Innovative Dosage Forms E-Book

• Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
• Kategorie: Wissenschaft und neue Technologien
• Serie: Methods and Principles in Medicinal Chemistry
• Sprache: Englisch

Seitenzahl: 899

Veröffentlichungsjahr: 2019

Beschreibung

Teaches future and current drug developers the latest innovations in drug formulation design and optimization

This highly accessible, practice-oriented book examines current approaches in the development of drug formulations for preclinical and clinical studies, including the use of functional excipients to enhance solubility and stability. It covers oral, intravenous, topical, and parenteral administration routes. The book also discusses safety aspects of drugs and excipients, as well as regulatory issues relevant to formulation.

Innovative Dosage Forms: Design and Development at Early Stage starts with a look at the impact of the polymorphic form of drugs on the preformulation and formulation development. It then offers readers reliable strategies for the formulation development of poorly soluble drugs. The book also studies the role of reactive impurities from the excipients on the formulation shelf life; preclinical formulation assessment of new chemical entities; and regulatory aspects for formulation design. Other chapters cover innovative formulations for special indications, including oncology injectables, delayed release and depot formulations; accessing pharmacokinetics of various dosage forms; physical characterization techniques to assess amorphous nature; novel formulations for protein oral dosage; and more.

-Provides information that is essential for the drug development effort
-Presents the latest advances in the field and describes in detail innovative formulations, such as nanosuspensions, micelles, and cocrystals
-Describes current approaches in early pre-formulation to achieve the best in vivo results
-Addresses regulatory and safety aspects, which are key considerations for pharmaceutical companies
-Includes case studies from recent drug development programs to illustrate the practical challenges of preformulation design

Innovative Dosage Forms: Design and Development at Early Stage provides valuable benefits to interdisciplinary drug discovery teams working in industry and academia and will appeal to medicinal chemists, pharmaceutical chemists, and pharmacologists.

Leseprobe

Table of Contents

Cover

Preface

1 Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development

1.1 Introduction

1.2 Polymorphism Impact on Drug/Excipient Properties

1.3 Critical Impact of Polymorphic Form of API on Processing and Formulation

1.4 Conclusion

References

2 Strategies for the Formulation Development of Poorly Soluble Drugs via Oral Route

2.1 Introduction

2.2 Quality by Testing (QbT) and Quality by Design (QbD)

2.3 Linking the Formulation to the Clinical Phase

2.4 Defining the Formulation Strategy

2.5 Nanosuspensions

2.6 Solid Dispersion

2.7 Lipid‐Based Drug Delivery Systems

2.8 Micellar System

2.9 Mesoporous Silica Particles

2.10 Conclusion

References

3 Effect of Residual Reactive Impurities in Excipients on the Stability of Pharmaceutical Products

3.1 Introduction

3.2 Reactive Impurities in the Excipients and Their Impact on Drug Stability

3.3 Impact of Reactive Impurities on Drug–Excipient Compatibility

3.4 Risk Assessment for API Incompatibilities and Mitigation Strategies

3.5 Assessment of Incompatibilities of API with Excipients

3.6 Design and Selection of Drug Substance

3.7 Formulation Strategies to Circumvent API Degradation

3.8 Inhibition of Oxidative Degradation

3.9 Super‐Refined Excipients

3.10 Packaging and Storage

3.11 Concluding Remarks

References

4 Preclinical Formulation Assessment of NCEs

4.1 Introduction

4.2 Significance of Various Properties of NCEs in Early Drug Discovery

4.3 Formulation Strategies to Improve Properties of NCEs

4.4 Preclinical Formulation Assessment of Oral, Parenteral, and Topical Dosage Forms

4.5 Case Studies

4.6 Conclusion and Future Perspectives

References

5 Regulatory Aspects for Formulation Design – with Focus on the Solid State

5.1 The Understanding of “Regulatory”

5.2 Formulation Design

5.3 An Extended Timescale

5.4 Solubility Data

5.5 Impact of Solubility and Dissolution Rate on Formulation Design

5.6 Single and Multicomponent Systems

5.7 Analytical Techniques for the Characterization of the Solid State

5.8 Control of Solid‐state Constitution

5.9 Regulatory Consideration of Solid Compounds

5.10 Conclusions and Recommendations

Disclaimer

References

6 Insight into Innovative Applications of Parenteral Formulations

6.1 Introduction

6.2 Factors Affecting Development of Sustained‐/Controlled‐Release Formulations

6.3 Overview of Sustained and Controlled Release Parenteral Formulations

6.4 Case Studies

6.5 Conclusion

6.6 Future Prospects

References

7 Assessing Pharmacokinetics of Various Dosage Forms at Early Stage

7.1 Introduction

7.2 Definition of Pharmacokinetics

7.3 Case Studies

7.4 Summary

References

8 Transdermal Medical Devices: Formulation Aspects

8.1 Introduction

8.2 Microneedles

8.3 Laser‐Assisted Ablation: Skin Pretreatment

8.4 Iontophoresis

References

9 Physical Characterization Techniques to Access Amorphous Nature

9.1 Introduction

9.2 Screening Techniques for Amorphization

9.3 Characterization of Amorphous Materials

9.4 Summary

9.5 Future Prospects

References

10 Design and Development of Ocular Formulations for Preclinical and Clinical Trials

10.1 Introduction

10.2 Ocular Anatomy and Physiology

10.3 Ocular Routes of Administration

10.4 Drug Discovery in Ophthalmology

10.5 Topical Drug Administration

10.6 Posterior Segment Delivery

10.7 Conclusion

References

11 Preclinical Safety Aspects for Excipients: Oral, IV, and Topical Routes

11.1 Introduction

11.2 General Considerations

11.3 Undesired Side Effects of Excipients

11.4 Novel Excipients

11.5 Rationale in Selecting an Excipient

11.6 Conclusions

References

12 Formulation of Therapeutic Proteins: Strategies for Developing Oral Protein Formulations

12.1 Introduction

12.2 Types of Proteins Used in Therapeutic Indications

12.3 Important Physicochemical Properties of Proteins for Formulation Development

12.4 Existing Route of Administrations of Protein Formulations

12.5 Developmental Aspects of Oral Protein Formulations

12.6 Clinical Application of Oral Protein Formulations

12.7 Case Studies of Oral Protein Formulations

12.8 Conclusion

References

Index

End User License Agreement

List of Tables

Chapter 1

Table 1.1 Polymorphism incidence for single‐component NCE from several data sour...

