1. Research Article
Carboxymethyl Starch Excipients for Drug Chronodelivery
Pompilia Ispas-Szabo,1
Patrick De Koninck,1
Carmen Calinescu,1
and Mircea Alexandru Mateescu1,2
Received 27 June 2016; accepted 12 September 2016
Abstract. Carboxymethyl starch (CMS) is a pH-responsive excipient exhibiting also
interesting properties for applications in delayed drug delivery systems. This work was aimed
to investigate the release properties of monolithic and dry-coated tablets based on ionic
sodium CMS and on protonated CMS, formulated with three model tracers: acetaminophen,
acetylsalicylic acid (ASA), and sodium diclofenac. The sodium or protonated CMS were
obtained from the same CMS synthesis by controlling the final pH of reaction media. The
two forms of CMS were confirmed by the Fourier transform infrared spectroscopy. The
in vitro dissolution profiles for monolithic and double core tablets were different and allowed
a better understanding of characteristics of the two excipient forms. It was found that the
protonated CMS exhibited a better stability in simulated gastric fluid in comparison to its
sodium salt in monolithic dosage forms, whereas both excipients afforded a complete gastric
protection of drugs when formulated as dry-coated dosages. Determination of water uptake
and erosion rate of monolithic matrices based on the two CMS forms showed different
mechanisms involved in the delivery of the three model active molecules in simulated
intestinal media. When pancreatic enzymes were added in dissolution media, the drug release
was accelerated showing that CMS is still a substrate for alpha-amylase. Both sodium and
protonated starch excipients, formulated as dry-coated dosages, afforded a good gastro-
protection and allowed a drug chronodelivery at various intervals up to 4–5 h. They could be
considered as an alternative for delayed delivery and a solvent-free coating procedure.
KEY WORDS: chronodelivery; drug delivery; dry-coating; pH-responsive; starch derivatives.
INTRODUCTION
Many studies are presently dedicated to orally adminis-
trated active agents targeted to a specific segment of gastro-
intestinal tract (1, 2). Various polymer coatings having func-
tional properties are used for gastric protection, and a large
number of applications are associated to a pH or time-
dependent delayed drug release (3, 4). Starch is a well-known
excipient in the pharmaceutical formulations, and usually, it is
used as filler, binder, or disintegrant (5, 6). It was previously
shown that physical and chemical modifications of starch have
an impact on its morphology, and the behavior of starch
excipients could be tailored via these procedures (7, 8). Thus,
the kinetics of dissolution and the mechanisms that govern the
drug release from a matrix based on a starch derivative can be
adjusted by tailoring factors that contribute to gel formation, gel
network structure, swelling, and matrix erosion (9). The physical
and structural properties of the polymer itself, the interactions
between the polymeric chains or between the polymer chains
and the dissolution medium can also explain the properties of a
polymeric matrix (10, 11). By chemical modification of starch
(i.e., etherification and esterification), anionic or cationic
derivatives can be obtained, generating Bintelligent^ polymers
able to respond to pH changes. Differently, to metacrylate
coatings that can provide pH functionality but do not have
swelling characteristics, the proposed carboxymethyl starch
(CMS) is able to bring together properties of a hydrogel and
of an enteric coating in a unique material. These conventional
pH-dependent polymers (i.e., Eudragit L and hydroxyprolyl
methyl cellulose phatalate) are largely used in the industry as
enteric coatings, they cannot be used for tablet preparation by
direct compression without addition of other excipients. CMS
has very good compaction properties and plays also a role of
binder-generating tablets with good mechanical properties
(hardness varying between 28 and 35 kp and even overpassing
the maximal detection limit of 35 kp). Rao and collab. (12)
studied HPMC, sodium carboxymethylcellulose (NaCMC), and
Carbopol 934 matrices. Tablets were prepared with polymers
alone or their mixtures. A combination of nonionic HPMC and
anionic NaCMC polymers resulted in matrices generating a near
zero-order release of diclofenac sodium. The dissolutions tests
were done only in phosphate buffer (pH 7.4) and the drug was
1
Department of Chemistry and PharmaQAM Center, Université du
Québec à Montréal, CP 8888, Branch. A, Montreal, Quebec H3C
3P8, Canada.
2
To whom correspondence should be addressed. (e-mail:
mateescu.m-alexandru@uqam.ca)
AAPS PharmSciTech (# 2016)
DOI: 10.1208/s12249-016-0634-8
1530-9932/16/0000-0001/0 # 2016 American Association of Pharmaceutical Scientists

2. wet granulated with a filler prior to be compressed with other
excipients in tablet form (12).
