Solid State Development and Processing of Pharmaceutical Molecules E-Book

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

Seitenzahl: 1070

Veröffentlichungsjahr: 2021

Beschreibung

Solid State Development and Processing of Pharmaceutical Molecules

A guide to the lastest industry principles for optimizing the production of solid state active pharmaceutical ingredients

Solid State Development and Processing of Pharmaceutical Molecules is an authoritative guide that covers the entire pharmaceutical value chain. The authors—noted experts on the topic—examine the importance of the solid state form of chemical and biological drugs and review the development, production, quality control, formulation, and stability of medicines.

The book explores the most recent trends in the digitization and automation of the pharmaceutical production processes that reflect the need for consistent high quality. It also includes information on relevant regulatory and intellectual property considerations. This resource is aimed at professionals in the pharmaceutical industry and offers an in-depth examination of the commercially relevant issues facing developers, producers and distributors of drug substances. This important book:

• Provides a guide for the effective development of solid drug forms
• Compares different characterization methods for solid state APIs
• Offers a resource for understanding efficient production methods for solid state forms of chemical and biological drugs
• Includes information on automation, process control, and machine learning as an integral part of the development and production workflows
• Covers in detail the regulatory and quality control aspects of drug development

Written for medicinal chemists, pharmaceutical industry professionals, pharma engineers, solid state chemists, chemical engineers, Solid State Development and Processing of Pharmaceutical Molecules reviews information on the solid state of active pharmaceutical ingredients for their efficient development and production.

