Asian J. Pharm. Tech. 2013; Vol. 3: Issue 1, Pg 09-15 [AJPTech.

]


9


ISSN- 22315705 (Print) www.asianpharmaonline.org
ISSN- 22315713 (Online)


RESEARCH ARTICLE

Preparation and Evaluation of Solid Dispersion of Terbinafine
Hydrochloride

Subhashis Debnath
1
*, Gampa Vijay Kumar
2
, S.V. Satyanarayana
3

1
Seven Hills College of Pharmacy, Tirupati-517561, Andhra Pradesh, India.
2
Vikas Institute of Pharmaceutical Sciences, Andhra Pradesh, India.
3
Jawaharlal Nehru Technological University, Anantapur, Andhra Pradesh, India.
*Corresponding Author E-mail: [email protected]


ABSTRACT:
Terbinafine hydrochloride is a synthetic antifungal drug. It is slightly soluble in water (3mg/ml) and having high
permeability through stomach. This results in poor bioavailability after oral administration. Therefore solid dispersion
of terbinafine HCl with polyethylene glycol - 6000 (PEG 6000) and mannitol were prepared with a view to increase its
water solubility. In this study solid dispersion of the drug were prepared by melting method and the drug was taken
with carrier in the proportions of (1:1, 1:2 and 1:3). The rate of dissolution of terbinafine HCl was increased with the
proportion of (1:3) (Drug : PEG 6000) when compared to the other formulations. In order to predict and correlate the
release behavior of the drug from the polymer matrix the dissolution data were fitted in to a suitable model to describe
the drug release behavior from polymeric system. The surface morphology of the prepared solid dispersion and drug
alone were examined by SEM analysis. The SEM result shows that in the case of solid dispersion of terbinafine HCl,
particles were in almost amorphous form, which indicates a reduction in particle size.

KEY WORDS: antifungal, bioavailability, solid dispersion, polymer matrix, SEM


INTRODUCTION:
Oral bioavailability of a drug depends on its solubility
and/or dissolution rate, and dissolution may be the rate
determining step for the onset of therapeutic activity.
Therefore efforts to increase drug dissolution of drug are
often needed. Methods available to improve dissolution
include salt formation, micronization and addition of
solvent or surface active agents. Solid dispersion (SD) is
one of such methods and it involves a dispersion of one or
more active ingredients in an inner carrier or matrix in solid
state prepared by melting, dissolution in solvent or melting-
solvent method.

Fungal infections are common in human beings, which are
either topical or severe systemic infections.




Received on 18.09.2012 Accepted on 13.12.2012
Asian Pharma Press All Right Reserved
Asian J. Pharm. Tech. 3(1): Jan.-Mar. 2013; Page 09-15

Invasive fungal infections are being identified with an ever-
increasing frequency in premature infants, immuno-
compromised hosts, and patients receiving
immunosuppressive agents and those with acquired
immuno- deficiency syndrome (AIDS). The prevention of
fungal infections has been improved by the antifungal agent
such as Terbinafine.

Terbinafine hydrochloride is a synthetic allylamine
antifungal compound. It is currently employed as an agent
against fungal infections of toes or fingernails caused by the
fungus, Tinea unguium. It has shown activity in vitro
against most strains of other microorganisms including
Candida albicans. Terbinafine hydrochloride is a slightly
water-soluble (3mg/ml) drug therefore its release rate is
slow, resulting in drug concentrations in the body fluids
which are well below the Minimum Inhibitory
Concentrations. In the present study, a solid dispersion
system composed of water soluble inert material was
designed and developed to enhance the availability and
efficacy of antifungal drug Terbinafine HCl
1-5
.
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10
MATERIAL AND METHOD:
Materials:
Terbinafine HCl (Arobindo Pharmaceuticals, Hyderabad),
Mannitol (Finar Chemicals Pvt Ltd, Ahmadabad),
Polyethylene Glycol (Oxford Laboratories, Mumbai),
Methanol (SD Fine Chemicals Ltd, Mumbai).

Methods:
I.R Spectroscopy to predict the Compatibility of
polymer with drug:
I.R spectroscopy can be used to investigate any possible
interaction between the selected carrier mannitol and
polyethylene glycol - 6000 and the drug terbinafine HCl
and also to identify the compatibility between the drug and
polymer.

Preparation of solid dispersions
Solid dispersion of terbinafine hydrochloride was prepared
by melting method. The composition is shown in table
No:1. In melting method the drug and carrier (polyethylene
glycol 6000 and manitol) were mixed in 1:1, 1:2, and 1:3
ratios in a china dish and heated on a paraffin bath. The
mixture was poured on a tile and cooled. The resulted
solidified mass was dried pulverised and passed through
sieve # 100
6-8
.

