Acta Poloniae Pharmaceutica ñ Drug Research, Vol. 69 No. 4 pp.

581ñ590, 2012 ISSN 0001-6837

Polish Pharmaceutical Society

SOLUBILITY ENHANCEMENT OF SIMVASTATIN: A REVIEW

GHULAM MURTAZA*

Department of Pharmaceutical Sciences, COMSATS Institute of Information Technology,

Abbottabad 22060, Pakistan

Abstract: Fairly soluble drugs in gastrointestinal (GI) media exhibit complete oral absorption, and thus good
bioavailability. About 40% of drugs are not soluble in water in practice and therefore are slowly absorbed,
which results in insufficient and uneven bioavailability and GI toxicity. Thus, most exigent phase of drug
development practice particularly for oral dosage forms is the enhancement of drug solubility and thereby its
oral bioavailability. Solubility, an important factor to achieve desired plasma level of drug for pharmacological
response, is the phenomenon of dissolution of solid in liquid phase resulting in a homogenous system. This
review describes various traditional and novel methodologies proposed for solubility enhancement of simvas-
tatin, and ultimately improvement in its bioavailability. For simvastatin, solubility is a crucial rate limiting fac-
tor to achieve its desired level in systemic circulation for pharmacological response. Thus, problematic solu-
bility of simvastatin is a main challenge for dosage form developing researchers. Various procedures, illustrat-
ed in this review, have been successfully employed to improve the simvastatin solubility for its bioavailability
enhancement; however, successful improvement essentially depends on the assortment of technique. Among all
the solubility enhancement techniques, solid dispersion method, in terms of ease and efficiency is most prom-
ising and routinely employed technique to resolve the solubility problems of simvastatin.

Keywords: techniques, solubility, polymers, surfactants, absorption, bioavailability

Fairly soluble drugs in gastrointestinal (GI) increase in solubility of hydrophobic drugs for con-
media exhibit complete oral absorption, and thus verting to oral dosage forms.
good bioavailability. About 40% of drugs are not There are numerous chemical molecules which
soluble in water in practice and therefore are slowly experience low aqueous solubility troubles.
absorbed, which results in insufficient and uneven Although these molecules have prospective pharma-
bioavailability and GI toxicity (1). Thus, most exi- codynamic feature, they exhibit low bioavailability
gent phase of drug development practice particular- attributable to poor aqueous solubility, and there-
ly for oral dosage forms is the enhancement of drug fore, these molecules turn into abortive entities.
solubility thereby its oral bioavailability. Therefore, it is a very tough assignment in drug
Bioavailability refers to the limit of therapeutically development to improve aqueous solubility of drug
active drug that approaches the systemic circulation (6).
and thus, is available at the site of action (2). There Simvastatin (SV, Fig. 1), an inactive lactone, is
are two reasons proposed for poor aqueous solubili- cholesterol lowering agent and a lipid lowering
ty of drugs (3): (i) high lipophilicity and (ii) strong agent developed synthetically from a fermentation
intermolecular forces which cause the insolubiliza- product of Aspergillus terreus. After oral ingestion,
tion of drugs (2). Various approaches have been pro- simvastatin is hydrolyzed to the analogous β-
posed to enhance solubilization of poorly water sol- hydroxyacid form. This is a major metabolite and an
uble drugs for the improvement of their bioavail- inhibitor of 3-hydroxy-3-methylglutaryl coenzyme
ability (4). The methodologies commonly used for A (HMG CoA) reductase, the enzyme that catalyzes
drug solubilization includes micronization, chemical the conversion of HMG-CoA to mevalonate, the
modification, pH adjustment, solid dispersion, com- rate-limiting step in the biosynthesis of cholesterol
plexation, co-solvency, micellar solubilization and (7ñ9).
hydrotropy (5). This review is prepared to narrate SV is a white, crystalline and non-hygroscopic
different traditional and novel methodologies for the powder having log P = 4.4 and glass transition tem-

* Corresponding author: e-mail: [email protected], mobile: +92-314-2082826, fax: +92-992-383441

