`
`2400
`
`Fig. 2a. Tablet holder for the large cell.
`{All measurements are expressed in mm unless
`'
`noted otherwise.)
`
`aw
`
`
`
`
`
`Filter chamber
`
`
`
`starts-
`
`t
`_.‘
`92010.2 '
`
`Sieve-40 mesh
`(1: 0.2 w 30.45
`
`
`
`Score for the
`toblet holder
`
`
`oostoos
`L'——to3}
`
`
`E=diometer
`
`
`
`
`
`
`Fig. 3. Small cell for tablets and capsules.
`ii measurements are expressed in mm unless
`noted otherwise.)
`
`
`3 'e 0n a level higher than the reservoir flasks. Tube
`“are as short asdpossible. Use polytei' tubing with a
`fir diameter an
`chemically inert flangedend con-
`
`..Suilahility Test and Dissolution Mediumr—Proceed
`“9de Dissolution (711}.
`
`Physical Tests / Drug Release
`
`{724)
`
`1T95
`
`6.5
`
`0.5
`
`
`
`Fig. 3a. Tablet holder for the small cell.
`(All measurements are expressed in mm unless
`noted otherwise.)
`
`".r
`
`' Procedure—Place the glass beads into the cell s ecified in the
`monograph. Place 1 dosagetorm unit on top of t e 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 indi-
`vidual monograph. Repeat the test with additional dosage-form
`units.
`-
`-
`
`Where capsule shells interfere with the analysis,- remove the
`contents of not less than 6 capsules as completely as possible,
`and dissolve the empty capsule shells in the specified volume of
`Dissolution Medium. Perform the analysis as directed in the
`individual monograph. Make any necessary correction. Correc—
`tion factors greater than 25% of the labeled content are unac-
`ceptable.
`Time—The test-time points, generally three. are expressed in
`hours. Specimens are to be withdrawn within a tolerance of i 2%
`of the stated time.
`
`Interpretation—Unless otherwise specified in the individual
`monograph, the requirements are met if the quantities of active
`ingredient dissolved from the units tested conform to Acceptance
`Tobie 1. Continue testing through the three levels unless the
`results conform at either L1 or LZ. Limits on the amounts of
`active ingredient dissolved are expressed in terms of the
`r-
`centage of labeled content. The limits embrace each value 0 (2;,
`the amount dissolved at each specified fractional dosing interval.
`
`Delayed-release (Enteric-coated) Articles—
`General Drug Release Standard
`Use Method A or Method B and the apparatus specified in
`the individual mono raph. Conduct the Apparatus Suitability
`Test as directed un er Dissolution (711). 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 mono-
`graphk
`Acid Stage—Place 750 m1. of 0.1 N hydrochloric acid in the
`vessel, and assemble the apparatus. Allow the medium to equil»
`ibrate to a temperature of 3‘? i 0.5”. Place 1 tablet or 1 capsule
`in the apparatus, cover the vessel, and operate the apparatus'for
`2 hours at the rate specified in the monograph.
`SHIRE EX. 2018 Part 2
`KVK v. SHIRE
`IPRZQl8:00293
`
`p. 21
`p. 21
`
`SHIRE EX. 2018 Part 2
`KVK v. SHIRE
`IPR2018-00293
`
`

`

`
` USP 23 ..
`
`-
`-
`{ “DD
`I
`ire-u
`
`'
`
`I “malt
`:gjnliflf
`‘: at (“dc
`1:41.161 d
`e! to 111
`; gmdfr?
`. “an“!
`5,}.- ass:
`melee
`o “3‘
`
`1
`E
`1
`'
`
`.
`i
`E
`l
`
`l 3
`
`1
`
`_
`.
`Interpretation—Unless otherWise specified in llle -
`mono aph, the r uirements are met if the vamp-Iguana“
`ingre ient dissolve from the units tested coniom 10.4 “first,
`Table 3. Continue testing through the three megs "Emilee,
`results of both stages conform at an earlier levc!‘ Th “it“ It:
`1,? in Acceptance Table 3 is 75% dissolved unless othcél'alue u
`i led in the individual monograph. The quantity, Q,
`'3‘ tact.
