Solid-State Chemistry
`of Drugs
`
`SECOND EDITION
`
`Stephen R. Byrn
`Ralph R. Pfeiffer
`Joseph G. Stowell
`
`SSCI, Inc. • West Lafayette, Indiana
`www.ssci-inc.com
`
`Argentum EX1012
`
`Page 1
`
`

`

`SSCI, Inc., 3065 Kent Avenue, West Lafayette, Indiana 47906-1076
`www .ssci-inc.com
`
`Second Edition© 1999 SSCI, Inc. Published 1999. All Rights Reserved.
`
`Printed in the United States of America
`Printing History: 03 02 01 00 99
`
`5 4 3 2 1
`
`Neither this book nor any part may be reproduced or transmitted in any form or by any means, elec(cid:173)
`tronic or mechanical, including photocopying, microfilming, and recording, or by any information
`storage and retrieval system, without permission in writing from the publisher.
`
`The citation of trade names or names of manufacturers in this book is not to be construed as an en(cid:173)
`dorsement or as approval by SSCI, Inc. of the commercial products or services referenced herein; nor
`should the mere reference herein to any drawing, specification, chemical process, or other data b€
`re(cid:173)
`garded as a license or as a conveyance of any right or permission to the holder, reader, or any 01 her
`person or corporation, to manufacture, reproduce, use, or sell any patented invention or copyrighted
`work that may in any way be related thereto. Registered names, trademarks, etc., used in 1his booK,
`even without specific indication thereof, are not to be considered unprotected by law.
`
`Library of Congress Cataloging-in-Publication Data
`
`Byrn, Stephen R.
`Solid-State Chemistry of Drugs I Stephen R. Byrn, Ralph R. Pfeiffer, Joseph G.
`Stowell-2nd ed.
`xvii, 576 p. :ill.; 24 cm.
`Includes bibliographical references and index.
`ISBN 0-967-06710-3
`ISBN 0-967-06711-1 (paperback student edition only)
`1. Pharmaceutical Chemistry. 2. Solid state chemistry. 3. Chemistry, Pharma(cid:173)
`ceutical. I. Title.
`QV744.B995s
`615'.19
`
`1999
`
`The publisher offers a discount paperback edition of this book to registered students
`only. Quantity discounts on the hardover ediiiuo are also vai!able.
`
`Printed on acid-free paper.
`
`Cover illustration: The figures are space-filling representations of prednisolone 21-
`tert-butylacetate crystal packing diagrams. On the top is Form IV illustrating the
`densely packed crystal lattice. On the bottom is Form V showing the oxygen(cid:173)
`accessible tunnels produced by desolvation.
`
`Page 2
`
`

`

`In memory of Peggy Etter
`I11 memory ofPeggy Etter
`
`
`
`Page 3
`
`

`

`Drugs as Molecular Solids
`'This chapter provides a general overview of solid-state chemistry of drugs.
`
`Specifically, it treats the impact on pharmaceuticals of solid-state chemistry,
`the crystalline state, amorphous solids, moisture uptake, patents, and physical
`In many cases, a subject is introduced in this
`as well as chemical transformations.
`chapter and addressed in depth in a latar chapter. It is hoped that the reader will gain an
`appreciation of what this discipline encompasses by reading this chapter.
`
`1.1
`
`ROLE OF SOLID-STATE TECHNOLOGY IN THE PHARMACEUTICAL INDUSTRY
`
`Figure 1.1 depicts the central role that solid-state research plays in the pharmaceutical
`industry. Reflection on the part of anyone even slightly familiar with the industry will
`confirm many of the connections shown in Figure 1.1, but some specific examples will
`further point out how important these connections can be in given cases.
`Solid pharmaceuticals exist as polymorphs, solvates, or in amorphous forms,
`collectively described as solid forms. Figure 1.2 shows the solubility behavior of two
`polymorphs with time. It is clear that the solubility of each of the solid forms is de(cid:173)
`creasing because of the crystallization of a more stable crystal form (Carless et al.,
`1968). Thus, this figure illustrates the effect of polymorphic change on suspension
`stability. Obviously these changes reflect on the stability of the product as well as
`
`Manufacturing
`
`Development
`
`Research
`
`Formulation &
`Drug Delivery
`
`Marketing &
`Further Product
`Improvements
`
`Figure I.I A diagram of the role of solid-state studies in the pharmaceutical industry.
`
`3
`
`Page 4
`
`

