INTRODUCTION:

The concept of sustained released formulation was developed to eliminate need for multiple dose regimens.⁴ Multiple unit drug delivery systems are more convenient than single unit drug delivery system as it improves patient convenience and compliance due to less frequent administration. It also reduces the fluctuation in steady state levels and therefore better control of disease condition and reduced intensity of local or systemic side effects. It enhances safety margin of high potency drugs due to better control of plasma levels. It increases utilization of drug enabling reduction in total amount of dose administered. The reduction in health care costs through improved therapy, shorter treatment period, less frequency of dosing, reduction in personal time to dispense, administer and monitor patients.¹³

A market survey reveals that a significant proportion of solid dosage forms available are coated. Immediately following completion of coating process, curing is carried out. In preset study coated solids are generally stored at temperatures above glass transition temperature of polymer to further promote coalescence of film and ensure a homogeneous distribution of plasticizer. The microstructure of polymer is altered and mechanical, adhesive and drug release properties of film without further aging effect is dependent on number of factors, including the type of and concentration of plasticizer, temperature and storage conditions. The storage temperature should be about 10⁰C above the glass transition temperature. Higher the curing temperature cause excessive tackiness and agglomeration of solid dosage form.^35-39

One of most important stages in development of sustained release pellets is coating of pellets. In aqueous based coating systems, aqueous dispersions are recommended to avoid drawbacks such as health hazard, risk of explosion during coating, and environmental factors. After coating with aqueous polymer dispersions coalescence of colloidal polymer particles into homogeneous film is often incomplete. With decrease in temperature, coalescence of polymer occurs leading to prolonged drying time.^26-31

Diltiazem HCl is calcium channel blockers and widely used in the treatment of angina pectoris, systemic hypertension and supraventricular arrhythmias. It is model water soluble drug. It has an extensive and highly variable hepatic first pass metabolism following oral administration having half life of 4.5 hours. So it is a suitable candidate for sustained drug delivery system to avoid frequent dose administration and improve patient compliance and therapeutic efficacy. Surelease brings technological advances with dependable, reproducible extended release profiles that are consistent from laboratory to pilot and production scale processes. It is a complete ready to use system.

Hence, it was envisaged to develop aqueous based film coating for sustained release profile of diltiazem HCI using surelease dispersion.

MATERIALS AND METHODS:

Materials:

Diltiazem HCl was obtained gratis sample from Zim Laboratories (India)Microcrystalline cellulose pH 101 and PVP K-30 were obtained from Signet Chemical Corporation (India) Surelease (E-7-19050)was obtained from Colorcon (India).All solvents and chemicals were of analytical reagent grade.

Optimization of pellets:

In preliminary trials for development of placebo pellets by extruder-spheronization process, the following optimization parameters were studied.

Moisture level:

Extrudes were prepared with different moisture concentration as shown in table 3 and spheronized at 1500 rpm speed for 20 minutes.

Table 1 Composition of pellets with different moisture levels

Sr. No.	Formulation code	Quantity of MCC PH 101 (g)	Quantity of PVP K-30 (g)	Moisture content (%)
1	F1	50	1	90
2	F2	50	1	100
3	F3	50	1	110
4	F4	50	1	115
5	F5	50	1	120

Spheronization time and friction plate speed:

Pellets were prepared at varying spheronization time and friction plate speed as shown in table 2.

Table 2 Composition of pellets at different spheronization time and friction plate Speed

Sr. No.	Formulation code	Quantity of MCC PH 101 (g)	Quantity of PVP K-30 (g)	Spheronization time (Min)	Friction plate speed (rpm)
1	F6	50	1	1	400
2	F7	50	1	3	400
3	F8	50	1	5	400
4	F9	50	1	10	400
5	F10	50	1	20	400
6	F11	50	1	1	800
7	F12	50	1	3	800
8	F13	50	1	5	800
9	F14	50	1	10	800
10	F15	50	1	20	800
11	F16	50	1	1	1000
12	F17	50	1	3	1000
13	F18	50	1	5	1000
14	F19	50	1	10	1000
15	F20	50	1	20	1000
16	F21	50	1	1	1500
17	F22	50	1	3	1500
18	F23	50	1	5	1500
19	F24	50	1	10	1500
20	F25	50	1	20	1500
21	F26	50	1	1	2500
22	F27	50	1	3	2500
23	F28	50	1	5	2500
24	F29	50	1	10	2500
25	F30	50	1	20	2500

Load size and spheronization time

Pellets were prepared at varying load size and spheronization time as shown in table 3.Spheronization speed 1500 rpm was kept constant.

