SOLID DISPERSIONS
Poorly water soluble
compounds have solubility and dissolution related bioavailability problems.
The solubility behavior of drugs remains one of the most challenging aspects in
formulation development. Currently only 8% of the new molecules have both high solubility
and permeability. The drugs therapeutic efficacy depends upon the
bioavailability and ultimately upon the solubility. Salt formation, particle
size reduction, etc. have commonly been used to increase the dissolution rate
of drugs, there are some practical limitations with these techniques the
desired bioavailability enhancement may not always be achieved. Solid
dispersion seems to be a viable technique for overcoming this problem. In this
review, it is intended to discuss the recent advances related on the area of
solid dispersion. Finally industrially feasible alternative approaches in the
manufacture of solid dispersion have been highlighted.(V. Kamalakkannan.et.al)
The
term solid dispersion refers to a group of solid products consisting of at
least two different components, generally a hydrophilic matrix and a
hydrophobic drug. The matrix can be either crystalline or amorphous.(1)The drug
can be dispersed molecularly, in amorphous particles (clusters) or in
crystalline particles.(2)
Classification
3
On the basis of fast release
mechanisms solid dispersions are classified into six groups, they are:-
1. Simple
Eutectic Mixtures
2. Solid
solution
3. Glass
solution and Glass suspension
4. Amorphous
precipitation of drug in crystalline carrier
5. Compounds
or complex formation between drug and carrier
6. Any
combination among the above.
1.
Simple Eutectic Mixtures 4,5
It
is prepared by rapid solidification of
the fused liquid of two components which show complete liquid miscibility and
negligible solid solubility. Thermodynamically such a system is regarded as
intimately blended physical mixture of its two crystalline components. These
systems are also prepared by fusion method. When an eutectic composed of a
poorly soluble drug is exposed to water or GI fluids, the carrier may be
released into an aqueous medium in fine crystalline form. The increase of
specific area due to this reduction of particle size generally increases the rates
of dissolution and oral absorption of poorly soluble drugs.
Figure1:Eutectic mixture
.
The
following factors may contribute to faster dissolution rate of drug dispersed
in the eutectic:-
·
Increase in drug solubility.
·
Solubilization effect by the carrier
which completely dissolves in a short time in diffusion in a short time in
diffusion layer surrounding drug particles.
·
Absence of aggregation and agglomeration
between fine crystallites of pure hydrophobic drug.
·
Excellent wettability and dispersibility
of a drug as the encircling soluble carrier readily dissolves and causes water
to contact as wet drug particles.
·
Crystallization of drug in a Meta stable
form after solidification from fused solution, which has high solubility.
Examples of eutectics include;
1.
Paracetamol-urea
2.
Griseofulvin-urea
3.
Griseofulvin-succinic acid.
Solid solution and eutectics, which
basically melts, are easily to prepare and economically with no solvents involved,
the method however cannot be applied to
- Drugs which fail to crystallize from mixed melt.
- Thermo labile drugs.
·
Carriers
such as succinic acid that decompose at melting point.
2. Solid solutions 6,7,8
Solid
solutions, compared to a liquid solution are made up of a solid solute
dissolved in a solid solvent. it is
often called a “ mixed crystal” because the two components crystallize together
in a homogenous phase system. Goldberg et al. suggested that a solid solution
of poorly soluble drug in a rapidly soluble carrier achieves a faster
dissolution than an eutectic mixture because the particle size of drug in a
solid solution is reduced to a minimum state.i.e. Molecular size.
The solid solution according to
extent of miscibility between two components can be classified into two groups
1. Continuous solid solution,
2. Discontinuous solid solution
.1.
Continuous solid solutions
The two components are
miscible or soluble at solid state in all proportions. No established solution
of this kind has been shown to exhibit fast release dissolution properties. the
faster dissolution rate would be
obtained if the drug is present as a minor compartment.
2.
Discontinues solid solutions
Here there is only limited
solubility of a solute in a solid solvent in this group of solid solutions.
3.
Glass solutions and Glass suspensions 9
The concept of formation of glass
solution was first introduced by Chiou and Riegelman, as another potential
modification of dosage forms in increasing dissolution and absorption. a glass
solution is a homogenous, glassy system in which a solute is usually obtained by abrupt quenching of the melt. Many compounds
have been shown to be able to form glasses readily upon cooling from liquid
state. These compounds include sucrose, glucose, ethanol and 3- methyl hexane.
