Solubility Enhancement of Lumefantrine by Hot Melt Extrusion Process

 

Rakshith Shetty¹, Vaishnavi Tallapaneni², Sreenivasa Reddy M², Nayanabhirama Udupa², Srinivas Mutalik², Vijay Kulkarni*¹, Vinay Rao¹, Aravind Kumar Gurram¹

¹STEER Life India Pvt Ltd, Bengaluru 560058, Karnataka State, India.

²Department of Pharmaceutics, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal 576104, Karnataka State, India

 

ABSTRACT:

Lumefantrine is a BCS class -II drug having a poor aqueous solubility. There is a need for improvement in solubility, in order to enhance the therapeutic efficacy and reduce the dose. Hence in the present work, the solubility of lumefantrine is enhanced by formulating solid dispersions of lumefantrine using a hot melt extrusion process in a twin-screw processor using three different polymers such as Kollidon VA64, Soluplus and HPMC AS at a weight ratio of 1:2, 1:3 and 1:4, processed at different barrel temperatures and screw speeds. The obtained solid dispersions were characterized by differential scanning calorimetry and solubility studies. Solid dispersions prepared with KollidonVA64 and Soluplus showed a clear extrudate indicating a complete amorphous conversion of the lumefantrine at all the three ratios evaluated. Increase in polymer concentration, increased the solubility of the lumefantrine. With Kollidon VA 64 and Soluplus, lumefantrine to polymer ratio of 1:4 showed the highest increase in solubility, compared to that of the pure lumefantrine.

 

 

 

INTRODUCTION:

Administration of dosage form orally is widely preferred. Most of the drugs discovered and which are under developmental stage possess a poor water solubility, due to which these molecules exhibit poor efficacy, as a result of lower bioavailability.(1)

 

Solubility enhancement of poorly water soluble molecules are being done by various methods like nanosizing, co-solvency, cyclodextrin encapsulation,  micellar solubilization, solubility alteration by pH modification etc. (2). But all these are batch processes using organic solvents with multiple unit operations, hence a continuous and a solvent free process like hot melt extrusion was used for the formulation development.

 

 

Extrusion by hot melt process has been used in industries since 1930’s. (3). It was used initially in the processing of rubber, plastic and food. Pharmaceutical industries applied this process in the 1970’s (4). Hot melt extrusion is a process in which the material is exposed to heat and mechanical shear by the elements, leading to conversion  and dispersion of drug in the polymeric matrix (5). The process is used in the development of tablets, capsules, implants etc. A  hot melt extruder consists of  (a) Volumetric/gravimetric feeder which delivers the material to be processed into the extruder processing zone at a desired rate, (b) Screw elements fixed to a shaft, which can be co-rotating or counter rotating, that receives the feed material, which is exposed to heat, and shear leading to phase transformation and kneading followed by extrusion through a die of desired aperture size, fitted at the exit of the extruder and then chopping cooled extrudes using a downstream equipment. (3)

 

Based on the no of screw shafts in the extruder, it is of 2 types: Extruder having a single screw shaft, known as single screw extruder and extruder having two screw shafts, known as twin screw extruder. Generally, co rotating extruders are normally used in processing, which provide a lesser shear compared to counter rotating extruders. Co rotating extruder with removable elements in the screw shaft are generally used, as it gives the flexibility of interchanging the elements to obtain an desired degree of residence time or energy, imparted by usage of various kneading elements in combination with conveying elements.(2) In the present study hot melt extrusion technology is used for the development of solid dispersion of lumefantrine with polymers in a co-rotating twin screw extruder.

 

Lumefantrine is an antimalarial drug, used in the pharmacotherapy of malaria caused by falciparum protozoa through anopheles mosquito, generally administered along with artemether. The strength available in the market is lumefantrine/artemether 120 mg / 20 mg.

 

Malaria is a life threatening disease caused by falciparum parasite (6). This is the reason for major mortalities, especially in African countries.(7). Artemether on oral ingestion is quickly absorbed and attains C_max within two hrs of consumption.  Lumefantrine is a lipophilic compound, whose absorption starts after two hours and C_max reaches at 8 hrs of dosing and should be administered with a high lipid meal, to a get an desirable absorption (8).

 

Lumefantrine is a yellow coloured crystalline powder having a solubility in chloroform, ethyl acetate and dichloromethane with a poor solubility in water.

