J Therm Anal Calorim (2014) 116:1091–1100
DOI 10.1007/s10973-014-3769-4
Compatibility study between chitosan and pharmaceutical
excipients used in solid dosage forms
M. A. V. Pereira • G. D. Fonseca • A. A. Silva-Júnior •
M. F. Fernandes-Pedrosa • M. de F. V. de Moura •
E. G. Barbosa • A. P. B. Gomes • K. S. C. R. dos Santos
Received: 24 September 2013 / Accepted: 15 March 2014 / Published online: 10 April 2014
Ó Akadémiai Kiadó, Budapest, Hungary 2014
Abstract Microcrystalline cellulose is an excipient
widely used in solid dosage forms as adsorbent, suspending
agent, diluent, and disintegrant, depending on the per-
centage employed in the formulation. The structural simi-
larity between cellulose and chitosan and the ecological
advantage in the manufacturing process of chitosan have
justified and reinforced the study of this polysaccharide as
a novel pharmaceutical excipient. Nevertheless, it still does
not appear to be present as constituent in any marketed
medicine due to the absence of regulatory hurdles to
standardize its physicochemical and functional specifica-
tions as well as its compatibility with other formulation
ingredients. The physical compatibilities between chitosan
and the most excipients used in solid dosage forms, such as
diluents (microcrystalline cellulose, starch, lactose mono-
hydrate, dicalcium phosphate dihydrate, and calcium car-
bonate), disintegrants (sodium starch glycolate, and
croscarmellose sodium), and glidants (magnesium stearate,
talc, sodium lauryl sulfate, and colloidal silicon dioxide),
were studied by thermal analysis and FT-IR. In order to
facilitate the IR spectra interpretations, an ad hoc algorithm
was used to generate theoretical spectra to be compared
with the respective experimental ones. Chitosan proved to
be physically compatible with microcrystalline cellulose,
M. A. V. Pereira  G. D. Fonseca  A. A. Silva-Júnior 
M. F. Fernandes-Pedrosa  E. G. Barbosa 
A. P. B. Gomes  K. S. C. R. dos Santos (&)
Departamento de Farmácia, Universidade Federal do Rio Grande
do Norte, Av. Gal. Gustavo Cordeiro de Farias s/n, Natal,
RN 59012-570, Brazil
e-mail: katiasolange@ccs.ufrn.br
M. de F. V. de Moura
Instituto de Quı́mica, Universidade Federal do Rio Grande do
Norte, Campus Universitário, Natal, RN 59072-970, Brazil
starch, lactose, sodium starch glycolate, croscarmellose
sodium, talc, colloidal silicon dioxide, and sodium lauryl
sulfate. Moreover, chitosan raises the thermal stability of
cellulose from 310 to 330 °C. Once the amino groups of
chitosan were able to form coordination complexes with
divalent cations of dicalcium phosphate dihydrate, calcium
carbonate, and magnesium stearate, they were considered
incompatible with chitosan.
Keywords Excipients  Solid dosage forms 
Compatibility studies  Chitosan  Thermal analysis
Introduction
An excipient has been defined by Pharmacopoeial Forum
(1995) as ‘‘any component, other than the active substances,
intentionally added to the formulation of a dosage form’’ [1].
However, the traditional concept of excipient has undergone
considerable evolution: from simple, chemically and phar-
macologically inert vehicle to essential adjuvant, guarantee-
ing and optimizing the performance of a modern medicinal
product [1, 2]. Excipients in solid dosage forms are composed
by mixture of adjuvants, such as diluents, binders, disinte-
grants, lubricants, glidants, and surfactants [2–4]. They permit
the efficient manufacturing of capsules and tablets and affect
the physical and chemical characteristics of the active ingre-
dients as well as its bioavailability [3].
Microcrystalline cellulose (MC) is widely used as an
excipient. In solid dosage forms, it can be used as adsorbent,
suspending agent, diluent, and disintegrant [5]. The structural
similarity between MC and chitosan, a copolymer of gluco-
samine and N-acetylglucosamine obtained by partial deacet-
ylation of chitin [6, 7], has justified the study of this
polysaccharide as a novel pharmaceutical excipient. They
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1092 M. A. V. Pereira et al.

