MA N Y P H A R M A C E U T I C A L and cosmetic processessuch as new ingredient selections, formulation

preparations, material packaging, and shelf storage areassociated with a complex flow of materials. The appli-cation and acceptance of pharmaceuticals and cosmeticsare also dependent on the flow properties of the finalproduct. Therefore, rheological measurements, an im-portant route to revealing the flow and deformation be-haviors of materials, cannot only improve efficiency inprocessing but can also help formulators and end usersfind pharmaceutical and cosmetic products that are opti-mal for their individual needs. In general, rheologicalmeasurements on pharmaceutical and cosmetic materi-als are performed for the following reasons: 1) to under-stand the fundamental nature of a system; 2) for qualitycontrol of raw materials, final products, and manufactur-ing processes such as mixing, pumping, packaging, andfilling; and 3) to study the effect of different parameterssuch as formulation, storage time, and temperature onthe quality and acceptance of a final product.

Pharmaceutical and cosmetic materials range in con-sistency from fluid to solid. Semisolid products are themost difficult materials to characterize rheologically be-cause they combine both liquid and solid propertieswithin the same material. The majority of pharmaceuti-cal materials are ointments, creams, pastes, and gels—allsemisolids. Few rheological publications have addressedthe dominant viscoelastic nature of a semisolid materialin a detailed sense. To understand these complex flows,commercial medical creams, shampoos, and a children’scough syrup were tested using the S T R E S S T E C Hrheometer (ATS RheoSystems, Bordentown, NJ, F i g u re1). In this article, basic rheological terms and an interpre-tation on the relationship between rheological responseand material structure will be presented.

Steady shear flow curves

A flow curve, viscosity (η) versus shear rate (γ̇) ,across a wide range of shear rates can provide importantinformation about storage stability; optimal conditionsfor mixing, pumping, and transferring; and end-user ap-plications. It also provides important information re-garding the ways in which the structure changes to com-ply with the applied shear in different conditions, suchas storage, processing, and application. The rheologicalbehavior of the material may change as a result of thesef o r c e s . If the shear rate changes during an application,the internal structure of the sample will change and thechange in stress or viscosity can then be seen.

Typical flow curves are shown in F i g u re 2. Newton-ian flow (A curve) is the simplest type, displaying as h e a r-independent viscosity while the material issheared. Water and some low-molecular-weight mineraloils are typical examples of Newtonian fluids. Pseudo-

Application Note

12 / JULY 1998

The rheology of pharmaceutical and cosmetic semisolids

BY PETER HERH, JULLIAN TKACHUK, SPENCER WU,MONIKA BERNZEN, AND BRUCE RUDOLPH

M r. Herh is Applications Manager, and Mr. Tkachuk is Pro d u c tM a n a g e r, ATS RheoSystems, 52 Georgetown Rd., Bordentown, NJ08505, U.S.A.; tel.: 609-298-2522; e-mail: atsrh e o s y s t e m s @ i n t e r -netmci.com. Dr. Wu is Business Development Manager, AT SRheoSystems, New York, NY; tel.: 718-261-9891. Ms. Bernzen isApplications Manager, R E O L O G I C A Instruments A B , S c h e e l e -vagen 30, S-223 63 Lund, Sweden; tel.: 011 46 46 127760. Mr.Rudolph is National Sales Manager, ATS RheoSystems, 150 Di -vadale Dr., Toronto M4G 2P6, Canada; tel.: 416-422-5474.

plastic or shear thinning fluids (B curve) display viscos-ity reduction while the shear rate increases. Typical ex-amples of these are colloidal systems. The colloidalstructure breaks down while shear rate increases, dis-playing reduced viscosity. Dilatant or shear thickeningflow (C curve), in which viscosity increases with shearrate, is seldom encountered in the pharmaceutical andcosmetics fields.

Thixotropy

Time-dependent flow measures the increase or de-crease in viscosity with time, while a constant shear isapplied. The flow is called thixotropic if viscosity de-creases with time, or rheopetic if it increases. The mostdesirable type of flow behavior encountered in pharma-ceutical or cosmetic products is thixotropic flow.

Thixotropic behavior describes a degradation of thestructure during the loaded phase; thus, a reduction inviscosity with time occurs when shear is applied. Dur-ing the relieved phase, the original structure is recover-able. The extent of structural recovery is dependent onthe time allowed for the recovery. Therefore, a thixo-tropic material will have a shear thinning behaviorwhen a gradually increasing shear is applied. This is be-cause the orientation of the structure’s molecules orparticles will change to align with the flow direction.H o w e v e r, its original orientation can be restored over aperiod of time after the external force is removed. T h e r eis a delay in time for the structure to recover com-p l e t e l y. A thixotropic loop, the region between curvesfor the increasing and decreasing shear rate ramps, isshown in F i g u re 3 for a medical cream. A t h i x o t r o p i cloop represents the deformation history of a materialand provides qualitative information about its time de-pendence. The loop area indicates how fast the samplestructure will recover after the load is removed. T h eloop area is dependent on the sample nature and on thelength of time that passes after the load is removed.This test is related to the kinetics of structural change asencountered in aggregated colloidal dispersions. If thestructures in the material are broken apart by shearingand cannot reform completely during the ramp-downperiod, a thixotropic loop can be seen. In other words,viscosity (or stress) during the ramp-down period willbe lower than that in the ramp-up shearing period.

