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USP 37 General Information / á1724ñ Semisolid Drug Products 1273

á1724ñ SEMISOLID DRUG drugs, as the primary factor that impacts bioavailability and
clinical performance are the barrier properties of the epithe-
PRODUCTS—PERFORMANCE lia to which the product is applied (epidermal or mucosal
tissues). Although product performance tests do not directly
TESTS measure bioavailability and relative bioavailability (bioequi-
valence), they can detect in vitro changes that may corre-
spond to altered in vivo performance of the dosage form.
SCOPE These changes may arise from changes in physicochemical
characteristics of the drug substance and/or excipients or to
The scope of this general chapter is to provide general in- the formulation itself, changes in the manufacturing proc-
formation for performance testing of semisolid drug prod- ess, shipping and storage effects, aging effects, and other
ucts, various types of equipment employed for such testing, formulation and/or process factors.
and potential applications of the performance testing. At present, a product performance test is available to eval-
uate in vitro drug release for creams, ointments, lotions, and
PURPOSE gels. Several available apparatus can be used for this evalua-
tion, including the vertical diffusion cell, immersion cell, and
This chapter provides general information about perform- a special cell used with USP Apparatus 4. Because of the sig-
ance testing of semisolid drug products, the theory and ap- nificant impact of in vitro test parameters, such as release
plications of such testing, information about the availability media, porous membrane and dosing, and the interaction
of appropriate equipment, and likely developments in per- of these parameters with a given drug product, the primary

General Chapters
formance testing of semisolid drug products. General chap- use of in vitro drug release testing is comparison testing in
ter Topical and Transdermal Drug Products—Product Quality which any difference in delivery rate is undesirable. Drug re-
Tests á3ñ provides information related to product quality lease testing is most suitable for evaluation of small formula-
tests for topical and transdermal dosage forms, Drug Release tion and process changes, manufacturing site changes, and
á724ñ provides procedures and details for testing drug re- stability testing. The evaluation or comparison of large for-
lease from transdermal systems, and this chapter á1724ñ mulation changes may provide unmeaningful results, unless
provides procedures for determining drug release from sem- extensive validation is performed to select test parameters
isolid dosage forms. that ensure that the sensitivity of the test is meaningfully
correlated with in vivo performance. The only required reg-
INTRODUCTION ulatory use of the in vitro release test is to determine the ac-
ceptability of minor process and/or formulation changes in
This chapter provides general information for in vitro test- approved semisolid dosage forms (see FDA Guidance for In-
ing of semisolid drug products. Semisolid dosage forms in- dustry—Nonsterile Semisolid Dosage Forms—Scale-Up and
clude creams, ointments, gels, and lotions. Semisolid dos- Postapproval Changes: Chemistry, Manufacturing, and Con-
age forms may be considered extended-release prepara- trols; In Vitro Release Testing and In Vivo Bioequivalence Docu-
tions, and their drug release depends largely on the formu- mentation; available at http://www.fda.gov/downloads/
lation and manufacturing process. The release rate of a giv- Drugs/GuidanceComplianceRegulatoryInformation/Guidan-
en product from different manufacturers is likely to be differ- ces/UCM070930.pdf).
ent. This chapter provides general information for testing in vi-
tro performance of semisolid drug products.
DRUG PRODUCT QUALITY AND
PERFORMANCE TESTS IN VITRO PERFORMANCE TESTS

A USP drug product monograph contains tests, analytical Theory

procedures, and acceptance criteria. Drug product tests are
divided into two categories: (1) those that assess general The diffusion cell is a reliable and reproducible means of
quality attributes, and (2) those that assess product per- measuring drug release from semisolid dosage forms. A
formance, e.g., in vitro release of the drug substance from thick layer of the semisolid product under evaluation is
the drug product. Quality tests assess the integrity of the placed in contact with a medium in a reservoir, and the lat-
dosage form, but performance tests, such as drug release, ter acts as a receptor when the drug substance diffuses
assess attributes that relate to in vivo drug performance. through the formulation, across the membrane, and into
Taken together, quality and performance tests are intended the reservoir. Diffusion occurs across an inert, highly perme-
to ensure the identity, strength, quality, purity, comparabili- able support membrane. The membrane is intended to keep
ty, and performance of semisolid drug products. the product and the receptor medium separate and distinct.
Details of drug product quality tests for semisolid drug Membranes should offer the least possible diffusional resist-
products can be found in chapter á3ñ. Product performance ance and should not be rate controlling. Samples are with-
tests for semisolid drug products are conducted to assess drawn from the receptor chamber, typically at 1-h intervals
drug release from manufactured pharmaceutical dosage over a 4–6 h period.
forms. In vitro performance tests for semisolid products do After a short lag period, release of drug from the semisolid
not, however, directly predict the in vivo performance of dosage form is kinetically described by diffusion of a chemi-
cal out of a semi-infinite medium into a sink. The momenta-

