Design and Development of Taste Masked Cefpodoxime Dispersible Tablets

Suriyaprakash TNK^*, Sumathi Arumugam, Soumya Sreejith

¹Department of Pharmaceutics, Al Shifa College of Pharmacy, Poonthavanam (P.O.), Kizattur, Perinthalmanna, Malappuram (Dt.), Kerala. Pin – 679 325.

*Corresponding Author E-mail: tnksuri@gmail.com

ABSTRACT:

Cefpodoxime proxetil (CP), a broad-spectrum cephalosporin antibiotic is used in this advanced era for treating acute bacterial infections. It has slightly bitter taste, poor water solubility and requires immediate release of drug from the dosage form, which serves the aim of fabricating CP as a dispersible tablet. The present study was undertaken to formulate taste masked cefpodoxime proxetil dispersible tablets by direct compression method. Different techniques for taste masking such as use of sweeteners and flavours, complexation with beta cyclodextrin and particle coating with stearic acid were studied. The blend was subjected to pre-compression studies such as angle of repose, bulk density, tapped density, compressibility index and Hausner ratio. After compression, the dispersible tablets were characterized using various tests such as hardness, weight variation, disintegration, water absorption, drug content, in vitro release, microbiological studies, taste evaluation and accelerated stability studies. The method of particle coating with stearic acid has shown excellent taste masking efficiency and flow properties for the powder blend. Different concentrations of stearic acid (2.5%, 5% and 7.5%) were used; out of which 5% stearic acid has shown better results. Antimicrobial assay proved that optimized formulation of CP dispersible tablet exhibits significant antimicrobial activity against Escherchia coli, Bacillus subtilis and Staphylococcus epidermidis.

KEYWORDS: Cefpodoxime, Dispersible tablets, Stearic acid, Taste masking, Antimicrobial assay

INTRODUCTION:

The oral route is the most common way of administering drugs and among the oral dosage forms, tablets of various types are the most common of solid dosage forms in contemporary use^1,2. Compared to other oral dosage forms, tablets are the manufacturer’s dosage form of choice because of their relatively low cost of manufacture, package and shipment; increased stability and virtual tamper resistance³. Tablets represent unit dosage forms in which one usual dose of the drug has been accurately placed. By comparison, liquid dosage forms are usually designed to contain multiple dose of medication in the same container. Such dosage measurements are typically in error by a factor ranging from 20 to 50% when the drug is self administered by the patient⁴.

