pellets

M Srujan Kumar et al. / JPBMS, 2012, 18 (05)

1 Journal of Pharmaceutical and Biomedical Sciences© (JPBMS), Vol. 18, Issue 18

Available online at www.jpbms.info

JPBMS

JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL SCIENCES

Formulation and Evaluation of Multiunit Pellet System of Venlafaxine Hydrochloride

*M. Srujan Kumar1, Binayak Das1, S.V.S.Rama Raju2 1Department of Pharmaceutics, Samskruti college of Pharmacy,Kondapur,R.R District,Hyderabad,India.

2Department of Pharmaceutics, C.L.Baid Metha College of pharmacy, Chennai, India.

Abstract: Compaction of multiparticulate, commonly called MUPS, is one of the more recent and challenging technologies that combine the advantages of both tablets and pellet-filled capsules in one dosage form. Venlafaxine is an anti depressant, having an elimination half-life of 5±2 hrs and its maximum daily dose is 300mg. Since the drug belongs to BCS class I, it is necessary to retard dissolution to ensure extended release of drug. The objective of the study is to prepare venlafaxine extended release pellets by extrusion spheronization technology, coating them with mixture of rate controlling polymers Ethyl cellulose and different grades of (Hydroxy propyl methyl cellulose (HPMC) using Wurster process to achieve the desired dissolution pattern and compressing the pellets into tablets. The pellets were analyzed for the parameters such as bulk density, tapped density, compressibility index, Hausner’s ratio and the results were found to be within the limits. Drug release rate was more when compared with the innovator sample. The Venlafaxine hydrochloride extended release pellets were compressed into the tablets. The dissolution profile of the prepared Venlafaxine hydrochloride extended release tablets were compared with that of Innovator (VENLAR). Finally conclude like extended release pellets in tablets of formulation (F9) have more drug release rate rather than innovator (VENLAR) and it have better Bioavailability. Keywords: Extrusion and Spheronization, HPMC, MUPS, multiparticulate, wurster process.

Introduction: The oral route of administration of drugs is the most important method for achieving systemic effects. In the process of absorption of drug from oral route dissolution is the rate limiting step. Since the drug belongs to BCS class I, it is necessary to retard dissolution to ensure extended release of drug. Venlafaxine is an anti depressant, having an elimination half-life of 5±2 hrs and its maximum daily dose is 300mg. Hence it is an ideal candidate for extended release formulation. The objective of the study is to prepare venlafaxine extended release pellets by extrusion spheronization technology and further coating them with mixture of rate controlling polymers Ethyl cellulose and hydroxy propyl methyl cellulose using Wurster process to meet the desired dissolution pattern and compressing the pellets into tablets. Modified release can be categorized into delayed release and extended, or prolonged, release. The primary aims of using delayed release are to protect the drug from an un favorable environment in the gastrointestinal tract, to protect the gastrointestinal tract from high, local concentrations of an irritating drug compound, or to target a specific region of absorption or action. Delayed release products are typically enteric-coated or targeted to the colon. Extended release products aim at releasing the drug continuously at a predetermined rate to ncrease the patient compliance1, 2. The method pelletization technique developed in the early 1960s and since then researched and discussed extensively. Interest in the technology is still strong, as witnessed by the extent of coverage of the topic in scientific meetings and symposium proceedings, as well as in scientific literature. The technology is unique in that it

is not only suitable for manufacture of pellets high drug loading but it also can be used to produce extended release pellets in certain situations in a single step and thus can obviate the need for subsequent film coating. Pellets are agglomerates of fine powders or granules of bulk drugs and excipients. They consist of small, free-flowing, spherical or semi-spherical solid units, typically from about 0.5 mm to 1.5 mm, and are intended usually for oral administration1, 2. Pellets are agglomerates of fine powders or granules of bulk drugs and excipients. They consist of small, free-flowing, spherical or semi-spherical solid units, typically from about 0.5 mm to 1.5 mm, and are intended usually for oral administration. Implants of small, sterile cylinders formed by compression from medicated masses are also defined as pellets in pharmacy. Pellets can be prepared by many methods, the compaction and drug layering techniques being the most widely used today. Regardless of which manufacturing process used, pellets have to meet the following requirements. 1. They should be near spherical and have a smooth surface; both considered optimum characteristics for subsequent film coating. 2. The particle size range should be as narrow as possible. The optimum size of pellets for pharmaceutical use are considered between 600 and 1000 µm. 3. The pellets should contain as much as possible of the active ingredient to keep the size of the final dosage form within reasonable limits. In the last two decades, pellets have established their place for many reasons. Pellets offer a great flexibility in pharmaceutical solid dosage form design and development. They flow freely and

