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Developing Solid Oral Dosage Forms

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Porter

Brief Table of Contents

Copyright Page

Dedication

Foreword

List of Contributors

I. Theories And Techniques In The Characterization Of Drug Substances And Excipients

Chapter 1. Solubility of Pharmaceutical Solids

Chapter 2. Crystalline and Amorphous Solids

Chapter 3. Analytical Techniques in Solid-state Characterization

Chapter 4. Salt Screening and Selection

Chapter 5. Drug Stability and Degradation Studies

Chapter 6. Excipient Compatibility

Chapter 7. Theory of Diffusion and Pharmaceutical Applications

Chapter 8. Particle, Powder, and Compact Characterization

Chapter 9. Polymer Properties and Characterization

Chapter 10. Applied Statistics in Product Development

II. Biopharmaceutical And Pharmacokinetic Evaluations Of Drug Molecules And Dosage Forms

Chapter 11. Oral Absorption Basics

Chapter 12. Oral Drug Absorption, Evaluation, and Prediction

Chapter 13. Fundamentals of Dissolution

Chapter 14. Dissolution Testing of Solid Products

Chapter 15. Bioavailability and Bioequivalence

Chapter 16. In Vivo Evaluation of Oral Dosage Form Performance

Chapter 17. In Vitro–In Vivo Correlations

III. Design, Development, And Scale-Up Of Formulation And Process

Chapter 18. Integration of Physical, Chemical, Mechanical, and Biopharmaceutical Properties in Solid Oral Dosage Form Development

Chapter 19. Improving the Oral Absorption of Poorly Soluble Drugs Using SEDDS and S-SEDDS Formulations

Chapter 20. Rational Design of Oral Modified-Release Drug Delivery Systems

Chapter 21. Development of Modified-Release Solid Oral Dosage Forms

Chapter 22. Analytical Development and Validation for Solid Oral Dosage Forms

Chapter 23. Statistical Design and Analysis of Long-term Stability Studies for Drug Products

Chapter 24. Packaging Selection for Solid Oral Dosage Forms

Chapter 25. Clinical Supplies Manufacture

Chapter 26. Specification Setting and Manufacturing Process Control for Solid Oral Drug Products

Chapter 27. Scale-up of Pharmaceutical Manufacturing Operations of Solid Dosage Forms

Chapter 28. Process Development, Optimization, and Scale-up

Chapter 29. Process Development and Scale-up of Wet Granulation by the High Shear Process

Chapter 30. Process Development, Optimization, and Scale-up

Chapter 31. Development, Scale-up, and Optimization of Process Parameters

Chapter 32. Development, Optimization, and Scale-up of Process Parameters

Chapter 33. Development, Optimization, and Scale-up of Process Parameters

Chapter 34. Development, Optimization, and Scale-up of Process Parameters

Chapter 35. Process Analytical Technology in Solid Dosage Development and Manufacturing

IV. Selected Topics In Product Development

Chapter 36. The Product Development Process

Chapter 37. Product Registration and Drug Approval Process in the United States

Chapter 38. Modern Pharmaceutical Quality Regulations

Chapter 39. Intellectual Property Law Primer

Chapter 40. Product Lifecycle Management (LCM)

