Abhijit Moon et al.

/ Journal of Pharmacy Research 2011,4(3),564-566

Research Article
ISSN: 0974-6943 Available online through
www.jpronline.info
Formulation and evaluation of press -coated indomethacin tablets for pulsatile drug delivery system
Abhijit Moon*, Manish Kondawar, Rohit Shah
Department of Quality Assurance, Appasaheb Birnale College of Pharmacy, Sangli 416416
Received on: 10-11-2010; Revised on: 18-12-2010; Accepted on:18-02-2011

ABSTRACT
An oral press-coated tablet was developed by means of direct compression and wet granulation to achieve the time-controlled tablet with a distinct predetermined
lag time. This press-coated tablet containing Indomethacin in the inner core was formulated with an outer shell by different weight ratios of hydrophobic polymer
of ethylcellulose powder and hydrophilic polymer hydroxy propyl methyl cellulose. The effect of the formulation of an outer shell comprising both hydrophobic
polymer and hydrophilic polymer on the time lag of drug release was investigated. The typical pulsatile profile was shown by tablets prepared by direct compression
and wet granulation method. The release profile of the press-coated tablet exhibited a time period without drug release (time lag) followed by a rapid and complete
release phase. In vitro drug release study shows that as hydrophilic polymer increases lag time decrease. Press coated tablets coated by dry mixing and by wet
granulation showed variations in lag time. As compared to dry mixed blend method wet granulation method gives less lag time.

Key words: Press-coated tablet, lag time, ethylcellulose, hydroxy propyl methyl cellulose, pulsatile drug delivery system.
1. INTRODUCTION
Oral controlled release drug delivery systems offer a number of advantages over the predetermined period of time after which the drug is dissolved and rapidly released.
conventional immediate release delivery preparations. These systems are designed to
deliver the drugs at a controlled and predetermined rate thus maintaining their therapeu- Morning stiffness associated with pain at the time of awakening is a diagnostic criterion
tically effective concentration in systemic circulation for prolonged periods. On the other of the rheumatoid arthritis and these clinical circadian symptoms are supposed to be
hand, for certain therapies a pulsatile drug release pattern, where the drug is released after outcome of altered functioning of hypothalamic–pitutary–adrenocortical axis. [ 8 ]
well-defined lag time, exhibits significant advantages. It is well documented that most of Chronopharmacotherapy for rheumatoid arthritis has been recommended to ensure that the
the body functions display circadian rhythms, e.g. heart rate, stroke volume, blood highest blood levels of the drug coincide with peak pain and stiffness. A pulsatile drug
pressure, blood flow, body temperature, gastric-pH. Moreover, in a number of organs their delivery system that can be administered at night (bed time) but that release drug in early
functions vary with the time of the day. It is increasingly recognized that there are morning would be a promising chronopharmaceutic system.
rhythmic and temporal patterns in the manifestation of many disease states. The symp-
toms for a number of diseases, such as bronchial asthma, myocardial infraction, angina This study focused on the development of press-coated pulsatile release tablets to treat
pectoris, hypertension, rheumatic diseases, etc. follow a circadian rhythm. [1] rheumatoid arthritis. The press–coated tablet investigated in current study consist of rapid
release core tablet which is press–coated with Hydroxy Propyl Methyl Cellulose which is
Circadian rhythms are self-sustaining, endogenous oscillations that occur with a period- swellable polymer and Ethyl Cellulose, a hydrophobic polymer, which is long been used
icity of about 24 Hours. [2] Interestingly, the term circadian is derived from the Latin circa as drug release rate controlling polymer. The purpose of study was to design the simple,
which means “about” and dies which can be defined as “a day”. Normally, circadian single pulse technique and to investigate the effect of type and amount of hydrophobic and
rhythms are synchronized according to internal biologic clocks related to the sleep-wake hydrophilic polymer mix together in outer coating on drug release.
cycle. Our circadian rhythm is based on sleep-activity cycle and is influenced by our
genetic makeup and thereby affects our body’s function throughout day and night (24-hour 2. MATERIALS AND METHODS
period). Circadian rhythm regulates many body functions in humans like metabolism, 2.1. Materials
physiology, behavior, sleep pattern, hormone production. [3] As many conditions show Indomethacin, a non-steroidal anti-inflammatory drug, was chosen as model drug (Cipla
circadian pattern, advantage could be taken by timing and adjusting the administration of Pharma, kurkumbh). Microcrystallline cellulose (Avicel PH- 102), Magnesium stearate
drugs according to the circadian rhythm of the disease. and Starch were procured from Research Lab, Mumbai. Croscarmellose sodium (Ac-Di-
Sol) was used as superdisintegrant and procured from Loba chemie Pvt. Ltd. Mumbai.
In a number of reports it is documented that there are day-night variations in blood Polyvinylpyrrolidone (PVP, K90) used as binder procured from Fine Chem Industries,
pressure of the Hypertensive patient. [4, 5] Francesco Portaluppi and Ramón C. Hermida Mumbai. Hydroxy Propyl Methyl Cellulose K4M (HPMC K4M) and Ethyl cellulose
reported that all established determinants of cardiac arrhythmias like imbalanced auto- were procured from Loba chemie Pvt. Ltd. Mumbai and Sigma chemicals, Bangalore
nomic tone, circulating levels of catecholamines, increased heart rate and blood pressure respectively.
show circadian variations and underlie the genesis of the circadian pattern of cardiac
arrhythmias. [6] Gwen S. Skloot reported a sharp increase in the incidence of asthamatic 2.2 Formulation of rapid release core tablets (RRCT)
attacks during early morning hours. [7] Based on these findings drug delivery and therapy The rapid release core tablets were prepared using a KBr hydraulic press with suitable flat
should be modified to achieve an effective drug level at the required time. This can be punches. The core was made of the suitable mixture of powder blends of Indomethacin,
achieved by adapting a pulsatile drug delivery system of a suitable drug. Consequently, Microcrystalline Cellulose (MCC, Avicel PH-102), Croscarmellose Sodium (Ac-Di-Sol),
the administration of a drug formulated in such a delivery system, i.e. taken at bedtime and corn starch (Table 1). All above ingredients were dry blended for 20 minutes followed
with a programmed start of drug release in early morning hours, could offer a more effective by addition of Magnesium Stearate. The mixture was then further blended for 10 minutes.
therapy than a typical controlled release drug delivery system, provided that the most The 125 mg of the resultant mixture then directly compressed at a pressure of 1 ton for 1
appropriate drugs are administrated. minute using 9 mm punch and die.

