design and in vitro evaluation of novel sustained-release matrix tablets for lornoxicam based on the...
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Pharmaceutical Development and Technology, 2010; 15(2): 139–153
R E S E A R C H A R T I C L E
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
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: [email protected]
(Received 17 March 2009; revised 20 May 2009; accepted 20 May 2009)
Introduction
The goal of sustained-release (SR) delivery systems is to provide desirable drug delivery profile that can achieve predictable plasma levels. However, physiological varia-bles 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 dem-onstrate 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 char-acterized 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 micro-environmental 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
ISSN 1083-7450 print/ISSN 1097-9867 online © 2010 Informa UK LtdDOI: 10.3109/10837450903059371
AbstractThe 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 hydroxypropylmeth-ylcellulose 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 contain-ing 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 pH-Modifiers to prepare tablets that meet the reported sustained-release specifications.
Keywords: Lornoxicam; sustained-release; compatibility; basic pH-modifiers; matrix tablets
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as organic acids within the SR delivery systems to over-come pH-dependent release of weakly basic drugs.[3,5–8] 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 man-agement of peri/postoperative pain associated with different surgeries.[12] Moreover, lornoxicam shows bet-ter 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 devel-oping 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 supe-rior 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 symp-toms. 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 materi-als. After verification of the compatibility of lornoxicam among different excipients visually and by using differen-tial scanning calorimetry (DSC) and Fourier-transformed
infrared spectroscopy (FTIR), matrix tablets were pre-pared by direct compression. In order to reach the pre-fixed goal, the effect of two basic pH-modifiers, sodium bicarbonate and magnesium oxide, on the release char-acteristics 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 stear-ate was provided by Prolabo, Paris, France. Magnesium oxide (MgO) was obtained from Dr Paul Lohmann Gmbh KG Chemische Fabric, Weserbergland, Germany. Sodium bicarbonate (NaHCO
3) was purchased from
El-Nasr pharmaceutical chemicals company, Cairo, Egypt. All other chemicals and solvents were of analyti-cal 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 lor-noxicam were added to 20 mL 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 1 h then were shaken for seven days at 25 ± 0.5°C using a thermostati-cally 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
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Lornoxicam matrix tablets containing basic pH-modifiers 141
K100M, Avicel PH 102, magnesium oxide, sodium bicar-bonate, and magnesium stearate were prepared by mix-ing in weight ratio of 1:1. The prepared mixtures were evaluated for possible interactions via the following tests: (a) visual inspection, (b) differential scanning calorim-etry and (c) Fourier-transform infrared spectroscopy.
Visual inspection
Samples of the prepared physical mixtures of lornoxi-cam with the previously mentioned excipients were sub-jected to weekly visual examination during their storage period that extended for twelve weeks at 40°C/75% rela-tive humidity (RH).
Differential Scanning Calorimetry (DSC)
DSC analysis was performed using Shimadzu differen-tial scanning calorimeter (DSC-60, Shimadzu, Kyoto, Japan). The apparatus was calibrated with purified indium (99.9%). Samples (3–4 mg) were placed in flat-bottomed aluminium pan and heated at a constant rate of 10°C/min in an atmosphere of nitrogen in a tempera-ture range of 20–400°C. The DSC studies were performed for pure drug, pure excipients, and for the drug-excipient powder mixtures.
Fourier-Transform Infrared Spectroscopy (FTIR)
The FTIR spectra of pure drug, pure excipients, and drug-excipient powder mixtures stored for 12 weeks at 40°C/75% RH were recorded using FTIR spectrophotom-eter (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 4000– 400 cm−1 at ambient temperature.
Preparation of HPMC matrix tablets containing lornoxicam
Matrix tablets with theoretical weight of 100 mg con-taining 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 (8 mg/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 concentra-tion of 2% in water at 20°C.[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 100 mg.[19] Magnesium
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 30 min by means of a pestle in a glass mortar. Thereafter, the powder blend was mixed with magnesium stearate for another 30 min. The resultant powder mixtures of exactly 100 mg were directly compressed into tablets using a single-punch tablet machine (Rotary Tabletting Machine, CMB3-16, Cadmach, Ahmedabad, India) equipped with 7 mm round, flat, and plain punches. The force of compression was adjusted so that hardness of all the prepared tablets ranged from 5.5–6.5 kg. The detailed compositions of the prepared matrix tablets formulations are given in Table 1.
