FORMULATION, EVALUATION AND CHARACTERIZATION OF LUMEFANTRINE Ã¢â‚¬â€œ PEG BASED SOLID DISPERSION

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www.wjpr.net Vol 5, Issue 7, 2016.

68

FORMULATION, EVALUATION AND CHARACTERIZATION OF

LUMEFANTRINE – PEG BASED SOLID DISPERSION

Calister E. Ugwu, Nicholas C Obitte and Oluchi B Madu

Department of Pharmaceutical Technology and Industrial Pharmacy, University of Nigeria,

Nsukka, 410001, Nigeria.

ABSTRACT

Poor aqueous solubility of drugs presents one of the major challenges

to be tackled in order to improved oral bioavailability of some drugs.

Lumefantrine is one of such drug with solubility and permeability

challenges. Fusion method was used in preparing lumefantrine PEG

solid dispersion. Different drug: carrier ratios (1:1, 1:2 and 1:3) were

used. Solubility study of the drug was carried out. The following

evaluation studies were done: percentage yield, loading efficiency,

micromeritics properties, in vitro release profile. Then, characterized

using differential scanning calorimetry (DSC) and wide angle x-ray

diffraction (WAXD). The result showed that lumefantrine showed

highest solubility in PEG 6000, Kollidon® 12 PF and kolliphor® HS 15 as 98.36 ± 0.03, 96. 99 ± 0. 01 and 95.76 ± 0.11 mg/ ml respectively. The batch Pk17 had the

highest loading efficiency (L.E) of 88.20 ± 0.22 %. There was significant variation (p < 0.5)

in the L.E of SDs formulation (Pk 10 – 21) and (P1 – 9) without Kollidon® 12 PF. This variation might be due to high solubilizing capacity of Kollidon® 12 PF. The batch Pk17 also exhibited the highest release profile amomg the batches. The DSC and WAXD results also

showed less crystalline products with higher solubilization potential and also characterized

the formulation as a eutectic solid dispersion. Lumenfantrine – PEG loaded solid dispersion

with Kollidon 12 PF had an improvement on the solubility and dissolution rate of the drug

with potential inhibition of crystal formation.

KEYWORDS: lumefantrine, PEG 6000, Kollidon® 12 PF, Solid dispersion.

Volume 5, Issue 7, 68-86. Research Article ISSN 2277– 7105

*Corresponding Author Calister Ugwu

Department of

Pharmaceutical Technology

and Industrial Pharmacy,

University of Nigeria,

Nsukka, 410001, Nigeria. Article Received on 30 April 2016,

Revised on 20 May 2016, Accepted on 11 June 2016

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69 INTRODUCTION

Poor aqueous solubility of drugs presents one of the major challenges to be tackled in order to

improve bioavailability of some drugs. Dissolution profile of drug is an important factor to

determine how bioavailable the drug will be in vivoly. An oral bioavailability of poorly water

soluble drugs (PWSDs) depends mainly on the solubility of such drug.[1-4] Researchers have been making efforts to improve the dissolution rate of the PWSDs using different approaches.

Many techniques have been reported to improve the solubility of PWSDs such as the use of

adsorbent,[5,6] hydrotropes and co solvent,[7] surfactants,[8] liquid compacts,[9] co-precipitate,[10] interactive mixtures,[11] fast releasing microparticles,[12] solid dispersion,[13,14] complexation with cyclodextrin.[15,16] Solid dispersion (S.D) is one of the excellent means of enhancing drug dissolution rate and bioavailability of poorly aqueous drug. Solid dispersion

is a dispersion of one or more active ingredients in an inner carrier or matrix in solid state

prepared by different methods.[17] This may produce either crystalline or amorphous state formulation. The drug can be dispersed molecularly in amorphous or in crystalline materials.

SD improves drug solubility by the various mechanisms: by reducing the particle size, by

increasing porosity, by converting the crystalline forms of drug into amorphous form, etc.