`

`4
`
`Chapter 1 Drugs as Molecular Solids
`
`1.0
`
`~ 0.8
`E
`....
`~ 0.6
`iii
`~
`~ 0.4
`e
`
`0
`II)
`.0
`ct 0.2
`
`o suspended Form II with slight shaking
`0 suspended Form II with mechanical shaking
`b. suspended Form IV with mechanical shaking
`
`0
`
`2
`
`Time(hr)
`
`6
`
`Figure 1.2 Decrease in absorbance of a cortisone acetate Form II solution in the presence of sus(cid:173)
`pended Form II or Form IV as a function of time (Carless et al., 1968).
`
`• Solution
`
`_ _ _ _ _ _ _ _ _ / · 6.63 i,m suspension
`
`......... __ _____
`/
`I .1·
`I ----·,.
`
`/ '
`
`29.96 i,m suspension
`
`/'/'
`=--·
`
`4
`
`8
`
`12
`
`16
`20
`Time (hours)
`
`24
`
`28
`
`Figure 1.3 Blood levels of phenobarbitone versus time after intramuscular injection of two prepara(cid:173)
`tions with different particle sizes (redrawn from Miller and Fincher 1971 ).
`
`regulatory issues, quality control, formulation, and drug bioavailability. Figure 1.3
`depicts the effect of particle size on the dissolution rate of phenobarbitone and illus(cid:173)
`trates the role of solid-state technology in the formulation and drug delivery, quality
`control, and regulatory areas.
`Studies of hydrocortisone tert-butylacetate and prednisolone tert-butylacetate (Byrn
`eta/. , 1988; Lin etal., 1982) and dihydrophenylalanine (Ressler, 1972) show thatdif
`ferent crystal forms of these substances have different chemical reactivity. For exam(cid:173)
`ple, the hexagonal crystal form of both hydrocortisone tert-butylacetate and predniso(cid:173)
`lone tert-butylacetate oxidizes in the solid state whereas the other crystal forms of these
`two pharmaceuticals are chemically stable.
`The shape and particle size of the solid drug substance can have an important effect
`on the flowability, syringeability, filterabiUty, tableting behavior, and bulk
`density of the drug. For example a suspension of plate-shaped crystals may be in-
`
`-
`
`Page 5
`
`

`

`1.2 The Crystalline State: Basic Concepts
`
`5
`
`0
`
`0
`
`hydrocortisone 21-tert-butylacetate
`
`cortisone 21-tert-butylacetate
`
`jected through a small needle with greater ease than one o( needle-shaped crystals.
`Similarly, the tableting behavior of plate-shaped crystals would differ from that of nee(cid:173)
`dle-shaped crystals. Furthermore, the shape and size of the particles is generally related
`to the internal crystal structure of the solid. Thus, the internal structure of the solid
`material can dramatically influence the bulk properties of the drug. These properties in
`turn relate to formulation, manufacturing, patents, quality control, regulatory, and pos(cid:173)
`sibl) other areas indicated in Figure 1.1.
`
`1.2 THE CRYSTALLINE STATE: BASir:: CONCEPTS
`
`An understanding of the solid-state chemistry of drugs begins with a statement of sev(cid:173)
`eral general points:
`
`• most drugs are used in a crystalline form
`• crystals are held together by molecular forces
`• the arrangement of molecules in a crystal determine its physical properties
`• the physical properties of a drug can affect its performance
`
`We can then proceed to learn how an understanding of the crystalline state leads to un(cid:173)
`derstanding of drug properties. (A treatment of non-crystalline, or amorphous, solids
`is given in Chapter 12.)
`To accommodate the general reader in following this discussion of the crystalline
`state, brief definitions of some terms are listed in a glossary at the end of the book.
`Many of the terms may require further explanations which will be given when appro(cid:173)
`priate.
`
`A. p ACK ING AND SYMMETRY
`
`One definition of a crystal is that of a solid in which the component molecules are ar(cid:173)
`ranged, or "packed," in a highly ordered fashion. When the specific local order, de(cid:173)
`fined by the unit cell, is rigorously preserved without interruption throughout the
`boundaries of a given particle, that particle is called a single crystal. This ordered
`packing leads to a structure with very little void space, which explains why most sub(cid:173)
`stances are more dense in their solid state than in their liquid state. By way of illustra(cid:173)
`tion, Figure 1.4 shows a projection of a unit cell and also shows how tightly the mole(cid:173)
`cules are packed in a typical crystalline substance such as glycine.
`Looking at this example and contemplating the enormous number of crystalline
`compounds known to modem science, not to mention those to be discovered, it be-
`
`Page 6
`
`

