Taste masking of paracetamol encapsulated in chitosan-coated alginate beads

Journal Pre-proof Taste masking of paracetamol encapsulated in chitosan-coated alginate beads Samah Hamed Almurisi, Abd Almonem Doolaanea, Muhammad Eid Akkawi, Bappaditya Chatterjee, Md Zaidul Islam Sarker PII:

S1773-2247(19)31577-1

DOI:

https://doi.org/10.1016/j.jddst.2020.101520

Reference:

JDDST 101520

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 16 October 2019 Revised Date:

31 December 2019

Accepted Date: 11 January 2020

Please cite this article as: S.H. Almurisi, A.A. Doolaanea, M.E. Akkawi, B. Chatterjee, M.Z. Islam Sarker, Taste masking of paracetamol encapsulated in chitosan-coated alginate beads, Journal of Drug Delivery Science and Technology (2020), doi: https://doi.org/10.1016/j.jddst.2020.101520. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.

CRediT author statement Samah Hamed: Conceptualization, Methodology, Validation, Formal analysis, Writing Original Draft, Writing - Review & Editing. Abd Almonem Doolaanea: Conceptualization, Methodology, Resources, Writing - Review & Editing, Supervision, Funding acquisition. Muhammad Eid: Methodology, Formal analysis, Writing - Review & Editing. Bappaditya Chatterjee: Writing - Review & Editing. Md Zaidul Sarker Writing - Review & Editing.

TASTE MASKING OF PARACETAMOL ENCAPSULATED IN CHITOSAN-COATED ALGINATE BEADS

a

Samah Hamed Almurisi , Abd Almonem Doolaanea 5

d

Bappaditya Chatterjee , Md Zaidul Islam Sarker

a,b,*

,

c

Muhammad Eid Akkawi ,

a

a

Department of Pharmaceutical Technology, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan 25200, Malaysia b

10

IKOP Sdn Bhd, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan 25200, Malaysia c

Department of Pharmacy Practice, Kulliyyah of Pharmacy, International Islamic University Malaysia, Kuantan 25200, Malaysia

d

Department of Pharmaceutics, SPPSPTM, SVKM’s NMIMS (Deemed to be University), 400056, Mumbai, India

15

* Correspondence: [email protected]; Tel.: +60136238628

1

Abstract Taste masking is required for bitter drugs to enhance patient compliance, especially among the 20

paediatric population. Paracetamol, the first line for paediatricians to treat pain and fever, is known for its bitter taste. This study aimed to mask the bitter taste of paracetamol and explore the potential of alginate microencapsulation in palatability improvement. Chitosan-coated paracetamol alginate beads were optimized using electrospray to obtain spherical beads with size below 1.5 mm. The encapsulation efficiency (EE) of the uncoated beads decreased with

25

increased gelation time to reach 5±1.32% at 60 min. Chitosan coating enhanced EE to 50-76% depending on chitosan type and concentration. EE significantly improved to 99.0±1.1% by saturating the gelation bath with paracetamol. In vitro taste masking test and in vivo palatability evaluation using 12 human volunteers demonstrated that dry chitosan-coated paracetamol alginate beads were superior to the wet ones for taste masking, which was similar to the

30

marketed paracetamol suspension and even better in aftertaste evaluation. This indicates that the microencapsulation in alginate with further chitosan coating can compensate for the usage of sweetening and flavouring agents. This helps to formulate paediatric dosage forms with minimal undesired excipients. Keywords: Alginate; Chitosan; Electrospray; Beads; Taste Masking; Paracetamol; Palatability

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2

1. Introduction Taste is a critical factor that determines the successful penetration and commercial of oral formulation to the market. Since several drugs have an unpleasant taste especially liquid dosage 40

forms, medications often contain flavours and sweeteners to mute the bitterness associated with the actives and excipients. Despite these efforts, many medications still possess an unpleasant taste and/or aftertaste. This causes some consumers to avoid and/or dread taking medications due to the unpleasant taste. Paracetamol is the first line choice for paediatricians to treat pain and fever according to national and international guidelines (Conaghan, Arden, Avouac, Migliore, &

45

Rizzoli, 2019) but it has a bitter taste. The obnoxious bitter taste is one of the biggest problems in completing the treatment in paediatric and sensitive patients because most of the population cannot tolerate the bitter taste of drugs and vomit out, which ultimately leads to suboptimal therapeutic value, grimace, and mental stress. One of the most effective methods to mask the unpleasant taste of the drug is by using

50

microencapsulation technique. Microencapsulation is a common method for generating an external coating of one material covering another material, which is utilized for masking the undesirable flavours and aroma, it is a simple and attractive technique for taste masking with relatively less adverse effect to the consumers (Khor, Ng, Kanaujia, Chan, & Dong, 2017). The multi-unit of multiparticulate products such as beads are superior to single-unit solid dosage

55

forms like tablet and capsule in term of patient acceptability. The small size particles are easier to swallow compared to the single-unit formulations and thus, are more acceptable for certain populations (Engelen, Van Der Bilt, Schipper, & Bosman, 2005).

