spreading of semisolid formulations - pharmtech

harmaceutical semisolid preparations include ointments,pastes, cream emulsions, gels, and rigid foams. Theircommon property is the ability to cling to the applica-tion surface for a reasonable period of time before they

are washed off or worn off. They usually serve as vehicles fortopically applied drugs, as emollients, or as protective or oc-clusive dressings, or they may be applied to the skin and mem-branes such as the rectal, buccal, nasal, and vaginal mucosa, ure-thral membrane, external ear lining, or the cornea (1). Thesepreparations are widely used as a means of altering the hydra-tion state of the substrate (i.e., the skin or the mucous mem-brane) and for delivering the drugs (topical or systemic) bymeans of the topical–mucosal route.

One of the serious problems associated with the formulationand manufacture of topical–mucosal preparations is the estab-lishment of reliable techniques for their characterization, mainlybecause of the complexity of their physical structure (2). Con-sumer preference for such products depends on various prop-erties of the preparation, collectively known as the textural pro-file, which includes appearance, odor, extrudability (whenapplicable), initial sensations upon contact with the skin, spread-ing properties, tackiness, and residual greasiness after applica-tion (3). Ultimate acceptability and clinical efficacy of suchpreparations require them to possess optimal mechanical prop-erties (ease of removal from the container, spreadability on thesubstrate), rheological properties (viscosity, elasticity, thixotropy,flowability), and other desired properties such as bioadhesion,desired drug release, and absorption (4).

The efficacy of topical therapy depends on the patient spread-ing the formulation in an even layer to deliver a standard dose.The optimum consistency of such a formulation helps ensurethat a suitable dose is applied or delivered to the target site. Thisis particularly important with formulations of potent drugs. Areduced dose would not deliver the desired effect, and an ex-cessive dose may lead to undesirable side effects. The deliveryof the correct dose of the drug depends highly on the spreada-bility of the formulation. Spreadability, in principle, is relatedto the contact angle of the drop of a liquid or a semisolid prepa-ration on a standardized substrate and is a measure of lubric-ity, which is directly related to the coefficient of friction (5).Spreadability is subjectively assessed at shear rates varying from102 to 105 s�1. The rate of shear during spreading, � s�1, is cal-

84 Pharmaceutical Technology SEPTEMBER 2002 www.pharmtech.com

Spreading of Semisolid FormulationsAn UpdateAlka Garg, Deepika Aggarwal, Sanjay Garg, and Anil K. Singla*

Alka Garg and Deepika Aggarwal aredoctoral scholars at the University Institute ofPharmaceutical Sciences, Panjab University,Chandigarh, India; Sanjay Garg, PhD, isan assistant professor at the National Instituteof Pharmaceutical Education and Research inPunjab, India; and Anil K. Singla, PhD, is aprofessor and chairman at the UniversityInstitute of Pharmaceutical Sciences, PanjabUniversity, Chandigarh, India.

*To whom all correspondence should be addressed.

PA considerable problem associatedwith the manufac-ture of topically ap-plied pharmaceuti-cal products is theestablishment of

reliable techniques for their characterization.The efficacy of a topical therapy depends onthe patient spreading the drug formulation inan even layer to administer a standard dose.Spreadability is therefore an important char-acteristic of these formulations and is respon-sible for correct dosage transfer to the targetsite, ease of application on the substrate,extrudability from the package, and mostimportant, consumer preference. This articlediscusses the various aspects of spreading,including the factors affecting it, the tech-niques available for its assessment, and vari-ous additives and interactions that can alterthe spreadability of the final formulation.

IMA

GE

10

0


culated using the following equation for plane laminar flow be-tween two parallel plates:

in which v is the relative velocity of the plates (cm s�1) and d isthe distance between them (cm); that is, a measure of thicknessof the film between the skin surfaces (3).

Factors affecting spreadingTo assess the spreadability of a topical or a mucosal semisolidpreparation, the important factors to consider include hard-ness or firmness of the formulation, the rate and time of shearproduced upon smearing, and the temperature of the target site(3). The rate of spreading also depends on the viscosity of theformulation, the rate of evaporation of the solvent, and the rateof increase in viscosity with concentration that results fromevaporation (6).

Formulation characteristics. Formulation characteristics, in-cluding viscosity, elasticity, and rheology, are the most importantfactors in the development and final behavior of semisolid for-mulations. Increasing the viscosity of the delivery vehicle increasesits retention time at the target site but also decreases its spreada-bility. Therefore, consistency of these formulations (varying fromfluid to very stiff texture) plays the most important role in theirfinal behavior, including their spreading qualities on the sub-strate. Spreadability can be measured with various types of vis-cometers and varies according to the formulator’s requirement.

In suspension ointments, a logarithmic regression with a neg-ative correlation was found between viscosity and degree ofpenetration, and a significant linear regression correlation wasfound between degree of penetration and spreadability (7). Thiscorrelation was further confirmed by Hegdahl and Gjerdet andVennat, Gross, and Pourrat (8,9), who proved the existence ofa strong negative correlation between the spreadability and vis-cosity of elastomeric materials. Also, spreadability of a formu-lation is inversely proportional to its cohesiveness because strongcohesive forces within a formulation retard its flowability andthereby its spreadability on the substrate. Therefore, the cohe-siveness of the selected ingredients must be considered duringthe development of topical and mucosal formulations (10). Inaddition, each formulation must be specifically designed ac-cording to the desired purpose of its use, site of application,and patient acceptability. Spreadability of a formulation can beeither increased or decreased as desired by the formulator tosuit the end purpose.

Increasing the viscosity of timolol eye drops by adding sodiumcarboxymethylcellulose increased the effect three- to ninefold ascompared with that of nonviscous drops. The ocular penetra-tion increased as a result of longer corneal contact, and systemicabsorption decreased as the result of slower spreading of the so-lution on the nasal mucosa (11). Nyman-Pantelidis et al. inves-tigated the effect of viscosity on the retrograde spread of twoenema formulations and found a statistically significant differ-ence in the spread between the low-viscosity and the high-viscosity enema (12). The low-viscosity enema spread over a largerarea in the lower colon, mainly in the first 15 min following ad-ministration. In contrast, the enema with higher viscosity spread

� � vd

over a very small part of the rectum and took a longer time tospread over the rectal mucosa. Also, the rate and extent of spread-ing was more variable with the latter formulations.

In another study, Ivens et al. compared the application andspreading of four different pharmaceutical vehicles, includingsolutions, ointments, creams, and low-viscosity creams, andfound the spreadability and retention of the ointment to be bet-ter than those of the other three (13). Whereas the ointmentspread evenly in the test area, other formulations were unevenlyspread and provided a lower dose in the periphery. The rapidevaporation of water from creams and solutions influences thespreadability and results in an uneven topical dose within thetreated area. The formulations also must be spread quickly andat multiple sites to ensure correct dosage. Besides having theadvantage of spread, ointments have the disadvantage of sticki-ness, staining, and poor patient compliance.

In a very recent study, a thermoreversible gel formulationwas evaluated as a possible barrier to the transmission ofpathogens that cause sexually transmitted diseases, includingHIV and herpes simplex virus. It was found that this gel spreadevenly in the vagina and coated the herpes virus or entrappedit in its micelles, thereby hindering its attachment to the targetcells and inhibiting its infectivity (14).

