Pharmaceutical Crystals E-Book

Tong Li

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 938

Veröffentlichungsjahr: 2018

Beschreibung

An important resource that puts the focus on understanding and handling of organic crystals in drug development Since a majority of pharmaceutical solid-state materials are organic crystals, their handling and processing are critical aspects of drug development. Pharmaceutical Crystals: Science and Engineering offers an introduction to and thorough coverage of organic crystals, and explores the essential role they play in drug development and manufacturing. Written contributions from leading researchers and practitioners in the field, this vital resource provides the fundamental knowledge and explains the connection between pharmaceutically relevant properties and the structure of a crystal. Comprehensive in scope, the text covers a range of topics including: crystallization, molecular interactions, polymorphism, analytical methods, processing, and chemical stability. The authors clearly show how to find solutions for pharmaceutical form selection and crystallization processes. Designed to be an accessible guide, this book represents a valuable resource for improving the drug development process of small drug molecules. This important text: * Includes the most important aspects of solid-state organic chemistry and its role in drug development * Offers solutions for pharmaceutical form selection and crystallization processes * Contains a balance between the scientific fundamental and pharmaceutical applications * Presents coverage of crystallography, molecular interactions, polymorphism, analytical methods, processing, and chemical stability Written for both practicing pharmaceutical scientists, engineers, and senior undergraduate and graduate students studying pharmaceutical solid-state materials, Pharmaceutical Crystals: Science and Engineering is a reference and textbook for understanding, producing, analyzing, and designing organic crystals which is an imperative skill to master for anyone working in the field.

Leseprobe

Table of Contents

Cover

Preface

1 Crystallography

1.1 Introduction

1.2 History

1.3 Symmetry

1.4 Principles of X‐ray Diffraction

1.5 Structure Determination

1.6 Powder Methods

1.7 Crystal Structure Prediction

1.8 Crystallographic Databases

1.9 Conclusions

References

2 Nucleation

2.1 Introduction

2.2 Classical Nucleation Theory

2.3 Nonclassical Nucleation

2.4 Application of Primary Nucleation

2.5 Secondary Nucleation

2.6 Summary

References

3 Solid‐state Characterization Techniques

3.1 Introduction

3.2 Techniques

3.3 Case Study LY334370 Hydrochloride (HCl)

3.4 Summary

References

4 Intermolecular Interactions and Computational Modeling

4.1 Introduction

4.2 Foundation of Intermolecular Interactions

4.3 Intermolecular Interactions in Organic Crystals

4.4 Techniques for Intermolecular Interactions Evaluation

4.5 Advances in Understanding Intermolecular Interactions

References

5 Polymorphism and Phase Transitions

5.1 Concepts and Overview

5.2 Thermodynamic Principles of Polymorphic Systems

5.3 Stabilities and Phase Transition

5.4 Impact on Bioavailability by Polymorphs

5.5 Regulatory Consideration of Polymorphism

5.6 Novel Approaches for Preparing Solid State Forms

5.7 Hydrates and Solvates

5.8 Summary

References

6 Measurement and Mathematical Relationships of Cocrystal Thermodynamic Properties

6.1 Introduction

6.2 Structural and Thermodynamic Properties

6.3 Determination of Cocrystal Thermodynamic Stability and Supersaturation Index

6.4 What Phase Solubility Diagrams Reveal

6.5 Cocrystal Discovery and Formation

6.6 Cocrystal Solubility Dependence on Ionization and Solubilization of Cocrystal Components

6.7 Conclusions and Outlook

References

7 Mechanical Properties

7.1 Introduction

7.2 Characterization of Mechanical Properties

7.3 Structure–Property Relationship

7.4 Conclusion and Future Outlook

References

8 Primary Processing of Organic Crystals

8.1 Introduction

8.2 Primary Manufacturing: Processing Materials to Yield Drug Substance

8.3 Challenges During Solidification Processing

8.4 Summary and Concluding Remarks

References

9 Secondary Processing of Organic Crystals

9.1 Introduction

9.2 Secondary Manufacturing–Processing Materials to Yield Drug Products

9.3 Summary and Concluding Remarks

References

10 Chemical Stability and Reaction

10.1 Introduction

10.2 Overview of Organic Solid‐state Reactions

10.3 Mechanisms of Organic Solid‐state Reactions

10.4 Kinetics of Chemical Reactions: From Homogeneous to Heterogeneous Systems

10.5 Factors Affecting Chemical Stability

10.6 Strategies to Prevent Chemical Reactions

References

11 Crystalline Nanoparticles

11.1 Introduction

11.2 Top‐down Technology

11.3 Bottom‐up Technology

11.4 Nanoparticle Stabilization

11.5 Applications

11.6 Characterization of Crystalline Nanoparticles

References

Index

End User License Agreement

List of Tables

Chapter 01

Table 1.1 Crystallographic data from X‐ray structure determinations of seven ROY polymorphs.

Table 1.2 Laue and point groups of all crystal systems.

Chapter 03

Table 3.1 Saturated aqueous salt solutions and relative humidity values at 25 °C [95].

Table 3.2 Summary of LY334370 HCl crystalline forms [105].

Chapter 04

Table 4.1 Overview of intermolecular forces.

Table 4.2 Condensed Fukui functions and dual descriptors of the carbonyl oxygen and the pyridyl nitrogen of the 2‐(phenylamino)nicotinic acid single molecule in its planar (a) and twisted (b) conformations, computed by B3LYP/6‐311G++(2d,p) in gas phase.

Chapter 05

Table 5.1 Properties of a drug substances that affected by the internal structures.

Table 5.2 Blood levels (μg/100 ml) for different suspensions of chloramphenicol palmitate.

Table 5.3 Possible solvents to form solvates with drugs and organic compounds.

Chapter 06

Table 6.1 Cocrystal p

K

sp

values.

Table 6.2 Cocrystal and salt p

K

sp

values of lamotrigine.

Table 6.3 Key stability indicators of solid‐state forms.

Table 6.4 Influence of pH and solubilizing agents on

K

eu

values.

Table 6.5 Eutectic point concentrations and solid phases for NVP‐MLE/ NVP system measured in water at 25 °C [38].

Table 6.6 Ionization (

δ

I

) and solubilization (

δ

S

) terms used to calculate cocrystal solubility according to Equations (6.19), (6.20), and (6.22).

a

Table 6.7 Homogeneous equilibrium reactions and associated constants corresponding to ionization and micellar solubilization of cocrystal components.

Table 6.8

S

*

deviations due to coformer solubilization.

Chapter 08

Table 8.1 Class III solvents recommended for solidification processing of pharmaceutical drug substances.

Table 8.2 Descriptions of powder flowability with reference to expulsion of air voids upon agitation.

Table 8.3 A brief list of some SMOC materials subject to polymorphism as a result of crystallization conditions.

Table 8.4 Examples of small‐molecule organic crystalline hydrates and solvates.

Table 8.5 Polymorphic transformation rates of sulfamerazine Form II in various solvents.

Table 8.6 Summary of suggestions for PAT strategies associated with crystallization process monitoring and control of product quality attributes.

