Original Article

Investigation of the Rheological Properties of Ointment Bases as a Justification of the Ointment Composition for Herpes Treatment


  • Tanya IVKO
  • Lydmila KIENKO
  • Larisa BOBRYTSKA
  • Halyna KUKHTENKO
  • Tamara GERMANYUK

Received Date: 03.07.2020 Accepted Date: 24.02.2021 Turk J Pharm Sci 2021;18(5):628-636 PMID: 34719191


Combinatorial drugs are among the leading pharmacotherapeutic agents, including those used for the treatment of herpetic infections, which require complex treatment. We have developed a soft dosage form of ointment, which includes acyclovir and miramistin, which have antimicrobial, anti-inflammatory, and local immunoadjuvant activity. The study aimed to investigate the rheological properties of ointment bases in order to substantiate the composition of a soft dosage form with antiviral effect using the active ingredients miramistin and acyclovir.

Materials and Methods:

The object of the study was to determine the heterogeneous and homogeneous composition models of the bases made using a wide range of excipients. Structural and mechanical studies were performed using the “Rheolab QC” rotary viscometer by Anton Paar (Austria) with coaxial cylinders CC27/S-SN29766. The rheological parameters were investigated at a temperature of 25°C±0.5°C. The samples were thermostated using a thermostat MLM U15c. The batch of sample weighing about 15.0±0.5 g was placed in the container of an external stationary cylinder. The required temperature of the experiment was set and the thermostating time was 20 min. The device is equipped with RheoPlus 32 V3.62 software.


The rheological behavior of the model compositions was analyzed in terms of indicators, such as yield strength, hysteresis square, coefficients of dynamic flow, and mechanical stability. It was found that all samples have a non-Newtonian pseudoplastic type of flow. The model of spreading optimums was used to evaluate consumer properties. According to the rheological parameters, it is advisable to use the sample based on paraffin and vaseline oil for further research.


The findings from this study will be relevant in the development of the soft dosage form for the treatment of herpes viral diseases.

Keywords: Ointment bases, soft dosage forms, rheology, structural and mechanical properties


Soft dosage forms are dispersed systems with a viscous-plastic dispersed medium characterized by a non-Newtonian type of flow.1 Their viscosity at a given temperature and shear stress varies non-linearly, depending on the shear rate.2,3

When developing the composition of soft dosage drugs, much attention is paid to the study of their rheological properties and the structural and mechanical parameters determine the stability of viscose-dispersed systems.4 A comprehensive study of rheological characteristics is of both theoretical and practical interest, since they can be an effective and objective criterion for quality control at the stage of creation, production, storage, and use of drugs.5,6 The rheological properties affect the release of medicinal substances, therapeutic efficacy of drugs, consumer requirements (the process of extrusion from tubes, convenience, and ease of lubrication on the skin), and production characteristics (the process of dispersion and packaging).7,8,9

Soft dosage forms are complex systems that contain a base and active ingredients.10 Properly selected base provides the necessary speed and completeness of the medicinal substances released, comfort in usage, and stability during storage of drugs.11,12 Therefore, the study of the structural and mechanical properties of ointment bases is an important step in the development of soft dosage forms.13,14,15

Today, combinatorial drugs are among the leading pharmacotherapeutic agents, including those used for the treatment of herpetic infections, which require complex treatment. Choice of drug combination allows the expansion of drug action and the complex influence on diseases, enhances the activity of every ingredient, improves tolerability, and reduces side effects.16,17,18,19

Herpetic infections occur in the form of mono-, mixed and coinfections and can be asymptomatic (latent), in an acute, chronic persistent form with a recurrent course, as well as in the form of an atypical chronic active infection.20 Currently, the combined drugs are leading among pharmacotherapeutic agents, including the treatment of herpetic infections, which require complex treatment. Drug combination choice allows to expand the range of action of the drug and the complex influence on the disease, activity of the every ingredient, as well to improve tolerability.21,22,23,24,25,26 We have developed a soft dosage form in the form of an ointment, which includes acyclovir [TEVA Pharmaceutical and Chemical (Hang-zhou) Co., Ltd, China] and miramistin (Infamed LLC, Russia), which has antimicrobial, anti-inflammatory and local immunoadjuvant action.