ISSN NO- 2230 – 7885 CODEN JPBSCT

Research article



pack easily without significant difficulties, resulting in uniform and reproducible fill weight of capsules and tablets. Successful film coating is applied on pellets due to their ideal spherical shape and a low surface area to volume ratio. Pellets composed of different drugs are blended and formulated in a single dosage form. This approach facilitates the delivery of two or more drugs, chemically compatible or incompatible, at the same sites or different sites in the gastrointestinal tract even pellets with different release rates of the same drug is supplied in a single dosage form. The most important reason for the wide acceptance of multiple-unit products is the rapid increase in popularity of oral controlled-release dosage forms. Controlled-release oral solid dosage forms are usually intended either for delivery of the drug at a specific site within the gastrointestinal tract or to sustain the action of drugs over an extended period With pellets, the abovementioned goals are obtained through the application of coating materials (mainly different polymers), providing the desired function or through the formulation of matrix pellets to give the desired effect. The advantage of multiple-unit products as a controlled-release dosage form believed to be their behaviour in vivo because of their advantageous dispersion pattern in the gastrointestinal tract and their special size characteristics. The transit time of a gastrointestinal drug delivery system along the gastrointestinal tract is the most limiting physiological factor in the develop of a controlled-release gastrointestinal drug delivery system targeted to once-a-day medication. Gastro-intestinal transit time, greatly affects the bioavailability of a drug from an orally administered controlled release preparation. Gastric transit of both single and multiple-unit solid dosage forms prolonged in a fed stomach compared to a fasting one1, 2, 3. Extrusion and spheronization: The concept of multiparticulate dosage forms introduced in the 1950’s with the increasing use of multiparticulate controlled release (CR) oral dosage forms, in recent times there has been a rise in interest in the methods of preparing these dosage forme. A method that has gained increased usage over the past few years is that of extrusion and spheronization.it has extensively as a potential technique and also as a future method of choice for preparation of multiparticulate CR dosage forms. This is a multi step process involving dry mixing, wet granulation, extrusion, spheronization, drying and screening. The first step is dry mixing of the drug and excepients in a suitable mixer followed by wet granulation, in which the powder is converted into a plastic mass that is easily extruded. The extruded strands transferred into a spheronizer, where they are instantaneously broken into short spherical rods on contact with the rotating friction plate and pushed outward and up the stationary wall of the processing chamber by centrifugal force. Finally, owing to gravity, the particles fall back to friction plate, and the cycles repeated until the desired sphericity achieved. Extrusion-spheronization is a multistep process involving a number of unit operations and equipment. However, the most critical part of processing equipment dictates the outconme of overall quality of pellets.

Figure 1: Overview of the Formulation of ER Pellets

Extrusion: Shaping of the wet mass into long rods are called as extrusion. A variety of extruders, which differ in design features and working principles, are currently on market and can be classified as screw-fed extruder, gravity-fed extruder and ram extruder. Screw-fed extruder have screws that rotate along the horizontal axis and hence transport the materials horizontally, they may axial or radial screw extruders. The product temperature controlled during extrusion by jacketed barrels. In radial extruders, the transport zone is short, and the material extruded radially through screens mounted around the horizontal axis of the screws. Gravity-fed extruders include the rotating cylinder and rotating gear extruders, which differ primarily in the design of two counter-rotating cylinders. In the rotating cylinder extruder, one of the two counter rotating cylinders is hallow and perforated, where as the other cylinder is solid and acts as a pressure roller. In ram extruders, piston displaces and forces the materials through a die at the end. Ram extruders preferred during formulation development they designed to allow for measurement of the rheological properties of formulation. In an extrusion-spheronization process, formulation components such as filler, lubricants and ph modifiers play a critical role in producing pellets with desired attributes. The granulated mass must plastic and sufficiently cohesive and self lubricating during extrusion. During the spheronization step, it is essential that the extrudates break at appropriate length and have sufficient surface moisture to enhance the formulaion of uniform spherical pellets. Excepients play an important role during extrusion spheronization than during with other pelletization process. they facilitate extrusion and determine the spherecity of the wet pellets, imparts strength and integrity of the pellets. Microcrystalline cellulose (MCC) is the most commonly used excipient in extrusion spheronization it leads to the formation of round spheres with desirable characteristics. During spheronization, moisture entrapped in the MCC microfibrils adds plasticity to the extrudates into spherical pellets. The pellet properties can be affected by many operational variables during the extrusion stage, the spheronization stage, or the drying stage. Both drying technique and drying temperature have a considerable affect on the pellet structure and properties. The variables that affect the final pellet qualities are screen pressure, screen hole diameter,



extruder type and speed, the type of friction plate, and spheronization time, speed and load. There is considerable interaction between spheronization time and spheronization load. With small and large spheronization loads, the yield of large pellets increases with longer spheronization time, an effect that is exacerbated by faster spheronization speed. Unsuitable processing parameters lead to pellet with poor qualities. Spheronization: During the third phase of extrusion spheronization process the extrudates dumped on to the spinning plate of the spheroniser, call the friction plate, where the extrudate broken up into smaller cylinders with a length equal to there diameter, those plastic cylinders rounded due to frictional forces. In the spheronization process different stages are distinguished depending on the shape of the particles, I.e; starting from a cylinder over a cylinder with rounded edges, dumbbells and elliptical particles to eventually perfect spheres. Baert and remon (1993) suggested that another pellet forming mechanism might exist. In this mechanism twisting of a cylinder occurs after the formation of cylinders with rounded edges, finally resulting in the breaking of the cylinder into two distinct parts. Both parts have round and flat side. Due to rotational and frictional forces involved in the spheronization process the edges of the flat side fold together like a flower forming the cavity observed in certain pellets. The spheronization of a product usually takes 2-10 minutes. A rotational speed of friction plate in the range between 200 and 400 RPM would be satisfactory to get highly spherical pellet. This statement is in a sharp contrast with most reports indicating the use of spheronization speeds exceeding 400 RPM. This contradiction are explained by the fact that not the absolute speed is important but the speed in combination with the diameter of the friction plate. From those two parameters the plate peripheral velocity is calculated and this data should be compared instead of absolute rotational speed of the friction plate. The friction plate has a grooved surface to increase the frictional forces. Two types of geometry of the grooves exist, cross hatch geometry where the grooves from right angles and radial geometry where a radial pattern used. Figure 2: Mechanism of pellet formation

A special kind of spheronizer designed by NICA-systems with a lip around the rim of the friction plate which claims to reduce the milling affect of the friction plate resulting in small amount of fines. Depending upon composition of formulation, substance soluble in the granulation liquid might migrate to the outside of the pellets during spheronization, leading to an in homogeneous distribution of the substance throughout the pellet. Snapshot of spheronization process:

Figure 3: Snap shot of spheronization process

Courtesy :- http://spheronizer.com/html/spheronization.html Wurster process The wurster process can appropriately be described as an upward moving, highly expanded pneumatically transported bed of pellets coupled with a downward-moving, more condensed, fluidized bed of pellets on the periphery of a vertical column. The two beds separated by tubular central partition. As the pellets pass through the atomizer they wetted by the coating fluid and then subjected to drying conditions created by the heated conveying air moving upwardly in the column. The partially coated solid pellets move downwardly in a weightless condition along the periphery of the column, where further drying occurs. When the solid pellets reach the lower end of the column those directed back into the upwardly moving bed and the entire process repeated. The air pump, heater, provides the heated support air for the process, and the distribution plate directs the proper volume of air to the central and peripheral regions of the column. The proper adjustment of the air flow, the temperature, and fluid application rate is critical to the successful operation of the process. Obviously, the drying kinetics is influenced by air flow rate and the temperature of the air. This kinetics in turn dictates the fluid application rate. Since drying is a cooling process. The temperature of the pellet surface is lower than either the inlet or exhaust air temperature. This permits the coating of heat-sensitive materials, since process conditions are adjusted so that the exhaust temperature will not exceed the temperature in which the product can tolerate. Thus, it is readily apparent that the drying kinetics are enhanced by increasing either the air flow rate or air temperature while maintaining the fluid application rate constant1, 2. From the literature survey: Steven H. Neau et al., (2010) evaluated the potential of coarse ethyl cellulose (CPEC) and high molecular weight polyethylene oxide (PEO) as excipients in the production of beads by extrusion-spheronization. CPEC was investigated as a diluents and PEO as an extrusion aid and a binder. Beads manufactured with caffeine as a model drug. release studies were conducted, and the bead size, shape, yield, and friability determined. The results confirmed that immediate release, spherical beads with low friability and narrow size distribution to be produced with minimum amounts of MCC3. Fridrun podczeck et al., (2009) has studied influence of adding two concentrations (5 and 25% ) of non-ionic surfactants, one hydrophilic and the other hydrophobic, plus mixtures of equal parts of the two, on the rheological properties of a mixture of equal parts of microcrystalline cellulose and ibuprofen with water by capillary rheometry .



The mixtures are also used to form pellets by extrusion-spheronization and their in vitro dissolution in simulated intestinal fluid measured. The 25% level of each of the surfactant formulations provided a rapid release of drug (100% within 30 minutes) but the 5% level and the mixed surfactant formulations provided lower drug release profiles4. Lieven Baert et al., (2009) produced pellet formulation containing a high drug loaded (80%) of the poorly soluble HIV-protease inhibitor darunavir, using wet extrusion-spheronization with K-carrageenan or microcrystalline cellulose (MCC) as pelletization aid. When compared with MCC pellets the bioavailability of darunavir was substantially improved by sixty fold in K-carrageenan pellets, likely due to their better disintegration behavior5. Podczeck F. et al., (2008) investigated the ability to incorporate non-ionic surfactants into pellets produced from MCC by the process of extrusion-spheronization and the properties of the pellets. A hydrophilic surfactant, polysorbate 60 (PS 60), and two hydrophobic surfactants, sorbitan monostearate (S 60) and sorbitan monooleate (S 80), Were included in the water used to form pellets in the concentration ranging from 5 to 95%. The highest concentration of the surfactant in water that is used to form pellets ranged from 50% for S 60, to 80% for S 80 and 95% for PS 60. The maximum amount of surfactant, which would be incorporated into final pellet, however, was found approximately 22.5% for both hydrophobic surfactants and 32.5% for hydrophilic surfactant6. Sriamornsak et al., (2007) has investigated the possibility in producing alginate-based pellets by extrusion-spheronization and also to improve the formation of spherical alginate-based pellets by investigating the effect of additive in granulation liquid on characteristics and drug release from resulting pellets. Higher amount of 3% calcium chloride as granulating liquid, formulations showed higher mean dissolution time resulting from cross linking properties of calcium ions to the negative charges of alginate molecules7. Ramo ‘n Marti ‘nez-Pacheco et al., (2005) studied the utility including superdisintegrants (croscaramellose sodium or sodium starch glycolate) in microcrystalline cellulose extrusion-spheronization pellets as means of increasing the dissolution rate of hydrochlorothiazide. Drug dissolution rate was slightly higher in pellets prepared with sodium starch glycolate, propably because this disintegrants higher swelling capacity8. Steckel.H et al., (2003) successfully prepared chitosan pellets replacing MCC. pellets with a maximum of 50% (m/m) of chitosan could be produced using demineralized water and the mass fraction of chitosan within the pellets could be increased to 100% by using diluted acetic acid for the granulation step9. Ingunn tho et al., (2003) studied low-soluble pectin derivative, PA (degree of methoxylation, 10%) as an extrusion aiding excipient in pellet preparation by spheronisation /extrusion.

The substance has a high drug loading capacity and produces disintegrating pellets that are well suited for fast delivery of drugs with a low water-solubility. The pellets are also mechanically stable, compared to MCC10. Newton. J.M et al.,(2002) has experimented on five drug models , 4-para hydroxyl benzoic acid(4HBA), methyl, propyl and butyl benzoic acid and propyl gallate(PG) . All of similar chemical natures were mixed in different proportions (50-73.7%) with MCC (26.3-50%) plus various levels of water (26.9-50%). The wet powder mass extruded and spheronized under standard conditions. The pellets produced, evaluated in terms of their median diameter, their modal size range, the % within a given size range (0.7-1.7 mm) and their shape factor. For the majority of formulations, all drug models, except 4HBA, produced pellets11. Gayot .A et al.,(2002) successfully produced 400µm spheroids that is sprinkled on food to improve patient compliance particularly in case of children and old people. Gelucire 50/02 wetted with a sodium lauryl sulphate solution at 0.5% was used which showed plastic flow through the 400 µm diameter orifice12. Materials and methods: Table 1: List of Materials used

