LUPIN EX. 1007
`Lupin v. iCeutica
`US Patent No. 8,999,387
`
`Page 1
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`Physical Tests / (711) Dissolution
`
`277
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` Top
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`View
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`Side
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`' Basket-Rack
`
`Assembly '
`
`.
`
`15
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`'
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`_..1-——
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`5
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`9052
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`/
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`Fig. 1. Disintegration apparatus. (All dimensions are expressed in mm.)
`
`egrated except for fragments from the capsule
`__es fail to disintegrate completely, repeat the test
`‘capsules: not fewer than 16 of the total of 18
`tegrate completely.
`su1es—Proceed as directediunder Harcl Gelatin
`
`1) DISSOLUTION S
`
`apter is harmonized with the corresponding texts _;
`Phannacopoeia and/or the Japanese Pliarmaco-
`operas have undertaken not
`to make an i
`is harmonized chapter.
`'
`ut general chapter text that are national USP
`part of the harmonized text, are marked with
`_1fy_ this fact.
`edto determine compliance with the dissolution
`6 stated in the individual monograph,
`for
`(D'1(DO.- 0''1so=‘<
`9._.ffl "85CD*1D3... o5?T38"Q
`5
`33 C-0U}r»onO1
`
`' unit is defined as 1 tablet or 1 capsule or the amount specified. ‘Of
`' thetypes of apparatus described herein, use the one specified in the
`individual monograph. Where the label states that an article is
`ente1__‘ic_-coated, and where a dissolution or disintegration test that
`does_ not specifically state that it is to be applied to delayed-release
`- articles is included in the individual monograph, the procedure and
`interpretation given for Delayed~Release Dosage Forms is applied
`. u_nless'otherwise specified in the individual monograph. For hard or
`soft gelatin capsules and gelatin-coated tablets that do not conform to
`the Dissolution specification, repeat the test as follows. Where water
`or a medium with a pH _of less than 6.8 is specified as the Medium in
`the individual monograph, the same Medium specified may be used
`with the addition of purified pepsin that results in an activity of
`750,000 Units or less per 1000 mL. For media with a pH of 6.8 or
`'1 greater, pancreatin can be added to produce not more than 1750 USP
`. Units of protease activity per 1000 mL.
`USP Reference Standards (l1)———USP Chlorpheniramine Male-
`‘ate. Exten'cZed—Release Tablets RS (Drug Release Calibrator; Single
`Unit). USP Prednisone Tablets RS (Dissolution Calibrator; Disin-
`tegrating). USP Salicylic Acid Tablets RS (Dissolution Calibrator,
`Nondisintegrating). ,
`
`‘
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`Page 2
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`

`
`278
`
`(711) Dissolution / Physical Tests
`
`USP 30
`
`APPARATUS
`
`Apparatus 1 (Basket Apparatus)
`
`The assembly consists of the following: a vessel, which may be
`covered, made of glass or other inert, transparent material‘; a motor;
`a metallic drive shalt; and a cylindrical basket. The vessel is partially
`immersed in a suitable water bath of any convenient size or heated
`by a suitable device such as a heating jacket. The water bath or
`heating device permits holding the temperature inside the vessel at
`37 i 0.5° during the test and keeping the bath fluid in constant,
`smooth motion. No part of the assembly, including the environment
`in which the assembly is placed, contributes significant motion,
`agitation, or vibration beyond that due to the smoothly rotating
`stirring element. An apparatus that permits observation of the
`specimen and stirring element during the test
`is preferable. The
`Vessel is cylindrical, with a hemispherical bottom and ‘with one of
`the following dimensions and capacities: for a nominal, capacity of
`1 L, the height is 160 nun to 210 mm and its inside diameter is
`98 mm to 106 mm; ‘for a nominal capacity of 2 L, the height is 280
`mm to 300 rmn and its inside diameter is 98 rmn to 106 mm; and for
`a nominal capacity of 4 L, the height is 280 mm to 300 mm and its
`inside diameter is 145 rmn to 155 mm,. Its sides are flanged at the
`top. A fitted Cover may be used to retard evaporation? The shaft is
`positioned so that its axis is not more than 2 mm at any point from
`the vertical axis of the Vessel and rotates smoothly and without
`significant wobble that could affect the results. A speed—regulating
`
`device is used that allows the shaft rotation speed to be selected and
`maintained at the specified rate ‘given in the individual mono-
`graph,, within i4%.
