Solid state development and processing of pharmaceutical molecules: salts, cocrystals, and polymorphism
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| Sprache: | English |
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Weinheim
WILEY-VCH
[2022]
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| Schriftenreihe: | Methods and principles in medicinal chemistry
volume 79 |
| Schlagworte: | |
| Online-Zugang: | Kurzbeschreibung Inhaltsverzeichnis |
| Beschreibung: | xxiv, 548 Seiten Illustrationen, Diagramme 24.4 cm x 17 cm |
| ISBN: | 352734635X 9783527346356 |
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| 245 | 1 | 0 | |a Solid state development and processing of pharmaceutical molecules |b salts, cocrystals, and polymorphism |c edited by Michael Gruss |
| 264 | 1 | |a Weinheim |b WILEY-VCH |c [2022] | |
| 264 | 4 | |c © 2022 | |
| 300 | |a xxiv, 548 Seiten |b Illustrationen, Diagramme |c 24.4 cm x 17 cm | ||
| 336 | |b txt |2 rdacontent | ||
| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 490 | 1 | |a Methods and principles in medicinal chemistry |v volume 79 | |
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| 653 | |a Chemical Engineering | ||
| 653 | |a Chemie | ||
| 653 | |a Chemische Verfahrenstechnik | ||
| 653 | |a Chemistry | ||
| 653 | |a Drug Formulation & Delivery | ||
| 653 | |a Industrial Chemistry | ||
| 653 | |a Process Engineering | ||
| 653 | |a Prozesssteuerung | ||
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Datensatz im Suchindex
| _version_ | 1804182529838678016 |
|---|---|
| adam_text | CONTENTS
SERIES
EDITORS
PREFACE
XXI
PREFACE
XXIII
1
ASPECTS
FOR
DEVELOPING
AND
PROCESSING
SOLID
FORMS
1
MICHAEL
GRUSS
1.1
1.1.1
1.1.2
1.1.3
1.1.3.1
1.1.3.2
1.1.3.3
1.1.3.4
1.1.3.5
1.1.4
1.1.5
1.1.6
1.1.7
1.1.7.1
1.1.7.2
ASPECTS
FOR
DEVELOPING
AND
PROCESSING
SOLID
FORMS
1
INTRODUCTION
1
EDUCATION
AND
PERSONAL
BACKGROUND
1
SOCIETAL
IMPACT
-
FISHING
IN
FOREIGN
WATERS
4
MOTIVATION
4
THE
PERSONAL
DIMENSION
5
BEYOND
THE
IMPACT
ON
INDIVIDUALS
6
UNDERSTANDING
THE
MARKET
-
NOT
AN
EASY
TASK
7
BENEFITS
OF
AN
INTERDISCIPLINARY
MINDSET
9
THE
BASIS
FOR
MUTUAL
UNDERSTANDING
9
CRYSTALLIZATION
IS
A
SEPARATION,
NOT
A
SEPARATED
PROCESS
11
SOME
EARLY
INFORMATION
ABOUT
SOLID-STATE
PROPERTIES
13
DIGITALIZATION
(NOT
ONLY)
IN
THE
LABORATORY
13
PREREQUISITES
-
TECHNOLOGY
AND
PEOPLE
13
CONNECT
DATA
AND
THE
RIGHT
INFORMATION
FROM
SYNTHESIS
AND
ANALYSIS
15
1.1.7.3
1.1.7.4
1.1.7.5
1.1.8
1.1.8.1
1.1.8.2
1.1.8.3
CONTRIBUTIONS
AND
CHOICES
17
APPLICATION
OF
DIGITALIZATION
18
FULLY
DIGITALIZED
INFRASTRUCTURE
20
BASIC
TERMS
AND
CONCEPTS
IN
THE
WORLD
OF
SOLID
STATE
21
CRYSTALLINE
AND
AMORPHOUS
21
CRYSTALLIZATION
AND
PRECIPITATION
23
UNDERSTANDING
THE
PHASE
DIAGRAM
-
ANALYTICAL
CHARACTERIZATION
OF
THE
SOLID-LIQUID
AND
SOLID-SOLID
SYSTEMS
23
1.1.8.4
1.1.8.5
POLYMORPHISM
24
MULTI-COMPONENT
COMPOUNDS
-
SALT,
COCRYSTAL,
SOLVATE,
AND
HYDRATE
25
1.1.8.6
SOLVATES,
HYDRATES,
NON-SOLVATED
FORMS,
OR
ANSOLVATES
26
VI
CONTENTS
1.1.8.7
DISPERSED
PRIMARY
PARTICLES,
AGGREGATES,
AND
AGGLOMERATES
29
1.1.8.8
PARTICLE
SIZE
AND
PARTICLE
SIZE
DISTRIBUTION
(PSD)
29
1.1.9
INVESTIGATING
AND
UNDERSTANDING
THE
POLYMORPHIC
LANDSCAPE
29
1.1.10
PERFORMING
THE
CRYSTALLIZATION
31
1.1.11
OBJECTIVES
FOR
THE
OPTIMIZATION
OF
CRYSTALLIZATION
PROCESSES
AND
SOLID-STATE
PROPERTIES
32
1.1.12
IMPLEMENTATION
OF
IN
SILICO
AND
SIMULATION
TECHNIQUES
32
1.1.13
SAVING
THE
INVESTMENT
-
ADDRESSING
INTELLECTUAL
PROPERTY
RIGHTS
35
1.1.14
CONCLUDING
REMARKS
36
LIST
OF
ABBREVIATIONS
37
REFERENCES
38
2
DETERMINATION
OF
CURRENT
KNOWLEDGE
45
ANDRIY
KUZMOV
AND
RONAK
SAVLA
2.1
WHY
IS
IT
IMPORTANT
TO
SEARCH
FOR
RELEVANT
INFORMATION
BEFORE
STARTING
A
SOLID-STATE
PROJECT?
45
2.2
WHERE
TO
BEGIN
A
LITERATURE
SEARCH
FOR A
SOLID-STATE
PROJECT?
47
2.2.1
LITERATURE
SEARCH
48
2.2.1.1
FOCUSING
YOUR
LITERATURE
SEARCH
49
2.2.2
STAYING
ON
TOP
OF
THE
LATEST
PUBLICATIONS
51
2.3
PATENT
SEARCH
51
2.3.1
TYPES
OF
PATENT
REPORTS
52
2.3.2
UNDERSTANDING
THE
ELEMENTS
OF
PATENTS
53
2.3.3
PATENT
CLASSIFICATION
54
2.3.4
PATENT
DATABASES
56
2.3.4.1
FREE
PATENT
DATABASES
57
2.4
OTHER
USEFUL
RESOURCES
FOR
SOLID-STATE
PROJECTS
61
2.4.1
CAMBRIDGE
STRUCTURAL
DATABASE
61
2.4.2
CRYSTALLOGRAPHY
OPEN
DATABASE
62
LIST
OF
ABBREVIATIONS
62
REFERENCES
63
3
SYSTEMATIC
SCREENING
AND
INVESTIGATION
OF
SOLID-STATE
LANDSCAPES
67
ULRIKE
WERTHMANN
3.1
INTRODUCTION
67
3.2
GENERAL
ASPECTS
OF
SOLID-STATE
INVESTIGATIONS
IN
EARLY
DRUG
DISCOVERY
PHASE
68
3.3
TRANSITION
PHASE
FROM
LATE
STAGE
RESEARCH
TO
EARLY
STAGE
DEVELOPMENT
69
3.4
SOLID-STATE
CHARACTERISTICS
IN
PRECLINICAL
FORMULATIONS
70
3.5
API-CRYSTALLIZATION
STRATEGY
IN
CANDIDATE
PROFILING
PHASE
73
3.6
SELECTION
CRITERIA
OF
A
SUITABLE
SOLID
FORM
77
3.7
KNOWLEDGE
MANAGEMENT
79
3.8
CONTROL
OF
SOLID
FORM
PROPERTIES
IN
DEVELOPMENT
79
CONTENTS
|
VII
3.9
EXPLORATORY
CRYSTALLIZATION
EXPERIMENTS
80
LIST
OF
ABBREVIATIONS
87
REFERENCES
88
4.1
SOLID-STATE
CHARACTERIZATION
TECHNIQUES:
MICROSCOPY
91
LUIS
ALMEIDA
E
SOUSA
AND
CONSTANTA
CACELA
4.1.1
MICROSCOPY
91
4.1.1.1
OPTICAL
MICROSCOPY
91
4.1.1.1.1
BRIGHT-FIELD
MICROSCOPY
92
4.1.1.1.2
DARK-FIELD
MICROSCOPY
93
4.1.1.1.3
POLARIZED LIGHT
MICROSCOPY
93
4.1.1.1.4
OTHER
OPTICAL
MICROSCOPY
VARIANTS
95
4.1.1.2
ELECTRON
MICROSCOPY
96
4.1.1.2.1
SCANNING
ELECTRON
MICROSCOPY
96
4.1.1.2.2
TRANSMISSION
ELECTRON
MICROSCOPY
100
4.1.1.3
ATOMIC
FORCE
MICROSCOPY
101
4.1.1.4
MICROSCOPY
IN
REGULATORY
DOCUMENTS
103
LIST
OF
ABBREVIATIONS
103
REFERENCES
104
4.2
STANDARDS
AND
TRENDS
IN
ANALYTICAL
CHARACTERIZATION
-
X-RAY
DIFFRACTION
(XRD)
107
CLEMENS
KUHN
4.2.1
X-RAY
DIFFRACTION
107
4.2.1.1
INTRODUCTION
107
4.2.1.2
MEASUREMENT
PRINCIPLES
108
4.2.1.2.1
THE
CRYSTAL
LATTICE
108
4.2.1.2.2
THE
SPACE
GROUP
SYMMETRY
108
4.2.1.2.3
WHAT
DETERMINES
A
DIFFRACTION
PEAK
109
4.2.1.2.4
X-RAY
SCATTERING
TECHNICS
110
4.2.2
TECHNICS
110
4.2.2.1
SINGLE
CRYSTAL
X-RAY
DIFFRACTION
110
4.2.2.2
POWDER
X-RAY
DIFFRACTION
111
4.2.2.2.1
ALTERNATIVE
METHODS
FOR
STRUCTURE
DETERMINATION
111
4.2.3
INSTRUMENTATION
112
4.2.3.1
X-RAY
SOURCES
112
4.2.3.2
DIFFRACTOMETER
GEOMETRIES
113
4.2.3.2.1
REFLECTION
GEOMETRY
113
4.2.3.2.2
TRANSMISSION
GEOMETRY
114
4.2.3.2.3
BENCHTOP DIFFRACTOMETERS
115
4.2.3.3
DETECTORS
115
4.2.3.4
PEAK
ASYMMETRY
115
4.2.3.5
REPRODUCIBILITY
OF
DIFFRACTION
PATTERNS:
THE
TEXTURE
EFFECT
(PREFERRED
ORIENTATION)
116
4.2.3.6
DATABASES
OF
KNOWN
DIFFRACTION
PATTERNS
118
VIII
CONTENTS
4.2.4
MEASUREMENT
118
4.2.4.1
INSTRUMENT
CALIBRATION
118
4.2.4.2
SAMPLE
PREPARATION
119
4.2.5
DATA
EVALUATION
119
4.2.5.1
QUALITATIVE
PHASE
ANALYSIS
119
4.2.5.1.1
PHASE
IDENTIFICATION
OR
IDENTITY
CHECK
120
4.2.5.1.2
AMORPHOUS
CONTENT
121
4.2.5.2
QUANTIFICATION
122
4.2.5.2.1
BASED
ON
CALIBRATION
CURVE
123
4.2.5.2.2
BASED
ON
INTERNAL
STANDARD
ADDITION
123
4.2.5.23
BASED
ON
RIETVELD
REFINEMENT
123
4.2.53
ADVANCED
PHASE
ANALYSIS
124
LIST
OF
ABBREVIATIONS
125
REFERENCES
125
FURTHER
READING
127
4.3
STANDARDS
AND
TRENDS
IN
SOLID-STATE
CHARACTERIZATION
