Formulation and evaluation of lipid based taste masked granules of ondansetron HCl

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European Journal of Pharmaceutical Sciences journal homepage: www.elsevier.com/locate/ejps 5 6

Formulation and evaluation of lipid based taste masked granules of ondansetron HCl

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Q1

Vandana Kharb a,b,⇑, Vikas Anand Saharan c, Vivek Kharb d, Hemant Jadhav e, Suresh Purohit f a

Faculty of Pharmaceutical Sciences, Jodhpur National University, Boranada, Jodhpur, Rajasthan, India ASBASJS Memorial College of Pharmacy, Bela, District Ropar, Punjab, India c Department of Pharmaceutical Sciences, Sardar Bhagwan Singh PG Institute of Biomedical Sciences & Research, Balawala, Dehradun, Uttarakhand, India d Torrent Pharmaceuticals Ltd., Baddi, Himachal Pradesh, India e Birla Institute of Technology and Science (BITS), Pilani, Rajasthan, India f Department of Pharmacy, Institute of Medical Sciences, Banaras Hindu University, Varanasi, India b

Q2

a r t i c l e

i n f o

Article history: Received 11 January 2014 Received in revised form 10 May 2014 Accepted 15 May 2014 Available online xxxx Keywords: Glycerol monostearate Digestion Taste assessment Release mechanism

a b s t r a c t Introduction and aim: Various taste masking approaches comprising the excipients which delay the reach of the drug to taste buds are reported. Lipidic substances can act as release retarding agent and provides a matrix base responsible for suppressing the bitter taste of drug. This work was aimed to study the influence of different proportions of a lipid carrier on the inhibition of bitterness of the drug vis-a-vis in vitro release of drug from the granules. Methods: The lipid-matrix granules of ondansetron HCl with Geleol pellets (glycerol monostearate) were obtained by manual hot melt fusion technique. The prepared granules were characterized by SEM, DSC and XRD. The taste assessment of prepared granules was done by in vitro method based on drug release. Results: Distribution of drug inside the lipid-matrix granules was not properly analyzed by DSC and XRD, moreover these studies revealed no interaction between the drug and lipid. The dissolution tests displayed the significant retardation of drug release from the granules compared to pure drug and additionally indicated the attainment of matrix system via appearance of unbroken granules during in vitro testing. Higuchi relationship for drug release was obtained by drug release kinetics, which also revealed the functioning drug release mechanism, as diffusion controlled but the addition of hydrophilic substance (Cab-o-sil) has changed the mechanism of drug release. Conclusion: The proportions of Geleol and Cab-o-sil taken in granules had affected the dissolution profile. Higher amount of GE resulted in high taste masking ability. Ó 2014 Elsevier B.V. All rights reserved.

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1. Introduction Taste of the drug plays an important role in the acceptability/ palatability of its pharmaceutical formulation by patients in oral drug delivery and may result in compliance issues (especially in pediatrics or geriatrics) responsible for the commercial success of medicament. Hence, a general thought to overcome this particular hurdle of unpleasant taste while delivering drug to patients, aggravated the beginning of a pharmaceutical arena i.e. taste-masking. Since then onwards various methodologies and techniques were continuously developed in this area and, new taste-masking technologies and excipients are still emerging. These diverse technoloQ3 gies of masking the bitter taste of drug have been explained earlier ⇑ Corresponding author at: Faculty of Pharmaceutical Sciences, Jodhpur National University, Boranada, Jodhpur, Rajasthan, India. Mobile: +91 9417579575. E-mail address: [email protected] (V. Kharb).

in different context by many authors (Douroumis, 2010; Kharb et al., 2011; Joshi and Petereit, 2013). The field of taste masking has covered a major portion of pharmaceutical research work with varied bitter drugs. Several studies were reported where bitter drug was incorporated within or coated with waxy material or lipid carriers, viz. hard fat (WitocanÒ H) (Suzuki et al., 2004), glycerol distearate (Krause and Breitkreutz, 2008; Vaassen et al., 2012), stearic acid (Robson et al., 2000; Sheng et al., 2006) hydrogenated oil (Lubri wax 103) (Sugao et al., 1998), lecithin (Thai et al., 2012), glyceryl monostearate (Shiino et al., 2010; Yajima et al., 1999; Rao and Linkwong, 1991) to achieve taste masking. The taste masked formulations utilizing lipophilic substances may be manufactured by numerous processes, viz. melt pelletisation (Hamdani et al., 2002; Vaassen et al., 2012), hot-melt extrusion (Liu et al., 2001; Maniruzzaman et al., 2012), spray congealing (Yajima et al., 1999) and hot-melt coating (Achanta et al., 1997). All of these

http://dx.doi.org/10.1016/j.ejps.2014.05.012 0928-0987/Ó 2014 Elsevier B.V. All rights reserved.