Table 3 Composition of pellets at different load size and spheronization time

Sr. No.	Formulation code	Load size (g)	Quantity of PVP K-30 (g)	Friction plate speed (rpm)	Spheronization time (Min)
1	F31	20	1	1500	1
2	F32	20	1	1500	3
3	F33	20	1	1500	5
4	F34	20	1	1500	10
5	F35	20	1	1500	20
6	F36	50	1	1500	1
7	F37	50	1	1500	3
8	F38	50	1	1500	5
9	F39	50	1	1500	10
10	F40	50	1	1500	20
11	F41	100	1	1500	1
12	F42	100	1	1500	3
13	F43	100	1	1500	5
14	F44	100	1	1500	10
15	F45	100	1	1500	20
16	F46	100	1	1500	1

Development of pellets:

Microcrystalline cellulose was sifted through sieve # 60. PVP K-30 was dissolved in distilled water and was added to powder bend in gradual manner and after each addition; it was kneaded thoroughly to get suitable wet mass. The damp mass transferred into extruder to obtain extrudate. Extrudates were spheronised and dried at 45-50 °C. During development of pellets die-roller size (pore diameter) and speed of die-roller were 2 mm and 15 rpm respectively and spheronization parameters, friction plate type, groove size, were crosshatch pattern, 1 mm were constant respectively.

Drug loading

Table 4 Composition of pellets at different drug load

Sr. No.	Formulation code	MCC PH 101 (g)	Povidone K-30 (g)	Moisture level (%)	Diltiazem HCI
1	F 47	34	1	50	30
2	F 48	39	1	66	20
3	F 49	44	1	82	10

Procedure:

The MCC PH 101 was shifted through sieve # 60. MCC and diltiazem HCl were blended in geometric fashion using mortar. Povidone K-30 was dissolved in distilled water and was added to powder bend in manner.After each addition, it was kneaded thoroughly to get suitable wet mass. The damp mass transferred into extruder to obtain extrudate. Extrudates were spheronized at 1500 for 20 minutes for 30 and 20% loading in the spheronizer. Pellets produced were dried at 45-50 °C.

Coating of pellets:

The coating of diltiazem HCl pellets was done using Surelease aqueous dispersion.

Procedure:

Coating of pellets was done in pear shaped coating pan made of glass. 20 gm of pellets were accurately weighed and rotated. Surelease aqueous dispersion was sprayed over the cascading pellets using manual sprayer and hot air was blown to evaporate the solvent. The process was continued until the predetermined weight of coating material was deposited on pellets. Pellets of different coat build up were done.

Processing condition for surelease film coating:

Glass pear shaped coating pan was required for surelease film coating.at 30rpm.Hot air blower was required for drying. The minimum pressure required was 20 psi. The batch size was 25 gm.

Curing of pellets:

Immediately following the coating process the coated pellets were oven-cured at temperatures 45 and 65°C for 24 hours. The samples of coated but uncured pellets were prepared.

RESULTS:

Optimization of process variables for shape of pellets

Effect of moisture level on shape of pellets:

The moisture, it is necessary to give the powder masses its plasticity so that it can be extruded and shaped afterwards. It is an extremely important parameter in the extrusion spheronisation process. The size and shape of pellets was found to depend on amount of water added to form the damp mass before extrusion. It was observed that the moisture content in the range 105 to 110% respectively produced pellets of an acceptable quality. The increase in amount of water increased the diameter of pellets.

Effect of Spheronization Speed and time on shape of pellets:

At low speed of 400 rpm, it is observed that extrudate does not shortened and does not increased marginal width and dumbbell shaped pellets were formed. There were no spheronisation at 20 minutes on the plate. Doubling the speed to 800 rpm had reduced the length of pellets. Rounding takes a little longer but by 5 min the particles were well rounded and only slight further rounding takes place between this time .This found to be a critical machine feature for spheronisation. Operating the spheroniser at 1000 rpm produced a similar product to that at 800 rpm although there does appear to be an improved roundness after 10 minutes and after 20 minutes spherical pellets were formed. With high speeds of 1500-2500 rpm, there was further reduction in particle length and the rounding occurs more rapidly and more spherical pellets were formed.

Effect of load size and spheronization time on shape of pellets:

The standard extrudate was added to spheroniser in weights ranging from 20 to 100 g for periods between 1 and 20 minutes at a speed of 1500 rpm. The small loads of 20 g produced pellets of least spherical form; the higher loads of 50 g eventually produced spherical pellets. Increase in load size 100 g reduced the sphericity of pellets.

Effect of Drug loading on physical properties of pellets:

The standard extrudate was added to spheroniser in drug loading of 10% for periods between 1 and 20 min at a speed of 1500 rpm. The small loads of 10% produce pellets of least diameter and which eventually have most spherical form, the higher loads of 20% eventually produce round pellets but spherocity was less than 10% loaded pellets and increase in diameter was observed as compared to 10% loaded pellets. Increase in load size 30% reduced the sphericity of pellets and diameter of pellets. At 40% drug loading irregular pellets were observed.