TECHNIQUES
-
THERMAL
ANALYSIS
129
JUERGEN
THUN
AND
NIKOLAUS
MARTIN
4.3.1
INTRODUCTION
129
4.3.2
THERMAL
ANALYSIS
IN
DRUG
DEVELOPMENT
130
4.3.2.1
SOLID
FORM
LANDSCAPE
130
43.2.2
COMPATIBILITY
STUDIES
130
4.3.23
OTHER
APPLICATIONS
130
4.3.3
METHODS
131
4.33.1
DIFFERENTIAL
SCANNING
CALORIMETRY
131
4.33.1.1
TECHNIQUES
131
4.33.1.2
SAMPLE
PREPARATION
AND
MEASURING
PARAMETERS
131
4.3.3.13
EVALUATION
132
4.33.1.4
SPECIAL
APPLICATIONS
134
4.33.1.5
DETECTION
LIMITS
134
4.33.2
THERMOGRAVIMETRIC
ANALYSIS
134
4.33.2.1
TECHNIQUE
134
4.33.2.2
SAMPLE
PREPARATION
AND
MEASURING
PARAMETERS
135
4.3.3.23
EVALUATION
135
4.33.2.4
SPECIAL
APPLICATIONS
136
4.3.4
CASE
STUDIES
136
43.4.1
UNDERSTANDING
POLYMORPHIC
TRANSITIONS
136
43.4.2
THE
POWER
OF
ULTRA-FAST
HEATING
RATES
139
4.3.43
UNDERSTANDING
AMORPHOUS
PHASES
141
43.4.4
IDENTIFICATION
OF
SOLVATE
STRUCTURES
142
4.3.5
QUALITY
AND
REGULATORY
ASPECTS
144
4.3.6
OUTLOOK
145
ACKNOWLEDGMENTS
146
CONTENTS
IX
LIST
OF
ABBREVIATIONS
146
NOTES
146
REFERENCES
146
4.4
STANDARDS
AND
TRENDS
IN
SOLID-STATE
CHARACTERIZATION
TECHNIQUES:
INFRARED
(IR)
SPECTROSCOPY
151
DAGMAR
LISCHKE
4.4.1
INFRARED
(IR)
SPECTROSCOPY
151
4.4.1.1
INTRODUCTION
151
4.4.1.2
IR
SPECTROSCOPY
AS
IDENTITY
METHOD
FOR
DRUG
SUBSTANCES
152
4.4.1.2.1
TRANSMISSION
MODE
152
4.4.1.2.2
ATTENUATED
TOTAL
REFLECTANCE
(ATR)
152
4.4.1.2.3
SAMPLE
PREPARATION
153
4.4.1.2.4
ANALYSIS
AND
REPORTING
153
4.4.1.2.5
EXAMPLES
AND
LIMITATIONS
154
4.4.1.2.6
METHOD
VALIDATION
OF
IR
SPECTROSCOPY
IDENTIFICATION
AND
QUANTIFICATION
METHODS
155
4.4.1.3
APPLICATION
OF
IR
MICROSCOPY-IMAGING
METHODS
IN
DRUG
DEVELOPMENT
156
4.4.1.3.1
SPATIAL
RESOLUTION
156
4.4.1.3.2
MEASUREMENT
SETUPS
157
4.4.1.3.3
CASE
STUDIES
158
4.4.1.4
CONCLUSION
162
LIST
OF
ABBREVIATIONS
162
REFERENCES
163
4.5
TRANSMISSION
RAMAN
SPECTROSCOPY
-
IMPLEMENTATION
IN
PHARMACEUTICAL
QUALITY
CONTROL
165
MEIKE
ROMER
4.5.1
RAMAN
SPECTROSCOPY
-
FROM
RESEARCH
TO
BROAD
APPLICATIONS
IN
INDUSTRY
165
4.5.1.1
OBJECTIVE
165
4.5.1.1.1
HISTORY
165
4.5.1.1.2
INTRODUCTION
165
4.5.1.1.3
THE
RAMAN
EFFECT
166
4.5.2
ANALYTICAL
USE
OF
RAMAN
SPECTROSCOPY
FOR
PHARMACEUTICAL
PURPOSES
167
4.5.2.1
TRANSMISSION
RAMAN
SPECTROSCOPY
(TRS)
167
4.5.2.1.1
PRINCIPLES
OF
TRANSMISSION
RAMAN
SPECTROSCOPY
168
4.5.2.1.2
A
PRACTICAL
GUIDE
TO
A
SUCCESSFUL
BUSINESS
CASE
171
4.5.3
TRANSMISSION
RAMAN
SPECTROSCOPY
-
ANOTHER
PRACTICAL
GUIDE
173
4.5.3.1
EVALUATION
PHASE
174
4.5.3.1.1
PREFEASIBILITY
EVALUATION
174
4.5.3.1.2
FEASIBILITY
OF
A
PRODUCT
176
4.5.3.2
TRANSMISSION
RAMAN
METHOD
DEVELOPMENT
177
X|
CONTENTS
4.5.3.2.1
TRANSMISSION
RAMAN
SPECTROSCOPIC
METHOD
DEVELOPMENT
177
4.5.3.2.2
RISK
ANALYSIS
179
4.5.3.2.3
TRANSMISSION
RAMAN
MODEL
DEVELOPMENT,
CALIBRATION,
AND
VALIDATION
180
4.5.4
REGULATORY
ASSESSMENT
AND
GUIDELINES
180
LIST
OF
ABBREVIATIONS
181
REFERENCES
182
4.6
SOLID-STATE
CHARACTERIZATION
TECHNIQUES:
PARTICLE
SIZE
185
MARIA
PAISANA
AND
CONSTANTA
CACELA
4.6.1
INTRODUCTION
185
4.6.2
ANALYTICAL
METHODOLOGIES
USED
TO
MEASURE
PARTICLE
SIZE
187
4.6.2.1
SEDIMENTATION
187
4.6.2.2
ELECTROZONE
SENSING
187
4.6.2.3
SIEVING
188
4.6.2.4
MICROSCOPY
188
4.6.2.5
DYNAMIC
LIGHT
SCATTERING
188
4.6.2.6
LASER
DIFFRACTION
189
4.6.3
METHOD
DEVELOPMENT
FOR
PRECISE
PARTICLE-SIZE
MEASUREMENTS
BY
LASER
DIFFRACTION
189
4.6.3.1
INSTRUMENTATION
AND
MEASUREMENT
189
4.6.3.2
SELECTION
OF
AN
APPROPRIATE
OPTICAL
MODEL
190
4.6.3.3
SAMPLE
DISPERSION
191
4.6.3.3.1
WET
DISPERSION
192
4.6.3.3.2
DRY
DISPERSION
194
4.6.3.4
SAMPLE
REPRESENTATIVENESS
AND
OBSCURATION
195
4.6.3.5
READINESS
FOR
METHOD
VALIDATION
196
4.6.4
UNEXPECTED
RESULTS
AND
TROUBLESHOOTING
IN
LASER
DIFFRACTION
MEASUREMENT
197
4.6.4.1
INCONSISTENT
DISCONNECTED
PEAKS
197
4.6.4.2
REPEATABLE
ARTIFACT
PEAKS
199
LIST
OF
ABBREVIATIONS
199
REFERENCES
200
4.7
MICRO
COMPUTATIONAL
TOMOGRAPHY
203
SUSANA
CAMPOS
AND
CONSTANTA
CACELA
4.7.1
TOMOGRAPHY
IMAGING
TECHNIQUES
203
4.7.2
MICRO
X-RAY
COMPUTED
TOMOGRAPHY
SCAN
203
4.7.2.1
THE
USE
OF
CT
IN
THE
PHARMACEUTICAL
INDUSTRY
204
4.7.2.1.1
PCT
APPLIED
TO
DENSITY
DISTRIBUTION
AND
POROUS
CHARACTERIZATION
205
4.7.2.1.2
PCT
APPLIED
FOR
CHARACTERIZATION
OF
STRUCTURAL
FEATURES:
SIZE,
SHAPE,
AND
DIMENSIONS
AND
INTERFACES
207
4.7.2.1.3
PCT
APPLIED
TO
COATING
CHARACTERIZATION
207
4.7.2.1.4
PCT
APPLIED
TO
PERFORMANCE
EVALUATION
209
CONTENTS
XI
4.7.2.1.5
FOREIGN
MATTER
DETECTION
BY
PCT
210
LIST
OF
ABBREVIATIONS
211
NOTES
211
REFERENCES
211
4.8
IN
SITU
METHODS
FOR
MONITORING
SOLID-STATE
PROCESSES
IN
MOLECULAR
MATERIALS
215
ADAM
A.
L.
MICHALCHUK,
ANKE
KABELITZ,
AND
FRANZISKA
EMMERLING
4.8.1
IN
SITU
METHODS
FOR
MONITORING
SOLID-STATE
PROCESSES
IN
MOLECULAR
MATERIALS
215
4.8.1.1
THE
COMPLEXITY
OF
SOLID
MATERIALS
215
4.8.1.2
METHODS
TO
CONSIDER
216
4.8.1.3
METHODS
TO
MONITOR
CRYSTALLIZATION
KINETICS
FROM
SOLUTION
218
4.8.1.3.1
UV-VIS
SPECTROSCOPY
218
4.8.1.3.2
INFRARED
SPECTROSCOPY
219
4.8.1.4
MONITORING
CRYSTALLIZATION
FROM
SOLUTION:
FOLLOWING
SOLID
PRODUCT
FORMATION
221
4.8.1.4.1
LIGHT
SCATTERING
221
4.8.1.5
METHODS
TO
MONITOR
EXTRINSIC
SOLID
PROPERTIES
224
4.8.1.5.1
ACOUSTIC
EMISSION
224
4.8.1.5.2
THERMOGRAPHY
226
4.8.1.6
METHODS
TO
MONITOR
INTRINSIC
SOLID
PROPERTIES
228
4.8.1.6.1
X-RAY
DIFFRACTION
228
4.8.1.6.2
RAMAN
SPECTROSCOPY
232
4.8.1.7
BENEFITS
OF
COMBINING
METHODS
FOR
IN
SITU
MONITORING
236
4.8.1.8
SUMMARY
240
LIST
OF
ABBREVIATIONS
242
REFERENCES
243
4.9
APPLICATION
OF
PROCESS
MONITORING
AND
MODELING
249
JOCHEN
SCHOELL
AND
ROBERTO
IRIZARRY
4.9.1
IN-PROCESS
SOLID
FORM
MONITORING
TECHNIQUES
249
4.9.1.1
DIRECT
CHARACTERIZATION
TECHNIQUES
250
4.9.1.1.1
RAMAN
SPECTROSCOPY
250
4.9.1.1.2
NEAR
INFRARED
SPECTROSCOPY
252
4.9.1.2
INDIRECT
MONITORING
TOOLS
254
4.9.1.2.1
FOCUSED
BEAM
REFLECTANCE
MEASUREMENT
(FBRM)
254
4.9.1.2.2
MONITORING
PARTICLE
SHAPE
USING
IN-PROCESS
MICROSCOPY
256
4.9.1.2.3
MONITORING
SOLUTE
CONCENTRATION
256
4.9.1.3
ADVANTAGES
AND
CHALLENGES
OF
IN
SITU
SOLID
FORM
MONITORING
TECHNIQUES
257
4.9.2
QUANTIFICATION
METHODS
AND
APPLICATION
TO
SOLID
FORM
TRANSFORMATION
MODELING
258
4.9.2.1
MULTIVARIATE
DATA
ANALYSIS
259
XII
CONTENTS
4.9.2.2
4.9.2.3
DATA-DRIVEN
MODEL
FOR
CLD-PSD
PREDICTION
260
PROCESS
MODELING
OF
POLYMORPH
TRANSFORMATION
PROCESSES
262
LIST
OF
ABBREVIATIONS
265
REFERENCES
266
4.10
PHOTON
DENSITY
WAVE
(PDW)
SPECTROSCOPY
FOR
NANO
AND
MICROPARTICLE
SIZING
271
LENA
BRESSEL
AND
ROLAND
HASS
4.10.1
4.10.2
4.10.3
CLASSIFICATION
OF
PARTICLE
SIZING
TECHNOLOGIES
271
PARTICLE
SIZE
AND
SOLID
FRACTION
RANGES
272
PHOTON
DENSITY
WAVE
(PDW)
SPECTROSCOPY
-
THEORY,
INSTRUMENTATION,
AND
APPLICATION
EXAMPLES
275
4.10.4
4.10.5
4.10.6
4.10.7
4.10.7.1
4.10.7.2
4.10.8
PARTICLE
SIZING
BY
PDW
SPECTROSCOPY
277
SAMPLE
VERSUS
PROCESS
MEASUREMENTS
280
TECHNICAL
IMPLEMENTATION
AND
DATA
ACCESS
281
EXAMPLES
FOR
PROCESS
ANALYSIS
WITH
PDW
SPECTROSCOPY
282
CRYSTALLIZATION
OF
LACTOSE
283
PRECIPITATION
OF
BARIUM
SULFATE
284
SUMMARY
285
LIST
OF
ABBREVIATIONS
286
REFERENCES
287
5
IMPACT
OF
SOLID
FORMS
ON
API
SCALE-UP
289
SOPHIE
JANBON,
CLARE
MAYES,
AND
AMY
L.