Index

Table of Contents

Copyright Page

Dedication

Foreword

List of Contributors

I. Theories And Techniques In The Characterization Of Drug Substances And Excipients

Chapter 1. Solubility of Pharmaceutical Solids

1.1. Introduction

1.1.1. Implication of Solubility in Dosage Form Development

1.1.2. Basic Concepts of Solubilityand Dissolution

1.2. Thermodynamics of solutions

1.2.1. Volume of Mixing

1.2.2. Enthalpy of Mixing

1.2.3. Entropy of Mixing

1.2.4. Free Energy of Mixing

1.3. Theoretical estimation of solubility

1.3.1. Ideal Solutions

1.3.2. Effect of Crystallinity

1.3.3. Non-ideal Solutions

1.3.4. Regular Solution Theory

1.3.5. Aqueous Solution Theory

1.3.6. The General Solubility Equation (GSE)

1.4. Solubilization of drug candidates

1.4.1. Solubility Enhancement by pH Control and Salt Formation

1.4.2. Solubilization Using Complexation

1.4.3. Solubilization by Cosolvents

1.4.4. Solubilization by Surfactants (Micellar Solubilization)

1.4.5. Solubilization by Combinationof Approaches

1.5. Experimental determination of solubility

1.5.1. Stability of Solute and Solvent

1.5.2. Shakers and Containers

1.5.3. Presence of Excess Undissolved Solute

1.5.4. Determination of Equilibrium

1.5.5. Phase-separation

1.5.6. Determination of Solute Content in the Dissolved Phase

1.5.7. Experimental Conditions

Uncited References

Chapter 2. Crystalline and Amorphous Solids

2.1. Introduction

2.2. Definitions and Categorization of Solids

2.3. Thermodynamics and Phase Diagrams

2.3.1. Polymorphs

2.3.2. Solvates/Hydrates

2.3.3. Cocrystals

2.3.4. Amorphous Solids

2.4. Pharmaceutical Relevance and Implications

2.4.1. Solubility

2.4.2. Dissolution Rate and Bioavailability

2.4.3. Hygroscopicity

2.4.4. Reactivity and Chemical Stability

2.4.5. Mechanical Properties

2.5. Transformations among Solids

2.5.1. Induced by Heat

2.5.2. Induced by Vapor

2.5.3. Induced by Solvents

2.5.4. Induced by Mechanical Stresses

2.6. Methods of Generating Solids

2.6.1. Through Gas

2.6.2. Through Liquid

2.6.3. Through Solid

2.7. Amorphous Drugs and Solid Dispersions

2.7.1. Characteristics of Amorphous Phases

2.7.2. Characteristics of Amorphous Solid Dispersions

2.7.3. Crystallization of Amorphous Drugs and Dispersions

2.8. Special Topics

2.8.1. Polymorph Screening and Stable Form Screening

2.8.2. High Throughput Crystallization

2.8.3. Miniaturization in Crystallization

Uncited Reference

Chapter 3. Analytical Techniques in Solid-state Characterization

3.1. Introduction

3.2. Review of Analytical Techniques and Methods

3.3. Microscopic Methods

3.3.1. Optical Microscopy

3.3.2. Electron Microscopy

3.4. Thermal Analysis

3.4.1. Differential Scanning Calorimetry

3.4.2. Thermogravimetric Analysis

3.4.3. Microcalorimetry

3.5. Diffraction Methods

3.5.1. Single-crystal X-ray Diffraction

3.5.2. Powder X-ray Diffraction

3.6. Vibrational Spectroscopy

3.6.1. Infrared Spectroscopy

3.6.2. Raman Spectroscopy

3.6.3. Near-infrared

3.7. Solid-state Nuclear Magnetic Resonance Spectroscopy

3.8. Sorption Techniques

3.9. Other Techniques

3.10. Characterization of Solids Using Complementary Analytical Techniques

3.11. Conclusion

Acknowledgements

Chapter 4. Salt Screening and Selection

4.1. Introduction

4.2. Theoretical Considerations

4.2.1. pH-Solubility Profiles and the Role of pKa

4.2.2. Prediction of Salt Solubility and In Situ Salt Screening

4.2.3. Solubility and Dissolution Rate of Salts

4.2.4. Dissolution of Salts in GI Fluids

4.2.5. Impact of Salt Form on Other Solubilization Techniques

4.2.6. Effect of Salts on Chemical Stability

4.2.7. Potential Disadvantages of Salts

4.3. Practical Considerations

4.3.1. Drug Substance Considerations

4.3.2. Dosage Form Considerations

4.3.3. Toxicity Considerations

4.3.4. Salt and Form Screening and Selection Strategies

4.3.5. The Role of Automation and High Throughput Designs in Salt Screening

4.4. Conclusions

Uncited Reference

Chapter 5. Drug Stability and Degradation Studies

5.1. Introduction

5.2. Chemical stability

5.2.1. Solution Kinetics

5.2.2. Rate Equations

5.2.3. Elemental Reactions and Reaction Mechanism

5.2.4. Typical Simple Order Kinetics

5.2.5. Complex Reactions

5.2.6. Arrhenius Equation, Collision Theory, and Transition State Theory

5.2.7. Catalysts and Catalysis

5.2.8. pH-rate Profiles

5.2.9. Solid-state Reaction Kinetics

5.2.10. Solid-state Kinetic Models

5.2.11. Physical Parameters Affecting Solid-state Kinetics

5.2.12. The Role of Moisture

5.2.13. Topochemical Reactions

5.3. Common pathways of drug degradation

5.3.1. Hydrolysis

5.3.2. Oxidative Degradation

5.3.3. Photochemical Degradation

5.3.4. Other Degradation Pathways

5.4. Experimental approaches to studying the chemical degradation of drugs

5.4.1. Solution Thermal Degradation Studies

5.4.2. Solid-state Thermal Degradation Studies

5.4.3. Oxidative Degradation Studies

5.4.4. Photodegradation Studies

5.5. Physical stability and phase transformations[106]

5.5.1. Types of Phase Transformations

5.5.2. Mechanisms of Phase Transformations

5.6. Phase transformations during pharmaceutical processing106

5.6.1. Processes for Preparing Solid Dosage Forms and Associated Potential Phase Transformations

5.6.2. Anticipating and Preventing Phase Transformations in Process Development

Chapter 6. Excipient Compatibility

6.1. Introduction

6.2. Chemistry of Drug–Excipient Interactions

6.2.1. Influence of Water and Microenvironmental pH

6.2.2. Reactions with Excipients and their Impurities

6.2.3. Stabilizing Excipients

6.3. Current Practices

6.3.1. Experimental Design

6.3.2. Sample Preparation and Storage

6.3.3. Sample Analysis and Data Interpretation

6.4. Conclusions

Chapter 7. Theory of Diffusion and Pharmaceutical Applications

7.1. Introduction

7.1.1. Basic Equations of Diffusion

7.1.2. Solutions for Diffusion Equations

7.2. The diffusion coefficient and its determination

7.2.1. Steady State Flux Method

7.2.2. Lag Time Method

7.2.3. Sorption and Desorption Methods

7.3. Pharmaceutical applications

7.3.1. Controlled Release

7.3.2. Particle Dissolution

7.3.3. Packaging Study

7.4. Appendix

7.4.1. The Error Function and Its Application

7.4.2. Derivation of Solution by Separation of Variables

Chapter 8. Particle, Powder, and Compact Characterization

8.1. Introduction

8.2. Particle sizecharacterization

8.2.1. Light Microscopy

8.2.2. Scanning Electron Microscopy

8.2.3. Sieving

8.2.4. Light Diffraction

8.2.5. Importance/Impact of Particle Size Characterization

8.3. Powder characterization

8.3.1. Density

8.3.2. Flow

8.4. Compact (mechanical property) characterization

8.4.1. Important Mechanical Properties

8.4.2. Overview of Methods

8.4.3. Quasi-static Testing

8.4.4. Dynamic Testing

8.5. Conclusions

Chapter 9. Polymer Properties and Characterization

9.1. Introduction

9.1.1. Definition, Structure, and Nomenclature

9.1.2. Types of Homopolymers and Copolymers

9.2. Commonly used cellulose derivatives in solid oral products

9.3. Basic concepts and characterization of polymeric materials

9.3.1. Polymer Composition

9.3.2. Molecular Weight

9.3.3. Polymers in Solution

9.3.4. Structure–Property Relationships

9.4. Conclusion

Uncited References

Chapter 10. Applied Statistics in Product Development

10.1. Introduction

10.1.1. Statistics: A Tool for Decision Making and Risk Assessment

10.1.2. Sources of Uncertainty

10.1.3. Natural (Random) Variation

10.1.4. Systematic Error (Bias) and Blunders

10.2. Exploring data: types of data

10.2.1. Nominal (Categorical) Data

10.2.2. Ordinal Data

10.2.3. Numerical Data

10.2.4. Continuously Variable Data and Digitization Pitfalls

10.3. Exploring data: graphical techniques

10.3.1. Graphing Nominal Data

10.3.2. Bar Charts

10.3.3. Pie Charts

10.3.4. Graphing Univariate Numerical Data

10.3.5. Histograms

10.3.6. Quantile Plots

10.3.7. Box Plots

10.3.8. Graphing Bivariate Data

10.3.9. One Variable Nominal: Bar Graphs, Dot Plots, and Line Plots

10.3.10. One Variable Nominal: Box Plots

10.3.11. Both Variables Numeric and Random: Quantile–Quantile Plots

10.3.12. Both Variables Numeric: Scatterplots

10.3.13. Multivariate Data

10.3.14. Scatterplot Matrices

10.4. Data distributions

10.4.1. Binomial Distribution

10.4.2. Poisson Distribution

10.4.3. Normal (Gaussian) Distribution

10.4.4. Other Useful Distributions

10.5. Location: central tendencies

10.5.1. Data for Central Value and Dispersion Examples

10.5.2. Arithmetic Mean

10.5.3. Median

10.6. Dispersion

10.6.1. Range

10.6.2. Interquartile Range and Median Absolute Deviation from the Median

10.6.3. Variance and Standard Deviation

10.6.4. Coefficient of Variation

10.6.5. Multivariate Covariance and Correlation

10.6.6. Correlation and Causality

10.6.7. Error Propagation

10.7. Probability

10.7.1. Chebyshev’s Inequality

10.7.2. The Normal Probability Assumption

10.8. Interval estimation

10.8.1. Confidence Intervals

10.8.2. Prediction Intervals

10.8.3. Tolerance Intervals

10.8.4. Rounding

10.9. Process modeling and experimental design

10.9.1. Models, Parameters, and Hypotheses

10.9.2. Confidence Interval Estimation and Hypothesis Testing

10.9.3. Are Two Processes Different or the Same?

10.9.4. More Complex Models

10.9.5. Regression Models and the Analysis of Variance

10.9.6. One-way ANOVA with One Nominal Factor

10.9.7. Two-Way ANOVA with Two Nominal Factors

10.9.8. Regression Analysis with One Continuous Factor

10.9.9. Regression Analysis with Multiple Continuous Factors

10.9.10. Regression with Nominal and Continuous Variables (ANCOVA)

10.9.11. Nonlinear Models

10.9.12. Data Snooping (Data Mining)

10.9.13. Outliers

10.10. The measurement process

10.10.1. Models and Assay Design in Analytical Chemistry

10.10.2. Direct Assays (Titrations)

10.10.3. Slope–Ratio Assays

10.10.4. Parallel Line and Ligand-binding Assays

10.10.5. Calibration Lines and Curves

10.10.6. Accuracy, Precision, Bias, and Blunders

10.10.7. Detecting and Eliminating Bias

10.10.8. Precision

10.10.9. Short-term Repeatability

10.10.10. Long-term Reproducibility

10.10.11. Measurement Reliability Analysis Based on ANOVA with Random Factors

10.10.12. Measurement Reliability Analysis Based on Prior Information and In-process Standards

10.10.13. Reporting Measurement Reliability

10.10.14. Multivariate Methods

10.11. The production process

10.11.1. Controlled and Uncontrolled Factors

10.11.2. Response Surface Modeling: The Design Space

10.11.3. Classical Factorial Designs

10.11.4. Confounding Variables: Fractional Factorials

10.11.5. Screening Designs

10.11.6. Taguchi Designs

10.11.7. Model Assumptions

10.11.8. Choosing an Experimental Design

10.11.9. Data Analysis and Model Simplification

10.11.10. Evolutionary Operation

10.11.11. Process Stability and Capability

10.11.12. Statistical Process Control Revisited

10.11.13. In-process Monitoring and Control Using Process Analytical Technology

