Caracterização e compatibilidade farmacêutica de risperidona por análise térmica e não térmica (em Inglês)

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Thermochimica Acta 568 (2013) 148– 155
Contents lists available at SciVerse ScienceDirect
Thermochimica Acta
jo ur nal home p age: www.elsev ier .com/ locate / tca
isperidone – Solid-state characterization and pharmaceutical
ompatibility using thermal and non-thermal techniques
osiane Souza Pereira Daniela, Isabela Pianna Veroneza, Larissa Lopes Rodriguesa,
arcello G. Trevisana,b, Jerusa Simone Garciaa,∗
Laboratório de Análise e Caracterizaç ão de Fármacos – LACFar, Instituto de Química, Universidade Federal de Alfenas, Alfenas, Minas Gerais, Brazil
National Institute of Bioanalytics Science and Technology – INCTBio, Institute of Chemistry – UNICAMP, 13084-653, Campinas, São Paulo, Brazil
a r t i c l e i n f o
rticle history:
eceived 19 March 2013
eceived in revised form 20 June 2013
ccepted 24 June 2013
vailable online xxx
a b s t r a c t
A full solid-state characterization of risperidone was conducted using differential scanning calorimetry
(DSC), thermogravimetry (TG), powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy
(FT-IR) and scanning electron microscopy (SEM) to examine its physicochemical properties and polymor-
phism. The primary aim of this work was to study the compatibility of risperidone with pharmaceutical
excipients using DSC to obtain and compare the curves of the active pharmaceutical ingredient (API)
eywords:
PI-excipient compatibility
G
SC
T-IR
iquid chromatography
and the excipients with their 1:1 (w/w) binary mixtures. These same binary mixtures were turned to
room temperature and analyzed by FT-IR combined with principal component analysis (PCA) to evalu-
ate solid-state incompatibilities. The chemical incompatibilities of these samples were verified using a
stability-indicating liquid chromatography (LC) method to assay for the API and evaluate the formation
of degradation products. All of these methods showed incompatibilities between risperidone and the
excipients magnesium stearate, lactose and cellulose microcrystalline.
. Introduction
The solid-state characterization of an Active Pharmaceutical
ngredient (API) by suitable analytical methods, which is an impor-
ant step in the early stages of pharmaceutical research and
evelopment from both scientific and regulatory perspectives,
as resulted in many publications in this field [1–5]. The distinct
hysicochemical characteristics of different polymorphic forms of
 pharmaceutical solid can alter the in vivo activity of the API [6–8].
or example, the antibiotic 5-chloro-8-hydroxyquinoline exists in
wo different polymorphic forms, Forms I and II, which show a sol-
bility ratio of 1.5 for Form II/Form I [9]. Thus, if Form II is used
n a formulation that usually contains Form I, the bioavailability
s improved, which can result in toxicity in patients. In contrast,
f Form I is used instead of Form II, a suboptimal effect may be
roduced, resulting in decreased therapeutic efficacy.
However, APIs are not commonly administered as single ingre-
ients; they are often part of a formulation with one or more
on-medicinal agents, called excipients, which establish the pri-
ary features of the pharmaceutical product and contribute to the
hysical form, texture, stability, taste, and overall appearance [10].
∗ Corresponding author. Tel.: +55 3532991261.
E-mail addresses: jerusa.garcia@unifal-mg.edu.br,
erusa.garcia@gmail.com (J.S. Garcia).
040-6031/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
ttp://dx.doi.org/10.1016/j.tca.2013.06.032
© 2013 Elsevier B.V. All rights reserved.
The API-excipient association may cause two types of inter-
actions: a solid-state interaction [1,7,11,12] and a chemical
interaction [11,13,14]. A solid-state interaction can cause the API to
change its polymorphic form (through amorphization, crystalliza-
tion, or co-crystal formation) the excipient to solubilize the API or
intermolecular interactions to form between the functional groups
of various substances. However, solid-state interaction cannot be
considered an incompatibility if the excipients do not alter the
result of the API assay. Chemical reactions can occur between the
API and excipients that cause API degradation and the formation
of new degradation products or impurities. In this case, there is an
incompatibility between substances. Both chemical and solid-state
interactions can occur during the manufacture or storage of drug
products, and these interactions can result in changes to formula-
tion quality, safety and efficiency [11,15]. Therefore, API-excipient
compatibility studies are essential when deciding which excipi-
ents to use in a new formulation or when reformulating an existing
product [5,7,111].