S.No Active and inactive

pharmaceutical ingredients

Suppliers

1 Venlafaxine Matrix laboratories ltd, Hyd.

2 Microcrystalline cellulose (avicel PH 101) FMC Biopolymer, USA

3 Hydroxypropyl cellulose(Klucel) Aqualon , USA

4 Opadry Clear Colorcon , Goa 5 Ethylcellulose (Ethocel) DOW , USA

6 Hydroxyl propyl methyl cellulose DOW , USA

Table 2: List of Equipments used:

S.No Equipments Manufacturers 1 Electronic balance Mettler Toledo, USA. 2 Rapid mixer granulator Kevin, Ahmedabad. 3 Extruder Fuji paudal co.Ltd, Japan. 4 Spheronizer/MarumerizerTM Fuji paudal co.Ltd, Japan. 5 Rapid dryer Retsch, Germany. 6 Mechanical stirrer Heidolph, Germany. 7 Fluid bed coater Glatt, GmbH, Germany. 8 Mechanical sieve shaker Retsch, Germany. 9 Dissolution apparatus Electrolab, Mumbai.

10 UV-Visible spectrophotometer Shimadzu, Japan.

11 Tapped density apparatus USP Electrolab, Mumbai.

12 Tablet Punching machine Cadmach , Germany

Preparation of standard calibration graph of Venlafaxine hydrochloride: Preparation of standard solution of Venlafaxine hydrochloride: Stock solution: 100mg of venlafaxine HCl weighed accurately and transferred into a 100 ml volumetric flask. Then the volume made upto 100ml using water. Standard solution: 10ml of solution was withdrawn from the above stock solution and then made up to 100ml in



Another 100ml volumetric flask and this solution considered as standard solution (100µg/ml).

From the above standard solution 0.5, 1, 1.5, 2, 2.5ml was withdrawn and diluted to 10ml to get 5, 10, 15, 20, 25µg/ml concentration.

The solutions analysed spectrophotometrically at 226nm using UV visible spectrophotometer. Table 3: Standard Calibration Curve

S.No Concentration µg/ml UV Absorbance at 226 nm

1 0 µg/ml 0.00

2 5µg/ml 0.183±0.02

3 10µg/ml 0.358±0.02

4 15µg/ml 0.536±0.02

5 20µg/ml 0.710±0.02

6 25µg/ml 0.891±0.02

Formulation development: Preparation of pellets: Granulation: Venlafaxine HCl, microcrystalline cellulose (avicel PH 101), hydroxy propyl cellulose (klucel) passed through 30# mesh, and the sifted material transferred into rapid mixer granulator (Kelvin). Then the material allowed for dry mixing for 10 min by using impeller speed of 150 RPM and water was added for 3 min till formation of granules. Chopper run for 3 min at 1000 RPM to complete the granulation process. Preparation of pellets: The granules passed through Fuji Paudal extruder using 0.8 mm screen at 40 RPM, the obtained spaghetti like extrudates collected and placed on

Fuji paudal Marumerizer using 2mm plate. The spheronizer run at 800 RPM for 30 sec, 1800 RPM for 90 sec and 1300 RPM for 60 sec to get pellets of satisfactory sphericity. The pellets collected and dried in rapid dryer at 450C for 2 hrs and then sized through 16/30 mesh. Coating of pellets: Sub coating: Pellets loaded into fluid bed wurster and initial subcoating made with opadry clear at 4%build up. Polymer coating: polymer EC: HPMC coating was done in the ratio of 65:35 by giving 20% buildup to pellets. Preparation of Tablets: Granular part: Hydroxyl propyl cellulose, microcrystalline cellulose, aerosol, sodium stearyl fumarate blended in a roller compactor to form hard mass, then the resulting hard mass milled through 1.5mm screen and the obtained granules are passed through sieve no 20# mesh at top and 60# mesh at the bottom the particles retained on the 60# mesh considered as the granules and the particles passed through the sieve no 60# considered as fines, and the fines are again subjected to milling and the same cycle is repeated for several times to produce 60% of granule and 40% fines. Extra granular part: Sodium stearyl fumarate and aerosil taken for the lubrication purpose. Compression of tablet: Required amount of pellets were taken and mixed with granular part and extragranular part by mechanical agitation and compressed into tablets in a 16 mm oval shaped punch with a compression force of 5K.

Table 4: Formulation of venlafaxine hydrochloride pellets

Ingredient F 1 F 2 F 3 F 4 F5 F6 F7 F8 F9 F10 F11

Core spheroids

Venlafaxine HCl (Eq to venlafaxine)

