420〈891〉 Thermal Analysis / Physical Tests
USP 35
In addition, the method is reliable when the purity of the Solids (including sterile solids) that are packaged in sin-major component is greater than 98.5 mol% and the mater-gle-unit containers, with or without active or inactive ials are not decompod during the melting pha.
(W3)
added substances, that have been prepared from true Impurity levels calculated from thermograms are repro-solutions and freeze-dried in the final containers and are ducible and generally reliable within 0.1% for ideal labeled to indicate this method of preparation; and compounds.
Hard capsules, uncoated tablets, or film-coated tablets,Compounds that exist in polymorphic form cannot be containing 25 mg or more of a drug substance compris-ud in purity determination unless the compound is com-ing 25% or more, by weight, of the dosage unit or, in pletely converted to one form. On the other hand, DSC and (W4)
the ca of hard capsules, the capsule contents, except DTA are inherently uful for detecting, and th
erefore moni-that uniformity of other drug substances prent in toring, polymorphism.
lesr proportions is demonstrated by meeting the re-Procedure—The actual procedure and the calculations to quirements for Content Uniformity .
be employed for eutectic impurity analysis are dependent The test for Content Uniformity is required for all dosage on the particular instrument ud. Consult the manufactur-forms not meeting the above conditions for the 3Weight 3er’s literature and/or the thermal analysis literature for the Variation test.1
most appropriate technique for a given instrument. In any event, it is imperative to keep in mind the limitations of solid solution formation, insolubility in the melt, polymor-Table 1. Application of Content Uniformity (CU) and Weight
phism, and decomposition during the analysis.
Variation (WV) Tests for Dosage Forms
Do & Ratio of Drug Substance ≥25 mg <25 mg and or ≥25%<25%Dosage Form Type Subtype Uncoated WV CU 〈905〉 UNIFORMITY OF DOSAGE
蟑螂产卵
Film WV CU Tablets
Coated UNITS
Others CU CU Hard
WV CU
Suspension,emulsion,Capsules
This general chapter is harmonized with the correspond-Soft or gel CU CU ing texts of the European Pharmacopoeia and the Japane Pharmacopoeia . Portions of the general chapter text that are Solutions
WV WV
national USP text, and are not part of the harmonized text,Single are marked with symbols (33) to specify po-3N OTE —In this chapter, unit and dosage unit are nent
WV
WV
synonymous.3
Solution Solids in To ensure the consistency of dosage units, each unit in a freeze-single-unit batch should have a drug substance content within a nar-Multiple dried in containers
row range around the label claim. Dosage units are defined compo-final con-as dosage forms containing a single do or a part of a do nents
肉孜买买提tainer WV WV of drug substance in each unit. The uniformity of dosage Others
CU CU
units specification is not intended to apply to suspensions,Solutions in emulsions, or gels in unit-do containers intended for ex-unit-do ternal, cutaneous administration.
containers The term “uniformity of dosage unit” is defined as the 3and into degree of uniformity in the amount of the drug substance soft cap-among dosage units. Therefore, the requirements of this sules 3WV WV chapter apply to each drug substance being comprid in Others
CU CU
dosage units containing one or more drug substances, un-less otherwi specified elwhere in this Pharmacopeia.The uniformity of dosage units can be demonstrated by either of two methods, Content Uniformity or 3Weight 3 Varia-CONTENT UNIFORMITY
tion (e Table 1). The test for Content Uniformity of prepara-tions prented in dosage units is bad on the assay of the Select not fewer than 30 units, and proceed as follows for individual content of drug substance(s) in a number of
the dosage form designated.
dosage units to determine whether the individual content is Where different procedures are ud for assay of the prep-within the limits t. The Content Uniformity method may be aration and for the Content Uniformity test, it may be neces-applied in all cas.
sary to establish a correction factor to be applied to the The test for 3Weight 3 Variation is applicable for the follow-results of the latter.
