Formulation Development and Evaluation of

Asian Journal of Pharmacy and Technology. 8(2): April- June, 2018

ISSN

2231–5705 (Print) 2231–5713 (Online) DOI: 10.5958/2231-5713.2018.00011.9 Vol. 08| Issue-02| April- June 2018

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RESEARCH ARTICLE

Formulation Development and Evaluation of Mebeverine extended release Pellets K. Vanitha1. M. Venkataswamy1, Sanam Niharika1, Alluri Ramesh2 1

Department of Pharmaceutics, Vishnu Institute of Pharmaceutical Education and Research, Vishnupur, Narsapur, Medak, Telangana, India 2 Department of Pharmacology, Vishnu Institute of Pharmaceutical Education and Research, Vishnupur, Narsapur, Medak, Telangana, India *Corresponding Author E-mail: [email protected]

ABSTRACT: The present study was aimed to formulate and evaluate extended release Mebeverine hydrochloride pellets using surface layering technique. Mebeverine hydrochloride, an anti-spasmodic drug being highly water soluble with a half-life of 2h is suitable to develop extended action for treatment of irritable bowel syndrome. The drug polymer compatibility was defined by the FTIR studies in preformulation study. Calibration curve for the drug is plotted and checked the physicochemical properties. Five formulations (F1-F5) of Mebeverine hydrochloride pellets were prepared using different quantities of talc and other standard excipients. The prepared pellets were subjected to micrometric properties study and physicochemical characterization. In vitro drug release studies were performed for the pellets for 1.5, 3, 6, 12hrs. The optimized formulation F5 showed 93.32 % drug release after 12h showing that talc act as rate controlling agent. Scanning electron microscopy (SEM) studies revealed that the prepared pellets for Mebeverine hydrochloride are spherical in shape. The release profile for optimized formulation F5 was comparable with that of marketed formulation (MEVA SR) for Mebeverine hydrochloride. Accelerated stability study for the selected formulation was performed and resulted with unchanged results. Absorption kinetics showed that the drug release of the selected formulation follow First order kinetics with zero order mechanism.

KEYWORDS: Formulation development, Mebeverine, Extended release pellets. INTRODUCTION: Oral1,2 modified drug delivery systems can be classified in to two broad groups Single Unit dosage forms andamp; multiple unit dosage forms. Multiple unit dosage forms (MUDFs), such as granules, pellets, or mini tablets. The concept of MUDFs was initially introduced in 1950s. Received on 25.12.2017 Accepted on 18.02.2018 © Asian Pharma Press All Right Reserved Asian J. Pharm. Tech. 2018; 8 (2):71-77 . DOI: 10.5958/2231-5713.2018.00011.9

The production of MUDFs is a common strategy to control the release of drug as shown by the reproducibility of the release profiles when compared to the ones obtained with SUDFs. The development of mini matrices is a promising area in pharmaceutical research concerned with a high control over the release rate of the drug combined with a high flexibility on the adjustment of both the dose and the release of drugs and has attracted some attention in the 1990s. Like other MUDFs, several mini tablets can either be filled in to hard capsules or compacted in to bigger tablets. Then after disintegration, they release these sub-units as multiple dosage forms. There has been increasing

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interest in the development of MUDF’S incorporated into tablets instead of hard gelatin capsules in order to overcome the higher production costs of capsules. In contrast to Monolithic dosage forms multiple unit dosage forms offer several advantages. Pellets3,4 Pellet has been used to describe a variety of systematically produced, geometrically defined agglomerate obtained from diverse starting materials utilizing different processing conditions. They contain multiples of free-flowing, spherical or semi- spherical solid units which are smaller in size (0.5 mm to 1.5 mm), and are intended mostly for oral administration. The small sterile masses which are obtained from the compression of implants or sterile cylinders are termed as pellets in pharmacy. Regardless of which manufacturing process is used, pellets have to meet the requirements: 1. Spherical shape and smooth surface is considered as desired characteristics for uniform film coating. 2. The particle size of pellets should be in range of 6001000µm. 3. The quantity of the active ingredient in pellets should be maximum in order to maintain size of pellet.

