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The aim of the project was to develop a solid dispersion of piroxicam with skimmed milk as a carrier in order to increase the solubility and permeability of the drug.
6.1 Measurement of λmax
λmax of 10µg/ml solution was found to be 331 nm as shown in figure 5.1
6.2 Standard graphs of piroxicam
The data of standard graph of piroxicam in SGF- pH 1.2 phosphate buffer (table 5.1, figure 5.2) has shown good linearity over a concentration range of 2-12µg/ml with R2 value of 0.997. The equation of standard graph was y = 0.070x + 0.047.
The data of standard graph of piroxicam in SIF- pH 7.4 phosphate buffer
(table 5.2, figure 5.3) have shown good linearity over a concentration range of 5-25µg/ml with R2 value of 0.997. The equation of standard graph was y = 0.037x-0013.
The data of standard graph of piroxicam in distilled water (table 5.3, figure 5.4) have shown good linearity over a concentration range of 10-40µg/ml with R2 value of 0.992. The equation was y = 0.003x+0.002.
The data of standard graph of piroxicam in pH 4.5 phosphate buffer (table 5.4, figure 5.5) have shown good linearity over a concentration range of 4-20µg/ml with R2 value of 0.993. The equation of standard graph was y = 0.037x+0.006.
The equations were utilized in estimation of piroxicam of samples
6.3 Solubility Studies of SD and PM
The solubility data (table 5.5, figure 5.6) revealed that the solid dispersion powder of 1:4 (SD 4), and physical mixture of ratio 1:4 (PM4) have maximum solubility. The solubility of SD was almost double to that of the Pure Drug.The order of solubility was SD>PM>Pure Drug.
6.4 Invitro release studies
Dissolution profile of solid dispersion powder
Dissolution release of the solid dispersions were analyzed (table 5.6, figure 5.7) and SD4 was selected as the optimized ratio.
Dissolution profile of physical mixtures
Dissolution release of the physical were analyzed (table 5.7, figure 5.8) and PM4 was selected as the optimized ratio.
Dissolution profile of ODT
Dissolution of tablets was carried out (table 5.16, figure 5.15) and the results were satisfactory. 92 % of the drug released from the ODT with in 15 min which conforms to the standards of an ODT (85% release with in 45 mins).
Solid state characterization
Rearrangement of the crystal structure or complete loss of the long-range order (amorphization), or the formation of solid solutions or eutectics are among the common reasons that account for an increased dissolution rate of the APIs from solid dispersions (Leuner,2000). Moreover, the model drug, piroxicam, is known to exhibit polymorphism and is thus susceptible to various solid phase transformations during processing (Vrecer,Sheth). Hence, to gain an insight into the mechanism of improved dissolution rate of piroxicam from solid dispersions, the solid-state properties of these systems were investigated by means of XRD, DSC, SEM and FTIR (Sabiruddin Mirza, 2010).
6.5.1 Differential Scanning Calorimetry
DSC thermograms were analyzed qualitatively by examination of both peak temperature and the endothermic transition contour (Sahin, 2007). The thermogram of piroxicam pure drug is typical of crystalline anhydrous substances and is characterized by a sharp endothermic effect showing a sharp melting peak at 204.70C (figure 5.9). The DSC plot of solid dispersion showed broad peaks at 2000C and 1430C. Since the DSC peak value of SD is away from the piroxicam characteristic crystalline peak value and there is disappearance of the specfic drug peak it could be concluded that the drug in final formulation was less crystalline (more amorphous) and there is an interaction of the drug with the carrier and possible formation of an amorphous solid dispersion.
6.5.2 X-Ray Diffraction (Sahin, 2007).
XRD analysis was used to assess the degree of crystallinity of the solid dispersions.Piroxicam (PRX) showed major peaks at 2θ values of 14.500, 17.690, 27.390, 21.730, 27.790, 22.430,11.640 ,12.480, 16.690 ,26.750 (figure 5.10, pattern A). The diffraction pattern of SM (figure 5.10, pattern B) indicates a typical amorphous character with less detectable diffraction peaks. Analysis of XRD patterns of the selected solid dispersion(figure 5.10, pattern D) indicated that all the major peaks corresponding to piroxicam were disappeared which depicts the conversion of crystalline form of drug to amorphous form which can be attributed to the formation of solid dispersion.