Two basic classifications of solid dispersion (SD) are base on molecular arrangement

(eutectics, solid solution, micro fine crystalline matrix)[18,19] and secondly, based on carrier matrix used such as first, second and third generations.[20] When drug and polymer are miscible in molten form, the mixture that resulted is called a eutectic mixture. Moreover, in a

eutectic mixture, the melting point of the mixture is usually lower than the melting point of

the carrier in eutectic state where both the drug and carrier subsist in finely divided form

which provides higher surface area and enhanced dissolution rate of the drug. Some

substances have been proved to generate eutectic composition in order to improve dissolution

rates of PWSDs such substances include PEG, urea, and polyoxyethylene - polyoxypropylene

(Pluronic).[21]

Polyethylene glycol (PEG) is a polymer with low melting point, low toxicity, low

hydrophobicity and broad drug compatibility.[14,21,22–25] It is a polymer of oxidized ethylene. And it is usually transparent or white solid. Dispersion of PWSDs in PEG creates

hydrophilicity which will enhance the bioavailability of the drug. The uses of PEG as a

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70 nifedipine: PEG carrier solid dispersion.[27] PEGs of higher molecular grades (1500 - 20000) are used in SDs.[21] PEG is hydrophilic though its solubility in water decreases with increase in molecular weight and also has good solubility in some organic solvents. PEG 6000 has

also been reported to enhance the solubility and dissolution of etodolac by melting method.[28] PEG improves wettability of PWSDs using its amphipathic properties.[29] It can also alter melting point by adjusting the molecular weight. This means that when an adequate

molecular weight of PEG is selected, a lower melting point solid dispersion will be obtained.

Surfactants can be incorporated to enhance the miscibility between drug and polymer or to

inhibit drug crystallization during storage.[30]

Kollidon 12 PF is a water-soluble vinylpyrrolidone and vinyl acetate copolymer containing

the two components in a ratio of 6: 4. A substance containing both hydrophobic and

hydrophilic substance will improve surface activity of poor aqueous drug, controls solubility

barriers leading to enhance dissolution and improve absorption and bioavailability of poorly

water soluble drugs. Also, its vinyl acetate component, which is more hydrophobic, provides

less brittle films. This gives the product its favourable properties as a soluble binder and

film-forming agent, particularly for solid dosage forms. It improves solubility, prevents crystal

growth on the process of dilution when in contact with fluid, accelerate disintegration and

dissolution rate and give immediate release matrix of the drug.

Lumefantrine (lum) being a class IV agent in BCS has a serious challenge of poor solubility

and permeability. Solubility is the chief determinant of oral bioavailability and permeability.

Therefore, presentation of the drug in a eutectic or monotectic mixture will uniformly

increase the surface activity which might eliminates the impermeability stubbornness of the

drug and the synergistic solubilization by the excipients will equally improve dissolution.

This will be supported by the fact that gastrointestinal system has hydrophobic membrane

and lumefantrine, a PWSD, being molecularly dispersed in an amphipathic carrier will

enhance its penetration through the lipophilic membrane with ease. The dissolution rate of

solid dispersion continuously may tend to depreciate on aging or storage.[31] The formulation of lumefantrine SD in the presence of Kollidon 12 PF will inhibit crystal growth thereby

enhancing physical stability of the formulation on storage with improve dissolution rate. The

present research work was to formulate a eutectic mixture with less crystallinity and

improved molecular dispersion of drug so as to enhance physical stability, solubility,

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71 MATERIALS AND METHODS

Lumefantrine (CAS71963-77-4 Hangzhou Dayangchem co., Ltd, free gift); PEG 6000

(Qualikens, India); kolliphor® HS 15, kollidon® 12 PF (Povidone K 12, Eur., USP) and Kolliphor® EL (as free gift from BASF). All other reagents were of analytical grade.