Oral pulsatile administration could be useful for the treatment of certain diseases, such as 2.3 Formulation of powder blend for press – coated tablet
asthma, gastric ulcer, hypertension, ischemic heart disease, arthritis, etc., which exhibit Powder blend for press-coated tablet was prepared by dry blending together different
circadian rhythms. A pulsatile release profile is characterized by a lag time followed by compositions of the Ethylcelllose and HPMC K4M. These excipients were dry blended in
rapid and complete drug release. Most pulsatile systems are reservoir systems and different weight compositions in order to get suitable polymer composition. The compo-
usually covered with a barrier. This barrier can be dissolved, eroded or removed at a sition is given in the table 2. This composition is dry blended until uniformly blended
mixture is obtained. This mixture is then used for the preparation of press – coated tablet
using direct compression method (A1 – A6).
*Corresponding author.
2.4 Formulation of barrier layer granules for press – coated tablets
Abhijit S Moon,
Plot no. 44A Shri Laxmi Apurva Appt., A wet granulation process was used to prepare the barrier layer granules. The composi-
tions of ethylcellulose and HPMC K4M as given in the table 2 were wet granulated using
Congressnagar Nagpur. 440012
polivinylpyrrolidone (PVP, K90) as binder. 5% granulating solvent system was made by
Tel.: + 91-9975079896
E-mail:[email protected]

