Hot Melt Coating of Pellets for a Water Soluble Drug using Combination of Waxes

Pramod Salve*, Sushat Dubey, Nikhil Bali

University Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University Campus, Mahatma Jyotiba Fuley Shaikshanik Parisar, Amravati Road, Nagpur-440033, (M.S), India.

*Corresponding Author E-mail: pramodsalve77@yahoo.com

ABSTRACT:

Waxes retards drug release from dosage form based on their lipophilic characteristics. In this study, the effect of hot melt spray coated Verapamil pellets with composition of stearic acid, carnauba wax; glyceryl monostearate and polyethylene glycol on drug release and release kinetics were investigated. The verapamil pellets containing 70% microcrystalline cellulose (Avicel PH101) were prepared by extrusion-spheronization technique and spray coated with molten wax at various ratios and thickness in a hot-melt spray coating instrument. In-vitro drug release was studied using test method for Extended Release tablets USP 24. The drug release was decreased with increase in stearic acid concentration and addition of 5 % carnauba wax to stearic acid minimized initial burst release but it also retarded drug release. Glyceryl monostearate 30 %w/w as release modifier at 20 %w/w coating level provided desired drug release while PEG 6000 provided similar results at 2.5 %w/w concentration. The plot of log fraction drug unreleased versus time showed a good linear relationship. Glycerol monostearate at 30 %w/w as release modifier showed higher release rate in initial hours which declined with time and also R² value for first order release kinetics was found to be nearest to one indicating drug release was dependent on initial concentration present in pellets. A zero order release profile was obtained from verapamil HCl sustained release pellets prepared by hot melt spray coating of stearic acid with sitable combination of carnuba wax and PEG 6000.

KEYWORDS: Hot-melt spray coating; pellets; sustained release dosage form.

INTRODUCTION:

Conventional pharmaceutical dosage forms are being replaced by novel drug delivery systems which are safe, more efficacious and providing more patient compliance. Sustained release dosage forms are designed in such a way that they provide rapid onset of action and therapeutic response is maintained for prolonged period due to controlled release of drug from dosage form to maintain desired drug concentration in body fluids (7,8).

Various techniques have been utilized for development of sustained release dosage forms. Amongst various techniques available extrusion spheronization is one of most successful methods which came increasingly into use in late 1970s (10). Pellets having spherical shape are gaining more attention in designing extended release and controlled release preparations due to inherent advantages (19).

The film coating technology although most widely used for coating of granules, pellets and tablets to produce sustained release dosage forms but has several disadvantages. Film coating processes often require solvents. The use of organic solvents may lead to environmental problems, solvent residues and excessive costs of recovery. The aqueous solvent generally prolongs the duration of the coating process. In present environment of global competition and cost containment in pharmaceutical industry, it is necessary to develop novel coating process which is simple, efficient, precise and cost-effective and allow easy compliance with regulatory requirements. Under such demanding circumstances, promise of hot melt coating is attractive and provides various advantages (1) as it avoids the use of organic solvents and thus it is eco-friendly, has high application rate and shorter processing time.

The hydrophobic coating materials which are suitable for application in hot melt coating comprises waxes, fatty acid bases and hydrogenated vegetable oils. Due to low melting points, waxes are of interest for preparation of controlled release system by means of melt granulation, melt extrusion, melt pelletization, melt dispersion or spray congealing (46) which does not require use of organic solvents. The choice of coating agents depends primarily on its function such as retardation of drug release rate (13,15), prevention of environmental degradation, and masking of unpalatable taste in dosage form.

Verapamil HCl, the first calcium-channel blocker to be introduced for clinical use is a major drug used for the treatment of systemic hypertension. Due to its short half-life, Verapamil was originally administered 3 to 4 times daily. It is a relatively water soluble agent. Most of water soluble drugs, if not formulated properly, may readily release the drug at a faster rate, and are likely to produce toxic concentration of drug on oral administration. (14,21)

The objective of present study was to develop Verapamil HCl sustained release pellets by hot melt coating of waxes.