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1274 á1724ñ Semisolid Drug Products / General Information USP 37

ry release rate tracks the depth of penetration of the form- During release rate experiments, reasonable attempts
ing gradient within the semisolid. Beginning at the moment should be made to keep the composition of the formulation
when the receding boundary layer's diffusional resistance as- intact over the releasing period.
sumes dominance of the kinetics of release, the amount of
the drug released, m, becomes proportional to Öt (where t = Drug Release Rate Determination Using
time) for solution, suspension, or emulsion semisolid system Vertical Diffusion Cell Apparatus
alike. The momentary rate of drug release, dm/dt, becomes
proportional to 1/Öt, which reflects the slowing of drug re- Many vertical diffusion cell (VDC) systems are composed
lease with the passage of time. The reservoir is kept large so of 6-cell units. Each VDC cell assembly consists of two
that over the entire course of the experiment, the concen- chambers (a donor chamber and a receptor chamber) sepa-
tration of the drug released into a medium remains highly rated by a membrane and held together by a clamp, screw
dilute relative to the concentration of drug dissolved in the top, or other means (see Figure 1–Model A, Figure 2–Model B,
semisolid. In these circumstances, drug release is said to and Figure 3–Model C). Other diffusion cells that are similar
take place into a diffusional sink. in general design also can be used. In the donor chamber,
When a drug is totally in solution in the dosage form, the the semisolid dosage form sample sits on a synthetic, inert,
amount of drug released as a function of time can be descri- highly permeable support membrane. For the VDC Model
bed by Equation 1: A, the sample sits on the support membrane within the cavi-
ty of the sample chamber covered with a glass disk.
Typically, amounts of the semisolid sample NLT 200 mg
are used. Diffusive communication between the semisolid
General Chapters

where m is the amount of drug released into the sink per sample and the reservoir takes place through the support
cm2, C0 is the drug concentration in the releasing matrix, membrane. The membrane is intended to keep the drug
and D is the drug diffusion coefficient through the matrix. product sample and receptor medium separate and distinct.
A plot of m versus Öt will be linear with a slope of: A heating jacket or a suitable device should be used to
maintain the temperature within the cell. The release rate
experiment is carried out at 32 ± 1°, except in the case of
vaginal drug products for which the temperature should be
37 ± 1°. Usually a set of 6 cell assemblies are operated to-
Equation 2 describes drug release when the drug is in the gether at one time (i.e., single run). Sampling generally is
form of a suspension in the dosage form: performed over a 4–6 h time period, and the volume with-
drawn is replaced with stock receptor medium. To achieve
sink condition, the receptor medium must have a high ca-
pacity to dissolve the drug, and the drug concentration in
where Dm is the drug diffusion coefficient in the semisolid the receptor medium at the end of the test ideally should be
matrix, CS is the drug solubility in the releasing matrix, and as low as possible. For each cell, the amount of drug re-
Q is the total amount of the drug in solution and suspended leased (mg/cm2) at each sampling time (t1, t2, etc.) is deter-
in the matrix. When Q >> CS, Equation 2 simplifies to Equa- mined, and the cumulative amount released plotted versus
tion 3: Öt. The slope of the resulting line is a measure of the rate of
drug release. The test is often conducted with a group of 6
or 12 cells per test run. The average of 6 slopes for each test
and reference product is a measure of the drug release rate
A plot of m versus Öt will be linear with a slope of: from the dosage form.

Coarse particles may dissolve so slowly that the moving

boundary layer recedes to some extent behind the particles.
That situation introduces noticeable curvature in the Öt plot
because of a particle size effect.

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USP 37 General Information / á1724ñ Semisolid Drug Products 1275

General Chapters
Figure 1. Vertical diffusion cell–Model A (All dimensions are in mm. All diameters are ±0.5 mm. All lengths are ±2 mm).

