23 2.1 INTRODUCTION TO SOLID DISPERSION: The enhancement of oral bioavailability of poorly water-soluble drugs remains one of the most challenging aspects of drug development. Although salt formation, co-solubilization and particle size reduction have commonly been used to increase dissolution rate and thereby oral absorption and bioavailability of such drugs [10] , there are practical limitations of these techniques. The salt formation technique is not feasible for neutral compounds and also the synthesis of appropriate salt forms of drugs that are weakly acidic or weakly basic may often not be practical [14] . Even when salts can be prepared, an increased dissolution rate in the gastrointestinal tract may not be achieved in many cases because of the reconversion of salts into aggregates of their respective acid or base forms [13] . The solubilization of drugs in organic solvents or in aqueous media by the use of surfactants and cosolvents leads to liquid formulations that are usually undesirable from the viewpoints of patient acceptability and commercialization. Although particle size reduction is commonly used to increase dissolution rate, there is a practical limit to size reduction achieved by commonly used methods as controlled crystallization, grinding, pearl milling etc. The use of very fine powders in a dosage form may also be problematic because of handling difficulties and poor wettability due to charge development [12] . In 1961, Sekiguchi and Obi [96] developed a practical method whereby most of the limitations with the bioavailability enhancement of poorly water-soluble drugs can be overcome, which was termed as „Solid Dispersion‟ [52] . From conventional capsules and tablets, the dissolution rate is limited by the size of the primary particles formed after disintegration of dosage forms. In this case, an average particle size of 5 μm is usually the lower limit, although higher particle sizes are preferred for ease of handling, formulation and manufacturing. On the other hand,
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2.1 INTRODUCTION TO SOLID DISPERSION:
The enhancement of oral bioavailability of poorly water-soluble drugs remains
one of the most challenging aspects of drug development. Although salt formation,
co-solubilization and particle size reduction have commonly been used to increase
dissolution rate and thereby oral absorption and bioavailability of such drugs[10]
, there
are practical limitations of these techniques. The salt formation technique is not
feasible for neutral compounds and also the synthesis of appropriate salt forms of
drugs that are weakly acidic or weakly basic may often not be practical[14]
. Even when
salts can be prepared, an increased dissolution rate in the gastrointestinal tract may not
be achieved in many cases because of the reconversion of salts into aggregates of their
respective acid or base forms[13]
. The solubilization of drugs in organic solvents or in
aqueous media by the use of surfactants and cosolvents leads to liquid formulations
that are usually undesirable from the viewpoints of patient acceptability and
commercialization. Although particle size reduction is commonly used to increase
dissolution rate, there is a practical limit to size reduction achieved by commonly used
methods as controlled crystallization, grinding, pearl milling etc. The use of very fine
powders in a dosage form may also be problematic because of handling difficulties
and poor wettability due to charge development[12]
.
In 1961, Sekiguchi and Obi[96]
developed a practical method whereby most of the
limitations with the bioavailability enhancement of poorly water-soluble drugs can be
overcome, which was termed as „Solid Dispersion‟[52]
.
From conventional capsules and tablets, the dissolution rate is limited by the size
of the primary particles formed after disintegration of dosage forms. In this case, an
average particle size of 5 µm is usually the lower limit, although higher particle sizes
are preferred for ease of handling, formulation and manufacturing. On the other hand,
24
if a solid dispersion or a solid solution is used, a portion of the drug dissolves
immediately to saturate the gastrointestinal fluid and the excess drug precipitates out
as fine colloidal particles or oily globules of submicron size. Hence, due to promising
increase in the bioavailability of poorly water-soluble drugs, solid dispersion has
become one of the most active areas of research in the pharmaceutical field[49, 97]
.
2.1.1 DEFINITION AND TYPES OF SOLID DISPERSIONS:
2.1.1.1 Definition:
Solid dispersion technology is the science of dispersing one or more active
ingredients in an inert matrix in the solid stage to achieve an increased dissolution rate
or sustained release of drug, altered solid state properties and improved stability.
