The objective of this work was to study the coating process of nifedipine extended release pellets using Opadry and Opadry II, in a fluid bed coater with a Wurster insert. The coating process was studied using a complete experimental design of two factors at two levels for each polymer. The variables studied were the inlet air temperature and the coating suspension flow rate. The agglomerate fraction and coating efficiency were the analyzed response variables. The air temperature was the variable that most influenced the coating efficiency for both polymers. In addition, a study of the dissolution profiles of coated and uncoated pellets using 0.5% sodium lauryl sulfate in simulated gastric fluid without enzymes (pH 1.2) was conducted. The results showed a prolonged release profile for the coated and uncoated pellets that was very similar to the standards established by the U.S. Pharmacopoeia. The drug content and the release profiles were not significantly affected by storage at 40°C and 75% relative humidity. However, when exposed to direct sunlight and fluorescent light (light from fluorescent bulbs), the coated pellets lost only 5% of the drug content, while the uncoated ones lost more than 35%; furthermore, the dissolution profile of the uncoated pellets was faster.
The administration of drugs by oral dosage is the most typical, comfortable, and convenient way to release an active substance in an organism. Among the various pharmaceutical forms in which active substance release systems can be designed for oral use, pellets have attracted increasing interest due to several technological and therapeutic advantages [
The technique used to manufacture pellets is extrusion and spheronization. This process was first reported for use as a pharmaceutical application by two classic papers in 1970 [
The pellets are ideal for the application of coatings due to their spherical shape. The film coating application for pharmaceutical use may be chosen for functional or esthetic reasons. The functional objective of film coating is to form a barrier that protects the pellets from the environmental conditions and/or to modify the drug release profile.
Fluidized beds are widely used in the pharmaceutical industry for coating solid particles such as pellets, granules, and powders. Initially, the particles are fluidized by hot air, and the coating solution or suspension is sprayed over the particles. Due to the hot air, the solvent evaporates and forms a solid film that surrounds the core material. The main challenge of this process is to form a uniform and continuous film coating on the pellet surface. The complexity lies in the large number of variables involved in the process, which makes studying this coating process relevant to the pharmaceutical industry [
Teunou and Poncelet [
Albanez et al. [
Currently, the amount of commercially available polymeric suspensions and the variety of different required release profiles are very large. Polymeric suspensions are very well accepted by the pharmaceutical industry because the suspensions are easy to prepare and are of low cost. Among commercialized suspensions, aqueous forms are preferred because they cause less damage to the environment and do not pose poisoning risks.
Nifedipine is an active ingredient that is poorly soluble in water and is widely used as a calcium-blocking agent whose efficacy and tolerability have been demonstrated in numerous studies [
Due to its short half-life in vivo, immediate release doses of nifedipine should be given three times a day [
The development of controlled release forms is hampered by the low solubility of the molecule, which affects its absorption rate. Measures such as particle size reduction and polymer solid dispersion [
Considering all the above-mentioned advantages of multiparticulate systems and the need to protect nifedipine from light exposure, the purpose of this work was to develop nifedipine extended release multiparticulates produced by the extrusion/spheronization process [
Nifedipine was manufactured by Asmidhi Labs (India). Microcrystalline cellulose (MCC) 101, the main diluent in pellet manufacture, was obtained from Mingtai Chemical (Taoyuan Hsien, Taiwan). Lactose, used as a diluent, and polyvinylpyrrolidone (PVP-K30), used as a binder, were manufactured by Valdequímica Produtos Químicos Ltda (Brazil). Croscarmellose sodium manufactured by Amishi Drugs and Chemicals (Ahmedabad, Gujarat, India) was used as a disintegrant. Polyethylene glycol (PEG4000), used as a plasticizer and a lubricant, was manufactured by
The blending and granulation were performed in a planetary mixer. To extrude the dough, a roller extruder (model EX50, Zelus, São Paulo, Brazil) with a 1.0 mm screen was used at 50 rpm. For the spheronization step following the extrusion, a spheronizer was used (model ES-015, Zelus, Sao Paulo, Brazil) with a rotation velocity of 900 rpm and perpendicular-type spheronization plate grooves with a diameter of 23 cm. An oven with forced air circulation and temperature control (model 420-4D, Nova Ética, São Paulo, Brazil) was used to dry the pellets. A screen pack with steel screens with openings between 0.425 mm and 1.40 mm was used for particle size classification of the pellets. A UV/VIS spectrophotometer (Cary, Varian, USA) was used to determine the drug content of the pellets and the amount of released drug in the in vitro dissolution tests. A scanning electron microscope (LEO 440, Campinas, Brazil) was used for the morphological analysis of the pellets. In the dissolution tests, a dissolver (model 299, Nova Ética, São Paulo, Brazil) with 6 tanks, each with a capacity of 900 mL and temperature and rotation control, was used. The film coating was performed in a fluid bed coater with a Wurster insert, (model R-060, by Zelus, São Paulo, Brazil).
