2002
`
`THE UNITED STATES PHARMACOPEIA
`_ USP 25
`
`
`NF 20
`
`THE NATIONAL FORMULARY
`
`By authority of the United States Pharmacopeial
`Convention, Ina, meeting at Washington. D. G,
`April 12—16, 2000. Prepared by the Councilr of Experts
`and published by the Board of Trustees
`
`Oflieiol from January 1, 2002
`
`The designation on the cover of this publication, “USP NF
`2002," is for ease of identification only. The publication
`contains two separate compendia: The Pharmacopeia of the
`United States Twenty-fifih Revision, and the National
`Formulary, Twentieth Edition.
`
`UNITED STATES PHARMACOPEIAL CONVENTION, INC.
`12601 Twinbrook Parkway, Rockville, MD 20852
`
`Mylan v. MonoSol
`Mylan V. MonoSol
`IPR2017-00200
`IPR2017-00200
`MonoSol Ex. 2028
`MOHOSOIEX. 2028
`
`Page 1
`Page 1
`
`

`

`2082
`
`(905) Uniformity of Dosage Units / Physich Tests
`
`I
`0
`T _ T _ R exit] in
`AH!
`
`‘
`
`.
`
`(3)
`
`f
`I
`
`Primary standard {NBS}
`
`Benzor‘c A and
`
`
`
`Temperature —-
`
`Superimposed Thermograms Illustrating the Effect of Impurities on
`DSC Melting Peak Shape
`
`The parameters of melting (melting range, AH}, and calculated eu-
`tectic purity) are readily obtained from the thermogram of a single
`melting event using a small test specimen, and the method does not
`require multiple, precise actual temperature measurements. Thermo-
`grarn Itltnits are directly convertible to heat transfer, millicalories per
`SBCOII
`.
`.
`The lowering of the freezing point in dilute solutions by molecules
`of nearly equal size is expressed by a modified van't Hoff equation:
`
`0'?” _ an
`m— M} -(K 1).
`
`(1)
`
`in which T= absolute temperature in degrees Kelvin (°K), X2 = mole
`fraction of minor component (solute; impurity), AH = molar heat of
`fusion of the major component, R = gas constant, a‘ndK = distribution
`ratio of solute between the solid and liquid phases.
`Assuming that the temperature range is small and that no solid so-
`lutions are formed (K = 0), integration of the van't Hoff equation
`yields the following relationship between mple fraction of impurity
`and the melting-point depression:
`
`= (To _ Tm)“:
`RT“:
`
`I
`
`X2
`
`in which 72, = melting point of the pure compound, in cK, and Tm =
`melting point of the test specimen, in “K.
`With no solid solution formation, the concentration of impurity in
`the liquid phase at any temperature during the melting is inversely
`proportional to the fraction melted at that temperature, and the melt-
`ing-point depression is directly proportional to the mole fraction of
`impurity. A plot of the observed test specimen temperature, 1}, versus
`the reciprocal of the fraction melted, II F, at temperature I}, should
`yield a straight line with the slope equal to the melting-point depres-
`sion (12, - T,,). The theoretical melting point of the pure compound is
`obtained by extrapolation to 1." F = D:
`
`'
`
`(2)
`(3)
`(4)
`
`
`
`L
`I
`i,
`c
`c
`5
`
`[5)
`
`r
`
`r
`i
`
`r
`
`(2)
`
`(3}
`
`(4)
`
`(5)
`
`
`
`
`
`.
`:
`
`_
`
`
`
`{6)th
`Substituting the experimentally obtained values for I, - T... AH}, and
`
`T, in Equation 2 yields the mole fraction of the total eutectic impnmy Wgh
`which, when multiplied by 100, gives the mole percentage of total
`(1}
`r
`
`eutectic impurities.
`,
`'
`a
`;
`Deviations from the theoretical linear plot also may be due to solid
`r:
`
`solution formation (K at: 0), so that care must be taken in interpreting
`(
`the data.
`,
`,
`5
`To observe the linear effect of the impurity concentration on the
`
`melting-point depression, the impurity must be soluble in the liqurd
`
`phase or melt of the compound, but insoluble in the solid phase, Le,
`
`no solid solutions are formed. Some chemical similarities are nee:
`essary for solubility in the melt. For example, the presence of ionic
`
`compounds in neutral organic compounds and the occurrence of mu.
