Cover
Preface
1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development
1. 1.1 Introduction
2. 1.2 Polymorphism Impact on Drug/Excipient Properties
3. 1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation
4. 1.4 Conclusion
5. References
2 Strategies for the Formulation Development of Poorly Soluble Drugs via Oral Route
1. 2.1 Introduction
2. 2.2 Quality by Testing (QbT) and Quality by Design (QbD)
3. 2.3 Linking the Formulation to the Clinical Phase
4. 2.4 Defining the Formulation Strategy
5. 2.5 Nanosuspensions
6. 2.6 Solid Dispersion
7. 2.7 Lipid‐Based Drug Delivery Systems
8. 2.8 Micellar System
9. 2.9 Mesoporous Silica Particles
10. 2.10 Conclusion
11. References
3 Effect of Residual Reactive Impurities in Excipients on the Stability of Pharmaceutical Products
1. 3.1 Introduction
2. 3.2 Reactive Impurities in the Excipients and Their Impact on Drug Stability
3. 3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility
4. 3.4 Risk Assessment for API Incompatibilities and Mitigation Strategies
5. 3.5 Assessment of Incompatibilities of API with Excipients
6. 3.6 Design and Selection of Drug Substance
7. 3.7 Formulation Strategies to Circumvent API Degradation
8. 3.8 Inhibition of Oxidative Degradation
9. 3.9 Super‐Refined Excipients
10. 3.10 Packaging and Storage
11. 3.11 Concluding Remarks
12. References
4 Preclinical Formulation Assessment of NCEs
1. 4.1 Introduction
2. 4.2 Significance of Various Properties of NCEs in Early Drug Discovery
3. 4.3 Formulation Strategies to Improve Properties of NCEs
4. 4.4 Preclinical Formulation Assessment of Oral, Parenteral, and Topical Dosage Forms
5. 4.5 Case Studies
6. 4.6 Conclusion and Future Perspectives
7. References
5 Regulatory Aspects for Formulation Design – with Focus on the Solid State
1. 5.1 The Understanding of “Regulatory”
2. 5.2 Formulation Design
3. 5.3 An Extended Timescale
4. 5.4 Solubility Data
5. 5.5 Impact of Solubility and Dissolution Rate on Formulation Design
6. 5.6 Single and Multicomponent Systems
7. 5.7 Analytical Techniques for the Characterization of the Solid State
8. 5.8 Control of Solid‐state Constitution
9. 5.9 Regulatory Consideration of Solid Compounds
10. 5.10 Conclusions and Recommendations
11. Disclaimer
12. References
6 Insight into Innovative Applications of Parenteral Formulations
1. 6.1 Introduction
2. 6.2 Factors Affecting Development of Sustained‐/Controlled‐Release Formulations
3. 6.3 Overview of Sustained and Controlled Release Parenteral Formulations
4. 6.4 Case Studies
5. 6.5 Conclusion
6. 6.6 Future Prospects
7. References
7 Assessing Pharmacokinetics of Various Dosage Forms at Early Stage
1. 7.1 Introduction
2. 7.2 Definition of Pharmacokinetics
3. 7.3 Case Studies
4. 7.4 Summary
5. References
8 Transdermal Medical Devices: Formulation Aspects
1. 8.1 Introduction
2. 8.2 Microneedles
3. 8.3 Laser‐Assisted Ablation: Skin Pretreatment
4. 8.4 Iontophoresis
5. References
9 Physical Characterization Techniques to Access Amorphous Nature
1. 9.1 Introduction
2. 9.2 Screening Techniques for Amorphization
3. 9.3 Characterization of Amorphous Materials
4. 9.4 Summary
5. 9.5 Future Prospects
6. References
10 Design and Development of Ocular Formulations for Preclinical and Clinical Trials
1. 10.1 Introduction
2. 10.2 Ocular Anatomy and Physiology
3. 10.3 Ocular Routes of Administration
4. 10.4 Drug Discovery in Ophthalmology
5. 10.5 Topical Drug Administration
6. 10.6 Posterior Segment Delivery
7. 10.7 Conclusion
8. References
11 Preclinical Safety Aspects for Excipients: Oral, IV, and Topical Routes
1. 11.1 Introduction
2. 11.2 General Considerations
3. 11.3 Undesired Side Effects of Excipients
4. 11.4 Novel Excipients
5. 11.5 Rationale in Selecting an Excipient
6. 11.6 Conclusions
7. References
12 Formulation of Therapeutic Proteins: Strategies for Developing Oral Protein Formulations
1. 12.1 Introduction
2. 12.2 Types of Proteins Used in Therapeutic Indications
3. 12.3 Important Physicochemical Properties of Proteins for Formulation Development
4. 12.4 Existing Route of Administrations of Protein Formulations
5. 12.5 Developmental Aspects of Oral Protein Formulations
6. 12.6 Clinical Application of Oral Protein Formulations
7. 12.7 Case Studies of Oral Protein Formulations
8. 12.8 Conclusion
9. References
Index
End User License Agreement