Solubility studies

Different carrier and excipients were screened for solubilization of lumefantrine by saturation

solubility method. The solubility of lumefantrine in aqueous medium, kolliphor HS 15®, polyethylene glycol 6000, kollidon® 12 PF and kolliphor® EL was determined by dissolving excess amount of lumefantrine in 3 ml of each of the selected excipients in a test tube. The

test tubes were shaken at time intervals for 24 h under 25 ± 1o C. The supernatants were taken and assayed for lumefantrine content using UV/VIS spectrophotometer (Spectrumlab, 752s,

UK).

Preparation of lumefantrine solid dispersion by Fusion method

An 80 mg lumefantrine was accurately weighed and loaded in different lumefantrine: PEG

6000 ratios of 1:1, 1:2, and 1:3 as shown in Table 1. The drug was added in a crucible and

heated on an electric plate until it melted before the addition of the carrier, PEG 6000 and

other excipients. The molten mixtures (P1-P9 and Pk10 - 18) were cooled in an ice bath and

the solid mass was allowed to dry completely for some days in a calcium chloride desiccator.

The dried mass was crushed using a mortar and pestle, and passed through sieve of 52 mm

aperture size. [32-35] The yields of the batches were noted and percentage yield calculated. The physical mixture solid dispersions were also prepared by mixing all the excipients and drug

together at the same ratio in a mortar and pestle, pulverized and sieved using the same sieve

aperture. It was noted as batches Pk19-21. Then, stored in an airtight container and placed in

a desiccator for further use.

Table 1: Formula of lumefantrine- loaded solid dispersion by fusion and physical mixture method

Batches Lumefantrine PEG 6000 Kolliphor® HS 15 kolliphor® EL Kolliphon® 12 PF

P1 1 1

P2 1 2

P3 1 3

P4 1 1 0.5

P5 1 2 0.5

P6 1 3 0.5

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72

P8 1 2 0.5

P9 1 3 0.5

Pk10 1 1 0.5 1

Pk11 1 2 0.5 1

Pk12 1 3 0.5 1

Pk13 1 1 0.5 1

Pk14 1 2 0.5 1

Pk15 1 3 0.5 1

Pk16 1 1 0.5 0.5 1

Pk17 1 2 0.5 0.5 1

Pk18 1 3 0.5 0.5 1

Pk19 1 1 0.5 0.5 1

Pk20 1 2 0.5 0.5 1

Pk21 1 3 0.5 0.5 1

Percentage yield

Percentage practical yield is calculated to know the percent yield or efficiency of any

method.[36] The percentage yield is calculated as the ratio of the mass of the product obtained at the end of the process and the mass of initial substances added which included the drug and

the carrier as shown in equation 1.

Percentage yield (%) = ………... eq 1

Flow properties

The following micromeritics properties were carried out according to the following authors in

triplicate form.[37-40]

Bulk and tapped density

A 2 g of each of the samples was weighed out and placed in a 10 ml graduated cylinder. The

volume occupied by the powder was noted and recorded as the bulk volume. The bulk density

was obtained by dividing the mass of the powdered samples weighed out by the bulk volume

as seen in equation 2.

Bulk density = ……… eq 2

The cylinder was tapped on a wooden platform by dropping the cylinder from a height of one

inch at 2 sec interval until there was no change in volume. This volume was taken as the

tapped volume. The tapped density was calculated from equation 3.

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73 Flow rate and angle of repose

A funnel was properly clamped on the retort stand. The various samples with known weight

were gradually placed into the funnel with the orifice of the funnel closed. Upon opening the

orifice, the time it took for the entire powder sample in the funnel to flow out through the

orifice was noted. The height and radius of the powder heap was determined. This was done

in triplicate to get the mean flow rate (g/s) and angle of repose in degree (o).

