International Journal of Applied Pharmaceutics

ISSN- 0975-7058 Vol 12, Issue 3, 2020

Original Article
DISSOLUTION ENHANCEMENT AND FORMULATION OF FILM COATED TABLETS OF
LORNOXICAM BY PHASE TRANSITION METHOD: IN VITRO AND IN VIVO EVALUATION

REHAB AHMED ABDELMONEM1, RANIA MOSTAFA ABD EL GALIL2*, DOAA AHMED EL-SETOUHY3, MOHAMED
FARID EL-MILIGI3, MOHAMED AHMED EL-NABARAWI3
1Department of Industrial Pharmacy, Faculty of Pharmacy, Misr University for Science and Technology, 6th October City, Egypt,
2*Department of Pharmaceutics, Faculty of Pharmacy, Misr University for Science and Technology, 6th October City, Egypt, 3Department of
Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Egypt
Email: dr.raniamostafa@gmail.com
Received: 17 Jan 2020, Revised and Accepted: 23 Mar 2020
ABSTRACT
Objective: This study aimed to enhance the oral solubility and dissolution of poorly soluble lornoxicam by anti-solvent precipitation, and the
manufacture of oral tablets by the phase transition method.
Methods: The solvent was mixture of polyethylene glycol 400 and absolute ethanol. Three stabilizers Inutec SP1, Pluronic F127, Sucrose ester
S1670 at two concentrations and two matrix formers Mannitol, and Avicel PH102 were used to obtain 12 formulae. The formulae were
characterized regarding their infrared spectroscopy (IR), differential scanning calorimetry (DSC), particle size (PS) measurement, drug content and
dissolution. Further characterizations were done for the optimum formula by scanning electron microscopy (SEM) and X-ray diffraction (XRD). Four
tablet formulae were manufactured by phase transition method. The optimum tablets (T3) were evaluated through hardness, drug content,
disintegration, dissolution, IR, and stability studies. Finally, (T3) was compared to conventional tablets in New Zealand rabbits using crossover
design.
Results: The dissolution rate for the prepared formulae was enhanced, from 3.44 to 5.96 folds. Statistical significance was obtained using one and
two way ANOVA among formulae. The optimum tablet formula (T3) had hardness 5.637±1.57 kg, drug content 90.424±1.19%, disintegration time
341.5±9.62 s and the drug dissolved 72.107±0.0025%. Stability, after one month storage of the selected tablets at (25 °c/60% relative humidity),
was satisfactory. The absorption extent of lornoxicam from (T3) compared to the conventional tablets was higher.
Conclusion: Taken together, the obtained results confirmed successfully the potential of the promising formula (T3), over the conventional tablets
of lornoxicam.
Keywords: Lornoxicam, Anti-solvent precipitation, Phase transition method, In vivo study on rabbits
© 2020 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)
DOI: http://dx.doi.org/10.22159/ijap.2020v12i3.36867. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION combination of saccharides with the low and high moldability [9].
The tablet hardness was increased by the crystal change from an
Significant attention focused on nanomaterial based drug delivery amorphous to a crystal state by the conditioning process. This
has been propelled to the forefront by researchers. Owing to the method provides sufficient hardness and low disintegration time
fact that many emerging drug candidates have become more for tablets. Moreover, stability study was evaluated for a month,
hydrophobic and less water soluble, designing an adequate oral and in vivo study was also performed in rabbits to estimate the
dosage form as the oral route is the most common route for drug pharmacokinetic parameters for the optimized tablet formulation
administration due to its convenience has become challenging and (T3) and to calculate the relative bioavailability in comparison to
researchers frequently have to consider more complex drug delivery oral conventional tablets which was 2.04 folds higher.
platforms [1]. The potent Lornoxicam is used for anti-inflammatory and
analgesic purposes in osteoarthritis and rheumatoid arthritis [2, 3]. MATERIALS AND METHODS
Lornoxicam is slightly acidic with a pKa (acid dissociation constant)
of 4.7 and hence has limited dissolution in an acidic environment [4]. Materials
It is slightly lipophilic with an apparent partition coefficient of 1.8 Lornoxicam (C13H10Cl N3O4 S2, MW: 371.8192 g/mol) was a gift
(n-octanol/buffer pH 7.4) [5]. It exhibits low solubility and high from Global Napi drug company Ltd (6th October city, Egypt).
permeability (class II) [6]. This can make its absorption and Polyethylene glycol 400, LOBA Chemie, (India). Hydrochloric acid
dissolution rate limited and thus delay the onset of action. An from Scharlau, (Spain). Absolute ethanol 99.9% of International
enhancement in the solubility and the dissolution rate can firstly, Company for Sup. and Med. industries Alamia, (Egypt). Phosphate
improve its oral bioavailability, secondly, improve its therapeutic buffer PH 6.8 components (Sodium Chloride, Disodium hydrogen
efficiency and the patient compliance [7]. Anti-solvent precipitation phosphate, Potassium dihydrogen phosphate) from Adwic, El-Nasr
method is an effective bottom-up technique to prepare nanosized Pharmaceutical Chemicals Co., (Egypt). Avicel pH 102 FMC Co.,
drug particles [8]. The aim of the work is to speed up the dissolution (Penselvania, USA). Pluronic F127 from Sigma-Aldrich, Inc.,
of lornoxicam in the gastric pH 1.2 by its formulation as (Germany). Inutec SP1 from Beneo, (Germany). Sucrose ester S1670
nanoparticles utilizing anti-solvent precipitation technique, with the from Ryoto™ (Japan). The water was distilled de-ionized water.
aid of different stabilizers, Inutec SP1, Pluronic F127 or Sucrose Mannitol and Lactose anhydrous high melting point sugars from
ester S1670 at different concentrations followed by lyophilization of Adwic, El-Nasr Pharmaceutical Chemicals CO. (Egypt). Xylitol, low
the processed nanoparticles using either Mannitol or Avicel pH 102 melting point sugar alcohol, Xylisorb® and Lycoat® RS 720, medium
as matrix formers. The lornoxicam formula which showed the viscosity grade from Roquette Pharma (France). Pruv® (Sodium
optimum dissolution profile (F3) was selected for further stearyl fumarate), lubricant, from JRS Pharma (USA). Vivapharm®
characterization and formulation by phase transition of sugar HPMC E5-Hypromellose from JRS Pharma (USA). Sodium nitrite