 

 

Chemical structure of Lumefantrine:

Dosage regimen: Lumefantrine is administered for two days with a maximum of 24 tablets under fed conditions. The marketed brand available is “Coartem” uncoated tablets.(9) But it is known that, during the course of malarial infection, the patient will be unable to administer high amount of meal or any fatty food, leading to decreased efficacy due to malabsorption of lumefantrine. Hence solid dispersions of lumefantrine is developed in this study, to promote food independent absorption.

 

 

 

The simplest approach for solubility enhancement is the dispersion of the drug in the matrix of the polymer (3). Solid dispersion development is a suitable process for overcoming solubility challenges in development of delivery system for drugs having solubility issues like lower solubility with higher permeability and lower solubility with lower permeability. Extrusion by thermal processing is a majorly applied process for the development and manufacturing of dispersions of drug in the polymer as it results in an intimate blending. (10). Solid dispersions are the dosage forms were the active is wetted and dispersed at molecular level in the polymer. There are various types of this dosage form: 1. Eutectics: where the active and the polymeric matrix are both crystalline. 2. Solid solutions: active is in the molecular form within the polymer 3. Glass suspension: It is of 2 types; one in which the active is in crystalline form and the polymer is in amorphous form and the second type is in which both the active and the polymer are in amorphous form. 4. Glass solution: here the molecular form of the active is entrapped within amorphous polymer. For this to occur the drug should possess an inherent miscibility with the polymer. (2)

 

Various studies as per literature, on solubility enhancement of lumefantrine was carried out using a single screw extruder, which required an higher residence time to barrel temperature in order to obtain clear extrudates. (1). This in turn may degrade the drug and also decreases the overall productivity.

 

Hence the present study focuses on enhancing the aqueous solubility of lumefantrine, by formulating it in the form of solid dispersion in a co-rotating twin screw extruder which has a shorter residence time and is a readily scalable.

 

MATERIALS AND METHODS:

Lumefantrine was procured from IPCA labs, Mumbai, India. Kollidon VA 64 and Soluplus was procured from BASF polymers, Mumbai, India. HPMC AS was procured from Shin-Etsu, Japan.

 

Preparation of the physical mixture of Lumefantrine and Polymer:

Lumefantrine was sifted through #60 mesh, polymers were sifted through # 40 mesh. Then lumefantrine and the polymer were blended, followed by co sifting through #40 mesh. The composition of lumefantrine and polymer for each run is as given in table 1.

Table 1: Composition of Lumefantrine and Polymers:

Formulation	Kollidon VA64			Soluplus			HPMC AS
	F1	F2	F3	F4	F5	F6	F7	F8	F9
Weight Ratios	1:2	1:3	1:4	1:2	1:3	1:4	1:2	1:3	1:4
Drug (g)	60	60	60	60	60	60	60	60	60
Polymer (g)	120	180	240	120	180	240	120	180	240

 

 

Preparation of Solid Dispersion:

The blend of lumefantrine and polymer (weight ratio of lumefantrine to polymer is 1:2, 1:3 and 1:4) was feeded into the feed hopper of the twin screw extruder, then the feed hopper was calibrated for the desired feed rate in gm/min. The barrel temperature was set as required, temperature was allowed to stabilize to the set temperature. Screw speed was switched on at a lower speed initially, then the feed rate was gradually increased, with a proportional increase in screw speed and the material was extruded through a 3 mm die, fitted at the exit end of the extruder. The initial material was rejected, followed by collection of the clear extrudes in a SS vessel. Machine and processing conditions as mentioned in table-2 and 3

 

Table 2: Processor description:

Machine	Omicron 10
Manufactured by	Steer engineering Pvt Ltd, Bengaluru.
No of barrels	4 No’s
L/D	24
Feed rate (g/min)	15 Hz (2.54 g/min)
Screw configuration	Conveying elements and Kneading elements.
Die aperture size	3 mm

 

Table 3: Barrel temperature profile:

B4	B3	B2	B1
140 to 160 °C	140 to 160 °C	60 °C	25 °C
Processing zone having Kneading elements		Conveying and Transition zone	Feeding zone

 

Process parameters like torque, power, was recorded for each run and the extrudes were evaluated physically for clarity of dispersion.