`the individual monograph,is the total amount of a 1‘ SPCCintd'q
`dissolved in both the acid and buffer stages, expfeiigringfcd’t-t
`centagc of the labeled content. The 5% and 15% Value“; Pt:
`ceptartce Table 3 are percentages of the labeled mutants "1 -t.-
`these values and Q are in the same terms,
`5“ 1hr
`'
`
`Acceptance Table 3
`Number
`Tested
`.6
`6
`
`“He—a
`Criteria
`Each unit is not less than
`Average of 12 units (31 +933 ii“
`equal to or greater than Q, and n.
`l
`umt 1s less than Q ~— 15%.
`.1. B l
`Average of 24 units (Bl + ,9,
`rs equal to or greater than 9, nm’
`moi-1:35(glen El mats are less than )
`r"
`, an no unit is lcs
`;
`_ 251%.
`5 thin p
`
`
`“
`
`Level
`s,
`B;
`
`B;
`
`12
`
`Method B:
`
`Procedure (unless otherwise directed in the individual mum
`graph)—
`Acr'd Stage—Place 1000 mL of 0.1 N hydrochloric acid m It:
`vessel, and assemble the apparatus. Allow the medium In equil-
`ibratc to a temperature of 37 i 0.5“. Place 1 tablet or t raped:
`in the apparatus. cover the vessel, and operate the apparatus hr
`2 hours at the rate specified in the monograph. After 2 huun .-~:
`operation in 0.1 N hydrochloric acid, withdraw an aliquot cl tl‘:
`fluid, and proceed huntediately as directed under BtJfirStugr
`Perform an analysis of the aliquot using the Proccdnrr spa-
`ified in the test for Drug release in the individual monograph
`Unless otherwise specified in the individual monograph. 1hr
`requirements of this portion of the test are met if the qunlnitm
`based on the ercentage of the labeled content. of active mgr:-
`dient dissolvedJfrom the units tested conform to Accsptmuv 'litlllr
`2 under Method A. Continue testing through all
`levels tlnlcu
`the results of both acid and buffer stages conform at an cnler
`level.
`Refer Slogan—[NOTE#For this‘stage of the procedure. tut
`buffer that previously has been equilibrated to a lempcrullm u‘.
`37 i 0.5K} Drain the acid from the vessel, and add to [he vcssd
`i
`1000 mL o pH 6.8 phosphate buffer, prepared by mixifil! i“ -""
`lpparn
`_
`hydrochloric acid with 0.20 M tribasic sodium phosphate [‘1- 1".
`3mm,
`and adjusting, if necessary, with 2 N hydrochlonc acid In 7th
`mm
`sodium hydroxide to a pH of 6.8 t 0.05.
`[Norse—Thar no}
`1
`accomplished also by removing from the apparatus ll'lL VF“; m." in I
`containing the acid and replacing it with another vessel contain
`in“
`the buffer and transferring the dosage unit to the vessel caning:
`4
`tr?-
`the buffer.] Continue to operate the a paratus for 4? "1:1! 1“
`l
`or for the time specified lathe indivi ual monflgrapfi- "d m,
`
`end of the time period, withdraw an ahquot of t!" hills.“ N
`.
`perform the anal sis using the Procedure Spec11'1ed m1 :-
`or:
`{g "P. 0
`.
`.
`_ t
`“I
`Drug release int eindivtdual monograph. The 15‘" ””3
`cluded in a shorter time period than that spfilrlcd. “31:23 fiypf:
`Imam:
`stage if the requirement for minimum amount dose
`3?! Pk.
`at an earlier time.
`".1” mp.-
`flute r.
`lnter relation—Proceed as directed for [NW-"mm l
`' "ll-5
`alt a
`-
`Merho A.
`QT0t
`Ire
`-]
`.
`'
`. er
`Transdermal Debvery System?"Gen"3M
`,, In;
`Drug Release Standards
`”a D
`l
`.
`.
`‘
`01'
`Time—"The test—time points, generally thrfifiédai:Eggs. Sit“
`$131.2; 3
`terms ofthc labeled dosing interval, 0. express
`i I 5 Initiate!“
`'3
`’ Gel
`imens are to be withdrawn within a tolerance: or r‘ lhc Harm“:
`"maths”
`i 2% of the stated time, the tolerance that rcsu ts 1n
`:-
`Limc interval heir-m selected.
`p. 22
`
`
`c
`
`std ”3
`
`.
`
`.
`i
`
`1
`
`i
`
`li
`
`(724i Drug Release / Physical Tests
`
`Acceptance Table 1
`Number
`Tested
`
`Criteria
`
`[.1
`
`L;
`
`6
`
`6
`
`L3
`
`[2
`
`No individual value lies outside each
`of the stated ranges and no individ-
`ual value is less than the stated
`amount at the final 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
`amounLat the final test time.
