`Phormoceuticoi
`
`Dissolution Testing
`
`
`
`Edited by
`
`Jennifer Dressman
`Johann Wolfang Goethe University
`Frankfurt, Germany
`
`Johannes Kramer
`Phast GmbH
`Hamburg/Saar, Germany
`
`
`
`
`
`
`
`informa
`healthcare
`New York London
`
`ENDO - Ex. 2025
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`Amneal v. Endo
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`|PR2014-00360
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`ENDO - Ex. 2025
`Amneal v. Endo
`IPR2014-00360
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`

`

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`Informa Healthcare USA, Inc.
`52 Vanderbilt Avenue
`New York, NY 10017
`
`© 2009 by Informa Healthcare USA, Inc. (original copyright 2005 by Taylor & Francis Group, LLC)
`Informa Healthcare is an Informa business
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`No claim to original US. Government works
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`International Standard Book Number—10: 0—8247—5467—0 (Hardcover)
`International Standard Book Number—13: 978—0—8247—5467—9 (Hardcover)
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`Library of Congress Cataloging-in—Publication Data
`
`This book is d
`spouses, Tors;
`
`Pharmaceutical dissolution testing / Jennifer Dressman, Johannes Kramer, editors.
`p. ; cm.
`Includes bibliographical references and index.
`ISBN—13: 978—0—8247—5467—9 (alk. paper)
`ISBN—10: 0—8247—5467—0 (alk. paper)
`1. Drugs—-Solubility—-Testing. I. Dressman, J. B. (Jennifer B.) II. Kramer, Johannes, 1959—
`[DNLM: 1. Dosage Forms-—standards. 2. Drug Compounding. 3. Administration, Oral.
`4. Biological Availability. 5. Gastrointestinal Tract——metabolism. QV 778P53523 2005]
`R5189.P446 2005
`2005050291
`615'.10——dc22
`
`
`
`
`
`
`
`
`
`and the Informa Healthcare Web site at
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`
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`Visit the Informa Web site at
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`
`
`
`Transferred to Digital Print 2011
`
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`

`

`
`
`v._—-..—__.
`
`
`
`Compendial Testing Equipment:
`Calibration, Qualification, and
`Sources of Error
`
`VIVIAN A. GRAY
`
`V. A. Gray Consulting,‘Incorporated,
`Hockessin, Delaware, U.S.A.
`
`INTRODUCTION
`
`During the dissolution test, the hydrodynamic aspects of the
`fluid flow in the vessel have a major influence on the dissolu-
`tion rate (1). Therefore, the working condition of the equip-
`ment
`is of critical
`importance.
`In this
`chapter,
`the
`qualification and calibration of the equipment referred to in
`the
`two USP General Chapters
`related to
`dissolu-
`tion, < 711 > Dissolution and < 724> Drug Release (2), will
`be discussed. Sources of error when performing dissolution
`
`39
`
`