The diffraction pattern of the complex formed should be clearly distinct from that of the superimposition of each of the components if a true amorphous complex is formed.Crystallinity was determined by comparing some representative peak heights in the diffraction patterns of the binary systems with those of a reference.
The relationship used for the calculation of crystallinity was the relative degree of crystallinity (RDC)
Where, I Sample is the peak height of the sample under investigation and I reference is the peak height at the same angle for the reference with the highest intensity. The pure drug peak at 17.70 (2θ) was used for calculating the RDC of solid dispersion and physical mixture. The RDC values of the SD and PM were 0.210 and 0.295 respectively (table 5.8). RDC analyzed shows that there is a decrease in degree of crystallinity which means improvement in the amorphousness of the sample.
6.5.3 Scanning Electron Microscopy (Sahin,2007 and Topaloglu,1999)
SEM images of the samples (Figure 5.11) revealed that the particle size of piroxicam physical mixture is similar to that of the pure drug and possesses mostly amorphous particles of SM and some crystals of the drug.. There is a clear indication of formation of an amorphous complex i.e.,solid dispersion with decreased particle size which is may be attributed to the better solubility and dissolution profile of SD. The surface morphology of drug and SM also changed from smooth to rough which indicates change of solid state.
6.5.4 Fourier Transform Infra -Red Spectroscopy (Topaloglu,1999)
The FTIR spectra of samples of piroxicam are shown in figure 5.12. The pure drug showed numerous characteristic high intensity diffraction peaks demonstrating the crystalline nature of the drug.The diffused peaks in solid dispersion indicate the amorphization of drug.
Characteristic peaks attributable to the functional groups present in the molecule of drug were assigned to establish the identity of the drug compared to solid dispersion and physical mixture (table 5.9). FTIR spectra of Piroxicam reported characteristic peaks of C-H stretching, aromatic CH bending, C-S stretching, C=O stretching C=C,C=N ring stretching, asymmetric S(=O)2 stretching,symmetric S(=O)2 stretching, secondary amine N-H stretching at 2930, 830, 773, 618, 1577, 1630, 1434, 1529, 1351, 1149 and 3338 wavenumbers respectively (table 5.7). The peak at 1577 which is attributed for C=O stretching disappeared in SD which indicates there might be transformation of the drug in to amorphous state due to decarboxylation or new bond formation. Drug- excipient interactions play a crucial role with respect to the stability and potency of the drug. FTIR techniques have been used to study the physical and chemical interaction between drug and excipients used. In the spectra of liquisolid compact optimized formulation (Figure 5.15), the peaks characteristic to the excipients were present at almost same positions, where as piroxicam peaks were also present, but at a reduced intensity of absorption, indicating the trapping of the drug inside the carrier matrix. None of the spectra showed any peaks other than those assigned to PRX drug and excipients, which indicates the absence of any well-defined chemical interactions. Results showed that there is no difference between the IR patterns of the optimized formulation of piroxicam SD ODT and pure drug and all the excipients are compatible with the SD-SKM complex.
In the present investigation, the effect of % of sodium starch glycolate (X1) and % of aerosil (X2) on disintegration time (YDT) and wetting time (YWT) is studied using 32 factorial design. The design revealed wide variation (table 5.10). The data clearly indicate that the dependent variables are strongly dependent on the independent variables. The fitted equation relating the response YDT, YWT to the transformed factor are shown in equations and . The value of correlation coefficient (table 5.11) indicates good fit. The polynomial equation can be used to draw a conclusion after considering the magnitude of coefficient and the mathematical sign it carries (positive or negative). Results of ANOVA were depicted in table 5.12 and the predicted and measured values for optimized piroxicam solid dispersion tablets are shown in table 5.13. To demonstrate the effect of % of sodium starch glycolate (X1) and % of aerosil (X2) on disintegration time (YDT) and wetting time (YWT), the response surface plots ( Figures 5.13 and 5.14) were generated for the dependent variables YDT, YWT using Design- Expert ® Software (Stat- Ease Inc , Minneapolis).
6.6.1 Effect of formulation variables on disintegration time (YDT):
The effect of formulation variables i.e., % of sodium starch glycolate (X1) and % of aerosil (X2) on disintegration time (YDT) is given in the equation.