`
`mal decomposition may not be reflected in purity estimates. The ex.
`
`tent of these theoretical limitations has been only partially explorm'
`
`Impurities present from the synthetic route often are similar to thé
`end product, hence there usually is no problem of solubility in the
`
`melt. Impurities consisting of molecules of the same shape, sizé,‘
`
`and character as those of the major component can fit into the matrix'
`
`of the major component without disruption of the lattice, forming
`
`lid solutions or inclusions; such impurities are not detectable by DSC,
`
`Purity estimates are too high in such cases. This is more common with
`
`
`less-ordered crystals as indicated by low heats of fusion.
`3
`Fc
`Impurity levels calculated from thermograms are reproducible an .
`
`fiun,
`probably reliable within 0.1% for ideal compounds. Melting-paint
`dose
`determinations by scanning calorimetry have a reproducibility with
`[tx'
`a standard deviation of about 0.2”. Calibration against standardlf';
`the 5
`rnziy'ailow about 1" accuracy for the melting point, so that this tech».
`
`U;
`nique is comparable to other procedures.
`Compounds that exist in polymorphic form cannot be used in put-‘. Mm
`ity determination unless the compound is completely convened to-
`in {b
`
`one form. 0n the other hand, DSC and DTA are inherently usefillbr
`em
`,3:
`for detecting, and therefore monitoring, polymorphism.
`the,
`
`ProcedurFThe actual procedure and the calculations to be cm“;
`H
`
`ployed are dependent on the particular instrument used. Consult tilt-j; mg,
`manufacturer's literature and/or the thermal analysis literature forth}; 5
`of a,
`
`most appropriate technique for a given instrument. In any event. til-l;
`shel
`imperative to keep in mind the limitations of solid solution fonnattotl. 1“»
`'jts c
`
`insolubility in the melt, polymorphism, and decomposition duringilli;
`gm
`
`analysis.
`-
`indi-
`cacl
`liVe
`. “S
`Vldt
`.
`" indi
`(905) UNIFORMITY OF DOSAGE ‘
`the
`UNITS
`.-
`are
`v.3“
`
`lent
`
`'flVo
`
`[NOTE—In this chapter, unit and dosage unit are synonym if
`"‘
`:31"
`The uniformity of dosage units can be demonstrated by erth ,
`him
`
`two methods, weight variation or content uniformity. The 1'5qu.
`flog
`
`merits of this chapter apply both to dosage units containing a 51115
`I
`
`active ingredient and to dosage units containing two or more will
`-
`5
`
`ingredients; unless otherwise specified in the individual mono
`5E1“!
`they apply individually to each active ingredient in the produci
`. a
`
`Content Uniformity requirements may be applied in all cases. .
`‘7
`I
`for Content Uniformity is required for:
`. Prt
`_.
`(1)
`coated tablets, other than film-coated tablets containing 503-
`the
`'
`,
`‘.
`
`or more of an active ingredient that comprises 50% or mDYEI,
`I
`
`'
`weight) of one tablet;
`‘
`a
`. it:
`, I
`-‘
`transdermal systems;
`lbs
`
`'3
`-
`suspensions in single-unit containers or in and capsules;
`991
`inhalations (powders or solutions) packaged in premeterellp '
`3
`in;
`
`sage units (capsules and blister packages). Metered-dose “liar .
`'.
`tlu
`lers and dry powder inhalers containing drug inhfllW-
`'t
`llq
`powders in reservoirs conform to the requirements under
`r
`.41
`Page 2
`Page 2
`
`

`

`Physical Tests / (905) Uniformity of Dosage Units
`
`2083
`
`CONTENT UNIFORMITY
`
`For the determination of dosage-unit uniformity by assay of indi-
`vidual units, select not fewer than 30 units, and proceed as follows for
`the dosage form designated.
`[NOTE—In the case of metered-dose inhalers and dry powder in-
`halers containing drug inhalation powders in reservoirs, proceed as
`directed for Dose Uniformity over the Entire Contents under Aero-
`sols, Metered-Dose Inhalers, and Dry Powder Inhalers (601).