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1276 á1724ñ Semisolid Drug Products / General Information USP 37
General Chapters

Figure 2. Vertical diffusion cell–Model B (All dimensions are in mm. All diameters are ±0.5 mm. All lengths are ±2 mm).

Figure 3. Vertical diffusion cell–Model C (All dimensions are in mm. All diameters are ±0.5 mm. All lengths are ±2 mm).

of the donor and receptor chamber orifices may vary de-

The VDC body (i.e., donor and receptor chambers) usual- pending on the application. The receptor chamber orifice
ly is made from borosilicate glass, although different materi- should never be smaller than the orifice of the donor cham-
als may be used to manufacture the body and other parts of ber but should be fabricated to the same size as the donor
the VDC assembly. It is recommended that the cell assembly chamber orifice. The design of the VDC should facilitate
materials should not significantly react with, adsorb to, or proper alignment of the donor chamber and the receptor
absorb the test product or samples. The semisolid dosage orifice. The receptor chamber should be manufactured con-
form is placed on a membrane within the cavity of the dos- sistently with uniform height and geometry. All the cells
age chamber that can be occluded. The diameters of the or- should have the same nominal value, and the true volume
ifices of the donor chamber and receptor chamber, which should be measured for each individual cell. Care should be
define the dosage delivery surface area for the test, should taken to minimize the intercell volume variability.
be sized within ±5% of the specified diameter. The diameter

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USP 37 General Information / á1724ñ Semisolid Drug Products 1277

For the test, the VDC units are typically positioned in a TEST PROCEDURES: MODEL A
stirrer rack (not depicted) that holds multiple VDC units
(e.g., in sets of 6) in the correct orientation, providing mag- With the stirring mechanism in place, fill the receptor
netic stirring at a calibrated rate and facilitating the supply chamber with the specified medium with the stirrers rotat-
of circulating heated water flow to the water jacket of the ing and a positive meniscus covering the top of each cell.
VDC. The VDC rack is typically connected to a thermostati- Allow time for the medium to equilibrate to the specified
cally controlled water bath recirculator. temperature. Stop the stirrer before placing the test sample
The water from the circulating pump flows into the VDC on the cell. If necessary, saturate the membrane in the
heating jacket from the lower port and flows out from the specified medium (generally the receptor medium) for 30
upper port to facilitate the removal of any air bubbles min. Place the membrane on the donor chamber, and in-
formed in the heating jacket. A magnetic nonstick (Teflon- vert. Apply the material to be tested into the cavity of the
coated) stirring bar in the receptor chamber is used as the sample chamber, spreading the semisolid out to fill the en-
internal stirring mechanism. Aliquots of the receptor medi- tire cavity of the sample chamber. Place the filled sample
um are drawn via the sampling arm at intervals throughout chamber on the receptor chamber with the membrane
the test, and an equivalent volume of stock receptor medi- down and in contact with the receptor medium. During this
um replaced to the level of the calibration mark on the sam- procedure it is important to ensure that there are no bub-
pling arm. bles beneath the membrane. Then assemble the complete
MODEL A The thickness of the sample chamber normally is cell. When the assembly of all donor and receptor chambers
1.5 mm. This thickness should be sized within ±10% of the and remaining cell components (i.e., disk, alignment ring,
specified thickness. The glass support disk is used to occlude and clamp) have been completed, turn on the stirring de-