Table 1.2 Biopharmaceutical classification system.

Table 1.3 Key process parameters for each type of wet granulation.

Table 1.4 Thermodynamic and kinetic factors that are related to process paramete...

Chapter 2

Table 2.1 Differences in applications of quality by test (QbT) and quality by de...

Table 2.2 Phases of clinical development and the overall insights obtained from ...

Table 2.3 List of key oral nanosuspension‐based pharmaceutical products [15].

Table 2.4 Classification of solid dispersions.

Table 2.5 List of excipients that can be used for design of lipid‐based DDS.

Table 2.6 The lipid formulation classification system: characteristic features, ...

Table 2.7 Characterization of lipid‐based DDS.

Table 2.8 Desired properties of drugs for a successful design of lipid‐based DDS...

Table 2.9 Characterization considerations for a micellar system.

Chapter 4

Table 4.1 Use of preclinical formulations with respect to the study goals [13].

Table 4.2 Recommended concentration range for the excipient(s) used in early for...

Table 4.3 Various formulations and their characterization.

Chapter 5

Table 5.1 Terms for solubility as used in the European Pharmacopeia (8th Ed., 20...

Table 5.2 Analytical characterization techniques and field of application.

Table 5.3 Methods listed in Ph. Eur. in context of solid‐state characterization.

Table 5.4 Polymorphism explicitly addressed in the Common Technical Document (CT...

Table 5.5 Number of hits for searches on FDA website (as of 5 November 2017).

Chapter 6

Table 6.1 Nanotechnology‐based marketed parenteral formulations.

Chapter 7

Table 7.1 Pharmacokinetic studies in drug development.

Table 7.2 Selected pharmacokinetic parameters after intravenous administration (...

Table 7.3 Selected pharmacokinetic parameters (means) after oral administration ...

Table 7.4 Selected pharmacokinetic parameters (means) after oral administration ...

Chapter 9

Table 9.1 Thermal properties of the amorphous form of indomethacin produced by d...

Table 9.2 Comparison between dispersive and FT‐Raman spectroscopy [93].

Chapter 10

Table 10.1 Main components of the tear film.

Table 10.2 Main routes of administration for anterior segment therapy.

Table 10.3 Main routes of administration for posterior segment therapy.

Table 10.4 Examples of molecules used in ophthalmology and their discovery strat...

Table 10.5 Key molecular descriptors for new small molecule development in ophth...

Table 10.6 Examples of commercial products containing

in situ

gelling excipients....

Table 10.7 Marketed polymeric implants.

Table 10.8 Sustained‐release drug delivery systems currently available.

Chapter 11

Table 11.1 Common examples of adverse reactions to excipients.

Table 11.2 Recommended toxicology studies for the compound under investigation d...

Table 11.3 Estimated costs of a tiered testing toxicology program [12].

Table 11.4 Excerpt of search results of the Inactive Ingredient Database of Lact...

Table 11.5

Toxnet

databases.

Table 11.6 Tabular overview on safety data of lactose monohydrate.

Table 11.7 Volume guidelines for administration of compounds by the oral route o...

Table 11.8 Administration volumes considered as good practice (and possible maxi...

Table 11.9 Repeated intravenous infusion: dose volumes/rates (and possible maxim...

Chapter 12

Table 12.1 Examples of protein therapeutics in the market [4].

Table 12.2 Top 10 selling biologics in the world as of December 2017 [24].

Table 12.3 Probable routes of administration for proteins and peptides.

Table 12.4 Technologies under clinical development for oral delivery of peptides...

List of Illustrations

Chapter 1

Figure 1.1 Molecular structure of triamcinolone polymorphs A (light blue),...

Figure 1.2 Lattice packing of triamcinolone acetonide acetate polymorphs....

Figure 1.3 Superimposed view of donepezil form F (blue) and form K (red); ...

Figure 1.4 Phase energy versus temperature diagram for the (a) enantiotrop...

Figure 1.5 Concomitant polymorphism after crystallization of methoxyflavon...

Figure 1.6 Examples of tautomeric reactions.

Figure 1.7 Tautomeric forms of omeprazole; 5‐methoxy tautomer in form V (r...

Figure 1.8 Enantiomerism of L‐thalidomide and D‐thalidomide.

Figure 1.9 Representation of pseudopolymorphism events which involve the i...

Figure 1.10 Packing polymorphism of caffeine: glutaric acid cocrystal, (a)...

Figure 1.11 Predicted morphology and optical images of triamcinolone form ...

Figure 1.12 Dynamic vapor sorption isotherm of amisulpride forms I and II ...

Figure 1.13 Crystal structure of ranitidine form I with (a) slip planes (y...

Figure 1.14 3D images of clopidogrel polymorphs after compression, (left) ...

Figure 1.15 (a): Experimental solubility of pioglitazone form II in ▪,

N

,

N

Figure 1.16 A representation of diffusion layer dissolution, solute partic...

Figure 1.17 Dissolution profile of triamcinolone forms A, B, C, and monohy...

Figure 1.18 A schematic presentation showing different factors affecting s...

Figure 1.19

In vivo

performance of mebendazole polymorphs (A, B, and C). (...

Figure 1.20 Plasma concentration–time curves of methoxyflavone polymorphs ...

Figure 1.21 Chart summarizing all possible PIT mechanisms; (a): starting c...

Figure 1.22 PXRD pattern showing phase transformation of ribavirin R‐II to...

Figure 1.23 Transformation rates of mefenamic acid form II to form I follo...

Figure 1.24 PXRD patterns of piracetam form III after wetting with increas...

Figure 1.25 DSC thermograms of (a) transition endotherm of pure caffeine f...

Figure 1.26 Pressure–temperature phase diagram of an enantiotropic polymor...

Figure 1.27 Volume fraction transformation as a function of time for caffe...

Figure 1.28 Variable temperature X‐ray diffraction (VT‐XRD) pa...

Figure 1.29 Raman mapping image of pyrazinamide (PZA) spray dried with pol...

Chapter 2

Figure 2.1 The biopharmaceutics classification system (BCS) is shown in bl...

Figure 2.2 Classification based on the thermodynamic energy of the system....

Figure 2.3 Wet media milling process to manufacture nanosuspensions.

Figure 2.4 Schematics of piston‐gap homogenization method.

Figure 2.5 (a) Spherical micelle of an anionic surfactant (left) and a non...

