Characterization of Carvedilol physical mixture Characterization of Carvedilol was carried out compared to pure drug for saturation solubility studies, FTIR, DSC, SEM analysis, and in-vitro dissolution studies. A remarkable enhancement in solubility of Carvedilol in presence of sepitrap 4000 compared to pure Carvedilol was observed in saturation solubility studies. There was increase in solubility in case of physical mixture of Carvedilol with polymers which clearly indicated that use of novel solubilizer like β- cyclodextrin and PlasdoneK-30 is most useful for solubility enhancement of poorly soluble drugs. Physical mixture of Carvedilol and β-cyclodextrin and PlasdoneK-30 does not show any additional peaks and also retained principle IR peaks of pure Carvedilol, which indicates no interaction between Carvedilol and solubilizer. Overall results of FTIR showed that polymers can be used as solubilizer for pre-treatment of Carvedilol, as it is compatible with Carvedilol.
These results were supported by DSC thermogram, as peak broadening, reduction in intensity, and early onset as compared to pure Carvedilol indicate that polymers is useful in reduction of drug’s crystalline, which definitely affects its solubility. SEM images of Carvedilol and β-cyclodextrin and PlasdoneK-30 physical mixture show slight changes in its surface structure due to hydrogenated castor oil in solid form, which may not affect solubility enhancement. In-vitro dissolution study showed approximately fourfold increase in percent drug dissolution in physical mixture with polymers as compared to pure drug at end of 60 min Fig. 1. Carvedilol dissolution was significantly improved, mainly due to increase in both wet ability and localized solubilization. Overall characterization of Carvedilol and polymers as compared to pure Carvedilol showed positive effect of use of novel solubilizer for enhancement of solubility and dissolution rate, which will be further beneficial in development of pulsatile tablets to overcome absorption, a rate-limiting step.
FTIR (drug–polymer compatibility study)
FTIR spectra of physical mixtures of Carvedilol and β-cyclodextrin and PlasdoneK-30 polymers did not show any new peaks, indicating no new chemical bonds were created due to any interaction. FTIR spectra of Carvedilol, along with all excipients used for compression coating and in core tablet, did not show any appreciable change in characteristics of pure drug, indicating various polymers used for formulation were compatible and did not interact with Carvedilol shown in Fig. 2.
DSC study
Thermal analysis was employed in addition to FTIR studies to demonstrate any unexpected interaction between Carvedilol with β-cyclodextrin and Plasdone K-30 polymer used for pulsatile formulation, including Croscarmellose sodium, Microcrystalline Cellulose, Lactose, Magnesium Stearate, Talc, Sunset Yellow etc. A sharp endothermic peak with onset temperature of 115 °C and a peak at 117 °C corresponds to melting point of Carvedilol was observed in thermogram of pure Carvedilol. Physical mixture of Carvedilol showed broadening of peak with reducing peak intensity, and onset temperature. Peak broadening, reduction in intensity and early onset as compared to pure Carvedilol indicate that β-cyclodextrin and Plasdone K-30 mixture shows dominance of its amorphous form, which describes positive effect. DSC thermogram of Carvedilol with all excipients together showed onset at 115.48°C and peak at 117. 65°C indicating slight shift of peak with marked broadening, which corresponds to influence of other excipients used in formulation. DSC studies supported results of FTIR and which indicates there was compatibility between Carvedilol and all other additives used for press-coated pulsatile formulation. DSC thermogram of pure Carvedilol, physical mixture of Carvedilol with novel with all excipients are shown in Fig. 3
PXRD study
The X-ray diffractogram of the drug powder with excipients was characterized by the presence of sharp peaks indicative of the crystalline nature of drug. The XRD curve of shown in Fig. 4.
Evaluation of pre‑compression parameters for core tablet blend
Physical mixtures as per formulas of various batches of core tablets were evaluated for flow properties before compression. Values of bulk density, tapped density, Carr’s index, and Hausner’s ratio were calculated and depicted in Table 5. From physical properties of powder blends of various batches of core tablets, it was confirmed that all of them are suitable to formulate tablets using direct compression technique. Bulk density and tap density of powder blend for core tablet batch L1 were found to be 0.464 g/ml and 0.586 g/ml, respectively (Batch L1) was used for further development of pulsatile tablet). Hausner’s ratio of 1.23 further confirms good compressibility and passable flow property of the material, which is confirmed by Carr’s index of 22.04%.