Rate and time of shear. Care must be taken that the operativerate of shear for rheological measurement is attained in a timecomparable with the usual amount of time taken by the con-sumer to spread the preparation (3). In 1954, Kostenbauder andMartin approximated the rate of shear in the spreading of anointment on a surface using the equation

in which v is the velocity at which the ointment is being shearedand r is the thickness of the layer (15). They estimated the shear-ing rates for a pharmacist compounding an ointment with aspatula and for a consumer spreading an ointment on a sur-face such as skin as 200 s–1 and 120 s–1, respectively. A laterstudy demonstrated that 120 s–1 was the point of greatest resis-tance to flow at low rates of shear for ointment bases, thus con-firming the rates cited earlier (16). In addition, the later studyconcluded that the shearing region of 0–250 s–1 would be mostrelevant when characterizing the spreading properties of phar-maceutical semisolids.

Later, Langenbucher and Lange reported that for topicalpreparations, the apparent viscosity and spreading should bemeasured at 30–35 �C and at a shear rate of 104 s�1. This rateshould be reached in a 10-s period (17).

Temperature. In a series of studies, Boylan obtained rheogramsof 13 different pharmaceutical semisolids at various tempera-tures ranging from 20 to 35 �C using a Ferranti-Shirley cone-and-plate viscometer (16,18). Many of the preparations ap-peared to present a straight-line relationship between thixotropicarea and temperature, but the viscosity of ointments is reducedby a factor of 0.5 for every 5-�C rise in temperature. He sug-gested that measurements for rheological properties should bemade at several points in this temperature range to simulatemost temperatures of use. However, a thin film of materialrapidly warms to the respective temperature after spreading at

S � dvdr


the target site. This temperature also may vary as a result of ei-ther increased blood flow induced by rubbing or of individualphysiological conditions (17). Therefore, rheological experi-ments for correlation with spreadability must be performed ata suitable temperature according to the individual experiment.

Site of application. Pharmaceutical parameters of a formula-tion differ according to the target site of application. In thecase of topical formulations, evaporation of water after appli-cation affects the spread and retention. Ointments prove bet-ter in such cases because evaporation is minimal because oftheir oily character, whereas solutions and creams tend to ex-hibit poor spreadability and rapid removal (13). In a very earlystudy, Kostenbauder and Martin, after consulting several der-matologists, categorized pharmaceutical ointments into thefollowing three classes:� Class I consisted of ophthalmological ointments, which are

the softest products and possess the lowest viscosities. Theseointments spread at a shear rate as low as the action of a blinkof an eye.

� Class II consisted of common medicated ointments, whichalthough soft are stiff enough to stay at the point of applica-tion long enough to transfer the desired dose. They have aslightly higher viscosity than that of Class I ointments and re-quire a moderate shear to spread.

� Class III consisted of protective ointments, which are hardand stiff so they remain at the site of moist ulcerative areas(15).For preparations that are instilled in the mucosal cavities of

the body such as the vagina or the eye, thinning of the vehicleby the cavity fluids also plays a role in their final behavior. Inocular formulations, thinning and drainage after mixing withtear fluids must be critically considered (19). Similarly, in vagi-nal formulations the vehicle’s compatibility with the vaginalfluids, their dilution after administration, and subsequentdrainage depending on posture are important factors that gov-ern their behavior. The rheological properties after adminis-tration determine the critical functions of spreading and re-tention over the vaginal surfaces. Gels are usually the mostdesirable dosage forms for this route. A study that comparedfour different contraceptive gels and statistically evaluated theirshear thinning and viscoelasticity after application and subse-quent dilution found that all gels that were tested exhibitednon-Newtonian behavior, including shear thinning and visco-elasticity. The gels differed in their response to dilution withvaginal fluid simulant (20).

Measurement of spreadabilityAcknowledging that each individual applies semisolid formu-lations to the skin with a slightly different motion, stroke, andrate, any rheological estimation of this process, however good,involves some degree of error. Nevertheless, good approxima-tions can still be made. Tests and estimations are important tothe development of semisolid formulations and can influencetheir final behavior.

Wood et al. developed several techniques to measure variousrheological properties of pharmaceutical semisolids and lotions(21). They estimated the viscosity and elasticity required for ex-

trusion of a formulation from a plastic bottle with respect tothe bottle’s design, type of orifice, and thickness of the plastic.They also measured the shearing rates involved in high-speedtube filling and extrusion from collapsible tubes and assessedtheir effect on the formulation contained within. In anotherstudy they evaluated the increase in tackiness that occurs insome formulations as they dry and devised an empirical test tomeasure the cohesive–adhesive capability of skin surface dur-ing absorption after the rub-in.

Several authors have assessed spreadability using the theo-retical equation of plane laminar flow between parallel plates(17,22), whereas others have made evaluations with a correla-tion between non-Newtonian viscosities (23,24). The in vivomethods reported use techniques such as gamma scintigraphy(25) in addition to individual sensory assessment (17,26,27).

Parallel-plate method. The parallel-plate method is the mostwidely used method for determining and quantifying thespreadability of semisolid preparations. The advantages of themethod are simplicity and relative lack of expense. Also, theassemblies can be designed and fabricated according to indi-vidual requirements of the type of data required, the route ofadministration, the surface area to be covered, and the modelmembranes to be considered. On the other hand, the methodis less precise and sensitive, and the data it generates must bemanually interpreted and presented.

The spreading behavior of various Witepsol suppository baseswas tested between two Plexiglas plates at 37 �C, and optimumbases were selected on the basis of their spreading properties(28). Hadi et al. (29) evaluated polyethylene glycol ointmentbases for spreadability using a parallel-plate extensometer basedon the sliding-plates design. Later, Vennat et al. validated thespreading-diameter measurements of hydrogels on the basis ofcellulose derivatives and established the linearity of spreading-diameter measurement (30,31). The linear relationship betweenspreading diameter, viscosity, and the concentration of gellingagent depended on the cellulose derivative. The linear relation-ship between viscosity and spreading diameter was independentof the derivative. Good repeatability and reproducibility of thespreading measurement was found. The spreading capacity ofthe gel formulations was measured 48 h after preparation bymeasuring the spreading diameter of 1 g of the gel between two20 � 20 cm glass plates after 1 min. The mass of the upper platewas standardized at 125 g. Panigrahi et al. used a similar appa-ratus to assess the spreadability of lyncomycin hydrochloridegels (32). The following equation was used for the purpose:

in which S is the spreadability of the gel formulation, m is theweight (g) tied on the upper plate, l is the length (cm) of theglass plates, and t is the time taken (s) for the plates to slide theentire length.

DePaula et al. determined the spreadability of various oint-ment formulations by compressing the sample under severalglass plates of known weight (33). Twenty plates were subse-quently placed over the sample at 1-min intervals. The spread-ing areas reached by the sample were measured in millimeters

S � m � lt


in the vertical and the horizontal axes. The results were expressedin terms of the spreading area as a function of the applied massaccording to the following equation:

in which Si is the spreading area (mm2) resulting from the ap-plied mass i (g), and d is the mean diameter (mm) reached bythe sample. The spreading area was plotted against the plateweight to obtain the spreading profiles.

In another study, Arvouet-Grand et al. determined the spreada-bility of various oil-in-water creams by pressing 1 g of a samplebetween two 20 � 20 cm horizontal plates, the upper of whichweighed 125 g (34). The spread diameter (�) was measured after1 min. Under these experimental conditions, they applied theterm semistiff creams to samples with � �50 mm and semifluidcreams to those with � 50 mm but 70 mm. Lardy et al. re-cently used a very similar method to evaluate the spreadabilityof various test hydrogels (35). The 1 � 0.01 g gel sample wasplaced between two 20-cm2 horizontal glass plates, and � wasmeasured after 1 min. The mass of the upper plate was 125 � 1g. The study temperature was maintained at 21 � 0.5 �C, andthe gels were evaluated 48 h after their preparation. They werefinally graded from fluid to very stiff on the basis of the value of� obtained. Principal component analysis, a powerful statisti-cal method, was used to demonstrate the relationships amongthe various parameters that describe the consistency of the hy-drogels and their spreadability.

