Pharmaceutical Development and Technology, 2010; 15(2): 139153

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RESEARCH ARTICLE

Design and in vitro evaluation of novel sustained-release

matrix tablets for lornoxicam based on the combination
of hydrophilic matrix formers and basic pH-modifiers
Yassin El-Said Hamza, and Mona Hassan Aburahma
Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University, Cairo, Egypt

Abstract
The short half-life of lornoxicam, a potent non-steroidal anti-inflammatory drug, makes the development
of sustained-release (SR) forms extremely advantageous. However, due to its weak acidic nature, its release
from SR delivery systems is limited to the lower gastrointestinal tract which consequently leads to a delayed
onset of its analgesic action. Accordingly, the aim of this study was to develop lornoxicam SR matrix tablets
that provide complete drug release that starts in the stomach to rapidly alleviate the painful symptoms
and continues in the intestine to maintain protracted analgesic effect as well as meets the reported SR
specifications. The proposed strategy was based on preparing directly compressed hydroxypropylmethylcellulose matrix tablets to sustain lornoxicam release. Basic pH-modifiers, either sodium bicarbonate or
magnesium oxide, were incorporated into these matrix tablets to create basic micro-environmental pH
inside the tablets favorable to drug release in acidic conditions. All the prepared matrix tablets containing basic pH-modifiers showed acceptable physical properties before and after storage. Release studies,
performed in simulated gastric and intestinal fluids used in sequence to mimic the GI transit, demonstrate
the possibility of sustaining lornoxicam release by combining hydrophilic matrix formers and basic pHModifiers to prepare tablets that meet the reported sustained-release specifications.
Keywords: Lornoxicam; sustained-release; compatibility; basic pH-modifiers; matrix tablets

Introduction
The goal of sustained-release (SR) delivery systems is to
provide desirable drug delivery profile that can achieve
predictable plasma levels. However, physiological variables in gastrointestinal (GI) tract including GI pH, gastric
residence time, intestinal motility, and GI contents may
alter the in vivo drug release performance from peroral SR
systems.[1] Moreover, weakly acidic or basic drugs demonstrate pH-dependent release profiles based on their
ionizable groups. Depending on the pH of the release
medium or intestinal fluid, these drugs exist in either
their dissociated or non-dissociated form.[2] Thus, drugs
release from SR delivery systems, especially for weakly

acidic or basic drugs, may vary as a function of their

movement into various segments of GI tract that are characterized by different pH values. This leads to inefficient
drug delivery accompanied by high intra/inter-subject
variability.[3] Consequently, building greater control into
a dosage form, such as providing pH-independent drug
release, is desirable to assure reliable drug therapy.[4] This
approach has been addressed by incorporating different
pH-modifiers into SR delivery systems to keep the microenvironmental pH within and in the close vicinity of the
dosage form constant throughout the drug release phase,
hence producing medium independent drug release.
Towards this purpose, several attempts were reported in
literature based on the presence of acidic excipients such

Address for Correspondence: Mona Hassan Aburahma, Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Cairo University,
Kasr El-Aini Street, Cairo 11562, Egypt. Tel: +20 1046 13747. E-mail: mona_aburahma@hotmail.com
(Received 17 March 2009; revised 20 May 2009; accepted 20 May 2009)
ISSN 1083-7450 print/ISSN 1097-9867 online 2010 Informa UK Ltd
DOI: 10.3109/10837450903059371

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140 Y. El-Said Hamza and M.H. Aburahma

as organic acids within the SR delivery systems to overcome pH-dependent release of weakly basic drugs.[3,58]
These acidic excipients tend to keep the pH within the
delivery systems in the intestinal pH-range low and
thus increase drug solubility and release. However,
fewer studies have been carried out in order to achieve
pH-independent release of weakly acidic drugs from
SR delivery systems.[2,9] Added to that, it is reported that
an initial burst of drug release from SR delivery systems
followed by prolonged drug release phase that extends
over a defined period of time is required for successful
treatments using non-steroidal anti-inflammatory drugs
(NSAIDs). This release pattern assures the attainment
of maximum pain relief as quickly as possible as well as
avoids repeated drug administration due to its extended
release phase.[10]
Lornoxicam is an extremely potent member of the
oxicam group of NSAIDs[11] that is widely used in management of peri/postoperative pain associated with
different surgeries.[12] Moreover, lornoxicam shows better GI tolerability compared to other NSAIDs which is
extremely advantageous in terms of fewer side effects.[13]
However, due to its rapid elimination rate, repeated daily
administration of lornoxicam is required to achieve
long lasting and constant pain relief.[14,15] Added to that,
lornoxicam shows a distinct pH-dependent solubility
characterized by poor solubility in low pH conditions
present in the stomach[15] which consequently leads to
delay in its analgesic effect.
One of the most common methods used for developing SR formulations for different therapeutic agents
is to include them in matrix tablets as they are easily
manufactured, cost effective, and has broad regulatory
acceptance.[16] From the wide choice of possible matrix
forming
materials,
hydroxypropylmethylcellulose
(HPMC) was employed in the current study due to its
non-toxicity, capacity to accommodate high levels of
drug loading, good compressibility, as well as its superior matrix building abilities.[17]
Surprisingly, to date, no literature has been published
concerning SR formulations for lornoxicam although
this is highly desirable from therapeutic view point.[10]
Accordingly, the current study was undertaken to prepare
SR matrix tablets containing lornoxicam that are able to
promptly release lornoxicam in the stomach with the aim
of reaching high serum concentration in a short period of
time, ensuring rapid palliative effect for the painful symptoms. This action is then pursued by an extended-release
phase of lornoxicam to maintain its effective plasma level
for prolonged period of time. Three different viscosity
grades of HPMC, namely HPMC K4M, HPMC K15M,
and HPMC K100M were used as matrix-forming materials. After verification of the compatibility of lornoxicam
among different excipients visually and by using differential scanning calorimetry (DSC) and Fourier-transformed

infrared spectroscopy (FTIR), matrix tablets were prepared by direct compression. In order to reach the prefixed goal, the effect of two basic pH-modifiers, sodium
bicarbonate and magnesium oxide, on the release characteristics of lornoxicam from the prepared hydrophilic
matrices was investigated. Finally, the effect of storage
on physical characteristics and in vitro drug release from
selected tablets formulations was studied.

