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20 by nEwp0rt1 on Fri Dec 02 22:02:37 EST 2011
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 decomposed during the melting phase. (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-
used 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 case of hard capsules, the capsule contents, except
DTA are inherently useful for detecting, and therefore moni- that uniformity of other drug substances present in
toring, polymorphism. lesser 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
on the particular instrument used. Consult the manufactur- The test for Content Uniformity is required for all dosage
er’s literature and/or the thermal analysis literature for the forms not meeting the above conditions for the ✦Weight✦
most appropriate technique for a given instrument. In any Variation test.1
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
Dose & Ratio of
Drug Substance
≥25 mg <25 mg
and or
Dosage Form Type Subtype ≥25% <25%
〈905〉 UNIFORMITY OF DOSAGE Tablets
Uncoated
Film
WV
WV
CU
CU
UNITS Coated
Others CU CU
Hard WV CU
Suspension,
This general chapter is harmonized with the correspond- Capsules emulsion,
Soft
ing texts of the European Pharmacopoeia and the Japanese or gel CU CU
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 (✦✦) to specify this fact. compo-
✦NOTE—In this chapter, unit and dosage unit are
nent WV WV
synonymous.✦ Solids in Solution
To ensure the consistency of dosage units, each unit in a single-unit freeze-
batch should have a drug substance content within a nar- containers
Multiple
dried in
row range around the label claim. Dosage units are defined compo-
final con-
as dosage forms containing a single dose or a part of a dose nents
tainer WV WV
of drug substance in each unit. The uniformity of dosage
units specification is not intended to apply to suspensions, Others CU CU
emulsions, or gels in unit-dose containers intended for ex- Solutions in
ternal, cutaneous administration. unit-dose
The term “uniformity of dosage unit” is defined as the containers
✦and into
degree of uniformity in the amount of the drug substance
among dosage units. Therefore, the requirements of this soft cap-
chapter apply to each drug substance being comprised in sules✦ WV WV
dosage units containing one or more drug substances, un- Others CU CU
less otherwise specified elsewhere in this Pharmacopeia.
The uniformity of dosage units can be demonstrated by
either of two methods, Content Uniformity or ✦Weight✦ Varia-
tion (see Table 1). The test for Content Uniformity of prepara- CONTENT UNIFORMITY
tions presented in dosage units is based on the assay of the
individual content of drug substance(s) in a number of Select not fewer than 30 units, and proceed as follows for
dosage units to determine whether the individual content is the dosage form designated.
within the limits set. The Content Uniformity method may be Where different procedures are used for assay of the prep-
applied in all cases. aration and for the Content Uniformity test, it may be neces-
The test for ✦Weight✦ Variation is applicable for the follow- sary to establish a correction factor to be applied to the
ing dosage forms: results of the latter.
1 ✦European Pharmacopoeia and Japanese Pharmacopoeia text not accepted
by the United States Pharmacopeia: Alternatively, products listed in item (4)
Solutions enclosed in unit-dose 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%, based on process
(W2) that are packaged in single-unit containers and contain validation data and development data, and if there has been regulatory ap-
no active or inactive added substances; 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 unit
equals the assay result per dosage unit divided by the individual dosage unit
weight. See the RSD formula in Table 2.✦
Official from May 1, 2012
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USP 35 Physical Tests / 〈905〉 Uniformity of Dosage Units 421
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 (see 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
material that is removed from an individual container in
conditions of normal use, and express the results as deliv-
ered dose. Calculate the acceptance value (see Table 2).
Table 2
Variable Definition Conditions Value
Mean of individual contents (χ1,
χ2, …, χn), expressed as a per-
X centage of the label claim
χ1, χ2, …, χn Individual contents of the units
tested, expressed 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 (the 100s/X
sample standard deviation ex-
pressed as a percentage of the
mean)
M (case 1) to be applied when Reference value If 98.5% ≤X ≤101.5%, then M = X (AV = ks)
T ≤101.5 M = 98.5%
If X <98.5%, then (AV = 98.5 – X + ks)
M = 101.5%
If X >101.5%, then (AV = X – 101.5 + ks)
M (case 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 cases.)
L1 Maximum allowed acceptance L1 = 15.0 unless otherwise specified
value
Official from May 1, 2012
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422 〈905〉 Uniformity of Dosage Units / Physical Tests USP 35
Table 2 (Continued)
Variable Definition Conditions Value
L2 Maximum allowed range for On the low side, no dosage unit L2 = 25.0 unless otherwise 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 based on
an L2 value of 25.0.)
T Target content per dosage unit at
the time of manufacture, ex-
pressed as a percentage of the
label claim. Unless otherwise stat-
ed, T is 100.0%, or T is the man-
ufacturer’s approved target
content per dosage unit.
✦ WEIGHT✦ 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
sentative 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, expressed as percentage mal use. If necessary, compute the equivalent volume after
of label claim (see 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 30 from 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. Calculate the formity, except that the individual contents of the units are
content, expressed as percentage of label claim, of each replaced with the individual estimated contents defined
tablet from the ✦weight✦ 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 = wi × A/W
Hard Capsules
w1, w2, …, wn = individual ✦weights✦ of the units tested
Accurately weigh 10 capsules individually, taking care to A = content of drug substance (% of label claim)
preserve the identity of each capsule. Remove the contents obtained using an appropriate analytical
of each capsule by a suitable means. Accurately weigh the method
emptied shells individually, and calculate for each capsule W = mean of individual ✦weights✦
the net ✦weight✦ of its contents by subtracting the ✦weight✦ (w1, w2, …, wn)
of the shell from the respective gross ✦weight✦. Calculate
the drug substance content of each capsule from the ✦net
weight✦ of the individual capsule ✦content✦ and the result of
the Assay. Calculate the acceptance value. CRITERIA
Apply the following criteria, unless otherwise specified.
