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SEM-image textural features and drug release behavior of Eudragit-based matrix pellets
Journal of Drug Delivery Science and Technology xxx (2017) 1e7
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SEM-image textural features and drug release behavior of Eudragitbased matrix pellets Livia C. Sa-Barreto 1, Carmen Alvarez-Lorenzo, Angel Concheiro, Ramon Martinez-Pacheco, Jose L. Gomez-Amoza* Departamento de Farmacología, Farmacia y Tecnología Farmac eutica, RþD Pharma Group (GI-1645), Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 February 2017 Received in revised form 19 April 2017 Accepted 20 April 2017 Available online xxx
Matrix pellets of acetaminophen were prepared by extrusion-spheronization using a high proportion of several varieties of Eudragit; namely, 40% RSPO or RLPO, and 17% RS30D or RL30D. The pellets were characterized using textural analysis of gray-level scanning electron microscopy (SEM) images and through the cumulative pore volume distribution obtained by mercury intrusion porosimetry. Surface roughness and distribution of pores at pellet surface were characterized in terms of gray-level non uniformity (GLN) and fractal dimension of pellet surface. Both parameters were strongly dependent on the procedure followed to incorporate the polymer (in powder form or as liquid dispersion) and, to a lesser extent, on the polymer variety (RL or RS). The curing of pellets at 105 C for 30 min led to the smoothing out and to a decrease in the pore size at the surface, which notably slowed down acetaminophen release rate. Strong correlations between the drug release rate and the surface roughness of the pellets were found. © 2017 Elsevier B.V. All rights reserved.
Keywords: Eudragit® Pellets Textural analysis Gray-level non uniformity (GLN) Mercury intrusion porosimetry Pore size distribution at pellet surface
1. Introduction Surface roughness is a key parameter in diverse fields of materials science, including biomaterials and excipients [1]. Surface roughness strongly influences powder flow properties, wettability, friability and drug release pattern of solid dosage forms, and adhesion of polymers used for coatings [2e5]. Therefore, a correct design of drug formulations may strongly benefit from quantitative information about the surface roughness of starting materials and outcome products [6,7]. Among the several techniques proposed for surface characterization [8], contact or stylus profilometry measures the vertical movements of a sharp tip mounted on a cantilever resulting from the irregularities of the surface [9]. The main drawback of this approach is related to the damage or deformations that the movement of the tip may cause on the surface of soft materials, which may alter the results of the analysis [10]. If the material has appropriate light reflexion properties, this drawback can be avoided using non-contact or laser profilometry [10,11].
* Corresponding author. E-mail address: [email protected] (J.L. Gomez-Amoza). 1 ^ndia, University of Brasília (UnB), 72220-900, Present address: Faculty of Ceila Brasília - DF, Brazil.
Quantitative information about the texture and the fractal geometry of surfaces can also be obtained from image analysis of scanning electron microscopy (SEM) pictures [12,13]. Fractal analysis is a potent tool to measure the degree of complexity of structures that show self-similarity; i.e., when there is a power relationship between the size and the measurement scale [14,15]. Moreover, fractal analysis may be applied to the characterization of materials of very diverse nature [16e19]. The texture analysis of images provides information about the structural order of the surfaces as a function of the position, intensity and/or orientation of the pixels. For this purpose, parameters derived from the gray level cooccurrence matrix (GLCM) and of the number of consecutive cluster pixels in a given direction (run-length) (gray-level nonuniformity, GLN) are used [6,20]. The present work aims to elucidate the effect of the Eudragit® variety on the surface roughness of extrusion-spheronization pellets by means of analysis of SEM images. The pellets were prepared using microcrystalline cellulose as main component, and the Eudragit® variety was added either in powder form or as liquid dispersion. The formulations also contained acetaminophen. The effect of the application of a post-manufacturing treatment (thermal curing) on surface roughness was also evaluated. Finally, correlations between surface roughness of the pellets and drug release
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Please cite this article in press as: L.C. Sa-Barreto, et al., SEM-image textural features and drug release behavior of Eudragit-based matrix pellets, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.04.027
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(b) GLN. The 256 gray-level images were mapped to 16 gray levels. A collection of consecutive pixels with the same gray level in a given direction was a run [21]. For each direction, a two-dimensional matrix was computed (MATLAB R2007b, Mathworks Inc., Natick MA, USA); g(i, j) represents the number of runs of length j and gray level i. The run-length parameters were thus measured separately for the horizontal and vertical directions. GLN values were estimated as [10].