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 Abhijit Moon et al. / Journal of Pharmacy Research 2011,4(3),564-566
dissolving PVP into hot water by continuous stirring. The dump mass was prepared and 3. RESULTS AND DISCUSSION
passed through sieve no.18 to obtain the granules. The granules were dried in hot-air oven The pulsatile system described herein consist of two different components, the central rapid
at about 40°C for 24 hours and stored in airtight container and used as press-coating release core tablet made up of drug and other excipients and external barrier layer consisting
material to prepare press – coated pulsatile tablets (B1 – B6). of HPMC K4M and ethylcellulose. External layer consist of polymer materials and are
intended to regulate function of the system and modify the release of drug.
2.5 Preparation of press-coated tablets
The core tablets were press-coated with 300mg of powder blend/granules as given in The above system was prepared by a press – coating technique which is one of the novel
Table 3. 150mg of barrier layer material was weighed and transferred into a 13mm die then methods and has been applied for many drugs to develop the site- and/or time-controlled
the core tablet was placed manually at the centre. The remaining 150mg of the barrier layer release preparation. [11] This technique has many advantages such as short processing time
material was added into the die and compressed at a pressure of 2 tons for 1.5 minutes and limited steps, and low labour and energy requirements.
using KBr hydraulic press.
Based on the concept of chronotherapy or chronopharmacology, recent pharmaceutical
2.6 Evaluation of core and press – coated tablet investigations have focused on developing a site- or time-controlled drug delivery system for
2.6.1 Thickness: [9, 10] the treatment of various diseases. [11, 12] Drugs used for the ideal treatment of diseases should
Thickness of tablets was determined using Vernier caliper. Five tablets from batch were be administered only at the required time to maintain a therapeutic blood level. This reveals
used, and average values were calculated. that the drug release behaviour should be controlled by time rather than by rate. In order to
achieve the development of chronopharmaceutical dosage forms, the site and/ or time-
2.6.2 Average Weight: [9, 10] controlled release preparation with a designated initial lag time phase without drug release
To determine average weight, each tablet from formulation was weighed using an elec- followed by a rapid release phase should be investigated.
tronic balance (AUX-220, Shimadzu).
We have used press – coating technique to design a time-controlled disintegrating press-
2.6.3 Hardness: [9, 10] coated tablet by using ethylcellulose and HPMC K4M as an external coating shell.
The hardness was tested using Monsanto tester. The force is measured in kilograms. Ethylcellulose is used because its water insoluble behaviour along with its drug release rate
controlling property while HPMC K4M is used because of it hydrophilic, pore forming
2.6.4 Uniformity of content: nature.
The tablet from each batch was powdered individually and a quantity equivalent to 80mg
of Indomethacin was accurately weighed and dissolved in a suitable volume of 7.2 pH 3.1 Evaluation of press-coated tablets (core, direct compression and wet granulation)
phosphate buffer. After making suitable dilutions the final solution was analyzed spectro- The following tables shows the results of the evaluation of the core, direct compression and
photometrically at 320 nm. wet granulated tablets (table no. 4, 5, and 6 respectively).