Materials and methods

Materials
Lornoxicam was kindly provided by Delta Pharma, 10th
of Ramadan City, Egypt. Different viscosity grades of
HPMC (HPMC K4M, HPMC K15M, and HPMC K100M)
were generously donated by Colorcon, Midland, USA.
Avicel PH 102 (microcrystalline cellulose) was purchased
from FMC Corp., Pennsylvania, USA. Magnesium stearate was provided by Prolabo, Paris, France. Magnesium
oxide (MgO) was obtained from Dr Paul Lohmann
Gmbh KG Chemische Fabric, Weserbergland, Germany.
Sodium bicarbonate (NaHCO3) was purchased from
El-Nasr pharmaceutical chemicals company, Cairo,
Egypt. All other chemicals and solvents were of analytical grade and were used as received.
Determination of the saturated solubility of
lornoxicam in 0.1N HCl, in deionized water, and in
phosphate buffer of pH 6.8
The saturated solubility of lornoxicam in 0.1N HCl of
pH 1.2, in deionized water of pH 5.1, and in phosphate
buffer of pH 6.8 was determined. Excess amounts of lornoxicam were added to 20mL of the above-mentioned
media in screw capped glass vials. Next, these vials were
sonicated in an ultrasonic water bath (Model 275 T,
Crest Ultrasonics Corp., Trenton, USA) for 1h then were
shaken for seven days at 250.5C using a thermostatically controlled shaking water bath (Model 1083, GLF
Corp., Burgwedel, Germany) maintained at a speed of 50
strokes per min. Following that, the suspension in each
vial was withdrawn through 0.45 m Millipore filter and
the amount of lornoxicam dissolved in each medium
was determined spectrophotometrically by means of
UV spectroscopy (1601-PC Double beam spectrometer,
Shimadzu, Kyoto, Japan) with reference to its calibration
curve. Each experiment was carried out in triplicate.
Compatibility of lornoxicam with different tablets
excipients
Physical mixtures of lornoxicam with various tablets
excipients namely; HPMC K4M, HPMC K15M, HPMC

Lornoxicam matrix tablets containing basic pH-modifiers 141

K100M, Avicel PH 102, magnesium oxide, sodium bicarbonate, and magnesium stearate were prepared by mixing in weight ratio of 1:1. The prepared mixtures were
evaluated for possible interactions via the following tests:
(a) visual inspection, (b) differential scanning calorimetry and (c) Fourier-transform infrared spectroscopy.

Samples of the prepared physical mixtures of lornoxicam with the previously mentioned excipients were subjected to weekly visual examination during their storage
period that extended for twelve weeks at 40C/75% relative humidity (RH).

stearate was used as a lubricant at concentration of 1%

by weight.[20]
To make powder mixtures; the drug, polymer, and
Avicel PH 102 were thoroughly mixed for 30min by means
of a pestle in a glass mortar. Thereafter, the powder blend
was mixed with magnesium stearate for another 30min.
The resultant powder mixtures of exactly 100mg were
directly compressed into tablets using a single-punch
tablet machine (Rotary Tabletting Machine, CMB3-16,
Cadmach, Ahmedabad, India) equipped with 7mm
round, flat, and plain punches. The force of compression
was adjusted so that hardness of all the prepared tablets
ranged from 5.56.5kg. The detailed compositions of the
prepared matrix tablets formulations are given in Table 1.

Differential Scanning Calorimetry (DSC)

In vitro drug release studies

DSC analysis was performed using Shimadzu differential scanning calorimeter (DSC-60, Shimadzu, Kyoto,
Japan). The apparatus was calibrated with purified
indium (99.9%). Samples (34mg) were placed in flatbottomed aluminium pan and heated at a constant rate
of 10C/min in an atmosphere of nitrogen in a temperature range of 20400C. The DSC studies were performed
for pure drug, pure excipients, and for the drug-excipient
powder mixtures.

The release of lornoxicam from the prepared HPMC

matrix tablets was performed in a USP Dissolution
Tester (VK 7000 Dissolution Testing Station, Vankel
Industries Inc., NJ, USA), Apparatus II (Rotating paddle)
at a rotation of 100rpm.[21] The release studies were initially carried out in 400mL of 0.1N HCl maintained at
370.5C for a period of 2h followed by release in phosphate buffer of pH 6.8 achieved by adding 200mL of
0.2M tri-sodium ortho-phosphate solution, preheated
to 370.5C, to the release medium for the subsequent
6h.[22,23] At predetermined time intervals, aliquots from
the release medium were withdrawn through Millipore
membrane filter of 0.45 m pore size. Concentrations of
lornoxicam in the withdrawn samples were determined

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Visual inspection

Fourier-Transform Infrared Spectroscopy (FTIR)

The FTIR spectra of pure drug, pure excipients, and
drug-excipient powder mixtures stored for 12 weeks at
40C/75% RH were recorded using FTIR spectrophotometer (Model 22, Bruker, UK) according to the KBr disc
technique. The smoothing of the spectra and the base
line correlation procedures were applied. The spectra
were saved using a Lotus 123 computer program. The
FTIR measurements were performed in the scanning
range of 4000400cm1 at ambient temperature.
Preparation of HPMC matrix tablets containing
lornoxicam
Matrix tablets with theoretical weight of 100mg containing lornoxicam together with other excipients were
prepared by direct compression. The concentration of
lornoxicam was kept constant in all the prepared tablets
at 8% by weight (8mg/tablet). Different viscosity grades
of HPMC were chosen as polymeric matrix materials:
namely HPMC K4M, HPMC K15M, and HPMC K100M,
with reported nominal viscosity values of 4000, 15000,
and 100000 cP, respectively, when present in concentration of 2% in water at 20C.[18] Avicel PH 102 was selected
as tablets diluent to increasing the compressibility and
flowability of the ingredients as well as to maintain
the tablets weight constant at 100mg.[19] Magnesium

Table 1. Composition of the prepared HPMC matrix tablets containing

lornoxicam.
Composition
Avicel
Formulation Lornoxicam
Magnesium PH 102
code
(mg )
HPMC grade (% w/w) stearate
up to
F1
8
HPMC K4M
5
1%
100mg
F2
8
10
1%
100mg
F3
8
15
1%
100mg
F4
8
20
1%
100mg
F5
8
25
1%
100mg
F6
8
30
1%
100mg
F7

F8
F9
F 10
F 11

8
8
8
8

F 12

F 13
F 14
F 15
F 16
F 17
F 18

8
8
8
8
8
8

HPMC K15M

HPMC K100M

1%

100mg

10
15
20
25

1%
1%
1%
1%

100mg
100mg
100mg
100mg

30

1%

100mg

5
10
15
20
25
30

1%
1%
1%
1%
1%
1%

100mg
100mg
100mg
100mg
100mg
100mg

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142 Y. El-Said Hamza and M.H. Aburahma

spectrophotometrically by measuring their absorbances using a UV spectroscopy (1601-PC Double beam
spectrometer, Shimadzu, Kyoto, Japan) at max values of
372nm and 376.8nm when 0.1N HCl and phosphate
buffer of pH 6.8 were used as release medium, respectively. All the withdrawn samples were replenished with
equal volumes of same release medium to keep the
release volume constant throughout the experiment.
Release studies were carried out in triplicate and the
mean values were plotted versus time. Based on the
resultant release data, further modifications, by incorporating different classes of basic pH-modifiers, were
performed on selected matrix tablets in order to comply
with the release specifications reported for SR products.
Preparation of lornoxicam matrix tablets containing
basic pH-modifiers
In order to prepare lornoxicam matrix tablets with
micro-environmental pH-control; two different classes
of basic pH-modifiers,[2] water-soluble, namely sodium
bicarbonate versus water-insoluble, namely magnesium oxide, were incorporated into matrix tablets at
concentrations of either 5% or 10% by weight. Each
modifier was cogrounded with lornoxicam for 30min in
a glass mortar using a pestle, then the resultant blend
was incorporated into the matrix tablets using the same
procedures utilized for preparing HPMC matrix tablets.
The detailed compositions of the matrix tablets formulations containing basic pH-modifiers are presented in
Table 2. In vitro drug release studies for these tablets
were performed using the same procedures presented
formerly for HPMC matrix tablets.
Physical tests for the prepared matrix tablets
containing basic pH-modifiers
Tablet weight variation
Twenty tablets were randomly selected and accurately
weighed using an electronic balance (Sartorius GmbH,
Gottingen, Germany). The results are expressed as mean
values of 20 determinations.

