Development and Evaluation of Press Coated Time-Release Tablet of Nifedipine

Sarfaraz Md.*, Prasad Y., Reddy S.R., Doddayya H. and Udupi R.H.

Department of Pharmaceutics, N.E.T Pharmacy College, Mantralayam Road, Raichur-584103, Karnataka, India

*Corresponding Author E-mail: Sarfindia@gmail.com

ABSTRACT:

The aim of the study was to develop press coated time release tablets of nifedipine, from which the drug is released in a controlled manner to suite the Chronotherapeutics of the disease i.e., hypertension. The tablets, each consisting of a core and a coat, were prepared using compression coating technique. Core tablet was immediate-release formulation containing nifedipine soild dispersion of 1: 2 ratio with mannitol to enhance its solubility. The core tablet was then coated with a mixture of rate controlling polymers like polyethylene glycol (PEG6000) and hydroxyl propyl methyl cellulose (HPMC K100M) in different ratios to produce time release tablets of nifedipine. The core and press-coated tablets were evaluated for their physico-chemical properties, in-vitro release and stability studies. The in vitro drug release pattern indicated that type of polymer and its concentration had marked influence on the drug release from tablets. The drug release decreased with increasing amounts of HPMC K100M in the formulation. A lag time of 2 to 6 hrs was achieved with the polymers used. 2% sodium lauryl sulphate (SLS) was added as dissolution enhancer for dissolution study. The mechanism of drug release from all the press-coated tablets followed Higuchi model release kinetics with r² value 0.983 to 0.997. FT-IR and DSC studies revealed no chemical interaction between drug and polymers used.

KEYWORDS: Chronopharmacotherapy; Nifedipine; Time-release; Press-coated tablets; Lag time

INTRODUCTION:

Timed-release formulations are designed to release a drug at a predetermined time (the lag time) after administration. Orally administered timed-release dosage forms have been widely investigated for use in chronopharmacologic therapy, in site-specific drug delivery, in peptide drug absorption enhancement, and in avoiding pharmacokinetic drug–drug interactions¹. However, timed-release dosage forms often have poor bioavailability compared to immediate-release conventional dosage forms. This effect is thought to result from poor dissolution and absorption of the drug in the lower gastrointestinal (GI) tract, most commonly the ileum and the colon². Several timed-release technologies have been described.

These include use of a rupturable coating that surrounds multiple pellets loaded with the drug³; a compression-coated soluble barrier that erodes, surrounding a single unit-core tablet containing the drug^4,
5; and a swellable hydrogel plug which dislodges when swollen, set into a water-insoluble capsule body filled with the drug^{6, 7}of these formulations, compression-coated tablets are among the simplest to manufacture. Compression-coated tablets are composed of an inner core that contains an active pharmaceutical ingredient surrounded by an outer layer that slowly dissolves or disintegrates to make a lag time of drug release. A time-release formulation could allow drug release and a greater plasma drug concentration at the point in the circadian cycle when clinical signs develop or increase. Drugs that treat cardiovascular disease and asthma have been investigated for the chronopharmacotherapy⁸. Nifedipine is a dihydropyridine calcium channel blocker widely used in clinical practice to treat hypertension.

In this study, nifedipine was used as a model drug. The main objective of the study was to develop a time controlled release formulation based on a press-coating technique using rate controlling polymers. The intention was to maintain a lag time of 3 – 5 hrs, as the symptoms of hypertension are experienced in the early morning hours. The incorporation of drug as an immediate release formulation in the core is proposed to provide the drug to the patient at the right time of hypertensive attack.

MATERIALS AND METHODS:

Nifedipine was received as gift sample by Cipla Pvt Ltd., Kurkumbh Daund. Hydroxypropyl methyl cellulose was generously donated by Yasham Bio-Science Pvt. Ltd, Mumbai; Indion 414 was obtained as a gift sample from Ion-Exchange resin of India, Mumbai. Microcrystalline Cellulose was obtained as a gift sample from Asahi-Kasei Chemicals, Japan. All other chemicals/solvents used were of analytical grade.