Figure 2.6 Classification of surfactants based on charge.

Figure 2.7 Formation of the mesoporous silica particles with help from str...

Figure 2.8 Mean (

n

 = 12) plasma concentration versus time profiles after s...

Chapter 3

Figure 3.1 Different oxidation stages of organic molecules.

Scheme 3.1 Oxidative degradation of polymeric excipients.

Scheme 3.2 Oxidative degradation of raloxifene.

Scheme 3.3 Oxidative degradation of ibuprofen in the presence of polymeric...

Figure 3.2 Mechanism of the transition‐metal‐mediated oxidative degradatio...

Scheme 3.4 Oxidative degradation of RW416457.

Scheme 3.5 Mechanism of degradation of (a) BMS‐204352 and (b) irbesartan....

Scheme 3.6 Formation of

N

‐methyl fenfluramine through Eschweiler–Clarke‐ty...

Scheme 3.7 Degradation of (a) vigabatrin and (b) haloperidol by 5‐hydroxym...

Figure 3.3 Mechanism of Maillard degradation reaction.

Figure 3.4 Mechanism of formation of

N

‐methyl varenicline via Eschweiler–C...

Figure 3.5 Chemical structure of (a) HPMCAS, (b) HPMCP, (c) FK480; degrada...

Figure 3.6 (a) Mechanism of acid‐ or base‐catalyzed hydrolytic degradation...

Scheme 3.8 Hydrolytic degradation of fosinopril sodium in the presence of ...

Figure 3.7 Chemical structures of (a) betamethasone dipropionate (R = H) a...

Scheme 3.9 Copper‐catalyzed oxidative degradation of RG‐12915.

Figure 3.8 Mechanism of degradation of miconazole nitrate in the presence ...

Chapter 4

Figure 4.1 Preclinical formulation options to improve solubility.

Figure 4.2 Developing preclinical formulations for oral administration.

Figure 4.3 Developing preclinical formulations for parenteral administrati...

Chapter 6

Figure 6.1 Different formulation strategies adopted to deliver drugs throu...

Chapter 7

Figure 7.1 Reasons for withdrawal of drugs from development [1].

Figure 7.2 Plasma concentration time profile after intravenous administrat...

Figure 7.3 Plasma concentration time profile after oral administration of ...

Figure 7.4 Area under the curve (AUC) in a plasma concentration time profi...

Figure 7.5 Drug distribution after oral and intravenous administration.

Figure 7.6 Plasma concentration time profile after intravenous administrat...

Chapter 8

Figure 8.1 Histological cross‐section of the human skin.

Figure 8.2 Various approaches in transdermal drug delivery using microneed...

Figure 8.3 Scanning electron microscopy (SEM) images of Zosano Pharma's so...

Figure 8.4 (a) Syringe‐compatible MicronJet 600™ microneedle array and (b)...

Figure 8.5 (a) The microneedle patch is mounted on an adhesive backing and...

Figure 8.6 Creation of laser micropores: (a) laser beam hitting the skin a...

Figure 8.7 A schematic representation of transdermal iontophoretic deliver...

Figure 8.8 Commercial iontophoretic systems: (a) IontoPatch 80, Travanti P...

Chapter 9

Figure 9.1 Biopharmaceutical classification system.

Figure 9.2 Schematic representations of four common pathways to obtain amo...

Figure 9.3 Schematic depiction of the variation of enthalpy (or volume) wi...

Figure 9.4 Overview of solid dispersion process [105].

Figure 9.5 Types of solid dispersion [23].

Figure 9.6 Drug release mechanisms during the dissolution process, carrier...

Figure 9.7 Routes of producing solid dispersions.

Figure 9.8 Schematic description of mechanism of CAs and their advantages ...

Figure 9.9 Overlay of PXRD pattern (top to bottom) of melt‐quenched‐cooled...

Figure 9.10 Schematic representations of spray‐drying setup and list of di...

Figure 9.11 Schematic presentation of (a) milling process, (b) effect of m...

Figure 9.12 (a) Description of different components of vacuum compression ...

Figure 9.13 Schematic presentation of extrusion process in a rotating scre...

Figure 9.14 Bragg's law: X‐ray diffraction path exhibits interference when...

Figure 9.15 Difference between XRD patterns of crystalline/amorphous patte...

Figure 9.16 DSC thermogram of amorphous indomethacin prepared using differ...

Figure 9.17 (a) DSC thermograms for the various mixtures of crystalline an...

Figure 9.18 Tan delta signal for mixed amorphous and crystalline samples o...

Figure 9.19 LOD/LOQ comparisons between DMA and solution calorimetry for a...

Figure 9.20 Perfusion calorimetry response of 0.313% w/w and 0.625% amorph...

Figure 9.21 Calibration curve for α‐ and β‐lactose for solution calorimetr...

Figure 9.22 Crystal disorder (%) versus the density of the mixtures of cry...

Figure 9.23 Design of DVS intrinsic.

Figure 9.24 DVS data plot for micronized lactose [88].

Figure 9.25 DVS isotherms for amorphous content determination of amorphous...

Figure 9.26 (a) NH stretch of crystalline felodipine at 25, 40, 80, 120, 1...

Figure 9.27 Graphical plot estimating the area of hydrogen‐bonded NH stret...

Figure 9.28 ATR‐FTIR spectrum of 10% paracetamol in Eudragit® E extrudates...

Figure 9.29 FT‐Raman spectra for ketoprofen samples (displaying amorphous ...

Figure 9.30 Raman spectra of ibuprofen, PVP, and ibuprofen–PVP extrudates ...

Figure 9.31 DVS‐NIR data of crystallization of amorphous lactose samples [...

Figure 9.32 Comparison between the calculated crystallinity of unknown ind...

Figure 9.33 THz spectra of amorphous samples obtained from α‐ and γ‐form o...

Chapter 10

Figure 10.1 Anatomy of the eye.

Figure 10.2 Structure and composition of the tear film.

Figure 10.3 Precorneal fate of an instilled dose.

Figure 10.4 Topical routes of absorption.

Figure 10.5 Possible options to enhance the ocular bioavailability of drug...

Figure 10.6 PGF

2α

analog drug commercially available and developed as...

Figure 10.7 Relative miosis time AUC as a function of instilled volume of ...

Figure 10.8 Drug delivery systems for anterior segment diseases.

Chapter 11

Figure 11.1 Increasing data requirements for excipients dependent on the t...

