1391270670 (1)

www.wjpps.com Vol 3, Issue 2, 2014. 1578
Shaundarya Kumar et al. World Journal of Pharmacy and Pharmaceutical Sciences
BIOAVAILBILITY ENHANCEMENT OF ARTESUNATE USING
SOLID DISPERSION TECHNIQUES
Shaundarya Kumar *1
, Dr.Dinesh Chandra2
, Rakesh Singh3
, Vijay Kumar Singh4
,
Usha Rai5
, Vaibhav Prakash Srivastava6
*1
Kamala Nehru Institute of Management & Technology ,Sultanpur ,U.P.
2,3,5
Assit. Professor Kamala Nehru Institute of Management & Technology ,Sultanpur ,U.P.
4
Vishveshwarya Institute of Medical Sciences, G. B. Nagar,U.P.
ABSTRACT
In the present work, an attempt has been made to enhance solubility
and dissolution of poorly water soluble drug, Artesunate by preparing
solid dispersions using two hydrophilic polymers namely ,β-
cyclodextrin and PEG 6000.Drug carrier solid dispersions were
prepared by solvent Physical mixing method. Solid dispersions of
Artesunate with β-cyclodextrin and PEG 6000 markedly increase the
solubility and dissolution of solid dispersion compared to the free form
of Artesunate. The results were compared with marketed tablet of
Artesunate. The drug carrier interactions in the solid state were
investigated using saturated solubility studies, FTIR spectroscopy, X-
ray diffraction and differential scanning calorimeter. The developed
formulation overcome and alleviates the drawbacks and limitations of Artesunate sustained
release formulations and could possibility be advantageous in terms of increased
bioavailability of Artesunate.
Keywords: Artesunate, Solid dispersion. Bioavailability enhancement, β-cyclodextrin.
INTRODUCTION
Bioavailability refers to the rate and extent of the drug absorbed in the systemic circulation
after administration. Oral delivery, the most convenient mode of drug administration has
certain limitations, the most important being the low bioavailability of certain drugs. Drugs
having low bioavailability require to be administered at a higher dose as only a small fraction
of the administered dose is absorbed in the systemic circulation and reach the target site. 1
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Article Received on
17 November 2013,
Revised on 20 December
2013,
Accepted on 08 January
2014
*Correspondence for
Author:
Dr. Saundarya kumar
Kamala Nehru Institute of
Management & Technology,
Sultanpur ,U.P., India.

Absolute bioavailability measures the availability of the active drug in systemic
circulationafter non-intravenous administration (i.e., after oral, rectal, transdermal, and
subcutaneous administration). In order to determine absolute bioavailability of a drug, a
pharmacokinetic study must be done to obtain a plasma drug concentration vs time plot for
the drug after both intravenous (i.v.) and non-intravenous administration.
This measures the bioavailability of a certain drug when compared with another formulation
of the same drug, usually an established standard, or through administration via a different
route. When the standard consists of intravenously administered drug, this is known as
absolute bioavailability.2
Artesunate is indicated for the treatment of uncomplicated cases of malaria due to
Plasmodium falciparum strains which are susceptible to artesunate. The most recent official
guidelines on the appropriate use of antimalarial agents and local information on the
prevalence of resistance to antimalarial drugs must be taken into consideration for deciding
on the appropriateness of therapy with Artesunate. According to current WHO
recommendations, oral artesunate should be used as first line therapy for uncomplicated
falciparum malaria in combination with amodiaquine, sulfadoxine+pyrimethamine, or
mefloquine. 4-5
The term solid dispersion refers to a group of solid products consisting of at least two
different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can
be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous
particles (clusters) or in crystalline particles Therefore, based on their molecular
arrangement, six different types of solid dispersions can be distinguished. They are described
in Moreover, certain combinations can be encountered, i.e. in the same sample; some
molecules are present in clusters while some are molecularly dispersed. 6-8
The effect of the
particle size of the drug on their dissolution rates and biological availability was reviewed
comprehensively by Fincher. For drugs whose GI absorption is rate limited by dissolution
reduction of the particle size generally increases the rate of absorption and or total
bioavailability. This commonly occurs for drugs with poor water solubility. For example the
therapeutic dose of Griseofulvin was reduced to 50% by micronization and is also produced a
more constant and reliable blood level. Such enhancement of drug absorption could further be
increased several fold if a micronized product was used. Reduction of particle size can be
easily and directly accomplished by the first four methods and the resultant fine particles may

