active compounds release from semisolid dosage forms

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Active Compounds Release from Semisolid Dosage Forms

ANNA OLEJNIK, JOANNA GOSCIANSKA, IZABELA NOWAKAdam Mickiewicz University in Poznan, Faculty of Chemistry, ul. Umultowska 89b, 61-714 Poznan, Poland

Received 20 June 2012; revised 17 July 2012; accepted 18 July 2012

Published online 8 August 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/jps.23289

ABSTRACT: The aim of this paper is to review all the aspects of the in vitro release test-

ing (IVRT) from semisolid dosage forms. Although none of the official dissolution methods has

been specified for use with semisolid dosage forms, their utility for assessing release rates of

drugs from semisolid dosage forms has become a topic of considerable interest. One can expect

to overcome such complexity in the future, when the official “Topical and Transdermal Drug

Products—Product Performance Tests” will be published in an issue of the Pharmacopeial Fo-

rum. Many factors such as type of the dissolution medium, membrane, temperature, and speedhave an influence on the mechanism and kinetics of the release testing from gels, creams, and

ointments; therefore, those parameters have been widely discussed. © 2012 Wiley Periodicals,

Inc. and the American Pharmacists Association J Pharm Sci 101:4032–4045, 2012

Keywords: active transport; controlled release; diffusion; emulsions; formulation; gels; kinet-

ics; in vitro models

INTRODUCTION

In pharmaceutical industry, dissolution testing wasprimarily used as a fundamental tool in qualitycontrol of the solid oral dosage forms including immediate-/sustained-action tablets and capsules.1–3

However, this method was extended to analyzesemisolid dosage forms (such as creams, gels, andointments) as well. The method is known as in vitro

release testing (IVRT) because the active ingredienthas to diffuse and be released by the vehicle.4–7

Semisolid dosage forms cause distinctive problemsin the development of in vitro release technologiessimply because of the physicochemical properties of formulations and the specific physiological environ-ment in which they should release their content.8–11

Those products are complex formulations, which arecomposed of two phases (water and oil), one is an

external phase and the other is an internal phase(Fig. 1).12,13 The active compound is usually dissolvedin one of the above-mentioned phases. However, oc-casionally, the active compound is not fully soluble;therefore, a three-phase system is created because of the dispersing of the active compound in one or both of the phases. Diverse factors such as the size of the dis-persed particles, the interfacial tension between the

Correspondence to: Anna Olejnik (Telephone:+48-61-829-12-95;Fax: +48-61-829-12-07; E-mail: [email protected])

Journal of Pharmaceutical Sciences, Vol. 101, 4032–4045 (2012)

© 2012 Wiley Periodicals, Inc. and the American Pharmacists Association

phases, and the rheology of the formulation determinethe physical properties of the semisolid dosage form.

All of these factors have an influence on the releaseprofile of the active ingredient.4,8,9,11,13

In vitro release testing is recommended by the

United States Food and Drug Administration asa measure of “product sameness” during scale-upand postapproval changes for semisolids (SUPAC-SS). This method is routinely used during productdevelopment to fine-tune a formulation. However,the suggested uses of the tests to establish batch-to-batch uniformity, product certification, and possi-ble bioequivalence are fairly new and have been thesubject of much debate. It is important to properly

validate a release test before using it for productqualification.4,6,15–17 It must be reproducible and re-liable, and although it is not a measure of bioavail-

ability, the performance test must be capable of de-tecting changes in drug-release characteristics fromthe finished product. Changes in drug-release char-acteristics have the potential to alter the biologicalperformance of the drug in the dosage form. Suchchanges may be related to active or inactive/inert in-gredients in the formulation, physical or chemical at-tributes of the finished formulation, manufacturing

variables, shipping and storage effects, aging effects,and other formulation factors that are critical to thequality characteristics of the finished drug product.

An abundant literature exists on in vitro release of drugs present in suspension semisolid formulations.7

4032 JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 11, NOVEMBER 2012



ACTIVE COMPOUNDS RELEASE FROM SEMISOLID DOSAGE FORMS 4033

Figure 1. The basic constituents of various semisolid dosage forms (ointments, creams, and

gels).14

The first theoretical description of release from dis-persions in ointment bases was published by Higuchiin 1961.18 A key assumption in this derivation wasthat the drug diffuses into a perfect sink. The matrix-boundary layer model was later developed to accountfor the resistance of a diffusion layer at the surfaceof a matrix.19 Tojo20 described a graphical method forobtaining the intrinsic release, defined as being in-

dependent of diffusion-layer contributions, from realdata that can include such contributions. The matrix-boundary layer model was used by Bottari et al.21 in1977 for an analysis of benzocaine release from gelsthrough an inert membrane into a receptor fluid.

