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Micronized ethylcellulose used for designing a directly compressed time-controlled disintegration tablet
Journal of Controlled Release 70 (2001) 321–328 www.elsevier.com / locate / jconrel
Micronized ethylcellulose used for designing a directly compressed time-controlled disintegration tablet q Shan-Yang Lin*, Kung-Hsu Lin, Mei-Jane Li Biopharmaceutical Laboratory, Department of Medical Research and Education, Veterans General Hospital-Taipei Taipei, Taiwan, ROC Received 8 August 2000; accepted 10 November 2000
Abstract Ethylcellulose (EC) of varying particle sizes has been used as an outer coating layer to design a novel dry-coated tablet with time-controlled drug release. This dry-coated tablet, containing a core tablet of sodium diclofenac and an outer coating layer of EC, was prepared by direct compression. The drug release from dry-coated tablet exhibited an initial lag period that was dependent on the particle size of the EC powder, followed by a stage of rapid drug release. The smaller the EC particle size used the longer the lag time obtained, suggesting the particle size of EC powder could modulate the timing of drug release from such a dry-coated tablet. The period of the lag time for sodium diclofenac released from dry-coated tablets was correlated with the penetration distance of the solvent into dry-coated tablet by an in vitro dye penetration study. The densest packing of EC powders appeared on the upper and lower surfaces of dry-coated tablet after compression, resulting in a tight structure yielding a slower penetration of the solvent. Whereas loose packing of EC powders occurred in the middle of the lateral surface of dry-coated tablet, this loosely packed surface readily allowed solvent penetration and that finally caused the splitting of tablet shell into two halves in the dissolution medium. The results suggest that these dry-coated tablets prepared with different particle sizes of EC powder as an outer coating layer might offer a desirable release profile for drug delivery at the predetermined times and / or sites. 2001 Elsevier Science B.V. All rights reserved. Keywords: Ethylcellulose; Particle sizes; Dry-coated tablet; Time-controlled; Lag time; Disintegration
1. Introduction Recently, the concept of the chronopharmacokinetics and chronotherapy of drugs has been extensively utilized in clinical therapy for improving the drug efficacy and preventing the side effects and
q
This paper is the part IV of the studies on micronized ethylcellulose for dosage form design. *Corresponding author. Fax: 1886-22-875-1562. E-mail address: [email protected] (S.-Y. Lin).
tolerance of drugs [1–3]. The maintenance of a constant drug blood level in the body is not always desirable for optimal therapy. For ideal therapeutic efficacy a drug should be delivered only when and where it is needed and at the minimum dose required. To avoid developing tolerance and to follow the innate circadian rhythm, a reasonable and generally accepted rationale is a delivery system capable of releasing drugs, in a pulsatile fashion rather than continuous delivery, at predetermined times and / or sites following oral administration [4–7]. This novel system not only acts as a rate-controlled system but
0168-3659 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 00 )00360-6
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also delivers the drug when it is required, that is in a time-controlled fashion. A dry-coated tablet is one candidate for such a novel system to deliver a drug formulated in a core tablet released after eroding the hydrophilic or hydrophobic barrier of the outer coating layer and which would exhibit a pulsatile release of the drug [8–10]. The outer coating layer is a critical factor and must have a reliable tolerance in order to reach the predetermined site. This outer shell may delay the penetration of fluid, thereby inducing a long lag time prior to the start of drug release. Once the solvent penetrates into the interior core tablet, the core tablet will dissolve and / or swell to break the outer shell resulting in rapid drug release. From the viewpoint of practical manufacturing, however, the compressibility and compaction of the dry-coated tablet are the most important parameters and are highly dependent on the coating material. Ethylcellulose (EC) is a well-known water-insoluble polymer and is often used as a rate-controlling membrane to modulate the drug release from dosage forms with organic or aqueous coating techniques [11–14]. Although EC has also been added in tablet formulations to act as a retarding material, few papers have focused on the use of EC as a directly compressible excipient [15–18]. Our previous studies found that the plastic deformation was the predominant consolidation mechanism for EC compacts after direct compression [19] and the porosity of the EC compact was the major factor influencing water uptake and dissolution of the drug from the compact [20]. Moreover, EC particle size and type of excipient play an important role in controlling drug release from the direct-compressed EC compacts [21]. The purpose of this study was to design timecontrolled disintegrating dry-coated tablets by using
different grades of micronized EC powders. The drug release and disintegration behaviors of drycoated tablets were investigated. The penetration distance of the solvent into dry-coated tablet by an in vitro dye penetration study was also determined. The possible mechanism for time-controlled disintegration of this dry-coated tablet was proposed.
