10261265,96

Iranian Polymu Journal 1 Volume 5 Number 3 (1996)

Synthesis and Hydrolysis of Modified Polyvinyl Alcohols

Containing Ibuprofen Pendant Groups

Soudabeh Davaran and Ali Akbar Entezami

Polymer Chemistry Laboratory , Faculty of Chemistry, Tabriz University, Tabriz 51664, Iran

Rcceived: 21 May 1996; accepted 1D July 1996

ABSTRACT

Polyvinyl alcohol is used as a carrier polymer for attachment of non-steroidal

anti-inflammatory drugs such as ibuprofen via hydrolltically labile ester
bonds . For this purpose, methods have been developed for the modification
of polyvinyl alcohol with difunctional compounds such as chtoroethanol,
chloroacetic acid, and sallcylaldehyde so that one of their functional groups
is attached to polyvinyl alcohol and the other remain active for further
reaction with drug functional groups . Poly(hydroxyethylvinyl alcohol), poly-
(vinylchloroacetate), and poly(vinylsalicylaldetryde acetal) were prepared and
reacted with ibuprofen to produce polymer-drug conjugates . In vitro hetero-
geneous hydrolysis of the polymers was studied at physiological conditions.
Poly(vinyisalicylaldehyde acetal) containing ibuprofen groups was more
reactive towards hydrolysis . Ibuprofen was released by hydrolysis of ester
bond without the cleavage of cyclic acetal.

Key Words : ibuprofen, polyvinyl alcohol, polymeric prodrug, synthesis, controlled release

INTRODUCTION occurring polymers with functional groups of bio-

The synthesis and behaviour of bioactive polymeric
systems have attracted great interest in recent
years . In polymeric prodrug approach the drug is
linked to the polymer backbone via a degradable
chemical bond and it is slowly released under
appropriate condition . The polymeric prodrug can
be prepared in two different ways [1-4] . In the
first, the drug is converted to a polymerizable deri-
vative that is subsequently polymerized to afford
the drug pendant polymers . Polymeric prodrugs
have also been prepared by substitution of reactive
groups of the preformed synthetic or naturally
active compounds or one of their derivatives.
In some cases the best approach to prepare
polymeric carriers of pharmaceutically active com-
pounds is to modify preformed polymers. This
method offers the advantage of the availability of a
wide range of polymer types and also simplicity of
the reactions. The employing of hydrophilic poly-
mers with biodegradable backbones led to the pre-
paration of polymeric systems for oral or topical
administration [1] . One of the limitations of the
reactions on polymers is the fact that the reactivity
of the drug on the polymer chains may be low
when it is directly attached to the main chain of

