Drug release kinetics and fronts movement studies from methyl methacrylate (MMA) copolymer matrix tablets: effect of copolymer type and matrix porosity

Journal of Controlled Release 92 (2003) 69–82 www.elsevier.com / locate / jconrel

Drug release kinetics and fronts movement studies from methyl methacrylate (MMA) copolymer matrix tablets: effect of copolymer type and matrix porosity ´ C. Ferrero*, I. Bravo, M.R. Jimenez-Castellanos ´ Farmaceutica ´ ´ Gonzalez ´ , Facultad de Farmacia, Universidad de Sevilla, C / Professor Garcıa no. 2, Dpto. Farmacia y Tecnologıa 41012 Sevilla, Spain Received 3 March 2003; accepted 10 June 2003

Abstract Several methyl methacrylate (MMA) copolymers have recently been proposed as an alternative for the formulation of controlled-release matrix tablets. Copolymers were synthesised by free radical copolymerisation of methyl methacrylate with starch or cellulose derivatives and were alternatively dried by oven or freeze-drying techniques. Both the chemical composition and the drying technique were demonstrated to have a considerable influence on the physical properties of the copolymers. The present investigation was focused on the elucidation of the drug release mechanism from MMA copolymer matrices, using anhydrous theophylline as model drug. Drug release experiments were performed from free tablets. Radial drug release and fronts movement were also evaluated using special devices consisting of two Plexiglass  discs joined by means of four stainless steel screws. Mathematical analysis of release data was performed using Higuchi, Korsmeyer and Peppas equations and fronts movement was investigated using a colorimetric technique. The drug release rate and the relative positions of the fronts were studied as functions of the type of copolymer and the initial porosity of the tablets. Drug release was controlled mainly by diffusion and the release rate was found to be affected by the drying method and related to the area exposed to the dissolution medium. Three distinct fronts (water uptake, complete wetting, erosion) were observed during the release process and the dynamics of fronts movement confirmed the diffusional mechanism.  2003 Elsevier B.V. All rights reserved. Keywords: Controlled-release; Matrix tablets; Methyl methacrylate (MMA) copolymers; Release kinetic; Fronts movement

1. Introduction Recently, a new generation of copolymers combining semi-synthetic (cellulose and starch deriva-

*Corresponding author. Tel.: 134-95-455-6836; fax: 134-95455-6726. E-mail address: [email protected] (C. Ferrero).

tives) and synthetic (methacrylates) polymers [1] has been introduced as excipients for oral controlledrelease matrices. The monomer (methyl methacrylate) was grafted on starch or cellulose derivatives by free radical polymerisation, using Ce(IV) as an initiator. The products obtained were alternatively dried by two different methods: drying in a vacuum oven (5–10 mmHg) at 50 8C until constant weight or freeze-drying (freezing process at 220 8C for 24 h

0168-3659 / 03 / $ – see front matter  2003 Elsevier B.V. All rights reserved. doi:10.1016 / S0168-3659(03)00301-8

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and sublimation process at 100 mTorr and 250 8C) until powdered product was got. These polymers have been characterised by NMRtechniques to determine the structure of the organic compounds and by IR spectrophotometry to identify the functional groups [1]. The amorphous nature of the graft copolymers has also been confirmed using X-ray diffraction [2]. Nitrogen adsorption measurements and thermal analysis studies [3] allowed the determination of the specific surface area and glass transition temperature of these copolymers, that appeared to be dependent on polymer composition and drying method used. These factors played also an important role when evaluating the compressional characteristics of the powdered materials and the porous structure of tablets obtained from these copolymers [4]. When designing new matrix tablets, it is useful to identify the dominating release mechanisms. Although the kinetic equations developed for the study of drug release data fit from matrix systems are numerous, Higuchi [5], Korsmeyer et al. [6] and Peppas and Sahlin [7] ones are some of the release models with major appliance and best describing drug release phenomena [8]. However, in order to understand in greater detail the internal processes controlling drug release, different techniques (optical microscopy, image analysis, penetrometer and ultrasound measurements, NMR imaging, etc.) have been developed and reviewed in a previous paper [9]. In this regard, despite some limitations, the simplicity of Colombo et al. [10,11] method, the fact that it provides a well-defined geometry of the tablet, as well as the possibility of diffusion front determination, makes it very suitable for a routine analysis. For these reasons, a variation of this method was presented in a previous investigation [12] in order to widen it to uncoloured drugs and hydrophilic nonswellable matrices. The aim of this work was to ascertain the mechanism governing the drug release kinetics from systems prepared with anhydrous theophylline as model drug and MMA copolymers as matrix-forming materials. Attention has also been focused on the influence of the carbohydrate nature, drying process and matrix porosity on the mechanistic aspects of drug release from these matrices. The mathematical models mentioned above and the modified image

