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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 13  |  Issue : 3  |  Page : 312-316  

Soft-chewable paracetamol tablets by melt granulation method: Formulation and characterization


1 Department of Pharmaceutical Chemistry, Kulliyyah of Pharmacy, International Islamic University Malaysia, Jalan Gombak, Selangor, Malaysia
2 School of Physics and Materials Studies, Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam, Selangor, Malaysia
3 Centre for Drug Research, Universiti Sains Malaysia, Gelugor, Penang, Malaysia

Date of Submission28-Nov-2020
Date of Decision20-Jul-2021
Date of Acceptance16-Sep-2016
Date of Web Publication24-Nov-2021

Correspondence Address:
Dr. Awis Sukarni Mohmad Sabere
Kulliyyah of Pharmacy, International Islamic University, Pahang
Malaysia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpbs.JPBS_783_20

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   Abstract 


Background: Oral drug delivery is the most preferred route for drug administration in the world, with tablets being one of the most common dosage forms. However, some people, particularly children and the elderly, have difficulty swallowing the tablets. Chewable tablets are the dosage form that can address the issue while also providing a valuable masking effect on drug taste, allowing patients to swallow the drugs more easily. Materials and Methods: In this study, the chewable tablets were manufactured using the melt granulation method, which resulted in tablets with a chewy texture. The tablets contained paracetamol as well as Arabic gum, starch, agar, and mannitol. Results: The drug release profiles for the fragmented form showed that 50% of the drug was released within 4 min and 100% was released within 30 min of the dissolution process. The intact form released nearly 90% of the drug within 2 h. Conclusion: Formulation 2 was determined as the best formulation. This tablets' formulation had passed all characterization tests and displayed a moderate hardness and chewy texture.

Keywords: Chewable tablets, melt granulation, paracetamol


How to cite this article:
Sabere AS, Suhaimi NA, Ahmed QU, Mahat MM, Roslan NC, Azizi J. Soft-chewable paracetamol tablets by melt granulation method: Formulation and characterization. J Pharm Bioall Sci 2021;13:312-6

How to cite this URL:
Sabere AS, Suhaimi NA, Ahmed QU, Mahat MM, Roslan NC, Azizi J. Soft-chewable paracetamol tablets by melt granulation method: Formulation and characterization. J Pharm Bioall Sci [serial online] 2021 [cited 2021 Dec 8];13:312-6. Available from: https://www.jpbsonline.org/text.asp?2021/13/3/312/331071




   Introduction Top


Oral drug delivery represents the most preferable route of drug administration to elicit the therapeutic effects at the systemic level.[1] However, there are several barriers for young and older patients to take their oral medicines, such as swallowing difficulties or dysphagia, the involvement of caregivers, child reluctance, and polypharmacy in older generation.[2],[3] The prevalence of difficulties in swallowing the oral solid dosage form, especially among pediatrics[4] and geriatrics[5],[6] becomes a major concern as it can reduce patient compliance on the drug intakes. Freed et al.[7] mentioned that it is difficult or impossible for children and infants to swallow the solid dosage forms of most marketed compounds.

The acceptability of solid dosage forms not only occurred in pediatrics and geriatrics only, but it also becomes a problem among adolescents. Hansen et al.[8] revealed that adolescents have difficulties in administering oral medications, especially when swallowing tablets. Their study reported that adolescents are struggling to take their medications due to several factors including the taste and size of tablets, dislike feeling, and bodily discomfort such as the tablet was caught in their throat, nausea, and vomiting.

Due to these difficulties, some patients had already modified their medications to facilitate swallowing such as splitting or crushing of tablets and opening the capsules to produce smaller pieces of dosage form, then mixing them with food or dissolving in water.[3] However, the crushing of tablet can cause detrimental effects to health due to release profile and bioavailability alteration of medicines.[9]

This problem had triggered the pharmaceutical companies to develop oral dosage forms that can solve the difficulties in swallowing oral medications so that patients are compliance with their medications, thus the health benefits can be achieved. One of the approaches in the development of dosage forms that can improve patient acceptability and treatment outcomes is by formulating chewable tablets.[10],[11] Suzuki et al.[12] suggested that chewable tablets are the dosage form that can be produced easily and have a valuable masking effect on drug taste so that patients are more convenient to swallow the drugs.

This study formulates chewable tablets by incorporating the melt granulation method. Paracetamol used in the study act as a model drug and was chosen because of its high degradation temperature. The physical properties and in vitro release profile of the formulated tablets were determined and the best formulation that complies with pharmaceutical products is revealed.


   Materials and Methods Top


Materials

Paracetamol, mannitol, and starch were purchased from R and M Chemicals (United Kingdom), Arabic gum was purchased from Sigma-Aldrich (Germany), and agar was purchased from LCH Sdn Bhd (Malaysia).