Preparation of drug pellets: Charge sucrose spheres (#30/40) into clean dry coating pan and coat the above sucrose spheres with PVP-K30 solution till sucrose spheres are wetted. Continue process of wetting of spheres with PVP-K30 solution and feeding of mixed API-Excipient blend till complete consumption of blended powder is done. Pelletization time should be around 2 to 3 h. After completion of coating, the coated pellets are dried in coating pan by maintaining inlet temperature at 50 ± 2ºC for 3 h. Coating of drug pellets: A laboratory scale Fluid bed multiple processorswere used for coating of pellets. Charge the ethyl alcohol in a clean stainless steel vessel kept under homogenizer. Add ethyl cellulose and talc under stirring; continue stirring until to get homogenous solution (keep vessel under closed conditions). Coat drug pellets with ethyl cellulose coating solution. Drug loaded pellets were transferred into the FBC and coated with the above prepared coating solution. The air pressure was maintained at 3 - 3.5 kg/cm2bed temperature was maintained at 40 ± 2oC. The bed temperatures were noted at every 1h. In order to dry ethyl cellulose coated pellets, temperature is maintained at 50 ± 2oC for 3h. The conditions used in the coating are spray rate was 10-70 g/min, atomizing air pressure was 1-3 bar, fluidization air volume was 70-150 m3/h and inlet air temperature were adjusted in such a way that the drug coated pellets reaches a temperature of about 3742oC.

For the past two decades, pellets5-6 made their use promising for ideal characteristics. Due to free-flowing character of Pellets they are packed easily without any difficulties and hence flexibility in design and development of a uniform solid dosage form (uniform weight of capsules and tablets).The spherical shape and a low surface area-to- volume ratio of pellets made uniform film coating, two or more drugs can be Table 1: Five formulations of Mebeverine extended release pellets Formulation formulated in a single dosage form, chemically Ingredients F1 F2 F3 F4 F5 compatible or incompatible, at the same sites or different Powder Blend sites in the gastrointestinal tract different release rates of Mebeverine (gm) 250 250 250 250 250 the same drug can be supplied in a single dosage form. Mannitol (gm) 23.5 23.5 23.5 23.5 23.5 Multiple-unit dosage forms are showing a number of MCC (gm) 9.37 9.37 9.37 9.37 9.37 SLS (gm) 2 2 2 2 2 advantages over the single-unit dosage system.

MATERIALS AND METHODS: List of materials: Mebeverine-Nosch Pharma, Mannitol-Roquetta, MCCRoquetta, SLS-Degussa, Sucrose Pellets -Nosch Pharma, PVP-K30-Degussa, Eudragit-Degussa, Ethanol-Merk, Ethyl Cellulose M 50-Roquetta, Talc-Luzanac Pharma. METHOD OF FORMULATION7: Preparation of Drug-excipient blends: Mebeverine was mixed with the excipients mannitol and Micro crystalline cellulose. Hammer the following materials in a pulverizer and passed through #20 meshes. Blend the above material in a double cone blender by adding Sodium lauryl sulfate, for about 45 mins. Take ethyl alcohol and PVP-K30 or Eudragit and Homogenise to get a clear solution and filter it. Pass above solution through # 100 silk cloth filters, collect filtered solution in a clean stainless steel kettle. Then check the pH of the solution, should be 6-7.

Table 2: Five formulations of Mebeverine extended release pellets Ingredients Formulation F1 F2 F3 F4 F5 Coating of blended Powder Sucrose pellets (gm) 43 43 43 43 43 Drug Layering PVP-K30 (gm) 19.76 19.76 19.76 19.76 19.76 Eudragit (gm) 20 Ethanol (ml) Coating Ethyl Cellulose M-50 (gm) Ethyl alcohol (ml) Talc

240

240

240

240

240

10

10

10

10

10

300 100

300 100

300 75

300 60

300 50

Evaluation8 of pellets: 1. Moisture content: It was determined with Karl-Fischer method. About 30 to 40 ml of methanol is taken into titration vessel and the solvent is neutralized with standard K.F. reagent, then 0.3 g of the powdered pellet sample was accurately