Drug-release measurements from creams, gels, andointments, in connection with research on topical de-livery systems, have appeared in the literature formany years. Previously, the semisolid was placed indirect contact with a receptor liquid. A variation of this technique utilized an apparatus in which a screenloaded with a semisolid was lowered into the recep-

tor fluid. It is known that with these methods it is very important to guard against dissolution or dis-persion of the semisolid into the receptor. One can ex-pect the appearance of a physical disturbance of thesemisolid surface by the agitation needed to main-tain homogeneity within the receptor. Application of a membrane between the semisolid and the recep-tor was designed to prevent these artifacts.7 More-over, transport through the porous membrane is muchmore rapid than through the semisolid, but the mem-brane contributes to the overall diffusional resistance.

Until now, release testings of various types of ac-tive components from semisolid dosage forms were

Table 1. Examples of Active Compounds Applied in Release

Studies (w/o - water-in-oil, o/w - oil-in-water,

o/w/o-oil-in-water-in-oil)

Active Compound Semisolid Dosage Form References

Caffeine W/O emulsions, gels 22–25

Hydrocortisone Creams, ointment, lotions,

O/W, and O/W/O

emulsions

26–31

Acyclovir Creams 32Retinol O/W/O emulsions 33

Retinoic acid Creams 34,35

Ketoprofen Ointments, gels 36–38

Chlorpheniramine

maleate

Ointments, gels 39–41

Vitamin B12 Gels 42

Salicylic acid Ointments 43

Benzocaine Gels 21

Corticoids Ointments, creams 44,45

Phenol Ointments 46

Peptides Gels 47

Naproxen Ointments 48,49

Metronidazole W/O/W emulsions 50

Ibuprofen Ointments 51–53

Flurbiprofen Gels 54–56Heparin Gels 57–60

extensively studied and are presented in Table 1. Themain purpose of this article is to review all the aspectsof conventional and nonconventional IVRT methodsfor novel semisolid dosage forms. This review pro-

vides insight into the possible alternatives for active-component-release study design and the choices of dissolution medium, membrane, temperature, as wellas the speed for such tests.

DOI 10.1002/jps JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 11, NOVEMBER 2012



4034 OLEJNIK, GOSCIANSKA, AND NOWAK

METHODOLOGY OF IVRT

In 2009, two new draft United States Pharmacopeia(USP) general chapters on topical and transdermaldrug products were published in the Pharmacopeial

Forum ( PF ) 35(3), May–June 2009. The general chap-ters are <3>Topical and Transdermal Products—

Product Quality Tests and <725>Topical and Trans-

dermal Products—Product Performance Tests. Thispublication was followed by a 2-day workshop “USPWorkshop on Topical and Transdermal Drug Prod-ucts” held in USP Headquarters from 14 to 15September, 2009. In 2010, a revision to the proposednew general test chapter was published on the basisof the comments received during the public commentperiod and at the above-mentioned workshop. How-ever, one has to be aware that a new general chapter,<1724>Topical and Transdermal Drug Products—

Product Performance Tests, is under development andwill be published in a future issue of PF . After its

publication, a cross-reference to the new chapter willbe added to the general chapter <3>. As there areno effective directives in the pharmacopeia regard-ing the release system that should be employed, re-searchers have, therefore, designed different appara-tus and methods to carry out these tests. However,several considerations must be taken into account toobtain satisfactory, reliable, and repeatable results.The most important requirement is to choose the cor-rect quantities of the active ingredient and the othercomponents.61 The appropriate membrane, receptor,and temperature for the release testing must also be

selected.

