Formas Farmacêuticas Semi-sólidas de Uso tópico USP 33 (ingles)

Formas Farmacêuticas Semi-sólidas de Uso tópico USP 33

TOPICAL AND TRANSDERMAL
DRUG PRODUCTS—PRODUCT QUALITY
TESTS
i. Introduction
ii. Glossary of Terms
iii. Product Quality Tests for All Topically Applied
Drug Products
a. Product Quality Tests for Topical Drug
Products Intended for Local Action
b. Product Quality Tests for Transdermal
Drug Products
iv. Product Performance Test for Topical Drug
Products
v. In Vitro Drug Release from Semisolid Dosage
Forms
a. Theory
b. Application of In Vitro Drug Release
I. INTRODUCTION
Drug products topically administered via the skin fall
into two general categories: those applied to achieve local
action and those to achieve systemic effects. Local action
can occur at or on the surface of the skin (the
stratum corneum) and also in the epidermis and/or dermis.
Locally acting drug products include creams, gels,
ointments, pastes, suspensions, lotions, foams, sprays,
aerosols, and solutions. Creams, ointments, and gels
are generally referred to as semisolid dosage forms. Drug
products applied to the skin to achieve systemic effects
are referred to as self-adhering transdermal patches or
transdermal drug delivery systems (TDS).
Quality tests with procedures and acceptable criteria
for both types of topically administered drug products
can be divided into those that assess general quality attributes
and those that assess performance. The former
include identification, assay (strength), content uniformity,
pH, microbial limits, and minimum fill. The latter assess
drug release from the finished dosage form. For
locally acting topical drug products, a product performance
test exists only for semisolid formulations. TDS
are physical devices that are applied to the skin and vary
in their composition and method of fabrication. They release
their active ingredients by different mechanisms.
Several product performance tests are available to assess
in vitro drug release from TDS. Performance tests considered
for topically applied products may also be applicable
to drug products of similar composition when
administered by other routes of administration, e.g.,
ophthalmic drug products.

II. GLOSSARY OF TERMS
Definitions of topical drug products, brief information
about their manufacture, and a glossary of dosage form
names can be found in the general information chapter
Pharmaceutical Dosage Forms h1151i.

Absorption Bases—This class of bases may be divided
into two groups: bases that permit the incorporation
of aqueous solutions with the formation of a water-in-oil
emulsion (e.g., Hydrophilic Petrolatum and Lanolin, both
USP), and water-in-oil emulsions that permit the incorporation
of additional quantities of aqueous solutions (e.g.,
Lanolin, USP). Absorption bases also are useful as emollients.

Choice of Base—The choice of an ointment base depends
on 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 that contain
water, even though they may be more effective in
the latter.

Collodion—Collodion (pyroxylin solution; see USP
monograph Collodion) is a solution of nitrocellulose in
ether and acetone, sometimes with the addition of alcohol.
As the volatile solvents evaporate, a dry celluloid-like
film is left on the skin. Because the medicinal use of a collodion
depends on the formation of a protective film, the
film should be durable, tenacious in adherence, flexible,
and occlusive.

Creams—Creams are semisolid dosage forms that
contain one or more drug substances dissolved or dispersed
in a suitable base. This term traditionally has been
applied to semisolids that possess a relatively soft,
spreadable consistency formulated as either water-in-oil
or oil-in-water emulsions. However, more recently the
term has been restricted to products consisting of oilin-
water emulsions or aqueous microcrystalline dispersions
of long-chain fatty acids or alcohols that are water
washable and more cosmetically and aesthetically acceptable.

