Pharmaceutical
`Dissolution Testing
`
`
`
`© 2005 by Taylor & Francis Group, LLC© 2005 by Taylor & Francis Group, LLC
`
`MYLAN EXHIBIT 1032
`
`

`

`Pharmaceutical
`Dissolution Testing
`
`Edited by
`
`Jennifer Dressman
`Johann Wolfang Goethe University
`Frankfurt, Germany
`
`Johannes Krämer
`Phast GmbH
`Homburg/Saar, Germany
`
`
`
`© 2005 by Taylor & Francis Group, LLC© 2005 by Taylor & Francis Group, LLC
`
`

`

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`© 2005 by Taylor & Francis Group, LLC
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`

`

`1
`
`Historical Development of
`Dissolution Testing
`
`JOHANNES KRA¨ MER, LEE TIMOTHY GRADY,
`and JAYACHANDAR GAJENDRAN
`
`Phast GmbH, Biomedizinisches Zentrum,
`Homburg/Saar, Germany
`
`INTRODUCTION
`
`Adequate oral bioavailability is a key pre-requisite for any
`orally administered drug to be systemically effective. Dissolu-
`tion (release of the drug from the dosage form) is of primary
`importance for all conventionally constructed, solid oral
`dosage forms in general, and for modified-release dosage
`forms in particular, and can be the rate limiting step for the
`absorption of drugs administered orally (1). Physicochemi-
`cally, ‘‘Dissolution is the process by which a solid substance
`enters the solvent phase to yield a solution’’ (2). Dissolution
`of the drug substance is a multi-step process involving
`
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`2
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`Kra¨mer et al.
`
`heterogeneous reactions/interactions between the phases of
`the solute–solute and solvent–solvent phases and at the
`solute–solvent interface (3). The heterogeneous reactions that
`constitute the overall mass transfer process may be categor-
`ized as (i) removal of the solute from the solid phase, (ii)
`accomodation of the solute in the liquid phase, and (iii) diffu-
`sive and/or convective transport of the solute away from the
`solid/liquid interface into the bulk phase. From the dosage
`form perspective, dissolution of the active pharmaceutical
`ingredient, rather than disintegration of the dosage form, is
`often the rate determining step in presenting the drug in
`solution to the absorbing membrane. Tests to characterize the
`dissolution behavior of the dosage form, which per se also
`take disintegration characteristics into consideration, are
`usually conducted using methods and apparatus that have
`been standardized virtually worldwide over the past decade
`or so, as part of the ongoing effort to harmonize pharmaceuti-
`cal manufacturing and quality control on a global basis.
`the
`The history of dissolution testing in terms of
`evolution of the apparatus used was reviewed thoroughly by
`Banakar in 1991 (2). This chapter focuses first on the pharma-
`copeial history of dissolution testing, which has led to manda-
`tory dissolution testing of many types of dosage forms for
`quality control purposes, and then gives a detailed history
`of two newer compendial apparatus, the reciprocating cylin-
`der and the flow-through cell apparatus. The last section of
`the chapter provides some historical
`information on the
`experimental approach of Herbert Strieker’s group. His scien-
`tific work in combining permeation studies directly with a dis-
`solution tester, is very much in line with the Biopharmaceutic
`Classification System (BCS), but was published more than
`two decades earlier than the BCS (4) and can therefore be
`viewed as the forerunner of the BCS approach.
`
`FROM DISINTEGRATION TO DISSOLUTION
`
`Compressed tablets continue to enjoy the status of being the
`most widely used oral dosage form. Tablets are solid oral
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`© 2005 by Taylor & Francis Group, LLC
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`Historical Development of Dissolution Testing
`
`3
`
`dosage forms of medicinal substances, usually prepared with
`the aid of suitable pharmaceutical excipients. Despite the
`advantages offered by this dosage form, the problems asso-
`ciated with formulation factors remain to some extent enig-
`matic to the pharmaceutical scientist.