Selection of an Appropriate Membrane

The membranes used in in vitro release studieswere developed to provide a physical support andmaintain constant contact between the formulationand receiving medium.62 There are some impor-tant considerations that must be taken into ac-count when selecting a membrane for release stud-ies. The membranes selected for in vitro diffusionstudies should be commercially available, inert, and

should not exhibit any physical or chemical interac-tion with the formulation.6,62 Moreover, the mem-brane should be compatible with the receptor andoffer the least-possible resistance to the diffusion of the active compound.7,63 The synthetic membraneshave been widely used to determine the in vitro re-lease rate of an active compound from various top-ical formulations.16,24,27,64,65 The commercial avail-ability, stability, and ease of use make synthetic mem-branes highly desirable. In addition, they exhibit theadded benefit of ensuring batch-to-batch homogeneityand uniformity, which is often lacking with biologicalmembranes.

Companies, involved in the field of transdermal de-livery, concentrate on a few selective polymeric sys-tems. For example, Alza Corporation (Mountain View,California) mainly concentrates on ethylene vinyl ac-etate (EVA) copolymers or microporous polypropy-lene, and Searle Pharmacia (Peapack, New Jersey)concentrates on silicone rubber.66 Similarly, Color-

con (Dartford, Kent, UK) uses hydroxypropyl methyl-cellulose (HPMC) for matrix preparation for propra-nolol transdermal delivery, and Sigma (St. Louis, Mis-souri) uses ethylcellulose for an isosorbide dinitratematrix.67–69 The polymers utilized for transdermaldrug delivery system (TDDS) can be classified as:

• natural polymers, for example, cellulose deriva-tives, gelatin, waxes, gums, natural rubber, chi-tosan, and so on70;

• synthetic elastomers, for example, polybutadi-ene, polyisobutylene, silicone rubber, silastic

membrane (polydimethylsiloxane), nitrile, acry-lonitrile, and so on;

• synthetic polymers, for example, polyvinyl alco-hol, polyvinylchloride, polyethylene, polypropy-lene, polyacrylate, polyamide, polyurea,polyvinylpyrrolidone, polyvinylidene difluo-ride, polymethylmethacrylate, and so on.

In order to form a TDDS matrix, different polymers(such as cross-linked polyethylene glycol, eudragits,ethylcellulose, polyvinylpyrrolidone, and HPMC) areused. Other polymers such as EVA,71 silicone rub-

ber, and polyurethane72 are widely employed as rate-controlling membranes. Commonly used membranesin in vitro release tests (Table 2) are fluorophore hy-drophobic membrane, thermoplastic silicone polycar-bonate urethane (Carbosil R, DSM Biomedical, Berke-ley, CA), polysulfone, cellulose acetate, polytetraflu-oroethylene, spectrapore dialysis membrane, mixedesters of cellulose and natural skin (human,31,73

rat,45,68,70 rabbit, and mouse),31 reconstituted humanepidermis,74,75 Nylon, Teflon, and polycarbonate.2

The use of porous membranes facilitates the diffu-sion of drugs. The barrier potential of porous mem-

branes is determined by the possibility for a moleculeto enter and diffuse through the pores. This possi-bility is, in turn, affected by factors such as the rela-tive molecular size, molecular shape, and electrostaticinteractions between the diffusing molecule and themembrane.88 The pores of the membrane are filledwith a receptor medium so that the transfer of the ac-tive ingredient from the semisolid through the mem-brane involves partitioning into the liquid within thepores (Fig. 2). The kinetics of above-mentioned pro-cess is influenced by the thickness and porosity of the membrane, the viscosity of the receptor, and ad-ditionally the receptor/semisolid partition coefficient.

JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 11, NOVEMBER 2012 DOI 10.1002/jps




Table 2. Selected Membranes used in Release Studies (Co-TranTM, DuraporeTM, 3M, St.Paul, Minnesota)

Membrane Polymer Pore Size (:m) Nature References

Cellulose-based membrane

Benzoylated tubing Regenerated cellulose – Hydrophilic 17,76

Cellulose acetate Cellulose acetate 0.20, 0.45 Hydrophilic 11,32,77,78

Cellulose esters Cellulose esters 0.05, 0.20, 0.45 Hydrophilic 76,79

Cellulose nitrate Cellulose nitrate 0.45 Hydrophilic 76,77,80

Cuprophan Regenerated cellulose 0.45, 0.50 Hydrophilic 17,76,81 Visking Regenerated cellulose – Hydrophilic 17,82–84