2. Materials and methods
2.1. Materials Sodium diclofenac (,80 mesh, water content, 5%) was purchased from Syn-Tech (Taiwan, ROC). Six grades of EC with different particle sizes (4.0, 4.6, 6.0, 167.5, 224.3 and 398.0 mm) were supplied from Shin-Etsu (Tokyo, Japan). The physical properties of these EC powders are listed in Table 1 [19,20]. The water content for all EC powders was less than 1.2%, as determined by thermal analysis.
2.2. Preparation of dry-coated tablets The dry-coated tablets were prepared by using an IR spectrophotometric hydraulic press (Riken Seiki, Tokyo, Japan) under constant pressure. A 100-mg quantity of sodium diclofenac powder was directly compacted into a core tablet (7 mm in diameter) at the compaction pressure of 200 kg / cm 2 for 1 min. The dry-coated tablet was prepared according to the method of Ishino and Sunada [22]. A 140-mg quantity of different grades of EC powder was first filled into a die having a diameter of 10 mm, then the core tablet was manually placed in the center of the EC powder. The remaining 140 mg of EC powder was then poured into the die and compressed at 300
Table 1 Physical properties of different grades of ethylcellulose powders Grades Lot. no.
N-7-F 011032
N-10-F 012037
N-22-F 102043
N-7-G 402147
N-22-G 402146
N-100-G 007022
Average particle size (mm)a Viscosity (cps)b Mw c
4.0 6.2 58 000
4.6 9.6 80 000
6.0 22.0 123 000
167.5 6.2 58 000
224.3 22.0 123 000
398.0 84.9 230 000
a
Particle size was determined by laser-particle size analyzer. Viscosity was measured at 258C of a 5% (w / w) solution in a solvent of toluene–ethanol (80:20, w / w). c Mw , weight-average molecular weight. b
S.-Y. Lin et al. / Journal of Controlled Release 70 (2001) 321 – 328
323
photographs using a digital calipers (Mitsutoyo). The mean (n56) and standard deviation were obtained.
3. Results and discussion
3.1. Drug release from dry-coated tablets prepared with different particle sizes of EC powders Fig. 1. Ideal scheme of dry-coated tablet. Key: outer coating layer: different particle sizes of EC powder, core tablet: sodium diclofenac.
kg / cm 2 for 1 min to prepare the dry-coated tablet (total weight: 380 mg). Fig. 1 shows the ideal scheme of dry-coated tablet. The size of dry-coated tablet was about 4.2060.03 mm in thickness and 9.9860.02 mm in diameter, determined by using a digital calipers (Mitsutoyo, Tokyo, Japan).
2.3. In vitro drug release study The drug release from each dry-coated tablet was carried out in a USP dissolution paddle assembly (NRT-VS3, Toyama SanGyo, Japan) at 100 rpm and 3760.58C. Distilled water (pH 5.6) and phosphate buffer (pH 6.8) were used as dissolution media. The concentration of sodium diclofenac released from dry-coated tablets was determined spectrophotometrically at 276 nm (UV-160 A, Shimadzu, Japan). All the dissolution studies were performed in triplicate to obtain mean and standard deviation.