Chapter 12

Figure 12.1 Preformulation characterization parameters for therapeutic pro...

Figure 12.2 Degradation routes for proteins and peptides.

Figure 12.3 Popular methodologies used for protein and peptide delivery [2...

Figure 12.4 Classification of therapeutic proteins.

Figure 12.5 Resource requirement for development of protein formulations....

Figure 12.6 Transport mechanisms across the intestinal epithelium: (a) act...

Figure 12.7 Particulate systems for oral delivery of proteins and peptides...

Guide

Cover

Table of Contents

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Methods and Principles in Medicinal Chemistry

Edited by R. Mannhold, H. Buschmann, JÖrg HolenzEditorial BoardG. Folkerts, H. Kubinyi, H. Timmerman, H. van deWaterbeemd, J. Bondo Hansen

Previous Volumes of this Series:

Gervasio, F. L., Spiwok, V. (Eds.)

Biomolecular Simulations in Structure-based Drug Discovery

2018

ISBN: 978-3-527-34265-5

Vol. 75

Sippl, W., Jung, M. (Eds.)

Epigenetic Drug Discovery

2018

ISBN: 978-3-527-34314-0

Vol. 74

Giordanetto, F. (Ed.)

Early Drug Development

2018

ISBN: 978-3-527-34149-8

Vol. 73

Handler, N., Buschmann, H. (Eds.)

Drug Selectivity

2017

ISBN: 978-3-527-33538-1

Vol. 72

Vaughan, T., Osbourn, J., Jalla, B. (Eds.)

Protein Therapeutics

2017

ISBN: 978-3-527-34086-6

Vol. 71

Ecker, G. F., Clausen, R. P., and Sitte, H. H. (Eds.)

Transporters as Drug Targets

2017

ISBN: 978-3-527-33384-4

Vol. 70

Martic-Kehl, M. I., Schubiger, P.A. (Eds.)

AnimalModels for Human Cancer

Discovery and Development of Novel Therapeutics

2017

ISBN: 978-3-527-33997-6

Vol. 69

Holenz, JÖrg (Ed.)

Lead Generation Methods and Strategies

2016

ISBN: 978-3-527-33329-5

Vol. 68

Innovative Dosage Forms

Design and Development at Early Stage

Edited by Yogeshwar G. Bachhav

Copyright

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

1Impact of the Polymorphic Form of Drugs/NCEs on Preformulation and Formulation Development

MHD Bashir Alsirawan and Anant Paradkar

Center for Pharmaceutical Engineering Sciences, University of Bradford, Richmond Road, Bradford, BD7 1DP, UK

1.1 Introduction

Polymorphism is a well‐established phenomenon which describes the ability of a solid‐state molecular structure to be repetitively positioned in at least two different arrangements in three‐dimensional space. These different arrangements can result in different sets of physicochemical properties of the same molecular structure, which can significantly affect material behavior during handling, processing, and storing. Hence, polymorphism is crucial for many applications, including the pharmaceutical industry. Most drugs, whether already produced or newly discovered candidates, and usually referred to as new chemical entities (NCEs), are found as solids under normal conditions of temperature and pressure. Eighty‐five percent of active pharmaceutical ingredients (APIs) display pseudopolymorphism, including 50% having real polymorphism [1]. In addition, Cruz‐Cabeza et al. have listed polymorphic incidence of single‐component NCEs from the Cambridge Structure Database (CSD), European Pharmacopeia, and data from the extensive screening procedures performed in Roche and Lilly (Table 1.1) [2].

Table 1.1 Polymorphism incidence for single‐component NCE from several data source.

Source

Number of single NCEs

Polymorphism occurrence (%)

CSD

5941

37

European Pharmacopeia 2004

 598

42

Roche

  68

53

Lilly

  68

66

Consequently, polymorphism must be taken into consideration during every processing stage starting from early steps such as preformulation and formulation development, passing through processing, manufacturing, and storage, and eventually until consumption in humans.

1.1.1 Background

Polymorphism has been discussed and investigated by many reports [3–7]. Moreover, several definitions were made depending on the researcher or the field of research; McCrone (1965) defined polymorphism thus: “Polymorph is a solid crystalline phase of a given compound resulting from the possibility of at least two different arrangements of the molecule of that compound in the solid state.” Buerger defined polymorphism of a crystal as “molecular arrangements having different properties.” The definition by Purojit and Venugopalan states it is the “ability of a substance to exist as two or more crystalline phases that have different arrangements or conformations of the molecules in the crystal lattice” [3]. IUPAC defined the phase transition between polymorphs as the “reversible transition of a solid crystalline phase at a certain temperature and pressure (the inversion point) to another phase of the same chemical composition with a different crystal structure” [8]. Other definitions were similar to those previously mentioned, such as different crystal arrangements for the same chemical composition [9], or crystal systems of same elemental structure but with unlike unit cells [4]. Desiraju has debated the experimentality of McCrone's definition depending on previous observations of polymorphism cases where coexistence of two polymorphs within the same crystal is found with no distinctive phase separation or, in other cases, where two structures are very similar with a barely identified difference (divergence). Desiraju has suggested setting criteria to differentiate whether two arrangements are genuine polymorphs or belong to the same solid phase [6].

The first reported polymorphism event was discovered with calcium carbonate in 1788 by Kalporoth. In 1832, benzamide was the first organic molecule the polymorphism of which was observed by Wöhler and Liebig [10]. The first crystal structure of polymorphic form determined by X‐ray diffraction was for resorcinol in 1938 [11].

Although the term polymorphism seems specific, there is confusion around designating different structures as polymorphs. Moreover, reports follow different terminology rules depending on the fields of interest and background. To mitigate this confusion, other terms have arisen such as pseudopolymorphism or solvatomorphism. However, several reports do not encourage using these terms as it may create further confusion [7,12].

1.1.2 Types of Polymorphism

If we stick to the pure definition of polymorphism and exclude chemically nonsimilar structures, there are two primary types of polymorphism, conformational and packing polymorphism.

1.1.2.1 Conformational Polymorphism

This type of polymorphism resulted in molecules having flexible moieties which, in turn, have rotatable bonding. The rotational movement of a single bond in the molecular structure leads to a symmetry change and produces a new configuration, and, subsequently, a change in lattice packing [13]. A typical example of conformational polymorphism is ranitidine hydrochloride, which has two polymorphs, form 1 and form 2. Both phases are monoclinic, with the same space group but with only a difference in the conformation and disorder of nitroethenediamine moiety (Figure 1.1) [14]. Triamcinolone acetonide acetate, a drug commonly used for rheumatoid arthritis, exists in three polymorphic forms A, B, and C and a monohydrate; all these forms exhibit conformational variations (Figure 1.1) which result in different packing (Figure 1.2) [15].