They offer the greatest capabilities of all oral dosage forms for the greatest dose precision and the least content variability. In general, product identification is potentially the simplest and cheapest, requiring no additional processing steps when employing an embossed or monogrammed punch face. They may provide the greatest ease of swallowing with the least tendency for “hang – up” above the stomach, especially when coated, provided that the tablet disintegration is not excessively rapid. They have the best combined properties of chemical, mechanical and microbiological stability of all the oral dosage forms. Cefpodoxime proxetil is an advanced-generation drug used in the treatment of acute bacterial exacerbation of chronic bronchitis (AECB), group A beta-hemolytic streptococcal pharyngotonsillitis, and uncomplicated skin/skin structure infections. It requires immediate release of drug from the dosage form for treating the ailment, which makes cefpodoxime proxetil suitable candidate for dispersible tablets. Dispersible tablets are uncoated or film-coated tablets intended to be dispersed in water before administration giving a homogeneous dispersion. They combine benefits of liquid dosage forms with a solid dosage forms. They have less physical resistance than regular tablets; more sensitive to moisture and may degrade at higher humidity conditions. Therefore each tablet must be protected from the ambient humidity^5,6. It should be dispersed in a small amount (5 or 10ml) of liquid (clean water or milk) in a clean and appropriate container and can be softly stirred to aid dispersion before swallowing. As a portion of the active substance may remain in the container after swallowing, it is advisable to rinse it with a small amount of water or milk and swallow again. It must be used immediately after removal from the blister packaging. As for liquid formulations the taste of a dispersible tablet is a crucial parameter that will condition the acceptability by the patient and the adherence to treatment. Taste masking is obtained by the addition of flavor and sweetener to the formulation. Bitter sensation is often unpleasant resembling alkaline water, alkaloid poisons and spoiled foods. Most of the active pharmaceutical ingredients (APIs) usually fall under bitter category. Chemoreceptors for taste and olfaction respond to chemicals in an aqueous environment. Chemicals dissolved in saliva excite the taste receptors of the mouth, and airborne chemicals dissolved in epithelial mucus excite the olfactory receptors of the nose^7,8,9. The goal of taste abatement of bitter or unpleasant taste of drug has been achieved by using various techniques such as addition of flavouring and sweetening agents, microencapsulation or coating with inert agents, ion‐exchange resins, inclusion complexation, granulation, adsorption, prodrug approach, bitterness inhibitor and potentiators, multiple emulsion technique, liposome preparation, gel formation, solid dispersions, molecular complex, mass extrusion, pH modifiers, by effervescent agents, rheological modification and continuous multipurpose melt technology^10,11 . CP is a third generation orally administered cephalosporin antibiotic. It is mainly used in treatment of respiratory, urinary, skin and soft tissue infection caused by gram positive and gram negative bacteria. The formulation of dispersible tablets was aimed because many conventional tablets are available in adult strength; therefore the administration of accurate dosage for children is critical. Dispersible tablets can be formulated in pediatrics strength. Another drawback of conventional dosage form is swallowing difficulty which can be overcome by dispersible tablet formulation^12,13. Also, CP has an extremely bitter taste, so it was decided to mask the bitter taste by employing appropriate taste masking method^14,15.

METHODS:

The selected drug, CP was subjected to preformulation studies like physical characterization (viz. colour, odour and taste), solubility studies in buffers of various pH (1.2, 5.4 and 6.8) using sonicator at room temperature, particle size distribution of drug/final blend by sieving method, compatibility studies by preparing different blends of excipients with drug and stored at 40^oC/75%RH for one month and the water content was determined titrimetrically by Karl Fischer titration method. CP dispersible tablets were prepared by direct compression method. The preliminary trials (F1 to F6) were carried out for getting an optimized formula for dispersible tablets as given in Table 1. After analyzing pre- and post- compression parameters, taste masking techniques such as addition of flavours and sweeteners, inclusion complexation with β- cyclodextrin and particle coating with stearic acid, were employed for masking the bitter taste of CP^16,17.

Table 1. Optimized formula for dispersible tablets

Ingredients	F1 (mg)	F2 (mg)	F3 (mg)	F4 (mg)	F5 (mg)	F6 (mg)
Cefpodoxime Proxetil	131.20	131.20	131.20	131.20	131.20	131.20
Lactose Anhydrous	141.55	136.80	136.80	134.80	121.80	121.80
Pregelatinized Starch	21.00	----	----	----	----	----
Hydroxy Propyl Cellulose	----	18.00	18.00	18.00	9.00	9.00
Sodium Lauryl Sulphate	5.25	7.00	7.00	7.00	9.00	----
Tween 80	----	----	----	----	----	9.00
Crosscarmellose sodium	18.00	18.00	----	----	18.00	18.00
Cross povidone	----	----	18.00	----	18.00	18.00
Sodium Starch Glycolate	----	----		18.00	----	----
Aspartame	14.00	20.00	20.00	20.00	20.00	20.00
Sucralose	----	----	----	----	----	----
Straw berry flavor	8.00	8.00	8.00	10.00	10.00	10.00
Peppermint flavor	4.00	4.00	4.00	4.00	6.00	6.00
Tetraromemandrine flavour	----	----	----	----	----	----
Colloidal Silicon Dioxide	3.50	3.50	3.50	3.50	3.50	3.50
Magnesium Stearate	3.50	3.50	3.50	3.50	3.50	3.50
Total	350.00	350.00	350.00	350.00	350.00	350.00

Table 2. Coating compositions using different concentrations of stearic acid

Ingredients	SF1	SF2	SF3
Cefpodoxime Proxetil	131.90	131.90	131.90
Stearic Acid	3.30	6.60	9.89
Tween 80	0.07	0.13	0.20
Triethyl citrate	0.17	0.33	0.50
Crospovidone	0.10	0.20	0.30
IPA	q.s.	q.s.	q.s.

