Solid Dispersion Incorporated Microcapsules: Predictive Tools for Improve the Half Life and Dissolution Rate of Pioglitazone Hydrochloride

Veiw figure View Figure

Table 1. Data of absorption and standard absorptivity at different concentration

Download as

Veiw figure View Table

2.2. Phase Solubility Study

Solubility studies were performed according to the Higuchi ^[9] and Connors method. An excess amount of Pioglitazone hydrochloride was placed in to 50ml flask containing different concentration of polyvinyl pyrrolidone K30 and poly ethylene glycol 6000 separately in 25ml distilled water. All flasks were closed with stopper and covered with cellophane membrane to avoid solvent lose. The flasks were kept in the incubator shaker for 72h. After 72h the content of each flask was then filtered through Whatman filter paper; the filtrate was diluted and assayed spectrophotometrically (Shimadzu 1700UV spectrophotometer) for Pioglitazone HCl content at 269nm. All solubility measurements were performed in triplicate (Figure 2).

Figure 2. Phase solubility diagram of Pioglitazone hydrochloride in different carrier

Download as

Veiw figure View Figure

2.3. Preparation of Method
2.3.1. Preparation of Physical Mixture and Solid Dispersions

Physical mixtures were prepared by mixing the appropriate amount of Pioglitazone HCl and Polyvinyl pyrrolidone K30 (PVP K30) and Polyethylene glycol 6000 (PEG 6000) in pestle and mortar separately and passed through sieve # 60. Solid dispersions were prepared by solvent evaporation method. The carrier (PVP K30 and PEG 6000) and adding amounts of Pioglitazone HCl corresponding to ratio 1:1, 2:1, 3: 1 and 5:1 was accurately weighed and mixed properly. This physical mixture was solubilized in a common solvent that is in ethanol (25ml). The solvent was allowed to evaporate in hot air oven at 45°C ± 10°C. The process of evaporation was opted until the constant weight was obtained. This formulation was kept in dessicator for 24h under vacuum. Then, solid dispersion formulation was pulverized using a porcelain mortar and pestle. The pulverized powder was classified using the sieves (size 60# and 120# mesh) and the particle size fraction of 100-250mm was used for the study (Table 2).

Table 2. Composition of solid dispersions (SD) and physical mixtures (PM) of Pioglitazone Hydrochloride

Download as

Veiw figure View Table

2.3.2. Preparation of Solid Dispersion Incorporated Muco-Adhesive Microcapsules

Microcapsules are prepared by orifice- ionic gelation method ^{[10, 11]} by employing the Sodium alginate as a cell forming polymer and Sodium CMC, HPMC and Carbopol as muco-adhesive ^[12] polymers are dissolved in purified water in a corresponding ratio 1:1, 1:3 and 6:1 separately to form a homogenous polymer solution. Core material (solid dispersion of pioglitazone hydrochloride) equivalent to drug (1gm) is added to polymer solution and mixed thoroughly with a stirrer to form a viscous dispersion. The resulting dispersion is then added manually drop wise into CaCl₂ (10%w/v) solution through a syringe with a needle of size no. 18. The added drop lets are related in the CaCl₂ solution for 15 min to complete the curing reactions and to produce spherical rigid microcapsule. The microcapsules are collected by decantation, and the product thus separated, washed repeatedly with water and dried at 45°C for 12 hrs. (Table 3).

Table 3. Composition of different muco-adhesive microcapsules

Download as

Veiw figure View Table

3. Characterization of Solid Dispersion

3.1. Physical Characterization

The surface and internal structure of solid dispersion was observed through the Scanning Electron microscopy (SEM), by using the scanning electron microscope (SEM- LEICA S430, ). (Figure 6E, F).

3.2. Practical Yield

The percentage yield of Pioglitazone in solid dispersion was determined by using the formula:

3.3. Percentage Drug Content

The dispersion system equivalent to 25mg of Pioglitazone hydrochloride was taken in 25ml volumetric flask and dissolved in phosphate buffer (pH 7.4). The volume was made up to the mark with phosphate buffer (pH 7.4) and filtered. One ml of filtrate was further diluted to 10 ml with phosphate buffer (pH 7.4) and absorbance was recorded at 269nm. The amount of drug in each dispersion system was determined spectrophotometrically (Table 4).

Table 4. Drug Content of solid dispersion system

Download as

Veiw figure View Table

3.4. In Vitro Drug Release
3.4.1. Release in pH 7.4-Phosphate Buffer

In vitro release rate of Pioglitazone HCl alone and Pioglitazone HCl from solid dispersion of different samples was determined using single station USP dissolution test apparatus. The dissolution medium consisted of phosphate buffer (pH 7.4) was used. Samples of drug, solid dispersion equivalent with 100mg of drug were spread onto the surface of 900ml of preheated dissolution medium at 37°C. Aliquots of 2ml were withdrawn at regular intervals of time i.e. (5, 10, 15, 20, up to 120min) and the same is replaced with fresh dissolution medium each time. The samples obtained were filtered through Whatman filter paper no. 1. The filtrate was diluted up to 6ml with phosphate buffer (pH 7.4). Then the absorbance was measured at 269nm.