In vitro drug release studies
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 100 rpm.[21] The release studies were ini-tially carried out in 400 mL of 0.1 N HCl maintained at 37 ± 0.5°C for a period of 2 h followed by release in phos-phate buffer of pH 6.8 achieved by adding 200 mL of 0.2 M tri-sodium ortho-phosphate solution, preheated to 37 ± 0.5°C, to the release medium for the subsequent 6 h.[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
Table 1. Composition of the prepared HPMC matrix tablets containing lornoxicam.
Formulation code
Composition
Lornoxicam (mg ) HPMC grade (% w/w)
Magnesium stearate
Avicel PH 102 up to
F 1 8 HPMC K4M 5 1% 100 mg
F 2 8 10 1% 100 mg
F 3 8 15 1% 100 mg
F 4 8 20 1% 100 mg
F 5 8 25 1% 100 mg
F 6 8 30 1% 100 mg
F 7 8 HPMC K15M 5 1% 100 mg
F 8 8 10 1% 100 mg
F 9 8 15 1% 100 mg
F 10 8 20 1% 100 mg
F 11 8 25 1% 100 mg
F 12 8 30 1% 100 mg
F 13 8 HPMC K100M 5 1% 100 mg
F 14 8 10 1% 100 mg
F 15 8 15 1% 100 mg
F 16 8 20 1% 100 mg
F 17 8 25 1% 100 mg
F 18 8 30 1% 100 mg
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spectrophotometrically by measuring their absorb-ances using a UV spectroscopy (1601-PC Double beam spectrometer, Shimadzu, Kyoto, Japan) at
max values of
372 nm and 376.8 nm when 0.1 N HCl and phosphate buffer of pH 6.8 were used as release medium, respec-tively. 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 incor-porating 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 magne-sium oxide, were incorporated into matrix tablets at concentrations of either 5% or 10% by weight. Each modifier was cogrounded with lornoxicam for 30 min 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 formu-lations 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 variationTwenty 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 uniformityTen 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 spectros-copy (1601-PC Double beam spectrometer, Shimadzu, Kyoto, Japan) after a suitable dilution with reference to the calibration curve.
Tablet friabilityAccording 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 4 min 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-modifierSelected tablets were withdrawn from the dissolution vessels after 2 h from the release run and their pho-tographs 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 vicin-ity of the tablets; selected tablets were carefully placed in a dish containing 5 mL of 0.1 N 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-modifierStability study for selected tablets was carried under accel-erated temperature and RH conditions, 40°C ± 2°C/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.
Formulation code
Composition
Lornoxicam (mg )HPMC grade
(% w/w)
Basic pH- modifier
Magnesiumstearate Avicel PH 102up toType (%w/w)
F I 8 20% HPMCK4M NaHCo3
5 1 % 100 mg
F II 8 NaHCo3
10 1 % 100 mg
F III 8 MgO 5 1 % 100 mg
F IV 8 MgO 10 1 % 100 mg
F V 8 15% HPMCK15M NaHCo3
5 1 % 100 mg
F VI 8 NaHCo3
10 1 % 100 mg
F VII 8 MgO 5 1 % 100 mg
F VIII 8 MgO 10 1 % 100 mg
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Lornoxicam matrix tablets containing basic pH-modifiers 143
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 (ƒ
2) was cal-
culated according to the Equation:
f n Rt Tt22
t=1
n 0 550 log{[1+(1/ ) 100}( ) ].= − ⋅−∑
(1)
where n is the number of sampling points, Rt and T
t
are the mean percent released from reference (fresh) and from test (stored) at time t. f
2 represents a logarith-
mic transformation of the sum of squared error of differ-ences between the reference and test products over all time points.
A value of 100% for the similarity factor (ƒ2) 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 dis-similarity between release profiles.[29]
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 2–5 and in an anionic form at pH > 6.[12] It is clearly evident from Table 3 that lornoxi-cam 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 prob-ably attributed to the presence of lornoxicam molecules uncharged at lower pH-values, whereas at higher pH values lornoxicam molecules are negatively charged.