581
582 GHULAM MURTAZA

(CD), degradative products of starch produced by

the action of cyclodextrin-glycosyl transferase
(CGT), are the cyclic oligosaccharides and are fre-
quently employed as host molecules. Its three natu-
ral grades are α-cyclodextrin (α-CD), β-cyclodex-
trin (β-CD), and γ-cyclodextrin (γ-CD) (13). The
CDs have been previously employed in the
improvement of solubility and oral bioavailability of
glipizide (14), rofecoxib (15), piroxicam (16) and
carvedilol (17) by preparing their inclusion com-
plexes. Various techniques such as kneading
method, microwave irradiation method, supercriti-
Figure 1. Chemical structure of simvastatin cal anti-solvent technique and lyophilization/freeze
drying technique have been acclimatized to fabricate
the inclusion complexes of poorly water soluble
drugs with CDs. Following are the attempts which
perature of 25OC. Its formula weight is 418.56. It is have been made for the improvement of SV solubil-
practically insoluble in water (30 µg/mL), and 0.1 M ity and dissolution by inclusion complexation.
HCl (60 µg/mL). It is normally believed that com- Varshosaz et al. (18) presented this study to
pounds with very low aqueous solubility will exhib- enhance the dissolution rate of SV using spherical
it dissolution-controlled absorption and therefore anti-solvent induced-crystallization method. In this
reduced absorption, distribution and target organ method, SV solution prepared in boiling
delivery. Its biological half life and bioavailability dichloromethane was added to cold water (5OC), the
are 3 h and 5% indicating extensive first pass metab- non-solvent. After sedimentation, bridging solvent
olism in liver, respectively. It is well absorbed from (isopropyl acetate) was put in. Finally, the crystals
GIT (8, 9); therefore, it is vital to augment its aque- were amassed and dried for 12 h at 50OC in an oven.
ous solubility, dissolution rate and bioavailability No alteration in the drug after crystallization process
from its oral solid formulations. was observed as evident from the FTIR (Fourier
Numerous techniques have been presented for transform infrared spectroscopy) and DSC (differen-
the enhancement of solubility and dissolution of tial scanning calorimetry) data. The XRPD (powder
poorly soluble drugs. However, many of these meth- x-ray diffractometry analysis) exhibited minor
ods have constraints such as particles frequently reduction in height of the characteristic peaks. The
agglomerate and micronized powder possesses high particle size of spherical aggregates was about 37
energetic surface indicating poor flow feature (10). µm. The dissolution efficiency of SV up to 60 min
Complexation with cyclodextrin exhibits low drug increased to about 2-fold in phosphate buffer solu-
loading (11). Solid dispersion involves the use of tion having 0.5% sodium dodecyl sulfate (pH 7)
higher quantity of polymer(s) (12) and its scale up using the rotating paddle method. The spherical
procedure is complicated. Several polymers have crystals obtained exhibited improved solubility than
also been reported for the improvement of simvas- that of untreated powder probably by reason of par-
tatin solubility. Some of them are β-cyclodextrin, tial change to amorphous form. Their dissolution
arosil 200, PVP K30 and self-microemulsifying rate at 60 min was still 4-fold of untreated powder
agent. In this context, a detailed review of possibly when stored at 25OC and 84% relative humidity for
all previous presentations for the enhancement of 30 days.
solubility and dissolution of SV are given in Table Shiralashetti et al. (19) executed this study with
1. the purpose of observing the influence of prepara-
tion techniques on the solubility and dissolution of
Inclusion complex formation techniques SV β-CD and hydroxypropyl β-cyclodextrin (HPβ-
Inclusion complex formation procedure is one CD) inclusion complexes. Simple physical mixing,
of the most precisely employed techniques for the kneading and spray drying techniques were
enhancement of solubility, dissolution rate, and sub- employed to fabricate the complexes. In physical
sequently improved bioavailability of poorly water mixture, drug, β-CD and HPβ-CD in the molar
soluble drugs. Inclusion complexes are prepared by ratios of 1:1 were blended independently in a mortar
the addition of the non-polar molecule(s) (guest sub- for approximately 1 h with fixed trituration. The
stance) into other molecule(s) (host). Cyclodextrins mixture was then passed through sieve 100 followed
 Solubility enhancement of simvastatin: a review 583

by storage in the desiccators over fused calcium ry like uniformity followed by slow incorporation of
chloride (CaCl2). drug into the slurry with continuous trituration for 1
Kneading method involves the soaking of CDs h. Slurry was then dried in air at 25OC for 24 h, pul-
having little quantity of water or hydro-alcoholic verized, passed through sieve 100 and stored in des-
solution to transfer into a paste followed by its iccator over fused CaCl2. The same procedure was
kneading after the addition of drug. The kneaded repeated for the SV-HPβ-CD complex.. In spray
product is then dried and sieved if needed (20). In drying method, SV and β-CD were dissolved in iso-
laboratory, kneading can be attained by using a mor- propyl alcohol (IPA) and distilled water independ-
tar and pestle (21ñ24). In kneading method, SV with ently using a magnetic stirrer. Then, both the solu-
β-CD in the molar ratio of 1:1 was used. First, β- tions were mixed together with magnetic stirring for
cyclodextrin and a small amount of 50% methanol 30 min. The consequential solution was sprayed in
were mixed in mortar with trituration to obtain slur- the chamber from a nozzle with internal diameter of

Table 1. Techniques found in literature for solubility enhancement of simvastatin.

