http://informahealthcare.com/phd ISSN: 1083-7450 (print), 1097-9867 (electronic) Pharm Dev Technol, Early Online: 1–8 ! 2015 Informa Healthcare USA, Inc.. DOI: 10.3109/10837450.2015.1022792
RESEARCH ARTICLE
Formulation and in vitro evaluation of ketoprofen fast-dissolving tablets Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Universite De Sherbrooke on 04/10/15 For personal use only.
Tansel Comoglu, Ozge Inal, and Hajar Ben Yaacoub Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara University, Tandogan, Ankara, Turkey
Abstract
Keywords
Drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated as orally fast-disintegrating tablets (FDTs or ODTs). Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Despite advances in the FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast-disintegrating properties of the formulation. The unpleasant taste of the active drug usually masked by adding flavoring ingredients and sweeteners to improve taste and palatability but in this study a novel approach of using a polymer; Eudragit EPO and a granulation procedure of this polymer with the active drug was applied to mask the bitter taste of ketoprofen. In order to produce ketoprofen FDT formulations, a two-stepped procedure was followed; granulation process with the taste-masking agent (Eudragit EPO) and then direct compression (F3 and F4). In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of Eudragit EPO. As well as observing the effect of taste-masking agent, crospovidone and sodium starch glycolate were used in different concentrations (2, 4 and 8wt%) to examine the influence of superdisintegrants on FDT properties. All the FDTs containing 30 mg ketoprofen (F1, F2, F3 and F4) were evaluated by means of in vitro quality control tests.
Crospovidone, Eudragit EPO, ketoprofen, orally fast-disintegrating tablets, sodium starch glycolate, superdisintegrants, taste masking
Introduction In recent decades, a variety of pharmaceutical research has been conducted to develop new dosage forms. Considering quality of life, most of these efforts have been focused on ease of medication. Among the dosage forms developed to facilitate ease of medication, the orally fast-disintegrating tablet (FDT) is one of the most widely employed commercial products. FDTs are useful in patients, such as pediatric, geriatric, bedridden or developmentally disabled, who may face difficulty in swallowing conventional tablets or capsules and liquid orals or syrup, leading to ineffective therapy, with persistent nausea, sudden episodes of allergic attacks or coughing for those who have an active life style. The FDTs could be suitable for analgesics, neuroleptics, cardio vascular agents, antiallergics and drugs for erectile dysfunction1. The FDT has remarkable disintegration properties; it can rapidly disintegrate without water in the mouth within a few seconds. When an FDT is placed in the oral cavity, saliva quickly penetrates into the pores causing rapid disintegration. Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Undesirable taste is one of the important formulation problems that are encountered with many drugs. Despite advances in the
Address for correspondence: Tansel Comoglu, Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara University, 06100 Tandogan/Ankara, Turkey. Tel: +90 312 203 3164. E-mail: [email protected]
History Received 13 January 2015 Revised 19 February 2015 Accepted 20 February 2015 Published online 23 March 2015
FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. Tastemasking technologies are increasingly focused on aggressively bitter-tasting drugs such as the macrolide antibiotics, nonsteroidal anti-inflammatory drugs and penicillins. Taste masking of water-soluble bitter drugs, especially those with a high dose, is difficult to achieve by using sweeteners alone. As a consequence, more efficient techniques such as coating, microencapsulation and granulation have been used in combination with the sweeteners. Various investigators have patented orally disintegrating/dissolving systems containing taste-masked drugs1. Cumming et al.2 patented a taste-masked micro-matrix powder in which the ratio of a polymer compared to a drug having poor organoleptic properties was 6:1. Taste cationic masking can also be done by using Eudragit L-100 by employing drug:polymer ratio of 10:1. However, taste-masked micro-matrix powder prepared from cationic polymer is reported to be superior to that produced by using methacrylates. Becicka et al.3 patented a method for masking the taste of bitter pharmacological active ingredients. Dibutyl sebacate, water, ethylcellulose and polyethylene glycol were mixed and then loperamide HCl and cationic resin (Amberlite) were added to form a homogenous mixture. The granules of this mixture were prepared using rotary evaporator under vacuum at a temperature of 65 C. The dried granules were sieved and could be used for the preparation of orally fast-disintegrating dosage forms. The key parameters that are to be considered in the process of formulating a FDT are the taste and disintegration time. To achieve rapid disintegration, direct-compression FDT
2
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Table 1. Basic composition of ketoprofen FDT formulations.
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F1a
F2a
F3b
F4b
Ingredients (mg)
F1.1
F1.2
F1.3
F2.1
F2.2
F2.3
F3.1
F3.2
F3.3
F4.1
F4.2
F4.3
Ketoprofen Avicel PH 101 Eudragit EPO Mannitol Aerosil Magnesium stearate Crospovidone Sodium starch glycolate Aspartame Total
30 83 60 57.2 1.4 1.4 5 – 12 250
30 83 60 52.2 1.4 1.4 10 – 12 250
30 83 60 42.2 1.4 1.4 20 – 12 250
30 83 60 57.2 1.4 1.4 – 5 12 250
30 83 60 52.2 1.4 1.4 – 10 12 250
30 83 60 42.2 1.4 1.4 – 20 12 250
30 83 60 57.2 1.4 1.4 5 – 12 250
30 83 60 52.2 1.4 1.4 10 – 12 250
30 83 60 42.2 1.4 1.4 20 – 12 250
30 83 60 57.2 1.4 1.4 – 5 12 250
30 83 60 52.2 1.4 1.4 – 10 12 250
30 83 60 42.2 1.4 1.4 – 20 12 250
a
Contain pure ketoprofen–Eudragit EPO. Contain ketoprofen after the granulation process with Eudragit EPO.
b
formulations typically contain high levels of a superdisintegrant. Depending on the level and characteristics of the active pharmaceutical ingredient (API) and the desired release profile, the levels of superdisintegrant used can be 10–20 wt% of the formulation, and it can be higher or lower in some cases. Thus, in developing a FDT formulation for direct compression, choosing the optimal superdisintegrant is critical. Although the superdisintegrant primarily affects the rate of disintegration, when used at high levels it can also affect mouth feel, tablet hardness and friability4. In our study, effect of varying concentrations of different superdisintegrants such as crospovidone and sodium starch glycolate on disintegration time was studied. Crospovidone is an insoluble, neutral cross-linked homopolymer of N-vinyl-2-pyrrolidone. It is available in various particle sizes. The US Pharmacopeia defines sodium starch glycolate as the sodium salt of a carboxymethyl ether of starch or of a cross-linked carboxymethyl ether of starch5. Battu et al. studied the effect of varying concentrations of superdisintegrants such as croscarmellose sodium, sodium starch glycolate and crospovidone in fenoverine fast-disinintegrating tablets. They reported that the disintegration time of the best rapidly disintegrating tablet formulation among those tested was observed to be 15.9 s in vitro and 37.16 s in vivo which was formulated with crospovidone6. Ketoprofen is widely used for treatment of inflammation, pain or rheumatism. In conventional immediate release formulations, ketoprofen is rapidly and efficiently absorbed with peak plasma levels occurring within 0.5–2 h. The short half life and the low single-dose administration make ketoprofen a very good candidate for the formulation of modified dosage forms7. The objective of this study, is to develop a new solution by using a granulation process to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast-disintegrating properties of the formulation and to observe the effect of varying concentrations of two different superdisintegrants on disintegration time of the FDT formulation.
Experimental Materials Ketoprofen (Dolder, Germany), Eudragit EPO (Evonik Ro¨hm GmbH, Germany), Microcrystalline cellulose (Avicel PH 101; FMC Biopolymer, Philadelphia), Mannitol (Parteck Delta M, Merck, Germany), Aspartame (Deva Holding, Turkey), Aerosil (Evonik Ro¨hm GmbH, Germany), Polyvinyl povidon K-30 (Crospovidone; Fluka, Germany), Sodium starch glycolate (Explotab; JRS Pharma, Germany) and Magnesium stearate (Riedel de Haen, Germany).
