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

1827

Sagar et al. World Journal of Pharmaceutical Research

SOLUBILITY AND DISSOLUTION RATE ENHANCEMENT OF

ANTIFUNGAL VORICONAZOLE BY HOT MELT EXTRUSION AND

DEVELOPMENT OF SUSTAINED RELEASE TABLETS

Sagar J. Kanase,* Kishorkumar B.Burade, Ashok M.Khandekar, Ganesh R.Sawant,

Aruna R. Repal

Department of Biopharmaceutics, Government college of pharmacy, karad (M.S.) India.

ABSTRACT

This work studied Voriconazole27,28

solid dispersion (SD)4,5

formulation using mixture of Soluplus & KollidonVA64 melts at

temperatures lower than the melting point of Voriconazole using a twin

screw rotating extruder. The Voriconazole is BCS class II Antifungal

drug with low aqueous solubility 1,2,3

.The effects of two carriers and

parameters like mixing temperature, screw rotating speed, and

residence time were systematically studied. SEM, XRD, and FT-IR

were employed to investigate the evolution of Voriconazole

dissolution. DSC was used to quantitatively study the melting enthalpy

evolution of the drug. The aqueous solubility and dissolution rate of

prepared solid dispersion were significantly enhanced6,7

. Thus hot-melt

extrusion (HME) is a promising technology for improving solubility and dissolution profile

of Voriconazole . From the prepared solid dispersion, sustained release tablets were

formulated by direct compression method by using natural (Karaya gum) and semi synthetic

polymers (HPMC K100M). These sustained release tablets release the drug up to 12 hours in

predetermined rate. The formulated powder blend was evaluated for bulk density, tapped

density, compressibility index and angle of repose. The formulated tablets were evaluated for

physical characteristics of sustained release tablets such as thickness, hardness, friability,

weight variation and drug content. The tablets were evaluated for In-vitro drug release studies

by using USP type I dissolution test apparatus. The dissolution test was performed in 0.1 N

HCL for 2 hr and phosphate buffer pH 6.8 for 10 hrs. The in-vitro cumulative drug release

profile of all formulations F1-F11 at 12 hours showed 87.94% to 98.25% drug release,

Article Received on

30 April 2014,

Revised on 25 May

2014,

Accepted on 19 Jun 2014

*Correspondence for

Author

Sagar J. Kanase

Department of

Biopharmaceutics,

Government college of

pharmacy, karad (M.S.) India.

World Journal of Pharmaceutical Research SJIF Impact Factor 5.045

Volume 3, Issue 4, 1827-1853. Research Article ISSN 2277 – 7105


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respectively. Formulation F6 was best formulation ,gives satisfactory release (98.25%) for 12

hours.

Key Words:- Voriconazole, Hot Melt Extrusion,Soluplus, Kollidon VA 64,Karaya Gum

MATERIALS AND METHODS

Voriconazole was obtained as a gift sample from Mylan Pharma Pvt. Ltd. (India). Soluplus6,7

,

Kollidone VA6429

were generously gifted from BASF AG (Germany). All the chemicals

were of analytical grade purchased from LobaChemie, Mumbai,India. Distilled water was

used throughout the experiment.

Method of Preparation of Hot-Melt Extrudates17,18,19

Solid dispersions (SD) were prepared by hot melt extrusion in a Twin-screw extruder

(Manufactured by Thermo fisher scientific ). Extrusion parameters were adjusted for drug

and polymer are summarized in Table.1&2. Die used for extrusion was of 2 mm diameter.

Voriconazole was mixed with Soluplus8,9

, Kollidone VA6431

at drug/ polymer mass ratios of

1:3,1:6 using a mortar and pestle for 5 min. The prepared physical mixtures (PMs) were

extruded using a corotating twin-screw extruder at a screw speed of 100 rpm. The

temperatures for processing were selected based on the glass transition Tg of the polymers

and melting point of the drug13,14.

As a general rule, an extrusion process should be conducted

at temperatures 20–40 0C above the Tg of the polymer and at a temperature close to the

melting point of the drug. Parameters like Drug content, solubility, phase solubility,

dissolution rate were measured with the help of UV-spectroscopy.

