Pharmaceutical
`Dissolution Testing
`
`
`
`© 2005 by Taylor & Francis Group, LLC© 2005 by Taylor & Francis Group, LLC
`
`MYLAN EXHIBIT 1025
`
`

`

`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
`
`

`

`Published in 2005 by
`Taylor & Francis Group
`6000 Broken Sound Parkway NW, Suite 300
`Boca Raton, FL 33487-2742
`
`© 2005 by Taylor & Francis Group, LLC
`
`No claim to original U.S. Government works
`Printed in the United States of America on acid-free paper
`10 9 8 7 6 5 4 3 2 1
`
`International Standard Book Number-10: 0-8247-5467-0 (Hardcover)
`International Standard Book Number-13: 978-0-8247-5467-9 (Hardcover)
`
`This book contains information obtained from authentic and highly regarded sources. Reprinted material is
`quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts
`have been made to publish reliable data and information, but the author and the publisher cannot assume
`responsibility for the validity of all materials or for the consequences of their use.
`
`No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic,
`mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and
`recording, or in any information storage or retrieval system, without written permission from the publishers.
`
`For permission to photocopy or use material electronically from this work, please access www.copyright.com
`(http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive,
`Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration
`for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate
`system of payment has been arranged.
`
`Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only
`for identification and explanation without intent to infringe.
`
`Library of Congress Cataloging-in-Publication Data
`
`Catalog record is available from the Library of Congress
`
`Taylor & Francis Group
`is the Academic Division of T&F Informa plc.
`
`Visit the Taylor & Francis Web site at
`http://www.taylorandfrancis.com
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`12
`
`Dissolution Method Development:
`An Industry Perspective
`
`CYNTHIA K. BROWN
`
`Eli Lilly and Company, Indianapolis,
`Indiana, U.S.A.
`
`INTRODUCTION
`
`In today’s pharmaceutical industry, dissolution testing is a
`valuable qualitative tool that provides key information about
`the biological availability and/or equivalency as well as the
`batch-to-batch consistency of a drug. Therefore, a properly
`designed dissolution test is essential for the biopharmaceutical
`characterization and batch-to-batch control of the drug pro-
`duct. During drug development, dissolution testing is used
`to select appropriate formulations for in vivo testing, guide
`formulation development activities, and assess stability of
`the drug product under various packaging and storage
`requirements. For the dissolution test to be a useful drug
`351
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`352
`
`Brown
`
`characterization tool, the methodology needs to be able to
`discriminate between different degrees of product perfor-
`mance and thus, the collection of a multi-time point dissolu-
`tion profile is useful. At present, almost all solid oral dosage
`forms require dissolution testing as a quality control check
`before a product is introduced into the market place. For
`the dissolution test to be a useful quality control tool, the
`methodology should be simple, reliable and reproducible,
`and ideally be able to discriminate between different degrees
`of product performance (1).
`Dissolution testing is also used to identify bioavailability
`(BA) problems and to assess the need for further bioequiva-
`lence (BE) studies relative to scale-up and post-approval
`changes (SUPAC), where it can function as a signal of bioine-
`quivalence (2,3). The issuance of the Food and Drug Adminis-
`tration (FDA) guidance document, Waiver of
`In Vivo
`Bioavailability and Bioequivalence Studies for Immediate-
`Release Solid Oral Dosage Forms Based on a Biopharmaceu-
`tics Classification System, allows dissolution testing to be
`used as a surrogate for in vivo BE testing under certain
`circumstances
`(4). The Biopharmaceutics Classification
`System (BCS) is a scientific framework for classifying drug
`substances based on their aqueous solubility and intestinal
`permeability. When combined with the dissolution of the drug
`product, the BCS takes into account three major factors that
`influence the rate and extent of drug absorption from immedi-
`ate-release solid oral dosage forms: dissolution, solubility, and
`intestinal permeability (5). Based on the BCS framework,
`drug manufacturers may request waivers from additional in
`vivo studies (biowaivers) if their drug product meets certain
`criteria. In addition, the FDA’s guidance on BA and BE (6)
`allows biowaivers for additional strength(s) of immediate-
`release as well as modified-release drug products based
`on formulation proportionality and dissolution profile
`comparison.