Methods Micromeritic properties of taste-masked ketoprofen FDT blends Before compression, the mixture blends of all the formulations were subjected for pre-compression parameters such as bulk density, tapped density, Hausner ratio and compressibility index in order to compare the initial powder volume with the final (tapped) volume to predict the flowability of the FDT powder blends. Bulk density was determined by the USP method I; tapped density was determined by USP method II using a tapped density tester (Aymes, Turkey)5. Hausner ratio and compressibility index were calculated using Equations (1) and (2). Hausner ratio ¼ tapped density=bulk density
ð1Þ
Compressibility index % ¼ ðtapped density bulk densityÞ 100=tapped density ð2Þ Composition of ketoprofen FDTs and micromeritic properties of the FDT powder blends were given in Tables 1 and 2, respectively. Differential scanning calorimetry analysis Differential scanning calorimetry (DSC) analysis was performed with a Shimadzu apparatus equipped with a DSC 25 cell. Weighed samples (2 mg) of Ketoprofen, Eudragit EPO, Ketoprofen:Eudragit EPO physical mixture (drug:polymer ratio; 1:2) and Ketoprofen:Eudragit EPO taste-masked granules (drug:polymer ratio; 1:2) were scanned in Al pans pierced with a perforated lid at 10 C min1 in the 30–200 C temperature range, under static air8. Fourier transform infrared spectroscopy analysis Molecular properties on complexation were studied by Fourier transform infrared spectroscopy (FTIR). FTIR spectra of Ketoprofen, Eudragit EPO, Ketoprofen:Eudragit EPO physical mixture (drug:polymer ratio; 1:2) and Ketoprofen:Eudragit EPO taste-masked granules (drug:polymer ratio; 1:2) were obtained by KBr disc method9 (1:100 physical mixture; Shimadzu 8400S) in the range of 400–500 cm1. Preparation of taste-masked ketoprofen FDTs FDT formulations, containing 30 mg of ketoprofen were prepared with a two-stepped procedure in F3 and F4 formulations. In order
Ketoprofen fast-dissolving tablets 0.39 ± 0.11 0.55 ± 0.29 29.09 ± 0.27 1.41 ± 0.15 0.40 ± 0.28 0.54 ± 0.36 25.93 ± 0.26 1.35 ± 0.18 0.38 ± 0.22 0.53 ± 0.25 28.30 ± 0.15 1.39 ± 0.15
0.38 ± 0.15 0.54 ± 0.32 29.63 ± 0.27 1.42 ± 0.26
to prepare the taste-masked granules of ketoprofen in F3 and F4 formulations, Eudragit EPO was maintained at 50–55 C for 3 min in the oven and when Eudragit EPO started to melt, ketoprofen was added and mixed. This mixture was left to dry in the open air. The drug:taste masking agent ratio was maintained at 1:2. In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of taste-masking agent; Eudragit EPO10. In all the formulations (F1, F2, F3 and F4), formulation components other than the lubricant and glidant were accurately weighed and mixed in a cubic mixer (Erweka, Germany) for 15 min. The obtained blend was lubricated with magnesium stearate for another 5 min and the resultant mixture was directly compressed into tablets. The amount of all the tablet components other than superdisintegrants and mannitol (filler) were kept constant. Flat-faced tablets of 250 mg in weight and 11 mm in diameter were prepared utilizing an eccentric single punch tabletting machine (Korsch, Germany). Tablet thickness and hardness were maintained at 3.0 ± 0.1 mm and 3.5 ± 0.5 kg, respectively, for all of the formulations. Physical properties of FDT formulations were given in Table 3.
0.40 ± 0.21 0.54 ± 0.29 25.93 ± 0.22 1.35 ± 0.24 0.48 ± 0.28 0.66 ± 0.12 27.27 ± 0.19 1.38 ± 0.17
0.39 ± 0.32 0.54 ± 0.32 27.78 ± 0.31 1.38 ± 0.22
F4.2 F3.3 F3.2 F3.1 F2.3
3
Characterization of FDTs Weight variation Twenty FDT tablets were selected at random from each formulation and weighed individually (Sartorius BL 210S, Go¨ttingen, Germany). The individual weights were compared with the average weight for determination of weight variation. The diameter and thickness of FDTs (n ¼ 10) from each formulation were measured with a micrometer11.
The crushing tolerance of tablets, which is the force required to break a tablet by compression in the radial direction, was measured using a tablet hardness tester (Monsanto tablet hardness tester)12.
FDT formulations containing ketoprofen–Eudragit EPO taste-masked granules.
Measurement of friability
a
0.49 ± 0.23 0.68 ± 0.25 27.94 ± 0.26 1.39 ± 0.11 0.51 ± 0.19 0.64 ± 0.35 20.31 ± 0.24 1.25 ± 0.24 0.48 ± 0.21 0.64 ± 0.29 25.00 ± 0.09 1.33 ± 0.12 Bulk density (g/cm ) Tapped density (g/cm3) Compressibility (%) Hausner ratio
0.49 ± 0.22 0.64 ± 0.36 23.44 ± 0.11 1.31 ± 0.14
0.49 ± 0.24 0.66 ± 0.27 28.13 ± 0.20 1.35 ± 0.12
F2.2 F2.1 F1.1
F1.2
F1.3
3
F1
F2
Measurement of hardness
Table 2. Micromeritic properties of ketoprofen powder blends (n ¼ 3 ± SD).
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F4.1
F4a F3a
F4.3
DOI: 10.3109/10837450.2015.1022792
Ten tablets were weighed and put into the friabilitor (Roche Friabilitor, Ludwigshafen, Germany). Tablets were rotated at 25 rpm, then the friability percentage was calculated6. Measurement of wetting time and water absorption A piece of paper tissue (10.75 mm 12 mm) folded twice was placed in a culture dish (d ¼ 6.5 cm) containing 6 ml of water. A tablet was put on the paper, and the time for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R, was determined according to the following equation13: R ¼ 100 ðWa Wb Þ=Wb
ð3Þ
where Wa and Wb are the weight before and after water absorption, respectively. Determination of drug amount At the first step, 10 FDTs were weighed and finely powdered in a _ mortar (Ildam Kimya, Turkey). The average weight of a tablet was calculated. A sufficient quantity equivalent to the average weight of a tablet content was accurately weighed from the tablet powder and a little amount of ethyl alcohol was added to dissolve the active material and made up to the volume of 100 ml in a _ volumetric flask (Ildam Kimya, Turkey). It was sonicated for
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10 min and was filtered. Then 1 ml of this solution was taken and put into another volumetric flask. Then it was completed to 25 ml with pH 6.8 phosphate buffer and in this solution absorbance value at 261 nm was determined UV spectrophotometrically and with the aid of the calibration equation drug amount in the sample was calculated11. Dissolution studies In vitro drug release was determined using USP apparatus XXIV (paddle assembly) at 50 rpm maintained at 37 ± 5 C in 900 ml of pH 6.8 phosphate buffer as dissolution media. Percent drug release was determined by taking an aliquot of 5 ml at different time intervals, filtered through Whatmann filter paper and was assayed at 261 nm. An equal volume of fresh dissolution medium was replaced to maintain the original volume. The dissolution studies were carried out in triplicate14. Determination of taste of ketoprofen FDTs FDT formulations, containing physical mixture of ketoprofen and Eudragit EPO (F1.3 and F2.3) and containing tasted-masked ketoprofen–Eudragit EPO granules (F3.3 and F4.3) which have the highest superdisintegrant concentration (8%) were applied by a single blind study, based on taste comparison by nine volunteers from whom informed consent was obtained. Human volunteers selected for this study were aged between 25 and 40 years and were instructed to place the tablet on the center of their tongues. The FDT retained in the mouth for 30 s and then the mouth was thoroughly rinsed with distilled water. The next FDT formulation was tasted 10 min later. The volunteers were asked to evaluate the taste of the formulations as ‘‘very good, good, bitter or very bitter’’13.
Results and discussion
FDT formulations containing ketoprofen–Eudragit EPO taste-masked granules.
Physical properties of the tablet blend
a
F4.2 F2.2 F1.1
F1.3
F2.1 F1.2
F2.3
F3.1
F3.2
F3.3
F4.1
F4a F3a F2 F1
Table 3. Physical properties of ketoprofen FDT formulations (n ¼ 5 ± SD).
