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 851
SPECTROPHOTOMETRY AND LIGHT-SCATTERING
ULTRAVIOLET, VISIBLE, INFRARED, ATOMIC ABSORPTION, FLUORESCENCE, TURBIDIMETRY, NEPHELOMETRY, AND RAMAN MEASUREMENT
Absorption spectrophotometry is the
measurement of an interaction between
electromagnetic radiation and the molecules, or
atoms, of a chemical substance. Techniques
frequently employed in pharmaceutical analysis
include UV, visible, IR, and atomic absorption
spectroscopy. Spectrophotometric measurement in
the visible region was formerly referred to as
colorimetry; however,
it is more precise to use the term “colorimetry”
only when considering human perception of color.
Fluorescence spectrophotometry is the
measurement of the emission of light from a
chemical substance while it is being exposed to
UV, visible, or other electromagnetic radiation.
In general, the light emitted by a fluorescent
solution is of maximum intensity at a wavelength
longer than that of the exciting radiation,
usually by some 20 to 30 nm.
Light-Scattering involves measurement of
the light scattered because of submicroscopic
optical density inhomogeneities of solutions and
is useful in the determination of weight-average
molecular weights of polydisperse systems in the
molecular weight range from 1000 to several
hundred million. Two such techniques utilized in
pharmaceutical analysis are
turbidimetry and
nephelometry.
Raman
spectroscopy (inelastic light-scattering)
is a light-scattering process in which the
specimen under examination is irradiated with
intense monochromatic light (usually laser
light) and the light scattered from the specimen
is analyzed for frequency shifts.
The wavelength range
available for these measurements extends from
the short wavelengths of the UV through the IR.
For convenience of reference, this spectral
range is roughly divided into the UV (190 to 380
nm), the visible (380 to 780 nm), the near-IR
(780 to 3000 nm), and the IR (2.5 to 40 µm or
4000 to 250 cm
 1).COMPARATIVE UTILITY OF SPECTRAL RANGES
For many pharmaceutical
substances, measurements can be made in the UV
and visible regions of the spectrum with greater
accuracy and sensitivity than in the near-IR and
IR. When solutions are observed in 1-cm cells,
concentrations of about 10 µg of the specimen
per mL often will produce absorbances of 0.2 to
0.8 in the UV or the visible region. In the IR
and near-IR, concentrations of 1 to 10 mg per mL
and up to 100 mg per mL, respectively, may be
needed to produce sufficient absorption; for
these spectral ranges, cell lengths of from 0.01
mm to upwards of 3 mm are commonly used.
The UV and visible spectra
of substances generally do not have a high
degree of specificity. Nevertheless, they are
highly suitable for quantitative assays, and for
many substances they are useful as additional
means of identification.
There has been increasing
interest in the use of near-IR spectroscopy in
pharmaceutical analysis, especially for rapid
identification of large numbers of samples, and
also for water determination.
The near-IR region is
especially suitable for the determination of –OH
and –NH groups, such as water in alcohol, –OH in
the presence of amines, alcohols in
hydrocarbons, and primary and secondary amines
in the presence of tertiary amines.
The IR spectrum is unique
for any given chemical compound with the
exception of optical isomers, which have
identical spectra. However, polymorphism may
occasionally be responsible for a difference in
the IR spectrum of a given compound in the solid
state. Frequently, small differences in
structure result in significant differences in
the spectra. Because of the large number of
maxima in an IR absorption spectrum, it is
sometimes possible to quantitatively measure the
individual components of a mixture of known
qualitative composition without prior
separation.
The Raman spectrum and the
IR spectrum provide similar data, although the
intensities of the spectra are governed by
different molecular properties. Raman and IR
spectroscopy exhibit different relative
sensitivities for different functional groups,
e.g., Raman spectroscopy is particularly
sensitive to C–S and C–C multiple bonds, and
some aromatic compounds are more easily
identified by means of their Raman spectra.
Water has a highly intense IR absorption
spectrum, but a particularly weak Raman
spectrum. Therefore, water has only limited IR
“windows” that can be used to examine aqueous
solutes, while its Raman spectrum is almost
completely transparent and useful for solute
identification. The two major limitations of
Raman spectroscopy are that the minimum
detectable concentration of specimen is
typically 10
1
M to 102
M and that the impurities in many substances
fluoresce and interfere with the detection of
the Raman scattered signal.
Optical reflectance
measurements provide spectral information
similar to that obtained by transmission
measurements. Since reflectance measurements
probe only the surface composition of the
specimen, difficulties associated with the
optical thickness and the light-scattering
properties of the substance are eliminated.
Thus, reflectance measurements are frequently
more simple to perform on intensely absorbing
materials. A particularly common technique used
for IR reflectance measurements is termed
attenuated total reflectance (ATR), also known
as multiple internal reflectance (MIR). In the
ATR technique, the beam of the IR spectrometer
is passed through an appropriate IR window
material (e.g., KRS-5, a TlBr-TlI eutectic
mixture), which is cut at such an angle that the
IR beam enters the first (front) surface of the
window, but is totally reflected when it
impinges on the second (back) surface (i.e., the
angle of incidence of the radiation upon the
second surface of the window exceeds the
critical angle for that material). By
appropriate window construction, it is possible
to have many internal reflections of the IR beam
before it is transmitted out of the window. If a
specimen is placed in close contact with the
window along the sides that totally reflect the
IR beam, the intensity of reflected radiation is
reduced at each wavelength (frequency) that the
specimen absorbs. Thus, the ATR technique
provides a reflectance spectrum that has been
increased in intensity, when compared to a
simple reflectance measurement, by the number of
times that the IR beam is reflected within the
window. The ATR technique provides excellent
sensitivity, but it yields poor reproducibility,
and is not a reliable quantitative technique
unless an internal standard is intimately mixed
with each test specimen.
Fluorescence spectrophotometry is often
more sensitive than absorption
spectrophotometry. In absorption measurements,
the specimen transmittance is compared to that
of a blank; and at low concentrations, both
solutions give high signals. Conversely, in
fluorescence spectrophotometry, the solvent
blank has low rather than high output, so that
the background radiation that may interfere with
determinations at low concentrations is much
less. Whereas few compounds can be determined
conveniently at concentrations below 10
5
M by light absorption, it is not unusual to
employ concentrations of 107
M to 108
M in fluorescence spectrophotometry.
THEORY AND TERMS
The power of a radiant
beam decreases in relation to the distance that
it travels through an absorbing medium. It also
decreases in relation to the concentration of
absorbing molecules or ions encountered in that
medium. These two factors determine the
proportion of the total incident energy that
emerge. The decrease in power of monochromatic
radiation passing through a homogeneous
absorbing medium is stated quantitatively by
Beer's law, log10(1/T)
= A = abc, in which
the terms are as defined below.
Absorbance
[Symbol:
A]—
The logarithm, to the base 10, of the reciprocal of
the transmittance (T).
[NOTE—Descriptive
terms used formerly include optical density,
absorbancy, and extinction.]
Absorptivity [Symbol:
a]—
The quotient of the absorbance
(A) divided by the product of the
concentration of the substance
(c), expressed in g per L, and the absorption
path length (b) in cm.
[NOTE—It
is not to be confused with absorbancy index;
specific extinction; or extinction coefficient.]
Molar Absorptivity
[Symbol:
 ]—
The quotient of the absorbance
(A) divided by the product of the
concentration, expressed in moles
per L, of the substance and the absorption path
length in cm. It is also the product of the
absorptivity (a) and the
molecular weight of the substance.
[NOTE—Terms
formerly used include molar absorbancy index; molar
extinction coefficient; and molar absorption
coefficient.]
For most systems used
in absorption spectrophotometry, the
absorptivity of a substance is a constant
independent of the intensity of the incident
radiation, the internal cell length, and the
concentration, with the result that
concentration may be determined
photometrically.
Beer's law gives no
indication of the effect of temperature,
wavelength, or the type of solvent. For most
analytical work the effects of normal
variation in temperature are negligible.
Deviations from Beer's
law may be caused by either chemical or
instrumental variables. Apparent failure of
Beer's law may result from a concentration
change in solute molecules because of
association between solute molecules or
between solute and solvent molecules, or
dissociation or ionization. Other deviations
might be caused by instrumental effects such
as polychromatic radiation, slit-width
effects, or stray light.
Even at a fixed
temperature in a given solvent, the
absorptivity may not be truly constant.
However, in the case of specimens having
only one absorbing component, it is not
necessary that the absorbing system conform
to Beer's law for use in quantitative
analysis. The concentration of an unknown
may be found by comparison with an
experimentally determined standard curve.
Although, in the
strictest sense, Beer's law does not hold in
atomic absorption spectrophotometry because
of the lack of quantitative properties of
the cell length and the concentration, the
absorption processes taking place in the
flame under conditions of reproducible
aspiration do follow the Beer relationship
in principle. Specifically, the negative log
of the transmittance, or the absorbance, is
directly proportional to the absorption
coefficient, and, consequently, is
proportional to the number of absorbing
atoms. On this basis, calibration curves may
be constructed to permit evaluation of
unknown absorption values in terms of
concentration of the element in solution.
Absorption Spectrum—
A graphic representation of absorbance, or any
function of absorbance, plotted against wavelength
or function of wavelength.
Transmittance [Symbol:
T]—
The quotient of the radiant power transmitted by a
specimen divided by the radiant power incident upon
the specimen. [NOTE—Terms
formerly used include transmittancy and
transmission.]
Fluorescence Intensity [Symbol:
I]— An
empirical expression of fluorescence activity,
commonly given in terms of arbitrary units
proportional to detector response. The
fluorescence emission spectrum
is a graphical presentation of the spectral
distribution of radiation emitted by an activated
substance, showing intensity of emitted radiation as
ordinate, and wavelength as abscissa. The
fluorescence excitation spectrum
is a graphical presentation of the activation
spectrum, showing intensity of radiation emitted by
an activated substance as ordinate, and wavelength
of the incident (activating) radiation as abscissa.
As in absorption spectrophotometry, the important
regions of the electromagnetic spectrum encompassed
by the fluorescence of organic compounds are the UV,
visible, and near-IR, i.e., the region from 250 to
800 nm. After a molecule has absorbed radiation, the
energy can be lost as heat or released in the form
of radiation of the same or longer wavelength as the
absorbed radiation. Both absorption and emission of
radiation are due to the transitions of electrons
between different energy levels, or orbitals, of the
molecule. There is a time delay between the
absorption and emission of light; this interval, the
duration of the excited state, has been measured to
be about 10
9
second to 108
second for most organic fluorescent solutions. The
short lifetime of fluorescence distinguishes this
type of luminescence from phosphorescence, which is
a long-lived afterglow having a lifetime of 103
second up to several minutes.
Turbidance
[Symbol:
S]— The
light-scattering effect of suspended particles. The
amount of suspended matter may be measured by
observation of either the transmitted light
(turbidimetry) or the scattered light
(nephelometry).
Turbidity
[Symbol:
 ]—In
light-scattering measurements, the turbidity is the
measure of the decrease in incident beam intensity
per unit length of a given suspension.
Raman
Scattering Activity— The molecular property
(in units of cm4 per g)
governing the intensity of an observed Raman band
for a randomly oriented specimen. The scattering
activity is determined from the derivative of the
molecular polarizability with respect to the
molecular motion giving rise to the Raman shifted
band. In general, the Raman band intensity is
linearly proportional to the concentration of the
analyte.
USE OF REFERENCE STANDARDS
With few exceptions, the
Pharmacopeial spectrophotometric tests and
assays call for comparison against a USP
Reference Standard. This is to ensure
measurement under conditions identical for the
test specimen and the reference substance. These
conditions include wavelength setting,
slit-width adjustment, cell placement and
correction, and transmittance levels. It should
be noted that cells exhibiting identical
transmittance at a given wavelength may differ
considerably in transmittance at other
wavelengths. Appropriate cell corrections should
be established and used where required.
The expressions, “similar
preparation” and “similar solution,” as used in
tests and assays involving spectrophotometry,
indicate that the reference specimen, generally
a USP Reference Standard, is to be prepared and
observed in a manner identical for all practical
purposes to that used for the test specimen.
Usually in making up the solution of the
specified Reference Standard, a solution of
about (i.e., within 10%) the desired
concentration is prepared and the absorptivity
is calculated on the basis of the exact amount
weighed out; if a previously dried specimen of
the Reference Standard has not been used, the
absorptivity is calculated on the anhydrous
basis.
The expressions,
“concomitantly determine” and “concomitantly
measured,” as used in tests and assays involving
spectrophotometry, indicate that the absorbances
of both the solution containing the test
specimen and the solution containing the
reference specimen, relative to the specified
test blank, are to be measured in immediate
succession.
APPARATUS
Many types of
spectrophotometers are available. Fundamentally,
most types, except those used for IR
spectrophotometry, provide for passing
essentially monochromatic radiant energy through
a specimen in suitable form, and measuring the
intensity of the fraction that is transmitted.
Fourier transform IR spectrophotometers use an
interferometric technique whereby polychromatic
radiation passes through the analyte and onto a
detector on an intensity and time basis. UV,
visible, and dispersive IR spectrophotometers
comprise an energy source, a dispersing device
(e.g., a prism or grating), slits for selecting
the wavelength band, a cell or holder for the
test specimen, a detector of radiant energy, and
associated amplifiers and measuring devices. In
diode array
spectrophotometers, the energy from the source
is passed through the test specimen and then
dispersed via a grating onto several hundred
light-sensitive diodes, each of which in turn
develops a signal proportional to the number of
photons at its small wavelength interval; these
signals then may be computed at rapid chosen
intervals to represent a complete spectrum.
Fourier transform IR systems utilize an
interferometer instead of a dispersing device
and a digital computer to process the spectral
data. Some instruments are manually operated,
whereas others are equipped for automatic and
continuous recording. Instruments that are
interfaced to a digital computer have the
capabilities also of co-adding and storing
spectra, performing spectral comparisons, and
performing difference spectroscopy (accomplished
with the use of a digital absorbance subtraction
method).
Instruments are available
for use in the visible; in the visible and UV;
in the visible, UV, and near-IR; and in the IR
regions of the spectrum. Choice of the type of
spectrophotometric analysis and of the
instrument to be used depends upon factors such
as the composition and amount of available test
specimen, the degree of accuracy, sensitivity,
and selectivity desired, and the manner in which
the specimen is handled.
The apparatus used in
atomic absorption spectrophotometry has several
unique features. For each element to be
determined, a specific source that emits the
spectral line to be absorbed should be selected.
The source is usually a hollow-cathode lamp, the
cathode of which is designed to emit the desired
radiation when excited. Since the radiation to
be absorbed by the test specimen element is
usually of the same wavelength as that of its
emission line, the element in the hollow-cathode
lamp is the same as the element to be
determined. The apparatus is equipped with an
aspirator for introducing the test specimen into
a flame, which is usually provided by
air–acetylene, air–hydrogen, or, for refractory
cases, nitrous oxide–acetylene. The flame, in
effect, is a heated specimen chamber. A detector
is used to read the signal from the chamber.
Interfering radiation produced by the flame
during combustion may be negated by the use of a
chopped source lamp signal of a definite
frequency. The detector should be tuned to this
alternating current frequency so that the direct
current signal arising from the flame is
ignored. The detecting system, therefore, reads
only the change in signal from the
hollow-cathode source, which is directly
proportional to the number of atoms to be
determined in the test specimen. For
Pharmacopeial purposes, apparatus that provides
the readings directly in absorbance units is
usually required. However, instruments providing
readings in percent transmission, percent
absorption, or concentration may be used if the
calculation formulas provided in the individual
monographs are revised as necessary to yield the
required quantitative results. Percent
absorption or percent transmittance may be
converted to absorbance, A,
by the following two equations:
A =
2
log10 (100
% absorption)
or:
A =
2
log10 (% transmittance)
Depending upon the type of
apparatus used, the readout device may be a
meter, digital counter, recorder, or printer.
Both single-beam and double-beam instruments are
commercially available, and either type is
suitable.
Measurement of
fluorescence intensity can be made with a simple
filter fluorometer.
Such an instrument consists of a radiation
source, a primary filter, a specimen chamber, a
secondary filter, and a fluorescence detection
system. In most such fluorometers, the detector
is placed on an axis at 90
from that of the exciting beam. This right-angle
geometry permits the exciting radiation to pass
through the test specimen and not contaminate
the output signal received by the fluorescence
detector. However, the detector unavoidably
receives some of the exciting radiation as a
result of the inherent scattering properties of
the solutions themselves, or if dust or other
solids are present. Filters are used to
eliminate this residual scatter. The primary
filter selects short-wavelength radiation
capable of exciting the test specimen, while the
secondary filter is normally a sharp cut-off
filter that allows the longer-wavelength
fluorescence to be transmitted but blocks the
scattered excitation.