2.4. In vitro dye penetration study To determine the penetration behavior of solvent through the outer coating layer, the dry-coated tablet prepared with N-22-G of EC powder was used as a model. Six dry-coated tablets were placed on a gauge and carefully immersed in a methyl violet aqueous solution (1%, 378C) without shaking. At predetermined intervals a tablet was quickly sampled, wiped with filter paper, and vacuum-dried for 1 week at 258C. The dye-penetrated tablet was carefully dissected with a knife and the penetration distance of the dye aqueous solution was determined from the enlarged
The drug release profiles of sodium diclofenac from dry-coated tablets prepared with different particle sizes of EC powders in both distilled water and phosphate buffer (pH 6.8) are illustrated in Fig. 2. It is evident that the release performance of sodium diclofenac from these dry-coated tablets exhibited an initial lag period and then followed by its rapid release in both dissolution media. After the lag period, the shell of dry-coated tablets broke into two halves and caused a stage of rapid drug release. Obviously, the period of lag time was different and dependent on the particle size of the EC powders used. The smaller the EC particle size used the longer the lag time obtained (Fig. 3). The porosity and compaction of the outer coating layer prepared by different particle sizes of EC powder seems to be responsible for this result, which was similar to our previous results of EC compacts [19–21]. At the stage of rapid release, sodium diclofenac released from dry-coated tablets was slower in phosphate buffer (pH 6.8) than in distilled water (Fig. 2), presumably due to the lower solubility of sodium diclofenac in phosphate buffer (pH 6.8) [23]. In this study, the drug release from dry-coated tablet is mainly characterized by the initiation of drug release after a lag time, which was controlled by the splitting time of outer shell and the particle sizes of EC powder used. The release mechanism of dry-coated tablet might be belonged to the time-controlled release system with lag time, like as the time-controlled explosion system [24]. However, it was different from our previous studies on EC compacts in which there was no lag time for drug release [20,21]. The EC compacts made from the smaller particle size of EC powder gradually decreased in size and resulted in a slower release behavior. But the EC compacts prepared with larger particle size of EC powders exhibited more rapid disintegration and led to a faster drug release
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Fig. 2. Dissolution profiles of sodium diclofenac from dry-coated tablets in distilled water (A) and phosphate buffer, pH 6.8 (B). Key: Different particle sizes of EC: d, 4.0 mm; j, 4.6 mm; m, 6.0 mm; h, 167.5 mm; 앳, 224.3 mm; ♦, 398.0 mm (mean6standard deviation, n53).
behavior. In fact that the release pattern of sodium diclofenac was significantly different between drycoated tablets and compacts, indicating these two solid dosage forms had different release mechanisms. The release mechanism of sodium diclofenac from
EC compact was explained by the Fickian transport, as described in our previous study [21].
3.2. Water penetration into dry-coated tablets prepared with N-22 -G of EC powders
Fig. 3. Relationship between the lag time of drug released from dry-coated tablet and particle size of EC powder used. Key: Dissolution medium: distilled water (d, solid line) and phosphate buffer, pH 6.8 (♦, dotted line) (mean6standard deviation, n53).
The drug released from the dosage form may be defined as a mass transport phenomenon involving three processes: solvent penetration into the dosage form, dissolving the drug and diffusion out. The solvent penetration should be the first step in the process of drug dissolution. The lesser the penetration of solvent the slower the dissolution of drug, leading to the late of onset time of drug in the body. Fig. 2 clearly indicates a lag period and subsequent rapid release of sodium diclofenac from dry-coated tablets, suggesting solvent penetration through the outer coating layer plays an important role in this programmed delay. In order to evaluate the penetration of solvent into dry-coated tablet, the penetration distance of dye aqueous solution into the dry-coated tablet prepared with N-22-G of EC powder was measured at predetermined intervals. Fig. 4 shows the time-dependent coloration of the dye aqueous solution penetrated into the cross-sectional (A) and vertical (B) surroundings of outer coating layer of these dry-coated tablets. The penetration distance of the dye aqueous solution into the tablet was increased with time and clearly observed from the
S.-Y. Lin et al. / Journal of Controlled Release 70 (2001) 321 – 328
325
Fig. 4. Time-dependent coloration of the dye aqueous solution penetrated into the cross-sectional (A) and vertical (B) surroundings of outer coating layer of dry-coated tablets prepared with N-22-G of EC powder.
