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Comparison of pharmaceutical films prepared from aqueous polymeric dispersions using the cast method and the spraying technique
Colloids and Surfaces A: Physicochem. Eng. Aspects 337 (2009) 109–116
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Colloids and Surfaces A: Physicochemical and Engineering Aspects journal homepage: www.elsevier.com/locate/colsurfa
Comparison of pharmaceutical films prepared from aqueous polymeric dispersions using the cast method and the spraying technique a ˜ Luis Mendoza-Romero a , Elizabeth Pinón-Segundo , María Guadalupe Nava-Arzaluz a , a Adriana Ganem-Quintanar , Salomon Cordero-Sánchez b , David Quintanar-Guerrero a,∗ a División de Estudios de Posgrado (Tecnología Farmacéutica), Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Av. 1◦ de Mayo s/n, Cuautitlán Izcalli, 54740, Estado de México, México b Departamento de Química, Universidad Autónoma Metropolitana, Iztapalapa, Apdo. Postal 55-534, Distrito Federal, México
a r t i c l e
i n f o
Article history: Received 24 April 2008 Received in revised form 30 November 2008 Accepted 8 December 2008 Available online 13 December 2008 Keywords: Spraying technique Casting method Film-forming process Minimum film formation temperature Latex dispersion
a b s t r a c t This work focuses on: (i) the development of a device to form pharmaceutical films by a spraying technique. The principal idea is to simulate the film-coating operations; (ii) the investigation of some of the variables that influence the coating process (e.g., dispersion concentration, drying temperature and plasticizer presence) using Teflon plates and tablets as substrates; (iii) the evaluation of the quality of the films obtained by the spraying technique and the cast method. The results of this work showed a marked influence of the variables and the preparation method on the characteristics and quality of the films. Although the device proposed in this study does not reproduce all the factors involved in the coating process, it is a good tool to study and to predict film formation from latexes. © 2008 Elsevier B.V. All rights reserved.
1. Introduction The application of polymeric coatings to pharmaceutical dosage forms is used for decorative and protection purposes, as well as for functional purposes, in order to mask odors, flavors or colors; to improve appearance; and to facilitate their identification [1]. Pharmaceutical coating films provide a physical and chemical protection for the drug against the environment, in order to maintain the integrity of tablets during storage and shipping [2–4] and increase the solid’s resistance against rupture [5]. Additionally, they can be used to achieve enteric properties, to modulate the release of active ingredients, and to prevent the interaction of different therapeutic substances. The interest in coating technologies with latex dispersions arises from economic and environmental reasons [6–8]. Several authors [9–18] have studied the properties of pharmaceutical polymeric films prepared by the cast method from aqueous
∗ Corresponding author at: Bolognia 4-28, Bosques del Lago, Cuautitlán Izcalli, 54766, Estado de México, México. Tel.: +52 55 58 77 19 07; fax: +52 55 58 93 86 75. E-mail addresses: [email protected], [email protected] ˜ (L. Mendoza-Romero), [email protected] (E. Pinón-Segundo), lupita [email protected] (M.G. Nava-Arzaluz), [email protected] (A. Ganem-Quintanar), [email protected] (S. Cordero-Sánchez), [email protected] (D. Quintanar-Guerrero). 0927-7757/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.colsurfa.2008.12.004
or organic solutions or dispersions. In the case of latex dispersions, some problems have been detected, such as particle sedimentation during the drying process, which results in poorly uniform films; or, in the case of multilaminated films, dissolution of the previously formed films by the action of the solvent used to form the subsequent layers has been observed [19]. The film-forming mechanism from aqueous polymeric dispersions is a complex one, since particles dispersed in water have to coalesce to form a continuous film. It is generally considered that the film-forming mechanism takes place in three stages: (a) evaporation and particle coalescence (stage I), (b) particle deformation (stage II), and (c) particle–particle interdiffusion (stage III) [20–24]. During film formation, physical and mechanical properties are of great importance for film characterization, since they help to predict the stability and release rate of the coated forms. Usually, studies of this type are performed on free films [13,16,25–29]. In film formation with latex dispersions, it is common that many pharmaceutical polymers exhibit brittleness, which results in films with undesirable characteristics [30]. Therefore, plasticizers are frequently added to reduce minimum film formation temperature (MFFT) below the working temperature in order to favor coalescence, to improve mechanical properties, and to obtain effective crack-free films [12,15]. The plasticizers used for polymeric coating include polyols, organic esters, vegetable oils, glycerides, and even non-traditional
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plasticizers, such as n-alkenyl succinic anhydride or methylparaben [31–36]. Due to the great differences between the characteristics and properties of films formed by the cast method and those obtained by the spraying technique, it is very difficult to establish a predictive correlation. Therefore, it is highly advisable to use spraying techniques, which are more representative of the coating process, in order to prevent an erroneous result interpretation [2]. Several authors [18,37] have agreed that, by using a rotating cylinder, it is possible to predict the formation of uniform and reproducible films by the spraying technique on non-pharmaceutical substrates from aqueous polymeric solutions or dispersions. However, while there are reports on the use of experimental filmforming devices, these do not employ a pharmaceutical substrate. It is therefore reasonable to design a device for tablet coating by the spraying technique, with the aim of providing a rapid approach of a pharmaceutical film-forming process, reproducible and able to show the differences among substrates. Different factors, such as drying time, drying temperature, drying method, etc. [38], have been reported as critical in the formation of polymeric films by the spraying technique [39]. These factors should be optimized and controlled for each system in order to produce films with good technological properties. In addition, it is important to investigate the influence of some of these process variables, since their effect on film properties will depend on the preparation method. The objectives of this work were: (1) to develop a device for the formation of pharmaceutical films by the spraying technique based on rotating cylinder concept, allowing, on the one hand, to simulate rapidly some operational conditions of a pharmaceutical film-coating process, and on the other, to study the critical variables involved in film formation; (2) to coat a non-porous substrate (Teflon) by the cast method and the spraying technique (the former with the designed apparatus), in order to show the differences in the properties of the films obtained by the two methods; (3) to coat a pharmaceutical substrate (tablets) with the proposed spraying device, evaluating the macroscopic and microscopic characteristics of the films, in order to determine the usefulness and limitation of the device.
2. Experimental 2.1. Materials Three commercially-available aqueous dispersions were used: poly(ethyl acrylate, methyl methacrylate) trimethylammonioethyl methacrylate chloride 1:2:0.1 (Eudragit® RS 30D, 5% and 15%, w/w), poly(ethyl acrylate, methyl methacrylate) trimethylammonioethyl methacrylate chloride 1:2:0.2 (Eudragit® RL 30D, 5% and 15%, w/w), and poly(methacrylic acid, ethyl acrylate) 1:1 (Eudragit® L 30D55, 5% and 15%, w/w), which were kindly provided by HELM de México (Mexico). Glycerine triacetate (triacetin) was used as plasticizer and was obtained from Aldrich Chemical (U.S.A.). Teflon plates (0.5 cm × 0.5 cm, 0.79 mm thickness) and biconcave placebo tablets (formulation: microcrystalline cellulose PH 102 57.0%, anhydrous lactose 38.0%, magnesium stearate 1.0% and croscarmellose sodium 4.0%; 8 mm in diameter, 4 mm thickness) were used as substrates.
Table 1 Experimental matrix for cast and spray methods for Eudragit® RS 30D, Eudragit® RL 30D, and Eudragit® L 30D-55. Batch
Polymer content (%, w/w)
Plasticizer (%, w/w)a
Drying temperature (◦ C)
1 2 3 4 5 6 7 8 9 10 11 12
5 5 5 5 5 5 15 15 15 15 15 15
0 0 0 10 10 10 0 0 0 10 10 10
38.0 43.0 48.0 38.0 43.0 48.0 38.0 43.0 48.0 38.0 43.0 48.0
a
Based on polymer content.