Preparation of tablets:

Time release press-coated tablets consist of core tablet and coat layer.

1. Preparation of core tablet^9,10:

Core tablet were prepared by using solid dispersion of nifedipine; solid dispersion of nifedipine were prepared due to its low solubility and light sensitive nature. Solid dispersion containing nifedipine: mannitol (1:2) ratio was prepared by hot melt method. The obtained physical mixture was heated on heater at 175⁰C until they melted. Solidification was done by cooling to room temperature under ambient conditions. Afterwards, the mixture was pulverised, sieved, and the fraction ≤160µm was selected. The inner core tablets were prepared by using direct compression method. As shown in Table 1, powder mixtures of solid dispersion of nifedipine, microcrystalline cellulose (MCC, Avicel PH-102) and Indion 414 ingredients were dry blended for 20 minutes, followed by addition of magnesium stearate as lubricant. The mixtures were then further blended for 10 minutes. 100mg of resultant powder blend was compressed on 10 station rotary tablet machine (RIMEK Mini Tablet Press) using 6 mm flat punch.

2. Preparation of coat layer⁹:

The coat layer consists of PEG 6000 and HPMC K100M in different ratio as shown in Table 1. The mixture of HPMC K100M and PEG 6000 was passed through a sieve #80 and then thoroughly mixed in a bottle using tumbling method for a period of 10 minutes, 150 mg of resulting mixture of powder was used for the outer coat.

3. Preparation of press-coated tablets⁹:

The coat layer (powder mixture) of 150 mg obtained from different polymeric mixtures of different ratios was divided in to two fractions, each 75 mg to act as upper and lower coat. The press coating of tablets was performed using a rotary tablet machine (RIMEK Mini Tablet Press). A half amount of the powder (lower coat) was filled into the die to make a powder bed, in the centre of which core tablet was placed manually. Then, the remaining half of the coating material filled in the die (upper coat), and the contents were compressed under a sufficient compression force, using a flat punch 8 mm in diameter.

EVALUATION:

a) Micromeritic properties¹¹:

Flowability of the pure drug, solid dispersion and precompression mixture of core tablet was performed by measuring the angle of repose by fixed funnel method. A measured amount of the powder was allowed to flow through the funnel fixed at a constant height (h=2.5 cm) and mean diameter (2r) of the powder pile was measured to calculate the angle of repose as q = tan^-1 h/r. The loose bulk density (LBD) and tapped bulk density (TBD) of pure drug nifedipine, solid dispersion and precompression mixtures were determined using bulk density apparatus (Electro Lab, India) from 3 independent analyses. Carr`s index and Hausner`s ratio were calculated using LBD and TBD values.

b) Hardness¹²:

Monsanto hardness tester was used for the determination of the hardness. The tablet to be tested was held between a fixed and a moving jaw and reading of the indicator adjusted to zero. The force applied to the edge of the tablet was gradually increased by moving the screw knob forward until the tablet breaks. The reading was noted from the scale which indicates the pressure required in kg or lb to break tablets.

c) Uniformity of thickness:

The crown-to-crown thicknesses of 10 tablets from each batch were determined using vernier calipers. The thickness variation limits allowed are ± 5% of the size of the tablet (IP).

d) Friability¹¹:

Friability of the tablets was determined using Roche friabilator (Electro lab, Mumbai). This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inches in each revolution. Preweighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were dedusted using a soft muslin cloth and reweighed. The friability (F) is given by the formula:

F = (1- W₀/ W) × 100

Where, W₀ is the weight of the tablets before the test a

W is the weight of the tablet after the test.

e) Weight variation¹³:

Twenty tablets were randomly selected from each batch and weighed individually. The average weight and standard deviation was calculated.

f) Uniformity of drug content¹⁴:

For determination of drug content five tablets from each formulation were weighed individually, crushed and diluted to 100 ml with sufficient amount of phosphate buffer of pH 7.2. Then aliquot of the filtrate was diluted suitably and analyzed spectrophotometrically at 341 nm against blank.

