2000
`
`__ U_S_P_2_4 __ ....p.T_n_E_u_N_I_TE_n_s_T_A_T_E_s P_HA_RM:_A_c_o_P_EIA ___ I
`I
`NF 19
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeia/
`Convention, Inc., meeting at Washington, D. C.,
`March 9-12, 1995. Prepared by the Committee of
`Revision and published by the Board of Trustees
`
`Official from January 1, 2000
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twin brook Parkway, Rockville, MD 20852
`
`•
`
`1
`
`

`

`NOTICE AND WARNING
`
`Concerning U.S. Patent or Trademark Rights
`The inclusion in the Pharmacopeia or in the National Formulary of a monograph on any drug in
`respect to which patent or trademark rights may exist shall not be deemed, and is not intended
`as, a grant of, or authority to exercise, any right or privilege protected by such patent or
`trademark. All such rights and privileges are vested in the patent or trademark owner, and no
`other person may exercise the same without express permission, authority, or license secured
`from such patent or trademark owner.
`
`Concerning Use of USP or NF Text
`Attention is called to the fact that USP and NF text is fully copyrighted. Authors and others
`wishing to use portions of the text should request permission to do so from the Secretary of the
`USPC Board of Trustees.
`
`© 1999
`The United States Pharmacopeia! Convention, Inc.
`12601 Twinbrook Parkway, Rockville, MD 20852.
`All rights reserved
`ISSN 0195-7996
`ISBN 1-889788-03-1
`
`Printed by National Publishing, Philadelphia, PA
`
`-----······-· -------------··
`
`2
`
`

`

`8
`
`General Notices
`
`USP 24
`
`be taken, provided the measurement is made with at
`least equivalent accuracy and provided that any sub(cid:173)
`sequent steps, such as dilutions, are adjusted accord(cid:173)
`ingly to yield concentrations equivalent to those spec(cid:173)
`ified and are made in such manner as to provide at least
`equivalent accuracy. To minimize environmental im(cid:173)
`pact or contact with hazardous materials, apparatus and
`chemicals specified in Pharmacopeia! procedures also
`may be proportionally changed.
`Where it is directed in an assay or a test that a certain
`quantity of substance or a counted number of dosage
`units is to be examined, the specified quantity or num(cid:173)
`ber is a minimal figure (the singlet determination) cho(cid:173)
`sen only for convenience of analytical manipulation; it
`is P.ot intended to restrict the total quantity of substance
`or number of units that may be subjected to the assay
`or test or that should be tested in accordance with good
`manufacturing practices.
`Where it is directed in the assay of Tablets to
`"weigh and finely powder not less than" a given num(cid:173)
`ber, usually 20, of the Tablets, it is intended that a
`counted number of Tablets shall be weighed and re(cid:173)
`duced to a powder. The portion of the powdered tablets
`taken for assay is representative of the whole Tablets
`and is, in tum, weighed accurately. The result of the
`assay is then related to the amount of active ingredient
`per Tablet by multiplying this result by the average
`Tablet weight and dividing by the weight of the portion
`taken for the assay.
`Similarly, where it is directed in the assay of Cap(cid:173)
`sules to remove, as completely as possible, the contents
`of not less than a given number, usually 20, of the
`Capsules, it is intended that a counted number of Cap(cid:173)
`sules should be carefully opened and the contents quan(cid:173)
`titatively removed, combined, mixed, and weighed ac(cid:173)
`curately. The portion of mixed Capsules contents taken
`for the assay is representative of the contents of the
`Capsules and is, in tum, weighed accurately. The result
`of the assay is then related to the amount of active
`ingredient per Capsule by multiplying this result by the
`average weight of Capsule content and dividing by the
`weight of the portion taken for the assay.
`Where the definition in a monograph states the tol(cid:173)
`erances as being "calculated on the dried (or anhydrous
`or ignited) basis," the directions for drying or igniting
`the sample prior to assaying are generally omitted from
`the Assay procedure. Assay and test procedures may be
`performed on the undried or unignited substance and
`the results calculated on the dried, anhydrous, or ig(cid:173)
`nited basis, provided a test for Loss on drying, or
`Water, or Loss on ignition, respectively, is given in the
`monograph . Where the presence of mojsture or other
`volatile material may interfere with the procedure, pre(cid:173)
`vious drying of the substance is specified in the indi(cid:173)
`vidual monograph and is obligatory.