analysis method proposed have been chosen to evaluate the implications of these factors on the drug release properties of MMA-based matrix tablets.

2. Materials and methods

2.1. Materials Copolymers (batches SS01) synthesised by free radical copolymerisation of methyl methacrylate (MMA) and different carbohydrates (hydroxypropylstarch (HS), carboxymethylstarch (CS), hydroxypropylcellulose (HC)) were selected for the study. The products (HSMMA, CSMMA, HCMMA) were dried either in a vacuum oven (OD copolymers) or freeze-dried (FD copolymers) [1]. The OD products were crushed in a knives mill (Retsch, Haan, Germany) to obtain powdery samples. Anhydrous theophylline (Theophylline BP 80, Roig Farma, Barcelona, Spain, batch 1201094), with a mean particle size (standard deviation) by sieving of 105 (63) mm and a solubility in water at 37 8C of 0.011 g / ml, was chosen as model drug. Stearic acid (Estearina L2SM, Pulcra, Barcelona, Spain, batch 0055003) was selected as lubricant. Before use, the materials were stored at constant relative humidity (40%) and room temperature (20 8C).

2.2. Methods 2.2.1. Mixtures preparation Anhydrous theophylline (24%, w / w) and polymer (75%, w / w) were mixed for 15 min using a doublecone mixer (Retsch, Haan, Germany) at 50 r.p.m. After addition of stearic acid (1%, w / w), the mixing procedure was continued for a further 5 min. 2.2.2. Preparation of tablets The different mixtures were compacted into tablets using an instrumented [13] single punch tablet machine (Bonals AMT 300, Barcelona, Spain) running at 30 cycles / min. To investigate the compression characteristics of mixtures, a quantity of powder (500 mg) was preweighed and manually fed into the die (12 mm) and flat-faced compacts were prepared to have a constant breaking force of 70–80 N.

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Compression data were collected from three tableting cycles. In order to produce a sufficient number of tablets for physical testing, the machine was equipped with a forced feeding system and the mixtures were tableted in the same conditions outlined before (500 mg weight, 12 mm diameter, 70–80 N breaking force).

2.2.3. Standard physical test of tablets The physical testing of tablets was performed after a relaxation period of at least 24 h. The tablet average weight, the standard deviation (S.D.) and the relative standard deviation (R.S.D.) were obtained from 20 individually weighed (Mettler ¨ LJ16 analytical balance, Zurich, Switzerland) tablets according to European Pharmacopeia [14]. The thickness of 10 tablets was measured individually placing them in and parallel to the face of an electronic micrometer (Mitutoyo MDC-M293, Tokyo, Japan). The breaking force [14] of 10 tablets was determined by diametrical loading with a Schleuninger2E tester (Greifensee, Switzerland). Tablet friability [14] was calculated as the percentage weight loss of 20 tablets after 4 min at 25 r.p.m. in an Erweka TA (Heusenstamm, Germany) friability tester. Disintegration testing [14] was performed at 37 8C in distilled water (800 ml), using an Erweka ZT3 (Heuseustamm, Germany) apparatus without discs. The disintegration times reported are averages of six determinations. 2.2.4. Mercury porosimetry measurements Mercury porosimetry runs were undertaken using a Quantachrome Autoscan 33 (Boyton Beach, FL, USA) porosimeter with a 3-cc penetrometer. The volume of sample was roughly 1 / 3 that of the penetrometer capacity. Working pressures covered the range 1–33 000 p.s.i. and the mercury solid contact angle and surface tension were considered to be 1408 and 480 erg / cm 2 , respectively. Total porosity and pore size distributions were determined, in duplicate, for each tablet tested. 2.2.5. Drug release study Release experiments (six tablets) were performed

