The Effect of Core and Coating Composition on Drug Release from Directly Compressed Time-Controlled Release Tablets

Time-controlled and pulsatile releases are increasingly being considered as desirable modes of drug delivery because there is a growing awareness of the importance of circadian rhythms with respect to physiology, disease state, and drug action that has given rise to the related fields of chronopharmaceutics and chronopharmacology (1, 2). At present, the drug must be administered not only in the right amount at a proper rate but also at the right time. For many drugs, including antiasthmatic, antihistaminic, psychotropic, anaesthetic, cardiovascular active drugs, and nonsteroidal anti-inflammatory drugs, significant daily variations in pharmacokinetics or drug effects have been demonstrated in man, depending on physiological or physiopathological changes of circadian rhythmicity (3). Nocturnal symptoms and overnight decrements in lung function are a common part of the asthma clinical syndrome. Circadian changes are seen in normal lung function, which reaches a low point in the early morning hours. This dip is particularly pronounced in people with asthma. Because bronchoconstriction and exacerbation of symptoms vary in a circadian fashion, asthma is well suited for chronotherapy. Chronotherapies have been studied for asthma with oral corticosteroids, theophylline, and β₂ -agonists. Treatment strategies for nocturnal asthma are similar to those used to treat persistent asthma, although it is beneficial to dose medications to target optimum effect during periods of nocturnal worsening (4). The study has been carried out with salbutamol sulfate as an antiasthmatic drug.

Several studies have been published in which tablet cores were coated with directly compressed micronized ethylcellulose (EC) (5–7) and hydroxypropylcellulose (HPC) (8). There have been no published studies, however, involving the use of various grades of HPC (erodible and gellable polymer) combined with commercial grades of EC (rupturable polymer) on timed-release preparations, regardless of giving different release mechanisms of drug with different core composition.

Table I: Composition of core tablets.

The main objective of this study was to investigate whether compression coating could be used to produce tablets providing maximum in vitro drug release within 6–8 h after an evening dose taken at approximately 22:00. The basic idea behind the dosage-form development is to investigate the effect of core and coating composition on lag time and drug release from a directly compressed time-controlled release tablet.

Materials and methods

Materials. Salbutamol sulfate was chosen as a model drug and was a gift from Cipla Ltd. (Kurkumbh, India). Hydroxypropyl-cellulose (HPC HF and HPC EXF, batches 3523 and 4942, respectively), ethylcellulose (ECN 22 F, batch 40900), spray-dried compound of α-lactose monohydrate and maize starch (Starlac, batch YM007), microcrystalline cellulose (Avicel PH 101, batch 6442C), and croscarmellose sodium (Ac-Di-Sol, batch 7691) were gifts from Signet Chemicals (Mumbai, India). Magnesium stearate and colloidal silicon dioxide (Aerosil 200) were purchased from S.D. Fine Chemicals (Mumbai, India). The colorant Sunset Yellow was obtained as a gift from Ranbaxy Ltd. (Jejuri, India). All other reagents were of analytical grades.

Preparation of core tablets. The inner-core tablets were prepared using direct compression to perform various release kinetics, depending upon the release mechanism involved. Powder mixtures of salbutamol sulfate, Starlac, or Avicel PH 101, Ac-Di-Sol, and Sunset Yellow were dry blended for 20 min followed by the addition of magnesium stearate and Aerosil. The mixtures were further blended for 10 min and then compressed into tablets (average tablet weight = 75 mg) using a rotary tablet machine equipped with 6-mm concave faced punch. Sufficient pressure was applied to keep the hardness at 5 ± 0.33 kg/cm² . Table I lists the core compositions for one tablet.

Preparation of press-coated tablets. The press-coated tablets were prepared according to the method described by Fukui (8). All powder mixtures were passed through a sieve no. 44, and 150 mg of the powder mixture was used for the upper and lower shells. Press coating was performed using a rotary tablet machine. Half (150 mg) of the powder was filled into the die to make a powder bed, and the core tablet was placed manually in the center. The remaining half of the coating material was used to fill the die, and the contents were compressed under a sufficient compression force (total weight = 375 mg) using a concave punch 10 mm in diameter to keep the hardness of the coated tablet at 10 ± 0.34 kg/cm² .

Formulations for the outer shell of press-coated tablets. The formulation of the outer shell for the press-coated tablet using core tablet containing 4% Ac-Di-Sol and Starlac or Avicel PH 101 as filler was respectively prepared according to the following formulas:

• rupturable polymer (EC) combined with erodible polymer (HPC EXF): weight ratios of HPC EXF to EC N 22 F were 0:100%, 12.5:87.5%, 25:75%, 50:50%, 75:25%, 87.5:12.5%, and 100:0% w/w;

• gellable polymer (HPC HF) combined with erodible polymer (HPC EXF): weight ratios of HPC HF to HPC EXF were 0:100%, 12.5:87.5%, 25:75%, 50:50%, 75:25%, 87.5:12.5%, and 100:0% w/w.