`These changes in BE requirements that move away from
`the in vivo study requirement in certain cases and rely more
`on dissolution test results, emphasize the significance of
`dissolution test applications. In all cases where the dissolution
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`Dissolution Method Development: An Industry Perspective
`
`353
`
`test is used as a BE test, a link with a bioavailable product is
`established. With the advances in dissolution testing and the
`increased understanding of the scientific principles and
`mechanisms of dissolution testing, a clear trend has appeared
`where the dissolution test is not solely a traditional quality
`control test but may also be used as a surrogate to the in vivo
`BE test (7).
`For the dissolution test to be used as an effective drug
`product
`characterization and quality control
`tool,
`the
`method must be developed with the various end uses in
`mind. In some cases, the method used in the early phase
`of product and formulation development could be different
`from the final test procedure utilized for control of the
`product quality. Methods used for formulation screening or
`BA and/or bioequivalency evaluations may simply be
`impractical for a quality control environment. It is essential
`that with the accumulation of experience, the early method
`be critically re-evaluated and potentially simplified, giving
`preference to compendial apparatus and media. Hence, the
`final dissolution method submitted for product registration
`may not necessarily closely imitate the in vivo environment
`but should still test the key performance indicators of the
`formulation.
`To facilitate the development of appropriate dissolution
`tests several regulatory, pharmacopeial, and industrial orga-
`nizations have issued dissolution-related guidelines that
`provide information and recommendations on the develop-
`ment and validation of dissolution test methodology, the
`establishment of dissolution specifications, and the regulatory
`applications of dissolution testing (8–16). This chapter
`describes a systematic approach for the development of a dis-
`solution method. The information is organized and presented
`in sections that follow the chronological sequence of the
`method development process. These include the assessment
`of relevant physical and chemical properties of the drug,
`determination of the appropriate dissolution apparatus, selec-
`tion of the dissolution medium, determination key operating
`parameters, method optimization, and validation of the
`methodology.
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`354
`
`Brown
`
`PHYSICAL AND CHEMICAL PROPERTIES
`
`The first step in the development of a new dissolution test is
`to evaluate the relevant physical and chemical data for the
`drug substance. Knowledge of the drug compound’s physi-
`cal–chemical properties will facilitate the selection of dissolu-
`tion medium and determination of medium volume.
`Some of the physicochemical properties of the active
`pharmaceutical ingredient (API) that influence the dissolu-
`tion characteristics are:
`
`Ionization constants (pKa),
`Solubility as a function of pH,
`Solution stability as a function of pH,
`Particle size,
`Crystal form, and
`Common ion, ionic strength, and buffer effects.
`
`Two key physicochemical API properties to evaluate are
`the solubility and solution-state stability of the drug sub-
`stance as a function of pH. Knowledge of the pKa (or pKa’s)
`is useful because it defines the charge of the molecule in solu-
`tion at any given pH. Ideally, the drug substance’s solubility
`in the dissolution medium should not be the rate-limiting
`factor for the drug substance’s dissolution from the drug
`product. Hence, the dissolution rate should be characteristic
`of the release of the active ingredient from the dosage form
`rather than the drug substance’s solubility in the dissolution
`medium. When adjusting the composition of the medium to
`insure adequate solubility for the drug substance,
`the
`influence of surfactants, pH, and buffers on the solubility
`and stability of the drug substance need to be evaluated.
`The solution-state stability of the API must also be consid-
`ered in the design of a dissolution test because the molecule’s
`stability in various dissolution media may limit the pH range
`over which the drug product’s dissolution can be evaluated.
`Typically, the drug’s solution stability should be determined
`at 37C for 2 hr for immediate-release formulations and twice
`the designated testing time for sustained-release formula-
`tions (17).
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`Dissolution Method Development: An Industry Perspective
`
`355
`
`During the initial stages of a drug product’s develop-
`ment, a dissolution test should facilitate the formulation
`development and selection. During this phase of the drug
`development process bioavailability data is usually not avail-
`able. In the absence of BA, the dissolution medium selection
`should be based on the physicochemical properties, the formu-
`lation design, and the intended dose. The BCS provides a good
`framework for determining if the dissolution of the drug will
`be the rate-limiting factor in the in vivo absorption process.
