Page 1
`
`LUPIN EX. 1026
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`

`
` Dedication
`
`Disclaimer
`
`The laboratory procedures described herein may involve hazardous material. The authors,
`speaking for themselves, expressly disclaim any liability to users of these lab procedures
`and apparatus for consequential damages of any kind arising out of or connected with
`their use. Items of apparatus and test methodology described in this handbook are in-
`tended to illustrate proper techniques to obtain a quality analysis and are not to be
`considered official and/or required. Official compendia and regulatory requirements are
`to be considered the only authoritative source for such matters.
`
`Copyright © 2004 by Royal A. Hanson
`
`All rights reserved. No part of this book may be reproduced or used in any form or by
`any means whatsoever without the permission of the publisher except in the case of brief
`quotations embodied in critical articles or reviews.
`
`Printed in the United States of America
`2 1 10 9 8 7 6 5 4 3
`
`Library of Congress Control Number 2004115666
`
`Hanson. Royal, and Gray, Vivian
`Handbook of Dissolution Testing/Royal Hanson and Vivian Gray
`Includes bibliographical references and index
`ISBN 0—9761519—0—l (hardcover)
`
`Published by Dissolution Technologies, Incorporated
`9 Yorkridge Trail, Hockessin, DE 19707.
`www_dissolutiontech.com
`
`This, the Third Edition of the Handbook of Dissolution Testing, is
`
`dedicated to the memory of William A. Hanson, Ph.D., founder of
`Hanson Research Corporation. Dr. Hanson was a recognized pioneer
`and longtime leader in the field of dissolution testing.
`Prior to his death at the end of 1994, Dr. Hanson was a constant
`
`contributor to the evolution of test apparatus and procedures. His sig-
`nificant experiments in the field led to his completion of a Doctorate
`in Engineering with a dissertation on the variables encountered in phar-
`maceutical dissolution testing.
`Dr. Hanson supplemented his technical work by writing the Hand-
`book of Dissolution Testing in 1982, followed by a Second Edition in
`1991. As the field of dissolution testing continues to evolve, the authors
`are proud to follow in Dr. Hanson’s giant footsteps in presenting this
`Third Edition of his important book.
`
`
`
`Page 2
`
`

`
`1
`
`Overall
`
`Considerations
`
`()ver the last several decades, the dissolution test has grown from
`a pioneering prototype into a standardized test of pharmaceutical dos-
`age quality assurance. Considering industry’s significant investment in
`drug R&D, formulations, and clinical testing, the dissolution test has
`been proven to provide a simple, cost—efficient, yet rigorous laboratory
`test for drug release characteristics. For this reason alone, it is worthy
`of consideration by developing countries and the worldwide pharma-
`ceutical community.
`The second edition of this Handbook of Dissolution Testing (1991)
`
`was written when the methods, techniques and constraints of dissolu-
`tion testing had been established using Apparatus l (Basket) and Ap-
`paratus 2 (Paddle) as the techniques of choice. These two apparatus
`remain the dominant methods to analyze dissolution of immediate re-
`lease dosage forms. The USP has now added Apparatus 3 (Recipro-
`cating Cylinder), Apparatus 4 (Flow—Through Cell), Apparatus 5 (Pad-
`dle Over Disk), Apparatus 6 (Cylinder), and Apparatus 7 (Reciprocat-
`ing Holder) (l) and the EP has added the flow—through cell, recipro-
`cating cylinder and paddle over disk transdermal apparatus (2). All of
`these apparatus are described in detail in Chapters 3 and 4.
`As this Third Edition goes to press, a collaboration to harmonize the
`USP General Chapters Dissolution <711> and Drug Release <724>
`with the European Pharmacopeia and Japanese Pharmacopeia is nearing
`completion. This effort, led by the International Conference on Har-
`monization (ICH), will include coordination of many aspects of the
`general chapters. For example, equipment dimensions and specifica-
`
`Page 3
`
`

`
`Overall Considerations
`
`3
`
`testing. Disintegration testing was originally proposed in an attempt to
`establish minimum standards.
