1. INTRODUCTION:

Microcapsule system is one of the novel drug delivery system found applications in many areas of science and technology. Microencapsulation technology is an innovator in the encapsulation science. This technology forms a basis for the development of various micro and nano drug loaded capsules. This technology has wide applications in pharmaceuticals, cosmetics, agricultural industry, food technologies and textiles industry.

Microencapsulation is a process by which very tiny droplets or particles of liquid, solid or even gas material are surrounded or coated with a continuous film of polymeric material.

It includes Bioencapsulation which is more restricted to the entrapment of a biologically active substance (from DNA to entire cell or group of cells for example) generally to improve its performance or enhance its shelf life.^1,2

Microencapsulation techniques:

Various techniques are available for the encapsulation of core materials. Broadly the methods are divided into three types. Different types of microencapsulation techniques are-

1. Chemical methods:

Like Interfacial polymerization, In situ polymerization, Poly condensation

2. Physico-chemical methods:

Like Coacervation and phase separation, Sol-gel encapsulation, Supercritical CO₂ assisted microencapsulation

3. Physico-mechanical methods:

Like Spray drying and congealing, Fluid bed coating, Pan coating Solvent evaporation

HOT MELT GRANULATION METHOD^3-7:

Fluidized Hot-melt granulation is an agglomeration process (FHMG) granules are obtained by melting binders that are heated to near or above their melting point. FHMG is an innovative technique involving meltable binder to agglomerate fluidized dry powders. Fluidized Hot-melt granulation techniques have received enhancing attention due to the significant advantages compared to the other granulation methods. Fluidized hot melt granulation (FHMG) is recommended as promising technique. FHMG is simple and rapid granulation technique that enables a scientist to manipulate drug release rate depending on the properties and concentration of the meltable binder. It provides a sophisticated robust process for poorly soluble drug of oral dosage form. Proper selection & optimization of formulation, equipment & process related variable in Fluidized hot melt granulation can lead to successful scale up of Fluid-bed processing technology from the small scale to large scale production successfully.

Requirements of Hot Melt Granulation:

Amount of meltable binder is 10%-30% w/w with respect to that of fine solid particles is used. A Meltable binder suitable for melt a granulation has a melting point typically within the range of 60-80°C. Hydrophilic Meltable binders are used for prepare immediate-release dosage forms while the hydrophobic Meltable binders are preferred for prolonged-release formulations. The melting point of other fine solid particles should be at least 20°C more than that of the maximum processing temperature.

Applications in the pharmaceutical industry:

In pharmaceutical industry, melt extrusion has been used for various purposes, such as-

1. Improving the dissolution rate and bioavailability of the drug by forming a solid dispersion or solid solution.

2. Controlling or modifying the release of the drug.

3. Masking the bitter taste of an active drug.

4. Enhancing the tabletting compactability of poorly compactible high dose drugs.

5. Enhancing the chemical stability of highly water soluble drugs.

6. Preparation of fast dissolving tablets of poorly water soluble drugs.

7. Preparation of sustained release floating tablets.

Materials used in melt granulation^8-13:

Binders or matrix carriers:

In hot-melt extruded drug delivery systems, the active compound is embedded in a carrier formulation, often comprised of one or more “meltable” substances and other functional excipients. The meltable substance is generally a polymer or low melting point wax.

Lipids are considered as an alternative to polymer in the design of sustained drug delivery system due to their advantages such as low melt viscosity (thus avoiding the need of organic solvents for solubilization), absence of toxic impurities such as monomer catalysis and initiator, potential biocompatibility and biodegradability.

Plasticizers:

Plasticizers are typically low molecular weight compounds capable of softening polymers to make them more exible. The use of polymeric carriers in melt granulation often requires the incorporation of a plasticizer into the formulation to improve the processing conditions during the manufacturing of the extruded dosage form or to improve the physical and mechanical properties of the final product.

