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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 Scientic Liaison), Kris Derdzinski, Gary Ewing, Gordon Flynn, Howard Maibach,

Margareth Marques (USP Scientic 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 twogeneral categories, those applied for local actionand those for systemic effects. Local actions include

those 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) or transdermal 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, identi-cation, content uniformity, pH, microbial limits, andminimum ll and are part of the compendial mono-graph. Product performance tests are conducted to as-sess drug release from the nished 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 signicantly and may require differenttypes of apparatus. At present, a product performancetest exists only for semisolid formulations, specicallycreams, 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

Denitions 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 Dosage Forms h1151 i.

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 lm is left on the skin. Be-cause the medicinal use of a collodion depends on theformation of a protective lm, the lmshould be durable,tenacious in adherence, exible, and occlusive.

Creams

Creams are semisolid dosage forms that contain one or more 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-water emulsions. 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.

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

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

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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-water emulsion. 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 of small 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 specicterm is applicable, e.g., cream or ointment.

FoamsFoams are emulsied systems packaged in pressurized

containers or special dispensing devices that contain dis-persed gas bubbles, usually in a liquid continuous phase,that when dispensed has a uffy, 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 classied

as 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 uid, 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 of these four general classes.

Hydrocarbon Bases Hydrocarbon bases, known also

as oleaginous ointment bases, are represented by White 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 usedchiey for their emollient effects and are difcult to washoff. They do not dry out or change noticeably onaging.

Absorption Bases This class of bases may be dividedinto two groups: the rst 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 water and 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, or waxes. 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 of the nished 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.

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and Spectrophotometric Identication Tests h197 i). 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 identication method of the drugproduct formulation (see Near-infrared Spectrophotome-try h1119 i and Raman Spectroscopy h1120 i). Identica-tion solely by a single chromatographic retention timeis not regarded as specic. 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 h621 iand Thin-layer Chromatographic Identicationh201 i.Assay A specic and stability-indicating test should beused to determine the strength (content) of the drugproduct. See AntibioticsMicrobial Assays h81 i, h621 i,or Assay for Steroids h351 i. In cases when the use of non-specic assay is justied, e.g., Titrimetry h541 i, other sup-porting analytical procedures should be used to achieveoverall specicity. A specic procedure should be used

when there is evidence of excipient interference withthe nonspecic 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 h791 i, Viscosity h911 i, and Specic Gravity h841 i.Uniformity of Dosage Units This test is applicable for TDS 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 Dosage Units h905 i).Water Content A test for water content should be in-cluded when appropriate (see Water Determination

h921 i).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 h61 i and Microbiological Examination of Nonsterile Products: Tests for Specied Microorganisms h62 i.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 products 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 their content 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 Tests

h71 i).PRODUCT QUALITY TESTS FOR TOPICAL DRUG

PRODUCTS

General product quality tests such as identication, as-say, content uniformity (uniformity of dosage units), im-pur i t ie s , pH , wa te r con ten t , m ic rob ia l l im i t s ,antimicrobial preservative content, antioxidant preserva-tive content, and sterility should be performed for topical

drug products as described above. In addition, specictests for topical dosage forms, as described below, alsoshould be conducted.

Viscosity Rheological properties such as viscosity of semisolid dosage forms can inuence their drug delivery. Viscosity may directly inuence 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, specically viscosity, on drug product perfor-mance.

Depending on its viscosity, the rheological behavior of a semisolid drug product may affect its application totreatment site(s) and consistency of treatment and thusthe delivered dose. Therefore, maintaining reproducibil-ity of a products ow 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 of a semisolid dosage form is highly inuenced 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 specicmethodology 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-nicant 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 uid, owable semisolid