`The average value of the 24 units (L1
`+ L2 + L3) 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 more than 20% of labeled
`content below the stated amount at
`the final test time.
`
`After 2 hours of operation in 0.1 N hydrochloric acid-withdraw
`an aliquot of the fluid, and proceed immediately as directed under
`Buffer Stage.
`-
`.
`Perform an analysis of the aliquot using the Procedure spec-
`ified in the test for Drug release in the individual monograph. -
`Unless otherwise specified in the individual monograph, the
`requirements of this portion of the test are met if the quantities.
`based on the percentage of the labeled content, of active ingrez
`dient dissolved from the units tested conform to Acceptance Table
`2. Continue testing through all levels unless the results of both
`acid and buffer stages conform at an earlier level.
`
`Level
`
`A,
`
`A2
`
`A;
`
`_
`
`'
`
`Acceptance Table 2
`Number
`Tested
`
`Criteria
`
`6
`
`6
`
`‘
`
`l2
`
`No individual value exceeds 10% dis-
`solved.
`-
`Average of the 12 units (A, + A2) is
`' not‘more than l0% dissolved, and
`no individual unit is greater than
`25% dissolved
`Average of the 24 units (.41 + A; +
`A3) is not more than 10% dissolved,
`and no individual unit is greater
`than 25% dissolved.
`
`Buffer Stage—~[NOTE—Complete the operations of adding the
`buffer, and adjusting the pH within 5 minutes} With the sp-
`paratus operating at the rate specified in-the monogra l1, add to
`the fluid tn the vessel 250 ml...of 0.20 M tribasic so 'urn phos-
`phate that has been equilibrated to 3? :t: 0.5“. Adjust, if nec-
`essar , with 2 N hydrochloric acid or 2 N sodium hydroxide to
`a p
`of 6.8 i 0.05. Continue to operate the apparatus for 45
`minutes, or for the time specified in the individual monograph.
`At the end of the time period, withdraw an aliquot of the fluid,
`and crform the analysis using. the Procedure specified in the
`test or Drug release in the individual monograph; The test may
`be concluded in a shorter time period than that specified for the
`Buffer Stage if the requirement for minimum amount dissolved
`is met at an earlier time.
`-
`
`
`
`
`
`
`
`
`

`

`
`
`gm}, oven DISK—-
`"ruse—Use the paddle and vessel assembly from Ap-
`2 as described under Dissolution (7'11), with the addition
`"aless steel disk assemblyl designed for holding the trans
`
`'al system at the bottom of the vessel. The temperature is
`
`
`r-ificd at 32 i 0.5“. A distance of 25 :i: 2 mm between
`
`(idle blade and the surface of the disk assembly is .main—
`' during the test. The vessel may be covered during the
`
`minimize evaporation. The disk assembly for holding the
`
`email system is designed to minimize any “dead” volume
`rill“: disk assembly and the bottom of the vessel. The
`
`$55.11ny holds the system flat and is positioned such that
`case surface is parallel with the bottom of the paddle blade
`
`gate 4).
`
`
`
`
`. Q, no
`than 9,
`s thanQ
`
`
`
`Dissolution
`Vessel
`
`Paddle
`
`
`Fig. 4. Paddle Over Disk.
`.
`[All measurements are expressed in mm unless
`noted otherwise.)
`-
`
`
`
`this Suitability Test and Dissolution Medium—Proceed
`ted for Apparatus 2 under Dissolution ('ll 1}.
`
`filth—Place the stated volume of the Dissolution Me
`
`lhe vessel, assemble the apparatus without the disk as-
`
`d equilibrate the medium-to 32 i 0.5”. Apply the '
`.l system to the disk assembly, assuring that the release
`
`the system is as flat as possible. The system may be
`
`the disk by applying a suitable adhesive2 to the-disk
`
`Dry for 1 minute. Press the system, release surface
`
`.
`lathe adhesive—coated side of the disk assembly. If
`lifts is used to support the system, it is applied so that
`
`'
`has occur between the membrane'and the release sur-
`“ lllfl disk assembly flat at the bottom of the vessel
`
`ll’JaSe surface facing up and parallel to the edge of the
`
`.Sfimbly (stainless support disk) may be obtained from
`Corr.,_ash1ey Rd, Bedford, MA 01730.
