............................................................................. 45 31.1.5 So what can modern dissolution tester designer do for you regarding Vibration? .......... 46 31.1.6 What is different about these instruments with the newer critical design features?........ 46 31.1.7 Pump and Heater Installation .......................................................................................... 46 31.1.8 The Water Bath Installation ............................................................................................. 47 31.1.9 The Effect of Environmental Vibration Sources............................................................... 48 31.1.10 Conclusions ................................................................................................................. 48 32 Test Medium Preparation:.............................................................................................................. 49 33 Standard Solution Preparation: ...................................................................................................... 49 34 Sampling: ....................................................................................................................................... 50 35 Special precautions:....................................................................................................................... 50 36 Procedure:...................................................................................................................................... 51 37 Dissolution Automation: Basic Questionnaire. .............................................................................. 52 38 USP Reference Tablets Result Documentation (Example)..................................................... 55 38.1 Repeated Test..................................................................................................................... 55


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1

Automation Techniques in Dissolution Testing

On-line - closed loop ADS Automated closed loop Dissolution Test Systems Automated closed loop Dissolution Test Systems incorporating various spectrophotometer versions DTS 800 “All-in-One” Compact Dissolution Analyser Fully automated closed loop Dissolution Testing System including built-in sample transfer pump and Diode-Array UV/VIS Fibre Optic Spectrophotometer IDS 1000 “In-Situ” Fibre Optic Tablet Dissolution Test System Fibre Probes are used to analyse the active concentration directly inside the media, no more sample transfer, much shorter sample information, faster cleaning, lower running costs Off-line - open system DFC: Semi automated Dissolution Test Systems for online Sampling and/ob Media Preparation


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ToDo: Successful Dissolution Testing Software Platform WinDiss32 : 21CFR Part11 compliant Software, an Overview

2

A Guide to Successful Dissolution Testing

3

Introduction:

3.1

What do we need to do?

The perception of automation in dissolution testing differs greatly from user to user. If measurements are to be manually made then the most labour intensive stage is the taking of samples at the specified time periods as found in the company SOP (Standard Operating Procedure). This normally involves the taking of 6 samples according to the USP and most

Figure 1

other Pharmacopoeia, and therefore for manual operation, there is a requirement for a staggered stirrer start in most cases so that accurately timed sampling may be achieved. At this point the operator must also consider either replacing the collected sample volumes in the dissolution vessels with blank dissolution medium or keeping an accurate record of the volumes taken from each vessel so as to be able to calculate the true or corrected concentrations of subsequent samples. This is not so important for a “one-off” sampling as with USP Calibrator Tablets (for so called Suitability Tests) where only a single sample per vessel is required after 30 minutes. See Figure 1. A further complication can arise where sampling intervals are more frequent in the initial dissolution phase and drop to maybe one in every half hour in the final phase. Manual Sampling with an In-line 5 or 10 µm Filter (part No: 303-0105 + 303-0102) 5 µm or 10 µm Sinter Filter attached at the tip of the stainless steel sampling probe Order No. 31-63211-50 (10 µm ) - 31-63511-50 ( 5 µm)


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ToDo: Successful Dissolution Testing 3.2

How can we measure what is in the sample?

Then there is the measurement of the samples: these can be kept for a multiple analysis option in a fraction collector - auto sampler or measured directly in a spectrophotometer. The automation alternatives for this relatively labour intensive series of manipulations and measurements are based therefore on sample taking and sample measurement options. Automated tablet dissolution rate testing is normally performed using one, two, or a hybrid system of the available techniques. 3.3

Off-line or On-line?

Off-line refers to the use of switching or rotating valves when you have more test vessels than you have available flow cells (e.g., a spectrometer with a single flow cell) or you wish to use a Fraction Collector or an Auto Sampler. On-line refers to the use of a Dissolution Bath plus a Pump plus a UV / VIS spectrophotometer equipped with a Multi-Cell Changer. The multi-valve or port dissolution system (Off-line version) can allow the multiplexing of several dissolution baths at the same time for greater sample throughput with obvious cost per analysis benefits. This type of system requires more time in terms of initial method development, but once a protocol is established, then the method is ready to run without further intervention. Special care has to be given to possible “carry over or cross contamination” problems as all samples run through a common tubing line into the flow-cell of the spectrophotometer. Usually this techniques is used when the same drug but different batches (lots) has to be tested. Another off-line application is the use of a Fraction Collector or Auto Sampler The multi-cell dissolution system (On-line version) provides real time sample measurement. There is no volume lost and no contamination is possible between sample vessels or carry over from one sample sequence to the next due to individual tubing installation. Another feature is high sample throughput with the ability to analyse rapidly dissolving tablets as well as offering user friendly test method development.

4

Elements of Automation….

4.1

Off-line Systems (DFC)

The basic elements of an automated off-line dissolution system are the Dissolution Tester, a Sampler, and a pumping system. These are then generally controlled by the Dissolution Bath or with a PC and a special software package. There is one exception to this and this economic system comprises a Dissolution Tester (normally anyone of PHARMA TEST Dissolution series) plus a Pump and a Fraction Collector (Pharma Test PTFC 2, DSR, or ASP 2000). In this case control is enabled from the PHARMA TEST dissolution bath which has a connection to both the fraction collector PTFC2 and DSR and the pump. Sampling PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing intervals are programmed into the PHARMA TEST dissolution bath. Times required for the filling of connecting tubing, sampling time (to fill the vials), and the time required to empty the pump tubing back into the dissolution vessels are selected at the PHARMA TEST Fraction Collector or DSR Sample Handler. Although this basic off-line system is self contained, the user must be aware of the necessity to introduce relevant calculation factor to account for the loss of dissolution medium during successive samplings. This set up may also be controlled by PC and in this case all connections to the basic elements, i.e., dissolution tester, pump and fraction collector are made via the PC and the WinDiss32 software platform. The most economical DFC system comprises a Dissolution Tester, a Sampling Manifold an 8 channel Peristaltic Pump (IPC 8) and a PT FC 2 Fraction Collector. Control is either from the Fraction Collector side or via the keypad of the connected PTA Dissolution Bath. So sampling sequences are available at fixed intervals. Using a 16 or 24-channel peristaltic pump auto-media-refilling is possible too http://www.pharma-test.de/en/products/p20_8.htm

4.2

Peristaltic or Piston Pump for sample transportation

PT-PS80 Peristaltic Pump

CAT 8 Piston Pump

IPC Peristaltic Pump

A peristaltic pump is a liquid transportation device and as such not as accurate as a metering pump, piston pump, or syringe pump system. But for a lot of applications its use is possible if volume calibration is often done previous to its use. The dosing accuracy of a peristaltic pump depends on the quality of the pump tubing, the speed and of course a proper adjustment of the pump channels. The pumps are available with 8-, 16-, and 24-channels PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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The CAT valve less Piston Pump The piston pump is made from a cylinder and a piston which are dosing the media very precisely. The valve less pump doses between 0,2 - 10,00 ml/min. with an accuracy of ± 0.5% of the total volume. It includes a rinse port which protect the pumps against destruction by the used media. The CAT pump is available with 6-, 8-, and 12 pump heads. 4.3

DSR Sampling Robot - sampling, diluting, injecting

The Pharma Test DSR (Dissolution Sampling Robot) provides a neat solution to this automation procedure. To offer the highest volume precision, between 6, 8 and 12 Piston Pumps are used for sample removal and media refilling (if required). No time consuming pump calibration is needed. The advanced design of the system means that it is always ready for operation. The sample preparation station, Z-arm and needle, can be used to dispense into sealed vials or dilute and/or inject into a single cell Spectrophotometer. Keeping the samples in sealed vials helps avoid evaporation, specially if sustained release samples are tested. http://www.pharma-test.de/en/products/p20_6.htm 4.4

ASP 2000 Auto Sampler - sampling from up to 16 vessels - dilution - injection

The AUTO SAMPLER ASP 2000 and sample preparation features can be used to process samples collected from 1 or 2 dissolution baths or by other means, i.e., samples that are manually collected or collected by conventional Fraction Collector PTFC2 etc. PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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The ASP 2000 utilises two probes; a multiple probe consisting of up to 8 Needles which can be used for sampling and a single needle probe can be used for Dilution and or Injection into a UV/VIS Spectrophotometer or a HPLC System. The ASP 2000 is controlled by the WinDiss32 Software Platform. http://www.pharma-test.de/en/products/p30_10.htm 4.5 On-line HPLC Systems The WinDiss32-V3 integrated solutions provide a unique analytical system for customers to configure analysis for online and offline Dissolution testing using Pharma Test Dissolution instruments, ASP 2000 Sample Processing Unit and an Agilent HPLC using Chemstation™ software or a Waters™ System using Empower CDS software. And that is it. Let the system take care of the rest. The automatic tablet drop magazine makes sure that the tablets are dropped synchronously when required. The dissolution tester will start automatically and see that tool speed and bath temperature are maintained throughout the test. Samples can be transferred via a pump or syringe transfer module to the collection arm of the ASP 2000. The sets of collection tubes or HPLC vials will be filled in rotation. Sample tubing is emptied after every sample transfer, ready for the next sample set. An intelligent Z axis arm on the ASP 2000 now starts with sample transfer with or without dilution. If dilution is required then this is accomplished by transfer, dilution and mixing in a second set of vials. In the meantime, if a second set of samples is to be collected, then the Z axis arm will put the sample processing step on hold and then wait for the signal to start the pump and make a sample transfer from the dissolution vessels. Once finished, the sample processing will recommence. Injection into an HPLC pump is handled by the software. Full Communication…


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ToDo: Successful Dissolution Testing ALL data is collected: bath and vessel temperatures, tool speed rates, measured UV absorptions, calculated % of API dissolved, mg of API dissolved and current COMBINED Dissolution / HPLC status are displayed live on screen at all times. WinDiss32-V3 integrated solutions provide two way communication with Chemstation and Empower. Results are calculated in real time and are stored using the power of Oracle™ database and are available anywhere on the company’s network that has an WinDiss32-V3 integrated solutions client installed. This Automated Tablet Dissolution Analytical System provides unprecedented performance over and above that of any other HPLC dissolution system.

4.6

On-line Systems

The second popular configuration is more elaborate, but allows real time calculation of results using WinDiss32 software and is by definition PC controlled. In this case, the dissolution system elements have to be entered into the program structure and this includes the type of spectrophotometer used and whether it has a cuvette changer or not. These systems are practically regarded as being semiautomated as the operator still has to introduce the tablets and clean the system after use. The automated procedures are Sampling, Sample transportation, Measurement, Data Handling, and Reporting. With this spectrophotometer and multi-cell changer configuration, the basic automation elements are entered into the WinDiss32 program structure. This data, once installed, will cause the PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing software to further interrogate the user as to the configuration of the automation elements. Taking the spectrophotometer as an example, the program needs information as to whether there is a cuvette changer or not and if so, then is it a 6- or 8- way or more. This is vital information as the blank medium has to be compared to the reference cell, and zeroed at the appropriate wavelength. In the case of the 6 cell changer this is done on cell 1 at the start of the measurement cycle only, whereas with an 8 way changer, the blank medium is normally selected to be transferred to cell 7, with the standard (for concentration calculation) in cell 8. This means that the medium can be compared to the reference cell and zeroed at the start of each measurement sequence. After the zero has been established the measurement sequence is then cell 8, followed by cells 1 to 6. There are many Spectrophotometers available for connection to Pharma Test Dissolution systems. An ideal solution is the SA500 Diode Array UV/VIS Spectrophotometer which can be equipped with an 8-cell changer for cell sizes between 0.1 and 20mm path length or a 16cell changer with cells up to 10mm path length. All the control cycles, such as sampling intervals etc., are entered into the software framework, which is easy to manage as it is menu driven. Methods are constructed, stored and then selected for the appropriate product. Product specific data are entered and then attached to a stored method. Tests are then ready to run. Once obtained, product dissolution data are stored for printing and / or archiving. This archiving system may then be used at a later date to perform batch comparison.

5

Keeping the cost sensible….