The objects of the study were ointment bases (Table 1). The ointment bases, which have been developed using excipients that are widely used in soft dosage technology, were obtained were obtained at National University of Pharmacy, Department of Industrial Technology of Drugs. The excipients used includes propylene glycol (BASF SE, Germany),27 proxanol-268 (NPF “Perftoran” OJSC, Russia), polyethylene oxide-400 (Dow Chemical, Germany),28 vaseline oil (Borma wachs, Italy),27 paraffin (LLC “Novokhim,” Ukraine), cetostearyl alcohol (Guangzhou Yiming Chemical Material Co., Ltd., China),29 twin-80 (MN & Gustav Heess Ukraine, Ukraine), carbopol 934 (Kylin Chemicals Co., Ltd., China), triethanolamine (LLC “Novokhim”, Ukraine),27 corn oil (Nordolio, Italy), eucerit (LLC NPP “Electrogazokhim” Ukraine), aristoflex AVC (Clariant, Switzerland), vaseline (Balea, Germany),27 emulsifier “Solid-2” (LLC NPP “Electrogazokhim”, Ukraine), isopropylmyristate30 (MN & Gustav Heess Ukraine, Ukraine),23 and hydroxyethylcellulose (LLC “Linkchem”, Ukraine). The rheological (structural-mechanical) properties of the bases were determined using a “Rheolab QC” rotary viscometer (Anton Paar, Austria) with coaxial cylinders CC27/S-SN29766. The rheological parameters were investigated at a temperature of 25°C±0.5°C. The samples were thermostated using a thermostat MLM U15c.

The batch of sample weighing about 15.0±0.5 g was placed in the container of an external stationary cylinder; the required temperature of the experiment was set and the time of thermostating was 20 min. The device is equipped with RheoPlus 32 V3.62 software. Measurements of the rheological flow curve were performed in 3 stages:

1. Linear increase at the rate of shear velocity from 0.1 s-1 to 350 s-1 with 105 measurement points and duration of the measurement point is 1 s;

2. Constant shift at a speed of 350 s-1 for 1 s of duration;

3. Linear decrease at the rate of shear velocity from 350 s-1 to 0.1 s-1 with 105 measurement points and duration of the measurement point is 1 s

The range of the shear rate gradient 0.1-350 s-1 corresponds to the range speed of 0.075-270 revolutions per minute.

The device allows the measurement of tangential bias voltage (t) in the range of 0.5-3.0 104 Pa, gradient of the shear rate (γ) from 0.1 to 4000 s-1, and viscosity (h) from 1 to 106 Pa sec. Using RheoPlus 32 V3.62 software, the hysteresis square (A, Pa/sec) was calculated. The points (yield) strength (τ0, Pa) and viscosity at the infinite shear rate (η, Pa·s) was calculated using the Casson model:5,6

τ12 = τ0 + (η . γ.)12

where τ0 - yield strength, Pa;

η - dynamic viscosity, Pa∙s;

γ - shear rate, s-1

The Casson model describes an imperfect plastic type of flow, in which there is a disproportionate relationship between shear rate and stress and most closely corresponds to the nature of the flow of the investigated ointment bases.

A coefficient of dynamic flow was determined at the speed rates of 3.4 and 10.2 s-1, which correspond to the velocity of the palm, while soft dosage form distribution over the surface and viscosity of the system was determined at the velocity rates of 27.0 and 155 s-1, which display the velocity of the processing procedure while manufacturing. Based on the results obtained, the values of coefficients of the dynamic flow of the system were calculated by the formulas:5,6

Kd1 =η3.4 -η10.2η3.4.100%

Kd2 =η27 -η155η27.100%

where Kd1, Kd2 - the dynamic flow coefficients;

η - apparent viscosity at specified shear rates

For a more complete study of samples, the parameters of their mechanical stability (MS) were calculated. It is known that the optimal value of MS is 1.15 The MS value is defined as the ratio of the strength of the structure to failure (τ1) to the strength value after fracture (τ2) at a shear rate of 3.4 s-1, according to the formula:5,6


Statistical data was not used in this research.


To study the structural and mechanical properties of the experimental samples, complete rheograms of the dependence of the shear stress (t) from the shear rate gradient (γ) were constructed (Figure 1). A comprehensive assessment of the behavior of the ointment bases during the step-by-step destruction and subsequent restoration (Figure 1) also shows the dependence of viscosity from the shear rate. Sample values of the shear stress and viscosity of the model bases are given in Table 2.

The profile of rheological behavior depends on the composition of the ointment base and varies in a wide range of structural and mechanical parameters (Figure 1). All samples have a pseudoplastic type of flow and the viscosity of the samples decreases disproportionately with increasing shear rate. The samples were exposed to the flow in different ways, which is expressed in the value of the yield strength calculated by the Casson equation: 105.8 Pa, 1.3 Pa, 49.3 Pa, 12.6 Pa, 104.5 Pa, 77.2 Pa, 65.9 Pa, and 0.3 Pa for the samples № 1, № 2, № 3, № 4, № 5, № 6, № 7, and № 8, respectively (Figure 2, 3, 4, 5, 6, 7, 8).

