Appendix 1 - shodhganga.inflibnet.ac.inshodhganga.inflibnet.ac.in/bitstream/10603/7584/11/11_appendix.pdf · Appendix 1 Solubility ... Saturation solubility in biorelevant media

Appendix 1

Solubility enhancement of BCS Class II/IV drugs 270

Chapter 1.Introduction

Table 1.1. BCS Classification

Table 1.2. Lipid formulation classification system

Table 1.3. Physical properties and molecular dimension of Cyclodextrins

Table 1.4. Bond work index

Chapter 2.Preformulation studies

Section 2.1

Table 2.1.1.Evaluation of TEL

Table 2.1.2.Evaluation of CP

Table 2.1.3.Evaluation of Vitamin E TPGS

Table 2.1.4.Evaluation of PEG 6000

Table.2.1.5.Evaluation of PVPK 30

Table 2.1.6.Evalaution of Poloxamer 188

Table 2.1.7.Evalaution of β- cyclodextrin

Table 2.1.8. Evaluation of DPC

Table 2.1.9. Evaluation of NaHCO3

Table. 2.1.10.Evaluation of Capmul MCM

Table 2.1.11.Evaluation of tween 80

Chapter 3.Methodology

Part I:Analytical method development

Part II: Experimental for TEL

Table 3.1. Formulae for FaSSIF and FeSSIF

Table 3.2: Different ratios of β-CD:cross-linker used for synthesizing NSs

Table 3.3: Coding for different inclusion complexes

Table 3.4. Formulae for nanosuspensions of TEL

Table 3.5.Protocol for animal testing for pharmacokinetic parameters of TEL nanosuspension

Table 3.6.Actual values of independent variables for Box-Behnken design for TEL

Part III: Experimental for CP

Table 3.7. Formula for nanosuspensions of CP

Table 3.8. Formulations containing T80: PG (4:1) and Capmul MCM

Table 3.9. Formulations containing T80: TPGS (1:0.5) and Capmul MCM

Table 3.10. Protocol for animal testing for pharmacokinetic parameters of CP SNEDDS

Table 3.11. Formula for enriched nutrient broth

Table 3.12. Dilution series for microbiological test of CP SNEDDS

Table 3.13 Formula for tryptic soy broth

Table 3.14. Levels of two variables for 2 component mixture design for CP-SNEDDS

Table 3.15.Trials with various levels of the variables for CP SNEDDS

Chapter 4.Results and Discussion

Part I: Analytical method development

Section 4.1.TEL

Table 4.1.1.Calibration data of TEL in D.W.

Appendix 1


Table 4.1.2.Calibration data of TEL in 0.1N HCl

Table 4.1.3.Calibration data of TEL in phosphate buffer pH 6.8

Table 4.1.4.Calibration data of TEL in FaSSIF

Table 4.1.5.Calibration curve data of TEL in FeSSIF

Table 4.1.6.Calibration data for TEL by HPLC

Table 4.1.7.Peak area at different concentrations

Table 4.1.8. Linearity of relation between concentration and peak area

Table 4.1.9.Intraday and interday precision data

Table 4.1.10.Data for accuracy and recovery

Table 4.1.11.Calibration data for HPLC of TEL (Bioanalytical)

Section 4.2.CP

Table 4.2.1. Calibration data of CP in DW.

Table 4.2.2.Calibration data of CP in 0.1N HCl

Table 4.2.3. Calibration data of CP in phosphate buffer pH 6.8

Table 4.2.4. Calibration data of CP in FaSSIF

Table 4.2.5.Calibration data of CP in FeSSIF

Table 4.2.6. Calibration curve data of CP in USP medium

Table 4.2.7. Calibration curve data of CP by HPLC

Table 4.2.8. Peak area at different concentrations

Table 4.2.9. Linearity of relation between concentration and peak area

Table 4.2.10. Intraday and interday precision data

Table 4.2.11.Data for accuracy and recovery Table 4.2.12. Calibration curve for Cefpodoxime

Part II: Results and Discussion (TEL)