3

The biopolymer alginate was considered an optimal selection for microencapsulation. There is 60

increased interest in utilizing alginate gel in the form of beads because it is safe and capable to encapsulate medicines in very mild conditions without using high temperature. The gelation occurs when an aqueous sodium alginate solution is dropped into calcium chloride. Ion exchange between sodium ions from carboxylic acids on the sodium alginate molecules and calcium ion from the crosslinking solution results in crosslinking and forming a gel so-called as 'egg-box'

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structure. Alginate beads are frequently subjected to additional coating. Chitosan is extensively used as a coating material for alginate beads because it is non-toxic, biocompatible, biodegradable, and widely available at low cost. These properties make chitosan a promising excipient for pharmaceutical industry applications. Assessment of the effectiveness of taste masking is still a major challenge. The in vitro drug

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dissolution method testing is often used for taste assessment of pharmaceutical products at an early stage as an alternative to human test panels and animal models. The in vitro methods to evaluate the drug release in a simulated saliva buffer were used to evaluate taste masking efficiency after taste threshold is determined. If drug release exceeded the thresholds at a specific time, the formulation was considered to be poorly taste-masked, and vice versa (Keeley et al.,

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2019). Human taste panel is still the gold standard in taste masking effectiveness evaluation regardless of being expensive and is subjected to ethical considerations and inter-subject variability (Drašković, Medarević, Aleksić, & Parojčić, 2017). Several approaches have been reported to mask the bitter taste of paracetamol. The ion exchange technique was utilized to mask the taste of paracetamol, it was loaded onto cationic exchange

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resin (Indion-204) and prepared as a chewable tablet suitable for paediatric use (Helmy, El Kady, Khames, & Abd-elbary, 2011). The hot-melt extrusion (HME) was also applied for taste masking 4

purpose where paracetamol granules were prepared using Eudragit EPO® or Kollidon® (Maniruzzaman et al., 2012). Moreover, melt granulation using lipid excipients was employed in the formulation of sachets and chewable tablets (El-Refaie, El-Massik, Abdallah, & Khalafallah, 85

2014). Spray drying was another approach to mask paracetamol taste where paracetamol was encapsulated within the skin former composed of sodium caseinate and lecithin (Thi, Morel, Ayouni, & Flament, 2012). Spray congealing was also used in which paracetamol was encapsulated in lipid microspheres using Eudragit E100 (Guo et al., 2016). These studies tried to mask paracetamol taste in dosage forms suitable for paediatric use, either chewable tablets or

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multiparticulates, even though the suitability for paediatric use was not mentioned in many of them. Therefore, a method and formulation to mask paracetamol taste in a dosage form designed to suit paediatric patients are still needed. This study aimed to mask the unpleasant taste of paracetamol by encapsulating in alginate beads as multiparticulate dosage form suitable for paediatric use. The study attempted to formulate,

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characterise and optimise chitosan-coated paracetamol alginate beads. The taste masking effectiveness of the dry and wet beads was evaluated by both in vitro and in vivo methods.

2. Materials and methods 2.1 Material Guluronic acid-rich sodium alginate (molecular weight = 4.8 ×106 ± 1.8 × 105 Da, nominal of 100

viscosity = 300 mPa.s, M/G ratio = 0.59) was obtained from Manugel® DMB, ISP, USA. Paracetamol micronized powder was obtained from Zhengjian Kangle Pharmaceutical Co., Ltd. (Wenzhou, China), paracetamol particle size is (300-500 mesh, 30 -50 µm) based on material sheet data. Also, the size of paracetamol powder was measured using a laser diffraction particle 5

sizer (BT-9300H, Liaoning, China) and polydispersity of the microparticles was evaluated by 105

calculating the span value. The D50 was 184.9 ± 0.23 µm with monodisperse distribution wherein span value was 0.9.based on lab data. The cross-linkers calcium chloride was obtained from Merck KGAA (Darmstadt, Germany). High molecular weight (MW) chitosan with >75% degree of deacetylated and low MW chitosan with 75-85% degree of deacetylated were obtained from Sigma-Aldrich (St. Louis, Missouri United States). Panadol Children's Suspension and

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chewable tablet were purchased from local pharmacy retail. 2.2. Preparation of paracetamol beads by electrospray Paracetamol powder was added into 2% w/v sodium alginate solution and homogenized with the aid of magnetic stirrer to produce homogeneous suspension with 10% w/v drug loading. The collector solution (the gelling bath) was 1% w/v calcium chloride in distilled water. In order to

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minimize the concentration gradient of paracetamol across the alginate beads during gelation, collector solution was saturated with 1.5% w/v paracetamol. Alginate beads were prepared by electrospray technique as reported by Mawazi, Al-Mahmood, Chatterjee, Hadi, & Doolaanea. (2019). The suspension was extruded from the needle orifice and split into tiny droplets when an electrical voltage was applied between the needle and the collector solution. The beads were

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formed by crosslinking of alginate with calcium ions. The effect of electrical voltage and drying on beads size and shape were investigated. The electrical voltages used were 2, 4 and 6 kilovolts (kV) while other parameters were kept fixed such as flow rate 0.5 mL/min, the collection distance 5 cm, and needle size 18 gauge. After curing the beads in the collector solution for 10 min, the beads were harvested and washed with distilled water. The beads were kept as wet

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beads or dried in the oven at 50˚C for 12 hours. High and low MW chitosan were dissolved in the collector solution to study the effect of coating on the wet and dry beads. A stock solution of 6

1% w/v chitosan in diluted acetic acid and stock solution of 10% w/v calcium chloride was diluted to obtain final coating solutions of 0.1 or 0.3 % w/v of high or low molecular weight chitosan and 1% w/v calcium chloride. 130

2.3 Characterization of the beads 2.3.1 Size and shape Minimum of 10 beads were observed and their diameter was measured using an optical microscope. Sphericity factor was used to describe the alginate bead shape (Eqn. 1) because the 135

extent of deformation could not be differentiated by human vision. A bead is considered spherical if the sphericity factor is less than 0.05. 