`UNCOATED AND COATED TABLETS, HARD AND SOFT CAPSULES,
`SUPPOSITORIES, TRANSDERMAL SYSTEMS, ORAL SOLUTIONS IN SIN-
`GLE-UNIT CONTAINERS, SUSPENSIONS IN SINGLE-UNIT CONTAINERS,
`SYRUPS IN SINGLE-UNIT CONTAINERS, METERED-DOSE INHALERS,
`DRY POWDER INHALERS, INHALATIONS (POWDERS 0R SOLUTIONS)
`PACKAGED IN PREMETERED DOSAGE UNITS (CAPSULES AND BLISTER
`PACKAGES), INHALATIONS IN SINGLE-UNIT CONTAINERS, AND SO-
`LIDS (INCLUDING STERILE SOLIDS) IN SINGLE-UNIT —Assay 10 units
`individually as directed in the Assay in the individual monograph, un-
`less otherwise specified in the Procedurefor content uniformity. For
`oral solutions, suspensions, and syrups in single-unit containers, con-
`duct the Assay on the amount of Well-mixed material that drains from
`an individual container in not more than 5 seconds, and express the
`results as delivered dose. Where the amount of active ingredient in a
`single dosage unit differs from that required in the Assay, adjust the
`degree of dilution of the solutions andfor the volume of aliquots so
`that the concentration of the active ingredients in the final solution is
`of the same order as that obtained in the Assay procedure; or, in the
`case of a titrimetric assay, use a titrant of a different concentration, if
`necessary, so that an adequate volume of titrant is required (see Titri—
`nretty (541)); See also Procedures under Tests and Assays in the Gen-
`eral Notices and Requirements. If any such modifications are made in
`the Assay procedure set forth in the individual monograph, make the
`appropriate corresponding changes in the calculation formula and ti-
`tration factor.
`
`Where a special Procédnrejbr content uniformity is specified in
`the test for Lnrrjbrmitv ofdosage units in the individual monograph,
`make any necessary correction of the results obtained as follows.
`(1) Prepare a composite specimen ofa sufficient number of do-
`sage units to provide the amount of specimen called for in the Assay
`in the individual monograph plus the amount required for the special
`Procedurefin" content nmfiirmity in the monograph by finely powder-
`ing tablets or mixing the contents of capsules or oral solutions, syr-
`ups, suspensions, or solids in single-unit containers to obtain a
`homogeneous mixture. If a homogeneous mixture cannot be obtained
`in this manner, use suitable solvents or other procedures to prepare a
`solution containing all of the active ingredient, and use appropriate
`aliquot portions of this solution for the specified procedures.
`(2) Assay separate, accurately measured portions of the compo-
`site specimen of capsules or tablets or suspensions or inhalations or
`solids in single-unit containers, both (a) as directed in the Assay, and
`(b) using the special Procedure for content nmforntttyhin the mono-
`graph.
`(3) Calculate the weight of active ingredient equivalent to 1
`average dosage unit, by (a) using the results obtained by the Assay
`procedure, and by (b) using the results obtained by the special proce-
`dure.‘
`
`(4) Calculate the correction factor, F, by the formula:
`F=A/P,
`
`in which A is the weight of active ingredient equivalent to 1 average
`dosage unit obtained by the Assay procedure, and P is the Weight of
`active ingredient equivalent to 1 average dosage unit obtained by the
`special procedure. If
`
`A
`
`iOOIA -Pl
`
`is greater than 10, the use of a correction factor is not valid.
`(5) A valid correction may be applied only ifF is not less than
`1.030 nor greater than [.100, or, not less than 0.900 not greater than
`0.970. and if F is betWeen 0.970 and 1.030 no correction is required.
`
`Page 3
`Page 3
`
`
`l _ Uniformity over the Entire Contents (see Aerosols, Metered—
`Dose Inhalers. and Dry Powder Inhalers (601));
`" solids (including sterile solids) that are packaged in unit-dose
`
`i containers and that contain active or inactive added substances,
`. eXcept that the test for Weight Variation may be applied in the
`
`special situations stated below; and
`
`supposnones.