ROBERTSON
5.1
5.2
5.3
5.3.1
5.3.2
5.3.2.1
5.3.2.2
5.3.2.3
5.3.3
5.3.3.1
5.3.3.2
5.3.3.3
5.3.4
5.4
5.4.1
5.4.1.1
5.4.1.2
5.4.1.3
5.4.1.4
5.4.1.5
INTRODUCTION
289
BACKGROUND
290
SMALL-SCALE
CRYSTALLIZATION
DEVELOPMENT
291
FORM
SELECTION
291
SOLVENT
SELECTION
293
SOLVENT
SCREENING
293
SOLUBILITY
DIAGRAM
294
SOLUBILITY
MEASUREMENT
295
CRYSTALLIZATION
PROCESS
SELECTION
298
PROCESS
OUTLINE
SELECTION
298
PROCESS
OUTLINE
EVALUATION
299
PROCESS
EXPLORATION
300
PROCESS
DEVELOPMENT
CONCLUSIONS
302
CRYSTALLIZATION
SCALE-UP
302
CRYSTALLIZATION
PROCESS
ACCOMMODATION
303
VESSEL
SIZE
AND
MOC
304
AGITATION
304
HEAT
TRANSFER
305
SOLUTION
ADDITION
305
SOLID
ADDITION
305
CONTENTS
XIII
5.4.1.6
ALTERNATIVE
TECHNOLOGIES
306
5.4.2
RISKS
AND
COMMON
PROBLEMS
307
5.4.2.1
METASTABLE
FORMS
307
5.4.2.2
AMORPHOUS
307
5.4.2.3
SALT
STOICHIOMETRY
308
5.4.2.4
OILING
AND
PHASE
SEPARATIONS
308
5.4.3
ISOLATION
AND
DRYING
308
5.4.3.1
ISOLATION
309
5.4.3.2
DRYING
311
5.4.4
AGGLOMERATION
314
5.4.5
PARTICLE
SIZE
REDUCTION
314
5.4.5.1
DELUMPING
314
5.4.5.2
MILLING
AND
MICRONIZATION
314
5.4.5.3
STORAGE
AND
PACKING
315
5.4.6
SCALE-UP
CONCLUSIONS
315
5.5
PEOPLE
AND
SKILL
REQUIREMENTS
315
5.6
REGULATORY
REQUIREMENTS
315
5.6.1
PROCESS
DOCUMENTATION
316
5.6.2
SAFETY
316
5.6.3
QUALITY
AND
MANUFACTURABILITY
316
5.7
CLOSING
REMARKS
317
LIST
OF
ABBREVIATIONS
318
REFERENCES
318
6
IMPACT
ON
DRUG
DEVELOPMENT
AND
DRUG
PRODUCT
PROCESSING
325
SUSANNE
PAGE
AND
ANIKO
SZEPES
6.1
INTRODUCTION
325
6.2
PHARMACEUTICAL
PROFILING
327
6.3
FORMULATION
DEVELOPMENT
330
6.3.1
LIQUID
FORMULATIONS:
SOLUTIONS
AND
SUSPENSIONS
332
6.3.2
SOLID
DOSAGE
FORMS
335
6.3.3
SOLUBILITY
ENHANCED
FORMULATIONS
339
6.3.3.1
LIPID-BASED
FORMULATIONS
AND
DRUG
DELIVERY
SYSTEMS
339
63.3.2
SOLID
SOLUTIONS
AND
AMORPHOUS
SOLID
DISPERSIONS
343
6.4
PROCESS
DEVELOPMENT
AND
TRANSFER
TO
COMMERCIAL
MANUFACTURING
344
6.4.1
PARTICLE
SIZE
REDUCTION
345
6.4.2
BLENDING
345
6.4.3
GRANULATION
345
6.4.3.1
WET
GRANULATION
AND
DRYING
346
6.43.2
DRY
GRANULATION/ROLLER
COMPACTION
347
6.4.4
TABLET
COMPRESSION
347
6.4.5
FILM
COATING
348
6.5
CONTROL
STRATEGY
348
XIV
CONTENTS
6.6
REGULATORY
SUBMISSIONS
349
LIST
OF
ABBREVIATIONS
352
REFERENCES
353
7
WORKFLOW
MANAGEMENT
365
CHRISTIAN
GROFIE
7.1
7.2
7.3
7.3.1
7.3.2
7.3.3
7.3.4
7.4
7.4.1
7.4.2
7.4.3
7.4.4
7.4.5
7.4.6
7.4.7
7.4.8
7.4.9
7.4.10
7.4.11
7.4.11.1
7.4.11.2
7.4.11.3
7.4.12
7.4.13
7.5
7.5.1
7.5.2
7.5.3
7.5.4
7.5.5
7.6
7.7
7.7.1
7.7.2
7.7.3
7.7.4
7.7.5
7.7.6
7.7.7
MOTIVATION
365
WORKFLOW
MANAGEMENT
365
ORGANIZATION
OF
SOLID-STATE
DEVELOPMENT
BY
PROJECT
MANAGEMENT
366
STAKEHOLDERS
366
CMC
PROJECT
MANAGEMENT
367
SUBSTANCE
REQUIREMENT
PLAN
368
PRE-CMC
DATA
369
WORKFLOWS
IN
THE
ENVIRONMENT
OF
THE
CRYSTALLIZATION
LABORATORY
369
MICRO-PROJECT
MANAGEMENT
369
DEPENDENCIES
370
MATERIAL
FLOW
371
DESIGNATIONS
AND
CODE
ASSIGNMENT
371
ANALYTIC
DATABASE
SYSTEM
373
PHYSICAL
SAMPLE
TRANSFER
375
ANALYTIC
TRANSFER
TOOL
375
ANALYTICAL
PROCESSES
-
TIMELY
MEASUREMENT
376
SAMPLE
STORAGE
PROCESSES
377
DOCUMENTATION
378
REVIEW
PROCESS
FOR
ELN
DOCUMENTS
379
DOCUMENT
STATUS
379
MANUAL
ELN
REVIEW
PROCESS
380
ARCHIVE
PROCESS
381
COMMUNICATION
WITH
CROS
381
FUNDAMENTAL
LAB
PROCESSES
382
PROCESSES
IN
THE
SOLID-STATE
LAB
382
INITIAL
TESTING
382
SOLUBILITY
ESTIMATION
384
MANUAL
SCREENING
384
HIGH-THROUGHPUT
SCREENING
385
PROCESSES
FOR
REPLICA
EXPERIMENTS
AND
SCALE-UP
OF
SOLID
FORMS
387
DEVELOPMENT
OF
CRYSTALLIZATION
PROCESSES
387
SUPPORT
PROCESSES
388
ROUTE
SCOUTING
PROCESS
389
CRYSTALLIZATION
OF
IMPURITIES
AND
INTERMEDIATES
389
DOWNSTREAM
PROCESSES
389
SCALE-UP
AND
TECHNOLOGY
TRANSFER
PROCESS
390
ANALYTICAL
DEVELOPMENT
390
PREFORMULATION
391
FORMULATION
391
CONTENTS
I
XV
7.8
CONCLUSION
392
LIST
OF
ABBREVIATIONS
393
REFERENCES
393
8
DIGITALIZATION
IN
LABORATORIES
OF
THE
PHARMACEUTICAL
INDUSTRY
397
TANJA
S.
PICKER
8.1
INTRODUCTION
397
8.2
MOTIVATION
OF
DIGITALIZATION
IN
THE
LABORATORY
398
8.2.1
EXPECTATIONS
OF
THE
STAFF
398
8.2.2
INCREASING
THROUGHPUT
400
8.2.3
REPEATABILITY
400
8.2.4
ENHANCED
REQUIREMENTS
ON
DATA
INTEGRITY
400
8.2.5
CENTRALIZED
ARCHIVING
401
8.2.6
AD
HOC
ANALYSIS
401
8.2.7
THE
VALUE
OF
DATA
402
8.3
CATEGORIES
OF
LABORATORY
IT
SYSTEMS
403
8.3.1
DEVICES
403
8.3.2
LAB
EXECUTION
SYSTEMS
(LES)
AND
SCIENTIFIC
DATA
MANAGEMENT
SYSTEMS
(SDMS)
404
8.3.3
LAB
DATA
SYSTEMS
404
8.3.4
ENTERPRISE
RESOURCE
PLANNING
(ERP)
405
8.3.5
FURTHER
USE
OF
DATA
405
8.3.5.1
DATA
ANALYSIS
AND
REPORTING
405
8.3.5.2
BIG
DATA
ANALYTICS
AND
ARTIFICIAL
INTELLIGENCE
406
8.4
SYSTEM
INTERFACES
FOR
DATA
EXCHANGE
406
8.4.1
ADAPTERS
407
8.4.1.1
SERIAL
PORT
(RS232)
407
8.4.1.2
UNIVERSAL
SERIES
BUS
(USB)
407
8.4.1.3
ETHERNET
407
8.4.1.4
CABLE
LESS
CONNECTIONS
407
8.4.2
COMMUNICATION
MEDIUM
AND
PROTOCOLS
408
8.4.2.1
FILE-BASED
COMMUNICATION
408
8.4.2.2
ANSI/ISA-88
BATCH
CONTROL
(S-88)
408
8.4.2.3
OPEN
PLATFORM
COMMUNICATIONS
UNIFIED
ARCHITECTURE
(OPC
UA)
408
8.4.2.4
STANDARDS
IN
LAB
AUTOMATION
(SILA)
408
8.4.3
DATA
FORMATS
409
8.4.3.1
COMMON
DATA
FORMATS
(E.G.
TXT,
XML,
JSON)
409
8.4.3.2
ANALYTICAL
INFORMATION
MARKUP
LANGUAGE
(ANIML)
409
8.4.3.3
ALLOTROPE
DATA
FORMAT
(ADF)
410
8.5
IMPLEMENTATION
OF
IT
SOLUTIONS
411
8.5.1
IDENTIFICATION
OF
DIGITAL
GAPS
IN
THE
LAB
PROCESSES
411
8.5.1.1
CONTEXTUAL
INQUIRY
411
8.5.1.2
INTERACTION
ROOM
411
8.5.2
IMPLEMENTATION
APPROACH
412
XVI
CONTENTS
8.5.2.1
DESIGN
413
8.5.2.2
REALIZATION
415
8.5.2.3
VERIFICATION
415
8.5.2.4
ROLLOUT
416
8.6
CONCLUSION
416
LIST
OF
ABBREVIATIONS
416
REFERENCES
417
9.1
POLYMORPHS
AND
PATENTS
-
THE
US
PERSPECTIVE
421
KRISTI
MCINTYRE
9.1.1
INTRODUCTION
421
9.1.2
WHAT
IS
A
PATENT?
421
9.1.3
HOW
ARE
PATENTS
OBTAINED?
