Topical and Transdermal Drug Products - Semantic …...Topical and Transdermal Drug Products The Topical/Transdermal Ad Hoc Advisory Panel for the USP Performance Tests of Topical

Topical and Transdermal Drug Products

The Topical/Transdermal Ad Hoc Advisory Panel for the USP Performance Tests of Topical and Transdermal Dosage Forms:Clarence T. Ueda (Chair), Vinod P. Shah (USP Scientific Liaison), Kris Derdzinski, Gary Ewing, Gordon Flynn, Howard Maibach,

Margareth Marques (USP Scientific Liaison),a Howard Rytting,b Steve Shaw, Kailas Thakker, and Avi Yacobi.

ABSTRACT This Stimuli article provides general information about the test methods that should be employed toensure the quality and performance of topical and transdermal drug products. The term topical drug products refers toall formulations applied to the skin except transdermal delivery systems (TDS) or transdermal patches that will beaddressed separately.

INTRODUCTION

Drug products topically administered via the skin fallinto two general categories, those applied for local actionand those for systemic effects. Local actions includethose at or on the surface of the skin, those that exerttheir actions on the stratum corneum, and those thatmodulate the function of the epidermis and/or the der-mis. Common products in the former category includecreams, gels, ointments, pastes, suspensions, lotions,foams, sprays, aerosols, and solutions. Creams, oint-ments, and gels generally are referred to as semisoliddosage forms. The most common drug products appliedto the skin for systemic effects are referred to as self-adhering transdermal drug delivery systems (TDS) ortransdermal patches.

Two categories of tests, product quality tests and prod-uct performance tests, are performed with drug productsto provide assurances of batch-to-batch quality, reprodu-cibility, reliability, and performance. Product quality testsare performed to assess attributes such as assay, identifi-cation, content uniformity, pH, microbial limits, andminimum fill and are part of the compendial mono-graph. Product performance tests are conducted to as-sess drug release from the finished dosage form.

This Stimuli article provides general information aboutthe test methods that should be employed to ensure thequality and performance of topical and transdermal drugproducts. The term topical drug products refers to all for-mulations applied to the skin except transdermal deliverysystems (TDS) or transdermal patches that will be ad-dressed separately.

Topical dosage forms include solutions (for which re-lease testing is not indicated), collodion, suspensions,emulsions (e.g., lotions), semisolids (e.g., foams, oint-ments, pastes, creams, and gels), solids (e.g., powdersand aerosols), and sprays. The physical characteristicsof these dosage forms vary widely.

Therefore, the in vitro release test for those productsalso may differ significantly and may require differenttypes of apparatus. At present, a product performancetest exists only for semisolid formulations, specificallycreams, ointments, and gels. That test employs the ver-tical diffusion cell (VDC) system. The VDC system is sim-ple to operate and yields reliable and reproducible resultswhen employed by properly trained laboratory person-nel.

TDS or transdermal patches are physical devices ap-plied to the skin and vary in their composition and meth-od of fabrication. Therefore, they release their activeingredients by different mechanisms.

GLOSSARY OF TERMS

Definitions of topical drug products, some aspects re-lated to the manufacture of these products, and a glos-sary of dosage form names commonly used can be foundin General Information Chapter Pharmaceutical DosageForms h1151i.

Collodion

Collodion (pyroxylin solution; see USP monograph), isa solution of nitrocellulose in ether and acetone, some-times with the addition of alcohol. As the volatile solventsevaporate, a dry celluloid-like film is left on the skin. Be-cause the medicinal use of a collodion depends on theformation of a protective film, the film should be durable,tenacious in adherence, flexible, and occlusive.

Creams

Creams are semisolid dosage forms that contain one ormore drug substances dissolved or dispersed in a suitablebase. This term traditionally has been applied to semi-solids that possess a relatively soft, spreadable consis-tency formulated as either water-in-oil or oil-in-wateremulsions. However, more recently the term has been re-stricted to products consisting of oil-in-water emulsionsor aqueous microcrystalline dispersions of long-chainfatty acids or alcohols that are water washable and morecosmetically and aesthetically acceptable.

a Correspondence should be addressed to: Margareth Marques, PhD,Senior Scientist, Documentary Standards Division, US PharmacopeialConvention, 12601 Twinbrook Parkway, Rockville, MD 20852-1790;tel. 301.816.8106; e-mail [email protected] Deceased.

STIMULI TO THE REVISION PROCESSPharmacopeial ForumStimuli articles do not necessarily reflect the policies

Vol. 35(3) [May–June 2009]of the USPC or the USP Council of Experts750

#2009 The United States Pharmacopeial Convention, Inc. All Rights Reserved.

Sti

mul

ito

the

Rev

isio

nP

roce

ss

Emulsions

Emulsions are viscid, multiphase systems in which oneor more liquids are dispersed throughout another immis-cible liquid in the form of small droplets. When oil is thedispersed phase and an aqueous solution is the continu-ous phase, the system is designated as an oil-in-wateremulsion. Conversely, when water or an aqueous solu-tion is the dispersed phase and oil or oleaginous materialis the continuous phase, the system is designated as awater-in-oil emulsion. Emulsions are stabilized by emulsi-fying agents that prevent coalescence, the merging ofsmall droplets into larger droplets, and, ultimately, intoa single separated phase. Emulsifying agents (surfac-tants) act by concentrating at the interface betweenthe immiscible liquids, thereby providing a physical bar-rier that reduces the tendency for coalescence. Surfac-tants also reduce the interfacial tension between thephases, facilitating the formation of small droplets uponmixing. The term emulsion is not used if a more specificterm is applicable, e.g., cream or ointment.

Foams

Foams are emulsified systems packaged in pressurizedcontainers or special dispensing devices that contain dis-persed gas bubbles, usually in a liquid continuous phase,that when dispensed has a fluffy, semisolid consistency.

Gels

Gels (sometimes called Jellies) are semisolid systemsconsisting of either suspensions composed of small inor-ganic particles or large organic molecules interpene-trated by a liquid. When the gel mass consists of anetwork of small discrete particles, the gel is classifiedas a two-phase system (e.g., Aluminum Hydroxide Gel,USP). In a two-phase system if the particle size of the dis-persed phase is relatively large, the gel mass is sometimesreferred to as a magma (e.g., Bentonite Magma, NF).Both gels and magmas may be thixotropic, formingsemisolids after standing and becoming liquid when agi-tated. They should be shaken before use to ensure homo-geneity and should be labeled to that effect (see TopicalSuspensions, below). Single-phase gels consist of organicmacromolecules uniformly distributed throughout a liq-uid with no apparent boundary between the dispersedmacromolecule and liquid.

Lotions

Although the term lotion may be applied to a solution,lotions usually are fluid, somewhat viscid emulsiondosage forms for external application to the skin. Lotionsshare many characteristics with creams. See Creams, To-pical Solutions, and Topical Suspensions, herein.