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

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 inuence the products

shelf life, and its properties under extensive shear can in-uence its spreadability and, therefore, its applicationrate that will affect the safety and efcacy 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 specic 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 ow properties, formulators should giveclose attention to the shear history of the sample beingtested, such as the shear applied during the lling 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-cations can be directly attributed to a lack of attentionto this detail rather than a change of viscosity (or owproperties) 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 0.251.0 g) obtainedfrom a tube cut open to withdraw respective samples for

drug 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 aps 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 of drug and none is outside 85.0% to 115.0% and/or the 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-c ingredients used in the formulation do not lend them-selves to routine sterilization techniques, ingredients thatmeet the sterility requirements described under Sterility

h71 i, 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 under Ophthalmic Ointments h771 i). The nished ointmentmust be free from large particles and must meet the re-quirements for Leakage and for Metal Particles in h771 i.The immediate containers for ophthalmic ointmentsshall be sterile at the time of lling and closing. It is man-datory that the immediate containers for ophthalmicointments be sealed and tamper-proof so that sterilityis assured at time of rst use.

PRODUCT QUALITY TESTS FOR TOPICAL DRUGPRODUCTS

General product quality tests such as identication, as-say, content uniformity (uniformity of dosage units), im-pur i ti e s , pH , wa te r con ten t, m ic rob ia l l im i t s,antimicrobial preservative content, antioxidant preserva-tive content, and sterility should be performed for topicaldrug products. In addition, specic 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 and Transdermal Drug Products h3i.






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PRODUCT PERFORMANCE TEST FOR TOPICALDRUG PRODUCTS

A performance test for topical drug products musthave the ability to measure drug release from the nisheddosage 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 drug

release characteristics from the nished 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 nishedformulation, manufacturing variables, shipping and stor-age effects, aging effects, and other formulation factorscritical to the quality characteristics of the nished 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 change

in manufacturing site, and other changes as detailed inthe FDA Guidance for IndustrySUPAC-SS: Nonsterile Semisolid 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 and

the 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 ve- 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-innite medium into a sink. The momentary release rate

tracks the depth of penetration of the forming gradientwithin the semisolid. Beginning at the moment when thereceding boundary layers diffusional resistance assumesdominance of the kinetics of release, the amount of thedrug released, M , becomes proportional to p t (where t =time) for solution, suspension, or emulsion semisolid sys-tems alike. The momentary rate of release, dM/dt , be-comes proportional to 1/ p t , which reects the slowingof 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 cm 2

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

A plot of M vs p 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 dosage

form:

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

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

A plot of M vs p t will be linear with a slope of p 2QDmCs .Coarse particles may dissolve so slowly that the mov-

ing boundary layer recedes to some extent behind theparticles. That situation introduces noticeable curvaturein the p t 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, 200400

mg 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 orice), 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 45 hours, and the volume sampled isreplaced with fresh receptor medium. To achieve sink conditions, 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




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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 donor chamber and a receptor chamber, separated by a donor compartment and held together by a clamp (see Figure 1). 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 of the dosage compartment that is covered with a glass

disk.The diameters of the orices of the donor chamber and the dosage compartment, which denes the dosagedelivery area for the test, should be sized within 5% of the specied diameter. The receptor chamber oriceshould never be smaller than the orice of the donor chamber and should be fabricated to the same size asthe donor chamber orice. The design of the VDC shouldfacilitate proper alignment of the dosage compartmentand receptor orices.

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






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

The cell body should be manufactured consistently,with uniform height and geometry. Cells should appear the same, and their internal receptor volumes should fallwithin 20% of their specied 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 600800 rpm). The speed se-lected should ensure adequate mixing of the receptor media during the test.

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

Qualication Unless otherwise specied in the indivi-dual monograph, the qualication of the apparatus is de-monstrated by verifying the test temperature and speedrequirements are met, along with a performance verica-tion test (PVT). The PVT is passed if two tests of 6 cellscomply with FDAs SUPAC-SS requirements of a 90% con-dence interval. The PVT is performed by one analysttesting the specied reference standard in duplicate.The rst test with 6 cells is performed and is dened asthe reference. The second test of 6 cells is dened as

the test. The PVT is passed if the second test passes the90% condence interval with reference to the rst refer-ence test.