rate were investigated. 2. Experimental 2.1. Materials Microcrystalline cellulose (Avicel® PH101, batch 9120500001) and powdered acetaminophen (batch 93742000028) were from Guinama (Spain). Eudragit® RSPO (batch G031038154), Eudragit® RLPO (batch 0420536075), Eudragit® RS30D (batch G031118174) and Eudragit® RL30D (batch G040416066) were from Evonik Industries (Germany). 2.2. Pellets preparation Pellets with the composition shown in Table 1 were prepared as follows: i) mixing of dry components using a Turbula® T2C mixer at 30 rpm for 10 min, ii) wetting of the powder mixtures with water, or with the Eudragit aqueous dispersions plus water in a Kenwood planetary mixer for 10 min, iii) extrusion of wet masses in a Caleva extrusor fitted with a 1-mm mesh size and applying a rotation speed of 60 rpm, iv) spheronization in a Caleva 120 spheronizer fitted with 12-cm diameter bowl and 1-mm cross hatch spheronizer disc for 10 min at 1200 rpm, and iv) drying of pellets in an air oven at 40 C for 24 h. For the curing, portions of dried pellets were heated at 105 C for 30 min in a thermobalance Shimadzu EB-280 MOC (these formulations are identified with a t subscript). 2.3. Pellet characterization 2.3.1. Size and shape Feret diameter and shape factor (circularity) was determined through the analysis of at least 625 pellets using an optic microscope (Olympus SZ-CTV, software PC Imagen VGA 24 v. 2.1). 2.3.2. SEM analysis Pellet samples were mounted on double-sided tape on aluminum stubs and sputter-coated with gold/palladium, and micrographs were taken at appropriate magnification (500, scale factor 0.256 mm pixel1, for a detailed visualization of the surface) using a Leo VP-435 SEM (Leo Electron Microscopy, UK). Surface images were 600 600 pixels coded on 256 gray levels (black ¼ 0, white ¼ 255). The surface fractal dimension and GLN parameter were estimated as follows to characterize the roughness and the distribution of pores and holes appearing at the surface. (a) Fractal dimension of the pellet surface (Df). This was calculated by analyzing the Fourier amplitude spectrum (SPIP 4.6.0, Image Metrology A/S, Denmark). For different angles the Fourier profile was obtained and the logarithm of the frequency and amplitude coordinates calculated. The fractal dimension for each direction was then calculated as 2.0 minus the negative slope of the logelog curves (SPIP 4.6.0, Image Metrology A/S, Denmark).
Pm Pn GLN ¼
2
j¼1 gði; jÞ
i¼1
(1)
z
where z represents the number of run lengths on the whole image, m is the number of gray levels, and n represents the longest run length. (c) Pore size distribution at the pellets surface. Grain analysis modulus was used (SPIP 4.6.0, Image Metrology A/S, Denmark). The segmentation of the image was carried out applying an automatic threshold. Log-normal distribution was fit to the pore surface frequency distributions, and the geometric means (Dg) and the geometric standard deviations were estimated.
2.3.3. Microstructure Pore volume and pore size distributions were obtained by mercury intrusion porosimetry with a Micromeritics 9305 pore sizer (Norcross GA, USA), using a 3-ml powder penetrometer. Working pressures were in the 0.004e172.4 MPa range. 2.3.4. Acetaminophen release rate Amounts of pellets equivalent to 50 mg of acetaminophen were used in each test. The experiments were carried out in 900 mL water at 37 C and 50 rpm (USP apparatus II, Turu Grau, Spain). Drug concentration in the dissolution medium was determined spectrophotometrically at 243 nm (Agilent 8453, Germany). Drug release profiles were fitted to the modified Weibull equation using non-linear regression (GraphPad Prism v. 3.02, GraphPad Software Inc., San Diego, CA, USA) [12]:
M ¼ 1 eat
b
(2)
In this equation, M represents the fraction of drug dose dissolved at time t, and a and b are the scale and shape factors, respectively. The mean dissolution time (MDT) was calculated as follows [12]:
1 1 þ1 MDT ¼ ab $G b
(3)
where G represents the gamma function. 2.4. Statistical analysis Statistical analysis (ANOVA and multiple range tests) was
Table 1 Composition, size and shape of the pellets, and fractal dimension of pellet surface (Df). Mean values and, in parenthesis, standard deviation. Pellet formulations are designed by the name of the Eudragit® variety. #
Eudragit® variety
Eudragit®, w/w% in pellets
Avicel PH 101, w/w%
Drug, w/w%
Water, mL/100 g
Feret diameter, mm
Circularity
Df
1 2 3 4
RSPO RLPO RS30D RL30D
40 40 17 17
50 50 69 69
10 10 14 14
50 60 15 20
787.9 950.6 712.7 741.1
0.92 0.94 0.91 0.97
2.46 2.47 2.39 2.43
(116.8) (109.9) (149.0) (125.4)
(0.06) (0.05) (0.06) (0.02)
Please cite this article in press as: L.C. Sa-Barreto, et al., SEM-image textural features and drug release behavior of Eudragit-based matrix pellets, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.04.027