Analytical and physicochemical techniques such as Thermal
Analysis (Differential Scanning Calorimetry (DSC) and Ther-
mogravimetry (TG)), Powder X-ray Diffraction (PXRD), Fourier
transform Infrared (FT-IR) Spectroscopy and Scanning Electron
Microscopy (SEM) have been used to characterize APIs to obtain
information on the polymorphic state, particle size, powder mor-
phology, melting point, crystallinity and stability/degradation
[6,7,16,17]. DSC is an important, low-cost and useful tool to rapidly
dx.doi.org/10.1016/j.tca.2013.06.032
http://www.sciencedirect.com/science/journal/00406031
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mailto:jerusa.garcia@gmail.com
dx.doi.org/10.1016/j.tca.2013.06.032
imica Acta 568 (2013) 148– 155 149
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Table 1
Sample selection of control sets (Xc) and evaluation (Xe):.
Samplesa Before heatingb After heatingb
Risperidone (1) Xc (3) Xc(3)
Excipients (5) Xc (15) Xc (15)
Binary mixtures (5) Xc (15) Xe (15)
J.S.P. Daniel et al. / Thermoch
btain information regarding the possible interactions among
omponents of a formulation [11,14,15]. A DSC curve provides ther-
al parameters, including the melting point, melting enthalpy,
nd glass transition, and the crystallization and decomposition
emperatures of the API. In addition, interactions are evaluated
ccording to the appearance, shift or disappearance of endother-
ic or exothermic peaks and variations in the corresponding
nthalpy values in the thermal curves of the drug–excipient mix-
ures [11,15,18]. However, the thermal data should be interpreted
arefully to avoid erroneous conclusions because high temper-
tures may cause interactions that are not observed at room
emperature. Furthermore, not all solid-solid interactions indicate
 pharmaceutical incompatibility; therefore, DSC is commonly used
ith other analytical techniques, such as IR and Liquid Chromatog-
aphy (LC) [11,12,14].
Risperidone is the API evaluated in this work. It is isolated as
 white powder and is a benzoxazole derivate used for the treat-
ent of schizophrenia and other similar psychotic disorders. The
echanism of risperidone involves blocking the 5HT2A and D2
eceptors, and it is a member of the class of atypical antipsychotics,
hich are distinguished by better therapeutic efficiency and fewer
dverse effects than classical antipsychotics [19,20]. Many publi-
ations report the analysis of risperidone by LC with UV and MS
etection of the bulk powder, tablet and biological samples [21–23].
urthermore, the characterization of risperidone polymorphs, as
orms A, B and C, has been performed by IR, Raman and XRPD
24,25]. However, there are no publications concerning the com-
atibility between risperidone and excipients.
In this work, risperidone, the API, was characterized using tech-
iques including thermal analysis (TG and DSC), PXRD, IR and SEM.
he primary aim ofthis work was to study the compatibility of
isperidone with pharmaceutical excipients using DSC analysis.
olid-state incompatibilities were evaluated by FT-IR combined
ith Principal Component Analysis (PCA), and chemical incompat-
bilities were verified using a stability-indicating LC method.
. Material and methods
Risperidone, 99% purity, (batch #164014) was provided by
urofarma Laboratories Ltd., Brazil. The pharmaceutical grade
xcipients examined (99% purity) were magnesium stearate
Indukern, Brazil, batch #C216000), sodium lauryl sulfate (Basf,
razil, batch #8625338), starch (Cargil, Brazil, batch #7858),
icrocrystalline cellulose (Blanver, Brazil, batch #135000020) and
nhydrous lactose (M Cassab, Brazil, batch #1320013819).
Binary mixtures of the API-excipient were prepared in a 1:1
w/w) ratio in a polyethylene container (3 cm height × 2 cm diam-
ter). The samples were homogenized by vortexing for 1 min, and
tainless steel balls (2 mm diameter) were used to mix the samples.