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Hardness (kg) 3.5 ± 0.21 3.5 ± 0.20 3.5 ± 0.03 3.8 ± 0.24 4.0 ± 0.24 3.5 ± 0.36 3.8 ± 0.21 4.0 ± 0.22 4.3 ± 0.31 4.4 ± 0.24 3.5 ± 0.24 4.0 ± 0.34 Friability (%) 0.24 ± 0.06 0.21 ± 0.11 0.22 ± 0.25 0.15 ± 0.25 0.17 ± 0.17 0.15 ± 0.20 0.32 ± 0.12 0.33 ± 0.25 0.28 ± 0.17 0.26 ± 0.20 0.24 ± 0.19 0.24 ± 0.29 Content uniformity (%) 101.92 ± 0.32 99.45 ± 0.34 100.03 ± 0.26 100.04 ± 0.36 99.97 ± 0.28 100.78 ± 0.26 99.83 ± 0.37 100.13 ± 0.26 101.57 ± 0.72 102.36 ± 0.27 100.59 ± 0.28 101.37 ± 0.31 Wetting time (s) 15.1 ± 0.13 12.5 ± 0.18 10.1 ± 0.21 12.4 ± 0.22 18.0 ± 0.14 25.2 ± 0.20 17.1 ± 0.17 16.9 ± 0.23 15.4 ± 0.24 18.0 ± 0.26 21.3 ± 0.25 24.2 ± 0.17 Water absorption (%) 65.35 ± 0.11 69.56 ± 0.11 65.47 ± 0.09 82.61 ± 0.16 81.82 ± 0.17 83.22 ± 0.24 94.27 ± 0.22 91.24 ± 0.23 92.41 ± 0.27 95.24 ± 0.19 95.83 ± 0.17 95.00 ± 0.11
Pharm Dev Technol, Early Online: 1–8
F4.3
4
Since, the flow properties of the powder mixture are important for the uniformity of mass of the tablets, the flow of the powder mixture was analyzed before compression to tablets. Low Hausner’s ratio (between 1.31 ± 0.14 and 1.42 ± 0.26), compressibility index (20.31 ± 0.24 to 29.63 ± 0.27) values indicated a fairly good flowability of powder mixture (Table 2). As the tablet powder mixture was free flowing, tablets produced were of uniform weight with acceptable weight variation (4.68%) due to uniform die fill. Hardness (3.5 ± 0.03 to 4.4 ± 0.24 kg/cm2) and friability loss (0.15 ± 0.20 to 0.33 ± 0.25%) indicated that tablets had a good mechanical resistance. Drug content was found to be high (99.45 ± 0.34 to 101.57 ± 72) and uniform in all the ketoprofen FDT formulations (Table 3). Characterization of ketoprofen–Eudragit EPO granules In order to investigate the interaction between ketoprofen and Eudragit EPO in FDT formulations, DSC thermograms of ketoprofen, Eudragit EPO and ketoprofen:Eudragit EPO physical mixture, ketoprofen:Eudragit EPO taste-masked granules were studied (Figure 1). Physical mixture of ketoprofen: Eudragit EPO (1:2) (Figure 1C) as well as taste-masked granules (Figure 1D) showed the characteristic sharp endothermic peak of ketoprofen which infers to a crystalline state for ketoprofen in FDT formulations15,16. Tg point for Eudragit EPO (55.6 C; Figure 2C) was observed in physical mixture; however for the taste-masked granules this peak disappeared due to the melting process of Eudragit EPO (Figure 2D). According to Eerikainen et al., the disappearance of Tg peak for Eudragit was explained with the interaction between ketoprofen and polymer. Acting as a
DOI: 10.3109/10837450.2015.1022792
Ketoprofen fast-dissolving tablets
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Figure 1. DSC thermograms of (A) ketoprofen, (B) Eudragit EPO, (C) ketoprofen: Eudragit EPO physical mixture (drug:polymer ratio 1:2) and (D) ketoprofen:Eudragit EPO tasted-masked granules (drug:polymer ratio 1:2).
plasticizer for the polymer, ketoprofen lowers the Tg point of Eudragit near room temperature, thus it could not be detected16. Contrarily, existence of sharp endothermic peak of ketoprofen with a little shifting (92.45 C) and the disappearance of Tg peak for Eudragit in DSC thermogram of taste-masked granules, was thought and related with the granulation process occurred between ketoprofen and Eudragit EPO. In order to investigate the molecular interaction between drug and polymer formulations, FTIR spectrums of ketoprofen, Eudragit EPO and ketoprofen:Eudragit EPO physical mixture, ketoprofen:Eudragit EPO taste-masked granules were also studied. Due to its carboxylic groups, ketoprofen can interact with the functional group of polymers. The carbonyl peaks in the IR spectra of ketoprofen was recorded at 1690 cm1 and 1650 cm1 in various literatures10,16,17 and have been assigned to dimeric –COOH carbonyl group and ketonic carbonyl group stretching vibrations, respectively16. As shown in Figure 2(A), a broad band of ketoprofen was observed for CH aromatic ring 3000 cm1, for acid C¼O at 1690 cm1 and for ketone C¼O at 1650 cm1. There is also a characteristic aromatic ring at 1589 cm1 and 1450 cm1 for ketoprofen. Eudragit EPO is a polymer which has strong stretching vibration of carbonyl moiety of ester groups at 1724 cm1 and also secondary amino groups which are capable of accepting proton from an acid molecule at 2820 cm1 and 2770 cm1 10,16,17. These characteristic bands of Eudragit EPO are also found in Figure 2(B). The –COOH groups of ketoprofen molecule should interact with the polymer at these characteristic bands and lead to a disruption of the –COOH dimer of the crystalline ketoprofen. This dimer formation by the –COOH groups of polymer and drug should be observed from the peaks 1700 cm1 16. Selection of the superdisintegrant and effect of superdisintegrant concentration on ketoprofen release The most important parameter that needs to be optimized in the development of FDTs is the wetting time of tablets as wetting is the first step of disintegration and dissolution. In the present study, wetting time for ketoprofen FDTs were determined as between 10.1 ± 0.21 and 24.2 ± 0.17 s fulfilling the official requirements (53 min) for orodispersible tablets. It is observed that tablets containing crospovidone, increasing level of crospovidone had an effect on the wetting times of the FDTs containing
ketoprofen–Eudragit EPO physical mixture or ketoprofen– Eudragit EPO granules. A decrease was noted in the wetting times with an increase in the crospovidone concentration (2–8%). However, wetting time increased (p50.05) with the increase in sodium starch glycolate concentration in FDTs. It indicates that an increase in the sodium starch glycolate concentration had a negative effect on the wetting time of the FDTs. At higher levels, formation of a viscous gel layer by sodium starch glycolate might have formed a thick barrier to the further penetration of the medium and hindered the wetting or leakage of tablet contents. Thus, tablet wetting is retarded to some extent with tablets containing sodium starch glycolate. The faster wetting of FDTs containing crospovidone may be attributed to its rapid capillary activity and pronounced hydration with little tendency to gel formation. Thus, these results suggest that the wetting times can be decreased by using wicking type of disintegrants (crospovidone). These results are in consistent with literature findings6,13,18. The influence of superdisintegrants on the dissolution of ketoprofen from the FDTs is shown in Figure 3 and Table 4. The in vitro dissolution studies stated that FDTs containing ketoprofen–Eudragit EPO granules (F3 and F4) did not affect on the rate of dissolution when compared with FDTs containing ketoprofen and Eudragit EPO as a physical mixture (F1 and F2). According to the t50% and t90% (time for 50% and 90% of drug release) values for FDTs, it is observed that superdisintegrants and their different concentrations (2%, 4% and 8%) affected the dissolution rate. t50% and t90% values increased (p50.05) with increase in the level of sodium starch glycolate. While t50% and t90% values did not change (p40.05) with the increase in the level of crospovidone. These results indicated that dissolution parameter values of crospovidone and sodium starch glycolate containing tablets are in consistent with the wetting time values observed. Taste-masking evaluation of ketoprofen FDTs Taste comparison of ketoprofen FDTs containing ketoprofen– Eudragit EPO either as a physical mixture (F1.3 and F2.3) or as a taste-masked granules (F3.3 and F4.3) were subjected in human volunteers and all the nine volunteers reported FDTs having ketoprofen–Eudragit EPO taste-masked granules as being ‘‘very good’’ on the perception scale and FDTs containing ketoprofen– Eudragit EPO as a physical mixture were also evaluated as
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(A) 250 %T 225 200 175 150 125 100 75
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50 4000
3750
3500
3250
3000
2750
2500
2250
2000
1750
1500
1250
1000
750
500
2000
1750
1500
1250
1000
750
500
2000
1750
1500
1250
1000
750
500
2000
1750
1500
1250
1000
750
500
1/cm
(B) 250 %T 225 200 175 150 125 100 75 50 4000
3750
3500
3250
3000
2750
2500
2250 1/cm
(C) 225 %T 200 175 150 125 100 75 50 4000
3750
3500
3250
3000
2750
2500
2250 1/cm
(D) 180 %T 160 140 120 100 80 60 40 4000
3750
3500
3250
3000
2750
2500
2250 1/cm
Figure 2. FTIR spectra of (A) ketoprofen, (B) Eudragit EPO, (C) ketoprofen: Eudragit EPO physical mixture (drug:polymer ratio 1:2) and (D) ketoprofen:Eudragit EPO tasted-masked granules (drug:polymer ratio 1:2).