Leseprobe

Table of Contents

Cover

Series Page

Title Page

Copyright

Series Editors Preface

Preface

1 Aspects for Developing and Processing Solid Forms

1.1 Aspects for Developing and Processing Solid Forms

References

2 Determination of Current Knowledge

2.1 Why Is it Important to Search for Relevant Information Before Starting a Solid‐State Project?

2.2 Where to Begin a Literature Search for a Solid‐State Project?

2.3 Patent Search

2.4 Other Useful Resources for Solid‐State Projects

References

Notes

3 Systematic Screening and Investigation of Solid‐State Landscapes

3.1 Introduction

3.2 General Aspects of Solid‐State Investigations in Early Drug Discovery Phase

3.3 Transition Phase from Late Stage Research to Early Stage Development

3.4 Solid‐State Characteristics in Preclinical Formulations

3.5 API‐crystallization Strategy in Candidate Profiling Phase

3.6 Selection Criteria of a Suitable Solid Form

3.7 Knowledge Management

3.8 Control of Solid Form Properties in Development

3.9 Exploratory Crystallization Experiments

References

4.1 Solid‐State Characterization Techniques: Microscopy

4.1.1 Microscopy

References

4.2 Standards and Trends in Analytical Characterization – X‐ray Diffraction (XRD)

4.2.1 X‐ray Diffraction

4.2.2 Technics

4.2.3 Instrumentation

4.2.4 Measurement

4.2.5 Data Evaluation

References

Further Reading

Notes

4.3 Standards and Trends in Solid‐State Characterization Techniques – Thermal Analysis

4.3.1 Introduction

4.3.2 Thermal Analysis in Drug Development

4.3.3 Methods

4.3.4 Case Studies

4.3.5 Quality and Regulatory Aspects

4.3.6 Outlook

Acknowledgments

References

Notes

4.4 Standards and Trends in Solid‐State Characterization Techniques: Infrared (IR) Spectroscopy

4.4.1 Infrared (IR) Spectroscopy

References

4.5 Transmission Raman Spectroscopy – Implementation in Pharmaceutical Quality Control

4.5.1 Raman Spectroscopy – From Research to Broad Applications in Industry

4.5.2 Analytical use of Raman Spectroscopy for Pharmaceutical Purposes

4.5.3 Transmission Raman Spectroscopy – Another Practical Guide

4.5.4 Regulatory Assessment and Guidelines

References

4.6 Solid‐state Characterization Techniques: Particle Size

4.6.1 Introduction

4.6.2 Analytical Methodologies Used to Measure Particle Size

4.6.3 Method Development for Precise Particle‐size Measurements by Laser Diffraction

4.6.4 Unexpected Results and Troubleshooting in Laser Diffraction Measurement

References

4.7 Micro Computational Tomography

4.7.1 Tomography Imaging Techniques

4.7.2 Micro X‐ray Computed Tomography Scan

Notes

References

4.8 In Situ Methods for Monitoring Solid‐State Processes in Molecular Materials

4.8.1 In Situ Methods for Monitoring Solid‐State Processes in Molecular Materials

References

4.9 Application of Process Monitoring and Modeling

4.9.1 In‐process Solid Form Monitoring Techniques

4.9.2 Quantification Methods and Application to Solid Form Transformation Modeling

References

4.10 Photon Density Wave (PDW) Spectroscopy for Nano‐ and Microparticle Sizing

4.10.1 Classification of Particle Sizing Technologies

4.10.2 Particle Size and Solid Fraction Ranges

4.10.3 Photon Density Wave (PDW) Spectroscopy – Theory, Instrumentation, and Application Examples

4.10.4 Particle Sizing by PDW Spectroscopy

4.10.5 Sample Versus Process Measurements

4.10.6 Technical Implementation and Data Access

4.10.7 Examples for Process Analysis with PDW Spectroscopy

4.10.8 Summary

References

5 Impact of Solid Forms on API Scale‐Up

5.1 Introduction

5.2 Background

5.3 Small‐Scale Crystallization Development

5.4 Crystallization Scale‐Up

5.5 People and Skill Requirements

5.6 Regulatory Requirements

5.7 Closing Remarks

References

6 Impact on Drug Development and Drug Product Processing

6.1 Introduction

6.2 Pharmaceutical Profiling

6.3 Formulation Development

6.4 Process Development and Transfer to Commercial Manufacturing

6.5 Control Strategy

6.6 Regulatory Submissions

References

7 Workflow Management

7.1 Motivation

7.2 Workflow Management

7.3 Organization of Solid‐State Development by Project Management

7.4 Workflows in the Environment of the Crystallization Laboratory

7.5 Processes in the Solid‐State Lab

7.6 Development of Crystallization Processes

7.7 Support Processes

7.8 Conclusion

References

8 Digitalization in Laboratories of the Pharmaceutical Industry

8.1 Introduction

8.2 Motivation of Digitalization in the Laboratory

8.3 Categories of Laboratory IT Systems

8.4 System Interfaces for Data Exchange

8.5 Implementation of IT Solutions

8.6 Conclusion

References

9.1 Polymorphs and Patents – the US Perspective

9.1.1 Introduction

9.1.2 What Is a Patent?

9.1.3 How Are Patents Obtained?

9.1.4 United States Patent Law

Notes

References

9.2 Polymorphs and Patents – The EU Perspective

9.2.1 European Patent Applications and European Patents

9.2.2 Decisions of Technical Boards of Appeal of the EPO

9.2.3 Jurisdiction of the Federal Patent Court and the German Federal Supreme Court

9.2.4 Assessing Validity of a Patent or the Chances of Success

9.2.5 Interaction with Patent Professionals

References

10 Regulatory Frameworks Affecting Solid‐State Development

10.1 Introduction – The Need for Regulation in Pharmaceutical Industry

10.2 Solid‐State Forms to Be Used for Drugs

10.3 General Regulatory Considerations for Pharmaceutical Solid‐State Forms

10.4 Regulatory Framework for Pharmaceutical Salts

10.5 Regulatory Framework for Co‐crystals

10.6 Summary

References

11 Opportunities and Challenges for Generic Development from a Solid‐state Perspective

11.1 The Birth of a New Drug and the Generic Siblings that Will Follow – Two Different Mindsets

11.2 Portfolio Management – How Is a Portfolio Constructed and Maintained?

11.3 Challenges in Developing a Generic Product from the Solid‐state Perspective

11.4 Generic Solid‐state Development

11.5 Success Factors

References

Index

End User License Agreement

List of Tables

Chapter 1

Table 1.1 Categories in the German DESTATIS GENESIS‐online database (as of 2...

Table 1.2 Example for a synthesis procedure.

Table 1.3 Naming of common solvate forms.

Table 1.4 Nomenclature for compounds with crystal water.

Chapter 2

Table 2.1 Are different solid states considered to be the “same” by regulato...

Table 2.2 PubMed search results when entering “ibuprofen solid state polymor...

Table 2.3 CPC section codes.

Table 2.4 The most common CPC subclasses that may be used to categorize phar...

Table 2.5 Physical–chemical properties indexed by the CPC system.

Table 2.6 Different numbers of results obtained when using varying search st...

Chapter 3

Table 3.1 Important aspects of solid form control for formulation.

Table 3.2 Key aspects of different screening types.

Table 3.3 Definition of different categories for physico‐chemical properties...

Table 3.4 Synthesized batches from medicinal chemistry available at that tim...

Table 3.5 Analytical characterization of batch no. 4.

Table 3.6 Results of first crystallization experiments (exploratory screen t...

Table 3.7 Experimental details of the HT screening setup.

Table 3.8 Results of 400 mg crystallization experiments (screen type “Form E...

Table 3.9 Head‐to‐head comparison of solid form properties of Form VI and ci...

Chapter 4-3

Table 4.3.1 Overview of thermal data obtained by standard DSC.

Table 4.3.2 Overview of thermal data obtained by standard DSC and by applyin...

Table 4.3.3 Weight loss during decomposition of calcium oxalate monohydrate.

Chapter 4-5

Table 4.5.1 Comparison of FT‐IR, NIR, and Raman spectroscopy.

Table 4.5.2 Comparing relevant costs of shifting products to TRS100 from HPL...

Table 4.5.3 Definition and terminology of the different steps in transmissio...

Table 4.5.4 Variation in Raman settings for the same matrix.

Table 4.5.5 Regulatory guidance documents supporting TRS method development ...

Chapter 4-6

Table 4.6.1 Dispersants in decreasing order of polarity.

Chapter 4-8

Table 4.8.1 Overview of major analytical techniques for in situ monitoring o...

Table 4.8.2 Type of experiment to which the technique has been applied is in...

Chapter 4-9

Table 4.9.1 Advantages and challenges of solid form monitoring techniques.

Chapter 4-10

Table 4.10.1 Classification of particle size characterization methods into s...

Chapter 5

Table 5.1 Selection guide for crystallization process type.

Chapter 6

Table 6.1 Developability and other parameters according to the MCS (ideal pr...

Table 6.2 Phase transitions and their underlying mechanisms.

Chapter 8

Table 8.1 Solid‐state laboratory processes, supported by IT solutions.

Chapter 9-2

Table 9.2.1 Hitlist of search for “polymorph” in the EPO decision database (...

Table 9.2.2 Hitlist of search for “polymorph” in the decision database of th...

Chapter 10

Table 10.1 Chapters within the CTD which might be relevant with regard to so...

List of Illustrations

Chapter 1

Figure 1.1 The crystallization laboratory – integrated in pharmaceutical dev...

Figure 1.2 The complexity of solid compounds in pharmaceutical applications....

Figure 1.3 Tasks and duties for solid‐state development and processing.

Figure 1.4 Sampling procedure for a filtration process.

Figure 1.5 Triangle of project management.

Figure 1.6 Level and complexity of digitalization.

Figure 1.7 Hierarchy and Interoperability of departmental IT systems. ERP, e...

Figure 1.8 Fully digitalized IT and lab system landscape for a solid‐state l...

Figure 1.9 (a) Arrangement with long‐range order, (b) mainly amorphous, arra...

Figure 1.10 Schematic representation of potential interconversions between p...

Figure 1.11 Acetaldehyde, a geminal diol – an organic compound “containing” ...

Figure 1.12 (a) Dispersed primary particles, (b) aggregates, and (c) agglome...

Figure 1.13 Polymorphic landscape derived from experimental findings. MM, mo...

Figure 1.14 Various applications for simulation of chemical and pharmaceutic...

Figure 1.15 Calculated temperature distribution after seeding in a cooled mi...

Chapter 2

Figure 2.1 Visual depiction of the search results that will be returned when...

Chapter 3

Figure 3.1 Different phases of API‐characterization within Research.

Figure 3.2 Microscopic picture of natrosol suspensions (heterogeneous mixtur...

Figure 3.3 Polymorph transformation within natrosol suspension. Pattern A: X...

Figure 3.4 Crystallization of amorphous material within natrosol suspension....

Figure 3.5 Recrystallization of amorphous material within a solid dispersion...

Figure 3.6 Exemplary XRPD‐diagrams of compound B to illustrate six different...

Figure 3.7 HT crystallization setup for compound A on a 96‐well plate.

Figure 3.8 Image of the final kapton crystallization plate (a); results of t...

Chapter 4-1

Figure 4.1.1 Polarized light microscope images of (a) crystalline drug parti...

Figure 4.1.2 SEM image of Cu, Zn‐superoxide dismutase composite particles co...

Figure 4.1.3 SEM image of particles in a carrier‐based formulation for DPI. ...

Figure 4.1.4 Comparison of particle size distribution of two different batch...

Figure 4.1.5 AFM image of the surface of clear (on the left) and colored (on...

Chapter 4-2

Figure 4.2.1 Schematics of the two basic geometries used in powder X‐ray dif...