List of Tables

Chapter 1
1. Table 1.1 Polymorphism incidence for single‐component NCE from several data sour...
2. Table 1.2 Biopharmaceutical classification system.
3. Table 1.3 Key process parameters for each type of wet granulation.
4. Table 1.4 Thermodynamic and kinetic factors that are related to process paramete...
Chapter 2
1. Table 2.1 Differences in applications of quality by test (QbT) and quality by de...
2. Table 2.2 Phases of clinical development and the overall insights obtained from ...
3. Table 2.3 List of key oral nanosuspension‐based pharmaceutical products [15].
4. Table 2.4 Classification of solid dispersions.
5. Table 2.5 List of excipients that can be used for design of lipid‐based DDS.
6. Table 2.6 The lipid formulation classification system: characteristic features, ...
7. Table 2.7 Characterization of lipid‐based DDS.
8. Table 2.8 Desired properties of drugs for a successful design of lipid‐based DDS...
9. Table 2.9 Characterization considerations for a micellar system.
Chapter 4
1. Table 4.1 Use of preclinical formulations with respect to the study goals [13].
2. Table 4.2 Recommended concentration range for the excipient(s) used in early for...
3. Table 4.3 Various formulations and their characterization.
Chapter 5
1. Table 5.1 Terms for solubility as used in the European Pharmacopeia (8th Ed., 20...
2. Table 5.2 Analytical characterization techniques and field of application.
3. Table 5.3 Methods listed in Ph. Eur. in context of solid‐state characterization.
4. Table 5.4 Polymorphism explicitly addressed in the Common Technical Document (CT...
5. Table 5.5 Number of hits for searches on FDA website (as of 5 November 2017).
Chapter 6
1. Table 6.1 Nanotechnology‐based marketed parenteral formulations.
Chapter 7
1. Table 7.1 Pharmacokinetic studies in drug development.
2. Table 7.2 Selected pharmacokinetic parameters after intravenous administration (...
3. Table 7.3 Selected pharmacokinetic parameters (means) after oral administration ...
4. Table 7.4 Selected pharmacokinetic parameters (means) after oral administration ...
Chapter 9
1. Table 9.1 Thermal properties of the amorphous form of indomethacin produced by d...
2. Table 9.2 Comparison between dispersive and FT‐Raman spectroscopy [93].
Chapter 10
1. Table 10.1 Main components of the tear film.
2. Table 10.2 Main routes of administration for anterior segment therapy.
3. Table 10.3 Main routes of administration for posterior segment therapy.
4. Table 10.4 Examples of molecules used in ophthalmology and their discovery strat...
5. Table 10.5 Key molecular descriptors for new small molecule development in ophth...
6. Table 10.6 Examples of commercial products containingin situ gelling excipients....
7. Table 10.7 Marketed polymeric implants.
8. Table 10.8 Sustained‐release drug delivery systems currently available.
Chapter 11
1. Table 11.1 Common examples of adverse reactions to excipients.
2. Table 11.2 Recommended toxicology studies for the compound under investigation d...
3. Table 11.3 Estimated costs of a tiered testing toxicology program [12].
4. Table 11.4 Excerpt of search results of the Inactive Ingredient Database of Lact...
5. Table 11.5Toxnetdatabases.
6. Table 11.6 Tabular overview on safety data of lactose monohydrate.
7. Table 11.7 Volume guidelines for administration of compounds by the oral route o...
8. Table 11.8 Administration volumes considered as good practice (and possible maxi...
9. Table 11.9 Repeated intravenous infusion: dose volumes/rates (and possible maxim...
Chapter 12
1. Table 12.1 Examples of protein therapeutics in the market [4].
2. Table 12.2 Top 10 selling biologics in the world as of December 2017 [24].
3. Table 12.3 Probable routes of administration for proteins and peptides.
4. Table 12.4 Technologies under clinical development for oral delivery of peptides...