`,_$931 Hate devices may be used, provided. they do not
`
`.. ill“ . or interfere with the specimen being tested.
`9” Corning, 355 Medical Adhesive 18.5% in Freon
`
`:
`_
`..;equiva1ent.'
`.
`mans
`“PmPhan, Type 150 pm, 11 a 0.51am thick, an inert,
`
`t15.
`_
`[$10816 material, which is available from ENKA AG,
`
`11 the
`.
`- .Ccve Circle, Corona DeiMar, CA 92625, or.LifeMed
`Delano Blvd, Compton. CA 90220-
`
`
`
`Physical Tests / Drug Release
`
`(724)
`
`1797
`
`paddle blade and surface of the Dissolution Medium. The bot-
`tom edge of the paddle is 25 i 2 mm from the surface of the
`disk assembly.
`Immediately operate the apparatus at the rate
`specified in the monograph. At each sampling time interval,
`withdraw a specimen from a zone midway between the surface
`of the Dissolution-Medium and the top of the blade, not less
`than 1 cm from the vessel wall. Perform the analysis on each
`sampled aliquot as directed in the individual monograph, cor-
`rectlng for any volume losses, as necessary. Repeat the test with
`additional transdermal systems.
`Interpretation—«Unless otherwise specified in the individual
`monograph, the requirements are met if the quantities of active
`ingredient released from the system conform to Acceptance Table
`4 for transdermal drug delivery systems. Continue testing through
`the three levels unless the results conform at either L1 or L1.
`
`6
`
`6
`
`L1.
`
`L;
`
`
`Acceptance Table 4
`Number
`
`Tested
`Level
`Criteria
`No individual value lies outside the
`stated range.
`The average value of the 12 units (L1
`+ L2) lies within the stated range.
`No individual value is outside the
`stated range by more than 10% of
`the average of the stated range.
`.
`The average value of the 24 units (L1
`-+- L; + L3) lies within the stated
`range. Not more than 2 of the 24
`units are outside the stated range by
`more than 10% of the average of the
`stated range; and none of the units
`is outside thestated range by more
`than 20% of the average of the stated
`
`range.
`
`Apparatus 6—Cylinder—
`APPARATUS—Use the vessel assembly from Apparatus I as
`described under Dissolution (ill), except to replace the basket
`and shaft with a stainless steel Cylinder stirring element and to
`. maintain the temperature at 32 i 0.5” during the test. The shaft
`and cylinder components of the stirring element are fabricated
`of stainless steel
`to the specifications shown in Figure 5. The
`dosage unit is placed on the cylinder at the beginning of each
`test.- The distance between. the inside bottom of the vessel and
`the cylinder is maintained at 25 :i: 2 mm during the test.
`Dissolution Medium—Use the medium specified in the indi- I
`vidual monograph (see Dissolution (711)).
`Procedure—Place the stated volume of the Dissolution Me—
`dium in the vessel of the apparatus specified in the individual
`monograph, assemble the apparatus, and equilibrate the Disso—
`lurion Medium to 32 i 0.
`. Unless otherwise directed in the
`individual monograph, prepare the test system prior to test as
`follows. Remove the protective liner from the system, and place
`the adhesive side on a piece of Cuprophan3 that is not less than
`1 cm larger on all sides than the system. Place the system, Cu-
`prophan covered side down, on a clean surface, and apply a suit—
`able adhesive2 to the exposed Cuprophan borders. If necessary,
`apply additional adhesive to the back of the system. Dry for 1
`minute. Carefully apply the adhesive-coated side of the system
`to the exterior of the cylinder such that the long axis of the system
`fits around the circumference of the cylinder. Press the Cupro-
`phan covering to remove tra ped air bubbles. Place the cylinder
`in the apparatus, and imme lately rotate at the rate specified in
`the individual monograph. Within thetime, interval specified, or
`at each of the times stated, withdraw a‘ quantity of Dissolution
`Medium for analysis from a zone midway between the surface
`of the Dissolution Medium and the to of the rotating cylinder,
`'not less than 1 cm from the vessel wal . Perform the analysis as
`directed in the individual monograph, correcting for any volume
`losses as necessary. Repeat the test with additional transdermal
`drug delivery systems.
`Interpretation—Unless otherwise specified in the individual
`monograph, the requirements are met if the quantities of active
`ingredient released from the svstem conform to Accentonee Table
`p. 23
`p. 23
`
`

`

`1 798
`
`(724)
`
`Drug Release / Physical Tests
`
`Fowholssetl.llldfo. /-_
`molly spaced on 2.540
`lid. be or 6.14% 0.5'
`angle to swim.