`

`_—..—-—-‘..-—
`
`40
`
`Gray
`
`tests and using dissolution equipment will be examined in
`detail later in the chapter.
`
`QUALIFICATION
`
`To ensure that equipment is fit for its intended purpose, there
`is a series of qualifying steps that the analyst or vendor
`should apply to analytical instrumentation (3,4). Equipment
`can be evaluated through a series of tests or procedures
`designed to determine if the system meets an established
`set of specifications governing the accepted operating para—
`meters. The successful completion of such tests justifies that
`the system operates and performs as expected. There are four
`components of instrument qualification: design, installation,
`operational, and performance.
`
`A. When developing a dissolution method, the design
`qualification is built into the apparatus selection
`process. The dosage form and delivery system
`process will dictate at least initially the equipment
`of choice. For example, the first choice for a beaded
`product may be United States Pharmacopeia (USP)
`Apparatus 3, which is designed to confine the beads
`in a screened-in cylinder.
`B. The installation qualification consists of the proce-
`dures used to verify that an instrument has been
`assembled in the appropriate environment and is
`functioning according to pre-defined set of limits
`and tolerances. The data should be documented
`throughout the procedure, especially the hardware
`installation. Safety issues should be addressed.
`For example,
`setting up the fully automated
`dissolution equipment requires the proper plumb-
`ing, hot water source and pressure, electrical wir-
`ing
`and
`voltage,
`and
`drainage
`capability.
`Dissolution equipment should be installed on a
`stable bench top, free of environmental sources of
`vibration.
`
`Compendial Testing Equipment
`
`41
`
`C. During operational qualification the analyst or
`vendor would assess if the equipment works as
`specified, generating appropriately documented
`data. The procedures will verify that the instru-
`ment’s individual operational units are functioning
`within a given range or tolerance, reproducibly.
`For the dissolution apparatus, the water bath tem-
`perature and spindle assembly and shaft rpm speed
`would be obvious operational parameters.
`D. Performance qualificationis conducted to ensure
`that the system is in a normal operating environ-
`ment producing or performing designated set of
`tasks within the established specifications. In disso-
`lution testing,
`the physical parameters such as
`centering, wobble, height of paddle or basket
`attached to shaft, speed, and temperature are per—
`formance qualifications. However, most important
`is the equipment performance with a known pro-
`duct, in many cases this is the calibration procedure
`using the calibrator tablets supplied by USP.
`
`QUALIFICATION OF NON-COMPEN DIAL
`EQUIPMENT
`
`In dissolution testing of novel dosage forms, non-compendial
`equipment may be used. Some examples of non-compendial
`equipment are the rotating bottle, mini paddle, mega paddle
`(5), peak vessel, diffusion cells, chewing gum apparatus, and
`unique cell designs for USP Apparatus 4.
`In all cases,
`compendial equipment should be the first choice and there
`should always be justification, including data, showing why
`official equipment is not suitable.
`
`Methods
`
`If the equipment is a commercial product, the installation and
`operational qualifications can be obtained from the equipment
`vendor. This would include the vendor specifications and
`
`

`

`42
`
`Gray
`
`Compendial Testing Equipment
`
`43
`
`tolerances for the equipment. If it is an in-house design, then
`the process becomes more difficult. The first objective would
`be to look for adjustments and moving parts. Obtain a'base-
`line of operational parameters, such as agitation rate (rpm),
`dip speed, flow rate, temperature, alignment, and/or volume
`control. After enough historical data have been obtained,
`examine the data for reproducibility, assessing the variability
`of the various components. If the analyst is satisfied that the
`equipment performs consistently, then choose ranges or limits
`based on this data. Then develop a per-run performance
`checklist based on these parameters.
`
`Calibration
`
`Non-compendial equipment, and in some cases compendial
`apparatus (Apparatus 4, for example), do not have calibrator
`tablets. In this case, an in-house calibrator tablet can be
`designated. This should be a product that is readily available
`with a large amount of reproducible historical data generated
`on the equipment. Evaluation of mechanical parameters such
`as agitation rate, volume control, alignment, etc. may be suffi-
`cient in some cases, circumventing the need to develop a
`calibrator tablet. However, it should be determined if there
`is some unique aspect of the equipment that can only be
`detected using a calibrator tablet. Currently, with Apparatus
`1 and 2, vibration and vessel irregularities must be detected
`with the USP calibrator tablets, as there are no other practi-
`cal measuring tools available to the analyst.
`
`Hydrodynamics
`
`The dissolution fluid flow characteristics should consist of
`a predictable pattern that is free of irregularities or variable
`turbulence. Observations of the product dissolution behavior
`are critical when choosing a dissolution apparatus.
`If
`there are aberrant or highly variable data that can be attrib-
`uted to the apparatus, then it may be unsuitable for that
`product.
`
`Other Considerations
`
`When using non-compendial equipment, the transferability
`to
`another
`site
`or
`laboratory should be
`considered.
`Non-compendial equipment for quality control testing or at
`a contract laboratory could present problems of ruggedness.
`Therefore, ruggedness should be thoroughly evaluated before
`considering transferring product
`testing to another site,
`which uses a similar piece of equipment. For non-compendial
`as with compendial equipment, it is necessary to have ade-
`quate documentation, often with a log book, to keep track of
`maintenance, problems, repairs and product performance.
`Regular calibration, mechanical and/or chemical, should be
`documented and an appropriate time interval between cali-
`brations determined. A standard operating procedure on
`operation, maintenance and calibration should be included.
`In addition, training and training documentation is critical.
`Further, the cleaning of all equipment parts is important,
`with special attention paid to parts that may be hard to clean
`and lead to contamination or residue build up.
`
`COMPENDIAL APPARATUS
`
`Apparatus 1 and 2
`
`The USP Dissolution General Chapter < 711 > describes the
`basket (Apparatus 1) and paddle (Apparatus 2) in detail.
`There are certain variations in usage of the apparatus that
`occur in the industry and are allowed with proper validation.
`The literature contains a recommendation for a new USP
`
`general chapter for dissolution testing (6). In this article, gui-
`dance for method validation and selection of equipment is
`described. It may be a useful guide when showing equipment
`equivalence to compendial equipment.
`
`Calibration or Apparatus Suitability Test
`
`In < 711 > , there is a paragraph titled the Apparatus Suit-
`ability test. In this paragraph, the use of the USP calibrator
`tablets (Fig. 1) is required. There is some debate as Whether
`
`

