SOLID-STATE PROPERTIES OF
`PHARMACEUTICAL MATERIALS
`
`STEPHEN R. BYRN
`GEORGE ZOGRAFI
`XIAOMING (SEAN) CHEN
`
`Gilead 2012
`I-MAK v. Gilead
`IPR2018-00126
`
`Page 1 of 55
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-14 08:26:52.
`
`

`

`This edition first published 2017
`© 2017 John Wiley & Sons, Inc.
`
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`Library of Congress Cataloging-in-Publication Data:
`Names: Byrn, Stephen R., author. | Zografi, George, author. | Chen, Xiaoming (Sean), author.
`Title: Solid-state properties of pharmaceutical materials / Stephen R. Byrn, George Zografi,
`Xiaoming (Sean) Chen.
`Description: Hoboken, NJ : John Wiley & Sons, 2017. | Includes index.
`Identifiers: LCCN 2017005555 (print) | LCCN 2017008527 (ebook) | ISBN 9781118145302 (cloth) |
`ISBN 9781119264446 (Adobe PDF) | ISBN 9781119264453 (ePub)
`Subjects: LCSH: Solid state chemistry. | Solid dosage forms–Properties.
`Classification: LCC QD478 .B96 2017 (print) | LCC QD478 (ebook) | DDC 615.1028/4–dc23
`LC record available at https://lccn.loc.gov/2017005555
`
`Cover images: (Background) © Mimi Haddon/Getty images; (Inset images) Aeinleng, Nunchanit et al. “Physicochemical Performances of Indomethacin in
`Cholesteryl Cetyl Carbonate Liquid Crystal as a Transdermal Dosage.” AAPS PharmaSciTech 13.2 (2012): COVER. PMC
`Cover design by Wiley
`
`Set in 10/12pt TimesLTStd by Aptara Inc., New Delhi, India
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`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-14 08:26:52.
`
`Page 2 of 55
`
`

`

`1 S
`
`OLID-STATE PROPERTIES AND PHARMACEUTICAL
`DEVELOPMENT
`
`1.1
`
`INTRODUCTION
`
`Solid-state chemistry and the solid-state properties of phar-
`maceutical materials play an ever increasing and important
`role in pharmaceutical development. There is much more
`emphasis on physical characterization since the release of
`the International Committee on Harmonization (ICH) Q6A
`guidance on specifications. This guidance directs the scientist
`to determine what solid form is present in the drug substance
`(active pharmaceutical ingredient [API]) and drug product. It
`directs the manufacturer to “know what they have.” Addition-
`ally, the ICH Q8 guidance on development and the ICH Q9
`guidance on risk management require a firm understanding
`of how the medicine was developed and any risks involved.
`There are many more poorly soluble drugs under devel-
`opment. In many cases, the solid form of the API and
`the solid form and formulation in the drug product deter-
`mine apparent solubility that in turn determines blood lev-
`els. That is, the formulation determines bioavailability and
`therapeutic response. In these cases, it is even more impor-
`tant to physically characterize the API form and the formu-
`lations. Furthermore, the vast majority of medicines (drug
`products) are solids and those drug products that are not
`solids often start with solid APIs. In addition to solubil-
`ity and bioavailability, the solid form may affect stability,
`flow, compression, hygroscopicity, and a number of other
`properties.
`This book focuses on solid-state properties of pharmaceu-
`tical materials and methods of determining these properties.
`The authors have made every effort to include examples and
`
`case studies in order to illustrate the importance of knowing
`what you have. This book will focus on solid-state prop-
`erties and general strategies for physical characterization.
`Case studies and practical examples will be emphasized. In
`many respects, this book will illustrate that a medicine is
`more than a molecule. Additional goals include providing a
`full physical/analytical/operational definition of the different
`solid forms as well as other terms frequently used in phar-
`maceutical materials science including: polymorph, solvate,
`amorphous form, habit, nucleation, transformation, dissolu-
`tion, solubility, and stability.
`
`1.2 SOLID-STATE FORMS
`
`Pharmaceutical materials can exist in a crystalline or amor-
`phous state. Figure 1.1 illustrates the crystalline state as a
`perfectly ordered solid with molecules (circles) packed in an
`orderly array. Figure 1.1 illustrates an amorphous material
`as a disordered material with only short-range order. Crys-
`talline materials give an X-ray diffraction pattern because
`Bragg planes exist in the material (see Figure 1.2). Amor-
`phous materials do not give a diffraction pattern (Figure 1.2).
`Of course, there are many interesting cases where a phar-
`maceutical material shows an intermediate degree of order
`falling somewhere between the highly ordered crystalline
`state and the disordered amorphous state. From a thermody-
`namic point of view, crystalline materials are more stable but
`the rate of transformation of amorphous materials to crys-
`talline materials can be highly variable [1].
`
`Solid-State Properties of Pharmaceutical Materials, First Edition. Stephen R. Byrn, George Zografi and Xiaoming (Sean) Chen.
`© 2017 John Wiley & Sons, Inc. Published 2017 by John Wiley & Sons, Inc.
`
`Page 3 of 55
`
`1
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`