`
`
`
`
`
`Maximum
`rooms 0.300 —.
`
`TOLERANCES:
`$00!?
`
`.
`FINISH:
`all surfaces 32
`mirrolneh rrns.
`Decrease before
`final assembly or
`red one eyll'l oer.
`
`MM‘ERIAL:
`304 stainless steel
`
`3.6?0
`
`This adapter
`section to be
`used for
`large systems.
`
`
`
`
`
`
`
`
`
`4 for transdermnl drug delivery systems. Continue rem"
`the three levels unless the results conform at aim, ngoihiom
`A
`rattle ’l—Reciprocating Disk-—~[Nmn__T .
`1-
`maypgfiso be specified for use with solid oral «5%?qu
`”mums—The assembly consists of a set of Volum .1
`calibrated or tared solution containers made of 3:355 um“!
`suitable inert material} a motor and drive assemb1y to rec?! "it!
`the system vertically and to index the system horizomglfimle
`different row of vessels automatically if decirect and a set ¥ [0 s
`shaped sample holders (see Figure 6). The solution .0: slut.
`
`are partially immersed in a suitable water bath of any Comm.
`size that
`its maintaining the temperature inside menial
`
`miners at 32 :l: 0.50 during the test. No part of the a“: 00e-
`
`_,
`.
`including the environment in which the assembly is piaqdmbb.
`
`tributes significant motion. agitation. or vibration btyend'm -
`due to the smooth. vertically reciprocating sample holder
`that
`'
`
`paratus that permits observation 0 the system and holding ’.
`“I
`
`the test is preferable. Use the size container and sampm his)?
`as specified in the individual monograph.
`d“
`
`Dissolution Medium—Use the Dissolution Medium
`-'
`
`in the individual monograph (see Dissolution (711)), mun“!
`
`.
`Procedure—Remove the transdermal system from its backi
`.
`.
`;
`Press the system onto a dry, unused piece of Cuprophan3 or equIii-i
`
`atom with the adhesive side against the Cuprophan. taking can
`.
`._.
`to eliminate air bubbles between the Cuprophan and the trim,
`
`I
`I"
`surface. Attach the system to a suitable size sample holder with
`Z
`a suitable O-nng such that the back of the system is adjmm to
`
`and centered on the bottom of the sample holder. Trim the exam —.
`.
`Cuprophan With a sharp blade. Suspend each sample holder from
`
`a vertically reciprocating shaker such that each system is con.
`tinuously immersed in an accurately measured volume of my.
`
`solution Medium within a calibrated container pre-cQuifibnm}
`
`to 32 i 0.5". Reciprocate at a frequency of about 30 cycles per
`
`minute with an amplitude of about 1.9 cm for the specified lime
`in the mediums eetfied for each time point. Perform the analyg‘a
`
`as directed in
`e individual monograph. Repeat the test with
`additional transdermal drug delivery systems.
`
`”2.2224
`
`Fig. 5. Cylinder Stirring Element“
`(All measurements are expressed in em unless
`noted otherwise.)
`
`A
`
`0.!143 Radius
`
`. 0. 31"?5 Diameter - Press fit to head
`
`
`
`(mien! drawing -* Design or shape may very}
`
`D
`
`C
`
`Ulrnenelons are in centimeters.
`
`
`acne
`and
`came
`
`
`Svflflm"
`A {Diameter}
`5
`C
`Motel-lo“
`D
`Materlnl‘
`(not shown)
`1.61m!I
`1.423
`0.9525
`0.4750
`SSIVT
`30fi8
`35 {P
`Parker Z—1I5 -V684~ 75
`
`2.5 ¢l111I
`5|:‘l'l'lz
`
`Tern'
`10 am:
`
`1.778
`2.6924
`
`3.1750
`5.0292
`
`0.9525
`0.7620
`
`0.7620
`0.5350
`
`0.4750
`0.3810
`
`0.3310
`0. 5505
`
`55 {VT
`SSFVT
`
`30,43
`3.890
`
`SSIVT , 30.43
`SS/VT
`51.01
`
`58/?
`SSIP
`
`38”"
`SSH”
`
`Porter 2-01_6~V884-75
`Parker 2-022-V854-3'5
`
`Parker 2- lad—V854-75
`Parker 2-225-‘0’384-75
`
`' Typical system sizes.