`In the case of
`conventional (immediate-release) solid oral drug products,
`the release properties are mainly influenced by disintegration
`of the solid dosage form and dissolution of drug from the dis-
`integrated particles. In some cases, where disintegration is
`slow, the rate of dissolution can depend on the disintegration
`process, and in such cases disintegration can influence the
`systemic exposure, in turn affecting the outcome of both bioa-
`vailability and bioequivalence studies. The composition of all
`compressed conventional tablets should, in fact, be designed
`to guarantee that they will readily undergo both disintegra-
`tion and dissolution in the upper gastrointestinal (GI) tract
`(1). All factors that can influence the physicochemical proper-
`ties of the dosage form can influence the disintegration of the
`tablet and subsequently the dissolution of the drug. Since the
`1960s, the so-called ‘‘new generation’’ of pharmaceutical
`scientists has been engaged in defining, with increasing
`chemical and mathematical precision, the individual vari-
`ables in solid dosage form technology, their cumulative effects
`and the significance of these for in vitro and in vivo dosage
`form performance, a goal that had eluded the previous
`generation of pharmaceutical scientists and artisans.
`As already mentioned, both dissolution and disintegra-
`tion are parameters of prime importance in the product
`development strategy (5), with disintegration often being
`considered as a first order process and dissolution from drug
`particles as proportional to the concentration difference of
`the drug between the particle surface and the bulk solution.
`Disintegration usually reflects the effect of formulation and
`manufacturing process variables, whereas the dissolution
`from drug particles mainly reflects the effect of solubility and
`particle size, which are largely properties of the drug raw
`material, but can also be influenced significantly by proces-
`sing and formulation. It is usually assumed that the dissolu-
`tion of drug from the surface of the intact dosage form is
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`4
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`Kra¨mer et al.
`
`negligible, so tablet disintegration is key to creating a larger
`surface area from which the drug can readily dissolve. However,
`tablet disintegration in and of itself may not be a reliable indica-
`tor of the subsequent dissolution process, so the tablet disinte-
`gration tests used as a quality assurance measure may or may
`not be a an adequate indicator of how well the dosage form will
`release its active ingredient in vivo. Only where a direct
`relationship between disintegration and dissolution has been
`established, can a waiver of dissolution testing requirements
`for the dosage form be considered (6).
`Like disintegration testing, dissolution tests do not prove
`conclusively that the dosage form will release the drug in vivo
`in a specific manner, but dissolution does come one step
`closer, in that it helps establish whether the drug can become
`available for absorption in terms of being in solution at the
`sites of absorption. The period 1960–1970 saw a proliferation
`of designs for dissolution apparatus (7). This effort led to the
`adoption of an official dissolution testing apparatus in the
`United States Pharmacopeia (USP) and dissolution tests with
`specifications for 12 individual drug product monographs in
`the pharmacopeia. These tests set the stage for the evolution
`of dissolution testing into its current form.
`
`DISSOLUTION METHODOLOGIES
`
`The theories applied to dissolution have stood the test of time.
`Basic understanding of these theories and their application
`are essential for the design and development of sound dissolu-
`tion methodologies as well as for deriving complementary
`statistical and mathematical techniques for unbiased dis-
`solution profile comparison (3).
`In the 1960s and 1970s, there was a proliferation of
`dissolution apparatus design. With their diverse design speci-
`fications and operating conditions, dissolution curves
`obtained with them were often not comparable and it was
`gradually realized that a standardization of methods was
`needed, which would enable correlation of data obtained with
`the various test apparatus. As a result,
`the National
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`© 2005 by Taylor & Francis Group, LLC
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`Historical Development of Dissolution Testing
`
`5
`
`Formulary (NF) XIV and USP XVIII and XIX (8) standardized
`both the apparatus design and the conditions of operation for
`given products. With these tests, comparable results could be
`obtained with the same apparatus design, even when the appa-
`ratus was produced by different equipment manufacturers.
`
`PERSPECTIVE ON THE HISTORY OF
`COMPENDIAL DISSOLUTION TESTING
`
`. . . it would seem that prompt action of certain remedies
`must be considerably impaired by firm compression. ...