`

`2
`
`SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
`
`FIGURE 1.1
`Idealized view of crystalline (left panel) and amorphous (right panel) material. In
`this two-dimensional figure, the molecules are viewed as circles.
`
`Crystals of a pharmaceutical material from different
`sources can vary greatly in their size and shape. Typical parti-
`cles in different samples may resemble, for example, needles,
`rods, plates, and prisms. Such differences in shape are col-
`lectively referred to as differences in morphology. This term
`merely acknowledges the fact of different shapes. It does not
`distinguish among the many possible reasons for the different
`
`shapes. Naturally, when different compounds are involved,
`different crystal shapes would be expected as a matter of
`course. When batches of the same substance display crystals
`with different morphology, however, further work is needed
`to determine whether the different shapes are indicative of
`polymorphs, solvates, or just habits. Because these distinc-
`tions can have a profound impact on drug performance, their
`
`FIGURE 1.2 X-ray diffraction pattern of three samples, crystalline,
`amorphous.
`
`low crystallinity, and
`
`Page 4 of 55
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`

`

`careful definition is very important to our discourse. At this
`time, only brief definitions are presented.
`
`r Polymorphs: When two crystals have the same chemical
`composition but different internal structure (molecular
`packing), they are polymorphic modifications, or poly-
`morphs (think of the three forms of carbon: diamond,
`graphite, and fullerenes). Polymorphs can result from
`different molecular packing, different molecular confor-
`mation, different tautomeric structure, or combinations
`of these.
`r Solvates: These crystal forms, in addition to containing
`molecules of the same given substance, also contain
`molecules of solvent regularly incorporated into a unique
`structure (think of wet, setting plaster: CaSO4 + 2H2O →
`⋅2H2O).
`CaSO4
`r Habits: Crystals are said to have different habits when
`samples have the same chemical composition and the
`same crystal structure (i.e., the same polymorph and unit
`cell) but display different shapes (think of snowflakes).
`
`Together, these solid-state physical modifications of a com-
`pound are referred to as crystalline forms. When differences
`between early batches of a substance are found by micro-
`scopic examination, for example, a reference to “form” is
`particularly useful in the absence of information that allows
`the more accurate description of a given variant batch (i.e.,
`polymorph, solvate, habit, or amorphous material). The term
`pseudopolymorphism is applied frequently to designate sol-
`vates. These solid-state modifications have different physical
`properties.
`
`SOLID-STATE FORMS
`
`3
`
`To put these important definitions into a practical con-
`text, we consider two cases (aspirin and flufenamic acid)
`in which a drug was crystallized from several different sol-
`vents and different-shaped crystals resulted in each exper-
`iment. Although sometimes dramatically different shapes
`were obtained upon changing solvents for the various crys-
`tallizations, the final interpretations in the two cases are dif-
`ferent. For aspirin, X-ray powder diffraction showed that all
`crystals regardless of shape had the same diffraction pattern.
`Thus, the different shaped crystals are termed crystal habits.
`For flufenamic acid, the different shaped crystals had differ-
`ent X-ray powder diffraction patterns. Subsequent analysis
`showed that the crystals did not contain solvent. Thus these
`different crystals are polymorphs.
`Further analysis of the crystals from this case provides
`the single crystal structure. The single crystal structure
`gives the locations of the atoms relative to a hypothetical unit
`cell. The unit cell is the smallest building block of a crys-
`tal. Figure 1.3 shows the unit cell of Form I of flufenamic
`acid. This unit cell contains four flufenamic acid molecules.
`Figure 1.4 shows a space-filling model of the contents of
`the flufenamic acid Form I unit cell. This figure illustrates
`Kitaigorodskii’s close-packing theory, which requires that
`the molecules pack to minimize free volume [2].
`Amorphous materials will be discussed in Chapter 6. In
`this introductory chapter as mentioned briefly above, amor-
`phous materials have no long range order and are thermody-
`namically metastable. An amorphous solid is characterized
`by a unique glass transition temperature Tg, the temperature
`at which it changes from a glass to a supercooled liquid or
`rubbery state. When T rises above Tg, the rigid solid can
`
`CF3
`
`HN
`
`COOH
`
`a
`
`0
`
`0
`
`c
`
`FIGURE 1.3 Single crystal structure the Form I polymorph of flufenamic acid (structure shown
`on the right panel).
`
`Page 5 of 55
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`