183

s.•~m si . . a rlyd Lysls of Modified Polyvinyl Alcohols
the polymer. This may be caused by steric hind-
rance of the neighbouring side groups . In fact the
limited efficiency of polymeric prodrugs is a
reflection of the limited loading and a too slow
hydrolysis of the drug from polymer backbone.
This problem has been overcome by spacing the
reactive groups from the main chain via spacer
arms . 'the bridging groups or spacer arms must be
inserted to aid hydrolysis or enzymatic breakdown
of the labile bonds . The activity can also be contro-
lled by varying the degree and type of substitution
along the backbone of a polymer selected.
Advantage of such polymer reactions are
that the molecular weight and the molecular
weight distribution of the polymer have already
hcen established [11.
Polyhydric synthetic polymers such as poly-
vinyl alcohol (PVA) are generally used in pharmac-
eutical materials as a hydrophilic non-ionic poly-
mer . It has found many applications as gel carriers,
diluents and solubilizers and widely used in suspen-
sion, diffusion matrix and coating processings.
Chemically controlled systems in which the
bioactive agents are covalently linked to polyvinyl
alcohol backbone have been developed for control-
led or sustained release purpose 1.5—8].
Polymer-drug conjugates of non-steroidal
anti-inllammatoly drugs (NSAIDs) such as ibupro-
fen and indomethacin have become important as
polymeric prodrugs 19-11] . These systems have
been developed in order to minimize delivery
problems and reduce gastrointestinal side effects
by controlling the rate, duration, and site of
release . This kind of polymeric prodrugs have been
designed for localized and prolonged duration of
drug action by parcntral administration (121, or as a
dermal prodrug 1131.
In the present article the synthesis of modi-
fied polyvinyl alcohols containing ibuprofen pen-
dant groups is described . The drug is attached
directly to polymer backbone or to the terminal
Functional group of a specially designed spacer
arm . Modification of PVA has been carried out by
hydroxycthylation, chloraacetylation, and acetaliza-
tum or the polymer by convenient methods . The
structural modification of PVA alter some proper-
184
ties of parent polymer such as hydrophilicity, solub-
ility in organic solvents, degree of substitution by
drug molecules. and ability of the polymer-drug
conjugate to undergo hydrolysis under mild con
ditions.
FTIR and 1H NMR spectroscopies confirm-
ed the structure of the polymer-drug conjugates . In
order to estimate the hydrolysis behaviour, the
polymers were hydrolyzed in aqueous buffer solu-
tions under physiological conditions.
EXPERIMENTAL
Materials and Instruments
Ibuprofen was purchased from Aldrich . PVA,
chloroacetic acid, salicylaldehyde, chloroethanol
sodium hydroxide . pyridine, and dimethylformami-
de were all obtained from Merck . Ibuprofen acyl
Chloride (rx- m ct hyl -4- (2 - met hylp ropyl) b enzene
acetylchloride) was prepared according to the
method described by Shanhhag et al . 1141.
1 H NMR spectra were recorded on a JOEL
90 spectrometer in dimethyl suiphoxide(DMSO-
d5) . The FTIR spectra were recorded by a 4300
Shimatzu spectrophotometer.
llydroxyethylation of PVA with Chloruethanol
The amount of 2.3 of Na was dissolved in 50 mL
absolute ethanol . The excess of ethanol was eva-
porated in vaccum . The remaining sodium ethoxide
was soluhilized into 50 mL of anhydrous DMSO
under nitrogen, and 3 g of PVA (M w 72,000) was
added . The mixture was stirred vigorously to give a
gelatinous product . The residual alcohol was remo-
ved with a gentle N 2 current . The resulting sodium
polyvinyl alcoholate was dissolved in 50 mL DMSO
and 6.44 g (80 mmol) of freshly distilled chloro-
ethanol was added . The mixture was stirred l4 h at
room temperature . The polymer solution was pre-
cipitated into methanol to give a flocculent white
solid.
Chloroacetylation of PVA with Chlaroacetic Acid
PVA (10 g) and para-tnluenesulphonic acid (1 g)
were dissolved in 50 mL 1,2-dichlorocthanc at
1raru611r Pr,h•nvrr .T, .i,,,iur Ynha,+c s Nu,reher i (1990