not produce the expected faster dissolution and absorption. Another inherent disadvantage of
these pure fine powders of poorly soluble drugs is their poor wettability in water. The
significance of the solid dispersion technique was strengthened by the demonstration of
Chiou and Riegelman of the fast and almost complete absorption of the insoluble
Griseofulvin in man and dogs while the ommercial micronized Griseofulvin was
incompletely absorbed (30 – 60 %). They used polyethylene glycol6000 as a dispersion
carrier. The main advantages of using water soluble polymers as carriers are their no toxicity
and general applicability to most drugs. The main advantages of using water –soluble
polymers as carriers are their no toxicity and general applicability to most drugs. 9
Cyclodextrins are bucket-shaped oligosaccharides produced from starch. As a result of their
molecular structure and shape, they possess a unique ability to act as molecular containers by
entrapping guest molecules in their internal cavity. The resulting inclusion complexes offer a
number of potential advantages in pharmaceutical formulations. Cyclodextrins are crystalline,
nonhygroscopic, cyclic oligosaccharides derived from starch. Cyclodextrins are used to form
inclusion complexes with a variety of drug molecules resulting primarily in improvements to
dissolution and bioavailability due to enhanced solubility and improved chemical and
physical stability. 10
Methods employed to improve dissolution rate of drugs
increasing the surface area
a. Micronization or particle size reduction.
b. Use of surfactants (to increase surface area by proper wetting).
c. Solid dispersions using highly water soluble carriers11
Method of preparation of solid dispersion
Sekiguchi et al., (1961) reported the formulation of eutectic mixture that leads to
enhancement of solubility of water soluble drugs and thereby bioavailability.
1. Co-precipitation-Most widely used method in the laboratory. Polymers is dissolved in
water and the guest is added while stirring the Polymer solution. The precipitate can be
collected by decanting, centrifugation or filtration. The precipitate may be washed with small
amount of water or other water miscible solvent such as ethyl alcohol, methanol or acetone
and dried.
12

2. Kneading Technique - Polymer can be added to water as high as 50-60% solids and
stirred. The aqueous phase will be saturated with the Polymer in solution. Guest molecules
will complex with the Polymer in solution and, as the Polymer complex saturates the water
phase, the complex will crystallize or precipitate out of the aqueous phase, and complex can
be collected in the same manner as with the co-precipitation method. 13
3. Dry mixing - some guests can be complexed by simply adding guest to the Polymer and
mixing them together. The amount of mixing time required is variable and depends on the
guest. The method is performed at ambient temperature.
4. Paste complexation - This is a variation of slurry method. Only a small amount of water
is added to form a paste, which is mixed with the Polymer using a mortar and pestle. The
amount of time required is dependent on the guest. The resulting complex can be dried
directly or washed with a small amount of water and collected by filtration and
centrifugation.
14
MATERIALS AND METHODS
Materials
1. Drug – Artesunate
2. β-cyclodextrin
2. Polyethylene glycol 6000.
3. Methanol.
4. Potassium dihydrogen phosphate.
5. Sodium hydroxide.
6. Distilled water.
Instruments
1. Electronic single pan balance.
2. Water bath.
3. Desiccators.
4. Digital tablet dissolution test apparatus –
5. UV spectrophotometer – shimadzu – UV -1700.
7. X-RD (IIT. Ropar)
8.I.R..

PREPARATION OF SOLID COMPLEXES
Complexes of ART & β-CD, ART with β-CD & PEG-6000 were prepared in the molar ratio
of 1:1(on the basis of phase solubility study) by different methods like Physical mixing,
Kneading,and Fusion method.).
Physical Mixture
Physical mixture was prepared by triturating ART & β -CD, ART with β -CD & PEG-6000
together for 30 min in a clean and dry glass mortar until a homogeneous mixture was
obtained. And then was forced through sieve no 100.
Kneading Method
ART & β -CD, ART with β -CD & PEG-6000 was mixed separately in glass mortar along
with water to obtain a homogeneous paste. The drug (either in powder form or as solution
with minimum quantity of methanol) was then slowly added to the paste and the mixture was
triturated for 1 hr. during the process the water content was empirically adjusted to maintain
the consistency of the paste. Methanol was added to assist dissolution of ART during the
process. The paste was dried at room temp., pulverized and forced through sieve no 100.
Fusion Method
ART and β-CD, ART with β-CD & PEG-6000 were thoroughly mixed and placed in a sealed
container with a small amount of water. The contents are heated to about 1000C and then
removed and dried. The mass was then pulverized and forced through sieve no 100. The
composition of solid dispersion shown in table 1. 18-23
Table N. 1. Composition of solid complexes by using ART & β-CD
Type of
formulation
ART:β -CD
(molar ratio)
Solid dispersion
Method
Media
APM 1:1 Physical Mixing ……..
AKW 1:1 Kneading Water
AKM 1:1 Kneading
Methanol +
Water
AFW 1:1 Fusion Water