OH interactions [4], the latter can lead to enhance or decrease

OH OH dissolution rate of a drug from a dosage form [24]. Com-
HO 2
O O HO 2
O
O HO O cellulose paring with MC, chitosan (with different molecular masses
O 2 O
OH and different degrees of deacetylation) enhances the disso-
OH OH lution rates of poorly water-soluble drug [25] since it acts as a
‘‘molecular sponge’’ [26]. Besides, the MC manufacturing is
a nonecological process in which the raw material comes
from fibrous plants [24], while chitosan is processed mainly
CH3 CH3
from crustacean exoskeleton [6, 7] which can be industrially
O OH O
NH NH
exploited instead of be discarded. These both biopharma-
HO 2
O O HO 2
O ceutical and ecological aspects justify the relevance to study
O O HO O O chitin
2 and regulate chitosan as a pharmaceutical excipient.
NH
OH OH
Practically, all types of analytic methods can be utilized
O
CH3
for quality control of the excipients. However, their com-
patibility evaluation is mainly carried out using thermal
Parcial analysis [3]. According to the definition presented by the
Deacetylation International Confederation of Thermal Analysis and Calo-
rimetry (ICTAC), thermal analysis is ‘‘a group of techniques
CH3 in which a physical property of a substance is measured while
OH O the substance is subjected to a controlled temperature pro-
NH2 NH
HO 2 O HO 2 gramme’’ [27]. The most widely used techniques are dif-
O O
O O HO 2 O O chitosan ferential thermal analysis (DTA), differential scanning
NH2 calorimetry (DSC) and thermogravimetry/derivative ther-
OH OH
mogravimetry (TG/DTG) [28]. Consequently, the tempera-
Fig. 1 Chemical structure representations of cellulose (MC), chitin, ture and energy associated with events, such as melting,
and chitosan oxidation and reduction reactions, glass transition, boiling,
sublimation, decomposition, crystallization, or gel-to-liquid
differ in the substituent in carbon-2, where hydroxyl groups of crystal transition can be evaluated [29]. When such events
MC are replaced by amino (in deacetylated units) or acet- are evaluated for mixtures of drug–drug, drug–excipient, or
amido (in acetylated units) groups of chitosan (Fig. 1). Chitin excipient–excipient, possible interactions may be discerned
is estimated to be produced annually almost as much as MC. from DSC curves by appearance, shift, or disappearance of
Chitin as well as chitosan has become a material of great DSC peaks, especially the melting peak, and/or variations in
interest not only as an under-utilized resource but also as a new expected enthalpy values [27–29]. In addition, FT-IR spec-
functional biomaterial of high potential in various fields, and troscopy also could be used to investigate chemical inter-
the recent progress in chitin chemistry is quite significant [8]. actions as a supplementary technique in order to confirm the
Several authors have reviewed the use of chitosan as results obtained by the thermal analysis [30]. Once possible
adjuvant in capsules and tables [9–12]. However, the interactions can affect the vibration of groups on molecular
development of new excipients has been slow, a fact partly segments of the single compound, the appearance of new
related to not only cost but also regulatory hurdles to dem- absorption bands, broadening of bands, or alteration in the
onstrate that they are safe for human use [13] and compatible intensity of bands in the spectra are the main characteristics
with other formulation ingredients [2]. Due to its biocom- to evidence the occurrence of interactions [31].
patibility, biodegradability, and low toxicity [12–14], The present study evaluated the compatibility of chito-
chitosan has the potential to be a safe pharmaceutical san with other pharmaceutical adjuvants being widely used
excipient for the nonparenteral administration route [13]. in solid pharmaceutical formulations. MC, starch, lactose
Some studies have demonstrated its compatibility with some monohydrate, dicalcium phosphate dihydrate (DCP), and
drugs, such as metoclopramide [15], mirtazapine [16], calcium carbonate (CC) were the selected diluents. Sodium
anastrozole [17], aceclofenac [18], clarithromycin [19], starch glycolate (SSG) and croscarmellose sodium (CCS)
ketorolac tromethamine [20], metformin [21], losartan were the chosen desintegrants, while magnesium stearate
potassium [22], and dexamethasone sodium phosphate [23], (MS), talc, sodium lauryl sulfate (SLS), and colloidal sil-
but there was no information about its compatibility with icon dioxide (CSD) were the selected glidants. For this
other traditional excipients employed in the manufacture of investigation, individual components as well as binary
solid dosage forms. Although drug–excipient interactions mixtures of chitosan and excipients were studied by DSC,
occur more commonly compared to excipient–excipient TG/DTG, and FT-IR.