Emulsions—Emulsions are viscid multiphase systems
in which one or more liquids are dispersed throughout
another immiscible liquid in the form of small droplets.
When oil is the dispersed phase and an aqueous solution
is the continuous phase, the system is designated an oilin-
water emulsion. Conversely, when water or an aqueous
solution is the dispersed phase and oil or oleaginous
material is the continuous phase, the system is designated
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)
act by concentrating at the interface between the
immiscible liquids, thereby providing a physical barrier
that reduces the tendency for coalescence. Surfactants
also reduce the interfacial tension between the phases,
facilitating the formation of small droplets upon mixing.
The term emulsion is not used if a more specific term is
applicable, e.g., cream or ointment.

Foams—Foams are emulsified systems packaged in
pressurized containers or special dispensing devices that
contain dispersed gas bubbles, usually in a liquid continuous
phase, that when dispensed have a fluffy, semisolid
consistency.

Gels—Gels (sometimes called jellies) are semisolid systems
that consist of either suspensions composed of
small inorganic particles or large organic molecules interpenetrated
by a liquid. When 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, USP). 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, NF). Both
gels and magmas may be thixotropic, forming semisolids
after standing and becoming liquid when agitated. They
should be shaken before use to ensure homogeneity and
should be labeled to that effect (see Topical Suspensions,
below). Single-phase gels consist of organic macromolecules
uniformly distributed throughout a liquid with no
apparent boundary between the dispersed macromolecule
and liquid.

Hydrocarbon Bases—Hydrocarbon bases, known
also as oleaginous ointment bases, are represented by
White Petrolatum and White Ointment (both USP). Only
small amounts of an aqueous component can be incorporated
into these bases. Hydrocarbon bases keep medicaments
in prolonged contact with the skin and act
as occlusive dressings. These bases are used chiefly for
their emollient effects and are difficult to wash off. They
do not ‘‘dry out’’ or change noticeably on aging.

Lotions—Although the term lotion may be applied to
a solution, lotions usually are fluid, somewhat viscid
emulsion dosage forms for external application to the
skin. Lotions share many characteristics with creams.
See Creams, Topical Solutions, and Topical Suspensions,
herein.

Ointments—Ointments are semisolids intended for
external application to the skin or mucous membranes.
They usually contain less than 20% water and volatiles
and more than 50% hydrocarbons, waxes, or polyols
as the vehicle. Ointment bases recognized for use as vehicles
fall into four general classes: hydrocarbon bases,
absorption bases, water-removable bases, and water-soluble
bases. Each therapeutic ointment possesses as its
base one of these four general classes.

Ophthalmic Ointments—Ophthalmic ointments
are semisolids for application to the eye. Special precautions
must be taken in the preparation of ophthalmic
ointments. They are manufactured from sterilized ingredients
under rigidly aseptic conditions, must meet
the requirements under Sterility Tests h71i, and must be
free of large particles. The medicinal agent is added to
the ointment base either as a solution or as a micronized
powder.

Pastes—Pastes are semisolid dosage forms that contain
a high percentage (often_50%) of finely dispersed
solids with a stiff consistency and intended for topical application.
One class is made from a single-phase aqueous
gel (e.g., Carboxymethylcellulose Sodium Paste, USP). The
other class, the fatty pastes (e.g., Zinc Oxide Paste, USP),
consists of thick, stiff ointments that do not ordinarily
flow at body temperature and therefore serve as protective
coatings over the areas to which they are applied.

Powders—Powders are solids or mixture of solids in a
dry, finely divided state for external (or internal) use.

Sprays—Sprays are products formed by the generation
of droplets of solution containing dissolved drug
for application to the skin or mucous membranes. The
droplets may be formed in a variety of ways but generally
result when a liquid is forced through a specially designed
nozzle assembly. One example of a spray dosage
form is a metered-dose topical transdermal spray that delivers
a precisely controlled quantity of solution or suspension
on each activation.