`Hence, the pH solubility of the drug and the intended dose
`are essential parameters to consider early in the dissolution
`method development process.
`Once you have a good understanding of the physical–
`chemical properties of the drug substance, the key properties
`of the dosage form, i.e., type, label claim, and release mechan-
`ism, need to be considered. The most appropriate dissolution
`testing apparatus and dissolution medium can be selected
`based on the physical–chemical properties of the drug sub-
`stance and the key properties of the dosage form. Dosage forms
`can be designed to provide immediate release, delayed release,
`or extended (controlled) release. Determining the type of
`release and anticipated site of in vivo absorption will facilitate
`the selection of dissolution media, testing apparatus, and test
`duration.
`
`DISSOLUTION APPARATUS SELECTION
`
`The choice of apparatus is based on knowledge of the formula-
`tion design and practical aspects of dosage form performance in
`the in vitro test system. Dissolution testing is conducted on
`equipment that has demonstrated suitability, such as described
`in the 2003 United States Pharmacopeia (USP) under the
`general chapters of Dissolution and Drug Release (10,11). The
`basket method (USP Apparatus 1) is routinely used for solid
`oral dosage forms such as capsule or tablet formulations at
`an agitation speed of 50–100 rpm, although speeds of up to
`150 rpm have been used. The paddle method (USP Apparatus
`2) is frequently used for solid oral dosage forms such as tablet
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`356
`
`Brown
`
`and capsule formulations at 50 or 75 rpm. The paddle method
`is also useful for the testing of oral suspensions at the recom-
`mended paddle speed of 25–50 rpm. The reciprocating cylinder
`(USP Apparatus 3) has been found to be especially useful for
`bead-type modified-release dosage forms. The flow-through cell
`(USP Apparatus 4) may offer advantages for some modified-
`release dosage forms, especially those that contain active ingre-
`dients with limited solubility. Additionally, the reciprocating
`cylinder or the flow-through cell may be useful for soft gelatin
`capsules, bead products, suppositories, or poorly soluble drugs.
`By design, both the reciprocating cylinder and the flow-through
`cell allow for a controlled pH change of the dissolution medium
`throughout the test, which allows the apparatus to be easily
`utilized for physiological evaluations of the dosage form during
`development. The paddle over disk (USP Apparatus 5) and the
`cylinder (USP Apparatus 6) have been shown to be useful for
`evaluating and testing transdermal dosage forms. The recipro-
`cating holder (USP Apparatus 7) has been shown to have appli-
`cation to non-disintegrating oral modified-release dosage forms,
`as well as to transdermal dosage forms.
`In general, compendial apparatus and methods should be
`used as a first approach in drug development. To avoid unne-
`cessary proliferation of equipment and method design,
`modifications of compendial equipment or development and
`use of alternative equipment should be considered only when
`it has been proven that compendial set up does not provide
`meaningful data for a given dosage form. In these instances,
`superiority of the new or modified design has to be proven
`in comparison to the compendial design.
`Table 1 outlines the current status of scientific develop-
`ment for the dissolution or release testing from various
`dosage forms and recommends, where possible, the dissolu-
`tion apparatus of ‘‘first choice’’ (13). Refer also to Chapter 2
`for further description of the USP apparatus.