Section 4.3. Saturation solubility studies

Table 4.3.1. Saturation solubility of TEL in various media

Section 4.4.Nanosponges

Table 4.4.1. Percent porosity of β-CD and NS

Table 4.4.2. Drug content in binary and ternary complexes

Table 4.4.3. Saturation solubility in DW

Table 4.4.4. Saturation solubility in 0.1 N HCl, phosphate buffer pH 6.8

Table 4.4.5. Saturation solubility in biorelevant media

Table 4.4.6. Percent release of TEL complexes in DW

Table 4.4.7. Percent release of TEL complexes in 0.1 N HCl

Table 4.4.8. Percent release of TEL complexes in buffer pH 6.8

Table 4.4.9. Drug content of stability study samples

Table 4.4.10. Percent release of IC6 in 0.1N HCl

Section 4.5.Nanosuspensions/Nanocrystals

Table 4.5.1 Solubility of TEL in various solvents

Appendix 1


Table 4.5.2. Particle size analysis of TEL nanosuspensions

Table 4.5.3.Saturation solubility in DW Table 4.5.4.Saturation solubility in 0.1 N HCl, phosphate buffer p H 6.8 Table 4.5.5.Saturation solubility in biorelevant media Table 4.5.6.Dissolution data of NC-TEL in various media

Table 4.5.7.Dissolution parameters of TEL nanosuspension spray coated Espheres in 0.1N HCl

Table 4.5.8. Model fitting of dissolution of TEL nanosuspension spray coated Espheres Table 4.5.9. Residual sum of squares for model fitting of dissolution data in 0.1 NHCl

Table 4.5.10. Residual sum of squares for model fitting of dissolution data in pH 6.8 buffer

Table 4.5.11. Drug content in stability samples of pellets

Table 4.5.12. Percent transmittance of nanosuspension at various pH

Table 4.5.13.Pharmacokinetic parameters of TEL nanosuspension

Table 4.5.14. Optimization of SnCl2

Table 4.5.15.Optimization of pH Table 4.5.16.Optimization of mixing time

Table 4.5.17. In vitro stability of radiolabelling

Table 4.5.18. Organ distribution of TEL-nanosuspension

Table 4.5.19. Cardiovascular parameters for TEL nanosuspension

Table 4.5.20. Various parameters of ECG studies of TEL nanosuspension

Table 4.5.21. Microscopic findings of sub-acute oral toxicity studies

Table 4.5.22.Response parameters for various runs of the experimental design

Table 4.5.23.ANOVA for Response surface quadratic model

Part III: Results and Discussion (CP)

Section 4.6. Saturation solubility studies

Table 4.6.1.Saturation solubility of CP in various media


Table 4.7.1.Saturation solubility of CP in various media Table 4.7.2.Saturation solubility of CP in biorelevant media Table 4.7.3. Dissolution data of NS-CP in various media

Table 4.7.4.Model fitting of dissolution of NS-CP in 0.1NHCl

Section 4.8.Nanosuspensions/Nanoparticles Table 4.8.1. Particle size analysis of CP nanosuspensions

Table 4.8.2. Saturation solubility of CP nanoparticles in various media

Table 4.8.3. Saturation solubility of CP nanoparticles in biorelevant media Table 4.8.4. Dissolution data of NP-CP coated pellets in various media

Table 4.8.5. Release kinetics of dissolution of NP-CP coated pellets in phosphate buffer

Section 4.9.SNEDDS

Table 4.9.1. Saturation solubility of CP in various oils, surfactants and co-surfactants

Table 4.9.2.Percent transmission of Smix:tween 80: propylene glycol(4:1) &oil:Capmul MCM Table 4.9.3.Percent transmission of: tween 80:TPGS (1:0.5) & Capmul MCM in various media

Table 4.9.4. Globule size distribution and zeta potential of CP-SNEDDS

Table 4.9.5. Cloud point of CP-SNEDDS formulations

Table 4.9.6. Emulsification time for CP-SNEDDS formulations

Table 4.9.7. Rheological data of CP-SNEDDS formulations

Appendix 1


Table 4.9.8. Saturation solubility in DW Table 4.9.9. Saturation solubility at various pH Table 4.9.10. Saturation solubility in biorelevant media

Table 4.9.11. Dissolution data of CP-SNEDDS in DW

Table 4.9.12. Dissolution data of CP-SNEDDS in 0.1NHCl

Table 4.9.13.Amount of CP diffused at different time intervals

Table 4.9.14. Micromeritic properties of SNEDDS adsorbed on various adsorbents

Table 4.9.15.Dissolution data of CP,CP-SNEDDS & SNEDDS coated Espheres in buffers/DW