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photograph. Obviously, the absorption of the methyl violet dye on the white surface of dry-coated tablet was increased with time and the coloration of the surface became dense. Moreover, the coloring of the surrounding layer for outer coating shell penetrated by dye solution was clearly observed. This implies that the lag time for sodium diclofenac released from dry-coated tablets might be dependent on the penetration time of solvent into the tablet. It has been reported that water penetration in a planar matrix system obeys the boundary retreat mechanism [22,25]; the penetration distance (Xt ) from the surface after time (t) is expressed as Xt 5 Kp t 1 / 2 , where Kp is the penetration rate constant. In the present study, the penetration distance of the dye aqueous solution into dry-coated tablets prepared with N-22-G of EC powder was determined and is shown in Fig. 5. Since the lag time for dry-coated tablets prepared with N-22-G of EC powder was about 40 min, thus penetration distance was measured at predetermined intervals and finally ended in 25 min after immersion in methyl violet aqueous solution. After 40 min, the dry-coated tablet was broken into halves. It clearly shows that the penetration distance of dye aqueous solution into the
Fig. 5. Relationship between the penetration distance of dye aqueous solution into dry-coated tablets prepared with N-22-G of EC powder and the square root of time. Key: ♦, the compressed (XCb ) surface; d, the lateral (XLb ) surfaces.
compressed (XCb ) and lateral (XLb ) surfaces of drycoated tablet linearly increased with the square root of time, indicating that water penetration into drycoated tablet obeyed the diffusion mechanism [22,25,26]. The mean Kp values (n56) for the compressed and lateral surfaces of dry-coated tablet were 0.087 (r50.97) and 0.198 (r50.99) mm / min 1 / 2 , respectively. This reveals that water penetration into the lateral surface of dry-coated tablet was faster than through the compressed surfaces. The thicker track of the dye at the lateral surface is more distinct than the thinner track at the compressed surface, as evidenced in Fig. 4B. In the period of lag time, water was continuously penetrated through the outer coating shell into the inner core and dissolved drug. The higher concentration of drug solution dissolved then causes the higher osmotic pressure in the inner layer of dry-coated tablet to induce the breaking process and to rapidly drug release [27].
3.3. Mechanism of time-controlled disintegration of a dry-coated tablet prepared with N-22 -G of EC powders From the observations of dissolution study, we found that after a lag time each dry-coated tablet broke into halves across the lateral surface resulting in a subsequent rapid release of sodium diclofenac. The lag time and rapid release from each dry-coated tablet were dependent on the different particle sizes of EC used, providing different time-controlled releasing properties. The sudden splitting of drycoated tablets after the lag period is important for this time-control. A model for time-controlled release system by this dry-coated tablet is proposed in Fig. 6. In the course of preparation, the dense core tablet was compressed together with EC powders to result in an asymmetric configuration of the internal structure in dry-coated tablet. Due to the heterogeneous composition, the compressed and lateral surfaces of dry-coated tablet exhibited a different packing property of the EC powder used. We suppose that the tight structure and dense packing of EC powder after compression should be similar on the upper and lower compressed surface, since after dissolution there was no destruction. However, loose packing of EC powder occurs in the middle of the lateral
S.-Y. Lin et al. / Journal of Controlled Release 70 (2001) 321 – 328
327
Fig. 6. Internal structure and possible mechanism of time-controlled disintegration of a dry-coated tablet.
surface. This loose packing at the lateral surface readily allows water channels for solvent penetration, which causes the lateral cleavage in dry-coated tablet to rapidly drug release. After dissolution, two halves of outer coating shells were observed in the dissolution medium. Furthermore, the osmotic pressure induced by the higher concentration of soluble sodium diclofenac in the inner core of dry-coated tablet might also play an important role in this breaking process [27].
4. Conclusions The results of this investigation show that different particle sizes of water-insoluble EC powders were successfully used as an outer coating layer to prepare dry-coated tablets. These dry-coated tablets exhibited two stages of release performance, a period of lag time and rapid drug release, which was mainly dependent upon the different particle sizes of EC powder used. The asymmetric internal structure and penetration of solvent through the lateral surface of dry-coated tablets is likely responsible for the twostages of drug release. The influence of various parameters such as compression force, weight of the outer coating layer and pH on the time-controlled disintegration of this type of dry-coated tablet will be the subject of future investigation. The poor flowability of EC powder will be improved for direct compression.