Compared to current practice based on polymeric
coatings applied via fluidized bed procedure, the novel CMS
derivatives can offer a simpler alternative to achieve an
increased gastro-protection of oral solid formulations. The
carboxyl groups of CMS seem able to enhance the tablet
stability by the well-known dimerization of carboxylic groups
and by hydrogen bonds (13, 14). The dosage forms obtained
by dry compression can pass the stomach and deliver the drug
in the duodenum, upper intestine, jejunum, or colon.
The CMS was previously described as a functional excipient
used to formulate monolithic tablets containing small molecules
(15), proteins (16), and microorganisms (17). The rationale of
starch carboxymethylation was first to produce a pH-responsive
matrix which can modulate the liberation of the active agents
through the intestinal tract. Secondly, the CMS was proposed as a
novel pH-responsive excipient for gastric protection and delivery
of bioactive agents (16–19). The presence of carboxylic groups on
starch chains contributes to an enhanced gastric stability by
protonation inducing a compaction of tablets in acidic fluid and
to a higher hydration, swelling, or erosion in the intestinal media.
Formulations of small molecules with a similar but not identical
high amylose CM-starch excipient were also described by
Brouillet, Bataille and Cartilier (20), Nabais et al., (21), generating
pH-independent sustained release profiles when amounts of
additional loading (about 27% sodium chloride) were added in
the monolithic tablets. For these forms, the sustained release was
controlled by swelling and diffusion mechanisms. It was also
reported that the sodium salt form of CMS of high degree of
substitution, obtained in a nonaqueous medium, generated a
sustained release even in the absence of NaCl adds in the
formulation. Furthermore, the protonated form presented a better
control release (22, 23) pointing out that the monolithic tablets of
CM(H)S provided a longer release time compared with CM(Na)S
and the release time that increases with the protonation ratio
(PR). The extent of substitution plays also a role: CM(H)S (DS
0.11) with PR up to 50% showed relatively low sensitivity to pH of
dissolution medium, and sustained release pattern was almost
independent of tablet pre-incubation in SGF and of drug loading.
The CM(H)S (DS 0.20) was more sensitive to pH and showed an
accelerated release rate in SIF. Interesting to note that during
storage, the highly protonated CM(H)S showed a decrease in
solubility and a progressive structural alteration due to hydrogen-
bonded carboxyl groups, phenomena which translates in an
acceleration of release rate of formulated drug (23).
The CMS-based formulations proposed by the present
study differ from the prior art in terms of characteristics of
excipients and on the design of dosage forms. The CMS
excipients were synthesized in an aqueous phase with
different final pH of the reactional medium such as to obtain
protonated CMS(H) or sodium CMS(Na) forms. Dry-coated
dosage forms consisting in a core and an outer layer which
completely surrounds the tablet core were also studied.
Generally, the nature of the external layer is essential in
reaching the predetermined delivery site (24). Different
model active molecules, such as acetaminophen (neutral),
ASA (acidic), and diclofenac (salt), were proposed to study
the release properties of monolithic and dry-coated tablets
either based on CM(Na)S or CM(H)S excipient. Sodium
carboxymethyl cellulose (NaCMC), a conventional anionic
polymer with carboxyl groups, was considered for
comparison.
All three active molecules are classified as non-steroidal
anti-inflammatory drugs, and sodium diclofenac and ASA
being particularly known as having undesired side effects (i.e.,
gastric mucosa irritation (25), increased stomach acidity). To
prevent this inconvenience, their dissolution in the stomach is
currently avoided by enteric coated dosage forms (26) or by
co-administration of some proton pump inhibitors (27–29) or/
and H2 blockers (30–32). As the presence of carboxyl groups
on starch plays an important role in the protection of the
active agent and the stabilization of the dosage form in the
gastric acidity, the aim of this study was to evaluate and to
compare in vitro the extent of protection offered by the
proposed protonated and sodium CMS excipients to the three
model molecules formulated as monolithic and dry-coated
tablets and also to determine the patterns of their release in
simulated intestinal conditions. The hypothesis was that CMS
could be used as excipient for gastro-protection and delayed
release forms prepared via a solvent-free procedure.
MATERIALS AND METHODS
Materials
High amylose starch (Hylon VII) was obtained from the
National Starch (Bridgewater, NJ, USA). The derivatization
agent (monochloroacetic acid), sodium carboxymethyl cellu-
lose (NaCMC) DS 0.7; MW 90 000 Da, acetaminophen, ASA,
and sodium diclofenac were from Sigma-Aldrich (St-Louis,
MO, USA). Pancreatin porcine, with 200 USP units/mg
amylase activity, 16 USP units/mg lipase activity, and 200
USP units/mg protease activity, was obtained from A&C
American Chemicals Ltd. (Montreal, Quebec, Canada).