Most fluorometers use
photomultiplier tubes as detectors, many types
of which are available, each having special
characteristics with respect to spectral region
of maximum sensitivity, gain, and electrical
noise. The photocurrent is amplified and read
out on a meter or recorder.
A
spectrofluorometer differs from a filter
fluorometer in that filters are replaced by
monochromators, of either the prism or the
grating type. For analytical purposes, the
spectrofluorometer is superior to the filter
fluorometer in wavelength selectivity,
flexibility, and convenience, in the same way in
which a spectrophotometer is superior to a
filter photometer.
Many radiation sources are
available. Mercury lamps are relatively stable
and emit energy mainly at discrete wavelengths.
Tungsten lamps provide an energy continuum in
the visible region. The high-pressure xenon arc
lamp is often used in spectrofluorometers
because it is a high-intensity source that emits
an energy continuum extending from the UV into
the IR.
In spectrofluorometers,
the monochromators are equipped with slits. A
narrow slit provides high resolution and
spectral purity, while a large slit sacrifices
these for high sensitivity. Choice of slit size
is determined by the separation between exciting
and emitting wavelengths as well as the degree
of sensitivity needed.
Specimen cells used in
fluorescence measurements may be round tubes or
rectangular cells similar to those used in
absorption spectrophotometry, except that they
are polished on all four vertical sides. A
convenient test specimen size is 2 to 3 mL, but
some instruments can be fitted with small cells
holding 100 to 300 µL, or with a capillary
holder requiring an even smaller amount of
specimen.
Light-scattering
instruments are available and consist in general
of a mercury lamp, with filters for the strong
green or blue lines, a shutter, a set of neutral
filters with known transmittance, and a
sensitive photomultiplier to be mounted on an
arm that can be rotated around the solution cell
and set at any angle from
135
to 0
to +135
by a dial outside the light-tight housing.
Solution cells are of various shapes, such as
square for measuring 90
scattering; semioctagonal for 45,
90,
and 135
scattering; and cylindrical for scattering at
all angles. Since the determination of molecular
weight requires a precise measure of the
difference in refractive index between the
solution and solvent, [(n
n0)/c],
a second instrument, a differential
refractometer, is needed to measure this small
difference.
Raman spectrometers
include the following major components: a source
of intense monochromatic radiation (invariably a
laser); optics to collect the light scattered by
the test specimen; a (double) monochromator to
disperse the scattered light and reject the
intense incident frequency; and a suitable
light-detection and amplification system. Raman
measurement is simple in that most specimens are
examined directly in melting-point capillaries.
Because the laser source can be focused sharply,
only a few microliters of the specimen is
required.
Change
to read:
PROCEDURE
Absorption Spectrophotometry
Detailed instructions
for operating spectrophotometers are
supplied by the manufacturers. To achieve
significant and valid results, the operator
of a spectrophotometer should be aware of
its limitations and of potential sources of
error and variation. The instruction manual
should be followed closely on such matters
as care, cleaning, and calibration of the
instrument, and techniques of handling
absorption cells, as well as instructions
for operation. The following points require
special emphasis.
Check the instrument
for accuracy of calibration. Where a
continuous source of radiant energy is used,
attention should be paid to both the
wavelength and photometric scales; where a
spectral line source is used, only the
photometric scale need be checked. A number
of sources of radiant energy have spectral
lines of suitable intensity, adequately
spaced throughout the spectral range
selected. The best single source of UV and
visible calibration spectra is the
quartz-mercury arc, of which the lines at
253.7, 302.25, 313.16, 334.15, 365.48,
404.66, and 435.83 nm may be used. The
glass-mercury arc is equally useful above
300 nm. The 486.13-nm and 656.28-nm lines of
a hydrogen discharge lamp may be used also.
The wavelength scale may be calibrated also
by means of suitable glass filters, which
have useful absorption bands through the
visible and UV regions. Standard glasses
containing didymium (a mixture of
praseodymium and neodymium) have been used
widely, although glasses containing holmium
were found to be superior.
 StandardUSP29
holmium oxide solution has superseded the
use of holmium glass.1
The wavelength scales of near-IR and IR
spectrophotometers are readily checked by
the use of absorption bands provided by
polystyrene films, carbon dioxide, water
vapor, or ammonia gas.
For checking the photometric scale, a number
of standard inorganic glass filters as well
as standard solutions of known
transmittances such as
USP29
potassium dichromate are available.2
Quantitative
absorbance measurements usually are made on
solutions of the substance in liquid-holding
cells. Since both the solvent and the cell
window absorb light, compensation must be
made for their contribution to the measured
absorbance. Matched cells are available
commercially for UV and visible
spectrophotometry for which no cell
correction is necessary. In IR
spectrophotometry, however, corrections for
cell differences usually must be made. In
such cases, pairs of cells are filled with
the selected solvent and the difference in
their absorbances at the chosen wavelength
is determined. The cell exhibiting the
greater absorbance is used for the solution
of the test specimen and the measured
absorbance is corrected by subtraction of
the cell difference.
With the use of a
computerized Fourier transform IR system,
this correction need not be made, since the
same cell can be used for both the solvent
blank and the test solution. However, it
must be ascertained that the transmission
properties of the cell are constant.
Comparisons of a test
specimen with a Reference Standard are best
made at a peak of spectral absorption for
the compound concerned. Assays prescribing
spectrophotometry give the commonly accepted
wavelength for peak spectral absorption of
the substance in question. It is known that
different spectrophotometers may show minor
variation in the apparent wavelength of this
peak. Good practice demands that comparisons
be made at the wavelength at which peak
absorption occurs. Should this differ by
more than ±1 nm from the wavelength
specified in the individual monograph,
recalibration of the instrument may be
indicated.
TEST PREPARATION
For determinations
utilizing UV or visible
spectrophotometry, the specimen
generally is dissolved in a solvent.
Unless otherwise directed in the
monograph, determinations are made at
room temperature using a path length of
1 cm. Many solvents are suitable for
these ranges, including water, alcohols,
chloroform, lower hydrocarbons, ethers,
and dilute solutions of strong acids and
alkalies. Precautions should be taken to
utilize solvents free from contaminants
absorbing in the spectral region being
used. It is usually advisable to use
water-free methanol or alcohol, or
alcohol denatured by the addition of
methanol but not containing benzene or
other interfering impurities, as the
solvent. Solvents of special
spectrophotometric quality, guaranteed
to be free from contaminants, are
available commercially from several
sources. Some other analytical
reagent-grade organic solvents may
contain traces of impurities that absorb
strongly in the UV region. New lots of
these solvents should be checked for
their transparency, and care should be
taken to use the same lot of solvent for
preparation of the test solution and the
standard solution and for the blank.
No solvent in
appreciable thickness is completely
transparent throughout the near-IR and
IR spectrum. Carbon tetrachloride (up to
5 mm in thickness) is practically
transparent to 6 µm (1666 cm
1).
Carbon disulfide (1 mm in thickness) is
suitable as a solvent to 40 µm (250 cm1)
with the exception of the 4.2-µm to
5.0-µm (2381-cm1
to 2000-cm1)
and the 5.5-µm to 7.5-µm (1819-cm1
to 1333-cm1)
regions, where it has strong absorption.
Other solvents have relatively narrow
regions of transparency. For IR
spectrophotometry, an additional
qualification for a suitable solvent is
that it must not affect the material,
usually sodium chloride, of which the
cell is made. The test specimen may also
be prepared by dispersing the finely
ground solid specimen in mineral oil or
by mixing it intimately with previously
dried alkali halide salt (usually
potassium bromide). Mixtures with alkali
halide salts may be examined directly or
as transparent disks or pellets obtained
by pressing the mixture in a die.
Typical drying conditions for potassium
bromide are 105
in vacuum for 12 hours, although grades
are commercially available that require
no drying. Infrared microscopy or a
mineral oil dispersion is preferable
where disproportionation between the
alkali halide and the test specimen is
encountered. For suitable materials the
test specimen may be prepared neat as a
thin sample for IR microscopy or
suspended neat as a thin film for
mineral oil dispersion. For Raman
spectrometry, most common solvents are
suitable, and ordinary (nonfluorescing)
glass specimen cells can be used. The IR
region of the electromagnetic spectrum
extends from 0.8 to 400 µm. From 800 to
2500 nm (0.8 to 2.5 µm) is generally
considered to be the near-IR (NIR)
region; from 2.5 to 25 µm (4000 to 400
cm1)
is generally considered to be the
mid-range (mid-IR) region; and from 25
to 400 µm is generally considered to be
the far-IR (FIR) region. Unless
otherwise specified in the individual
monograph, the region from 3800 to 650
cm1
(2.6 to 15 µm) should be used to
ascertain compliance with monograph
specifications for IR absorption.
Where values for
IR line spectra are given in an
individual monograph, the letters
s, m, and
w signify
strong, medium, and weak absorption,
respectively; sh
signifies a shoulder,
bd signifies a band, and
v means very.
The values may vary as much as 0.1 µm or
10 cm
1,
depending upon the particular instrument
used. Polymorphism gives rise to
variations in the IR spectra of many
compounds in the solid state. Therefore,
when conducting IR absorption tests, if
a difference appears in the IR spectra
of the analyte and the standard,
dissolve equal portions of the test
substance and the standard in equal
volumes of a suitable solvent, evaporate
the solutions to dryness in similar
containers under identical conditions,
and repeat the test on the residues.
In NIR
spectroscopy much of the current
interest centers around the ease of
analysis. Samples can be analyzed in
powder form or by means of reflectance
techniques, with little or no
preparation. Compliance with in-house
specifications can be determined by
computerized comparison of spectra with
spectra previously obtained from
reference materials. Many pharmaceutical
materials exhibit low absorptivity in
this spectral region, which allows
incident near-IR radiation to penetrate
samples more deeply than UV, visible, or
IR radiation. NIR spectrophotometry may
be used to observe matrix modifications
and, with proper calibration, may be
used in quantitative analysis.
In atomic
absorption spectrophotometry, the nature
of the solvent and the concentration of
solids must be given special
consideration. An ideal solvent is one
that interferes to a minimal extent in
the absorption or emission processes and
one that produces neutral atoms in the
flame. If there is a significant
difference between the surface tension
or viscosity of the test solution and
standard solution, the solutions are
aspirated or atomized at a different
rate, causing significant differences in
the signals generated. The acid
concentration of the solutions also
affects the absorption processes. Thus,
the solvents used in preparing the test
specimen and the standard should be the
same or as much alike in these respects
as possible, and should yield solutions
that are easily aspirated via the
specimen tube of the burner-aspirator.
Since undissolved solids present in the
solutions may give rise to matrix or
bulk interferences, the total
undissolved solids content in all
solutions should be kept below 2%
wherever possible.
CALCULATIONS
The application of
absorption spectrophotometry in an assay
or a test generally requires the use of
a Reference Standard. Where such a
measurement is specified in an assay, a
formula is provided in order to permit
calculation of the desired result. A
numerical constant is frequently
included in the formula. The following
derivation is provided to introduce a
logical approach to the deduction of the
constants appearing in formulas in the
assays in many monographs.
The Beer's law
relationship is valid for the solutions
of both the Reference Standard
(S) and the test specimen
(U):
in which
AS
is the absorbance of the Standard
solution of concentration
CS;
and AU
is the absorbance of the test specimen
solution of concentration
CU.
If CS
and CU
are expressed in the same units and the
absorbances of both solutions are
measured in matching cells having the
same dimensions, the absorptivity,
a, and the
cell thickness, b,
are the same; consequently, the
two equations may be combined and
rewritten to solve for
CU:
Quantities of
solid test specimens to be taken for
analysis are generally specified in mg.
Instructions for dilution are given in
the assay and, since dilute solutions
are used for absorbance measurements,
concentrations are usually expressed for
convenience in units of µg per mL.
Taking a quantity, in mg, of a test
specimen of a drug substance or solid
dosage form for analysis, it therefore
follows that a volume (VU),
in L, of solution of concentration
CU
may be prepared from the amount of test
specimen that contains a quantity
WU,
in mg, of the drug substance
[NOTE—CU
is numerically the same whether
expressed as µg per mL or mg per L],
such that:
The form in which
the formula appears in the assay in a
monograph for a solid article may be
derived by substituting
CU
of equation (3) into equation (4). In
summary, the use of equation (4), with
due consideration for any unit
conversions necessary to achieve
equality in equation (5), permits the
calculation of the constant factor (VU)
occurring in the final formula:
The same
derivation is applicable to formulas
that appear in monographs for liquid
articles that are assayed by absorption
spectrophotometry. For liquid dosage
forms, results of calculations are
generally expressed in terms of the
quantity, in mg, of drug substance in
each mL of the article. Thus it is
necessary to include in the denominator
an additional term, the volume
(V), in mL, of the test
preparation taken.
Assays in the
visible region usually call for
comparing concomitantly the absorbance
produced by the Assay
preparation with that produced by
a Standard
preparation containing
approximately an equal quantity of a USP
Reference Standard. In some situations,
it is permissible to omit the use of a
Reference Standard. This is true where
spectrophotometric assays are made with
routine frequency, and where a suitable
standard curve is available, prepared
with the respective USP Reference
Standard, and where the substance
assayed conforms to Beer's law within
the range of about 75% to 125% of the
final concentration used in the assay.
Under these circumstances, the
absorbance found in the assay may be
interpolated on the standard curve, and
the assay result calculated therefrom.
Such standard
curves should be confirmed frequently,
and always when a new spectrophotometer
or new lots of reagents are put into
use.
In
spectrophotometric assays that direct
the preparation and use of a standard
curve, it is permissible and preferable,
when the assay is employed infrequently,
not to use the standard curve but to
make the comparison directly against a
quantity of the Reference Standard
approximately equal to that taken of the
specimen, and similarly treated.
Fluorescence Spectrophotometry
The measurement of
fluorescence is a useful analytical
technique. Fluorescence
is light emitted from a substance in an
excited state that has been reached by the
absorption of radiant energy. A substance is
said to be fluorescent
if it can be made to fluoresce. Many
compounds can be assayed by procedures
utilizing either their inherent fluorescence
or the fluorescence of suitable derivatives.
Test specimens
prepared for fluorescence spectrophotometry
are usually one-tenth to one-hundredth as
concentrated as those used in absorption
spectrophotometry, for the following reason.
In analytical applications, it is preferable
that the fluorescence signal be linearly
related to the concentration; but if a test
specimen is too concentrated, a significant
part of the incoming light is absorbed by
the specimen near the cell surface, and the
light reaching the center is reduced. That
is, the specimen itself acts as an “inner
filter.” However, fluorescence
spectrophotometry is inherently a highly
sensitive technique, and concentrations of
10
5
M to 107
M frequently are used. It is necessary in
any analytical procedure to make a working
curve of fluorescence intensity versus
concentration in order to establish a linear
relationship. All readings should be
corrected for a solvent blank.
Fluorescence
measurements are sensitive to the presence
of dust and other solid particles in the
test specimen. Such impurities may reduce
the intensity of the exciting beam or give
misleading high readings because of multiple
reflections in the specimen cell. It is,
therefore, wise to eliminate solid particles
by centrifugation; filtration also may be
used, but some filter papers contain
fluorescent impurities.
Temperature regulation
is often important in fluorescence
spectrophotometry. For some substances,
fluorescence efficiency may be reduced by as
much as 1% to 2% per degree of temperature
rise. In such cases, if maximum precision is
desired, temperature-controlled specimen
cells are useful. For routine analysis, it
may be sufficient to make measurements
rapidly enough so that the specimen does not
heat up appreciably from exposure to the
intense light source. Many fluorescent
compounds are light-sensitive. Exposed in a
fluorometer, they may be photo-degraded into
more or less fluorescent products. Such
effects may be detected by observing the
detector response in relationship to time,
and may be reduced by attenuating the light
source with filters or screens.
Change of solvent may
markedly affect the intensity and spectral
distribution of fluorescence. It is
inadvisable, therefore, to alter the solvent
specified in established methods without
careful preliminary investigation. Many
compounds are fluorescent in organic
solvents but virtually nonfluorescent in
water; thus, a number of solvents should be
tried before it is decided whether or not a
compound is fluorescent. In many organic
solvents, the intensity of fluorescence is
increased by elimination of dissolved
oxygen, which has a strong quenching effect.
Oxygen may be removed by bubbling an inert
gas such as nitrogen or helium through the
test specimen.
A semiquantitative
measure of the strength of fluorescence is
given by the ratio of the fluorescence
intensity of a test specimen and that of a
standard obtained with the same instrumental
settings. Frequently, a solution of stated
concentration of quinine in 0.1 N sulfuric
acid or fluorescein in 0.1 N sodium
hydroxide is used as a reference standard.