The yield strength is an indicator that shows the force at which the dispersed system begins to flow. In accordance with the value, it is possible to draw a conclusion about how easily the system will be squeezed out, whether the self-flow of the system will be observed, and about the adhesive properties of the drug. Thus, since the sample № 8 has low rheological parameters, the system has a pronounced ability to self-flow due to insufficient concentration of gelling agent.4,5,6 The plan of the experiment envisages a stepwise increase in the rate of destruction of the dispersed system, the flow reflected in the ascending curve, and a subsequent decrease in the rate with the same step. The flow of the system is described by a descending curve.

The ascending curve is located above the descending one and this arrangement of curves is called positive thixotropy, since there are such dispersed systems that have antitixotropic or reopective properties. In such systems, the ascending and descending curves are opposite. The investigated ointment bases were restored to varying degrees and the surface area between the ascending and descending curves indicates the thixotropy of the system or ability to recover.11,15 On one hand, the smaller the area of the hysteresis loop, the faster the system recovers and, on the other hand, the larger the area, the easier the system is distributed on the surface and on a larger surface area. The first aspect is important in the production process and speaks of the reproducibility of the structured system after the technological process of processing, while the other is important as a consumer indicator of quality. The hysteresis square for base № 1, № 2, № 3, № 4, № 5, № 6, № 7, and № 8 was 38780.5 Pa/s, 30887.8 Pa/s, 40.2 Pa/s, 17242.8 Pa/s, 49174, 4 Pa/s, 49521.1 Pa/s, 82587.0 Pa/s, and 319.5 Pa/s. respectively.

During the period of destruction of structured systems by means of increasing speed of rotation of the internal cylinder, there is a rarefaction of systems, which never comes to an end because some share of communications is restored back, even at high speeds. The viscosity at the infinite shear rate calculated by the Casson model was 0.39 Pa/s, 0.54 Pa/s, 0.83 Pa/s, 0.72 Pa/s, 0.88 Pa/s, 0, 34 Pa/s, 0.44 Pa/s, and 0.65 Pa/s for sample № 1, № 2, № 3, № 4, № 5, № 6, № 7, and № 8, respectively (Table 3). According to this indicator, the most resistant to the applied shear force is sample № 8, which had a hydroxyethylcellulose base. Emulsion samples are liquefied to the greatest extent.

The behavior of dispersed systems during destruction is also evaluated by the coefficients of dynamic flow and MS. The coefficient of dynamic flow Кd1 at shear rates of 3.4 and 10.3 s-1 varies in the range from 34.8% to 95.9%. The coefficient of dynamic flow Кd2 is in the range of even higher values, since systems at higher shear rates are destroyed to a greater extent. The coefficient of MS, calculated as γ 3,4 s-1, serves as a measure of the assessment of the restoration of the structure after the full cycle of destruction-restoration. The closer the calculated value is to 1, the faster the system recovers, thus indicating a high instantaneous thixotropic properties. From Table 2, we see that the lowest value of the MS index was recorded by sample № 8, which was made using hydroxyethylcellulose. For gel systems, this behavior is typical because as the speed of rotation of the cylinder increases, there is elongation of the molecules of macromolecular matter and, after the cessation of the driving force, the structured orientation of the molecule is restored. In emulsion dispersed systems, which include samples № 3, № 4, № 5, and № 6, the change in viscoplastic properties is due to the sol-gel transition and such systems are restored over time. Homogeneous hydrophobic dispersed systems (samples № 2 and № 7) recover more slowly and the reason for this may be a violation of thermodynamic equilibrium in the system as a result of forced mixing of one layer relative to another or because the viscosity of hydrophobic systems is sensitive to temperature changes.

Samples № 6 and № 7 (Figure 1) have an unstable flow at high shear rates, which can be interpreted as an unstable structure that can stratify over time.

Sample № 2 (based on paraffin and vaseline oil) has a stable homogeneous flow over the entire range of the shear rates, the system is easily propelled, and is characterized by good consumer properties according to the optimum lubrication. According to the set of the rheological parameters, we consider it expedient to use the sample of the ointment base № 2 for further research on the development of the composition of the ointment with antiviral activity.


The structural and mechanical activity of the ointment bases was studied with help of the rotary viscometer “Rheolab QC” by Anton Paar (Austria) with coaxial cylinders CC27/S-SN29766. It was found that all samples have a non-Newtonian pseudoplastic type of flow. It is established that the ointment base № 2, which includes vaseline oil and paraffin, exhibits a homogeneous rheological flow.

Further research will focus on the development of composition of ointments with the antiviral effect.

Conflict of interest: No conflict of interest was declared by the authors. The authors are solely responsible for the content and writing of this paper.

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