Polymeric-based membrane

AN 69 Polyacrylonitrile – Hydrophilic 17,76

Biodyne Polyamide 0.45 Hydrophilic 76

Supor Polyethersulfone 0.20, 0.45, 0.80 Hydrophilic 35,74,76

Tuffryn Polysulfone 0.45 Hydrophilic 22,23,35,76

Nuclepore Polycarbonate 0.10 Hydrophobic 76

Cyclopore Polycarbonate 0.01, 0.10 Hydrophilic 74,76

Celgard 3500 Polypropylene 0.05 Hydrophobic 76

Folioxane C6 Silicon – Hydrophobic 22

Co-TranTM membrane Microporous polyethylene film – Hydrophobic 45

Nylon Polyamide 0.20, 0.45 Hydrophilic 9,31,32,35

DuraporeTM Polyvinylidene difluoride 0.45 Hydrophilic 10,85

Silicon Polydimethylsiloxane – Hydrophobic 17,86,87

Figure 2. Mechanism of the active ingredient transfer

from semisolid through the porous membrane into the re-

ceptor fluid.

In order to obtain the best results, the membraneshould have high porosity and minimal thickness.7

In general, cellulose membranes have been widelyused for quality control tests,24,26,89,90 whereas cellu-lose nitrate has been used as a model for the gastricbarrier.91 It is worth mentioning that these mem-branes are reported to be more permeable than bi-ological membranes for allowing the passage of adiffusing molecule regardless of the physicochemicalcharacteristics of the investigated compound.88 Com-

mercially available cellulose membranes contain anumber of softener, preservative, and plasticizer addi-tives, which may have an influence on the diffusion of the active compound. Therefore, the removal of thesesubstances is required. Because they are usually wa-ter soluble, the membrane can be rinsed with dis-tilled water before soaking in the receptor medium.88

However, nonporous membranes such as silicone arealso used in release studies. These membranes arerelatively inert, lipophilic, and provide an ideal en-

vironment for the permeation of lipophilic molecules.Silicone membranes can be used as a human skinsubstitute when evaluating in vitro release char-acteristics of a drug from topical or transdermalformulations.88

In addition, some researchers recommend pretreat-ing the membrane by soaking in the receiving mediumor isopropyl myristate.22,35,45 After adding the sam-ple, the absence of air bubbles underneath the mem-brane should be checked as well.

The diffusion of the active compound from asemisolid dosage formulation into a receiving mediumis determined by the following three processes:

(a) active compound release from the semisoliddosage form itself,

(b) passage of the active compound through themembrane, and

(c) clearance of the active compound from below themembrane.

When neither of the last two processes are ratelimiting, it is only the thermodynamic activity of theinvestigated molecule in the semisolid formulationthat is a significant determinant of drug release.18

If the physical properties of the formulation itself are





important, diffusion through the base should be therate-limiting step.7 Therefore, it is worth mentioning that the membrane and the receptor medium shouldbe highly permeable and accessible to the active com-pound in the formulation to affect drug release.

Receptor (Receiving Medium)

It is advisable to use a receptor that resembles thephysiological condition of the skin. To maximize par-titioning from the semisolid and transport throughpores of the membrane, the receptor fluid should benonvicious and should exhibit high solvency for theactive ingredient. The pH of medium is also a signifi-cant factor, which should be taken into consideration.The choice of the pH of medium should be based onsuch factors as the pH of the formulation and thepH-solubility profile of the active ingredient and thepH of the target membrane.92 The pH of the recep-tor medium should be adjusted to be in the rangeof 5–6± 0.05 to reflect physiological skin conditions.

As a rule of thumb, the selected receptor should re-lease a sufficient amount of the active ingredientwithin a reasonable time period.35 The commonlyused receptor medium for water-soluble drugs is anaqueous buffer. However, for products formulatedwith a water-insoluble active compound, the selectionof an appropriate receptor medium to maintain sinkcharacteristics is a challenge.64 In order to facilitateand monitor drug release from such topical formula-tions, it may be necessary to alter the receptor fluid’spH, to add surfactants and/or complexing agents suchas cyclodextrins,16 or to use nonaqueous medium in

which the drug is more soluble.93 The use of hydroal-coholic solutions as the receptor media for lipophilicdrugs such as triamcinoloneacetate,45,94 betametha-sone dipropionate,64 and rooperol tetraacetate11 hasbeen reported.