Technique Methods Polymer Reference

Anti-solvent induced- Polymer not involved Varshosaz et al. (18)
crystallization method
Simple physical mixing, Hydroxypropyl Shiralashetti et al. (19)
Inclusion kneading and spray drying β-cyclodextrin
complex methods
formation Simple physical mixing, Polyethylene glycol PEG 6000 Mandal et al. (25)
techniques kneading and fusion (PEG) 4000,
methods or hydroxypropyl
β-cyclodextrin
Supercritical anti-solvent Hydroxypropyl Jun et al. (26)
(SAS) method β-cyclodextrin
Combination of
adsorption equilibrium Polymer not involved Zhang et al. (30)
and solvent evaporation
method
Solid Solvent evaporation Hydroxypropyl Pandya et al. (34)
dispersion by spray drying and methylcellulose-K3LV
techniques rota-evaporation methods
Physical mixtures and Polyethylene glycol-4000 Silva et al. (35)
melting method
Ball milling method Polyvinylpyrrolidone/vinyl Zhang et al. (36)
acetate copolymer
(PVP/VA64)
Spray drying method PVP Ambike et al. (37)
Solvent evaporation Margulis-Goshen
from spontaneously Polymer not involved and Magdassi (38)
formed oil-in-water
micro-emulsions method
Solubilization Self-microemulsifying Polymer not involved Meng and Zheng (39)
by surfactants method
techniques
Microemulsion method Polymer not involved Lee et al. (40)
Emulsification method Polymer not involved Ding et al. (41)
Antisolvent Polymer not involved Oh and Lee (42)
recrystallization method
Milling method Polymer not involved Zimper et al. (43)
Particle size
reduction Nano-precipitation Patil et al. (45)
techniques method
584 GHULAM MURTAZA

0.7 mm under the atomization pressure of 1.5 The products were analyzed in liquid state by
kg/cm2 with a feed rate of 3 mL/min. The inlet tem- phase solubility studies and in the solid state by
perature was set at 80OC and outlet temperature at 60 DSC, XRD and FTIR. The type, ratios of drug to
± 2OC. The vacuum and aspirator in the system were carriers and selection of the method of preparations
60 mmWC and 45%, respectively. The same proce- of solid dispersions markedly influenced the disso-
dure was adopted to prepare inclusion complex of lution rate. The highest dissolution rate of SV was
SV-HPβ-CD. The product thus obtained was stored achieved from the inclusion complex prepared with
in a desiccator till its analysis. HPβ-CD by kneading method. Marked increase in
Then, the inclusion complexes were assessed dissolution rate was observed from solid dispersions
for phase solubility and in vitro release behavior. systems, compared with those in physical mixtures
The physicochemical analysis such as DSC and X- and pure drug alone. The highest enhancement in
ray diffractometry (XRD) of complexes elaborated wettability and dissolution rate of SV was achieved
that no endothermic and specific diffraction peaks of from the SV-HPβ-CD solid dispersions (1:1) pre-
SV was found in both the inclusion complexes. The pared by the kneading process. This could be due to
results showed the conversion of SV from crys- the amorphous nature formed and dissolved of
talline to the amorphous form. There was a marked 100% of drug was achieved within 60 min.
increase in the aqueous solubility and dissolution Accordingly, this amorphous solid dispersions could
rates of drug in inclusion complexes as compared be valuable for supplementary formulation as an
