Design and Evaluation of Tramadol HCl Sustained Release Matrix Tablets

INTRODUCTION

Oral drug delivery¹ has been known for decades as the most widely utilized route of administration among all the routes that have been employed for the systemic delivery of drug via various pharmaceutical products of different dosage forms. The reasons that the oral route achieved such popularity may be due to its ease of administration and the belief that oral administration of the drug is well absorbed. A suitable formulation design is essential to achieve a systemic approach for the successful development of an oral pharmaceutical dosage form.

Rationale of sustained and controlled drug delivery

The basic rationale for controlled drug delivery is to alter the pharmacokinetic and pharmacodynamics of pharmacological active moieties by using novel drug delivery system or by modifying the molecular structure and physiological parameters inherent in the selected route of administration.² It is desirable that the duration of drug action becomes more a design property of a rate controlled dosage form and less or not at all a property of the drug molecules properties, inherent kinetics. Thus optional design of controlled release systems necessitates a thorough understanding of the pharmacokinetics and pharmacodynamics of the drugs.

Sustained and controlled release drug delivery systems:

Over the past 30 years, as the expense and complications involved on marketing new drug entities have increased, with concomitant recognition of the therapeutic advantages of controlled drug delivery, greater attention has been focused on development of sustained or controlled release drug delivery systems. The attractiveness of these dosage forms is due to awareness to toxicity and infectiveness of drugs when administered or applied by conventional method in the form of tablets, capsules, injectable, ointments, etc.

Usually conventional dosage form produces wide- ranging fluctuation in drug concentration in the bloodstream and tissues with consequent undesirable toxicity and poor efficiency. These factors as well as factors such as repetitive dosing and unpredictable absorption lead to the concept of controlled delivery systems. The goal in designing sustained or controlled delivery system is to reduce the frequency of the dosing or to increase effectiveness of the drug by localization at the site of action, reducing the dose required or providing uniform drug delivery.

Potential advantages of sustained and controlled drug therapy:

All controlled release products share the common goal of improving drug therapy over that achieved with their non-controlled counter parts. This improvement in drug therapy is represented by several below mentioned potential advantages of the use of controlled release systems³

A) Avoid patient compliance problems

B) Employ less total drug

i. Minimize or eliminate local and systemic side effects.

ii. Obtain less potentiation or reduction in drug activity with chronic use. iii. Minimizing drug accumulation with chronic dosing.

C) Improves efficiency in treatment.

i. Improve bioavailability of some drugs.

ii. Make use of special effects e.g. sustained release aspirin for morning relief of arthritis by dosing before bedtime.

Various formulations were designed by using polymers, a few examples include:

Ganesh et al⁴ prepared and evaluated sustained release matrix tablet of diclofenac sodium using natural polymer cashew nut tree gum. A better sustained drug release (50.65%) was obtained with the matrix tablet made-up of the Carbopol than with the cashew nut tree gum and HPMC. S.K. Singh et al⁵ formulated and studied evaluation of mucoadhesive tablet and influence of some hydrophilic polymers on the release rate and in vitro evaluation using different mucoadhesive polymers namely guar gum, xanthan gum, and Methocel (HPMC k15m and HPMC k100m). The combination of HPMC K15: HPMCK100: xanthan gum (1:2:1) and HPMC K 100: xanthan gum (2:2) showed a greater bio adhesive strength as compared to single gum and other hydrophilic polymer combination tablet. Subramaniam Kannan et al⁶ formulated and evaluated sustained release tablets of aceclofenac using hydrophilic matrix system, HPMC grade of polymer as retarding agent. Hosseinali Tabandehet al⁷ prepared Aspirin matrix tablets with ethylcellulose (EC), Eudragit RS100 (RS), and Eudragit S100 (S) by direct compression technique. Low viscosity grades have shown more sustained release pattern, which may be due to extensive plastic deformation of thesegrades of ethylcellulose even at low compression pressures. The 22-cps grade of ethylcellulose was selected in this study. JaberEmamiet al⁸ prepared sustained-release matrix tablets of flutamide by direct compression method using different polymers. Cellulose ethers (HPMC and NaCMC), natural gums (guar and xanthan gums), and compressible Eudragits (RSPO and RLPO) and their combinations were used in different ratios to examine their influence on tablet properties and drug release profile. Tablets were evaluated by measurement of hardness, friability, content uniformity, weight variation, and drug release pattern. All the tablets met the pharmacopoeial requirements for physical tests, based on USP 29. Almost in all formulations, with increasing the percentage of polymer, release rate decreased, though drug release pattern was mainly dependent on the type of polymer. Formulations (containing 25% HPMC and 40% RSPO) met the desired requirements for a sustained-release dosage form.