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in an automatic dissolution apparatus 2 (Aidec, Barcelona, Spain) [14] as a function of time (12 h). Distilled water (900 ml) maintained at 3760.5 8C was used as dissolution medium and tablets were tested with a paddle rotation speed of 50 r.p.m. Filtered samples (2.8 ml) were withdrawn at specified time intervals via a peristaltic pump (Hewlett-Packard 8452A diode-array UV-vis spectrophotometer, Waldbronn, Germany). Theophylline release was monitored continuously at 272 nm on a Hewlett-Packard 8452A diode-array UV-vis spectrophotometer. In a second series of experiments, special devices [15] were used in order to obtain a rigorous radial release. The tablets were locked between two transparent Plexiglass  discs by means of four stainless steel screws. The upper disc was carved with concentric circles (from 8 to 20 mm of diameter), so that the tablet could be placed just in the center. The assembled devices (three replicates) were introduced into the vessels of the dissolution apparatus and tested for 24 h in the same conditions as previously. For both studies, drug release data (Mt /M` #0.6) were analysed according to Higuchi [5] (1), Korsmeyer et al. [6] (2) and Peppas and Sahlin [7] (3) equations: M ]t 5 k t 1 / 2 M`

(1)

M ]t 5 k9 t n M`

(2)

M ]t 5 k d t m 1 k r t 2m M`

(3)

where Mt /M` is the drug released fraction at time t (the drug loading was considered as M4 ), k, k9 are kinetic constants characteristic of the drug / polymer system, t is the release time, n is the release exponent that depends on the release mechanism and the shape of the matrix tested [16], k d , k r are the diffusion and relaxation rate constants, respectively, m is the purely Fickian diffusion exponent for a device of any geometrical shape which exhibits controlled release. The optimum values for the parameters present in each equation were determined by linear or non-

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linear least-squares fitting methods with SPSS  7.5 software. The determination coefficient (r 2 ) and the F-ratio probability were used to test the applicability of the release models.

2.2.6. Fronts movement study Fronts movement measurements were effected as described elsewhere [12]. Methylene blue (0.004%, w / v) was added to the dissolution medium (900 ml distilled water) in order to improve the visualisation of the different fronts. The experiment was carried out, in duplicate, in the same conditions as the radial release studies (37 8C and 50 r.p.m.). At defined time intervals (10, 30, 60, 90, 120, 180, 240, 360, 480, 600, 720, 1440 min), the devices were removed from the dissolution apparatus and photographed by means of a camera (Canon, EOS) provided with a macro (1:1) and an intermediate ring. Focal distance was kept constant during all measurements. The photographs were scanned (Scanrom 4E, Taiwan) and analysed by computer using Corel Draw  7 software. Fig. 1A shows a photograph of the tablet (top view) just before its introduction into the dissolution medium (t50). The concentric circles carved on the top of the devices were taken as reference (dotted blue lines) to adjust the photograph to the rulers. The initial diameter of the tablet (continuous blue lines), as well as the position of the different fronts (pink, green and yellow lines), were obtained by placing tangent lines to these boundaries (Fig. 1) and seeing the corresponding values in the rulers. Four measurements at the two equatorial axes were made to allow precise measurement of fronts positions versus time. The interface between the matrix and the dissolution medium at the beginning of the experiment (initial diameter) was referred as position 0. The inward fronts movement was represented by a negative value, while the outward movement was indicated by a positive one. 2.2.7. Statistical analysis Compression data from the different mixtures were statistically analysed by one-way analysis of variance (ANOVA) using SPSS  7.5 software. PostANOVA analysis was carried out according to Bonferroni’s multiple comparison tests. Results were quoted as significant when P,0.05.