Table 4.9.16.Dissolution data of CP,CP-SNEDDS & SNEDDS coated Espheres in USP

dissolution medium

Table 4.9.17. Model fitting of dissolution of CP-SNEDDS in 0.1N HCl and pH 6.8 buffer

Table 4.9.18. Residual sum of squares for model fitting of dissolution data in 0.1N HCl

Table 4.9.19. Residual sum of squares for model fitting of dissolution data in pH 6.8 buffer

Table 4.9.20.Evaluation of stability samples of CP SNEDDS

Table 4.9.21.Pharmacokinetic parameters of CP-SNEDDS

Table 4.9.22. Absorbance data of serially diluted conventional preparation of CP and CP-

SNEDDS for S. aureus


SNEDDS for B. subtilis


SNEDDS for E.coli

Table 4.9.25.Optimization of SnCl2

Table 4.9.26.Optimization of pH

Table 4.9.27.Optimization of mixing time

Table 4.9.28. In vitro stability of radiolabelling

Table 4.9.29.Organ distribution of CP-SNEDDS

Table 4.9.30. Microscopic findings of sub-acute oral toxicity studies

Table 4.9.31. Results of response parameter for mixture design trials

Table 4.9.32.ANOVA for partial sum of squares

Table 4.9.33.Evaluation of scale up batch of TEL nanosuspension

Table 4.9.34.Evaluation of scale up batch of CP SNEDDS

Appendix 2


LIST OF FIGURES

Chapter 1:Introduction

Figure 1.1. Structure of Sulindac

Figure 1.2. Types of Cyclodextrins.

Figure 1.3.Toroidal structure of Cyclodextrin

Figure 1.4. Crosslinking of β-CD with diphenyl carbonate

Chapter 2: Preformulation studies

Section 2.1

Figure 2.1.1. UV spectrum of TEL

Figure 2.1.2. FT-IR spectra of TEL

Figure 2.1.3. DSC thermogram of TEL Figure 2.1.4. UV spectrum of CP

Figure 2.1.5. FT-IR spectra of CP

Figure 2.1.6. DSC thermogram of CP

Figure 2.1.7. FT-IR spectra of Vitamin E TPGS

Figure 2.1.8. FT-IR spectra of PEG 6000

Figure 2.1.9. FT-IR spectra of PVPK 30

Figure 2.1.10. FTIR spectra of Poloxamer 188

Figure 2.1.11. FT-IR spectra of β-CD

Section 2.2

Figure 2.2.1.FTIR spectra of A= TEL; B= β CD;C = NS; D = Drug loaded NS; E = NaHCO3

added Drug loaded NS

Figure 2.2.2. IR spectra of A=TEL,B= PVPK30 C=TEL-PVP

Figure 2.2.3. IR spectra of A=TEL,B= PEG 6000, C=TEL-PEG6000

Figure 2.2.4.IR spectra of A=TEL,B=P188 C=TEL-P188

Figure 2.2.5. IR spectra of A=TEL, B= TPGS,C=TEL-TPGS

Figure 2.2.6.IR spectra of A=CP, B=NS, C=CP-NS

Figure 2.2.7.IR spectra of A=CP, B=CP-Capmul MCM, C=CP-tween 80,D=CP-TPGS

Figure 2.2.8.IR spectra of A=CP, B=CP-P188, C=CP-TPGS,

Chapter 4:Results and Discussion


Section 4.1.TEL

Figure 4.1.1.Calibration curve of TEL(DW)

Figure 4.1.2 Calibration curve of TEL(0.1N HCl)

Figure 4.1.3. Calibration curve of TEL(phosphate buffer pH 6.8)

Figure 4.1.4.Calibration curve of TEL(FaSSIF)

Figure 4.1.5 Calibration curve of TEL(FeSSIF)

Figure.4.1.6.Calibration curve for TEL(HPLC)

Figure 4.1.7.Representative chromatogram of TEL(HPLC)

Figure 4.1.8.Chromatogram of control (plasma)

Figure 4.1.9.Representative chromatogram of TEL extracted from plasma

Appendix 2


Figure 4.1.10. Calibration curve of TEL by HPLC (Bioanalytical)

Section 4.2.CP

Figure 4.2.1. Calibration curve of CP in DW

Figure 4.2.2. Calibration curve of CP in 0.1N HCl

Figure 4.2.3. Calibration curve of CP in phosphate buffer pH 6.8.

