Formulation Development and Evaluation of Fast Disintegrating Sustained Release Pellets Containing Verapamil Hydrochloride Tablets by Fluidized Bed Processor

Jagruti J. Pansare*, Rajendra K. Surawase

Department of Pharmaceutics, Loknete Dr. J. D. Pawar College of Pharmacy, Manur, Tal. Kalwan- 423501 Dist.-Nashik, (MH) India.

*Corresponding Author E-mail: pansarejagruti2402@gmail.com

ABSTRACT:

This study aimed to developed novel fast disintegrating sustained release pellets containing tablet by using Fluidized Bed processor. Verapamil HCl used as a model drug for the formulation. Fluidized bed processor was used for coating of drug and polymer on the sugar spheres. To overcome the problem of swallowing for paediatric, geriatric, psychiatric, bedridden patients, uncooperative patients or for active patients who are busy and travelling and may not access to we aim to formulate the fast-disintegrating tablet. The superdisintigrant are commonly use like cross povidone, sodium starch glycolate which disintegrate tablet rapidly. It is assumed that, after the disintegration of tablets, pellets within tablets which are reside in GIT for several hours and gradually released a drug in controlled way. Eudragit RS 30D and ethyl cellulose were used as a sustained release polymer. Coating of spheres with sustained release film is achieved by bottom spray processor of FBP. Proper pellets coating film thickness, and concentration of polymers’, ensure obtaining desirable VH release profile for extended period of time, was defined. X composition of tablet with pellets were examined in order to obtained formulation, from which VH release would mostly appropriate pellets before compressing. Compression of pellets into tablet, being a modern technological process than enclosing them into hard gelatine capsule. The optimized batch evaluated by studied the effect of compression force, tablet hardness and friability and drug release from the pellets by sustained release manner.

Graphical Abstract:

KEYWORDS: Verapamil Hydrochloride, Coated Sustained release pellets, Superdisintigrant, FDT, Fluidized bed processor.

INTRODUCTION:

Verapamil HCl is the class of calcium channel ion influx inhibitor, which is used in the treatment of hypertension, angina, supraventricular tachycardia characterized by pH dependent solubility¹. Verapamil HCl is considered as an ideal drug for formulation because of high frequency of administration and short biological half-life².

The development of an appropriate dosage form is desirable, swallowing is the major problem with the paediatric, geriatric, psychiatric, bedridden patients, uncooperative patients³ or for active patients who are busy and travelling and may not access to water (also who are unable to swallow the tablets properly or high dose of tablets⁴ (approximately 500-1000mg), to overcome this problem, we aim to formulate the fast-disintegrating tablet. The superdisintigrant are commonly use like croscarmellose sodium, sodium starch glycolate^5,6 which disintegrate tablet rapidly.

Once-a-day sustained release formulations provide an additional advantage for the pediatric and adult patient population where compliance as an issue. Sustained release orally disintegrating tablets can offer advantage of both fast-disintegrating technology⁷ and sustained release technology, which provide additional clinical value to patients. Sustained release fast disintegrating tablet should be able to disintegrate completely⁸ in mouth without releasing drug from the pellets until it reaches to its site of absorption whether to stomach or small intestine and releasing the drug at predetermined rate. The sustained release polymers are HPMC, Eudragit or ethyl cellulose has more drug retardant property. Drug retardation is directly proportional to the thickness of polymer coating.⁹

Compression of pellets into tablet is a modern technological process in pharmaceutical industry; however it is much more ideal than enclosing them in hard gelatine capsule. A larger dose can be immersing into a tablet. Pellets are the type of modified drug delivery system they are agglomerate a fine powder or granules of bulk drug and excipients¹⁰. They are consisting of small, free flowing, spherical or semi-spherical solid unit which are intended usually for oral administration. As drug-delivery systems become more sophisticated, the role of pellets in the design and development of dosage forms is increasing. A generally accepted view is that pellets perform better in vivo than single unit dosage form, as they spread out through the length of the intestine cause less irritation, slower transit through the colon and give a more reproducible drug release.