alcohols into oral film coated tablets. Mizumoto et al., reported that from Adwic, El-Nasr Pharmaceutical Chemicals CO. (Egypt).
oral disintegrating tablets could be manufactured using a Acetonitrile 80%, 0.1% Formic acid, tertiary butyl methyl ether
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(HPLC grade) were provided by Merck (Darmstadt, Germany). The experiment was done in triplicate and the mean values of
Lornoxicam® 8 mg (Global Pharmaceutical Industries, Egypt) was cumulative percentage drug dissolved were plotted versus time [18].
used as a reference tablet in in vivo studies.
PS analysis
Methods
The size of different lornoxicam nano formulations and poly dispersity
Preparation of nanosized lornoxicam through anti-solvent index (PDI) were measured by dynamic laser light scattering (Nano–
precipitation method Zetasizer, Malvern ZS, Zen 3600, England). Before analysis 2 mg of
the drug nanoparticles of different formulae was dispersed in 15 ml
Lornoxicam nanoparticles were produced through anti-solvent of deionized water and sonicated for 2 min. The measurements were
precipitation followed by freeze-drying. A mixture of absolute done in triplicate [19].
ethanol and the co-solvent polyethylene glycol 400 in a ratio of 2:3
respectively was used as the solvent for lornoxicam [10]. Dissolution SEM
of lornoxicam was affected by ultrasonication until completely
dissolved using (ultrasonicator LC 60 H, Elma, Germany). Precooled The external morphology of raw lornoxicam and the lornoxicam
freshly double distilled water was used as anti-solvent containing nanoparticles formula of choice were examined through scanning
one of three stabilizers which are Pluronic F127 with concentrations electron microscopy (Quanta 250, FEG, Holland). Particles of the
(0.02% w/v, and 0.08% w/v) [11], Inutec SP1 with concentrations representative samples were fixed on SEM stub using double-sided
(0.005% w/v, and 0.009% w/v) [12] and Sucrose ester S1670 with adhesive tape. Before observation, the formulae were coated with a
concentrations (0.001% w/v, and 0.002% w/v) [13]. Lornoxicam thin layer of gold [20].
solution was completely poured into the anti-solvent (containing a XRD
certain concentration of surfactant) in a ratio 1:5 with vigorous
magnetic stirring using (Magnetic stirrer, 1200 Hot plate and stirrer, The solid state of raw lornoxicam and the lornoxicam nanoparticles
Jenway, UK). Lornoxicam nanoparticles immediately precipitated formula of choice were examined using an x-ray diffractometer
from the solution upon mixing. After stirring for a predetermined (Philips, X’Pert Pro, Netherlands) with secondary Monochromator.
time the nanoparticle suspension was sonicated using the probe The current and voltage using Cu-radiation were generated at 35 mA
sonicator (Sonics vibra cell, 20 KHZ±50 HZ, USA) under controlled and 45 kV, respectively. The angular range was scanned from 0 ° to
temperature using an ice-bath with continuous sonication for 5 min. 60 ° of 2θ, with a scanning speed 0.02 °/s [21].
The obtained nanoparticles were concentrated by centrifugation at
13500 rotations per minute (rpm) for 15 min at 4 °C using cooling Statistical analysis
centrifuge (Sigma, 3-30 K, D-37520, Germany). After the Statistical analysis of the results was performed using one way
centrifugation, the supernatant was replaced with fresh double ANOVA followed by Post hoc analysis using Dunnett's test in terms
distilled water for washing. The collected nanoparticles were of particle size, percentage drug content, while using two way
redispersed in deionized water containing cryoprotectants ANOVA followed by Post hoc analysis using Dunnett's test in terms
(mannitol 3% w/v or avicel at ratio 1:1w/w), prefrozen at–40 °C for of percentage drug dissolved at (5, 20, and 60 min) of nano formulae
2 h, and subsequently lyophilized at –40 °C for 48 h to obtain and raw lornoxicam using SPSS software version 24 (Statistical
lornoxicam nanoparticles powder [14]. Package for the Social Science; SPSS Inc., Chicago, IL, USA). The level
Characterization of different lornoxicam nano formulations of significance was set at 0.05, and (*p<0.05) was considered to be
statistically significant.
DSC
Preparation of film coated tablets by phase transition of sugar
DSC patterns were done for the raw drug, excipients, and the alcohols
formulae using the DSC instrument (Shimadzu, Model TA ─ 50, ESI,
Kyoto, Japan). Temperature range was 20 ─ 300 °C and the heating The optimum nanoparticle formula (F3) was prepared in the form of
rate were 10 °C/min. [15]. rapid release tablet using the phase transition method, a
combination of two types of sugar alcohols was used, either
IR mannitol as the high sugar alcohol (166-168 °C) and xylitol as low
melting point sugar alcohol (93-95 °C) or lactose as higher melting
The infrared spectra were done for the raw drug, excipients, and the point sugar alcohol (201.6-203.3 °C) and xylitol such that the ratio
formulae which were recorded over a wave number range of 4000 between the low and the high melting point sugar alcohols was 1:19.
cm-¹ to 400 cm-¹ (IR Affinity-1, Shimadzu, Kyoto, Japan) [16]. The sugar alcohols were mixed in a bottle for 3 min, with the
Drug content determination concentration of the low melting point sugar alcohol in the mixture
being set at 5%. The mixture was compressed by a single punch
Lornoxicam content of different nanoparticle formulae was machine (Karishma Pharma Machines, India) under the following
determined by dissolving 10 mg of each formula in 100 ml conditions: weight, 150 mg; compression pressure, 500 kgf; punch, 7
phosphate buffer pH 6.8 using sonicator, then the absorbance was mm in diameter. The obtained tablets were coated by HPMC E-5 for
measured spectrophotometrically at 376 nm (UV-Vis T1 and T3, while T2 and T4 were coated using Lycoat RS 720; the
spectrophotometer, Shimadzu UV-1650 PC double beam–Japan) coating process was manual by spraying, then tablets were placed in
using phosphate buffer pH 6.8 as the blank and the percentage drug a drying oven to heat at 97 °C for 30 min. Finally, tablets were
content was calculated. Each experiment was carried out in allowed to cool at room temperature [22-24].
triplicate, and the mean drug content in each formulation was
determined [17]. Characterization of tablets