123
Compatibility study between chitosan and pharmaceutical excipients 1093

Materials and methods

Materials

Chitosan of medium molecular mass was purchased from

Aldrich Chemical Company, with a degree of acetylation chitosan
of 0.15 and a viscosimetric average molecular mass of
145 kDa. Pharmaceutical grade excipients were supplied MC
by Natural Pharma (MC); Corn Products (starch); starch
Magnesita (talc); Pharmanostra (SLS, lactose monohy-
drate, and CSD—aerosilÒ); Unimim (CC); Blanver Farm- lactose

Mass loss/%
oquı́mica (SSG and CCS); Budenheim (DCP); and Nitika talc

Chemicals (MS). DCP

Binary mixtures
CCS
Excipient–excipient physical mixtures (2 mg) in a ratio of
1:1 (w/w) were prepared by simply mixing with a spatula SSG
and analyzed by DSC and TG/DTG. SLS

Differential scanning calorimetry (DSC) MS

CSD

The DSC curves of chitosan, excipients, and binary mix-

tures 1:1 (chitosan:excipient) were obtained on a Shimadzu
Calorimeter Model DSC-60A. Samples (2 mg) were ana- 20 %
CC
lyzed in sealed aluminum sample pans with a N2 atmo-
sphere flowing at 50 mL min-1 and a heating rate of 0.00 200.00 400.00 600.00 800.00

10 °C min-1, and within the temperature interval between Temperature/°C

20 and 500 °C. The calibration was done using the melting
points of the standards indium (m.p. 156.6 °C) and zinc
(m.p. 419.6 °C). The sample curves were analyzed using
TASYS software developed by Shimadzu.
Thermogravimetry (TG/DTG)
The Dynamic Thermogravimetric curves of chitosan and
excipients were recorded using Shimadzu Thermobalance,
Model DTG-60H. The analysis of samples (1–6 mg) was
performed in alumina crucible, with N2 flow of
50 mL min-1, heating rate of 10 °C min-1 in the temper-
ature range of 20–900 °C. The calibration was done with
calcium oxalate monohydrate and zinc. The samples curves
were analyzed using TASYS software developed by
Shimadzu.
Fig. 2 TG curves of pure excipients
Theoretical IR spectra
Theoretical spectra for binary mixtures were produced
using a linear combination of pure compounds’ spectrum.
The combination was obtained using an ad hoc algorithm
[32] that normalizes all spectra and combines the spectrum
based on the molar composition in the physical mixture.
The molecular masses of all samples were considered;
however, for the analyzed polymers, the average molecular
mass was used in calculations. The experimental spectra
obtained for the binary mixtures were compared to the
expected theoretical spectra in order to identify the
appearing or fading peaks.

IR spectroscopy Results and discussion

The spectra of the individual compounds and binary mix-
tures were performed on an ATR-FTIR Spectrometer
(IRprestige-21 Shimadzu) between 700 and 4000 cm-1, at
an optical resolution of 1.0 cm-1 and averaged over 20
scans.
Thermal analysis
The interactions between pharmaceutical ingredients, which
lead to changes in the chemical, physical, and therapeutic
properties of the pharmaceutical dosage form, are termed as

123
1094 M. A. V. Pereira et al.

chitosan chitosan

MCC chitosan + CCS

CCS

SLS
SSG
Endo Heat flow/mW.mg–1

chitosan + SSG
chitosan + MCC

Heat flow/mW.mg–1
chitosan + starch
chitosan + SLS

starch

Endo
MS
lactose
chitosan + DCP
chitosan + lactose

chitosan + MS
chitosan + talc
CSD
DCP

mW.mg–1
chitosan + CSD

CC
talc mW.mg–1

0.00 100.00 200.00 300.00 400.00 500.00

Temperature/°C chitosan + CC

0.00 100.00 200.00 300.00 400.00 500.00

Fig. 3 DSC curves of pure chitosan, MC, starch, lactose, DCP, and
talc (continuous lines); and its binary mixtures 1:1 with chitosan
(dashed lines)
incompatibilities [29]. DSC has been proposed to be a rapid
method for evaluating physicochemical interactions between
components of the formulation through the comparison of
thermal curves of pure substances with the curve obtained
from a 1:1 physical mixture [30]. Figure 2 shows the TG
curves of all the pure excipients used in the compatibility
study. The DSC curves obtained for pure and chitosan-
mixed excipients are presented in Figs. 3 and 4. The main
thermoanalytic data obtained from the thermal curves are
summarized in Table 1.
The DSC curve of chitosan showed an endothermic peak
corresponding to dehydration between 22 and 90 °C, which
coincides with the first mass loss of 11.4 % between 23 and
214 °C in the TG curve. The polymer decomposi-
tion started above 280 °C as an exothermic event
(Tpeak/DSC = 308 °C) with an accentuated mass loss of
39.5 % between 281 and 314 °C, followed by a gradual
mass loss of 47.1 % up to 518 °C.
Temperature/°C
Fig. 4 DSC curves of pure chitosan, CCS, SSG, SLS, MS, CSD, and
CC (continuous lines); and its binary mixtures 1:1 with chitosan
(dashed lines)
MC as well as chitosan presented also presented some
sample moisture and decomposed in two steps second its
DSC curve. The first endothermic peak at 53 °C was
attributed to dehydration. The first endothermic transition at
332 °C was the main step of decomposition since the most
part of the initial mass (Dm = 83.9 %) was lost between
306 and 344 °C in the TG curve. Above 349 °C, the mass
loss is gradual (Dm = 9.7 %) and lasts up to 420 °C. It
could be noticed that chitosan has a slight greater loss of
water (11.4 %) than MC (10.4 %) and that chitosan needs
more energy to dehydrate (DH = 281.7 J g-1) than MC
(DH = 115.6 J g-1). Agrawal and co-workers [26]
observed that the interaction of water with the polymer is
stronger for chitosan than for MC because the bound water
content can result from the interaction of water molecules
with polar hydroxyl groups in MC, but with polar hydroxyl
and amine groups in chitosan.

