Solubility Enhancement
of Poorly Soluble Drugs
Manali
Maheshwar Patil.*, Momin Abrarul Haque, Bhakti Narayan Patil, Mayur Suresh
Reddy, Ankita Bhagoji Dupare.
M. S. College of
Pharmacy, Gaurapur-Kudus Rd, Dist. Palghar, Maharashtra, India.
Abstract: The solubility behavior of drugs remains one of the most challenging
parts of formulation development. High solubility and permeability are
found in only 8% of the novel compound.
The drug's therapeutic effectiveness depends upon bioavailability
and ultimately upon solubility. Salt formation, particle size reduction,
etc. have commonly been used to increase the dissolution rate of drugs,
there are some practical restrictions with these techniques the desired
bioavailability enhancement may not always be achieved. Solid dispersion
seems to be an applicable technique for overcoming this problem. In this
review, it is intended to discuss recent advances related to the area of
solid dispersion. Finally, industrially achievable alternative approaches
in the manufacture of solid dispersion have been highlighted.
Keywords: Solid dispersion, Solubility, poorly soluble drugs, Bioavailability
|
Corresponding Author:
Manali Maheshwar Patil Email
ID:
manalipatil05312@gmail.com
Contact: 7796324482
|
Article History
Received: 15/10/2023
Accepted: 25/10/2023 Published: 01/11/2023
|
INTRODUCTION:
Solubility
is defined quantitatively as the concentration of the solute in a saturated
solution at a certain temperature, and qualitatively as the spontaneous
interaction of two or more substances to form a homogenous molecular
dispersion. A saturated solution is one in which the solute and solvent are in
equilibrium.1
Solubility
enhancement is an important metric to consider when developing a formulation
for an orally delivered medication with low water solubility. Almost 90% of
medications are taken orally.2
To
increase the dissolving rate, solubility, and oral absorption of weakly
water-soluble medicines, the solid dispersion (SD) approach has been widely
used.3 The maximum concentration of the drug solute dissolved in the
solvent under certain temperature, pH, and pressure conditions is referred to
as drug solubility. The therapeutic effectiveness of a medicine is determined
by its bioavailability and, ultimately, the solubility of drug molecules.4
SOLID
DISPERSION:
The term ‘solid dissipation’ has been employed
to describe a family of lozenge forms whereby the medicine is dispersed in a
biologically inert matrix, generally to enhance oral bioavailability.5
They first proposed the conformation of a eutectic admixture of an inadequately
water-answerable medicine is physiologically inert, fluently answerable
carriers and the carriers are introduced in the time 169 by Chiou and
Riegelman.6
To
circumvent the limited bioavailability of lipophilic medications, solid
dispersion was originally introduced by generating eutectic mixes of
pharmaceuticals with water-soluble carriers. The development of solid
dispersions as a practically viable way for increasing the bioavailability of poorly
water-soluble pharmaceuticals overcome previous limits such as salt formation,
cosolvent solubilization, and particle size reduction.
TYPES
OF SOLID DISPERSION:
1.
Eutectic
mixture:7,8,9
Simple
eutectic mixtures are made up of two substances that are entirely miscible in
liquid form but only to a very small extent in solid form.
These are made by quickly solidifying the fused melt
of two substances that exhibit total liquid miscibility and minimal solid
solubility.
In an aqueous medium, a mixture of poorly
water-soluble medicines is dissolved. The carrier is quickly dissolved,
releasing a better crystal form of the drug.
2.
Amorphous
precipitation in crystalline matrix:10
The main difference between this and simple eutectic
mixes is that the medication precipitates out in an amorphous form.
The drug's molecular size is decreased to that of a
particle in a solid solution.
In crystalline urea, sulfathiazole precipitated as an
amorphous substance.
3.
Solid
solution:11
Solid solutions are
similar to liquid solutions in that they only include one phase, regardless of
the number of components.
In stable solutions, the
drug's particle length has been reduced to its smallest possible size, or the
molecular dimensions and the dissolving charge are determined by the service's
dissolution charge.
Two categories of solid solutions exist:
a.
Continuous solid solution
b.
Discontinuous solid solution
a.
Continuous
solid solution
The components are in all amounts miscible in a
continuous solid solution. This implies, in theory, that the molecules of the
two components' respective molecules have stronger bonds than those of the
other molecules.
b.
Discontinuous
solid solution
There are restrictions on each component's solubility
in the other component in the case of discontinuous solid solutions.