Please cite this article in press as: Kharb, V., et al. Formulation and evaluation of lipid based taste masked granules of ondansetron HCl. Eur. J. Pharm. Sci. (2014), http://dx.doi.org/10.1016/j.ejps.2014.05.012

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manufacturing processes circumvent the use of organic solvents which may lead to environmental, health and safety problems for patients and personnel engaged in manufacturing, and excessive costs for recovery (Barthelemy et al., 1999; Gowan and Bruce, 1995; Kharb et al., 2011). Recently, hot-melt extrusion technique has come up and gained attention of researchers regarding its effectiveness in taste masking purposes (Maniruzzaman et al., 2013, 2012). ONS, a potent competitive serotonin 5HT-3 receptor antagonist, is used in prophylaxis of postoperative or chemotherapy or radiotherapy-induced emesis (Sheshala et al., 2011). ONS is sparingly soluble in water and has low dose, i.e. 4–8 mg (BP, 2009). Moreover, it has intensely bitter taste, which makes it difficult to administer to pediatric patients. In this study a solventless method, hot melt fusion (HMF) was employed to addresses the potential solution to the unpleasant feel of bitter tasting ondansetron hydrochloride (ONS) using glyceryl stearate as taste mask carrier. Generally it is recommended that for such type of method, only the low melting range lipids or waxes (having melting point 20–25 °C above room temperature) should be used and Geleol (GE) fits into this criterion, being inert and have melting point between 55 and 60 °C (Rowe et al., 2009). The influence of incorporated lipid on the drug release behavior and further on taste masking was also investigated. Some other studies on taste masking of ONS have been reported, which were based on complexation of drug with Eudragit EPO (Khan et al., 2007), and microencapsulation within different polymers, viz. chitosan, Methocel E 15 LV and EE100 (Bora et al., 2008), but our approach is quite different from the reported studies and requires no organic solvent.

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2. Materials and methods

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2.1. Materials

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123

Ondansetron hydrochloride dihydrate (ONS) was obtained as gift sample from Tirupati Medicare Ltd. (H. P., India). Geleol pellets (glycerol monostearate, glyceryl stearate) (Code: 5154PPD, Batch: 133005, manufactured by Gattefosse, France) was provided as a gift sample by Gattefosse India Pvt. Ltd. (Mumbai, India). Cab-OSil M-5P was provided as a gift sample by Cabot Sanmar Limited, Tamil Nadu, India. Dibasic potassium was purchased from Merck Specialities Pvt. Ltd. (Mumbai, India). Hydrochloric acid (HCl) was purchased from Fisher scientific, (Mumbai, India). All other chemicals and solvents used are of analytical grade. Double distilled water was prepared using in-house distillation unit.

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2.2. Methods

125

2.2.1. Preparation of lipid-matrix granules of ONS by hot melt fusion The accurately weighed amount of GE (quantity based on the batches designed) was placed in a porcelain dish and melted over a thermostatically controlled water bath at 75 °C. When a uniform molten mass was obtained, the accurately weighed amount of ONS (equivalent to dose, 8 mg) and Cab-o-sil, if used, was added to the melted lipid and mixed with a glass rod. When all the ONS was incorporated, the molten mass was allowed to cool to room temperature. The resulting congealed mass was sifted manually by passing through a sieve of mesh-22 (average aperture size; 710 lm) to obtain the matrix granules. Various compositions of the prepared ONS incorporated lipid-matrix granules are given in Table 1.

81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109

114 115 116 117 118 119 120 121 122

126 127 128 129 130 131 132 133 134 135 136 137 138 139 140

2.2.2. Particle size classification and validation of granulation methodology Screening of the prepared lipid-matrix granules was done by sieve shaker to obtain uniform granules. The size distribution of

lipid-matrix granules was evaluated by sieve analysis, using a gyratory sieve shaker (Pritec, Scientific Engineering Corp., Delhi, India) with six standard sieves (British standard sieve series; Sieve No. 22, 30, 44, 60, 85 and 120). The granules were shaken for 10 min. This process was repeated three times and % weight retained on each sieve was calculated and is given in Table 2. The sieves were also observed for their integrity after each trial.