We, at Pharma Test are offering three complete systems which have not only differing degrees of sophistication but which also offer affordable options to cover all budgets. These PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing are the ADS options. Select a suitable Spectrophotometer of the list of available Drivers and include it into the WinDiss32 software platform. As the WinDiss32 Software offers a huge variety of different pump, spectrophotometer, sampler and dissolution bath drivers the advantage to the user is obvious: qualify and validate the software package once and stay flexible in the use of your equipment. If there is a need to change just qualify and validate a new driver instead of a new software product. 5.1

ADS-DT70

The most economical offer is the ADS-DT70 system and this comprises a 7-stirrer flip-back PT-DT70 Dissolution Tester, an in-situ Sampling Manifold including Teflon tubing installation, an 8 channel Peristaltic Pump and the WinDiss32 software platform including all necessary drivers and cables. Sampling sequences are controlled from the software. Prior through an in-line filter primed samples are pumped in a closed loop from the dissolution vessel to the sample cuvette inside the cell changer of the spectrophotometer of your choice. The pump is halted and the measurement sequence started. As there are only 7 vessels in the PT-DT70 and 6 are reserved for the samples, the 7th is normally allotted to the blank medium which is pumped through cuvette 7. This is where the blank is zeroed (at the start of a measurement sequence). Options for the concentration calculation are either using the 8th cuvette inside the cell changer of the spectrophotometer filled with standard or entering in a known 100% Absorbance value for the active material under study. Alternatively one can use a standard profile (Calibration curve which must be stored before hand) or an Absorbance / mg

interpolation. All results from successive real time measurements are displayed on the PC screen and immediately stored. At the end of the pre-programmed sequence, the dissolution PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing / time profile as well as the final concentration of active in solution may be displayed or printed prior to storage. http://www.pharma-test.de/en/products/p30_3.htm 5.2

ADS-PTWS100

The next step is to have a 6-vessel Lift-Up PTWS 100 system with staggered stirrer start option and an in-situ Sampling Manifold, an 8 channel Peristaltic Pump and the WinDiss32 software platform including all necessary drivers and cables. As with all sampling systems reusable in-line filters are attached to the sampling tubes which are permanently placed in the dissolution vessel according to the USP directive which states that the sampling point must be exactly half way between the dissolution medium surface and the top of the paddle. At the appropriate pre-programmed time the pump will be switched on and the sample lines to the cuvettes filled as before. As the PTWS 100 is fitted with 6 vessels, then cuvette 8 can be filled with a fresh standard and civette 7 with a Blank Reference. From this vessels a reading is taken each time prior to the measurement sequence. This has an advantage in that minor variations in absorbance values encountered over a series of measurements can be compensated for as each set of measurements is made relative to a standard which has been treated in exactly the same way as the samples. At the end of the pre-programmed sequence, the dissolution / time profile as well as the final concentration of active in solution may be displayed or printed prior to storage.

http://www.pharma-test.de/en/products/p30_1.htm PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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5.3

ADS-PTWS610

There is the lift-up 8 vessel (6 in front and 2 in the back) PTWS 610 based configuration with a staggered stirrer start option, with EPE Auto-sampling Manifold, with ITM individual media temperature monitoring system attached to the EPE, manual Tablet Drop Magazine, 8 channel Peristaltic Pump and WinDiss32 software platform including all necessary drivers and cables. The added advantage of this option is that the sampling probes of the EPE are only in the dissolution medium when sampling is required and during this time the media temperature is measured and stored. The EPE and ITM are raised out of the bath after the sampling sequence is complete. This fulfils the other school of thought that sampling probes should only be in the solution for a minimum period so as to avoid unnecessary solution perturbation. Again, the sampling tubes may be fitted with 5 or 10 micron in-line filters so as to avoid the passage of insoluble excipients into the measurement cells. As the DT8, the PTWS 610 option is fitted with 8 vessels, so cuvette 8 can be filled with a fresh standard

each time prior to the measurement sequence. http://www.pharma-test.de/en/products/p30_5.htm 5.4

ADS-PTWS1210

There is the lift-up 12 vessel (6 in front and 6 in the back plus 2 extra beakers) PTWS 1210 based configuration, with EPE-12 Auto-sampling Manifold, with ITM individual media temperature monitoring system attached to the EPE, manual Tablet Drop Magazine, 16 PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing channel Peristaltic Pump and the WinDiss32 software platform including all necessary drivers and cables. The added advantage of this option is that 2 batches of tablets can be tested at the same time within the same environment and that the sampling probes of the EPE-12 are only in the dissolution medium when sampling is required. The EPE-12 and ITM are raised out of the bath after the sampling sequence is complete. Again, the sampling tubes may be fitted with 5 or 10 micron in-line filters so as to avoid the passage of insoluble excipients into the measurement cells. The PTWS 1210 option is fitted with two rows of 6 vessels taking the samples plus 2 extra vessels, so cuvette 16 can be filled with a fresh standard each time prior to the measurement sequence while cell 15 can be filled with Blank

medium. http://www.pharma-test.de/en/products/p30_8.htm 5.5

ADS-PTWS310

There is the lift-up 4+4 vessel (4 in front and 4 in the back) PTWS 310 based configuration, with EPE Auto-sampling Manifold, with ITM individual media temperature monitoring system attached to the EPE, 8 channel Peristaltic Pump and the WinDiss32 software platform including all necessary drivers and cables. Also the PTWS310 uses the sampling probes of the EPE which are only in the dissolution medium when sampling is required. In addition a ITM Media Temperature Monitoring system is attached to record and file the actual media temperature during sampling. The EPE and ITM are raised out of the bath after the sampling sequence is complete. Again, the sampling tubes may be fitted with 5 or 10 micron in-line PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing filters so as to avoid the passage of insoluble excipients into the measurement cells. The PTWS 310 option is fitted with 8 vessels, 6 taking the samples plus 2 extra vessels, so cuvette no. 8 can be filled with a fresh standard each time prior to the measurement sequence while cell 7 can be filled with Blank medium. Also the PTWS310 comes with a manual Tablet Drop Magazine as the drop of the samples and stirrer start will be done

simultaneously as all samples are measures simultaneously. http://www.pharma-test.de/en/products/p30_4.htm 5.6

Spectrophotometers Drivers.

Although the basic systems may be linked to any spectrophotometer having both 6, 8, o 16 cell changer and of which a Driver is available for the WinDiss32 Software Platform we would like to recommend the use of the SA500 Photo Diode Array Spectrophotometer or the T70 Monochromator double beam UV/VIS Photometer. The obvious advantage for the customer is what we call “system responsibility”. All instruments incorporated with the automated Dissolution System are made by PHARMA TEST and so serviceable by Pharma Test and its authorized dealers. Another important advantage using a PDA (DAD) spectrophotometer compared to a common Monochromator one is the very high scanning speed compared to a standard monochromatic instrument. In less than 12 ms a full scan within the range of 190 to PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing 1000 nm is taken and transferred. This reduces sampling sequence time to 1 minute offering full scan information. There are many other varieties of spectrometer to which a Pharma Test Dissolution Bath may be connected. The requirement as far as the software is concerned is that there is a suitable “Driver” in the WinDiss32 software architecture to allow various command communications to take place. Below is a list, which is by no means exhaustive, of the alternative spectrometers currently controllable under WinDiss32: Pharma Test (SA 500 Diode Array - 8 or 16 cell changer) Pharma Test (T70+ UV/VIS Double Beam - 8 cell changer) Agilent (Diode Array 8453A 6, 7 or 8 cell changers) Perkin Elmer (Lambda series - 8 or 16 cell changers) Shimadzu (1201, 1202,1601. 2401, 2501 - 6 or 8 cell changers ) Pye (8600 and 8625 - 6 or 8 cell changers) Büchi (901) Cecil (2000, 3000, 5000, 6000, 8000, 9000 series - 6 or 8 cell changer) Jasco 500 and 700 series - 8 cell changer Varian (Carry 50 - 8/18 cell changer) Analytik Jena (Specord Series - 8/16 cell changer) Thermo Scientific (Evolution Series - 8 cell changer) Beckman Coulter (DU 600, 700, 800 - 8 cell changer) Chemspec (350 - 8 cell changer) The end-user may select any spectrophotometer of the above list or include the one has already and wishes to extend its use to dissolution testing. In this case the special spectrophotometer “Driver” has to be ordered in addition to the standard WinDiss32 software along with a dissolution bath and a pump option (either peristaltic or piston). http://www.pharma-test.de/en/products/p160_1.htm

6

On-line HPLC operation

Elements of Automation…. The basic elements of an automated dissolution system of which the sampled media should be analysed using a HPLC system are the Dissolution Tester, an EPE sampling system, a Pumping system, an Auto-Sampler ASP 2000 or DSR, and a HPLC detection system. These are then generally controlled with a PC and the WinDiss32 software pack. Full system control and data management can be offered using the WinDiss32-V3 software program which is capable to communicate with an Agilent Pump, Detector and the Chemstation software or a Waters Pump, Detector and Empower software. In this configuration, the dissolution system elements have to be entered into the WinDiss32-V3 program structure and this includes the sampling sequences, any requested dilution of sampled media, and injection timing. The media will be injected via a switchable Injection Valve of the ASP 2000 into the Pump of the HPLC system. Analysis information, such as integration time etc. has to be programmed at the HPLC software, Chemstation, Empower, or other. Both systems are connected to synchronize the sample injection and transfer result PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing data. Still these systems are regarded as being semi-automated as the operator still has to introduce the tablets and clean the system the system after use. The automated procedures are: Sampling - Sample collection - Dilution - Injection controlled by the WinDiss32-V3 software Integration Timing - Measurement Data are handled by the HPLC system software Data Evaluation and Reporting All the control cycles, such as sampling intervals, dilution factors, injection times etc., are entered into the WinDiss32-V3 software framework, which is easy to manage as it is menu driven. Methods are constructed, stored and then selected for the appropriate product. Product specific data are entered and then attached to a stored method. Tests are then ready to run. Once obtained, product dissolution data are stored for printing and / or archiving. This archiving system may then be used at a later date to perform batch comparison. Sample injection is controlled by the HPLC Integrator which supplied a workable signal to inject the consequent sample into the loop. This configuration can be connected to Agilent, Waters and most other HPLC systems used. Some examples of system configurations available in the WinDiss32-V3 software are shown below: • • • • •

Dissolution System with PTFC 2 Fraction Collector (Off-line) Dissolution System with ASP 2000 or DSR Auto Sampler (Off-line) Dissolution System with Photometer and Multi-Cell Changer (On-line, closed loop) Dissolution System with PTFC 2 Fraction Collector or Auto Sampler ASP 2000 or DSR and Photometer (On-line) Dissolution System with 2 Dissolution Baths and Photometer with 16-cells (On-line, closed loop)

http://www.pharma-test.de/en/products/p30_10.htm PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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7

DTS 800 The “All-in-One” Compact Dissolution Analyser

The DTS 800 Dissolution Analyser offers a unique opportunity to have all components normally associated with on-line Dissolution Automation in an integrated package. The Dissolution tester, the sample transfer Pump, the Spectrophotometer and all UV flow-through cells. The advantages are: • • • • •

Low space requirement in valuable Lab areas Faster sampling sequences due to shorter tubing Components optimised for Dissolution All components are easily accessible Total environmental vibration suppression

The DTS 800 is equipped with a motorized Tablet Drop Magazine which also doubles as a low-loss vessel cover. It uses the EPE Auto Sampling System which holds also the ITM Media Temperature monitoring system to withdraw the samples off the dissolution vessels. The sampling ferrules are only inside the media as long as the sampling takes place. Also precise positioning of all sampling ferrules is secured and automatically adjusted according to the media volume in use. The standard supply scope include a set of stainless steel batch coded Monoshaft Stirrers with Paddle Adapters (USP App. 2). The built-in 8-channel Peristaltic pump uses inert Ismaprene Tubing for the sample transfer. The flow-through cells are placed inside the 8-cell changer of the SA 500 Diode Array UV/VIS Spectrophotometer. The cell changer can hold 8 cells with a maximum path length of 20 mm and as small as 0.1

mm.. The DTS 800 is controlled by the WinDiss32 Software Platform also included in the supply scope. http://www.pharma-test.de/en/products/p30_11.htm PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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8