Figure 1.1 Molecular structure of triamcinolone polymorphs A (light blue), B (red and green), C (orange), and MH (blue).

Source: Bučar et al. 2015 [14] and Wang et al. 2017 [15]. Adapted with permission of ACS.

Figure 1.2 Lattice packing of triamcinolone acetonide acetate polymorphs.

Source: Wang et al. 2017 [15]. Adapted with permission of ACS.

1.1.2.2 Packing Polymorphism

In this type, the configuration and bond orientation between two structures is identical, yet the arrangement and backing of this conformation in a three‐dimensional structure is not similar. Most of the pharmaceutical materials have flexible moieties; thus, it is rare to observe packing polymorphism in the field. Donepezil, which is used in the palliative treatment of Alzheimer's disease, has two packing polymorphs, forms K and F. The conformation similarity of the two forms was investigated by superimposing their structure using Mercury 3.3, a 3D structure visualization and measurement program. Root‐mean‐square deviation (RMSD) was then calculated and found to be insignificant (0.0624 Å) supporting the identical confirmation (Figure 1.3) [16].

Figure 1.3 Superimposed view of donepezil form F (blue) and form K (red); (a) crystallographic A axis view, (b) 90° angle view where an axis is horizontally positioned, the packing of two polymorphs are translated (green double‐headed arrows). However, (c) superimposed molecular structures show identical conformations, meaning that the two phases are packing polymorphs.

Source: Part et al. 2016 [16]. Adapted with permission of American Chemical Society.

1.1.3 Thermodynamic‐Based Classification of Polymorphism

Polymorphic interconversion is primarily governed by the thermodynamic state of the material, and as per thermodynamic rules, both temperature and pressure determine the thermodynamic stability of a certain polymorph. Polymorphism type depends on the nature of solid‐phase transition with respect to temperature or pressure and can be divided into monotropic and enantiotropic (Figure 1.4). Understanding and identifying the transition nature of polymorphs is crucial for establishing optimum parameters for crystallization, screening [17], processing, and storage of active ingredients and excipients [18,19].

Figure 1.4 Phase energy versus temperature diagram for the (a) enantiotropic and (b) monotropic interconversion for two polymorphic phases FI and FII.

1.1.3.1 Enantiotropic Polymorphism

In enantiotropic polymorphism, one polymorph (let us call it form I) is considered the most stable at a certain temperature and pressure, at which the other polymorph (form II) is not stable, usually called metastable. On the other hand, the metastable form II becomes stable when reaching different temperature or pressure zones or reaching transition temperature Tt or pressure Pt. Simultaneously, the stable form I becomes metastable and a phase transition from form I to form II takes place. In some cases, a third polymorph (form III) is found and it has a third temperature or pressure zone, above specific transition temperature or pressure, where it becomes the most stable among others.

1.1.3.2 Monotropic Polymorphism

This type describes the case where one polymorph is considered the most stable in a wide range of temperatures reaching high transition levels, higher than the melting point of the other forms which are all considered to be metastable polymorphs under their melting point.

Two thermodynamic rules can be applied, which basically rely on thermal analysis to distinguish the type of polymorphism. These rules are heat of fusion and heat of transition, and may be referred to as Burger–Ramberger rules [20]. To describe these rules, let us propose two polymorphs form I and TFIITt form II, where form I is more stable under normal temperature or before heating. The heat of fusion rule states that if the polymorph with the higher melting point has lower fusion enthalpy compared to the other form, the relationship between the two polymorphs is enantiotropic. However, if the higher melting point form has higher enthalpy of fusion, the polymorphism is monotropic. In the case of the heat of transition rule, polymorphs I and II are monotropic if the transition from form II to I is exothermic; or enantiotropic if the transition from form I to II is endothermic. It should be noted that the interconversion is reversible in enantiotropic systems and irreversible in monotropic polymorphism [4].

Moreover, enantiotropic polymorphs have a defined transition temperature (Figure 1.3) and can be determined experimentally. Conversely, monotropic systems have no observable transition temperature, yet there is a theoretical transition point that can be calculated using the Bauer–Brandl equation 1.1):

(1.1)

where and are the melting enthalpy of forms I and II, respectively, and Tm, I and Tm, II are the melting points of forms I and II, respectively.

1.1.4 Concomitant Polymorphism

Concomitant polymorphism describes the case where more than one solid phase displays simultaneous nucleation and crystal growth under the same conditions and within the same batch. The reason behind concomitant polymorphism is a struggle between kinetically and thermodynamically stable polymorphs [21]. In other words, the kinetic and thermodynamic phases have a slight free energy difference [22]. This event may occur momentarily as the kinetically stable phase could convert rapidly to the thermodynamically stable phase, and in most cases the event is temporary and not observed due to the polymorphic conversion with time, or after predisposition to water or solvent (recrystallization or dissolution) [21]. The appearance of concomitant polymorphism can depend on the nature of crystallization solvent, temperature, and solution concentration [23].

Concomitant polymorphism poses a challenge to preformulation scientists when controlling the formation of a specific and desired polymorph. Several cases of APIs which exhibit concomitant polymorphism have been reported. A concomitant polymorphism of methoxyflavone, a nonsteroidal anabolic flavone, was reported. Thermodynamically stable form A and kinetically form B have a negligible difference in lattice energies and appear simultaneously after crystallization (Figure 1.5). Form B can transform to form A under the influence of temperature [24]. The relative nucleation and crystal growth rate is a crucial factor in controlling polymorphic appearance; furthermore, higher growth rate will govern the presence of the phase at the end of crystallization. Two polymorphs of donepezil, forms I and II, can appear concomitantly. The nucleation rate of form I is slower than that of form II, yet crystal growth is higher in form I. As a result, form I appears at the beginning of the process followed by form II, which dominates its presence at the end of the process [16].

Figure 1.5 Concomitant polymorphism after crystallization of methoxyflavone form A (bulk shape) and form B (needle shape).

Source: Gong et al. 2016 [24]. Adapted with permission of American Chemical Society.

