Spherical crystals of celecoxib to improve

solubility,dissolution rate and micromeritic

properties (2014)
AUTHOR :
VENKADARI RAMMOHAN GUPTA
SRINIVAS MUTALIK
MADHOBHAI M. PATEL
GIRISH K. JANI

REVANDA TRI ARIDIANTO

17334029
KELAS K
Celecoxib spherical agglomerates were prepared with polyvinylpyrrolidone (PVP) using acetone, water and
chloroform as solvent, non-solvent and bridging liquid, respectively. The agglomerates were characterized by
differential scanning calorimetry (DSC), X-ray diffraction (XRD), IR spectroscopic studies and scanning electron
microscopy (SEM). The IR spectroscopy and DSC results indicated the absence of any interactions between drug and
additives. XRD studies showed a decrease in crystallinity in agglomerates. The crystals exhibited significantly
improved micromeritic properties compared to pure drug. The loading efficiency (% or mg drug per 100 mg crystals)
was in the range of 93.9 ± 2.3 and 97.3 ± 1.3% (n= 3) with all formulations. The aqueous solubility and dissolution
rate ofthe drug from crystals was significantly p < 0.05) increased (nearly two times). The solubility and in vitro drug
release rates increased with an increase in PVP concentration (from 2.5 to 10%). The SEM studies showed that the
crystal posseses a good spherical shape with smooth and regular surface.
 background
Direct tabletting of pharmaceutical materials is desirable to reduce the cost of production (1). However, compressing
a high-dosed drug directly requires good micromeritic properties, such as flowability, and good and reproducible
compression behavior. Spherical crystallization technique transforms directly the fine particles produced in
crystallization or in the reaction process into a spherical shape. Agglomerates exhibit improved secondary
characteristics, like flowability and compressibility, so that direct tabletting or coating is possible without further
processing (mixing, agglomeration, sieving, etc) (2, 3). Celecoxib, a non-steroidal anti-inflammatory drug (NSAID),
is the first selective cyclooxygenase-2 inhibitor used in the treatment of osteoarthritis and rheumatoid arthritis in adult
patients (4). Celecoxib exhibits poor flow and compression characteristics and is hence a suitable candidate for
spherical crystallization process to improve the flow properties and compressibility. Also, celecoxib shows
incomplete and poor oral bioavailability due to low aqueous solubility (5). Hence, the improvement of aqueous
solubility in such a case is a valuable goal to improve therapeutic efficacy (6). Apart from particle enlargement, this
technique has also been applied for various purposes such as taste masking and particle size enlargement (7–10).
Spherical crystallization of celecoxib with hydroxypropyl methyl cellulose has been investigated to improve the
micromeritic properties of celecoxib but the aqueous solubility of spherical crystallized drug was not satisfactorily
improved (11). There are no reports available on the spherical crystallization of celecoxib by using a more
hydrophilic polymer, polyvinyl pyrrolidone K-30 (PVP), to improve aqueous solubility and dissolution rates in
addition to improving its micrometric properties, and hence the present work has been under taken with this
objective.
 theory
Celecoxib was a gift sample from Aurobindo Pharma, India. PVP was purchased from s.d. Fine Chemicals, India. All
other chemicals used were of analytical reagent grade. This medication is a nonsteroidal anti-inflammatory drug
(NSAID), specifically a COX-2 inhibitor, which relieves pain and swelling (inflammation). It is used to treat arthritis,
acute pain, and menstrual pain and discomfort. The pain and swelling relief provided by this medication helps you
perform more of your normal daily activities.This drug works by blocking the enzyme in your body that makes
prostaglandins. Decreasing prostaglandins helps to reduce pain and swelling.
 method
Spherical crystallization
A solution of celecoxib (2 g) in acetone (3 mL) was added to a solution of hydrophilic polymer (PVP, 2.5–10%, m/V)
in 100 mL distilled water. The mixture was stirred continuously using a mechanical stirrer (Remi Motors, India) at
500 rpm to obtain spherical agglomerates. The bridging liquid (chloroform, 0.5 mL) was added dropwise. The
agglomerates were separated by filtration using Whatman filter paper (No. 1) and dried for 24 h at room temperature.
The physical mixture of drug and polymer (celecoxib + PVP) was prepared by triturating 1:1 ratio of celecoxib and
PVP using mortar and pestle.

Micromeritic properties
The particle size distribution was studied by the sieve analysis method (12). The shape of the crystals was observed
under an optical microscope (10x magnification) attached to a computer. The loose bulk density (LBD) and tapped
bulk density (TBD) of plain celecoxib and its spherical crystals were determined using a bulk density test apparatus
(Kumar Industries, India). Carr’s index and Hausner’s ratio were calculated using LBD and TBD values (13).The
angle of repose was assessed by the fixed funnel method (12). A known amount of agglomerates was allowed to flow
through a funnel fixed at a constant height (h) and the height and diameter (2r) of the pile of powder were measured
to calculate the angle of repose as tg a = h/r.
Drug loading
The drug loading efficiency of crystals was determined by dissolving 100 mg of crystals in 100 mL of ethanol,
followed by measuring the absorbance of appropriately diluted solution spectrophotometrically (PharmaSpec UV-
1700, UV-Vis spectrophotometer, Shimadzu) at 253.5 nm