Acknowledgements This work was supported by National Science Council, Taipei, Taiwan, Republic of China (NSC89-2314-B075-041).
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Micronized ethylcellulose used for designing a directly compressed time-controlled disintegration tablet q Shan-Yang Lin*, Kung-Hsu Lin, Mei-Jane Li Biopharmaceutical Laboratory, Department of Medical Research and Education, Veterans General Hospital-Taipei Taipei, Taiwan, ROC Received 8 August 2000; accepted 10 November 2000
Abstract Ethylcellulose (EC) of varying particle sizes has been used as an outer coating layer to design a novel dry-coated tablet with time-controlled drug release. This dry-coated tablet, containing a core tablet of sodium diclofenac and an outer coating layer of EC, was prepared by direct compression. The drug release from dry-coated tablet exhibited an initial lag period that was dependent on the particle size of the EC powder, followed by a stage of rapid drug release. The smaller the EC particle size used the longer the lag time obtained, suggesting the particle size of EC powder could modulate the timing of drug release from such a dry-coated tablet. The period of the lag time for sodium diclofenac released from dry-coated tablets was correlated with the penetration distance of the solvent into dry-coated tablet by an in vitro dye penetration study. The densest packing of EC powders appeared on the upper and lower surfaces of dry-coated tablet after compression, resulting in a tight structure yielding a slower penetration of the solvent. Whereas loose packing of EC powders occurred in the middle of the lateral surface of dry-coated tablet, this loosely packed surface readily allowed solvent penetration and that finally caused the splitting of tablet shell into two halves in the dissolution medium. The results suggest that these dry-coated tablets prepared with different particle sizes of EC powder as an outer coating layer might offer a desirable release profile for drug delivery at the predetermined times and / or sites. 2001 Elsevier Science B.V. All rights reserved. Keywords: Ethylcellulose; Particle sizes; Dry-coated tablet; Time-controlled; Lag time; Disintegration
1. Introduction Recently, the concept of the chronopharmacokinetics and chronotherapy of drugs has been extensively utilized in clinical therapy for improving the drug efficacy and preventing the side effects and
q
This paper is the part IV of the studies on micronized ethylcellulose for dosage form design. *Corresponding author. Fax: 1886-22-875-1562. E-mail address: [email protected] (S.-Y. Lin).
tolerance of drugs [1–3]. The maintenance of a constant drug blood level in the body is not always desirable for optimal therapy. For ideal therapeutic efficacy a drug should be delivered only when and where it is needed and at the minimum dose required. To avoid developing tolerance and to follow the innate circadian rhythm, a reasonable and generally accepted rationale is a delivery system capable of releasing drugs, in a pulsatile fashion rather than continuous delivery, at predetermined times and / or sites following oral administration [4–7]. This novel system not only acts as a rate-controlled system but
0168-3659 / 01 / $ – see front matter 2001 Elsevier Science B.V. All rights reserved. PII: S0168-3659( 00 )00360-6
322
S.-Y. Lin et al. / Journal of Controlled Release 70 (2001) 321 – 328
also delivers the drug when it is required, that is in a time-controlled fashion. A dry-coated tablet is one candidate for such a novel system to deliver a drug formulated in a core tablet released after eroding the hydrophilic or hydrophobic barrier of the outer coating layer and which would exhibit a pulsatile release of the drug [8–10]. The outer coating layer is a critical factor and must have a reliable tolerance in order to reach the predetermined site. This outer shell may delay the penetration of fluid, thereby inducing a long lag time prior to the start of drug release. Once the solvent penetrates into the interior core tablet, the core tablet will dissolve and / or swell to break the outer shell resulting in rapid drug release. From the viewpoint of practical manufacturing, however, the compressibility and compaction of the dry-coated tablet are the most important parameters and are highly dependent on the coating material. Ethylcellulose (EC) is a well-known water-insoluble polymer and is often used as a rate-controlling membrane to modulate the drug release from dosage forms with organic or aqueous coating techniques [11–14]. Although EC has also been added in tablet formulations to act as a retarding material, few papers have focused on the use of EC as a directly compressible excipient [15–18]. Our previous studies found that the plastic deformation was the predominant consolidation mechanism for EC compacts after direct compression [19] and the porosity of the EC compact was the major factor influencing water uptake and dissolution of the drug from the compact [20]. Moreover, EC particle size and type of excipient play an important role in controlling drug release from the direct-compressed EC compacts [21]. The purpose of this study was to design timecontrolled disintegrating dry-coated tablets by using
different grades of micronized EC powders. The drug release and disintegration behaviors of drycoated tablets were investigated. The penetration distance of the solvent into dry-coated tablet by an in vitro dye penetration study was also determined. The possible mechanism for time-controlled disintegration of this dry-coated tablet was proposed.
