Researeh Article

Meth0 for Sollibility and Dissolufion Rate Eahanceinent of Tbuprofen

Using Block Copotymes Poloxamer 407

Rec**'v"*! 25 $eytemhcr 2025; sccepied J3 Jonusry 20J6,' puhlishtd online 27 Jan++ary 2016

mixtures of ibuprofen and polorarncr u'erc prepare d in tluee differc ni ratios (:1 0.2 . I:0.fi, and 1:
0.7fi. respcm*eIy} using o '•ratcr jacketed high shear mircr. 7n vitro dissolution and sa rura tion so4ubiliry
studies were carried out for ttie dnig. physiml mixtures, and formulations for all ratim in dc-ionized
water , 0.1S HG {pH - 1.'2), and phmphaic buffer (pH - 7.2). Thermo and physical characterization of
samples was done using mu‹Jul* cd digcccatial scanning ¢alorinJctry (mDSC), X-ray Number diJ
racfiori (SRD). md in frarc'J spcctrcscogy (MTTR)- Fiua proper+in were cvalua led usiag a pcwder
rheomc ter. Maximum solubility enhancement y*u sccn in aodic media for fused foe-rnuJajioa* flare
rtjc rauo ):0.25 bad )8-fold increase. /o vfizo disscluooa srudics showed disso)+iuoa rare
cnhariccracnl for gdysical mJxtcr«s aod th< fortauJañons in afl II+rcc media. Thc most pronmccd
effect wm seen for fortauJation (I:0.75) in acidic
+acdia there rfic ciJniutorivc dmg release a'as fi8.27% while for drug, it was ñ.67'X°. Modcl
ir+dependent suiti*tic«t methods and AN'ONA based methods were used Jo cbcck tIjc sigriJJ\cctire
nF diffcrcncc in tha dissolution profiles. Thermograms kom a›D8 ' sfiacd a characteristic peak for all
formulatfoas with T@,# of azocnd 45”C wt+ich suggested foroiadoo of a <utcctic zaizlur<. SRD data
displayed rfiat cg'stat- line nature of ibuproFcn was intact in the foroiuJarions. Tbis work sfiows dtc
cFfw•\ of cutcctic fom›auon and miccJTar so)ubilixarion between ibuprofcn and polosamcr a j Ific
given ratios on iu soIubi]jg/ and

¥£V WOft Dei: dissulution ra le fusioti Inc tliod; ibtj prolcn; polczamcr: solubiti y

]NTRODUCMON
Systemic bioavailability of poorly soluble drugG mainly
belonging to the Biopharroacee tics Classification Sys tern
(BOX) class II category has f›een a major challenge foe the
pharmaceuücai Industry. A prcreguisite lar such drugs before
tlsey get abmrbed into the blood sttewn is iheir soltibiliiy in
body ßuids. Low aqucous solflbiliiy iniposes lots o£
hindrances tn fprrriula lion developrrien t a nd el m ical trials in
terms of optimum dissol uiion rate in order to achtete je
required plasrqa concentrations, stability of forrnulafions,
etc. f 1) L•o p§ tcebni9ues have ben employGd In the past
for GOlubü ify enh ancem en1 file soIid dispersions (2),
nanosizi ng and nticrojt¡zatjon (3), cutccfic cñxrurcs (4), co-
crystals and salt (ocm al fioa (5), polymorghs (6), cooplsaation
(J), sur4actants and other GyJrcphi)ic (›oIyracrs (8).
fusion raelhod fcr makiog solid dispersions and eutcctic
misturu of poorly soluble drugs witfi hydropfrtlic polymers
' Arnold and Marie Sch w'artz CoHcge of Ph arm*cy and Head lb Sci-
ences. Division of Pttsrmaccui:icat Sciences. Long Islond
University.
Brmk lyn, New YorF I1Z01, USA
' To w h o m cocr ce po n dc noc Qtr ou1 d be a ddresscd. (c - G
ai1: rutcab.da•e8liu.ed u)
has been used widely in the pasi for solubility enhancement
and possible improvement in bioavailabiliiy of these drugs
(9). It involves tfie use of polymers (e.g.. Polosamers t I O).
some
$ ra6oz of polyethylene gtycols (I1)) wbien melt at
relatively tow temperatures (60—90° C) (12). This technj9ue
along yitn hot melt extrusio» allows mixing of drug and
polar at a molecular leveI without the psc of organic solvents.
Major advantages of this ocood arc absence ot tbc risk of
csidua] so)venTs unlike other solid dispersion techniques
nvu]ving use of solvents, eusy prnoessing in terms of Irving,
end mgroved rrhseibility of drug and polymer at relatively low
temperatures (13). to addition to enhancement of sob ubiI›ty,
fusion method
bus also been employed £oi controlled and modified release
a pplicat ion usin g b ydropliobi c pop y mers lik e glyce ry1
behenfl ie ( 14), s learic acid (1 S). camauba wax (16). etc. Scppe
of the current study was to prepare and evaluate the
polenGal of Poloxamer 407 (Luirelo F12'7 NF Prof) in
improving the solubility and dissolution rate of model BCS
class II drug ibuprofen.
Polozamers arc a group of non-ionic bIocL-copoly
mers consisting of polyethylene oxide (PEO) and
polypropylene oxide (PPO) units (-PEO-PPO-PEO-). Tbtro
arc different grades of Po)oxamer avaHa ble, and tficy differ in
the chain length nf PEO and PPO units. Poloxamer 407 is used
a.s a
 AgüI
2008 ybg