1. STANDARD CALIBRATION CURVE FOR ARTESUNATE IN PHOPHATE
BUFFER
preparation of phosphate buffer solution -ph 6.8
13.61 grams of potassium dihydrogen phosphate and 3.128 grams of sodium hydroxide were
dissolved in 2 liters of distilled water.
Procedure
100 mg Artesunate pure drug was taken into a 100ml standard flask and dissolved in distilled
water. The volume of stock solution was made up to 100 ml with distilled water. From the
above stock solution, 10 ml was transferred into a 100 ml volumetric flask and volume was
adjusted to 100 ml that corresponded to 100 µg/ml Artesunate in solution. From that solution
different aliquots of 0.2, 0.4, 0.6, 0.8, and 1.0 ml were transferred to 10ml volumetric flask,
volume was adjusted with distilled water, which gave a concentration of 2, 4, 6, 8,10 and 12
µg/ml of final standard solution and absorbance of final standard solution was measured at
251.8 nm.The data are given in table 2. 25-29.
Table. 2: U.V.spectrophotometric data of artesunate
Concentration (ppm) Absorbance*
0 0
1 0.050
2 0.103
3 0.156
4 0.209
5 0.259
6 0.312
7 0.365
8 0.425
9 0.485
10 0.565
RESULTS AND DISCUSSION
PREPARATION OF SOLID DISPERSION
ART & β -CD, ART with β -CD & PEG-6000 was mixed separately in glass mortar along
with water to obtain a homogeneous paste. The drug (either in powder form or as solution
with minimum quantity of methanol) was then slowly added to the paste and the mixture was
triturated for 1 hr. during the process the water content was empirically adjusted to maintain

the consistency of the paste. Methanol was added to assist dissolution of ART during the
process. The paste was dried at room temp., pulverized and forced through sieve no 100.
STANDARD CURVE
The standard curve relating the absorbance and concentration of Artesunate (Table No-2,
Figure No-1) was used to estimate the concentration of Artesunate released from the solid
dispersion formulations and from the marketed samples of Artesunate.
Fig :1. Calibration Curve of Artesunate In Phophate Buffer 7.4
DIFFERENTIAL SCANNING COLORIMETRY(DSC) The DSC thermogram of the drug
depicts a sharp endothermic peak at 161.82° corresponding to the melting transition
temperature of Artesunate.
The DSC thermo gram of Artesunate shown in Fig.2.
MASS SPECTRUM: A fast atomic bombardment mass spectrum (FAB-MS) of ART was
obtained on a JEOL SX-102 spectrometer. The mass spectrum of ART clearly indicates the
exact molecular weight as of ART (Figure 3).
Fig:2. DSC Thermogram of Pure Artesunate

Fig:3. Mass spectra of Artesunate
FOURIER-TRANSFORM INFRARED SPECTROSCOPY
The FTIR spectra were obtained by using an FTIR spectrometer – 430 (JASCO, Japan).The
sample (Artesunate, Polymer) were previously ground and mixed thoroughly with potassium
bromide in the ratio1:1.5 (Sample: KBr) respectively. The scanning range was 4000 to 400
cm-1. FTIR spectrum of pure drug Artesunate & complex shown in fig 4,5.
Fig. 4..FTIR spectrum of pure drug Artesunate
Figure 5.FTIR spectrum of APM (ART with β—CD
complex prepare by physical mixing).

Drug Content
First of all, the actual drug content in each formulation was determined. The results are
reported in Table 3,. As can be seen, all the formulation showed a good agreement between
theoretical and actual drug content. The comparison of drug content of different formulation
shown in fig 6.
Table 3. Drug content of ART+ β-CD complexes (% Drug content)
Formulation Theoretical drug
content in 100mg
Practical drug
content
in 100mg (mean n=3)
% Drug
content
APM 27.64 27.02 97.75
AKW 27.64 26.93 97.43
AKM 27.64 27.06 97.15
ASE 27.64 27.08 97.98
AFU 27.64 27.11 98.08
Figure.6. comparison of % Drug content drug content of different formulation
SATURATION SOLUBILITY OF DIFFERENT FORMULATIONS OF
ARTESUNATE.
The saturation solubility of pure ART and its complexes with β -CD is shown in table 4. The
saturation solubility of pure ART is 11.9µg/ml while the saturation solubility of all other
complex prepared by various methods exhibited dramatic increase in the saturation solubility.
APM and PEG-6000 (complex prepared by physical mixing) showed a lower value for

