Production, Characterization and Parametric Optimization of Dual

Modified Cross Linked-Acetylated Potato Starch as Disintegrant for

Tablet Formation

Seyoum Misganaw Mengstu1; Sintayehu Mekuria Hailegiorgis 1*

1 Chemical Engineering department, College of Biological and Chemical Engineering, Biotechnology and
Bioprocess Center of Excellence, Addis Ababa Science and Technology University, P.O.Box, 16417, Addis
Ababa, Ethiopia

*Corresponding Author: email: sintayehu.mekuria@aastu.edu.et; sintmek2009@gmail.com;

Telephone: +251909779416

The objective of this research work was to produce, characterize, and optimize the parameters of modified potato
starch from local potatoes and identify the physicochemical properties of native, cross -linked, acetylated and dual
crosslinked acetylated potato starch disintegrant for tablet formation. Modified starch production was carried out by
cross-linked and acetylated methods using modified agents of Sodium-hexa-metal phosphate (SHMP) and acetic
anhydride (AA), respectively. The native and modified potato starch were characterized by Fourier transform infrared
spectra (FTIR), differential scanning calorimetry (DSC), rapid visco analyzer (RVA), and x -ray diffraction (XRD).
The potato starch modification parameters included reaction temperature, reaction time, pH, concentration of
modifying agent (AA), and concentration of NaOH catalyst. Reaction temperature (40, 60, 80℃), modified agent
concentration (10, 20, 30%), and Time (40, 55, 70 min) have been selected as the major study parameters based on
the preliminary experiments. The parameters were optimized statistically using the response surface methodology of
Box Behnken design methodology for dual crosslinked acetylated potato starch and the responses acetyl content. The
optimized results of modification parameters were reaction temperature 40.2164℃, reaction time 69.8462 min, and
concentration of modifying agent (AA) 21.9241%w/w and the response of the acetyl content obtained with optimized
factors were 1.32% ± 0.077. The disintegration time, disintegration efficiency ratio, crushing strength, and friability
of dually crosslinked acetylated potato starch tablets were 29.2 ± 0.29 min, 500 ± 0.985 N/min, 92.35 ± 0.857 N and
0.63 ± 0.082%w/w. The dual crosslinked acetylated potato starch was used as disintegrant for tablet formation at the
concentration of 10% active ingredient (paracetamol), 50% magnesium stearate as lubricant 10% and other fillers by
direct compression mechanism.

1. Introduction

Many plants' cereal bowls, roots, tubers, biopolymer characteristics. The origin of
seeds, and fruits are sources of starch, a type starch can have an impact on the starch
of carbohydrate with semicrystalline granules because of variations in form, size,
structure, and chemical content.[1]. There are
many sources of starches in the world. They
are isolated from different parts of the plant
such as cereals (corn and wheat), tubers
(potato), and roots (cassava, taro, sweet
potato, arrowroot) [2]. Nowadays, the
number of researches increase to cope with
accelerating global needs so that the sources
also increase, such as ginger, cocoyam,
sorghum, plantain, rye, barley, yam, enset,
and colocasia have also been researched [3].
The Starch molecular structure, physical,
chemical, biochemical properties,
functionality, and uses are studied on
different intensive research over many
decades, occupying a vast body of published
literature reporting its preparative and
analytical methods[4]. The application area
of starch is diversified, as a result the
production techniques become diverse in
native starch (NSs) and numerous starch
modifications[5]. Starch granules are
composed of amylose and amylopectin,
which is 98-99% of the dry weight [6]. They
also contain non-starch components such as
ash, lipids, proteins, and phosphate groups.
Amylose is essentially a linear polymer in
which the anhydroglucose units are
predominantly linked through -D-(1-4)
glucosidic bonds. Amylose can form
inclusion complexes with a large number of
linear, polar and nonpolar compounds, such
as long chain fatty acids, fatty alcohols,
monoglycerides, and flavor, forming
molecular inclusion complexes by wrapping
around the ligand and forming a left-handed
helix. The amylopectin molecule is branched
and formed by anhydroglucose units joined at
-1,4 and -1,6 glycosidic bonds (polymers
of α-1-4 linked glucopyranose with α-1-6
branches) [7].
Starch is the carbohydrate reserve of the plant
kingdom, mainly deposited in the seeds,
tubers, or roots of plants and corresponds to
60 to 80% of the dry weight of the material
[8]. It consists mainly of amylose (20–30% of
the starch granules) and amylopectin (in a
proportion of 70–80%).
Starch from the tubers of Ethiopian potato
(Plectranthus edulis and Lamiaceae family)
proximate composition of the starch on a dry
weight basis was found to be 0.14% ash,
0.21% lipid, 0.43% protein, and 99.2%
amylose and amylopectin [4]. For use in
pharmaceutical technology, unprocessed
native starches are structurally weak and
functionally limited. As a result, starch is
chemically or physically changed to make it
suitable for industrial application [9]. A
benefit of potato for starch production is the
easy accessibility and produce high starch.
Starch is used as a binder, diluent, and
disintegrant in the pharmaceutical sector.
During the production of tablets, freshly
made starch pastes with a concentration of 5-
20%w/w are frequently utilized and 15%
weight-to-weight is the optimum starch
content for tablets [10]. The starch molecule's
functional groups are changed as a result of
the chemical modification, dramatically
altering the physicochemical properties [11].
It entails adding functional groups to the
starch molecule while leaving the shape and
size distribution untouched. The starch
behavior, gelatinization ability,
retrogradation, and paste characteristics all
undergo major modifications as a result. The
stability of intermolecular connections at
various sites and locations is aided by such
alterations. The starch source, reaction
conditions (reactant concentration, pH,
temperature, reaction time, and the presence
of a catalyst), type of substituent, degree of
substitution (DS), difficulty with salts,
covalent cross-linking, and the distribution of
the substituents in the starch molecule are
among the factors that affect the chemical
and functional properties of modified
starches [12].
The functionality of starch is altered through
chemical modification. The chemistry used
to modify starch is fairly simple and mostly
consists of reactions involving the hydroxyl
groups of the starch polymer. Starch may be
chemically altered to produce starch with
useful functional qualities that may be used
in the food and pharmaceutical industries.
The derived starch has better properties as
tablet excipients especially in direct
compression manufacture of pharmaceutical
tablets. A disintegrant is an excipient
included in a pharmaceutical formulation to
achieve the breakup of solid dosage forms
such as tablets or granules into smaller
discrete particles [13]. Disintegration is a
critical step in the process of drug release and
absorption as it exposes a larger surface area
for the drug to more easily and quickly go
into solution. This accelerates the dissolution
process, drug release, and absorption to
achieve the desired therapeutic activity of the
drug. Starch is a cheap and convenient
disintegrant which is thought to exert this
action as a result of the swelling properties of
its particles in the presence of water leading
to the disruption of the solid bridges and other
binding forces in the dosage form. The extent
of swelling is a function of the source or type
of starch which is reflective of the relative
proportion and conformation of the amylose
and amylopectin in the particular starch [14].
Weak associative forces in a starch could be
an indication of its potential as a disintegrant.
Disintegrant action could also be due to the
formation of channels through which fluids
2. Materials and Methods
2.1. Materials
The raw material (potato) used for used for
the present research work was collected from
Holleta Agricultural Institute, West Shewa,
around Addis Ababa special zone of Oromia,
which is 39 km from Addis Ababa in the
West. The potato was placed in an internally
lined polypropylene bag to avoid sample
contamination and brought to Addis Ababa
Science and Technology University,
Chemical Engineering Research laboratory
for further investigation. All chemicals used
throughout this study were attaining the
analytical reagent grade and maximum
2.2.Methods
2.2.1. Proximate analysis of raw potato
The chemical composition such as; amylose
content, amylopectin, ash value, protein
content, fat content, and moisture content
were investigated to know the chemical
composition of raw potato.
2.2.2. Modified starches Production
2.2.2.1. Production of Cross-linked
Potato Starch (CLPS)
are able to penetrate the solid dosage form
allowing the dissolution of the drug.
purity. The chemicals used were sodium
metabisulphite (98%, India), sodium
hydroxide (99%, India), sodium carbonate
(99.5%, India), sodium hexametha
phosphate, SHMP (68%, China), distilled
water (99.9%, AASTU), acetic anhydride
(99%, China) hydrochloric acid (35%,
China), Orto-phosphoric acid (85%, India),
diethyl ether ( >99.6%), sulphuric acid (98%,
Ethiopia) hydrogen peroxide (96%,
Germany), ethanol (99%, German), and
iodine (>99.8%, India) solution were used in
laboratory work.
Cross-linking of potato starch was performed
using the method described by Woo & Seib
[20]. The native starch (50g, dry basis) can
disperse into 100 ml distilled water mix for
30 min using a mixer. Then, prepare the
solution containing sodium carbonate (0.8g)
in 20 ml and SHMP at three different
concentrations 10, 20, 30 (%) dissolved in 25
ml amount of distilled water individually and
add into the solution containing native star
and then adjust the PH of the solution until
becoming 11 by the solution which
containing sodium hydroxide (0.6%, w/w) in %𝑌𝑖𝑒𝑙𝑑 𝑜𝑓 𝑐𝑟𝑜𝑠𝑠𝑙𝑖𝑛𝑘𝑒𝑑 𝑠𝑡𝑎𝑟𝑐ℎ
distilled water then stirring until the solution 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑐𝑟𝑜𝑠𝑠𝑙𝑖𝑛𝑘𝑒𝑑 𝑠𝑡𝑎𝑟𝑐ℎ 𝑥100
= (2.10)
completely homogenous by a magnetic 𝑤𝑒𝑖𝑔ℎ𝑡 𝑜𝑓 𝑛𝑎𝑡𝑖𝑣𝑒 𝑠𝑡𝑎𝑟𝑐ℎ

