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Journal of Drug Delivery and Therapeutics

Open Access to Pharmaceutical and Medical Research

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Open Access Full Text Article                                                                        Research Article

Formulation and Evaluation of Sustained release tablet of Trazodone hydrochloride by using Synthetic Polymer RS100 and RL 100

Anil B. Panchal ¹*, Supriya V. Mudgulkar ²

¹ Assistant Professor Department of Pharmaceutics Delight college of pharmacy Koregaon Bhima, Pune. Maharashtra, India-412216.

² M. Pharmacy Student Department of Pharmaceutics SBSPM’S B. pharmacy college, Ambajogai. Maharashtra, India-431517.

INTRODUCTION

Oral route is the oldest and convenient route for the administration of therapeutics agents because of low cost of therapy and ease of administration leads to higher level of patient compliance¹.The goal of an extended-release dosage form is to maintain therapeutic drug level in plasma for extended period of time^2,3.The primary benefits of a sustained release dosage form in comparison with conventional dosage form, maintains uniform drug plasma concentration over an extended period of time and hence the uniform therapeutic effect is achieved⁴.

Trazodone is serotonin-2 receptor antagonist that also decreases extracellular gamma-amino-butyric acid (GABA) levels in the cerebral cortex. Through the blockade of 5-hydroxytryptamine2A receptors. Trazodone therefore a psychoactive compound with sedative and anti- depressant properties^5,6. Poly acrylates and polymethacrylate, the glassy substances, are commonly referred to by the trade name eudrilid. The commonly used eudrilid for the preparation of controlled release formulations are eudrilid RL, eudrilid RS. Eudragit RL and eudrilid RS, are ammonia methacrylate copolymers. The ammonium groups are present as salts and are mainly responsible for independent pH permeability of the polymers⁷.There is challenge to the pharmaceutical technologist for developing oral controlled-release tablets for highly water-soluble drugs with constant release rate. If water soluble containing drugs if not formulated properly then most of these drugs, may be readily release the drug at a faster rate and are likely to produce toxic concentrations when administered orally⁸.

MATERIALS: 

Trazodone hydrochloride was received as a gift sample from Teva pharmaceutical ltd. Goa. Eudragit RS100 and Eudragit RL100 were gifted from Vikram Thermon India Ltd. Gujrat, Ahmadabad. Other excipients as like PVP K30, Magnesium stearate, Lactose, Talc gifted from Indira college of pharmacy, Nanded.

METHODS:

Drug excipient compatibility study: Compatibility study was carried for pure trazodone hydrochloride and combination of trazodone HCL with excipients. The FT-IR spectra for pure drug and polymer were recorded using potassium bromide disk method. Samples were prepared in potassium bromide disk by means of a hydrostatic press. Spectral measurements were obtained by powder diffuse reflectance on a FT-IR spectrophotometer (Shimadzu, 8033) in the wave number region 400-4000 cm-1.

Differential Scanning Calorimetry (DSC):

Thermal analysis was carried out using a differential scanning calorimeter (SHIMADZU DSC 60 PLUS). 

Tests of conditions: 

Temperature range:  30˚C to 300 ˚C

Heating/Cooling rate: 5 ˚C / min. 

Gas: Nitrogen;                                               

Flow rate: 100 ml. / min. 

Determination of absorption maxima:

10 µg/ml solutions were taken to determine absorption maxima. Initially blank buffer solution was kept and scanned in the region of 200 – 400 nm. Then sample was kept for analysis and scanned in the same region. Absorption maxima were found to be 246.40 nm. Hence all further analysis was carried out at 246.40nm in pH 1.2 buffer and 6.8 pH phosphate buffer.

Preparation of Standard Calibration Curve: The solution of different 5 µg/ml – 40 µg/ml concentration of trazodone hydrochloride was prepared in pH 1.2 phosphate buffer and 6.8 phosphate buffer. The absorbance of these samples was noted shown at 246.40 nm by using double beam UV – spectrophotometer. The graph of absorbance V/s concentration in µg/ml was plotted. The R² value of this graph was calculated to see the linearity of the absorbance against concentration.

FORMULATION OF TRAZODONE HCl TABLET

TABLE 1: Composition of All Batches (quantity in mg / tablet)

Total Weight of Tablet = 450mg

Evaluation parameter of sustained release tablet of Trazodone Hydrochloride 

Post compression parameter:

Physical appearance: The general appearance of tablets, its visual identity and overall elegance is essential for consumer acceptance.

Hardness Test: The hardness of tablet of each formulation was checked by using Monsanto Hardness tester in terms of kg / cm².

Friability Test:

This test performed to evaluate the ability of tablets to withstand abrasion in packaging, handling and transporting. Initial weight of 10 tablet is taken and these are placed in the friabilator, rotating at 25 rpm for 4 min. The difference in the weight is noted and expressed . It should be perfectly below 1.0%.

% Friability = [(W₁-W₂)/W₁] X 100

Where, W₁= weight of tablets before test, W₂ = weight of tablets after test. 