General Chapters
the semisolid dosage form. A receptor cell mixer and stirrer vice, which constitutes the start of the test or time zero.
magnet are used as the internal stirring mechanism. Sampling is generally performed over a 4–6 h time period.
MODELS B AND C Classic styles of VDC are depicted in Fig- Follow the specified sampling procedure, and collect an ali-
ure 2 and Figure 3 and illustrate minor design variations quot from each cell receptor chamber for analysis. With the
among qualified models. stirrer stopped and using a syringe, replace the withdrawn
volume with stock receptor medium warmed to the specific
Test Procedures: General temperature, and resume stirring. During the sampling and
medium replenishment process(es), ensure that bubbles are
Before initiating testing, analysts should determine the not introduced into the cell.
volume of each VDC with the internal stirring device in
place. During the entire test, the temperature of the recep- TEST PROCEDURES: MODELS B AND C
tor medium should be maintained at 32 ± 1°, or 37 ± 1° for
vaginal preparations. The rotational stirring rate tolerance A nonstick (Teflon-coated) stir bar is placed within the re-
should be ±10% of the rate in the method (normally 600 ceptor chamber of the VDC. The membrane specified in the
rpm). The rate of stirring should ensure adequate mixing of test method is clamped atop the O-ring, if present, between
the receptor medium during the test period. Samples from the aligned donor and receptor chambers of the VDC. The
each cell should be obtained at the specified times in the exposed periphery of the joint between the donor and re-
method within a tolerance of ±2 min. Unless the method ceptor compartments is sealed (e.g., circumscribed by
specifies otherwise, the qualification of the apparatus has stretched paraffin wax film).
been verified when analysts determine that the test temper- The receptor chamber is filled with receptor medium via
ature and stirring rate are within their specified require- the sampling arm, unless it is already filled before the mem-
ments and a satisfactory performance verification test (i.e., brane is mounted. The VDC assembly is tilted in multiple
drug release rate) results. Unless otherwise specified in the orientations and inspected to ensure that any air bubbles
method, degas the medium using an appropriate techni- trapped beneath the membrane, or within the receptor
que. Determine the amount of drug in the receptor medium chamber, can escape via the sampling arm port. The vol-
sample aliquots using a validated analytical procedure. ume of receptor medium is adjusted to the calibrated level
The following sections provide instructions for proper use marked on the sampling arm port. The membrane is al-
of Models A, B, and C. lowed to equilibrate with the receptor medium, in situ, for
at least 30 min prior to the application of the dosage form,
or may be pre-incubated with a wetting solution (typically
the receptor medium), as specified in the test method.

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1278 á1724ñ Semisolid Drug Products / General Information USP 37

The VDC units are positioned in a stirrer rack. It is recom-

mended that about 10–20 cm of slack should be available in
the tubing connecting the ports of the VDC water jacket to
the VDC rack to facilitate subsequent manipulation of the
VDC during the test. The temperature set point of the water
bath is adjusted before dosing so that the membrane is at
the correct temperature. This can be verified by measuring
the membrane temperature before dosing, using a calibra-
ted infrared thermometer.
The stirring is initiated and can be maintained continu-
ously throughout the test. The dosage form is evenly dis-
pensed directly onto the membrane surface. The amount of
sample recommended is NLT approximately 1.0 mL/cm2 or
1.0 g/cm2 to ensure a pseudo-infinite dose condition.
Spreading of the sample typically starts at the outer edge
and proceeds in an inward spiral pattern to assure full cover-
age of the edges of the dose area without air gaps. The
placement of the sample constitutes the start of the test or
time zero. The donor chamber is subsequently sealed with
an occlusive film to prevent loss of any volatile components
General Chapters

of the test formulation. The underside of the membrane is

checked for air bubbles and, if any are seen, they are elimi-
nated by tilting the apparatus in a manner that allows the
air bubbles to escape. The receptor volume is confirmed at
the calibrated volume mark and adjusted as necessary.
Before sample collections, typically every hour over the 4–
6 h period following the introduction of the sample, the vol-
ume in the sampling arm is confirmed approximately 10
min before sampling and is adjusted to the calibration mark
on the sampling arm as necessary. At predetermined inter-
vals after starting the test, typically hourly for 6 h, analysts
collect aliquots of the receptor medium (e.g., 150 mL) via Figure 4. Immersion cell–Model A–Cell components.
the sampling arm, drawing from the well-mixed center of
the receptor chamber. The VDC assembly is inspected for air
bubbles, which are eliminated as necessary. Receptor medi-
um is replaced to bring the receptor volume back to the lev-
el indicated on the sampling arm of the VDC.

Drug Release Rate Determination Using

Immersion Cell Apparatus

The cell consists of the following components (see Figure

4 and Figure 5 for Model A, and Figure 6 and Figure 7 for
Model B): a retaining or lock ring that secures the mem-
brane to the cell body and ensures full contact with the
sample; a washer that provides a leakproof seal between
membrane, retaining ring, and cell body; the membrane
(usually a synthetic membrane) that should retain the sam-
ple in the sample compartment; and the cell body that pro-
vides a variable depth reservoir for the sample. Model A also
has an adjustment plate that allows operators to vary the
volume of the reservoir within the cell body. The plate can
be placed at the appropriate height for each test and can be
completely removed to facilitate cleaning. An O-ring paired
with the adjustment plate prevents leakage.