IDS 1000 “In-Situ” Fibre Optic Dissolution Test System

IDS or In situ Dissolution System is about the application of direct measurement technology to Dissolution Testing. Traditionally, dissolution testing is carried out on solid dosage forms using a standard dissolution tester. Samples of the dissolving active within the dosage form are taken for estimation from the dissolution tester either manually, or using more automated means such as a pump which has been connected to a suitable measurement device, usually a UV Spectrophotometer. Using IDS 1000, not only can the whole process of sample measurement be automated, but can also be self contained, such that there is no need for samples to be pumped out of the dissolution vessels to external measurement facilities such as a spectrometer, because all that is needed for the measurements to be made is contained within the confines of the instrument itself. How does it work? In the first instance the introduction of tablets or other dosage forms is as with a conventional dissolution instrument using a synchronous Tablet Drop Magazine. The instrument is started according to the WinDiss32 Dissolution Software control, but the sampling sequences have been replaced by direct measurement technology within the dissolution vessel itself, with each measurement cycle accomplished in seconds rather than minutes. The in situ measurement is carried out using fibre optic probes which are located in the shafts of the dissolution tools, i.e., a paddle or a basket (Apparatus 2 or 1). The fibre optic probe which stays in position inside the shaft can be equipped with various path length inserts for different active concentrations and extinction coefficient ranges. The hollow stirrer shaft than will be reinserted and the next analysis started. Stirrer shaft positioning is fixed so no immersion depth setting is required after the system has been installed. Why is it different? This system is different for many reasons and brings a really new dimension to dissolution measurement. For example the fibre optic probes are easily accessible and can have various cell paths attached. In situ probe placement means fast measurement times and no fluid circulation. No more pump tubing to be qualified or fail during a dissolution run. It also means that there is no fluid perturbation inside the vessel from sampling probes as used in conventional measurement cycles. It is also different from other instruments, in which attempts have been made to use fibre optic measurements, as this system has only one built in diode array spectrophotometer, but is still able to operate with 9 separate fibre optic sensor paths which are multiplexed to a central sampling unit. The biggest difference is that all IDS 1000 components, including the built-in Diode Array spectrophotometer are contained in a single housing, so that all optical components have a fixed geometry. This coupled with no externally pumped liquids not only allows us to have very fast sampling sequences (useful for fast disintegrating and fast dissolving actives) but also means that the system does not contain unnecessary hardware, whilst still offering the advantage of a self validation routine (SST or System Suitability Test) for all the on-board measurement hardware. This validation routine is activated before the start of each analysis. The combination of self validation, speed, precision and no external fluid circulation are very attractive options. The built in TIDAS Diode Array Spectrophotometer also means that single PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing wavelength measurements are no longer made, but whole spectra may be accumulated to optimise the analytical wavelength used. This also allows the use of first derivative techniques in order to analyse multi-component formulations with overlapping

absorption curves. http://www.pharma-test.de/en/products/p30_9.htm

9

The WinDiss32 Software Platform

WinDiss32 means: design your automated Dissolution System which perfectly suits the applications you need it for: •

Off-line Dissolution including Fraction Collector with and without auto media refilling


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ToDo: Successful Dissolution Testing • •

•

• • •

Off-line Dissolution including Sample Handling Systems for sample dilution and sample transfer into Septa closed vials, sample injection into UV/VIS Photometer Off-line Dissolution including Auto Sampler which can handle up to 12 vessel dissolution vessels, dilute samples, inject into UV/VIS spectrophotometer or HPLC systems Closed-Loop on-line Dissolution using various brands of Dissolution Baths, Pumps and Spectrophotometers. Allows to add more or less any existing instrument to the system as long as it can be controlled by one of the available Drivers Closed Loop on-line Dissolution for up to 12 dissolution vessels and UV/VIS or HPLC injection Hybrid Systems including Sample Collectors and UV/VIS or HPLC Systems Online HPLC Dissolution Testing

Unique Path Solution Technology Driver Linkage with Unique Solution Path Technology. WinDiss32 Supports a wide range of Baths, Auto Samplers and Other Detectors. It uses a unique Solution Path Technology. Configuration for different analysis requires no additional reprogramming. Support for Closed and Open Loop for UV and HPLC systems. WINDISS 32 can operate with USP I, II, III and IV methods. Expanded capability for HPLC Collect and store samples in Auto Samplers to perform online dilution, mixing and measurement on the ADS. User Administration The WinDiss32 Administration allows the system administrator to enter details of users to access the system. The user Logon name, full name and password are configured for each user with Group or individual access rights. Individual access to the system is by a unique user name and password and the users full name is displayed whenever the user logs on successfully. Dynamic Report Editor The WinDiiss32 report organiser allows users to produce customised reports with the right information by selecting from a combination of objects such as Method Header, Data tables, Method parameters, Graphs and the company logo. These details may include any parameter measured during the test such as bath Temperature, Paddle speed, Time Intervals as well as Absorbance, Concentration and % Dissolved. Any number of pages can be selected with automatic page numbering. CFR Compliance The WinDiss32 Software is fully 21CFR Part 11 and GAMP 4 compliant.


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10 Dissolution Automation: Key Points for Consideration What is a Dissolution Test and Why Do We Do It? A dissolution test is a means of identifying and proving the availability of active drug materials in their delivered form. Many active materials are only required at the milligram or even microgram level in order to achieve the desired pharmacological effect. As the delivery of a mg amount of active material to the subject is not realistic, we have to employ bulking agents in order to present medication in a form which is easy to administer. These non-active bulking agents such as microcrystalline cellulose (e.g., Avicel) and silica (e.g., Aerosil) can have an effect on the way that the active material is released or what is referred to as its bio-availability. We need to define the availability of the active material as this will have a bearing on the dosage available after ingestion. A dissolution test simulates this availability and allows the prediction of the time for complete release of the material from the dosage form. It also gives important Quality Control information as to how much of the active material was in the dosage form and whether this concentration conforms to the expected dosage. The need for a control of this sort was identified after the Thalidomide disaster in the 1960’s, where this particular material was overdosed to expectant mothers who were in labour pain, with the result that many children were born with severe deformities. Until this time, the only quality control test employed was a tablet disintegration test. The development of what we now see as the typical dissolution test has long and involved, as changes to the way that we control health products have to be verified many times over before they are accepted as a norm. For example, the original dissolution vessels were actually like normal beakers, with a flat bottom. The original “tools” were only baskets and when a need was identified for an alternative tool type then the paddle emerged as a likely alternative. The only problem was that the paddle rotations made the tablet (for example) race around the base of the beaker and so the dissolution rate was affected more by excess mechanical stress than by the effect of stirred medium “washing” over the tablet surface. So the round bottomed dissolution vessel was born. This allowed the use of the paddle tool without the excessive mobility of the tablet form witnessed when using the flat bottomed flasks. The tablet had to more or less rest in a central position under the base of the tool. This is an important development as the majority of analytical dissolution procedures today use paddles (USP Apparatus 2) rather than the basket options (USP Apparatus 1). In fact, one of the most important physical parameters to observe in a modern USP dissolution vessel is that there are no dimples in the bottom of the vessel that will cause the tablet to revolve around the vessel base. The recent introduction of the “V” shaped bas dissolution vessel has met with little acceptance (and certainly no USP acceptance) probably because the tablet dissolution rates are too exaggerated with this vessel form. In the very beginning there were only single station dissolution testers with one vessel and one tablet per vessel. Now the standard USP tests require that 6 samples from the same PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing batch are measured and compared, which gives a better statistical picture of the tablets in any one batch. But of course there are many types of medication forms which not only have different chemical characteristics but which also vary greatly in their concentration levels. In order to try and get around the problem of preparations which are designed to deliver maybe 800 to 1000 mg of active material with good chromophores, high extinction coefficients and hence good UV absorption characteristics, a series of bigger dissolution vessels was introduced. These were 2, 4 and 5 litres. This solution was a little cumbersome and awkward at the 4 and 5 litre level because of the volumes concerned and also because of the size of the water baths needed to house the temperature controlled environment in which the vessels are immersed and at which the dosage forms are to be analysed (normally at 37°C). So in the 1970’s, the flow through cell system was introduced by Ciba Geigy which allowed for a continuous flow of medium over a tablet held in the path of the medium flow by a suitable tablet holder. In this case fresh or recycled medium may be passed over the tablet surface and the rate of active dissolution monitored. This eventually became accepted as the USP Apparatus 4. Other tools were now introduced to cope with other dosage forms and dissolution rates. The 1980’s saw the introduction of the “Reciprocating Disc” and what has been now referred to as the “Bio-Diss” or USP Apparatus 3. Again, acceptance of this method has been limited. Other dissolution tools such as trans-dermal patch holders, suppository dissolution cells and cream diffusion cells have also been introduced to cope with specific special dosage forms. However it must be stated that the majority of dissolution studies today are performed using either a paddle or basket tool. Perhaps the most significant tool to be introduced in recent years is the “Woods” apparatus or the intrinsic dissolution cell. In this case the active material alone is pressed into a quasi tablet form with only a single surface of known surface area showing. The dissolution profiles of these materials can then be acquired. The importance of this is that with the advent of combinatorial chemistry, many homolgues of the same parent compound can be produced in more or less “pure” forms, by virtue of the low quantities in which they are synthesised. Impurities can be greatly reduced by producing micro quantities of organic materials and as many as 150 different homologues of the same parent compound can be produced in a short period of time and the bio-availability investigated. This is in huge contrast to the production of “Kilo” quantities of test active materials required for testing, as seen in the not too distant past. Purification of these materials was often a long task. This has a great bearing on the engineering of sustained release products (less side effects than those of a single high dose product) as hydro-phobic groups can be added to the parent compound in order to modify the active’s solubility characteristics and hence the dissolution of the active into the blood stream or across the blood-gut barrier.


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10.1 Which dosage forms can we characterise with a dissolution test? We can investigate most dosage forms such as: • Tablets: round or oblong (coated or uncoated): fast or slow disintegrating. • Dragees : sugar or film coated • Hard and soft gel formulations • Suppositories • Trans-dermal (patches) For example, let’s look at pain control. There are various tablet forms for pain control; some have anti-inflammatory effects and some don’t. Compare the following: • • • •

Asprin (ASA) polished but not coated : normal dose 375 mg per tablet. Paracetamol polished by not coated : normal dose 500 mg per tablet Ibruprofen coated : normal dose 200, 400 mg per tablet Ibruprofen capsule with gel spheres: Slow Release : normal dose 100mg per tablet

These are all various tablet forms to do the same job. 10.2 The Dissolution test is made up of the following processes: • • • •

Dissolution of the active into a medium (water, buffer, gastric or intestinal juice) Estimation and monitoring of the dissolution time Estimation of the levels of the dissolved active using a suitable measurement technology Documentation of the test methods and the results

10.3 We have looked at the various dissolution options.

10.3.1 What about measurement techniques? Normal options:

• • •

UV-VIS Spectrophotometer (main applications) HPLC (special applications) Flame Photometry (very special application)

10.3.2 How do I know which technique should be used?

• • •

UV Spectrometry is used for the bulk of (mainly) single component analyses. HPLC is used for low concentrations or for multi-component analysis Flame Photometry can be used for potassium measurements for example.


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ToDo: Successful Dissolution Testing 10.3.3 Why can’t I always use a UV-VIS Spectrometer?

•

UV measurements can be quite sensitive (depends on chromophore or UV absorbing component in the active material) but it lacks selectivity, so gives poor resolution for multi-component mixtures such as vitamins tablets for instance.

•

HPLC offers excellent sensitivity as well as greatly enhanced selectivity by virtue of the separation technology in the chromatographic process. The main drawback is the link between the dissolution tester and the HPLC unit in that filtration down to 0.45 microns must be achieved before injecting a sample into the HPLC column, otherwise the system will fail and the column will block. There are also price considerations. HPLC has been referred to as High Price Liquid Chromatography.

