Formulation and in vitro evaluation of Diltiazem controlled release tablets

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Introduction

Controlled release DDS release drug at rates, which are significantly different from conventional dosage forms. The controlled release dosage forms are designed to control the rate of drug delivery, target the delivery of the drug to a tissue and/or maintain the duration of therapeutic efficacy [1]. Oral drug delivery is the most widely utilized route of administration among all the routes that have been explored for systemic delivery of drugs via pharmaceutical products of different dosage form. Oral route is considered most natural, convenient and safe due to its ease of administration, patient acceptance, and cost effective manufacturing process [2]. Pharmaceutical products designed for oral delivery are mainly immediate release type or conventional drug delivery systems, which are designed for immediate release of drug for rapid absorption [3]. Diltiazem hydrochloride is a Calcium channel and broadly utilized in the treatment of specific kinds of cardiovascular issues [4]. The therapeutic impacts of Diltiazem hydrochloride are identified with its capacity to hinder the flood of calcium particles in cardiovascular and vascular smooth muscle during membrane depolarization [5]. A basic dosing plan with more than once every day administration of the antihypertensive agent is known to expand patient compliance [6].

Materials Diltiazem was obtained from Hetero labs, HYD. HPMC, Carbopol 934 were procured from Synpharma Research Labs, Hyderabad, and other chemicals the reagents used were of analytical grade.

Methodology

FT-IR study [7] Compatibility of the drug with excipients was determined by FT-IR spectral analysis, this study was carried out to detect any Changes on chemical constitution of the drug after combined it with the excipients. The samples were taken for FT-IR study.

Preparation method Table 1: Formulation of Controlled release tablets of Diltiazem Ingredients(mg) F1 F2 F3 F4 Diltiazem 100 100 100 100 HPMC K5M 50 100 -- -- Carbopol 934 -- -- 50 100 Povidone 10 10 10 10 Microcrystalline cellulose 135 85 135 85 Talc 2 2 2 2 Magnesium Stearate 3 3 3 3 Total wt 300 300 300 300 Preparation method: [8] Different tablet formulations were prepared by wet granulation method. The formulations are composed of polymers HPMC K5M, and carbopol 934. All powders were passed through 100-mesh sieve. The microcrystalline and the polymer were mixed uniformly. Drug was added to the polymers and blended for 20 min. Solution of PVP K30 added to the above mixture for making dump mass. Dump mass was passed through sieve no.40 and dried the granules for 2 hrs at 50o c. The resulting granules were mixed with magnesium Stearate and talc in polyethylene bag for 10 min. The lubricated granules were compressed using 10mm punch (single punch tablet machine) in to tablets. Compression pressure was adjusted during tableting of each formula to get the tablet hardness in the range of 5 to 7 Kg/cm3. The total weight of tablet was kept at 300 mg.

Evaluation of tablet [9, 10, 11] Weight variation Twenty tablets were randomly selected form each batch and individually weighed. The average weight and standard deviation of 20 tablets was calculated. The batch passes the test for weight variation test if not more then two of the individual tablet weight deviate from the average weight by more than the percentage.

Thickness Twenty tablets were randomly selected form each batch and there thickness was measured by using vernier caliper. Thickness of three tablets from each batch was measured and mean was calculated.

Hardness Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm2. Three tablets were randomly picked and hardness of the tablets were determined.

Friability Friability test is performed to assess the effect of friction and shocks, which may often cause tablet to chip, cap or break. Roche friabilator was used for the purpose. This device subjects a number of tablets to the combined effect of abrasion and shock by utilizing a plastic chamber that revolves at 25 rpm dropping the tablets at distance of 6 inches with each revolution. Twenty tablets were weighed and placed in the Roche friabilator, which was then operated for 25 rpm for 4 min. After revolution Tablets were dedusted and reweighed. Compressed tablets should not loose more than 1% of their weight.

The percentage friability was measured using the formula, % F = {1-(Wo/W)} ×100 Where, % F = friability in percentage Wo = Initial weight of tablet W = weight of tablets after revolution Content Uniformity The drug content was determined by triturating tablets in a mortar and pestle. The 100 mg of sample powder was dissolved in 6.8 phosphate buffer. The solution was filtered through Whattmann filter paper. The filtrate was analyzed by U.V. spectrophotometer (LAB INDIA).

In- Vitro Release study In-Vitro drug release studies were carried out using Tablet dissolution test apparatus USP II at 50 rpm. The dissolution medium consisted of 900 ml of Standard buffer pH 1.2 for the first 2 hrs, followed by pH 6.8 for remaining period of time. Temperature maintained at 371. The sample of 5ml was withdrawn at predetermined time intervals and an equivalent amount of fresh dissolution fluid equilibrated at the same temperature was replaced. From that 5 ml sample, 1 ml sample was withdrawn and placed in a 10 ml volumetric flask. The diluted samples were assayed.

Stability studies The success of an effective formulation can be evaluated only through stability studies. The prepared controlled release Matrix tablets of Diltiazem were placed on plastic tubes containing desiccant and stored at ambient conditions, such as at room temperature, 40±2oc and refrigerator 2-8oc for a period of 90 days.

Results and Discussion

Compatibility Study Compatibility studies were performed using IR spectrophotometer. The IR spectrum of pure drug and physical mixture of drug and polymer were studied.

Fig 1: FTIR Spectra of Diltiazem Fig 2: FTIR Spectra of physical mixture of drug and excipients Compatibility studies were performed using IR spectrophotometer. The IR spectrum of pure drug and physical mixture of drug and excipients were studied. The characteristic absorption of peaks were obtained as above and as they were in official limits (±100 cm-1) the drug is compatible with excipients.

Evaluation Studies Weight variation All the formulated (F1 to F4) tablets passed weight variation test as the % weight variation was within the pharmacopoeial limits of 7.5% of the weight. The weights of all the tablets were found to be uniform with low standard deviation values.

Thickness Tablets mean thickness were uniform in F1 to F4 formulations and were found to be in the range of 3.12mm to 3.21 mm.

Hardness The measured hardness of tablets of each batch ranged between 5.18 to 5.25 kg/cm2. This ensures good handling characteristics of all batches.

Friability The % friability was less than 1% in all the formulations ensuring that the tablets were mechanically stable.

Content Uniformity The percentage of drug content for F1 to F4 was found to be between 94.56% and 98.86% of Diltiazem it complies with official specifications.

Table 2: Results of Evaluation parameters of tablets F. No.

In-vitro Dissolution Study Table 3: In vitro release data of tablet F1 to F4 Time (hrs.) F1 F2 F3 F4 0 0 0 0 0 Fig 3: In vitro drug release studies of (F1-F4) Formulations Stability studies There was no significant change in physical and chemical properties of the tablets of formulation F-4 after 3 months. Parameters quantified at various time intervals were shown; Table 4: Results of stability studies of optimized formulation F4 Formulation Code Parameters Initial 1st Month 2nd Month 3rd Month Limits as per Specifications F-4 250C/60%RH 85 % F-4 300C/75% RH 85 % F-4 400C/75% RH 85 %

Conclusion

In subsequent studies, the prepared tablets were evaluated. Among all the formulations F4 showed a better drug release over 8 hours of time and it released over 98.12 % of the drug out of 8 formulations with a controlled effect. Data of in-vitro drug release were fit into different equations and kinetic models to explain the release kinetics of Diltiazem from the controlled release tablet. It also found to be that there was no interaction between the drug and polymer in all the formulations. Among all the formulations, the optimized formulation F4 fulfilled all the objectives.