Accessed from 1.202.191.189 by sttage1 on Mon Feb 25 22:04:21 EST 2013USP 36Substituting the experimentally obtained values for To − Tm,∆Hf, and To in equation (2) yields the mole fraction of thetotal eutectic impurity, which, when multiplied by 100,gives the mole percentage of total eutectic impurities.Deviations from the theoretical linear plot also may bedue to solid solution formation (KD ≠ 0), so that care mustbe taken in interpreting the data.To observe the linear effect of the impurity concentrationon the melting-point depression, the impurity must be solu-ble in the liquid phase or melt of the compound, but insolu-ble in the solid phase, i.e., no solid solutions are formed.Some chemical similarities are necessary for solubility in themelt. For example, the presence of ionic compounds in neu-tral organic compounds and the occurrence of thermal de-composition may not be reflected in purity estimates. Theextent of these theoretical limitations has been only partiallyexplored.Impurities present from the synthetic route often are simi-lar to the end product, hence there usually is no problem ofsolubility in the melt. Impurities consisting of molecules ofthe same shape, size, and character as those of the majorcomponent can fit into the matrix of the major componentwithout disruption of the lattice, forming solid solutions orinclusions; such impurities are not detectable by DSC. Purityestimates are too high in such cases. This is more commonwith less-ordered crystals as indicated by low heats offusion.In addition, the method is reliable when the purity of themajor component is greater than 98.5 mol% and the mater-ials are not decomposed during the melting phase.Impurity levels calculated from thermograms are repro-ducible and generally reliable within 0.1% for ideal com-pounds.Compounds that exist in polymorphic form cannot beused in purity determination unless the compound is com-pletely converted to one form. On the other hand, DSC andDTA are inherently useful for detecting, and therefore moni-toring, polymorphism.Procedure—The actual procedure and the calculations tobe employed for eutectic impurity analysis are dependenton the particular instrument used. Consult the manufactur-er’s literature and/or the thermal analysis literature for themost appropriate technique for a given instrument. In anyevent, it is imperative to keep in mind the limitations ofsolid solution formation, insolubility in the melt, polymor-phism, and decomposition during the analysis.Physical Tests / 〈905〉 Uniformity of Dosage Units431among dosage units. Therefore, the requirements of thischapter apply to each drug substance being comprised indosage units containing one or more drug substances, un-less otherwise specified elsewhere in this Pharmacopeia.The uniformity of dosage units can be demonstrated byeither of two methods, Content Uniformity or xWeightx Varia-tion (see Table 1). The test for Content Uniformity of prepara-tions presented in dosage units is based on the assay of theindividual content of drug substance(s) in a number ofdosage units to determine whether the individual content iswithin the limits set. The Content Uniformity method may beapplied in all cases.The test for xWeightx Variation is applicable for the follow-ing dosage forms:Solutions enclosed in unit-dose containers and into softcapsules;Solids (including powders, granules, and sterile solids)that are packaged in single-unit containers and containno active or inactive added substances;Solids (including sterile solids) that are packaged in sin-gle-unit containers, with or without active or inactiveadded substances, that have been prepared from truesolutions and freeze-dried in the final containers and arelabeled to indicate this method of preparation; andHard capsules, uncoated tablets, or film-coated tablets,containing 25 mg or more of a drug substance compris-ing 25% or more, by weight, of the dosage unit or, inthe case of hard capsules, the capsule contents, exceptthat uniformity of other drug substances present inlesser proportions is demonstrated by meeting the re-quirements for Content Uniformity.