Statistical analysis
The results were analyzed by two tailed Student’s t-test using the Graph Pad Instat Software (GPIS; Version: 1.13)
(20). The mean dissolution time (MDT) was calculated using the Origin software.
 Result and discussion
Formulation development
Spherical agglomerates of celecoxib were prepared by the simple agglomeration technique using a three solvent
system. It involves a good solvent, a poor solvent and a bridging liquid. The selection of these solvents depends on
the miscibility of the solvents and the solubility of drug in individual solvents. Accordingly, acetone, chloroform and
water were selected as a good solvent, bridging liquid and poor solvent, respectively. These solvents have been used
successfully in previous studies. Chloroform, although currently not widely used, has shown high application in the
formation of spherical crystals (11, 14). Hence, this solvent system was used in the present study. Agglomerates were
formed by agitating the crystals in a liquid suspension and adding a bridging liquid, which preferentially wets the
crystal surface to cause binding. The addition of bridging liquid (chloroform) promotes the formation of liquid
bridges between the drug crystals to form spherical agglomerates. The spherically agglomerated crystals are formed
by coalescence of these dispersed crystals (15). Generally hydrophilic materials, like hydroxypropyl methylcellulose,
hydroxypropyl cellulose, etc., are used to impart strength and sphericity to the agglomerates (11, 14). However, the
aqueous solubility of celecoxib inspherical crystals was not satisfactorily improved by using hydroxypropyl
methylcellulose (11). In this study, PVP, which is comparatively more hydrophilic, was used to increase aqueous
solubility of the drug along with improving the micromeritic properties.
Micromeritic properties
The mean particle diameter of agglomerates is shown in Table. The pure drug exhibited a very small particle size
(85.55 ± 10.25 µm, n = 3) whereas the size of prepared 178 agglomerates was found between 201.12 ± 10.18 and
235.11 ± 12.23 µm, n = 3, which is significantly different from that of pure drug (p < 0.05). There was uniformity in
batch-to-batch with respect to the size range of crystals. The size of the crystals increased with an increase in the PVP
concentration. The shape of the crystals, when observed using an optical microscope (figures not shown), was
spherical in all the prepared crystal formulations.

The results of loose bulk density (LBD) and tapped bulk density (TBD) are presented in Table II. These parameters
were used to assess the packability of the crystals. The pure drug powder was more bulky and fluffy, which was
indicated by the lowest LBD value (0.30 ± 0.01 g mL–1, n = 3). The highest TBD value (0.52 ± 0.02 g mL–1, n = 3) of
pure drug indicates a high intergranular space between particles. In contrast, the spherical agglomerates exhibited
higher LBD (0.37 ± 0.01 to 0.42 ± 0.01 g mL–1, n = 3) and TBD (0.41 ± 0.01 to 0.45 ± 0.01 g mL–1, n = 3) values
(12). These results indicate good packability of the prepared spherical crystals when compared with pure celecoxib.
 Table Micromeritic properties of agglomerates and pure drug

Particle size
LBD TBD Carr’s index Hausner’s Angle of
Spherical Crystal (µm)
(g mL–1) (g mL–1) (%) Ratio repose (°)

PVP (2,5 %) 0.42 ± 0.01b 0.45 ± 0.01 b 10.20 ± 1.51 b 1.18 ± 0.01 b 29.31 ± 1.23 201.12 ± 10.18 b

PVP (5,0 %) 0.40 ± 0.02b 0.45 ± 0.01 b 10.10 ± 2.36 b 1.10 ± 0.02 b 26.47 ± 2.3 218.13 ± 12.10 b

PVP (7,5 %) 0.37 ± 0.01b 0.41 ± 0.01 b 10.00 ± 2.12 b 1.10 ± 0.01 b 25.61 ± 1.89 230.25 ± 11.77 b

PVP (10,0 %) .39 ± 0.01 b 0.44 ± 0.01 b 10.10 ± 2.69 b 1.10 ± 0.01 b 22.88 ± 1.65 235.11 ± 12.23 b

Pure Celecoxib 0.30 ± 0.01 0.52 ± 0.02 42.00 ± 2.36 1.69 ± 0.03 - 85.55 ± 10.25

LBD – loose bulk density, TBD – tapped bulk density.

A Mean ± SEM, n = 3.
B Significantly different compared to pure celecoxib (p < 0.05)
The results of Carr’s index, Hausner’s ratio and angle of repose of spherical crystals in comparison with pure drug are
presented in Table II. These parameters were used to assess the flow and compressibility properties of the
agglomerates. Carr’s index and Hausner’s ratio of pure drug were 42.00 ± 2.36% and 1.69 ± 0.03 (n = 3),
respectively, indicating extremely poor flow properties. The powder could not pass through the funnel during the
angle of repose experiment. The poor flow of celecoxib could be due to the irregular shape and high fineness of the
powder, which posed hurdles in the uniform flow from the funnel. On the other hand, all the prepared crystals
exhibited low Carr’s index, Hausner’s ratio and angle of repose values, indicating excellent flow properties and
compressibility (Carr’s index: 10.00 ± 2.12 to 10.20 ± 1.51%, n = 3; Hausner’s ratio: 1.10 ± 0.01 to 1.18 ± 0.01, n =
3; angle of repose: 22.88 ± 1.65 to 29.31 ± 1.23°, n = 3). The improved flowability and compressibility of spherical
agglomerates may be due to the sphericity, regular and larger size of crystals (11, 13, 15). Among all the prepared
properties
 CONCLUSIONS
The present study shows that spherical agglomerates of celecoxib prepared with PVP exhibited improved
micromeritic properties in addition to improving the solubility and dissolution rate. This technique may be applicable
for producing oral solid dosage forms of celecoxib with improved dissolution rate and oral bioavailability. However,
in vivo studies are required to confirm these results.
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