The risperidone sample was characterized by DSC, TG, PXRD,
T-IR and SEM. The binary mixtures were also analyzed by DSC
o determine whether there were changes in the thermal curves.
R analyses were performed on the samples (before and after heat-
ng) to monitor changes in the absorption bands of risperidone. The
nfrared results were then subjected to PCA using Matlab R2012a
oftware. TG analyses were performed to evaluate the thermal sta-
ility of risperidone in the API-excipient mixture. In addition, LC
nalyses were performed to confirm and compare the results.
.1. Differential scanning calorimetry
The DSC curves were obtained using a DSC Calorimeter (model
SC7020, SII Nano Technology, Japan) under a dynamic atmosphere
f nitrogen (50 mL min−1) with a heat flow of 10 ◦C min−1 from
0 to 500 ◦C using open aluminum crucibles. The instrument was
a Number of samples in parenthesis;
b Number of spectra in parenthesis considering the analysis in triplicate.
calibrated with an indium standard. The calibration parameters
were obtained by using the temperature of the extrapolated peak
to determine the fusion temperature (Tonset = 156.6 ◦C) and fusion
enthalpy (�Hf = 28.5 J g−1) of indium standard.
2.2. Thermogravimetric analysis
TG measurements were performed using a thermobalance
(model TG/DTA7300, SII Nano Technology, Japan) under a dynamic
atmosphere of nitrogen (50 mL min−1) with a heat flow of
10 ◦C min−1 from 30 to 500 ◦C using open aluminum crucibles. The
equipment was calibrated using an indium standard for tempera-
ture and an alumina calibration weight for mass.
2.3. Powder X-ray diffraction
PXRD was performed using a diffractometer (model Ultima IV,
Rigaku, Japan) with measurements of 2� ranging from 5◦ to 55◦ at
40 kV and 30 mA. The sample was prepared according to USP 32
instructions (procedure 941) [26].
2.4. Infrared spectroscopy
The infrared analyses were performed using an Fourier Trans-
form Infrared spectrometer (model IRAffinity-1, Shimadzu TM,
Japan) coupled to a Attenuated Total Reflectance (ATR) sampling
accessory with ZnSe waveguides (model Pike MiracleTM, Pike
TechnologiesTM, USA). The spectra were recorded at room temper-
ature using 32 scans, a resolution of 4 cm−1, and a range from 4000
to 600 cm−1 (characterization) or from 1800 to 600 cm−1 (chemo-
metrics), corresponding to the fingerprint region. All spectra were
recorded in triplicate.
2.5. Principal component analysis
Spectroscopic techniques generate large data matrices, which
may be complex and difficult to interpret. An alternative when
extracting critical information from large data sets is multi-
variate analysis, which is called chemometrics when applied to
chemical-specific applications [26]. In this work, to improve the
interpretation of the results from the FT-IR spectra of the samples
before and after heating, the spectral data were subjected to chemo-
metrics analysis via PCA. This was a multivariate projection method
used to extract and display systematic variation in a data set, and its
use allows the number of variables in a multivariate data set to be
reduced while retaining the variation present in the data set to the
greatest extent possible [27]. Ayala et al. employed PCA to analyze
the spectral data from the Raman analysis of aripiprazole in order
to evaluate its thermal stability [26]. Haware et al. used PCA for the
exploratory analysis of data from the FT-IR and PXRD analyses of
pharmaceutical mixtures of acetylsalicylic acid.
The obtained spectra of all samples (the five excipients, risperi-
done and the five binary mixtures, before and after DSC heating)
were loaded into Matlab (Matworks Inc.). The spectra were divided
into control (Xc) and evaluation (Xe) groups. Table 1 shows the spec-
tra of each excipient and risperidone (before and after heating). The
150 J.S.P. Daniel et al. / Thermochimica Acta 568 (2013) 148– 155
F al ana
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ig. 1. (a) X-ray diffractogram of risperidone: 5–55◦2�, 40 kV; 30 mA; (b) Therm
itrogen, 50 mL min−1; open aluminum crucibles), DSC (30–200 ◦C; 10 ◦C min−1; atm
f risperidone: (i) 500×; (ii) 5000× and (iii) 10,000× magnification.
pectra of the binary mixtures at the initial times were used as the
ontrols (Xc), and the spectra of the binary mixtures after heating
ere used as the evaluation group (Xe).
