-----------------~-,
`
`j
`
`@~·2.:ol!"
`~
`NOV 0 8 2006
`
`_.
`
`2007
`
`USP 30
`
`NF 25
`
`Volume 1
`
`THE UNITED STATES PHARMACOPEIA
`
`THE NATIONAL FORMULARY
`
`By authority of The United States Pharmacopeial
`Convention, meeting at Washington, D.C, March 9-13,
`2005. Prepared by the Council of Experts and published
`by the Board of Trustees
`Official from May 1, 2007
`
`"USP NF
`The designation on the cover of this publication,
`2007,"
`is for ease of identification only. The publication
`contains two separate compendia: The United States
`Pharmacopeia, Thirtieth Revision, and the National
`Formulary, Twenty-Fifth Edition.
`
`KNCB3[, ",t; :;-:-ENS.OLSON & BEAR, LLP
`~AO MAI~J8T.
`14TH FLOOR
`IRVINE. CA 92614
`
`THE UNITED STATES PHARMACOPEIAL CONVENTION
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`LUPIN EX. 1008
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`Page 1
`
`

`
`General Information
`
`/
`
`(1092) The Dissolution Procedure
`
`579
`
`--'--'-
`
`(SF 39
`
`e of label claim dissolved at each specified testing
`fhe rercenl~gbereported for each individual dosage unit The
`!lItiflals~o~a e dissolved,
`the range (highest,
`lowest) of dissolu-
`.••-sn perceIn goeffi'cient of variation (relative
`standard deviation]
`,•."
`d ne C
`oon.an
`b r(,ported.
`shoulde U iformity Test-Content
`uniformity testing on the test
`lots should be performed as described in USP.
`content
`;roduct
`lndrderence
`
`WAIVER REQUIREMENTS
`
`for the 200-
`study requirements
`r of in vivo bioequivalence
`.•
`r
`to
`\\al~~ th efthe generic tablet product may be granted pursuant
`JIlg str~~?O 22(d)(2) provided the followmg condltlOns are met:
`;1 C~he200-mg tablet
`is proporti~nally
`similar
`in both active and
`rive ingredients to the finn s 600-mg tablet which has been
`J
`.
`I
`i
`mac
`.'
`he ref
`duct
`demonstrated to be bioequiva ent
`to t e rererence pro uct m
`
`~i:~:200_mgtablet of the generic product meets dissolution test
`requirements.
`
`-
`
`(1091) LABELING OF INACTIVE
`INGREDIENTS
`
`for
`
`labeling of
`guidelines
`chapter provides
`This infonnational
`.
`.
`inactiveingredients present
`in dosage forms.
`aSSOCIatIons
`trade
`of
`Within the past
`few years
`a number
`have adopted voluntary
`representingpharmaceutical manufacturers
`ouidelinesfor the disclosure
`and labelmg of inactive mgredlents.
`Thisis helpful
`to individuals who are sensitive
`to particular
`substancesand who wish to identify the presence or confirm the
`absenceof such substances
`in drug products. Because of the actions
`of
`these associations,
`the
`labeling
`of
`therapeutically
`inactive
`ingredientscurrently is deemed to constitute good phannaceutical
`practice.
`by these associations
`represented
`Although the manufacturers
`sold in this
`country,
`not
`all
`produce most of
`the products
`manufacturers,repackagers, or labelers here or abroad are members
`of these associations.
`Further,
`there
`are
`some
`differences
`in
`associationguidelines. The guidelines presented here are designed
`tohelp promote consistency in labeling.
`Inaccordance with good pharmaceutical practice, all dosage forms
`[NOTE-forrequirements on parenteral and topical preparations,
`see
`theGeneral Notices]
`should be labeled to state the identity of all
`added substances
`(therapeutically
`inactive
`ingredients)
`present
`therein,including colors, except
`that
`flavors and fragrances may
`belisted by the general
`term "flavor"
`or "fragrance."
`Such listing
`shouldbe in alphabetical order by name and be distinguished from
`theIdentification statement of the active ingredient(s) .