stirrer. The starch suspensions were

Determination of peak viscosity and
maintained at (40, 60, 80) ℃ while stirring
degree of cross-linking (DCL)
and held at these temperatures for (40, 55, 70)
A viscometer, often known as an Ostwald
min contact time. Adjust the pH at 6.5 by 1.5
viscometer, operates according to Poiseuille's
N hydrochloric acid of the suspension, after
law. Poiseuille's law states that in the case of
cooling to room temperature, to terminate the
fluids flowing laminarly, the flow rate of the
reaction. The CLS slurries were then
liquid can be expressed as the ratio of
recovered by centrifuging at 3,000 rpm for 15
pressure difference to viscous resistance.
min and the starch solution was washed 3
According to the fluid's viscosity and tube
times in distilled water (3*100ml) and kept in
length, the value of viscous resistance varies
the open air for 10 minutes until the starch
directly. Inverse relationships exist between
cake decant (the slurring and filtering steps
the viscous resistance value and the tube's
were repeated twice) filtered through by
radius's fourth power [21]. The term
decantation process after the cake become
"capillary viscometer" also applies to an
clean filter by a Buchner funnel and dried in
Ostwald viscometer. It typically makes use of
a hot air oven at 50℃ for 24 h. The materials
the rate of flow of liquid through a capillary
were then powdered using a mortar and
tube to determine the viscosity of the fluid.
pestle, passed through a 200 μm mesh sieve,
For this purpose, the fluids are typically made
and packed in an air-tight container. The
to flow through a capillary tube between two
percentage yield of cross-linked indicates
marked points and the time taken by the fluid
how much crosslinked potato starches were
to flow between the two points marked on the
produced after it reacts with the crosslinking
glass tube is noted with the help of a
agent (SHMP). Percentage yields of dry basis
stopwatch. The Degree of cross-linking
cross-linked potato starch were determined
affects many properties of the starch such as
according to the method described by the
swelling power, viscosity, solubility, and
Association of Official Analytical Chemists
paste in order to identify which degree of
with slight modification [16].
cross-linking is suitable for the property of
the starch to produce the excipient of the
drug. The method of determining DCL of the steps were repeated twice)filtered through by
modified starches was determined from the decantation process after the cake become
viscosity values, according to [22]. clean filter by a Buchner funnel, and then
oven-dried at 50 ˚C for 48 h. finally grounded
(𝐴 − 𝐵 )𝑥100
𝐷𝐶𝐿 = (2.11) the modified starch until the starch passed
𝐴
through 200 µm and packed an airtight
where A is the peak viscosity of native starch
container. Yield (%) of modified starch was
and B is the peak viscosity of CLPS.
calculated on a starch dry weight basis.
2.2.2.2. Preparation of Acetylated Potato
2.2.2.3. Dual Crosslinked Acetylated
Starch (APS)
Modified Starch Preparation
Acetylation of potato starch (K) with acetic
The preparation of dual modified
anhydride (AA) was performed as follows
potato starch was done in two steps. The dual
[22]. The native starch (10 g, dry basis) was
modified potato starch was obtained first
dispersed in distilled water (110 ml) and
crosslink the potato starch with SHMP at
stirred for 30 minutes at 25°C. Acetic
different concentrations and then acetylate
anhydride was added dropwise 10%, 20%,
the crosslinked potato starch with different
and 30% (based on the dry weight of starch)
concentrations of acetic anhydride. Dual
and prepared the solution of NaOH in 0.4
crosslinked acetylated potato starch was done
molarity concentration and add the NaOH
by reacting the crosslinked potato starch with
solution into the starch solution until the pH
acetic anhydride (AA) was performed as
becomes within the range of 8.0-8.4while
follows [23]. The crosslinked potato starch
maintaining constant stirring by a magnetic
(10 g, dry basis) was dispersed in distilled
stirrer. The reaction vessel was sealed and the
water (110 ml) and stirred for 30 minutes at
reaction mixtures were heated to (40, 60, 80)
25°C. Acetic anhydride was added dropwise
℃, and held at this temperature for (40, 55,
10%, 20%, and 30% (based on the dry weight
70) a minute while stirring. The pH of the
of crosslinked starch) and prepared the
starch suspension was then adjusted to 4.5
solution of NaOH in 0.4 molarity
with 0.5 N HCl, then starch solution was
concentration and add the NaOH solution
washed 3 times in distilled water (300ml) and
into the starch solution until the pH becomes
kept in the open air for 10 minutes until the
within the range of 8.0-8.4while maintaining
starch cake decant (the slurring and filtering
constant stirring by a magnetic stirrer. The
reaction vessel was sealed and the reaction
mixtures were heated to (40, 60, 80) ℃, and
held at this temperature for (40, 55, 70) min
while stirring. The pH of the starch
suspension was then adjusted to 4.5 with 0.5
N HCl, then starch solution was washed 3
times in distilled water (300ml) and kept in
the open air for 10 minutes until the starch
cake decant (the slurring and filtering steps
were repeated twice)filtered through by
decantation process after the cake become
clean filter by a Buchner funnel, and then
oven-dried at 50˚C for 48 h. finally grounded
the modified starch until the starch passed
through 200 µm and packed an airtight
container. Yield (%) of modified starch was
calculated on a starch dry weight basis.
Percentage yields of dry acetylated potato
starch were determined according to the
method described by the Association of
Official Analytical Chemists with slight
modification [16].
Yield (%)of acetyl starch
Weight of acetyl starch
= ∗ 100% (2.12)
Weight of native starch
Degree of Substitution (DS) or Degree of
Acetylation Determination
The method is described by Colossi was
employed to determine the DS [46]. First,a 1g
sample of DCL-AC was placed in a 250 ml
flask, and 50 ml of distilled water was added.
The flask was agitated, heated to 100℃ over
a water bath, held at this temperature for 30
min, and cooled; 40 ml of 0.5 N potassium
hydroxide was added while swirling. The
flask was stoppered and then allowed to stand
for 72 h with occasional swirling. The excess
alkali was then back titrated with standard 0.5
N hydrochloric acid using phenolphthalein as
an indicator. This method was also equivalent
to dual crosslinked acetylated potato starch.
The acetyl content of dual crosslinked
acetylated potato starch were esterification
reactions. The acetyl content of dual cross
like-acetylated potato starch was given in Eq.
(3.5).
(𝑉2 − 𝑉1) 𝑥 𝑁 𝑥 43
%𝐴 = 𝑥100% (2.13)
𝑚 𝑥 1000
where, A - acetyl content, V1- the volume of
0.5 N HCl in mL used for titration of 1 g
native starch(ml), V2- the volume of 0.5 N
HCl in mL used for titration of 1 g sample
(blank, ml), N- the normality of HCl solution,
m -the weight of the sample.
Degree of substitution
162 x %A
= (2.14)
(43 x100) − (42x %A)
where A acetyl content, 43, molecular weight
of the acetyl group, 162 molecular weight of
the hydro-glucose unit
 2.3. Physicochemical characterization of
starch
2.3.1. Density
True density determination fluid
displacement method was utilized using
xylene as the immersion fluid. 2 g of starch
samples were placed in a volumetric flask (25
ml), which was then filled with xylene and
weighed following the determination of the
weight of the empty volumetric flask and the
volumetric flask filled with xylene. Xylene
was added in such a way that it washes down
and overlays the sample. After 10 min, the
sediment starch was stirred with a small glass
stirring rod to release entrapped air. It was
measured as measurements.
𝑊1 x sg
Density (ρ) = (2.15)
(𝑊1 + 𝑊2 − 𝑊3 )
where, W1= Weight (g) of a starch sample,
W2= Weight (g) of a volumetric flask filled
with xylene, W 3= Weight (g) of volumetric
flask plus sample plus xylene left after
displaced by the sample, and Sg= Specific
gravity of xylene (g/ml) (0.87).
2.3.2. pH Determination
The pH of Potato starch was determined
using the method described by Nwachukwu,
[24]. It was done by shaking a 1% w/v
dispersion of the starch in water for 5 min and
the pH was determined using a digital pH
meter.
2.3.3. Analysis of Fourier Transform
Infrared (FTIR) Spectra
The sample was first ground in a mortar to
reduce the average particle size. About 5-10
mg of the samples were equilibrated at 50 ℃
for 24 h and finely ground in a mortar to
produce a uniform particle size. The samples
were diluted with an oily mulling agent in a
mortar and pestle. FTIR of native starch,
cross-linked, acetylated and dual crosslinked
acetylated starch measures with spectrum 65
FT-IR (Perkin Elmer). Samples were
recorded at a resolution of 4 cm -1 and wave
numbers ranged between 4000-400 cm-1 with
the number of 4 scans using potassium
bromide (KBr) pellets. Then transfer the data
into a graph by using Origin lab software.
2.3.4. Determination of Starch Hydration
Capacity
The hydration capacity of the starch was
determined by using the method of Jubril
[25]. A 1g weight of starch was placed in a
plastic centrifuge tube; 10 ml distilled water
was added and then closed. The contents
were shaken for 2 min, and then allowed to
stand for 10 min, and immediately
centrifuged at 1000 rpm for 10 min in a bench