Figure 4.2.4. Calibration curve of CP in FaSSIF

Figure 4.2.5. Calibration curve of CP in FeSSIF

Figure 4.2.6. Calibration curve of CP in USP medium

Figure 4.2.7.Calibration curve of CP by HPLC

Figure 4.2.8. Representative chromatogram of CP by HPLC

Figure 4.2.9. Chromatogram of Control (plasma)

Figure 4.2.10. Representative Chromatogram of Cefpodoxime from rat plasma

Figure 4.2.11. Calibration curve for Cefpodoxime



Figure 4.4.1. Schematic representation of chemical reaction between β-CD and DPC.

Figure 4.4.2. NMR spectra of (A) β-CD; (B) NS2.

Figure 4.4.3. Phase-solubility profiles

Figure 4.4.4. Phase solubility diagram in water.

Figure 4.4.5. Solution state interaction studies of TEL

Figure 4.4.6. 3D image of depicting dimensions of TEL molecule

Figure 4.4.7. 3D image showing possible mode of entrapment of TEL in β CD structure

Figure 4.4.8. 3D image showing possible mode of entrapment of TEL in NS structure

Figure 4.4.9. Inclusion complex of β-CD and TEL

Figure 4.4.10.Saturation solubility in various media

Figure 4.4.11. FTIR spectra of A= TEL; B= β- CD; C = NS; D = Drug loaded NS; E =

NaHCO3 added Drug loaded NS.

Figure 4.4.12. DSC spectra of A= TEL, B= β – CD, C=NS, D= Drug loaded NS; E =

NaHCO3added Drug loaded NS.

Figure 4.4.13. PXRD spectra of A= TEL , B= β – CD,C=NS , D= Drug loaded NS.

Figure 4.4.14. SEM of (A) TEL; (B) β- CD; (C) NS; (D) Drug loaded NS.

Figure 4.4.15.Dissolution profiles of TEL complexes in DW

Figure 4.4.16.Dissolution profiles of TEL complexes in 0.1 N HCl

Figure 4.4.17. Dissolution profiles of TEL complexes in buffer pH 6.8.

Section 4.5:Nanosuspensions/Nanocrystals

Figure 4.5.1. Particle size distribution of TEL nanosuspension(T0)








Appendix 2




Figure 4.5.11. Average particle size of TEL nanosuspensions

Figure 4.5.12.Stern model showing the course of the potential in the electrical double layers

Figure 4.5.13.Adsorbed polymer layer shift the plane of shear from particle surface

Figure 4.5.14.Saturation solubility of TEL and NC in different media

Figure 4.5.15.IR spectra of A)TEL,B)PVPK30, C)TEL-PVPK30

Figure 4.5.16. IR spectra of A)TEL,B)PEG6000,C)TEL-PEG6000

Figure 4.5.17. IR spectra of A)TEL, B) P188,C)TEL-P188

Figure 4.5.18. IR spectra of A)TEL, B)TPGS,C)TEL-TPGS

Figure 4.5.19. DSC thermograms of A) TEL B) NC-TEL

Figure 4.5.20. PXRD spectra of A] TEL, B] NC-TEL

Figure 4.5.21. Specific surface area A] Plain TEL B] NC-TEL

Figure 4.5.22. Contact angle of A] Plain TEL B] NC-TEL

Figure 4.5.23. SEM of A) TEL B) NC-TEL

Figure 4.5.24. Gas chromatogram of A) DCM B) NC- TEL

Figure 4.5.25.SEM of A] Plain Espheres B] Nanosuspension coated Espheres

Figure 4.5.26. Qt30min for TEL, NC-TEL and pellets Figure 4.5.27. Dissolution profile of TEL nanosuspension spray coated Espheres in 0.1NHCl

Figure 4.5.28. Particle size distribution of nanosuspension (T8) kept at room temperature Figure 4.5.29. Particle size distribution of nanosuspension (T8) kept at 40 ºC /75% RH

Figure 4..5.30. Particle size distribution of nanosuspension (T8) kept under refrigeration Figure 4.5.31. Plasma concentration-time profile for A] TEL and B] TEL-Nanosuspension

Figure 4.5.32. Effect of TEL-NS and plain TEL on 1] Systolic blood pressure,2] Diastolic

blood pressure,3] Mean arterial blood pressure (MABP)