In general, shear thinning measures how easily thestructure can be broken and the loop area indicates therecovery extent of that broken structure during the ex-perimental time. The information obtained from thistype of experiment is valuable in many situations. Forexample, a suspension formulation must have proper

fluidity during application and preparation; a certainconsistency is required so that the particles can be dis-persed effectively in the container or so that film can beformed uniformly after application. Therefore, it is im-portant for the disturbed structures to rebuild at a suit-able rate upon resting in order to have proper film for-mation and sedimentation resistance.

Yield stress phenomena

The yield stress measurement is crucial for pharma-ceutical products in determining not only their shelf lifebut also ease of application for the end user.

Yield stress (τy) is defined as the minimum shearstress required to initiate flow. Yield stress can be meas-ured using a stress ramp experiment. The yield stress ofa commercial children’s cough syrup was measured inthis way (F i g u re 4). Yield stress can also be defined asthe stress below which a material will not exhibit a flu-idlike behavior. This means that subjecting a material tostresses less than the yield stress will lead to a nonper-manent deformation or a slow creeping motion over thetime scale of the experiment. The exact yield stress forthis material is 1.262 Pa. This measurement was ob-

Figure 1 The STRESSTECH rheometer.

Figure 2 Typical flow curves.

Figure 3 Thixotropic loop of a medical cream.

AMERICAN LABORATORY / 13

tained from Analyse (Rheologica, Lund, Sweden) anal-ysis software. The concept of yield stress, the minimumshear stresses required to cause flow, is only an approx-imation since this stress value is experimental time de-pendent. Almost all substances will eventually flow ifthe time scale for imposing a shear stress (howeversmall) is long enough. However, in general, the higherthe static yield value, the more readily a medium willmaintain particles in suspension with minimal sedimen-tation. Thus, the magnitude of the static yield valuemay be used as one of the criteria for controlling sedi-mentation during storage and the ease of using or proc-essing a product.

Dynamic oscillatory experiments

Although rotational experiments provide informationconcerning the flow properties of a system such as yieldvalue, thixotropy, and steady flow curve, they are only apart of the complete rheological characterization of asystem. Dynamic oscillation testing is a much morepowerful tool to reveal the secrets of the microscopicstructures of a viscoelastic material; therefore, it is moreattractive and useful from a practical point of view.

Strain sweep is utilized to determine the linear vis-coelastic region of a material system for performing asubsequent dynamic test. F i g u re 5 shows the results ofstrain sweep on two medical emulsion creams. T h emaximum strain up to which G′ remains constant iscalled the critical strain. The critical strain, which indi-

cates the minimum energy needed to disrupt the struc-ture, is dependent on the dispersion quality. Therefore, ifthe difference in the critical strain of two creams isknown, the different extent of dispersion of particles oringredients can be measured. The higher the criticalstrain, the better the system is dispersed. The criticalpoint can also be called dynamic yield stress if a G′ v e r-sus stress curve is presented. By extrapolating the linearportion, the shear stresses of the same two creams can beread from the separation point, as shown in F i g u re 6.The presence of a dynamic yield stress of suitable mag-nitude may be used as a criterion to determine whether,for example, a vehicle will maintain suitable semisolidproperties under shear. A semisolid has a weak structure,and does not recover this structure after a brief restingperiod; therefore, a dynamic yield value should be usedinstead of static yield stress to assess film formation andsag resistance of a layer of material applied on a surface.

Oscillatory shear measurements can be explainedfrom an instrumentation point of view: A s i n u s o i d a lshear stress (or strain) smaller than the critical value isimposed on a fluid, and the amplitude of the resultingstrain (or stress) and the phase angle between the im-posed stress and the output strain are measured. Experi-m e n t a l l y, this can be accomplished by commanding asmall sinusoidal displacement or strain (within the linearviscoelastic range) on the emulsion under a controlledfrequency or temperature sweep. In general, the materialcan respond to this type of deformation through twomechanisms: elastic energy storage and viscous energ y

dissipation. Quantitatively, these responses can be repre-sented as storage modulus (G′), energy stored per unitvolume, and loss modulus (G″), energy dissipated perunit deformation rate per unit volume. Storage modulus( G′) is proportional to the extent of the elastic compo-nent (contributed by crosslinking, entanglement, and/oraggregation) of the system, and loss modulus (G″) isproportional to the extent of the viscous component(contributed by the liquidlike portion) of the system.Ty p i c a l l y, the strength of interaction of internal structurein an emulsion is measured by the magnitude of the ratioG″/ G′ = tan δ which is called the damping factor (δ i sphase angle). The smaller the tan δ (or the greater G′) ,the stronger the interaction.