`J’
`
`In the early stages of pharmaceutical development, the goal was an
`“elegant” tablet: a tablet of beauty that did not chip, deteriorate or
`change color. Of course, the harder" the tablet, the less likely it was to
`chip or fracture during packaging Tor shipment.
`Hardness can be increased by inereasing the binding agent and com-
`pression forces. Unfortunately, hardness can be increased to the point
`where the tablet will not disintegrate in the alimentary tract and where
`the only release of drug will arise from the relatively small surface area
`of the outside of the dosage form. In 1997, an important discovery by
`Ralph Shangraw, et al. (3) showed that many vitamin products con-
`taining folic acid were not meeting the standard of dissolving within
`an hour. This has important implications for the absorption of drugs in
`vivo. Even.today, physicians have observed non-disintegrated tablets
`in patients’ stools.
`The disintegration test was introduced to avoid such problems. The
`apparatus consists of six vertical tubes, each about one inch (25 mm) in
`diameter, arranged in a rack with a 10-mesh screen attached to the under
`surface. The tubes are moved 5.5 cm up and down 30 times/minute while
`submerged in water or simulated intestinal fluid at body temperature (37
`°C). To help the process along, a complicated plastic disc “hammers”
`the tablet during the up-and-down movement (Figure 1-1).
`The disintegration test has been official since 1950 (USP XV), and
`it had enjoyed international acceptance. Various modifications have
`been introduced, one incorporating a l0—mesh screen on the top of the
`tubes to keep capsules from floating out. Also available is a sophisti-
`cated apparatus that registers the time for total tablet disintegration and
`plots results on a digital printer. The tablet is said to pass the test when
`no palpable mass remains on the 10-mesh screen after the designated
`time, typically 30 minutes for ordinary tablets and 60 minutes for en-
`teric-coated tablets.
`
`
`
`The test had been mandatory for oral dosage forms for more than
`40 years, but its elimination and replacement with a universal disso-
`lution standard was encouraged in Pharmacopeial Forum in 1981 (4)
`probably because the disintegration test in general had little statistical
`correlation with bioavailability (5). In the early 1960s,
`the industry
`recognized that the ultimate solution of a drug depends upon two fac-
`tors: the disintegration of the tablet and the deaggregation of the par-
`ticles in the tablet. That process is outlined in Figure 1-2 (and will
`receive greater attention in Chapter 2).
`
`Page 4
`
` 2
`
`HANDBOOK OF DISSOLUTION TESTING
`
`tions, equipment modifications, and use of validated sinkers and auto-
`mated equipment are included (see Chapter 7 for more details).
`
`Why Dissolution Testing?
`
`Besides accommodating the obvious need for meeting the legal re-
`quirements for compendial drugs, dissolution testing is increasingly
`used to test special oral dosage forms now listed in the compendia.
`Those dosage forms include vitamins, herbals, veterinary drugs, chew-
`able tablets, suppositories, suspensions, soft gelatin capsules, creams,
`ointments, gels, transdermal systems, and the vast ever-increasing num-
`ber of extended-release preparations. In addition, there are new product
`types and dosage forms under development, such as chewing gums,
`powders, granules, dispersions, microparticles, stents, liposomes, nano-
`spheres and implants, which may require dissolution testing. The phar-
`maceutical industry will continue to use dissolution testing as a laud-
`able quality control measure for their production operations. They also
`are acutely aware that the worldwide sociological trend is toward ex-
`tension of regulation. In the pharmaceutical business, as in any other,
`it pays to anticipate future developments.
`Dissolution testing, of course, is a regular quality control procedure in
`good manufacturing practices (GMP). Whether or not its numbers have
`been correlated with biological effectiveness, the standard dissolution test
`is a simple and inexpensive indicator of a product’s physical consistency.
`If one batch differs widely from. others in its dissolution characteristics,
`or if the dissolution times of production batches show a consistent trend
`upwards or downwards, it sounds a sure warning that some factor in the
`raw material, formulation, or process is out of control.