Enhancement of Solubility, Dissolution and Bioavailability of lbuprofen in

Solid Dispersion Systems
l/iadhuri NEWA, Krishnd Hari Bruvsox, Jong Oh Koi, Jong Seob Ian, Jung Ae Koi,
Bong Kyu Yoo, long S0o Woo, Han Gon Caoi,* and Chul S00n LONG'
College of Pharmacy, Yningiom University, 214-1 Dae-dong, Kyuiigsoii. Ky+ngbuk 7I2—749. Soitlh Korea.
Received Mch 20, 200'7i accepted January 11, 2008

T• i-grov• iu soiosiiig, disco\Baan, ana bioawiI»bxiiy; roup area—goiyetxyleoe giy•oi eooo fr'EG 8r o4)
60GId dTGperslona (GgS) wjtb dlfferegt drug Ioadiggs web progazed, ehar8cferized by seabniog electrob ii-
eraseogy (YES) g•d dJffereotiel seanofng celoWetry {OEC), and evNuated for solubility, in-vñ zo Please, ar+d oral
bioeyaJabtfity of i bjJgroFen In raps. Lyles oF ia dñ ñ doel sarface grogerttes doriz+q mel t4og aod solidifirati00 As
revealed by YES micrograghs in direted the foranaTion of egectl ve SDs. Absez+ce or sf+iFtiag towards tfTe Inwer
nieldng temperature of the drug peak In SDs rind pfiysicH mixtures to DSC study Indicated the possibilities
of
drug—polymer intemctions. Qutckey releese of ibupref'en tion SDs in mt intestine resulted in G signibc•nt in-
crease In AUC rind Cp„, and a significant decrease In 7qp over pure itiuproFen. Prelimlnary results of this
study suggested that the prepnretion of' lbuprofen SDs using PER 8000 as a meltsble hydrophilic poly mew
carrier could bt a promi.slog apptosch to lrnprm'e solubility, dissolunon ana bioTvailabilliy of ibuprofen.
hey wo•fis rhume ten ; sol id dispersion; polycthy le ne glycol 8000; solubil iry; d rejoint ion; bîom'aiIabi lily

