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Please cite this article in press Avinash V.Dhobale et al., Solubility enhancement techniques- A Review, Indo Am.
J. P. Sci, 2018; 05(04).
Permeation
across
Dissolution biomembrane Drug
Solid Disintegration Solid Drug in
dosage drug solution at the in the
form Deaggregation particles absorption body
site
RDS for RDS for
Lipophilic Hydrophilic
drugs drugs
Figure 1.1: Two rate determining steps (RDS) in the absorption of drugs from orally administered formulations.
Use of surfactants: palmitate is more water soluble than the A and the C
forms (Paul BM and Michael JJ, 2008).
The surface active agents enhance dissolution rate
primarily by promoting wetting and reducing the Pseudopolymorphs:
surface tension between liquid and particle surface.
The stochiometric type of adducts where the solvent
They are generally used in concentration below their
molecules are incorporated in the crystal lattice of the
critical micelle concentration (CMC) values since
solid are called as the solvates. The solvates can exist
above CMC the drug entrapped in the micelle
in different crystalline forms called as
structure fails to partition in the dissolution fluid.
Pseudopolymorphs. When the solvent in association
Non ionic surfactants like polysorbates are widely
with the drug is water, the solvate is known as
used. Surfactants have been added to solid
hydrate. Generally, the anhydrous form of a drug has
dispersions to improve the dissolution rate of poorly
greater aqueous solubility than the hydrates. On the
water-soluble drugs (Aungst BJ et al., 1977). They
other hand, the organic (nonaqueous) solvates have
have also been used to improve miscibility between
greater aqueous solubility than the nonsolvates for
drug and polymer or simply to inhibit drug
example the n-pentanol solvate of fludrocortisones
crystallization during storage. In one study, the
and succinylsulfathiazole are more water soluble than
miscibility of griseofulvin was increased from
their nonsolvated forms. In case of organic solvates,
3%w/w to 40%w/w in PEG6000 by adding 5%w/w
if the solvent is toxic, they are not of therapeutic use
of sodium dodecyl sulfate (Wulff M, 1996).1.2.2.3.
(Brahmankar and Jaiswal, 2006).
Use of salt formsThe aqueous solubility of a poorly
soluble drug can be improved by the selection and Selective adsorption on insoluble carriers:
preparation of an appropriate salt. The formulation
scientist must then determine the resulting A highly active adsorbent such as the inorganic clay
like bentonite can enhance the dissolution rate of
physicochemical properties and assess the sensitivity
poorly water soluble drugs like indomethacin,
of the product to the environmental and chemical
griseofulvin and prednisone by maintaining the
conditions likely to be encountered in handling and
concentration gradient at its maximum. The two
storage. In addition, formation of the salt may also
reasons suggested for the rapid release of drugs from
reduce the toxicity and modify the pharmacological
the surface of clays are: the weak physical bonding
activity of the drug. Therefore, it is recommended
that salt forms be screened early in the between the adsorbate and the adsorbent, and
preformulation investigations to allow clinical hydration and swelling of the clay in the aqueous
evaluation of those candidates deemed suitable by media (Brahmankar and Jaiswal, 2006).
virtue of their physicochemical properties (Steven Drug dispersion in carriers:
HN, 2008).
Alteration in pH of the drug microenvironment: The drug can be dispersed in the hydrophilic carriers
The aqueous solubility of some drugs can be as:
increased by adjusting the pH. Eutectic mixtures
This can be achieved by addition of the suitable Solid dispersions (non-molecular) or
buffers to the formulation e.g. buffered aspirin Solid solutions
tablets. A Solid solution is a binary system comprising of a
Use of metastable polymorphs: solid solute molecularly dispersed in solid solvent.