Table No. 5: Pre-compression evaluation of core tablet blend
Batch Code
|
Bulk Density* (g/cm3)
|
Tapped Density* (g/cm3)
|
Angle of Repose* (°)
|
Bulkiness (cm3/gm)
|
Carr’s Compressibility Index (%)*
|
Hausner’s
ratio*
|
L1
|
0.464±0.02
|
0.586±0.02
|
25.24±0.14
|
2.3407
|
22.4±0.03
|
1.23±0.01
|
L2
|
0.475±0.01
|
0.567±0.03
|
29.61±0.15
|
2.4281
|
20.5±0.01
|
1.24±0.01
|
L3
|
0.467±0.03
|
0.597±0.01
|
26.47±0.13
|
2.4304
|
21.6±0.02
|
1.26±0.03
|
L4
|
0.439±0.02
|
0.549±0.04
|
29.80±0.15
|
2.4972
|
21.7±0.02
|
1.24±0.05
|
Evaluation of post compression parameters of core tablets
Core tablets from each batch were evaluated for average weight, thickness, disintegration time, drug content, hardness, and % friability. Tablets showed good weight uniformity, as indicated by low value of relative standard deviation (RSD≤ 1%). Tablet thickness was found in range of 0.302±0.04 mm to 0.328±0.03 mm. Core tablets, which contain 10% disintegrant in their composition show disintegration time of 32±0.078 s, which was closer to core tablet composition containing 12.5% disintegrant; hence, core tablet batch L1 was further used to develop press-coated pulsatile tablet. Drug content uniformity of tablet was found to comply with official specification, as assay value was found to be in range of 97.52±0.08 to 99.65±0.23% of theoretical value. Tablet hardness varied from 2.8±0.2 to 3.5±0.6 kg/cm2 , which was sufficient for core tablet as it was compressed again in subsequent step of pulsatile formulation. Tablets passed friability test, as all batches were within Pharmacopoeia limit (F ≤ 1%). Results of various post-compressional parameters are reported in Table 6.
Table No. 6: Post-compression evaluation of core tablets
Batch Code
|
Average Weight (mg)
|
Thickness (mm)*
|
Hardness (kg/cm2)*
|
Friability (%)*
|
Disintegration Time(sec)*
|
% Drug content [n=3]
|
L1
|
99.0
|
0.302±0.04
|
3.2±0.02
|
0.197±0.003
|
32±0.078
|
98.87±0.44
|
L2
|
98.3
|
0.312±0.03
|
3.5±0.06
|
0.104±0.007
|
37±0.240
|
99.65±0.23
|
L3
|
99.5
|
0.328±0.03
|
2.8±0.02
|
0.132±0.001
|
34±0.015
|
97.52±0.08
|
L4
|
98.1
|
0.311±0.02
|
3.5±0.04
|
0.146±0.005
|
39±0.317
|
98.02±0.31
|
In‑vitro dissolution study of core tablet
The drug release study of the core tablets was performed as mentioned in the experimental study. The maximum drug release was observed at 30min. Hence, these core tablets can be used as immediate release tablets in formulation of Press-coated tablets for treatment of hypertension. The cumulative drug release profile of the immediate release tablets is shown in Table 7. As the concentration of CCS was increased, the disintegration time decreased and dissolution rate of drug increased. From the observations, L1 was selected as best formulation since it showed maximum drug release in 30 minutes with greater disintegration rate. This batch was further used to formulate press-coated tablets.
TableNo.7: Cumulative Drug Release data of immediate release core tablets
Sr.
No
|
Time (min)
|
% Cumulative drug release*
|
L1
|
L2
|
L3
|
L4
|
1
|
0
|
0.00±0.00
|
0.00±0.00
|
0.00±0.00
|
0.00±0.00
|
1
|
5
|
25.21±0.12
|
23.63±0.13
|
29.73±0.13
|
25.35±0.13
|
2
|
10
|
43.44±0.15
|
42.19±0.15
|
43.57±0.12
|
48.49±0.12
|
3
|
15
|
79.56±0.14
|
77.61±0.12
|
67.50±0.12
|
75.27±0.15
|
4
|
20
|
86.81±0.12
|
85.96±0.13
|
78.48±0.13
|
81.61±0.13
|
5
|
25
|
95.67±0.12
|
88.49±0.12
|
89.18±0.14
|
87.69±0.13
|
6
|
30
|
98.58±0.13
|
92.34±0.12
|
95.73±0.15
|
90.88±0.12
|
In-vitro drug release study of solid dispersion
a. Saturation solubility of prepared solid dispersions in various solvents-
The solubility of spray dried solid dispersions of Carvedilol in distilled water, 0.1N HCl (pH 1.2) and in phosphate buffer (pH 6.8) was determined so as to select an appropriate batch of solid dispersion for further formulation of tablets. The increase in solubility was found to be linear with respect to the increase in the concentration of carrier. The batch SD6 with drug to Plasdone K-30 ration of 1:3 showed greater increase in the solubility as compared to β-cyclodextrin. This is due to the greater hydrophilicity of Plasdone K-30 than β-cyclodextrin. PVP polymers cause a reduction in the interfacial tension between the drug and the dissolving solution. Moreover, it was suggested that Plasdone K-30 might form soluble complexes with the drug. Also the wettability and porosity of the particles was also increased. The results of solubility study of solid dispersion of Carvedilol are tabulated in Table No.8.