2. Materials and methods
2.1. Materials Sodium diclofenac (,80 mesh, water content, 5%) was purchased from Syn-Tech (Taiwan, ROC). Six grades of EC with different particle sizes (4.0, 4.6, 6.0, 167.5, 224.3 and 398.0 mm) were supplied from Shin-Etsu (Tokyo, Japan). The physical properties of these EC powders are listed in Table 1 [19,20]. The water content for all EC powders was less than 1.2%, as determined by thermal analysis.
2.2. Preparation of dry-coated tablets The dry-coated tablets were prepared by using an IR spectrophotometric hydraulic press (Riken Seiki, Tokyo, Japan) under constant pressure. A 100-mg quantity of sodium diclofenac powder was directly compacted into a core tablet (7 mm in diameter) at the compaction pressure of 200 kg / cm 2 for 1 min. The dry-coated tablet was prepared according to the method of Ishino and Sunada [22]. A 140-mg quantity of different grades of EC powder was first filled into a die having a diameter of 10 mm, then the core tablet was manually placed in the center of the EC powder. The remaining 140 mg of EC powder was then poured into the die and compressed at 300
Table 1 Physical properties of different grades of ethylcellulose powders Grades Lot. no.
N-7-F 011032
N-10-F 012037
N-22-F 102043
N-7-G 402147
N-22-G 402146
N-100-G 007022
Average particle size (mm)a Viscosity (cps)b Mw c
4.0 6.2 58 000
4.6 9.6 80 000
6.0 22.0 123 000
167.5 6.2 58 000
224.3 22.0 123 000
398.0 84.9 230 000
a
Particle size was determined by laser-particle size analyzer. Viscosity was measured at 258C of a 5% (w / w) solution in a solvent of toluene–ethanol (80:20, w / w). c Mw , weight-average molecular weight. b
S.-Y. Lin et al. / Journal of Controlled Release 70 (2001) 321 – 328
323
photographs using a digital calipers (Mitsutoyo). The mean (n56) and standard deviation were obtained.
3. Results and discussion
3.1. Drug release from dry-coated tablets prepared with different particle sizes of EC powders Fig. 1. Ideal scheme of dry-coated tablet. Key: outer coating layer: different particle sizes of EC powder, core tablet: sodium diclofenac.
kg / cm 2 for 1 min to prepare the dry-coated tablet (total weight: 380 mg). Fig. 1 shows the ideal scheme of dry-coated tablet. The size of dry-coated tablet was about 4.2060.03 mm in thickness and 9.9860.02 mm in diameter, determined by using a digital calipers (Mitsutoyo, Tokyo, Japan).
2.3. In vitro drug release study The drug release from each dry-coated tablet was carried out in a USP dissolution paddle assembly (NRT-VS3, Toyama SanGyo, Japan) at 100 rpm and 3760.58C. Distilled water (pH 5.6) and phosphate buffer (pH 6.8) were used as dissolution media. The concentration of sodium diclofenac released from dry-coated tablets was determined spectrophotometrically at 276 nm (UV-160 A, Shimadzu, Japan). All the dissolution studies were performed in triplicate to obtain mean and standard deviation.