4.
Substitutional
solid dispersion:12
Only when the size of the
solute molecules differs from the size of the solvent molecules by around 15%
or less is substitution possible.
In this type of solution system, the solid molecules
that make up the crystal lattice of the solid solvent are substituted for the
solvent molecules.
5.
Interstitial
solid solution:13
The interstitial spaces between the solvent molecules
in the crystal lattice are occupied by the dissolved molecules. The ratio of
solvent to solute molecules should not be greater than 0.59.
The dissolved molecules fill the gaps between the
solvent molecules in the crystal lattice.
6.
Glass
suspension & solution:14
A homogenous glassy system with a solute that
dissolves in it is called a glass solution.
When a solute dissolve in a glassy solvent, the result
is a homogeneous, glassy system known as a glass solution or glass suspension.
ADVANTAGES:15,16,17,18
Ø Reduction in particle size results in high surface area
resulting in increased dissolution.
Ø Improvement in wettability with carriers with surface
activity increases the dissolution profile.
Ø Particle with higher porosity is produced and this
hastens the drug release profile.
Ø Converts drug from crystalline to amorphous form thus
improving the dissolution and
Bioavailability.
Ø It has rapid dissolution rates.
Ø Increase the absorption rate of drugs.
Ø Reduce the crystalline structure of the drug into an
amorphous form.
Ø Prepare rapid disintegration oral tablets.
Ø Mask the taste and cover the drug substance.
Ø Scalable process and production of common oral solid
doses.
Ø It is Simple to formulate and analyze.
Ø It is Simple to produce and fast-track
DISADVANTAGES:19
Ø Poor scale-up for manufacturing.
Ø Instability of solid dispersion.
Ø Moisture and temperature have a bad effect on solid
dispersion.
Ø Stability problem of vehicles and drugs.
Ø Physicochemical properties reproducibility.
Ø The method of preparation is expensive.
Ø It is difficult to prepare solid dispersions in a dosage
form.
Ø Laborious and expensive methods of preparation.
Ø Reproducibility of physicochemical characteristics.
PROCESS
OF SOLUBILISATION: 20
The
process of solubilization consists of the breaking of inter-ionic and
intermolecular bonds in the solute, the separation of the molecules of the
solvent to provide space in the solvent for the solute and interaction between
the solvent and the solute molecule or ion.
When
the Solubilisation process occurs breakdown of the solute bond occurs and holes
can be seen as shown in Figure 1.
When
the solubilization process occurs, solid molecules break down because of the
breaking of intermolecular bonding shown in Figure 2.
About
freed solid molecule is integrated with the solvent shown in Figure 3.
FACTOR AFFECTING THE SOLUBILITY:
21,22,23
The
solubility depends upon the nature and composition of the solvent medium the
physical form of the solid, the temperature, and the pressure of the system.
factors that affect solubility are the following
1.
Particle
size
Particle size effect on the
solubility. The size of the solid particle influences the solubility because as
a particle becomes smaller, the surface area to volume ratio will increase. The
larger surface area allows greater interaction with the solvent and enhances
the solubility.
2.
Temperature
Solubility
is affected by the temperature. A few solid solutes are less soluble in hot
solutions. The solubility of the
material can be increased by increasing the temperature of the solvent. For Ex:
in all gases, solubility decreases as the temperature of the solution
increases.
3.
Molecular
size
Solubility is affected by the
molecular size of the particle. Higher molecular weight and larger molecules
result in a decrease in a substance's solubility. Larger molecules are more
difficult to surround with solvent molecules.
4.
Nature
of solute & solvent
The nature of solute and
solvent depends on the concentration of solute in a specific amount of solvent
t at a specific amount of temperature. Only a little bit of lead (II) chloride
can dissolve in water, while a lot of more zinc chloride can dissolve in the
same amount of water. Different substances have different abilities to dissolve
in water. The larger difference in the solubilities of these two substances is
the result of differences in their nature.
5.
Pressure
For solids and liquid solutes,
solubility is not affected by the change in their pressure but for gaseous
solutes, solubility increases as pressure increases and decreases as pressure
decreases. For solids and liquid solutes, changes in pressure have practically
not affected solubility.
6.
Polarity
The polarity of the solute and
solvent molecules affects the solubility. Generally, like dissolves like means
non-polar solute molecules will dissolve in the non-polar solvents, and polar
solute molecules will dissolve in the polar solvents. The polar solute
molecules have a positive and a negative end of the molecule.