Procedure Unless otherwise specied in the individualmonograph, degas the medium using an appropriatetechnique. With the stirring device in place, ll the VDCwith the specied media and allow time for it to come toa temperature of 32 8C. If necessary, saturate the mem-brane in the specied 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 ll the entire cavity of the dosage

compartment. 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 specied 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 of the 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 Drug

ReleasedCreams 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 specied in the individual mono-graph, the release requirements are met if the followinghave been achieved:

The Amount Released (mg/cm 2) at a given time ( t 1, t 2,etc.) is calculated for each sample as follows:

whereAu = Area of the current sampleAs = Average area of the standardC s = Concentration of the standard, mg/mLV c = Volume of the diffusion cell, mL

AR = Amount released, mg/cm2

Ao = Area of the orice, cm 2V s = Volume of the sample aliquot, mL.

For each cell the individual amount released is plottedvs time, and the slope of the resulting line (rate of drugrelease, ux) 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 Test Batch (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 of the table and the Reference Slopes are listed across the




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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 8 th and 29 th T/R Ratiosare extracted and converted to percent (multiply by100). To pass the rst 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 per product tested. All 324 individual T/R Ratios are calcu-lated and ordered lowest to highest. The 110 th and the215 th ratios are evaluated against the specication of 75% to 133.33%.

No third stage is suggested.

PVT Method for USP Hydrocortisone CreamReference Standard

Materials and Equipment USP Hydrocortisone Cream Reference Standard; 25-mm, 0.45- mm hydrophilic polysulfone [N OTE a suitablelter is Tuffryn available from www.pall.com] membranelters; vacuum ltration apparatus consisting of a lter holder with a medium or ne-porosity sintered glassholder base, funnel with a 250-mL capacity, and mag-netic stirrer; small and smooth jewelers 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 Preparation Mix 60 mL of USP Alcohol with 140 mL of water to pre-pare a 30% alcoholic media. Degas the media by lteringthrough a 47-mm, 0.45- mm membrane by vacuum ltra-tion. Assemble the ltration apparatus placing a mag-netic stir bar (approximately 1in 0.25 in) in thereceiving ask. Place the apparatus on a magnetic stirringplate, and spin the bar at a moderate rate. Apply vacuumand pass the media through the lter while stirring. After all media have passed through the lter, continue stirringwhile maintaining a vacuum for 2 min. Applying vacuumand stirring beyond 2 min may change the composition

of the wateralcohol media. Care should be taken to en-sure that the period of time that the media is under vac-uum after the ltration 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 Apparatus Set the circulating bath to a temperature (typically32.5 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 Preparation Carefully lift one membrane at its very edge with jew-

elers 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 of the 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 over the membrane, lling 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 Test Fill 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: 600800 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 RS6TS1 TS1/RS1 TS1/RS2 TS1/RS3 TS1/RS4 TS1/RS5 TS1/RS6TS2 TS2/RS1 TS2/RS2 TS2/RS3 TS2/RS4 TS2/RS5 TS2/RS6TS3 TS3/RS1 TS3/RS2 TS3/RS3 TS3/RS4 TS3/RS5 TS3/RS6TS4 TS4/RS1 TS4/RS2 TS4/RS3 TS4/RS4 TS4/RS5 TS4/RS6TS5 TS5/RS1 TS5/RS2 TS5/RS3 TS5/RS4 TS5/RS5 TS5/RS6TS6 TS6/RS1 TS6/RS2 TS6/RS3 TS6/RS4 TS6/RS5 TS6/RS6






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Sampling Procedure At 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. After the sixth cell has been sampled, resume the stirrer rotation.

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 lters [N OTE a suitable lter is Tuffryn availablefrom www.pall.com]; HPLC System with UV detector capable of 10- mL injections; 50 mm 3.9 mm columnthat contains 5 mm packing L1.Procedure

Mobile Phase Preparation

Prepare and degas a sufcient volume of mobile phaseto complete the analysis of the samples collected. For each 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 Preparation Obtain a portion of appropriately dried Hydrocorti-

sone Cream Reference Standard. Prepare a stock hydro-cortisone standard solution at a concentration of approximately 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 a

working 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; ow 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 specied.