centrifuge. The supernatant decanted and the
weight of the wet starch was recorded. The
hydration capacity was determined using the
equation below:
𝑊𝑠
Hydration capacity = (2.16)
𝑊𝑑
where Ws and Wd are the weights of the
sediment and dry sample, respectively.
2.3.5. Swelling Power and Solubility
Determination
The swelling power (SP) and solubility of
starch were determined using the method
described elsewhere [26]. Starch samples
(0.5 g each) were dispersed in distilled water
(10 ml) in preweighed centrifuge tubes.
Aqueous dispersions of starch samples were
heated at reasonable intervals between 20°C
and 85°C for 30 min, with shaking every 5
min and then left to cool to room temperature.
Each sample was then centrifuged at 3000
rpm for 15 min and analyzed for the weight
of sediment per gram of starch on dry weight
basis. The supernatant liquid obtained at each
Point was dried in a hot air oven for 2 h at
130℃ and weighed after cooling in a
desiccator. All determinations were done in
triplicate. The percent solubility (%S) and SP
were determined according to Eq.3.17 and
3.18, respectively. Point was dried in a hot air
oven for 2 h at 130℃ and weighed after
cooling in a desiccator. All determinations
were done in triplicate. The percent solubility
(%S) and SP were determined according to
Eq.3.17 and 3.18, respectively.
𝑊𝑎 x100%
%S = (2.17)
𝑊𝑐
100%
%SP = x 𝑊𝑏 (2.18)
Wc x (100 − s)
where, Wa is the weight (g) of soluble
material in the supernatant, Wb is Weight (g)
of the precipitate, s is solubility, and Wc is the
Weight (g) of a starch sample.
2.3.6. Pasting Properties
Pasting involves heat-mediated granular
swelling, the transformation of starch
granules in excess water from an ordered to
disordered state, exudation of the molecular
components, and eventually the total rapture
of the starch granules [27]. RVA
measurement starch and modified starch
flour pasting properties were determined
using a Rapid Visco-Analyzer model (RVA)
with the software program Thermocline for
Windows (TCW) according to AACC
method 61-02 [28]. Each starch sample 3 g
was mixed with 25 L of distilled water in an
RVA sample canister. The idle temperature
was set at 50°C, and the following 12.5-
minute test profile was run: (1) held at 50°C
for 1.0 min, (2) linearly ramped up to 95°C in
3.8 min, (3) held at 95°C for 2.5 min, (4)
linearly ramped down to 50°C in 3.8 min and 2.3.8. X-ray diffraction (XRD) analysis
(5) held at 50°C for 1.4 min. The viscosity is The crystalline and amorphous structures of
either in RVA or arbitrary unit (cP). native and modified potato starch were
2.3.7. Thermal properties revealed using an X-ray diffraction
technique. The scattered intensity of an X-ray
Differential scanning calorimeter (DSC) is
beam hitting a native and modified starch
the thermo analytical technique in which the
sample as a function of incident and scattered
difference in the amount of heat required to
angle, polarization, and wavelength or energy
increase the temperature of the sample and
support these techniques. X-ray diffraction
reference is measured as a function of
analysis of the samples provides information
temperature. Both the sample and the
about the atomic structure of materials and is
reference are maintained at nearly the same
based on the elastic scattering of X-rays from
temperature throughout the experiment.
the electron clouds of the individual atoms
Differential scanning calorimeter (DSC)
within the system. X-ray diffraction (XRD)
analysis was done for native potato starch
was used to determine whether the native and
samples, crosslinked, acetylated and for dual
modified starch nature was crystalline or
crosslinked acetylated potato starch. The
amorphous. The analysis was performed by
Crucible with the sample was set in the
(XRD-7000 X-RayDIFFRACTOMETER,
(SKZ1052B Differential scanning
Japan) using a Cu-Kα (=0.15406 Å) radiation
calorimeter, Germany) with integrated
source operating under a voltage of 40 kV
Synchronous Thermal analyzer software. The
and a current of 30 mA. The diffraction angle
experiment was done at the temperature of
(2θ) varied from 8º to 80º. The X-ray
25–200°C with a heating rate of 10°C/min
diffraction patterns were collected in
under the Nitrogen Gas flow with a flow rate
continuous scan mode at a scan rate of
of 50 cm3/min. Differential Scanning
3℃/min.
Calorimeter (DSC) measurement is the
measure of heat flow pattern of the native and 2.4. Experimental design for starch
modified potato starch which served as a modification process
standard displayed on the monitor attached to To investigate the peak viscosity of
the TA-60 unit of the calorimeter as crosslinked potato starch and acetyl content
described in the analysis of carbon produced of dual crosslinked acetylated potato starch at
from lignocellulose materials.
different operating conditions, one variable at
a time (OVAT) and statistical tools of
response surface methodology (RSM) were
studied. The OVAT results were input in
order to study the interaction effect of process
variables using response surface
methodology followed by box Behnken
design (BBD). Important parameters that
mostly affect the starch modification
parameters were selected, among others, after
surveying different articles. These factors are
solution pH, reaction time, reaction
temperature, concentration of modifying
agent, and concentration of catalyst (NaOH).
In this research work, modification
parametric optimizations of dual crosslinked
acetylated potato starch were investigated to
identify the optimum interaction effect of
parameters on the response. The crosslinked
potato starch was modified by acetylating the
crosslinked starch by acetic anhydride (AA)
for dual crosslinked acetylated potato starch
modification. SHMP were the modifying
agent for crosslinking of potato starch and
AA was the modifying agent of dual
crosslinked acetylated potato starch.
2.4.1. Effect of individual process
parameters (OVAT)
The effect of each parameter on the acetyl
content of dual crosslinked acetylated potato
starch was studied based on one factor-at--at-
a time approach. In this approach, only the
effect of one variable was examined while the
other factors were assumed to be constant.
Starch modification experiments were
conducted to investigate the effect of pH,
concentration of modifying agent, reaction
time, concentration of catalyst (NaOH), and
temperature on the acetyl content of dual
crosslinked acetylated potato starch. The
response of acetyl content was determined
using (Equation 3.5 above).
2.4.1.1. Effect of temperature on acetyl
content
The effect of temperature on acetyl content of
acetylated potato starch was studied at
different temperatures (20, 40, 60, 80, and
100℃) with an acetic anhydride
concentration of 20%w/w, solution pH 8,
reaction time, 55 min, and catalyst (NaOH)
concentration 0.8%w/w. Finally, the
percentage of acetyl content were determined
from the relation mentioned in Equation 3.5
above, so that the sample with the highest
value can be selected as the best condition for
acetylation of potato starch.
2.4.1.2. Effect of reaction time on acetyl
content
The effect of reaction time on the acetyl
content was studied for different values of
time (25, 40, 55, 70, and 85 min) at a constant
value of pH 8, temperature 60℃,
Concentration of acetic anhydride 20 wt.%
and concentration of NaOH 0.8%w/w.
2.4.1.3. Effect of acetic anhydride (AA)
concentration on acetyl content
The effect of acetic anhydride modifying
agent on the acetyl content was studied for
different values of acetic anhydride
concentrations (10, 20, 30, 40, and 50%w/w)
at a constant temperature 60℃, pH 8,
reaction time 55 min and concentration of
catalyst (NaOH) 0.8%w/w.
2.5. Preparation and Evaluation of Tablets
2.5.1. Production of Tablets
The tablet was made by direct compression,
the process by which tablets are compressed
directly from the powdered active drug
substances and modified starch excipient into
a firm compact without employing the
process of granulation. Filler capacity of
native CLPS, APS, and dual modified starch
as per the method described by [29]. Each
modified starch was blended with the active
site of a tablet (paracetamol) in a Turbula
mixer (Willy A. Bachofen AG, Turbula 2TF,
Basel, Switzerland) for 10 min followed by
addition of 0.5% lubricant (magnesium
2.4.1.4. Effect of pH on acetyl content
The effect of pH on acetyl content was
studied for different values of pH (2, 4, 6, 8,
10) at a constant temperature of 60℃,
reaction time 55 min, AA concentration 20
wt.% and concentration of NaOH 0.8 wt.%.
2.4.1.5. Effect of catalyst (NaOH) on
acetyl content
The effect of NaOH catalyst on acetyl content
was studied for different values of NaOH
concentration (0.6, 0.8, 1.2, 1.4, and 1.8
wt.%) at a constant temperature of 60℃,
reaction time 55min, AA concentration 20
wt.% and pH 8.
stearate) further blended for 5 min. Tablets
were compressed in a single punch tablet
press (Korsch EKO, Berlin, Germany), fitted
with 10 mm flat faced punches, at a fixed
compression pressure. Tablets of 500 mg
containing paracetamol (20%, 30%, and 40%
(tablets above 40% loading were more friable
and unable to sustain drug release)),
magnesium stearate and starch powder (5-
10%). Paracetamol was used as the active
ingredient to make a tablet with the
disintegrating agent of modified starch.
Modified starch was used as disintegrant
agent in the production of tablets by direct
compression method.