123
Compatibility study between chitosan and pharmaceutical excipients 1095

Table 1 Thermoanalytic data of excipients and their binary mixtures 1:1 with chitosan
Excipient Dehydration Fusion Decomposition
DSC TG DSC DSC TG
Tpeak/ DH/ DT/ Dm/ Tpeak/ DH/ Tpeak/ DH/ DT/ Dm/
°C J g-1 °Ca % °C J g-1 °C J g-1 °Ca %

Chitosan 58 281.7 25–33 11.3 ¯ ¯ 308;¯ 180.9;¯ 281–314; 337–518 39.5; 47.1
MC 53 115.6 33–90 10.5 ¯ ¯ 332; 357 214.3; 267.6 306–344; 349–420 83.9; 9.7
Chitosan ? MC 52 66.1 ¯ ¯ ¯ ¯ 355 66.7 ¯ ¯
Starch 72 194.9 24–37 14.3 ¯ ¯ 285; 315 8.7; 343.2 306–325; 377–385 65.8; 15.6
Chitosan ? starch ¯ ¯ ¯ ¯ ¯ ¯ 307 51.8 ¯ ¯
Lactose 147 63.4 120–165 4.7 217 133.0 243; 295 104.2; 170.2 250–282; 289–320 21.7; 41.8
Chitosan ? lactose 149 18.8 ¯ ¯ 216 42.6 307 89.0 ¯ ¯
DCP 190 ¯ 471–573 2.8 ¯ ¯ ¯ ¯ 662–729 39.4
Chitosan ? DCP ¯ ¯ ¯ ¯ ¯ ¯ 317 174.4 ¯ ¯
Talc ¯ ¯ ¯ ¯ ¯ ¯ ¯ ¯ ¯ ¯
Chitosan ? talc ¯ ¯ ¯ ¯ ¯ ¯ 308 67.7 ¯ ¯
CCS 76 167.4 36–72 17.8 ¯ ¯ 303;¯ 621.0;¯ 281–315; 347–417 45.9; 10.4
718–738; 824–874 20.4–3.9
Chitosan ? CCS ¯ ¯ ¯ ¯ ¯ ¯ 308 157.8 ¯ ¯
SSG 59 141.0 43–92 6.9 ¯ ¯ 288;¯ 45.5;¯ 275–297; 873–741 39.3; 47.7
Chitosan ? SSG ¯ ¯ ¯ ¯ ¯ ¯ 270 119.1 ¯ ¯
SLS 95; 107 3.7; 21.1 71–76;¯ 0.9;¯ 192 52.7 214; 267 101.4; 155.2 195–258 71.0
Chitosan ? SLS 94 12.5 ¯ ¯ 192 28.2 223 51.5 ¯ ¯
MS 89; 107 37.8; 2,8 67–97 3.7 115 1.22 346; 394 458.9; 392.5 299–347; 374–409 17.0; 51.7
431 65.4 418–444 15.0
Chitosan ? MS ¯ ¯ ¯ ¯ ¯ ¯ 298; 358 9.5; 114.0 ¯ ¯
CC ¯ ¯ ¯ ¯ ¯ ¯ ¯ ¯ 605–737 39.2
Chitosan ? CC ¯ ¯ ¯ ¯ ¯ ¯ 305 88.0 ¯ ¯
a
DT ranges between Tonset and Tendset