`Shaft and basket components of the stirring element are fabricated
`of stainless
`steel,
`type 316, or other
`inert material,
`to the
`specifications shown in Figure 1. A basket having a gold coating
`of about 0.0001 inch (2.5 pm) thick may be used. A dosage unit is
`placed in a dry basket at the beginning of each test. The distance
`between the inside bottom of the vessel and the bottom of the basket
`is maintained at 25 i 2 mm during the test.
`
`Apparatus 2 (Paddle Apparatus)
`
`Use the assembly fi'om Apparatus 1, except that a paddle formed
`from a blade and a shaft is used as the stirring element. The shaft is
`positioned so that its axis is not more than 2 mm fiom the vertical
`axis of the vessel at any point and rotates smoothly without
`significant wobble that could affect the results. The vertical center
`line of the blade passes through the axis of the shaft so that the
`bottom of the blade is flush with the bottom of the shaft. The paddle
`conforms to the specifications shown in Figure 2. The distance of
`25 i 2 rrnrr between the bottom of the blade and the inside bottom of
`the vessel is maintained during the test. The metallic or suitably
`inert, rigid blade and shaft comprise a single entity. A suitable two-
`part detachable design may be used provided the assembly remains
`firmly engaged during the test. The paddle blade and shaft may be
`coated with a suitable coating so as to make them inert. The dosage
`unit is allowed to sink to the bottom of the vessel before rotation of
`
`
`
`Vent hcle
`2.0 t 0.5 mm diameter
`
`Retention spring with
`3 tang: on 120' centers
`
`Clear cpenhg
`20,2 :' L0,.‘ mm‘
`
`era:
`3.0mm
`
`:1.o'mm
`open _
`
`Note———Maxlmum allowable runout at “A”
`is :l:1.0 mm when the part ls rotated on
`center line axis with basketvmounted.
`
`6.3 to 6.5 or
`9.4 to'1o.1 mrn‘
`
`’
`
`Screen 0.1).
`22.2 a 1.0 mm
`
`Screen with welded seam:
`0.25—0.31 mm wire diameter
`with wire openings of 0.36~O.44 mm.
`[Note~After welding, the
`screen may be slightly
`altered]
`
`- - 25.0 x $.Un1m
`
`Fig. 1. Basket Stirring Element
`
`teste .
`‘ Th: materials should not sorb, react, or interfere with the specimen being
`’ If a cover is used, it provides sufficient openings to allow ready insertion of
`the therrnometer and withdrawal of specimens.
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`Page 3
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`Physical Tests / (711) Dissolution
`
`279
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`and a motor and drive assembly to reciprocate the cylinders
`vertically inside the vessels and, if desired, index the reciprocating
`cylinders horizontally to a different row of vessels. The vessels are
`partially immersed in a suitable water bath of an convenient size
`that permits holding the temperature at 37 _-i; O.5° uring the test. No
`part of the assembly,
`including the environment
`in which the
`’ assembly is placed, contributes significant motion, agitation, or
`- vibration beyond that due to the smooth, vertically reciprocating
`cylinder. A, device is used that allows the reciprocation rate to be
`selected and maintained at
`the specified dip rate ‘given in the
`individual monograph, within i5%. An apparatus that permits
`observation of the specimens and reciprocating cylinders is
`preferable. The vessels are provided with an evaporation cap that
`remains in place for the duration of the test. The components
`conform to the dimensions shown in Figure 3 unless otherwise
`specified ‘in the individual" monograph,
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`
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`eblade is started. A small, loose piece of nonreactive material,
`ot more than a few turns of wire helix, may be attached to
`
`sage units that would otherwise float. An alternative sinker device
`
`shown in Figure 2a. Other validated sinker devices may be used.