Figure 4.5.33. Histopathology of heart A] Control, B] Plain TEL, C] TEL-NS Figure 4.5.34. Histopathology of kidney A] Control, B] Plain TEL, C] TEL-NS Figure 4.5.35. Histopathology of liver A] Control, B] Plain TEL, C] TEL-NS

Figure 4.5.36. Contour plot of effect of TPGS concentration & rotation speed on particle size

Figure 4.5.37. Contour plot of effect of TPGS concentration & stirring time on particle size

Figure 4.5.38. Contour plot of effect of speed of rotation & time of stirring on particle size

Figure 4.5.39. Predicted vs Actual values of responses

Figure 4.5.40. Plot of residuals

Part II: Results and Discussion (CP)

Section 4.7.Nanosponge

Figure 4.7.1. Phase solubility plot for NS-CP

Figure 4.7.2. Solution state interaction studies of NS-CP

Figure 4.7.3 Saturation solubility in various media

Figure 4.7.4 Comparative dissolution profile of CP and NS-CP in various media

Figure 4.7.5. IR spectra of A=CP, B=NS C=NS-CP

Figure 4.7.6. DSC thermograms of A=CP, B=NS, C=NS-CP

Figure 4.7.7. PXRD spectra of A] CP, B] β-CD,C] NS,D] NS-CP

Figure 4.7.8. 3D image showing dimensions of CP molecule

Section 4.8.Nanosuspensions/Nanoparticles

Figure 4.8.1. Particle size distribution of CP nanosuspension (C0)


Appendix 2







Figure 4.8.8. Average particle size of nanosuspensions

Figure 4.8.9. Saturation solubility of NP-CP in various media

Figure 4.8.10. FTIR spectra of A] CP B] NP-CP

Figure 4.8.11. DSC Spectra A] CP,B] Poloxamer 188,C]TPGS,D] NP-CP

Figure 4.8.12. PXRD A] CP, B] NP-CP

Figure 4.8.13.SEM of A] CP, B] NP-CP

Figure 4.8.14. Specific surface area of A] Plain CP B] NC-CP Figure 4.8.15. Contact angle of A] Plain CP B] NP-CP

Figure 4.8.16. Comparative dissolution profile of NP-CP in various media

Figure 4.8.17.Model fitting of dissolution of NP-CP in phosphate buffer

Section 4.9.SNEDDS

Figure 4.9.1. Saturation solubility of CP in various oils, surfactants and co-surfactants

Figure 4.9.2. γ vs log Csa for surfactant-cosurfactant

Figure 4.9.3. Ternary phase diagrams of Smix: tween 80: propylene glycol and oil: Capmul

MCM with Smix ratio of A] 4:1, B] 3:1, C] 2:1, D] 1:1

Figure 4.9.4. Ternary phase diagrams of Smix: tween 80: TPGS and oil: Capmul MCM

with Smix ratio of A] 1:0.75, B] 1:0.5, C] 1:0.25

Figure 4.9.5. Globule size of CP-SNEDDS

Figure 4.9.6. Zeta potential of SNEDDS

Figure 4.9.7. Frequency distribution of globule size of CP-SNEDDS(C1)





Figure 4.9.12. Emulsification time for CP-SNEDDS formulations

Figure 4.9.13.Diffusion-time profile of CP-SNEDDS and CP

Figure 4.9.14. SEM of A] Plain Espheres B] SNEDDS coated Espheres

Figure 4.9.15. Qt30min for CP ,CP SNEDDS and Espheres

Figure 4.9.16. Model fitting of dissolution of CP-SNEDDS in phosphate buffer

Figure 4.9.17.Plasma concentration-time profile for A] CP and B] CP-SNEDDS

Figure 4.9.18.Histopathology of heart A] Control, B] CP, C] CP-SNEDDS

Figure 4.9.19.Histopathology of kidney A] Control, B] CP, C] CP-SNEDDS

Figure 4.9.20.Histopathology of liver A] Control, B] CP, C] CP-SNEDDS

Figure 4.9.21. Plot of predicted vs actual for the response parameter

Appendix 2


LIST OF FIGURES

Chapter 1:Introduction

Figure 1.1. Structure of Sulindac

Figure 1.2. Types of Cyclodextrins.