Table No.1: Experimentally optimized parameters of Solid Dispersion Systems

Batch Formulation type

Drug : Polymer : Plasticizer

Ratio Speed

(rpm)

Residence

time

(min)

Melt

pressure

(bars)

Batch

size

(gm)

V1 VRC: Soluplus : Kolliphor P 407 1: 3:0.3 100 17 20 28

V2 VRC: Soluplus : Kolliphor P 407 1:6:0.6 100 16 20 49

V3 VRC: Kollidon VA64 : Kolliphor P 407 1:3:0.3 100 18 20 28

V4 VRC: Kollidon VA64 : Kolliphor P 407 1:6:0.6 100 17 20 49

Table No.2: Temperature zones in Hot melt extrusion process

Sr.no Zones Temperature ( 0C)

01 Zone 1 25

02 Zone 2 40

03 Zone 3 90

04 Zone 4 125

05 Zone 5 140


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06 Zone 6 160

07 Zone 7 160

08 Zone 8 160

Saturation Solubility Studies

Solubility studies were carried out in distilled water according to the method reported by

Higuchi and Connors. Excess quantity of voriconazole and / or prepared solid dispersion

were introduced in 20 mL of distilled water and shaken for 24 hours at room temperature.

The content of each flask was then filtered through a Whatmann filter paper. The filtrate was

then diluted and assayed spectrophotometrically at 255 nm. Each solubility was determined

in triplicate (n=3). The results obtained from saturation solubility studies were statistically

analyzed15

. The saturation solubility studies were shown in Table.3 & Fig.1

Table No.3: Saturation Soubility of Voriconazole

Figure No.1: Saturation solubility of pure Voriconazole and solid dispersion batches

Estimation of Drug Content for Hot Melt Extrudates

Solid dispersion of Voriconazole equivalent to 20mg was weighed and transferred into a

100ml volumetric flask. To this small quantity of methanol was added to dissolve. It was

Batch Conc.(µg/ml) Conc.(mg/ml)

VRC 13.9 0.01390

V1

26.15 0.02615

V2 19.3 0.01930

V3 27.25 0.02725

V4 18.3 0.01830


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shaken occasionally for about 15 minutes and the volume was made up to 100ml by adding

0.1N HCL. The solution was filtered by using a Whatman filter paper with a pore size 0.45

μm. The filtrate was subsequently diluted with 0.1N HCL and the absorbance was measured

at 255 nm using 0.1N HCL as blank. This test was repeated six times (N=6).16

The drug

content studies were shown in Table.4 & Fig.2

Table No.4: Drug contents of Hot Melt Extrudates

Formulation Batch Drug Content

(%)

V1 97.88

V2 96.55

V3 98.99

V4 96.44

The drug content of formulations given in table No. and Figure No. . In case of Kollidon

VA 64 , batch V3 In ratio 1:3 shows 98.99% of drug content and is greater than batch batch

V1 (97.88),V2 (96.55) and V4(96.44). So batch V3 was optimized batch for formulation of

sustained release tablet.

Figure No.2: Drug content of all the batches of solid dispersion.

In Vitro Dissolution Studies for Hot Melt Extrudates

Voriconazole has been reported to have have very less aqueous solubility .Therefore to

maintain sink condition ,0.1N HCL was used as a release medium for the in vitro release

studies of Voriconazole. In vitro dissolution studies were carried out using USP type II

(Paddle) dissolution apparatus (LABINDIA 8000, Mumbai) at rotation speed 100 rpm was

used for study. Dissolution of untreated drug and solid dispersion was carried out on an


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equivalent of 200 mg of Voriconazole with 0.1 N HCL as dissolution media. The volume and

temperature of dissolution Voriconazole has been reported to have very less aqueous

solubility .To maintain sink media were 900 ml and 37 ± 0.20c respectively. After a fixed

time interval 5 mal of sample withdrawn (sink conditions was maintained) and analyzed by

using UV-Visible spectrophotometer (Shimdzu-1700, Tokyo, Japan) by analytically validated

methods(r2

=0.999 ).The dissolution profiles were show in Table.5 & Fig.3.

Table No.5: % Cumulative Drug release of Hot Melt Extrudates

Formulation Batch

% Cumulative Drug release

VRC

58.5

V1 95.85

V2 90

V3 98.32

V4 93.37

Fig.No.3: Dissolution Profiles of Prepared solid dispersion by Hot Melt Extrusion In

Comparison With Pure Drug.