3. Results and discussion

3.1. Preparation of tablets Although a thorough study on densification behaviour of MMA copolymers has been presented in a previous paper [4], as the addition of drug to direct compression tablet matrices could produce substantial changes in compaction profiles, some compression data [17–19] obtained from the different mixtures are summarised in Table 1. The applied pressure (P) required to obtain tablets from the mixtures with a breaking force of 70–80 N was significantly (P,0.05) lower for FD samples. These mixtures were also characterised by higher plasticity values. The evaluation of the elastic recovery (ER) parameter resulted in statistically (P,0.05) larger values for the mixtures obtained from OD copolymers. The accommodation of theophylline particles in the voids between FD copolymer particles might justify the smallest expansion in the mixtures obtained from these derivatives. The effect of the lubricant is not clear, as some authors [20] have pointed out an increase of the elastic nature of materials in presence of the lubricant and others [21] a decrease. As a result of the evaluation of the compression data, FD mixtures were shown as the formulations with higher binding capacity.

3.2. Standard physical test of tablets Results from the physical testing of tablets are also illustrated in Table 1. All tablets obtained from the different mixtures satisfied the requirements specified in European Pharmacopeia [14] related to weight uniformity test. The tablet thickness ranged between 4.1 and 4.7 mm, being FD mixtures the ones with larger values, which might be related to a more porous structure in these tablets. The breaking force test [14] confirmed the values of 70–80 N for all batches. Friability has diminished [4] with the addition of theophylline and stearic acid, with values around 1% [14]. Tablets from OD mixtures presented the highest values, according to their lower binding capacity. The similar results for OD-HCMMA and FD-HCMMA tablets could be due

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Fig. 1. Photographs obtained from the fronts movement study: (A) matrix tablet at t50 h; (B) OD-CSMMA matrix tablet at t58 h; (C) FD-CSMMA matrix tablet at t58 h. The dotted blue lines are the reference lines used to adjust the photograph. The continuous blue lines represent the initial position of the tablet. Water uptake, complete wetting and erosion fronts are represented by pink, green and yellow lines, respectively.

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Table 1 Compression parameters and tablet test results for the different mixtures: maximum applied upper punch pressure (P), plasticity (Pl), elastic recovery (ER), average weight and relative standard deviation (R.S.D.), thickness, breaking force (BF), friability (F ), disintegration time (t d ) Mixture

P (MPa)

Pl (%)

ER

Weight (mg)

Thickness (mm)

BF (N)

F (%)

td (min)a

OD-HSMMA

112.34 (0.22) 95.39 (1.92) 111.26 (1.96) 63.91 (0.18) 167.89 (4.68) 80.19 (3.97)

89.34 (0.77) 91.83 (0.20) 85.12 (3.31) 92.74 (0.73) 76.55 (1.19) 87.96 (1.72)

0.213 (0.006) 0.179 (0.004) 0.237 (0.007) 0.053 (0.005) 0.242 (0.011) 0.138 (0.004)

507.1 (4.8) R.S.D.50.95% 507.6 (6.3) R.S.D.51.24% 491.3 (4.2) R.S.D.50.85% 513.3 (9.2) R.S.D.51.79% 500.2 (4.4) R.S.D.50.88% 500.6 (11.7) R.S.D.52.34%

4.350 (0.011) 4.369 (0.007) 4.127 (0.009) 4.731 (0.005) 4.063 (0.014) 4.291 (0.013)

78 (4) 79 (4) 73 (3) 79 (3) 78 (4) 74 (5)

1.08

.30

0.79

.30

1.42

.30

0.60

.30

1.12

.30

1.17

.30

FD-HSMMA OD-CSMMA FD-CSMMA OD-HCMMA FD-HCMMA a

Tablets manufactured from FD mixtures remained practically intact after 30 min. OD tablets suffered a slight attrition, very important for tablets obtained from OD-HCMMA.

to the slightly lower breaking force noticed for the last ones. None of the tablets disintegrated after 30 min. Tablets obtained from FD mixtures maintained their physical integrity after the test whereas tablets from OD mixtures suffered some attrition, particularly OD-HCMMA matrices. These results could be related to the highest friability, the lowest plasticity and the largest elastic recovery values found for OD matrices.