Figure 1.3.Toroidal structure of Cyclodextrin

Figure 1.4. Crosslinking of β-CD with diphenyl carbonate

Chapter 2: Preformulation studies

Section 2.1

Figure 2.1.1. UV spectrum of TEL

Figure 2.1.2. FT-IR spectra of TEL

Figure 2.1.3. DSC thermogram of TEL Figure 2.1.4. UV spectrum of CP

Figure 2.1.5. FT-IR spectra of CP

Figure 2.1.6. DSC thermogram of CP

Figure 2.1.7. FT-IR spectra of Vitamin E TPGS

Figure 2.1.8. FT-IR spectra of PEG 6000

Figure 2.1.9. FT-IR spectra of PVPK 30

Figure 2.1.10. FTIR spectra of Poloxamer 188

Figure 2.1.11. FT-IR spectra of β-CD

Section 2.2

Figure 2.2.1.FTIR spectra of A= TEL; B= β CD;C = NS; D = Drug loaded NS; E = NaHCO3

added Drug loaded NS

Figure 2.2.2. IR spectra of A=TEL,B= PVPK30 C=TEL-PVP

Figure 2.2.3. IR spectra of A=TEL,B= PEG 6000, C=TEL-PEG6000

Figure 2.2.4.IR spectra of A=TEL,B=P188 C=TEL-P188

Figure 2.2.5. IR spectra of A=TEL, B= TPGS,C=TEL-TPGS

Figure 2.2.6.IR spectra of A=CP, B=NS, C=CP-NS

Figure 2.2.7.IR spectra of A=CP, B=CP-Capmul MCM, C=CP-tween 80,D=CP-TPGS

Figure 2.2.8.IR spectra of A=CP, B=CP-P188, C=CP-TPGS,

Chapter 4:Results and Discussion


Section 4.1.TEL

Figure 4.1.1.Calibration curve of TEL(DW)

Figure 4.1.2 Calibration curve of TEL(0.1N HCl)

Figure 4.1.3. Calibration curve of TEL(phosphate buffer pH 6.8)

Figure 4.1.4.Calibration curve of TEL(FaSSIF)

Figure 4.1.5 Calibration curve of TEL(FeSSIF)

Figure.4.1.6.Calibration curve for TEL(HPLC)

Figure 4.1.7.Representative chromatogram of TEL(HPLC)

Figure 4.1.8.Chromatogram of control (plasma)

Figure 4.1.9.Representative chromatogram of TEL extracted from plasma

Appendix 2


Figure 4.1.10. Calibration curve of TEL by HPLC (Bioanalytical)

Section 4.2.CP

Figure 4.2.1. Calibration curve of CP in DW

Figure 4.2.2. Calibration curve of CP in 0.1N HCl

Figure 4.2.3. Calibration curve of CP in phosphate buffer pH 6.8.

Figure 4.2.4. Calibration curve of CP in FaSSIF

Figure 4.2.5. Calibration curve of CP in FeSSIF

Figure 4.2.6. Calibration curve of CP in USP medium

Figure 4.2.7.Calibration curve of CP by HPLC

Figure 4.2.8. Representative chromatogram of CP by HPLC

Figure 4.2.9. Chromatogram of Control (plasma)

Figure 4.2.10. Representative Chromatogram of Cefpodoxime from rat plasma

Figure 4.2.11. Calibration curve for Cefpodoxime



Figure 4.4.1. Schematic representation of chemical reaction between β-CD and DPC.

Figure 4.4.2. NMR spectra of (A) β-CD; (B) NS2.

Figure 4.4.3. Phase-solubility profiles

Figure 4.4.4. Phase solubility diagram in water.

Figure 4.4.5. Solution state interaction studies of TEL

Figure 4.4.6. 3D image of depicting dimensions of TEL molecule

Figure 4.4.7. 3D image showing possible mode of entrapment of TEL in β CD structure

Figure 4.4.8. 3D image showing possible mode of entrapment of TEL in NS structure

Figure 4.4.9. Inclusion complex of β-CD and TEL

Figure 4.4.10.Saturation solubility in various media

Figure 4.4.11. FTIR spectra of A= TEL; B= β- CD; C = NS; D = Drug loaded NS; E =

NaHCO3 added Drug loaded NS.

Figure 4.4.12. DSC spectra of A= TEL, B= β – CD, C=NS, D= Drug loaded NS; E =

NaHCO3added Drug loaded NS.