`

`6
`
`Chapter 1 Drugs as Molecular Solids
`
`Figure 1.4 A close packed layer of glycine molecules in a crystal projected on the ac plane. The
`heavy gray lines show the van der Waals radii of the atoms (the hydrogens have been
`omitted for clarity).
`
`comes obvious there must be a remarkable variety of structures found in different crys(cid:173)
`tals. What factors, then, determine the crystal structure of a given compound?
`When the question "In how many different ways can varied-shaped molecules be
`packed?" is put on a mathematical basis, it has been shown that certain symmetry ele(cid:173)
`ments (or, symmetry operations) are involved and that all possible combinations of
`these can be summarized in exactly 230 ways, called space groups. The symmetry
`operations are listed in Table 1.1. Formal representations of the 230 space groups,
`which encompass all seven crystal systems and all possible combinations of symme(cid:173)
`try operations, are found in the International Tables for Crystallography (1987).
`To understand how the packing of a crystal structure is described by the symmetry
`operations of the space group it may be helpful to regard the following example (see
`Figure 1.5). Figure 1.5 shows a diagram of the symmetry elements in space group
`Pmm2. The P means that the space group is primitive rather than body-centered or
`face-centered. The mm2 means that the cell contains mirror planes (m) perpen-
`
`rotation axis
`
`screw axis
`
`Table t. I The Symmetry Elements of Crystal Packinga
`Description
`Symmetry Element
`When a rotation of 360°/n results in the same structure, then the crystal con(cid:173)
`tains an n-fold rotation axis. For crystals, n is restricted to 1, 2, 3, 4, and 6.
`Ann-fold screw axis exists when a rotation of 360°/n followed by a transla(cid:173)
`tion parallel to the axis of rotation brings the structure into coincidence.
`Ann-fold rotatory-inversion axis exists when a rotation of 360°/n followed
`rotatory-inversion axis by inversion results in the same structure.
`A mirror plane exists when a reflection through that plane resu s m he same
`structure.
`A glide plane exists when reflection through a mirror plane followed by
`glide plane
`translation brings the structure into coinc:1dence.
`a Note that a crystal containing only one enantiomer of a chi:al compound cannot fall into a space
`group containing any one of the last three symmetry elemenls in Table l. l.
`
`mirror plane
`
`-
`
`Page 7
`
`

`

`1.2 The Crystalline State: Basic Concepts
`
`7
`
`2
`
`mirror planes that
`intersect the a axis
`
`mirror planes that
`intersect the b axis
`
`two-fold rotation axes
`parallel to the c axis
`
`/
`
`Figure 1.5 Symmetry elements for spac,~ group Pmm2.
`
`dicular to both the a and b axes and a two-fold rotation axis along the c axis.
`Talcing block 1 at position (x,y,z) and reflecting it across the mirror that intersects
`the a axis at 1/:!ll, block 2 is obtained. Reflecting block 2 across the mirror that inter(cid:173)
`sects the b axis at ½b generates block 3, and block 4 results from block 3 being re(cid:173)
`flected across the mirror at ½:l. [In actual cases, of course, these blocks are molecules,
`but the operations are the same and thus the x, y, z coordinates of each atom in mole(cid:173)
`cule 1 are translated to the corresponding (1-x,y,z) in the first step, to (l-x,1-y ,z) in
`the next step, and (x, 1-y ,z) in the last step.] Note that this combination of mirror
`planes necessarily creates the two-fold rotation axes parallel to the c axis. These steps,
`in any order, are continued into the neighboring unit cells. In this exercise we are, in a
`sense, mimicking actual crystal growth.
`
`B. FORCES RESPONSIBLE FOR CRYSTAL PACKING
`
`At this point, it is appropriate to consider the forces responsible for holding crystals
`together. Ionic crystals are held together by ionic bonds while organic crystals are
`held together largely by non-covalent interactions. These non-covalent interactions
`are either hydrogen-bonding or non-covalent attractive forces. Both hydrogen(cid:173)
`bonding and non-covalent attractive interactions result in the formation of a regular ar(cid:173)
`rangement of molecules in the crystal. Non-covalent attractive interactions, which
`are sometimes called non-bonded interactions, depend on the dipole moments, po(cid:173)
`larizability, and electronic distribution of the molecules. Hydrogen bonding, of course,
`requires donor and acceptor functional groups. Another important factor is the sym(cid:173)
`metry of the molecules. Kitaigorodskii ( 1961) provided a review of the forces holding
`crystals together in his classic book Organic Chemical Crystallography. 1be two-
`
`Page 8
`
`

