European Journal of Pharmaceutical Sciences 112 (2018) 146–151

Contents lists available at ScienceDirect

European Journal of Pharmaceutical Sciences

journal homepage: www.elsevier.com/locate/ejps

Drug-excipient compatibility assessment of solid formulations containing T

meloxicam
Lucas Melo da Silveiraa, Ariadne Botto Fiorota, Thiago Padovani Xaviera, Maria Irene Yoshidab,
⁎
Marcelo Antonio de Oliveiraa,
a
Centro Universitário Norte do Espírito Santo, UFES, Rodovia BR 101 Norte, km 60, Bairro Litorâneo, 29932-540 São Mateus, ES, Brazil
b
Departamento de Química, Universidade Federal de Minas Gerais, Av. Presidente Antônio Carlos, 6627 – 31270-901 Belo Horizonte, MG, Brazil

A R T I C L E I N F O A B S T R A C T

Keywords: Meloxicam (MLX) is a non-steroidal anti-inflammatory cyclooxygenase (COX) inhibitor that is used to relieve
Meloxicam inflammation and pain. MLX has a preferential affinity for COX-2, which is associated with a lower incidence of
Thermal analysis gastrointestinal side effects. The drug belongs to Class II of the Biopharmaceutical Classification System (BCS) in
Compatibility which dissolution is the limiting step of its bioavailability. In view of this classification, carrying out further
Pharmaceutical formulations
studies regarding the compatibility of MLX with excipients and the mechanisms and kinetics of its degradation
reactions is fundamental because any changes would directly influence the quality of the product. The aim of the
present work is to evaluate solid pharmaceutical formulations containing MLX found on the market to define the
more suitable excipients to improve the stability of the pharmaceutical formulations. Thermal analysis techni-
ques were used to characterize and evaluate the compatibility between the drug and the excipients present in the
market formulations. In the evaluation of its solid-state kinetics, MLX raw material under inert conditions had a
shelf life of approximately 6 years. In the study of compatibility between the drug and excipients, MLX was
found to be incompatible with magnesium stearate after DSC analysis under binary mixtures, which was con-
firmed by stress studies and chromatographic analyzes.

1. Introduction

Meloxicam (MLX) is a nonsteroidal anti-inflammatory drug (NSAID)

that inhibits prostaglandin synthesis by inhibiting cyclooxygenase
(COX) activity and is used to combat inflammation and its symptoms.
Low doses of MLX are considered preferentially selective due to its 10-
fold greater affinity for the COX-2 subtype. This characteristic is gen-
erally associated with a lower incidence of gastrointestinal side effects
(Engelhardt et al., 1996; Katzung, 2014).
Solid-state kinetic studies are performed to evaluate drug stability
The molecular formula of MLX is C14H13O4N3S2, and its molecular
and to provide insights into possible reaction mechanisms. These stu-
structure is shown in (A). MLX has a molar mass of 351.38 g mol− 1, a
dies are typically performed using thermogravimetry (TG), with either
melting point of 254 °C, and an octanol/water partition-coefficient (Log
isothermal or non-isothermal methods, which include adjusted mathe-
P) of 3.43. MLX exhibits low solubility in aqueous media as well as high
matical models that consider degradation rates and the reaction order.
permeability and is thus classified as a class II drug under the
Using the Arrhenius equation, the thermodynamic parameters can be
Biopharmaceutical Classification System (BCS) (Yazdanian et al.,
calculated, including the rate constant, pre-exponential factor and ac-
2004). Dissolution is the rate-limiting step of absorption for drugs with
tivation energy (Khawam and Flanagan, 2006; Zhou et al., 2003).
low solubility and high permeability (class II). Therefore, it is important
Solid-state kinetic models are classified as accelerating, deceler-
to evaluate the factors that influence absorption and, thus, bioavail-
ating, linear or sigmoidal based on the shape of conversion-versus-time
ability through studies during the development stages of pharmaceu-
curves. Therefore, equations that describe thermal decomposition are
tical products.

⁎
Corresponding author.
E-mail addresses: marcelo.oliveira@ufes.br, oliveirama.ufes@gmail.com (M.A. de Oliveira).

https://doi.org/10.1016/j.ejps.2017.11.015
Received 6 July 2017; Received in revised form 1 November 2017; Accepted 16 November 2017
Available online 22 November 2017
0928-0987/ © 2017 Elsevier B.V. All rights reserved.
L.M. da Silveira et al. European Journal of Pharmaceutical Sciences 112 (2018) 146–151

Table 1
Identification and classification of the products evaluated in this study and their respective listed excipients.