Light-Scattering
Turbidity can be
measured with a standard photoelectric
filter photometer or spectrophotometer,
preferably with illumination in the blue
portion of the spectrum. Nephelometric
measurements require an instrument with a
photocell placed so as to receive scattered
rather than transmitted light; this geometry
applies also to fluorometers, so that, in
general, fluorometers can be used as
nephelometers, by proper selection of
filters. A ratio turbidimeter combines the
technology of 90
nephelometry and turbidimetry: it contains
photocells that receive and measure
scattered light at a 90
angle from the sample as well as receiving
and measuring the forward scatter in front
of the sample; it also measures light
transmitted directly through the sample.
Linearity is attained by calculating the
ratio of the 90
angle scattered light measurement to the sum
of the forward scattered light measurement
and the transmitted light measurement. The
benefit of using a ratio turbidimetry system
is that the measurement of stray light
becomes negligible.
In practice, it is
advisable to ensure that settling of the
particles being measured is negligible. This
is usually accomplished by including a
protective colloid in the liquid suspending
medium. It is important that results be
interpreted by comparison of readings with
those representing known concentrations of
suspended matter, produced under precisely
the same conditions.
Turbidimetry or
nephelometry may be useful for the
measurement of precipitates formed by the
interaction of highly dilute solutions of
reagents, or other particulate matter, such
as suspensions of bacterial cells. In order
that consistent results may be achieved, all
variables must be carefully controlled.
Where such control is possible, extremely
dilute suspensions may be measured.
The specimen solute is
dissolved in the solvent at several
different accurately known concentrations,
the choice of concentrations being dependent
on the molecular weight of the solute and
ranging from 1% for Mw
= 10,000 to 0.01% for Mw
= 1,000,000. Each solution must be very
carefully cleaned before measurement by
repeated filtration through fine filters. A
dust particle in the solution vitiates the
intensity of the scattered light measured. A
criterion for a clear solution is that the
dissymmetry, 45
/135
scattered intensity ratio, has attained a
minimum.
The turbidity and
refractive index of the solutions are
measured. From the general 90
light-scattering equation, a plot of
HC/
versus C is made
and extrapolated to infinite dilution, and
the weight-average molecular weight,
M, is calculated
from the intercept, 1/ M.
Visual
Comparison
Where a color or a
turbidity comparison is directed,
color-comparison tubes that are matched as
closely as possible in internal diameter and
in all other respects should be used. For
color comparison, the tubes should be viewed
downward, against a white background, with
the aid of a light source directed from
beneath the bottoms of the tubes, while for
turbidity comparison the tubes should be
viewed horizontally, against a dark
background, with the aid of a light source
directed from the sides of the tubes.
In conducting limit
tests that involve a comparison of colors in
two like containers (e.g., matched
color-comparison tubes), a suitable
instrument, rather than the unaided eye, may
be used.
1
USP29
National Institute of Standards and Technology (NIST),
Gaithersburg, MD 20899: “Spectral Transmittance
Characteristics of Holmium Oxide in Perchloric
Acid,” J. Res. Natl. Bur. Stds.
90, No. 2, 115
(1985).
USP29
The performance of an uncertified filter should be
checked against a certified standard.
2
For
further detail regarding checks on photometric scale
of a spectrophotometer, reference may be made to the
following NIST publications: J.
Res. Nalt. Bur. Stds.
76A, 469 (1972) [re: SRM 93l, “Liquid
Absorbance Standards for Ultraviolet and Visible
Spectrophotometry” as well as potassium chromate and
potassium dichromate]; NIST Spec.
Publ. 260–116 (1994) [re: SRM 930 and SRM
1930, “Glass Filters for Spectrophotometry”.USP29
Auxiliary Information— Staff Liaison : Gary E. Ritchie, M.Sc., Scientific Fellow
Expert
Committee : (GC05) General Chapters 05
USP29–NF24
Page 2770
Pharmacopeial
Forum : Volume No. 30(5) Page 1703
Phone
Number : 1-301-816-8353
Change to read:
1225
VALIDATION OF COMPENDIAL
 PROCEDURES1S
(USP29)
Change
to read:
Test procedures for
assessment of the quality levels of
pharmaceutical
articles1S
(USP29) are subject to various
requirements. According to Section 501 of the
Federal Food, Drug, and Cosmetic Act, assays and
specifications in monographs of the United
States Pharmacopeia and the National Formulary
constitute legal standards. The Current Good
Manufacturing Practice regulations [21 CFR
211.194(a)] require that test methods, which are
used for assessing compliance of pharmaceutical
articles1S
(USP29) with established
specifications, must meet proper standards of
accuracy and reliability. Also, according to
these regulations [21 CFR 211.194(a)(2)], users
of analytical methods described in
USP–NF are not
required to validate the accuracy and
reliability of these methods, but merely verify
their suitability under actual conditions of
use. Recognizing the legal status of
USP and
NF standards, it is
essential, therefore, that proposals for
adoption of new or revised compendial analytical
procedures1S
(USP29) be supported by sufficient
laboratory data to document their validity.
The text of this
information chapter harmonizes, to the extent
possible, with the Tripartite International
Conference on Harmonization (ICH) documents
Validation of Analytical
Procedures and the
Methodology extension text, which are
concerned with analytical procedures included as
part of registration applications submitted
within the EC, Japan, and the USA.
1S
(USP29)
Change
to read:
SUBMISSIONS TO THE COMPENDIA
Submissions to the
compendia for new or revised analytical
procedures1S
(USP29) should contain sufficient
information to enable members of the
USP
Council of Experts and its Expert Committees1S
(USP29) to evaluate the relative
merit of proposed procedures. In most cases,
evaluations involve assessment of the clarity
and completeness of the description of the
analytical
procedures,1S
(USP29) determination of the need
for the
procedures,1S
(USP29) and documentation that
they have been appropriately validated.
Information may vary depending upon the type of
method involved. However, in most cases a
submission will consist of the following
sections.
Rationale—
This section should identify the need for the
procedure1S
(USP29) and describe the capability of
the specific
procedure1S
(USP29) proposed and why it is
preferred over other types of determinations. For
revised procedures, a comparison should be provided
of limitations of the current compendial
procedure1S
(USP29) and advantages offered by the
proposed
procedure.1S
(USP29)
Proposed
Analytical Procedure— This section should
contain a complete description of the analytical
procedure1S
(USP29) sufficiently detailed to
enable persons “skilled in the art” to replicate it.
The write-up should include all important
operational parameters and specific instructions
such as preparation of reagents, performance of
system suitability tests, description of blanks
used, precautions, and explicit formulas for
calculation of test results.
Data
Elements— This section should provide
thorough and complete documentation of the
validation of the analytical
procedure.1S
(USP29) It should include summaries of
experimental data and calculations substantiating
each of the applicable analytical performance
characteristics. These characteristics are described
in the following section.
Change
to read:
VALIDATION
Validation of an
analytical
procedure1S
(USP29) is the process by which it
is established, by laboratory studies, that the
performance characteristics of the
procedure1S
(USP29) meet the requirements for
the intended analytical applications. Typical
analytical performance characteristics that
should be considered in the validation of the
types of
procedures1S
(USP29) described in this document
are listed in
Table 1.
Because opinions may differ with respect to
terminology and use, each of the performance
characteristics is defined in the next section
of this chapter, along with a delineation of a
typical method or methods by which it may be
measured.
Table
1. Typical Analytical Characteristics
Used in Method Validation
In the case of compendial
procedures,1S
(USP29) revalidation may be
necessary in the following cases: a submission
to the USP of a revised analytical
procedure;1S
(USP29) or the use of an
established general
procedure1S
(USP29) with a new product or raw
material (see below in Data
Elements Required for Validation).
The ICH documents give
guidance on the necessity for revalidation in
the following circumstances: changes in the
synthesis of the drug substance; changes in the
composition of the drug product; and changes in
the analytical procedure.
Analytical Performance Characteristics
Definition— The accuracy of an
analytical
procedure1S
(USP29) is the closeness of
test results obtained by that
procedure1S
(USP29) to the true value. The
accuracy of an analytical
procedure1S
(USP29) should be established
across its range.
Determination— In the case of the
assay of a drug substance, accuracy may be
determined by application of the analytical
procedure1S
(USP29) to an analyte of known
purity (e.g., a Reference Standard) or by
comparison of the results of the
procedure1S
(USP29) with those of a
second, well-characterized
procedure,1S
(USP29) the accuracy of which
has been stated or defined.
In the case of
the assay of a drug in a formulated
product, accuracy may be determined
by application of the analytical
procedure1S
(USP29) to synthetic
mixtures of the drug product
components to which known amounts of
analyte have been added within the
range of the
procedure.1S
(USP29) If it is not
possible to obtain samples of all
drug product components, it may be
acceptable either to add known
quantities of the analyte to the
drug product (i.e., “to spike”) or
to compare results with those of a
second, well-characterized
procedure,1S
(USP29) the accuracy
of which has been stated or defined.
In the case of
quantitative analysis of impurities,
accuracy should be assessed on
samples (of drug substance or drug
product) spiked with known amounts
of impurities. Where it is not
possible to obtain samples of
certain impurities or degradation
products, results should be compared
with those obtained by an
independent
procedure.1S
(USP29) In the absence
of other information, it may be
necessary to calculate the amount of
an impurity based on comparison of
its response to that of the drug
substance; the ratio of the
responses of equal amounts of the
impurity and the drug substance
(relative1S
(USP29) response
factor) should be used if known.
Accuracy is
calculated as the percentage of
recovery by the assay of the known
added amount of analyte in the
sample, or as the difference between
the mean and the accepted true
value, together with confidence
intervals.
The ICH
documents recommend that accuracy
should be assessed using a minimum
of nine determinations over a
minimum of three concentration
levels, covering the specified range
(i.e., three concentrations and
three replicates of each
concentration).
Assessment
of accuracy can be accomplished in a
variety of ways, including
evaluating the recovery of the
analyte (percent recovery) across
the range of the assay, or
evaluating the linearity of the
relationship between estimated and
actual concentrations. The
statistically preferred criterion is
that the confidence interval for the
slope be contained in an interval
around 1.0, or alternatively, that
the slope be close to 1.0. In either
case, the interval or the definition
of closeness should be specified in
the validation protocol. The
acceptance criterion will depend on
the assay and its variability and on
the product. Setting an acceptance
criterion based on the lack of
statistical significance of the test
of the null hypothesis that the
slope is 1.0 is not an acceptable
approach.1S
(USP29)
Precision
Definition— The precision of an
analytical
procedure1S
(USP29) is the degree of
agreement among individual test results when
the
procedure1S
(USP29) is applied repeatedly
to multiple samplings of a homogeneous
sample. The precision of an analytical
procedure1S
(USP29) is usually expressed
as the standard deviation or relative
standard deviation (coefficient of
variation) of a series of measurements.
Precision may be a measure of either the
degree of reproducibility or of
repeatability of the analytical
procedure1S
(USP29) under normal operating
conditions. In this context, reproducibility
refers to the use of the analytical
procedure in different laboratories, as in a
collaborative study. Intermediate precision
(also
known as ruggedness)1S
(USP29) expresses
within-laboratory variation, as on different
days, or with different analysts or
equipment within the same laboratory.
Repeatability refers to the use of the
analytical procedure within a laboratory
over a short period of time using the same
analyst with the same equipment.
1S
(USP29)
Determination— The precision of an
analytical
procedure1S
(USP29) is determined by
assaying a sufficient number of aliquots of
a homogeneous sample to be able to calculate
statistically valid estimates of standard
deviation or relative standard deviation
(coefficient of variation). Assays in this
context are independent analyses of samples
that have been carried through the complete
analytical procedure from sample preparation
to final test result.
The ICH
documents recommend that
repeatability should be assessed
using a minimum of nine
determinations covering the
specified range for the procedure
(i.e., three concentrations and
three replicates of each
concentration or using a minimum of
six determinations at 100% of the
test concentration).
Specificity
Definition— The ICH documents define
specificity as the ability to assess
unequivocally the analyte in the presence of
components that may be expected to be
present, such as impurities, degradation
products, and matrix components. Lack of
specificity of an individual analytical
procedure may be compensated by other
supporting analytical procedures.
[NOTE—Other
reputable international authorities (IUPAC,
AOAC-I)1S
(USP29) have preferred the
term “selectivity,” reserving “specificity”
for those procedures that are completely
selective.] For
the
tests
discussed1S
(USP29) below, the above
definition has the following implications:
Identification Tests: ensure the
identity of the analyte.
Purity Tests: ensure that all the
analytical procedures performed allow an
accurate statement of the content of
impurities of an analyte (e.g., related
substances test, heavy metals limit,
organic volatile
impurities).1S
(USP29)
Assays: provide an exact result,
which allows an accurate statement on
the content or potency of the analyte in
a sample.
Determination— In the case of
qualitative analyses (identification tests),
the ability to select between compounds of
closely related structure that are likely to
be present should be demonstrated. This
should be confirmed by obtaining positive
results (perhaps by comparison to a known
reference material) from samples containing
the analyte, coupled with negative results
from samples that do not contain the analyte
and by confirming that a positive response
is not obtained from materials structurally
similar to or closely related to the
analyte.
In the case of
analytical
procedures1S
(USP29) for
impurities, specificity may be
established by spiking the drug
substance or product with
appropriate levels of impurities and
demonstrating that these impurities
are determined with appropriate
accuracy and precision.
In the case of
the assay, demonstration of
specificity requires that it can be
shown that the procedure is
unaffected by the presence of
impurities or excipients. In
practice, this can be done by
spiking the drug substance or
product with appropriate levels of
impurities or excipients and
demonstrating that the assay result
is unaffected by the presence of
these extraneous materials.
If impurity or
degradation product standards are
unavailable, specificity may be
demonstrated by comparing the test
results of samples containing
impurities or degradation products
to a second well-characterized
procedure (e.g., a Pharmacopeial or
other validated procedure). These
comparisons should include samples
stored under relevant stress
conditions (e.g., light, heat,
humidity, acid/base hydrolysis,
oxidation). In the case of the
assay, the results should be
compared; in the case of
chromatographic impurity tests, the
impurity profiles should be
compared.
The ICH
documents state that when
chromatographic procedures are used,
representative chromatograms should
be presented to demonstrate the
degree of selectivity, and peaks
should be appropriately labeled.
Peak purity tests (e.g., using diode
array or mass spectrometry) may be
useful to show that the analyte
chromatographic peak is not
attributable to more than one
component.
Detection Limit
Definition— The detection limit is a
characteristic of limit tests. It is the
lowest amount of analyte in a sample that
can be detected, but not necessarily
quantitated, under the stated experimental
conditions. Thus, limit tests merely
substantiate that the amount of analyte is
above or below a certain level. The
detection limit is usually expressed as the
concentration of analyte (e.g., percentage,
parts per billion) in the sample.
Determination— For noninstrumental
procedures,1S
(USP29) the detection limit is
generally determined by the analysis of
samples with known concentrations of analyte
and by establishing the minimum level at
which the analyte can be reliably detected.
For
instrumental procedures, the same
approach1S
(USP29) may be used as
for noninstrumental
procedures.1S
(USP29) In the case of
procedures1S
(USP29) submitted for
consideration as official compendial
procedures,1S
(USP29) it is almost
never necessary to determine the
actual detection limit. Rather, the
detection limit is shown to be
sufficiently low by the analysis of
samples with known concentrations of
analyte above and below the required
detection level. For example, if it
is required to detect an impurity at
the level of 0.1%, it should be
demonstrated that the procedure will
reliably detect the impurity at that
level.
In the case of
instrumental analytical procedures
that exhibit background noise, the
ICH documents describe a common
approach, which is to compare
measured signals from samples with
known low concentrations of analyte
with those of blank samples. The
minimum concentration at which the
analyte can reliably be detected is
established. Typically acceptable
signal-to-noise ratios are 2:1 or
3:1. Other approaches depend on the
determination of the slope of the
calibration curve and the standard
deviation of responses. Whatever
method is used, the detection limit
should be subsequently validated by
the analysis of a suitable number of
samples known to be near, or
prepared at, the detection limit.
Quantitation Limit
Definition— The quantitation limit is
a characteristic of quantitative assays for
low levels of compounds in sample matrices,
such as impurities in bulk drug substances
and degradation products in finished
pharmaceuticals. It is the lowest amount of
analyte in a sample that can be determined
with acceptable precision and accuracy under
the stated experimental conditions. The
quantitation limit is expressed as the
concentration of analyte (e.g., percentage,
parts per billion) in the sample.
Determination— For noninstrumental
procedures,1S
(USP29) the quantitation limit
is generally determined by the analysis of
samples with known concentrations of analyte
and by establishing the minimum level at
which the analyte can be determined with
acceptable accuracy and precision.