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carried out using Statgraphics Centurion XVI (Statpoint Technologies Inc., Warrenton, Virginia). 3. Results and discussion Eudragit® varieties are common excipients of solid dosage forms because these acrylic polymers either in the bulk or in the coating can endow the formulations with pH-dependent or sustained release profiles [22,23]. In particular, we focused on varieties that are available both as powder material and as aqueous dispersions. Eudragit® RSPO and RLPO are copolymers of ethyl acrylate, methyl methacrylate and a methacrylic acid ester with quaternary ammonium groups (trimethylammonioethyl methacrylate chloride). Both varieties are commercially available as powder insoluble in water with pH-independent swelling, but differ in permeability because the different content in the ammonium salt groups [24]. In RS varieties the monomers proportion is 1:2:0.1, which leads to low permeability systems, while in RL varieties the monomers proportion is 1:2:0.2, which makes the copolymer permeable. These same copolymers are available as aqueous dispersion at 30% under the name Eudragit® RS30D and RL30D. The pellets were prepared with the highest proportion of these Eudragit® varieties (Table 1) that enabled a facile processing by extrusion-spheronization. Greater proportions would cause problems due to overweting of RS30D and RL30D masses, and to deformation of the extrusion mesh provoked by RSPO and RLPO masses. 3.1. Influence of Eudragit® variety The values of Feret diameter and circularity of pellets (Table 1) indicated that neither aggregation nor erosion occurred during the
3
spheronization step. The pellets were observed using SEM (Fig. 1) and several pictures were taken to be used for the surface roughness analysis through the estimation of the fractal dimension (Table 1) and GLN (Table 2). Chappard et al. [10] observed that surface roughness values obtained using profilometry are highly correlated with Df (positive correlation) and GLN (negative correlation) parameters estimated from SEM image analysis. Therefore, SEM images are valuable tools for the characterization of the roughness of surfaces with complex topography. To do that, the 2D SEM image (i.e., a flat x-y map of pixels) is transformed into a 3D image using the gray level as the z dimension [10]. Flat, smooth solids fit well in the two-dimensional Euclidean plane; as the surface roughness increases, the Df values become higher than 2. Pellets prepared with the powdered Eudragit® varieties (RSPO and RLPO) had Df values (estimated as explained in section 2.3.2.a) greater than pellets prepared with RS30D and RL30D dispersions (although no statistical analysis was possible since there was one estimate per batch). Furthermore, these later pellets exhibited greater GLN values (Table 2). These findings indicate that the surface of pellets prepared with powdered Eudragit® is rougher than that of pellets prepared with the polymer dispersions [6]. Statistical analysis (ANOVA) of GLN confirmed that the physical state of the Eudragit® product (powder or dispersion) is the only significant factor (F1,6 d.f. ¼ 105.62; a < 0.01) and that the copolymer composition does not influence GLN values. The size distributions of pores at the pellets surface (Fig. 2) were in good agreement with the differences found in surface roughness. Surface of pellets prepared with powdered Eudragit® had pores with mean diameters 2e3 times greater than that of pellets prepared with Eudragit® dispersions (Table 2). On the other hand, the empty intragranular spaces, which were estimated using Hg
Fig. 1. SEM micrographs of the surface of pellets prepared with different Eudragit varieties.
Please cite this article in press as: L.C. Sa-Barreto, et al., SEM-image textural features and drug release behavior of Eudragit-based matrix pellets, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.04.027
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Table 2 Gray level non-uniformity (GLN) values, geometric mean of the pore size distribution at the pellet surface (Dg), parameters a and b of Eq (2) estimated by non-linear regression, and mean dissolution time (MDT) calculated using Eq (3) for non-cured pellet formulations. Eudragit®
GLN*
RSPO RLPO RS30D RL30D
2.68$104 2.80$104 3.60$104 3.45$104
In parenthesis, *standard deviation,
**
(1.84$102) (1.01$103) (3.45$103) (2.69$102)
Dg**, mm
a***, h-b
b***
8.96 8.06 3.05 2.86
4.21 (0.12) 33.80 (5.69) 2.89 (0.59) 23.00 (3.61)
0.841 1.414 0.887 1.737
geometric standard deviation, and
(3.34) (2.71) (3.61) (2.89)
MDT*, h (0.004) (0.055) (0.132) (0.050)
0.20 0.08 0.33 0.15
(0.01) (0.01) (0.05) (0.01)
***
standard error of the estimate.
Fig. 2. Pore size distribution of pores at the surface of pellets prepared with the Eudragit varieties shown in the legend.
Fig. 4. Acetaminophen release profiles from pellets prepared with the Eudragit varieties shown in the legend.
intrusion porosimetry, were very similar for all pellets with values ranging from 0.02 to 0.03 cm3 g-1 (Fig. 3). Acetaminophen release profiles and the values of parameters a, b and MDT are shown in Fig. 4 and Table 2, respectively. Two clearly different groups can be detected. Fitting of modified Weibull equation (Eq. (2)) to drug release profiles from pellets prepared with Eudragit® RLPO and RL30D led to values of a >20 and values of b > 1; whereas fitting for pellets prepared with Eudragit® RSPO or RS30D provided a <5 and b < 1. According to Macheras and Dokoumetzidis [25], values of b as high as those of pellets prepared with RLPO and RL30D are indicative of a heterogeneous dissolution process, which is typical of hardly wettable systems. Eudragit® RLPO and RL30D led to values of a 6-fold greater than those observed with RSPO or RS30D, which is explained by the higher permeability of RL varieties compared to RS varieties [15]. Accordingly, acetaminophen MDT values from RS pellets were
twice those of RL pellets (F1, 8 d.f. ¼ 84.55; a < 0.01). Furthermore, despite Eudragit® RS30D and RL30D were incorporated at a quite lower net percentage (17% vs. 40% powdered varieties), they caused a remarkable delay in the drug release profile. This means that the incorporation as aqueous dispersion allows for more homogeneous distribution of the polymer and leads to smoother surfaces with smaller pores.