Figure 4.2.2 Example for the effect of asymmetry due to “umbrella effect” on...

Figure 4.2.3 Effect of preferred orientation on relative intensities (simula...

Figure 4.2.4 Powder X‐ray diffraction patterns (simulations) of fumaric acid...

Figure 4.2.5 Diffractograms depicting visibility of amorphous fractions (pow...

Chapter 4-3

Figure 4.3.1 Principle of power compensation differential scanning calorimet...

Figure 4.3.2 Principle of heat flux DSC.

Figure 4.3.3 Standard DSC thermogram showing glass transition, crystallizati...

Figure 4.3.4 Arrangements of (a) top‐loading, (b) bottom‐loading, and (c) si...

Figure 4.3.5 Standard TGA thermogram of calcium oxalate monohydrate.

Figure 4.3.6 Low‐temperature DSC experiment.

Figure 4.3.7 Simulated XRPD pattern from single‐crystal structure solution o...

Figure 4.3.8 Cyclic DSC experiment starting with Form A.

Figure 4.3.9 Cyclic DSC experiment starting with Form B.

Figure 4.3.10 DSC of Form B using a heating rate of 1000 K s

−1

.

Figure 4.3.11 Standard DSC experiment of an amorphous material.

Figure 4.3.12 Cyclic DSC of the same amorphous material as the one shown in ...

Figure 4.3.13 Modulated DSC of the same amorphous material as the one shown ...

Figure 4.3.14 Example of crystallization probability depending on storage te...

Figure 4.3.15 Thermogravimetric analysis of calcium oxalate monohydrate.

Figure 4.3.16 Three‐dimensional representation of the evolved gas analysis b...

Chapter 4-4

Figure 4.4.1 A multiple reflection ATR system.

Figure 4.4.2 Overlay of ATR IR spectra of Oxatomide anhydrate (full line) an...

Figure 4.4.3 FTIR spectra of the carbamazepine – malonic acid system. (a) Ca...

Figure 4.4.4 Detector setups.

Figure 4.4.5 Example of an NIR imaging of a tablet.

Figure 4.4.6 Single score plots of the multivariate analysis of the tablet....

Figure 4.4.7 Corresponding NIR spectra of calculated scores.

Figure 4.4.8 Corresponding mid‐IR spectra of selected fields of interest bas...

Figure 4.4.9 Diffuse reflectance infrared spectra of cellulose (green line),...

Figure 4.4.10 Classification image of a 13 mm tablet showing the distributio...

Figure 4.4.11 From left to right: Individual chemical maps of carbamazepine ...

Chapter 4-5

Figure 4.5.1 Jablonski energy diagram (simplified).

Figure 4.5.2 Raman spectroscopic configurations with (a) typical diffuse ref...

Figure 4.5.3 Transmission Raman spectrum of pure Tramadol.

Figure 4.5.4 Return of investment for (a) low volume products, low labor cos...

Figure 4.5.5 Decision tree for main factors: API concentration and colorants...

Figure 4.5.6 (a) Spectra of DoE blends of a product colored by the API conce...

Figure 4.5.7 Example of a powder DoE model (LV: latent variable).

Figure 4.5.8 Different Raman settings of the same data set varying laser pow...

Chapter 4-6

Figure 4.6.1 Representation of different particle‐size distribution curves (...

Figure 4.6.2 Illustration of common laser diffraction instrumentation config...

Figure 4.6.3 Examples of different powder dispersion behaviors into differen...

Figure 4.6.4 Example of a titration curve with increasing ultrasound energy....

Figure 4.6.5 Example of a distribution containing a disconnected peak (red)

Figure 4.6.6 Example of a particle‐size distribution by volume (a) using two...

Chapter 4-7

Figure 4.7.1 3D μCT reconstructed images from a round tablet (perspective vi...

Figure 4.7.2 Density distribution in X–Y cross section by CT scan for a halv...

Figure 4.7.3 3D μCT reconstructed images for the honeycomb architecture tabl...

Figure 4.7.4 μCT 3D image of a tablet core and coating (a), the core only (b...

Figure 4.7.5 μCT image of a coated tablet to evaluate coating layer thicknes...

Figure 4.7.6 3D μCT reconstructed images “after 24 hours in the dissolution ...

Figure 4.7.7 μCT scan showing a metallic particle in a tablet.

Chapter 4-8

Scheme 4.8.1 General classification of analytical techniques for monitoring ...

Figure 4.8.1 Controlling supersaturation levels to selectively nucleate poly...

Figure 4.8.2 Schematic representation of a light scattering experiment.

Figure 4.8.3 (a) Intensity data from attenuation coefficient against the 90°...

Figure 4.8.4 Acoustic emission profiles for (a) citric acid and (b) citric a...

Figure 4.8.5 In situ time‐resolved temperature monitoring for solid‐state pr...

Figure 4.8.6 Representation of the 2D diffraction image of the Si standard (...

Figure 4.8.7 (a) Bragg scattering from a crystalline material within an X‐ra...

Figure 4.8.8 Monitoring mechanochemical transformations by in situ real‐time...

Figure 4.8.9 Low‐frequency Raman monitoring of the conversion of carbamazepi...

Figure 4.8.10 Monitoring the mechanochemical Knoevenagel condensation betwee...

Figure 4.8.11 Realistic schematics of in situ real‐time monitoring of solid‐...

Figure 4.8.12 (a) In situ temperature data in the milling jar during the for...

Figure 4.8.13 Combining multiple techniques to following mechanochemical rea...

Chapter 4-9

Figure 4.9.1 (a) In situ polymorphic mass fraction profiles of taltirelin th...

Figure 4.9.2 (a) Observed versus predicted relative content for PLS model. (...

Figure 4.9.3 FBRM measurement principle: (a) the rotating laser inside the p...

Figure 4.9.4 Temperature, antisolvent addition, and FBRM profile of an unsee...

Figure 4.9.5 In‐process micrographs of a solvent‐mediated transformation of ...

Figure 4.9.6 Solubility curves and crystallization profile of the solute con...

Figure 4.9.7 Predicted versus observed amount of Form I particles depending ...

Figure 4.9.8 Comparison of PSD data estimated from CLD measurements: (a) usi...

Figure 4.9.9 Model architecture to predict 1D and 2D PSDs from CLD measureme...

Figure 4.9.10 PSD determination by image analysis characterizing minor and m...

Figure 4.9.11 (a) Waterfall plot of time‐resolved Raman spectra data of the ...

Chapter 4-10

Figure 4.10.1 Sizing ranges (a) and volume fraction ranges (b) for common pa...

Figure 4.10.2 Particle diameter as function of volume fraction for different...

