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Poorly Water Soluble Drugs: Change in Solubility for Improved Dissolution

Characteristics a Review

Article  in  Global Journal of Pharmacology · February 2014

DOI: 10.5829/idosi.gjp.2014.8.1.81201

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Global Journal of Pharmacology 8 (1): 26-35, 2014
ISSN 1992-0075
© IDOSI Publications, 2014
DOI: 10.5829/idosi.gjp.2014.8.1.81201

Poorly Water Soluble Drugs: Change in Solubility for

Improved Dissolution Characteristics a Review

Balvinder Dhillon, Narendra Kr. Goyal, Rishabha Malviya and Pramod K. Sharma

Department of Pharmacy, School of Medical and Allied Sciences,

Galgotias University, Greater Noida, U.P., India

Abstract: The aim of this review is to study various parameters to improve the solubility and bioavilability of
poorly water soluble drugs. The oral route of administration is the most preferred and widely acceptable route
of delivery due to ease of ingestion for many drugs. Drugs with slow dissolution rate show the incomplete
absorption leading to low bioavilability when orally administered. Various approaches such as micronization,
solid dispersion, complexation, hydrotrophy, co-solvency, use of surfactant, sonocrystallization, particle size
reduction, micro emulsion, nanosuspensions, cryogenic Techniques has been used to enhance the solubility
of poorly water soluble drugs. In this review authors discussed about various Techniques used to enhance
absorption and bio avilability of drugs and various patents available on solubility enhancement.

Key words: Bioavilability Dissolution Solubility Enhancement

INTRODUCTION In the biopharmaceutical classification system (BCS)

drugs are classifying on the basis of aqueous solubility
The oral route is the most common and preferred and membrane permeability. Many poor water soluble
route for drug administration due to its convenience and drugs come to the BCS classes of II and IV [4]. The
ease to ingestion [1].When drug administered orally in process of drug absorption from oral route for such types
solid dosage form like tablet, capsule; firstly it undergo of drugs is occurs via dissolution rate limiting step. So
dissolution in the GI fluids before absorption. For various that it is important to increase dissolution of these drugs
poorly soluble drugs bioavailability is limited by the to give maximum therapeutic effect of these drugs. Before
dissolution rate. In the development of pharmaceutical studying the many Techniques to increase dissolution it
dosage form, many difficulties arise due to poor water is importance to understand the dissolution process. In
soluble drugs. Therapeutic efficacy of a drug depends the dissolution process solid substance (Active
upon the solubility of drug molecules. Solubility can be Pharmaceutical Ingredients) comes into the solution. The
defined as qualitatively as well as quantitatively. solubility of drug is directly proportional to its dissolution
Quantitatively solubility can be defined as the solute rate as per Noyes- Whitney equation and hence solubility
concentration in a saturated solution at a particular is an important parameter of a drug for determination of
temperature. Whereas qualitative it can be defined as the its absorption and dissolution rate hence its
spontaneous interaction of two substances to produces bioavailability. Parameters such as Particle size, salt form,
a homogenous molecular dispersion [2]. solubility, wettability, complexation, polymorphism etc.
The absorption of drug from solid dosage forms affect the rate of dissolution and hence can be used to
generally occurs by two processes as follow: increase solubility of poorly water soluble drug.
The aqueous solubility of a drug is a critical factor
In vivo drug dissolution to produce a solution. to evaluate the oral bioavailability of orally administered
Dissolved drug was transport of the across the poorly water soluble drugs. The modificationin the
gastrointestinal membrane [3]. dissolution profile of these lipophilic drug molecules