Drug content uniformity

Ten tablets were weighed individually, crushed, and the
drug was extracted in phosphate buffer of pH 6.8. The
solution was filtered through a 0.45 m millipore filter
and the drug content was determined by UV spectroscopy (1601-PC Double beam spectrometer, Shimadzu,
Kyoto, Japan) after a suitable dilution with reference to
the calibration curve.
Tablet friability
According to the BP specifications,[24] a sample of 20
tablets was placed in the drum of a tablet friability test
apparatus (FAB-2, Logan Instruments Corp., NJ, USA).
The drum was adjusted to rotate 100 times in 4min then
the tablets were removed from the drum, dedusted and
accurately weighed. This process was repeated for all
tablets formulations and the percentage weight loss was
calculated.
Morphological examination of matrix tablets
containing basic pH-modifier
Selected tablets were withdrawn from the dissolution
vessels after 2h from the release run and their photographs were recorded using an optical computer
microscope (Intel Corp., Santa Clara, USA) in order to
examine their morphological appearance after exposure
to release medium in comparison to dry tablets. Aiming
to visualize the micro-environmental pH in close vicinity of the tablets; selected tablets were carefully placed in
a dish containing 5mL of 0.1N HCl to which one drop of
thymol-blue, a pH-indicator, was added. The change in
the colour of the solution present in the dish and in close
vicinity of the tablets was carefully monitored.[25]
Stability study for matrix tablets containing basic
pH-modifier
Stability study for selected tablets was carried under accelerated temperature and RH conditions, 40C 2C/75%
5% RH, maintained using saturated solution of NaCl,[26]
in stability chambers for a period of 12 weeks.[27,28] The
stored tablets were visual inspection for any changes in
color and/or appearance every week. Evaluation of the

Table 2. Composition of the prepared HPMC matrix tablets containing lornoxicam and basic pH-modifiers.
Composition
Basic pH- modifier
Formulation
HPMC grade
code
Lornoxicam (mg )
(% w/w)
Type
(%w/w)
Magnesiumstearate Avicel PH 102up to
5
1%
100mg
FI
8
20% HPMCK4M
NaHCo3
10
1%
100mg
F II
8
NaHCo3
F III
8
MgO
5
1%
100mg
F IV
8
MgO
10
1%
100mg
5
1%
100mg
FV
8
15% HPMCK15M
NaHCo3
10
1%
100mg
F VI
8
NaHCo3
F VII
8
MgO
5
1%
100mg
F VIII
8
MgO
10
1%
100mg

Lornoxicam matrix tablets containing basic pH-modifiers 143

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tablets drug content, friability, and in vitro release was

repeated at the end of the storage period using the same
procedures utilized for the fresh ones. Release profiles
of the fresh and stored tablets were compared according
to the model independent mathematical approach of
Moore and Flanner.[29] The similarity factor (2) was calculated according to the Equation:
f2 = 50 log{[1+(1/n ) ( Rt Tt )2 ]

n 0.5
100}
t=1


(1)

where n is the number of sampling points, Rt and Tt

are the mean percent released from reference (fresh)
and from test (stored) at time t. f2 represents a logarithmic transformation of the sum of squared error of differences between the reference and test products over all
time points.
A value of 100% for the similarity factor (2) suggests
that the test and reference profiles are identical. Values
between 50 and 100 indicate that the release profiles are
similar, whereas smaller values imply an increase in dissimilarity between release profiles.[29]

analysis,[3032] since it is considered as a rapid method for

evaluating any possible incompatibilities between drug
and excipients.[33,34] The 1:1 weight ratio of drug to excipient was chosen because it maximizes the likelihood
of observing any possible interactions.[32,34] The DSC
thermograms of pure lornoxicam, pure excipients, and
their 1:1 physical mixtures are shown in Figure 1. The
DSC thermogram of lornoxicam (Figure 1a) exhibited
a sharp exothermic peak at 232.5C which corresponds
to its melting and decomposition.[11] Regarding the DSC
scans of pure excipients; the thermograms of all grades
of HPMC, namely K4M, K15M, and K100M, showed a
faintly endothermic effect ranging from 50120C that
might be ascribed to their dehydration and an exothermic effect above 300C that might be attributed to their
decomposition (Figure 1b, 1c and 1d). Avicel PH 102
showed a slightly exothermic effect above 300C that
might be attributed to its decomposition (Figures 1e). A
broad shallow endothermic peak was observed in case
of magnesium stearate at 119.36C due to its dehydration (Figure 1f ). Concerning the DSC of the utilized
basic pH modifiers; a characteristic endothermic effect
below 100C was observed in the thermogram of sodium
bicarbonate (Figure 1g), however the thermogram of

Results and discussion

Saturated solubility of lornoxicam in 0.1N HCl, in
deionized water, and in phosphate buffer of pH 6.8
The saturated solubility of lornoxicam in media with
different pH-values is compiled in Table 3. Lornoxicam
is a weak acid with pKa value of 5.5.[15] It is present as a
zwitterion in the pH range of 25 and in an anionic form
at pH > 6.[12] It is clearly evident from Table 3 that lornoxicam is poorly soluble in aqueous media, particularly in
media with pH value lower than its pKa value and shows
higher solubility in media with pH value above its pka
value, i.e. pH 6.8. This pH-dependent solubility is probably attributed to the presence of lornoxicam molecules
uncharged at lower pH-values, whereas at higher pH
values lornoxicam molecules are negatively charged.

Table 3. Saturated solubility of lornoxicam in different media at

250.5C (mean SD, n=3).
Media tested
Mean drug solubility (mg/mL)SD
0.1N HCl (pH 1.2)
0.0060.002
Deionized water (pH 5.1)
0.0210.009
Phosphate buffer (pH 6.8)
0.3050.083

(a)

Compatibility of lornoxicam with different tablet

excipients
Visual inspection
The stored powder mixtures of lornoxicam with different
tablets excipients did not show any change in color or
appearance (e.g. discoloration, caking, liquefaction, formation of clumps). This represents a good preliminary
indication of physical stability.
Differential Scanning Calorimetry (DSC)
The compatibility of lornoxicam with the aforementioned excipients was investigated using DSC

(a)

(b)

100

200

300

Temprature C

(c)

(i)
(j)

(d)

(k)

(e)

(l)

(f)

(m)

(g)

(n)

(h)

(o)

400

100

200

300

400

Temprature C

Figure 1. DSC Thermograms of (a) lornoxicam; (b) HPMC K4M; (c)

HPMC K15M; (d) HPMC K100M; (e) Avicel PH 102; (f ) magnesium
stearate; (g) sodium bicarbonate; (h) magnesium oxide (i) physical
mixture of lornoxicam and HPMC K4M; (j) physical mixture of lornoxicam and HPMC K15M; (k) physical mixture of lornoxicam and
HPMC K100M; (l) physical mixture of lornoxicam and Avicel PH
102; (m) physical mixture of lornoxicam and magnesium stearate;
(n) physical mixture of lornoxicam and sodium bicarbonate; and
(o) physical mixture of lornoxicam and magnesium oxide.

