JOURNAL

HUMANTECH
MULTI DISCIPLINE SCIENTIFIC JOURNAL
VOL 2 NO 3 MARCH 2022 E-ISSN :
2809-1612, P-ISSN : 2809-1620

Comparable dissolution test of paracetamol tablets

Denis Thessalonians Ernest Adam1, I Gusti Ngurah Agung Dewantara Putra2

1,2Udayana University

Email correspondence: agungdp09@[Link]

Article Info:
Received : March 7, 2022 Approved : March 11, 2022 Published : March 15, 2022

ABSTRACT

The dissolution test was carried out to determine the effect of

the formulation and fabrication processes on the dissolution
profile in estimating the bioavailability and bioequivalence
between the test product and the reference. The dissolution
test was compared using 3 different dissolution media,
namely hydrochloric acid medium pH 1.2 or simulated gastric
fluid without enzymes, citrate buffer medium pH 4.5 and
phosphate buffer medium pH 6.8 or simulated intestinal fluid
without
Keywords enzymes. The first study used Panadol tablets which were
:
Dissolution test
randomly selected as many as 12 tablets. The results were
in then compared using two independent model methods,
comparison,
tablet namely the difference factor (f1) and the similarity factor (f2).
paracetamo Based on these,similarity factoron all three media is in the
l
acceptable range of 50-100.
Another study conducted testing using Paracetamol samples
purchased from Rochem, Turkey. The results obtained are in
accordance with USP guidelines i.e. conventional Paracetamol
tablets must be dispensed at least 80% of the labeled amount
in 30 minutes. In another study also compared the dissolution
profiles of 4 coated and uncoated tablets. All formulations
within the first 45 minutes have drug release of more than
85%.

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PRELIMINARY
Drug products circulating in Indonesia consist of patent drug products,
products with trademarks and generic products with logos. Generic drugs are an
alternative choice for the public because they are cheaper than drugs with trade
names. This happened because of the emphasis on production and promotion
costs. Price competition followed by strict control will lead to the availability of
high quality generic drug products at affordable prices (Ministry of Health RI,
1989).
Provision of information to the public is intended to make generic drug
substitution occur, where the choice of drug is not fully determined by the doctor,
but the public also has authority over the drug they buy. Affordable prices must
also be followed by the quality of these drugs. Information about the quality of a
drug product is needed to give the public confidence in the drug product.
Therefore, information is needed regarding the quality of drug products.
Information that can support the quality of a drug so that it can be substituted for
generic drugs is the bioequivalence test (Shargel, 1999).
The dissolution test was carried out as a preliminary test to determine the
effect of the formulation and fabrication processes on the dissolution profile in
estimating the bioavailability and bioequivalence between the test products and
the controls. Comparable dissolution tests can also be used to ensure similarities
in quality and properties of drug products with minor changes in formulation or
manufacture after drug marketing authorization (National Drug Administration,
2004). Pharmaceutical preparations should meet three main criteria,
namely:safety(safe),efficacy(effect), andquality(quality). For innovator products,
evaluations regarding these three things have been carried out comprehensively
and thoroughly, starting from pre-clinical trials, clinical trials, to postmarketing
surveillance at very high costs. However, for generic drug products (copy drugs), it
is required to fulfill the equivalence test requirements both in vitro and in vivo
(National Food and Drug Administration, 2004).
A comparative dissolution test was carried out aiming to compare the
dissolution profiles between the test products and the innovator product. This test
is also an initial study before the in vivo equivalence test is carried out. Several
drug products that require an in vitro equivalence test (compared dissolution test),
namely the first drug product that does not require in vivo studies and the second
drug product "copy” which only differ in the strength of the dissolution test is
acceptable for lower strength based on the dissolution profile comparison,
including fast- release tablets, capsules containing slow-release granules, slow-
release tablets (National Food and Drug Administration, 2004).
Paracetamol is widely used in most prescriptions because it is safe in
standard doses. From measuring the pharmaceutical quality of a preparation
containing the active ingredients and the same dosage and the same route of
administration, it does not guarantee the same pharmaceutical availability. This
is caused by the formulation modifications made by each factory. The rate of
release is the stage that most determines the speed of drug bioavailability
(Suhesti and Rachmani, 2018).
Quality tests were conducted on two selected paracetamol tablet products to
determine whether the products were pharmaceutically equivalent. The