422
9.1.4
UNITED
STATES
PATENT
LAW
422
9.1.4.1
TAPENTADOL
HYDROCHLORIDE
423
9.1.4.1.1
TAPENTADOL
HYDROCHLORIDE
FORM
A
HELD
NOT
OBVIOUS
423
9.1.4.1.2
TAPENTADOL
HYDROCHLORIDE
FORM
A
WAS
FOUND
TO
HAVE
UTILITY
424
9.1.4.2
PAROXETINE
HYDROCHLORIDE
HEMIHYDRATE
424
9.1.4.2.1
PHC
HEMIHYDRATE
HISTORY
425
9.1.4.2.2
MEANING
OF
CRYSTALLINE
PAROXETINE
HYDROCHLORIDE
HEMIHYDRATE
425
9.1.4.2.3
PHC
HEMIHYDRATE:
INFRINGED,
BUT INVALID
FOR
ANTICIPATION
426
9.1.4.3
RANITIDINE
HYDROCHLORIDE
426
9.1.4.3.1
HISTORY
OF
RHC1
FORM
2
426
9.1.4.3.2
RHC1
FORM
2
NOT
ANTICIPATED
BY
EXAMPLE
32
427
9.1.4.4
CEFDINIR
427
9.1.4.5
AMLODIPINE
BESYLATE
428
9.1.4.5.1
HISTORY
OF
AMLODIPINE
BESYLATE
428
9.1.4.5.2
AMLODIPINE
BESYLATE
FOUND
OBVIOUS
428
9.1.4.6
CONCLUDING
REMARKS
429
NOTES
429
REFERENCES
430
9.2
POLYMORPHS
AND
PATENTS
-
THE
EU
PERSPECTIVE
431
OLIVER
BROSCH
9.2.1
EUROPEAN
PATENT
APPLICATIONS
AND
EUROPEAN
PATENTS
431
9.2.1.1
INTRODUCTION
431
9.2.1.2
SUMMARY
OF
THE
PROCESSING
OF
APPLICATIONS
AND
PATENTS
BEFORE
THE
EUROPEAN
PATENT
OFFICE
(EPO)
431
9.2.1.3
ECONOMIC
FACTORS
432
9.2.1.4
UNITARY
PATENTS
433
9.2.1.5
PROTECTION
OF
POLYMORPHS
AND
SOLID
FORMS
IN
GENERAL
433
9.2.1.6
POLYMORPH
SCREENING
434
9.2.2
DECISIONS
OF
TECHNICAL
BOARDS
OF
APPEAL
OF
THE
EPO
435
9.2.2.1
DECISION
T
777/08
OF
24
MAY
2011
435
9.2.2.2
DECISION
T
1555/12
DATED
29
APRIL
2015
435
CONTENTS
XVII
9.2.23
DECISION
T
2114/13
DATED
12
OCTOBER
2016
442
9.2.2.4
DECISION
T
2397/12
DATED
12
MARCH
2018
442
9.2.2.5
DECISION
T
246/15
DATED
13
NOVEMBER
2018
442
9.2.3
JURISDICTION
OF
THE
FEDERAL
PATENT
COURT
AND
THE
GERMAN
FEDERAL
SUPREME
COURT
443
9.2.3.1
DECISION
KRISTALLFORMEN
GERMAN
FEDERAL
COURT
443
9.23.2
DECISION
XZR
58/08
DATED
15
MARCH
15
2011
443
9.2.33
DECISIONXZR
98/09
DATED
15
MAY
2012
444
9.23.4
DECISION
X
ZR
110/16
DATED
7
AUGUST
2018
444
9.2.4
ASSESSING
VALIDITY
OF
A
PATENT
OR
THE
CHANCES
OF
SUCCESS
445
9.2.5
INTERACTION
WITH
PATENT
PROFESSIONALS
446
LIST
OF
ABBREVIATIONS
447
REFERENCES
447
10
REGULATORY
FRAMEWORKS
AFFECTING
SOLID-STATE
DEVELOPMENT
449
CHRISTOPH
SEAL
10.1
INTRODUCTION
-
THE
NEED
FOR
REGULATION
IN
PHARMACEUTICAL
INDUSTRY
449
10.2
SOLID-STATE
FORMS
TO
BE
USED
FOR DRUGS
451
10.3
GENERAL
REGULATORY
CONSIDERATIONS
FOR
PHARMACEUTICAL
SOLID-STATE
FORMS
453
10.4
REGULATORY
FRAMEWORK
FOR
PHARMACEUTICAL
SALTS
454
10.4.1
PHARMACEUTICAL
EQUIVALENCE
AND
PHARMACEUTICAL
ALTERNATIVES
454
10.4.2
BIOEQUIVALENCE
456
10.4.3
THERAPEUTIC
EQUIVALENCE
458
10.4.4
BIOWAIVERS
458
10.4.5
REGULATORY
APPROVAL
FOR
PHARMACEUTICAL
SALTS
460
10.4.5.1
REGULATORY
APPROVAL
PATHWAYS
IN
THE
UNITED
STATES
460
10.4.5.2
REGULATORY
APPROVAL
PATHWAYS
IN
THE
EUROPEAN
UNION
461
10.4.6
REGULATORY
APPROVAL FOR POLYMORPHS
463
10.4.7
POLYMORPHISM
IN
PHARMACOPOEIAS
469
10.5
REGULATORY
FRAMEWORK
FOR
CO-CRYSTALS
471
10.6
SUMMARY
476
LIST
OF
ABBREVIATIONS
476
REFERENCES
477
11
OPPORTUNITIES
AND
CHALLENGES
FOR
GENERIC
DEVELOPMENT
FROM
A
SOLID-STATE
PERSPECTIVE
481
LUDITH
ARONHIME
AND
MIKE
TEILER
11.1
THE
BIRTH
OF
A
NEW
DRUG
AND
THE
GENERIC
SIBLINGS
THAT
WILL
FOLLOW
-
TWO
DIFFERENT
MINDSETS
481
11.1.1
GENERICS
481
11.1.2
PROPRIETARY
PRODUCTS
482
11.1.3
API
AND
SOLID
STATE
483
XVIII
CONTENTS
11.1.3.1
GENERICS
483
11.1.3.2
PROPRIETARY
483
11.2
PORTFOLIO
MANAGEMENT
-
HOW
IS
A
PORTFOLIO
CONSTRUCTED
AND
MAINTAINED?
484
11.2.1
ACTIVITIES
AND
TIMELINES
484
11.2.1.1
STRATEGY
484
11.2.1.2
VALUE
484
11.2.1.3
FACTORS
IMPACTING
ON
TIMING
-
WHEN
AND
HOW
DOES
A
PRODUCT
SHOW
UP
ON
A
GENERIC
COMPANY
S
RADAR
SCREEN?
485
11.2.2
TIMING
487
11.2.2.1
WHEN
IS
ON-TIME?
487
11.2.3
MARKET-SPECIFIC
CONSIDERATIONS
BASED
ON
LOCAL
LEGISLATION
AND
ADMINISTRATION
(OB,
PIV,
VARIOUS
EXCLUSIVITIES
-
US,
EU,
JP,
ETC.)
489
11.2.3.1
PATENTS
THROUGH
THE
EYES
OF
THE
REGULATORY
AUTHORITIES
489
11.2.3.2
DATA
EXCLUSIVITY
(DATA
PROTECTION)
489
11.2.3.3
SALTS
AND
ESTERS
490
11.2.3.4
THINK
GLOBAL,
ACT
LOCAL
490
11.2.4
SOURCES
TO
EVALUATE
A
PROJECT
491
11.2.4.1
GOVERNMENT
AND
REGULATORY
AGENCIES
491
11.2.4.2
ANALYST
REPORTS
AND
COMPANY
FINANCIAL
REPORTS
492
11.2.4.3
PAY
DATA
SOURCES
492
11.2.5
EVALUATION
TOOLS
493
11.2.5.1
BUSINESS
CASE
493
11.2.5.2
QUALITY
TARGET
PROJECT
PROFILE
(QTPP)
493
11.2.6
CRITERIA
FOR
IDENTIFYING
PROMISING
PROJECTS
493
11.2.7
CRITERIA
FOR
BUILDING A ROBUST
PORTFOLIO
494
11.3
CHALLENGES
IN
DEVELOPING
A
GENERIC
PRODUCT
FROM
THE
SOLID-STATE
PERSPECTIVE
495
11.3.1
IMPLICATIONS
IN
DEVELOPING
FORMULATION
WITH
A
METASTABLE
API
496
11.3.2
THE
STABILITY
QUESTION
497
11.3.2.1
POLYMORPHIC
STABILITY
IN
DRY
CONDITIONS
497
11.3.2.2
POLYMORPHIC
STABILITY
IN
WET
CONDITIONS
(SLURRY)
498
11.4
GENERIC
SOLID-STATE
DEVELOPMENT
498
11.4.1
GENERAL
498
11.4.2
PREDEVELOPMENT
PHASE:
SOLID-STATE
STRATEGY
499
11.4.2.1
REVIEW
OF
THE
SOLID
STATE,
ESPECIALLY
THE
POLYMORPH
PATENT
LANDSCAPE
499
11.4.2.2
DESIGN-AROUND
CONSIDERATIONS
500
11.4.3
CRYSTAL FORMS
DISCOVERY
503
11.4.3.1
IMPORTANCE
OF
THE
CRYSTAL
FORMS
DISCOVERY
STAGE
503
11.4.3.2
NEW
CRYSTAL
FORMS
UNPREDICTABILITY
503
11.4.3.3
PRAGMATIC
QUESTIONS
ABOUT
CRYSTAL
FORMS
SEARCH
504
11.4.3.4
LATE-APPEARING
POLYMORPHS
505
11.4.3.5
IRREPRODUCIBILITY
OF
PROCEDURES
506
11.4.3.6
ANALYTICAL
FOCUS
507
CONTENTS
XIX
11.4.4
TARGET
SELECTION
507
11.4.4.1
SOLUBILITY
508
11.4.4.2
MORPHOLOGY
509
11.4.4.3
SOLID-STATE
STABILITY
509
11.4.4.4
ADDITIONAL
FACTORS
509
11.4.5
PROCESS
DEVELOPMENT
IN
THE
LABORATORY
SCALE
510
11.4.5.1
PROCESS
DEVELOPMENT
510
11.4.5.2
THERMODYNAMIC
STABILITY
RELATIONSHIPS
510
11.4.5.3
SOLUBILITY
CURVES
510
11.4.5.4
API
TARGET
511
11.4.5.5
ANALYTICAL
METHODS
FOR
POLYMORPHIC
PURITY
512
11.4.6
SCALE-UP
CHALLENGES
512
11.4.6.1
CONTROL
OF
CRYSTAL
FORM
512
11.4.6.2
CONTROL
OF
PARTICLE
SIZE
AND
MORPHOLOGY
513
11.4.6.3
LOT-TO-LOT
VARIABILITY
513
11.4.6.4
ANALYTICAL
FOCUS
514
11.4.7
PHARMA
DEVELOPMENT
515
11.4.7.1
THE
TETRAHEDRON
PRINCIPLE
AND
CONSISTENCY
AMONG
LOTS
516
11.4.7.2
THE
EFFECT
OF
MICRONIZATION
ON
AMORPHOUS
CONTENT
IN
CRYSTALLINE
APIS
516
11.4.7.3
SOLID-STATE
STABILITY
UPON
STORAGE
517
11.4.8
IMPACT
ON
FORMULATION
517
11.4.9
SUMMARY
OF
TIMELINES
FOR
SOLID-STATE
ACTIVITY
518
11.4.10
INTELLECTUAL
PROPERTY
(IP)
STRATEGIES
AND
ACTIVITIES
519
11.5
SUCCESS
FACTORS
520
11.5.1
SUCCESSFUL
BIOSTUDY
520
11.5.2
SUCCESSFUL
LAUNCH
521
11.5.3
GENERIC
COMMERCIAL
SUCCESS
522
LIST
OF
ABBREVIATIONS
523
REFERENCES
524
INDEX
531
|
| adam_txt |
CONTENTS
SERIES
EDITORS
PREFACE
XXI
PREFACE
XXIII
1
ASPECTS
FOR
DEVELOPING
AND
PROCESSING
SOLID
FORMS
1
MICHAEL
GRUSS
1.1
1.1.1
1.1.2
1.1.3
1.1.3.1
1.1.3.2
1.1.3.3
1.1.3.4
1.1.3.5
1.1.4
1.1.5
1.1.6
1.1.7
1.1.7.1
1.1.7.2
ASPECTS
FOR
DEVELOPING
AND
PROCESSING
SOLID
FORMS
1
INTRODUCTION
1
EDUCATION
AND
PERSONAL
BACKGROUND
1
SOCIETAL
IMPACT
-
FISHING
IN
FOREIGN
WATERS
4
MOTIVATION
4
THE
PERSONAL
DIMENSION
5
BEYOND
THE
IMPACT
ON
INDIVIDUALS
6
UNDERSTANDING
THE
MARKET
-
NOT
AN
EASY
TASK
7
BENEFITS
OF
AN
INTERDISCIPLINARY
MINDSET
9
THE
BASIS
FOR
MUTUAL
UNDERSTANDING
9
CRYSTALLIZATION
IS
A
SEPARATION,
NOT
A
SEPARATED
PROCESS
11
SOME
EARLY
INFORMATION
ABOUT
SOLID-STATE
PROPERTIES
13
DIGITALIZATION
(NOT
ONLY)
IN
THE
LABORATORY
13
PREREQUISITES
-
TECHNOLOGY
AND
PEOPLE
13
CONNECT
DATA
AND
THE
RIGHT
INFORMATION
FROM
SYNTHESIS
AND
ANALYSIS
15
1.1.7.3
1.1.7.4
1.1.7.5
1.1.8
1.1.8.1
1.1.8.2
1.1.8.3
CONTRIBUTIONS
AND
CHOICES
17
APPLICATION
OF
DIGITALIZATION
18
FULLY
DIGITALIZED
INFRASTRUCTURE
20
BASIC
TERMS
AND
CONCEPTS
IN
THE
WORLD
OF
SOLID
STATE
21
CRYSTALLINE
AND
AMORPHOUS
21
CRYSTALLIZATION
AND
PRECIPITATION
23
UNDERSTANDING
THE
PHASE
DIAGRAM
-
ANALYTICAL
CHARACTERIZATION
OF
THE
SOLID-LIQUID
AND
SOLID-SOLID
SYSTEMS
23
1.1.8.4
1.1.8.5
POLYMORPHISM
24
MULTI-COMPONENT
COMPOUNDS
-
SALT,
COCRYSTAL,
SOLVATE,
AND
HYDRATE
25
1.1.8.6
SOLVATES,
HYDRATES,
NON-SOLVATED
FORMS,
OR
ANSOLVATES
26
VI
CONTENTS
1.1.8.7
DISPERSED
PRIMARY
PARTICLES,
AGGREGATES,
AND
AGGLOMERATES
29
1.1.8.8
PARTICLE
SIZE
AND
PARTICLE
SIZE
DISTRIBUTION
(PSD)
29
1.1.9
INVESTIGATING
AND
UNDERSTANDING
THE
POLYMORPHIC
LANDSCAPE
29
1.1.10
PERFORMING
THE
CRYSTALLIZATION
31
1.1.11
OBJECTIVES
FOR
THE
OPTIMIZATION
OF
CRYSTALLIZATION
PROCESSES
AND
SOLID-STATE
PROPERTIES
32
1.1.12
IMPLEMENTATION
OF
IN
SILICO
AND
SIMULATION
TECHNIQUES
32
1.1.13
SAVING
THE
INVESTMENT
-
ADDRESSING
INTELLECTUAL
PROPERTY
RIGHTS
35
1.1.14
CONCLUDING
REMARKS
36
LIST
OF
ABBREVIATIONS
37
REFERENCES
38
2
DETERMINATION
OF
CURRENT
KNOWLEDGE
45
ANDRIY
KUZMOV
AND
RONAK
SAVLA
2.1
WHY
IS
IT
IMPORTANT
TO
SEARCH
FOR
RELEVANT
INFORMATION
BEFORE
STARTING
A
SOLID-STATE
PROJECT?