Product identification Excipients Classification

Tablets Lab 1 Sodium citrate dihydrate, lactose monohydrate, microcrystalline cellulose, povidone, silicon dioxide, magnesium stearate, Reference drug
crospovidone
Lab 2 Copovidone, lactose, sodium citrate anhydrous, magnesium stearate, colloidal silicon dioxide, microcrystalline cellulose Generic drug
and Sicovit Indigotine lake
Lab 3 Microcrystalline cellulose, sodium citrate dihydrate, copovidone, crospovidone, silicon dioxide, magnesium stearate, Generic drug
lactose monohydrate
Lab 4 Microcrystalline cellulose, sodium citrate, croscarmellose sodium, lactose, silicon dioxide, magnesium stearate Generic drug
Lab 5 Sodium citrate, lactose, microcrystalline cellulose, silicon dioxide, crospovidone, magnesium stearate Generic drug
Lab 6 Monohydrate lactose, microcrystalline cellulose, sodium citrate, crospovidone, povidone, magnesium stearate, colloidal Generic drug
silicon dioxide
Lab 7 Sodium citrate dihydrate, dibasic calcium phosphate, lactose, sodium, croscarmellose, colloidal silicon dioxide, magnesium Biosimilar drug
stearate
Lab 8 Copovidone, lactose, sodium citrate anhydrous, magnesium stearate, colloidal silicon dioxide, microcrystalline cellulose, Biosimilar drug
Sicovit Indigotine lake
Lab 9 Microcrystalline cellulose, lactose monohydrate, povidone, ethyl alcohol, silicon dioxide, magnesium stearate, Biosimilar drug
crospovidone
Capsules Lab 10 Not listed Manipulated formulation
Lab 11 Not listed Manipulated formulation