Since the two components crystallize together in a
Polymorphism describes the existence of a drug in homogeneous one phase system, solid solution are
two or more crystalline forms, each of which also called as molecular dispersion or mixed crystals.
possesses a different space lattice arrangement but is Because of reduction in particle size to the molecular
chemically identical. There are two types of level, solid solution show greater aqueous solubility
polymer: and faster dissolution than eutectic and solid
1. Enantiomeric polymorph is the one which can be dispersions. They are generally prepared by fusion
reversibly changed into another form by altering method whereby a physical mixture of a solute and
the temperature or pressure solvent are melted together followed by rapid
2. Monomeric polymorph, which is unstable at all solidification. Such system, prepared by fusion is
often called as melts (Vasanthavada M et al., 2008).
temperature and pressure.
Metastable polymorphs is more soluble than the Eutectic mixture:
stable polymorph of a drug that exhibits These systems are also prepared by fusion method.
polymorphism e.g. B form of chloramphenicol Eutectic melts differ from solid solution in that the
Figure 1.2: Conformation and numbering of the CDs (Wei-Qin and Hong, 2008)
Figure 1.3: Physical shape of the CD molecule (Wei-Qin and Hong, 2008)
Solid preparations: Thixotropic nature of suspensions can be
controlled.
Oral bioavailability of poor water-soluble
Physical stability of the dispersed system
drugs can be improved by enhancement of
can be improved.
the dissolution rate and/or apparent
solubility (via supersaturation in the 3. Semisolid preparations:
gastrointestinal fluids).
Topical bioavailability can be improved by
Physical stability of compounds in their
the enhanced release of a drug from
metastable forms (such as amorphous) can
ointment or suppository bases.
be enhanced by the inhibition or prevention
Water-absorbing capacity of oleaginous and
of crystal growth.
water-in-oil bases can be improved by
Content uniformity of a small amount of a
hydrophilic CDs.
drug in bulky diluents can be ensured by an
increase in dispersibility and fluidity. 4. Injectable Preparations:
Shelf life of drugs can be extended by
Solubility and/or stability of the drug in
increasing their stability.
water can be improved.
1. Liquid preparations: Drug-induced hemolysis and muscular tissue
damage can be reduced.
Solubility and/or stability of the drug in
Solubilized products can be prepared by
water can be improved.
freeze-drying CD complexes if needed for
2. Suspensions and emulsions
enhanced stability.
Caking, creaming, and phase transitions can
Suspensions for parenteral use can be
be suppressed by the protective sheath of
prepared by reducing the drug to a fine
CDs.
powder containing the CD complex by use Solid solution— is a system in which the drug
of ball milling. remains dissolved in the vehicle in at room
temperature and upon aging (Godfried OA,
4.SOLID DISPERSION: 2001).
Solid dispersion— is a system in which the Coevaporates— Solid dispersion is prepared by
concentration of the drug is in excess of its solvent removal processes (Godfried OA, 2001).
saturation solubility at room temperature. The
excess drug separates as solid phase, which is Coprecipitates— Solid dispersion is obtained
dispersed in the vehicle in crystalline or when a precipitate of the drug and carrier is
amorphous forms. The term refers to the obtained by treating the solution containing the
dispersion of one or more active ingredients in drug and the carrier with another solvent
an inert carrier or matrix at solid state prepared (Godfried OA, 2001).
by the solid dispersion techniques. The
The advantage of solid dispersion compared with
dispersion of drug or drugs in solid diluent or
conventional capsules and tablet formulations is
diluents by traditional mechanical mixing is not
shown in (Figure 1.6).
included in this category (Godfried OA, 2001).
Disintegration Disintegration
Figure 1.4:Schematic representation of the bioavailability enhancement of poorly water soluble drug by solid
dispersion technique (Serajuddin ATM, 1999)
The mechanism suggested for enhanced solubility drugs, solid dispersion has become one of the most
and rapid dissolution of dispersion is when the active areas of research in pharmaceutical field
dispersion is exposed to water, the soluble carrier (Leuner and Dressman, 2001).
dissolves rapidly leaving the insoluble drug in a state
of microcrystalline dispersion of very fine particles. 4.1. The basic mechanisms responsible for
For conventional capsules and tablets, the dissolution increasing solubility of the drugs
rate is limited by size of primary particles formed (Ford JL, 1986):
after the disintegration of dosage form. In this case an Wetting of drug improved by direct
average particle size of 5um is usually the lower contact of the drug with the hydrophilic
limit, although higher particle size is preferred for matrix.
