Original article

iq.unesp.br/ecletica

| Vol. 44 | n. 3 | 2019 |

Characterization of nimesulide and development of immediate release

tablets
Helvécio Vinícius Antunes Rocha+ , Rachel de Sousa Augusto , Livia Deris Prado , Erika Martins de Carvalho

Oswaldo Cruz Foundation (Fiocruz), Institute of Technology in Drugs, 4365 Brasil Av., Manguinhos, Rio de Janeiro, Brazil

+Corresponding author: Helvécio Vinícius Antunes Rocha, email address: helvecio.far@gmail.com

ARTICLE INFO Keywords:

1. nimesulide
Article history: 2. raw material characterization
Received: December 22, 2018 3. dissolution profile
Accepted: March 30, 2019 4. powder flow
Published: July 4, 2019 5. formulation development

ABSTRACT: This paper aims to characterize nimesulide

raw materials from different manufacturers and to develop
immediate release tablets, in order to register a generic
product. Also, raw material characteristics and the tablets
final properties were investigated in order to establish a
different specification for quality control. Two micronized
and one non-micronized nimesulide samples were obtained
from different manufacturers and were characterized by
thermal analysis, spectroscopic techniques, morphological
analysis, flowability and biopharmaceutical evaluation. The
samples belong to the same polymorph. The formulations
design and the choice of the production process were carried
out based on the results obtained in the characterization
assessments. The proposed formulations showed different
dissolution behavior. One formulation was selected and then
the dissolution was evaluated in different dissolution media
containing varying concentrations of surfactant, in order to verify if the concentration of 2% (v/v) of polysorbate 80, recommended by
the Brazilian Pharmacopoeia, would be overestimating the bioavailability of the drug. The results showed that the percentage of
surfactant present in the dissolution medium directly impacts the amount of dissolved drug. The selected formulation demonstrated
promising results to proceed with the bio batches manufacture and the pharmaceutical equivalence study.

1. Introduction to 6.5), attributed to the presence of a sulfonamide

group1,2. It is practically insoluble in water (about
Nimesulide is a nonsteroidal sulfonamide and 10 μg/mL) and soluble in methanol and ethanol at
belongs to the class of anti-inflammatory drugs room temperature4. Based on Biopharmaceutics
(NSAIDs) that demonstrates a selectivity for Classification System (BCS), nimesulide is
COX-2 (cyclo-oxygenase-2) and, therefore, has considered a class 2 drug, characterized by low
anti-inflammatory, analgesic and antipyretic solubility and high permeability. Thus, its
activities1,2. When administered in recommended dissolution may represent a limiting step in drug
dosage demonstrates low incidence of side effects absorption process3.
and is better tolerated than other NSAIDs, such as According to one study reported in the
diclofenac, ketoprofen, naproxen and piroxicam1. literature, crystallization of nimesulide in different
Nimesulide is a sulfonanilide derivative, with a organic solvents affects some physicochemical
melting point around 143 °C2,3. According to the properties such as melting point, solubility and
literature, it is a weakly acidic (pKa approximately dissolution profile, indicating the existence of

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polymorphs5. Other studies describe the existence and the final properties of the tablets in order to
of two polymorphs of nimesulide: form I (usually establish a different specification for quality
used in the pharmaceutical industry) and form control.
II6,7.
Some studies discuss the characterization of 2. Materials and methods
nimesulide and demonstrated that DSC and X-ray
diffraction techniques are promising in identifying 2.1. Materials
polymorphs of nimesulide7. Additionally, the
literature contains several studies using Samples of nimesulide from three different
spectroscopy in the form of infrared manufacturers were coded as NM1 (sample non-
complementary to other analytical techniques7-10. micronized), NM2 and NM3 (micronized). The
In terms of biopharmaceutical evaluation, a excipients microcrystalline cellulose 101
study obtained different values of intrinsic (Mingtai), lactose monohydrate 80 (DFE Pharma),
dissolution rate of nimesulide polymorphs I and sodium lauryl sulfate (Nuclear), docusate sodium
II. However, the analysis of the graph in this study (Shin-Etsu Chemical), sodium starch glycolate
demonstrates that there was no linearity, affecting (Ecadil), low substituted hydroxypropyl cellulose
the results obtained in IDR7. Other studies using (Shin-Etsu Chemical), polyvinylpyrrolidone K-30
the intrinsic dissolution with this drug were not (Boai Niki) and magnesium stearate (Magnesia),
found, as well as studies using the wettability test. previously tested and approved according to the
Allied to such trials, the powder dissolution has USP18, were used. Standard sample of nimesulide
been used in biopharmaceutical evaluation11,12, was supplied by National Institute for Quality
because there are some important factors that can Control in Health, with purity of 99.80% and
impact on the assay results, for example, Nisulid®, Aché Laboratory, as the reference
wettability, crystallinity, particle size and surface medicine.
area13.
The formulation studies evaluated the 2.2. Evaluation of the active pharmaceutical
nimesulide tablets dissolution profile and found ingredient according to pharmacopoeia criteria
that drug release is not achieved even by testing
the presence of surfactant at different Samples NM1, NM2 and NM3, were analyzed
concentrations in the dissolution medium14,15. according to the methodologies described in the
Reducing the particle size of the drug to Brazilian Pharmacopoeia4. The tests included
microparticles has been shown to significantly identification, which used the method of infrared
increase the dissolution and bioavailability of spectroscopy (spectrometer infrared model
drugs. This is achieved by increasing the contact Nicolet 6700 FT-IR, Thermo Scientific), heavy
surface, which has a positive impact on the metals, loss on drying, sulfated ash and dosing.
dissolution rate and possibly absorption16. One This last one, followed the recommendations
method to reduce particle size is by established in the method B of the Brazilian
micronization17 however, although there are Pharmacopeia, which uses spectrophotometry
advantages regarding the optimization of the absorption in the ultraviolet (LAMBDA 25,
dissolution of drugs with low solubility, PerkinElmer) and the absorbance readings were
micronizing should be carefully considered, performed at 392 nm.
because this can result in low density problems
and inadequate flow. Accordingly, with respect to 2.3. Differential scanning calorimetry (DSC)
flowability, the literature reports a previous study
evaluating the fluidity, in which it was The DSC analysis was performed with a
demonstrated that nimesulide has no good flow differential exploratory calorimeter instrument
properties9. model 60, Shimadzu. The samples were weighed
The objective of this study was the (about 3 mg) and encapsulated in aluminum
characterization of nimesulide samples from crucibles with lid closed. The DSC curves were
different manufacturers and the development of obtained under heating rates of 5, 10, 20 and
immediate release tablets, in order to register a 40 °C/min over a temperature from 25 to 200 °C,
generic product. It was also tried to make some a flow rate of 50 mL min-1 of argon gas. Assays
correlation between raw material characteristics