`Dissolution data are also useful in the early stages of drug devel— /
`opment and formulation. In the early stages of development, researchers
`may take steps to optimize drug and dosage-form characteristics that
`will influence subsequent bioavailability data.
`
`Disintegration Tests
`
`More than fifty years ago, it was recognized that unless an oral dos-
`age form disintegrated into small aggregates, the body could not absorb
`it efficiently. A unique apparatus was devised to establish a standard
`for disintegration. Its description is still published in USP, but now the
`trend is to omit disintegration specifications and to include dissolution
`
`Page 4
`
`

`
`Overall Considerations
`
`5
`
`Rate measured by the
`disintegration test
`
`
`
`Rate measured by the
`dissolution test
`
`Solid dosage form
`
`A}
`
`
`
`
`
`Disintegration from gross
`tablet size to particles of
`various sizes (depending
`on formulation): <2 mm '
`diameter
`
`Deaggregation: breakdown into
`discrete particles that greatly
`increase surface area, providing
`solid-liquid interface and beginning
`dissolution: <0.25 mm diameter
`
`Figure 1-2 The three stages in the dissolution process.
`
`cies, and compendial standards groups. A prominent pharmaceutical
`manufacturer forcibly brought the matter into focus by a routine in-
`vestigation of identical competitive products. Bioavailability tests in—
`dicated a substantial difference in the performance of the two items,
`which were otherwise pharmaceutically identical according to all then—
`existing tests for physical properties.
`The matter was brought to the attention of compendial committees,
`and a study of various dissolution test methods was inaugurated. At
`that time, the major concern involved life-saving drugs, particularly
`
`Page 5
`
`
`
` 4
`
`HANDBOOK OF DISSOLUTION TESTING
`
`T
`5.5-cm stroke, 30/minute
`
`Media 37 °C
`
`1000—mL Beaker
`
`6 Glass Tubes,
`1-inch diameter
`
`Plastic Disks
`(when specified)
`Tablet
`
`10—Mesh Screen
`
`Figure I -1 USP disintegration testing apparatus. (See USP <70]>
`Disintegration.)
`'
`
`From the pattern shown in the diagram it is apparent that the dis-
`solution rate includes the time factor resulting from the disintegration
`process. It also becomes obvious that dissolution testing includes dis— ‘
`integration time and, therefore, that if dissolution data become man-
`datory, then disintegration information becomes superfluous.
`During the period 1990-1995, many USP disintegration tests were
`replaced with dissolution tests, and the disks were removed from
`<70l> Disintegration USP General chapter. Disks may still be called
`for in individual USP monographs.
`
`Early Dissolution Test Development
`In the early 1960s, problems regarding the bioavailability of drugs
`were receiving more and more attention from industry, regulatory agen-
`
`Page 5
`
`

`
`Overall Considerations
`
`7
`
`
`
`Simple
`Drive Motor
`
`‘
`
`Lab Apparatus
`stand
`
`
`
`
`
`Prototype
`Basket-mixer
`
`1-L Resin Vessel
`
`Dosage
`
`Hot Plate
`
`Figure 1-3 An early primitive dissolution tester. (Note basket-propel
`ler assembly.)
`
`Method 3 (not to be confused with today’s Apparatus 3) was intro-
`duced for indomethacin capsules because of a pre—established database.
`That method used a modification of the existing disintegration equip-
`ment (described above) and has not been extended to any other drug.
`This method has since been eliminated from the USP.
`
`As initially specified, the primary dissolution method included the
`rotating basket in essentially the same dimensions as now. It featured
`a 0.25-inch (6.35 mm) shaft, a 37 °C water bath, and a standard 1000-
`mL resin flask similar to the one now specified but with a flat or con-
`cave indention at the apex of the bottom. Any speed-controlled stirring
`device able to operate at 100 rpm : 4% could be used, although other
`speeds were allowed.
`
`Page 6
`
`
`
` 6
`
`HANDBOOK OF DISSOLUTION TESTING
`
`those with a narrow range between ineffective and toxic blood levels.