`" ss/vr = Elther stainless steel or virgin Teflon.
`' SSIP F Either stainless steel or Plexiglas.
`
`Fig. 6. Reciprocating Disk Sample Holder.‘
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`“ The cylinder stirring element is available from Accurate'Tool,
`Inc, 25 Disc SL. Stamford, CT 06907. or from Van—Kc] In-
`dustries. Inc, 36 Meridian Rd. Edison, NJ [38820.
`
`.
`_
`_
`5 The materials should not sorb. react will? or mtcr
`the a col men bein tested.
`--
`'
`5 Tito reciprocating disk sample holder may bipgiglailfld
`
`ALZA Corp, 950 Page Mill Rd, Palo Alto, C
`
`Kol Industries, "-
`p. 24
`
`[em
`
`.
`
`I
`
`-.
`
`
`
`
`
`

`

`
`" ”elation—Unless otherwise specified in the individual
`Fit, the re uirements are met if the quantifies of active
`“t released tom the system conform to Acceptance Table
`
`ermal drug delivery systems. Continue testing through
`
`Nil-I 'e levels unless the results conform at either L; or Lg.
`
`
`
`
`7 26) ELECTROPHORESIS
`' phorcsis refers to the migration of electrically charged
`
`colloids. molecules, or other particles when dissolved or
`
`ed in an electrolyte through which an electric current is
`
`
`'5 upon the type of apparatus used, electrophoretic meth-
`may be divided into two categories, one called free solution
`
`, “g boundary electrophoresis and the other called zone
`
`'iopllflttl’ls-
`.
`.
`.
`free solution method, a buffered solution of proteins in
`
`.aped cell is subjected to an electric current which causes
`
`mains to form a series of layers in order of decreasing
`
`,which are separated by boundaries. Only a part of the
`
`moving protein is physically separated from-the other pro-
`
`hut cssnunation of-the moving boundaries using a schlieren
`
`system provides data for calculation of mobilities and
`
`{ion an the qualitative and quantitative composition of
`
`protein mixture.
`
`m electrophoresis, the sample is introduced as a narrow
`
`spot in a column, slab, or film of buffer. Migration of
`
`patients as narrow zones permits their complete separa«
`
`emitting of the separated zones by thermal convection is
`
`ad by stabilizing the electrolyte in a porous matrix such
`tiered solid. or a fibrous material such as paper, or a gel
`
`as starch, agar, or polyacrytamide.
`
`rious methods of zone electrophoresis are widely employed.
`
`électraphorest‘s, particularly the variant called dirk electro-
`
`'
`s, is especially useful for protein separation because of its
`
`' lving wer.
`.
`
`leetro
`resis, which is employed by the compendium, is
`
`in more detail following the presentation of some the-
`
`_ principles and methodological practices, which are shared
`
`'
`_ 3 degrees by all electrophoretic methods.
`.- .electrophorettc migration observed for
`rticles of a par-
`
`=
`substance depends on characteristics 0 the particle, pri-
`tits electrical charge, its size or molecular weight, and its
`
`‘11: well as characteristics and operating parameters of the
`These latter include the pH, ionic strength, viscosity and
`
`lure of the electrol e, density or cross-linking of an
`
`mg matrix such as ge , and the voltage gradient employs .
`
`.of Charge, Particle Size, Electrolyte Wscosity, and
`.9; Gradient—Electrically charged particles migrate toward
`
`trade of opposite charge, and molecules with both positive
`game char 'es move in a direction dependent on the net
`
`The rate migration is directly related to the ma
`'tude
`flint charge on the particle and is inversely relat
`to the
`
`$3: g‘article, which in turn is directly related to its mo-
`13 1.
`
`large spherical
`rticles, for which Stokes’ law is valid,
`.elcctrophorettc mobility. on, which is inversely related
`I power of the radius as depicted inthe equation:
`
`
`
`
`
`Q
`It
`Homfl=_.__
`E
`6rm'
`
`
`
`is the velocity of the particle, E is the voltage gradient
`on the_electrolyte, Q is the charge on the particle, :- is
`
`l: radius, and 7t is the viscosity of the electrolyte. This
`
`I3:"lill'ttt'oton is strictly valid only at infinite dilution .and
`'5-
`“cc eta stabilizing matrix such as paper or a gel;
`
`hilld Peptides up to molecular weights of at least 5000,
`
`‘t
`l. In the presence-of stabilizing media, do not obey
`
`“'ufind their electrophoretic behavior is best deseribed
`
`10r- of the type:
`
`
`
`“a”
`
`
`Q
`.