10.4 How should we take a sample for analysis? • •

Manually Automatically

10.4.1 How can we take a sample for manual analysis?

• •

Use a pipette Use a purpose made sampler with filter and syringe, like the PHARMA TEST MDS System

10.4.2 Why should I filter the sample?

Although the idea is to allow the active material to dissolve into solution the bulking agents or excipients will not dissolve. Consider the case for a fast disintegrating tablet such as the USP Prednisone Calibrator tablet. You have to remove the particulate matter from the solution to be measured. 10.4.3 What size filter should I use?

Most powdered excipients have a particle size of at least 50 microns and above. However don’t forget that these particles may also carry un-dissolved active, so removal of these particles from the sample at the point of sampling is necessary so that absorbed active will not continue to dissolve out into the sample. Use: • •

5 or 10 micron filter for UV measurements 0.45 micron filter for HPLC analysis


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10.5 How can I use my UV Spectrometer to look at various materials with different absorbencies and different concentration levels? You can always use a dilutor for higher concentration analyses. Easier is to have several different path lengths in the UV sample cell. In most cases, you can use a 1mm, 5mm and 10mm cell to cover most analytical requirement.

10.6 How do I know that my response from the UV measurement is linear? This has to be checked out, but generally speaking most materials will give a linear UV absorbance versus concentration ratio up to about 1.0 AU (Absorption Units). Some materials are also able to give a linear response up to 2.0 AU, but this should be avoided. Once the linearity is proven, use a standard which has a concentration within about ± 10 to 15% of the sample to be measured. This is GAP or Good Analytical Practice. 10.6.1 What are the steps or “Unit Processes” needed in a typical analysis?

• • • • • • • • •

Medium preparation Medium degassing and dosing Standard preparation Introduce the sample Stirring the sample solution Sampling Analyse the sample Calculate the concentration Print out the results

10.7 Medium Preparation • All aqueous media should be filtered down to 0.45 microns. • Check pH of buffer solutions • Use of SDS or SLS as wetting agent 10.8 Medium Degassing and Dosing • Use USP method for degassing • Use preheating to aid degassing of medium (up to 41°C) • Keep medium stirred or circulating during degassing • Dispense medium as smoothly as possible to avoid re-aeration • Use the PHARMA TEST PT-DDS4 media degassing and dosing system


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10.9 Standard Preparation • Prepare standard according to SOP • Use medium to prepare standard • Standard concentration should be within ± 10 to 15% of sample concentration 10.10 Introduce the Sample • Make sure that the samples are stored dry • Use tweezers for tablet transfer to dissolution vessel • Run 6 samples at the same time (USP requirement) • For manual sampling drop tablets in a time delay (staggered start) 10.11 Stirring the Sample Solution • Use the correct tool for the job • Pharma Test has special “chuck” system for staggered starts • Good idea to check tool rpm (speed) before the run starts • Check vessel temperature 10.12 Sampling • Always try and use front end filters • Check for sample adsorption on filter medium • Use the correct filter size: 5 to 10 microns for UV and 0.45 microns for HPLC • Transfer samples to clean tubes for analysis: single sample or multiple samples? 10.13 Analyse the Sample • Check the cuvette size required for the analysis • Use larger cell path for lower concentrations • UV: try and use a double or split beam instrument where possible • Check measurement cuvette against a blank at frequent intervals (drift) 10.14 Calculate the concentration • Use measured value from sample against the standard • Compensate for the true standard weight against the SOP value • Don’t forget blank corrections when using a single beam instrument


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10.15 Print Out the Results • Hard or soft copy : single test or dissolution profile • Soft copy following latest 11 CFR part 21 rules

11 Automation: What can I automate and what are the benefits? 11.1 Why Should I Automate? • Greater sample throughput • Less human error • Eliminate systematic errors • More flexibility for operator (can do other jobs) 11.2 What Can I Automate? • Medium preparation • Medium dispensing • Tablet introduction • Sampling • Analysis • Calculation of results • Documentation 11.3 Medium Preparation using the PHARMA TEST Media Prep and Dosing System • Use the PT DDS for medium preparation • Prepares up to 25 litres of medium in one go • Follows USP directives 11.4 Medium Dispensing • Delivers medium at right temperature to start analysis • Saves a lot of time • Approximate ROI time between 3 and 6 months 11.5 Tablet Introduction • Use tablet drop magazine - synchronous tablet drop used for closed loop and auto sampling systems • Gives synchronous tablet introduction to all six vessels • No need to use tweezers • Tablet handling minimised 11.6 Sampling • Use sampling manifolds • Use either stationary (in-situ) sampling tubes or EPE auto sampling system • EPE sampler only in solution when required • Filters can easily be attached to sample tubes


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ToDo: Successful Dissolution Testing 11.7 Analysis • Use suitable program such as WinDiss32© program from PHARMA TEST • Use flow through cuvettes with cuvette changer • Program regular blank check prior to sampling from vessels • Blank correction is automatic • Automatic standard check at each measurement cycle • Samples automatically pumped to the Spectrometer • Offers Multi-Component analysis • Pump control delivers samples to Spectrometer at correct time • Spectrometer control for automated AU readings 12 Calculation of Results • Use suitable program such as WinDiss32© program from Pharma Test • Possibility to include blank, evaporation, media loss, corrections • Use standards, or a theoretical 100% standard value or calibration curve • Present results in AU, mg or %age dissolved. 12.1 Documentation • Use suitable program such as WIN DISS© program from Pharma Test • Use script file protocol to tailor make hard copy documentation • Produce dissolution profiles with full graphics • Produce batch comparison statistics • Save all data according to new 11 CFR part 21 rules 13 Automated System Options • Dissolution Tester with PTFC2 Fraction Collector: Off-line automation • Dissolution Tester with DSR Dissolution Sampling Robot for online Dilution and sealed vial filling: Off-line automation • Dissolution Tester with ASP 2000 AutoSampler for online Dilution, sealed vial filling, sample transfer into a connected Spectrophotometer • Dissolution Tester with UV-VIS Spectrometer: closed loop On-line automation • Combination of the two (Hybrid Systems) • HPLC automation, media dilution via ASP2000 AutoSampler 14 Automation: Limitations and potential Problems • Know the limits • Water Quality • Deaerated Medium • Filtration of Medium and Samples • Adsorption of Active Material • Concentration differences • Buffer Changes • Poor Absorption or No Chromophores


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15 Know the Limits • Is my measurement method able to cope with the sample • What is the LOD (Limit of Detection) of my method 16 Water Quality • All water should be demineralised and filtered to 0.45 microns 17 Deaerated Medium • All media should now be deaerated • USP tests require deaerated media, especially Prednisone test • How to keep media deaerated • Can I make enough medium for a series of tests 18 Filtration of Medium and Samples • Use Büchner type flasks to pre-filter medium and or water. • For samples, use a pre-filtration at the vessel end to 5 or 10 microns • Use pre-filter to eliminate clogging of lower porosity in-line filters • Use a 0.45 micron filter for security and also for HPLC 19 Absorption of Active Materials in Automated Systems • One of the least studied phenomena • Check for absorption on tubing (e.g., Oestrogens on Tygon tubing) • Check for active absorption on filter media • Check for absorption on pump tubing (even with PTFE tubing systems) 20 Concentration Differences • Use a Dilutor (ASP 2000 or DSR System) • Have sets of different path length cuvettes (0,1, 0,5, 1.0, 2,5, 5.0, 10 and 20 mm) • High concentrations: smaller path length, lower concentrations: bigger path length 21 Buffer Changes • Buffer change required to test some enteric coated tablets • Normal change required from pH 1.2 to pH 6.8 (buffered) • Use CAT Pump and ASP System driven by WinDiss32 software • Can be automated even with Agilent Chem Station and Waters Empower software 22 Poor Absorption • Some materials have poor absorption characteristics in UV region • Some materials have no Chromophores (e.g., slow release Potassium formulations) • Use alternative technology: Fraction Collector and Flame Photometry. 23 What is impossible to Automate ? • Most samples can be analysed automatically but price might be prohibitive • Samples which require difficult manipulation: multiple dilutions for example • In line filtration can be expensive • Some automation requires the use of robots PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing 24 What does PHARMA TEST offer ? • Analytical solutions, not just equipment • Technical know-how • Installation and User Training • Back-up Support • Experience with automatic measurements • Good selection of UV Spectrometers in WinDiss32 program • Easy to follow sample routing from Dissolution Tester to Spectrometer • Variety of tubing types for sample transport • On-line and Off-line systems or both together • Semi- and full automation • Questionnaire for optimum tailor made system configuration

25 SOP : USP Dissolution Instrument Calibration or PQ Key Words: Dissolution Tester Calibration OQ PQ Suitability Test Calibrator Tablets Test Medium Preparation UV VIS Spectrometer Cells (Cuvettes) 25.1 Introduction: This text is designed to form the basis of an SOP for the PQ or Performance Qualification of a dissolution bath using USP ST tablets (calibrator tablets). Prior to this test, it is necessary to perform an OQ on the specific instrument to be tested as an unsatisfactory mechanical status of the instrument will have a bearing on the performance of the dissolution characteristics of the equipment in general. Just as a guide, please see Table 1 below for an idea as to the source and size of errors presented by various mechanical failures.

Table 1:

Factors affecting the PQ results:

Type Temperature Speed Vibration Centricity Dissolved Gas Media pH Media Contamination Sampling Position


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Rating not too significant significant significant reasonable significant reasonable significant not too significant