141

2.2.3. Surface morphology of lipid-matrix granules The size and the surface characteristics of the produced lipidmatrix granules before and after dissolution were studied with a scanning electron microscope (Jeol JSM-6100, Japan or S-3400N, Hitachi, Japan). The lipid-matrix granules were subjected to dissolution tests for 2 h and the contents of dissolution vessel were filtered to extract the granular mass which was fed to lyophilizer (Lyophilizer, FD-5-3, Allied Frost, New Delhi, India) for 12 h to obtain the dried mass. Sample of lipid matrix granules was mounted on stub and coated with a layer of gold using a sputter coater (JFC-1100). The samples were scanned at 5 kV voltage and photographed at magnification of 230 and 1600.

148

2.2.4. Physical state of ONS in lipid-matrix granules Differential scanning calorimetry (DSC) thermograms were recorded using scanning calorimeter (Mettler, Switzerland) to characterize the thermal properties of ONS and GE and also to investigate the physical state of ONS in the lipid matrix granules. Samples (2–5 mg) were placed in flat bottomed aluminum pan and heated at a constant rate of 10 °C/min. The samples were scanned from 35 to 400 °C.

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– Powder X-ray diffraction of the individual components, physical mixture and lipid-matrix granules were taken with a view to examine the changes in the physical form of ONS caused by the HMF technique during the preparation of matrix. The X-ray diffraction patterns were recorded using Xpert-pro diffractometer (Pan Anytical, Netherlands) with Cu Ka filter generated at 45 kV voltage and 40 mA current over a diffraction angle of 2h.

168

142 143 144 145 146 147

149 150 151 152 153 154 155 156 157 158 159

161 162 163 164 165 166 167

169 170 171 172 173 174 175 176

2.2.5. Drug assay of lipid-matrix granules The lipid-matrix granules were assayed for the drug using an Q4 earlier reported procedure (Albertini et al., 2003; Passerini et al., 2002). A variable amount of granules, theoretically equivalent to 2 mg of drug was accurately weighed and dissolved in 100 ml of 0.1 N HCl (pH 1.2) buffer. The mixture was heated to 70 °C to melt the lipid carrier. Mixture was shaken and allowed to cool at room temperature with intermittent shaking. Finally, the solution was filtered and then analyzed UV spectrophotometrically at 310 nm to record the absorbance. The drug content was determined using the standard calibration curve developed in 0.1 N HCl.

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2.2.6. In vitro dissolution studies The in vitro release of ONS from granules was performed in eight station USP type II (Labindia Disso 2000, Lab India Ltd., Mumbai, India) dissolution test apparatus containing 500 ml of 0.1 N HCl solution (pH 1.2) as the dissolution media, stirred at 50 rpm (procedure is as per BP, 2009). The matrix granules were placed in dissolution medium maintained at 37 ± 0.5 °C. Aliquots (5 ml) of the dissolution medium were withdrawn at specified time intervals, filtered and analyzed at 310 nm using a double beam UV visible spectrophotometer (Shimadzu UV Pharma Spec-1700 Kyoto, Japan). An equal fresh volume of the dissolution medium was immediately added to compensate the loss in dissolution medium. The percentage of ONS released was determined using the calibration curve developed in respective media. A correction factor (Ci) was applied to take into account any loss of the drug (Singh

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V. Kharb et al. / European Journal of Pharmaceutical Sciences xxx (2014) xxx–xxx Table 1 Composition and characteristics of lipid-matrix granules prepared by hot melt fusion method.

a

Batch

ONS amount (mg)

GE amount (mg)

G1 G2 G3 G4 G5 G6 G6A1 G6A2 G6A3

100 100 100 100 100 100 100 100 100

150 500 1200 1500 1800 2000 1979 1958 1937

Cab-o-sil amount (mg)

Drug assay (%)

In vitro taste assessment (conc. (mg/ml) ± SDa

21 42 63

84.45 86.62 88.37 88.75 89.88 90.05 90.19 90.43 91.18

58 ± 1.04 50.5 ± 0.9 40 ± 1.01 36.4 ± 0.6 29.8 ± 0.83 18 ± 0.45 19.42 ± 0.66 20 ± 0.69 21 ± 0.59

Average of three readings.

Table 2 Sieve test data of different batches of lipid-matrix granules.

a

Sieve no. (BSS 410/1969 Mesh)

Aperture size (lm)

22 30 44 60 85 120 Fines Loss

710 500 355 250 180 125

Weight percentages retained (meana ± SD) G6

G6A1

G6A2

G6A3

All passes 25.12 ± 1.98 51.08 ± 1.11 17.22 ± 2.71 4.03 ± 1.32 1.13 ± 0.75 0.72 ± 0.06 0.69 ± 0.02

All passes 23.71 ± 3.22 52.11 ± 1.95 18.01 ± 1.03 3.06 ± 0.88 1.72 ± 0.67 0.67 ± 0.09 0.7 ± 0.01

All passes 23.33 ± 2.34 52.27 ± 2.67 18.32 ± 1.87 3.35 ± 0.99 1.13 ± 0.71 0.74 ± 0.08 0.83 ± 0.04

All passes 23.25 ± 2.27 51.28 ± 2.13 19.37 ± 1.48 3.21 ± 0.96 1.15 ± 0.44 0.92 ± 0.06 0.81 ± 0.03

Average of three independent readings, SD = standard deviation.