Transdermal Delivery Systems (TDS)—TDS are
self-contained, discrete dosage forms that, when applied
to intact skin, are designed to deliver the drug(s) through
the skin to the systemic circulation. Systems typically
comprise an outer covering (barrier), a drug reservoir
that may have a drug release-controlling membrane, a
contact adhesive applied to some or all parts of the system
and the system/skin interface, and a protective liner
that is removed before the patient applies the system.
The dose of these systems is defined in terms of the release
rate of the drug(s) from the system and surface area
of the patch and is expressed as mass per unit time for a
given surface area. With these drug products, the skin
typically is the rate-controlling membrane for the drug
input into the body. The total duration of drug release
from the system and system surface area also may be
stated.
TDS work by diffusion: the drug diffuses from the drug
reservoir, directly or through the rate-controlling
membrane and/or contact adhesive if present, and then
through the skin into the general circulation. Typically,
modified-release systems are designed to provide drug
delivery at a constant rate so that a true steady-state
blood concentration is achieved and maintained until
the system is removed. Following removal of the system,
blood concentration declines at a rate consistent with
the pharmacokinetics of the drug.

Topical Aerosols—Topical aerosols are products that
are packaged under pressure. The active ingredients are
released in the form of fine liquid droplets or fine powder
particles upon activation of an appropriate valve system.
A special form is a metered-dose aerosol that delivers an
exact volume (dose) per each actuation.

Topical Solutions—Topical solutions are liquid preparations
that usually are aqueous but often contain other
solvents such as alcohol and polyols that contain one or
more dissolved chemical substances intended for topical
application to the skin or, as in the case of Lidocaine Oral
Topical Solution, USP, to the oral mucosal surface.

Topical Suspensions—Topical suspensions are liquid
preparations that contain solid particles dispersed in a
liquid vehicle intended for application to the skin. Some
suspensions labeled as lotions fall into this category.

Water-removable Bases—Water-removable bases
are oil-in-water emulsions (e.g., Hydrophilic Ointment,
USP) and are more correctly called creams (see Creams,
above). They also are described as ‘‘water-washable’’ because
they may be readily washed from the skin or clothing
with water, an attribute that makes them more
acceptable for cosmetic purposes. Some medicaments
may be more effective in these bases than in hydrocarbon
bases. Other advantages of the water-removable bases
are that they can 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, NF, 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,
above).

III. PRODUCT QUALITY TESTS FOR ALL TOPICALLY
APPLIED DRUG PRODUCTS
Universal tests are listed below and should be applied
to all topically applied drug products.
Description—A qualitative description of the dosage
form should be provided. The acceptance criteria should
include the final acceptable appearance. If color changes
during storage, a quantitative procedure may be appropriate.
It specifies the content or the label claim of the
article.

Identification—Identification tests are discussed in
Procedures under Tests and Assays in the General Notices
and Requirements. Identification tests should establish
the identity of the drug or drugs present in the article
and should discriminate between compounds of closely
related structure that are likely to be present. Identity
tests should be specific for the drug substances. The most
conclusive test for identity is the infrared absorption
spectrum (see Spectrophotometry and Light-Scattering
h851i and Spectrophotometric Identification Tests h197i).
If no suitable infrared spectrum can be obtained, other
analytical techniques can be used. Near infrared (NIR)
or Raman spectrophotometric methods also could be acceptable
for the sole identification of the drug product
formulation (see Near-infrared Spectrophotometry
h1119i and Raman Spectroscopy h1120i). Identification
solely by a single chromatographic retention time is
not regarded as specific. However, the use of two chromatographic
procedures for which the separation is
based on different principles or a combination of tests
in a single procedure can be acceptable. See Chromatography
h621i and Thin-layer Chromatographic Identification
Test h201i.

Assay—A specific and stability-indicating test should
be used to determine the strength (content) of the drug
product. See Antibiotics—Microbial Assays h81i, Chromatography
h621i, or Assay for Steroids h351i. In cases when
the use of a nonspecific assay is justified (e.g., Titrimetry
h541i), other supporting analytical procedures should be
used to achieve overall specificity. A specific procedure
should be used when there is evidence of excipient interference
with the nonspecific assay.