classified based on distinct processes. These processes are controlled by
nucleation and diffusion mechanisms as well as by reactions in the
limiting phase, and they include geometric and physicochemical as-
pects, depending on the rate-limiting step of the reaction (Khawam and
Flanagan, 2006).
Pharmaceutical companies that produce reference, generic or bio-
similar drugs provide a list of some of the excipients present in me-
loxicam tablets, such as microcrystalline cellulose, corn starch, mag-
nesium stearate, disodium citrate dihydrate, lactose, povidone and
colloidal silicon dioxide, among others. Assessing the compatibility
between these excipients and the drug is important for evaluating the
stability of the pharmaceutical formulations. Many drug-excipient
compatibility studies are performed using differential scanning calori-
metry (DSC), such as those for imatinib mesylate (Łaszcz et al., 2007)
and trioxsalen (Lima et al., 2014).
In compatibility assessments performed with DSC, a given interac-
tion can be identified as a shift in the melting point, changes in the peak
shape or area, the development of a transition, and/or an increase or
decrease in the number of peaks due to the mixture of components.
However, after the binary mixing of 2 components, shifts in the tran-
sition temperature and peak shape and area invariably occur and do not
necessarily represent a harmful interaction, so these changes need to be
carefully evaluated (Oliveira et al., 2011).
DSC is the most common thermal analysis method, as it is fast and
simple. DSC is used to measure differences in the heat flow between a
sample and a reference material as a function of a heating and cooling
cycle. In pharmaceutical sciences, DSC is used in the thermal char-
acterization and assessment of drug purity, in the assessment of the
stability and compatibility of formulation components and in the
identification of polymorphisms by determining the enthalpy of crys-
talline formations (Balestrieri et al., 1996; Oliveira et al., 2011).
Compatibility studies using DSC are examined in conjunction with
assessments of the intrinsic stability of a raw drug, where degradation
by stress is evaluated. Taken together, these 2 types of analysis can
reveal potentially incompatible excipients as well as unstable condi-
tions, thus improving drug development.
The objective of the present study is to assess solid pharmaceutical
formulations containing MLX that are available in Brazil and to define
the excipients that improve drug stability.
2. Materials and methods
Analyses were performed with MLX tablets and capsules found on
the Brazilian market, and the following excipients were present in the
formulations: starch; microcrystalline cellulose (MC); copovidone
(copov); magnesium stearate (MS); dibasic calcium phosphate anhy-
drous (CPA); calcium phosphate dihydrate (CPD); lactose (lacto); red
iron oxide (IO); talc; mannitol; stearic acid (SA), trisodium citrate (SC);
croscarmellose (CCS); sodium starch glycolate (SSG); sodium lauryl
sulphate (SLS); colloidal silicon dioxide (CSD); povidone K-30 (PVP);
and crospovidone (PVPP).
For solid-state kinetic analysis, 3 mg of MLX was weighed into tin
cups and analysed using a DTG60 (Shimadzu). The temperatures used
for the analysis were 228, 231, 234 and 237 °C with a heating rate of
10 °C min− 1 under 50 mL min− 1 nitrogen flow for 1 h. The tempera-
ture range was selected based on an assessment of the TG and DSC
curves for MLX and thermal characterization.
For compatibility assessment, DSC curves were obtained using a
DSC50 cell (Shimadzu) under 50 mL min− 1 nitrogen flow with heating
to 400 °C at 10 °C min− 1. Approximately 1 mg of sample was weighed
into tin cups and partially sealed. The tests were performed with sam-
ples of a) MLX; b) excipients of formulations available on the market; c)
binary mixtures of excipient and MLX at 1:1 to increase the probability
of an interaction between the drug and the excipient; and d) multi-
component mixtures (formulations available on the market). The results
were analysed by comparing the DSC curves and assessing changes in
the melting range of the drug in the mixtures. HPLC analysis was also
applied to the API/excipient mixtures to confirm the DSC results.
The market formulations listed in Table 1 were also subjected to
quality control tests defined by the Brazilian Pharmacopoeia. However,
due to the lack of a monograph on meloxicam in the Brazilian Phar-
macopoeia, the British Pharmacopoeia was used to perform the dis-
solution tests (Brazil, 2010; British Pharmacopeia Commission, 2013).
For assessment of the intrinsic stability (forced degradation) of the
drug, 20 mL aliquots of an MLX stock solution (0.5 mg mL− 1 in acet-
onitrile) were pipetted into individual volumetric flasks each con-
taining 20 mL of a previously prepared stress solution (0.1 M NaOH,
0.1 M HCl, 3% H2O2 or 0.05% FeSO4) plus 40 mL of methanol. The
forced degradation study was carried out by exposing MLX to the fol-
lowing stress conditions for 4 h: water (neutral hydrolysis); 0.1 M
NaOH (basic hydrolysis); 0.1 M HCl (acid hydrolysis); 3% H2O2 (oxi-
dation); 0.05% FeSO4; dry heat at 60 °C; and UV radiation. After ex-
posure, samples were diluted to 0.04 mg mL− 1 in methanol, and ali-
quots were sampled for high-performance liquid chromatography
(HPLC) analysis.
Chromatographic analyses were performed by HPLC coupled to an
ultraviolet diode array detector (UV/DAD) (Waters e2695/2998 PAD)
to assess the intrinsic stability of MLX. The method was optimized and
validated to quantify the drug and possible degradation products using
a C18 column (250 × 4.6 mm, 5 μm, Varian) at 25 °C with

147
L.M. da Silveira et al. European Journal of Pharmaceutical Sciences 112 (2018) 146–151

60 initially obtained at a 10 °C min− 1 heating rate for the isolated drug,

excipients, drug-excipient binary mixtures (1:1), and multicomponent
50 mixtures. Fig. 3 displays the DSC curves for the binary mixtures.
Possible incompatibilities with MLX are identified in Fig. 3, as in-
2 40 dicated by the disappearance and/or shift of the drug's melting peak
when mixed with lactose, stearic acid, sodium lauryl sulphate, sodium

DSC (mV)
30 starch glycolate, povidone, magnesium stearate, red iron oxide and
TG(mg)

mannitol.
TG 20
The DSC curve of the MLX/lactose mixture suggested incompat-
1
ibility due to the absence of the peak corresponding to the drug.
DTG
DSC However, according to Oliveira et al. (2011), a drug can be solubilized
10
by an excipient in a mixture, and thus, the typical melting peak cor-