`

`4
`
`SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
`
`It is possible to make a “top 10” list of the differences
`between crystalline and amorphous materials. Crystalline
`materials have the following characteristics:
`
`1. higher purity,
`2. More physically and chemically stable, crystalline
`hydrate > anhydrous crystal > amorphous
`3. lower solubility,
`4. narrow and (usually) higher melting point range,
`5. harder,
`6. brittle – slip and cleavage,
`7. directionally dependent properties – anisotropy,
`8. less compressible,
`9. better flow and handling characteristics, and
`10. less hygroscopic.
`
`From this list, it is clear that crystalline materials are gen-
`erally more desirable unless they are so insoluble that they
`cannot be used as medicines.
`Not only do polymorphs show different X-ray powder
`diffraction patterns but they also have different unit cells,
`and different properties including thermal properties [6]. Fig-
`ure 1.5 shows the different crystal packing of the Forms I and
`II of sulfathiazole.
`Additionally, polymorphs are characterized as monotropic
`or enantiotropic depending upon their thermal properties
`[9, 10].
`
`r Monotropic polymorphs exist if the transition tem-
`perature between forms is greater
`than the melt.
`In monotropic polymorphs, one form is most stable
`throughout the temperature range.
`r Enantiotropic polymorphs exist if the transition tem-
`perature between forms occurs before melting. In this
`case, one form is more stable at one temperature. At a
`
`FIGURE 1.4 Space filling drawing of the unit cell of flufenamic
`acid Form I.
`
`flow and the corresponding increase in molecular mobility
`can result in crystallization or increased chemical reactiv-
`ity of the solid. Several historic papers describe some addi-
`tional details of amorphous materials. Pikal and coworkers at
`Eli Lilly showed that amorphous materials can have lower
`chemical stability [3], and Fukuoka et al. showed amorphous
`materials had a tendency to crystallize [4]. Nevertheless, in
`some cases, amorphous forms have been historically used
`as products. An excellent example is novobiocin [5], which
`exists in a crystalline and an amorphous form. The crys-
`talline form is poorly absorbed and does not provide thera-
`peutic blood levels; in contrast, the amorphous form is readily
`absorbed and is therapeutically active. Further studies show
`that the solubility rate of the amorphous form is 70 times
`greater than the crystalline form in 0.1 N HCl at 25◦C when
`particles <10 micron are used.
`
`FIGURE 1.5 Crystal packing and unit cells (grey) of Forms I (left panel) and II (right panel)
`of sulfathiazole. The grey and black molecules in Form I indicate two unrelated molecules in the
`asymmetric unit. Source: Kruger and Gafner, 1971 [7, 8]. Redrawn from data published.
`Page 6 of 55
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`