`
`_
`
`Apparatus 3 (Reciprocating Cylinder)
`
`NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA
`
`
`
`
`
`
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`
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`The assembly consists of a set of cylindrical, fla_t—bottomed glass
`eis; a set of glass reciprocating cylinders; inert fittings (stainless
`31 type 316 or other suitable material), and screens that are made
`
`'7 uitable nonsorbing and nonreactive material and that are
`ned to fit the tops and bottoms of the reciprocating cylinders;
`
`
`
`NOTES-
`
`(1 ) A and B dimensions
`
`are not to vary more
`than 0.5 mm when part
`Is rotated on center line
`axis.
`(2) Tolerances are :t 1.0
`mm unless otherwise
`stated.
`
`
`
`9.;4.tb, zogsinm diémetar
`
`
`
`
`
`1.2 it 0.2. mm radius E
`
`' "
`
`
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`4.1.5 mm radius
`
`_
`
`"‘
`
`r
`
`'
`
`.,_.
`" '-
`I
`
`
`4-=.,_o: :t;:ILQ min i
`.
`
`v
`-742Q’mm}"lb‘75.0fiIn'm
`
`.
`
`'5:
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`:
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`i
`
`2
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`
`
` __
`.
`A
`"
`‘
`-.;
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`
`I
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`Fig. 2. Paddle Stining Element
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`Page 4
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`

`
`280 y
`
`(711) Dissolution / Physical Tests
`
`
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`USP 30
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` l
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`*‘;\‘=i'-\'I -Ill-lilll
`l
`iillillliilli llllll
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`
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`A: Acid-resistant wire clasp
`B: Acid-resistant wire support-
`
`3.5-4.0
`
` /
`
`A
`
`Fig. 2a. Alternative sinker. All dimensions are expressed in mm.
`
`/
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`Air holes
`
`Evaporation cap
`
`3.9 i 0.1 diameter
`
`diameter
`6-8
`Type 316 stainless steel
`Alr holes
`8.9 i 0.1 diameter
`Mesh screen
`
`
`
`66.8i1
`
`
`
`180:1
`
`Glass vessel
`
`Glass reciprocating
`cylinder
`
`Mesh screen
`
`100i1
`
`181:1
`
`Fig. 3. Apparatus 3 (reciprocating cylinder)
`
`
`
`Apparatus 4 (Flow-Through Cell)
`
`_The assembly consists of a reservoir and a pump for the
`Dissolution Medium; a flow-through cell; and a water bath that
`mamtams the Dissolution Medium at 37 i 0.5°. Use the specified
`cell size ‘as given in the individual monograph,.
`The pump forces the Dissolution Medium upwards through the
`flow-through cell. The pump has a delivery range between 240 and
`960 mL per hour, with standard flow rates of 4, 8, and 16 mL per
`minute. It must deliver a constant flow (i5% of the nominal flow
`rate);
`the flow profile is sinusoidal with a pulsation of 120 i 10
`pulses per minute.
`
`The flow—through cell (see Figures 4 and 5), of transparent and
`inert material, is mounted vertically with a filter system (specified in
`the individual monograph) that prevents escape of undissolved
`particles from the top of the cell; standard cell diameters are 12 and
`22.6 mm; the bottom cone is usually filled with small glass beads of
`about 1—m1n diameter with one bead of about 5 mm positioned at the
`apex to protect the fluid entiy tube; and a tablet holder (see Figures 4
`and 5) is available for positioning of special dosage forms,
`for
`example, inlay tablets. The cell is innnersed in a water bath, a11d the
`temperature is maintained at 37 i O.5°.
`
`Page 5
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`

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`92010.2 I
`I
`922.6102
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`Filter chamber
`.
`
`Sieve 40 mesh
`d=O.2 w=O.45
`
`Score for the
`tablet holder
`
`Physical Tests /
`
`(711) Dissolution
`
`281
`
`V
`
`Eeaiota
`
`-
`Filter chamber
`
`.