 

Sphericity factor (SF) =   



(Eqn. 1)

Dmax is the beads maximum diameter and Dmin is the bead minimum diameter. 2.3.2 Encapsulation efficiency (EE) 140

Paracetamol-loaded beads were added into phosphate buffer pH 6.8 then agitated well to completely dissolve the beads. The solution was filtered and the drug content was quantified spectrophotometrically at 243 nm. The paracetamol content was estimated using a calibration curve prepared with known drug concentrations in the range of 0.5–10 µg/mL with R2 = 0.9998. Encapsulation efficiency was calculated using the following equations:

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Encapsulation efficiency (%) =

    

     

7

× 100

(Eqn. 2)

Full factorial design (32) was used to study the effect of gelation time (10, 35 and 60 min) and pH of the gelation bath (2.0, 5.0 and 8.0) on the encapsulation efficiency. The pH of gelation bath was modified with different buffers: pH 2.0 (HCl buffer), pH 5.0 (acetate buffer) and pH 8.0 (phosphate buffer).

150

2.3.3 Differential Scanning Calorimetric Analysis (DSC) The thermograms of alginate, chitosan, calcium chloride, paracetamol, dry blank beads, and dry chitosan-coated paracetamol alginate beads were analysed by using DSC 214 Polyma instrument from NETZSCH (Selb, Germany). About 3.5 mg of each sample was enclosed in an aluminium crucible and exposed to a certain thermal range (25˚C – 300˚C) under constant nitrogen flow (50

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mL/min) at a heating rate of 10˚C/min.

2.3.4 Attenuated Total Reflection-Fourier Transform Infrared Spectral (ATR-FTIR) ATR-FTIR spectra of alginate, chitosan, paracetamol, dry blank beads and dry chitosan-coated paracetamol alginate beads were examined. The samples were firmly clamped against the ATR diamond crystal and scanned in the range of 4000-400 cm-1 with less than 90 force for 8 scan 160

accumulation at 2 cm-1 resolution using a Perkin Elmer’s ATR-FTIR spectrometer (L1600401 Spectrum Two DTGS, Llantrisant, UK).

2.3.5 HPLC analysis A high-performance liquid chromatography (HPLC) method was used in order to detect 165

paracetamol. HPLC was performed using HPLC system (HPLC Prominence LC20A, Shimadzu Corporation, Japan). The column used was ZORBAX Eclipse Plus C18 4.6 x 250 mm column with a pore size of 5 µm (Agilent Technologies). The flow rate was 1.5 mL/min and the column 8

temperature was set at 25 ± 2˚C. The detection wavelength was 243 nm with a running time of 12 min per sample to determine the retention time and peak area of paracetamol. The percentage 170

drug loading was calculated using a pre-determined calibration curve.

2.3.6 In vitro drug release In vitro drug release studies of the optimised wet and dry chitosan-coated paracetamol alginate beads containing 120 mg of paracetamol were carried out using USP Apparatus 2 (paddle) at 175

37±0.5 ºC in 750 mL of 0.1 M hydrochloric acid buffer (pH 1.2) for 2 h followed by 2 h in 0.2 M phosphate buffer (pH = 6.8). The pH of release medium was modified from 1.2 to 6.8 by adding 250 mL of 0.2 M tribasic sodium phosphate to the dissolution medium then adjusting the pH to 6.8 ± 0.05 with 2 M hydrochloric acid or 2 M sodium hydroxide. At scheduled intervals (15, 20, 30, 45, 60, 120, 135, 150, 165, 180, and 240 min), 3 mL samples were taken

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and replaced with an equal volume of a fresh dissolution medium. The aliquots were diluted and analysed for drug content using a spectrophotometer at 243 nm. Marketed paracetamol suspension and chewable tablet (Panadol®) containing 120 mg of paracetamol were used for release profile comparison.

2.3.7 Analysis of in Vitro Drug Release Kinetics and Mechanism 185

The in vitro drug release data were evaluated kinetically using common mathematical models as shown in Eqn. 3, Eqn. 4, Eqn. 5 and Eqn. 6. •

Zero-order model : Qt = Q0 + K0t

•

First-order model : log Qt = log Q0 + K1t/ 2.303 (Eqn. 4)

•

Higuchi model : Qt = KH √

(Eqn. 3)

(Eqn. 5) 9

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•

Korsmeyer–Peppas model: Mt/M∞ = KK tn

(Eqn. 6)

where Qt is the amount of drug dissolved in time t; Q0 is the initial amount of drug in the solution (most times Q0 = 0); Qi = is the initial amount of drug in the pharmaceutical dosage form; Qr is the amount of drug remaining as a solid state at time t; Mt/M∞ = is the fractional drug release; K0, K1, KH, and KK are the zero-order, first-order, Higuchi’s, and Korsmeyer’s 195

release constants respectively; and (n) is the diffusion exponent suggesting the nature of the release mechanism. When n is ≤ 0.43, it is Fickian release (diffusion-controlled release). The n value between 0.43 and 0.85 is defined as a non-Fickian release (anomalous transport). When n is ≥ 0.85, it is case-II transport (relaxation-controlled release). The capability of these models to predict the drug release is determined by the coefficient of determination (R2), the highest R2

200

indicates the best model. Furthermore, the equation of first-order kinetic model was used to determine T50, % values which are the time required to dissolve 50%, respectively of the drug in the pharmaceutical dosage form. The similarity factor (f2) of the drug dissolved percentage between the test and the reference products was calculated based on Eqn. 7: f2 = 50.log {[1+ (1/n) ∑t=1n (Rt- Tt)2]-0.5 .100} (Eqn. 7)

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where n is the number of dissolution time points, and Rt and Tt are the reference and test dissolution values at time t. f2 value of 50 or greater (50-100) ensures sameness or the equivalent of two curves and, thus, the performance of the two products. The mathematical calculations were produced by the Excel add-in software DDSolver (Zhang et al., 2010).