Characterization of Hot Melt Extrudates

FTIR Spectral Analysis11

Infrared spectra of pure drug, Soluplus, Kollidon VA 64 and its solid dispersion were

recorded by KBr pellet method using Fourier Transform Infrared Spectrophotometer

(BRUKER 8400S). A base line correction was made using dried potassium bromide and then

spectra of dried mixtures of drug and solid dispersion with potassium bromide were recorded.

The Samples were prepared by KBr pellet press method. The scanning range was 400 to4000

cm-1 . The spectra 1 were shown in Figures 4.


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[A]

[B]

[C]


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[D]

[E]

[F]

Figure No.4:- FTIR spectra of pure Voriconazole ,polymers and solid dispersion . A :

Voriconazole , B: Kollidon VA 64, C: Voriconazole + Soluplus (1:3) , D: Voriconazole +

Kollidon VA 64 (1:3) , E : Voriconazole + Soluplus (1:6) , F: Voriconazole + Kollidon

VA 64 (1:6).


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Differential Scanning Colorimetry (DSC)

The DSC studies were performed for pure drug, Soluplus, Kollidon VA 64 and its solid

dispersion were carried out in an open aluminum pans at 10° C/min heating range. The

temperature range used was30–300°C20,21

.The thermograms were shown in Figures 5.

[A]

[B]


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[C]

[D]

[E]


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[F]

[G]

Figure No.5:- DSC of pure Voriconazole ,polymers and solid dispersion . A :

Voriconazole , B: Soluplus , C : Kollidon VA 64, D: Voriconazole + Soluplus (1:3) , E:

Voriconazole + Kollidon VA 64 (1:3) , F : Voriconazole + Soluplus (1:6) , G:

Voriconazole + Kollidon VA 64 (1:6).

X-Ray Powder Diffraction

The XRPD data of pure drug , Soluplus, Kollidon VA 64 and prepared solid dispersion were

recorded on a Philips Analytical X-ray-PW 3710 ( Phillips,Almedo, The Netherlands)

diffractometer with tube anode Cr over the interval 10-70°/2Өunder following set of

conditions: The generator tension (voltage): 40 kV and generatorcurrent: 30 mA22

. The

XRPD were shown in Figures 6.


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Position [2θ] [A]

Position [2θ][B]

Position [2θ][C]


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Position [2θ][D]

Position [2θ][E]

Figure No.6:- XRPD patterns of pure Voriconazole , polymers and solid dispersion A :

Voriconazole B: Soluplus , C: Voriconazole + Soluplus (1:3) , D:Kollidon VA 64 ,E :

Voriconazole + Kollidon VA 64 (1:3).

Particle Morphology10

Morphological evaluation of the optimized formulations was carried out by JSM-6400

Scanning electron microscope (JEOL,Tokyo,Japan).sample was fixed on aluminium stubs

with conductive double sided adhesive tape and coated with gold by sputter coater at 50 mA

for 50 s. Particle morphology was also tested by Polarizer Light Microscope (Lawrence and

Mayo) of different formulations.26


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[A]

[B]

[C]

Figure No.7: SEM photographs of pure drug and best solid dispersion batches. A:

Voriconazole, B: Voriconazole + Soluplus (1:3) ,C: Voriconazole + Kollidon VA 64

(1:3).


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Formulation of Sustained Release Tablets12,23,25

Sustained release tablets containing optimized solid dispersion were prepared by direct

compression method using KBr Press to produce convex faced tablets weighing 250 mg

each with a diameter of 08 mm.

By Direct Compression Technique

The direct compression technique was selected for developing Sustained release tablets. In

direct compression technique all materials accurately weighed like solid dispersion complex,

Hydroxy Propyl Methyl Cellulose K 100,Gum Karaya, Lactose, talc and magnesium stearate

passed through a 40 mesh prior to mixing. The solid dispersion complex was properly mixed

mixed with, Hydroxy propyl methyl cellulose K 100, magnesium stearate gum karaya ,

lactose and talc. Then mixture was subjected to compression using KBr Press. The saturation

solubility of batch V3 was found to be highest (27.25µg/ml) out of all four batches & selected

for formulation of sustained release tablet. The compositions of various tablet formulations

were given in Table.6.