The flow rate of powder (g/s) = ………... eq 4

The angle of repose (θ) = tan-1

………. eq 5

Compressibility index and Hausner’s quotient

Compressibility index and Hausner’s Quotient were calculated as,

Carr’s Index (%) = ……….eq 7

Hausner’s quotient = ………. eq 8

Determination of loading efficiency

An equivalent of 80 mg of lumefantrine was weighed out from each of the batches and placed

in a beaker containing 10 ml of methanolic HCL and stirred to dissolve the solid dispersion.

The volume was then made up to 100 ml with methanolic HCL and thoroughly mixed. The

resulting solution was filtered and analyzed spectrophotometrically at a wavelength of 335

nm using a UV spectrophotometer (Spectrumlab 752s, UK). This was done in triplicate. The

methanolic- HCL was used as blank. The loading efficiency (%) was calculated using the

following formula.

Loading efficiency = x ………. eq 9

In vitro release studies

The release studies of the drug were carried out with batches P5, Pk17, Pk20 and pure

lumefantrine were studied in simulated intestinal fluid, SIF, (pH, 6.8), and simulated gastric

fluid, SGF, (pH, 1.2). The USP paddle method was adopted using 900 ml of the dissolution

medium maintained at temperature of 37 ± 1o C set at 100 rpm. A known quantity (equivalent of 80 mg) of lumefantrine solid dispersion was filled into a hard gelatin capsule and dropped

into the dissolution medium. A 5 ml aliquot of the dissolution medium was collected at the

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74 set at same condition was added to replace the withdrawn sample so as to maintain a constant

volume throughout the experiment. The collected samples of the released medium were

analyzed at a wavelength of 335 nm using UV spectrophotometer (spectrumlab 752s, UK).

Differential scanning calorimetry (DSC).

Melting transitions and changes in heat capacity of pure lumefantrine, the excipients and

Batch Pk17 were determined using a differential scanning calorimeter (Netzsch DSC 204 F1,

Geratebau, GmbH, selb, Germany). About 2- 10 mg of each sample was weighed into

aluminum pan, hermetically sealed and the thermal behavior determined within the range

20-400 o C at a heating rate of 10 K/min under a 20 ml/min nitrogen flux. The thermal properties and enthalpies were noted.

The crystallinity index (C.I) was used to evaluate the degree of crystallinity of the carrier

matrix. This was determined from the enthalpy of the transition. [41]

C. I = ………. eq 10

Wide angle x –ray diffraction (WAXD)

WAXD diffractograms of drug, P5, P17 and P20 were recorded using a Panalytical Xpert Pro

Diffractometer (PANalytical, JB Eindhoven, Netherlands) with a copper line as the source of

radiation. Standard runs using a 40-kV voltage, a 40-mA current, and a scanning rate of 0.02°

min-1 over a 2Ɵ range of 3– 40° were used.

RESULTS AND DISCUSSION

Solubility profile of lumefantrine in different excipients.

Solubility studies were carried out to know how soluble the drug will be in various

excipients. This will ascertain amount of lumefantrine that can be loaded in the formulation.

That is, the ability of the different excipients to accommodate large amount of the

hydrophobic drug. The aqueous medium (water) exhibited a very poor solubility of the drug

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75 Figure: 1. A graph of solubility profile of lumefantrine.

Preparation of solid dispersion by Fusion

Lumefantrine solid dispersions were prepared using fusion or melt method with PEG 6000

and other materials to obtain batches P1-9 and Pk10 -18. While batches P19- P21 were

prepared by physically mixing all the components at different ratios without application of

heat in order to monitor if there will be any degradation of the drug by the method. The

lumefantrine solid dispersions were formulated in such a way that batches P1-3 produced

second generation SDs.[42, 43] Also, batches P4 – 9 contained different surfactants, Kolliphor HS 15 and Kolliphor EL to generate third generation SDs [44, 45]. While the batches Pk10- 18 and Pk19- 21 contained Kolliphor 12 PF (crystallization inhibitor) in the presence of the

surfactant(s) to generate multi-component generation of solid dispersion by fusion and

physical mixture respectively.