Glass formation is a common in many polyhydroxy molecules such as sugars,
presumably due to their strong hydrogen bonding which may prevent their
crystallization. Polymers possessing
linear, flexible chains can freeze into a glass state to transparency and
brittleness. Glass formulation can occur for the pure substance itself or when
in presence of other components. The strength of chemical binding in a glass
solution is much less compared to that in a solid solution. Hence, dissolution
rate of drugs in the glass solution is faster than in solid solution. Citric
acid melt is highly viscous and can be drawn into a thread or sheet .after
standing at 37 0C for a few days, a hard brittle and transport glass
can be attained. Glassy solutions were obtained after cooling melts 5 and 20%
Griseofulvin, 10% Phenobarbital and 10% Hexabarbitol.
4.
Amorphous precipitations of a drug in a crystalline carrier 10
Instead of forming a simple eutectic mixture in which both
drug and the carrier crystalline simultaneously form a solvent method of
preparation, the drug may also precipitate out in an amorphous form in
crystalline carrier. The amorphous form is the highest energy form of pure drug
and has faster dissolution and absorption rates than crystalline form.
Amorphous Novobicin has 10fold
higher solubility than its crystalline form; amorphous sulphathiazole dispersed in crystalline urea was believed to be primary contributing in increasing its
oral absorption in man.
Method’s of
preparations
Melting
Method
The melting or fusion method was first proposed by
Sekiguchi and Obi to prepare fast release solid dispersion dosage forms(11).
The physical mixture of a drug and a water-soluble carrier was heated directly
until it melted. The melted mixture was then cooled and solidified rapidly in
an ice bath under rigorous stirring. The final solid mass was crushed,
pulverized, and sieved. Such a technique was subsequently employed with
some modification by Goldberg et al and Chiou and Riegelman. The solidified
masses were often found to require storage of 1 or more days in a desiccator at
ambient temperatures for hardening and ease of powdering. Some systems, such as
griseofulvin and citric acid, were found to harden more rapidly if kept at 37_
or higher temperatures. The melting point of a binary system is dependent upon
its composition, i.e., the selection of the carrier and the weight fraction of
the drug in the system(12).
Advantages
- Simplicity of method.
- Super saturation of a solute or a drug in a system can often be obtained by quenching the melt rapidly from high temperature.
Disadvantages
- Some drugs or carriers may decompose or evaporate during fusion process at high temperatures. For e.g. Succinic acid.
B. Griseofulvin is quite volatile and may also partially decompose by dehydration near
its melting point
2.
Solvent method
It
has been used for a long time in the preparation of solid solutions or mixed
crystals of organic or inorganic compounds. They are prepared by dissolving a
physical mixture of two solid components in components in a common solvent,
followed by evaporation of the solvent.(13).
Figure 2: A schematic
representation of preparation of solid dispersion by solvent evaporation
technique.
Advantages
Thermal decomposition of drugs or
carriers can be prevented because of low temperature required for the
evaporation of organic solvents.
Disadvantages
- High cost of preparation.
- Difficulty in completely removing the solvent.
3. Difficulty
in producing crystal forms.
3.
Melting solvent method
It was shown 5-10% w/w of liquid compounds
could be incorporated into polyethylene glycol 6000 without significant loss of
its solid property. Hence its first possible to prepare solid dispersions by first dissolving a drug in a suitable
liquid solvent and then incorporating the solution directly into a melt of
polyethylene glycol, without removing liquid solvent.
Advantage
It
possess advantages of both above methods.
Disadvantage
From practical stand point, it is only limited to drugs with a low
therapeutic dose example below 50mg the feasibility of the method was
demonstrated on spirinolactone- polyethylene glycol 6000 and Griseofulvin-polyethylene
glycol 6000 systems.
4. Hot melt extrusion method 14
In this
method for pharmaceutical dosage forms a blend of active ingredients, polymeric
carrier and other processing aids including plasticizers and antioxidants is
heated and softened. It has many advantages over traditional methods to prepare
sustained release dosage forms, because hot melt extrusion is advent free
process, there are no concerns with solvent handling or recovery after
processing. It is simple and continuous process for preparation of tablets and
granulations. the process is faster and there were fewer steps than the wet granulation method. When the
extrudate is cooled at room temperature the polymeric thermal binder solidifies
and bonds the excipients together to form a matrix. This technique has been
previously been used successfully to prepare pharmaceutical dosage forms.
Follniers et al in 1994 extruded sustained release diltiazem granules.