Table 1: Composition of press-coated time release tablets of nifedipine

Formulation code	CORE PART (100 mg)				COAT LAYER (150 mg)
Formulation code	Nifedipine solid dispersion (mg)	Mcc (mg)	Indion 414 (mg)	Mg. stearate (mg)	PEG 6000 (mg)	HPMC K100M (mg)
F1	88	10	1	1	135	15
F2	88	10	1	1	120	30
F3	88	10	1	1	105	45
F4	88	10	1	1	90	60

g) Dissolution studies:

The dissolution study of core tablet was carried out in acid buffer pH 1.2 and pH 7.2 phosphate buffer in presence of 2% SLS, as dissolution enhancer. Further after coating, the prepared time release press-coated tablets were also subjected to in-vitro dissolution studies. In both cases 8 station USP dissolution apparatus (Electro Lab, TDT-O8L, Mumbai) was used. The dissolution studies of press coated tablets was carried out in acid buffer of pH 1.2 with 2% sodium lauryl sulphate for 2 hrs and in phosphate buffer of pH 7.2 with 2% sodium lauryl sulphate for next 10 hrs at 37± 0.5⁰ C and 75 rpm. At regular time interval, 5 ml of sample was withdrawn from the dissolution medium and replaced with equal volume of fresh medium. After filtration and appropriate dilution, the samples were analyzed at 341 nm for nifedipine against blank using UV-Visible spectrophotometer. The amount of drug present in the samples was calculated using standard curve. During the dissolution study the whole apparatus was shielded from light to prevent degradation of nifedipine.

h) FT-IR Study:

The compatibility between drug and polymer was detected by IR spectra obtained on Shimadzu 8400, Japan made. The pellets were prepared on KBr-press. The spectra were recorded over the wave number range of 4000 to 500 cm-1.

i) DSC Study:

Thermogram were obtained by using a differential scanning calorimeter (DSC Q20 V24.4 Build 116, Japan) at a heating rate of 100C/min over a temperature range of 35-3000 ºC. The sample was hermetically sealed in an aluminum crucible. Nitrogen gas was purged at the rate of 10 ml/min for maintaining inert atmosphere.

j) Stability studies¹⁵:

The stability study of the selected formulations was carried out according to ICH guidelines at 40±2oC/75±5% RH for one month by storing the samples in stability chamber (Lab-care, Mumbai).

RESULT AND DISCUSSION:

Table 2: Micromeritic properties of drug and core tablet

	*Angle of repose (θ)**	*Carr’s Index (%)**	Hausner’s *ratio(%)**
Nifedipine	52.16 ± 0.28	23.54 ± 0.25	1.42 ± 0.02
Nifedipine solid dispersion	38.98±0.84	21.32±0.15	1.07 ± 0.01
Core tablet	30.15± 0.12	16.29±0.12	1.14± 0.03

*Average of 3 determinations.

Micromeritic properties:

The pure drug nifedipine showed angle of repose value of 52.16º indicating poor flow properties. The flow property was improved in the form of solid dispersion with a value of 38.98º. It was further promoted to good flow range by addition of lubricants in the precompression mixture as shown by the angle of repose value of 30.15º. Table 2.