2.1.1.2 Types of Solid Dispersions:
A) Simple Eutectic Mixture:
Eutectic mixture of a sparingly water-soluble drug and a highly water-soluble
carrier may be regarded thermodynamically as an intimately blended physical mixture
of its two crystalline components (Fig. 2.1). These systems are usually prepared by
melt fusion method. When the eutectic mixture is exposed to water, the soluble carrier
dissolves leaving the drug in a microcrystalline state which gets solubilized rapidly.
The increase in surface area is mainly responsible for increased rate of dissolution[98]
.
Fig. 2.1: Hypothetical Phase Diagram of Eutectic Mixture
25
B) Solid Solutions:
Solid solutions consist of a solid solute dissolved in a solid solvent. These systems
are generally prepared by solvent evaporation or co-precipitation method, whereby
guest solute and carrier are dissolved in a common volatile solvent such as alcohol.
The solvent is allowed to evaporate, preferably by flash evaporation. As a result, a
mixed crystal containing amorphous drug in crystalline carrier is formed because the
two components crystallize together in a homogenous single phase system. Such
dispersions are also known as „Co-precipitates‟ or „Co-evaporates‟. This system
would be expected to yield much higher rates of dissolution than simple eutectic
systems. Because, the basic difference between solid solution and eutectic mixture is
that the drug is precipitated out in an amorphous form in solid dispersion/solution
while it is in crystalline form in eutectics[99, 100]
.
Solid solution can generally be classified according to the extent of miscibility
between the two components or the crystalline structure of the solid solution[101]
.
(i) Continuous solid solutions
(ii) Discontinuous solid solution
(iii) Substitutional solid solution
(iv) Interstitial solid solution
i) Continuous Solid Solutions:
In this system, the two components are miscible or soluble at solid state in all
proportions (Fig. 2.2). No established solid solution of this kind has been shown to
exhibit faster dissolution properties, although it is theoretically possible. It is obvious
that a faster dissolution rate would be obtained if the drug were present as a minor
component. However, the presence of a small amount of the soluble carrier in the
26
crystalline lattice of the poorly soluble drugs may also produce a dissolution rate
faster than the pure compound with similar particle size.
Fig. 2.2: Hypothetical Phase Diagram of Continuous Solid Solution
ii) Discontinuous Solid Solution:
In this system (Fig. 2.3), in contrast to the continuous solid solution, there is only
a limited solubility of a solute in a solid solvent. Each component is capable of
dissolving the other component to a certain degree above the eutectic temperature.
However, as the temperature is lowered, the solid solution regions become narrower.
The free energy of stable and limited solid solutions is also lower than that of pure
solvent.
Fig. 2.3: Hypothetical Phase Diagram of Discontinuous Solid Solution
27
iii) Substitutional Solid Solution:
As shown in Fig. 2.4, in this type of solid solution, the solute molecule substitutes
for the solvent molecules in the crystal lattice of the solid solvent. It can form a
continuous or discontinuous solid solution. The size and steric factors of the solute
molecules play a decisive role in the formation of solid solution. The size of the solute
and the solvent molecule should be as close as possible.
Fig. 2.4: Substitutional Solid Solution
iv) Interstitial Solid Solution:
The solute (guest) molecule occupies the interstitial space of the solvent (host)
lattice (Fig. 2.5). It usually forms only a discontinuous (limited) solid solution. The
size of the solute is critical in order to fit into the interstices. It was found that the
apparent diameter of the solute molecules should be less than that of the solvent in
order to obtain an extensive interstitial solid solution of metals.
Fig. 2.5: Interstitial Solid Solution
28
C) Glass Solution:
A glass solution is a homogenous system in which a glassy or a vitreous carrier
solubilizes drug molecules in its matrix[102]
. PVP dissolved in organic solvents
undergoes a transition to a glassy state upon evaporation of the solvent[103]
. The glassy
or vitreous state is usually obtained by an abrupt quenching of the melt. It is
characterized by transparency and brittleness below the glass transition temperature
(Tg). On heating, it softens progressively without a sharp melting point.