Table No.6: Composition of sustained release tablet of Voriconazole

Ingredients F1

(mg) F2

(mg) F3

(mg) F4

(mg) F5

(mg) F6

(mg) F7

(mg) F8

(mg) F9

(mg) F10

(mg) F11

(mg)

Solid

Dispersion 100 100 100 100 100 100 100 100 100 100 100

Karaya gum 05 10 15 20 25 30 35 40 45 50 55

HPMC

K100M 55 50 45 40 35 30 25 20 15 10 05

Lactose 85 85 85 85 85 85 85 85 85 85 85

Magnesium

stearate 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Talc 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5

Total 250 250 250 250 250 250 250 250 250 250 250

Evaluation of Tablets

Physical parameters such as weight variation, hardness and friability were evaluated for

prepared tablets. The prepared sustained release tablets were further evaluated for physical

parameters like drug content and in-vitro dissolution studies and their results were shown in

Tables.7 & 8.


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Table No.7: Characterization of blend for Sustained release tablets

Formulation Bulk

Density

(gm/ml)

Tapped

Density

(gm/ml)

Hausner

ratio

Compressibility

Index

(%)

Angle of

repose

F1 0.36±0.81 0.43±0.52 1.1±0.002 16.27±0.24 25.54±0.33

F2 0.36±0.01 0.46±0.45 1.2±0.006 21.73±0.13 28.23±0.12

F3 0.39±0.54 0.45±0.02 1.15±0.008 13.33±0.48 27.12±0.55

F4 0.37±0.11 0.42±0.59 1.13±0.007 11.90±0.87 24.23±0.79

F5 0.38±0.02 0.45±0.77 1.18±0.003 15.54±0.19 25.33±0.12

F6 0.39±0.98 0.46±0.15 1.17±0.001 15.21±0.14 22.15±0.18

F7 0.38±0.61 0.45±0.21 1.18±0.005 15.55±0.74 23.18±0.48

F8 0.36±0.11 0.45±0.14 1.25±0.008 20.00±0.19 25.01±0.41

F9 0.37±0.14 0.42±0.54 1.13±0.007 11.90±0.01 23.73±0.33

F10 0.38±0.07 0.44±0.12 1.15±0.009 13.63±0.17 25.19±0.49

F11 0.37±0.55 0.45±0.87 1.21±0.005 17.77±0.12 23.09±0.28

Table No.8: Physical parameter of sustained release tablet of Voriconazole

Formulation Thickness

(mm)

Hardness

(Kg/cm2)

Friability

(%)

Weight

Uniformity

Content

Uniformity

F1 3.50±0.02 4.2±0.23 0.81±0.21 Complies 98.33±0.56

F2 3.48±0.23 4.3±0.02 0.90±0.37 Complies 97.35±0.35

F3 3.51±0.63 4.1±0.68 0.85±0.62 Complies 97.69±0.94

F4 3.54±0.68 4.9±0.77 0.78±0.96 Complies 99.30±0.03

F5 3.51±0.07 3.9±0.97 0.67±0.39 Complies 97.78±0.97

F6 3.52±0.45 4.0±0.06 0.55±0.12 Complies 99.85±0.15

F7 3.55±0.40 4.2±0.02 0.59±0.48 Complies 96.89±0.04

F8 3.47±0.78 4.5±0.15 0.79±0.18 Complies 97.45±0.15

F9 3.24±0.14 4.3±0.10 0.83±0.02 Complies 98.45±0.47

F10 3.45±0.76 4.8±0.09 0.71±0.11 Complies 98.85±0.44

F11 3.51±0.19 4.1±0.12 0.89±0.07 Complies 97.90±0.09

In-Vitro Drug Release Studies24,26

All the formulated sustained release tablets of Voriconazole were subjected to in-vitro release

studies using 0.1N HCl (pH 1.2) for first two hours and phosphate buffer pH 6.8 for

remaining hours. The in-vitro drug release of all eleven formulations of sustained release

tablets was shown in Table. 9 and Fig.8-9.