2.6.5 Friability: [9, 10] Table 4: Evaluation of core tablet

For each formulation, the friability of 6 tablets was determined using the Roche friabilator
Parameter Observation
(Lab Hosp.).
Thickness 0.15 ± 0.015 cm
2.7 In vitro drug release study of press – coated tablets Hardness 2.30 ± 0.25 kg/cm2
Average Weight 124.21 mg
In-vitro dissolution studies were performed on the press-coated tablets prepared by direct Friability (%) 0.7612 (%) ± 0.14
compression method, and wet granulation method (5%PVP) at 370 ± 0.5 °C using 7.2 pH
phosphate buffer in USP apparatus II with the paddle speed 100 rpm. 5 ml of filtered Table 5: Evaluation press-coated tablets (direct compression)
aliquot was withdrawn at pre-determined time intervals and replaced with 5 ml of fresh 7.2
pH phosphate buffer solution maintained at the same temperature. The samples were Batch Average Hardness Thickness Friability Drug
Weight (mg) Kg/cm2 (cm) % content %
analysed at 320 nm using a UV spectrophotometer. The lag time and percentage release
was determined for the each formulation. B1 425.15 10.70 ± 1.25 0.308 ± 0.14 0.624 ± 0.25 99.23
B2 424.26 10.90 ± 1.41 0.311 ± 0.12 0.728 ± 0.15 99.17
B3 423.11 10.31 ± 2.12 0.307 ± 0.14 0.752 ± 0.14 98.64
2.7 Stability Study B4 426.31 10.51 ± 2.30 0.310 ± 0.12 0.851 ± 0.12 98.45
After determining the drug content, the optimized batches of tablet were monitored up to B5 425.82 9.24 ± 1.14 0.304 ± 0.14 0.898 ± 0.13 98.69
1 month at accelerated stability conditions of temperature and relative humidity (400 ± 20C B6 423.52 9.23 ± 1.33 0.302 ± 0.13 0.925 ± 0.23 99.56
/75%± 5%RH). Samples were withdrawn after one month and characterized for Appear-
ance, Weight, Thickness, Hardness, drug content, drug release.The choice of appropriate Table 6: Evaluation press-coated tablets (5 %PVP)
storage condition during accelerated stability study is necessary to predict the long term Batch Average Hardness Thickness Friability Drug
stability of Indomethacin tablet. The humidity during storage is also extremely impor- Weight (mg) Kg/cm2 (cm) % Content (%)
tant, considering the hygroscopic nature of hydrophilic polymers. A1 425.10 9.95 ±1.81 0.311 ±0.10 0.7233 ±0.20 98.69
A2 424.98 9.98 ±1.21 0.309 ±0.11 0.6442 ±0.14 99.23
Therefore for the present study, accelerated temperature and relative humidity (400 ± 20C / A3 424.26 9.61 ± 1.31 0.307 ±0.14 0.6923 ±0.14 98.15
75%± 5%RH) were selected during stability. A4 426.12 8.92 ± 1.24 0.301 ±0.10 0.7466 ±0.16 99.71
A5 425.22 9.42 ± 2.36 0.306 ±0.10 0.7154 ±0.18 98.64
Table 1: Composition of core tablet A6 425.00 10.30 ± 2.25 0.308 ±0.12 0.7341 ±0.13 98.45
Ingredients Quantity

Indomethacin 80 mg 3.2 In vitro dissolution of press-coated tablets

Microcrystalline Cellulose (MCC, Avicel PH-102) 30 mg Ethylcellulose (EC) is a well-known water-insoluble polymer that has long been used as a
Cross-carmellose Sodium (Ac-Di-Sol) 2 mg
rate-controlling membrane in medication dosage forms to regulate drug release. This
Starch 12 mg
Magnesium Stearate 1 mg function can be further and effectively controlled by the amount of external shell used, and the
Total weight of tablet 125 mg excipients added to the external shell. One of the purpose of this study was to investigate the
influence of the type and amount of excipients mixed with EC powder in the external shell
Table 2: Formulation composition for press-coating material on the time-lag and time-controlled disintegrating or rupturing function of press-coated
Direct compression Wet granulation HPMC K4M (%) Ethylcellulose (%) tablets. For this we added hydrophilic polymer hydroxy propyl methyl cellulose K4M
batches batches (HPMC) to the EC in the external shell. HPMC belonging to a water-soluble polymer with
the viscous property of gelation might delay the tablet disintegration.
A1 B1 25 75
A2 B2 33.33 66.66
A3 B3 41.66 58.33 All press-coated tablets showed pulsatile release behaviour with distinct lag time. Fig 1and
A4 B4 50 50 2 shows the dissolution profile of the press-coated tablets. The profiles clearly indicate that
A5 B5 58.33 41.66
A6 B6 66.66 33.33 Indomethacin released from the press-coated tablet exhibited a unique release profile, de-
pending on the amount of HPMC/EC used. This profile was composed of an induction
Table 3: Formulation of press – coated tablet (425 mg) DB: Dry blend, G: Granules period (time lag) followed by a rapid release phase. The drug was rapidly and completely
EC: Ethyl cellulose, HPMC K4M: Hydroxy propyl methyl cellulose released from the press-coated tablet after a lag period of several hours in the initial drug
HPMC K4M : EC % ratio DB/G 25:75 33.33:66.66 41.66:58.33 50:50 58.33: 41.66 66.66:33.33 delivery profile, depending on the weight ratios of EC and HPMC. After the lag time is over
the external shell of the press-coated tablet directly ruptured or broke into 2 halves to permit
DB :Core tablet300mg : 125mg A1 Tab A2 Tab A3 Tab A4 Tab A5 Tab A6 Tab rapid drug release. The sudden splitting of the outer shell of press-coated tablets after the lag
G :Core tablet 300mg : 125mg B1 Tab B2 Tab B3 Tab B4 Tab B5 Tab B6 Tab period is a key factor to achieve the time-controlled delivery. The drug was immediately