`

`8
`
`Chapter 1 Drugs as Molecular Solids
`
`volume Structure Correlations (Btirgi and Dunitz, 1994) describes in detail the modem
`view of crystal packing.
`The symmetry (or lack of symmetry) of a molecule determines how it is packed in
`the crystal and, in some cases, determines the overall symmetry of the crystal. Mole(cid:173)
`cules with symmetries that allow them to fit together in a close-packed arrangement
`generally form better crystals and crystallize more easily than irregular molecules. This
`factor is not always evident from molecular models.
`Several researchers have described crystal packing forces in specific classes of
`compounds. Reutzel and Etter (1992) evaluated the conformational, hydrogen(cid:173)
`bonding, and crystal-packing forces of acyclic imides. Crystal-packing forces in
`bi phenyl fragments were evaluated by Brock and Minton ( 1989); Gavezzotti and De(cid:173)
`siraju (1988) have analyzed packing energies and packing parameters for fused-ring
`aromatic hydrocarbons.
`Kitaigorodskii (1961) has advanced the close-packing theory to explain the
`forces holding crystals together. He suggested that the basic factor that affects free en(cid:173)
`ergy is the packing density which affects f:i.H, enthalpy. The denser or more closely
`packed crystal has the smaller free energy. This means that the heat of sublimation
`(and, to a first approximation, melting point) increases as the packing density increases
`and, that in a series of polymorphs, the densest polymorph is the most stable. This is
`the molecular basis of the density rule which states that if one modification of a mo(cid:173)
`lecular crystal has a lower density than the other, it may be assumed to be less stable at
`absolute zero (Burger and Ramberger, 1979a). However, it is important to note that
`there are exceptions to this rule. Some exceptions probably arise because strong hy(cid:173)
`drogen bonds can negate less dense packing (e.g., ice) thereby causing the less dense
`polymorph to be more thermodynamically more stable (Burger and Ramberger,
`1979a-b). Brock et al.(1991) studied the validity of Wallach's rule, which states that
`the racemic crystals of a pair of enantiomers are denser and thus more stable than crys(cid:173)
`tals of the individual enantiomers, and showed that, for the 65 chiral/racemic pairs in(cid:173)
`vestigated, the racemic crystals are only -1 % more dense than the corresponding chiral
`crystals (yet the racemates are less dense for many individual pairs).
`Kitaigorodskii ( 1961) also pointed out the importance of symmetry which affects
`f:i.S, entropy. The free energy of a crystal undoubtedly increases as the number of cry(cid:173)
`tallographically independent molecules in the crystal increases. Thus high symme(cid:173)
`try, which reduces the number of independent molecules in a crystal, increases the free
`energy of the crystal and conflicts with the reduction in free energy gained from close
`packing. The magnitude of these opposing effects varies from structure to structure.
`
`C. HYDROGEN BONDING
`
`Of the various forces that hold organic molecules in the solid, hydrogen bonding is
`perhaps the most important. Etter (1990) has reviewed the extent and types of hydro(cid:173)
`gen bonding that can exist in solids and pointed out that polar organic molecules in so(cid:173)
`lution tend to form hydrogen-bonded aggregates. These aggregates are precursors to
`the crystals which form when the solution is supersaturated. This concept helps to ex(cid:173)
`plain the many different hydrogen-bonding motifs seen in different solids.
`Several different types of carboxylic acids have been studied. For example, in o(cid:173)
`alkoxybenzoic acids, the presence of dimers or the formation of intramolecular hydro(cid:173)
`gen bonds depends on the state of the sample. In o-anisic acid, dimers are observed in
`
`I
`
`Page 9
`
`