Pellets can divide into desired dose strength without formulation or process changes and also provide different release profile at same or different stie of action of git. Pelletized product not only offer flexibility in dosage form design and development but also utilized to improve the safety and efficacy of bioactive agent11.

In present study, the sustained release pellets are formulated by fluidized bed processor. Fluidized bed processor is widely used equipment is coating, granulation, palletization, drying of pharmaceutical manufacturing¹². Fluidized bed processor is made up of stainless steel and it contains exhaust air duct, coating chamber, funnel like modification, support screen, air atomization nozzle, liquid feed for nozzle, atomizing air supply, fluidizing air supply¹³. The most commonly used fluid bed process for coating in pharmaceutical industry is the bottom spray (wurster) process. A fluid bed is a bed of solid particle through which hot air is passed at high pressure through air distribution plate/bottom of container. The particles are lifted from the bottom and suspended in air stream. This condition is known as air stream. With the help of spray nozzle granulating liquid or coating solution¹⁴ is sprayed to produces granules or coating of particles respectively and then dried with hot air.

Parts of Fluidized Bed Processor

1. Dial gauge

2. atomization air nipple

3. Control switch (regulator) for inlet airflow and atomization air.

4. HMI(4”)

5. filter housing assembly

6. Expansion chamber

7. product container.

8. Lower plenum

9. port for top spray nozzle

10. temperature sensor

11. Port for bottom spray nozzle^15-16

MATERIALS AND METHODS:

Material:

Verapamil HCl (Balaji drugs), HPMC, pvpk30, Eudragit, ethyl cellulose, sodium lauryl sulphate, talc, isopropyl alcohol, sodium starch glycolate, lactose, magnesium stearate, mannitol.

Equipment:

Fluidized Bed Processor (Acg- Miniquest -f), Tablet punching machine (Cemach), Dissolution apparatus (Electrolux USP), UV-spectrophotometer (Lab-India), Disintegration test apparatus (Electrolab).

Method:

Composition of sustained release pellets (coating mixture)

DRUG layering (Seal coating)

Table 1: Dug layering

Sr. No.	Ingredients	Concentration (mg)
1	Verapamil HCl (Drug)	180
2	HPMC	45
3	PVP K30	30
4	Sodium lauryl sulphate	0.2
5	Isopropyl alcohol	180
6	Talc	22
7	Sugar sphere	400
8	Water	Q.S

Formulation of verapamil HCL SR pellets:

The formulation was prepared by solution layering technique was performed in fluidized bed processor (ACG-MINIQUEST-F).

Solution layering technique

1. Sub coating

2. Drug coating

3. Functional coating

Take a sugar sphere, and then dissolve HPMC 5cp in boiled distilled water. The mixture was sprayed on sugar sphere as sub coating. Verapamil HCL was suspended in water or organic solvent of PVP k30, sodium lauryl sulphate, talc, IPA. The layering solutions were sprayed on sub coated sugar spheres to achieve a drug loading as a second layer of coating. Functional coating is achieved by coating the water insoluble drug retardant polymer. As shown in table. 3

Polymer coating:

Table 2: Polymer coating and tablet composition

Sr. No.	Ingredients	F1	F2	F3	F4	F5	F6	F7	F8	F9
1.	Drug Loaded Pellets(mg)	860	860	860	860	860	860	860	860	860
2.	Eudragit RS 30D (%)	1	2	3	-	-	-	1	2	3
3.	Ethyl cellulose (%)	-	-	-	1	2	3	1	2	3
4.	Ethanol	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S	Q.S
Composition of Fast disintegrating pellets containing tablets
5.	Sustained release drug containing pellets	860	860	860	860	860	860	860	860	860
6.	Sodium starch glycolate	45	45	45	27	27	27	36	36	36
7.	Cross povidone	15	26	37	15	26	37	15	26	37
8.	Talc	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5	0.5
9.	Lactose	15	15	15	15	15	15	15	15	15
10.	Mg. Stearate	1	1	1	1	1	1	1	1	1
11.	Methyl paraben	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
12.	Propyl paraben	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5	1.5
13.	Mannitol	61.	50	54	79	68	57	85	56	48