Chapter 09

Table 9.1 Fracture toughness (

K

1

C

) values for select materials.

Table 9.2 Examples of solid‐state transformations of various pharmaceutical materials induced during milling.

Table 9.3 Overview of size‐enlargement methods used in 2° manufacturing of SMOC.

Table 9.4 Risk assessment of primary stresses and impacts during granulation processing of SMOC materials.

Chapter 11

Table 11.1 Nanocrystal products in development and on the market.

Table 11.2 Dermal delivery of crystalline nanoparticles.

List of Illustrations

Chapter 01

Figure 1.1 Materials science perspective of the steps involved in transforming a molecule to a medicine.

Figure 1.2 (a) Crystal polymorphs of ROY highlighting the diverse colors and shapes of crystals grown from different solutions and (b) photomicrographs showing the concurrent cross nucleation of the R polymorph on Y04 produced by melt crystallization and (c) single crystals of YT04 grown by seeding a supersaturated solution.

Figure 1.3 Symmetry operations of mirror, threefold rotation, and glide are depicted on a photograph of a hand. The symbol for a mirror is a solid line, for a threefold rotation a triangle (), and for a glide a dashed line.

Figure 1.4 Wallpaper design by M. C. Escher. Lattice points are indicated by circles; the lattice is drawn as lines. It does not matter which reference point is chosen; the same lattice is always obtained. There is no symmetry besides translation. The lattice type is oblique and the plane group is p1. Each unit cell contains two birds, one black and one white.

Figure 1.5 Wallpaper design by M. C. Escher. Assume the grey and white spiders are equivalent and a symmetry operation transforming a grey spider into a white one or vice versa is considered valid. Lattice points are indicated by black circles; the lattice is drawn as black lines. Symmetry elements are drawn in white (fourfold axes, twofold axes, mirrors, and glides). The lattice type is

square

and the plane group is

p

4

gm

. Each unit cell contains 4 spiders, the asymmetric unit ½ spider.

Figure 1.6 In classical crystals (ignoring quasicrystals), only twofold, threefold, fourfold, and sixfold rotation are compatible with translation. Attempts to tile a floor with, for example, pentagons or heptagons will leave gaps.

Figure 1.7 Models of all five sixfold screw axes (built by Ellen and Peter Müller in 2010). From left to right: 6

1

, 6

5

, 6

2

, 6

4

, 6

3

. It can be seen that 6

1

/6

5

and 6

2

/6

4

are enantiomeric pairs, i.e. mirror images of one another or, in other words, the right‐ and left‐handed versions of the same screw.

Figure 1.8 Unit cell, defined by lattice vectors (

a

,

b

,

c

) and angles (

α

,

β

,

γ

), the basic building block used to construct the three‐dimensional crystal lattice.

Figure 1.9 Seven crystal systems, defined by the shape of the unit cell. (Trigonal and hexagonal have the same metric symmetry, but are separate crystal systems.)

Figure 1.10 View of streetlamps from a hotel room in Chicago in 2010. The image on the right side is the exact same view as the one on the left; only it was taken through the curtain fabric. All strong and point‐like light sources show significant diffraction.

Figure 1.11 Bragg’s law derived from partial reflection of two parallel planes.

Figure 1.12 Between the points of a crystal lattice in real space, there are Bragg planes. Each set of Bragg planes corresponds to one set of Miller indices. The Miller indices

h

,

k

,

l

correspond to the reciprocal values of the points at which the planes cut the unit cell axes closest to the origin. Each set of Bragg planes corresponds to one reflection. Each reflection is identified by the corresponding Miller indices

h

,

k

,

l

. The positions of the reflections form another lattice, the reciprocal lattice. There is a vector

d

perpendicular to each set of Bragg planes; its length is equivalent to the distance between the corresponding Bragg planes. Each reflection

h

,

k

,

l

marks the endpoint of the scattering vector

s

 = 1/

d

. The length of

s

is inversely related to the distance between the Bragg planes.

Figure 1.13 Ewald construction. The Ewald sphere has the radius 1/

λ

. Points C, O, P, and Q mark the position of the crystal, the origin of the reciprocal lattice, the point where the diffracted beam exits the Ewald sphere (corresponding to the endpoint of

s

on the surface of the sphere), and the point where the primary beam enters the Ewald sphere, respectively. Through rotation of the crystal, all

s

‐vectors that are shorter than 2/

λ

can be brought into a position in which they end on the surface of the Ewald sphere.

Figure 1.14 Projection of a unit cell along the crystallographic

b

‐axis (i.e. in [

h

, 0,

l

] projection) in presence of a

c

‐glide plane coinciding with the

a

‐

c

‐plane. In this projection the unit cell seems to be cut in half which, in turn, doubles the volume of the corresponding reciprocal unit cell. Reflections corresponding to this projection will be according to the larger reciprocal cell, which means that reflections of the class

h

0 

l

with

l

 ≠ 2

n

are not observed, i.e. systematically absent.

Figure 1.15 Electron density of a hypothetical one‐dimensional crystal with a three‐atomic molecule in the unit cell (top right). This density function can be represented fairly well in terms of just three sine waves: The first sine wave has a frequency of 2 (i.e. there are two repeats of the wave across the unit cell); its phase is chosen that one maximum is aligned with the two lighter atoms on the left of the unit cell and the other one is with the heavier atom on the right. The second one has a frequency of 3; it has a different amplitude and also a different phase (one maximum is aligned with the heavier atom on the right of the unit cell). The third sine wave with a frequency of 5 also has a different amplitude, and its phase is chosen so that two of this wave’s peaks are lined up with the two lighter atoms to the left of the unit cell. Adding up the three sine waves results in the thick curve at the bottom left of the figure. These sine waves are the “electron density waves” mentioned in the text above, and the frequencies of 2, 3, or 5 correspond to the “electron density wavelengths.” The top left of the figure shows the Fourier transformation of the unit cell, corresponding to the diffraction pattern, together with the one‐dimensional Miller indices. The three sine waves can be identified as the three strongest reflections. The intensities of the reflections correspond to the amplitudes of the sine waves in the right‐hand side of the figure, and the frequencies of the sine waves correspond to the respective Miller indices (2, 3, and 5). Unfortunately, the phases are not encoded in the diffraction pattern.

Figure 1.16 Molecular model of a Cp

*

ring in a crystal structure refined with isotropic (left) and anisotropic (right) displacement parameters.

Figure 1.17 Rietveld plot of racemic fexofenadine hydrochloride showing the fit of the experimental PXRD pattern (dots) to the simulated pattern (solid line) for the powder structure model [inset]. The vertical tick marks represent the theoretical peak positions.

Figure 1.18 Conformation of a single molecule of simvastatin (left) and molecular packing in crystalline simvastatin (right) with interatomic

1

H–

13

C distances and intermolecular contacts (marked by arrows) established by solid‐state NMR spectroscopy. Disorder of the terminal ester was proposed by X‐ray diffraction.

Figure 1.19 Crystal energy landscape of a model pharmaceutical. Each point represents a mechanically stable 3D structure ranked in order of lattice energy and crystal packing efficiency or packing index. Experimentally observed crystal structures found by solid form screening are encircled.