Corresponding Autrhor: Balvinder Dhillon, Department of Pharmacy, School of Medical and Allied Sciences, Galgotias
University, Plot No.2, Sector 17-A, Yamuna Expressway, Greater Noida, Gautam Buddh Nagar,
Uttar Pradesh, India. Cell: +91-8588036501.
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 Global J. Pharmacol., 8 (1): 26-35, 2014

without changing the molecular structure can be to give better results compare to cationic surfactant (such
possible by various Techniquesused toenhancement as cetyltrymethyl ammonium bromide) for solubility
of aqueous solubility of drug candidates. Some of enhancement [9].
these Techniques include particle size reduction,
solid dispersion,crystal modification, lipid based Complexation [10]:
system, pH modification, use of surfactant of delivery in Physical Mixture: In this, the drug and suitable polymer
dosage form [5]. To increase solubility of hydrophobic in different ratios is triturated in a mor for approximately
drugs, generally water soluble excipients such as one hour. Then the mixture is sieved through sieve no. 80
carbohydrates, surfactant, superdisintegrants and stored in desiccators with fused NaCl.
andpolymers (e.g.-polyvinyl pyrrolidone, polyethylene
glycols, hydroxypropyl methylcellulose, mannitoletc.) are Kneading Method: In this method drug and suitable
used [6, 7]. polymer in different ratios is mixed in a mor and triturated
with small quantity of solventto prepare slurry. The drug
Importance of Solubility Enhancementincludes [8]: is then added slowly into the slurry with constant stirring.
The slurry which is prepared then air dried at 25°C for 24
Solubility is one of the important parameters to hrs. The product is prepared and sieved through sieve #
achieve preferred concentration of drug in Systemic 80 and stored in desiccator with fused NaCl.
circulation for achieving required pharmacological
response. Co-precipitation method: In this method the active drug
Poorly water soluble drugs frequently require high and suitable polymer are mixed with different molar ratios.
doses and need high dosage regimens inorder to Then it is dissolved in solvent and distilled water at a
influence therapeutic plasma concentrations after oral room temperature. The mixture is stirred for one hour at
administration. room temperature and the solvent will be evaporated. The
Low aqueous solubility is the main problem precipitateobtained as a crystalline powder is pulverised
encountered with preparationand development of and sieved through sieve # 80 and stored in dessicator.
new chemical entities as well as for generic drugs.
For orally administered drugs solubility is the one of Co-solvency: Organic solvent such as water miscible
the important rate limiting parameter to reach their solvents is used to enhance the aqueous solubility of a
desired concentration in complete circulation for water insoluble drug [11]. Water and solvents which are
pharmacological response. soluble in water form a solution called co-solvent. PEG
Water is the solvent of excellent for liquid 300,ethanol,propylene glycol are some of the solvents
pharmaceutical formulations. which are used in preparation of co-solvent mixtures. For
Most of the drugs like weakly acidic or weakly basic example 5-40% concentration of solid binary system
having poor aqueous solubility. comprising polyethylene glycol 6000 has been used to
Poorly water soluble drugs having slow drug enhance the solubility and dissolution of meloxicam.
absorption leads to insufficient and gastrointestinal Many thousand times co-solvencyenhances the
mucosal toxicity and variable bioavilability. solubility of poorly soluble compounds compared to the
aqueous solubility of the drug.In the design of many
Techniques for Solubility Enhancement: different formulations,co-solvency had been highly
utilized. The co-solvency mainly used in parenteral
Use of Surfactant: To increase both dissolution of dosage forms because of the most surfactants give the
drug,surfactants are used. The basic mechanism behind irritating effects and many co-solvents show the low
the action of surfactant is that the wetting is firstly toxicity, due to the more ability to make co-solvents to
promoted so that penetration of dissolution fluid in to the solubilise nonpolar drugs. Low toxic co-solvents used for
solid drug particles can be increased. Poorly water soluble parenteral dosage forms are glycerine, propylene glycol,
drug had been studied which is used a series of co- polyethylene glycol and ethanol [12].
solvent and surfactant. Among the various types of
surfactants, ionic surfactants werepreferred over others Solid dispersion: For increasing the absorption,
for better solubilising agents. In most cases the anionic dissolution and therapeutic effectiveness of drugs in
surfactants (such as sodium dodecyl sulphate) was found dosage forms, a widely used and most suitable