For
instrumental procedures, the same
approach1S
(USP29) may be used as
for noninstrumental
procedures.1S
(USP29) In the case of
procedures1S
(USP29) submitted for
consideration as official compendial
procedures,1S
(USP29) it is almost
never necessary to determine the
actual quantitation limit. Rather,
the quantitation limit is shown to
be sufficiently low by the analysis
of samples with known concentrations
of analyte above and below the
quantitation level. For example, if
it is required that an analyte be
assayed at the level of 0.1 mg per
tablet, it should be demonstrated
that the
procedure1S
(USP29) will reliably
quantitate the analyte at that
level.
In the case of
instrumental analytical
procedures1S
(USP29) that exhibit
background noise, the ICH documents
describe a common approach, which is
to compare measured signals from
samples with known low
concentrations of analyte with those
of blank samples. The minimum
concentration at which the analyte
can reliably be quantified is
established. A typically acceptable
signal-to-noise ratio is 10:1. Other
approaches depend on the
determination of the slope of the
calibration curve and the standard
deviation of responses. Whatever
approach1S
(USP29) is used, the
quantitation limit should be
subsequently validated by the
analysis of a suitable number of
samples known to be near, or
prepared at, the quantitation limit.
Linearity and Range
Definition of Linearity— The
linearity of an analytical
procedure1S
(USP29) is its ability to
elicit test results that are directly, or by
a well-defined mathematical transformation,
proportional to the concentration of analyte
in samples within a given range.
Thus,
in this section, “linearity” refers to the
linearity of the relationship of
concentration and assay measurement. In some
cases, to attain linearity, the
concentration and/or the measurement may be
transformed. (Note that the weighting
factors used in the regression analysis may
change when a transformation is applied.)
Possible transformations may include log,
square root, or reciprocal, although other
transformations are acceptable. If linearity
is not attainable, a nonlinear model may be
used. The goal is to have a model, whether
linear or nonlinear, that describes closely
the concentration-response relationship.1S
(USP29)
Definition of Range— The range of an
analytical
procedure1S
(USP29) is the interval
between the upper and lower levels of
analyte (including these levels) that have
been demonstrated to be determined with a
suitable level of precision, accuracy, and
linearity using the
procedure1S
(USP29) as written. The range
is normally expressed in the same units as
test results (e.g., percent, parts per
million) obtained by the analytical
procedure.1S
(USP29)
Determination of Linearity and Range—
Linearity should be established across the
range of the analytical procedure. It should
be established initially by visual
examination of a plot of signals as a
function of analyte concentration of
content. If there appears to be a linear
relationship, test results should be
established by appropriate statistical
methods (e.g., by calculation of a
regression line by the method of least
squares).
1S
(USP29) Data from the
regression line itself may be helpful to
provide mathematical estimates of the degree
of linearity. The correlation coefficient,
y-intercept, slope
of the regression line, and residual sum of
squares should be submitted.
The range of
the
procedure1S
(USP29) is validated
by verifying that the analytical
procedure1S
(USP29) provides
acceptable precision, accuracy, and
linearity when applied to samples
containing analyte at the extremes
of the range as well as within the
range.
ICH recommends
that, for the establishment of
linearity, a minimum of five
concentrations normally be used. It
is also recommended that the
following minimum specified ranges
should be considered:
Assay of a Drug Substance (or a finished
product): from 80% to 120% of the
test concentration.
Determination of an Impurity:
from 50% to 120% of the
acceptance
criterion.1S
(USP29)
For Content Uniformity: a minimum
of 70% to 130% of the test
concentration, unless a wider or more
appropriate range based on the nature of
the dosage form (e.g., metered-dose
inhalers) is justified.
For Dissolution Testing:
±20% over the specified range (e.g., if
the
acceptance
criteria1S
(USP29) for a
controlled-release product cover a
region from 20%, after 1 hour, and up to
90%, after 24 hours, the validated range
would be 0% to 110% of the label claim).
1S
(USP29)
Robustness
Definition— The robustness of an
analytical
procedure1S
(USP29) is a measure of its
capacity to remain unaffected by small but
deliberate variations in
procedural
parameters listed in the procedure
documentation and provides an indication of
its suitability1S
(USP29) during normal usage.
Robustness
may be determined during development of the
analytical procedure.1S
(USP29)
System Suitability
If measurements
are susceptible to variations in
analytical conditions, these should be
suitably controlled, or a precautionary
statement should be included in the
procedure.1S
(USP29) One consequence of
the evaluation of robustness and
ruggedness should be that a series of
system suitability parameters is
established to ensure that the validity
of the analytical
procedure1S
(USP29) is maintained
whenever used. Typical variations are
the stability of analytical solutions,
different equipment, and different
analysts. In the case of liquid
chromatography, typical variations are
the pH of the mobile phase, the mobile
phase composition, different lots or
suppliers of columns, the temperature,
and the flow rate. In the case of gas
chromatography, typical variations are
different lots or suppliers of columns,
the temperature, and the flow rate.
System suitability
tests are based on the concept that the
equipment, electronics, analytical
operations, and samples to be analyzed
constitute an integral system that can
be evaluated as such. System suitability
test parameters to be established for a
particular
procedure1S
(USP29) depend on the type
of
procedure1S
(USP29) being evaluated.
They are especially important in the
case of chromatographic
procedures.
Submissions1S
(USP29) to the USP should
make note of the requirements under the
System Suitability
section in the general test chapter
Chromatography
621.
Data
Elements Required for
1S
(USP29) Validation
Compendial
test
requirements1S
(USP29) vary from highly
exacting analytical determinations to
subjective evaluation of attributes.
Considering this
broad
variety,1S
(USP29) it is only logical
that different test
procedures1S
(USP29) require different
validation schemes. This chapter covers only
the most common categories of
tests1S
(USP29) for which validation
data should be required. These categories
are as follows:
Category I— Analytical
procedures1S
(USP29) for quantitation of major
components of bulk drug substances or active
ingredients (including preservatives) in
finished pharmaceutical products.
Category II— Analytical
procedures1S
(USP29) for determination of
impurities in bulk drug substances or
degradation compounds in finished pharmaceutical
products. These
procedures1S
(USP29) include quantitative
assays and limit tests.
Category III— Analytical
procedures1S
(USP29) for determination of
performance characteristics (e.g., dissolution,
drug release).
Category IV— Identification tests.
For each
1S
(USP29) category,
different analytical information is
needed. Listed in
Table 2 are data elements that
are normally required for each of
these
categories.1S
(USP29)
Table 2. Data
Elements Required for
1S
(USP29) Validation
Already
established general
procedures
(e.g., titrimetric determination of
water, bacterial endotoxins)1S
(USP29) should be
revalidated to verify their accuracy
(and absence of possible interference)
when used for a new product or raw
material.
The validity of an
analytical
procedure1S
(USP29) can be verified
only by laboratory studies. Therefore,
documentation of the successful
completion of such studies is a basic
requirement for determining whether a
procedure1S
(USP29) is suitable for
its intended application(s).
Current
compendial procedures are also subject
to regulations that require
demonstration of suitability under
actual conditions of use.1S
(USP29) Appropriate
documentation should accompany any
proposal for new or revised compendial
analytical procedures.Auxiliary Information— Staff Liaison : Horacio N. Pappa, Ph.D., Sr. Scientist and Latin American Liaison
Expert
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41
WEIGHTS AND BALANCES
The intent of this section is
to bring the requirements for weights into
conformity with American National Standard ANSI/ASTM
E617, “Laboratory Weights and Precision Mass
Standards.” This standard is incorporated by
reference and should be consulted for full
descriptions and information on the tolerances and
construction of weights.1
Pharmacopeial tests and assays require balances that
vary in capacity, sensitivity, and reproducibility.
Unless otherwise specified, when substances are to
be “accurately weighed” for
Assay, the weighing is to be performed with a
weighing device whose measurement uncertainty
(random plus systematic error) does not exceed 0.1%
of the reading. Measurement uncertainty is
satisfactory if three times the standard deviation
of not less than ten replicate weighings divided by
the amount weighed, does not exceed 0.001. Unless
otherwise specified, for titrimetric limits tests,
the weighing shall be performed to provide the
number of significant figures in the weight of the
analyte that corresponds to the number of
significant figures in the concentration of the
titrant.
The class designations below
are in order of increasing tolerances.
Class 1.1 weights are used for
calibration of low-capacity, high-sensitivity
balances. They are available in various
denominations from 1 to 500 mg. The tolerance for
any denomination in this class is 5 µg. They are
recommended for calibration of balances using
optical or electrical methods for accurately
weighing quantities below 20 mg.
Class 1 weights are designated
as high-precision standards for calibration. They
may be used for weighing accurately quantities below
20 mg. (For weights of 10 g or less, the
requirements of class 1 are met by
USP XXI class M.)
Class 2 weights are used as
working standards for calibration, built-in weights
for analytical balances, and laboratory weights for
routine analytical work. (The requirements of class
2 are met by USP XXI class
S.)2
Class 3 and class 4 weights
are used with moderate-precision laboratory
balances. (Class 3 requirements are met by
USP XXI class S-1; class 4
requirements are met by USP XXI
class P.)2
A weight class is chosen so
that the tolerance of the weights used does not
exceed 0.1% of the amount weighed. Generally, class
2 may be used for quantities greater than 20 mg,
class 3 for quantities of greater than 50 mg, and
class 4 for quantities of greater than 100 mg.
Weights should be calibrated periodically,
preferably against an absolute standard weight.
1 Copies of ASTM
Standard E 617-81 (Reapproved 1985) may be obtained
from the American Society for Testing and Materials,
1916 Race Street, Philadelphia, PA 19103.
2
Note that the designations S and P no longer
designate weight classes but rather weight grades,
that is, design limitations such as range of density
of materials, surface area, surface finish,
corrosion resistance, and hardness.
Auxiliary Information— Staff Liaison : Horacio N. Pappa, Ph.D., Sr. Scientist and Latin American Liaison
Expert
Committee : (GC05) General Chapters 05
USP29–NF24
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Phone
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Pharmaceutical aerosols are
products that are packaged under pressure and
contain therapeutically active ingredients that are
released upon activation of an appropriate valve
system. They are intended for topical application to
the skin as well as local application into the nose
(nasal aerosols), mouth (lingual aerosols), or lungs
(inhalation aerosols). These products may be fitted
with valves enabling either continuous or
metered-dose delivery; hence, the terms “[DRUG]
Metered Topical Aerosols,” “[DRUG] Metered Nasal
Aerosols,” etc.
The term “aerosol” refers to
the fine mist of spray that results from most
pressurized systems. However, the term has been
broadly misapplied to all self-contained pressurized
products, some of which deliver foams or semisolid
fluids. In the case of Inhalation
Aerosols, the particle size of the delivered
medication must be carefully controlled, and the
average size of the particles should be under 5 µm.
These products are also known as metered-dose
inhalers (MDIs). Other aerosol sprays may contain
particles up to several hundred micrometers in
diameter.
The basic components of an
aerosol system are the container, the propellant,
the concentrate containing the active ingredient(s),
the valve, and the actuator. The nature of these
components determines such characteristics as
particle size distribution, uniformity of dose for
metered valves, delivery rate, wetness and
temperature of the spray, spray pattern and velocity
or plume geometry, foam density, and fluid
viscosity.
Types of
Aerosols
Aerosols consist of
two-phase (gas and liquid) or three-phase (gas,
liquid, and solid or liquid) systems. The
two-phase aerosol consists of a solution of
active ingredients in liquefied propellant and
the vaporized propellant. The solvent is
composed of the propellant or a mixture of the
propellant and cosolvents such as alcohol,
propylene glycol, and polyethylene glycols,
which are often used to enhance the solubility
of the active ingredients.
Three-phase systems
consist of a suspension or emulsion of the
active ingredient(s) in addition to the
vaporized propellants. A suspension consists of
the active ingredient(s) that may be dispersed
in the propellant system with the aid of
suitable excipients such as wetting agents
and/or solid carriers such as talc or colloidal
silicas.
A foam aerosol is an
emulsion containing one or more active
ingredients, surfactants, aqueous or nonaqueous
liquids, and the propellants. If the propellant
is in the internal (discontinuous) phase (i.e.,
of the oil-in-water type), a stable foam is
discharged; and if the propellant is in the
external (continuous) phase (i.e., of the
water-in-oil type), a spray or a quick-breaking
foam is discharged.
Propellants
The propellant supplies
the necessary pressure within an aerosol system
to expel material from the container and, in
combination with other components, to convert
the material into the desired physical form.
Propellants may be broadly classified as
liquefied or compressed gases having vapor
pressures generally exceeding atmospheric
pressure. Propellants within this definition
include various hydrocarbons, especially
halogenated derivatives of methane, ethane, and
propane, low molecular weight hydrocarbons such
as the butanes and pentanes, and compressed
gases such as carbon dioxide, nitrogen, and
nitrous oxide. Mixtures of propellants are
frequently used to obtain desirable pressure,
delivery, and spray characteristics. A good
propellant system should have the proper vapor
pressure characteristics consistent with the
other aerosol components.
Valves
The primary function of
the valve is to regulate the flow of the
therapeutic agent and propellant from the
container. The spray characteristics of the
aerosol are influenced by orifice dimension,
number, and location. Most aerosol valves
provide for continuous spray operation and are
used on most topical products. However,
pharmaceutical products for oral or nasal
inhalation often utilize metered-dose valves
that must deliver a uniform quantity of spray
upon each valve activation. The accuracy and
reproducibility of the doses delivered from
metering valves are generally good, comparing
favorably to the uniformity of solid dosage
forms such as tablets and capsules. However,
when aerosol packages are stored improperly, or
when they have not been used for long periods of
time, valves must be primed before use.
Materials used for the manufacture of valves
should be inert to the formulations used.
Plastic, rubber, aluminum, and stainless steel
valve components are commonly used. Metered-dose
valves must deliver an accurate dose within
specified tolerances.
Actuators
An actuator is the fitting
attached to an aerosol valve stem, which when
depressed or moved, opens the valve, and directs
the spray containing the drug preparation to the
desired area. The actuator usually indicates the
direction in which the preparation is dispensed
and protects the hand or finger from the
refrigerant effects of the propellant. Actuators
incorporate an orifice that may vary widely in
size and shape. The size of this orifice, the
expansion chamber design, and the nature of the
propellant and formulation influence the
delivered dose as well as the physical
characteristics of the spray, foam, or stream of
solid particles dispensed. For inhalation
aerosols, an actuator capable of delivering the
medication in the proper particle size range and
with the appropriate spray pattern and plume
geometry is utilized.
Containers
Aerosol containers usually
are made of glass, plastic, or metal, or a
combination of these materials. Glass containers
must be precisely engineered to provide the
maximum in pressure safety and impact
resistance. Plastics may be employed to coat
glass containers for improved safety
characteristics, or to coat metal containers to
improve corrosion resistance and enhance
stability of the formulation. Suitable metals
include stainless steel, aluminum, and
tin-plated steel. Extractables or leachables
(e.g., drawing oils, cleaning agents, etc.) and
particulates on the internal surfaces of
containers should be controlled.
Manufacture
Aerosols are usually
prepared by one of two general processes. In the
“cold-fill” process, the concentrate (generally
cooled to a temperature below 0
)
and the refrigerated propellant are measured
into open containers (usually chilled). The
valve-actuator assembly is then crimped onto the
container to form a pressure-tight seal. During
the interval between propellant addition and
crimping, sufficient volatilization of
propellant occurs to displace air from the
container. In the “pressure-fill” method, the
concentrate is placed in the container, and
either the propellant is forced under pressure
through the valve orifice after the valve is
sealed, or the propellant is allowed to flow
under the valve cap and then the valve assembly
is sealed (“under-the-cap” filling). In both
cases of the “pressure-fill” method, provision
must be made for evacuation of air by means of
vacuum or displacement with a small amount of
propellant vapor. Manufacturing process controls
usually include monitoring of proper formulation
and propellant fill weight and pressure testing,
leak testing, and valve function testing of the
finished aerosol. Microbiological attributes
should also be controlled.
Extractable Substances
Since pressurized inhalers
and aerosols are normally formulated with
organic solvents as the propellant or the
vehicle, leaching of extractables from the
elastomeric and plastic components into the
formulation is a potentially serious problem.
Thus, the composition and the quality of
materials used in the manufacture of the valve
components (e.g., stem, gaskets, housing, etc.)
must be carefully selected and controlled. Their
compatibility with formulation components should
be well established so as to prevent distortion
of the valve components and to minimize changes
in the medication delivery, leak rate, and
impurity profile of the drug product over time.