Figure 1.20 Full interaction maps for trimethoprim polymorphs, (a) Form I (AMXBPM12) and (b) Form II (AMXBPM13), showing hydrogen bond acceptor, hydrogen bond donor, and hydrophobic CH “hot spots.” The solid‐dashed circles highlight hydrogen bonding partners just outside the hot spots, indicating that the interaction geometries are not well represented in the CSD. The dashed circles point to where a hot spot near an NH donor is missing, presumably due to steric hindrance within the crystal conformers.

Chapter 02

Figure 2.1 Free energy diagram of nucleation involving the dual processes of interfacial creation and growth of clusters and the appearance of critical clusters.

Figure 2.2 Schematic illustration of all possible changes in the size of a cluster of

m

molecules (solid lines) and the change in the size of critical cluster

n

*

by attachment and detachment of monomers only according to the Szilard–Farkas model (dash lines). The diminishments in concentration of

m

‐sized clusters due to the

m

 → 

n

*

transitions (the arrows leaving size

m

) and the increases because of

n

*

 → 

m

transitions (the arrows ending at size

m

).

Figure 2.3 Schematic representation of the MSZW (the regime between the bottom line and top or dash line) along with different crystallization pathways represented by the arrowed lines. The bottom line is the solubility curve, the top line is the limit of metastable zone with instantaneous nucleation, and the dash line is the limit of metastable zone without nucleation.

Figure 2.4 Interfacial tensions among three phases (foreign particle and crystalline deposit solid phases as well as solution phase).

Figure 2.5 The two alternative pathways leading from solution to solid crystal. Top: the concomitant evolutions of density fluctuation with structure order of clusters, as proposed by classical nucleation theory. Bottom: the density fluctuation prior to the development of structure order of clusters so that the initial formed clusters are dense, liquid‐like and crystalline order appears later on, as postulated by two‐step mechanism.

Figure 2.6 Free energy

G

along with two possible pathways for nucleation of crystals from solution.

E

1

,

E

0

, and

E

2

are the barriers for developing a dense liquid‐like cluster, for decay of the cluster, and for formation of an ordered cluster within cluster, respectively. Δ

G

L‐L

represents the free energy of formation of the dense liquid phase [4].

Figure 2.7 Schematic representation of the difference in nucleation pathway between PNCs (left) and CNT (right).

Figure 2.8 Schematic representation of temperature–energy diagram for enantiotropic (solid lines) and monotropic (dash lines) systems. The subscript I, II, and L denote polymorphs I and II and the liquid, respectively;

t

represents the transition point, and

m

is the melting point.

Figure 2.9 Schematic representation of solvent‐dependent self‐association leads to the formation of two different building units (building unit I in solvent A, building unit II in solvent B), which determine the crystal packing and thus the formation of the crystalline phases Form I and Form II, respectively.

Figure 2.10 Schematic diagram of the two‐stage nucleation process. (1) Unsaturated solution, (2) formation of oil droplets, (3) nucleation in oil droplets, and (4) final products.

Figure 2.11 The ternary phase diagram of β‐alanine–water–isopropanol system at 25 °C (0.1 MPa). Region 1: solid–liquid equilibrium phase I. Region 2: solid–liquid–liquid equilibrium phase. Region 3: solid–liquid equilibrium phase II. Region 4: liquid–liquid equilibrium phase. Region 5: unsaturated liquid phase.

Figure 2.12 SEM images of morphology of β‐alanine crystallization obtained under different operation conditions: (a) normal crystallization (point 1 → point 1′ in Figure 2.11), (b) crystallization with LLPS (point 2 → point 2′ in Figure 2.11), (c) quasi‐emulsion solvent diffusion crystallization (point 3 → point 3′ in Figure 2.11), and (d) quasi‐emulsion solvent diffusion crystallization with LLPS (point 4 → point 4′ in Figure 2.11).

Figure 2.13 Secondary nucleation induced by collisions of crystals with stirrer’s surfaces (b) in comparation to the stand still stirrer (a).

Figure 2.14 Operation profile of a typical crystallization trajectory to control crystal size distribution by avoiding the uncertainties in the primary nucleation.

Chapter 03

Figure 3.1 Steps leading to crystal/powder formation.

Figure 3.2 (a) Packing diagram from a single‐crystal structure determination showing the 100 plane in red and (b) simulated pattern from the single‐crystal structure solution compared with an experimental XRPD pattern.

Figure 3.3 XRPD patterns of crystalline (top), poorly crystalline (middle), and amorphous material (bottom).

Figure 3.4 DSC of a pharmaceutical compound showing endothermic (83.38, 168.79 °C) and exothermic (139.45 and 172.90 °C) transitions.

Figure 3.5 TGA curve (top) showing weight loss as a function of temperature (right axis) and the derivative of the weight loss (left axis).

Figure 3.6 DRIFTS spectra for Fast‐Flo (a), anhydrous (b), and hydrated (c) lactose.

Figure 3.7 Raman spectra of olanzapine Forms 1 and 2.

Figure 3.8

13

C CP/MAS spectra of different solvate hydrates of finasteride (structure in inset). From top to bottom: ethyl acetate, tetrahydrofuran, isopropanol, and dioxane solvate hydrate, where the term solvate hydrate is used to indicate a 2 : 1 molecular ratio of finasteride to both organic solvent and water.

Figure 3.9 Different equilibration conditions in an automated moisture sorption system. Closed circles are sorption and open circles are desorption.

Figure 3.10 Examples of moisture balance curve. (a) Amorphous, (b) deliquescence, (c), highly crystalline, (d–g) hydrate formation, and (h) crystallization.

Figure 3.11 (a) XRPD patterns and (b) optical micrographs of LY334370 HCl crystalline forms, with a scale of 10 μm/division.

Figure 3.12 DSC curves of LY334370 HCl crystalline forms, from top to bottom: Form I, Form II, Form III, dihydrate, acetic acid solvate.

Figure 3.13 SSNMR spectra of the LY334379 HCl crystalline forms, from top to bottom: Form I, Form II, Form III, dihydrate, acetic acid solvate.

Figure 3.14 Water sorption isotherms for LY334370 HCl crystalline forms.

Figure 3.15 Relationship between LY4334370 HCl forms.

Chapter 04

Figure 4.1 Molecular crystal packing of (a) benzene (refcode: BENZEN), (b) deuterothiophene (refcode: ZZZUXA02), and (c) urea (refcode: UREAXX02).

Figure 4.2 Examples of different hydrogen‐bonding motifs with their corresponding graph sets.

Figure 4.3 Supramolecular synthons employed in crystal engineering.

Figure 4.4 (a) Hirshfeld surface and (b) two‐dimensional fingerprint plot for Form I of aspirin (refcode: ACSALA 02).

Figure 4.5 Interlayer hydrogen bonding motifs in (a) Form I (refcode: ACSALA02) and (b) Form II (refcode: ACSALA13) of aspirin. Hydrogen bonding is denoted as dashed line.

