Formulation and evaluation of a Gastro- retentive Drug Delivery of System of Rifaximin as Floating Tablet

Table .1: Materials used in the study of Rifaximin FDDS.

Table 2: Equipment used in the study of Rifaximin FDDS.

METHODS

UV Spectroscopic method for analysis of Rifaximin FDDS

Preparation of 0.1N HCl:

N HCl was prepared by taking the 8.5ml concentrated HCl and make up the volume to1000 mL with distilled water.

Measurement of λmax:

To find the maximum absorbance of drug, 100μg/ml drug solution in suitable medium was scanned over the range of 400-200nm by using UV- Visible spectrophotometer (Shimadzu UV-1800).

Procedure for construction of standard graph of Rifaximin in 0.1N HCl

Stock solution of the drug was prepared by dissolving 10mg of drug in 100ml of 0.1N H C l . From this stock solution 5-40µg/ml concentrations were prepared after suitable dilutions. The absorbance of each test solutions was measured at λmax of 231nm using UV-Visible spectrophotometer against 0.1N HCl.

Formulation method development

Accurately weighed quantities of polymers and MCC were taken in a mortar and mixed geometrically, to this required quantity of Rifaximin was added and mixed slightly with pestle (Li S et al., 2002). Accurately weighed quantity of sodium bicarbonate was taken separately in a mortar and powdered with pestle. The powder is passed through sieve No. 40 and mixed with the drug blend which is also passed through sieve No. 40. The whole mixture was collected in a plastic bag and mixed for three minutes. To this magnesium stearate was added and mixed for five minutes, later talc was added and mixed for two minutes (Rama Rao. T, et al., 2014). The formulation compositions were shown in table 5.3, 5.4 and 5.5.

Table .3: Composition of floating matrix tablets of Rifaximin with HPMC K250 PH PRM

Evaluation of final blend

The Final blend of all formulations was evaluated for bulk density, tapped density, compressibility index (CI), hausner ratio and angle of repose.

Evaluation of floating matrix tablets of Rifaximin

Weight variation

Twenty tablets from each batch were individually weighed in grams on an analytical balance. The average weight and standard deviation were calculated, individual weight of each tablet was also calculated using the same and compared with average weight.

Thickness

The thickness in millimeters (mm) was measured individually for ten pre-weighed tablets by using Vernier calipers. The average thickness and standard deviation were reported.

Hardness

Tablet hardness was measured using a Monsanto hardness tester. The crushing strength of the ten tablets with known weight and thickness of each was recorded in kg/cm2 and the average hardness, and the standard deviation was reported.

Friability

Twenty tablets were selected from each batch and weighed. Each group of tablets was rotated at 25 rpm for 4 minutes (100 rotations) in the Roche Friabilator. The tablets were then dusted and re-weighed to determine the loss in weight. Friability was then calculated as per weight loss from the original tablets (NishatNasrin, et al., 2008)

In vitro buoyancy studies The in vitro buoyancy was determined by floating lag time. The tablets were placed in a 100 ml beaker containing 0.1N hydrochloric acid. The time required for the tablet to rise to the surface and float was determined as floating lag time (Penners G, et al., 1997). The duration of time for which the dosage form constantly remained on the surface of medium was determined as the total floating time.

Drug content

Twenty tablets were taken, powdered. The powder equivalent to one dose each was transferred to a 100 ml volumetric flask and 0.1N HCl was added. The volume was then made up to the mark with 0.1N HCl. The solution was filtered and diluted suitably and drug content in the samples was estimated using UV-spectrophotometer at 231 nm

In vitro drug release studies

The in vitro drug release study was performed for tablets using USP Type II dissolution apparatus using 900ml of 0.1N HCl at a temperature of 37±0.5ºC at 50 rpm. 5 ml of sample was collected at 0, 2, 4, 6, 8, 12, 16, 20, 24   hours and   the   same volume of fresh media was replenished the drug content in the samples was estimated using UV visible spectrophotometer at 231 nm

Drug-excipient compatibility studies

Fourier transform infrared spectroscopy (FTIR)

The spectral analysis can be used to identify the functional groups in the pure drug and drug- excipient compatibility. Pure Rifaximin FTIR spectra, physical mixtures and optimized formulation were recorded by using FTIR (SHIMADZU). Weighed quantity of KBr and drug-excipients were taken in the ratio 100: 1 and mixed by mortar. The samples were made into pellet by the application of pressure (Maarten Janssenet al., 2016). Then the FTIR spectras were recorded in the wavelength region between 4000 and 400cm−1

Stability studies

Stability testing was conducted at 40°C ± 2°C/75% RH ± 5% RH for 3 months using stability chamber (Thermo Lab, Mumbai). Samples were withdrawn at predetermined intervals 0, 30, 90- and 180-days period according to ICH guidelines (Lalit Kumar Tyagi and Mohan Lal Kori 2014). Various in vitro parameters like drug content, floating lag time and in vitro release studies were evaluated.