Figure 4.10.3 Particle diameter as function of volume fraction for an aqueou...

Figure 4.10.4 Experimental particle diameter of various aqueous monomodal, m...

Figure 4.10.5 Schematic experimental setup of a PDW spectrometer.

Figure 4.10.6 Reduced scattering coefficient calculated by Mie theory for a ...

Figure 4.10.7 Schematic representation of the sensing zone close to the prob...

Figure 4.10.8 Absorption coefficient, reduced scattering coefficient, and te...

Figure 4.10.9 Optical coefficients

μ

a

and

μ

s

′ as well as particle ...

Figure 4.10.10 Reduced scattering coefficient at 982 nm as function of time ...

Chapter 5

Figure 5.1 Overview of the crystallization development process alongside app...

Figure 5.2 Example of a form transformation diagram showing relationship bet...

Figure 5.3 Criteria for solvent selection.

Figure 5.4 Solubility curve.

Figure 5.5 Particle size distribution (PSD) showing bimodality as a result o...

Figure 5.6 Dynamic solubility measurement.

Figure 5.7 Potential factors to consider when scaling up a crystallization p...

Figure 5.8 CFD models of addition to two different vessel configurations. Th...

Figure 5.9 Examples of spherical agglomerates resulting from oiling out duri...

Figure 5.10 Example of video imaging showing a transient oil phase occurring...

Figure 5.11 Image on left shows a crystals which have been slurry washed, sa...

Figure 5.12 Lumps formed as a result of compression on the centrifuge.

Figure 5.13 Impact of water levels on breakage forces seen during drying.

Figure 5.14 Image of lumps which have formed during agitated drying.

Figure 5.15 Image of a crystal fractured as a result of desolvation during d...

Chapter 6

Figure 6.1 The galenical tetrahedron.

Figure 6.2 Pharmaceutical development – key aspects which are covered during...

Figure 6.3 Summary of factors that proved to have an impact (bold) and that ...

Figure 6.4 Summary of factors that proved to have an impact (bold) and that ...

Figure 6.5 Adapted and modified decision tree from [157] to set acceptance c...

Chapter 7

Figure 7.1 Generic subproject plan for controlling early solid‐state develop...

Figure 7.2 Solid‐state screen form in the analytic database (ACDLabs) is sho...

Figure 7.3 Example for ELN document status workflow.

Chapter 8

Figure 8.1 Hierarchical categories of laboratory information systems. ERP, e...

Figure 8.2 Interaction room digital, a well‐proven approach in digitalizatio...

Figure 8.3 Recommended software development process based on general GAMP pr...

Figure 8.4 SCRUM process. Content in red is needed in regulated areas.

Chapter 10

Figure 10.1 Decision trees for polymorphism as given by ICH Q6A. The three d...

Figure 10.2 Decision trees for polymorphism as given by the FDA “Guidance fo...

Chapter 11

Figure 11.1 Energy–temperature diagrams (top) and solubility curves (bottom)...

Figure 11.2 Schematic summary of solid‐state characterization activities for...

Guide

Cover

Table of Contents

Series Page

Title Page

Copyright

Series Editors Preface

Preface

Begin Reading

Index

WILEY END USER LICENSE AGREEMENT

Pages

ii

iii

iv

xxi

xxii

xxiii

xxiv

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

180

181

182

183

184

185

186

187

188

189

190

191

192

193

194

195

196

197

198

199

200

201

203

204

205

206

207

208

209

210

211

212

213

215

216

217

218

219

220

221

222

223

224

225

226

227

228

229

230

231

232

233

234

235

236

237

238

239

240

241

242

243

244

245

246

247

248

249

250

251

252

253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

281

282

283

284

285

286

287

288

289

290

291

292

293

294

295

296

297

298

299

300

301

302

303

304

305

306

307

308

309

310

311

312

313

314

315

316

317

318

319

320

321

322

323

325

326

327

328

329

330

331

332

333

334

335

336

337

338

339

340

341

342

343

344

345

346

347

348

349

350

351

352

353

354

355

356

357

358

359

360

361

362

363

364

365

366

367

368

369

370

371

372

373

374

375

376

377

378

379

380

381

382

383

384

385

386

387

388

389

390

391

392

393

394

395

397

398

399

400

401

402

403

404

405

406

407

408

409

410

411

412

413

414

415

416

417

418

419

420

421

422

423

424

425

426

427

428

429

430

431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

462

463

464

465

466

467

468

469

470

471

472

473

474

475

476

477

478

479

480

481

482

483

484

485

486

487

488

489

490

491

492

493

494

495

496

497

498

499

500

501

502

503

504

505

506

507

508

509

510

511

512

513

514

515

516

517

518

519

520

521

522

523

524

525

526

527

528

529

530

531

532

533

534

535

536

537

538

539

540

541

542

543

544

545

546

547

548

549

Methods and Principles in Medicinal Chemistry

Edited by

R. Mannhold, H. Buschmann, J. Holenz

Editorial Board

G. Folkers, H. Kubinyi, H. Timmerman, H. van de Waterbeemd, J. Bondo Hansen

Bachhav, Y. (Ed.)

Innovative Dosage Forms

Designs and Development at Early Stage

2019

ISBN: 978‐3‐527‐34396‐6

Vol. 79

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.)

Animal Models for Human Cancer

Discovery and Development of Novel Therapeutics

2017

ISBN: 978‐3‐527‐33997‐6

Vol. 69

Solid State Development and Processing of Pharmaceutical Molecules

Salts, Cocrystals, and Polymorphism

Volume 79

Edited byMichael Gruss

Volume Editor

Dr. Michael GrußSolid State ConceptsHermannstr. 852062 AachenGermany

Series Editors

Prof. Dr. Raimund MannholdRosenweg 740489 DüsseldorfGermany

Dr. Helmut BuschmannSperberweg 1552076 AachenGermany

Dr. Jörg HolenzGRT TherapeuticsGrunenthal Boston Pain Innovation Hub1 BroadwayCambridge MA 02142United States

Cover Illustration: Gunther Schulz usingiStock #17264342 / alwyncooper

All books published by WILEY‐VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.:applied for

British Library Cataloguing‐in‐Publication DataA catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche NationalbibliothekThe Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2022 WILEY‐VCH GmbH, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Print ISBN: 978‐3‐527‐34635‐6ePDF ISBN: 978‐3‐527‐82305‐5ePub ISBN: 978‐3‐527‐82306‐2oBook ISBN: 978‐3‐527‐82304‐8

Series Editors Preface

Michael Gruß works as an independent scientific consultant for the pharmaceutical, chemical, and nutrition industry, and he is known and well recognized as an expert in this field. During his industrial career, he conducted solid‐state investigations on pharmaceutical drug substances and intermediates. He is author or co‐author of more than 15 patent applications in the field of salts, cocrystals, and polymorphs, and some of the drugs are globally marketed.