In the above equation, b1 bears negative sign indicating an increase in the % of SSG (X1) and % of aerosil (X2) decreased the disintegration time, b12 bears negative sign in the same equation indicating the interaction effect of X1X2 decreased the disintegration time, b11 and b22 bears positive sign which indicates that the interaction effect of X1X1 and X2X2 increased the disintegration time.
The relationship between dependent and independent variables was further elucidated using contour plots and 3D plots. The effects of X1 and X2 and their interaction on YDT is given in Figure 5.13. It could be seen that increase in % of SSG and % of aerosil had a negative effect on YDT.
6.6.2 Effect of formulation variables on wetting time (YWT):
The effect of formulation variables i.e., % of sodium starch glycolate (X1) and % of aerosil (X2) on disintegration time (YWT) is given in the equation.
In the above equation, b1 bears negative sign indicating an increase in the % of SSG (X1) and % of aerosil (X2) decreased the wetting time, b12 bears positive sign in the same equation indicating the interaction effect of X1X2 increased the disintegration time, b11 bears positive sign which indicates that the interaction effect of X1X1 increased the wetting time and b22 bears negative sign which indicates that the interaction of X2X2 decreases the wetting time.
The relationship between dependent and independent variables was further elucidated using contour plots and 3D plots. The effects of X1 and X2 and their interaction on YDT is given in Figure 5.14. It could be seen that increase in % of SSG and % of aerosil had a negative effect on YDT.
Characterization of Fast Disintegrating Tablet
6.7.1 Pre-Compression Properties - Micromeritic properties
The powder blends of solid dispersions were evaluated for their flow properties, the results were shown in Table 5.14. Angle of repose (θ) was in the range from 26.3±0.163 to 29.9±0.294 which indicate good flow of the powder for all formulations. The values of bulk density were found to be in the range from 0.34±0.016 to 0.43±0.012gm/cm3, the tapped density was in the range of 0.50±0.016 to 0.71±0.02 gm/cm3. The Carr's index (%) was found to be in the range 36.13±0.205 of 44.59±0.219, the Hausner's ratio was found to be in the range of 0.7±0.016 to 11.20±0.024. These values indicate that the micromeritic properties of all the powder blends for tabletting are within the limits and they exhibit good flow properties and have good compressibility.
6.7.2 Post Compression Properties
The ODT's prepared were evaluated for the post compression parameters and the results were shown in Table 5.15. The thickness of the solid dispersion ODT's was found to be in the range of 2.67 - 2.96 mm.
The hardness of the ODTs was measured by monsanto hardness tester and was found to be ranging from 2.41 - 2.63 kg/cm2. The friability was found to be varying from 0.56±0.09 to 0.74±0.11% which was below 1% for all the formulations, which is an indication of good mechanical resistance of the tablet. The weight variation for different formulations (F1-F9) showed satisfactory results. For estimation of drug content in the ODT formulations, assay studies were performed which showed satisfactory results i.e., piroxicam tablets must contain not less than 90% and not more than 110% of the labeled amount of piroxicam.
6.8 Ex-vivo intestinal permeation studies - Permeation data analysis
The cumulative amount of drug permeated (Q) was plotted against time
(table 5.17 and figure 5.17).The steady state ¬‚ux (Jss) calculated for the Pure drug, PM and SD were 0.00084, 0.00108 and 0.00152 mcg/cm2/hr respectively.The permeability coef¬cient (Kp) of the drug through intestine was found to be 0.84, 1.08, 1.52 cm/hr for Pure drug, PM and SD respectively.The enhancement ratio (ER) was calculated by using the following equation:
The ER values for PM and SD were found to be 1.29 and 1.80 respectively which indicates that the SD permeated more than that of the PM than that of the pure drug.( Alekhya Gurrapu,2011).
Stability studies of the optimized formulation
To determine the change in in-vitro release profile, wetting time, drug content and disintegration time on storage, a temperature sensitivity study of prepared formulations was performed at 40ËšC/75% ± 5% RH for three months. Samples tested after 3 months showed no significant change in wetting time (YWT), drug content (%) and disintegration time (YDT) (Table 5.18), relative to the initial batch which indicate that the prepared solid dispersion ODT. When dissolution release data after storage compared with before storage using paired ttest as shown in table 5.18, indicating an insignificant (P > 0.05) difference in the dissolution profile.Table 5.18 also indicates that there was close proximity in disintegration and wetting time and acceptable variation was observed in drug content of tablets before and after temperature sensitivity studies.