Sampling Time

In order to determine the release profile of an activecompound, six samples are recommended. Sampling is carried out at regular intervals with the replace-ment of the medium. Sampling points vary depending on the solubility of the active ingredient. However, it

is suggested that samples should be collected over atleast a 6-h period, taking not less than five samples(typical samples intervals are 0.25, 0.5, 1, 2, 4, and6 h), although at times, a duration greater than 24 hmay be required.6

It has been reported that there is a specific timewindow during which samples for release experi-ments should be taken.6 Ideally, samples should beremoved at times when the influence of the membraneand its associated stagnant layer disappears andbefore excessive drug depletion from the semisoliddosage form being tested has taken place. There aretwo reasons to explain the rationale behind withdraw-

ing the samples during this time window. First, it hasbeen shown that the migration of an active compoundfrom a semisolid dosage form to a receptor mediumoccurs as a series of successive diffusional steps.95,96

In the primary step, the membrane, together withan unstirred layer at its surface, has been shown toprovide some resistance to the diffusion of the ac-

tive compound and therefore affects the release rateof the active compound.6 However, in other cases, adiffusional layer can be formed within the semisolidmatrix and can be the rate-controlling element. Con-sequently, sampling time should start when the in-fluence of the membrane and its associated stagnantlayer has disappeared.6 Second, in accordance withtheoretical permeation models, a plot of the amountof active compound released versus the square rootof time should be linear if drug release from a for-mulation is diffusion controlled or if diffusion is therate-controlling element within the dosage form.95,96

It has been reported that active compound releasefrom semisolid dosage forms may deviate from lin-earity at extended times, and the deviation usuallyoccurs when more than approximately 35%–45% of the investigated molecule has been released.6

Temperature of Analysis

In case of semisolid dosage forms, the test temper-ature is typically set at 32± 0.5◦C to reflect theusual skin temperature. Deviations might be justi-fied when products are for specific sites of action;for example, vaginal creams may be tested at 37 ±0.5◦C.11,16,35,90,97 However, the use of excessively high

temperatures may melt the base or the product being tested or cause significant physical changes to sucha product, which in turn may change the resistanceof the matrix to active compound diffusion into thereceptor medium and should, therefore, be avoided.6

Chattaraj and Kanfer32 investigated the effect of the temperature on the release characteristics of acy-clovir from different creams.32 The release of acy-clovir, using a cellulose acetate as the membrane,was measured at 32◦C and 37◦C. The results indicatethat this relatively small difference in temperatureappeared to have a significant effect on the release

of the active compound from creams. The tempera-ture effect is probably because of the nature of thesemisolid dosage forms, which would account for thedifference in release seen as a result of the heat sensi-tivity of the components of the creams. Vehicles usedto formulate semisolid dosage forms would becomeless viscous with increasing temperature and therebyfacilitate the release of the drug.32

APPARATUS FOR IVRT

The choice of the apparatus used in release studies de-pends on the physicochemical properties of the dosage





formulations. All parts of the devices that may con-tact with the formulation or medium should be chem-ically inert and, therefore, should not react with thetest product. Moreover, all metal parts of the devicesmust be made from a suitable stainless steel or coatedwith an appropriate material.98

Franz Cell and its Modifications

The Franz cell apparatus (known as the verticaldiffusion cell) has been the standard system usedfor the study of semisolid drug formulations since19785,11,16,24,29,64,90,94,99–101 and is recommended bythe USP.102 This device consists of two primary cham-bers—a jacket glass receptor (typically 12.5mL in vol-ume) and a glass sampling port. These chambers areseparated by a membrane that is usually synthetic,although an animal skin can be used. A schematicpicture of the Franz diffusion cell is shown inFigure 3. The test product should be added in a con-trolled amount to the upper side of the membrane inthe top chamber.6 The bottom chamber is filled withthe sampling fluid from which the samples are col-lected at regular intervals for the analysis. The exper-iment determines the amount of the active ingredientthat has been released through the membrane at eachtime point. The main advantages of the Franz cell areits ease of operation and its large sample size, whichensures consistent results. Moreover, the technique issimple, reliable, reproducible, and suitable for in situ

gels, creams, and ointments measurements. One hasto keep in mind that air bubbles at the membrane–liq-uid interface cause poor precision in the data. The

choice of the right membrane is crucial because themembrane can also control the diffusion of the activecompound.