`the composition of all compressed tablets should be such
`that they will readily undergo disintegration and solution
`in the stomach. [C. Caspari, ‘‘A Treatise on Pharmacy,’’
`1895, Lea Bros., Philadelphia, 344.]
`
`Tableting technology has had more than a century of
`development, yet the essential problems and advantages of
`tablets were perceived in broad brush strokes within the
`first years. Compression, powder flow, granulation, slugging,
`binders, lubrication, and disintegration were all appreciated
`early on, if not scientifically, at least as important considera-
`tions in the art of pharmacy. Industrial applications of tablet-
`ing were not limited to drugs but found broad application in
`the confectionery and general chemical industry as well. Poor
`results were always evident and, already at the turn of the
`20th century, some items were being referred to as ‘‘brick-
`bats’’ in the trade.
`With the modern era of medicine, best dated as starting
`in 1937, tablets took on new importance. Modern synthetic
`drugs, being more crystalline, were generally more amenable
`to formulation as solid dosage forms, and this led to greater
`emphasis on these dosage forms (9). Tableting technology
`was still largely empirical up to 1950, as is evidenced by the
`literature of the day. Only limited work was done before
`1950, on drug release from dosage forms, as opposed to disin-
`tegration tests, partly because convenient and sensitive
`chemical analyses were not yet available. At that time, disso-
`lution discussions mainly revolved around the question of
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`6
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`Kra¨mer et al.
`
`whether the entire content could be dissolved and was mostly
`limited to tablets of simple, soluble chemicals or their salts.
`The first official disintegration tests were adopted in
`1945 by the British Pharmacopoeia and in 1950 by the USP.
`Even then,
`it was recognized that disintegration testing
`is an insufficient criterion for product performance, as
`evidenced by the USP-NF statement that ‘‘disintegration does
`not imply complete solution of the tablet or even of its active
`ingredient.’’ Real appreciation of the significance of drug
`release from solid dosage forms with regard to clinical relia-
`bility did not develop until there were sporadic reports of
`product failures in the late 1950s, particularly vitamin pro-
`ducts. Work in Canada by Chapman et al., for example,
`demonstrated that formulations with long disintegration
`times might not be physiologically available. In addition,
`the great pioneering pharmacokineticist John Wagner
`demonstrated in the 1950s that certain enteric-coated pro-
`ducts did not release drug during Gl passage and that this
`could be related to poor performance in disintegration tests.
`Two separate developments must be appreciated in
`discussing events from 1960 onward. These enabled the field
`to progress quickly once they were recognized. The first was
`the increasing availability of reliable and convenient instru-
`mental methods of analysis, especially for drugs in biological
`fluids. The second, and equally important development, was
`the fact that a new generation of pharmaceutical scientists
`were being trained to apply physical chemistry to pharmacy,
`a development largely attributable, at least in the United
`States, to the legendary Takeru Higuchi and his students.
`Further instances in which tablets disintegrated well (in
`vitro) but were nonetheless clinically inactive came to light.
`Work in the early 1960s by Campagna, Nelson, and Levy
`had considerable impact on this fast-dawning consciousness.
`By 1962, sufficient industrial concern had been raised to
`merit a survey of 76 products by the Phamaceutical Manufac-
`turers of America (PMA) Quality Control Section’s Tablet
`Committee. This survey set out to determine the extent of
`drug dissolved as a function of drug solubility and product
`disintegration time. They found significant problems, mostly
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`© 2005 by Taylor & Francis Group, LLC
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`Historical Development of Dissolution Testing
`
`7
`
`occurring with drugs of less than 0.3% (30 ug/mL) solubility in
`water, and came within a hair of recommending that dissolu-
`tion, rather than disintegration, standards be set on drugs of
`less than 1% solubility.
`Another development that occurred between 1963 and
`1968 that continues to confabulate scientific discussions of
`drug release and dissolution testing was the issue of generic
`drug approval. During this period, drug bioavailability
`became a marketing, political, and economic issue. At first,
`generic products were seen as falling short on performance.