Fig. 3. Cumulative pore size distributions (mercury intrusion porosimetry) of pellets prepared with different Eudragit varieties. The arrows indicate the volume due to the intragranular empty spaces.
3.2. Effect of the thermal curing DSC analysis (data not shown) evidenced that none changes in the drug occur during heating at 105 C for more than 30 min. Thus, the curing was carried out heating the pellets at 105 C for 30 min. Compared to previous reports that involved treatment at lower temperatures (50-70 C, 24 h) [26,27], our curing process allowed for shortening the curing time in a very remarkably amount (30 min vs. 24 h). GLN values and pore size distribution at the surface (Table 3) were estimated from image analysis of SEM micrographs (Fig. 5). For all formulations, the thermal curing of pellets caused a smoothing out (10e30% increase in GLN) and a shift in the pore size distribution (Fig. 6) to smaller values (50% lower Dg). As it was previously reported [26e29], these changes are due to the movement of the polymer chains at high temperatures. The interdiffusion of chains leads to thinner networks with lower porosity and greater tortuousness. The changes occurred mainly at the pellets surface while the inner structure only underwent minor modifications (Fig. 7) compared to that of non-treated pellets. The changes at the surface of the pellets caused a remarkable slowdown in acetaminophen release rate (Fig. 8, Table 3), in particular when the polymer is incorporated in powder form (35e75% increase in MDT with respect to non-cured pellets). Similar effects have been described by Abbaspour et al. [27] and have been attributed to an increase in the plastic behavior of the pellets that facilitated the tableting avoiding fractures at pellet
Please cite this article in press as: L.C. Sa-Barreto, et al., SEM-image textural features and drug release behavior of Eudragit-based matrix pellets, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.04.027
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Table 3 Gray level non-uniformity (GLN) values, geometric mean of the pore size distribution at the pellet surface (Dg), parameters a and b of Eq (2) estimated by non-linear regression, and mean dissolution time (MDT) calculated using Eq (3) for pellets that underwent curing at 105 C for 30 min. Eudragit®
GLN*
RSPOt RLPOt RS30Dt RL30Dt
3.17$104 3.08$104 4.04$104 4.43$104
In parenthesis, *standard deviation,
**
(4.95$102) (9.41$102) (5.66$101) (1.83$103)
Dg**, mm
a***, h-b
b***
4.13 4.20 1.42 1.30
3.43 (0.11) 8.81 (0.20) 3.03 (0.05) 14.90 (2.56)
0.902 1.147 1.097 1.493
geometric standard deviation, and
(2.74) (2.41) (2.92) (2.29) ***
MDT*, h (0.019) (0.006) (0.056) (0.058)
0.27 0.14 0.35 0.15
(0.01) (0.01) (0.02) (0.01)
standard error of the estimate.
Fig. 5. SEM micrographs of pellet surfaces that underwent the thermal treatment.
Fig. 6. Pore size distribution of pores at the surface of pellets prepared with the Eudragit varieties shown in the legend that underwent the thermal treatment.
Fig. 7. Cumulative pore size distributions (mercury intrusion porosimetry) of pellets prepared with different Eudragit varieties that underwent the thermal treatment. The arrows indicate the volume due to the intragranular empty spaces.
Please cite this article in press as: L.C. Sa-Barreto, et al., SEM-image textural features and drug release behavior of Eudragit-based matrix pellets, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.04.027
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pellets and the drug release rate may be used as a predictive tool for the design of pellets and, foreseeably, other drug dosage forms. Acknowledgements This work was supported by Xunta de Galicia (Axudas para Grupos de Referencia Competitiva ED431C 2016/008), MICINN (SAF2014-52632-R) Spain, and FEDER. The authors acknowledge Evonik Industries for providing Eudragit® samples, and Image Metrology A/S for a temporal software license. References
Fig. 8. Acetaminophen release profiles from pellets that underwent the thermal treatment.
surface. In our case, the changes in drug release profiles may be due to the modification of the pore size at pellet surface. This assumption is supported by the linear correlation found between acetaminophen MDT and mean pore size at the surface (Fig. 9). The higher permeability of RL varieties makes RL-based pellets slightly less sensitive to the thermal curing (slope 0.011), compared to RSbased pellets (slope 0.020). 4. Conclusions Image analysis of SEM micrographs and the pore size distributions obtained using mercury intrusion porosimetry provide useful information for a detailed characterization of the surface texture and the inner structure of pellets. Similar intragranular porosity was observed for all tested formulations, but pellets prepared with Eudragit® in powder form showed remarkably higher surface roughness and greater pores at the surface compared to those prepared with Eudragit® dispersions. The greater the pores at the surface of pellets were, the faster the drug release. Thermal curing of pellets appears as an useful means to smooth down the surface and to decrease the size of pores at the surface and, consequently, to slowdown drug release rate. In sum, the physical state of the Eudragit® variety (powder or dispersion) notably affect to the surface properties of the pellets, and the fractal analysis of SEM images can be pointed out as a versatile, simple alternative to the use of profilometry for the characterization of surface structure of solid dosage forms. Correlations between the surface roughness of the
Fig. 9. Linear dependence of the mean dissolution time on the mean pore size at pellet surface.