PERCENTAGE YIELD

In the result of the percentage yield, the solid dispersion batches have good recoveries in the

range of 60 - 94 % as shown in Table 2. The batches prepared by physical mixture method

(Pk19-21) showed highest yield than the formulations prepared by fusion method. This

decrease in the yields of SD formulations prepared by fusion method might be due to the

transference losses. Generally, the yields were appreciable as none was below 60 % recovery.

This is an indication that the fusion technique adopted was a reliable one.

LOADING EFFICIENCY

From the result as shown in Table 2, batches Pk17 had the highest loading efficiency (L.E) of

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76 15:Kolliphor® EL: Kollidon® 12 PF in the ratio of 1:2:0.5: 0.5: 1. The combination of the two to three solubilizers plus the binding and crystallization inhibition of Kollidon 12 PF in that

ratio were appropriate to obtain SD products with good loading efficiency. There was

significant variation (p < 0.5) in the L.E of SDs formulation (Pk 10 – 21) and other

generation SD formulations (P1 – 9) that do not contain Kollidon® 12 PF. This variation might be due to high solubilizing capacity of Kollidon® 12 PF.

Table: 2 The results of percentage yield and loading efficiency (%) of the formulations. Batches Yield (%) L.E (%)± Sd

P1 67.88 34.30±0.50

P2 63.80 41.10±0.20

P3 70.40 38.10±0.41

P4 60.36 48.73±0.10

P5 87.70 55.80±0.32

P6 69.80 52.50±0.40

P7 62.24 55.00±0.12

P8 74.88 55.70±0.17

P9 71.72 54.60±0.30

P10 66.67 72.50±0.22

P11 72.76 65.40±0.34

P12 79.03 75.30±0.15

P13 69.19 73.80±0.32

P14 82.44 75.50±0.21

P15 68.55 74.00±0.09

P16 89.24 80.20±0.23

P17 90.80 88.20±0.22

P18 88.21 81.50±0.33

P19 90.58 65.14±0.13

P20 94.62 69.58±0.14

P21 93.00 68.24±0.11

L. E = loading efficiency; Sd standard deviation

FLOW PROPERTIES

The measurement of the flow properties of powders is essential before encapsulation and

tableting because variation in particle flow will automatically cause variation in tablet weight

and uneven distribution of active ingredient. The bulk and tapped densities of the whole

formulations were in the ranged of 0.366 ± 0.04 to 0.500 ± 0.02 (g/.ml). The Carr’s Index

and Hausner’s quotient showed excellent and good flowability of all the formulations. The

flow rate and angle of repose of batches Pk10 – 21 exhibited excellent flow properties while

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77 Table: 4 Results of the micromeritics properties of the formulation.