`

`1.2 The Crystalline State: Basic Concepts
`9
`the solid state while intramolecular hydrogen bonds are observed in dilute solution.
`However, in o-ethoxybenzoic acid, only intramolecular hydrogen bonds are observed
`in both the solid state and in solution (Etter, 1990).
`
`o-methoxybenzoic acid
`o-ethoxybenzoic acid
`in the solid state
`in solution
`in solution and in the solid state
`Etter et al. ( 1988) also studied the hydrogen bonding in salicylamide derivatives
`and pointed out that two types of hydrogen bonding patterns are possible in these com(cid:173)
`pounds. One pattern involves an intramolecular -N-H .. ·OH- hydrogen bond and
`an intermolecular -0--H .. ·O=C hydrogen bond while the other pattern involves an
`intermolecular-N-H-··OH- hydrogen bond and an intramolecular -0-H···O=C
`hydrogen bond.
`
`H..._
`
`,..-R OCN?
`
`H
`
`?
`
`Intra: NH···· OH
`Inter: G=O··· .. HO
`
`Intra: G=O·····HO
`Inter: NH .... OH
`Etter and co-workers (1990a) defined a system which uses a graph set to classify
`and symbolically represent the different types of hydrogen bonds that can be formed.
`A short representation of the different graph sets is shown in Figure 1.6. A graph set
`motif designator (C for intermolecular chains or catemers, R for intermolecular rings,
`D for discrete or other finite sets, and S for intramolecular hydrogen bonds) is assigned
`by identifying the size or degree of the hydrogen-bond pattern G, the number of ac(cid:173)
`ceptors a, the number of donors d, and the total number of atoms n in that pattern. This
`designation takes the form: ~(n).
`Etter (1990b) also developed rules governing hydrogen bonding in solid organic
`compounds. Hydrogen-bond donors and acceptors in solids are classified either as
`"reliable" or "occasional" donors and acceptors and are listed in Table 1.2. Using these
`classifications, three rules were devised:
`I . All reliable proton donors and acceptors are used in hydrogen
`bonding.
`2. Six-membered ring intramolecular hydrogen bonds form in prefer(cid:173)
`ence to intermolecular hydrogen bonds.
`
`Page 10
`
`