Table 3.5: Paracetamol tablet formulation by using CLPS, APS, and dual CLPS-APS as a filler
(F1-Formulation)
Ingredients of tablet (%) F1 F2 F3 F4
Paracetamol (%) 52 52 52 32
CLPS (%) 46 - - -
APS (%) - 46 - -
Dual CLPL-APS (%) - - 46 56
Mg Stearate (%) 10 10 10 10
Total (mg) 500 500 500 500

2.5.2. Evaluation of the Formed Tablets 2.5.2.2. Crushing Strength

2.5.2.1. Weight and Thickness Crushing strength of the tablets was

determined with the crushing strength tester
Randomly selected 10 tablets and weighed
individually on an analytical balance, and (Schleuniger, 2E/205, Switzerland). Ten

then the average weight and standard
deviations were calculated. Tablet thickness
was measured using a sliding caliper scale.
tablets were taken randomly from each batch
and the crushing strengths of the tablets were
measured individually and the means and
standard deviations were calculated.

2.5.2.3. Tensile Strength

The diametral compression test was

performed to assess the influence of
compression pressure and composition on the
tablet resistance. The radial tensile strength
was calculated using the data obtained from
the crushing strength, diameter, and thickness
of the tablet.

2F
σ= (2.19)
πDT
Where, σ is the tensile strength, F is the force systems where there is a change in the surface
required to break the tablet, D is the diameter area and diameter of the particles or tablets
of the tablet, and T is the tablet thickness. (Eq. 3.23) [28].

2.5.2.4. Friability Q t = Q 0 − k0 t (2.20)

lnQ t = lnQ 0 − k1t (2.21)

The friability was conducted on ten tablets of
known weight using a friability tester Qt
= kH√t (2.22)
(ERWEKA, TAR 20, Germany). The drum Q0

was rotated at 25 rpm for 4 min. The tablet 3

√Q 0 − 3√Q t = k HCt (2.23)
samples were then removed and dedusted and
reweighed. Loss of tablet weight with respect where k0, k1, kH, and kHC are the release rate

to the initial value was then calculated as constants for the zero-order, first-order,

percent friability. Higuchi, and Hixson-Crowell rate equations,

2.5.2.5. Tablet release kinetics
The mechanism governing drug release
kinetics, the results of the in vitro release
profile were fitted into a number of kinetic
models. The zero-order rates in Equation
3.20 describes systems in which the
medication concentration has no impact on
the drug release rate, which runs at a constant
rate. The first-order model describes the
release from systems where the release rate is
respectively. Q0 is the initial amount of drug
in the tablet, and Qt is the amount of
medication released over time t. Dissolution
data can be further evaluated with the use of
the Korsemeyer- Peppas equation in order to
create a model that will represent a better fit
for the formulation (Eq. 3.24)
Qt
= kt n (2.24)
Q0
𝑄
where, 𝑄𝑡 is the fraction of drug released at
0

concentration dependent and is expected to
decrease exponentially (Eq. 3.21). Higuchi
asserts that the process by which drugs are
liberated from an insoluble matrix depends
on Fickian diffusion and is square root time-
dependent (Eq. 3.22). The Hixson-Crowell
cube root law describes the release from
time t, k is the kinetic constant, and n is the
diffusional exponent. The value of the
exponent can be used to characterize the
mechanism of drug release.
2.5.2.6. Disintegration Time
The disintegration time was calculated using
the United States Pharmacopoeia's

disintegration test for uncoated tablets (USP
30/NF25, 701>, 2007). A disintegration
tester (CALEVA, G.B. Caleva Ltd., UK)
loaded with 0.1 N HCl solution kept at 37℃
as the immersion fluid was used to test six
tablets at a time. When all fragments made it
through the wire mesh, the tablets were
deemed to have fully broken down. Six pills'
average disintegration time and standard
deviation were calculated. The standards of
disintegration time for uncoated tablets were
less than 45 min and for coated tablets less
than 1 h. The disintegration time of uncoated
tablets was carried out through the assemble
apparatus when the device for raising and
lowering the basket-rack assembly is at rest
and its cylinder is in the extreme position and
with 2.5 L of water in the cylindrical jar,
adjust the apparatus until the level of fluid in
the jar coincides approximately with the mid-
line of the upper plastic plate. Then, maintain
the temperature of the fluid at 37 oC by a
suitable means of controlling, remove the
basket-rack assembly from the water, and
disassemble.
2.5.2.7. Disintegration efficiency ratio
(DER)
The disintegration efficiencies (DER) were a
measure of the balance between mechanical
and disintegrant properties of tablets. It was
calculated using the formula given below.
C
( s)
Fr
DER= (2.25)
DT
where: Cs is the crushing strength, Fr is
friability, and DT is the disintegration time.
3. Results and Discussion
3.1. Results
3.1.1.Proximate analysis of raw potato
From the physical and chemical property
analysis of potato starch, it was observed that
potato starch 11.82 ± 0.0025% w/w,
moisture, 0.25±0.0016% w/w crude ash,
0.3±0.0216 % w/w crude protein, 0.17 ±
0.0016% w/w crude fat, and 87.46±0.93%
w/w total starch. The results of very low
contents of protein and fat indicated that the
potato starch was very pure and that the
residual protein had been thoroughly
removed during isolation. The isolated potato
starch contained 30.52 ± 0.47% w/w amylose
and 56.94 ± 0.46% w/w amylopectin. The
yield of the native, cross-linked, acetylated
and dual crosslinked acetylated was in the
range of 25 ± 0.34% w/w, 86.34 ± 0.834%
w/w, 87.63 ± 0.834% w/w and 84.42 ± 0.78%
w/w respectively. According to
Gebremariam’s study for potato, the
proximate composition of the starch on a dry
weight basis was found to be 0.20%w/w ash,
0.05% w/w fat, 0.20%w/w protein, moisture
content 13.5%w/w and 29.3%w/w amylose
starch. In this paper, the proximate potatoes was an insignificant difference.
composition of the starch on a dry weight However, with higher levels of acetylation,
basis was found to be 0.25 ± 0.0016 ash, 0.3 crosslinking, and dual modification (caused
± 0.0216 fat, 0.17± 0.016 protein, 30.52 ± by the combined impact of acetylation and
0.47%w/w and 87.46±0.93% w/w starch. The cross-linking), the density varies. Similar
present research work has almost similar findings have been made in acetylated
results with Gebremariam’s study, but there starches by Gonzalez and Perez [30]. It's
are some differences in the moisture content possible that the mass's compactness is what
and fat content results. The difference might causes the increase in absolute density
be the difference in storage time of raw potato brought on by cross-linking. Absolute
and the presence of retrogradation of starch. density was improved in PUSA-44, which
had a substantially greater amylose
3.1.2. Density of native starch and
concentration [31].
modified starch
The density of native, crosslinked,
acetylated, and dual crosslinked acetylated