with the drug alone and its physical mixture. appropriate competitive formulation.
Besides, spray dried complexes performed better in In another study, Jun et al. (26) prepared sim-
all the evaluated factors as compared to the com- vastatin-inclusion complex with HPβ-CD using
plexes fabricated by other methods. supercritical anti-solvent (SAS) procedure to inves-
Mandal et al. (25) executed this study with tigate the improvement in aqueous solubility and
the purpose of observing the influence of prepara- the dissolution rate of drug, consequently improv-
tion techniques on the solubility and dissolution of ing its bioavailability. Phase solubility diagram,
simvastatin-PEG 4000, PEG 6000 or HPβ-CD DSC, XRPD, FT-IR and scanning electron
inclusion complexes. Simple physical mixing, microscopy (SEM) tests were used to evaluate the
kneading and fusion techniques were employed to inclusion complexation in aqueous solution and
fabricate the complexes. In physical mixture, drug, solid state. The phase solubility diagram with HPβ-
PEG 4000, PEG 6000 or HPβ-CD in the molar CD was categorized as A(L)-type at all tempera-
ratios of 1:1, 1:3, 1:5 were blended independently tures conditions, showing the configuration of 1:1
in a mortar for approximately 1 h with fixed tritu- stoichiometric inclusion complex. The apparent
ration. The mixture was then passed through sieve complexation constants (K(1:1)) evaluated from
80 followed by storage in the desiccators over phase solubility diagram were 774, 846 and 924
fused calcium chloride (CaCl 2). In kneading Mñ1) at 25, 37 and 45 ± 0.5OC, respectively. No
method, SV with HPβ-CD in the molar ratio of 1:1 endothermic and typical diffraction peaks related to
was used. First, β-cyclodextrin and a small amount SV was found for the inclusion complex in DSC
of 50% (v/v) alcohol were mixed for 45 min in and XRPD. FT-IR study elaborated the presence of
mortar with trituration to obtain slurry like unifor- intermolecular hydrogen bonds between SV and
mity followed by slow incorporation of drug into HPβ-CD in inclusion complex, showing the devel-
the slurry with continuous trituration for 1 h. opment of amorphous form. The results of aqueous
Slurry was then dried in air at 60OC, pulverized, solubility and dissolution tests signified that there
passed through sieve 80 and stored overnight in was a remarkable increase in the dissolution rates of
desiccator and named as KNCD (representing inclusion complex, compared with the physical
ìkneading cyclodextrinî). In melting method, mixture and simvastatin alone. In conclusion, the
solid dispersions of SV and carrier PEG 4000 or narrated process could be a valuable process for the
PEG 6000 in the molar ratios of 1:1, 1:3, 1:5 were development of the inclusion complex of SV with
prepared by the melting method. The carrier was HPβ-CD for significant increase in its solubility
melted in a water bath at 70OC, the solid drug was and dissolution rate.
incorporated with stirring to make a homogenous
mixture. In a freezing mixture of ice, the mixture Solid dispersion
was then cooled swiftly and stored in a desiccator
for 24 h. Then, the dispersion was ground in a Solid dispersion is an assembly of solid prod-
mortar and passed through sieve 80. ucts consisting of no less than two unlike con-
 Solubility enhancement of simvastatin: a review 585