`Throughout a monograph that includes a test for Loss
`on drying or Water, the expression "previously dried"
`without qualification signifies that the substance is to
`be dried as directed under Loss on drying or Water
`(gravimetric determination).
`Unless otherwise directed in the test or assay in the
`individual monograph or in a general chapter, USP Ref(cid:173)
`erence Standards are to be dried before use, or used
`
`without prior drying, specifically in accordance with
`the instructions given in the chapter USP Reference
`Standards (11), and on the label of the Reference Stan(cid:173)
`dard. Where the label instructions differ in detail from
`those in the chapter, the label text is determinative.
`In stating the appropriate quantities to be taken for
`assays and tests, the use of the word ''about'' indicates
`a quantity within 10% of the specified weight or vol(cid:173)
`ume. However, the weight or volume taken is accu(cid:173)
`rately determined and the calculated result is based
`upon the exact amount taken. The same tolerance ap(cid:173)
`plies to specified dimensions.
`Where the use of a pipet is directed for measuring a
`specimen or an aliquot in conducting a test or an assay,
`the pipet conforms to the standards set forth under Vol(cid:173)
`umetric Apparatus (31), and is to be used in such man(cid:173)
`ner that the error does not exceed the limit stated for a
`pipet of its size. Where a pipet is specified, a suitable
`buret, conforming to the standards set forth under Vol(cid:173)
`umetric Apparatus (31), may be substituted. Where a
`"to contain" pipet is specified, a suitable volumetric
`flask may be substituted.
`Expressions such as "25.0 mL" and "25.0 mg,"
`used with respect to volumetric or gravimetric meas(cid:173)
`urements, indicate that the quantity is to be "accurately
`measured" or "accurately weighed" within the limits
`stated under Volumetric Apparatus (31) or under
`Weights and Balances (41).
`The term ''transfer'' is used generally to specify a
`quantitative manipulation.
`The term "concomitantly," used in such expressions
`as "concomitantly determine" or "concomitantly mea(cid:173)
`sured, ' ' in directions for assays and tests, is intended
`to denote that the determinations or measurements are
`to be performed in immediate succession. See also Use
`of Reference Standards under Spectrophotometry and
`Light-Scattering (851).
`Blank Determination-Where it is directed that "any
`necessary correction" be made by a blank determina(cid:173)
`tion, the determination is to be conducted using the
`same quantities of the same reagents treated in the same
`manner as the solution or mixture containing the por:
`tion of the substance under assay or test, but with the
`substance itself omitted.
`Desiccator-The expression "in a desiccator" spec(cid:173)
`ifies the use of a tightly closed container of suitable
`size and design that maintains an atmosphere of low
`moisture content by means of silica gel or other suitable
`desiccant.
`A ''vacuum desiccator'' is one that maintains the
`low-moisture atmosphere at a reduced pressure of not
`more than 20 mm of mercury or at the pressure des(cid:173)
`ignated in the individual monograph.
`Dilution-Where it is directed that a solution be di(cid:173)
`luted "quantitatively and stepwise," an accurately
`measured portion is to be diluted by adding water or
`other solvent, in the proportion indicated, in one or
`more steps. The choice of apparatus to be used should
`take into account the relatively larger errors generally
`associated with using small-volume volumetric appa(cid:173)
`ratus (see Volumetric Apparatus (31)).
`
`3
`
`

`

`USP 24
`
`Physical Tests I (711) Dissolution
`
`1941
`
`given in the manufacturer's operating instructions. If the sample
`must be degassed under vacuum, follow the recommendations in
`the individual monographs and the instructions in the operating
`manual for the pycnometer.
`The measurement sequence above describes the procedure for the
`gas pycnometer shown in Figure 1. If the pycnometer differs in
`operation or in construction from the one shown in Figure 1, follow
`the operating procedure given in the manual for the pycnometer.
`Repeat the measurement sequence for the same powder sample
`until consecutive measurements of the sample volume, V,, agree to
`within 0.2%. Unload the test cell and measure the final powder
`weight, w. Calculate the pycnometric density, p., of the sample ac(cid:173)
`cording to Equation 2.