3.3. Mercury porosimetry measurements As knowledge of the porous structure may help in the prediction of water diffusivity, results from

mercury intrusion–extrusion porosimetry are compiled in Table 2. A similar trend to that described for the tablets obtained from the different copolymers [4] was seen in case of the mixtures. So, tablets from FD mixtures showed larger surface area, porosity and mean pore radius values than the ones obtained from OD mixtures, in accordance to the higher thickness values (Table 1). According to IUPAC definitions [22], the mean pore radius revealed the presence of mesopores in the matrices under study, following the order HSMMA.CSMMA.HCMMA. The pore size distribution profiles from the mixtures (Fig. 2) resembled the ones derived from the different copolymers [4]: unimodal profile for HSMMA derivatives, bimodal profile for CSMMA

Table 2 Parameters characterising the porous structure of theophylline-MMA copolymer matrices (calculated by mercury intrusion-extrusion porosimetry) Mixture

Total surface area (m 2 / g)

Porosity (%)

Mean pore radius ˚ (A)

Median pore radius ˚ (A)

OD-HSMMA FD-HSMMA OD-CSMMA FD-CSMMA OD-HCMMA FD-HCMMA

10.761 11.188 15.256 19.187 12.377 15.153

25.3 (1.9)a 27.3 (2.6)a 25.9 (1.5)b 32.5 (2.3)b 20.0 (0.8)c 23.7 (1.1)c

459.9 467.5 325.0 353.8 293.3 303.4

9466 (1123) 7144 (1070) 5807 (1098) 1896 (692) 14 350 (1895) 5985 (568)

a

Unimodal distribution. Bimodal distribution. c Intermediate behaviour. b

(0.211) (0.281) (0.154) (0.340) (0.067) (0.945)

(38.9) (73.2) (22.2) (35.8) (11.3) (1.0)

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Fig. 2. Pore size distribution profiles of matrices obtained from the different mixtures: (a) HSMMA derivatives; (b) CSMMA derivatives; (c) HCMMA derivatives.

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products and intermediate behaviour for HCMMA copolymers. However, a higher contribution of smaller pores could be seen for FD derivatives, which was in agreement with the larger surface areas and the median pore radius shifting to smaller values in these tablets (Table 2). We can conclude that the addition of theophylline and stearic acid to the copolymers under study did not alter the porosity pattern observed for tablets obtained from these copolymers. However, the addition of both components resulted in closer porosity and mean pore radius for the blended mixtures.

3.4. Drug release study Fig. 3 illustrates the drug release profiles from matrices prepared from the different mixtures. The studies were performed over 12 h and a higher percentage of drug release was observed for matrices containing OD copolymers compared with the ones with FD derivatives. So, FD matrices showed a similar behaviour, with 56–61% theophylline released at the end of the experiment. Likewise, ODHSMMA and OD-CSMMA matrices were associated

Fig. 3. Release profiles of anhydrous theophylline (over 12 h) from formulated tablets of HSMMA (d), CSMMA (j) and HCMMA (m) copolymers. OD products are represented by closed symbols and FD products by open ones. The bars show the standard deviation (n56).

to a 71% drug release in 12 h, but OD-HCMMA tablets completely released the drug in about 10 h. Furthermore, matrices from FD copolymers remained nearly intact after the dissolution process while matrices containing OD derivatives experimented a slight attrition of the tablet surface, being OD-HCMMA matrices the more liable to erosion. This behaviour was in agreement with the disintegration test (Table 1) and could explain the highest standard deviations in these tablets (Fig. 3). The strongly retarded drug release and non-disintegration behaviour of FD matrices could be attributed to the better binding properties of these polymers (Table 1). As specified in Section 2, release data analysis was carried out according to Higuchi [5], Korsmeyer et al. [6] and Peppas and Sahlin [7] equations and the main parameter values are listed in Table 3. For Peppas model, m50.44 was used as the matrices under study presented an aspect ratio (diameter / thickness) around 3. Matrices containing FD derivatives provided the best fit to the different models. The accurate fit to Higuchi equation, the n values from Korsmeyer equation equal to 0.49 and the prevalence of k d over k r in Peppas equation revealed a drug release mechanism controlled mainly by drug diffusion, with diffusion rate constants around 0.022 min 21 / 2 . On the other hand, the tablets being nearly intact, when visually inspected after drug release, confirmed the absence of erosion. Different authors [23–25] have also postulated a diffusion mechanism when evaluating the drug release mechanism from matrices obtained from acrylic / methacrylic copolymers. In contrast, the OD matrices behaviour was not so clear. OD-HSMMA and OD-CSMMA matrices showed, in general, a good fit to the different equations and the Fickian diffusion seemed to be the dominant mechanism controlling drug release, although the release rate was faster compared with their corresponding FD matrices. OD-HCMMA tablets exhibited the poorest fit and matrix erosion might play an important role as a value of n50.69 was obtained from Korsmeyer equation. Nevertheless, the contribution of k r in Peppas equation was negligible compared with k d . This could be due to a disintegration process more than a chain relaxation

