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Journal of Drug Delivery Science and Technology

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Development and evaluation of taste-masked paracetamol chewable tabletsusing a polymer and/or wax dispersion technique

Tanikan Sangnim, Kampanart Huanbutta∗

Faculty of Pharmaceutical Sciences, Burapha University, 169, Saensook, Muang, Chonburi, 20131, Thailand

A R T I C L E I N F O

Keywords:Chewable tabletTaste maskingParacetamolDispersion

A B S T R A C T

Chewable tablets are easy-to-use dosage formulations and widely applied in pediatric dosage forms. However,the chewable tablets have to disintegrate in the mouth before swallowing, which makes the chewable tabletdosage forms inappropriate for bitter active ingredients. In this study, a polymer (Eudragit® EPO) and/or wax(cetyl alcohol, stearic acid, or beeswax) dispersion technique has been used to overshadow the unpleasant tasteof paracetamol. The chewable tablet made from Eudragit® EPO dispersion showed low disintegration and dis-solution due to its low water solubility. While the wax or the mixture of cetyl alcohol and Eudragit® EPO-basedtablets had fast disintegration (11.50–35.40 s) and the drug release were> 90% in 45min. The taste-maskingstudy in human volunteers revealed that the chewable paracetamol tablets prepared from drug dispersion im-proved the taste of the paracetamol chewable tablets without wax/Eudragit® EPO dispersion. The mixture ofcetyl alcohol and Eudragit® EPO dispersion could mask bitter taste better than those of cetyl alcohol. In con-clusion, cetyl alcohol together with Eudragit® EPO could be efficiently used in the formulation of taste-maskedparacetamol chewable tablets that complied with the United States Pharmacopeia standard.

1. Introduction

Chewable tablets have been widely used in pediatric and geriatricdosage forms because they are beneficial to children or adults who havedifficulty in swallowing [1]. These dosage forms can disintegrate in thepatient's mouth by the chewing mechanism. Thereafter, a smooth tex-ture upon disintegration is swallowed, and the drug is absorbed in thegastrointestinal tract. Therefore, the chewable tablet can improvebioavailability through bypassing disintegration (that increases dis-solution). Moreover, it improves patient acceptance and conveniencebecause water is not necessary for drug administration. The key factorsof the chewable tablet formulation are excipients. Choosing an appro-priate excipient to perform a specific function in tablet formulation,including disintegration or lubrication, can be critical to achieve ac-ceptable manufacturing performance. A sweetening agent is anotherimportant excipient for the taste masking of the active ingredients.However, only a sweetening agent might not completely overshadowthe unpleasant taste of the drug. Consequently, several techniques, suchas taste blending, overshadowing, and chemical and physical mod-ifications of drugs, are introduced together with the sweetening agentto overcome the problem [2].

Among various taste-masking techniques, the physical modificationof drugs is an efficient method and offers feasibility in industrial

manufacturing. Nevertheless, drug dissolution might be affected by aphysical modification technique. Numerous methods can be conductedfor physical modification, including drug coating to delay drug dis-solution in the patient mouth [3]. Several substances such as hydro-philic polymers and meltable/degradable waxes have been applied tocoat the active ingredient for taste-masking purposes. Methacrylic acidand methacrylic ester copolymers (Eudragit E 100, RL 30D, RS 30D,L30D-55, and NE 30D) have been effectively applied for taste maskingwith polymer coat levels varying from 10% to 40%, depending on thedrug bitterness [4]. Stearic acid (SA) was also used to mask the taste ofthe model drug (satranidazole) in granulation form [5]. Suitable typeand amount of coating materials, including a coating technique, play avital role in taste-masking efficiency.

This study aimed to develop and evaluate the taste-masked para-cetamol chewable tablets using the polymer and/or wax dispersiontechnique. The selected model drug was paracetamol, and the coatingmaterials were Eudragit EPO, cetyl alcohol (CA), SA, and beeswax(BW). The drug was dissolved or dispersed in different portions of thecoating materials. Subsequently, the coated drug powder was mixedwith other excipients and prepared in the form of granules before ta-bleting. The different formulations of the chewable tablets were fabri-cated and physically evaluated. Lastly, taste and mouth feeling after thechewing of the optimized tasted-masked paracetamol tablet were

https://doi.org/10.1016/j.jddst.2019.101361Received 12 August 2019; Received in revised form 27 September 2019; Accepted 28 October 2019

∗ Corresponding author.E-mail address: kampanart@go.buu.ac.th (K. Huanbutta).