27
 Global J. Pharmacol., 8 (1): 26-35, 2014

pharmaceutical technique is Solid dispersion. “The term processed with a twin-screw extruder. The process
SD can be defined as the distribution of one or more includes embedding a drug in a polymer although shaping
active ingredients (hydrophobic) in an inactive carrier the composite material to form a pharmaceutical product.
or matrix (hydrophilic) at solid state. Solid dispersion The drug/carrier mix is simultaneously melted,
mentions to a group of solid products containing of at standardizedand then extruded and shaped as tablets,
least two different components, generally a hydrophobic pellets, granules, sticks, sheets or powder [14].
drug and a hydrophilic matrix. The matrix can be either
amorphous or crystalline. The drug can be isolated Solvent Evaporation Method: Solvent evaporation method
molecularly, in amorphous particles (clusters) or in is very useful method where formation of solution is the
crystalline particles. The most commonly used solvents first step containing physical mixture of the carrier and
for solid dispersions includes methanol, water, ethanol, drug dissolved in a common solvent.In the second step
DMSO, chloroform, acetic acid. the removal of solvent resulting the solid dispersion
The most frequently used hydrophilic carriers for formation. Theproduct is crushed, pulverized and sieved
solid dispersions such as, through an appropriate mesh number sieve. This allowed
them to produce a solid solution of the extremely
First Generation Carriers: Example: Crystalline carriers: lipophilic drug in the highly water soluble carrier such as
Organic acids, Urea, Sugars. polyvinylpyrrolidone. An important requirement for the
manufacture of a solid dispersion using the solvent
Second Generation Carriers: Fully synthetic polymers method is that both the drug and the carrier are
include polyethyleneglycols (PEG) andpovidone (PVP), sufficiently soluble in the solvent.
polymethacrylates. Natural product based polymers are
mainly used by cellulose derivatives, such as Melting Solvent Method (Melt Evaporation): Here the
hydroxypropylmethylcellulose (HPMC) solid dispersions are organized by dissolving the drug in
orhydroxypropylcellulose, ethyl cellulose or sch appropriate liquid solvent and then including the solution
derivatives, such as cyclodextrins. directly into the melt of polyethylene glycol, which is then
evaporated until a clear, solvent free film is left. The film
Third Generation Carriers: Example: Surface active self- is dried to constant weight. The 5-10% (w/w) of liquid
emulsifying carriers: Tween 80, poloxamer 408 and compounds can be combined into polymer without
Gelucire 44/14. significant loss of its solid property. It is possible that the
Solid dispersions can be prepared by various particular solvent or dissolved drug may not be miscible
methods as described below: with the melt of the polymer. Liquid solvent are also used
and affect the polymorphic form of the drug, which
Fusion Method (Melting Method): The fusion or melting precipitates as the solid dispersion [15].
method, first suggested by Sekiguchi and Obi includes
the preparation of physical mixture of a drug and a water- Sonocrystallization: Sonocrystallization is a new particle
soluble carrier and heating directly whenever the mixture engineering technique to increase solubilityand
is melted. The melted mixture is then solidified quickly in dissolution of hydrophobic drugs and to study its effect
an ice-bath under stirring. The final solid mass is on crystal properties of drug. Recrystallization of poorly
crumpled, pulverized and sieved. However several soluble materials using antisolvents and liquid solvents
substances, either drugs or carriers, may decompose or has also been employed successfully to decrease particle
evaporates through the fusion process which employs size by using ultrasound. Sonocrystallization employs
high temperature. These problems could be overcome by ultrasound power characterized by a frequency range
heating the physical mixture in a closed container or of 20-100 kHz for inducing crystallization. Most
melting it under vacuum or in the presence of inert gas applications use ultrasound in the range 20 kHz-5
such as nitrogen to prevent oxidative degradation of MHzMelt sonocrystallization (MSC) is promising
carrier or drug [13]. technique of sonocrystallization to find porous,
amorphous material with high stability [16].
Melt Extrusion Method: This method is similar as the melt
method where polymer processing technology useful Supercritical Fluid Method: A supercritical fluid (SCF)
and intense mixing of drug/carrier mix is naturally can be defined as a dense non-condensable fluid, is