7.
Polymorphs
Polymorphs can vary in melting
point. Hence the melting point of the solid is related to solubility, so
polymorphs will have different solubilities. The capacity for a substance to the
crystallize in more than one crystalline form is polymorphism.
8.
Rate
of solution
The
rate of solution is a detection of how fast substances dissolve in solvents.
Various factors affecting the rate of
solution are-
·
Size of the particles
·
Temperature
·
Amount of solute already dissolved.
·
Stirring
METHODS
OF SOLID DISPERSION:
1.
Kneading
method:24,25
In
this technique, the carrier is penetrated with water and transformed into a
paste. The drug is then added and agglomerated for a specific time. The
agglomerated mixture is then dried and passed through a sieve if necessary.
A mixture of accurately measured drug and carrier is wetted with solvent
and agglomerated thoroughly for some time in a glass mortar.
2.
Solvent
melting method:26
This
method possesses the unique advantages of both the fusion and solvent
evaporation methods. The accurately measured drug is dissolved in an organic
solvent. The solution is incorporated into the melt of mannitol and cooled
suddenly, and the mass is kept in the desiccator for complete drying.
3.
Spray
drying method:27
This
method possesses the unique advantages of both the fusion and solvent
evaporation methods. The accurately measured drug is dissolved in an organic
solvent. The solution is incorporated into the melt of mannitol and cooled
suddenly, and the mass is kept in the desiccator for complete drying.
4.
Supercritical
fluid method:28
The process of supercritical fluid has
emerged as an alternative method to the solvent method, forming small particle
size precipitation and low organic matter content, with better flow. We used
this technique due to the advantages associated with its use, as a non-toxic
gas, non-flammable, inexpensive, and low critical temperature, making it
attractive in the processing of heat-sensitive drugs and the process of solvent
removal extremely controlled.
5.
Co
grinding method:29
The physical mixture of drug and carrier
is mixed for a specific time employing a blender at a particular speed. The
mixture is charged into the chamber of a vibration ball mill.
Ex. chlordiazepoxide and mannitol.
6.
Gel
entrapment technique:30
Hydroxyl propyl methyl cellulose is
dissolved in an organic solvent to form a clear and transparent gel. The
organic solvent evaporated is done under the vacuum. Solid dispersions are
reduced in size by glass mortar and sieved by the Gel entrapment technique.
7.
Melting/Fusion
method:31
Drugs and carriers are mixed by using a
mortar and pestle. To form a homogenous dispersion the mixture is heated at or
above the melting point of all the components.
E.g., Albendazole and urea.
8.
Solvent
evaporation method:32
In this technique, both the drug and
carrier are dissolved in an organic solvent. After the complete dissolution,
the solvent is evaporated. Removal of organic solvents such as chloroform from
the large masses of material it may be difficult because the solid dispersions
are usually amorphous and it may be viscous and waxy.
9.
Dropping
method:33
The dropping technique, developed by
Ulrich et al. (197) to provide the crystallization of different chemicals, is a
new procedure for producing round particles from melted solid dispersions. This
method not only simplifies the manufacturing process but also gives a higher
dissolution rate. The size and shape of the particles can be affected by
factors such as the viscosity of the melt and the size of the pipette.
10.
Direct
capsule filling:34
Direct filling of hard gelatin capsules
with the liquid melt of solid dispersions to avoid grinding-induced changes in
the crystallinity of the drug.
11.
Lyophilization
technique:35
Freeze-drying
involves the transfer of heat and mass and forms the product under preparation.
Lyophilization is a mixing technique where the drug and carrier are dissolved
in a common solvent, frozen, and sublimed to obtain a lyophilized molecular
dispersion.35
12.
Electrospinning
method:36
It is used in the polymer
industry and combines solid dispersion technology with nanotechnology. In this
process, a liquid stream of a drug or polymer solution is subjected to a
potential between 5 and 2 kV.
VARIOUS
TECHNIQUES USED IN SOLUBILITY ENHANCEMENT
I.CHEMICAL MODIFICATION
1.
Ph
adjustment:37
Poorly water-soluble drugs
with parts of the molecule that can be protonated (base) or deprotonated (acid)
may clearly of Ph be dissolved in water by applying a pH change. The principle
of pH adjustment is used for both oral and parental administration. Poor
water-soluble drugs may dissolve in water by applying a pH change.