169.7 169.7 169.7 169.7 169.7 169.7 169.7 169.7 169.7 169.7 169.7

MCC (PH 101) 165.3 134.3 134.3 134.3 134.3 134.3 165.3 165.3 134.3 165.3 165.3

Lactose(Granular 200) 100 55 55 55 75 100 100 75 55 50 75

HPC(Klucel EXF) 10 6 10 6 10 10 6 1 6 6 10

Water QS

Total core spheroids 445 365 369 365 389

414 441 391 365 391 420

Sub coat

HPMC 4 cps 14 10.5 10.5 10.5 10.5 10.5 14 10.5 10.5 14.5 15.5

Talc 6 4.5 4.5 4.5 4.5 4.5 4.5 6 4.5 6 6

Total sub coated spheroids

465 380 384 380.0 404 429 459.5 407.5 380 411.5 441.5

EC coating

Ethyl cellulose 20 cps 56 45 45 66.6 56 66.6 75 75 56.2 75 75

HPMC 4 cps 10.5 11 12 16.2 12.5 12.5 17 17 13.7 12 15

PEG 400 3.5 6 7 8.88 9.5 9 11 11.5 7.5 13 15

Total EC Coated spheroids

535 442 448 471.8 482 516.8 562.5 511 457.5 511.5 546.5



Table 5: Preparation of MCC granules Preparation of MCC granules %w/w

MCC 101 93 Aerosil 2

HPC LH 11 5 Total 100

Table 6: Compression of Tablets

Compression of Tablets using EC coated spheroids

Trial 1 Trial 2

Ingredient (CP3) eq to 75 mg

venlafaxine (CP3) eq to 150 mg

venlafaxine mg/tab mg/tab

EC coated Spheroids 228.75 457.5

MCC Granules 653.25 657.5

Aerosil 9 10 Sodium stearyl

fumarate 9 10

Total tablet weight 900 1135

Evaluation Evaluation of Pellets [Lachmann et al., 1987] The pellets evaluated for in process quality control test. The following tests performed for ER pellets 1. Determination of Bulk Density and Tapped Density: An accurately weighed quantity of the granules/ powder (W) was carefully poured into the graduated cylinder and volume (V0) measured. Then the graduated cylinder was closed with lid and set into the tap density tester (USP). The density apparatus set for 100 tabs and after that the volume (Vf) measured and continued operation till the two consecutive readings were equal (Lachman et al., 1987). The bulk density and the tapped density calculated using the following formulae.

Bulk density = W/V0

Tapped density = W/Vf

Where, W= Weight of the powder

V0 = Initial volume Vf = final volume

2. Compressibility Index (Carr’s Index): Carr’s index (CI) is an important measure that can be obtained from the bulk and tapped densities. In theory, the less compressible a material the more flowable it is (Lachman et al., 1987). CI = (TD-BD) x 100/TD Where, TD is the tapped density and BD is the bulk density.

Table 7: Carr’s Index Values

S.No. Carr’s Index Properties 1 5-12 Free flowing 2 13-16 Good 3 18-21 Fair 4 23-35 Poor 5 33-38 Very poor 6 >40 Extremely poor

3. Hausner’s Ratio: It is the ratio of tapped density and bulk density. Hausner found that this ratio related to interparticle friction and, as such, could be used to predict powder flow properties. Generally a value less than 1.25 indicates good flow properties, which is equivalent to 20% of Carr’s index.

4. Particle size distribution: 100gms of pellets shifted into a sieve shaker where a series of sieves was placed (16#, 22#, 25# and 30#). The machine was run for 5 minutes, all the meshes were taken out and retained granules collected by respective mesh and the percentage retention of pellets by that mesh calculated. 5. Friability Test: From each batch, 6.5gms of pellets accurately weighed and placed in the friability test apparatus (Roche friabilator). Apparatus was operated at 25 rpm for 4 minutes and pellets observed while rotating. The tablets were then taken after 100 rotations, the pellets were taken out and intact pellets again weighed collectively after removing fines using sieve#44. % friability calculated as follows

% Friability = (W1 – W2) x 100/W1 Where W1 = Initial weight of the 20 tablets.

W2 = Final weight of the 20 tablets after testing.

Friability values below 0.8% are generally acceptable. 6. In-vitro drug release: In vitro drug release of the samples carried out using USP-type 1 dissolution apparatus (Basket type). The dissolution medium, used was water 900ml (as specified by the office of generic drugs USFDA), placed into the dissolution flask maintaining the temperature of 37±0.5oC and 100 RPM. Accurately weighed pellets were placed in each flask of dissolution apparatus. The apparatus allowed to run for 24hours. Samples measuring 10ml withdrawn using cannula attached to a syringe. The samples were filtered through 45µm filter, which was in line with syringe. The fresh dissolution medium replaced every time with same amount of sample. Filtered samples were suitably diluted with water (1ml diluted to 10ml) and analyzed at 226nm. The cumulative percentage drug release calculated. Evaluation of tablets: 1. Thickness: Twenty tablets from the representative sample were randomly taken and individual tablet thickness measured by using digital vernier caliper. Average thickness and standard deviation values calculated. 2. Hardness: Tablet hardness measured by using Monsanto hardness tester. From each batch six tablets were measured for the hardness and average of six values noted along with standard deviations. 3. Friability Test: From each batch, ten tablets were accurately weighed and placed in the friability test apparatus (Roche friabilator). Apparatus operated at 25 rpm for 4 minutes and tablets were observed while rotating. The tablets were then taken after 100 rotations, dedusted and reweighed. The friability calculated as the percentage weight loss. Note: No tablet should stick to the walls of the apparatus. If so, brush the walls with talcum powder. There should no capping also. % friability was calculated as follows:

% Friability = (W1 – W2) x 100/W1

Where W1 = Initial weight of the 20 tablets. W2 = Final weight of the 20 tablets after testing.

Friability values below 0.8% are generally acceptable.



4. Weight Variation Test: To study weight variation individual weights (WI) of 20 tablets from each”formulations were“noted using electronic balance. Their average weight (WA) calculated. Percent weight variation was calculated as follows. Average weights of the tablets along with standard deviation values calculated.

% weight variation = (WA–WI) x 100/ WA

As the total tablet weight was 120 mg, according to IP 1996, out of twenty tablets ±7.5 % variation can be allowed for not more than two tablets. According to USP 2004, ±10% weight variation can be allowed for not more than two tablets out of twenty tablets. 5. In -Vitro Drug Release Characteristics: In vitro drug release: in vitro drug release of the samples carried out using USP-type II dissolution apparatus (Paddle type). The dissolution medium, used was water 900ml (as specified by the office of generic drugs USFDA), placed into the dissolution flask maintaining the temperature of 37±0.5oC and 100 RPM. Tablets placed in each flask of dissolution apparatus. The apparatus was allowed to run for 24hours. Samples measuring 10ml were withdrawn using cannula attached to a syringe. The samples filtered through 45µm filter, which was in line with syringe. The fresh dissolution medium was replaced every time with same amount of sample. Filtered samples were suitably diluted with water (1ml diluted to 10ml) and analyzed at 226nm. The cumulative percentage drug release calculated and compared with the innovator product (Effexor). Results and discussion: Pre-Formulation studies: Table 8: Preformulation Studies of API (Venlafaxine Hydrochloride)