According to Keshary and coworkers,103,104 the de-sign of the Franz cell does not provide for adequate so-lution hydrodynamics, appropriate mixing efficiency,and the temperature control that are necessary for

Figure 3. Schematic picture of the typical Franz diffusion

cell.78

quantitative permeation tests. Therefore, they intro-duced several modifications to the original Franz cellapparatus. In comparison with the receptor compart-ment of the original Franz cell, their newly devel-oped diffusion cell has a shorter cylindrical receptorcompartment and is completely enclosed by a water

jacket. A star-headed magnetic stirrer is employed to

agitate the receptor medium. Because of these modi-fications, the equilibrium temperature of the receptormedium is better maintained. Moreover, the solution-mixing efficiency is improved, and the thickness of the boundary diffusion layer is decreased.103

The Hanson Microette (Hanson Research Corpo-ration, Chatsworth, CA) employs six vertical, au-tomated Franz diffusion cells that have 15mmdiameters.6 Figure 4 presents sampling from one cell.The Hanson Microette system simultaneously sam-ples and collects from all six cells. Each cell is filledwith a receptor solution from the medium beaker. Theamount of test formulation is checked and then placedon the membrane in the cell. On program command,the stirrer stops working, and the appropriate amountof the aliquot of fresh replacement medium is injectedfrom the precision syringe pump into the capillarymedium. The sample lines are cleaned by a wash cy-cle just before the sampling takes place.6

Paddle-Over-Disk

Another technique that can be used is the USP No.5 [European Pharmacopeia (PhEur) 2.9.4.1] paddle-over-disk method.5 The formulation is filled into theUSP stainless steel disk and placed on the bottom of a

release vessel filled with the receptor medium (Fig. 5).The analysis is performed by using stirring paddles(25 mm above the surface of the disk) at 50 rpm. Inthis method, the membrane is not required. Only thestainless steel is employed to perform the role of thebarrier. The main disadvantage of this technique isthe possibility for the formulation to dissolve in the re-ceptor medium. Thus, dissolution is measured ratherthan release. However, this method could be usefulto carry out release testing of products that do notdissolve in the receptor medium.105

Enhancer Cell Assembly

Enhancer cell, designed by Vankel Technology Group(Cary, North Carolina), is another apparatus that isused for release testing of semisolid formulations.106

The enhancer method resembles the paddle-over-disktechnique. However, in this case, the use of a mem-brane is required. In addition, the paddle over extrac-tion cell method is recommended by PhEur 2.9.4.2.The Vankel release system comprises a bath with six

vessels (200 mL). A circulator pump can be used toattain a constant temperature. The inner diameter of the Vankel enhancer cell is 21 mm, which gives a sur-face area of 345.44mm2.78 An enhancer cell composed





Figure 4. Schematic representation of Hanson Microette sampling system (redrawn from

Ref. 6).

Figure 5. Apparatus No. 5–-paddle-over-disk. The disk

assembly is used to hold the system flat and is positioned

parallel with the bottom of the paddle blade.102

of Teflon consists of a cap, an O-ring, a membrane, anda drug reservoir (Fig. 6). The dosage volume of thecell body is adjusted with a special tool that is used

to increase or decrease the depth of the reservoir. Thecell is filled with the product to be tested, and thenthe membrane and O-ring are placed over the sam-ple surface. The top cap is screwed on, and a specialalignment tool is used to position the O-ring and to fitthe membrane securely to the sample. The assemblyis available with 4.0, 2.0, or 0.5 cm2 surface areas. Theadvantage of the enhancer cell method is its availabil-ity to most researchers and manufacturers45 becausea basic USP dissolution apparatus is used. The large

volume range makes it easier to adapt this systemto study the release of products containing low con-centrations of active ingredients or ingredients thatare difficult to analyze.90 Moreover, the method re-quires fewer accessories and reduces the time andcost needed for setting up the equipment. The appli-cation of enhancer cells made of Teflon prevents theformulation from interacting with the cell. Such prob-lems can occur when using glass diffusion cells.45 Thedisadvantage of the enhancer cell is that the temper-ature equilibrium between the formulation and thereceptor phase could take a finite time because Teflon