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SEM-image textural features and drug release behavior of Eudragitbased matrix pellets Livia C. Sa-Barreto 1, Carmen Alvarez-Lorenzo, Angel Concheiro, Ramon Martinez-Pacheco, Jose L. Gomez-Amoza* Departamento de Farmacología, Farmacia y Tecnología Farmac eutica, RþD Pharma Group (GI-1645), Facultad de Farmacia, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain
a r t i c l e i n f o
a b s t r a c t
Article history: Received 1 February 2017 Received in revised form 19 April 2017 Accepted 20 April 2017 Available online xxx
Matrix pellets of acetaminophen were prepared by extrusion-spheronization using a high proportion of several varieties of Eudragit; namely, 40% RSPO or RLPO, and 17% RS30D or RL30D. The pellets were characterized using textural analysis of gray-level scanning electron microscopy (SEM) images and through the cumulative pore volume distribution obtained by mercury intrusion porosimetry. Surface roughness and distribution of pores at pellet surface were characterized in terms of gray-level non uniformity (GLN) and fractal dimension of pellet surface. Both parameters were strongly dependent on the procedure followed to incorporate the polymer (in powder form or as liquid dispersion) and, to a lesser extent, on the polymer variety (RL or RS). The curing of pellets at 105 C for 30 min led to the smoothing out and to a decrease in the pore size at the surface, which notably slowed down acetaminophen release rate. Strong correlations between the drug release rate and the surface roughness of the pellets were found. © 2017 Elsevier B.V. All rights reserved.
Keywords: Eudragit® Pellets Textural analysis Gray-level non uniformity (GLN) Mercury intrusion porosimetry Pore size distribution at pellet surface
1. Introduction Surface roughness is a key parameter in diverse fields of materials science, including biomaterials and excipients [1]. Surface roughness strongly influences powder flow properties, wettability, friability and drug release pattern of solid dosage forms, and adhesion of polymers used for coatings [2e5]. Therefore, a correct design of drug formulations may strongly benefit from quantitative information about the surface roughness of starting materials and outcome products [6,7]. Among the several techniques proposed for surface characterization [8], contact or stylus profilometry measures the vertical movements of a sharp tip mounted on a cantilever resulting from the irregularities of the surface [9]. The main drawback of this approach is related to the damage or deformations that the movement of the tip may cause on the surface of soft materials, which may alter the results of the analysis [10]. If the material has appropriate light reflexion properties, this drawback can be avoided using non-contact or laser profilometry [10,11].
* Corresponding author. E-mail address: [email protected] (J.L. Gomez-Amoza). 1 ^ndia, University of Brasília (UnB), 72220-900, Present address: Faculty of Ceila Brasília - DF, Brazil.
Quantitative information about the texture and the fractal geometry of surfaces can also be obtained from image analysis of scanning electron microscopy (SEM) pictures [12,13]. Fractal analysis is a potent tool to measure the degree of complexity of structures that show self-similarity; i.e., when there is a power relationship between the size and the measurement scale [14,15]. Moreover, fractal analysis may be applied to the characterization of materials of very diverse nature [16e19]. The texture analysis of images provides information about the structural order of the surfaces as a function of the position, intensity and/or orientation of the pixels. For this purpose, parameters derived from the gray level cooccurrence matrix (GLCM) and of the number of consecutive cluster pixels in a given direction (run-length) (gray-level nonuniformity, GLN) are used [6,20]. The present work aims to elucidate the effect of the Eudragit® variety on the surface roughness of extrusion-spheronization pellets by means of analysis of SEM images. The pellets were prepared using microcrystalline cellulose as main component, and the Eudragit® variety was added either in powder form or as liquid dispersion. The formulations also contained acetaminophen. The effect of the application of a post-manufacturing treatment (thermal curing) on surface roughness was also evaluated. Finally, correlations between surface roughness of the pellets and drug release
http://dx.doi.org/10.1016/j.jddst.2017.04.027 1773-2247/© 2017 Elsevier B.V. All rights reserved.
Please cite this article in press as: L.C. Sa-Barreto, et al., SEM-image textural features and drug release behavior of Eudragit-based matrix pellets, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.04.027
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(b) GLN. The 256 gray-level images were mapped to 16 gray levels. A collection of consecutive pixels with the same gray level in a given direction was a run [21]. For each direction, a two-dimensional matrix was computed (MATLAB R2007b, Mathworks Inc., Natick MA, USA); g(i, j) represents the number of runs of length j and gray level i. The run-length parameters were thus measured separately for the horizontal and vertical directions. GLN values were estimated as [10].