The extractable profiles of a representative
sample of each of the elastomeric and plastic
components of the valve should be established
under specified conditions and should be
correlated to the extractable profile of the
aged drug product or placebo, to ensure
reproducible quality and purity of the drug
product. Extractables, which may include
polynuclear aromatics, nitrosamines,
vulcanization accelerators, antioxidants,
plasticizers, monomers, etc., should be
identified and minimized wherever possible.
Specifications and limits
for individual and total extractables from
different valve components may require the use
of different analytical methods. In addition,
the standard USP biological testing (see the
general test chapters
Biological Reactivity Tests, In Vitro
87
and
Biological Reactivity Tests, In Vivo
88)
as well as other safety data may be needed.
Labeling
Medicinal aerosols should
contain at least the following warning
information on the label as in accordance with
appropriate regulations.
Warning—
Avoid inhaling. Avoid spraying into eyes or onto
other mucous membranes.
NOTE—The statement “Avoid inhaling” is
not necessary for preparations specifically
designed for use by inhalation. The phrase “or
other mucous membranes” is not necessary for
preparations specifically designed for use on
mucous membranes.
Warning—
Contents under pressure. Do not puncture or
incinerate container. Do not expose to heat or store
at temperatures above 120
F (49
C). Keep out of reach of children.
In addition to the
aforementioned warnings, the label of a drug
packaged in an aerosol container in which
the propellant consists in whole or in part
of a halocarbon or hydrocarbon shall, where
required under regulations of the FDA, bear
either of the following warnings:
Warning—
Do not inhale directly; deliberate inhalation of
contents can cause death.
Warning—
Use only as directed; intentional misuse by
deliberately concentrating and inhaling the contents
can be harmful or fatal.
711
DISSOLUTION
This test is provided to
determine compliance with the dissolution
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. Where the
label states that an article is enteric-coated, and
a dissolution or disintegration test that does not
specifically state that it is to be applied to
enteric-coated articles is included in the
individual monograph, the test for
Delayed-Release Articles
under
Drug
Release
724
is applied unless otherwise specified in the
individual monograph. For hard or soft gelatin
capsules and gelatin-coated tablets that do not
conform to the Dissolution
specification, repeat the test as follows. Where
water or a medium with a pH of less than 6.8 is
specified as the Medium in
the individual monograph, the same
Medium specified may be
used with the addition of purified pepsin that
results in an activity of 750,000 Units or less per
1000 mL. For media with a pH of 6.8 or greater,
pancreatin can be added to produce not more than
1750 USP Units of protease activity per 1000 mL.USP Reference Standards 11—
USP Prednisone
Tablets RS (Dissolution
Calibrator, Disintegrating).
USP Salicylic
Acid Tablets RS
(Dissolution Calibrator,
Nondisintegrating). Apparatus 1— The assembly consists of the following: a covered vessel made of glass or other inert, transparent material1 ; a motor; a metallic drive shaft; and a cylindrical basket. The vessel is partially 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 ± 0.5
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 beyond 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 L, the height is 160 mm to 210 mm and its
inside diameter is 98 mm to 106 mm; for a nominal
capacity of 2 L, 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 L, 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
evaporation2.
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-regulating device is used that allows
the shaft rotation speed to be selected and maintained
at the rate specified in the individual monograph,
within ±4%.
Shaft and basket components of the stirring
element are fabricated of stainless steel, type
316 or equivalent, to the specifications shown
in
Figure
1.
;)
Fig. 1. Basket Stirring
Element
Unless otherwise specified
in the individual monograph, use 40-mesh cloth.
A basket having a gold coating 0.0001 inch (2.5
µm) 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. ;)
Fig. 2. Paddle Stirring
Element
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 certificate for that calibrator in the apparatus tested. Dissolution Medium— Use the solvent specified in the individual 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, specimens are to be withdrawn only at the stated times, within a tolerance of ±2%. Procedure for Capsules, Uncoated Tablets, and Plain Coated Tablets— Place the stated volume of the Dissolution Medium (±1%) in the vessel of the apparatus specified in the individual monograph, assemble the apparatus, equilibrate the Dissolution Medium 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
Dissolution Medium and the top
of the rotating basket or blade, not less than 1 cm 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
calculation. 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
monograph4.
Repeat 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 contents
of not fewer than 6 capsules as completely as
possible, and dissolve the empty capsule shells
in the specified volume of
Dissolution 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 Tablets, and Plain Coated Tablets— Use this procedure where Procedure for a Pooled Sample is specified in the individual monograph. 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 withdrawn, 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 monograph, the requirements are met if
the quantities of active ingredient dissolved from
the units tested conform to the accompanying
Acceptance
Table.
Continue testing through the three stages unless the
results conform at either S1
or S2. The quantity,
Q, is the amount of
dissolved active ingredient specified in the
individual monograph, expressed as a percentage of
the labeled content; the 5%, 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.
Acceptance Table
Pooled
Sample— Unless otherwise specified in the
individual monograph, the requirements are met if
the quantities of active ingredient dissolved from
the pooled sample conform to the accompanying
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
dissolved active ingredient specified in the
individual monograph, expressed as a percentage of
the labeled content.
Acceptance Table for a
Pooled Sample
1 The materials should
not sorb, react, or interfere with the specimen
being tested.
2
If a cover is used, it provides sufficient openings
to allow ready insertion of the thermometer and
withdrawal of specimens.
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 µm or less, with vigorous
stirring, and continue stirring under vacuum for
about 5 minutes. Other validated 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 substances that
would interfere with the analysis.
Auxiliary Information— Staff Liaison : William E. Brown, Scientist
Expert
Committee : (BPC05) Biopharmaceutics05
USP29–NF24
Page 2673
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Number : 1-301-816-8380
Capsules are solid dosage
forms in which the drug is enclosed within either a
hard or soft soluble container or “shell.” The
shells are usually formed from gelatin; however,
they also may be made from starch or other suitable
substances. Hard-shell capsule sizes range from No.
5, the smallest, to No. 000, which is the largest,
except for veterinary sizes. However, size No. 00
generally is the largest size acceptable to
patients. Size 0 hard gelatin capsules having an
elongated body (known as size OE) also are
available, which provide greater fill capacity
without an increase in diameter. Hard gelatin
capsules consist of two, telescoping cap and body
pieces. Generally, there are unique grooves or
indentations molded into the cap and body portions
to provide a positive closure when fully engaged,
which helps prevent the accidental separation of the
filled capsules during shipping and handling.
Positive closure also may be affected by spot fusion
(“welding”) of the cap and body pieces together
through direct thermal means or by application of
ultrasonic energy. Factory-filled hard gelatin
capsules may be completely sealed by banding, a
process in which one or more layers of gelatin are
applied over the seam of the cap and body, or by a
liquid fusion process wherein the filled capsules
are wetted with a hydroalcoholic solution that
penetrates into the space where the cap overlaps the
body, and then dried. Hard-shell capsules made from
starch consist of two, fitted cap and body pieces.
Since the two pieces do not telescope or interlock
positively, they are sealed together at the time of
filling to prevent their separation. Starch capsules
are sealed by the application of a hydroalcoholic
solution to the recessed section of the cap
immediately prior to its being placed onto the body.
The banding of hard-shell
gelatin capsules or the liquid sealing of hard-shell
starch capsules enhances consumer safety by making
the capsules difficult to open without causing
visible, obvious damage, and may improve the
stability of contents by limiting O2
penetration. Industrially filled hard-shell capsules
also are often of distinctive color and shape or are
otherwise marked to identify them with the
manufacturer. Additionally, such capsules may be
printed axially or radially with strengths, product
codes, etc. Pharmaceutical-grade printing inks are
usually based on shellac and employ FDA-approved
pigments and lake dyes.
In extemporaneous prescription
practice, hard-shell capsules may be hand-filled;
this permits the prescriber a latitude of choice in
selecting either a single drug or a combination of
drugs at the exact dosage level considered best for
the individual patient. This flexibility gives
hard-shell capsules an advantage over compressed
tablets and soft-shell capsules as a dosage form.
Hard-shell capsules are usually formed from gelatins
having relatively high gel strength. Either type may
be used, but blends of pork skin and bone gelatin
are often used to optimize shell clarity and
toughness. Hard-shell capsules also may be formed
from starch or other suitable substances. Hard-shell
capsules may also contain colorants, such as D&C and
FD&C dyes or the various iron oxides, opaquing
agents such as titanium dioxide, dispersing agents,
hardening agents such as sucrose, and preservatives.
They normally contain between 10% and 15% water.
Hard gelatin capsules are made
by a process that involves dipping shaped pins into
gelatin solutions, after which the gelatin films are
dried, trimmed, and removed from the pins, and the
body and cap pieces are joined. Starch capsules are
made by injection molding a mixture of starch and
water, after which the capsules are dried. A
separate mold is used for caps and bodies, and the
two parts are supplied separately. The empty
capsules should be stored in tight containers until
they are filled. Since gelatin is of animal origin
and starch is of vegetable origin, capsules made
with these materials should be protected from
potential sources of microbial contamination.
Hard-shell capsules typically
are filled with powder, beads, or granules. Inert
sugar beads (nonpareils) may be coated with active
ingredients and coating compositions that provide
extended-release profiles or enteric properties.
Alternatively, larger-dose active ingredients
themselves may be suitably formed into pellets and
then coated. Semisolids or liquids also may be
filled into hard-shell capsules; however, when the
latter are encapsulated, one of the sealing
techniques must be employed to prevent leakage.
In hard gelatin capsule
filling operations, the body and cap of the shell
are separated prior to dosing. In hard starch shell
filling operations, the bodies and caps are supplied
separately and are fed into separate hoppers of the
filling machine. Machines employing various dosing
principles may be employed to fill powders into
hard-shell capsules; however, most fully automatic
machines form powder plugs by compression and eject
them into empty capsule bodies. Accessories to these
machines generally are available for the other types
of fills. Powder formulations often require adding
fillers, lubricants, and glidants to the active
ingredients to facilitate encapsulation. The
formulation, as well as the method of filling,
particularly the degree of compaction, may influence
the rate of drug release. The addition of wetting
agents to the powder mass is common where the active
ingredient is hydrophobic. Disintegrants also may be
included in powder formulations to facilitate
deaggregation and dispersal of capsule plugs in the
gut. Powder formulations often may be produced by
dry blending; however, bulky formulations may
require densification by roll compaction or other
suitable granulation techniques.
Powder mixtures that tend to
liquefy may be dispensed in hard-shell capsules if
an absorbent such as magnesium carbonate, colloidal
silicon dioxide, or other suitable substance is
used. Potent drugs are often mixed with an inert
diluent before being filled into capsules. Where two
mutually incompatible drugs are prescribed together,
it is sometimes possible to place one in a small
capsule and then enclose it with the second drug in
a larger capsule. Incompatible drugs also can be
separated by placing coated pellets or tablets, or
soft-shell capsules of one drug into the capsule
shell before adding the second drug.
Thixotropic semisolids may be
formed by gelling liquid drugs or vehicles with
colloidal silicas or powdered high molecular weight
polyethylene glycols. Various waxy or fatty
compounds may be used to prepare semisolid matrices
by fusion.
Soft-shell capsules made from
gelatin (sometimes called softgels) or other
suitable material require
large-scale
production methods. The soft gelatin shell is
somewhat thicker than that of hard-shell capsules
and may be plasticized by the addition of a polyol
such as sorbitol or glycerin. The ratio of dry
plasticizer to dry gelatin determines the “hardness”
of the shell and may be varied to accommodate
environmental conditions as well as the nature of
the contents. Like hard shells, the shell
composition may include approved dyes and pigments,
opaquing agents such as titanium dioxide, and
preservatives. Flavors may be added and up to 5%
sucrose may be included for its sweetness and to
produce a chewable shell. Soft gelatin shells
normally contain 6% to 13% water. Soft-shell
capsules also may be printed with a product code,
strength, etc. In most cases, soft-shell capsules
are filled with liquid contents. Typically, active
ingredients are dissolved or suspended in a liquid
vehicle. Classically, an oleaginous vehicle such as
a vegetable oil was used; however, nonaqueous,
water-miscible liquid vehicles such as the
lower-molecular-weight polyethylene glycols are more
common today due to fewer bioavailability problems.
Available in a wide variety of
sizes and shapes, soft-shell capsules are both
formed, filled, and sealed in the same machine;
typically, this is a rotary die process, although a
plate process or reciprocating die process also may
be employed. Soft-shell capsules also may be
manufactured in a bubble process that forms seamless
spherical capsules. With suitable equipment, powders
and other dry solids also may be filled into
soft-shell capsules.
Liquid-filled capsules of
either type involve similar formulation
technology
and offer similar advantages and limitations. For
instance, both may offer advantages over dry-filled
capsules and tablets in content uniformity and drug
dissolution. Greater homogeneity is possible in
liquid systems, and liquids can be metered more
accurately. Drug dissolution may benefit because the
drug may already be in solution or at least
suspended in a hydrophilic vehicle. However, the
contact between the hard or soft shell and its
liquid content is more intimate than exists with
dry-filled capsules, and this may enhance the
chances for undesired interactions. The liquid
nature of capsule contents presents different
technological problems than dry-filled capsules in
regard to disintegration and dissolution testing.
From formulation, technological, and
biopharmaceutical points of view, liquid-filled
capsules of either type have more in common than
liquid-filled and dry-filled capsules having the
same shell composition. Thus, for compendial
purposes, standards and methods should be
established based on capsule contents rather than on
whether the contents are filled into hard- or
soft-shell capsules.
DELAYED-RELEASE CAPSULES
Capsules may be coated,
or, more commonly, encapsulated granules may be
coated to resist releasing the drug in the
gastric fluid of the stomach where a delay is
important to alleviate potential problems of
drug inactivation or gastric mucosal irritation.
The term “delayed-release” is used for
Pharmacopeial monographs on enteric coated
capsules that are intended to delay the release
of medicament until the capsule has passed
through the stomach, and the individual
monographs include tests and specifications for
Drug release (see
Drug
Release
724)
or Disintegration (see
Disintegration
701).
EXTENDED-RELEASE CAPSULES
Extended-release capsules
are formulated in such manner as to make the
contained medicament available over an extended
period of time following ingestion. Expressions
such as “prolonged-action,” “repeat-action,” and
“sustained-release” have also been used to
describe such dosage forms. However, the term
“extended-release” is used for Pharmacopeial
purposes and requirements for
Drug release (see
Drug
Release
724)
typically are specified in the individual
monographs.PRESERVATION, PACKAGING, STORAGE, AND LABELING
Containers—
The container is that which
holds the article and is or may be in direct contact
with the article. The immediate
container is that which is in direct contact with
the article at all times. The closure
is a part of the container.
Prior to being filled, the
container should be clean. Special precautions
and cleaning procedures may be necessary to
ensure that each container is clean and that
extraneous matter is not introduced into or onto
the article.
The container does not
interact physically or chemically with the
article placed in it so as to alter the
strength, quality, or purity of the article
beyond the official requirements.
The Pharmacopeial
requirements for the use of specified containers
apply also to articles as packaged by the
pharmacist or other dispenser, unless otherwise
indicated in the individual monograph.
Tamper-Evident Packaging — The container or
individual carton of a sterile article intended for
ophthalmic or otic use, except where
extemporaneously compounded for immediate dispensing
on prescription, shall be so sealed that the
contents cannot be used without obvious destruction
of the seal.
Articles intended for
sale without prescription are also required
to comply with the tamper-evident packaging
and labeling requirements of the FDA where
applicable.
Preferably, the
immediate container and/or the outer
container or
protective packaging
used by a manufacturer or distributor for
all dosage forms that are not specifically
exempt is designed so as to show evidence of
any tampering with the contents.
Light-Resistant Container
(see Light Transmission
under
Containers
661)—
A light-resistant container protects the contents
from the effects of light by virtue of the specific
properties of the material of which it is composed,
including any coating applied to it. Alternatively,
a clear and colorless or a translucent container may
be made light-resistant by means of an opaque
covering, in which case the label of the container
bears a statement that the opaque covering is needed
until the contents are to be used or administered.
Where it is directed to “protect from light” in an
individual monograph, preservation in a
light-resistant container is intended.
Where an article is
required to be packaged in a light-resistant
container, and if the container is made
light-resistant by means of an opaque
covering, a single-use, unit-dose container
or mnemonic pack for dispensing may not be
removed from the outer opaque covering prior
to dispensing.
Well-Closed Container— A well-closed
container protects the contents from extraneous
solids and from loss of the article under the
ordinary or customary conditions of handling,
shipment, storage, and distribution.
Tight
Container— A tight container protects the
contents from contamination by extraneous liquids,
solids, or vapors; from loss of the article; and
from efflorescence, deliquescence, or evaporation
under the ordinary or customary conditions of
handling, shipment, storage, and distribution; and
is capable of tight reclosure. Where a tight
container is specified, it may be replaced by a
hermetic container for a single dose of an article.