Figure 4.4.13. PXRD spectra of A= TEL , B= β – CD,C=NS , D= Drug loaded NS.

Figure 4.4.14. SEM of (A) TEL; (B) β- CD; (C) NS; (D) Drug loaded NS.

Figure 4.4.15.Dissolution profiles of TEL complexes in DW

Figure 4.4.16.Dissolution profiles of TEL complexes in 0.1 N HCl

Figure 4.4.17. Dissolution profiles of TEL complexes in buffer pH 6.8.

Section 4.5:Nanosuspensions/Nanocrystals









Appendix 2




Figure 4.5.11. Average particle size of TEL nanosuspensions

Figure 4.5.12.Stern model showing the course of the potential in the electrical double layers

Figure 4.5.13.Adsorbed polymer layer shift the plane of shear from particle surface

Figure 4.5.14.Saturation solubility of TEL and NC in different media

Figure 4.5.15.IR spectra of A)TEL,B)PVPK30, C)TEL-PVPK30

Figure 4.5.16. IR spectra of A)TEL,B)PEG6000,C)TEL-PEG6000

Figure 4.5.17. IR spectra of A)TEL, B) P188,C)TEL-P188

Figure 4.5.18. IR spectra of A)TEL, B)TPGS,C)TEL-TPGS

Figure 4.5.19. DSC thermograms of A) TEL B) NC-TEL

Figure 4.5.20. PXRD spectra of A] TEL, B] NC-TEL

Figure 4.5.21. Specific surface area A] Plain TEL B] NC-TEL

Figure 4.5.22. Contact angle of A] Plain TEL B] NC-TEL

Figure 4.5.23. SEM of A) TEL B) NC-TEL

Figure 4.5.24. Gas chromatogram of A) DCM B) NC- TEL

Figure 4.5.25.SEM of A] Plain Espheres B] Nanosuspension coated Espheres

Figure 4.5.26. Qt30min for TEL, NC-TEL and pellets Figure 4.5.27. Dissolution profile of TEL nanosuspension spray coated Espheres in 0.1NHCl

Figure 4.5.28. Particle size distribution of nanosuspension (T8) kept at room temperature Figure 4.5.29. Particle size distribution of nanosuspension (T8) kept at 40 ºC /75% RH

Figure 4..5.30. Particle size distribution of nanosuspension (T8) kept under refrigeration Figure 4.5.31. Plasma concentration-time profile for A] TEL and B] TEL-Nanosuspension

Figure 4.5.32. Effect of TEL-NS and plain TEL on 1] Systolic blood pressure,2] Diastolic

blood pressure,3] Mean arterial blood pressure (MABP)

Figure 4.5.33. Histopathology of heart A] Control, B] Plain TEL, C] TEL-NS Figure 4.5.34. Histopathology of kidney A] Control, B] Plain TEL, C] TEL-NS Figure 4.5.35. Histopathology of liver A] Control, B] Plain TEL, C] TEL-NS

Figure 4.5.36. Contour plot of effect of TPGS concentration & rotation speed on particle size

Figure 4.5.37. Contour plot of effect of TPGS concentration & stirring time on particle size

Figure 4.5.38. Contour plot of effect of speed of rotation & time of stirring on particle size

Figure 4.5.39. Predicted vs Actual values of responses

Figure 4.5.40. Plot of residuals

Part II: Results and Discussion (CP)

Section 4.7.Nanosponge

Figure 4.7.1. Phase solubility plot for NS-CP

Figure 4.7.2. Solution state interaction studies of NS-CP

Figure 4.7.3 Saturation solubility in various media

Figure 4.7.4 Comparative dissolution profile of CP and NS-CP in various media

Figure 4.7.5. IR spectra of A=CP, B=NS C=NS-CP

Figure 4.7.6. DSC thermograms of A=CP, B=NS, C=NS-CP

Figure 4.7.7. PXRD spectra of A] CP, B] β-CD,C] NS,D] NS-CP

Figure 4.7.8. 3D image showing dimensions of CP molecule

Section 4.8.Nanosuspensions/Nanoparticles



Appendix 2







Figure 4.8.8. Average particle size of nanosuspensions

Figure 4.8.9. Saturation solubility of NP-CP in various media

Figure 4.8.10. FTIR spectra of A] CP B] NP-CP

Figure 4.8.11. DSC Spectra A] CP,B] Poloxamer 188,C]TPGS,D] NP-CP

Figure 4.8.12. PXRD A] CP, B] NP-CP

Figure 4.8.13.SEM of A] CP, B] NP-CP

Figure 4.8.14. Specific surface area of A] Plain CP B] NC-CP Figure 4.8.15. Contact angle of A] Plain CP B] NP-CP