Figure 4.6 Hydrogen‐bonding motifs and crystal packing in (a) Form

α

(refcode: TOKSAO) and (b) Form

δ

(refcode: TOKSAO03) of 2‐(phenylamino) nicotinic acid.

Figure 4.7 Packing motifs of molecular pairs extracted from the crystal structure of benzoic acid (refcode: BENZAC12), featuring (a) carboxyl dimer; (b, d, and e) π–π stacking; (c) hydrogen bonding between the carbonyl oxygen and the phenyl ring; and (f–h) close contacts between phenyl rings.

Figure 4.8 Intermolecular interaction energy computed by MP2 and DFT‐D levels of theory for molecular pairs extracted from the crystal structure of benzoic acid.

Scheme 4.1 Energy derivatives and response functions.

Figure 4.9 Isosurfaces of the single molecule of tolfenamic acid Form I : (a) highest occupied molecular orbital, (b) lowest occupied molecular orbital, (c) electrophilic Fukui function, (d) nucleophilic Fukui function, (e) dual descriptor, and (f) electron density. The values of isosurfaces are 0.02 a.u. for the frontier orbitals and electron density and 0.002 a.u. for the Fukui functions and dual descriptor, respectively.

Figure 4.10 Hirshfeld surfaces of the hydrogen‐bonded dimer mapped with crystal‐based (top of each motif) and molecule‐based (bottom of each motif) (a) nucleophilic and (b) electrophilic Fukui functions. Hirshfeld surfaces of the π–π stacking mapped with crystal‐based (top of each motif) and molecule‐based (bottom of each motif) (c) nucleophilic and (d) electrophilic Fukui functions.

Chapter 05

Figure 5.1 Examples of polymorph: diamond and graphite.

Figure 5.2 Molecular conformations of the spiperone molecule in polymorphic form I (a) and II (b) and its corresponding unit cell (c) and (d).

Figure 5.3 Chemical structure of 5‐methyl‐2‐[(2‐nitrophenyl)amino]‐3‐thiophenecarbonitrile (ROY) (a); red, orange, and yellow crystal of 5‐methyl‐2‐[(2‐nitrophenyl)amino]‐3‐thiophenecarbonitrile (b) conformations of ROY (c).

Figure 5.4 Flowchart of the polymorphic system.

Figure 5.5 Energy–temperature plots for a monotropic system.

H

is enthalpy,

G

is free energy,

T

is temperature, subscript f refers to fusion, and subscript m indicates melting point.

Figure 5.6 Energy–temperature plots for an enantiotropic system.

H

is enthalpy,

G

is free energy,

T

is temperature, subscript f refers to fusion, subscript m indicates melting point, and subscript t symbolizes the transition point.

Figure 5.7 Phase diagram of pressure vs. temperature for single‐component monotropic system.

Figure 5.8 Phase diagram of pressure vs. temperature for single‐component enantiotropic system.

Figure 5.9 Gibbs free energy–temperature plots for a monotropic system (a) and an enantiotropic system (b) in which the system is cooled from point A, the arrows indicating the changing direction in the diagram.

Figure 5.10 Plot of Gibbs free energy vs. the radius of cluster, where

is the activation free energy of the cluster and

r

c

represents the mean radius of the critical clusters.

Figure 5.11 Competing crystallization of form I and form II (a); activation free energy of nucleation for form I and form II (

).

G

initial represents the partial free energy in the supersaturated solution, and

G

form I or II symbolizes the partial free energy of form I or form II (b).

Figure 5.12 Enantiotropic system which has a temperature‐dependent rate of transformation between form II and form I.

Figure 5.13 Scheme of the reactivity of the α‐, β‐, and γ‐crystalline forms of trans‐2‐ethoxycinnamic acid upon exposure to ultraviolet light.

Figure 5.14 The mean blood serum levels obtained with chloramphenicol palmitate suspension containing various percentages of form B and form A (ranging from 100% form B to 0% form B).

Figure 5.15 Decision tree/flowchart for polymorph.

Figure 5.16 Hydrates and anhydrate produced by evaporations under different temperatures.

Figure 5.17 Idealized moisture uptake profile for a compound has anhydrate, monohydrate, and dihydrate.

Figure 5.18 Deliquescence process.

Figure 5.19 Behavior of hydrate crystals upon heating to 40 °C A (thymine) B (cytosine).

Chapter 06

Figure 6.1 Multicomponent crystalline forms that can be used to alter the physicochemical properties of an active pharmaceutical ingredient (API) or drug without changing molecular structure [22].

Figure 6.2 Examples of two strategies used to form cocrystals of carbamazepine: (a) carbamazepine–saccharin, which maintains cyclic carboxamide homosynthon, and (b) carbamazepine–succinic acid, which disrupts carboxamide homosynthon in favor of a heterosynthon between carboxamide and dicarboxylic acid [12].

Figure 6.3 Solubilities and regions of thermodynamic stability for cocrystal and crystalline drug are not fixed but vary with solution conditions such as (a) pH, (b) drug solubilizing agents, and (c) coformer concentration. The intersection of the cocrystal and drug solubility curves represents a transition point, where

S

cocrystal

 = 

S

drug

. The thermodynamic stability of the cocrystal relative to drug can be determined from their solubility ratios >1, = 1 or <1, where SA = 1 is the transition point.

Figure 6.4 SA–SR diagram of (1 : 1) cocrystals with three different aqueous solubilities. Cocrystal solubility advantage over drug or supersaturation index (SA) decreases in a predictable way with increasing drug solubilization (SR

drug

), according to the equation in the plot. The dashed line indicates SA = 1. Intersections of cocrystal SA and SA = 1 lines represent the SR

drug

at which

S

cocrystal

 = 

S

drug

and identify transition points. In this example transition points are at

values of 4, 100, and 10 000 for the corresponding cocrystals. Cocrystal is more soluble than drug below

and becomes less soluble than drug above this

value.

Figure 6.5

C

max

is a kinetic parameter determined by the rates of cocrystal dissolution and drug precipitation.

C

max

is not proportional to cocrystal SA as the relation between dissolution and precipitation rates shifts with SA.

C

max

will decrease and may elude detection as precipitation rates become much higher than dissolution.

Figure 6.6 Diagram illustrating how cocrystal solubility (S

CC

), cocrystal supersaturation index (SA), and transition points can be obtained from eutectic point measurements. The eutectic point here refers to 1 : 1 cocrystal and drug solid phases in equilibrium with a solution at given pH, additive concentrations, and temperature. The terms are described in the text.

Figure 6.7 Flowchart of representative method to determine equilibrium solution eutectic concentrations of cocrystal components. In this case, the solid phases at equilibrium are cocrystal and drug.

Figure 6.8 Concentrations of drug (carbamazepine, CBZ) and coformer (salicylic acid, SLC) at the eutectic point for the 1 : 1 CBZ‐SLC cocrystal and CBZ dihydrate system in pH 3.0 aqueous solutions with and without surfactant (sodium lauryl sulfate, SLS). In the absence of surfactant, [SLC]

eu

 > [CBZ]

eu

, and

K

eu

 > 1, indicating that the cocrystal is more soluble than the drug. This situation is inverted in 1% SLS, where [CBZ]

eu

 > [SLC]

eu

and

K

eu

 < 1, indicating that the cocrystal is less soluble than the drug. The solid phases at the eutectic point are the cocrystal and CBZ dihydrate, which is the drug solid form in equilibrium with cocrystal in aqueous media. The evaluation of

K

eu

and SA = 

S

cocrystal

/

S

drug

is described in the text.

