Karuna DS.et al. / International Journal of Pharmacy, 4(4), 2014, 166-172.

International Journal of Pharmacy

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Print ISSN: 2249 7692

DEVELOPMENT OF ARTEMETHER AND LUMEFANTRINE FIXED

DOSE COMBINATION TABLETS: PREPARATION,
CHACTERIZATION AND IN-VITRO EVALUTION
Karuna DS* Rasheedhabanu A K, Ubaidulla U, Grace Rathnam
Department of Pharmaceutics, C. L. Baid Metha College of Pharmacy, Chennai, Tamilnadu, India.

ABSTRACT
The objective of this paper was to formulate and evaluate fixed dose combinations of two anti-malarial drugs,
Artemether and lumefantrine. The drug-drug interactions were studied using FTIR and granules were prepared by wet
granulation method using various superdisintegrants. The results of FTIR study revealed that combination of two drugs was
acceptable. The prepared formulations were evaluated for various parameters like thickness, hardness, friability, disintegration
time and in vitro drug release studies. The hardness, friability and disintegration time of optimized formulation F3 was found 4
to 5 kg/cm2, 0.05 to 0.07% and 2 to 3 minutes respectively. The dissolution profile of the tablet revealed that Artemether and
lumefantrine were released more than 90% within 180 min, 60 min respectively. The dissolution profiles of formulation F3 and
innovator product were compared by calculating similarity factor (f2) which was found to 50.08 and 69.65 for ART and LUMI
respectively. The stability data reveals that the F3 showed a negligible change in drug content after storage in various
conditions for three months according to ICH guidelines. Hence, it is finally concluded that the studied fixed dose combination
tablet can be considered for treatment of malaria.

Key words: Artemether, Lumefantrine, Fixed dose combination tablet.

INTRODUCTION
The development of fixed-dose combinations
(FDCs) is becoming increasingly important from a public
health perspective. Such combinations of drugs are being
used in the treatment of a wide range of conditions and are
particularly useful in the management of HIV/AIDS,
malaria and tuberculosis, which are considered to be the
foremost infectious disease threats in the world today.
WHO definition for fixed-dose combination (FDC) is a
combination of two or more actives in a fixed ratio of
doses [1,2]. Fixed dose combination products are
acceptable only when the dosage of each ingredient meets
the requirement of a defined population group and when
the combination has a proven advantage over single
compounds administered separately in therapeutic effect,
safety or compliance [3]. Fixed dose combination drug
products contain more than one API in a fixed dose,
allowing the patient to reduce the number of drug products
to be taken. Improved patient compliance is the
fundamental purpose of the fixed dose combinations
product. Many studies suggested that simplifying drug
regimens by reducing number of pills may improve patient
adherence, lower disease level and save health service use
and cost [4,5].
Malaria is a major health problem with at least
300 to 500 million people diagnosed with the illness every
year [6]. Effective treatment is dependent on the use of an
efficacious anti malarial that is taken according to an
optimized regimen. Poor adherence, which exposes
parasites to suboptimal drug concentrations, can lead to
poor clinical outcomes and undermine community-level