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:

Modied 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 bottom

of a modied, 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 ow cell of USPApparatus 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 xed 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 signicantly because of differences in their composition and fabrication. TDS sys-tems can be categorized as (1) liquid form, ll, and sealsystems, (2) peripheral adhesive systems, or (3) matrix

systems. 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 inuence 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 dosageforms semipermeable lm 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 for transdermal 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 h905 i). Assay of excipient(s) critical to the performance of theproduct should be considered; e.g., residual solvent con-tent can affect certain patches.




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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 90 8 or 180 8 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 of

detecting sudden drug release, such as leakage, fromthe TDS should be performed. Although form, ll, 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 for transdermal drug products also must have the ability tomeasure drug release from the nished dosage form,must be reproducible and reliable, and must be capableof detecting changes in drug release characteristics fromthe nished product. Again, the latter have the potential

to 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 n-ished preparation, manufacturing variables, shippingand storage, age, and other critical-to-quality character-istics of the nished dosage form.

When based on sound scientic principles, productperformance tests canbe used for pre- and postmanufac-turing purposes such as during the product research anddevelopment phase, as a basic quality control tool, for demonstrating 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 modied paddle method, issimpler and is applicable formost types, sizes, andshapesof TDS.

Apparatus 5 (Paddle over Disk Method)

Apparatus Use the paddle and vessel assembly fromApparatus 2 as described in Dissolution h711 i, with theaddition of a stainless steel disk assembly ( 1) designedfor holding the transdermal system at the bottom of the 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 disk assembly 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 at and is positioned so that the release surface isparallel with the bottom of the paddle blade (see Figure 2).

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 h711 i.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 asat as possible. The system may be attached to the disk






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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 at at the bottom of the vessel with the re-lease surface facing up and parallel to the edge of the

paddle 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 specied 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 specied inthe individual monograph, the requirements are met if the 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 Number Tested

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 of the 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% of the 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

h711

i, but replace the basket and shaft

with 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 specications 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.




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

Dissolution Medium Use the medium specied in theindividual monograph (see h711 i).Procedure Place the stated volume of the DissolutionMedium in the vessel of the apparatus specied 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) that

is 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 systemts 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 specied in the individual monograph. Within the time interval specied, or at each of the timesstated, withdraw a quantity of Dissolution Medium for

analysis from a zone midway between the surface of the 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 specied inthe individual monograph, the requirements are met if

the 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-






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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 of any convenient size that permits maintaining the tem-perature, T , inside the containers at 32 0.5 8C or withinthe allowable range, as specied 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 specied in the individualmonograph.

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

Fig. 5a. Transdermal System HolderAngled Disk.




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Fig. 5b. Transdermal System HolderCylinder.

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 between

the 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-ed in the individual monograph (see h711 i).

Procedure Suspend each sample holder from a verti-cally reciprocating shaker so that each system is continu-ously immersed in an accurately measured volume of Dissolution Medium within a calibrated container pre-equilibrated to temperature, T . Reciprocate at a fre-quency of about 30 cycles/min with an amplitude of about 2 cm, or as specied in the individual monograph,for the specied time in the medium specied for eachtime point. Remove the solution containers from thebath, cool to room temperature, and add sufcient 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, rst time point around 1hour, second around 50% of total drug release, and thirdaround 85% drug release. Unless otherwise specied in

the individual monograph, the requirements are met if the quantities of the active ingredients released fromthe system conform to Acceptance Table 1 under Dissolu-tion h711 i for transdermal drug delivery systems, or asspecied 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 Products

h3i and Product Performance Tests: Topical and Transder-mal Drug Products h725 i. Both of these appear elsewherein this issue of Pharmacopeial Forum .ACKNOWLEDGMENT

The authors acknowledge the helpful suggestions of Loice 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-polytef mesh 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.




transdermal stim article

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