2.3.8 In vitro taste masking assessment 210

An in vitro taste masking method was used to evaluate the taste masking efficacy of the wet and dry uncoated paracetamol alginate beads prepared at different electrical voltages (2, 4, 6 kV) and 10

the wet and dry chitosan-coated paracetamol alginate beads using various types and concentrations of chitosan. The mini-column method is one of the drug release methods to evaluate the efficacy of taste masking (Gittings, Turnbull, Roberts, & Gershkovich, 2014). The 215

arrangement of the apparatus is shown in Fig. 1. The beads containing 125 mg of paracetamol were packed into the mini-column. The phosphate buffer solution of pH 6.8 was kept at 37 ± 0.1˚C using a water bath (Memmert water bath WNB 14) then flowed continuously through the beads at a flow rate of 1 mL/min for 5 min using a peristaltic pump (Shenchen pump YZ1515x). The eluent was collected at each minute and tested for drug content using spectrophotometer at

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243 nm. 2.3.9 In vivo taste masking assessment In vivo taste masking evaluation was performed on twelve volunteers from whom informed consent was first obtained (approved by IIUM Research Ethics Committee (IREC), ID NO. IREC 2018-214). The included subjects (6 males and 6 females) were healthy, English speaking,

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educated (minimum secondary education), and between the ages of 18-35 years old. The volunteers excluded from the study were smokers, had a disease that might influence the taste sense such as cough and flu or using prescribed medication, pregnant mothers, and had an allergy to any component in the formulations. Taste threshold of paracetamol was first determined. The subjects were asked to taste aqueous solutions of paracetamol starting from a

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very diluted solution escalating to higher concentrations by keeping 10 mL of the solution for 20 seconds in the oral cavity (Dasankoppa, Sholapur, Swamy, & Sajjanar, 2017). The concentrations screened were 0.5, 1.5, 1.75, 1.9, 2, 2.25, 2.5 and 3 mg/mL. After that, the volunteers were asked to give their feedback in a scoring pattern as followed: 0-no bitter taste; 1slightly bitter taste; 2-bitter taste; 3-very bitter taste; 5-intensely bitter taste. The minimum 11

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concentration at which the volunteers just started feeling the bitter taste is known as the threshold concentration (Pimparade et al., 2015). The palatability of the optimised wet and dry chitosancoated paracetamol alginate beads were evaluated and the paracetamol powder and marketed paracetamol suspension (Panadol®) were used as references for comparison. All tested samples or products contained 200 mg of paracetamol. It should be noted that the paracetamol beads

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prepared in this study did not contain any flavour, sweetener or colour. This is because the objective of the current study is to determine how far the encapsulation of paracetamol in chitosan-coated alginate beads can enhance the palatability of paracetamol. Likert scales of 5 points were used to assess all aspects of the palatability as smell, taste, taste masking, texture, aftertaste. Likert scales of 5 points were used to assess the palatability aspects of smell, taste,

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taste masking, texture, and aftertaste with 1 indicating the most negative response, 3 indicating an average or neutral response and 5 is the most positive response. For the smell and aftertaste tests, paracetamol powder was considered the reference. While, Panadol suspension was the reference for taste masking and texture.

2.3.10 Statistical analysis 250

All results were taken in triplicate. Statistical analysis of data was performed using One-way analysis of variance (ANOVA) followed by post hoc Tukey’s test and p-values < 0.05 was considered significant. The non-parametric Kruskal-Wallis test was applied on the palatability taste evaluation data. The statistical significance was calculated by the Kruskal-Wallis test with p-values < 0.05 to be considered as significant. The scores given by all individuals were

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averaged and expressed as median with interquartile range (IQR) for non-normally distributed numeric variables. IBMSPSS® version 22 was used for analyses.

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3. Results and discussion 3.1 Effect of electrical voltages, drying, and chitosan coating on size and shape of the beads The size, shape and surface characteristics were different between the wet and dry uncoated 260

paracetamol alginate beads prepared at 2, 4, & 6 kV (Fig. 2). Wet beads had a white colour attributed to the paracetamol that distributes uniformly in the bead matrix and smooth surface. On the other hand, the morphology of the beads changes from the smooth surface of wet beads to roughly round with many edges when dried. Besides that, the drying process influences both the size and shape of the beads. The size of the beads decreased, and the shape fluctuates between

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spherical at 2 and 4 kV and non-spherical beads at 6 kV. This attributes to the collapse of the gel network and volume shrinkage due to loss of water. The size of beads is important for paediatric dosage forms. The US Food and Drug Administration (2014) states that the target bead size up to 2.5 mm to 2.8 mm is the maximum limit. This range is based on the reviewed studies on human mastication and the drug products

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approved, which contain beads up to 2.4 mm with recognized safety and efficacy. However, the experimental data suggested that the cut-off bead sizes should not exceed 1.5 mm for paediatric patients (Nagavelli et al., 2010). Furthermore, a spherical bead is a desirable characteristic for feed products to improve aesthetic quality. Consequently, the beads that combine between acceptable size (< 1.5 mm) and spherical shape (SF < 0.05) were wet beads prepared at 6 kV and

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dry beads prepared at 4 kV. Wet paracetamol alginate beads prepared at 6 kV and dry paracetamol alginate beads prepared at 4 kV were subjected to chitosan coating at various MW and concentrations as presented in Table 1. Chitosan coating did not produce significant changes in the bead size (p-value > 0.05) either wet or dry and the bead shape was spherical (SF < 0.05) in all cases. Furthermore, the size of wet

13

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and dry uncoated paracetamol alginate beads and chitosan-coated paracetamol alginate beads were similar (p-value > 0.05). 3.2 Effect of pH and gelation time on encapsulation efficiency (EE) The capability of the beads to encapsulate the drug is the decisive factor for the choice of the preparation method and composition. Initially, the effects of two factors, pH of the gelation path