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et al., 1997) as shown in Eq (1). The drug release results were taken as the average of six readings in order to minimize the error as a result of variations. Standard deviations were also calculated.

208

  n1 Vs X Vt Ci ¼ Ai þ Ai Vt i¼1 Vt  Vs

203 204

206

209 210 211 212 213 214 215 216 217

218 220 221 223 224 226

ð1Þ

where Ci = corrected absorbance of the ith observation, Ai = observed specific absorbance, Vs = sample of the dissolution media withdrawn, Vt = total volume of dissolution medium. 2.2.7. Drug release kinetics Data obtained from the in vitro drug release study was analyzed by different kinetic models and fitted into corresponding equations (Costa and Lobo, 2001) in order to evaluate the release mechanism of ONS from the lipid-matrix granules. The kinetic models used were represented by the following Eqs. (2)–(6):

Zero order model : Q t ¼ Q 0 þ K 0 t

ð2Þ

First order model : log Q t ¼ log Q 0 þ K 1 t=2:303

ð3Þ

pffiffi Higuchi model : Q t ¼ K h t

ð4Þ

227 1=3 W0

229

Hixson and Crowell cube root model :

230 232

Korsmeyer and Peppas model : Mt =M1 ¼ Kt n

233 234 235 236 237 238 239 240 241 242



W 1=3 t

¼ K st

ð5Þ ð6Þ

where Qt and Mt refer to amount of the drug release at time t, Q0 is the initial amount of drug present at time equal to zero, Wt and W0 represents the amount of the drug at zero and t, M1 is the amount of drug dissolved at infinite time. The terms K0, K1, Kh, Ks, and K are the release kinetic constants for zero-order, first-order, Higuchi, Hixson Crowell and Korsmeyer and Peppas model. The model fitting using Eqs. (2)–(6) was done with DD Solver (Zhang et al., 2010). 2.2.8. Taste masking ability In vitro evaluation of the taste masking efficiency of lipid-matrix granules was performed in order to determine effective bitterness

inhibition. The taste masking ability of prepared granules was checked by in vitro methods where a delayed drug release from the matrix in early 5 min. was considered as main in vitro parameter for successful taste masking. There are several methods reported that have been used for taste masking evaluation of pharmaceutical products, where formulations were suspended in the prescribed vehicle for making test sample followed by taste masking intensity rating (Anand et al., 2008, 2007; Gao et al., 2006; Shirai et al., 1993; Sugao et al., 1998). Lipid-matrix granules, equivalent to 8 mg of ONS were accurately weighed on electronic digital balance (Model-AX200, Shimadzu corporation, Kyoto, Japan), and placed in a volumetric flask containing 25 ml phosphate buffer pH 6.8 and stirred for 5 min. The mixture was filtered and the filtrate was analyzed for ONS concentration at 310 nm by UV spectrophotometer. ONS release in the phosphate buffer pH 6.8 (simulated saliva) was compared to the threshold bitterness concentration of ONS. If the concentration of drug in the simulated saliva was less than the bitterness threshold of ONS, then the formulation was considered taste masked.

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3. Results

262

The various batches of lipid-matrix granules prepared by the manual HMF method are shown in Table 1 and all appeared white powder. The temperature during the HMF method was 75 °C, which was less than the melting point of ONS (186.73 °C as per DSC results) and hence ONS has not melted during the process instead it was suspended or got dispersed in the molten lipid (GE) which acted as a thermal binder for HMF process and helped in the formation of matrix granules.

263

3.1. Particle size classification of lipid-matrix granules

271

During the sieve analysis of granules the integrity of sieves was maintained throughout the experimentation. The lipid-matrix granules having the size fraction in the range of 355–500 lm showed maximum yield (Table 2). Hence, this particular granular size fraction was collected and stored in a dessicator and used

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for further studies. Moreover, granules having larger size, especially within the selected size range are reported to exhibit slower release of drug in comparison to the smaller size granules which could facilitate taste masking (Witzleb et al., 2011).

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3.2. Assay for drug

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The percentage of drug (Table 1) in all the prepared lipid matrix granules batches varied between 84.45% and 91.18%. Further, the addition of Cab-o-sil improved the uniformity of drug distribution because of its suspending ability which prevented the sedimentation of ONS in the molten lipid mixture during HMF process.