0 -10
0 100 200 300 400 500 600
Temperature (°C)
Fig. 1. DSC, TG and DTG curves for MLX obtained at 10 °C min− 1 under nitrogen flow
(50 mL min− 1).
methanol:H3PO4 0.005% v/v (70:30) at 1.0 mL min− 1 as the mobile
phase, detection at 355 nm and an injection volume of 20 μL (Brezovska
et al., 2013; British Pharmacopeia Commission, 2013).
3. Results and discussion
The drug was thermally stable up to approximately 263 °C based on
the TG curve obtained at a heating rate of 10 °C min− 1 (Fig. 1). The
DTG curve, the first derivative of a TG curve, indicated that MLX de-
composition occurs in 1 step with a peak at 267.7 °C and 78.3% mass
loss. The DSC curve for MLX (Fig. 1) displayed a typical endothermal
peak corresponding to drug melting at 260.3 °C, with the Tonset at
257.3 °C and a 497.4 J g− 1 heat of fusion. Fig. 1 also shows that the
melting and degradation of MLX initiated concurrently.
In regards to the solid-state degradation kinetics, MLX was con-
sidered to be stable, with an Ea of 691.28 J mol− 1, calculated as the
slope of the isothermal decomposition curve multiplied by the gas
constant (Fig. 2). T90 was approximately 6 years based on the ln(t) at
25 °C, calculated by extrapolation, which shows low reactivity of the
drug in the solid state under inert conditions.
Solid-state reactions can occur in drugs and formulations, possibly
initiating alterations in their stability, solubility, dissolution rates and
bioavailability. Therefore, compatibility studies are needed to ensure
that potential physical and chemical interactions between a drug and
excipient do not compromise the stability of the drug (Byrn et al., 2001;
Mura et al., 2002).
In the drug-excipient compatibility tests, the DSC curves were
3.55
3.50 y = 83.98x - 13.24
3.45 r = 0.9950
3.40
ln t (min)
Endo
responding to the drug does not appear. This effect could explain the
0
lack of an MLX peak when mixed with lactose, as lactose melting
(Tpeak = 217 °C; Tonset = 209 °C) occurs first, solubilizing the drug.
Thus, lactose would still be considered compatible.
700 800
The DSC curve for the MLX/stearic acid mixture also seems to show
incompatibility. However, similar to the phenomenon described for the
MLX/lactose mixture, the thermal event of stearic acid melting occurs
before drug melting, indicating that the melting of this excipient leads
to solubilization of the drug. Stearic acid is a fatty acid that melts at
approximately 60 °C and solubilizes MLX, which is highly soluble in the
organic phase. Stearic acid is an important alternative when a given
drug is incompatible with magnesium stearate, a substitution that has
been reported previously and is considered compatible (Li and Wu,
2014; Oliveira et al., 2011).
To evaluate a possible incompatibility between MLX and sodium
lauryl sulphate, sodium starch glycolate and povidone, DSC curves were
also obtained at a 20 °C min− 1 heating rate (Fig. 4). Increasing the
heating rate is a typical procedure that allows better visualization of
thermal events and confirmation of incompatibility. Despite yielding
lower accuracy in regards to the temperature of thermal events, higher
heating rates can provide further clarifications.
Fig. 4 shows the DSC curves at 20 °C min− 1 for MLX, SLS and the
binary mixture MLX/SLS. The observed changes in the MLX peak in the
DSC curve of the binary mixture suggest drug-excipient incompatibility.
However, the DSC curve for SLS reveals that it has a lower degradation
temperature relative to the MLX melting point. This pattern prevents
the assessment of compatibility using the DSC method given that upon
initiation of degradation, sequential reactions may occur, hindering the
interpretation of the results. Regarding the thermal behaviour of SLS,
Pereira et al. (2014) reported that DSC curves display 4 typical en-
dothermal events that correspond to a dehydration peak at 92 °C, a
melting peak at 191 °C and 2 decomposition peaks at approximately
200–270 °C.
Fig. 4 also displays the DSC curves at 20 °C min− 1 for assessment of
the compatibility between MLX and povidone. Due to the shift in the
MLX melting peak in the binary mixture DSC curve, povidone is con-
sidered incompatible with MLX given that no other event associated
with the excipient could have confounded the interpretation. Previous
reports regarding the thermal behaviour of povidone have shown that
the povidone DSC curve displays a single endothermal event corre-
sponding to dehydration (Zhao, 2014).
Another excipient incompatible with MLX was sodium starch gly-