Ointments

Ointments are semisolids intended for external appli-cation to the skin or mucous membranes. They usuallycontain 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 intofour general classes: hydrocarbon bases, absorptionbases, water-removable bases, and water-soluble bases.Each therapeutic ointment possesses as its base one ofthese four general classes.

Hydrocarbon Bases—Hydrocarbon bases, known alsoas ‘‘oleaginous ointment bases,’’ are represented byWhite Petrolatum and White Ointment (both USP). Onlysmall amounts of an aqueous component can be incor-porated into these bases. Hydrocarbon bases serve tokeep medicaments in prolonged contact with the skinand act as occlusive dressings. These bases are usedchiefly for their emollient effects and are difficult to washoff. They do not ‘‘dry out’’ or change noticeably onaging.

Absorption Bases—This class of bases may be dividedinto two groups: the first consists of bases that permitthe incorporation of aqueous solutions with the forma-tion of a water-in-oil emulsion (e.g., Hydrophilic Petrola-tum and Lanolin, both USP), and the second groupconsists of water-in-oil emulsions that permit the incor-poration of additional quantities of aqueous solutions(Lanolin, USP). Absorption bases also are useful asemollients.

Water-removable Bases—Water-removable bases areoil-in-water emulsions (e.g., Hydrophilic Ointment,USP), and are more correctly called ‘‘creams’’ (seeCreams, above). They also are described as ‘‘water-wash-able’’ because they may be readily washed from the skinor clothing with water, an attribute that makes themmore acceptable for cosmetic purposes. Some medica-ments may be more effective in these bases than in hy-drocarbon bases. Other advantages of the water-removable bases are that they may be diluted with waterand that they favor the absorption of serous discharges indermatological conditions.

Water-soluble Bases—This group of so-called ‘‘grease-less ointment bases’’ comprises water-soluble constitu-ents. Polyethylene Glycol Ointment, NF is the onlypharmacopeial preparation in this group. Bases of thistype offer many of the advantages of the water-remova-ble bases and, in addition, contain no water-insolublesubstances such as petrolatum, anhydrous lanolin, orwaxes. They are more correctly called Gels (see Gels,above).

Choice of Base—The choice of an ointment base de-pends on many factors, such as the action desired, thenature of the medicament to be incorporated and itsbioavailability and stability, and the requisite shelf life ofthe finished product. In some cases, it is necessary to usea base that is less than ideal in order to achieve the sta-bility required. Drugs that hydrolyze rapidly, for example,are more stable in hydrocarbon bases than in bases thatcontain water, even though they may be more effectivein the latter.

STIMULI TO THE REVISION PROCESSPharmacopeial Forum Stimuli articles do not necessarily reflect the policies

Vol. 35(3) [May–June 2009] of the USPC or the USP Council of Experts 751


Stim

ulito

theR

evisionP

rocess

Ophthalmic Ointments

Ophthalmic ointments are semisolids for applicationto the eye. Special precautions must be taken in the prep-aration of ophthalmic ointments. They are manufacturedfrom sterilized ingredients under rigidly aseptic condi-tions, must meet the requirements under Sterility Testsh71i, and must be free of large particles. The medicinalagent is added to the ointment base either as a solutionor as a micronized powder.

Pastes

Pastes are semisolid dosage forms that contain a highpercentage (often � 50%) of finely dispersed solids witha stiff consistency intended for topical application. Oneclass is made from a single-phase aqueous gel (e.g., Car-boxymethylcellulose Sodium Paste, USP). The other class,the fatty pastes (e.g., Zinc Oxide Paste, USP), consists ofthick, stiff ointments that do not ordinarily flow at bodytemperature and therefore serve as protective coatingsover the areas to which they are applied.

Powders

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

Sprays

Sprays are products formed by the generation of drop-lets of solution containing dissolved drug for applicationto the skin or mucous membranes. The droplets may beformed in a variety of ways but generally result from for-cing the liquid through a specially designed nozzle as-sembly. One example of a spray dosage form is ametered-dose topical transdermal spray that delivers aprecisely controlled quantity of solution or suspensionon each activation.

Topical Aerosols

Topical aerosols are products that are packaged underpressure. The active ingredients are released in the formof fine liquid droplets or fine powder particles upon acti-vation of an appropriate valve system. A special form is ametered-dose aerosol that delivers an exact volume(dose) per each actuation.

Topical Solutions

Topical solutions are liquid preparations, that usuallyare aqueous but often contain other solvents such as al-cohol and polyols that contain one or more dissolvedchemical substances intended for topical application tothe skin, or, as in the case of Lidocaine Oral Topical Solu-tion USP, to the oral mucosal surface.

Topical Suspensions

Topical suspensions are liquid preparations that con-tain solid particles dispersed in a liquid vehicle intendedfor application to the skin. Some suspensions labeled as‘‘Lotions’’ fall into this category.

Transdermal Delivery Systems

Transdermal delivery systems (TDS) are self-contained,discrete dosage forms that, when applied to intact skin,are designed to deliver the drug(s) through the skin tothe systemic circulation. Systems typically comprise anouter covering (barrier), a drug reservoir that may havea drug release–controlling membrane, a contact adhe-sive applied to some or all parts of the system and thesystem/skin interface, and a protective liner that is re-moved before the patient applies the system. The doseof these systems is defined in terms of the release rateof the drug(s) from the system and surface area of thepatch and is expressed as mass per unit time for a givensurface area. With these drug products, the skin typicallyis the rate-controlling membrane for the drug input intothe body. The total duration of drug release from the sys-tem and system surface area may also be stated.

TDS work by diffusion: The drug diffuses from the drugreservoir, directly or through the rate-controlling mem-brane and/or contact adhesive if present, and thenthrough the skin into the general circulation. Typically,modified-release systems are designed to provide drugdelivery at a constant rate so that a true steady-stateblood concentration is achieved and maintained untilthe system is removed. Following removal of the system,blood concentration declines at a rate consistent withthe pharmacokinetics of the drug.

PRODUCT QUALITY TESTS—GENERAL

The International Conference on Harmonization (ICH)Guidance Q6A (available at www.ich.org) recommendsspecifications (tests, procedures, and acceptance criteria)to ensure that commercialized drug products are safeand effective at release and during shelf life. Tests thatare universally applied to ensure safety and efficacy in-clude description, identification, assay, and impurities.

Description—A qualitative description of the dosageform should be provided. The acceptance criteria shouldinclude the final acceptable appearance. If color changesduring storage, a quantitative procedure may be appro-priate. It specifies the content or the label claim of thearticle.