10.11.14. Process Wellness

10.12. Software

10.13. Summary

Selected Bibliography

II. Biopharmaceutical And Pharmacokinetic Evaluations Of Drug Molecules And Dosage Forms

Chapter 11. Oral Absorption Basics

11.1. Barriers to oral drug delivery

11.1.1. Intestinal Barrier

11.1.2. Hepatic Barrier

11.2. Pathways of Drug Absorption

11.2.1. Paracellular Diffusion

11.2.2. Passive Diffusion

11.2.3. Carrier-mediated Transport

11.2.4. Active Transport

11.2.5. Facilitated Transport

11.3. Pathways of drug metabolism

11.3.1. Phase I Metabolism

11.3.2. Phase II Enzymes

11.4. Pathways of drug elimination

11.4.1. P-glycoprotein (P-gp)

11.4.2. Multidrug-resistance Associated Proteins (MRPs)

11.4.3. Organic Anion Transporters

11.5. Coupling of Enzymes and Efflux Transporters

11.5.1. Double Jeopardy Theorem

11.5.2. Revolving Door Theorem

11.6. Physico-chemical factors affecting drug absorption

11.6.1. Lipophilicity

11.6.2. Size

11.6.3. Charge

11.6.4. Solubility

11.6.5. Dissolution

11.7. Biological factors affecting drug absorption

11.7.1. Transit Time

11.7.2. pH

11.7.3. Food

11.7.4. Luminal Enzymes

11.8. Summary

Chapter 12. Oral Drug Absorption, Evaluation, and Prediction

12.1. Introduction

12.2. Biopharmaceutics classification system (BCS)

12.2.1. FDA Guidance on Biowaivers

12.2.2. Scientific Basis for BCS

12.3. Intestinal permeability evaluation: cultured cells

12.3.1. Caco-2 cells

12.3.2. Madin–Darby Canine Kidney Cells (MDCK)

12.3.3. Other Cells

12.3.4. Limitations of Cultured Cell Models

12.4. Intestinal permeability evaluation: ex-in vivo

12.4.1. The Everted Gut Sac Technique

12.4.2. Ussing Chamber

12.4.3. In Situ Method

12.4.4. Intestinal Perfusion in Man

12.5. In silico methods

12.5.1. CAT Model

12.5.2. Quantitative Structure Bioavailability Relationships (QSBR)

12.5.3. Quantitative Structure Permeability Relationships (QSPR)

12.6. Future trends

12.7. Conclusion

Chapter 13. Fundamentals of Dissolution

13.1. Introduction

13.2. Mechanism and theories of solid dissolution

13.2.1. Thermodynamic Considerations

13.2.2. Dissolution by Pure Diffusion

13.2.3. Diffusion Layer Model

13.2.4. Convective Diffusion Model

13.3. Planar surface dissolution

13.3.1. Intrinsic Dissolution Rate

13.3.2. Convective Diffusion Model for Flow Past a Planar Surface

13.4. Particulate dissolution

13.4.1. Diffusion Layer-based Dissolution Models

13.4.2. Convective Diffusion-based Particulate Dissolution Model

13.4.3. Dissolution Under Non-sink Conditions

13.4.4. Effects of Particle Shape

13.4.5. Polydispersity Effects

Chapter 14. Dissolution Testing of Solid Products

14.1. Introduction

14.2. Components of Dissolution Test Method Development

14.2.1. Dissolution Apparatuses

14.2.2. Analytical Assay

14.2.3. Medium Selection

14.3. Dissolution Tests for Immediate-release Products

14.3.1. Dissolution Tests for Tablets or Solid-Filled Capsule Products

14.3.2. Dissolution Tests for Liquid-filled Capsule Products

14.3.3. Method Development for Quality Control of Immediate-release Products

14.4. Drug Release Test Methods for Modified-release Products

14.4.1. Drug Release Test Methods for Enteric Coated Products

14.4.2. Drug Release Test Methods for Extended-release Products

14.5. Statistical Comparison of Dissolution Profiles

14.6. Specifications

14.6.1. Method Validation

14.6.2. Acceptance Criteria

14.7. In Vitro–In Vivo Correlation (IVIVC)

14.7.1. Developing an IVIVC

14.7.2. Setting Specifications Using an IVIVC

14.8. Summary and Future State

Chapter 15. Bioavailability and Bioequivalence

15.1. General background

15.2. Definitions and key concepts

15.2.1. Bioavailability

15.2.2. Bioequivalence

15.2.3. Pharmaceutical Equivalence and Therapeutic Equivalence

15.3. Statistical concepts in bioequivalence studies

15.3.1. Selection and Transformation of Pharmacokinetic Measures

15.3.2. Variability in Pharmacokinetic Measures of Bioavailability

15.3.3. Statistical Criteria for Evaluating Bioequivalence

15.3.4. Bioequivalence Study Designs and Other Statistical Considerations

15.4. Other general components of bioequivalence studies

15.4.1. Study Populations

15.4.2. Biofluid Matrices

15.4.3. Bioanalytical Methods

15.4.4. Drug Moieties

15.5. International regulatory perspectives

15.5.1. US Food and Drug Administration

15.5.2. European Agency for the Evaluation of Medicinal Products

15.5.3. Health Canada

15.5.4. Japanese Ministry of Health, Labour and Welfare

15.6. Waivers based on the biopharmaceutical classification system

15.7. Summary

Chapter 16. In Vivo Evaluation of Oral Dosage Form Performance

16.1. Introduction

16.2. General Purpose of in vivo Performance Evaluations

16.3. Animal Pharmacokinetic Evaluations

16.3.1. Animal Species Selection

16.3.2. Animal Data Extrapolation

16.4. Human Pharmacokinetic Evaluations

16.4.1. Bioavailability and Bioequivalence

16.4.2. Effects of Food and Other Substances on Oral Drug Absorption

16.4.3. Effects of Gastric pH on Oral Drug Absorption

16.4.4. Regional Absorption Site Assessments and Imaging Studies

16.5. In vivo Pharmacokinetic Metrics

16.6. In vivo Absorption Pattern Diagnostics

16.7. Generic Alternative: Opportunity or Threat?

16.8. Summary

Chapter 17. In Vitro–In Vivo Correlations

17.1. Introduction

17.1.1. In Vitro–In Vivo Correlation (IVIVC)

17.1.2. IVIVC and Product Development

17.2. Development and Assessment of an IVIVC

17.2.1. Study Design and General Considerations

17.2.2. IVIVC Modeling

17.2.3. Evaluation of a Correlation

17.3. Considerations in IVIVC Development

17.3.1. In Vivo Absorption Versus In Vitro Test Considerations

17.3.2. Drug and Formulation Considerations

17.4. Ivivc Development Strategies and Approach

17.4.1. Strategy and General Approach

17.4.2. Design of a Predictive In Vitro Test

17.5. Applications and Limitations

17.5.1. Setting Dissolution Specifications

17.5.2. Supporting Waiver of In Vivo Bioavailability Studies

17.5.3. Limitations and Additional Considerations

17.6. Cases Studies

17.6.1. Effect of Solubility on IVIVC

17.6.2. Developing a Predictive In Vitro Test

17.6.3. Illustration of Setting an Optimal Dissolution Specification

17.7. Summary

Uncited References

III. Design, Development, And Scale-Up Of Formulation And Process

Chapter 18. Integration of Physical, Chemical, Mechanical, and Biopharmaceutical Properties in Solid Oral Dosage Form Development

18.1. Introduction

18.2. Physical and Chemical Properties

18.2.1. Aqueous Solubility

18.2.2. Dissolution Rate

18.2.3. Partition Coefficient

18.2.4. Permeability

18.2.5. Ionization Constant

18.2.6. Polymorphism

18.2.7. Crystallinity

18.2.8. Particle Size, Particle Morphology, and Surface Area

18.2.9. Derived Properties: Density and Porosity

18.2.10. Melting Point

18.2.11. Hygroscopicity

18.2.12. Chemical Stability

18.3. Mechanical Properties

18.3.1. Compression and Compaction

18.3.2. Mechanical Property Characterization

18.3.3. Practical Implications of Mechanical Property Characterization

18.4. Biopharmaceutical Properties

18.4.1. The Biopharmaceutical Classification System (BCS)

18.4.2. BCS Class I: High Solubility and High Permeability

18.4.3. BCS Class II: Low Solubility and High Permeability

18.4.4. BCS Class III: High Solubility and Low Permeability

18.4.5. BCS Class IV: Low Solubility and Low Permeability

18.4.6. Further Clarifications of the BCS

18.4.7. Biopharmaceutical Drug Disposition Classification System (BDDCS)

18.5. Concluding Remarks

Chapter 19. Improving the Oral Absorption of Poorly Soluble Drugs Using SEDDS and S-SEDDS Formulations

19.1. Introduction

19.2. Overview of SEDDS and S-SEDDS formulations

19.2.1. Growth in the Number of SEDDS/S-SEDDS Publications

19.2.2. Marketed SEDDS Formulations

19.3. Review of Scientific Literature Dealing with Both the Development of SEDDS/S-SEDDS Formulations, and Oral Bioavailability

19.3.1. Year 2008: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles

19.3.2. Year 2007: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles

19.3.3. Year 2005–2003: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles

19.3.4. Year 2003–2000: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles

19.3.5. Year 1999–1992: Key Publications on SEDDS Formulations in the PubMed Database, and Related Articles

19.4. Case Studies on the Development of SEDDS and S-SEDDS Formulations

19.4.1. Case Study on the Development of a SEDDS Formulation of Drug X

19.4.2. Development of Supersaturatable S-SEDDS Formulations

19.5. Proposed Pathways for Enhanced Oral Absorption of Poorly Soluble Drugs with SEDDS and S-SEDDS Approach

19.5.1. Drug Absorption Pathway

19.5.2. The Enterocyte Absorption of Highly Lipophilic Compounds

19.5.3. Significance of the Glycocalyx in Absorption of Drugs from SEDDS/S-SEDDS Formulations

19.6. Conclusions

Acknowledgements

Chapter 20. Rational Design of Oral Modified-Release Drug Delivery Systems

20.1. Introduction

20.2. Oral Modified Release Technologies and Drug Delivery Systems

20.2.1. Common Oral Extended-release Systems

Other Common Oral Modified-release Systems

Materials Used for Modifying Drug Release

20.3. Rational Design of Modified-release Systems

20.3.1. Identification of the Clinical Need and Definition of the In Vivo Target Product Profile

20.3.2. Feasibility Study

20.3.3. Selecting the Modified-release System and Testing System Design

20.3.4. Case Studies: Impact of Drug Property and Formulation Design

20.4. Summary

Chapter 21. Development of Modified-Release Solid Oral Dosage Forms

21.1. Introduction

21.2. Development of modified-release solid oral products

21.2.1. Rational Development Approach

21.2.2. Preformulation Studies

21.2.3. Dosage Form Development

21.2.4. Product and Process Understanding

21.3. Technology transfer

21.5. Intellectual property considerations

21.6. Summary

Chapter 22. Analytical Development and Validation for Solid Oral Dosage Forms

22.1. Introduction

22.2. Analytical Method Development and Validation Strategy

22.3. Category of analytical method and method development

22.3.1. Identification

22.3.2. Potency Assay

22.3.3. Impurities[10–13]

22.3.4. Dissolution[14–25]

22.3.5. Blend Homogeneity and Dosage Uniformity

22.3.6. Cleaning Test Method Development

22.3.7. Other Analytical Techniques

22.4. Analytical Method Validation

22.4.1. Verification of Compendial Methods

22.4.2. Characterization of Reference Standard

22.4.3. Stability Indicating Method

22.4.4. High Performance Liquid Chromatography Co-elution Peak Evaluation

22.4.5. Forced Degradation Studies

22.4.6. Method Validation Parameters

22.5. Method transfers (MT) and inter-laboratory qualification (ILQ)

22.5.1. Definition

22.5.2. Potency

22.5.3. Related Substance Assay

22.5.4. Residual Solvent Assay

22.5.5. Dissolution or Release Assay

22.7. Conclusions

Uncited Reference

Chapter 23. Statistical Design and Analysis of Long-term Stability Studies for Drug Products