stituents, normally a hydrophilic medium and a In a study, solubility and dissolution of SV was
hydrophobic drug. The most commonly used improved using hydrophilic, low viscosity grade
hydrophilic carriers for solid dispersions include polymer ñ hydroxypropylmethylcellulose (HPMC-
polyvinylpyrrolidone (PVP), polyethylene glycols K3LV). The co-solvent evaporation method was
(PEG) and Plasdone-S630 (PS630). Surfactants like employed for successful encapsulation of hydropho-
Tween-80, docusate sodium, myrj-52, pluronic-F68 bic drug (SV) in polymer micelles of HPMC-K3LV.
and sodium lauryl sulfate, are also commonly insert- Solvent evaporation was achieved by spray drying
ed in the solid dispersion. Solid dispersions using and rota-evaporation techniques. In rota-evapora-
appropriate hydrophilic carriers were used in the tion, Pandya et al. (34) applied co-solvent evapora-
solubility improvement of celecoxib (27), halo- tion technique for improvement of solubility and
fantrine (28) and ritonavir (29). There are various dissolution rate of SV. The solvent evaporation of
techniques like hot melt (fusion) method, solvent SV-HPMC-K3LV (1:1, w/w) solution was conduct-
evaporation method and hot melt extrusion to for- ed using Buchi rota-evaporator (Buchi Rotavapor,
mulate solid dispersion of hydrophobic drugs to R215, Buchi, Switzerland). Two grams of simvas-
enhance their aqueous solubility. Following are the tatin in 100 mL of methanol and 2 g of HPMC-
attempts made for the improvement of SV solubility K3LV in 60 mL of distilled water were dissolved
and dissolution by solid dispersion. and both solutions mixed to get a clear solution fol-
Zhang et al. (30) developed spherical mesocel- lowed by its evaporation at 253 torr pressure and
lular foam (MCF) loaded with SV via a procedure 60OC for 0.5 h in rota-evaporator. In spray drying,
involving a combination of adsorption equilibrium the solvent evaporation of SIM and HPMC-K3LV
and solvent evaporation, aimed to be orally adminis- (1:1) solution was conducted using spray dryer (LU-
tered, capable to enhance the dissolution rate and 222, Advanced, Labultima, India). Two grams of
improve the drug loading aptitude. Spherical MCF simvastatin in 70 mL of methanol and 2 g of HPMC-
having an incessant 3-D pore system was produced K3LV in 30 mL of distilled water were dissolved
using a surfactant (Pluronic 123 triblock polymer) and mixing both solutions gave a clear solution. The
and a co-surfactant (cetyltrimethylammonium bro- solvent evaporated at inlet 110OC and outlet 60OC,
mide). Based on the drug release rate and the drug feed pump speed 10 mL/min and aspiration 45%.
loading efficiency, the spherical MCF and fibrous The spray dried mixture of drug with HPMC-K3LV
SBA-15 were compared. The physicochemical eval- was achieved in 20ñ30 min.
uation revealed the successful incorporation of SV The DSC, XRD, SEM, and FTIR tests were
into the MCF host. The results indicated that spheri- also applied to evaluate formulations. Results
cal MCF has a high drug loading efficiency up to showed the alteration of crystalline SV into its
37.5%, and higher than that of fibrous SBA-15, with amorphous form. There was a remarkable increase
a pore diameter of 6.5 nm. It was concluded that in the dissolution rate of SV in co-solvent-evaporat-
faster release rate of SV was acquired from spherical ed mixtures, compared to simvastatin alone. It could
MCF compared with SBA-15 and pure crystalline be due to the surfactant property of low HPMC-
SV using enzyme-free simulated intestinal fluid (pH K3LV (viscosity grade HPMC), which improves the
6.8). In solvent evaporation, both the drug and the wettability of SV and therefore enhances its solubil-
carrier are dissolved in a common solvent followed ity. Consequently, this technique also showed prom-
by the evaporation of solvent under vacuum to pre- ising encapsulation efficiency and generated amor-
pare a solid solution. Many studies have proposed phous form of SV, which exhibited better solubility
the solid dispersion of meloxicam (31), naproxen and dissolution than the crystalline SV.
(32) and nimesulide (33) using solvent evaporation Silva et al. (35) prepared the solid dispersions
technique. Major benefit of the solvent evaporation of SV with polyethylene glycol (PEG 4000) using
technique is the prevention of thermal decomposition different drug:carrier ratios by the melting method.
of drugs or carriers because of the low temperature Physical mixtures (PM) in the same ratios were also
needed for the evaporation of organic solvents. prepared for comparison. The products were inves-
Hovewer, some disadvantages related with this tigated by XRPD, DSC and infrared spectroscopy
process are the higher expenditure of formulation and solubility studies. Solid dispersions samples
development, the complexity in entire removal of were evaluated by high performance liquid chro-
liquid solvent, the possible unfavorable consequence matography (HPLC) to assess stability. The XRPD
of the added solvent on the chemical stability of the results demonstrated the presence of SV and PEG
drug, the assortment of a common volatile solvent, crystalline. A possible decrease of crystallite size
and the obscurity of reproducing crystal forms. was also observed. The obtained thermograms and
586 GHULAM MURTAZA