Identification—Identification tests are discussed in Pro-cedures under Tests and Assays in the General Notices andRequirements. Identification tests should establish theidentity of the drug or drugs present in the article andshould discriminate between compounds of closely re-lated structure that are likely to be present. Identity testsshould be specific for the drug substances. The most con-clusive test for identity is the infrared absorption spec-trum (see Spectrophotometry and Light-scattering h851i




Sti

mul

ito

the

Rev

isio

nP

roce

ss

and Spectrophotometric Identification Tests h197i). If nosuitable infrared spectrum can be obtained, other analy-tical techniques can be used. Near infrared (NIR) or Ra-man spectrophotometric methods also could beacceptable as the sole identification method of the drugproduct formulation (see Near-infrared Spectrophotome-try h1119i and Raman Spectroscopy h1120i). Identifica-tion solely by a single chromatographic retention timeis not regarded as specific. However, the use of two chro-matographic procedures for which the separation isbased on different principles or a combination of testsin a single procedure can be acceptable. See Chromatog-raphy h621i and Thin-layer Chromatographic Identificationh201i.

Assay—A specific and stability-indicating test should beused to determine the strength (content) of the drugproduct. See Antibiotics—Microbial Assays h81i, h621i,or Assay for Steroids h351i. In cases when the use of non-specific assay is justified, e.g., Titrimetry h541i, other sup-porting analytical procedures should be used to achieveoverall specificity. A specific procedure should be usedwhen there is evidence of excipient interference withthe nonspecific assay.

Impurities—Process impurities, synthetic by-products,and other inorganic and organic impurities may be pres-ent in the drug substance and excipients used in themanufacture of the drug product. These impurities arecontrolled by the drug substance and excipients mono-graphs. Organic impurities arising from the degradationof the drug substance and those arising during the man-ufacturing process of the drug product should be moni-tored.

In addition to the universal tests listed above, the fol-lowing tests may be considered on a case-by-case basis:

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

Uniformity of Dosage Units—This test is applicable forTDS and for dosage forms packaged in single-unit con-tainers. It includes both the mass of the dosage formand the content of the active substance in the dosageform. The test can be performed by either content uni-formity or weight variation (see Uniformity of DosageUnits h905i).

Water Content—A test for water content should be in-cluded when appropriate (see Water Determinationh921i).

Microbial Limits—The type of microbial test(s) and ac-ceptance criteria should be based on the nature of thedrug substance, method of manufacture, and the in-tended use of the drug product. See Microbiological Ex-amination of Nonsterile Products: Microbial EnumerationTests h61i and Microbiological Examination of NonsterileProducts: Tests for Specified Microorganisms h62i.

Antimicrobial Preservative Content—Acceptance cri-teria for preservative content in multidose productsshould be established. They should be based on the lev-

els of antimicrobial preservative necessary to maintainthe product’s microbiological quality at all stagesthroughout its proposed usage and shelf life (see Antimi-crobial Effectiveness Testing h51i).

Antioxidant Preservative Content—If antioxidant pre-servatives are present in the drug product, tests of theircontent normally should be determined.

Sterility—Depending on the use of the dosage form,e.g., ophthalmic preparations, sterility of the productshould be demonstrated as appropriate (see Sterility Testsh71i).

PRODUCT QUALITY TESTS FOR TOPICAL DRUGPRODUCTS

General product quality tests such as identification, as-say, content uniformity (uniformity of dosage units), im-pur i t ies , pH, water content , microb ia l l imi t s ,antimicrobial preservative content, antioxidant preserva-tive content, and sterility should be performed for topicaldrug products as described above. In addition, specifictests for topical dosage forms, as described below, alsoshould be conducted.

Viscosity—Rheological properties such as viscosity ofsemisolid dosage forms can influence their drug delivery.Viscosity may directly influence the diffusion rate of drugat the microstructural level. Yet semisolid drug productswith relatively high viscosity still can exhibit high diffu-sion rates when compared to semisolid products of com-paratively lower viscosity. These observations emphasizethe importance of rheologic properties of semisolid do-sage forms, specifically viscosity, on drug product perfor-mance.

Depending on its viscosity, the rheological behavior ofa semisolid drug product may affect its application totreatment site(s) and consistency of treatment and thusthe delivered dose. Therefore, maintaining reproducibil-ity of a product’s flow behavior at the time of release is animportant product manufacturing control to maintainand demonstrate batch-to-batch consistency. Mostsemisolid dosage forms, when sheared, exhibit non-Newtonian behavior. Structures formed within semisoliddrug products during manufacturing can show a widerange of behaviors, including shear thinning viscosity,thixotropy, and structural damage that may be irreversi-ble or only partially reversible. In addition, the viscosity ofa semisolid dosage form is highly influenced by such fac-tors as the inherent physical structure of the product,product sampling technique, sample temperature for vis-cosity testing, container size and shape, and specificmethodology employed in the measurement of viscosity.

A variety of methods can be used to characterize theconsistency of semisolid dosage forms, such as penetro-metry, viscometry, and rheometry. With all methods sig-nificant attention is warranted to the shear history of thesample. For semisolids, viscometer geometries typicallyfall into the following categories: concentric cylinders,cone-plates, and spindles. Concentric cylinders and spin-dles typically are used for more fluid, flowable semisolid




Stim

ulito

theR

evisionP

rocess

dosage forms. Cone-plate geometries are more typicallyused when the sample size is small or the test samples aremore viscous and less flowable.

When contemplating what viscosity parameter(s) totest, one must consider the properties of the semisoliddrug product both ‘‘at rest’’ (in its container) and as itis sheared during application. The rheological propertiesof the drug product at rest can influence the product’sshelf life, and its properties under extensive shear can in-fluence its spreadability and, therefore, its applicationrate that will affect the safety and efficacy of the drugproduct. Further, although it is necessary to preciselycontrol the temperature of the test sample during the vis-cosity measurement, one should link the specific choiceof the temperature to the intended use of the drug prod-uct (e.g., skin temperature for external application ef-fects).

Because semisolid dosage forms frequently displaynon-Newtonian flow properties, formulators should giveclose attention to the shear history of the sample beingtested, such as the shear applied during the filling opera-tion, shear applied dispensing the product from its con-tainer, and shear introducing the sample into theviscometer. The point of reemphasizing this aspect is thatconsiderable variability and many failures to meet speci-fications can be directly attributed to a lack of attentionto this detail rather than a change of viscosity (or flowproperties) of the drug product.

Tube (Content) Uniformity—Tube uniformity is the de-gree of uniformity of the amount of active drug sub-stance among containers, i.e., tubes containingmultiple doses of the semisolid topical product. The uni-formity of dosage is demonstrated by assay of top, mid-dle, and bottom samples (typically 0.25–1.0 g) obtainedfrom a tube cut open to withdraw respective samples fordrug assay.

Various topical semisolid products may show somephysical separation at accelerated storage temperaturesbecause emulsions, creams, and topical lotions are proneto mild separation due to the nature of the vehicle.

The following procedure should be followed for test-ing 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. Thencarefully cut the tube around the upper rim andpry open the two ‘‘flaps’’ to expose the semisolid.

2. At the batch release and/or designated stability timepoint remove and test 0.25- to 1.0-g samples fromthe top, middle, and bottom of a tube. If assay valuesfor those tests are within 90.0% to 110.0% of the la-beled amount of active drug, and the relative stan-dard deviation (RSD) is not more than 6%, thenthe results are acceptable.