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 Global J. Pharmacol., 8 (1): 26-35, 2014

additional novel nanosizing and solubilisation enhancement. However, the mechanical forces essential
technology, which application has been improved in to comminution, such as grinding and milling often impart
recent years. A SCF process permits the micronization of significant amounts of physical stress upon the drug
drug particles within sub-micronlevels. Supercritical product which may induce degradation. The thermal
fluids are fluids whose temperature and pressure are stress which may occur during comminution and spray
greater than critical pressure (Tp) and critical temperature drying is also a concern when processing thermo
(Tc). At near-critical temperature, SCFs are highly sensitive or unstable active compounds. Using traditional
compressible, permitting moderate changes in pressure to approaches for nearly insoluble drugs may not be able to
greatly change the density and mass transport increase the solubility up to desired level [19].
characteristics of a fluid that mostly determine its
solvent power. Once the drug particles are solubilised Micronization: Micronization is another conventional
within SCF, they may be recrystallised at significantly technique for the particle size reduction. Micronization
reduced particle size. Water and Carbon dioxide are the enhance the dissolution rate of drugs through increased
most commonly used supercritical fluids. The SCF surface area, it does not enhance equilibrium solubility.
process can create nanoparticulate suspensions of Decreasing the particle size of these drugs, which
particles 5-2,000 nm in diameter. Eg. Increasing water causeenhance in surface area, improve their rate of
solubility of etraconazole with water soluble polymer dissolution. Micronization of drugs is done bymilling
HPMC by using supercritical fluid processing [17]. techniques by rotor stator colloid mills, jet mill and so
forth micronization is not appropriate for drugs having
Hydrotrophy: The term hydrotropy refers to enhance in a high dose number because it does not change the
solubility of insoluble or slightly soluble drugs inwater by saturation solubility of the drug [20, 21].
the addition of additives. The mechanism by which it
increases solubility is more closely associated to Micro Emulsion: Micro emulsion is known as a system of
complexation involving a weak interaction between the water,oil which is thermodynamically stable liquid
hydrotrophic agents and the solute. Somehydrotrophic solution. A micro emulsion can be divided of four
agents used are sodium benzoate, urea, sodium alginate, component system such as internal phase, external phase,
sodium acetate etc.Inhydrotrophy techniques many surfactant and cosurfactant, Non-ionic surfactant like
different class of drugs like anti-viral, antipyretic, anti- labrafil and tweens with high hydrophile-lipophlie
tumour, antinflammatory and analgesic drugs used for balances which are used to formation of oil-in water
solubility enhancement. Hydrotrophy technique is applied droplets during the production.In micro emulsion
for solubility enhancement of riboflavin, nimesulide, technique, many equipment are used such as water
nifidepine and xanthine derivatives such as caffeine and bath, stirring rod, volumetric flask and homogenizer.
theophylline [18]. Micro emulsion is known as the isotropic, clear pre
concentrate, thermodynamically stable translucent
Particle Size Reduction: The solubility of drug is often system which is containing a mixture of oil, hydrophilic
essentially related to drug particle size; as a particle solvent and hydrophilic surfactant dissolved in a poorly
becomessmaller, the surface area to volume ratio water soluble drug [22].
increases. The larger surface area permits greater
interaction with the solvent which causes an increase in Nano-suspension: Nano-suspension is defined as a
solubility. biphasic systems which consist of nano sized
drugparticles stabilized by surfactants for topical and oral
There are two methods to reduce the particle size. use or pulmonary and parenteral administration.
They are: Innano-suspension technology, promising candidate had
been developed for efficient delivery of hydrophobic
Conventional Methods: Conventional methods of particle drugs [23]. Poorly soluble drugs that are insoluble in both
size reduction, like comminution and spray drying, rely oils and water was applied in nano-suspension
upon mechanical stress to disaggregate the active technology. In nano-suspension the particle size
compound. Particle size reduction is thus authorizing distribution of the solid particles is less than onemicron
reproducible, efficient and economicmeans of solubility with the range of particle size between 200 and 600