`
`DISSOLUTION MEDIUM SELECTION
`
`For batch-to-batch quality testing, selection of the dissolution
`medium is based, in part, on the solubility data and the dose
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`Dissolution Method Development: An Industry Perspective
`
`357
`
`Table 1 Apparatus Recommended Based on Dosage Form Type
`
`Type of dosage form
`
`Release method
`
`Solid oral dosage forms
`(conventional)
`Oral suspensions
`Oral disintegrating tablets
`Chewable tablets
`
`Transdermals—patches
`Topicals—semisolids
`Suppositories
`
`Chewing gum
`
`Powders and granules
`
`Microparticulate formulations
`Implants
`
`Basket, paddle, reciprocating
`cylinder, or flow-through cell
`Paddle
`Paddle
`Basket, paddle, or reciprocating
`cylinder with glass beads
`Paddle over disk
`Franz cell diffusion system
`Paddle, modified basket, or dual
`chamber flow-through cell
`Special apparatus [European
`Pharmacopoeia (PhEur)]
`Flow-through cell (powder/granule
`sample cell)
`Modified flow-through cell
`Modified flow-through cell
`
`range of the drug product in order to ensure that sink condi-
`tions are met. The term sink conditions is defined as the
`volume of medium at least greater than three times that
`required to form a saturated solution of a drug substance. A
`medium that fails to provide sink conditions may be justifi-
`able if it is shown to be more discriminating or if it provides
`reliable data which otherwise can only be obtained with the
`addition of surfactants. When the dissolution test is to indi-
`cate the biopharmaceutical properties of the dosage form, it
`is more important that the test closely simulate the environ-
`ment in the GI tract than necessarily produce sink conditions
`for release. Therefore, it is not always possible to develop one
`dissolution test or select one dissolution medium that ensures
`batch-to-batch control as well as monitoring the biopharma-
`ceutical aspects of the drug product.
`formulations
`The dissolution characteristics of oral
`should be evaluated over the physiologic pH range of 1.2–
`6.8 [1.2–7.5 for modified release (MR) formulations]. During
`method development, it may be useful to measure the pH
`before and after a run to see if the pH changes during the test,
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`358
`
`Brown
`
`especially if the buffer capacity of the chosen medium is low.
`Selection of the most appropriate medium for routine testing
`is then based on discriminatory capability, ruggedness, stabi-
`lity of the analyte in the test medium, and relevance to in vivo
`performance where possible.
`For very poorly soluble compounds, aqueous solutions
`may contain a percentage of a surfactant (e.g., sodium lauryl
`sulfate, Tween 80 or CTAB) that is used to enhance drug
`solubility. The need for surfactants and the concentrations
`used should be justified. Surfactants can be used as either a
`wetting agent or, when the critical micelle concentration
`(CMC) is reached, to solubilize the drug substance. The sur-
`factant’s CMC depends upon the surfactant itself and the
`ionic strength of the base medium. The amount of surfactant
`needed for adequate drug solubility depends on the surfactant
`CMC and the degree to which the compound partitions into
`the surfactant micelles. Because of
`the nature of
`the
`compound and micelle interaction, there is typically a linear
`dependence between solubility and surfactant concentration
`above the CMC. If a compound is ionizable, surfactant concen-
`tration and pH may be varied simultaneously, and the
`combined effect can substantially change the solubility char-
`acteristics of the dissolution medium. Table 2 lists dissolution
`medium selection criteria as defined in regulatory, industry,
`and compendial guidances.
`The BCS describes the classification of compounds
`according to solubility and permeability (6). Biorelevant med-
`ium is a term used to describe a medium that has some rele-
`vance to the in vivo dissolution conditions for the compound.