 

Processing Conditions:

Barrel temperature, feed rate and screw speed are considered as critical process parameters in a hot melt extrusion process significantly affecting the critical quality attributes of the extrudes. Screw speeds were varied between 300 rpm to 800 rpm and barrel temperature from 140 to 160 ºC and feed rate was kept constant. Torque (Newton meter) and Power (Watts) were monitored in the Human machine interface during each run and clarity of extrudes was considered as a response variable for successful run. Specific mechanical energy (SME) was calculated for the runs using the formula: SME is the amount of energy imparted by motor through the screw shaft on the material being processed:

 

SME (kw.hr/kg) = Power (kw)

Feed rate (kg/hr)

 

Process Optimization:

Extrusion was carried out at a fixed feed rate, using varied barrel temperature and screw speeds for each ratio of lumefantrine and polymer (Kollidon VA 64/Soluplus/ HPMC AS). At a lower barrel temperature, the screw speed was kept lower, which can impart a higher energy on the material being processed and at a high barrel temperature, screw speed was kept higher, which imparts a higher energy input on the material being processed. The ranges are as given in table 4.

 

Table 4: Experimental runs for process optimization of solid dispersion of Lumefantrine with Kollidon VA 64, Soluplus and HPMC AS at different ratios.

Sl. No.	Weight ratio of Lumefantrine: Polymer	Barrel Temperature (⁰C)	Screw speed (rpm)
1	1:2	140 150 160	300 600 800
2	1:3	140 150 160	300 600 800
3	1:4	140 150 160	300 600 800

 

Analytical Method Development:

Preparation of stock solution for lumefantrine

Standard stock solution:

A stock solution containing 1 mg/ml of pure lumefantrine was prepared by dissolving 100 mg of lumefantrine in sufficient amount of methanol and the volume was made up to 100 ml with methanol in a 100 ml volumetric flask.

 

Working standard solution:

1 ml of the stock solution was further diluted to 100 ml with distilled water to obtain a working standard solution containing 10 µg/ml.

 

Determination of λ_max:

The working standard solution was subjected to UV scanning from 200 to 400 nm on UV-Visible spectrophotometer using methanol as blank. The scanning showed that the λ_max for lumefantrine in methanol was 235 nm. All further UV readings were performed at 235 nm. Linearity was observed between 2 to 20 µg/ml.

 

Preparation of sample solution:

Twenty tablets were weighed and powdered. The fine powder, equivalentto12.5mgof lumefantrine, was weighed and transfer redintoa 100 ml volumetric flask and dissolved using distilled water. This mix ture was sonicated for (30min) and then filtered through a 0.45 µm what man filter paper. After filtration, aliquot solutions were prepared by taking 0.1 ml in volumetric flasks and made up to volume with distilled water to yield concentration of lumefantrine in the linearity range. The amount of lumefantrine was calculated from the related linear regression equations of the standard plot.

 

Calculation is done by using the formula of:

 

 

S.A = Sample Absorbance

P = Potency of Lumefantrine

STD.A = Standard Absorbance

STD.CON = Standard Concentration

S.CON = Sample Concentration

 

Evaluation of Solid Dispersions:

a) Differential Scanning Calorimetry:

Thermograms of Lumefantrine were recorded by simultaneous Differential Scanning Calorimeter (Model: Q200, Manufactured by: TA instruments). Each sample was scanned in a hermetic aluminium panat10 ºC/min over the range of 50-200 ºC with an empty aluminium pan used as reference. Samples were heated under nitrogen atmosphere. The flowrate of nitrogen was 50ml/min.

 

 

b) Equilibrium solubility study in distilled water:

100 mg equivalent weight of solid dispersion was weighed in a 25 ml conical flask. 10 ml distilled water was added, the flask was kept on a constant temperature water bath and allowed to shake at 50 rpm for 4 hours. The sample was filtered through 0.8-micron syringe filter, suitably diluted if required and absorbance was measured on UV-visible spectrophotometer at λ_max 235 nm. The quantity of lumefantrine dissolved in water was calculated from the calibration curve.

 

RESULTS AND DISCUSSIONS:

Lumefantrine+ Kollidon VA64 Extrudes

A blend of lumefantrine and Kollidon VA 64 of various ratios were processed at different temperatures and screw speeds. All the trials resulted in a clear extrudesas shown in table-5.

 

Table 5: Effect of screw speed and barrel temperature on the clarity of extrudes and specific mechanical energy for processing of solid dispersion of Lumefantrine with Kollidon VA 64 at various ratios:

Sl. No.	Weight ratio of Lumefantrine: Kollidon VA64	Barrel Temperature (⁰C)	Screw speed (rpm)	Clarity of extrudes	Power (kw)	SME (kw.hr/kg)
1	1:2	140 150 160	300 600 800	Clear Clear Clear	0.022 0.075 0.082	0.144 0.493 0.538
2	1:3	140 150 160	300 600 800	Clear Clear Clear	0.023 0.071 0.084	0.150 0.465 0.551
3	1:4	140 150 160	300 600 800	Clear Clear Clear	0.023 0.071 0.083	0.150 0.466 0.544

Evaluation of Solid Dispersion (SD) with Kollidon VA 64

 

 

Fig 1: Sharp endothermic melting peak of lumefantrine was observed. This indicates the crystalline nature of the drug.