2.
Salt
formation:38
It
is the most common and effective method of enhancing solubility and dissolution
rates of acidic and basic drugs.
3.
Co-crystallization:
It
is also specified as molecular complexes. Only three of the co-crystallizing
agents are classified and generally recognized as safe. The presence of
saccharin, nicotinamide, and acetic acid limits its use in medicine.
4.
Co-solvency:39
The solubility of
a poorly water-soluble drug can be increased continuously by the addition of a
water-miscible solvent in which the drug has a good solubility known as a
co-solvent. The co-solvent system works by decreasing the interfacial tension
between the aqueous solution and hydrophobic solute.
5.
Hydrotropic:
40 It is a
solubilization phenomenon whereby the addition of a large amount of a second
solute increases the aqueous solubility of another solute. hydrotropic is a
solubilization phenomenon whereby the addition of a large amount of a second
solute increases the aqueous solubility of the existing solute.
6.
Solubilizing
agent:41
The solubility of poorly
soluble drugs can be improved by various solubilizing materials like PEG 400 is
improving the solubility of hydrochlorothiazide.
II.PHYSICAL MODIFICATION
1.
Particle size reduction:42
The
size of the solid particle affected the solubility because as a particle
becomes smaller, the surface area to volume ratio increases.
Particle
size reduction can be attained by micronization and nanosuspension.
a)
Micronization:
The
particle size reduction technique enhances the solubility and dissolution rate
of poorly water-soluble drugs due to the enormous surface that is generated.
In
micronization, the size of the drug particles plays a big role in how well the
drug can dissolve. So, the smaller the particles, the better the solubility.
The
process is also called “Micro-milling”. Examples of a drug whose
bioavailability have been increased by micronization include griseofulvin and
several steroidal and sulpha drugs.
b)
Nanonization:43
It
is another technique to achieve the particle size reduction and has been
employed for the drugs including tarazepide, atovaquone, amphotericin-B,
paclitaxel, and buparvaquone.
Recently,
various nanonization systems have been developed to increase the dissolution
rates and bioavailability of numerous drugs that are poorly soluble in water.
Nanosuspensions
are prepared by homogenization and wet milling process.
Methods:
-Precipitation
technique
-
Media milling
-
High-pressure homogenization
-
Combined precipitation and homogenization.
2.
Modification of crystal habit:
a)
Polymorphs
They are depending upon the
internal structure, a solid can exist either in a crystalline or amorphous form
polymorphism.
Polymorphs are of two types:
Enantiotropy
Monotropic
b)
Pseudo
polymorphs
The stoichiometric type of
force where the solvent molecules are in corporate in the crystal lattice of
the solid is called the solvate and the trapped solvent is the solvent of
crystallization.
3.
Complexation:44,45
Complexation is
the union between two or more molecules to form a non-bonded entity with a
well-defined stoichiometry. It relies on relatively poor forces such as London
forces, hydrogen bonding, and hydrophobic interactions.
Approaches to Make Complexes:
·
Physical
blending method
·
Kneading
method
·
Co-precipitation
technique
·
Solution/
solvent evaporation
·
Neutralization
precipitation method
·
Milling/
grinding technique
·
Atomization/spray
drying method
·
Lyophilization
·
Microwave
irradiation method
·
Supercritical
antisolvent technique.
4.
Solubilization
by surfactant:
Surfactants are more useful as absorption
enhancers and enhance both the dissolution rate and permeability of the drug.
a)
Microemulsion:46
The
term microemulsion was first introduced by Jack H. Shulman in 159. The
microemulsion is a four-component system composed of an external phase as well
an internal phase, a surfactant, and a co-surfactant. Non-ionic surfactants,
such as tweens and labrafil with high hydrophilic-lipophilic balances are often
used to ensure immediate formation of o/w droplets during manufacturing.
b)
Self-microemulsion
drug delivery system: 47
This
is an anhydrous system of microemulsion. It is composed of oil, surfactant, and
cosurfactant it can form o/w microemulsion. when they dispersed in an aqueous
phase under gentle agitation. A combination of ionic and non-ionic surfactants
is also more effective.
5.
Drug
dispersion in a carrier:
By using
these three factors that help the particle size of a drug decrease to submicron
level are the use of solid solution, the use of eutectic mixture, the use of
solid dispersion
a)
Solid
solution:
A solid solution is a binary
system consisting of a solid solute molecular dispersed in a solid solvent.