Ketoprofen fast-dissolving tablets
DOI: 10.3109/10837450.2015.1022792
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Figure 3. Dissolution ketoprofen FDTs.
profiles
7
of
Table 4. In vitro dissolution parameters in pH 6.8 phosphate buffer (n ¼ 3). Code
D5 (%)a
D10 (%)a
D15%a
t50% (min)a
t90% (min)b
F1.1 F1.2 F1.3 F2.1 F2.2 F2.3 F3.1 F3.2 F3.3 F4.1 F4.2 F4.3
56.80 ± 2.52 66.78 ± 1.11 79.70 ± 3.91 12.74 ± 1.86 48.15 ± 2.87 59.69 ± 3.07 17.80 ± 1.46 20.12 ± 1.39 28.35 ± 1.03 7.13 ± 1.86 14.82 ± 2.91 26.10 ± 3.07
65.59 ± 1.15 81.82 ± 3.64 89.17 ± 1.94 86.16 ± 4.48 68.04 ± 0.68 78.43 ± 1.54 19.49 ± 3.12 33.87 ± 2.21 58.60 ± 2.42 53.82 ± 2.33 47.54 ± 2.75 38.23 ± 2.52
86.11 ± 2.64 90.59 ± 1.99 95.21 ± 2.31 94.82 ± 3.20 90.68 ± 2.08 87.72 ± 2.26 87.37 ± 1.23 90.75 ± 1.82 95.29 ± 1.56 95.09 ± 2.53 89.31 ± 1.23 85.10 ± 2.59
430 430 430 430 430 430 430 430 430 430 430 430
430 430 430 430 430 430 430 430 430 430 430 430
a
D5, D10, D15: percent of drug dissolved in 5, 10 and 15 min. t50%, t90% : time to dissolve 50% and 90% of drug from tablets.
b
Table 5. Evaluation of taste-masking effect of FDTs on selected formulations (n ¼ 9). Volunteer 1 2 3 4 5 6 7 8 9
F1.3
F2.3
F3.3
F4.3
Very good Good Good Good Good Good Good Very good Very good
Good Good Bitter Bitter Very good Very good Good Good Bitter
Very good Very good Very good Very good Very good Very good Very good Very good Good
Very good Very good Very good Very good Very good Very good Very good Very good Good
‘‘good’’ with one exception reported as ‘‘bitter taste’’ (Table 5). The taste-masking study of both FDTs with or without granulation process with the taste-masking agent revealed significant masking of bitter taste of ketoprofen, which F3.3 and F4.3 FDTs were found more promising.
Conclusion Pre-compressional parameters for ketoprofen FDTs indicated fair flow properties. Post-compressional parameters and in vitro
dissolution results were also studied. All the ketoprofen FDT formulations satisfied the requirements of FDA for rapid dissolving tablets and allowed 485% drug to be dissolved within 30 min (Table 4). Among the investigated superdisintegrants; crospovidone is found more effective with its highest tried concentration (8%). This result is attributed to its rapid capillary activity and pronounced hydration with little tendency to gel formation. Preparation of ketoprofen–Eudragit EPO taste-masked granules allowed a marked improvement of the initial drug taste in FDT formulations. The use of drug-Eudragit EPO granules are expected to enable FDTs with a better patient compliance. It is also determined that Eudragit EPO did not affect the dissolution rate. Finally, it can be told that a taste improvement can be maintained with drug-Eudragit EPO granulation procedure comparing with its physical mixture usage in FDT formulations. It is also concluded that superdsintegrants play a major role in FDTs, and crospovidone with a high concentration like 8% improves the wetting time of FDTs. Finally, it can be concluded that, the ‘‘patient-friendly dosage form’’ of bitter drugs, especially for pediatric, geriatric, bedridden and non-cooperative patients, can be successfully formulated using this novel drug-polymer granulation technique.
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Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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References 1. Goel H, Rai P, Rana V, Tiwary AK. Orally disintegrationg systems: innovations in formulation and technology. Recent Patents Drug Deliv Formul 2008;2:258–274. 2. Cumming KI, Harris E. Taste-masked formulations. US Patent 2000; 6,153,220. 3. Becicka BT, Michalson ET. Composition and method for taste masking. US Patent App 2006;11/451,622. 4. Camarco W, Ray D, Druffner A. Selecting superdisintegrants for orally disintegrating tablet formulations. Pharm Tech [Online] 2006. Available from: http://www.pharmtech.com/selecting-superdisintegrants-orally-disintegrating-tablet-formulations [last accessed 09 Jan 2015]. 5. The United States Pharmacopeia (24). Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2000. 6. Battu SK, Repka MA, Majumdar S, Madhusudan Rao Y. Formulation and evaluation of rapidly disintegrating fenoverine tablets: effect of superdisintegrants. Drug Dev Ind Pharm 2007;33: 1225–1232. 7. Comoglu T, Sava¸ser A, Ozkan Y, et al. Enhancement of ketoprofen bioavailability by formation of microsponge tablets. Pharmazie 2007;62:51–54. 8. Comoglu T, Unal B. Preparation and evaluation of an orally fast disintegrating tablet formulation containing a hydrophobic drug. Pharm Dev Technol 2015;20:60–64.
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9. Aydogan E, Comoglu T, Pehlivanoglu B, et al. Process and formulation variables of pregabalin microspheres prepared by w/o/o double emulsion solvent diffusion method and their clinical application by animal modeling studies. Drug Dev Ind Pharm [Early Online] 2014;1–10 .DOI:10.3109/ 03639045.2014.948452. 10. Jyothi Rani L, Abbulu K, Nagabushan Rao T, Akhila A. Formulation and evaluation of fast dissolving tablets of lornoxicam. Int J Pharm 2013;3:579–586. 11. Comoglu T. Formulation and evaluation of carbamazepine fast disintegrating tablets. Pharma Indus 2010;72:150–158. 12. Prasad BBSG, Gupta VRM, Subramanian NS, et al. Formulation and evaluation of taste masked orodispersible tablets of amlodipine besylate by direct compression. Int Res J Pharm 2013;4:123–130. 13. Kulkarni AP, Khedkar AB, Lahotib SR, Dehghanb MHD. Development of oral disintegrating tablet of rizatriptan benzoate with inhibited bitter taste. Am Euroasian J Sci Res 2012;7:47–57. 14. Mishra DN, Bindal M, Singh SK, Vijaya Kumar SG. Spray dried excipient base: a novel technique for the formulation of orally disintegrating tablets. Chem Pharm Bull 2006;54:99–102. 15. Vittal GV, Deveswaran R, Bharath S, et al. Formulation and characterization of ketoprofen liquisolid compacts by Box-Behnken design. Int J Pharm Investig 2012;2:150–156. 16. Eerikainen H, Peltonen L, Raula J, et al. Nanoparticles containing ketoprofen and acrylic polymers prepared by an aerosol flow reactor method. AAPS PharmSciTech 2004;5:Article 68. 17. Khan S, Kataria P, Nakhat P, Yeole P. Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapiddisintegrating tablets. AAPS PharmSciTech 2007;8:Article 46. 18. Mallijarkuna Setty C, Prasad DVK, Gupta VRM, Sa B. Development of fast dispersible aceclofenac tablets: effect of functional superdisintegrants. Indian J Pharm Sci 2008;70:180–185.