In vitro dissolution studies Uniformity of weight

The dissolution experiment of raw lornoxicam (8 mg) and The test was carried out according to the British Pharmacopoeia
lornoxicam nanoparticle formulae (equivalent to 8 mg of (BP) [25]. Twenty tablets from each formula, were individually
lornoxicam) were carried out using the USP dissolution tester weighed and the mean of tablet weights was calculated. Results are
apparatus (II) (Dis 6000, Pharmatron, Switzerland). The stirring presented as mean value±standard deviation (SD).
speed was 100 (rpm), the temperature was 37.0±0.5 °C and 900 ml Tablet friability
of 0.1 N HCl pH 1.2 was used as the dissolution medium. Aliquots of
5 ml were collected after 5, 10, 15, 20, 25, 30, 40, 50 and 60 min and Twenty tablets, from each formula, were accurately weighed and
immediately supplemented with the same volume of fresh medium. placed in the drum of friabilator (Thermonik type, Campbell
Finally, the concentrations of the collected aliquots were determined electronics, India). The tablets were rotated at 25 (rpm) for a period
spectrophotometrically against a blank at 372 nm in acidic medium. of 4 min and then removed, dedusted and accurately re-weighed.

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The percentage loss in weight was calculated and taken as a measure the two formulations: Lornoxicam® 8 mg film coated tablets as a
of friability [25]. reference product and the optimized formula tablets (T3) (8 mg).
Twelve healthy male New Zealand rabbits (2.0─2.5 kg) participated
Tablet hardness in the study, and were randomly assigned into two groups of equal
According to the British Pharmacopoeia, ten tablets from each size. The study procedure performed was approved by the Ethics
formula, were tested using hardness tester (Thermonik type, Committee of Faculty of Pharmacy, Cairo University (PI 1947),
Campbell electronics, India). The mean hardness was calculated in Egypt. The animals were kept in individual cages under well-defined
kg±SD [25]. and standardized conditions (humidity, and temperature controlled
room), fed with standard food and water access, and allowed to fast
Drug content uniformity overnight for 12 h [29]. On the study day, each rabbit in the first
group received equivalent amount to (8 mg) of conventional tablet
Randomly selected ten tablets from each formula were assayed for
(Treatment A). The tablets were placed gently into the mouth of the
drug content uniformity. Lornoxicam was assayed by dissolving one
rabbits and swallowed with the aid of the water. Rabbits of the
tablet in phosphate buffer pH 6.8 [26] with the aid of an ultra
second group received equal doses of lornoxicam through oral
sonicator (Elma Sonicator, Germany) for one hour to ensure
administration of optimum formula (T3) (Treatment B). From the
complete dissolution. Lornoxicam was assayed
start of the study time, the rabbits remained at the study site under
spectrophotometerically at λmax 372 nm, using UV spectroscopy
controlled dietary and liquid intake until the end of the study day.
(Shimadzu-1650 PC double beam, Japan). The percentage of
The washout time was one week. Venous blood samples (250 µl)
lornoxicam was calculated as the mean of three recordings±SD.
were collected in heparinized glass tubes to prevent blood clotting at
In vitro disintegration time the following scheduled time intervals: 0 (predose), 15, 30, 45, 60,
90 min, 2, 3, 4, 6, 8, 12, 15, and 24 h after administration of both
Disintegration times of the prepared tablets were determined with treatments. Plasma was immediately separated from the blood cells
six tablets in 900 ml of simulated gastric fluid Kept at 37±0.5 °c via centrifugation (3000 rpm) for 10 min (Centurion Scientific Ltd.,
using (Thermonik type, Campbell electronics, India). According to Chichester, UK), kept in glass tubes and then deep frozen at ─ 25 °C
European Pharmacopoeia (2009) specifications [27]. The till assayed.
disintegration time was defined as the time necessary for the tablet
to completely disintegrate until no solid residue remains or only a Instrumentation
trace amount of soft residue remains on the screen. A digital
The analysis was performed using a Shimadzu Prominence
stopwatch was used to measure the disintegration time to the
(Shimadzu, Japan) series LC system equipped with degasser (DGU-
nearest second. All results are presented as mean value±SD.
20A3) and solvent delivery unit (LC-20AD) with an auto-sampler
In vitro dissolution studies (SIL-20A). The system was used to inject 25 µl aliquots of the
processed samples on a C18, 100A (50×4.6 mm) (Phenomenex,
The dissolution profiles of lornoxicam in tablets compared with the USA), 5 µm particle size. A sensitive and validated LC-MS/MS was
raw drug were determined in a dissolution tester (Hanson Vision adopted for the separation and quantitation of lornoxicam using
Elite 8, USA) following the USP Paddle Method. All tests were Torsemide as an internal standard (IS) [30]. The mobile phase
conducted in 900 ml simulated gastric fluid without enzymes at pH consisted of acetonitrile and 0.1% formic acid in water (80:20 v/v)
1.2. The dissolution medium was maintained at a temperature of was pumped at 1 ml/min. MS/MS detection in positive ion mode
37±0.5 °c with a paddle rotation speed at 100 (rpm). The amount of using AB Sciex (Foster City, CA, USA) API-3200 mass spectrometer