Lucero et al. used a Ranvier-type manual microtome to studythe compression deformation (i.e., spreading) of hydrophilicgels of �-tocopherol (36). The microtome that was used had aperfectly flat 5-cm-diameter plate, a 1.2-cm-diameter screwbore, and a 0.68-mm thread. A sequence of masses of 80, 150,300, and 500 g equivalent to compression stresses of 3302, 6191,12383, and 20638 dynes/cm2 respectively, were placed on thecylinder of a 77-mm3 sample under ambient conditions. Theduration of each application of force was 1 min of compres-sion with 30-s rest intervals. To evaluate the resulting defor-mation by each of the stresses, photographic plates were printedwith the areas of spreading produced using a lamp of constantintensity placed at the same location. Also, these areas were de-

S i � d 2 � 4

termined by a direct reading of the perimeter by means of aplanimeter.

Subjective assessment. As the name suggests, subjective assess-ment is based on the sensory assessment of human volunteers.This mode of measurement is closest to the true spreadability as-sessment because the results are generated from the individualfeel of the formulation. However, because it requires human as-sessment it is unpredictable and variable, and the element of re-producibility is reduced because the individual attributes of thesubjects are involved. Therefore an element of bias always exists.

Lagenbucher and Lange described spreadability as a measureof viscosity correlated to subjective preference. Oils with vis-cosities ranging between 0 and 10 P at 35 �C were presented totest subjects who rated the ease with which the formulation couldbe spread on the backs of their hands. The scores obtained wereplotted against the viscosity of the sample. The most-acceptableviscosity does not mean the most-viscous sample but the onewith the best spreadability according to the test subjects (17).

DeMartine and Cussler predicted various subjective attrib-utes of liquid texture (26). They stated that subjective spreada-bility and viscosity are perceived as the shear stress on the fin-gers, whereas subjective stickiness of a formulation is perceivedas the time frame during which the finger is pulled away fromthe sticky surface. Figure 1 shows a correlation between fingergeometry and two parallel plates. Assuming that when fingersmove against each other in an oscillating motion with constantamplitude and for a constant period of time, the finger veloc-ity varies little with changes in objective liquid viscosity. Firstthey developed equations for the thickness of the fluid film onthe fingers as a function of time, and then using those equa-tions they developed more equations for predicting spread-ability, viscosity, and stickiness. Subjective spreadability wasfound to be inversely proportional to the shear stress. It wasalso proportional to the ratio of viscosity of the sample to thesteady velocity of the fingers. For each textural characteristic,the study used panels of between 15 and 24 members of bothsexes ranging in age from 20 to 50 years who had not beentrained before the present work.

Aust et al.’s study of sensory or skin-feel approach for theevaluation of creams and lotions included a panel of nine judgeswho rated various skin-feel attributes, including spreadingcharacteristics (27). The participants applied the test formu-lations to the inside surface of their forearm and scored the at-tributes numerically.

Solutions, ointments, creams, and low-viscosity creams weretested on 29 healthy volunteers who applied a fixed amount (0.1g) to the abdominal skin to assess the best vehicle for topicaltherapy. Ointment proved to be the vehicle of choice becauseit ensured even spreading and retention and therefore a correctdose transfer (13).

Master-curve method. The master-curve method combines thethe advantages of both the subjective assessment of spreadabilityand the use of instrumental measurements. It was brought for-ward by Barry et al. who, in their many studies, coupled the sen-sory assessment of spreadability with the master-curve conceptderived from rheological measurement of viscosities of the testsamples (3,37–40). The method determined the relationship

Fluid Z X

V

Z

rr

F

Figure 1: Schematic representation of finger geometry as two parallelplates (26). V � finger velocity, Z � thickness of the sample, X �shearing stress, F � shear force between the fingers, r � radius of thefinger.


between the shear stress and the shear rate that operated dur-ing the spreading of topical preparations on the skin by deriv-ing from the master curves for lipophilic preparations and hy-drophilic preparations, including oil-in-water emulsions andaqueous gels (3,38). A panel of volunteers compared a series offormulations that varied in consistency from mobile liquids tostiff semisolids with a range of Newtonian silicone oils of var-ious viscosities. The participants spread the materials on theinner surface of their forearm. The mean temperature of theparticipants’ inner surface of the forearm was approximately34 �C, the rates of shear varied approximately from 400 to 2500s�1, and the shear stresses varied from 40 to 6000 Nm�2. Thepanel indicated which oil appeared to possess the same spread-ing properties as each test formulation. Flow curves of the ma-terials were obtained with a Ferranti–Shirley cone-and-plateviscometer and the intersection of the rheogram of the test for-mulation, and the selected Newtonian oil provided estimatesof the shearing conditions that operate during spreading of thedermatological formulation on the skin. A double logarithmicplot of shear stress against shear rate provided a master curve.The preferred region of this master curve was bounded by � 400–700 s�1 and 200–700 Nm�2. The panel then rated thesame preparation in terms of preferred spreadability. Thesedata, superimposed on the master curve, suggested the opti-mum and preferred spreading conditions for maximum patientacceptability. The data obtained indicated a dynamic relation-ship between the rate of shear, the relative viscosity, and thethickness of the oil film on the skin.

This procedure for continuous shear rheometry provides asound basis for assessing the rheological behavior of a mater-

ial under moderate shear conditions (see Figure 2). Suzuki etal. showed that the sensory-perceived property of the productconsistency, and therefore spreadability, is closely related toBarry’s ground state (i.e., the state in which the structure of theviscoelastic material is flexed but not destroyed) (23).

In vivo studies. In vivo studies are the best possible assessmentmethod for any pharmaceutical research. Little work has beendone in vivo for the measurement of spreadability of semisolids,but a few animal and human study data are available. These stud-ies bypass all elements of bias and instrumental limitations andgive an accurate picture in terms of the biological environment.

Animal models. Grant and Liversidge, in an attempt to assess therheological behavior of fatty suppository bases and their spread-ing characteristics, developed a method using rats (41). The ratswere deprived of food for 24 h, and their intestine was com-pletely purged to remove any fecal pellets. The suppository thenwas inserted into the rectum, and the rectum was sealed witha cyanoacrylate ester adhesive. The rats then were placed in acage with food and euthanized after the allotted time. The deadanimals were dissected, and the distance of ingression of thesuppository base containing dye was measured from the exter-nal anal sphincter.

Richardson et al. studied the distribution and retention of anovel bioadhesive intravaginal delivery system based on HYAFF(a chemically modified hyaluronic acid ester) microspheres ina sheep model (42). In a preliminary experiment, the dimen-sions of the ovine vaginal cavity were outlined and imaged bygamma scintigraphy after administration of a suitable volumeof 99mTechnitium (99mTc)-labeled gellan gum. The gum solu-tion gels after administration into the vagina and is hence ableto fully fill and outline the cavity. The data collected then wasused for subsequent comparison with the distribution of theradiolabeled HYAFF formulations. In other groups of sheep,99mTc-HYAFF microspheres were either administered as a drypowder or suspended in a vaginal pessary, and the distributionand intensity of radioactivity in the genital tract was measuredduring a period of 12 h.