influence degree linear 10-30% 20-50% ± 5-15% ± 50% ± 5-10% ± 20-45% 1-3%


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ToDo: Successful Dissolution Testing Generally, the OQ will allow the operator to have a good overview of the mechanical status of the instrument prior to starting a PQ suitability test with tablets. These tests (apart from checking the operation of peripheral features such as bath illumination and function light operation) will provide tests for the capacity and stability of the heating system, the pumped water flow rate, the stability of the tool rotation speed, the centring of the tools in the dissolution vessel, the wobble at the end of the tool shaft and the depth of the tool with respect to the base of the vessel itself. Characteristics such as tool wobble and accuracy of tool rotation speeds are well documented and clearly laid out in the USP guidelines. Assuming that the OQ has provided a satisfactory status for the instrument under test, the PQ can move on to the tablet testing stage. 25.2 General Description: The following unit processes have to be undertaken during the procedure of an automated Dissolution System: 1. Have always clean vessels, no scratches at inner surface 2. Fill vessels with medium (weighing medium is more accurate). 3. Qualify pump flow rate 4. Qualify blank at each cell position (automatic system) 5. Qualify standard at each cell position (automatic system) 6. Flush system: check background adsorption values. 7. Check blank at independent Spectrometer if required (for manual sampling) 8. Check standard at independent Spectrometer if required (for manual sampling) 9. Perform the USP test with appropriate tablets. 10. Take samples after 30 minutes (automatic program) 11. Take samples after 30 minutes (manual sampling option) 12. Measure manual samples in independent Spectrometer (if required) 12. Tabulate AU values and then calculate percentages. 25.3 Details of the above: 1. Fill vessels with medium: a) The medium has to be selected according to the test that is to be done. This is either Phosphate Buffer, pH 7.4 for Salicylic Acid or Demineralised water or Prednisone. b) Select the volume to be dispensed: 900g for Salicylic Acid or 500g for Prednisone. The tolerance of the dispensed weight is ± 1%. c) Both media must be deaerated according to the USP Specification. d) Once the volume has been dispensed the tests should be started as soon as possible, if the USP test is to be done. e) Turn the pump on and wait for the fresh blank to flow through the system and return to the dissolution bath. Note the time taken for this to happen. This value has to be used in the Method set up for the final analysis as flushing time previous to the measurement PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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2. Qualify pump flow rate: a) Once the liquid is flowing back into the dissolution vessel, measure the flow rate. This can be done using a graduated 10ml cylinder. b) Adjust the tension on any channel which shows a marked difference in flow rate and if the tube is beyond this, then replace the whole set of peristaltic pump tubes. 3. Qualify blank at each cell position (automatic system). a) If necessary, initialise the Spectrometer and if a cell changer carousel is fitted, click on the position normally reserved for the blank (this is normally position 7 using an 8 cell changer). b) Now select and enter a wavelength: 242nm for Prednisone and 296nm for Salicylic Acid. c) Do an AUTO ZERO of the spectrometer and wait. A series of 0000’s should be displayed in the appropriate display. d) Move the cuvette selector to the position normally reserved for the standard (this maybe position 8 for an 8 cell changer). e) Record the “Blank” value of the media at this position. f) Select cell positions 1 through 6 (the sample positions) and record the Blank values. g) With reasonably matched cells, the absorption values should be in agreement within ± 0.00XX units at each position. h) If this is not the case, the cells have to be inspected and the windows examined for any surface contamination, either inside or outside. i) When replacing cells, please be careful to tighten but not over tighten the screw thread connectors. 4. Qualify Reference Standard at each cell position (automatic system) a) Undo the connection from the dissolution bath output to the input of the peristaltic pump. b) If necessary, attach feeder tubes which will allow you to pass standard from a suitable beaker directly into the pump and from there into the cell changer. c) Pump the Reference Standard through the system for the flushing (sampling) time that you have entered, say 45 seconds for example. d) Stop the pump, and wait for about 5 seconds e) Follow the same procedure as above for the Blank, BUT do not press the AUTO ZERO function at cell 7 this time. Record the standard AU values at each of the cells including the blank position. If the standard has been made correctly, then all position’s AU’s should agree within the range of ± 0.00XX AU. f) If some values are too high, then check the cell out. If values are too low, then check the pumping efficiency of the tubing, as some of the standard may be diluted with the blank. Another reason is that the flushing (sampling) time may not be long enough. Extend the pumping time before doing any dramatic changes and retest again. PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing g) Run through measurement sequence to qualify the positioning of the cells at the correct orientation to the incident and transmitted light. 5. Flush system: check background adsorption values. a) Remove the feeder tubes from the Reference Standard beaker and turn on the pump for about 10 seconds. b) Rinse and dry the feeder tubes. c) Using the same procedure as with loading the Reference Standard, repeat the sequence this time by replacing the beaker of standard with a beaker of Blank medium. d) Pump this through for double the time needed to load the standard. e) Recheck the Blank values at each of the cell positions and record them. The agreement should be much as before. Some drift may have occurred with the spectrometer, but the values should still be close to those measured before. f) Empty the dissolution vessels and clean them out for the next stage. 6. Check Blank at independent Spectrometer if required (for manual sampling). a) This can be done easily to make sure that any other manually filled cuvette or cell used is giving a reasonable agreement as to the Blank value obtained with the automatic system. b) Use the instrument Auto Zero function to zero the Blank in the measurement cell. The sample cell should be filled with Blank and this should be zeroed either against another cuvette in the Blank position (in the spectrometer) or against air if another cuvette is not available. c) In the case of Salicylic Acid, a 1mm sample cell has to be used; the use of a 1mm flow cell adapted to take a female Luer in line connector is a great bonus. Manual 1mm cells are difficult to use and especially hard to flush. The flow-through 1mm cell with the female Luer adaptation allows the easy filling, flushing and successive introduction of samples, without recourse to difficult manipulations or sample dilution by 10 times (if a 10mm cell were to be used). d) The Blank for the Prednisone test can be run in a 10mm cell. 7. Check standard at independent Spectrometer if required (for manual sampling) a) Having cleaned and dried the manual cell, place the Reference Standard solution in it and record the value for the standard. This should be in close agreement with the values obtained using the automated system. b) If the 1mm flow cell adaptation is to be used it is sufficient to blow out the blank with a syringe full of air and flush with standard twice. Record the values. 8. Perform the USP test with appropriate tablets. a) The vessels must now be cleaned and filled with fresh deaerated medium. b) Start the automatic sequence as soon as possible after the last vessel has been filled and placed in the dissolution tester. PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing c) Before starting, check and note the medium temperature in each vessel. d) Do not use Helium to sparge the medium. e) For preference, use a degasser which also conforms to the USP methodology and preheats the medium whist degassing it. This minimises the delay before starting the test proper. f) Store the tablets either in the bottle provided or better in a desiccator prior to the start of the test. g) Do not handle the tablets or expose them to sources of moisture prior to the test. h) Wear thin rubber medical examination gloves (powder free) and if necessary pull some of the tablets out on to a clean tissue or better, remove them one by one from the bottle supplied using large tweezers. Today’s Tablets come in Blister Packages. i) In the case of Salicylic Acid tablets and as the tablet quality is so poor, you will have to dedust the tablets prior to use and this can be done using a dry tissue paper (preferably coloured) to the point where the tablets almost start to shine at the surface. At this point the tablet is sufficiently dedusted. If the tablet is not dedusted then the surface powder will dissolve into the medium very quickly and may give a higher than expected apparent dissolution rate. j) In the case of Prednisone tablets, they seem to be very influenced by dissolved gasses. Although this was more by accident than design, it does highlight the need for effective degassing and a quick start of the test once the medium is dosed and in the bath. k) In the automatic program the Blanks will be run and recorded in the program architecture and then you will be prompted to drop the tablets. 9. Take samples after 30 minutes (automatic program) a) The program has to be constructed such that samples of the dissolved active are taken after an interval of 30 minutes. Both tests for all types of tools used (Apparatus 1 and 2) require the same sampling conditions. b) As the sampling is done automatically, the sampling ferrules will either be in the solution permanently or will be lowered into the solution prior to sampling (PHARMA TEST EPE system). c) Sampling will start at the 30 minute interval less the time entered in for sample line prefilling (flushing), e.g., 45 seconds. d) The instrument will then go through the measurement sequence and record the displayed values in the results protocol. e) There will be an automatic calculation of the percentages of active dissolved. f) If any of the values fall outside the specified range, then the whole test must be repeated until either the failures are eliminated. g) The instrument has been declared unfit for use pending mechanical parameter investigation. Or the media was improperly deaerated (often the reason for failures). The USP criterion for tablet test failure and the pattern of repeat tests is clearly laid out in the relevant guide.


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ToDo: Successful Dissolution Testing 10. Take samples after 30 minutes (manual sampling option) a) When sampling manually, be aware that dry filter elements at the end of the sampling ferrules may be one of the reasons for differences between manual and automatic measurements. See the addendum: Differences between automatic and manual measurements. 11. Measure manual samples in independent Spectrometer (if required) a) Manually taken samples should be filtered in line and not centrifuged or filtered later as undissolved active will continue to dissolve, so if attached to particulate matter such as residual excipients. b) These samples may then be transferred to a test tube for further analysis. c) Record all results in an appropriate table and calculate the percentage dissolved active. 12. Tabulate AU values and then calculate percentages. a) Suitable tables for recording the AU values and the resultant percentages are available from PHARMA TEST. b) Automatic calculations cannot be adjusted unless the file containing these adjusted values is saved under a different file name. c) Manual samples may yield different values to those obtained automatically. Again, refer to the addendum text at the end of this SOP for alternative reasons for these differences. d) Values can be calculated manually according to the calculation formulae which can be seen in the accompanying test for this SOP, available from PHARMA TEST.

26 Differences between Automatic and Manual Measurements. We have also to ask ourselves why these occur? This is a often seen phenomenon and is therefore not unusual. There are several reasons: a) Has the automatic method itself been validated? b) Has each component of the automatic system been validated? This applies also to the Pump and the Spectrometer as to the ability of the pump to produce a similar flow rate through each of the tubes and deliver a sample which is representative of the vessel from which it came at the same time in each of the flow cells. c) Has the Spectrometer been validated as to its condition. If yes, then was it with the cell changer (probably not). If it was validated with the sample changer, was it validated with the cells in it. What was the medium with which the cells were validated in conjunction with the spectrometer. In the case of the USP materials, i.e., the standard Prednisone solution for example, then each of the cells should be validated first with demineralised water for the Blank and then validated with the standard solution so that each position can be evaluated for the 100% dissolved active solution PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing and that the transition from Blank to 100% solution shows no effects of carryover. If carryover is detected, then maybe the pumping system is at fault (insufficient volume pumped through the system) so that there is a significant mixing of the blank and the 100% solution. In the USP test this would easily have an influence on the final result as there is only one measurement point between 0% and the final result. d) There is also an effect known as occlusion. This is highlighted in the attached Question and Answer form from the Dissolutions Solutions Network page available from the internet. Occlusion is a point on the dissolution profile at which the drug substance is no longer released into the medium. Some drug substance may be reabsorbed onto the excipient material during the automatic sampling sequence. This could happen with material which is filtered out is held at the filter surface through which the solution to be analysed has to pass. e) There can also be adsorption of the material at the filter surface, especially if the filter is dry. This is the case with manual sampling where each of the filters is dry. In the automatic system the filter is immersed and therefore wet from the start of the measurement cycle and is certainly wet at the end of the 30 minutes measurement period. f)

There is then the time lag between the automatic sampling which is synchronous and the manual sampling which is consecutive. For manual testing a staggered start option with the Dissolution Bath is preferable. Although this is only a small time difference, the manual sampling from the vessels is more realistic than the automatic sampling as the automatic sequence starts about 30 to 40 seconds prior to the 30 minute sampling time. Therefore solution in the cuvettes is “younger” than that in the manual sampling syringes.

g) There is also position of sampling. In our experience the filter position for manual sampling is not as repeatable as that with automatic sampling, especially with a 500ml volume where the space between the top of the tool and the surface is only a couple of cm. h) Pump tubing quality. This has more or less been outlined in points (b) and (c).

27

The Tablets

The Tablet tests are designed to be done with both Baskets (USP Apparatus 1) and Paddles (USP Apparatus 2). If a dissolution tester is set up for one particular test only then the instrument must be so marked on the USP test sticker and then the instrument may then be tested for either paddles or baskets. The test Tablets themselves fall into two categories: disintegrating and non-disintegrating. The disintegrating Tablets are made of Prednisone plus normal fillers and bulking agents and are currently produced with an active concentration of 10mg (as of LOT N). The non-disintegrating Tablets are made up of pure Salicylic Acid and are currently produced with an active concentration of 300mg (as LOT O). One Tablet is used in each of the 6 vessels to be calibrated. Generally, both tools (Apparatus 1 and 2) are used for both tablet tests. This means four tests have to be performed. The PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing current “Lot” must be used and this applies to the standards also. Both the Tablets and the Reference Standards should be stored as per the description outlined in the USP guidelines. The drying guidelines for both Tablets and standards are also to be found on the container labels, and will generally require the use of a desiccator for some time prior to the start of the test. The vessels themselves have to be scrupulously clean and contain no apparent flaws or aberrations. Glass can chip, plastic vessels can be scratched (shows only when dry!). Internal undesirable features such as dimples at the base of the dissolution vessel will cause the tablet to race around and give a (generally) too high dissolved active measurement. Once the solutions have been carefully loaded into the dissolution vessels, then the Tablets should be taken as directly as possible from the bottles or the storage point in the desiccator and introduced into the dissolution vessel. Tablets should not be allowed to lie around prior to use, especially if they are left resting on vessel covers and the like which are close to sources of moisture. The preparation of the medium should follow the guidelines as indicated in the calibration certificates, which are delivered with every lot of calibrator tablets. Some helpful hints are included under the heading of Test Medium Preparation below. Tests may be started in either a staggered (manual sampling) or synchronous manner (automated systems). Sampling should be made as per the USP guidelines, i.e., half way between the top of the tool and the surface of the medium itself, at least 1cm away from the wall of the vessel. Automatic measurement methods have to be qualified and may give quite different results from manual measurement methods with syringe and filter. The reasons for this are many. Automated methods must be validated. The USP test gives good results using manual sampling and measurement, provided that all other systematic error sources have been eliminated. A reasonable series of checks to eliminate any problems revolve around the efficiency of sample transportation from the dissolution tester to the measurement device, which is normally a UV VIS Spectrometer (or possibly a Fraction Collector). The most obvious and often encountered problem is that of tubing on peristaltic pumps. Almost nobody relieves the pressure on these tubes when the device is out of use and the life expectancy is therefore very limited. In these cases, the tubing can be split and / or the tubing so squashed, that the pumping efficiency is greatly reduced, so that sample is not correctly transported from the tester to the measurement device. The answer is of course to qualify the pump and make sure that delivered volume rates are as exact as possible from channel to channel. This can be easily checked and technically should be done before the start of every estimation in order to validate the pumping efficiency. You also may use a Piston Pump which is absolutely precise and requires less qualification work. Small leaks of either liquid out, or air in, are another source of error. Adsorption of active material on either the tubing walls or on the filter have also been responsible for low estimations. This can easily be overlooked as more often than not these test materials fall out of the scope of the normal products measured on the instrument. Sometimes filters may become clogged. It is our experience that 10μ polypropylene filters are not so prone to clogging. However, these filters should be wetted and have liquid pumped around the system through them (with Blank medium for example) in order to eliminate entrapped air in the filter membrane itself. Whatever the sampling method, samples PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing should always be taken through a filter and never be centrifuged after sampling. Also be aware of sample carry over, especially if the quartz flow through cells in the spectrometer have been qualified with a standard solution and not efficiently flushed. Lastly some ideas about the tools themselves. These should be qualified in terms of their depth relative to the bottom of the dissolution vessel. Additionally, we have found that starting with the paddles (Apparatus 2) with say Prednisone and then installing the baskets (Apparatus 1), doing the two tests for Prednisone and Salicylic Acid with the Baskets and then reinstalling the Paddles for the last test reduces the qualification time required for the tools as well as allowing the most effective use of medium preparation devices such as the PT-DDS. Efficient bulk degassing of medium can provide enough ready to-go-solution to suffice for both tests so that reaeration time is kept to a minimum and temperature equilibration periods are eliminated, which can also reduce the cost per analysis.