Materials and methods

Materials

Stearic acid (S.D. Fine Chem. Ltd. India), Carnauba wax (S.D. Fine Chem. Ltd., India), Glyceryl monostearate, [GMS] (S.D. Fine Chem. Ltd., India) and Polyethylene glycol, [PEG] (S.D. Fine Chem. Ltd., India) were used as waxes in coating composition. Verapamil hydrochloride (ZIM Laboratories, India) and microcrystalline cellulose (Avicel PH101, Asahi Chemical, Japan) were used as a model drug and a spheronizing aid respectively. Starch and PVP K-30 used as binder were procured from ZIM Laboratories, India

Preparation of Verapamil HCl core pellets

Microcrystalline cellulose and Verapamil HCl were passed through sieve # 60 and accurately weighed. All the powders were blended by geometric dilution method using mortar and pestle. Aqueous binder solution of PVP K-30 was added to powder blend in gradual manner and after each addition, it was kneaded thoroughly in order to get optimum wet mass. The damp mass was extruded through extruder. Extrudates were spheronized in a spheronizer. The resulting pellets were dried at 45-55 °C for 24 hours. The composition of core pellets is shown in Table 1.

Table 1 Composition of core pellets

Sr. No.	Formulation batch	Binder	Concentration of aqueous solution (%w/v)	Verapamil HCl (gm)	Avicel PH 101 (gm)
1	C1	Starch Paste	3	15	35
2	C2	Starch Paste	4	15	35
3	C3	PVP K30	3	15	35
4	C4	PVP K30	4	15	35

Preparation of wax coated pellets

Figure 1: Schematic diagram of Hot Melt Spray Coating Device

A hot melt spray coating instrument was developed in our laboratory. The schematic diagram of instrument used for wax coating is shown in figure 1. The wax coating instrument consists of a round baffled coating pan, jacketed reservoir for molten wax with thermostat mounted on top of a spray gun, electrical heating element for heating atomization air and a compressor to provide air under pressure. A temperature regulator and a pressure regulator were used to control temperature and pressure of hot air respectively.(23)

Specified quantities of pellets in the coating pan were preheated using hot air. The molten wax above its melting point along with hot air was then sprayed onto the ladling pellets with intermittent heating. The cycle of spraying and heating was continued till desired weight gain was achieved. The parameters for wax coating are shown in the Table 2.

Table 2 Constant parameters for wax coating

Sr. No.	Parameters	Values
1	Spray rate	2 (gm/min)
2	Atomization air pressure	5 (lb/in^2)
3	Temperature of hot air through nozzle	70 °C
4	Distance of spray nozzle from pellet bed	5 cm
5	Temperature of molten wax inside reservoir	80-85 °C
6	Batch size	30 gm
7	Pan rotation speed	35 rpm

The formulation batches as per coat composition and coating levels are shown in Table 3.

Table 3 Formulation batches as per coat composition and coating level

Formulation batch	Coat Composition (%w/w)				Coating Level (%w/w)
	Stearic acid	Carnauba wax	Glyceryl monosterate	Polyethylene glycol 6000
F1	100	-	-	-	5
F2	100	-	-	-	10
F3	100	-	-	-	20
F4	95	5	-	-	10
F5	95	5	-	-	20
F6	92.5	5	2.5	-	10
F7	90	5	5	-	10
F8	92.5	5	2.5	-	20
F9	90	5	5	-	20
F10	85	5	10	-	20
F11	80	5	15	-	20
F12	65	5	30	-	20
F13	92.5	5	-	2.5	20
F14	90	5	-	5	20

Evaluation of pellets

Size distribution

Mean pellet diameter of pellets was determined by sieve analysis of samples. It was carried out by shaking 10, 14 and 20 sieves # arranged on automatic sieve shaker at a frequency of 60 Hz for 5 minutes with a load of 40 gm of pellets on topmost sieve. Mean pellet diameter (d_avg) of pellets was determined using the following formula:

d_avg =

Surface topography studies

Surface topography of coated pellets from optimized formulations was studied by scanning electron microscopy [SEM] (Phillips 500, Germany). The pellet sample before and after dissolution study was used. Gold sputter coating (Bio-Rad, Germany) of samples was done by using 18 mA current at 2.5 kV.

Drug content

Accurately weighed quantity of wax coated pellets equivalent to 120 mg of Verapamil HCl was added to 1 liter pH 1.2 buffer and heated to 65 °C to melt the wax and magnetically stirred for 24 hours to extract the drug. The solution was filtered and drug content was determined spectrophotometrically at 278 nm.