Human volunteers. In studies on human volunteers, the nonin-vasive technique of gamma scintigraphy has proved to be a veryvaluable means to assess novel formulations aimed at optimiz-ing retention and spread locally or in systemic drug delivery.This technique is the most effective method for studying thespreading and retention of pharmaceutical semisolids for in-sertion in mucosal cavities.

Nyman-Pantelidis et al. investigated the retrograde spread oftwo budesonide enema formulations with different viscosities(12). Three female and two male patients were given the enemaformulations containing budesonide and an unabsorbable radio-active marker (99mTc-labeled human serum albumin micro-colloid), and the spread was monitored by gamma scinti-graphy. In a similar study, Wilding et al. used the same tech-nique to evaluate the colonic spreading of a rectal foam enemain patients with quiescent ulcerative colitis (43). A single ad-ministration of a mesalazine foam enema containing 99mTc wasconducted on 10 patients, and the spread of labeled Tc was as-sessed during a period of 4 h by gamma scintigraphy.

Brown et al. assessed the vaginal spreading and clearance of

Log

shea

r st

ress

Log shear rate

O

LE

G

O

O

Figure 2: Combination of master curves for lipophilic (L), hydrophilicgels (G), and oil-in-water emulsions (E) showing the acceptable rangeof viscosities for spreading on the skin (shaded area) and the optimumvalues (O) (38). Reproduced with permission from Wiley & Sons, NewYork, NY.


a radiolabeled, fatty-based pessary formulation and a putative,bioadhesive gel formulation (Replens, Columbia LaboratoriesInc., Aventura, FL) in six healthy postmenopausal female vol-unteers during a 6-h period using gamma scintigraphy (25). Thestudy was also designed to investigate whether any of the for-mulation was capable of migrating across the cervix into theupper genital tract. The formulations were administered intothe posterior fornix of the volunteers, and immediately a sani-tary dressing was applied to contain any leakage of the formu-lation. Dispersion and spreading of the formulation within thevagina was monitored throughout the study day using a gammacamera within a 40-cm field of view and fitted with a low-energy parallel hole collimator. Anterior and posterior imagesof 60-s duration were acquired at predetermined intervals. Foranalysis, the images were displayed on a color monitor, and theextent of spreading was assessed in terms of the anatomical lo-cation of the tracer. It was also observed that following place-ment of the formulation in the posterior fornix, no spread intothe cavity of the uterus or beyond was observed in any of thevolunteers for either the pessary or the gel formulation.

Miscellaneous methods. In addition to the methods previouslydescribed for spreadability measurement, some techniques orinstruments originally designed for other purposes have beenused for the measurement of spreadability of semisolids. Fourof the instruments are described in this section.

Viscometers and penetrometers. Viscometers are by far the oldest

and most widely used instruments for the measurement ofspreadability. They measure spreadability as a function of vis-cosity of the formulation. Cone-and-plate viscometers are bestsuited for estimating the viscosity of semisolids. The Ferranti-Shirley cone-and-plate viscometer was used by Boylan as earlyas 1967 to evaluate the spreading properties of semisolids, andhe described various advantages and disadvantages of usingthe instrument for this purpose. The advantages included theprovision of a multipoint rheogram, the ease of maintaininga constant shearing rate for an indefinite period of time, anda shearing geometry that closely duplicates that of the appli-cation of the materials with a circular motion on the skin. Inaddition, it subjects all portions of the sample to uniform shear-ing stress. The disadvantages included slippage between therotating portion of the viscometer and the sample during mea-surement. However, rheological procedures by which thespreading properties of pharmaceutical semisolids can be re-producibly measured were presented (18). In addition, Barryet al. in their series of studies mentioned previously in this ar-ticle correlated sensory assessment of spreadability to viscos-ity measured using a Ferranti-Shirley viscometer.

Penetrometers, usually used to measure the viscosity and con-sistency of semisolids, also can be used to determine the spread-ability of semisolids (44). The following equation can be usedto yield the spreadability index of a formulation using a conepenetrometer:

Circle/eINFO 96

INFORM � INTRODUCE � INFLUENCE � INSTRUCT

ARTICLES

NEWS ITEMS

ADVERTISEMENTS

¤

PharmaceuticalTechnologyTechnologyNORTH AMERICA

MARY CLARK

ADVANSTAR MARKETING SERVICES

800-822-6678 ext. 226541-984-5226 Fax: 541-686-5731Email: [email protected]

Reprints of Pharmaceutical Technology articles,advertisements, news items or special announcementsare available through Advanstar Marketing Services.Customized to meet your specific needs, reprints arehighly effective when you use them to:� Develop direct-mail campaigns� Provide product/service literature� Create trade show distribution materials� Present information at conferences and seminars

Extend your coverage to your website. Custom reprint packages include an E-Print of

the same article to post on your website.


in which Po is the yield value for the sample (g/cm2), dp is thedepth of penetration of the cone (cm), m is the weight of thecone plus the weight of other moving parts of the instrument(g), and nj is the constant (�2), the precise value of which de-pends on the properties of the sample. Kb can be calculatedusing the following equation:

in which ap is the half-life of the cone angle.Extending the yield values obtained from the penetrometer,

the spreadability index can be calculated using the followingequation:

in which Si is the spreadability index, Po[u] is the yield valuebefore working the sample, and Po[w] is the yield value afterworking the sample on a roller mill for 30 min. The factor 0.75is derived from a comparison of penetrometer data with panelparticipants’ assessment of spreadability.

Various other penetrometers also have been used to deter-mine a statistical correlation coefficient between spreadabilityand firmness, including a needle penetrometer, a cone pene-trometer, a sectilometer, and a FIRA-NIRD extruder. Spreada-bility data obtained in this way agreed closely with the consumer-panel assessment of the same formulations, and in fact theinstrumental technique proved to be more sensitive to smallvariations in spreadability. A highly significant correlation wasidentified between instrumental measurements of spreada-bility and hardness, the latter being assessed using a sectilome-ter (44). The regression equation used was

The standard deviation was 43.4 g, and confidence limits at 5%significance levels were given as � 86.7 g. It was concluded thatalthough the most important factor affecting spreadability washardness, certain other factors may also exert minor influences.

Texture analyzers. Texture profile analysis (TPA) was used by re-searchers to determine the mechanical and physical properties ofsemisolid systems (4,10). These properties include compressi-bility, cohesiveness, adhesiveness, hardness, and physical proper-ties. The texture analyzer (model TA-XT2, Stable Microsystems,Surrey, UK) has an analytical probe that is depressed two timesinto the sample at a defined rate to a desired depth, allowing apredefined recovery period between the end of the first and thebeginning of the second compressions. The TPA characteristicsof the sample are evaluated from the resultant force–time curve.This precise and convenient method allows a small sample to pro-vide a large amount of data pertaining to the physical propertiesof the semisolid formulations in a desired form. The data can bestatistically evaluated and presented with ease.

Spread meters. Spread meters are specially designed to measure

Resistance to spreading(g) �90.9 �2.63 �hardness(mg)

Si �Po (u) �0.75(Po [u] �Po [w])

K b � ( 1 ) cos(2ap) cot(ap)

Po �m �K b

(d p)n j

spreading of semisolid preparations. These mechanized andimprovised parallel-plate instruments provide accurate, repro-ducible, and statistically relevant data.

