Risperidone

Solid-state
characterization
compatibility using thermal and non-thermal techniques

and

pharmaceutical

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 polymorphism. 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) 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 evaluate 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.
The solid-state characterization of an Active Pharmaceutical Ingredient (API) by suitable analytical
methods,
The API-excipient association may cause two types of interactions: 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, crystallization, 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 formulation quality, safety and efficiency
In this work, risperidone, the API, was characterized using techniques including thermal analysis (TG and
DSC), PXRD, IR and SEM. The primary aim of this work was to study the compatibility of risperidone
with pharmaceutical excipients using DSC analysis. Solid-state incompatibilities were evaluated by FT-IR
combined with Principal Component Analysis (PCA), and chemical incompatibilities were verified using
a stability-indicating LC method
The infrared analyses were performed using an Fourier Transform 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 temperature using 32 scans, a resolution of4 cm1 , and a range from 4000 to 600 cm1
(characterization) or from 1800 to 600 cm1 (chemometrics), corresponding to the fingerprint region. All
spectra were recorded in triplicate.
IR analyses were performed on the samples (before and after heating) to monitor changes in the
absorption
bands
ofrisperidone.
The
infrared results were then subjected to PCA using Matlab R2012a software.
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 cm1 ). However, spectral variations were not visually observed in the mixtures 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 cm1 , whereas in the mixtures with
microcrystalline cellulose (Fig. 6b) and anhydrous 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 cm1 . In the mixture
with starch, changes in the lower intensity bands from 1300 to 1500 cm1 were observed. Similar results
were obtained for the other binary mixtures (data not shown).

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
products 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 ofthe DSC results.