Microwave-assisted graft copolymerization of amino acid based monomers onto starch and their use as drug carriers

Article abstract of DOI:10.1016/j.carbpol.2014.01.028

This paper describes the synthesis of two amino acid-based monomer and their graft copolymerization onto starch and utilization of the prepared graft copolymers as drug carriers. The two monomers were synthesized and reacted with acryloyl chloride to get

Full text of DOI:10.1016/j.carbpol.2014.01.028

Carbohydrate Polymers 106 (2014) 440–452
Contents lists available at ScienceDirect
Carbohydrate Polymers
journal homepage: www.elsevier.com/locate/carbpol
Microwave-assisted graft copolymerization of amino acid based
monomers onto starch and their use as drug carriers
Ali Y.A. Alfaifia, Mohamed H. El-Newehya,b, E.S. Abdel-Halima,∗, Salem S. Al-Deyaba
a Petrochemical Research Chair, Department of Chemistry, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
b Department of Chemistry, Faculty of Science, Tanta University, Tanta 31527, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes the synthesis of two amino acid-based monomer and their graft copolymerization
onto starch and utilization of the prepared graft copolymers as drug carriers. The two monomers were
synthesized and reacted with acryloyl chloride to get the corresponding acryloylamino acid, which were
further grafted onto starch using the microwave-assisted grafting technique. All factors affecting the effi-
ciency of the grafting reaction were studied and the prepared graft copolymers were fully characterized.
Atenolol, as a model drug in the form of salt was immobilized onto the graft copolymers by ionic bonds
and the loading was confirmed by use of FT-IR, TGA and NMR. The drug release was studied in both acidic
and alkaline media and it was found that the release takes place in alkaline medium rather than in acidic
medium and this indicates that these polymers can be used as carriers for drugs whose target is the colon.
Received 11 November 2013
Received in revised form 8 January 2014
Accepted 9 January 2014
Available online 21 January 2014
Keywords:
Microwave
Grafting
Starch
Atenolol
© 2014 Elsevier Ltd. All rights reserved.
Drug delivery
1. Introduction
ber of drug required to be admitted to the body during treatment
period as well. Also, the use of controlled-release drug delivery
The use of microwave irradiation instead of conventional heat-
ing offers the advantages of pollution reduction, low cost and high
productivity, this is in addition to simple handling and processing
(Lidstrom, Tierney, Wathey, & Westman, 2001; Osman, El-Newehy,
Al-Deyab, & El-Faham, 2012). Recently, the utilization of microwave
irradiation in organic synthesis and polymerization reaction has
become a popular technique (Al-Hazimi, El-Faham, Gazzali, &
Al-Farhan, 2012; Ghazzal, El-Faham, Abd-Megeed, & Al-Farhan,
2012; Osman et al., 2012). Many researchers reported the use
of microwave-assisted synthesis in the preparation of different
types of flocculants based on natural polymers, like polyacrylamide
grafted inulin (Rahul, Jha, Sen, & Mishra, 2014), polymethyl-
methacrylate grafted psyllium (Mishra, Sinha, Dey, & Sen, 2014),
polyacrylamide grafted agar (Rani, Mishra, Sen, & Jha, 2012) and
polyacrylamide grafted Casein (Sinha, Mishra, & Sen, 2013).
system enables the drug to be targeted only to desired organs or tis-
sues (Friend, 2005; George & Abraham, 2006; Kenawy, El-Newehy,
Abdel-Hay, & Raphael, 2001; Kenawy, El-Newehy, Abdel-Hay, &
Ottenbrite, 2008; Van den Mooter, Weuts, De Ridder, & Blaton,
2006; Yan, Zhuo, & Zheng, 2001).
Moreover, amino acids, as constituents of the peptides, when
incorporated into synthetic or natural polymers, by means of for
example grafting, they can give totally new biomaterials having a
wide variety of properties, which can be modulated by changing
the components of the macromolecular backbone during synthe-
sis. Over the past decades, natural polymers such as cellulose, starch
and chitosan can be used in designing biomaterials, which can find
a wide range of application areas such as in controlled-release drug
delivery systems and biocompatible scaffolds in the field of tis-
sue engineering. Moreover, modification of polysaccharide using
grafting as a powerful method improves its properties as well as
enlargement its use.
The utilization of drug delivery systems based on polymeric
materials improves the drug’s efficiency, reduces the drug’s tox-
icity, reduces the drug’s side effects and improves the recovery
percentages. In general, the controlled-release drug delivery sys-
tems were found to increase the therapeutic activity of the drug,
and on the other hand decrease its side effects and reduces the num-
In the past decades, polymer–drug conjugates were used to
develop highly advanced controlled-release drug delivery sys-
tems, which could to great extent improve the drug’s therapeutic
efficiency (Babazadeh, 2007, 2008; El-Newehy, Elsherbiny,
&
Mori, 2013; Hoste, Winne, & Schacht, 2004; Kenawy, El-Newehy,
et al., 2008; Kenawy, Abdel-Hay, El-Newehy, & Ottenbrite, 2008;
Khandare & Minko, 2006; Nichifor, Schacht, & Seymour, 1997).
Optimization of the therapeutic properties of drugs, safety and
∗
Corresponding author.
E-mail address: essamya@yahoo.com (E.S. Abdel-Halim).
0144-8617/$ – see front matter © 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.carbpol.2014.01.028