2.4. In vitro dye penetration study To determine the penetration behavior of solvent through the outer coating layer, the dry-coated tablet prepared with N-22-G of EC powder was used as a model. Six dry-coated tablets were placed on a gauge and carefully immersed in a methyl violet aqueous solution (1%, 378C) without shaking. At predetermined intervals a tablet was quickly sampled, wiped with filter paper, and vacuum-dried for 1 week at 258C. The dye-penetrated tablet was carefully dissected with a knife and the penetration distance of the dye aqueous solution was determined from the enlarged
The drug release profiles of sodium diclofenac from dry-coated tablets prepared with different particle sizes of EC powders in both distilled water and phosphate buffer (pH 6.8) are illustrated in Fig. 2. It is evident that the release performance of sodium diclofenac from these dry-coated tablets exhibited an initial lag period and then followed by its rapid release in both dissolution media. After the lag period, the shell of dry-coated tablets broke into two halves and caused a stage of rapid drug release. Obviously, the period of lag time was different and dependent on the particle size of the EC powders used. The smaller the EC particle size used the longer the lag time obtained (Fig. 3). The porosity and compaction of the outer coating layer prepared by different particle sizes of EC powder seems to be responsible for this result, which was similar to our previous results of EC compacts [19–21]. At the stage of rapid release, sodium diclofenac released from dry-coated tablets was slower in phosphate buffer (pH 6.8) than in distilled water (Fig. 2), presumably due to the lower solubility of sodium diclofenac in phosphate buffer (pH 6.8) [23]. In this study, the drug release from dry-coated tablet is mainly characterized by the initiation of drug release after a lag time, which was controlled by the splitting time of outer shell and the particle sizes of EC powder used. The release mechanism of dry-coated tablet might be belonged to the time-controlled release system with lag time, like as the time-controlled explosion system [24]. However, it was different from our previous studies on EC compacts in which there was no lag time for drug release [20,21]. The EC compacts made from the smaller particle size of EC powder gradually decreased in size and resulted in a slower release behavior. But the EC compacts prepared with larger particle size of EC powders exhibited more rapid disintegration and led to a faster drug release
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Fig. 2. Dissolution profiles of sodium diclofenac from dry-coated tablets in distilled water (A) and phosphate buffer, pH 6.8 (B). Key: Different particle sizes of EC: d, 4.0 mm; j, 4.6 mm; m, 6.0 mm; h, 167.5 mm; 앳, 224.3 mm; ♦, 398.0 mm (mean6standard deviation, n53).
behavior. In fact that the release pattern of sodium diclofenac was significantly different between drycoated tablets and compacts, indicating these two solid dosage forms had different release mechanisms. The release mechanism of sodium diclofenac from
EC compact was explained by the Fickian transport, as described in our previous study [21].
3.2. Water penetration into dry-coated tablets prepared with N-22 -G of EC powders
Fig. 3. Relationship between the lag time of drug released from dry-coated tablet and particle size of EC powder used. Key: Dissolution medium: distilled water (d, solid line) and phosphate buffer, pH 6.8 (♦, dotted line) (mean6standard deviation, n53).
The drug released from the dosage form may be defined as a mass transport phenomenon involving three processes: solvent penetration into the dosage form, dissolving the drug and diffusion out. The solvent penetration should be the first step in the process of drug dissolution. The lesser the penetration of solvent the slower the dissolution of drug, leading to the late of onset time of drug in the body. Fig. 2 clearly indicates a lag period and subsequent rapid release of sodium diclofenac from dry-coated tablets, suggesting solvent penetration through the outer coating layer plays an important role in this programmed delay. In order to evaluate the penetration of solvent into dry-coated tablet, the penetration distance of dye aqueous solution into the dry-coated tablet prepared with N-22-G of EC powder was measured at predetermined intervals. Fig. 4 shows the time-dependent coloration of the dye aqueous solution penetrated into the cross-sectional (A) and vertical (B) surroundings of outer coating layer of these dry-coated tablets. The penetration distance of the dye aqueous solution into the tablet was increased with time and clearly observed from the
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Fig. 4. Time-dependent coloration of the dye aqueous solution penetrated into the cross-sectional (A) and vertical (B) surroundings of outer coating layer of dry-coated tablets prepared with N-22-G of EC powder.