The control Xc and Xe sets were defined by two matrixes with
imensions of 51 rows (spectra of 17 samples in triplicate) by 624
olumns (spectral points) and 15 rows by 624 columns, respec-
ively. The PCA multivariate model was performed using Xc and
as evaluated with the new samples of Xe using preprocessing
ean-centering and leave-one-out. The best model was chosen
sing the smallest value of the root mean square error of the cross
alidation (RMSECV). Principal Component Analysis was conducted
sing PLS toolbox 6.1 (Eigenvector Research Inc.).
The FT-IR spectrum of risperidone after heating was inserted
n the Xc to establish a null hypothesis. In this manner, all spectral
esidues of the binary mixtures after heating result from the inter-
ctions between the API and the excipients and not from the solid
tate (crystalline to amorphous) of the API.
.6. Scanning electron microscopy
SEM was performed using a field emission scanning electron
icroscope (model JSM-6340F, JEOL, Japan) after vacuum-coating
ith gold and using direct analysis by SEM (500×; 5000×;
0,000×).
.7. Liquid chromatography
The LC analysis was performed using an Ultimate 3000 LC sys-
em (Thermo Scientific, California). Deionized water was prepared
sing a Milli-Q Academic water purification system from Millipore
São Paulo, SP, Brazil). HPLC grade methanol CROMASOLV® ≥99.9%
nd acetic acid ≥99.9% from Sigma–Aldrich (St. Louis, MO, USA)
nd analytical grade ammonium acetate from ISOFAR (Duque de
axias, RJ, Brazil) were used to prepare the mobile phase. The chro-
atographic conditions were chosen according to United States
harmacopeia 32 [26]. The chromatographic column used was an
clipse Plus C18 (Agilent), 4.6 mm × 100 mm, with a 3.5 �m particle
ize. The mobile phase consisted of a gradient of a methanol:pH 6.5
lysis of risperidone: TG and DTG curves (30–500 ◦C; 10 ◦C min−1; atmosphere of
ere of nitrogen, 50 mL min−1; open aluminum crucibles); (c) SEM photomicrograph
ammonium acetate buffer according to USP 32. The flow rate was
1.5 mL min−1, the column temperature was maintained at 35 ◦C, the
detection wavelength was 275 nm, and the injection volume was
20 �L.
To prepare the standard solution of risperidone and other sam-
ples, a mixture of water:methanol:pH 6.5 ammonium acetate
buffer at a ratio of 9:10:1 was used as the diluent. The concen-
trations of the standards were 0.02, 0.05, 0.10, 0.15, 0.20 and
0.25 mg mL−1. The peak area was used for the calibration curve.
3. Results and discussion
3.1. Characterization
The data show that risperidone is a crystalline substance with
a well-defined diffraction X-ray patternand a fusion peak in the
DSC curve. These properties are important to ensure that the DSC
technique is appropriately utilized in the proposed compatibility
studies [15,18].
The PXRD pattern (Fig. 1a) has peaks at 2� at 6.8, 10.5, 11.3,
14.1, 14.7, 15.3, 16.3, 18.4, 18.8, 19.7, 21.2, 22.3, 23.0, 25.2, 28.3
and 28.8, corresponding to form C of the API [25]. The results
of the thermal analysis are shown in Fig. 1b, and the DSC curve
presents an endothermic peak with Tonset at 170.52 ± 0.02 ◦C, Tp
(temperature of peak) at 172.6 ± 0.4 ◦C and Tf (temperature of the
extrapolated endset) at 175.3 ± 0.1 ◦C. This peak corresponds to the
fusion of risperidone, and there is no demonstrated loss in mass at
this temperature, as shown by the TG curve and in the literature
(169–173 ◦C) [20]. The DTG (Derivate of TG curve) presented two
peaks corresponding to the mass losses observed in the TG. The first
mass loss (a decrease of 38.01%) occurred in the temperature range
from 230.3 to 367.3 ◦C. The second mass loss occurred in the tem-
perature range from 367.3 to 516.5 ◦C, and resulted in a decrease
of 22.31%. The fusion enthalpy was 101.91 J g−1.
