Formulation and Evaluation of Press-Coated Tablets of Tramadol

 

Nikunja B. Pati^*, Dr. V R M Gupta, Swapna Velivela

Pulla Reddy Institute of Pharmacy, Domadugu, Gummadidala, Sangareddy-502313.

 

ABSTRACT:

Press coated tablets have been proposed to achieve release of drug after a desired lag period. These are formulated with intention to be used mainly in the therapy of those diseases and symptoms which depend on circadian rhythms. A core formulation containing Tramadol as model drug is coated by compression with different polymeric barrier layers (press-coated systems) in different weight ratios. The core serves as reservoir, and the barrier layer surrounding it protect and avoids the core from releasing drug during the lag phase. The coatings erode/dissolve, rupture at the required time. The dissolution profiles of uncoated cores and press-coated devices were compared. The coating is expected to prevent drug release from the core until the polymeric shell is completely eroded or swollen. Nine formulations were prepared and evaluated for various parameters. The effect of the erodible barrier can be modified by use of swellable polymeric shell. It can be concluded from the study that press coated based pulsatile release formulations are suitable for Tramadol. Formulation F4 possessed good lag time of nearly 5hrs and showed pulsatile drug delivery pattern. Based on the results, desired delivery of Tramadol could be achieved using 60% w/w (F4) tablets compressed coated with L-Hydroxy Propyl Cellulose.

 

 

 

INTRODUCTION:

The goal in drug delivery research is to develop formulations that meet therapeutic needs relating to particular pathological conditions^[1]. Research in chronotherapeutics field has demonstrated the importance of biological rhythms in drug therapy. According to this, if the symptoms of disease display circadian variations, drug release should also follow time. Variations in physiological and pathophysiological functions in time, and need for variations of drug plasma concentration has brought a new approach to the development of drug delivery systems- chronopharmaceutical drug delivery^[2].

 

In chronopharmacotherapy, drug administration is synchronized with circadian rhythms^[3]. If the peak of symptoms occurs at daytime, a conventional dosage forms can be administrated just before the symptoms are worsening.

 

If symptoms of the disease became worse during the night or in the early morning, the timing of drug administration and nature of the drug delivery system needs careful consideration. In this case, modified-release dosage forms must be used^[4].

 

These systems are beneficial for the drugs having chronopharmacological behaviour (where night time dosing is required), first-pass effect and having specific site of absorption in gastro intestinal tract (GIT)^[5].

 

Conventional slow-release (SR) medications are formulated to ensure a near-constant drug concentration^[6,7]. From the viewpoint of therapeutic optimization, maintaining a constant blood level for a drug in the human body is questionable. Long-term constant drug concentration exposed in blood and tissues may induce many problems such as tolerance of drug and activation of physiological system^[8]. Recently, chronotherapy has been extensively applied in clinical therapy by modulating the dosing regimen of drug administration according to physiological needs^[9]. Chronotherapy of a medication may be accomplished by the appropriate timing of conventionally formulated tablets and capsules and a drug-delivery system to synchronize drug concentrations to rhythms in disease activity. Diseases wherein PDDS are promising include asthma, peptic ulcer, cardiovascular diseases, arthritis, and hypercholesterolemia^[10]. The pathophysiology of arthritis and patients with osteoarthritis tend to have less pain in the morning but more at night; while those with rheumatoid arthritis, have pain that usually peaks in the morning and decreases throughout the day^[11]. In the present work, we examined the drug Tramadol HCl is a synthetic centrally acting aminocyclohexal analgesic that acts as an opioid agonist with selectivity for μ receptor have demonstrated that this drug is an effective agent for moderate to severe pain. Most of the water soluble drug containing formulations release the drug at a faster rate and likely to produce toxic concentrations of the drug on oral administration^[12].

 

Tramadol HCl is a highly water soluble and permeable drug belonging to BCS class I and likely to prove toxic at the given concentrations. The dose of Tramadol HCl is 50-100 mg daily by oral route in divided doses. Tramadol is available in both immediate and extended release dosage forms in the market^[13]. It requires dosing every 5 hours in order to maintain optimal relief of chronic pain. Tramadol HCl is used in the management of moderate to severe chronic pain and neuropathic pain^[14,15] including treating rheumatoid arthritis^[16], showing proofs of circadian rhythms and peak symptoms in the early morning. It has good oral bioavailability and good absorption throughout the GIT. To provide sufficient lag phase, retarding the drug release for the treatment of rheumatoid arthritis, this approach was selected. In case of conventional formulation, it was difficult to achieve the desired clinical effect, because it elicited patient's incompliance of administration in the early morning to coordinate the rhythm of rheumatoid arthritis, due to rapid absorption of the conventional formulation as it is having a half-life of ≈5.5 h^[17,18].