List of Illustrations

Chapter 1
1. Figure 1.1 Molecular structure of triamcinolone polymorphs A (light blue),...
2. Figure 1.2 Lattice packing of triamcinolone acetonide acetate polymorphs....
3. Figure 1.3 Superimposed view of donepezil form F (blue) and form K (red); ...
4. Figure 1.4 Phase energy versus temperature diagram for the (a) enantiotrop...
5. Figure 1.5 Concomitant polymorphism after crystallization of methoxyflavon...
6. Figure 1.6 Examples of tautomeric reactions.
7. Figure 1.7 Tautomeric forms of omeprazole; 5‐methoxy tautomer in form V (r...
8. Figure 1.8 Enantiomerism of L‐thalidomide and D‐thalidomide.
9. Figure 1.9 Representation of pseudopolymorphism events which involve the i...
10. Figure 1.10 Packing polymorphism of caffeine: glutaric acid cocrystal, (a)...
11. Figure 1.11 Predicted morphology and optical images of triamcinolone form ...
12. Figure 1.12 Dynamic vapor sorption isotherm of amisulpride forms I and II ...
13. Figure 1.13 Crystal structure of ranitidine form I with (a) slip planes (y...
14. Figure 1.14 3D images of clopidogrel polymorphs after compression, (left) ...
15. Figure 1.15 (a): Experimental solubility of pioglitazone form II in ▪, N,N
16. Figure 1.16 A representation of diffusion layer dissolution, solute partic...
17. Figure 1.17 Dissolution profile of triamcinolone forms A, B, C, and monohy...
18. Figure 1.18 A schematic presentation showing different factors affecting s...
19. Figure 1.19 In vivo performance of mebendazole polymorphs (A, B, and C). (...
20. Figure 1.20 Plasma concentration–time curves of methoxyflavone polymorphs ...
21. Figure 1.21 Chart summarizing all possible PIT mechanisms; (a): starting c...
22. Figure 1.22 PXRD pattern showing phase transformation of ribavirin R‐II to...
23. Figure 1.23 Transformation rates of mefenamic acid form II to form I follo...
24. Figure 1.24 PXRD patterns of piracetam form III after wetting with increas...
25. Figure 1.25 DSC thermograms of (a) transition endotherm of pure caffeine f...
26. Figure 1.26 Pressure–temperature phase diagram of an enantiotropic polymor...
27. Figure 1.27 Volume fraction transformation as a function of time for caffe...
28. Figure 1.28 Variable temperature X‐ray diffraction (VT‐XRD) pa...
29. Figure 1.29 Raman mapping image of pyrazinamide (PZA) spray dried with pol...
Chapter 2
1. Figure 2.1 The biopharmaceutics classification system (BCS) is shown in bl...
2. Figure 2.2 Classification based on the thermodynamic energy of the system....
3. Figure 2.3 Wet media milling process to manufacture nanosuspensions.
4. Figure 2.4 Schematics of piston‐gap homogenization method.
5. Figure 2.5 (a) Spherical micelle of an anionic surfactant (left) and a non...
6. Figure 2.6 Classification of surfactants based on charge.
7. Figure 2.7 Formation of the mesoporous silica particles with help from str...
8. Figure 2.8 Mean (n = 12) plasma concentration versus time profiles after s...
Chapter 3
1. Figure 3.1 Different oxidation stages of organic molecules.
2. Scheme 3.1 Oxidative degradation of polymeric excipients.