`
`(701) DISINTEGRATION
`This test is provided to determine compliance with the limits on
`Disintegration stated in the individual monographs except where
`the label states that the tablets or capsules are intendea for use as
`troches, or are to be chewed, or are designed as modified-release
`dosage forms (see Drug Release (724) ). Determine the type of units
`under test from the labeling and from observation, and apply the
`appropriate procedure to 6 or more dosage units.
`For the purposes of this test, disintegration does not imply com(cid:173)
`plete solution of the unit or even of its active constituent. Complete
`disintegration is defined as that state in which any residue of the
`unit, except fragments of insoluble coating or capsule shell, re(cid:173)
`maining on the screen of the test apparatus is a soft mass having
`no palpably firm core.
`
`APPARATUS
`The apparatus9 consists of a basket-rack assembly, a 1000-mL,
`low-form beaker, 142 to 148 mm in height and having an outside
`diameter of 103 to 108 mm for the immersion fluid, a thermostatic
`arrangement for heating the fluid between 35° and 39°, and a device
`for raising and lowering the basket in the immersion fluid at a
`constant frequency rate between 29 and 32 cycles per minute
`through a distance of not less than 5.3 em and not more than 5.7
`em. The volume of the fluid in the vessel is such that at the highest
`point of the upward stroke the wire mesh remains at least 2.5 em
`below the surface of the fluid and descends to not less than 2.5 em
`from the bottom of the vessel on the downward stroke. The time
`required for the upward stroke is equal to the time required for the
`downward stroke, and the change in stroke direction is a smooth
`transition, rather than an abrupt reversal of motion. The basket-rack
`assembly moves vertically along its axis. There is no appreciable
`horizontal motion or movement of the axis from the vertical.
`Basket-rack Assembly-The basket-rack assembly consists of
`six open-ended transparent tubes, each 7.75 ± 0.25 em long and
`having an inside diameter of 20.7 to 23 mm and a wall 1.0 to 2.8
`mm thick; the tubes are held in a vertical position by two plastic
`plates, each 8.8 to 9.2 em in diameter and 5 to 7 mm in thickness,
`with six holes, each 22 to 26 mm in diameter, equidistant from the
`center of the plate and equally spaced from one another. Attached
`to the under surface of the lower plate is a woven stainless steel
`wire cloth, which has a plain square weave with 1.8- to 2.2-mm
`mesh apertures and with a wire diameter of 0.60 to 0.655 mm. Th.e
`parts of the apparatus are assembled and rigidly held by means of
`three bolts passing through the two plastic plates. A suitable means
`is provided to suspend the basket-rack assembly from the raising
`and lowering device using a point on its axis.
`The design of the basket-rack assembly may be varied somewhat
`provided the specifications for the glass tubes and the screen mesh
`size are maintained.
`Disks-The use of disks is permitted only where specified in
`the monograph. If specified in the individual monograph, each tube
`is provided with a cylindrical disk 9.5 ± 0.15 mm thick and 20.7
`± 0.15 mm in diameter. The disk is made of a suitable, transparent
`plastic material having a specific gravity of between 1.18 and 1.20.
`Five parallel 2-mm holes extend between the ends of the cylinder.
`One of the holes is centered on the cylindrical axis. The other holes
`
`are centered 6 mm from the axis on imaginary lines perpendicular
`to the axis and parallel to each other. Four identical trapezoidal(cid:173)
`shaped planes are cut into the wall of the cylinder, nearly perpen(cid:173)
`dicular to the ends of the cylinder. The trapezoidal shape is sym(cid:173)
`metrical; its parallel sides coincide with the ends of the cylinder
`and are parallel to an imaginary line connecting the centers of two
`adjacent holes 6 mm from the cylindrical axis. The parallel side of
`the trapezoid on the bottom of the cylinder has a length of 1.6 mm,
`and its center lies at a depth of 1.8 mm from the cylinder's circum(cid:173)
`ference. The parallel side of the trapezoid on the top of the cylinder
`has a length of 9.2 mm, and its center lies at a depth of 2.6 mm
`from the cylinder's circumference. All surfaces of the disk are
`smooth. If the use of disks is specified in the individual monograph,
`add a disk to each tube, and operate the apparatus as directed under
`Procedure.