Other chemicals were all reagent grade and used without
further purification.
Pepsin-free simulated gastric fluid (SGF, pH 1.2) and
simulated intestinal fluid containing or not pancreatin (SIF,
pH 6.8) were prepared following the USP 2015 (33).
Synthesis of CMS Polymeric Material
The CMS was synthesized by etherification of the starch
with monochloroacetic acid in alkaline medium as previously
described (17, 34, 35) with minor modifications. Thus, an
amount of 140 g of high amylose starch (Hylon VII) was
suspended in 340 mL of distilled water and warmed at 50°C in
a Hobart planetary mixer under continuous stirring. Then,
470 mL of an aqueous 1.5 M NaOH solution were added to
the reaction medium. After 20 min of homogenization at
50°C, 90 mL of a 10 M NaOH solution were added to
transform the starch into a more reactive alkoxide form,
favoring thus its nucleophilic substitution. For the starch
substitution, 96 g of monochloroacetic acid, dissolved in a
minimum volume of water, were rapidly added, and the
reaction was carried out at 50°C for 80 min. Then, the
suspension was separated into two equal parts to obtain the
two forms of CMS: sodium CM(Na)S and protonated
CM(H)S. For CM(Na)S form, the suspension was neutralized
with acetic acid at room temperature, whereas for CM(H)S
form, the pH of the suspension was decreased to 2.5 by
Ispas-Szabo et al.

3. addition of 1 M HCl, and the suspension was homogenized
for 30 min under continuous stirring. For drying of CMS from
the two reaction media, acetone was first added until
complete precipitation of CM(Na)S and of CM(H)S; then,
the two obtained slurries were washed several times by
resuspending and filtration with acetone to water ratio
(85:15, v/v). At the end of this procedure, pure acetone was
added to dry the two CMS forms which were then kept
overnight for air drying at room temperature. Finally, the
powders were ground in a blender and sieved to retain
particles with granulometry between 75 and 300 μm to
prepare monolithic and dry-coated tablets.
The novel excipients were characterized by the Fourier
transform infrared (FTIR) spectroscopy and direct titration
(for the determination of degree of substitution), and the
properties of the CM(Na)S and CM(H)S matrices were
evaluated by tests of water uptake (monolithic matrices),
erosion (monolithic matrices), and in vitro dissolution profiles
in simulated gastric and intestinal media containing or not
digestive enzymes (monolithic and dry-coated matrices).
Fourier Transform Infrared Spectroscopy
The FTIR spectroscopic analysis was carried out using a
BOMEM (Hartmann & Braun) spectrometer (Model MB-
series, Quebec, Canada). Before analysis, CM(Na)S and
CM(H)S powders were dried in a desiccator prior to prepare
the KBr discs. Samples of 10 mg of each powder were mixed
with 90 mg of KBr, and for each sample, about 80 mg of the
mix was used to compress a thin disc of 13 mm diameter
(4 T). Spectra from 4000 to 400 cm−1
were recorded at 4 cm−1
resolution with a total of 48 scans for each sample.
Determination of CMS Degree of Substitution
The degree of substitution (DS) was determined by
titration of carboxyl groups with 0.2 M NaOH solution. For
the CM(Na)S form, the conversion of carboxylate into
carboxylic group was done prior to titration by treating the
polymeric powder with a solution of 0.1 N HCl followed by
precipitation, filtration, and washing to eliminate HCl excess.
Thus, 1.5 g of sodium CMS form was suspended, under
stirring, in 40 mL 0.1 N HCl solution for 20 min, then
precipitated with acetone, filtered and washed with acetone to
water ratio (70:30, v/v), and, finally, filtered and washed with
pure acetone. The powder was dried in an oven at 50°C; then,
a quantity of 1 g of this powder was dissolved in 50 mL water
and titrated with 0.2 M NaOH. For the CM(H)S form, the
same quantity of powder was directly suspended in 50 mL
water and then titrated.