A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
441
NH2
3 wt% NaOHaq
O
NH
+
R
O
COOH
R
Cl
COOH
(N-A-L-Phe) (II)
(N-A-L-Ala) (III)
R= Ph
R = CH3
L-Phenylalanine
L-Alanine
Acryloyl Chlorid (AC)
(I)
R= Ph
R = CH3
Scheme 1. Monomer synthesis; N-acryloyl-L-phenylalanine (N-A-L-Phe) (II) and N-acryloyl-L-alanine (N-A-L-Ala) (III).
affectivity can be controlled by the design of polymeric drug
2.2. Instruments and characterization techniques
delivery systems [10,11]. The drug can be fixed directly onto the
polymer backbone or via a spacer in which the carrier is a poly-
meric material and could be either inert synthetic polymer or
natural biodegradable one (Babazadeh, 2008; El-Newehy et al.,
2013).
Amino acids, the constitutional components of both peptides
and accordingly the higher proteins are capable of constructing
highly ordered hierarchical structures, which may scale from few
nanometers to several micrometers. Synthetic polymers containing
amino acids can be used in different applications such as station-
ary phases with chiral recognition properties (Babazadeh, Edjlali,
& Rashidian, 2007), absorbents for different metal ions (Oishi,
Lee, Nakagawa, Onimura, & Tsutsumi, 2002), controlled-release
drug delivery systems and biocompatible materials (Barbucci,
Casolaro, & Magnani, 1991; Lekchiri, Morcellet, & Morcellet,
1987).
Microwave (Monowave 300, Anton paar) maximum filling vol-
umes of 6 mL and 20 mL, for 10 mL vial and 30 mL vial, respectively.
Maximum operation pressure 30 bar, Maximum IR temperature
300 ◦C, Max fiber-optic temperature 300 ◦C, Maximum power
850 W, Vial material is borosilicate glass and silicon carbide, Cap
material is PEEK and Seal material is Teflon-coated silicone.
1H NMR spectra were recorded by use of JEOL JNM-PM X90 Si-
NMR Spectroscopy instrument. Thermogravimetric analysis (TGA)
was carried out by use of TA-Q500 System. 5–10 mg sample was
heated in the temperature range of 30–800 ◦C at a heating rate of
10 ◦C min−1 under inert nitrogen atmosphere.
Fourier-transformer infrared (FT-IR) spectra were recorded
using TENSOR 27, Bruker. UV spectra was recorded by use of
PerkinElmer Lambda 35 UV–vis spectrophotometer.
Starch as a natural polymer that can be obtained from agro-
sources, is abundant in nature, renewable, and biodegradable
polymer (Bentolila et al., 2000; Casolaro & Barbucci, 1991).
In addition, starch is a promising material in drug delivery
specifically to the colon, non-food applications as well as the pro-
duction of biodegradable plastics drug delivery (C¸ algeris, C¸ akmakc¸ ı,
Ogan, Kahraman, & Kayaman-Apohan, 2012; Casolaro & Barbucci,
1991; Curvelo, de Carvalho, & Agnelli, 2001)
The work in the present study aims at optimizing the grafting
conditions for amino acid-based polymers onto starch to pre-
pare amino acid-based polymers-grafted-starch as a carrier for
drugs. Grafting process was carried out by use of low concen-
tration of potassium persulfate as an initiator, using microwave
(MW) irradiation technique. The effect of grafting time, temper-
ature and the monomer/starch ratio were studied. The structure
of the prepared amino acid-based monomers-grafted-starch was
confirmed by Fourier transform infrared (FTIR) spectra, elemen-
tal microanalysis (as nitrogen percent (N%)) as well as NMR
spectra. In addition, the native and grafted starch samples were
characterized by TGA. The grafting process was found to be
temperature and duration dependent, in addition to its great
dependence on the monomer/starch ratio. Atenolol was used
as a model drug in this study and its loading and controlled
release from the amino acid-grafted-starch were extensively stud-
ied.
2.3. Monomers synthesis
N-acryloyl-L-phenylalanine (N-A-L-Phe) (II) and N-acryloyl-L-
alanine (N-A-L-Ala) (III) were synthesized according to a reported
method [11], in which L-phenylalanine (150 mmol) was dissolved
in 100 mL of 3 wt% aqueous NaOH and then was kept at 0 ◦C in an
ice-bath. Acryloyl chloride (160 mmol) was added dropewise and
at the end of the addition, the reaction mixture was kept under
continuous stirring for 2 h. The mixture was then acidified to pH
1–3 using 6 N HCl, and stirring was continued for an additional 1 h
at 25 ◦C. The resulting mixture was extracted with ethyl acetate
(100 mL) for three times and dried over anhydrous manganese sul-
phate. The solution was filtered and concentrated on rotavapor
to one fourth. The residual solution was purified by the column
chromatography technique, by use of ethyl acetate as an eluent
(Scheme 1).
2.4. Microwave assisted grafting of monomers onto starch
2.4.1. Microwave assisted synthesis of
starch/Poly(N-acryloyl-L-phenylalanine) graft copolymer
(S/PAPhe) (VI)
Calculated amount of (N-A-L-Phe) (II), dissolved in water, was
added to starch in water slurry. These components were mixed
well and then transferred, quantatively to the microwave reaction
vessel (30 mL), together with catalytic amount of potassium per-
sulfate (KPS) initiator (0.090 g) and the reaction vessel was claimed
on the turntable of the microwave oven. The microwave irradiation
time is adjusted to the desired duration. After the irradiation time
is vanished, the reaction vessel was removed from the microwave
oven and its contents were allowed to cool to the room temper-
ature and the kept as such at room temperature for extra 24 h in
order for the grafting reaction to be completed. The graft copoly-
mer in the form of gel-like mass was poured from the microwave
reaction vessel into a beacker containing excess amount of ace-
tone in order to precipitate the graft copolymer and separate it
2. Experimental
2.1. Materials
Starch (Corn starch) (73% amylopectin and 27% amylose), acry-
loyl chloride and atenolol were purchased from Aldrich. L-alanine
(98%) and L-phenylalanine (98%) were purchased from ACROS. All
other chemicals, materials and solvents were of laboratory grade
and were used as received without any further purifications.

442
A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
R
m
OH
O
O
COOH
N
O
H
O
NH
K2S2O8 / Vit. C
O
OH
+
OH
O
O
O
80oC / 1 bar
O
n
R
COOH
(N-A-L-Phe) (II)
n
OH
Starch
OH
(S/PAPhe) (VII)
R = CH3 (S/PAAla) (VIII)
R= Ph
R = Ph
R = CH3 (N-A-L-Ala) (III)
(VI)
K2S2O8
.
+
O
+
St
Starch
OH
St
O
NH
O
Microwave
Irradiation
NH
R
COOH
R
COOH
N-Acryloyl-L-amino acid
Homopolymerization
n
O
NH
R
COOH
O
NH
Graft copolymerization
R
COOH
n
St
O
Poly(N-acryloyl-L-amino acid)
O
NH
R
COOH
Starch/poly(N-acryloyl-L-amino acid) graft copolymer
Scheme 2. Microwave-assisted grafting of N-acryloyl-L-phenylalanine (N-A-L-Phe) (II) and N-acryloyl-L-alanine (N-A-L-Ala) (III) onto starch (VI); (S/PAPhe) (VII); (S/PAAla)
(VIII).
from any homopolymer and other reaction ingredients. The sys-
tem is filtered and the obtained precipitate was washed several
times with acetone and allowed to dry and finally grinded to fine
particles.
The mixture was kept under continuous stirring for 2 h at room
temperature. The product was diluted with excess distilled water
and then evaporated on Rotavapor till dryness in order to remove
the excess hydrochloic acid (Scheme 3).
2.4.2. Microwave assisted synthesis of N-Acryloyl-L-Alanine
grafted starch (S/PAAla) (VIII)
2.6. Immobilization of drug onto monomer grafted starch
The entitled compound was synthesized according to the same
procedure described above using the following quantities; (0.33 g)
starch (VI) was dissolved in 10 mL of distilled water and different
ratios of (N-A-L-Ala) (III) were dissolved, each in (7 mL) distilled
water. Microwave irradiation was performed at 80 ◦C, for 3 min
(Scheme 2).
2.6.1. Immobilization of drug onto N-acryloyl-L-phenylalanine
grafted starch (S/PAPhe-ate) (XI)
N-acryloyl-L-phenylalanine grafted starch (S/PAPhe) (VII)
(1.31 mmol) was added to a (5 mL) sodium bicarbonate solu-
tion (1.19 mmol in distilled water) and kept under continuous
stirring for 1 h. Atenolol hydrochloride (Ate.HCl) (X) (1.38 mmol)
was added and the stirring was continued for extra 2 h. The
reaction product was separated by filtration, washed thoroughly
with an excess amount of distilled water and was finally
dried in a vacuum oven at 40 ◦C overnight to get 91.2% yield
(Scheme 4).
2.5. Synthesis of atenolol hydrochloride (Ate.HCl) (X)
Concentrated hydrochloric acid (4 mL) was added, dropwise to a
cold atenolol solution (IX) (3.75 mmol in 15 mL of distilled at 0 ◦C).