In-vitro drug release studies

In-vitro drug release from wax coated pellets was done using USP dissolution test apparatus I in pH 1.2 buffer for 1 hour and in pH 6.8 phosphate buffer for 2-8 hours. Dissolution medium 5 ml was withdrawn at regular intervals of 1 hour. The volume withdrawn was replaced by fresh volume of dissolution medium to maintain sink conditions. The filtered samples were analyzed spectrophotometrically at 278 nm and cumulative percentage of drug released was calculated.

Application of release kinetics

To describe kinetics of drug release from wax coated pellets, mathematical models: zero order, first order and Higuchi square root of time model were used. The criteria for selecting most appropriate model were based on goodness of fit test.

Differential scanning calorimetric studies

Differential scanning calorimetric thermograms of (a) Stearic acid (b) Carnauba wax (c) Glyceryl monostearate (d) Polyethylene glycol 6000 (e) Physical mixture I of Stearic acid, Carnauba wax and Glyceryl monostearate (as in coat composition) (f) Physical mixture II of Stearic acid, Carnauba wax and Polyethylene glycol 6000 (g) Molten mixture I of Stearic acid, Carnauba wax and Glyceryl monostearate (as in coat composition) and (h) Molten mixture II of Stearic acid, Carnauba wax and Polyethylene glycol 6000 were studied using Mettler Toledo S R system at a heating rate of 5 °C per minute from 30 to 150 °C.

RESULTS AND DISCUSSION:

Preparation of Verapamil core pellets

Core pellets containing 30 %w/w Verapamil HCl alongwith microcrystalline cellulose were prepared.

Evaluation of Verapamil pellets

Size distribution

Size distribution studies of uncoated pellets has shown that PVP K30 at 3 %w/v concentration provided pellets with higher yield as 75 % pellets were in region of 10/14 sieve size. Mean pellet diameter of formulation batches C₁, C₂, C₃ and C₄ were found to be 1.363, 1.541, 1.478 and 1.602 mm respectively. The size distribution of uncoated pellets is shown in Table 4.

Table 4: Size distribution of uncoated pellets

Sr. No.	Formulation batch	Size Distribution
		Yield (%)	Mean Pellet Diameter (mm)
1.	C1	75	1.363
2.	C2	71	1.541
3.	C3	68	1.478
4.	C4	62	1.602

Surface topography studies

Morphological details of coated pellets were observed under SEM. Photographs of sectioned and intact pellets before dissolution and after dissolution studies are shown in Figure 2. In sectioned pellets, a continuous layer of wax on pellet surface was observed indicating efficiency of hot melt spray coating process.

Figure 2. SEM photograph of sectioned and intact pellets

Figure 3. Surface topography of pellets

In surface topography studies at 500x magnifications (Fig.3), formation of cracks were observed after dissolution studies on initial smooth pellets of formulation batch F₁₂ while the pellets of formulation batch F₁₃ showed formation of small pores. This indicates that drug might have released through the cracks or pores formed during dissolution studies.

Drug content

The drug content of pellet batches was found to be within range of 94% to 98.67%.The crushing strength was found to be between 3 to 5 kgs.The values for drug content and crushing strength are shown in Table 5.

Table 5 Drug content and Crushing strength of wax coated pellets

Sr. No.	Formulation batch	Drug content (%) (Mean ± SD)	Crushing strength (Kg) (Mean ± SD)
1	F1	98.20±0.32	3.00±0.23
2	F2	97.00±1.31	3.40±0.20
3	F3	95.10±2.31	3.52±0.30
4	F4	98.13±0.51	4.32±0.34
5	F5	94.73±1.61	5.00±0.28
6	F6	98.67±0.63	4.20±0.24
7	F7	94.53±1.35	4.18±0.22
8	F8	95.23±2.28	4.82±0.27
9	F9	96.17±2.51	4.78±0.27
10	F10	95.87±1.83	4.42±0.30
11	F11	95.38±1.43	4.16±0.35
12	F12	94.04±1.10	3.58±0.23
13	F13	97.17±0.63	4.94±0.25
14	F14	97.31±0.51	4.78±0.27
		(n= 3)	(n=20)

In-vitro drug release studies

Effect of coating level

Figure 4. Effect of coating level on in- vitro drug release

As shown in Fig. 4, formulation batch F₁ has shown more than 90 % drug release in 2 hours indicating 5 %w/w coating of stearic acid was insufficient to retard drug release from pellets.