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USP 37 General Information / á1724ñ Semisolid Drug Products 1279

General Chapters

Figure 5. Immersion cell–Model A assembled in a mini vessel.

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1280 á1724ñ Semisolid Drug Products / General Information USP 37
General Chapters

Figure 6. Immersion cell–Model B–Cell components.

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USP 37 General Information / á1724ñ Semisolid Drug Products 1281

immersion cell components as specified by the device man-

ufacturer. Carefully place the completed assembly into the
bottom of the dissolution vessel with the membrane facing
up. The appropriate preheated medium may be preloaded
in the vessel or can be added after immersion of the immer-
sion cell to start the test. Samples from at least 5 time points
should be obtained in the steady-state (linear) portion of the
drug release profile. The data points are cumulative and ex-
pressed as concentration per surface area, typically per cm2,
as a function of the square root of time. Sampling is gener-
ally performed over a 4–6 h time period. The slope of the
line is the in vitro release rate of drug from the product. At
the end of the test period, dismantle the cell and examine
the contents for anything unusual that could explain any
anomalous data (e.g., leaks, bubbles, etc.).

QUALIFICATION

USP Apparatus 2 should be qualified according to the pro-

General Chapters
cedure described in Dissolution á711ñ.
Figure 7. Immersion cell–Model B assembled in a vessel.
Drug Release Determination Using USP
The immersion cell can be used with USP Apparatus 2 (see Apparatus 4 (Flow-Through Cell)
general chapter Dissolution á711ñ) with vessel volumes that
vary from 100 mL up to 4 L, but the 150- or 200-mL vessels The adapter for semisolid dosage forms (see Figure 8) is
are the most commonly used. A flat-bottom variation of the used with the 22.6-mm cell of USP Apparatus 4 described in
150- or 200-mL vessel can be used to avoid the issue of Dissolution á711ñ. The adapter consists of a reservoir and a
dead space under the cell when it is used in a round-bottom ring to hold the membrane. The reservoir is available in dif-
vessel. If analysts are going to use a 150- or 200-mL vessel ferent sizes that can accommodate from 400 to 1200 mL of
with USP Apparatus 2, then the appropriate modifications product. The use of the USP Apparatus 4 cells ensures con-
must be made, including holders for the small-volume ves- trol of temperature and hydrodynamics. The temperature
sels and replacement of the standard paddle with the ap- can be maintained either at 32.0 ± 0.5° or 37.0 ± 0.5°, de-
propriate paddle. It also may require repositioning of any pending on the intended site of the administration of the
automated sampling device and/or manifold. The water formulation. The flow rate should comply with the require-
bath or vessel heater should be set to have the medium ments of Dissolution á711ñ with a sinusoidal flow profile with
temperature at 32.0 ± 0.5° or 37.0 ± 0.5°. a pulsation of 120 ± 10 pulses/min and a precision of ±5%
Before loading the cells and placing the medium in the of the nominal flow rate.
vessel, set the paddle height, which is 1.0 ± 0.2 cm above
the surface of the membrane. All other operational parame-
Procedure
ters, such as level, vibration, wobble, etc., should be set at
the same conditions defined for USP Apparatus 2. The small-
The membrane, which may be soaked in the receptor me-
volume condition is qualified by first using the standard Ap-
dium beforehand, is loaded in the membrane ring using the
paratus 2 setup and Performance Verification Test, Apparatus
provided tool. The membrane should be large enough to
1 and 2 (see Dissolution á711ñ).
overlap the top edge of the reservoir body with a diameter
Cut the membrane to an appropriate size. If necessary,
of 18 mm. The sample is loaded into the reservoir. The oth-
soak the membrane in the receptor medium for at least 30
er side of the tool can be used to hold the reservoir while
min before loading. If the membrane is thick, a longer soak-
loading the sample. If necessary, the excess of sample can
ing time period may be necessary. Prepare the immersion
be removed using a spatula. Screw the membrane ring onto
cell components as specified by the device manufacturer.
the sample reservoir. Ensure that the membrane is free of
Fill the reservoir dosage area with the sample under test.
wrinkles while screwing.
Ensure that the reservoir is filled to the top in order to mini-
Remove the semisolid sample adapter from the tool, and
mize the possibility of air bubble formation between the sur-
slide it into the cylindrical part of the 22.6-mm cell with the
face of the sample and the membrane. A uniform surface
membrane facing downward. Vertical positioning within the
can be obtained with the aid of a spatula. The typical quan-
cell can be adjusted using the tablet holder scoring, if de-
tity of sample is between 300 mg and 2 g, depending on
sired (see Figure 9). If the lower position is chosen, release
the type of immersion cell used. An excess of sample is nee-
can be higher due to the proximity to the flow inlet. The
ded to obtain a steady-state drug release rate. Using forceps
system is typically configured as a closed system (see Figure
or tweezers, remove the membrane from the soaking medi-
10), but in some cases, an open system can be used. The
um and place it over the top of the sample compartment.
prepared cell is inserted in a heating jacket.
Ensure that the membrane is free of wrinkles. Assemble the