`

`44
`
`Gray
`
`Compendial Testing Equipment
`
`45
`
`
`
`Figure 1 USP calibrator tablets, prednisone and salicylic acid.
`(Courtesy of Erweka, GmbH, Heusenstamm, Germany.)
`
`the calibrator tablets are misnamed, since the tablets do not
`correct or adjust any parameter. During calibration, the ana—
`lyst is given a set of ranges that need to be met by each
`calibrator tablet. The results of the calibration tell the analyst
`whether the apparatus is suitable. The calibrator tablets have
`a long history (7). The major reason for the calibrator tablets,
`and this remains a major reason for them today, is the ability
`of the tablets to pick up vibration effects. The Dissolution
`Committee within Pharmaceutical Research Manufacturers
`of America (PhRMA) formerly known as Pharmaceutical Man-
`ufacturers of America (PMA) conducted the collaborative stu—
`dies that determined the aforementioned ranges for the initial
`USP calibrator tablets. These collaborative studies included
`20—30 laboratories that performed dissolution tests on the cali-
`brator tablets using both the basket and paddle dissolution
`apparatus at different speeds. This procedure is still followed
`today for new batches of calibrator tablets and the results of
`the studies are published in the Pharmacopeial Forum (PF)
`of the USP to inform the scientific community how the range
`specifications are obtained and show the detailed statistical
`analysis (8). Within the PhRMA Dissolution Committee, there
`was a Dissolution Calibration Subcommittee. This subcommit-
`tee’s purpose was to examine the dissolution bath calibration
`and look for ways to reduce testing without relaxing the stan-
`
`dards for operating the equipment. For example, mechanical
`calibration was studied thoroughly as an alternative to using
`the calibrator tablet testing (9,10).
`
`Heating Jacket
`
`A water-less bath method is stated in < 711 > as an alterna—
`
`tive way to heat the vessels other than a conventional water
`bath (11). As shown in Figure 2, the vessels are heated with
`a water jacket and are not submerged into a water bath. With
`this bath, as with all testers that use the basket apparatus,
`when the basket shaft with the basket is introduced into
`
`the vessel medium, the temperature will drop slightly. There-
`
`
`
`Figure 2 Water bath-less dissolution testing equipment. (Cour—
`tesy of Distek, Inc., North Brunswick, New Jersey, USA.)
`
`

`

`46
`
`Gray
`
`Compendial Testing Equipment
`
`47
`
`
`
`Figure 3 Peak vessel. (Courtesy of VanKel, a member of the Var-
`ian, Inc. Life Science Business, Cary, North Carolina, USA.)
`
`fore, equilibration or stabilization of the vessel medium
`temperature is necessary before beginning the run.
`
`Peak Vessel
`
`This vessel is designed to eliminate “mounding or coning” by
`having a cone molded into the bottom of the glass vessel, see
`Figure 3. The peak vessel is non-compendial, but may have
`utility with products that contain dense excipients that can
`have a tendency to cone rather than disperse freely inside
`the vessel (12).
`
`Clip and Clipless Baskets
`
`Two types of basket shafts are commercially available to the
`analyst. One type has an O-ring inset in the disk at the end
`of the shaft with the basket fitting snuggly around the O—ring.
`The other has three clips attached to the disk at the end of the
`shaft. The basket is attached by fitting between the clips and
`the disk. The latter design is described in < 711 >. The two
`designs are shown in Figure 4. A recent study (13) compared
`
`
`
`
`
`Figure 4 Two basket attachment designs: On the left is the
`O-ring design and on the right is the three-pronged USP Apparatus
`1 design.
`
`these two types of basket shafts using the two USP calibrator
`tablets, prednisone and salicylic acid, and three development
`products. The study concluded that there was no difference
`between the two basket shaft types for the three development
`products and USP salicylic acid tablets. However, the USP
`prednisone calibrator tablets did show a significantly different
`dissolution rate, with a higher dissolution rate using the
`clipped basket shaft design. The clipped basket shaft is the
`official USP design; however, there are some drawbacks to
`this design. The clips protrude and disturb the fluid flow in
`the vessel. In addition, the clips can weaken over time and
`cause the basket to be attached too loosely to the shaft—
`increasing the chance for wobble. Further, when using robotic
`dissolution testers, a robotic arm can remove the O-ring-type
`basket more efficiently.
`Since the O-ring style is not an official design, the analyst
`should show that it does not give results different from the
`clipped shafts when testing the product. As part of validation,
`the two basket shaft types should be compared and equivalence
`shown. If the types do not give comparable results, there
`could be problems with technology transfer. In addition, if a
`
`