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Table No. 9: In Vitro Dissolution Data of Voriconazole sustained release tablets

Time

(Hr) F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11

0 0 0 0 0 0 0 0 0 0 0 0

1 7.8 8.01 9.3 9.6 7.68 9.5 8.3 7.84 7.9 9.0 8.6

2 17.06 18.21 17.23 18.21 17.11 18.24 16.28 16.39 16.06 17.23 19.21

3 24.5 21.04 20.56 21.84 23.16 24.09 22.81 24.74 24.07 21.56 21.44

4 34.15 30.19 29.45 31.55 35.16 34.43 32.46 35.19 35.15 29.75 34.55

5 40.12 37.78 36.45 39.51 41.56 41.27 38.22 40.48 40.62 39.45 39.01

6 48.10 44.02 45.21 46.88 47.15 47.19 44.87 47.06 44.10 45.91 48.88

7 54.33 51.98 52.46 51.02 53.19 53.59 52.44 52.18 54.03 53.46 51.92

8 61.29 60.33 64.19 63.15 64.23 63.68 62.33 60.68 61.59 64.29 60.15

9 79.12 80.12 83.01 82.16 79.99 83.08 78.64 80.19 80.12 80.01 81.18

10 88.01 89.64 88.06 87.94 86.89 87.18 86.01 89.05 88.61 89.56 87.94

11 - - - 93.25 94.98 94.15 92.15 - 93.25 - -

12 - - - - - 98.25 97.05 - - - -

Figure No. 8: Comparative Dissolution profile of formulation F1, F2, F3, F4 & F5

Figure No.9: Comparative Dissolution profile of formulation F6, F7, F8, F9,F10 & F11


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RESULTS

Saturation Solubility

Table.3 shows results of saturation solubility studies. The solubility of hot melt extrudate

was found to be increased than pure voriconazole. The batch V1 i.e Voriconazole with

soluplus (1:3) shows greater solubility than batch V2 Voriconazole with soluplus (1:6). The

batch V3 i.e Voriconazole with kollidon VA 64 in the ratio of 1:3 shows greater solubility

than batch V4 i.e Voriconazole with kollidon VA 64 (1:6). There was 1.88 , 1.38, 1.96 and

1.31 folds increase in solubility than pure voriconazole. The batch V3 shows 27.25 µg/ml

solubility and there was 1.96 fold increase in solubility than pure voriconazole , so that batch

V3 was considered as best batch out of all batches of solid dispersion.The increased

saturation solubility is an inverse function of particle size. Based on Noyes-Whitney equation

an increase in saturation solubility leads to an increase in dissolution velocity. The solubility

of drug increased due to;

1. Hydrophilic nature of polymers,

2. Slight reduction in crystallinity ,

3. Reduction in particle size,

4. Increased wettability due to adsorption on the surface.

FTIR Study

The IR spectra of pure Voriconazole showed peak at 620 ,689.2 ,752.9 cm-1 indicating

stretching of Phenyl ring with strong peak (=C-H & C=C ), peaks at 752.9 ,842.5 ,863.7

,963.8 indicating stretching of Aromatic (C-H) groups. Peaks at 1080 -1360 cm-1 indicating

stretching of C-N deformation. Peak at 1665±15 indicting stretching of C=N

deformation.Peaks at 2887,2946 ,2995 ,shows C-H sp3 carbon strong ,multibanded peaks.

Peaks from 515 -690 shows presence of halide (Fluoro) grops. Peaks at 1725 -1760 indicting

presence of OH group attached to hydrocarbon chain(Butanol). These peaks seemed to be

retained at almost the same wave number with same intensity in the spectra of solid

dispersion which indicate that the absence of any potential physical or chemical interaction

between drug and polymer and other additives, Hence drug and polymer were found to be

compatible with the drug.


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Differential Scanning Calorimetry(DSC)

The DSC thermograms show that the crystalline Vorconazole was characterized by a single,

sharp melting endotherm at 128.750C . Disappearance of the melting endotherm in the DSC

scan of SD suggested that the drug may be converted to the amorphous form during the

extrusion process with DSC thermograms of used polymers. But melting peak was observed

in physical mixture. In physical mixture, small endotherm instead of sharp melting point

was observed. This might be because of interaction of Voriconazole and polymer in DSC

pan during heating ramp. On heating polymer gets melted far before drug’s melting point so

drug starts interacting with rubbery polymer. When temperature rises to melting point of

drug, drug has already been solubilized into molten polymer and hence exhibits broad

melting endotherm .