The formulation batch F₂ has shown 75% drug release in 8 hours but more than 40 % drug was released in 2 hours which might be due to initial bursting of pellets. After dissolution studies it was observed that some pellets were totally intact while others burst out due to internal stress.

The formulation batch F₃ released only 40% drug in 8 hours and as compared to F₂ high retardation in drug release was observed due to higher coating level.

Effect of carnauba wax

Figure 5. Effect of carnauba wax on in- vitro drug release

As shown in Fig. 5, the addition of 5% carnauba wax to stearic acid in formulation batch F₄ minimized initial burst release from pellets but it also retarded drug release from pellets as only 60 % drug was released in 8 hours.

Carnauba wax also improved coat stiffness as shown in crushing strength studies in Fig. 5. Formulation batch F₅ significantly retarded drug release from pellets and only 25% drug release was observed in 8 hours.

Effect of Release modifier

Figure 6. Effect of glyceryl monostearate on in-vitro drug release at 10 % w/w coating level

The effect of release modifiers glyceryl monostearate and polyethylene glycol 6000 is shown in Fig. 6.

Glyceryl monostearate

The formulation batch F₆ and F₇ were prepared with glyceryl monostearate as release modifier at 2.5 and 5 %w/w concentration respectively at 10 % w/w coating level.

Formulation batch F6 has shown about 70% drug release in 8 hours with no initial burst release, whereas, formulation batch F₇ has shown 80 % drug release in 8 hours but about 50 % drug was released in 2 hours. Formulation batch F₇ was failed to comply USP drug release test I of Verapamil HCl.

Coat stiffness provided by 10 %w/w coating might be insufficient to withstand internal stress developed in pellets and was responsible for high drug release rate from pellets in initial hours.

Figure 7: Effect of glyceryl monostearate on in-vitro drug release at 20 % w/w coating level

Fig. 7 shows influence of various concentrations of glyceryl monostearate such as 2.5, 5, 10, 15 and 30 % on drug release from formulation batches F₈, F₉, F₁₀, F₁₁ and F₁₂ respectively at 20 %w/w coating level.

No significant improvement in drug release was observed with increase in proportion of glyceryl monostearate up to 15 %w/w level. The formulation batch F₁₂ with a 30 %w/w concentration of GMS as release modifier have shown 88 % release in 8 hours. The formulation batch F₁₂ complied USP drug release test I for Verapamil HCl at all time points.

Polyethylene glycol 6000

Figure 8. Effect of polyethylene glycol 6000 on in-vitro drug release

Formulation batch F₁₃ and F₁₄ were prepared with PEG 6000 as release modifier at 2.5 and 5 %w/w concentration levels. Formulation batch F₁₃ released 93 % drug in 8 hours and also complied USP drug release test I for Verapamil HCl. The high drug release rates from F₁₃ and F₁₄ might have occurred due to water soluble nature of polyethylene glycol 6000.

Cumulative percentage drug release from formulation batch F₁₂ and F₁₃ complied with percentage release range of USP drug release test I at all time points as shown in Table 6.

Table 6: Comparison of drug release with USP criteria

Time (Hour)	Cumulative % drug released
	USP test I	Formulation batch F12	Formulation batch F13
1	10-21	11.6	13.7
2	18-33	21.3	18.3
3.5	35-60	54.5	43.5
5	50-82	71.3	63.7
8	NLT 85	87.3	93.0

Drug release kinetics

Results of goodness of fit test for drug release models are shown in Table 7

Table 7: R² value of various release models for formulation batch F₁₂ and F₁₃

Model	R Value
	Batch F12	Batch F13
Zero-order	0.9695	0.9961
First-order	0.9911	0.9302
Higuchi	0.9562	0.9326

In-vitro dissolution profile of formulation batch F₁₂ containing 30 %w/w glycerol monostearate as release modifier has shown higher release rate in initial hours which decline with time and is shown in figure 9. Also R² value for first order release kinetics was found to nearest to one indicating drug release from formulation batch F₁₂ was dependent on initial drug concentration present in pellets.