Aitkin-Nichol et al in 1992 and Replica and co workers in 1994 reported on properties
of hot melt extruded sustained release matrix tablets. Tablets containing
Polyethylene oxide were reported by Zhang and Mcgnity in 2000.
Dropping
method
The dropping method was developed by Ulrich et al.
to facilitate the crystallization of different chemicals, is a new procedure
for producing round particles from melted solid dispersions. This technique may
overcome some of the difficulties inherent in the other methods.
A solid dispersion of a melted drug– carrier mixture
is pipetted and then dropped onto a plate, where it solidifies into round
particles. The size and shape of the particles can be influenced by factors
such as the viscosity of the melt and the size of the pipette, because
viscosity is highly temperaturedependent, it is very important to adjust the
temperature so that when the melt is dropped onto the plate it solidifies to a
spherical shape. Produce solid dispersions by the dropping method at an
industrial level developed by Rotoform; Sandvik Process Systems Co, Sandviken,
Sweden (15).
The important advantage of the dropping method does
not use organic solvents and therefore, has none of the problems associated
with solvent evaporation. The method also avoids the pulverization, sifting and
compressibility difficulties encountered with the other melt methods.
Disadvantages of the dropping method, only
thermostable drugs can be used and the physical instability of solid
dispersions is a further challenge.
Although there is still much work to do in this
field (better size distribution, uniformity and stability), the dropping method
is a promising approach in the formulation of solid dispersions. Simplifying
the formulation process for the dropping method may overcome manufacturing
difficulties.
PHYSICAL
MIXTURE METHOD
The physical mixtures were prepared by weighing the calculated amount of drug and carriers and then mixing them in a glass mortar by triturating. The resultant physical mixtures were passed through 44-mesh sieve and stored in desiccators until used for further studies. (16).
CO-
GRINDING METHOD
The calculated amounts of drug and carriers where weighed and mixed together with one ml of water. The damp mass obtained was passed through a 44-mesh sieve; the resultant granules were dispersed in Petri dishes and dried at 60°C under vacuum, until a constant weight was obtained. The granules obtained were stored in desiccators until used for further studies.(17).
METHODS
FOR THE CHARACTERIZATION OF SOLID DISPERSIONS
PARTICLE
SIZE
Scanning electron microscopy (SEM) polarization microscopy method is used
to study the microscopic surface morphology of drug and carriers and sometimes
the polymorphism of drug. The fine dispersion of drug particles in the carrier
matrix may be visualized.
DISSOLUTION
TESTING
Drugs having intrinsic dissolution rate < 0.1 mg/cm2//min usually
exhibit dissolution rate limited absorption. Comparison of dissolution profile
of drug, physical mixtures of drug and carrier and solid dispersion may help to
indicate the mechanism of improved release of drug in the formulation
(solubilization / wetting / particle size reduction).
INFRARED
SPECTROSCOPY
Infrared spectroscopy (IR) helpful in determining the solid state of the
drug (molecular dispersion, amorphous, crystalline or a combination) in the
carrier regardless of the state of the carrier. Crystallinities of under 5-10%
cannot generally be detected. It also used to study the interaction occur
between drug and polymer by matching the peaks of spectra. The absence of any
significant change in the IR spectral pattern of drug & polymer physical
mixture indicated the absence of any interaction between the drug and the
polymer.
DIFFERENTIAL
SCANNING CALORIMETRY
A frequently used technique to detect the amount of crystalline material
is Differential Scanning Calorimetry (DSC). (18) It help to study the changes
in the physical state of solid dispersion may occur during heating, and the
presence of polymer may influence the melting behavior of drug (e.g. melting
point depression). Results need to be confirmed by another technique.
Crystallinities under 2% cannot generally be detected.
X-Ray
DIFFRACTION
Powder X-ray diffraction can be used to qualitatively detect material
with long range order. Sharper diffraction peaks indicate more crystalline
material. Recently developed X-ray equipment is semiquantitative.
ADVANTAGES
OF SOLID DISPRESION
Generally, solid dispersion is
mainly used
o To reduced particle size
o To improve weetability
o To improve porosity of drug
o To decrease the crystalline structure of drug in to amorphous form
o To improve dissolvability in water of a poorly water-soluble drug in a pharmaceutical
o To mask the taste of the drug substance
o To prepare rapid disintegration oral tablets.
o To reduced particle size
o To improve weetability
o To improve porosity of drug
o To decrease the crystalline structure of drug in to amorphous form
o To improve dissolvability in water of a poorly water-soluble drug in a pharmaceutical
o To mask the taste of the drug substance
o To prepare rapid disintegration oral tablets.