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1282 á1724ñ Semisolid Drug Products / General Information USP 37
General Chapters

Figure 8. Adapter for topical dosage forms in USP Apparatus 4 (All dimensions are in mm).

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USP 37 General Information / á1724ñ Semisolid Drug Products 1283

with the slope of the line representing the in vitro release

rate.

Calculation of Rate and Amount of Drug

Released

Calculate the drug release rate using the following steps.

Amount released (mg/cm2) at a given time (t1, t2, etc.)
(ARi) is calculated for each sample:
Amount released at t1AR1 = (AU1/AS) × CS × 1000 × (VC/A0)

Amount released at t2AR2 = (AU2/AS) × CS × 1000 × (VC/A0) +

[AR1 × (VS/VC)]

AR = amount of drug released (mg/cm2)

General Chapters
AU = response (e.g., peak area, or peak height or ab-
sorbance) from the Sample solution
AS = average response (e.g., peak area, or peak height
Figure 9. Vertical positioning of the insert using the tablet or absorbance) from the Standard solution
holder scoring (all dimensions are in mm). CS = concentration of the Standard solution (mg/mL)
VC = volume of the diffusion cell (mL)
AO = area of the orifice (cm2)
VS = volume of sample taken (mL)
For each cell, the individual amount of drug released is
plotted versus the square root of time. The slope of the re-
sulting line is the rate of drug release. The average of 6
slopes for each test and reference products represents the
drug release rate of the dosage form, and serves as the
standard for the drug product.

Application of Drug Release

Figure 10. Closed system configuration.
The product performance test can be used to assess same-
The defined volume of release medium is introduced in ness of the drug product after post-approval changes. Be-
the reservoir. Unless otherwise specified, the medium should cause common testing artifacts, such as air bubbles and
be deaerated in order to minimize the risk of air bubbles. A membrane defects, yield measurements that are not nor-
deaeration procedure is described in Dissolution á711ñ, but mally distributed, a nonparametric statistical technique is
other validated deaeration techniques can be used. The res- used to evaluate the test results. The Mann-Whitney U test is
ervoir can be adapted to the volume needed in order to used to calculate the 90% confidence interval for the ratio
achieve sink conditions and to ensure precision of the ana- of the slopes between the test and the reference batches.
lytical method. Typical volumes range from 50 to 1000 mL, This is illustrated by the following example in which the ini-
but values above and below this range also can be used as tial drug product batch is referred to as the reference batch
the formulation demands. (R) and the changed or subsequent batch is referred to as
When the pump is switched on, the medium will be pum- the test batch (T). The individual amounts of drug released
ped through the cell. This represents the time zero of the from R is plotted versus time, and the resulting slopes are
test. Typical flow rates are 16 mL/min and 24 mL/min, but determined. Those are the reference slopes. The process is
flow rate is a method-development parameter and must be repeated for the test batch (T).
optimized accordingly. The flow passing through the cell The T/R slope ratios are calculated for each test-to-refer-
ensures both agitation and renewal of the receptor medium ence slope. This procedure is facilitated with a table where
at the interface with the membrane. the values for the slopes for test and reference batches are
Sampling can be performed either manually or automati- listed down the left side and across the top of the table, re-
cally directly from the medium reservoir, thus ensuring no spectively. The T/R slope ratios are then determined. See Ta-
interference with the flow cell and its contents. An automa- ble 1.
ted fraction collector may be appropriate for release periods After the T/R ratios have been calculated, they are ordered
longer than 6 h. After quantification, plot the amount of from the lowest to the highest. The 8th and 29th T/R ratios
drug release per surface area versus the square root of time,

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1284 á1724ñ Semisolid Drug Products / General Information USP 37