Method

Chewable tablets formulation

Chewable tablet formulation was prepared using the melt granulation method and involved several parts. For the first part, agar was combined with water in a ziplock bag and sealed. The bag was placed in the heated water at 60°C and left for 30 min to bloom. For the second part, Arabic gum was mixed with water in a small bowl and set aside. The mixture was continuously stirred until it is smooth and fully hydrated.

Then, mannitol was mixed with water and brings to boil. Arabic gum from the second part was added and followed by agar (first part) into mannitol while stirring the mixture. After all, the excipients were mixed together, followed by the addition of a 100 mg of paracetamol and stirred homogeneously. Finally, the mixture was poured into the nonstick mold and allowed to cool completely.

Physical characterization

Weight uniformity

Twenty units of tablets were taken randomly, weighed individually, and the average mass was determined. It was then ensured that not more than two of the individual masses deviate from the average mass by more than the percentage deviation and none deviates by more than twice of that percentage.[13]

Tablet dimensions and tensile strength

The thickness and diameter of the tablets were measured using a digital Vernier caliper.[14] These values then were used to determine the tensile strength of the tablets.

Tensile strength test is intended to determine the crushing resistance of tablets that was measured by the force applied to disrupt them by crushing. The tablets were placed between the jaws and 10 tablets were measured by taking care that all fragments of tablets, which have been removed prior to the test.[13] To calculate the tensile strength, which is a fundamental measurement of the mechanical strength of tablet, the tablet hardness is normalized for the shape and size.[15],[16] The tensile strength, σd, was calculated using the following equation:



where Fd is the tablet hardness, D is the tablet diameter, and t is the tablet thickness.[12]

Friability test

A friability test was conducted to ensure the ability of tablets to withstand the shocks during processing, handling, transportation, and shipment.[14] Tablets were carefully dedusted before testing. Ten tablets were accurately weighed and placed in the Sotax Friabilator (USP) drum. The drum was rotated 100 times at 25 rpm and then, the tablets were removed. Any loose dust from the tablets was removed and accurately weighed. The percentage of weight loss was then calculated.[13]

Content uniformity

The individual contents of active substances were determined based on British Pharmacopoeia.[13] Ten tablets were taken randomly and crushed. Hundred milligram equivalent of paracetamol was taken from the powder and dissolved into 50 mL of 0.1 M HCl. The sample was taken from the flask and filtered through a 0.45 μm syringe filter. 0.5 mL of filtrate was taken and diluted to 100 mL of 0.1 M HCl and the absorbance was measured at 245 nm spectrophotometrically.

Disintegration test

Six tablets were tested using a disintegration tester (Sotax DT2) using 0.1 M HCl as a medium at a temperature of 37°C. Time taken for the tablets to be disintegrated was recorded.

In vitro release profile

The dissolution study was carried out using a dissolution bath following the method by Dille et al.[17] A 900 mL of 0.1 M HCl was used and the paddle was rotated at 100 rpm. Three tablets from each intact form and fragmented form were tested. Ten milliliter of sample was withdrawn and filtered for every 2 min, then every 15 min, and hourly until 6 h. The absorbance of the samples was measured at 245 nm spectrophotometrically.


   Results and Discussion Top


Chewable tablets formulation

A range of chewable tablets was prepared using formulae stated in [Table 1].
Table 1: The chewable tablets formulations

Click here to view


Based on the initial observation, the tablets of Formulation 1 showed chewable tablets characteristics, such as moderate hardness and chewy texture. However, the tablets were slightly crumbly when the pressure was applied on it. The amount of agar and starch was found to increase in Formulation 2, producing a more robust solid dosage, along with moderate hardness and chewy texture. The developed formulation was very soft molten before casted onto the mold. However, this paste has transformed into a solid dosage form with sufficient hardness upon cooling. For the Formulation 3, the paste was difficult to fill into the mold and the produced tablets were even harder than Formulation 2.

Physical characterization

Weight uniformity test

According to the British Pharmacopeia,[13] the tablets with a weight of more than 250 mg should possess not more than 2 of the individual masses to deviate from the average mass by more than 5% deviation. We found that six of the tablets were out of range for Formulation 1. Meanwhile, all of the tablets from Formulation 2 were found to be within the range and only one tablet from Formulation 3 was out of range. This means that Formulation 1 did not comply with the British Pharmacopoeia's specification.