`

`10
`
`Chapter 1 Drugs as Molecular Solids
`
`D
`
`C(4)
`
`oc�
`I R
`
`S(6)
`
`Ri(8l
`
`Figure 1.6 Etter graph sets describing different hydrogen bond motifs where D designates a discrete or
`other finite set, C a chain or catemer, S an intramolecular ring, and R designates an in­
`termolecular ring. The number of hydrogen-bond acceptors in rings is superscripted, the
`number of hydrogen-bond donors is subscripted, and the total number of atoms in the hy­
`drogen-bond pattern is in parentheses (Etter, 1990; Bernstein et al., 1995).
`
`3. The best proton donors and acceptors remaining after intramolecu­
`lar hydrogen bond formation will form intermolecular hydrogen
`bonds.
`These rules apply quite well to hydrogen bonding of small molecules. However,
`in
`some larger molecules (e.g., erythromycins), factors dictated by the geometry of the
`molecule as well as the large number of donors and acceptors present may make it im­
`possible to satisfy all these rules.
`It has been demonstrated that the systematic study of cocrystals (crystals which
`contain an ordered arrangement of two different neutral molecules that are not solvent
`molecules) can lead to insight concerning the factors influencing hydrogen bonding in
`crystals (Etter and Baures, 1988; Etter et al., 1990a-b, Etter and Adsmond, 1990; Etter
`and Reutzel, 1991 ). An important aspect of this research into hydrogen bonding is the
`realization that cocrystals can form and crystallize from certain solutions that contain
`more than one molecular species. Cocrystals are often formed between hydrogen-bond
`donor molecules and hydrogen-bond acceptor molecules. The geometry and nature of
`hydrogen bonding in cocrystals can be described using the above rules. Among the
`cocrystals studied by Etter's group were cocrystals inv0lving ureas with keluues, car­
`---- ·
`boxylic acids with 2-aminopyridine (see Figure 1.7), as well as adenine or cytosine
`with many acidic organic compounds including carboxylic and N-acyl-amino acids.
`The urea cocrystals are especially interesting because so many can be studied. Other
`cocrystal systems investigated by Etter's group include:
`
`•
`
`1.2 The Crystalline State: Basic Concepts
`
`11
`
`Type
`
`Functional Group Involved
`
`Table 1.2 Reliable and Occasional Hydrogen Bond Donors and Acceptors
`'-. .,..H ....
`
`'-. .,..H .......
`
`Reliable Donor
`
`0
`
`'•,
`
`)L .,..H ....
`
`0
`
`'•,
`
`r H-.. : ...
`)L .,..H ........
`r H .......
`�
`
`'-. .,..R
`
`7 H .......
`)L .,..R
`7 H .......
`-C-H .......
`
`\
`
`I
`
`:tN/
`
`I
`
`Occasional Donor )LH_.... ..
`
`-\
`H .......
`
`H .......
`
`Reliable Acceptors
`
`N
`)L"" :tJ(
`OH
`····-.. �
`/f'--
`
`I
`······-�
`
`.,........s......___
`
`,)y,
`
`I
`
`I
`
`,.........o, H
`
`Occasional Acceptors
`
`-CI
`
`,.........o,
`
`Etter, 1990; Bernstein et al., 1995
`
`\ -N .......
`I
`
`I
`.... ..-::N
`,...
`···o,... 'o···
`................................................................................................................................................................................
`pyrimidines, pyridines ........... carboxylic acids
`pyridine-N-oxides ........... acids, alcohols, amines
`triphenylphosphine oxides ........... acids, amides, alcohols, ureas, sulfonamides, amines, water
`carboxylic acids ........... other carboxylic acids, amides
`m-dinitrophenylureas ........... acids, ethers, phosphine oxides, sulfoxides, nitroanilines
`imides ........... other imides, amides
`!he fo�ation of cocrystals may also be important in explaining certain drug-excipient
`mteractions.
`Panunto et al. (1987) have reviewed hydrogen bond formation in crystalline ni­
`troanilin�s. They showed that hydrogen bonding occurred between the amino group
`and the rutro group even though the nitro group is only an occasional acceptor. In gen­
`eral, they found that the donor hydrogen from the amino group is placed equidistant
`
`Page 11
`
`

`

`1.2 The Crystalline State: Basic Concepts
`
`ll
`
`Table 1.2 Reliable and Occasional Hydrogen Bond Donors and Acceptors
`
`Type
`
`Functional Group Involved
`
`........_
`
`.,..H ....
`...
`0
`
`~O_,..H ...... .
`
`........_
`
`.,..H ........
`
`r
`
`H· .. : ...
`
`........_
`
`.,..R
`
`7
`
`H .......
`
`~.,..H ........
`
`r
`
`H .......
`
`~ . , . .R 7
`
`H .......
`
`- \
`H .......
`
`H .......
`
`\ -C-H .......
`I
`
`Reliable Donor
`
`Occasional Donor
`
`Reliable Acceptors
`
`Occasional Acceptors
`
`-CI
`
`/o........_
`
`I
`N
`'o····
`
`...
`····o-::-
`
`Etter, 1990; Bernstein et al., 1995
`
`\ -N .......
`I
`
`pyrimidines, pyridines ........... carooxylic acids
`pyridine-N-oxides ........... acids, alcohols, amines
`triphenylphosphine oxides ........... acids, amides, alcohols, ureas, sulfonamides, amines, water
`carboxylic acids ........... other carooxylic acids, amides
`m-dinitrophenylureas ........... acids, ethers, phosphine oxides, sulfoxides, nitroanilines
`imides ........... other imides, amides
`
`The formation of cocrystals may also be important in explaining certain drug-excipient
`interactions.
`Panunto et al. (1987) have reviewed hydrogen bond formation in crystalline ni(cid:173)
`troanilines. They showed that hydrogen bonding occurred between the amino group
`and the nitro group even though the nitro group is only an occasional acceptor. In gen(cid:173)
`eral, they found that the donor hydrogen from the amino group is placed equidistant
`
`Page 12
`
`