* all quantities in mg

Table 3: Coating process parameters of FBP

Sr. No.	Processing parameters	Setting
1.	Wurster insert	Bottom spray
2.	Batch size	30gm
3.	Mesh size	425 μm in diameter
4.	Nozzle diameter	0.06mm
5.	Preheating temperature	38℃
6.	Preheating time	5 min
7.	Atomizing air pressure	1.0-1.6 bar
8.	Product temperature	35℃
9.	Inlet temperature	38℃
10.	Purging time	3 sec
11.	Spray rate	1.5 ml/min
12.	Fluidizing pressure	1.2 bar
13.	Time	30 min

Compression of pellets into fast disintegrating tablet:

Tableting excipients, sodium starch glycolate, talc, lactose, magnesium stearate, mannitol was mixed manually in mortar pestle for 5 min, then pellets were added into tableting mixture and compressed by tablet punching machine (Cemach) by 12mm of punch.

RESULT AND DISCUSSIONS:

Organoleptic properties:

Verapamil hydrochloride received was White crystalline powder, free of odour and bitter in taste.

Melting point:

Melting point of Verapamil is 150-155 ℃. determination of melting point is performed by capillary tube method.

Solubility:

Verapamil HCl is Soluble in water, sparingly soluble in Ethanol and practically insoluble in ether.

UV-Spectrum of Verapamil hydrochloride:

Determination of λ max of Verapamil hydrochloride in Water: The Ultra-violet spectroscopic absorbance of verapamil hydrochloride was done in Water at the 270ʎ max

Fig. 1: Spectrum of Verapamil Hcl in Water

Absorbance of Verapamil Hcl at λ=270nm

Table 4: Absorbance of Verapamil HCl in given conc.

*Conc (µɡ/ml)*	Absorbance
10	0.036
20	0.042
30	0.052
40	0.076
50	0.102

Calibration curve of verapamil hydrochloride in water:

Fig. 2: Absorbance of Verapamil HCl

FTIR study:

Fig. 3: FTIR Spectra of Verapamil HCl

It is conclude that, organoleptic properties, solubility, meting point, Uv spectrum and FTIR study results are complies with IP, so the result proved that the Verapamil HCl is pure drug and it is suitable for formulation and devlopment of formulation.

Precompresssion evaluation of pellets:

Table 5: precompression evaluation of pellets

Sr. No.	Formulation Code	Bulk Density (gm/ml)	Tapped Density (gm/ml)	Angle of Repose ( ̊ )	Carr’s Index (%)	Hausner’s Ratio
1	F1	0.48	0.54	27.05	11.11	1.22
2	F2	0.40	0.46	30.15	13.04	1.15
3	F3	0.51	0.55	24.15	7.27	1.07
4	F4	0.45	0.55	37.55	18.18	1.22
5	F5	0.50	0.56	26.41	10.71	1.11
6	F6	0.51	0.57	28.10	10.52	1.12
7	F7	0.45	0.55	37.20	25.61	1.22
8	F8	0.40	0.47	28.48	14.89	1.17
9	F9	0.42	0.52	30.19	19.20	1.23

Post compression evaluations of tablets

Table 6: Post compression evaluations of tablets

Sr. No.	Formulation code	Weight variation (mg)	Hardness (mm)	Friability (%)	Disintegration time (sec)	Percent Drug Content
1	F1	999	4.32	0.65	27	91.66
2	F2	1000	4.38	0.74	25	93.26
3	F3	1000	4.25	0.48	21	97.75
4	F4	998	5.28	0.51	24	88.52
5	F5	999	5.30	0.53	31	90.23
6	F6	1000	5.44	0.56	30	94.91
7	F7	1002	4.51	0.90	34	85.56
8	F8	998	4.54	0.81	36	81.46
9	F9	1002	4.61	0.92	38	79.65

The weight variation obtained for all the formulations in the range of 998 to 1002mg. The wight variation of tablets are within the range. The hardness of the tablets of all the formulation was found in the range of 4.25 to 5.56kg/cm² which is good or in the acceptable range. The friability was found to be in the range 0.48 to 0.90%.