`

`43
`
`Gray
`
`Compendial Testing Equipment
`
`49
`
`
`
`engaged during the test. If this aspect is satisfied then no
`particular equivalence validation needs to occur. During cali-
`bration this apparatus using this two—part design would be
`assessed for significant wobble.
`
`Sinkers
`
`Sinkers are used for floating or sticking of dosage forms. The
`description of sinkers in <711> is brief and not detailed. An
`example of a hand—made USP sinker is shown in Figure 6. In
`Figure 7, the sinker described in the Japanese Pharmaco-
`poeia (JP) is pictured, but several other sinkers are available
`commercially. Since <711> contains the statement that
`other validated sinkers'may be used, any of these designs
`could be considered.
`
`Figure 5 Detachable basket and paddle apparatus device. (Cour-
`tesy of Erweka, GmbH, Heusenstamm, Germany.)
`
`Deaeration
`
`regulatory agency performs the dissolution test on a product
`using the USP procedure,
`the results obtained could be
`different.
`
`Single Entity, Including Two-Part Detachable
`Shaft Design
`
`In Figure 5, an example of the two-part detachable design is
`shown. As < 711 > states,
`the assembly must be firmly
`
`
`
`Figure 6 A hand-made sinker.
`
`The compendium contains a note in <711> that requires
`that air bubbles be removed if they change the results of
`the test. The suggested method found as a footnote in
`<711> uses heat followed by filtration under vacuum. There
`is a plethora of methods for deaeration (14), an earlier method
`was to boil and cool the medium. There are also several
`
`varieties of automated deaeration equipment. The mechan-
`
`
`
`Figure 7 The sinker required in the Japanese Pharmacopeia.
`(Courtesy of VanKel, a member of the Varian, Inc. Life Science
`Business, Cary, North Carolina, USA.)
`
`

`

`50
`
`Gray
`
`
`
`Figure 8 Deaeration equipment. (Courtesy of Hanson Research
`Corporation, Chatsworth, California, USA.)
`
`ism for the. equipment shown in Figure 8 uses a thin film
`vacuum;
`that
`is, pre—heated dissolution media is slowly
`injected through a spray-disbursing nozzle into a closed ves-
`sel. As the media is sprayed, vacuum is applied to remove
`gasses. The closed chamber will fill to a pure-adjusted volume
`
`
`
`
`
`Compendial Testing Equipment
`
`51
`
`
`
`Figure 9 Deaeration equipment. (Courtesy of Distek, Inc., North
`Brunswick, New Jersey, USA.)
`
`level (typically 900 mL) and then, media is subsequently dis-
`pensed into the dissolution flasks. With the equipment shown
`in Figure 9, the media is filtered, heated and degassed under
`vacuum, and precisely dispensed in individual volumes into
`each vessel.
`
`Automated Sampling
`
`Modification of the apparatus to accomplish automation is
`allowed by <711>. One example is hollow shaft sampling
`as illustrated in Figure 10 (15). This method is theoretically
`within the stated sampling location of the text of <711>,
`although there may be question about the concentration of
`sample surrounding the shaft. This and other sampling tech-
`niques, for example in—residence probes, are convenient sam-
`pling tools but should be properly validated.
`
`Apparatus 3
`
`We have now started to discuss the equipment in the USP
`Drug Release General Chapter (< 724 > ). The reciprocating
`cylinder, as shown in Figure 11, has special utility for beaded
`products along with the capability of changing medium by
`
`