rate were investigated. 2. Experimental 2.1. Materials Microcrystalline cellulose (Avicel® PH101, batch 9120500001) and powdered acetaminophen (batch 93742000028) were from Guinama (Spain). Eudragit® RSPO (batch G031038154), Eudragit® RLPO (batch 0420536075), Eudragit® RS30D (batch G031118174) and Eudragit® RL30D (batch G040416066) were from Evonik Industries (Germany). 2.2. Pellets preparation Pellets with the composition shown in Table 1 were prepared as follows: i) mixing of dry components using a Turbula® T2C mixer at 30 rpm for 10 min, ii) wetting of the powder mixtures with water, or with the Eudragit aqueous dispersions plus water in a Kenwood planetary mixer for 10 min, iii) extrusion of wet masses in a Caleva extrusor fitted with a 1-mm mesh size and applying a rotation speed of 60 rpm, iv) spheronization in a Caleva 120 spheronizer fitted with 12-cm diameter bowl and 1-mm cross hatch spheronizer disc for 10 min at 1200 rpm, and iv) drying of pellets in an air oven at 40 C for 24 h. For the curing, portions of dried pellets were heated at 105 C for 30 min in a thermobalance Shimadzu EB-280 MOC (these formulations are identified with a t subscript). 2.3. Pellet characterization 2.3.1. Size and shape Feret diameter and shape factor (circularity) was determined through the analysis of at least 625 pellets using an optic microscope (Olympus SZ-CTV, software PC Imagen VGA 24 v. 2.1). 2.3.2. SEM analysis Pellet samples were mounted on double-sided tape on aluminum stubs and sputter-coated with gold/palladium, and micrographs were taken at appropriate magnification (500, scale factor 0.256 mm pixel1, for a detailed visualization of the surface) using a Leo VP-435 SEM (Leo Electron Microscopy, UK). Surface images were 600 600 pixels coded on 256 gray levels (black ¼ 0, white ¼ 255). The surface fractal dimension and GLN parameter were estimated as follows to characterize the roughness and the distribution of pores and holes appearing at the surface. (a) Fractal dimension of the pellet surface (Df). This was calculated by analyzing the Fourier amplitude spectrum (SPIP 4.6.0, Image Metrology A/S, Denmark). For different angles the Fourier profile was obtained and the logarithm of the frequency and amplitude coordinates calculated. The fractal dimension for each direction was then calculated as 2.0 minus the negative slope of the logelog curves (SPIP 4.6.0, Image Metrology A/S, Denmark).
Pm Pn GLN ¼
2
j¼1 gði; jÞ
i¼1
(1)
z
where z represents the number of run lengths on the whole image, m is the number of gray levels, and n represents the longest run length. (c) Pore size distribution at the pellets surface. Grain analysis modulus was used (SPIP 4.6.0, Image Metrology A/S, Denmark). The segmentation of the image was carried out applying an automatic threshold. Log-normal distribution was fit to the pore surface frequency distributions, and the geometric means (Dg) and the geometric standard deviations were estimated.
2.3.3. Microstructure Pore volume and pore size distributions were obtained by mercury intrusion porosimetry with a Micromeritics 9305 pore sizer (Norcross GA, USA), using a 3-ml powder penetrometer. Working pressures were in the 0.004e172.4 MPa range. 2.3.4. Acetaminophen release rate Amounts of pellets equivalent to 50 mg of acetaminophen were used in each test. The experiments were carried out in 900 mL water at 37 C and 50 rpm (USP apparatus II, Turu Grau, Spain). Drug concentration in the dissolution medium was determined spectrophotometrically at 243 nm (Agilent 8453, Germany). Drug release profiles were fitted to the modified Weibull equation using non-linear regression (GraphPad Prism v. 3.02, GraphPad Software Inc., San Diego, CA, USA) [12]:
M ¼ 1 eat
b
(2)
In this equation, M represents the fraction of drug dose dissolved at time t, and a and b are the scale and shape factors, respectively. The mean dissolution time (MDT) was calculated as follows [12]:
1 1 þ1 MDT ¼ ab $G b
(3)
where G represents the gamma function. 2.4. Statistical analysis Statistical analysis (ANOVA and multiple range tests) was
Table 1 Composition, size and shape of the pellets, and fractal dimension of pellet surface (Df). Mean values and, in parenthesis, standard deviation. Pellet formulations are designed by the name of the Eudragit® variety. #
Eudragit® variety
Eudragit®, w/w% in pellets
Avicel PH 101, w/w%
Drug, w/w%
Water, mL/100 g
Feret diameter, mm
Circularity
Df
1 2 3 4
RSPO RLPO RS30D RL30D
40 40 17 17
50 50 69 69
10 10 14 14
50 60 15 20
787.9 950.6 712.7 741.1
0.92 0.94 0.91 0.97
2.46 2.47 2.39 2.43
(116.8) (109.9) (149.0) (125.4)
(0.06) (0.05) (0.06) (0.02)
Please cite this article in press as: L.C. Sa-Barreto, et al., SEM-image textural features and drug release behavior of Eudragit-based matrix pellets, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.04.027