The coating solution was prepared with the calculated composition as given in Table 2. The solvent was stirred under the mechanical stirrer for 5 minutes. Followed by the addition of triethyl citrate, stearic acid and tween 80 were added to the vortex of the solvent under stirring and continued stirring for 10 minutes after adding each ingredient. CP and crosspovidone were sifted through sieve # 60. The spray solution was passed at a rate of 3 ml/minute under an atomization pressure of 1.2 kg/cm² rotated at 3 rpm. After a specific period of time the spray was halted and allowed the granules to dry in a stream of hot air^18,19,20. The coated granules were sifted through sieve # 60, subjected to another coat of spray, dried, again sifted through sieve # 40 and used for further studies^21,22. The coated granules were compressed into tablets by direct compression with a weight of 350 mg using 10.5 mm FFBE punches. Prior to compression the powder blends were evaluated for pre-compression parameters²³. In vitro dispersion time was measured by dropping a tablet in a 10 ml measuring cylinder containing 6 ml of water. In vitro disintegration time was studied by using disintegration test apparatus. The drug content was estimated by assay procedure for dispersible tablet as per USP. The in vitro dissolution studies of CP dispersible tablets was carried out using USP Type II dissolution apparatus containing 900 mL of pH 3 glycine buffer maintained at 37±0.5^oC at a speed of 75 rpm. Aliquot of samples (5 mL) were withdrawn at a specific time of 30 minutes and the absorbance was measured at 259 nm spectrophotometrically. FTIR studies were done to detect the possible interactions between the drug and excipients by KBr pellet technique using Fourier Transform IR spectrophotometer (Perkin Elmer, RXi FTIR system). DSC studies were conducted to confirm possible interactions or phase transformations between drug and excipients. The stability studies were carried out as per ICH guidelines at 40±2⁰C/75±5% RH for 6 months. The antimicrobial susceptibility of CP dispersible tablets was tested by Kirby –Bauer antibiotic sensitivity test using Mueller Hinton agar medium. In this method filter paper discs of uniform size were impregnated with different concentrations of CP and then placed on the surface of an agar plate that has been seeded with the microorganisms (Escherichia coli, Bacillus subtilis and Staphylococcus epidermidis) to be tested. The efficacy of drug was determined by measuring the diameter of the zone of inhibition that results from diffusion of the drug into the medium surrounding the disc. The susceptibility of the organism to a drug was determined by measuring the size of the zone of inhibition.

RESULTS:

The present study was undertaken to formulate taste masked CP dispersible tablets by direct compression method. The following preformulation studies were preformed on CP and excipients. The Organoleptic properties like colour, odour, and taste of the API were evaluated. The colour of CP was found to be white to light yellowish white powder; odourless or having faint odour and has very bitter taste. The angle of repose was found to be 35^o71’. The bulk and tapped densities were determined as 0.240 g/cm³ and 0.274 g/cm³ respectively. The Hausner ratio and compressibility index were found to be 1.142 and 12.5 % respectively. The above results revealed that the flow property was not sufficient for direct compression hence slugging should be done before compression. From the particle size analysis it was concluded that 90% of the drug was found to be less than 10µ and the mean particle size was found to be 5.657µ. Solubility analysis is important because the drug has to dissolve in the solvents and also in the dissolution medium used. CP was found to be very slightly soluble in water, slightly soluble in ether, soluble in acetonitrile and in methanol and freely soluble in dehydrated alcohol. The solubility of CP in buffers of various pH 1.2, 5.4 and 6.8 was found to be 5.8, 0.45 and 0.38 mg/mL respectively. CP exhibited a pH dependent solubility phenomenon in various aqueous buffers; very high solubility was observed in acidic pH values, while the solubility dropped rapidly as the pH increases. The drug excipients compatibility studies were performed by preparing blend of different excipients with drug and stored at 40^oC/ 75% RH for one month. The blend was evaluated for every 15 days for changes like caking, liquefaction, discoloration and odour formation. From the drug excipients compatibility study, it was observed that there was no change or interaction between drug and excipients and it was concluded that the excipients selected for the formulation were compatible with CP. The water content was determined as 3.5 % titrimetrically by Karl Fischer titration. Before compression, the blend was subjected to various evaluation studies such as angle of repose, bulk density, tapped density, compressibility index and Hausner ratio and the results were given in Table 3. The results revealed that the blend evaluation parameters were found to be within the limits indicating average flow properties.