A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
443
OH
OH
H
H2
N
O
O
N
0oC
O
O
+
HCl
Cl
H2N
H2N
Atenolol (Ate)
(IX)
(Ate.HCl)
(X)
Scheme 3. Synthesis of atenolol hydrochloride (Ate.HCl) (X).
2.6.2. Immobilization of drug onto N-Acryloyl-L-Alanine grafted
starch (S/PAAla-ate) (XII)
at 37 ◦C, like the body temperature. All experiments were done
in triplicate and the cumulative amount of released atenolol was
recorded, based on calculating the amount of the drug released with
time.
The entitled compound was immobilized in the same way as
described above, but using the following quantities; N-acryloyl-
L-alanine grafted starch (S/PAAla) (VIII) (1.97 mmol), sodium
bicarbonate (1.72 mmol) and atenolol hydrochloride (Ate.HCl) (X)
(2.04 mmol) to get 95% yield (Scheme 4).
3. Results and discussion
3.1. Monomer synthesis
2.7. Determination of total atenolol content
The
amino
acid-carrying
monomers,
N-acryloyl-L-
2–5 mg of the material was shaken and suspended well in 3 mL
of alkaline solution, of pH 9.0 (diluted sodium hydroxide solu-
tion). The suspension was kept during the measuring time always
at 60 ◦C, in a thermostatic conditions and the released amount
of atenolol was estimated by use of a UV spectrophotometer at
ꢀmax = 224 nm.
phenylalanine (A-L-Phe-OH, II) and N-acryloyl-L-alanine
(A-L-Ala-OH, III), were prepared by reacting acryloyl chloride
with L-phenylalanine and L-alanine, respectively, according to
a previously reported method [1,3]. When acryloyl chloride is
reacted with the sodium salt of certain amino acid in aqueous
solution, and this is followed by acidification of the reaction
medium, the obtained product will be mixture of acrylamide and
the corresponding amino acid. The resulting mixture in the form
of white precipitate is extracted with ethyl acetate for at leasat
three times and the extract is concentrated on rotavapor. The
obtained residue is purified by use of column chromatography
and ethyl acetate is used as an eluent. The yield of N-acryloyl-
L-phenylalanine (A-L-Phe-OH, II) was 51% and its m.p. is 126 ◦C,
2.8. In vitro drug release
The amount of released atenolol (IX) was estimated, as a func-
tion of time using a UV spectrophotometer at (ꢀmax = 224 nm).
Known amount of the graft copolymer-atenolol adducts (5 mg) was
introduced into a (3 mL) vial, containing phosphate buffer solution
at different pH values, namely, 2, 7 and 9 keeping the temperature
R
m
O
COOH
OH H2
N
H
O
O
N
O
O
+
Cl
OH
O
O
H2N
n
(Ate.HCl) (X)
OH
R = Ph
(S/PAPhe) (VII)
R = CH3
(S/PAAla) (VIII)
NaHCO3
- NaCl
R
m
O
COO
NH2
OH
N
H
O
O
OH
O
O
O
n
OH
O
NH2
(XI)
R = Ph
R = CH3
(XII)
Scheme 4. Immobilization of Ate.HCl (X) onto (S/PAPhe) (XI) and (S/PAAla)(X.