RESEARCH ARTICLE
Formulation and in vitro evaluation of ketoprofen fast-dissolving tablets Pharmaceutical Development and Technology Downloaded from informahealthcare.com by Universite De Sherbrooke on 04/10/15 For personal use only.
Tansel Comoglu, Ozge Inal, and Hajar Ben Yaacoub Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara University, Tandogan, Ankara, Turkey
Abstract
Keywords
Drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated as orally fast-disintegrating tablets (FDTs or ODTs). Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Despite advances in the FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast-disintegrating properties of the formulation. The unpleasant taste of the active drug usually masked by adding flavoring ingredients and sweeteners to improve taste and palatability but in this study a novel approach of using a polymer; Eudragit EPO and a granulation procedure of this polymer with the active drug was applied to mask the bitter taste of ketoprofen. In order to produce ketoprofen FDT formulations, a two-stepped procedure was followed; granulation process with the taste-masking agent (Eudragit EPO) and then direct compression (F3 and F4). In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of Eudragit EPO. As well as observing the effect of taste-masking agent, crospovidone and sodium starch glycolate were used in different concentrations (2, 4 and 8wt%) to examine the influence of superdisintegrants on FDT properties. All the FDTs containing 30 mg ketoprofen (F1, F2, F3 and F4) were evaluated by means of in vitro quality control tests.
Crospovidone, Eudragit EPO, ketoprofen, orally fast-disintegrating tablets, sodium starch glycolate, superdisintegrants, taste masking
Introduction In recent decades, a variety of pharmaceutical research has been conducted to develop new dosage forms. Considering quality of life, most of these efforts have been focused on ease of medication. Among the dosage forms developed to facilitate ease of medication, the orally fast-disintegrating tablet (FDT) is one of the most widely employed commercial products. FDTs are useful in patients, such as pediatric, geriatric, bedridden or developmentally disabled, who may face difficulty in swallowing conventional tablets or capsules and liquid orals or syrup, leading to ineffective therapy, with persistent nausea, sudden episodes of allergic attacks or coughing for those who have an active life style. The FDTs could be suitable for analgesics, neuroleptics, cardio vascular agents, antiallergics and drugs for erectile dysfunction1. The FDT has remarkable disintegration properties; it can rapidly disintegrate without water in the mouth within a few seconds. When an FDT is placed in the oral cavity, saliva quickly penetrates into the pores causing rapid disintegration. Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Undesirable taste is one of the important formulation problems that are encountered with many drugs. Despite advances in the
Address for correspondence: Tansel Comoglu, Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara University, 06100 Tandogan/Ankara, Turkey. Tel: +90 312 203 3164. E-mail: [email protected]
History Received 13 January 2015 Revised 19 February 2015 Accepted 20 February 2015 Published online 23 March 2015
FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. Tastemasking technologies are increasingly focused on aggressively bitter-tasting drugs such as the macrolide antibiotics, nonsteroidal anti-inflammatory drugs and penicillins. Taste masking of water-soluble bitter drugs, especially those with a high dose, is difficult to achieve by using sweeteners alone. As a consequence, more efficient techniques such as coating, microencapsulation and granulation have been used in combination with the sweeteners. Various investigators have patented orally disintegrating/dissolving systems containing taste-masked drugs1. Cumming et al.2 patented a taste-masked micro-matrix powder in which the ratio of a polymer compared to a drug having poor organoleptic properties was 6:1. Taste cationic masking can also be done by using Eudragit L-100 by employing drug:polymer ratio of 10:1. However, taste-masked micro-matrix powder prepared from cationic polymer is reported to be superior to that produced by using methacrylates. Becicka et al.3 patented a method for masking the taste of bitter pharmacological active ingredients. Dibutyl sebacate, water, ethylcellulose and polyethylene glycol were mixed and then loperamide HCl and cationic resin (Amberlite) were added to form a homogenous mixture. The granules of this mixture were prepared using rotary evaporator under vacuum at a temperature of 65 C. The dried granules were sieved and could be used for the preparation of orally fast-disintegrating dosage forms. The key parameters that are to be considered in the process of formulating a FDT are the taste and disintegration time. To achieve rapid disintegration, direct-compression FDT
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Table 1. Basic composition of ketoprofen FDT formulations.
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F1a
F2a
F3b
F4b
Ingredients (mg)
F1.1
F1.2
F1.3
F2.1
F2.2
F2.3
F3.1
F3.2
F3.3
F4.1
F4.2
F4.3
Ketoprofen Avicel PH 101 Eudragit EPO Mannitol Aerosil Magnesium stearate Crospovidone Sodium starch glycolate Aspartame Total
30 83 60 57.2 1.4 1.4 5 – 12 250
30 83 60 52.2 1.4 1.4 10 – 12 250
30 83 60 42.2 1.4 1.4 20 – 12 250
30 83 60 57.2 1.4 1.4 – 5 12 250
30 83 60 52.2 1.4 1.4 – 10 12 250
30 83 60 42.2 1.4 1.4 – 20 12 250
30 83 60 57.2 1.4 1.4 5 – 12 250
30 83 60 52.2 1.4 1.4 10 – 12 250
30 83 60 42.2 1.4 1.4 20 – 12 250
30 83 60 57.2 1.4 1.4 – 5 12 250
30 83 60 52.2 1.4 1.4 – 10 12 250
30 83 60 42.2 1.4 1.4 – 20 12 250
a
Contain pure ketoprofen–Eudragit EPO. Contain ketoprofen after the granulation process with Eudragit EPO.
b
formulations typically contain high levels of a superdisintegrant. Depending on the level and characteristics of the active pharmaceutical ingredient (API) and the desired release profile, the levels of superdisintegrant used can be 10–20 wt% of the formulation, and it can be higher or lower in some cases. Thus, in developing a FDT formulation for direct compression, choosing the optimal superdisintegrant is critical. Although the superdisintegrant primarily affects the rate of disintegration, when used at high levels it can also affect mouth feel, tablet hardness and friability4. In our study, effect of varying concentrations of different superdisintegrants such as crospovidone and sodium starch glycolate on disintegration time was studied. Crospovidone is an insoluble, neutral cross-linked homopolymer of N-vinyl-2-pyrrolidone. It is available in various particle sizes. The US Pharmacopeia defines sodium starch glycolate as the sodium salt of a carboxymethyl ether of starch or of a cross-linked carboxymethyl ether of starch5. Battu et al. studied the effect of varying concentrations of superdisintegrants such as croscarmellose sodium, sodium starch glycolate and crospovidone in fenoverine fast-disinintegrating tablets. They reported that the disintegration time of the best rapidly disintegrating tablet formulation among those tested was observed to be 15.9 s in vitro and 37.16 s in vivo which was formulated with crospovidone6. Ketoprofen is widely used for treatment of inflammation, pain or rheumatism. In conventional immediate release formulations, ketoprofen is rapidly and efficiently absorbed with peak plasma levels occurring within 0.5–2 h. The short half life and the low single-dose administration make ketoprofen a very good candidate for the formulation of modified dosage forms7. The objective of this study, is to develop a new solution by using a granulation process to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast-disintegrating properties of the formulation and to observe the effect of varying concentrations of two different superdisintegrants on disintegration time of the FDT formulation.
Experimental Materials Ketoprofen (Dolder, Germany), Eudragit EPO (Evonik Ro¨hm GmbH, Germany), Microcrystalline cellulose (Avicel PH 101; FMC Biopolymer, Philadelphia), Mannitol (Parteck Delta M, Merck, Germany), Aspartame (Deva Holding, Turkey), Aerosil (Evonik Ro¨hm GmbH, Germany), Polyvinyl povidon K-30 (Crospovidone; Fluka, Germany), Sodium starch glycolate (Explotab; JRS Pharma, Germany) and Magnesium stearate (Riedel de Haen, Germany).