Figure 6.9 Drug and coformer eutectic concentrations at different pH values for (a) NVP‐MLE, (b) NVP‐SAC, and (c) NVP‐SLC. For the NVP‐MLE cocrystal, [MLE]

eu

 > [NVP]

eu

at all pH values, indicating that the cocrystal is more soluble than the drug. SAC and SLC cocrystals have [NVP]

eu

 < or > than 2[SAC]

eu

and 2[SLC]

eu

. This behavior indicates that these cocrystals exhibit a pH

max

. For NVP‐SAC pH

max

is between pH 1.2 and 2.4. For NVP‐SLC, pH

max

is between pH 1.2 and 3.2. Therefore, cocrystal solubilities are lower, equal, or higher than drug depending on pH. The solid phases at the eutectic points are cocrystal and NVP hemihydrate, which is the drug solid form in equilibrium with cocrystal in aqueous media.

Figure 6.10 Predicted and experimental

K

eu

and SA (

S

cocrystal

/

S

drug

) values for 1 : 1 (full line) NVP‐MLE and 2 : 1(dashed line) NVP‐SAC and NVP‐SLC cocrystals.

K

eu

is a key indicator of SA.

K

eu

dependence on pH reveals the cocrystal pH

max

and the cocrystal increase in solubility over drug as pH increases. At pH

max

,

K

eu

 = 1 for 1 : 1 cocrystals and

K

eu

 = 0.5 for 2 : 1 cocrystals. Log axes are used due to the large range of values. Symbols represent experimental values. The numbers next to data points indicate pH at eutectic point or equilibrium pH. The lines were not fitted to the data but were calculated from the logarithmic forms of Equations (6.7) and (6.8).

Figure 6.11 Predicted (full lines) and observed (symbols) behavior of cocrystal solubility advantage (SA) as a function of drug solubilization ratio (SR

drug

) for danazol‐hydroxybenzoic acid (DNZ‐HBA), pterostilbene–caffeine (PTB‐CAF), and carbamazepine–saccharin (CBZ‐SAC) cocrystals. Cocrystal SA predicted from equations using only experimentally determined cocrystal SA

aq

. The dotted line at SA = 1 indicates the line of equal cocrystal and drug solubilities, SA = 1.

Figure 6.12 Phase solubility diagram showing the dependence of solid‐phase equilibria on solution composition. Drug, coformer, and cocrystal are represented by A, B, and AB. Cocrystal solubility, line

S

AB

, decreases with increasing coformer concentration and intersects the coformer and drug solubility curves,

S

A

and

S

B

, at eutectic points represented by

c

1

and

c

2

. The solution is saturated with both A and AB at

c

1

and with B and AB at c

2

. The filled circle refers to a cocrystal solubility in a solution of 1 : 1 molar ratio of cocrystal components. Solubilities of pure components are represented by lines

S

A

and

S

B

.

Figure 6.13 CBZ‐4ABA phase solubility diagram in ethanol demonstrates the influence of coformer concentration on the solubilities of drug (open diamond), coformer (filled diamond), 2 : 1 cocrystal (open circles), and 1 : 1 cocrystal (open square).

Figure 6.14 Triangular phase diagram of the CBZ, 4ABA, ethanol system shows the stability domains and corresponding solution‐/solid‐phase compositions. In this solvent and at the temperature studied, the domain of existence (2) of the pure 2 : 1 cocrystal. By comparison, the domain of existence (3) of the pure 1 : 1 cocrystal is quite narrow and may be found at high coformer to drug ratios (greater than 12).

Figure 6.15 Common supramolecular synthons formed with carboxylic acids, amides, pyridines, and other aromatic nitrogens.

Figure 6.16 Different synthons in carbamazepine: 4‐aminobenzoic acid cocrystals (CBZ‐4ABA): (a) carboxamide homosynthon of the 1 : 1 CBZ‐4ABA, (b) tetrameric amide‐acid heterosynthon of the 2 : 1 CBZ‐4ABA, and (c) amide‐acid‐H

2

O heterosynthon of the 2 : 1 CBZ‐4ABA‐H.

Figure 6.17 Rapid

in situ

cocrystal screening by RCM in microliter (96‐well plates) by Raman microscopy, indicating spectral changes between drug crystals (carbamazepine) and its cocrystals [23, 40].

Figure 6.18 Cocrystal solubility is determined by the fate of its molecular constituents in solution. This diagram shows cocrystal solution‐phase interactions for a cocrystal RHA composed of nonionizable drug (R) and ionizable coformer (HA) as well as the associated equilibria common to pharmaceutical dosage forms, including dissociation, complexation, ionization, and solubilization.

K

sp

represents the cocrystal solubility product,

K

a

is the ionization constant,

K

c

is the complexation constant, and

and

are the solubilization constants for HA and R, respectively.

Figure 6.19 Schematic illustration of the equilibria between the cocrystal solid phase and its components in the aqueous and micellar solution pseudophases. This scheme represents preferential micellar solubilization of the drug component, which leads to excess coformer in the aqueous phase.

Figure 6.20 Solubility‐pH profiles for (a) 1 : 1 HAHX cocrystal calculated using

, (b) 1 : 1 RHA cocrystal calculated using Equation (6.26), (c) 2 : 1 R

2

HAB cocrystal calculated using

, and (d) 1 : 1 BH

2

A and 2 : 1 B

2

HA cocrystals calculated using

and

, respectively.

K

sp

values were either experimentally determined or estimated from published work for the selected cocrystal(s) in each graph (a) indomethacin–saccharin (IND‐SAC) [33], (b) carbamazepine–saccharin (CBZ‐SAC) [33], (c) carbamazepine‐4‐aminobenzoic acid hydrate (CBZ‐4ABA‐H), and (d) nevirapine‐maleic acid (NVP‐MLE), nevirapine–saccharin (NVP‐SAC), and nevirapine‐salicylic acid (NVP‐SLC) [23, 28]. Symbols represent experimentally measured data.

Figure 6.21 Solubilities and transition points of carbamazepine (CBZ) cocrystals and carbamazepine dihydrate (CBZH) induced by sodium lauryl sulfate (SLS) preferential solubilization of CBZ for (a) 1 : 1 carbamazepine–saccharin (CBZ‐SAC) and (b) 2 : 1 carbamazepine‐4‐aminobenzoic acid hydrate (CBZ‐4ABA‐H). Transition points are characterized by a solubility (

S

*

) and a solubilizing agent concentration (CSC) (dashed lines). Both

S

*

and CSC vary with cocrystal aqueous solubility and stoichiometry. Symbols represent experimentally measured cocrystal (○) and drug (Δ) solubility values. Predicted drug and cocrystal solubilities (solid lines) were calculated according to Equation (6.26), and

, with the thermodynamic values listed in Ref. [35].