444
A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
Table 1
amino acid-based polymers-grafted-starch as a drug carrier as
shown in Scheme 2.
Elemental microanalysis of compounds II, III and (VI–XII).
Grafting process was carried out in the presence of a low con-
centration of potassium persulfate initiator using microwave (MW)
irradiation techniques. The effect of grafting time, temperature and
the monomer/starch ratio were studied. The structure of the pre-
pared amino acid-based monomers-grafted-starch was confirmed
by Fourier transform infrared (FT-IR) spectra, elemental microanal-
ysis (as nitrogen percent (N%)) as well as NMR spectra. The thermal
properties of both native and grafted starch samples were investi-
gated by use of TGA.
Compound
code
C%
H%
N%
Calculated Found Calculated Found
Calculated Found
II
III
VI
VII*
VIII*
XI
65.72
50.31
44.44
56.48
47.36
53.84
54.70
57.68 5.93
49.76 6.28
39.88 6.17
46.94 5.78
35.97 5.92
46.74 6.80
41.39 7.01
5.29
6.22
6.84
5.89
5.61
6.78
6.06
6.389
9.78
–
3.68
4.60
6.49
7.36
5.93
9.89
–
2.48
0.42
2.73
3.91
XII
while the yield of N-acryloyl-L-alanine (A-L-Ala-OH, III) was 43%
3.2.1. Microwave assisted synthesis of
N-acryloyl-L-phenylalanine grafted starch (S/PAPhe) (VII)
and its m.p. 162–164 ◦C (Scheme 1).
3.2.1.1. Effect of temperature. The same procedure mentioned
above for microwave-assisted grafting was carried out at different
temperatures (60, 70, 80 and 100 ◦C) using the following quantities;
starch (VI) (0.33 g), suspended in 10 mL of distilled water and (N-
A-L-Phe) (II) (0.33 g), dissolved in (7 mL) water and the microwave
irradiation was performed for 3 min.
The temperature at which the grafting process is conducted has
noticeable effect on the grafting process. Different grafting trials
were carried out at different temperatures, namely, 60, 70, 80 and
100 ◦C. The FT-IR spectra displayed in Fig. 1a indicate that 80 ◦C
is the optimum temperature for the microwave-assisted grafting
of (APhe) onto starch, that the FT-IR spectra at this temperature
show two absorption bands at 1729 and 1657 cm−1, which are cor-
responding to the carboxylic carbonyl group and amide carbonyl
group, respectively. In addition to the appearance of absorption
band at 1456 cm−1 which is attributed to (C N).
3.1.1. Characterization of N-acryloyl-L-phenylalanine
(N-A-L-Phe) (II) and N-Acryloyl-L-Alanine (N-A-L-Ala) (III)
The synthesized monomers were characterized using 1H
Nuclear Magnetic Resonance, 13C Nuclear Magnetic Resonance and
Fourier Transform Infra-Red Spectroscopy and the results are listed
below:
(a) for N-Acryloyl-L-Phenylalanine (N-A-L-Phe) (II): 1H NMR
(400 MHz, DMSO-d6, ppm, from Si(CH3)4): ı 3.1 (m, 2 H,), 4.5
(m, 1 H), 5.56 (d, J = 10.0 Hz, 1 H), 6.10 (dd, 1 H), 7.24 (m, 5
H), 8.46 (d, 1 H), 8.48 (s, 1 H). 13C NMR (400 MHz, DMSO-
d6, ppm, from Si(CH3)4): ı 173.5 ( COOH), 165.0 ( CO2NH ),
138.1 ( CH2 Ar), 131.8, 129.6, 126.3 ( CH CH2, Ar.), 54.1
(>CHCO2H), 37.28 (>CHCH2 ) ppm. FT-IR (KBr): Character-
istic absorption peaks were observed at 3343 cm−1 (N H,
amide), 3028 cm−1 (C H, Aromatic), 2920 and 1651 cm−1 (C C,
vinylic), 1818 cm−1 (C O, carboxylic), 1711 cm−1 (C O, amide),
1454 cm−1 (C C), 1438–1065 cm−1 (C N).
3.2.1.2. Effect of time. The same procedure mentioned above for
microwave-assisted grafting was carried out but for different time
intervals (2.0 min, 2.5 min, 3.0 min and 5.0 min) at the same tem-
perature 80 ◦C using the following quantities; starch (VI) (0.33 g),
suspended in 10 mL of distilled water and (N-A-L-Phe) (II) (0.33 g),
dissolved in (7 mL) water.
(b) for N-Acryloyl-L-Alanine (N-A-L-Ala) (III): 1H NMR (400 MHz,
DMSO-d6, ppm, from Si(CH3)4): ı 8.4 (1H, CONH ), 6.28–6.25
(2H, CH CH2), 5.6 (1H, CH CH2), 4.26 (1H, >CHCO2H),
1.3 (3H, CH3) ppm. 13C NMR (400 MHz, DMSO-d6, ppm,
from Si(CH3)4): ı 174.6 ( COOH), 164.8 ( CHCONH ), 131.8
(CH CH2), 126.1 ( CH CH2), 48.0 ( CHCOOH), 17.7 ( CH3)
ppm. FT-IR (KBr): characteristic absorption peaks were
observed at 3307 (N H, amide), 3080 ( CH3), 2991, 1550
(C C, vinylic), 1952 (C O, carboxylic), 1732 (C O, amide), 1460
The grafting process was found to be enhanced with increas-
ing the irradiation time, keeping constant microwave power and
temperature. The optimum duration for the said grafting process
was found to be 3 min. This is attributed to the availability of more
microwave energy, which results in improving the initiation effi-
ciency by generating more free radicals. As shown in Fig. 1b, 3 min
represents the optimum exposure time, which is proved by the
(C C), 1460–1066 (C N) cm−1
.
In addition to the above mentioned characterizations, the struc-
ture of the prepared monomers was confirmed by elemental
microanalysis and the obtained results are found to be in a good
agreement with the calculated ones, as shown in Table 1.
presence of the two absorption bands at 1664 cm−1 and 1648 cm−1
,
which are corresponding to the carboxylic carbonyl group and
amide carbonyl group, respectively.
3.2. Microwave assisted synthesis
3.2.1.3. Effect of monomer/starch ratio. The same procedure men-
tioned above for microwave-assisted grafting was carried out but
different monomer/starch ratio (1, 1.5, 2 and 2.5) at the same tem-
perature 80 ◦C and for the same irradiation period (3 min) using
the following quantities, starch (VI) (0.33 g), suspended in 10 mL of
The aim of this work is to identify the appropriate conditions
for grafting a candidate synthesized monomers (N-Acryloyl-L-
Phenylalanine and N-Acryloyl-L-Alanine) onto starch to prepare
Table 2
Microwave assisted synthesis of Starch/Poly(N-acryloyl-L-phenylalanine) graft copolymer (S/PAPhe) (VII) and N-Acryloyl-L-alanine (S/PAAla) grafted starch (VIII) with
different starch/monomer ratio.
Code
VI
II or III
Ratio
Time of
irradiation
(min)
Temperature
(◦C)
Ratio
Wt. (mg)
0.33
Wt. (mg)
VII
or
VIII
1.0
1.5
2.0
2.5
0.330
0.495
0.660
0.825
1
3
80

A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
445
Fig. 1. FT-IR of (a) (S/PAPhe) (VII) at different temperature; (b) (S/PAPhe) (VII) at different time; and (c) (S/PAPhe) (VII) using different monomer ratio.