Impurities—Process impurities, synthetic by-products,
and other inorganic and organic impurities may
be present in the drug substance and excipients used
in the manufacture of the drug product. These impurities
are controlled by the drug substance and excipients
monographs. Organic impurities arising from the degradation
of the drug substance and those arising during
the manufacturing process of the drug product should
be monitored.
In addition to the universal tests listed above, the following
specific tests may be considered on a case-bycase
basis.

Physicochemical Properties—These are properties
such as pH h791i, Viscosity h911i, and Specific Gravity
h841i.

Uniformity of Dosage Units—This test is applicable
for TDS and for dosage forms packaged in single-unit
containers. It includes both the mass of the dosage form
and the content of the active substance in the dosage
form. The test can be performed by either content uniformity
or weight variation (see Uniformity of Dosage
Units h905i).

Water Content—A test for water content should be
included when appropriate (see Water Determination
h921i).

Microbial Limits—The type of microbial test(s) and
acceptance criteria should be based on the nature of
the drug substance, method of manufacture, and the intended
use of the drug product. See Microbiological Examination
of Nonsterile Products: Microbial Enumeration
Tests h61i and Microbiological Examination of Nonsterile
Products: Tests for Specified Microorganisms h62i).

Antimicrobial Preservative Content—Acceptance
criteria for preservative content in multidose products
should be established. They should be based on the
levels of antimicrobial preservative necessary to maintain
the product’s microbiological quality at all stages
throughout its proposed usage and shelf life (see Antimicrobial
Effectiveness Testing h51i).

Antioxidant Preservative Content—If antioxidant
preservatives are present in the drug product, tests of
their content normally should be determined.
Sterility—Depending on the use of the dosage form
(e.g., ophthalmic preparations), sterility of the product
should be demonstrated as appropriate (see Sterility Tests
h71i).

III. a. PRODUCT QUALITY TESTS FOR TOPICAL
DRUG PRODUCTS INTENDED FOR LOCAL ACTION
Additional tests for locally acting topical dosage forms
are provided in this section. Some of these may also be
used for some nitroglycerin semisolids.
Viscosity—Rheological properties such as viscosity of
semisolid dosage forms can influence their drug delivery.
Viscosity may directly influence the diffusion rate of a
drug at the microstructural level. Yet semisolid drug
products with comparatively high viscosity still can exhibit
high diffusion rates when compared to semisolid
products of comparatively lower viscosity. These obser-
vations emphasize the importance of rheologic properties
of semisolid dosage forms, specifically viscosity, on
drug product performance.
Depending on its viscosity, the rheological behavior of
a semisolid drug product may affect its application to
treatment site(s) and consistency of treatment and thus
the delivered dose. Therefore, maintaining reproducibility
of a product’s flow behavior at the time of release is an
important product manufacturing control that manufacturers
should use to maintain and demonstrate batch-tobatch
consistency. Most semisolid dosage forms, when
sheared, exhibit non-Newtonian behavior. Structures
formed within semisolid drug products during manufacturing
can show a wide range of behaviors, including
shear thinning viscosity, thixotropy, and structural damage
that may be irreversible or only partially reversible. In
addition, the viscosity of a semisolid dosage form is
highly influenced by factors such as the inherent physical
structure of the product, product sampling technique,
sample temperature for viscosity testing, container size
and shape, and specific methodology employed in the
measurement of viscosity.
A variety of methods can be used to characterize the
consistency of semisolid dosage forms, including penetrometry,
viscometry, and rheometry. With all methods
significant attention is warranted to the shear history of
the sample. For semisolids, viscometer geometries typically
fall into the following categories: concentric cylinders,
cone-plates, and spindles. Concentric cylinders
and spindles typically are used for more fluid, flowable
semisolid dosage forms. Cone-plate geometries are more
typically used when the sample size is small or the test
samples are more viscous and less flowable.
When contemplating what viscosity parameter(s) to
test, one must consider the properties of the semisolid
drug product both ‘‘at rest’’ (in its container) and as it
is sheared during application. The rheological properties
of the drug product at rest can influence the product’s
shelf life, and its properties under extensive shear can influence
its spreadability and, therefore, its application
rate that will affect the safety and efficacy of the drug
product. Further, although it is necessary to precisely
control the temperature of the test sample during the viscosity
measurement, one should link the specific choice
of the temperature to the intended use of the drug product
(e.g., skin temperature for external application effects).
Because semisolid dosage forms frequently display
non-Newtonian flow properties, formulators should give
close attention to the shear history of the sample being
tested, such as the shear applied during the filling operation,
shear applied dispensing the product from its container,
and shear when introducing the sample into the
viscometer. The point of reemphasizing this aspect is that
considerable variability and many failures to meet specifications
can be directly attributed to a lack of attention
to this detail rather than a change of viscosity (or flow
properties) of the drug product.