23.1. Introduction

23.2. Stability Study Objectives

23.3. Regulatory Guidance

23.4. Test Methods and Data Management

23.5. Modeling Instability

23.5.1. Stability Study Variables

23.5.2. A Statistical Model for Instability

23.6. Long-term Stability Study Design

23.6.1. Full and Reduced Designs

23.6.2. Bracketing

23.6.3. Matrixing

23.6.4. Stability Design Generation

23.6.5. Comparing Stability Designs

23.7. Determination of Shelf Life

23.7.1. Definition of Shelf Life

23.7.2. Model Pruning

Simple ANCOVA for the Fixed Batch Case

Model Pruning for More Complex Studies

23.7.3. Simple Fixed Batch Case

23.7.4. Simple Random Batch Case

23.7.5. Shelf Life Estimation in More Complex Studies

23.8. Release Limit Estimation

23.9. Probability of Future Out-of-specification Stability Test Results

23.9.1. Random Batch Model for Prediction

23.9.2. Prior Distributions for Model Parameters

23.9.3. Predicted Quantities of Interest

23.9.4. Implementation in WinBUGS

Model

Data

23.9.5. Results

23.9.6. Bayesian Prediction Using SAS Proc MIXED

Chapter 24. Packaging Selection for Solid Oral Dosage Forms

24.1. Introduction

24.1.1. Definitions

24.1.2. General Considerations

24.2. Material Considerations

24.2.1. Containers

24.2.2. Determination of Container Moisture Vapor Transmission Rate

24.2.3. Gas Absorbers

24.2.4. Drug Products

24.3. Linking Packaging Property with Drug Property

24.3.1. The Use of Moisture Vapor Transmission Rate per Unit Product for Container Comparison

24.3.2. Modeling of Moisture Uptake by Packaged Products

24.4. Post-approval Packaging Changes

Uncited References

Chapter 25. Clinical Supplies Manufacture

25.1. Introduction

25.2. Strategy of clinical supplies manufacture

25.2.1. Clinical Plan

25.2.2. Clinical Supplies Liaison

25.2.3. Lean Manufacturing

25.2.4. Cross-functional Training

25.2.5. Outsourcing of Manufacturing and Packaging

25.2.6. New Technology

25.3. Good manufacturing practice (GMP) Considerations in manufacturing clinical supplies

25.3.1. Current Good Manufacturing Practice (cGMP) Considerations

25.3.2. A Risk-based Approach

25.4. Cleaning Validation and Verification

25.4.1. Cleaning Validation Versus Cleaning Verification

25.4.2. Swab Test Acceptance Criteria

25.4.3. Swab Selection

25.4.4. Analytical Methodologies

25.4.5. Analytical Method Validation

25.5. Summary

Chapter 26. Specification Setting and Manufacturing Process Control for Solid Oral Drug Products

26.1. Introduction

26.2. Specifications for the drug substance

26.3. Specifications for clinical trial materials

26.3.1. Early Development Stage (Phases 1 and 2)

26.3.2. Late Develo­­pment Stage (Phase 3)

26.4. Specifications for commercial drug products

26.4.1. Product In-house Release Specifications and Regulatory Specifications

26.4.2. Product Stability and Expiration Date

26.5. Process Control for Solid Oral Drug Products

26.5.1. In-process Material Tests and Quality Attributes

26.5.2. Powder Blending Uniformity

26.5.3. Statistical Methodology for Process Control

26.5.4. Process Analytical Technology (PAT) and In-process Controls

26.6. Analytical procedures

26.7. Conclusions

Chapter 27. Scale-up of Pharmaceutical Manufacturing Operations of Solid Dosage Forms

Chapter 28. Process Development, Optimization, and Scale-up

28.1. Introduction

28.2. Common powder handling equipment

Objective of the Section

28.2.1. Processing Steps Prior to Final Blending

28.2.2. Final Blending

28.2.3. Intermediate Bulk Containers

28.3. Typical flow and segregation concerns

Objective of the Section

28.3.1. Common Flow Problems

28.3.2. Flow Patterns

28.3.3. Common Segregation Mechanisms

28.4. Measurement of flow properties

Objective of the Section

28.4.1. Cohesive Strength Tests: Preventing Arching and Ratholing

28.4.2. Bulk Density

28.4.3. Permeability

28.4.4. Segregation Tests

28.5. Basic equipment design techniques

Objective of the Section

28.5.1. Reliable Funnel Flow Design (Preventing a Rathole)

28.5.2. Reliable Mass Flow Designs for the Bin, Chute, and Press Hopper

28.5.3. Minimizing Adverse Two-phase Flow Effects

28.5.4. Minimizing Segregation in the Blender-to-Press Transfer Steps

Chapter 29. Process Development and Scale-up of Wet Granulation by the High Shear Process

