INTRODUCTION:

Sustained release systems the oral route of administration has been investigated the most, because of flexibility in dosage forms design that the oral route offers¹. With many drugs, the basic goal of therapy is to achieve a steady-state blood level or tissue level that is therapeutically effective and nontoxic for an extended period of time. To achieve better therapeutic action various types of drug delivery systems are available, out of which sustained release systems are gaining much importance because of their wide advantages over others like ease of administration, convenience and noninvasiveness².

The goal of any drug delivery system is to provide a therapeutic amount of drug to the proper site of the body, to achieve promptly and then maintain the desired therapeutic drug concentration that elicits the desired pharmacological action (s) and to minimize the incidence and the severity of unwanted adverse effects. To achieve this goal, it would be advantageous and more convenient to maintain a dosing frequency to once, or at most, a twice-daily regimen. An appropriately designed extended release dosage form can be a major advance in this direction compared to conventional immediate release dosage form. The development of improved method of drug delivery system have received a lot of attention in last decades³.

A large number of preparations deliver drugs in immediate release form that are absorbed in the upper regions of the small intestine, an increasingly important group of products frequently referred to as modified, controlled, or extended-release delivery systems are designed to deliver drug in the entire gastrointestinal (GI) tract but always in a controlled manner^4-6.

Matrix tablets are one of the most widely used dosage forms within controlled release techniques in pharmaceutical manufacturing standards, as drug release rates are controlled mainly by the type and proportion of excipients used in the preparations and no complex production procedures such as coating and pillarization are required⁷.

Among various technologies available, monolithic matrices-matrix tablets continue to be popular because of simple processing technologies required, reproducibility, and stability of the materials and dosage form as well as ease of scale-up operation⁸.

There is a continuously growing interest of the pharmaceutical industry for drug delivery in sustained or controlled release form. There is also a high interest for dosage formulations allowing high loading, particularly for drugs requiring high therapeutic concentrations in circulation. For this purpose, various polymeric systems were studied and interesting release kinetics was obtained from pharmaceutical dosage forms such as microparticles, nanospheres and microcapsule tablets with high loading capacity. Analysis of the release data for these forms showed the effects of drug solubility and loading as well as the influence of the characteristics of polymer or of the other excipients on the release mechanism. In the monolithic dosage forms, the size and the weight of the tablets are important parameters. There is a need for controlled release system to realize formulation with smaller amount of polymeric excipients able to control the release of higher amounts of drug from high loading dosages⁹.

Matrix tablet are oral dosage form, where the drug is dispersed throughout the three dimensional structure of hydrogel. The drug release occurs due to diffusion of the drug through the pores in hydrogel. HPMC is a macropourous hydrogel with 0.1-1μm pore size, the drug is released from these pores. Hence, electrolytes were used as release modifiers, which controls the drug release rate form the dosage form. HPMC K4M grade a low density hydrogel has been used due to basic advantage as well as hydrogel materials resembles natural living tissue more than any other class of synthetic biomaterials and exhibits excellent biocompatibility. The drug release is diffusion controlled or swelling controlled¹¹.

Ideally a drug to provide desired therapeutic action should arrive rapidly at the site of action in optimum concentration, remain there for the desire time, be excluded from other site and get rapidly removed from the site of planned. The fact that absorption rate of drug into the body can be decreased by reduction of the rate of release of the drug from the dosage form is one of the most recent and interesting result of pharmaceutical research¹².

Once a day or at the most twice a day formulation is a holy grail of sorts for scientists working with oral dosage forms. A sustained release preparation that makes once or twice daily administration of drug possible might be an advantageous dosage form, especially in long-term therapy¹⁴.

MATERIALS AND METHODS:

Materials:

Ornidazole was obtained as a gift sample from Ipca Labs Ltd. Ratlam; directly compressible Dried Mucilage were obtained from dried seeds of ocimum bacilicum, Sodium Starch Glycolate, Sodium Saccharine, Sucrose, Magnesium Stearate were obtained from Research Lab Fine Chem. Industries Mumbai; All other chemicals used were of analytical grade.

Experimental Part:

Dispersible tablets of ornidazole were prepared by direct compression method. Accurately weighed ingredients were finely powdered and kept separately. The weighed ingredients were mixed by the principle of geometrical order to obtain a uniform mixture. The different ratios of the mixture are represented in Table 1 and the formulations were identified as F1, F2, F3, F4, F5 and F6 respectively. Each batch of powder mixture was undergone for compression using sixteen station single rotary tabletting machine (Sunmach Pharma machinery pvt. Ltd., Ahmedabad) using biconvex round punches. The obtained tablet were collected and stored in well closed amber coloured bottle for evaluation¹⁵.