Fig 1A: Glass transition temperature of Kollidon VA 64 was observed between 68 °C to 93 °C, indicating the amorphous nature of the polymer.

Fig 1B: Here the glass transition temperature of Soluplus is between 60 to 80°C, indicating the amorphous nature of the polymer.

 

Fig 1 C: The solid dispersion of lumefantrine with Kollidon VA 64 processed at 160 ºC and 800 rpm screw speed with a weight ratio of 1:3had no endothermic melting peak of drug, indicating amorphous transformation.

Fig 1D: The solid dispersion of lumefantrine with Kollidon VA 64 processed at 140 ºC and 300 rpm screw speed with a weight ratio of 1:3 had no endothermic melting peak of drug, indicating amorphous transformation.

Fig 1 E: The solid dispersion of lumefantrine with Kollidon VA 64 processed at 160 ºC and 800 rpm screw speed with a weight ratio of 1:4 had no endothermic melting peak of drug, indicating amorphous transformation.

Fig 1 F: The solid dispersion of lumefantrine with Kollidon VA 64 processed at 140 ºC and 300 rpm screw speed with a weight ratio of 1:4 had no endothermic melting peak of drug, indicating amorphous transformation.

 

DSC:

DSC studies were performed on lumefantrine and solid dispersions of lumefantrine: Kollidon VA 64 at a weight ratio of 1:3 and 1:4 at a low barrel temperature with low screw speed (low shear) and higher barrel temperature with a higher screw speed (High shear). Due to the presence of kneading elements at low screw speed, there will be a minimal energy imparted on the material being processed and at higher screw speeds, there will be a maximum energy imparted on the material being processed. SD of Lumefantrine and Kollidon VA 64 lead to disappearance of the endothermic peaks. The absence of melting endothermic peak in solid dispersion of lumefantrine with polymer in different ratios indicated
the loss of crystallinity of lumefantrine. DSC thermogram of lumefantrine and polymers is as per fig 1 to 1B and its solid dispersion with Kollidon VA 64 at varied process parameters are as shown in Fig.1C to 1F.

 

Equilibrium solubility study:

The solid dispersions prepared at a similar screw speeds of 300 rpm and at a barrel temperature between 140 to 160 °C was used for the solubility study. This was carried out by measuring the amount of lumefantrine dissolved at various ratios and number of folds enhancement in solubility compared with that of plain lumefantrine as shown in table-6.

 

Table 6: Solubility Data of Lumefantrine with Kollidon VA 64 at varied ratios:

Plain Drug (µg/ml)	Weight ratio of Lumefantrine: Kollidon VA64	Barrel Temperature (rpm)	Amount of drug dissolved (µg/ml)	Number of Folds Enhancement in solubility
0.817	1:4	140 (300) 150 (300) 160 (300)	444 398.51 373.60	543.45 487.77 457.28
	1:3	140 (300) 150 (300) 160 (300)	43.30 38.10 44.60	52.99 46.63 54.59
	1:2	140 (300) 150 (300) 160 (300)	44.237 38.65 35.78	54.14 47.30 43.79

 

The solubility study indicated that Lumefantrine: Kollidon VA 64 at a weight ratio of 1: 4, showed a maximum improvement in solubility, followed by 1:3 and then 1:2.

 

Lumefantrine + Soluplus Extrudes:

A blend of lumefantrine and soluplus of various ratios was processed at different temperatures and screw speeds. All the trials resulted in clear extrudes as shown in table 7.

 

Table 7: Effect of screw speed and barrel temperature on the Clarity of extrudes and specific mechanical energy for processing of solid dispersion of Lumefantrine with Soluplus at various ratios.