drug used was equivalent to 8 mg. At specified time intervals (5, 10, was used for quantitation. The analytical data were processed by
15, 20, 25, 30, 40, 50, and 60 min), 5 ml aliquots were withdrawn Analyst Software version 1.6 (Applied Biosystems Inc., Foster city,
and replaced with equal volume of fresh medium to maintain the CA) [31].
sink condition. Samples were assayed for drug content
spectrophotometerically at 372 nm [28]. Cumulative amount of drug Standard solution and sample preparation
dissolved in the preparations was calculated according to the
To prepare the standard calibration samples, aliquots of 1 ml rabbit
calibration equation. Dissolution studies were performed in
plasma were spiked with lornoxicam stock solution (50 ng/ml) and
triplicates (n=3).
an aliquot of 100 µl of Torsemide solution the internal standard (IS)
IR to produce calibration standards at the following concentrations: 1,
3, 12.5, 100, 300, 625, 1000 ng/ml. For sample preparation, 1 ml of
Samples of (2-3 mg) was ground with dry potassium bromide rabbit plasma and 100 µl of Torsemide solution (IS) was vortexed in
powder, and compressed into discs. The IR spectra were recorded 10 ml glass tubes for 1 min. Five milliliters of tertiary butyl methyl
(IR Affinity-1, Shimadzu, Kyoto, Japan) for tablet formulae, and the ether were added vortexed for another 1 min then centrifuged at
excipients. The test was done in triplicates [16]. 3000 (rpm) for 10 min. The organic layer (3 ml) was transferred to
clean glass tube and evaporated to dryness using centrifugal vacuum
Statistical analysis
concentrator at 45 °C. The dry residue was reconstituted in 200 µl
The experimental results were analyzed using SPSS software version mobile phase and an aliquot of 20 µl of this solution was loaded into
24. One way ANOVA was used to show the significance of the LC-MS/MS.
difference between formulae at a level of 0.05 in terms of hardness,
Pharmacokinetic parameters and statistical calculations
disintegration time and dissolution. Post hoc analysis was
performed using the Scheffe test. Peak concentrations (Cmax) and peak times (Tmax) were derived directly
from the experimental points. The other pharmacokinetic parameters;
Stability study
(AUC0-24, AUC0-∞, Kel and t½e) were computed by non-compartmental
A stability test was done for the optimum tablet formula (T3) analysis using Kinetica Software (version 4.4.1). The pharmacokinetic
prepared by direct compression using the phase transition method. parameters of the two tested formulations (test and reference) were
The storage conditions were set at 25 °c/60% relative humidity compared by using non-parameteric for independent samples (Mann-
(RH) for one month in waterproof containers in desiccator Whitney’s test) using the SPSS software version 24. The significance of
containing saturated solution of sodium nitrite. Evaluation tests the difference was determined at (*p<0.05).
were done for the fresh and the stored tablets; after a week, two
weeks and four weeks for their lornoxicam content, tensile strength, RESULTS
disintegration time and in vitro release [24]. Preparation of nanosized lornoxicam through anti-solvent
In vivo studies precipitation method

The design of this study was a comparative, randomized, single dose, Lornoxicam nanoparticles were prepared by the anti-solvent
two-way crossover open-label study performed in two phases using precipitation method. The drug solution was introduced to generate

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high supersaturation, results in a high nucleation rate and produces a many parameters as stirring rate; higher stirring rate favored the
large number of nuclei, which reduced the solute mass for subsequent formation of smaller and more uniform drug particles, also the drug
growth. The growth of nucleating crystals could be arrested by using a concentration and the solvent volume ratio [33]. The preparation
stabilizer through a steric or electrostatic mechanism [32]. For temperature; a lower temperature can inhibit the particle growth,
hydrophobic drugs like lornoxicam, water is most commonly used as therefore the particles with small size were formed as a result of the
anti-solvent. In terms of the solvent, blend of absolute ethanol and high nucleation rate and low growth rate at low temperature [34].
polyethylene glycol 400 in a ratio 2:3 screened by trial and error was After several trials and errors, the parameters of the method were,
used. The solubilization power was correlated with the co-solvent three stabilizers Inutec SP1, Pluronic F127, Sucrose ester S1670, each
polarity; the greater the difference in polarity between the two in two different ratios above and below their critical micelle
solvents the greater the power of solubilization [10]. The stabilizer concentrations of 0.009% w/v, 0.1% w/v, and 0.0014% w/v
needs to have a good affinity for the drug particles, possesses a fast respectively [11-13], the temperature of anti-solvent below 3 °C, the
diffusion rate and effective adsorption onto the drug particle surface. stirring rate was 1500 (rpm), the ratio between the solvent and anti-
So, the choice of appropriate solvent–stabilizer pair is empirical. The solvent was 1:5, the composition of the different formulae has
physical state of the formed particles was significantly influenced by complied in table 1.

