International Journal of Therapeutic Applications, Volume 6, 2012, 8 - 13
SOLUBILITY ENHANCEMENT OF POORLY HYDROPHILIC DRUGS BY USING
DIFFERENT NEWER TECHNIQUES: A REVIEW
Varshney, H. M.1, Chatterjee, A.*1
1
Department of Pharmaceutics, Faculty of Pharmacy, Jaipur College of Pharmacy, Jaipur, Rajasthan-302022,
India
expressed as a concentration, molality, mole
(1)
fraction, mole ratio, etc. .
ABSTRACT
Therapeutic effectiveness of a drug
depends upon the bioavailability and
ultimately upon the solubility of drug
molecules. In case of the oral administration
solubility is one of the important parameter for
achieving desired concentration of drug in
systemic circulation for pharmacological
response to be shown. Currently, 40% of the
drugs are poorly water soluble which produce
side effects such as gastric irritation, peptic
ulceration etc. whereas only 8% of new drug
candidates have shown both high solubility and
permeability. Dissolution rate, absorption,
distribution and excretion of a moiety depend
upon its solubility characteristics. On the basis
of solubility, drugs are classified into four
classes of the BCS classification. Solubility
challenges are faced in the Class II and Class IV
of the BCS system (where dissolution becomes
the rate limiting step for the absorption of
drug) which comprises of newer generation of
NSAIDs
like
Zaltoprofen,
Aceclofenac,
Flurbiprofen, their older congeners like
Indomethacin, Ibuprofen, Ketoprofen and
Diclofenac; anti-diabetics Gliclazide, Glipizide ;
newer calcium channel blockers (CCBs) like
Nimodipine, Felodipine. Till date various
methods of ameliorating the solubility has
been suggested, current write up is devoted to
the novel methods introduced in recent times
wiz. hydrotropy, sono crystallization, hot melt
extrusion technique, steam aided granulation,
floating granulation, dried nano suspensions,
spherical agglomeration, liquisolid technology,
cryo techniques .
The major problem faced during the oral
administration of active agent is the bioavailability
factor, which ultimately depends on the solubility
of the agent. 40% of the drugs discovered are
hydrophobic which produce side effects such as
gastric irritation, peptic ulceration etc. whereas
only 8% of new drug candidates have shown both
(2-3)
high solubility and permeability.
The knowledge
of solubility and permeability lineaments of the
active agents led the way to the BCS (
Biopharmaceutics classification system) given by
Dr. Gordon Amidon, comprising of four classes of
drugs (Table-1). Problematic classes include the
Class
I
II
III
IV
Table 1: BCS classification
Permea- SolubiExamples
bility
lity
High
High
Metoprolol
High
Low
Glibenclamide
Low
High
Cimetidine
Low
Low
Hydrochlorothiazide
Class II and Class IV (Fig.-1).
Keywords:
Bioavailability,
Solubility
enhancement, Novel methods, Dissolution
Characteristics.
(4)
Fig.1 BCS Classification
(4)
Lower the solubility, less it gets dissolved in the
INTRODUCTION
*Corresponding author:
Mr. Arindam Chatterjee
PG Student [M. Pharm. (Pharmaceutics)]
Mob:- 09887097804
Email: a.chatterjee@gmail.com
According to IUPAC, solubility may be defined
as The a alytical co positio of a saturated
solution, expressed in terms of the proportion of a
designated solute in a designated solvent, is the
solubility of that solute. The solubility may be
8
International Journal of Therapeutic Applications, Volume 6, 2012, 8 - 13
(12)
Cefixime.
Pandey and co-workers used
hydrotropic phenomenon of Potassium acetate for
analytical estimation of ketoprofen tablet dosage
(13)
form. (Table 2)
surrounding media, lesser it is available for
(5)
therapeutic effectiveness. Therefore solubility is
an essential factor for drug effectiveness,
independent of the route of administration. Poorly
soluble drugs are often a challenging front for
formulators in the industry. Conventional
approaches like , use of surfactants,
micronization, salt formation, pH regulation , cosolvency for augmentation of solubility have
limited applicability, especially when the drugs are
poorly soluble simultaneously in aqueous and in
non-aqueous media. Therefore interest in finding
newer methods to increase solubility and
dissolution rate is growing.