Compatibility of lornoxicam with different tablet excipients
Visual inspectionThe stored powder mixtures of lornoxicam with different tablets excipients did not show any change in color or appearance (e.g. discoloration, caking, liquefaction, for-mation of clumps). This represents a good preliminary indication of physical stability.
Differential Scanning Calorimetry (DSC)The compatibility of lornoxicam with the afore-mentioned excipients was investigated using DSC
analysis,[30–32] 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 excipi-ent 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 232.5°C 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 50–120°C that might be ascribed to their dehydration and an exother-mic effect above 300°C that might be attributed to their decomposition (Figure 1b, 1c and 1d). Avicel PH 102 showed a slightly exothermic effect above 300°C that might be attributed to its decomposition (Figures 1e). A broad shallow endothermic peak was observed in case of magnesium stearate at 119.36°C due to its dehydra-tion (Figure 1f). Concerning the DSC of the utilized basic pH modifiers; a characteristic endothermic effect below 100°C was observed in the thermogram of sodium bicarbonate (Figure 1g), however the thermogram of
Table 3. Saturated solubility of lornoxicam in different media at 25 ± 0.5°C (mean ± SD, n = 3).
Media tested Mean drug solubility (mg/mL) ± SD
0.1N HCl (pH 1.2) 0.006 ± 0.002
Deionized water (pH 5.1) 0.021 ± 0.009
Phosphate buffer (pH 6.8) 0.305 ± 0.083
0 100 200 300 400
Temprature °C
0 100 200 300 400
Temprature °C
(a) (a)
(i)(j)
(k)
(l)
(m)
(n)
(o)
(b)(c)
(d)
(e)
(f)
(g)(h)
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 lor-noxicam 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.
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144 Y. El-Said Hamza and M.H. Aburahma
magnesium oxide show a slight endothermic effect above 300°C (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 dif-ferences 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 ther-mal method of analysis, should not be used individu-ally to detect any inherent incompatibility. It has to be supported by other non-thermal techniques, such as FTIR.[30–32] Therefore, the latter was considered in con-junction with DSC to reach a definite conclusion.
Fourier-Transform Infrared Spectroscopy (FTIR)The FTIR spectrum of pure lornoxicam, pure excipi-ents, and their 1:1 physical mixtures are shown in Figure 2. The FTIR spectrum of lornoxicam showed a characteristic peak at 3090 cm−1 corresponding to –NH stretching vibration. Intense absorption peak was found at 1642 cm−1 due to the stretching vibration of the C = O group in the primary amide. Other peaks were observed at 1597 cm−1 and at 1559 cm−1 and were assigned to bending vibrations of N–H group in the secondary amide. The stretching vibrations of the O = S = O group appeared at 1157 cm−1, 1387 cm−1, and at 1336 cm−1. Other promi-nent peaks appeared at 827. 94 cm−1 corresponding to –CH aromatic ring bending and heteroaromatics and at 766. 8 cm−1 due C–Cl 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
4000 3000 2000 1000 400 4000 3000 2000 1000 400
Wavenumbers Wavenumbers
(a)
(b)
(c)
(d)
(e)
(f)
(g)
(h) (o)
(n)
(m)
(l)
(k)
(j)
(i)
(a)
(%) T
rans
mitt
ance
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.
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Lornoxicam matrix tablets containing basic pH-modifiers 145
same positions. Moreover, these spectra can be simply regarded as the superposition lornoxicam and the inves-tigated excipients. This could indicate the absence of chemical interaction between the drug and the excipi-ents confirming the DSC results presented formerly.
In vitro drug release studiesFigure 3 illustrates the in vitro release profiles of lornoxi-cam 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 0.1 N HCl of pH 1.2 for 2 h followed by phosphate buffer of pH 6.8 for the sequential 6 h.[39] Moreover, the release sampling duration lasted 8 h as the total GI transit time for oral dosage forms in humans is reported to be approximately 8 h.[40]
Due to its distinct pH-dependent solubility, lornoxi-cam showed an extremely slow dissolution in acidic conditions, in fact, less than 10% of the drug was dis-solved after 2 h. 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 prob-ably 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 1.2–6.8. 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 depend-ing 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 com-pared 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.[44–46] 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 diffu-sion 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 267 kDa, 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 matri-ces 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 influ-enced 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 et al.[41] who observed minor changes in meto-prolol release rates when high concentrations of differ-ent viscosity grades of HPMC were employed in matrix tablets.