2.3. Minimum film formation temperature 15 ml of the dispersion (15%, w/w, with and without plasticizer) were placed in a circular Teflon mould (10 cm in diameter). The dispersion was dried for 24 h, starting at 25 ◦ C with 1 ◦ C increments until the MFFT for each dispersion was found. The MFFT was determined as the temperature at which a clear, crack-free film was obtained. 2.4. Film preparation 2.4.1. Cast method Polymeric films were prepared with the three types of dispersions. 15 ml of the dispersion for every system were poured on circular Teflon moulds (10 cm in diameter) and left to dry for 24 h. Table 1 shows the matrix of the experiments performed with this method. 2.4.2. Spraying technique 2.4.2.1. Design of the film formation apparatus. The device used, designed and assembled by the authors, is shown in Fig. 1. The apparatus has the advantage of allowing an easy and rapid modification of some critical variables involved, such as drying temperature, flow, and spraying pressure, while simulating the film-coating operations. Functioning conditions were optimized in a previous work [40] but they can be modified depending on the purpose pursued. In this work, Teflon plates (0.5 cm × 0.5 cm) or biconcave placebo tablets (8 mm in diameter), previously attached to the rotating cylinder of the device with double-sided adhesive tape, (Fig. 1), were sprayed with the dispersion (under constant stirring) at a pressure of 0.2 MPa and a mean spray flow of 1.7 ml/min. The
2.2. Polymeric dispersions A known amount of triacetin was dissolved in 50 ml of water, adjusting the concentration with the required volume of dispersion (for a desired polymer concentration) and water. The resulting dispersion was then magnetically stirred for 2 h [33].
Fig. 1. Schematic representation of the rotatory spraying device. (A) Air inlet (DeVILBISS, U.S.A.), (B) stirrer (Amphenols Control Div. U.S.A.), (C) latex dispersion, (D) magnetic stirrer (Barnstead Int. U.S.A.), (E) peristaltic pump (Masterflex, Mexico), (F) spray gun (Walter Pilot, Mexico), (G) rotating drum (15 cm high, 30 cm in diameter), (H) drying system (Milwuakke, Mexico), and (I) infrared thermometer (OAKTON® , Temptestr® IR, México).
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cylinder was maintained at a rotation speed of 72 rpm, and the coating time was 1 h. The dispersion volume sprayed per area on the Teflon plates and on placebo tablets was equivalent to that used on Teflon moulds by the cast method. The distance between the spraying gun and the rotating cylinder was 15.5 cm, assuring a covered area of at least 90% of the rotating cylinder’s width. The drying gun was placed after the spraying pan in order to avoid any kind of interference, the drying distance (between 4 and 5 cm) was such as to maintain the substrate’s temperature (which was constantly monitored on the substrate’s surface with an infrared thermometer).
Table 2 Minimum film formation temperature (MFFT) for Eudragit® RS 30D, Eudragit® RL 30D, and Eudragit® L 30D-55 polymeric films (standard deviation in parentheses) at a polymer concentration of 15% (w/w). Polymer dispersion
Triacetin % (w/w)a
MFFTb (◦ C)
Eudragit® RS 30D
0 10
47.3 ± (0.4) <25
Eudragit® RL 30D
0 10
38.3 ± (0.4) <25
Eudragit® L 30D-55
0 10
27.33 ± (0.4) <25
a
2.4.2.2. Film formation. As with the cast method, the influence of drying temperature, plasticizer presence, and dispersion concentration on film continuity was assessed. Table 1 shows the matrix of the proposed experiments. As can be observed, three different drying temperature levels are considered. Although coating by spraying is usually carried out at a drying temperature between 40 and 50 ◦ C [38], in our case, a lower temperature (38.0 ◦ C) was selected, for this was the minimum temperature that allowed water to be eliminated. At lower temperatures, tablets would wear out and become extremely wet, thus loosing their integrity. The highest temperature level was set at 48.0 ◦ C, since this is the usual temperature range for pharmaceutical film-coating operations. 2.4.3. Film thickness Film thickness was only evaluated in the batches 6 and 12 obtained by both processes because they formed a continuous films with the three polymer dispersions. Film thickness in cast method was measured with a micrometer (Digitrix-MARKII, Cole Parmer Instrument Co., Mexico), (with the three dispersions used: Eudragit® RS 30D, Eudragit® RL 30D and Eudragit® L 30D-55). In the spray technique film thickness was measured by scanning electron microscopy (SEM). The coated tablets were dried and shadowed in a cathodic evaporator with a gold layer (∼20 nm thick, Ion sputter JFC-1100, JEOL). Then, film thickness of the tablets was observed by SEM using a JSM-25 SII scanning electron microscope (JEOL, Japan). (IROSCOPE, SI-PHF, U.S.A.). 2.4.4. Film-tablet morphology The quality of the films obtained by the cast method and by the spraying technique was assessed by optical microscopy (IROSCOPE, SI-PHF, U.S.A.). Additionally, the quality of the films obtained on tablets was assessed by scanning electron microscopy with the aim of determining film continuity [41,42].
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b
Based on polymer content. Data reported as the mean ± SD of three samples.
As can be seen in Table 2, Eudragit® RS 30D has the highest MFFT, followed by Eudragit® RL 30D and Eudragit® L 30D-55. The inclusion of 10% triacetin (w/w) (based on polymer content) reduced the MFFT below 25 ◦ C for the three polymeric dispersions. This concentration was chosen based on previous studies [47], where it was found that an adequate plasticizing effect cannot be obtained below this critical concentration. 3.2. Cast method The cast method is a well-known film-forming method for latex dispersions, since it provides information about film characteristics [2,37]; however, formation conditions are static and do not fully represent the characteristics of films formed by the spraying technique in a pharmaceutical film-coating process. The formulation and process conditions used in this work to obtain continuous films by this method were relatively simple, as can be seen in the experimental design. As discussed later, it was only necessary to fulfill one of the following conditions: the use of 10% plasticizer (w/w) or a drying temperature higher than the MFFT, regardless of the two concentrations and the type of latex dispersions used. The results of film formation (Table 3) show that, in those experiments where triacetin was used (batches 4–6 and 10–12), continuous and transparent films, with a clear and homogeneous appearance were obtained, irrespectively of the drying temperature. Seen through optical microscopy, the films were found to be homogeneous, continuous, and virtually transparent, as can be confirmed for Eudragit® RS 30D, indicating a good compatibility between triacetin and the polymer [48], and, as mentioned before, it is the plasticizer of choice for this type of polymers [26]. In batches 4–6 and 10–12, 10% triacetin (w/w) reduced the MFFT to <25 ◦ C for the three dispersions used (Table 2). This is due to a reduction in the intermolecular forces of polymers, which leads to less energy
3. Results and discussion 3.1. Minimum film formation temperature Table 2 summarizes the MFFTs for polymeric dispersions. MFFT determination is necessary in order to select the appropriate working temperature for film formation by both methods. The values obtained are consistent with those reported by other authors [38]. In film formation, the plasticizer is one of the main components of the formulation [43]. Triacetin was used as plasticizer due to its well-known effects on reducing the tendency to obtain brittle films with methacrylic acid copolymers [30], and because it has been widely used in polymeric film research [27]. Furthermore, it shows a good aqueous solubility (77.8 ± 0.5 mg/ml) [15], which enables it to distribute itself in the dispersion medium and then spread to the polymer to weaken intermolecular attraction forces [44], increasing the flexibility of polymeric chains and reducing the vitreous transition temperature [45,46].
Table 3 Casting latex film formation on Teflon moulds, using latex dispersions of Eudragit® RS 30D, Eudragit® RL 30D and Eudragit® L 30D-55. Batch
1 2 3 4 5 6 7 8 9 10 11 12
Film formation Eudragit® RS 30D
Eudragit® RL 30D
Eudragit® L 30D-55
− − + + + + − − + + + +
+ + + + + + + + + + + +
+ + + + + + + + + + + +
(+) Formation, (−) no formation. Data reported from three samples.