TableNo.8: Saturation Solubility of various batches of solid dispersion
Batch
|
Polymer
|
Drug: Polymer
|
Solvents
|
Code
|
ratio
|
Distilled water*
|
0.1NHCl (pH 1.2)*
|
Phosphate buffer(pH 6.8)*
|
SD1
|
β- cyclodextrin
|
1:1
|
0.3854±0.2
|
0.8754±0.3
|
0.6749±0.4
|
SD2
|
1:2
|
0.6749±0.2
|
0.9916±0.2
|
0.8443±0.1
|
SD3
|
1:3
|
0.8357±0.4
|
1.2837±0.4
|
1.3786±0.1
|
SD4
|
Plasdone K-30
|
1:1
|
0.3774±0.3
|
1.8412±0.3
|
0.7692±0.2
|
SD5
|
1:2
|
0.8576±0.4
|
2.6348±0.4
|
1.0428±0.3
|
SD6
|
1:3
|
1.1729±0.4
|
4.1587±0.2
|
1.4287±0.2
|
b. The dissolution profiles of solid dispersion batches
The dissolution profiles of solid dispersion batches are shown in table No. 9. It was evident that the pure drug exhibited a slow dissolution even after 60 minutes where the percentage of drug dissolved after 60 minutes only reached about 18.58±0.02%. This is due to the hydrophobicity, poor wetability and/or agglomeration of Carvedilol particles resulting into hindering its dissolution. All solid dispersions showed enhanced dissolution rate compared to pure Carvedilol that might be due to the effect of hydrophilic carriers on drug wetability and solubility. These results could be attributed to the general phenomenon of particle size reduction of Carvedilol particle during the spray drying operation. Also solubilization, molecular/colloidal dispersion of drug in the mixture and reduction in the drug crystallinity (i.e. polymorphic transformation of drug crystals) that were obtained via the formulation of solid dispersions using spray dryer could have contributed to the increase in solubility. The batch SD6 with Carvedilol to Plasdone K-30 ratio of 1:3 showed the maximum drug release as compared to the other batches. The drug release profile of the solid dispersion batches is shown in table No. 9.
Table No.9: Cumulative % drug release data of Solid dispersion batches
Sr.
No
|
Time
(min)
|
% Cumulative drug release*
|
Pure drug
|
SD1
|
SD2
|
SD3
|
SD4
|
SD5
|
SD6
|
1
|
0
|
0.00±0.00
|
0.00±0.00
|
0.00±0.00
|
0.00±0.00
|
0.00±0.00
|
0.00±0.00
|
0.00±0.00
|
2
|
10
|
3.31±0.03
|
12.45±0.05
|
19.34±0.06
|
26.47±0.05
|
32.67±0.03
|
39.57±0.03
|
43.56±0.03
|
3
|
20
|
5.73±0.01
|
33.48±0.06
|
39.37±0.03
|
37.46±0.02
|
48.29±0.01
|
47.67±0.03
|
58.26±0.02
|
4
|
30
|
8.06±0.03
|
48.87±0.05
|
46.35±0.02
|
52.67±0.03
|
54.42±0.03
|
59.34±0.01
|
69.41±0.06
|
5
|
40
|
11.41±0.02
|
66.48±0.04
|
59.14±0.03
|
68.77±0.03
|
63.97±0.03
|
69.44±0.02
|
84.19±0.03
|
6
|
50
|
13.67±0.02
|
75.95±0.06
|
76.73±0.03
|
80.91±0.01
|
71.26±0.01
|
76.99±0.01
|
89.61±0.04
|
7.
|
60
|
18.58±0.02
|
79.37±0.04
|
81.16±0.01
|
88.38±0.03
|
78.96±0.03
|
89.76±0.03
|
93.39±0.06
|
Differential Scanning Calorimetry (DSC) study of optimized solid dispersion batch (SD6)-
The DSC thermogram of solid dispersion showed a disappearance of the endothermic peak which was observed in the DSC curve for pure Carvedilol and also there was change in the peak intensity shown in Fig No. 5. The absence of endothermic peak might be due to the formation of solid dispersion of the drug in the presence of hydrophilic polymer where the crystalline drug could be transformed into an amorphous state. This amorphousness might be related to the intermolecular hydrogen bonding and complexation between drug and Plasdone K-30, respectively. The thermogram of spray dried particles of Carvedilol showed change in the melting point which is shown as a broad peak at 950C. Such change in the melting point indicates changes in the crystalline state of Carvedilol after spray drying process. Also, the melting temperature of solid dispersion decreases with decreasing their particle size. The melting temperature increases as the particle size increases. Thus, as the particle size decreases surface area-to-volume ratio of the particle increases. The larger surface area allows a greater interaction with the solvent and ultimately enhances the solubility of the drug.
Scanning Electron Microscopy (SEM) of solid dispersion batch SD6-
SEM images of the prepared Carvedilol solid dispersion is shown in Fig.6. The particles of the solid dispersion were found to be spherical in shape. The particle size of the spray dried particles is also decreased. This is essential to enhance the solubility. SEM showed smooth surface of Carvedilol solid dispersion particles with greater number of pores which indicated that there is increase in the porosity and hence the dissolution rate of these particles was also increased. This shows that transformation of the crystalline drug into amorphous state has occurred with enhanced solubilization and dissolution rate of the spray dried particles.