Process parameter were optimized for physical properties of pellets and it was observed that spherical pellets formed from the base formula at moisture content 110%, load size 50 g, spheronization speed 1500-2500 rpm, and spheronization time for 20 minutes.

Evaluation of drug loaded pellets:

Drug content determination:

With loading dose of 10-30%, the drug content was found to be 99.69, 99.15 and 98.86% respectively.

Physical characterization of drug loaded pellets:

The physical properties like size, yield (%), shape, density and friability of selected batches were evaluated.

Coating of drug loaded diltiazem HCl pellets:

The coating of 20 and 30% loaded pellets were done in conventional coating pan with hand spray gun. The pellets of 12-14 # were selected for coating. Pellets of different coat build up viz. 5, 7, 9, 11, 13, and 15% were produced.

Curing of films:

Immediately following the coating process the coated pellets were oven-cured at temperatures 40 and 65°C for period of 24 hours. Additionally, samples of coated but uncured pellets were prepared. The cured and uncured pellets were then subjected to dissolution studies in pH 1.2 and 6.8 phosphate buffer.

In vitro drug release study of cured and uncured pellets:

In vitro drug release studies of the cured and uncured pellets were carried in USP type I apparatus using 900 mL of pH 1.2 phosphate buffer for the first 2 hours and 900 mL of pH 6.8 phosphate buffer for next 10 hours. The speed of rotation of paddle was fixed at 100 rpm and the temperature was maintained at 37±0.5 °C. The release of the drug was analyzed using UV-spectrophotometric method at 236 nm.

Figure 1 Effect of coating load on release of diltiazem HCl from 20% w/w loaded uncured pellets

To study the effect of the coating load on the release of diltiazem HCl from uncured pellets, the release from batches A1 to A6 were evaluated. The results are shown in figure 1. The batch A6 coated up to 15% polymer load retains drug for a period of more than 12 hours and release only 7.9268% as compared with batches A1 to A5 release, drug 89.555, 65.296, 29.947, 19.372 and 10.513% respectively. The coating load of the polymer is increased the coating thickness is increased. Thus, batch A6, which has the most highly thick polymer coat shows a much slower rate of drug release as compared to batches A1 to A5.

Figure 2 Effect of coating load on release of diltiazem HCl from 20% w/w loaded pellets cured at 40°C for 24 hours

To study the effect of the coating load on the release of diltiazem HCl from pellets cured at 40°C for 24 hours, the release from batches A7 to A12 were evaluated. The results are shown in figure 2.

Figure 3 Effect of coating load on release of diltiazem HCl from 20% w/w loaded pellets cured at 65°C for 24 hours

To study the effect of the coating load on the release of diltiazem HCl from pellets cured at 65°C for 24 hours, the release from batches A13 to A18 were evaluated. The results are shown in figure 3.

Figure 4 Effect of coating load on release of diltiazem HCl from 30% w/w loaded uncured pellets

To study the effect of the coating load on release of diltiazem HCl from uncured pellets, the release from batches A19 to A24 were evaluated. The results are shown in fig 4.

Figure 5 Effect of coating load on release of diltiazem HCl from 30% w/w loaded pellets cured at 40°C for 24 hours

To study the effect of the coating load on release of diltiazem HCl from pellets cured at 40°C for 24 hours, the release from batches A25 to A30 were evaluated. The results are shown in fig 5.

Figure 6 Effect of coating load on release of diltiazem HCl from 20% w/w loaded pellets cured at 65°C for 24 hours

To study the effect of the coating load on release of diltiazem HCl from pellets cured at 65°C for 24 hours, the release from batches A31to A36 were evaluated. The results are shown in fig 6.

Figure 7 Effect of drug loading on release of diltiazem HCl from the pellets

The effect of drug loading on release of diltiazem HCl was studied in two formulations; batch A9, A18 and A27 containing 20 and 30% w/w drug respectively as shown in figure 7.

Figure 8 Effect of curing condition on release of diltiazem HCl from the coated pellets

The effect of curing conditions (40°C and 65°C for 24 hours) on release of drug from surelease coated pellets was studied using the batches A1, A7, and A13. The other variables, coating load of polymer and drug loading were kept constant. The results are tabulated in table and plotted in fig 8.

DISCUSSION:

Effect of speed on pellets:

At low speed, no rounding of pellets was observed operating spheronization at high speed (1500-2500) produced highly spherical pellets.

Effect on coating load on 20%w/w loaded pellets:

As shown in figure 2, the batch A12 coated up to 15% polymer load retains drug for a period of more than 12 hours and release only 5.229% as compared with batches A1 to A5 release the drug 73.244, 21.062, 12.356, and 5.229% respectively. The batch A12, which has the most highly thick polymer coat, shows a much slower rate of drug release as compared to batches A7 to A11. These results are obtained by curing at temperature 40⁰C for 24 hours.

