Design and Development of
Novel Synergistic Formulation of Pravastatin and Aspirin for the Treatment of
Atherosclerosis and its Evaluation
Pramod S. Salve*, Nikhil Bali, Navleen Saini
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
Received on 30.04.2015 Accepted on 17.05.2015
© Asian Pharma Press All Right Reserved
Asian J. Pharm. Tech. 2016;
6(2): 61-69.
DOI: 10.5958/2231-5713.2016.00009.X
ABSTRACT:
Coronary artery diseases (CAD) represent a condition
in which the blood supply to the heart muscle is partially or completely
blocked. In atherosclerosis, the hardening of arteries occurs with decreasing
elasticity of the arteries. For management of disease, cholesterol lowering
agents like Pravastatin and anti-platelet agent like aspirin are commonly used.
Various studies have shown that these agents when given in combination results
in synergistic pharmacological activity, however they are not chemically
compatible. In present work, formulation approaches utilizes principles of
pelletization and coating technologies to form a stable drug delivery system.
The enteric coating of the core aspirin pellets was done using Eudragit L 100
(6%) with polyethylene glycol 6000 (0.6%) till 2.5, 5 and 7.5 % weight gain was
obtained. A barrier coating on enteric coated pellets was applied using
hydroxyl propyl methyl cellulose (HPMC) 15 cps solution. For the layering of
Pravastatin over the barrier coated pellets, Pravastatin was dispersed in 2.5%
HPMC solution. The coating solution was
sprayed over the pellets till a dose strength equivalent to 10 mg of
Pravastatin per 250 mg of pellets was obtained. The optimized pellets were subjected
to evaluation of drug content, bulk density, crushing strength, friability,
size distribution, packing ability and in-vitro drug release, stability studies
and in-vivo performance using trition X 100 induce hyperlipidaemia rat model.
The developed formulation showed an effective cholesterol lowering effect as
compared to standard marked formulation of Pravastatin. It indicates the
development of stable combination formulation in which aspirin forms the
enteric coated sustained release core and that of Pravastatin fast releasing
outer layers of the pellets.
KEY WORDS: Atherosclerosis, Pravastatin, aspirin, pelletization,
trition X 100 induce hyperlipidaemia rat model.
INTRODUCTION:
In the United States, cardiovascular disease is
leading cause of death among both sexes, and coronary artery disease is the
most common type of cardiovascular disease, occurring in about 5 to 9 % of
people aged 20 and older. On average, men develop it about 10 years earlier
than women, because until menopause, women are protected from disease by high
levels of estrogen. However, after menopause, it becomes more common among
women [1, 2]. Arteriosclerosis, hardening of arteries, is a general term for
several diseases in which wall of an artery becomes thicker and less elastic.
Atherosclerosis develops when levels of cholesterol in the blood injure artery's
lining, causing an inflammatory reaction and enabling cholesterol and other
fatty materials to accumulate there [2].
Pravastatin, is a competitive inhibitor of
3-hydroxy-3-methyl CoA reductase an
enzyme that catalyses the rate limiting step in cholesterol biosynthesis
resulting in up regulation of low density lipoproteins (LDL) receptors in
response to the decrease in intracellular cholesterol. It is administered in
its active form as a sodium salt and 34% of oral dose is absorbed. Peak plasma
concentration of drug is reached 1-1.5 hours after dosing and elimination
half-life is approximately 77 hours [11, 12]. Aspirin, a non-steroidal
anti-inflammatory agent also inhibits platelet activation and aggregation for
the lifetime of the platelet by irreversibly inhibiting prostaglandin
cyclooxygenase. Peak plasma levels of aspirin occur within 1-2 hours of dosing
and the plasma half-life is approximately 6 hours [12].
Today, the scenario of pharmaceutical drug delivery is
changing from conventional dosage form to new drug delivery system with main
objective of patient compliance. Combination formulation of two or more active
ingredients, are being designed to combat many clinical conditions like
cardiovascular diseases [9, 10]. Since patient with coronary artery diseases
have to take multiple medications for long period of time. Thus today
pharmaceutical industries are diverting more towards developing the combination
formulation for diseases with multiple manifestations [6].