28 Medium Deaeration: This is a really common problem. The effects are really noticeable with the Prednisone test. Although previous lots based around the 50mg tablets were generally well behaved, the newer 10mg formulations have shown up (an accidental) sensitivity to poorly deaerated media. Excessive degassing (a curious term referred to in some private correspondence) will yield too low results and inadequate degassing will yield too high results. The general feeling is that the inter tablet variation within the overall stated ranges can be quite large anyway and this is very much dependent on the particular bottle as well as the tablet storage conditions. Another tip is to avoid excessive heating. If you follow the directions in the accompanying USP literature then heating to 41°C will possibly (depending on the “manipulations” involved) lead to a medium temperature in the vessel of about 39.5°C. This will require about 1.5hrs to equilibrate to the 36.5° to 37.5°C operational range and the media is nearly re-aerated again. The use of a lower target temperature of say 38.5°C may prove beneficial. Some people have also turned on the paddles (for example) in order to try and speed up the temperature equilibration. The net effect here is to help nature re-establish what we have just tried to eliminate, i.e., aeration. Excessive pouring or decanting techniques from a great height will also add to the “folded in” air. There is also a general movement away from alternative “established” deaeration techniques. The use of Helium (which does not really degas as it rather replaces nitrogen and oxygen with helium) is really frowned upon now and several multinational sites have been sent warning letters to desist with this practise, so this is a good time to switch. The use of ultrasound is also now not recommended.


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ToDo: Successful Dissolution Testing It is well to remember that although most media is re-aerated after about one hour (especially with paddle rotation) it is the effect in the opening time frame of the measurement that shapes the dissolution rate and hence the profile; this applies even for slow release products where the release profile may be collected over a period of 12 hours for example. Apart from anything else, poorly deaerated media can be easily spotted as tablets will collect bubbles around them and restrict the surface area in contact with the medium and baskets will have large sections of their mesh blocked with trapped air. Tapping the shaft of the basket holder is not advised as a remedy!

29 Other Observations: During the lifetime of the Lot M Prednisone tablets, the ranges had to be extended for both the paddles and the baskets. The baskets were extended (at 100RPM) from 88% to 91%. The paddles had the limit dropped from 28% (at 50RPM) to 23%. This brings out a very important difference between the “European” and “US” designed instruments, as the drop in the limit for the paddle test was principally to incorporate baths of European manufacture. Most US bath manufacturers have large gantries from which the tools are suspended, so that the locking chucks and the bearings (i.e., the paddle supports) are quite removed from the paddle tool itself. This means that the European models have less detectable wobble at the tool end; therefore the greater wobble on US models will give a larger dissolved active profile than those of European manufacture where the tool is very much closer to both the supporting bearing and chuck, resulting in lower dissolution levels for the same tablet. Hence the change. It has been found that the deaeration of dissolution medium can effect the results of a dissolution test in either higher or lower profiles. Besides the time consuming manual method which is recommended using a 0.45 micron filter, drawing a vacuum and stirring through the entire process. The PHARMA TEST Media Deaeration and Dosing System PT-DDS offers continuous medium circulation under vacuum and heating up to max. 60°C. It has been proven to be a very efficient method. Dosing is controlled by using a built-in electronic load cell which can be calibrated against a 1 kg standard weight. Picture # 1: left hand side vessel shows non-deaerated medium while the right vessel is deaerated

1


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2

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4

5

Picture # 2: again shows non deaerated media, a lot of non-dispersed particles float on top of the medium, while within deaerated media (Picture # 3) these particles are floating throughout the whole medium. Picture # 4: a USP calibrator tablet (Prednisone) inside non-deaerated medium, the medium is not clear and a lot of non dispersed particles float arround the stirrer. Picture # 5: shows also a USP calibrator tablet from the same batch but inside deaerated medium, it’s visible that the medium is clear and a lot less non dispersed particles float around. All pictures have been taken at the same time.

30 Vibration Vibration is certainly a party stopper for Prednisone Tests. In a recent article by Vivian Gray (Dissolution Technologies - Volume14, February 2007) vibration problems are mentioned as a source of errors in routine use of dissolution techniques. Sources of Vibration may be: • Lab shakers • Centrifuges • Fume Hoods • Slamming doors (especially Prednisone Apparatus 1) • Fridges • Old pumps on the floor. • Worn belts and bearings in Dissolution Testers. • Bath Heating Systems including Pumps and Heaters • Stepper Motor Drives • On site construction work • Passing traffic Vibration up to about 0.4 µm does not change the Dissolution Profile significantly. But if vibration exceeds 0.4 µm you will measure about 40-50% higher Prednisone release rates. All PHARMA TEST Dissolution Baths are equipped with VibroBan vibration absorbers so measurable vibration at the vessels is always less than 0.25 µm


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31 The Influence of Vibration on Dissolution Tests It has become apparent in the recent past, that vibration within the Tablet Dissolution testing environment is a real issue. Although this may not have been too apparent in the normal routine dissolution testing, the real impact of vibration has become a focal point as a result of the Prednisone “Calibrator Tablet” tests which generally have to be performed every 6 months on each instrument within the testing environment. Prednisone tablets are referred to as “Disintegrating” tablets as they break down in the medium very quickly to form a powdered mass, either in the basket (Apparatus 1) or as a fairly well defined cone under the Paddle (Apparatus 2). The second system validation test is made using Salicylic Acid tablets which are “non-disintegrating”, so they keep their form throughout the test and just dissolve away slowly. The Prednisone tablet is 10mg in active content and so it has a large percentage of excipients present; in contrast, the Salicylic Acid tablet is made entirely of Salicylic Acid with no excipients present. 31.1 What can go wrong? The discussion will be limited to the Prednisone tablets as their dissolution rate is more affected by the vibration issues under discussion. However, the influences of the sources outlined below can have an effect on all types of dissolution tests and their influences cannot always be absolutely defined. Their elimination or minimisation however, will lead to a corresponding reduction in systematic errors, which is to be desired. Up to this point, there were certain “anomalies” noted with Prednisone tests and a lot of the more spurious results that were obtained as a result of these tests were put down to various causes, normally the quality of the Tablets themselves. Shooting the messenger seemed to be an easy option in some quarters. The issue of test reliability appeared to become a particular problem when the formulation was changed from a 50mg tablet to a 10mg tablet. Up to this point there were no particular influences noted with the 50mg formulation. The 10mg formulation however, presented some challenges to the operator and his / her working environment and it became apparent that the dissolution release rate was greatly influenced by two main factors: Dissolved gasses, and Vibration On many occasions, the combination of poor de-aeration and vibration can work together to produce all manner of strange effects. The dissolved gasses issue can be easily resolved using a suitable de-aeration technique. At this point it is reasonable to draw a difference between “degassing” and “de-aeration”. Degassing is a technique whereby dissolved gasses with a high solubility product can be displaced by dissolving in a gas with a lower solubility product. Typically, Helium can be used to displace both Nitrogen and Oxygen in aqueous media. De-aeration, on the other hand, is a method by which we can physically remove the dissolved gasses from the medium. If we follow the USP requirements, then this can be achieved by a combination of heating, vacuum and circulation (ref.1). Medium de-aeration today is a well defined subject and should not be an issue. 31.1.1 So this takes care of the De-aeration issue. What about Vibration?

Vibration sources can be very diverse in origin. Some of the sources are listed below: Internal sources - External sources - Intermittent and operational sources PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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31.1.2 Internal Sources

The Heater / Circulator These basically arise from the instrument construction and the types of components used to manufacture the machine. The first major source is that of the external heater /circulator. These devices are normally of a basic design with a reasonably powered pump which takes water from the bath, circulates it through a heater element and then returns it to the bath. Unfortunately this is one of the least developed parts of the instrument package and therefore because of the generally “low cost” design are not in any way vibration proofed and sit on the work bench beside the dissolution bath and rumble away. These devices generate a lot of 50/60Hz noise which is transmitted through to the dissolution bath. The construction of the lab bench can also prove to be an amplifier for this “transmission”. The Drive Motor The next source is that of the tool rotational motor, drive belts and bearings. The rotational motor can be a source of vibration. It normally is a DC motor with a gearbox attached. The gearbox has to be maintained and checked for squeaks and rattles. The Drive Belts The drive belts fall into two classes: those which are expected to drive all tool shafts from a single belt and those which have a high contact angle with the drive shaft mechanism (so multiple belt drives). Generally, the quality of the belt will play a big role in the generation of higher frequency vibration which is then transmitted down the tool shaft which adds another enforced dimension to the tablet disintegration and dissolution process. Noise generated in this way will turn the tool shaft into a type of ultrasonic disintegration probe resulting in higher dissolution rates, especially for Apparatus 1 baskets. The effect is not so profound with Apparatus 2 paddles, probably due to the relative dissociation of the tool and the tablet and the damping effect of the medium. Using Prednisone with Apparatus 1, you can tell if there has been significant high frequency vibration transmission by the amount of “escaped” powder at the base of the dissolution vessel. Inspection of the belts will show immediately if there has been some wear and if they are shiny, then the impact on the metal or plastic drive cog wheels at the top of tool shaft will be to generate noise. You can either replace the belts or use a silicone grease based PTFE loaded spray (sparingly) which will smooth out the noise. The effect of this type of loaded lubricant can be quite dramatic. The Bearings The bearings themselves can be either lubricated for life or grease packed (generally in older models). The bearings are not generally checked for wear and tear themselves but are tested as a function of the tool wobble or run-out test which is part of the OQ procedure. Of course there is the need to distinguish between tool wobble and bearing induced wobble. The bearing contribution to the overall wobble can be easily measured at the part of the tool which passes through the bearing and is located at the top of the dissolution tester head. If the tools are in a sealed (“capped”) bearing then this is not possible. Your only guide will then be the wobble or run out at the end of the tool shaft. However, the bearing/tool wobble may not be totally indicative of bearing noise. Wobble measurements may not show up sporadic bearing noise (typically a low frequency knocking). This can influence the dissolution rate very significantly especially with Apparatus 1 baskets. Excessive tool wobble may be PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing indicative of distorted tools or worn bearings. An experienced investigator will be able to feel and pin point any unusual bearing behaviour. 31.1.3 External Sources