Table 3.1. Density of native and modified starch

Potato Starch (PS) Density

Native 1.46
Crosslinked 1.48
Acetylated 1.49
Dual crosslinked-acetylated 1.47

crosslinked acetylated is 5.6. This is because

3.2. Basic Characteristics of Native and
Modified Starch of for acetylation of potato starch
modification, used acetic anhydride as
3.2.1. pH Determination modifying agent which is acid and resulted
The PH value of modified starch is different, the APS acidic. In crosslinked potato starch,
APS is acidic property which is 4.65, CLPS the modifying agent was SHMP, which is a
is near to neutral which is 6.80, and Dual type of salt. After the reaction of SHMP and
starch occur near to the neutral compound
CLPS produced. In the dual crosslinked
acetylated process, the near neutral CLPS
was acetylated with acetic anhydride produce
acidic PH value 5.5 of dual modified potato
starch. This indicates some components of
the acid were neutralized during the
replacement of the crosslinked starch by
acetyl groups.
3.2.2. Analysis of Fourier Transform
Infrared Spectroscopy (FTIR)
In native potato starch (NPS), 3253.2cm
absorption peak were occurred due to the
presence of O-H stretching modes in alcohols
and phenols. The O-H-peaks due
carboxylic acids show a very broad and less
intense peak between 3400 and 3200 cm .
The change in peak shape is a result of the
different degree of hydrogen bonds in alcohol
and carboxylic acids. These peaks change
significantly with the polarity of the solvent.
They usually become sharper if the polarity
of the solvent increases. The 2935.6 cm-1
absorption peak indicates C-H stretching,
which shows the presence of alkane and sp 3
hybridized compounds. The 1637.2 cm -1
indicates that there were carbonyl functional
groups and C=O stretching in the starch
molecule. The peak absorption 1353 cm -1
shows the presence of C-O-C function of
ethers and esters. The absorption band around
995.1 cm-1 indicates the C-O functional
group. The graph of FTIR can help to
determine the starch whether modified or not
by observing the IR absorption peak of the
sample. The characteristic IR absorption
peaks of CLPS are observed at 3288 cm-1
due to –O–H stretching vibrations, and the
intense absorption peak that occurred at
2931.3 cm-1 was presumably originated from
the stretching vibrations of the –C-H group.
Another characteristic absorption band due to
-1
–C=C stretching vibrations in the medium
appearance of the aromatic ring was
presented at 1639.2 cm -1. The characteristic
to
absorption band occurred due to the –C–H
stretching were shown at 1149.4 originated
-1
from the stretching vibrations of –P=O-
group. The absorption band of 991.3 cm -1
was presented the stretching of C-O
functional group.
The characteristic IR absorption peak APS
was observed at 3318.9 cm -1 due to –O–H
stretching vibrations, and the intense
absorption peak occurred at 2931.3 cm -1 due
to stretching weak –O–H. Another
characteristic absorption band due to –C=O
stretching vibrations in the medium
appearance of the aromatic ring was
presented at 1153.2 cm -1. The 991 and 574
cm-1 were another absorption band of FTIR
results in APS grouped in –S=O and –C-H
stretching, respectively. In this study, FTIR
data tell as native starch modified or not, in
CLPS of FTIR data 1149.4 cm -1 stretching
vibration tell as there was cross-linking of the
native starch with phosphorus content
compound, so the starch hydroxyl functional
group can replace by SHMP functional group
and in APS of FTIR data 1153.2 cm -1
stretching vibration which shows that native
starch hydroxyl group replace by –C=O
functional group of acetic anhydrides this
implies that starch was acetylated. The
process of acetylation was happened when
hydroxyl groups were replaced by acetyl.

1639.2 757.2
1365.4 1149.4
2921.6 516.2
3288.09
991.3
Transmittance(a.u)

1153.2 769 574

2931.3
3318.9 1710.7
1359.2 991
2921.7 1143.6 759.8

3311.2
520.7

2935.6
APS 1637.2
1353
993 854
CLPS 1153.2
3253.2 DCL-AC
574.6
NPS
995.1

4000 3500 3000 2500 2000 1500 1000 500

Wave number (cm-1)

Figure 3.1: FTIR characterization of native (NPS), crosslinked (CLPS), acetylated (APS), and
dual crosslinked acetylated (DCL-AC) potato starch
In the dual crosslinked acetylated 3.2.3. Determination of Starch Hydration
modification, the crosslinked potato starch Capacity
was substituted by the acetate group. The The hydration capacity of native potato
characteristic IR absorption was observed at
starch (NPS), crosslinked potato starch
-1
3311.2 cm due to alcohol -O-H stretch (CLPS), acetylated potato starch (APS), and
stretching vibration. This occurs due to the dual crosslinked acetylated potato starch
replacement of hydroxyl groups by acetyl
(DCL-AC)was 1.68±0.38%, 2.39±1.476%,
-1
groups. The absorption peak at 2921.7 cm
2.7±0.54%, and 2.55±1.03% by using
was indicated weak -C-H stretching in the
figure 3.2. The starch hydration capacity
chain when the acetate group goes to replace
become increased when starch-modified. In
the crosslinked potato starch by SHMP.
this research work, the hydration of NS was
Another absorption peak was occurred at
the lowest of those three modifications.
-1
1359.2 cm which represent medium -CH3
When comparing the hydration capacity of
on the chain of crosslinked starch. The
CLPS, APS and DCL-AC, APS had more
-1
absorption peak was also shown at 993 cm
potential to hold water. This is because the
that present C-4-OH stretching of the glucose
acetic anhydride is more corrosive than other
residues of disaccharides. The absorption
modifying agents and then APS was holding
peak was shown at 759.8 cm -1 indicate cis
more water than others. The dual crosslinked
=C-H out of plane bending. This explains
acetylated potato starch was balanced, with
step-wise preparation of binding sites for
the strong hydration capacity of acetylation
replacing the phosphate groups containing
and the mechanical strengthen effect of
crosslinked starch by acetyl groups.
crosslinked potato starch.
 4.0

3.5

Hydration capacity (%)

3.0

2.5

2.0

1.5

1.0

0.5

0.0
NPS CLPS APS DCLAC
Starch types

Figure 3.2: Hydration capacity of native and modified starch

3.2.4. Swelling Power and Solubility

Determination

Figure 3.3: Effect of temperature on solubility and swelling power of starch

Time Effect on Swelling Power and Solubility
As expected, the swelling power and dual crosslinked acetylated potato starch was
solubility of the starches increased with time. found to increase considerably from 9.5 – 23,
Solubility of cross-linked, acetylated and 15 – 29 and 11-26.5 as well as swelling power
also increasing from 2 – 3.1, 1.6– 3 and 1.7- when the time increase. Acetylated starch
3. From these results, both solubility and was contained the most soluble and swelling
swelling increased in acetylated, cross-linked power.
and dual crosslinked acetylated potato starch

Figure 3.4: Effect of time on solubility and swelling power of starch

Concentration Effect on Swelling Power and Solubility

The solubility and swelling power of cross-
linked and acetylated potato starch at a
concentration ranging between 10 and
50%wt. As expected, the swelling power and
solubility of the starches increased with
concentration. Solubility of cross-linked,
acetylated and dual crosslinked acetylated
potato starch was found to increase
considerably from 40 – 62, 45 – 61, and 21-
60 as well as swelling power also increasing
from 0.7 -1.8, 4.5 – 20 and 2.3-9. From these
results, both solubility and swelling increased
in acetylated, cross-linked and dual
crosslinked acetylated potato starch when the
concentration increase. Acetylated starch was
more solubility and swelling power value
than cross-linked starch.
 Figure 3.5: Concentration of AA effect on solubility and swelling power of starch
3.2.5. Pasting Properties
The pasting properties of native, crosslinked,
acetylated, and dual crosslinked acetylated
potato starch were analyzed by using a rapid
visco analyzer. For the native potato starch,
the time and temperature of gelatinization
start was 2.7 min and 71.9°C; the peak
viscosity was 11610 cP, at 95.5°C, reached at
approximately 3.33 min, with this being a big
opposing force of the potato starch paste,
which corroborates the thickening sample
capacity. The RVA viscosity characteristics
of native and modified starches were shown.
The crosslinked potato starches’
gelatinization temperature and time were
started at 2.9 minutes and 73.5°C. The peak
viscosity, final viscosity, peak time were
6189 cP, 9570 cP, and 6.4 min.
The potato starch was cross-linked with
modifying agent concentration of sodium
hexametaphosphate (SHMP) (10, 20, 30%)
showing an increase in the final viscosity.
The gelatinization temperature and time of
acetylated potato starch were started at
71.9℃- and 2.7-min. Peak viscosity and peak
time were also 1413cP and 4.67min. The
gelatinization temperature and time of dual
crosslinked acetylated potato starch were
started at 72.6℃ and 2.85 min. The setback
was related to the rate of retrogradation, in
this study the starch cross-linked at a lower
concentration of SHMP was found to be
higher. Cross-linking of molecular chains
makes the starch granules more ordered and
consequently more energy would be required
for swelling [33]. After dual modification of
cross-linked acetylated, due to the
introduction of carboxyl functional groups,
the setback value decreased significantly
compared to native and cross-linked potato retrogradation rate and an increase in
starch. The starch granules will be gelatinization temperature. These
strengthened through cross-linking to make phenomena are connected to the amorphous
them more resistant to acidic media, heat, and chains' decreased mobility as a result of
shearing [33]. According to the study, cross- intermolecular bridges in the starch granule
linked starch results in a decrease in [34].