ease of handling, formulation and manufacturing. On Polymorphic forms.
the other hand, if a solid dispersion is used, a portion Reduced particle size or particle
of drug dissolves immediately to saturate the agglomeration.
gastrointestinal fluid and excess drug precipitates out Formation of higher energy states.
as colloidal particles or oily globules of submicron Formation of amorphous states-the drug
size. Because of such early promises in has higher energy in the amorphous state
bioavailability enhancement of poorly water-soluble
Shaping device
Polymer
Excipient
Tablets
Drug
Granulation
Extruder
o Pellets
o
Figure 1.5: Scheme of hot melt extruder (Leuner and Dressman, 2000)
2) Hot-spin-melting: produce stable solid dispersions by melt
agglomeration in a rotary processor.
A further alternative for processing thermolabile
substances is by hot-spin-melting. Here, the drug and 4.4 Solvent method
carrier are melted together over an extremely short
In this method both the guest molecule and the
time in a high speed mixer and, in the same
carrier are dissolved in common organic solvent
apparatus, dispersed in air or an inert gas in a cooling
followed by total removal of solvent to constant
tower. Some drugs that have been processed into
weight. Solid dispersions and solutions that are
solid dispersions using hot-spin-melting to date
manufactured by the solvent evaporation method are
include testosterone, progesterone and dienogest.
described as the Coevaporates. An important
3) MeltrexTM prerequisite for the manufacture of solid dispersion
using solvent method is that both the drug and the
MeltrexTM is a patented solid dispersion
carrier should be sufficiently soluble in the solvent.
manufacturing process, also on the basis of the
The solvent can be removed by any one of a number
melting process. The crucial elements in the
of methods such as vacuum rotary dryer, freeze
MeltrexTM technology is the use of a special twin
drying, spray drying etc. Temperature for solvent
screw extruder and the presence of two independent
evaporation is usually in range of 23-65ºC. It must be
hoppers in which the temperature can vary over a
remembered that when an organic solvent is to be
broad temperature range. This process permits a
removed, small variations in the conditions used can
reduced residence time of the drug in the extruder,
lead to quite large changes in product performance.
allowing a continuous mass flow and avoiding
Another point to consider is the importance of
thermal stress to the drug and excipients.
thoroughly removing all of the solvent, since most of
Additionally, it is possible that the application of this
the organic solvents used have toxicity issues.
technique to protect drugs susceptible to oxidation
and hydrolysis by complete elimination of oxygen Advantage:
and moisture from the mixture. 1) The method is suitable for thermolabile
materials.
4) Melt agglomeration
2) Many polymers that could not be utilized for
Melt agglomeration allows the preparation of solid the melting method due to their high melting
dispersions in conventional high shear mixers. It is points (e.g. PVP) could be now considered
made by adding the molten carrier containing the as carrier possibilities.
drug to the heated excipients, by adding the molten Limitations:
carrier to a heated mixture of drug and excipients, or 1) High cost of processing.
by heating a mixture of the drug, carrier and 2) Large quantity of organic solvent is
excipients to a temperature within or above the required.
melting range of the carrier. It is also possible to 3) Difficulty in complete removal of the
solvents.
4) Possible adverse effect of remaining solvent 5) Freeze-drying: The basic freeze-drying process
on stability of drug. consists of dissolving the drug and carrier in a
5) Selection of volatile common solvent. common solvent, which is immersed in liquid
6) Finding a suitable solvent that will dissolve nitrogen until it is fully frozen. Then, the frozen
both the drug and carrier is very difficult and solution is further lyophilized.
sometimes impossible. This is because most
6) Use of Supercritical Fluids (SCF): The use of
of the carriers are hydrophilic whereas most
SCF, substances existing as a single fluid phase
of the drugs are hydrophobic organic
above their critical temperature and critical pressure,
substances. This may be further complicated
is an efficient method in obtaining solid dispersions.