Table 5. Drug release kinetics data of different formulations

Download as

Veiw figure View Table

3.4.2. Drug Release Kinetics Studies

In order to understand the kinetics and mechanism of drug release, the results of the in vitro drug release study were fitted with various kinetic equations like zero order, first order, Weibull model, Korsmeyer -peppas model, Hill equation, Michaelis- Menten model. The kinetic model that best fits the dissolution data was evaluated by comparing the regression coefficient (r) values obtained in various models. (Table 5).

Figure 3. (A) Comparative % release of pure drug and different formulations containing PVP K30 as carrier, (B). Comparative % release of pure drug and different formulations containing PEG 6000 as carrier, (C) Comparative % CDR of different formulations

Download as

Veiw figure View Figure

3.5. Analytical Testing of Solid Dispersion
3.5.1. Fourier Transforms Infrared Spectroscopy

FT-IR spectra (500-4000cm^-1) were obtained on a Nicolet Avatar 37-DTGS FT-IR spectrophotometer (Nicolet) with a resolution of 4 cm^-1. KBr pellets were prepared by gently mixing 1mg sample with 200mg potassium bromide.

3.5.2. X-Ray Diffraction

Diffraction patterns were obtained at room temperature on a Philips PW 1710 Diffractrometer (Philips, Holland). Samples were exposed to Cu Ka radiation, wavelength 1.54060Å through 1 x slits from 5.025 to 59.685 2q with a step size of 0.60° 2q and a count time of 1 sec. per step; the generator was set to 40 kV and 30mA.

4. Characterization of Microcapsules

4.1. Physical Characterization

The surface and inner part of the microspheres was observed through the Scanning Electron microscopy (SEM), (SEM) was performed for surface and inner morphological characterization of microspheres using the scanning electron microscope (SEM- LEICA S430, ). (Figure 6).

Figure 4. FTIR Spectra of (a). Pioglitazone HCL, (B). PVP K30, (C). PEG 6000, (D). PMA13, (E). PMB13, (F). A13, (G). B13

Download as

Veiw figure View Figure

Figure 5. XRD Spectra of (a) Pioglitazone HCL, (B) PVP K30, (C) PEG 6000, (D) PMA13, (E) PMB13, (F) A13, (G) B13

Download as

Veiw figure View Figure

Figure 6. SEM photographs of Pioglitazone (A) microcapsules with size ranging approximately from 300 to 900μm, (B) Individual microcapsules (C) microcapsules showing the size 353.33μm, (D) Surface topography analysis of microcapsules, (E) Internal structure of solid dispersion of sample B13 and (F) show the amorphous and A13 show the crystalline stage

Download as

Veiw figure View Figure

4.2. Particle Size Distribution

Different sizes of microcapsules in a batch were separated by sieving method using a range of standard sieves (#10, #22, #44, #52 and # 60). The amount retained on different sieves was weighed. From the obtained data, weight percent retained on different sieves and average size of microcapsules were calculated.

4.3. Practical Yield:

The percentage yield of Pioglitazone in the microencapsulated product is determined by using the formula:

Table 6. Characterization of muco-adhesive microcapsules

Download as

Veiw figure View Table

4.4. Percentage Drug Content

About 500mg of microcapsule was accurately weighed and transfer in to 1000ml beaker, which contain 900ml of 7.4 phosphate buffer at 37°C. The phosphate solution was steered continuously until all the microcapsules were dissolved. Drug loading was determined by U.V Photometric method at 269nm.

(Microencapsulation efficiency) was calculated by the following formula:

4.5. Encapsulation Efficiency

The encapsulation efficiency of microcapsules was calculated by using the formula:

Figure 7. FIR of (A) Pioglitazone HCl, (B) Sodium alginate, (C) Carbopol, (D) Sodium CMC, (E) HPMC, (F) Mixture of A, B and C, (G) Mixture of A, B and D, (H) Mixture of A, B and E

Download as

Veiw figure View Figure

4.6. Fourier Transforms Infrared Spectroscopy

FT-IR spectra (500-4000 cm^-1) were obtained on a Nicolet Avatar 37- DTGS FT-IR spectrophotometer (Nicolet) with a resolution of 4 cm^-1. KBr pellets were prepared by gently mixing 1 mg sample with 200 mg potassium bromide (Figure 7).

4.7. In-Vitro Drug Release
4.7.1. Release in pH 7.4-Phosphate Buffer

In vitro release rate of Pioglitazone HCl from microcapsules of different samples was determined using single station USP dissolution test apparatus. The dissolution medium consisted of phosphate buffer (pH 7.4) was used. Samples of drug, microcapsules equivalent with 100mg of drug was spread onto the surface of 900 ml of preheated dissolution medium at 37°C. Aliquots of 5 ml were withdrawn at regular intervals of time i.e. (.5, 1, 2, and 3 up to 18 hour) and the same is replaced with fresh dissolution medium each time. The samples obtained were filtered through Whatman filter paper no. 1. The filtrate was diluted up to 6ml with phosphate buffer (pH 7.4). Then the absorbance was measured at 269nm (Figure 8).

Figure 8. Comparative drug release of various compositions

Download as

Veiw figure View Figure

4.7.2. Drug Release Kinetics Studies

Table 7. Microspheres adherence capacity

Download as

Veiw figure View Table