Preparation of Monolithic and Dry-Coated Tablets
Monolithic and dry-coated tablets were obtained by
direct compression (Carver press, Wabash, IN, USA) using
only the active tracers and one or another of the two
proposed CMS excipients. Thus, monolithic tablets of
500 mg containing 20% tracer were obtained by dry
compression (3 T) with acetaminophen, ASA, or sodium
diclofenac powder, in one direct compression step of homog-
enous dry mixtures of active agent and starch derivative using
a 13-mm plate double-faces punch. For dry-coated tablets,
two compression steps were required: in the first step, the
powder mix containing 100 mg active agent and 50 mg starch
derivative was compressed (2.5 T, 9 mm plate faces punch) to
obtain a tablet core, followed by a second compression (3 T,
13 mm plate faces punch) of this core with 350 mg of
excipient powder placed as outer layer to get the dry-coated
tablets. No additional excipients were used for both types of
tablets, such as to avoid interferences or contributions of
other materials. Another series of monolithic and dry-coated
tablets were prepared for each active principle by direct
compression using NaCMC instead of CMS. The drug
loading, punch sizes, and compression parameters were
identical as for CMS series.
Irrespective to the matrix composition or of the
compressing procedure used, the final size and shape of
tablets were kept unchanged, and they were in the range of
12.89 ± 0.34 mm in diameter and 2.87 ± 0.09 mm in thickness.
In Vitro Dissolution Tests
The capacities of CM(H)S, CM(Na)S, and NaCMC to
afford gastric stability of various active molecules were tested
using monolithic and dry-coated tablets. The dissolution
kinetics was followed in a Distek®
dissolution 2100A paddle
system under rotation at 100 rpm and 37°C. The gastric
resistance of the tablets was tested in 900 mL of pepsin-free
simulated gastric fluid (SGF) at pH 1.2 (33) for 2 h (37°C).
Subsequently, the drug release from the tablets was tested in
900 mL of simulated intestinal fluid (SIF), containing or not
pancreatin, at pH 6.8 (33) for 22 h (37°C). All formulations
were tested in SGF followed by incubation in SIF. A
simulation of in vivo conditions was obtained by adding
pancreatin in the dissolution medium. Drug dissolution tests
were carried out for each CMS derivative. Each active
molecule was formulated with CM(Na)S, CM(H)S, and
NaCMC as monolithic and dry-coated tablets. The release
kinetics in both media were determined by spectrophotome-
try at 280 nm for acetaminophen, at 246 nm for ASA and at
274 nm for sodium diclofenac.
Water Uptake and Erosion of CMS Tablets
For a better understanding of mechanisms controlling
the drug release, water uptake and erosion of the CMS
matrices were determined using active-free tablets under
conditions similar to those used for the dissolution tests.
Tracer-free CM(Na)S and CM(H)S monolithic tablets were
placed for 2 h in dissolution vessels containing pepsin-free
SGF medium (37°C and 100 rpm). Then, three series of
experiments were conducted: (i) the tablets were transferred
into 50 mL SIF medium without pancreatin, (ii) the tablets
were transferred into 50 mL SIF medium containing pancre-
atin, and (iii) the tablets were transferred into 50 mL of 8 M
urea solution. After different periods of incubation in SIF
(containing or not pancreatin) or in urea, hydrated monolithic
tablets were removed from the dissolution medium, blotted
with tissue paper to eliminate the surface aqueous excess,
weighed (values recorded for water uptake experiment), and
then, placed for drying in an oven at 50°C (values recorded
for erosion experiment). The remaining dry weight was
Carboxymethyl Starch Excipients for Drug Chronodelivery

4. determined until constant mass. The percentage of water
uptake and erosion were determined gravimetrically and
calculated according to Freichel and Lippold (36), Kavanagh
and Corrigan (37), and Sunghtongjeen et al. (38).
%Wateruptake ¼ Ww tð Þ–W0
À Á
=W0 Â 100 ð1Þ
%Erosion ¼ W0–Wd tð Þ
À Á
=W0 Â 100 ð2Þ
where Ww(t) is the weight of the wet tablet at time t, W0, the
initial dry weight of the tablet, and Wd(t), the remaining dry
weight of the tablet at time t.
RESULTS
The two forms CM(H)S (Fig. 1a) and CM(Na)S (Fig. 1b)
were obtained at a degree of substitution DS = 0.129 as they
were prepared starting from the same synthesis batch.
The FTIR analysis revealed some structural differences
between non-modified starch, CM(Na)S, and CM(H)S
(Fig. 2). The CM(Na)S presents two new characteristic bands,
one at 1417 cm−1
and one at 1603 cm−1
which overlaps that at
1643 cm−1
. The bands at 1417 cm−1
and 1603 cm−1
are
attributed to vibration of carboxylate (−COO−
) groups
(Fig. 2a). For the CM(H)S, a band is always present at
1603 cm−1
, and a new one appeared at 1735 cm−1
(Fig. 2b)
assigned to carboxylic (−COOH) groups (39). The FTIR
patterns suggest that sodium CMS was under carboxylate
form, whereas CM(H)S was, in its majority, in the carboxylic
form, but still presented some carboxylate groups.