by the fact that different polymorphic forms
It ensures a very fine dispersion of the hydrophobic
of the same drug may be obtained if
drug in the hydrophilic carrier. Carbon dioxide (CO2)
different solvents are used.
is the most commonly used SCF because is
7) Plasticization of some polymers such as
chemically inert, non-toxic and nonflammable. This
PVP has occurred with the use of some
technique consists of dissolving the drug and the
solvents.
carrier in a common solvent that is introduced into a
8) The ecological and subsequent economic
particle formation vessel through a nozzle,
problems associated with the use of organic
simultaneously with CO2. When the solution is
polymers make solvent-based methods more
sprayed, the solvent is rapidly extracted by the SCF,
and more problematic.
resulting in the precipitation of solid dispersion
Differences in solvent evaporation processes are particles on the walls and bottom of the vessel. The
related to the solvent evaporation procedure, which use of processes using SCF reduces particle size,
usually include vacuum drying, heating of the residual solvent content, without any degradation,
mixture on a hot plate, slow evaporation of the and often results in high yield.
solvent at low temperature, the use of a rotary
7) Co-precipitation: Another common process is
evaporator, spray-drying, freeze-drying and the use
the co-precipitation method, in which a non-solvent
of supercritical fluids (SCF), co-precipitation method,
is added dropwise to the drug and carrier solution,
and Spin-coated films technique (Teo filo
under constant stirring. In the course of the non-
Vasconcelos, 2007).
solvent addition, the drug and carrier are co-
1) Vacuum drying: Solvent is evaporated in precipitated to form microparticles. At the end, the
vacuum at reduced pressure to avoid higher heating resulted microparticle suspension is filtered and
temperature. Also it is possible to remove the solvent dried.
traces more completely.
8) Spin-coated films technique: Spin-coated films
2) Heating on a hot plate: This is the simple is a new process to prepare solid dispersions by the
method of solvent evaporation in which volatile solvent evaporation method, which consists of
solvent is removed by heating the mixture of drug dissolving drug and carrier in a common solvent that
and carrier dissolved in the solvent at constant is dropped onto a clean substrate highly spinned.
temperature. Solvent is evaporated during spinning. This process
is indicated to moisture sensitive drugs since it is
3) Use of a rotary evaporator: Rotary evaporator
performed under dry conditions
can be used to maintain constant temperature and a
high level of vacuum during evaporation of the 4.5 Fusion-solvent method
solvent. Also it is possible the recovery of the solvent
In this method, a carrier(s) is/are melted and the
from the condenser and the solvent vapors are not
drug(s) is/are incorporated in the form of solution. If
released in the environment.
the carrier is capable of holding a certain proportion
4) Spray drying: Spray-drying is one of the most of liquid yet maintaining its solid properties, and if
commonly used solvent evaporation procedures in the liquid is innocuous, the need of solvent removal
the production of solid dispersions. It consists of is eliminated. This method is particularly useful for
dissolving or suspending the drug and carrier, then drugs that have high melting points or that are
spraying it into a stream of heated air flow to remove thermolabile.