Sl. No	Weight ratio of Lumefantrine: Soluplus	Barrel Tempera-ture (°C)	Screw speed (rpm)	Clarity of extrudes	Power (kw)	SME (kw.hr/kg)
1	1:2	140 150 160	300 600 800	Clear Clear Clear	0.023 0.073 0.082	0.151 0.479 0.538
2	1:3	140 150 160	300 600 800	Clear Clear Clear	0.022 0.071 0.085	0.144 0.466 0.557
3	1:4	140 150 160	300 600 800	Clear Clear Clear	0.024 0.074 0.084	0.157 0.485 0.551

 

Evaluation of solid Dispersion (SD) with soluplus:

DSC studies were performed on solid dispersions of lumefantrine: soluplus at a weight ratio of 1:3 and 1:4proportions. SD of lumefantrine and soluplus lead to disappearance of this melting endothermic peak.

 

The absence of melting endothermic peak in solid dispersion of lumefantrine with Soluplus in different ratios indicated the loss of crystal line nature of lumefantrine.

 

DSC thermogram of solid dispersions of lumefantrine with soluplus at various ratios at varied barrel temperatures and screw speeds are as shown in Fig 2A to 2D:

 

Fig. 2A: The solid dispersion of lumefantrine with Soluplus processed at 160°C and 800 rpm screw speed with a weight ratio of 1:3 had no endothermic melting peak of drug indicating amorphous transformation.

Fig2B: The solid dispersion of lumefantrine with Soluplus at 160°C and 800 rpm screw speed with a weight ratio of 1:4 had no endothermic melting peak of drug indicating amorphous transformation.

Fig 2C: The solid dispersion of lumefantrine with Soluplus at 140°C and 300 rpm screw speed with a weight ratio of 1:3 had no endothermic melting peak of drug indicating amorphous transformation.

Fig 2D: DSC thermogram of drug SD with Soluplus 1:4 at 140 °C at 300 rpm, had no endothermic melting peak of drug indicating amorphous transformation.

Table 8: Solubility Data of Lumefantrine with Soluplus:

 

Equilibrium Solubility Study of Lumefantrine with Soluplus:

Equilibrium solubility study of solid dispersion of lumefantrine with soluplus was done and amount of lumefantrine dissolved at various ratios is as shown in Table 8:

 

Equilibrium solubility study of solid dispersion of lumefantrine with soluplus was carried out and number of folds enhancement in solubility compared with plain lumefantrine is as shown in Table 8.

 

The solubility study indicated that lumefantrine: soluplus at a weight ratio of 1: 4, showed a maximum improvement in solubility, followed by 1:3 and 1:2.

 

Lumefantrine + HPMC AS Extrudes:

A blend of lumefantrine and HPMC AS at a weight ratio of 1:2 to 1:4 were processed at different barrel temperatures and screw speeds. Clarity of extrudes is as given in Table 9.

 

Table 9: Effect of screw speed and barrel temperature on the Clarity of extrudes

Sl. No	Weight ratio of Lumefantrine: HPMC AS	Barrel Temperature (°C)	Screw speed (rpm)	Clarity of extrudes
1	1:2	140 150 160	300 600 800	Not clear Not clear Not clear
2	1:3	140 150 160	300 600 800	Not clear Not clear Not clear
3	1:4	140 150 160	300 600 800	Not clear Not clear Not clear

 

Extrusion of lumefantrine with HPMC AS did not result in amorphous solid dispersion at any of the ratios evaluated, hence no further evaluation was carried out.

 

Extrusion with all the polymers like Kollidon VA 64 and Soluplus, irrespective of there ratio with lumefantrine, showed an increase in specific mechanical energy imparted on the material, with an increase in screw speed.

 

 

CONCLUSIONS:

Both Soluplus and Kollidon VA 64 can be preferred polymers for preparation of solid solution of lumefantrine by hot melt extrusion process in a twins crew extruder, at a lumefantrine: polymer weight ratio of 1:4.

 

Concentration of polymer played a significant role in solubility enhancement, with a highest solubility enhancement at a lumefantrine: polymer weight ratio of 1:4.

 

Following process can be further scaled up to a higher diameter twin screw extruder, which can be used as a continuous and economical process for large volume manufacturing of lumefantrine extrudes with polymer, which can be further milled by using downstream zones such as chill roll flaker, then blended with other extra granular ingredients and compressed. Dissolution studies of the compressed tablets can be evaluated. The developed process can be used for the manufacturing of an affordable product for the pharmacotherapy of malaria, epidemic in various parts of the world.

 

ACKNOWLEDGEMENT:

The authors are grateful to Manipal college of Pharmaceutical sciences, Manipal for their facilities

 

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

 

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Received on 22.12.2018          Modified on 19.01.2019

Accepted on 20.02.2019        © RJPT All right reserved