Solid-State Chemistry
`of Drugs
`
`SECOND EDITION
`
`Stephen R. Byrn
`Ralph R. Pfeiffer
`Joseph G. Stowell
`
`SSCI, Inc. • Wes~ ~fayette, Indiana
`WY.lW .SSCl-lllC.COffi
`
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`

`
`Polymorphs
`
`s discussed in Chapter 1, polymorphs exist when two crystals have the same
`chemical composition but different internal structure, including different unit
`cell dimensions and different crystal packing. Compounds that crystallize as
`polymorphs can show a wide range of different physical and chemical
`properties, including different melting points and spectral properties. Polymorphs can
`also differ in their solubility. density, hardness, and crystal shape. While some com(cid:173)
`pounds may exist in only two polymorphs, others may exist in many polymorphs
`(e.g., progesterone has five polymorphs and water has nine polymorphs). Control of
`polymorphism is particularly important for pharmaceuticals where changing the poly(cid:173)
`morph can alter the bulk properties, dissolution rate, bioavailability, chemical stability,
`or physical stability of a drug. The clearest indication of the existence of polymorphs
`comes from the X -ray crystallographic examination of single crystals of the various
`samples that are known to have the same composition. Often, however, X-ray powder
`diffraction is sufficient to establish the existence of polymorphs.
`There is, unfortunately. no standard numbering system for polymorphs. In the lit(cid:173)
`erature, the various polymorphs have been designated by Roman numerals (preceded
`by the word "Form," e.g., Form I), Greek letters (with the suffix "-form," e.g., a(cid:173)
`form), or in some cases, capital letters (similar to the Roman numeral system). To add
`to the confusion, some of numbering schemes of polymorphs also include solvates
`(e.g., the a- and y-forms of indomethacin are anhydrates, yet the /)-form is the benzene
`solvate). Furthermore, some polymorphs have been identified only by their crystallo(cid:173)
`graphic classification (e.g., the two polymorphs of (±)-/)-promedol are designated the
`monoclinic form and the rhombohedral form). It has been suggested that polymorphs
`be numbered consecutively in the order of their stability at room temperature or by their
`melting point. This of course would lead to confusion upon the discovery of a new
`polymorph having intermediate stability or melting point and thus requiring renumber(cid:173)
`ing of the existing polymorph system. It has also been suggested that polymorphs be
`numbered consecutively in the order of discovery, but this requires knowledge of their
`history and a timely access to that information. Whatever the numbering system, it is
`imperative that it be consistent. Thus, when a new polymorph is discovered and
`characterized, the designation of the new polymorph should be the next increment in the
`
`143
`
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`

`
`144 Chapter 10 Polymorphs
`
`previous system. However, this is not always practical when more than one laboratory
`is involved in the development process at the same time.
`
`Table 10.1 Crystallograph
`4-Chlorophenc
`
`\
`
`10.1 CLASSIC EXAMPLES OF POLYMORPHISM
`
`This section summarizes several classic examples of polymorphism which have ap(cid:173)
`peared in the chemical literature.
`
`A. 4-CHLOROPHENOL
`
`C l - o -OH
`
`4-chlorophenol
`
`The crystal structure of both the thermodynamically stable (a) and unstable (/1) forms
`of 4-chlorophenol have been determined (Perrin and Michel, 1973a-b ). Both forms
`belong to the same space group (P2dc); they both have the same number of molecules
`per unit cell (Z = 8) and nearly identical densities, yet they have different cell parame(cid:173)
`ters (see Table 10.1). The crystal structure of the J3-form projected on the (100) plane
`is shown in Figure 10.1. The packing consists of tetramers of molecules connected by
`hydrogen bonding. The crystal packing of the a-form (shown in Figure 10.2) also
`consists of tetramers connected by hydrogen bonds, but the arrangement of the rings is
`slightly different than that of the /3-form. Although the J3-form converts to the a-form,
`no detailed studies of this transformation have been reported.
`
`a-F
`p
`
`1:
`
`Parameter
`Space Group
`a(A)
`b(A)
`c(A)
`/3
`z
`Peale (g em-')
`v (A3)
`a Perrin and Michel, 1973a.
`
`122(
`
`Figure 10.1 Projection of the crystal structure of the /3-form of 4-chlorophenol (. chlorine atom,
`®hydroxyl group) (Perrin and Michel, 1973b).
`
`Figure 10.2 Projection of t
`e hydroxyl gn
`
`B. DIBENZ[a,h]ANTHRA
`
`In an early study of polyr
`fil)r]anthracene (1,2:5,6-;
`1947; 1956). Although tl:
`r-~-•""' (Table 10.2) and
`
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`