(W1)(W2)(W3)(W4)The test for Content Uniformity is required for all dosageforms not meeting the above conditions for the xWeightxVariation test.1Table 1. Application of Content Uniformity (CU) and WeightVariation (WV) Tests for Dosage FormsDose & Ratio ofDrug Substance≥25 mg<25 mgandor≥25%<25%WVCUWVCUCUCUWVCUDosage FormTabletsTypeUncoatedCoatedHardSubtypeFilmOthersSuspension,emulsion,or gelSolutions〈905〉 UNIFORMITY OF DOSAGEUNITSThis general chapter is harmonized with the correspond-ing texts of the European Pharmacopoeia and the JapanesePharmacopoeia. Portions of the general chapter text that arenational USP text, and are not part of the harmonized text,are marked with symbols (xx) to specify this fact.xNOTE—In this chapter, unit and dosage unit are synony-mous.xTo ensure the consistency of dosage units, each unit in abatch should have a drug substance content within a nar-row range around the label claim. Dosage units are definedas dosage forms containing a single dose or a part of a doseof drug substance in each unit. The uniformity of dosageunits specification is not intended to apply to suspensions,emulsions, or gels in unit-dose containers intended for ex-ternal, cutaneous administration.The term “uniformity of dosage unit” is defined as thedegree of uniformity in the amount of the drug substanceCapsulesSoftSinglecompo-nentCUWVCUWVWVSolutionfreeze-dried infinal con-tainerOthersWVSolids insingle-unitcontainersMultiplecompo-nentsWVCUWVCUEuropean Pharmacopoeia and Japanese Pharmacopoeia text not acceptedby the United States Pharmacopeia: Alternatively, products listed in item (4)above that do not meet the 25mg/25% threshold limit may be tested foruniformity of dosage units by Mass Variation instead of the Content Uniform-ity test if the concentration relative standard deviation (RSD) of the drugsubstance in the final dosage units is not more than 2%, based on processvalidation data and development data, and if there has been regulatory ap-proval of such a change. The concentration RSD is the RSD of the concentra-tion per dosage unit (w/w or w/v), where concentration per dosage unitequals the assay result per dosage unit divided by the individual dosage unitweight. See the RSD formula in Table 2.x1xOfficial from August 1, 2013Copyright (c) 2013 The United States Pharmacopeial Convention. All rights reserved.Accessed from 1.202.191.189 by sttage1 on Mon Feb 25 22:04:21 EST 2013432〈905〉 Uniformity of Dosage Units / Physical TestsTable 1. Application of Content Uniformity (CU) and WeightVariation (WV) Tests for Dosage Forms (Continued)Dose & Ratio ofDrug Substance≥25 mg<25 mgandor≥25%<25%USP 36Hard CapsulesAccurately weigh 10 capsules individually, taking care topreserve the identity of each capsule. Remove the contentsof each capsule by a suitable means. Accurately weigh theemptied shells individually, and calculate for each capsulethe net xweightx of its contents by subtracting the xweightxof the shell from the respective gross xweightx. Calculatethe drug substance content of each capsule from the xnetweightx of the individual capsule xcontentx and the result ofthe Assay. Calculate the acceptance value.Dosage FormSolutions inunit-dosecontainersxand intosoft cap-sulesxOthersTypeSubtypeWVCUWVCUSoft CapsulesAccurately weigh 10 intact capsules individually to obtaintheir gross xweightsx, taking care to preserve the identity ofeach capsule. Then cut open the capsules by means of asuitable clean, dry cutting instrument such as scissors or asharp open blade, and remove the contents by washingwith a suitable solvent. Allow the occluded solvent to evap-orate from the shells at room temperature over a period ofabout 30minutes, taking precautions to avoid uptake or lossof moisture. Weigh the individual shells, and calculate thenet contents. Calculate the drug substance content in eachcapsule from the xweightx of product removed from theindividual capsules and the result of the Assay. Calculate theacceptance value.CONTENT UNIFORMITYSelect not fewer than 30 units, and proceed as follows forthe dosage form designated.Where different procedures are used for assay of the prep-aration and for the Content Uniformity test, it may be neces-sary to establish a correction factor to be applied to theresults of the latter.Solid Dosage FormsAssay 10 units individually using an appropriate analyticalmethod. Calculate the acceptance value (see Table 2).Liquid or Semi-Solid Dosage FormsAssay 10 units individually using an appropriate