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Fig. 2. Photographs of the casting latex films prepared from Eudragit® RS 30D. Batches 1, 4–6.
being required to achieve polymeric particle coalescence [20]. It was also possible to obtain continuous films with a clear and homogeneous appearance when drying was performed at the MFFT or at a higher temperature (batches 1–3 and 7–9 for Eudragit® RL 30D and Eudragit® L 30D-55 and batches 3 and 9 for Eudragit® RS 30D) (Table 3). These results were obtained for the two concentrations assessed (5% and 15%, w/w), which is reasonable considering that drying temperature is fundamental to form continuous films by the cast method, and it should be higher than the MFFT. As expected, in those experiments where no plasticizer was present and the drying temperature was lower than the MFFT (Table 3, batches 1–2 and 7–8 for Eudragit® RS 30D), the films had a great number of fractures, as shown in Fig. 2 (batch 1), since an incomplete coalescence occurs due to the lack of plasticizer [20], thus producing poor-quality films. Photographs of some of the films obtained with Eudragit® RS 30D are shown in Fig. 2. Batch 1 shows a poor-quality film, whereas batches 4–6 were homogeneous and continuous. 3.3. Spraying latex films 3.3.1. Design and construction of a device for film formation by spraying As mentioned above, the film formation process is a complex one, entailing approximately 20 variables [38]. Therefore, it is necessary to control some of these variables, especially those involved in film functionality and stability. In the polymeric film-forming process, polymer concentration is a determining variable, but so are the application conditions in the spraying technique. Among these, the most important variables to be considered are spraying flow, temperature, and drying time, since they are related to the amount of solvent in the system, and the way it is eliminated will have important effects on film characteristics [39]. Bearing this in mind, a device was developed based on the rotating cylinder concept to simulate the film-forming process by spraying on placebo tablets. The device was designed to study some critical process variables, such as spray flow, pressure, and distance, and also to
Fig. 3. Photographs of spraying latex film formation on Teflon plates and on tablets for the 12 batches prepared.
help assess the influence of dispersion concentration, plasticizer presence, and drying temperature on film properties. It is true that different aspects of industrial film-coating are not considered such as a real evaporative process, the mutual tablet rubbing, the differences of spraying on tablets which are in random movement, etc., the device is an interesting tool as first approach to identify and to study the effect of different critical variables involved in the film formation from latexes. 3.3.2. Spraying latex on Teflon plates and tablets In the experiments where continuous films were obtained in Teflon plates and tablets, these were transparent with the three polymeric dispersions used (Fig. 3). It is generally considered that transparent films are obtained when full coalescence of the polymeric particles takes place [26]. In some batches, such as 1 and 7, a powdery film was formed due to the film-forming conditions (drying temperature 38 ◦ C, 5% or 15%, w/w, without the use of a plasticizer), and therefore, an incomplete polymeric particle coalescence is assumed [49,50]. Film thickness values obtained by the cast method on Teflon plates and by spraying on tablets are shown in Table 4. As can be
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Table 4 Thickness of casting and spraying films obtained with Eudragit® RS 30D, Eudragit® RL 30D, and Eudragit® L 30D-55 at 5% and 15% (w/w). Batch
Film thickness (m) Casting
6 12
Spraying
Eudragit® RS 30D
Eudragit® RL 30D
Eudragit® L 30D-55
Eudragit® RS 30D
Eudragit® RL 30D
Eudragit® L 30D-55
103.9 ± 4.3 315.0 ± 14.0
108.3 ± 6.3 337.8 ± 26.8
129.6 ± 14.2 358.9 ± 36.8
97.4 ± 7.3 286.7 ± 11.9
113.5 ± 9.2 325.7 ± 9.6
123.1 ± 6.4 346.5 ± 15.2
Data reported as the mean ± SD of three samples.
seen, the thickness of the films obtained by both methods is very similar, indicating that films may be comparable, but not necessarily particle arrangement. The results of film formation on Teflon plates show wide differences between the films obtained by the cast method (Table 3) and those obtained by the spraying technique (Table 5), even though the same substrate was used. This indicates that the film-forming method determines the characteristics of the films, and leads us to consider that the film-forming method should be as similar as possible to that used in a pharmaceutical film-coating operation, in order to obtain results that are more representative of the real process. The results show that the characteristics of the films obtained by the spraying technique using diverse substrates (Teflon plates and placebo tablets) are not the same because of the different nature of the substrates: the latter being completely hydrophobic and the former less hydrophobic. This behavior shows that when the operating conditions of the device are adequately optimized, the type of substrate has a fundamental role on the formation of continuous films. Film formation appears to be easier on tablets that on Teflon plates; this behavior may be explained by the fact that film formation occurs more easily in hydrophilic than in hydrophobic substrates.
be formed; otherwise, films with undesirable characteristics will be obtained [20,39]. The results of film formation for the three dispersions used are shown in Table 5. In order to observe the influence of the drying temperature, those batches in which drying was performed without the presence of the plasticizer will be discussed. In those batches where drying was carried out at 38.0 ◦ C (10 ◦ C higher than the MFFT for Eudragit® L 30D-55), 43.0 ◦ C, and 48.0 ◦ C (10 ◦ C higher than the MFFT for Eudragit® RL 30D, and more than 20 ◦ C higher than the MFFT for Eudragit® L 30D-55) (batches 1–3 and 7–9) no continuous films were formed on either substrate. Although it is known that a continuous film is formed when the drying temperature is adjusted to 10 ◦ C above the MFFT [39,53], this was not the case (Fig. 4). Particle ordering probably took place due to solvent evaporation [54], but interfacial forces were not strong enough for particles to coalesce [20], thus yielding a discontinuous and incomplete film with a cracked appearance [39]. This behavior was seen for the two concentrations assessed, 5% and 15% (w/w). This is not surprising, since the film-forming process is dependent of several factors [20,21,38,43]. While drying temperature is one of the most important variables, it does not by itself define film formation; rather, the combination of other factors is required [43], such as the presence of a plasticizer, which is discussed below.
3.3.2.1. Effect of drying temperature. Drying is a very important part of film formation, and a determining factor throughout the whole process. It is considered that drying takes place in three stages [51,52]: in the initial stage, water evaporates from the surface until the interfacial area of the surface begins to decrease as a result of film formation and the concentration of polymeric particles increases (60–70% volume/fraction). In the second stage, the evaporation of the solvent decreases, the particles come into irreversible contact and are completely arrayed. The third stage marks the onset of film formation. Therefore, it is unquestionable that drying temperature will be determining for film properties at the end of the process. If drying is complete and adequate, a continuous film will
3.3.2.2. Effect of plasticizer. Several studies have demonstrated that film properties are affected by the amount and type of plasticizer [13,34]. In this study, (Table 5), it was not possible to obtain continuous films for batches 1–3, and 7–9, where no triacetin was used, including the experiments in which the drying temperature was
Table 5 Spraying latex film formation on Teflon plates and on tablets using latex dispersions of Eudragit® RS 30D, Eudragit® RL 30D and Eudragit® L 30D-55. Batch
Film formation Eudragit® RS 30D
1 2 3 4 5 6 7 8 9 10 11 12
Eudragit® RL 30D
Eudragit® L 30D-55
Teflon
Tablet
Teflon
Tablet
Teflon
Tablet
− − − − − + − − − − − +
− − − − + + − − − − + +
− − − − + + − − − − + +
− − − + + + − − − + + +
− − − − + + − − − − + +
− − − + + + − − − + + +
(+) Formation, (−) no formation. Data reported from three film samples.