Fourier-Transform Infrared Spectroscopy (FTIR)

The FTIR spectrum of pure lornoxicam, pure excipients, and their 1:1 physical mixtures are shown in
Figure 2. The FTIR spectrum of lornoxicam showed a
characteristic peak at 3090cm1 corresponding to NH
stretching vibration. Intense absorption peak was found
at 1642cm1 due to the stretching vibration of the C=O
group in the primary amide. Other peaks were observed
at 1597cm1 and at 1559cm1 and were assigned to
bending vibrations of NH group in the secondary amide.
The stretching vibrations of the O=S=O group appeared
at 1157cm1, 1387cm1, and at 1336cm1. Other prominent peaks appeared at 827.94cm1 corresponding to
CH aromatic ring bending and heteroaromatics and
at 766.8cm1 due CCl bending vibration (Figure 2a).
It is clear evident that the FTIR spectra of the physical
mixtures of lornoxicam with different excipients showed
the presence of lornoxicam characteristic bands at their

magnesium oxide show a slight endothermic effect

above 300C (Figure 1h). Similar findings have been
reported by other authors.[35,36] Basically, lornoxicam
exothermic peak was evident in all the thermograms
of its physical mixtures with the mentioned excipients
which might indicate compatibility. However, noticeable
broadening in lornoxicam peak intensity was observed
in some thermograms. This is probably attributed to differences in geometry of the mixture samples as reported
by other authors.[37,38] In conclusion, the observed DSC
results ruled out the incidence of any incompatibility
between lornoxicam and the investigated excipients.
Nevertheless, it is stated that DSC analysis, being a thermal method of analysis, should not be used individually to detect any inherent incompatibility. It has to be
supported by other non-thermal techniques, such as
FTIR.[3032] Therefore, the latter was considered in conjunction with DSC to reach a definite conclusion.

(%) Transmittance

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144 Y. El-Said Hamza and M.H. Aburahma

(a)

(a)

(b)

(i)

(c)

(j)

(d)

(k)

(l)

(e)

(m)

(f)

(n)

(g)

(o)

(h)

4000

3000

2000

Wavenumbers

1000

400 4000

3000

2000

1000 400

Wavenumbers

Figure 2. FTIR Spectra of (a) lornoxicam; (b) HPMC K4M; (c) HPMC K15M; (d) HPMC K100M; (e) Avicel PH 102; (f ) magnesium stearate; (g)
sodium bicarbonate; (h) magnesium oxide (i) physical mixture of lornoxicam and HPMC K4M; (j) physical mixture of lornoxicam and HPMC
K15M; (k) physical mixture of lornoxicam and HPMC K100M; (l) physical mixture of lornoxicam and Avicel PH 102; (m) physical mixture of
lornoxicam and magnesium stearate; (n) physical mixture of lornoxicam and sodium bicarbonate; and (o) physical mixture of lornoxicam and
magnesium oxide.

Lornoxicam matrix tablets containing basic pH-modifiers 145

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same positions. Moreover, these spectra can be simply

regarded as the superposition lornoxicam and the investigated excipients. This could indicate the absence of
chemical interaction between the drug and the excipients confirming the DSC results presented formerly.
In vitro drug release studies
Figure 3 illustrates the in vitro release profiles of lornoxicam from the prepared HPMC matrix tablets containing
different concentrations and viscosity grades of HPMC.
To simulate the conditions that exist as tablets transit in
humans GI tract, the release studies were performed in
0.1N HCl of pH 1.2 for 2h followed by phosphate buffer
of pH 6.8 for the sequential 6h.[39] Moreover, the release
sampling duration lasted 8h as the total GI transit
time for oral dosage forms in humans is reported to be
approximately 8h.[40]
Due to its distinct pH-dependent solubility, lornoxicam showed an extremely slow dissolution in acidic
conditions, in fact, less than 10% of the drug was dissolved after 2h. However, complete drug dissolution
was displayed when the pH of the release medium
was converted to 6.8. It is clearly evident that all matrix
tablets prepared using HPMC K4M, HPMC K15M, and
HPMC K100M employed at concentrations of 5% and
10% failed to sustain lornoxicam release. This is probably attributed to the extensive disintegration of these
tablets at the beginning of the release study which
prevented the formation of a continuous gel layer on
their surfaces that is responsible for modulation of
drug release process.[16] In these cases, complete drug
release took place after changing the pH of the release
medium from 1.26.8. On the other hand, matrix tablets
containing 15% and 20% of different viscosity grades of
HPMC were able to keep their integrity and therefore
they showed control on lornoxicam release depending on both the viscosity grade and concentration of
HPMC used. In these cases, it was remarkable that at
same polymer concentration, tablets prepared using
the highest viscosity grade polymer, HPMC K100M,
showed more extended-release profiles when compared to the corresponding tablets prepared using
lower viscosity grades polymers, HPMC K4M or HPMC
K15M. This observation is in concordance with that
reported in literature by several research groups.[4446]
The observed discrepancy in drug release patterns
when employing different cellulose grades in the tablets
can be explained by the fact that the hydrated gel layer
of HPMC K100M is more viscous and less erodible than
that of the lower viscosity grades, HPMC K4M or HPMC
K15M, thus provides a stronger barrier for drug diffusion which consequently causes slower drug release.[45]
Added to that, it is reported that the average molecular
weights of HPMC K4M, K15M, and K100M polymers are
equal to 96, 134, and 267kDa, respectively.[46] Actually,