A gas cylinder is a
metallic container designed to hold a gas
under pressure. As a safety measure, for
carbon dioxide, cyclopropane, helium,
nitrous oxide,
and oxygen, the Pin-Index Safety System of
matched fittings is recommended for
cylinders of Size E or smaller.
NOTE—Where packaging and storage in a
tight container or a
well-closed container
is specified in the individual monograph, the
container used for an article when dispensed on
prescription meets the requirements under
Containers—Permeation
671.
Hermetic
Container— A hermetic container is impervious
to air or any other gas under the ordinary or
customary conditions of handling, shipment, storage,
and distribution.
Single-Unit Container— A single-unit
container is one that is designed to hold a quantity
of drug product intended for administration as a
single dose or a single finished device intended for
use promptly after the container is opened.
Preferably, the immediate container and/or the outer
container or protective packaging shall be so
designed as to show evidence of any tampering with
the contents. Each single-unit container shall be
labeled to indicate the identity, quantity and/or
strength, name of the manufacturer, lot number, and
expiration date of the article.
Single-Dose Container
(see also Containers for
Injections under
Injections
1)—
A single-dose container is a single-unit container
for articles intended for parenteral administration
only. A single-dose container is labeled as such.
Examples of single-dose containers include prefilled
syringes, cartridges, fusion-sealed containers, and
closure-sealed containers when so labeled.
Unit-Dose
Container— A unit-dose container is a
single-unit container for articles intended for
administration by other than the parenteral route as
a single dose, direct from the container.
Unit-of-Use Container— A unit-of-use
container is one that contains a specific quantity
of a drug product and that is intended to be
dispensed as such without further modification
except for the addition of appropriate labeling. A
unit-of-use container is labeled as such.
Multiple-Unit Container— A multiple-unit
container is a container that permits withdrawal of
successive portions of the contents without changing
the strength, quality, or purity of the remaining
portion.
Multiple-Dose Container
(see also Containers for
Injections under
Injections
1)—
A multiple-dose container is a multiple-unit
container for articles intended for parenteral
administration only.
Poison
Prevention Packaging Act— This act (see the
Website, www.cpsc.gov/businfo/pppa.html)
requires special packaging of most human oral
prescription drugs,
oral controlled drugs, certain nonoral prescription
drugs, certain
dietary supplements,
and many over-the-counter (OTC) drug preparations in
order to protect the public from personal injury or
illness from misuse of these preparations (16 CFR §
1700.14).
The immediate packaging of
substances regulated under the PPPA must comply
with the special packaging standards (16 CFR §
1700.15 and 16 CFR § 1700.20). The PPPA
regulations for special packaging apply to all
packaging types including reclosable,
nonclosable, and unit-dose types.
Special packaging is not
required for drugs dispensed within a hospital
setting for inpatient administration.
Manufacturers and packagers of bulk-packaged
prescription drugs do not have to use special
packaging if the drug will be repackaged by the
pharmacist. PPPA-regulated prescription drugs
may be dispensed in nonchild-resistant packaging
upon the request of the purchaser or when
directed in a legitimate prescription (15 U.S.C.
§ 1473).
Manufacturers or packagers
of PPPA-regulated OTC preparations are allowed
to package one size in nonchild-resistant
packaging as long as popular-size, special
packages are also supplied. The nonchild-resistant
package requires special labeling (18 CFR §
1700.5).
Various types of
child-resistant packages are covered in ASTM
International Standard D-3475, Standard
Classification of Child-Resistant Packaging.
Examples are included as an aid in the
understanding and comprehension of each type of
classification.
Storage
Temperature and Humidity— Specific directions are
stated in some monographs with respect to the
temperatures and humidity at which Pharmacopeial
articles shall be stored and distributed (including the
shipment of articles to the consumer) when stability
data indicate that storage and distribution at a lower
or a higher temperature and a higher humidity produce
undesirable results. Such directions apply except where
the label on an article states a different storage
temperature on the basis of stability studies of that
particular formulation. Where no specific storage
directions or limitations are provided in the individual
monograph, but the label of an article states a storage
temperature that is based on stability studies of that
particular formulation, such labeled storage directions
apply (see also
Pharmaceutical
Stability
1150).
The conditions are defined by the following terms.
Freezer—
A place in which the temperature is maintained
thermostatically between
25
and
10
(13
and 14
F).
Cold—
Any temperature not exceeding 8
(46
F).
A refrigerator is a cold
place in which the temperature is maintained
thermostatically between 2
and 8
(36
and 46
F).
Cool—
Any temperature between 8
and 15
(46
and 59
F).
An article for which storage in a
cool place is directed may, alternatively, be
stored and distributed in a
refrigerator, unless otherwise specified by
the individual monograph.
Room
Temperature— The temperature prevailing in a
working area.
Controlled
Room Temperature— A temperature maintained
thermostatically that encompasses the usual and
customary working environment of 20
to 25
(68
to 77
F);
that results in a mean kinetic temperature
calculated to be not more than 25;
and that allows for excursions between 15
and 30
(59
and 86
F)
that are experienced in pharmacies, hospitals, and
warehouses. Provided the mean kinetic temperature
remains in the allowed range, transient spikes up to
40
are permitted as long as they do not exceed 24
hours. Spikes above 40
may be permitted if the manufacturer so instructs.
Articles may be labeled for storage at “controlled
room temperature” or at “up to 25”,
or other wording based on the same mean kinetic
temperature. The mean kinetic temperature is a
calculated value that may be used as an isothermal
storage temperature that simulates the nonisothermal
effects of storage temperature variations. (See also
Pharmaceutical Stability
1150.)
An article for which
storage at Controlled
room temperature is directed may,
alternatively, be stored and distributed in
a cool place,
unless otherwise specified in the individual
monograph or on the label.
Warm—
Any temperature between 30
and 40
(86
and 104
F).
Excessive
Heat— Any temperature above 40
(104
F).
Protection
from Freezing— Where, in addition to the risk
of breakage of the container, freezing subjects an
article to loss of strength or potency, or to
destructive alteration of its characteristics, the
container label bears an appropriate instruction to
protect the article from freezing.
Dry Place—
The term “dry place” denotes a place that does not
exceed 40% average relative humidity at
Controlled Room Temperature
or the equivalent water vapor pressure at other
temperatures. The determination may be made by
direct measurement at the place or may be based on
reported climatic conditions. Determination is based
on not less than 12 equally spaced measurements that
encompass either a season, a year, or, where
recorded data demonstrate, the storage period of the
article. There may be values of up to 45% relative
humidity provided that the average value is 40%
relative humidity.
Storage in a container
validated to protect the article from
moisture vapor, including storage in bulk,
is considered a dry place.
Storage under
Nonspecific Conditions— Where no specific
directions or limitations are provided in the
Packaging and storage section
of individual monographs or in the article's labeling,
the conditions of storage shall include storage at
controlled room temperature, protection from moisture,
and, where necessary, protection from light. Articles
shall be protected from moisture, freezing, and
excessive heat, and, where necessary, from light during
shipping and distribution. Active pharmaceutical
ingredients are exempt from this requirement.
Labeling—
The term “labeling” designates all labels and other
written, printed, or graphic matter upon an immediate
container of an article or upon, or in, any package or
wrapper in which it is enclosed, except any outer
shipping container. The term “label” designates that
part of the labeling upon the immediate container.
A shipping container
containing a single article, unless such
container is also essentially the immediate
container or the outside of the consumer
package, is labeled with a minimum of product
identification (except for controlled articles),
lot number, expiration date, and conditions for
storage and distribution.
Articles in this
Pharmacopeia are subject to compliance with such
labeling requirements as may be promulgated by
governmental bodies in addition to the
Pharmacopeial requirements set forth for the
articles.
Amount of
Ingredient per Dosage Unit— The strength of a
drug product is expressed on the container label in
terms of micrograms or milligrams or grams or
percentage of the therapeutically active moiety or
drug substance, whichever form is used in the title,
unless otherwise indicated in an individual
monograph. Both the active moiety and drug substance
names and their equivalent amounts are then provided
in the labeling.
Pharmacopeial articles
in capsule, tablet, or other unit dosage
form shall be labeled to express the
quantity of each active ingredient or
recognized nutrient contained in each such
unit; except that, in the case of unit-dose
oral solutions or suspensions, whether
supplied as liquid preparations or as liquid
preparations that are constituted from
solids upon addition of a designated volume
of a specific diluent, the label shall
express the quantity of each active
ingredient or recognized nutrient delivered
under the conditions prescribed in
Deliverable Volume
698.
Pharmacopeial drug products not in unit
dosage form shall be labeled to express the
quantity of each active ingredient in each
milliliter or in each gram, or to express
the percentage of each such ingredient (see
Percentage Measurements),
except that oral liquids or solids intended
to be constituted to yield oral liquids may,
alternatively, be labeled in terms of each
5-mL portion of the liquid or resulting
liquid. Unless otherwise indicated in a
monograph or chapter, such declarations of
strength or quantity shall be stated only in
metric units (see also
Units of Potency in these
General Notices).
Use of
Leading and Terminal Zeros— In order to help
minimize the possibility of errors in the dispensing
and administration of drugs, the quantity of active
ingredient when expressed in whole numbers shall be
shown without a decimal point that is followed by a
terminal zero (e.g., express as 4 mg [not 4.0 mg]).
The quantity of active ingredient when expressed as
a decimal number smaller than 1 shall be shown with
a zero preceding the decimal point (e.g., express as
0.2 mg [not .2 mg]).
Labeling
of Salts of Drugs— It is an established
principle that Pharmacopeial articles shall have
only one official name. For purposes of saving space
on labels, and because chemical symbols for the most
common inorganic salts of drugs are well known to
practitioners as synonymous with the written forms,
the following alternatives are permitted in labeling
official articles that are salts: HCl for
hydrochloride; HBr for hydrobromide; Na for sodium;
and K for potassium. The symbols Na and K are
intended for use in abbreviating names of the salts
of organic acids; but these symbols are not used
where the word Sodium or Potassium appears at the
beginning of an official title (e.g., Phenobarbital
Na is acceptable, but Na Salicylate is not to be
written).
Labeling
Vitamin-Containing Products— The vitamin
content of an official drug product shall be stated
on the label in metric units per dosage unit. The
amounts of vitamins A, D, and E may be stated also
in USP Units. Quantities of vitamin A declared in
metric units refer to the equivalent amounts of
retinol (vitamin A alcohol). The label of a
nutritional supplement shall bear an identifying lot
number, control number, or batch number.
Labeling
Botanical-Containing Products— The label of
an herb or other botanical intended for use as a
dietary supplement bears the statement, “If you are
pregnant or nursing a baby, seek the advice of a
health professional before using this product.”
Labeling
Parenteral and Topical Preparations— The
label of a preparation intended for parenteral or
topical use states the names of all added substances
(see Added Substances in
these General Notices and
Requirements, and see
Labeling
under
Injections
1),
and, in the case of parenteral preparations, also
their amounts or proportions, except that for
substances added for adjustment of pH or to achieve
isotonicity, the label may indicate only their
presence and the reason for their addition.
Labeling
Electrolytes— The concentration and dosage of
electrolytes for replacement therapy (e.g., sodium
chloride or potassium chloride) shall be stated on
the label in milliequivalents (mEq). The label of
the product shall indicate also the quantity of
ingredient(s) in terms of weight or percentage
concentration.
Labeling
Alcohol— The content of alcohol in a liquid
preparation shall be stated on the label as a
percentage (v/v) of C2H5OH.
Special
Capsules and Tablets— The label of any form
of Capsule or Tablet intended for administration
other than by swallowing intact bears a prominent
indication of the manner in which it is to be used.
Expiration
Date and Beyond-Use Date— The label of an
official drug product or nutritional or dietary
supplement product shall bear an expiration date.
All articles shall display the expiration date so
that it can be read by an ordinary individual under
customary conditions of purchase and use. The
expiration date shall be prominently displayed in
high contrast to the background or sharply embossed,
and easily understood (e.g., “EXP 6/89,” “Exp. June
89,” or “Expires 6/89”). [NOTE—For
additional information and guidance, refer to the
Nonprescription Drug Manufacturers Association's
Voluntary Codes and Guidelines of
the OTC Medicines Industry.]
The monographs for
some preparations state how the expiration
date that shall appear on the label is to be
determined. In the absence of a specific
requirement in the individual monograph for
a drug product or nutritional supplement,
the label shall bear an expiration date
assigned for the particular formulation and
package of the article, with the following
exception: the label need not show an
expiration date in the case of a drug
product or nutritional supplement packaged
in a container that is intended for sale
without prescription and the labeling of
which states no dosage limitations, and
which is stable for not less than 3 years
when stored under the prescribed conditions.
Where an official
article is required to bear an expiration
date, such article shall be dispensed solely
in, or from, a container labeled with an
expiration date, and the date on which the
article is dispensed shall be within the
labeled expiry period. The expiration date
identifies the time during which the article
may be expected to meet the requirements of
the Pharmacopeial monograph, provided it is
kept under the prescribed storage
conditions. The expiration date limits the
time during which the article may be
dispensed or used. Where an expiration date
is stated only in terms of the month and the
year, it is a representation that the
intended expiration date is the last day of
the stated month. The beyond-use date is the
date after which an article must not be
used. The dispenser shall place on the label
of the prescription container a suitable
beyond-use date to limit the patient's use
of the article based on any information
supplied by the manufacturer and the
General Notices and
Requirements of this Pharmacopeia.
The beyond-use date placed on the label
shall not be later than the expiration date
on the manufacturer's container.
For articles requiring
constitution prior to use, a suitable
beyond-use date for the constituted product
shall be identified in the labeling.
For all other dosage
forms, in determining an appropriate period
of time during which a prescription drug may
be retained by a patient after its
dispensing, the dispenser shall take into
account, in addition to any other relevant
factors, the nature of the drug; the
container in which it was packaged by the
manufacturer and the expiration date
thereon; the characteristics of the
patient's container, if the article is
repackaged for dispensing; the expected
storage conditions to which the article may
be exposed; any unusual storage conditions
to which the article may be exposed; and the
expected length of time of the course of
therapy. The dispenser shall, on taking into
account the foregoing, place on the label of
a multiple-unit container a suitable
beyond-use date to limit the patient's use
of the article. Unless otherwise specified
in the individual monograph, or in the
absence of stability data to the contrary,
such beyond-use date shall be not later than
(a) the expiration date on the
manufacturer's container, or (b) 1 year from
the date the drug is dispensed, whichever is
earlier. For nonsterile solid and liquid
dosage forms that are packaged in
single-unit and unit-dose containers, the
beyond-use date shall be 1 year from the
date the drug is packaged into the
single-unit or unit-dose container or the
expiration date on the manufacturer’s
container, whichever is earlier, unless
stability data or the manufacturer’s
labeling indicates otherwise.
The dispenser must
maintain the facility where the dosage forms
are packaged and stored, at a temperature
such that the mean kinetic temperature is
not greater than 25
.
The plastic material used in packaging the
dosage forms must afford better protection
than polyvinyl chloride, which does not
provide adequate protection against moisture
permeation. Records must be kept of the
temperature of the facility where the dosage
forms are stored, and of the plastic
materials used in packaging.
Pharmaceutical Compounding— The label on the
container or package of an official compounded
preparation shall bear a beyond-use date. The
beyond-use date is the date after which a compounded
preparation is not to be used. Because compounded
preparations are intended for administration
immediately or following short-term storage, their
beyond-use dates may be assigned based on criteria
different from those applied to assigning expiration
dates to manufactured drug products.
The monograph for an
official compounded preparation typically
includes a beyond-use requirement that
states the time period following the date of
compounding during which the preparation,
properly stored, is to be used. In the
absence of stability information that is
applicable to a specific drug and
preparation, recommendations for maximum
beyond-use dates have been devised for
nonsterile compounded drug preparations that
are packaged in tight, light-resistant
containers and stored at controlled room
temperature unless otherwise indicated (see
Stability Criteria and
Beyond-Use Dating under
Stability of Compounded
Preparations in the general tests
chapter
Pharmaceutical Compounding—Nonsterile
Preparations
795).
Guidelines for
Packaging and Storage Statements in
USP–NF Monographs—
In order to provide users of the
USP–NF with proper guidance on how to package and
store compendial articles, every monograph in the
USP–NF is required to have a
packaging and storage specification.
For those instances where,
for some reason, storage information is not yet
found in the Packaging and
storage specification of a monograph, the
section Storage Under
Nonspecific Conditions is included in the
General Notices as
interim guidance. The Storage
Under Nonspecific Conditions statement is
not meant to substitute for the inclusion of
proper, specific storage information in the
Packaging and storage
statement of any monograph.