In vitro dissolution profiles for the three tracers were
different and depended on drug molecule solubility. Aqueous
solubility of acetaminophen at 25°C is 14.3 mg/mL and is not
varying with pH (40). The pKa of ASA is 3.5. Thus, at a pH
1.2 it will be mostly in the protonated state and having
relatively low solubility (4 mg/mL at 37°C). At a pH 4.5, it
will be mostly in the ionized state and its solubility will be
significantly greater. At a pH 6.8, it will be nearly completely
ionized and maximal solubility (more than 200 mg/mL) will
be attained (41).
Diclofenac sodium has weak acidic properties (pka about
4) and its solubility depends also on the pH of the medium. It
is low soluble in water, very slightly soluble in phosphate
buffer at pH 6.8, and practically insoluble in hydrochloric acid
at pH 1.1 (26, 42). Contrary to some literature reports,
diclofenac sodium did not undergo intramolecular cyclization
in acidic conditions; in fact, this substance loses Na+
in acidic
solutions decreasing its solubility. The analytical techniques
employed (DSC, DRX, EDS, IR) give evidence for the
chemical structure modification of diclofenac sodium once it
has been treated with an acidic solution (43).
Thus, when acetaminophen and ASA were formulated as
monolithic tablets with CM(H)S, the percentages of drugs
released in the first 2 hours in SGF (Fig. 3I a, b) were similar
(20–25%) whereas the sodium diclofenac (Fig. 3I c) was not
released at all in the acidic medium (due to its reduced
solubility in this medium). Such dissolution pattern afforded
by CM(Na)S and by CM(H)S in SGF is particularly
advantageous for whose drugs where release in stomach is
known to produce undesired side effects. After the passage in
Fig. 1. Schematic representation of phenomena occurring in CMS tablets in presence of SGF (a) and SIF (b).
Protonated CM(H)S form is generating an in situ outer gel layer by dimerization of carboxylic groups keeping the
tablet core dry (a). In SIF, the tablet is completely swollen due to presence of carboxylate groups which exert
repulsive interactions and attract more water between carbohydrate chains (b)
Ispas-Szabo et al.

5. the simulated intestinal medium, all monolithic tablets
provided a good controlled liberation of drugs and quasi-
linear profiles. For all three active agents, faster release
profiles were found when formulated with CM(Na)S com-
pared to those formulated with CM(H)S (Fig. 3I). Thus, for
acetaminophen and ASA formulated with CM(Na)S matri-
ces, the liberation patterns were slightly accelerated versus
liberation from the CM(H)S matrices (Fig. 3I a, b). Differ-
ently, for sodium diclofenac formulated with CM(H)S as
monolithic tablets, a release profile typically associated with a
delayed release was obtained (Fig. 3I c). Pancreatin in the
SIF accelerated the release from both types of matrices,
irrespective to the drug incorporated. For the three active
molecules, the drug liberation was faster from the
CM(Na)S than from the CM(H)S matrices but the release
was efficiently controlled.
CMS derivatives offered more effective control of active
molecules release during the gastric transit when formulated
as dry-coated dosage forms. Based either on CM(H)S or
CM(Na)S, dry-coated tablets afforded a complete gastric
protection of tablet shape and no liberation during 2 h in SGF
for all tested active molecules (Fig. 3II) whereas with
monolithic tablets, a limited release in acidic medium was
found for acetaminophen and ASA (20–25%). Furthermore,
a delay for several hours in SIF was observed for all drugs
when formulated as dry-coated tablets. Similar dissolution
profiles were obtained for all three active agents (acetamin-
ophen, ASA, and sodium diclofenac) with no release,
followed by sudden accelerated release of whole amounts of
active agents with slightly differing dissolution patterns in SIF
(Fig. 3II a–c).
When the three active agents were formulated with
NaCMC, the obtained tablets exhibited weaker gastric
protection and mechanical properties compared with
CM(Na) S. Table I summarizes the dissolution time of
90% of drug released from CMC and CMS (both as
sodium salts) matrices. The release times of all drugs from
NaCMC-based tablets were shorter and did not exhibit a
chronodelivery profile. Furthermore, capping phenomena
are conducted to marked variation between tablets with
the same drug.