The possible interactions between components are
derived or deduced from the DSC curves by appearance,
shift, or disappearance of DSC peaks, especially the
melting peak, and/or variations in expected enthalpy values
[28, 29]. When thermal analysis is conducted to study
drug–excipient compatibility, the efforts are concentrated
to identify if there is any displacement of the drug0 s
melting point in drug–excipient physical mixtures. How-
ever, since both chitosan and the most studied excipients
degrade prior to melting, there are no melting points to be
monitored, hindering the results’ interpretation. In these
cases, other events such as dehydration and decomposition
were also evaluated. Even if interactions occured earlier
than the decomposition steps, different decomposition
temperatures could be expected because the resulting
compound could decompose in higher or lower tempera-
tures than pure excipients.
In the DSC curve of the binary mixture 1:1 between
chitosan and MC, the endothermic event between 36 and
78 °C was attributed to the simultaneous dehydration of the
two polymers, since the peak temperatures of the dehy-
dration were 53 and 58 °C for MC and chitosan, respec-
tively. The onset temperature of the first decomposition
step of the MC in binary mixture occurred at higher tem-
perature (331 °C) than the MC alone (315 °C) in DSC
curves, which indicated that this combination enhanced the
thermal stability of the resulting polymer. Moreover, the
difference between theoretical and experimental enthalpies
has proven the occurence of interaction. The expected
enthalpy value for the endothermic step of MC decompo-
sition in the equimass mixture was -107.2 J g-1, which
amounts to the half of that obtained for the pure compound,
but the measured decomposition enthalpy of -66.7 J g-1
was 38 % lower than the expected one.
It is known that glass transition temperature (Tg) is the
temperature over which the polymer converts from a glass-
like state, i.e., restricted motion of the polymeric chains, to
a rubber-like state in which the increased relaxation leads
to a loss in rigidity [33]. Chitosan and MC have Tg values
of about 150 and 190 °C [34] respectively, which were not