`

`different temperature the other form is most stable. For
`flufenamic acid, Form I is most stable above the tran-
`sition temperature of 42◦C and Form III is most stable
`below the transition temperature. Practically, this means
`that slurrying at room temperature will convert Form I
`to Form III.
`
`Crystalline solvates contain solvents regularly incorporated
`into the crystal lattice. When the solvent is water the solid
`form is called a hydrate. Solvates and hydrates do not have
`the same composition as unsolvated materials. Solvates and
`hydrates are sometimes referred to as pseudopolymorphs or
`solvatomorphs. Interestingly, it is possible for solvates and
`hydrates to be polymorphic. In such a case one has polymor-
`phic solvates. Kuhnert Brandstatter in her 1971 book showed
`photomicrographs of 16 solvates of estradiol [11]. Figure 1.6
`shows the crystal structure of caffeine monohydrate. The
`crystal of caffeine is built up by stacking the layers shown in
`Figure 1.6 on top of each other. Thus the hydrate molecules
`are in tunnels in this solid form.
`It is important to note that the FDA (Food and Drug
`Administration) has defined polymorphs as “different crys-
`talline forms of the same drug substance. This may include
`solvation or hydration products (also known as pseudopoly-
`morphs) and amorphous forms. Per the current regulatory
`scheme, different polymorphic forms are considered the same
`active ingredients.” Thus, for purposes of registration, sci-
`entists are directed to define polymorphs more broadly to
`include amorphous forms, solvates, and hydrates.
`Cocrystals, that is, two component crystals, are another
`solid material of interest. Like solvates, the new crystalline
`
`SOLID-STATE FORMS
`
`5
`
`FIGURE 1.7 Crystal structure of a cocrystal (2-methoxy-4-
`nitrophenol-4-(dimethylamino) pyridine (2:1)). The unit cell param-
`eters are a = 6.880, b = 38.40, c = 8.454, and the space group is
`Pna21. Source: Burger and Ramberger, 1979 [9, 10]. Reproduced
`with the permission of Springer.
`
`structure imparts different properties including solubility,
`stability, and mechanical properties to the material. Of special
`interest are cocrystals with altered solubility or stability. Fig-
`ure 1.7 shows the crystal structure of a cocrystal of phenol and
`2-methoxy-4-nitrophenol–4-(dimethylamino)pyridine (2:1)
`[12]. The FDA has recently released a draft guidance defining
`cocrystals as “Solids that are crystalline materials composed
`of two or more molecules in the same crystal lattice.”
`Pharmaceutical salts are substances formed by a reaction
`of an acid and a base. The FDA has suggested the follow-
`ing definition of salts as “Any of numerous compounds that
`result from replacement of part or all of the acid hydrogen
`of an acid by a metal or a radical acting like a metal: an
`ionic or electrovalent crystalline compound. Per the current
`regulatory scheme, different salt forms of the same active
`moiety are considered different active ingredients.” When
`a carboxylic acid reacts with an amine a salt is typically
`formed (Scheme 1.1). However, the degree of proton transfer
`can vary depending on the acidity and basicity of the reacting
`groups. The FDA definition seems to encompass all of these
`materials.
`
`RCOOH + H2N − R′ ⟶ RCOO− ⋯ H3N+ − R
`
`FIGURE 1.6 Projection of the crystal structure of caffeine
`hydrate on the ab plane. Source: Burger and Ramberger, 1979
`[9, 10]. Reproduced with the permission of Springer.
`
`Page 7 of 55
`
`SCHEME 1.1
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`

`

`6
`
`SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
`
`FIGURE 1.8 Crystal packing of calcium tolfenamate trihydrate showing hydrogen bonding net-
`work. The directions of the unit cell axis are (a) vertical, (c) across, and (b) out of the plane of the
`paper. Source: Atassi, 2007 [13]. Reproduced with the permission of Purdue University.
`
`Figure 1.8 shows the crystal structure of calcium tolfe-
`namate trihydrate. It is clear that the unit cell is composed
`of regions containing mostly hydrocarbon functional groups
`and regions containing polar functionalities. This type of
`crystal packing is typical for salts.
`
`1.3
`
`ICH Q6A DECISION TREES
`
`In 1995, Byrn et al. from Purdue University and the FDA pub-
`lished a paper using decision trees to describe a strategy to
`identify the best solid form early in development. In this way,
`it is possible to ensure uniformity of solid form in clinical
`trials and resolve solid-state issues before critical stages of
`development. The decision trees also suggested appropriate
`analytical methods for control. Four decision trees were pre-
`sented: polymorphs, hydrates/solvates, desolvated solvates,
`and amorphous forms [14].
`In the late 1990s, the ICH used a similar decision tree
`approach to describe how specification for the solid form
`in drug substances (API) and drug product should be deter-
`mined. Several decision trees were presented in the ICH
`Q6A document including decision trees on particle size and
`polymorphs. The ICH utilized the broadened definition of
`polymorphs that includes hydrates, solvates, and amorphous
`
`forms. The ICH decision trees are divided into three ques-
`tions as shown in Figures 1.9–1.11.
`These three decision trees outline a strategy that is widely
`used during drug development. Most firms conduct an early
`polymorph screen to address question number 1. Once new
`forms have been identified, they are physically characterized
`(solubility, stability, melting point) and an effort is made to
`understand whether these differences in properties will affect
`drug product safety, performance, or efficacy. If the different
`solid forms can affect safety, efficacy, or performance then
`question 3 is addressed by determining whether drug product
`testing can detect changes in ratios of these forms. Addition-
`ally, the ratios of forms are monitored during stability studies
`to make sure changes that affect performance, safety, or effi-
`cacy do not occur. Using this strategy, it is possible to find
`the best solid form for development rapidly.
`
`“BIG QUESTIONS” FOR DRUG
`1.4
`DEVELOPMENT
`
`In addition to selecting the solid form, Table 1.1 lists other
`critical issues/measurements required for drug development.
`Another way to think about drug development is to think
`of this process in terms of answering a series of questions
`we call the “Big Questions.” These must be answered to be
`
`Page 8 of 55
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`