`
`10.1 Classic Examples of Polymorphism
`
`145
`
`Table 10.1 Crystallographic Parameters for Two
`4-Chlorophenol Polymorphs
`
`Parameter
`
`a-Forma
`
`f:J-Formb
`
`Space Group
`a(A)
`b(A)
`c(A)
`{3
`z
`Peale (g cm-3
`V(A3)
`a Perrin and Michel, l973a. b Perrin and Michel, l973b.
`
`P2 1/c
`4.14
`12.85
`23.20
`93.00°
`8
`1.38
`1232.5
`
`P2t!C
`8.84
`15.726
`8.790
`92.61°
`8
`1.40
`1220.7
`
`)
`
`bora tory
`
`tave ap-
`
`J) forms
`h forms
`IOlecules
`parame-
`0) plane
`:!cted by
`1.2) also
`rings is
`a-form,
`
`Figure 10.2 Projection of the crystal structure of the a-form of 4-chlorophenol (. chlorine atom,
`@)hydroxyl group) (Perrin and Michel, 1973a).
`
`B. DIBENZ[a,h]ANTHRACENE
`
`dibenz[a,h ]anthracene
`{1,2:5,6-dibenzanthracene)
`
`ine atom,
`
`In an early study of polymorphism, the crystal structures of Forms I and II of dibenz(cid:173)
`[a,h]anthracene (1,2:5,6-dibenzanthracene) were determined (Robertson and White,
`1947; 1956). Although the forms have the same density, they belong to different space
`groups (Table 10.2) and have quite different packing. The crystal packing of Form I
`
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`

`
`146
`
`Chapter 10 Polymorphs
`
`(orthorhombic form) is shown in Figure 10.3 and the crystal packing of Form ll
`(monoclinic form) is shown in Figure 10.4.
`
`Table 10.2 Crystallographic 1
`Dibenz[a,h]anthra
`
`Parameter
`Space group
`a(A)
`b(A)
`c(A)
`/3
`z
`Peale (g cm-3)
`v <A3>
`V/molecule
`
`F<
`f
`
`I
`9
`
`141
`35
`
`Robertson and White, 1947; R
`
`C. ACRIDINE
`
`Acridine crystallizes in fi
`Schmidt, 1955). The cry!
`and are shown in Figures
`forms appear to be quite si1
`
`Table 10.3 Crystal Parameter
`
`a-For
`
`Parameter
`Space group
`a(A)
`b<A>
`c(A)
`/3
`z
`Peale (g cm-3 )
`V(A3)
`V/Z(N)
`Habit
`Herbstein and Schmidt, 1955
`
`P2th
`16.18
`18.88
`6.08
`95.67'
`8
`1.27
`1848.:
`231.1
`Needle
`
`Figure 10.3 Crystal packing of Form I (orthorhombic form) of dibenz[a,h]anthracene (Robertson and
`White, 1947).
`
`Figure 10.4 Crystal packing drawing of Form II (monoclinic form) of dibenz[a,h]anthracene (Robert(cid:173)
`son and White, 1956).
`
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`