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and gelation time on EE of the uncoated paracetamol alginate beads was investigated as shown in Fig. 3. The pH of the gelation path did not produce any effect on EE. On the other hand, increases the gelation time reduced EE from 33.92 ± 1.12% at 10 min gelation time to as low as 5 ± 1.32% at 30 min. The leakage of drug molecules from the beads through the porous calcium alginate beads attributes to the low EE (Iliescu et al., 2014). Although paracetamol is sparingly

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soluble in water (13 mg/mL at 25 ˚C), the relatively large volume of gelation bath (about 50 mL to encapsulate 1000 mg of paracetamol) can dissolve the significant amount of paracetamol. The dissolved paracetamol is lost from the alginate beads during gelation by simple diffusion due to the existent of the significant concentration gradient between bead interior and exterior media. In resemblance, ampicillin that is slightly soluble in water (20.26 mg/mL at 25 ˚C) exhibited a very

295

low EE of about 15% with a gelation time of one hour (Anal & Stevens, 2005; Liu, Chang, Wu, & Chiang, 2006). In contrast, high EE was observed when the encapsulated material was lipophilic like Nigella sativa oil (100.09% after 20 min of gelation time)(Alkhatib, Mohamed, & Doolaanea, 2018). The low drug solubility in the calcium chloride solution prevents the drug from leaking during bead preparation.

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The EE increase significantly by the addition of 0.1% w/v, 0.3% w/v of high MW chitosan and 0.3% w/v of low MW chitosan on the gelation bath. On the other hand, the addition of 0.1% w/v of low MW chitosan has no effect on the EE enhancement. The electrostatic interactions between 14

positively charged amine groups of chitosan and negatively charged carboxyl groups of alginate produce alginate-chitosan complex. This complex blocks up the large pore of calcium alginate305

beads and forms a polyelectrolyte complex membrane on the surface of beads which ultimately reduced the diffusion of the compound. The crosslink density and consequently the thickness and strength of the chitosan membrane significantly improved at higher concentration. This means that the concentration of chitosan increases the number of chitosan molecules diffuse into the alginate hydrogels (Nikoo, Kadkhodaee, Ghorani, Razzaq, & Tucker, 2018). However, when

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chitosan concentration exceeded 0.3% w/v it led to increased surface tension and viscosity of the gelation bath causing the beads to stick on the surface and to have a tear shape. Another approach reported to enhance the EE is to saturate calcium chloride solution with the drug to minimize the concentration gradient across the alginate beads during gelation (Nikoo et al., 2018). Thus, paracetamol was added to the gelation bath at 15 mg/mL to saturate the

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solution. The saturation solubility of paracetamol was firstly determined by adding an excess amount of paracetamol into 1% w/v of calcium chloride solution and stirred at 25˚C for 24 h then filtration and measuring dissolved paracetamol concentration using UV-Vis spectrophotometer at 234 nm. This approach achieved improved EE to about 99.0 ± 1.1%. Since this method theoretically has a significant amount of the drug to be wasted in the gelation bath, the

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encapsulation was attempted by recycling the gelation bath several times to be industrially more practical. It was found that the same gelation bath can be used at least three times with no significant difference in the EE (99.99 ± 0.01%, 99.99 ± 0.01%, and 96.18 ± 1.09%, respectively).

15

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Table 1. Effect of chitosan coating on the size and encapsulation efficiency (EE) of paracetamol alginate beads prepared at 6 kV in wet beads and at 4 kV in dry beads. Chitosan coating types

Chitosan concentration % (w/v)

Uncoated beads

_

High MW chitosan-coated paracetamol alginate beads High MW chitosan-coated paracetamol alginate beads Low MW chitosan-coated paracetamol alginate beads Low MW chitosan-coated paracetamol alginate beads

0.1 0.3 0.1 0.3

EE (%) Bead size (mm) Wet Dry Beads beads 1.32 ± 1.39 ± 0.03 0.09 1.33 ± 1.39 ± 0.03 0.05 1.35 ± 1.42 ± 0.08 0.04 1.32 ± 1.39 ± 0.02 0.05 1.34 ± 1.39 ± 0.08 0.08

33.92 ± 1.12% 53.25 ± 1.91% 76.6 ± 3.99% 32.9 ± 1.6 56.9 ± 20.7%.

3.3 Differential Scanning Calorimetric (DSC) Analysis 330

Paracetamol thermogram presents a sharp endothermic event at 170.5˚C (Fig. 4) indicating the melting temperature (Tm), which corresponds to the values stated in the literature (169 – 172˚C) (Klimova & Leitner, 2012). The DSC thermogram of sodium alginate exhibited a broad endothermic peak at 82˚C and an exothermic peak at 253.7˚C, attributed to the water evaporation and decomposition of sodium alginate respectively. Besides that, DSC of the chitosan polymer

335

showed an endothermic peak at 86.2˚C that has been attributed to the water evaporation. In the blank beads, the decomposition endothermic peak of sodium alginate at 253.7˚C was shifted to higher value at 276.3˚C due to the formation of an egg-box structure of alginate with calcium ions (Lupo, Maestro, Gutiérrez, & González, 2015). Furthermore, paracetamol peak was presented in chitosan-coated paracetamol alginate beads but slightly shifted to 172˚C

340

corresponding to its melting point. This indicates the absence of any interaction between the drug and the polymers in the formulated beads. 16

3.4 ATR-FTIR In the spectrum of sodium alginate (Fig. 5), the band around 1024 cm-1 (C-O-C stretching) is attributed to its saccharide structure. In addition, the bands at 1596 cm-1 and 1408 cm-1 are 345

assigned to the asymmetric and symmetric stretching peaks of carboxylate salt groups, and the band at 3251cm-1 assigned to O-H stretching (Sartori, Finch, Ralph, & Gilding, 1997). A broad band at 3356 cm-1 observed in chitosan spectra corresponding to the amine and hydroxyl groups. The peak at 2864 cm-1 was caused by C-H stretching, the absorption band of the carbonyl (C=O) stretching of the secondary amide (amide I band) at 1655 cm-1, and the bending vibrations of the