3. If at least 1 value of the testing described above isoutside 90.0% to 110.0% of the labeled amount ofdrug and none is outside 85.0% to 115.0% and/orthe RSD is more than 6%, then test an additional 3randomly sampled tubes using top, middle, and bot-tom samples as described. Not more than 3 of the 12determinations should be outside the range of 90%

to 110.0% of the labeled amount of drug, noneshould be outside 85.0% to 115.0%, and the RSDshould not be not more than 7%.

4. For very small tubes (e.g., 5 g or less), test only topand bottom samples, and all values should be withinthe range of 90.0% to 110.0% of the labeledamount of drug.

pH—When applicable, semisolid drug products shouldbe tested for pH at the time of batch release and desig-nated stability test time points for batch-to-batch moni-toring. Because most semisolid dosage forms containvery limited quantities of water or aqueous phase, pHmeasurements may be warranted only as a quality con-trol measure, as appropriate.

Particle Size—Particle size of the active drug substancein semisolid dosage forms is determined and controlledat the formulation development stage. When applicable,semisolid drug products should be tested for any changein the particle size or habit of the active drug substance atthe time of batch release and designated stability testtime points (for batch-to-batch monitoring) that couldcompromise the integrity and/or performance of thedrug product, as appropriate.

Ophthalmic Dosage Forms—Ophthalmic dosage formsmust meet the requirements of Sterility h71i. If the speci-fic ingredients used in the formulation do not lend them-selves to routine sterilization techniques, ingredients thatmeet the sterility requirements described under Sterilityh71i, along with aseptic manufacture, may be employed.Ophthalmic ointments must contain a suitable substanceor mixture of substances to prevent growth of, or to de-stroy, microorganisms accidentally introduced when thecontainer is opened during use, unless otherwise direc-ted in the individual monograph or unless the formulaitself is bacteriostatic (see Added Substances underOphthalmic Ointments h771i). The finished ointmentmust be free from large particles and must meet the re-quirements for Leakage and for Metal Particles in h771i.The immediate containers for ophthalmic ointmentsshall be sterile at the time of filling and closing. It is man-datory that the immediate containers for ophthalmicointments be sealed and tamper-proof so that sterilityis assured at time of first use.

PRODUCT QUALITY TESTS FOR TOPICAL DRUGPRODUCTS

General product quality tests such as identification, as-say, content uniformity (uniformity of dosage units), im-pur i t i e s , pH, water content , microbia l l imi ts ,antimicrobial preservative content, antioxidant preserva-tive content, and sterility should be performed for topicaldrug products. In addition, specific tests for topical dos-age forms, such as viscosity, tube (content) uniformity,and particle size also should be conducted. For details,see General Chapter Product Quality Tests: Topical andTransdermal Drug Products h3i.




Sti

mul

ito

the

Rev

isio

nP

roce

ss

PRODUCT PERFORMANCE TEST FOR TOPICALDRUG PRODUCTS

A performance test for topical drug products musthave the ability to measure drug release from the finisheddosage form. It must be reproducible and reliable, andalthough it is not a measure of bioavailability, the perfor-mance test must be capable of detecting changes in drugrelease characteristics from the finished product. The lat-ter have the potential to alter the biological performanceof the drug in the dosage form. Those changes may berelated to active or inactive/inert ingredients in the for-mulation, physical or chemical attributes of the finishedformulation, manufacturing variables, shipping and stor-age effects, aging effects, and other formulation factorscritical to the quality characteristics of the finished drugproduct.

Product performance tests can serve many useful pur-poses in product development and in postapproval drugproduct monitoring. They provide assurance of equiva-lent performance for products that have undergonepostapproval raw material changes, relocation or changein manufacturing site, and other changes as detailed inthe FDA Guidance for Industry—SUPAC-SS: NonsterileSemisolid Dosage Forms, Manufacturing Equipment Adden-dum, Dec 1998, available at http://www.fda.gov/cder/guidance/1722dft.pdf.

Vertical Diffusion Cell Method

Theory—The vertical diffusion cell (VDC) system is a sim-ple, reliable, and reproducible means of measuring drugrelease from semisolid dosage forms. A thick layer of thetest semisolid is placed in contact with a reservoir. Diffu-sive communication between the delivery system andthe reservoir takes place through an inert, highly perme-able support membrane. The membrane keeps the prod-uct and the receptor medium separate and distinct.Membranes are chosen to offer the least possible diffu-sional resistance and not to be rate controlling. Samplesare withdrawn from the reservoir at various times. Inmost cases, a five- to six-hour time period is all that isneeded to characterize drug release from a semisolid,and when this is the case samples usually are withdrawnhourly.

After a short lag period, release of drug from the semi-solid dosage form in the VDC system is kinetically de-scribable by diffusion of a chemical out of a semi-infinite medium into a sink. The momentary release ratetracks the depth of penetration of the forming gradientwithin the semisolid. Beginning at the moment when thereceding boundary layer’s diffusional resistance assumesdominance of the kinetics of release, the amount of thedrug released, M, becomes proportional to

pt (where t =

time) for solution, suspension, or emulsion semisolid sys-tems alike. The momentary rate of release, dM/dt, be-comes proportional to 1/

pt, which reflects the slowing

of drug release with the passage of time. The reservoir iskept large so that drug release is into a medium that re-mains highly dilute over the entire course of the experi-

ment relative to the concentration of drug dissolved inthe semisolid. In this circumstance, drug release is saidto take place into a diffusional sink.

When a drug is totally in solution within the dosageform, the amount of drug released as a function of timecan be described by:

where:M = amount of drug released into the sink per cm2

Co = drug concentration in releasing matrixD = drug diffusion coefficient through the matrix.

A plot of M vsp

t will be linear with a slope of

The following equation describes drug release whenthe drug is in the form of a suspension within the dosageform:

whereCs = drug solubility in the releasing matrixDm = drug diffusion coefficient in the semisolid matrixQ = total amount of the drug in solution and suspended inthe matrix.

When Q>>Cs, the previous equation simplifies to:

A plot of M vsp

t will be linear with a slope ofp2QDmCs.Coarse particles may dissolve so slowly that the mov-

ing boundary layer recedes to some extent behind theparticles. That situation introduces noticeable curvaturein the

pt plot because of a particle size effect. During re-

lease rate experiments, every attempt should be made tokeep the composition of the formulation intact over thereleasing period.

In Vitro Drug Release Using the VDC—A VDC system isused to determine in vitro release of semisolid (cream,ointment, and gel) preparations. Typically, 200–400mg of a cream, ointment, or gel is spread evenly over asuitable synthetic inert support membrane. The mem-brane, with its application side up, is placed in a verticaldiffusion cell (typically of 15-mm diameter orifice), e.g., aFranz cell. The release rate experiment is carried out at 32� 1 8C, except in the case of vaginal creams for which thetemperature should be 37 � 1 8C. Sampling generally isperformed over 4–5 hours, and the volume sampled isreplaced with fresh receptor medium. To achieve sinkconditions, the receptor medium must have a high ca-pacity to dissolve or carry away the drug, and the recep-tor media should not exceed 10% of Cs (drug solubility in




Stim

ulito

theR

evisionP

rocess

the releasing matrix) at the end of the test. The test isdone with groups of 6 cells. Results from 12 cells, 2 runsof 6 cells, are used to document the release rate.