Suppression of sharp endotherm in physical mixture indicates the favorable interaction

between drug and polymer. Melt extrudate SD had no distinct melting endotherm for the

Voriconazole which indicates the drug exists in the amorphous state in SD. The DSC

analyses revealed complete conversion of crystalline Voriconazole into stable amorphous

form. The formation of amorphous solid dispersion is attributed to the molecular interaction

between drug and polymer. Drug–polymer miscibility is the key factor for the stability of

amorphous pharmaceutical solid dispersion systems; partial miscibility or poor solubility can

result in the formation of concentrated drug domains that may be prone to recrystallization

after production and during storage.The DSC thermograms of soluplus have shown

endothermic peak at 52 °C. The thermograms were recorded and were shown in the Based on

the solubility, dissolution and DSC study, SD F3 was selected as optimized formulation for

further solid state characterization study. This was further supported by XRD . Kollidon VA

64 and Soluplus have their Tg, 70°C and 103°C, respectively. So we can expect during

heating polymer get rubbery earlier, and interact with drug before temperature reaches to

melting point of Voriconazole. Further, DSC thermograms suggested that type of plasticizer

have no effect on crystallinity of Voriconazole. Drug to polymer miscibility and ratio play

dominating role in amorphization of drug.

X-Ray Diffraction Study

The X-ray diffractograms are shown in Fig.6 XRD of Voriconazole consist of sharp multiple

peaks, indicating the crystalline nature of the drug with specific % crystallinity. In the case of

SD (about 2 gm) when exposed to X-ray beam, shows disappearance of most of the


1845


crystalline characteristic peak intensities of Voriconazole . This indicates liable decrease in

the crystalline nature of Voriconazole inside SD system which confirms amorphous nature of

Voriconazole. In the XRD of Voriconazole peak intensities observed at (2h) 89, 177, 265,

353, 441, 529, 617, 705, 793, 881, 969, 1057, 1145, 1233 and 1321. Characteristic peaks of

Voriconazole observed at 2100, 4100, 900, 2750, 3600, 1800, 700, 4200, 2250, 1000, 1300,

2500, 1800, 1100, 800, 700, 1000 and 700 related to its % crystallinity while these peaks

disappeared in all SD systems. In the case of melt extrudates from V1 and V3 intense peaks

of Voriconazole vanished and percentage crystallinity also decreases substantially. While in

the stability studies of melt extrudates from V1 and V3 the intensity of Voriconazole

characteristic peaks has disappeared or decreased to satisfactory amount after 3 months

further confirms no recrystallization of Voriconazole in SD. From the XRD studies of both

fresh and aged SD systems confirms the amorphous nature of Voriconazole with the

polymers after HME.

Particle Morphology

SEM micrographs of pure VRC and SD are shown in Fig.7. From the SEM micrograph it was

evident that HME of VRC resulted in a significant particle size reduction of VRC. SEM

micrographs of pure VRC revealed large crystalline blocks, whereas SD was was found to be

without sharp edges. The SD appeared to be agglomerated with rough surface owing to the

presence of polymer. Surface interaction between drug and polymer was observed at

molecular level.

In-Vitro Drug Release Studies of Sustained Release tablets of Voriconazole

All the formulated sustained release tablets of Voriconazole were subjected to in-vitro release

studies using 0.1N HCl (pH 1.2) for first two hours and phosphate buffer pH 6.8 for

remaining hours. The in-vitro cumulative drug release profile of all formulations F1-F11 at

12 hours showed 87.94% to 98.25% drug release, respectively. Formulation F6 was best

formulation ,gives satisfactory release (98.25%) for 12 hours.

Kinetics of Drug release from Voriconazole SR tablets

To know the mechanism of drug release , from developed formulation, in vitro data were

treated according to zero order kinetics (CPR Vs Time), first order kinetics (log CPR Vs

Time ), koresmeyer-peppas kinetic model (log CPRVs log time ), Hixson-crowell kinetic

model ( cubic root of unreleased fraction of drug Vs time ) and Weibull kinetic model. The

regression coefficient (R2) was taken as criteria for selecting the most appropriate model.