RESULTS AND DISCUSSIONS OF RIFAXIMIN FDDS

Construction of standard graph of Rifaximin in acidic buffer (0.1N HCl) pH 1.2

Rifaximin is a UV absorbing molecule with specific chromophores in the structure that absorb at a particular wave length. The λ max of the drug for analysis was determined by taking scan of the drug sample solution in the entire UV region as shown in Figure 6.1.

Figure 1: UV scan of Rifaximin.

Table 4:  Spectrophotometric data for the estimation of Rifaximin.

Figure .2: Standard graph of Rifaximin at a λmax.

The correlation coefficient (R2) of the standard curve was found 0.99. Linearity range and calibration curve was presented in Table 6.1 and Figure 6.2

Evaluation of pre-compression parameters of prepared powder blends of Rifaximin FDDS

The prepared blends were evaluated for different pre-compression parameters and results were shown in Table 6.2.

Table 5 Evaluation of pre-compression parameters of prepared powder blends of Rifaximin formulations.

Above parameters are communicated as average ± standard deviation; (n=3).

The results of bulk densities formulations bearing F1 to F7 were reported to be in the range of 0.52g/cc to 0.78g/cc.

The findings of tapped density formulations F1 to F7 were reported to be in the range of 0.58g/cc to 0.85g/cc.

The angle of repose of all the formulations was found to be satisfactory. The formulations of had angle of repose in the range of 23- 31 thus indicating good flow properties of all the blends.

The compressibility index of all the formulation were found to be in the range of 11-23%. These findings indicated that all formulations exhibited good flow properties.

The Hausner’s ratio values in the space of 1 to 1.2%. These findings designated that the all the batches of formulations exhibited good flow criteria.

Quality control test for Rifaximin floating tablets

Figure .3: Rifaximin floating tablets.

The prepared tablets were evaluated for different post compression and tablets were shown in Figure 6.3.

Table 6: Evaluation of post compression parameters of Rifaximin floating tablets

The post compression parameters of all the formulations were evaluated and presented in Table 6.3.

The maximum weight variation of the formulations was found to be 0.4% which was in the limit allowed that is ± 5% of total tablet weight.

The suitable hardness for compressed tablets is considered as a vital function for the end user. The deliberated crushing strength of fabricated tablets of formulations F1-F21 trended between 6.0- 7.0kg/cm2.

The thickness of all the formulations ranges from 4-4.5 mm.

The friability of all prepared formulation between 0.52-0.78%, the friability properties limits are in between 0-1%.

The drug content of all formulation is in between 95.49-99.18%, drug content depends on the angle of repose since the angle of repose indicates uniform flow nature of powder blend which makes the drug to evenly distribute in all the formulation and to maintain content uniformity in all batches. Tablets of all batches had floating lag time below 60 seconds regardless of viscosity and content of HPMC because of evolution of CO2 resulting from the interaction between sodium bicarbonate and dissolution medium, entrapment of gas inside the hydrated polymeric matrices enables the dosage form to float by lowering the density of the matrices. Total floating time for the Rifaximin with HPMC formulations were more than 24 h. The floating lag time and total floating time of Repagline floating tablets were shown in Figure 6.4.

(a)                    After 36 sec.

(b) After 24 h

Figure 6.4: (a) In vitro buoyancy lag time of the optimized formulation F21 (b) after 24 hours

In vitro drug release studies of Rifaximin floating tablets

The in vitro drug release study was performed for Rifaximin floating tables using USP Type II apparatus. The results of percent cumulative drug release from floating tablets were shown in Table 6.4, 6.5 and 6.6.

Table 7: In vitro cumulative % drug release profile of Rifaximin floating tablets F1-F7.

Above parameters are communicated as average ± standard deviation;

Figure 4: In vitro cumulative % drug release profile of Rifaximin floating tablets F1-F7.

Drug excipient interactions by FTIR spectroscopy

The infra-red spectrum analysis of Rifaximin pure drug and combination blend of optimized formulation were done using KBr pellets and resulting spectrums were shown in figure 6.16 and 6.17.

Figure 6.16: FTIR spectroscopy of Rifaximin pure drug.

Figure 5: FTIR spectroscopy of Rifaximin optimized formulation F21.

FTIR spectrums were mainly used to determine if there is any interaction between the drug and any of the excipients used. The Rifaximin FTIR spectra showed peaks of 3250, 2935, 1758 and 1552cm-1 due to–C=C-H stretching, -C- H stretching, - C=O stretching and –N-H2 bending respectively. The presence of characteristic absorption bands of Rifaximin p u r e drug and optimized floating tablet (F21) containing Rifaximin suggest that there was no interaction between the drug and excipients used in the formulation

Stability studies: The tablets of optimized formulation were evaluated for various parameters at specified stability period kept at temperature of 40±20C and relative humidity of 75%±5%RH.

Table 8: Parameters after accelerated stability study of optimized Formulation F2