The target release profile parameters for SR products were reported as follows; after 2 h, 20–50% of the drug is released, 45–75% of the drug is released after 4 h, and finally 75–105% of the drug is release after 8 h.[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 6–8 h in the lower GI tract.[43] Consequently, for assessment and comparison with these release specifications; the percent of drug released from the prepared matrix tab-lets after 2, 4, and 8 h 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 8 h, though they showed an initial delay in drug release during the first 2 h 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 differ-ent basic pH-modifiers, namely sodium bicarbonate and magnesium oxide, to these tablets formulations in concentration of 5% and 10%. These modifiers presum-ably 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
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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
corresponding tablets formulations prepared without magnesium oxide. Being practically water-insoluble, magnesium oxide presence in the tablets hinders drug
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Time (hours)Lornoxicam Powder F 1 (5 % HPMC K4M) F 2 (10 % HPMC K4M)F 3 (15 % HPMC K4M) F 4 (20% HPMC K4M) F 5 (25 % HPMC K4M)F 6 (30% HPMC K4M)
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Lornoxicam Powder F 7 (5 % HPMC K15M) F 8 (10% HPMC K15M)F 9 (15 % HPMC K15M) F 10 (20 % HPMC K15M) F 11 (25 % HPMC K15M)F 12 (30 % HPMC K15M)
pH=6.8pH=1.2(b)
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Time (hours)Lornoxicam Powder F 13 (5 % HPMC K100M) F 14 (10% HPMC K100M)F 15 (15 % HPMC K100M) F 16 (20 % HPMC K100M) F 17 (25 % HPMC K100M)F 18 (30% HPMC K100M)
pH=6.8pH=1.2(c)
0 1 2 3 4 5 6 7 8
0 1 2 3 4 5 6 7 8
0 1 2 3 4 5 6 7 8
Figure 3. In vitro release profiles of lornoxicam from HPMC matrix tablets performed in 0.1 N HCl of pH 1.2 for 2 hours and in phosphate buffer of pH 6.8 for the subsequent 6 hours at 37 ± 0.5°C. (a) HPMC K4M (b) HPMC K15M (c) HPMC K100M.
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Lornoxicam matrix tablets containing basic pH-modifiers 147
diffusion and/or medium infiltration into the tablets. On the other hand, the incorporation of sodium bicar-bonate 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
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 pres-ence of 5% and 10% sodium bicarbonate respectively, disintegrated when exposed to the release medium.
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F 2(10% HPMC K4M)
F 3(15% HPMC K4M)
F 4(20% HPMC K4M)
F 5(25% HPMC K4M)
F 7(5% HPMC K15M)
F 8(1% HPMC K15M)
F 9(15% HPMC K15M)
F 10(20% HPMC K15M)
F 11(25% HPMC K15M)
F 13(5% HPMC K100M)
F 14 10% HPMC K100M)
F 15(15% HPMC K100M)
F 16(20% HPMC K100M)
F 17(25% HPMC K100M)
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.
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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 hydra-tion. This gel layer is characterized by less entangled polymeric chains due to formation of a porous poly-meric 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 et al.[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
used. As expected, in tablets belonging to formulations F V and F VI, increasing the concentration of sodium bicarbonate from 5–10%, led to a marked acceleration in the extent of lornoxicam release. Sodium bicarbo-nate leaches out of the tablets thereby create pores in the matrix structure. At high sodium bicarbonate con-centration, 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 micro-environmental 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 dissolu-tion in the release medium that allowed a decrease in tortuosity and/or an increase in the matrix porosity. For
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Lornoxicam Powder F 4 F I (5% NaHCo3)F II (10% NaHCo3) F III (5% MgO) F IV (10% MgO)
pH=6.8pH=1.2(a)
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Time (hours)Lornoxicam Powder F 9 F V(5% NaHCo3)F VI(10% NaHCo3) F VII(5% MgO) F VIII(10% MgO)
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Figure 5. Effect of incorporating different basic pH-modifiers on lornoxicam release from HPMC matrix tablets performed in 0.1 N HCl of pH 1.2 for 2 hours and in phosphate buffer of pH 6.8 for the subsequent 6 hours at 37 ± 0.5°C. (a) Tablets contain 20% of HPMC K4M (b) Tablets contain 15% of HPMC K15M.