Tube (Content) Uniformity—Tube uniformity is the
degree of uniformity of the amount of active drug substance
among containers, i.e., tubes containing multiple
doses of the semisolid topical product. The uniformity of
dosage is demonstrated by assay of top, middle, and bottom
samples (typically 0.25–1.0 g) obtained from a tube
cut open to withdraw respective samples for drug assay.
Various topical semisolid products may show some
physical separation at accelerated storage temperatures
because emulsions, creams, and topical lotions are prone
to mild separation due to the nature of the vehicle.
The following procedure should be followed for testing
tube uniformity of semisolid topical dosage forms:

1. Carefully remove or cut off the bottom tube seal and
make a vertical cut up the face of the tube. Then
carefully cut the tube around the upper rim and
pry open the two ‘‘flaps’’ to expose the semisolid.

2. At the batch release and/or designated stability time
point remove and test 0.25- to 1.0-g samples from
the top, middle, and bottom of a tube. If assay values
for those tests are within 90.0%–110.0% of the labeled
amount of active drug, and the relative standard
deviation (RSD) is not more than 6%, then
the results are acceptable.

3. If at least one value of the testing described above is
outside 90.0%–110.0% of the labeled amount of
drug and none is outside 85.0%–115.0% and/or
the RSD is more than 6%, then test an additional
three randomly sampled tubes using top, middle,
and bottom samples as described. Not more than
3 of the 12 determinations should be outside the
range of 90%–110.0% of the labeled amount of
drug, none should be outside 85.0%–115.0%, and
the RSD should not be not more than 7%.

4. For very small tubes (e.g., 5 g or less), test only top
and bottom samples, and all values should be within
the range of 90.0%–110.0% of the labeled amount
of drug.

pH—When applicable, semisolid drug products should
be tested for pH at the time of batch release and designated
stability test time points for batch-to-batch monitoring.
Because most semisolid dosage forms contain
very limited quantities of water or aqueous phase, pH
measurements may be warranted only as a quality control
measure, as appropriate.

Particle Size—Particle size of the active drug substance
in semisolid dosage forms is determined and controlled
at the formulation development stage. When
applicable, semisolid drug products should be tested
for any change in the particle size or habit of the active
drug substance at the time of batch release and designated
stability test time points (for batch-to-batch monitoring)
that could compromise the integrity and/or
performance of the drug product, as appropriate.

Ophthalmic Dosage Forms—Ophthalmic dosage
forms must meet the requirements of Sterility Tests
h71i. If the specific ingredients used in the formulation
do not lend themselves to routine sterilization techniques,
ingredients that meet the sterility requirements
described under Sterility Tests h71i, along with aseptic
manufacture, may be employed. Ophthalmic ointments
must contain a suitable substance or mixture of substances
to prevent growth of, or to destroy, microorganisms
accidentally introduced when the container is
opened during use, unless otherwise directed in the individual
monograph or unless the formula itself is bacteriostatic
(see Added Substances under Ophthalmic Ointments
h771i). The finished ointment must be free from large
particles and must meet the requirements for Leakage
and for Metal Particles in Ophthalmic Ointments h771i.
The immediate containers for ophthalmic ointments
shall be sterile at the time of filling and closing. It is mandatory
that the immediate containers for ophthalmic
ointments be sealed and tamper-proof so that sterility
is assured at time of first use.

