World Journal of Pharmaceutical Research Kathpalia et al

www.wjpr.net Vol 3, Issue 4, 2014.

1244

Kathpalia et al. World Journal of Pharmaceutical Research

DEVELOPMENT AND EVALUATION OF A READY TO USE

ANTIMALARIAL ORAL SUSPENSION

Harsha Kathpalia*, Chetan Phadke

Department of Pharmaceutics, Vivekanand Education Society‟s College of Pharmacy,

HashuAdvani Memorial Complex, Behind Collector Colony, Chembur (E), Mumbai-

400074, India.

ABSTRACT

Some physiologically active agents such as antibiotics, anti malarial

are chemically unstable in water-based oral suspensions. Non-aqueous

suspensions can be produced which are extremely palatable, are ready-

to-use, without any reconstitution and need not be refrigerated to

maintain the potency of the active ingredient and have a longer shelf

life relative to conventional dry syrup formulations. A ready-to-use

anhydrous suspension of a moisture sensitive antimalarial which can

be stored at room temperature was prepared and evaluated for its

organoleptic properties, sedimentation behavior, redispersibility,

moisture content, viscosity, accelerated physical and chemical stability.

The formulations showed improved redispersibility and no caking

tendency. The products exhibited longer shelf-life at ambient

conditions.

KEYWORDS: Anhydrous vehicle, anti malarial, ready-to-use, stability, sweetener,

thickener.

INTRODUCTION

Marketed moisture sensitive antimalarial suspensions are generally available as dry syrups

and before dispensing it to patient, need to be reconstitution with a diluent. After

reconstitution, suspension requires refrigeration to maintain the potency of the medicament(s)

over the recommended duration of treatment. In dry syrup formulation, if powder is diluted

with an inaccurate volume of diluent or if the liquid and dry components are not properly

mixed, then it leads to formation of suspension having non-uniform dosing due to clumping

World Journal of Pharmaceutical Research SJIF Impact Factor 5.045

Volume 3, Issue 4, 1244-1259. Research Article ISSN 2277 – 7105

Article Received on

18 April 2014,

Revised on 14 May 2014,

Accepted on 07 June 2014

*Author for Correspondence

Harsha Kathpalia

Department of Pharmaceutics,

Vivekanand Education

Society‟s College of

Pharmacy, HashuAdvani

Memorial Complex, Behind

Collector Colony, Chembur

(E), Mumbai-400074, India.


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and/or doses which are either super-potent or sub-potent depending upon the amount of

diluent added. Reconstituted suspension is stable only upto 14 days under refrigeration

condition [1, 2]

.

Non-aqueous suspensions can be administered without reconstitution i.e. “ready-to-use”,

pleasant to taste and need not be refrigerated to preserve the strength of the active

ingredient.A ready-to-use suspension has an acceptable shelf life at normal and elevated

temperatures without refrigeration and in addition, has less inter-subject variability[3]

. This is

a viable option for products that may have to be reconstituted where the water supply and

storage facilities are poor. Furthermore, the composition of these suspensions is such that no

special production techniques or packaging components are required. Instead standard filling

equipment and containers such as plastic or glass bottles may be utilized [4]

.

To acquire physical stability is major challenge encountered in developing a good aqueous

suspension [5]

. "The three major issues associated with aqueous suspensions are i) inadequate

dispersion of the particles in the vehicle, ii) settling of the dispersed particles and iii) caking

of these particles in the sediment so as to resist redispersion." These problems can be easily

solved by choosing an edible oil as dispersion vehicle.

The aim of the present study is to furnish a ready-to-use oil based, liquid antimalarial

suspension for oral administration having good shelf life and taste characteristics relative to

conventional dry syrup formulation.