3. Scheme 3.2 Oxidative degradation of raloxifene.
4. Scheme 3.3 Oxidative degradation of ibuprofen in the presence of polymeric...
5. Figure 3.2 Mechanism of the transition‐metal‐mediated oxidative degradatio...
6. Scheme 3.4 Oxidative degradation of RW416457.
7. Scheme 3.5 Mechanism of degradation of (a) BMS‐204352 and (b) irbesartan....
8. Scheme 3.6 Formation of N‐methyl fenfluramine through Eschweiler–Clarke‐ty...
9. Scheme 3.7 Degradation of (a) vigabatrin and (b) haloperidol by 5‐hydroxym...
10. Figure 3.3 Mechanism of Maillard degradation reaction.
11. Figure 3.4 Mechanism of formation of N‐methyl varenicline via Eschweiler–C...
12. Figure 3.5 Chemical structure of (a) HPMCAS, (b) HPMCP, (c) FK480; degrada...
13. Figure 3.6 (a) Mechanism of acid‐ or base‐catalyzed hydrolytic degradation...
14. Scheme 3.8 Hydrolytic degradation of fosinopril sodium in the presence of ...
15. Figure 3.7 Chemical structures of (a) betamethasone dipropionate (R = H) a...
16. Scheme 3.9 Copper‐catalyzed oxidative degradation of RG‐12915.
17. Figure 3.8 Mechanism of degradation of miconazole nitrate in the presence ...
Chapter 4
1. Figure 4.1 Preclinical formulation options to improve solubility.
2. Figure 4.2 Developing preclinical formulations for oral administration.
3. Figure 4.3 Developing preclinical formulations for parenteral administrati...
Chapter 6
1. Figure 6.1 Different formulation strategies adopted to deliver drugs throu...
Chapter 7
1. Figure 7.1 Reasons for withdrawal of drugs from development [1].
2. Figure 7.2 Plasma concentration time profile after intravenous administrat...
3. Figure 7.3 Plasma concentration time profile after oral administration of ...
4. Figure 7.4 Area under the curve (AUC) in a plasma concentration time profi...
5. Figure 7.5 Drug distribution after oral and intravenous administration.
6. Figure 7.6 Plasma concentration time profile after intravenous administrat...
Chapter 8
1. Figure 8.1 Histological cross‐section of the human skin.
2. Figure 8.2 Various approaches in transdermal drug delivery using microneed...
3. Figure 8.3 Scanning electron microscopy (SEM) images of Zosano Pharma's so...
4. Figure 8.4 (a) Syringe‐compatible MicronJet 600™ microneedle array and (b)...
5. Figure 8.5 (a) The microneedle patch is mounted on an adhesive backing and...
6. Figure 8.6 Creation of laser micropores: (a) laser beam hitting the skin a...
7. Figure 8.7 A schematic representation of transdermal iontophoretic deliver...
8. Figure 8.8 Commercial iontophoretic systems: (a) IontoPatch 80, Travanti P...
Chapter 9
1. Figure 9.1 Biopharmaceutical classification system.
2. Figure 9.2 Schematic representations of four common pathways to obtain amo...
3. Figure 9.3 Schematic depiction of the variation of enthalpy (or volume) wi...
4. Figure 9.4 Overview of solid dispersion process [105].
5. Figure 9.5 Types of solid dispersion [23].
6. Figure 9.6 Drug release mechanisms during the dissolution process, carrier...
7. Figure 9.7 Routes of producing solid dispersions.
8. Figure 9.8 Schematic description of mechanism of CAs and their advantages ...