Table 2: Various Agents Used For Hydrotropic
(10-15)
Solubilization of Drugs
Drug
Additive used to exhibit
Hydrotropism
METHODS OF AMELIORETING SOLUBILITY
Pharmaceutical industry has been plagued by
solubility problems for years. Various methods
have been devised by number of authors but with
advancing introduction of the molecules day by
day newer and efficient methods are required.
Here in this piece of review we would take up
some new methods which were introduced in last
few decades.
Cefadroxil
Potassium acetate, potassium
citrate, sodium acetate, urea
Paracetamol,
Diclofenac
Sodium
Sodium Acetate,Urea
Theophylline
Sodium salicylate
Nifedepine
Sodium salicylate
Ketoprofen
Urea, sodium Citrate
2) Hot Melt Extrusion (HME) Technique
Hot melt extrusion process has been used since
(14)
1930 in plastic industry . Extrusion can be simply
defined as the process of forming a new material
(the extrudate) by forcing it through an orifice or
die under controlled conditions, such as
temperature, mixing, feed-rate and pressure.
HME technique is utilized in the formulation
development of poorly water-soluble because of
the enhanced dissolution properties, absorption
(16-17)
and therapeutic efficacy.
Advantages of this
technique include no requirement of solvent,
polymers itself act as binders. (Table-3)
1) Hydrotropy
Hydrotropy describes the increase in the
solubility of a less soluble solute by the addition of
fair concentrations of alkali metal salts of various
organic acids. Hydrotropes are the compounds
having both an anionic group and a hydrophobic
aromatic ring or ring system. Essentially the
anionic group increases the hydrophilicity and the
ring system interacts with the solute to be
dissolved. The term Hydrotropy was coined by Carl
(6)
Neuberg in 1916 but the practical implications
were introduced as late as 1976 by Thoma and coworkers. In 1985, Saleh co-workers broadened the
virtue of hydrotropic compounds by including the
cationic, anionic or neutral molecules having an
(7)
aromatic ring structure. Hydrotropic polymers
were later on added to the list, Park and coworkers,2003,2010,
indentified
NPicolylnicotinamide (PNA) was one of the best
hydrotropes
for
paclitaxel;
N,
Ndiethylnicotinamide
(DENA)
and
N,
Ndimethylbenzamide (DMBA) were also used as
(8-9)
solubility enhancers.
Maheshwari and coworkers increased solubility of Paracetamol using
Urea and of aceclofenac using mixed hydrotropic
(10)
phenomenon using Urea and Sodium acetate.
Sodium acetate was used as a hydrotropic agent to
increase the mass transfer coefficient of salicylic
(11)
acid by Theneshkumar and co-workers.
Hydrotropy has been used by Tambe and coworkers for developing a chromatographical and
spectrophotometrical method of estimation of
Table 3 Hot Melt Extrusion Technique and its
(18-23)
Applications
Drug
Polymer
Ibuprofen
Ethyl cellulose
Nifedipine
Poly (oxy) ethylene
glycol
Nimodipine
HPMC, PVA, Eudragit
Itraconazole
HPMC
3) Steam Aided Granulation
Steam granulation technique was invented by
Karl Hammer in the year 1982; this method entails
an introduction of stream of steam into a bed of
(24)
particles which are to be granulated. Rodriguez
and co-workers, 2001, prepared Diclofenac–
Polyethylene glycol 4000 accelerated-release
granules which showed enhanced dissolution
(25)
properties than pure drug and physical mixture.
Albertini and co-workers, 2002-03, developed
improved release piroxicam granules using
8
International Journal of Therapeutic Applications, Volume 6, 2012, 8 - 13
different
excipients
like,
β-lactose
and
Polyvinylpyrrolidone of two grades (PVP K-12 and
PVP K-90) having better dissolution characteristics.
Steam has better penetrability than water and also
leaves a thin layer of water on the particles which
(26-27)
can be easily aloofed afterwards.
enhanced dissolution properties of D-α-tocopherol
polyethylene glycol stabilized nanosuspensions of
(32)
indomethacin, loviride, phenytoin. Chaubal and
Popsecu,2008, studied the efficiency of this
(33)
technique.