MATERIALS

Lumefantrine was procured from IPCA Labs and Cipla Ltd. Mumbai. Colloidal silicon

dioxide (AEROSIL 200, SYLOID-244FP) was obtained from W. R. Grace &Co. India Pvt

Ltd. Butylatedhydroxylanisole (BHA), Butylatedhydroxyltoluene (BHT), Methyl paraben,

Propyl paraben, Anhydrous citric acid, Menthol were of LR grade quality. Aspartame from

Rubicon Research Pvt Ltd, Acesulfame potassium (SUNETT)from SBS sugar free agency

Pvt Ltd and Monoammoniumglycyrrhizinate (MAGNASWEET-MM100)from Mafco

worldwide corporation were obtained. Medium chain triglyceride (MIGLYOL-812) was

obtained from Subhash chemicals, Pune.


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METHOD

Oil based oral suspensions containing Lumefantrine 120mg/5ml were prepared as given in

the Table 1.

Table 1. Composition of non-aqueous oral suspension

Ingredient Quantity (g/100ml) Role of

Ingredient C1 C2 M1 M2 S1

Lumefantrine 2.4 2.4 2.4 2.4 2.4

Active

Ingredient

Butylatedhydroxyanisole

(BHA) 0.01% 0.01% 0.01% 0.01% 0.01%

Antioxidant

Butylatedhydroxytoluene

(BHT) 0.01% 0.01% 0.01% 0.01% 0.01%

Antioxidant

Anhydrous citric acid 0.01% 0.01% 0.01% 0.01% 0.01% Antioxidant

Methyl paraben 0.18% 0.18% 0.18% 0.18% 0.18% Preservative

Propyl paraben 0.02% 0.02% 0.02% 0.02% 0.02% Preservative

Colloidal silicon dioxide

(Aerosil-200) 1.5 - 1 - -

Viscosity

builder


(Syloid-244FP) - 2 - 2.5 2

Viscosity

builder

Aspartame 1 1 1 1 1 Sweetener

Acesulfame potassium (Sunett) 0.5 0.5 0.5 0.5 0.5 Sweetener

Monoammoniumglycyrrhizinate

(Magnasweet-MM100) 0.05% 0.05% 0.05% 0.05% 0.05%

Flavour and

sweetness

enhancer

Menthol 0.2 0.2 0.2 0.2 0.2

Taste masking

agent

Virgin coconut oil q.s.

100ml

q.s.

100ml - - -

Vehicle

Medium chain triglyceride

(Miglyol-812) - -

q.s.

100ml

q.s.

100ml -

Vehicle

Refined sunflower oil - - - -

q.s.

100ml

Vehicle

Method of preparation of suspension

1. All the antioxidants and preservatives were dissolved in little quantity of oil under

stirring.

2. In the above mixture, viscosity builder was added under stirring till it was dispersed fully.

3. The sweeteners and taste masking agent were added to the above dispersion and the

resulting dispersion was triturated.

4. Then, the drug was taken in the mortar and little quantity of the triturated dispersion was

added to it slowly with attrition until uniform dispersion was obtained.

5. The final volume was made up with the oil.


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Evaluation[1, 2]

Organoleptic properties

The suspension was evaluated for the general appearance, odor and taste.

Sedimentation Volume

Sedimentation volume (Vs) of the formulation was determined using following formula.

Where,

Hu = ultimate height of the sediment

Ho = initial height of the total suspension.

The height of the sediment was noted at particular time intervals. The Hu/Ho ratios were

obtained and plotted on Y-axis with time on X-axis. Formulations with different grades of

colloidal silicon dioxide at different concentrations were evaluated for the sedimentation

behavior.

Particle Size

Particle size determination was carried out using optical microscopy.

The particle size of the suspended active substance can greatly in fluences properties of oral

suspension.

Ease of redispersibility as such and after freeze-thaw cycling [6]

Twenty milliliter suspension samples were subjected to 3 cycles of 40C & 30

0C each of 24

hours and studied for their physical instability like caking.

The suspension was allowed to settle in a stoppered measuring cylinder. The cylinder was

inverted through 1800 and number of inversions necessary to restore a homogeneous

suspension was determined. If the homogeneity of the suspension was attained in one

inversion, then the suspension was considered 100% easily redispersible. Every additional

inversion decreases the percentage of ease of redispersibility by 5%.

Rheological studies [7]

A Brookfield digital rotational viscometer was used to measure the viscosity of the

suspension in centipoise.Viscosities were determined in triplicate at ambient temperature.