29.1. Introduction

29.2. Principles of Wet Granulation and Process Consideration

29.3. Purpose of Wet Granulation

29.4. Common wet Granulation Equipment used for Manufacture

29.5. Equipment Selection Considerations

29.6. Introduction to the Wet Granulation Process

29.6.1. Granule Growth Stages

29.6.2. Granule Size Change Mechanism during Granulation Process

29.6.3. Process Considerations for Particle Size Growth

29.7. Overall Consideration for Process Parameters

29.7.1. Pre-blend Stage

29.7.2. Infusion Stage I

29.7.3. Infusion Stage II

29.7.4. Wet Mass Stage

29.7.5. Popular End Point Observations

29.7.6. Example: Typical Considerations for a High Shear Granulation Process

29.8. Complexity of Wet Granulation

29.9. Common Issues

29.10. Considerations of Process Design

29.10.1. Identify Impact from Active Pharmaceutical Ingredient (API) and Other Raw Materials

29.10.2. Proper Selection of Which Type of Equipment to be Used

29.10.3. Understand the Impact of Process Parameters

29.10.4. Select a Design that Reduces the Sensitivity of End Point Determination

29.10.5. Utilize the Contribution from Each Stage and Maintain a Balanced Design

29.10.6. Consideration of the Design of the Equipment

29.11. Impact of Process Parameters for the High Shear Process

29.11.1. Function of Parameters

29.11.2. Amount of Granulation Agent

29.11.3. Extent of Wet Mass Time

29.11.4. Peripheral Speed/Tip Speed

29.11.5. Temperature of Granulation Agent

29.11.7. Method of Infusion

29.11.8. Design of Granulation Equipment

29.11.9. Different Drying Methods

29.11.10. Difference in Chopper Application

29.11.11. Impact by Residue Heat and by Residual Materials in Multi-batch Consecutive Process

29.12. End Point Determination

29.12.1. Consideration of End Point

29.12.2. Common Methods for End Point Determination in Production

29.12.3. Manufacturing Considerations

29.13. Application of Process Analytical Technology (PAT)

29.14. Design of Experiment (DOE)

29.15. Statistical Aids for Process Control

29.16. Scale-up and Process Measurement of Granulation

29.16.1. End Point Determination

29.16.2. End Point Scale-up

29.16.3. Practical Considerations

29.17. Best Practices

29.17.1. Consideration of Robust Process

29.17.2. Emerging Concept of Process Design and Control

29.18. Principles and Scale-up of foam Granulation

29.18.1. Introduction

29.18.2. Experimental

29.18.3. Results and Discussion

29.18.4. Conclusion of Foam Granulation Study

29.19. Bottom Lines

Uncited References

Chapter 30. Process Development, Optimization, and Scale-up

30.1. Overview of the Fluid-bed Granulation Process

30.2. Equipment Design

30.2.1. Batch-wise Models

30.2.2. Semi-continuous Design

30.2.3. Continuous Models

30.3. Fluid-bed Hydrodynamics

30.3.1. Product Temperature and Moisture Content Profiles through Fluid-bed Processing

30.3.2. Moisture Mass Balance during the Fluid-bed Process

30.4. Mechanisms of Agglomeration

30.4.1. Phases in Granule Growth

30.4.2. Bonding Mechanisms

30.5. Formulation and Process Variables and their Control

30.5.1. Formulation Variables

30.5.2. Key Process Variables

30.5.3. Granule Growth under Drier Conditions (Low Moisture Content of Wet Granules during the Granulation Process)

30.5.4. Granule Growth under Wetter Conditions (High Moisture Content of Wet Granules)

30.6. Scale-up Considerations

30.6.1. Batch Size and Equipment Selection

30.6.2. Spray Rate Scale-up

30.6.3. Rotary Disk Speed Scale-up

30.6.4. Rational Scale-up

30.6.5. Scale-up Via Semi-continuous (Batch-continuous) Processing

30.6.6. Scale-up Via Continuous Processing

30.7. Summary

Acknowledgements

Chapter 31. Development, Scale-up, and Optimization of Process Parameters

31.1. History

31.2. General Operational Principles

31.3. Reasons to use Roller Compaction

31.4. Advantages and Disadvantages of Roller Compaction

31.4.1. Advantages

31.4.2. Disadvantages

31.5. Feed system

31.6. Roll designs

31.7. Compaction theory

31.8. Deaeration

31.9. Control mechanisms

31.10. Scale-up

31.10.1. Scale-up Throughput Calculations

31.10.2. Scale-up for Achieving Consistent Sheet Density

31.11. Case studies

31.11.2. Bulk Densities of Various Materials Before and After Roller Compaction

31.11.3. Effect of Compaction Pressure on Bulk Density

31.11.4. Compaction of Aspirin

31.11.5. Troubleshooting

31.12. Application of process analytical technology to roller compaction

31.13. Roller compactor suppliers

Uncited References

Chapter 32. Development, Optimization, and Scale-up of Process Parameters

32.1. Introduction

32.2. Operational Principles of Compression by Rotary Press

32.3. Best Practice

32.4. Tool Design

32.4.1. Terminology

32.4.2. Common Tooling Standards

32.4.3. EU, TSM, B, and D Type Punches

32.4.4. Recent Innovations

32.4.5. Cup Depth, Overall Length, and Working Length

32.4.6. Tooling Options

32.4.7. Tool Configuration for Small and Micro Tablets

32.4.8. Tapered Dies

32.5. Tablet Designs

32.5.1. Tablet Shapes

32.5.2. Tablet Face Configurations

32.5.3. Undesirable Shapes

32.5.4. Tablet Identification

32.5.5. Bisects

32.5.6. Steel Types

32.5.7. Inserted Dies

32.5.8. Multi-tip Tooling

32.5.9. Punch Tip Pressure Guide

32.6. Care of Punches and Dies

32.7. Tooling Inspection

32.8. Tooling Reworking

32.9. Press Wear

32.10. Purchasing Tablet Compression Tooling

32.11. Consideration of Tooling

32.12. Scale-up of Compression

32.12.1. Compaction and Compression

32.12.2. Tableting Failure

32.12.3. Main Factors of Tableting

32.12.4. Compaction Event

32.12.5. Tableting Time Definitions

32.12.6. Dwell Time and Contact Time

32.12.7. Tableting Geometry

32.12.8. Tableting Scale-up

Uncited References

Chapter 33. Development, Optimization, and Scale-up of Process Parameters

Chapter 34. Development, Optimization, and Scale-up of Process Parameters

34.1. Introduction

34.2. Basic Design

34.3. HS Wurster Considerations

34.4. Coating and Process Characteristics

34.5. Processing Examples

34.6. Process Variables

34.6.1. Batch Size

34.6.2. Fluidization Pattern

34.6.3. Atomizing Air Pressure and Volume

34.6.4. Nozzle Port Size

34.6.5. Evaporation Rate

34.6.6. Product Temperature

34.7. Case Studies for Layering and Fine Particle Coating

34.8. Scale-up of Wurster Processing

34.8.1. Batch Size

34.8.2. Spray Rate

34.8.3. Droplet Size and Nozzle Considerations

34.8.4. Process Air Volume

34.8.5. Process Air and Product Temperatures

34.8.6. Mass Effects

34.9. Summary

Chapter 35. Process Analytical Technology in Solid Dosage Development and Manufacturing

35.1. Introduction

35.2. Regulatory Developments

35.2.1. The FDA: Process Analytical Technology (PAT) Guidance

35.2.2. United States Pharmacopeia (USP)

35.2.3. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

35.2.4. American Society for Testing and Materials (ASTM) Standards

35.3. Process Analytical Technology (PAT) Tools

35.3.1. Analytical Techniques

35.3.2. Chemometrics and Multivariate Analysis

35.4. Process Analytical Technology (PAT) Applications

35.4.1. Raw Material Identification

35.4.2. Blending

35.4.3. Granulation

35.4.4. Near-infrared Monitoring of Fluid-bed Drying

35.4.5. Encapsulation

35.4.6. Compression

35.4.7. Coating

35.5. Conclusion

Uncited References

IV. Selected Topics In Product Development

Chapter 36. The Product Development Process

36.1. Introduction

36.1.1. Organizational Considerations

36.1.2. The Target Product Profile: A Strategic Development Process Tool

36.2. Summary of the Drug Development Process

36.3. Preclinical Research

36.3.1. Discovery Research

36.3.2. Preclinical Development

36.4. Clinical Research

36.4.1. Phase 1

36.4.2. Phase 2

36.4.3. Phase 3

36.4.4. Pre-new Drug Application (NDA) Meeting and the New Drug Application

36.5. Concluding Remarks

Chapter 37. Product Registration and Drug Approval Process in the United States

37.1. Background for Product Registration in the United States

37.2. The New Drug Application (NDA) and Review Process

37.2.1. Food and Drug Administration (FDA) Interactions

37.2.2. New Drug Applications (NDA)

37.2.3. Common Technical Document (CTD)

37.2.4. User Fees

37.2.5. New Drug Application (NDA) Review Process

37.3. Generic Drug Product Registration and Review Process

37.3.1. Food and Drug Administration (FDA), Center for Drug Evaluation and Research (CDER), Office of Generic Drugs

37.3.2. Abbreviated New Drug Application (ANDA)

37.3.3. Abbreviated New Drug Application (ANDA) Review Process

37.4. Post-approval Activities for New Drug Applications and Abbreviated New Drug Applications

37.4.1. Reports

37.4.2. Changes to an Approved Application (21CFR314.70)

37.5. Other Considerations for New Drug Applications and Abbreviated New Drug Applications

37.5.1. Supplemental Applications (21CFR314.71)

37.5.2. Establishment Registration and Drug Listing Requirements for Foreign Establishments (21CFR 207.40)

37.6. Pre-approval Inspection (PAI)

37.6.1. Background and Purpose

37.6.2. On-site Inspection

37.6.3. Preparation

37.6.4. Outcome of the Pre-approval Inspection

37.6.5. Summary

Chapter 38. Modern Pharmaceutical Quality Regulations

38.1. Introduction

38.2. Issues with QbT and the Old Pharmaceutical Quality Assessment System

38.3. Quality by Design

38.4. Question-based Review for Generic Drugs

38.5. QbR Questions Embody QbD

38.5.1. Questions Related to Desired Product Performance

38.5.2. Questions Related to Product Design

38.5.3. Questions Related to Process Design

38.5.4. Questions Related to Process Understanding and Control

38.6. Conclusions

38.A1. Appendix:[22] QbR Questions

2.3. Introduction to the Quality Overall Summary

Chapter 39. Intellectual Property Law Primer

39.1. Introduction

39.2. Patent Prosecution

39.2.1. Types of United States Patent Applications

39.2.2. Standards for Patentability

39.2.3. The United States Utility Patent Application

39.2.4. Representative Pharmaceutical Related Patent Subject Matter and Claims

39.3. Patent Enforcement/litigation

39.3.1. Example: Patentability Versus Freedom to Operate

39.3.2. Patent Infringement Litigation

39.3.3. Remedies for Patent Infringement

39.3.4. Defenses to Patent Infringement

Chapter 40. Product Lifecycle Management (LCM)

40.1. Introduction

40.2. Basic Patent Laws Governing the Life of Pharmaceutical Products

40.3. Lifecycle Management Through Salts, Crystal Forms and Formulations

40.4. Extension of Product Lifecycle by Shortening Product Development Time

40.5. Lifecycle Management Through New Drug Delivery Systems

40.5.1. Modified-Release

40.5.2. Formulations with Enhanced Bioavailability

40.5.3. Examples of Successful New Drug Delivery Systems

40.6. Lifecycle Management Through Fixed Combination Products

40.6.1. Benefit of Fixed Combination Products

40.6.2. Clinical Challenges

40.6.3. Technical Challenges

40.6.4. Business Challenges

40.7. Conclusions

Bibliography

Index

Copyright Page

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Dedication

This work is dedicated to Drs R.D. Schoenwald, J. Keith Guillory, L.E. Matheson, E.L. Parrott, D.R. Flanagan, D.E. Wurster, P. Veng-Pedersen and the late D.J.W. Grant

By generously sharing their experience, time and wisdom, what they've taught us is well beyond what we learned in school

We are also forever indebted to our families for their love, understanding, and sacrifice

Foreword

Physical pharmacy, the application of physico-chemical principles to the solution of problems related to dosage forms is, as a discipline, rapidly disappearing from curricula in colleges of pharmacy. It is being replaced by an emphasis on communication skills and pharmacotherapeutics. Biopharmaceutics and pharmacokinetics, sciences that arose from the efforts of such early physical pharmacists as Sidney Riegelman, Milo Gibaldi, Gary Levy, John Wagner and Edward Garrett, are still considered essential, at least for the present. In graduate programs in pharmaceutics, physical pharmacy has taken a back seat to such fashionable and fundable areas as genetics and tissue scaffolding. Yet, the demand for the skills of the physical pharmacist remains strong in the pharmaceutical industry. That is why this textbook fills an important need.