`An'l‘zn’
`"
`is 3. Shape factor generally in the range of 4 to 6-, which
`”"88 dependence of the mobility on the square of the
`
`
`
`Physical Tests / Electrophoresis
`
`(726)
`
`1799
`
`In terms of molecular weight, this implies an inverse
`radius.
`dependence of mobility on the 175 power of the molecular weight.
`Effect opr—The direction and rate of migration of molecules
`containing a variety of ionizable functional groups, such as amino
`acids and roteins, depends upon the pH of the electrolyte. For
`instance, t mobility of a sunple amino acid such as glycine
`varies with pH approximately as shown in Figure l. The pK,
`values of 2.2 and 9.9 coincide With the inflection points of the
`sigmoid portions of the plot. Since the respective functional groups
`are 50% ionized at the pH values where pH = pKa, the electro-
`horetic mobilities at these points are half of the value observed
`or the fully ionized cation and anion obtained'at very low and
`very high pH, respectively. The zwitterion that- exists at the
`itppermediate pH range is electrically neutral and has zero mo~
`i ity.
`
`RelativeMobility
`
`anode
`TowardcathodeoToward
`
`
`Jag-«g
`
`Fig. l.
`
`Eflcct of [cute Strength and Temperature—Electrophoretic
`mobility decreases with Increasing ionic strength of the support-‘
`ing electrolyte.
`Ionic strength, p, is defined as:
`
`a = nssctzl,
`
`where C, is the concentration of an ion in moles per liter and Zr
`is its valence,'and the sum is calculated for all ions in the solution.
`For buffers in which both the anion and cation are univalent,
`ionic strength is identical with molarity.
`-
`Ionic strengths of electrolytes employed in electrophoresis com-
`monly range from about 0.01 to 0.10. A suitable strength is
`somewhat dependent on the sample composition, since the buffer
`capacity must be great enough to maintain a constant pH over
`the area of the component zones. Zones become sharper or more
`compact as ionic strength is increased.
`Temperature affects mobility indirectly, since the viscosity, at,
`of the supporting electrolyte is temperature-dependent. The vis-
`cosity of water decreases at a rate of about 3% per “C in the
`range of 0° to 5" and at a sli
`tIy lower rate in the vicinity of
`room temperature. Mobility,
`erel'ore, increases with increasing
`electrolyte temperature.
`Considerable heat is evolved as a result of current passing
`through the supporting electrolyte. This heat increases with the
`up lied voltage and with increasing ionic strength. Particularly
`in
`rger apparatus, despite the circulation of a coolant, this heat
`produces a temperature gradient across the bed which may lead
`to distortion of the separated macs. Therefore, practical consid-
`erations and the design of the particular apparatus dictate the
`choice of ionic strength and operating voltage.
`Effect of a Stabilizing Medium, Electroosmosls—When an
`electrical current is parsed through an electrolyte contained in a
`lass tube or contained between plates of glass or plastic, a bulk
`fiow of the electrolyte toward one of the electrodes is observed.
`This flow is called electroosmosis.
`It results from the surface
`charge on the walls of the flparatus, which arises either from
`ioniaable functional grou
`i
`erent in the structural material or
`from ions adsorbed on
`e cell walls from the electrolyte con-
`tacting them. The effect is usually increased when the cell is
`p. 25
`p. 25
`
`

`

`
`
`
`1940
`
`(1151) Pharmaceutical Dosage Forms / General Information
`
`
`
`In support of the U. S.
`and uniformity in drug nomenclature.
`Adopted Names program (see Preface), of which the U. S. Phar~
`macopeial Convention is a cosponsor, the USP Committee of
`Revision gives consideration to the adeption of the U. S. Adopted
`Name, if any, as the official title for any compound that attains
`compendial recognition.
`-
`A compilation of the U. S. Adopted Names (USAN) published
`from the start of the USAN program in 1961, as well as other
`names for drugs, both current and retrospective, is provided in
`USAN and theUSP Dictionary ofDrug Nantes. This publication .
`is intended to serve as a book of names useful for identifying and
`distinguishing all kinds of names. for drugs, whether public or
`proprietary or chemical or code-designated names.2
`A nonproprietary name of a drug serves numerous and varied
`purposes, its principal function being to identify the substance to
`which it applies by means of a designation that may be used by .