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carried out using Statgraphics Centurion XVI (Statpoint Technologies Inc., Warrenton, Virginia). 3. Results and discussion Eudragit® varieties are common excipients of solid dosage forms because these acrylic polymers either in the bulk or in the coating can endow the formulations with pH-dependent or sustained release profiles [22,23]. In particular, we focused on varieties that are available both as powder material and as aqueous dispersions. Eudragit® RSPO and RLPO are copolymers of ethyl acrylate, methyl methacrylate and a methacrylic acid ester with quaternary ammonium groups (trimethylammonioethyl methacrylate chloride). Both varieties are commercially available as powder insoluble in water with pH-independent swelling, but differ in permeability because the different content in the ammonium salt groups [24]. In RS varieties the monomers proportion is 1:2:0.1, which leads to low permeability systems, while in RL varieties the monomers proportion is 1:2:0.2, which makes the copolymer permeable. These same copolymers are available as aqueous dispersion at 30% under the name Eudragit® RS30D and RL30D. The pellets were prepared with the highest proportion of these Eudragit® varieties (Table 1) that enabled a facile processing by extrusion-spheronization. Greater proportions would cause problems due to overweting of RS30D and RL30D masses, and to deformation of the extrusion mesh provoked by RSPO and RLPO masses. 3.1. Influence of Eudragit® variety The values of Feret diameter and circularity of pellets (Table 1) indicated that neither aggregation nor erosion occurred during the
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spheronization step. The pellets were observed using SEM (Fig. 1) and several pictures were taken to be used for the surface roughness analysis through the estimation of the fractal dimension (Table 1) and GLN (Table 2). Chappard et al. [10] observed that surface roughness values obtained using profilometry are highly correlated with Df (positive correlation) and GLN (negative correlation) parameters estimated from SEM image analysis. Therefore, SEM images are valuable tools for the characterization of the roughness of surfaces with complex topography. To do that, the 2D SEM image (i.e., a flat x-y map of pixels) is transformed into a 3D image using the gray level as the z dimension [10]. Flat, smooth solids fit well in the two-dimensional Euclidean plane; as the surface roughness increases, the Df values become higher than 2. Pellets prepared with the powdered Eudragit® varieties (RSPO and RLPO) had Df values (estimated as explained in section 2.3.2.a) greater than pellets prepared with RS30D and RL30D dispersions (although no statistical analysis was possible since there was one estimate per batch). Furthermore, these later pellets exhibited greater GLN values (Table 2). These findings indicate that the surface of pellets prepared with powdered Eudragit® is rougher than that of pellets prepared with the polymer dispersions [6]. Statistical analysis (ANOVA) of GLN confirmed that the physical state of the Eudragit® product (powder or dispersion) is the only significant factor (F1,6 d.f. ¼ 105.62; a < 0.01) and that the copolymer composition does not influence GLN values. The size distributions of pores at the pellets surface (Fig. 2) were in good agreement with the differences found in surface roughness. Surface of pellets prepared with powdered Eudragit® had pores with mean diameters 2e3 times greater than that of pellets prepared with Eudragit® dispersions (Table 2). On the other hand, the empty intragranular spaces, which were estimated using Hg
Fig. 1. SEM micrographs of the surface of pellets prepared with different Eudragit varieties.
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Table 2 Gray level non-uniformity (GLN) values, geometric mean of the pore size distribution at the pellet surface (Dg), parameters a and b of Eq (2) estimated by non-linear regression, and mean dissolution time (MDT) calculated using Eq (3) for non-cured pellet formulations. Eudragit®
GLN*
RSPO RLPO RS30D RL30D
2.68$104 2.80$104 3.60$104 3.45$104
In parenthesis, *standard deviation,
**
(1.84$102) (1.01$103) (3.45$103) (2.69$102)
Dg**, mm
a***, h-b
b***
8.96 8.06 3.05 2.86
4.21 (0.12) 33.80 (5.69) 2.89 (0.59) 23.00 (3.61)
0.841 1.414 0.887 1.737
geometric standard deviation, and
(3.34) (2.71) (3.61) (2.89)
MDT*, h (0.004) (0.055) (0.132) (0.050)
0.20 0.08 0.33 0.15
(0.01) (0.01) (0.05) (0.01)
***
standard error of the estimate.
Fig. 2. Pore size distribution of pores at the surface of pellets prepared with the Eudragit varieties shown in the legend.
Fig. 4. Acetaminophen release profiles from pellets prepared with the Eudragit varieties shown in the legend.
intrusion porosimetry, were very similar for all pellets with values ranging from 0.02 to 0.03 cm3 g-1 (Fig. 3). Acetaminophen release profiles and the values of parameters a, b and MDT are shown in Fig. 4 and Table 2, respectively. Two clearly different groups can be detected. Fitting of modified Weibull equation (Eq. (2)) to drug release profiles from pellets prepared with Eudragit® RLPO and RL30D led to values of a >20 and values of b > 1; whereas fitting for pellets prepared with Eudragit® RSPO or RS30D provided a <5 and b < 1. According to Macheras and Dokoumetzidis [25], values of b as high as those of pellets prepared with RLPO and RL30D are indicative of a heterogeneous dissolution process, which is typical of hardly wettable systems. Eudragit® RLPO and RL30D led to values of a 6-fold greater than those observed with RSPO or RS30D, which is explained by the higher permeability of RL varieties compared to RS varieties [15]. Accordingly, acetaminophen MDT values from RS pellets were
twice those of RL pellets (F1, 8 d.f. ¼ 84.55; a < 0.01). Furthermore, despite Eudragit® RS30D and RL30D were incorporated at a quite lower net percentage (17% vs. 40% powdered varieties), they caused a remarkable delay in the drug release profile. This means that the incorporation as aqueous dispersion allows for more homogeneous distribution of the polymer and leads to smoother surfaces with smaller pores.