`However later it turned out that the older formulations, that
`had been marketplace innovators, were often short on perfor-
`mance compared to the newly formulated generic products.
`To better compare and characterize multi-source (gen-
`eric) products, the USP-NF Joint Panel on Physiological
`1)
`(Table
`Availability was set up in 1967
`under Rudolph
`Blythe, who already had led industrial attempts at standardi-
`zation of drug release tests. Discussions of the Joint Panel led
`to adoption, in 1970, of an official apparatus, the Rotating
`Basket, derived from the design of the late M. Pernarowski,
`long an active force in Canadian pharmaceutical sciences. A
`commercial reaction flask was used for cost and ruggedness.
`The monograph requirements were shepherded by William
`J. Mader, an industrial expert in analysis and control, who
`directed the American Pharmaceutical Association (APhA)
`Foundation’s Drug Standards Laboratory. William A. Hanson
`prepared the first apparatus and later commercialized a
`series of models.
`The Joint Panel proposed no in vivo requirements, but
`individual dissolution testing requirements were adopted in
`12 compendial monographs. USP tests measured the time to
`attain a specified amount dissolved, whereas NF used the
`more workable test for the amount dissolved at a specified
`time. Controversy with respect to equipment selection and
`methodology raged at the time of the first official dissolution
`tests. As more laboratories entered the field, and experience
`(and mistakes!) accumulated, the period 1970–1980 was one
`of intensive refinement of official test methods and dissolution
`test equipment.
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`© 2005 by Taylor & Francis Group, LLC
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`8
`
`Kra¨mer et al.
`
`Table 1 USP Timeline from 1945–1999
`
`1945–1950
`1962
`1967
`
`1970
`1971–1974
`
`1975
`
`1976
`
`1977
`1978
`
`1979
`1980
`
`1981
`
`1982
`1984
`1985
`
`1990
`
`1995
`
`1997
`
`1999
`
`Disintegration official in Brit Pharmacon and USP
`PMA Tablet Committee proposes 1% solubility threshold
`USP and NF Joint Panel on Physiological Availability
`chooses dissolution as a test chooses an apparatus
`Initial 12 monograph standards official
`Variables assessment; more laboratories, three
`Collaborative Studies by PMA and Acad. Pharm. Sci
`First calibrator tablets pressed; First Case default proposed
`to USP
`USP Policy—comprehensive need; calibrators Collaborative
`Study
`USP Guidelines for setting Dissolution standards
`Apparatus 2—Paddle adopted; two Calibrator Tablets
`adopted
`New decision rule and acceptance criteria
`Three case Policy proposed; USP Guidelines revised; 70
`monographs now have standards
`Policy adopted January, includes the default First Case,
`monograph proposals published in June
`Policy proposed for modified-release dosage forms
`Revised policy adopted for modified-release forms
`Standards now in nearly 400 monographs; field considered
`mature; Chapter < 724 > covers extended-release and
`enteric-coated
`Harmonization: apparatus 4—Flow- through adopted;
`Apparatus 3 Apparatus 5, 6, 7 fortransdermal drugs
`Third Generation testing proposed—batch phenomenon;
`propose reduction in calibration test number
`FIP Guidelines for Dissolution Testing of Solid Oral
`Products; pooled analytical samples allowed
`Enzymes allowed for gelatin capsules reduction from 0.1 N
`to 0.01 N Hcl
`
`Later, a second apparatus was based on Poole’s use of
`available organic synthesis round-bottom flasks as refined
`by the St. Louis laboratory. Neither choice of dissolution
`equipment proved to be optimal, indeed, it may have been
`better if the introduction of the two apparatus had occurred
`in the reverse order. With time, the USP would go on to offer
`a total of seven apparatuses, several of which were introduced
`primarily for products applied to the skin.