The percentages of water uptake for both CM(Na)S and
CM(H)S monolithic tablets (Fig. 4) showed a fast hydration and
an outer gel forming at the contact with SGF. Subsequent
incubation in SIF (containing or not pancreatin) or in urea
resulted in an enhanced hydration either for CM(Na)S or
CM(H)S with the aqueous fluid diffused into the CMS matrices
and a subsequent enlargement of the gel layer. In pancreactic-free
SIF, a moderate increase of water uptake for CM(Na)S tablets was
observed during the first 6–8 h, followed by its decreasing up to
24 h due to dissolution of the matrix (Fig. 4a). Lower percentages
of water uptake were obtained for the same matrix in a SIF-
containing pancreatin or in an urea medium, both following the
same profiles (Fig. 4a). For these matrices, after a few hours in
dissolution media, the erosion became determinant (Fig. 5a),
explaining thus the apparent decrease of water uptake. Contrary
to CM(Na)S, the CM(H)S matrices presented a high swelling in
the three media (SIF with or without pancreatin, and urea
medium), with an increase (instead of decrease) of water uptake
percentages (Fig. 4b), indicating for CM(H)S a lower erosion
phenomenon than that of CM(Na)S matrices (Fig. 5a, b). For the
CM(H)S matrix, water uptake was higher in 8 M urea than in SIF
containing or not pancreatin (Fig. 4b).
The CM(Na)S matrix presented a higher erosion
compared to that of CM(H)S matrix. Thus, either in 8 M
urea or in SIF-containing pancreatin, the CM(Na)S mono-
lithic tablets presented 100% of erosion after 14–15 h of
dissolution. The erosion was 100% but with a lesser rate in
the absence of pancreatin (Fig. 5a). Differently, after 24 h of
dissolution the CM(H)S tablets showed only 40% of erosion
in the presence of pancreatin and, respectively, 20 and 10%
erosion in the absence of pancreatin or in 8 M urea (Fig. 5b).
For both matrices, the presence of pancreatin (with alpha-
amylase activity) in SIF significantly increased the erosion
rate of CM-starch excipients compared with that in the
absence of pancreatin (SIF only), when the erosion rate of
the matrix was lower.
a
b
Fig. 2. Fourier transform infrared spectroscopy of starch (high
amylose starch) and of its carboxymethyl derivatives. a Sodium
CM(Na)S form. b Protonated CM(H)S form. Arrows indicate peaks
generated by derivatisation: a presence of carboxylate group (1417
and 1603 cm−1
) and b presence of protonated carboxylic (1735 cm−1
)
and of carboxylate (1417 and 1603 cm−1
) groups
Carboxymethyl Starch Excipients for Drug Chronodelivery

6. DISCUSSION
The solubility properties of the starch derivative are
influenced by the pH of the environmental medium due to
the presence of carboxylic functional groups (44). The
CM(Na)S form usually is water-soluble (22,23), and the
degree of solubility is determined by the DS. The CM(H)S
form (which still may present some carboxylate groups) is less
soluble in water, being thus an interesting excipient for
sustained drug release. Such as already reported, the substi-
tution of starch significantly appears at O-2 position. In fact,
starch carboxymethylation generally proceeds in the order
O-2 > O-6 > O-3 (45–47). The 1
H NMR spectroscopy studies
of decomposed CM-HAS (by perchloric acid) allow the
evaluation of the distribution of the CM functional groups
within the glucose units (47). The same technique was applied
to determine the DS of CM-HAS and succinate-starch (48).
Both excipients, sodium and protonated form of CMS,
afforded a good gastro-protection and tablet integrity and this
can be explained by the protonation of the carboxyl groups in
gastric acidity acting as a buffer retaining protons and forming
a compact gel layer around the tablet, keeping the shape and
protecting thus the inside of the tablet from acidity (19). In
case of NaCMC, a higher DS (0.7) compared with CM(Na)S
and the conformation of polysaccharidic chains (linear
instead helical) may explain their lower capacity to provide
gastric protection and chronodelivery properties. A more
advanced comparison between CMSs, NaCMC, and other
a
b
c
Fig. 3. Dissolution profiles from monolithic (I) and dry-coated (II) tablets based on sodium or protonated carboxymethyl starch, loaded with
20% of acetaminophen (a), ASA (b), or sodium diclofenac (c). The pills were maintained 2 h in pepsin-free SGF followed by incubation in SIF
containing or not pancreatin (USP apparatus II, 100 rpm, 37°C). Mt is the amount of drug released at time t, and Minf is the total drug release
over 24 h (n = 3). The arrow indicates the passage from SGF to SIF media
Ispas-Szabo et al.

7. pH-dependent conventional polymers will be the subject of a
separate report.