Application of Drug Release—The drug release resultscan be utilized for purposes such as ensuring productsameness after scale-up and post-approval relatedchanges or successive batch release comparison.

The VDC assembly consists of two chambers, a donorchamber and a receptor chamber, separated by a donorcompartment and held together by a clamp (see Figure1). This type of cell is commonly used for testing the invitro release rate of topical drug products such as creams,gels, and ointments. Alternative diffusion cells that con-form to the same general design and size can be used.

The VDC body normally is made from borosilicateglass, although different materials may be used to manu-facture the body and other parts of the VDC assembly.None of the materials should react with or absorb thetest product or samples.

In the donor compartment, the semisolid dosage formsample sits on a synthetic membrane within the cavity ofthe dosage compartment that is covered with a glassdisk.

The diameters of the orifices of the donor chamberand the dosage compartment, which defines the dosagedelivery area for the test, should be sized within � 5% ofthe specified diameter. The receptor chamber orificeshould never be smaller than the orifice of the donorchamber and should be fabricated to the same size asthe donor chamber orifice. The design of the VDC shouldfacilitate proper alignment of the dosage compartmentand receptor orifices.

Figure 1. Vertical diffusion cell. (All measurements are expressed in mm unless noted otherwise).




Sti

mul

ito

the

Rev

isio

nP

roce

ss

The thickness of the dosage compartment normally is1.5 mm. This thickness should be sized within � 10% ofthe specified thickness.

The cell body should be manufactured consistently,with uniform height and geometry. Cells should appearthe same, and their internal receptor volumes should fallwithin � 20% of their specified volume.

Volume—Before conducting testing, determine the truevolume of each receptor chamber in the VDC. The vol-ume of each VDC should be determined with the internalstirring device in place.

Temperature—The temperature of the receptor mediaduring the test should remain within � 1.0 8C of the tar-get temperature (typically 32 8C).

Speed—The rotational speed tolerance is � 10% fromthe target speed (normally 600–800 rpm). The speed se-lected should ensure adequate mixing of the receptormedia during the test.

Sampling Time—Samples should be taken at the speci-fied times within a tolerance of � 2% or � 2 min, which-ever is greatest.

Qualification—Unless otherwise specified in the indivi-dual monograph, the qualification of the apparatus is de-monstrated by verifying the test temperature and speedrequirements are met, along with a performance verifica-tion test (PVT). The PVT is passed if two tests of 6 cellscomply with FDA’s SUPAC-SS requirements of a 90% con-fidence interval. The PVT is performed by one analysttesting the specified reference standard in duplicate.The first test with 6 cells is performed and is defined asthe reference. The second test of 6 cells is defined asthe test. The PVT is passed if the second test passes the90% confidence interval with reference to the first refer-ence test.

Procedure—Unless otherwise specified in the individualmonograph, degas the medium using an appropriatetechnique. With the stirring device in place, fill the VDCwith the specified media and allow time for it to come toa temperature of 32 8C. If necessary, saturate the mem-brane in the specified media (generally receptor media)for 30 min. Place the membrane on the dosage compart-ment and invert. Apply the material that will be testedinto the cavity of the dosage compartment, and spreadthe material out to fill the entire cavity of the dosagecompartment.

Assemble each of the prepared dosage compartmentsto each VDC with the membrane down and in contactwith the receptor media. During this application it is im-portant to ensure that there are no bubbles under themembrane. When all dosage compartments and the re-maining components are in place, turn on the stirring de-vice, which constitutes time zero.

Follow the specified sampling procedure and collectan aliquot from each VDC for analysis. Ensure that duringthe sampling process bubbles are not introduced into thecell. Exercise care during sampling and replenishment ofthe medium in order not to introduce bubbles.

With some cells it is acceptable to have up to threebubbles under the membrane if the bubbles are less than1 mm in diameter. With some cells, bubbles may be re-moved from the receptor chamber during the test by tip-ping the cell as long as this process is required only onetime per position.

Calculation of Rate (Flux) and Amount of DrugReleased

Creams and ointments are considered extended-release preparations. Their drug release largely dependson the formulation and method of preparation. The re-lease rate of a given drug product from different manu-facturers is likely to be different. It is assumed that thedrug release of the product is linked to the clinical batch.

Unless otherwise specified in the individual mono-graph, the release requirements are met if the followinghave been achieved:

The Amount Released (mg/cm2) at a given time (t1, t2,etc.) is calculated for each sample as follows:

whereAu = Area of the current sampleAs = Average area of the standardCs = Concentration of the standard, mg/mLVc = Volume of the diffusion cell, mLAR = Amount released, mg/cm2

Ao = Area of the orifice, cm2

Vs = Volume of the sample aliquot, mL.For each cell the individual amount released is plotted

vs time, and the slope of the resulting line (rate of drugrelease, flux) is determined. The average of 6 + 6 slopesrepresents the drug release of the dosage form andserves as the standard for the drug product.

Application of Drug Release

The drug release results can be utilized for purposessuch as ensuring product sameness after SUPAC-SS–re-lated changes or successive batch release comparison.This is illustrated by the following example where the in-itial drug batch is referred to as Reference Batch (R) andthe changed or subsequent batch is referred to as TestBatch (T). The individual amount released from R isplotted vs time, and the resulting slope is determined.These are the reference slopes. The process is repeatedto determine the test slopes.

The T/R Ratios are calculated for each Test-to-Refer-ence Slope. This is most easily done by creating a tablein which the Test Slopes are listed down the left side ofthe table and the Reference Slopes are listed across the




Stim

ulito

theR

evisionP

rocess

top of the table. The T/R ratios are then calculated andentered in the body of the table where the rows and col-umns intersect (Table 1).

After the T/R Ratios have been calculated they are or-dered from lowest to highest. The 8th and 29th T/R Ratiosare extracted and converted to percent (multiply by100). To pass the first stage these ratios must fall withinthe range of 75% to 133.33%.

If the results do not meet this criterion, the FDA SUPAC-SS guidance requires that 4 more tests of 6 cells eachmust be run, resulting in 12 additional slopes per producttested. The T/R ratios are calculated for all 18 slopes perproduct tested. All 324 individual T/R Ratios are calcu-lated and ordered lowest to highest. The 110th and the215th ratios are evaluated against the specification of75% to 133.33%.

No third stage is suggested.

PVT Method for USP Hydrocortisone CreamReference Standard

Materials and EquipmentUSP Hydrocortisone Cream Reference Standard; 25-

mm, 0.45-mm hydrophilic polysulfone [NOTE—a suitablefilter is Tuffryn available from www.pall.com] membranefilters; vacuum filtration apparatus consisting of a filterholder with a medium or fine-porosity sintered glassholder base, funnel with a 250-mL capacity, and mag-netic stirrer; small and smooth jeweler’s forceps; depres-sion porcelain color plate; Diffusion Cell System with 6diffusion cells and temperature control circulator; andsampling syringe or device and collection vials.