Taste Masking of Bitter Drug:

Different approaches undertaken to mask the bitter taste of drug.

Direct compression by using sweeteners and flavours-Taste is highly bitter in nature and could not be masked by using only sweetener hence there was need to change in approach¹⁶.

Coating of API by using Polymer- The taste of formulation was not found satisfactory; hence the need is to go with another technique ¹⁷.

Taste masking by microencapsulation- Taste of the tablet was found to be very bitter, considered to be non-palatable¹⁸.

Taste Masking by Repeated Coating/Adsorption- taste was masked sufficiently by coating of dried mucilage to the drug, hence one more coating was provided to previously coated material¹⁹.

Evaluation of Tablets:

Calibration curve:

Calibration curve of ornidazole in buffer pH 0.1N HCL Accurately weighed ornidazole was dissolved to make the solution in range of 2 to 12μg/mL using the buffer solution. Absorbance of each concentration was measured using U.V. Spectrophotometer Jasco, Japan (Model V-530 & V-630) at 277 nm and the absorbance was plotted against concentration of drug solution²⁰.

Compatibility studies:

Compatibility between the drug and the excipients were studied using Fourier Transform Infrared (FTIR) spectrophotometer (Shimadzu) using KBr disc method²².

Physical characterization:

The stored tablets were analyzed for the different parameters such as weight variation, hardness, and percentage friability²¹.

Uniformity of Dispersion:

Tablets were placed in 100 ml of water and stirred gently until completely dispersed. A smooth dispersion is obtained which passes through a sieve screen with a nominal mesh aperture of 710 mm (sieve number 22).

In-vitro Disintegration time

Conventional DT apparatus was used for determination of disintegration time of dispersible tablet at 24º to 26º and operated for 3 minutes.

In vitro Drug Release

The in vitro release tests were performed using the USP XXIV type II (paddle method) dissolution test apparatus (ElectrolabTDT-08L, India). The tablets were placed in dissolution vessel containing 900ml of buffer (pH 0.1 N HCL) maintained at 37 ± 0.5° C. The paddle rotation speed was kept at 50 rpm. In all experiments, an aliquot of 5.0 ml dissolution samples was withdrawn at predetermined time intervals, and replaced with an equal volume of the fresh medium to maintain the total volume constant. Samples were diluted and filtered through a Whatman filter paper no.41 and assayed by UV spectrophotometry at 277 nm. Cumulative percentage of drug released from the tablets were calculated and plotted as a function of time²².

Stability studies:

Accelerated stability studies were carried out for the optimized formulation in predicting the shelf life. The study was carried out by ICH guidelines at a temperature 40ºC/75% RH²².

RESULTS AND DISCUSSION:

Direct compression method was utilized here for the manufacturing of Dispersible tablets of ornidazole. Different batches of tablets were manufactured using different combination of super-disintegrants. Primary evaluation tests of the tablets were carried out and from the results, it is clear that the technique adopted is suitable of the process. Compatibility studies were carried out to study the chemical interaction between drug and the excipients. After interpreting the FTIR spectra, there was no interaction observed for the drug while combining with the excipients. From the FTIR spectral analysis, the drug is compatible with the excipients²³. The prepared tablets were taken for hardness evaluation using Monsanto Hardness tester. From the results, the hardness of the tablets were found in the range of 30-40 N, proved for its adequate strength. Weight variation test performed for each tablet and the obtained report showed that the tablets having the weights in the range of 600-605 mg. All the tablets passed the weight variation test as the average percentage weight variation within the limit of IP standards²⁴. Thicknesses of the tablet were measured and the obtained report proved that all the tablet having uniform thickness. The Smooth dispersion completely passes through Sieve number 22 which facilitate Uniformity of Dispersion²⁵. The various results are reported in Table 2. In-vitro disintegration time is measured by the time taken to undergo complete disintegration. Rapid and uniform disintegration of tablets were observed in all the formulations²⁶. The report shows the disintegration time for all the formulations in the range of 45 to 75 seconds fulfilling the official standards²⁷. Based on the in-vitro disintegration time, the formulation (F6) showed a fast disintegration time of 45 second. Thus the formulation can be selected as the ideal formulation²⁸. In-vitro dissolution studies were also carried out to optimise the ideal formulation. Test was carried out by USP Type II apparatus. The dissolution of ornidazole from the tablet is recorded in Table 3 and the corresponding plots are represented in Figure.No.1. From the parameters the formulation F6 showed good release profile for the time specified and selected as the ideal formulation²⁹. The uniformity in the release profile may be due to the presence of super disintegrants in the correct ratio for the formulation. Thus it is selected as the ideal formulation. Stability study for the optimized formulation was carried out for a period of 30 days at 40ºC/75% RH according to ICH guidelines, in predicting the shelf life of the formulation. Physical appearance and drug content of the formulation were studied during this period²⁹. From the results, it was found that the ideal formulation does not have major degradation and can be predicted for a good shelf life³⁰. The obtained results were tabulated in Table 4.