80 °C. To this solution was added 35 .3 g (0.37
mol) of chloroacetic acid . The mixture was stirred
at 75–80 `C for 2 h. After cooling to room temper-
ature, the polymer was precipitated by cold etha-
nol, dissolved in a solution of Na 2 CO 3 in acetone
and reprecipitated several times into ethanol.
Acetalyzation of PVA with Salicylaldehyde
A mixture of PVA (10 g), salicylaldehyde (16 .33 g),
and 5% aqueous H2SO4 (10 mL) in 100 ml. H2O
was stirred at 30–40 °C for 8 h. The precipitated
polymer was filtered and dissolved in DMSO . The
polymer solution was reprecipitated by a large
amount of methanol.
Esterification of Ibuprofen with Hydroxyethylated
PVA
A mixture of 7 g poly(hydroxyethyl vinyl alcohol)
and 16 g NaOH in 100 mL H 2 O was stirred at
40–50 °C. To this solution was added a solution of
38 g ibuprofen acyl chloride in 90 mL methyl ethyl
ketone (MEK), and 10 mL toluene at -5 ' C. The
mixture was stirred vigorously at -5 'C for 2 h, and
then at room temperature for overnight . The
organic layer was separated, washed with water,
dried and evaporated. The solid product was dis-
solved in MEK and precipitated with methanol
II-120 (1 :1) to afford a white solid of polymer-drug
conjugate (PVA–D1).
Alkylation of Polyvinyl Chloroacetate with
Ibuprofen Potassium Salt
Polyvinyl chloroacetate (3 g) was dissolved in 50
mL N,N-dimethylformamide (DMF) at 50–60 °C.
To this solution was added 1 .32 g (56 mmol) ibu-
profen, 8 g (58 mmol) K2CO 3 and 0 .1 g 18-crown
ether-6 . The mixture was stirred at 35–40 ' C for
20 h and filtered. The solution was precipitated
with H 2 O/acetone (1 :4), washed with acetone and
dried in vacuum to produce a white solid polymer
of alkylated polyvinyl chloroacetate (PVA-D2).
Reaction of Polyvinyl Salicylaldehyde Acetal with
Ibuprofen Acyl Chloride
Polyvinyl salicylaldehyde acetal (2 g) was dissolved
in 50 mL anhydrous pyridine at 50 ' C . Ibuprofen
Iranian Polymer Journal / Volume 5 Number 3 (1996)
Davaran S . nal.
acyl chloride (12 g) was added. The mixture was
stirred overnight at 50 °C . After cooling to room
temperature the polymer was precipitated into cold
MeOH. The polymer was collected and dried in
vacuum (PVA-D3).
Method of Hydrolysis
The polymers were dried in vacuum at room
temperature, and screened with a 200 mesh sieve.
The powdered polymer (20 mg) was poured in 5
mL of aqueous buffer solution (phosphate buffer
pH 8), at 37 ' C . The mixture was conducted into a
cellophane membrane dialysis hag . The bag was
closed and transferred into a flask containing 25
mL of the same buffer solution maintained at 37
' C . The external buffer solution was continuously
stirred and a 3 mL sample was removed at selected
intervals and 3 mL of buffer was replaced . The
quantity of hydrolyzate was analyzed by means of
UV spectrophotometer and determined from the
calibration curve obtained previously under similar
condition.
Determination of Degree of Substitution
An accurately weighed amount of the polymer-
drug conjugate (5 mg) was dissolved in 25 mL of
0.1 N NaOH and the solution was heated to 60 ' C
for 10 min in a water bath. After cooling a 500,uL
sample was withdrawn and added to 500 uL of 0 .1
N HCl. The resulting solution was assessed for ibu-
profen by UV spectrophotometry.
RESULTS AND DISCUSSION
The modification of PVA was performed so as to
produce appropriate sites for drug attachment
along the polymer chain via special arm. At the
first approach ibuprofen acyl chloride was reacted
with hydroxyethylated polyvinyl alcohol (PVAI) to
produce a polymer with ibuprofen pendant groups
attached to the hydroxyethyl arms (PVA-D1).
Ikeda et al . [15] synthesized the hydroxyethylated
PVA by reaction of the polymer with ethylene
oxide in presence of sodium ethoxide.
The analogous polymer was prepared in high
185

tiynrhe-aix . +nd flvd rn Iv.is nr Modified Polyvinyl Nwhuls
EtONa,DMSO
__CH2—CII 1 `CII,--CH
CIC:H,CII,O H
OH
PVA
ACII 2 —CH 1
is Ihuprult:n
yield by reacting of metalated PVA with chloro-
ethanol . The PVA can undergo metalation by ex-
change with alcoholate or with dimsylsudium (the
metalated derivative of DMSO) . where upon it can
be reacted with alkyl halides to yield vinyl units.
The PVA1 was esterified with ibuprofen acyl chlor-
ide in a mixed solvent system consisting of a
hydrophilic sol v ent (MEK), a hydrophobic organic
solvent (toluene), and aqueous solution of alkaline
hydroxides (Scheme I) . The IR and 'H-NMR
spectral data (registered in DMSO-d 6 ) of PV .A1
and PVA-D1 were consistent with their chemical
structures . We considered the integrated intensities
of the side chain methylene groups at 6 : 3 .7 ppm
and the signal of the aromatic protons at 6 : 7—7 .4
ppm . The IR spectrum PVA-D1 showed a sharp
peak at 1735 cm - ' corresponding to the formation
of an ester linkage.
In the second approach a difunctional spacer
group was inserted between the drug and polymer
backbone by esterification of the drug with poly-
vinyl chloroacetate (PVA2) in which the polymer
was reacted with potassium salt of ibuprofen . In
tact the reaction is a simple alkylation method for
preparation of esters under mild condition
(Scheme II) . The reaction was carried out in di-
186
CI-1 2 — CH
OH n-tn m
OCH 2CH2OH
PVAI
Cl
CH2 —CH
n-m
OH OC:H ?C:H 2q —CH—(( }}—Bu-i"'
q CII:j ~I
PVA-Dl
Scheme I
polar aprotic sol vents such as DMF and catalyzed
by crown ether which chelates the potassium ions.
Crown ether strongly hind metal ions such as Na*
and K* into the ether cavity by the coordination of
oxygen atoms. Since the crown units in 18-crown
ether-6 are specific to potassium ions, the reaction
of potassium salt of ibuprofen with polymer was
catalyzed by crown ether . This situation is caused
by the ion-pair formation of the carboxylate anion
with potassium ion captured by the crown ether.
Comparison of elemental analysis data showed that
the substitution of chloromethyl groups in PVA-
D2 is about 85% . I H-NMR Spectrum represented
resonance signals at 6 : 1 .4, 4.1, and 3 .8 ppm,
assigned to the CH 2 chain, CH chain and CH2 side
chain (of chloromethyl groups), respectively . The
IR spectrum represented the peaks around 3300
cm -1 (OH groups), 1761) cm - ' (ester carbonyl of
chloroacetate group), and 1690 cm - ' (ester carbo-
nyl of spacer arm).
In the third approach PVA was reacted with
sillxvlalcichydc to produce a cyclic six-membered
aceta] ring . The acctalization reaction markedly
improved the solubility behaviour of PVA in org-
anic solvents and increased the degree of substitu-
tion which led to the high loading of the drug . in
o 3 049ol
Irarrrun Ynfy-urrr Juarniul i f'rrkrrrre S Nro p