Table 9: Calibration Graph

S.No Concentration

µg/ml

UV Absorbance 226 nm

1 0 0.00

2 5 0.183±0.02

3 10 0.358±0.02

4 15 0.536±0.02

5 20 0.710±0.02

6 25 0.891±0.02

Figure 4: Standard Calibration Curve of Venlafaxine hydrochloride Pre-Formulation studies Table 10 : Bulk Density, Tap Density, Carr’s Index, Hausner’s Ratio Of Venlafaxine Hydrochloride Pellets

Formulation code

Bulk density (g/cc)

Tap density (g/cc)

Carr’s Index (%)

Hausner’s ratio

F1 0.234 0.220 3.54 0.56 F2 0.324 0.320 3.24 0.43 F3 0.236 0.356 2.93 0.45 F4 0.421 0.254 3.87 0.36 F5 0.286 0.296 4.12 0.78 F6 0.412 0.342 4.23 0.99 F7 0.221 0.456 3.56 0.56 F8 0.332 0.451 4.56 0.68 F9* 0.61 0.592 5.71 1.06 F10 0.286 0.523 3.67 0.83 F11 0.312 0.561 3.12 0.41

*The pellets were analyzed for the parameters such as bulk density, tapped density, compressibility index, Hausner’s ratio and the results were found to be within the limits. Bulk density and tapped density values range between 0.446 – 0.480 gm/cc and 0.539 – 0.637g/cc tabulated and the values were found to be within limits Compressibility index has proposed as an indirect measure of bulk density, size, shape, surface area and cohesiveness of materials. Compressibility index values ranges between 5-12% for F1 to F11 formulations and the values tabulated. Hausner’s ratio it is the ratio of tapped density and bulk density. Hausner found that this ratio related to interparticle friction and, as such, could be used to predict powder flow properties. Generally a value less than 1.25 indicates good flow properties, which is equivalent to 20% of Carr’s index. Table 11: Particle Size Distribution of Venlafaxine hydrochloride

Sieve number % Cumulative retains

#16 0

#18 2.9

#20 31.0

#25 95.0

#30 100

Formulation development Based on the literature search and reference product review, prototype development initiated with preparation of core spheroids by extrusion spheronization technique and coating the spheroids with an extended release rate controlling polymer by wurster process. The composition is given in table 5.

Pre Formulation Studies

S.No Characteristics Results

1 Nature White

2 Solubility water

3 Bulk Density (gm/ml) 0.61

4 Tapped Density(gm/ml) 0.592

5 Carr’s Index (%) 5.71

6 Hausner’s Ratio 1.06



Table 12: Optimization of Microcrystalline Cellulose

Batch details Trial with45% w/w MCC in core spheroids

Trial with50% w/w MCC in core spheroids



Observation Fines generation during spheronization Satisfactory spheroids Satisfactory spheroids. Tablet over weight

*From the table 13 it is observed that the spheroids with MCC concentration of 50% and 55% were found satisfactory hence 55% has been finalized. Table 13: Optimization of Hydroxy Propyl Cellulose

Batch details Trial without HPC Trial with0.5% w/w HPC in core spheroids

Trial with1% w/w HPC in core spheroids

Trial with1.5% w/w HPC in core spheroids

Observation More Fines generation during spheronization

Satisfactory spheroids, acceptable fines generation Satisfactory spheroids. Dumble shaped spheroids

Table 14: Selection of Extruder Screen

Batch Details 0.6mm screen 0.8mm screen 1mm screen

Observation Spheroids found smaller with lesser yield of #16/30 mesh fraction

Spheroids found with optimum yield of #16/30 mesh fraction

Spheroids found bigger with lesser yield of #16/30 mesh fraction

Table15: Optimization of Binder Concentration Medium: Water (900ml) Apparatus: Basket (100 RPM)

Time (Hours)

% cumulative drug Release

Innovator F5(0.5% HPMC) F9(1%HPMC) F4(0.7%HPMC)

2 19 21 21 21 4 38 42 41 41 8 67 67 63 63

12 87 88 86 86 20 103 107 102 102

*No much significant change is observed with change in binder concentration 0.5% is considered as optimum concentration.

Table 16: Optimization of extruder speed Batch

Details 30 RPM 40 RPM 50 RPM

Observation Satisfactory Spheroids Satisfactory Spheroids Satisfactory Spheroids

Table 17: Selection of Spheronization Plate

Batch Details 2 mm chequered plate 3 mm chequered plate

Observation Satisfactory spheroids 85% yield of # 16/30 mesh fraction

Satisfactory spheroids 85% yield of # 16/30 mesh fraction

Table 18 :Optimization of Spheronization Speed and Time

Batch details Spheronization Speed(2mm plate) Time process Physical observation

Extrudates of 0.8mm screen at 40 RPM

800RPM 30 to 60 sec Cutting into small pieces and uniform distribution

of extrudates

Satisfactory spheroids 1700-1800RPM 2 to 3 minutes spheronization

1300RPM 30 sec Smoothening of spheroid surface



Table 19: Optimization of spheronization speed and time

Batch details Time Spheronization Speed(2mm plate) Physical observation


30 sec

800 RPM

Beadlets

1minutes Beadlets

2minutes Beadlets

3minutes Beadlets

4minutes Dumble shape


1minutes

1300 RPM

beadlets

2minutes Beadlets

3 minutes Dumble shape



1minutes

1600 RPM

beadlets



4 minutes Spheroids with irregular shape

Extrudates Of 0.8mm screen at 40 RPM

1minutes

1700 RPM

Beadlets


3 minutes Spheroids with irregular shape

4 minutes Spheroids (fines generated)

Extrudates Of 0.8mm screen at 40 RPM

1minutes

1800 RPM

Dumble shape 2 minutes Spheroids with irregular shape 3 minutes Spheroids but still irregular shape 4 minutes Spheroids (fines generated)