MATERIALS AND METHODS

Tramadol hydrochloride was obtained from Alkem Pvt. Ltd., Mumbai and HPMC K100M was purchased from Colorcon. The remaining materials (Microcrystalline cellulose, Xanthan gum, Pvp k-30, Iso propyl alcohol, Magnesium stearate, and Talc) were procured from SD Fine –Chem Pvt, Mumbai and were used as received.

Preformulation Study⁹

Drug sample was evaluated for color, odor, taste, appearance, melting point, and solubility.

Construction of Calibration Curve: Standard Stock solution:Accurately weighed 100 mg of Tramadol HCl was dissolved in 100 mL of 0.1N HCl. The resultant solutions were having concentration of 1000 µg/mL (1.1 mg/mL). 10 mL of this solution was further diluted up to 100.0 mL with 0.1NHCl and to give a solution of concentrations 100 µg/mL. This resultant solution is used as working stock solution for further study. Further dilutions were prepared from the same solution.

Preparation of calibration curve for tramadol hydrochloride by ultraviolet visible spectroscopy: Appropriate aliquots were pipetted out from the standard stock solution in to a series of 10 mL volumetric flasks. The volume was made up to the mark with 0.1N HCl to get a set of solutions having the concentration range of 5, 10, 15, 20 and 25 µg/mL for Tramadol HCl . Absorbances of the above solutions were measured at 272 nm and a calibration curve of absorbance against concentration was plotted and the drug follows the Beer’s & Lambert’s law in the concentration range of 5-25 µg/mL. The regression equation and correlation coefficient was determined.

Apparent Bulk Density: The bulk density was determined by transferring the accurately weighed sample of powder to the graduated measuring cylinder.10 The initial volume and weight was noted. Ratio of weight of the sample was calculatedby using the formula; Density = Mass/Volume

Tapped Density: Weighed powder sample was transferred to a graduated cylinder and was placed on the tap density apparatus, the equipment was operated for fixed number of taps (200). The tapped density was determined by the formula; Density = Mass/Tapped Volume

Carr’s Compressibility index (%): Based on the apparent bulk density and the tapped density, the percentage Compressibility of the bulk drug was determined by the formula; Carr’s index (%) = [(Tapped density-Bulk density) / Tapped density] X 100

Hausner’s Ratio: 10It indicates the flow properties of powder and is calculated using the formula; Hausner’s ratio = Tapped density/ Bulk density. If Hausner’s ratio is less than 1.25 indicates good flow and if it is more than 1.25 indicates poor flow.

Angle of Repose: The flow property was determined by measuring the angle of repose. It is the maximum angle that can be obtained between the free standing surface of a powder heap and the horizontal. Angle of repose= tan-¹ (h/r); where, h = height r = radius.

Procedure: Twenty grams of the sample was taken and passed through the funnel slowly to form a heap. The height of the powder heap formed was measured and the circumference formed was drawn with a pencil on the graph paper. The radius was measured and the angle of repose was determined. This was repeated three times for a sample. 

Formulation development

Preparation of tablets

Drug and polymer (Xanthan gum) pass through 40 # mesh separately and then transfer it to a poly bag and mix it for 3 min. Add binder (PVPK-30) dissolved in isopropyl alcohol which is used as a granulating agent. Above drug-polymer blend is granulated by using binder solution. Add another polymer (HPMC K100M), diluents and other excipients to the above mixture. Finally add the Glidant (Magnesium Stearate) and Lubricant (Talc) to the above blend and mix it for 2min. Compress the above lubricated blend into tablets by using 8mm round punches

Evaluation of tablets

After formulating a tablet, evaluation is mandatory to ensure the quality of a product. There are various standards that have been set in the various pharmacopoeias regarding the quality of pharmaceutical tablets. These include the diameter, size, shape, thickness, weight, hardness, friability, buoyancy test and dissolution studies. 

Physical Appearance

The general appearance of a tablet is essential for consumer acceptance. The control of general appearance involves the measurement of size, shape, colour, presence or absence of odour, taste, etc.