D) Compound or Complex Formation:
This system is characterized by complexation of two components in a binary
system during solid dispersion preparation. The availability of drug from complex or
compound depends on the solubility, association constant and intrinsic absorption rate
of complex. Rate of dissolution and gastrointestinal absorption can be increased by
the formation of a soluble complex with low association constant[104]
.
E) Amorphous Precipitation:
Amorphous precipitation occurs when drug precipitates as an amorphous form in
the inert carrier. The higher energy state of the drug in this system generally produces
much greater dissolution rates than the corresponding crystalline forms of the drug. It
is postulated that a drug with high super cooling property has more tendency to
solidify as an amorphous form in the presence of a carrier. Hence, amorphous
precipitation is rarely observed[105]
.
Fig. 2.6: Amorphous Precipitation
29
2.1.2 MECHANISM OF DISSOLUTION RATE ENHANCEMENT:
Corrigan[106]
reviewed the understanding of the mechanism of release from solid
dispersion. The increase in drug dissolution rate from solid dispersion system can be
attributed to a number of factors like particle size, crystalline or polymorphic forms
and wettability of drug etc. It is very difficult to show experimentally that any one
particular factor is more important than another. The main reasons postulated for the
observed improvements in dissolution from these systems are as follows[52]
:
a) Reduction of Particle Size:
In case of glass solution, solid solution and amorphous dispersions, particle size is
reduced. This may result in enhanced dissolution rate due to increase in the surface
area. Similarly, it has been suggested that the presentation of particles to dissolution
medium as physically separate entities may reduce aggregation.
b) Solubilization Effect:
The carrier material, as it dissolves, may have a solubilization effect on the drug.
Enhancement in solubility and dissolution rate of poorly soluble drugs is related to the
ability of carrier matrix to improve local drug solubility as well as wettability[107]
.
c) Wettability and Dispersibility:
The carrier material may also have an enhancing effect on the wettability and
dispersibility of the drug due to the surfactant action reducing the interfacial tension
between hydrophobic drug particle and aqueous solvent phase, increasing the
effective surface area exposed to the dissolution medium. This also retards
agglomeration or aggregation of the particles, which can slow down the dissolution.
d) Conversion of Polymorphic Nature of Solute:
Energy required to transfer a molecule from crystal lattice of a purely crystalline
solid is greater than that required for non-crystalline (amorphous) solid. Hence
30
amorphous state of a substance shows higher dissolution rates. But the amorphous
solids also demonstrate lack of physical stability due to natural tendency to form
crystals. Thus formation of metastable dispersions with reduced lattice energy would
result in faster dissolution rate and comparatively acceptable stability.
2.1.3 SELECTION OF CARRIER:
One of the most important steps in the formulation and development of solid
dispersion for various applications is selection of carrier. The properties of carrier
have a major influence on dissolution characteristics of the drug. A material should
possess following characteristics to be suitable carrier for increasing dissolution[108]
:
i. Freely water-soluble with intrinsic rapid dissolution properties
ii. Non-toxic nature and pharmacologically inertness
iii. Thermal stability preferably with low melting point especially for melt method
iv. Solubility in a variety of solvents and should pass through a vitreous state upon
solvent evaporation for the solvent method
v. Ability to increase the aqueous solubility of the drug
vi. Chemical compatibility and not forming a strongly bonded complex with drug.
2.1.4 POLYMERS USED IN SOLID DISPERSIONS:
A variety of polymers is offered as carriers for formulation of solid dispersion.
Table 2.1 represents various categories and examples of carriers. Some polymers used
in solid dispersions are as follows:
A) Polyethylene Glycols (PEG):
The term polyethylene glycols refer to compounds that are obtained by reacting
ethylene glycol with ethylene oxide. PEGs with molecular weight more than 300,000
are commonly termed as polyethylene oxides.