`The name of an inactive ingredient
`should be taken from the
`current edition of one of
`the following
`reference works
`(in the
`(1) the United States Pharmacopeia
`followingorder of precedence):
`(2) USAN and the USP Dictionary of
`orthe National Formulary;
`Drug Names;
`(3) CTFA Cosmetic Ingredient Dictionarv;
`(4) Food
`Chemicals Codex. An ingredient
`not
`listed
`in any
`of
`the
`aforementioned
`reference works
`should
`be
`identified
`by its
`common or usual
`name
`(the name
`generally
`recognized
`by
`consumers or health-care professionals)
`or, if no common or usual
`nameis available, by its chemical or other technical name.
`An ingredient
`that may be, but not always is, present
`in a product
`should be qualified by words such as "or" or "may also contain."
`The name of an ingredient whose identity is a trade secret may be
`OmIttedfrom the list if the list states" and other ingredients." For the
`purposes of this guideline, an ingredient
`is considered to be a trade
`secretonly if its presence confers a significant competitive advantage
`upon its manufacturer
`and if its identity cannot be ascertained by the
`Useof modem analytical
`technology.
`An incidental
`trace ingredient having no functional or technical
`effect on the product
`need not be listed
`unless
`it has been
`demonstrated to cause sensitivity reactions or allergic responses.
`
`should be listed on the label of a container of
`Inactive ingredients
`a product
`intended for sale without prescription,
`except
`that
`in the
`case of a container
`that
`is too small,
`such information may be
`contained in other labeling on or within the package.
`
`(1092) THE DISSOLUTION
`PROCEDURE:
`DEVELOPMENT
`AND VALIDATION
`
`The USP dissolution procedure is a performance test applicable to
`many dosage forms, It is one test in a series of tests that constitute
`the dosage form's public specification (tests, procedures
`for the tests,
`acceptance
`criteria). To satisfy the performance
`test, USP provides
`test chapters Disintegration
`(701), Dissolution
`the general
`(711),
`and Drug Release (724). These chapters provide information about
`conditions
`of
`the procedure.
`For
`dissolution,
`these
`include
`information
`about
`(1) medium,
`(2) apparatus/agitation
`rate,
`(3)
`study design,
`(4) assay, and (5) acceptance
`criteria. Overall
`the
`dissolution procedure yields data to allow an accept/reject decision
`relative to the acceptance criteria, which are frequently based on a
`regulatory decision. This chapter provides recommendations
`on how
`to develop and validate a dissolution procedure.
`
`GENERAL COMMENTS
`a dissolution
`The dissolution
`procedure
`requires
`an apparatus,
`medium,
`and test
`conditions
`that provide
`a method
`that
`is
`discriminating
`yet sufficiently rugged and reproducible
`for day-to-
`day operation and capable of being transferred between laborato~es.
`The
`acceptance
`criteria
`should be representative
`of multiple
`batches with the same nominal
`composition
`and manufacturing
`process,
`typically including key batches used in pivotal studies, and
`representative of performance
`in stability studies.
`capable. of
`The procedure should be appropriately discriminating,
`distinguishing significant changes in a composition or manufactunng
`process that might be expected to affect
`in vivo performance.
`It is
`also possible for the procedure to show differences between batches
`when no significant difference is observed in vivo. This situation
`requires careful evaluation of whether
`the procedure is too sensitive
`or appropriately discriminating. Assessing the results from multiple
`batches
`that
`represent
`typical
`variability
`in composition
`and
`manufacturing
`parameters may assist
`in this
`evaluation.
`It
`is
`sometimes valuable to intentionally vary manufacturing
`parameters,
`such as
`lubrication,
`blend time,
`compression
`force, or drying
`parameters,
`to further characterize the discriminatory
`power of the
`procedure.
`the dissolution test should appropriately
`With regard to stability,
`reflect relevant changes in the drug product over time that are caused
`by temperature, humidity, photosensitivity,
`and other stresses.
`A properly designed test should result
`in data that are not highly
`variable
`and should not be associated with significant
`analytical
`solution stability problems. High variability in results can make it
`difficult
`to identify
`trends
`or effects
`of
`formulation
`changes.
`Dissolution results may be considered highly variable if the relative
`standard deviation (RSD)
`is greater than 20% at time points of 10
`minutes or less and greater
`than 10% RSD at
`later time points. I
`However, most dissolution results exhibit
`less variability than this.