It was observed that when these two agents were given
in combination, synergistic pharmacological activity results [6, 7]. The main
complication encountered with these two drugs was incompatibility of aspirin
with statin especially Pravastatin, a hydrophilic statin with limited side
effects compared to other statins. Aspirin is acidic compound and Pravastatin a
very acid labile basic compound when both are formulated together aspirin get
hydrolyzed with degradation of Pravastatin [6, 12]. For developing a stable
combination formulation of Pravastatin with aspirin, pelletization and coating
technologies are explored.
Pellets offer better statistical assurance of complete
drug release as the risk of dose dumping is minimized. High local concentration
of drug, which may inherently be irritating, can be avoided. As pellets
uniformly distributed throughout the gastrointestinal tract, they invariably
maximize drug absorption, reduce peak plasma fluctuations and minimize
potential side effects without appreciably lowering bioavailability [3, 4]. Control
release pellets enable a smoother absorption sorption profile. Combined
delivery of two or more bioactive agent, which may or may not be chemically
compatible at the same site or at different site within gastrointestinal tract
is possible [5, 6].
The aim of present study is to develop stable
combination formulation containing Pravastatin and aspirin for the management
of CAD (atherosclerosis). The sustaining of aspirin release which needs
multiple dosing and hence reducing dosing intervals is envisaged. To achieve
the above objectives, drug is incorporated in core pellets and another as
coated layer with a barrier coating with hydrophilic polymer hydroxyl propyl
methyl cellulose.
MATERIALS:
Pravastatin sodium was obtained as gratis sample from
Biocon Pvt. Ltd (India). Aspirin was obtained from Zim Laboratories (India).
Microcrystalline cellulose was obtained from Chemfields Ltd. (India). Hydroxy
propyl methyl cellulose was obtained from Colorcon (India). Eudragit L100 was
procured from Rohm Pharma (India). Polyethylene glycol 6000 was purchased from
S. D. Fine Chemicals (India).
EXPERIMENTAL METHODS:
A] Preparation of enteric
coated Aspirin pellets
Three formulation batches A1, A2 and A3 of core
aspirin pellets containing aspirin and microcrystalline cellulose (MCC) PH 101
in ratio of 75:25, 50:50, and 25:75 respectively were prepared by extrusion
spheronization technique at the speed of 1500 rpm for 10 minutes using water as
binder (Table 1). No significant changes were observed in the physical properties
of core pellets prepared with different ratios of drug: MCC PH 101. Hence 75:25
drug:MCC PH 101 ratio was optimized to reduce dose size. The pellets of 10-14 # were selected for
coating as small pellets create agglomeration problem while large pellets are
not suitable for animal ingestion during in-vivo study. The 6% w/v
solution of Eudragit L100 with 10 %w/v PEG 6000 in isopropyl alcohol having 44
cps viscosity was used for coating core aspirin pellets.
Table.1. Composition of core
aspirin pellets
Sr. No |
Formulation batch |
Microcrystalline Cellulose PH 101 (% w/w) |
Aspirin (% w/w) |
Binder |
1 |
A1 |
25 |
75 |
Water |
2 |
A2 |
50 |
50 |
Water |
3 |
A3 |
75 |
25 |
Water |
B] Preparation of Eudragit
L100 coating solution
Weighed quantity of Eudragit L100 was dissolved in IPA
and transferred PEG 6000 solution under stirring condition. Talc was dispersed
in solution and stirring continued until uniform solution was obtained (Table
2). Coating process was done in conventional coating pan on batch size of 25 g.
Coating solution at pressure of 20 psi was sprayed over cascading aspirin
pellets rotating at speed of 30 rpm. The process continued till 2.5, 5 and 7.5
% coating weight gain was achieved.