Tamura et al. used a spread meter having a 115.5-g glass plate(Rigosha and Co. Ltd., Tokyo, Japan) for the assessment ofspreadability of an oil-in-water–type cyclosporine gel ointment(45). Spread diameters of the samples were measured at 1 minafter the beginning of compression at 20 �C. In another study,a spread meter (model 419, Rigosha and Co. Ltd., Tokyo, Japan)was used to measure the spreadability of gel ointments of indo-methacin. A 0.45-mL sample of the ointment was placed in thesample hole on the spread meter. The spread diameter mea-sured after 1 min was read at 25 �C. This spread area was usedas an index of spreadability (46).

Improvement of spreadability Because spreadability is such an important factor in the devel-opment of a wide variety of dosage forms ranging from topi-cal and mucosal semisolids to lotions and drops, specific effortsare required to achieve the desired formulation characteristics.Various pharmaceutical excipients have been used to improvethe lubricity and spreadability of topical–mucosal formulations.These include various polymers, surface active agents, and manyother miscellaneous materials.

Polymers. Various polymers have been added to formulationsto improve their spreadability. Product cohesiveness has beenfound to be significantly affected by its degree of polymericconcentration, and in nearly all cases increased polymer con-centration has led to increased viscosity of the formulation.Thermal gelation temperatures also play an important part ina formulation’s behavior. Therefore the selection of polymercombinations and their relative ratios plays a very importantrole in formulation development and must be carefully con-sidered to achieve the desired spreadability.

When various hydroxyethylcellulose (HEC) gels were for-mulated alone and in combination with polyvinylpyrrolidone(PVP) and polycarbophil (PC), it was observed that increasingthe concentration of HEC from 1 to 3% led to increased hard-ness and cohesiveness, and a further increase from 3 to 5% hadan opposite effect. When PVP or PC were used in combinationwith HEC, product cohesiveness depended on the individualpolymer ratios (10).

For hydroxypropyl methylcellulose (HPMC) gels, Ferrari etal. reported that the gel strength or cohesiveness increased asthe concentration of the polymer was increased (47). In a quan-titative evaluation of the changes of dynamic surface tensionand therefore the spreading behavior of HPMC aqueous solu-tions, various concentrations of the same were tested againstAvicel PH-101 (FMC Corp., Philadelphia, PA) tablets. It wasobserved that by increasing the concentration of HPMC andthereby increasing the viscosity, the dynamic contact angle val-ues also increased, thus decreasing the spreading behavior ofthe polymer solution on the tablet surface. It was also notedthat the presence of a hydrophilic-type plasticizer improves thespreading pattern (48). McTaggart and Halbert suggested thatthe gel strength of HPMC gels is related to the degree of cross-linking in the polymer network (49).


To identify optimum bases for vaginal suppositories withspreading (upon melting) as a parameter, it was determined thatSuppocire NA was the best lipophilic base and polyethylene gly-col (PEG), a macrogel with low molecular weight, was the besthydrophilic base. The use of Suppocire was strongly reco-mmended for formulating suppositories for the treatment ofvaginitis (50). Hadi further stated that the type and amount ofPEG used greatly affects the spreadability of ointment bases (29).PEG 2000 and PEG 6000 showed the best results as suppositorybases in a comparative study of PEGs of various grades. PEG200 and PEG 400 have been used to impart desired flow prop-erties to ophthalmic ointments (51). Semisynthetic glycerides,as with Witepsols (H5, H15, W25) (Condea Chemie, Hamburg,Germany), which consist of solid lipid nanoparticles, and Sup-pocires (AIM, NAI, A, AP) (Gattefossé, Weil-Am-Rhein, Ger-many), which consist of semisynthetic glycerides (C8–C18), havebeen studied as suppository bases, and the Suppocires showedbetter spreading properties (52).

A comparison of the spreadability of various light-bodiedelastomeric and reversible hydrocolloidal impression materialsshowed that polysulfide had the maximum spreading ability, fol-lowed by silicones, hydrocolloids, and polyether materials (8).

DePaula et al. prepared ointments of Achyrocline satureioidesspray-dried extracts with various adjuvants, including colloidalsilicone dioxide, MCC plus colloidal silicone dioxide (1:1), and�-cyclodextrin plus colloidal silicone dioxide (1:1), each in aglyceryl monostearate base (33). The physical properties, in-cluding spreading, viscosity, and pH were compared, and it wasconcluded that the best spreading area was reached by the oint-ment prepared with the spray-dried extract containing MCCplus colloidal silicone dioxide. Silicone dioxide alone gave thelowest value, indicating the desireability of incorporating thispolymer (33).

An FAPG base (Syntex Pharmaceuticals Limited, St. IvesHouse, Maidenhead, Berks, UK), which is a mixture of propy-lene glycol, stearyl alcohol, polyethylene glycol, and glycerinecombined to form a gel-like structure with a crystalline network,was investigated as a vehicle for dermatological formulations,and its rheological properties have been studied. This base is amixture of propylene glycol, stearyl alcohol, PEG, and glycerolcombined to form a gel-like structure with a crystalline network.Patient acceptance of skin spreadability was assessed using themaster-curve concept. The spreading properties were close tothe preferred values for maximum patient acceptance (3,38,40).

Surfactants. Surfactants, or surface-active agents, are am-phiphilic compounds that form oriented monolayers at inter-faces and exhibit higher equilibrium concentrations at inter-faces than do those in a bulk solution. They exhibit severalcharacteristics, including detergency, foaming, wetting, emul-sifying, solubilizing, and dispersing. These agents are an inte-gral part of the formulation of disperse systems for drugs andcosmetics and impart the desired physical characteristics andphysical stability to these systems. Overall, they are responsi-ble for the rheological properties of a formulation (53). Grantand Liversidge demonstrated the importance of the rheologi-cal properties of a suppository base in terms of the release andabsorption of the drugs entrapped within (41). Softigen 701

(Condea Chemie), which is a polyethylene glycol–caprylic glyc-eride, and stearyl heptanoate are agents known to enhance thespreading of Witepsol suppository bases (28). In water-in-oilointment bases with high water content, Miglyol gel (stear-alkonium hectorite-propylene carbonate) (Condea Chemie),which is an ester of saturated coconut and palm kernel oil–derived caprylic–capric fatty acids; Span 80 (sorbitan mono-oleate); and Imwitor 780K (isostearyl diglyceryl succinate)(Condea Chemie), which is an ester from diglycerol isostearicacid and succinic acid, were found to be the best emulsifyingagents for imparting favorable consistency, low thixotropy, andgood spreadability to the bases (54). On the other hand, spread-ability was found to decrease with the increasing levels of te-gins (glyceryl esters) when they were incorporated in lipophilicbases (55). In yet another study, Eros and Hunyadvari investi-gated the effect of spans (sorbitans) on the physical propertiesof ointments and concluded that the spreading of an ointmentdecreases with the increasing length of the carbon chain of thefatty acid residues of the sorbitans (56).

Sodium dodecyl sulphate as a salivary substitute was used toimprove the lubricity of the saliva at a bovine enamel interface,and it reduced the interocular friction (57). Statherin, which isa salivary acidic proline-rich protein and is another excipientused as a boundary lubricant on enamel, exhibits comparablelubricity to amphipathic molecules such as Gramicidin-S andsodium dodecyl sulphate (58). Various organomodified siliconeemulsifiers have also been shown to improve spreading and lu-bricity along with other formulation parameters in topical for-mulations (59). Polyoxyethylated glycerides (e.g., Nikkol TMGS-5, [Nikko Chemicals Co. Ltd., Tokyo, Japan]) have been used asemulsifiers and spreading agents in various oral solutions andhydrogel ointments (45, 60).