Fig. 3. Cumulative pore size distributions (mercury intrusion porosimetry) of pellets prepared with different Eudragit varieties. The arrows indicate the volume due to the intragranular empty spaces.
3.2. Effect of the thermal curing DSC analysis (data not shown) evidenced that none changes in the drug occur during heating at 105 C for more than 30 min. Thus, the curing was carried out heating the pellets at 105 C for 30 min. Compared to previous reports that involved treatment at lower temperatures (50-70 C, 24 h) [26,27], our curing process allowed for shortening the curing time in a very remarkably amount (30 min vs. 24 h). GLN values and pore size distribution at the surface (Table 3) were estimated from image analysis of SEM micrographs (Fig. 5). For all formulations, the thermal curing of pellets caused a smoothing out (10e30% increase in GLN) and a shift in the pore size distribution (Fig. 6) to smaller values (50% lower Dg). As it was previously reported [26e29], these changes are due to the movement of the polymer chains at high temperatures. The interdiffusion of chains leads to thinner networks with lower porosity and greater tortuousness. The changes occurred mainly at the pellets surface while the inner structure only underwent minor modifications (Fig. 7) compared to that of non-treated pellets. The changes at the surface of the pellets caused a remarkable slowdown in acetaminophen release rate (Fig. 8, Table 3), in particular when the polymer is incorporated in powder form (35e75% increase in MDT with respect to non-cured pellets). Similar effects have been described by Abbaspour et al. [27] and have been attributed to an increase in the plastic behavior of the pellets that facilitated the tableting avoiding fractures at pellet
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Table 3 Gray level non-uniformity (GLN) values, geometric mean of the pore size distribution at the pellet surface (Dg), parameters a and b of Eq (2) estimated by non-linear regression, and mean dissolution time (MDT) calculated using Eq (3) for pellets that underwent curing at 105 C for 30 min. Eudragit®
GLN*
RSPOt RLPOt RS30Dt RL30Dt
3.17$104 3.08$104 4.04$104 4.43$104
In parenthesis, *standard deviation,
**
(4.95$102) (9.41$102) (5.66$101) (1.83$103)
Dg**, mm
a***, h-b
b***
4.13 4.20 1.42 1.30
3.43 (0.11) 8.81 (0.20) 3.03 (0.05) 14.90 (2.56)
0.902 1.147 1.097 1.493
geometric standard deviation, and
(2.74) (2.41) (2.92) (2.29) ***
MDT*, h (0.019) (0.006) (0.056) (0.058)
0.27 0.14 0.35 0.15
(0.01) (0.01) (0.02) (0.01)
standard error of the estimate.
Fig. 5. SEM micrographs of pellet surfaces that underwent the thermal treatment.
Fig. 6. Pore size distribution of pores at the surface of pellets prepared with the Eudragit varieties shown in the legend that underwent the thermal treatment.
Fig. 7. Cumulative pore size distributions (mercury intrusion porosimetry) of pellets prepared with different Eudragit varieties that underwent the thermal treatment. The arrows indicate the volume due to the intragranular empty spaces.
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pellets and the drug release rate may be used as a predictive tool for the design of pellets and, foreseeably, other drug dosage forms. Acknowledgements This work was supported by Xunta de Galicia (Axudas para Grupos de Referencia Competitiva ED431C 2016/008), MICINN (SAF2014-52632-R) Spain, and FEDER. The authors acknowledge Evonik Industries for providing Eudragit® samples, and Image Metrology A/S for a temporal software license. References
Fig. 8. Acetaminophen release profiles from pellets that underwent the thermal treatment.
surface. In our case, the changes in drug release profiles may be due to the modification of the pore size at pellet surface. This assumption is supported by the linear correlation found between acetaminophen MDT and mean pore size at the surface (Fig. 9). The higher permeability of RL varieties makes RL-based pellets slightly less sensitive to the thermal curing (slope 0.011), compared to RSbased pellets (slope 0.020). 4. Conclusions Image analysis of SEM micrographs and the pore size distributions obtained using mercury intrusion porosimetry provide useful information for a detailed characterization of the surface texture and the inner structure of pellets. Similar intragranular porosity was observed for all tested formulations, but pellets prepared with Eudragit® in powder form showed remarkably higher surface roughness and greater pores at the surface compared to those prepared with Eudragit® dispersions. The greater the pores at the surface of pellets were, the faster the drug release. Thermal curing of pellets appears as an useful means to smooth down the surface and to decrease the size of pores at the surface and, consequently, to slowdown drug release rate. In sum, the physical state of the Eudragit® variety (powder or dispersion) notably affect to the surface properties of the pellets, and the fractal analysis of SEM images can be pointed out as a versatile, simple alternative to the use of profilometry for the characterization of surface structure of solid dosage forms. Correlations between the surface roughness of the
Fig. 9. Linear dependence of the mean dissolution time on the mean pore size at pellet surface.
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Please cite this article in press as: L.C. Sa-Barreto, et al., SEM-image textural features and drug release behavior of Eudragit-based matrix pellets, Journal of Drug Delivery Science and Technology (2017), http://dx.doi.org/10.1016/j.jddst.2017.04.027