Methods Micromeritic properties of taste-masked ketoprofen FDT blends Before compression, the mixture blends of all the formulations were subjected for pre-compression parameters such as bulk density, tapped density, Hausner ratio and compressibility index in order to compare the initial powder volume with the final (tapped) volume to predict the flowability of the FDT powder blends. Bulk density was determined by the USP method I; tapped density was determined by USP method II using a tapped density tester (Aymes, Turkey)5. Hausner ratio and compressibility index were calculated using Equations (1) and (2). Hausner ratio ¼ tapped density=bulk density
ð1Þ
Compressibility index % ¼ ðtapped density bulk densityÞ 100=tapped density ð2Þ Composition of ketoprofen FDTs and micromeritic properties of the FDT powder blends were given in Tables 1 and 2, respectively. Differential scanning calorimetry analysis Differential scanning calorimetry (DSC) analysis was performed with a Shimadzu apparatus equipped with a DSC 25 cell. Weighed samples (2 mg) of Ketoprofen, Eudragit EPO, Ketoprofen:Eudragit EPO physical mixture (drug:polymer ratio; 1:2) and Ketoprofen:Eudragit EPO taste-masked granules (drug:polymer ratio; 1:2) were scanned in Al pans pierced with a perforated lid at 10 C min1 in the 30–200 C temperature range, under static air8. Fourier transform infrared spectroscopy analysis Molecular properties on complexation were studied by Fourier transform infrared spectroscopy (FTIR). FTIR spectra of Ketoprofen, Eudragit EPO, Ketoprofen:Eudragit EPO physical mixture (drug:polymer ratio; 1:2) and Ketoprofen:Eudragit EPO taste-masked granules (drug:polymer ratio; 1:2) were obtained by KBr disc method9 (1:100 physical mixture; Shimadzu 8400S) in the range of 400–500 cm1. Preparation of taste-masked ketoprofen FDTs FDT formulations, containing 30 mg of ketoprofen were prepared with a two-stepped procedure in F3 and F4 formulations. In order
Ketoprofen fast-dissolving tablets 0.39 ± 0.11 0.55 ± 0.29 29.09 ± 0.27 1.41 ± 0.15 0.40 ± 0.28 0.54 ± 0.36 25.93 ± 0.26 1.35 ± 0.18 0.38 ± 0.22 0.53 ± 0.25 28.30 ± 0.15 1.39 ± 0.15
0.38 ± 0.15 0.54 ± 0.32 29.63 ± 0.27 1.42 ± 0.26
to prepare the taste-masked granules of ketoprofen in F3 and F4 formulations, Eudragit EPO was maintained at 50–55 C for 3 min in the oven and when Eudragit EPO started to melt, ketoprofen was added and mixed. This mixture was left to dry in the open air. The drug:taste masking agent ratio was maintained at 1:2. In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of taste-masking agent; Eudragit EPO10. In all the formulations (F1, F2, F3 and F4), formulation components other than the lubricant and glidant were accurately weighed and mixed in a cubic mixer (Erweka, Germany) for 15 min. The obtained blend was lubricated with magnesium stearate for another 5 min and the resultant mixture was directly compressed into tablets. The amount of all the tablet components other than superdisintegrants and mannitol (filler) were kept constant. Flat-faced tablets of 250 mg in weight and 11 mm in diameter were prepared utilizing an eccentric single punch tabletting machine (Korsch, Germany). Tablet thickness and hardness were maintained at 3.0 ± 0.1 mm and 3.5 ± 0.5 kg, respectively, for all of the formulations. Physical properties of FDT formulations were given in Table 3.
0.40 ± 0.21 0.54 ± 0.29 25.93 ± 0.22 1.35 ± 0.24 0.48 ± 0.28 0.66 ± 0.12 27.27 ± 0.19 1.38 ± 0.17
0.39 ± 0.32 0.54 ± 0.32 27.78 ± 0.31 1.38 ± 0.22
F4.2 F3.3 F3.2 F3.1 F2.3
3
Characterization of FDTs Weight variation Twenty FDT tablets were selected at random from each formulation and weighed individually (Sartorius BL 210S, Go¨ttingen, Germany). The individual weights were compared with the average weight for determination of weight variation. The diameter and thickness of FDTs (n ¼ 10) from each formulation were measured with a micrometer11.
The crushing tolerance of tablets, which is the force required to break a tablet by compression in the radial direction, was measured using a tablet hardness tester (Monsanto tablet hardness tester)12.
FDT formulations containing ketoprofen–Eudragit EPO taste-masked granules.
Measurement of friability
a
0.49 ± 0.23 0.68 ± 0.25 27.94 ± 0.26 1.39 ± 0.11 0.51 ± 0.19 0.64 ± 0.35 20.31 ± 0.24 1.25 ± 0.24 0.48 ± 0.21 0.64 ± 0.29 25.00 ± 0.09 1.33 ± 0.12 Bulk density (g/cm ) Tapped density (g/cm3) Compressibility (%) Hausner ratio
0.49 ± 0.22 0.64 ± 0.36 23.44 ± 0.11 1.31 ± 0.14
0.49 ± 0.24 0.66 ± 0.27 28.13 ± 0.20 1.35 ± 0.12
F2.2 F2.1 F1.1
F1.2
F1.3
3
F1
F2
Measurement of hardness
Table 2. Micromeritic properties of ketoprofen powder blends (n ¼ 3 ± SD).
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F4.1
F4a F3a
F4.3
DOI: 10.3109/10837450.2015.1022792
Ten tablets were weighed and put into the friabilitor (Roche Friabilitor, Ludwigshafen, Germany). Tablets were rotated at 25 rpm, then the friability percentage was calculated6. Measurement of wetting time and water absorption A piece of paper tissue (10.75 mm 12 mm) folded twice was placed in a culture dish (d ¼ 6.5 cm) containing 6 ml of water. A tablet was put on the paper, and the time for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R, was determined according to the following equation13: R ¼ 100 ðWa Wb Þ=Wb
ð3Þ
where Wa and Wb are the weight before and after water absorption, respectively. Determination of drug amount At the first step, 10 FDTs were weighed and finely powdered in a _ mortar (Ildam Kimya, Turkey). The average weight of a tablet was calculated. A sufficient quantity equivalent to the average weight of a tablet content was accurately weighed from the tablet powder and a little amount of ethyl alcohol was added to dissolve the active material and made up to the volume of 100 ml in a _ volumetric flask (Ildam Kimya, Turkey). It was sonicated for
T. Comoglu et al.
10 min and was filtered. Then 1 ml of this solution was taken and put into another volumetric flask. Then it was completed to 25 ml with pH 6.8 phosphate buffer and in this solution absorbance value at 261 nm was determined UV spectrophotometrically and with the aid of the calibration equation drug amount in the sample was calculated11. Dissolution studies In vitro drug release was determined using USP apparatus XXIV (paddle assembly) at 50 rpm maintained at 37 ± 5 C in 900 ml of pH 6.8 phosphate buffer as dissolution media. Percent drug release was determined by taking an aliquot of 5 ml at different time intervals, filtered through Whatmann filter paper and was assayed at 261 nm. An equal volume of fresh dissolution medium was replaced to maintain the original volume. The dissolution studies were carried out in triplicate14. Determination of taste of ketoprofen FDTs FDT formulations, containing physical mixture of ketoprofen and Eudragit EPO (F1.3 and F2.3) and containing tasted-masked ketoprofen–Eudragit EPO granules (F3.3 and F4.3) which have the highest superdisintegrant concentration (8%) were applied by a single blind study, based on taste comparison by nine volunteers from whom informed consent was obtained. Human volunteers selected for this study were aged between 25 and 40 years and were instructed to place the tablet on the center of their tongues. The FDT retained in the mouth for 30 s and then the mouth was thoroughly rinsed with distilled water. The next FDT formulation was tasted 10 min later. The volunteers were asked to evaluate the taste of the formulations as ‘‘very good, good, bitter or very bitter’’13.
Results and discussion
FDT formulations containing ketoprofen–Eudragit EPO taste-masked granules.