In vitro dissolution study. To verify how the composition of the core and the barriers interferes with the drug-release profile from the cores, the in vitro release behavior of the uncoated cores and press-coated tablets were tested. The test was carried out in a USP dissolution paddle assembly (model DT 60, Veego, India) at 37 ± 0.5 °C using 0.1 N HCl (first fluid; simulated gastric fluid) for the first 2 h. The tablets then were transfered to 6.8 pH phosphate buffer (second fluid; simulated intestinal fluid) solution. Aliquots of dissolution fluid were removed at specified time intervals and assayed for the amount of salbutamol sulfate released by a spectrophotometer (UV 1700, Shimadzu, Japan) at wavelengths of 224.5 and 225 nm for 0.1 N HCl and 6.8 pH phosphate buffer, respectively. The in vitro release patterns of the cores were studied visually by taking images of the tablets in a Petri plate containing dissolution medium. All dissolution studies were performed in triplicate (n = 3) to obtained mean and standard deviation.

Erosion study of press-coated tablets. The erosion study of press-coated tablets was designed to determine whether the prevailing release mechanism of salbutamol sulfate from the coated devices depends on the types of core composition. The percentage of erosion from the press-coated tablets was determined in the dissolution medium just before lag time. At predetermined time points (before lag time), the tablets were removed from the dissolution medium, carefully blotted with tissue paper to remove surface water, and weighed. The percentage of erosion was calculated as follows (9):

in which W_t is the weight of wet tablet at time t and W₀ is the weight of the dry coated tablet.

Results and discussion

In vitro dissolution study of core tablets. Figure 1 and Figure 2 show the release profiles of salbutamol sulfate from the uncoated tablets prepared with Starlac and Avicel PH 101 as a filler, respectively. Upon contact with the dissolution medium, core tablets prepared using Starlac as a filler started to erode and released the drug. Starlac is a coprocessed excipient consisting of lactose monohydrate and maize starch (85:15) (10). As a result of both hydration and disintegrant properties of Starlac, upon contact with the dissolution medium, this core tablet erodes and provides release within 12 min. No significant effect from Ac-Di-Sol was observed on the release pattern of the drug. Core tablets prepared with Avicel PH 101 as a filler, upon contact with the dissolution medium tablets, swelled, disintegrated, and released the drug. As the amount of Ac-Di-Sol increased, the drug release increased. Figure 3 shows the release pattern of albutamol sulfate from the uncoated tablets prepared using Starlac and Avicel PH 101 as a filler.

Figure 1

Figure 2

In vitro dissolution study of press-coated tablets. Rupturable polymer (EC) combined with erodible polymer (HPC EXF). As shown by Figure 4 and Figure 5, when rupturable polymer (EC N 22 F) combined with erodible polymer (HPC EXF), lag time increased with an increasing weight ratio of EC N 22 F to HPC EXF. Using EC N 22 F alone resulted in the shortest lag time compared to any weight ratio of EC N 22 F to HPC EXF. This occurs because EC is semipermeable in nature and, although it is naturally insoluble in the dissolution medium, it penetrates the coating layer of the tablet when used alone. After hydration of the core, the drug was released.

Figure 3

For tablets in which EC was used with HPC EXF, and as a result of the solubility of HPC EXF, upon contact with the dissolution medium, HPC EXF hydrated and formed a compact with EC. In addition, the hydrophobicity of EC retards the hydration of HPC EXF. Therefore, the dissolution medium did not penetrate the outer-coating layer but the coating eroded slowly.

Figure 4

Press-coated tablets containing Starlac as a filler in the core tablet showed drug release after the coating layer eroded because upon contact with the dissolution medium, Starlac starts to erode and the Ac-Di-Sol present was unable to generate sufficient internal pressure to cause a bursting of the outer-coating layer. Press-coated tablets containing Avicel PH 101 as a filler in the core tablet showed drug release after some erosion of outer shell and when the dissolution medium hydrates the core tablet. The Ac-Di-Sol in the core tablet swelled and generated sufficient internal pressure to burst the outer shell. Obviously, the erosion of the outer coating shell of core tablet containing Starlac as a filler was higher than that of tablets containing Avicel PH 101 as the filler (see Figure 6). The order of the time lag changed according to the weight ratio of EC N 22 F to HPC EXF mixture containing Starlac as a filler as follows: 87.5:12.5% (9.5 h), 75:25% (8.5 h), 50:50% (7 h), 25:75% (6.5 h), and 12.5:87.5% (5.5 h). The order of the time lag changed according to the weight ratio of EC N 22 F to HPC EXF mixture containing Avicel PH 101 as filler as follows: 87.5:12.5% (8.5 h), 75:25% (7.5 h), 50:50% (6.5 hrs), 25:75% (6 hrs), and 12.5:87.5% (5 h).