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were performed in triplicate. Different heating 2.8. Wettability

rates were used.
The analysis was conducted with a tensiometer
2.4. Fourier transform Infrared spectroscopy Krüss, DSA 100 at room temperature by sessile
drop method. Approximately 300 mg were
The FTIR spectra were record using a Thermo compressed in the form of discs using 800 psi for
Scientific, model Nicolet 6700 FT-IR, over a 1 min with the aid of a hydraulic press. The liquid
range from 4000 to 400 cm-1 at a resolution of drop (water saturated with nimesulide) was
4 cm-1. IR samples were analyzed directly without dispensed onto the surface of the sample and the
sample preparation. images were captured immediately. The
instrument calculated the contact angle by fitting
2.5. X-Ray Powder Diffraction mathematical expression to the shape of the drop.

The XRPD patterns of the samples were record 2.9. Powder dissolution
on an X-ray D8 diffractometer (Bruker) equipped
with Lynxeye XE detector and with Cu as tube Powder dissolution was performed with a
anode (Kα radiation with λ = 1.5418 Ǻ). The dissolutor Distek, model 6100, and the conditions
diffraction patterns were record under the were as follows: 900 mL of potassium phosphate
following conditions: voltage 40 kV, 40 mA and buffer solution adjusted to pH 7.4, with 2.0%
fixed divergence slit using configuration of 2 polysorbate 80 (w/w) at 37 ± 0.5 °C and stirred
range from 4 to 50°, with a step size of 0.02° and with apparatus II (paddle) at 75 rpm rotating
a step time of 0.1 s. The identification of the speed. Approximately 100.0 mg of nimesulide
crystal structure was performed using the database were added directly to the vessels and aliquots of
Cambridge Structural Database (CSD)19 and 10 mL were collected after 5, 10, 15, 20, 30, 45,
calculated XRD pattern was prepared using the 60 and 90 min, without replacing the medium.
program Mercury 3.720. Aliquots were filtered through 45 µm
polytetrafluoroethylene filter, diluted and the
2.6. Determination of particle size distribution absorbance measured in a spectrophotometer
using laser diffraction analysis (LAMBDA 25, PerkinElmer) at a wavelength of
392 nm. The tests were performed in triplicate. A
Particle size distribution was obtained by the comparison of the dissolution profiles dispersion
laser diffraction method with a Malvern was made by calculating the difference factor
equipment, Model 2000E Mastersizer, using the (F1), the similarity factor (F2) and the dissolution
liquid mode, a measurement range of 0.1-500 μm efficiency (DE). The DE values were submitted to
and obscuration between 17 and 23%. The statistical analysis of variance (one-way ANOVA)
suspension of 500 mg of nimesulide was prepared followed by Tukey test and considered significant
with an aqueous solution containing 0.5% p < 0.05.
polysorbate 80, in a total of around 30 mL. It was
necessary to use ultrasound (USC 2800A, Unique) 2.10. Determination of flowability
with speed 10.
The evaluation of the flowability was carried
2.7. Scanning Electron Microscopy (SEM) out by the bulk and tapped density, Carr index,
Hausner ratio, repose angle and flow through an
To study the morphology of NM samples, orifice determination. The densities were
SEM was performed on a Quanta 400 microscope determined according method I of USP18, using
(FEI), at a voltage 10 kV, using 500 and 16000x the equipment Tap Density Tester (Nova Ética).
magnification. Small amounts of sample were The values were used to calculate the Carr’s index
adhered on a metal stub using double-sided and Hausner ratio. For the determination of repose
adhesive carbon tape, which were then vacuum- angle and flow through an orifice was used
coated (0.6 mbar) with a thin layer of gold in a Granulate GTB Tester Equipment (Erweka) with
BAL-TEC SCD 005 sputter coater at room different diameter orifices and rotation speed to
temperature. determine the optimal test conditions and