`The source of the variability should be investigated when practical,
`and attempts
`should
`be made
`to reduce
`variability whe~ever
`possible. The two most
`likely causes
`are the formulation
`Itself
`(e.g .. drug substance,
`excipients,
`or manufacturing
`process)
`or
`artifacts
`associated with the test procedure
`(e.g., coning,
`tablets
`sticking to the vessel wa,lLQ1::,.hasketscreen) Visual observations are
`Classification
`System is outlined
`in the FDA
`I The Biophamlaceutics
`Guidance for Industry: Waiver of In Vivo Bioavaiiability
`and Bioequivalence
`Studies
`for
`Immediate-Release
`Solid Oral Dosage Forms Based
`on a
`Svstem, August 2000; http://www.fda.goy/
`Biopharmaceutics
`Classification
`accessed 6/2212005.
`cder/guidance/3618fnl.htm.
`
`t, three.
`period
`
`: ouldbe
`fasting
`
`ignedto
`I, thle\:.
`:ollowing
`
`600-mg
`
`capsule
`high·fal
`
`600-mg
`
`·~tsunder
`. ast. The
`: fast and
`2, taken
`er fastmr
`of wate~
`., be used
`at least4
`Subjecs
`ilie study.
`'he study.
`~twillbe
`r the test
`% of the
`;t admin-
`
`-Subject
`.orts, and
`ts to the
`
`lioequiv·
`samples
`.~ in vivo
`::t reser«
`~mes the
`; greater.
`'approval
`.ioequiv
`
`2 dosage
`ying the
`hod (see
`cnced by
`mine the
`
`Page 2
`
`

`
`580
`
`(1092) The Dissolution Procedure / General
`
`information
`
`and
`the source of the variability
`for understanding
`often helpful
`whether
`the dissolution test
`itself is contributing to the variability.
`Any time the dosage contents do not disperse freely throughout
`the
`vessel in a uniform fashion, aberrant results can occur. Depending on
`the problem,
`the usual remedies include changing the apparatus type,
`speed of agitation, or deaeration; consideration and/or examination
`of
`sinker
`type;
`and changing
`the composition
`of
`the. medium.
`Modifications
`to the apparatus may also be useful, WIth proper
`justification and validation.
`Many causes of variability can be found in the formulation and
`manufacturing
`process.
`For
`example,
`poor
`content
`uniformity,
`process
`inconsistencies,
`a reaction taking place at different
`rates
`during
`dissolution,
`excipient
`interactions
`or
`interference,
`film
`coating,
`capsule
`shell aging, and hardening
`or softening
`the
`dosage
`form on stability may be
`sources
`of variability
`and
`interferences. During routine
`testing of
`the product,
`variability
`outside the expected range should be investigated from analytical,
`formulation,
`and processing perspectives.
`
`of
`
`MEDIUM
`
`as a dissolution
`justification
`this
`
`Physical and chemical data for the drug substance and dosage unit
`need to be determined before selecting the dissolution medium. Two
`key properties
`of the drug are the solubility
`and solution st.ate
`stability of the drug as a function of the pH value. When selectmg
`the composition of the medium,
`the influence of buffers, pH value,
`and surfactants on the solubility and stability of the drug need to be
`evaluated. Key properties
`of
`the dosage
`unit
`that may affect
`dissolution
`include
`release mechanism (immediate,
`delayed,
`or
`modified) and disintegration rate as affected by hardness,
`friability,
`presence of solubility enhancers, and presence of other excipients.
`Generally, when developing a dissolution procedure, one goal is to
`have sink conditions, defined as the volume of medium at least three
`times that required in order
`to form a saturated solution of drug
`substance. When sink conditions are present,
`it is more likely that
`dissolution results will reflect
`the properties of the dosage form, A
`medium that fails to provide sink conditions may be acceptable if it
`is shown to be more discriminating
`or otherwise
`appropriately
`justified.
`solvent mixture
`an aqueous-organic
`Using
`medium is discouraged;
`however, with proper
`type of medium may be acceptable.
`Purified water is often used as the dissolution medium, but is not
`ideal
`for several
`reasons. First,
`the quality of the water can vary
`depending on the source of the water, and the pH value of the water
`is not controlled. Second,
`the pH value can vary from day to day and
`can also change during the run, depending on the active substance
`and excipients. Despite
`these
`limitations, water
`is inexpensive,
`readily available,
`easily disposed of, ecologically
`acceptable,
`and
`suitable for products with a release rate independent of the pH value
`of the medium.