Table 1: Composition of different lornoxicam nano formulae

Formula Inutec SP1 Pluronic F127 Sucrose ester S1670 Mannitol Avicel pH 102
(% w/v) (% w/v) (% w/v) (% w/v) (mg)
F1 0.009 3
F2 0.009 30
F3 0.005 3
F4 0.005 30
F5 0.02 3
F6 0.02 30
F7 0.08 3
F8 0.08 30
F9 0.002 3
F10 0.002 30
F11 0.001 3
F12 0.001 30
*All the formulae contain 30 mg lornoxicam

Fig. 1 (a): DSC thermograms of Lornoxicam (D), Mannitol, F1, F3, F5, F7, F9 and F11

Characterization of nanoparticles above 300 °C that might be attributed to its melting or decomposition.
Mannitol showed a sharp endothermic peak at 167 °C. It was evident
DSC that the exothermic peaks corresponding to both mannitol and
avicel were preserved in the thermograms of all formulae. The
The compatibility of lornoxicam with the excipients was investigated lornoxicam exothermic peak was also evident in all of the
using DSC since it is considered as a rapid method for evaluating the thermograms of its formulae which might indicate compatibility.
possible incompatibilities between drugs and excipients [35]. The However, noticeable broadening in lornoxicam peak intensity was
DSC thermograms of raw lornoxicam, different formulae and the observed in some thermograms. This is probably attributed to the
excipients are shown in fig. 1. Lornoxicam DSC thermogram differences in geometry of the mixture samples reported by other
exhibited a sharp exothermic peak at 233.8 °C corresponding to drug authors [37]. Therefore, further compatibility investigation was
melting [36]. Avicel pH 102 showed a slightly exothermic effect performed applying infrared spectroscopy study.

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Fig. 1(b): DSC thermograms of Lornoxicam (D), Avicel, F2, F4, F6, F8, F10 and F12

IR obtained at 1157 cm-1, 1387 cm-1, 1336 cm-1 were due to stretching
vibrations of O═S═O group. Other prominent peaks appeared at
The Fourier-transform infrared spectra (FTIR) of lornoxicam and 827.94 cm-1 corresponding to–CH aromatic ring bending and at
the formulae were recorded and presented in fig. 2. It is clearly 766.8 cm-1 due to C–Cl bending vibration. It was clearly evident that
apparent that the IR spectrum of lornoxicam showed a characteristic the IR spectra of the different formulae showed no significant
peak at 3090 cm-1 corresponding to–NH stretching vibration. An difference in peak intensities and wavelengths indicating the
intense absorption peak was found at 1642 cm-1 due to the absence of chemical interaction between the drug and the excipients
stretching vibration of the C═O group in the primary amide. Other confirming the DSC results presented formerly. Therefore, the latter
peaks were observed at 1597 cm-1 and at 1559 cm-1 showed the was considered in conjunction with DSC to reach a definite
bending vibrations of the N–H group in secondary amide. Peaks conclusion of drug excipient compatibility [38].

Fig. 2: FTIR spectra of Lornoxicam (D) and nanoparticles formulations

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Drug content determination temperature during mixing, rate of mixing, drug concentration,
solvent/anti-solvent ratio, the choice of stabilizers used and their
Table 2 showed the average percentage drug content of different concentrations, cryoprotectants used, all played roles in degree of
formulae, which ranged from 25.759±0.119% to 100.508±0.034% supersaturation and the nucleation rates which offer the potential to
and the standard deviation from triplicate determinations. It is produce a large number of submicrometer particles in the final
evident that some formulae had high drug content and some were suspension, if the growth can be arrested by stabilizers [32]. The
low; this is probably attributed to the number of nuclei formed at statistical analysis showed a significant difference between formulae
the solvent/anti-solvent interface and the influence of concentration by one way ANOVA followed by Dunnett’s test, and the highest
on the viscosity [39]. The process parameters including the effect of content was in F3.

Table 2: Percentage drug content of different formulae

Formula Drug content (%)
F1 88.436±0.001
F2 58.366±0.063
F3 100.508±0.034
F4 25.759±0.119
F5 96.606±0.165
F6 59.453±0.307
F7 67.195±0.123
F8 83.210±0.123
F9 87.05±0.035
F10 50.647±0.240
F11 75.047±0.038
F12 44.926±0.039
*All values are (mean±SD (standard deviation), n= 3)

In vitro dissolution studies According to Noyes-Whitney equation, the drug release rate is
linearly proportional to the surface area exposed to the medium
In vitro dissolution studies for raw lornoxicam and the processed [41]. The accelerated dissolving rate of lornoxicam nanoparticles
nanoparticles were done using the 8 mg dose [40] for one hour in could be mainly ascribed to their greater surface area in comparison
0.1N HCl at pH 1.2. The cumulative percentage of the drug dissolved with the raw drug. The results showed that the use of stabilizers
as a function of time from the prepared lyophilized formulae is (Inutec SP1, or Pluronic F127, or Sucrose ester S1670) in
illustrated in fig. 3. The general features of lornoxicam dissolution concentrations near or lower than their critical micelle
profiles revealed a high initial flash dissolve within the first 15 min concentrations, was effective in inhibiting crystal growth due to the
from F1 (69.108%) and F3 (65.794%). The highest amount of drug presence of the hydrodynamic boundary layer surrounding the
dissolved after one hour was from F3 (74.484%), F5 (75.375%), F6 nanocrystals as well as adsorption of the polymer molecules on the
(75.735%), which show insignificant differences between them growing crystal faces [42]. The mechanism of polymer adsorption on
(*P˃0.05), while F11 showed the lowest amount of drug dissolved the crystal surface can be explained on the basis of hydrogen
(43.762%). It was clearly observed that the percentage of drug bonding between drug molecules and polymer. Two way ANOVA
dissolved from raw lornoxicam was very slow (12.7%) after one followed by Dunnett's test in terms of percentage lornoxicam
hour. However, it was apparent that lornoxicam dissolution dissolved at given time intervals (5, 20, 60 min) from nanoparticles
significantly (*p˂0.05) improved when the anti-solvent precipitation formulae and raw lornoxicam using Tukey HSD and Dunnett two
method used and nanoparticles produced, from 3.4 to 5.96 folds. sided showed significant difference (*P˂0.05).