Table. 2. Preparation of
Eudragit L100 coating solution
Ingredients |
Quantity (%) |
Eudragit L100 |
6.0 |
Polyethylene glycol 6000 (PEG 6000) |
0.6 |
Talc |
1.0 |
Isopropyl alcohol (IPA) |
85 |
Water |
5.0 |
Barrier coating of enteric
coated aspirin pellets
The coating procedure for aspirin pellets was followed
for barrier coating using hydroxyl propyl methyl cellulose (HPMC) 15 cps as
coating material. The composition of barrier coating solution is shown in table
3. As aspirin and Pravastatin are chemically incompatible (prone to chemical
degradation), HPMC coating is used to prevent their direct physical contact in
a single unit dosage form.
Table 3. Composition used for preparation of barrier
coating solution
Ingredients |
Quantity (%) |
Function |
HPMC 15 cps |
2.5 |
Polymer for
coating |
Diethyl phthalate |
0.5 |
Plasticizer |
Titanium dioxide |
0.5 |
Opacifier |
Cetyl alcohol |
0.5 |
Stabilizer |
Talc |
0.5 |
Lubricant |
Dichloromethane |
66 |
Solvent |
Layering of pravastatin over
precoated aspirin pellets
The pre-weighed quantity of pravastatin sodium was
dispersed in 2.5 %w/v HPMC solution. The dispersed drug solution was coated over
precoated aspirin pellets with barrier coating to prevent contact between
pravastatin and aspirin. The coating solution was sprayed over pellets until
the pellets gain the desirable weight equivalent to 10 mg of pravastatin dose
in 250 mg of pellets.
Evaluation of Aspirin pellets
1] In-vitro drug release
study of combination formulation
The in-vitro
release of drug from pellets was performed in triplicate using by USP dissolution
test apparatus type I (basket method) using 900 mL of pH 1.2 phosphate buffer
for 2 hrs and pH 6.8 phosphate buffer for 6-8 hrs. The sample size was taken is
equivalent to 10 mg of pravastatin and 150 mg of aspirin. The filtered samples
of pravastatin and aspirin were analyzed spectrophotometrically at 237 nm and
265 nm respectively.
2] Surface Topography study
Surface topography of coated pellets from optimized
formulation was studied using scanning electron microscopy (SEM). The samples were sputtered with gold for 15
min. (JEOL JFC- 1100E ion sputtering device) before characterization with
SEM. The electric current used for
sputtering was 10 mA and the sputtering gas was argon.
3] Assessment of
Antihyperlipidemic activity of combination formulation
Experimental Animals
Sprague Dawley rats of either sex (200-250 g) were
used. Animals were housed in well ventilated standard condition of temperature
(25 ± 1 °C) and kept them for 18 hrs fasting with free access to water before
study.
Trition X 100 induced
hyperlipidemic rat model
Hyperlipidemia in rats was induced by surfactant
triton X 100. The systemic administration of surfactant triton to rats or mice
results in a biphasic elevation of plasma cholesterol and triglycerides. It
increases the serum cholesterol level sharply 2-3 times after 24 hrs (Phase-I).
The hypercholesterolemia decreases nearly to control levels within next 24 hrs
(Phase-II). The test drugs employed or the solvent for control are administered
simultaneously with triton injection for 22 hrs thereafter. Serum cholesterol
analysis were made 6, 24, 48 hrs after triton injection [8, 9].
