Synthesis and characterization of new theophylline and chlordiazepoxide prodrug polymers based on maleimide

Article abstract of DOI:10.14233/ajchem.2018.21634

In this work, two new drug substituted monomers and new homogenous and heterogeneous polymers were synthesized which loaded with medicinal properties to extend the controlled drug. The first step includes the preparation maleimic acid (L1) and (L2) via re

Full text of DOI:10.14233/ajchem.2018.21634

Asian Journal of Chemistry; Vol. 30, No. 12 (2018), 2788-2792
A
SIAN
J
OURNAL OF HEMISTRY
C
https://doi.org/10.14233/ajchem.2018.21634
Synthesis and Characterization of New Theophylline and
Chlordiazepoxide Prodrug Polymers based on Maleimide
*
LAYALI ABDULLAH ABBAS and MOHANAD MOUSA KAREEM
Department of Chemistry, College of Science, University of Babylon, P.O. Box 4, Hilla, Iraq
*
Corresponding author: E-mail: mohanad_1972@yahoo.com
Received: 6 August 2018; Accepted: 20 September 2018;
Published online: 31 October 2018;
AJC-19149
In this work, two new drug substituted monomers and new homogenous and heterogeneous polymers were synthesized which loaded
with medicinal properties to extend the controlled drug. The first step includes the preparation maleimic acid (L1) and (L2) via reaction
of maleic anhydride with 5-amino salicylic acid. Then compound L2 was converted to its corresponding acyl chloride derivative which
reacted with amino drugs (theophylline and chlordiazepoxide, afforded L3 and L4 monomers, respectively. Homogeneous polymers (L5
and L6) prepared through polymerization reaction of free radicals of monomers (L1) and (L2) under nitrogen atmosphere using methyl
ethyl ketone peroxide (MEKP) as initiator. Heterogeneous polymers (L7 and L8) prepared through polymerization reaction of free
radicals of monomers (L1 and L2), separately with acrylic acid under nitrogen atmosphere using MEKP as initiator. All these prepared
1
13
monomers and polymers were characterized by FTIR, H NMR and C NMR. Controlled drug release and swelling % was studied in
different pH values at 37 ºC. Intrinsic viscosities were measured at 25 ºC with Ostwald viscometer and applied the characteristic of
solubility for these polymers and studied the biological activities.
Keywords: Homopolymerization, Heteropolymerization, Swelling, Drug delivery system.
they may become a feasible cure for endocrine-related cancers
9]. These polymers are defined to be sensitive to specific enzymes
INTRODUCTION
[
Maleic anhydride is a chemical compound, which used
that are visible in diseased tissue, the drugs are remained atta-
ched to the polymer until the enzymes are associated with the
diseased tissue are present and this process remarkably decreased
the damage to healthy tissue [9].
Lately, assorted drug delivery techniques are being advanced
like alteration of the actual drug or conjugations of the drug to
another carrier molecules and the polymer prodrug synthesis
has been swiftly growing technique [10]. Prodrugs involve
the integration of drug molecules with the carrier molecule,
thus the integration of a drug molecule with a polymer forms
a polymeric prodrug [11]. Different polymers have been
synthesized and used as carrier molecules in which the drug
molecule can be implanted [12].
in several applications of industrial chemistry [1]. Maleic anhy-
dride structure contains two acidic carbonyl groups and a double
bond and can be easily polymerized in the presence of free
radical catalysts as well as under gamma and UV radiations
2-4].
Maleimides derivatives prepared from maleic anhydride
by treatment with amines followed by dehydration [5], where
N-substituted maleimides are prepared from the amino group
is replaced with alkyl or aryl groups, respectively followed by
ring closure to produce N-substituted maleimide [6]. While,
N-phenylmaleimide prepared from the reaction of maleic
anhydride with aniline in ethyl ether at room temperature [7].
Maleimides have been polymerized by addition polymerization
with either free radical or anionic initiation.
[
The prodrug molecules contains drug and polymeric back-
bone, targeting group, spacer and solubilizing agent where
each component has a specific important role to play for the
drug action. The used polymeric backbone can be biodegrad-
able or inert in action, while the spacer utilized for indicating
Prodrug polymers are drug molecules held in polymer
molecules act as drug delivery system. Polymer drugs have
been used in various bioactive applications [8] and therefore
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(

Vol. 30, No. 12 (2018)
Synthesis and Characterization of New Theophylline and Chlordiazepoxide Prodrug Polymers 2789
the target site and the rate at which the drug is being released from
the prodrug which can be either through hydrolysis or enzymatic
action [13,14].