Fig. 4. Scanning electron micrographs of the film-tablet surface prepared from Eudragit® RL 30D. Batch 2, (A) 45× and (B) 10,000×.
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Fig. 5. Scanning electron micrographs of the film-tablet surface prepared from Eudragit® RS 30D. Batch 4, (A) 45× and (B) 10,000×.
Fig. 6. Scanning electron micrographs of the film-tablet surface prepared from batch 10 at 45×. (A) Eudragit® RL 30D and (B) Eudragit® L 30D-55.
48.0 ◦ C (batches 3 and 9). These results are consistent with those reported by Felton and McGinity [34], where film formation does not succeed if less than 10% of plasticizer is used. In batches where triacetin was used, the film formation was dependent on the substrate and the polymer dispersion used. By using Teflon plates as substrate, it was not possible to obtain continuous films in batches 4 and 10 with the three polymer dispersions. With Eudragit® RS 30D (Table 5, batch 5), triacetin reduced the MFFT below 25 ◦ C, and despite having a wide effect in reducing film fractures, the temperature was too low, and no continuous films were formed. In all other batches where triacetin was used (batches 6 and 12 for Eudragit® RS 30D and batches 5, 6, 11 and 12 for Eudragit® RL 30D and Eudragit® L 30D-55) continuous films were always obtained. These were homogeneous and virtually transparent when analyzed by optical microscopy. When using tablets as substrate, a drying temperature of 38.0 ◦ C and triacetin, film formation was also dependent on the polymer dispersion used. With Eudragit® RS 30D in batches 4 and 10 (Table 5 and Fig. 5) the temperature was too low, and no continuous films were formed. This temperature provides the necessary energy for efficient water evaporation, but not for particle ordering and coalescence [21]. As can be seen for Eudragit® RL 30D and Eudragit® L 30D-55 (batch 10), continuous films were formed (Fig. 6), since the MFFTs for these dispersions are lower than 0 ◦ C [38], which favors a complete coalescence and the formation of a continuous film. When triacetin was used and the drying temperature was 43.0 ◦ C (batches 5 and 11) and 48.0 ◦ C (batches 6 and 12), continuous films were formed as can be seen in Fig. 7 for batch 12 for Eudragit® L 30D-55, because, in addition to promoting particle ordering, deformation, and fusion, the presence of the plasticizer provided good elastic properties for the formation of a continuous film. This behavior was seen with the two dispersion concentrations assessed.
Eudragit® L 30D-55 (Table 5, batch 10) at a 15% concentration, since under these conditions the MFFT of the polymeric dispersion is lower than 25 ◦ C, and the drying temperature was sufficient to cause particle coalescence, while in batch 4, at a 5% concentration (Fig. 8), even if continuous films were obtained, they occasionally present microscopic cracks or, as in this case, microscopic pores (3–80 m). At this concentration, the drying temperature was not enough for a complete coalescence to take place among particles, due to the greater amount of water to be evaporated and the lower amount of polymer available to form a continuous film.
3.3.2.3. Effect of polymer content. The film-forming process involves particle coalescence, i.e., particle compacting, deformation, cohesion, and interdiffusion, and polymer concentration has a determining influence on film properties [55]. Continuous films were obtained with the dispersions of Eudragit® RL 30D and
Fig. 7. Scanning electron micrographs of the film-tablet surface prepared from Eudragit® L 30D-55. Batch 12, (A) 45× and (B) 10,000×.
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the plasticizer was present and the drying temperature was above 43.0 ◦ C. The results on tablets using Eudragit® RS 30D showed continuous films when the plasticizer was present and the drying temperature was 48.0 ◦ C. With Eudragit® RL 30D and Eudragit® L 30D-55, continuous films were obtained when the plasticizer was present, and the drying temperature was higher than 38.0 ◦ C. In tablets it was found that dispersion concentration has an effect on the continuity of the films obtained with Eudragit® RL 30D and Eudragit® L 30D-55, since when films were formed with triacetin at a drying temperature of 38.0 ◦ C and at a 5% dispersion concentration, they occasionally showed small microscopic pores. There are clear differences between the characteristics of films obtained by the cast method and those obtained by the spraying technique on a non-pharmaceutical substrate. In the cast method, it was not possible to obtain continuous films only when the plasticizer was not present and when drying was performed under the MFFT of the polymer dispersion; in all other cases, continuous films were obtained. These data were similar for the three dispersions assessed. The data presented in this project are being used in the development of a numerical simulation of film formation. Acknowledgements Fig. 8. Scanning electron micrographs of the film-tablet surface prepared from Eudragit® RL 30. Batch 4, (A) 45× and (B) 10,000×.
While it is true that there is an extensive bibliography on the influence of several factors on film formation (i.e., plasticizer, drying temperature, dispersion concentration, etc.), one of the main objectives of this work was to determine the usefulness of the spraying apparatus. It was demonstrated that the properties of the films obtained by the spraying technique were dependent on the substrate used. Although the device proposed shows some drawbacks previously commented, we believe that it can provide a good first approximation to design the development of a coating process, due to the fact that it is easy to modify preparative variables and then to study the influence of these on the film-forming process at pharmaceutical film-coating operations, in order to obtain a better interpretation of critical parameters involved. 4. Conclusions It was possible to develop a device for the formation of pharmaceutical films by spraying. The device proved to be a good tool to study, in an easy way, the operational film-forming conditions, it is a good first approximation to begin the development of pharmaceutical film-coating process and also to identify critical variables involved in the film-forming process. The system showed to be useful for the formation of films on substrates of different nature, which allowed the investigation on pharmaceutical substrates (tablets), something that had not been done until now with devices of this type. It was possible to study the influence of some of the critical variables involved in a film-forming process, such as dispersion concentration, drying temperature, and plasticizer presence on film properties using Teflon plates and tablets as substrates, in order to determine the usefulness and limitations of the device. With the use of the spraying technique, the variables assessed had a great influence on the characteristics of the films obtained on both substrates. Using Teflon plates with Eudragit® RS 30D, continuous films were obtained when the plasticizer was present and the drying temperature was 48.0 ◦ C. With Eudragit® RL 30D and Eudragit® L 30D-55, continuous films were obtained when
The authors are grateful to Mr. Rodolfo Robles for his technical assistance during the SEM experiments. L. Mendoza-Romero acknowledges to CONACyT (México), COMECyT (Estado de México) and DGEP (UNAM, México) for the grants received. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37]
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[38] J.W. McGinity, Eudragit aqueous dispersions as pharmaceutical controlled release coatings. Processing and equipment considerations for aqueous coatings, in: Aqueous polymeric coatings for pharmaceutical dosage forms, 2nd ed., Marcel Dekker, New York, 1997, pp. 267–326. [39] H.U. Petereit, W. Weisbrod, Eur. J. Pharm. Biopharm. 47 (1999) 15. [40] L. Mendoza-Romero, D. Tamayo-Esquivel, A. Ganem-Quintanar, D. QuintanarGuerrero, Proc. Int. Symp. Rev. Soc. Quim. Méx. 47 (2003) 191. [41] M. Joanicot, K. Wong, J. Marquet, Y. Chevalier, C. Pichot, C. Graillat, P. Lindner, L. Rios, B. Cabane, Prog. Coll. Polym. Sci. 81 (1990) 175. [42] R.C. Rowe, Int. J. Pharm. 43 (1988) 155. [43] A.L. Felton, Film coating of oral dosage forms, in: Encyclopedia of Pharmaceutical Technology, Marcel Dekker Inc., 2002, pp. 1–21. [44] U. Iyer, W.H. Hong, N. Das, I. Ghebre-Sellassie, Pharm. Technol. 14 (9) (1990) 68. [45] J. Verhoeven, R. Schaeffer, J.A. Bouwstra, H.E. Junginger, Polymer 30 (10) (1989) 1946.