Batches BD(g/ml)±Sd TD(g/ml)±Sd C.I (%)± Sd HQ± Sd FR(g/s)±Sd AOR (o )± Sd

P1 0.454 ±0.01 0.483±0.02 6.004 1.064 6.4±.0.01 28±0.13

P2 0.454±0.01 0.469±0.6 3.198 1.033 6.6±0.01 26±0.11

P3 0.441±0.05 0.469±0.6 5.970 1.063 6.5±0.04 25±0.12

P4 0.405±0.01 0.429±0.3 5.594 1.059 7.2±0.01 28±0.14

P5 0.427±0.03 0.429±0.3 0.466 1.004 7.0±0.05 30±0.10

P6 0.405±0.01 0.441±0.01 8.163 1.089 6.8v0.10 30±0.11

P7 0.394±0.01 0.441±0.01 10.657 1.129 6.7±0.12 30±0.10

P8 0.384±0.02 0.417±0.2 7.914 1.086 6.6±0.03 26±0.11

P9 0.394±0.01 0.405±0.03 2.716 1.028 6.5±0.02 26±0.12

Pk10 0.375±0.1 0.384±0.06 2.344 1.024 7.8±0.01 27±0.07

Pk11 0.384±0.06 0.405±0.03 5.185 1.055 7.4±0.05 24±0.13

Pk12 0.384±0.06 0.405±0.2 5.185 1.055 7.6±0.10 26±0.08

Pk13 0.357±0.3 0.384±0.01 7.031 1.078 7.8±0.01 27±0.14

Pk14 0.349±0.04 0.384±0.01 9.114 1.100 7.5±0.03 25±0.16

Pk15 0.349±0.04 0.375±0.01 6.933 1.074 7.6±0.20 26±0.08

Pk16 0.375±0.02 0.384±0.01 2.343 1.024 7.4±0.05 24±0.30

Pk17 0.357±0.02 0.366±0.04 2.459 1.025 7.5±0.01 25±0.13

Pk18 0.357±0.02 0.375±0.01 4.800 1.050 7.5±0.03 25±0.51

Pk19 0.429±0.01 0.500±0.02 14.200 1.166 7.7±0.06 26±0.10

Pk20 0.417±0.05 0.469±0.01 11.087 1.125 7.8±0.04 28±0.12

Pk21 0.405±0.01 0.441±0.03 8.163 1.089 7.8±0.21 26±0.50

BD = bulk density; TD = tapped density; C. I = Carr’s index; HQ = Hausners’ quotient; FR =

flow rate; AOR = angle of repose; and Sd = standard deviation.

In vitro release profile of the lumefantrine-loaded solid dispersions.

The in vitro release of lumefantrine from the solid dispersion batches was studied using 900

ml of freshly prepared simulated intestinal fluid (SIF) pH, 6.8, and simulated gastric fluid

(SGF) pH, 1.2 maintained at 37 ± 1 o C. The results of the in vitro drug release of the pure drug, P5, Pk17 and Pk20 were shown in Figure 2 and 3. Their release rate exhibited gradual

release rate in both the medium. The results revealed that at T45 in SGF, the SD formulations with kollidon® 12 PF (Pk17 and Pk20) released about 80 % of the drug except batch P5 and pure drug. This was due to an effect of Kollidon® 12 PF with activity as an immediate releasing agent and its solubilization effect. Also the batch Pk17 depicted the highest drug

released batch. This might be due to the fusion SD technique used to molecularly dispersed

the drug in the carrier unlike in the physical mixture that involved ordinary mixing. While in

SIF only batch Pk17 were able to release up to 80 % of the drug at T45. This might be attributed to the effect of molecular dispersion of drug in the excipients leading to high

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78 in the release profile of drug in the SIF medium. It was observed that the release profile of

lumefantrine from the batches in SGF (pH, 1.2) was higher than in SIF (pH 6.8). This might

be due to the fact that lumefantrine is a basic drug and will release more at acidic pH. Also

from the results obtained, the batches of the lumefantrine-loaded SDs released more because

[image:11.595.145.447.193.368.2]

they had a greater dilution potentials than the pure drug sample.

Figure. 2: Drug release profile of solid dispersions in simulated gastric fluid (pH, 1. 2)

Figure 3: Drug release profile of lumefantrine solid dispersion in SIF (pH, 6.8)

Differential scanning profile

DSC was carried out in order to study the thermotropic behaviour of lumefantrine and other

excipients used in solid dispersion formulation. It provides useful information about the solid

state properties (crystalline and amorphous) of solid materials. The thermal properties of

[image:11.595.149.453.429.609.2]

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79 of the solid dispersions Pk17 were determined as shown in Fig.4 – 7. Pure lumefantrine

sample showed a sharp peak at 133.4 o C. PEG 6000 showed a peak at 67.1 o C. Kolliphor® HS 15, Kollidon® 12 PF and Kolliphor ® EL had the thermal melting peaks at 65.65, 65.6 and 58.8 o C respectively. In the thermogram of lumefantrine loaded SD batch P17 showed a melting peak at 66.0 o C without the indication of lumefantrine peak. This sharp decrease or disappearance of the drug melting peak might signify the well spread of fine crystal form of