Speed ramp test: The spindle (spindle no. LV 63) was rotated in the suspension at increasing

shear rates i.e. 10, 20, 30, 50, 60 and 100rpm. At each speed, the corresponding dial reading


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was noted. The speed was then lowered gradually and viscosities were again noted and the

conclusion was drawn from the graph.

Time sensitivity test: The suspensions were studied for change in viscosity with time at a

fixed rpm. The spindle (spindle no. LV 63) was rotated at a fixed rpm in the suspension for a

period of 30 minutes. At each specific time interval, the corresponding dial reading was

noted. Graph of log viscosity Vs time was plotted and conclusion was drawn from the graph.

Moisture content determination by Karl Fischer titrimetry

The water content of the suspension was determined by Karl Fischer titrimetry (Automatic

Potentiometric Titrator, AT-38C, Spectralab).

Assay[8]

An assay was performed on HPLC (Shimadzu-DGU/20A5/Proximal degassor, HIQSIL C8

column 150 x 4.6 mm, 5µm) as per authorized USP salmous standard version 1 for

determining the content of Lumefantrine.

5gms of suspension was weighed in 200 ml volumetric flask; to it 20 ml of 10%w/v

orthophosphoric acid was added and sonicated for 25 minutes. Then, 120 ml of acetonitrile

was added and sonicated for further 20 minutes. It was allowed to cool at room temperature

and diluted up to 200 ml with acetonitrile. Solution was filtered through membrane filter

(GF/C) and analyzed by HPLC method.

Chromatographic conditions

Parameters Specifications

Column Waters symmetry C18 (150mm x 4.6 mm)

Mobile phase composition Buffer: Acetonitrile (30:70)

Flow rate 1.0 ml/min

Injection volume 20µl

Detector wavelength 380 nm

Run time 8 minutes

In-vitro dissolution test[8]

The dissolution studies were performed using a US Pharmacopeia XXXIII type II dissolution

test apparatus. The sample equivalent to 120mg Lumefantrine was placed in each of the

dissolution vessels containing 1000 ml of dissolution media maintained at 37.0±0.5°C and

stirred at 100 rpm. A 5ml aliquot was withdrawn from the dissolution medium at

predetermined intervals of 15, 30 and 45 minutes period. Every time the sample withdrawn


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was replaced by fresh dissolution medium maintained at the same temperature. The sample

removed was filtered, diluted and analyzed by measuring the absorbance using a

spectrophotometer (UV 150-02, Shimadzu Corporation, Kyoto, Japan) at wavelength 342nm

after suitable dilution. Amount of drug dissolved at various time intervals was calculated for

all the formulations. According to the Authorized USP SALMOUS standard version 1 of

Artemether and Lumefantrine for oral suspension, 60% of the amount of Lumefantrine

should dissolve in 40 minutes.

i) Dissolution rate study in official dissolution media

Dissolution study was carried out in 1%w/v Benzalkonium chloride (BKC) in 1000ml of

0.1N hydrochloric acid (HCl).

ii) Dissolution rate study in unofficial dissolution media[9]

Dissolution study was carried out in 2%w/v Myrj-52 (Polyethyeneglycol-40-stearate) in

1000ml of 0.005M HCl.

iii) Dissolution rate study in Bio-relevant media

1 dose (53.6 gms) of Ensure nutritional powder (Abbott Laboratories) was dissolved in

1000ml of 1%w/v Benzalkonium chloride solution containing 0.1N HCl. The drug was

extracted in chloroform and then analyzed at 342nm using UV-Vis spectrophotometer.

Stability Studies

Stability of the selected formulation was monitored at 400C/75%RH and 25

0C/60%RH for a

period of three months in amber colored glass bottles with screw cap. The formulation was

visually inspected for appearance, sedimentation volume, redispersibility and evaluated for

viscosity, particle size, moisture content, drug content and in-vitro dissolution study.

RESULTS AND DISCUSSION

Results of evaluation tests of Lumefantrine oil based suspensions are shown in Table2.