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purpose of this study was to compare the dissolution profile of paracetamol

tablets on the market. Acetaminophen or paracetamol is an analgesic-
antipyretic drug that is popularly used in the community to relieve headaches,
minor aches, and fever.
Acetaminophen is widely used in most prescriptions because it is safe

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in standard doses (Suhesti and Rahmani, 2018). Paracetamol is a non-steroidal

anti-inflammatory drug (NSAID) and is most commonly prescribed. General
indications are used as an analgesic and antipyretic in cases of fever, headache,
pain and other minor ailments. In general, paracetamol is safe for human use in
recommended doses. However, paracetamol overdose can lead to potentially
fatal liver damage and in rare patients, normal doses can cause the same. In
addition, the safety and efficacy of pharmaceutical dosage forms can be
guaranteed when they have reliable quality (Yuliani, 2015).

Chemical Structure

Molecular C8H9NO2
formula Other Paracetamol,
name
acetaminophen 4'-
Chemical
Hydroxyacetanilide
name
151,16
Molecular
weight
White crystalline powder, odorless, slightly
Description
bitter taste. 168C – 172 0C
Meltingpoint
5.3 – 6.5
pH
Solubility Soluble in 70 parts cold water, in 20 parts hot
water, 7 parts ethanol, 13 parts acetone, 40 parts
glycerol, 9 parts propylene glycol, soluble in
methanol, dimethylformamide, ethylenechloride,
ethyl acetate, alkaline hydroxide solutions, slightly
soluble in ether and chloroform.
Stability Tablets made by wet granulation usinggelatin
paste are not affected by high humidity
compared to those using povidone. Stable at
temperatures up to 450C. In the form of a
solution is not stable to light. Absorbs
insignificant amounts of moisture at 25ºC and
90% humidity.
Incompatibility It has been reported that paracetamol binds
to nylon and rayon surfaces by the hydrogen
bonding mechanism.
Storage In a tightly closed, opaquecontainer

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Table [Link] monograph (Ministry of Health RI, 2014)

Paracetamol is readily absorbed from the gastrointestinal tract with peak

plasma concentrations occurring approximately 10 to 60 minutes after oral
dosing. Paracetamol is distributed into body tissues, through the placenta and
in breast milk. Paracetamol is metabolized

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mainly in the liver and excreted in the urine as glucuronide and sulfate
conjugates. Paracetamol is administered orally or as a rectal suppository for mild
to moderate illness and for fever. Paracetamol can also be given by intravenous
infusion for the short-term treatment of moderate pain, particularly after surgery
and fever. Paracetamol is the antipyretic analgesic of choice. Paracetamol
indications for relief of mild to moderate pain, treatment of fever. Drug
interactions with chronic overuse of ethanol may increase the risk of
hepatotoxicity. The oral dose is usually 0.5 to 1 g every 4 to 6 hours up to a
maximum of 4 g daily (Martindale, 2009).

RESEARCH METHODS
The method used is the literature study method. The library used is in the
form of scientific articles that have been published in national and international
journals. Search for scientific articles is done online on portals such asGoogle
Scholar, ResearchGate, and other sources with main keywords in the form of
dissolution test and paracetamol tablets. Based on the search, journal screening
was carried out so that 3 main journals were obtained regarding the
paracetamol tablet dissolution test.

RESEARCH RESULTS AND DISCUSSION

Drug products circulating in Indonesia consist of patent drug products,
products with trademarks and generic products with logos. Generic drugs are an
alternative choice for the public because they are cheaper than drugs with trade
names. This happened because of the emphasis on production and promotion
costs. Price competition followed by strict control will lead to the availability of
high quality generic drug products at affordable prices (Ministry of Health RI,
1989).
Based on the Decree of the Minister of Health Number 069/Menkes/SK/II/
2006 concerning the Highest Retail Price (HET) and the Minister of Health Decree
Number 068/Menkes/SK/II/2006 regarding the inclusion of generic names on
packaging, the aim is to rationalize drug prices and provide information to the
public. Provision of information to the public is intended to make generic drug
substitution occur, where the choice of drug is not fully determined by the doctor,
but the public also has authority over the drug they buy. Affordable prices must
also be followed by the quality of these drugs.
Information about the quality of a drug product is needed to give the public
confidence in the drug product. Therefore, information is needed regarding
the quality of drug products.
Bioequivalence test is a comparative bioavailability test designed to show
bioequivalence between test products and comparator drug products (BPOM,
2004). Bioequivalence tests are carried out because the method of fabrication and
formulation can affect the bioavailability of these drug products (Abdou, 1989).
Bioavailability is the amount and speed of the active substance in a drug that
reaches or is available in the systemic circulation in intact or active form after
administration of the drug product, measured by its level in the blood against
time or from its excretion in the urine. Products are declared bioequivalent if they
have pharmaceutical equivalents (containing the same active substance) or are
pharmaceutical alternatives (containing the same active substance,