Procedure

Receptor Medium PreparationMix 60 mL of USP Alcohol with 140 mL of water to pre-

pare a 30% alcoholic media. Degas the media by filteringthrough a 47-mm, 0.45-mm membrane by vacuum filtra-tion. Assemble the filtration apparatus placing a mag-netic stir bar (approximately 1in � 0.25 in) in thereceiving flask. Place the apparatus on a magnetic stirringplate, and spin the bar at a moderate rate. Apply vacuumand pass the media through the filter while stirring. Afterall media have passed through the filter, continue stirringwhile maintaining a vacuum for 2 min. Applying vacuumand stirring beyond 2 min may change the composition

of the water–alcohol media. Care should be taken to en-sure that the period of time that the media is under vac-uum after the filtration is complete is limited to 2 min.

Immediately transfer the degassed receptor mediumto a suitable receptor medium bottle and stopper. Placethe receptor medium bottle in the jacketed beaker andallow the media to equilibrate for 30 min before use.

Preparation of ApparatusSet the circulating bath to a temperature (typically

32.5 8C) that will maintain the temperature in the diffu-sion cells at 32 8C during the test. Place the appropriatemagnetic stirrer in each diffusion cell. Allow the system toequilibrate for at least 30 min before beginning the test.

Sample PreparationCarefully lift one membrane at its very edge with jew-

eler’s forceps. Place the membrane on a paper tissue, andblot any extreme excess solution (a slight excess solutionis desired). Carefully place the membrane in the center ofthe dosage compartment. Place the dosage compart-ment, with the membrane centered on the underside,onto a tissue and press down on the compartment. Ap-ply an appropriate amount of Hydrocortisone Cream Ref-erence Standard (between 200 mg and 400 mg) on topof the membrane and inside of the dosage compartmentcavity. Use a spatula to carefully smooth the material overthe membrane, filling the entire cavity of the dosagecompartment. Wipe any excess material from the surfaceof the dosage compartment. Repeat for a total of 6 sam-ple preparations.

Performing the TestFill the diffusion cells with receptor media, and allow

time to equilibrate to 32 8C. Ensure that the stirrers arenot rotating and that there is a positive meniscus cover-ing the complete top of each diffusion cell. Place theglass disk on top of the dosage compartment againstthe sample. Place the dosage compartment/glass disk as-sembly on the top of the diffusion cell, avoiding bubbles.Inspect under the membrane for bubbles. Assemble thecell. Repeat for each cell.

Begin the test according to the following test para-meters: temperature: 32 8C; stir speed: 600–800 rpm; to-tal test time: 6 h; sampling times: 1, 2, 3, 4, and 6 h.

Table 1. Calculation of T/R Ratios

RS1 RS2 RS3 RS4 RS5 RS6

TS1 TS1/RS1 TS1/RS2 TS1/RS3 TS1/RS4 TS1/RS5 TS1/RS6









Sti

mul

ito

the

Rev

isio

nP

roce

ss

Sampling ProcedureAt each of the stated sampling times, collect a sample

from each cell as follows:Stop the stirrer 30 sec before sampling. Repeat sam-

pling procedure for each cell in order from 1 to 6. Afterthe sixth cell has been sampled, resume the stirrerrotation.

High-performance Liquid Chromatography(HPLC) Hydrocortisone Analysis

USP Hydrocortisone Cream Reference Standard; ace-tonitrile, HPLC grade; water, HPLC grade; USP alcohol,95%; 47-mm, 0.45-mm hydrophilic polysulfone mem-brane filters [NOTE—a suitable filter is Tuffryn availablefrom www.pall.com]; HPLC System with UV detectorcapable of 10-mL injections; 50 mm � 3.9 mm columnthat contains 5 mm packing L1.

Procedure

Mobile Phase PreparationPrepare and degas a sufficient volume of mobile phase

to complete the analysis of the samples collected. Foreach 1 L of mobile phase mix 200 mL of acetonitrile with800 mL of water. If necessary, adjust the mobile phasecomposition to achieve an approximate retention timeof 7 min for the hydrocortisone peak.

Standard PreparationObtain a portion of appropriately dried Hydrocorti-

sone Cream Reference Standard. Prepare a stock hydro-cortisone standard solution at a concentration ofapproximately 0.20 mg/mL in USP alcohol. A solutionof 20 mg hydrocortisone in 100 mL of USP alcohol is sug-gested for the stock standard preparation. Prepare aworking standard solution by making a 5-fold dilutionof the stock standard in a solution of 30:70 USP alco-hol/water mixture. For example, dilute 2 mL to 10 mL.

Chromatographic Conditions

Wavelength—242 nm; flow rate: 1 mL/min; injectionvolume: 10 mL; run time: 10 min; column: 50 mm �3.9 mm C-18, 5-mm (Symmetry); mobile phase:20/80 acetonitrile/water. Begin the analysis by making5 replicate injections of the working hydrocortisone stan-dard solution for system suitability.

System Suitability Requirements—Relative standarddeviation: < 2%; tailing factor: NMT 1.5. Make single in-jections of each of the samples obtained during the in vi-tro release testing. Bracket injections of samples withsingle standard injections after the analysis of the 2-hsamples, 4-h samples, and 6-h samples. Calculate the re-sults as specified.

Other Test Systems

Other diffusion-type cell devices are available as poten-tial apparatus for drug release testing from topical/der-mal drug products. However, only limited data areavailable for these devices. USP will consider these de-

vices for inclusion in this General Chapter after they arevalidated and collaborative study data have been evalu-ated. The devices currently include:

Modified Holding Cell—A sample of semisolid dosageform is placed in an inert holding cell with a suitablemembrane separating the dosage form from the recep-tor medium. The holding cell is positioned at the bottomof a modified, reduced-volume dissolution vessel of theUSP Apparatus 2 type and is stirred with a mini paddle.

USP Apparatus 4 (Flow-through Cell) with a Trans-cap Semisolid Cell—A sample of the semisolid dosageform is placed in the trans-cap cell with a suitable mem-brane separating the dosage form from the receptor me-dium. The trans-cap cell with membrane facing upwardis inserted into the 22.6-mm flow cell of USP Apparatus 4(Flow-through Cell).

Extraction Cell—A sample of the semisolid dosage formis placed in an inert extraction cell with a suitable mem-brane separating the dosage form from the receptor me-dium. The test is performed using the USP Apparatus 2assembly with the extraction cell positioned at the bot-tom of the dissolution vessel.