Polymorphism presents opportunities as well as challenges. Investigation of the properties of different forms of a commercial drug can lead to new products with improved onset time, greater bioavailability, sustained release properties, or other therapeutic enhancements. New forms can bring improvements in manufacturing costs or API purity.

The potential for solid form variation does not end at API production. Solid form issues remain through formulation, manufacture, storage, and use of drug product. It is common to observe form transformation during standard manufacturing operations like wet granulation and milling. Excipient interactions and compaction can induce form changes. Changes can occur in the final dosage form over time.

Whenever there is a specification failure in drug product or drug substance, solid form changes should be considered in the search for causes. Particularly, symptomatic is failure to meet melting point or dissolution specifications. Changes in humidity, crystallization conditions, or crystallization solvent can produce unwanted forms.

Due to the importance of solid‐phase characteristics in pharmaceutical industry, several brilliant review articles and books have been published.

The current volume entitled Solid‐State Development and Processing of Pharmaceutical Molecules in our book series Methods and Principles in Medicinal Chemistry is focused on specific aspects of salts, cocrystals, and polymorphism in drug development. The book compiles general concepts and their latest applications along with well‐selected case studies considering experiences and publications from the last 10 to 12 years. It considers new developments in science and knowledge that has been contributed by academic and industrial researchers during the last decade.

This book clearly goes beyond the classical description of solid‐state properties. It encourages out‐of‐the‐box thinking and allows a look beyond the science. In defining the scope of the book, one intention was to allow the identification of beneficial synergies for successful integration of solid‐state form development workflows into general management strategies for R&D and production.

The editors would like to thank Michael and all contributing authors for such a successful compilation, which will stimulate the awareness of the impact of solid‐state‐related topics and enhance the importance of salts, cocrystals, and polymorphic forms throughout the pharmaceutical value chain.

Aachen, Düsseldorf and BostonHelmut BuschmannJuly 2021Raimund MannholdJörg Holenz

Preface

“[…] Cuius rei demonstrationem mirabilem sane detexi. Hanc marginis exiguitas non caperet.” Pierre de Fermat wrote a note that states that no three positive integers a, b, and c satisfy the equation an + bn = cn for any integer value of n greater than 2 in a copy of his book of the Arithmetica of Diophantos of Alexandria. The quote translates to “I have discovered a truly remarkable proof of this theorem which this margin is too small to contain.”

The present edition of “Solid‐State Development and Processing of Pharmaceutical molecules” may be considered as a margin that is likewise too small to cover all aspects of relevance and interest in this vast field addressed in the title. However, it is an attempt to collect and consider at least some aspects which are important from an industrial perspective on developing and processing crystalline forms in the pharmaceutical value chain.

Being a topic of some interest already since many years, solid‐state investigation of crystalline pharmaceuticals gained more and more attention and commercial relevance in the last 20–25 years. Nevertheless, approaches to cover the challenges and obstacles coming along with the peculiarities of crystalline pharmaceutical molecules and their development and processing are manifold. Although sophisticated analytical devices are available on the market to investigate solid forms, not every project can be supported by all technical and personal intelligence. There are limitations framed by limited resources of financial funding and manpower. Eventually, no excuses count when safety and efficacy of medicines are of concern. However, if not all, but many routes lead to Rome.

Some of the routes are presented in this edition. Readers are called to wisely select the right means and measures for their particular projects. Besides the essential and unavoidable basics to reach the goal, there are add‐ons and nice‐to‐haves that may shorten the route to process understanding and market entrance.

Starting with important general considerations in Chapter 1, the subsequent chapters lighten the road along solid‐state development and processing. Chapter 2 describes entry points into a solid‐state‐related project. Investigation of the polymorphic landscape is exemplified in Chapter 3 and complemented by Chapter 4 which is divided into 10 subchapters describing various solid‐state characterization techniques. Treatment of solid pharmaceutical drug substances upon scale‐up is covered in Chapter 5, while Chapter 6 considers the challenges for Drug Product development and manufacturing. From my perspective often neglected but essential support processes addressing simplification of daily routines, best practices and documentation are described in Chapters 7 and 8. Chapter 9 covers ensuring the return of investment by the protection of intellectual property, while Chapter 10 addresses the regulatory aspects of relevance. Last but not least, the perspective of extension of the value chain of pharmaceutical molecules is given in Chapter 11.

Clearly, without all the authors who accepted to contribute, this edition would never have been possible. Thank you a lot. You made this book to a valuable collection of practical knowledge and expertise. It was my pleasure and honor to cooperate with you. Sincere thanks to Wiley‐VCH, namely Dr. Frank Weinreich, Stefanie Volk, and N. Kiruthigadevi for answering my questions and acting behind the scenes to drive this publication, as well as Felix Bloeck who worked with the graphic designers on the book cover. Finally, I would especially like to thank Dr. Helmut Buschmann for his everlasting supportive initiative to motivate and develop people.

AachenMichael GrussJuly 2021

1Aspects for Developing and Processing Solid Forms

Michael Gruss

Dr. Michael Gruß – Solid State Concepts, Hermannstr. 8, 5062 Aachen, Germany

1.1 Aspects for Developing and Processing Solid Forms

1.1.1 Introduction

Due to progressing through time and space, we constantly learn and forget. We lose things out of sight and focus on the ones that are of most importance and interest. Consequently, we cannot keep pace on every single field of technology and science. Career pathways are manifold. It is fairly natural that people in management positions who take over the responsibility to direct companies, departments, or groups cannot be experts in all the domains falling under their responsibility. Therefore, they have to educate themselves and rely on their staff, employees, team members, suppliers, contract organizations and consultants, and the assessments delivered. Decisions are made on such a base. Those decisions determine the commercial fate of the business, which in turn determines the well‐being of those who gave input into the decisions. A circle of life? Will just the fittest survive?

1.1.2 Education and Personal Background

Some lack of knowledge and understanding of impact and relations may occur especially in fields that are typically not in the focus of a general chemical, medicinal, or pharmaceutical curriculum. Organic compounds constitute the majority of active pharmaceutical ingredients (API) very often in the form of crystalline solids. Nevertheless, solid‐state‐related topics for organic compounds are treated in introductory organic synthetic textbooks, like the Organikum[1], just on a few pages that do not go much into the details. Crystallization (including selection of the solvent, recrystallization, and crystallization from the melt) is explained in two pages, and structure analysis by means of X‐ray is mentioned in another page.