Table 1. Comparison of Test and Reference Slopes

RS1 RS2 RS3 RS4 RS5 RS6
TS1 TS1/RS1 TS1/RS2 TS1/RS3 TS1/RS4 TS1/RS5 TS1/RS6
TS2 TS2/RS1 TS2/RS2 TS2/RS3 TS2/RS4 TS2/RS5 TS2/RS6
TS3 TS3/RS1 TS3/RS2 TS3/RS3 TS3/RS4 TS3/RS5 TS3/RS6
TS4 TS4/RS1 TS4/RS2 TS4/RS3 TS4/RS4 TS4/RS5 TS4/RS6
TS5 TS5/RS1 TS5/RS2 TS5/RS3 TS5/RS4 TS5/RS5 TS5/RS6
TS6 TS6/RS1 TS6/RS2 TS6/RS3 TS6/RS4 TS6/RS5 TS6/RS6

are identified and converted to percent (multiplied by 100). Table 1. Nuclear Spin Values as a Function of Mass and Atomic
These values represent the 90% confidence interval for the Numbers
ratio of test to reference release rates. To pass first stage Mass Atomic Nuclear Spin
testing, those ratios must be within the range of 75%– Number Number (I)
133.33%. Odd Even or odd 1/2, 3/2, 5/2 ...
If the results do not meet this criterion, four additional Even Even 0
tests of 6 cells should be performed, resulting in 12 addi- Even Odd 1, 2, 3 ...
tional slope determinations for each product tested. The T/R
slope ratios for all 18 slopes for each product tested are de- The angular momentum creates a magnetic moment, m,
termined. All 324 individual T/R slope ratios are ordered which is parallel to and directly proportional to r.
General Chapters

from the lowest to the highest. To pass this second stage m = gr = gIh [3]
testing, the 110th and 215th slope ratios, representing the
90% confidence interval, must be within the range of 75%– where g is the magnetogyric ratio and is a constant for all
133.33%. nuclei of a given isotope, regardless of their position in a
molecule.
Nuclei that have a spin quantum number I ¹ 0, when
placed in an external uniform static magnetic field, align
á1761ñ APPLICATIONS OF with respect to the field in (2I + 1) possible orientations.
Thus, for nuclei with I = 1/2, which includes most isotopes
NUCLEAR MAGNETIC of analytical significance (Table 2), there are two possible
orientations, corresponding to two different energy states.
RESONANCE SPECTROSCOPY The energies of these two states are ± mB0, and their separa-
tion is

PRINCIPLES OF NMR E = mB0 − (− mB0) = 2mB0 [4]

with more nuclei populating the lower energy state (−mB0)

Nuclear magnetic resonance (NMR) spectroscopy is an than the higher energy state (+mB0). The populations are in
analytical technique based on the magnetic properties of accordance with the Boltzmann distribution:
certain atomic nuclei. NMR is similar to other types of spec-
troscopy in that absorption of electromagnetic energy at N+/N− = exp(−E/kT) [5]
characteristic frequencies provides analytical information.
where N+ and N− are the populations of the high and low
NMR differs from other types of spectroscopy because the
energy states, respectively; k is the Boltzmann constant; and
discrete energy levels between which the transitions take
T is the temperature in K.
place are created by placing the nuclei in a magnetic field of
A nuclear resonance is the transition between these states,
strength H0. Although the initial field strength of the applied
and upward as well as downward transitions are possible. In
field is H0, when the sample is inserted into the magnet, the
a static magnetic field the nuclear magnetic axis precesses
field strength throughout the sample becomes B0, defined
(Larmor precession) about the B0 axis. The precessional an-
as follows:
gular velocity is often referred to as the Larmor frequency,
B0 = mSH0 [1] w0, and is related to B0:

in which mS is the magnetic susceptibility of the sample.

Atomic nuclei behave as if they were spinning on the nu-
clear axis. The angular momentum, r0, of the nucleus is
characterized by a spin quantum number (I). The maximum
observable component of the angular vector, r, is
r = Ih/2p = I h [2]
in which h is Planck’s constant and h is modified Planck’s
constant.
Table 1 shows the values of I as a function of the mass If energy from an oscillating radio-frequency (rf) field is in-
number and the atomic number. troduced, then resonance is achieved when the rf frequency

Official from August 1, 2014

Copyright (c) 2014 The United States Pharmacopeial Convention. All rights reserved.