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so the effect will be the same, both in efficacy and safety (BPOM, 2004; Shargel,
1999).
The in-vitro equivalence test can be carried out using a comparable
dissolution test using 3 different dissolution media, namely
hydrochloric acid pH 1.2 or simulated gastric fluid without enzymes, citric
buffer medium pH 4.5 and phosphate buffer medium pH 6.8 or simulated
intestinal fluid without enzymes (FDA, 2020). This comparative dissolution test
aims to compare the dissolution profiles of the test products to the innovator
products, where the tests are also preliminary studies before in- vitro equivalence
tests are carried out.
Based on Rathnayake's researchet al. (2014) with the titleDetermination of In-
Vitro
Equivalence Paracetamol TabletsA study was conducted to see whether the two
brands of paracetamol tablets were equivalent using the in-vitro method. The
first stage of this research was carried out by testing the quality of the two
selected paracetamol tablet products to find out whether they met the
pharmaceutical requirements according to the British Pharmacopeia 2012.
The second stage was determined in-vitro equivalence of the two products
using the biowaiver testing procedure provided byWorld Health
Organization(WHO).
The dissolution test was carried out using different dissolution media. The
dissolution media used were HCl solution pH 1.2, acetate buffer pH 4.5 and
phosphate buffer solution pH 6.8. The tablets used were Panadol tablets which
were randomly selected as many as 12 tablets for dissolution testing. The results
were then compared using two independent model methods, namely the
difference factor (f1) and the similarity factor (f2). Based on the results of
Rathnayeka's researchet al., (2014), the two paracetamol tablet products tested
met all the requirements of the 2012 British [Link] factor
calculated for the three dissolution [Link] factorin HCl media with a pH
of 1.2 which is 56.18, for acetate buffer media with a pH of 4.5 which is 51.17 and
in phosphate buffer media with a pH of 6.8 which is 51.44. Based on
these,similarity factorin the three media is in the acceptable range of 50-100 for
the profile similarity in the three dissolution media. The two products were also
stated to be bioequivalent to the in-vitro reference product, thus it can be
concluded that the two products can be substituted for each other during clinical
practice (HHS/FDA, 1997).
According to the journal by Ozyilmazet al. (2020) who discussed quality testing
on
conventional tablets with the difference (f1) and similarity (f2) factors used to
evaluate dissolution data. Testing using Paracetamol samples purchased from
Rochem, Turkey. Three different brands of Paracetamol tablets (500 mg) were
selected and titled PAR A (Batch: 010), PAR B (Batch: 05), PAR C (Batch: 004). The
first method used was the preparation of a standard stock of paracetamol by
dissolving paracetaml in 0.1 N HCl at a concentration of 100 µg/mL. Then the
maximum absorbance was determined by UV spectroscopy at 243 nm. The
analytical parameters needed for paracetamol testing are determined by the

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ANOVA test. Then do the determination of LOD and LOQ. Characteristics of in vitro
quality control of paracetamol tablets can be done by determining the thickness
and diameter, test
Hardness, friability test, weight variation, disintegration test, content
uniformity test, dissolution test, and dissolution profile comparison. The
difference factor (f1) is proportional to the mean difference between the three
profiles, while the similarity factor (f2) is inversely proportional to the mean
squared difference among the three profiles with an emphasis on greater
differences between time points (Ozyilmaz et al., 2020 ).

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PAR BPAR C
f1values 6.505.93
f2values 77.6379.41
Table 2. Difference (f1) and similarity factor (f2) for reference (PAR A) with
test products (PAR B and C) (Ozyilmazet al., 2020)

Figure 1. Dissolution profile of conventional paracetamol tablets (Ozyilmazet al.,

2020)