Table 3. Evaluation of pre-compression parameters

Formulation code	Bulk density (g/cm³)	Tapped density (g/cm³)	Compressibility Index (%)	Hausner’s ratio	Angle of repose (θ)
F1	0.325	0.497	34.736	1.532	38.12
F2	0.517	0.652	20.689	1.26	38.1
F3	0.456	0.587	23.325	1.304	35.7
F4	0.459	0.615	25.29	1.3384	36.19
F5	0.438	0.579	25.75	1.346	33.69
F6	0.456	0.609	25.12	1.33	30.5
FS1	0.456	0.609	25.12	1.33	31.9
FS2	0.521	0.687	24.137	1.328	30.98
FS3	0.485	0.647	25	1.33	31.43

Table 4. Evaluation of post-compression parameters

Parameters	F1	F2	F3	F4	F5	F6	FS1	FS2	FS3
Average weight (mg)	358	356	354	357	353	355	356	352	349
Thickness (mm)	4.14	4.15	4.26	4.22	4.21	4.28	4.18	4.15	4.19
Hardness (kg/cm²)	4.6	4.5	5.13	5.5	5.1	5.2	5.1	4.9	5.5
Friability (%)	0.214	0.123	0.211	0.29	0.416	0.28	0.134	0.156	0.245
Disintegration time (sec)	25	24	40	40	45	35	35	45	47
Drug content (%)	99.82	100.1	99.05	98.75	99.45	98.21	98.57	99.42	99.89
Wetting time (sec)	25	15	22	24	19	21	18	22	27
Water absorption ratio %)	99.76	98.75	107.43	109.12	99.45	101.15	98.75	105.43	99.08

Through in vitro dissolution study, the drug release was found to be maximum in F6, when tween 80 was used as solubility enhancer rather than sodium lauryl sulphate. In F2, F3 and F4 containing crosscarmellose sodium, cross povidone and sodium starch glycolate as superdisintegrant, in vitro drug release was found to be 79.23, 76.46 and 71.84 % respectively. In F5 and F6, containing combination of cross carmellose sodium and crosspovidone the release was 75.20 and 81.8 % respectively as shown in Figure 1. Among all these six trials, F6 was selected as an optimized formula for preparing dispersible tablets, on which different taste masking techniques such as use of sweeteners and flavours, complexation with beta cyclodextrin and particle coating with stearic acid were applied. The trial formulations F7, F8 and F9 were prepared by direct compression method employing addition of flavours and sweetners for taste masking purpose and evaluated which showed acceptable parameters coincides with pharmacopoeial specifications for weight variation, drug content, disintegration time and fineness of dispersion. The results of in vitro release studies showed the drug release of 87.24, 86.09 and 91.90 % for F7, F8 and F9 was respectively at the end of 30 minutes. The rapid release might be due to the effect of superdisintegrant and surfactant. In F7 aspartame was used as sweetener and a combination of strawberry and peppermint flavours were used; in F8 sucralose was used instead of aspartame; in F9 aspartame was used and instead of strawberry flavour here teatraromemandrine flavour was used. Out of these three trials, the trial F9 showed the better taste masking effect when compared with trial F7 and F8.