`Digoxin is an example, because the physician must establish in a ti-
`trated dosage the effective but nontoxic dosage levels for each patient.
`If the patient switches brand sources of this medication, it naturally
`follows that the second brand must closely approximate the first in its
`ability to sustain therapeutic blood levels. Studies suggested that this
`ability could be correlated to some degree with dissolution rate char-
`acteristics.
`Coordination of the studies was assigned to William Mader, director
`of the Drug Standards Laboratories (later evolved into the USP labo-
`ratory) in Washington, D.C., USA, which operated alongside the com-
`pendial groups. Mader took on a formidable job; evaluation and selec-
`tion of a new and official test procedure affecting the pharmaceutical
`and medical professions, regulatory agencies, and drug manufacturers
`constitutes an awesome and agonizing task. Everyone in industry, gov-
`ernment, and academia who suggested methodology seemed to have a
`private ax to grind. Through that period, Bill Hanson’s experimental
`machine shop worked closely with Mader, supplying him with a variety
`of baskets and stirring devices that would easily have challenged the
`imagination of Rube Goldberg. (An example of one early prototype
`design is shown in Figure 1-3.)
`Each device had to be tested and evaluated on its ability to discrim-
`inate between subtle variations in dissolution characteristics, on the
`repeatability of results from test to test and on its adaptability as com-
`pletely as possible to existing, standard laboratory apparatus. The latter
`criterion was most difficult to assess, because it is always possible to
`design sophisticated tests and equipment that are more functional than
`existing hardware. Nevertheless,
`the cost of dissolution testing ulti-
`mately is borne by the (already) overburdened consumer, and the test
`cost—effectiveness in terms of overall health care costs must remain a
`consideration.
`Helping Mader with his project at the Drug Standards Laboratory
`was Dr. Tim Grady, who later took over as director when Mader retired.
`This pioneering dissolution research continued, and the variables af-
`fecting consistent and repeatable results were studied for more than ten
`years.
`The task had fallen to Mader to forge the first widely accepted dis-
`solution test procedure, and it was published in NF XIII in 1970. Dis-
`solution test methods were made a part of the specification for five
`drugs: indomethacin capsules, and acetohexamide, methandrostenolone,
`methylprednisolone, and sulfamethoxazole tablets.
`
`Page 6
`
`

`
`Overall Considerations
`
`9
`
`evaluation of test results. Compendial requirements for the use of the
`calibrators ensured that the alignment and geometric specifications of
`the stirring apparatus would be more rigidly followed; ultimately, even
`the wide ranges allowed with the cgalibrators cannot be met unless the
`equipment is properly aligned.
`_'_‘:'*‘J
`USP continues its research and evaluation of dissolution test technique
`and methodology to this day.
`'I‘he3'i.most recent collaborative study is
`published in the Pharmacopeial Forum (14), The USP Dissolution Cal-
`ibrator Tablet Collaborative Study—An overview of the 1996 process.
`
`Calibrators
`USP now specifies the calibration of dissolution equipment using
`disintegrating and non-disintegrating calibrator tablets (prednisone and
`salicylic acid) available through their headquarters at 12601 Twinbrook
`Parkway, Rockville, MD 20852, USA. The performance—value ranges
`for calibrating equipment are not outlined in the compendium, but they»
`appear in certificates that come with the calibrator tablets. The allowed
`ranges are wide, and it is a point of discussion for those involved in
`establishing the ranges; the debate about calibrator tablets continues.
`The PhRMA (Pharmaceutical Research and Manufacturers of America)
`Dissolution committee undertook a study to examine mechanical cali-
`brations as a possible replacement for calibrator tablets (9). USP, along
`with other experts and equipment manufacturers, continues to examine
`the use of calibrator tablets and Ways to ensure the equipment is work-
`ing properly. There will be much work in the area in the future.
`European scientists are less than enthusiastic about the use of cali-
`brators. One report points out the difficulties of non-uniforrnity and
`instability of calibrator tablets and argues that strict geometry, close
`tolerances, and a regular check of the dynamic parameters of dissolu-
`tion equipment are the only reliable means of ensuring standardized
`performance (15).
