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DEVELOPMENT OF ARTEMETHER AND LUMEFANTRINE FIXED DOSE

COMBINATION TABLETS PREPARATION, CHACTERIZATION AND IN-VITRO
EVALUTION

Article  in  International Journal of Pharmacy · January 2014

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

International Journal of Pharmacy

www.ijpjournal.org
e-ISSN: 2249 – 7684
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 products contain more than one API in a fixed dose,
(FDCs) is becoming increasingly important from a public allowing the patient to reduce the number of drug products
health perspective. Such combinations of drugs are being to be taken. Improved patient compliance is the
used in the treatment of a wide range of conditions and are fundamental purpose of the fixed dose combinations
particularly useful in the management of HIV/AIDS, product. Many studies suggested that simplifying drug
malaria and tuberculosis, which are considered to be the regimens by reducing number of pills may improve patient
foremost infectious disease threats in the world today. adherence, lower disease level and save health service use
WHO definition for fixed-dose combination (FDC) is a and cost [4,5].
combination of two or more actives in a fixed ratio of Malaria is a major health problem with at least
doses [1,2]. Fixed dose combination products are 300 to 500 million people diagnosed with the illness every
acceptable only when the dosage of each ingredient meets year [6]. Effective treatment is dependent on the use of an
the requirement of a defined population group and when efficacious anti malarial that is taken according to an
the combination has a proven advantage over single optimized regimen. Poor adherence, which exposes
compounds administered separately in therapeutic effect, parasites to suboptimal drug concentrations, can lead to
safety or compliance [3]. Fixed dose combination drug poor clinical outcomes and undermine community-level

Corresponding Author:- Karuna DS Email:[email protected]

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benefits by increasing the risk of resistance and onward combinations tablet was shown in Table 01. Each tablet
transmission. Resistance to anti-malarial drugs is caused by containing about (240 mg) of fixed drug combination was
the ability of the parasite to survive or multiply in the prepared by Wet granulation method. The ingredients were
presence of anti-malarial drug concentrations that normally weighed accurately and MCC, half quantity of aerosol and
destroy the parasite or control their multiplication. Due to sifted thoroughly and sieved thoroughly #100 mesh. The
the high resistance of Plasmodium falciparum, there has blend containing drug and other raw material were mixed
been the urgent need for drug combination therapy [7]. in an octagonal blender for 15 minutes. The binder solution
Artemisinin drugs, including artemether and artesunate, are was prepared by adding HPMC to required quantity of
now used as first-line treatment in some countries in South- polysorbate 80 and isopropyl alcohol and stirring for 45
East Asia, but they are recommended combination with mins. Add the binder solution to dry mixture to form wet
other anti-malarial drugs, such as amodiaquine, mass. The screened wet granules were kept in tray drier at
lumefantrine or sulphadoxine-pyrimethamine [8]. White et 60oC. The dried granules were passed through a #20 mesh.
al reported that combination therapy may slow the parasite Weigh accurately remaining aerosol, Croscarmellose
developing resistance to the drug [9]. sodium was passed through #40 mesh and add to dried
Artemether has a rapid onset of action and is granules and mix for 3 mins. Previously sifted #40mash
rapidly eliminated from the plasma (half life of two to magnesium stearate was added to the granular blend and
three hours [10]. Lumefantrine is cleared more slowly and lubricated for 2 mins. Then this final blend was mixed in
has a longer elimination half life (approximately 4.5 days) an octagonal blender for 10 minutes. The final lubricated
[11]. The rationale behind this combination is that blend was compressed using 19.2X11.6 mm, oval shaped
artemether initially provides rapid symptomatic relief by punch to get the target weight and adequate hardness.
reducing the number of parasites present before
lumefantrine eliminates any residual parasites. Artemether- Weight Variation
lumefantrine also reduces gametocyte carriage and thus Twenty tablets from each composition were
should have an impact on malaria transmission [12]. The weighed individually and average weight was calculated.
objective of the present investigation was to develop fixed Then the individual tablet weights were compared to the
dose combination of artemether and lumefantrine tablets. average tablet weight.
The release characters of the formulation was compared
with coartem® tablet. The dissimilarity factor (f1) and S.No Average weight of a tablets % Deviation
similarity factor (f2) was applied to find level of 1 80mg or less ± 10
pharmaceutical equivalence. 2 80-250mg ± 7.5
3 Above 250mg ±5
MARERIALS AND METHODS
Materials Hardness
Artemether and Lumefantrine was a gift sample Hardness is defined as the force required for
from M/s. Mangalam Drugs. Other materials are used in breaking a tablet at diametric compression test and it is
the study such Hydroxyl propyl cellouse, Polysorbate 80, termed as tablet crushing strength. Hardness of the
Micro crystalline cellouse was a gift sample from Welming prepared formulations was determined using Erweka
Pharmaceuticals, India. Isopropyl alcohol, Croscarmelose, hardness tester. It was expressed in kg/cm2.
Magnesium stearate and Aerosil was purchased from Loba
chemicals Pvt Ltd, Mumbai. Friability
Friability test is performed to assess the effect of
Methods friction and shocks, which may often cause or break.
Drug and Excipients compatibility Study by FT-IR Roche friabilator was used for the purpose. This device
Analysis subjects a number of tablets to the combined effect of
Drug and Excipients compatibility was studied abrasion and shock by utilizing a plastic chamber that
using FTIR spectroscopy (FTIR 1615, Perkin Elmer, revolves at 25 rpm dropping the tablets at a distance of 6
USA). The sample was prepared using potassium bromide inches with each revolution. Normally, a preweighed
(KBr) discs. Before taking the spectrum of the sample, a tablets sample is placed in friabilator, which is then
blank spectrum of air background was taken. The mixture operated for 100 revolutions. The tablets are then dusted
was taken and compressed under 10-ton pressure in a and reweighed. Conventional compressed tablets that lose
hydraulic press to form a transport pellet. The pellets were less than 0.5 to 1 % of their weight are generally consider
scanned from 4000-400 cm-1 in IR spectrophotometer. acceptable.