(C, C-OH), 106.387-147.024 (6C,Ar-C), 151.176 (2C, N-C=O),
160.275 (2C, N-C=O), 166.711 (C, N-C=O). Elemental anal.
calcd. (found) % for L : C, 56.65 (56.68); H, 3.00 (3.01); N,
2
In order to examine the possibility of obtaining better
polymers from N-substituted maleimide, we reported here the
synthesis of N-[5-salicylic maleimide] monomer and its
polymerization and co-polymerization with acrylic acid. The
physical, spectral and thermal properties have been studied to
characterize the homo- and co-polymers.
6.00 (8.98).
Synthesis of monomer drugs (L
maleimide (L ) (1 mmol, 0.2 g) is added to 3 mmol of triethyl-
amine (Et N) in 10 mL of DMSO, then 1 mmol of SOCl is
3
and L
4
): 5-Salicylic
2
3
2
added at room temperature. It was then added (1 mmol) of
drugs (theophylline and chlorodiazepoxide) and left for (0.5 h),
cooled reaction mixture was poured crushed ice, left for 0.5 h.
Finally the black product was filtered and crystallized from
dichloromethane (Scheme-I).
EXPERIMENTAL
The densities of polymer samples were determined at 25
ºC by the displacement method with a single stem pycnometer
Compound L
3
: m.f. C18
H
13
O
6
N , m.p. 210-212 ºC, yield
5
-1
[15] using water as non-solvent. The intrinsic viscosity (η) meas-
59 %. IR (KBr, νmax, cm ): 3287 (OH alcohol), 3106 (C-H bend.
2
3
urements were carried out in acetone at 30 ºC using an Ostwald
viscometer suspended level viscometer. The IR spectra measure-
ments were recorded using a device Fourier Trans Infrared
sp ), 2982 and 2918 (C-H bend. sp ), 1709 (C=O in six mem-
bered imide ring), 1663 (C=O amide), 1553 and 1492 (C=C,
arom.), 1439 (C-H bend.), 1288 (C-N str. phenyl ring). H NMR
(300 MHz, TMS, δ ppm): 6.60 (s, H, OH), 7.30-7.90 (m, 3H,
Ar-H), 6.90-7.20 (d, 2H, HC=CH), 9.80 (s, H, C=CH), 3.12
1
-1
1
Spector Promoter-Shimadzu within range (4000-400 cm ). H
NMR was taken at 300 MHz in DMSO-d on aVXR-300 spectro-
meter. Tetramethylsilane was used as reference. C NMR spectra
were recorded at 75.5 MHz in DMSO-d on Bruker-300A spectro-
6
13
(s, 3H, CH
3
), 3.60 (s, 3H, CH
3
), 1.2 (ethanol solvent), 2.5 (DMSO).
), 31 (C, CH ),
13
6
C NMR (300 MHz, TMS, δppm): 29.649 (C, CH
3
3
meter. Starting chemical compounds were obtained from Fluka
or Aldrich.
45.648 (C, C-OH), 106.387, 147.024 (6C,Ar-C), 151.176 (2C,
N-C=O), 160.275 (2C, N-C=O), 166.711 (C, N-C=O). Elemental
1
Synthesis of maleimic acid (L ): Mixtureofmaleicanhydride
anal. calcd. (found) % for L
3
: C, 54.68 (52.70); H, 3.29 (3.48);
(
1.0 g, 0.002 mmol.) with 5-aminosalicylic acid (0.7g, 0.005
N 17.72 (17.22).
mmol.) was heated gently with constant stirring for 30 min.