`A regular check of equipment with USP calibrators in order to de-
`termine drift or gradual failure in performance is usually a necessary 1
`routine in GMP laboratories. This includes situations where equipment
`is moved and reinstalled in another lab. Calibrator tests also carry the
`
`added benefit of “system suitability”; that is, calibrators provide a mon-
`itor of not only the experimental conditions but the analytical technique
`as well.
`
`It has been suggested that in-house calibrators should be used as
`standards and should be run simultaneously with each dissolution test
`
`Page 7
`
`itJ1
`11
`EA
`
`5 E
`
` 8
`
`HANDBOOK OF DISSOLUTION TESTING
`
`Development of Dissolution Testing Standards
`Once the dissolution test became official, information from industri-
`al, academic, and regulatory laboratories expanded the literature. A
`series of collaborative tests were conducted for various drugs and the
`relative standard deviation (coefficient of variance) in the results from
`different laboratories turned out to be wider than expected.
`Repeatability of analytical results from laboratory to laboratory and
`within narrow limits is essential where the specified dissolution rate for
`a drug is set at a minimum percent dissolved in a stated time and where
`the product in question dissolves just a few percentage points above
`that minimum. For example, prednisolone tablets have a minimum dis-
`solution rate of 80% dissolved in 30 minutes. If the manufacturer and
`
`outside laboratories or both report numbers in the 84-88% range but
`the regulatory agency reports numbers in the 77-79% range, a serious
`legal problem develops (that is, when 84-88% pass but 77-79% does
`not).
`Clearly, when two laboratories are within i 5 absolute percentage
`points but are above and below the limits, precise definitions and con-
`trol of all equipment and analytical Variables are necessary. Problems
`of this sort have actually occurred with both U.S. and Canadian regu-
`latory agencies. During the 1970s and later, a vast amount of research
`was performed to determine the effect of outside variables. Summaries
`were published and serve as a valuable reference for analysts conduct-
`ing dissolution tests (6-11).
`A significant step toward standardizing dissolution methods occurred
`with the introduction of calibrator tablets. Salicylic acid tablets dem-
`onstrated remarkably consistent and stable dissolution characteristics,
`(12), but they are non-disintegrating dosage forms. A large batch of a
`prednisone/lactose formulation was prepared to serve as a disintegrating
`counterpart to the salicylic acid tablets. Several laboratories then par-
`ticipated in a collaborative study to determine dissolution rates of both
`of these tablets in tests using identical protocols.
`The results of these studies provided a foundation to define and con-
`trol Variable inputs to the current dissolution protocol (13). A two-
`sigma range was established as the first crude criterion for calibrating
`equipment and methods. The ranges allowed may now seem inordi-
`nately wide, but they were a place to start.
`Publication of those results stimulated more extensive research into
`
`dissolution technique and instrumentation. The compendia added re-
`strictions on vibration and dissolved gas and expanded the statistical
`
`Page 7
`
`

`
`Overall Considerations
`
`11
`
`rotating basket method has enjoyed more than 30 years of extensive
`testing for numerous dosage forms. It has been modified, and the of-
`ficial method (Apparatus 1) is described in Chapter 3.
`The basket method represents ~an§13ttempt to constrain the position of
`the dosage form in order to provide the maximum probability of a
`consistent solid—liquid interface. This method has several disadvantages:
`a tendency for gummy substances‘?-to clog the basket screen, extreme
`sensitivity to dissolved gases in the’ dissolution fluid, inadequate flow
`rates when particles leave the basket and float in the medium, and
`constmction difficulties when automated methods are attempted.
`Paddle Method. Originally developed by Poole (19),
`the paddle
`method was modified through the work of scientists at US Food and
`Drug Administration (FDA)’s National Center
`for Drug Analysis
`(NCDA) in St. Louis, Missouri, USA. It consists essentially of a ro-
`tating paddle with a blade of specific dimensions conforming to the
`inside radius of a round-bottomed flask. This method (Apparatus 2)
`overcomes many of the disadvantages of the rotating basket, but it
`requires careful precision in the geometry of the paddle and flask and
`suffers from unacceptable variations in dissolution data following even
`minor changes in paddle orientation. Its convenience for automated
`systems, however, is its strong point.