[46] L.E. Dechesn, Mechanical Properties of Polymers and Composites, Marcel Dekker, New York, 1974, V 1. ˜ [47] L. Mendoza-Romero, J.J. Escobar-Chavez, E. Pinon-Segundo, A. GanemQuintanar, D. Quintanar-Guerrero, in: Proceedings of the 5th World Meeting on Pharmaceutics, Biopharm. Pharm. Technol. (2006). [48] H. Shan-Yang, L. Chau-Jen, L. Yih-Yih, Pharm. Res. 8 (9) (1991) 1137. [49] M.A. Winnik, Y. Wang, F. Haley, J. Coatings Tech. 64 (811) (1992) 51. [50] S.T. Eckersley, A. Rudin, J. Coatings Tech. 62 (780) (1990) 89. [51] G.W. Poehlein, J.W. Vanderhoff, R. Witmeyer, J. Polym, Preprints 16 (1) (1975) 268. [52] J.W. Vanderhoff, E.B. Bradford, W.K. Carrington, J. Polym. Sci. Polym. Symp. 41 (1973) 155. [53] K. Nijenhuis, S. Zohrevand, J. Coll. Int. Sci. 284 (2005) 129. [54] A. Van Tent, K. Nijenhuis, J. Coll. Int. Sci. 232 (2000) 350. [55] S. Zohrehvand, R. Cai, B. Reuvers, K. Nijenhuis, A. Boer, J. Coll. Int. Sci. 284 (2005) 120.
Contents lists available at ScienceDirect
Colloids and Surfaces A: Physicochemical and Engineering Aspects journal homepage: www.elsevier.com/locate/colsurfa
Comparison of pharmaceutical films prepared from aqueous polymeric dispersions using the cast method and the spraying technique a ˜ Luis Mendoza-Romero a , Elizabeth Pinón-Segundo , María Guadalupe Nava-Arzaluz a , a Adriana Ganem-Quintanar , Salomon Cordero-Sánchez b , David Quintanar-Guerrero a,∗ a División de Estudios de Posgrado (Tecnología Farmacéutica), Facultad de Estudios Superiores Cuautitlán, Universidad Nacional Autónoma de México, Av. 1◦ de Mayo s/n, Cuautitlán Izcalli, 54740, Estado de México, México b Departamento de Química, Universidad Autónoma Metropolitana, Iztapalapa, Apdo. Postal 55-534, Distrito Federal, México
a r t i c l e
i n f o
Article history: Received 24 April 2008 Received in revised form 30 November 2008 Accepted 8 December 2008 Available online 13 December 2008 Keywords: Spraying technique Casting method Film-forming process Minimum film formation temperature Latex dispersion
a b s t r a c t This work focuses on: (i) the development of a device to form pharmaceutical films by a spraying technique. The principal idea is to simulate the film-coating operations; (ii) the investigation of some of the variables that influence the coating process (e.g., dispersion concentration, drying temperature and plasticizer presence) using Teflon plates and tablets as substrates; (iii) the evaluation of the quality of the films obtained by the spraying technique and the cast method. The results of this work showed a marked influence of the variables and the preparation method on the characteristics and quality of the films. Although the device proposed in this study does not reproduce all the factors involved in the coating process, it is a good tool to study and to predict film formation from latexes. © 2008 Elsevier B.V. All rights reserved.
1. Introduction The application of polymeric coatings to pharmaceutical dosage forms is used for decorative and protection purposes, as well as for functional purposes, in order to mask odors, flavors or colors; to improve appearance; and to facilitate their identification [1]. Pharmaceutical coating films provide a physical and chemical protection for the drug against the environment, in order to maintain the integrity of tablets during storage and shipping [2–4] and increase the solid’s resistance against rupture [5]. Additionally, they can be used to achieve enteric properties, to modulate the release of active ingredients, and to prevent the interaction of different therapeutic substances. The interest in coating technologies with latex dispersions arises from economic and environmental reasons [6–8]. Several authors [9–18] have studied the properties of pharmaceutical polymeric films prepared by the cast method from aqueous
∗ Corresponding author at: Bolognia 4-28, Bosques del Lago, Cuautitlán Izcalli, 54766, Estado de México, México. Tel.: +52 55 58 77 19 07; fax: +52 55 58 93 86 75. E-mail addresses: [email protected], [email protected] ˜ (L. Mendoza-Romero), [email protected] (E. Pinón-Segundo), lupita [email protected] (M.G. Nava-Arzaluz), [email protected] (A. Ganem-Quintanar), [email protected] (S. Cordero-Sánchez), [email protected] (D. Quintanar-Guerrero). 0927-7757/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.colsurfa.2008.12.004
or organic solutions or dispersions. In the case of latex dispersions, some problems have been detected, such as particle sedimentation during the drying process, which results in poorly uniform films; or, in the case of multilaminated films, dissolution of the previously formed films by the action of the solvent used to form the subsequent layers has been observed [19]. The film-forming mechanism from aqueous polymeric dispersions is a complex one, since particles dispersed in water have to coalesce to form a continuous film. It is generally considered that the film-forming mechanism takes place in three stages: (a) evaporation and particle coalescence (stage I), (b) particle deformation (stage II), and (c) particle–particle interdiffusion (stage III) [20–24]. During film formation, physical and mechanical properties are of great importance for film characterization, since they help to predict the stability and release rate of the coated forms. Usually, studies of this type are performed on free films [13,16,25–29]. In film formation with latex dispersions, it is common that many pharmaceutical polymers exhibit brittleness, which results in films with undesirable characteristics [30]. Therefore, plasticizers are frequently added to reduce minimum film formation temperature (MFFT) below the working temperature in order to favor coalescence, to improve mechanical properties, and to obtain effective crack-free films [12,15]. The plasticizers used for polymeric coating include polyols, organic esters, vegetable oils, glycerides, and even non-traditional
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plasticizers, such as n-alkenyl succinic anhydride or methylparaben [31–36]. Due to the great differences between the characteristics and properties of films formed by the cast method and those obtained by the spraying technique, it is very difficult to establish a predictive correlation. Therefore, it is highly advisable to use spraying techniques, which are more representative of the coating process, in order to prevent an erroneous result interpretation [2]. Several authors [18,37] have agreed that, by using a rotating cylinder, it is possible to predict the formation of uniform and reproducible films by the spraying technique on non-pharmaceutical substrates from aqueous polymeric solutions or dispersions. However, while there are reports on the use of experimental filmforming devices, these do not employ a pharmaceutical substrate. It is therefore reasonable to design a device for tablet coating by the spraying technique, with the aim of providing a rapid approach of a pharmaceutical film-forming process, reproducible and able to show the differences among substrates. Different factors, such as drying time, drying temperature, drying method, etc. [38], have been reported as critical in the formation of polymeric films by the spraying technique [39]. These factors should be optimized and controlled for each system in order to produce films with good technological properties. In addition, it is important to investigate the influence of some of these process variables, since their effect on film properties will depend on the preparation method. The objectives of this work were: (1) to develop a device for the formation of pharmaceutical films by the spraying technique based on rotating cylinder concept, allowing, on the one hand, to simulate rapidly some operational conditions of a pharmaceutical film-coating process, and on the other, to study the critical variables involved in film formation; (2) to coat a non-porous substrate (Teflon) by the cast method and the spraying technique (the former with the designed apparatus), in order to show the differences in the properties of the films obtained by the two methods; (3) to coat a pharmaceutical substrate (tablets) with the proposed spraying device, evaluating the macroscopic and microscopic characteristics of the films, in order to determine the usefulness and limitation of the device.