the solvent. Van Drooge et al. (2006) prepared an
4.6Carriers used in Solid Dispersion:
alternative solid dispersion by spraying a povidone
and diazepam solution into liquid nitrogen, forming a Carriers used in Solid Dispersion includes
suspension that was then lyophilized. Polyethylene glycol (PEG); Polyvinylpyrrolidone
(PVP); Polyvinyl alcohol (PVA); crosspovidone
(PVP-CL); polvinylpyrrolidone-polyvinylacetate is to heat the reference and test samples in such a way
copolymer (PVPPVA); Cellulose derivatives such as that the temperature of the two is kept identical. If an
Hydroxypropyl methylcellulose (HMPC), energy-requiring phase transition occurs in the test
Hydroxypropyl cellulose (HPC), Carboxymethyl- sample, extra heat is applied to this sample so that its
ethyl cellulose (CMEC), Hydroxypropyl-methyl temperature climbs at the same rate as in the
cellulose phthalate (HPMCP); Polyacrylates and reference. The additional heat required is recorded
polymethacrylates, Urea; Sugar such as mannitol, and used to quantitate the energy of the phase
Sorbitol, Chitosan, etc.; polyols and their polymers; transition. Exothermic transitions, such as conversion
Emulsifiers e.g. Tween80, SLS, Bile salts and their of one polymorph to a more stable polymorph, can
derivatives, etc.; Organic acids and their derivatives also be detected. Lack of a melting peak in the DSC
e.g. Citric acid, succinic acid, nicotonamide, etc.; and of a solid dispersion indicates that the drug is present
Other carriers such as pentaerythritol, phospholipids, in an amorphous rather than a crystalline form. Since
Collagel, etc. (Leuner and Dressman, 2000). the method is quantitative in nature, the degree of
crystallinity can also be calculated for systems in
4.7 Characterization of solid dispersions:
which the drug is partly amorphous and partly
Methods for the characterization of solid dispersions crystalline. However, crystallinities of fewer than 2%
are as follows: cannot generally be detected with DSC.
1) Dissolution testing
X-ray diffraction (XRD):
2) Thermoanalytical methods: differential
thermoanalysis and hot stage microscopy The principle behind X-ray diffraction is that when
3) Calorimetric analysis of the solution or an X-ray beam is applied to the sample, interference
melting enthalpy for calculation of entropy bands can be detected. The angle at which the
change interference bands can be detected depends on the
4) X-Ray diffraction wavelength applied and the geometry of the sample
5) Spectroscopic methods, e.g. IR spectroscopy with respect to periodicities in the structure.
6) Microscopic methods including polarization Crystallinity in the sample is reflected by a
microscopy and scanning electron characteristic fingerprint region in the diffraction
microscopy pattern. Owing to the specificity of the fingerprint,
Among these, the most important methods are crystallinity in the drug can be separately identified
Thermoanalytical, X-ray diffraction, Infrared from crystallinity in the carrier. Therefore, it is
spectroscopy and measurement of the release rate of possible with X-ray diffraction to differentiate
the drug. In addition to characterizing the solid between solid solutions, in which the drug is
dispersion, these methods can be used to differentiate amorphous, and solid dispersions, in which it is at
between solid solutions (molecularly dispersed drug), least partly present in the crystalline form, regardless
solid dispersions in which drug is only partly of whether the carrier is amorphous or crystalline.
molecularly dispersed and physical mixtures of drug However, crystallinities of under 5±10% cannot
and carrier. Due to the complex composition of these generally be detected with XRD.
preparations, it is often difficult to delineate precisely
Fourier Transform Infrared Spectroscopy (FT-
between molecularly dispersed and not molecularly
IR):
dispersed systems and different analytical methods
may yield disparate results. It is usually assumed that Structural changes and lack of a crystal structure can
dispersions in which no crystallinity can be detected lead to changes in bonding between functional groups
are molecularly dispersed and the absence of which can be detected by infrared spectroscopy.
crystallinity is used as a criterion to differentiate Since not all peaks in the IR spectrum are sensitive to
between solid solutions and solid dispersions. crystalline changes, it is possible to differentiate
Thermoanalytical methods include all that examine a between those that are sensitive to changes in
characteristic of the system as a function of crystallinity and those that are not.
temperature. Of these, differential scanning
calorimetry (DSC) is the most highly regarded 5. MULTICOMPONENT SOLID DISPERSION:
method (Leuner and Dressman, 2000). Ternary agents have been added to solid dispersion of
Differential scanning calorimetry (DSC): two components either to enhance drug dissolution
rate or to overcome manufacturing or stability issues.
DSC enables the quantitative detection of all Surfactants have been added to solid dispersions to
processes in which energy is required or produced improve the dissolution rate of poorly water-soluble
(i.e. endothermic and exothermic phase drugs (Aungst BJ, 1977). They have also been used
transformations). The usual method of measurement to improve miscibility between drug and polymer or