Then the entire reaction mixture was cooled externally. The
greenish yellow solid 5-aminosalicylic maleimic acid was
filtered and dried at 50 ºC afforded greenish yellow compound
Compound L
4
: m.f. C27
H
19
O
5
N
4
Cl, m.p. 102-105 ºC, yield
-1
76 %. IR (KBr, νmax, cm ): 3400 (OH alcohol), 2919 and 2852
3
(C-H bend. sp ), 1667 (C=O amide), 1486 and 1433 (C=C,
1
arom.), 1286 (C-N str.), 696 (C-Cl bend.). H NMR (300 MHz,
L
1
having molecular formula C11
9
H NO
6
, yield: 93 %, m.p. 191
TMS, δ ppm): 6.47 (s, H, OH), 1.30 (s, H, CH), 3.53 (s, 3H, N-
-
ν
194 ºC [16,17]. It was recrystallized from methanol. IR (KBr,
max, cm ): 3307 (OH alcohol), 3500 and 2500 (OH carboxylic
CH
3
), 6.99 (d, 2H, CH=CH), 7.12, 7.38, 8.15 (3H, Ar-H
-1
phenol.), 7.21, 7.48, 7.32 (3H, Ar-H with Cl), 7.34, 7.45, 7.44
(3H, Ar-H). C NMR (300 MHz, TMS, δ ppm): 17.84 (C,
CH ), 20.56 (C, C-Cl), 45.50 (C, C-OH), 122.79, 129.28,
106.387, 147.024 (6C, Ar-C), 151.176 (2C, N-C=O), 160.275
(2C, N-C=O), 166.711 (C, N-C=O). Elemental anal. calcd.
13
acid), 1677 (C=O in a six membered imide ring), 1526 (C=O
carboxylic acid), 1484 and 1447 (C=C, arom.), 1377 (C-H
bend.), 1191 (C-N str.), 846 (cis-CH=CH phenyl ring). H
3
1
NMR (300 MHz, TMS, δ ppm): 4.14 (s, H, OH), 6.43, 6.98 (
2H, HC=CH), 7.15 (s, H, Ar-H), 7.69 (s, H, Ar-H),7.86 (s, H,
(found) % for L : C, 62.97 (64.11); H, 3.69 (3.49); N 10.88
4
Ar-H), 8.15 (s, H, N-H),10.41(H, COOH), 10.57 (H, COOH),
C NMR (300 MHz, TMS, δ ppm): 142.859 (2C, HC=CH),
(9.12).
13
Homo-polymerization of synthesized drug substituted
monomer (L and L ): In a dry polymer tube, a mode of mono-
1
12.897 (C, C-OH), 133.321 (6C, Ar-C), 117.233, 157.590
5
6
(
C, N-C=O), 162.959 (C,COOH), 166.668 (C, COOH). Elem-
mer was prepared (0.5 g) and 15 mL of toluene and (0.05 g)
of the initiator methyl ethyl ketone peroxide (MEKP ) passed
nitrogen gas for (10 min) after which the tube was sealed tightly
and placed in a water bath at 90 ºC for 2 h when the polymeri-
zation is completed with the formation of precipitate. The preci-
pitate was washed with ether and then dry in oven at 50 ºC [18]
(Scheme-I).
ental anal. calcd. (found) % for L : C, 52.69 (52.68); H, 3.59
(
1
3.60); N, 5.58 (5.60).
Synthesis of 5-salicylic maleimide (L
0.5 g, 0.1 mol), sodium acetate (0.326 g, 0.2 mol) and 5mL
2
): Maleimic acid (L )
1
(
acetic anhydride in 5mL of DMF were mixed and reacted for
h at 45 ºC . The cooled mixture was poured into crushed ice.
Yellow needles of 5-salicylic maleimide was filtered, washed
with 5 % NaHCO solution and dried at 55 ºC for several hours.
The product was further recrystallized from chloroform
afforded black (viscous) compound L having molecular formula
NO ; yield: 91 %. IR (KBr, νmax, cm ): 3287 (OH alcohol),
106 (C-H), 2982 and 2918 (C-H), 1709 (C=O in six membered
imide ring), 1663 (C=O amide), 1553 and 1492 (C=C, arom.),
2
-1
Compound L : Colour: brown, IR (KBr, νmax, cm ): 3350
5
3
3
(OH alcohol), 2981 and 2914 (C-H bend. sp ), 1704 (C=O in
six membered imide ring), 1664 (C=O amide), 1553 and 1490
1
2
(C=C, arom.), 1288 (C-N str., phenyl ring). H NMR (300 MHz,
-1
C
3
11
H
7
5
TMS, δ ppm): 6.50 (s, H, OH), 8.10, 7.70, 7.40 (3H, Ar-H),
9.80 (s, H, C=CH) , 3.50 (s, 3H, CH
3
), 3.30 (s, 3H, CH
3
).