Table 1: Composition of Solid dispersion
Formulation
Code
Carrier Drug :
Carrier
Method Of Preparation
M1 Mannitol 1:1 Melting method
M2 1:2
M3 1:3
P1 Polyethy
lene
glycol
1:1 Melting method
P2 1:2
P3 1:3


Fig 1: Formulation of solid dispersion by fusion method
Preparation of physical mixtures
For the sake of comparison, physical mixtures having the
same composition of the solid dispersions were prepared by
simply triturating the drugs and the polymers in a porcelain
mortar. The mixtures were then sieved (sieve no 100) and
stored for further evaluation. The formulation code of the
different physical mixtures are M4(physical mixture
Drug:Mannitol 1:1), M5(physical mixture Drug:Mannitol
1:2), M6(physical mixture Drug:Mannitol 1:3), P4(physical
mixture Drug:PEG 1:1), P5( physical mixture Drug:PEG
1:2) and P6 (physical mixture Drug:PEG 1:3)
3-9
.

Evaluation of Solid Dispersion
Estimation of drug content:
The formulation equivalent to 50 mg of terbinafine
hydrochloride was weighed and transferred to a 50 ml flasks.
Formulations were kept in 25 ml of distilled water and
sonicated for 72 hours, after 72 hours the content of each
flasks were then filtered through Whatman filter paper.
Filtrate were diluted properly and absorbance were
determined using UV Visible spectrophotometer at 283 nm
7-12
.

Dissolution Studies:
A quantity of solid dispersion, which will theoretically
contain a drug content of 100 mg of drug, was calculated
from each drug loaded batch. The invitro dissolution studies
were done to compare the rate of dissolution of solid
dispersions with that of pure drug Terbinafine
hydrochloride and physical mixtures. The test was
performed in USP II apparatus using 900ml phosphate
buffer solution at pH 7.4, 50 rpm and temperature 37 1
0
C.
The drug content was analyzed by UV Spectrophotometer
at 283 nm.

The change in amount of drug release after formation of
solid dispersion and physical mixture of the drug and carrier
were compared
6,7-13
.

Determination of kinetics of drug release
Release behavior of the drug from the dosage form:
In order to predict and correlate the release behavior of the
drug from the polymer matrix it is necessary to fit in vitro
release data in to a suitable model. Hence the dissolution
data were fitted according to the well-known exponential
equation, which is often used to describe the drug release
behavior from polymeric system.
The equation, which is used to describe drug release
mechanism, is:
m
t
/ m
8
= k t
n

Where m
t
/ m
8
is the fraction release of the drug t is the
release time k is the constant which indicates the
properties of the macromolecular polymer system, and n
is the release exponent indicative of the mechanism of
release. The n value was used for the analysis of drug release
mechanism from the drug-loaded solid dispersion
14-18
.

Order of drug release:
To determine the order of drug release graphs were plotted
between cumulative % of drug remaining to be released vs.
time and log remaining cumulative percent vs. time
14-18
.
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11
Scanning Electron Microscopy (SEM)
A scanning electron microscope (SEM) is a type of electron
microscope that images a sample by scanning it with a
high-energy beam of electrons in a raster scan pattern. The
electrons interact with the atoms that make up the sample
producing signals that contain information about the
sample's surface topography, composition, and other
properties such as electrical conductivity etc.

The particles were placed on a gold-coated plate and
maintained for at least for 12 hours at room temperature in a
desiccator for complete dryness of the sample. The dried
sample was coated with a thin layer of gold and the particle
size was determined using scanning electron microscope.
The scanning electron microscopy was done for physical
mixture of drug and carrier and prepared solid
dispersion
6,10,12
.


Figure no 2: Solid dispersion of drug with mannitol and drug with
PEG Before passing through sieve no 80

RESULT AND DISCUSSION:
Preparation of solid dispersions
The solid dispersion were prepared using the different
concentration of polymers (PEG-6000 and manitol) by
fusion method, enabled to get free flowing nature powder.
The developed method was found to be more beneficial in
term of lower time consumption, fewer processing steps, no
use of organic solvent and dried nature of finished products.

Estimation of drug content
Drug content of the solid dispersions was found to be
between 91 % and 98.8 %. All the physical mixtures and
solid dispersions showed the presence of high drug content. It
indicates that the drug is uniformly dispersed in the powder
formulation. Therefore, the method used in this study appears
to be reproducible for preparation of solid dispersion.