446
A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
Table 3
Elemental microanalysis of (S/PAPhe) (VII); and (S/PAAla) (VIII) with different (M/S)
ratio.
Polymer code
VII
M/S ratioa
C%
H%
6.18
6.11
35.97
5.26
N%
1.0/1
1.5/1
2.0/1
2.5/1
39.70
43.45
46.94
37.82
0.20
1.50
2.48
1.18
VIII
1.0/1
1.5/1
2.0/1
2.5/1
40.78
38.00
35.97
34.49
6.47
6.31
35.97
5.40
0.67
0.26
0.42
0.50
a
M/S ratio = monomer/starch ratio.
distilled water and different ratios of (N-A-L-Phe) (II) or (N-A-L-Ala)
(III), dissolved in (7 mL) water as shown in Table 2.
Fig. 2. FTIR of (S/PAAla) (VIII) using different monomer ratio.
Graft yield was found to increase with each increase in the
monomer/starch ratio and the optimum graft yield was obtained
on using monomer/starch ratio of 2:1, considering the same
microwave irradiation time of 3.0 min and the same power and
temperature. The increase in the graft yield by increasing the
monomer/starch ratio is attributed to the more availability of
monomer units in the vicinity of the grafting site of polysaccha-
ride. Upon increasing the monomer/starch ratio up to 2.5, the graft
yield decreases again which may be due to the priority of forming
homopolymer at this high monomer/starch ratio. The improvement
of the grafting process at monomer/starch ratio of 2:1 is also clear
from the FT-IR spectra in Fig. 1c that the spectra show the presence
of the two absorption bands at 1727 and 1664 cm−1, which are cor-
responding to the carboxylic carbonyl group and amide carbonyl
group, respectively.
in the value of Ton as the monomer ratio increase and then
increase again with M/S (2.5/1). This may be due to the grafted
polyacrylamide onto starch. The same conclusion was observed
with the temperature at which the grafted copolymer losses
its 50%.
3.2.2. Microwave assisted synthesis of N-Acryloyl-L-Alanine
grafted starch (S/PAAla) (VIII)
N-Acryloyl-L-Alanine grafted starch (S/PAAla) (VIII) was pre-
pared as described earlier for N-acryloyl-L-phenylalanine grafted
starch (S/PAPhe) (VII) at 80 ◦C for three minutes. In a similar
way, the effect of the monomer/starch ratio was studied just
to show the effect of the bulk group of the immobilized amino
acids.
In addition the same conclusion was confirmed by elemental
microanalysis (as nitrogen percent (N%)) in which the nitrogen
percent changed in the order (N% (M/S ratio); 0.2(1/1), 1.5(1.5/1),
2.48(2/1), 1.18(2.5/1). The nitrogen percent reached maximum of
2.48% with M/S ratio of (2/1) which in a good agreement with the
FTIR results as shown in Table 3.
3.2.2.1. Effect of monomer/starch ratio. Graft yield was found to
decrease upon increasing the monomer/starch ratio and the opti-
mum ratio was found to be 1:1 for exposure time of 3.0 min at 80 ◦C.
The decrease in the graft yield may be due to the priority of forming
homopolymer at this high monomer/starch ratio. The improvement
of the grafting process at monomer/starch ratio of 1:1 is also clear
from the FT-IR spectra in Fig. 2 that the spectra showed the presence
of the two absorption bands at 1763 and 1695 cm−1, which are cor-
responding to the carboxylic carbonyl group and amide carbonyl
group, respectively.
In addition the same conclusion was confirmed by elemental
microanalysis (as nitrogen percent (N%)) in which the nitrogen
percent changed in the order (N% (M/S ratio); 0.2(1/1), 1.5(1.5/1),
2.48(2/1), 1.18(2.5/1). The nitrogen percent reached maximum of
0.67% with M/S ratio of (1/1) which in a good agreement with the
FTIR results as shown in Table 3.
3.2.1.4. Thermal analysis of (S/PAPhe) (VII) with different (M/S) ratios.
The thermal degradation analysis was done with a heating rate of
10 ◦C min−1 under nitrogen atmosphere. For polymer (IV), the ini-
tial weight loss at 30–100 ◦C is due to the presence of moisture, and
the second loss of 7% at 100–223 ◦C is due to the loss of CO2 followed
by a weight loss of 16.4% at 223–274 ◦C, which is due to the degra-
dation of the grafted amino acid. The rate of weight loss of 25.7%
over 274 ◦C is due to the degradation of the polymer backbone. It
started to decompose at (Ton) 234 ◦C and left a residue of 50.5% at
600 ◦C. For starch (VI), the initial weight loss of 3.2% at 30–100 ◦C
is due to the presence of moisture, and the second loss of 83.29% at
100–400 ◦C is due to the degradation of the starch backbone. The
rate of weight loss of 6.64% over 400 ◦C is due to the degradation of
the polymer reminder. It started to decompose at (Ton) 304 ◦C and
left a residue of 6.54% at 600 ◦C.
3.2.2.2. Thermal analysis of (S/PAAla) (VIII) with different (M/S) ratios.
The thermal degradation analyses were done with heating rate
of 10 ◦C min−1 under nitrogen atmosphere. For polymer (IV), the
initial weight loss of 2% at 30–100 ◦C is due to the presence of
moisture, and the second loss of 4.6% at 100–211 ◦C is due to the
loss of CO2 followed by a weight loss of 30.6% at 211–320 ◦C is due
Table 4 summarizes the TGA results of (S/PAPhe) (VII) with dif-
ferent (M/S) ratios. The TGA of polymer (V) showed a decrease
Table 4
TGA results of (S/PAPhe) (VII) with different (M/S) ratios.
(M/S) ratio
Distribution of volatile ranges (temperature range) (◦C)
Residue (%) at 600 ◦
C
Ton (◦C)
50% Loss at (◦C)
Moisture
30–150
CO2 evolution & Grafted group
150–225
Starch
225–450
Remainder
450–600
(1.0/1)
(1.5/1)
(2.0/1)
(2.5/1)
5.93
3.85
3.75
3.20
72.82
6.87
4.61
2.05
8.83
57.13
61.68
13.64
9.73
6.29
4.80
6.07
338
321
287
265
278
25.78
24.90
34.10
330
347
349