Weight variation (14)

20 tablets were taken and weighed individually on a digital weighing balance. Average weight was calculated and the individual tablet weight was compared to the average. The tablet pass the U.S.P. test if no more that 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limit.

Average weight = weight of 20 tablets

                        20

Swelling characteristics of tablet

The extent of swelling was measured in term of percent weight gain by the tablets. The swelling behaviour of formulation was studied. One tablet from each formulation was kept in petri dish containing pH 1.2 buffer and pH 6.8 for 12 hours. At the end of each hour tablet was withdrawn soaked with tissue paper and weighed. Then after every hours. Swelling index of tablet was calculated using formula :

S.I. ={ ( Mt –Mo }  100

Where,          

SI – Swelling index

Mt – Weight of tablet at time ‘t’

Mo – Weight of tablet at time ‘0’.in mg .

In Vitro drug release study (15)

The in vitro drug release studies for the prepared formulation were conducted for a period of 12 hrs using an EDT 08LX dissolution tester USP Type - II apparatus (rotating paddle) set at 50 rpm and a temperature of 37± 0.5°C formulation was placed in the 900ml of the medium. For first 2 hr tablet was placed in 1.2pH medium which was replaced with 6.8pH phosphate buffer for remaining 10 hours. At specified intervals 5ml samples were withdrawn from the dissolution medium and replaced with fresh medium to keep the volume constant. The absorbance of the sample solution was analyzed at 246.40 nm for the presence of model drug, using a UV-visible spectrophotometer.

RESULT AND DISCUSSION

Absorption maxima were found to be 246.40 nm, Given in figure number one. Hence all further analysis was carried out at 246.40 nm in pH 1.2 buffer and 6.8 pH phosphate buffers.

Drug Excipients Compatibility Study by Using FTIR:

In the present study FTIR data of the drug and excipients was compared with standard spectrum of pure Trazodone hydrochloride was shown in figure.The characteristics peak associated with specific functional group and bonds of the molecular and their presence / absence in the polymer carrier formulation were noted. The IR spectra showed that there was no significant evidence for interaction between the drug and excipients.

Differential Scanning Calorimetry

DSC Thermograms of pure Trazodone Hydrochloride, blend of polymer with drug were determined. Pure Trazodone HCl showed a sharp peak at 228.44̊ C corresponding to its melting point. There was no appreciable change in the melting endotherms of physical mixture compared to that of pure drug Trazodone hydrochloride. Absence of any new endothermic peak or disappearance or shift of endothermic peak confirms that there was no interaction and hence polymers were compatible with drug.

Pre compression parameter: As the result of evaluation test given in table, the granules of all formulations where evaluated for LBD & TBD. The values of LBD & TBD ranged from 0.505 ± 0.15 to 0.578 ± 0.12 and 0.520±0.18 to 0.622±0.13 respectively.

The values obtained for Compressibility index for all formulations were calculated in Compressibility index value ranges between 6.37% to 12.37 % indicating that the granules have the required flow property. Hausner’s ratio was determined from the ratio of tapped density to poured density, and it was found in the range of 1.06 to 1.14 that means the granules was free flowing. The Hausner’s ratio values for all the final batches are given in the table. The values obtained for angle of repose for all formulations were calculated and the values were found to be in the range from 14.37 °C to 18.55 °C. This indicates good flow property of granules for compression.

Post compression parameters: 

The prepared sustained release tablets were evaluated for, Tablets mean thickness were almost uniform in all the ten formulations. The diameter & thickness of the tablet ranges between 09.68mm to 10.04mm & 5.43mm to 5.73mm respectively.   The measured hardness of tablets of each batch ranged between 5.5 to 6.5 kg/cm². This ensures good handling characteristics of all batches. The values of friability test were calculated. The % friability was found ranges between 0.71 to 0.95 % which was less than 1% in all the formulation ensuring that the tablets were mechanically stable. The percentage weight variation for all formulations were all the tablets passed weight variation test as the % weight variation was within the pharmacopoeia limits of ± 5 % of the weight. The weights of all the tablets were found to be uniform with low standard deviation value.weight variation range between 438 to 459 mg.

Trazodone hydrochloride is an antidepressant chemically unrelated to tricyclic, tetracyclic, or other known antidepressant agents. Trazodone is used primarily in the treatment of mental depression or depression / anxiety disorders. As the conventional doses release the trazodone hydrochloride in just minutes and therefore the therapeutic concentration are maintained for a short period of time generating a need for administration of another dose.

Therefore an attempt was made to maintain the therapeutic concentration for longer period of time. This was achieved by developing sustained release drug delivery system. These sustained release tablets mainly prepared for release of the drug for longer period of time i.e., 12 hours and utilizing the drug to full extent avoiding unneccessary frequency of dosing.

The sustained or controlled release formulation provide plasma concentration of Trazodone for at least 12 hr that was effective treating one or more of the symptoms of depression. In the sustained release formulation provide effective amount of trazodone for treating disorders for example improving sleep architecture. Trazodone HCl having Biological half-life 3-6 hrs due to need of frequent dosing for depression patient. Hence attempt had been made formulate sustained release of trazodone HCl.