`of an oral formulation should be
`The dissolution characteristics
`evaluated in the physiologic pH range of 1.2 to 6.8 (1.2 to 7.5 for
`modified-release
`formulations). During method development,
`it may
`be useful
`to measure
`the pH before and after a run to discover
`whether
`the pH changes during the test. Selection of
`the most
`appropriate
`conditions
`for
`routine
`testing
`is
`then
`based
`on
`discriminatory
`capability,
`ruggedness,
`stability of the analyte in the
`test medium, and relevance to in vivo performance, where possible.
`Typical media for dissolution may include the following
`(not
`listed in order of preference): dilute hydrochloric
`acid, buffers in the
`physiologic
`pH range of 1.2 to 7.5, simulated gastric or int~stinal
`fluid (with or without
`enzymes), water, and surfactants
`(WIth or
`without
`acids or buffers)
`such as polysorbate
`80, sodium lauryl
`sulfate, and bile salts.
`'
`The molarity of the buffers and acids used can influence
`solubilizing effect, and this factor may be evaluated.
`(as
`For compounds with high solubility and high permeability
`defined by the Biophannaceutics Classification System),
`the choice
`of medium and apparatus may be influenced by the referenced FDA
`Guidance'.
`solutions may
`aqueous
`compounds,
`soluble
`For very poorly
`of a surfactant
`(e.g.,
`sodium lauryl
`sulfate,
`contain a percentage
`polysorbate,
`or lauryldimethylamine
`oxide) that
`is used to. enhance
`drug solubility. The need for surfactants and the concentrations used
`
`the
`
`can be justified by showing profiles at several diffe
`tions. Surfactants can be used either as wetting agent8~ft'~onc,
`the drug substance.
`.t~:,8oIUbilizt
`
`Volume
`
`the vol'
`apparatus,
`for basket and paddle
`Normally,
`dissolution medium is 500 mL to 1000 mL, with 900 111L UJ:neof~
`connnon volume. The volume can be raised to between ~thellJOst
`using larger vessels and depending on the concentratio' and4l,
`conditions of the drug; justification for this procedure isn andsink
`eAleC1ed.
`
`.
`
`Deaeration
`
`the medium sh~~
`of
`of deaeration
`significance
`The
`determined, because air bubbles can interfere with the test d be
`basket mesh. Further, bubbles can cause particles to clin~;to\h
`to dissolution if present on the dosage tIts,
`acting as a barrier
`
`apparatus and vessel walls. On the other hand, bubbles onihe do e
`unit may increase buoyancy,
`leading to an increase in the dissol~~ge
`~ate, or ~nay d~crease the availa1;>lesurface <l!ea,leading to a deere:
`~nthe dissolution rate. ~ dearation ~ethod .ISdescnbed as a footnote
`m the Procedure
`section under Dissolution
`(711). Typicalste
`include l:eating ~e medium,
`filtering, and drawing a vacuumfof!
`short penod of tune. Other methods of deaeration are availableand
`in routine use throughout
`the industry. Media containing SUrfactants
`are not usually deaerated because the process
`results in excessive
`foaming. To determine whether
`deaeration
`of
`the medi)llliis
`necessary,
`results
`from dissolution
`samples
`run in. nondeaerated
`medium and deaerated medium should be compared.
`.
`
`Enzymes
`
`in the dissolution medium is pennittedin
`The use of enzymes
`accordance with Dissolution
`(711) when dissolution failures occur
`as a result of cross-linking with gelatin capsules or gelatin,coated
`products.
`
`(IVIVC)
`
`In Vitro-In Vivo Correlation
`An in-depth discussion on IVIVC can be found in ~n Vitr.oandln
`Vivo Evaluation
`of Dosage Forms
`(1088). A bnef dISCUSSIOn
`follows.
`Biorelevant medium is a medium that has some relevance to thein
`vivo performance
`of
`the dosage unit. Choice
`of a biorelevant
`medium is based on (1) a mechanistic
`approach that considersthe
`absorption site, if known, and (2) whether
`the rate-limiting stepto
`absorption is the dissolution or permeability
`of the compound-h
`some cases,
`the biorelevant medium will be different
`from the test
`conditions chosen for the regulatory test, and the time p~ints m:ealso
`likely to be different.
`If the compound
`dissolves qUlcklymthe
`stomach and is highly permeable, gastric emptying ti~e mar be the
`rate-limiting
`step to absorption.