`
`PROCEDURE
`Uncoated Tablets-Place 1 tablet in each of the six tubes of the
`basket and operate the apparatus, using water maintained at 37 ±
`2° as the immersion fluid unless otherwise specified in the individ(cid:173)
`ual monograph. At the end of the time limit specified in the mono(cid:173)
`graph, lift the basket from the fluid, and observe the tablets: all of
`the tablets have disintegrated completely. If" 1 or 2 tablets fail to
`disintegrate completely, repeat the test on 12 additional tablets: not
`less than 16 of the total of 18 tablets tested disintegrate completely.
`Plain Coated Tablets-Apply the test for Uncoated Tablets, op(cid:173)
`erating the apparatus for the time specified in the individual
`monograph.
`Delayed-release (enteric coated) Tablets-Place 1 tablet in each
`of the six tubes of the basket and, if the tablet has a soluble external
`coating, immerse the basket in water at room temperature for 5
`minutes. Then operate the apparatus using simulated gastric fluid
`TS maintained at 37 ± 2° as the immersion fluid. After 1 hour of
`operation in simulated gastric fluid TS, lift the basket from the fluid,
`and observe the tablets: the tablets show no evidence of disintegra(cid:173)
`tion, cracking, or softening. Operate the apparatus, using simulated
`intestinal fluid TS maintained at 37 ± 2° as the immersion fluid,
`for the time specified in the monograph. Lift the basket from the
`fluid, and observe the tablets: all of the tablets disintegrate com(cid:173)
`pletely. If 1 or 2 tablets fail to disintegrate completely, repeat the
`test on 12 additional tablets·: not less than 16 of the total of 18
`tablets tested disintegrate completely.
`Buccal Tablets-Apply the test for Uncoated Tablets. After 4
`hours, lift the basket from the fluid, and observe the tablets: all of
`the tablets have disintegrated. I( 1 or 2 tablets fail to disintegrate
`completely, repeat the test on 12 additional tablets: not less than 16
`of the total of 18 tablets tested disintegrate completely.
`Sublingual Tablets-Apply the test for Uncoated Tablets. Ob(cid:173)
`serve the tablets within the time limit specified in the individual
`monograph: all of the tablets have disintegrated. If 1 or 2 tablets
`fail to disintegrate completely, repeat the test on 12 additional tab(cid:173)
`lets: not less than 16 of the total of 18 tablets tested disintegrate
`completely.
`Hard Gelatin Capsules--Apply the test for Uncoated Tablets.
`Attach a removable wire cloth, which has a plain square weave with
`1.8- to 2.2-mm mesh apertures and with a wire diameter of 0.60 to
`0.655 mm, as described under Basket-rack Assembly, to the surface
`of the upper plate of the basket-rack assembly. Observe the capsules
`within the time limit specified in the individual monograph: all of
`the capsules have disintegrated except for fragments from the cap(cid:173)
`sule shell. If 1 or 2 capsules fail to disintegrate completely, repeat
`the test on 12 additional capsules: not less than 16 of the total of
`18 capsules tested disintegrate completely.
`Soft Gelatin Capsules-Proceed as directed under Hard Gelatin
`Capsules.
`
`(711) DISSOLUTION
`This test is provided to determine compliance with the dissolu(cid:173)
`tion requirements where stated in the individual monograph for a
`tablet or capsule dosage form. Of the types of apparatus described
`herein, use the one specified in the individual monograph. ~here
`the label states that an article is enteric-coated, and a dissolutiOn or
`
`4
`
`

`

`1942
`
`(711) Dissolution I Physical Tests
`
`USP 24
`
`6.3 to 6.5 or
`9.4 to 10.1 mm
`
`Vent hole
`2.0 ± 0.5 mm diameter
`
`disintegration test that does not specifically state that if is to be
`applied to enteric-coated articles is included in the individual mono(cid:173)
`graph, the test for Delayed-release Articles under Drug Release
`(724) is applied unless otherwise specified in the individual mono(cid:173)
`graph. For hard gelatin capsules that do I)Ot conform to the Dis(cid:173)
`solution specification, repeat the test as follows. Where water is not
`specified as the Medium in the individual monograph, the same
`Medium specified in the monograph may be used with the addition
`of not more than 3.2 g of purified pepsin having an activity of 800
`to 2500 units per mg of protein, or not more than 5 g of pancreatin,
`per 1000 mL of Medium, as appropriate. Pepsin is added to acidic
`media, while pancreatin is appropriate for media at or above a pH
`of 6.8. Where the monograph specifies water as the Medium , a
`second medium of either 0.1 N hydrochloric acid with pepsin or
`pH 6.8 phosphate buffer with pancreatin, depending on the drug
`solubility, may be used with the concentration of pepsin or pancre(cid:173)
`atin being the same as above.