Figure 1. In vitro drug release from formulations F1-F6

The formulations, F10 and F11 used the technique of inclusion complexation with beta cyclodextrin. The HPLC assay results showed that the drug content of the complex in F10 was only 24.5% and also the percentage yield was too low which indicates drug degradation. In F11, tween 80 was incorporated to the solvent in complexation process in order to enhance solubility but upon stirring a brownish yellow coloured precipitate was obtained. Thus inclusion complexation method for taste masking was found to be not suitable for the drug of choice. The coating of drug with stearic acid was done by pan coating method which enables taste masking by reducing the direct exposure of drug with taste buds. The waxy coating may decrease the dissolution of drug in the gastric environment which can be overcome by incorporating surfactant, plasticizers and superdisintegrants to the coating solution. The surfactant Tween 80 increases the wetting and the plasticizers triethyl citrate gives flexibility to the film which enhances the dissolution. The superdisintegrant crosspovidone is incorporated to enhance the disintegration of the granules by erosion when it is comes in contact with the gastric fluid. Among the three taste masking methods, particle coating with stearic acid was found to be an excellent method in attaining palatability by masking the undesirable taste of CP. In this method the effect of different concentrations of stearic acid (2.5, 5 and 7.5 %) were studied. The prepared tablets were evaluated for pre- and post- compression parameters and the results revealed that it comply with the specifications. The in vitro drug release of SF1, SF2 and SF3 was found to be 90.06, 88.92 and 68.91% respectively. As the concentration of stearic acid increases in the coating formula the drug release from the formulation was found to be reduced. Although maximum drug release was found in F13, the taste masking efficacy was high for F14 which have been selected as the optimized formulation for preparing CP dispersible tablets. The stability study of CP dispersible tablets was carried out at 40±2^oC/75±5% RH for a period of six months. The results revealed that there was no significant change in color, disintegration time, drug content, water content and in vitro drug release which indicates that the formulation was stable.

DISCUSSION:

The formulation of taste masked CP dispersible tablets 100 mg was aimed because many conventional tablets are available in adult strength; therefore the administration of accurate dosage for children is critical. Also, CP has an extremely bitter taste so it was decided to mask the bitter taste by employing various taste masking methods. Preformulation, precompression and postcompression studies were carried out to optimize various formulation factors. Among the three selected taste masking techniques, to mask the bitter taste of CP, particle coating with stearic acid were given efficient results. Out of 15 trial formulations, first six trials (F1 to F6) were carried out to optimize the general formula for preparing dispersible tablets. Then, five trials (F7 to F11) were prepared for selecting efficient taste masking technique, from which particle coating with stearic acid was selected for further studies. Then three trials were formulated by using different concentrations of stearic acid (2.5, 5 and 7.5%), out of which FS2 had shown better results for taste masking efficiency as well as in vitro drug release of 88.92 % after 30 minutes. The results of post compression parameters have fulfilled the requirements for dispersible tablets. Also F9, employed flavor and sweetener addition technique had shown acceptable taste masking efficiency with 91.90 % of drug release after 30 minutes. IR spectroscopic studies of optimized formulation (FS2) indicated that the drug was compatible with all the excipients used in the formulation. The stability studies of optimized formulation at 40±2°C/75±5% RH for a period of six months indicated that no significant changes in appearance, disintegration time, dissolution, assay and water content. These results have proved that the optimized formulation was stable and also exhibited significant antimicrobial activity against Ecoli, Bacillus Subtilis and Staphylococcus epidermidis. Thus, it was concluded that taste masked CP dispersible tablets could be successfully formulated by direct compression method adopting particle coating with stearic acid taste masking technique.

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Received on 25.08.2016 Modified on 26.09.2016

Research J. Pharm. and Tech. 2017; 10(1): 239-244.

DOI: 10.5958/0974-360X.2017.00050.6