`
`Steve 40 mesh
`
`Score for the
`tablet holder
`
`'
`
`'
`
`_,lL_,zo.a:o.05
`
`'
`
`QO.8.+.0.05
`L—u2:s)
`
`Q=dlameter
`
`E=dlameter
`
`arge cell for tablets and capsules (top) Tablet holder for the
`cell (bottom) (All measurements are expressed in mm unless
`noted otherwise.)
`
`Fig. 5. Small cell for tablets and capsules (top) Tablet holder for the
`small cell (bottom) (All measurements are expressed in mm unless
`noted otherwise.)
`'
`'
`
`r The apparatus uses ‘a clamp mechanism and two O-rings" to
`assemble the cell. The pump is separated fiom the dissolution unit in
`order to shield the latter against any vibrations originating from the
`pump. The position of the pump should not be on a level higher than
`the reservoir flasks. Tube connections are as short as possible. Use
`suitably inert tubing, such as polytef, with about 1.6-mm inner
`diameter and chemically inert flanged-end connections.
`
`Page 6
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`

`
`282
`
`(711) Dissolution / Physical Tests
`
`USP 30
`
`APPARATUS SUITABILITY
`
`The determination of suitability of a test assembly to perform
`dissolution testing must include conformance to the dimensions and
`tolerances of the apparatus as given above. In addition, critical test
`parameters that have to be monitored periodically during use include
`volume and temperature of the Dissolution Medium, rotation speed
`(Apparatus 1 and Apparatus 2), dip rate (Apparatus 3), and flow rate
`of medium (Apparatus 4).
`Determine the acceptable performance of the dissolution test
`assembly periodically. ‘The suitability for the individual apparatus is
`demonstrated by the Apparatus Suitability Test.
`Apparatus Suitability Test, Apparatus 1 and 2—lndividually
`test 1 tablet of the USP Dissolution Calibrator, Disintegrating Type
`and 1 tablet of USP Dissolution Calibrator, Nondisintegrating Type,
`according to the operating conditions specified. The apparatus is
`suitable if the results obtained are within the acceptable range stated
`in the certificate for that calibrator in the apparatus tested.
`Apparatus Suitability Test, Apparatus 3—lndividual1y test 1
`tablet of the USP Drug Release Tablets (Single Unit) according to
`the operating conditions specified. The apparatus is suitable if the
`results obtained are within the acceptable range stated in the
`certificate.
`
`Apparatus Suitability Test, App'aratus 4—[To corne.],
`
`Time——Where a single time specification is given, the test may be
`concluded in a shorter period if the requirement for minimum
`amount dissolved is met. Specimens are to be withdrawn only at the
`stated times within a tolerance of i2%.
`Immediate—Release
`‘Procedure for a Pooled _Sample for
`Dosage Forms—Use this procedure where Procedure for a
`Pooled Sample is specified in the individual monograph. Proceed
`as directed in Procedure for Apparatus 1 and Apparatus 2 in
`Immediate-Release Dosage Forms. Combine equal volumes of the
`filtered solutions of the six‘ or
`twelve individual specimens
`withdrawn, and use the pooled sample as
`the test specimen,
`Determine the average amount of the active ingredient dissolved in
`the pooled sample.,
`
`EXTENDED-RELEASE DOSAGE FORMS
`
`Proceed as directed for Immediate-Release Dosage Forms.
`Dissolution Medium——Proceed as directed for Immediate-Re~
`lease Dosage Forms.
`Time——The test—time points, generally three, are expressed in
`hours.
`
`DELAYED—RELEASE DOSAGE FORMS
`
`PROCEDURE
`
`NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA
`
`Apparatus 1 and Apparatus 2
`
`IMMEDIATE-RELEASE DOSAGE FORMS
`
`Use Method A or Method B and the apparatus specified ‘in the
`individual monograph,. All test times stated are to be observed
`within a tolerance of i2%, unless otherwise specified.
`Method A—
`
`Procedure ‘(unless otherwise directed in the individual
`monograph),-
`ACID STAGE—Place 750 1nL of 0.1N hydrochloric acid in the
`vessel, and assemble the apparatus. Allow the medium to equilibrate
`to a temperature of 37 i 0.5°. Place 1 dosage unit in the apparatus,
`cover the vessel, and operate the apparatus at the specified rate
`‘given in the monograph,.
`'
`After 2 hours of operation in 0.1 N hydrochloric acid, withdraw an
`aliquot of the fiuid, and proceed immediately as directed under
`Bufler Stage.
`Perform an analysis of the aliquot using a suitable assay method.
`‘The procedure is specified in the individual monograph.,
`BUFFER sTAGE—[NoTE—Cornplete the operations of adding the
`buffer and adjusting the pH within 5 rninutes.]
`With the apparatus operating at
`the rate specified ‘in the
`monograph,, add to the fluid in the vessel 250 mL of 0.20M
`tribasic sodium phosphate that has been equilibrated to 37 i- 0.5°.
`Adjust,
`if necessary, with 2N hydrochloric acid or 2N sodium
`hydroxide to a pH of 6.8 i 0.05. Continue to operate the apparatus
`V
`for 45 minutes, or for the specified time ‘given in the individual
`monograph,. At the end of the time period, withdraw an aliquot of ,.
`the fluid, and perform the analysis using a suitable assay method.
`‘The procedure is specified in the individual monograph. The test
`may be concluded in a shorter time period than that specified for the
`Bufler Stage if the requirement for the minimum amount dissolved is
`met at an earlier tirne.,
`Method B—
`
`Drain the acid from the vessel, and add to the vessel 1000 mL of pH
`
`Procedure ‘(unless otherwise directed in the individual
`monograph),—
`ACID STAGE—Place 1000 mL of 0.lN hydrochloric acid in the
`vessel, and assemble the apparatus. Allow the medium to equilibrate
`to a temperature of 37 i 0.5°. Place 1 dosage unit in the apparatus,
`cover the vessel, and operate the apparatus at the rate specified ‘in
`the monograph,. After 2 hours of operation in 0.1 N hydrochloric
`acid, withdraw an aliquot of the fluid, and proceed irmnediately as
`directed under Bufler Stage.
`Perform an analysis of the aliquot using a suitable assay method.
`‘The procedure is specified in the individual morrograph.,
`BUFFE1} sTAGE—[NoTE—For this stage of the procedure, use buffer
`that previously has been equilibrated to a temperature of 37 i 0.5‘’.]
`
`Place the stated volume of the Dissolution Medium (:|_-1%) in the
`vessel of the specified apparatus
`‘given in the individual
`monograph,, assemble the apparatus, equilibrate the Dissolution
`Medium to 37 i 0.5°, and remove the thermometer. Place 1 dosage
`unit in the apparatus, taking care to exclude air bubbles from the
`surface of the dosage unit, and immediately operate the apparatus at
`the specified rate ‘given in the individual monograph,. Within the
`time interval specified, or at each of the times stated, withdraw a
`specimen from a zone midway between the surface of the
`Dissolution Medium and the top of the rotating basket or blade,
`not less than 1 cm fi'om the vessel wall. [NoTE—Where multiple
`sampling times are specified, replace the aliquots withdrawn for
`analysis with equal volumes of fresh Dissolution Medium at 37° or,
`where it can be shown that replacement of the medium is not
`necessary, correct for the volume change in the calculation. Keep the
`vessel covered for the duration’ of the test, and verify the temperature
`of the mixture under test at suitable tirnes.] Perform the analysis ‘as
`directed in the individual monograph, using a suitable assay
`method.3 Repeat the test with additional dosage form units.
`If automated equipment is used for sampling or the apparatus is
`otherwise modified, verification that the modified apparatus will
`produce results equivalent
`to those obtained with the standard
`apparatus described in this general chapter is necessary.
`Dissolution Medium—A suitable dissolution medium is used.
`Use the solvent specified ‘in the individual monograph,. The
`volume specified refers to measurements made between 20° and 25°.
`If the Dissolution Medium is a buffered solution, adjust the solution
`so that its pH is within 0.05 unit of the specified pH ‘given in the
`individual monograph,. [NOTE—Dissolved gases can cause bubbles
`to form, which may change the results of the test. If dissolved gases
`influence the dissolution results, dissolved gases should be removed
`prior to testing.4]
`
`3 Test specimens are filtered immediately upon sampling unless filtration is
`demonstrated to be unnecessary. Use an inert filter that does not cause
`adsorption of the active ingredient or contain extractable substances that
`would interfere with the analysis.
`“ One method of deaeration is as follows: Heat the medium, while stirring
`gently, to about 41°, immediately filter under vacuum using a filter having a
`porosity of 0.45 pm or less, with vigorous stirring, and continue stirring under
`vacuum for about 5 minutes. Other validated deaeration techniques for
`removal of dissolved gases may be used.
`
`i
`ii5,I
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`.21.
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`Page 7
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`

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`SP-. 3 0
`
`Physical Tests / (711) Dissolution
`
`283
`
`3 phosphate buffer, prepared by mixing 0.1 N hydrochloric acid
`th 0_20M tribasic sodium phosphate (3 : 1) and adjusting,
`if
`cessaiy, with 2N hydrochloric acid or 2 N sodium hydroxide to a
`of 6.8 -l_- 0.05.
`[NOTE—This may also be accomplished by
`moving from the apparatus the vessel containing the acid and
`._.
`acing it with another vessel containing the buffer and transferring
`osage unit to the vessel containing the buffeiz]
`V
`ontinue to operate the apparatus for 45 minutes, or for the
`ecifled time ‘given in the individual monograph, At the end of
`'in'1e period, withdraw an aliquot of the fluid, and perform the
`‘sis using a suitable assay method. ‘The procedure is specified
`ndividual monograph. The test may be concluded in a shorter
`period than that specified for the Bufler Stage if the requirement
`minimum amount dissolved is met at an earlier time,
`
`9 Apparatus 3 (Reciprocating Cylinder)
`
`LNOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA
`
`IMMEDIATE-RELEASE DOSAGE FORMS
`
`e the thermometer. Place 1 dosage-
`_
`unit in each of the six reciprocating cylinders, taking care to
`de air bubbles from the surface of each dosage unit, and
`ediately operate the apparatus as specified ‘in the individual
`ograph,. During the upward and downward stroke,
`the
`iiprocating cylinder moves through a total distance of 9.9 to
`" cm. Within the time interval specified, or at each of the times
`fed, raise the reciprocating cylinders and withdraw a portion of the
`iftion under test from a zone midway between the surface of the
`Dissblution Medium and the bottom -of each vessel. Perform the
`alysis as directed ‘in the individual monograph, If necessary,
`eat the test with additional dosage—form units.
`‘
`'
`=
`-
`Dissolution Medium—Proceed as directed for Immea’z'ate—Re-
`3'e_Dosage Forms under Apparatus I‘ and Apparatus 2.
`I 11iie—Proceed as direc_ted for Immediate-Release Dosage Forms
`r Apparatus I and Apparatus 2.
`
`up
`
`EXTENDED-RELEASE DOSAGE FORMS
`
`Proceed as directed for Immedz'ate~Release Dosage Forms under
`rip’ ratus 3.
`ssolution Medium—Proceed as directed for Extended-Release
`sage Forms under Apparatus I and Apparatus 2.
`Ti1ne—Proceed as directed for Extended—ReZease Dosage Forms
`der Apparatus I and Apparatus 2.
`
`Apparatus 4 (Flow-Through Cell)
`IIMMEDIIATE-RELEASEIDOSAGE EoRMs V
`
`A1
`
`Q
`
`Place the glass beads_ into the cell specified ‘in the monograph,
`Place 1 dosage unit on top of the beads or,-if specified ‘in the
`monograph” on a wire carrier. Assemble the filter head, and fix the
`parts together by means of a suitable clamping device. Introduce by
`the pump the Dissolution Medium warmed to 37 i 0.5° through the
`bottom of the cell to obtain the flow rate specified ‘in the individual
`monograph, and measured with an accuracy of 5%. Collect the
`eluate by fractions at each of the times stated. Perform the analysis as
`directed ‘in the individual monograph,. Repeat
`the test with
`additional dosage—foirn units.