1.1.5 Debatable Polymorphism Cases

These types are considered by many researchers as imperfect or pseudopolymorphism. Unlike the known variations found in basic polymorphism, the structures under this category have variations within the chemical structure which results in a change in crystal confirmation of packing.

1.1.5.1 Tautomeric Polymorphism or Tautomerism

Tautomerism is a simultaneous interconversion of isomeric organic compounds resulting from proton transfer caused by the presence of strong electronegative atoms such as O or N. Tautomerism depends on the presence of weakly acidic functional groups such as amines, amides, ketones, and lactams. The transformations are classified as chemical reactions and primarily consist of interconverting pairs such as keto‐enol, oxime‐nitroso, amine‐imine, amide‐imidic acid, and lactam‐lactim reaction (Figure 1.6).

Figure 1.6 Examples of tautomeric reactions.

Source: Braga et al. 2014 [25]. Adapted with permission of Bentham Science Publishers Ltd.

Tautomerism transition occurs at solution or melt state, where the reaction is at equilibrium, while at solid state, the crystallization of different tautomers causes a unit cell structure producing polymorphs with tautomeric origin. Ranitidine hydrochloride form 2 is found to consist of a tautomeric mixture (50 : 50) of enamine and nitronic acid, which takes place in the nitroethenediamine group [26]. In addition, omeprazole tautomerism takes place in solution state with 5‐methoxy–6‐methoxy transition. However, in solid state, both tautomers exist continuously at the molecular level or as solid solution (Figure 1.7) [27].

Figure 1.7 Tautomeric forms of omeprazole; 5‐methoxy tautomer in form V (right), and 6‐methoxy tautomer in form I (left).

Source: Bhatt et al. 2007 [27]. Adapted with permission of Royal Society of Chemistry.

1.1.5.2 Enantiomerism/Stereoisomerism

The concept describes structures having a similar composition of atoms and bonding; however, they differ in the three‐dimensional arrangement or orientation of the atoms. This type of structural change is also considered a chemical reaction as it requires the deconstruction of a covalent bond to allow a new covalent bond to form, resulting in a configuration that is the mirror image of the first structure. Most organic molecules that comprise asymmetric or chiral carbon exhibit this phenomenon, and therefore are named chiral.

Enantiomerism is a crucial property in the pharmaceutical and pharmacological fields, as nearly 50% of the drugs are chiral and 90% of them are marketed as racemate equimolar mixtures (containing both isomers). Moreover, different isomers exhibit different pharmacokinetic and pharmacodynamic properties. The advancement in chiral drug design has produced safer and more effective candidates [28]. One of the examples of chiral or enantiomeric drugs is thalidomide which displays two enantiomers, (S)‐thalidomide and (R)‐thalidomide (Figure 1.8). Thalidomide was used for motion sickness, but it turned out that L‐isomer is teratogenic and the therapeutic activity comes from the D‐isomer.

Figure 1.8 Enantiomerism of L‐thalidomide and D‐thalidomide.

1.1.5.3 Pseudopolymorphism

The utilization of the term pseudopolymorphism supports part of the definition of polymorphism “having the same chemical composition” as it describes molecules with different crystal structures caused by the presence of a secondary heterostructure within the crystal lattice (e.g. water, solvent, coformer, etc.) (Figure 1.9) [12]. However, the U.S. Food and Drug Administration (FDA) still consider hydrates, solvates, cocrystals, and amorphous phase as polymorphs [29–31].

Figure 1.9 Representation of pseudopolymorphism events which involve the incorporation of a heterostructure within the crystal lattice compared to polymorphism.

However, some of these forms such as cocrystals tend to be polymorphic with their own structure [32]. For example, caffeine: glutaric acid cocrystal displays enantiotropic packing polymorphism; stable FII and metastable FI (Figure 1.10) [33,34].

Figure 1.10 Packing polymorphism of caffeine: glutaric acid cocrystal, (a) FI and (b) FII.

Source: Trask et al. 2005 [33]. Adapted with permission of American Chemical Society.

1.2 Polymorphism Impact on Drug/Excipient Properties

Different molecular conformation or packing for a compound provides specific characteristics and hence it necessitates formulation to utilize certain handling, processing, or storage procedures. These characteristics can be categorized as physicochemical or mechanical properties, which are described in detail further.

1.2.1 Physicochemical Properties

Physicochemical properties are related to both physical and chemical features of molecular structure (e.g. presence of hydrophobic/hydrophilic groups, inter‐ and intramolecular bonding, crystal structure, etc.). Physicochemical properties include melting point, density, hygroscopicity, refractive index, surface activity, crystal habit, color, physical stability, and performance properties. Later involve solubility, dissolution rate, and bioavailability (which are interrelated). These properties are further described in detail due to their importance in pharmaceutical development (see Section 2.3). The difference in melting points originates from the variation in molecular interaction and lattice energy among polymorphs. Refractive index can be defined as the ratio of light speed in a vacuum to the speed of light within the crystal at a certain wavelength and temperature. Anisotropic crystals obtain multiple refractive index values, and hence are called birefringent, whereas isotropic crystals obtain a single refractive index, and thus are called non‐birefringent. Refractive index is mainly determined by crystal structure and molecular arrangements; therefore, different polymorphs will exhibit different refractive index and birefringence. This property can be detected by polarized light microscopy, and it is used to identify different polymorphs or phase transitions

Crystal color and shape are primarily dependent on the molecular conformation or packing in the crystal lattice which results in different macroscopic orientation within the crystal structure. Crystal color can be determined depending on how the light is absorbed and reflected by the crystal lattice, which changes according to lattice conformation [35,36]. Crystal morphology is dictated by the crystal growth mechanism of crystal nuclei faces. Therefore, the growth of crystal nuclei having different crystal packing results in morphological variations. Triamcinolone exhibits three polymorphs and a monohydrate having different crystal shapes (Figure 1.11) [15]

Figure 1.11 Predicted morphology and optical images of triamcinolone form A, B, C, and monohydrate (MH).

Source: Wang et al. 2017 [15]. Adapted with permission of American Chemical Society.