analyticalmethod. Carry out the assay on the amount of well-mixedmaterial that is removed from an individual container inconditions of normal use, and express the results as deliv-ered dose. Calculate the acceptance value (see Table 2).Solid Dosage Forms Other Than Tablets andCapsulesProceed as directed for Hard Capsules, treating each unitas described therein. Calculate the acceptance value.Liquid Dosage FormsAccurately weigh the amount of liquid that is removedfrom each of 10 individual containers in conditions of nor-mal use. If necessary, compute the equivalent volume afterdetermining the density. Calculate the drug substance con-tent in each container from the mass of product removedfrom the individual containers and the result of the Assay.Calculate the acceptance value.Calculation of Acceptance ValueCalculate the acceptance value by the formula:in which the terms are as defined in Table 2.xCalculation of Acceptance ValueCalculate the acceptance value as shown in Content Uni-formity, except that the individual contents of the units arereplaced with the individual estimated contents definedbelow.χ1, χ2, …, χnw1, w2, …, wnA===individual estimated contents of the unitstested, where χi = wi × A/Windividual xweightsx of the units testedcontent of drug substance (% of label claim)obtained using an appropriate analyticalmethodmean of individual xweightsx (w1, w2, …, wn)WEIGHTx VARIATIONCarry out an assay for the drug substance(s) on a repre-sentative sample of the batch using an appropriate analyti-cal method. This value is result A, expressed as percentageof label claim (see Calculation of Acceptance Value). Assumethat the concentration (weight of drug substance perweight of dosage unit) is uniform. Select not fewer than 30dosage units, and proceed as follows for the dosage formdesignated.Uncoated or Film-Coated TabletsAccurately weigh 10 tablets individually. Calculate thecontent, expressed as percentage of label claim, of eachtablet from the xweightx of the individual tablet and theresult of the Assay. Calculate the acceptance value.W=Official from August 1, 2013Copyright (c) 2013 The United States Pharmacopeial Convention. All rights reserved.Accessed from 1.202.191.189 by sttage1 on Mon Feb 25 22:04:21 EST 2013USP 36Physical Tests / 〈905〉 Uniformity of Dosage Units433CRITERIAApply the following criteria, unless otherwise specified.Solid, Semi-Solid, and Liquid Dosage FormsThe requirements for dosage uniformity are met if the ac-ceptance value of the first 10 dosage units is less than orequal to L1%. If the acceptance value is > L1%, test thenext 20 units, and calculate the acceptance value. The re-quirements are met if the final acceptance value of the 30dosage units is ≤ L1%, and no individual content of xanyxdosage unit is less than [1 − (0.01)(L2)]M nor more than[1 + (0.01)(L2)]M xas specifiedx in the Calculation of Accep-tance Value under Content Uniformity or under xWeightx Vari-ation. Unless otherwise specified, L1 is 15.0 and L2 is 25.0.Table 2VariableDefinitionMean of individual contents (χ1,χ2, …, χn), expressed as a per-centage of the label claimIndividual contents of the unitstested, expressed as a percentageof the label claimSample size (number of units in asample)Acceptability constantSample standard deviationConditionsValueXχ1, χ2, …, χnnksIf n = 10, then k =If n = 30, then k =2.42.0RSDM (case 1) to be applied whenT ≤101.5Relative standard deviation (thesample standard deviation ex-pressed as a percentage of themean)Reference value100s/XIf 98.5% ≤X ≤101.5%, thenIf X <98.5%, thenIf X >101.5%, thenM (case 2) to be applied whenT >101.5Reference valueIf 98.5 ≤X ≤T, thenIf X <98.5%, thenIf X >T, thenAcceptance value (AV)M = X (AV = ks)M = 98.5%(AV = 98.5 – X + ks)M = 101.5%(AV = X – 101.5 + ks)M = X(AV = ks)M = 98.5%(AV = 98.5 – X + ks)M = T%(AV = X – T + ks)General formula:L1L2Maximum allowed acceptancevalueMaximum allowed range fordeviation of each dosage unittested from the calculated valueof M(Calculations are specified abovefor the different cases.)L1 = 15.0 unless otherwise specifiedOn the low side, no dosage unitresult can be less than [1–(0.01)(L2)]M, while on the highside, no dosage unit result canbe greater than [1 + (0.01)(L2)]M. (This is based on an L2value of 25.0.)L2 = 25.0 unless otherwise specifiedTTarget