`USP Reference Standards (11)-USP Prednisone Tablets RS
`(Dissolution Calibrator, Disintegrating). USP Salicylic Acid Tab(cid:173)
`lets RS (Dissolution Calibrator, Nondisintegrating) .
`Apparatus 1-The assembly consists of the following: a covered
`vessel made of glass or other inert, transparent material'; a motor;
`a metallic drive shaft; and a cylindrical basket. The vessel is par(cid:173)
`tially immersed in a suitable water bath of any convenient size or
`placed in a heating jacket. The water bath or heating jacket permits
`holding the temperature inside the vessel at 37 ± OS 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 be(cid:173)
`yond that due to the smoothly rotating stirring element. 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 liter, the height is 160 mm to 210 mm
`and its inside diameter is 98 mm to 106 mm; for a nominal capacity
`of 2 liters, the height is 280 mm to 300 mm and its inside diameter
`is 98 mm to 106 mm; and for a nominal capacity of 4 liters, the
`height is 280 mm to 300 mm and its inside diameter is 145 mm to
`155 mm. Its sides are flanged at the top. A fitted cover may be used
`to retard evaporation. 2 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. A speed-reg(cid:173)
`ulating device is used that allows the shaft rotation speed to be
`selected and maintained at the rate specified in the individual mono(cid:173)
`graph, within ±4%.
`Shaft and basket components of the stirring element are fabri(cid:173)
`cated of stainless steel, type 316 or equivalent, to the specifications
`shown in Figure I. Unless otherwise specified in the individual
`monograph, use 40-mesh cloth. A basket having a gold coating
`0.0001 inch (2.5 J.Lm) thick may be used. The 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 basket is maintained at 25
`± 2 mm during the test.
`Apparatus 2-Use the assembly from 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 at any point from the vertical axis of the vessel and rotates
`smoothly without significant wobble. 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 ± 2 mm
`between 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 that may be coated with a suitable inert
`coating. The dosage unit is allowed to sink to the bottom of the
`vessel before rotation of the blade is started. A small, loose piece
`of nonreactive material such as not more than a few turns of wire
`helix may be attached to dosage units that would otherwise float.
`Other validated sinker devices may be used.
`
`1 The materials should not sorb, react. or interfere with the spec(cid:173)
`imen being tested.
`2 If a cover is used. it provides sufficient openings to allow ready
`insertion of the thermometer and withdrawal of specimens.
`
`Retention spring w1th ~~
`
`3 tangs on 120° centers
`"'-.,
`
`1
`1
`
`5.1 ± 0.5 mm
`
`:H .
`
`- ---.-
`
`±0.02 mm
`
`Fig. I. Basket Stirring Element.
`
`9.4 to 10.1 mm diameter
`before coating
`
`NOTES-
`(1) Shaft and blade material'
`303 (or equivalent)
`stainless steel.
`(2) A and 8 dimensions are
`not to vary more than
`0.5 mm when part is
`rotated on 'i. axis.
`(3) Tolerances are fT.Omm,
`unless otherwise stated.
`
`--------21~:1-';'m::r:.
`
`~--~~--~
`
`f0.5mm
`j_
`
`4 Of1.0mm
`
`'I ---.----~.~~--~r---~1__1_
`r-1•1----- 74.0 mm to 75,0 mm - - - - ; .. ~1 ~
`
`Fig. 2. Paddle Stirring Element.
`
`·.
`
`5
`
`

`

`USP 24
`
`Physical Tests I (721) Distilling Range
`
`1943
`
`Apparatus Suitability Test-Individually 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 certif(cid:173)
`icate for that calibrator in the apparatus tested.
`Dissolution Medium-Use the. solvent specified in the individ(cid:173)
`ual monograph. If the Dissolution Medium is a buffered solution,
`adjust the solution so that its pH is within 0.05 unit of the pH
`specified in the individual monograph. [NOTE-Dissolved gases can
`cause bubbles to form, which may change the results of the test. In
`such cases, dissolved gases should be removed prior to testing. 3)
`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. If two or more times are specified, spec(cid:173)
`imens are to be withdrawn only at the stated times, within a tol(cid:173)
`erance of ± 2%.