Table 3.2: Pasting properties of native, crosslinked, acetylated, and dual crosslinked-acetylated
potato starch

Peak Final Set

Samples viscosity Break Trough viscosity back Pasting Peak

down temp. time

(cP) (cP) (cP) (cP) (cP) (℃) (min)

NPS 11610 10200 1410 3195 1785 71.9 3.33

CLPS 6189 3618 2571 9570 6999 73.5 6.4
APS 1413 460 953 1345 392 71.9 4.67
DCLAC 1440 262 1178 2002 824 72.6 6.73

The plot of pasting property was generated by rapid visco analyzer (RVA) measurement given
below.
The dual-modified starch swelled more modified starch underwent more
slowly and started at a higher temperature rearrangement during the cooling step than
than the native starch, which swelled quickly. its native counterpart. This pattern was
The crosslinking is responsible for the dual- connected to the dual-modified starch's
modified potato starch's limited swelling. higher shear rate and the restructuring of the
Since acetylation lessens the starch's starch chains that are formed at higher levels
hydrophilicity, water diffusion through the during heating.
starch granules starts more slowly. When creating filmogenic solutions, the
Crosslinking and acetylation decreased the pasting profile of dual-modified potato starch
diffusion of water into the starch granules' is crucial. It is clear that the dual modification
centers, resulting in a reduction in the creates a structure that is susceptible to
granules' disintegration. However, the dual- disruption by heating and shearing, resulting
in linear chains that are arranged to create a
viscous paste. The pasting temperature of
crosslinked potato starch was slightly higher
than the others. This was because of
strengthening the bonding between starch
chains through cross-links might
have increased the resistance of the granules
to swelling leading to higher transition
temperature of gelatinization. The native
potato starch was achieved the highest peak
viscosity; this is because the modified starch
exhibited improved water absorption
capacity and water solubility index.
3.2.6.Thermal properties (DSC)
The thermal analysis of native, crosslinked,
acetylated and dual crosslinked acetylated
potato starch was shown in figure 3.7. The
onset temperature (To), peak temperature
(Tp)and conclusion temperature (Tc) of native
potato starch was 48.5℃, 78℃ and 108℃.
The gelatinization of native potato starch was
started at the onset temperature. The peak
temperature (melting) of native potato starch
was the highest, because the molecules of
native potato starch have a higher tendency
towards water hydration. The onset
temperature, peak temperature, and
conclusion temperature of crosslinked potato
starch was 50, 80.9, and 110℃. The cross-
linking with SHMP did not change the onset
and peak temperatures significantly, whereas
the conclusion temperature and enthalpy
increased with increasing degree of cross-
linking [23]. The effects of cross-linking on
starch's thermal transition properties vary
depending on the cross-linking agent's
concentration and type, the reaction
environment, and the starch's botanical
source [33].
The onset temperature, peak temperature,
and conclusion temperature of acetylated
potato starch was 68, 78.3, and 104.5℃.
These characteristics were decreased by
acetylation, which weakened the starch. After
derivatization, the gelatinizationtemperatures
were lowered, which caused the starch
molecules' intragranular and intergranular
binding forces to diminish. Enthalpy of
gelatinization measures crystallinity
generally and serves as a sign of lost
molecular order [35]. The drop in ΔHg
indicates that the acetyl group disturbs the
double helices in the granule's amorphous
region. Additionally, adding bulky groups to
the biopolymer's backbone makes it more
flexible structurally, which lowers the
gelatinization temperature of the modified
starch. Less crystals following alteration are
consistent with a decrease in temperature
parameters, with a cooperative melting
process aided by more swelling. The onset
temperature, peak temperature, and
conclusion temperature of dual crosslinked [37]. Lower ΔH values mean that the double-
acetylated potato starch was 48.5, 79.5, and helical structures can be broken apart with
105℃. The crosslinking strengthened the less energy. ΔH and the relative crystallinity
crystalline structure of starch granules, of starch granules are positively correlated.
making the crystallites more difficult to melt. The percentage of ordered structure and the
The substitution with acetyl or stability of the crystalline regions are often
hydroxypropyl groups weakens the hydrogen lower in starch samples with lower ΔH values
bonds between starch chains and facilitates [38]. The gelatinization temperatures are a
water penetration and absorption into the measure of the perfection of starch
starch granules, thereby increasing the initial crystallites. In figure 3.7, the peak
rate of plasticization of the amorphous temperature is the highest due to native
regions [36]. The gelatinization temperature potato starches’ hydrophilic nature. The
range (Tc-To) represents changes in the findings of this study are similarly in
double-helical structures' interlaced starch agreement with earlier studies' findings that
chains' types, size of their crystallites, degree gelatinization temperature falls as
of crystal perfection, and crystalline shapes substitution rises [36].

Figure 3.7: DSC analysis of native, crosslinked, acetylated, and dual crosslinked-acetylated
potato starch
In the region between onset temperature (To)
and the conclusion temperature (Tc), a phase
transition from crystalline structure in to
amorphous structure occurred. At To the
crystalline form of native starch was began
melting and when reached Tp the final
melting process end. From the onset
temperature to peak temperature the
endothermic process was occurred and when
reached peak temperature, the final melting
(amorphous structure occurred) ended [39].
After peak temperature, the melted molecules
were started to regain their crystalline
structure. At the conclusion temperature, the
final structure of the starch molecules was
accomplished. In general, dual crosslinked
acetylated potato starch was compensated the
drawbacks of each modification mechanism.
The dual modified potato starch indicated the
broadened gelatinization temperature range
and ΔHgel, due to the strengthening effect by
crosslinking and hydrogen bond breakage by
acetylation leads to a counter balance
between crosslinking amylopectin and
substitution by acetyl groups [23]. This
conforms with other previously done findings
[31] . The increment in peak gelatinization
temperature of the dual crosslinked
acetylated potato starch increases the
application range of native potato starch.
3.2.7. X-ray diffraction (XRD) analysis
of native and modified starch
Starches are categorized into the A-, B-, and
C-types based on the structural arrangement
of lamellae [40]. The orthorhombic and
hexagonal unit cells of the A- and B-types of
amylopectin, respectively, differ from each
other despite having the same helix shape
[41]. Potato starch contains B-type structural
arrangement [40]. The crystallinity of the
native potato starch was enhanced as
revealed by the increase in the peak height as
well as width at 2θ values around 5.78°,
15.2°, 17.3°, 17.36°, 22.48°, 26.86°, as
shown figure 3.8 A. The native starch
diffractogram showed a prominent
diffraction peak at 2θ =17.36° and a few
minor peaks at (34.6°, 63.86° and 75.94°).
This crystal form matched the B-type starch
that may be found in potatoes and other root
plants [19]. Both the very strong peak at 2θ
=17.36° and the minor peak at 2θ >26.86°, for
0<= θ<=80° occurred in the x-ray diffraction
pattern of native potato starch. In native
potato starch x-ray diffraction studies,
intermolecular association occurs through a
recrystallization process. The amylopectin in
the amylose-amylopectin-water system can
be thought of as a precipitating agent that
helps the amylose aggregate [42].
Crystalline structure of acetylated starch. The
authors failed to specify whether the
amorphous regions were amorphous lamellae
inside the amylopectin molecule or the gaps
between blocklets [44]. Based on the X-ray
diffraction pattern, the dual modification
(crosslinked acetylated)
affected the way the double helices of the
amylopectin chains were arranged (Figure
3.8), and the crystallinity level (CL) reduced
from 23.6% for native starch to 18.4% for
dual-modified potato starch [39]. The
diffraction peaks
acetylated potato starch were occurred on
15.52°, 27.96°, 33.62°, 50.92°, 69.04° and
76.8°. The highest diffraction peak of the
dual modified potato starch was 17.28°,
which is similar to native potato starch. At the
lower values of 2θ, the dual modified potato
starch had the least peaks until it reached the
potato starch maximum diffraction peak. This is because
treating starch with multipurpose chemicals
that can create ether or ester links between the
hydroxyl groups of the starch molecules,
crosslinking reactions produce intra- and
intermolecular covalent bonds in sporadic
of dual crosslinked locations across the starch chains and
stabilize the granules [39].