`

`52
`
`Gray
`
`Compendial Testing Equipment
`
`53
`
`USP 3 (Bio-Dis)
`
`
`
`Figure 10 Hollow shaft autosampler. (Courtesy of Sotax Corpora-
`tion, Horsham, Pennsylvania, USA.)
`
`removing the dosage unit and placing it in another pH
`medium. This apparatus has been found to be useful for both
`immediate and controlled-release products (16).
`
`Calibration
`
`This equipment has one calibrator tablet: a single tablet pro-
`duct,
`chlorpheniramine
`extended-release
`tablets
`(drug-
`release calibrator, single unit). It has been found that this
`equipment is not particularly sensitive to vibration and has
`reliable and consistent operation (17).
`
`Apparatus 4
`The flow-through cell is especially useful for diesolution rate-
`]imited products, where sink conditions may be hard to obtain
`(18,19). The operation of the flow-through cell. is illustrated
`in Figure 12. A closer look at the tablet holders is shown in
`Figure 13. This particular apparatus can be utilized as either
`a closed or open system. In Figure 14, the closed system mode,
`
`
`
`
`
`50M LEVEL
`AT BOTTOM OF STROKE
`
`TOP SCREEN MESH
`PDLYPROP ~{LIENE
`
`‘ ELLETS
`
`INNER
`VESSEL
`STROKE
`
`
`OUIER VESSEL
`LOCATED IN BATH
`A1 CONTROLLED
`TENPERAIURE
`
`HOTTDH SCREEN MESH
`POLYPROPYLENE
`
`Figure 11 Apparatus 3. (Courtesy of VanKel, a member of the
`Varian, Inc. Life Science Business, Cary, North Carolina, U.S.A.)
`
`including on-line ultraviolet sampling using flowcells, is illu—
`strated. Notice that there is no part of the equipment design
`that allows for waste lines or sampling ports. The system
`would conserve medium, continuing to recycle the testing
`liquid. The open system mode, which is typical in dissolution
`testing, is shown in Figure 15. With the flow-through cell
`design, this system uses a copious amount of medium for
`the test, especially if the test is continued for many hours.
`
`Calibration
`
`The performance of the apparatus has been studied using the
`USP prednisone and salicylic acid tablets (20), but to date
`there are no official calibrator tablets for Apparatus 4. As
`
`

`

`54
`
`Gray
`
`Compendial Testing Equipment
`
`55
`
`Test‘Sample
`
`I EFI'flersystem
`
`Figure 12 Schematic of Apparatus 4. (Courtesy of Sotax Corpora-
`tion, Horsham, Pennsylvania, USA.)
`
`the critical instrument parameters
`mentioned previously,
`should be measured and limits or ranges set. For this equip-
`ment, flow rate is the most critical factor. The medium must
`also deaerated.
`
`
`
`Figure 13 Apparatus 4 tablet holders.
`GmbH, Heusenstamm, Germany.)
`
`(Courtesy of Erweka,
`
`Figure 14 Schematic of the Apparatus 4 as a closed system.
`(Courtesy of Sotax Corporation, Horsham, Pennsylvania, USA.)
`
`
`
`
`Figure 15 Schematic of the Apparatus 4 as an open system.
`(Courtesy of Sotax Corporation, Horsham, Pennsylvania, USA.)
`
`