The time between the initiation and completion of drug
release was very narrow for sodium diclofenac from both
types of sodium and protonated CMS excipients, in the
absence or in the presence of pancreatic enzymes. In the
literature, there were other attempts to formulate diclofenac
sodium using swellable and erodible buffered matrices (49).
The authors noticed the diclofenac solubility issue and
proposed HPMC (neutral hydrophilic polymer) combined
with approx. 8% of a pH-dependent polymer (Eudragit L100-
55) and phosphate buffers able to ensure a microenviron-
mental pH between 6.2 and 8.3. The mentioned study did not
investigate the Diclofenac sodium dissolution profiles in SGF
and was not focused on dry coating and chronodelivery
aspects. Furthermore, the low concentration of Eudragit
Table I. Characteristics of Tablets Based on CMC and CMS
Parameter Acetaminophen Aspirin Diclofenac sodium
Monolithic Dry coated Monolithic Dry coated Monolithic Dry coated
CMC tablet hardness (kp) 20.6 ± 1 19.6 ± 2 19.7 ± 1 18.9 ± 1.5 19.2 ± 1.3 18.5 ± 1
Time (h) 90% drug
dissolved and observation
of tablets after swelling
2 h in SGF
CMC 4.5 ± 0.6 h
Light multicapping;
significant erosion
CMC 5. 6 ± 0.8 h
Mantle detached
CMC 3.6 ± 0.5 h
Light capping
CMC 3.5 ± 1.7 h
Mantle detached;
very high
variability
CMC 4.6 ± 0.8 h
Multicapping
CMC 6.3 ± 2 h
Mantle
detached
CMS 10 h/6 h*
Good shape
CMS 13.2 h/7.6 h*
Good shape
CMS 11 h/6.2 h*
Good shape
CMS 13.5 h/6.2 h*
Good shape
CMS 7.6 h/
4.6 h*
Good shape
CMS 10.5 h/
6.3 h*
Good shape
Note: (1) No pancreatin was added for CMC because these enzymes are not able to degrade this excipient. (2) The SD were not added for
CMS tablets; they can be seen in Fig. 3I, IIa–c
All tablets with 20% loading for each active principle were obtained in the same conditions (punch size and compression forces). Both
polymers were sodium salts and no additional excipients were used. CMS tablets were incubated without and with (*) pancreatin
CMC carboxymethyl starch, SGF simulated gastric fluid
a
b
Fig. 4. Water uptake of monolithic tablets based on sodium (a) or
protonated (b) carboxymethyl starch. Drug-free monolithic tablets
were treated for 2 h in pepsin-free SGF, followed by 22 h incubation
in SIF (containing or not pancreatin) or in 8 M urea solution (n = 3)
a
b
Fig. 5. Erosion of sodium (a) and protonated (b) carboxymethyl
starch monolithic tablets. Drug-free tablets were treated for 2 h in
pepsin-free SGF followed by SIF without pancreatin or SIF-
containing pancreatin or urea solution 8 M (n = 3)
Carboxymethyl Starch Excipients for Drug Chronodelivery

8. L100-55 in the matrices is related more to erosion mecha-
nisms than to matrix forming capacity.
As a general characteristic, the presence of pancreatin in the
SIF accelerated the release for all chosen drugs from the dry-
coated CMS forms but still preserving the release profiles. For
acetaminophen and ASA liberated from dry-coated tablets, the
release time of 90% drug was longer in the absence of pancreatin
(5–9 h), compared to 3–4 h in the presence of pancreatin alpha-
amylase enzyme. To our knowledge, this is the first investigation
on the effect of CMS excipient protonation on the drug release of
the dry-coated with same excipient tablets. Various lag-times in the
release pattern of dry-coated tablets can be achieved by altering
the thickness of the outer layer (50).
Itwaspreviouslyshownthatthepresenceofcarboxylicgroups
on starch chains can contribute to a good stabilization of the CM-
starch matrix in gastric fluid (16, 17, 35), having also a major impact
on matrix swelling and erosion, contributing to the mechanisms of
drug release. The swelling of tablets based on CM(Na)S can be
modulated by the DS of the polymer. A swelling increase at higher
DS of the CM(Na)S is due to more hydration favored by Na+
(17).
This also explained the fast swelling of the tablet following the
exchange of protons with cations (Na+
) with the passage from
gastric in intestinal medium. Even if the starch is modified, it still
presents a certain susceptibility to amylolysis under alpha-amylase
action, and this depends on the DS of starch (17). A moderate
carboxymethylation still allows the alpha-amylase access to the
alpha-1,4-glucosidic links as hydrolysis sites.