`

`Chapter 1 Drugs as Molecular Solids
`1:2
`between the acceptor oxygens of the nitro group. The geometry of this interaction ap(cid:173)
`pears to be controlled by the lone pair directionality of the nitro groups.
`This elegant work by Etter on graph set definitions and qualitative hydrogen(cid:173)
`bonding rules can greatly assist the understanding of the interaction of molecules in the
`solid state and presumably also in solution. Further discussion of hydrogen bonding in
`salts is included in Chapter 5.
`
`1.3 A GIVEN SUBSTANCE CAN CRYSTALLIZE IN DIFFERENT WAYS
`Apart from exhibiting differences in size, crystals of a substance from different sources
`can vary greatly in their shape. Typical particles in different samples may resemble, for
`example, needles, rods, plates, prisms, etc. Such differences in shape are collectively
`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 dif(cid:173)
`ferent 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
`distinctions can have a profound impact on drug performance, their careful definition is
`very important to our discourse. At this time, only brief definitions are presented, but
`an exhaustive treatment of each will be given later.
`
`Acids that form I :2 and I: I cocrystals
`
`Q - c o 2H H 3C - o -C 02H
`
`0,0-
`
`~ IJ
`
`C02H
`
`d/
`
`C02H
`
`Acids that form only I: I cocrystals
`
`QO,H
`
`CO,H One of two
`polymorphs wns
`ohimned mily
`from solution .
`
`< -
`
`C02H
`
`C02H
`
`Acids that form I: I and 2: I cocrystals
`
`CC02H The 2: I cocrystal
`was obtained only by
`solid-state grinding.
`
`C02H
`
`Figure 1.7 Observed stoichiometries of cocrystals of2-aminopyridine with the compounds listed here
`(Etter and Adsmond, 1990).
`
`Page 13
`
`

`

`1.3 A Given Substance can Crystallize in Different Ways
`
`13
`
`Polymorphs - When two crystals have the same chemical composition
`but different internal structure (molecular packing) they are poly(cid:173)
`morphic modifications, or polymorphs. (fhink of the three forms
`of carbon: diamond, graphite, and fullerenes.)
`Solvates - These crystal forms, in addition to containing molecules of
`the same given substance, also contain molecules of solvent regu(cid:173)
`larly incorporated into a unique structure. (Think of wet, setting
`plaster: CaS04 + 2 H20 ~ CaS04·2H20)
`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.
`(fhink of snowflakes.)
`Together, these solid-state modifications of a compound are referred to as crystal(cid:173)
`line forms. When differences between early batches of a substance are found by mi(cid:173)
`croscopic examination, for exrunple, a reference to "form" is particularly useful in the
`absence of information that a11ows the more accurate description of a given variant
`batch (i.e., polymorph, solvatc, habit, or amorphous material). The term pseudo(cid:173)
`polymorphism is applied frequently to designate solvates.
`To put these important definitions into a practical context, let us look at two cases
`in which a drug was crystallized from several different solvents and different-shaped
`crystals resulted in each experiment. (See Figures 1.8 and 1.9.)
`Although sometimes dramatically different shapes were obtained upon changing
`solvents for the various crystallizations, the final interpretations in the two cases were
`significantly different. Figures 1.8 and 1.9 can be used to illustrate the application of
`the terminology defined in the previous paragraphs. Upon first seeing these pictures, it
`might be asked: "Although each of these drugs shows different morphology with dif(cid:173)
`ferent treatment, are the different-shaped crystals polymorphs, solvates or merely dif(cid:173)
`ferent habits?" After various investigations (cf. Methods, Chapter 2) it was concluded
`that all forms of the aspirin (Figure 1.8) have the same structure and therefore each is a
`different habit of the aspirin crystal. The various crystals of ,8-estradiol, however,
`were found to exist as a number of solvate forms (two unsolvated forms are also
`known but not shown in Figure 1.9). At this point we are aware that: a given structure
`can form crystals of quite different shapes; and a given drug may exist in more than one
`crystal structure or crystal form (i.e., polymorph or solvate).
`
`hexane
`
`C
`
`benzene
`
`0
`
`ethanol
`
`CJ
`
`acetone
`
`.o
`
`chloroform
`
`Figure 1.8 Aspirin crystals grown from different solvents.
`
`Page 14
`
`