Table2. Evaluation results of physico-chemical studies

Parameters

Evaluated M1 M2 C1 C2 S1

Appearance Greenish

yellow

viscous

liquid

Greenish

yellow

viscous

liquid

Greenish

yellow

viscous

liquid

Greenish

yellow

viscous

liquid

Slightly

greenish

yellow viscous

liquid

Odor No odor No odor

Smell of

coconut oil

Smell of

coconut oil

Smell of

sunflower oil


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Taste and

Palatability

Sweet,

palatable

Sweet,

palatable

Sweet,

palatable

Sweet,

palatable

Sweet,

palatable

Sedimentation

Volume (After

24hrs)

0.85 0.9 0.9 0.85 0.8

Median Particle

size (μm) 37.32 21.58 29.62 27.70 26.13

Redispersibility

(%) as such 100 100 90 95 100

Redispersibility

after freeze-thaw

cycling

95 95 80 90 90

Viscosity in cP

(Spindle no. 63,

at 100rpm)

199 238 431 175 189

Moisture content

(%) 0.195 0.24 0.356 0.296 0.358

The prepared formulations of Lumefantrine oil based suspension were found to possess an

excellent redispersibility property with optimum particle size. Sedimentation studies showed

that the sedimentation volume of all formulations is close to 1, which indicated that the

formulations were optimum and acceptable. The viscosity of all the formulations was such

that it would be easily pourable from the container and also showed a shear thinning effect.

Sedimentation volume

Figure 1:Comparative sedimentation rate of suspensions

The Hu/Ho ratios were calculated and graph of sedimentation rate Vs time was plotted for

each formulation. Graph at time zero starts at 1.0, with the curve then gradually sloping


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downward to the right as time proceeds. The formulation producing least slope values were

considered to have good suspendibility.

The formulations C1 and M2 were found to have good sedimentation but, viscous in nature

and less pourable. Thus, the formulations M1 and C2 were found to have satisfactory

suspendibility.

Rheological studies

Figure 2: Time sensitivity test of suspensions

Figure 3: Speed ramp test of suspensions

Speed ramp test and Time sensitivity test can help in determining the flow behavior of the

suspension on storage and on shaking.

In speed ramp test, if the upward-curve and downward-curve overlap the fluid is time-

independent. If they don't, the fluid is time dependent. If the upward curve indicates a higher

viscosity than the downward curve, the fluid is thixotropic. If the upward curve indicates


1252


lower viscosity than the downward curve, the fluid is rheopectic. Formulations M1, C2 were

showed time dependent behavior and thixotropic nature. Since, there was a decrease in

viscosity with increasing shear rate; it indicated pseudoplastic nature of suspension. In time

sensitivity test, if there is a change in fluid's viscosity over time, it indicates time-dependent

behavior of the suspension. If there is decrease in viscosity, it indicates thixotropy andif there

is increase in viscosity, it indicates rheopexy. Formulations M1, M2 and C2 showed time-

dependent behavior and thixotropic nature.

From graph, it was concluded that formulations M1, M2 and C2 have thixotropic and

pseudoplastic nature which is desirable for a good suspension.

Moisture content analysis

The initial moisture content of all formulations is given in Table2. Since the all suspensions

contains less than about 0.5%w/v moisture, they can be termed as „anhydrous‟.

Assay

Assay results of Lumefantrine in selected formulations were listed in Table 3.

Table 3. Assay of Lumefantrine in selected formulations

Sr.

No. Formulations

Lumefantrine

(%)

1 M1 96.16

2 C2 98.14

3 M2 96.41

The assay values of Lumefantrine in selected formulations complied with the acceptance

criteria for assay given in the USP specification which is 95% to 105% of Lumefantrine.

In-vitro dissolution rate study

i) Dissolution rate profile of Lumefantrine

Figure4:Comparative dissolution profile of Lumefantrine in suspensions


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Dissolution profile of Lumefantrine in all formulations failed to comply with USP

specifications.

Probable reasons for poor dissolution rate could be-

1) Floating of sample on surface of dissolution media i.e. improper dispersion of sample into

the dissolution media;

2) Drug has poor affinity to aqueous dissolution media.