-1
Compound L : Colour: Black, IR (KBr, νmax, cm ): 3400
6
1
3
1
439 (C-H bend.), 1288 (C-N str.), 827(phenyl ring). H NMR
(OH alcohol), 2874 (C-H bend. sp ), 1715 (C=O in six mem-
(
300 MHz, TMS, δ ppm): 5.70 (s, H, OH),7.51-8.71 (m, 3H,
bered imide ring), 1670 (C=O amide), 1489 and 1446 (C=C,
arom.), 1288 (C-N str.), 552 (C-Cl bend.). H NMR (300 MHz,
13
1
Ar-H), 6.8-7.30 (d, 2H, HC=CH), 10.56 (s, H, COOH). C NMR
300 MHz, TMS, δ ppm): 29.649 (C, CH ), 31 (C, CH ), 45.648
(
3
3
TMS, δ ppm): 6.92 (H, OH), 1.23 (H, CH), 3.50 (3H, N-CH ),
3

2
790 Abbas et al.
Asian J. Chem.
1
3
-1
7
.09-7.51 (H,Ar-H). C NMR (300 MHz, TMS, δ ppm): 17.84
), 20.559 (C, C-Cl), 45.502 (C, C-OH), 122.789, 129.284,
06.387, 147.024 (6C, Ar-C), 151.176 (2C, N-C=O), 160.275
Compound L
7
: Colour: black, IR (KBr, νmax, cm ): 3136-
(C, CH
3
2963 (OH carboxylic acid), 3300 (OH alcohol), 2963 (C-H
bend. sp ),1708 (C=O in six membered imide ring), 1665 (C=O
amide), 1553 (C=C, arom.), 1178 (C-N str.). H NMR (300
3
1
(
1
2C, N-C=O), 166.711 (C, N-C=O).
Copolymerization of synthesized drug substituted mono-
MHz, TMS, δ ppm): 5.44 (H, OH), 6.90-8.20 (H, Ar-H), 8.60
mer (L
7
and L
8
): In a dry polymer tube a mode of monomer
(H, C=CH), 3.07 (s, H, CH
COOH).
3
), 3.37 (H, CH-COOH), 10.35 (H,
was prepared (0.5 g) and then added acrylic acid with the same
number of moles of drug monomer and 15 mL of toluene and
-1
Compound L : Colour: dark brown, IR (KBr, νmax, cm ):
8
(
0.05 g) of initiator methyl ethyl ketone peroxide (MEKP)
(3460-2961) (OH carboxylic acid), 3100 (OH alcohol), 2961
(C-H bend. sp ), 1719 (C=O in six membered imide ring), 1618
3
passed the nitrogen gas for 10 min, after which the tube was
sealed tightly and placed in a water bath at 90 ºC for 2 h, when
the polymerization is completed with the formation of preci-
pitate. The precipitate was washed with ether and then dry in
oven at 50 ºC [18] (Scheme-I).
(C=O amide), 1490 and 1450 (C=C, arom.), 1284 (C-N str.),
1
1035 (C-Cl bend.). H NMR (300 MHz, TMS, δ ppm): 6.40
(H, OH), 1.23 (H, CH
2
), 4.2 (3H, N-CH ), 6.50-8.51 (H, Ar-H),
3
3.62 (H, CH-COOH), 10.37 (H, COOH).
HOOC
O
NH2
HN
CHCl3
0–5 °C
+
O
O
O
HOOC
HOOC
Maleic anhydride
OH
OH
5-Aminosalicylic acid
(L1)
O
O
N
HOOC
OH
H
N
N
(L2)
CH3
N
O
Cl
O
H
N
H3C
O
N
N
N
CH3
HO
O
C
N
N
O
CH3
O
n
N
Cl
O
HO
O
N
(L4)
O
C
N
H3C
n
O
N
N
O
O
CH3
(
L3)
HO
HO
O
C
O
C
N
O
N
O
N
N
CH3
CH3
N
N
H
C
N
O
N
O
HO
HO
Cl
O
Cl
O
CH2
n
x
y
COOH
O
N
O
N
O
C
N
O
C
N
(L6)
(L8)
H3C
O
O
H3C
O
O
N
N
N
N
H
C
N
O
N
O
CH2
n
x
y
CH3
CH3
COOH
(
L5)
(L7)
1 8
Scheme-I: Synthesis route of compounds (L -L )

Vol. 30, No. 12 (2018)
Synthesis and Characterization of New Theophylline and Chlordiazepoxide Prodrug Polymers 2791
TABLE-2
SWELLING RATIO (%) AND RELEASE OF DRUG FOR HOMOPOLYMER AND COPOLYMER AT pH = 2.2 AND 8.0 AT 310 K
L5 L6 L7 L8
Time
pH = 2.2
Abs.
pH = 8.0
Abs.
pH = 2.2
Abs.
pH = 8.0
Abs.
pH = 2.2
Abs.
pH = 8.0
Abs.
pH = 2.2
Abs.
pH = 8.0
% Abs.