31
B) Polyvinyl Pyrrolidone (PVP):
PVPs have molecular weights ranging from 10,000 to 700,000. It is soluble in
solvents like water, ethanol, chloroform and isopropyl alcohol. PVP is not suitable for
preparation of solid dispersions prepared by melt method because it melts at a very
high temperature above 275ºC, where it gets decomposed.
C) Polymers and Surface Active Agent Combinations:
The addition of surfactants to dissolution medium lowers the interfacial tension
between drug and dissolution medium and promotes the wetting of the drug thereby
they enhance the solubility and dissolution of drug. Ternary dispersion systems have
higher dissolution rates than binary dispersion systems[109]
.
D) Cyclodextrins:
Cyclodextrins are primarily used to enhance solubility, chemical protection, taste
masking and improved handling by the conversion of liquids into solids by
entrapment of hydrophobic solute in hydrophilic cavity of CD[38-41]
. Advantages of
CD include increasing the stability of the drug, release profile during gastrointestinal
transit through modification of drug release site and time profile, decreasing local
tissue irritation and masking unpleasant taste.
E) Phospholipids:
Phospholipids are major structural components of cell membranes.
Phosphotidylcholine was first isolated from egg yolk and brain. In phosphatidyl
ethanolamine and phosphatidyl serine, the choline moiety is replaced by ethanolamine
and serine respectively. Other phospholipids that occur in tissues include
phosphotidyl ethanolamide, phosphotidyl serine and phosphotidyl glycerol. Naturally
occuring lecithins contain both a saturated fatty acid and unsaturated fatty acids with
some exceptions[72]
.
32
Table 2.1: Materials used as carrier for solid dispersion
Sr. No. Category Examples
1 Sugars
Dextrose, Sucrose, Galactose, Sorbitol,
Maltose, Xylitol, Mannitol[67]
, Lactose[64]
2 Acids Citric acid, Succinic Acid[68]
3 Polymeric materials
PVP[56]
, PEG[58]
, Celluloses like HPMC[60]
,
HEC, HPC, Pectin, Galactomannan, CDs[38]
4 Insoluble/ enteric polymer HPMC[60]
, Phthalate, Eudragits[71]
5 Surfactants
Polyoxyethylene stearate, Renex,
Poloxamers[63]
, texafor, Deoxycholic acid,
Tweens, Spans[65]
6 Miscellaneous
Pentaerythritol, Pentaerythrityl tetra acetate,
Urea[62]
, Urethane, Hydroxy alkyl xanthins
2.1.5 METHODS OF PREPARATION OF SOLID DISPERSIONS:
A) Fusion Process:
The fusion process is technically less difficult method of preparing dispersions
provided the drug and carrier are miscible in the molten state. Drug and carrier
mixture of eutectic composition is molten at temperature above its eutectic
temperature. Then molten mass is solidified on an ice bath and pulverized to a
powder. Since a super saturation of the drug can be obtained by quenching the melt
rapidly (when solute molecules are arrested in solvent matrix by instantaneous
solidification), rapid congealing is favoured. The solidification is often performed on
stainless steel plates to facilitate rapid heat loss. A modification of the process
involves spray congealing from a modified spray drier onto cold metal surfaces.
33
Decomposition should be avoided during fusion but is often dependent on
composition and affected by fusion time, temperature and rate of cooling. Therefore,
to maintain drug content and physicochemical stability of formulation at an
acceptable level, fusion must be effected at a temperature only just in excess of that
which completely melts both drug and carrier.
B) Solvent Evaporation Process:
Solid dispersion prepared by solvent removal process was termed by Bates et
al.[110]
as „Coprecipitates‟. But these systems should more correctly, be designated as
„Coevaporate‟, a term that has been recently adopted.
The solvent evaporation process uses organic solvents, the agent to intimately mix
the drug and carrier molecules and was initially used by Tachibana and Nakamura[111]
,
where, chloroform was used to co-dissolve β-carotene and PVP to form Co-evaporate.