2%w/v Myrj-52 solution and Biorelevent dissolution media were also tried to check

dissolution rate of selected formulations. Since, formulation M1 showed better dissolution

result compared to others. Hence, this formulation was further studied.

ii) Dissolution rate study in unofficial dissolution media and Bio-relevant media

mimicking fed state

Figure5:Comparative dissolution profile of formulation M1 in 2%w/v Myrj dissolution

media and Biorelevent dissolution media

Dissolution rate of Lumefantrine in 2%w/v Myrj-52 solution failed to comply with USP

specifications and dissolution rate of Lumefantrine was same as official media. Dissolution

rate of formulation M1 for Lumefantrine in Biorelevent media (Ensure dissolution media)

showed significant improvement compared with official dissolution media and 2%w/v Myrj-

52 solution. Also, it complied with USP dissolution specification.

Therefore, on basis of dissolution studies carried out in unofficial dissolution media and

Biorelevent dissolution media, it was concluded that official dissolution conditions could be

inappropriate for dissolution study of Lumefantrine oil based suspensions.


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Stability Studies

Table 4. Stability study data of selected formulation M1of Lumefantrine suspension at

the end of 3 months interval

Test parameters Initial 25°C ± 60%RH 40°C ± 75%RH

Appearance Yellowish green,

pourable liquid

Yellowish green,

pourable liquid

Yellowish green,

pourable liquid

Taste and Palatability Sweet, palatable Sweet, palatable Sweet, palatable

Odor No smell No smell Slight smell

Sedimentation rate

(After 24 hours) 0.85 0.95 0.95

Particle size (μm) 37.32 53.18 60.29

Redispersibility as such (%) 100 95 90

Redispersibility after freeze-

thaw cycling (%) 95 90 85

Viscosity (cP) 199 234 500

Moisture content (%) 0.195 0.349 0.413

Assay (%) Lumefantrine 96.16 95.44 95.37

In-vitro dissolution rate (%)

in USP dissolution media 52.28 50.17 49.99

There was change in particle size at the end of 3 months but it was within acceptable range. A

significant increase in viscosity at accelerated temperature was observed on storage, but after

shaking it showed shear thinning effect. The drug content and moisture content were found to

be within limits throughout 3 months interval at both the conditions studied.There was no

significant physico-chemical change observed during accelerated stability studies.

FIGURES

Figure 1:Comparative sedimentation rate of suspensions


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Figure 2: Time sensitivity test of suspensions

Figure 3: Speed ramp test of suspensions

Figure 4:Comparative dissolution profile of Lumefantrine in suspensions


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Figure 5:Comparative dissolution profile of formulation M1 in 2%w/v Myrj dissolution

media and Biorelevent dissolution media

TABLES

Table 1. Composition of non-aqueous oral suspension

Ingredient Quantity (g/100ml) Role of

Ingredient C1 C2 M1 M2 S1

Lumefantrine 2.4 2.4 2.4 2.4 2.4

Active

Ingredient

Butylatedhydroxyanisole

(BHA) 0.01% 0.01% 0.01% 0.01% 0.01% Antioxidant

Butylatedhydroxytoluene

(BHT) 0.01% 0.01% 0.01% 0.01% 0.01% Antioxidant

Anhydrous citric acid 0.01% 0.01% 0.01% 0.01% 0.01% Antioxidant

Methyl paraben 0.18% 0.18% 0.18% 0.18% 0.18% Preservative

Propyl paraben 0.02% 0.02% 0.02% 0.02% 0.02% Preservative


(Aerosil-200) 1.5 - 1 - -

Viscosity

builder


(Syloid-244FP) - 2 - 2.5 2

Viscosity

builder

Aspartame 1 1 1 1 1 Sweetener

Acesulfame potassium (Sunett) 0.5 0.5 0.5 0.5 0.5 Sweetener

Monoammoniumglycyrrhizinate

(Magnasweet-MM100) 0.05% 0.05% 0.05% 0.05% 0.05%

Flavour and

sweetness

enhancer

Menthol

0.2 0.2 0.2 0.2 0.2

Taste

masking

agent

Virgin coconut oil q.s.