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3.3. Taste masking ability

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The taste masking ability of ONS lipid matrix granules was determined by in vitro drug release test because none of the excipient incorporated in taste masked ONS granules was having bitter taste. Cab-o-sil is reported to be tasteless while Geleol is having slight fatty taste (Rowe et al., 2009). It is only the ONS which is contributing bitter feel to the formulation. Hence, in vitro drug release test could be a good surrogate for taste assessment especially for this type of formulation where drug release is prevented or delayed in the oral cavity by embedding the drug in hydrophobic lipid. ONS bitterness in drug release medium was evaluated by measuring drug release and comparing it with bitterness threshold concentration. A clear and more quantifiable table of human taste evaluation vs the drug concentration has been reported in our earlier publications (Kharb et al., 2014; Dev et al., 2014), which was correlated with in vitro drug release at initial time points for the purpose of bitterness evaluation and reducing the reliance of taste panel for bitterness assessment during formulation optimization studies. In vitro taste assessment of all the prepared batches (G1–G6) was carried out to determine the release of ONS at 5 min in phosphate buffer pH 6.8 (Table 1). The results of in vitro drug release showed that ONS amount decreased in order G1 > G2 > G3 > G4 > G5 > G6 due to increase in the amount of lipid carrier used in the same order (Fig. 1). Drug release was less than 22 lg/ml at 5 min from G6 formulation. An another study reported 22 lg/ml as bitterness threshold of ONS (Dev, 2012). Therefore, it is anticipated that bitter taste perception of ONS has been effectively masked in G6 formulation. Hence, G6 formulation was selected for further studies.

283 284 285

289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316

Fig. 1. Bar diagram representing the release of ONS from lipid matrix granules in Phosphate buffer pH 6.8 at initial 5 min during in vitro taste assessment test.

3.4. In vitro drug release

317

Based on the results of in vitro taste assessment studies, the four lipid-matrix granule batches having lowest bitter taste perception and prepared by manual HMF process with (G6) and without Cabo-sil (G6A1-G6A3) were investigated for in vitro release of ONS and their dissolution profiles are displayed in Fig. 2. The in vitro dissolution in 0.1 N HCl solution (pH 1.2) was carried out to determine the influence of taste masking methodology on the bioavailability or dissolution profile of the drug. During dissolution the matrix granules did not disintegrate in dissolution media to smaller particles but remained intact. It can clearly be observed from Table 3 that incorporating the ONS in GE led to a delayed drug release compared to pure ONS. After 5 min about 9.43% of drug had released from the G6 batch and this amount had increased to nearly 33.86% after one hour, and only 39.41% of the ONS release was achieved after 120 min. Slower drug release was attained with the G6 batch of lipid matrix granules and for that reason, the incorporation of a hydrophilic substance might enhance the release of drug from lipid carrier. Some reports are already available where addition of hydrophilic excipients like mannitol, hydroxypropylmethylcellulose, aerosil resulted in enhanced drug release from the wax/lipid matrices (Parab et al., 1986). Three different concentrations of Cab-o-sil (1, 2 and 3% w/w) were employed. It can be seen in Fig. 2 that drug dissolution from the batches containing Cab-osil was slightly slower at the beginning but after about 20 to 30 min the percent drug dissolution was found to be higher than G6 batch (without Cab-o-sil). This is most probably due to the swellling properties of Cab-o-sil (CAB-O-SIL ÒM-5P Brochure, 2014). The three batches G6A1 to G6A3 containing 1%, 2% or 3% of Cab-o-sil showed 48.29%, 60.78% and 69.21% of drug release after 120 min. A higher amount of Cab-o-sil has led to faster drug dissolution due to its gelation abilities.

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3.5. Drug release kinetics

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Drug release kinetic analysis was applied on the in vitro drug dissolution data of the four batches (G6, G6A1, G6A2 and G6A3) until the last sampling time, i.e. 90 min. The values of different drug release parameters, viz. diffusional exponent (n), determination coefficient (r2) and release rate constants (K) obtained from lipid-matrix granules are shown in Table 4. The best fit of the dissolution data was investigated on the basis of highest magnitude of determination coefficient and lowest AIC values (Akaike Information Criteria), and appears to follow the Higuchi model (coefficient:

350

Fig. 2. Drug release profile in 0.1 N HCl buffer pH 1.2 for taste masked ONS embedded lipid-matrix granules and pure drug (ONS).