123
1096
detected under the conditions used in our experiments. As
the physical mixture of polymers was submitted to higher
temperatures than for the Tg values of chitosan and MC, the
enhanced polymeric chains’ mobility could have formed a
more thermostable blend than the pure polymers before the
decomposition steps. However, since the interactions
observed at high temperatures may not always be relevant
under ambient conditions [30], these polymers are con-
sidered compatible to be used in the manufacture of solid
dosage forms by powder compression (tablets) or filling
(capsules).
The DSC curve of starch showed that this polysaccha-
ride has an endothermic peak at 72 °C due to dehydration,
corresponding to a mass loss of 14.3 % between 24 and
37 °C in the TG curves. This excipient remained thermo-
stable until 273 °C, when decomposition takes place as an
accentuated mass loss of 65.8 % between 306 and 325 °C.
Above 370 °C, the second stage of decomposition contin-
ues as a gradual mass loss of 15.6 %. In the curve of the
binary mixture 1:1 (chitosan:starch) could be noticed a
small exothermic peak at 307 °C, which coincides with the
chitosan’s decomposition temperature. However, since
both decompositions of starch and chitosan had occurred in
the same temperature range and exhibited enthalpies with
opposite signs, the resulting lower enthalpy
(DH = 51.8 J g-1) may not necessarily indicate physical
interaction of components within the mixture.
The thermal behavior of lactose was characterized by
the occurrence of various events. The DSC curve showed
an endothermic peak at 147 °C corresponding to the
dehydration, a small exothermic peak at 171 °C due to the
crystalline transition and melting at 217 °C. Above 225 °C,
lactose decomposition started as two endothermic steps
with peak temperatures of 243 and 295 °C, followed by an
exothermic peak at 332 °C due to the carbonization [35] of
the residue. From TG curve could be noticed several levels
of mass loss, which coincide with thermal events observed
in DSC curve: 4.7 % of the initial mass was lost by
dehydration, 21.7 and 41.8 % were lost in the two steps of
decomposition, and 12.9 % was lost by the carbonization
of the residue. Above 440 °C, lactose showed a gradual
mass loss of 18.0 % until the end of the experiment at
900 °C. According to the DSC curve of the binary mixture
1:1 (chitosan:lactose), both dehydration and melting point
temperatures of lactose in the mixture were occurring at the
same temperatures as those for lactose alone, but with
enthalpy values being almost 41 and 36 % lower than the
expected ones, respectively. The decrease in enthalpy of
fusion and the absence of other relevant thermal events in
the DSC curve of the binary mixture have suggested that
these materials present some levels of physical interaction.
The DSC curve of DCP reported by other authors
[36, 37] was associated with the loss of water of hydration,
123
M. A. V. Pereira et al.
which usually occurs in two steps. The DSC curve of DCP
showed a discrete endothermic event around 190 °C rela-
ted to the second step of dehydration, once the first step
was not evidenced in our experiments. In the TG curve, the
decomposition occurred between 662 and 729 °C in which
39.4 % of the initial mass was lost, remaining almost 58 %
in the form of ashes due to the inorganic residue. In the
curve of the binary mixture 1:1 (chitosan:DCP) could be
noticed that the chitosan decomposition occurred as a
broader peak slightly shifted to higher temperature
(Tpeak/DSC = 317 °C). Moreover, the measured enthalpy of
174.4 J g-1 is almost double the expected theoretical value
(90.5 J g-1), indicating a strong interaction due to heating.
It is well known that talc presents no significant thermal
events in the studied temperature ranges of DSC and TG
curves [30, 38]. The thermal behavior of the binary mixture
1:1 (chitosan:talc) showed the same endothermic and
exothermic characteristics as those of chitosan, indicating
the presumable absence of incompatibility.
The thermal behavior of CCS (Fig. 4) was characterized
by an endothermic peak at 76 °C followed by an exother-
mic one at 303 °C, which corresponds to dehydration and
decomposition, respectively, in accordance with Fathy and
co-workers [39]. In the meantime, the TG curve (Fig. 3)
showed four stages of mass loss: from the beginning of the
TG run until 72 °C, 17.8 % of the initial mass is lost. The
second mass loss of 45.9 % between 281 and 315 °C
corresponds to the first step of decomposition observed at
DSC curve. Above 320 °C, decomposition continued to
occur as a gradual mass loss of
10.4 %, followed by an accentuated mass loss of 20.4 %
between 718 °C and 738 °C, with the remaining 5.5 % in
the form of ash residues. The thermoanalytic profile of the
binary mixture 1:1 (chitosan:CCS) showed an exothermic
peak at 308 °C, which coincides with the chitosan’s
decomposition. Since both chitosan and CCS decomposi-
tions have occurred in the same temperature range, the
expected enthalpy value in equimass mixture was
401.0 J g-1, which is equivalent to the half of the sum of
that measured for pure compounds. The experimental
enthalpy of 157.8 J g-1 is 60.6 % lower than the expected
for the binary mixture, suggesting a possible physical
interaction between these polymers.
The DSC curve of SSG showed two endothermic events
with peaks at 59 and 288 °C, which correspond to dehy-
dration and the first decomposition step, respectively. The
TG curve presented a 6.9 % initial mass loss attributed to
dehydration of SSG up to 92 °C. The thermal decomposi-
tion started at 275 °C, when an accentuated mass loss of
39 % occurred in the first step up to 297 °C. Between 317
and 741 °C, 47.7 % of the remaining initial mass was lost
in a second and prolonged decomposition step, with the
remaining 6.1 % in the form of ash due to inorganic
Compatibility study between chitosan and pharmaceutical excipients
sodium. The DSC curve of the binary mixture 1:1 (chito-
san: SSG) had preserved mainly the thermal behavior of
SSG, and the enthalpy value of the first step of decompo-
sition varied proportionally to the single compound con-
tents, evidencing the absence of the incompatibility
between chitosan and SSG.
The analytic profile of SLS was marked by the occur-