Corresponding Author:- Karuna DS Email:-karunaspharma@gmail.com

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benefits by increasing the risk of resistance and onward
transmission. Resistance to anti-malarial drugs is caused by
the ability of the parasite to survive or multiply in the
presence of anti-malarial drug concentrations that normally
destroy the parasite or control their multiplication. Due to
the high resistance of Plasmodium falciparum, there has
been the urgent need for drug combination therapy [7].
Artemisinin drugs, including artemether and artesunate, are
now used as rst-line treatment in some countries in South-
East Asia, but they are recommended combination with
other anti-malarial drugs, such as amodiaquine,
lumefantrine or sulphadoxine-pyrimethamine [8]. White et
al reported that combination therapy may slow the parasite
developing resistance to the drug [9].
Artemether has a rapid onset of action and is
rapidly eliminated from the plasma (half life of two to
three hours [10]. Lumefantrine is cleared more slowly and
has a longer elimination half life (approximately 4.5 days)
[11]. The rationale behind this combination is that
artemether initially provides rapid symptomatic relief by
reducing the number of parasites present before
lumefantrine eliminates any residual parasites. Artemether-
lumefantrine also reduces gametocyte carriage and thus
should have an impact on malaria transmission [12]. The
objective of the present investigation was to develop fixed
dose combination of artemether and lumefantrine tablets.
The release characters of the formulation was compared
with coartem tablet. The dissimilarity factor (f1) and
similarity factor (f2) was applied to find level of
pharmaceutical equivalence.
MARERIALS AND METHODS
Materials
Artemether and Lumefantrine was a gift sample
from M/s. Mangalam Drugs. Other materials are used in
the study such Hydroxyl propyl cellouse, Polysorbate 80,
Micro crystalline cellouse was a gift sample from Welming
Pharmaceuticals, India. Isopropyl alcohol, Croscarmelose,
Magnesium stearate and Aerosil was purchased from Loba
chemicals Pvt Ltd, Mumbai.
Methods
Drug and Excipients compatibility Study by FT-IR
Analysis
Drug and Excipients compatibility was studied
using FTIR spectroscopy (FTIR 1615, Perkin Elmer,
USA). The sample was prepared using potassium bromide
(KBr) discs. Before taking the spectrum of the sample, a
blank spectrum of air background was taken. The mixture
was taken and compressed under 10-ton pressure in a
hydraulic press to form a transport pellet. The pellets were
scanned from 4000-400 cm-1 in IR spectrophotometer.
Formulation procedure of Fixed dose combination
tablets
Formulations composition of fixed drug
combinations tablet was shown in Table 01. Each tablet
containing about (240 mg) of fixed drug combination was
prepared by Wet granulation method. The ingredients were
weighed accurately and MCC, half quantity of aerosol and
sifted thoroughly and sieved thoroughly #100 mesh. The
blend containing drug and other raw material were mixed
in an octagonal blender for 15 minutes. The binder solution
was prepared by adding HPMC to required quantity of
polysorbate 80 and isopropyl alcohol and stirring for 45
mins. Add the binder solution to dry mixture to form wet
mass. The screened wet granules were kept in tray drier at
60oC. The dried granules were passed through a #20 mesh.
Weigh accurately remaining aerosol, Croscarmellose
sodium was passed through #40 mesh and add to dried
granules and mix for 3 mins. Previously sifted #40mash
magnesium stearate was added to the granular blend and
lubricated for 2 mins. Then this final blend was mixed in
an octagonal blender for 10 minutes. The final lubricated
blend was compressed using 19.2X11.6 mm, oval shaped
punch to get the target weight and adequate hardness.
Weight Variation
Twenty tablets from each composition were
weighed individually and average weight was calculated.
Then the individual tablet weights were compared to the
average tablet weight.
S.No Average weight of a tablets % Deviation
1 80mg or less 10
2 80-250mg 7.5
3 Above 250mg 5
Hardness
Hardness is defined as the force required for
breaking a tablet at diametric compression test and it is
termed as tablet crushing strength. Hardness of the
prepared formulations was determined using Erweka
hardness tester. It was expressed in kg/cm2.
Friability
Friability test is performed to assess the effect of
friction and shocks, which may often cause or break.
Roche friabilator was used for the purpose. This device
subjects a number of tablets to the combined effect of
abrasion and shock by utilizing a plastic chamber that
revolves at 25 rpm dropping the tablets at a distance of 6
inches with each revolution. Normally, a preweighed
tablets sample is placed in friabilator, which is then
operated for 100 revolutions. The tablets are then dusted
and reweighed. Conventional compressed tablets that lose
less than 0.5 to 1 % of their weight are generally consider
acceptable.
Initial weight Final weight
% Friability (F ) 100
Initial weight
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Disintegration Time
USP disintegration apparatus used basket rack