Optimization of sub coating Medium: Water Volume: 900ml (Venlafaxine hydrochloride 75mg), Apparatus: Basket (100 RPM) Table 20:Optimization of sub coating

Time (Hours)

% Drug Release

Innovator F8

(Without subcoating)

F7 (3% sub coated) F9 (5% sub coated) F3 (7% sub coated)

2 19 34 31 21 15 4 38 57 55 41 32 8 67 80 78 68 55

12 87 91 90 88 76 20 103 111 110 105 96

Figure 5 : Dissolution Profile of Optimization of subcoating

*From the table 20 and fig.9 it was observed that formulations (F7, F9, and F3) were sub coated with different concentrations of HPMC and the dissolution profiles were compared with the Innovator (VENLAR), formulation F9 showed the similar release profile to that of Innovator

(VENLAR), so formulation F9 was selected as the desired formulation with subcoating concentration of 5%. Optimization of Controlled Release Coating Build Up Medium: Water (900 ml) Apparatus: Basket (100 RPM)

Table 21: Optimization of Controlled Release Coating Build Up

Time (Hours)

% Drug Release

Innovator F2

16% build up of EC/HPMC

F9 16% build up of EC/HPMC

F1 24% build up of EC/HPMC

2 19 24 21 10

4 38 46 41 32

8 67 69 68 55

12 87 90 88 77

20 103 107 105 94



Figure 6: Dissolution Profile of Optimization of controlled release coating

*From the table 22 and fig.10 it was observed that formulations (F2, F9, and F1) were optimized for controlled release coating build up with different concentrations of 16% build up of EC/HPMC, and 24% build up of EC/HPMC the dissolution profiles were compared with the Innovator (VENLAR), formulation F9 showed the similar release profile to that of Innovator (VENLAR), so formulation F9 was selected as the desired formulation with controlled release coating of 16% build up of EC/HPMC. Optimization of Coating and Channeling Agent Ratio: Medium: Water (900ml) Apparatus: Basket (100 RPM) Table 22: Optimization of Coating and Channeling Agent Ratio

Time (Hours)

% Drug Release

Innovator F10

EC:HPMC =60:40

F9 EC:HPMC

=60:40

F11 EC:HPMC

=60:40

2 19 25 21 11 4 38 48 41 33 8 67 71 68 60

12 87 93 88 81 20 103 110 105 99

Figure 7: Dissolution Profile of Optimization 0f coating & chanelling agent ratio

*From the table 22 and fig.11 it was observed that formulations (F10, F9, and F11) were optimized for coating and channeling agent ratio with different ratio’s of EC: HPMC (60:40), the dissolution profiles were compared with the Innovator (VENLAR), formulation F9 showed the similar release profile to that of Innovator (r), so formulation F9 was selected as the desired formulation with coating and channeling agent ratio of EC/HPMC (60:40). Evaluation tests for the Prepared Venlafaxine hydrochloride Tablets Required amount of pellets were taken and mixed with granular part and extra granular part by mechanical agitation and compressed into tablets in a 16 mm oval shaped punch with a compression force of 5KN, the composition for the tablets was given in table 7. The compressed tablets were evaluated for various post compression parameters like weight variation, hardness, friability etc. The results are shown in table 24.

Table 23: Evaluation tests for the Prepared Venlafaxine hydrochloride Tablets

Formulations Weight

variation (mg)

Friability (%)

Hardness (kg/cm2) Thickness

F1* Passes 0.97 9 6.38

F2 Passes 0.98 8 6.45

*Visually examined tablets from each formulation batch showed (oval) shaped compressed tablets. Hardness, friability, thickness, weight variation of each formulation was analyzed for formulations F1 to F2 and all formulations were found to have good hardness, friability, thickness, weight variation, so they were taken for further studies. In - Vitro Dissolution Study of Venlafaxine hydrochloride pellets. Dissolution Profile: The dissolution test were carried out in water were taken at predetermined time intervals and after suitable dilutions absorbance was measured with the help of UV spectrophotometer at 226 nm and the percentage drug released at various time intervals calculated.

Table 24: Dissolution Profile

Time (hours)

% Drug release

Innovator F1 F2 F3 F4 F5 F6 F7 F8 F9 F10 F11

2 19 10 24 15 21 21 30 31 34 21 25 11

4 38 32 46 32 41 42 53 55 57 41 48 33

8 67 55 69 55 63 67 74 78 80 68 71 60 12 87 77 90 76 86 88 86 90 91 88 93 81 20 103 94 107 96 102 107 105 110 111 105 110 99

Figure 8: Dissolution Profile comparison of all the formulations of pellets



*Dissolution profile for the formulations (F1, F3 and F11) had poor dissolution profile, formulation (F9) showed good drug result when compared to that of Innovator (VENLAR 75mg), and so it had been selected as desired formulation for compressing into the tablet

In - Vitro Dissolution Study of Venlafaxine hydrochloride Tablets. Table 25 : Dissolution Profile:

Time

(hours)