content per dosage unit atthe time of manufacture, ex-pressed as a percentage of thelabel claim. Unless otherwise stat-ed, T is 100.0%, or T is the man-ufacturer’s approved targetcontent per dosage unit.Official from August 1, 2013Copyright (c) 2013 The United States Pharmacopeial Convention. All rights reserved.Accessed from 1.202.191.189 by sttage1 on Mon Feb 25 22:04:21 EST 2013434〈911〉 Viscosity / Physical TestsUSP 36water or oil bath stabilized at the temperature specified inthe individual monograph, and control the temperature to±0.1°, unless otherwise specified in the individual mono-graph. Maintain the viscometer in a vertical position for atime period of NLT 30 min to allow the sample tempera-ture to reach equilibrium. Close tube (M), and raise thelevel of the liquid in tube (N) to a level about 8mm abovemark (E ≡ h1). Keep the liquid at this level by closing tube(N) and opening tube (M). Open tube (N), and measurethe time required for the level of the liquid to drop frommark (E ≡ h1) to (F ≡ h2), using an appropriate accuratetiming device. [NOTE—In Table 1, the minimum flow timeshould be 350 s for size no. 1, and 200 s for all other sizes.In Table 2, the minimum flow time should be 300 s for sizeno. 0, and 200 s for all other sizes.]Calibration: Calibrate each viscometer at the test tempera-ture by using fluids of known viscosities of appropriate vis-cosity standards to determine the viscometer constant, k.The viscosity values of the calibration standards shouldbracket the expected viscosity value of the sample liquid.Determine the viscometer constant at the same tempera-ture as the sample liquid under test.Calculate the viscometer constant, k, in mm2/s2, from theequation:k = η/(ρ × t)ηρt= known viscosity of the liquid (mPa·s)= density of the liquid (g/mL)= flow time for the liquid to pass from the uppermark to the lower mark (s)Calculation of kinematic and Newtonian viscosities ofsample fluid: A capillary viscometer is chosen so that theflow time, t, ranges between 200 and 1000 s, and thekinematic energy correction is typically less than 1%. If theviscosity constant, k, is known, use the following equationto calculate the kinematic viscosity, v, in mm2/s, from theflow time, t, in s.v = k × tIf the density of the fluid is known at the temperature of theviscosity measurement, then the Newtonian viscosity, η, inmPa·s, is calculated by the following equation:η = v × ρ〈911〉 VISCOSITY—CAPILLARYVISCOMETER METHODSThe following procedures are used to determine the viscosity ofa Newtonian fluid, i.e. a fluid having a viscosity that is inde-pendent of the shearing stress rate or rate of shear. Unlessotherwise directed in the individual monograph, use MethodI.•METHOD I. UBBELOHDE-TYPE CAPILLARY VISCOMETERApparatus: The determination may be carried out with anUbbelohde-type capillary viscometer (Figure 1) that has thespecifications described in Table 1 or Table 2. Figure 1. Ubbelohde-Type Capillary ViscometerProcedure: Fill the viscometer through tube (L) with a suf-ficient quantity of the sample liquid that is appropriate forthe viscometer being used or by following the manufactur-er’s instructions. Carry out the experiment with the tube ina vertical position. Fill bulb (A) with the liquid, and alsoensure that the level of liquid in bulb (B) is below the exitto the ventilation tube (M). Immerse the viscometer in aρ= density of the fluid (g/mL)The flow time of the fluid under examination is the mean ofNLT three consecutive determinations. The result is valid ifthe percentage of the relative standard deviation (%RSD)for the three readings is NMT 2.0%.•METHOD II. OSTWALD-TYPE CAPILLARY VISCOMETERApparatus: The determination may be carried out with anOstwald-type capillary viscometer (Figure 2).Table 1NominalConstant of Viscometer (mm2/s2)0.010.030.10.31.03.01030100MeasurableKinematicViscosity Range(mm2/s)3.5–106–3020–10060–300200–1,000600–3,0002,000–10,0006,000–30,00020,000–100,000Internal Diameter of Tube,R (mm) (±2%)0.640.841.151.512.062.743.704.076.76Volume of Bulb,C (mL) (±5%)5.65.65.65.65.65.65.65.65.6Internal Diameter of Tube,N (mm)2.8–3.22.8–3.22.8–3.22.8–3.23.7–4.34.6–5.44.6–5.45.6–6.46.8–7.5SizeNumber11A22A33A44A5Official from August 1, 2013Copyright (c) 2013 The United States Pharmacopeial Convention. All rights reserved.