R² value for formulation batch F₁₃ has shown zero-order release kinetic model as best fit model shown in figure 10. In-vitro dissolution profile of formulation batch F₁₃ containing 2.5 %w/w PEG 6000 as release modifier showed gradual increase in release rate with time indicating concentration independent drug release from coated pellets.

Differential Scanning Calorimetric Studies

The DSC thermograms of waxes individually (Fig.11, 12, 13, 14), the physical mixtures I (Fig. 15) and II (Fig. 16) and molten mixture I (Fig. 17) and II (Fig. 18) are shown respectively.

Figure 11. DSC thermogram of stearic acid

Figure 12. DSC thermogram of carnauba wax

Figure 13. DSC thermogram of glyceryl monostearate

Figure 14. DSC thermogram of polyethylene glycol 6000

Figure 15. DSC thermogram of physical mixture I

Figure 16. DSC thermogram of physical mixture II

Figure 17. DSC thermogram of molten mixture I

Figure 18. DSC thermogram of molten mixture II

All waxes individually as well as their physical mixtures I and II and molten mixtures I and II showed single endothermic peak, indicating formation of single homogenous phase. Molten mixture I and II showed shifting of endothermic peaks by approximately 1 °C towards lower temperature side as compared to stearic acid might be due to formation of low melting wax crystals after solidification of molten mixture.

CONCLUSION:

In the present studies, sustained release pellets of Verapamil HCl were prepared using a solvent less hot melt lipid spray coating technique. The pellets containing 30 %w/w Verapamil HCl were prepared by extrusion spheronization using microcrystalline cellulose, starch paste and PVP-30 as binder. Stearic acid owing to its lipophilic properties and low melting point was selected as coating material. Stearic acid coating, 5 %w/w has not provided sustained release while 10 %w/w and 20 %w/w coatings provided sustained release but desired drug release profile was not obtained. Carnauba wax 5 %w/w was added to stearic acid to improve coat strength and to minimize burst effects of pellets. It was found that waxes did not show a functional coating and other materials have to be added to improve drug release. Glyceryl monostearate and PEG 6000 were added to improve drug release. Formulation batch with 30 %w/w GMS as release modifier at 20 %w/w coating level provided desired drug release while PEG 6000 provided similar results at 2.5 %w/w concentration only which might be due to its water soluble nature. Drug release kinetics has shown that formulations containing GMS as release modifier followed first order release kinetics, while formulation batch with PEG followed zero order release kinetics.

REFERENCES:

1. Achanta, A.S., Adusumilli, P.S., James, K.W., Rhodes, C.T. Development of Hot melt coating method. Drug Dev. Ind. Pharm. 23, 1997:441- 449.

2. Achanta, A.S., Adusumilli, P.S., James, K.W., Rhodes, C.T.. Hot-melt Coating: Water Sorption Behavior of Excipient Films. Drug Dev. Ind. Pharm., 27, 2001: 241-250.

3. Agrawal, A.M., Howard, M.A., Neau, S.H. 9,. Extruded and Spheronized beads containing no microcrystalline cellulose: Influence of formulation and process variables. Pharm. Dev. Technol., 2004:197-217.

4. Asker, A.F., Motari, A.M., Abdel-Khalek, M.M..A study of some factors affecting in-vitro release of drug from prolonged release granulation: 2. Effect of method of preparation. Pharmazie., 26, 1971a:213-214.

5. Asker, A.F., Motari, A.M., Abdel-Khalek, M.M., A study of some factors affecting in-vitro release of drug from prolonged release granulation: 1. Effect of dissolution retardant. Pharmazie., 26, 1971b:170-172.

6. Bathelemy, P., Laforet, J.P., Farah, N., Joachim, J. Compritol® 888 ATO: An innovative hot-melt coating agent for prolonged release drug formulations. European J. Pharm. Biopharm., 47, 1999: 87-90.

7. Charies Chao, S.L., Robinson, J.R. Sustained Release Drug Delivery Systems: The Science and Practice of Pharmacy, Vol.II, 19th Ed., Mack Publishing Company, Eston, 1995:1660.