`Choice of a biorelevant medium is based on a mechanistic
`approach that considers the absorption site, if known, and
`whether the rate-limiting step to absorption is the dissolution
`or permeability of the compound. In some cases, the biorele-
`vant medium will be different from the test conditions chosen
`for the regulatory test and the time points are also likely to be
`different. If the compound dissolves quickly in the stomach
`and is highly permeable, gastric emptying time may be the
`rate-limiting step to absorption. In this case, the dissolution
`test is to demonstrate that the drug is released quickly under
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`Dissolution Method Development: An Industry Perspective
`
`359
`
`Table 2 Recommended Dissolution Medium Composition and
`Volume for Rotating Basket or Rotating Paddle Apparatus
`
`Volume
`
`pH
`
`Additives
`
`pH 1–6.8; above pH
`6.8 with
`justification—not
`to exceed pH 8
`
`Enzymes, salts,
`surfactants with
`justification
`
`500–1,000 mL;
`900 mL
`historical;
`1,000 mL
`recommended
`for future
`development
`500–1,000 mL; up
`to 2,000 mL for
`drug with
`limited
`solubility
`
`Buffered aqueous
`solution pH 4–8 or
`dilute acid
`solutions (0.001 N
`HCl to 0.1 N HCl)
`
`Enzymes, salts,
`surfactants
`balanced against
`loss of discrim-
`inatory power;
`enzymes can be
`used for cross-
`linking of gelatin
`capsules or
`gelatin-coated
`tablets
`Determined per
`product
`
`Surfactants
`recommended for
`water poorly
`soluble drug
`products—need
`and amount
`should be
`justified; enzymes
`use need case-by-
`case justification;
`utilized for the
`cross-linking of
`gelatin capsules
`or gelatin-coated
`tablets
`
`Guidance or
`compendial
`reference
`
`Federation
`International
`Pharmaceutique
`(FIP) (23)
`
`United States
`Pharmacopeia
`(USP) (10–12)
`
`World Health
`Organization
`(WHO) (16),
`European
`Pharmacopoeia
`(PhEur) (14),
`Japanese
`Pharmacopoeia
`(JP) (15)
`FDA (8,9)
`
`Determined per
`product
`
`Adjust pH to within
`0.05 units of the
`prescribed valued
`
`500, 900, or
`1,000 mL
`
`pH 1.2–6.8; higher
`pH justified case-
`by-case—in
`general not to
`exceed pH 8
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`360
`
`Brown
`
`typical gastric (acidic) conditions. On the other hand, if disso-
`lution occurs primarily in the intestinal tract (e.g., a poorly
`soluble, weak acid), a higher pH range (e.g., simulated intest-
`inal fluid with a pH of 6.8) will be more appropriate (18).
`The fed and fasted state may also have significant effects
`on the absorption or solubility of a compound. Compositions of
`media that simulate the fed and fasted states can be found in
`the literature (19) (see also Chapter 5). These media reflect
`changes in the pH, bile concentrations, and osmolarity after
`meal intake and therefore have a different composition than
`that of typical compendial media. They are primarily used
`to establish in vitro–in vivo correlations during formulation
`development and to assess potential food effects and are not
`intended for quality control purposes. For quality control
`purposes, the substitution of natural surfactants (bile compo-
`nents) with appropriate synthetic surfactants is permitted
`and encouraged because of the expense of the natural
`substances and the labor-intensive preparation of
`the
`biorelevant media.
`
`KEY OPERATING PARAMETERS
`
`Media: Volume, Temperature, Deaeration
`
`As shown in Table 2, the recommended volume of dissolution
`medium is 500–1000 mL, with 900 mL as the most common
`volume when using the basket or paddle apparatus. The
`volume can be raised to between 2 and 4 L, depending on
`the concentration and sink conditions of the drug, but proper
`justification is expected.
`The standard temperature for the dissolution medium is
`37  0.5C for oral dosage forms. Slightly increased tempera-
`tures such as 38  0.5C have been recommended for dosages
`forms such as suppositories. Lower temperatures such as
`32  0.5C are utilized for topical dosage forms such as trans-
`dermal patches and topical ointments.
`The significance of deaeration of the medium should be
`determined on a case-by-case basis, as air bubbles can inter-
`fere with the test results and act as a barrier to dissolution
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`Dissolution Method Development: An Industry Perspective
`
`361
`
`if present on the dosage unit or basket mesh. Additionally, air
`bubbles can cause particles to cling to the apparatus and
`vessel walls. On the other hand, bubbles on the dosage unit
`may increase the buoyancy and lead to an increase in the dis-
`solution rate, or decrease the dissolution rate by decreasing
`the available surface area. Consequently, the impact of med-
`ium deaeration may be formulation dependent, such that
`some formulations will be sensitive to the presence of dis-
`solved air in the dissolution while other formulations will be
`robust. To determine if deaeration of the medium is neces-
`sary, a comparison between dissolution data generated with
`non-deaerated medium vs. dissolution data generated with
`deaerated medium should be performed.