Yang and co-workers, 2011,
enhanced the dissolution profile of Itraconazole
(34)
using HPMC as stabilizers.
4) Floating Granulation
6) Spherical Agglomeration
Patel and co-workers, 2010, developed a novel
technique
called
floating
granules
for
enhancement of the solubility of poorly soluble
drugs by extending the mean gastric residence
time. Ibuprofen and Furosemide are poorly water
soluble drugs having good permeability in the
stomach but lower in intestine. So they should
spend more time in the stomach but gastric
emptying time being 30 min-2 hrs is insufficient for
complete absorption. Ibuprofen granules were
Technique
Hot melt Extrusion
Floating Granulation
Liquisolid Technique
Ultra cryo milling
Sono crystallization
Spherical agglomeration is a process which is
combined unit process of crystallization,
Agglomeration and Spheronization. The resultant
crystals can be designated as spherical
agglomerates. Due to the their spherical shape,
the particle characterization properties such as
flowability and compressibility of the obtained
crystals are more, which makes it more viable for
direct tableting or coating without any further
Table 4 Summary of Techniques
Active Principle
Polymer
Ibuprofen
Ethyl cellulose
Nifedipine
Poly (oxy) ethylene glycol
Itraconazole
HPMC
Nimodipine
HPMC, PVA, Eudragit
Furosemide
Gelucire
Ibuprofen
H dro lprop l β- cyclodextrin
Piroxicam
Microcrystalline cellulose
Indomethacin
Propylene glycol,
Microcrystalline cellulose
Carbamazepine
PEG, HPMC, PVP
Glyburide
Propylene glycol,
Microcrystalline cellulose
Phenytoin
PVP
Flurbiprofen
Valdecoxib
Paraffin oil
Progesterone
-
Ref.
20
21
22
23
28
29
40
41
42
43
49
52
53
54
processing ( size separation etc.). In this process
aggregates of crystals are formed by liquid bridges.
The agglomerates are formed by agitating the
crystals in a liquid suspension in presence of
binding agent. The binding liquid should be
immiscible in the suspending medium but capable
of joining the particles which are processed. This
technique is used to increase solubility, dissolution
(35)
and hence bioavailability of hydrophobic drugs.
Dixit and co-workers,2010-11, increased the
solubility of Mefenamic acid and Indomethacin
(36-37)
using this technique.
made by simply fusing with Gelucire 44/14 which
showed a 3 hrs. residence time with 100% drug
release. Furosemide granules with Hydroxylpropyl
β- cyclodextrin were prepared by three methods
such as kneading method, physical mixture and
solvent evaporation method which dissolved
(28-29)
completely in 30 mins.
5) Dried Nano Suspensions
Nanosuspension are sub nanosized colloidal
dispersion stabilized by the use of surface active
agents. Pharmaceutical nanosuspensions are
defined as dispersion of finely divided drug
particles in a vehicle for all the routes of
administration. The particle sizes varies from 200(30-31)
600 nm.
Dried nanosuspensions are prepared
by spray freeze drying or lyophillization.
Eerdenbrugh and co-workers, 2008, displayed the
7) Lquisolid Technology
Liquisolid technique is used to prepare
compacts or compressible forms of liquid dosage
form like that solutions or suspension of
hydrophobic active agents. Basic principle implies
9
International Journal of Therapeutic Applications, Volume 6, 2012, 8 - 13
characteristics of Carbamazepni and Danazol ;
(46-47)
later on applied to Bovine serum albumin.
Atmospheric Spray freeze drying by Wang and coworkers,2006, in 2006 also showed the properties
(48)
of solubility enhancement.
Niwa, T., and
coworkers, 2012, used a novel method of ultracryo millimg and co-grinding technique to produce
nanoparticles of Phenytoin with improved
dissolution profile, in this technique liquid nitrogen
jet was used for grinding Phenytoin and PVP to
(49)
produce finer , uniform shape and size particles.
conversion of liquid form in to a dried powdered
form which has free flow, non adhesive properties
by mixing it with a suitable carrier and a coating
(38-39)
agent.