2. Experimental 2.1. Materials Three commercially-available aqueous dispersions were used: poly(ethyl acrylate, methyl methacrylate) trimethylammonioethyl methacrylate chloride 1:2:0.1 (Eudragit® RS 30D, 5% and 15%, w/w), poly(ethyl acrylate, methyl methacrylate) trimethylammonioethyl methacrylate chloride 1:2:0.2 (Eudragit® RL 30D, 5% and 15%, w/w), and poly(methacrylic acid, ethyl acrylate) 1:1 (Eudragit® L 30D55, 5% and 15%, w/w), which were kindly provided by HELM de México (Mexico). Glycerine triacetate (triacetin) was used as plasticizer and was obtained from Aldrich Chemical (U.S.A.). Teflon plates (0.5 cm × 0.5 cm, 0.79 mm thickness) and biconcave placebo tablets (formulation: microcrystalline cellulose PH 102 57.0%, anhydrous lactose 38.0%, magnesium stearate 1.0% and croscarmellose sodium 4.0%; 8 mm in diameter, 4 mm thickness) were used as substrates.
Table 1 Experimental matrix for cast and spray methods for Eudragit® RS 30D, Eudragit® RL 30D, and Eudragit® L 30D-55. Batch
Polymer content (%, w/w)
Plasticizer (%, w/w)a
Drying temperature (◦ C)
1 2 3 4 5 6 7 8 9 10 11 12
5 5 5 5 5 5 15 15 15 15 15 15
0 0 0 10 10 10 0 0 0 10 10 10
38.0 43.0 48.0 38.0 43.0 48.0 38.0 43.0 48.0 38.0 43.0 48.0
a
Based on polymer content.
2.3. Minimum film formation temperature 15 ml of the dispersion (15%, w/w, with and without plasticizer) were placed in a circular Teflon mould (10 cm in diameter). The dispersion was dried for 24 h, starting at 25 ◦ C with 1 ◦ C increments until the MFFT for each dispersion was found. The MFFT was determined as the temperature at which a clear, crack-free film was obtained. 2.4. Film preparation 2.4.1. Cast method Polymeric films were prepared with the three types of dispersions. 15 ml of the dispersion for every system were poured on circular Teflon moulds (10 cm in diameter) and left to dry for 24 h. Table 1 shows the matrix of the experiments performed with this method. 2.4.2. Spraying technique 2.4.2.1. Design of the film formation apparatus. The device used, designed and assembled by the authors, is shown in Fig. 1. The apparatus has the advantage of allowing an easy and rapid modification of some critical variables involved, such as drying temperature, flow, and spraying pressure, while simulating the film-coating operations. Functioning conditions were optimized in a previous work [40] but they can be modified depending on the purpose pursued. In this work, Teflon plates (0.5 cm × 0.5 cm) or biconcave placebo tablets (8 mm in diameter), previously attached to the rotating cylinder of the device with double-sided adhesive tape, (Fig. 1), were sprayed with the dispersion (under constant stirring) at a pressure of 0.2 MPa and a mean spray flow of 1.7 ml/min. The
2.2. Polymeric dispersions A known amount of triacetin was dissolved in 50 ml of water, adjusting the concentration with the required volume of dispersion (for a desired polymer concentration) and water. The resulting dispersion was then magnetically stirred for 2 h [33].
Fig. 1. Schematic representation of the rotatory spraying device. (A) Air inlet (DeVILBISS, U.S.A.), (B) stirrer (Amphenols Control Div. U.S.A.), (C) latex dispersion, (D) magnetic stirrer (Barnstead Int. U.S.A.), (E) peristaltic pump (Masterflex, Mexico), (F) spray gun (Walter Pilot, Mexico), (G) rotating drum (15 cm high, 30 cm in diameter), (H) drying system (Milwuakke, Mexico), and (I) infrared thermometer (OAKTON® , Temptestr® IR, México).
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cylinder was maintained at a rotation speed of 72 rpm, and the coating time was 1 h. The dispersion volume sprayed per area on the Teflon plates and on placebo tablets was equivalent to that used on Teflon moulds by the cast method. The distance between the spraying gun and the rotating cylinder was 15.5 cm, assuring a covered area of at least 90% of the rotating cylinder’s width. The drying gun was placed after the spraying pan in order to avoid any kind of interference, the drying distance (between 4 and 5 cm) was such as to maintain the substrate’s temperature (which was constantly monitored on the substrate’s surface with an infrared thermometer).
Table 2 Minimum film formation temperature (MFFT) for Eudragit® RS 30D, Eudragit® RL 30D, and Eudragit® L 30D-55 polymeric films (standard deviation in parentheses) at a polymer concentration of 15% (w/w). Polymer dispersion
Triacetin % (w/w)a
MFFTb (◦ C)
Eudragit® RS 30D
0 10
47.3 ± (0.4) <25
Eudragit® RL 30D
0 10
38.3 ± (0.4) <25
Eudragit® L 30D-55
0 10
27.33 ± (0.4) <25
a
2.4.2.2. Film formation. As with the cast method, the influence of drying temperature, plasticizer presence, and dispersion concentration on film continuity was assessed. Table 1 shows the matrix of the proposed experiments. As can be observed, three different drying temperature levels are considered. Although coating by spraying is usually carried out at a drying temperature between 40 and 50 ◦ C [38], in our case, a lower temperature (38.0 ◦ C) was selected, for this was the minimum temperature that allowed water to be eliminated. At lower temperatures, tablets would wear out and become extremely wet, thus loosing their integrity. The highest temperature level was set at 48.0 ◦ C, since this is the usual temperature range for pharmaceutical film-coating operations. 2.4.3. Film thickness Film thickness was only evaluated in the batches 6 and 12 obtained by both processes because they formed a continuous films with the three polymer dispersions. Film thickness in cast method was measured with a micrometer (Digitrix-MARKII, Cole Parmer Instrument Co., Mexico), (with the three dispersions used: Eudragit® RS 30D, Eudragit® RL 30D and Eudragit® L 30D-55). In the spray technique film thickness was measured by scanning electron microscopy (SEM). The coated tablets were dried and shadowed in a cathodic evaporator with a gold layer (∼20 nm thick, Ion sputter JFC-1100, JEOL). Then, film thickness of the tablets was observed by SEM using a JSM-25 SII scanning electron microscope (JEOL, Japan). (IROSCOPE, SI-PHF, U.S.A.). 2.4.4. Film-tablet morphology The quality of the films obtained by the cast method and by the spraying technique was assessed by optical microscopy (IROSCOPE, SI-PHF, U.S.A.). Additionally, the quality of the films obtained on tablets was assessed by scanning electron microscopy with the aim of determining film continuity [41,42].
111
b
Based on polymer content. Data reported as the mean ± SD of three samples.
As can be seen in Table 2, Eudragit® RS 30D has the highest MFFT, followed by Eudragit® RL 30D and Eudragit® L 30D-55. The inclusion of 10% triacetin (w/w) (based on polymer content) reduced the MFFT below 25 ◦ C for the three polymeric dispersions. This concentration was chosen based on previous studies [47], where it was found that an adequate plasticizing effect cannot be obtained below this critical concentration. 3.2. Cast method The cast method is a well-known film-forming method for latex dispersions, since it provides information about film characteristics [2,37]; however, formation conditions are static and do not fully represent the characteristics of films formed by the spraying technique in a pharmaceutical film-coating process. The formulation and process conditions used in this work to obtain continuous films by this method were relatively simple, as can be seen in the experimental design. As discussed later, it was only necessary to fulfill one of the following conditions: the use of 10% plasticizer (w/w) or a drying temperature higher than the MFFT, regardless of the two concentrations and the type of latex dispersions used. The results of film formation (Table 3) show that, in those experiments where triacetin was used (batches 4–6 and 10–12), continuous and transparent films, with a clear and homogeneous appearance were obtained, irrespectively of the drying temperature. Seen through optical microscopy, the films were found to be homogeneous, continuous, and virtually transparent, as can be confirmed for Eudragit® RS 30D, indicating a good compatibility between triacetin and the polymer [48], and, as mentioned before, it is the plasticizer of choice for this type of polymers [26]. In batches 4–6 and 10–12, 10% triacetin (w/w) reduced the MFFT to <25 ◦ C for the three dispersions used (Table 2). This is due to a reduction in the intermolecular forces of polymers, which leads to less energy
3. Results and discussion 3.1. Minimum film formation temperature Table 2 summarizes the MFFTs for polymeric dispersions. MFFT determination is necessary in order to select the appropriate working temperature for film formation by both methods. The values obtained are consistent with those reported by other authors [38]. In film formation, the plasticizer is one of the main components of the formulation [43]. Triacetin was used as plasticizer due to its well-known effects on reducing the tendency to obtain brittle films with methacrylic acid copolymers [30], and because it has been widely used in polymeric film research [27]. Furthermore, it shows a good aqueous solubility (77.8 ± 0.5 mg/ml) [15], which enables it to distribute itself in the dispersion medium and then spread to the polymer to weaken intermolecular attraction forces [44], increasing the flexibility of polymeric chains and reducing the vitreous transition temperature [45,46].