Ibuprofcn is a non-steroidal anti-inflammatory dnig that might be feasible. However, tne maditienal melting methods
has been widely used in the tmatment of mild to moderate have been reported to be a.ssociated with many processing
pain and fever. As its scrum concentrations and analgesic ef- difficulties such as the temperature and shear rate control. re-
fect are correlated, rapid ibuprofen absorpLion could be a producibility, scalability etc. Although for many drugs in-
prerequisite for ifie quick onset of its action. Because of high eluding ibuprofen, SDs by melt agglomerations in fiigb shear
membrane gconeabilify, eztcnt of ibuprufen absorption ag- mixccs usinga hut solution oF melta6lc hydrophilic carriers
proaches up io 1 00%. Dissolution thjjs becomes the tate lim- as a binding solution have been claimed to be advaniageous
iting step for absorption, and the quick release of ibuprofen industrially, ' they were also associatcd with many disad-
in the gastroinfcsiinaJ tract following oral administration is vantagcs, e.g. separate melting of polymer with or without
désirable. ' Various formulations sucli as prodfugs,’* inel u- drug was an extra step that could make tlje process compl i-
sion complexes,’* microcapsules,’* etc. o1° ibuprofen were de- cated and costly, ihe yîeld in many cases was low b<cause of‘
veloped. However the dissolution rate and the oml bioavail- tht poIyrner/dnig loss while pouring into the powder mix.
ability of ibuprofen from thèse formulations diffemd wide ly, and tfie promesses themselves wtre very much similar to
methods were time consuming and costly, and some formuJa- tfie wet granulation method used in iaG let manufacturing
tions were bulky with poor flow charactnristics and handling process, thus making them relatively more denianding in
difficulties. terms of time and techno]ogy. Thougl the drying was not
Solid dispersions (SDs) of poorly water soluble drugs in necded, in many ceses, the î mprovement in ‹lrug dissolution
hydrophil ic carrier matrix have hecn reported to improve was lawnr compared ro rfic SDs of equivaient composition
their solubility and dissolution rate.“" Morcover they arc preparcd by melting method. In addition, use ot inert filiers
also proven to enfance their bioavailabiiity by incieasing such as lactose ers. might increase the buck and the price of
iheir saturation solubility in gastrointesrinal fluids. Howmer, thè se formulations.“' Tberefore, it would be an advantnge
ibupmI‘en SDs using sol vent or solveur-meJting method if the formation of ibuprofen SDs couJd be achie•cd using a
could be problcmatic b608U50, it might not be always easy io rapid, tess cxpensivt, consultable and reproduciblG
process." f-ind a common solvwif, large volumes of solvants and Iong Pt›lyethyltjag lycols (PEGs) are semicrystalline
polynjcrs
^• "o• •* ^••"•s • ‹ghi be necessary to enable complète that have been used extensively in the SDs prepatation for
d*ssoluf*on of botb corup onents, and the common methods their wetting, solubilizing and surface acô ve properties."
such as vacuum drying, spray-drying, spraying on sugar They ljave been reported to enhance the solubiliry, dissolu-
heads using a fluidizcd bcd coating system, lyophilization etc tion and bioavailability of many poorly water soluble dnigs
used for the removal où organic solvants from SDB could usirig various teehn iquts 1 ncluding melting agglomération,
make the process relatively mom complicaied, ledious and an‹l melttng. Extent of their absorption appears to bc depend-
costly. In addition, they might also assnciate with the solvant ent on their molecular rights and tite more complète ab-
rclated wrvéonmental probleme.' ' Although, SDs hy nielting sorptions have been reported for PEGs with lowcr molccular
could be problematie (for drugs wfth lligher meltiHg tcmper- weights. But the absorption is much more limited in the case
ature) because of the possible thermal unsiability of the com- ot PEGs with highcr molecular weights. Hence, the polyeth-
ponents, and the hardening où mefts resulting into difficulties ylene glycol 8000 (PEG 80£10) was empiricaily selecied as a
in tht puJverization for subséquent tö rmulation; in case of meltable polymer for its low meltiiig point, surfactam proper-
ibuprofcn because of its low melting tempeiamre, melting ties and orai safety. In this smdy, to irnprove its solubility,
at lower kmperature using meltablt hydrophilic polyniers dissolution and bioavailability, low mehing temperature of
 Cheniistry: Bulgarian Journal ofScience Education, Volume 21, Number 1, 2012
IlpupoDuu uayk-u 6 06pa306anuemo