A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
447
to the degradation of the grafted amino acid. The rate of weight
3.3.2. Characterization of N-Acryloyl-L-Alanine grafted starch
(S/PAAla) (VIII) (M/S ratio: 2/1)
loss of 46.7% over 320 ◦C is due to the degradation of the polymer
backbone. It started to decompose at (Ton) 261 ◦C and left a residue
of 15.4% at 600 ◦C. For starch (VI), the initial weight loss of 3.2%
at 30–100 ◦C is due to the presence of moisture, and the second
loss of 83.29% at 100–400 ◦C is due to the degradation of the starch
backbone. The rate of weight loss of 6.64% over 400 ◦C is due to the
degradation of the polymer reminder. It started to decompose at
(Ton) 304 ◦C and left a residue of 6.54% at 600 ◦C.
3.3.2.1. FT-IR spectra. FTIR spectra were measured to show the
new functional groups introduced onto the structure of (S/PAAla)
(VIII), as is presented in Fig. 3a. Characteristic absorption bands
were recorded at 3398 cm−1 for (N H, amide), 1763 cm−1 for (C O,
carboxylic), 1694 cm−1 for (C O, amide) and 1403–1020 cm−1 for
(C N).
Table 5 summarizes the TGA results of (S/PAAla) (VIII) with dif-
ferent (M/S) ratios. The TGA of polymer (VIII) showed an increase in
the value of Ton as the monomer ratio increases. This may be due to
decrease in the grafted polymer onto starch. The same conclusion
was observed with the temperature at which the grafted copolymer
losses its 50%.
3.3.2.2. Nuclear magnetic resonance spectroscopy (NMR). 1H NMR
and 13C NMR characterizations were carried out for the drug immo-
bilized onto N-Acryloyl-L-Alanine Grafted Starch and the results
were as follow
(a) for 1H NMR (400 MHz, DMSO-d6, ppm, from Si(CH3)4): ı 11 (m,
1 H), 8 (k, 1 H), 1.43 (n, 3 H), 4.64 (l, 1 H), 2.93 (j, 1 H), 3.73 (i, 1
H), 3.73 (b,d, 1H), 2 (c, e, 2, 1H).
3.3. Immobilization of drug onto N-acryloyl-L-phenylalanine
grafted starch (St-g-A-Ph-ate) (XI) and N-Acryloyl-L-Alanine
grafted starch (St-g-A-Ala-ate) (XII)
(b) for 13C NMR (400 MHz, DMSO-d6, ppm, from Si(CH3)4): ı 174.9
(l, COOH), 175.1 (j, CO2NH ), 51.0 (k, >CHCO2H), 16.9, 16.2
(f,m, > CH3),104.2 (a, > CHO), 74.1, 68.4,74 (b,c,e, >CH), 76.7,
77.9 (g,h, >CH2).
3.3.1. Characterization of N-acryloyl-L-phenylalanine grafted
starch (S/PAPhe) (VII) (M/S ratio: 2/1)
N-acryloyl-L-phenylalanine grafted starch (S/PAPhe) (VII) was
prepared using microwave with a M/S ratio of 2/1 at 80 ◦C for 3 min.
The product was characterized by FTIR spectra, 1H & 13C NMR,
elemental microanalysis as well as thermogravimetric analysis
(TGA).
3.3.2.3. Elemental microanalysis. In addition the above charac-
terizations, the structure of (S/PAAla) (VIII) was confirmed by
elemental microanalysis and the found results were found to
be in a good agreement with the calculated ones as shown in
Table 2.
3.3.1.1. FT-IR spectra. FT-IR spectra of the drug immobilized onto
N-Acryloyl-L-Phenylalanine Grafted Starch were measured to assign
the functional groups introduced to graft copolymer backbone
after the immobilization. The IR spectra are presented in Fig. 3
and they showed characteristic absorption peaks at 3411 (N H,
amide), 1727 (C O, carboxylic), 1657 (C O, amide), 1447–1024
3.4. Sythesis of atenolol hydrochloride(Ate.HCl) (X)
Atenolol hydrochloride (Ate.HCl) (X) was prepared by addi-
tion of concentrated hydrochloric acid 0.01 M to a cold solution
of atenolol (Ate) (IX) in water as shown in Scheme 3. The prod-
uct was obtained via evaporation on Rotavapor till dryness to
remove excess hydrochloic acid to get Ate.HCl (m.p. 157 ◦C; Ate.
m.p. 152 ◦C). In addition to that, the obtained product (X) was con-
firmed by addition of silver nitrate (AgNO3) to Ate.HCl solution, in
which we get white precipitate of AgCl.
(C N) cm−1
.
3.3.1.2. Nuclear magnetic resonance spectroscopy (NMR). 1H NMR
and 13C NMR characterizations were carried out for the drug
immobilized onto N-Acryloyl-L-Phenylalanine Grafted Starch and the
results were as follow:
The FTIR spectra of the formed product (X) showed char-
acteristic absorption peaks were observed at 3198–3071 cm−1
(N H, amide), 1649 cm−1 (H2N
(C N).
C
O, amide) and 1403–1020 cm−1
(a) for 1H NMR (400 MHz, DMSO-d6, ppm, from Si(CH3)4): ı 11 (m,
1 H), 8 (k, 1 H), 7.12 (p,q,r,s,t, 5 H), 3.16 (n, 2 H), 4.25 (l, 1 H),
2.73 (j, 1 H), 3.73 (i, 1 H), 3.73 (b,d,1H), 2 (c,e, 2, 1H).
(b) for 13C NMR (400 MHz, DMSO-d6, ppm, from Si(CH3)4): ı 174.9
(l, COOH), 175.1 (j, CO2NH ), 139.5 (n, CH2 Ar), 127.8,
128.6, 126 (o,p,q,r,s, CH CH2, Ar.), 55.9 (k, >CHCO2H), 36.7
(m, >CHCH2 ).
3.5. Immobilization of atenolol hydrochloride (Ate.HCl) onto
N-acryloyl-L-phenylalanine grafted starch (St-g-A-Ph-Ate) (XI)
and N-Acryloyl-L-Alanine grafted starch (St-g-A-Ala-Ate) (XII)
N-acryloyl-L-phenylalanine Grafted Starch (St-g-A-Ph-Ate) (XI)
and N-Acryloyl-L-Alanine Grafted Starch (St-g-A-Ala-Ate) (XII)
were prepared by reaction of Ate.HCl (X) with (S/PAPhe) (VII) and
(S/PAAla) (VIII), respectively at room temperature as indicated
in Scheme 4. The reaction was stirred for 3 h, and the prod-
uct was filtered, washed with excess amount of distilled water
and was dried in oven under vacuum at 40 ◦C overnight (91.2%
yield).
The elemental analyses data of (St-g-A-Ph-Ate) (XI) as listed
in Table 2 showed that (Found/Calculated (%)), C: 53.84/46.74; H:
6.80/6.78; N: 6.49/2.73.
In similar way, the elemental analyses data of (St-g-A-Ala-Ate)
(XII) as listed in Table 2 showed that (Found/Calculated (%)), C:
54.70/41.39; H: 7.01/6.06; N: 7.36/3.91.
3.3.1.3. Elemental microanalysis. In addition the above characteri-
zations, the structure of (S/PAPhe) (VII) was confirmed by elemental
microanalysis and the found results were found to be in a good
agreement with the calculated ones as shown in Table 2.
3.3.1.4. Thermal analysis of (S/PAPhe) (VII). The thermal degrada-
tion analysis were done with heating rate of 10 ◦C min−1 under
nitrogen atmosphere. For (S/PAPhe) (VII) with (M/S ratio; 2/1), the
initial weight loss of 3.75% at 30–150 ◦C is due to the presence
of moisture, and the second loss of 4.61% at 150–225 ◦C is due to
the loss of decarboxylation and degradation of amino acid moiety
followed by a weight loss of 61.68% at 225–450 ◦C is due to the
degradation of is due to the degradation of the starch backbone.
The rate of weight loss of 4.8% over 450 ◦C is due to the degradation
of the polymer reminder. It started to decompose at (Ton) 265 ◦C
and left a residue of 24.9% at 600 ◦C as shown in Table 4.
Based on the nitrogen analysis, the percent of immobilized
atenolol for (St-g-A-Ph-Ate) (XI) and (St-g-A-Ala-Ate) (XII) was
found to be 42.1% and 53.1%, respectively.

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A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
Fig. 3. FTIR spectra of (a) (S/PAAla) (VIII); (b) (S/PAPh-ate) (XI); (c) (S/PAAla-ate) (XII).