`In this case,
`the dissolution test
`should demonstrate
`that
`the drug is released quickly under typIcal
`gastric (acidic) conditions. On the other hand,
`if dissolution OCC,UIS
`primarily in the intestinal
`tract (e.g., for a poorly soluble, weak ac~~J)'
`,a higher pH range (e.g., simulated intestinal
`fluid with a pH of .
`may be more appropriate. The fe~ and fasted s~ates may also ha~
`significant
`effects on the absorption or solubility of a compoun .
`Compositions of media that simulate the fed and fasted s~atescanb~e
`found in the literature. These media reflect changes
`e
`111 pH,
`concentrations,
`and osmolarity after meal intake and ~herefor.eha~ a
`from that of typical compendial n:edia. T.ey
`composition different
`are primarily used to establish in vitro-in vivo correlations dunng
`formulation development
`and to assess potential
`For quality contIto)
`not
`intended
`for quality
`control purposes.
`purposes,
`the substitution of natural
`surfactants
`(bile componen sd
`with appropriate
`synthetic surfactants
`is permitted and encour~er.
`because of the expense of the natural
`substances
`intensive preparation of the biorelevant media.
`
`food eff~cts and~1
`
`and the Ia °
`
`-,'
`
`Page 3
`
`

`
`uSP 30
`
`General
`
`information /
`
`(1092) The Dissolution Procedure
`
`581
`
`APPARATUS/AGITATION
`Apparatus
`
`The choice of apparatus is based on knowledge of the formulation
`'go and the practical aspects of dosage form performance in the in
`desl
`test system. For solid oral dosage forms, Apparatus
`1 and
`d
`1
`VItrO
`fr
`aratus 2 are use most
`equent y.
`AP\V!lenApparatus
`official
`another
`1 or 2 is not appropriate,
`aratus may be used. Apparatus 3 (Reciprocating Cylinder) has
`~~nfound to be especially useful
`for bead-type modified-release
`sage forms. Apparatus
`4 (Flow-Through
`Cell) may
`offer
`d~vantagesfor modified-release
`dosage forms
`that contain active
`In addition, Apparatus
`a gredients with limited solubility.
`3 or
`~ aratus 4 may have utility for
`soft gelatin
`capsules,
`bead
`drugs. Apparatus
`5
`pftJucts, suppositories,
`or poorly
`soluble
`(paddleover Disk)
`and Apparatus
`6 (Rotating Cylinder)
`have
`beenshown to be useful
`for evaluating
`and testing transdennal
`dosageforms. Apparatus
`7 (Reciprocating Holder) has been shown
`to haveapplication to nondisintegrating
`oral modified-release dosage
`fonns,as well as to transdennal
`dosage forms,
`for example, a basket
`Somechanges can be made to the apparatus;
`meshsize other than the typical 40-mesh basket
`(e.g., 10, 20, 80
`mesh)may be used when the need is clearly documented
`by
`supportingdata. In countries where available mesh sizes vary from
`theUSP-specified mesh value, basket material with the nearest
`metricdimension should be used. Care must be taken that baskets
`areuniform and meet
`the dimensional
`requirements
`specified under
`Dissolution (711).
`If the basket
`screens become
`clogged during
`dissolutionof capsule or tablet formulations,
`it may be advisable to
`switchto the paddle method. The volume can be increased from the
`typical900 to 1000 mL by using 2- and 4-L vessels
`to assist
`in
`meetingsink conditions
`for poorly soluble drugs.
`A noncompendial apparatus may have some utility with proper
`justification,qualification, and documentation of superiority over the
`standardequipment. For example,
`a small-volume
`apparatus with
`minipaddles and baskets may be considered for low-dosage strength
`products.The rotating bottle or static tubes (jacketed stationary tubes
`enclosedwith a water jacket and equipped with a magnetic stirrer)
`mayalso have utility for microspheres and implants, peak vessels for
`eliminating coning,
`and modified flow-through
`cells
`for
`special
`dosageforms, including powders and stents,
`
`Sinkers
`
`When sinkers are used, a detailed description of the sinker must be
`statedin the written procedure.