Table. 4. Treatment groups
Groups |
Treatment and route of administration |
Number of animals (SD rats) |
Dose |
Non hyperlipidemic control |
Vehicle (Glycerin) (oral) |
05 |
0.5-1 mL |
Hyperlipidemic control |
Triton (s.c) |
05 |
200 mg/kg |
Hyperlipidemic animals treated with market
formulation |
Triton (S.C) + Market formulation (Oral) |
05 |
Pravastatin 10 mg/kg |
Hyperlipidemic animals treated with combination
formulation |
Triton (S.C) + Combination formulation (Oral) |
05 |
245 mg pellets equivalent to 10 mg pravastatin |
Results
and Discussion
A] Preparation of core
pellets
Effect of moisture level on
physical properties of pellets
Table. 6. Effect of moisture level on physical
properties of pellets
Sr. No |
Material |
Moisture (%) |
Size distribution (#) |
Shape |
Yield (%) |
1 |
Drug-MCC |
25 |
14- 18 |
Spherical |
> 60 |
2 |
Drug-MCC |
50 |
14- 18 |
Spherical |
< 90 |
3 |
Drug-MCC |
75 |
10- 18 (wide) |
Dumble + Spherical |
< 90 |
Effect of spheronization
speed and time on physical properties pellets
Table. 7. Effect of
spheronization speed and time on physical properties of pellets
Sr. No. |
Material |
Spheronization
speed (rpm) |
Spheronization
Time (min) |
Shape of
pellets |
Size of
pellets (mm) |
1 |
Drug-MCC |
500 |
10 |
Dumble |
Above 2.5 |
2 |
Drug-MCC |
500 |
15 |
Dumble |
Above 2.5 |
3 |
Drug-MCC |
750 |
10 |
Dumble |
Above 2 |
4 |
Drug-MCC |
750 |
15 |
Dumble +
Spherical |
Above 2 |
5 |
Drug-MCC |
1000 |
10 |
Dumble +
Spherical |
Above 2 |
6 |
Drug-MCC |
1000 |
15 |
Spherical |
1- 2 |
7 |
Drug-MCC |
1500 |
10 |
Spherical |
1-2 |
8 |
Drug-MCC |
1500 |
15 |
Spherical |
1-2 |
B] Enteric coating of core
aspirin pellets
Effect of different coating
levels on drug release.
The comparative release profile of 5% and 7.5% of
aspirin in pH 1.2 and 7.5 phosphate buffer is shown in figure 1.
Fig.1. Comparative drug release profile of aspirin
at different coating levels
In-vitro drug release profile of optimized enteric
coated pellets
Figure. 2. In-vitro drug release curve of aspirin
In-vitro dissolution profile of optimized combined
formulation
In-vitro drug release curve of pravastatin at pH
1.2 and aspirin at pH 6.8 in optimized formulation is shown in figure 3.
Figure. 3. In-vitro
drug release curve of combination pellet formulation
Table 8 enlists correlation coefficient values
calculated from kinetic models for combination formulation. The mechanism of
drug release from coated pellets was determined by fitting the in-vitro
release profiles with zero order, first order, Higuchi, Hixson-Crowell,
Korsmeyer-Peppas kinetics models [17]. The highest correlations were observed
with Korsmeyer-Peppas model. Korsmeyer-peppas equation gave higher value for
the correlation coefficient as compared to other release kinetic models. The
curve fitting of drug release data to peppas equation indicates that the drug release
was due to diffusion and erosion through coated pellets.
Table. 8. Correlation
coefficient values for combination formulation
Sr. No. |
Release Kinetics model |
Correlation coefficient |
1 |
Zero order |
0.997 |
2 |
First order |
0.9958 |
3 |
Higuchi |
0.9983 |
4 |
Hixson-crowell |
0.9989 |
5 |
Korsmeyer-peppas |
1.000 |
Fourier’s Transform Infra-Red
(FT-IR) study
The FT-IR spectra of aspirin, pravastatin, aspirin +
pravastatin, HPMC, HPMC + pravastatin are shown in figures 4, 5, 6, 7 and 8
respectively. The FT-IR peaks (in cm-1) and its functional groups
are shown in table 9.