 

MATERIALS:

Tramadol hydrochloride was procured from MSN labs Hyd. L-HPC (Hydroxy propyl cellulose) sample was procured from Agilent Pharma. Other chemicals were purchased from Himedia, Mumbai and were of analytical grade. PVP, Microcrystalline cellulose, Lactose were obtained from SD Fine Chem Ltd., Mumbai.

 

METHODS:

Drug Excipients Compatibility Study:

The pure drug, mixture of optimized formulation, physical mixture of coating material and drug and core tablet mixture were subjected to IR spectroscopy using FT-IR spectrophotometer (IR Affinity-1, Shimadzu). Their spectra were obtained over the wave number range of 4000 – 400 cm^-1.

 

Preparation of Core Tablet containing drug:

The core tablets of Tramadol HCl were prepared by direct compression technique. Different core tablets were prepared and the best composition was chosen based on evaluation parameters for this study. The selected core tablets contained 50 mg of drug, 13 mg of Lactose, 10 mg of Polyox 303 WSR, 5 mg PVP and 2 mg of magnesium stearate.

 

Firstly Drug, Polyox and PVP were mixed thoroughly. Lactose and magnesium stearate was added and mixed uniformly. Powder was compressed into 5-mm flat tablets with use of a single station tablet machine (Remi Mini Press, Ahemdabad, India). The core tablets were evaluated for hardness, thickness, content uniformity, friability and disintegration.

 

Preparation of Compression-Coated Tablets:

On compliance with the above mentioned tests, the core tablets were compression coated with different weight ratios (w/w) of hydrophobic erodible polymer blend. Initially 50% of the coat powder (hydrophobic erodible polymer blend) was placed in the die cavity then, the core tablet was carefully positioned at the centre of the die cavity which was filled with the remainder of the coat powder. It was then compressed around the core tablet by using 10-mm round, flat, plain punches at pressure of 175 kg/cm². Formulations of press coated tablet were shown in Table 1. The press coated tablets were further evaluated for hardness, thickness, content uniformity, friability and disintegration and lag time.

 

Table no. 1: Formulations of press coated tablets:

	F1	F2	F3	F4	F5	F6	F7	F8	F9
Core tablet (mgs)
Drug	50	50	50	50	50	50	50	50	50
Polyox	10	10	10	10	10	10	10	10	10
Lactose	15	15	15	15	15	15	15	15	15
PVP	5	5	5	5	5	5	5	5	5
Mg St.	2	2	2	2	2	2	2	2	2
Coat powder (mgs x 2)
EC	50	---	---	75	---	---	100	---	---
E S100	---	50	---	---	75	---	---	100	---
L-HPC	---	---	50	---	---	75	---	---	100
MCC	10	10	10	10	10	10	10	10	10
HPMC K100	15	15	15	15	15	15	15	15	15
NaHCO3	10	10	10	10	10	10	10	10	10

 

Drug Content of Core Tablet:

The core tablet was finely powdered and quantity of the powder equivalent to 10 mg of drug was accurately weighed and transferred to volumetric flask containing 100 ml of 0.1N HCl and mixed thoroughly. One milliliter of filtrate with suitable dilution was estimated for drug content at 271 nm using double beam spectrophotometer (Shimadzu Corporation, Japan, UV-1700).

 

Characterization of Core and Press Coated Tablet:

All the pre and post compression parameters were evaluated for both core and press coated tablets as per the pharmacopoeial standards. The evaluated pre compression parameters were angle of repose, bulk and tapped density, compressibility index (Carr’s index) and Hausner’s ratio. The post compression parameters evaluated for both core and press coated tablets were thickness, hardness and uniformity of weight. The core tablets were specifically evaluated for disintegration time and drug content (assay) whereas the press coated tablets was assessed for percentage friability. All tablet parameters were complied with Pharmacopoeial standards and the results are expressed as mean ± standard deviation, given in Tables.