Hygroscopicity is the measure of moisture uptake, sorption, and retention from the atmosphere (humidity), neighboring liquids (mostly water), or solids in contact. Both thermodynamic and kinetic factors are involved in this process. Hygroscopicity is a crucial property in pharmaceutical development as it has a direct impact on other properties such as solubility, dissolution rate, and stability [37]. Dynamic vapor sorption is a very popular technique in assessing the hygroscopicity of materials; it measures the mass change as a function of relative humidity level (RH, %) at isothermal conditions, called sorption isotherms [38]. Different polymorphs can show varied moisture uptake behavior. This can be attributed to the variation in lattice structure, intermolecular interactions, and positioning of hydrophilic/hydrophobic molecular arrangement. Dynamic vapor sorption analysis of amisulpride forms I and II (Figure 1.12) shows that moisture uptake by form II is lower compared to that of form I [39].

Figure 1.12 Dynamic vapor sorption isotherm of amisulpride forms I and II at 25 °C.

Source: Zhang and Chen 2017 [39]. Adapted with permission of Elsevier.

1.2.2 Mechanical Properties

Mechanical properties are related to crystal behavior while subjected to mechanical stress such as compression or shear forces. These properties include plasticity, tensile strength, compressibility, or overall manufacturability. Different polymorphs that exhibit variations in terms of morphology, structural geometry, presence of defects or slip planes, density, or lattice strength mostly obtain different mechanical properties.

Morphology change caused by polymorphism can affect flowability and compressibility. However, the crystal shape can be changed while preserving the polymorph integrity using various crystal engineering approaches [40].

The presence of slip planes has been linked by many reports to superior compactability. Slip planes are comprised of crystallographic planes having the most vulnerable bonds attaching them to other planes. Slip planes accommodate compression force and use it to slide over neighboring planes, improving compressibility and deformation. However, active slip planes should be distinguished because the presence of weak hydrogen bonding across the plane can prevent plane sliding, thereby making it inactive. For example, ranitidine FI, although it contains slip planes within its crystal lattice, displays poor deformation which may be attributed to the presence of weak hydrogen bonding (Figure 1.13) [41]. The most popular example is the change in mechanical properties among paracetamol polymorphs. Metastable orthorhombic form II crystal structure is superior in compressibility compared to the monoclinic form I [42]. Therefore, polymorphic composition should be monitored and controlled before initiating direct compression of paracetamol. Form II obtains slip planes which enhance its deformation and plasticity, producing more coherent compacts [43]. Furthermore, sulfathiazole form III tablets were found to have the highest crushing force due to the presence of the slip plane in form III crystal structure which grants it excellent compressibility [44].

Figure 1.13 Crystal structure of ranitidine form I with (a) slip planes (yellow box) and (b) presence of weak hydrogen bonding (yellow dots).

Source: Khomane and Bansal 2013 [41]. Adapted with permission of Elsevier.

Variations in molecular density due to different crystal packing between polymorphs can also affect compressibility. It is proposed that stable polymorphs obtain denser packing and stronger intermolecular interactions which are more difficult to deform as in the case of metoprolol [45]. Other reports also found that true density negatively impacts compressibility but improves compactability, which results in higher tensile strength, as was the case with ranitidine polymorphs [46].

In addition, clopidogrel exhibits high true density in metastable form I, which results in low compressibility; yet it displays better properties for tableting compared to the less dense stable form II. It should be noted that form II structure involves stronger hydrogen bonding, which is reflected by the higher heat of fusion compared to form I.

Further investigation was performed on clopidogrel compressibility using synchrotron radiation X‐ray microtomography (SR‐μ CT) and 3D reconstruction analysis. This revolutionary and nondestructive method enables the visualization and quantification of deformation after compression. Form II shows better deformation and compressibility compared to form I. Moreover, the distribution of particles within the tablet was different among the two polymorphs. Deformation was assessed on the basis of change of sphericity, volume, and ellipsoid parameters. Deformation of form I particles was found to be mediated by plastic–elastic mechanism, while form II exhibits brittle fracture mechanism [47]. SR‐μ CT tomographic 3D images show how form I disc‐shaped particles got flattened, while form II particles were crushed and lost their shape (Figure 1.14).

Figure 1.14 3D images of clopidogrel polymorphs after compression, (left) form I, and (right) form II, (a) and (d) are the overall particle content in tablets, (b) and (e) uncompressed or particles present in tablet core; (c, f) are compressed particles at the surface on the tablet.

Source: Yin et al. 2016 [47]. https://creativecommons.org/licenses/by/4.0/(CC BY 4.0).

1.2.3 Impact of Polymorphism on In Vivo Performance

The development of drugs with appropriate in vivo performance and pharmacokinetics to satisfy the regulatory guidelines is paramount in the pharmaceutical industry. Furthermore, the selection of a specific polymorph of API for final product manufacturing could have a significant impact on the in vivo profile of that drug product. Polymorphism can alter both solubility and chemical stability of the compound, which are great influencers of bioavailability.

1.2.3.1 Effect of Polymorphism on Solubility

Solubility, from the perspective of solid polymorphism, is a thermodynamic concept that describes the case where solid‐state solute and liquid solvent coexist in equilibrium state. Equilibrium state indicates that the two phases have equal temperatures, pressures, and free energies. Solubility is an intensive property which is independent of the amount of solute but rather is affected by the nature of the solid phase.

Poorly soluble compounds are commonly divided into brick dust or grease ball materials. The brick dust materials have strong lattice energies which make it difficult to break the structure within the solvent. Grease ball materials are extremely hydrophobic and have low affinity to aqueous media including gastrointestinal fluids. The two effects could be concomitant in the case of NCEs with poor solubility, necessitating the application of further formulation techniques.

Intrinsic solubility is governed by the Gibbs free energy of solubilization (∆Gsol), which should obtain a value less than 0 for the solubility reaction to take place. ∆Gsol can be mathematically obtained using the general Eq. (1.2).

(1.2)

where ∆Hsolu is the solubility enthalpy, ∆Ssolu is the entropy of solubilization, and T is the temperature in kelvin.

Solubilization enthalpy (∆Hsolu) can be defined as the amount of energy, or heat, absorbed or released to initiate the solubility reaction. ∆Hsolu could have a positive or a negative value, if the reaction is endothermal or exothermal, respectively. ∆Hsolu is mainly composed of two parts (Eq. (1.3)), crystal lattice enthalpy ∆Hlatt, which is related to the cohesion energy within solute particles, and solvation enthalpy ∆Hsolv which is related to solute–solvent interactions.