Product Quality Tests for Transdermal DeliverySystems

TDS are physical devices that deliver their active ingre-dient at a fixed rate over a prolonged period of time, e.g.,from days to as long as one month. Their methods of de-livery or release mechanisms vary significantly because ofdifferences in their composition and fabrication. TDS sys-tems can be categorized as (1) liquid form, fill, and sealsystems, (2) peripheral adhesive systems, or (3) matrixsystems. The latter two categories include the subcate-gories of monolithic, matrix, multi-laminate, and drug-in-adhesive systems. Moreover, recent advances in thedesign of novel transdermal drug delivery systems hasexpanded the list of basic TDS categories further, includ-ing, systems that employ iontophoresis, heat-assisteddrug delivery, or micro-needles.

In all three principal TDS categories, the drug is in solu-tion or suspension. Factors that can influence drug re-lease and, therefore, the performance of TDS dosageforms include changes in formulation composition invol-ving the adhesive, solvents, viscosity-modifying agents,permeation enhancers, and changes in the dosageform’s semipermeable film or laminate.

The product quality tests for transdermal drug deliverysystem include assay, content uniformity, homogeneity,and adhesive test.

Uniformity of dosage units—This test is applicable fortransdermal systems and for dosage forms that are pack-aged in single-unit containers. It includes both the massof the dosage form and the content of the active sub-stance in the dosage form. It can be done by either con-tent uniformity or weight variation (see h905i).

Assay of excipient(s) critical to the performance of theproduct should be considered; e.g., residual solvent con-tent can affect certain patches.




Stim

ulito

theR

evisionP

rocess

Adhesive Test—Three types of adhesive tests generallyare performed to ensure the performance of the TDSdosage forms. These are the peel adhesion test, tack test,and shear strength test. The peel adhesion test measuresthe force required to peel away a transdermal patch at-tached to a stainless steel test panel substrate at panel an-gles of 908 or 1808 following a dwell time of 1 min andpeel rate of 300 mm/min.

The tack test is used to measure the tack adhesiveproperties of TDS dosage forms. With this test a probetouches the adhesive surface with light pressure, andthe force required to break the adhesion after a brief per-iod of contact is measured.

The shear strength or creep compliance test is a meas-ure of the cohesive strength of TDS dosage forms. Twotypes of shear testing are performed: dynamic and static.During dynamic testing the TDS is pulled from the testpanel at a constant rate. With the static test the TDS issubjected to a shearing force by means of a suspendedweight.

Leak Test—A test that is discriminating and capable ofdetecting sudden drug release, such as leakage, fromthe TDS should be performed. Although form, fill, andseal TDS are more likely to display leak problems, allTDS should be checked for sudden drug release (dosedumping) during release testing of the dosage form.

Product Performance Tests for TDS

As with topical drug products, a performance test fortransdermal drug products also must have the ability tomeasure drug release from the finished dosage form,must be reproducible and reliable, and must be capableof detecting changes in drug release characteristics fromthe finished product. Again, the latter have the potentialto alter the desired pharmacologic effect(s) of the activeingredient. Such changes could be related to active or in-active/inert ingredients in the formulation or physicaldosage form, physical or chemical attributes of the fin-ished preparation, manufacturing variables, shippingand storage, age, and other critical-to-quality character-istics of the finished dosage form.

When based on sound scientific principles, productperformance tests can be used for pre- and postmanufac-turing purposes such as during the product research anddevelopment phase, as a basic quality control tool, fordemonstrating product similarity, or for demonstratingcompliance with FDA guidelines (e.g., approval andpostapproval changes in the dosage form).

In vitro drug release methods for transdermal patchesinclude USP Apparatus 5 (Paddle over Disk Method), Ap-paratus 6 (Rotating Cylinder Method), or Apparatus 7(Reciprocating Holder Method). In general, it has beenfound that Apparatus 5, a modified paddle method, issimpler and is applicable for most types, sizes, and shapesof TDS.

Apparatus 5 (Paddle over Disk Method)

Apparatus—Use the paddle and vessel assembly fromApparatus 2 as described in Dissolution h711i, with theaddition of a stainless steel disk assembly (1) designedfor holding the transdermal system at the bottom ofthe vessel. Other appropriate devices may be used, pro-vided they do not absorb, react with, or interfere with thespecimen being tested (2). The temperature should bemaintained at 32 � 0.5 8C. During the test maintain adistance of 25 � 2 mm between the paddle blade andthe surface of the disk assembly. The vessel may be cov-ered during the test to minimize evaporation. The diskassembly for holding the transdermal system is designedto minimize any dead volume between the disk assemblyand the bottom of the vessel. The disk assembly holds thesystem flat and is positioned so that the release surface isparallel with the bottom of the paddle blade (see Figure2).

Fig. 2. Paddle over Disk. (All measurements are expressed inmm unless noted otherwise.)

Apparatus Suitability Test and Dissolution Medium—Proceed as directed for Apparatus 2 in h711i.

Procedure—Place the stated volume of the DissolutionMedium in the vessel, assemble the apparatus withoutthe disk assembly, and equilibrate the medium to 32 �0.5 8C. Apply the transdermal system to the disk assem-bly, ensuring that the release surface of the system is asflat as possible. The system may be attached to the disk




Sti

mul

ito

the

Rev

isio

nP

roce

ss

by applying a suitable adhesive (3) to the disk assembly.Dry for 1 min. Press the system, release surface side up,onto the adhesive-coated side of the disk assembly. If amembrane (4) is used to support the system, it shouldbe applied in such a way that no air bubbles occur be-tween the membrane and the release surface. Place thedisk assembly flat at the bottom of the vessel with the re-lease surface facing up and parallel to the edge of thepaddle blade and surface of the Dissolution Medium.The bottom edge of the paddle should be 25 � 2 mmfrom the surface of the disk assembly. Immediately startoperation of the apparatus at the rate specified in themonograph. At each sampling time interval, withdrawa specimen from a zone midway between the surfaceof the Dissolution Medium and the top of the blade, notless than 1 cm from the vessel wall. Perform the analysis

on each sampled aliquot as directed in the individualmonograph, correcting for any volume losses, as neces-sary. Repeat the test with additional transdermal systems.

Sampling Time—The test time points, generally three,are expressed in hours. Specimens should be withdrawnwithin a tolerance of � 15 min or � 2% of the statedtime; select the tolerance that results in the narrowesttime interval.

In Vitro Release Criteria—Unless otherwise specified inthe individual monograph, the requirements are met ifthe quantities of active ingredient released from the sys-tem conform to Acceptance Table 1 for transdermal drugdelivery systems. Continue testing through the three lev-els unless the results conform at either L1 or L2.

Acceptance Table 1

Level NumberTested

Criteria

L1 6 No individual value lies outside the stated range.

L2 6 The average value of the 12 units (L1 + L2) lies within the stated range. No in-dividual value is outside the stated range by more than 10% of the average ofthe stated range.

L3 12 The average value of the 24 units (L1 + L2 + L3) lies within the stated range. Notmore than 2 of the 24 units are outside the stated range by more than 10% ofthe average of the stated range, and none of the units is outside the statedrange by more than 20% of the average of the stated range.