`Flow-Through Methods. Proposed by many but most extensively
`studied by Langenbucher (20), flow-through methods involve constrain-
`ing the dosage form in a cell and pumping dissolution fluid through
`that cell.
`'
`
`Langenbucher studied the geometry of the cell and the variables
`introduced by variable and/or pulsating flow rates. Although the system
`has not been used extensively in the United States, its obvious advan-
`tages in maintaining sink conditions for drugs with low solubility, but
`high dosage amounts, which saturate in volumes more than 25% of
`specified media volume, suggest benefits. The method also has the add-
`ed advantage of inherent adaptability to automated sampling tech-
`niques, The flow-through method is now official in the United States
`(Apparatus 4) and the European Pharmacopeia, and may be considered
`for drugs that impose saturation problems with the basket or paddle
`methods.
`
`Reciprocating Cylinder Apparatus. The reciprocating cylinder is now
`listed in USP as Apparatus 3 for extended—release dosage forms. This is
`a unique system that “floats” deaggregated particles in a reciprocating
`stream. It has advantages of lower volume of solvent; ease of pH change;
`reduced dwell time to avoid degradation; ease of automated sampling;
`
`Page 8 A
`
`.«as-,_.1m...,...«z.-:.......
`
`
`
`
`
`10
`
`HANDBOOK OF DISSOLUTION TESTING
`
`(16). Such a method provides the maximum assurance against inad-
`vertent equipment malfunction, but practical difficulties arise because
`USP specifies increments of six tests and most commercial dissolution
`equipment provides only six vessels. Manufacturers using this tech-
`nique have run stations of 12 vessels, placing their in-house calibrator
`in at least two. Dissolution test stations with seven or eight stirrers have
`become commercially available.
`
`Methods of Dissolution Testing
`
`Many schemes have been reported for the determination of disso-
`lution rate. A detailed review of these is inappropriate for this publi-
`cation. In sum, though, all methods involve providing a renewable sol-
`id—liquid interface between the dosage form and the dissolution fluid,
`ensuring that this can be defined and controlled and is thus repeatable-
`which is more easily said than done! The controlled flow of fluid over
`a solid introduces requirements of maintaining the surface of the solid
`in a position exposed to a non-accelerating flow——quite a requirement
`for a tablet that moves about because of the similarity of its density to
`that of the liquid or for a tablet that disintegrates into various buoyant
`particles that float in the stream.
`Most of the variations in dissolution methods have been devised to
`bring such variables under control. Unfortunately, some of the methods
`are applicable only to unique dosage forms and become unsatisfactory
`with others. The only methods that will be discussed in detail in this
`manual are those that are already established in the compendia or are
`likely to receive serious consideration as official methods in the next
`few years. Some excellent methods must be omitted, but that is no
`reflection on their probable value or unique characteristics. For various
`reasons, it is unlikely they will be seriously considered as official meth-
`ods in the near future. The spin—filter method of Shah and co—workers
`(17), for example, solves a number of the problems of dissolution test-
`ing, largely by avoiding the clogging of the filters used in automated
`sampling. It seems unlikely, however, that their spin filter method will
`ever be universally accepted in the compendia because of cost, com-
`plexity, and the unrealistic manufacturing tolerances required to avoid
`vibration and other disturbances; considerations that are added to ob-
`
`vious problems of maintenance and operation.
`The methods to be discussed are briefly described below.
`Basket Method. Originally proposed by Pernarowski (18) and mod-
`ified to become the first official method adopted in USP in 1970, the
`
`Page 8
`
`

`
`Overall Considerations
`
`13 -
`
`- Reciprocating. A sophisticated development from the old disinte-
`gration test, reciprocating agitation moves the dosage form up and
`down in a succession of media. These apparatus are illustrated in Fig-
`ures 3-4 and 4-6. This is used as
`drive in USP Apparatus 3 and 7.