ing dosage forms:
13探险旅行
European Pharmacopoeia and Japane Pharmacopoeia text not accepted by the United States Pharmacopeia: Alternatively, products listed in item (4)Solutions enclod in unit-do containers and into soft above that do not meet the 25 mg/25% threshold limit may be tested for (W1)uniformity of dosage units by Mass Variation instead of the Content Uniform-capsules;
ity test if the concentration relative standard deviation (RSD) of the drug Solids (including powders, granules, and sterile solids)substance in the final dosage units is not more than 2%, bad on process (W2)
that are packaged in single-unit containers and contain validation 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-no active or inactive added substances;
tion per dosage unit (w/w or w/v), where concentration per dosage unit equals the assay result per dosage unit divided by the individual dosage unit weight. See the RSD formula in Table 2.3
USP 35Physical Tests / 〈905〉 Uniformity of Dosage Units421
Solid Dosage Forms Calculation of Acceptance Value
Assay 10 units individually using an appropriate analytical Calculate the acceptance value by the formula: method. Calculate the acceptance value (e Table 2).
Liquid or Semi-Solid Dosage Forms
in which the terms are as defined in Table 2.
Assay 10 units individually using an appropriate analytical
method. Carry out the assay on the amount of well-mixed传统经济
material that is removed from an individual container in
conditions of normal u, and express the results as deliv-
ered do. Calculate the acceptance value (e Table 2).
Table 2
Variable Definition Conditions Value
Mean of individual contents (χ1,
χ2, …, χn), expresd as a per-
X centage of the label claim
χ1, χ2, …, χn Individual contents of the units
tested, expresd as a percentage
of the label claim
n Sample size (number of units in a
sample)
k Acceptability constant
If n = 10, then k = 2.4
If n = 30, then k = 2.0
s Sample standard deviation
RSD Relative standard deviation (the100s/X
sample standard deviation ex-
presd as a percentage of the
mean)
M (ca 1) to be applied when Reference value
If 98.5% ≤X ≤101.5%, then M = X (AV = ks) T ≤101.5M = 98.5%
If X <98.5%, then(AV = 98.5 – X + ks)
法国的美食M = 101.5%
If X >101.5%, then(AV = X – 101.5 + ks)
M (ca 2) to be applied when Reference value
M = X
If 98.5 ≤X ≤T, then
T >101.5
(AV = ks)
M = 98.5%
If X <98.5%, then
(AV = 98.5 – X + ks)
M = T%
If X >T, then(AV = X – T + ks) Acceptance value (AV)General formula:
(Calculations are specified above
for the different cas.)
L1Maximum allowed acceptance L1 = 15.0 unless otherwi specified
value
422〈905〉 Uniformity of Dosage Units / Physical Tests
USP 35
Table 2 (Continued)
Variable
除夕的来历和传说
Definition
Conditions
Value
L2
Maximum allowed range for On the low side, no dosage unit L2 = 25.0 unless otherwi specified
deviation of each dosage unit result can be less than
tested from the calculated value [1–(0.01)(L2)]M, while on the of M
high side, no dosage unit result can be greater than [1 +
(0.01)(L2)]M. (This is bad on an L2 value of 25.0.)
T
Target content per dosage unit at the time of manufacture, ex-presd as a percentage of the label claim. Unless otherwi stat-ed, T is 100.0%, or T is the man-ufacturer’s approved target content per dosage unit.
3
WEIGHT 3 VARIATION
Liquid Dosage Forms
Carry out an assay for the drug substance(s) on a repre-Accurately weigh the amount of liquid that is removed ntative sample of the batch using an appropriate analyti-from each of 10 individual containers in conditions of nor-cal method. This value is result A, expresd as percentage mal u. If necessary, compute the equivalent volume after of label claim (e Calculation of Acceptance Value ). Assume determining the density. Calculate the drug substance con-that the concentration (weight of drug substance per
tent in each container from the mass of product removed weight of dosage unit) is uniform. Select not fewer than 30from the individual containers and the result of the Assay .dosage units, and proceed as follows for the dosage form Calculate the acceptance value.
designated.
Calculation of Acceptance Value
Uncoated or Film-Coated Tablets
Calculate the acceptance value as shown in Content Uni-Accurately weigh 10 tablets individually. Ca
lculate the formity , except that the individual contents of the units are content, expresd as percentage of label claim, of each replaced with the individual estimated contents defined tablet from the 3weight 3 of the individual tablet and the below.
result of the Assay . Calculate the acceptance value.
