Chapter - 3 Theoretical Analysis

CHAPTER - 3
THEORITICAL ANALYSIS

3.1 SCOPE
There are number of compounds with good pharmacological activity showing
high lipophilicity and slight water solubility as the fundamental physicochemical
characteristics. In the case of the orally administered formulation the lipophilic drugs
show the poor GI absorption because of the solubility or dissolution rate to water, so
the oral bioavailability is low and its variation is large. Therefore the clinical efficacy
of these drugs is sometimes not realized (1, 5, 43, 44).
Over the years, nanoemulsions have attracted increased interest as potential
drug delivery systems. This is due to their transparency, long-term stability and ease
of preparation. These properties along with their ability for incorporating drugs of
different lipid solubility are some of the reasons why nanoemulsion is using as one of
the important dosage form in recent days (1, 4, 5, 46).
Nanoemulsion are low viscous, thermodynamically stable and optically
transparent dispersions of organic phase and water stabilized by an interfacial film of
a surfactant, combined with a cosurfactant. In recent days in the fled of
pharmaceutics, nanoemulsion are used as vehicles to deliver many lipophilic drugs
because of their ease of preparation, thermodynamic stability and good appearance
(12, 47).
Nanoemulsion is a vital candidate for oral delivery of lipophilic drugs because
of its ability to increase drug solubilization as it is having less particle size and more
surface area.
O/W nanoemulsion is the formulation which is expected to increase the
solubility by dissolving poorly water soluble compounds into oil phase and to enhance
oral bioavailability, and it is also possible for this formulation to raise lymph
directivity and to avoid hepatic first pass metabolism depending on the kind of oil.
Enhancement of GI absorption by o/w nanoemulsion has been demonstrated for
cyclosporine, halofantrine and ramipril (2, 5, 6, 41). Terbinafine Hydrochloride is
used as a potent antifungal agent. This drug belongs to an allyl amine class. It has
broadspectrum activity against dimorphic fungi, dermatophytes, yeasts and molds (48,
49, 50). The drug inhibits squalene epoxidase which is used as an important enzyme
(present in fungal and mammalian cell systems) in ergosterol biosynthesis. It is highly

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lipid soluble drug and it is used both orally and as a topical application for cutaneous
mycoses, depending on the severity and specific nature of the mycoses. Thus in this
research work a novel o/w nanoemulsion formulation is tried which enhances the oral
bioavailability of the poorly water soluble terbinafine HCl. The objectives of the
present work include development and characterization of o/w nanoemulsion
containing terbinafine HCl, improve oral bioavailability by lymphatic transport and
reduce hepatic first-pass metabolism and to reduce the dose required to produce same
pharmacological effect where by dose related side effects can be reduced.

3.2 DRUG PROFILE

3.2.1 Terbinafine Hydrochloride

Terbinafine HCl is a fine crystalline powder. It is of white to off-white colour.
This drug is very less soluble in water but it is easily soluble in methylene chloride
and methanol. It is chemically, known

(E)-N-(6,6-dimethyl-2-hepten-4-ynyl)-N-methyl-1-naphthalenemethanamine
hydrochloride. Empirical formula of Terbinafine HCl is C21H25N. Its molecular
weight is 327.90, and the structural formula of Terbinafine HCl is given below:

Fig. 3.1: Structure of Terbinafine HCl

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Dosage forms
This drug is available as various formulations like cream, gel, tablet, solution,
powder and linament

Pharmacologic category
It is used as Anti fungal agent.

Adverse effects
It is having various side effects like liver test abnormalities, urticaria,
gastrointestinal symptoms (which includes dyspepsia, diarrhea, and abdominal pain),
rashes, taste disturbances, and pruritus. Lupus Erythematosus, Hepatotoxicity, Smell
Disturbance which includes Loss of Smell, Taste Disturbance which includes Loss of
Taste, Depressive Symptoms, Skin Reactions, Hematologic Effects.