III. b. PRODUCT QUALITY TESTS FOR
TRANSDERMAL DRUG PRODUCTS
The product quality tests for TDS drug products include
assay, content uniformity, homogeneity, and adhesive.
Uniformity of Dosage Units—This test is applicable
for TDS and for dosage forms that are packaged in singleunit
containers. It includes both the mass of the dosage
form and the content of the active substance in the dosage
form. It can be done by either content uniformity or
weight variation (see Uniformity of Dosage Units h905i).
Assay of excipient(s) critical to the performance of the
product should be considered; e.g., residual solvent content
can affect certain patches.

Adhesive Test—Three types of adhesive tests generally
are performed to ensure the performance of the TDS
dosage forms. These are the peel adhesion test, tack test,
and shear strength test. The peel adhesion test measures
the force required to peel away a transdermal patch attached
to a stainless steel test panel substrate at panel angles
of 908 or 1808 following a dwell time of 1 minute
and peel rate of 300 mm/minute.
The tack test is used to measure the tack adhesive
properties of TDS dosage forms. With this test a probe
touches the adhesive surface with light pressure, and
the force required to break the adhesion after a brief period
of contact is measured.
The shear strength or creep compliance test is a measure
of the cohesive strength of TDS dosage forms. Two
types of shear testing are performed: dynamic and static.
During dynamic testing the TDS is pulled from the test
panel at a constant rate. With the static test the TDS is
subjected to a shearing force by means of a suspended
weight.

Leak Test—A test that is discriminating and capable
of detecting sudden drug release, such as leakage, from
the TDS should be performed. Although form, fill, and
seal TDS are more likely to display leak problems, all
TDS should be checked for sudden drug release (dose
dumping) during release testing of the dosage form.

IV. PRODUCT PERFORMANCE TEST FOR TOPICAL
DRUG PRODUCTS
A performance test for topical drug products must
have the ability to measure drug release from the finished
dosage form. It must be reproducible and reliable, and
although it is not a measure of bioavailability, the performance
test must be capable of detecting changes in drug
release characteristics from the finished product. The latter
have the potential to alter the biological performance
of the drug in the dosage form. Those changes may be
related to active or inactive/inert ingredients in the formulation,
physical or chemical attributes of the finished
formulation, manufacturing variables, shipping and storage
effects, aging effects, and other formulation factors
critical to the quality characteristics of the finished drug
product. Product performance tests can serve many useful
purposes in product development and in postapproval
drug product monitoring. They provide
assurance of equivalent performance for products that
have undergone postapproval raw material changes, relocation
or change in manufacturing site, and other
changes as detailed in the FDA’s Guidance for Industry
SUPAC-SS: Nonsterile Semisolid Dosage Forms; Scale-Up
and Postapproval Changes: Chemistry, Manufacturing,
and Controls; In Vitro Release Testing and In Vivo Bioequivalence
Documentation (May 1997) (available at
www.fda.gov/cder/guidance/1447fnl.pdf). In this general
chapter, a USP performance test for semi-solid dosage
forms to support batch release is considered. Details
of the procedure are provided in the general chapter Topical
and Transdermal Drug Products—Product Performance
Tests h725i (proposed).