TherationaleofinvestigationofCM(Na)SandCM(H)Sin8M
ureawasthe understanding ofthe roleof hydrogenbondingonour
excipients. Urea has been widely used as a complexing agent for
organic acids in investigations of hydrogen-bonding phenomena
and as chelator in supramolecular assemblies (51, 52). As a
chaotropic agent, urea has already been used for investigation of
crosslinkedstarchasexcipientsfordrug-sustainedrelease(7,53).In
fact, urea may contribute to the partial destabilization of the
hydrogen bonds already established in the matrix. The CM(H)S
waslesscompacted,withahigherwateruptakein8Mureamedium
suggesting an initial stronger stabilization by hydrogen bonding
than for CM(Na)S matrix. This behavior together with the release
patterns support the role of self-assembling of polysaccharidic
chains in starch derivatives as a key aspect in controlling the matrix
formation and implicitly drug liberation.
It was also found that from both CM(Na)S and CM(H)S
matrices, the delivery of the small molecules seems modu-
lated by duodenal alpha-amylase starting with the upper
intestine. The differences between the acetaminophen, ASA,
or sodium diclofenac delivery from CM(Na)S and from
CM(H)S monolithic tablets can be explained by drug
solubility and also by different percentages of water uptake
and erosion of the two monolithic matrices.
The degree of protonation of CMS matrices can also play
an important role in the modulation of delivery of the active
molecules due to the process of deprotonation/ionization (the
exchange protons/cations) during the passage from gastric to
intestinal (neutral) medium. Thus, in the acidic medium, the
CM(Na)S monolithic tablets exchange the cations (Na+
) for
protons (H+
) at the surface layer surrounding the matrices,
resulting in compact outer gel structures. With the transit a
neutral medium (SIF), the protonated carboxyl groups,
located at the outer gel layer of the monolithic tablets, will
gradually change the protons for cations. This will facilitate
hydration, swelling, erosion, and polymeric material
dissolution in the simulated intestinal medium.
In the case of CM(H)S monolithic tablets, most of carboxylic
groups are present in CM(H)S form (Fig. 1a) and carboxylic
groups from neighboring chains are stabilized by hydrogen-
mediated dimerization. Then, in a neutral media, the protonated
carboxyl groups present on the starch will slowly and gradually
change the protons for cations (Fig. 1b). In this case, the H+
/Na+
exchange process is longer due to presence of more protonated
carboxyl groups either at the surface and in the interior of the
CM(H)S monolithic tablets, contrary to the CM(Na)S monolithic
tablets, where the protonated acidic groups are located in majority
at the surface of the tablet. Therefore, this will contribute to a
longer sustained liberation of the active molecules in the intestinal
medium when formulated with CM(H)S.
CONCLUSION
The presence of ionic groups, either in sodium or protonated
form on the carboxymethyl starch chains, has a major impact on
polymer water uptake/erosion, controlling the mechanism of drug
release. Using CM(Na)S and CM(H)S excipients, monolithic and
dry-coatedtabletswereformulatedtodelaytheliberationingastric
fluid and then gradually release active agents over a 12-h period.
The stabilization of starch-based matrices is governed by self-
assembling phenomena where hydrogen bonding (mainly in SGF)
and ionic repulsions (mainly in SIF) are involved in gel formation
and its swelling. These chronodelivery patterns are particularly
useful for formulation of drugs targeted for lower intestine or for
colon delivery. The CM(H)S monolithic formulations may provide
a greater effectiveness in the controlled delivery of medication for
the treatment of chronic conditions (i.e., ulcerative colitis, inflam-
matoryboweldiseases).Withthedry-coatedtabletsbased onCMS
excipient, it is possible to liberate whole the amount of drug at the
desired time during the intestinal transit. This proposed approach
could be applied for all drugs exhibiting an irritating action at the
stomach level and having an extended absorption window.
The formulations with the proposed CMS excipients may also
represent advantageous alternatives replacing the wet coating
procedure and eliminating a manufacturing step. A further
advantageofCMSexcipientisthatit cangenerateaBhomologous^
coating based on the same material instead application of enteric
coatingwithvariousmaterials.Auniqueexcipientforcoreanddry-
coatingmayfacilitatetheformulationandprocessingflow.Thedry-
coated tablets either based on CM(Na)S or CM(H)S excipients
afforded a good chronodelivery of the proposed model drugs.
ACKNOWLEDGMENTS
Thanks are due to NSERC of Canada for the financial
support of this research (MAM) and for a Canada fellowship
for doctoral studies (CC).
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