Fig. 3(a): Percentage lornoxicam dissolved from F1 to F6 in 0.1 N HCl, compared with raw lornoxicam, (mean±SD, n=3)

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Fig. 3(b): Percentage lornoxicam dissolved from F7 to F12 in 0.1 N HCl, compared with raw lornoxicam, (mean±SD, n=3)

PS analysis not only the nucleation rate, but also the diffusion–controlled growth
rate [43]. The lornoxicam nanoparticles were significantly
The particle size distribution of lornoxicam nanoparticles using zeta- smaller and more uniform than the raw lornoxicam, which
sizer was determined. The mean particle size and polydispersity indicates better solubility [44]. The increase in mean particle size
index of the prepared nanoparticles were calculated from the
and the polydispersity index (PDI ˃ 0.5) in some formulae could have
autocorrelation function of the intensity of the light scattered from
been caused by the aggregation of particles during the freeze-drying. It
the particles. It could be seen that the mean particle size of the
can thus be concluded that the stabilizers used are effective in
nanoparticles obtained via the anti-solvent precipitation method
ranged from 333.45 nm to 741.825 nm which were shown in table 3. arresting the particle growth, but may not be very effective to prevent
aggregation. Statistical analysis showed significant difference between
Particle size formation includes several steps, namely particle formulae by one way ANOVA followed by Dunnett’s test, and the
nucleation, molecular growth and agglomeration or aggregation, and smallest size was F3. Therefore, the latter was considered in
their rate determines the final particle size and its distribution. The conjunction with dissolution study to reach a definite conclusion of
driving force for this process is the supersaturation, which determines enhancement of dissolution due to reduction of particle size.

Table 3: Particle size measurements for different formulae

Formula Size (nm) PDI
F1 365.825±1.375 0.778±0.053
F2 566.525±10.124 0.558±0.028
F3 338.725±13.025 0.78±0.018
F4 461.925±14.875 0.607±0.045
F5 333.45±14.45 0.718±0.025
F6 647.475±18.825 0.425±0.035
F7 349.825±22.425 0.825±0.071
F8 502.725±20.275 0.506±0.021
F9 362.925±6.075 0.889±0.000
F 10 687.062±14.388 0.347±0.031
F 11 655.000±24 0.813±0.033
F 12 741.825±15.275 0.412±0.033
*All values are (mean±SD, n=3), PDI (Polydispersity index)

Fig. 4: Representative SEM for (a) Raw drug, (b) F3

SEM particles exhibited irregular shape and a broad size distribution. F3

with the stabilizers used showed spherical or twisted cuboid shape
Morphology of raw lornoxicam and the selected nanoparticles in whole. Under high magnification, it could be clearly evident that
formula (F3) were shown in fig. 4. It can be observed that raw drug these agglomerates or particle assemblies were composed of a large

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number of individual nanoparticles with a size of approximately 300 13.47 °, 14.31 °, 15.10 °, 18.91 °, 20.51 °, 21.53 °, 22.97 °, 24.70 °,
nm. 25.40 °, 28.08 °, 30.49 ° and 45.84 °, indicating the crystalline nature
of the drug, while the diffractograms of the selected nanoparticle
XRD formulae showed a disappearance of some diffraction peaks and
X-ray diffraction analysis was performed to investigate the effect of reduction in intensity of the remaining peaks, indicating that the
the anti-solvent precipitation method on the crystallinity of processed particles were in amorphous form. The amorphous state
lornoxicam in the nanoparticles formulae, where the selected of the lornoxicam nanoparticles would also help accelerate the drug
nanoparticle formulation and the raw lornoxicam powder were dissolving rate as well [41]. These promising results encourage for
compared in fig. 5. The diffraction pattern of lornoxicam revealed further studies on optimum formula into tablet form and in vivo
several sharp, high-intensity peaks observed at (2θ) angles of 8.78 °, study for enhancement of oral bioavailability of lornoxicam.

Fig. 5: XRD patterns of Lornoxicam (D) and F3

Preparation of film coated tablets by phase transition of sugar sugar alcohols in order to produce rapid disintegrating tablets of
alcohols sufficient hardness and low disintegration time, we use these
benefits for preparation of oral tablets in an acidic medium and the
The optimum formula (F3) was prepared using the phase transition
results were satisfied. The objectives of this study are to produce
method by direct compression. The phase transition method was
oral film coated tablets, which has a sufficient hardness for handling,
chosen as it is new, simple method of preparing rapid disintegrating
as before processing the tablets were fragile, low disintegration time
tablets without any special apparatus, focused on the compactability
and can be manufactured by commonly used production methods
of saccharides using a combination of low and high compactability
and equipment. The composition of tablet formulae manufactured
saccharides [45]. Although, this novel preparation method reported
by the phase transition method was shown in table 4.
by Mizumoto et al., focused on the melting point of saccharides and

Table 4: Composition of tablet formulae (T1, T2, T3, and T4)

Components T1 T2 T3 T4
Powder 59.455 49.085 60.897 53.774
Lubricant (Pruv) 1.17 1.17 1.17 1.17
Xylitol 4.468 4.987 4.396 4.753
Mannitol 84.907 94.758 - -
Lactose - - 83.537 90.303
HPMC (E-5) 2% - 2% -
LycoatRS720 - 2% - 2%
Total weight 150 150 150 150
*All the tablet formulae components are in (mg)