Tablets dimensions, and tensile strength

There are no pharmacopoeial specifications for the thickness of tablets, either the actual value or its uniformity. However, it is a vital attribute to control as it can potentially affect the accuracy of packing of tablets into blisters or tubes. It is also indirectly related to the hardness and tensile strength of a tablet.[18]

In common with tablet thickness, there are no specific pharmacopoeial specifications for the values of the tensile strength of tablets. The measured value is dependent on the size and shape of the tablet as well as the formulation and the compression parameters used. However, it is important to ensure that a correct value of the tensile strength be obtained; if the value is too low, the tablet will be very delicate and unable to withstand further processing or transport; too high may be adversely affected high the dissolution profile. [Figure 1] summarizes the dimensions and tensile strength of the chewable tablets.
Figure 1: Diameter (a), Thickness (b), Hardness (c), and Tensile Strength (d) of the chewable tablets

Click here to view


Based on the results, both Formulation 1 and Formulation 3 showed almost similar tensile strength, at 0.046 MPa and 0.043 MPa, respectively. Formulation 2 on the other hand showed a lower tensile strength value, at approximately 2/3 of the tensile strength of the others. These results suggested that Formulation 2 is the softest texture among all the formulations. According to the study done by Mahat et al.[19] on the sensory evaluation and mechanical properties of functional gummy in the Malaysian market, the most preferable gummy texture was the softest chewable gummy, as chosen by one-third of the respondents.

Friability test

The maximum loss of mass after the test should not exceed 1.0% of the initial mass to comply with the friability test.[13] It was found that the percentage of weight loss for Formulation 1, 2, and 3 were 55.29%, 0.95%, and 1.18%, respectively. As mentioned in the initial observation of the chewable tablets formulation in Section 3.1, the tablets were slightly crumbly. During the tumbling process, tablets of Formulation 1 were fractured and crumbled. This is probably due to the less amount of starch present within the tablets, in which a sufficient amount is required to act as a binding agent compared to the other formulations. Since Formulation 1 has already failed 2 tests, further tests are dropped. Tablets of Formulation 3 were found to have exceeded the specification, too. However, since the value was not too far off from the specification, it was considered for the next tests.

Content of uniformity

According to British Pharmacopoeia,[13] the results are considered to comply with the uniformity content requirement if all of the individual contents are within 85%–115% (15% deviation). The percentage of content deviations for Formulation 2 were between 1.08% and 8.45%, while for the Formulation 3, the deviations were between 2.72% and 8.66%. Thus, both the formulations have complied with the specification.

Disintegration test

The average of disintegration time for Formulation 2 was 1 h 28 min. The disintegration time was found to be longer compared to the normal tablets. This is due to the disintegration process that was assumed, happening in the mouth through the chewing mechanism. Hence, this disintegration time had only represented the condition where the tablets are swallowed without been chewed.

However, the tablets of Formulation 3 were found to not completely break into small pieces and pass through the mesh after more than 5 h. This means, in the event where the tablet is accidentally swallowed, it will not completely disintegrate, which can affect the drug dissolution in the gastrointestine. The tablet is likely to be removed from the body before it can be absorbed. Therefore, Formulation 3 was dropped to undergo the in vitro dissolution test.

In vitro release profile

There are two types of release profiles were observed in this study: intact form and fragmented form. Intact form represents the dissolution profile of the tablets as a whole, while the fragmented form represents the dissolution profile of the tablets after been chewed. These two profiles are important because there is a possibility of the patient to accidentally swallow the tablets without chewing it first. [Figure 2] illustrates the drug release profiles of both forms.
Figure 2: Drug release profiles of intact form and fragmented form

Click here to view


The result for intact form tablets showed that more than 50% of the drugs were released within 1 h and have reached almost 90% within 2 h. This means that in the event where the patient accidentally swallows the tablet, it will release the drug slowly within 2 h period, providing an extended-release mechanism.

Meanwhile, the fragmented form already released more than 50% of the drugs within 4 min of the dissolution process and was completely released within 30 min. According to British Pharmacopoeia,[13] for immediate-release tablets specification, 75% of the drugs need to be dissolved within 45 min. This suggests that chewable tablets are classified as immediate-release tablets. Chewable tablets needed the chewing mechanism so that the drugs were absorbed rapidly into the body system.


   Conclusion Top


The gummy-chewable tablets of various formulations were presented in this study. They were manufactured using the melt granulation method by incorporating paracetamol as a model drug. Based on the evaluation of the physical properties of chewable tablets, Formulation 2 was determined to be the best formulation because the produced tablets possessed a moderate hardness and chewy texture. Furthermore, this tablet's formulation had passed all characterization tests for pharmaceutical products, based on British Pharmacopoeia. The tablets had an immediate-release profile in the fragmented form, with 100% of the drug released within 30 min of the dissolution process. Meanwhile, in the intact form, it displayed an extended-release profile. These findings pave the way for the pharmaceutical industry to use the melt granulation method to produce chewable tablets.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Mahat MM, Sabere AS, Shafiee S, Nawawi MA, Hamzah HH, Jamil MA, et al. The sensory evaluation and mechanical properties of functional gummy in the Malaysian market. Preprints 2020:11. 2020100213. [doi: 10.20944/preprints202010.0213.v1].  Back to cited text no. 19
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1]



 

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