Scientists entering the pharmaceutical industry today often lack the fundamental knowledge that is reflected in the chapters contained in this book. Many of the researchers entering industry have backgrounds in chemical engineering or organic chemistry. Their exposure to the principles of physical pharmacy is a deficit that must be overcome by on-the-job training and by extensive study. It is in the areas of preformulation, the development of new and sophisticated drug delivery systems, and the day-to-day work of optimizing the effects of new drug entities that this knowledge is most needed. There are, of course, many textbooks that deal with specific subjects important to the industrial pharmacist, focusing on tablets, capsules, disperse systems, parenterals, etc. However, there is a critical need for a comprehensive treatment of the science underlying each of these special areas, together with practical applications of the science that results in quality dosage forms. Questions related to solubility, dissolution, chemical and physical stability, interfacial phenomena, and the absorption and distribution of drug molecules are common to all. Consequently, a single textbook that brings together experts in all of these subjects can be an invaluable asset to the novice industrial scientist. Each chapter in this book contains a useful bibliography of references that can provide for ready access to current research in the field. We should be grateful that these authors have taken time from their busy schedules to share their knowledge and experience with all of us.

List of Contributors

Gregory E. Amidon (Chapter 8)

University of Michigan, Ann Arbor, MI, USA

Thomas Baxter (Chapter 28)

Jenike & Johanson Inc., Tyngsboro, MA, USA

James E. Brady (Chapter 9)

Aqualon Division, a Business Unit of Hercules Inc., Wilmington, DE, USA

Geoff Carr (Chapter 22)

Patheon Inc., Ontario, Canada

Wei Chen (Chapters 25 & 26)

Eli Lilly and Company, Indianapolis, IN, USA

Yisheng Chen (Chapters 7, 14, 24 & 37)

Novast Laboratories (China) Ltd, Nantong, China

Tom Dürig (Chapter 9)

Aqualon Division, a Business Unit of Hercules Inc., Wilmington, DE, USA

Walter Dziki (Chapter 35)

Abbott Laboratories, North Chicago, IL, USA

Xingchun (Frank) Fang (Chapter 22)

Novast Laboratories (China) Ltd., Nantong, China

Douglas R. Flanagan (Chapters 7 & 13)

University of Iowa, Iowa City, IA, USA

Ronald C. Freeze (Chapter 22)

Abbott Laboratories, Abbott Park, IL, USA

Joseph Fuchs (Chapter 39)

Rockey, Depke & Lyons, LLC, Chicago, IL, USA

Ping Gao (Chapter 19)

Abbott Laboratories, Chicago, IL, USA

Xiaorong He (Chapter 18)

Asymchem Laboratories, Morrisville, NC, USA

Steven F. Hoff (Chapter 37)

Abbott Laboratories, Abbott Park, IL, USA

Ming Hu (Chapter 11)

University of Houston, TX, USA

Richard Hwang (Chapters 25 & 26)

Pfizer Global R&D, Ann Arbor, MI, USA

Min Jiang (Chapter 35)

Abbott Laboratories, North Chicago, IL, USA

Wenlei Jiang (Chapter 38)

US Food and Drug Administration, Rockville, MD, USA

David Jones (Chapter 34)

OWI-Consulting Inc, Ramsey, NJ, USA

David LeBlond (Chapter 23)

Abbott Laboratories, Wadsworth, IL, USA

Michael Levin (Chapters 29 & 32)

Metropolitan Computing Corporation (MCC), East Hanover, NJ, USA

Ping Li (Chapter 40)

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Lirong Liu (Chapters 29, 31, 32 & 33)

Pfizer Inc., Morris Plains, NJ, USA

Zhongqiu Liu (Chapter 11)

Southern Medical University, Guangzhou, China

Michelle Long (Chapter 14)

Abbott Laboratories, North Chicago, IL, USA

Sean Mackey (Chapter 35)

Abbott Laboratories, Abbott Park, IL, USA

Walt Morozowich (Chapter 19)

Prodrug and Formulation Consultant, Kalamazoo, MI, USA

Deanna Mudie (Chapter 8)

University of Michigan, Ann Arbor, MI, USA

Eric Munson (Chapter 3)

University of Kansas, Lawrence, KS, USA

Ajit S. Narang (Chapter 6)

Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Dale Natoli (Chapter 32)

Natoli Engineering Company, St. Charles, MO, USA

Brian Pack (Chapter 25)

Eli Lilly and Company, Indianapolis, IN, USA

Stuart Porter (Chapter 33)

International Specialty Products, Wayne, NJ, USA

William R. Porter (Chapters 5 & 10)

Abbott Laboratories, Abbott Park, IL, USA

James Prescott (Chapter 28)

Jenike & Johanson Inc., Tyngsboro, MA, USA

Yihong Qiu (Chapters 17, 20 & 21)

Abbott Laboratories, Abbott Park, IL, USA

Krishnaswamy S. Raghavan (Chapter 6)

Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Venkatramana M. Rao (Chapters 1 & 6)

Bristol-Myers Squibb Co., New Brunswick, NJ, USA

Lisa Ray (Chapter 25)

Eli Lilly and Company, Indianapolis, IN, USA

Gary Sackett (Chapters 31 & 33)

Vector Corporation, Marion, IA, USA

Ritesh Sanghvi (Chapter 1)

Forest Laboratories Inc., Farmingdale, NY, USA

Pamela J. Secreast (Chapter 8)

Pharm Optima, Portage, MI, USA

Kathleen Seitz (Chapters 15 & 16)

Centocor Research & Development, Inc., Malvern, PA, USA

Nancy E. Sever (Chapter 35)

Abbott Laboratories, North Chicago, IL, USA

Sherwin Shang (Chapter 9)

Abbott Laboratories, North Chicago, IL, USA

Z. Jesse Shao (Chapter 30)

Arena Pharmaceuticals, Inc., San Diego, CA, USA

Paul Sheskey (Chapter 31)

The Dow Chemical Company, Midland, MI, USA

Timothy J. Smith (Chapter 31)

Vector Corporation, Marion, IA, USA

Suchinda Stithit (Chapters 25 & 26)

Century Pharmaceuticals, Indianapolis, IN, USA

John Strong (Chapter 27)

Abbott Laboratories, North Chicago, IL, USA

Wei-Qin (Tony) Tong (Chapters 4 & 40)

Teva Pharmaceuticals USA, Sellersville, PA, USA

Lev Tsygan (Chapter 32)

Metropolitan Computing Corporation (MCC), East Hanover, NJ, USA

Lynn Van Campen (Chapter 36)

University of Wisconsin, Madison, WI, USA

Jianzhou (Jake) Wang (Chapter 13)

Gorbec Pharmaceutical Services, Durham, NC, USA

Stephen Wang (Chapter 11)

Schering-Plough, Kenilworth, NJ, USA

Martin Warman (Chapter 35)

Martin Warman Consultancy Ltd, Swalecliffe, Kent, UK

Ken Yamamoto (Chapter 30)

Pfizer Global R&D, Groton, CT, USA

Yongsheng Yang (Chapter 12)

US Food and Drug Administration, Silver Spring, MD, USA

Lawrence X. Yu (Chapters 12 & 38)

US Food and Drug Administration, Rockville, MD, USA

Erika A. Zannou (Chapter 40)

Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

Geoff G. Z. Zhang (Chapters 2 & 5)

Abbott Laboratories, North Chicago, IL, USA

Guohua Zhang (Chapter 21)

Novast Laboratories (China) Ltd., Nantong, China

Jack Y. Zheng (Chapters 25 & 26)

Eli Lilly and Company, Indianapolis, IN, USA

Deliang Zhou (Chapters 2 & 5)

Abbott Laboratories, North Chicago, IL, USA

Honghui Zhou (Chapters 15 & 16)

Centocor Research & Development, Inc., Malvern, PA, USA

Haijian (Jim) Zhu (Chapter 1)

Forest Laboratories Inc., Farmingdale, NY, USA

Hao Zhu (Chapter 15)

Centocor Research & Development, Inc., Malvern, PA, USA

Part I. Theories And Techniques In The Characterization Of Drug Substances And Excipients