`Procedure for Capsules, Uncoated Tablets, and Plain Coated
`Tablets-Place the stated volume of the Dissolution Medium
`( ± I%) in the vessel of the apparatus specified in the individual
`monograph, assemble the apparatus, equilibrate the Dissolution Me(cid:173)
`dium to 37 ± 0.5°, and remove the thermometer. Place 1 tablet or
`1 capsule in the apparatus, taking care to exclude air bubbles from
`the surface of the dosage-form unit, and immediately operate the
`apparatus at the rate specified 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 Dis(cid:173)
`solution Medium and the top of the rotating basket or blade, not
`less than I em from the vessel wall. [NOTE-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 cal(cid:173)
`culation. Keep the vessel covered for the duration of the test, and
`verify the temperature of the mixture under test at suitable times.]
`Perform the analysis as directed in the individual monograph.• Re(cid:173)
`peat the test with additional dosage form units.
`If automated equipment is used for sampling and the apparatus
`is modified, validation of the modified apparatus is needed to show
`that there is no change in the agitation characteristics of the test.
`Where capsule shells interfere with the analysis, remove the con(cid:173)
`tents of not less than 6 capsules as completely as possible, and
`dissolve the empty capsule shells in the specified volume of Dis(cid:173)
`solution Medium . Perform the analysis as directed in the individual
`monograph . Make any necessary correction. Correction factors
`greater than 25% of the labeled content are unacceptable.
`Procedure for a Pooled Sample for Capsules, Uncoated Tab(cid:173)
`lets, and Plain Coated Tablets-Use this procedure where Pro(cid:173)
`cedure for a Pooled Sample is specified in the individual mono(cid:173)
`graph. Proceed as directed under Procedure for Capsules, Uncoated
`Tablets, and Plain Coated Tablets. Combine equal volumes of the
`filtered solutions of the six or twelve individual specimens with(cid:173)
`drawn, and use the pooled sample as the test solution. Determine
`the average amount of the active ingredient dissolved in the pooled
`sample.
`Interpretation-
`Unit Sample-Unless otherwise specified in the individual mono(cid:173)
`graph, the requirements are met if the quantities of active ingredient
`dissolved from the units tested conform to the accompanying Ac(cid:173)
`ceptance Table. Continue testing through the three stages unless the
`results conform at either S 1 or S2 • The quantity, Q, is the amount
`of dissolved active ingredient specified in the individual mono(cid:173)
`graph , expressed as a percentage of the labeled content; the 5%,
`
`3 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 1-lm or less, with vigorous stirring,
`and continue stirring under vacuum for about 5 minutes. Other val(cid:173)
`idated deaeration techniques for removal of dissolved gases may be
`used.
`4 If test specimens are filtered, use an inert filter that does not
`cause adsorption of the active ingredient or contain extractable sub(cid:173)
`stances that would interfere with the analysis.
`
`15%, and 25% values in the Acceptance Table are percentages of
`the labeled content so that these values and Q are in the same terms.
`
`Stage
`
`Number
`Tested
`6
`6
`
`12
`
`Acceptance Table
`
`Acceptance Criteria
`Each unit is not less than Q + 5%.
`Average of 12 units (S 1 + S2) is equal to
`or greater than Q, and no unit is less
`than Q- 15%.
`Average of 24 units (SI + s2 + SJ) 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%.
`
`Pooled Sample-Unless otherwise specified in the individual .
`monograph , the requirements are met if the quantities of active in(cid:173)
`gredient dissolved from the pooled sample conform to the accom(cid:173)
`panying Acceptance Table for a Pooled Sample. Continue testing
`through the three stages unless the results conform at either S1 or
`S2• The quantity, Q, is the amount of disso1ved active ingredient
`specified in the individual monograph, expressed as a percentage of
`the labeled content.
`
`Acceptance Table for a Pooled Sample.
`Number
`Tested
`
`Acceptance Criteria
`
`Stage
`
`S1
`
`S2
`
`S3
`
`6
`
`6
`
`12
`
`Average amount dissolved is not less than
`Q + 10%.