As shown in figure 3, the batch A17 coated up to 15% polymer load retains drug for a period of more than 12 hours and release only 14.501% as compared with batches A13, A14, retaining the drug for 6 and 8 hours respectively. The batch A12, which has the most highly thick polymer coat, shows a much slower rate of drug release as compared to batches A13 to A17. These results are obtained by curing at temperature 65⁰C for 24 hours.

At small loads of 20% w/w produced pellets of least spherical form, the higher loads of 50 g eventually produced spherical pellets. Increase in load size 100 g reduced the sphericity of pellets. It would appear that at too low a load, there were insufficient pellets to interact with each other and pellets plate interaction dominated, while at the higher loads, there were too many pellets to interact with the plate and granule/granule interaction. So 50 gm is optimized load size for development of pellets.

Effect of coating load on 30%w/w loaded uncured pellets:

As shown in figure 4, the batch A24 coated up to 15% polymer load retains drug for a period of more than 12 hours and release only 31.335% as compared with batches A19, retard the drug for 8 hours. The batch A24, which has the most highly thick polymer coat, shows a much slower rate of drug release as compared to batches A19 to A23.

Effect of coating load on 30%w/w loaded pellets cured at 40°C for 24 hours:

As shown in figure 5, the batch A30 coated up to 15% polymer weight gain sustains drug for a period of more than 12 hours and release only 26.804 % as compared with batch A25, retard the drug for 10 hours. The batch A30, which has the most highly thick polymer coat, shows a much slower rate of drug release as compared to batches A25 to A29.

Effect of drug loading on release of diltiazem HCl from the pellets:

It was observed that as the drug loading increased from 20% w/w of the pellet weight to 30% w/w of pellet weight, the release rate of the drug also increased .Thus, the batch containing 30% w/w of the drug, releases the drug more rapidly as compared to the batches containing lesser amount of the loaded drug.

Effect of curing condition on release of diltiazem HCl from the coated pellets:

It can be clearly seen from data presented in figure 8, as the curing condition, batch A1 showed release slower than batch A7 (untreated or uncured). In comparison, the untreated pellets showed faster rate of drug release compared with the pellets thermally treated at 40°C. It appeared that as the treatment temperature at 40°C, there was a corresponding decrease in the rate of drug release. Upon curing at 40°C, there was still polymer chain movements and further coalescence of the polymer particles in the coat formed.

Batch A13 show increase in drug release as compared to other batches. Thus, it can be concluded that at curing temperature 40°C increases the coalescence of the polymer particles and retards the release of the entrapped drug. Thereafter, further increase in the curing temperature at 65°C resulted in a faster release than with uncured beads.

Effect of load on 10%w/w loaded pellets:

The small drug loads of 10 %w/w produce pellets of the least diameter and which eventually have the most spherical form, the higher loads of 20 % eventually produced round pellets granules but spherocity was less than 10 % loaded pellets and increase in diameter as compared to 10 % loaded pellets. Increase in load size 30 % reduced the spherocity of pellets and increase in diameter of pellets was observed. At 40 % drug loading irregular pellets were formed. In fact, loading ranges from 10-30 % appears to be optimum. Load size at this speed as the pellets granules approach the spherical form more rapidly.

In vitro drug release studies:

For uncured pellets In vitro drug release studies revealed that as the coating load was increased the drug release was retarded. So the cumulative amount of drug release was decreased.

Effect of temperature on cured pellets:

For pellet cured at 40°C in comparison to untreated pellets, cured pellets showed slower rate of drug release. Upon curing at 40°C, there was still polymer chain movements and further coalescence of polymer globules in the coat formed. It appeared that as treatment temperature was increased up to 40°C, there was a corresponding decrease in rate of drug release. Further increase in curing temperature higher than 60°C resulted in a faster release as compaired to uncured pellets.

In vitro drug release profile

In vitro drug release profile of different formulations was compared with the marketed diltiazem HCl (Angizem SR 90 mg) capsules. Best batch was selected using the similarity factor (¦₂) by comparing the release profiles of optimized formulations with that of marketed diltiazem HCl (Angizem SR 90 mg) capsule. Batch A7, A2, A15, A34, A36 show ¦₂ values 67.20, 52.11, 52.81, 52.92, 53.39 respectively. Moisture content, spheronization speed, spheronization time, load size, and curing temperature, and curing time should be 110%, 1500 rpm, 20 min., 50 gm, 40°C, 24 hours respectively.

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Received on 20.08.2011 Modified on 15.09.2011

Research J. Pharm. and Tech. 4(10): Oct. 2011; Page 1596-1603