100ml

q.s.

100ml - - - Vehicle

Medium chain triglyceride

(Miglyol-812) - -

q.s.

100ml

q.s.

100ml - Vehicle

Refined sunflower oil - - - -

q.s.

100ml Vehicle


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Table2. Evaluation results of physico-chemical studies

Parameters

Evaluated M1 M2 C1 C2 S1

Appearance Greenish

yellow

viscous

liquid

Greenish

yellow

viscous

liquid

Greenish

yellow

viscous

liquid

Greenish

yellow

viscous

liquid

Slightly

greenish

yellow

viscous liquid

Odor No odour No odour

Smell of

coconut oil

Smell of

coconut oil

Smell of

sunflower oil

Taste and

Palatability

Sweet,

palatable

Sweet,

palatable

Sweet,

palatable

Sweet,

palatable

Sweet,

palatable

Sedimentation

Volume (After

24hrs)

0.85 0.9 0.9 0.85 0.8

Median Particle

size (μm) 37.32 21.58 29.62 27.70 26.13

Redispersibility

(%) as such 100 100 90 95 100

Redispersibility

after freeze-thaw

cycling

95 95 80 90 90

Viscosity

(Spindle no. 63,

at 100rpm)

199 238 431 175 189

Moisture content

(%) 0.195 0.24 0.356 0.296 0.358

Table 3. Assay of Lumefantrine in selected formulations

Sr.

No. Formulations

Lumefantrine

(%)

1 M1 96.16

2 C2 98.14

3 M2 96.41

Table 4. Stability study data of selected formulation M1 of Lumefantrine suspension at

the end of 3 months interval

Test parameters Initial 25°C ± 60%RH 40°C ± 75%RH

Appearance Yellowish green,

pourable liquid

Yellowish green,

pourable liquid

Yellowish green,

pourable liquid

Taste and Palatability Sweet, palatable Sweet, palatable Sweet, palatable

Odor No smell No smell Slight smell

Sedimentation rate

(After 24 hours) 0.85 0.95 0.95

Particle size (μm) 37.32 53.18 60.29

Redispersibility as such (%) 100 95 90

Redispersibility after freeze-

thaw cycling (%) 95 90 85


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Viscosity (cP) 199 234 500

Moisture content (%) 0.195 0.349 0.413

Assay (%) Lumefantrine 96.16 95.44 95.37

In-vitro dissolution rate (%)

in USP dissolution media 52.28 50.17 49.99

CONCLUSION

Improved suspend ibility and redispers ibility results in an improved product because less

shaking of the suspension is required before dosing and allows the product to have a longer

shelf-life. Since, the moisture sensitive drug in the oily vehicle shows significantly improved

stability in the ready-to-use suspension form as it prevents hydrolysis of the drug. Such

ready-to-use suspension is very suitable in conditions as in remote areas and in the third

world countries where the people suffering from malaria are large in numbers and illiterate

people cannot understand the direction for use of dry syrups requiring reconstitution and

storage at refrigeration condition.

The oil used in the non-aqueous suspension may improve the absorption of Lumefantrine in-

vivo apparently due to digestion of the oil and subsequent solubilization of the drug. The oil

may also facilitate the transport of Lumefantrine across the intestinal membrane10

. Further

study is needed to optimize dissolution media mimicking the in-vivo fed conditions for oil

based formulations, since Lumefantrine is orally absorbed lipophilic antimalarial drug with

less bioavailability and its absorption is enhanced in the presence of food.

ACKNOWLEDGEMENT

We are thankful to principal of VES College of Pharmacy, Chembur, Mumbai for providing

the facilities to carry out this work and also thankful to IPCA Lab. and Cipla Ltd. for

providing Lumefantrine.I am grateful to University Grant Commission for granting me a

Junior Research fellowship for the project.

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ready to use paediatric antibiotic suspension. Int J Advances Pharm Nanotech

2011;1(2):71–7.


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8. Google. Authorized USP SALMOUS standard version 1, Lumefantrine and artemether

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World Journal of Pharmaceutical Research Kathpalia et al