Fig. 4: % Drug content

In vitro dissolution studies:

The release rate of Verapamil hydrochloride tablets was determined using Dissolution Testing Apparatus 2 (paddle method). The dissolution test was performed using 900 ml of O.1 N HCl buffer for 2 h followed by pH 6.8 Phosphate buffer for 24 h. A sample 5ml of the solution was withdrawn from the dissolution apparatus hourly and the samples were replaced with fresh dissolution medium. The samples were filtered through a Whattman filter paper and diluted to a suitable concentration with of pH 0.1 N HCl buffer for 2 h followed by pH 6.8 Phosphate buffer for 24 h. Absorbance of these solutions was measured at 270 nm using a UV Spectrophoto-meter¹⁷.

In-vitro dissolution study:

Table 7: In-vitro dissolution study

Time (hr.)	F1	F2	F3	F4	F5	F6	F7	F8	F9
0.1N HCl
0	0	0	0	0	0	0	0	0	0
1	12.66	11.45	13.15	15.22	18.65	16.18	16.20	12.40	14.23
2	19.29	20.25	19.52	22.25	20.17	22.65	22.68	16.25	18.64
pH 6.8 Phosphate buffer
3	32.66	31.15	31.11	28.30	25.79	25.45	16.18	21.18	22.99
4	42.42	45.88	40.26	30.16	32.71	31.89	31.89	27.45	31.38
6	51.53	52.87	45.38	34.19	37.49	40.56	40.57	32.16	39.37
8	58.31	61.25	52.44	40.78	46.20	48.18	48.45	38.41	46.28
10	61.45	65.77	59.12	49.49	54.17	54.13	54.30	48.25	50.13
12	68.52	68.56	63.11	56.93	62.71	60.14	60.18	52.15	57.17
14	70.22	71.56	69.45	63.64	70.46	66.24	66.24	58.39	64.23
16	75.44	78.65	75.66	72.92	78.36	79.36	70.36	69.37	72.12
18	81.36	85.22	82.13	80.54	82.64	89.47	76.47	73.24	76.87
20	88.24	89.66	88.27	90.71	85.22	92.84	80.84	78.45	79.34
22	-	91.45	93.12	-	88.91	-	85.22	82.75	85.14
24	-	-	98.65	-	-	-	90.54	87.45	-

Fig. 5: Percent drug release profile F1-F3 batches

Fig. 6: Percent drug relase profile F4-F6

Fig 7: % Drug release profile of F7-F9 batches

CONCLUSION:

In Conclusion, the article provide novel concept of fast disintigrating sustained release tablets of drug having short half life and ph-Sensitive property. It is most essential in preparing pelltes for compression to avoid film damage and deformation during the process. Damage of film may change the drrug release rate. Due to the large size of conventional tablet, aimed to formulate fast disintigrating tablet with modified relase. Selecting polymer for coating not only for its diffusion property but also for physical properties like resistance to compressing. Eudragit and ethyl cellulose are use as a retardant polymer, But Eudragit RS30D 24 hr. drug release. Ethyl cellulose show upto 20-22hr drug release. Combination of Eudragit RS 30D and E.C shows less drug release as compare to other. So F3 batch is optimized. The disintigration time of F3 batch is also less. So, it disintigrate early and shows more drug release. Compressiblity of all tablet formulation proceed properly. Sticking of tablet to the punch was not observed. The tablets which are obtained after compression had a smooth surface, On which distributed darker points showing the pellets location were visible.

ACKNOWLEDGEMENT:

We are grateful to the teacher’s and Principal of Loknete Dr. J. D. Pawar College of Pharmacy, Manur, Tal. Kalwan for their helpful guidance.

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