The choice of solvent and its removal rate are critical parameters affecting the
quality of the solid dispersion. Since the chosen carriers are generally hydrophilic and
the drugs are hydrophobic, the selection of a common solvent is difficult and its
complete removal, necessitated by its toxic nature, is imperative. Vacuum evaporation
may be used for solvent removal at low temperature and also at a controlled rate.
More rapid removal of the solvent may be accomplished by freeze-drying. The
difficulties in selecting a common solvent to both drug and carrier may be overcome
by using an azeotropic mixture of solvent in water.
C) Fusion Solvent Method:
This method consists of dissolving the drug in a suitable solvent and incorporating
the solution directly in the melt of carrier. If the carrier is capable of holding a certain
proportion of liquid yet maintains its solid properties and if the liquid is innocuous,
34
then the need for solvent removal is eliminated. This method is particularly useful for
drugs that have high melting points or they are thermo-labile.
D) Supercritical Fluid Process:
Supercritical CO2 is a good solvent for water-insoluble as well as water-soluble
compounds under suitable conditions of temperature and pressure. Therefore, it has
potential as an alternative for conventional organic solvents used in solvent based
processes for forming solid dispersions due to its favorable properties of being non-
toxic and inexpensive. The process consists of the following steps[27, 28]
:
i. Charging the bioactive material and suitable polymer into the autoclave.
ii. Addition of supercritical CO2 under precise conditions of temperature and
pressure, that causes polymer to swell
iii. Mechanical stirring in the autoclave
iv. Rapid depressurization of the autoclave vessel through a computer controlled
orifice to obtain desired particle size.
The temperature condition used in this process is fairly mild (35-75°C), which
allows handling of heat sensitive biomolecules, such as enzymes and proteins.
2.1.6 ADVANTAGES AND DISADVANTAGES OF SOLID DISPERSIONS:
The advantages of solid dispersion include the rapid dissolution rates that result in
increased bioavailability and a reduction in pre-systemic metabolism. The latter
advantage may occur due to saturation of the enzyme responsible for
biotransformation of the drug or inhibition of the enzyme by the carrier, as in the case
of morphine-tristearin dispersion[112]
. Both can lead to the need for lower doses of the
drug. Other advantages include transformation of the liquid form of the drug into a
solid form (e.g. clofibrate and benzoyl benzoate can be incorporated into PEG 6000 to
give a solid, avoiding polymorphic changes and thereby bioavailability problems[113]
)
35
and protection of certain drugs by PEGs against decomposition by saliva to allow
buccal absorption.
The disadvantages of solid dispersion are related mainly to stability issue. Several
systems have shown changes in crystallinity and a decrease in dissolution rate with
aging[114, 115]
. Moisture and temperature have a more prominent deteriorating effect on
solid dispersions than on physical mixtures. Some solid dispersion may not lend them
to easy handling because of tackiness.
Fig. 2.7: Pharmaceutical Applications of Solid Dispersion
36
2.1.7 FUTURE PROSPECTS:
Despite many advantages of solid dispersion, issues related to preparation,
reproducibility, formulation, scale up and stability has limited its use in commercial
dosage forms for poorly water-soluble drugs. Successful development of solid
dispersion systems for preclinical, clinical and commercial use has been feasible in
recent years due to the availability of surface active and self-emulsifying carriers with
relatively low melting points. The preparation of dosage forms involves the
solubilization of drug in melted carriers and the filling of the hot solutions into hard
gelatin capsules because of the simplicity of manufacturing and scale-up processes,
the physicochemical properties and as a result, the bioavailability of solid dispersions
are not expected to change significantly during the scale-up. For this reason, the
popularity of the solid dispersion system to solve difficult bioavailability issues of
poorly water-soluble drugs will grow rapidly. As the dosage form can be developed
and prepared using small amount of drug substance in early stages of the drug
development process, the system might have an advantage over such other commonly
used bioavailability enhancement techniques such as micronization and soft gelatin
encapsulation.