Plasticization of the polymer is generally attributed to the inter-molecular secondary valence forces, addition of a plasticizer, a melt granulation process can be conducted at lower temperatures and with less torque. Generally, both the active ingredient and the polymer will be more stable during the granulation process due to these improved processing conditions.

Other Processing Aids:

Anti-oxidants:

Ascorbic acid, Butylated hydroxyanisole, Butylated hydroxytoluene and vitamin E.

Lubricants:

Magnesium stearate, Aerosil 1000 etc.

2. MATERIALS AND METHODS:

2.1 Materials:

Drug- Diltiazem Hydrochloride.

Polymers and Excipients- Stearic acid, Guargum, HPMC K100 M, Carbapol 940, Ethyl Cellulose, Sodium Bicarbonate, Lactose, Aerosil.

2.2 Method:

Stearic acid was dissolve at 60-70 C in Petridis then required amount of polymer like HPMC K100 M, Carbapol 940, Ethyl Cellulose was added to it then sodium bicarbonate was added to it then Lactose and Aerosil were added to it then finally drug was added and it was cool to form a congeal mass then this was passed through sieve no 100 and was dried and then evaluation tests were performed.

Table No -1 Formulation of Oral Floating Microencapsules of Diltiazem Hydrochloride

Ingredients	F1	F2	F3	F4	C1	C2	C3	C4
Diltiazem Hcl (mg)	30	30	30	30	30	30	30	30
Steric acid (mg)	500	500	500	500	500	500	500	500
GlycerylMonosterate	-	-	-	-	500	500	500	500
HPMC K100	-	-	1%	-	-	-	1%	-
Gaurgum	-	-	-	1%	-	-	-	1%
Carbopol 940	1%	-	-	-	1%	-	-	-
Ethylcellulose	-	1%	-	-	-	1%	-	-
Sodium Bicarbonate	1.5%	1.5%	1.5%	1.5%	1.5%	1.5%	1.5%	1.5%
Aerosil (mg)	50	50	50	50	50	50	50	50
Lactose (mg)	50	50	50	50	50	50	50	50

3. EVALUATION PARAMETERS^14-19

3.1 Determination of λ max:

The standard solutions of Diltiazem hydrochloride were scanned in the range of 200-400 nm against 0.1N HCl solution as a blank. Diltiazem hydrochloride showed maximum absorbance at 240 nm.

Calibration curve of Diltiazem hydrochloride in 0.1N HCl buffer:

Preparation of standard stock solution:

A standard stock solution containing 1000 μg/ml was prepared by dissolving 100 mg of Diltiazem hydrochloride in100 ml of 0.1N. HCl solution.

Preparation of the test solution:

Diltiazem hydrochloride:

The standard stock solution containing 1000μg/ml of Diltiazem hydrochloride, was prepared in 0.1 N HCl, from this stock solution pipette out and dilutions were prepared as 2., 4, 6, 8, 10 µg/ml and absorbance was taken at 305 nm.

3.2 Preformulation studies:

In the preformulation studies Bulk density, Tapped

density, Compressibility index, Hausner’s ratio, Angle of repose, were performed.

3.3 Particle size determination:

Particle size determination was performed by optical microscopy method. First stage and eye piece micrometer were taken then microscope was calibrated using stage and eyepiece micrometer. Then the solution of microencapsules was prepared then it was spread on slide as a thin film and was observed under this microscope and particle size was detected.

3.4 Floating lag time:

In this test 100 mg of Floating Microencapsules was added into the 900 ml dissolution vessel containing 0.1N HCl at 37 C. It is the time the formulation took to emerge on surface of dissolution medium is referred as floating lag time.

3.5 Floating duration:

In this test 100 mg of Floating Microencapsules was added into the 900ml dissolution vessel containing 0.1N HCl at 37 C. The time that formulation took to remain constantly floating on surface of dissolution medium is referred as duration of floating.

3.6 Percentage Drug Entrapment Efficacy (%DEE):

The yield of microencapsules were determined by comparing the whole weight of Microencapsules formed against the combined weight of the copolymer and drug.