Researchers such as Spiras and coworkers,1999, and
Javadzadeh
and coworkers,2005-06, used various grades of cellulose,
starch and sorbitol as carrier material; Silica and its
modified grades as coating materials; propylene
glycols, polysorbates, glycerin and fixed oils as
solvents. Advantages of this technique includes
greater bioavailability, increased dissolution
properties, working cost is less than capsular
dosage form as compacts are later on compressed
into tablets, sustained release dosage forms have
(40-42)
been developed using this technique.
. Singh
and co-workers, 2012, formulated liquisolid tablets
of Glyburide using PVP and microcrystalline
cellulose for improved dissolution characteristics
(43)
than direct compressed tablets.
9) Sono Crystallization
Application of ultrasound energy to modify the
nucleation of a crystallization process is known as
sono crystallization. The energy of ultrasound
fashions consecutive compression and expansion.
After several cycles a bubble forms and grows then
collapses. The collapse of the bubble provides
Fig. 2 Process of Sonocrystallization
(47)
energy to promote the nucleation process. (Figure
2) This results in a highly repeatable and
predictable crystallization process. Applying
Ultrasound to crystallization results in:
8) Cryo Techniques
Cryo techniques include Spray freezing drying(
SFD), thin film freezing(TFF) and spray freezing into
liquid(SFL), which gives rise to amorphous
nanostructured
aggregates
having
higher
(43)
dissolution rates. Spray freeze drying invented
by Erik Thuse, Lewis F, Ginnete And Robert R.
Derby in the year 1964, is a combination of
atomization and lyophillisation. It entails spraying
of a solution containing the required drug of
interest into liquified gase like N2, O2, Argon etc.
the droplets generated by spraying gets
(45)
condensed into porous spherical particles. Spray
freezing into liquid is similar to SFD where the drug
solution is sprayed below the liquefied gases to
produce particles which are lyophilized later on.
Williams and co-workers, 2002, 2004 used spray
freezing into liquid to enhance the dissolution
10
Nucleation at the lowest level of
supersaturation where the crystallization
overcomes the tendency of the compound to
re-dissolve in the solution
Narrowing of the metastable zone width
Narrow particle size distribution
Decrease in the level of cooling necessary to
achieve crystallization
Highly
repeatable
crystallization
Polymorph control
and
predictable
International Journal of Therapeutic Applications, Volume 6, 2012, 8 - 13
Crystallization consists of two major events:
4. URL:
Nucleation: Solute molecules gather into
clusters and reach a critical size to constitute
nuclei.
5.
Crystal growth: Subsequent growth of the
nuclei.
6.
The ultrasound energy creates sequential
compression then expansion. Over several cycles a
bubble forms and grows then collapses. The
collapse of the bubble provides energy to
encourage the nucleation process at the earliest
possible point in time. This results in highly
(50)
repeatable and predictable crystallization. Two
of the methods used in industrial level are
Ultrasound Mediated Amorphous to Crystalline
Transition (UMAX®) and Dispersive Crystallization
with Ultrasound (DISCUS®) for the development of
(51)
inhalational
drug
delivery.
Kamel,2008,
enhanced the dissolution characteristics of
Flurbiprofen using melt sonocrystallization
(52)
technique
, Chaudhari and co-workers,2009,
(53)
studied the process on Valdecoxib and Paradkar
and co-workers,2010, analyzed the various
(54)
polymeric form of Progesterone.
7.
8.
9.
10.
CONCLUSION
Various technologies have been introduced for
the enhancement of solubility of poorly
hydrophilic drugs. The basic approaches involve
the interaction of a hydrophillic molecule with a
poorly soluble drug to give rise a phenomena of
increased solubility, which in turn increase the
bioavailability
and
intrinsic
activity
(pharmacological activity). Older methods had the
problem of irregular shape or size, larger particle
sizes which to lead to irregular dissolution
characteristics or toxicity problems as in case of
surfactants. Novel methods have shown the
properties of uniform shape and size which when
either used in combination or individually will have
a potential for the dissolution enhancement of the
newer chemical entities to be introduced in the
future.
11.
12.
13.
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