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Table 3 Mathematical modelling and drug release kinetics from MMA copolymers-based tablets Mixture

Higuchi equation 2

k (min 21 / 2 )

r

OD-HSMMA

0.027

FD-HSMMA

0.021

OD-CSMMA

0.028

FD-CSMMA

0.023

OD-HCMMA

0.074

FD-HCMMA

0.022

0.9962 (F 53715) 0.9994 (F 529845) 0.9989 (F 512942) 0.9997 (F 557590) 0.9947 (F 51136) 0.9999 (F 5361052)

Korsmeyer equation

Peppas equation 2

n

k9 (min 2n)

r

0.43

0.043

0.49

0.023

0.48

0.032

0.49

0.024

0.69

0.027

0.49

0.024

0.9991 (F 515128) 0.9998 (F 586537) 0.9996 (F 536332) 0.9999 (F 5131388) 0.9909 (F 5654) 0.9999 (F 5213855)

kd (min 20.44 )

kr (min 20.88 )

r2

0.047

24310 24

0.032

5310 25

0.043

24310 25

0.033

10 24

0.132

20.003

0.029

3310 24

0.9994 (F 510441) 0.9998 (F 540000) 0.9999 (F 552399) 0.9998 (F 556392) 0.9976 (F 51058) 0.9999 (F 5350156)

k, Higuchi kinetic constant; n, release exponent; k9, Korsmeyer kinetic constant; k d , Peppas diffusion kinetic constant; k r , Peppas relaxation kinetic constant; r 2 , determination coefficient; F, F distribution for residual variance analysis (P50.000).

occurring in OD-HCMMA matrices. Theophylline would be released by diffusion from the tablet fragments, which might explain the insignificant contribution of the second term in Peppas equation. Although the methodology for the application of Peppas equation [7] proposes the determination of F (Fickian release fraction) and R /F (relaxation / diffusion ratio) parameters, as k r values were numerically very small (even negative for OD matrices), F and R /F data were not calculated. Ford et al. [26] have also obtained negative values for k r in tablets prepared with HPMC and promethazine hydrochloride and considered that the relaxation transport, instead of being an additive term, was inhibiting the drug release. In order to relate drug release and fronts movement data, release studies were also performed clamping the tablets between Plexiglass  discs [15], where only radial drug release was allowed. The results of Fig. 4 indicate no drastic change in the release profiles (over 24 h) compared with free tablets, although a decrease in the amount of drug release could be noticed (28–35% after 24 h). A comparison of the quantity of theophylline released after 12 h (10 h for OD-HCMMA) from both dissolution studies showed a reduction in the radial release around two to three times compared with the global release (OD-HCMMA matrices experimented

a four times reduction). The global surface exposed to the dissolution medium (367–404 mm 2 ) was 2.5 times higher than the radial surface (141–178 mm 2 ). These results seem to indicate that the initial amount of area exposed to the dissolution medium determines the amount of drug release (the global drug release for OD-HCMMA matrices would be higher because of tablet disintegration). The values from Table 4 support this behaviour. Radial drug release from matrices containing the copolymers was governed mainly by drug diffusion. The slower rate observed (around 0.009 min 21 / 2 ) was due to a considerable decrease in the release surface available. Furthermore, the Plexiglass  devices avoided OD-HCMMA matrices disintegration observed from the free tablets, which could explain the marked reduction in the quantity of drug released. So, we would agree with Colombo et al. [27] when stated that the kinetics of the releasing area modification of the system are responsible for the drug release kinetics, whereas the amount of area exposed to the dissolution medium determines the amount of drug released.