17.16
17.36

17.3
NPS 15.16
21.68
24.1 CLPS
15.2
Intensity (a.u)

Intensity (a.u)

20.04 22.48
25.84
24.18 33.46
12.18
5.78 26.86 10.74
34.6 49.56

53.28
42.94
57.52
61.64
5.5 71.64 76.32

63.86 75.94

10 20 30 40 50 60 70 80 10 20 30 40 50 60 70 80

2Ɵ (Degree) 2Ɵ (Degree)
 17.28
17.2

22.1
22.22
19.6
APS 15.52
15.3 23.96 DCL-AC
Intensity (a.u)

Intensity (a.u)
13.38 23.96
33.62
11.64 34.82 35.64
30.8
37.8 40.94
10.5 43.08
44.36
48.24 50.92

5.76 54.34

65.7 68.66 61.54 69.04

76.8

10 20 30 40 50 60 70 80
10 20 30 40 50 60 70 80
2Ɵ (Degree)
2Ɵ (Degree)

Figure 3.8.: XRD analysis of native, crosslinked, acetylated and dual-crosslinked acetylated
potato starch

3.3. Starch Modification Experiment and Effect of individual process parameters

3.3.1. Effect of reaction temperature on acetyl content

The percentage of acetyl content of dual the percentage of acetyl content were
crosslinked acetylated potato starch with decreased, this shows the starch molecules
elevated solution temperature as shown in were gelatinized due to acetylation reaction.
Figure 3.9 below. The percentage of acetyl This study fit with previous researches,
content of dual modified potato starch were because the main reasons of starch
increased from 1.2% to 1.81% when the modification by acetylation were to minimize
temperature was increased from 20℃ to the gelatinization temperature [47]. When
60℃, due to the increment of rate constant gelatinization temperature begins, the
for esterification reaction by exothermic percentage of acetylation decreases, due to
reaction [23]. After, 60℃ temperature and the lack of active sites for the reaction occurs.
 Figure 3.9: Effect of temperature on acetyl content
3.3.2. Effect of reaction time on acetyl content
The percentage of acetyl content of dual
crosslinked acetylated potato starch with
elevating reaction time as shown in Figure
3.10 below. The percentage of acetyl content
of dual modified potato starch were increased
from 1.18% to 1.8% when the time was
increased from 25 min to 55 min and
continued almost constant in an increasing
manner due to the increment of replacement
of hydroxyl group by acetyl group. After, 55
min of reaction time, the percentage of acetyl
content increase in the slow process due to
the formation of more reacted complexes
over time. When acetylation occurs, time has
a considerable impact on the conversion of
the OH- group to the CH3CO- group. This is
anticipated because more CH3CO- groups
will gradually replace OH- groups over time
[48]. When the duration of the reaction
increased above the prescribed value, the
percentage of acetyl content approaches to
slow and constant value [49].
 Figure 3.10: Effect of reaction time on acetyl content
anhydride concentration rises within the
3.3.3. Effect of Acetic anhydride (AA)
study range, the acetyl percent rises. This
concentration on acetyl content
could be explained by an increased
The effects of acetic anhydride (modifying availability of acetic anhydride molecules
agent) concentration on acetyl content of dual near the starch molecules at higher
crosslinked acetylated potato starch were esterifying agent concentrations. Since the
directly related. As the concentration of starch hydroxyls are known to be immobile,
acetic anhydride concentration increases the presence of acetic anhydride molecules
from 10 %wt. to 50%wt., the acetyl content close to the hydroxyl groups were necessary
of dual modified increases from 1.55% to 1.8 for the reaction to occur [49].
as shown in figure 3.11 below. As acetic
 Figure 3.11: Effect of AA concentration on acetyl content
3.3.4. Effect of pH on acetyl content
The acetyl content of dual crosslinked
acetylated potato starch was insignificant as
compared to other factors like reaction
temperature, reaction time, and concentration
of modifying agent. As the pH of the starch
solution increases from 2 to 10, the acetyl
content of the dual crosslinked acetylated
potato starch was continued with a small
variation decrement from 1.66% to 1.65%
and then begun to increase 1.67% to 1.673%.
This indicates the increment of pH affects the
acetyl content with small deviations. For
Figure 3.12: Effect of pH on acetyl content
3.3.5. Effect of catalyst (NaOH)
concentration on acetyl content
The effects of NaOH concentration on acetyl
content of dual crosslinked acetylated potato
starch were insignificant as shown in Figure
every 1 deviation in pH, the acetyl content
resulted in in less than 0.003%, which is an
insignificant effect as shown figure 3.12
below. The insignificant effects of pH in the
dual crosslinked acetylated potato starch
occurred due to insufficient activation of the
hydroxyl groups of starch by nucleophilic
attack of the anhydride moieties [50]. Thus,
based on its insignificant effect on the
response (acetyl content) and literature of
previous researches, the pH was not
considered in the optimization.
3.13. In dual crosslinked acetylated, the
molecules of starch were first held by the
crosslinking agents of SHMP, which
strengthen the bond in the starch. When the
crosslinked potato starch was acetylated with
acetic anhydride replacement of the acetylated potato starch insignificantly
crosslinked phosphate groups by acetyl increases from 1.7%wt. to 1.72%wt, which
group, which results in the increment of the indicates a slight effect on the response. As
amorphous region. Thus, the negative effect indicated in figure 3.8, the NaOH
of crosslinked was compensated by concentration was not significantly affecting
acetylation. When the concentration of the response acetyl content and in literature
NaOH increases from 0.6%wt. to 1.4%wt., the effect of this parameter was not included
the acetyl content of the dual crosslinked in the optimization.

Figure 3.13: Effect of NaOH concentration on acetyl content

3.3.6. Estimation of combined effects of
the factors
The Central composite design is used to
determine the significant effects of the
process
parameters (reaction temperature, reaction
time, and concentration of modifying agent)
on the removal efficiency of methylene blue.
By making the other variables constant, the
effect of interaction of two variables at a time
on the responses was investigated and
presented using contour and 3D response
surface plots.
3.3.6.1. Interaction effect of reaction
temperature and time
Figure 3.16A illustrates the 3D plot of the
interaction effect of reaction temperature and
reaction time at a constant initial
concentration of the modifying agent (20%).
The acetyl content (%) gets increased with
the increase in reaction time, and the acetyl
content (%) of dual crosslinked-acetylated the coefficient of 0.0275, which is very low.
potato starch, becomes decreased with It also has a significant effect on the removal
increasing in reaction temperature. From the efficiency as shown in (Table 3.5) with p-
coded equation 4.1 above, the combined value of greater than 0.0001, which is 0.0241.
effect of reaction temperature and reaction The combined effects of those two
time affects the acetyl content positively with parameters were almost insignificant.

Figure 3.15: Response surface 3D plot of interaction effects, (A) (temperature and time), (B)
(temperature and concentration), and (C) (time and concentration)
3.3.6.2. Interaction effect of temperature and concentration of modifying agent
As shown in Figure 3.16B, it illustrates the
3D plot of the interaction effect of reaction
temperature and concentration of modifying
agent at a constant time (55 min). The
response acetyl content (%) increases at some
prescribed points, when the concentration of
the modifying agent increases. But, the acetyl
content (%) increased at some point and
decreased when the temperature increased.
The interactive effect of temperature and
concentration increases up to some point
3.3.6.3. Interaction effect of reaction time and concentration of modifying agent
The interaction effect of reaction time and
concentration of modifying agent (AA) on
acetyl content increase the percentage of
acetyl content of dual crosslinked acetylated
potato starch up to the desired point. As
shown Figure 3.16C, as time increases, the
percentage of acetyl content increases,
because as the duration of the reaction is
increased, consuming much number of
reactants [23]. Whereas the concentration of
modifying agent (AA) increased, the
percentage of acetyl content increases up to
some desired point. This result is also
supported by the ANOVA result which
showed that the interaction of concentration
and reaction time has an insignificant effect
on the acetyl content with a p-value of not
less than 0.0001 (Table 3.7).
(optimum region) and then decreased. This is
due to the inactivation of starch molecules at
high temperature and the starch complex
formed as the concentration of the modifying
agent increases. In equation 4.1 above,
coefficient of interaction effect was -0.025,
which indicates their interactive effect on
acetyl content was negative. The interactive
effect resulted in the reduction of acetyl
content.
3.4. Formulation of Tablets
The tablets were formed by a direct
compressor, which contains the active
ingredient (Paracetamol 50%w/w), modified
starch (10%w/w), lubricants (10%) and other
ingredients. In this research work, tablets
were made from native and modified starch
(for crosslinked potato starch at temperature
60℃, time 55 min and crosslinking agent
sodium hexametaphosphate 20%wt; for
acetylated potato starch at temperature 60℃,
time 55 min and concentration of modifying
agent acetic anhydride 20%w/w; for dual
crosslinked-acetylated potato starch at
optimized modification parameters,
temperature 40.2℃, time 69.85 min and
concentration of modifying agent acetic
anhydride 21.924%w/w). The tablet that
contains APS needed more lubricant as a
result of the side of the tablet stack on the
compressor. When the tablet containing
CLPS was relatively smooth, side of the
tablet. But, dual crosslinked acetylated potato
starch improved the stacking pattern of APS
and reduced the viscosity of CLPS, which
makes the tablet sustained release of active
ingredients. On the other hand APS moisture
content is higher than CLPS and dual
crosslinked acetylated potato starch one sit’s
difficult to compressor until all moisture out
from the surface [23]. When compare the
density of APS denser than CLPS and dual
crosslinked acetylated potato starch. So, the
3.4.1. Basic Characteristics of Tablet
Weight, Tensile Strength, Crushing, Strength, and Thickness
As shown in Tables 3.10 and 3.11, the tablets
containing the dual crosslinked acetylated
potato starch weight, tensile strength, and
Table 3.10: Characteristics of the tablet of dual crosslinked acetylated potato starch
tablet that contains APS is easy to form a
more compact tablet as a result of the volume
of APS is lower than CLPS. To get the more
compact tablet, the density should be large
with a small volume. The cross-linking and
acetylation improved the bonding observed
during tableting. Improved bonding due to
cross-linking and acetylation led to increased
compaction which in effect resulted in higher
crushing strength. The degree of substitution
of CLS by acetate functional groups was
found to greatly modulate drug release, and
the dual modified starch was able to make the
tablet easily disintegrate for sustained release
application.
crushing strength were investigated to know
more about the behavior of the tablet.
 Tensile
Crushing strength
Run Weight(g) Thickness(mm) Diameter(mm) strength(N) (10^6)
1 0.445 5 9.8 63 0.82
2 0.454 5 9.83 62 0.8
3 0.465 5 9.7 73 0.93
4 0.445 5 9.8 62 0.72
5 0.4425 5 9.88 70 0.88
6 0.48 5 9.85 62 0.84
7 0.456 5 9.78 70 0.93
8 0.465 5 9.83 65 0.85
9 0.453 5 9.87 63 0.86
10 0.467 5 9.8 68 0.89