Besides, still a predominant perception of solid‐state characterization techniques, in particular X‐ray powder diffraction (XRPD), is that the investigations are expensive. Admittedly, XRPD is not as widely distributed and readily accessible as spectroscopic and chromatographic techniques. Consequently, solid compounds and dosage forms are primarily characterized by the analytical techniques that are easily available. It is perfect to assess purity profiles and determine the solubility and dissolution profiles. Unfortunately, it is not sufficient to analyze the liquid state because that does not reveal much about the properties of the material in the solid state. Additional processing knowledge is also needed to design and modify solid‐state properties.

Our current position, our educational background, as well as the social and technical environment that surrounds us determine the perception of threads and opportunities.

As long as during chemical development or production, solid‐state‐caused obstacles can be overcome by some, maybe magic and not really understood, measures that everything is fine or, more precisely, appears to be fine, at least for the moment. No further resources, time, and money are invested to understand the cause–effect relations. How long will this satisfaction for saving money last? Who is eventually paying the bill for lack of thoroughly understanding the processes and interdependencies? The advice is to implement solid‐state experts into CMC or other development and processing teams. Taking the advantage and benefit from the different perspective, they can add to discussions and innovations.

In the past 20–30 years, solid‐state development became more and more important in the pharmaceutical industry. Many treatises in print and online cover a broad variety of aspects that can be subsumed under the roof of solid‐state development. This concerns not just molecules that are API but also many other compounds classified as fine chemicals, agrochemicals, explosives, or those having a relevance for nutrition products. The eye‐catching word is mainly “polymorphism” that, along with similar terms like “polymorph” and “pseudo‐polymorph” or terms often discussed in the context like “hydrate”, “solvate”, “salt”, “cocrystal”, “co‐crystal”, or “amorphous”, was and still is worthwhile to cause attention.

The attention culminated to a hype that has today become a scientific and commercial important field of sound investigation to ensure proper development and subsequent successful marketability of products in general. However, in the world of pharmaceuticals, the interest is beyond commercial aspects related to ensuring safety and efficacy of the products dedicated to reduce suffering from diseases or curing patients.

Consequently, many stakeholders are involved in solid‐state research, development, manufacturing, and commercialization. But it is also the other way round. Chemists and pharmacists who are active in the field of development and processing of solid compounds have lots of interfaces to other departments from which they get or to whom they deliver information and materials as exemplified for a crystallization laboratory in Figure 1.1.

Figure 1.1 The crystallization laboratory – integrated in pharmaceutical development and manufacturing.

Obviously, every single discipline can consider itself as the most important and thus justifies its position in the center of this representative arrangement. Actually, the center of Figure 1.1 only represents the point of view and maybe the self‐conception. Solid‐state development, particularly for pharmaceutical applications, is a complex and ever‐changing setup involving and needing lots of disciplines for successfully mastering the development and manufacturing workflows.

Looking behind the scenes, stepping somewhat back from the science but without neglecting the importance of a sound understanding of the basics and the implementation of solid‐state‐related processes is the intention of the following chapters constituting this edition. Every chapter was contributed by someone who is an expert in his or her particular field, someone who illuminates the aspects of his or her domain with the awareness of being a part of the whole. While reading the chapters, consider its topic as standing in the center of the arrangement (Figure 1.1). Development and processing of solid compounds and forms is apparently enlightened from different perspectives. Therefore, some aspects are covered not just by one author. When there is light, then there is shadow. Not every aspect can be treated, especially because the chapters were intentionally written from a subjective standpoint and perspective. Personal preferences, experiences, and peculiarities directed the content. Other perspectives and considerations may well exist.

Solid‐state development and processing is nothing that can be handled as an isolated aspect of pharmaceutical R&D or manufacturing, although a lack of general understanding of the foundations, disregarding the essential impact the solid state has on process and eventually product quality, is surprisingly still around in the industries.

This is understandable from one perspective. Dedicated experts are typically required to address the many topics showing up in the course of pharmaceutical research and particular pharmaceutical development and manufacturing. All of them are well trained and have skills in their particular sciences or businesses. Education at university is focusing on the formation of domain experts. As a drawback, less time is typically available to look to the left and to the right, forward and beyond of the own field of expertise.

As a consequence, all those experts eventually involved in versatile R&D and manufacturing teams have the duty to ensure that their colleagues (or “interfaces”) also get an understanding of the impact of their particular field of expertise for the whole process and vice versa. All participants in R&D and manufacturing processes have the obligation to accentuate the need and significance of the topics addressed by themselves and their laboratories or departments. There is a necessity for people having the capability to act as coaches, teachers, and trainers; devoted to their field of expertise but not trapped therein; on the contrary, open minded and willing to share knowledge. People dedicated to draft, construct, and maintain their part of the development and production, as well as of business processes.

Getting the knowledge out of the heads. What is important to share? What should others know about your business? Besides sciences, what is also important to communicate to make industrial and commercially oriented environments work?

The intention is to cover the most essential topics in industrial, mainly pharmaceutical, environments that are related to the manifold of properties and characteristics solid compounds have.

1.1.3 Societal Impact – Fishing in Foreign Waters

The societal impact or the impact of society – human being are creating the society they live in and individuals are formed by the society they live in. Dealing with societal, economical, and historical impact on science and business is typically not a field harvested by a solid‐state expert. Other businesses and sciences treating sociological relations, management, or national economy usually consider topics like this. Professionals in these fields have experiences, tools, and know the sources for research and how to investigate developments and interrelations. Therefore, the following is layman's reflection on societal aspects.

1.1.3.1 Motivation

Why trying to cover this topic? First, because it is interesting. Second, it has some relevance to start with this consideration now. As long as individuals are present who eyewitnessed or even designed the initial pharmaceutical solid‐state development, or worked on the implementation of the current status, it is possible to get insights not just based on figures and statistics. They can talk and report about motivations, desires, challenges, dead ends, hopes, and obstacles. The dimension of personal experiences and observations is important and worth to be told.

A comparison might help. It is a bit as if a chemist, well educated and trained in organic chemistry, attempts to cover topics related to solid‐state aspects, like designing a crystallization process or investigating a solid‐state landscape. Why are not the experts doing the job? Answers are manifold: “Not a big task, let's just have a look”, or there is no solid‐state expert around, or the expert is packed with other projects, or nobody is aware that a solid‐state expert would probably have a different perspective and appropriate education, better tools, and experiences to do the job.

Usually the attempt to “just let's do it” fails. It might lead to some results. Maybe that these results are good enough to decide that, probably at a first glance, no further investigation is necessary or meaningful. Time will show whether the project dies or whether it is interesting enough to follow up.