Darxran S. et al.

LCH2–CH n CICH 2 COOH rL

H2–CH CH2 –CH +
TsOH
OH OH n-m O
1
CCH2C1
PVA2 II
II
OH

PVA2 +CH2–CH CH2 –CH

F ~
K2CO 3iDMF 1n-m
OH O
I CH3
CCH2 OCCH (•) Bu–i

PVA-D2
0 0
N

Scheme II

4_CH2–CH+ Ph(OH)CHO ) H2 O H 2 –CH –

OH
JJJ H'
., D xx OH 1–x
HO

PVA3

pyridine Cl

CH 2 –CH CH 2 —ry- -
pI O 0 ..x CH3
x 1—x
C=O OCCH ti) Bu–i
fl
CH – CH3 0

Bu—

PVA-D3

Scheme 111

Iranian Po'flner Journal I Yak+me 5 Number 3 (1996) 187


5p3lhcsi, and Hydrniy,i .s of Modified Po5'.inyl Alcohols
Table 1 . Degree of substitution (DS) and glass
temperatures for polymers synthesized.
Polymer DS(%)
PVA-D1 2 .s
PVA-D2 3 .6
PVA-D3 9 .1
order to overcome the hydrophobicity of acetalized
polymer, the salieylaldehyde was employed for
acctalization . The phenolic hydroxy groups of sali-
cylatldehyde can he reacted with acyl chloride to
produce ester linkage . In this sense the acetal
group acts as a bridging group between the drug
and main chain of polymer. Polyvinyl salicylaldc-
hyde acetal (PVA3) was synthesized according to
the method reported by Hayashi et al . [16] with a
slight modification (Scheme III) . The 1 H-NMR
spectrum represented the cyclic CH groups in
acetal at r3 . 4.6 ppm and aromatic photons of the
drug at 6 : 7—7 .4 ppm.
The degree. of substitution in PVA-D1 was
determined by an exhaustive hydrolysis method,
and has been expressed as the:
% ibuprofen release(mg)!conjugate(mg).
The values along with glass transition temperatures
(T,) were determined from differential scanning
calorimetry curves presented in Table 1.
Drug Release by Hydrolysis of Polymeric Pro-
drugs
The hydrolysis reactivity of the polymer-drug add-
ucts was studied in physiological condition . The
polymers were dispersed in buffer solution and the
hydrolysis was performed in a heterogeneous
system . The hydrolysis solution was detected by
UV spectrophotometer . Figures l—3 show the
commulative concentration of released drug as a
function of time.
As shown in Figure 3, hydrolysis proceeds
more efficiently at alkalin pH . This is considered to
he due to the protonation of the tree hydroxy
groups Jilting the polymer chain in acidic condition .
188
transition
T€ (C)
2s
33
Figure 1 . Release of ibuprofen from PVA-D1 : phosphate
buffer, pH 8, 37 ' C.
The electropositive charge of the polymer chains
cause both intramolecular and intermolecular
repulsion, and the approach of the H + ions to the
ester groups is prevented . Furthermore, the rever-
sibility of acid catalyzed hydrolysis can decrease the
overall percent of hydrolysis . The PVA-Dl was
stable against aqueous hydrolysis in acidic media.
Therefore the hydrolysis behaviour of the polymers
were compared in a phosphate buffer solution at
pH 8.5 and 37 `C. All polymeric prodrugs released
ibuprofen gradually under mild conditions. The
order of hydrolytic rate of the polymers was as
follows, PVA-D3>PVA-D2>PVA-Dl . In PVA-
D2 two hydrolyzable ester bonds are present.
Detection of hydrolysis solution during the react-
ion time revealed that the hydrolysis occur exclu-
sively from position 2 (Scheme IV).
Cleavage of the ester bond from position 2
led to the liberation of ibuprofen groups and only
hydroxyacetate units remained along the polymer
bunion l'r1rmer Journal 1 Volume 5 Number .i (199(}


Davaran S. el al.