Table 3 Casting latex film formation on Teflon moulds, using latex dispersions of Eudragit® RS 30D, Eudragit® RL 30D and Eudragit® L 30D-55. Batch
1 2 3 4 5 6 7 8 9 10 11 12
Film formation Eudragit® RS 30D
Eudragit® RL 30D
Eudragit® L 30D-55
− − + + + + − − + + + +
+ + + + + + + + + + + +
+ + + + + + + + + + + +
(+) Formation, (−) no formation. Data reported from three samples.
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Fig. 2. Photographs of the casting latex films prepared from Eudragit® RS 30D. Batches 1, 4–6.
being required to achieve polymeric particle coalescence [20]. It was also possible to obtain continuous films with a clear and homogeneous appearance when drying was performed at the MFFT or at a higher temperature (batches 1–3 and 7–9 for Eudragit® RL 30D and Eudragit® L 30D-55 and batches 3 and 9 for Eudragit® RS 30D) (Table 3). These results were obtained for the two concentrations assessed (5% and 15%, w/w), which is reasonable considering that drying temperature is fundamental to form continuous films by the cast method, and it should be higher than the MFFT. As expected, in those experiments where no plasticizer was present and the drying temperature was lower than the MFFT (Table 3, batches 1–2 and 7–8 for Eudragit® RS 30D), the films had a great number of fractures, as shown in Fig. 2 (batch 1), since an incomplete coalescence occurs due to the lack of plasticizer [20], thus producing poor-quality films. Photographs of some of the films obtained with Eudragit® RS 30D are shown in Fig. 2. Batch 1 shows a poor-quality film, whereas batches 4–6 were homogeneous and continuous. 3.3. Spraying latex films 3.3.1. Design and construction of a device for film formation by spraying As mentioned above, the film formation process is a complex one, entailing approximately 20 variables [38]. Therefore, it is necessary to control some of these variables, especially those involved in film functionality and stability. In the polymeric film-forming process, polymer concentration is a determining variable, but so are the application conditions in the spraying technique. Among these, the most important variables to be considered are spraying flow, temperature, and drying time, since they are related to the amount of solvent in the system, and the way it is eliminated will have important effects on film characteristics [39]. Bearing this in mind, a device was developed based on the rotating cylinder concept to simulate the film-forming process by spraying on placebo tablets. The device was designed to study some critical process variables, such as spray flow, pressure, and distance, and also to
Fig. 3. Photographs of spraying latex film formation on Teflon plates and on tablets for the 12 batches prepared.
help assess the influence of dispersion concentration, plasticizer presence, and drying temperature on film properties. It is true that different aspects of industrial film-coating are not considered such as a real evaporative process, the mutual tablet rubbing, the differences of spraying on tablets which are in random movement, etc., the device is an interesting tool as first approach to identify and to study the effect of different critical variables involved in the film formation from latexes. 3.3.2. Spraying latex on Teflon plates and tablets In the experiments where continuous films were obtained in Teflon plates and tablets, these were transparent with the three polymeric dispersions used (Fig. 3). It is generally considered that transparent films are obtained when full coalescence of the polymeric particles takes place [26]. In some batches, such as 1 and 7, a powdery film was formed due to the film-forming conditions (drying temperature 38 ◦ C, 5% or 15%, w/w, without the use of a plasticizer), and therefore, an incomplete polymeric particle coalescence is assumed [49,50]. Film thickness values obtained by the cast method on Teflon plates and by spraying on tablets are shown in Table 4. As can be
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Table 4 Thickness of casting and spraying films obtained with Eudragit® RS 30D, Eudragit® RL 30D, and Eudragit® L 30D-55 at 5% and 15% (w/w). Batch
Film thickness (m) Casting
6 12
Spraying
Eudragit® RS 30D
Eudragit® RL 30D
Eudragit® L 30D-55
Eudragit® RS 30D
Eudragit® RL 30D
Eudragit® L 30D-55
103.9 ± 4.3 315.0 ± 14.0
108.3 ± 6.3 337.8 ± 26.8
129.6 ± 14.2 358.9 ± 36.8
97.4 ± 7.3 286.7 ± 11.9
113.5 ± 9.2 325.7 ± 9.6
123.1 ± 6.4 346.5 ± 15.2
Data reported as the mean ± SD of three samples.
seen, the thickness of the films obtained by both methods is very similar, indicating that films may be comparable, but not necessarily particle arrangement. The results of film formation on Teflon plates show wide differences between the films obtained by the cast method (Table 3) and those obtained by the spraying technique (Table 5), even though the same substrate was used. This indicates that the film-forming method determines the characteristics of the films, and leads us to consider that the film-forming method should be as similar as possible to that used in a pharmaceutical film-coating operation, in order to obtain results that are more representative of the real process. The results show that the characteristics of the films obtained by the spraying technique using diverse substrates (Teflon plates and placebo tablets) are not the same because of the different nature of the substrates: the latter being completely hydrophobic and the former less hydrophobic. This behavior shows that when the operating conditions of the device are adequately optimized, the type of substrate has a fundamental role on the formation of continuous films. Film formation appears to be easier on tablets that on Teflon plates; this behavior may be explained by the fact that film formation occurs more easily in hydrophilic than in hydrophobic substrates.
be formed; otherwise, films with undesirable characteristics will be obtained [20,39]. The results of film formation for the three dispersions used are shown in Table 5. In order to observe the influence of the drying temperature, those batches in which drying was performed without the presence of the plasticizer will be discussed. In those batches where drying was carried out at 38.0 ◦ C (10 ◦ C higher than the MFFT for Eudragit® L 30D-55), 43.0 ◦ C, and 48.0 ◦ C (10 ◦ C higher than the MFFT for Eudragit® RL 30D, and more than 20 ◦ C higher than the MFFT for Eudragit® L 30D-55) (batches 1–3 and 7–9) no continuous films were formed on either substrate. Although it is known that a continuous film is formed when the drying temperature is adjusted to 10 ◦ C above the MFFT [39,53], this was not the case (Fig. 4). Particle ordering probably took place due to solvent evaporation [54], but interfacial forces were not strong enough for particles to coalesce [20], thus yielding a discontinuous and incomplete film with a cracked appearance [39]. This behavior was seen for the two concentrations assessed, 5% and 15% (w/w). This is not surprising, since the film-forming process is dependent of several factors [20,21,38,43]. While drying temperature is one of the most important variables, it does not by itself define film formation; rather, the combination of other factors is required [43], such as the presence of a plasticizer, which is discussed below.