3.5. Fronts movement study With the purpose of obtaining useful information

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Fig. 4. Radial release profiles of anhydrous theophylline (over 24 h) from formulated tablets of HSMMA (d), CSMMA (j), HCMMA (m) copolymers. OD products are represented by closed symbols and FD products by open ones. The bars show the standard deviation (n53).

for a better understanding of the drug release mechanism from the different matrices, fronts movement kinetics were evaluated. As mentioned in Section 2, a variation of Colombo et al. [10,11] method was recently introduced [12].

The photographs obtained from the matrices (Fig. 1B,C) revealed the absence of swelling and gel layer formation. As a clear gel layer was not detected, a new denomination for the fronts observed in these matrices has been suggested [12]. Three fronts could be clearly distinguished from the centre to the periphery of the matrix: water uptake front (between dry-partial wet polymer), complete wetting front (distinguishes a partial hydrated zone from a complete wet one) and erosion front (between the external surface of the matrix and the dissolution medium). Fronts movement kinetics (over 12 h) depicted in Fig. 5 showed a nearly constant erosion front movement, which agrees with the absence of swelling in these matrices. As no swelling or erosion (the tablet diameter remained about constant) could be detected, it seems that copolymer tablets behave as matrices where the drug is released by diffusion through the porous structure. As no gel layer was formed, a sharp distinction between solid and dissolved drug (diffusion front) could not be distinguished; nevertheless, complete wetting and water uptake fronts movement might contribute to the elucidation of drug release mechanism. So, the fast water uptake observed might be due to the water penetration through capillaries and higher size pores. The dark blue layer growing up over time might be the result of complete wetting, i.e., the whole polymer structure (smaller pores and

Table 4 Mathematical modelling and radial drug release kinetics from MMA copolymers-based tablets Mixture

Higuchi equation

Korsmeyer equation

Peppas equation

k (min 21 / 2 )

r2

n

k9 (min 2n)

r2

kd (min 20.44 )

kr (min 20.88 )

r2

OD-HSMMA

0.009

0.54

0.007

10 24

0.009

0.56

0.006

0.012

10 24

OD-CSMMA

0.008

0.51

0.008

0.011

9310 25

FD-CSMMA

0.009

0.52

0.008

0.010

10 24

OD-HCMMA

0.009

0.51

0.009

0.015

22310 25

FD-HCMMA

0.007

0.50

0.007

0.9991 (F 522701) 0.9977 (F 58260) 0.9969 (F 56415) 0.9988 (F 516132) 0.9866 (F 51475) 0.9897 (F 51918)

0.011

FD-HSMMA

0.9996 (F 555329) 0.9997 (F 566032) 0.9996 (F 551132) 0.9991 (F 521584) 0.9972 (F 57168) 0.9981 (F 510661)

0.009

9310 25

0.9999 (F 5176298) 0.9999 (F 574591) 0.9997 (F 535918) 0.9998 (F 558422) 0.9992 (F 511294) 0.9987 (F 57190)

k, Higuchi kinetic constant; n, release exponent; k9, Korsmeyer kinetic constant; k d , Peppas diffusion kinetic constant; k r , Peppas 2 relaxation kinetic constant; r , determination coefficient; F, F distribution for residual variance analysis (P50.000).

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intraparticle permeation) was participating in water uptake. In general, water uptake and complete wetting fronts seemed to move faster in matrices containing

79

freeze-dried copolymers, which would be consistent with the highest initial porosity in these matrices (Table 2). The least differences detected for HSMMA matrices with regard to pore size dis-

Fig. 5. Water uptake (d), complete wetting (j) and erosion (m) fronts positions over time for matrices containing: (a) HSMMA derivatives; (b) CSMMA derivatives; (c) HCMMA derivatives. OD products are represented by closed symbols and FD products by open ones. The bars show the standard deviation (n52).