 

Dissolution study performed for core tablets:

Drug dissolution rate was studied by using USP XXIII dissolution test (USP type-II Apparatus, Lab India DS 8000). The dissolution bath was maintained at 37°C ± 0.5°C at 50 rotations per minute (RPM). Samples of 5 ml were withdrawn from dissolution medium at predetermined intervals and replaced with same volume of fresh dissolution media. For core tablets, dissolution study was carried out for 8 hrs. For press coated tablets it was carried out for 12hrs. The samples were assayed for drug content by measuring the absorbance at 276 nm using UV-Visible spectrophotometer (PG Analyticals-T60).

 

RESULTS AND DISCUSSION:

Drug excipient compatibility:

Drug and excipient compatibility was confirmed by comparing spectra of FTIR analysis of pure drug with that of excipients used in the formulation. It was found that there was no chemical interaction between the drug and the excipients used as; there were no changes in the characteristic peaks of drug in the IR spectra of mixture of the drug and excipients as compared to IR spectra of pure drug.

 

The IR spectrum of the pure drug and drug in the optimized formulation has been tabulated in Table no. 2 and shown in the Figure no. 1 and 2. IR studies have shown no interaction between drug and excipients.

 

Table no. 2: FTIR scan data for drug in pure state and in formulation:

FTIR peaks	Wavenumber (cm-1)
	O-H stret.	C=C aromatic stret.	O-H bend.	C-N stret.	C-O stret.
Pure Drug	3306.03	1606.65	1409.44	1288.49	1242.20
Formulation	3412.08	1606.65	1383.97	1289.46	1243.42

 

 

 

Figure no. 1: FTIR scan of pure drug

 

 

Figure no. 2: FTIR scan of drug in the optimized formulation

Pre-compression characterization:

Core tablet blend:

The flow properties of the optimized core formulation blend are shown in the Table 3. The results obtained for angle of repose (θ) was 28.565° which fall within the official range for good flow i.e. <30^º. Therefore, the blend has good flow property.

 

The bulk and tapped density of core tablet blend were 1.72 gm/cc and 1.44 gm/cc respectively. Carr’s index calculated was found to be 18.06% indicating that the blend has a good flow property. Whereas, Hausner’s ratio analysed was 1.19 representing a good flow.

 

Table no. 3: Pre-compression study results for core tablet blend:

Bulk density	Tapped density	Angle of Repose	Carr’s Index	Hausner’s Ratio
1.72 g/cc	1.44 g/cc	26.565°	18.06%	1.19

 

Post-compression characterization of core tablets:

All the evaluated parameters performed for core tablets are shown in the Table no. 4. The hardness of core tablets was nearly 2.5 kg/cm², therefore ensuring appropriate strength. The thickness observed was 3.5 mm and is even for all tablets. All the (80 mg) tablets selected from passed uniformity of weight test prescribed in IP. The individual weight of different batch tablets was within the official limits (±10%) of % deviation from average weight. The disintegration time of core tablet was nearly 8 min 13 sec. The % drug content of all the core tablets 98.05 ± 1.028 %, which was also within the acceptable limits.

 

Dissolution study of core tablets:

Based on the results obtained from the dissolution study of core tablets in 0.1N HCl shown in Fig. 3 and Table no. 5, the core tablet formulation provided an extended release of 80% within 7.235 hrs, zero-order drug release with 0.983 R² and 12.68 K value and the mechanism of drug release was found to be Fickian diffusion and therefore was selected to further formulate the press-coated tablets.

 

 

Figure 3: % Cummulative drug release vs. time graph for core tablet.

 

Table no. 4: Post-compression Characterization of Core tablet:

 

Table no. 5: Drug Release Kinetics of the core tablet:

 

Table no. 6: Pre-compression study results for coat powder blend:

Formulations	Bulk density (g/cc)	Tapped density (g/cc)	Angle of Repose (º)	Carr’s Index (%)	Hausner’s Ratio
F1	0.712 + 0.03	0.818 +0.04	33.60	12.95	1.15
F2	0.690 + 0.03	0.85 +0.07	24.54	18.82	1.23
F3	0.574 + 0.01	0.650 +0.03	26.98	11.69	1.13
F4	0.711 + 0.02	0.821 +0.04	36.03	13.39	1.15
F5	0.697 +0.03	0.819 +0.03	27.05	14.89	1.18
F6	0.61 + 0.01	0.69 +0.03	22.44	15.25	1.13
F7	0.727 + 0.01	0.837 +0.02	34.33	13.17	1.15
F8	0.735 + 0.02	0.844 +0.06	31.56	12.98	1.15
F9	0.709 + 0.02	0.832 +0.03	31.03	14.78	1.17