`

`56
`
`Gray
`
`Compendial Testing Equipment
`
`57
`
`
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`Figure 16 The watchglass—patch—polytef mesh sandwich. (Cour-
`tesy ofHanson Research Corporation, Chatsworth, California, USA.)
`
`Calibration
`
`.
`.l .:
`
`»
`:4
`
`!t‘:.
`
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`‘35:"-
`'-‘-
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`iii-"E.”hA'uLiwl-EL—‘Jgtn’
`
`Figure 17 Apparatus 6. (Courtesy of Erweka, GmbH, Heusen-
`stamm, Germany.)
`
`Apparatus 5
`This apparatus is primarily used for the transdermalpatch.A
`variation of the apparatus is noted in a footnote in <724>. It
`is called the watchglass—patch—polytef mesh sandwich , and is
`favored by the US Food and Drug Administration (FDA) as
`the equipment of choice for transdermal patches. A diagram
`in Figure 16 illustrates how the system is assembled.
`
`'
`
`If the eqlflpment passes the calibration for basket and pad-
`dles, then It can be assumed that the spindle assemblies,
`motor, and drlve belt are functioning prOperly. The analyst
`may be able to teSt the WObble using equipment that assesses
`the run out measurement for the basket.
`
`Apparatus 7
`
`Calibration
`This apparatus uses the paddle as the stirring element. in a
`typical volume of medium. If the equipment passes calibra—
`tion for Apparatus 2, it is suitable for this application.
`
`I
`I:
`
`This apparatus has many design configurations, some apply-
`mg to transdermal patches and others to oral dosage forms, in
`partlcular the osmotic pump extended-release tablet.
`.Calibration
`
`Apparatus 6
`The rotating cylinder is shown in Figure 17. It also in used for
`transdermal patches and can be lengthened for larger patches
`using an adapter.
`
`There are no calibrator tablets available for this apparatus.
`The approach to performance qualification would be as out-
`hned prev10usly, that is, to determine the critical parameters,
`which in this case will include dip rate and volume control.
`
`

`

`58
`
`SOURCES OF ERROR
`
`
`
`When performing dissolution testing, there are many ways
`that the test may generate erroneous results: The test1ng
`equipment and its environment, handling of
`the sample,
`Formulation,
`in situ reactions, automation and analytical
`techniques can all be the cause of errors and variability.
`The physical dissolution of the dosage form should be unen-
`cumbered at all times. Certain aspects of the equipmentcah-
`bration process may show these errors as well as close Visual
`observation of the test. The essentials of the test are accuracy
`of results and robustness of the method. Aberrant and unex-
`pected results do occur, however, and the analyst should be
`well trained to examine all aspects of the dissolution test
`and observe the equipment in operation.
`
`Drug Substance Properties
`Knowledge of drug properties, especially solubility in surfac-
`tants or as a function of pH, is essential. One could ant1c1pate
`precipitation of the drug as the pH changes in solutlon, or if
`release from the dosage form leads to supersaturation ofthe test
`media. Be aware that preparation of a standard solution may be
`more difficult than expected. It is customary to use a small
`amount of alcohol to dissolve the standard completely. A h1story
`of the typical absorptivity range of the standard can be very use—
`ful to determine if the standard has been prepared properly.
`
`Drug Product Properties
`Highly variable results indicate that the method is not robust,
`and this can cause difficulty in identifying trends and effects of
`formulation changes. Two major causal factors influence varla-
`bility: mechanical and formulation. Mechamcal causes can
`arise from the dissolution conditions chosen. Carefully observe
`the product as it dissolves. An apparatus or speed change may
`be necessary. The formulation can have poor content un1for—
`mi ty, additionally, reactions and/or degradatmn may be occur -
`ring in site. The film coating may cause stlclnng to'the vessel
`walls. Upon aging, capsule shells are known for pelhcle forma-
`
`Gray
`
`Compendial Testing Equipment
`
`59
`
`tion and tablets may become harder or softer, depending upon
`the excipients and drug interaction with moisture, which in
`turn may affect the dissolution and disintegration rate.
`
`Equipment
`
`Major components of dissolution equipment are the tester
`(including typically, but not limited to, spindle assemblies,
`belt, motor, tension adjuster, and circulator pump and hoses),
`water bath, paddles, baskets and shafts, vessels, samplers,
`and analyzers. Mechanical aspects, such as media tempera-
`ture, paddle or basket speed, shaft centering and wobble,
`and vibration can all have a significant impact on the dissolu-
`tion of the product. Mechanical and chemical calibration
`should therefore be conducted periodically, usually every 6
`months, to ensure that the equipment is working properly.
`In <711>, there is a requirement for the analyst to
`perform the apparatus suitability test using USP calibrator
`tablets. USP calibrator tablets come with certificates identify-
`ing appropriate ranges. The apparatus suitability test is
`designed to detect sources of error associated with improper
`operation and inadequate condition of
`the equipment
`(9,10,21). Two calibrators are used; USP prednisone tablets,
`10 mg, and USP salicylic acid tablets, 300 mg. Use of each
`of these types of calibrator tablets involves calibrator-specific
`considerations. The salicylic acid tablets should be brushed
`before using to remove fine particles. This task should be
`performed in a hood to avoid breathing the irritating dust.
`Use whole tablets, and check whether the tablets are chipped
`or nicked. Since this tablet dissolves through erosion and is
`pure compressed salicylic acid, minor chips or nicks have no
`significant effect on the dissolution rate, if large chunks are
`missing results may be affected. The buffer should be pre-
`pared according to USP Reagent (Buffers) section.
`The prednisone tablets use deaerated water as the med-
`ium. There are numerous methods for deaeration of medium
`(14,22). As mentioned above, there are also automated methods
`available. The method described in <711> uses heat, filtra-
`tion, and vacuum. Helium sparging is also a typical method
`
`