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V. Kharb et al. / European Journal of Pharmaceutical Sciences xxx (2014) xxx–xxx Table 3 Drug release from taste masked lipid-matrix granules of ONS in 0.1 N HCl solution pH 1.2. Time (min.)

Drug release (%) ± std. dev.

5 10 15 20 30 45 60 90

ONS

G6

G6A1

G6A2

G6A3

68 ± 2.34 95 ± 2.67 99.89 ± 2.94 100 ± 1.5

9.436 ± 2.95 13.082 ± 1.15 17.285 ± 1.09 20.721 ± 1.51 23.924 ± 1.57 28.278 ± 2.52 33.857 ± 3.76 39.413 ± 2.11

10.639 ± 1.84 14.872 ± 1.43 20.386 ± 2.66 23.214 ± 2.52 30.798 ± 2.61 37.419 ± 3.55 45.198 ± 3.65 48.295 ± 3.59

12.607 ± 2.56 19.447 ± 2.68 23.601 ± 2.71 30.330 ± 1.65 39.060 ± 1.69 50.306 ± 2.83 56.578 ± 1.95 60.781 ± 2.76

14.691 ± 2.51 23.701 ± 2.34 31.285 ± 2.32 38.271 ± 3.62 46.697 ± 2.62 53.878 ± 3.51 62.194 ± 2.75 69.217 ± 2.88

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0.9790–0.9954) rather than first order, Hixson crowell and zero order models, thus indicating a diffusion-controlled mechanism (Ozyazici et al., 2006). Similar Higuchi’s square root of time kinetics has also been reported previously with glyceryl monostearatebased implants of cefazolin (Allababidi and Shah, 1998). The first 60% of drug dissolution data was also fitted in Korsmeyer-Peppas equation in order to find out diffusional exponent value. The exponent n value of G6 batch was 0.4769 and hence release of ONS from the granules of G6 batch could be described as Fickian while the n values are slightly higher than 0.5 for other three batches (G6A1:0.5118; G6A2:0.5148; G6A3:0.5206), representing the little anomalous drug transport governed by both Fickian and relaxation mechanism. The drug release rate constant (K) of the lipid-matrix granules (Table 3) was found to follow the order G6A3 > G6A2 > G6A1 > G6. The magnitude of kinetic rate constant is highest for G6A3 batch (7.5339) and lowest for G6 batch (4.6840) of granules which signified that the G6 batch (without Cab-o-sil) releases the drug more slowly as compared to A series of G6 granular batches containing Cab-o-sil, this might be due to the hydrophilic propensity of Cab-o-sil (CAB-O-SIL ÒM-5P Brochure, 2014).

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3.6. Surface morphology of lipid-matrix granules

380

389

The lipid-matrix granules (G6) were characterized by scanning electron microscopy (SEM) and photographs of lipid formulations at different magnifications are shown in Fig. 3. The SEM pictures of granules before dissolution (Fig. 3a–c) displayed that granules were irregular and not uniform in shape. Furthermore, the surface of matrix granules is not smooth or plane but consists of separate layers or flakes and hence, dissolution medium can easily penetrate into the granules. The photomicrographs of granules after dissolution (Fig. 3c and d) showed diffused surface which might be due to the dissolution of ONS in the penetrating release media.

390

3.7. Physical state of ONS in lipid-matrix granules

391

Physical state of ONS in GE matrix granules was also examined by DSC and XRD techniques. The thermogram of pure ONS, GE, their physical mixture (1:5 w/w), and the lipid-matrix granules (G6) are depicted in Fig. 4. ONS showed sharp endothermic melting peak at 186.73 °C that is in agreement with literature value (Salem et al., 2001). The DSC curve of GE showed a transition peak at

359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377

381 382 383 384 385 386 387 388

392 393 394 395 396

66.26 °C corresponding to its melting point. DSC thermogram of physical mixture shows two endothermic peaks at 182.73 °C and 66 °C, symbolizing that the melting point of both ONS and GE got shifted to a lower temperature. This little change in the endothermic peak of ONS was due to the mixing of drug and lipid, which lowered their purity, thus resulting in a slight broader and lower melting point, which does not represent any incompatibility. However, it was observed that the lipid-matrix formulation (G6) showed no endotherm corresponding to the melting point of ONS. This suggests that ONS might be dissolved in the lipid-matrix as the temperature was raised up to its melting point during the DSC run, another possibility could be inconclusiveness to determine the physical state of ONS in lipid-matrix G6 formulation as this technique is not sensitive enough to detect crystalline materials present at these low concentrations (ONS amount in G6; 4.76% w/w). XRD analysis was also performed to confirm the results of DSC studies. XRD patterns of ONS shows sharp high intensity peaks at diffraction angles 2h of 6.30°, 12.37°, 20.44°, 23.47°, 24.41°, 25.75°, 25.98°, 27.50°, 30.38° which are characteristic of the ONS, indicating its crystalline nature (Fig. 5). XRD pattern of GE also showed characteristic peak observed at 19.52°, 22.84° and 23.55° indicating its relatively low crystallinity. The diffraction pattern of lipid granules was almost similar to that of GE except two slight peaks at diffraction angles 2h of 12.32° and 27.73°, which might be again due to the low concentration of the ONS in the final formulation. Hence, no interpretation about the physical form of the drug in the lipid-matrix granules could be possible by this study.