% Drug release

Innovator F1 F2 2 19 21 19 4 38 41 47 8 67 68 65

12 87 88 86 20 103 105 101

Figure 9: Dissolution Profile comparison of all the formulations of tablets

*Pellets of formulation (F9) have been selected for compressing into the tablets, MCC granules are added in equal quantities to the 75mg and 150mg tablets of formulation (F9). The tablet having 75mg (F1) showed good drug result with the Innovator (VENLAR), when compared with the formulation (F2). Summary and conclusion: Based on the literature search and reference product review, prototype development initiated with preparation of core spheroids by extrusion spheronization technique and coating the spheroids with an extended release rate controlling polymer by wurster process. Spheroids with MCC concentration of 50% and 55% found satisfactory hence 55% has finalized. Spheroids with HPC concentration of 1% in core spheroids found satisfactory, hence it has finalized. Optimization of binder concentration done with HPMC concentration of 0.5%, 1%, 0.7%. No much significant

change is observed with change in binder concentration 0.5% is considered as optimum concentration. Optimization of binder concentration done with concentration of 3%, 5%, 7%.the formulation with 5% found satisfactory, hence it has finalized. Optimization of controlled release coating builds up16% build up of EC/HPMC of formulation (F9). The result found similar to that of Innovator (VENLAR 75mg). The pellets were analyzed for the parameters such as bulk density, tapped density, compressibility index, Hausner’s ratio and the results were found within the limits. Extended release pellets have minimum volume in size, greater surface area and more surface activity. The area of the drug loaded pellets release rate was also more. And also there was no need of disintegration time for pellets in capsules. Small volumes of pellets enter into the systemic circulation very fast. Moreover there was no accumulation of drug in the body. Drug release rate was more when compared with the innovator sample. The Venlafaxine hydrochloride extended release pellets compressed into the tablets. It showed good results in formulation of stable dosage. The dissolution profile of the prepared Venlafaxine hydrochloride extended release tablets compared with that of Venlafaxine hydrochloride extended release capsules (Venlar) of the product. The release found more in the case of pellets loaded in tablets. The desired formulation was found to be formulation (F9), due to its release profile was more when compared to the Innovator (VENLAR) and dissolution profile of Venlafaxine hydrochloride extended release tablets was compared with that of innovator (VENLAR). The release was found similar to that of innovator. So the prepared product said to be equivalent with innovator. Finally conclude like extended release pellets in tablets of formulation (F9) have more drug release rate rather than innovator (VENLAR) and it have better Bioavailability. Nowadays Venlafaxine hydrochloride marketed formulations (VENLAR.VENLEF) loaded in pellets. The present formulation was compressed into a tablet; it is more advantageous when compared to the pellets that loaded in pellets by low cost, less chance of degradation.

References: 1. Aulton M.C., 2002. ‘Pharmaceutics, The science of dosage form design’.,2nd edition:414-18. 2. Sellassie G.,1989. ‘pharmaceutical pellatization technology, Marcel Dekker’., 37:1-13. 3. Steven H. Neau ., Michelle Y. Chow., Gregory A. Hileman., Manzer J. Durrani., Ferdous Gheyas., Barry A. Evans. ‘Formulation and process conciderations for beads containing carbopol 974P,NF resin made by extrusion-spheronization’., European Journal of Pharmaceutics and biopharmaceutics.,2000; 199:129-40. 4. Fridrun podczeck ., Ana Maghetti., Michael Newton J., 2009. ‘ The influence of non-ionic surfactants on the rheological properties of drug/microcrystalline cellulose/water mixtures and their use in the preparation and drug release performance of pellets prepared by extrusion/spheronization’. , European Journal of Pharmaceutical Sciences.,37:334-40.

5. Lieven Baert ., Markus Thommes., Gerben van t Klooster., Marian Geldof., Laurent Schueller., Jan Rosier., Peter Kleinebudde., ‘Improved bioavailability of darunavir by use of κ-carrageenan versus microcrystalline cellulose as pelletisation aid’., European Journal of Pharmaceutics and Biopharmaceutics., 2009; Volume 72: 614-20. 6. Podczeck F., Alessi P., Newton J.M., ‘The preparation of pellts containing non-ionic surfactants by extrusion and spheronization’., International Journal of Pharmaceutics. 2008;36:36-40. 7. Ramo ‘n Marti ‘nez-Pacheco., Consuelo Souto., Alberto Rodríguez., Silvia Parajes., ‘A comparative study of the utility of two super disintegrants in microcrystalline cellulose pellts prepared by extrusion –spheronization’., European Journal of Pharmaceutics and biopharmaceutics., 2005; 61:94-99. 8. Sriamornsak ., Jurairat Nunthanid., Manee Luangtana-anan., Satit Puttipipatkhachorn., ‘Alginate-based pellets prepared by extrusion-spheronizaton, a preliminary study



on the effect of additive in granulating liquid’., European Journal of Pharmaceutics and biopharmaceutics., 2007; 67:227-35. 9. Ramo ‘n Marti ‘nez-Pacheco., Consuelo Souto., Alberto Rodríguez., Silvia Parajes., ‘A comparative study of the utility of two super disintegrants in microcrystalline cellulose pellts prepared by extrusion –spheronization’., European Journal of Pharmaceutics and biopharmaceutics., 2005; 61:94-99. 10.Steckel.H ., Mindermann-Nogly .F., ‘Production of chitosan pellets by extrusion and spheronization’., European Journal of Pharmaceutics and biopharmaceutics.,2003; 557:107 11.Ingunn tho ., Sverre Arne Sande., Peter Kleinebudde., 2003. ‘ Disintegration pellets form a water insoluble pectin

derivative eproduced by extrusion/spheronisation’.,European Journal of Pharmaceutics and biopharmaceutics.,2003; 56:371-80 12. Newton J.M., Sousa., Sousa. A., Podczeck. F., ‘Factors influencing the physical characteristics of pellets obtained by extrusion and spheronization’., International Journal of Pharmaceutics.,2002; Vol 232:91-106. 13. Gayot .A ., Dupont.,Flament M.P.,Leterme P.,Farah N., ‘ Developing a study method for producing 400µm spheroids’., International Journal of Pharmaceutics.,2002; 247:159-65. 14. Rabis kova M ., Pérez J. P., ‘Influence of drying technique on theophylline pellets prepard by extrusion-spheronization’., International Journal of Pharmaceutics.,2002; 242:349-51.

Source of funding: - None Conflict of Interest: - Not declared.

Corresponding Author:- M.Srujan Kumar.(Asst.Professor) Samskruti college of Pharmacy Kondapur,R.R District,Hyderabad,India-501301.

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