Mass of microencapsules obtained

% Practical yield = –––––––––––––––––––––––––––––––– X 100

Total weight of drug and polymer used

3.7 Drug Content Uniformity:

Accurately weighed microencapsules equivalent to 100 mg were suspended in 100 ml of 0.1 N HCL, it was shake for 30 min and kept for 24hrs. Next day it was stirred for 5 min and filtered. After suitable dissolution, the drug content in the filtrate was analyzed spectro photo metrically at using Shimadzu UV spectrophotometer.

The drug content uniformity was calculated by-

Actual drug content

Percentage Drug Entrapment Efficiency = ––––––––––––––––– X 100

Theoretical drug content

3.8 Filled capsules parameter:

a. Capsule appearance:

The prepared capsule was evaluated visually.

b. Capsule lock length:

The capsules lock length was determined using Vernier caliper. Six capsules from each batch of formulation were used and mean lock length value and stand.

c. Weight variation:

To study the weight variation, 20 capsule of each formulation were weighed using an electronic digital balance. The average weight of each capsule was calculated and the percentage deviation in weight was calculated.

3.9 In vitro dissolution study:

An in vitro release study was carried out using dissolution test apparatus USP Type II (Paddle Method). Dissolution parameters used for the study are-

1) Dissolution media- 900 ml of Hydrochloric acid buffer solution of pH 1.2

2) Temparature- 37 C ± 0.2 C

3) Speed of rotation (RPM)- 50

3.10 Drug Kinetic study:

The release data obtained from various batches were studied with respect to effect of drug: polymer ratio. To analyze the mechanism of drug release from the formulation, the dissolution profile of optimized batches was fitted to zero order, first-order, Higuchi, Hixson-Crowell, Korsemeyer and Peppas models to ascertain the kinetic modeling of drug release.

4. RESULT AND DISCUSSION:

4.1Calibration curve of Diltiazem Hydrochloride in 0.1 N Hydrochloric Acid

100 of drug Diltiazem Hydrochloride was dissolved in 0.1 N Hydrochloric Acid Buffer and volume was make up to 100 ml. And dilutions were made as 2, 4, 6, 8, 10 µg/ml and absorbance was taken at 240 nm. It is given in table no 5

4.2 Preformulation Studies:

All the preformulation studies like bulk density, tap density, angle of repose etc, physical characterization of drug sample, Analytical characterization of drug sample were performed.

Table No 2 -Calibration curve of Diltiazem hydrochloridein 0.1 N Hydrochloric Acid

Sr.No	Concentration (ug/ml)	Absorbance
1.	2	0.115
2.	4	0.214
3.	6	0.322
4.	8	0.425
5.	10	0.52

Fig No 1- Calibration curve Diltiazem hydrochloride in 0.1 N HCl

Table No 3 - Preformulation Testing of Floating Microencapsules of Diltiazem HCl

Sr. No.	Formulation Code	Bulk density (gm/cm3)	Tapped density (g/cm³)	Compressibility Index (%)	Hausner Ratio	Angle of Repose (θ)
1	F1	0.54 ±0.21	0.62 ±0.29	11.96 ±0.17	1.14 ±0.17	26.57 ±0.33⁰
2	F2	0.62 ± 0.23	0.69 ±0.27	11.11 ±0.33	1.13 ±0.22	27.51 ±20⁰
3	F3	0.57 ±0.098	0.63 ±0.19	9.71 ±0.25	1.11 ±0.16	29.05 ±0.21⁰
4	F4	0.65 ± 0.13	0.71 ±0.17	9.68 ±0.29	1.11 ±0.20	28.52 ±0.26⁰
5	C1	0.54 ± 0.33	0.59 ±0.13	8.60 ±0.12	1.09 ±0.16	29.60 ±0.32⁰
6	C2	0.56 ±0.20	0.77 ±0.19	27.78 ±0.22	1.38 ±0.13	30.76 ±0.22⁰
7	C3	0.58 ±0.22	0.65 ±0.22	10.47 ±0.31	1.12 ±0.21	27.51 ± 0.19⁰
8	C4	0.63 ±0.11	0.70 ±0.15	11.25 ±0.18	1.13 ±0.13	29.38 ±0.28⁰