REDUCED
PARTICLE SIZE
Solid dispersions represent the last state on particle size reduction,
and after carrier dissolution the drug is molecularly dispersed in the
dissolution medium. Solid dispersions apply this principle to drug release by
creating a mixture of a poorly water soluble drug and highly soluble carriers.A
high surface area is formed, resulting in an increased dissolution rate and,
consequently, improved bioavailability (19).
IMPROVED
WETTABILITY
The enhancement of drug solubility is related to the drug wettability
improvement verified in solid dispersions (20). It was observed that even carriers
without any surface activity, such as urea (Sekiguchi and Obi, 1964) improved
drug wettability. Carriers with surface activity, such as cholic acid and bile
salts. When used, can significantly increase the wettability property of drug.
Moreover, carriers can influence the drug dissolution profile by direct dissolution
or co-solvent effects (21)(22).
INCREASE
POROSITY
Particles in solid dispersions have been found to have a higher degree of
porosity (23). The increase in porosity also depends on the carrier properties,
for example, solid dispersions containing linear polymers produce larger and
more porous particles than those containing reticular polymers and, therefore,
result in a higher dissolution rate (24). The increased porosity of solid
dispersion particles also hastens the drug release profile.
DRUGS
IN AMORPHOUS STATE
Poorly water soluble crystalline drugs, when in the amorphous state tend
to have higher solubility (25). The enhancement of drug release can usually be
achieved using the drug in its amorphous state, because no energy is required
to break up the crystal lattice during the dissolution process (26). In solid
dispersions, drugs are presented as supersaturated solutions after system
dissolution, if drugs precipitate it is as a metastable polymorphic form with
higher solubility than the most stable crystal form (Leuner and Dressman, 2000,
Karavas et al., 2006). For drugs with low crystal energy (low melting
temperature or heat of fusion), the amorphous composition is primarily dictated
by the difference in melting temperature between drug and carrier. For drugs
with high crystal energy, higher amorphous compositions can be obtained by
choosing carriers, which exhibit specific interactions with them (27).
ALTERNATIVE STRATEGIES
LYOPHILISATION TECHNIQUE
Freeze-drying involves transfer of heat and mass to and from the product
under preparation. This technique was proposed as an alternative technique to
solvent evaporation. Lyophilisation has been thought of a molecular mixing
technique where the drug and carrier are co-dissolved in a common solvent,
frozen and sublimed to obtain a lyophilized molecular dispersion. (28)
SPRAYING ON SUGAR BEADS
USING FLUIDIZED BED COATING
The approach involves fluidized bed coating system, where-in a drug-carrier
solution is sprayed onto the granular surface of excipients or sugar spheres to
produce either granules ready for tableting or drug-coated pellets for
encapsulation in one step. This method has been applied for both controlled-and
immediate-release solid dispersions (29)
For e. g.,
Itraconazole coated on sugar sphere, is made by layering onto sugar beads a
solution of drug and hydroxypropylmethylcellulose (HPMC) in an organic solvent
of dichloromethane and ethanol.
DIRECT CAPSULE FILLING
The filling of semi solid materials into hard gelatin capsules as melts,
which solidify at room temperature, was first done in1978. Direct filling of
hard gelatin capsules with the liquid melt of solid dispersions avoids
grinding-induced changes in the crystallinity of the drug. A surfactant must be
mixed with the carrier to avoid formation of a drug-rich surface layer (e.g.,
poly-sorbate80 with PEG, phosphatidyl choline with PEG). The temperature of the
molten solution should not exceed ~70-C because it might compromise the
hard-gelatin capsule shell.
THE USE OF SURFACTANT
The utility of the surfactant systems in solubilization is well known.