Formulation procedure of Fixed dose combination Initial weight  Final weight

tablets % Friability (F )   100
Formulations composition of fixed drug Initial weight

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Disintegration Time formulating a convenient dosage form for administration

USP disintegration apparatus used basket rack and to achieve better patient compliance. The present
assembly contains 6 glass tubes are 3 inches long open at research was carried out to develop a stable, fixed dose
the top and held against 10 mesh screen at the bottom. A combination of Artemether and Lumefantrine. These two
tablet whose disintegration to be tested was placed in a drugs are indicated the successful treatment of malaria.
tube 16 tablets in each tube and basket rack assembly was The API was subjected to preformulation study, which
positioned in a beaker containing disintegration medium encompasses the accelerated drug- drug and drug-
specified in pharmacopeia at 37±2oC such that the tablet excipients compatibility was studied by FTIR. The
remains 2.5cm below the surface of disintegration medium spectram of the pure drugs and combination with
in upward movement and descend it is not closer than 2.5 excipients were shown in the Figure 01. There is no
cm from the bottom of the beaker. A standard motor driven considerable change in drug characterization peaks and the
device was used to remove the basket assembly containing results obtained with drug- drug and drug- excipients
tablets up and down through zero distance of 5-6 cm at a showed good compatibility.
frequency of 28-52 cycles / minutes. The time at which no Fixed dose combination of Artemether and
fine core of a tablet was present above the mesh was noted Lumefantrine is formulated by wet granulation technique.
as a disintegration time of a tablet. The formulations composition was shown in Table 01. In
the successful tablet formulation the selected tablets were
DISSOLUTION STUDIES studied for their quality control test via Appearance,
In vitro dissolution studies of Artemether Thickness, Hardness, Weight variation, and Disintegration
In vitro dissolution studies for all tablet time and in- vitro dissolution study and assay. The
formulations were performed by using USP dissolution test evaluation parameters of the all the formulations was
apparatus (Apparatus II, Paddle type, 37ºC) at 75 rpm for shown in Table 02. The formulated tablets physical
180 minutes. The dissolution medium was used 900 ml of attributes such as percentage weight variation, Hardness,
water. At different time intervals a 10 ml of the sample was DT, Friability, Assay all of which were found to be within
taken and analyzed for drug content at 210 nm by HPLC. pharmacopieal limits.
A 10 ml fresh dissolution medium was added to make the In vitro dissolution profiles of the formulations
volume after each sample withdrawal. were shown in Figure 02 and Table 3 and 4. The results
indicated that concentration of super disintegrants.(i.e)
In vitro dissolution studies of Lumefantrine Crospovidone and Croscarmellose sodium significantly
In vitro dissolution studies for all tablet improved the release property of the drug. The result
formulations were performed by using USP dissolution test indicated that superdisintegrants may improve water
apparatus (Apparatus II, Paddle type, 37ºC) at 100 rpm for wicking mechanism into porous network of tablet resulting
60 minutes. The dissolution medium was used 900 ml of in rapid release [13,14]. Dissimilarity (f1) factor of
0.1 M HCL with benzylkonium chloride (BKC). At formulations F-1, F-2, F-3 and F-4 were found to ART-
different time intervals a 10 ml of the sample was taken 8.54 & LUMI -18.34, ART-4.79 & LUMI-18.35, ART-
and analyzed for drug content at 380 nm by HPLC. A 10 14.70 & LUMI-4.88 and ART-5.01& LUMI-16.93
ml fresh dissolution medium was added to make the respectively. Similarity (f2) factor of formulations F-1, F-
volume after each sample withdrawal. 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
Stability Studies and ART-72.32& LUMI-44.15 respectively. By comparing
Stability studies were performed to check the the Dissimilarity (f1) and similarity (f2) factor with that of
effect of environmental condition or storage conditions on the commercial formulation follows less dissimilar and
formulation. Optimized batch F3 was kept in accelerated highest similarity within given range. The similarity factor
stability condition at 250C temperature 60±5% relative (f2) value for formulation F3 was 50.08 and 69.65 for ART
humidity and 400C temperature 75±5% relative humidity and LUMI respectively.
for a period 3 months as per International Conference on The stability report of optimized formulation did
Harmonization (ICH) guidelines. The samples were not show any significant changes in physicochemical
withdrawn at 1, 2 and 3 months intervals evaluation was parameters and drug content as shown in Table 05.
carried out for physical appearance and percentage drug Stability studies were carried out for optimized tablet
content. formulation at 25±2ºC/60 ± 5%RH and 40±2ºC/75 ± 5%
RH for a period of 3 months shows good stability in Blister
RESULTS AND DISCUSSION packing.
Recent advances in oral drug delivery system
aims to enhance safety and efficacy of drug molecules by

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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 dose combinations of Artemether and Lumefantrine tablet
Artemether and Lumefantrine was successfully developed. comparable to innovator product and fulfilling the
Physiochemical properties like appearance, thickness, objective of the study.
hardness, weight variation, and disintegration time of
formulation F3 was showed good results. In vitro drug ACKNOWLEDGEMENT
release profile of formulation F3 was similar to innovator Authors are thankful to Indian Institute of
product. No significant change was observed in the drug Technology, Madras and C.L.Baid Metha College of
content, physical properties and dissolution rate of these Pharmacy, Chennai for providing necessary facilities to
tablets after the storage period 3 months at 40±2ºC/75 ± carry out this research.

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