A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
449
Fig. 4. In vitro release profile of atenolol from (a) (S/PAPhe-ate) (XI); (b) (S/PAAla-ate) (XII) in phosphate buffer with various pH at the body temperature (37 ◦C).
Fig. 5. In vitro release profile of atenolol from (S/PAPhe-ate) (XI) and (S/PAAla-ate) (XII) in phosphate buffer of (a) pH 9; (b) pH 7, at the body temperature (37 ◦C).

450
A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
Table 5
TGA results of (S/PAAla) (VIII) with different (M/S) ratios.
(M/S) ratio
Distribution of volatile ranges (temperature range) (◦C)
Residue (%) at 600 ◦
C
Ton (◦C)
50% Loss at (◦C)
Moisture
30–150
CO2 evolution & Grafted group
150–225
Starch
211–400
Remainder
400–600
(1.0/1)
(1.5/1)
(2.0/1)
(2.5/1)
4.78
4.19
3.88
3.52
9.98
62.21
6.23
5.6
55.26
10.62
51.89
49.57
9.56
284
25.24
26.00
19.58
306
275
327
330
320
328
314
347
349
268
carboxylic), 1639 cm−1 (H2N
(C N).
C
O, amide) and 1398–1022 cm−1
Generally, for both adducts (XI) and (XII) the percent of N
increase in comparison to the started copolymers (VII) and (VIII),
respectively as shown in Table 2.
In addition, FTIR spectroscopy was used to investigate the
immobilization of Ate.HCl (X) onto (S/PAPhe) (VII) and (S/PAAla)
(VIII) as presented in Fig. 3b and c. As shown in Fig. 3b, (St-g-
A-Ph-Ate) (XI) showed characteristic absorption peaks at 3198
3.6. In vitro drug release
The rate of atenolol release from both (S/PAPhe-ate) (XI) and
(S/PAAla-ate) (XII) was studied at various pH values, namely, pH 2.0,
pH 7.0 and pH 9.0. The rate of drug release is expected to be depend-
ent on the microstructure of the polymer grafted onto starch, how
bulky is the amino acid moiety, the hydrophilicity and the pH of
the release medium (El-Newehy et al., 2013).
(N H, amide), 1666 (C O, carboxylic), 1649 (H2N
C O, amide),
1403–1020 (C N) cm−1
.
As shown in Fig. 3c (St-g-A-Ala-Ate) (XII) showed characteris-
tic absorption peaks at 3183 cm−1 (N H, amide), 1665 cm−1 (C O,
Fig. 6. In vitro release profile of atenolol from (S/PAPhe-ate) (XI) and (S/PAAla-ate) (XII) in phosphate buffer (pH 2) at the body temperature (37 ◦C).