Clinical pharmacology
The drug Terbinafine is an allylamine antifungal agent, it inhibits ergosterol
biosynthesis. This ergosterol is present in the fungal cell membrane and it a vital
substance of the fungal cell membrane. Terbinafine HCl inhibits ergosterol
biosynthesis by the inhibition of a enzyme named squalene epoxidase. Due to that
fungal cell dies primarily as a result of increased permeability of the membrane by the
high concentrations of squalene. Based on the concentration of Terbinafine and the
species of fungal test in vitro, it may be fungicidal. Clinical significance of the in vitro
data is still unknown. The drug terbinafine is active against various strains of the
microorganisms both in clinical infections and in vitro.

Pharmacokinetics
Terbinafine HCl absorb well when administered through orally that is more
than 70% but bioavailability of the drug decreased up to 40% due to first pass
metabolism when it is administered as tablet formulation. It takes two hour for the
drug to reach peak plasma concentration (Cmax) which is 1mcg/ml after a single dose
of 250 mg. The area under the curve (AUC) of the drug is nearly 4.56 mcg.h/mL.
When the drug, in the form of Terbinafine tablets given with food there is an increase
in the AUC of Terbinafine HCl (less than 20%).

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It has also observed that this drug is completely bound with the plasma protein
(>99% bound to plasma proteins) and for Terbinafine HCl there are no binding sites
which is specific. Terbinafine is well distributed to the skin and sebum. This drug
possess half-life of 200 to 400 hr, which indicates that it takes more time for the
elimination of Terbinafine from various tissues such as adipose and skin. Before
excretion this drug undergoes high metabolism by the enzymes present in the liver
and its bioavailability decreases. (48-50).

3.3 EXCIPIENTS PROFILE

3.3.1 Tween 80
Structure:

Fig. 3.2: Structure of Tween 80

Molecular formul : C24H44O6

Molecular weight : 428.6
Synonyms : Polysorbate 80, Ethoxylated sorbitan monooleate

Form : Yellow to amber colour, Viscous liquid

Solubility in water : 5-10g /100 mL at 25oC

Density : 1.08g/ mL at 20oC

Boiling point : >100o

HLB Value : 15

Refractive index : 1.47

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Use : Non-ionic surfactant (1, 12, 5)

3.3.2 Mannitol
Mannitol is a sugar molecule; that is, it is derived by reduction from a sugar,
with a molecular weight of 182.17 g/mol, and a density of 1.52 g/ml. Other sugar
alcohols include xylitol and sorbitol. Sorbitol and Mannitol are isomers of each other,
orientation of the hydroxyl group (-OH) on carbon two is the only difference between
mannitol and sorbitol. Solutions of mannitol in water are mildly acidic and sometimes
this type of solutions is treated to lower the pH of the solution. Solubility of D-
Mannitol has found to be 22g/ 100mL water (25 °C), and a relative sweetness of 50
(sucrose=100). It melts in between 165 and 169 °C , and boils at 295 °C, indicating
that it has a greater boiling point(49).

Fig. 3.3: Structure of d-mannitol

Table. 3.1: Physicochemical,Biological and Pharmalogical properties of Mannitol

SYNONYMS Manna sugar

DEFINITION Mannitol is derived from sugar by

reduction.

CHEMICAL FORMULA (C6H8(OH)6)

STRUCTURAL FORMULA

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MOLECULAR WEIGHT 182.172

DESCRIPTION Mannitol is a white, crystalline,

organic compound

BIOAVAILABILITY ~7%

METABOLISM Hepatic:negligible

HALF LIFE 100 minutes

EXCRETION Renal:90%

SYNTHESIS It is formed by the fructose

hydrogenation that is formed
either from Starch or sugar.
Though starch is economic than
sucrose, the transformation
process of starch is more
complicated. Eventually, it
provides a syrup containing about
42% fructose, 52% dextrose, and
6% maltose,sucrose is simply
hydrolyzed into an invert

sugar syrup, In both cases

mentoned above, the syrups are
purified chromatographically to
obtain 90-95% fructose. It is then
hydrogenated by using nickel
catalyst into isomeric mixture of
sorbitol and mannitol. It yield

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product which is typically

50%:50%.