`
`© 2005 by Taylor & Francis Group, LLC
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`

`Historical Development of Dissolution Testing
`
`9
`
`At the time, the biopharmaceutical problems, such as
`with low-solubility drugs, both in theoretical terms and in
`actual clinical failures were already well recognized. The
`objective of the Joint Panel was to design tests which could
`determine whether tablets dissolved within a reasonable
`volume, in a commercial flask. In those days, drugs were often
`prescribed in higher doses, so the volume of the dissolution
`vessels in terms of providing an adequate volume to enable
`complete dissolution of the dose had to be taken into design
`consideration. Over the last 35 years there has been a trend
`to develop more potent drugs, with attendant decrease in
`doses required (with notable exceptions, especially anti-infec-
`tives). For example, an antihypertensive may have been
`dosed at 250 mg, but newer drugs in the same category
`coming onto the market might be dosed as low as 5 mg. Sub-
`sequently, there has been a change in the amount of drug that
`needs to get dissolved for many categories of drugs. Neverthe-
`less, a few monographs (e.g., digoxin tablets) have always pre-
`sented a challenge to design of dissolution tests. The following
`factors exemplify typical problems associated with the devel-
`opment of dissolution tests for quality control purposes:
`
`1. The need to have a manageable volume of dissolution
`medium.
`2. The development of less-soluble compounds as drugs
`(resulting in problems in achieving complete dissolu-
`tion in a manageable volume of medium).
`Insufficient analytical sensitivity for low-dose drugs,
`especially at higher media volumes (as illustrated in
`the USP monograph on digoxin tablets).
`
`3.
`
`It should be remembered that in 1970, when drug-
`release/dissolution tests first became official through the
`leadership of USP and NF, marketed tablets or capsules in
`general simply did not have a defined dissolution character.
`They were not formulated to achieve a particular dissolution
`performance, nor were they subjected to quality control by
`means of dissolution testing. Moreover, the U.S. Food and
`Drug Administration (FDA) was not prepared to enforce
`dissolution requirements or to even to judge their value.
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`© 2005 by Taylor & Francis Group, LLC
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`10
`
`Kra¨mer et al.
`
`The tremendous value of dissolution testing to quality
`control had not yet been established, and this potential role
`was perceived in 1970 only dimly even by the best placed
`observers. Until the early 1970s, discussions of dissolution
`were restricted to the context of in vivo–in vitro correlation
`(IVIVC) with some physiologic parameter. The missing link
`between the quality control and IVIVC aims of dissolution
`testing was that dissolution testing is sensitive to formulation
`variables that might be of biological significance because
`dissolution testing is sensitive in general to formulation
`variables.
`Between 1970 and 1975, it became clear that dissolution
`testing could also play a role in formulation research and
`product quality control. Consistent with this new awareness
`of the value of dissolution testing in terms of quality control
`as well as bioavailability, USP adopted a new policy in 1976
`that favored the inclusion of dissolution requirements in
`essentially all tablet and capsule monographs. Thomas Med-
`wick chaired the Subcommittee that led to this policy. Due
`to lack of industrial cooperation, the policy did not achieve full
`realization. Nevertheless, by July 1980 the role of dissolution
`in quality control had grown to appeareance in 72 mono-
`graphs, most supplied by USP’s own laboratory under the
`direction of Lee Timothy Grady, and FDA’s laboratory under
`the direction of Thomas P. Layloff. USP continued to
`(Fig.
`1)
`adopt further dissolution apparatus designs
`and
`refine the methodology between 1975 and 1980, as shown in
`Table 1.
`Over the years, dissolution testing has expanded beyond
`ordinary tablets and capsules—first to extended-release and
`delayed-release (enteric-coated) articles, then to transder-
`mals, multivitamin and minerals products, and to Class
`Monographs for non-prescription drug combinations. (Note:
`at the time, ‘‘sustained-release’’ products were being tested,
`unofficially, in the NF Rotating Bottle apparatus).
`Tablets and capsules that became available on the
`market in the above time frame often showed 10–20% relative
`standard deviation in amounts dissolved. The FDA’s St. Louis
`Laboratories results on about 200 different batches of drugs
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`© 2005 by Taylor & Francis Group, LLC
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`Historical Development of Dissolution Testing
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`11
`
`Figure 1 Rotating basket method. Source: From Ref. 10.