The pellets were prepared by the extrusion/spheronization process. The mixing of the powders and addition of a 1% w/w methanol aqueous solution were performed in a planetary mixer. The wet mass was passed through a gravity feed lab-scale radial extruder immediately thereafter. Batches of 270 g were spheronized at 900 rpm for 40 seconds in a lab-scale spheronizer. The pellets were dried in a hot air oven at 50°C for 24 h. The formulation that was tested is shown in Table
Powder mass fractions used in the preparation of extended release nifedipine pellets.
Material | w/w (%) |
---|---|
PEG4000 | 15.0 |
Microcrystalline cellulose (MCC) | 26.5 |
Lactose | 26.5 |
Croscarmellose sodium | 2.0 |
Methocel | 1.0 |
PVP-K30 | 4.0 |
Nifedipine | 25 |
In the Wurster process, a coating solution is sprayed on a particle bed moved by an ascending gas stream. The solution coats the particle in a simultaneous process of wetting and drying to form a layer with specific characteristics (Figure
Schematic representation of the Wurster process.
The airflow rate used in the tests was 1.9 × 10−2 kg/s, 1.15 times higher than that of minimum fluidization, as the pellets produced were Geldart’s group D (density: 1455 kg/m3 and medium diameter: 1.04 × 10−3 m) particles. The initial mass of pellets was 350 g, with the size distribution shown in Table
Size distribution of the pellets used in the coating experiments.
Size range (mm) | Opadry II | Opadry | ||
---|---|---|---|---|
|
% |
|
% | |
1.18 < |
67 | 19 | 82 | 24 |
1.00 < |
154 | 44 | 146 | 42 |
0.85 < |
95 | 27 | 87 | 25 |
0.71 < |
34 | 10 | 35 | 10 |
|
||||
Total | 350 | 100 | 350 | 100 |
A two-level factorial design was performed for each polymer to identify the influential variables in the coating process, which are inlet air temperature (55 and 65°C) and suspension flow rate (5.53 and 6.64 g/min for Opadry; 5.37 and 6.46 g/min for Opadry II), in the coating process. This design determines which factors have important effects on the response as well as how the effect of one factor varies with the level of the other factors. Three runs were performed at the central point (60°C and 6.09 g/min for Opadry; 60°C and 5.92 g/min, Opadry II). The response variables were the coating efficiency and the agglomerate fraction, which are defined as follows. The coating efficiency (
As shown in Table
Theoretical weight gain in the coating process.
Test | Opadry II | Opadry |
---|---|---|
|
|
|
1 | 7.4 | 10.5 |
2 | 10.8 | 11.9 |
3 | 10.8 | 11.7 |
4 | 10.9 | 11.7 |
5(C) | 11.4 | 11.4 |
6(C) | 11.2 | 9.3 |
7(C) | 11.0 | 10.6 |
The drug content of both coated and uncoated pellets was determined by powdering 300 mg of the pellets. The drug was then extracted with a methanol solution. The filtered extract was assayed spectrophotometrically at a wavelength of 350 nm (according to graphs of the absorbance spectrum and information obtained from the USP XXXII). The drug content determination was performed in triplicate, and all tests were performed in the absence of light and using glassware wrapped in aluminum foil.
Both uncoated and coated pellets were subjected to dissolution studies to verify the extended release profile. In this analysis, 0.5% sodium lauryl sulfate in simulated gastric fluid without enzymes (pH 1.2) at 37°C was used as the dissolution medium for 12 h. Apparatus 1 (basket) was used at 100 rpm. Two replicate samples of approximately 50 mg of particles were put in the baskets. A sample of 5 mL from each vessel was filtered using a 0.45
Opadry and Opadry II are fully formulated dry coating systems that are dispersible in water and use (hydroxypropyl methylcellulose) HPMC and (polyvinyl alcohol) PVA, respectively, in their formulations. These polymers contain titanium dioxide in their formulations, which may protect the microgranules from exposure to light, thus avoiding drug degradation. The suspension containing Opadry was prepared with 12% w/w of powder dispersed in water, and the suspension containing Opadry II was prepared with 20% w/w powder in water. The rheology of the coating suspensions was determined using a Brookfield Rheometer.