`
`1 When the test for Content Ifiriflormity is not required, the test for
`H E2s:I:Qa 8I;"< cr0 c:"U'0LT“(Da. 5 ‘-< O H: .—.5"(a '6‘:20§5IN EEmE.’O5on
`fig products containing 50 mg.or more ofan active ingredient corn'
`
`'3, hprising 50% or more, by weight, of the dosage unit or, m the case
`
`of hard capsules, the capsule contents, except that uniformity of
`
`other active ingredients present in lesser proportions is demon-
`
`strated by meeting Content [niij'orrnity requirements;
`‘
`liquid-tilled soft capsules other than sofi capsules containing
`suspenstons;
`
`‘ solids (including sterile solids) that are packaged in single-unit
`
`containers and contain no added substances, whether active or
`‘ inactive;
`
`solids (including sterile solids) that are packaged in single—unit
`
`containers, with or without added substances, whether active or
`
`,inactive, that have been prepared from true solutions and freeze-
`
`'dried in the final containers and are labeled to indicate this meth-
`
`od of preparation; and
`‘
`
`solutions for inhalation. oral solutions, and syrups when these
`
`' articles are packaged in single-unit containers.
`
`
`mam
`has?
`VDS'
`
`WEIGHT VARIATION
`
`
`For the determination of dosage-unit uniformity by weight varia-
`
`pn, select not fewer than 30 units, and proceed as follows for the
`
`1; sage form designated.
`.
`[NOTE—Specimens other than these test units may be drawn from
`
`e same batch for Assay determinations]
`:Uncoated and Film-Cbated Tablets—Weigh accurately 10 ta-
`
`lets individually. From the result of the Assay, obtained as directed
`
`the individual monograph, calculate the content of active ingredi-
`tin each of the 10-.tablets, assuming homogeneous distribution of
`in active ingredient.
`
`l; Hard Capsules—Weigh accurately 10 capsules individually, tak-
`lvg care to preserve the identity of each capsule. Remove the contents
`
`leach capsule by a suitable means. Weigh accurately the emptied
`
`1 ells individually, and calculate for each capsule the net weight of
`
`is contents by subtracting the Weight of the shell from the respective
`_ss weight. From the results ofthe Assay, obtained as directed in the
`
`ndividual monograph, calculate the content of active ingredient in
`
`ch of the capsules, assuming homogeneous distribution of the ac—
`
`‘
`e ingredient.
`
`Soft Capsules—Determine the net weight of the contents of indi-
`
`ll'l
`. ,dual capsules as followa. Weigh accurately the 10 intact capsules
`iyidually to obtain their ngs weights, taking care to preserve
`
`Elm Identity of each capsule. Then cut open the capsules by means
`‘
`ffii suitable clean, dry cutting instrument such as scissors or a sharp
`
`“Pen'blade, and remove the contents by washing with a suitable sol-
`
`‘(Eftl- Allow the occluded solvent to evaporate from the shells at room
`ed
`erature over a period of about 30 minutes, taking precautions to
`
`§V01d uptake or loss ofmoisture. Weigh the individual shells, and cal-
`clllale the net contents. From the results of the Assay, obtained as di—
`
`retied in the individual monograph, calculate the content of active
`
`l"gradient in each of the capsules, assuming homogeneous distribu—
`I 011 of the active ingredient.
`Solids (Including Sterile Solids) in Single-Unit Containers—
`‘ Doceed as directed for Hard Capsules, treating each unit as described
`
`therein.
`. H P Sfllutions for Inhalation Packaged in Single-Unit Containers—
`g trUcCed as directed for Hard Capsules, treating each unit as described
`,1. herein.
`"-e Oral Solutions and Syrups Packaged in Single-Unit Contain-
`_ fithrsr-Weigh accurately the amount of liquid that drains in not more
`._
`c an 5 seconds from each of 10 individual containers. If necessary,
`.ipmpute the equivalent volume after determining the apparent den-
`‘
`:cny- From the result of the Assay, obtained as directed in the indivi—
`.13“! monograph, calculate the content of active ingredient in the
`‘
`3 :-"l13!d drained from each of the [0 units.