Chapter 1. Solubility of Pharmaceutical Solids

1.1. Introduction

1.1.1. Implication of Solubility in Dosage Form Development

The solubility of a drug is one of its most important physico-chemical properties. The determination of drug solubility and ways to alter it, if necessary, are essential components of pharmaceutical development programs. The bioavailability of an orally administered drug depends primarily on its solubility in the gastrointestinal tract and its permeability across cell membranes. This forms the basis for the biopharmaceutical classification system (BCS).[¹] Drug molecules are required to be present in a dissolved form, in order for them to be transported across biological membranes. Therefore, low aqueous solubility can either delay or limit drug absorption. Knowledge of the solubility of a drug is also important when direct administration into the blood stream is desired. Injectable formulations usually require a drug to be in solution for administration. In addition, a drug solution is preferred for conducting pharmacological, toxicological, and pharmacokinetic studies during the drug development stage. Thus, poor aqueous solubility not only limits a drug’s biological application, but also challenges its pharmaceutical development. As a result, investigation into approaches for solubility enhancement has been a regular feature of pharmaceutical research for several decades. The need for such approaches has been on a rise following the introduction of combinatorial chemistry and high throughput screening techniques to the drug discovery arena. The advent of these techniques, resulting in a rapid development of libraries of pharmaceutically active compounds, has led to a greater number of highly active compounds. At the same time, it has resulted in generation of a far higher percentage of extremely lipophilic and poorly water-soluble compounds adding more challenges to formulation development. It has been reported[²] that more than a third of the compounds registered by Pfizer in the late 1990s had solubilities that were lower than 5 μg/ml.

While solubility enhancement remains one of the primary areas of focus during the drug development phase, there are several situations that may require solubility reduction. Development of sustained release products, taste masking, and enhancement of chemical stability are examples of such situations.

Knowledge of solubility also finds application in developing analytical methods for drugs. Reverse phase liquid chromatography is one of the most widely used techniques for pharmaceutical separation and analysis. Separation is based on the differential affinity of the solute towards the mobile phase and the stationary phase, which is a direct outcome of its solubility in these phases. The analysis of concentration using UV spectroscopy is also performed on drug solutions.

Based on the above discussion, it should be clear that solubility plays an important role in several avenues of pharmaceutical research. As a consequence, the determination of solubility remains one of the most commonly conducted experiments for any new compounds. While solubility experiments are sometimes perceived as trivial, accurate determination of solubility is a challenging exercise. A number of experimental variables may affect the solubility results, inducing high degrees of scatter in the data.[³] This builds a strong case for the applicability of tools for estimation of solubility based on theoretical calculations. While most of these calculation approaches are useful with respect to providing reasonable estimation and time saving, they can never completely replace the experimentally determined values.

This chapter is written with the intent of developing a thorough understanding of the concepts of solubility. The various physico-chemical forces and factors that determine the solubility of a solute in a solvent will be discussed in detail. The thermodynamics of solubilization and various theoretical models for its estimation have also been included. Considerable emphasis has been laid on the techniques used for solubility enhancement along with practically relevant examples. In addition, the various aspects of solubility determination experiments including challenges and strategies to overcome them are discussed.

1.1.2. Basic Concepts of Solubilityand Dissolution

A true solution is a homogenous mixture of two or more components on a molecular level. Any sample collected from such a mixture will be representative of the entire bulk. In a two-component system, the component present in larger proportion is generally referred as the solvent, and the other as the solute.

When a solute is placed in contact with a solvent, mixing occurs due to the propensity of all molecules towards randomization, resulting in an increase in overall entropy of the system. The solute molecules start to break away from the surface and pass into the solvent system. The detached solute molecules are free to move randomly throughout the solvent bulk forming a uniform solution. Some of these solute molecules strike the bulk solute surface and redeposit on it. Initially, when the concentration of solute molecules is low in the solution, the number of molecules leaving the bulk solute surface is much higher. As the solvent bulk starts becoming saturated with the solute molecules, the redeposition process starts to accelerate. Once sufficient solute molecules have populated the solvent bulk, the rate of molecules leaving becomes equal to the rate of redeposition (dynamic equilibrium). The concentration of the solute in the solvent at which this equilibrium is reached is defined as the thermodynamic solubility. The rate at which the equilibrium is achieved is the dissolution rate. Thus, solubility is an equilibrium concept, while dissolution is a kinetic phenomenon. Both are dependent on the experimental conditions, including temperature. The dissolution rate of a solute in a solvent is directly proportional to its solubility, as described by the Noyes–Whitney equation:[⁴,⁵](1.1)

where:

dM/dt is the rate of mass transfer

D is the diffusion coefficient (cm²/sec)

A is the surface area of the drug (cm²)

h is the static boundary layer (cm)

Cs is the saturation solubility of the drug

Ct is the concentration of the drug at time (t).

Solubility is expressed in units of concentration including percentage on a weight or volume basis, mole fraction, molarity, molality, parts, etc. The US Pharmacopeia and National Formulary describe solubility as the number of milliliters of solvent required to dissolve 1 gram of the solute.

It follows from the previous discussion that the equilibrium solubility of a solute will depend on its relative affinities towards solvent molecules and fellow solute molecules. Thus, the strength of molecular interactions, both inter and intra, affect solubility. While a detailed description of these interactions can be found in any physical chemistry book, they are discussed here briefly.

Ionic Interactions

Pure ionic interactions occur between two oppositely charged ions. Such interactions are relevant to pharmaceutical salts and ion pairs. An ion can also interact with a polar molecule (ion–dipole) or induce a dipolar character to a non-polar molecule (ion-induced dipole). When sodium chloride is dissolved in water, the free sodium and chloride ions interact with polar water molecules such that the positive head of water molecules interact with the chloride ions, while the negative head of water molecules interact with the sodium ions. By virtue of these interactions, pharmaceutical salts generally have a higher solubility than their free form. The strength of ionic interactions depends on the electrostatic charge density on the interacting ions, as well as the media properties, including dielectric constant and temperature.

van der Waals Interactions

Two molecules with permanent dipole moments can interact, when placed in sufficiently close proximity (dipole–dipole or Keesom interaction). The molecules will try to arrange in a manner to minimize the energy associated with them. Thus, the positive head of one molecule will position close to the negative head of the other molecule. The positioning, however, may not be ideal due to geometric constraints and random thermal motion of the participating molecules (entropic influence). As a consequence a situation arises where the participating molecules, on average, spend more time in an aligned position. Strongly polar molecules can induce polar attributes to non-polar molecules to result in dipole-induced dipole (Debye) interactions. The strength of van der Waals interactions is a direct outcome of the dipole moment and polarizability of the participating molecules, and is also affected by the media properties such as temperature.

Dispersion Interactions

Also known as London forces, dispersion interactions occur between any adjacent pair of atoms or molecules when they are present in sufficiently close proximity. These interactions account for the attractive forces between non-ionic and non-polar organic molecules, such as paraffin and many pharmaceutical drugs. The origin of these forces remains unclear, but it is believed that at any given instance molecules are present in a variety of distinct positions due to thermal oscillations. These positions give rise to a temporary molecular dissymmetry resulting in a dipole-type characteristic. This instantaneous dipole then induces polar character to the neighboring molecules and starts interacting with them.

Hydrogen Bonding

These interactions occur between hydrogen bond donating groups and strong electronegative atoms such as halogens, oxygen, and nitrogen. Hydrogen atoms become associated with electronegative atoms by virtue of electrostatics, and result in the formation of hydrogen bridges. These interactions are prevalent in aqueous and alcoholic systems. A large number of drugs are involved in either inter- or intra-molecular hydrogen bonding. The aqueous solubility of a drug is directly related to its hydrogen bonding capability. The higher water solubility of phenol, as compared to benzene and toluene, can be attributed to the former’s hydrogen bonding nature. The evolving field of cocrystals is based on the hydrogen bond interactions between molecules of drug and the cocrystal former. The strength of hydrogen bond interactions depends upon the electronegativity of the participating atoms, as well as the temperature of the media. Since the requirement of ideal positioning is highest for hydrogen bonding interactions, they are more sensitive to temperature than other interactions.

1.2. Thermodynamics of solutions

In order to grasp the concepts of solubility, it is essential to understand the basic thermodynamics of mixing. This section covers the various thermodynamic aspects that dictate the process of mixing.

1.2.1. Volume of Mixing

The volume of mixing, ΔVmix, is the difference between the physical volume occupied by the mixture (Vuv) and the sum of physical volumes occupied by the solute (Vu) and solvent (Vv):(1.2)

A negative volume of mixing is indicative of strong inter-molecular interactions between the solute and solvent molecules. Aqueous solutions of strong electrolytes have significantly large negative volumes of mixing, due to strong hydration of ions in the solution.[³] In the case of most pharmaceutically active compounds the volume of mixing is small and can be ignored.