rence of various endothermic events. In the DSC curve, this
compound has dehydrated in two peaks [40] at 35 and
107 °C. The peak at 192 °C is close to those found by other
authors [40, 41] and was attributed to the melting point
temperature [5]. The next two endothermic events in the
temperature ranges of 209–231 and 233–276 °C were
attributed to the two steps of decomposition. Dehydration
was responsible for a mass loss of 0.9 % between 71 and
76 °C in the TG curve, while decomposition occurred as an
accentuated mass loss of 71.0 % between 195 and 258 °C.
The inorganic residue left after ignition at 900 °C was
28 % of the initial mass. In the DSC curve of the binary
mixture 1:1 (chitosan:SLS) could be noticed that there was
no displacement of the melting point temperature of SLS,
and the measured enthalpy of fusion (DH = 28.2 J g-1) is
closer to that of the expected value (26.4 J g-1). The same
behavior was observed in the first step of decomposition, in
which the theoretical enthalpy value (50.7 J g-1) is very
closer to that experimentally obtained for the mixture
(DH = 51.5 J g-1). These findings suggest that these two
compounds can be considered physically compatible.
Another important observation was that SLS has interfered
in the moisture content of chitosan since the peak at 58 °C
disappeared. As a surfactant, LSL may have decreased the
solid–liquid interfacial tension, facilitating the removal of
water and its evaporation as a consequence of the heating
in the conducted experiments.
The obtained DSC curve for MS agreed with the pre-
vious information about its thermal behavior [30, 35].
Dehydration occurred in two steps with peaks at 89 and
107 °C. The peak at 115 °C attributed to the melting point
was partially overlapped by the second dehydration stage,
and so the enthalpy involved in this transition could not be
calculated. MS proved to be thermostable up to 325 °C,
when decomposition begins in several stages: a first
endothermic peak at 346 °C followed by two exothermic
others at 394 and 431 °C. In the TG curve, 4.5 % of the
initial mass was lost due dehydration between 67 and
97 °C. The mass losses caused by decomposition also
occurred in three different rates, in accordance with the
DSC findings: 17.0, 51.7, and 15.0 % of the initial mass
were lost, respectively, in the temperature ranges of
299–347, 374–409, and 418–444 °C. From 500 °C, there
was no more mass loss, with the remaining 9.7 % in the
form of ash due to inorganic magnesium. As seen in DSC
curve obtained from binary mixture 1:1 (chitosan:MS), all
1097
characteristic events of both compounds seem to have been
suppressed after physical mixture, specially the melting
point of MS, which indicate a strong interaction between
chitosan and MS.
In accordance with the literature for the thermal
behavior of CSD [30, 35], this compound does not present
any thermal event in the investigated DSC and TG tem-
perature ranges. The curve of the binary mixture 1:1
(chitosan:CSD) does not show any characteristic peak of
chitosan, but since the characteristic absence of signals of
CSD could be due to the predominant behavior after
mixture, there was no evidence to assume that these
materials are incompatible. On the other hand, this result
was insufficient to attest the compatibility between these
compounds, and it needs to be confirmed by other analytic
techniques such as FTIR.
The DSC curve of CC did not present any thermal event
in the investigated temperature range (0–500 °C), in
accordance with Sanders and Gallagher’s observation [42],
which showed that CC presented just one endothermic
event above 600 °C due to its decomposition in calcium
oxide (CaO) and carbon dioxide (CO2). The TG curve
confirmed the occurrence of a single mass loss of 39.2 %
due to the decomposition between 605 and 737 °C, with
the remaining 52.4 % in the form of ash due to inorganic
calcium. The resultant DSC curve of the binary mixture 1:1
(chitosan:CC) had preserved the analytic profiles of both
the compounds. The measured area of the chitosan
decomposition peak at 305 °C (DH = 88.0 J g-1) was
very closer to the calculated value (90.5 J g-1), which
indicates the presumable physical compatibility between
chitosan and CC.
Infrared Analysis
The FT-IR spectroscopy could be used as a supplementary
technique in order to investigate the possible chemical
interaction between excipients and to confirm the results
obtained by the thermal analysis. It is the most suitable
technique of the nondestructive spectroscopic methods and
has become an attractive method in the analysis of phar-
maceutical solids, since the materials are not subjected to
thermal or mechanical energy during samples preparation
[30]. When the FT-IR spectra are a summation of the
characteristic traces obtained with the individual compo-
nents present in the physical mixtures, this indicates that
there was no chemical interaction between the studied
compounds [43]. This is the reason why we proposed the
acquisition of the theoretical spectrum to be compared to
the experimental spectrum of the binary mixture.
The absence of incompatibility indicated by thermal
analysis for chitosan’s mixture with talc and SSG was
confirmed by FT-IR since each experimental spectrum
123
1098
Fig. 5 Experimental
(continuous lines), and
theoretical (dashed lines) IR
spectra of the binary mixtures of
SLS, CC, DCP, and MS with
chitosan
Transmittance/%
3900
could be entirely superimposed to the respective theoretical
spectrum. Although the DSC curves of starch and CSD was
not conclusive about its thermal compatibility with chito-
san, the experimental spectra of its mixtures with chitosan
demonstrated great correlation with the theoretical ones,
confirming that chitosan is compatible with these excipi-
ents. FT-IR results also confirmed the compatibility of
chitosan with MC, lactose, and CCS although DSC curves
have indicated some levels of interaction under heating
conditions. The indication of solid–solid interaction by
thermal analysis must not be necessarily interpreted as a
pharmaceutical incompatibility [31] since the interactions
observed at high temperatures may not always be relevant
at room temperature [30]. On the other hand, the binary
mixtures of chitosan with SLS and CC have not demon-