SEM (Fig. 1c) demonstrated the API particle shape to be crys-
tal flakes, as classified by United States Pharmacopeia 32 [26]. This
determination is important because the crystal morphology of API
J.S.P. Daniel et al. / Thermochimica Acta 568 (2013) 148– 155 151
using
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Fig. 2. IR spectrum of risperidone: at room temperature 
nfluences the physical properties, such as particle orientation, dis-
olution rate, compaction and compressibility behavior, packing
nd powder flow [28].
The characteristic absorption bands of risperidone are observed
n the IR spectrum (Fig. 2): 3064 cm−1, the weak band of C H
tretching of the aromatic ring; 1643 cm−1, the strong band of
 O stretching of the ı-lactam ring; 1610 and 1534 cm−1, the
ntermediate to strong bands of C C stretching of the aromatic
ing and the intermediate to weak bands at region A correspond-
ng to C N and C O angular deformations of the oxazole ring;
352 cm−1, the intermediate band of C N stretching of the oxa-
ole ring; 1192 cm−1, the intermediate band corresponding to the
ertiary amine of the piperidine ring; and 1129 cm−1, the strong
and corresponding to the aryl fluoride [29].
.2. Compatibility study
In compatibility studies, thermoanalytical techniques com-
only are a reliable screening method for stable pharmaceutical
xcipients and can be performed within a few hours [30–32]. The
G/DTG curves of the physical mixtures of the API and excipi-
nt may predict when decomposition will occur, as shown by the
xperimental data. A typical non-interaction profile by TG analysis
s shown in Fig. 3a and corresponds to risperidone, microcrystalline
ellulose and their 1:1 physical mixture [15].
ig. 3. (a) TG of risperidone, microcrystalline cellulose and mixture; (b) TG of
isperidone, anhydrous lactose and mixture. 30–500 ◦C; 10 ◦C min−1; atmosphere
f nitrogen, 50 mL min−1; open aluminum crucibles.
 32 scans, resolution of 4 cm−1, at range 4000–600 cm−1.
The microcrystalline cellulose showed a first mass loss event
from room temperature to approximately 100 ◦C, with a loss of
4.8% moisture, followed by another mass loss event occurring at
a temperature range from 272 to 387 ◦C. In the mixture, the first
mass loss corresponded to the moisture of microcrystalline cel-
lulose (2.7%, at room temperature to approximately 100 ◦C), and
the second event began at 230 ◦C and represented the beginning
of risperidone mass loss. Therefore, microcrystalline cellulose does
not affect the thermal stability of risperidone and vice versa. Similar
results were obtained with the TG curves of magnesium stearate,
sodium lauryl sulfate and starch.
However, the TG curve of the binary mixture of anhydrous
lactose and risperidone showed the accelerated thermal decompo-
sition of risperidone (Fig. 3b). In this case, the first mass loss event
of the mixture (at 181 ◦C) occurred at a temperature lower than
those for the API (230 ◦C) or the excipient (207 ◦C) alone. Similar
interactions were observed by TG analysis when lactose was mixed
with captopril [33], venlafaxine [7], olanzapine [16] or propranolol
hydrochloride [33].
The DSC curves obtained for the API and excipients are shown
in Fig. 4a. In this figure, the melting temperature range of risperi-
done (170.5 to 175.3 ◦C) does not overlap with the thermal events
from the evaluated excipients. The thermal profiles of the mixtures
were expected to be a superposition of the DSC curves from the
mixture components. Therefore, any change in the shape, Tonset or
�Hf is indicative of some interaction between risperidone and the
excipients [15]. If no such interaction occurs, the Tonset value of the
mixture should be equivalent to that of the API alone (170.5 ◦C),
and the �Hf value should be half of the value of the API sample
(51.0 J g−1), i.e., only half of each mg of the mixture corresponds to
risperidone. Chemical (degradation, hydrolysis, or oxidation) and
solid-state incompatibilities (solubilization or polymorphism) can
be detected by changes in the DSC profile of mixtures using an
API standard as the reference [11,16,34]. Generally, a peak shift,
enthalpy reduction or the total disappearance of peak are the most
commonly observed changes.