Eudragit RL100 and Eudragit RS100 are insoluble in aqueous media but they are permeable and both have pH-independent release profile. The permeability of Eudragit RS100 and RL100 in aqueous media was due to the presence of quaternary ammonium groups in their structure; Eudragit RL 100 has a greater proportion of these groups and such as is more permeable than Eudragit RS100. Eudragit RL100 reduced the drug release due to the a reduction in the penetration of solvent molecule in to system. The rate of release was controlled by the permeability of matrix structure. The dissolution rate was studied using 900 ml of 0.1N Hydrochloride (pH 1.2) for first 2 hrs followed by phosphate buffer (pH 6.8) for the remaining hours under sink condition using USP dissolution apparatus type II. The results reveal that batch F1, F2, F3, F4, F5 and F6, showed drug release as 75.22% for 11 hrs, 74.02% for 12 hrs, 71.20% for 12 hrs, 88.06% for 12hrs, 78.75 for 12 hrs, 68.25 for 12 hrs. In – vitro drug release data of optimized formulation (Batch F4) pass zero order Model as it has highest r2 value (0.954) as well as Higuchi model having r2 value (0.954) among other models which indicate the release mechanism govern by diffusion from matrix. In the present study diffusion value of exponent is 0.890 therefore release of the formulations was mainly by Anomalous (non- Fickian) transport.

TABLE 2: calibration data of trazodone hcl in ph 1.2

TABLE 3: Calibration data of Trazodone HCL in pH 6.8 phophate buffer

TABLE 4: Pre- compression parameters 

All the values represent mean ± Standard deviation (n=3)

TABLE 5: Post compression parameter

TABLE 6: Swelling Study of Batch F 1 to F 6

 TABLE 7: Percent drug Release of batch F1 to F6

TABLE 8: Kinetic Analysis of In–Vitro Release of F4 Batch of sustained release Tablet 

TABLE 9: FTIR Interpretation of Trazodone HCL and Formulation

FIGURE 2: UV Spectra (λ _max) of Trazodone HCL Drug

FIGURE 3: Linearity curve of Trazodone HCL in pH 6.8       FIGURE 4: Linearity curve of Trazodone Hcl in pH 1.2

Figure 5: FTIR Spectrum of RS 100

FIGURE 6: FTIR Spectrum of Trazodone HCl with RS 100

FIGURE 7: FTIR Spectrum of RL 100

FIGURE 8: DSC spectrum of pure Drug Trazodone HCl

FIGURE 9: DSC spectrum of RS 100

FIGURE 10: DSC Spectrum of RL 100

FIGURE 11: DSC Spectrum of batch F4

FIGURE 12: Comparative in-vitro release graph for formulation F1 – F6 batches

Release kinetics of best optimized batch 

FIGURE 13: Zero order release of Batch F4

FIGURE 14: First order kinetic model of Batch F4

FIGURE 15: Higuchi model of Batch F 4

FIGURE 16: Korsmeyer – peppas Equation Batch F4

FIGURE 17: HIXON CROWEL RELEASE OF BATCH F 4

CONCLUSION:

In the present study an attempt has been made to Formulate and evaluate sustained release tablet of Trazodone HCl using different polymer like RS 100 and RL 100. FTIR and DSC study showed compatibility between drug and excipients. Among all batches Batch F4 showed 88.06% drug release at 12 hr. In-Vitro drug release data of optimized formulation F4 pass zero order as well as Higuchi model having r2 value (0.954) among other models. Diffusion value of exponent was found to be 0.890 respectively. Therefore release of the formulations was mainly by Anomalous (non – Fickian) transport. The n value indicates a non-fickian or anomalous diffusion pattern. This means that both the diffusion and erosion mechanism were prevalent. Hence we concluded that once daily sustained release tablet of Trazodone hydrochloride having satisfactory sustained release profile which may provide an increased therapeutic efficacy.

Future scope:

The present study successfully formulated and evaluated sustained release tablets of Trazodone Hydrochloride using synthetic polymers Eudragit RS100 and RL100, with Batch F4 showing the most promising release profile. Future research can focus on conducting in-vivo pharmacokinetic and pharmacodynamic studies to validate the therapeutic efficacy and bioavailability of the optimized formulation in clinical settings. Stability studies under various conditions are also essential to determine the shelf life and storage requirements of the developed tablets. Additionally, the formulation process can be optimized for large-scale manufacturing to ensure reproducibility and economic feasibility. Exploring alternative or combination polymers may further enhance the control over drug release. Development of modified drug delivery systems such as gastro-retentive or mucoadhesive tablets could offer targeted drug delivery, and studies on patient compliance would provide practical insights into the formulation’s acceptance in real-world use, especially for chronic conditions like depression.

Acknowledgement: None 

Conflicts of Interests: There are no conflicts of interest.

Funding: Nil 

Authors Contributions: All the authors have contributed equally.

Source of Support: Nil 

Informed Consent Statement: Not applicable. 

Data Availability Statement: The data presented in this study are available on request from the corresponding author. 

Ethics approval: Not Applicable.

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