Pharmaceutical semisolid materials may be classi-fied as either viscoelastic liquids or viscoelastic solids.Frequency sweep is a useful tool when characterizingthe microstructure of a viscoelastic material. A p p l y i n ga constant strain below the critical value (as seen inFigure 4) and a frequency ramp reveals the microstruc-tures of a material through the response of that materialto different shear rates. In suspensions or emulsion ma-terials at low frequency, elastic stress relaxes easilyand viscous stress then dominates to exhibit a higherloss modulus (G″) than the storage modulus (G″), asshown in F i g u re 7 for a commercial shampoo. Sincegels and creams cannot relax quickly and are highlyelastic at the same frequency range, the storage modu-lus (G′) is higher than the loss modulus (G″), as shownin F i g u re 8 for the gellike medical cream. A s e m i d i l u t e

Figure 4 The yield stress measurement for children’s coughsyrup.

Figure 5 The strain sweep for two creams;closed symbol,cream A;open symbol, cream B.

Figure 6 The strain sweep for two creams;closed symbol,cream A;open symbol, cream B.

Figure 7 The frequency sweep of a commercial shampoo.Figure 8 The frequency sweep of a medical cream. Figure 9 The frequency sweep of the children’s cough syrup.

14 / JULY 1998

Results using a S T R E S S T E C H rheometer for creep/recovery measurements at different stresses (40, 100,and 120 Pa) on a medical emulsion cream are shown inF i g u re 11. In this experiment, the compliance is depen-dent on the applied stress. At stresses higher than theyield stress (108.7 Pa), the compliance Jc increases withtime in a nonlinear manner. The creep curves with anupward curvature, indicating that the structure breaksdown quickly under the influence of the shear stressand a viscosity reduction should occur.

Rheometer system setup

S T R E S S T E C H is a modular product with a widerange of measuring systems and accessories. Measuringsystems are available as concentric cylinders, cone/plate, parallel plate, double concentric cylinders, closed/pressure cells, and dynamic mechanical analysis (DMA)for torsion and tension with autotension function. Spe-cial measuring systems for low volume, high shear rates,and high sensitivity are also available. The measuringgeometries can be made in stainless steel, titanium,polycarbonate, or any user-defined material. The instru-ment is supplied standard with a patented Diff e r e n t i a lPressure Quantitative Normal Force Sensor for repro-ducible sample loading history, thermal expansionmeasurements, and quantitative normal stress measure-ments. The diffusion air bearing has low inertia withhigh axial and radial mechanical stiffness. S T R E S S-TECH HR, a high-resolution version of the instrument,allows measurements at microradian displacement andextremely low applied torques.

Electronic unit

Instrument electronics are contained within the me-chanical unit and the instrument is built around a dedi-cated, high-speed, 32-bit CPU. This consolidation en-hances performance and versatility due to electricalconnections on the motherboard bus rather than throughcables to a separate electronics cabinet. In addition,valuable bench space is kept to a minimum. The motorcontrol is based on digital rather than analog drive tech-n o l o g y. The unit incorporates a built-in diagnostic sys-tem and quick diagnostic service port for service engi-neers. Also included is a modem port for remote controloperation and fault diagnostics for service. The electron-ics power supply is designed to operate on a line voltageof 180–260 V or 90–140 V and an operating frequencyof 47–63 Hz.

Software package presentation

The multitasking standard software is a true M i c ro-s o f t® (Bellevue, WA) Windows™-based rheologicalpackage, which has many advantages to the user. T h ecomputer is not dedicated to simply running the instru-ment and is available for other uses when makingmeasurements. The computer can be used for printingprevious results, writing a report, or performing meas-urements with another instrument. The software runsunder both Windows 3.1 and Windows 95.

The standard package offers measuring programsdesigned to be user friendly with few subdialogue lev-els and a generally recognizable design. Experimentmethod and analysis are available in the following testmodes: viscometry, yield stress, constant rate, oscilla-tion, oscillation stress sweep, oscillation strain control,c r e e p / r e c o v e r y, compare, analyze, time-temperature su-perposition, and spectrum transformation.