According to the guidelines, f1 value must be between 0-15, f2 must range

from 50 -
100. Results (PAR B and PAR C) with reference (PAR A), the resulting f1 has a
dissolution profile similar to the reference, according to table 1. The dissolution
results in the table are in accordance with USP guidelines i.e. conventional
Paracetamol tablets must be released at least 80% of the labeled amount in 30
minutes (USP 32). The results obtained that all the tested tablets released the
active ingredients as expected explained the basic therapeutic effect of the
dosage forms.
Based on Todorovic's researchet al.(2018), determined and compared the
dissolution profiles of 4 paracetamol direct-release tablet formulations and to
determine the effect of excipients on the kinetics of paracetamol dissolution. The
sample used is paracetamol tablets with a dose (dose of 500 mg). Formulations A
and B are tabletsimmediate releasewhich is not coated while formulations C and D
are tabletsimmediate releaseuncoated. In determining the tablet dissolution
profile, this study used the United States Pharmacopoeia (Apparatus II) method
(USP41 / NRF35) and phosphate buffer pH 6.8 as a medium. Paracetamol release
was observed for 60 minutes (using 6 time points). Then the paracetamol
concentration was measured using the UV/Vis spectrophotometry method (243
nm wavelength). Stock solution was made and calibration was also carried out.
The dissolution profiles were compared
using model-independent methods (difference factors and similarity factors),
statistical methods (ANOVA-based method and paired T Test p <0.05) and
dependent methods (to determine the kinetics of paracetamol release).

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Figure 2. Dissolution Profiles of Formulations A, B, C and D in Phosphate Buffer pH

6.8
(Todorovicet al.,2018)

Terms of the tablet must have 85% of the content released within the first 45
minutes. Analysis of Figure 2 namely formula D is the fastest, and releases more
than 85% content (90.08 ± 2.7%) in the first 5 minutes. Formulation A was in
second position (83.97 ± 4.05%), followed by formulation B (66.20 ± 3.51%) and
formulation C (27.91 ± 6.54%). At 16 minutes, all formulations released more than
85% of the content (formulation A 98.22 ± 1.77, formulation B 87.65 ± 3.03,
formulation C 97.72 ± 1.83, and formula D 101.11 ± 2.7). The value of the similarity
factor f2, the required range is (50-100), but is not relevant for comparing the
profiles of the formulations tested because the requirement is that at least two of
the cumulative release percentages used for the calculation of f2 must be below
85%.

Table 2. The value of the difference factor f1 and the similarity factor f2 for
formulations A, B, C and D (Todorovicet al.,2018)
formulation A B C D
difference A / 0.08 0.11 0.20
7 0 0
factors (f1) 0.09 / 0.14 0.29
B
5 8 6
C 0.14 0.12 / 0.31
7 0 6
D 0.23 0.31 0.34 /
5 6 0
Similarity A / 50,6 31.9 19,1
8 5 0
factors (f2) 50,6 / 38.0 19,2
B
8 5 7

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C 31.9 38.0 / 15,4

5 5 6
D 19,1 19,2 15,4 /
0 7 6

All formulations within the first 45 minutes have drug release of more than
85%. Formula D containing a superdesintegrator releases 90% of the content
within the first 5 minutes.
Although based on the difference values and the similarity factors the formulations
were not significantly different, the ANOVA-based method showed that the
formulations A and

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B, B and C, and B and D formulations were statistically different at all 6 time

points, all formulations having parallel profiles. The release of paracetamol from
formulations A and D is best explained by a first-order kinetic model, whereas the
release of formulations B and C by a logistic model.

CONCLUSION
Based on the results of Rathnayeka's researchet al. (2014), the two
paracetamol tablet products tested met all the requirements of the 2012 British
Pharmacopeia.
Similarity factorthe three media were in the acceptable range of 50-100 for similar
profiles in the three dissolution media and both products were declared
bioequivalent to in-vitro reference products. Thus the two products can be
substituted for each other during clinical practice. On research journal by
Ozyilmazet al.(2020) was tested using Paracetamol samples purchased from
Rochem, Turkey with 3 different brands (PAR A; PAR B; and PAR C). Results (PAR B
and PAR C) with reference (PAR A), the resulting f1 has a similar dissolution profile
already in accordance with USP guidelines i.e. conventional Paracetamol tablets
must be released at least 80% of the labeled amount in 30 minutes. And on
Todorovic's researchet al.(2018), tested paracetamol tablets with a dose (dose of
500 mg), formulations A and B were tabletsimmediate releasewhich is not coated
while formulations C and D are tabletsimmediate releaseuncoated. All formulations
within the first 45 minutes have drug release of more than 85%. The release of
paracetamol from formulations A and D is best explained by a first-order kinetic
model, while the release of formulations B and C by a logistic model.

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