colate (Fig. 4), for the same reason as povidone. The thermal behaviour
3.35 of sodium starch glycolate shows 2 events, 1 endothermal event with a
peak at 60 °C corresponding to dehydration and 1 exothermal event
3.30
with a peak at approximately 290 °C corresponding to decomposition
3.25 (Lima et al., 2014; Pereira et al., 2014).
3.20 The results demonstrate that the compatible excipients are starch,
microcrystalline cellulose, copovidone, anhydrous dibasic calcium
0.196 0.197 0.198 0.199 0.200 phosphate, calcium phosphate dihydrate, lactose, talc, stearic acid,
2 -1 trisodium citrate, croscarmellose, colloidal silicon dioxide and crospo-
1/T x 10 (K )
vidone.
Fig. 2. Arrhenius plot based on the results obtained from the isotherms for 10% MLX The incompatible excipients identified by DSC included magnesium
mass loss.
stearate, red iron oxide, povidone, sodium starch glycolate and

148
L.M. da Silveira et al. European Journal of Pharmaceutical Sciences 112 (2018) 146–151

Fig. 3. DSC curves obtained at 10 °C min− 1

A B under nitrogen flow (50 mL min− 1) for MLX and
MLX/mannitol binary mixtures (1:1).
MLX/starch
MLX/SA
MLX/celul
MLX/SC
MLX/copov
MLX/CCS

Intensity / a.u.
MLX/lactose
Intensity / a.u.

MLX/SSG
MLX/MS
MLX/CPA MLX/CSD
MLX/SLS
MLX/CPD
MLX/IO MLX/PVP

MLX/talc
MLX/PVPP
Endo

MLX Endo MLX

273 323 373 423 473 523 573 623 673 723 273 323 373 423 473 523 573 623 673 723
Temperature (K) Temperature (K)

SLS Lab1

Lab2
MLX/SLS
Lab3
Intensity / a.u.

Lab4

SSG Lab5
Intensity / a.u.

Lab6
MLX/SSG

Lab7
Endo

MLX
PVP
273 323 373 423 473 523 573 623 673 723
MLX/PVP Temperature / K
Fig. 5. DSC curves at 10 °C min− 1 under nitrogen flow (50 mL min− 1) for MLX and
Endo

formulations produced by different laboratories.

273 323 373 423 473 523
Temperature / K
−1
Fig. 4. DSC curves at 20 °C min under nitrogen flow (50 mL min− 1) for MLX, SLS, SSG,
PVP and binary mixtures (MLX/SLS, MLX/SSG and MLX/PVP).
mannitol.
In a given formulation, the substitution of povidone with another
excipient is advised, and the best alternative is crospovidone, which
was compatible with MLX. For sodium starch glycolate, a super-
disintegrant, an alternative substituent would be croscarmellose, which
exhibited no issues when mixed with the drug.
The DSC curves corresponding to the multicomponent mixtures
(Fig. 5) showed that all of the tested formulations had compatibility
issues between the drug and the excipients, as the MLX melting peak
was absent. This absence could have been due to the presence of ex-
cipients that were incompatible with the drug or due to the presence of
lactose in the formulations.
MLX
Notably, the red iron oxide present in some of the formulations is a
573 623 673 723 pigment used in tablet coating, and it is present in low amounts.
Additionally, this compound is added after granulation and compres-
sion, further reducing its contact with the drug; thus, incompatibility
effects between red iron oxide and MLX are likely negligible.
The incompatibilities identified by the DSC were evaluated using
HPLC methods, in order to confirm each incompatibility. Studies were
conducted following exposure of the MLX samples to each incompatible
excipient (magnesium stearate, povidone, sodium starch glycolate and
mannitol) in the ratio of 1:1 mixtures. Binary samples (MLX-Excipient
1:1) were submitted to temperatures of 50, 60 and 70 °C, in liquid
medium, with dilutions and concentrations identical to those of the
intrinsic stability study. Samples were withdrawn hourly for HPLC
evaluation. After a 4 h assay, only the MLX-Magnesium Stearate (1:1)
displayed a significant reduction of the drug, with degradation of about
20% of MLX. This reduction confirms the incompatibility of MLX with
magnesium stearate, although studies on degradation kinetics must be
still carried out. There was no reduction in the peak area of MLX for the
other excipients evaluated, indicating no compatibility problems at the