saturation solubility than that of other complexes, the low saturation solubility can be
attributed to poor complexation efficiency during physical mixing.
Table4. Saturation solubility data of different formulation of Artesunate with β-CD
Formulation Saturation solubility (µg/ml)
Pure ART 11.95 ± 0.84
APM 78.90 ± 2.11
AKW 135.78 ± 2.31
AKM 141.47 ± 2.67
ASE 104.99 ± 2.67
AFU 119.82 ± 2.48
Mean saturation solubility ± SD (n=3)
X-RAY DIFFRACTOMETRY
The X-ray diffractometry (XRD) pattern of Artesunate and its various complexes with β-CD
& ART, β-CD & PEG -6000 are shown fig 7-8 (peak search data). The XRD pattern of
Artesunate has sharp peak at different angle (2θ) higher intensity 6.72 θ, 14.17θ, 18.97 θ,
22.18 θ, 25.85θ show a tripical crystalline pattern showed diffraction peaks with a higher
number of reflections of higher intensity indicating a crystalline structure. The spectrum of β-
CD reveled fewer number of very poor intensity reflections corresponding to inter planner
distance of 9.7, .6.0, 5.7, 4.9,3.3 Å at 57.81, 30.78,41.27,32.05 and 20.270 respectively.
Fig 7. XRD pattern (raw data) of Pure Artesunate

Fig 8. XRD Pattern of APKW (ART with β-CD &PEG-6000 complex prepared by
kneading method employing water as solvent
CHARACTERIZATION OF PREPARED TABLETS.
Table 5. Characterization of prepared tablets of different complexes by using β-CD
Formulation Average wt
(mg)
Thickness
(mm)
Hardness
(Kg/cm2)
Percentage
friability
Disintegration
time (sec)
Pure
Artesunate
200 ± 5.24 3.74 ± 0.08 5.56 ± 0.17 0.632 282
APM 200 ± 7.11 3.72 ± 0.05 5.61 ± 0.18 0.624 260
AKW 200 ± 6.47 3.94 ± 0.04 5.41 ± 0.15 0.645 224
AKM 200 ± 6.71 3.91 ± 0.02 5.35 ± 0.18 0.671 210
ASE 200 ± 5.78 3.81 ± 0.09 5.29 ± 0.13 0.682 296
AFU 200 ± 6.73 3.96 ± 0.11 5.22 ± 0.14 0.667 301
Mean ± S.D.; (n=20) (n=10) (n=10) (n=10)
(n=10)
IN VITRO DRUG RELEASE
Different formulations of ART were compressed into tablets as per the composition given in
table 6. the tablet thickness and hardness were in the range of 3.6-3.8 mm and 5-6 Kg/cm2,
respectively. Fig.9, show in-vitro drug release profile of different formulations of Artesunate
in tablet form. Pure Artesunate was characterized by only 56% drug release within 100 min
in phosphate buffer (pH 7.4) Physical mixtures presented slight improvement in drug release

and saturation solubility this could be attributed to the improved wetability of drug particles
by the physical presence of β-cyclodextrins.
Table.6 : Dissolution profile of different formulation of ART & β-CD in phosphate
buffer 7.4
Time(min)
%DrugReleasefromtheformulations(mean;n=3)
ART APM AKW AKM ASE AFU
0 0 0 0 0 0 0
10 10.52 13.17 32.43 40.43 25.17 28.34
20 15.52 18.22 41.23 48.13 41.23 40.13
30 20.27 26.12 55.12 65.14 55.48 49.24
40 22.4 30.1 65.1 75.24 64.12 58.12
50 26.52 35.23 72.13 82.12 69.4 65.15
60 31.43 40.43 78.24 92.21 72.43 73.23
70 35.54 45.15 82.02 94.1 74.13 76.12
80 38.42 50.13 84.13 96.12 78.55 81.13
90 42.53 55.12 86.31 97.13 80.1 85.41
100 45.53 61.44 88.14 97.85 84.15 90.11
Fig 9, Graph of Dissolution profile of different formulation of ART with β-CD.
Mean dissolution time.
In order to calculate mean dissolution time (MDT) of pure Artesunate, its physical mixture,
and complexes with β-CD, & β-CD with PEG-6000 the mean (n=3) of cumulative drug

release (µg) was used. The obtained values of MDT for all the formulations are presented in
table 7and fig 10.
Table 7. Mean dissolution time of different ART β-CD, & ART β-CD with PEG-6000
complex formulations.
Formulation Mean dissolution time(min)
ART 38.10
APM 34.78
APPM 34.20
AKW 21.52
APKW 18.63
AKM 14.36
APKM 12.84
ASE 28.12
APSE 27.13
AFU 30.92
TPFU 33.43
Fig.10. Mean dissolution time of different ART β-CD, & ART β-CD with PEG-6000
complex formulations
FORMULATION STABILITY STUDY
Based on the result of initial characterization the kneaded formulations (AKM, and APKM)
were thought to be the superior formulations and hence were subjected to accelerated stability
study.