45
2.2
WHERE
TO
BEGIN
A
LITERATURE
SEARCH
FOR A
SOLID-STATE
PROJECT?
47
2.2.1
LITERATURE
SEARCH
48
2.2.1.1
FOCUSING
YOUR
LITERATURE
SEARCH
49
2.2.2
STAYING
ON
TOP
OF
THE
LATEST
PUBLICATIONS
51
2.3
PATENT
SEARCH
51
2.3.1
TYPES
OF
PATENT
REPORTS
52
2.3.2
UNDERSTANDING
THE
ELEMENTS
OF
PATENTS
53
2.3.3
PATENT
CLASSIFICATION
54
2.3.4
PATENT
DATABASES
56
2.3.4.1
FREE
PATENT
DATABASES
57
2.4
OTHER
USEFUL
RESOURCES
FOR
SOLID-STATE
PROJECTS
61
2.4.1
CAMBRIDGE
STRUCTURAL
DATABASE
61
2.4.2
CRYSTALLOGRAPHY
OPEN
DATABASE
62
LIST
OF
ABBREVIATIONS
62
REFERENCES
63
3
SYSTEMATIC
SCREENING
AND
INVESTIGATION
OF
SOLID-STATE
LANDSCAPES
67
ULRIKE
WERTHMANN
3.1
INTRODUCTION
67
3.2
GENERAL
ASPECTS
OF
SOLID-STATE
INVESTIGATIONS
IN
EARLY
DRUG
DISCOVERY
PHASE
68
3.3
TRANSITION
PHASE
FROM
LATE
STAGE
RESEARCH
TO
EARLY
STAGE
DEVELOPMENT
69
3.4
SOLID-STATE
CHARACTERISTICS
IN
PRECLINICAL
FORMULATIONS
70
3.5
API-CRYSTALLIZATION
STRATEGY
IN
CANDIDATE
PROFILING
PHASE
73
3.6
SELECTION
CRITERIA
OF
A
SUITABLE
SOLID
FORM
77
3.7
KNOWLEDGE
MANAGEMENT
79
3.8
CONTROL
OF
SOLID
FORM
PROPERTIES
IN
DEVELOPMENT
79
CONTENTS
|
VII
3.9
EXPLORATORY
CRYSTALLIZATION
EXPERIMENTS
80
LIST
OF
ABBREVIATIONS
87
REFERENCES
88
4.1
SOLID-STATE
CHARACTERIZATION
TECHNIQUES:
MICROSCOPY
91
LUIS
ALMEIDA
E
SOUSA
AND
CONSTANTA
CACELA
4.1.1
MICROSCOPY
91
4.1.1.1
OPTICAL
MICROSCOPY
91
4.1.1.1.1
BRIGHT-FIELD
MICROSCOPY
92
4.1.1.1.2
DARK-FIELD
MICROSCOPY
93
4.1.1.1.3
POLARIZED LIGHT
MICROSCOPY
93
4.1.1.1.4
OTHER
OPTICAL
MICROSCOPY
VARIANTS
95
4.1.1.2
ELECTRON
MICROSCOPY
96
4.1.1.2.1
SCANNING
ELECTRON
MICROSCOPY
96
4.1.1.2.2
TRANSMISSION
ELECTRON
MICROSCOPY
100
4.1.1.3
ATOMIC
FORCE
MICROSCOPY
101
4.1.1.4
MICROSCOPY
IN
REGULATORY
DOCUMENTS
103
LIST
OF
ABBREVIATIONS
103
REFERENCES
104
4.2
STANDARDS
AND
TRENDS
IN
ANALYTICAL
CHARACTERIZATION
-
X-RAY
DIFFRACTION
(XRD)
107
CLEMENS
KUHN
4.2.1
X-RAY
DIFFRACTION
107
4.2.1.1
INTRODUCTION
107
4.2.1.2
MEASUREMENT
PRINCIPLES
108
4.2.1.2.1
THE
CRYSTAL
LATTICE
108
4.2.1.2.2
THE
SPACE
GROUP
SYMMETRY
108
4.2.1.2.3
WHAT
DETERMINES
A
DIFFRACTION
PEAK
109
4.2.1.2.4
X-RAY
SCATTERING
TECHNICS
110
4.2.2
TECHNICS
110
4.2.2.1
SINGLE
CRYSTAL
X-RAY
DIFFRACTION
110
4.2.2.2
POWDER
X-RAY
DIFFRACTION
111
4.2.2.2.1
ALTERNATIVE
METHODS
FOR
STRUCTURE
DETERMINATION
111
4.2.3
INSTRUMENTATION
112
4.2.3.1
X-RAY
SOURCES
112
4.2.3.2
DIFFRACTOMETER
GEOMETRIES
113
4.2.3.2.1
REFLECTION
GEOMETRY
113
4.2.3.2.2
TRANSMISSION
GEOMETRY
114
4.2.3.2.3
BENCHTOP DIFFRACTOMETERS
115
4.2.3.3
DETECTORS
115
4.2.3.4
PEAK
ASYMMETRY
115
4.2.3.5
REPRODUCIBILITY
OF
DIFFRACTION
PATTERNS:
THE
TEXTURE
EFFECT
(PREFERRED
ORIENTATION)
116
4.2.3.6
DATABASES
OF
KNOWN
DIFFRACTION
PATTERNS
118
VIII
CONTENTS
4.2.4
MEASUREMENT
118
4.2.4.1
INSTRUMENT
CALIBRATION
118
4.2.4.2
SAMPLE
PREPARATION
119
4.2.5
DATA
EVALUATION
119
4.2.5.1
QUALITATIVE
PHASE
ANALYSIS
119
4.2.5.1.1
PHASE
IDENTIFICATION
OR
IDENTITY
CHECK
120
4.2.5.1.2
AMORPHOUS
CONTENT
121
4.2.5.2
QUANTIFICATION
122
4.2.5.2.1
BASED
ON
CALIBRATION
CURVE
123
4.2.5.2.2
BASED
ON
INTERNAL
STANDARD
ADDITION
123
4.2.5.23
BASED
ON
RIETVELD
REFINEMENT
123
4.2.53
ADVANCED
PHASE
ANALYSIS
124
LIST
OF
ABBREVIATIONS
125
REFERENCES
125
FURTHER
READING
127
4.3
STANDARDS
AND
TRENDS
IN
SOLID-STATE
CHARACTERIZATION
TECHNIQUES
-
THERMAL
ANALYSIS
129
JUERGEN
THUN
AND
NIKOLAUS
MARTIN
4.3.1
INTRODUCTION
129
4.3.2
THERMAL
ANALYSIS
IN
DRUG
DEVELOPMENT
130
4.3.2.1
SOLID
FORM
LANDSCAPE
130
43.2.2
COMPATIBILITY
STUDIES
130
4.3.23
OTHER
APPLICATIONS
130
4.3.3
METHODS
131
4.33.1
DIFFERENTIAL
SCANNING
CALORIMETRY
131
4.33.1.1
TECHNIQUES
131
4.33.1.2
SAMPLE
PREPARATION
AND
MEASURING
PARAMETERS
131
4.3.3.13
EVALUATION
132
4.33.1.4
SPECIAL
APPLICATIONS
134
4.33.1.5
DETECTION
LIMITS
134
4.33.2
THERMOGRAVIMETRIC
ANALYSIS
134
4.33.2.1
TECHNIQUE
134
4.33.2.2
SAMPLE
PREPARATION
AND
MEASURING
PARAMETERS
135
4.3.3.23
EVALUATION
135
4.33.2.4
SPECIAL
APPLICATIONS
136
4.3.4
CASE
STUDIES
136
43.4.1
UNDERSTANDING
POLYMORPHIC
TRANSITIONS
136
43.4.2
THE
POWER
OF
ULTRA-FAST
HEATING
RATES
139
4.3.43
UNDERSTANDING
AMORPHOUS
PHASES
141
43.4.4
IDENTIFICATION
OF
SOLVATE
STRUCTURES
142
4.3.5
QUALITY
AND
REGULATORY
ASPECTS
144
4.3.6
OUTLOOK
145
ACKNOWLEDGMENTS
146
CONTENTS
IX
LIST
OF
ABBREVIATIONS
146
NOTES
146
REFERENCES
146
4.4
STANDARDS
AND
TRENDS
IN
SOLID-STATE
CHARACTERIZATION
TECHNIQUES:
INFRARED
(IR)
SPECTROSCOPY
151
DAGMAR
LISCHKE
4.4.1
INFRARED
(IR)
SPECTROSCOPY
151
4.4.1.1
INTRODUCTION
151
4.4.1.2
IR
SPECTROSCOPY
AS
IDENTITY
METHOD
FOR
DRUG
SUBSTANCES
152
4.4.1.2.1
TRANSMISSION
MODE
152
4.4.1.2.2
ATTENUATED
TOTAL
REFLECTANCE
(ATR)
152
4.4.1.2.3
SAMPLE
PREPARATION
153
4.4.1.2.4
ANALYSIS
AND
REPORTING
153
4.4.1.2.5
EXAMPLES
AND
LIMITATIONS
154
4.4.1.2.6
METHOD
VALIDATION
OF
IR
SPECTROSCOPY
IDENTIFICATION
AND
QUANTIFICATION
METHODS
155
4.4.1.3
APPLICATION
OF
IR
MICROSCOPY-IMAGING
METHODS
IN
DRUG
DEVELOPMENT
156
4.4.1.3.1
SPATIAL
RESOLUTION
156
4.4.1.3.2
MEASUREMENT
SETUPS
157
4.4.1.3.3
CASE
STUDIES
158
4.4.1.4
CONCLUSION
162
LIST
OF
ABBREVIATIONS
162
REFERENCES
163
4.5
TRANSMISSION
RAMAN
SPECTROSCOPY
-
IMPLEMENTATION
IN
PHARMACEUTICAL
QUALITY
CONTROL