`
`of Form II
`
`Table 10.2 Crystallographic Parameters for Two
`Dibenz[a,h]anthracene Polymorphs
`
`10.1 Classic Examples of Polymorphism
`
`147
`
`Parameter
`Space group
`a(A)
`b(A)
`c(A)
`fJ
`z
`Peale (g cm-3)
`V(A3)
`V/molecule
`
`Form I
`
`Pcab
`8.22
`11.39
`15.14
`90.0°
`4
`1.29
`1417.5
`354.4
`
`Form II
`
`P2t
`6.59
`7.84
`14.17
`103.5°
`2
`1.29
`711.9
`355.9
`
`Robertson and White, 1947; Robertson and White, 1956.
`
`C. AcRIDINE oco ~
`
`N
`
`acridine
`
`~obertson and
`
`Acridine crystallizes in five polymorphs as shown in Table 10.3 (Herbstein and
`Schmidt, 1955). The crystal structures of the a- and y-forms have been determined
`and are shown in Figures 10.5 and 1 0.6, respectively. The crystal packing of these
`forms appear to be quite similar although the cell parameters are obviously different.
`
`Table 10.3 Crystal Parameters of the Various Polymorphs of Acridine
`
`Parameter
`Space group
`a(A)
`b(A)
`c(A)
`fJ
`z
`Peale (g cm-3)
`V(A3)
`VIZ (A')
`Habit
`
`a-Form
`
`P2tla
`16.18
`18.88
`6.08
`95.67°
`8
`1.27
`1848.2
`231.0
`Needles
`
`fJ-Form
`A a
`16.37
`5.95
`30.01
`141.33°
`8
`1.29
`1826.3
`228.3
`Plates
`
`y-Form
`
`PIUlb
`17.45
`8.89
`26.37
`90.00°
`16
`1.15
`4090.8
`255.7
`Laths
`
`.5-Form
`P2t2t2l
`15.61
`6.22
`29.34
`90.00°
`12
`1.24
`2848.7
`237.4
`Laths
`
`£-Form
`
`P2 1/n
`11.37
`5.98
`13.64
`98.67°
`4
`1.29
`918.2
`229.5
`Prisms
`
`Herbstein and Schmidt. 1955
`
`;ene (Robert-
`
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`

`
`\
`
`148
`
`Chapter IO Polymorphs
`
`p························································~
`
`-~&:P ~ &:P
`c?r~c?r
`'~ i
`~····················· ~
`
`Figure 10.5 Crystal packing of acridine a-form with 0
`acridine ring (Phillips, 1956).
`
`representing the nitrogen atom of the
`
`Figure 10.6 Crystal packing of acridine y-form with ED representing the nitrogen atom of the acridine
`ring (Phillips et al., 1960).
`
`10.2 CONFORMATIONAL AND CONFIGURATIONAL POLYMORPHISM
`
`In this section, two special types of polymorphism will be discussed. Conformational
`polymorphism occurs when a molecule adopts a significantly different conformation in
`different crystal polymorphs (Bernstein, 1987). (The term "significantly different" is
`open to interpretation.) This term does not adequately describe cases where different
`types of isomers crystallize in different forms. Thus an additional term--configura(cid:173)
`tional polymorphism-is defined. Configurational polymorphism exists when different
`
`configurations (i.e., cis,
`forms.
`Crystallization of ci.
`occurs whenever the pu
`forms in separate crystal:
`The crystallization of eqt
`cantly more interest. W
`phism can be used to is1
`crystalline form.
`
`A. TRI-a-NAPHTHYLB•
`
`tri-a-naphth:
`For
`
`Brown and Sujishi (1948
`with the following obsen
`
`I . Two crystalli
`2. The metastab
`room tempen
`3. The dissociat
`stable form.
`4. Removal off'
`naphthylboro
`
`Based on these results,
`above. In these forms, th•
`that the NH3 is connected
`and the less hindered side
`ence in dissociation press1
`the same conformer of tri·
`being the most sterically h
`Unfortunately, while
`formational polymorphisn
`The example, neverthele!
`polymorph formation.
`
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`