`

`14
`
`~ ~
`
`Chapter 1 Drugs as Molecular Solids ~''
`
`methanol
`
`ethanol
`
`1-propanol
`
`b •
`
`0
`
`• 2-propanol
`
`1-hexanol
`
`acetic acid
`
`4-methyl-2-pentanone
`
`diethyl ether
`
`tetrahydrofuran
`
`benzene
`
`?~~~
`
`'
`
`.../¾ .
`1,4-dioxane
`
`<>
`~ -~a::.
`
`chlorobenzene
`
`Figure 1.9
`
`,B-Estradiol pseudopolymorph crystals (solvate and crystallizing solvent are indicated,
`Kuhnert-Brandstlitter, 1971).
`
`1.4
`
`PROPERTIES THAT AFFECT PHARMACEUTICAL BEHAVIOR
`
`The familiar example of pure carbon in its three fonns-diamond (tetrahedral lattice),
`graphite (polyaromatic sheets), and fullerenes (polyaromatic spheresHramatizes the
`profound effect that differences in crystal structure can have on the properties of a- (cid:173)
`solid. Similar effects can apply to other solid compounds, including drugs. The com-
`plex nature of manufacturing operations and regulatory requirements peculiar to the
`pharmaceutical industry thus demands an even closer look at how the properties of a
`given drug can vary with each of its solid-state forms. Given the endless chemical va-
`riety of modem drug molecules it becomes obviou~ why solid-state studies are vital to
`the thorough characterization of pharmaceuticals.
`Many physicochemical properties of a drug (see Table 1.3) vary when the solid(cid:173)
`state structure of the substance is altered. The practical significance of any of these dif(cid:173)
`ferences will, of course, vary from case to case.
`Other properties of drug crystals that are of concern primarily in pharmaceutical
`operations also need to be addressed. These are properties that vary even when the
`crystal structure is fixed and are directly or indirectly related to surface relationships and
`thus largely controlled by crystal habit and size distribution (see Table 1.4 ). These
`
`Page 15
`
`

`

`1.5 Properties that affect Pharmaceutical Behavior
`
`15
`
`Table 1.3 Properties of a Compound that Depend on Structure Differences
`
`Density
`Hardness
`Cleavage
`S )lubility
`
`Water Uptake
`Optical Properties
`Electrical Properties
`Thermoanalytical Behavior
`
`Solid-State Reactivity
`Physical Stability
`Chemical Stability
`
`Ta hie 1.4 Some Areas Where Control of Solid Form and Size Distribution are Important
`
`Yield
`Filtr_tion
`Washing
`Drying
`
`Milling
`Dissolution
`Mixing
`Suspension Formulation
`Tableting
`Lyophilization
`Flowability
`- - - - -- - -- - - - - - - - - - -
`
`variables determine how particles behave with respect to neighboring particles (and
`upon exposure to solvent or solvent vapor) and thus the physical properties of pow(cid:173)
`ders.
`At this point, the concept that these crystal properties are directional is introduced.
`In discussing symmetry and space groups (see Sec. 1.2A), it is important to convey the
`notion that unit cells contain different symmetry elements along their axes. A necessary
`consequence of this fact is that most drug crystals have different properties in different
`directions, or alternatively stated, the chemistry on the different faces of a drug crystal
`may be quite differellt. Both the structure and the properties, in short, are anisot(cid:173)
`ropic. For example, one face of a crystal may be studded with carboxyl groups
`whereas another face might be entirely occupied by phenyl moieties, thus giving rise to
`some relatively hydrop