`
`Whit.-
`er. °j_
`PETE:
`Eig‘fé:
`mph",
`'3 my
`-
`) ms
`tor:
`
`, dw
`‘ ha;
`",
`fl
`“0e
`705
`
`_
`
`
`
`

`

`5'
`[NOTE—A dosage unit is defined as the discharged spray ab
`by actuation of the valve that number of times defined in the Inletan
`J;
`as lhc minimum recommended dose. Follow the labeled ins
`b
`‘
`for shaking and firing. For collection of the dosage unit,
`cumin '
`directed in the test for Uniformith ol'Dosnge Units under
`Bed 35“
`Metered-Dose Inflation, and Dry Powder Inhoienr (Gel) E:09501.11 "
`modify the dosage-unit sampling apparatus so that it is Ea “Bat
`.-
`quantitatively capturing the delivered dose li'orn the prepami
`lested.] Unless otherwise specified in the individual monogm H‘
`‘l
`.
`requirements for dosage unil'omiity are met iftlie amount oftfiéla o
`ingredient discharged in not more than 1 of the 10 dosage “minds.
`determined from the Content Uniformity method lies outgi'dts
`.
`
`range of 75.0% to 125.0% ofthe label claim and no unit is Gunilla
`the range of65.0% to 135.0% ofthe label claim. lf2 or 3 dDSage'u Ids? .'
`are outside the range of 75.0% to 125.0% oflabel claim, but not n
`“7:
`side the range of 65.0% to 135.0% of label claim, test 20 addifig -"_."
`
`units. The requirements are met if not more than 3 units ofthe 3011111
`outside the range of75.0% to 125.0% of label claim and mum?!“ .
`I
`‘
`outside the range of 65.0% to 135.0% of label claim.
`15 ,1
`]"-
`Dry Powder Inhalers
`
`[NOTE—Powders for inhalation packaged in single-unit containm-a 1'
`
`are subject to content uniformity testing requirements. When these_ a
`are used in a specific dry powder inhaler, the uniformity of dosage".
`
`units, as delivered through the mouthpiece, is to be measured. ‘A dog...
`
`sage unit is defined as the amount of drug discharged from the mm, s ,
`piece of the dry powder inhaler following the loading and discharges.
`ofthe recommended dose. Follow the labeled instructions for loading.,?‘
`the inhaler: For collection of the dosage unit from the inhaler. proceed-L.
`as directed in the test for wafer-mitt) ofDosage Units under Aerosols
`Metered—Dose Inhalenr, and Dry Powder Inhalers (601).] Unless“
`otherwise specified in the individual monograph, the requirements
`of dose uniformity are met if the amount of the active ingredient dis.- . '
`charged in not more than 1 of the 10 dosage units, as determined fronts .,"
`the Content Uniformity method, lies outside the range of 75.0% toi-
`125.0% of the labeled claim, and no amount is outside the range‘oii
`
`65.0% to 135.0% of the labeled claim. If2 or 3 dosage units areoht-
`
`side the range of 75.0% to 125.0% of the labeled claim, but not out-fl?
`side the range of 65.0% to 135.0% of the labeled claim, test an: "
`additional units. The requirements are met if not more than 3 unitsl' .-
`ofthe 30 are outside ofthe range of75.0% to 125.0% ofthe labeled:
`claim, and no unit is outside the requirement of65.0% to 135.0%jof
`the labeled claim.
`- nt -
`
`_
`
`-
`
`.
`
`.1
`
`,
`
`
`
`
`
`
`
`_
`
`.
`
`(B) [ftl'ie Average oftlte Limits Specy‘ied in the Potency Definition; _
`in the Individual Monograph is Greater than 100.0 Percent—
`
`If the average value of the dosage units tested is 100.0 percent on
`less, the requirements are as in (A).
`I
`If the‘average value of the dosage units tested is greater than or
`equal to the average of the limits specified in the potency defint-u ‘-
`tion in the individual monograph, the requirements are as In (Al:
`except that the words “label claim" are replaced by ttte‘wm’fiIS
`“label claim multiplied. by the average of the limits specified In.
`the potency definition in the monograph divided by 100’ .
`If the average value of the dosage units tested is between 1.00
`percent and the average of the limits specified in the potent}I d?"
`finition in the individual monograph, the requirements are 55 I“
`(A), except that the words “label claim" are replaced. by the
`words “labei claim multiplied by the average value UHF“?
`sage units tcsted (expressed as a percent of label claim) leld‘i
`by 100".
`
`( 1)
`
`(2)
`
`(3)
`
`(911) VISCOSITY
`Viscosity is apropertyofliquids that is closely relatedto therest;
`
`tance to flow. It is defined in terms of the force required to move we
`plane surface continuously past another under specified steady-:0“.