`
`available showed that variation tend to be greatest for slowly
`dissolving drugs. Newer formulations, developed using disso-
`lution testing as one of the aids to product design, are much
`more consistent. Another early problem in dissolution testing
`was lab-to-lab disagreement in results. This problem was
`essentially resolved when testing of standard ‘‘calibrator’’
`tablets were added to the study design, for which average
`dissolution values had to comply with the USP specifications
`to qualify the equipment in terms of its operation. Every
`calibrator batch produced since the inaugauration of calibra-
`tors has been subjected to a Pharmaceutical Manufactorers of
`America (PMA)/Pharmaceutical Research and Manufacturers
`of America (PhRMA) collaborative study to determine accep-
`tance statistics. Originally, calibrators were adopted to pick
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`12
`
`Kra¨mer et al.
`
`up the influence on dissolution results due to vibration in the
`equipment, failures in the drive chains and belts, and opera-
`tor error. In fact, perturbations introduced in USP equipment
`are usually detected by at least one of the two types of calibra-
`tors (prednisone or salicylic acid tablets). Although the cali-
`brators were not adopted primarily to test either deaeration
`or temperature control, they proved to be of value here, too.
`As a follow-up, the USP developed general guidelines on de-
`aeration early in the 1990s, presently favoring a combination
`of heat and vacuum. In the late 1990s, the number of tests to
`qualify an apparatus was halved. Yet even today, an appara-
`tus can fail the calibrator tablet tests, since small individual
`deviations in the mechanical calibration and operator error
`can combine to produce out of specification results for the cali-
`brator. Thus, the calibrators are an important check on oper-
`ating procedures, especially in terms of consistency between
`labs on an international basis.
`In addition to the increasing interest in dissolution as a
`quality control procedure and aid to development of dosage
`forms, bioavailability issues continued to be raised through-
`out the 1970–1980 period, as clinical problems with various
`oral solid products dissolution and bioavailability continued
`to crop up. Much of the impetus behind the bioavailability
`discussions came from the issue of bioequivalence of drugs
`as this relates to generic substitution. In January 1973,
`FDA proposed the first bioavailability regulations. These
`were followed in January 1975 by more detailed bioequiva-
`lence and bioavailability regulations, which became final in
`February 1977. A controversial issue in these regulations
`proved to be the measurement of the rate of absorption. The
`1975 revision proposal was the first to contain the concept
`of an in vitro bioequivalence requirement, which reflected
`the growing awareness of the general utility of dissolution
`testing at that time.
`A major wave of generic equivalents were introduced to
`the U.S. market following the Hatch–Waxman legislation in
`the early 1970s and ANDA applications to the FDA provided
`the great majority of IVIVC available to USP for non-First
`Case standards setting during the following years.
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`Historical Development of Dissolution Testing
`
`13
`
`From the USP perspective, digoxin tablets became and
`remained the benchmark for the impact of dissolution on bioa-
`vailability. It is a life-saving and maintaining drug, has a low
`therapeutic index, is poorly soluble, has a narrow absorption
`window (due to p-glycoprotein exotransport) and it is formu-
`lated using a low proportion of drug:excipients due to its high
`potency. Correlation between dissolution and absorption was
`first shown for digoxin in 1973. The official dissolution stan-
`dard that followed was the watershed for the entire field. It
`is interesting to note that clinical observations for digoxin
`tablets were made in only few patients. Similarly, the original
`concerns of John Wagner over prednisone tablets were based
`on observations in just one patient. The message from these
`experiences is that decisive bioinequivalences can be picked
`up even in very small patient populations.
`At the time the critical decisions were made, it seemed
`that diminished bioavailability could usually be linked to
`formulation problems. Scientists recognized early that when
`the rate of dissolution is less than the rate of absorption,
`the dissolution test results can be predictive of correlation
`with bioavailability or clinical outcome. At that time, there
`was little recognition that intestinal and/or hepatic metabo-
`lism mattered, an exception being the phenothiazines. So
`the primary focus was on particle size and solubility. Observa-
`tions with prednisone, nitrofurantoin, digoxin and other
`low-solubility drugs were pivotal to decision making at the
`time, since the dissolution results could be directly linked to
`clinical data. Scientists recognized that it is not the solubility
`of the drug alone that is critical, but that the effective surface
`area from which the drug is dissolving also plays a major role,
`as described by the Noyes–Whitney equation, which describes
`the flux of drug into solution as a mathematical relationship
`between these factors.