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weighed and transferred into titration vessel. The In-vitro release studies for Mebeverine hydrochloride contents are titrated with Karl Fischer reagent to end pellets: point and determined the moisture content. In11-13 vitro drug release was determined using USP Type-I dissolution testing apparatus (basket method). 2. Flow properties: Weigh accurately, about 200 mg of Mebeverine Bulk and tapped density of pellets was determined using hydrochloride pellets filled into each of the dissolution USP bulk densityapparatus. The bulk density, tapped baskets. Dissolution flasks, containing 750 ml of 0.1 N densities were determined initially from whichHausner’s HCl previously has been equilibrated to the temperature ratio was calculated. The angle of repose was determined of 37oC±0.5oC. Start the apparatus and run for 1.5 h. using fixed funnel method. Withdraw 5 ml aliquot and replace with 5 ml of fresh 0.1 N HCl. Take the above 5 ml aliquot in 25 ml volumetric 3. Sieve analysis: flask and make up to the volume with 0.1 N HCl. After A series of sieves were arranged in the order of their completion of 2 h in 0.1 N HCl add 250 ml of 0.2 M decreasing porediameter (increasing sieve number) tribasic sodium phosphate so that the pH gets adjusted to (sieve # 10, 12, 14 and 18). Twenty grams of 6.8. Continue the dissolution apparatus and collect the Mebeverine hydrochloride pellets was weighed sample and repeat the same for every 3, 6, and 12 h. The accurately and transferred to sieve # 10 which was kept sample solutions were diluted and spectrophotometry on top. The sieves were shaken for about 10 min. Then was carried out at a wavelength of 254 nm. the pellets retained on each sieve were taken, weighed separately and amount retained was expressed in terms Accelerated stability studies: of percentage. Accelerated stability studies14-21 of the selected formulation F5 was conducted at 40oc±2/ 75% RH for 4. Abrasion resistance: three months and samples were collected for three A pre-weighed sample (approximately 10 g) was placed months and analyzed for drug release. in an abrasiondrum that was configured to raise and drop the pellets from 200 mm. The stress levels on pellets RESULTS AND DISCUSSION: were enhanced by adding 1 mm glass beads. After 100 Extended release pellets were developed for an anti revolutions at 25 rpm, the mass retained on the sieve spasmodic drug with a view to deliver the drug in a (1190 μm) was weighed and the abrasion resistance was controlled manner using fluidized bed processor calculated as the percentage loss of mass between initial technique. The details of results and discussion were and final weights of each pellet batch. Each batch is given in the following sections. analyzed in triplicate. Preformulation studies: 5. Pellet shape analysis: Estimation of Mebeverine hydrochloride: To understand changes in the surface morphology, the The drug estimation was made in 0.1 N HCl and topography of pellets was analyzed with help of phosphate buffer pH 6.8 at λ max of 254 nm using UV scanning electron microscopy9-10. A small amount of spectrophotometer (Schimadzu UV – 1700). Calibration pellets was spread on glass stub. Afterwards, the stub curve obeyed Beer –Lambert’s law. containing the sample was placed in the scanning electron microscope chamber. The scanning electron photomicrograph was taken at the acceleration voltage of 4 kV, chamber pressure of 19.7 mm Hg at different magnification levels. Estimation of drug content for Mebeverine hydrochloride pellets: Five grams of pellets are grinded in a motor to a fine powder; equivalent to 200 mg of drug accurately weighed which is dissolved with few drops of distilled water and made up to the mark in 100 ml volumetric flask. The solution is kept for sonication followed by cyclomixing and absorbance is measured at λ max of 256 nm. Fig 1: Mebeverine standard curve

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Drug-excipient compatibility studies for Mebeverine hydrochloride: FT-IR studies for Mebeverine hydrochloride were conducted. The FT-IR scans for Mebeverine hydrochloride drug and for mixtures of Mebeverine with different excipients and Mebeverine hydrochloride pellets are taken. The data obtained from the FT-IR

indicated that the characteristic bands obtained for the pure drug are retained in the formulation mixture as well as in the prepared pellets. These studies indicated a prima – facie evidence of compatibility of drug and excipients used in the formulation.