One major focus of the future research will be the identification of new surface
active and self-emulsifying carriers for solid dispersion. Only a small number of such
carriers are currently available for oral use. Some carriers that are used only for
topical applications of drug may be qualified for oral use by conducting appropriate
toxicological testing. One limitation in the development of solid dispersion systems is
inadequate drug solubility in carrier, so a wider choice of carriers will increase the
success of dosage form development.
37
Research should also be directed towards identification and synthesis of new
possibilities of vehicles or excipients that would retard or prevent crystallization of
drugs from super-saturated systems. Attention must be given to any physiological,
pharmacological and toxicological effects of carriers. Many of the surface active and
self-emulsifying carriers are lipoidal in nature, so potential roles of such carriers on
drug absorption, especially on their inhibitory effects on CYP-3 based drug
metabolism and p-glycoprotein mediated drug efflux will require careful
consideration.
In addition to bioavailability enhancement, much recent efforts and advances in
the research on solid dispersion systems are directed towards the development of
extended release dosage forms.
Physical and chemical stability of both drug and carrier in a solid dispersion are
major developmental issues, so future research needs to be directed to address various
stability issues. The semisolid and waxy nature of solid dispersions poses unique
stability problem that might not be seen in other types of solid dosage forms.
Predictive methods are necessary for the investigation of any potential drug
crystallization and its impact on dissolution and bioavailability. Also possible drug-
carrier interactions must also be investigated.
38
2.2 REVIEW OF LITERATURE:
Sekiguchi and Obi[96]
in 1961 first demonstrated the unique approach of solid
dispersion to reduce the particle size and increase dissolution and absorption rate.
They proposed the formation of eutectic mixture of poorly soluble drug such as
sulfathiazole with physiologically inert, easily water-soluble carrier such as urea. The
eutectic mixture was prepared by melting the physical mixture of drug and carrier,
followed by a rapid solidification process. Upon exposure to aqueous fluid, the active
drug was expected to be released into the fluids as fine, dispersed particles because of
the fine dispersion of the drug in the solid eutectic mixture and the rapid dissolution
of the soluble matrix.
Goldberg et al. [99, 100, 107]
in a series of reports in 1965-66, presented a detailed
experimental and theoretical discussion on advantages of solid solution over the
eutectic mixture.
Tachibana and Nakamaru[111]
reported a novel method for preparing aqueous
colloidal dispersions of β-carotene by using water-soluble polymers such as polyvinyl
pyrrolidone. They dissolved the drug and the carrier in a common solvent and then
evaporated the solvent completely. A colloidal dispersion was obtained when the co-
precipitate was exposed to water.
Chiou and Riegelman[52]
advocated the application of glass solution to increase
dissolution rate. They used PEG 6000 as a dispersion carrier. It is demonstrated that
the pharmaceutical technique of solid dispersion can play an important role in
increasing dissolution, absorption and therapeutic efficacy of drugs in future.
Therefore, a thorough understanding of its fast release principles, methods of
preparation, selection of suitable carriers, determination of physical properties,
limitations and disadvantages is essential in its practical and effective applications.
39
Duncan et al. [103]
discussed the nature of glassy state with particular emphasis on
the molecular processes associated with glass transitional behavior and the use of
thermal methods for characterizing the glass transition temperature. The practicalities
of such measurements, the significance of the accompanying relaxation endotherm
and plasticization effects are considered. The advantages and difficulties associated
with the use of amorphous drugs were outlined, with discussion given regarding the
problems associated with physical and chemical stability. Also, the principles of
freeze drying were described, including discussion of the relevance of glass
transitional behavior to product stability.
Xiaolin et al. [116]
studied hydrogen bonding patterns and strength in a series of
structurally related compounds. Seven 1, 4-dihydropyridine calcium channel blockers
were evaluated. They found that H-bonding patterns (acceptor group) varied between
the crystalline compounds, but were remarkably consistent in the amorphous
compounds. Thus the acceptor group in the amorphous phase is not necessarily the
same as in the crystalline counterpart.