Apparatus 6 (Rotating Cylinder Method)

Apparatus—Use the vessel assembly from Apparatus 1as described in h711i, but replace the basket and shaftwith a stainless steel cylinder stirring element and main-tain the temperature at 32 � 0.5 8C during the test. Theshaft and cylinder components of the stirring element are

fabricated from stainless steel to the specifications shownin Figure 3. The dosage unit is placed on the cylinder atthe beginning of each test. The distance between the in-side bottom of the vessel and the cylinder is maintainedat 25 � 2 mm during the test.




Stim

ulito

theR

evisionP

rocess

Fig. 3. Cylinder Stirring Element (5). (All measurements are expressed in cm unless noted otherwise.)

Dissolution Medium—Use the medium specified in theindividual monograph (see h711i).

Procedure—Place the stated volume of the DissolutionMedium in the vessel of the apparatus specified in the in-dividual monograph, assemble the apparatus, and equi-librate the Dissolution Medium to 32 � 0.5 8C. Unlessotherwise directed in the individual monograph, preparethe test system before the test as follows:

Remove the protective liner from the system, andplace the adhesive side on a piece of Cuprophan (4) thatis not less than 1 cm larger on all sides than the system.Place the system, Cuprophan-covered side down, on aclean surface, and apply a suitable adhesive (3) to the ex-posed Cuprophan borders. If necessary, apply additionaladhesive to the back of the system. Dry for 1 min. Care-fully apply the adhesive-coated side of the system to theexterior of the cylinder so that the long axis of the systemfits around the circumference of the cylinder. Press theCuprophan covering to remove trapped air bubbles.Place the cylinder in the apparatus, and immediately ro-tate at the rate specified in the individual monograph.Within the time interval specified, or at each of the timesstated, withdraw a quantity of Dissolution Medium for

analysis from a zone midway between the surface ofthe Dissolution Medium and the top of the rotating cylin-der, not less than 1 cm from the vessel wall. Perform theanalysis as directed in the individual monograph, correct-ing for any volume losses as necessary. Repeat the testwith additional transdermal drug delivery systems.

Sampling Time—Proceed as directed for Apparatus 5.

In Vitro Release Criteria—Unless otherwise specified inthe individual monograph, the requirements are met ifthe quantities of active ingredient released from the sys-tem conform to Acceptance Table 1 for transdermal drugdelivery systems. Continue testing through the three lev-els unless the results conform at either L1 or L2.

Apparatus 7 (Reciprocating Holder Method)

Apparatus—The assembly consists of a set of volumetri-cally calibrated or tared solution containers made of glassor other suitable inert material (6), a motor and drive as-sembly to reciprocate the system vertically and to indexthe system horizontally to a different row of vessels auto-




Sti

mul

ito

the

Rev

isio

nP

roce

ss

matically if desired, and a set of suitable sample holders[see Figure 4 (2) and Figures 5a and 5b). The solution con-tainers are partially immersed in a suitable water bath ofany convenient size that permits maintaining the tem-perature, T, inside the containers at 32� 0.5 8C or withinthe allowable range, as specified in the individual mono-graph, during the test. No part of the assembly, includ-ing the environment in which the assembly is placed,

should contribute motion, agitation, or vibration beyondthat due to the smooth, vertically reciprocating sampleholder.

An apparatus that permits observation of the systemand holder during the test is preferable. Use the size con-tainer and sample holder specified in the individualmonograph.

Fig. 4. Reciprocating Disk Sample Holder (7).

Fig. 5a. Transdermal System Holder—Angled Disk.




Stim

ulito

theR

evisionP

rocess

Fig. 5b. Transdermal System Holder—Cylinder.

Sample Preparation A—Attach the system to be testedto a suitable sample holder with 2-cyano acrylate glue.

Sample Preparation B—Press the system onto a dry, un-used piece of Cuprophan (4), nylon netting, or equiva-lent with the adhesive side against the selectedsubstrate, taking care to eliminate air bubbles betweenthe substrate and the release surface. Attach the systemto a suitably sized sample holder with a suitable O-ring sothat the back of the system is adjacent to and centeredon the bottom of the disk-shaped sample holder or cen-tered around the circumference of the cylindrical-shapedsample holder. Trim the excess substrate with a sharpblade.

Sample Preparation C—Attach the system to a suitableholder as described in the individual monograph.

Dissolution Medium—Use the Dissolution Medium speci-fied in the individual monograph (see h711i).

Procedure—Suspend each sample holder from a verti-cally reciprocating shaker so that each system is continu-ously immersed in an accurately measured volume ofDissolution Medium within a calibrated container pre-equilibrated to temperature, T. Reciprocate at a fre-quency of about 30 cycles/min with an amplitude ofabout 2 cm, or as specified in the individual monograph,for the specified time in the medium specified for eachtime point. Remove the solution containers from thebath, cool to room temperature, and add sufficient solu-tion (water in most cases) to correct for evaporativelosses. Perform the analysis as directed in the individualmonograph. Repeat the test with additional drug deliv-ery systems as required in the individual monograph.

Sampling Time—Proceed as directed for Apparatus 5.

In Vitro Release Criteria—Drug release should be mea-sured at least at 3 time points, first time point around 1hour, second around 50% of total drug release, and thirdaround 85% drug release. Unless otherwise specified in

the individual monograph, the requirements are met ifthe quantities of the active ingredients released fromthe system conform to Acceptance Table 1 under Dissolu-tion h711i for transdermal drug delivery systems, or asspecified in the individual monograph. Continue testingthrough the three levels unless the results conform ateither L1 or L2.

NOTE

This Stimuli article is subdivided into 2 chapters: Prod-uct Quality Tests: Topical and Transdermal Drug Productsh3i and Product Performance Tests: Topical and Transder-mal Drug Products h725i. Both of these appear elsewherein this issue of Pharmacopeial Forum.

ACKNOWLEDGMENT

The authors acknowledge the helpful suggestions ofLoice Kikwai, Erika Stippler, and Will Brown of USP andSatish Asotra of Taro Pharmaceuticals.

REFERENCES

1. Disk assembly (stainless support disk) is availablefrom www.millipore.com.

2. A suitable device is the watchglass-patch-polytefmesh sandwich assembly available as the Transder-mal Sandwich from www.hansonresearch.com.

3. Use Dow Corning, MD7-4502 Silicone Adhesive65% in ethyl acetate, or the equivalent.

4. Use Cuprophan, Type 150 pm, 11 � 0.5-mm thick,an inert, porous cellulosic material, which is availablefrom www.medicell.co.uk or www.varianinc.com.

5. The cylinder stirring element is available fromwww.varianinc.com.

6. The materials should not sorb, react with, or interferewith the specimen being tested.

7. The reciprocating disk sample holder is available atwww.varianinc.com.




Sti

mul

ito

the

Rev

isio

nP

roce

ss

Documents

Topical and Transdermal Drug Products - Semantic …...Topical and Transdermal Drug Products The Topical/Transdermal Ad Hoc Advisory Panel for the USP Performance Tests of Topical