Table. 9. FT-IR peaks and
functional groups
Sr. No. |
Material |
Peak cm-1 |
Characteristic functional group |
1 |
Aspirin |
800-650 1700 1600-1400 |
Ar-H C=O Aromatic ring |
2 |
Pravastatin Sodium |
4600-4000 3400-3000 3000-2500 1700 1300-1200 |
Aliphatic C-H O-H C-H C=O CH3CO- |
3 |
HPMC |
3400-3000 1600-1400 4600-4000 |
O-H CH3CO- Aliphatic CH- |
Figure. 4. FTIR
spectra of aspirin
Figure. 5. FTIR spectra of
pravastatin sodium
Figure. 6. FTIR spectra of
hydroxypropyl methyl cellulose
Figure. 7. FTIR
spectra of mixture (aspirin: pravastatin) in 1:1 ratio
Figure. 8. FTIR spectra of
Pravastatin: HPMC in 1:1 ratio
Differential Scanning
Calorimetry (DSC) study
Differential scanning calorimetry thermo gram of
aspirin, pravastatin sodium and 1:1 mixture of drugs are shown in figures 9, 10
and 11 respectively.
Figure. 9. DSC thermogram of aspirin
Figure. 10. DSC thermogram of pravastatin sodium
Figure. 11. DSC thermogram of
pravastatin: aspirin (1:1) mixture
Surface Topography of Pellets
Morphological details of the coated pellets were
observed under scanning electron microscopy (SEM). Photograph of coated intact
pellets was shown in figure 12
Figure. 12. Surface
Topography of pellets
Pharmacological screening of
combination formulation for antihyperlipidemic activity
Figure 13. Total
Serum Cholesterol in rats
Figure 14. Total
Triglycerides level in rats
Figure 15. HDL cholesterol
levels in rats
Figure
16. VLDL cholesterol levels in rats
Figure 17. LDL cholesterol
levels in rats
The reduced cholesterol and triglycerides levels are
shown in figures 13, 14, 16 and 17 respectively while raised HDL cholesterol
levels are shown in figure 15.
DISCUSSION:
A] Effect of moisture level
on physical properties of pellets
From table 10, it is observed that, the size and shape
of pellets was found to depend on the amount of water added to form the damp
mass before extrusion. The increase in amount of water increased the pellets
diameter where as low amount of moisture resulted in reduction of the yield of
pellets [18, 22, 25]. Thus, the amount of moisture was kept at 50 % to get
desired size pellets with maximum yield.
B] Effect of spheronization
speed and time on physical properties pellets
At the speed of 1500 rpm for 10 minute desired size
pellets (1-2 mm) were obtained (15, 16, 20) hence 1500 rpm and 10 minute was
selected as optimized speed and time for the formulation of the core pellets
and the time period.
C] Effect of different
coating levels on drug release
From figure 1 the result revealed that, 2.5 % coating
weight gain failed to give enteric effect whereas at 5 % and 7.5 % coating
levels, drug release in pH 1.2 buffer was less than 5 % and 3 % respectively.
The 7.5 % coating level also resulted in sustaining the release of aspirin in
pH 6.8 buffer for > 6 hrs and was selected as optimum coating level. Both
the coating levels 5 % and 7.5 % had released < 5 % of aspirin in pH 1.2
buffer after 2 hrs, complying with the official requirement for enteric coated
dosage formulations. Pellets with 5% coating levels released > 95 % of drug
in later 4 hrs in pH 6.8 buffer whereas pellets with 7.5 % coating level only
release 72.60 % in 4 hrs. After 6 hrs, 99 % aspirin was released from pellets
coated up to 5% coating weight gain, whereas only 88.43% aspirin was released
after 6 hrs from pellets coated up to 7.5 % weight gain. Hence, 7.5 % coating
weight gain was selected as optimum coating level which provide the enteric
effect and sustains the release of aspirin (19, 24, 26).
D]
In-vitro drug release profile of optimized enteric coating batch
Figure 2 shows that, release of aspirin < 3% was
observed in pH 1.2 buffer for first 2 hours complying with the official
standard for enteric coated dosage form. In pH 6.8 phosphate buffer,
formulation shown sustained release of aspirin, 88.43% release in later 6 hrs.