Fluorocarbons. Fluorocarbons and fluorocarbon moieties com-prise a vast family of synthetic compounds. They have recentlyfound numerous applications in the pharmaceutical industrybecause of their special properties, including exceptional chemi-cal and biological inertness, low surface tension, excellent spread-ing characteristics, unique hydro- and lipophobicity, high den-sity, high fluidity, absence of protons, and magnetic susceptibilitysimilar to that of water. Fluorinated lipids and fluorinated sur-factants can be used to elaborate and stabilize various colloidalsystems such as various types of emulsions, vesicles, and tubulesas well as have the potential to be used for controlled-releasedrug delivery. Fluorinated amphiphiles have helped provide avariety of stable reverse and multiple emulsions and gels withexcellent spreading properties. These compounds, with theirpolar heads, are significantly more surface active than their hy-drocarbon analogues and thus display a greater tendency toform well-ordered stable supramolecular assemblies (61–63).Their potential as pulmonary, topical, and ophthalmologicaldrug delivery agents and as skin protection barriers is being in-vestigated widely (64).

Miscellaneous. It has been observed that the levels of colloidalsilicone oxide–dioxides, which are 2% in suppository bases,inhibit the spreading of molten suppositories. However, withtriglyceride bases and with cocoa butter, as much as 3% silicacan be added to improve the flow characteristics of molten sup-


positories (65). Colloidal silicone dioxide, coupled with �-cyclodextrin or microcrystalline cellulose, was shown to en-hance the oil-index values of an herbal ointment, thereby im-parting better spreading properties (33). Glycerine, when addedto formulations, also helped impart the desired rheological characteristics (66). Cyclomethicone has been widely used as abase fluid to formulate a variety of cosmetic and toiletry prepa-rations because it imparts desirable lubricating and spreadingproperties (67).

A comparative study of the hygroscopicity and viscosity ofglycerine, propylene glycol, and sorbitol and their effects on themoisture loss, spreading, and stability of nonionic and ionic oil-in-water lotions and cream emulsions found that all these poly-ols offered protection against water loss and provided emol-liency, good spreadability, and stability to both lotions and creams. The effect varied with the concentration and relativehumidity of the polyol used, and sorbitol offered the best results.

Low doses of eucalyptus oil have been used to improve thesurface properties of various surfactants including ALEC (AbbotLabs, North Chicago, IL), which is a combination of dipalmi-toyl lecithin and phosphatidyl glycerol; Exo-surf (Abbott Labs),which is a synthetic surfactant containing cetyl alcohol, colfos-ceril palmitate, and tyloxapol; beractant (Survanta, AbbottLabs), which is an exogenous surfactant; and a binary mixtureof dipalmitoylphosphatidylcholine and phosphatidyletha-nolamine (2:3). Eucalyptus oil–enriched surfactants form an

open membranous structure, thereby exhibiting better surfaceactivity (68).

Lucero et al. described the effects of two antioxidants—ascorbic acid (AA) and butylated hydroxytoluene (BHT)—onthe spreadability of �-tocopherol gel formulations (36,69). Car-bomer 940 (DFS Products, Honiton, Devon, UK) was used asthe gelling agent. �-Tocopherol gels were individually preparedwith the two antioxidants and one without an antioxidant, andthe three preparations were compared for their spreading charac-teristics. Both AA and BHT reacted with the carbomer and ex-hibited significantly different properties. In gels with BHT, hy-drogen bonds were produced between the hydroxyl groups of�-tocopherol and those of BHT and the free radicals �C�O ofthe carbomer, thereby leading to an unwinding of the polymerresin and an accompanying rise in the viscosity and thickeningand hence reduced spreading. In gels with AA a repulsion is cre-ated between the like (negative) charges originating in AA andthe carbomer, leading to the loss of spiral structure of the resinand thus higher viscosity. However, this union still exhibits a sta-tistically significant and improved spreading because the repul-sion of the like charges forms hydrogen bonds between the hy-droxyl groups of dehydroascorbic acid (an intermediate formedby oxidation of AA) and the carboxyls of the polymer. This unionis very easily broken under pressure because of the nature ofthese bonds. This formulation therefore exhibits very goodspreading characteristics.

Circle/eINFO 60


Phospholipids such as phosphatidylcholine and triolein intheir hydrated, liquid crystalline state gave large values of spread-ing pressures, thereby enhancing the spreadability of vesicularformulations (70,71). The use of physiological lipids that arenormally present in the tear fluid (i.e., phospholipids, saturatedand unsaturated fatty acids, and triglycerides) in eye drops pro-vides better spreading behavior of these formulations in the eyebecause of the small size of the lipid particles (53).

The addition of neutral oils such as Miglyol 812 and Estasan,which is a medium-chain triglyceride consisting of glyceryl tricaprylate–caprate, each in a 5% concentration, had a favor-able effect on the spreading properties of a vaginal suppositorybase (72).

Various drugs can also modify the spreading properties ofthe base of a topical preparation, thereby altering its rheologi-cal properties. Sodium valproate, when added to fatty bases, in-creases the viscosity notably and therefore necessitates the useof a spreadability aid. The addition of sodium valproate wasfound to increase the viscosity of Witepsol H-15/Span 80 andSuppocire As2–aerosil combinations when formulating sup-positories. The active substance suspended in the molten baseprovides nuclei for the crystallization of high-melting-pointglycerides, thus accelerating the separation and subsequent sedi-mentation of the suspended matter, altering the flow proper-ties of the formulation (73).

ConclusionSpreadability is a very important property in the developmentof semisolid preparations meant for topical–mucosal routes.Because it is responsible for the overall performance of a for-mulation, it must be carefully taken into consideration and pro-cedures must be devised for its effective measurement duringthe formulation development stages. To date, little effort hasbeen directed toward this issue and more work must be appliedto its study.

On the basis of existing literature, an appropriate method forthe evaluation of spreadability can be chosen or custom-designed according to the formulator’s need. Various polymers,plasticizers, and other materials can be incorporated into a for-mulation to alter its spreading characteristics. The polymersthat can be used, their compatibility with the active ingredient,the prospective route of administration, and the rate and timeof shear are among the most important parameters to be con-sidered at the time of formulation development. The methodto be used for assessing the spreadability must be selected care-fully and modified according to individual requirements.

References1. B. Idson and J. Lazarus, “Semisolids,” in The Theory and Practice

of Industrial Pharmacy, L. Lachman, H.A. Lieberman, and J.L.Kanigs, Eds. (Lea and Febiger, Philadelphia, PA, 2d ed., 1987), pp.215–244.

2. S. Tamburic et al.,“A Comparison of Electrical and Rheological Tech-

Circle/eINFO 73 Circle/eINFO 74

Pharmaceutical Technology SEPTEMBER 2002 103

niques for the Characterization of Creams,” Int. J. Pharm. 137 (June),243–248 (1996).

3. B.W. Barry and A.J. Grace, “Sensory Testing of Spreadability: Investi-gation of Rheological Conditions Operative During Application ofTopical Preparations,” J. Pharm. Sci. 61 (3), 335–341 (1972).

4. D.S. Jones, A.D. Woolfson, and A.F. Brown,“Texture, Viscoelastic, andMucoadhesive Properties of Pharmaceutical Gels Composed of Cel-lulose Polymers,” Int. J. Pharm. 151 (May), 223–233 (1997).

5. G. Duggin,“Softening Skin with Emollient Ingredients,” Manufactur-ing Chemist 67 (6), 27–31 (1996).

6. R.W. Rance, “Studies of the Factors Controlling the Action of HairSprays. Part I: The Spreading of Hair Spray Resin Solutions on Hair,”J. Soc. Cosm. Chem. 24 (7), 501–522 (1973).