the increase in polymer molecular weight is coupled

with an increase in the entanglement of the polymer
macromolecules. This leads to decrease in water and
drug diffusion coefficients and therefore decrease in
drug release. Furthermore, the polymer dissolution
rate decrease with increasing molecular weight, i.e.
the dissolution rate decrease in the rank order HPMC
K4M > K15M > K100M.[47] Surprisingly, all the matrices prepared using different viscosity grades of HPMC
employed at concentrations of 25% and 30% showed
comparable release profiles. This result suggests that,
in these conditions, the drug release is no longer influenced by the viscosity grade of HPMC and implies that
viscosities of the hydrated matrices may be identical
when different viscosity grades of HPMC are present in
high concentrations.[48] A similar trend was reported by
Nellore etal.[41] who observed minor changes in metoprolol release rates when high concentrations of different viscosity grades of HPMC were employed in matrix
tablets.
The target release profile parameters for SR products
were reported as follows; after 2h, 2050% of the drug
is released, 4575% of the drug is released after 4h, and
finally 75105% of the drug is release after 8h.[49] Added
to that, it is stated that successful SR formulations
must also show pH-independent drug release that
start in upper GI tract and continue for nearly 68h
in the lower GI tract.[43] Consequently, for assessment
and comparison with these release specifications; the
percent of drug released from the prepared matrix tablets after 2, 4, and 8h were extracted directly from the
release data and were graphically depicted in Figure 4.
It is quite evident that none of the prepared matrices
fulfilled the target release profile parameters for SR
products. However, only matrix tablets belonging to
formulations F 4 and F 9, that contained 20% HPMC
K4M and 15% HPMC K15M, respectively, complied
with the SR requirements concerning the percentage
of drug release after 4 and 8h, though they showed an
initial delay in drug release during the first 2h of the
release study performed in acidic medium. Therefore,
further optimization was attempted for these tablets
formulations aiming to achieve the target in vitro SR
profile. This was attempted by incorporation of different basic pH-modifiers, namely sodium bicarbonate
and magnesium oxide, to these tablets formulations in
concentration of 5% and 10%. These modifiers presumably increase the micro-environmental pH within, and
in the close vicinity of the swollen gel layer of the matrix
tablets and thus increase the solubility and release of
the drug in acidic pH.[3]
The release profiles of the prepared HPMC matrix
tablets containing basic pH-modifiers are graphically
presented in Figure 5. It is clearly evident that all the
prepared tablets formulations containing magnesium

146 Y. El-Said Hamza and M.H. Aburahma

oxide, present in either 5% or 10% concentrations,
showed a marked decrease in the extent of lornoxicam
release in phosphate buffer of pH 6.8 compared to the

Percent Lornoxicam
Released

pH=6.8

pH=1.2
100
80
60
40
20
0

Time (hours)
Lornoxicam Powder
F 3 (15 % HPMC K4M)
F 6 (30% HPMC K4M)

Percent Lornoxicam
Released

(b)

F 1 (5 % HPMC K4M)
F 4 (20% HPMC K4M)

pH=1.2

100

F 2 (10 % HPMC K4M)

F 5 (25 % HPMC K4M)

pH=6.8

80
60
40
20
0

Time (hours)
Lornoxicam Powder
F 9 (15 % HPMC K15M)
F 12 (30 % HPMC K15M)
(c)
Percent Lornoxicam
Released

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(a)

corresponding tablets formulations prepared without

magnesium oxide. Being practically water-insoluble,
magnesium oxide presence in the tablets hinders drug

F 7 (5 % HPMC K15M)
F 10 (20 % HPMC K15M)

pH=6.8

pH=1.2

100

F 8 (10% HPMC K15M)

F 11 (25 % HPMC K15M)

80
60
40
20
0

Lornoxicam Powder
F 15 (15 % HPMC K100M)
F 18 (30% HPMC K100M)

4
Time (hours)

F 13 (5 % HPMC K100M)
F 16 (20 % HPMC K100M)

F 14 (10% HPMC K100M)

F 17 (25 % HPMC K100M)

Figure 3. In vitro release profiles of lornoxicam from HPMC matrix tablets performed in 0.1N HCl of pH 1.2 for 2 hours and in phosphate buffer
of pH 6.8 for the subsequent 6 hours at 370.5C. (a) HPMC K4M (b) HPMC K15M (c) HPMC K100M.

Lornoxicam matrix tablets containing basic pH-modifiers 147

diffusion and/or medium infiltration into the tablets.
On the other hand, the incorporation of sodium bicarbonate into HPMC matrix tablets increased lornoxicam
release during the early stages of the release study, i.e. in
0.1N HCl, compared to the corresponding formulation

Percent Lornoxicam
Released

100
80
60
40
20
0

Percent Lornoxicam
Released

(b)

F1
(5% HPMC K4M)

F2
F3
F4
F5
F6
(10% HPMC K4M) (15% HPMC K4M) (20% HPMC K4M) (25% HPMC K4M) (30% HPMC K4M)

100
80
60
40
20
0

F7
F 12
F8
F9
F 10
F 11
(5% HPMC K15M) (1% HPMC K15M) (15% HPMC K15M) (20% HPMC K15M) (25% HPMC K15M) (30% HPMC K15M)

(c)
100

Percent Lornoxicam
Released

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(a)

prepared without sodium bicarbonate. It was also

observed that matrix tablets belonging to formulations
F I and F II, which contained 20% HPMC K4M in presence of 5% and 10% sodium bicarbonate respectively,
disintegrated when exposed to the release medium.

80
60
40
20
0

F 13
F 14
F 15
F 16
F 17
F 18
(5% HPMC K100M) 10% HPMC K100M) (15% HPMC K100M) (20% HPMC K100M) (25% HPMC K100M) (30% HPMC K100M)

% released after 2 hours

% released after 4 hours

% released after 8 hours

Figure 4. The percentages of lornoxicam released after 2, 4, and 8 hours from HPMC matrix tablets. (a) HPMC K4M (b) HPMC K15M (c) HPMC
K100M.

It is well known that HPMC can modify drug release

rate by forming of a gelatinous layer on the surface of the
tablets. However, the presence of sodium bicarbonate in
these matrix tablets caused the formation a structurally
different gel layer on the tablets surface upon hydration. This gel layer is characterized by less entangled
polymeric chains due to formation of a porous polymeric network that resulted from the rapid dissolution
of sodium bicarbonate upon contact with the acidic
release medium. This consequently led to lowering of
the gel resistance and weakening in tablets structures
which accordingly disintegrated in the release medium.
Similar observations were reported by Amaral etal.[50]
On the contrary to that, matrix tablets belonging to
formulation F V and F VI, that contained 15% HPMC
K15M in presence of 5% or 10% sodium bicarbonate,
were able to maintain their integrity throughout the
whole release study. This may be due to the higher
degree of polymeric entanglement when using the
higher viscosity grade of HPMC, HPMC K15M, was
(a)

used. As expected, in tablets belonging to formulations

F V and F VI, increasing the concentration of sodium
bicarbonate from 510%, led to a marked acceleration
in the extent of lornoxicam release. Sodium bicarbonate leaches out of the tablets thereby create pores in
the matrix structure. At high sodium bicarbonate concentration, the porosity and segregation of the gel layer
present on the tablets surfaces increase allowing better
diffusion and release of lornoxicam. Conclusively, the
presence of magnesium oxide or sodium bicarbonate
had opposite effects on lornoxicam release from HPMC
tablets: The former displayed a negative influence due
to its relative inability to elevate the tablets microenvironmental pH; besides, its poor solubility reduced
the matrix erosion process and consequently hindered
drug diffusion and release, whereas the latter had a
positive effect due to its capability to elevate the tablets
micro-environmental pH as well as its rapid dissolution in the release medium that allowed a decrease in
tortuosity and/or an increase in the matrix porosity. For

pH=1.2

pH=6.8

Percent Lornoxicam
Released

100
80
60
40
20
0

Time (hours)
Lornoxicam Powder
F II (10% NaHCo3)
(b)
Percent Lornoxicam
Released

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148 Y. El-Said Hamza and M.H. Aburahma

F4
F III (5% MgO)

F I (5% NaHCo3)
F IV (10% MgO)
pH=6.8

pH=1.2

100
80
60
40
20
0

Time (hours)
Lornoxicam Powder
F VI(10% NaHCo3)