Figure 6. Schematic picture of the enhancer cell with its

elements (on the left). On the right, the enhancer cell inside

the vessel.6

Figure 7. Picture of inverted rotating cylinder.105

is a poor conductor of heat with a small heat transfer

coefficient. This requires the cells and the formula-tion to be stored at the study temperature before use.This temperature control is especially important dur-ing the evaluation of drug release from ointments thattake a longer time to equilibrate.45

Inverted Enhancer Cell

In this method, a machined, round cavity of Teflon orstainless steel is used as the holder of the test prod-uct (Fig. 7). The cylinder filled with formulations isplaced into a standard release vessel and rotated, usu-ally at 50 rpm.105 In contrast to the above-mentionedmethods, the use of a membrane is not required. Fur-thermore, this method can be used only with productsthat do not dissolve in the receiving medium. It is es-pecially useful in the case of hydrophobic ointmentbases comprising the solubilized drug.

The Rotating Cylinder Method (USP Apparatus 6/PhEur2.9.4.3)

This method is similar to the USP basket-type disso-lution apparatus, except that the system is attachedto the surface of a hollow cylinder immersed in amedium at 32± 0.5◦C.5,104 The shaft and cylindercomponents of the stirring element are fabricated

from stainless steel to the specifications shown inFigure 8. The dosage unit is placed on the cylinderat the beginning of each test. The distance betweenthe inside bottom of the vessel and the cylinder ismaintained at 25± 2 mm during the test.5,102

The Flow-Through Cell Diffusion Apparatus

In flow-through cells, the receptor medium con-tinuously flows through the acceptor compart-ment, and, as a result, the medium is refreshedcontinually.89,90,107 The apparatus consists of a reser-

voir with a release medium, a pump, and a waterbath (Fig. 9). The pump is used to force the releasemedium upward through the vertically placed flow-through cell. The bottom part is filled with glass beads(1 mm diameter) and with one additional bead (5 mmdiameter), which is employed to protect the fluid en-try tube. In order to measure the release rate of theactive compound from a semisolid formulation, an in-

sertion cell is placed inside the flow-through cell. Thedissolution liquid is generally collected in a separatereservoir as it leaves the insertion cell. Fractions areremoved at specified intervals and analyzed. The flow-through cell device is specifically used for lipophilicsolid dosage forms.89,90,107

The application of an “insertion cell” offers distinctadvantages compared with the Franz cells because itis easier to use and readily adaptable for use with theflow-through apparatus. Moreover, it does not sufferfrom the problem of having to remove air bubbles atthe membrane–liquid interface, which commonly oc-

curs when using Franz cells.

89

Additionally, it should be mentioned that typicalIVRT apparatus consist of six cells. For each run, thetwo products (reference product and test product) be-ing compared should be placed in six cells accord-ing to the pattern illustrated in the Figure 10. Thisprocedure will help to ensure an unbiased compari-son in the event of a systematic error difference be-tween runs. The assignment of products to cells (i.e.,whether the reference product or the test product isplaced in the “upper left corner cell” of the appara-tus) can be made randomly or systematically (i.e.,alternating the pattern for each successive run). In

the case of nonstandard equipment, which consists of other than six cells, the same pattern of experimentalruns is still valid. It should be mentioned that in ap-paratus with only a single cell, the runs of referencetests and product tests should be intermixed.108

KINETICS OF IVRT

The release from delivery systems can be followed bythree main models, that is, Higuchian kinetics, zero-order kinetics, and first-order kinetics, taking into ac-count the Fickian diffusion laws.





Figure 8. Cylinder stirring element. All measurements are expressed in cm unless noted

otherwise (redrawn from Ref. 102).

Figure 9. Schematic picture of flow-through cell for semisolids forms (on the left). On the

right, schematic diagram of a flow-through dissolution apparatus.78

Figure 10. Experimental run according to SUPAC-SS guidance (different cell assignment a

and b). Test represents the postchange lot (Test product) and reference represents the prechange

lot (reference product).108





Modeling Diffusion

Diffusion can occur in a double diffusion cell, wherea concentrated solute solution is separated from thereceptor fluid by a semipermeable membrane.109,110

During the diffusion process, the solute passes from aregion of high concentration (donor compartment) toa region of low concentration (receptor compartment)through a membrane as a barrier. The decrease of thesolute concentration in the donor compartment is fol-lowed by the increase in the concentration in the ac-ceptor compartment. Until an equilibrium is reached,the process proceeds and a steady state is reached.111

The diffusion coefficient through the semipermeablemembrane can be measured by kinetic methods whenthe concentrations in the donor and acceptor com-partments are checked.112 Diffusion coefficients canbe defined by using Fick’s first and second laws of dif-fusion, which are appropriate when a membrane actsas a rate-controlling step for the release of bioactive

molecules.