7. I. Eros and J. Szuts,“Investigation of Consistence of Ointments of Sus-pension Type, Part III: Relations among the Results of the DifferentInvestigating Methods,” Gyogyszereszet. 29 (10), 369–373 (1985).

8. T. Hegdahl and N.R. Gjerdet, “Flowing of Light-Bodied Elastic Im-pression Materials,” Acta. Odontol. Scand. 39 (1), 33–38 (1981).

9. B. Vennat, D. Gross, and A. Pourrat, “Procyanidin Gels Based on Cel-lulose and Carrageenan Derivatives,” Drug Dev. Ind. Pharm. 18 (14),1535–1548 (1992).

10. D.S. Jones, A.D. Woolfson, and A.F. Brown,“Texture Analysis and FlowRheometry of Novel, Bioadhesive, Antimicrobial Oral Gels,” Pharm.Res. 14 (4), 450–457 (1997).

11. K. Kyyronen and A. Urtti, “Improved Ocular:Systemic AbsorptionRatio of Timolol by Viscous Vehicle and Phenylephrine,” Invest. Oph-thalmol. Vis. Sci. 31 (9), 1827–1833 (1990).

12. M. Nyman-Pantelidis et al.,“Pharmacokinetics and Retrograde ColonicSpread of Budesonide Enemas in Patients with Distal Ulcerative Coli-tis,” Aliment. Pharmacol. Ther. 8 (6), 617–622 (1994).

13. U.I. Ivens et al., “Ointment is Evenly Spread on the Skin, in Contrastto Creams and Solutions,” Br. J. Dermatol. 145 (2), 264–267 (2001).

14. J. Piret et al.,“Thermoreversible Gel as a Candidate Barrier to Preventthe Transmission of HIV-1 and Herpes Simplex Virus Type 2,” Sex.Transm. Dis. 28 (8), 484–491 (2001).

15. H.B. Kostenbauder and A.N. Martin, “A Rheological Study of SomePharmaceutical Semisolids,” J. Am. Pharm. Soc. 43, 401–407 (1954).

16. J.C. Boylan, “Rheological Studies of Selected Pharmaceutical Semi-solids,” J. Pharm. Sci. 55 (7), 710–715 (1966).

17. F. Langenbucher and B. Lange,“Prediction of the Application Behav-iour of Cosmetics from Rheological Measurements,” Pharm. Acta. Hel-vetiae. 45 (9), 572–582 (1970).

18. J.C. Boylan,“Rheological Estimation of the Spreading Characteristicsof Pharmaceutical Semisolids,” J. Pharm. Sci. 56 (9), 1164–1169 (1967).

19. D.A. Benedetto, D.O. Shah, and H.E. Kaufman, “The Instilled FluidDynamics and Surface Chemistry of Polymers in the Preocular TearFilm,” Invest. Ophthalmol. 14 (12), 887–902 (1975).

20. D.H. Owen, J.J. Peters, and D.F. Katz,“Rheological Properties of Con-traceptive Gels,” Contraception 62 (6), 321–326 (2000).

21. J.H. Wood, G. Catacalos, and S.V. Lieberman, “Adaptation of Com-mercial Viscometers for Special Applications in Pharmaceutical Rhe-ology—II,” J. Pharm. Sci. 52, 375–378 (1963).

22. N.L. Henderson, P.M. Meer, and H.B. Kostenbauder, “ApproximateRates of Shear Encountered in Some Pharmaceutical Processes,” J.Pharm. Sci. 50 (9), 788–791 (1961).

23. K. Suzuki et al., “Non-Newtonian Flow of Water-in-Oil Emulsions,”Bull. Chem. Soc. Japan 42 (10), 2773–2777 (1969).

24. M. Van Ooteghm, “Rate of Structural Breakdown of Petrolatums,”Pharm. Acta. Helv. 43 (5), 264–272 (1968).

25. J. Brown et al., “Spreading and Retention of Vaginal Formulations inPostmenopausal Women as Assessed by Gamma-Scintigraphy,” Pharm.Res. 14 (8), 1073–1078 (1997).

26. M.L. DeMartine and E.L. Cussler, “Predicting Subjective Spread-ability, Viscosity, and Stickiness,” J. Pharm. Sci. 64 (6), 976–982(1975).

27. L.B. Aust et al.,“Descriptive Analysis of Skin Care Products by a TrainedPanel of Judges,” J. Soc. Cosm. Chem. 38 (11–12), 443–449 (1987).

28. T. Keller, H.W. Zulliger, and R. Niederer, “Simple Model for Measur-

Circle/eINFO 75


ing Spreadability of Suppository Bases,” Acta. Pharm. Technol. 28 (4),277–286 (1982).

29. I.A. Hadi et al., “Formulation of Polyethylene Glycol Ointment BasesSuitable for Tropical and Subtropical Climates,” Acta. Pharm. Hung.59 (3), 137–142 (1989).

30. B. Vennat, D. Gross, and A. Pourrat, “Hydrogels Based on CelluloseDerivatives: Validation of the Spreading Diameter Measurement,” STPPharm. Sci. 4 (6), 453–457 (1994).

31. B. Vennat et al., “Comparison of the Physical Stability of AstringentHydrogels Based on Cellulose Derivatives,” Drug Dev. Ind. Pharm. 21(5), 559–570 (1995).

32. L. Panigrahi et al., “Formulation and Evaluation of Lincomycin HClGels,” Ind. J. Pharm. Sci. 59 (6), 330–332 (1997).

33. I.C. De Paula et al., “Development of Ointment Formulations Pre-pared with Achyrocline satureioides Spray-Dried Extracts,” Drug Dev.Ind. Pharm. 24 (3), 235–241 (1998).

34. A. Arvouet-Grand et al., “Formulation of Propolis Extract EmulsionsPart I: O/W Creams Based on Nonionic Surfactants and Various Con-sistency Agents,” Drug Dev. Ind. Pharm. 21 (16), 1907–1915 (1995).

35. F. Lardy et al., “Functionalisation of Hydrocolloids. Principal Com-ponent Analysis Applied to the Study of Correlations between Para-meters Describing the Consistency of Hydrogels,” Drug Dev. Ind. Pharm.26 (7), 715–721 (2000).

36. M.J. Lucero, J. Vigo, and M.J. Leon, “A Study of Shear and Compres-sion Deformations on Hydrophilic Gels of Alpha-Tocopherol,” Int. J.Pharm. 111 (October), 261–269 (1994).

37. B.W. Barry and A.J. Grace, “Sensory Testing of Spreadability: Investi-gation of the Rheological Conditions Operative during the Applica-tion of Topical Preparations,” J. Pharm. Sci. 61 (March), 335–341(1972).

38. B.W. Barry and M.C. Meyer, “Sensory Assessment of Spreadability ofHydrophilic Topical Preparations,” J. Pharm. Sci. 62 (8), 1349–1354(1972).

39. B.W. Barry, “Continuous Shear, Viscoelastic, and Spreading Proper-ties of New Topical Vehicle, FAPG Base,” J. Pharm. Pharmacol. 25,131–137 (1973).

40. B.W. Barry and M.C. Meyer,“Viscoelastic and Continuous Shear Prop-erties of Carbopol Gels,” J. Pharm. Pharmacol. 26 (Suppl), 129–130 (1974).