397

4. Discussion

425

Lipids are being widely getting utilized in coating and extrusion techniques because of their melting behavior that avoids the need of any solvent system (Faham et al., 2000; Passerini et al., 2002; Krause and Breitkreutz, 2008). It is expected that the taste masked formulation containing the lipid component remains intact in the mouth because of the absence of lipases in salivary fluid moreover, the hydrophobic nature of lipid could also result in its low wettability or solubility, which consecutively reduces the drug release in oral cavity to such a low extent that the achieved drug concentration is below the bitterness perception or threshold concentration of the drug. Some other investigators have also concluded in their

426

Table 4 The determination coefficient (r2) and the statistical parameters for lipid-matrix granules obtained from various release kinetic models. Granule batches

G6 G6A1 G6A2 G6A3

Hixon-Crowell

Higuchi

r2

Zero-order K0

r2

First-order K1

r2

Ks

r2

Kh

r2

Korsmeyer-Peppas n

K

0.6314 0.6884 0.6868 0.5939

0.5476 0.6919 0.8792 0.9971

0.7811 0.8678 0.9191 0.9097

0.0071 0.0099 0.0144 0.0184

0.7371 0.8198 0.8663 0.8426

0.0021 0.0029 0.0041 0.0051

0.9954 0.9852 0.9790 0.9843

4.2872 5.3875 6.8474 7.8390

0.9965 0.9855 0.9794 0.9922

0.4769 0.5118 0.5148 0.5206

4.684 5.1481 6.4684 7.5339

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Fig. 3. Representative scanning electron photomicrographs of taste masked lipid-matrix granules (G6 batch): before dissolution at 230 (a), 500 (b) and 1600 (c); after dissolution at 300 (d) and 1600 (e).

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study that low drug release rates reduce the probability of a bitter taste perception in the mouth (Suzuki et al., 2004; Breikreutz et al., 2003) because only the sufficient amount of dissolved drug could interact with the taste buds and induce taste perception. The particle size of the lipidic formulations has a great impact on the taste masking ability as revealed by the earlier work of researchers. Michalk et al. (2008) concluded that specific surface area played an important role, the particles having smaller specific surface area, irrespective of the size showed less interaction with the release medium which resulted in reduction in the drug release during short time intervals and hence better taste masking ability. This type of dependency in the amount of drug release and particle’s surface was observed only when drug is very slightly soluble in the dissolution medium. In contrast Witzleb et al. (2011) compared the two particle size fractions. The particles with smaller size showed faster dissolution than particles with larger mesh size because of higher over all surface area of smaller particles than the larger particles. The faster dissolution was observed during the long time dissolution run but during the short time the lipid layer on the surface of particles was sufficient to prevent drug

dissolution and hence provided taste masking ability. The findings of these researchers clearly pointed out that drug release patterns from lipid particles show high dependencies on particle size and homogeneity of the matrix, and to minimize this effect we used granules of a defined size range, i.e. size fraction in the range of 355–500 lm, for characterization and evaluation studies. In this study taste masking was desired but without prolonging the drug release. Hence, to attain faster release, hydrophilic substance (Cab-o-sil) was incorporated into the matrix. Cab-o-sil has silanol groups on its surface which provides hydrophilic character to it and in addition it exhibit high specific surface area (200 m2/g) (CAB-O-SIL ÒM-5P Brochure, 2014). All these factors could be responsible for greater absorption of dissolution medium and in turn higher gelation ability of the formulation containing Cab-osil. During the in vitro release of ONS from lipid matrix granules it was assumed that the drug first dissolved in the gel layer formed by Cab-o-sil and then subsequently diffused out of this layer, the whole process took 20 or 30 min. Hence, drug release was lower at the initial dissolution points because of the slow absorption of dissolution medium penetrating into the lipid matrix granules by

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Fig. 4. DSC thermogram of ONS (a), GE (b), ONS and GE physical mixture (1:5 w/w) (c), and taste masked lipid-matrix granules batch G6 (d).