Fig 1: FT-IR studies

Characterization of Mebeverine hydrochloride pellets: 1. Flow properties of Mebeverine hydrochloride pellets: All the different formulations of Mebeverine hydrochloride pellets are subjected for evaluating the flow properties. Table 2: Flow properties of Mebeverine hydrochloride pellets Formulation Bulk Density Tapped Density Hausner’s code (g/ml) (g/ml) ratio F1 0.441 ± 0.003 0.524 ± 0.004 1.18 F2 0.587 ± 0.008 0.651 ± 0.004 1.10 F3 0.698 ± 0.004 0.742 ± 0.003 1.06 F3 0.559 ± 0.003 0.658 ± 0.005 1.12 F5 0.532 ± 0.005 0.605 ± 0.003 1.13

than 1% for all formulations. The percentage moisture content ranges from 1 to 1.75 % for different formulation. Assay results were found to be well within the specifications for all nine formulations (93.37 to 98.97%). Table 3: Physicochemical hydrochloride pellets Formulation Parameter code Abrasion Resistance F1 0.56 ± 0.01 F2 0.55 ± 0.04 F3 0.71 ± 0.04 F4 0.54 ± 0.04 F5 0.57 ± 0.07

characterization

Assay (%) 93.37 95.32 98.34 96.98 98.97

of

Mebeverine

Moisture content (%) 0.72 0.98 0.85 0.69 0.89

In- vitro dissolution studies: The prepared pellets are subjected to in vitro release studies in 0.1 N Hcl for 1.5 h and followed by phosphate buffer pH 6.8 for another 10 h as dissolution media using USP Type I dissolution apparatus. The data obtained from the study was shown in the Table7.3 and recorded in Figure 7.2 from various formulations. It is evident that the drug release was found to be in range of 60.96 to 93.32% for the formulations in 12 h. Thus the studies indicated that drug release was consistent for all formulations. The effect of polymers and ethyl cellulose was clearly indicated in the release studies. From these 3. Physicochemical characterization of Mebeverine studies, the formulations F5 is optimized as the drug hydrochloride pellets: release is more consistent and found to be highest in 12 The prepared pellets were subjected to physicochemical h. Further, the optimized formulation F5 was used to characterization. The results obtained from these studies compare with marketed formulation MEVA SR. are recorded. Abrasion resistance was found to be less 2. Particle size distribution for Mebeverine hydrochloride pellets: The various formulations of Mebeverine hydrochloride pellets are subjected for particle size distribution by sieve analysis. The percentage of pellets retained on different sieves (#16, #18) after shaking the sieve shaker for the specified period for all five formulations are obtained. From the obtained results, the particle size distribution revealed that, all the formulations passed the test.

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Asian Journal of Pharmacy and Technology. 8(2): April- June, 2018 Table 4: Dissolution profile of the Formulations. Medium Time(h) % Cumulative Drug Release F1 F2 0.1N HCl 0 0 0 1.5 16.04 16.27 6.8pH 3 31.69 30.97 Phosphate 6 48.64 46.10 buffer 12 60.96 58.25 Table 5: Kinetic Model Fitting for Formulation F5: CUMULA TIME ROOT LOG LOG TIVE (%) (T) ( T) (%) (T) RELEASE RELEASE Q 0 0 0 25.37 1.5 1.225 1.404 0.176 51.07 3 1.732 1.708 0.477 70.02 6 2.449 1.845 0.778 93.32 12 3.464 1.970 1.079

F3 0 25.25 40.83 63.19 78.20

LOG (%) REMAIN

2.000 1.873 1.690 1.477 0.825

F4 0 25.25 49.18 65.03 83.40

F5 0 25.37 51.07 70.02 93.32

Marketed Product 0 22.00 45.96 73.39 92.67

RELEASE RATE (CUMULATIVE % RELEASE / t)

1/CUM% RELEASE

PEPPAS log Q/100

16.913 17.023 11.670 7.777

0.0394 0.0196 0.0143 0.0107

-0.596 -0.292 -0.155 -0.030

% Drug Remaining

100 74.63 48.93 29.98 6.68

Fig 3: In-vitro release kinetics of Mebeverine hydrochloride ER optimized F5 (Zero order)

Fig 5: In-vitro release kinetics of Mebeverine hydrochloride ER optimized F5 (Peppas)

Fig 4: In-vitro release kinetics of Mebeverine hydrochloride ER optimized F5 (Higuchi)

Fig 6: In-vitro release kinetics of Mebeverine hydrochloride ER optimized F5 (First order)

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showed satisfactory drug release and percentage of known impurities was found to be nil and unknown impurities were within the limits. Thus the stability showed good correlation with the ICH Quality and Stability Guidelines.