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discriminate the flowability profiles of the nimesulide content in tablets by ultraviolet

samples. absorption spectrophotometry at a wavelength of
392 nm. The assay was performed in triplicate
2.11. Formulation design with the standard solution and the sample
solution.
The galenic batches were prepared in amounts
about 600 to 800 g. The wet granulation was 2.14. Dissolution profile
conducted with a high shear granulator capacity
4 L (TMG 1/6, Glatt), for the initial powder Initially, the dissolution profiles were
mixture and the wetting with the binder solution. performed using the conditions recommended by
After the granulation, the wet mass was passed the Brazilian Pharmacopoeia4, with the reference
through a mesh of 4 mm using the oscillating product and the galenic batches who presented the
granulator (K-70, Lawes). The drying of the results of physical tests (hardness, disintegration
granulate was performed in a fluidized bed (midi and friability) most promising. The analytical
Glatt, Glatt), at a temperature of 45 °C under a conditions were: 900 mL of potassium phosphate
controlled flow. The end point was determined by buffer, pH 7.4, containing 2.0% (v/v) polysorbate
drying the residual humidity using an infrared 80 and stirred with paddle at a rotation speed of
balance (IV2500, Gehaka) and was established a 75 rpm. Aliquots of 10 mL were removed after 5,
range between 2 and 3%. After drying, the 10, 15, 20, 30 and 45 min, without replacing the
granulate was normalized with a mesh of 1.5 mm medium, maintaining sink conditions throughout
in the oscillating granulator. Then, this granulate the test. The amount of drug dissolved was
was transferred to a V-blender, capacity 2 L determined by reading on a spectrophotometer
(66/10, Lawes), to perform the mixing of the (UV-1800, Shimadzu) in the ultraviolet region at a
excipients that were added in the extra granular wavelength of 392 nm. Then, one of the galenic
phase. Finally, the compression was performed on formulations, which showed the same type of
a rotating compressor (2000 10PSC, Lawes), dissolution to the reference product has been
fitted with punches of 10 mm flat. The process selected to perform additional dissolution profiles
control was carried out by checking the weight, studies. For this, was used the dissolution medium
hardness, friability and disintegration of the potassium phosphate buffer, pH 7.4, containing
tablets. For such determinations was used the polysorbate 80 in concentrations of 1.0% and
following equipments: semi-analytical balance, 0.5%. The others analytical conditions were
capacity 200 g (Sartorius), portable durometer maintained. The dissolution profiles were
(TBH100, Erweka), friability tester (TA10, compared using dissolution efficiency (DE) and
Erweka) and disintegrator (301-1, Nova Ética). their values were submitted to statistical analysis
of variance (one-way ANOVA) followed by
2.12. Evaluation of galenic batches Tukey test and considered significant p < 0.05.

The tablets were analyzed by the average 3. Results

weight, hardness, friability and disintegration,
conducted as described in Brazilian 3.1. Evaluation of the active pharmaceutical
Pharmacopoeia4, and the comparative dissolution ingredient according to pharmacopoeia criteria
profile, was carried out with the Nisulid®
reference drug. The results of heavy metals, loss on drying,
sulfated ash and dosing match the specifications
2.13. Dosing of the Brazilian Pharmacopoeia4 and are presented
in Table 1.
The analysis was performed according to the
Brazilian Pharmacopoeia4, which quantifies the

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Table 1. Results of heavy metals, loss on drying, sulfated ash, dosing, contact
angle of NM1, NM2 and NM3 samples.
Sample
NM1 NM2 NM3
Heavy metals (ppm) < 20 ppm < 20 ppm < 20 ppm
Loss on drying (%) 0.19 0.21 0.34
Sulfated ash (%) 0.04 0.03 0.03
Dosing (%) 99.5 99.2 99.6
Contact angle (°) 80.7 ± 1.7 79.1 ± 3.0 78.8 ± 3.3
(average ± SD)

3.2. Differential scanning calorimetry (DSC) 1588 cm-1), that presented weak intensity peaks,
all the others functional groups of nimesulide
The DSC curves obtained for NM1, NM2 and demonstrated medium intensity peaks.
NM3 samples, measured at a heating rate of
5 °C/min showed a single sharp endothermic peak 3.4. X-Ray Diffraction
at approximately 149 °C in accordance with the
melting point measurements (Figure 1). The same The X-ray diffraction patterns of NM1, NM2
results were obtained in the DSC curves for NM1 and NM3 samples (Figure 2) presented
sample under other conditions as 10, 20 and characteristic peaks at approximately 2θ = 17.07,
40 °C min-1. In addition, NM2 and NM3 showed 18.14, 19.35 and 21.60°. The samples comparison
identical results. For NM1, NM2 and NM3 data clearly showed that the micronization process
samples, the baseline of DSC curves was similar did not change the NM structure. The results were
and display that the thermal capacity was not compared with the data of NM polymorphs I and
changed by micronization process. II calculated from CSD and are also shown in
Figure 2.

Figure 1. DSC curves from bottom to top NM1, NM2

and NM3 samples at a heating rate of 5 °C/min.

3.3. Infrared Spectroscopy

The FTIR spectra of all samples were Figure 2. X-Ray diffraction patterns of the samples
NM1, NM2 and NM3 and calculated patterns of the
equivalent (data not shown). The IR spectrum
polymorphs I and II of nimesulide obtained from the
showed the NH at 3278 cm-1, a band at 1149 cm-1 CDCC (The Cambridge Crystallographic Data Centre).
assigned to the symmetric deformation of SO2
group, NO2 stretching frequencies at 1330 cm-1
and 1588 cm-1 and a band at 1246 cm-1 assigned
to the COC. Except for the NH and NO2 (at