V. IN VITRO DRUG RELEASE FROM SEMISOLID
DOSAGE FORMS
V. a. THEORY
The vertical diffusion cell (VDC) system is a simple, reliable,
and reproducible means of measuring drug release
from semisolid dosage forms. A thick layer (200–400 mg)
of the test semisolid is placed in contact with a reservoir.
Diffusive communication between the delivery system
and the reservoir takes place through an inert, highly permeable
support membrane. The membrane keeps the
product and the receptor medium separate and distinct.
Membranes are chosen to offer the least possible diffusional
resistance and not to be rate controlling. Samples
are withdrawn from the reservoir at various times. In
most cases, a 5- to 6-hour time period is all that is needed
to characterize drug release from a semisolid, and when
this is the case samples usually are withdrawn hourly.
After a short lag period, release of drug from the semisolid
dosage form in the VDC system is kinetically describable
by diffusion of a chemical out of a semiinfinite
medium into a sink. The momentary release rate
tracks the depth of penetration of the forming gradient
within the semisolid. Beginning at the moment when the
receding boundary layer’s diffusional resistance assumes
dominance of the kinetics of release, the amount of the
drug released, M, becomes proportional to p t (where
p t = time) for solution, suspension, or emulsion semisolid
systems alike. The momentary rate of release, dM/dt,
becomes proportional to 1/p t , which reflects the slowing
of drug release with the passage of time. The reservoir
is kept large so that drug release is into a medium
that remains highly dilute over the entire course of the
experiment relative to the concentration of drug dissolved
in the semisolid. In this circumstance drug release
is said to take place into a diffusional sink.
When a drug is totally in solution within the dosage
form, the amount of drug released as a function of time
can be described by:
M = 2 _ Cop D _ t / p
where:
M = amount of drug released into the sink per cm2
Co = drug concentration in releasing matrix
D = drug diffusion coefficient through the matrix.
A plot of M vs p t will be linear with a slope of
2 _ Cop D/ p
Equation 2 describes drug release when the drug is in
the form of a suspension within the dosage form:
M = p 2 _ Dm _ Cs(Q – Cs / 2)t
where:
Dm = drug diffusion coefficient in the semisolid matrix
Cs = drug solubility in the releasing matrix
Q = total amount of the drug in solution and suspended
in the matrix.
When Q44Cs, Equation 2 simplifies to Equation 3.
M = p 2 _ Q _Dm_ Cs _ t
A plot of M vs p t will be linear with a slope of
p 2QDmCs.
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
t plot because of a particle size effect. During release rate
experiments, every attempt should be made to keep the
composition of the formulation intact during the releasing
period.

V. b. APPLICATION OF DRUG RELEASE
Drug release results can be utilized for purposes such as
ensuring product sameness after SUPAC-SS-related
changes or successive batch release comparisons. This
is illustrated by the following example in which the initial
drug batch is referred to as Reference Batch (R) and the
changed or subsequent batch is referred to as Test Batch
(T). The individual amount released from R is plotted vs
time, and the resulting slope is determined. These are the
reference slopes (RS). The process is repeated to determine
the test slopes (TS).
The T/R ratios are calculated for each Test to Reference
Slope. This is facilitated if one creates a table where the
TS are listed down the left side of the table and the RS are
listed across the top of the table. The T/R ratios are then
calculated and entered in the body of the table.
After the T/R ratios have been calculated they are ordered
from lowest to highest. The 8th and 29th T/R ratios
are extracted and converted to percent (multiply by
100). To pass the first stage these ratios must fall within
the range of 75%–133.33%.
If the results do not meet this criterion, the SUPAC-SS
Guidance requires that four more tests of six cells each
should be run, resulting in 12 additional slopes per product
tested. The T/R ratios are calculated for all 18 slopes
per product tested. All 324 individual T/R ratios are calculated
and ordered lowest to highest. The 110th and the
215th ratios are evaluated against the specification of
75%–133.33%.
Third stage testing is not suggested.&1S (USP33)


Fonte: Pharmacopeial Forum
Vol. 35(3) [May–June 2009]
2009 The United States Pharmacopeial Convention All