149
L.M. da Silveira et al.
Neutral hydrolysis
Acid hydrolysis
Basic hydrolysis
Intensity / a.u.
Oxidation
Metalic ions
Dry heat
UV light
MLX
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time / min
Fig. 6. MLX chromatograms before and after exposure to stress conditions, including
neutral hydrolysis, acid hydrolysis, basic hydrolysis, oxidation, exposure to metal ions,
heat and UV radiation, at 60 °C for 4 h.
temperatures and conditions analysed. Magnesium stearate is a known
catalyst of chemical reactions, widely used in pharmaceutical for-
mulations with the aim of improving the manufacturing process, opti-
mizing the sliding and lubricating capacity of the powder in the pro-
duction of tablets and capsules.
To assess intrinsic stability under stress conditions, MLX was sub-
jected to distinct conditions of forced degradation and was then as-
sessed for the potential formation of degradation products (Guideline,
2006). The tested conditions were aqueous medium (neutral pH), acidic
medium (HCl), basic medium (NaOH), oxidative stress (H2O2), ex-
posure to metal ions (Fe2 +), heat and UV radiation. Following exposure
to the stress conditions, samples were analysed by HPLC. The drug was
unstable in basic medium (basic hydrolysis), as shown in Fig. 6.
The HPLC method was optimized and validated using specificity,
linearity, precision, accuracy, the detection limit, the quantification
limit and robustness tests (Guideline, 2005). MLX had a retention time
of 5.4 min, and the performance parameters were retention factor (k′)
= 1.8; number of theoretical plates (N) = 4550 plates/column; peak
tailing factor (Tf) = 1.05; and peak resolution (Rs) = 10 relative to the
degradation products in the basic medium (3.1 min retention time). The
results were satisfactory given that they are in agreement with the
limits defined for each parameter, as follows: k′ > 0.5, N > 2000
plates/column; Tf equal or lower than 2; and Rs > 2 (Ribani et al.,
2004). Additionally, the results of the validation tests were satisfactory
with a detection limit of 0.36 μg mL− 1 and a quantification limit of
1.10 μg mL− 1.
The results of the physico-chemical quality control test for the drugs
available on the Brazilian market (Lab 1 to Lab 11), as defined by the
British pharmacopoeia (British Pharmacopeia Commission, 2013), are
listed in Table 2.
The identification test was made by comparing the retention time of
the main peak of the chromatogram of the sample solution and that of
the standard solution, and the confirmation was performed with UV
spectrophotometry during the HPLC assay (British, 2013). All samples
were approved for the drug identification test.
The hardness was performed with 10 tablets, using a durometer,
spiral spring, model 298, brand Nova Ética. The hardness test is not
specified in the MLX monograph (British, 2013). According to the
150
European Journal of Pharmaceutical Sciences 112 (2018) 146–151
Brazilian Pharmacopoeia, in the general methods, the test is only in-
formative and the results must be presented in Newton (Brazil, 2010).
The friability was performed on the model 300, brand Nova Ética,
after 100 rotations. According to the specifications of the Brazilian
Pharmacopoeia, there should be no loss > 1.5% of the total mass of the
tablets tested, therefore all samples are approved in this test (Brazil,
2010).
Disintegration was performed on the model 301-3, brand Nova
Ética, using water maintained at 37 ± 1 °C as the immersion liquid,
according to the general specifications. Disintegration time cannot ex-
ceed 30 min; all samples were satisfactory (Brazil, 2010).
The assay, the content uniformity and the dissolution test were
conducted as recommended in the British Pharmacopoeia (British,
2013).
According to the British Pharmacopoeia specifications (British,
2013), the assay must be between 95.0 and 105.0% of the labeled
amount. The results indicate that all laboratories were approved ac-
cording to the results, showing that the samples found on the market
are in conformity with the declared content on the packages.
The content uniformity (CU) method was performed for the assay of
the uniformity of dosage units. The acceptance value (A.V.) was cal-
culated according to the British Pharmacopoeia, with the limit value
being 15.0 for 10 units (tablets/capsules) tested (British, 2013). The
results of the content uniformity of each MLX formulation and the re-
spective acceptance values (Table 2) were satisfactory.
Dissolution was performed as recommended in the British
Pharmacopoeia (British, 2013). According to the acceptance criteria (Q
+ 5%), where Q is established with a value of 70%, all samples were
approved, with the exception of Lab10 and Lab11, which obtained
values lower than those recommended by the pharmacopoeia.
4. Conclusions
MLX displays thermal stability up to 263 °C and decomposes in a
single step with a peak at 267.7 °C and 78.3% mass loss. The MLX
melting peak occurs at 260.3 °C, with the Tonset at 257.3 °C and a heat of
fusion of 497.4 J g− 1.
The solid-state degradation kinetics of MLX followed the Avrami-
Erofeev A4 model, with a calculated Ea of 691.28 J mol− 1 and a cal-
culated T90 of approximately 6 years, showing low reactivity of the
drug in the solid state.
DSC (Differential Scanning Calorimetry) is an extremely rapid
technique in detecting possible incompatibilities in pharmaceutical
formulations, and has been widely used in preformulation studies.
However, it is emphasized that the DSC is very high temperatures,
which does not happen in the storage conditions of the medicines. The
compatible excipients found by DSC were starch, microcrystalline cel-
lulose, copovidone, calcium phosphate dibasic anhydrous, calcium
phosphate dihydrate, lactose, talc, stearic acid, trisodium citrate, cros-
carmellose, colloidal silicon dioxide, and crospovidone. The in-
compatible excipients initially identified by DSC were magnesium
stearate, red iron oxide, povidone, sodium starch glycolate, and man-
nitol.
Incompatibility with the excipient magnesium stearate was con-
firmed after stress studies and HPLC analysis, with a drug reduction of
about 20% under the conditions studied. This evinces that this is the
most significant incompatibility among all excipients evaluated. Other
incompatible excipients in the DSC analysis, such as povidone, sodium
starch glycolate and mannitol, may have no significant degrading ef-
fects on the drug, since such effects were not identified in HPLC ana-
lyzes under the conditions evaluated.
For incompatible excipients, the suggested substitutions are to re-
place magnesium stearate with stearic acid. These incompatibilities
could potentially compromise the stability of the drug, affecting its
efficiency.
Regarding intrinsic stability, MLX displayed instability in basic
L.M. da Silveira et al. European Journal of Pharmaceutical Sciences 112 (2018) 146–151