The particles were subjected to scanning electron microscopy with an LEO 440 Stereoscan microscope. This analysis aimed to visualize the surface morphology. The samples were mounted onto circular aluminum stubs with double-sided carbon tape and then coated with platinum.
For a commercial product, the guarantee of stability is vital for its safety and efficacy during storage and use. In this study, coated and uncoated pellets were stored under stress conditions of 40°C and 75% relative humidity. The drug content and dissolution profiles were measured after 30, 60, 90, and 180 days.
For the photostability study, the samples were exposed to a fluorescent light and daylight for ten days. The drug content and dissolution profiles were measured.
The polymeric suspensions were prepared at the maximum concentration following the manufacturer’s indications: 12% w/w Opadry and 20% w/w Opadry II. For both coating suspensions (Opadry and Opadry II), the shear stress varies linearly with the deformation rate; in other words, the shear stress is directly proportional to the velocity gradient. Therefore, the two polymeric suspensions, Opadry II and Opadry behave as in the model proposed by Isaac Newton and are thus Newtonian fluids. The experimental curves for shear stress and viscosity are shown in Figure
Viscosity values of coating suspensions.
Opadry II | Opadry | ||
---|---|---|---|
Test | µ (kg/m·s) | Test | µ (kg/m·s) |
A | 0.0486 | A | 0.0735 |
B | 0.0484 | B | 0.0737 |
C | 0.0488 | C | 0.0735 |
Mean | 0.0486 ± 0.00014 | Mean | 0.0736 ± 0.00010 |
Experimental curves forshear stress versus deformation rate (Opadry II (a) and Opadry (b)).
The viscosity of the polymeric suspension of Opadry II is much lower than that of the Opadry suspension, although its solid content is higher. The low viscosity of Opadry II results in excellent and uniform droplet size, improving its performance in the coating process when compared with that of Opadry, which presented higher viscosity values (Table
Dissolution tests were performed with the uncoated pellets according to the methods described in Section
Absolute values
Time (h) | Amount dissolved (%), experimental | Amount dissolved (%), Pharmacopeia |
---|---|---|
1 | 27.1 ± 2.5 | 10–35 |
4 | 56.7 ± 2.4 | 40–67 |
12 | 80.5 ± 1.6 | Not less than 80 |
Dissolution profile of uncoated pellets in 0.5% sodium lauryl sulfate in simulated gastric fluid without enzymes (pH 1.2).
Coating experiments were performed for each polymer (Opadry and Opadry II) using a 22 factorial design. The aim of this analysis was to investigate the influence of process variables on the coating performance and was determined by the two response variables
Influence of process variables on coating performance with the different polymers.
Test |
|
|
Opadry II | Opadry | ||
---|---|---|---|---|---|---|
|
|
|
|
|||
1 |
|
|
13.9 | 55.4 | 32.7 | 51.5 |
2 |
|
|
12.2 | 98.2 | 14.4 | 86.7 |
3 |
|
|
2.8 | 71.8 | 13.7 | 66.1 |
4 |
|
|
4.8 | 80.2 | 2.9 | 68.1 |
5(C) | 0 | 0 | 12.8 | 82.7 | 13.3 | 74.9 |
6(C) | 0 | 0 | 11.6 | 83.2 | 14.6 | 77.2 |
7(C) | 0 | 0 | 11.4 | 79.3 | 16.6 | 69.8 |
Pareto chart of effects: coating efficiency,
Pareto chart of effects: agglomerate fraction,
Pareto chart of effects: coating efficiency,
Pareto chart of effects: agglomeration fraction,
The variable that most influenced the coating efficiency was the air temperature. The coating performed at higher temperatures and flow rates (test 2; Table
The suspension flow rate was the only factor that significantly influenced the agglomerate fraction when the pellets were coated with a polymeric suspension of Opadry II (Figure
The variance analysis showed that the regression is significant for the predictive linear models of the coating efficiency (for both Opadry and Opadry II) and the agglomerate fraction (only for Opadry). The response surfaces of the predictive models for coating efficiency are shown in Figures
Response surface for the coating efficiency of Opadry II.
Response surface for the coating efficiency of Opadry.
Response surface for the agglomerate fraction of Opadry.
The response surfaces indicate that elevated inlet air temperature and flow rate increase the efficiency of the coating process; however, an elevated suspension flow rate increases the agglomerate fraction during the coating process.