Makoto Otsuka et al. [117]
studied effect of humidity on the physicochemical
properties of amorphous forms of cimetidine using differential scanning calorimetry,
isothermal micro-calorimetry and X-ray diffraction analysis. They suggested that the
crystallization process consists of an initial stage of the nuclei formation and a final
stage of crystal growth.
Urbanetz et al. [118]
investigated improvement in the storage stability of
nimodipine by preventing recrystallization. The first approach in order to prevent
recrystallization was the development of thermodynamically stable solid solutions by
using solvents added to enhance the solubility of nimodipine in the carrier material.
The second approach was to enhance storage stability by the addition of
40
recrystallization inhibitors to super-saturated solid solutions, thereby delaying the
transformation of the metastable super-saturated system to the thermodynamically
stable state. Stabilization by solubility enhancement was only successful at drug
loadings not exceeding 10% (w/w) using polyethylene glycol 300 as solubility
enhancing additive, while for second approach povidone K17 effectively prevents
recrystallization in solid solutions containing 20% (w/w) of nimodipine during storage
at 25°C over silica gel.
Paradkar et al. [119]
emphasized on stability aspects of formulated solid dispersion
of anti-inflammatory drug, valdecoxib with hydrophilic carriers selected PVP K30
and HPC by spray-drying method. The evaluation of SD system suggests that the drug
was transformed into its amorphous form to elicit increased dissolution rate. During
stability testing, saturation solubility of spray-dried valdecoxib dropped drastically
within 15 min. While, there was gradual decrease in saturation solubility and
dissolution rate of solid dispersion, over the period of 3 months, showing
comparatively enhanced stability.
Paradkar et al. [120]
, in another study, prepared solid dispersions of glibenclamide
and polyglycolized glycerides (Gelucire®) with the aid of silicon dioxide (Aerosil®
200) as an adsorbent by spray-drying technique. The study demonstrated the high
potential of spray-drying technique for obtaining stable free flowing SDs. Moreover
in vivo study in Swiss Albino mice also justified the improvement in the therapeutic
efficacy of amorphous drug in SDs over pure drug. SDs also showed improved
stability which could be due to the hydrogen bonding between the drug and the
carriers and the adsorption on the surface of amorphous silicon dioxide.
Ozeki et al. [121]
applied solid dispersion approach for controlled release of
phenacitin by the formation of an inter-polymer complex between methyl cellulose
41
and carbopol using 6 different molecular weights of methyl cellulose. The effect of
the ratio of polymer and molecular weight of methyl cellulose on the phenacitin
release was studied. The results of the study also clarify the mechanism of drug
release from the granules with help of semi-empirical mathematical model.
Seo et al. [122]
formulated solid dispersions of diazepam by melt agglomeration
method for improving the dissolution rate. Lactose monohydrate was melt
agglomerated with polyethylene glycol (PEG) 3000 and Gelucire® 50/13 as meltable
binders in a high shear mixer. The binders were added either as a mixture of melted
binder and diazepam by a pump-on procedure or by a melt-in procedure of solid
binder particles. Different drug concentrations, maximum manufacturing temperatures
and cooling rates were investigated. It was found that it is possible to increase the
dissolution rate of diazepam by melt agglomeration. A higher dissolution rate was
obtained with a lower drug concentration.
Chen et al. [123]
prepared solid dispersion of a model drug ABT- 963 with pluronic
by cooling the hot melt of the drug in the carrier. Results showed that, ABT-963
formed a eutectic mixture with Pluronic F68. Both the drug and poloxamer were
crystalline in the solid dispersion with a wide range of composition of each
component. The solid dispersion substantially increased the in vitro dissolution rate of
ABT-963 which was attributed to enhanced hydration of drug in a viscous micro-
environment formed by immediate release of poloxamer. Dosing of the dispersion to
fasted dogs resulted in a significant increase in oral bioavailability. These results
suggested that poloxamer is a promising material for developing solid dispersion.
Gines et al. [124]
, in 1995, studied thermal behavior of Gelucire® 53/10-cinnarizine
binary systems. It was noted from the analytical thermal techniques employed like
42
DSC and hot stage microscopy (HSM), that the molten Gelucire was able to dissolve
the crystals of cinnarizine.