So this is the mechanical side; but what about the environment directly around the instrument? Almost no attention is paid to environmental sources. Only on some rare occasions is there such an influence that the lab is more or less forced to concede that there have been hidden forces at work. A typical example was that of a 12 position bath placed in a laboratory where most of the instrument was resting on an old weighing table (so really stable) and the rest of the instrument (about the last 1/3) was resting on an extension to this weighing table which was made from “kitchen” style worktop with a thin metal frame as a support. During the Prednisone tests it was noted 3 times that vessels 5 and 6 as well as 11 and 12 were failing the test when 1, 2, 3 and 4 in the front row as well as 7, 8, 9 and 10 in the back row were well within the range. The answer was a BET Surface Area Analyser which uses a high vacuum pump to de-gas powdered samples prior to analysis. The pump is running more or less full time and from experience, is usually the least serviced part of the instrument system. The pump was resting on the floor but only about 0.5 metres from the base of the frame support. The vibration transmission was easily spotted in the poorly supported dissolution vessels as a series of concentric ring patterns in the surface of the media. With the pump off, all was well. This was by no means, the only potential culprit. Old fridges with ancient compressors are also a good source. 31.1.4 Intermittent and Operational Sources

The trouble with any intermittent problem is that it is just that, i.e., it may not always be there. The best example is the slamming door. Portable A/C units can also be a problem. Intermittent sources can also be operator generated. Some instruments have electric head drives (to raise and lower the head) and some are manually operated, either with a pneumatically assisted swing head or with a guided vertical drop. Both of these mechanisms can be sources of problems if not smoothly placed into the operating position. This again, is particularly the case with Apparatus 1 baskets. Sudden movements while the Prednisone Tablet is in the process of disintegrating can fire a shower of tablet material out of the basket and into the medium. A failed test is not far off. With swing head which opens and closes with a movement through approximately 135°, a slow gentle placing of the head in the working position will avoid problems. This situation seems to have greatly improved with the transition to the new LOT POE203 from the previous O0C056 LOT. Values for baskets also appear to be much tighter in range. With the vertical drop mechanisms, there is a tendency for the drive way to be a little harsh in its transition into the working position. Additional pressure to move the head can result in a hard hitting arrival which again, will drive more of the disintegrating formulation out from a basket than should be allowed for a successful test.


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31.1.5 So what can modern dissolution tester designer do for you regarding Vibration?

Modern test instrument design using up-to-date materials should be designed with the dissolution user in mind and not just for cheap construction. As far as the USP is concerned it has been noted that there is only a brief mention of vibration requirements consisting of the statement that “no part of the assembly, including the environment in which the assembly is placed, contributes significant motion, agitation or vibration beyond that due to the smoothly rotating stirring element” (ref. 3). Other publications have also been mindful of the potential errors in terms of dissolution testing and amongst the biggest influences were vibration and medium de-aeration (ref.4). Various studies have been carried out to try and quantify the effects of vibration on the resulting release rate of Prednisone tablets in particular. Some co-workers have also carried out exhaustive tests in order to investigate the effects of vibration on both older and newer instrument types and to provide definitive proof that the introduction of some critical design features can result in instruments that are the most developed available and that they represent a truly foresighted view of the future requirements of the dissolution user. The total findings regarding our investigations are available upon request (ref.5). The effect of vibration on instruments from various suppliers has also been investigated and is documented in existing literature (ref. 3). The method of vibration analysis and investigation was also reviewed by this independent body and the results make quite interesting reading. The main points are that: 1. How you measure vibration and how you quote it is important. 2. Are you measuring vibration in one axis or are some axes being “damped”? 31.1.6 What is different about these instruments with the newer critical design features?

The main differences come from the quality of construction and detailed research aimed at making a better all round instrument that is already prepared for all the forthcoming potential changes that may be applied to the Operational Qualification of dissolution instruments. These changes are a hotbed of discussion at the moment of going to press (ref. 6), but these issues need to be investigated and acted upon, not so much to conform to any new rules that may arise, but because we must strive to produce an instrument which not only passes any test that is currently, or may be, required but also for the ease of the operator who has to use the instrument on a daily basis. Main advantages of the Dissolution Testers with implemented critical design features. The main advantages are outlined below: 31.1.7 Pump and Heater Installation

The heating of the water bath section in a dissolution tester is normally the last point on the development list for most instrument manufacturers. This is generally limited to a “me too” type of heated circulator, which sits on the workbench just beside the dissolution tester. Most of these heated circulators have one control sensor with a fixed mounted pump mechanism. The first issue is the safety of the heating system and with Pharma Test units there is a safety sensor as well as a control sensor. The second issue is the accessibility and construction of the heating elements which coincidentally contains the circulation pump. The heating system is shown below in figure 1. It is conveniently accessed via a small drawer unit without having to disturb the positioning of the bath itself. It also contains a safety sensor PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing after the heating element as well as a safety over-temperature switch and a thermal fuse, items missing in several current designs. The built-in vibration suppression is illustrated below: sprung support platform to eliminate any vibration from

quick disconnects for rapid access to water bath

You can see that the pump is suspended on a sprung platform and this eliminates virtually all potential vibration sources from the pumped heating system. Compare this with bench mounted heater/circulators. 31.1.8 The Water Bath Installation

The water bath is also set up for vibration damping. This design has also taken into account the impact of environmental vibration sources such as fridges, pumps, A/C systems and the like which are an intrinsic part of modern laboratory installations. The vibration damping is clearly shown below:

metal encased rubber isolation feet

specialised polymeric vibration absorbing feet

You will note from the figure above that the first line of defence against environmental vibration is the installation of metal encapsulated rubber feet. This mechanically “decouples” the dissolution tester from the work bench. These feet also allow the easy levelling of the dissolution tester prior to installation. The second line of defence is the installation of unique, specialised polymeric vibration dampers (Vibroban™) purely for the water bath isolation from the rest of the dissolution tester. This effectively provides a second decoupling mechanism to insure that almost all vibration emanating from the working environment is eliminated. The effects of this system in the face of external environmental vibration sources can be seen below. The results clearly show the huge influence of vibration while doing a Prednisone dissolution test. PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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31.1.9 The Effect of Environmental Vibration Sources

Vessel

a) Vibration 40.11 41.95 43.45 46.90 43.68 45.98 43.68

No b) Absorbers 56.90 61.15 62.07 61.38 53.22 55.98 58.45

Without c) Absorbers 43.51 42.30 45.98 42.41 45.40 44.60 44.87

With

1 2 3 4 5 6 mean a) no vibration b) with vibration (0.5 μm) and instrument without vibration absorbers c) with vibration (0.5 μm) and instrument with vibration absorbers

Certainly compared to the results shown above, the effects of vibration in most available instruments compared to instruments which contain these critical features are certainly important enough to take into account when choosing a new Dissolution Tester. 31.1.10 Conclusions

Many problems can arise within the laboratory environment to detrimentally influence the dissolution process. Some of these issues such as de-aeration of the dissolution medium can be effectively handled with modern medium preparation instruments which are widely available. Issues such as vibration, both intrinsic and environmental have different effects on different makes of instrument. It has been illustrated on more than one occasion that “thinking outside the box” and implementing some critical features based on intensive R&D offers a multi directional approach to eliminating factors which are detrimental to the whole dissolution process and not just certain aspects therein. In this way users can be offered an unrivalled degree of security in the dissolution process which not only meet current requirements, but will afford an additional buffer so as to be prepared for proposed norms which are currently under discussion.


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32 Test Medium Preparation: The solutions which you should prepare for the tests are as follows: 1. Prednisone: Demineralised Water: This has no real preparation except that it should be filtered to 0.45μ. It may then be treated using the pre-heating and circulation method with the additional application of vacuum. In our experience the level of vacuum for successful results is around the 500mB level. In the case of the DDS, the vacuum will switch itself out at this point and then keep the vacuum applied throughout the heating and circulation cycle (to remove any extra gas which may come out from the medium as a function of circulation and reduced pressure. The DDS 2 will prepare about 25 litres of demineralised water in about 35 minutes. The total requirement for the standard test is about (min) 16 litres. 2. Salicylic Acid: Phosphate Buffer, pH7.4 This is a pH 7.4 ± 0. 05 solution of Phosphate buffer, which is 0.05M in strength. It is made up by weighing out approximately 67.7g ± 0.5g of potassium dehydrogen orthophosphate and 15.6g ± 0.5g of sodium hydroxide pellets into a large container using a balance accurate to two decimal places. Add 10 litres of water, filtered to 0.45 μ, and mix thoroughly to dissolve all the material before transferring to the degassing device. You will need approximately 15 to 20 litres of this medium. The pH should be measured and recorded for the PQ protocol.

33 Standard Solution Preparation: 1. Prednisone: in demineralised water: With the advent of the 10mg test tablet and a test volume of only 500ml, the Reference Standard has to be carefully made. In order to minimise errors we have found that 10mg weighed out into a clean, dry 100ml volumetric flask is a reasonable start. This is well within the scope of a five place balance. The weight should be recorded for the PQ protocol. If you attempt to disperse and then dissolve the Prednisone directly in a small quantity of water, then there will be some small amount of agglomerated product floating around in lumps. The addition of a small amount of Ethanol (AR or analytical grade) will help to disperse the powder into finer particles and then the business of dissolving will be achieved over a shorter period of time. You are allowed to add up to 2% of Ethanol as a function of the total volume according to USP rules. Once the powder has dissolved, then make up to the mark, agitate for a few more minutes and then take an aliquot of 10ml and make up to 50ml with demineralised water in a volumetric flask. This will now give a standard which will represent exactly the 10mg of Prednisone in 500ml of water required as the 100% standard. The typical absorbance for this product in a 10mm path length cuvette will be around 0.84 AU. This is within the limit of the AU range recommended for a standard which is about 1.0 AU. Dilution of this Reference Standard should be made in order to be within approximately 10% of the expected sample values. The solution should always be made freshly on a daily basis. The adsorption value for this Reference Standard solution will increase day by day if left at room temperature. PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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2. Salicylic Acid: in phosphate buffer: Once again, it is really important to get the Reference Standard right. The 100% dissolved active is 300mg in 900ml. This gives a concentration of 333.4mg in a litre. As the Reference Standard is supplied in 125mg lots, then we suggest that you take a 33.34mg amount weighed into a clean, dry 100ml volumetric flask. Again, the use of Ethanol is recommended in order to first disperse the material in order to get a better rate of solvation. As the extinction coefficient for this moiety is fairly large and the concentration quite high, we have to employ either a dilution stage (typically by 10) or we can use a 1mm flow-through cell in our measurement spectrometer. Using a manual fill 1mm cell is not the easiest thing to do and the threat of substantial carryover from one sample to the next is very significant. Therefore we can advise, based on a positive experience, that you can successfully employ a flow through 1mm cuvette (cell) with a syringe female luer line connection at one end of the Teflon tubing for sample injection and the other end placed in a beaker to collect waste or reclaim the sample. The advantage of this system is that : 1. there is no need for dilution, 2. no need for difficult manipulations of a conventional 1mm path length cell, and 3. easier cell flushing and sample introduction, greatly cuts down the analysis time. The typical adsorption for this concentrated standard is 0.82 AU. Again the Reference Standard should be diluted to be within approximately 10% of the expected sample values. As with all solutions, each Standard should be clearly labelled as to its contents, the date of preparation, the expiry date and the operators name or initials. Buffers and aqueous media prepared with the PT-DDS Medium Preparation instrument, can have all of the above information as well as target temperature, deaeration time with and without vacuum, buffer expiry date and buffer batch number entered directly in to the preprogrammed method parameters, which can later be printed out as part of the results protocol. Allowable errors: a 1% error in the weight of medium dispensed is allowed.

34 Sampling: Samples should be taken by the use of an in line filter attached to the end of a stainless steel tube which has been suitably formed to accept a filter at on end and a female luer socket at the other (which allows a syringe to be attached).