Characterization of tablets heating probably influences the hardness of tablets. It is well known
that the tablet hardness decreases with increasing the pore size in
All formulations resulted in successfully elegant tablets that case of common compressed tablets [49, 50]. However, the tablet
withstood manual handling. As shown in table 5, the tablets were hardness increased with the pore size after heating, this probably
located within the acceptable weight variation range. According to due to diffusion of melted xylitol in tablets and then solidified again
compendial standards, the tablets comply with the friability test as when left at room temperature after heating so the hardness
the weight loss during the friability test was less than 1%, indicating increased due to greater bonding surface area between the powder
that the tablets were non-fragile and could be handled easily. The particles [51, 52]. It was evident that tablet formulae (T3, T4)
mean hardness value ranged from 3.88 to 6.79 Kg. It was apparent containing lactose became harder after heating, compared with that
that the tablet hardness was affected by the heating process and low of tablet formulae (T1, T2) containing mannitol, this is probably due
meting point sugar alcohol content. All the tablets containing about to fine particle size of lactose powder than that of mannitol, which
5% xylitol showed hardness above 2 kilo pond (kp). It is generally produces a greater bonding surface area with xylitol when melted.
recognized that sufficient hardness would be 2 kp or higher [46, 47]. Added to that, (T4) was the hardest formula due to the greater
Xylitol in tablets would melt at 93 °C, since the melting point of content of lactose than that in (T3). There was significant difference
xylitol is 93-95 °C [48]. Accordingly, the melting of xylitol caused by between formulae (*P˂0.05) by one way ANOVA using post hoc

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followed by Scheffe test, which showed homogeneity between (T3, their faster disintegration. The disintegration time of T3 and
T4). In vitro disintegration studies showed that (T1, T2) were of conventional tablets were also compared and the results were
longer disintegration times compared with (T3, T4), added to that 341.5±9.62 s, and 490±10 s respectively. In T2 and T4 the film
(T1, T3) were of lower disintegration time compared with (T2, T4). coating was Lycoat RS720 [54]; (hydroxyl propyl Pea starch) of
These probably attributed to the composition of (T3, T4); which medium viscosity and formed more cohesive films, that are less likely
contain amorphous form saccharide (lactose anhydrous) [53] by to break up or dissolve easily than HPMC E-5 (hydroxyl propyl methyl-
virtue of its fine particles and high solubility, the tablet formulae cellulose) which is of low viscosity. There was statistical significance
acquired hardness and brittleness and these were apparent in (*P˂0.05) between formulae regarding the disintegration time by one
superior hardness of (T3, T4) over (T1, T2) and at the same time way ANOVA using post hoc followed by Scheffe test.

Table 5: Characterization of tablets

Formula Weight variation Hardness Drug content Friability Disintegration time Drug Content uniformity
(mg) (kg) (%) (%) (s) (%)
T1 146.43±1.36 3.88±1.03 88.79±5.34 0 381±16.39 90.34±3.59
T2 146.53±0.52 3.54±0.94 87.74±2.57 0.68±0.67 415±25.11 85.825±3.28
T3 146.93±1.35 5.62±1.42 90.42±1.19 0.10±0.03 341. 5±9.62 93.330±3.37
T4 148.33±1.51 6.80±1.25 85.54±2.91 0.23±0.09 364.3±10.63 81.853±4.44
*All values are (mean±SD, n=3)

In vitro dissolution studies confirmed that the phase transition method provided the tablets
with sufficient hardness while keeping its quick disintegration and
In film coated tablets the dissolving percentage in T1 and T3 were
dissolution rate. These results correlate well with disintegration
superior over the rest of the formulae which were 76.346±0.005 and
time testing results, where HPMC E-5 film coating resulted in shorter
72.107±0.002 respectively. It was also evident in fig. 6 that the
disintegrating time than that of lycoat. These results were confirmed
preparing method or the excipients used have no retarding effect on
statistically by one way ANOVA using post hoc followed by Scheffe
the release of lornoxicam from tablets compared with the
test, showed an insignificant difference (*P>0.05) and homogeneity
dissolution profile of optimum nanoparticle formula; such that the
between F3, (T1, T2, T3, T4) and between (T1, T2, T3, T4).
dissolving percentage from F3 was 74.484±0.005. It was also

Fig. 6: In vitro dissolution profiles of tablet formulae in gastric simulated fluid at pH 1.2 and 37 °C, (mean±SD, n=3)

Fig. 7: FTIR spectra of tablet formulae compared with raw lornoxicam

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IR and drug content of the selected tablets (T3). The hardness and
disintegration time of tablets slightly increased with storage time.
The IR spectra of different tablet formulations and pure excipients used These data suggested that the xylitol content (5%) in the formula; used
were recorded and presented in fig. 7. It was clearly apparent from tablet as low melting point sugar alcohol which was responsible during the
formulations that the characteristic peaks of lornoxicam were at their heating process in phase transition method for inter-particle bonds
same positions with the different excipients used in tablet formulations. between high melting point sugar alcohol (lactose) particles, required
Moreover, these spectra can be simply regarded as the superimposition a long time to return to a crystalline solid. Analyzing the dissolution
of lornoxicam spectrum and the investigated excipients spectra. This data of the stored and fresh tablets indicated that storing the tablets at
could indicate the absence of chemical interaction between drug and the specified conditions (25 °C/60% RH) had no marked effect on
excipients in different tablet formulations. drug dissolution as shown in fig. 8. In addition, sugar alcohols are
Stability studies very sensitive to humidity, so that it is important for formulation
development to select the moisture-proof packaging to prevent
The visual and physical inspection of the selected tablets (T3) changing of tablet properties under the humidity condition. The
conditioned at 25 °C/60% RH for one month [24] revealed no observed stability of lornoxicam in T3 tablets can be attributed to
remarkable changes in the physical characteristic (texture, color, the lyophilization process which can enhance the product stability in
and porosity). Also, no remarkable change in the thickness, diameter the dry state [55, 56].