`The following deaeration method is described as a foot-
`note in the 2003 United States Pharmacopeia (USP) under
`the general chapter Dissolution (10). The USP deaeration
`method requires heating of the medium, followed by filtration,
`and drawing of a vacuum for a short period of time. Other
`deaeration methods such as room temperature filtration, soni-
`cation, and helium sparging are described in literature (20,21)
`and are routinely used throughout the industry. The deaera-
`tion method needs to be clearly characterized, since the
`method chosen might impact the dissolution release rate
`(13). It should be noted that dissolution tests using the flow-
`through cell method could be particularly sensitive to the
`deaeration of the medium. Media containing surfactants are
`not usually deaerated after the surfactant has been added
`to the medium because of excessive foaming. In some labora-
`tories, the base medium is deaerated prior to the addition of
`the surfactant.
`
`Sinker Evaluation
`
`Currently, the Japanese Pharmacopoeia (JP) is the only phar-
`macopeia that requires a specific sinker device for all capsule
`formulations. The USP recommends a few turns of a nonreac-
`tive material wire when the dosage form tends to float (12) (see
`Chapter 2 for illustrations of the Japanese and USP sinkers).
`Because sinkers can significantly influence the dissolution
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`362
`
`Brown
`
`profile of a drug product, detailed sinker descriptions and the
`rationale for why a sinker is used should be stated in the writ-
`ten procedure. When comparing different sinkers (or sinkers
`versus no sinkers), a test should be run concurrently with
`each sinker. Each sinker type should be evaluated based on
`its ability to maintain the dosage at the bottom of the vessel
`without inhibiting drug release.
`Sinkers can significantly influence the dissolution profile
`of a drug. Therefore, the use of sinkers should be part of the
`dissolution method validation. If equivalent sinkers are iden-
`tified during the sinker evaluation and validation, the equiva-
`lent sinkers should be listed in the written dissolution test
`procedure. When a dissolution method utilizes a dissolution
`sinker and is transferred to another laboratory, the receiving
`laboratory should duplicate the validated sinker design(s) as
`closely as possible.
`
`Analytical Detection
`
`For determination of the quantitative step in the dissolution
`method,
`information regarding the spectral,
`chromato-
`graphic, electrochemical, and/or chemical characteristics of
`the drug substance should be considered. The quantitative
`method needs to provide adequate sensitivity for the accurate
`determination of the analyte in the dissolution medium. Since
`formulations are likely to change during product develop-
`ment, it is usually advantageous to use high-performance
`liquid chromatography (HPLC) detection procedures. How-
`ever, because of the ease of automation and faster analysis
`time, UV detection methods are more desirable for the routine
`quality control testing of products.
`Filtration of the dissolution sample aliquot is usually
`needed prior to quantitation. Filtration of the dissolution
`samples is usually necessary to prevent undissolved drug
`particles from entering the analytical sample and dissolving
`further. Also, filtration removes insoluble excipients that
`may otherwise cause a high background or turbidity. Prewet-
`ting of the filter with the medium is usually necessary. Filters
`can be in-line, at the end of the sampling probe, or both. The
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`Dissolution Method Development: An Industry Perspective
`
`363
`
`pore size can range from 0.45 to 70 mm. The usual types are
`depth, disk, or flow-through filters. However, if the excipient
`interference is high, or the filtrate has a cloudy appearance,
`or the filter becomes clogged, an alternative type of filter or
`pore size may need to be evaluated.
`Adsorption of the drug(s) to the filter needs to be evalu-
`ated. If drug adsorption occurs, the amount of initial filtrate
`discarded may need to be increased. If results are still unsui-
`table, an alternative filter material should be sought. Centri-
`fugation of samples is generally not recommended, as
`dissolution can continue to occur during centrifugation and
`there may be a concentration gradient in the supernatant.
`A possible exception might be compounds that adsorb to all
`common filters.
`
`Sampling Time Points and Specifications
`
`Key operating parameters that may change (or be optimized)
`throughout a product’s development and approval cycle are
`dissolution sampling time points and dissolution limits or spe-
`cifications by which the dissolution results should be evalu-
`ated. The results generated from the dissolution test need to
`be evaluated and interpreted based on the intended purpose
`of the test. If the test is used for batch-to-batch control, the
`results should be evaluated in regard to the established limits
`or specification value. If the test is being utilized as a charac-
`terization test (i.e., biopharmaceutical evaluations, formula-
`tion development studies, etc.)
`the results are usually
`evaluated by profile comparisons.