The software includes possibilities to link user-designed methods including instrument setup and zerogapping using the Windows Recorder icon and ProjectSoftware (ATS RheoSystems). The dialogue windowshave many storable, editable functions for unique test-ing requirements, and can be reset to default values us-ing default buttons. An example is the Oscillation Fre-

quency Step measuring program, in which stresses, de-lay times, integration periods, and sample sizes can beset individually for all frequencies. Another example isthe zooming function, which is present in both the Vi s-cometry Stress Step and Oscillation Frequency Step,allowing any number of steps and increments to be se-lected. The instrument also performs controlled strainand constant shear rate measurements, and is providedwith automatic gap adjustments and compensation us-ing a Normal Force Sensor. The system enhancesmeasurement reproducibility since the sample loadinghistory is reproduced identically each time, using aconstant loading force.

The rheometer is operated with a separate power sup-ply unit that is intended to be left on continuously. T h i sreduces start-up times and makes it possible for the in-strument processor to maintain values as gap and otheru s e r-defined settings.

Temperature control cells are available that use circu-lating fluid, resistive heating, adiabatic cooling, andcryogenic cooling; the range –180 °C to 500 °C is cov-ered. All measuring geometries are supported(cone/plate/parallel plate, concentric cylinder, and solidin torsion). A closed cell for operation at elevated withfull oscillatory capabilities is available.

The rheometer is produced according to ISO 9001regulations and is tested to operate according to the elec-tromagnetic compatibility rules within the EuropeanC o m m u n i t y. The instrument is tested to be labeled withthe CE mark. The V I S C O T E C H rheometer (ATS Rheo-S y s t e m s) features full upgradeability capability to theSTRESSTECH research-grade rheometer, as the user’sneeds and requirements change. The application specificS P E C T E C H DSR (dynamic shear rheometer) is de-signed for asphalt tests according to A A S H TO T P 5 .

Conclusion

This article has reviewed all the important rheologi-cal characterizations with all the genuine results from aSTRESSTECH rheometer, and the detailed interpreta-tion to correlate the rheological responses with thephysicochemical properties of different commercialsemisolid products. The rheological characterizationsfor pharmaceutical and cosmetic semisolids provideimportant information for engineers to facilitate theirdaily production and processing for their products. To-d a y, most formulators also count on rheological resultsto develop customer-favored products for surviving inthe competitive market. Therefore, a reliable rheometerand understanding rheology are becoming necessaryfor pharmaceutics and cosmetics manufacturers.

solution, such as the children’s cough syrup, exhibits aG′ > G″ scenario at low frequencies and a G″ > G′ s c e-nario at high frequencies, as shown in F i g u re 9. T h efrequency at crossover point is a function of the relax-ation time of the internal structures of the syrup.

Creep/recovery

Because of the relatively low consistency of manypharmaceutical formulations, it is often difficult to applysmall enough stresses to remain in the linear viscoelasticregion for an oscillation test. The creep/recovery test istherefore an alternative for obtaining the relaxation timeand viscoelastic properties of a material. A c o n s t a n tstress below yield stress is applied to the material andthe deformation is monitored with time. Compliance (J)is defined as the reciprocal of modulus, J = 1/G = γ/τ,where G is modulus and γ is strain. The value and shapeof the creep compliance curve are fundamentally impor-tant. Subjected to a constant stress, the strain of an idealelastic material would be constant and the materialwould return to the original shape when the stress wasremoved. In contrast, an ideal viscous material wouldshow a steady flow, producing a linear response to stresswith the inability to recover any of the imposed defor-mation. Viscoelastic materials (e.g., semisolid pharma-ceutical products) will exhibit a nonlinear response tostrain and, due to their ability to partially recover struc-ture by storing energ y, will show a final deformationless than the initial deformation. F i g u re 10, which illus-trates typical creep behavior of a viscoelastic material,displays a creep/recovery test result for a medical creamwith a S T R E S S T E C Hr h e o m e t e r.

In general, the creep compliance-time curve can besubdivided into three regions (see Figure 9). Curve A - Bis the region of instantaneous compliance, where bondsbetween the primary structural units stretch elastically.Curve BC is the time-dependent retarded elastic regionwith compliance JR. Curve CD is the linear region withsteady-state compliance J. Some bonds rupture; there-fore, the time required for them to reform is in excess ofthe test period. Thus, the released entities can flow pasteach other. Upon removal of the stress, a recovery oc-curs, and this is represented by DF. There is an instanta-neous elastic recovery (DE) with the same magnitude asAB, followed by a retarded elastic recovery equivalentto the retarded region of the creep curve. Some bondswere irreversibly broken in the creep region, and theoriginal structure is never recovered completely. How-e v e r, the degree of recovery after creep can be repre-sented by the recoverable compliance Jo r, which isequivalent to AH (Jo c) .

Figure 10 The creep/recovery of a medical cream.Figure 11 The effect of stress on the creep/recovery re -sponse of an emulsion cream.

APPLICATION NOTE cont.