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 Abhijit Moon et al. / Journal of Pharmacy Research 2011,4(3),564-566
released from a core tablet after rupturing the surrounding outer shell, caused by a pressure RH 75% ± 5%) (Table No 7). There was little bit but no large difference was observed in the
build-up within the core system. evaluation of the optimized batch. The dissolution study of the optimized batch at zero
month and one month show some changes in drug release profile (Fig. 3). Both the
Press coated tablets A1Tab-A6Tab formulations showed distinct lag time as given Fig. 1. It dissolution study show the typical pulsatile profile but drug release was somewhat decrease.
showed that lag time decreases with increasing concentration of HPMC K4M.
Ethylcellulose(EC) is semipermiable but naturally insoluble in water. When HPMC K4M Table 7: Different Parameters of stability study
was in low concentration in the formulation its hydration property was retarded by the EC.
Parameter At Temp. 400 ± 20 C RH 75% ± 5%
When the concentration of hydrophilic polymer was increased i.e. HPMC K4M, hydration
A4 A4
property of the system increases causing more rapid dissolution or rupturing of the external
Zero month One month
shell resulting in the reduction in lag time. Thus the dissolution or rupturing of the external Appreance Off white Off white
layer depends on the composition of the formulation which determines the lag time. HPMC Weight (mg) 424.91 424.85
K4M was responsible for the rapid dissolution or rupturing of the external layer as character- Thickness (mm) 0.309 ± 0.12 0.309 ± 0.05
istics of such hydrophilic material is to absorb water and then swelling therefore when Hardness (Kg/cm2 ) 10.41 ± 2.12 10.20 ± 0.21
concentration of HPMC K4M was increased lag time decreases. % Drug content 99.22 ± 0.245 98.23 ± 0.87

Press coated tablets B1Tab-B6Tab formulations (wet granulation) showed distinct lag time 120
as given in Fig. 2. Here also the difference in lag time was because of the different concentra-
tion HPMC K4M and EC. But here in case of the wet granulation lag time was less as 100
compared to the direct compression batches. This might be because of wet granulation and

% Drug Release
use of PVP which increases the dissolution rate of formulation when used as wet binder as 80
compared to direct compression. The PVP which is used in wet granulation method is
hydrophilic in nature which achieves rapid hydration leads to rapid penetration of dissolu- 60
Zero month
tion medium through outer barrier layer as compared with dry mixing method.
40
One month
120.000
Cumulative % Drug Release

20
100.000
BATCH B1 0
80.000
BATCH B2 -20 0 2 4 6 8 10
60.000 Time (hrs)
BATCH B3
40.000
BATCH B4
20.000 Fig 3: In vitro drug release study of optimized batch zero month and one
BATCH B5
month
0.000 BATCH B6
0 2 4 6 8 10 ACKNOWLEDGMENT
-20.000
Time (hrs) The authors are thankful to cipla pharma kurkumbh for providing Indomethacin, to Fine
Chem Industries for providing polivinylpyrrolidone (PVP, K90) as gift samples.
Fig. 1. In vitro drug release of Indomethacin for tablets prepared by dry blend.
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Source of support: Nil, Conflict of interest: None Declared

Journal of Pharmacy Research Vol.4.Issue 3. March 2011 564-566