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3.5. Particle size distribution using laser 3.6. Scanning electron microscopy (SEM)
diffraction
The images of the samples under study,
The average size of particles results, the values obtained by SEM at 500x magnification for NM1
of particles smaller than 10% (d10), 50% (d50), and 16.000x for NM2 and NM3 samples, are
and 90% (d90) and the results of dispersibility shown in Figure 4. The NM1 sample presented
indices (span) was obtained with the samples from the highest particle sizes between 25.2 and
different manufacturers of nimesulide. The NM3 103.5 μm, which was previously expected because
sample showed the smallest particle size (d10 = is the IFA non-micronized, while the micronized
1.28; d50 = 6.57 and d90 = 20.61), followed very NM2 and NM3 samples showed particles in the
closely by the NM2 sample (d10 = 2.09; d50 = range of 364.8 nm to 3.5 μm (Figure 4 B, C). The
8.46 and d90 = 20.89) and, finally, the non- micronization process led to the formation of
micronized sample (NM1) showed the largest aggregates.
particle size (d10 = 10.34; d50 = 33.85 and d90 =
76.52). Comparison of dispersibility indices 3.7. Wettability
indicate that NM3 sample has the greater
nonuniformity of particle size distribution (DI = Table 1 presents the results for all samples,
2.94), followed by NM2 sample (DI = 2.22) and, being observed that, using the method of the
finally, NM1 sample (DI = 1.96). The particle size sessile drop and water as wetting agent, they were
distribution graphs are shown in Figure 3. all near 80°.

3.8. Powder dissolution

Comparison of dissolution dispersion profiles

of NM1, NM2 and NM3 samples is shown in
Figure 5 and the values of F1, F2 and DE were
established. The F1 and F2 values (15.26 and
46.23, respectively) confirm that the NM1 and
NM3 samples showed the greatest differences
between the profiles. The result of F1 for the
micronized samples (NM2 and NM3) also showed
a high value (12.36) and a considerably borderline
result for the F2 parameter (50.55). Less expected,
the F1 and F2 values that showed the greatest
similarity was when the dissolution profiles of
NM1 (non-micronized) and NM2 (micronized)
were compared (3.33; 69.29). The DE values were
statistically analyzed by ANOVA and significant
differences were detected (p < 0.05). However,
when using the Tukey test, it was found that there
were no significant differences between the DE
values of NM1 and NM2 profiles (DE = 71 ± 2
Figure 3. Particle size measurements obtained by
LASER diffraction from bottom to top NM1, NM2 and and 74 ± 5, respectively), while the significant
NM3 samples. differences were encountered between the profiles
NM1 and NM3, NM2 and NM3 (DE = 83 ± 1).

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Figure 4. Scanning electron microscopy of the samples NM1, NM2 and NM3 from top to down, with measurements with increase of
500, 20Kv for NM1 and 16.000 X for NM2 and NM3.

3.9. Determination of flowability

3.9.1. Bulk and tapped density, compressibility

index and Hausner ratio

The values obtained in bulk and tapped

densities tests and the flow ratings of nimesulide
samples found for the compressibility index and
Hausner ratio were established according to the
recommendations by USP18 and are shown in
Table 2. Densities obtained for the sample NM1,
although slightly larger, still represent lower
Figure 5. Powder dissolution profiles of NM1, NM2 density values. The lower values for the densities
and NM3 samples in 900 ml of potassium phosphate of NM2 and NM3 samples are consistent with
butter, pH 7.4, containing 2.0% polysorbate 80 (V/V), their smaller size particles.
using paddle apparatus at 75 RPM.

Table 2. Data obtained from the DSC curves Tonset, Tpeak and enthalpy (∆H) for the samples
NM1, NM2 and NM3 in different heating rates.
Properties Sample Heating rate (°C/min)
5 10 20 40
Tonset ± SD (°C) NM1 148.3 ± 0.3 148.5 ± 0.3 149.0 ± 0.6 150.8 ± 0.7
NM2 147.9 ± 0.3 148.2 ± 0.4 148.8 ± 0.5 149.8 ± 0.4
NM3 147.6 ± 0.2 147.8 ± 0.3 148.6 ± 0.4 149.8 ± 0.3
Tpeak ± SD (°C) NM1 149.8 ± 0.3 150.8 ± 0.3 152.5 ± 0.5 157.0 ± 0.6
NM2 149.2 ± 0.3 150.1 ± 0.3 151.4 ± 0.5 153.5 ± 0.5
NM3 149.1 ± 0.2 149.4 ± 0.3 151.2 ± 0.4 154.0 ± 0.3
∆H ± SD (J/g) NM1 121.6 ± 0.3 111.8 ± 0.4 112.2 ± 0.6 120.1 ± 0.7
NM2 111.8 ± 0.4 110.7 ± 0.8 111.7 ± 0.5 116.7 ± 0.6
NM3 109.7 ± 0.3 109.7 ± 0.4 107.6 ± 0.5 113.0 ± 0.4

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3.9.2. Determination of repose angle and flow obtained by the flow through orifice are shown in
through orifice Figure 6 and the results are featured in Table 2.

The repose angle could not be determined due

to the poor flowability of the samples. The graphs

Figure 6. Graphs oof low through orifice of NM1, NM2 and NM3 samples.

3.10. Development and evaluation of nimesulide (Table 3) used only the micronized samples, NM2
tablets obtained in galenic batches and NM3, due to the better results in powder
dissolution than the API non-micronized
The design of the galenic formulations batches (Figure 5).
was conducted with the excipients commonly
used in the pharmaceutical industry, besides the 3.10.1. Physical parameters of the tablets and
excipients present in the reference product dosing
formulation. The excipients lactose monohydrate,
microcrystalline cellulose, The results of weight, hardness, friability and
hydroxypropylcellulose, sodium starch glycollate, dosing were all satisfactory. The disintegration
docusate sodium, hydrogenated vegetable oil and test showed some unsatisfactory results,
magnesium stearate are present in the formulation represented by L5 batch with a relatively high
of Nisulid®. The galenic batches used the same disintegration time (L5 = 9’ 30”), especially when
excipients except by the hydrogenated vegetable compared to the reference product, (1’ 15”)
oil and formulations with polyvinylpyrrolidone K- besides L6 that was out of specification (L6 =
30 and pregelatinized starch as a binder in place greater than 30’). Therefore, it was decided not to
of hydroxypropylcellulose, and sodium lauryl perform the dissolution profiles of these batches.
sulfate, as the surfactant, instead of sodium
docusate were also tested. The galenic batches

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Table 3. Flowability measurements of NM1, NM2 and NM3 samples (n=3).