Table. 8. Dissolution data of AKM & APKM during stability study at Different time
intervals.
Time
%DrugReleasefromtheformulations(mean;n=3)
Initial After3months
AKM APKM AKM APKM
0 0.00 0.00 0.00 0.00
10 40.43 40.48 36.38 46.58
20 48.13 48.18 57.84 52.14
30 65.14 65.12 69.13 68.23
40 75.24 74.82 72.42 77.53
50 82.12 81.13 75.10 85.12
60 92.21 90.1 76.23 89.43
70 94.1 93.23 78.12 90.93
80 96.12 95.25 80.92 92.94
90 97.13 97.25 82.71 94.21
100 97.85 98.37 84.24 95.11
Fig. 11. Dissolution profile of ART & APKM during stability study
Table 9. Physical properties of batches kept for stability studies.
BATCH 0 DAYS 30DAYS
DT
(Sec)
FRIABILITY
(%)
ASSAY
(%)
DT
(Sec)
Percentage
friability
ASSAY
(%)
Pure Artesunate 24 0.632 96.34% 24 0.632 97.34%
APPM 29 0.622 103.15% 28 0.622 102.15%
APKW 22 0.641 102.7% 23 0.641 101.7%
APKM 23 0.667 101.4% 99.4%
APSE 22 0.683 98.62& 97.99%
APFU 28 0.665 99.21% 99.21%

DISCUSSION
The phase solubility study showed that the solubility of Artesunate increases linearly as a
function of β-CD and PEG-6000 over the entire concentration range and was characteristic of
the AL type of curve and it suggests that water-soluble complex was formed in solution.
Solubility studies showed a significant, linear increase in the aqueous solubility of the
Artesunate with increasing concentration of β-CD, maximum concentration of β-CD
(15mM/L) so improvements in the saturation solubility of Artesunate.
The complex of Artesunate with β-CD & PEG-6000 prepared successfully by the physical
mixing, kneading, solvent evaporation and fusion methods in the molar ratio of 1:1. This was
confirmed by FTIR and XRD studies. These in all five method employing kneading method
using methanol-water as solvent employing exhibited the fastest and highest in vitro
dissolution rate when compared to the tablet of pure Artesunate, and during stability study
there was very slight decrease in its dissolution profile. Cyclodextrins (CDs) improve
solubility significantly they are still limited in their drug inclusion capacity and retain
disadvantageous processing characteristics for oral dosage forms; the volume of CD
complexes is often much greater than the volume of drug alone, which may severely limit
the types of delivery technologies that may be employed The saturation solubility of the
drug in the freeze-dried complex and spray-dried complex was increased to 29.33±1.08
mg/ml and 28.76±0.56mg/ml respectively A very high increase of the drug dissolution rate
was found in case of freeze-dried and spray-dried product due to the formation of soluble
inclusion complex, amorphisation of the drug and consequently solubility increase and better
wettability.
CONCLUSION
Thus it can be concluded that Artesunate should contain a stabilizing agent to protect its
conversion in lactone form. Here, β-CD and PEG-6000 proved a better stabilizing agent than
buffering agent, which not only increased the solubility of the drug but also acts as a
stabilizer in drug formulation. Thus the complexation of Artesunate has a dual advantage
over the existing formulation. The results of drug content of the physical mixture, kneaded
ternary and Fused complexes are in good agreement with the theoretical value. The kneaded
ternary showed 101.37%±0.12 of drug due to lesser drug loss as compared to the spray dried
ternary which showed drug content of 83.84%±1.11

ACKNOWLEDGEMENT
Words are less to express my deep sense of gratitude to my guide Dr. Dinesh Chandra (HOD)
Department of Pharmaceutics, KNIMT,Sultanpur .I would like to thanks Usha for helping me
each and every time. My research wouldn't have seen the day's light without their constant
motivation.
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Glibenclamide with Gelucire 50/13Department of Pharmaceutics, College of Pharmacy,
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29. Hassan Sadraeia, Golamreza Asghari b, Mostafa Shamsa, b Antidiarrhoeal Action of
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Dicyclomine a Department of Pharmacology, School of Pharmacy and Pharmaceutical
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