From the Research Laboratories

B u3c.waogameaocume na60pamopuu

SOLUBILITY AND DISSOLUTION

ENHANCEMENT OF IBUPROFEN
BY SOLID DISPERSION TECHNIQUE USING PEG 6000-PVP K 30 COMBINATION
CARRIER

M. Saquib Hasnain, Amit Kumar Nayak

Seemanta Institute ofPharmaceutical Sciences, INDIA

Abstract. Ibuprofen solid dispersions were prepared with the objective of solubility
and dissolution improvement using PEG 6000-PVP K 30 combination carrier by solvent
evaporation technique. The saturation solubility and in vitro dissolution studies showed
remarkable improvement in solubility and drug dissolution of these new ibuprofen solid
dispersions over pure ibuprofen, ibuprofen solid dispersions using PEG 6000 and PVP K
30, individually and physical mixtures. The in vitro drug dissolution from these new
ibuprofen solid dispersions was followed Hixson-Crowell model. The XRD and DSC
studies indicated the transformation of crystalline ibuprofen (in pure drug) to amorphous
ibuprofen (in solid dispersions using PEG 6000-PVP K 30 combination) by the solid
dispersion technology. Stability studies of these solid dispersions does not show any
significant changes (p < 0.05) in drug content and drug dissolved in 60 minutes (Q60 min,
%) within 6 months study periods (at 25 ± 2 0C and 60 ± 5 % RH). This study concluded
that the improved solubility as well as drug dissolution of these new ibuprofen solid
dispersions using PEG 6000-PVP K 30 combination may be attributed to improved
wettability, and reduction in drug crystallinity, which can be modulated by appropriate
level of hydrophilic carriers.
Keywords: solid dispersion, ibuprofen, solubility, dissolution, polyethylene glycol, polyvinyl
pyrrolidone

118
 Solubility and dissolution rate enhancement of ibuprofen by co-milling with •T, polymeric
excipients
Amjad Hussain"' , Geoff Smith b", Karrar A. Khan , Nadeem Irfan Bukhari% Nicholas I. Pedge c, Irina Ermolina
a
Universicy College Of Pharmacy, University of the Punjab, Lahore, Pakistan b Lace-
ster School of Pharmacy, De Montfort university, Leicester, UK

AscaZenecg phamtaceutical Technndov and Development, Macclesfield, UK

ARTICLE INFO ABSTRACT

Keywords: The aim of this study was to enhance the kinetic solubility• and dissolution rate of ibuprofen by co-milling with poor soluble drugs different excipients and to establish the
underlying mechanism(s) for such enhancement. In the first-part, two Ball milling excipients (HPMC and soluplus) were selected from seven, and the optimal ball-milling parameters of speed
and Solubility Dissolution enhancementrate time (18 Hz, 15 min) were determined based on solubility-enhancement and flow-ability criteria. In the secondParticle size part. co-milling of
different weight-ratios of ibuprofen-to-excipient was carried out and solubility and dissolution content rates were determined. Mechanisms of biopharmaceutical enhancement
were studied by SEM, laser diffraction, DSC, and FTTR analysis Of the co-mixtures. Ibuprofen solubility (0.09 mg/ml, for un-rnilled) was increased by factors of 4—5 and 10-20 for HPMC and
soluplus, respectively. fie weakening of crystals, stabilization of the amorphous phase and an increase in solid-state hydrogen bonding are the likely mechanisms for this enhancement.
Reductions in Q70% dissolution time were also observed, by a factor of 4 and 7 for ibuprofen:HMPC and ibuprofen:soluplus co-milled mixtures, respectively. Although, there were similar
reductions in particle size, dispersjbility and degree of amorphization in both mixtures, the higher dissolution rate for soluplus. over that for HPMC, must be due to the additional solubilization
contribution to the kinetic solubility provided by soluplus.