strated a good overlapping of its respective theoretical and
experimental FT-IR spectra, in contrast to DSC thermal
observations, which did not detect significant changes in
the thermoanalytic profile of these compounds. Interactions
of chitosan with DCP and MS were duly confirmed by both
FT-IR and thermal analyses.
Figure 5 shows the IR spectra of the binary mixture of
chitosan with the four excipients that do not demonstrate
good correlation between theoretical and experimental
spectra.
The theoretical and experimental IR spectra of the bin-
ary mixture between chitosan and SLS showed two regions
indicated by arrows that presented the greatest deviations.
The broad band between 3000 and 3600 cm-1 was attrib-
uted to O–H stretching which corresponds to structural
123
M. A. V. Pereira et al.
chitosan + SLS
chitosan + CC
chitosan + DCP
chitosan + MS
3600 3300 3000 2700 2400 2100 1800 1500 1200 900
Wavenumber/cm–1
water within chitosan. This observation demonstrates that
SLS actually interferes in the water content of chitosan
since DSC analysis of the binary mixture showed the same
effect. Another divergence was observed in the higher field
of the IR spectrum. The bands at 993, 1016, and
1082 cm-1 were more intense in the physical mixture than
in SLS alone. However, there was no displacement of the
absorption bands corresponding to the symmetric
(1,085 cm-1) and asymmetric (1,217 cm-1) stretch of SO2,
indicating that SLS has not formed a new salt or complex
onto chitosan.
In the cases of CC, DCP, and MS, all of them showed
deviations between theoretical and experimental spectra
(indicated by arrows) by the appearance of new absorption
bands between 900 and 1200 cm-1. This wavenumber
range is the IR region in which bands of symmet-
ric and asymmetric stretching vibrations of ionized groups
are usually observed. Probably, chitosan has interacted
with these salts in the same way. In fact, CC, DCP, and MS
have a common feature: they are salts that have divalent
cations as counter ion, Ca?2 or Mg?2. This is the key
characteristic to explain the mechanism of interaction.
Chitosan is a low-cost sorbent useful for binding heavy
metals from contaminated water and its ability to form
complexes with metal ions is well documented in the lit-
erature [44–46]. The complexing main sites of chitosan are
the nitrogen atom of the amino groups in deacethylated
units and the oxygen atom of the hydroxyl groups, since
both nitrogen and oxygen atoms have a lone pair or lone
pairs of electrons that can bind a proton. However, the
Compatibility study between chitosan and pharmaceutical excipients
attraction of the electrons pair by the atom nucleus is
stronger in oxygen than in nitrogen, which makes nitrogen
the greatest electron pair donor to form coordination
complexes with metal cations. Heavy metal binding can be
hindered by nonmetal cations, and among these, Ca?2 has
caused the major inhibition [45], suggesting that nonmetal
cations can compete for the same binding sites of chitosan.
From these observations, it could be concluded that Ca?2
and Mg?2 are also able to form coordinate complexes with
chitosan. Since the complexes are formed by coordination
bonds between nitrogen atoms of two deacetylated units of
chitosan and one divalent cation, this complexation did not
occur with monovalent cations, and it was not observed in
the tested Na?-containing excipients (CCS, SSG, and
SLS).
This work demonstrates that chitosan can form com-
plexes with divalent cations in solid–solid associations
although adsorption properties of chitosan to bind ions in
aqueous solutions had already been well documented. The
associations of chitosan and CC, DCP, or MS in excipients
for solid formulation are not indicated because they interact
with chitosan in the absence of either water or heating,
compromising the stability of the solid dosage form during
storage. Once the amino groups of chitosan are able to
complex with cations by a nonselective mechanism, pos-
sible interactions could happen with other drugs or excip-
ients marketed as divalent cation salts.
Conclusions
The compatibilities of chitosan with some pharmaceutical
excipients were studied by DSC, TG/DTG, and FT-IR
techniques. Although thermal analysis being a versatile and
simple technique to perform and interpret evidences of
interactions between excipients, its results were not always
conclusive, especially because the polymer characteriza-
tion is a difficult goal to be attained. Comparison between
theoretical (obtained using an ad hoc algorithm) and
experimental IR spectra was carried out to confirm the
results obtained by the thermal analysis, and it proved to be
a useful tool to identify excipient–excipient interactions.
Both DSC and FT-IR results demonstrated that chitosan is
compatible with talc and SSG, and FT-IR analysis proved
that starch and CSD are compatible with chitosan even
when DSC results was not conclusive. Despite thermal
analysis having shown some levels, of interaction of
chitosan with MC, lactose, and CCS at high temperatures,
FT-IR indicated that these interactions did not occur at
room temperature, and they are considered to be compat-
ible with chitosan. The combination of MC and chitosan
seems to be advantageous in the syntheses of new bioma-
terials and blends for food and medical applications due to
1099
the enhancement of the thermal stability of MC from 310 to
330 °C. SLS and CC are considered to be compatible in
DSC analysis, but FT-IR spectra indicated that some
interaction had occurred. Since SLS has interacted with the
moisture content of chitosan, they are classified as com-
patible. On the other hand, CC and the last excipients, DCP
and MS, proved to form coordinate complexes with
chitosan. They are considered as incompatible with chito-
san since changes in chemical structure of the excipients
impair its functionality. Interactions of chitosan with DCP
and MS are the strongest ones among the studied excipients
since they were confirmed by both DSC and FT-IR
analysis.
Acknowledgements The authors thank the National Council of
Technological and Scientific Development (CNPq) and Rio Grande
do Norte Research Foundation (FAPERN) for their financial support.
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