For the packaging portion
of the statement, the choice of containers is
given in the General Notices
and includes Light-Resistant
Container, Well-Closed Container, Tight
Container, Hermetic Container, Single-Unit
Container, Single-Dose Container, Unit-Dose
Container, and
Unit-of-Use Container. For most
preparations, the choice is determined by the
container in which it is to be dispensed (e.g.,
tight, well-closed, hermetic, unit-of-use, etc).
For active pharmaceutical ingredients (APIs),
the choice would appear to be tight,
well-closed, or, where needed, a light-resistant
container. For excipients, given their typical
nature as large-volume commodity items, with
containers ranging from drums to tank cars, a
well-closed container is an appropriate default.
Therefore, in the absence of data indicating a
need for a more protective class of container,
the phrase “Preserve in well-closed containers”
should be used as a default for excipients.
For the storage portion of
the statement, the choice of storage
temperatures presented in the
General Notices includes
Freezer, Cold, Cool, Room
Temperature, Controlled Room Temperature, Warm,
Excessive Heat, and
Protection from Freezing. The definition
of a dry place is provided if protection from
humidity is important.
For most preparations, the
choice is determined by the experimentally
determined stability of the preparation and may
include any of the previously stated storage
conditions as determined by the manufacturer.
For APIs that are expected to be retested before
incorporation into a preparation, a more general
and nonrestrictive condition may be desired. In
this case, the specification “room temperature”
(the temperature prevailing in a working area)
should suffice. The use of the permissive room
temperature condition reflects the stability of
an article over a wide temperature range. For
excipients, the phrase “No storage requirements
specified” in the Packaging
and storage statement of the monograph
would be appropriate.
Because most APIs in the
USP–NF have associated
Reference Standards, special efforts should be
considered to ensure that the Reference
Standards' storage conditions correspond to the
conditions indicated in the
USP–NF monographs.
The Packaging, Storage,
and Distribution Expert Committee may review
questionable Packaging and
storage statements on a case-by-case
basis. In cases where the
Packaging and storage statements are
incomplete, the monographs would move forward to
publication while the
Packaging and storage statements are
temporarily deferred.
PRESERVATION, PACKAGING, STORAGE, AND LABELING
Containers—
The container is that which
holds the article and is or may be in direct contact
with the article. The immediate
container is that which is in direct contact with
the article at all times. The closure
is a part of the container.
Prior to being filled, the
container should be clean. Special precautions
and cleaning procedures may be necessary to
ensure that each container is clean and that
extraneous matter is not introduced into or onto
the article.
The container does not
interact physically or chemically with the
article placed in it so as to alter the
strength, quality, or purity of the article
beyond the official requirements.
The Pharmacopeial
requirements for the use of specified containers
apply also to articles as packaged by the
pharmacist or other dispenser, unless otherwise
indicated in the individual monograph.
Tamper-Evident Packaging — The container or
individual carton of a sterile article intended for
ophthalmic or otic use, except where
extemporaneously compounded for immediate dispensing
on prescription, shall be so sealed that the
contents cannot be used without obvious destruction
of the seal.
Articles intended for
sale without prescription are also required
to comply with the tamper-evident packaging
and labeling requirements of the FDA where
applicable.
Preferably, the
immediate container and/or the outer
container or
protective packaging
used by a manufacturer or distributor for
all dosage forms that are not specifically
exempt is designed so as to show evidence of
any tampering with the contents.
Light-Resistant Container
(see Light Transmission
under
Containers
661)—
A light-resistant container protects the contents
from the effects of light by virtue of the specific
properties of the material of which it is composed,
including any coating applied to it. Alternatively,
a clear and colorless or a translucent container may
be made light-resistant by means of an opaque
covering, in which case the label of the container
bears a statement that the opaque covering is needed
until the contents are to be used or administered.
Where it is directed to “protect from light” in an
individual monograph, preservation in a
light-resistant container is intended.
Where an article is
required to be packaged in a light-resistant
container, and if the container is made
light-resistant by means of an opaque
covering, a single-use, unit-dose container
or mnemonic pack for dispensing may not be
removed from the outer opaque covering prior
to dispensing.
Well-Closed Container— A well-closed
container protects the contents from extraneous
solids and from loss of the article under the
ordinary or customary conditions of handling,
shipment, storage, and distribution.
Tight
Container— A tight container protects the
contents from contamination by extraneous liquids,
solids, or vapors; from loss of the article; and
from efflorescence, deliquescence, or evaporation
under the ordinary or customary conditions of
handling, shipment, storage, and distribution; and
is capable of tight reclosure. Where a tight
container is specified, it may be replaced by a
hermetic container for a single dose of an article.
A gas cylinder is a
metallic container designed to hold a gas
under pressure. As a safety measure, for
carbon dioxide, cyclopropane, helium,
nitrous oxide,
and oxygen, the Pin-Index Safety System of
matched fittings is recommended for
cylinders of Size E or smaller.
NOTE—Where packaging and storage in a
tight container or a
well-closed container
is specified in the individual monograph, the
container used for an article when dispensed on
prescription meets the requirements under
Containers—Permeation
671.
Hermetic
Container— A hermetic container is impervious
to air or any other gas under the ordinary or
customary conditions of handling, shipment, storage,
and distribution.
Single-Unit Container— A single-unit
container is one that is designed to hold a quantity
of drug product intended for administration as a
single dose or a single finished device intended for
use promptly after the container is opened.
Preferably, the immediate container and/or the outer
container or protective packaging shall be so
designed as to show evidence of any tampering with
the contents. Each single-unit container shall be
labeled to indicate the identity, quantity and/or
strength, name of the manufacturer, lot number, and
expiration date of the article.
Single-Dose Container
(see also Containers for
Injections under
Injections
1)—
A single-dose container is a single-unit container
for articles intended for parenteral administration
only. A single-dose container is labeled as such.
Examples of single-dose containers include prefilled
syringes, cartridges, fusion-sealed containers, and
closure-sealed containers when so labeled.
Unit-Dose
Container— A unit-dose container is a
single-unit container for articles intended for
administration by other than the parenteral route as
a single dose, direct from the container.
Unit-of-Use Container— A unit-of-use
container is one that contains a specific quantity
of a drug product and that is intended to be
dispensed as such without further modification
except for the addition of appropriate labeling. A
unit-of-use container is labeled as such.
Multiple-Unit Container— A multiple-unit
container is a container that permits withdrawal of
successive portions of the contents without changing
the strength, quality, or purity of the remaining
portion.
Multiple-Dose Container
(see also Containers for
Injections under
Injections
1)—
A multiple-dose container is a multiple-unit
container for articles intended for parenteral
administration only.
Poison
Prevention Packaging Act— This act (see the
Website, www.cpsc.gov/businfo/pppa.html)
requires special packaging of most human oral
prescription drugs,
oral controlled drugs, certain nonoral prescription
drugs, certain
dietary supplements,
and many over-the-counter (OTC) drug preparations in
order to protect the public from personal injury or
illness from misuse of these preparations (16 CFR §
1700.14).
The immediate packaging of
substances regulated under the PPPA must comply
with the special packaging standards (16 CFR §
1700.15 and 16 CFR § 1700.20). The PPPA
regulations for special packaging apply to all
packaging types including reclosable,
nonclosable, and unit-dose types.
Special packaging is not
required for drugs dispensed within a hospital
setting for inpatient administration.
Manufacturers and packagers of bulk-packaged
prescription drugs do not have to use special
packaging if the drug will be repackaged by the
pharmacist. PPPA-regulated prescription drugs
may be dispensed in nonchild-resistant packaging
upon the request of the purchaser or when
directed in a legitimate prescription (15 U.S.C.
§ 1473).
Manufacturers or packagers
of PPPA-regulated OTC preparations are allowed
to package one size in nonchild-resistant
packaging as long as popular-size, special
packages are also supplied. The
nonchild-resistant package requires special
labeling (18 CFR § 1700.5).
Various types of
child-resistant packages are covered in ASTM
International Standard D-3475, Standard
Classification of Child-Resistant Packaging.
Examples are included as an aid in the
understanding and comprehension of each type of
classification.
Storage
Temperature and Humidity— Specific directions are
stated in some monographs with respect to the
temperatures and humidity at which Pharmacopeial
articles shall be stored and distributed (including the
shipment of articles to the consumer) when stability
data indicate that storage and distribution at a lower
or a higher temperature and a higher humidity produce
undesirable results. Such directions apply except where
the label on an article states a different storage
temperature on the basis of stability studies of that
particular formulation. Where no specific storage
directions or limitations are provided in the individual
monograph, but the label of an article states a storage
temperature that is based on stability studies of that
particular formulation, such labeled storage directions
apply (see also
Pharmaceutical
Stability
1150).
The conditions are defined by the following terms.
Freezer—
A place in which the temperature is maintained
thermostatically between
25
and
10
(13
and 14
F).
Cold—
Any temperature not exceeding 8
(46
F).
A refrigerator is a cold
place in which the temperature is maintained
thermostatically between 2
and 8
(36
and 46
F).
Cool—
Any temperature between 8
and 15
(46
and 59
F).
An article for which storage in a
cool place is directed may, alternatively, be
stored and distributed in a
refrigerator, unless otherwise specified by
the individual monograph.
Room
Temperature— The temperature prevailing in a
working area.
Controlled
Room Temperature— A temperature maintained
thermostatically that encompasses the usual and
customary working environment of 20
to 25
(68
to 77
F);
that results in a mean kinetic temperature
calculated to be not more than 25;
and that allows for excursions between 15
and 30
(59
and 86
F)
that are experienced in pharmacies, hospitals, and
warehouses. Provided the mean kinetic temperature
remains in the allowed range, transient spikes up to
40
are permitted as long as they do not exceed 24
hours. Spikes above 40
may be permitted if the manufacturer so instructs.
Articles may be labeled for storage at “controlled
room temperature” or at “up to 25”,
or other wording based on the same mean kinetic
temperature. The mean kinetic temperature is a
calculated value that may be used as an isothermal
storage temperature that simulates the nonisothermal
effects of storage temperature variations. (See also
Pharmaceutical Stability
1150.)
An article for which
storage at Controlled
room temperature is directed may,
alternatively, be stored and distributed in
a cool place,
unless otherwise specified in the individual
monograph or on the label.
Warm—
Any temperature between 30
and 40
(86
and 104
F).
Excessive
Heat— Any temperature above 40
(104
F).
Protection
from Freezing— Where, in addition to the risk
of breakage of the container, freezing subjects an
article to loss of strength or potency, or to
destructive alteration of its characteristics, the
container label bears an appropriate instruction to
protect the article from freezing.
Dry Place—
The term “dry place” denotes a place that does not
exceed 40% average relative humidity at
Controlled Room Temperature
or the equivalent water vapor pressure at other
temperatures. The determination may be made by
direct measurement at the place or may be based on
reported climatic conditions. Determination is based
on not less than 12 equally spaced measurements that
encompass either a season, a year, or, where
recorded data demonstrate, the storage period of the
article. There may be values of up to 45% relative
humidity provided that the average value is 40%
relative humidity.
Storage in a container
validated to protect the article from
moisture vapor, including storage in bulk,
is considered a dry place.
Storage under
Nonspecific Conditions— Where no specific
directions or limitations are provided in the
Packaging and storage section
of individual monographs or in the article's labeling,
the conditions of storage shall include storage at
controlled room temperature, protection from moisture,
and, where necessary, protection from light. Articles
shall be protected from moisture, freezing, and
excessive heat, and, where necessary, from light during
shipping and distribution. Active pharmaceutical
ingredients are exempt from this requirement.
Labeling—
The term “labeling” designates all labels and other
written, printed, or graphic matter upon an immediate
container of an article or upon, or in, any package or
wrapper in which it is enclosed, except any outer
shipping container. The term “label” designates that
part of the labeling upon the immediate container.
A shipping container
containing a single article, unless such
container is also essentially the immediate
container or the outside of the consumer
package, is labeled with a minimum of product
identification (except for controlled articles),
lot number, expiration date, and conditions for
storage and distribution.
Articles in this
Pharmacopeia are subject to compliance with such
labeling requirements as may be promulgated by
governmental bodies in addition to the
Pharmacopeial requirements set forth for the
articles.
Amount of
Ingredient per Dosage Unit— The strength of a
drug product is expressed on the container label in
terms of micrograms or milligrams or grams or
percentage of the therapeutically active moiety or
drug substance, whichever form is used in the title,
unless otherwise indicated in an individual
monograph. Both the active moiety and drug substance
names and their equivalent amounts are then provided
in the labeling.
Pharmacopeial articles
in capsule, tablet, or other unit dosage
form shall be labeled to express the
quantity of each active ingredient or
recognized nutrient contained in each such
unit; except that, in the case of unit-dose
oral solutions or suspensions, whether
supplied as liquid preparations or as liquid
preparations that are constituted from
solids upon addition of a designated volume
of a specific diluent, the label shall
express the quantity of each active
ingredient or recognized nutrient delivered
under the conditions prescribed in
Deliverable Volume
698.
Pharmacopeial drug products not in unit
dosage form shall be labeled to express the
quantity of each active ingredient in each
milliliter or in each gram, or to express
the percentage of each such ingredient (see
Percentage Measurements),
except that oral liquids or solids intended
to be constituted to yield oral liquids may,
alternatively, be labeled in terms of each
5-mL portion of the liquid or resulting
liquid. Unless otherwise indicated in a
monograph or chapter, such declarations of
strength or quantity shall be stated only in
metric units (see also
Units of Potency in these
General Notices).
Use of
Leading and Terminal Zeros— In order to help
minimize the possibility of errors in the dispensing
and administration of drugs, the quantity of active
ingredient when expressed in whole numbers shall be
shown without a decimal point that is followed by a
terminal zero (e.g., express as 4 mg [not 4.0 mg]).
The quantity of active ingredient when expressed as
a decimal number smaller than 1 shall be shown with
a zero preceding the decimal point (e.g., express as
0.2 mg [not .2 mg]).
Labeling
of Salts of Drugs— It is an established
principle that Pharmacopeial articles shall have
only one official name. For purposes of saving space
on labels, and because chemical symbols for the most
common inorganic salts of drugs are well known to
practitioners as synonymous with the written forms,
the following alternatives are permitted in labeling
official articles that are salts: HCl for
hydrochloride; HBr for hydrobromide; Na for sodium;
and K for potassium. The symbols Na and K are
intended for use in abbreviating names of the salts
of organic acids; but these symbols are not used
where the word Sodium or Potassium appears at the
beginning of an official title (e.g., Phenobarbital
Na is acceptable, but Na Salicylate is not to be
written).
Labeling
Vitamin-Containing Products— The vitamin
content of an official drug product shall be stated
on the label in metric units per dosage unit. The
amounts of vitamins A, D, and E may be stated also
in USP Units. Quantities of vitamin A declared in
metric units refer to the equivalent amounts of
retinol (vitamin A alcohol). The label of a
nutritional supplement shall bear an identifying lot
number, control number, or batch number.
Labeling
Botanical-Containing Products— The label of
an herb or other botanical intended for use as a
dietary supplement bears the statement, “If you are
pregnant or nursing a baby, seek the advice of a
health professional before using this product.”
Labeling
Parenteral and Topical Preparations— The
label of a preparation intended for parenteral or
topical use states the names of all added substances
(see Added Substances in
these General Notices and
Requirements, and see
Labeling
under
Injections
1),
and, in the case of parenteral preparations, also
their amounts or proportions, except that for
substances added for adjustment of pH or to achieve
isotonicity, the label may indicate only their
presence and the reason for their addition.
Labeling
Electrolytes— The concentration and dosage of
electrolytes for replacement therapy (e.g., sodium
chloride or potassium chloride) shall be stated on
the label in milliequivalents (mEq). The label of
the product shall indicate also the quantity of
ingredient(s) in terms of weight or percentage
concentration.
Labeling
Alcohol— The content of alcohol in a liquid
preparation shall be stated on the label as a
percentage (v/v) of C2H5OH.
Special
Capsules and Tablets— The label of any form
of Capsule or Tablet intended for administration
other than by swallowing intact bears a prominent
indication of the manner in which it is to be used.
Expiration
Date and Beyond-Use Date— The label of an
official drug product or nutritional or dietary
supplement product shall bear an expiration date.
All articles shall display the expiration date so
that it can be read by an ordinary individual under
customary conditions of purchase and use. The
expiration date shall be prominently displayed in
high contrast to the background or sharply embossed,
and easily understood (e.g., “EXP 6/89,” “Exp. June
89,” or “Expires 6/89”). [NOTE—For
additional information and guidance, refer to the
Nonprescription Drug Manufacturers Association's
Voluntary Codes and Guidelines of
the OTC Medicines Industry.]