Figure 4.8.16. Comparative dissolution profile of NP-CP in various media

Figure 4.8.17.Model fitting of dissolution of NP-CP in phosphate buffer

Section 4.9.SNEDDS

Figure 4.9.1. Saturation solubility of CP in various oils, surfactants and co-surfactants

Figure 4.9.2. γ vs log Csa for surfactant-cosurfactant

Figure 4.9.3. Ternary phase diagrams of Smix: tween 80: propylene glycol and oil: Capmul

MCM with Smix ratio of A] 4:1, B] 3:1, C] 2:1, D] 1:1

Figure 4.9.4. Ternary phase diagrams of Smix: tween 80: TPGS and oil: Capmul MCM

with Smix ratio of A] 1:0.75, B] 1:0.5, C] 1:0.25

Figure 4.9.5. Globule size of CP-SNEDDS

Figure 4.9.6. Zeta potential of SNEDDS






Figure 4.9.12. Emulsification time for CP-SNEDDS formulations

Figure 4.9.13.Diffusion-time profile of CP-SNEDDS and CP

Figure 4.9.14. SEM of A] Plain Espheres B] SNEDDS coated Espheres

Figure 4.9.15. Qt30min for CP ,CP SNEDDS and Espheres

Figure 4.9.16. Model fitting of dissolution of CP-SNEDDS in phosphate buffer

Figure 4.9.17.Plasma concentration-time profile for A] CP and B] CP-SNEDDS

Figure 4.9.18.Histopathology of heart A] Control, B] CP, C] CP-SNEDDS

Figure 4.9.19.Histopathology of kidney A] Control, B] CP, C] CP-SNEDDS

Figure 4.9.20.Histopathology of liver A] Control, B] CP, C] CP-SNEDDS

Figure 4.9.21. Plot of predicted vs actual for the response parameter

Appendix 3

Solubility enhancement of some BCS Class II/IV 278

Abbreviations

An: Absorption number NMP: N-methyl pyrrolidone

AUC: Area under curve NP-CP: Nanoparticles of cefpodoxime proxetil

AUMC: Area under first moment curve PDI: Polydispersity index

BCS: Biopharmaceutical classification system PEG: polyethylene glycol

CD: Cyclodextrin PG: Propylene glycol

Cmax: Peak plasma concentration PM: Physical mixture

CMC: Critical micelle concentration PVP: polyvinylpyrrolidone

CP: Cefpodoxime proxetil SEDDS: Self emulsifying drug delivery system

CP-NS: Nanosponges of cefpodoxime proxetil SMEDDS: Self microemulsifying drug delivery system

CP-NP: Nanoparticles of cefpodoxime proxetil SNEDDS: Self nanoemulsifying drug delivery system

CP-SNEDDS:SNEDDS of cefpodoxime proxetil TEL: Telmisartan

DCM: Dichloromethane TEL-NC: Telmisartan nanocrystals

DMSO: Dimethyl sulfoxide TEL-NS: Telmisartan nanosuspension

DPC: Diphenyl carbonate TPGS: Tocopherol polyethylene glycol succinate

Dn: Dissolution number T80: Tween 80

Do: Dose number Tmax: Time to reach peak plasma concentration

DW: Distilled water

FaSSIF: Fasting state simulated intestinal fluid

FeSSIF: Fed state simulated intestinal fluid

HLB: Hydrophilic lipophilic balance

Kel: Elimination rate constant

MRT: Mean residence time

NC-TEL: Nanocrystals of telmisartan

NS : Nanosponges

NS-CP: Cefpodoxime nanosponge

Appendix 4

Solubility enhancement of some BCS Class II/IV drugs 279

Appendix 4


Appendix 4


Appendix 4


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Appendix 1 - shodhganga.inflibnet.ac.inshodhganga.inflibnet.ac.in/bitstream/10603/7584/11/11_appendix.pdf · Appendix 1 Solubility ... Saturation solubility in biorelevant media