Figure 6.22

S

*

and CSC values for a cocrystal and its constituent drug in two different solubilizing agents, a and b.

S

*

is constant, and CSC varies with the extent of drug solubilization by the solubilizing agent. Drug is solubilized to a greater extent by a than by b, and thus CSC

a

 < CSC

b

. The curves were generated from Equations (6.32) and (6.33) with parameter values

S

D,aq

 = 0.5 mM,

S

CC,aq

 = 2.4 mM (

K

sp

 = 5.76 mM

2

), and

= 1.5 and 0.5 mM

−1

for solubilizing agents a and b, respectively.

Chapter 07

Figure 7.1 Elastic deformation under (a) tension, (b) shear, and (c) hydrostatic pressure.

Figure 7.2 A classical stress–strain curve.

Figure 7.3 Stress–strain curves. (a) A specimen undergoes brittle fracture if it breaks at point C before plastic yield takes place. (b) Comparison of materials exhibiting different degree of brittleness (A > D > C > B). Mechanical rigidity follows the order of A > B > C > D.

Figure 7.4 Classification of crystal mechanical responses to an external stress.

Figure 7.5 Models for different mechanical response of a crystal to stress. (a) Elastic deformation, (b) plastic deformation, (c) more extensive plastic deformation with time under a constant tensile force, and (d) brittle fracture.

Figure 7.6 The interplay between crystal structure and crystal geometry determines mechanical behavior of single crystals. Needle‐shaped crystals tend to break more easily along the long axis. (a) Brittle/elastic, (b) brittle/elastic/hard, (c) shearing, (d) bending, (e) elastic, (f) brittle/elastic, and (g) bending/plastic.

Chapter 08

Figure 8.1 Predicted BFDH morphology of (a) acetaminophen (CCDC refcode HXZCAN

01

) crystals and (b) orotic acid (CCDC refcode OROTAC) crystals.

Figure 8.2 Schematic emphasizing the branch of SMOC manufacturing that involves primary (1°) processing or bulk raw materials production. Exclamation points are meant to emphasize that the structure following processing will dictate the eventual properties of the processed material.

Figure 8.3 Schematic for a single‐component cooling crystallization scheme highlighting the relationships between the solution stable zone, metastable zone, and labile zone.

Figure 8.4 Schematic outlining drug development activities. Drug product (left) and drug substance (right) development are performed in parallel. Feedback between the two separate process streams is required in support of ever‐increasing requirements of both viable products and materials needed to produce them. Following approval, both process streams need to function efficiently to supply a sustainable market supply of reproducible drug product and drug substance to the market for many years.

Figure 8.5 A schematic representation of a batch crystallization sequence used to generate solid organic crystalline materials.

Figure 8.6 Schematics of (a) mixed suspension‐mixed product removal (MSMPR) continuous crystallizer. (b) Multistage plug flow reactor (PFR) system.

Figure 8.7 Examples of the sulfathiazole crystals obtained from different water :

n

‐propanol mixtures.

Figure 8.8 Photomicrographs of lysozyme crystal slurries prepared under different crystallization conditions. (a) isometric crystals, (b–d) different crystal aggregates, and (e) needlelike crystals. Slurries were obtained by different stirring conditions during the crystallization process.

Figure 8.9 Free energy–temperature diagram for hypothetical enantiotropic solids I and II, exhibiting a solid transition temperature

T

tr

= 50 °C. Following the trajectory between points 1 and 2 represents heating Form‐I through

T

tr

without melting. Spontaneous conversion from Form‐I to II follows the free energy trajectory between points 2 and 3. Re‐cooling Form‐II through

T

tr

(between points 3 and 4) results in eventual re‐conversion to Form‐I along the free energy path from point 4 to 1.

Figure 8.10 Descriptive nomenclature for particle sizing used in pharmaceutical 1° and 2° manufacturing.

Figure 8.11 (a) Schematic of a shear cell for determining powder flow properties. (b) Simplified yield data typical of a shear cell measurement. Note: Yield loci are often interpreted in terms of Mohr circle plots. For details of this interpretation, see Hiestand [41] and Schwedes [42].

Figure 8.12 Solubility–temperature diagrams for (a) hypothetical enantiotropic solids I and II. The dashed lines each corresponds to the metastable supersaturation curves (per Figure 8.3) for the respective forms; (b) hypothetical monotropic solids I and II. As in (a), the dashed lines each corresponds to the metastable supersaturation curves for the respective forms.

Figure 8.13 Unit cells for (a) sulfamerazine Form II (CCDC refcode SLFNMA

02

) and (b) sulfamerazine Form I (CCDC refcode SLFNMA

01

).

Figure 8.14 Recrystallization behavior of aqueous solutions of famotidine relative to concentration and nucleation temperature. Conditions in zone I result in solidification of Form B, zone II result in a mixture of Forms A and B, while zone III result in Form A. According to the legend of the original publication, (–) represents the solubility curve of Form A, (⋯) represents the solubility curve of Form B, and (–·–) represents the supersaturation curve of Form B (high temperature) and Form A (low temperature).

Figure 8.15 Asymmetric unit and unit cells from crystal structures of (a) famotidine Form A (CCDC refcode

FOGVIG04

) and (b) famotidine Form B (CCDC refcode

FOGVIG03

). Dashed lines in asymmetric units show intramolecular H‐bonds that contribute to conformational differences.

Figure 8.16 Evaporative crystallization of nitrofurantoin (NF) from different water–acetone mixtures (S1–S6). As shown, S1 was supersaturated with NF to begin with, S2 began with a saturated solution, and S3–S6 each began as undersaturated solutions. Evaporation of the cosolvent mixture resulted in increasing water activities as acetone was removed more quickly. The increasing supersaturation with solvent evaporation occurred at different rates for each solution, and the unique profiles each resulted in different mixtures of Form I and Form II monohydrates in the final product.

Figure 8.17 Examples of different classes of SMOC hydrates: (a) Class I (isolated site) hydrate, cephradine∙2H

2

O (CSD refcode: MIHZUA), (b) Class II (channel) hydrate, caffeine∙H

2

O (CSD refcode: CAFINE

01

), and (c) Class III (ion‐associated) hydrate, fenethazine∙HCl·H

2

O (CSD refcode: DIKSOF).

Figure 8.18 Solvent‐mediated transformation schematic for two polymorphs, A and B. Ostwald’s rule of stages suggests that at a given crystallization temperature, Form B may nucleate and grow first (points 1–2). Below

C

s,B

, metastable solid redissolves, driving nucleation and growth of the stable Form A.

Figure 8.19 SEM illustrating nucleation and growth at 25 °C of carbamazepine·2H

2

O on the surfaces of anhydrous carbamazepine in slightly supersaturated aqueous solutions (

S

= 1.15) containing 0.5% sodium lauryl sulfate.

Figure 8.20 (a) Predicted morphology of RDX using the attachment energy procedure, assuming growth in a vacuum. (b) Observed growth of RDX crystals grown from γ‐butyrolactone.

Figure 8.21 Scanning electron micrographs of aspirin crystals solidified from (a) acetone and (b) ethanol.