Figure 5

Gellable polymer (HPC HF) combined with erodible polymer (HPC EXF). Figure 7 and Figure 8 show the increase in lag time and decrease in the release rate of salbutamol with increasing weight ratio of HPC HF to HPC EXF. These figues confirm barrier layer effectiveness and core composition effectiveness in delaying the release starts. The press-coated tablet with erodible shells (HPC EXF) show the same release kinetics of the cores once the time lags are omitted. When the gellable shells are used instead, the release start can be delayed, and the release rate can be decreased dramatically (12). Tablets containing a 12.5:87.5% w/w ratio of HPC HF to HPC EXF formed a gel-like structure upon contact with dissolution medium. Because of the high percentage of HPC EXF, however, this structure was not very firm and eroded and gelled simultaneously. Tablets containing Avicel PH 101 as a core-tablet filler showed drug release by a bursting of the inner core followed by a rupturing of the outer shell. The pressure generated in the core tablet was enough to rupture the outer shell after some erosion of the outer shell and led to a 7-h lag time followed by a release lasting 1 h.

Figure 6

Tablets containing Starlac as a filler in the inner core showed a slight delay in drug release and release rate. Upon contact with the dissolution medium, Starlac present in the core tablet eroded, and the pressure generated in the inner core was unable to rupture the outer shell. The drug was released only upon complete erosion of the outer shell. Tablets containing Starlac also showed a slightly longer lag time compared with those containing Avicel PH 101 as a filler in the core tablet. Tablets containing a combination of HPC HF and HPC EXF in a 25:75% w/w weight ratio showed almost the same release pattern of salbutamol sulfate after a time lag. The difference was only in the delay in the time lag to salbutamol sulfate release. The erosion of the outer coating shell of the core tablet containing Starlac as a filler was greater than that of the tablets containing Avicel PH 101 as a filler (see Figure 9).

Figure 7

A 50:50% w/w combination of HPC HF and HPC EXF formed a tougher gel-like structure upon contact with the dissolution medium. Because tablets containing Avicel PH 101 as a filler were hydrophobic, they required more time to hydrate upon contact with the dissolution medium to diffuse out salbutamol sulfate from the gell-like structure of the outer shell. The hydration and disintegrant properties of Starlac present in the core tablet resulted in a rapid drug release and a slower lag time compared with the formulation containing Avicel PH 101 as filler. The pressure generated upon the swelling of Ac-Di-Sol with Avicel PH 101 as filler was not sufficient to break the outer shell because of the tough gel-like structure formed on the outer shell. Obviously, the erosion of the outer-coating shell of the core tablet containing Starlac was lower than when Avicel PH 101 was used as as filler (see Figure 9).

Figure 8

A photograph of the formulation containing 50:50% w/w HPC HF to HPC EXF at the 20th hour also suggests the proper hydration effect of the core and shows the possible mechanism of release of salbutamol sulfate from this formulation (see Figure 10). Formulation containing a higher weight ratio of HPC HF to HPC EXF showed more delay in the release of salbutamol sulfate and an increase in the time lag to start the release of salbutamol sulfate.

Figure 9

Conclusion

Various drug-release mechanisms were observed by incorporating different polymers into the outer shell and different core compositions. By deepening the knowledge of polymeric materials' behavior in dosage forms and, in particular, their application in the press-coating of different core compositions such as those proposed in this study, a safe and more accurate targeting of the drug from dosage forms can be achieved.

Figure 10

Shilpa P. Chaudhari and Praveen D. Chaudhari* are professors of pharmaceutics at Padm. Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research, Pune University, India, tel. +91 9850179873, fax +91 22 27421097, pdchaudhari_21@yahoo.comChetan J. Mistry is a research scientist at the Torrent Research Centre, India. Manohar J. Patil, PhD, is head of the Department of Pharmacognosy at Padm. Dr. D.Y. Patil Institute of Pharmaceutical Sciences and Research. Nilesh S. Barhate is a research and development officer at Blue Cross Laboratories, India.

*To whom all correspondence should be addressed.

Submitted: Sept. 26, 2006. Accepted: Oct. 11, 2006.

Keywords: controlled release, coating, excipients, direct compression, formulation, solid dosage forms, tableting

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