`

`60
`
`Gray
`
`for deaeration. The level of dissolved oxygen and other gases is
`related to the presence of bubbles. Bubbles are common and
`will cause problems in non-deaerated medium. In <711>, it
`is stated that bubbles can interfere with dissolution test results
`and should be avoided. Dissolved air can slow down dissolution
`by creating a barrier; either adhering to the tablet surface or to
`basket screens, or particles can cling to bubbles on the glass
`surface of the vessel or shafts. Dissolution tests should always
`be performed immediately after deaeration. It is best not to
`have the paddle rotating before adding the tablet, as paddle
`movement will reaerate the medium.
`When preparing standard. solutions, be sure to dry the
`reference standard properly, preferably on the day of use.
`Care should be taken to ensure that the drug powder is
`completely dissolved. In the case of prednisone reference stan-
`dard, the powder becomes very hard upon drying, making it
`slower to dissolve. Dissolving the powder first in a small
`amount of alcohol helps to overcome this problem.
`Vibration interference is a common problem with disso-
`lution equipment (23'). Careful leveling of the top plate and
`lids is critical. Within the spindle assembly,
`the hearings
`can become worn and cause vibration and wobble of the shaft.
`The drive belts should be checked for wear and dirt. The ten—
`sion adjustments for the belt should be optimized for smooth
`operation. Surging of spindles, though difficult to detect with-
`out closely scrutiniaing the tester operation, can cause
`spurious results. Vessels need to be locked in place so that
`they are not moving with the flow of water in the bath.
`External vibration sources might include other equipment
`on bench tops such as shakers, centrifuges, or sonicators. Local
`construction in the area or within the building is a common,
`though often overlooked, source ofvibration. The testers should
`not be near hoods or significant airflow sources. Additionally,
`heavy foot traffic and door slamming should be avoided.
`These days, the water bath itself is rarely a source of
`vibration because the design has been changed to eliminate
`noisy circulators near the bath. Measuring the temperature
`of the medium in all the vessels, rather than just one, can
`assure the temperature uniformity. The bath water level
`
`Compendial Testing Equipment
`
`61
`
`should always be maintained at the top of the vessels to
`ensure uniform heating of the medium. Lastly, the water bath
`should contain clean water so that observations of the dissolu-
`tion test can be performed clearly and easily.
`Close inspection of USP Apparatus 1 and 2 before use
`can help identify sources of error. Obviously, dimensions
`should be as specified. In cases of both baskets and paddles,
`shafts must be straight and true. The paddles are sometimes
`partially coated with Teflon. This coating can peel and
`partially shed from the paddle, causing flow disturbance of
`hydrodynamics within the vessel. Paddles can rust and
`become nicked or dented; this can adversely affect dissolution
`hydrodynamics and. he a source of contamination. Thorough
`cleaning of the paddles is also important, to preclude carry
`over of drug or medium.
`The baskets need special care and examination. They can
`become frayed, misshapen, or warped with use. Screen mesh
`size may change over time, especially when used with acidic
`medium. Baskets are especially prone to gelatin or excipient
`build up if not cleaned immediately after use.
`I
`Vessals have their own set of often-overlooked problems.
`Vessels are manufactured from. large glass tubing. Then the
`vessel bottom is individually rounded. Depending upon tech-
`niques of the heatingfshaping process,
`irregular surfaces
`can occur and the uniformity of vessel bottom roundness
`can vary. Cheaply made vessels are notorious for
`this
`problem. Close examination of vessels when newly purchased
`is very important, as surface irregularity can cause dissolu-
`tion results to differ significantly. Another common problem
`with vessels is residue build up either from