chromatograms showed no incompatibility between Ambike et al. (37) obtained free flowing, sta-
components of solid dispersions and physical mix- ble, amorphous solid dispersions of SV, a drug with
tures. A great effect on SV solubility and release rate relatively lower Tg, by spray drying technique. In
was found in the SV solid dispersions with PEG this method, SV was suspended in dichloromethane
4000 in all percentages. Solid dispersions of SV either alone or in combination with PVP (1:1 or 1:2,
with PEG caused a significant augment of drug sol- w/w ratio between drug and PVP). This suspension
ubility with almost 100% increase at 1:5 drug:poly- was spray dried with anticipated amount of Aerosil
mer ratio. The enhancement of drug release in the 200 (1:1, 1:1:1, 1:2:2 parts by weight of SV, Aerosil
solid dispersions might be a result of the reduction 200 and PVP, respectively). To overcome the con-
in the crystallite size, as well as, the surface tension straints of spray drying method for amorphization of
lowering influence of polymer, causing an enhance- low Tg drugs, combination of solid dispersions and
ment in wettability and dispersibility of SV. surface adsorption techniques has been attempted.
Zhang et al. (36) investigated the development Solid dispersions 1:2:2 was choosed as the opti-
of kinetics of a solid dispersion of SV with an amor- mized product on the basis of powder features, drug
phous copolymer using ball milling and compared content, saturation solubility and practicability of
the stability of developed products. They ball milled processing into tablets. In physicochemical evalua-
the physical mixtures of quench-cooled amorphous tion, scanning electron microscopy (SEM), DSC,
SV and polyvinylpyrrolidone/vinyl acetate copoly- and XRPD analyses verified the presence of amor-
mer (PVP/VA64) in weight ratios of 1:1 and 1:4 for phous form in solid dispersions 1:2:2. The IR spec-
3ñ40 min. With increased milling time, the two Tgs troscopy exhibited the prospect of hydrogen bond-
(glass transition temperatures) (29.5OC for the drug ing between SV and PVP in solid dispersions. Also,
and 108.5OC for the polymer) primarily present in the there was dramatical increase in the rate and extent
1:4 samples progressively shifted nearer to each of in vitro drug release of solid dispersions 1:2:2.
other and ultimately outlined a single Tg at 91OC During accelerated stability studies of solid disper-
after 30 min, which agreed to the predicted Tg at sions 1:2:2, inconsequential decline in dissolution
89.2OC using Gordon-Taylor equation, demonstrat- was found with no confirmation of crystallinity.
ing the development of a one phase solid dispersion. Moreover, comparative in vivo study in rats also jus-
On the other hand, samples at the 1:1 ratio still tified the improvement in therapeutic efficacy of
demonstrated two Tgs (at 74.4OC and 101.5OC) after solid dispersions 1:2:2, compared to pure SV.
30 min milling, disclosing a two phase system with Consequently, this study reveals promising ability
fractional miscibility. These two separate phases of spray drying method for finding stable amor-
were compiled by drug to polymer ratios of 0.46:0.54 phous solid dispersions of low Tg drugs.
and 0.11:0.89, respectively. Additionally, milling of
these samples for another 10 min revealed no sup- Solubilization by surfactants
plementary variation in thermal performance. Surfactants are molecules having distinctive
Intermolecular hydrogen bonding happening polar and non-polar parts. A large number of surfac-
between the two constituents was noticed by tants contain a hydrocarbon part attached to a polar
DRIFTS (diffuse reflectance IR Fourier-transform group. The polar group can be anionic, cationic,
spectroscopy) for all milled samples. Amorphous SV zwitterionic or nonionic. When small polar mole-
in physical mixtures with PVP/VA64 without cules are inserted, they can mount up in the
milling tended to transfer back to the crystalline form hydrophobic core of the micelles (5) resulting in a
during storage at 45OC. Samples at both weight ratios decrease in surface tension, however, in an increase
after milling for 10 min revealed a spectacular in solubility of drug within an organic solvent (12).
enhancement in stability although only a small part Following are the attempts made for the improve-
of drug had structured a single amorphous phase with ment of SV solubility and dissolution involving sol-
polymer. There was no notable increase in stability ubilization by surfactants.
under the conditions studied by further milling. Both Margulis-Goshen and Magdassi (38) evaluated
MT (modulated temperature) DSC and DRIFTS a method for the preparation of nanoparticles of SV
could be employed to analyze the kinetics of solid by solvent evaporation from spontaneously formed
dispersion development during milling. The 1:4 drug oil-in-water micro-emulsions. In this study, freeze-
polymer mixtures produced a one phase solid disper- drying technique was applied to convert micro-
sion while 1:1 drug-polymer mixtures did not. It emulsions containing a volatile solvent as an oil
materializes a completely miscible system for physi- phase into nanoparticles in the form of dry non-oily
cal stabilization of amorphous SV. flakes. The loading efficiency of SV in nanoparti-
 Solubility enhancement of simvastatin: a review 587