8. Chien Y.W..Controlled Release Drug Administration: Logic, Novel Drug Delivery Systems, Dekker, New York, 1882:1-11.

9. Chopra, R., Alderborn, G., Newton,J.M., Podezeck, F.( The Influence of Film Coating on Pellet Properties.Phram. Dev. Technol., 7, 2002: 59-68.

10. Connor R.E., Schwartz J.B. Pharmaceutical Pelletization Technology, Dekker, New York, (1989):187-216.

11. Costa, P., Sausa, J. Modeling and Comparison of Dissolution Profiles. Eur. J. Pharm. Sci., 13, 2001:123-133.

12. Cusimano, A.G., Becker, C.H. (1968).Spray-congealed formulations of sulfaethyl thiadiazole (SETD) and waxes for prolonged-release medication. J. Pharm. Sci., 57, 1104-1112.

13. Dredan, J., Zelko, R., Bihari, E., Racz, I., Gondar, E. Effect of Polysorbates on Drug Release from Wax Matrices. Drug Dev. Ind. Pharm., 24, 1998: 573-576.

14. El-Gazayerly, O., Rakkanka, V., Ayers, J. Novel Chewable sustained release tablet containing Verapamil Hydrochloride.Pharm. Dev. Technol., 9, 2004:181-188.

15. El-Shanawany. Sustained release of Nitrofurantoin from inert wax matrix. J. Control. Rel., 26, 1993:11-19.

16. Faham, A., Prinderre, P., Farah, M., Eichler, K.D., Kalantzis, G., Joachim, J. Hot-melt coating technology I. Influence of compritol® 888 ATO and Granules size on Theophylline release. Drug Dev. Ind. Phram., 26, 2000:167-176.

17. Fekete, R., Zelko, R., Marton, S., Racz, I. Effect of the formulation parameters on characteristics of pellets. Drug Dev. Ind. Pharm., 24, 1998: 1073-1076.

18. Fonner, D.E., Banker, G.S., Swai, J. Micromeritics of Granular Pharmaceutical Solids. J. Pharm. Sci., 55, 1966:181-186.

19. Ghebre S,. Pellets: A General overview, in Pharmaceutical Pelletization Technology, Dekker, New York, 1989: 1-12.

20. Griffin E.N., Meabergall, P.J. Release Kinetics of Controlled Release Multiparticulate Dosage Form prepared using Hot Melt Fluid Bed Coating Method. Pharm. Dev. Technol., 1999:117-124.

21. Hamid, I.S., Becker, C.S. Release study of Sulfaethyl thiadiazole (SETD) from a tablet dosage form prepared from Spray-congealed formulations of SETD and wax. J. Pharm. Sci., 59, 1970:511-514.

22. Ito, R., Golman, B., Shinohara, K. Controlled Release of Core Particle Coated with Soluble Particles in Impermeable layer. J. Chem. Engg. 35, 2002:40-45.

23. Johm, P.M., Becker, C.H. Surfactant effects on Spray congealed formulations of Sulfaethyl thiadiazole-wax. J. Pharm. Sci., 57, 1968:584-589.

24. Jozwiakowski, M.J., Jones, D.M., Franz, R.M. Characterization of Hot-melt Fluid Bed coating process for fine granules. Pharm. Res., 7, 1990: 1119-1126.

25. Kidokoro, M., Sasaki, K., Haramishi, Y., Matahira, N. Effect of Crystallization behavior of polyethylene glycol 6000 on properties of granules prepared by Fluidized Hot-melt Granulation (FHMG). Chem. Pharm. Bull., 51, 2003:487-493.

26. Lustig-Gustafsson, C., Kaur Johal, H., Podezeck, F., Newton, J.M. The influence of water content and drug solubility on the formulation of pellets by extrusion and spheronization. European J. Pharm. Sci., 8, 1999:147-152.

27. Montousse, C., Pruvost, M., Rodriguez, F., Brossard, C. Extrusion Spheronization manufacture of Gelucire® Matrix Beads. Drug Dev. Ind. Pharm., 25, 1999:75-80.