F9
F VII(5% MgO)

F V(5% NaHCo3)
F VIII(10% MgO)

Figure 5. Effect of incorporating different basic pH-modifiers on lornoxicam release from HPMC matrix tablets performed in 0.1N HCl of pH 1.2
for 2 hours and in phosphate buffer of pH 6.8 for the subsequent 6 hours at 370.5C. (a) Tablets contain 20% of HPMC K4M (b) Tablets contain
15% of HPMC K15M.

assessment and comparison with the release requirements of SR products, the percentage of drug released
after 2, 4, and 8h were extracted from the release data
and were graphically depicted in Figure 6. It is clearly
evident that only tablets belonging to formulation
F VI complied with the reported release specifications
concerning SR products. The percentages of lornoxicam released from these tablets were 34.45% after 2h,
and 68.15% and 85.19% after 4 and 8h, respectively.
Moreover, these tablets also illustrated a burst release
of nearly 30% their drug content during the first 30min
of the release study, so they are expected to overcome
the disadvantages associated with the delayed dissolution of lornoxicam in acidic conditions.
Physical tests for the prepared matrix tablets containing
basic pH-modifiers
The comparison of physical properties of the prepared
matrix tablets are shown in Table 4. The weight of tablets
formulations ranged from 100.23102.70mg. All tablets
formulations prepared in this study met the pharmacopeial requirements for weight variation tolerance. Drug

Percent Lornoxicam Released

(a)

(b)

uniformity results were found to be good among different tablets formulations, and the percentage of drug
content was more than 97%. Tablets hardness is not an
absolute indicator of strength. Another measure of a
tablets strength is friability.[51] In the present study, the
percentage friability for all the formulations was below
1% indicating that the friability is within the compendial
limits. Therefore, all the tablet formulations showed
acceptable physical properties and complied with the
Table 4. Characterization of the prepared HPMC matrix tablets
containing basic pH-modifiers.
Formulation Average weight Average drug content
code
(mg) SD
(%) SD
Friability (%)
FI
101.401.51
100.651.20
0.39
F II
102.632.49
101.002.12
0.48
F III
101.602.03
98.501.56
0.33
F IV
102.701.23
99.504.38
0.34
FV
100.232.00
99.450.92
0.38
F VI
102.201.47
99.651.48
0.30
F VII
100.802.41
98.701.70
0.45
F VIII
102.271.40
97.252.05
0.35

100
80
60
40
20
0

Percent Lornoxicam Released

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Lornoxicam matrix tablets containing basic pH-modifiers 149

F4

F II (10% NaHCo3)

F III (5% MgO)

F IV (10% MgO)

F V (5% NaHCo3) F VI (10% NaHCo3)

F VII (5% MgO)

FVIII (10% MgO)

F I (5% NaHCo3)

100
80
60
40
20
0

F9

% released after 2 hours

% released after 4 hours

% released after 8 hours

Figure 6. The percentages of lornoxicam released after 2, 4, and 8 hours from HPMC matrix tablets containing basic pH-modifiers. (a) Tablets
contain 20% of HPMC K4M (b) Tablets contain 15% of HPMC K15M.

150 Y. El-Said Hamza and M.H. Aburahma

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reported pharmacopoeial specifications. Finally, it is

worth noting that lornoxicam matrix tablets belonging to formulation F VI, composed of 15% of HPMC
K15M and 10% sodium bicarbonate, complied with the
release specifications for SR products and also exhibited
acceptable weight variation, drug content, and friability. Hence, these matrix tablets were chosen for further
investigations.
Morphological examination of matrix tablets
containing basic pH-modifier
The photographs of tablets belonging to formulation F
VI before and after dissolution for two hours in 0.1N
HCl are depicted in Figure 7. Upon contact with the
release medium, these tablets swell as the solvent molecules penetrate into the matrix system along the pores
formed due to the rapid leaching of sodium bicarbonate into the release medium causing polymeric chains
relaxation.[3] Moreover, it is obvious that these tablets
showed anisotropic swelling phenomenon with preferential expansion in the axial direction due to relaxation of the compression forces imposed on the tablets
during tableting process. A similar phenomenon was
observed in previously published studies by Conti
etal.[52] and by Papadimitriou etal.[53] who related the
predominantly axial relaxation of HPMC compacts to
the relief of stress induced during their compaction.
Furthermore, the changes in micro-environmental pH
of the selected tablets matrices were visualized with
the aid of thymol-blue as a pH indicator.[3] Thymol-blue
colour transits from red to yellow at pH range of 1.22.8
and changes from yellow to blue at pH higher than 7.
As clearly shown in Figure 8, the red solution (formed
as a result of adding one drop of thymol-blue to 0.1N
HCl) that surrounds the tablet gradually faded and was
converted to yellow colour which indicates that pH
of this solution progressively increases from 1.22.8.
Furthermore, after one hour, a blue ring surrounding
the tablet boarders became visible which indicate the
presence of a region with high pH value near the tablets boarders. Concisely, these observations are attributed to the leaching of NaHCO3 from the tablets when
exposed to the dissolution medium creating a basic
micro-environment pH in the vicinity surrounding the
tablets.
Stability study for matrix tablets containing basic
pH-modifier
A drug product may undergo changes in its physicochemical characteristics during storage and these
changes can affect the bioavailability of drug from dosage forms. A unit of solid oral dosage form such as a
tablet has to meet pharmacopeial specifications, such
as drug content, friability, and release during its shelf
life.[54] Accordingly, the effect of storage at 40C/75%

(a)

(b)

Figure 7. Photographs of directly compressed HPMC matrix tablets

containing basic pH-modifier before and after dissolution for 2 hour
in 0.1N HCl. (a) top view (b) side view.

(a)

(b)

Figure 8. Photographs of directly compressed HPMC matrix tablets

containing basic pH-modifier. (a) Immediately after the tablet was
immersed in 0.1N HCl containing one drop of thymol blue; (b) After
one hour showing a blue region of high pH region around the tablet
due to leaching of sodium bicarbonate from the tablet into the indicators solution.