Physico Chemical evaluation of nifedipine press coated tablet:

In order to avoid the effect of tablet hardness and thickness on in vitro drug release, these two parameters have been maintained at specific values i.e. hardness at about 2-3 kg/cm² and thickness at about 1.15±0.02 mm for core tablet to maintain its physical strength while placing core tablet manually on centre of lower bed. The results of physicochemical evaluation of tablets are given in Table 3. The press-coated tablets of nifedipine were found uniform with respect to hardness (4.3± 0.35 to 4.9± 0.28 kg/cm²) and thickness (3.92±0.04 to 4.34± 0.03 mm). The hardness of the tablets with different polymer concentration was adjusted accordingly to proper lag time. The friability (0.41± 0.01 to 0.60± 0.03%) and weight variation (0.84±0.16 to 1.28±0.65%) of tablets were found within prescribed limits. Drug content for core tablet was found to be (95.65%) and it ranged from (91.17± 0.49 to 94.23± 0.16%) for press coated tablets. Some loss in drug content of press-coated tablets than in core tablet was probably due to very light sensitive nature of drug molecule. Hence core tablets containing drug and press coated tablets of core could be prepared satisfactorily by direct compression method.

In vitro release study:

The in vitro release of nifedipine from core tablet was 82.12% and 89.52% in pH 1.2 and pH 7.2 phosphate buffer respectively in 10 minutes, revealing more drug is released in the alkaline pH (Fig. 1). Dissolution of nifedipine from press coated tablets was studied in the presence and absence of dissolution enhancer 2% SLS. The findings showed that incorporation of 2% SLS in the dissolution medium improved the dissolution of nifedipine, as indicated in Fig. 2. The press coated tablet F2 released 78.28% with 2% SLS and 64.57% without SLS. Hence for further studies dissolution medium with 2% SLS was used for all other formulations. The press coated tablets of nifedipine showed lag time that ranged from 2 to 6 hrs (F1 to F4). As the amount of HPMC K100M increases in the formulation, the lag time also increases due to formation of a viscous gel around the core tablet.

Table 3: Physico-chemical evaluation of press-coated time release tablets of nifedipine

Code	Hardness⁺(kg/cm²)	Thickness^†(mm)	Friability^†(%)	*Weight variation (%)**	Drug content^ (%)**
Core tablet	2.5± 0.33	1.15±0.02	0.87±0.12	0.89±.15	95.65± 0.13
F1	4.6± 0.30	3.92±0.04	0.60± 0.03	1.10±0.48	92.55± 0.21
F2	4.9± 0.28	4.03±0.02	0.43± 0.06	1.28±0.65	94.23± 0.16
F3	4.3± 0.35	4.07±0.03	0.41± 0.01	1.15±0.75	92.93± 0.38
F4	4.6± 0.40	4.34± 0.03	0.46± 0.04	0.84±0.16	91.17± 0.49

All values are expressed as mean SD±⁺n=6, ^†n=10, ^*n=20, ^**n=3.

FTIR Studies:

The FT-IR spectra of pure drug, core tablet and optimized formulation (F2) were taken for the characterization studies. The data indicated that the IR spectra of above formulations had got lot of similarity with IR spectra of pure drug. Further it was also clear from the spectra that the change in position of characteristic bands of the drug molecule was negligible and was within limit of the absorption range. Hence it could be viewed that no appreciable change had taken place in characteristics of the pure drug in each formulation. (Fig. 4 - 6)

DSC Studies:

DSC thermogram study was performed for further establishing characterization of the formulation. The thermogram for pure drug and optimized formulation F2 were taken. (Fig. 7 and 8). The thermogram of pure drug showed an endothermic peak at 168 ºC corresponding to melting point of drug. The literature survey of drug profile indicated that the drug has melting range of 168 – 174 ºC. The DSC thermogram of formulation F2 was almost similar in appearance and the endothermic peak indicated melting point at 167.29 ºC. The thermograms did not indicate worth mentioning difference in melting points, suggesting that drug has almost same melting point in its formulation. Hence it was concluded that drug had not interacted with the polymer.