Literature survey was also done for profiling of selected drug candidate-
Gliclazide (GLZ) for formulation of solid dispersion.
Glowka et al. [125]
evaluated bioavailability of gliclazide from some formulations
including conventional gliclazide tablet formulation as well as sustained release
formulation. It demonstrates poor dissolution rate of gliclazide.
Ozkan et al. [126]
prepared inclusion complexes of GLZ with β-CD using two
methods viz. neutralization and recrystallization. The study showed the inadequacy of
dissolution rate of gliclazide and emphasized on the need of solubility enhancement.
Cham et al. [127]
formulated inclusion complex of GLZ and β-CD by liquid/liquid
extraction method and neutralization method. The solid complex by liquid/liquid
extraction demonstrated a faster release profile attributed to decreased particle size
and wettability of hydrophobic GLZ.
Vijayalakshmi et al.[128]
attempted the solubility enhancement of GLZ by
inclusion complex with HP-β-CD and incorporated the solubility enhanced drug in a
matrix forming polymer (sodium carboxymethyl cellulose) for designing oral
controlled release tablets. The in vivo study was conducted on Newzealand rabbits.
The bioavailability obtained from the standardized solubility enhanced GLZ tablets
was greater than that of the tablets containing untreated gliclazide.
Abou-Auda et al. [129]
studied effect of β-CD complexation on solubility,
bioavailability as well as pharmacodynamic activity of GLZ. The prepared binary
system showed increased dissolution rate which can be correlated with
pharmacokinetic as well as hypoglycemic study in Beagle Dogs.
43
2.3 OBJECTIVES:
Solubility of a drug plays a very important role in dissolution and hence
absorption of drug which ultimately affects its bioavailability. Poorly soluble drugs
particularly of BCS Class II represent a problem for their scarce availability.
Gliclazide (GLZ) is a second generation hypoglycemic sulfonylurea oral
hypoglycemic agent used in the treatment of non insulin dependent diabetes mellitus
(NIDDM). Due to its short-term action, GLZ has been considered suitable for
diabetic patients with renal impairment and for elderly patients those have reduced
renal function and follow a sulphonyl urea treatment which may increase the risk of
hypoglycemia[130]
.
The remarkable recede in the therapeutic application and efficacy of gliclazide as
immediate release oral dosage forms is its very low aqueous solubility and inter-
individual variability in its bioavailability mainly because of its hydrophobic
molecular nature and crystalline characteristics[126-129, 131]
.
Hence, considering the factors affecting solubility and bioavailability, attempts
have been made to apply the principles of solid dispersion techniques to enhance the
dissolution and oral bioavailability of gliclazide with following objectives:
1. Formulation of solid dispersion for the improvement of solubility and
dissolution characteristics of gliclazide
2. Characterization and confirmation of amorphous dispersion
3. Characterization of solubility, dissolution rate and stability
4. In vivo evaluation of bioavailability
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2.4 PLAN OF WORK:
1. Literature survey
2. Procurement of materials
3. Experimental
A. Drug authentication
B. Compatibility study
C. Calibration curve of gliclazide
D. Phase solubility study
E. Formulation of solid dispersion.
F. Evaluation and characterization of solid dispersion:
a. Drug content
b. Interaction study
c. Thermal study
d. Assessment of crystallinity
e. In vitro dissolution study
f. In vivo pharmacodynamic study
4. Stability study of optimized formulation
5. Compilation of data
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2.5 DRUG PROFILE:
GLICLAZIDE[132-135]
Gliclazide (GLZ) is a second generation sulphonylurea, oral hypoglycemic agent
used in the treatment of non-insulin-dependant diabetes mellitus (NIDDM or Type-II
diabetes mellitus). GLZ improves defective insulin secretion and may reverse insulin
resistance observed in patients with NIDDM. These actions are reflected in blood
glucose level which is maintained during short and long-term administration and is
comparable with that achieved with other sulphonylurea agents.