350

N-H (N-acetylated residues, amide II band) at 1587 cm1 (Sankalia, Mashru, Sankalia, & Sutariya, 2007). The peaks at 1422 cm-1 and 1375 cm-1 belong to the N-H stretching of the amide and ether bonds and N-H stretching (amide III band), respectively. The peaks observed at 1067 cm-1 and 1026 cm-1 were the secondary hydroxyl group (characteristic peak of -CH-OH in cyclic alcohols, C-O stretch) and the primary hydroxyl group (characteristic peak of -CH2-OH in

355

primary alcohols, C-O stretch) (Chen et al., 2004). In addition, the absorption band at 1587 cm-1 of chitosan shifted to 1595 cm-1 after interaction with alginate in the blank beads, and the stretching vibration of -OH and -NH2 at 3356 cm-1 shifted to 3330 cm-1 and becomes broad. The ATR-FTIR spectrum of paracetamol exhibited vibrational peak for O-H and CH3 stretching at 3321 cm-1 and 3160 cm-1, respectively. Vibrational peaks at 1649 cm-1 and 1608 cm-1 were

360

assigned to C=O and C=C stretching, respectively. The N-H amide II bending appeared at 1560 cm-1. Asymmetrical bending in C-H bond appeared at 1504 cm-1, and C-C stretching peak appeared at 1435 cm-1. The absorption peaks at 1369-1326 cm-1 and 1258-1224 cm-1 were assigned to the symmetrical bending in C-H and C-N (aryl) stretching. Furthermore, a paradisubstituted aromatic ring and out of plane ring deformation of phenyl ring appeared at about

17

365

807 cm-1 and 502 cm-1, respectively. In chitosan-coated paracetamol alginate bead spectrum, the asymmetrical stretching of COO- groups of sodium alginate shifted from 1596 cm-1 to 1607 cm-1 and the symmetrical stretching of COO- groups shifted from 1408 cm-1 to 1420 cm-1. The stretching vibration of -OH and -NH2 of chitosan shifted from 3356 cm-1 to 3319 cm-1 and becomes broad as a result of the interaction between alginate and chitosan. On the other hand,

370

paracetamol peaks were observed at similar wavenumbers such as 807 cm-1 and 502 cm-1 after encapsulation. These results indicate an electrostatic interaction between carboxylic groups of alginate and amine groups of chitosan to form the polyelectrolyte complex. They also indicate that paracetamol molecules were physically located in the polymeric network with no interactions with the polymers.

375

3.5 HPLC analysis The chitosan-coated paracetamol alginate beads show a peak at 3.37 which is the same retention time of the pure drug material, confirming that paracetamol was not degraded during the electrospray process. The peak purity index of paracetamol peak was 1, which is higher than the single point threshold of 0.999 that indicating no impurities in paracetamol peak. Similar results

380

observed in the study conducted by Illangakoon et al. (2014) that prepared paracetamol fibers using electrospinning method by applied 15 kV that means the applied of electrical voltage did not affect the stability of paracetamol. Moreover, the percentage of drug loading in the beads was determined by HPLC following the construction of a calibration curve, the drug loading was 103.27 ± 0.081 that considered very high drug loading.

385

3.6 In vitro drug release of paracetamol Paracetamol release from optimised wet or dry chitosan-coated paracetamol alginate beads was completed in the gastric simulated buffer of pH 1.2 (Fig. 6). According to previous studies, chitosan-coated alginate beads could enhance the prolonged release of a drug because of the pH18

dependent drug release whereby the percentage of drug released in the acidic medium is quite 390

low and most of the drug release occurred at alkaline conditions as previously reported for celecoxib (Segale, Giovannelli, Mannina, & Pattarino, 2016), and Nimodipine (Rajendran & Basu, 2009). These are poorly soluble drugs and belong to Class II (low solubility–high permeability) in the Biopharmaceutical Classification System (BCS). On the other hand, the initial burst release in gastric condition was also observed in some drugs such as diltiazem (El-

395

Kamel, Al-Gohary, & Hosny, 2003), and ranitidine (Jaiswal et al., 2009) that belonging to Class I (high solubility–high permeability) and Class III (high solubility–low permeability), respectively. It appears that the solubility of the drug in the dissolution medium is an important factor. Paracetamol belongs to Class I that exhibits high solubility and high permeability (Charalabidis, Sfouni, Bergström, & Macheras, 2019). Therefore, paracetamol escape from the

400

polymeric matrices through the pores of beads and little or no controlled release occurred. Besides that, the micronized nature of paracetamol powder used in this study contributed to the facilitated solubility and diffusion through the pores. In vitro release profiles of wet and dry chitosan-coated paracetamol alginate beads were compared with commercial paracetamol suspension and chewable tablet (Panadol®). In the first

405

30 min, the release of paracetamol from wet beads and paracetamol suspension was faster and statistically different (p-value < 0.05) compared to the dry beads and chewable tablet. In order to further assess the mechanism of the drug release, the cumulative release profiles were fitted into zero-order, first-order, Higuchi, and Korsmeyer–Peppas models. The results of the regression analysis data and the values of exponent (n) are shown in Table 3. The most proper model fitted

410

to the data was the first-order model based on the highest R2. Furthermore, the values of diffusion exponent in Korsmeyer–Peppas model in all formulations were less than 0.45,

19

indicating that the drug release from the beads followed Fickian release (diffusion-controlled release). The T50% (demanded time for releasing 50% of the drug) is dissolution parameter that can be utilized to analyse the dissolution profile of different paracetamol formulations. 415

Paracetamol suspension showed the fastest drug release (T50% = 10.15 min) followed by wet chitosan-coated paracetamol alginate beads (T50% = 12.32 min); dry chitosan-coated paracetamol alginate beads (T50% = 19.65 min), and paracetamol chewable tablet (T50% = 21.14 min), respectively. Furthermore, the wet and dry chitosan-coated paracetamol alginate beads were different in term of drug release profile based on the similarity factor f2 where f2 was

420

43.08. Wet chitosan-coated paracetamol alginate beads were similar to paracetamol suspension (f2 = 55.88) while dry chitosan-coated paracetamol alginate beads were similar to paracetamol chewable tablets (f2 =64.51).