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Lornoxicam matrix tablets containing basic pH-modifiers 149
assessment and comparison with the release require-ments of SR products, the percentage of drug released after 2, 4, and 8 h 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 lornoxi-cam released from these tablets were 34.45% after 2 h, and 68.15% and 85.19% after 4 and 8 h, respectively. Moreover, these tablets also illustrated a burst release of nearly 30% their drug content during the first 30 min of the release study, so they are expected to overcome the disadvantages associated with the delayed dissolu-tion of lornoxicam in acidic conditions.
Physical tests for the prepared matrix tablets containing basic pH-modifiersThe comparison of physical properties of the prepared matrix tablets are shown in Table 4. The weight of tablets formulations ranged from 100.23–102.70 mg. All tablets formulations prepared in this study met the pharmaco-peial requirements for weight variation tolerance. Drug
uniformity results were found to be good among dif-ferent 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
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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.
Table 4. Characterization of the prepared HPMC matrix tablets containing basic pH-modifiers.
Formulation code
Average weight (mg) ± SD
Average drug content (%) ± SD Friability (%)
F I 101.40 ± 1.51 100.65 ± 1.20 0.39
F II 102.63 ± 2.49 101.00 ± 2.12 0.48
F III 101.60 ± 2.03 98.50 ± 1.56 0.33
F IV 102.70 ± 1.23 99.50 ± 4.38 0.34
F V 100.23 ± 2.00 99.45 ± 0.92 0.38
F VI 102.20 ± 1.47 99.65 ± 1.48 0.30
F VII 100.80 ± 2.41 98.70 ± 1.70 0.45
F VIII 102.27 ± 1.40 97.25 ± 2.05 0.35
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reported pharmacopoeial specifications. Finally, it is worth noting that lornoxicam matrix tablets belong-ing 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 friabil-ity. Hence, these matrix tablets were chosen for further investigations.
Morphological examination of matrix tablets containing basic pH-modifierThe 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 mol-ecules penetrate into the matrix system along the pores formed due to the rapid leaching of sodium bicarbo-nate into the release medium causing polymeric chains relaxation.[3] Moreover, it is obvious that these tablets showed anisotropic swelling phenomenon with pref-erential expansion in the axial direction due to relaxa-tion of the compression forces imposed on the tablets during tableting process. A similar phenomenon was observed in previously published studies by Conti et al.[52] and by Papadimitriou et al.[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 1.2–2.8 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 1.2–2.8. 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 tab-lets boarders. Concisely, these observations are attrib-uted to the leaching of NaHCO
3 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-modifierA drug product may undergo changes in its physi-cochemical characteristics during storage and these changes can affect the bioavailability of drug from dos-age 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 40°C/75%
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 didn’t 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 com-piled 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 com-paring 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
(a) (b)
Figure 7. Photographs of directly compressed HPMC matrix tablets containing basic pH-modifier before and after dissolution for 2 hour in 0.1 N 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 indi-cators solution.
Table 5. Effect of storage on the physical properties of tablets belonging to formulation F VI.
Physical properties investigated
Fresh tablets Stored tablets
Average drug content (%) ± SD
99.65 ± 1.48 97.84 ± 0.803
Friability (%) 0.30 0.61
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Lornoxicam matrix tablets containing basic pH-modifiers 151
and Flanner.[29] The computed f2 value was 63.58% indi-
cating that the release profiles of fresh and stored tab-lets 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.
Conclusion
In the current study, HPMC matrix tablets that provide initial burst drug release in acidic medium followed by an extended-release phase for 8 h was successfully designed for lornoxicam. This was attempted by incor-porating 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’ micro-environmental pH. This can be achieved through the incorporation of pH-modifiers in an inexpensive and
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.
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