Adsorption of surfactant on solid surface can modify their hydrophobisity,
surface charge, and other key properties that govern interfacial processes such
as flocculation/dispersion, floatation, wetting, solubilization, detergency,
enhanced oil recovery and corrosion inhibition. Surfactants have also been
reported tocause solvation /plasticization, manifesting in reduction of melting
the active pharmaceutical ingredients, glass transition temperature and the
combined glass transition temperature of solid dispersions. Because of these
unique properties, surfactants have attracted the attention of investigators
for preparation of solid dispersions. Two of the important surface-active
carriers used are Gelucire 44/14and Vitamin ER-alpha-
tocopherylpolyethyleneglycol 1000 succinate (TPGS). In which Gelucire44/14 has
commonly been used in solid dispersion for the bioavailability enhancement of
drugs. A commonly used surfactant, Polysorbate 80, when mixed with solid PEG,
has also been reported to be an alternative surface-active carrier.(30)
ELECTROSTATIC
SPINNING METHOD
This technology used in the polymer industry combines solid solution/dispersion
technology with nanotechnology (31).This technology is now applied in the
pharmaceutical field (32). Electrospinning is a process in which solid fibers
are produced from a polymeric fluid stream solution or melt delivered through a
millimeter-scale nozzle. In this process, a liquid stream of a drug/polymer
solution is subjected to a potential between 5 and 30 kV. When electrical
forces overcome the surface tension of the drug/polymer solution at the air
interface, fibers of submicron diameters are formed. As the solvent evaporates,
the formed fibers can be collected on a screen to give a nonwoven fabric, or
they can be collected on a spinning mandril. The fiber diameters depend on
surface tension, dielectric constant, feeding rate, and electric field strength
(33). Water-soluble polymers would be useful in the formulation of immediate
release dosage forms, and water-insoluble (both biodegradable and
nonbiodegradable) polymers are useful in controllable dissolution properties.
Fabrics generated by water-soluble carriers could be used in oral dosage
formulations by direct incorporation of the materials into a capsule.
Itraconazole/HPMC nanofibers have been prepared using this technique (34)
SUPER
CRITICAL FLUID (SCF) TECHNOLOGY
This technology has been introduced in the late 1980s and early 1990s,
From the very beginning of supercritical fluid particle generation research,
the formation of biocompatible polymer and drug-loaded biopolymer
micro-particles for pharmaceutical applications has been studied intensively by
a number of researcher groups CFs either as solvent: rapid expansion from
supercritical solution (RESS) or antisolvent: gas antisolvent (GAS),
supercritical antisolvent (SAS), solution enhanced dispersion by supercritical
fluids (SEDS) and/or dispersing fluid: GAS, SEDS, particles from gas-saturated
solution (PGSS). Conventional methods, i.e. Spray drying, solvent evaporation
and hot melt method often result in low yield, high
residual solvent content or thermal degradation of the active substance. In the
supercritical fluid carbon dioxide is used used as
either a solvent for drug and matrix or as an anti-solvent (35)(36).
When supercritical CO2 is used as solvent, matrix and drug are dissolved
and sprayed through a nozzle, into an expansion vessel
with lower pressure and particles are immediately formed. The adiabatic
expansion of the mixture results in rapid cooling. This technique does not
require the use of organic solvents and since CO2 is considered environmentally
friendly, this technique is referred to as ‘solvent free’. The technique is
known as Rapid Expansion of Supercritical Solution (RESS). However, the
application of this technique is very limited, because the solubility in CO2 of
most pharmaceutical compounds is very low (<0.01wt-%)
(37) and decreases with increasing polarity.
Different acronyms were used by various authors to denote micronization
processes: aerosol solvent extraction system (ASES), precipitation with a
compressed fluid antisolvent (PCA), gas anti-solvent (GAS), solution enhanced
dispersion by supercritical fluids (SEDS) and supercritical anti-solvent (SAS).
The SAS process involves the spraying of the solution composed of the solute
and of the organic solvent into a continuous supercritical phase flowing concurrently
use of supercritical carbon dioxide is advantageous as it is much easier to
remove from the polymeric materials when the process is complete, even though a
small amount of carbon dioxide remains trapped inside the polymer; it poses no
danger to the patient. In addition the ability of carbon dioxide to plasticize
and swell polymers can also be exploited and the process can be carried out
near room temperature Moreover, supercritical fluids are used to lower the
temperature of melt dispersion process by reducing the melting temperature of
dispersed active agent. The reason for this depression is the solubility of the
lighter component (dense gas) in the forming phase
(heavier component).
Pharmaceutical applications
In
addition to absorption enhancement, the solid dispersion may have numerous
pharmaceutical applications which remain to be further explored .it is possible
that such a technique can be used
- To
obtain a homogenous distribution of small amount of drugs at solid state.
- To
stabilize unstable drugs.
- To
dispense liquid or gaseous compounds
- To
formulate a faster release priming dose in a sustained release dosage form.
To
formulate sustained release dosage or prolonged release regimens of soluble
drugs by using poorly soluble or insoluble carriers.(38)
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