425

Table 2. Mathematical models of different formulations, F1: Wet chitosan-coated paracetamol alginate beads, F2: Dry chitosan-coated paracetamol alginate beads, F3: Paracetamol suspension, and F4: Paracetamol chewable tablets. Formulations

Zero-order

First-order

Higuchi model

F1

R2 = - 1.11 k0= 0.62

R2 = 0.98 k1= 0.056

R2 = 0.37 kH= 8.48

F2

R2 = - 0.15 k0 = 0.62

R2 = 0.99 k1 = 0.035

R2 = 0.73 kH = 8.27

R2 = 0.92 kKP = 25.74 n = 0.27

F3

R2 = - 0.46 k0 = 0.63

R2 = 0.99 k1 = 0.068

R2 = 0.16 kH = 8.73

R2 = 0.95 kKP = 42.47 n = 0.19

F4

R2 = 0.002 k0= 0.62

R2 = 0.97 k1= 0.033

R2 = 0.76 kH = 8.25

R2 = 0.88 kKP = 22.37 n = 0.29

20

Korsmeyer– Peppas model R2 = 0.98 kKp= 45.68 n = 0.15

3.7 In vitro taste mask evaluation For successful taste masking, the drug should not dissolve in the mouth or the drug dissolved is less than the threshold to be recognized by taste buds. The higher amount of drug released or 430

faster release rate causes a more bitter drug. Threshold evaluation for paracetamol indicated that 2 mg/mL is the threshold concentration, which is close to the reported value in the literature (Suzuki, Onishi, Takahashi, Iwata, & Machida, 2003). The release of paracetamol in the wet and dry uncoated paracetamol alginate beads was lower than the paracetamol bitterness threshold (Fig. 7 a & b). These outcomes indicate the effectiveness of alginate encapsulation for taste

435

masking. However, taste masking efficacy varies based on the size of the beads whereby the reduction of beads size by applying higher electrical voltages resulted in reducing the taste masking efficacy. It is well known that a decrease in particle size corresponds to the increase in the surface area of the particles and hence the dissolution rate. Additionally, it was noted that bead drying reduced paracetamol release and provided taste masking efficacy significantly

440

higher than the wet beads (p-value < 0.05). Dehydration of the beads caused them to shrink, reducing the pore size and resulting in a more compact structure (DeGroot & Neufeld, 2001). As mention before, the size of the beads should not exceed 1.5 mm in paediatrics formulations. To provide a balance between the appropriate bead size for paediatric formulations and taste masking efficacy, the wet beads prepared at 6 kV and dry beads prepared at 4 kV were further

445

coated with chitosan to improve the taste masking efficacy. The wet chitosan-coated paracetamol alginate beads significantly reduced paracetamol release (p-value < 0.05) compared to the wet uncoated beads and enhanced the taste masking efficiency except in 0.1% w/v high MW chitosan that was similar to the uncoated beads (p-value > 0.05). On the other hand, the dry uncoated paracetamol alginate beads were similar to the dry chitosan21

450

coated paracetamol alginate beads except in the case of 0.3% w/v low MW chitosan, which provided the highest taste masking efficacy (Fig. 7 c & d). Chitosan coating reduced paracetamol release and improved drug retention inside the beads. This is attributed to the electrostatic interaction between alginate carboxylate groups and amine chitosan groups, which results in a coating membrane around the beads. Low MW chitosan was superior to high MW of chitosan

455

because it provides a denser membrane structure and it appears to interact with sodium alginate more than chitosan of higher molecular weights (Krasaekoopt, Bhandari, & Deeth, 2004; Yan, Khor, & Lim, 2001). Despite that the higher concentrations of chitosan provide a more taste masking efficacy but increasing the concentration to more than 0.3% w/v led to deformation of bead shape. Overall, the dry chitosan-coated paracetamol alginate beads coated with 0.3 %w/v

460

low MW chitosan provided the greatest taste masking efficacy. Besides that, the dry form of the beads is preferred over the wet form due to the easier handling and storage and more precision in weighing. 3.8 In vivo taste masking assessment The perception of bitterness was assessed in each volunteer using different concentrations of

465

paracetamol. The threshold of drug bitterness was selected based on the minimum drug concentration that initiates the bitter taste. 10 out of 12 of the volunteers found that the concentration from 0.5 to 1.9 mg/ml to be tasteless (Score 0) and 2 mg/ml was the minimum paracetamol concentration at which most of the volunteers just started feeling the bitter taste (Score 1- slightly bitter). Therefore, the threshold concentration of paracetamol was considered

470

to be at 2 mg/ml, which is in agreement with the result from Suzuki, Onishi, Takahashi, Iwata, & Machida (2003) study. The results of the palatability test of smell, taste masking, texture, and aftertaste with a human taste panel are presented in Fig. 8. The formulations were ranked on a