`A
`Dissolution Medium—Proceed as directed for Immea'z‘ate-Re-
`lease Dosage Forms under Apparatus 1 and Apparatus 2.
`Time—Proceed as directed for Immediate-Release Dosage Forms
`under Apparatus I and Apparatus 2.
`
`EXTENDED-RELEASE DOSAGE
`Proceed as directed for Imrnedz'ate—Release Dosage Forms under
`Apparatus 4.
`'
`~
`’
`‘Dissolution Medium—_—Proceed as directed for Immediate-Re
`lease Dosage Forms under Apparatus 4.
`_
`"
`Q
`Time—Proceed as directed for Immediate-Release Dosage Forms
`under Apparatus 4..
`-
`.
`-
`v
`
`A DELAYED-RELEASE DosAGE FORMS .
`
`Proceed as directed for Delayed-Release Dosage Forms under
`Apparatus I and Apparatus 2, using the specified media.
`Time—Proceed as directed for Delayed-Release Dosage Forms
`under Apparatus I and Apparatus 2.
`'
`
`. INTERPRETATION
`
`Immediate-Release Dosage Forms
`
`Unless otherwise specified ‘in the individual monograph,, the
`requirements are met if the quantities of active ingredient dissolved
`from the dosage units tested conform to Acceptance Table 1.
`Continue testing through the three stages unless the results confonn
`at either S1 or S2. The quantity, Q, is the amount of dissolved active
`ingredient ‘specified in the individual monograph,, expressed as a
`percentage of the labeled content of the dosage unit; the 5%, 15%,
`and 25% values in Acceptance Table 1 are percentages of the labeled
`content so that these values and Q are in the same terms.
`
`DELAYED—RELEASE DOSAGE FORMS
`
`,, Proceed as described for Delayed-Release Dosage Forms, Method
`3. under Apparatus I and Apparatus 2 using one row ‘of vessels for
`he acid stage media and the following row of vessels for the buffer
`ge media and using the volume of medium specified (usually 300
`/)I
`
`Time—Proceed as directed for Immediate-Release Dosage Forms
`der Apparatus I and Apparatus 2.
`
`»
`
`Stage
`S1
`S2;
`
`‘
`
`:
`
`' S3
`
`Number
`Tested
`i
`6_ ‘V
`' 6
`
`'
`
`'
`
`‘f
`
`12
`
`Acceptance Table 1
`
`”
`
`Acceptance Criteria
`' Each unit is not less than Q + 5%.
`Average of 12 units (S, + S2) is equal to or
`' ‘greater than Q, and no unit is less than
`Q — 15%.
`‘
`Average of 24 units (S, + S, + S3) is equal to
`or greater‘ than Q, not more than 2 units
`are less than Q ~ 15%, and no unit is less
`than Q — 25%.
`
`
`
`Page 8
`
`

`
`284
`
`(711) Dissolution / Physical Tests
`
`USP
`
`Delayed-Release Dosage Forms
`
`NOT ACCEPTED BY THE JAPANESE PHARMACOPOEIA.
`
`)
`
`Acid Stage—-—Unless otherwise specified ‘in the individual
`monograplr,, the requirements of this portion of the test are met"
`the quantities, based on the percentage of the labeled content"
`active ingredient dissolved from the units tested conforr
`Acceptance Table 3. Continue testing through all levels unles
`results of both acid and buffer stages conform at an earlier lev
`
`Level
`
`Number
`Tested
`
`A,
`A2
`
`A2
`
`6
`6
`
`12
`
`Acceptance Table 3
`
`Criteria
`
`No individual value exceeds 10% dissolve
`Average of the 12 units (A, + A2) is not mo
`than 10% dissolved, and no individual
`unit is greater than 25% dissolved.