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 Global J. Pharmacol., 8 (1): 26-35, 2014

nm.Various methods which are used for preparation of polyethylene glycol. Particularly enhanced
Nano-suspension such as High Pressure Homogenization solubility is shown where a small amount of
in water (Dissocubes), media milling (nanocrystal), water is also included. The development may be
combination of Precipitation and High-Pressure used in a wide variety of applications, such as for
Homogenization (Nanoedege) and High Pressure pharmaceutical, antimicrobial, agricultural and
Homogenization in non-aqueous media (Nanopure) [24]. personal care products.
Various Techniques Are Used in Nano-suspension Are: Sandeep et al. [27] has invented Dissolution
enhanced controlled drug delivery system for
Precipitation Technique: The drug isdissolved in a poorlywater soluble drugs by using a solid
solvent in the precipitation technique and then dispersion of a poorly water-soluble or insoluble
addedto non-solvent to precipitate the crystals. drug and found enhanced dissolution in an aqueous
Nano-suspension of Naproxen, Danazol, prepared by medium. The invention further discloses a process of
precipitation technique to improve oralbioavailability and preparation of these controlled-release dosage forms.
rate of dissolution. William et al. [28] has invented Solid pharmaceutical
dispersions with enhanced bioavailability which
Media Milling (Nanocrystals and Nanosystem): By provide Spray dried solid dispersions including a
using high-shear media mills, the nanosuspensions are sparingly soluble drug and hydroxyl
prepared. The milling chamber charged with water, milling propylmethylcellulose acetate succinate (HPMCAS)
mediastabilizer and drug is rotated at a very high shear provide enhanced aqueous solubility and/or
rate at temperatures for several days (at least 2-7 bioavailability in the use environment.
days). The milling medium which composed of Zirconium Philip et al. [29] has invented Methods of increasing
oxide or highly cross-linked polystyrene resin or glass. solubility of poorly soluble compounds and methods
of making and using formulations of such
Cryogenic Techniques: Cryogenic techniques are used to compounds that related to novel soluble forms of
progress the dissolution rate of drugs by producing planar ring structured organic compounds such as
nanostructured amorphous drug particles with high flavonoids and their production. The invention
degree of porosity at very low temperature conditions. relates to a wide variety of applications of the
This Cryogenic techniques can be defined by the type of formulations of the invention. The subject invention
injection device (capillary, ultrasonic nozzle, pneumatic contains novel soluble forms and various
and roy), location of nozzle (above or under the liquid formulations of flavonoids. Further, the invention
level) and the composition of cryogenic liquid (N2, O2, includes novel methods of manufacturing the
hydro fluoro alkanes and organic solvents). After in this flavonoid formulations.
processing, dry powder can be found by different type of Mani et al. [30] have invented Solubility enhanced
drying processes including- spray freeze drying, vacuum terpene glycoside(s) by inclusion complexes
freeze drying, atmospheric freeze drying and comprising a substantially pure terpene glycoside
lyophilisation (for removal of solvent) [25]. and at least one cyclodextrins, wherein the solubility
of the inclusion complex is greater than the solubility
Patents for Solubility Enchancement: of the substantially pure terpene glycoside alone.
He also study the methods for improving the taste of
Wurn et al.[26] has invented a method to enhance an orally ingestible composition and an inclusion
solubility of an active compound by combining an complex comprising at least two substantially pure
active compound (having an aqueous solubility that terpene glycosides and at least one cyclodextrins.
is less than or equal to about 10 mg/mL), with an Bilgic et al. [31] has invented Solubility and Stability
amount of methoxypolyethylene glycol which is Enhancing Pharmaceutical Formulation that relates
sufficient to enhance the aqueous solubility of the to pharmaceutical preparations comprising a
active compound. Enhancement of aqueous combination of a therapeutic agent with solubility
solubility for this combination may be significantly problem and a therapeutic agent with stability
greater than that of an active compound in problem and the methods for the preparation and
combination with an equivalent amount of the uses.