165
MEIKE
ROMER
4.5.1
RAMAN
SPECTROSCOPY
-
FROM
RESEARCH
TO
BROAD
APPLICATIONS
IN
INDUSTRY
165
4.5.1.1
OBJECTIVE
165
4.5.1.1.1
HISTORY
165
4.5.1.1.2
INTRODUCTION
165
4.5.1.1.3
THE
RAMAN
EFFECT
166
4.5.2
ANALYTICAL
USE
OF
RAMAN
SPECTROSCOPY
FOR
PHARMACEUTICAL
PURPOSES
167
4.5.2.1
TRANSMISSION
RAMAN
SPECTROSCOPY
(TRS)
167
4.5.2.1.1
PRINCIPLES
OF
TRANSMISSION
RAMAN
SPECTROSCOPY
168
4.5.2.1.2
A
PRACTICAL
GUIDE
TO
A
SUCCESSFUL
BUSINESS
CASE
171
4.5.3
TRANSMISSION
RAMAN
SPECTROSCOPY
-
ANOTHER
PRACTICAL
GUIDE
173
4.5.3.1
EVALUATION
PHASE
174
4.5.3.1.1
PREFEASIBILITY
EVALUATION
174
4.5.3.1.2
FEASIBILITY
OF
A
PRODUCT
176
4.5.3.2
TRANSMISSION
RAMAN
METHOD
DEVELOPMENT
177
X|
CONTENTS
4.5.3.2.1
TRANSMISSION
RAMAN
SPECTROSCOPIC
METHOD
DEVELOPMENT
177
4.5.3.2.2
RISK
ANALYSIS
179
4.5.3.2.3
TRANSMISSION
RAMAN
MODEL
DEVELOPMENT,
CALIBRATION,
AND
VALIDATION
180
4.5.4
REGULATORY
ASSESSMENT
AND
GUIDELINES
180
LIST
OF
ABBREVIATIONS
181
REFERENCES
182
4.6
SOLID-STATE
CHARACTERIZATION
TECHNIQUES:
PARTICLE
SIZE
185
MARIA
PAISANA
AND
CONSTANTA
CACELA
4.6.1
INTRODUCTION
185
4.6.2
ANALYTICAL
METHODOLOGIES
USED
TO
MEASURE
PARTICLE
SIZE
187
4.6.2.1
SEDIMENTATION
187
4.6.2.2
ELECTROZONE
SENSING
187
4.6.2.3
SIEVING
188
4.6.2.4
MICROSCOPY
188
4.6.2.5
DYNAMIC
LIGHT
SCATTERING
188
4.6.2.6
LASER
DIFFRACTION
189
4.6.3
METHOD
DEVELOPMENT
FOR
PRECISE
PARTICLE-SIZE
MEASUREMENTS
BY
LASER
DIFFRACTION
189
4.6.3.1
INSTRUMENTATION
AND
MEASUREMENT
189
4.6.3.2
SELECTION
OF
AN
APPROPRIATE
OPTICAL
MODEL
190
4.6.3.3
SAMPLE
DISPERSION
191
4.6.3.3.1
WET
DISPERSION
192
4.6.3.3.2
DRY
DISPERSION
194
4.6.3.4
SAMPLE
REPRESENTATIVENESS
AND
OBSCURATION
195
4.6.3.5
READINESS
FOR
METHOD
VALIDATION
196
4.6.4
UNEXPECTED
RESULTS
AND
TROUBLESHOOTING
IN
LASER
DIFFRACTION
MEASUREMENT
197
4.6.4.1
INCONSISTENT
DISCONNECTED
PEAKS
197
4.6.4.2
REPEATABLE
ARTIFACT
PEAKS
199
LIST
OF
ABBREVIATIONS
199
REFERENCES
200
4.7
MICRO
COMPUTATIONAL
TOMOGRAPHY
203
SUSANA
CAMPOS
AND
CONSTANTA
CACELA
4.7.1
TOMOGRAPHY
IMAGING
TECHNIQUES
203
4.7.2
MICRO
X-RAY
COMPUTED
TOMOGRAPHY
SCAN
203
4.7.2.1
THE
USE
OF
CT
IN
THE
PHARMACEUTICAL
INDUSTRY
204
4.7.2.1.1
PCT
APPLIED
TO
DENSITY
DISTRIBUTION
AND
POROUS
CHARACTERIZATION
205
4.7.2.1.2
PCT
APPLIED
FOR
CHARACTERIZATION
OF
STRUCTURAL
FEATURES:
SIZE,
SHAPE,
AND
DIMENSIONS
AND
INTERFACES
207
4.7.2.1.3
PCT
APPLIED
TO
COATING
CHARACTERIZATION
207
4.7.2.1.4
PCT
APPLIED
TO
PERFORMANCE
EVALUATION
209
CONTENTS
XI
4.7.2.1.5
FOREIGN
MATTER
DETECTION
BY
PCT
210
LIST
OF
ABBREVIATIONS
211
NOTES
211
REFERENCES
211
4.8
IN
SITU
METHODS
FOR
MONITORING
SOLID-STATE
PROCESSES
IN
MOLECULAR
MATERIALS
215
ADAM
A.
L.
MICHALCHUK,
ANKE
KABELITZ,
AND
FRANZISKA
EMMERLING
4.8.1
IN
SITU
METHODS
FOR
MONITORING
SOLID-STATE
PROCESSES
IN
MOLECULAR
MATERIALS
215
4.8.1.1
THE
COMPLEXITY
OF
SOLID
MATERIALS
215
4.8.1.2
METHODS
TO
CONSIDER
216
4.8.1.3
METHODS
TO
MONITOR
CRYSTALLIZATION
KINETICS
FROM
SOLUTION
218
4.8.1.3.1
UV-VIS
SPECTROSCOPY
218
4.8.1.3.2
INFRARED
SPECTROSCOPY
219
4.8.1.4
MONITORING
CRYSTALLIZATION
FROM
SOLUTION:
FOLLOWING
SOLID
PRODUCT
FORMATION
221
4.8.1.4.1
LIGHT
SCATTERING
221
4.8.1.5
METHODS
TO
MONITOR
EXTRINSIC
SOLID
PROPERTIES
224
4.8.1.5.1
ACOUSTIC
EMISSION
224
4.8.1.5.2
THERMOGRAPHY
226
4.8.1.6
METHODS
TO
MONITOR
INTRINSIC
SOLID
PROPERTIES
228
4.8.1.6.1
X-RAY
DIFFRACTION
228
4.8.1.6.2
RAMAN
SPECTROSCOPY
232
4.8.1.7
BENEFITS
OF
COMBINING
METHODS
FOR
IN
SITU
MONITORING
236
4.8.1.8
SUMMARY
240
LIST
OF
ABBREVIATIONS
242
REFERENCES
243
4.9
APPLICATION
OF
PROCESS
MONITORING
AND
MODELING
249
JOCHEN
SCHOELL
AND
ROBERTO
IRIZARRY
4.9.1
IN-PROCESS
SOLID
FORM
MONITORING
TECHNIQUES
249
4.9.1.1
DIRECT
CHARACTERIZATION
TECHNIQUES
250
4.9.1.1.1
RAMAN
SPECTROSCOPY
250
4.9.1.1.2
NEAR
INFRARED
SPECTROSCOPY
252
4.9.1.2
INDIRECT
MONITORING
TOOLS
254
4.9.1.2.1
FOCUSED
BEAM
REFLECTANCE
MEASUREMENT
(FBRM)
254
4.9.1.2.2
MONITORING
PARTICLE
SHAPE
USING
IN-PROCESS
MICROSCOPY
256
4.9.1.2.3
MONITORING
SOLUTE
CONCENTRATION
256
4.9.1.3
ADVANTAGES
AND
CHALLENGES
OF
IN
SITU
SOLID
FORM
MONITORING
TECHNIQUES
257
4.9.2
QUANTIFICATION
METHODS
AND
APPLICATION
TO
SOLID
FORM
TRANSFORMATION
MODELING
258
4.9.2.1
MULTIVARIATE
DATA
ANALYSIS
259
XII
CONTENTS
4.9.2.2
4.9.2.3
DATA-DRIVEN
MODEL
FOR
CLD-PSD
PREDICTION
260
PROCESS
MODELING
OF
POLYMORPH
TRANSFORMATION
PROCESSES
262
LIST
OF
ABBREVIATIONS
265
REFERENCES
266
4.10
PHOTON
DENSITY
WAVE
(PDW)
SPECTROSCOPY
FOR
NANO
AND
MICROPARTICLE
SIZING
271
LENA
BRESSEL
AND
ROLAND
HASS
4.10.1
4.10.2
4.10.3
CLASSIFICATION
OF
PARTICLE
SIZING
TECHNOLOGIES
271
PARTICLE
SIZE
AND
SOLID
FRACTION
RANGES
272
PHOTON
DENSITY
WAVE
(PDW)
SPECTROSCOPY
-
THEORY,
INSTRUMENTATION,
AND
APPLICATION
EXAMPLES
275
4.10.4
4.10.5
4.10.6
4.10.7
4.10.7.1
4.10.7.2
4.10.8
PARTICLE
SIZING
BY
PDW
SPECTROSCOPY
277
SAMPLE
VERSUS
PROCESS
MEASUREMENTS
280
TECHNICAL
IMPLEMENTATION
AND
DATA
ACCESS
281
EXAMPLES
FOR
PROCESS
ANALYSIS
WITH
PDW
SPECTROSCOPY
282
CRYSTALLIZATION
OF
LACTOSE
283
PRECIPITATION
OF
BARIUM
SULFATE
284
SUMMARY
285
LIST
OF
ABBREVIATIONS
286
REFERENCES
287
5
IMPACT
OF
SOLID
FORMS
ON
API
SCALE-UP
289
SOPHIE
JANBON,
CLARE
MAYES,
AND
AMY
L.