Table 2
Results of physico-chemical quality control assays of the drugs available on the Brazilian market.

Sample Identification Assay (% L.V.) Hardness (kgf) Friability Disintegration Dissolution Content Uniformity

Lower value Highest value Lower value (%) RSD (%) Average SD A.V.

Lab 1 In accordance 99.0 8.7 9.0 < 1.5% 4′20″ 78 4.35 96.5 2.18 7.1
Lab 2 In accordance 103.5 5.0 8.5 < 1.5% 6′ 76 6.18 103.0 1.92 3.3
Lab 3 In accordance 96.5 6.9 7.2 < 1.5% 5′20″ 87 3.34 97.2 2.71 7.6
Lab 4 In accordance 97.5 5.5 8.5 < 1.5% 15″ 88 1.67 99.3 3.69 8.8
Lab 5 In accordance 97.1 4.2 4.7 < 1.5% 2′35″ 92 0.82 103.1 1.69 2.6
Lab 6 In accordance 98.7 2.0 2.9 < 1.5% 2′20″ 88 2.36 99.0 2.13 5.1
Lab 7 In accordance 98.5 4.9 5.9 < 1.5% 25″ 91 2.19 97.2 5.55 14.2
Lab 8 In accordance 104.2 5.0 6.1 < 1.5% 30″ 80 4.13 104.4 4.16 7.5
Lab 9 In accordance 100.6 3.5 3.6 < 1.5% 25″ 76 5.58 103.8 1.57 1.6
Lab 10 In accordance 99.8 – – – 14′ 5 19.08 100.5 2.18 5.3
Lab 11 In accordance 98.4 – – – 10′40″ 28 15.51 96.8 3.77 10.5

L.V. = labeled value.

A.V. = acceptance value.