(1.3)

∆Hlatt, in the case of solid‐state materials, where pressure and volume change can be neglected, is the energy required to form the lattice structure when gaseous phases bond together. Since bonding formation is an exothermic process, ∆Hlatt always obtains a negative value; hence, −∆Hlatt is always positive. Equation (1.3) involves two competing forces at equilibrium state, the solute–solute bonding ∆Hlatt, which is governed by the physical bonding within the crystal structure, and solute–solvent bonding ∆Hsolv which is related to the solute–solvent chemical affinity or polarity (high affinity means ∆Hsolv is highly negative, while low affinity means a low negative or a positive value). If solute–solvent affinity is high enough to overcome lattice energy, the negativity of Hsolv overcomes the −∆Hlatt value. This will result in a negative value of ∆Hsolu, meaning that overall solubilization is exothermal. Moreover, the solubilization will occur spontaneously as, according to Eq. (1.2), the ∆Gsolu value will obtain a negative value.

On the other hand, if the lattice energy, or −∆Hlatt value, is high enough to overcome ∆Hsolv, ∆Hsolu will obtain a positive value. In this case, based on Eq. (1.2) and depending on the entropy–temperature value T∆Ssolu, two scenarios are possible. The first is that T∆Ssolu is high enough to overcome ∆Hsolu, leading to a negative ∆Gsolu, which means that solubilization is endothermic and can occur spontaneously provided enough energy is supplied to the reaction. The second scenario happens if T∆Ssolu cannot overcome ∆Hsolu, resulting in a positive ∆Gsolu, and thus solubility does not take place.

Therefore, ∆Hsolu is crucial for the formulators, and it is targeted to enhance the solubility either by reducing lattice energy (decreasing −∆Hlatt) or by increasing the affinity between the solute and solvent (decreasing ∆Hsolv). Lowering lattice energy is performed by manipulating the solute physical structure, such as converting to amorphous form, solvate, salt, cocrystal, or the polymorph. Nevertheless, changing the solute–solvent interaction is associated with changing chemical composition, e.g. complexation, ionization, micellar solubilization, and prodrug formation.

Polymorphism, which results in different molecular conformation or packing, leads to a change in the lattice energy value and therefore a change in the solubility. The metastable form at a certain temperature has lower lattice energy than the stable form, and hence has higher solubility at the same temperature. In addition, the solubility differences between several polymorphs have been investigated and it was found that the solubility ratio between metastable and stable forms ranges from 1: 1–10 times [48]. Form C of phenylbutazone is 1.5 times more soluble than form A. Ritonavir, a protease inhibitor, has two polymorphs, the stable form II and metastable form I, which have significant solubility differences, approximately 4 : 1 in ethanol/water mixtures [49].

Conventional solubility determination has been discussed by many reviews and it involves preparing a saturated solution of the desired solute–solvent system using a shake‐flask method. This is done by adding excess of solute to the solvent, agitation, or stirring for a certain time at a certain temperature and pressure, and subsequent filtration. If the solvent is aqueous, pH measurement or adjustment must be performed using a pH meter, and standard buffer systems, respectively. The next step is to determine the concentration of aliquots, which is measured using gravimetric, spectroscopic, or chromatographic techniques. Commonly, the solubility is investigated using the range of solvents (mostly water, buffers, and ethanol), temperatures, and pH level [50].

The process is exhaustive, stagnant, and requires a decent amount of sample, which is difficult to supply in the early stages of drug development. In addition, it requires expertise in the solid–liquid equilibria (SLE) field, including phase rule, phase diagrams, and thermodynamics. Moreover, solubility determination of metastable polymorphs is very tricky in terms of physical stability as metastable polymorphs tend to undergo solution‐mediated phase transformation and convert to the stable form.

The solubility of polymorphic materials can be determined using thermal methods or be predicted using computational and mathematical models. Experimental thermal data can be utilized assuming that crystal lattice cohesion is the only controlling factor. In this case, solubility is referred to as ideal solubility (Sideal). Lattice energy can be represented as the melting or fusion enthalpy, neglecting heat capacity change after melting, and used to calculate the ideal solubility using the van 't Hoff equation 1.4). The equation is a deferential correlation between solubility/temperature change and enthalpy of fusion.

(1.4)

where ln S is the natural logarithm of fractional solubility, T is the temperature in kelvin, R is the ideal gas constant, and ∆Hfus is the enthalpy of fusion, which can be also referred to as enthalpy of melting. Enthalpy of melting can be determined experimentally using differential scanning calorimetry (DSC). Moreover, the van 't Hoff equation is integrated to produce Eq. (1.5)

(1.5)

where ∆Hm is the melting enthalpy and Tm and T are the melting point and temperature, respectively. However, this method discards the contribution of the solvent–solute effect which is necessary to obtain realistic solubility (Eq. (1.6)).

(1.6)

where γ the activity coefficient of solute in the solvent.

The van 't Hoff equation (1.7) can be also employed to calculate the enthalpy of solubilization, depending on two solubility values at two distinct temperatures which are determined either experimentally or computed via prediction models. In this case, the solubility values are considered realistic, and thus the enthalpy value can be referred to as solubilization instead of melting enthalpy as the solvent contribution is present [51].

(1.7)

Solubility prediction of NCEs before conducting experimental measurement can save a lot of time and effort by avoiding to deal with extremely low‐soluble candidates and focusing on the development of more suitable compounds. Quantum‐mechanics‐dependent computational methods such as lattice energy minimization algorithms combined with molecular dynamics (MD) can determine predicted solubility curves [51].

Moreover, mathematical models such as modified Apelblat equation, λh equation, van 't Hoff equation, ideal model, Wilson model, nonrandom two‐liquid model (NRTL), and universal quasichemical model (UNIQUAC) are used to predict solubility curves as a function of temperature (kelvin). The calculated values are commonly used to correlate experimental data and to calculate solubilization enthalpy, entropy, and Gibbs free energy.

For example, experimental solubility of pioglitazone form II [52] in several solvents (Figure 1.15a) was calculated as a function of temperature and correlated to λh, van 't Hoff, and ideal model with good agreement. Furthermore, the van 't Hoff equation was applied to calculated solubilization enthalpy, entropy, and Gibbs free energy depending on the linear relationship between the natural logarithm of experimental solubilities and reciprocal of temperature (Figure 1.15b). Enthalpy of solubilization can be calculated from the slope of the van't Hoff plot. Similarly, the polymorphic solubilities of buspirone hydrochloride [53], mefenamic acid [54], and clopidogrel [55] in several solvents were investigated experimentally and correlated with the mathematical models.

Figure 1.15 (a): Experimental solubility of pioglitazone form II in ▪, N,N