Properties Sample
NM1 NM2 NM3
Bulk density ± SD (g/mL) 0.45 ± 0.01 0.20 ± 0.02 0.19 ± 0.02
Tapped density ± SD (g/mL) 0.69 ± 0.01 0.28 ± 0.02 0.26 ± 0.02
Compressibility index (rating) 34.78 (very poor) 26.53 (poor) 27.69 (poor)
Hausner ratio (rating) 1.53 (very poor) 1.36 (poor) 1.38 (poor)
Repose angle ND ND ND
Flow through orifice (s/100 g* 18.8 (17.0-21.3) ± 61.0 (32.7-112.0) ± 189.6 (52.7-323.1)
– RSD %) 11.78% 72.69% ± 71.34%
ND not determined
* The results expressed are the average obtained regarding the determination in triplicate samples. The values in
brackets refer to the range found in the analysis, with minimum and maximum values.

3.10.2. Dissolution profile

3.10.2.1. Dissolution profiles conducted

according to the criteria of the Brazilian
Pharmacopoeia

Initially, the dissolution profiles were

performed with the galenic batches L1, L2, L3,
L4, L7 and the reference product using the
conditions recommended by the Brazilian
Pharmacopoeia4 and are shown in Figure 7. In
these tests, the reference product showed values
greater than 85% of dissolution in 15 minutes, Figure 7. Overlap of L1, L2, L3, L4, L7 dissolution
while only L2 and L3 batches showed a very fast profiles and the reference product (R) using the
dissolution profile, same behavior of the reference pharmacopoeic parameters (BF 5, 2010).
product. The statistical analysis has shown that
DE values of L2 and L3 dissolution profiles (DE 3.10.2.2. Dissolution profile in potassium
= 84.95 and 84.02, respectively) are not phosphate buffer, pH 7.4, containing different
significantly different (p > 0.05). However, it was concentrations of polysorbate 80
decided to select the L2 batch for the evaluation
of the influence of the surfactant in the medium The curves of dissolution profiles containing
dissolution recommended by the Brazilian different concentrations of polysorbate 80
Pharmacopoeia (polysorbate 80 2.0%) in different obtained with the tablets of L2 batch and Nisulid®
concentrations. is illustrated in Figure 8. The presented results
show a reduction in drug release as the
concentration of polysorbate 80 has been reduced.
In all assessed surfactant concentrations, the test
product and the reference product remained values
above 85% over 15 minutes maintaining the very
rapid dissolution classification and making it
unnecessary the determination of F2. The
dissolution efficiency was calculated to compare
dissolution profiles. There was a reduction in DE
when the concentration of the surfactant was
gradually removed from the dissolution medium.

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This occurred for both the L2 batch (DE = 84.95; Previous studies reported the melting point of
82.21 and 80. 41, respectively with 2.0% NM form I over the range of 148.9 to 151.0 °C
polysorbate, 1.0% and 0.5%) as for the reference and enthalpy (∆H) of 102.97 J/g and 127.4 J g-1
9,22,23
product (DE = 90. 83; 90. 53 and 87.05, in the . These studies used different analysis
same conditions). Statistical analysis by ANOVA conditions of each other and from this work,
revealed that the dissolution profiles are especially regarding the purge gas, heating rate
statistically different (p < 0.05) and the Tukey’s and the types of crucible. Thus, although the
test identified that in each condition evaluated results are very close to the literature data, such
(polysorbate 80 2.0%, 1.0% and 0.5%), the differences limit a more reliable correlation.
dissolution profile of L2 batch was statistically A study reported that NM form I is the most
different from the reference product. The sodium thermodynamically stable and has a transition
lauryl sulfate present in the formulation would temperature over the range of 144-147 °C (∆H =
enhance the percentage of this surfactant in the 107.63 J/g)7. Otherwise, polymorph II has an
dissolution medium at a maximum of 0,1%. endotermic event at 140 °C and suffers a
transition to polymorph I (melting point at 144 °C
and ∆H = 105.97 J/g)6,7. The DSC curves
(Figure 1) of all NM samples showed similar
thermal behavior to that of polymorph I.
There are not major differences between the
FTIR spectra of NM1, NM2 and NM3 samples
that could be used to distinguish among
polymorph I and II. Only the characteristic bands
of nimesulide were identified, so although this
technique is often used to discriminate between
polymorphs in this case it was inconclusive7,10.
The X-ray powder diffraction is the standard
method to distinguish between different
Figure 8. Overlap of dissolution profiles of L2 batch polymorphs. In the case of nimesulide, there are
and the reference product (R) in potassium phosphate noticeable differences in the peak position of form
buffer, pH 7.4, containing different concetrations of I (2θ = 17.15, 18.13, 19.34 and 21.66°) and form
poysorbate 80 (2.0%, 1.0% and 0.5%). II (2θ = 18.91, 22.15 and 26.14°)6. In addition,
diffraction patterns in the CSD revealed peaks at
4. Discussion 2θ = 17.38, 18.38, 19.62 and 22.00° for form I and
2θ = 19.10, 22.44 and 25.84° for form II. The
The pharmacopoeia tests related to the heavy XRPD patterns of nimesulide samples analyzed
metals determination, loss on drying, sulfated ash correspond to the form I, although the NM1 (non-
and dosing, performed with NM1, NM2 and NM3 micronized sample) have shown differences in
samples were approved by the specifications of peak intensities (Figure 2). Besides, the literature
the Brazilian Pharmacopoeia 2010 (Table 1). The mentions the occurrence of preferred orientation
differences between the dosing of galenic batches in X-ray diffraction of nimesulide samples,
(approximately 95%) and the reference product resulting in peaks of different intensities, but
(100.16%) are assigned to the manual transfers of always in the same position, which characterizes
high shear for oscillating granulator, and hence to the same crystalline arrangement.
the fluidized bed, procedures that, in industrial A review of the particle size distribution
scale, occur in an automatic way. graphs (Figure 3) allows to observe the presence
The DSC curves of NM1, NM2 and NM3 of more than one population of particle sizes,
showed a single endothermic event close to primarily evidenced in micronized samples (NM2
149 °C (Figure 1). The evaluation of the Tonset, and NM3) below 1 µM, which represents a
Tpeak and ∆H values obtained in different heating bimodal distribution curve. Often, micronization
rate showed slightly lower values to the causes difficulties in a good dispersion, assigned
micronized samples (NM2 and NM3, around 110- to cohesive interparticle properties and
120 J/g). This phenomenon is widely described in electrostatic forces provided by the particles that
the literature regarding DSC21. are subjected to this process. The sample NM1