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Cab-o-sil (Albertini et al., 2004). Later on the drug started to dissolve in the preformed gel layer and eventually diffused into outer dissolution medium resulting in an improved drug release. Hence, Cab-o-sil acted as a channeling agent for this lipid-matrix system. It was expected that ONS release from GE based insoluble, nondisintegrating matrix could be achieved by diffusion, erosion and digestion or by a combination of these (Jannin et al., 2006; Savolainen et al., 2002). The effect of erosion mechanism on dissolution was considered negligible in case of granules because of their small size. Therefore, it was probable that diffusion of dissolved drug through the matrix would be the rate limiting step which governs the drug release. Enzymatic saponification of lipid, would also play an important role in the in vivo release of the drug

because if the lipid-matrix granules were exposed to gastro-intestinal fluid the lipid matrix would be rapidly degraded by human gastric and pancreatic lipases resulting in enhanced drug dissolution or faster drug release (Bakala N’ Goma et al., 2012). Such type of study was earlier carried out by researchers on the release of praziquantel from the lipids, viz. glyceryl tripalmitate, glyceryl dibehenate, glyceryl monostearate, cetyl palmitate and solid paraffin in the biorelevant medium containing pancreatic lipase, bile salts and phospholipids and they found that drug release from glyceryl monostearate matrices was much faster in biorelavant medium than in HCl because of both solubilisation and enzymatic degradation of the lipid, whereas there was hardly any difference for the other lipids (Witzleb et al., 2012). Furthermore, the

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the bitterness of ONS. The delayed in vitro dissolution of ONS from a GE based lipid-matrix granules was considered to be due to hydrophobic nature of lipid and this low drug release further ensures the taste masking of bitter tasting ONS. The drug release kinetics showed that in vitro release of ONS is mainly induced by diffusion mechanism and hence, drug dissolution was enhanced by incorporation of a hydrophilic substance into the lipid-matrix which further had changed the release mechanism to anomalous transport. In vivo enzymatic degradation of the lipid would certainly play a crucial role in drug release characteristics and hence requires in vivo experimentation.

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Sohi et al. (2004).

Fig. 5. XRD pattern of ONS (a), GE (b), and taste masked lipid-matrix granules of batch G6 (c).

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lipophilicity of GE could also reduce the penetration of dissolution medium into the matrix there by decreasing its wettability which in turn could be another mechanism responsible for drug retardation from GE based lipid-matrix granules (Peh et al., 2000). Therefore, to investigate the correct mechanism behind the drug release, kinetic release studies were conducted. The results revealed that Higuchi square root model was operative for the prepared granules. The exponent n values obtained from Korsmeyer-Peppas model signified a pure Fickian diffusion, as a dominant drug release mechanism only for G6 granules while the other batches showed anomalous release behavior which could be due to the addition of swellable Cab-o-sil in those batches. Such type of increase in exponent value due to swelling tendency of excipients was also reported in previous study (Ozyazici et al., 2006). Hence, it can be concluded that lipophilicity, diffusion and in vivo enzymatic degradation of GE would govern the overall release of ONS from matrix granules. DSC and the XRD studies were inconclusive to determine the physical state of ONS in GM matrix granules as both of these techniques could not detect the crystalline materials present below their limit of detection (5% w/w). The amount of ONS in the G6 batch was lower than 5% w/w and therefore, was not detected by above mentioned techniques. There are several examples in the literature where DSC and XRD techniques were not capable of detecting process induced transformations in the physical form of the drug especially in the low drug load formulations (Kalivoda et al., 2012; Wardrop et al., 2006). Therefore, some authors have utilized qualitative techniques like polarized microscopy, hot stage microscopy (Albertini et al., 2004; Wardrop et al., 2006), to evaluate the potential of drug physical form changes. While Kalivoda et al. (2012) had utilized other indirect methods for the assessment of drug solid form changes in the formulations e.g. dissolution testing, chemical stability during storage. Hence, any of the above mentioned method could help in accurate judgment of solid state of ONS in lipidic granules. Further, studies are ongoing in this direction.

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5. Conclusion

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It is anticipated that the GE acted as release retarding agent and the amount of both, GE and hydrophilic agent (Cab-o-sil) had affected the dissolution profile of ONS incorporated in the lipid matrix granules. Higher amount of GE were capable of suppressing

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Acknowledgements

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We highly acknowledge Tirupati Medicare Ltd. (H. P., India), Gattefosse India Pvt. Ltd. (Mumbai, India) and Cabot Sanmar Ltd., (Tamil Nadu, India) for providing gift samples of ONS Geleol pellets and Cab-o-sil respectively.

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