N=3

Table No 4: Various Characterization of Floating Microencapsulation of Diltiazem Hydrochloride

Formulation code	%DEE	Drug content Uniformity (%)	Floating lag time (Sec)	Floating Time (Hr)
F1	91	60	Immediate	>12
F2	94	70	Immediate	>12
F3	92	65	Immediate	>12
F4	99	70	Immediate	>12
C1	96	68	Immediate	>12
C2	95	62	Immediate	>12
C3	90	64	Immediate	>12
C4	92	66	Immediate	>12

Table no 5: Other Evaluation Parameters of Floating Microecapsules Diltiazem HCl.

Parameters	F1	F2	F3	F4	C1	C2	C3	C4
Capsule Lock Length	15.6	15.6	15.6	15.6	15.6	15.6	15.6	15.6
Weight Variation	Passes	Passes	Passes	Passes	Passes	Passes	Passes	Passes

Table No 6- Showing % Invitro Drug Release of Diltiazem Hydrochloride

Sr. No	Time (hr)	% Drug Release
		F1	F2	F3	F4	C1	C2	C3	C4
1	0	0	0	0	0	0	0	0	0
2	2	60.59	46.74	42.70	13.86	26.55	25.40	50.20	45.01
3	4	70.46	62.94	69.29	39.83	56.58	78.50	55.45	69.87
4	6	78.61	84.94	76.23	65.84	91.83	83.78	72.82	78.60
5	8	96	89.07	83.87	78.60	-	95.41	83.86	88.49
6	10	-	92.05	92.04	90.23	-	-	94.33	95.51
7	12	-	-	95.60	99.56	-	-	-	-

The pre formulation studies like Bulk density, Tapped density, %Compressibility, Hausners ratio and angle of repose were performed and these are mentioned in above table. The values were lies in between Bulk density 0.54 ±0.21- 0.65 ± 0.13, Tapped density 0.59 ±0.13- 0.77 ±0.19, % Compressibility 9.71 ±0.25- 27.78 ±0.22, Hausners ratio 1.09 ±0.16 - 1.38 ±0.13, and Angle of Repose 26.57 ±0.33 - 30.76 ±0.22

4.3 Particle size determination:

The size of microencapsules was obtained by Optical microscopy using Stage and eyepiece microscope. The size was found to be 0.149 ± 0.011 mm. for optimized batch.

% Drug Entrapment Efficiency (%DEE):

The yield of microencapusles were determined by comparing the whole weight of beads formed against the combined weight of the copolymer and drug. %DEE of formulated microencapsules was found to be 90 to 99%. The optimized batch F4 gives %DEE as 99%.

Drug Content Uniformity:

All the prepared formulations show drug content uniformity in the range of 60-70% The optimized batch show drug content uniformity 70%.

Floating Lag time :

Floating lag time of all the prepared formulations was observed by visual examination. All the prepared formulations show Floating lag time to immediate. And the optimized batch F4 show immediate floating after entering in 0.1 N HCl and show floating for more than 12 hrs.

Floating Duration:

All prepared formulation show floating duration more than 12 hours.

C. Evaluation of Filled Capsule:

· Physical Description

· Colour : White

· Weight of empty capsule : 66±4 mg

Capsules of different formulations were subjected to various evaluation tests, such as capsule lock length, uniformity of weight, drug content. All formulations showed uniform capsule lock length. The weight variation test was carried out as per official method and the per cent deviation of formulation was found to be within limit.

4.5 In vitro dissolution study:

An in vitro release study was carried out using dissolution test apparatus USP Type II (Paddle Method).