(
h)
%
%
%
%
%
%
%
1
2
3
4
5
0.5939 0.091 0.5864 0.483 0.8899 0.109 1.5858 0.851 0.1983 0.121 0.6106 0.354 1.7943 0.251 1.3757 0.665
0.7501 0.130 0.8830 0.534 1.0395 0.139 1.6584 0.862 0.3993 0.151 0.7648 0.492 1.9192 0.259 1.5706 0.722
0.9055 0.145 1.0211 0.654 1.1471 0.152 1.7807 0.893 0.5012 0.182 1.0648 0.541 2.1357 0.278 1.6981 0.798
1.0185 0.172 1.4231 0.639 1.3081 0.181 2.4528 0.951 0.6980 0.199 1.2621 0.591 2.3453 0.301 1.9507 0.881
1.2996 0.203 1.8553 0.601 1.5581 0.211 2.9583 0.998 0.8510 0.223 1.5558 0.732 2.5831 0.344 2.3973 0.999
Physical properties of polymers
addition of nucleophilic difunctional reagents, to give linear
polymers.
It is also known that interlocking polymers have a solvent
resistance because of the tangent that is specific to chain motion
Solubility: Synthesized monomer, homopolymer and
copolymers were highly soluble in acetone, DMSO, whereas
partial or soluble in H O, ethanol, diethyl ether, toluene and
2
[
19]. However polymerization is caused by the proliferation
chloroform indicating the presence of polar group.
of solvent molecules in the polymer network within the crys-
talline network in the process of bloating in polymers with
high molecular weight and volume changes causing polymer
collapse during the process of mechanical stress through the
process of bloating is known as the degree of polymer tangle,
because the more the degree of entanglement challenged resis-
tance to swelling and thus carried out the process of swelling
of these polymers.
Density and viscosity: The density of homopolymers and
copolymer were determined at 25 ºC using densito 30px meter.
Density values of homopolymers and copolymers are given
Table-1. Viscosity determinations of 5-salicylic maleimide in
acetone were carried out at the same concentration of homo-
polymer and copolymer in acetone at 25 ºC using an Ostwald
viscometer with a capillary diameter of 0.49 mm. The density,
intrinsic viscosity and average molecular weight (M
present polymer samples are listed in Table-1.
w
) of the
Conclusion
In this work, new drug substituted monomers and their
new homogenous and heterogeneous polymers were synthe-
sized which loaded with medical properties to extended the
TABLE-1
PROPERTY OF VISCOSITY AND THE DENSITY
OF PHARMACEUTICAL POLYMERS
controlled drug. Homogeneous polymers (L
through polymerization reaction of free radicals of monomers
and L ) under nitrogen using MEKP as initiator. Heterogen-
eous polymers (L and L ) prepared through polymerization
reaction of free radicals of the monomers (L and L ) separately
5
6
and L ) prepared
3
Compd. No.
Intrinsic viscosity (dl/g)
Density (g/cm )
L5
L6
L7
L8
0.61
0.63
0.62
0.60
0.785
0.783
0.782
0.787
(L
1
2
7
8
3
4
with acrylic acid under nitrogen using methyl ethyl ketone
peroxide as initiator.All these prepared monomers and polymers
Swelling and release: The rapid release of homo- (L
5
and
1
13
were characterized by FTIR and H NMR, C NMR spectro-
scopies. Controlled drug release and swelling % was studied
in different pHs values at 37 ºC.
L
6
) and copolymers (L and L ) was studied. Acid and base
7
8
functions were used where hydrolysis was gradual. As a phar-
maceutical unit of the hydrolysis of polymers loaded with drugs
when pHs = 2.2 and 8. Table-2 shows the pharmacological
release is progressively and concluded that at the end of process
of drug liberation after 5 h and appeared that the drug release
in the basal environment faster than the acid center, which is
CONFLICT OF INTEREST
The authors declare that there is no conflict of interests
regarding the publication of this article.
−
probably due to the attack at the nucleus of ion (OH ). The
carbon atom of carbonyl group is more stronger than proton
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