“Just let's do it” reflects the approach in this part of the section to consider mutual interaction between people or society and pharmaceutical solid‐state chemistry. Unfortunately, these economical and societal aspects of pharmaceutical solid‐state development and about the historical development‐related interactions between society and science are not yet covered accordingly. There is a hope that in future someone will do so properly.

While reflecting this challenge with others, the response was like “who could be interested and would spent time on reading?” Maybe nobody is interested. However, there are always people acting for some years in their field of expertise and have observed and contributed to changes. Certainly, these individuals are curious to read a summary and a reflection about the topic and fields of expertise they spent years of their lives on.

The likelihood for realizing such a project is naturally larger for widespread general topics like computer technology or popular sciences like flights to the moon, exemplified by [2–6].

The hope is that someone picks up the idea and starts with economical, societal, and historical research on this small but important niche in pharmaceutical science with more adequate means, knowledge, and resources than attempted here.

1.1.3.2 The Personal Dimension

Any action consequently leads to a reaction. Probably, every student of natural science has heard in the first physics lectures about Isaac Newton who formulated this as his third law of motion “Law III: To every action there is always opposed an equal reaction: or the mutual actions of two bodies upon each other are always equal, and directed to contrary parts” [7].

This consideration is not limited to physical bodies moving in the three‐dimensional physical world. There is also always an impact in a nonmaterial sense, an impact on ideas, thoughts, and desires. This impact is the essence of advancement in general and technological progress in particular. Realization of progress is only possible because the fourth dimension, time, is also affected. Progress is not possible without a change of states in time. The qualitative and quantitative identification of change is only possible if a prior state is compared to a later state of a system or society.

Being asked by one of the series editors if I am interested to edit a book on pharmaceutical solid‐state development, it took me a while to make my decision. I wondered, what can I, what can we as authors, contribute to the society of solid‐state experts or community of people who strive to learn about solid‐state development and processing that has not yet been reported before? Moreover, it was not just me among the authors who has asked himself this question.

Before I decided to dive into this project, my understanding was that everything of importance for investigating the solid state was already told. In this very moment, while typing these lines and editing the contributions of the other authors, I am convinced that this is certainly not the case.

For sure, progress is always made and there will always be new developments and new inventions and discoveries, as in all sciences. In addition, there will be old, sometimes forgotten, stories told in a new fashion. Actually, this is not what I had in mind.

What in particular is untold is our subjective perception and perspective. Having the opportunity to write from and about someone's subjective position in this area is an argument that is convincing to start editing and writing. The burden and chance to communicate our very personal view on the “Solid‐State development and processing of pharmaceutical molecules” is appreciated. We have the chance to communicate about those aspects and topics we personally consider of being of interest and value for the community. We have the chance, and responsibility, to make a personal selection of scientific themes, topics, references, and examples that are worthwhile to address in the context of industrial tasks. We have the chance to act, to influence, and impact. This will for sure lead to reactions: affirmative or contrary. Regardless of its nature, every reaction will itself be of further impact on personal thinking and therefore on thinking of the community.

This is already a societal impact of solid‐state development. People, certainly not for the first time, agreed to spend a significant part of their time to restitute partly to the society what they received from others. There were many who taught and trained them to acquire and prosper particularly specialized and sometimes singular and rare skills. The motivation that drives each individually can be manifold. It might be the chance to spread the personal view, it might be the chance to summarize and share a particular sequence of business life, it might also be to face a particular personal challenge, and it might well be the option to publish and to promote personal career. It might be something else or a mixture of the preceding. These willing authors differentiated themselves from those who objected to contribute. Some of those who rejected concluded a personal calculation that taking the time to contribute is not what they like to do or that it would not pay off for them or their business. Some questioned if anyone might read the chapter, the book. Some were stopped by illnesses, by other duties, or by supervisors who preferred seeing them to work (in a more direct manner) for the company or protected them to not burn themselves. Solid‐state development and processing as well as many of the other branches in the pharmaceutical value chain with all their facets have for sure a societal impact and are impacted by society.

1.1.3.3 Beyond the Impact on Individuals

The aforementioned addresses the personal dimension of societal impact. There is another dimension, an even larger one worth to be addressed. What is the impact that the investigation of the solid state has on organizations? How do these organizations act, develop, and influence science, regulations, businesses, and consequently societies?

It was Albert Einstein who realized that the experience of a chronological sequence, which we usually call history, depends on the perspective of the observer and whether events appear to be (i.e. are) simultaneous or one after the other. Apart from this relativistic point of view on events, the speed of experiencing and learning for human beings is usually chronological. “Standing on the shoulder of giants”, often attributed to Isaac Newton, but going back at least to the twelfth century [8], summarizes how the accumulation of knowledge and progress establishes. Individuals learn from and build on the experiences of others. The essence of enterprises, often praised, sometimes forgotten (as reflected by the term human resources), is the sum of all the individuals working for these companies. One way to reflect on their collective achievements is that economical figures illustrate the financial value of a company. Besides, there is also a social value. There are examples where the social value of an organization correlates with the economic value [9].

1.1.3.4 Understanding the Market – Not an Easy Task

In particular, the pharmaceutical industry in Europe itself, represented by the European Federation of Pharmaceutical Industries and Associations (EFPIA), annually presents their economic and societal contribution [10,11].

There are other potential sources for data, like statistical offices. Unfortunately, figures are usually not broken down to an extent where the impact of solid‐state‐related activities becomes visible. This same issue occurs with official statistical data acquired, for example, by the German statistical office (Statistisches Bundesamt, DESTATIS) as published in the GENESIS‐online database (https://www-genesis.destatis.de) or the European Commission as published in the Eurostat database (https://ec.europa.eu/eurostat/web/science-technology-innovation/data/database).

Because the categories are very generally defined (see Table 1.1), no information can be derived and assigned particularly to the impact of such a niche like “solid‐state activities” on turnover or number of employees.

Table 1.1 Categories in the German DESTATIS GENESIS‐online database (as of 2019‐08‐14).

Code

Content (category)

Translation of content

WZ08‐72

Forschung und Entwicklung

Research and Development

WZ08‐721

Forschg.u.Entwicklg. in Natur‐u.ä. Wissenschaften

Research and Development in natural and similar sciences

WZ08‐7211

Forschung und Entwicklung in Biotechnologie

Research and Development in biotechnology

WZ08‐7219

Sonstige Forschg.u.Entwicklg. von Naturwiss. u.Ä.

Other Research and Development in natural and similar sciences

WZ08‐74

Sonst. freiberufl.,wissenschaftl. u. techn.Tätigk.