Fig No 1- % Drug release of batches F1-F4

Fig No 2 - % Drug release of batchs C1-C4

4.7 Kinetic Studies:

The release data obtained from various batches was studied with respect to effect of drug: polymer ratio, diluents ratio. Dissolution data of drug from prepared in situ gel at different time periods was plotted as cumulative % drug release v/s time. The dissolution data so obtained was fitted to various kinetic models like Zero Order, First order, Higuchi, Korsmeyer-Peppas models. It was found that the optimized batch F8 follow Zero order model.

The drug release kinetics from all the batches were calculated, which was illustrated as follows-

Table No 7 : Kinetic Study of Floating Microencapsules of Diltiazem Hydrochloride

Batch	Zero order	First order	Matrix	Peppas	Hixon crowell	Best Model fit
F1	0.5989	0.8918	0.9952	0.9852	0.6915	Matrix
F2	0.6323	0.9444	0.9449	0.8686	0.9334	Matrix
F3	0.8168	0.9940	0.9878	0.9764	0.9746	First Order
F4	0.9938	0.8553	0.9509	0.9798	0.9635	Zero Order
C1	0.5492	0.6929	0.9918	0.9805	0.9786	Matrix
C2	0.6198	0.5320	0.8680	0.7790	0.5830	Matrix
C3	0.7689	0.8780	0.9696	0.9438	0.8842	Matrix
C4	0.7164	0.8454	0.9579	0.9327	0.8436	Matrix

5. SUMMARY AND CONCLUSION:

There are many reasons towards microencapsulation. In some cases, the core must be isolated from its surroundings, as in isolating vitamins from the deteriorating effects of oxygen, retarding evaporation of a volatile core, improving the handling properties of a sticky material or isolating a reactive core from chemical attack. There are several reasons why substances may be encapsulated.

1. To control release of the active components for delayed (timed) release or long-acting (sustained) release.

2. The drugs, which are sensitive to oxygen, moisture or light, can be stabilized by microencapsulation.

3. Incompatibility among the drugs can be prevented by microencapsulation.

4. Many drugs have been microencapsulated to reduce toxicity and GI irritation.

5. Alteration in site of absorption can also be achieved by microencapsulation.

6. Toxic chemicals such as insecticides may be microencapsulated to reduce the possibility of sensitization of factorial person.

7. To enhanced stability.

In the present study some natural and synthetic polymers were used like guargum, carbapol 940, HPMC K100 M, ethyl cellulose with bases like steric acid alone and in combination of stearic acid and glyceryl mono stearate. Where batches F1 to F4 were of stearic aacid alone as base and batches C1 to C4 were of combination of stearic acid and glycerine monostearate in 1:1 ratio. Among these batches batch F1 shows drug release for 8 hrs and gives drug release to 96%. batch F2 gives result to 10 hrs as 92%, batch F3 gives result for 12 hrs and shows release as 95.60%, batch F4 gives release foe 12 hrs and gives result as 99.56%, batch C1 gives release for 6 hrs as 91.83%, batch C2 gives result for 8 hrs as 95.41%, batch C3 gives result for 10 hrs as 94.33% and batch C4 gives drug release for 10 hrs as 95.51%.

The optimised batch F4 was of polymer Guargum 1% which is a natural polymer which shows sustained release tendency for any drug delivery system. In this formulation batch F4 having Guargum as polymer in the concentration of 1% gives maximum drug release for12 hrs. as 99.56% and gives sustained release for 12 hrs. Where other polymers like HPMC K100 m, Ethyl Cellulose, and Carbapol 940 was unable to give sustain release. This batch also shows % DEE as 99%, drug content uniformity 70%, floating lag time immediate and floats for more than 12 hrs.

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Received on 25.06.2019 Modified on 27.07.2019

Research J. Pharm. and Tech. 2020; 13(1): 227-232.

DOI: 10.5958/0974-360X.2020.00046.3