A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
451
3.6.1. Effect of pH
work and the completion of all requirements of research No (P-
S-12-0667). Also, Authors would like to thank Prof. Dr. Salem
Al-Deyab, Supervisor of Petrochemical Research Chair, for his support
for the completion of my thesis by using the available instrument
in Petrochemical Research Chair’s Labs and doing characteriza-
tion.
The rate of atenolol release was investigated in media having
various pH values; pH 2.0 (stomach), pH 7 (physiological fluids) and
pH 9.0 (colon). It was found that the rate of atenolol release from
(S/PAPhe-ate) (XI) and (S/PAAla-ate) (XII) is low in acid medium,
indicating high hydrolytical stability against the strongly acidic
medium inside the stomach. On the other hand, the rate of atenolol
release was found to reach its maximum value in alkaline medium
(inside the colon).
References
The release study was carried out at fixed temperature 37 ◦C, for
a duration of 48 h. At these conditions, (S/PAPhe-ate) (XI) released
94.6% and 76.2% of their drug contents at pH 9.0 and pH 7, respec-
tively as shown in Fig. 4a and it released 30.1% of its drug content
at pH 2.0 after 2 h under the same conditions as shown in Fig. 6.
The total amount of atenolol released from (S/PAAla-ate) (XII)
represent 95.3% and 91.6% of its drug content at pH 9.0 and pH 7,
respectively, when the release is carried out at 37 ◦C for 48 h as
shown in Fig. 4b. Moreover, (S/PAAla-ate) (XII) released 27.8% of
its drug content at pH 2.0 after 2 h under the same conditions as
shown in Fig. 6.
Al-Hazimi, H. M., El-Faham, A., Gazzali, M., & Al-Farhan, K. (2012). Microwave irradia-
tion: A facile, scalable and convenient method for synthesis of N-phthaloylamino
acids. Arabian Journal of Chemistry, 5, 285–289.
Babazadeh, M. (2007). Synthesis, characterization, and in vitro drug-release prop-
erties of 2-hydroxyethyl methacrylate copolymers. Journal of Applied Polymer
Science, 104(4), 2403–2409.
Babazadeh, M. (2008). Design, synthesis and in vitro evaluation of vinyl ether type
polymeric prodrugs of ibuprofen, ketoprofen and naproxen. International Journal
of Pharmaceuticals, 356(1/2), 167–173.
Babazadeh, M., Edjlali, L., & Rashidian, L. (2007). Application of 2-hydroxyethyl
methacrylate polymers in controlled release of 5-aminosalicylic acid as a colon-
specific drug. Journal of Polymer Research, 14(3), 207–213.
Barbucci, R., Casolaro, M., & Magnani, A. (1991). The role of poly electrolytes
in the permeability control of insulin: Behavior of poly(N-acryloyl-glycine)
grafted on porous cellulose membrane. Journal of Controlled Release, 17(1),
79–88.
Bentolila, A., Vlodavsky, I., Ishai-Michaeli, R., Kovalchuk, O., Haloun, C., & Domb, A. J.
(2000). Poly(N-acryl amino acids): A new class of biologically active polyanions.
Journal of Medicinal Chemistry, 43(13), 2591–2600.
Casolaro, M., & Barbucci, R. (1991). An insulin-releasing system responsive to glu-
cose: Thermodynamic evaluation of permeability properties. The International
Journal of Artificial Organs, 14(11), 732–738.
Curvelo, A. A. S., de Carvalho, A. J. F., & Agnelli, J. A. M. (2001). Thermoplastic
starch–cellulosic fibers composites: Preliminary results. Carbohydrate Polymers,
45(2), 183–188.
C¸ algeris, I., C¸ akmakc¸ ı, E., Ogan, A., Kahraman, M. V., & Kayaman-Apohan, N. (2012).
Preparation and drug release properties of lignin–starch biodegradable films.
Starch, 64(5), 399–407.
El-Newehy, M. H., Elsherbiny, A., & Mori, H. (2013). Synthesis of amino acid-based
polymers having metronidazole moiety and study of their controlled release in
vitro. Journal of Applied Polymer Science, 127(6), 4918–4926.
Friend, D. R. (2005). New oral delivery systems for treatment of inflammatory bowel
disease. Advanced Drug Delivery Reviews, 57(2), 247–265.
George, M., & Abraham, T. E. (2006). Polyionic hydrocolloids for the intestinal deliv-
ery of protein drugs: Alginate and chitosan. Journal of Controlled Release, 114(1),
1–14.
Ghazzal, M., El-Faham, A., Abd-Megeed, A., & Al-Farhan, Kh. (2012). Microwave-
assisted synthesis, structural elucidation and biological assessment of
2-(2-acetamidophenyl)-2-oxo-N phenyl acetamide and N-(2-(2-oxo-
2(phenylamino)acetyl)phenyl) propionamide derivatives. Journal of Molecular
Structure, 1013, 163–167.
3.6.2. Effect of polymer microstructure
The effect of the polymer microstructure on the release of
atenolol from (S/PAPhe-ate) (XI) and (S/PAAla-ate) (XII) was
studied based on the change in the amino acid moiety from phen-
ylalanine to alanine.
The profiles of drug release from (S/PAPhe-ate) (XI) and
(S/PAAla-ate) (XII) at pH 9 (alkaline pH) are illustrated in Fig. 5a
and b). The release studies were carried out for 48 h, and in tripli-
cate experiments. The (S/PAPhe-ate) (XI), showed release of 94.6%
from its drug content after 48 h at 37 ◦C. Alanine-based copolymer,
(S/PAAla-ate) (XII) showed the same results, in which 95.3% of its
drug content was released under the same conditions. Generally,
the obtained results indicated that there is no remarkable effect of
changing the amino acid structures on the rate of atenolol release,
suggesting that the amino acid moiety bulkiness and hydrophilicity
have no significant effect of on the extent of drug release.
4. Conclusion
Hoste, K., Winne, K. D., & Schacht, E. (2004). Polymeric prodrugs. International Journal
of Pharmaceuticals, 277(1/2), 119–131.
Kenawy, E., El-Newehy, M. H., Abdel-Hay, F. I., & Raphael, M. O. (2001). New degrad-
able hydroxamate linkages for controlled drug delivery. Biomacromolecules, 8,
196–201.
Khandare, J., & Minko, T. (2006). Polymer–drug conjugates: Progress in polymeric
prodrugs. Progress in Polymer Science, 31(4), 359–397.
Kenawy, El-R., El-Newehy, M. H., Abdel-Hay, F. I., & Ottenbrite, R. M. (2008, January).
Effect of temperature and pH on the drug release rate from a polymer conjugate
system. Polymer International, 57(1), 85–91.
Kenawy, E. R., Abdel-Hay, F., El-Newehy, M., & Ottenbrite, R. M. (2008). Effect of
temperature and pH on the drug release rate from a polymer conjugate system.
Polymer International, 57, 85–91.
Lekchiri, A., Morcellet, J., & Morcellet, M. (1987). Complex formation between
copper (II) and poly(N-methacryloyl-L-asparagine). Macromolecules, 20(1),
49–53.
Lidstrom, P., Tierney, J., Wathey, B., & Westman, J. (2001). Microwave-assisted
organic synthesis a review. Tetrahedron, 57, 9225–9283.
Mishra, S., Sinha, S., Dey, K. P., & Sen, G. (2014). Synthesis, characterization and appli-
cations of polymethylmethacrylate grafted psyllium as flocculant. Carbohydrate
Polymers, 99, 462–468.
In this study, amino acid-based monomers containing phen-
ylalanine and alanine were synthesized. These amino acid-based
monomers were grafted onto starch as a natural polymer using
microwave technique. Factors affecting the efficiency of the graft-
ing reaction, like monomer/starch ratio and grafting temperature
and duration were studied and the obtained results revealed
that optimum temperature for the microwave-assisted grafting of
(APhe) is 80 ◦C and the optimum reaction duration with constant
microwave power is 3 min. The optimum monomer/starch ratio for
Phe and Ala was found to be 2:1 and 1:1, respectively, for exposure
time of 3.0 min at 80 ◦C.
The obtained graft copolymer was used as stationary phase for
immobilization of drugs and finally studying the release of the drug.
Based on the nitrogen analysis, the obtained results revealed that
the percent of immobilized atenolol for (St-g-A-Ph-Ate) (XI) and
(St-g-A-Ala-Ate) (XII) was found to be 42.1% and 53.1%, respec-
tively. The release was found to takes place in alkaline medium
rather than in acidic medium and factors like bulkiness and the
hydrophilicity of the amino acid moiety were found to have no
significant effect on the drug release.
Nichifor, M., Schacht, E.,
& Seymour, L. W. (1997). Polymeric prodrugs of 5-
fluorouracil. Journal of Controlled Release, 48(2/3), 165–178.
Oishi, T., Lee, Y. K., Nakagawa, A., Onimura, K., & Tsutsumi, H. (2002). Syntheses
and polymerizations of novel chiral poly(acrylamide) macromonomers and their
chiral recognition abilities. Journal of Polymer Science. Part A: Polymer Chemistry,
40(11), 1726–1741.
Osman, S. M., El-Newehy, M. H., Al-Deyab, S. S., & El-Faham, A. (2012). Microwave
synthesis and thermal properties of polyacrylate derivatives containing itaconic
anhydride moieties. Chemistry Central Journal, 6, 85–90.
Acknowledgments
Rahul, R., Jha, U., Sen, G., & Mishra, S. (2014). A novel polymeric flocculant based on
polyacrylamide grafted inulin: Aqueous microwave assisted synthesis. Carbo-
hydrate Polymers, 99, 11–21.
Authors would like to thank to King Abdulaziz City for Sci-
ence and Technology (KACST) to provide financial support for this

452
A.Y.A. Alfaifi et al. / Carbohydrate Polymers 106 (2014) 440–452
Rani, G. U., Mishra, S., Sen, G., & Jha, U. (2012). Polyacrylamide grafted Agar: Synthesis
and applications of conventional and microwave assisted technique. Carbohy-
drate Polymers, 90, 784–791.
Van den Mooter, G., Weuts, I., De Ridder, T., & Blaton, N. (2006). Evaluation of Inutec
SP1 as a new carrier in the formulation of solid dispersions for poorly soluble
drugs. International Journal of Pharmaceuticals, 316(1/2), 1–6.
Sinha, S., Mishra, S., & Sen, G. (2013). Microwave initiated synthesis of polyacryl-
amide grafted Casein (CAS-g-PAM) – Its application as a flocculant. International
Journal of Biological Macromolecules, 60, 141–147.
Yan, G. P., Zhuo, R. X., & Zheng, C. Y. J. (2001). Study on the anticancer drug
5-fluorouracil-conjugated polyaspartamide containing hepatocyte-targeting
group. Journal of Bioactive and Compatible Polymers, 16(4), 277–293.