9. Figure 9.9 Overlay of PXRD pattern (top to bottom) of melt‐quenched‐cooled...
10. Figure 9.10 Schematic representations of spray‐drying setup and list of di...
11. Figure 9.11 Schematic presentation of (a) milling process, (b) effect of m...
12. Figure 9.12 (a) Description of different components of vacuum compression ...
13. Figure 9.13 Schematic presentation of extrusion process in a rotating scre...
14. Figure 9.14 Bragg's law: X‐ray diffraction path exhibits interference when...
15. Figure 9.15 Difference between XRD patterns of crystalline/amorphous patte...
16. Figure 9.16 DSC thermogram of amorphous indomethacin prepared using differ...
17. Figure 9.17 (a) DSC thermograms for the various mixtures of crystalline an...
18. Figure 9.18 Tan delta signal for mixed amorphous and crystalline samples o...
19. Figure 9.19 LOD/LOQ comparisons between DMA and solution calorimetry for a...
20. Figure 9.20 Perfusion calorimetry response of 0.313% w/w and 0.625% amorph...
21. Figure 9.21 Calibration curve for α‐ and β‐lactose for solution calorimetr...
22. Figure 9.22 Crystal disorder (%) versus the density of the mixtures of cry...
23. Figure 9.23 Design of DVS intrinsic.
24. Figure 9.24 DVS data plot for micronized lactose [88].
25. Figure 9.25 DVS isotherms for amorphous content determination of amorphous...
26. Figure 9.26 (a) NH stretch of crystalline felodipine at 25, 40, 80, 120, 1...
27. Figure 9.27 Graphical plot estimating the area of hydrogen‐bonded NH stret...
28. Figure 9.28 ATR‐FTIR spectrum of 10% paracetamol in Eudragit® E extrudates...
29. Figure 9.29 FT‐Raman spectra for ketoprofen samples (displaying amorphous ...
30. Figure 9.30 Raman spectra of ibuprofen, PVP, and ibuprofen–PVP extrudates ...
31. Figure 9.31 DVS‐NIR data of crystallization of amorphous lactose samples [...
32. Figure 9.32 Comparison between the calculated crystallinity of unknown ind...
33. Figure 9.33 THz spectra of amorphous samples obtained from α‐ and γ‐form o...
Chapter 10
1. Figure 10.1 Anatomy of the eye.
2. Figure 10.2 Structure and composition of the tear film.
3. Figure 10.3 Precorneal fate of an instilled dose.
4. Figure 10.4 Topical routes of absorption.
5. Figure 10.5 Possible options to enhance the ocular bioavailability of drug...
6. Figure 10.6 PGF_2α analog drug commercially available and developed as...
7. Figure 10.7 Relative miosis time AUC as a function of instilled volume of ...
8. Figure 10.8 Drug delivery systems for anterior segment diseases.
Chapter 11
1. Figure 11.1 Increasing data requirements for excipients dependent on the t...
Chapter 12
1. Figure 12.1 Preformulation characterization parameters for therapeutic pro...
2. Figure 12.2 Degradation routes for proteins and peptides.
3. Figure 12.3 Popular methodologies used for protein and peptide delivery [2...
4. Figure 12.4 Classification of therapeutic proteins.
5. Figure 12.5 Resource requirement for development of protein formulations....
6. Figure 12.6 Transport mechanisms across the intestinal epithelium: (a) act...
7. Figure 12.7 Particulate systems for oral delivery of proteins and peptides...