Physical properties of the tablet blend
a
F4.2 F2.2 F1.1
F1.3
F2.1 F1.2
F2.3
F3.1
F3.2
F3.3
F4.1
F4a F3a F2 F1
Table 3. Physical properties of ketoprofen FDT formulations (n ¼ 5 ± SD).
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Hardness (kg) 3.5 ± 0.21 3.5 ± 0.20 3.5 ± 0.03 3.8 ± 0.24 4.0 ± 0.24 3.5 ± 0.36 3.8 ± 0.21 4.0 ± 0.22 4.3 ± 0.31 4.4 ± 0.24 3.5 ± 0.24 4.0 ± 0.34 Friability (%) 0.24 ± 0.06 0.21 ± 0.11 0.22 ± 0.25 0.15 ± 0.25 0.17 ± 0.17 0.15 ± 0.20 0.32 ± 0.12 0.33 ± 0.25 0.28 ± 0.17 0.26 ± 0.20 0.24 ± 0.19 0.24 ± 0.29 Content uniformity (%) 101.92 ± 0.32 99.45 ± 0.34 100.03 ± 0.26 100.04 ± 0.36 99.97 ± 0.28 100.78 ± 0.26 99.83 ± 0.37 100.13 ± 0.26 101.57 ± 0.72 102.36 ± 0.27 100.59 ± 0.28 101.37 ± 0.31 Wetting time (s) 15.1 ± 0.13 12.5 ± 0.18 10.1 ± 0.21 12.4 ± 0.22 18.0 ± 0.14 25.2 ± 0.20 17.1 ± 0.17 16.9 ± 0.23 15.4 ± 0.24 18.0 ± 0.26 21.3 ± 0.25 24.2 ± 0.17 Water absorption (%) 65.35 ± 0.11 69.56 ± 0.11 65.47 ± 0.09 82.61 ± 0.16 81.82 ± 0.17 83.22 ± 0.24 94.27 ± 0.22 91.24 ± 0.23 92.41 ± 0.27 95.24 ± 0.19 95.83 ± 0.17 95.00 ± 0.11
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F4.3
4
Since, the flow properties of the powder mixture are important for the uniformity of mass of the tablets, the flow of the powder mixture was analyzed before compression to tablets. Low Hausner’s ratio (between 1.31 ± 0.14 and 1.42 ± 0.26), compressibility index (20.31 ± 0.24 to 29.63 ± 0.27) values indicated a fairly good flowability of powder mixture (Table 2). As the tablet powder mixture was free flowing, tablets produced were of uniform weight with acceptable weight variation (4.68%) due to uniform die fill. Hardness (3.5 ± 0.03 to 4.4 ± 0.24 kg/cm2) and friability loss (0.15 ± 0.20 to 0.33 ± 0.25%) indicated that tablets had a good mechanical resistance. Drug content was found to be high (99.45 ± 0.34 to 101.57 ± 72) and uniform in all the ketoprofen FDT formulations (Table 3). Characterization of ketoprofen–Eudragit EPO granules In order to investigate the interaction between ketoprofen and Eudragit EPO in FDT formulations, DSC thermograms of ketoprofen, Eudragit EPO and ketoprofen:Eudragit EPO physical mixture, ketoprofen:Eudragit EPO taste-masked granules were studied (Figure 1). Physical mixture of ketoprofen: Eudragit EPO (1:2) (Figure 1C) as well as taste-masked granules (Figure 1D) showed the characteristic sharp endothermic peak of ketoprofen which infers to a crystalline state for ketoprofen in FDT formulations15,16. Tg point for Eudragit EPO (55.6 C; Figure 2C) was observed in physical mixture; however for the taste-masked granules this peak disappeared due to the melting process of Eudragit EPO (Figure 2D). According to Eerikainen et al., the disappearance of Tg peak for Eudragit was explained with the interaction between ketoprofen and polymer. Acting as a
DOI: 10.3109/10837450.2015.1022792
Ketoprofen fast-dissolving tablets
5
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Figure 1. DSC thermograms of (A) ketoprofen, (B) Eudragit EPO, (C) ketoprofen: Eudragit EPO physical mixture (drug:polymer ratio 1:2) and (D) ketoprofen:Eudragit EPO tasted-masked granules (drug:polymer ratio 1:2).
plasticizer for the polymer, ketoprofen lowers the Tg point of Eudragit near room temperature, thus it could not be detected16. Contrarily, existence of sharp endothermic peak of ketoprofen with a little shifting (92.45 C) and the disappearance of Tg peak for Eudragit in DSC thermogram of taste-masked granules, was thought and related with the granulation process occurred between ketoprofen and Eudragit EPO. In order to investigate the molecular interaction between drug and polymer formulations, FTIR spectrums of ketoprofen, Eudragit EPO and ketoprofen:Eudragit EPO physical mixture, ketoprofen:Eudragit EPO taste-masked granules were also studied. Due to its carboxylic groups, ketoprofen can interact with the functional group of polymers. The carbonyl peaks in the IR spectra of ketoprofen was recorded at 1690 cm1 and 1650 cm1 in various literatures10,16,17 and have been assigned to dimeric –COOH carbonyl group and ketonic carbonyl group stretching vibrations, respectively16. As shown in Figure 2(A), a broad band of ketoprofen was observed for CH aromatic ring 3000 cm1, for acid C¼O at 1690 cm1 and for ketone C¼O at 1650 cm1. There is also a characteristic aromatic ring at 1589 cm1 and 1450 cm1 for ketoprofen. Eudragit EPO is a polymer which has strong stretching vibration of carbonyl moiety of ester groups at 1724 cm1 and also secondary amino groups which are capable of accepting proton from an acid molecule at 2820 cm1 and 2770 cm1 10,16,17. These characteristic bands of Eudragit EPO are also found in Figure 2(B). The –COOH groups of ketoprofen molecule should interact with the polymer at these characteristic bands and lead to a disruption of the –COOH dimer of the crystalline ketoprofen. This dimer formation by the –COOH groups of polymer and drug should be observed from the peaks 1700 cm1 16. Selection of the superdisintegrant and effect of superdisintegrant concentration on ketoprofen release The most important parameter that needs to be optimized in the development of FDTs is the wetting time of tablets as wetting is the first step of disintegration and dissolution. In the present study, wetting time for ketoprofen FDTs were determined as between 10.1 ± 0.21 and 24.2 ± 0.17 s fulfilling the official requirements (53 min) for orodispersible tablets. It is observed that tablets containing crospovidone, increasing level of crospovidone had an effect on the wetting times of the FDTs containing
ketoprofen–Eudragit EPO physical mixture or ketoprofen– Eudragit EPO granules. A decrease was noted in the wetting times with an increase in the crospovidone concentration (2–8%). However, wetting time increased (p50.05) with the increase in sodium starch glycolate concentration in FDTs. It indicates that an increase in the sodium starch glycolate concentration had a negative effect on the wetting time of the FDTs. At higher levels, formation of a viscous gel layer by sodium starch glycolate might have formed a thick barrier to the further penetration of the medium and hindered the wetting or leakage of tablet contents. Thus, tablet wetting is retarded to some extent with tablets containing sodium starch glycolate. The faster wetting of FDTs containing crospovidone may be attributed to its rapid capillary activity and pronounced hydration with little tendency to gel formation. Thus, these results suggest that the wetting times can be decreased by using wicking type of disintegrants (crospovidone). These results are in consistent with literature findings6,13,18. The influence of superdisintegrants on the dissolution of ketoprofen from the FDTs is shown in Figure 3 and Table 4. The in vitro dissolution studies stated that FDTs containing ketoprofen–Eudragit EPO granules (F3 and F4) did not affect on the rate of dissolution when compared with FDTs containing ketoprofen and Eudragit EPO as a physical mixture (F1 and F2). According to the t50% and t90% (time for 50% and 90% of drug release) values for FDTs, it is observed that superdisintegrants and their different concentrations (2%, 4% and 8%) affected the dissolution rate. t50% and t90% values increased (p50.05) with increase in the level of sodium starch glycolate. While t50% and t90% values did not change (p40.05) with the increase in the level of crospovidone. These results indicated that dissolution parameter values of crospovidone and sodium starch glycolate containing tablets are in consistent with the wetting time values observed. Taste-masking evaluation of ketoprofen FDTs Taste comparison of ketoprofen FDTs containing ketoprofen– Eudragit EPO either as a physical mixture (F1.3 and F2.3) or as a taste-masked granules (F3.3 and F4.3) were subjected in human volunteers and all the nine volunteers reported FDTs having ketoprofen–Eudragit EPO taste-masked granules as being ‘‘very good’’ on the perception scale and FDTs containing ketoprofen– Eudragit EPO as a physical mixture were also evaluated as
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(A) 250 %T 225 200 175 150 125 100 75
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Figure 2. FTIR spectra of (A) ketoprofen, (B) Eudragit EPO, (C) ketoprofen: Eudragit EPO physical mixture (drug:polymer ratio 1:2) and (D) ketoprofen:Eudragit EPO tasted-masked granules (drug:polymer ratio 1:2).