χ1, χ2, …, χn
=individual estimated contents of the units tested, where χi = w i × A/W
Hard Capsules
w 1, w 2, …, w n =individual 3weights 3 of the units tested
A
=
content of drug substance (% of label claim)Accurately weigh 10 capsules individually, taking care to obtained using an appropriate analytical prerve the identity of each capsule. Remove the contents method
of each capsule by a suitable means. Accurately weigh the emptied shells individually, and calculate for each capsule W =
mean of individual 3weights 3the net 3weight 3 of its contents by subtracting the 3weight 3 (w 1, w 2, …, w n )床可以对着窗户吗
of the shell from the respective gross 3weight 3. Calculate the drug substance content of each capsule from the 3net weight 3 of the individual capsule 3content 3 and the result of CRITERIA
the Assay . Calculate the acceptance value.
Apply the following criteria, unless otherwi specified.
星星花
Soft Capsules
Solid, Semi-Solid, and Liquid Dosage Forms
Accurately weigh 10 intact capsules individually to obtain their gross 3weights 3, taking care to prerve the identity of The requirements for dosage uniformity are met if the ac-each capsule. Then cut open the capsules by means of a ceptance value of the first 10 dosage units is less than or suita
ble clean, dry cutting instrument such as scissors or a equal to L1%. If the acceptance value is > L1%, test the sharp open blade, and remove the contents by washing next 20 units, and calculate the acceptance value. The re-with a suitable solvent. Allow the occluded solvent to evap-quirements are met if the final acceptance value of the 30orate from the shells at room temperature over a period of dosage units is ≤ L1%, and no individual content of 3any 3about 30 minutes, taking precautions to avoid uptake or dosage unit is less than [1 − (0.01)(L2)]M nor more than [1loss of moisture. Weigh the individual shells, and calculate + (0.01)(L2)]M 3as specified 3 in the Calculation of Acceptance
the net contents. Calculate the drug substance content in each capsule from the 3weight 3 of product removed from the individual capsules and the result of the Assay . Calculate the acceptance value.
Solid Dosage Forms Other Than Tablets and
Capsules
Proceed as directed for Hard Capsules , treating each unit as described therein. Calculate the acceptance value.
USP 35
Physical Tests / 〈911〉 Viscosity 423
Value under Content Uniformity or under 3Weight 3 Variation .Engler instrument usually are reported at 20°C and 50°C. A Unless otherwi specified, L1 is 15.0 and L2 is 25.0.
particularly convenient and rapid type of instrument is a ro-tational viscosimeter, which utilizes a bob or spindle im-merd in the test specimen and measures the resistance to movement of the rotating part. Different spindles are availa-ble for given viscosity ranges, and veral rotational speeds generally are available. Other rotational instruments may have a stationary bob and a rotating cup. The Brookfield,Rotouisco, and Stormer viscosimeters are examples of rotat-〈911〉 VISCOSITY
ing-bob instruments, and the MacMichael is an example of the rotating-cup instrument. Numerous other rotational in-struments of advanced design with special devices for read-Viscosity is a property of liquids that is cloly related to ing or recording, and with wide ranges of rotational speed,the resistance to flow. It is defined in terms of the force have been devid.
required to move one plane surface continuously past an-Where only a particular type of instrument i
s suitable, the other under specified steady-state conditions when the individual monograph so indicates.
space between is filled by the liquid in question. It is de-For measurement of viscosity or apparent viscosity, the fined as the shear stress divided by the rate of perature of the substance being measured must be ac-The basic unit is the poi; however, viscosities commonly curately controlled, since small temperature changes may encountered reprent fractions of the poi, so that the lead to marked changes in viscosity. For usual pharmaceuti-centipoi (1 poi = 100 centipois) proves to be the more cal purpos, the temperature should be held to within convenient unit. The specifying of temperature is important ±0.1°.