 

 

Table no 7: Post-compression Characterization of Press-coated tablets:

Formulations	Hardness (kg/cm2)	Thickness (mm)	Avg. Wt. (mgs)	Swelling Index (%)	Lag Time(hrs)
F1	6.5± 0.04	0.5	251	42.54	3.5
F2	6.2± 0.05	0.5	252	50.63	2
F3	6.8± 0.16	0.5	250	61.92	4.5
F4	6.8± 0.12	0.6	296	49.28	4.5
F5	6.6±0.08	0.7	295	60.52	2.5
F6	7.2± 0.25	0.6	298	66.36	5
F7	7.0± 0.13	0.7	346	52.43	7
F8	6.8± 0.55	0.7	342	67.60	3.5
F9	7.4±0.22	0.7	349	27.93	5.5

 

Press coating material blend:

The flow properties of different outer coating material formulation are shown in the Table 6. The results for angle of repose (θ) obtained was found to vary from 22.44-36.03 which indicates all the coating material having fairly good flow property and can be used for press coating. Carr’s index calculated showed to vary from 12.98-19.71% indicating that all the blends have excellent flow property. Whereas, Hausner’s ratio analyzed is in 1.15-1.19 range representing a good flow for all the formulation coat powder blends.

 

Post-compression characterization of press coated tablets:

All the evaluated parameters result obtained from different formulations of press coated tablets is shown in Table no. 7. Hardness of various press coated tablets were in range of 6.2 ± 0.0 – 7.4 ± 0.22 kg/cm². The thickness observed was from 5 mm to 7 mm, it was found to be increasing with the weight of coat powder blend. The press coated tablets selected from different formulation passed the uniformity of weight test prescribed in IP. The individual tablet weights when compared with average weight were within the official limit (±5%) of % deviation. The friability of all press coated tablet formulations were within the acceptable limits of 1%. The swelling index was found to vary with the concentration as well as the type of polymers used. Where, the main contribution towards swelling of the tablets was the HPMC K-100M used.

 

Dissolution study of press coated tablets:

Tablets were subjected to dissolution in 0.1 N HCl (pH 1.2). The dissolution study of these formulations was performed in order to understand the effect of different polymers and their increasing concentrations. This will inform regarding the suitable polymer among all and its concentration. The formulation was optimized based on the criteria of attaining the desired value of lag time and dissolution profile.

 

The extension in drug release profile was attributed to both the erodible polymer (Ethyl cellulose, L-Hydroxy propyl cellulose and Eudragit S-100) as well as the swellable polymer (HPMC K100). Formulations F3, F4 and F6 were found to possess optimum lag time of 4.5-5 hrs as well as drug release profile. F4 was formulated with Ethyl cellulose with 50 mg concentration, whereas, F3 and F6 were formulated with L-Hydroxy propyl cellulose with 50 mg and 75 mg concentrations respectively. The lag times were found to be increasing with increase in the weight of the polymer coat material blend in press coated tablet formulations. But the effect of Eudragit S-100 in the formulations on lag time was found to be un-justifying.

 

All formulations prepared with Eudragit S-100 did not show good drug release profile or sufficient lag time. The % cumulative drug release versus time graphs has been projected in Figure 4, 5, 6 to study the effect of individual polymer.

 

 

Figure 4: % CDR vs time graphs for all Press-coated tablet formulations with Ethyl Cellulose.

 

 

Figure 5: % CDR vs time graphs for all Press-coated tablet formulations with Eudragit S-100.

 

 

Figure 6: % CDR vs time graphs for all Press-coated tablet formulations with L-Hydroxy Propyl Cellulose.

 

CONCLUSION:

From the present study it could be concluded that EC and HPC serves as a potential candidates in the formulating a time controlled release drug delivery systems with a defined lag time. In comparison to EC, HPC has shown more consistent and predictable lag time. The chosen weight ratios of polymers were sufficient to conclude the results. Among all, it can be concluded that formulation with L-HPC of 50 mg concentration was most appropriate to obtain preferred lag time. The amount of HPMC K100 was suitable in maintaining the lag time in the formulations without hindering the results. It helps in increasing the permeability of the press coat, thereby causing pore formation for the drug release after certain lag time.

 

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Accepted on 24.06.2018          © RJPT All right reserved

Research J. Pharm. and Tech 2018; 11(9): 4129-4134.