`- Fluid Movement. Known as a_,’flow-through system, this agitation
`holds the dosage form relatively stationary while a controlled stream
`of media is pumped past it. A schematic is illustrated in Figure 3-5.
`This is used as the drive in USP Apparatus 4.
`- Percutaneous Absorption. This agitation is used to study the re-
`lease or transfer of a dosage form from or through membranes. Typical
`applications are topical and transdermal formulations. This apparatus is
`illustrated in Figures 4-7 and 4-84.
`
`Defining an Apparatus
`
`The apparatus used in a specific dissolution test or method includes
`an agitation method as described above, and details of dosage form
`mounting within the system. Other parameters of the system are also
`defined,
`including temperature, flow rates, dissolution medium, and
`constraints on environmental input variables, such as external vibration.
`In this handbook, each apparatus is described in as much detail as
`current compendia have established. Solid dosage form methods are
`described in Chapter 3 and special dosage forms in Chapter 4.
`
`Use of Dissolution Test Data
`Dissolution testing is a useful method for: ensuring the bioequiva—
`lence of different batches of solid dosage forms when a rank—ord_er
`correlation between dissolution characteristics and bioavailability has
`been established (this is most likely in situations where dissolution is
`rate limiting in the dissolution/absorption system for the drug-—see
`Chapter 2 for further discussion); monitoring formulation and manu-
`facturing processes by quality control personnel; and establishing the
`intrinsic dissolution rate (see Chapter 2), which is somewhat useful in
`screening compounds being considered for new drug applications
`(NDA’s).
`Finally and most basically, the FDA requires dissolution tests in reg-
`ulatory filings for all oral dosage forms and many other dosage forms
`as well. This is true of the regulatory agencies in most other industrial
`countries. It is likely that dissolution testing will increase and will be-
`come more complicated and more global in the future.
`
`Page 9
`
`
`
`12
`
`HANDBOOK OF DISSOLUTION TESTING
`
`correlation with the database from the now-discarded rotating bottle ap-
`paratus; and impressive correlations with bioavailability data (21).
`Transdermal Dissolution Testing. Apparatus for this testing is dis-
`cussed in Chapter 4. Several methods are now in the USP for these
`dosage forms, and the vertical diffusion cell is under current consid-
`eration for semisolid formulations and topicals. Chapter 4 also discusses
`the testing of other novel and special dosage forms.
`
`Classification of Dissolution Techniques
`
`At present, USP accepts the following methods of dissolution testing:
`(See Chapters 3 and 4 for a detailed discussion on each apparatus.)
`
`USP Apparatus Number
`
`Suitable for
`
`Agitation Method
`
`1 (Basket)
`
`2 (Paddle)
`
`Solids, Beads
`
`Rotating Stirrer
`
`Solids, Suspensions
`
`Rotating Stirrer
`
`3 (Reciprocating Cylinder)
`
`Solids, Beads
`
`Reciprocation
`
`4 (Flow-Through Cell)
`
`§,:1viV‘if;r]:°fn‘i:;1antS
`
`Fluid Movement
`
`5 (Paddle Over Disk)
`
`Transdermal Patches
`
`Rffiatiflg stirrer
`
`6 (Cylinder)
`
`Transdermal Patches
`
`Rotating; Stirfef
`
`7 (Reciprocating Holder)
`
`§$indSSdenfla1Pat°heS’
`
`Reciprocation
`
`To these may be added the following noncompendial method:
`
`Percutaneous Absorption
`(Diffusion Cell)
`
`Topicals, Transdermals,
`Implants
`
`Fluid Movement
`
`Agitation Methods
`Each dissolution technique offers a unique means to provide a con-
`trolled flow of solvent over the surface of the solute, i.e. the solid-
`liquid interface. Four agitation methods can be used:
`- Rotating Stirrer. This is based on the original dissolution test drive.
`It rotates the dosage form or stirs the medium in which the dosage form
`is held. Many variations are commercially available as illustrated in
`Figures 3-2, 3-3, 4-4 and 4-5. This is used as the drive in current USP
`Apparatus 1, 2, 5 and 6.