ROBERTSON
5.1
5.2
5.3
5.3.1
5.3.2
5.3.2.1
5.3.2.2
5.3.2.3
5.3.3
5.3.3.1
5.3.3.2
5.3.3.3
5.3.4
5.4
5.4.1
5.4.1.1
5.4.1.2
5.4.1.3
5.4.1.4
5.4.1.5
INTRODUCTION
289
BACKGROUND
290
SMALL-SCALE
CRYSTALLIZATION
DEVELOPMENT
291
FORM
SELECTION
291
SOLVENT
SELECTION
293
SOLVENT
SCREENING
293
SOLUBILITY
DIAGRAM
294
SOLUBILITY
MEASUREMENT
295
CRYSTALLIZATION
PROCESS
SELECTION
298
PROCESS
OUTLINE
SELECTION
298
PROCESS
OUTLINE
EVALUATION
299
PROCESS
EXPLORATION
300
PROCESS
DEVELOPMENT
CONCLUSIONS
302
CRYSTALLIZATION
SCALE-UP
302
CRYSTALLIZATION
PROCESS
ACCOMMODATION
303
VESSEL
SIZE
AND
MOC
304
AGITATION
304
HEAT
TRANSFER
305
SOLUTION
ADDITION
305
SOLID
ADDITION
305
CONTENTS
XIII
5.4.1.6
ALTERNATIVE
TECHNOLOGIES
306
5.4.2
RISKS
AND
COMMON
PROBLEMS
307
5.4.2.1
METASTABLE
FORMS
307
5.4.2.2
AMORPHOUS
307
5.4.2.3
SALT
STOICHIOMETRY
308
5.4.2.4
OILING
AND
PHASE
SEPARATIONS
308
5.4.3
ISOLATION
AND
DRYING
308
5.4.3.1
ISOLATION
309
5.4.3.2
DRYING
311
5.4.4
AGGLOMERATION
314
5.4.5
PARTICLE
SIZE
REDUCTION
314
5.4.5.1
DELUMPING
314
5.4.5.2
MILLING
AND
MICRONIZATION
314
5.4.5.3
STORAGE
AND
PACKING
315
5.4.6
SCALE-UP
CONCLUSIONS
315
5.5
PEOPLE
AND
SKILL
REQUIREMENTS
315
5.6
REGULATORY
REQUIREMENTS
315
5.6.1
PROCESS
DOCUMENTATION
316
5.6.2
SAFETY
316
5.6.3
QUALITY
AND
MANUFACTURABILITY
316
5.7
CLOSING
REMARKS
317
LIST
OF
ABBREVIATIONS
318
REFERENCES
318
6
IMPACT
ON
DRUG
DEVELOPMENT
AND
DRUG
PRODUCT
PROCESSING
325
SUSANNE
PAGE
AND
ANIKO
SZEPES
6.1
INTRODUCTION
325
6.2
PHARMACEUTICAL
PROFILING
327
6.3
FORMULATION
DEVELOPMENT
330
6.3.1
LIQUID
FORMULATIONS:
SOLUTIONS
AND
SUSPENSIONS
332
6.3.2
SOLID
DOSAGE
FORMS
335
6.3.3
SOLUBILITY
ENHANCED
FORMULATIONS
339
6.3.3.1
LIPID-BASED
FORMULATIONS
AND
DRUG
DELIVERY
SYSTEMS
339
63.3.2
SOLID
SOLUTIONS
AND
AMORPHOUS
SOLID
DISPERSIONS
343
6.4
PROCESS
DEVELOPMENT
AND
TRANSFER
TO
COMMERCIAL
MANUFACTURING
344
6.4.1
PARTICLE
SIZE
REDUCTION
345
6.4.2
BLENDING
345
6.4.3
GRANULATION
345
6.4.3.1
WET
GRANULATION
AND
DRYING
346
6.43.2
DRY
GRANULATION/ROLLER
COMPACTION
347
6.4.4
TABLET
COMPRESSION
347
6.4.5
FILM
COATING
348
6.5
CONTROL
STRATEGY
348
XIV
CONTENTS
6.6
REGULATORY
SUBMISSIONS
349
LIST
OF
ABBREVIATIONS
352
REFERENCES
353
7
WORKFLOW
MANAGEMENT
365
CHRISTIAN
GROFIE
7.1
7.2
7.3
7.3.1
7.3.2
7.3.3
7.3.4
7.4
7.4.1
7.4.2
7.4.3
7.4.4
7.4.5
7.4.6
7.4.7
7.4.8
7.4.9
7.4.10
7.4.11
7.4.11.1
7.4.11.2
7.4.11.3
7.4.12
7.4.13
7.5
7.5.1
7.5.2
7.5.3
7.5.4
7.5.5
7.6
7.7
7.7.1
7.7.2
7.7.3
7.7.4
7.7.5
7.7.6
7.7.7
MOTIVATION
365
WORKFLOW
MANAGEMENT
365
ORGANIZATION
OF
SOLID-STATE
DEVELOPMENT
BY
PROJECT
MANAGEMENT
366
STAKEHOLDERS
366
CMC
PROJECT
MANAGEMENT
367
SUBSTANCE
REQUIREMENT
PLAN
368
PRE-CMC
DATA
369
WORKFLOWS
IN
THE
ENVIRONMENT
OF
THE
CRYSTALLIZATION
LABORATORY
369
MICRO-PROJECT
MANAGEMENT
369
DEPENDENCIES
370
MATERIAL
FLOW
371
DESIGNATIONS
AND
CODE
ASSIGNMENT
371
ANALYTIC
DATABASE
SYSTEM
373
PHYSICAL
SAMPLE
TRANSFER
375
ANALYTIC
TRANSFER
TOOL
375
ANALYTICAL
PROCESSES
-
TIMELY
MEASUREMENT
376
SAMPLE
STORAGE
PROCESSES
377
DOCUMENTATION
378
REVIEW
PROCESS
FOR
ELN
DOCUMENTS
379
DOCUMENT
STATUS
379
MANUAL
ELN
REVIEW
PROCESS
380
ARCHIVE
PROCESS
381
COMMUNICATION
WITH
CROS
381
FUNDAMENTAL
LAB
PROCESSES
382
PROCESSES
IN
THE
SOLID-STATE
LAB
382
INITIAL
TESTING
382
SOLUBILITY
ESTIMATION
384
MANUAL
SCREENING
384
HIGH-THROUGHPUT
SCREENING
385
PROCESSES
FOR
REPLICA
EXPERIMENTS
AND
SCALE-UP
OF
SOLID
FORMS
387
DEVELOPMENT
OF
CRYSTALLIZATION
PROCESSES
387
SUPPORT
PROCESSES
388
ROUTE
SCOUTING
PROCESS
389
CRYSTALLIZATION
OF
IMPURITIES
AND
INTERMEDIATES
389
DOWNSTREAM
PROCESSES
389
SCALE-UP
AND
TECHNOLOGY
TRANSFER
PROCESS
390
ANALYTICAL
DEVELOPMENT
390
PREFORMULATION
391
FORMULATION
391
CONTENTS
I
XV
7.8
CONCLUSION
392
LIST
OF
ABBREVIATIONS
393
REFERENCES
393
8
DIGITALIZATION
IN
LABORATORIES
OF
THE
PHARMACEUTICAL
INDUSTRY
397
TANJA
S.
PICKER
8.1
INTRODUCTION
397
8.2
MOTIVATION
OF
DIGITALIZATION
IN
THE
LABORATORY
398
8.2.1
EXPECTATIONS
OF
THE
STAFF
398
8.2.2
INCREASING
THROUGHPUT
400
8.2.3
REPEATABILITY
400
8.2.4
ENHANCED
REQUIREMENTS
ON
DATA
INTEGRITY
400
8.2.5
CENTRALIZED
ARCHIVING
401
8.2.6
AD
HOC
ANALYSIS
401
8.2.7
THE
VALUE
OF
DATA
402
8.3
CATEGORIES
OF
LABORATORY
IT
SYSTEMS
403
8.3.1
DEVICES
403
8.3.2
LAB
EXECUTION
SYSTEMS
(LES)
AND
SCIENTIFIC
DATA
MANAGEMENT
SYSTEMS
(SDMS)
404
8.3.3
LAB
DATA
SYSTEMS
404
8.3.4
ENTERPRISE
RESOURCE
PLANNING
(ERP)
405
8.3.5
FURTHER
USE
OF
DATA
405
8.3.5.1
DATA
ANALYSIS
AND
REPORTING
405
8.3.5.2
BIG
DATA
ANALYTICS
AND
ARTIFICIAL
INTELLIGENCE
406
8.4
SYSTEM
INTERFACES
FOR
DATA
EXCHANGE
406
8.4.1
ADAPTERS
407
8.4.1.1
SERIAL
PORT
(RS232)
407
8.4.1.2
UNIVERSAL
SERIES
BUS
(USB)
407
8.4.1.3
ETHERNET
407
8.4.1.4
CABLE
LESS
CONNECTIONS
407
8.4.2
COMMUNICATION
MEDIUM
AND
PROTOCOLS
408
8.4.2.1
FILE-BASED
COMMUNICATION
408
8.4.2.2
ANSI/ISA-88
BATCH
CONTROL
(S-88)
408
8.4.2.3
OPEN
PLATFORM
COMMUNICATIONS
UNIFIED
ARCHITECTURE
(OPC
UA)
408
8.4.2.4
STANDARDS
IN
LAB
AUTOMATION
(SILA)
408
8.4.3
DATA
FORMATS
409
8.4.3.1
COMMON
DATA
FORMATS
(E.G.
TXT,
XML,
JSON)
409
8.4.3.2
ANALYTICAL
INFORMATION
MARKUP
LANGUAGE
(ANIML)
409
8.4.3.3
ALLOTROPE
DATA
FORMAT
(ADF)
410
8.5
IMPLEMENTATION
OF
IT
SOLUTIONS
411
8.5.1
IDENTIFICATION
OF
DIGITAL
GAPS
IN
THE
LAB
PROCESSES
411
8.5.1.1
CONTEXTUAL
INQUIRY
411
8.5.1.2
INTERACTION
ROOM
411
8.5.2
IMPLEMENTATION
APPROACH
412
XVI
CONTENTS
8.5.2.1
DESIGN
413
8.5.2.2
REALIZATION
415
8.5.2.3
VERIFICATION
415
8.5.2.4
ROLLOUT
416
8.6
CONCLUSION
416
LIST
OF
ABBREVIATIONS
416
REFERENCES
417
9.1
POLYMORPHS
AND
PATENTS
-
THE
US
PERSPECTIVE
421
KRISTI
MCINTYRE
9.1.1
INTRODUCTION
421
9.1.2
WHAT
IS
A
PATENT?
421
9.1.3
HOW
ARE
PATENTS
OBTAINED?
422
9.1.4
UNITED
STATES
PATENT
LAW
422
9.1.4.1
TAPENTADOL
HYDROCHLORIDE
423
9.1.4.1.1
TAPENTADOL
HYDROCHLORIDE
FORM
A
HELD
NOT
OBVIOUS
423
9.1.4.1.2
TAPENTADOL
HYDROCHLORIDE
FORM
A
WAS
FOUND
TO
HAVE
UTILITY
424
9.1.4.2
PAROXETINE
HYDROCHLORIDE
HEMIHYDRATE
424
9.1.4.2.1
PHC
HEMIHYDRATE
HISTORY
425
9.1.4.2.2
MEANING
OF
"
CRYSTALLINE
PAROXETINE
HYDROCHLORIDE
HEMIHYDRATE
"
425
9.1.4.2.3
PHC
HEMIHYDRATE:
INFRINGED,
BUT INVALID
FOR
ANTICIPATION
426
9.1.4.3
RANITIDINE
HYDROCHLORIDE
426
9.1.4.3.1
HISTORY
OF
RHC1
FORM
2
426
9.1.4.3.2
RHC1
FORM
2
NOT
ANTICIPATED
BY
EXAMPLE
32
427
9.1.4.4
CEFDINIR
427
9.1.4.5
AMLODIPINE
BESYLATE
428
9.1.4.5.1
HISTORY
OF
AMLODIPINE
BESYLATE
428
9.1.4.5.2
AMLODIPINE
BESYLATE
FOUND
OBVIOUS
428
9.1.4.6
CONCLUDING
REMARKS
429
NOTES
429
REFERENCES
430
9.2
POLYMORPHS
AND
PATENTS
-
THE
EU
PERSPECTIVE
431
OLIVER
BROSCH
9.2.1
EUROPEAN
PATENT
APPLICATIONS
AND
EUROPEAN
PATENTS
431
9.2.1.1
INTRODUCTION
431
9.2.1.2
SUMMARY
OF
THE
PROCESSING
OF
APPLICATIONS
AND
PATENTS
BEFORE
THE
EUROPEAN
PATENT
OFFICE
(EPO)
431
9.2.1.3
ECONOMIC
FACTORS
432
9.2.1.4
UNITARY
PATENTS
433
9.2.1.5
PROTECTION
OF
POLYMORPHS
AND
SOLID
FORMS
IN
GENERAL
433
9.2.1.6
POLYMORPH
SCREENING
434
9.2.2
DECISIONS
OF
TECHNICAL
BOARDS
OF
APPEAL
OF
THE
EPO
435
9.2.2.1
DECISION
T
777/08
OF
24
MAY
2011
435
9.2.2.2
DECISION
T
1555/12
DATED
29
APRIL
2015
435
CONTENTS
XVII
9.2.23
DECISION
T
2114/13
DATED
12
OCTOBER
2016
442
9.2.2.4
DECISION
T
2397/12
DATED
12
MARCH
2018
442
9.2.2.5
DECISION
T
246/15
DATED
13
NOVEMBER
2018
442
9.2.3
JURISDICTION
OF
THE
FEDERAL
PATENT
COURT
AND
THE
GERMAN
FEDERAL
SUPREME
COURT
443
9.2.3.1
DECISION
"
KRISTALLFORMEN
"
GERMAN
FEDERAL
COURT
443
9.23.2
DECISION
XZR
58/08
DATED
15
MARCH
15
2011
443
9.2.33
DECISIONXZR
98/09
DATED
15
MAY
2012
444
9.23.4
DECISION
X
ZR
110/16
DATED
7
AUGUST
2018
444
9.2.4
ASSESSING
VALIDITY
OF
A
PATENT
OR
THE
CHANCES
OF
SUCCESS
445
9.2.5
INTERACTION
WITH
PATENT
PROFESSIONALS
446
LIST
OF
ABBREVIATIONS
447
REFERENCES
447
10
REGULATORY
FRAMEWORKS
AFFECTING
SOLID-STATE
DEVELOPMENT
449
CHRISTOPH
SEAL
10.1
INTRODUCTION
-
THE
NEED
FOR
REGULATION
IN
PHARMACEUTICAL
INDUSTRY
449
10.2
SOLID-STATE
FORMS
TO
BE
USED
FOR DRUGS
451
10.3
GENERAL
REGULATORY
CONSIDERATIONS
FOR
PHARMACEUTICAL
SOLID-STATE
FORMS
453
10.4
REGULATORY
FRAMEWORK
FOR
PHARMACEUTICAL
SALTS
454
10.4.1
PHARMACEUTICAL
EQUIVALENCE
AND
PHARMACEUTICAL
ALTERNATIVES
454
10.4.2
BIOEQUIVALENCE
456
10.4.3
THERAPEUTIC
EQUIVALENCE
458
10.4.4
BIOWAIVERS
458
10.4.5
REGULATORY
APPROVAL
FOR
PHARMACEUTICAL
SALTS
460
10.4.5.1
REGULATORY
APPROVAL
PATHWAYS
IN
THE
UNITED
STATES
460
10.4.5.2
REGULATORY
APPROVAL
PATHWAYS
IN
THE
EUROPEAN
UNION
461
10.4.6
REGULATORY
APPROVAL FOR POLYMORPHS
463
10.4.7
POLYMORPHISM
IN
PHARMACOPOEIAS
469
10.5
REGULATORY
FRAMEWORK
FOR
CO-CRYSTALS
471
10.6
SUMMARY
476
LIST
OF
ABBREVIATIONS
476
REFERENCES
477
11
OPPORTUNITIES
AND
CHALLENGES
FOR
GENERIC
DEVELOPMENT
FROM
A
SOLID-STATE
PERSPECTIVE
481
LUDITH
ARONHIME
AND
MIKE
TEILER
11.1
THE
BIRTH
OF
A
NEW
DRUG
AND
THE
GENERIC
SIBLINGS
THAT
WILL
FOLLOW
-
TWO
DIFFERENT
MINDSETS
481
11.1.1
GENERICS
481
11.1.2
PROPRIETARY
PRODUCTS
482
11.1.3
API
AND
SOLID
STATE
483
XVIII
CONTENTS
11.1.3.1
GENERICS
483
11.1.3.2
PROPRIETARY
483
11.2
PORTFOLIO
MANAGEMENT
-
HOW
IS
A
PORTFOLIO
CONSTRUCTED
AND
MAINTAINED?