35 Special precautions: The Salicylic Acid tablets are very dusty and often stuck together. If the tablets are placed in the dissolution medium as they stand, then you will run a risk of obtaining a high value for the dissolution results after 30 minutes. De-dust the tablets prior to dropping them in the dissolution vessel by gently rubbing them with a clean dry (non-abrasive) paper towel until PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing you almost “shine” them up. If you have a chipped or cracked tabled which has to be discarded, try rubbing one of these with a green or blue paper hand towel and just see how much comes off. Well worth the experiment!

36 Procedure: Prednisone: This test requires 500g of pre-heated, degassed medium, per vessel. Tablets may be taken straight from the Bottle or Blister in which they were supplied and added to the dissolution vessels. These are fast disintegrating types and will first sink to the bottom of the vessel. Make sure that the tablet is located directly under the blade of the paddle so that it forms a mount directly under the base of the paddle itself. The basket test at 50rpm will allow almost none of the tablet mass to be released from basket itself. 1. A paddle speed of 50 RPM should be selected on the dissolution tester for this test using Apparatus 2 2. A basket speed of 50RPM should be selected on the dissolution tester for this test using Apparatus 1. 3. The absorbance of each sample and the standard should be measured at 242nm. Set the UV Spectrometer accordingly. 4. Each test is run for 30 minutes. 5. A total of six tests must be run. 6. Any failure on any station means a re-run of another 6 tests. 7. The tests can be started simultaneously or can have a staggered start to facilitate easier sampling (10 to 20 seconds between drops). 8. Use the following equation to calculate the percentage dissolved active:

%dissolved = AU Sample x AU Standard

Wt. of standard used (mg) x 100 10

Salicylic Acid: This test requires 900g of pre-heated, degassed medium, per vessel. Tablets may be taken straight from the Bottle or Blister in which they were supplied and added to the dissolution vessels. These are non-disintegrating types and will first sink to the bottom of the vessel. Make sure that the tablet is located directly under the blade of the paddle or in the case of the basket, stays within the confines of the floor of the basket and does not float. 1. A paddle speed of 100 RPM should be selected on the dissolution tester for this test using Apparatus 2 2. A basket speed of 100RPM should be selected on the dissolution tester for this test using Apparatus 1. 3. The absorbance of each sample and the standard should be measured at 296nm. Set the UV Spectrometer accordingly. 4. Each test is run for 30 minutes. 5. A total of six tests must be run. 6. Any failure on any station means a re-run of another 6 tests. PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing 7. The tests can be started simultaneously or can have a staggered start to facilitate easier sampling (10 to 20 seconds between drops). 8. Use the following equation to calculate the percentage dissolved active:

%dissolved

= AU Sample AU Standard

Wt. of standard used (mg) 33.34

x

x

100

37 Dissolution Automation: Basic Questionnaire. In order to quote the most suitable automated Dissolution System we would like you to answer this questionnaire: 1. Do you want to work : a)

On line (on line is defined by a closed loop system with a spectrometer and multi-cell cuvette changer)

c)

Off line (off line is defined as working with a PTFC 2 fraction collector either with a peristaltic or syringe pump - Sampling only)

d)

Off line including Sample Dilution (is defined as working with a DSR Sampling Robot or ASP 2000 Auto Sampler for direct online Dilution and/or dispensing into sealed Vials)

e)

Both or Hybrid System (is defined as an on line and off line: possible using PTFC 2 Fraction Collector and a Photometer with multi-cell changer)

f)

HPLC injection (requires auto sampler ASP2000 and injection system communicates with HPLC for sample injection - data evaluation done by HPLC System software

g)

HPLC fully control system (requires auto sampler and injection system communicates with HPLC system for sample injection and data transfer from integrator to WinDiss32-V3 software. Reporting supplied by WinDiss32 Dissolution program)

h)

In-Situ using Fiber Optics (does not need any pump or tubing - can measure each 15 seconds all 8 vessels, uses PDA Diode Array UV/VIS Photometer wavelength range either 200-6000 nm or 200-1000 nm)

Answer: a ( ) b ( ) c ( ) d ( ) e


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( ) g ( )

h

(


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)

ToDo: Successful Dissolution Testing 2. UV/VIS spectrophotometer If you want to work “on line - closed loop”, then which spectrometer do you wish to use? We recommend the use of a Diode Array Photometer such as the SA500 (full system responsibility from one supplier only) Answer: ……………………………………………. (Spectrometer brand and type). Cell changer exists ? Yes ( ) No ( ) if yes how many channels ? 6 ( ) 7 ( ) 8 ( ) 16 ( ) 2a. Flow cells If you need flow cells for the spectrometer changer, do you have a preference? a) b) c)

Starna, or Hellma. QS which path length do you require ? 0.1mm ( ) 0.5 mm ( ) 1.0 mm ( ) 2.5 mm ( ) 5.0 mm ( ) 10 mm ( ) 20 mm ( ) or other_____

Answer: a

( ) b

( )

3. HPLC injection: If you want to inject samples on-line into a HPLC system, then which system do you wish to use? Answer: Isocratic Pump Type: …………………………………………… Detector Type: ………………………………. Software Suite and Version:…………………………………. (pls. tell us brand and type - manufacturing year). 4. Sampling Method In terms of sampling, we have either in situ (sample probe remains always inside the media) or an Automatic manifold (EPE) which enters the solution with sampling probes only when the actual sampling is required. Do you have a preference? (This can affect the model type offered) a) or b)

In situ - (always in media sample probes) available for PT-DT7/70, DT8, PTWS100, Auto Sampling System - EPE (only available for PTWS 300/310, PTWS600/610, PTWS 1200/1210)

Answer: a ( )

b


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( )


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5. Filtration We have a choice of primary filters which are either 10 micron or 5 micron; which type is best suited? a) b) c)

10 micron, or 5 micron. other, like 0.45 micron

Answer: a

( )

b

( )

c (

)

Do you need any further filtering down to say 0.45 microns as your product changes colour of the dissolution media ? Answer: Yes ( )

No

( )

6. Dilution You may do Dilution at present when sampling manually and measuring the concentration in a UV/VIS spectrophotometer using a 10 mm cuvette. Using a closed loop (on-line) dissolution system Dilution can be avoided using various flow-cell sizes offering different path-length. The range includes flow-cell path length from 0.1 mm, 0.2 mm, 0.5 mm - 1mm, 2mm, 5mm and 10 mm. Using a 1 mm flow cell instead of the 10mm cuvette you are using in your manual method offers a dilution factor of 1:10. Which one will you require ? none ( ) 1:10 ( ) 1:20 ( ) 1:50 ( ) 1:100 ( ) Do you need to dilute the sample from the very first sampling or later ? need to dilute all the time ( ) need to dilute after ….. hrs. ( ) 7. Online Dilution Besides the use a various path length cells its possible to Dilute the sample online if the DSR or ASP 2000 System is attached to the Dissolution Bath. a)

The DSR Sampling Robot can be connected directly to a PTA Dissolution Bath Type DT8, PTWS 100, PTWS 310, a PTWS 600/610, or a PTWS 1200/1210. There is no need to use a PC or software, sampling information is programmed via the keypad of the Dissolution Bath. Its also possible to attach the DSR to any other make of Dissolution Bath and program all sampling information using the DSR keypad. Only online injection into a Spectrophotometer is possible. http://www.pharma-test.de/en/products/p20_6.htm

b)

The ASP 2000 Auto Sampling System can be connected to any Dissolution Bath. The entire System will be controlled by the WinDiss32 Software. Samples can be diluted and injected online into a connected Spectrophotometer or even a HPLC System


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ToDo: Successful Dissolution Testing http://www.pharma-test.de/en/products/p30_10.htm Which system will you prefer ? Answer: System a) ( )

System b)

( )

8. Absorbance problems Do any of your active materials react with or are absorbed by polypropylene? Answer: Yes ( )

No. ( ) (Filter material is PP)

9. Which tubing material do you need ? We supply tubing for sample loops PTFE. Do you need any other material, like FEP? a) b)

PTFE is fine Need other: ___________________________

Answer: a ( ) b ( ) 10. Sample transportation (pumps) For sample transportation, we can offer either a peristaltic pump or a syringe pump. Within a closed loop system no media will be lost. The peristaltic pump is fine for closed loop (i.e., on line systems), but a piston pump is recommended for off line (Fraction collector) systems and auto samplers. This is because of the sure degradation with time of the peristaltic pump tubes which are under a lot of pressure during their working life. Fractions need to be accurately taken as they remove liquid from the dissolution vessels. Do you need : a) b) c)

Peristaltic Syringe pump. Piston Pump

Answer: a ( ) b ( ) c ( ) 11. Sampling only = off-line operation (PTFC 2 Fraction Collector) If you are working off line, would you like simultaneous refilling of the fraction which has been removed from the dissolution vessel (applies to peristaltic pumps only). Do you need refilling? http://www.pharma-test.de/en/products/p20_8.htm a) b)

Yes No.

Answer: Yes ( )

No ( )


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ToDo: Successful Dissolution Testing 12. sampling and injection (Auto Sampler DSR and ASP 2000) Would you require refilling of the fraction which has been removed from the dissolution vessel ? Answer: Yes ( )

No ( )

Do you need to dilute the sample previous to injection ? Answer: Yes ( )

No ( )

Which Dilution do you need: 1:10 ( ) 1:20 ( ) 1:50 ( ) 1:100 ( ) 13. Media Change while dissolution testing - CAT Pump, ASP2000 Do you need to have medium exchange (applies to USP Apparatus 1 or 2 using Sinkers)? http://www.pharma-test.de/en/products/p10_6.htm a) b)

Yes No.

Answer: Yes ( )

No ( )

14. Dissolution Volume Do you need to work with larger dissolution volumes? We are able to offer a variety of larger vessels, not only the standard 1 liter version. Do you need: http://www.pharma-test.de/en/products/po10.htm a) b) c)

1 liter 2 liter 4 to 5 liter versions

Answer: a ( ) b ( ) c

( )

15. Media Degassing and Filling The use of degassed dissolution media is preferable, are you using a degassing system, which one ? Remark: - Helium has relatively high running costs - Ultra Sonic is often insufficient as the volume you need to degas for a dissolution run is at least 6 ltr. - Heating, vacuum and filtration is very time consuming http://www.pharma-test.de/en/products/p10_11.htm PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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ToDo: Successful Dissolution Testing a) b) c) d)

Helium Ultra Sonic Heating, vacuum and filtration (FDA recommended) None

Answer: a ( ) b ( ) c


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( )

d

( )


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38

Parameter

USP Reference Tablets Result Documentation (Example)

Specification

Result each Vessel

1 Temperature Buffer before Start Test Stirring speed Start Test

36.5° - 37.5°C

Temperature Buffer at the End of Test Stirring Speed End Test

36.5° - 37.5°C

Measured AU % dissolved at 30 Minutes

See also Remark 1 Au See also Remark 1 %

Parameter

Specification

2

Vessel Number 3 4

5

6

11

12

Pass

Fail

NA

OK

NOK

NA

48 - 52 96 - 104

48 - 52 96 - 104

Result each Vessel


36.5° - 37.5°C


36.5° - 37.5°C



8

Vessel Number 9 10

48 - 52 96 - 104

48 - 52 96 - 104

Remarks 1:

all data have refer to the specifications of the Batch Report supplied with the USP Reference Tablets


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38.1

Parameter

Repeated Test

Specification

Result each Vessel


36.5° - 37.5°C


36.5° - 37.5°C



Parameter

Specification

2

Vessel Number 3 4

5

6

11

12

Pass

Fail

NA

OK

NOK

NA

48 - 52 96 - 104

48 - 52 96 - 104

Result each Vessel


36.5° - 37.5°C


36.5° - 37.5°C



8

Vessel Number 9 10

48 - 52 96 - 104

48 - 52 96 - 104

Remarks 1:

all data have refer to the specifications of the Batch Report supplied with the USP Reference Tablets

© PHARMA TEST AG, 2009/2010 PHARMA TEST AG Siemensstrasse 5 D-63512 Hainburg (GER)

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