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Table 5 Apparent diffusion coefficients (obtained from Higuchi rate constant) for drug release studies OD-HSMMA 2

D9 (cm / min)

3.1310

24

FD-HSMMA 1.8310

24

OD-CSMMA 3.2310

tribution (Fig. 2) could explain the similar complete wetting front movement. In contrast, the more important contribution of smaller pores in tablets obtained from FD-CSMMA and FD-HCMMA would justify the faster movement of this front compared with their corresponding OD derivatives. Among the OD matrices, OD-CSMMA ones showed the fastest water uptake and complete wetting fronts movement. OD-HSMMA tablets presented a faster water uptake than OD-HCMMA ones, while the wetting front movement was similar for both systems. OD-HSMMA and OD-CSMMA matrices had a similar porosity but the last ones were characterised by smaller mean and median pore radius (Table 2); however, the water uptake was faster in these matrices. This could be due to the influence of the pore size distribution on the penetration of a wetting liquid into a tablet [28,29]. Rapid penetration of the largest pores in OD-HSMMA matrices isolates other areas of finer pore structure from which air cannot escape. These areas then make no contribution to the overall uptake of liquid. The clear bimodality detected for OD-CSMMA matrices (Fig. 2) yielded larger parts of the pore structure participating in water uptake. In case of FD matrices, the water uptake front movement was more similar in the different matrices and the slowest complete wetting front movement was detected for FDHSMMA ones, which would be related to the lowest percentage of smaller pores. Finally, it is worthwhile to denote that, after a 24-h dissolution time period, water has reached the centre of the tablet in all matrices with the exception of OD-HCMMA ones, with the lowest porosity values (Table 2). For each pair of copolymers tested, the drug release rate from the systems (Table 3) was found to vary inversely with tablet porosity and mean pore radius (Table 2). Korsmeyer et al. [6] have also found these results in matrices containing HPMC and potassium chloride and gave a possible explanation in the air trapped within the tablets acting as a transport barrier. Consequently, as the initial porosity

24

FD-CSMMA 2.0310

24

OD-HCMMA 2.5310

23

FD-HCMMA 2.1310 24

of the tablets increases, the initial air content increases leading to slower drug release. However, in our case, the inverse relationship between porosity and drug release could be seen only when matrices from the same copolymer are evaluated, which makes us think in the contribution of another factor. Table 5 shows the approximate values for the apparent diffusion coefficient D9, obtained from the Higuchi rate constant. D9 is expressed as D/t, where t is the tortuosity of the matrix and D is the effective diffusion coefficient of the drug in the dissolution medium. D9 values were smaller for matrices obtained from FD derivatives, which means higher tortuosity values and increased diffusional resistance for these tablets. These results would explain the slower diffusion rate in these matrices in spite of their higher porosity and quicker water penetration. An important conclusion derived from this study is the behaviour of the copolymer tablets as inert matrices, where drug is released through the porous structure. The absence of swelling and gel formation, as well as the presence of nearly intact matrices (except OD-HCMMA ones) after the dissolution test, confirmed these results. The drug release and fronts movement studies showed that, in a first stage, the water uptake was essential for drug dissolution but, after that, drug diffusion through the porous structure controlled the release kinetic.

4. Conclusions MMA copolymers were shown to be a suitable material to control the release of anhydrous theophylline. This study further confirmed that diffusion was the predominant release mechanism, as the Higuchi linear square root of time relationship was the best model to describe the drug release kinetics from tablets containing these copolymers. Deviation from linearity occurred only when tablets broke open before completion of drug release. The drying method had a significant influence on dissolution be-

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haviour. Freeze-drying process seems to induce a slower release in comparison to oven-dried copolymers and the tablets obtained from FD derivatives kept their shapes during disintegration and dissolution studies. Fronts movement data were consistent with and complementary to the drug release kinetics observed. The porosity and tortuosity of the porous network influenced the water penetration and drug release rate from the matrices under study.

Acknowledgements This work has been supported by a F.P.I. grant from the Spanish Government and was part of a project (MAT98-0488 and MAT2001-3874-C02-01) ´ y Cultura (Spain). from Ministerio de Educacion

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