the drug into the molten carrier. The presence of one peak indicated molecular dispersion of

the drug into the carrier giving the formulation a eutectic or monotectic mixture. And the

slight shift in the melting temperature of the carrier portrays a characteristic of a eutectic

mixture. There was also a decrease in enthalpy and crystallinity index of the carrier matrix

decreasing as a result of the loaded drug. The presence of other substances also may result to

change in thermal behavior of carrier matrix in a manner that the melting temperature and

enthalpy change will be dependent on the nature of the component interaction. From the

calculated crystallinity index (C.I), the formulation produced a less crystalline product with

C.I of 0.7469. This was as a result of decrease in the enthalpy of the carrier from - 34.17 to –

25.52 mW/mg. A decrease in enthalpy mainly indicates less crystallinity of the matrix. [49, 50] Then, the carrier matrix produced a weak matrix (due to distortion of crystal arrangement of

individual carrier after melting and solidification). This might have created several spaces for

[image:12.595.143.456.499.733.2]

drug localization. [49 -52] As a result of the less crystallinity this will generate more spaces for drug localization and improvement on the loading efficiency of the carrier.

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[image:13.595.140.458.13.842.2] [image:13.595.143.449.77.277.2]

80 Figure 5: DSC thermogram of PEG 6000

Figure 6: DSC thermogram of Kolliphor® HS 15

[image:13.595.146.452.328.517.2]

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81 Wide angle x-ray diffraction (WAXD)

The diffraction patterns of the batches P5, Pk12, Pk17, and Pk20 are shown in Figure 8- 9. At

25 o (2 Theta) the following intensities were obtained 3800, 3400, 2100 and 2000 count per sec for batches P5, PK12, Pk17and Pk20 respectively. These showed that P5 was more

crystalline in nature followed by Pk 12, Pk17 and Pk20. The formulation Pk 17 and 20 being

less crystalline will entrap more drug than formulation P5 and Pk12. The batches P5

formulation portrayed the sharpest reflections showing that some of the hydrocarbon chains

carriers were stiff and fully extended. [53] The batches Pk 17, 20 and 12 in the descending order of less crystallinity. This has been confirmed by DSC as the C.I depicted less

crystallinity of the SD. The batches with less crystal states will creates more pores within the

solid matrix which will enhance drug incorporation, solubility, dissolution and

[image:14.595.147.453.489.701.2]

bioavailability.

Figure: 8. WAXD diffractorgrams of Batch Pk17.

Batch c Peg A 12 represents P5; Batch c Peg 1 represents Pk12; Batch c Peg A 20 represents Pk 20

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82 CONCLUSION

Lumefantrine – PEG based solid dispersions were formulated with a low molecular weight

povidone grade, Kollidon® 12 PF, a solubilizer and crystallization inhibitor. The fusion method of solid dispersion technique adopted was reliable as there was an appreciable

percentage recovery of all the formulations in the range of 60 – 89 %. Lumefantrine showed

highest solubility in PEG 6000, Kollidon® 12 PF and then, kolliphor® HS 15 which were selected for the formulation. Increased solubilization produced by Kollidon® 12 PF was in synergism with other solubilizers (Kolliphor HS 15 and Kolliphor EL) and with an optimized

drug: carrier ratio (1:2) led batch Pk17 as the most optimized batch with the highest loading

efficiency of 88.20 ± 0.22 % and drug released. There was significant variation (p < 0.5) in

the L.E of SDs formulation (Pk 10 – 21) and other generation SD formulations (P1 – 9). This

variation might be due to high solubilizing capacity of Kollidon® 12 PF. The DSC and WAXD results also showed less crystalline products with higher solubilization potential and

also characterized the formulation as a eutectic mixture. This strategic technology improved

the poor aqueous solubility of the drug and will equally enhance the poor permeability of

lumefantrine as it was molecularly dispersed in a molten carrier and will evatually fight

malaria parasites without resistance.

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