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a) Zero order kinetic model

Figure No.10 :- Zero order kinetic model

b) First order kinetic model

Figure No.11:- First order kinetic model

c) Higuchi Model

Figure No.12:- Higuchi model


1847


d) Korsemeyer-Peppas model

Figure No.13 :- Korsemeyer-Peppas model

e) Hixson -Crowell model

Figure No.14:- Hixson -Crowell model

The relationship obtained from data fitting to above models are described in table No .From

above result it was found that formulation did not show any linearity in case of first order

kinetics (R2 =0.981) and similar results obtained in case of Higuchi model. In case of Hixson-

Crowell model, it was found that R2

value is 0.957, indicating that drug release rate is limited

by drug particle dissolution rate and by diffusion that might occur through polymer matrix.

According to this kinetics, geometrical shape of pharmaceutical dosage form diminishes

proportionally over the time. The data also shows fair linearity in case of Zero order

(R2=0.994). The shape parameter was found to be 1 indicating linear shaped curve. Kinetic

studies were observed as Case – II release mechanism of drug through polymeric membrane

was found through diffusion and rate of diffusion is controlled by swelling of polymer.


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Table No.10 :-Order kinetics for drug release

Order Kinetics R2

Zero Order 0.99

First Order 0.819

Hixson-Crowell 0.917

Higuchi 0.955

Korsemeyer-Peppas 0.986

From in-vitro dissolution study it was concluded that the formulation F6 containing Karaya

gum and HPMC K100M in the ratio 1:1 was taken optimized formulation of sustained release

tablet for 12 hours release as it fulfills all the requirement of sustained release tablet Kinetic

studies were observed as Case – II release mechanism of drug through polymeric membrane

was found through diffusion and rate of diffusion is controlled by swelling of polymer.

Stability Studies of formulations at (400C/75%RH)

30

Table 11 : Stability studies result of Voriconazole SR tablets at (400C/75%RH):-.

Parameters Initial After 30 days After 60 days After 90 days

Physical appearance White to

off white

No change No change No change

Weight variation (mg) 248±2.84 248±2.34 247±1.51 248±1.23

Thickness (mm) 3.49±1.90 3.49±1.87 3.49±1.16 3.48±0.98

Hardness (kg/cm2) 4.2±0.85 4.2±0.23 4.2.±0.64 4.1±0.99

Friability (%) 0.72±0.15 0.71±0.05 0.7±0.08 0.68±0.06

Drug content(%/tablet) 101.48±0.6 101.14±0.34 100.11±0.29 100.01±0.87

In-vitro drug release

Time (Hrs) % Cumulative drug release

1 9.5 9.6 9.2 9.4

2 18.24 16.45 17.15 17.84

3 24.09 23.84 23.90 24.01

4 34.43 33.15 33.41 33.08

5 41.27 39.01 39.38 40.18

6 47.19 46.19 47.68 48.12

7 53.59 52.09 54.18 53.23

8 63.68 61.60 61.88 62.45

9 83.08 84.14 82.47 83.40

10 87.18 86.97 87.86 87.09

11 94.15 95.01 93.15 94.19

12 98.25 98.2 98.10 98.16

DISCUSSION

Comparative evaluation using two Solubilizing polymers exposed the drug polymer

miscibility characterized with the help of essential analytical techniques proves the

productivity and industrial practicability of HME. Dissolution rate enhancement of


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Voriconazole was achieved by preparing amorphous glassy dispersions with Soluplus and

Kollidone VA64 polymers by hot melt extrusion. The crystalline Voriconazole was converted

to the amorphous state during the extrusion process with all polymers. Enhanced physical

stability of the Soluplus and KollidoneVA64 HME formulation is attributed to drug–polymer

interactions. Prepared bio-enhanced stable hot melt extruded Voriconazole SD systems

using Soluplus and Kollidone VA64 would definitely enhanced therapeutic importance of

Voriconazole as single drug candidate use, eventually solved the problem of poor solubility.

Infra-red spectroscopy studies indicated no interaction between drug and carrier. The drug

was completely miscible in water-soluble carrier. The enthalpy of melting of the drug in solid

dispersion was gradually decreased compared to pure drug, as revealed by DSC

thermograms. The XRD study showed that the drug was present in amorphous form. DSC,

XRD, IR data confirms that Voriconazole may be converted to stable amorphous form using

HME technology. Scanning microscopic analysis reveals smooth surface morphology as well

as molecular interaction in prepared HME SD. HME formulations are less susceptible to

recrystallization , perhaps due to the solubilising effect of the Soluplus. The improvement in

the dissolution rate is in order of Voriconazole with Kollidon VA 64 > Soluplus. . In all

Kollidone VA64 of BASF found to be superior to that of soluplus in terms of all solubility

and dissolution behavior.

