Development And Characterization of Olmesartan Microspheres Prepared by Ionotropic Gelation Method

Table 1: Formulation trials for Olmesartan microspheres

Evaluation of olmesartan microspheres

Particle size

The 100 microspheres were evaluated with respect to their size and shape using optical microscope fitted with an ocular micrometer and a stage micrometer. The particle diameter was measured randomly by optical microscope. Angle of repose, Bulk density, tapped density; Compressibility index and Hausner’s ratio were evaluated according to the reported procedure.

Drug entrapment efficiency and % yield

To determine the incorporation efficiency, 10 mg of formulated microspheres were thoroughly crushed by triturating and suspended in required quantity of methanol followed by agitation to dissolve the polymer and extract the drug. After filtration, suitable dilutions were made and drug content assayed spectrophotometrically at 259 nm. Each batch should be examined for drug content in a triplicate manner.

In vitro drug release studies

Release rate of drug from sodium alginate microspheres was carried out using USP type II dissolution apparatus with 900 ml of 0.1N HCl (pH 1.2) as dissolution medium. Accurately weighed amount of microspheres from each batch were subjected to dissolution studies in triplicate manner. At appropriate intervals up to 12 h, specific volume of aliquots was withdrawn and the same volume was replaced analyzed for the concentration of drug by UV spectrophotometer at 259 nm.

Kinetic Modeling of Drug Release

In order to understand the kinetics and mechanism of drug release, the result of the in vitro dissolution study of microspheres were fitted with various kinetic equations like Zero order as cumulative percentage drug release Vs. time, first order as log percentage of drug remaining to be released Vs. time, Higuchi’s model cumulative percentage drug released Vs. square root of time. r² and K values were calculated for the linear curves obtained by regression analysis of the above plots.

To analyze the mechanism of drug release from the tablets the in vitro dissolution data was fitted to zero order, first order, Higuchi’s release model and Korsmeyer – Peppas model. Drug Excipients Drug Compatibility Studies

The drug excipients compatibility studies were carried out by Fourier Transmission Infrared Spectroscopy (FTIR) method, SEM and Differential Scanning Colorimetry.

Fourier Transform Infrared Spectroscopy (FTIR)

FTIR spectra for pure drug, physical mixture and optimized formulations were recorded using a Fourier transform Infrared spectrophotometer. The analysis was carried out in Shimadzu-IR Affinity 1 Spectrophotometer. The samples were dispersed in KBr and compressed into disc/pellet by application of pressure. The pellets were placed in the light path for recording the IR spectra. The scanning range was 400-4000 cm-1 and the resolution was 1 cm-1.

Differential Scanning Calorimetry (DSC)

Differential Scanning Calorimetry (DSC) studies were carried out using DSC 60, having TA60 software, Shimadzu, Japan. Samples were accurately weighed and heated in sealed aluminum pans at a rate of 10°C/ min between 25 and 350°C temperature rang under nitrogen atmosphere. Empty aluminum pan was used as a reference.

SEM studies

The surface and shape characteristics of pellets were determined by scanning electron microscopy (SEM) (HITACHI, S-3700N). Photographs were taken and recorded at suitable magnification.

Stability studies

The stability study of the optimized formulation was carried out under different conditions according to ICH guidelines. The optimized microspheres were stored in a stability chamber for stability studies (REMI make). Accelerated Stability studies were carried out at 40°C / 75% RH for the best formulations for 6 months. The microspheres were characterized for the percentage yield, entrapment efficiency & cumulative % drug released during the stability study period.

RESULTS AND DISCUSSION

Formulation of Microspheres of Olmesartan

Micromeritic properties of formulated Olmesartan sodium alginate microspheres (Figure 1) were shown in Table 2; all the formulations were evaluated and found to be within the IP limits. Percentage yield and entrapment efficiency of all the fourteen formulations were evaluated and depicted in Table 3. The formulation F8 shown the good percentage yield and entrapment efficiency when compared with other formulations of 99.86% and 97.68%.

Fig. 1: Normal microspheres of Olmesartan

Table 2 : Micromeritic properties of formulated Olmesartan sodium alginate microspheres

Table 3 : Percentage drug yield and entrapment efficiency of Olmesartan microspheres

In Vitro Drug Release Studies: In vitro drug release studies were carried out and depicted in Table 4 & 5 and Figure 2 & 3. Among all the formulations F8 showed best drug release of 99.98 ± 5.28% within 12 h when compared with other formulations.

Table 4: In vitro cumulative % drug release of Olmesartan Ethyl Cellulose microspheres formulations (F1-F5)

Table 5: In vitro cumulative % drug release of Olmesartan HPMC K100 microspheres formulations (F6-F10)

Figure 2 : In vitro cumulative % drug release of Olmesartan Ethyl Cellulose microspheres formulations (F1-F5)

Fig 3 : In vitro cumulative % drug release of Olmesartan HPMC K100 microspheres formulations (F6-F10)

Mathematical modeling of optimized formula of microspheres:

In the view of establishment of release mechanism and quantitatively interpreting and translate mathematically the dissolution date being plotted (Figure 4, 5, 6  and Table 6). From the above results it is apparent that the regression coefficient value closer to unity in case of zero order plot i.e. 0.632 indicates that the drug release follows a zero-order mechanism. This data indicates a lesser amount of linearity when plotted by the first order equation. Hence it can be concluded that the major mechanism of drug release follows zero order kinetics.

Further, the translation of the data from the dissolution studies suggested possibility of understanding the mechanism of drug release by configuring the data in to various mathematical modeling such as Higuchi and Korsmeyer plots.

The mass transfer with respect to square root of the time has been plotted, revealed a linear graph with regression value close to one i.e. 0.9763 starting that the release from the matrix was through diffusion. Further the n value obtained from the Korsmeyer plots i.e. 0.912 suggest that the drug release from microspheres was anomalous Non fickian diffusion.

Table 6 : Release order kinetics of optimized microspheres

Figure 4: Zero order plot for the optimized formulation of Olmesartan micropsheres F8

Figure 5: First order plot for the optimized formulation of Olmesartan microspheres F8

Figure 6: Higuchi plot for the optimized formulation of olmesartan microspheres F8

Drug Excipients Compatibility Studies

FT-IR studies

There was no alteration in peaks of Olmesartan pure drug (Figure 7) and optimized formulation (Figure 8), suggesting that there was no interaction between drug & excipients. There is additional peaks appeared or disappeared hence no significant changes in peaks of optimized formulation was observed when compared to pure drug, indicating absence of any interaction.

Scanning Electron Microscopy

The external and internal morphology of controlled release microspheres were studied by Scanning Electron Microscopy.

Morphology of the various formulations of Olmesartan microspheres prepared was found to be discrete and spherical in shape (Figure 9). The surface of the Olmesartan microspheres was rough due to higher concentration of drug uniformly dispersed at the molecular level in the sodium alginate matrices. There are no crystals on surface which states that is drug is uniformly distributed.

CONCLUSION

Olmesartan loaded microspheres were prepared by ionotropic gelation method. From the results it concluded that formulation F8 was found to be satisfactory results in terms of excellent Micromeretic properties, particle size, yield of microsphere, entrapment efficiency, swelling index and highest in vitro drug release of in a sustained manner with constant fashion over extended period for 12h compared with marketed product in 12 h. The drug and excipients were compatible studied by using FTIR. Drug release from olmesartan microspheres followed Zero order and Higuchi model. It was suggested that mechanism of drug release from microspheres was diffusion controlled. The prepared microspheres were spherical in shape studied by SEM studies. The optimized formulation F8 was stable.