Table 5. Effect of storage on the physical properties of tablets

belonging to formulation F VI.
Physical properties
Fresh tablets
Stored tablets
investigated
Average drug content
99.651.48
97.840.803
(%) SD
Friability (%)
0.30
0.61

RH for 12 weeks on the physical properties and in

vitro release of tablets belonging to formulation F VI
was investigated. All the stored tablets didnt show
any change in their colour or appearance throughout
the storage period. The physical characteristics of the
stored tablets in comparison to fresh ones are compiled in Table 5. It is evident that the drug content of
tablets belonging to formulation F VI remained within
the acceptable limits.[21] A slight increase in tablets
friability was observed compared to the fresh ones.
Figure 9 presents the release profiles of the fresh and
stored tablets belonging to formulation F VI. Evidently,
a slight decrease in drug release was observed on comparing the fresh tablets to the stored tablets. However,
even with this decrement, the stored tablets complied
with the reported specifications of sustained-release
products. In order to assess the effect of storage on the
release characteristics objectively, the mean release
data of fresh and stored tablets were analyzed using the
model independent mathematical approach of Moore

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Percent Lornoxicam
Released

Lornoxicam matrix tablets containing basic pH-modifiers 151

pH=1.2

100

pH=6.8

80
60
40
20
0

Time (hours)
Fresh Tablets

Stored Tablets

Figure 9. In vitro release profiles of lornoxicam from fresh and stored HPMC matrix tablets belonging to formulation F VI performed in 0.1N HCl
of pH 1.2 for 2 hours and in phosphate buffer of pH 6.8 for the subsequent 6 hours at 370.5C.

and Flanner.[29] The computed f2 value was 63.58% indicating that the release profiles of fresh and stored tablets belonging to formulation F VI could be considered
similar and that the storage at the specified conditions
had no marked effect on the release of the drug from its
tablets formulation. Similar results were reported in the
literature by several research groups when they studied
the effect of storage under accelerated conditions on
the physical properties and the release characteristics
of HPMC tablet matrices.[27,44,55,56]
Based on the results presented in the current study,
further in vivo studies for matrix tablets belonging to
formulation F VI are ongoing and will be published later
to assess their therapeutic effectiveness in comparison
with immediate release formulations.

easy to scale-up process that does not require special

production equipments.

Acknowledgements
The authors are deeply grateful to Colorcon Corp.,
(Midland, USA) for providing gift samples of different
viscosity grades of HPMC.
Declaration of interest: The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of the paper.

References
Conclusion
In the current study, HPMC matrix tablets that provide
initial burst drug release in acidic medium followed
by an extended-release phase for 8h was successfully
designed for lornoxicam. This was attempted by incorporating water soluble basic pH-modifier exemplified
by sodium bicarbonate into selected matrix tablets
formulations.
Results obtained demonstrated that tablets belonging
to formulation FVI, composed of 15% of HPMC K15M
and 10% sodium bicarbonate, possessed acceptable
physical properties and elicited the required in vitro
release pattern, before and after storage, that coincides
with the purpose set for this study.
In conclusion, HPMC swellable tablets can provide a
useful tool for retarding drug release. Besides, the drugs
release profiles of these tablets can be further modified
and tailored, according to their pharmacokinetics and
therapeutic needs, by manipulating the tablets microenvironmental pH. This can be achieved through the
incorporation of pH-modifiers in an inexpensive and

1.

2.

3.

4.
5.
6.

7.

8.

Grundy JS, Foster RT. The nifedipine gastrointestinal therapeutic system (GITS). Evaluation of pharmaceutical, pharmacokinetic and pharmacological properties. Clin Pharmacokinet
1996;30(1):2851.
Riis T, Bauer-Brand A, Wagner T, Kranz H. pH-independent drug
release of an extremely poorly soluble weakly acidic drug from
multiparticulate extended release formulations. Eur J Pharm
Biopharm 2007;65(1):7884.
Varma MV, Kaushal AM, Garg S. Influence of micro-environmental pH on the gel layer behavior and release of a basic
drug from various hydrophilic matrices. J Control Release
2005;103(2):499510.
Timmins P, Delargy AM, Howard JR. Optimization and characterization of a pH-independent extended-release hydrophilic
matrix tablet. Pharm Dev Technol 1997;2(1):2531.
Siepe S, Lueckel B, Kramer A, Ries A, Gurny R. Strategies for the
design of hydrophilic matrix tablets with controlled microenvironmental pH. Int J Pharm 2006;316(12):1420.
Narisawa S, Nagata M, Hirakawa Y, Kobayashi M, Yoshino H. An
organic acid-induced sigmoidal release system for oral controlled release preparations. III. Elucidation of the anomalous drug
release behavior through osmotic pumping mechanism. Int J
Pharm 1997;148(1):8591.
Espinoza R, Hong E, Villafuerte L. Influence of admixed
citric acid in the release profile of pelanserin hydrochloride from HPMC matrix tablets. Int J Pharm 2000;201(2):
165173.
Streubel A, Siepmann J, Dashevsky A, Bodmeier R. pHindependent release of a weakly basic drug from water-

152 Y. El-Said Hamza and M.H. Aburahma

9.
10.
11.

Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Inst Biotechnologica UNAM on 11/03/14
For personal use only.

12.
13.
14.

15.
16.
17.
18.
19.
20.
21.

22.
23.

24.
25.
26.

27.

28.
29.
30.

31.

insoluble and -soluble matrix tablets. J Control Release

2000;67(1):101110.
Rao VM, Engh K, Qiu Y. Design of pH-independent controlled release matrix tablets for acidic drugs. Int J Pharm
2003;252(12):8186.
Maggi L, Machiste EO, Torre ML, Conte U. Formulation of biphasic release tablet containing slightly soluble drugs. Eur J Pharm
Biopharm 1999;48(1):3742.
The Merck Index. 13th. ed. Whitehouse Station, NJ: Merck & Co.
Inc.; 2001.
Homdrum EM, Likar R, Nell G. Xefo Rapid: A novel effective
tool for pain treatment. Eur Surg 2006;38(5):342352.
Kidd B, Frenzel W. A multicenter, randomized, double blind
study comparing lornoxicam with diclofenac in osteoarthritis.
J Rheumatol 1996;23(9):16051611.
Balfour JA, Fitton A, Barradel LB. Lornoxicam. A review of
its pharmacology and therapeutic potential in the management of painful and inflammatory conditions. Drugs
1996;51(4):639657.
Skjodt NM, Davies NM. Clinical pharmacokinetics of
Lornoxicam. A short half-life oxicam. Clin Pharmacokinet
1998;34(6):421428.
Alderman DA. A review of cellulose ethers in hydrophilic matrices for oral controlled-release dosage forms. Int J Pharm Tech
Prod Mfr 1984;5(3):19.
Salsa T, Veiga G, Pina ME. Oral controlled-release dosage forms.
I. Cellulose ether polymers in hydrophilic matrices. Drug Dev
Ind Pharm 1997;23(9):292938.
Pharmaceutical excipients from Dow water soluble polymers.
2002. Accessed from the website: http://www.dow.com.
Lopes CM, Sousa Lobo JM, Pinto JF, Costa P. Compressed
mini-tablets as a biphasic delivery system. Int J Pharm
2006;323(12):93100.
Armstrong NA. Tablet manufacture. In: Encyclopedia of pharmaceutical technology. 3rd ed. USA: Informa Healthcare; 2007.
p 3660.
Al-Taani BM, Tashtoush BM. Effect of microenvironment pH
of swellable and erodable buffered matrices on the release
characteristics of diclofenac sodium. AAPS Pharm Sci Tech
2003;4(3):article 43.
Liew CV, Chan LW, Ching AL, Heng PW. Evaluation of sodium
alginate as drug release modifier in matrix tablets. Int J Pharm
2006;309(12):2537.
Pignatello R, Ferro M, Puglisi G. Preparation of solid dispersions
of nonsteroidal anti-inflammatory drugs with acrylic polymers
and studies on mechanisms of drug-polymer interactions. AAPS
Pharm Sci Tech 2002;3(2):article 10.
The
British
Pharmacopoeia.
British
Pharmacopoeia
Commission. London: HMSO; 2007 (electronic version).
Varma MV, Kaushal AM, Garg S. Influence of micro-environmental
pH on the gel layer behavior and release of a basic drug from various hydrophilic matrices. J Control Release 2005;103(2):499510.
Bodmeier R, Paeratakul O. Constant potassium chloride
release from microporous membrane-coated tablets prepared with aqueous colloidal polymer dispersions. Pharm Res
1991;8(3):355359.
Kumar SM, Chandrasekar MJ, Gopinath R, Srinivasan R,
Nanjan MJ, Suresh B. In vitro and in vivo studies on HPMCK-100M matrices containing naproxen sodium. Drug Deliv
2007;14(3):163169.
Rey H, Wagner KG, Wehrle P, Schmidt PC. Development of
matrix-based theophylline sustained-release microtablets.
Drug Dev Ind Pharm 2000;26(1):2126.
Moore JW, Flanner HH. Mathematical comparison of dissolution profiles. Pharm Tech 1996;20(6):6474.
Kerc J, Srcic S, Urleb U, Kanalec A, Kopler B, SmidKorbar J. Compatibility study between acetylcysteine and
some commonly used tablet excipients. J Pharm Pharmacol
1992;44(6):515518.
Joshi BV, Patil VB, Pokharkar VB. Compatibility studies between carbamazepine and tablet excipients using
thermal and non-thermal methods. Drug Dev Ind Pharm
2002;28(6):687694.