Hot melt extrusion is very versatile technique for enhancement in dissolution of poorly

soluble drug. Preliminary studies of solubility and miscibility of drug and polymer is

prerequisite for further processing of hot melt extrusion. Transition of polymorphic state of

drug from crystalline to amorphous form depends on type of polymer used and drug to

polymer ratio. Increase in amount of polymer reduces the crystallinity of drug because of

higher chance of formation of molecular dispersion rather than solid dispersion.

CONCLUSION

The present study has shown that it is possible to increase the solubility and dissolution rate

of poorly soluble drug voriconazole by preparing it as solid dispersion with carriers. The

solid dispersion exhibited faster dissolution characteristics as compared to that of pure drug.

This was due to solubilizing effect of the complexing agent. It was found that the solid

dispersion prepared by the hot melt extrusion method release the drug rapidly than the pure

drug. The sustained release tablets of Voriconazole prepared with natural (Karaya gum) and


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semi synthetic polymers (HPMC K100M) (F6) showed best result when compared to pure

drug and other tablet formulations.

Future Prospects: The main concerns with solid dispersions have been the ability to scale-

up the manufacturing method and the physical stability of the dispersion. The application of

hot melt extrusion to the production of solid dispersions is a particularly important

breakthrough for the scale-up of solid dispersion manufacture. The Poor bioavailability is a

major limitation in successful drug delivery by oral route. Lot of research work is focused on

oral bioavailability enhancement of the poorly absorbed drugs. It is necessary to understand

the reason behind the poor bioavailability before designing a delivery system. Despite many

advantages of solid dispersions, issues related to preparation, reproducibility, formulation,

scale up and stability limited its use in commercial dosage forms for poorly water soluble

drugs. However, successful development has been feasible in recent years due to availability

of surface-active and self-emulsifying carriers with relatively low melting points .

The application of HME technology in the pharmaceutical industry has tended to focus on the

development of bio-enhanced formulations to increase the efficacy of poorly water soluble

compounds. There has also been an increase in the application of HME for the development

of controlled release formulations, in the form of pellets, beads or minimatrices, and as

means to facilitate the continuous processing of products to reduce the number of

manufacturing unit operations. The production of multiparticulate dosage forms using HME

has been investigated using hot melt pelletization and, lately, the use of die, face-cutting the

polymer extrudate to produce HME pellets shows the continuing utilization of technology

from the plastics industry for pharmaceutical manufacturing.

The two major advantages that the HME process offers to the pharmaceutical industry is a

fast continuous manufacturing process and a suitable method for moisture sensitive thermo

stable drugs Pharmaceutical applications of the HME process include the sustained release

(SR) or delayed release (DR) systems, films for transdermal or transmucosal drug delivery,

solubility or bioavailability enhancement, taste masking and for making amorphous materials.

HME has been used to improve the bioavailability of drug substances by formation of

molecular dispersions Hot-melt extrusion was found to be an excellent technique in preparing

Voriconazole solid dispersions using Soluplus and Kollidon VA 64 be a great tool for

improvement in dissolution and bio-availability of Voriconazole. HME, a relatively new

technology offers a suitable method for formulating moisture sensitive thermo stable drugs.


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There are a few limitations with the hot melt extrusion process such as the requirement of

high process knowledge, scale up issues, GMP compliance and high initial cost but all these

limitations can be overcome once the process and the desired parameters are firmed HME

definitely offers the intellectual property advantage and has numerous applications in the

field of SR dosage forms, solubility and bioavailability enhancement and taste masking. New

chemical entities that demonstrate a low bioavailability due to solubility issues are prime

candidates for HME. This technology certainly appears to have an immense potential to

revolutionize the development and manufacturing of many new dosage forms and novel drug

delivery systems.

ACKNOWLEDGEMENTS

The authors express their gratitude to BASF Pharma PVT Ltd. and Mylan Pharma Pvt. Ltd.

(India) for providing the gift samples.The authors are thankful to the Government College of

Pharmacy, Karad. for providing the facilities to carry out the research work.

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