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non-micronized has a particle size population NM2 and NM3, in the powder dissolution, these
below 5 µm, but less significant compared with samples did not demonstrate similar behavior,
the population of particle sizes below 1 µM which can be verified by NM3 superior
detected in micronized samples. performance relatively to NM2 (Figure 5). The
During the development of a solid dosage non-micronized sample (NM1) presented larger
formulation, the knowledge of the size and particle sizes when compared to micronized
distribution of particle size can be used to guide samples and, however, in the powder dissolution,
the selection of a process by direct compression or NM1 showed values near NM2. Thus, other
wet granulation. The results obtained from laser factors that impact the powder dissolution results
diffraction were used together with the results of should be considered as the presence of
the flowability evaluation in order to complement electrostatic charge and the trend to agglomerate,
the choice of manufacturing process of nimesulide which could undertake the performance of NM2
tablets. sample.
The data obtained by SEM confirmed the It was also not possible to establish a direct
results of particle size distribution by laser relationship of the results obtained in the
diffraction, in which NM1 sample also showed wettability with the results of powder dissolution
much higher particle sizes compared to the NM2 because, as mentioned above, the values of
and NM3 samples (Figure 4). Additionally, the contact angles provided by the samples of
presence of a population of particles with sizes nimesulide were very close (Table 1).
close to 1 µM in NM2 and NM3 samples and The evaluation of flowability brought together
5 µm in NM1 sample, observed in the particle size the results of different methods in order to make
distribution by laser diffraction, were also more complete the understanding of the flow
observed in the SEM. The image of NM1, properties of the samples under study. The
although demonstrating a certain variability in densities obtained for the NM1 are low (Table 2),
their morphology, shows elongated particles. The showed values slightly higher the other samples.
images of NM2 and NM3 micronized samples The literature shows results of bulk and tapped
showed greatest similarity regarding the particle density for nimesulide samples near to that of the
sizes and can also be observed the formation of non-micronized NM1. However, for the tapped
aggregates (Figure 4B and C). density, the referenced study used a different
The results of the wettability test were all close method, making questionable the correlation to
to 80° (Table 1) and, in accordance with literature, the results presented here13. The lower values for
the values close to 90° predict a poor wettability24. the densities of NM2 and NM3 can be explained
Although the literature does not present studies by the effect of the micronization process, which
applying wettability test with nimesulide, some results in powders having greater adhesion
works with other drugs were conducted, in which between the particles and therefore a greater
the results of the contact angles were correlated tendency to agglomerate. The result is a poor flow
with water solubility25,26,27. material with low apparent density.
When the aim is the development of a tablet The determination of the compressibility index
formulation, the low solubility of the drug is an and Hausner ratio showed that all samples did not
aspect that reflects negatively on its have good flow properties (Table 2). Considering
bioavailability. The powder dissolution tests that the higher values for compressibility index
served as an important tool to complement the and Hausner ratio indicate stronger interparticle
biopharmaceutical evaluation of nimesulide interactions and undesirable flow characteristics29,
samples. The literature revealed some studies it would be expected that micronized samples,
using powder dissolution tests with nimesulide NM2 and NM3, would demonstrate the worst
samples and the results have a certain proximity to results of flow. However, they presented better
that found in this study22,28. However, the studies flowability rating than that exhibited by the
referenced used different analytical conditions, sample NM1 (non-micronized).
especially with regard to the dissolution medium One possible explanation for the discrepancies
and the rotation apparatus, which compromise the between the results found in the various
correlation results. flowability assessments lies in the qualitative
Differently from the laser diffraction results, scale of classification for flow properties adopted
which showed a very small difference between by official compendia, for example, the US