41. D.J.W. Grant and G.G. Liversidge,“Influence of Physico-Chemical In-teractions on Properties of Suppositories, Part III,” Drug Dev. Ind.Pharm. 9 (162), 247–266 (1983).

42. J.L. Richardson, J. Whetstone, and L. Illum, “Gamma-Scintigraphy asa Novel Method to Study the Distribution and Retention of a Bioad-hesive Vaginal Delivery System in Sheep,” J. Controlled Rel. 42 (No-vember), 133–142 (1996).

43. I.R. Wilding et al., “Colonic Spreading of a Non-ChlorofluorocarbonMesalazine Rectal Foam Enema in Patients with Quiescent UlcerativeColitis,” Aliment. Pharmacol. Ther. 9 (2), 161–166 (1995).

44. P. Sherman, Rheological Properties of Foodstuff (Academic Press Inc.Ltd, London, UK, 1970).

45. T. Tamura et al.,“Evaluation of O/W Type Cyclosporine Gel Ointmentwith Commercially Available Oral Solution,” Drug Dev. Ind. Pharm.23 (3), 285–291 (1997).

46. K. Takayama et al., “Formulation Design of Indomethacin Gel Oint-ment Containing D-Limonene Using Computer Optimization Tech-nology,” Int. J. Pharm. 61 (June), 225–234 (1990).

47. F. Ferrari et al., “Description and Validation of an Apparatus for GelStrength Measurements,” Int. J. Pharm. 109 (August), 115–124 (1994).

48. Z. Riedl et al., “The Effect of Temperature and Polymer Concentra-tion on Dynamic Surface Tension and Wetting Ability of Hydroxy-propylmethylcellulose Solutions,” Drug Dev. Ind. Pharm. 26 (12),1321–1323 (2000).

49. L.E. McTaggart and G.W. Halbert, “Assessment of Polysaccharide Gelsas Drug Delivery Vehicles,” Int. J. Pharm. 100 (November), 199–206(1993).

50. G. Regdon, S. Gombkoto, and B. Selmeczi,“Formulation and In VitroStudy of Antibacterial Vaginal Suppositories,” Pharm. Acta. Helv. 69(3), 141–148 (1994).

Circle/eINFO 76

Pharmaceutical Technology SEPTEMBER 2002 105

51. D.W. Newton, C.H. Becker, and G. Torosian, “Physical and ChemicalCharacteristics of Water-Soluble, Semisolid, Anhydrous Bases for Pos-sible Opthalmic Use,” J. Pharm. Sci. 62 (9), 1538–1542 (1973).

52. J.C. Chaumeil et al., “Formulation of Suppositories ContainingImipramine and Clomipramine Chlorhydrates,” Drug Dev. Ind. Pharm.14 (15–17), 2225–2239 (1988).

53. M.M. Rieger, “Surfactants,” in Pharmacetical Dosage Forms: DisperseSystems, H.A. Lieberman, M.M. Reiger, and G.S. Bankers, Eds. (Mar-cel Dekker, Inc., New York, NY, 1988) 285–366.

54. I. Eros, E. Ugri-Hunyadvari, and E. Soos-Csanyi, “Preparation andTesting of New W/O Emulsion-Type Ointment Base Materials,” Acta.Pharm. Hung. 54 (5), 99–108 (1984).

55. I. Eros, G. Kedvessy, and I. Mile, “Investigation of Lipogels Contain-ing Tegins, Part I: Study of Formation of Structure,” PharmazeutischeIndustrie 45 (2), 203–207 (1983).

56. I. Eros and E. Hunyadvari, “Recent Contributions on the Relation-ships between the Structure, Properties, and Stability of Ointmentsand Surface Active Substances. Part I,” Pharma. Int. 1 (3), 11–13 (1974).

57. E.S. Reeh, W.H. Douglas, and M.J. Levine,“Lubrication of Saliva Sub-stitutes at Enamel-to-Enamel Contacts in an Artificial Mouth,” J. Pros-thet. Dent. 75 (6), 649–656 (1996).

58. W.H. Douglas et al.,“Statherin: A Major Boundary Lubricant of HumanSaliva,” Biochem. Biophys. Res. Comm. 180 (1), 91–97 (1991).

59. D.T. Floyd, B.J. Sarnecki, and B.A. Macpherson, “Getting the Mostfrom Your Screens,” Soap Perf. Cosm. 29 (3), 26–27 (1996).

60. Physicians’ Desk Reference, R. Arkey, Ed. (Medical Economics DataProduction Co., Montvale, NJ, 4th ed., 1995) p. 2183.

61. M.P. Krafft and J.G. Riess,“Highly Fluorinated Amphiphiles and Col-loidal Systems and Their Applications in the Biomedical Field: A Con-tribution,” Biochimie. 80 (5–6), 489–514 (1998).

62. M.P. Krafft, “Fluorocarbons and Fluorinated Amphiphiles in DrugDelivery and Biomedical Research,” Adv. Drug Deliv. Rev. 47 (2–3),209–28 (2001).

63. J.G. Riess and M.P. Krafft, “Fluorinated Materials for In Vivo OxygenTransport (Blood Substitutes), Diagnosis, and Drug Delivery,” Bio-materials 19 (16), 1529–1539 (1998).

64. J.G. Riess and M.P. Krafft,“Advanced Fluorocarbon-Based Systems forOxygen and Drug Delivery and Diagnosis,” Artif. Cells Blood Substit.Immobil. Biotechnol. 25 (1–2), 43–52 (1997).

65. J.J. Tukker, W. Van Vught, and C.J. DeBlaey,“The Addition of ColloidalSilicone Oxide to Suspension Suppositories, Part I: The Impact onRheological Behaviour In Vitro and In Vivo,” Acta. Pharm. Technol. 29(3), 187–194 (1983).

66. H. Endo et al., “Development of Glycerin Povidone-Iodine SugarPreparation,” Japan. J. Hosp. Pharm. 20 (3), 185–189 (1994).

67. R.L. Goldemberg, J.A. Tassoff, and A.J. Di Sapio, “Silicones in ClearFormulations,” Drug Cosmet. Ind. 138 (2), 34–44 (1986).

68. R. Banerjee and J.R. Bellare, “In Vitro Evaluation of Surfactants withEucalyptus Oil for Respiratory Distress Syndrome,” Respir. Physiol.126 (2), 141–151 (2001).

69. M.J. Lucero, J. Vigo, and M.J. Leon,“The Influence of Antioxidants onthe Spreadability,” Drug Dev. Ind. Pharm. 20 (14), 2315–2322 (1994).

70. T. Handa and M. Nakagaki,“Monolayer–Bilayer Equilibrium of Phos-pholipid: Stabilization of Neutral Lipid Droplets in Aqueous Mediumand Catabolism of Plasma Lipoproteins,” Adv. Colloid. Interface Sci.38, 45–67 (1992).

71. T. Handa, H. Saito, and K. Miyajima, “Eutectic Mixed Monolayers inEquilibrium with Phospholipid-Bilayers and Triolein-Liquid Phase,”Biophys J. 64 (6), 1760–1765 (1993).

72. G. Regdon et al., “Formulation and Analysis of Suppositories Con-taining Papaverine Hydrochloride, Part II: In Vitro Membrane Diffu-sion Studies,” Acta. Pharm. Hung. 61 (6), 303–309 (1991).

73. M.V. Margarit, I.C. Rodriguez, and A. Cerezo, “Rheological Study ofRectal Preparations of Sodium Valproate,” Drug Dev. Ind. Pharm. 18(1), 79–92 (1992). PT

Circle/eINFO 77

spreading of semisolid formulations - pharmtech

Documents