`the professional and lay public free from the restrictions asso-
`ciated with registered trademarks. Teaching in pharmacy and
`medicine requires a common designation, especially for a drug
`that is available from several sources or is incorporated into a
`combination drug product; nonproprietary names facilitate com—
`munication among physicians; nonprOprietary names must be used
`as the titles' of the articles recognized by official drug compendia;
`a nonproprietary name is esiential to .the pharmaceutical manu—
`facturer as a' means of protecting trademark rights in the brand
`name for the article concerned; and, finally, the manufacturer is
`obligated by federal law to include the established nonpropriet'ary
`name in advertising and labeling.
`-
`_'
`.
`Under the terms of the Drug Amendments of 1962 to the
`Federal Food, Drug, and Cosmetic Act, which became law Oe-
`tober 10, 1962, the Secretary. of Health and Human Services is.
`authorized to designate an official name for any drug wherever
`deemed “necessary or desirable in the interest of usefulneSs and
`simplicity.” 3
`'
`.
`_
`The CommiSsioner of Food and Drugs and the Secretary of
`Health and Human Services published in the Federal Register
`regulations effective November. 26, .1984, which state, in part: .
`Sec. 299.4 Established names of drugs.
`(e)
`“The Food and Drug Administration will not routinely
`designate official names under section 508 of the act. As a
`result1 the established name under section 502(e} of the act
`will ordinarily be- either the compendial name of 'the drug or,
`if there is no compendial name, the common or usual name of
`the drug. Interested persons, in the absence of the designation
`by the Food and Drug Administration of an official name, may .
`rely on as the established name for any drug the current com—
`pendial name or the USAN adopted name listed in USAN and
`the USP Dictionary ofDrag Nomes._. . .“ 4
`'
`'
`It will be noted that the monographs on the biologics, which.
`are produced under licenses issued by the Secretary of the U.‘ S.
`Department of Health and Human Services, represent a special
`case. Although efforts continue tot-yard achieving uniformity, there
`may be 'a difference between, the respective title requiredfby
`federal law and the'USP title. Such differences are fewer than
`in past revisions of the Pharmacopeia. The USP title, where
`different from the FDA Bureau of Biologics title, does not con-
`stitute a synonym for labeling purposes; the conditions of licensing
`the biologic concerned require that each such article be desig—
`nated by the name appearing in' the product license issued to the
`manufacturer. Where a USP title differs from 'the title in the
`federal regulations,'the former has been adopted with a view to
`usefulneSS and simplicity and conformity with the principles gov—'
`
`erning the selection of monograph titles generally. '
`
`'
`
`2 USAN and the USP Dictionary ofDrag Names is obtainable
`on order from the USAN Division, USP Convention, Inc., 12601
`Twinbrmk Parlovay, Rockville, MD 20852.
`.
`3 F.D.&C. Act, Sec. 508 i358].
`-
`‘l 53 Fed. Reg. 5369' (1988) amending 21 CFR § 299.4.
`
`(1 151) - PHARMACEUTICAL
`DOSAGE FORMS
`Desag'e forms are provided for most of the Pharmacopeial drug
`substances, but the processes for the preparation of many of them
`
`are, in general, beyOnd thelscopc of the Pharmacopeia
`dition to defining the dosage forms, this section
`'
`erai principles involved in the manufacture Omefi of Bite
`pitticularlfi on a small scale. Other information that is [bent
`ars on t e use of the Pharmampeial substances in tin But-n
`raneous compounding of dosage forms.
`Empo-
`
`BIOAVAILABILITY '
`
`-
`Bioavailability, or the extent to which the therapeutic c
`mm of a pharmaceutical dosage form intended for oral or lentil"
`use is available for absorption is influenced by a variety of f opus!
`Among the inherent factors known to affect absorption aim“
`method of manufacture or method of compounding; the ac .lh“
`size and crystal form or polymorph of the drug Substangcllld”
`the diluents and excl 'ients used in formulating the dosage f lmd
`including fillers, bin ers, disintegrating agents, lubricants (-jm'
`ings, solvents, suspending agents, and dyes. Lubricants and 2371'
`ings are foremost among these. The maintenance of a dcmdl
`strably high degree of bioavailability requires particular attend)”-
`to all aspects of production and quality control that may m .u.”
`the nature of the finished dosage form.
`‘ m
`
`STABIHTY
`
`The term “stability," with respect to a drug dosage form. te