The DSC curves of risperidone and its binary mixtures (Fig. 4b)
as well as the corresponding values of Tonset and �Hf are given
in Table 2. The fusion enthalpy and fusion temperature values
obtained from risperidone and the binary mixtures are presented as
the average values ± confidence interval (CI) obtained from at least
three replicates. The differences among samples were determined
using ANOVA, and p < 0.05 was considered significant, according
to the Scott–Knott test. In general, the Tonset from binary mixtures
was slightly shifted away from the reference value. A small decrease
in the Tonset was observed with the anhydrous lactose, microcrys-
talline cellulose, starch and sodium lauryl sulfate mixtures, which
may be due to the partial miscibility between the components of
the mixtures, as described by Pani et al. and Ford et al. [12,18]. The
magnesium stearate mixture presented a Tonset slightly higher than
expected. The results related to the Tonset values were not conclusive
152 J.S.P. Daniel et al. / Thermochimica Acta 568 (2013) 148– 155
Fig. 4. (a) DSC curves of risperidone and the isolated excipient; (b) DSC curves of risperidone and binary mixtures 1:1 (w/w) risperidone/excipient. 30–500 ◦C; 10 ◦C min−1;
atmosphere of nitrogen, 50 mL min−1; open aluminum crucibles.
empe
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Fig. 5. Risperidone IR spectra before and after DSC analysis at room t
egarding the compatibilities between mixture components. Thus,
nly �Hf was used as an evaluation parameter in this compatibility
tudy.
The mixtures containing sodium lauryl sulfate and starch exhib-
ted values of �Hf statistically equivalent to the expected value.
hus, there was no change in the �Hf values, and no incompati-
ilities were detected in these samples. The fusion enthalpy was
maller than expected for the mixtures of API with anhydrous
actose, microcrystalline cellulose and magnesium stearate. Thus,
here were some interactions between risperidone and these three
xcipients. Many compatibility studies show interactions between
ther APIs and magnesium stearate [5,7,11,12,14], microcrystalline
ellulose [1,7,14] and anhydrous lactose [10,13].
In this study, a strategy involving FT-IR, DSC and multivariate
nalysis to identify API-excipient incompatibilities was employed,
n contrast to the visual comparison previously described [7,12,14].
he samples were analyzed by ATR FT-IR immediately after prepa-
ation. Subsequently, they were heated from 30 ◦C to 200 ◦C using
able 2
emperature of fusion (Tonset) and enthalpy of fusion (�Hf) values to binary mixtures
:1 (w/w) Risperidone/excipient(average ± CI, n = 3). Values in the same column
ollowed by the same letters showed no significant differences (P < 0.05) according
o Scott Knott test.
Sample Average ± CI
�Hf (mJ mg−1) Tonset(◦C)
Risperidone 102.0 ± 0.3 (a) 170.52 ± 0.02 (a)
Risperidone + anhydrous lactose 38 ± 2 (b) 168.6 ± 0.3 (b)
Risperidone + microcrystalline cellulose 37 ± 8 (b) 169.2 ± 0.1 (b)
Risperidone + starch 47 ± 5 (a) 169.13 ± 0.04 (b)
Risperidone + sodium lauryl sulfate 44 ± 6 (a) 169.6 ± 0.4 (b)
Risperidone + magnesium stearate 36 ± 8 (b) 170.9 ± 0.3 (c)
rature using 32 scans, resolution of 4 cm−1, at range 4000–600 cm−1.
a DSC apparatus. After this procedure, the samples were cooled to
room temperature (30 ◦C), and the ATR FT-IR analysis was repeated.
The main purpose of this experiment was to identify if the enthalpy
reduction observed in some binary mixtures showed alterations
in the risperidone absorption fingerprint (1800 to 600 cm−1). The
risperidone infrared spectra before and after heating showed a sim-
ilar absorption profile, meaning that the drug is thermostable over
the temperature range of the DSC experiment (30 ◦C to 200 ◦C,
10 ◦C min−1). The same procedure was performed on the each
excipient, and the results were similar, as only insignificant varia-
tions in the spectra were observed (Fig. 5).