1.2.2. Enthalpy of Mixing

The enthalpy of mixing, (ΔHmix), is the difference between the sum of enthalpies of the solute (Hu), the solvent (Hv), and of the mixture, (Huv):(1.3)

From a strictly enthalpic standpoint, mixing is favored if ΔHmix is negative. The excess enthalpy is liberated in the form of heat (exothermic process).

The energy of mixing (ΔEmix) is related to the enthalpy of mixing as:(1.4)

As previously mentioned, ΔVmix is small, and therefore the values of ΔEmix and ΔHmix are close to one another.

1.2.3. Entropy of Mixing

The entropy of a pure system is a measure of the randomness of its molecules. Mathematically:(1.5)

where:

Ω is the number of ways molecules can be present in the system.

Since Ω is always equal to or greater than unity, entropy is either zero or positive. The entropy of a mixture, (ΔSmix), is related to the number of ways the solute and solvent molecules can exist in pure forms, and in mixture:(1.6)

Generally, the molecules have more freedom to move around in a mixture, i.e., Ωmix is greater than Ωuv. As a consequence ΔSmix is usually positive. However, in rare situations where the molecules have less freedom in the mixture (solute molecules undergoing complexation-like interactions with solvent molecules),[⁶,⁷]ΔSmix can be negative.

The entropy of mixing is related to the composition of the solution as:(1.7)

where:

Xu and Xv are the mole fractions of the solute and solvent, respectively, in the mixture.

In a two component system Xv=1−Xu; ΔSmix can be written as:(1.8)

(1.9)

It follows from Equation 1.7 that ΔSmix will be highest for solutions containing equimolar amounts of solute and solvent molecules.

The slope of entropy of mixing as a function of solution composition is given by:(1.10)

It follows from Equation 1.10 that the slope will be highest in dilute solutions (when either Xu or Xv is small). Thus, the manifestation of entropy is highest in dilute solution, which explains why thermodynamically there is some miscibility between all systems.

1.2.4. Free Energy of Mixing

The free energy of mixing, ΔGmix, determines the possibility and extent of two compounds mixing to form a solution. It combines the effects of enthalpy and entropy on mixing and is mathematically described as:(1.11)

where:

T is the temperature in °Kelvin.

Like any thermodynamic process, mixing will occur if the free energy of mixing is negative. On the other hand, if the free energy of mixing is greater than zero there will be phase-separation. As mentioned in the previous section, solubility depends on the temperature of the system. It follows from Equation 1.11 that an increase in temperature will increase the effect of entropy, thus making mixing more favored. In addition, temperature may also affect ΔHmix, particularly for hydrogen-bonded solvents such as water. It is well known that the strength of hydrogen bonding interactions is very sensitive to temperature. An increase in temperature makes the self-associated structure of water weaker. Since the self-associated structure of water is primarily responsible for poor aqueous solubility of non-polar solutes, including drugs, increasing the temperature thereby facilitates their solubility.

1.3. Theoretical estimation of solubility

While solutions of all states of matter (gas, liquid, and solid) exist in practice, the focus of this chapter will be on solutions comprising of liquid solvent, since these systems are most commonly encountered and have highest relevance in the pharmaceutical field. The backbone of the concepts discussed here may be applied to other systems, with some modifications.

1.3.1. Ideal Solutions

In an ideal solution the strength and density of interactions between the solute molecules and the solvent molecules are equal to that in the solution. In other words, the solute–solvent interactions are equal in magnitude to the solute–solute interactions and solvent–solvent interactions. Thus, the solute and solvent molecules have no preference in terms of interacting with other molecules present in the solutions. This results in the enthalpy (

) and volume of mixing (

) being 0. Such solutions rarely exist in practicality, but understanding the concept of ideal mixing provides a good platform to understand more complex systems. A solution comprising of solute and solvent bearing very close structural resemblance (in terms of functionality and size) may make nearly ideal solutions. A solution of water in heavy water nearly fits the description of an ideal solution.

The entropy of mixing of an ideal solution (

) is given by Equation 1.7. The partial molar entropy of mixing of the solute in a dilute solution is given by:(1.12)

Since Xu is always less than 1,

is positive. The free energy of mixing for an ideal solution (

), which is the difference between the enthalpy and entropy of mixing, will therefore always be negative. Thus, in ideal solutions, a liquid solute will be miscible with the solvent in all proportions.(1.13)

1.3.2. Effect of Crystallinity

In the case of an ideal solution of a crystalline solute, more considerations are required. As discussed above, the solute molecules have no preference in terms of interacting with other molecules in the solution. However, if the solute exists as a crystalline solid, the enthalpic component related to the crystallinity of the solute also warrants consideration. In other words, the liquid solute molecules are free to move around in the solution while the crystalline solute molecules have to be removed from the crystal lattice before they can start moving around. Mathematically, this can be stated as:(1.14)

The process is conceptually similar to melting of a solid, which is followed by dissolution of the liquid solute molecules, and is governed by the same interactions as melting.

The effect of crystallinity of a solid on its solubility is described by the Clausius–Clapyron equation:(1.15)

represents the ideal solubility of the crystal and the effect of crystallinity on the solubility.

According to Kirchoff’s law, the energy of an irreversible process is equal to the energy of a series of reversible processes between the same end points. Therefore, the irreversible enthalpy of melting at any temperature T(

) can be described as the sum of the enthalpies for the following three reversible processes: heating the solid to its melting point, Tm (quantified by the heat capacity of the solid); melting the solid at its melting point (enthalpy of fusion); and cooling the liquid back down to T (quantified by the heat capacity of the liquid). The heat of melting at T, can thus be related to its value at the melting point as:(1.16)

and

are the heat capacities of the crystal and liquid form, respectively.

Combining Equations 1.15 and 1.16, the effect of crystallinity can be calculated to be:(1.17)

where:

ΔCpm is the heat capacity of melting.

According to the van’t Hoff expression, the heat capacity of melting is close to zero. The Hildebrand[⁸] expression states that the heat capacity of melting is equal to the entropy of melting (ΔHm/Tm). This expression has been used by several workers including Prausnitz et al.,[⁹] Grant et al.,[¹⁰] and Mishra.[¹¹] Later, Mishra and Yalkowsky[¹²] compared the mathematical significance of the two expressions and concluded that the results using either expression are close for solids melting below 600°K. Thus, Equation 1.17 can be simplified to the following form:(1.18)

Equation 1.18 may be further simplified by applying Walden’s rule for entropy of melting. Walden[¹³] showed that the entropy of melting of coal tar derivatives, which can be assumed to represent organic solids like drugs, is constant at approximately 6.9R. Martin et al.,[¹⁴] Dannenfelser et al.,[¹⁵] and Jain et al.[¹⁶]have successfully verified and extended the applicability of Walden’s rule to several organic nonelectrolytes. Applying this approximation the effect of crystallinity on the solubility of crystalline solute at 25°C can be calculated by:(1.19)

where:

MP is the melting point of the solute expressed in °C.

The obvious interpretation of Equation 1.19 is that the effect of crystallinity will be greater for high melting solutes. It is intuitive that a high melting crystalline solid will offer greater resistance towards solubilization. It also follows that an increase in temperature will diminish the effect of crystallinity and therefore, result in increased solubility.

For liquid solutes, where there is a complete absence of crystallinity, Equation 1.19 should be omitted while calculating the solubility. The effect of crystallinity on solubility can be easily followed by referring to Figure 1.1.

Figure 1.1. Role of crystallinity in solubility of solids. Modified from a presentation by Dr Kenneth Morris (Short Course on Solubility and Solubilization of Drugs, 2007)

1.3.3. Non-ideal Solutions

Nearly all solutions encountered in the pharmaceutical arena are not ideal. Non-ideal solutions or real solutions are formed when the affinity of solute molecules for each other is different than that towards the solvent molecules or vice versa. In either case, the enthalpy of mixing is not ideal. This results in a deviation from ideality that is related to the activity coefficient of the solute. The activity of a solute in a solution is equal to the product of its concentration and activity coefficient as:(1.20)

where:

γu is the activity coefficient of the solute.

The mole fraction solubility of a crystalline solute in a non-ideal solution can be calculated by combining Equations 1.19 and 1.20:(1.21)

In the case of ideal solutions, γu is 1 and the solubility is ideal.

The mathematical meaning of γu is derived using various theories depending upon the type of solute and solvent molecules. Two of the most commonly accepted theories are regular solution theory and aqueous solution theory.

1.3.4. Regular Solution Theory

This theory is applicable largely to non-hydrogen bonding systems. According to the theory, γu is a function of following three steps in which mixing occurs:

Removal of a solute molecule from the solute surface. This involves breaking of solute–solute bonds, and the work required to accomplish this is given by Wuu.

Removal of a solvent molecule from bulk to create a cavity in which the solute molecule can fit. This involves breaking of solvent–solvent bonds and the work required for this is given by Wvv.

Insertion of the free solute molecule in the created cavity. This results in gain of work, which is given by Wuv. The cavity filling involves surfaces of both solute and solvent molecules, and that is why the total work gained is 2Wuv.

The total work is therefore equal to