E] Fourier’s Transform
Infra-Red (FT-IR) study
From table 13 and figures 4, 5, 6, 7 and 8, it was
concluded that FT-IR spectra of drug mixture shown that there was presence of
interaction, while in optimized drug mixture with excipients no such changes in
peaks were observed.
F] Differential Scanning
Calorimetry (DSC) study
The thermo gram of aspirin is shown in figure 9
indicates the sharp endothermic peak at 150 oC corresponding to its
melting. The thermo gram of pravastatin is shown in figure 10 shows the
endothermic peak at 142o C corresponding to its melting point. While
in thermo gram of mixture shown in figure 11 the peak of aspirin shifted to 180
oC and that of pravastatin to 95 oC with one extra exothermic
peak in thermo gram reveals the presence of interaction.
G] Pharmacological screening
of combined formulation for antihyperlipidemic activity
i) Effect of Triton on rats
cholesterol levels
The subcutaneous injection of triton X-100 (200 mg/kg)
significantly increased the serum cholesterol levels in rats up to 50 % within
24 hours than normal levels. After 24 hrs, it shown the decline in raised
cholesterol levels, while in case of HDL levels, the serum cholesterol levels
does not show significant rise as compared to normal HDL levels after triton
administration.
ii) Effect of treatment of formulation
on cholesterol levels
In order to check the antihyperlipidemic activity of
combination formulation, the rats were treated with combination formulation and
compared with the marketed formulation. After formulation administration the
blood samples were collected after 6 hrs, 24 hrs and 48 hrs respectively and
centrifuged (150x g, 10 minutes) for collection of serum and analyzed for total
triglycerides and total cholesterol. The in-vivo study revealed that the
increased levels of cholesterol by triton X-100 injection were declined to
normal ranges following the treatment with formulation.
iii) Effect of treatment of
formulation on the hyperlipidemic parameters
The results obtained from in-vivo study of
formulation revealed that the raised cholesterol and triglycerides level with
triton return to normal levels. While the formulation shown the positive rise
in the HDL cholesterol levels with no effect of triton. From figures 13, 14,
15, 16 and 17, it reveals that formulation have significant antihyperlipidemic
activity which reduced the raised cholesterol levels and raised HDL levels.
CONCLUSION:
In the present study, the combination formulation of
pravastatin along with aspirin was developed for the treatment of coronary
artery diseases by exploring the pelletization and coating technology. The core
aspirin pellets were coated with 6 %w/v polymer solution of Eudragit L100,
followed by protective coating with 2.5 %w/v solution of HPMC. Pravastatin was then layered over protective
layer by dispersing the drug in 2.5 %w/v HPMC 15 cps solution and coating to
the desired dose strength. Thus by exploring the pelletization and coating
technology a stable combination formulation was developed.
ACKNOWLEDGEMENT:
The authors would like to thank University
Grant Commission (UGC), New Delhi for the financial assistance and authors
would also like to thank, Head of the Department of Pharmaceutical Sciences,
R.T.M Nagpur University, Nagpur, India for constant encouragement and support
for the work.
CONFLICT OF INTEREST:
The authors declare no conflict of interest.
ETHICAL
APPROVALS:
The animal study was conducted according to
the protocol approved by Institutional Animal Ethics Committee (IAEC)
(CPCSEA-IAEC/Proposal No.11/22/1/2013) of Department of Pharmaceutical
Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, India.
REFERENCES:
1. Farmer JA, Guillermo TA. Atherosclerosis and
inflammation. Current atherosclerosis report. 4(2);2002: 92-98
2. Nakamura T, Kugiyama K. Triglycerides and
Remnant Particles as Risk Factors for
Coronary Artery Diseases. Current atherosclerosis reports. 8;2000:
107-10.
3. Kwiterovich PO. The antiatherogenic role of
high-density lipoprotein cholesterol. Am J
Cardiol. 82(9A);1998: 13Q-21Q.