CH f fCH2-CH } CH 2 -CH~
f L q 1 L D

CCH2CI _ 2 CH3

0 C-CH 2 - q C- CH Bu-i
II II

qH
[CH 2 -CH C
] H2 -CH
[
CH 2 -CH-}- # a- HOCH 2COOH
q Q J{ OH J
I I
CCH2C1 CCH 2OH ibuprofen glycolic acid
Ii
0 0
1 L
vinyl chieroacetate v inyl hydroxyacetate
Scheme IV

0 1q 20 30 40 50

Time (h) Time (h)

Figure 2. Release of ibuprofen from PVA-02 ; hydrochloric Figure3. Release of ibuprofen from PVA-D3 at 37 'C;
and buffer pH=1 (series 1) and phosphate buffer pH-=13 .5 phosphate buffer pH .8 .5 (series 1), hydrochloric acid
(series 2) buffer pH–1 (series 2), phosphate buffer pH 7 .4 (series 3).

Iranian Pr1 fl7 Iuurna! 1 Ynlumr 5 Number a9 q(i,i 189


Synrhesic ~Ild Hydrolysis . of Modified Polyvinyl Alcohols
chain. The formation of hydroxyethyl group can
increase the hydrophilicity of the intermediate
copolymer by progress of reaction . This possibly
accounts for the high degree of hydrolysis in PVA-
D2 compared to PVA-D I . The hydrophilicity q f
polymer in aqueous solution can he an important
factor in ester hydrolysis of side chains. Decreased
hydrolyzibility of the ester bond located at position
l may be account for by steric hindrance of poly-
mer chains . However, the spectroscopic data
revealed that the hydrolysis may occur at both
positions after 24 h . Ibuprofen and glycolic acid are
the main products of the complete hydrolysis
(Scheme IV).
Esters derived horn polyvinyl salicy'laldchyde
(PVA-D3) was more reactive towards hydrolysis
compared to PVA-D2 and PVA-D1 . This can be
considered by this fact that esters of aromatic
alcohols: can he hydrolyzed faster than the
aliphatic alcohols ; following the general rule, the
more acidic the alcohol the better the leaving
group . The polymer showed a negligible release of
salicylaldchydc at 37 'C and indeed was active only
after 3 days at raised temperature . Figure 3 shows
the pH dependence of the hydrolysis of the
PVA-D3 at 37 °C. At the phosphate buffer (pH
8 .5) the cumulative concentration was increased
after about 15 h . This can be explained by the
simultaneous hydrolysis of aliphatic and phenolic
ester bonds which in turn change the water-
swellable characteristics of the polymer . The
polymers were more water-swellahle as hydrolysis
proceeded and furthermore groups on the interior
became more accessible . Such phenomena could
even lead to autoauxleration . In a solution of pH
7 .4, the polymeric prodrug releases ibuprofen
molecules relatively slower compared to the
solution of pH's 8 .5 and 1.
CONCLUSION
An efficient method for the synthesis of hydro-
philic macromolecular compounds comprized of
ibuprofen and modified PVA units have been
developed . The properties of the polymers are
190
dominated by PVA, while the hydroxy groups of
the spacer arms provide convenient anchors for
attachment of the appropriate pendant drugs . The
distance between the reactive groups and the hydr-
olysis reactivity is controlled by the type and size
of spacer groups . Two approaches were used for
the modification of PVA: first changing the
hydroxyl groups to a more active functional group
and second the reaction of PVA with di.functional
compound, so that one of its functional groups
reacts with PVA and the other remains active for
drug attachment. In vitro hydrolysis studies showed
the potential utility of the polymers as a macro-
molecular prodrugs . Recognizing that the thera-
peutic efficacy of polymer conjugates is governed
by the physiochemical properties such as the rate
of drug regeneration . Further progress in this field
may arise from optimization of the physiochemical
properties.
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Ironical Polymer Journal 1 Volume 5 Nlrraher .3 (1996) 191