Soft Capsules
Accurately weigh 10 intact capsules individually to obtain Solid, Semi-Solid, and Liquid Dosage Forms
their gross ✦weights✦, taking care to preserve the identity of
each capsule. Then cut open the capsules by means of a The requirements for dosage uniformity are met if the ac-
suitable clean, dry cutting instrument such as scissors or a ceptance value of the first 10 dosage units is less than or
sharp open blade, and remove the contents by washing equal to L1%. If the acceptance value is > L1%, test the
with a suitable solvent. Allow the occluded solvent to evap- next 20 units, and calculate the acceptance value. The re-
orate from the shells at room temperature over a period of quirements are met if the final acceptance value of the 30
about 30 minutes, taking precautions to avoid uptake or dosage units is ≤ L1%, and no individual content of ✦any✦
loss of moisture. Weigh the individual shells, and calculate dosage unit is less than [1 − (0.01)(L2)]M nor more than [1
the net contents. Calculate the drug substance content in + (0.01)(L2)]M ✦as specified✦ in the Calculation of Acceptance
each capsule from the ✦weight✦ 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.
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USP 35 Physical Tests / 〈911〉 Viscosity 423
Value under Content Uniformity or under ✦Weight✦ Variation. Engler instrument usually are reported at 20°C and 50°C. A
Unless otherwise 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-
mersed in the test specimen and measures the resistance to
movement of the rotating part. Different spindles are availa-
ble for given viscosity ranges, and several rotational speeds
generally are available. Other rotational instruments may
have a stationary bob and a rotating cup. The Brookfield,
〈911〉 VISCOSITY Rotouisco, and Stormer viscosimeters are examples of rotat-
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 closely 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 devised.
required to move one plane surface continuously past an- Where only a particular type of instrument is 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 shear strain. temperature of the substance being measured must be ac-
The basic unit is the poise; however, viscosities commonly curately controlled, since small temperature changes may
encountered represent fractions of the poise, so that the lead to marked changes in viscosity. For usual pharmaceuti-
centipoise (1 poise = 100 centipoises) proves to be the more cal purposes, the temperature should be held to within
convenient unit. The specifying of temperature is important ±0.1°.
because viscosity changes with temperature; in general, vis- Procedure for Cellulose Derivatives—Measurement of
cosity decreases as temperature is raised. While on the abso- the viscosity of solutions of the high-viscosity types of
lute scale viscosity is measured in poises or centipoises, for methylcellulose is a special case, 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 centistokes) commonly viscosimeter may be adapted (cf. ASTM, D-1347) to the
is used. 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 methylcellulose solutions.
the same temperature, i.e., kinematic viscosity = (absolute
viscosity)/(density). The sizes of the units are such that vis- Calibration of Capillary-Type Viscosimeters—Determine
cosities in the ordinary ranges are conveniently expressed in the viscosimeter constant, k, for each viscosimeter by the
centistokes. The approximate viscosity in centistokes at use of an oil of known viscosity.*
room temperature of ether is 0.2; of water, 1; of kerosene, Ostwald-Type Viscosimeter—Fill the tube with the exact
2.5; of mineral oil, 20 to 70; and of honey, 10,000. amount of oil (adjusted to 20.0 ± 0.1°) as specified by the
Absolute viscosity can be measured directly if accurate manufacturer. Adjust the meniscus of the column of liquid
dimensions of the measuring instruments are known, but it in the capillary tube to the level of the top graduation line
is more common practice to calibrate the instrument with a with the aid of either pressure or suction. Open both the
liquid of known viscosity and to determine the viscosity of filling and capillary tubes in order to permit the liquid to
the unknown fluid by comparison with that of the known. flow into the reservoir against atmospheric pressure.
Many substances, such as the gums employed in phar- [NOTE—Failure to open either of these tubes will yield false
macy, have variable viscosity, and most of them are less values.] Record the time, in seconds, for liquid to flow from
resistant to flow at higher flow rates. In such cases, a given the upper mark to the lower mark in the capillary tube.
set of conditions is selected 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 closed. Adjust the meniscus of the column of liquid in the
for measurement must be closely 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
Measurement of Viscosity—The usual method for meas- liquid to flow into the reservoir against atmospheric pres-
urement of viscosity involves the determination of the time sure. [NOTE—Failure to open the vent tube before releasing
required for a given volume of liquid to flow through a the capillary tube will yield false values.] Record the time, in
capillary. Many capillary-tube viscosimeters have been de- seconds, for the liquid to flow from the upper mark to the
vised, but Ostwald and Ubbelohde viscosimeters are among lower mark in the capillary tube.
the most frequently used. Several types are described, with Calculations—
directions for their use, 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-
pressed on arbitrary scales that vary from one country to k = v/d t
another, there being several corresponding instruments. The
most widely used are the Redwood No. I and No. II, the in which v is the known viscosity of the liquid in centipoises,
Engler, the Saybolt Universal, and the Saybolt Furol. Each of d is the specific gravity of the liquid tested at 20°/20°, and t
these instruments uses arbitrary units that bear the name of is the time in seconds 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 these 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 methylcellulose, choose an oil the vis-
100°F and 210°F; Redwood instruments may be used at sev- cosity of which is as close as possible to that of the type of methylcellulose to
eral temperatures up to 250°F; and values obtained on the be determined.
Official from May 1, 2012
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