Fig 7: In-vitro release kinetics of Mebeverine hydrochloride ER optimized F5 (HIX_COR)

Fig 10: SEM of the Mebeverine HCl pellets of optimized formulation F5 Table 6: Accelerated stability studies of selected formulation F5 Month % Drug Release 0 1.5 h 3h 6h 12 h 0 0 25.37 51.24 70.36 92.88 1 0 25.63 50.07 69.38 92.02 2 0 24.89 52.43 70.56 93.75 3 0 25.14 51.69 70.12 93.04

SUMMARY: Fig 8: Dissolution profile of five formulations

Fig 9: Comparison of selected formulation with marketed

Pellet shape analysis for Mebeverine pellets by scanning electron microscopy: Scanning electron photomicrographs of optimized formulation of Mebeverine hydrochloride pellets were taken. Acceptable shape was obtained indicating perfect sphericity of pellets as described in Figure. Accelerated stability studies: Accelerated stability studies of the selected formulation F5 was conducted at 40oc±2/ 75% RH for three months and samples were collected for every month and analyzed for drug release. The in-vitro dissolution profile

Mebeverine is an anti-spasmodic drug with a short halflife of 2 hrs and plasma protein binding of 75%. The drug is more powerful than papaverine in blocking the spasm of smooth muscle and in relieving the carbacholinduced spasm of the sphincter of Oddi. These compounds act directly on the gut muscles at the cellular level to relax them. Mebeverine HCl which used to normalizes the small bowel motility. In the present study the drug was formulated into pellets for extending the release of drug using different concentrations of talc as coating to drug coated non pariel seeds using surface layering pelletization technique along with other standard excipients. Preformulation studies for the drug as flow properties, calibration curve and drug excipient compatibility studies are performed. From the flow properties study conducted shows that the results are within the limits. The calibration curve of drug showed good regression value 0.999 (R2) and obeyed BeerLambert’s Law at λmax of 254 nm. The FT-IR scans for Mebeverine hydrochloride drug and for mixtures of Mebeverine with different excipients, and Mebeverine hydrochloride pellets are taken. The data obtained from the FT-IR indicated that the characteristic bands obtained for the pure drug are retained in the formulation mixture and showed no interaction between the drug and selected polymers. These studies indicated a prima – facie evidence of compatibility of drug and excipients used in the formulation. Evaluation studies were conducted for the various formulations of pellets

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developed. The pellets showed bulk density, tapped density and Hausner’s ratio within the limits. The angle of repose of the pellets indicated the good flow. The pellets showed good resistance to abrasion and the percentage drug retained within the pellets was good. The moisture content was found within the limits showing that the drying process was carried out with uniform conditions. In-vitro dissolution studies of pellets formulations showed good drug release for the all formulations where it concluded that talc can also be used as release controlling agent. The attempt to incorporate the talc in the formulation for extended release came out with a productive result. The formulation F5 showed better dissolution profile that is comparable to and slightly greater than the marketed product. Hence the F5 is selected as best and optimized. SEM was conducted to evaluate the shape of optimized formulation where it showed the spherical shape of the pellet. Accelerated stability studies of the selected formulation showed the same drug release after the time period under the specified conditions. Absorption kinetics was studied by regression analysis. The drug release pattern of the selected best formulation followed First order kinetics.

REFERENCES: 1. 2. 3. 4. 5. 6. 7. 8.

9. 10. 11.

CONCLUSION: Oral multi particulate drug delivery systems of extended release Mebeverine hydrochloride in the form of pellets were successfully developed. In-vitro dissolution studies of pellets formulations showed good drug release for the all formulations where it concluded that talc can also be used as release controlling agent. The attempt to incorporate the talc in the formulation for extended release came out with a productive result. The formulation F5 showed better dissolution profile that is comparable to and slightly greater than the marketed product. Hence the F5 is selected as best and optimized. SEM was conducted to evaluate the shape of optimized formulation where it showed the spherical shape of the pellet. The optimized formulations showed gradual release and the release is comparable with marketed formulation. Thus, the drug layering technique using talc delayed the drug release for Mebeverine hydrochloride pellets to the desired extent.

ACKNOWLEDGEMENT:

12. 13.

14.

15.

16.

17.

18.

The authors are grateful to the authorities of Vishnu Institute of Pharmaceutical Education and Research, 19. Vishnupur, Narsapur, Medak for the facilities.

CONFLICT OF INTEREST:

20.

The authors declare no conflict of interest. 21.

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