3.3.2.1. Effect of drying temperature. Drying is a very important part of film formation, and a determining factor throughout the whole process. It is considered that drying takes place in three stages [51,52]: in the initial stage, water evaporates from the surface until the interfacial area of the surface begins to decrease as a result of film formation and the concentration of polymeric particles increases (60–70% volume/fraction). In the second stage, the evaporation of the solvent decreases, the particles come into irreversible contact and are completely arrayed. The third stage marks the onset of film formation. Therefore, it is unquestionable that drying temperature will be determining for film properties at the end of the process. If drying is complete and adequate, a continuous film will
3.3.2.2. Effect of plasticizer. Several studies have demonstrated that film properties are affected by the amount and type of plasticizer [13,34]. In this study, (Table 5), it was not possible to obtain continuous films for batches 1–3, and 7–9, where no triacetin was used, including the experiments in which the drying temperature was
Table 5 Spraying latex film formation on Teflon plates and on tablets using latex dispersions of Eudragit® RS 30D, Eudragit® RL 30D and Eudragit® L 30D-55. Batch
Film formation Eudragit® RS 30D
1 2 3 4 5 6 7 8 9 10 11 12
Eudragit® RL 30D
Eudragit® L 30D-55
Teflon
Tablet
Teflon
Tablet
Teflon
Tablet
− − − − − + − − − − − +
− − − − + + − − − − + +
− − − − + + − − − − + +
− − − + + + − − − + + +
− − − − + + − − − − + +
− − − + + + − − − + + +
(+) Formation, (−) no formation. Data reported from three film samples.
Fig. 4. Scanning electron micrographs of the film-tablet surface prepared from Eudragit® RL 30D. Batch 2, (A) 45× and (B) 10,000×.
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Fig. 5. Scanning electron micrographs of the film-tablet surface prepared from Eudragit® RS 30D. Batch 4, (A) 45× and (B) 10,000×.
Fig. 6. Scanning electron micrographs of the film-tablet surface prepared from batch 10 at 45×. (A) Eudragit® RL 30D and (B) Eudragit® L 30D-55.
48.0 ◦ C (batches 3 and 9). These results are consistent with those reported by Felton and McGinity [34], where film formation does not succeed if less than 10% of plasticizer is used. In batches where triacetin was used, the film formation was dependent on the substrate and the polymer dispersion used. By using Teflon plates as substrate, it was not possible to obtain continuous films in batches 4 and 10 with the three polymer dispersions. With Eudragit® RS 30D (Table 5, batch 5), triacetin reduced the MFFT below 25 ◦ C, and despite having a wide effect in reducing film fractures, the temperature was too low, and no continuous films were formed. In all other batches where triacetin was used (batches 6 and 12 for Eudragit® RS 30D and batches 5, 6, 11 and 12 for Eudragit® RL 30D and Eudragit® L 30D-55) continuous films were always obtained. These were homogeneous and virtually transparent when analyzed by optical microscopy. When using tablets as substrate, a drying temperature of 38.0 ◦ C and triacetin, film formation was also dependent on the polymer dispersion used. With Eudragit® RS 30D in batches 4 and 10 (Table 5 and Fig. 5) the temperature was too low, and no continuous films were formed. This temperature provides the necessary energy for efficient water evaporation, but not for particle ordering and coalescence [21]. As can be seen for Eudragit® RL 30D and Eudragit® L 30D-55 (batch 10), continuous films were formed (Fig. 6), since the MFFTs for these dispersions are lower than 0 ◦ C [38], which favors a complete coalescence and the formation of a continuous film. When triacetin was used and the drying temperature was 43.0 ◦ C (batches 5 and 11) and 48.0 ◦ C (batches 6 and 12), continuous films were formed as can be seen in Fig. 7 for batch 12 for Eudragit® L 30D-55, because, in addition to promoting particle ordering, deformation, and fusion, the presence of the plasticizer provided good elastic properties for the formation of a continuous film. This behavior was seen with the two dispersion concentrations assessed.
Eudragit® L 30D-55 (Table 5, batch 10) at a 15% concentration, since under these conditions the MFFT of the polymeric dispersion is lower than 25 ◦ C, and the drying temperature was sufficient to cause particle coalescence, while in batch 4, at a 5% concentration (Fig. 8), even if continuous films were obtained, they occasionally present microscopic cracks or, as in this case, microscopic pores (3–80 m). At this concentration, the drying temperature was not enough for a complete coalescence to take place among particles, due to the greater amount of water to be evaporated and the lower amount of polymer available to form a continuous film.
3.3.2.3. Effect of polymer content. The film-forming process involves particle coalescence, i.e., particle compacting, deformation, cohesion, and interdiffusion, and polymer concentration has a determining influence on film properties [55]. Continuous films were obtained with the dispersions of Eudragit® RL 30D and
Fig. 7. Scanning electron micrographs of the film-tablet surface prepared from Eudragit® L 30D-55. Batch 12, (A) 45× and (B) 10,000×.
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the plasticizer was present and the drying temperature was above 43.0 ◦ C. The results on tablets using Eudragit® RS 30D showed continuous films when the plasticizer was present and the drying temperature was 48.0 ◦ C. With Eudragit® RL 30D and Eudragit® L 30D-55, continuous films were obtained when the plasticizer was present, and the drying temperature was higher than 38.0 ◦ C. In tablets it was found that dispersion concentration has an effect on the continuity of the films obtained with Eudragit® RL 30D and Eudragit® L 30D-55, since when films were formed with triacetin at a drying temperature of 38.0 ◦ C and at a 5% dispersion concentration, they occasionally showed small microscopic pores. There are clear differences between the characteristics of films obtained by the cast method and those obtained by the spraying technique on a non-pharmaceutical substrate. In the cast method, it was not possible to obtain continuous films only when the plasticizer was not present and when drying was performed under the MFFT of the polymer dispersion; in all other cases, continuous films were obtained. These data were similar for the three dispersions assessed. The data presented in this project are being used in the development of a numerical simulation of film formation. Acknowledgements Fig. 8. Scanning electron micrographs of the film-tablet surface prepared from Eudragit® RL 30. Batch 4, (A) 45× and (B) 10,000×.
While it is true that there is an extensive bibliography on the influence of several factors on film formation (i.e., plasticizer, drying temperature, dispersion concentration, etc.), one of the main objectives of this work was to determine the usefulness of the spraying apparatus. It was demonstrated that the properties of the films obtained by the spraying technique were dependent on the substrate used. Although the device proposed shows some drawbacks previously commented, we believe that it can provide a good first approximation to design the development of a coating process, due to the fact that it is easy to modify preparative variables and then to study the influence of these on the film-forming process at pharmaceutical film-coating operations, in order to obtain a better interpretation of critical parameters involved. 4. Conclusions It was possible to develop a device for the formation of pharmaceutical films by spraying. The device proved to be a good tool to study, in an easy way, the operational film-forming conditions, it is a good first approximation to begin the development of pharmaceutical film-coating process and also to identify critical variables involved in the film-forming process. The system showed to be useful for the formation of films on substrates of different nature, which allowed the investigation on pharmaceutical substrates (tablets), something that had not been done until now with devices of this type. It was possible to study the influence of some of the critical variables involved in a film-forming process, such as dispersion concentration, drying temperature, and plasticizer presence on film properties using Teflon plates and tablets as substrates, in order to determine the usefulness and limitations of the device. With the use of the spraying technique, the variables assessed had a great influence on the characteristics of the films obtained on both substrates. Using Teflon plates with Eudragit® RS 30D, continuous films were obtained when the plasticizer was present and the drying temperature was 48.0 ◦ C. With Eudragit® RL 30D and Eudragit® L 30D-55, continuous films were obtained when
The authors are grateful to Mr. Rodolfo Robles for his technical assistance during the SEM experiments. L. Mendoza-Romero acknowledges to CONACyT (México), COMECyT (Estado de México) and DGEP (UNAM, México) for the grants received. References [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] [32] [33] [34] [35] [36] [37]
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