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photograph. Obviously, the absorption of the methyl violet dye on the white surface of dry-coated tablet was increased with time and the coloration of the surface became dense. Moreover, the coloring of the surrounding layer for outer coating shell penetrated by dye solution was clearly observed. This implies that the lag time for sodium diclofenac released from dry-coated tablets might be dependent on the penetration time of solvent into the tablet. It has been reported that water penetration in a planar matrix system obeys the boundary retreat mechanism [22,25]; the penetration distance (Xt ) from the surface after time (t) is expressed as Xt 5 Kp t 1 / 2 , where Kp is the penetration rate constant. In the present study, the penetration distance of the dye aqueous solution into dry-coated tablets prepared with N-22-G of EC powder was determined and is shown in Fig. 5. Since the lag time for dry-coated tablets prepared with N-22-G of EC powder was about 40 min, thus penetration distance was measured at predetermined intervals and finally ended in 25 min after immersion in methyl violet aqueous solution. After 40 min, the dry-coated tablet was broken into halves. It clearly shows that the penetration distance of dye aqueous solution into the
Fig. 5. Relationship between the penetration distance of dye aqueous solution into dry-coated tablets prepared with N-22-G of EC powder and the square root of time. Key: ♦, the compressed (XCb ) surface; d, the lateral (XLb ) surfaces.
compressed (XCb ) and lateral (XLb ) surfaces of drycoated tablet linearly increased with the square root of time, indicating that water penetration into drycoated tablet obeyed the diffusion mechanism [22,25,26]. The mean Kp values (n56) for the compressed and lateral surfaces of dry-coated tablet were 0.087 (r50.97) and 0.198 (r50.99) mm / min 1 / 2 , respectively. This reveals that water penetration into the lateral surface of dry-coated tablet was faster than through the compressed surfaces. The thicker track of the dye at the lateral surface is more distinct than the thinner track at the compressed surface, as evidenced in Fig. 4B. In the period of lag time, water was continuously penetrated through the outer coating shell into the inner core and dissolved drug. The higher concentration of drug solution dissolved then causes the higher osmotic pressure in the inner layer of dry-coated tablet to induce the breaking process and to rapidly drug release [27].
3.3. Mechanism of time-controlled disintegration of a dry-coated tablet prepared with N-22 -G of EC powders From the observations of dissolution study, we found that after a lag time each dry-coated tablet broke into halves across the lateral surface resulting in a subsequent rapid release of sodium diclofenac. The lag time and rapid release from each dry-coated tablet were dependent on the different particle sizes of EC used, providing different time-controlled releasing properties. The sudden splitting of drycoated tablets after the lag period is important for this time-control. A model for time-controlled release system by this dry-coated tablet is proposed in Fig. 6. In the course of preparation, the dense core tablet was compressed together with EC powders to result in an asymmetric configuration of the internal structure in dry-coated tablet. Due to the heterogeneous composition, the compressed and lateral surfaces of dry-coated tablet exhibited a different packing property of the EC powder used. We suppose that the tight structure and dense packing of EC powder after compression should be similar on the upper and lower compressed surface, since after dissolution there was no destruction. However, loose packing of EC powder occurs in the middle of the lateral
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Fig. 6. Internal structure and possible mechanism of time-controlled disintegration of a dry-coated tablet.
surface. This loose packing at the lateral surface readily allows water channels for solvent penetration, which causes the lateral cleavage in dry-coated tablet to rapidly drug release. After dissolution, two halves of outer coating shells were observed in the dissolution medium. Furthermore, the osmotic pressure induced by the higher concentration of soluble sodium diclofenac in the inner core of dry-coated tablet might also play an important role in this breaking process [27].
4. Conclusions The results of this investigation show that different particle sizes of water-insoluble EC powders were successfully used as an outer coating layer to prepare dry-coated tablets. These dry-coated tablets exhibited two stages of release performance, a period of lag time and rapid drug release, which was mainly dependent upon the different particle sizes of EC powder used. The asymmetric internal structure and penetration of solvent through the lateral surface of dry-coated tablets is likely responsible for the twostages of drug release. The influence of various parameters such as compression force, weight of the outer coating layer and pH on the time-controlled disintegration of this type of dry-coated tablet will be the subject of future investigation. The poor flowability of EC powder will be improved for direct compression.
Acknowledgements This work was supported by National Science Council, Taipei, Taiwan, Republic of China (NSC89-2314-B075-041).
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