`

`“BIG QUESTIONS” FOR DRUG DEVELOPMENT
`
`7
`
`FIGURE 1.9
`ICH Q6A question 1 on polymorphs: Can different polymorphs be formed? Source:
`ICH Harmonized Tripartite Guideline, 1999. Reproduced with the permission of ICH.
`
`FIGURE 1.10
`ICH Q6A question 2 on polymorphs: Do the forms have different properties (sol-
`ubility, stability, melting point)? Source: ICH Harmonized Tripartite Guideline, 1999. Reproduced
`with the permission of ICH.
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`Page 9 of 55
`
`

`

`8
`
`SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
`
`FIGURE 1.11
`ICH Q6A question 3 on polymorphs: Does products performance testing provide
`adequate control I polymorph ratio changes (e.g., dissolution)? Source: ICH Harmonized Tripartite
`Guideline, 1999. Reproduced with the permission of ICH.
`
`able to develop a drug to clinical trials and beyond. These
`questions are as follows:
`
`r What is the structure of the compound?
`r What is the likely dose?
`r What is the route of administration and desired dosage
`form?
`r What is the indication?
`r How difficult is it to synthesize?
`r How soluble is the compound/formulation?
`r How well is the compound absorbed? What is its BCS
`(Biopharmaceutical Classification System) class?
`r What is the toxicology of the compound? What is its
`NOAEL (no-observed-adverse-effect-level)? What is its
`MTD (maximum tolerated dose)?
`
`Page 10 of 55
`
`TABLE 1.1 Critical Issues for Drug Development
`
`Polymorph selection
`Chemical synthesis
`Salt selection (optional)
`Assay/Impurities
`Particle size
`Physical characterization and properties
`Dissolution/solubility
`Consistency
`Stability
`Validated methods/processes
`Regulatory issues
`Intellectual property
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`