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Pharmacopeia. Thus, the CI and HR parameters which are factors related to the high cohesion of
have low discriminatory power, especially for the its particles. In this way, it is understandable that
poor flow samples. the flow evaluation methods may have discordant
The repose angle and the flow through orifice results.
tests were carried out in the same equipment. The Based on the results presented in flowability
tests with NM1, NM2 and NM3 samples were assessments, particle size distribution and SEM
conducted using the following funnel openings and considering the aim of the development of a
10, 15 and 25 mm. However, no flow was solid dosage formulation, the direct compression
detectable. Then there was used the opening of process becomes less suitable than the wet
15 mm and tested four (4) speeds available on the granulation, due to the high possibility of
machine (1, 2, 3 and 4). The NM1 sample showed problems related to the flow in the hopper and
flowability with speed 1 (one), but for the NM2 inadequate die filling that promotes, consequently,
and NM3 samples, it was necessary to use the nonuniformity of mass and content.
speed 4, maximum permitted by the equipment. The average weight values found for galenic
The different experimental conditions undertake, batches are close to the average weight displayed
somehow, the discussion of results. Still, it is for the reference product (about 400 mg) and the
possible establish some considerations concerning results were all satisfactory. The tablet hardness
the flow properties of the samples under study. results obtained with the galenic batches showed
The results confirmed the estimation of poor correlation with those of friability, in which the
flow for this API, previously provided by other L2, L3, L5, L6 and L7 batches showed the lowest
tests. Plus, it is also possible verify that no hardness values (close to 5.0 kgf) and the higher
reproducibility was observed in the tests friability values (near 0.42%) and the tablets
performed in triplicate. The NM1, non- obtained with the L1 and L4 galenic batches
micronized, revealed superior flow properties demonstrated higher strength, both to rupture
compared to the other samples. It is also possible (hardness assay about 7.0 kgf) and abrasion
assign a worse flow for NM3 sample, which also (friability percentage about 0.35%).
showed less uniform behavior (Figure 6). L2 and L3 batches have the same formulation
In general, all samples showed erratic flow and the same process by only changing the
behavior, which indicates that an unstable manufacturer of API (Table 3). The differences in
formation and destruction process of the arc results of particle size and hardness were not
dominates the flow process. This process is also significant, preventing a direct correlation
evidenced by the standard in “steps” where the between these tests.
powder flow rate accelerates periodically, The L4 batch has the same qualitative and
probably due to the destruction of the formed ar. quantitative excipients that can influence the
It is known that the micronization process compressibility from the L2 and L3 batches but
promotes a tendency to increased electrostatic showed higher hardness (mean = 7.1 kgf). The
charge. Thus, NM2 and NM3 samples have two difference was in the granulation process
important properties that contribute to a poor (Table 3) including a higher time to addition the
flow: low-density particles and, supposedly, high granulating solution and a longer mixture for the
electrostatic charge. Unfortunately, for this work, L4 batch. Possibly, these process variations allow
it was not possible to assess electrostatic density. adequate wetting of the powders, resulting in
The results obtained in flow assessment tests stronger granules and, consequently, in longer
allow identify a discrepancy between the disintegration time and slower dissolution
determinations of the CI and HR and flow through compared to the values shown by L2 and L3
orifice. The flow through orifice provided more batches.
realistic results, demonstrating, numerically, the Regarding disintegration test, L1 batch has the
characteristic of poor flow for nimesulide. As same qualitative composition of L2 and L3, but
mentioned above, HR and CI values may not be the surfactant (sodium lauryl sulfate) was used in
discriminatory and may cause unreal results flow different ways. L1 showed the highest values in
to powders that are particularly characterized by hardness assay (7.5 kgf). These differences had a
poor flow. Furthermore, the samples NM1, NM2 negative impact on the disintegration of the tablets
and NM3 have particle sizes that are considered obtained with this batch (L1 = 6’ 40”), which had
small (< 80 µM) besides low density values, twice the disintegration time of L2 and L3 batches

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(L2 = 3’ 18” and L3 = 3’ 10”). The L4 batch used statistical analysis of ED values showed similarity
another surfactant (sodium docusate) and its between these profiles (p > 0.05).
disintegration time (4’ 10”) was higher than the The dissolution efficiency values were
L2 and L3 batches. L5 and L6 formulations are calculated and L2 batch had the highest result (DE
closest qualitatively of the reference product, but = 84.95), although quite near the value presented
showed more extensive disintegration times and by L3 (DE = 84.02). L4 and L7 shown next values
L6, in this assay, was disapproved (L5 = 9’ 30” (L4 = 80.92 and L7 = 79.67) and the L1 batch
and L6 = greater than 30’). Obviously, this cannot showed the lowest DE value (76.61). The DE
attribute similarity or difference by not being values were subjected to statistical analysis by
aware of the percentages of each agent in the ANOVA and Tukey test, and it was found that all
reference product formulation. The L7 galenic galenic batches formulations and Nisulid® differ
batch used different binder and surfactant and had significantly (p < 0.05) and the L2 and L3 batches
the shortest disintegration time (1’ 23”). do not present significant differences between the
Regarding Nisulid®, the tablet format is convex DE values (p > 0.05). The L4 batch showed a
which facilitates the maintenance of abrasion dissolution profile similar to those of L2 and L3,
resistance, observed by the low value friability but with lower dissolution mean values and,
(0.27%), although its hardness is lower (4.9 kgf) particularly at 15 minutes, there was not reached
as compared to galenic batch. The disintegration 85% (although it was close), which results in the
time of the reference product was 1’ 15”. classification as a rapid dissolving formulation,
Accordingly, it can be concluded that the step distinct from that presented by Nisulid® and by
in which the surfactant is added to the the L2 and L3 batches. As occurred with L4, L7
formulation, as well as tablet hardness, directly not reached 85% drug release within 15 minutes,
alter the disintegration time and, therefore, can be despite having very close behavior (Figure 7) and
used as auxiliary tools to discriminate between it is also classified as a rapid dissolving
nimesulide formulations. formulation.
In the dosing assay, all galenic batches showed An interesting feature of the L7 dissolution
results close to 95% of the labeled value, and for profile lies in the result obtained in the first
Nisulid® tablets there was obtained 100.2%. All sampling time, which was superior in almost 10%
results meet the specification preconized in the when compared with the result obtained with L3.
Brazilian Pharmacopoeia. One possible explanation is the dual nature of the
The dissolution profiles achieved in pregelatinized starch, that acts not only as a binder
pharmacopoeia conditions demonstrated that the but also as a disintegrate, which may be
formulations of the L2 and L3 batches and the maximizing the release of the API in this initial
reference product exhibited very rapid dissolution time. The result of the disintegration assay (83 s)
with results of the amount of dissolved drug above confirms this hypothesis, considering the smallest
85% in 15 minutes and thus the value of F2 loses time shown.
its discriminative relevance. Although the statistical analysis has shown that
Whereas L2 and L3 batches are formulations DE values of L2, L3 and L4 batches are not
that differ only in the API manufacturer, it is significantly different (p > 0.05), it was decided to
interesting correlate the results obtained in the select the L2 batch for complementary tests. Even
dissolution profile and the data obtained in API if the L2 has showed the greatest dissolution of
characterization, particularly in particle size, values, there is a considerable difference between
wettability and powder dissolution assessments. L2 and the reference product in the first sampling
The results of particle size analysis by laser times (t = 5 min and t = 10 min).
diffraction and wettability were quite close. In terms of bioequivalence, the literature
However, in the powder dissolution, NM3 showed reports that nimesulide has rapid oral absorption2.
dissolution of approximately 10% higher than A Brazilian study evaluated the bioequivalence of
NM2 and further such profiles showed statistically nimesulide tablets and Nisulid® and there were
significant differences (p < 0.05). Although NM3 found for Cmax values equivalent to 5.30 and 4.52
biopharmaceutical properties were higher than ng mL-1 and Tmax of 2.23 and 3.32 h, respectively,
observed with NM2, the L2 and L3 formulated for the reference and test products30.
product showed near dissolution results and Analyzing such data from the literature and
based on the dissolution assessments designed to