Fick’s First Law

The diffusion of molecules is define as rate of masstransfer (d M /dt) and is expressed as flux ( J ). Flux isdefined as the rate of mass transfer through a unitsurface area of a barrier (membrane).113,114

J = 0.5d M

Sdt

where d M —change in mass, g, S–barrier surface area,

cm2

, dt–change in time, s. Flux units g s-1

cm-2

and areusually expressed as kg m−2 s−1.There is a direct correlation between the flux and

the concentration gradient. This relationship is ex-pressed by the following equation:

J = − DdC

d x

where dC–change in concentration of the solute, D—diffusion coefficient of the solute cm2 /s, and d x-–change in distance, cm.

Fick’s Second Law

In case of Fick’s second law, the change in concen-tration with time in a definite spatial region ( x, y, z) istaken into account. This law states that the change inconcentration with time at a specific location is pro-portional to change in the concentration gradient atthat point in time.

∂C

∂t = D

∂2C

∂ x2 +

∂2C

∂ y2 +

∂2C

∂ z2

where x, y, and z are the spatial coordinates.

Table 3. Equations for Release Kinetics111

Model Equation

Zero order F = kt

First order ln F = kt

Higuchian F = kt1/2

F —the fraction of active compound released from semisolid, k-–therelease constant, and t—time.

Higuchian Model

The amount of the released active compound changeswith the appropriate rate during the analysis. The re-lease of water-soluble and poorly water-soluble drugsfrom semisolids was studied by Higuchi.18,96 Today,the Higuchi equation is considered to be one of thewidely used and the most well-known controlled-release equations. According to him, the release of a drug depends upon its diffusion.

His general equation is given below:

M t

M 0= K

1/2t

where M t—amount of drug released in time t, M 0—initial amount of the drug released, and t—timerequired.

In addition, two theoretical models have been sug-gested, one in which the active compound exists asa suspension in the base (Model I) and the other inwhich the active compound exists as a solution in thebase (Model II). In accordance with Higuchi,1896,115

the resulting plot should be linear for the controlled

release of the active component in the suspension:

Q = (2C0Cs Dt)1/2, Cs << C0

or in solution

Q = 2C0

Dt

B

1/2

where Q–amount of the drug released per unit areaof sample, C0–initial concentration of the drug in thesemisolid, Cs–solubility of the drug in the semisolid

matrix, D–diffusion coefficient of the drug in thesemisolid, and t–expired time. A plot of the amountof the active compound released per unit membranearea (mg/cm2) versus the square root of time shouldresult in a straight line. The slope of the line presentsthe release rate of the active component. The plot ob-tained from the kinetic data shows that the efficiencyof the active compound released from the semisoliddosage form (Table 3) .

The zero-order release model is similar to theHiguchian kinetics; however, the release remains con-stant over a period of time because the releasing sur-face is constant. The zero-order model refers to the





assumption that the average pore size in the deliverysystem is smaller than the size of the investigatedcompound. In practice, zero-order release is usuallyconverted to the first-order model.116,117

CONCLUSIONS

The controlled release of active compounds fromsemisolid dosage forms is a significant factor in esti-mating the efficiency of the active compounds. There-fore, controlled-release studies have been carried outin quality control laboratories. Such research permitsus to assess a product’s activity after introducing anychanges in composition, in apparatus, or in the pro-duction process. Release tests of drugs from creams,gels, and ointments, in conjunction with solubility,particle size, and crystalline form, are important fora proper characterization of newly developed prod-ucts, and thus their potential therapeutic effect can

be predicted. For this reason, it is essential to se-lect the appropriate release test conditions mentionedin this article (temperature, sampling time, receptor,membrane, and type of apparatus).

ACKNOWLEDGMENTS

The authors would like to thank the National Sci-ence Center for the financial support (N N204 403040;2011–12).

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