cles was evaluated by dispersing the flakes in water crystallization. The particles size of microemulsion
followed by filtration through a 0.1 µm pore size fil- was approximately 90ñ300 nm. The dissolution rate
ter. The filtrate was used to assess the SV concen- (< 5%) of marketed formulation (ZocoÆ) was very
tration. The results indicated that > 95% of the drug low and almost negligible, compared to that of the
was present in amorphous particles (size < 100 nm) SMEDDS formulations, which was much higher
after freeze-drying. The dissolution studies showed and faster, reaching 40ñ50% and 90ñ100% in simu-
a remarkable increase in dissolution rate from the lated gastric and simulated intestinal media, respec-
tablets containing the flakes of SV nanoparticles, tively. The SMEDDS was found very successful for
compared with conventional tablets. The X-ray dif- the enhancement of solubility and dissolution of SV
fraction test exhibited that resulting SV nanopartic- by preparing stable isotropic and transparent
ulate flakes were originally amorphous, but a slow microemulsion with nano-sized particles.
crystallization process occurred when the formula- Polyglycerol diisostearate ethoxylates with two
tion was stored at room temperature. hydrophobic chains were prepared by the reacting
Meng and Zheng (39) stated that self- polyglycerol diisostearate with ethylene oxide as
microemulsifying drug delivery systems are valu- follows (41): 50 g of polyglycerol diisostearate
able to get better bioavailability of simvastatin by (PGDIS) and 0.2 g of potassium hydroxide (KOH)
enhancing their apparent solubility through solubi- were mixed in autoclave and heated to about 70OC
lization. To achieve this goal, an empirical experi- under nitrogen atmosphere. Then, ethylene oxide
mental model was utilized to simulate the effect of was introduced gradually into the autoclave to main-
the mixture compositions on SV apparent quantita- tain temperature at 100ñ110OC and pressure
tive solubility. The reduced cubic polynomial equa- between 0.15 and 0.20 MPa. Acetic acid was then
tion successfully modeled the development of SV used for the neutralization of final products followed
apparent solubility. Response surface diagram was by filtration through celite. The surface features
presented to show a scale of possible SV apparent such as cloud temperature, water solubility, critical
solubility in a range of 0.0024 ~ 29.0 mg/mL. micelle concentration, the solubilizing capacity and
Additionally, this procedure proved that SV appar- emulsification of polyglycerol diisostearate ethoxy-
ent solubility was primarily affected by microemul- lates for simvastatin were explored as compared to
sion quantity and advised that the drug precipitation those of Tween-80. The critical micelle concentra-
would occur in GIT by reason of dilution by GI flu- tions of all polyglycerol diisostearate ethoxylates
ids. Moreover, the developed model can be helpful were < 0.01 mM/L, and it was lower than that of
in formulation designing to improve drugís apparent Tween-80. Polyglycerol diisostearate ethoxylates
solubility and avoid its precipitation. exhibited better emulsification than Tween-80. To
Microemulsion based formulation of SV was enhance the SV solubility in micelles, polyglycerol
prepared to enhance its solubility and dissolution diisostearate ethoxylates also were better than
(40). SV solubility was evaluated after interacting Tween-80.
with different saturated substances like fatty acids, The phase behavior of simvastatin and lovas-
oils, surfactant and co-surfactant at 25OC over 24 h. tatin in solvent mixtures of dichloromethane (DCM)
Drug solubility data were used to construct phase and supercritical carbon dioxide (CO2) has been
diagrams forming optimal microemulsion regions at explored to elaborate a principle for ascertaining
room temperature on the basis of electric conductiv- operating circumstances in the particle configuration
ity and visual stability. The self-microemulsifying of the drugs by a supercritical antisolvent recrystal-
drug delivery system (SMEDDS) was formulated by lization procedure using DCM and CO2 as a solvent
heating at 40OC until a clear solution was formed. and antisolvent, respectively. Oh and Lee (42)
The SMEDDS consisted of drug, oil, surfactant and determined the solubilities of the statin drugs in
co-surfactant. The USP (XXIII) paddle method in DCM + CO2 at different conditions of temperature
simulated gastric (pH 1.2) and intestinal (pH 6.8) and pressure by evaluating the cloud positions of the
fluid was employed to investigate the dissolution solutions having dissimilar compositions. A mixture
rate of SMEDDS. Laser scattering particle analyzer of the drug + DCM + CO2 was arranged and con-
was used to measure the microemulsion size after verted into a homogeneous single-phase solution by
exposing SMEDDS to distilled water. compression. When the solution reached a cloud
The solubility of SV was over 130 mg/mL in position, it turned into clouds and the drug precipi-
light fatty alcohol and carbonates oils. The improve- tation occurred. Thus, the cloud position symbolized
ment in the solubility and stability of the drug was the phase conversion from the single-phase to the
also observed with co-solvent addition without re- two phase solution and behaved as the margin
588 GHULAM MURTAZA