Figure 8.22 (a) Representation of Young’s experiment, showing the relationship between the liquid surface tension,

γ

L

, solid surface tension,

γ

S

, and interfacial tension between the two

γ

SL

. The magnitude of the contact angle (

θ

) represents the ease with which a droplet spreads on a solid surface. (b) Values of

θ

= 0° reflect perfect wetting, while

θ

= 180° reflect no wetting. Values in between, such as θ < 90°, represent some coherency of interactions between the solid and liquid across the interface, but not so much as to fully exceed the value surface tension of the liquid droplet.

Figure 8.23 Contact angle measurements of water on different surfaces of aspirin (CSD refcode ACSALA

01

) crystals [5]. Note that the larger value of q corresponds with the (100) face, which is dominated by the carboxyl portion of the aspirin molecules, while the smaller value of

θ

corresponds with the (002) face, cross‐sections the unit cell to expose more atoms capable of hydrogen bonding.

Chapter 09

Figure 9.1 (a) Extreme layering in orotic acid (CCDC refcode OROTAC

01

) and (b) intraplanar packing of orotic acid [5].

Figure 9.2 Herringbone packing pattern for acetaminophen (CCDC refcode: HXACAN

01

) [5].

Figure 9.3 Stresses and transformations involved in processing of SMOCs.

Figure 9.4 Schematic emphasizing the branch of SMOC processing that involves secondary (2°) processing, or raw materials manipulation. Exclamation points are meant to emphasize that the structure following processing will dictate the eventual properties of the processed material.

Figure 9.5 Molar volume (

M

V

) and glass transition temperature (

T

g

) for 27 SMOC materials subjected to continuous cryogenic impact milling. Materials to the left of the decision boundary (○) are resistant to complete disordering as a result of continuous milling, while materials to the right of the decision boundary (Δ) completely disorder as a result of continuous milling. The dashed decision boundary separating the two groups of materials represents the original bivariate model from Lin et al. [10], while the solid boundary represents the revised model including the materials in the expanded library.

Figure 9.6 Possible solid‐state phase transformations occurring as a result of milling.

Figure 9.7 Rate of gaba‐L formation increased with increasing exposure to high‐shear mechanical stress in a planetary mill (50 °C, 11% RH).

Figure 9.8 Formation of gaba‐L in milled samples stored for 24 hours at 25 °C under different relative humidity conditions (○) 81% RH and (□) 0% RH.

Figure 9.9 Relative particle adsorption of (a) irregular, rough‐textured small guest particles on regularly shaped, large host particles [80]; (b) regular, smooth‐textured, small guest particles adsorbed on regularly shaped, smooth‐textured large host particles; (c) regular, smooth, small guest particles on irregular, rough‐textured, large host particles [78].

Figure 9.10 Progression of granule formation typical of high‐shear wet granulation. The materials are initially (a) dry mixed to form a homogeneous blend; (b) wetting initiates liquid bridge formation; (c) agglomerates proceed through the pendular and funicular stages as more liquid bridges build, eventually reaching (d) the capillary endpoint, where interparticulate liquid bridges are maximized. Overwetting can lead to (e) droplet stage, where the particles become dissolved or suspended in the granulating fluid, leading to batch failure. The process is finished when (f) solvent is removed by drying agglomerates.

Figure 9.11 Possible transformations that can occur during wet granulation when formation of a hydrate is involved.

Figure 9.12 Interconversions of chlorpromazine·HCl (CPZ) involving hydration/dehydration experienced during wet granulation and drying.

Figure 9.13 PXRD patterns of (a) σ‐mannitol after wet granulation and vacuum drying and (b) σ‐mannitol prior to wet granulation and drying. For comparison, the PXRD pattern of (c) β‐mannitol is provided, demonstrating a σ to β transition as a consequence of this process.

Figure 9.14 Gibbs free energy vs. temperature (G–T) phase diagrams for two related polymorphs, Form I and Form II. By comparison (a) monotropically related polymorphs are characterized by intersection with the liquidus line at a temperature greater than the transition temperature (

T

tr

), while (b) enantiotropes intersect the liquidus line at temperatures greater than the transition temperature (

T

tr

).

Figure 9.15 FT‐Raman spectra of (from top to bottom) Compound A·HCl, Compound A free base amorphous solid, spectral subtraction of placebo from active granules prepared using absolute ethanol, spectral subtraction of placebo from active granules prepared using 96% ethanol, and spectral subtraction of placebo from active granules prepared using 90% ethanol. Panel (a) show granules prepared with no delay between granulation and drying, while panel (b) shows spectra for granules held for four hour between wet granulation and drying [117].

Figure 9.16 Overview of the powder compaction process.

Figure 9.17 Crystal structures for (a) Form I of 2‐amino‐5‐nitropyrimidine (CCDC refcode

PUPBAD01

) and (b) Form II of sulfamerazine (CCDC refcode

SLFNMA01

) obtained from Cambridge Crystallographic Database [5]. In Sun and Kiang [4], slip planes identified by visualization from the crystal structure and calculated using the

E

A

method agreed for

PUPBAD01

, while they disagreed for

SLFNMA01

.

Figure 9.18 (a) Orientation of slip plane normal (SPN) and slip direction (SD) to applied compressive stress. Deformation occurs by slip, when the resolved shear stress on the highlighted plane resolves to exceed a critical value (

τ

crit

). (b) Example of slip planes preferentially oriented with SD parallel to compressive axis. The entirety of the compressive load is resolved on the slip plane, allowing for maximal dislocation motion and plastic deformation. (c) Example of slip planes preferentially oriented perpendicular to compressive load. With

λ

= 90°, no shear components of the load are resolved on the slip planes, preventing deformation by slip.

Figure 9.19 Chlorpropamide enantiotropes, Form A and Form C. Transformation requires conformational changes, facilitated by slip on a common plane. The figures shown above each conformer view each crystal structure oriented with its slip plane parallel to the page (slip vector indicated). Spheres represent mass centers for the molecules and illustrate a collective displacement in the slip plane as the molecules conform during deformation.

Figure 9.20 The DM

3

approach of pharmaceutical process outcome analysis.

Chapter 10

Figure 10.1 Categories of drug degradation and examples of degradation mechanisms.

Figure 10.2 (a) Schematic representation of template‐directed solid‐state reactivity; (b) and (c) examples of stacked alignment induced by resorcinol functionality (small molecule template) [18].

Figure 10.3 Solid‐state thermal reaction of aspirin.

Figure 10.4 Drug substances containing (a) an ester linkage and (b) and amide linkage. The labile bonds are indicated by a dashed line.

Figure 10.5 Oxidation of hydrocortisone 21‐

tert

‐butylacetate.

Figure 10.6 Energy potential generated by interactions with neighboring molecules in the crystal. Reactant and transition state molecules in the crystal are illustrated.

Figure 10.7 Photodimerization of trans‐cinnamic acid.

Figure 10.8 Various classes of organic molecules capable of undergoing topochemical reactions in the solid state upon exposure to ultraviolet light: (a) fumaryl derivatives, (b)

trans

‐cinnamic acid heterocyclic analogues, (c) butadiene derivatives, (d) coumarins, and (e) diacetylene derivatives.