`It may be useful
`to evaluate different
`sinkers, recognizing
`that
`sinkers
`can significantly
`influence
`the
`dlSso!utionprofile of a dosage unit. When transferring the procedure,
`the,SInkers should be duplicated as closely as possible in the next
`faclhty.There are several
`types of commercially available sinkers. A
`methodfor making sinkers by hand, sinkers that are similar
`to "a
`in Apparatus
`2 (Paddle
`few turns of wire helix"
`as described
`Apparatus) under Dissolution
`(711),
`is described below.
`Materials-Use
`316 stainless
`steel wire or other
`inert material,
`Fically 0.032 inch/20 gauge; and cylinders of appropriate diameter
`~,
`cork borers). Sizes are shown in the accompanying table.
`
`Capsule
`~hell
`Type
`#0, elongated
`#1 and #2
`~nd
`#4
`
`Length of
`Wire (cm)
`12
`10
`8
`
`Diameter
`Size (cm)
`0.8
`0.7
`0.55
`
`Cork Bore
`Number
`4
`3
`2
`
`a
`coil around
`length of wire,
`the specified
`Procedure--Cut
`cYlmderof the appropriate size, and use small pliers to curve in the
`nds.Use caution, because wire ends may be rough and may need to
`e
`b
`e filed.
`the sinker material and construction
`is handmade,
`If the sinker
`procedure instructions
`should be documented;
`if a commercial sinker
`ISused, the vendor part number should be reported.
`
`Agitation
`capsule or tablet formulations, Apparatus 1
`For immediate-release
`(baskets) at 100 rpm or Apparatus 2 (paddles) at 50 or 75 rpm are
`most commonly
`used. Other agitation speeds
`and apparatus
`are
`acceptable with appropriate justification.
`Rates outside 25 to 150 rpm are usually inappropriate because of
`the inconsistency
`of hydrodynamics
`below 25 rpm and because of
`turbulence above 150 rpm. Agitation rates between 25 and 50 rpm
`are generally
`acceptable
`for suspensions.
`For dosage
`forms
`that
`exhibit coning (mounding) under the paddle at 50 rpm,
`the coning
`can be reduced by increasing the paddle
`speed to 75 rpm,
`thus
`reducing the artifact and improving the data. If justified, 100 rpm
`may be used, especially for extended-release products. Decreasing or
`increasing the apparatus rotation speed may be justified if the profiles
`better reflect
`in vivo performance and/or the method results in better
`discrimination without adversely affecting method reproducibility.
`for
`Selection of the agitation and other study design elements
`modified-release
`dosage
`forms
`is similar
`to that
`for
`immediate-
`release products. These elements should conform to the requirements
`and specifications given in Dissolution (711) when the apparatus has
`been appropriately calibrated.
`
`STUDY DESIGN
`Time Points
`
`dosage forms, the duration of the procedure
`For immediate-release
`is typically 30 to 60 minutes;
`in most cases, a single time point
`specification is adequate for Phannacopeial
`purposes.
`Industrial and
`regulatory concepts of product comparability and performance may
`require
`additional
`time points, which may also be required
`for
`product
`registration or approval. A sufficient number of time points
`should be selected to adequately
`characterize
`the ascending
`and
`plateau
`phases
`of
`the
`dissolution
`curve. According
`to the
`Biophannaceutics Classification System referred to in several FDA
`Guidances, highly soluble, 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 drug substance within 15 minutes. For these types of products
`a one-point
`test will suffice. However, most products do not fall into
`this category. Dissolution
`profiles of
`immediate-release
`products
`typically show a gradual
`increase reaching 85% to 100% at about 30
`to 45 minutes. Thus, dissolution time points in the range of 15,20,
`30, 45, and 60 minutes
`are usual
`for most
`immediate-release
`products. For
`rapidly dissolving products,
`including suspensions,
`useful
`information may be obtained from earlier points, e.g., 5 to 10
`minutes. For slower-dissolving
`products,
`time points later than 60
`minutes may be useful. Dissolution test
`times for compendial
`tests
`are usually
`established
`on the basis of an evaluation
`of
`the
`dissolution profile data.
`studies.
`So-called infinity points can be useful during development
`To obtain an infinity point, the paddle or basket speed is increased at
`the end of the run for a sustained period (typically 15 to 60 minutes),
`after which time an additional sample is taken. Although there is no
`requirement
`for 100% dissolution in the profile,
`the infinity point can
`provide data that may supplement content uniformity data and may
`provide useful
`information about formulation characteristics during
`initial development or about method bias.
`For an extended-release dosage form, at least three test time points
`are chosen to characterize
`the in vitro drug release profile
`for
`Phannacopeial
`purposes. Additional sampling times may be required
`for drug approval purposes. An early time point, usually 1 to 2
`hours,
`is chosen to show that
`there is little probability
`of dose
`dumping. An intermediate time point
`is chosen to define the in vitro
`release profile of the dosage form, and a final time point is chosen to
`show the essentially complete release of the drug. Test
`times and
`specifications 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 determined for each active
`ingredient.
`
`~tra.
`iIize
`
`the
`OSI
`L.
`ink
`ed.
`
`in
`cur
`ted
`
`Ue...
`
`A•
`
`s
`
`Page 4
`
`

`
`---------------
`
`582
`
`(1092) The Dissolution Procedure / General
`
`information
`
`USP 30
`
`isr .
`
`weighi
`them
`encour
`experir
`formu!
`
`in whi:
`and A,
`respect
`label c
`NOT]
`fiuishe,
`becaus
`inam
`blend(
`potenti
`profile,
`If th
`tion-c-:
`subtra(
`be nee
`drugs(
`demon
`proced
`absenc
`should
`
`Lim
`solutio
`lowest
`during
`~>
`recoty;~
`cell~i\
`
`Filters
`
`necessary to
`is usually
`samples
`the dissolution
`of
`Filtration
`the analytical
`prevent undissolved
`drug particles
`from entering
`sample and further dissolving. Also,
`filtration removes
`insoluble
`excipients
`that may otherwise cause high background
`or turbidity
`Prewetting of the filter with the medium may be necessary.
`.
`Filters can be in-line or at the end of the sampling probe or both
`The pore size can .range from 0.45 to 70 um, The .usual
`types of
`filters are depth, disk, and flow-through. However,
`If the excipient
`interference is high,
`if the filtrate has a cloudy appearance, or if the
`filter becomes
`clogged,
`an alternative
`type of filter or pore size
`should be evaluated.
`.
`Adsorption of the drug(s) onto the filter needs to be evaluated.If
`the amount of initial filtrate discarded rna
`drug adsorption occurs,
`need to be increased.
`Ifresults
`are still unsuitable, an alternativefilt~
`material may be sought.
`by preparing a suitable
`Filter validation may be accomplished
`standard solution or a completely dissolved sample solution (e.g,
`prepared as a typical sample in a vessel or a sample put in a beake;
`and stirred with a magnetic stirrer for 1hour). For standard solutions
`compare
`the results
`for
`filtered
`solutions
`(after discardingth~
`appropriate volume)
`to those for the unfiltered solutions. For sample
`solutions, compare the results for filtered solutions (after discarding
`the appropriate volume) to those for centrifuged, unfiltered solutions
`
`Centrifugation
`
`Centrifugation of samples is not preferred, because dissolution can
`continue to occur and because there may be a concentration gradient
`in the supernatant. A possible exception might be for compounds
`that adsorb onto all common filters.
`
`ASSAY
`
`The usual assay for a dissolution sample is either spectrophoto·
`metric determination or HPLC. The preferred method of analysisis
`spectrophotometric
`determination
`because results can be obtained
`faster,
`the analysis
`is simpler, and fewer solvents are used. HPl.lC
`interference ··from
`methods
`are used when
`there
`is
`significant
`excipients or among drugs in the formulation to improve analytical
`sensitivity and/or when the analysis can be automated.
`It maybe
`useful
`to obtain data for the drug with a stability-indicating assay
`(e.g., HPLC chromatograms)
`in the medium of choice, even if the
`primary assay is based on a spectrophotometric method.
`
`VALIDATION
`The validation topics described in this section are typicalbut,~~t
`all-inclusive. The validation elements addressed may vary, d~pen;
`ing on the phase of development or the intended use for the data:
`The acceptance
`criteria are presented as guidelines only andD1~y
`differ
`for some products. Firms
`should document
`the approbfu~
`acceptance
`criteria
`for
`their products
`in pertinent SOPs,'
`ee
`considerations may be important
`for special dosage forms·Fct
`the pro lin
`extent
`of validation
`depends
`on the phase
`of
`development. Full validation takes place by the time of Ph~stions
`a
`the van
`.. g
`clinical
`studies. Validation
`studies
`should address
`associated with different profile time points. For products COll!~O
`more than a single active ingredient,
`the dissolution methodn~e",
`be validated for each active ingredient.!:
`
`i
`
`;').