`<
`Average of the 24 units (A, + A2 + A2) is n
`more than 10% dissolved, and no indivi
`ual unit is greater than 25% dissolved "
`
`. Buffer Stage-—Unless otherwise specified ‘in the individ
`monograph” the requirements are met if the quantities of act
`ingredient dissolved from the units tested conform to Acceptan _,
`Table 4. Continue testing through the three levels unless the resul ‘
`of both stages conform at an earlier level. The value of Q
`Acceptance Table 4 is 75% dissolved unless otherwise specified .
`the individual monograph, The quantity, Q,
`‘specified inthe
`individual monograph,
`is the total amount of active ingredi
`dissolved in both the Acid and Bufler Stages, expressed as
`percentage of the labeled content. The 5%, 15%, and 25% values
`Acceptance Table 4 are percentages of the labeled content so that
`these values and Q are in the same terms.
`
`
`
`Acceptance Table 4
`
`Level
`
`Number
`Tested
`
`-
`Criteria
`
`B,
`B2
`
`B2
`
`6
`6
`
`12
`
`Each unit is not less than Q + 5%.
`Average of 12 units (B, + B2) is equal to
`or greater than Q, and no unit is less than‘
`Q ~ 15%.
`Average of 24 units (B, + B2 + B2) is equa
`to or greater than Q, not more than 2 units
`are less than Q ~ 15%, and no unit is less‘
`than Q — 25%.
`
`Page
`
`‘Immediate-Release Dosage‘ Forms‘ Pooled S_ample—Unless
`otherwise specified in the individual monograph, the requirements
`are met if the quantities of active ingredient dissolved from the
`pooled sample conform to _the accompanying Acceptance Tablefor a
`Pooled Sample. Continue testing through the three stages unless the
`results conform at either S, or S2." The quantity, Q, is the amount of
`dissolved active ingredient ‘specified in the individual monograph,
`expressed as a percentage of the labeled content.
`5
`v
`
`Acceptance Table for a Pooled Sample
`, Number
`Tested
`—-
`6
`
`Acceptance Criteria
`Average amount dissolved is not less
`than Q_+ 10%.
`Average amount dissolved (S, -- S2) is
`equal to or greater than Q + 5%.
`Average amount dissolved (S, ~ S2 +
`S2) is equal to or greater than Q.
`
`»
`
`6
`
`12
`
`Stage
`S,
`
`S2
`
`S2
`
`Ext-ended-Release Dosage Forms
`
`Q
`
`Unless otherwise specified ‘in the individual monograph,, the
`requirements are met if the quantities of active ingredient dissolved
`fiom the dosage units tested conform to Acceptance Table 2.
`Continue testing through the three levels unless the results conform
`at either L, or L2. Limits on theamounts of active ingredient
`dissolved are expressed in terms of the percentage of labeled content.
`The limits embrace each value of Q,-, the amount dissolved at each
`specified fractional dosing interval. Where more than one range is
`specified ‘in the individual monograph,,
`the acceptance criteria
`apply individually to each range.
`
`~ Acceptance Table 2
`
`Level
`
`L,
`
`‘L2
`
`Number
`Tested
`
`6
`
`6
`
`-
`
`L2 I
`
`12
`
`~
`
`Criteria
`No individual value lies outside each of the
`stated ranges and no individual value is
`less than the stated amount at thefinal test
`time.
`- The average value of the 12 units (L, + L2)
`lies within each of the stated ranges and
`is not less than the stated amount at the
`final test time; none is more than 10% of
`labeled. content outside each of the stated
`ranges; and none is more than 10% of
`labeled content below the stated amount
`at the final test time.
`The average value of the 24 units (L, + L2 +
`L2) lies within each of the stated ranges,
`and is not less than the stated amount at the
`final test time; not more than 2 of the 24
`units are more than 10% of labeled content
`outside each of the stated ranges; not more
`than 2 of the 24 units are more than 10%
`of labeled content below the stated amount
`at the final test time; and none of the units is
`more than 20% of labeled content outside
`each of the stated ranges or -rnore than 20%
`of labeled content below the stated amount
`at the final test time.
`’
`
`t
`
`Page 9