Fig. 8: Comparison between dissolution profiles of T3 in fresh and after 4 w of storage condition, mean of readings (n=3)±SD

In vivo study and pharmacokinetic analysis was observed that the AUC0-24 in T3 was higher than that of
conventional tablets by more than 2 folds, similarly the AUC 0-∞ was
The calibration curve of lornoxicam showed a linear response across higher by 1.99 folds. These results showed that the amount of drug
the concentration range used from 1 to 1000 ng/ml. The assay absorbed through the optimum formula T3 was remarkably higher
method showed a linear relationship between lornoxicam than that from conventional tablets. The relative bioavailability was
concentration and its peak area ratio to the internal standard and improved by 203.794%. Finally, the elimination half-life was slightly
the determination coefficient (R2) was found to be 0.997. As the shorter in T3 than conventional tablets and this indicated the
assay method can be used for the quantitative determination of the effectiveness and the rapid action of T3 and it was consistent with
drug in plasma [57]. The mean plasma concentration-time curves the pharmacokinetics theory, in which an increase in absorption
following the administration of Lornoxicam® 8 mg tablets and T3 should not affect elimination. The statistical analysis comparing the
tablets were shown in fig. 9 and the mean pharmacokinetic pharmacokinetics parameters between the two treatments was the
parameters were reported in table 6. Results showed that the Cmax of non-parametric test Mann-Whitney for independent samples
T3 was 1408.92±62.194 ng/ml compared with 707.203±62.011 showed that the mean rank of T3 in (Cmax, AUC0-24, AUC0-∞, and Kel)
ng/ml for Lornoxicam® (conventional tablets). The Cmax increased by were higher than that in conventional tablets and showed significant
1.99 folds indicating that T3 tablets, improved oral absorption of difference (*P˂0.05) regarding (Cmax, AUC0-24, and AUC0-∞), while no
lornoxicam. The Tmax was the same in both T3 and conventional significance regarding (Tmax, Kel, and t½e) and these results were
tablets which were consistent with reported values (1-2 h) [58]. It confirmed by Wilcoxon W and Z-calculated tests.

Fig. 9: Mean plasma lornoxicam concentrations±SD, (n=3), following administration of T3 and Lornoxicam®tablets in rabbits

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Table 6: The mean pharmacokinetic parameters±SD, (n=3), of lornoxicam after administration of T3 and Lornoxicam® tablets to rabbits
Parameters CPmax Tmax AUC (0-24) AUC (0-∞) K el t½e *RB% (relative bioavailability)
(ng/ml) (h) (ng. h/ml) (ng. h/ml) (h-1) (h)
T3 1408.92 1.5 16574.22 29640.267 0.054 13.58 203.794 %
±62.19 ±0 ±577.97 ±2570.368 ±0.015 ±2.690
Lornoxicam® tablets 707.20 1.5 8132.82 14924 0.045 16.715 ------
±62.01 ±0 ±232.46 ±2485.450 ±0.012 ±5.164

CONCLUSION suspension: in vitro and in vivo study. Int J Pharm Pharm Sci
2016;8:136-42.
The dissolution of lornoxicam was successfully enhanced by 9. Agiba AM, Eldin AB. Insights into formulation technologies and
producing nanoparticles through anti-solvent precipitation using novel strategies for the design of orally disintegrating dosage
three different stabilizers Inutec SP1, Pluronic F127, Sucrose ester forms: a comprehensive industrial review. Int J Pharm Pharm
S1670. F3 which was formulated using Inutec SP1 displayed Sci 2019;11:8-20.
superior dissolution profile, drug content and small particle size. It 10. Lee JH, Chun IK. Effects of various vehicles and fatty acids on
was taken as the optimum formula and successfully manufactured the skin permeation of lornoxicam. J Pharm Invest
into rapid release film coated tablets through the novel method 2012;42:235-41.
(phase transition of sugar alcohols) by direct compression. T3 was 11. Lin Y, Alexandridis P. Temperature-dependent adsorption
the optimum tablet formula, which showed a superior dissolution of Pluronic F127 block copolymers on to carbon black
profile, drug content, hardness, and disintegration time. Stability particles dispersed in aqueous media. J Phys Chem B
study on T3 showed, that the storage conditions did not affect the 2002;106:10834-44.
lornoxicam content, or the in vitro release, but slightly increase the 12. Srinarong P, Hämäläinen S, Visser MR, Hinrichs WL, Ketolainen
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and its rapid absorption to provide effective and efficient tablets of 13. Soultani S, Ognier S, Engasser JM, Ghoul M. Comparitive study of
lornoxicam by the oral route. some surface active properties of fructose esters and commercial
ACKNOWLEDGMENT sucrose esters. Colloids Surfaces: A Physicochemical Engineering
Aspects 2003;227:35-44.
The authors are thankful to Misr University for Science and 14. Lonare AA, Patel SR. Antisolvent crystallization of poorly water
Technology, College of Pharmacy and Cairo University Faculty of soluble drugs. Int J Chem Eng Appl 2013;4:337-41.
Pharmacy for providing all the necessary equipment and support. 15. Dumas JP, Gibout S, Zalewski L. Interpretation of calorimetry
experiments to characterize phase change materials. Int J
FUNDING
Therm Sci 2014;78:48-55.
Nil 16. Hasson KJ, Ghareeb MM. Evaluation of innovative co-processed
additive for direct compression tablets using atorvastatin and
AUTHORS CONTRIBUTIONS diazepam as model drugs. Int J Pharm Pharm Sci 2016;8:201-7.
17. Gattani S, Moon R. Formulation and in vitro evaluation of tablet
All the authors have contributed equally.
containing gliclazide nanocrystals for solubility and dissolution
CONFLICT OF INTERESTS enhancement using soluplus. Int J Pharm Sci Res 2018;9:133-9.
18. Raghad AN, Hind EZ. Enhancement of candesartan cilexetil
The authors declare that they have no conflict of interest. dissolution rate by using different methods. A J Pharm Clin Res
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