`conditions when the space beavecn is filled by the liquid m 011,553,116
`It is defined as the shear stress divided by the rate of shear stram- red
`basic unit is the poise; however, viscosities commonly enqounjewo
`represent fractions of the poise, so that the centt'poise (1 pm,“ 3' of
`centipoises) proves to be the more convenient unit. The spcmfymgre;
`temperature is important because viscosity changes with tempera
`Page 4
`Page 4
`
`.
`
`
`
`a
`
`.
`
`1'
`
`2034
`
`(911) Viscosity / Pigvsicol Tests
`
`(6) If Flies between 1.030 and 1.100, or between 0.900 and
`0.970, calculate the weight of active ingredient in each dosage unit
`by multiplying each of the weights found using the special procedure
`byF
`
`Calculation of the Relative Standard Deviation
`
`The use of preprogmmmed calculators or computers is accepta-
`ble. A manual mathematical method is as follows:
`s = sample standard deviation.
`RSD = relative standard deviation (the sample standard devia-
`tion gpressed as a percentage of the mean).
`X = mean of the values obtained from the units tested, expressed
`as a percentage of the label claim.-
`n = number of units tested.
`.r,, 17,, x,
`x, = individual values (.r,) of the units tested. ex-
`pressed as a percentage of the label claim.
`
`, _ _
`n—l
`
`_ [Elan — "Err
`
`100:
`D 51? _
`X
`
`RS
`
`Criteria
`
`Apply the following criteria, unless otherwise specified in the
`individual monograph.
`(A) [ft/12 Average ofthe-Lintits Specified in the Potency Definition
`in the Individual Monograph is 100.0 Pement or Less—
`COMPRESSED TABLETS (COATED OR UNCOATED). SUPPOSITORIES.
`ORAL SOLUTIONS l'N SINGLE-UNIT CONTAINERS. SYRUPS 1N SINGLE-
`UNlT CONTAINERS, SUSPENSIONS IN SINGLE-UNIT CONTAINERS, SO-
`LIDS (INCLUDING STERILE SOLIDS) 1N SINGLE-UNIT CONTAINERS,
`AND STERILE SOLIDS FOR PARENTERAL use —Un1ess otherwise spe-
`cified in the individual monograph, the requirements for dosage uni-
`formity are met if the amount of the active ingredient in each ofthe 10
`dosage units as determined from the Weight Variation or the Content
`Uitifierigr method lies within the range of 85.0% to 115.0% of the
`label claim and the Relative standard deviation is less than or equal to
`6.0%.
`1f 1 unit is outside the range of 85.0% to 115.0% oflabel claim
`and no unit is outside the range of75.0% to 125.0% oflabel claim, or
`if the Relative standard deviation is greater than 6.0%, or ifboth con-
`ditions prevail, test 20 additional units. The requirements are met if
`not more than 1 unit ofthe 30 is outside the range of 85.0% to 115.0%
`oflabcl claim and no unit is outside the range of75.0% to 125.0% of
`label claim and the Reitttive standard deviation ofthe 30 dosage units
`does not exceed 7.8%.
`
`Capsules, Transdermal Systems, lnhalatlons (In Single-Unit
`Containers), and Molded Tablets—Unless otherwise specified in
`the individual monograph, the requirements for dosage uniformity
`are met if the amount of the active ingredient in not less than 9 of
`the 10 dosage units as determined from the Weight l/hrintionor the
`Content Uniformity method lies within the range of 85.0% to
`115.0% oflabel claim and no unit is outside the range of 75.0% to
`125.0% of label claim and the Relative standard deviation of the 10
`dosage units is less than or equal to 6.0%.
`1f2 or 3 dosage units are outside the range of85.0% to 115.0%
`oflabel claim, but not outside the range of 75.0% to 125.0% ot'label
`claim, or if the Relative standard deviation is greater than 6.0% or if
`both conditions prevail, test 20 additional units. The requirements are
`met if not more than 3 units of the 30 are outside the range of 85.0%
`to 115.0% of label claim and no unit is outside the range of 75.0% to
`125.0% of label claim, and the Relative standard deviation of the 30
`dosage units does not exceed 7.8%.
`Metered-Dose Topical Aerosols—
`
`