`

`r What biomarkers are available to monitor clinical trials?
`r What doses should be used for Phase 2 clinical trial?
`r What are its solid-state properties and physical charac-
`terization?
`r How chemically stable is the compound?
`r How physically stable is the compound?
`r How well will the powder flow?
`r Is moisture an issue?
`r What is the design, composition, and manufacturing
`procedure of the formulation/product?
`
`As has already been discussed, the solubility of the compound
`is a critical quality attribute important for specifications and
`development. The solubility of a solid substance is the con-
`centration at which the solution phase is in equilibrium with
`a given solid phase at a stated temperature and pressure.
`Under these conditions, the solid is neither dissolving nor
`continuing to crystallize. Note that the definition implies the
`presence of a specific solid phase. Once determined under the
`stated conditions, however, we can talk about the “solubility”
`of a given phase (e.g., a specific polymorph or pseudopoly-
`morph) as a quantity, even in the absence of that solid phase.
`Use of the term “equilibrium” in connection with crystalliz-
`ing systems requires clarification. When a substance exists in
`more than one crystal form, that is, when other polymorphs
`are possible, only the least soluble of these at a given tem-
`perature is considered the most physically stable form at that
`temperature, all others are considered to be metastable forms.
`In given cases, a solution of a substance may be in apparent
`equilibrium with one of these metastable phases for a long
`time, in which case, the system is in metastable equilibrium
`and is expressing the thermodynamic solubility of that solid
`form.
`It is important to stress the difference between poly-
`morphs and solvates (pseudopolymorphs) at this point. If
`a solvate/pseudopolymorph exists, it is always (with few
`exceptions) the most stable form in the solvent that produces
`the pseudopolymorph.
`Undersaturation pertains to solutions at a lower concentra-
`tion than the saturation value (i.e., diluted solutions). Crystals
`will dissolve in undersaturated solutions. Saturation is the
`state of a system where the solid is in equilibrium with the
`solution, or in other words, the solution will neither dissolve
`crystals nor let them grow (i.e., the concentration of the solu-
`tion represents the solubility value for that crystalline phase).
`Supersaturation pertains to solutions that, for one reason or
`another (e.g., rapid cooling of a saturated solution without
`forming crystals), are at a higher concentration than the satu-
`ration value. Supersaturation is required for crystals to grow.
`The solubility and permeability are combined to deter-
`mine the BCS class (Table 1.2). BCS class I drugs dis-
`solve easily and are easily transported into the blood stream
`
`ACCELERATING DRUG DEVELOPMENT
`
`9
`
`TABLE 1.2 Biopharmaceutical Classification System (BCS)
`
`BCS Classification
`
`Solubility
`
`Permeability
`
`BCS class I
`BCS class II
`BCS class III
`BCS class IV
`
`High
`Low
`High
`Low
`
`High
`High
`Low
`Low
`
`because they are highly permeable with respect to the mem-
`branes in the gastrointestinal (GI) tract. BCS class III and
`IV drug have poor permeability and are generally difficult
`to develop. BCS class II drugs are of the greatest interest to
`pharmaceutical scientists because the structure of the solid,
`the formulation, its physical character, and many other fac-
`tors are likely to have a significant effect on bioavailabil-
`ity and ultimately safety, performance, and efficacy. Several
`important drugs that are widely prescribed are BCS Class
`II including atorvastatin calcium, celecoxib, efavirenz, irbe-
`sartan, lopinavir, medroxyprogesterone acetate, raloxifene
`hydrochloride, simvastatin, and warfarin sodium. Of the mar-
`keted drugs nearly 70% are in BCS Class I or II with 31%
`being in BCS Class II. It has been estimated that as high as
`80% of the drugs under development are BCS Class II.
`
`1.5 ACCELERATING DRUG DEVELOPMENT
`
`Accelerating drug development has been a goal of pharma-
`ceutical scientists for many years. In 1995, Colin Gardner of
`Merck introduced a flow chart showing synthesis of the API
`and development of clinical supplies for first in human trials
`in 1 year. In this early flow chart, drug substance synthesis
`and process development were carried out in parallel with
`preformulation/formulation design/development and safety
`studies. Despite the early introduction of the concept that an
`IND (investigational new drugs) can be submitted in 1 year,
`it has been difficult to achieve this goal except in very favor-
`able cases. One of the difficulties is the availability of API,
`and another one of the difficulties is accelerating toxicology
`studies.
`IND-I-GO
`introduced their
`In 2007, Aptuit/SSCI
`(INDIGO) program offering fast development in a Contract
`Research Organization (CRO) environment. INDIGO was
`tailored to working with BCS Class II compounds and poorly
`soluble compounds. This INDIGO offering was supported
`by an example case study on the poorly soluble drug itra-
`conazole and was summarized in a recent publication [15].
`Additionally, Byrn et al. and Byrn and Henck outlined strate-
`gies based on solid-state chemistry for reducing development
`time [16,17]. These publications contained much more detail
`on how to carry out screens and are discussed in more detail
`below. In this same timeframe, Chorus a Lilly-based firm
`focused on fast development introduced their strategy for
`
`Page 11 of 55
`
`Copyright © 2017. John Wiley & Sons, Incorporated. All rights reserved.
`
`Byrn, Stephen, et al. Solid State Properties of Pharmaceutical Materials, John Wiley & Sons, Incorporated, 2017. ProQuest Ebook Central, http://ebookcentral.proquest.com/lib/nyli/detail.action?docID=4915572.
`Created from nyli on 2018-03-02 15:27:18.
`
`

`

`10
`
`SOLID-STATE PROPERTIES AND PHARMACEUTICAL DEVELOPMENT
`
`accelerated development to Phase II [18]. In this early pub-
`lication, they suggested that it was possible to develop a
`compound to Phase II in 30 months for $3 million dollars in
`contrast to the industry average of 42 months and $30 million
`dollars. The Chorus approach involves a virtual company that
`heavily uses preferred CROs. Chorus has been quite success-
`ful, and Lilly has now established Chorus as an independent
`entity.
`In this same timeframe, PricewaterhouseCoopers intro-
`duced a concept of limited launch with what they have termed
`a “live license” that permits a company to market a drug under
`very restricted conditions. In one manifestation of this con-
`cept, they suggested launch of a drug after 1.5 years. The
`details of this strategy are not clear, but it appears that the
`proposal involves intr