Figure 10.9 Illustration of structural imperfections in crystalline materials: (a) vacancy, (b) interstitial point defect, (c) screw dislocation, (d) edge dislocation, (e) twin boundaries, and (f) grain boundaries.

Figure 10.10 Appropriate molecular orientation for reaction due to stacking faults in 9‐cyanoanthracene crystals.

Figure 10.11 Degradation mechanism of cefoxitin sodium.

Figure 10.12 Prodrugs with improved chemical stability compared with the parent active molecule: (a) aspirin, (b) hetacillin, and (c) tenofovir disoproxil fumarate.

Chapter 11

Figure 11.1 Structure of media mill and schematic representation of the media milling process.

Figure 11.2 Structure of Z‐type and Y‐type chamber of microfluidizer.

Figure 11.3 Structure of piston‐gap homogenizer.

Figure 11.4 Schematic illustration of confined impinging jets reactor (a) and the contour plots of mean mixture fraction (b).

Figure 11.5 Structure of T‐ (a) and Y‐ (b) confined impinging jet mixers and incorporation of a sonication probe into the mix‐head to enhance mixture.

Figure 11.6 Fast liquid jet mixing in millimeter channels: three‐dimensional diagrammatic sketch (a) and cross‐sectional configuration (b).

Figure 11.7 Geometry and grids of multiple inlet vortex mixers with two inlets (a) and four inlets (b); flash nanoprecipitation with symmetric (c) and asymmetric (d) arrangement of the inlet streams.

Figure 11.8 Schematic representation of HGCP process. (1: casing; 2: packed rotator; 3: motor; 4: liquid distributors; 5: flow meters; 6: seal ring; 7: outlet; 8: pump; 9, 10: liquid storage containers).

Figure 11.9 Adsorption of polymers on the surface of crystals is a competition of crystal growth. Strong and fast adsorption at full coverage balanced with slow desorption will result in successful stabilization. Otherwise, crystals will grow up. The adsorbed polymers provide steric hindrance, electrostatic repulsion, or dual protection to stabilize crystals.

Figure 11.10 Increased dissolution crystalline nanoparticles are mainly ascribed to the increased total surface area.

Figure 11.11 Illustration of DLS/PCS, LD, and coulter counter. DLS measures the light scattered from a laser that passes through a colloidal solution and by analyzing the modulation of the scattered light intensity as a function of time, the hydrodynamic size of particles and particle agglomerates can be determined. LD measure the light intensity distribution pattern of the forward scattered light resulted by particles irradiated with a laser beam. Side scattered light and backward scattered light are also detected. Light intensity distribution data are thus obtained by analysis of various sensing elements. Particles are dispersed in electrolyte for coulter counter. Each particle passes through the aperture and results in a voltage pulse proportional to the particle volume. Therefore, coulter counter can measure the absolute number of particles per volume unit of different size classes.

Figure 11.12 Illustration and measurement of zeta potential.

Guide

Cover

Table of Contents

Begin Reading

Pages

iii

iv

xiii

xiv

xv

xvi

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

44

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

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

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

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

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

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

324

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

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

396

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

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

Pharmaceutical Crystals

Science and Engineering

Edited by

Tonglei Li

Department of Industrial and Physical Pharmacy, Purdue UniversityWest Lafayette, IN, USA

Alessandra Mattei

AbbVie Inc.North Chicago, IL, USA

This edition first published 2019© 2019 John Wiley & Sons, Inc.

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.

The right of Tonglei Li and Alessandra Mattei to be identified as the authors of the editorial material in this work has been asserted in accordance with law.

Registered OfficeJohn Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA

Editorial Office111 River Street, Hoboken, NJ 07030, USA

For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.

Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats.

Limit of Liability/Disclaimer of WarrantyIn view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of experimental reagents, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each chemical, piece of equipment, reagent, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.

Library of Congress Cataloging‐in‐Publication Data

Names: Li, Tonglei, 1967– editor. | Mattei, Alessandra, 1977 June 18– editor.Title: Pharmaceutical crystals : science and engineering / edited by Tonglei Li, Alessandra Mattei.Description: First edition. | Hoboken, NJ : John Wiley & Sons, 2018. | Includes bibliographical references and index. |Identifiers: LCCN 2018016966 (print) | LCCN 2018031765 (ebook) | ISBN 9781119046202 (Adobe PDF) | ISBN 9781119046349 (ePub) | ISBN 9781119046295 (hardcover)Subjects: LCSH: Crystals–Structure. | Pharmaceutical chemistry. | Drug development.Classification: LCC QD921 (ebook) | LCC QD921 .P478 2018 (print) | DDC 548–dc23LC record available at https://lccn.loc.gov/2018016966

Cover design by WileyCover image: Courtesy of Tonglei Li

List of Contributors

Stephen R. ByrnDepartment of Industrial and Physical PharmacyPurdue UniversityWest Lafayette, INUSA

Katie L. CavanaghDepartment of Pharmaceutical SciencesUniversity of MichiganAnn Arbor, MIUSA

Junbo GongSchool of Chemical Engineering and TechnologyTianjin UniversityTianjinP.R. China

Rahul V. HawareCollege of Pharmacy & Health SciencesCampbell UniversityBuies Creek, NCUSAandDepartment of Pharmaceutical SciencesArnold and Marie Schwartz College of PharmacyLong Island UniversityBrooklyn, NYUSA

Gislaine KuminekDepartment of Pharmaceutical SciencesUniversity of MichiganAnn Arbor, MIUSA

Tonglei LiDepartment of Industrial and Physical PharmacyPurdue UniversityWest Lafayette, INUSA

Yi LuKey Laboratory of Smart Drug Delivery of MOE and PLA, School of PharmacyFudan UniversityShanghaiP.R. China

Alessandra MatteiAbbVie Inc.North Chicago, ILUSA

Kenneth R. MorrisDepartment of Pharmaceutical Sciences, Arnold and Marie Schwartz College of PharmacyLong Island UniversityBrooklyn, NYUSA

Peter MüllerX‐Ray Diffraction FacilityMIT Department of ChemistryCambridge, MAUSA

Ann NewmanSeventh Street Development GroupKure Beach, NCUSA

Haichen NieDepartment of Industrial and Physical PharmacyPurdue UniversityWest Lafayette, INUSA

Susan M. Reutzel‐EdensSmall Molecule Design & Development, Eli Lilly & CompanyLilly Corporate CenterIndianapolis, INUSA

Naír Rodríguez‐HornedoDepartment of Pharmaceutical SciencesUniversity of MichiganAnn Arbor, MIUSA

Changquan Calvin SunDepartment of Pharmaceutics, College of PharmacyUniversity of MinnesotaMinneapolis, MNUSA

Weiwei TangSchool of Chemical Engineering and TechnologyTianjin UniversityTianjinP.R. China

Robert WenslowCrystal PharmatechNew Brunswick, NJUSA

Peter L.D. WildfongGraduate School of Pharmaceutical Sciences, School of PharmacyDuquesne UniversityPittsburgh, PAUSA

Wei Wu