`In the mid-70s, it was a generally expressed opinion that
`there could be as many as 100 formulation factors that might
`affect bioavailability or bioequivalence. In fact, most of the
`documented problems centered around the use of
`the
`hydrophobic magnesium stearate as a lubricant or use of a
`hydrophobic shellac subcoat in the production of sugar-coated
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`14
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`Kra¨mer et al.
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`tablets. At that time, products were also often shellac-coated
`both for elegance and for longer shelf life. In addition, inade-
`quate disintegration was still a problem, often related to
`disintegrant integrity and the force of compression in the
`tableting process. All four of these factors are sensitive to
`dissolution testing. Wherever there was a medically signifi-
`cant problem, a dissolution test was able to show the differ-
`ence between the nonequivalent formulations and this is, in
`general, still true today.
`In addition to the scientific aspects, much of the discus-
`sion around dissolution and bioequivalence really was and
`is a political, social, and economic argument. Because of reluc-
`tance on the part of the pharmaceutical industry to cooperate
`with USP, a default standard was proposed to the USP in
`1975. This proposal called for 60% dissolved at 20 min in
`water, testing individual units in the official apparatus and
`was based on observations by Bill Mader and Rudy Blythe
`in 1968–1970, who had demonstrated that one could start get-
`ting meaningful data at 20 min, consistent with typical disin-
`tegration times in those days. In 1981, a USP Subcommittee
`pushed forward the default condition, resulting in an explo-
`sion in the number of dissolution tests from 70 to 400 in
`1985, a five-fold increase in four years! Selection of a higher
`amount dissolved, 75%, made for tighter data, whilst the
`longer test time, 45 min, was chosen because it gave formula-
`tors some flexibility in product design to improve elegance,
`stability, and/or to reduce friability—in other words, a lot of
`considerations not directly linked to dissolution. Subse-
`quently, industrial cooperation improved, and later the FDA
`Office of Generic Drugs and the USP established a coopera-
`tion, with the FDA supplying both dissolution and bioavail-
`ability data and information to USP.
`Experience has demonstrated that where a medically
`significant difference in bioavailability has been found among
`supposedly identical products, a dissolution test has been effi-
`cacious in discriminating among them. A practical problem
`has been the converse, that is, dissolution tests are sometimes
`too discriminating, so that it is not uncommon for a clinically
`acceptable product to perform poorly in an official dissolution
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`Historical Development of Dissolution Testing
`
`15
`
`test. In such cases, the Committee of Revision has been mindful
`of striking the right balance: including as many acceptable
`products as possible, yet not setting forth dissolution specifica-
`tions that would raise scientific concern about bioequivalence.
`
`COMPENDIAL APPARATUS
`
`The USP 27, NF22 (11) now recognizes seven dissolution
`apparatus specifically, and describes them and, in some cases
`allowable modifications, in detail. The choice of the dissolu-
`tion apparatus should be considered during the development
`of the dissolution methods, since it can affect the results
`and the duration of the test. The type of dosage form under
`investigation is the primary consideration in apparatus
`selection.
`
`Apparatus Classification in the USP
`
`Apparatus 1 (rotating basket)
`Apparatus 2 (paddle assembly)
`Apparatus 3 (reciprocating cylinder)
`Apparatus 4 (flow-through cell)
`Apparatus 5 (paddle over disk)
`Apparatus 6 (cylinder)
`Apparatus 7 (reciprocating holder)
`
`The European Pharmacopoeia (Ph. Eur.) has also
`adopted some of the apparatus designs (12) described in the
`USP, with some minor modifications in the specifications.
`Small but persistent differences between the two have their
`origin in the fact that the American metal proces