FUNCTIONAL USES  Mannitol is used clinically

in Osmotherapy
 It is also having its role as a
facilitating agent (it transportation
various pharmaceuticals and
drugs directly into the brain).
 Mannitol may be administered in
cases of severe ciquatera poisoning

3.3.3 Polyethylene Glycol 6000

PEG - 6000 is a polymer which is having high molecular weight. It is a

polymer of ethylene oxide and is a blend of polymers with different degrees of
polymerisation. All PEGs are soluble in water, similarly PEG-6000 is also
freely soluble in water. Due to the above mentioned fact water can be used as
the solvent to dissolve PEG 6000 rather than using any organic solvent. PEG-
6000 used in th formulation of pills and tablets as it acts as a binder due to its
laminar structure. It is also used as dry lubricant in pharmacutica preparations .
PEG-6000 is also used as a mould release agent in rubber industry.
Polyethylene glycol, which is a polymer of condensation of the ethylene oxide
and water with a formula H(OCH2CH2)nOH, where n indicates the average
number of repeatin oxyethylene groups. The value of lies in between 4 to
about 180. When the n value is in between 2 to 4 (low molecular weight
members) they are known as diethylene glycol (n=2), triethylene glycol (n=3)
and tetraethylene glycol (n=4) respectively, which are produced as pure
compounds (49).

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Fig. 3.4: Structure of Polyethylene Glycol 6000

Table. 3.2: Physicochemical,Biological and Pharmalogical properties of Polyethylene

glycol 6000

SYNONYMS Macrogol
DEFINITION PEG - 6000 is a polymer of ethylene oxide which is a polymer
with high molecular weight
CHEMICAL H(OCH2CH2)nOH
FORMULA

STRUCTURAL

FORMULA

MW It is having MW of 5000 – 7000

DESCRIPTION Polyethylene glycol is commonly used in pharmacy

as it is odourless, nonvolatile non-toxic compound
and nonirritating. It is having different application in
pharmacy as solvent, ointment, dispensing agent,
vehicle, tablet excipients and suppository bases.

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FREEZING 56-630c
POINT

SOLUBILITY Soluble in water

FUNCTIONAL  Antidusting agent in agricultural formulations

USES
 Brightening effect and adhesion enhance in
electroplating and electroplating process.

 Cleaners, detergents and soaps with low

volatility and low toxicity solvent properties.

 Coupling agent, humectant, solvent and

lubricant in cosmetics and personal care bases

3.3.3 Olive oil

Olive oil is a mixture of fatty acid glycerides. It consists of high proportion

of unsaturated fatty acids. It is a type of fixed oil and collected from the fruit of Olea
europaea. It is appeared as a colorless, clear oily liquid. It is used widely in the food
preparation and as edible oil. It is also used in topical pharmaceutical formulations
and in cosmetics. It is non irritant and nontoxic material and suitable to use as an
excipients. It is having demulcent properties. It is also used in topical formulations
as an emollient.

Application in Pharmacy
Olive oil is used in various pharmaceutical formulations like liniments,
enemas, plasters, ointments, and soap. It is also used in the formulation of oral
capsules, solutions, vehicle for oily injections and emulsion. It has also been used in
ear wax softening (1, 39).

3.4 PLAN OF WORK

The work was proposed to be carried out on following stages-

STAGE 1: LITERATURE REVIEW

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STAGE 2: PREFORMULATION STUDIES

- Solubility studies for drug in different oils

- Compatibility Studies using FT-IR

STAGE 3: CONSTRUCTION OF PSEUDOTERNARY PHASE DIAGRAMS

- To select the range of formulation

STAGE 4: SELECTION OF FORMULATION FROM PHASE DIAGRAMS

- Thermodynamic stability studies

- Dispersibility tests

- Preparation of drug loaded batches

STAGE 5: CHARACTERIZATION
- Globule size, Zeta potential and Polydispersity Index

- Viscosity

- Conductivity

- Refractive index

- Transmittance

- Drug content

- TEM Studies

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- IN VITRO Release studies (Dialysis bag method)

STAGE 6: FORMULATION OF SOLID DISPERSION AND ITS EVALUATION

- Formulation of solid dispersion using different carrier

- Evaluation of the solid dispersion to select the best formulation

- Comparing Dissolution profile of the various formulation

STAGE 7: IN VIVO STUDIES

- Oral Bioavailability Studies in Wistar rats.
- Comparison the various formulation (GraphPad Prism 5.01)

STAGE 8: STABILITY STUDY

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