Other self‐employed, scientific, and technical activities

Even harder it is to get corporate data broken down to the affect and effect of pharmaceutical solid‐state activities. According to national laws, companies may have the obligation to publish their financial results. In Germany, e.g. public companies (AG) listed on the stock exchange and companies with limited liability (GmbH) disclose their accounting documents on a yearly basis to the operator of the Federal Gazette (i.e. Bundesanzeiger) or deposit them in the business register (i.e. Handelsregister) [12]. The data can be accessed via the Internet [13].

Following this approach to get insights into the historical development of solid‐state‐related businesses, it has to be taken into account that the level of detail is quite coarse as it lists the cumulative financial results of the enterprises per year. Therefore, possibly none of the financial figures can be attributed to solid‐state departments or even smaller working groups being just a part of a bigger chemical or pharmaceutical company.

Nevertheless, if the business of a company is mainly focused on solid‐state‐related services, the historical financial figures of this company can be considered, with some approximation, to reflect the development of solid‐state services over the years. Maybe not as a representative pars pro toto but at least as an example.

On the German market, the company Solid‐Chem GmbH, located in Bochum, is one of these focused companies. According to the company philosophy [14], they investigate the solid‐state chemistry of products and offer consulting and scientific support with also covering aspects dealing with drug products (DPs). Data about the company are available in the Bundesanzeiger. The company may serve, at least for the period of data published, as an example that reflects, based on its financial results, the necessity and importance of solid‐state investigations and services for the chemical and pharmaceutical industry. Unfortunately, data published in the Bundesanzeiger are not as comprehensive and telling as one might wish. In general, nothing is said about the number of employees and the wages paid nor is there information on the types of projects.

Another indication for the increased interest in pharmaceutical solid‐state activities is the acquisition of companies formerly specialized in the investigations of solid‐state topics and their implementation into larger contract development and manufacturing organizations (CDMO), exemplified by

SSCI, originally founded in 1991, acquired in 2006 by Aptuit, and since 2015 a division of

Albany Molecular Research

(

AMRI

).

Crystallics, originally founded in 2000, acquired by Ardena in 2016.

In the years between, the solid‐state facilities were part of several splits and mergers.

Pharmorphix, originally founded in 2003, acquired by Johnson Mathey in 2015.

Solid Forms Solutions, acquired by Avista Pharma early in 2018 subsequently acquired by Cambrex end of 2018.

Another observation is expansion of formerly focused expertise into service providers with an extended portfolio as well as formation of associations, as there are, for example,

Solvias

Crysforma, as part of

ICIQ

(

Institut Catalá d'Investigació Quimica

)

APC

CMAC

Although there are examples that the pharmaceutical industry divests solid‐state expertise, several CDMO have established in‐house solid‐state expertise to support development and manufacturing but may or may not offer this expertise as a separate service for third parties.

1.1.3.5 Benefits of an Interdisciplinary Mindset

There may be other approaches to get telling data. Maybe professional data providers or chemical or pharmaceutical societies have a deeper insight into the figures of their individual or corporate members. Maybe newspapers or major business consulting companies have a database that might give more answers about the societal impact and impact on society if properly analyzed and publicly distributed. Business, literature, or patent databases may, and certainly do, serve as a source, and the contents might be crawled by data mining algorithms. Data analytical tools could eventually process the results with respect to

publications, posters, conferences, whitepapers, webinars, and seminars

business figures, financial data, merger & acquisitions

applications, granted patents, application status (active, inactive)

dates, to put everything in chronological order

occurrence of terms in title, abstract, description, example, and claim

terms like polymorphism, salt, cocrystal, modification, Form A … Form Z, Form I … Form XVIIIC, Form α … Form Ω, and so on

various solid‐state characterization techniques

companies, assignees, inventors

… and more …

… and combinations thereof

As an example to demonstrate, the opportunities of combining several sources like patent and financial data may serve the valuation analysis for Norvasc® in which the attractiveness, i.e. sales threshold, to circumvent a secondary salt patent was estimated for products in the United States to be about $1.5 bn [15].

Such results combined with insights gained from sociological or historical research might generate new knowledge and understanding of relationships. This will certainly happen if data use rights and privacy laws allow and someone identifies a financial advantage or business case.

1.1.4 The Basis for Mutual Understanding

Terms used in science typically get a definition to provide a common base for conversation. Unfortunately, different actors think that different definitions are meaningful and correct to express the situation. Therefore, a range of definitions for terms evolve throughout time and space and a jargon is formed, while we are permanently exchanging thoughts to simplify and speed up communication and interaction.

Figure 1.2 illustrates an attempt to categorize the diversity of solid forms. Various potential combinations of solids can be formed by combining single components. In principle, the following categories apply:

Nature of compound

Degree of crystallinity (amorphous–crystalline; i.e. unordered–ordered)

Number of components (single–multiple) and ratio

Type of components (liquid–solid; aqueous–nonaqueous)

Nature of bonding, type of interaction (ionic–π–π interaction–van der Waals)

Number of solid forms having the same composition (polymorphism)

Homogeneity (purity, ideality) of the solid arrangement (pure–mixed phases; solid solutions)

Figure 1.2 The complexity of solid compounds in pharmaceutical applications. Amended chart based on Aitipamula et al. [16].

To make the image complete, combine elements from these categories.

A consideration of basic principles, terms, and aspects is provided and discussed throughout the years in details elsewhere, exemplified, without claiming completeness, by [17–35] and all the references mentioned therein.

The following sections and chapters emphasize some of the prerequisites and aspects to provide a base for a better understanding for solid‐state aspects of small molecules and the enormous impact on chemical and pharmaceutical development and processing.

1.1.5 Crystallization is a Separation, Not a Separated Process

Crystallization is the separation process that leads to solid crystalline material and is as such, together with other separation techniques, responsible for 40–90% of the spent capital and operating costs of industrial production [36].

Why crystallization? Crystallization is an acknowledged and well‐established purification step suitable to deplete impurities like by‐products, unreacted reagents, catalysts, or residual solvents introduced by the preceding synthesis. Therefore, crystallization is a perfectly suited unit operation to separate valuable material from waste or material that is supposed to be used in other value chains.

Moreover, why crystalline solid material? Materials in crystalline solid state generally exhibit superior stability properties than in amorphous or liquid state. Alteration processes like decomposition and chemical reaction (e.g. oxidation) are reduced due to low mobility of the constituents compared with amorphous or liquid state.

In course of the organic synthesis and the subsequent crystallization procedure, the solid material is in the suspension still in contact with solvent and impurities from the reaction. At this stage, in the slurry, changes in the solid form may continue to happen. Thermodynamically, more stable forms can evolve from metastable modifications or solvate formation can happen since at lower temperature another region of stability might have been reached. Due to increased concentration unintended precipitation of byproducts or impurities can happen or addition compounds may form.