between the whole dissolution and precipitation of Particle size reduction

the drug in DCM + CO2 mixture. Then, the cloud The techniques of size reduction involve the
position was measured by the following process. increase in surface area of particles with the
Any entrapped air in the cell was removed by decrease in particle size, resulting in the increase in
purging the cell with sufficient CO2 gas, and then the drug solubility (5). Size reduction involves well
cell was loaded with drug. Using a gastight syringe, established milling procedures, which are typical
DCM was injected into the cell followed by the part of formulation preparation and can be accom-
immediate positioning of piston. The amounts of the plished generally by micronization and nanosuspen-
drug and DCM loaded into the cell were determined sion (6). Sometimes, sonocrystallization technique
using a sensitive balance. Then, high-pressure cylin- is also used for particle size reduction (43).
der was employed to charge CO2 into the cell. The Following attempts have been made for the
amount of CO2 introduced into the cell was found improvement of SV solubility and dissolution
out by weighing the sample cylinder using a bal- involving particle size reduction.
ance, before and after loading. A hot, fine and short The dissolution rate of poorly water soluble
feed line (0.03 inches internal diameter, 10 cm long) BCS-class II and IV drugs can be enhanced by
was employed to reduce the quantity of CO2 lost reducing their particle size. On the other hand, the
during charging. main disadvantage of this procedure is the possible
At a desired temperature, the pressure genera- appearance of process related muddle such as the
tor was employed to compress the solution in the alteration in the molecular configurations of drugs,
cell by moving the piston located within the cell. which may elaborate changed features like solubili-
The magnetic stirrer was employed for agitation. As ty and dissolution rate and consequently, process
the pressure rose, the drug dissolved in the solvent related solid state alterations require to be observed.
mixture of DCM + CO2 becoming a single phase. On Zimper et al. (44) investigated the dissolution rates
thermal equilibrium with a single phase solution, the of milled and un-milled SV, screened the main
pressure was then gradually decreased at about 0.5 milling parameters, and optimized the milling
MPa/min until the solution changed into clouds. At process in connection with the opposing reactions,
a constant temperature, the cloud position signifying particle size and process related muddle by using a
the single-phase to two-phase conversion was char- central composite face centered drawing. Weighed
acterized as the pressure at which it was no longer drug samples (600 mg) were milled in 25 mL stain-
promising to visually monitor the stirring bar. Thus, less steel jars employing an oscillatory ball mill
a pressure-temperature (P-T) cloud point curve was (Mixer Mill MM301, Retsch GmbH and Co.,
created for a solvent mixture of DCM and CO2 with Germany) at 4OC. Processing times (5ñ60 min),
a definite quantity of the drug dissolved. milling frequency (5ñ25 Hz) and number of stain-
In short, the solubilities of the statins in the less steel balls (3ñ60 with a diameter of 4 mm) were
mixture of DCM + CO2 were established as func- opted using a central composite face centered design
tions of solvent composition, temperature and pres- (MODDE software version 7, Umetrics AB,
sure by calculating the cloud positions of the terna- Sweden). Silica gel was used to store the processed
ry mixtures of SV + DCM + CO2 and lovastatin + samples at 4OC. SEM and image analysis were
DCM + CO2 at different situations. High-pressure applied to assess particle size. XRPD and Raman
phase equilibrium apparatus equipped with a vari- spectra were applied to determine process induced
able-volume view cell was employed for this pur- disorder by partial least squares regression model-
pose. The solubility facts of SV and lovastatin are ing. Applicable and significant quadratic models
described in the DCM + CO2 mixtures with the were fabricated. The milling frequency, ball quanti-
DCM mole fractions in a range of 0.18ñ0.34 at a ty and milling time were the investigated milling
temperature range of 303.25ñ333.25 K and at pres- parameters at constant drug load, out of which
sures up to approximately 45 MPa. The cloud point milling frequency appeared as the most significant
phase behavior of a typical lower critical solution parameter for particle size as well as the process
temperature phase behavior was observed from ter- related muddle. An interacting influence on the
nary mixtures. The results showed that the drug sol- responses was exhibited by milling frequency and
ubility boosted with the augment in the DCM com- milling time. The optimum milling settings with the
position in solution and the system pressure at a maximum number of milling balls (60 balls with 4
constant temperature. Moreover, there was a mm diameter) was assessed to be at a milling fre-
decrease in drug solubility with the increase in tem- quency of 21 Hz and a milling time of 36 min with
perature. a resulting primary particle size of 1.4 µm and the
 Solubility enhancement of simvastatin: a review 589

process related muddle of 6.1% (assessed by Raman precipitation. The stirring rate and polymer concen-
spectroscopy) and 8.4% (assessed by XRPD), at a tration were varied to observe their effect on the
set optimization limit of less than 2 µm for particle properties of products. The obtained nanoparticles
size and greater than 10% for the process induced were filtered and dried using rota-evaportor under
muddle. This optimum response was analyzed vacuum at 50OC for 3ñ4 h.
experimentally and the process related muddle was
established to be 6.9% (± 2.2) by Raman spec- CONCLUSION
troscopy and 7.8% (± 2.3) by XRPD. The successive
intrinsic dissolution analysis exhibited that the For SV, solubility is a crucial rate limiting fac-
process related muddle was insignificant regarding tor to achieve its desired level in systemic circula-
the dissolution rate. The envisaged crucial particle tion for pharmacological response. Thus, problemat-
size (1.4 µm) could be corroborated by experimen- ic solubility of SV is a main challenge for dosage
tation; however, by reason of agglomeration of the form developing researchers. Various procedures,
primary particles, a dissolution rate improvement illustrated in this review, have been successfully
was not elaborated, emphasizing the significance of employed to improve the SV solubility for its
dissolution analysis at an initial stage of drug devel- bioavailability enhancement; however, successful
opment. improvement essentially depends on the assortment
The particle size reduction can also be of technique. Among all the solubility enhancement
achieved by nanosuspension (45). The exposed par- techniques, solid dispersion method, in terms of ease
ticulate area increases with the decrease in particle and efficiency, is the most promising technique to
size resulting in the increase in solubility. tenacity the solubility problems of SV. However,
Nanosuspension can also be achieved by precipita- there are many other methodologies that can also be
tion. In precipitation method, the drug substance is employed to enhance the solubility of SV.
dissolved in a solvent, and the resulting solution is
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