`For immediate-release dosage forms, the dissolution test
`duration is typically 30–60 min, with a single time point
`specification being adequate in most cases for routine batch-
`to-batch quality control for approved products. Typical speci-
`fications for the amount of active ingredient dissolved,
`expressed as a percentage of the labeled content (Q), are in
`the range of 75–80% dissolved. A Q value in excess of 80%
`is not generally used, as allowances need to be made for assay
`and content uniformity ranges. Since the purpose of specify-
`ing dissolution limits is to ensure batch-to-batch consistency
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`364
`
`Brown
`
`within a range that guarantees comparable biopharmaceuti-
`cal performance in vivo, specifications including test times
`are usually established based on an evaluation of dissolution
`profile data from pivotal clinical batches and confirmatory BA
`batches (8).
`When the test is utilized as a characterization tool (i.e.,
`biopharmaceutical evaluations, formulation development stu-
`dies, etc.) the results are usually evaluated by profile compar-
`isons.
`In this
`case,
`the product’s
`comparability and
`performance are evaluated by collecting additional sampling
`time points. For registration purposes, a plot of the percen-
`tage of the drug dissolved vs. time should be determined.
`Enough time points are to be selected to adequately charac-
`terize the ascending and plateau phases of the dissolution
`curve. According to the BCS referred to in several FDA
`guidance documents, highly soluble and highly permeable
`drugs formulated with rapidly dissolving products need not
`be subjected to a profile comparison if they can be shown to
`release 85% or more of the active ingredient within 15 min.
`For these types of products, a one-point test will suffice. When
`an immediate-release drug product does not meet the rapidly
`dissolving criteria, dissolution data from multiple sampling
`time points ranging from 10 to 60 min or longer are usually
`collected.
`So-called infinity points can be useful during develop-
`ment studies. To obtain an infinity point, the paddle or basket
`speed is increased significantly (e.g., 150 rpm) at the end of
`the run and the test is allowed to run for an extended period
`of time (e.g., 60 min), and then an additional sample is taken.
`Although there is no requirement for 100% dissolution in the
`profile, the infinity point can provide data that may provide
`useful
`information about the formulation characteristics
`during the initial development.
`For an extended-release dosage form, at least three test
`time points are chosen to characterize the in vitro drug-
`release profile for the routine batch-to-batch quality control
`for approved products. Additional sampling times may be
`required for formulation development studies, biopharmaceu-
`tical evaluations, and drug approval purposes. An early time
`
`© 2005 by Taylor & Francis Group, LLC
`
`

`

`Dissolution Method Development: An Industry Perspective
`
`365
`
`point, usually 1–2 hr, is chosen to show that there is little
`probability of dose dumping. Release at this time-point should
`not exceed values expected according to the mechanism of
`release and the intended overall-release profile. An inter-
`mediate time point is chosen to define the in vitro-release pro-
`file of the dosage form, and a final time point is chosen to show
`essentially complete release of the drug. Test times and speci-
`fications are usually established on the basis of an evaluation
`of drug-release profile data. For products containing more
`than a single active ingredient, drug release is to be deter-
`mined for each active ingredient. Extended-release specifica-
`tions are addressed in the USP under the general chapter
`In Vitro and In Vivo Evaluation of Dosage Forms (12) and
`the FDA’s guidance document Extended Release Oral Dosage
`Forms: Development, Evaluation, and Application of In
`Vitro/In Vivo Correlations (9).
`
`METHOD OPTIMIZATION
`
`When human BA data are available from several formulations,
`the dissolution test should be re-evaluated and optimized (if
`needed). The goal of dissolution method optimization is to iden-
`tify in vitro test conditions that adequately discriminate critical
`formulation differences or critical manufacturing variables.
`During the method optimization process, the biostudy formula-
`tions are tested using various medium compositions (e.g., pH,
`ionic strength, surfactant composition). The effect of hydrody-
`namics on the formulations should also be evaluated by varying
`the apparatus agitation speed. If a non-bioequivalent batch is
`discovered during a bioequivalency study and the in vivo
`absorption is dissolution rate limited (BCS Class 2), the dissolu-
`tion methodology should be optimized to differentiate the