Ketoprofen fast-dissolving tablets
DOI: 10.3109/10837450.2015.1022792
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Figure 3. Dissolution ketoprofen FDTs.
profiles
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of
Table 4. In vitro dissolution parameters in pH 6.8 phosphate buffer (n ¼ 3). Code
D5 (%)a
D10 (%)a
D15%a
t50% (min)a
t90% (min)b
F1.1 F1.2 F1.3 F2.1 F2.2 F2.3 F3.1 F3.2 F3.3 F4.1 F4.2 F4.3
56.80 ± 2.52 66.78 ± 1.11 79.70 ± 3.91 12.74 ± 1.86 48.15 ± 2.87 59.69 ± 3.07 17.80 ± 1.46 20.12 ± 1.39 28.35 ± 1.03 7.13 ± 1.86 14.82 ± 2.91 26.10 ± 3.07
65.59 ± 1.15 81.82 ± 3.64 89.17 ± 1.94 86.16 ± 4.48 68.04 ± 0.68 78.43 ± 1.54 19.49 ± 3.12 33.87 ± 2.21 58.60 ± 2.42 53.82 ± 2.33 47.54 ± 2.75 38.23 ± 2.52
86.11 ± 2.64 90.59 ± 1.99 95.21 ± 2.31 94.82 ± 3.20 90.68 ± 2.08 87.72 ± 2.26 87.37 ± 1.23 90.75 ± 1.82 95.29 ± 1.56 95.09 ± 2.53 89.31 ± 1.23 85.10 ± 2.59
430 430 430 430 430 430 430 430 430 430 430 430
430 430 430 430 430 430 430 430 430 430 430 430
a
D5, D10, D15: percent of drug dissolved in 5, 10 and 15 min. t50%, t90% : time to dissolve 50% and 90% of drug from tablets.
b
Table 5. Evaluation of taste-masking effect of FDTs on selected formulations (n ¼ 9). Volunteer 1 2 3 4 5 6 7 8 9
F1.3
F2.3
F3.3
F4.3
Very good Good Good Good Good Good Good Very good Very good
Good Good Bitter Bitter Very good Very good Good Good Bitter
Very good Very good Very good Very good Very good Very good Very good Very good Good
Very good Very good Very good Very good Very good Very good Very good Very good Good
‘‘good’’ with one exception reported as ‘‘bitter taste’’ (Table 5). The taste-masking study of both FDTs with or without granulation process with the taste-masking agent revealed significant masking of bitter taste of ketoprofen, which F3.3 and F4.3 FDTs were found more promising.
Conclusion Pre-compressional parameters for ketoprofen FDTs indicated fair flow properties. Post-compressional parameters and in vitro
dissolution results were also studied. All the ketoprofen FDT formulations satisfied the requirements of FDA for rapid dissolving tablets and allowed 485% drug to be dissolved within 30 min (Table 4). Among the investigated superdisintegrants; crospovidone is found more effective with its highest tried concentration (8%). This result is attributed to its rapid capillary activity and pronounced hydration with little tendency to gel formation. Preparation of ketoprofen–Eudragit EPO taste-masked granules allowed a marked improvement of the initial drug taste in FDT formulations. The use of drug-Eudragit EPO granules are expected to enable FDTs with a better patient compliance. It is also determined that Eudragit EPO did not affect the dissolution rate. Finally, it can be told that a taste improvement can be maintained with drug-Eudragit EPO granulation procedure comparing with its physical mixture usage in FDT formulations. It is also concluded that superdsintegrants play a major role in FDTs, and crospovidone with a high concentration like 8% improves the wetting time of FDTs. Finally, it can be concluded that, the ‘‘patient-friendly dosage form’’ of bitter drugs, especially for pediatric, geriatric, bedridden and non-cooperative patients, can be successfully formulated using this novel drug-polymer granulation technique.
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Declaration of interest The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.
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References 1. Goel H, Rai P, Rana V, Tiwary AK. Orally disintegrationg systems: innovations in formulation and technology. Recent Patents Drug Deliv Formul 2008;2:258–274. 2. Cumming KI, Harris E. Taste-masked formulations. US Patent 2000; 6,153,220. 3. Becicka BT, Michalson ET. Composition and method for taste masking. US Patent App 2006;11/451,622. 4. Camarco W, Ray D, Druffner A. Selecting superdisintegrants for orally disintegrating tablet formulations. Pharm Tech [Online] 2006. Available from: http://www.pharmtech.com/selecting-superdisintegrants-orally-disintegrating-tablet-formulations [last accessed 09 Jan 2015]. 5. The United States Pharmacopeia (24). Rockville, MD: The United States Pharmacopeial Convention, Inc.; 2000. 6. Battu SK, Repka MA, Majumdar S, Madhusudan Rao Y. Formulation and evaluation of rapidly disintegrating fenoverine tablets: effect of superdisintegrants. Drug Dev Ind Pharm 2007;33: 1225–1232. 7. Comoglu T, Sava¸ser A, Ozkan Y, et al. Enhancement of ketoprofen bioavailability by formation of microsponge tablets. Pharmazie 2007;62:51–54. 8. Comoglu T, Unal B. Preparation and evaluation of an orally fast disintegrating tablet formulation containing a hydrophobic drug. Pharm Dev Technol 2015;20:60–64.
Pharm Dev Technol, Early Online: 1–8
9. Aydogan E, Comoglu T, Pehlivanoglu B, et al. Process and formulation variables of pregabalin microspheres prepared by w/o/o double emulsion solvent diffusion method and their clinical application by animal modeling studies. Drug Dev Ind Pharm [Early Online] 2014;1–10 .DOI:10.3109/ 03639045.2014.948452. 10. Jyothi Rani L, Abbulu K, Nagabushan Rao T, Akhila A. Formulation and evaluation of fast dissolving tablets of lornoxicam. Int J Pharm 2013;3:579–586. 11. Comoglu T. Formulation and evaluation of carbamazepine fast disintegrating tablets. Pharma Indus 2010;72:150–158. 12. Prasad BBSG, Gupta VRM, Subramanian NS, et al. Formulation and evaluation of taste masked orodispersible tablets of amlodipine besylate by direct compression. Int Res J Pharm 2013;4:123–130. 13. Kulkarni AP, Khedkar AB, Lahotib SR, Dehghanb MHD. Development of oral disintegrating tablet of rizatriptan benzoate with inhibited bitter taste. Am Euroasian J Sci Res 2012;7:47–57. 14. Mishra DN, Bindal M, Singh SK, Vijaya Kumar SG. Spray dried excipient base: a novel technique for the formulation of orally disintegrating tablets. Chem Pharm Bull 2006;54:99–102. 15. Vittal GV, Deveswaran R, Bharath S, et al. Formulation and characterization of ketoprofen liquisolid compacts by Box-Behnken design. Int J Pharm Investig 2012;2:150–156. 16. Eerikainen H, Peltonen L, Raula J, et al. Nanoparticles containing ketoprofen and acrylic polymers prepared by an aerosol flow reactor method. AAPS PharmSciTech 2004;5:Article 68. 17. Khan S, Kataria P, Nakhat P, Yeole P. Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapiddisintegrating tablets. AAPS PharmSciTech 2007;8:Article 46. 18. Mallijarkuna Setty C, Prasad DVK, Gupta VRM, Sa B. Development of fast dispersible aceclofenac tablets: effect of functional superdisintegrants. Indian J Pharm Sci 2008;70:180–185.