becau viscosity changes with temperature; in general, vis-Procedure for Cellulo Derivatives—Measurement of cosity decreas as temperature is raid. While on the abso-the viscosity of solutions of the high-viscosity types of
lute scale viscosity is measured in pois or centipois, for methylcellulo is a special ca, since they are too viscous convenience the kinematic scale, in which the units are
for the commonly available viscosimeters. The Ubbelohde stokes and centistokes (1 stoke = 100 ce
ntistokes) commonly viscosimeter may be adapted (cf. ASTM, D-1347) to the is ud. To obtain the kinematic viscosity from the absolute measurement of the ranges of viscosity encountered in viscosity, the latter is divided by the density of the liquid at methylcellulo solutions.
the same temperature, i.e., kinematic viscosity = (absolute Calibration of Capillary-Type Viscosimeters—Determine viscosity)/(density). The sizes of the units are such that vis-the viscosimeter constant, k, for each viscosimeter by the cosities in the ordinary ranges are conveniently expresd in u of an oil of known viscosity.*
centistokes. The approximate viscosity in centistokes at Ostwald-Type Viscosimeter—Fill the tube with the exact room temperature of ether is 0.2; of water, 1; of kerone,amount of oil (adjusted to 20.0 ± 0.1°) as specified by the 2.5; of mineral oil, 20 to 70; and of honey, 10,000.
manufacturer. Adjust the meniscus of the column of liquid Absolute viscosity can be measured directly if accurate in the capillary tube to the level of the top graduation line dimensions of the measuring instruments are known, but it with the aid of either pressure or suction. Open both the is more common practice to calibrate the instrument with a filling and capillary tubes in order to permit the liquid to liquid of known viscosity and to determine the viscosity of flow into the rervoir against atmospheric pressure.
the unknown fluid by comparison with that of the known.[N OTE —Failure to open either of the tubes will yield fal Many substances, such as the gums employed in phar-values.] Record the time, in conds, for liquid to flow from macy, have variable viscosity, and most of them are less the upper mark to the lower mark in the sistant to flow at higher flow rates. In such cas, a given t of conditions is lected for measurement, and the
Ubbelohde-Type Viscosimeter—Place a quantity of the oil measurement obtained is considered to be an apparent vis-(adjusted to 20.0 ± 0.1°) in the filling tube, and transfer to cosity. Since a change in the conditions of measurement the capillary tube by gentle suction, taking care to prevent would yield a different value for the apparent viscosity of bubble formation in the liquid by keeping the air vent tube such substances, the instrument dimensions and conditions clod. Adjust the meniscus of the column of liquid in the for measurement must be cloly adhered to by the capillary tube to the level of the top graduation line. Open operator.
both the vent and capillary tubes in order to permit the liquid to flow into the rervoir against atmospheric pres-Measurement of Viscosity—The usual method for meas-sure. [N OTE —Failure to open the vent tube before releasing urement of viscosity involves the determination of the time the capillary tube will yield fal values.] Record the time, in required for a given volume of liquid to flow t
hrough a conds, for the liquid to flow from the upper mark to the capillary. Many capillary-tube viscosimeters have been de-lower mark in the capillary tube.vid, but Ostwald and Ubbelohde viscosimeters are among the most frequently ud. Several types are described, with Calculations—
directions for their u, by the American Society for Testing Calculate the viscosimeter constant, k, from the equation:
and Materials (ASTM, D-445). The viscosity of oils is ex-presd on arbitrary scales that vary from one country to k = v/d t
another, there being veral corresponding instruments. The most widely ud are the Redwood No. I and No. II, the in which v is the known viscosity of the liquid in centipois,Engler, the Saybolt Universal, and the Saybolt Furol. Each of d is the specific gravity of the liquid tested at 20°/20°, and t the instruments us arbitrary units that bear the name of is the time in conds for the liquid to pass from the upper the instrument. Standard temperatures are adopted as a mark to the lower mark.
matter of convenience with the instruments. For the *Oils of known viscosities may be obtained from the Cannon Instrument Co.,Saybolt instruments, measurements usually are made at
Box 16, State College, PA 16801. For methylcellulo, choo an oil the vis-100°F and 210°F; Redwood instruments may be ud at v-cosity of which is as clo as possible to that of the type of methylcellulo to be determined.
eral temperatures up to 250°F; and values obtained on the