Size & Shape: It can be dimensionally described & controlled. The thickness of a tablet is variable. Tablet thickness can be measured by micro-meter or by other device. Tablet thickness should be controlled within a ± 5% variation of standard value.

Weight variation test:¹¹ This is an in process quality control test to ensure that the manufacturers control the variation in the weight of the compressed tablets, different pharmacopoeia specify these weight variation tests.

Method: Twenty tablets were weighed individually and the average weight was calculated. The individual tablet weights are then compared to the average weight. Not more than two tablets should differ in their average weight by more than percentages stated in USP. No tablet must differ by more than double the relevant percentage.

Content Uniformity:¹¹ The content uniformity test is used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch

Method: Randomly select 30 tablets. 10 of these assayed individually. The Tablet pass the test if 9 of the 10 tablets must contain not less than 85% and not more than 115% of the labeled drug content and the 10th tablet may not contain less than 75% and more than 125% of the labeled content. If these conditions are not met, remaining 20 tablets assayed individually and none may fall outside of the 85 to 115% range.

Friability:¹²

Friction and shock are the forces that most often cause tablets to chip, cap or break. The friability test is closely related to tablet hardness and designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling and shipping. It is usually measured by the use of the Roche friabilator.

Method: Few tablets are weighed and placed in the apparatus where they are exposed to rolling and repeated shocks as they fall 6 inches in each turn within the apparatus. After four minutes of this treatment or 100 revolutions, the tablets are reweighed and the weight is compared with the initial weight. The loss due to abrasion is a measure of the tablet friability. The value is expressed as a percentage. A maximum weight loss of not more than 1% of the weight of the tablets being tested during the friability test is considered generally acceptable and any broken or smashed tablets are not picked.

The percentage friability was determined by the formula:

% friability = (W1-W2) / W1 X 100

W1 = Weight of tablets before test

W2 = Weight of tablets after test

Drug release:

The drug release from the tablets was investigated in a USP-II (paddle) apparatus, 900 mL of 0.1N HCl (50 rpm, 37°C). At predetermined time intervals, 5 mL samples were withdrawn and 1 mL is diluted to 10 mL and then analyzed with UV spectrophotometry at λ max, 272nm.

RESULTS AND DISCUSSION

All the preformulation parameters and post compression evaluation was performed and the results were tabulated.

Solubility data of tramadol HCl

The solubility of Tramadol HCl is different in solvents. It was observed that the drug is soluble in water and normal saline.

Standard graph of tramadol HCl in 0.1 N HCl

The construction of standard calibration curve of Tramadol HCl was done by using 0.1N HCl as the medium. Tramadol HCl was found to have the maximum absorbance at 272 nm. The standard graph of Tramadol HCl in 0.1 N HCl was constructed by making the concentrations of 1, 2, 3, 4 and 5µg/mL solutions. The absorbance of solutions was examined under UV-spectrophotometer at an absorption maximum of 272 nm. The standard graph of Tramadol HCl was constructed by taking the absorbance on Y-axis and concentrations on X-axis.

Evaluation of the prepared tablets for physical parameters:

All formulations were tested for Physical parameters like hardness, thickness, weight variation, friability and found to be within the Pharmacopoeia limits. The results of the tests were tabulated. The drug content of all the formulations was determined and was found to be within the permissible limit. This study indicated that all the prepared formulations were good.

CONCLUSION

The objective of the present study was to develop a Sustained release matrix tablets of Tramadol hydrochloride by which the drug release can be extended for a period of time. Systematic studies were conducted using different concentration of rate releasing polymer Xanthan gum and HPMC K100M for extending the drug release up to 10 hrs. All the prepared systems were evaluated for the different properties. Before the preparation of tablets, preformulation studies to find out the micromeritic properties to assess flowability, compressibility properties and solubility studies. Formulated tablets gave satisfactory results for various physical tablet evaluation parameters like tablet dimensions, hardness, friability, weight variation, content uniformity, all the formulations were found within the permissible range.Among all the formulations (F1-F5), it was observed that F3 containing 25mg of Xanthum Gum , 25mg HPMC, 50mg PVPKcan effectively control the drug release for a period of 10 h. So F3was found to be the best formulation in sustaining the drug release for an extended period of time.

ACKNOWLEDGEMENTS

The authors are very much thankful to the Director, Principal, Karnataka College of Pharmacy, Bengaluru, Karnataka for providing the facilities to carry out the research work.

Conflicts of interest

The authors declare no conflicts of interests.