Journal of Drug Delivery Science and Technology 54 (2019) 101361

Available online 30 October 20191773-2247/ © 2019 Elsevier B.V. All rights reserved.

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investigated among the volunteers.

2. Materials and methods

2.1. Materials

Paracetamol was obtained from T. Man Pharma Co., LTD(Thailand). CA, SA, and BW were purchased from PhitsanuchemicalsCo., LTD (Thailand), Sigma-Aldrich (Germany), and P.O. Drug Center(Thailand), respectively. Eudragit® EPO (EP) was a gift from EvonikDegussa (Thailand) Co., Ltd., Thailand. All other chemicals were ofstandard pharmaceutical grade.

2.2. Drug dispersion and tablet preparation

The model drug (paracetamol) was coated/dispersed by two tech-niques depending on the physical properties of the coating materials(Eudragit EPO or wax). The proper formulation from Table 1 was fur-ther developed to optimize physical properties, in vitro dissolutionprofile, and taste-masking efficiency.

2.3. Preparation of drug dispersion in Eudragit EPO

For paracetamol–EP dispersion preparation, 120mg of paracetamoland EP were dissolved in ethanol and then dried at 60 °C for 4 h. Thedispersion of drug in EP was milled by the oscillating granulator. Thegrinded drug dispersion was mixed with other excipients as presentedin Table 1 using a geometric dilution technique. Thereafter, the mixed

Table 1The formulation of taste-masked paracetamol chewable tablet.

Composition (mg) Formulation

EP CA1 SA BW

Paracetamol 120 120 120 120Eudragit EPO 240 – – –Cetyl alcohol – 240 – –Stearic acid – – 240 –Beeswax – – – 240Cocoa powder 100 100 100 100Mannitol 350 350 350 350Croscarmellose 20 20 20 20PVP K30 20 20 20 20Stevia 147 147 147 147Magnesium stearate 3 3 3 3

Table 2The formulation of taste-masked paracetamol chewable tablet using differentportion of cetyl alcohol and the mixture between cetyl alcohol and EudragitEPO as dispersing system.

Composition (mg) Formulation

CA1 CA2 CA3 CA4 CA-EP1 CA-EP2 CA-EP3

Paracetamol 120 120 120 120 120 120 120Eudragit EPO – – – – 35 28 43Cetyl alcohol 240 240 300 360 205 212 197Cocoa powder 100 100 100 100 100 100 100Mannitol 350 350 350 350 350 350 350Croscarmellose 20 20 20 20 20 20 20PVP K30 20 20 20 20 20 20 20Stevia 147 – 147 147 147 147 147Sucrose – 147 – – – – –Magnesium stearate 3 3 3 3 3 3 3

Fig. 1. SEM images of (A) paracetamol, milled dispersion of paracetamol in (B) Eudragit EPO, (C) cetyl alcohol and (D) mixture of Eudragit EPO and cetyl alcohol.

Table 3Physical evaluation of the prepared tablets using different dispersion materials.

EP CA1 SA BW

Hardness (N) 37.33 ± 6.66 42.5 ± 2.12 127 ± 0.50 NAThickness (mm) 6.39 ± 0.06 6.52 ± 0.16 6.28 ± 0.24 NADiameter (mm) 12.97 ± 0.02 13.01 ± 0.01 12.98 ± 0.01 NA

NA=data not available.

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powder was directly compressed into tablet form using a hydraulicpress (Specac Inc., USA) at a fixed compression force of 0.5 tons for 5 swith a 9.5-mm diameter flat-faced punch set.

2.3.1. Preparation of drug dispersion in waxFor wax dispersion preparation, the wax (CA, SA, or BW) was

melted at 70 °C for 10min before being blended with paracetamol untilthe wax dispersion became solid. The dispersion was ground by theoscillating granulator, and then the milled product from the wax dis-persion was mixed with the other excipients (Table 1). Subsequently,the tablets were prepared as described in the previous section.

2.3.2. Preparation of drug dispersion in Eudragit EPO and waxCA was selected to coat paracetamol together with EP to optimize

taste-masking efficiency. The optimized formulation development wasratio varying of CA and EP (Table 2). Paracetamol and EP were dis-solved in ethanol and then dried at 60 °C for 4 h to apply EP and CA inthe formulation. The dispersion of drug in EP was milled by the oscil-lating granulator. The grinded drug dispersion was dispersed in meltedCA until the wax dispersion became solid. The EP–CA dispersion wasground by the oscillating granulator, and then the milled product wasmixed with the other excipients. Lastly, the tablets were prepared asdescribed in the previous section.

Table 4Physical evaluation of the prepared tablets prepared from CA and/or EP.

CA1 CA2 CA3 CA4 CA-EP1 CA-EP2 CA-EP3

Hardness (N) 42.5 ± 2.12 92.00 ± 1.41 130 ± 1.53 134 ± 2.52 143 ± 5.66 118 ± 2.83 132 ± 1.41Thickness (mm) 6.52 ± 0.16 6.41 ± 0.16 6.30 ± 0.15 6.21 ± 0.09 6.33 ± 0.21 6.30 ± 0.01 6.23 ± 0.10Diameter (mm) 13.01 ± 0.01 13.04 ± 0.01 13.01 ± 0.01 13.02 ± 0.01 13.02 ± 0.01 13.02 ± 0.02 13.02 ± 0.00

Fig. 2. Disintegration time of the chewable tablet prepared from different dispersion systems.

Fig. 3. Drug release percent of the paracetamol chewable tablet prepared from different dispersion systems at 45min.

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2.4. Drug dispersion morphology

The morphology of paracetamol powder and the dispersion ofparacetamol in CA and EP were observed using scanning electron mi-croscopy (SEM; model Maxim 2000S, CamScan Analytical, UK) oper-ating at a high vacuum with an accelerating voltage of 15 kV and asample working distance of 10mm to monitor the physical status of thedrug and dispersion efficiency of the system. The samples for SEManalyses were mounted on a double-faced adhesive tape and sputter-coated with a thin (approximately 10 nm) layer of gold in a Balzers SCD050 (Balzers Union, Liechtenstein) coating unit at 20mA using an argongas purge.

2.5. Physical evaluation of tablet

The six prepared tablets were evaluated for the uniformity ofthickness, diameter, and hardness using an apparatus according toUSP22 tests (Erweka TBH 28, Frankfurt, Germany).

2.6. In vitro disintegration test

The in vitro disintegration test of the three prepared tablets fromeach formulation was performed using the disintegration tester(Erweka, ZT4, Heusentsamn, Germany). The process involved placingeach tablet onto the tube of the basket rack assembly of the

Fig. 4. Evaluation result diagram of the control (uncoated paracetamol) tablet and different formulations (EP, CA1, CA-EP1, CA-EP2, and CA-EP3) of the taste-masked paracetamol chewable tablet.

Fig. 5. Overall satisfaction of the control (uncoated paracetamol) tablet and different formulations (EP, CA1, CA-EP1, CA-EP2, and CA-EP3) of the taste-maskedparacetamol chewable tablet.

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disintegration apparatus without a disc. The assembly was positioned inthe beaker containing disintegration media (distilled water) maintainedat 37.0 °C ± 1 °C, and the time needed for the complete disintegrationof each tablet was recorded.

2.7. In vitro dissolution test

The United States Pharmacopeia (USP) dissolution tester type IIapparatus was utilized to examine the dissolution time. The instrumentwas set at a paddle speed of 75 rpm, and the dissolution medium was900mL of a phosphate buffer of pH 6.8 under a controlled temperatureof 37 °C ± 0.5 °C. The dissolution medium was withdrawn from 5mLafter 1, 2, 4, 6, 8, 10, 15, 30, 45, 60, and 120min. The drug dissolvedwas assessed using a UV/Vis-spectrophotometer (U-2900, Hitachi,Japan) at 243 nm [6]. The dissolution test was run in triplicate fromeach formulation.

2.8. Satisfaction evaluation

An in vivo study on the taste-masking and mouthfeel of the selectedformulations of paracetamol chewable tablets was conducted in sixhealthy human volunteers comprising two men and four women in theage range of between 20 and 25 years old. The volunteers were in-formed of the protocol and purpose of the study [7]. This study wasperformed in accordance with the regulations of the Declaration ofHelsinki [8]. The volunteers’ opinion on the product satisfaction wasrated by giving different score values for different topics (appearance,color, taste, flavor, texture, and overall satisfaction) using a nine-levelevaluation ranging from 1 to 9 [9]. For the nine-scale evaluation fromHedonic, the definition of level nine means extremely satisfied. A scoreof five is ordinary and is gradually reduced to 1, which means ex-tremely unsatisfied. The comments from the volunteers were also re-corded to explain the score results. The positive control tablet (un-coated paracetamol) and five more different formulations (EP, CA1,CA–EP1, CA–EP2, and CA–EP3) that passed the preliminary taste testwere selected to be evaluated in this step.

2.9. Statistical analysis

Analysis of variance and Levene's test for the homogeneity of var-iance were performed using SPSS version 17.0 for Windows (SPSS Inc.,USA). The post hoc testing (P < 0.05) of the multiple comparisons wasperformed by either the Scheffé test or the Games–Howell test de-pending on whether Levene's test was insignificant or significant, re-spectively.

3. Results and discussion

3.1. Drug-coating process and product appearance

The drug-coated dispersion in EP or/and wax was successfullyprepared. Paracetamol could be dissolved in wax and also in EP solu-tion. The drug dispersion was easily milled by the oscillating granu-lator. The flake-like particles were received from the drug-EP dispersionwhen the dispersion from wax was granule-like. The ground drug-polymer/wax dispersion was homogeneously mixed with the otherexcipients in the dry and wet states. Finally, the chewable tablet couldbe prepared from all formulations as presented in Tables 1 and 2, exceptthe formulation using BW as the taste-masking agent, because themelting point of BW is approximately 62°C-64 °C, which might bemelted by the heat generated from the milling process [10].

3.2. Drug dispersion morphology

Fig. 1 shows the SEM images of paracetamol and the dispersion ofparacetamol in CA and EP. Paracetamol was in rod and needle shape

crystal form as presented in Fig. 1A [11]. The milled dispersion ofparacetamol in EP was in an irregular shape with rough surface(Fig. 1B). The sieved dispersion of paracetamol in CA was also in anirregular shape, such as small flakes attached together (Fig. 1C).However, small drug particles were still found on the dispersion surfaceof CA or EP, indicating that the API might not be completely covered byEP or CA. On the other hand, paracetamol particles were rarely found inthe milled dispersion of the mixture of EP and CA (Fig. 1D).

3.3. Physical evaluation of tablet

Table 3 presents the physical evaluation data of the chewable tablet,including hardness, diameter, and thickness. The result expresses thatthe hardness of the chewable tablets prepared from the drug-SA dis-persion was dramatically and significantly (P < 0.05) higher thanthose of CA1 and EP, which might be because SA impacts particleformation and surface-enhancing particle adhesion and compaction[12]. The thickness and diameter of the tablet were monitored tocontrol the preparation process. The average ranges of the thicknessand diameter of the tablets were 6.28–6.52mm and 12.97–13.01mm,respectively. The BW dispersion could not be milled because it meltedduring the size reduction. Consequently, the tablets could not be pre-pared from the BW formula [10].

From the preliminary taste-masking test, it was found that CA dis-persion has the potential to mask bitterness of paracetamol. Therefore,the CA formula was further developed by varying the portion of CA andmixing it with EP (Table 2). Table 4 shows the physical evaluationresults of the chewable tablet prepared from the different proportion ofCA and the CA–EP mixture. As noticed from CA1 to CA4, an increase inthe portion of CA significantly (P < 0.05) raised tablet hardness. Thereason is that CA alters particle compressibility and compactibility [13]that increase the flowability and compactibility of the particles. AddingEP in different ratios (CA–EP1, CA–EP2, and CA–EP3) augmented thehardness of the tablets. The thickness and diameter of the tablets werein the range of 6.23–6.52mm and 13.01–13.02mm, respectively.

3.4. In vitro disintegration test

The in vitro disintegration times of all tablets are presented in Fig. 2.The chewable tablet prepared from EP had the longest disintegrationtime (370 ± 21.52 s) compared with the other formulations. Mean-while, those of SA, CA1, CA2, CA3, and CA4 provided short disin-tegration time ranging from 11.50 to 25.00 s. The addition of EP in CA(CA–EP1, CA–EP2, and CA–EP3) significantly (P < 0.05) extended thedisintegration period from 32.13 to 35.40 s because EP is practicallyinsoluble in water and some EP dispersion particles were larger than thesieve size of the disintegration testing basket, resulting in the retentionof EP dispersion particles in the basket [14]. On the other hand, themilled CA, SA, and CA–EP dispersion particles were smaller than thesieve size. Consequently, the disintegration times were shorter thanthose of EP.

3.5. In vitro dissolution test

Fig. 3 illustrates the percentage of drug release at 45min of theprepared chewable tablets. All of the paracetamol chewable tabletformulations passed the USP40 criterion: a drug (C8H9NO2) release ofmore than 75% (Q) of the labeled amount in 45min [15]. However, theEP formulation showed the lowest drug release at 84.04% ± 8.32%.This result is in agreement with the disintegration result that explainsthat EP has low solubility affecting low drug dissolution.

3.6. Taste-masking evaluation

The satisfaction in the different dimensions of the control tablet(uncoated paracetamol) and the different formulations of the taste-

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masked paracetamol chewable tablets are depicted in Fig. 4 in the formof a radar diagram. The tablet appearance and color were not notice-ably different between the control and other coated formulations. Thecontrol tablet had a very low score in terms of taste (2.83), the bitter-ness of which could not be overshadowed even by cocoa powder andstevia. The taste was slightly improved by coating with EP and CA, butthe texture or mouth feeling during chewing did not meet the volun-teers’ satisfaction. The EP formula gave a feeling of undissolvedpolymer flakes, and the CA formula left a greasy feeling in the mouthafter swallowing because EP does not dissolve in water and volunteersaliva resulting in gritty feeling in the mouth. CA left a waxy coating/layer on the tongue and oral cavity while chewing, thus resulting in agreasy feeling. Applying the mixture of CA and EP in the drug-coatingprocess significantly improved the taste and tablet texture. Specifically,bitter-masking ability, CA–EP1, CA–EP2, and CA–EP3 gained high tastescores that were 8.17, 7.5 and 8.83, respectively. Moreover, the overallsatisfaction of the CA–EP1, CA–EP2, and CA–EP3 formulae was over7.50, and the maximum score was 8.67 from those of CA–EP3, wherethe volunteers commented that it was not bitter at all (Fig. 5). The taste-masking success of using two type polymers in the coating processmight be because the drug was covered by two layers that were EP andCA in the inner and outer layers, respectively. This also led to reductionin the gritty and greasy feelings in the mouth caused by EP and CA,respectively, as explained by the previous study [5].

4. Conclusion

The polymer and wax dispersion technique is an efficient way tomask the bitter taste of paracetamol in chewable tablet dosage forms.The disintegration and dissolution of all the chewable tablets fabricatedfrom different dispersion systems passed the USP criteria. The mixturebetween EP and CA could mask the bitter taste of paracetamol betterthan one type of the dispersion materials. This indicates that the dis-persion technique has the potential to be applied as the bitter tastemasking of paracetamol or other drugs in the formulation of chewabletablets.

Declaration of competing interest

The authors report no conflicts of interest. The authors alone areresponsible for the content and writing of this article.

Acknowledgments

The authors acknowledge the Faculty of Pharmaceutical Science,

Burapha University for financial support under grant no. Rx1/2562.The authors also thank T.Man Pharma Co., LTD for chemicals support.Ms. Sunuttha Wingwon is acknowledged for technical work.

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jddst.2019.101361.

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