Comparing the FT-IR spectra before and after heating of the
three binary mixtures that showed enthalpy changes from DSC
(risperidone with magnesium stearate, microcrystalline cellulose
and anhydrous lactose), some variations were observed visually,
especially in the risperidone fingerprint region (1800 to 600 cm−1).
However, spectral variations were not visually observed in the mix-
tures that did not show enthalpy changes (risperidone:starch), as
shown in Fig. 6. The changes in the stearate mixture (Fig. 6a) are
more visible in the region between 1700 and 1300 cm−1, whereas
in the mixtures with microcrystalline cellulose (Fig. 6b) and anhy-
drous lactose (Fig. 6c), there is a reduction in the intensity of all
bands in addition to changes in the shapes of the bands between
1300 and 1000 cm−1. In the mixture with starch, changes in the
lower intensity bands from 1300 to 1500 cm−1 were observed. Sim-
ilar results were obtained for the other binary mixtures (data not
shown).
To develop an FT-IR method that was more robust than visual
comparison, all of the spectra from the samples (risperidone, excip-
ients and the binary mixtures) before and after DSC analysis were
submitted to Principal Component Analysis (PCA). The best PCA
model fitted to the Xc data set was obtained using cross-validation
J.S.P. Daniel et al. / Thermochimica Acta 568 (2013) 148– 155 153
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( ow); 
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ig. 6. Comparison between Infrared absorption spectra of four mixtures before a
below); (b) risperidone + microcrystalline cellulose before (above) and after (bel
one + starch before (above) and after (below). All samples were analyzed at 25 ◦C (
y leave-one-out, processing with mean-centering, and showed
ve principal components and an explained variance of 95.4%.
fter building the model, the Xe data sets were evaluated, and the
esidues of each sample were plotted (Fig. 7); the horizontal line
threshold obtained with a 99% confidence interval) identifies the
igher residual samples. Those samples located below the line show
pectra according to the expected profile obtained from the control
et spectra. In contrast, the samples located above the threshold
how significant changes in their spectra after heating. Spectra 1
o 51 include the triplicate analyses of the API and each excipient
efore and after heating and the binary mixtures before heating
ig. 7. PCA of all samples. Black points represent control group samples (API or isolated ex
epresent evaluated group samples (binary mixtures after heating). The samples analys
0–12: starch after heating; 13–15: R + starch; 16–18: microcrystalline cellulose; 19–21: m
agnesium stearate; 28–30: magnesium stearate after heating; 31–33: R + magnesium st
 + anhydrous lactose; 43–45: sodium lauryl sulfate; 46–48: sodium lauryl sulfate after 
 + microcrystalline cellulose after heating; 58–60: R + magnesium stearate after heating;
eating.
ter 200 ◦C heating: (a) risperidone + magnesium stearate before (above) and after
(c) risperidone + anhydrous lactose before (above) and after (below); (d) risperi-
(used as the control). Spectra 52 to 66 are the triplicates of the
binary mixtures after heating.
As shown, the points representing the mixtures with micro-
crystalline cellulose, magnesium stearate or anhydrous lactose are
above the upper horizontal line, indicating that significant changes
occur in those spectra. The same excipients, when heated, do not
fall within the superior quadrant, suggesting that the spectral dif-
ferences occur only in the presence of risperidone. Additionally,
these are the same samples that demonstrated enthalpy values
lower than expected for the DSC analysis. This correlation suggests
an incompatibility between risperidone and these three excipients
cipients before and after heating and binary mixtures before heating). Red triangles
is were done in triplicate: 1–3: risperidone (R); 4–6: R after heating; 7–9: starch;
icrocrystalline cellulose after heating; 22–24: R + microcrystalline cellulose; 25–27:
earate; 34–36: anhydrous lactose; 37–39: anhydrous lactose after heating; 40–42:
heating; 49–51: R + sodium lauryl sulfate; 52–54: R + starch after heating; 55–57:
 61–63: R + anhydrous lactose after heating; 64–66: R + sodium lauryl sulfate after
154 J.S.P. Daniel et al. / Thermochimica
Fig. 8. Chromatograms of samples after heating: (a) only risperidone; (b) risperi-
done + anhydrous lactose; (c) risperidone + microcrystalline cellulose; (d) risperi-
d
3
a
b
i
i
w
a
4
d
(
d
t
o
h
s
p
e
r
w
s
d
d
m
d
m
c
t
a
b
1
a
w
t
one + magnesium stearate. Analysis condition: column C-8, 4.6 mm × 100 mm,
.5 �m particle, 35 ◦C; mobile phase gradient of methanol:water:buffer ammonium
cetate pH 6.