`Average amount dissolved (S 1 + S2)
`equal to or greater than Q + 5%.
`Average amount dissolved (S 1 + S2 + S3)
`is equal to or greater than Q.
`
`is
`
`(721) DISTILLING RANGE
`To determine the range of temperatures within which an official
`liquid distils, or the percentage of the material that distils between
`two specified temperatures, use Method I or Method II as directed
`in the individual monograph. The lower limit of the range is the
`temperature indicated by the thermometer when the first drop of
`condensate leaves the tip of the condenser, and the upper limit is
`the Dry Point, i.e., the temperature at which the last drop of liquid
`evaporates from the lowest point in the distillation flask, without
`regard to any liquid remaining on the side of the flask, or the tem(cid:173)
`perature observed when the proportion specified in the individual
`monograph has been collected.
`[NOTE-Cool all liquids that distil below 80° to between 1 oo and
`15° before measuring the sample to be distilled.]
`
`Method I
`Apparatus-Use apparatus similar to that specified for Method
`II, except that the distilling flask is of 50- to 60-mL capacity, and
`the neck of the flask is 10 to 12 em long and 14 to 16 mm in
`internal diameter. The perforation in the upper insulating board, if
`one is ·used, should be such that when the flask is set into it, the
`portion of the. flask below the upper surface of the insulating ma(cid:173)
`terial has a capacity of 3 to 4 mL.
`Procedure-Proceed as directed for Method II, but place in the
`flask only 25 mL of the liquid to be tested.
`
`6
`
`

`

`Continuous Revision of the USP and the NF
`
`The need for continuously refining specifications
`and updating standards is a natural consequence of
`the introduction of new drugs and the accelerated
`growth of knowledge in the pharmaceutical sci(cid:173)
`ences.
`In order to keep the United States Pharmacopeia
`and the National Formulary abreast of these de(cid:173)
`velopments and to maintain the official standards
`accordingly, the main volume is revised regularly
`by Supplements. Interim Revision Announcements
`are issued between Supplements as necessary.
`
`Interim Revision Announcements pertaining to this
`volume of USP and NF are published in the journal,
`Pharmacopeia/ Forum. Reprints of Interim Re(cid:173)
`vision Announcements are available on order. A
`single copy of each Interim Revision Announcement
`is available without charge for each subscription to
`USP-NF. Each request should be sent to USPC at
`the address shown below. Corrections and revisions
`included in Interim Revision Announcements are
`incorporated in the next regular Supplement.
`
`Supplements to USP 23-NF 18 are issued seri(cid:173)
`ally as ntlcessary, with the Index in the latest Sup(cid:173)
`plement being fully cumulative with respect to all
`Supp/~fnents issued previously. Thus, in order to
`keep tKe compendia up to date, the user needs to
`keep all of the Supplements. Cumulation of the
`Supplements into a new main volume will occur
`whenever the amount of text in the Supplements
`becomes unwieldy for the user, or the logistics of
`publication so dictate. The publication cycle of main
`volumes may therefore vary from the five-year in(cid:173)
`terval characteristic of new main volumes published
`since 1950.
`
`Electronic publication of the USP-NF first oc(cid:173)
`curred in November 1992. The complete text of
`USP is available in a fully searchable electronic
`format for ease of use. It allows the user to conduct
`searches that would not have been cost effective or
`possible with the printed format, and provides fully
`integrated up-to-date text as it is updated with each
`Supplement.
`
`Inquiries, Comments, and Suggestions
`for revisions in the USP or NF text should be addressed to the Drug Standards Division:
`
`USPC, Inc.
`12601 Twinbrook Parkway
`Rockville, MD 20852 USA
`
`Telephone: 1-301-881-0666
`FAX: 1-301-816-8373
`Telex: 710828-9787
`Ordering Dept.: 1-800-227-8772
`
`Requests/ comments submitted
`
`DSD Subcommittee reviews requests/comments
`
`Publish in Pharmacopeia/ Forum for public review
`(In-process Revision or Pharmacopeia/ Previews)
`
`USP-NF Continuous Revision Process
`...
`...
`...
`...
`...
`...
`
`Subcommittee approves
`
`DSD Executive Committee approves
`
`Executive Committee of Revision approves
`
`Board of Trustees approves publication in USP-NF
`
`I I
`
`(
`
`7