1. Introduction
Milling and co-milling (which is defined as milling in the presence of
an excipient) are well known techniques that have a positive influence
on the kinetic solubility and dissolution rate of sparingly soluble drugs
(Jagadish et al., 2010; Szafraniec et al., 2017). These procedures have
been shown to provide a simple, effcient and economical method that
does not require any particularly sophisticated equipment (Fisher, 2007).
Moreover, the method has less environmental impact as it does not
require the use any organic solvent (Friedrich et al., 2005). Comilling
combines the advantages of a reduction in particle size and the
amorphization of a crystalline drug substance, Which are the benefit of
conventional milling of single materials, and have the additional bencfits
of improved wettability and solubilization that are provided by the co-
milled excipient (Mosharraf and Nyström, 1995). Furthermore, it may
also; i) prevent aggregation by the surface coverage of the charged
particles (produced by milling), ii) stabilize the amorphous phase in the
Abbreviations: PM. physical mixture; mPM, milled physical mixture; A, absorbance
• Corresponding author at: Pharmaceutical Technologies, Group, Leicester School Of Pharmacy, De Montfort University,
E-mail address: gsmith02@dmu.ac-uk (G. Smith).
solid state and iii) reduce the mechanical/thermal degradation of drugs
by moderating the effect of the heat generated on milling (Lin et al.,
2010).
Solubility is a physicochemical property of substance, which
depends on the thermodynamic properties of the crystal lattice (i.e. the
bonding energies which define the melting point) and the balance
between solute-solute and solute-solvent (solvation) interactions in the
solution state. The solute-solvent interactions may be changed by
adding other chemicals to the solvent, for example surfactants which
provide a micellar environment for the solubilization of the drug. It is
also important to remember that the solubility of a milled crystalline
material, containing metastable (partially amorphous) phase, represents
the kinetic solubility rather than thermodynamic/equilibrium solubility
(Brittain, 2014).
The rate of dissolution, which defines the rate of mass transfer from
the crystalline state to the dissolved (solution state) is coupled to the
solubility but is also impacted by attributes of the material such as the
Gateway, Leicester LEI 9BH,

https://doi.orgno.1016/j.ejps.2018.08.001
Received 15 March 2018; Received in revised form 15 June 2018; Accepted 1 August 2018 Available online 02 August 2018

0928-0987/ 2018 Published by Elsevier B.v.

0 2018 IJRAR April 201 8, Volume 5, Issue 2 www.ijrar.org (E-ISSN 2348-1269, P- ISSN 2349-5138)

DISSOLUTION AND SOLUBILITY

ENHANCEMENT OF IBUPROFEN USING SOLID DISPERSION
s.B. SAPKALI* v.N. SHRIKHANDEI, AMIT PAL2, B. S. BEDP
 Il)epartment of Pharmaceutics, Dr. Rajendra Gode College of pharmacy, Malkapur443101, Dist. Buldana,
Maharashtra

2
Department of Pharmaceutical Sciences, Dr. B. R. Ambedkar University, Agra, U.P

ABSTRACT
IJRAR19D149 International Journal of Research and Analytical Reviews (IJRAR) 762
0 wvvw.iirar.orq
The objective of work was to prepare and characterize solid dispersions of Ibuprofen using natural polymers viz.
xanthan gum, gaur gum and gum acacia to improve its aqueous solubility and rate of dissolution by solvent
evaporation technique. Solid dispersions showed marked improvement in the solubility behavior and improved drug
release. From all the formulations, IBII was found to be optimized formulation based on the characterization, solubility
and dissolution studies. The results obtained showed that the aqueous solubility and rate of dissolution was
significantly improved when formulated in solid dispersion as compare to pure drug. The enhancement of dissolution
rate depends on the nature and amount of the carrier and increases with the increase in the concentration of the
carrier. Increase in the dissolution rate may be attributed to; the reduced particle size of drug deposited on the surface
of carrier and enhanced wettability of the drug particles by the carrier. The optimized formulations were evaluated by
X-ray diffractometry (XRD), Differential scanning Calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR) and

Scanning electron microscopy (SEM).

Keywords: Ibuprofen, solid dispersions, Xanthan gum, gaur gum, gum acacia, solubility

INTRODUCTION:
Compounds having poorly aqueous solubility are increasingly posing challenge in the development of new
drug coming directly from synthesis or from high throughput screening have a very poor solubility [l]. It is well known
that drug efficacy can be severely limited by poor aqueous solubility, leading to low dissolution rate and thus result in
low absorption in gastrointestinal tract after oral administration hence compromising oral bioavailability. The
enhancement of oral bioavailability of poorly water soluble drugs remains one of the most challenging aspects of drug
development. Solid dispersion methods are extensively used to increase the dissolution property and oral
bioavailability of poorly water-soluble drugs, and numerous attempts have been reported for the past forty years [2,
3]. Methods for preparing solid dispersions, including a twin-screw extruder, ultra-rapid freezing, fusion, solvent
evaporation and spray drying, have been reported [4-8].