compaction than the native form, resulting in

3.4.2. Friability of tablets
Tablets made from APSs exhibited lower
friability than those tablets made from CLPS.
The loss in total weight of the tablets made
from APS due to friability was 0.46% but
those tablets made from CLASs ly in the
range of 0.73% in the formulations. Their
friability values were less than 1%, which
ensures that the formulated tablets were
mechanically stable. However, the friability
of native starch was 0.9%. Both CLPS and
APS were friability less than 1%, but NS had
corresponding friability values near to 1%,
and they did not advisable to use for the
pharmaceutical requirements [51]. The cross-
linked starches showed improved
higher crushing forces. It has been indicated
that crosslinking mainly occurs in
amylopectin. Therefore, the reinforcement of
amylopectin may lead to stronger (closer)
packing within the crystalline regions. Thus,
tablets from cross-linked starch would likely
have stronger packing than the native form.
However, cross-linking alone cannot increase
the crushing strength of the tablets since the
amorphous regions still disrupt crystalline
packing [52]. The table also displays an
increased crushing force in tablets prepared
from SAs. According to the literature, the
acetate moiety is found to be a very effective
bond forming substituent.
In general, an increase in tablet hardness
results in lower friability values and longer
disintegration times [54]. Conventional
compressed tablets that lose less than 1% of
their weight during the friability test are
generally considered acceptable.
3.4.3.Tablet release kinetics
Quantitative comparison of dissolution
profiles can be carried out using model-
dependent and model-independent methods.
The model-dependent methods rely on
selecting the proper mathematical model and
comparing the goodness of fit and changes in
fitted parameters. Model-independent
approaches provide a direct comparison of a
test profile with a reference profile, without
transforming to another mathematical
expression [55]. The drug release data
obtained were subjected to different drug
release models in order to establish the drug
release mechanisms and kinetics (Fig. 4.13).
The release data were treated according to
zero-order, first-order, Highuchi’s, and
Hixson-Crowell cube root law models.
 Figure 3.16: The release data from the different formulations fitted to various release kinetic
models; zero-order (A), first-order (B), Higuchi (C), Hixson-Crowell (D) and Korsmeyer-Peppas
(E) models.
important to form a gel with good physical
3.4.4. Disintegration time of tablets
stability. The introduction of substituent
The disintegration time of native starch was groups to starch chains improves their water
the smallest of the other modified starch holding capacity, probably leading to the
disintegrant tablets due to the existence of formation of a better matrix, which leads to
increased number of -OH groups [56]. That - the highest disintegration time [52].
OH groups can facilitate the disintegration Acetylated potato starch (APS) tablets had e
time as like dissolve-s like principle. The hydrophobic character and holds much water.
CLPS could not absorb enough water to APS tablets were holding up much water to
hydrate the polymer matrix, which is disintegrate tablet in swelling mechanism,
but until swelling reached the disintegration acetylated modification the most selective for
time were increase. The dual crosslinked disintegrant in tablet formation [58].
acetylated potato starch tablet was containing
3.4.5. Disintegration efficiency ratio
both APS and CLPS characteristics in
(DER)
compensation of each negation. The
The Disintegration efficiency ratios (DER)
disintegration times were increased until the
were a measure of the balance between
strengthening mechanism of crosslinking
mechanical and disintegrant properties of
effect balanced by swelling.
tablets. The DER was investigated by the
The dual crosslinked acetylated potato starch
ratio of crushing strength to the product of
disintegrant tablets were contained the
friability and disintegration time. The DERS
significant performance in mechanical
of the native potato starch tablet were the
strength for processing condition and ability
highest due to its smallest disintegration time.
in the formation of flow of particles inside the
The DER of the crosslinked potato starch
compressive areas of starch acetates [57].
(CLPS) tablet was the smallest due to its
The modification in mechanical strength for
highest mechanical strength effect when
processing and fluid flowability inside the
crosslinked with starch constituents.
molecule can make the dual crosslinked
 Figure 3.17: variation of disintegration time (A), friability (B), crushing strength, and
disintegration efficiency ratio, DER (D) of native and modified potato starch.

4. Conclusion
The potato starch modification by protein and fat indicated that the potato starch
crosslinking enhanced the native starch was very pure and that the residual protein
tensile strength, the absence of erosion, the had been thoroughly removed during
limited swelling, and the fact that increasing isolation.
cross-linking degrees resulted in increased
The XRD result shows that the native,
water uptake rate, drug release rate and
crosslinked, dual crosslinked-acetylated
equilibrium swelling and acetylation of the
potato starch has highly crystalline and
crosslinked starch increase swelling, clear
somewhat amorphous structures. The region
paste and increase resistance to
that contains amylose indicates amorphous
retrogradation. In this research, those two
and the region that contains amylopectin
mechanisms of starch modification were used
shows crystalline. The FTIR absorption
dually in step wise to compensate the
spectrums of native, crosslinked, acetylated,
negative effect of each other for tablet
and dual crosslinked-acetylated potato starch
excipient application. The potato starch
show the presence of different functional
contained 11.82 ± 0.0025% w/w moisture,
groups on their surface. The thermal
0.25 ± 0.0016%w/w crude ash, 0.3 ±
properties of native, crosslinked, acetylated,
0.0216%w/w crude protein, 0.17 ± 0.0016%
and dual crosslinked acetylated potato starch
w/w crude fat, and 87.46 ± 0.93% w/w total
were analyzed by DSC curve, which shows
starch. The results of very low contents of
an endothermic due to the evaporation of
water molecules and the exothermic peak is
due to the decomposition of
components. The pasting properties of native,
crosslinked, acetylated, and dual crosslinked
acetylated potato starch were analyzed by
Rapid visco analyzer (RVA). The RVA
curves indicated the flowability of starch
molecules when they form paste.
The preliminary experiment was performed
in the dual crosslinked acetylated potato
starch modification system in order to
investigate the effect of individual
parameters on the percentage of acetyl
content with different reaction temperature,
20, 40, 60, 80 and 100℃, reaction time 25,
40, 55, 70 and 85min, concentration of
modifying agent (AA) 10, 20, 30.40 and 50
%w/w, starch suspension pH 2, 4, 6,8 and 10,
and concentration of NaOH catalyst 0.6, 0.8,
1, 1.2 and 1.4%w/w of starch was contained
five levels of each factor. The pH of starch
Acknowledgements
This research was funded by Addis Ababa
Science and Technology University. The
authors would like to forward
admiration and thanks to
suspension and concentration of NaOH
catalyst were ignored in the selection of
starch parameters for optimization, due to their
insignificant effect on the response of acetyl
content (%) and literature studies. The three
levels of each three-process parameter,
reaction temperature, reaction time, and
concentration of modifying agent (AA) were
selected based on the highest percentage of
acetyl content from the preliminary starch
modification experiment, for optimization
using RSM BBD. The analysis of variance
(ANOVA) depicted that the quadratic model
was suitable for the responses and 3D surface
plots were used to determine the interaction
effects of the main factors. From the
experimental results, a maximum acetyl
content of 1.32 ± 0.077% w/w was obtained
at the optimum condition of reaction
temperature (40.2164℃), reaction time
(69.8462 min) and concentration of
modifying agent acetic anhydride (AA)
(21.924%w/w
Pharmaceutical Factory and Addis Ababa
Science and Technology University for
their sponsoring this study.
Cadila
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