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 Global J. Pharmacol., 8 (1): 26-35, 2014

Suck-Hyune et al. [32] has invented Conductive that of an active compound in combination with an
polymers having high solubility in organic solvent equivalent amount of polyethylene glycol.
and electrical conductivity and synthesizing process Particularly increase solubility is shown where a small
that related to a new process of synthesizing amount of water is also included. The invention may
conductive polymers from monomers substituted be used in a wide variety of applications, such as for
with amine group. The process offers simple pharmaceutical, antimicrobial, agricultural and
synthesizing steps for the conductive polymers personal care products.
without using other additives including stabilizers or Isaac et al. [36] has invented Process for enhancing
emulsifiers. The conductive polymers synthesized the solubilityof poorly soluble drugs is enhanced by
according to the present invention have highly a process that utilizes a twin-screw extruder
enhanced solubility in common organic solvents and comprising (i) a feed zone containing a first liquid and
electrical conductivity associated to conventional powder feed stations; (ii) a grinding/mixing zone
conductive polymers. Therefore, the conductive comprising a second liquid feed port located at an
polymers synthesized according to the present upstream portion of such zone; (iii) a granulation
process can be utilized in applications that involve zone containing a second powder feed station
high electrical conductivity, for example an electro- situated at an upstream portion of such zone and a
magnetic interference shield or a transparent third liquid feed port located at a downstream portion
electrode of thin film, as well as in specific of such zone; and (iv) a wet milling zone.
applications such as various conductive films, Argaw et al. [37] have invented Osmotic delivery of
polymer blends, fibers, battery electrodes or therapeutic compounds by solubility enhancement
conductive etch mask layer. due to inherent hydrophobicity or to saturation
Ravula Sayisiva et al. [33] has invented Solid lipid limitations in the core of the osmotic system which
dispersion for aqueous solubility enhancement of found appropriate for the osmotic delivery of
poorly water soluble drugs that related to a poorly glipizide and other hydrophobic drugs, but runs the
water soluble drug and a lipid material in the form of spectrum to other therapeutic agents with higher
lipid solid dispersion and their use in dosage form. aqueous solubility.
The said solid dispersions increase the bioavailability Ramachandran et al. [38] have invented “novel
of active agents, are convenient to administer and are solubility enhancer accomplished of being active
stable. The present invention also delivers a process in formulating safe and effective pharmaceutical
for the preparation of these lipid solid dispersions by preparations of partially soluble drugs.” The
spray drying a dispersion of poorly water soluble solubility enhancer is selected from dialkyl
drug and lipid excipients. substituted amides of fatty acids having C6 to C16
Liang et al. [34] has prepared and invented Stabilized carbon chain, preferably from N, N-dimethyl
solubility-enhanced formulations for oral delivery hexanamide, N, N-dimethyl octanamide, N, N-dialkyl
including vitamins and co-factors into self- decanamide, N, N-dialkyl dodecanamide or N, N-
emulsifying formulas (SEF) and optionally sorbing dialkyl hexadecanamide.
the SEF into pores of porous solid particulates, or Padmanabh et al. [39] has invented Osmotic delivery
making supersaturated solutions (SSS) and sorbing of therapeutic compounds. The present invention is
the SSS into pores of porous solid particulates. appropriate for the osmotic delivery of glipizide and
These preparations are useful as dosage forms with other hydrophobic drugs, but runs the spectrum to
oral availability. other therapeutic agents with higher aqueous
Bruce et al. [35] has invented Method to enhance solubilities, yet having a solubility limitation in an
aqueous solubility of poorly soluble drugs using osmotic dosage unit due to high drug load.
methoxypolyethylene glycol bycombining an active Davila et al. [40] has invented “Pharmaceutical
compound (having an aqueous solubility that is less composition for solubility enhancement of
than or equal to about 10 mg/ml), and an amount of hydrophobic drugs”and found that a pharmaceutical
methoxypolyethylene glycol that is sufficient to composition containing a drug and polyethylene
enhance the aqueous solubility of the active glycol (where the ratio of polyethylene glycol to drug
compound. Enhancement of aqueous solubility for by weight is from about 0.2:1 to about 10:1 and the
this combination may be significantly greater than polyethylene glycol has a melting point of at least

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 Global J. Pharmacol., 8 (1): 26-35, 2014