32. Mora PC, Cirri M, Mura P. Differential scanning calorimetry as a screening technique in compatibility studies of
DHEA extended release formulations. J Pharm Biomed Anal
2006;42(1):38.
33. Tomassetti M, Catalnabi A, Rossi V, Vecchio S. Thermal analysis
study of the interactions between acetaminophen and excipients in solid dosage forms and in some binary mixtures. J Pharm
Biomed Anal 2005;37(5):949955.
34. Corti G, Cirri M, Maestrelli F, Mennini N, Mura P. Sustainedrelease matrix tablets of metformin hydrochloride in combination with triacetyl-beta-cyclodextrin. Eur J Pharm Biopharm
2008;68(2):303309.
35. Vueba ML, Batista de Carvalho LA, Veiga F, Souza JJ, Pina ME.
Role of cellulose ether polymers on ibuprofen release from
matrix tablets. Drug Dev Ind Pharm 2005;31(7):653665.
36. Vueba ML, Batista de Carvalho LA, Veiga F, Souza JJ,
Pina ME. Influence of cellulose ether mixtures on ibuprofen
release: MC25, HPC and HPMC K100M. Pharm Dev Technol
2006;11(2):213228.
37. Siepmann J, Peppas NA. Modeling of drug release from delivery
systems based on hydroxypropyl methylcellulose (HPMC). Adv
Drug Deliv Rev 2001;48(23):139157.
38. Botha SA, Ltter AP. Compatibility study between naproxen and
tablet excipients using differential scanning calorimetry. Drug
Dev Ind Pharm 1990;16(4):673683.
39. Ribeiro L, Ferreira DC, Veiga FJ. In vitro controlled release
of vinpocetine-cyclodextrin-tartaric acid multicomponent
complexes from HPMC swellable tablets. J Control Release
2005;103(2):325339.
40. Davis SS, Hardy JG, Taylor MJ, Whalley DR, Wilson CG. A comparative study of the gastrointestinal transit of a pellet and tablet
formulation. Int J Pharm 1984;21(2):167177.
41. Nellore RV, Rekhi GS, Hussain AS, Tillman LG, Augsburger LL.
Development of metoprolol tartrate extended-release matrix
tablet formulations for regulatory policy consideration. J Control
Release 1998;50(13):247256.
42. Reynolds TD, Gehrke SH, Hussain AS, Shenouda LS. Polymer
erosion and drug release characterization of hydroxypropylmethylcellulose matrices. J Pharm Sci 1998;87(9):11151123.
43. Kuksal A, Tiwary AK, Jain NK. Formulation and in vitro, in vivo
evaluation of extended- release matrix tablet of zidovudine:
Influence of combination of hydrophilic and hydrophobic
matrix formers. AAPS Pharm Sci Tech 2006;7(1):article 1.
44. Ravi PR, Ganga S, Saha RN. Design and in vitro evaluation of zidovudine oral controlled release tablets prepared
using hydroxypropyl methylcellulose. Chem Pharm Bull
2008;56(4):518524.
45. Ochoa L, Igartua M, Hernandez RM, Gascon AR, Pedraz JL.
Preparation of sustained release hydrophilic matrices by melt
granulation in a high-shear mixer. J Pharm Pharmceut Sci
2005;8(2):132140.
46. Ju RT, Nixon PR, Patel MV. Drug release from hydrophilic matrices. 1. New scaling laws for predicting polymer and drug release
based on the polymer disentanglement concentration and the
diffusion layer. J Pharm Sci 1995;84(12):14551463.
47. Siepmann J, Streubel A, Peppas NA. Understanding and predicting drug delivery from hydrophilic matrix tablets using the
sequential layer model. Pharma Res 2002;19(3):306314.
48. Campos-Aldrete ME, Villafuerte-Robles L. Influence of the
viscosity grade and the particle size of HPMC on metronidazole release from matrix tablets. Eur J Pharm Biopharm
1997;43(2):173178.
49. Cohen JL, Hubert BB, Rhodes CT. The development of
USP dissolution and drug release standards. Pharm Res
1990;7(10):983987.
50. Amaral HM, Lobo JM, Ferreira DC. Effect of hydroxypropyl
methylcellulose and hydrogenated castor oil on naproxen
release from sustained release tablets. AAPS Pharm Sci Tech
2001;2(2):article 6.
51. Abdelbary GA, Tadros MI. Design and in vitro/in vivo evaluation
of novel nicorandil extended release matrix tablets based on
hydrophilic interpolymer complexes and a hydrophobic waxy
polymer. Eur J Pharm Biopharm 2008;69(3):10191028.

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52. Conti S, Maggi L, Segale L, Ochoa Machiste E, Conte U,

Grenier P, Vergnault G. Matrices containing NaCMC and
HPMC 2. Swelling and release mechanism study. Int J Pharm
2007;333(12):143151.
53. Papadimitriou E, Buckton G, Efentakis M. Probing the mechanisms of swelling of hydroxypropylmethylcellulose matrices. Int
J Pharm 1993;98(13):5762.
54. Nalluri BN, Chowdary KP, Murthy KV, Becket G,
Crooks PA. Tablet formulation studies on nimesulide and

meloxicam-cyclodextrin binary systems. AAPS Pharm Sci Tech

2007;8(2):article 36.
55. Ravi PR, Ganga S, Saha RN. Design and study of lamivudine oral
controlled release tablets. AAPS Pharm Sci Tech 2007;8(4):article
101.
56. Chopra S, Patil GV, Motwani SK. Release modulating hydrophilic
matrix systems of losartan potassium: Optimization of formulation using statistical experimental design. Eur J Pharm Biopharm
2007;66(1):7382.