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simulate physiological conditions and provided surfactant, obtaining around 90% of dissolution in
tools for the in vitro evaluation of bioavailability, 60 min21. Another study evaluating the dissolution
the evaluation of Cmax and Tmax would not of commercial nimesulide tablets in sodium
represent bioequivalence problems. This is phosphate buffer pH 7.4 supplemented with 1.0%
because, after 45 min (lower time to reach Cmax polysorbate 80 did not obtain values above 90% in
than those presented by the literature) L2 batch 60 min15.
and the reference product already reach the same Since both studies do not provide information
percentage of dissolution; so, it is expected the about the composition of the test product,
same release between the drug (test and reference) outcome differences found comparing with those
in vivo assays. showed here can be attributed to probable
The AUC parameter requires a more careful differences in formulations, given that the
analysis. Another study, mentioned a nimesulide excipients can act in direct mode in the dissolution
bioequivalence study that showed disapproved process. In addition to the important contribution
results, having been previously approved in the of excipients in the rate and extent of dissolution,
pharmaceutical equivalence, which reinforces the aspects such as, for example, the API particle size
alert for the interpretation of the results of this are striking features in the dissolution of solid
drug dissolution profiles31. Whereas nimesulide is dosage forms. These physicochemical properties
a class II drug in the BCS, which the dissolution is were not available in the referenced work, limiting
the limiting step for the absorption, it becomes further discussion.
mandatory a careful design of the dissolution test. The in vitro dissolution tests are used in quality
Thus, even if the medium is preconized by the control of medicines and the development of new
Brazilian Pharmacopoeia containing 2.0% formulations. Depending on the drug class, such
polysorbate 804, it was considered important as nimesulide (Class II in the BCS), the results of
evaluate the behavior of the L2 batch using the a dissolution study can be closely related with in
same potassium phosphate buffer established for vivo performance. For these drugs, difficulties in
Brazilian Pharmacopoeia but containing different selecting the dissolution medium are constantly
concentrations of surfactant. found, which must reproduce the physiological
The presented results show a reduction in drug conditions to ensure an in vitro-in vivo correlation
release amounts as the concentration of and to discriminate different formulations28.
polysorbate 80 has been reduced. Still, in all
assessed surfactant concentrations, the test and the 5. Conclusions
reference product values remained above 85%
over 15 minutes, maintaining the very rapid Differential scanning calorimetry and X-ray
dissolution classification and making it diffraction showed that all samples tested (NM1,
unnecessary the F2 calculation. However, the NM2 and NM3) presented polymorph I. The
dissolution efficiency was calculated as a tool to characterization of particle size showed good
compare dissolution profiles. Again, there was correlation with the density results and flow
observed a reduction of the obtained values of DE through orifice in which the micronized samples
as the concentration of the surfactant was showed worse flow behavior when compared with
gradually reduced in the dissolution medium. This the non-micronized sample. The scanning electron
occurred for both the L2 batch as for the reference microscopy confirmed the results of size and
product. Statistical analysis by ANOVA revealed particle size distribution carried out by laser
that the dissolution profiles are statistically diffraction.
different (p < 0.05) and Tukey’s test identified Although the wettability results were very
that in each condition evaluated (2.0%, 1.0% and close, the powder dissolution identified small
0.5% polysorbate 80), the dissolution profile of differences between the samples, demonstrating
L2 batch is statistically different from the that the dissolution of the NM3 sample
reference product. (micronized) was superior to the others. The
The literature reports a study evaluating the micronized samples exhibited higher IDR than the
dissolution profile of nimesulide tablets in a non-micronized one (NM1) and, in this case,
medium of phosphate buffer pH 7.4 containing surface properties such as roughness and
different concentrations of polysorbate 80. The microstructural factors may be involved.
highest release value was in the presence of 2.5%

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35 Eclética Química Journal, vol. 44, n. 3, 2019, 20-35

ISSN: 1678-4618
DOI: 10.26850/1678-4618eqj.v44.3.2019.p20-35