The suspension of Opadry II was favorable for increased coating efficiency, although its solid content was greater than that of the suspension of Opadry, because the suspension containing Opadry II had a much lower viscosity than the suspension containing Opadry; it also contained talc as a surfactant agent, which reduced the surface tension, promoting the spread of the suspension over the particle surface and improving its wettability. Moreover, the coating time with the Opadry II polymeric suspension is significantly lower than the process time of the Opadry polymeric suspension for the same mass gain.
The amount of the suspensions sprayed onto the pellets was sufficient for theoretical mass gains of 11%. This value was recommended by the manufacturer. The actual mass gains from the tests are shown in Table
Evaluation of coating experiments.
Test |
|
|
Opadry II | Opadry |
---|---|---|---|---|
|
|
|||
1 |
|
|
4.1 | 5.4 |
2 |
|
|
10.6 | 10.3 |
3 |
|
|
7.8 | 7.7 |
4 |
|
|
8.8 | 7.9 |
5(C) | 0 | 0 | 9.4 | 8.5 |
6(C) | 0 | 0 | 9.3 | 7.2 |
7(C) | 0 | 0 | 8.8 | 7.4 |
The coated pellets were submitted to in vitro dissolution tests. The results are shown in Figures
Dissolution of pellets coated with Opadry II.
Dissolution of pellets coated with Opadry.
The uncoated pellets have a rough, irregular surface, as shown in Figures
Uncoated pellets (150x).
Uncoated pellets (1500x).
Coated pellets (150x): (a) Opadry II; (b) Opadry.
Coated pellets (1500x): (a) Opadry II; (b) Opadry.
Coated pellets (1500x).
The accelerated stability tests (40°C, 75% rh) were performed as described in Section
Drug content with storage time under light stress.
Time (days) | Drug content of the pellets (%) | ||
---|---|---|---|
Uncoated | Opadry II | Opadry | |
0 | 24.4 ± 0.2 | 22.4 ± 0.3 | 22.1 ± 0.1 |
1 | 23.4 ± 0.2 | 21.9 ± 0.3 | 22.8 ± 0.2 |
2 | 22.4 ± 0.5 | 21.5 ± 0.1 | 21.6 ± 0.2 |
3 | 21.2 ± 0.4 | 21.4 ± 0.2 | 21.3 ± 0.3 |
6 | 16.6 ± 0.2 | 21.2 ± 0.2 | 21.0 ± 0.3 |
10 | 14.8 ± 0.1 | 21.1 ± 0.2 | 20.9 ± 0.2 |
Dissolution profiles of uncoated pellets before and after storage under stress conditions.
Dissolution profiles of pellets coated with Opadry II (test 5 (C)) before and after storage under stress conditions.
Dissolution profiles of pellets coated with Opadry (test 5 (C)) before and after storage under stress conditions.
Dissolution profiles of uncoated pellets after storage under light stress conditions.
Drug content fraction lost after storage under light stress conditions.
The statistical analysis of the coating process showed that the inlet air temperature and the interaction between the air temperature and the suspension flow rate influenced the coating efficiency with a 95% confidence level. The variable that most influenced the coating efficiency was the inlet air temperature. Higher suspension flow rates resulted in better coating efficiency but also favored agglomeration, which was expected. The coating performed at higher temperatures and flow rates resulted in improved processing efficiency, and the efficiency of the Opadry II polymer was very close to 100%. The coating time with the polymeric suspension of Opadry II was significantly lower compared to the processing time for the polymeric suspension of Opadry for the same mass gain. The suspension flow rate was the only factor that significantly influenced the agglomerate fraction when the pellets were coated with a polymeric suspension of Opadry II. In addition to the suspension flow rate, the inlet air temperature also significantly influenced the agglomerate fraction when the coating process was carried out with a polymeric suspension of Opadry. The response surfaces indicate that the path of maximum slope (higher agglomerate fraction) occurs when the coating process is carried out at high flow rates and low air temperatures. The in vitro dissolution studies showed that the nifedipine release profile was not affected by the polymeric coatings. However, the photostability studies showed that the coating of nifedipine extended release pellets is necessary because the dissolution profile and drug content were significantly altered for only the uncoated pellets when they were exposed to light.
Viscosity (
Shear stress (
Coating efficiency (%)
Actual mass gain (%)
Theoretical mass gain (%)
Agglomerate fraction (%)
Deformation rate (1/s)
Flow rate (g/min)
Temperature (°C)
Mass (g).
The authors declare that there is no conflict of interests regarding the publication of this paper.
This work was financially supported by FAPESP. The authors gratefully acknowledge the Mauá Institute of Technology (IMT) and UNICAMP for their support throughout the project. They are also grateful to Colorcon for supplying the necessary amounts of Opadry and Opadry II.