Fig 7: DSC thermogram of nifedipine pure drug

Fig 8: DSC thermogram of Formulation F2

CONCLUSION:

Press coated time release tablets of nifedipine can be obtained using direct compression technique. Solid dispersion of nifedipine using mannitol improved the solubility of drug. HPMC K100M and PEG 6000 mixture provide sufficient lag time for timed release of nifedipine useful for chronopharmacotherapy of hypertension. The results of in vitro dissolution tests indicate that amount of polymer in the formulation affects the drug release rate. These results also show that the in vitro lag time before drug release could be used to predict the in vivo lag time of drug release. Thus, press coated time-release formulations that control the plasma drug concentrations by design show promise as timed release drug delivery systems.

ACKNOWLEDGEMENT:

The authors are grateful to Cipla Pvt Ltd., Kurkumbh Daund, India for providing gift sample of nifedipine. The authors would like to acknowledge the Principal, N.E.T Pharmacy College, Raichur, India for providing facilities during research.

REFERENCES:

1. Sawada T et al. A new index, the core erosion ratio of compression-coated timed-release tablets predicts the bioavailability of acetaminophen. International Journal of Pharmaceutics. 265; 2003: 55-63.

2. Sako K et al. Relationship between gelation rate of controlled-release acetaminophen tablets containing polyethylene oxide and colonic drug release in dogs. Pharmaceutical Research. 13; 1996: 594-98.

3. Ueda Y et al. Development of a novel drug release system, time-controlled explosion system (TES). I. Concept and design. Journal of Drug Targetting. 2; 1994: 35-44.

4. Conte U et al. Press-coated tablets for time-programmed release of drugs. Biomaterials. 14; 1993: 1017-23.

5. Gazzaniga A et al. Oral delayed-release system for colonic specific delivery. International Journal of Pharmaceutics. 2; 1994: 77-83.

6. Wilding IR, Davis S S, Bakhshaee M, Stevens HNE, Sparrow RA and Brennan, J. Gastrointestinal transit and systemic absorption of captopril from a pulsed-release formulation. Pharmaceutical Research. 9; 1992: 654-57.

7. Krogel I and Bodmeier R. Pulsatile drug release from an insoluble capsule body controlled by an erodible plug. Pharmaceutical Research. 15; 1998: 474-81.

8. Lemmer B. Circadian rhythms and drug delivery. Journal of Controlled Release. 1991; 16: 63-74.

9. Kulkarni PA, Jaiswal M, Jawale SB, Shirolkar SV, Kasture PV. Development and evaluation of press coated tablets for chronopharmaceutical drug delivery using gellable and permeable polymers. Der Pharmacia Lettre. 2010; 2(4): 482-97

10. Zajc N, Obreza A, Beleb M, Srcic S. Physical properties and dissolution behaviour of nifedipine/mannitol solid dispersions prepared by hot melt method. International Journal of Pharmaceutics. 2005; 291: 51–58.

11. Lieberman HA, Lachman L and Schwartz JB. Pharmaceutical dosage forms: Tablets. Marcel Dekker, New York. 1990: 201- 43.

12. Gupta AK. Introduction to pharmaceutics. CBS Publications, New Delhi. 1993.

13. Lakade SH, Bhalekar MR. Formulation and evaluation of sustained release matrix tablets of anti-anginal drug, influence of combination of hydrophobic and hydrophilic matrix former. Research Journal of Pharmacy and Technology. 2008; 1(4): 410-13.

14. Mohsin AA, Nimbalakr NE, Sanaullah S, Aejaz A. Formulation and evaluation of mouth dissolving tablets of amitryptyline hydrochloride by direct compression technique. International Journal of Pharmacy and Pharmaceutical Sciences. 2010; 2(1): 204-10.

15. Costa P, Lobo JMS. Divisability of diltiazem matrix sustained release tablets. Pharmaceutical Development and Technology. 2001; 6 (3): 343-51.

Received on 25.07.2011 Accepted on 06.08.2011

Asian J. Pharm. Res. 1(3): July-Sept. 2011; Page 58-63