The monographs for
some preparations state how the expiration
date that shall appear on the label is to be
determined. In the absence of a specific
requirement in the individual monograph for
a drug product or nutritional supplement,
the label shall bear an expiration date
assigned for the particular formulation and
package of the article, with the following
exception: the label need not show an
expiration date in the case of a drug
product or nutritional supplement packaged
in a container that is intended for sale
without prescription and the labeling of
which states no dosage limitations, and
which is stable for not less than 3 years
when stored under the prescribed conditions.
Where an official
article is required to bear an expiration
date, such article shall be dispensed solely
in, or from, a container labeled with an
expiration date, and the date on which the
article is dispensed shall be within the
labeled expiry period. The expiration date
identifies the time during which the article
may be expected to meet the requirements of
the Pharmacopeial monograph, provided it is
kept under the prescribed storage
conditions. The expiration date limits the
time during which the article may be
dispensed or used. Where an expiration date
is stated only in terms of the month and the
year, it is a representation that the
intended expiration date is the last day of
the stated month. The beyond-use date is the
date after which an article must not be
used. The dispenser shall place on the label
of the prescription container a suitable
beyond-use date to limit the patient's use
of the article based on any information
supplied by the manufacturer and the
General Notices and
Requirements of this Pharmacopeia.
The beyond-use date placed on the label
shall not be later than the expiration date
on the manufacturer's container.
For articles requiring
constitution prior to use, a suitable
beyond-use date for the constituted product
shall be identified in the labeling.
For all other dosage
forms, in determining an appropriate period
of time during which a prescription drug may
be retained by a patient after its
dispensing, the dispenser shall take into
account, in addition to any other relevant
factors, the nature of the drug; the
container in which it was packaged by the
manufacturer and the expiration date
thereon; the characteristics of the
patient's container, if the article is
repackaged for dispensing; the expected
storage conditions to which the article may
be exposed; any unusual storage conditions
to which the article may be exposed; and the
expected length of time of the course of
therapy. The dispenser shall, on taking into
account the foregoing, place on the label of
a multiple-unit container a suitable
beyond-use date to limit the patient's use
of the article. Unless otherwise specified
in the individual monograph, or in the
absence of stability data to the contrary,
such beyond-use date shall be not later than
(a) the expiration date on the
manufacturer's container, or (b) 1 year from
the date the drug is dispensed, whichever is
earlier. For nonsterile solid and liquid
dosage forms that are packaged in
single-unit and unit-dose containers, the
beyond-use date shall be 1 year from the
date the drug is packaged into the
single-unit or unit-dose container or the
expiration date on the manufacturer’s
container, whichever is earlier, unless
stability data or the manufacturer’s
labeling indicates otherwise.
The dispenser must
maintain the facility where the dosage forms
are packaged and stored, at a temperature
such that the mean kinetic temperature is
not greater than 25
.
The plastic material used in packaging the
dosage forms must afford better protection
than polyvinyl chloride, which does not
provide adequate protection against moisture
permeation. Records must be kept of the
temperature of the facility where the dosage
forms are stored, and of the plastic
materials used in packaging.
Pharmaceutical Compounding— The label on the
container or package of an official compounded
preparation shall bear a beyond-use date. The
beyond-use date is the date after which a compounded
preparation is not to be used. Because compounded
preparations are intended for administration
immediately or following short-term storage, their
beyond-use dates may be assigned based on criteria
different from those applied to assigning expiration
dates to manufactured drug products.
The monograph for an
official compounded preparation typically
includes a beyond-use requirement that
states the time period following the date of
compounding during which the preparation,
properly stored, is to be used. In the
absence of stability information that is
applicable to a specific drug and
preparation, recommendations for maximum
beyond-use dates have been devised for
nonsterile compounded drug preparations that
are packaged in tight, light-resistant
containers and stored at controlled room
temperature unless otherwise indicated (see
Stability Criteria and
Beyond-Use Dating under
Stability of Compounded
Preparations in the general tests
chapter
Pharmaceutical Compounding—Nonsterile
Preparations
795).
Guidelines for
Packaging and Storage Statements in
USP–NF Monographs—
In order to provide users of the
USP–NF with proper guidance on how to package and
store compendial articles, every monograph in the
USP–NF is required to have a
packaging and storage specification.
For those instances where,
for some reason, storage information is not yet
found in the Packaging and
storage specification of a monograph, the
section Storage Under
Nonspecific Conditions is included in the
General Notices as
interim guidance. The Storage
Under Nonspecific Conditions statement is
not meant to substitute for the inclusion of
proper, specific storage information in the
Packaging and storage
statement of any monograph.
For the packaging portion
of the statement, the choice of containers is
given in the General Notices
and includes Light-Resistant
Container, Well-Closed Container, Tight
Container, Hermetic Container, Single-Unit
Container, Single-Dose Container, Unit-Dose
Container, and
Unit-of-Use Container. For most
preparations, the choice is determined by the
container in which it is to be dispensed (e.g.,
tight, well-closed, hermetic, unit-of-use, etc).
For active pharmaceutical ingredients (APIs),
the choice would appear to be tight,
well-closed, or, where needed, a light-resistant
container. For excipients, given their typical
nature as large-volume commodity items, with
containers ranging from drums to tank cars, a
well-closed container is an appropriate default.
Therefore, in the absence of data indicating a
need for a more protective class of container,
the phrase “Preserve in well-closed containers”
should be used as a default for excipients.
For the storage portion of
the statement, the choice of storage
temperatures presented in the
General Notices includes
Freezer, Cold, Cool, Room
Temperature, Controlled Room Temperature, Warm,
Excessive Heat, and
Protection from Freezing. The definition
of a dry place is provided if protection from
humidity is important.
For most preparations, the
choice is determined by the experimentally
determined stability of the preparation and may
include any of the previously stated storage
conditions as determined by the manufacturer.
For APIs that are expected to be retested before
incorporation into a preparation, a more general
and nonrestrictive condition may be desired. In
this case, the specification “room temperature”
(the temperature prevailing in a working area)
should suffice. The use of the permissive room
temperature condition reflects the stability of
an article over a wide temperature range. For
excipients, the phrase “No storage requirements
specified” in the Packaging
and storage statement of the monograph
would be appropriate.
Because most APIs in the
USP–NF have associated
Reference Standards, special efforts should be
considered to ensure that the Reference
Standards' storage conditions correspond to the
conditions indicated in the
USP–NF monographs.
The Packaging, Storage,
and Distribution Expert Committee may review
questionable Packaging and
storage statements on a case-by-case
basis. In cases where the
Packaging and storage statements are
incomplete, the monographs would move forward to
publication while the
Packaging and storage statements are
temporarily deferred.
Emulsions are two-phase
systems in which one liquid is dispersed throughout
another liquid in the form of small droplets. Where
oil is the dispersed phase and an aqueous solution
is the continuous phase, the system is designated as
an oil-in-water emulsion. Conversely, where water or
an aqueous solution is the dispersed phase and oil
or oleaginous material is the continuous phase, the
system is designated as a water-in-oil emulsion.
Emulsions are stabilized by emulsifying agents that
prevent coalescence, the merging of small droplets
into larger droplets and, ultimately, into a single
separated phase. Emulsifying agents (surfactants) do
this by concentrating in the interface between the
droplet and external phase and by providing a
physical barrier around the particle to coalescence.
Surfactants also reduce the interfacial tension
between the phases, thus increasing the ease of
emulsification upon mixing.
Natural, semisynthetic, and
synthetic hydrophilic polymers may be used in
conjunction with surfactants in oil-in-water
emulsions as they accumulate at interfaces and also
increase the viscosity of the aqueous phase, thereby
decreasing the rate of formation of aggregates of
droplets. Aggregation is generally accompanied by a
relatively rapid separation of an emulsion into a
droplet-rich and droplet-poor phase. Normally the
density of an oil is lower than that of water, in
which case the oil droplets and droplet aggregates
rise, a process referred to as creaming. The greater
the rate of aggregation, the greater the droplet
size and the greater the rate of creaming. The water
droplets in a water-in-oil emulsion generally
sediment because of their greater density.
The consistency of emulsions
varies widely, ranging from easily pourable liquids
to semisolid creams. Generally oil-in-water creams
are prepared at high temperature, where they are
fluid, and cooled to room temperature, whereupon
they solidify as a result of solidification of the
internal phase. When this is the case, a high
internal-phase volume to external-phase volume ratio
is not necessary for semisolid character, and, for
example, stearic acid creams or vanishing creams are
semisolid with as little as 15% internal phase. Any
semisolid character with water-in-oil emulsions
generally is attributable to a semisolid external
phase.
All emulsions require an
antimicrobial agent because the aqueous phase is
favorable to the growth of microorganisms. The
presence of a preservative is particularly critical
in oil-in-water emulsions where contamination of the
external phase occurs readily. Since fungi and
yeasts are found with greater frequency than
bacteria, fungistatic as well as bacteriostatic
properties are desirable. Bacteria have been shown
to degrade nonionic and anionic emulsifying agents,
glycerin, and many natural stabilizers such as
tragacanth and
guar gum.
Complications arise in
preserving emulsion systems, as a result of
partitioning of the antimicrobial agent out of the
aqueous phase where it is most needed, or of
complexation with emulsion ingredients that reduce
effectiveness. Therefore, the effectiveness of the
preservative system should always be tested in the
final product. Preservatives commonly used in
emulsions include methyl-, ethyl-, propyl-, and
butyl-parabens, benzoic acid, and quaternary
ammonium compounds.
See also
Creams and Ointments.
EXTRACTS AND FLUIDEXTRACTS
Extracts
are concentrated preparations of
vegetable or animal drugs
obtained by removal of the
active constituents of the
respective drugs with suitable
menstrua, by evaporation of all
or nearly all of the solvent,
and by adjustment of the
residual masses or powders to
the prescribed standards.
In the
manufacture of most extracts,
the drugs are extracted by
percolation. The entire
percolates are concentrated,
generally by distillation under
reduced pressure in order to
subject the drug principles to
as little heat as possible.
Fluidextracts are liquid
preparations of vegetable drugs,
containing alcohol as a solvent
or as a preservative, or both,
and so made that, unless
otherwise specified in an
individual monograph, each mL
contains the therapeutic
constituents of 1 g of the
standard drug that it
represents.
A
fluidextract that tends to
deposit sediment may be aged and
filtered or the clear portion
decanted, provided the resulting
clear liquid conforms to the
Pharmacopeial standards.
Fluidextracts may be prepared
from suitable extracts.
Gels
(sometimes called Jellies) are
semisolid systems consisting of
either suspensions made up of
small inorganic particles or
large organic molecules
interpenetrated by a liquid.
Where the gel mass consists of a
network of small discrete
particles, the gel is classified
as a two-phase system (e.g.,
Aluminum
Hydroxide Gel). In a
two-phase system, if the
particle size of the dispersed
phase is relatively large, the
gel mass is sometimes referred
to as a magma (e.g.,
Bentonite
Magma). Both gels and
magmas may be thixotropic,
forming semisolids on standing
and becoming liquid on
agitation. They should be shaken
before use to ensure homogeneity
and should be labeled to that
effect. (See
Suspensions.)
Single-phase gels consist of
organic macromolecules uniformly
distributed throughout a liquid
in such a manner that no
apparent boundaries exist
between the dispersed
macromolecules and the liquid.
Single-phase gels may be made
from synthetic macromolecules
(e.g.,
Carbomer) or from natural
gums (e.g.,
Tragacanth). The latter
preparations are also called
mucilages. Although these gels
are commonly aqueous, alcohols
and oils may be used as the
continuous phase. For example,
mineral oil can be combined with
a polyethylene resin to form an
oleaginous ointment base.
Gels can
be used to administer drugs
topically or into body cavities
(e.g.,
Phenylephrine Hydrochloride
Nasal Jelly).
Implants or
pellets are
small
sterile
solid masses
consisting
of a highly
purified
drug (with
or without
excipients)
made by
compression
or molding.
They are
intended for
implantation
in the body
(usually
subcutaneously)
for the
purpose of
providing
continuous
release of
the drug
over long
periods of
time.
Implants are
administered
by means of
a suitable
special
injector or
surgical
incision.
This dosage
form has
been used to
administer
hormones
such as
testosterone
or estradiol.
They are
packaged
individually
in sterile
vials or
foil strips.
Inhalations are drugs or solutions or suspensions of one or more drug substances administered by the nasal or oral respiratory route for local or systemic effect.
Solutions of drug substances in sterile water for inhalation or in sodium chloride inhalation solution may be nebulized by use of inert gases. Nebulizers are suitable for the administration of inhalation solutions only if they give droplets sufficiently fine and uniform in size so that the mist reaches the bronchioles. Nebulized solutions may be breathed directly from the nebulizer or the nebulizer may be attached to a plastic face mask, tent, or intermittent positive pressure breathing (IPPB) machine.
Another group of products, also known as metered-dose inhalers (MDIs) are propellant-driven drug suspensions or solutions in liquified gas propellant with or without a cosolvent and are intended for delivering metered doses of the drug to the respiratory tract. An MDI contains multiple doses, often exceeding several hundred. The most common single-dose volumes delivered are from 25 to 100 µL (also expressed as mg) per actuation.
Examples of MDIs containing drug solutions and suspensions in this pharmacopeia are Epinephrine Inhalation Aerosol and Isoproterenol Hydrochloride and Phenylephrine Bitartrate Inhalation Aerosol, respectively.
Powders may also be administered by mechanical devices that require manually produced pressure or a deep inhalation by the patient (e.g., Cromolyn Sodium for Inhalation).
A special class of inhalations termed inhalants consists of drugs or combination of drugs, that by virtue of their high vapor pressure, can be carried by an air current into the nasal passage where they exert their effect. The container from which the inhalant generally is administered is known as an inhaler.
An Injection is a preparation intended for parenteral administration or for constituting or diluting a parenteral article prior to administration (see Injections
1).
Each container of an Injection is filled with a volume in slight excess of the labeled “size” or that volume that is to be withdrawn. The excess volumes recommended in the accompanying table are usually sufficient to permit withdrawal and administration of the labeled volumes.
Lozenges are solid preparations, that are intended to dissolve or disintegrate slowly in the mouth. They contain one or more medicaments, usually in a flavored, sweetened base. They can be prepared by molding (gelatin and/or fused sucrose or sorbitol base) or by compression of sugar-based tablets. Molded lozenges are sometimes referred to as pastilles while compressed lozenges are often referred to as troches. They are usually intended for treatment of local irritation or infections of the mouth or throat but may contain active ingredients intended for systemic absorption after swallowing.
OINTMENTS
Ointments are semisolid preparations intended for external application to the skin or mucous membranes.
Ointment bases recognized for use as vehicles fall into four general classes: the hydrocarbon bases, the absorption bases, the water-removable bases, and the water-soluble bases. Each therapeutic ointment possesses as its base a representative of one of these four general classes.
Hydrocarbon Bases
These bases, which are known also as “oleaginous ointment bases,” are represented by White Petrolatum and White Ointment. Only small amounts of an aqueous component can be incorporated into them. They serve to keep medicaments in prolonged contact with the skin and act as occlusive dressings. Hydrocarbon bases are used chiefly for their emollient effects, and are difficult to wash off. They do not “dry out” or change noticeably on aging.
Absorption Bases
This class of bases may be divided into two groups: the first group consisting of bases that permit the incorporation of aqueous solutions with the formation of a water-in-oil emulsion (Hydrophilic Petrolatum and Lanolin), and the second group consisting of water-in-oil emulsions that permit the incorporation of additional quantities of aqueous solutions (Lanolin). Absorption bases are useful also as emollients.
Water-Removable Bases
Such bases are oil-in-water emulsions, e.g., Hydrophilic Ointment, and are more correctly called “creams.” (See Creams.) They are also described as “water-washable,” since they may be readily washed from the skin or clothing with water, an attribute that makes them more acceptable for cosmetic reasons. Some medicaments may be more effective in these bases than in hydrocarbon bases. Other advantages of the water-removable bases are that they may be diluted with water and that they favor the absorption of serous discharges in dermatological conditions.
Water-Soluble Bases
This group of so-called “greaseless ointment bases” comprises water-soluble constituents. Polyethylene Glycol Ointment is the only Pharmacopeial preparation in this group. Bases of this type offer many of the advantages of the water-removable bases and, in addition, contain no water-insoluble substances such as petrolatum, anhydrous lanolin, or waxes. They are more correctly called “Gels.” (See Gels.)
Choice of Base— The choice of an ointment base depends upon many factors, such as the action desired, the nature of the medicament to be incorporated and its bioavailability and stability, and the requisite shelf-life of the finished product. In some cases, it is necessary to use a base that is less than ideal in order to achieve the stability required. Drugs that hydrolyze rapidly, for example, are more stable in hydrocarbon bases than in bases containing water, even though they may be more effective in the latter
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