assembly contains 6 glass tubes are 3 inches long open at
the top and held against 10 mesh screen at the bottom. A
tablet whose disintegration to be tested was placed in a
tube 16 tablets in each tube and basket rack assembly was
positioned in a beaker containing disintegration medium
specified in pharmacopeia at 372oC such that the tablet
remains 2.5cm below the surface of disintegration medium
in upward movement and descend it is not closer than 2.5
cm from the bottom of the beaker. A standard motor driven
device was used to remove the basket assembly containing
tablets up and down through zero distance of 5-6 cm at a
frequency of 28-52 cycles / minutes. The time at which no
fine core of a tablet was present above the mesh was noted
as a disintegration time of a tablet.
DISSOLUTION STUDIES
In vitro dissolution studies of Artemether
In vitro dissolution studies for all tablet
formulations were performed by using USP dissolution test
apparatus (Apparatus II, Paddle type, 37C) at 75 rpm for
180 minutes. The dissolution medium was used 900 ml of
water. At different time intervals a 10 ml of the sample was
taken and analyzed for drug content at 210 nm by HPLC.
A 10 ml fresh dissolution medium was added to make the
volume after each sample withdrawal.
In vitro dissolution studies of Lumefantrine
In vitro dissolution studies for all tablet
formulations were performed by using USP dissolution test
apparatus (Apparatus II, Paddle type, 37C) at 100 rpm for
60 minutes. The dissolution medium was used 900 ml of
0.1 M HCL with benzylkonium chloride (BKC). At
different time intervals a 10 ml of the sample was taken
and analyzed for drug content at 380 nm by HPLC. A 10
ml fresh dissolution medium was added to make the
volume after each sample withdrawal.
Stability Studies
Stability studies were performed to check the
effect of environmental condition or storage conditions on
formulation. Optimized batch F3 was kept in accelerated
stability condition at 250C temperature 605% relative
humidity and 400C temperature 755% relative humidity
for a period 3 months as per International Conference on
Harmonization (ICH) guidelines. The samples were
withdrawn at 1, 2 and 3 months intervals evaluation was
carried out for physical appearance and percentage drug
content.
RESULTS AND DISCUSSION
Recent advances in oral drug delivery system
aims to enhance safety and efficacy of drug molecules by
formulating a convenient dosage form for administration
and to achieve better patient compliance. The present
research was carried out to develop a stable, fixed dose
combination of Artemether and Lumefantrine. These two
drugs are indicated the successful treatment of malaria.
The API was subjected to preformulation study, which
encompasses the accelerated drug- drug and drug-
excipients compatibility was studied by FTIR. The
spectram of the pure drugs and combination with
excipients were shown in the Figure 01. There is no
considerable change in drug characterization peaks and the
results obtained with drug- drug and drug- excipients
showed good compatibility.
Fixed dose combination of Artemether and
Lumefantrine is formulated by wet granulation technique.
The formulations composition was shown in Table 01. In
the successful tablet formulation the selected tablets were
studied for their quality control test via Appearance,
Thickness, Hardness, Weight variation, and Disintegration
time and in- vitro dissolution study and assay. The
evaluation parameters of the all the formulations was
shown in Table 02. The formulated tablets physical
attributes such as percentage weight variation, Hardness,
DT, Friability, Assay all of which were found to be within
pharmacopieal limits.
In vitro dissolution profiles of the formulations
were shown in Figure 02 and Table 3 and 4. The results
indicated that concentration of super disintegrants.(i.e)
Crospovidone and Croscarmellose sodium significantly
improved the release property of the drug. The result
indicated that superdisintegrants may improve water
wicking mechanism into porous network of tablet resulting
in rapid release [13,14]. Dissimilarity (f1) factor of
formulations F-1, F-2, F-3 and F-4 were found to ART-
8.54 & LUMI -18.34, ART-4.79 & LUMI-18.35, ART-
14.70 & LUMI-4.88 and ART-5.01& LUMI-16.93
respectively. Similarity (f2) factor of formulations F-1, F-
2, F-3 and F-4 were found to ART- 60.54 & LUMI -49.42,
ART-69.72 & LUMI-42.71, ART-50.08 & LUMI-69.65
and ART-72.32& LUMI-44.15 respectively. By comparing
the Dissimilarity (f1) and similarity (f2) factor with that of
the commercial formulation follows less dissimilar and
highest similarity within given range. The similarity factor
(f2) value for formulation F3 was 50.08 and 69.65 for ART
and LUMI respectively.
The stability report of optimized formulation did
not show any significant changes in physicochemical
parameters and drug content as shown in Table 05.
Stability studies were carried out for optimized tablet
formulation at 252C/60 5%RH and 402C/75 5%
RH for a period of 3 months shows good stability in Blister
packing.
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Figure 1. FTIR Spectra of (A) Artemether, (B) Lumifantrine, (C) Artemether+Lumifantrine