Dissolution Studies
To compare the release profile of various batches of the
solid dispersion and physical mixture of drug and carrier,
the in vitro release study was carried out on all the batches
by using USP II type apparatus.

Fig no 3: Solid dispersion of drug with mannitol and drug with
PEG after passing through sieve no 80

Table no 2: Percentage drug content of various solid dispersion
formulations
Sl.
No
Formulation Code Drug Content
(%)
1. M1(solid dispersion mannitol 1:1) 93.6
2. M2(solid dispersion mannitol 1:2) 94.2
3. M3(solid dispersion Mannitol 1:3) 94.6
4. M4(physical mixture Mannitol 1:1) 91
5. M5(physical mixture Mannitol 1:2) 94.5
6. M6(physical mixture Mannitol 1:3) 94.3
7. P1(solid dispersion PEG 1:1) 98
8. P2(solid dispersion PEG 1:2) 98.2
9. P3(solid dispersion PEG 1:3) 98.8
10. P4(physical mixture PEG 1:1) 95
11. P5( physical mixture PEG 1:2) 94.6
12. P6 (physical mixture PEG 1:3) 95.5

In vitro dissolution studies indicated that as concentration
of carrier increases, dissolution of drug improved.

The results of drug release from solid dispersion and
physica mixtures of PEG 6000 are shown in figure no 7-8
(table no 3). The formulation code P3 (Terbinafin
hydrochloride: PEG 6000 = 1:3) showed 93.81 % release in
60 minutes than other PEG solid dispersions whereas the
physical mixtures of same formulation released 75.95 % in
60 minutes, pure drug released 58.34 % of the drug in 60
minutes. In case of formulation M3 (with drug and Manitol
1:3) showed 91.39 % in 1hour, physical mixture of the
same ratio showed only 68.20% release. Compared with the
pure drug and physica mixture, the dissolution was found to
increase in the following order.

Pure drug < Physical mixture < solid dispersion
This may be due to the presence of polymer, which
increases wetting, dissolution of the drug by decreasing the
drug particle size in the course of the solid dispersion
preparation, polymorphic transformation of drug crystals
and chemical interactions between drug and carrier.

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Fig no 4: Graph of percentage drug content of various solid dispersion formulations

Table no 3: Cumulative % drug release of various solid dispersion formulations
SL.
No
Formulation code Cumulative % drug release
5 Min 10 Min 15 Min 30 Min 45 Min 60 Min
1. M1(solid dispersion mannital 1:1) 23.22 33.16 56.11 64.94 73.74 88.34
2. M2(solid dispersion mannitol 1:2) 29.86 35.23 56.21 67.71 74.61 89.4
3. M3(solid dispersion Mannitol 1:3) 33.4 38.41 58.07 70.46 73.49 91.39
4. M4(physical mixture Mannitol 1:1) 13.580 27.462 47.624 56.370 60.296 61.777
5. M5(physical mixture Mannitol 1:2) 19.692 31.7931 51.805 60.111 61.361 63.888
6. M6(physical mixture Mannitol 1:3) 21.88 33.101 55.770 64.650 66.57 68.20
7. P1(solid dispersion PEG 1:1) 24.321 35.365 57.64 67.15 78.15 89.21
8. P2(solid dispersion PEG 1:2) 31.506 36.545 57.195 69.58 79.25 90.63
9. P3(solid dispersion PEG 1:3) 34.27 39.185 59.28 71.945 80.08 93.81
10. P4(physical mixture PEG 1:1) 14.472 28.47 48.7 57.54 71.57 72.716
11. P5( physical mixture PEG 1:2) 20.89 32.39 53.23 61.53 73.98 74.8
12. P6 (physical mixture PEG 1:3) 22.66 34.157 54.88 63.95 65.79 75.95
13 T (Pure drug ) 13.37 24.03 32.49 43.72 50.08 58.34



Fig no 5: In vitro release profile of pure drug &solid dispersion of drug
(drug: mannitol,1:1,1:2,1:3)








Fig no6: In vitro release profile of physical mixture of pure drug &
mannitol(drug:mannitol,1:1,1:2,1:3)
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Fig no 7: In vitro release profile of pure drug & Solid Dispersion of
Drug.(drug:PEG6000,1:1,1:2,1:3)



Fig no 8: In vitro release profile of pure drug & physical mixture of
drug and polymer (drug:PEG6000,1:1,1:2,1:3)



Order of drug release:

Fig no 9 A: Korsmeyer Peppas graph of solid
dispersion of Drug: PEG 1:1

Fig no 9B: Korsmeyer Peppas graph of solid
dispersion of Drug: PEG 1:2


Fig no 10: Korsmeyer Peppas graph of solid dispersion
of Drug: PEG 1:3


Fig no 11: Korsmeyer Peppas graph of physical
mixture of Drug:PEG 1:1

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Even though the polymer is present in the physical mixture
the dissolution rate was lesser than solid dispersion. This
increase in dissolution rate of solid dispersion was
attributed to molecular/ colloidal dispersion of drug in
mixture. Higher the proportion of carrier there was a steep
increase in dissolution rate of drug. The release of drug
from solid dispersion and physical mixture using manitol is
given in figure no 5and 6.

When the data were fit into various kinetic models, it was
found that the matrix model is the best fit model for all. The
n value for the models are less then 0.5 in all the
formulations except physical mixtures, indicating the
mechanism of release as the diffusion with Ficks law. In
physical mixture, the n values are above 0.5, indicating the
mechanism of release as diffusion, which follows non-
Fickian law. The formulation of the hydrophilic matrix of
the carrier might be the reason for the diffusion of drug
from the matrix that follows the Fickian kinetics. Table no 4
shows the kinetic model fitting for the drug release data
15-18
.


Fig no 12: Korsmeyer Peppas graph of physical
mixture of Drug:PEG 1:2


Fig no 13: Korsmeyer Peppas graph of physical
mixture of Drug:PEG 1:3
Scanning Electron Microscopy (SEM)
The surface morphology of the prepared solid dispersion
and drug alone were examined by SEM analysis. Figure14
and 15 shows some selected SEM images of representative
samples. The terbinafine HCl crystals appeared as fine
needles with smooth surfaces, partially agglomerated in
bundles. The SEM result shows that in the case of solid
dispersion of terbinafine HCl particles were in almost
amorphous form, which indicates a reduction in particle
size. These observations provides the evidence of solid
dispersion formation.


Fig 14: SEM image of pure drug (terbinafine HCl)


Fig 15: SEM image solid dispersion of drug (terbinafine HCl:PEG
6000, 1:3)




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Table 4:Kinetic model fitting for the drug release data
Model M1 M2 M3 M4 M5 M6 P1 P2 P3 P4 P5 P6
Zero
Order
0.8976 0.919 0.9127 0.8.9 0.8723 0.8679 0.9824 0.9821 0.9823 0.9547 0.9476 0.9382
First
Order
0.9867 0.9812 0.9491 0.9938 0.9789 0.9964 0.989 0.986 0.9806 0.9947 0.9675 0.88
Korsm
eyer
Peppas
0.9541 0.9625 0.9636 0.913 0.9364 0.9317
N
Value
0.4956 0.433 0.4083 0.6101 0.552 0.5868

SUMMARY AND CONCLUSION:
Terbinafine HCl, an antifungal drug has poor water
solubility there by posing problems in their formulations, in
absorption leads to poor bioavailabity. The oral route of
drug administration is the most common method of delivery
due to convenience and ease of ingestion but it is
problematic if the drug is poorly water soluble. Among
numerous ways of enhancing drug dissolution, solid
dispersion of drug in a water soluble polymer or carrier is
one of the promising technique. The carrier used for the
preparation of solid dispersion of terbinafine HCl is
polyethylene glycol 6000 (PEG6000) and mannitol.Solid
dispersion of Terbinafine HCl was prepared by melting
methodand and evaluated for FT-IR, Drug content,
Dissolution test, Kinetics of drug release and SEM.Among
the different ratios of Terbinafine HCl :PEG6000
(1:1,1:2,1:3), 1:3 ratio of Terbinafine HCl and PEG 6000
has maximum release capacity of the drug (95%) after one
hour . In case of Terbinafine HCl: Manitol (1:1, 1:2, 1:3)
1:3 ratio of terbinafine HCl and manitol shows better result.
(Dissolution up to 91.39 % after 1 hour). This increase in
dissolution rate may be due to improved wettability by the
carrier. The dissolution rate of the drug increased with the
increment in carrier proportion. The release of the drug
from the solid dispersion follows non-Fickian laws. This
may be due to the formation of the hydrophilic matrix of the
carrier. The SEM result shows that in the case of solid
dispersion of terbinafine HCl particles were in almost
amorphous form, which indicates a reduction in particle
size, which provides the evidence of solid dispersion
formation.The present work clearly shows that the addition
of carrier to drug improves its dissolution rate and this
formulation can be used to increase the dissolution rate of
the less water soluble drug terbinafine HCl.

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