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Series Editors

Dr. Raimund Mannhold

Rosenweg 7

40489 Düsseldorf

Germany

Dr. Helmut Buschmann

Aachen, Germany

Sperberweg 15

52076 Aachen

Germany

Dr. Jörg Holenz

GSK

R&D Neurosciences TAU

1250 S. Collegeville Road, PA

United States

Volume Editor

Dr. Yogeshwar G. Bachhav

Adex Pharmaceutical Consultancy

Services, C‐201

Bharatkhand CHS

Tilaknagar, Chembur

400089 Mumbai

India

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Preface

Drug discovery and development is an outstandingly complex task. Technological innovations in biology, chemistry, and medicine have provided the pharmaceutical industry with a wealth of targets and molecules, with the potential to treat diseases formerly assumed intractable to drug therapy.

The consequential increase in complexity, both in terms of the molecules and their biological targets, combined with the increasing need to work in an efficient and cost‐constrained environment has necessitated an evolution in the role of pharmaceutical sciences in discovery support.

Because more and more drug candidates in the pipeline pose constraints such as poor solubility and stability, the development of an overall formulation strategy to support in vivo studies should be considered carefully as it can reduce cycle time and resources.

The in vivo studies performed in the preclinical setting can broadly be classified as pharmacology, pharmacokinetic, and toxicology studies. The goals and challenges of these studies are diverse.

Therefore, drug developers must consider many aspects when positioning a preclinical drug candidate to succeed in first‐in‐human clinical trials.

Besides many other factors, a biopharmaceutical assessment of drug substances is crucial for different phases of the development process. In an early phase, pharmaceutical profiling should help to rate candidate molecules in terms of their “drug‐like” properties.

The first step for a new molecule moving out of the discovery phase is the preformulation studies, or developability assessment. Indeed, preformulation work lays the foundation for choosing the right salt and polymorph, delivery technology, and formulation strategies.

Formulation approaches to deliver molecules in the preclinical setting include, besides many other innovative forms, the more traditional ones like suspensions, solutions, and amorphous dispersions administered as solids or in aqueous vehicles. Nowadays, advanced systems such as nanosuspensions and silica particles are also explored for this purpose.

The goals of preformulation studies are to choose the correct form of the drug substance, evaluate its physical and chemical properties, and generate a thorough understanding of the material's stability under the conditions that will lead to the development of a practical drug delivery system. Preformulation is a science that serves as a big umbrella for the fingerprinting of a drug substance or product both at the early and later stages of development in pharmaceutical manufacturing.

Traditionally, pharmaceutical scientists participated in the discovery teams only in the later phases of lead development or in the lead optimization phase, and their role was largely to assess the development risks (developability) of the molecule advancing to clinical dosing.

These activities, while important, have been augmented to include early discovery formulation support related to building a basic understanding of biology through in vivo target validation and demonstration of proof of mechanism.

The book in hand, edited by a very experienced pharmaceutical scientist with many years of experience in this preformulation field, has pointed out with the selected chapters a comprehensive view of actual research filed in this area. In particular, the following chapters are enclosed:

Impact of the polymorphic form of the drugs/NCEs on the preformulation and formulation development
Regulatory aspects for formulation design – with focus on the solid state
Effect of residual reactive impurities in excipients on the stability of pharmaceutical products
Assessing pharmacokinetics of various dosage forms at early stage
Preclinical safety assessment for excipients; oral, IV, and topical routes
Preclinical formulation assessment of NCEs
Strategies for the formulation development of poorly soluble drugs via oral route
Physical characterization techniques to access amorphous nature
Design and development of ocular formulations for preclinical and clinical trials
Insights into innovative applications of parenteral formulations
Transdermal medical devices: formulation aspects
Formulation of therapeutic proteins: strategies for developing oral protein formulations

The series editors are confident that this book and the highly actual topics will provide valuable benefits to interdisciplinary drug discovery teams working in industry and academia. Last but not least, we thank Yogeshwar Bachhav for excellently editing this volume as well as Frank Weinreich and Stefanie Volk from Wiley‐VCH for their valuable contributions to this project.

September 2018

Düsseldorf, FRG

Aachen, FRG

Boston, USA

Raimund Mannhold

Helmut Buschmann

Jörg Holenz

Innovative Dosage Forms

Design and Development at Early Stage

Copyright

Preface