4. Hebert PR, Hennekens CH. An overview of the randomized
trials of aspirin therapy in the primary prevention of vascular diseases, Arch
Intern Med. 160(20);2000: 3123-27.
5. Feher MD. Lipid lowering to delay the progression of coronary
artery disease. Heart. 89(4);2003: 451-58.
6. Athyros VG,
Mikhailidis DP. Effect of statins and aspirin alone and in combination on
clinical outcome in dyslipidaemic patients with coronary heart disease. A
subgroup analysis of the GREACE study. Platelets. 16(2); 2005: 65-71.
7. Pignone M, Earnshaw S, Tice JA, Pletcher MJ.
Aspirin, statins, or both drugs for the primary prevention of coronary heart
disease events in men: A cost-utility
analysis. Ann Intern Med. 144; 2006: 36-36.
8. Frantz ID, Hinkelman BT. Acceleration of
Hepatic cholesterol synthesis by Triton WR-1339. J. Exper. Med. 101; 1955:
225-32.
9. Vogel GH. Chapter M: Anti-atherosclerotic
activity, Drug Discovery and Evaluation, Pharmacological Assays, 2 nd Ed. Page:
1106, Springer
10. Newton JM. New Developments in pellets.
Euro. J Pharm. Biopharm. 1999:39-44.
11. Goodman L.S., Gilman A., “The
Pharmacological Basis of Therapeutics”, Mac Milan Publishing Co.9 th Ed. New
York, 1996.
12. The Merck index, An Encyclopedia of
Chemicals, Drugs and Biologicals: Merck Research Lab, Division of Merck and Co.
INC, White House Station. N.J; 12th Ed:
1323.
13. Connor RE, Schwartz J. in Pharmaceutical
Pelletization Technology (Ghebre-Sellassie, Eds.), Marcel Dekker, New York.
1989
14. Sousa JJ, Sousa A, Podezeck F, Newton JM.
Influence of Process conditions on drug release from pellets. Int. J Pharm.
144;1996: 159-69
15. Rodriguez EC, Torroada J. Micromeritic and
Packaging Properties of Diclofenac Pellets and effects of some formulation
variables. Drug Dev. Ind. Pharm. 27;2001: 847-55
16. Tomer G, Podezeck F, Newton JM. The
influence of model drugs on preparation of pellets by extrusion/Spheronization:
II. Spheronization parameters. Int. J Pharm. 231;2002: 107-19
17. Lustig-Gustafsson C, Kaur JH, Podezeck F,
Newton JM. The influence of water content and drug solubility on the
formulation of pellets by extrusion and spheronization, Euro J Pharm Sci. 1999;
8:147-52.
18. 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.
19. Chopra R, Alderborn G, Newton JM, Podezeck
F. The Influence of Film Coating on Pellet Properties. Pharm. Dev. Tech.
7;2002:59-68.
20. Korakianiti ES, Rekkas DM, Dallas PP.
Optimization of the Pelletization Process in a Fluid-Bed Rotor Granulator Using
Experimental Design. AAPS Pharma Sci Tech. 2002; 1(4): article 35.
21. 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: 413-22.
22. Fekete R, Zelko R, Marton RS, Racz I. Effect
of the formulation parameters on characteristics of pellets. Drug Dev. Ind.
Pharm. 24;1998: 1073-76.
23. Seitz AJ, Mehta SP, Yeager JL. Tablet
Coating, in: The Theory and Practice of Industrial Pharmacy. 3 rd Ed.,1987.
Varghese Publishing House, Bombay.
24. Achanta AS, Adusumilli PS, James KW, Rhodes
CT. Development of Hot melt coating method. Drug Dev. Ind. Pharm. 23;1997:
441-449.
25. Swarbrick J. Encyclopedia of Pharmaceutical
Technology. Marcel Dekker, Vol-5, New York,
1989.
26. McGinity JW. Aqueous Polymeric Coating for
Pharmaceutical Dosage Forms. Marcel Dekker, New York. 1989.