22

scale of 1-5, a higher score stood for better palatability. Paracetamol suspension was assigned the highest score of smell that is attributed to the orange flavouring agent while paracetamol powder, 475

dry and wet chitosan-coated paracetamol alginate beads were neutral. A neutral smell is rational because the formulations in this study were prepared without any flavouring agent. The taste masking score of wet chitosan-coated paracetamol alginate beads indicates that the wet beads slightly covered the paracetamol taste compared with the paracetamol suspension (p-value = 0.023). On the other hand, no significant difference was found between the taste masking score

480

of the dry chitosan-coated paracetamol alginate beads and the Panadol suspension (p-value = 1). This indicates an acceptable taste of the dry alginates that almost covers that paracetamol taste to a comparable extent of the marketed paracetamol suspension. The high sugar content in paediatric liquid medications is commonly used to mask the unpleasant taste of some active constituents and to provide more palatable forms. The sugar solution is used as a vehicle for

485

medicines and it is included in nearly all liquid paediatric formulations and this increases the risk for dental caries and gingivitis in children (Naik, Babu, & Doddamani, 2017). To reduce the amount of sugar in oral paediatric medications and to provide a complete taste masking, microencapsulation technique an alternative technique can be used to lower the diffusion of bitter substance from the saliva to the taste buds. By comparing the wet and dry chitosan-coated

490

paracetamol alginate beads, dry beads offer more taste masking efficiency based on both in vitro and in vivo taste evaluation test. The volunteers reported different texture for the products; the paracetamol suspension was pleasant and not gritty. On the other hand, the feeling of grittiness (i.e. rough mouthfeel) observes in both dry and wet chitosan-coated paracetamol alginate beads. This is common in multiparticulate delivery systems due to the presence of particles in the mouth

495

thus, limiting the palatability. Hence, it is recommended to be reconstituted in a suitable vehicle

23

for ease of administration (Lopez et al., 2016). The strongest bitter aftertaste score of paracetamol formulations was observed in the marketed paracetamol suspension which is similar to paracetamol powder (p-value = 1). The wet chitosan-coated paracetamol alginate beads and the dry chitosan-coated paracetamol alginate beads showed significant improvement in the 500

aftertaste score compared to paracetamol powder; (p-value = 0.24) and (p-value = 0.001), respectively. 4. Conclusion In the present study, paracetamol was encapsulated in sodium alginate beads using electrospray method with the additional coating with chitosan to improve the taste masking efficiency. Both

505

wet and dry beads were fabricated. The optimized chitosan-coated paracetamol alginate beads were of a size suitable for paediatric use (below 1.5 mm) with almost complete encapsulation efficiency. In vitro taste masking showed that chitosan helped to reduce paracetamol release from wet and dry chitosan-coated paracetamol alginate beads below the threshold concentration (2 mg/mL). The palatability test using human volunteers revealed that the wet beads slightly

510

masked the bitter taste of paracetamol while the dry beads performed almost similar to the marketed paracetamol suspension and even overcome the bitter aftertaste better than paracetamol suspension, which suffers from an unpleasant bitter aftertaste. This paediatric-suitable multiparticulate dosage form has the potential to mask paracetamol taste and reduce the aftertaste feeling without adding any flavouring or sweetening agents usually present in suspension dosage

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forms. Conflicts of Interest The authors report no conflict of interest. 24

Acknowledgements This work was funded by IIUM Research Initiative Grant Scheme (Grant Number. P-RIGS18 520

026-0026). The authors would like to thank Assoc. Prof. Dr. Farahidah Muhammad and the department of pharmaceutical technology at IIUM for technical and facilitation support. References Alkhatib, H., Mohamed, F., & Doolaanea. (2018). ATR-FTIR and spectroscopic methods for analysis of black seed oil from alginate beads. Int J App Pharm, 10(5), 147–152.

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Graphical abstract: Chitosan-coated paracetamol alginate beads induce taste masking of the paracetamol. The masking effect is assessed both in vitro and in vivo. Fig.1. Schematic diagram of the in vitro taste masking evaluation method. Fig.2. Size of paracetamol alginate beads prepared at different electrical voltages; a, b and C: wet beads; d, e and f: dry beads. Fig.3. Effect of (a) pH of gelation path, and (b) gelation time on encapsulation efficiency (EE%). Fig.4. DSC thermograms of alginate, chitosan, blank beads, and chitosan-coated paracetamol alginate beads. Fig.5. ATR-FTIR spectra of (a) sodium alginate, (b) chitosan, (c) blank beads, (d) paracetamol, and (f) chitosan-coated paracetamol alginate beads. Fig.6. In vitro release in HCl buffer pH 1.2 (2 h) and phosphate buffer pH 6.8 (2h) of F1: wet chitosan-coated paracetamol alginate beads, F2: dry chitosan-coated paracetamol alginate beads, F3: paracetamol suspension, and F4: paracetamol chewable tablets. Fig.7. In vitro taste masking using paracetamol release in simulated saliva buffer from (a) uncoated wet paracetamol alginate beads and (b) uncoated dry paracetamol alginate beads prepared at different electrical voltages; (c) wet chitosan-coated paracetamol alginate beads and (d) dry chitosan-coated paracetamol alginate beads prepared with different types and concentrations od chitosan. Fig.8. Palatability score of human taste panel (n =12, Median ± IQR); (a) smell, (b) taste masking, (c) texture, and (d) aftertaste). Similar letters denotes no significant difference (p-value < 0.05).

TASTE MASKING OF PARACETAMOL ENCAPSULATED IN CHITOSAN-COATED ALGINATE BEADS

Highlights •

Chitosan-coated paracetamol alginate beads were prepared by electrospray.

•

Encapsulation efficiency improved by saturating gelation bath with paracetamol.

•

Paracetamol release did not reach threshold concentration in vitro.

•

Paracetamol encapsulation masked the bitter taste in vivo.

•

Beads’ palatability with no sweetener was comparable to the commercial suspension.

Declaration of interests ☒ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: