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Chandrasekaran et al: Post-market In vitro Equivalency Evaluation of Paracetamol Tablets in Malaysia 1403

Research Paper

Post–market In vitro Equivalency Evaluation of Paracetamol

Tablets in Kedah, Malaysia

A. R. Chandrasekaran, Chen Yi Han, Alex Chin Yang Chung, Lim Wei Cheang, and Low Sing Ping

Pharmaceutical Technology Unit, Faculty of Pharmacy, AIMST University, Kedah- 08100, Malaysia.

Received March 15, 2011; accepted July 17, 2011

ABSTRACT

Six brands of paracetamol (acetaminophen) 500 mg tabletshave been evaluated using specific quality control tests foruniformity of weight, hardness, friability, content, disintegrationand dissolution with the aim to assess its bioequivalence. The

results obtained have been discussed in details usingmonographs in United States Pharmacopeia and British

Pharmacopoeia. In conclusion, despite some apparent minordifferences in tablet hardness and disintegration time profiles,the dissolution characteristics of various paracetamol tabletsappears to be similar and not significantly different from

various manufacturers.

KEYWORDS: Quality control tests; paracetamol; dissolution; dissolution efficiency; weight variation; disintegration.

Introduction

Post−market evaluation involves all activities

undertaken to obtain more data and information about a

product after it has been granted marketing

authorization and made available for public use. The

obtained quantitative and qualitative data could be

employed for product development and improvement of

the standard of the product as per the regulations.Regulatory agencies rely on limited information obtained

during clinical trials and, to some extent, scientific

literature as guides to granting marketing authorization

of medicines for public use. The post−market evaluation

is imperative to monitor the approved medicines in order

to adequately assess the quality, therapeutic

effectiveness and safety of medicines for the end user.

Post-market evaluation should be a continuous event

throughout the life of a drug product. Activities of post

market evaluation of a drug have been identified to

include: evaluation and investigation of reported drug

complaints and procedures for production and review of

product claims and labeling; public access to information

taken and reported to the regulatory agencies; and in

vitro testing of products for compliance to standards

(Hennessy, 1998).

In vitro testing or quality control of drugs is a set of

studies undertaken during production. Routine

laboratory testing of drugs in the market is crucial to

protect public health especially in developing countries

where counterfeit and substandard drugs have become a

major challenge to health care services. Counterfeit and

substandard medicines are a major cause of morbidity,

mortality, and diminished public confidence in drugs and

health structures (Kasim et al., 2004; Cockburn et al.,

2005).

China and India are known as the leading countries

in counterfeit drug production (Khan and Ghilzai, 2003)

Other countries are Pakistan, Egypt and Indonesia

(Raufu, 2003; Ngweluka et al., 2006; Oschekpe et al.,

2006). To reduce the cost of medicines especially for the

low income group of developing countries, the World

Health Organization (WHO) has continuously advocated

the use of generic brands (WHO, 2004), but this

approach has not provided sufficient evidence for the

substitution of one brand for another. The difference in

cost between a branded and generic medicine may be as

high as 90%. To assist in substitution of branded with

generic drugs for affordability and at the same time

achieve therapeutic efficacy, bioequivalence studies

become chief concern.

Bioequivalence has been described as the absence of

a significant difference in the rate and extent to which

the active ingredient or excipients in pharmaceutical

equivalents or pharmaceutical alternatives become

available at the site of drug action, when they are

administered at the same molar dose under similarconditions in an appropriately designed study (FDA,

1997; 2000; 2003).

Two pharmaceutical products are considered to be

equivalent when their bioavailability factors are so

similar that they are unlikely to produce clinically

relevant differences in therapeutic and adverse effects

(Polli et al., 1997; Chen et al., 2001; Meredith, 2003).

Generic substitution could be considered when a generic

copy of a reference drug contains an identical value of

the same active ingredient in the same dose formulation

1403

International Journal of Pharmaceutical Sciences and Nanotechnology

Volume 4 • Issue 2 • July –September 2011

MS ID: IJPSN-17-07-11-CHANDRASEKARAN

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1404 Int J Pharm Sci Nanotech Vol 4; Issue 2 • July−September 2011 and route of administration, as well as meet standards

for strength, purity, quality and identity. However

evidences over the years indicate that marketed

products with the same amount of active ingredient

exhibit marked differences in their therapeutic

responses (Rani, 2007).This may be due to the extent of absorption being dissimilar or perhaps due to different

excipients employed.

Bioequivalence studies focus on the release of the

drug from the formulation and subsequent absorption

into the systemic circulation. However, with the

introduction of the biopharmaceutical classification

system (BCS), in vivo bioequivalence studies could be

waived for immediate release solid oral dosage forms for

class I (high solubility and permeability) and class III

drugs (high solubility and low permeability) (Wu et al.,

2005; Polli,2008). Hence, only in vitro testing may be

used to determine bioequivalence for highly soluble and

highly permeable drugs. Dissolution testing, a substitute

for bioequivalence testing, is certainly a practical andeconomic approach in developing countries where

technology and resources are limited for in vivo studies.

One of the values of the dissolution test is that it can be

used to define characteristics of bioavailability problems

and assess the need for in vivo bioavailability. The

release of the active pharmaceutical ingredient from

drug product, the dissolution of the drug under

physiological conditions and the permeability across the

gastrointestinal tract determines the drug absorption.

Based on this, in vitro dissolution may be vital in

assessing in vivo performance. Dissolution testing also

serves as a tool to distinguish between acceptable and

unacceptable drug products (Anderson et al., 1998; Shah

et al., 1998; Shah, 2001).

Literature data are reviewed on the properties of

paracetamol (acetaminophen) related to the BCS.

According to the current BCS criteria, acetaminophen is

a BCS Class III compound. Differences in composition

seldom, if ever, have an effect on the extent of

absorption. However, some studies show differences in

rate of absorption between brands and formulations. In

particular, sodium bicarbonate, present in some drug

products, was reported to give an increase in the rate of

absorption, probably caused by an effect on gastric

emptying. In view of Marketing Authorizations (MAs)

given in a number of countries to acetaminophen drug

products with rapid onset of action, it is concluded that

the differences in rate of absorption were considered

therapeutically not relevant by the Health Authorities.Moreover, in view of its therapeutic use, its wide

therapeutic index and its uncomplicated

pharmacokinetic properties, in vitro dissolution data

collected according to the relevant guidance can be safely

used for declaring bioequivalence (BE) of two

acetaminophen formulations. Therefore, accepting a

biowaiver for immediate−release (IR) acetaminophen

solid oral drug products is considered scientifically

justified if the test product contains only those excipients

reported in this paper in their usual amounts and the

test product is rapidly dissolving, as well as the test

product fulfils the criterion of similarity of dissolution

profiles to the reference product (Yu et al., 2002).

The present study was undertaken to evaluate the

efficacy and justification of the generic substitution of

paracetamol in the Malaysian market. Paracetamol

(acetaminophen) is a widely used over−the−counter

(OTC) analgesic and antipyretic agent.

The ultimate objective of dissolution testing may be

described as ensuring adequate and reproducible

bioavailability without recourse to routine in vivo

testing. Drug release in the human body can be

measured in vivo by measuring the plasma or urine

concentrations in the subject concerned. However, there

are certain obvious impracticalities involved in

employing such techniques on a routine basis. These

difficulties have led to the introduction of official in vitro

tests, which are now rigorously and comprehensively

defined in the respective Pharmacopoeia.

Chemistry of Paracetamol. Chemical structure and

properties of paracetamol are listed below.

OH NH

CH

O

IUPAC Name : N-(4-hydroxyphenyl)acetamide

Chemical Formula : C8H9NO2

Molecular Weight : 151.17

Synonyms: 4'-hydroxyacetanilide; Tylenol; Paracetamol;

Paracetamolo; Paracetamole; P-acetamido-Phenol;

4'-hydroxyacetanilide; n-(p- Hydroxyphenyl)-Acetamide;

N-(4-hydroxyphenyl)-Acetamide; P-acetamidophenol;4-Acetamidophenol; Acetaminofen; Acetaminophen;

P-Acetaminophenol; N-acetyl-p-aminophenol; P-Acetylamino

Phenol; P-hydroxyacetanilide; Paracetamol; 4-hydroxy

Acetanilide; 4-hydroxyanilid Kyseliny Octove; N-(4-

hydroxyphenyl) Acetamide

Physical Properties:

(a) Physical state: white crystalline powder

(b) Melting point : 169 – 172 0C

(c) Solubility in water : sparingly soluble

(d) pH : 5.5 – 6.5

(e) Stability : stable in normal condition

Materials and MethodsMaterials. Standard paracetamol >99% was obtained

as a gift from a research colleague. Six different brands

of paracetamol tablets as shown in Table 1 were

purchased from retail pharmacies in Malaysia.

Standard materials from standard sources were used.

To perform dissolution testing, an Electrolab instrument

was used. A Monsanto hardness tester was used to test

the hardness. A UV − visible spectrophotometer from

GBC Cintralol was used. A disintegration tester from

Electrolab was used (Allen et al., 2004).

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Determination of Weight Uniformity. Twenty tablets

from each of the six brands were weighed individually

with an analytical weighing balance (Kern). The average

weight for each brand as well as the percentage

deviation from the mean value was calculated.

Hardness Test. The crushing strength was

determined with a tablet hardness tester (Monsanto).

Four tablets were randomly selected from each brand for

this test.

Friability Test. Ten tablets of each brand were

weighed and subjected to abrasion by employing a Roche

friabilator (Erweka Gmbh, Germany) at 25 rev/min for 4

minutes. The tablets were then weighed and compared,

with their initial weights and percentage friability being

obtained.

Disintegration Test. Tablet disintegration was

determined in the tablet disintegration tester (Es Eagle

Scientific Limited, Nottingham). Six tablets from each

brand were employed for the test in distilled water at37°C using the Educational Sciences Disintegration

Apparatus (Es Eagle Scientific Limited, Nottingham).

The disintegration time was taken to be the time no

particle remained on the basket of the system.

Dissolution Test. The dissolution test was

undertaken using USP apparatus I (basket method) in 6

replicates for each brand. Preparation of Phosphate

Buffer, pH 5.8: The rpm was set to 50.

Ten ml of the samples were withdrawn from

dissolution basket at various time intervals such as 0,

10, 20, 30, 45 and 60 min using a graduated pipette and

replaced with equal volume to maintain sink condition.

The samples were filtered and diluted 10 by 10 times

and the absorbance was measured at 243 nm. Theconcentration of each sample was determined from a

calibration curve obtained from pure samples of

paracetamol.

Results and Discussion

The research study has highly demonstrated the

formulation and in vitro equivalency evaluation of

paracetamol tablets. Six different brands of paracetamol

tablets were studied for their dissolution, disintegration,

weight variation and hardness. The six different brands

of paracetamol tablets are named accordingly by

alphabetical order as products A-F.

TABLE 1

Sample of paracetamol.

Code Brand Name Dosage form Country of Origin

A Tempol Tablets Malaysia

B Dhamol Tablets Malaysia

C Panadol Tablets Hong Kong

D Paracetamol Tablets India

E Poro Tablets Malaysia

F Ulphamol Tablets Malaysia

A summary of the results of uniformity of weight,

hardness test, friability and disintegration are as shown

in Table 2. Uniformity of weight, disintegration and

dissolution are compendial standards to assess the

quality of tablets while hardness and friability are

referred to as non-compendial standards althoughfriability is now included in the USP, 1995. Uniformity

of weight does serve as a pointer to good manufacturing

practices (GMP) as well as the amount of the active

pharmaceutical ingredient (API) paracetamol contained

in the formulation. All of the brands complied with the

USP specification.

The hardness or crushing strength assessed the

ability of tablets to withstand handling without

fracturing or chipping. It can also influence friability and

disintegration, as can be seen from Table 2. The harder a

tablet, the less friable and the more time it takes to

disintegrate. A force of about 4 kg is the minimum

requirement for a satisfactory tablet (Allen et al., 2004).

Hence, the tablets of all brands were satisfactory forhardness.

TABLE 2

Hardness, disintegration and weight variation test of paracetamol

tablets.

Product

Average

disintegration

(min)

Weight variation

test limit (gm)

Tablet

hardness

kg/square

inch

A 8.808 0.5223 to 0.5773 11.7

B 6.58 0.5320 to 0.5880 12.5

C 6.08 0.5618 to 0.6210 7.0

D 0.60 0.5585 to 0.6173 8.8

E 1.08 0.5715 to 0.6315 9.1

F 1.52 0.5715 to 0.6315 8.0

The compendia specification for friability is 1%.

Friability for all brands was below 1%. The friability test

was used to evaluate the tablets resistance to abrasion.

Disintegration could be directly related to dissolution

and subsequent bioavailability of a drug (FDA,

2009abcd). A drug incorporated in a tablet is released

rapidly as the tablet disintegrates; a crucial step for

immediate release dosage forms because the rate of

disintegration affects the dissolution and subsequently

the therapeutic efficacy of the medicine (Costa et al.,

2000; Gohel et al., 2005). All brands complied with the

compendial specifications for disintegration. It was

found that the results obtained from the disintegration

test for tablet product A was relatively slower than therest of the tablets products. Thus, tablet products D, E, F

were being readily available in the solution when

compared with tablet product A.

Weight Variation Test. The USP weight variation

test is done by weighing 20 tablets individually,

calculating the average weight and comparing the

individual tablet weight to the average weight. As per

pharmacopoeia, for tablets weight more than 250 mg,

percentage deviation is 5%. Paracetamol tablets of

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1406 Int J Pharm Sci Nanotech Vol 4; Issue 2 • July−September 2011 product A-I were of 500 mg and the weight variation fall

between the ranges.

The tablet meets the USP requirements if no more

than 2 tablets are outside the percentage limit and no

tablet differs by more than double the percentage limit.

Therefore, all of the tablets passed the test.

Hardness Test. The six different brands of

paracetamol tablets are tested for their hardness as well.

The standard for the hardness test is a 4 kg/square inch

gauge; it is considered minimum for a satisfactory tablet.

All products conformed to the standard of hardness test.

The hardness test reviewed the results as below:

According to USP specification, paracetamol tablets

should release more than 80% of drug at 30 min. From

the research carried out, we have found that product A

showed 96.23%, product B showed 88.03%, product C

showed 95.26%, product D showed 97.49%, product E

showed 93.75% and product F showed 96.41% of the

drug released at 30 min (Table 3). The results complied

with the USP specification.

TABLE 3

Release studies of paracetamol.

Time

Interval

(min)

Percentage release

A B C D E F

10 80.355 78.389 80.997 87.418 87.995 77.246

20 95.445 86.344 88.672 93.516 91.648 95.299

30 96.226 88.029 95.264 97.493 93.751 96.407

45 97.748 92.096 98.883 98.809 98.750 97.837

60 99.227 96.299 99.158 99.721 99.092 98.686

In disintegration testing, time taken for

disintegration of product A was relatively longer than

other products. Thus, product B, C, D, E and F were

more readily available in the solution. The high rate of

disintegration of a tablet indicates faster breakdown of a

tablet into smaller particles and thus, enhanced the

dissolution of the medicaments into the blood circulation,

increasing the bioavailability.

Conclusion

Based on the finding from this study, it is concluded

that, despite some apparent minor differences in tablet

hardness and disintegration time profiles, the

dissolution characteristics of various paracetamol tablets

appears to be similar and not significantly different from

various manufacturers.

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Address correspondence to: A.R. Chandrasekaran, Pharmaceutical

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08100, Malaysia. E-mail: [email protected]

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