28. Munday, D.L. Film Coated pellets containing Verapamil Hydrochloride: Enhanced Dissolution into neutral medium. Drug Dev. Ind. Pharm., 29, 2003:575-583.

29. Nakahara, N. U.S. Patent 3277520, 1996 Jan.

30. Newton, J.M. New Developments in pellets. European J. Pharm. and Biopharm., 1999: 39-44.

31. Pandey, V.P., Kannan, K., Manavalan, R., Desai, N. .In-vitro study on sustained release capsule formulation of Acetazolamide. Boll. Chem. Pharm., 142, 2003: 357-360.

32. Passerini, M., Perissuitti, B., Alberini, B., Voinovich, D., Moneghini, M., Rodriguez, L..Controlled release of Verapamil Hydrochloride from waxy microparticles prepared by spray congealing. J. Control. Rel., 88, 2003: 263-275.

33. Racz, I., Dredan, J., Antal, I., Gondar, E. Comparative Evaluation of Microcapsules Prepared by Fluidization Atomization and Melt Coating Process. Drug Dev. Ind. Pharm., 23, 1997:583-587.

34. Rodriguez, E.C., Torroada, J.J. Micromeritic and Packaging Properties of Diclofenac Pellets and Effects of some formulation variables. Drug Dev. Ind. Pharm., 27, 2001: 847-855.

35. Rodriguez, L., Albertini, B., Passerini, N., Cavallari, C., Giovannelli, L. Hot air coating Technique as a novel method to produce microparticles. Drug Dev. Ind. Pharm., 30, 2004:913-923.

36. Scott. M.W., Robinson, M.J., Pauls, J.F., Lantz, R.J. Spray Congealing: Particle size relationships using a centrifugal wheel Atomizer. J. Pharm. Sci., 53, 1964: 670-674.

37. Sipahigil, O., Dortunc, B. Preparation and in-vitro evaluation of Verapamil Hydrochloride and Ibuprofen containing carrageenan beads. Int. J. Pharm., 228, 2001:119-128.

38. Sousa, J.J., Sousa, A., Podezeck,F., Newton, J.M. Influence of Process conditions on drug release from pellets. Int. J. Pharm., 144, 1996:159-169.

39. Thoma, K., Ziegler, I. Investigations on Influence of type of extruder for pelletization by extrusion spheronization: II. Sphere characteristics. Drug Dev. Ind. Pharm., 24, 1998:413-422.

40. Tomer, G., Podezeck, F., Newton, J.M. The influence of model drugs on preparation of pellets by extrusion spheronization: II. Spheronizaiton parameters. Int. J. Pharm., 231, 2002:107-119.

41. Umprayn, K., Chitropas, P., Amarekajorn, S. Influence of Process Variables on Physical Properties of Pellets using Extruder and Spheronizer. Drug Dev. Ind. Pharm., 25, 1999: 45-61.

42. US Pharmacopoeia XXIV, US Pharmacopeial Convention, Rockville, MD, 2000:2059

43. Vaithiyalingam, S., Khan, M.A. Optimization and Characterization of controlled release multi-particulate beads formulated with a customized cellulose acetate butyrate dispersion. Int. J. Pharm.,234, 2002:179-193.

44. Valerie Fee, J., Grant, D.J., Newton, J.M. Influence of Hydrophobic Materials on Dissolution of a Non-disintegrating Hydrophilic Solid (Potassium Chloride). J. Pharm. Sci.,65,1976:182-187.

45. Walia, P.S., Stout, P.J., Turton, R. Preliminary Evaluation of an aqueous wax emulsion for controlled release coating. Pharm. Dev. Technol., 3, 1998:103-113.

46. Zhang, Yu-E., Tchao, R., Schwartz, J.B. Effect of processing methods and heat treatment on formulation of wax matrix tablets for sustained drug release. Pharm. Dev. Technol., 30, 2001:131-144.

47. Zimm, K.R., Schwartz, J.B., O'Connor, R.E. Drug release from a multiparticulate pellet system. Pharm Dev Technol., 1, 1996:37-42

Received on 14.05.2016 Modified on 25.05.2016

Accepted on 28.05.2016 © RJPT All right reserved

Research J. Pharm. and Tech. 2016; 9(6): 741-749

DOI: 10.5958/0974-360X.2016.00141.4