37°C), Exhibit rapid dissolution upon contact with enhancing tag. The present invention also features
physiological solvents, like water, gastrointestinal methods of responsible the structure of a get protein
fluids or saliva. using a fusion protein to stabilize the get protein in
Wagner et al. [41] has invented Enhanced solubility solution.
of magnesium halides, catalysts and polymerization Sylvia Rossi-Montero et al. [46] has invented
process using same that relates to magnesium halide Solubility enhancement of drugs in transdermal drug
compositions, catalysts made therefrom, methods delivery systems and method for the continuous and
of increasing the solubility of magnesium halides, controlled transdermal delivery of an active agent
methods of making magnesium halide compositions containing a pharmaceutically acceptable active
and catalysts, as well as methods of polymerization. agent carrier and cellulose derivative which provides
Roberto et al. [42] has invented Enhancement of a solubilizing and stabilizing effect on the active
oral bioavailability of non-emulsified formulation of agents combined therein.
prodrug esters with lecithin by formulating the ester David et al. [47] has invented Solubility
as non-emulsified formulation with lecithin; as well as enhancement of drugs in transdermal drug
a therapeutic composition of at least one antibiotic delivery systems and methods which is used a
and lecithin in a non-emulsified preparation; a composition and for the continuous and
method of treating infections with the non-emulsified controlled transdermal delivery of an active agent
formulation and a method for making tablets by direct including a pharmaceutically acceptable active agent
compression of blends of drugs with lecithin are carrier and cellulose derivative which provides a
disclosed. Non-emulsified formulations such as stabilizing and solubilizing effect on the active agents
solids, capsules, lozenges, tablets, suspensions, incorporated.
elixirs and solutions and exclude liposomes, Behl et al. [48] has invented Method for increasing
emulsion, lipid matrix systems and micro-emulsions. the solubility of morphine through the use of organic
Atul et al. [43] has invented Dosage forms for acid or its salts as a solubilizing agent. Particularly
increasing the solubility and extending the release suitable as solubilizing agents are salts of carboxylic
of drugs such as topiramate and phenytoin, dosage acids, includes gluconate, acetate, trate, aspartate,
forms and devices for enhancing controlled fumarate, citrate, lactate, malate, maleate, succinate
delivery of pharmaceutical agents by use of a drug and combinations. Pharmaceutical compositions of
core composition comprising a polymer carrier (e.g. morphine and organic acids or its salts as solubilizing
polyethylene oxide) and a surfactant (e.g. agents, found satisfactory.
poloxamer, polyoxyl stearate). The present invention Elke et al. [49] has invented Methods for enhancing
provides a means of delivering high doses of poorly the solubility of substantially water-insoluble
soluble drug in oral drug delivery systems that are compounds, by combining such compounds with a
convenient to swallow, for once-a-day water-soluble polymer e.g., polyalkylene oxide
administration. polymer or a cellulose ether, having a molecular
Richard et al. [44] has invented Particulate weight of from about 50,000 to 7,000,000 grams/per
compositions for improving solubility of poorly gram in an amount effective to enhance the water-
soluble agents that found particles for oral drug solubility of the compound in an acidic environment,
delivery prepared by spray-drying a dilute solution e.g., pH less than about 5.
of a poorly soluble agent. The particles include Jesus Miranda et al. [50] has invented Solubility
regions of poorly soluble agent wherein the parameter based on drug delivery system and method
dissolution rate enhancement was between about for altering drug saturation concentration that
2-fold and about 25-fold compared to the agent in provide the method of adjusting the saturation
bulk form. concentration of a drug in a transdermal composition
Alexey et al. [45] has invented Solubility and stability for application to the dermis, which contains mixing
enhancement tag for structural and ligand binding polymers having different solubility parameters, so
studies of proteins that provides methods of as to modulate the delivery of the drug. This results
stabilizing proteins in solution. The present invention in the ability to achieve a determined permeation rate
offers a method of solubilizing and stabilizing a get of the drug into and through the dermis. In one
protein in solution by making a fusion protein of the embodiment, a dermal composition of the present
get protein with a small solubility and stability invention includes a drug, an acrylate polymer and a

32
 Global J. Pharmacol., 8 (1): 26-35, 2014

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