medium (pH > 10.3) with rapid and complete degradation even at
room temperature.
For quality assessment of the MLX products available on the market
as tablets or capsules, the manufactured products had the best results,
and all were approved. Manipulated formulations of capsules, obtained
from pharmacies, they presented unsatisfactory results for the dissolu-
tion test. These results show that manufactured products are of higher
quality compared to manipulated formulations in pharmacies.
Acknowledgements
The authors thank the Espírito Santo Research Foundation
(Fundação the Amparo à Pesquisa e Inovação do Espírito Santo –
FAPES) and the National Council for Scientific and Technological
Development (Conselho Nacional de Desenvolvimento Científico e
Tecnológico – CNPq) for their financial support.
References
Balestrieri, F., Magrì, A.D., Magrì, A.L., Marini, D., Sacchini, A., 1996. Application of
differential scanning calorimetry to the study of drug-excipient compatibility.
Thermochim. Acta 285, 337–345.
Brazil, 2010. Brazilian Pharmacopoeia: Volume 1, 5th ed. 1 National Agency of Sanitary
Vigilance, Brasilia (546 p.).
Brezovska, M., Jampilek, J., Opatrilova, R., 2013. A review of HPLC methods used for
determining the presence of meloxicam. Curr. Pharm. Anal. 9, 69–76.
British Pharmacopoeia Commission, 2013. British Pharmacopoeia. TSO, London.
Byrn, S.R., Xu, W., Newman, A.W., 2001. Chemical reactivity in solid-state pharmaceu-
ticals: formulation implications. Adv. Drug Deliv. Rev. 48, 115–136.
Engelhardt, G., Bogel, R., Schnitzler, C., Utzmann, R., 1996. Meloxicam: influence on
arachidonic acid metabolism. Part II. In vivo findings. Biochem. Pharmacol. 51,
29–38.
Guideline, I. C. H. Q2 (R1), 2005. In: Validadation of Analytical Procedures: Text and
Methodology. International Conference on Harmonization of Technical Requirements
for Registration of Pharmaceuticals for Human Use.
Guideline, I. C. H. Q3B (R2), 2006. In: Impurities in New Drug Products. International
Conference on Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use.
KATZUNG, Bertram, G., 2014. Basic and clinical pharmacology, 12. ed. AMGH, Porto
Alegre.
Khawam, A., Flanagan, D.R., 2006. Solid-state kinetic models: basics and mathematical
fundamentals. J. Phys. Chem. B 110, 17315–17328.
Łaszcz, M., Kosmacińska, B., Korczak, K., Śmigielska, B., Glice, M., Maruszak, W.,
Groman, A., Beczkowicz, H., Żelazko, Ł., 2007. Tudy on compatibility of imatinib
mesylate with pharmaceutical excipients. J. Therm. Anal. Calorim. 88, 305–310.
Li, J., Wu, Y., 2014. Lubricants in pharmaceutical solid dosage forms. Lubricants 2,
21–43.
Lima, N.P.B., Lima, I.B., Barros, D.C., Oliveira, T., Raffin, F., de Lima de Moura, T.A.,
Medeiros, A.D., Gomes, A.B., Aragão, C.S., 2014. Compatibility studies of trioxsalen
with excipients by DSC, DTA, and FTIR. J. Therm. Anal. Calorim. 115, 2311–2318.
Mura, P., Gratteri, P., Faucci, M.T., 2002. Compatibility studies of multicomponent tablet
formulations: DSC and experimental mixture design. J. Therm. Anal. Calorim.
541–551.
Oliveira, M.A. De, Yoshida, M.I., Lima Gomes, E.C. De, 2011. Análise térmica aplicada a
fármacos e formulações farmacêuticas na indústria farmacêutica. Quim Nova 34,
1224–1230.
Pereira, M.A.V., Fonseca, G.D., Silva-Júnior, A.A., Fernandes-Pedrosa, M.F., de F V de
Moura, M., Barbosa, E.G., Gomes, A.P.B., dos Santos, K.S.C.R., 2014. Compatibility
study between chitosan and pharmaceutical excipients used in solid dosage forms. J.
Therm. Anal. Calorim. 116, 1091–1100.
Ribani, M., Bottoli, C.B.G., Collins, C.H., Jardim, I.C.S.F., Melo, L.F.C., 2004. Validação
em métodos cromatográficos e eletroforéticos. Quim Nova 27, 771–780.
Yazdanian, M., Briggs, K., Jankovsky, C., Hawi, A., 2004. The “high solubility” definition
of the current FDA guidance on biopharmaceutical classification system may be too
strict for acidic drugs. Pharm. Res. 21, 293–299.
Zhao, Z., 2014. Electrosprayed Core – Shell Solid Dispersions of Acyclovir Fabricated
Using an Epoxy-coated Concentric Spray Head 1967–1977.
Zhou, D., Schmitt, E.A., Zhang, G.G., Law, D., Vyazovkin, S., Wight, C.A., Grant, D.J.W.,
2003. Crystallization kinetics of amorphous nifedipine studied by model-fitting and
model-free approaches. J. Pharm. Sci. 92, 1779–1792.

151