CONCLUSION:

Ornidazole is generally possesses antidiarrheal actions. Presently, commercially these are available as conventional tablet. However, due to their intense bitter taste, the acceptability of ornidazole to pediatric applications is limited. In the present study it was, therefore, planned to mask the taste of ornidazole by Coating it with mucilage and formulation of its dispersible tablet dosage form for pediatric patients. The study was begun with the drug analysis. Procured samples of drug were characterized by IR spectral study, DSC study, melting point determination and its compatibility with other excipients is studied ^31-36. It was planned to mask bitter taste of drug by using mucilage. Taste evaluation revealed that the drug is effectively taste masked. Dispersible tablet formulations of drug- polymer complex were developed using sodium starch glycolate and as superdisintegrats, Sodium Saccharin and Sucrose as sweetening agent by direct compression method. Formulated tablet formulation, was found to be best after evaluation of all the parameters, viz., hardness, diameter, thickness, friability, dispersion time, and mouth feel. Dispersion time for formulation was found to be 54 seconds and score 9.0 was awarded by all volunteers on the scale of perception of bitterness. Drug release study revealed that coating did not affect the release behaviour of drug at pH 1.2.

On the basis of above findings, it can be concluded that taste masking of Ornidazole could be successfully achieved by repeated coating of polymer to he drug. The dispersible tablets formulated in the present study using mucilage possessed the best taste acceptance, mouth feel, and other tablet attributes. The formulation is further evaluated by using accelerated stability study.

Table-1: Formulation chart for Dispersible tablet of Ornidazole

Sr No.	Ingredients	F1	F2	F3	F4	F5	F6
1	Ornidazole	125	125	125	125	125	125
2	Dried Mucilage	125	375	625	375	375	375
3	Crospovidone	50	50	50	50	-	-
4	Crosscarmellose sodium	-	-	-	-	-	50
5	Sodium Starch Glycolate	-	-	-	-	-	50
6	Sodium Saccharine	5	5	5	5	5	5
7	Sucrose	15	15	15	15	15	15
8	Magnesium Stearate	30	30	30	30	30	30
Total weight		350	600	850	600	600	600

Table 2: Various physical parameters of the Dispersible tablets of Ornidazole

Parameters	F1	F2	F3	F4	F5	F6
Weight	600±5mg	600±5mg	600±5mg	600±5mg	600±5mg	600±5mg
Thickness	3.60 ± 0.5 2	3.60 ± 0.3	3.60 ± 0.3	3.60 ± 0.3	3.60 ± 0.4	3.60 ± 0.
Hardness	35± 0.5	32 ± 0.5	35 ± 0.5	31 ± 0.5	33 ± 0.5	30 ± 0.5
Disintegration Time (n=5)	75± 5 sec	59± 2 sec	72± 5 sec	48 ± 4sec	51 ± 4sec	45 ± 4sec
Friability	1.15 %	0.88%	0.48%	0.59%	0.55%	0.45%

Table-3: In-vitro Dissolution Profile of Ornidazole Mouth Dissolving Tablets

Time Min.	Percentage Cumulative Drug Release
Time Min.	F1	F2	F3	F4	F5	F6
0	0	0	0	0	0	0
5	72.8±1.26	73.1±1.55	82.5±1.88	89.9±1.8	95.8±2.8	97.8±1.72
10	82.1±2.12	84.5±1.34	89.9±1.09	94.5±1.21	96.7±1.02	99.1±1.22
15	83.6±1.63	88.6±2.11	92.1±1.42	95.8±1.56	97.5±1.08	99.89±1.14
20	84.1±1.33	92.1±2.66	92.4±1.29	96.7±1.83	97.6±1.84	100.8±1.96
30	84.3±2.11	92.8±1.74	93.1±1.36	96.8±1.8	97.9±2.08	100.3±2.31
45	84.2±2.06	93.1±1.8	93.2±1.40	96.9±1.64	97.23±2.12	100.9±1.81

Table-4: Stability Testing Parameters of the Optimized Formulation

Time (days)	Physical appearance	Drug Release (%)
0	Good	98.16±1.56
15	Good	97.56±1.62
30	Good	97.77±1.83

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Received on 16.03.2021 Modified on 28.04.2021

Res. J. Pharma. Dosage Forms and Tech.2021; 13(3):174-178.

DOI: 10.52711/0975-4377.2021.00031