`
`Specificity/Placebo Interference,·,,>,:,):
`"duly
`th~ results are not ~fes.
`that
`to de~onstrate
`is necessary
`It
`affected by placebo ~onstituents, other a.ct~vedrugs, of d~grsi(iJJkS'
`. The placebo consists of all ~he excipients
`and co~t!U~Witllout
`SInker, and capsule shell are also included when appropnate; ;.
`. Id .S.M·
`the active in
`edient. Placebo interference ma
`be
`et
`r
`dr
`S P MI·
`.
`T· Fie
`'caI
`S,
`cE vam, r.s., Martin, L.D.; DoWmg,
`·b'l AJ1a1yU
`Bou eau,
`.. ;
`Method Validation by Phase of Development, an Accepta e
`Technology 2004; 28(11):54-66.
`Practice. Pharmaceutical
`
`2
`
`Observations
`
`and
`of product dissolution
`and recordings
`Visual observations
`and
`are very useful because
`dissolution
`disintegration
`behavior
`can be
`indicative
`of variables
`in the
`disintegration
`patterns
`formulation
`or manufacturing
`process.
`To accomplish
`visual
`observation,
`proper
`lighting
`(with appropriate
`consideration
`of
`photodegradation)
`of the vessel contents and clear visibility in the
`bath are essential. Documenting
`observations by drawing sketches
`and taking photographs or videos can be instructive and helpful
`for
`those who are not able to observe the real
`time dissolution test.
`Observations
`are especially useful during method development
`and
`formulation optimization. Examples of typical observations
`include,
`but are not limited to, the following:
`
`2.
`
`4.
`
`1. Uneven distribution of particles throughout
`the vessel. This can
`occur when particles cling to the sides of the vessel, when there
`is coning or mounding
`directly under
`the apparatus, when
`particles
`float at the surface of the medium, when film-coated
`tablets stick to the vessel, and/or when off-center mounds are
`formed.
`Air bubbles on the inside of the vessel or on the apparatus or
`dosage unit. Sheen on the apparatus is also a sign of air bubbles.
`This observation would typically be made when assessing the
`need to deaerate the medium.
`3. Dancing or spinning of the dosage unit, or the dosage unit being
`hit by the paddle.
`Adhesion of particles to the paddle or the inside of the basket,
`which may be observed upon removal of the stirring device at
`the end of the run.
`sacs or
`such as transparent
`formations,
`Pellicles or analogous
`rubbery, swollen masses surrounding the capsule contents.
`Presence oflarge floating particles or chunks of the dosage unit.
`Observation
`of
`the disintegration
`rate
`(e.g.,
`percentage
`reduction in size of the dosage unit within a certain time frame).
`Complex disintegration
`of the coating of modified or enteric-
`coated products-for
`example,
`the partial opening and splitting
`apart
`(like a clamshell) or
`incomplete
`opening of the shell
`accompanied by the release of air bubbles and excipients.
`
`5.
`
`6.
`7.
`
`8.
`
`Sampling
`
`a
`syringes,
`uses plastic or glass
`sampling
`Manual-Manual
`stainless
`steel cannula that
`is usually curved to allow for vessel
`sampling,
`a filter, and/or a filter holder. The sampling site must
`conform to specifications under Dissolution (711).
`Autosampling-Autosampling
`is a useful alternative to manual
`test
`sampling,
`especially
`if
`the
`includes
`several
`time points.
`However, because regulatory labs may perform the dissolution test
`using manual
`sampling,
`autosampling
`requires
`validation with
`manual sampling.
`including semiautomated
`There are many brands of autosamplers,
`and fully automated systems. Routine performance checks, cleaning,
`and maintenance
`as described in the pertinent
`standard operating
`procedures or metrology documents are useful for reliable operation
`of these devices.
`Some instruments are equipped with sampling through the basket
`or paddle shaft. Proper validation (e.g., demonstrated equivalence to
`results with the usual sampling procedure) may be required.
`The disturbance of the hydrodynamics
`of the vessel by sampling
`probes
`should be considered and adequate validation performed to
`ensure that the probes are not introducing a significant change in the
`dissolution rate.
`should be
`procedures
`