Hence, the two compartments crystallize together in a homogenous one-phase
system – solid solutions are also called molecular dispersion or mixed
crystals.
b)
Solid
dispersion 48
Solid dispersion refers to a
group of solid products consisting of at least two components, such as a hydrophilic
matrix and a hydrophobic drug. The matrix can be crystalline amorphous.
The concept of solid
dispersion was originally invented by Sekiguchi and Obi, who investigated the
generation and dissolution performance of eutectic melts of sulfonamide drug
and a water-soluble carrier in the early 160s.
Various techniques to prepare
the solid dispersion of hydrophobic drugs to improve their aqueous solubility
are listed as follows:
•
Fusion
Process
•
Solvent
Method
•
Fusion-Solvent
Method
•
Spray
Drying
•
Lyophilization
(Spray Freeze Drying Method)
•
Hot-melt
Extrusion
APPLICATION:49,50
Solid
dispersion formulations were demonstrated to accelerate the onset of action for
drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs) where immediateness
of action is crucial in relieving acute pain and inflammation.
Ø To
stabilize the unstable drug.
Ø To
dispense liquid or gaseous substance in a solid dosage.
Ø To
formulate a sustained release regimen of soluble drugs by using less soluble or
insoluble carriers.
Ø Increases
oral bioavailability of bad water-soluble drugs.
Ø No
change in the chemical properties of the drug.
Ø Relatively
simple processing techniques.
Ø Uses
conventional equipment.
Ø A
metastable solid state causes increase disintegration.
Ø To
dispense liquid (up to 10%) or gaseous compounds in a solid dosage.
Ø to
formulate an immediate-release primary dose in a sustained released dosage
form.
Ø To
decrease the pre-systemic inactivation of medications like morphine and
progesterone.
Ø
To convert polymorphs in a given system
into the isomorphous, solid.
Characterization
of solid dispersions: 51,52
The
following are different methods of characterizing the solid dispersion;
1.
Drug -carrier miscibility
•
Hot stage microscopy
•
Differential scanning calorimetry
•
Powder X-ray diffraction
•
Spectroscopic methods like Raman
spectroscopy, and FT-IR spectroscopy.
•
NMR 1H Spin lattice relaxation time
2.
Physical Structure
·
Scanning electron microscopy
·
Surface area analysis
·
Surface properties
·
Dynamic vapor sorption
·
Inverse gas chromatography
·
Atomic force microscopy
·
Raman microscopy
3.
Amorphous content
•
Polarized light optical microscopy.
•
Hot stage microscopy
•
Humidity stage microscopy
•
DSC (MTDSC)
•
Powder X-ray diffraction
4.
Stability
·
Humidity studies
·
Isothermal Calorimetry
·
DSC (e.g., Temperature recrystallization)
·
Saturated solubility studies
5.
Dissolution enhancement
·
Dissolution
·
Intrinsic dissolution
·
Dynamic solubility
CONCLUSION:
For the poorly soluble medicines, solubility is the
most crucial factor in determining oral bioavailability. Dissolution of the
drugs is the rate-determining step for the oral absorption of poorly
water-soluble drugs, which can subsequently affect the in vivo absorption of
the drug. Currently, only 8% of new drug candidates have both more solubility
and permeability. Because of the solubility problem of many drugs, their
bioavailability of them gets affected and hence solubility enhancement is
necessary. Solid dispersion technology is one of the possible procedures that increase
the solubility of poorly soluble drugs.
The
various technologies discussed have been successful in the laboratory as well
as the scale-up. Some products have been marketed using technologies such as
surface-active carriers. Hence this technology is expected to form a base for
the use of many poorly water-soluble and water-insoluble
drugs in their solid-dispersion formulations shortly.
Solid
dispersions can increase the dissolution rate of drugs with poor
water-solubility, but the stability of these systems needs to be discussed, and
carriers need to be selected for drugs on a case-by-case basis. Solvent systems
consisting of mixtures of solvents can be used to optimize concentration in
solution processing parameters that influence the type of glass amorphous
system formed.
ACKNOWLEDGEMENT:
The
authors wish to thank Dr. Mohammad Hashim Mansoori (Principal) and Mr. Momin
Abrarul Haque professor of M. S. COLLEGE OF PHARMACY DEVGHAR, for their
constant encouragement, support, and inspiration to carry out this study.]
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