ecause a decreased melting enthalpy is generally associated with
nfrared spectra changes.
To identify solid-state or chemical incompatibilities, a stability-
ndicating chromatographic determination based on USP [26]
as performed on the same samples after DSC heating. The
nalysis of risperidone after heating shows a new peak at
.3 min with 4% of the area of the risperidone initial stan-
ard, and this peak corresponds to degradation product 1
Fig. 8a). This result shows that heating caused partial thermal
egradation of risperidone, which was considered in all binary mix-
ures.
The starch mixture presented a concentration similar to previ-
us values after heating, and its LC profile was equivalent to the
eated risperidone sample. The mixture of API and sodium lauryl
ulfate did not show peaks corresponding to the degradation
roduct, and the risperidone concentration in this sample was
quivalent to the reference value. Anhydrous lactose increased
isperidone degradation, and its final risperidone concentration
ith lactose shows a smaller area than the heated risperidone
ample; however, no new peaks were observed (Fig. 8b). The
ecrease in the risperidone area and the absence of new degra-
ation peaks can be explained by the TG results, which show a
ass loss at 181 ◦C, most likely due to the generation of volatile
egradation products of risperidone. The microcrystalline cellulose
ixture shows a peak corresponding to degradation product 1,
omprising 8% of the reference area (Fig. 8c), which is larger
han that observed in the heated risperidone sample, indicating
n increase in risperidone degradation. The magnesium stearate
inary mixture shows peaks corresponding to degradation product
 and one new peak at 11.3 min (Fig. 8d). All pure excipients before
nd after heating were analyzed by this method, and no new peaks
ere observed in the chromatogram.
The chromatography results confirm the initial data obtained by
hermal analysisand the combination of FT-IR with PCA.
[
 Acta 568 (2013) 148– 155
4. Conclusion
Risperidone was fully characterized using Thermal Analysis
(DSC and TG), IR, PXRD and SEM. The DSC analysis showed that
risperidone was compatible with starch and sodium lauryl sulfate
and that it was incompatible with magnesium stearate, lactose
and microcrystalline cellulose. The FT-IR analyses of the binary
mixtures after heating combined with PCA and LC determination
confirmed the incompatibilities of risperidone with magnesium
stearate, lactose and cellulose microcrystalline.
The incompatibility with magnesium stearate was a chemical
interaction in which degradation products were formed and then
detected using a suitable LC method. The decrease in the amount
of API in the lactose mixture occurred due to the formation of a
volatile degradation product observed by TG. Degradation prod-
ucts were not detected in the sample containing microcrystalline
cellulose, but the decrease in the risperidone enthalpy of fusion,
the spectral alterations in the FT-IR fingerprint, and the reduction
in the concentration shown by LC were sufficient to conclude that
there was an incompatibility resulting from a chemical interaction
in this mixture.
The agreement between the results from each technique
demonstrates that DSC was an efficient and rapid screening tool to
detect pharmaceutical incompatibilities between risperidone and
excipients. The combination of FT-IR with PCA was an important
tool to obtain complementary data regarding the compatibility of
an API with excipients and to improve the interpretation of the DSC
results.
Acknowledgements
The authors acknowledge to Conselho Nacional de Desen-
volvimento Científico e Tecnológico (CNPq), Coordenaç ão de
Aperfeiç oamento de Pessoal de Nível Superior (CAPES-Process
552387/2011-8). The authors thank Fundaç ão de Amparo à
Pesquisa do Estado de Minas Gerais (FAPEMIG-Processes APQ
00975-12 and APQ 01057-12) for financial support.
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