484
11.2.1
ACTIVITIES
AND
TIMELINES
484
11.2.1.1
STRATEGY
484
11.2.1.2
VALUE
484
11.2.1.3
FACTORS
IMPACTING
ON
TIMING
-
WHEN
AND
HOW
DOES
A
PRODUCT
SHOW
UP
ON
A
GENERIC
COMPANY
'
S
RADAR
SCREEN?
485
11.2.2
TIMING
487
11.2.2.1
WHEN
IS
"
ON-TIME?
"
487
11.2.3
MARKET-SPECIFIC
CONSIDERATIONS
BASED
ON
LOCAL
LEGISLATION
AND
ADMINISTRATION
(OB,
PIV,
VARIOUS
EXCLUSIVITIES
-
US,
EU,
JP,
ETC.)
489
11.2.3.1
PATENTS
THROUGH
THE
EYES
OF
THE
REGULATORY
AUTHORITIES
489
11.2.3.2
DATA
EXCLUSIVITY
(DATA
PROTECTION)
489
11.2.3.3
SALTS
AND
ESTERS
490
11.2.3.4
THINK
GLOBAL,
ACT
LOCAL
490
11.2.4
SOURCES
TO
EVALUATE
A
PROJECT
491
11.2.4.1
GOVERNMENT
AND
REGULATORY
AGENCIES
491
11.2.4.2
ANALYST
REPORTS
AND
COMPANY
FINANCIAL
REPORTS
492
11.2.4.3
PAY
DATA
SOURCES
492
11.2.5
EVALUATION
TOOLS
493
11.2.5.1
BUSINESS
CASE
493
11.2.5.2
QUALITY
TARGET
PROJECT
PROFILE
(QTPP)
493
11.2.6
CRITERIA
FOR
IDENTIFYING
PROMISING
PROJECTS
493
11.2.7
CRITERIA
FOR
BUILDING A ROBUST
PORTFOLIO
494
11.3
CHALLENGES
IN
DEVELOPING
A
GENERIC
PRODUCT
FROM
THE
SOLID-STATE
PERSPECTIVE
495
11.3.1
IMPLICATIONS
IN
DEVELOPING
FORMULATION
WITH
A
METASTABLE
API
496
11.3.2
THE
STABILITY
QUESTION
497
11.3.2.1
POLYMORPHIC
STABILITY
IN
DRY
CONDITIONS
497
11.3.2.2
POLYMORPHIC
STABILITY
IN
WET
CONDITIONS
(SLURRY)
498
11.4
GENERIC
SOLID-STATE
DEVELOPMENT
498
11.4.1
GENERAL
498
11.4.2
PREDEVELOPMENT
PHASE:
SOLID-STATE
STRATEGY
499
11.4.2.1
REVIEW
OF
THE
SOLID
STATE,
ESPECIALLY
THE
POLYMORPH
PATENT
LANDSCAPE
499
11.4.2.2
DESIGN-AROUND
CONSIDERATIONS
500
11.4.3
CRYSTAL FORMS
DISCOVERY
503
11.4.3.1
IMPORTANCE
OF
THE
CRYSTAL
FORMS
DISCOVERY
STAGE
503
11.4.3.2
NEW
CRYSTAL
FORMS
UNPREDICTABILITY
503
11.4.3.3
PRAGMATIC
QUESTIONS
ABOUT
CRYSTAL
FORMS
SEARCH
504
11.4.3.4
LATE-APPEARING
POLYMORPHS
505
11.4.3.5
IRREPRODUCIBILITY
OF
PROCEDURES
506
11.4.3.6
ANALYTICAL
FOCUS
507
CONTENTS
XIX
11.4.4
TARGET
SELECTION
507
11.4.4.1
SOLUBILITY
508
11.4.4.2
MORPHOLOGY
509
11.4.4.3
SOLID-STATE
STABILITY
509
11.4.4.4
ADDITIONAL
FACTORS
509
11.4.5
PROCESS
DEVELOPMENT
IN
THE
LABORATORY
SCALE
510
11.4.5.1
PROCESS
DEVELOPMENT
510
11.4.5.2
THERMODYNAMIC
STABILITY
RELATIONSHIPS
510
11.4.5.3
SOLUBILITY
CURVES
510
11.4.5.4
API
TARGET
511
11.4.5.5
ANALYTICAL
METHODS
FOR
POLYMORPHIC
PURITY
512
11.4.6
SCALE-UP
CHALLENGES
512
11.4.6.1
CONTROL
OF
CRYSTAL
FORM
512
11.4.6.2
CONTROL
OF
PARTICLE
SIZE
AND
MORPHOLOGY
513
11.4.6.3
LOT-TO-LOT
VARIABILITY
513
11.4.6.4
ANALYTICAL
FOCUS
514
11.4.7
PHARMA
DEVELOPMENT
515
11.4.7.1
THE
TETRAHEDRON
PRINCIPLE
AND
CONSISTENCY
AMONG
LOTS
516
11.4.7.2
THE
EFFECT
OF
MICRONIZATION
ON
AMORPHOUS
CONTENT
IN
CRYSTALLINE
APIS
516
11.4.7.3
SOLID-STATE
STABILITY
UPON
STORAGE
517
11.4.8
IMPACT
ON
FORMULATION
517
11.4.9
SUMMARY
OF
TIMELINES
FOR
SOLID-STATE
ACTIVITY
518
11.4.10
INTELLECTUAL
PROPERTY
(IP)
STRATEGIES
AND
ACTIVITIES
519
11.5
SUCCESS
FACTORS
520
11.5.1
SUCCESSFUL
BIOSTUDY
520
11.5.2
SUCCESSFUL
LAUNCH
521
11.5.3
GENERIC
COMMERCIAL
SUCCESS
522
LIST
OF
ABBREVIATIONS
523
REFERENCES
524
INDEX
531 |
| any_adam_object | 1 |
| any_adam_object_boolean | 1 |
| author2 | Gruß, Michael 1965- |
| author2_role | edt |
| author2_variant | m g mg |
| author_GND | (DE-588)120863022 |
| author_facet | Gruß, Michael 1965- |
| building | Verbundindex |
| bvnumber | BV047327471 |
| classification_rvk | VS 5000 VX 6000 |
| ctrlnum | (OCoLC)1287929784 (DE-599)DNB1214957218 |
| discipline | Chemie / Pharmazie |
| discipline_str_mv | Chemie / Pharmazie |
| format | Book |
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| genre | (DE-588)4143413-4 Aufsatzsammlung gnd-content |
| genre_facet | Aufsatzsammlung |
| id | DE-604.BV047327471 |
| illustrated | Illustrated |
| index_date | 2024-07-03T17:31:32Z |
| indexdate | 2024-07-10T09:09:00Z |
| institution | BVB |
| institution_GND | (DE-588)16179388-5 |
| isbn | 352734635X 9783527346356 |
| language | English |
| oai_aleph_id | oai:aleph.bib-bvb.de:BVB01-032730071 |
| oclc_num | 1287929784 |
| open_access_boolean | |
| owner | DE-29T DE-11 DE-19 DE-BY-UBM |
| owner_facet | DE-29T DE-11 DE-19 DE-BY-UBM |
| physical | xxiv, 548 Seiten Illustrationen, Diagramme 24.4 cm x 17 cm |
| publishDate | 2022 |
| publishDateSearch | 2022 |
| publishDateSort | 2022 |
| publisher | WILEY-VCH |
| record_format | marc |
| series | Methods and principles in medicinal chemistry |
| series2 | Methods and principles in medicinal chemistry |
| spelling | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism edited by Michael Gruss Weinheim WILEY-VCH [2022] © 2022 xxiv, 548 Seiten Illustrationen, Diagramme 24.4 cm x 17 cm txt rdacontent n rdamedia nc rdacarrier Methods and principles in medicinal chemistry volume 79 Produktionsprozess (DE-588)4123984-2 gnd rswk-swf Arzneimittelentwicklung (DE-588)4143176-5 gnd rswk-swf Festkörperchemie (DE-588)4129288-1 gnd rswk-swf Chemische Verfahrenstechnik (DE-588)4069941-9 gnd rswk-swf Wirkstoff (DE-588)4066383-8 gnd rswk-swf CG10: Prozesssteuerung CH30: Technische u. Industrielle Chemie CH62: Wirkstoffformulierung, Wirkstofftransport Chemical Engineering Chemie Chemische Verfahrenstechnik Chemistry Drug Formulation & Delivery Industrial Chemistry Process Engineering Prozesssteuerung Technische u. Industrielle Chemie Wirkstoffformulierung, Wirkstofftransport (DE-588)4143413-4 Aufsatzsammlung gnd-content Arzneimittelentwicklung (DE-588)4143176-5 s Wirkstoff (DE-588)4066383-8 s Festkörperchemie (DE-588)4129288-1 s Chemische Verfahrenstechnik (DE-588)4069941-9 s Produktionsprozess (DE-588)4123984-2 s DE-604 Gruß, Michael 1965- (DE-588)120863022 edt Wiley-VCH (DE-588)16179388-5 pbl Erscheint auch als Online-Ausgabe, PDF 978-3-527-82305-5 Erscheint auch als Online-Ausgabe, EPUB 978-3-527-82306-2 Erscheint auch als Online-Ausgabe, OBOOK 978-3-527-82304-8 Methods and principles in medicinal chemistry volume 79 (DE-604)BV035418617 79 X:MVB http://www.wiley-vch.de/publish/dt/books/ISBN978-3-527-34635-6/ Kurzbeschreibung DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=032730071&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism Methods and principles in medicinal chemistry Produktionsprozess (DE-588)4123984-2 gnd Arzneimittelentwicklung (DE-588)4143176-5 gnd Festkörperchemie (DE-588)4129288-1 gnd Chemische Verfahrenstechnik (DE-588)4069941-9 gnd Wirkstoff (DE-588)4066383-8 gnd |
| subject_GND | (DE-588)4123984-2 (DE-588)4143176-5 (DE-588)4129288-1 (DE-588)4069941-9 (DE-588)4066383-8 (DE-588)4143413-4 |
| title | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism |
| title_auth | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism |
| title_exact_search | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism |
| title_exact_search_txtP | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism |
| title_full | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism edited by Michael Gruss |
| title_fullStr | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism edited by Michael Gruss |
| title_full_unstemmed | Solid state development and processing of pharmaceutical molecules salts, cocrystals, and polymorphism edited by Michael Gruss |
| title_short | Solid state development and processing of pharmaceutical molecules |
| title_sort | solid state development and processing of pharmaceutical molecules salts cocrystals and polymorphism |
| title_sub | salts, cocrystals, and polymorphism |
| topic | Produktionsprozess (DE-588)4123984-2 gnd Arzneimittelentwicklung (DE-588)4143176-5 gnd Festkörperchemie (DE-588)4129288-1 gnd Chemische Verfahrenstechnik (DE-588)4069941-9 gnd Wirkstoff (DE-588)4066383-8 gnd |
| topic_facet | Produktionsprozess Arzneimittelentwicklung Festkörperchemie Chemische Verfahrenstechnik Wirkstoff Aufsatzsammlung |
| url | http://www.wiley-vch.de/publish/dt/books/ISBN978-3-527-34635-6/ http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=032730071&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
| volume_link | (DE-604)BV035418617 |
| work_keys_str_mv | AT grußmichael solidstatedevelopmentandprocessingofpharmaceuticalmoleculessaltscocrystalsandpolymorphism AT wileyvch solidstatedevelopmentandprocessingofpharmaceuticalmoleculessaltscocrystalsandpolymorphism |