`
`Page 9
`
`

`
`14
`
`HANDBOOK OF DISSOLUTION TESTING
`
`Role of USP in Dissolution Testing
`
`° General Chapters:
`<701> Disintegration
`<711> Dissolution
`
`<724> Drug Release
`<1087> Intrinsic Dissolution
`<1088> In Vitro and In Vivo Evaluation of Dosage Forms
`
`<1090> In Vivo Bioequivalence Guidances
`<1092> Dissolution Procedure: Development & Validation (pro-
`posed)
`<1225> Validation of Compendial Methods
`- Official Monographs for Drug Dosage Forms
`- USP Calibrator Tablets and Reference Standards
`- Co-sponsors Workshops with American Association of Pharmaceu-
`tical Scientists (AAPS) and FDA
`0 Training Courses, Annual Meetings, Open Committee Meetings and
`Forums
`
`Role of FDA in Dissolution Testing
`
`- Performs Off Shelf Testing
`- Performs Validation of NDA Methods
`
`0 Performs Inspections
`- Orders Recalls
`
`° Issues Product Approvals
`- Enforces USP
`- Publishes Guidances
`
`- Co-sponsors Workshops with AAPS, FIP and USP
`- Forms Task Forces
`- Researches and Evaluates New Methods and Technology
`
`Overall Considerations
`
`15
`
`References
`
`(1) “USP Dissolution General Chapter <711> and USP Drug Re-
`lease General Chapter <724>i-’V, 2004, United States Pharmaco-
`peia and National Formulary, Ignited States Pharmacopeial Con-
`venfion,Inc, 27miEdfljon,23Q3-2312.
`
`(2) “2.9.3. Dissolution Test for Solid Dosage Forms”, 2002, Euro-
`pean Pharmacopoeia, European Directorate for the Quality of
`Medicines of the Council of Europe, 4* Edition, Supplement 4.4,
`3247-3250.
`
`(3) Hoag, SW, Ramachandruni, H and Shangraw, RF, “Failure of Pre-
`scription Prenatal Vitamin Products to Meet USP Standards for
`Folic Acid Dissolution”, 1997, Journal of the American Phar-
`maceutical Association, 37(4), 397-400.
`
`(4) “USP Policy on Dissolution Standards”, 1981, Pharmacopeial
`Forum, 7, 1225-1226.
`
`(5) Wagner, J and Pernarowski, M, “Biopharmaceutics and Relevant
`Pharmacokinetics”, 1971, Drug Intelligence Publications.
`
`(6) Cox, D and Wells, C, “In Vitro Dissolution of Digitoxin Tablets”,
`1978, Internal Document, National Center of Drug Analysis.
`
`(7) Hanson, W, “Solving the Puzzle of Random Variables in Disso-
`lution Testing”, 1977, Pharmaceutical Technology, 1(5), 30-41.
`
`(8) Thakker, D, Naik, N, Gray, V and Sun S, “Fine Tuning of Dis-
`solution Apparatus”, 1980, Pharmacopeial Forum, 6(2), 177-
`185.
`
`(9) PhRMA Subcommittee on Dissolution Calibration: Brune, S,
`Bucko, J, Emr, S, Gray, V, Hippeli, K, Kentrup, A, Whiteman, D,
`Loranger, M and Oates, M, “Dissolution Calibrator: Recommen-
`dations for Reduced Chemical Testing and Enhanced Mechanical
`Calibration”, 2000, Pharmacopeial Forum, 26(4), 1149-1166.
`
`(10) Cox D and Furman, W, “Systematic Error Associated with Ap-
`paratus 2 of the USP Dissolution Test: Effects of Physical Align-
`ment of the Dissolution Apparatus”, 1982, Journal of Pharma-
`ceutical Sciences, 71(4), 451-452.
`
`
`
`
`
`Hamilton, JF, Moore, TW and Kerner, CM, “Reproducibility of
`Dissolution Test Results”, 1995, Pharm