A

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Figure 2. In vitro release profile of Fixed dose combination tablet

Table 1. Formulation composition of Fixed dose combination tablets

FORMULATIONS
S.No Materials
F1 F2 F3 F4
1 Lumefantrine 120 120 120 120
2 Artemether 20 20 20 20
3 MCC 84.75 81.50 80.50 78.50
4 Aerosil 5 4.75 4 3.5
5 Hydroxyl propyl cellulose 0.25 0.75 1.5 2
6 Croscarmellose sodium 2 4 5 7
7 Magnesium stearate 6 6 6 6
8 Polysorbate 80 2 3 3 3
9 Isopropyl alcohol qs qs qs qs

Table 2. Evaluation parameters of the formulations

Formulation Average Thickness Hardness Disintegration
Friability (%)
Code Weight (mg) (mm) (kg/cm2) time
F1 240.5 3.1 5 0.21 0min 45sec
F2 240 3.2 4.5 0.11 2min 20sec
F3 242.3 3 5 0.07 2min 40sec
F4 238.8 3.1 5 0.16 3min 18sec

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Table 3. In vitro dissolution profile of Lumefantrine

Time in minutes F1 F2 F3 F4 LUMI-COARTEM
0 0 0 0 0 0
10 45.59 37.95 50.86 38.54 54.5
15 55.56 45.77 58.67 46.54 62.87
30 70.90 61.06 75.91 62.38 77.05
45 77.99 72.89 85.76 73.74 83.15
60 83.11 79.10 92.04 80.72 85.89

Table 4. In vitro dissolution profile of Artemether

Time in minutes F1 F2 F3 F4 ART- COARTEM
0 0 0 0 0 0
30 38.42 48.68 36.46 37.16 30.46
60 56.89 68.30 63.27 53.16 63.27
90 68.25 77.72 78.04 58.44 78.04
120 74.86 83.06 85.85 67.28 85.85
180 81.92 89.08 93.85 74.66 93.85

Table 5. Stability study analysis report of the optimized formulation

Time Avg. Hardness Thickness Assay(%)
S.NO Temp.&RH DT
periods (M) Weight (mg) (kg/cm2) (mm) ART LUMI
0 242.6 5.1 2.9 2min 42sec 99.76 98.37
25 20c/ 1 242.6 5 2.8 2min 42sec 99.34 98.12
1
60% 5% 2 242.5 5 2.8 2min 41sec 98.87 97.96
3 242.5 5 2.8 2min 41sec 98.36 97.82
0 242.6 5.1 3.1 2min 43sec 99.76 98.37
40 20c/ 1 242.5 5 3 2min 42sec 99.12 97.65
2
75% 5% 2 242.5 5 3 2min 42sec 98.86 96.85
3 242.3 5 3 2min 40sec 97.22 96.10

CONCLUSION 5% RH. Hence the study result in the development of fixed

A fixed dose combination of tablet formulation of
Artemether and Lumefantrine was successfully developed.
Physiochemical properties like appearance, thickness,
hardness, weight variation, and disintegration time of
formulation F3 was showed good results. In vitro drug
release profile of formulation F3 was similar to innovator
product. No significant change was observed in the drug
content, physical properties and dissolution rate of these
tablets after the storage period 3 months at 402C/75
dose combinations of Artemether and Lumefantrine tablet
comparable to innovator product and fulfilling the
objective of the study.
ACKNOWLEDGEMENT
Authors are thankful to Indian Institute of
Technology, Madras and C.L.Baid Metha College of
Pharmacy, Chennai for providing necessary facilities to
carry out this research.

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