`
`10.2 Conformational and ConCtgUrational Polymorphism
`
`149
`
`configurations (i.e., cis,trans isomers or tautomers) crystallize in separate crystalline
`forms.
`Crystallization of cis,trans isomers in different crystalline forms is well known and
`occurs whenever the pure isomer is crystallized. Crystallization of pure tautomeric
`forms in separate crystals leads to what may be called tautomerizational polymorphism.
`The crystallization of equilibrating isomers in configurational polymorphs is of signifi(cid:173)
`cantly more interest. When this occurs, the phenomenon of configurational polymor(cid:173)
`phism can be used to isolate and study the individual isomers provided they exist in
`crystalline form.
`
`A. TRI-a-NAPHTHYLBORONAMINE
`
`tri-a-naphthylboronamine
`FormA
`
`tri-a-naphthylboronamine
`FormB
`
`Brown and Sujishi (1948) reported an early example of conformational polymorphism
`with the following observations:
`
`1. Two crystalline forms oftri-a-naphthylboronamine are found.
`2. The metastable Form A is converted to the stable Form B slowly at
`room temperature and rapidly above 100 oc.
`3. The dissociation pressure of the metastable form is higher than the
`stable form.
`4. Removal of NH3 from either form gives identical samples of tri-a(cid:173)
`naphthylboron.
`
`Based on these results, the two forms were suggested to have structures depicted
`above. In these forms, the conformation of the tri-a-naphthylboron is the same except
`that the NH3 is connected to the boron on the more hindered side for the unstable form
`and the less hindered side for the stable form. Thus these structures explain the differ(cid:173)
`ence in dissociation pressures of the two forms and the fact that removal of NH3 gives
`the same conformer of tri-a-naphthylboron. They also explain why the unstable form,
`being the most sterically hindered, can be converted to the stable form.
`Unfortunately, while tri-a-naphthylboron was one of the first suggestions of con(cid:173)
`formational polymorphism, it was never confirmed by X-ray crystallographic analysis.
`The example, nevertheless, points out some of the molecular factors that influence
`polymorph formation.
`
`7
`
`m of the
`
`the acridine
`
`•rmational
`mation in
`fferent" is
`~ different
`configura(cid:173)
`n different
`
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`
`Chapter 10 Polymorphs
`
`B. ETHYL 2-[(PHENYLMETHYL)AMIN0]-2-BUTENOATE
`
`--
`
`ethyl Z-2-[(phenylrnethyl)(cid:173)
`arnino ]-2-butenoate
`
`ethyl E-2-[(phenylrnethyl)(cid:173)
`arnino]-2-butenoate
`
`Infrared studies (Dabrowski, 1963) and NMR studies (Dudek and Volpp, 1963)
`indicate that the Schiff base ethyl 2-[(phenylmethyl)amino]-2-butenoate (ethyl {3-
`benzylaminocrotonate) exists in configurational polymorphs; the low-melting form (mp
`23 °C) has the cis- or Z-conformation and the high-melting form (mp 75-80 oq has the
`trans- or £-conformation. These conformers equilibrate in solution, but upon crystalli(cid:173)
`zation, the configurations shown are "frozen" out in their respective polymorphic
`structures.
`The crystal structure of the £-isomer has been determined in our laboratory (Shieh
`et al., 1983). Crystals of the £-isomer belong to space group P212121 with a =
`19.655 A., b = 5.778 A., and c = 10.632 A.. Figure 10.7 shows the structure of this
`isomer, and indeed it has the structure of the £-isomer suggested by spectroscopic
`evidence (Dudek and Volpp, 1963).
`The NMR and IR spectra of ethyl 2-[(phenylmethyl)amino]-2-butenoate are com(cid:173)
`pletely consistent with this assignment. A solution-NMR spectrum of the low-melting
`form (prepared by dissolving crystals at low temperature) indicates that it is indeed the
`Z-isomer (Dudek and Volpp, 1963). In this experiment the isomer present in the solid
`state predominates in solution because of the low temperature.
`In our laboratory we
`have studied the isomerization rate of the Z-isomer to the £-isomer at ambient tempera(cid:173)
`ture in DMSO where it is relatively rapid. Measurement of the rate of this reaction at
`various temperatures gives an activation energy of 56.9 kJ/mol.
`
`10.2
`
`The energies in kJ/mol
`been calculated using the CA
`employs semiempirical pote1
`each rotamer. These calcul
`determined by X-ray crysu
`although the E- and Z-isome
`
`C. 4-(N-CHLOROBENZYLIE
`
`The Schiff base 4-(N-chlc
`morphs (Bernstein and Hagl
`disordered, it can be seen th<
`the two polymorphs. Hen
`Conformational polymorphi
`10.11. In the stable (triclini
`(orthorhombic) form the pht
`with respect to the H-C 1
`these two forms is shown ir
`Molecular orbital and I;
`for conformational polymo1
`stein and Hagler, 1978).
`
`Figure 10.7 Stereoview of ethyl2-[(phenylmethyl)amino]-2-butenoate in the high-melting £-isomer:
`H 0, C e. N@, 0 e (Shiehet al., 1983).
`
`Figure 10.8 Stereoview of 4
`and Hagler, 1978;
`
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`

`
`10.2 Conformational and Configurational Polymorphism
`
`151
`
`The energies in kJ/mol for a number of rotamers of the E- and Z-isomers have
`been calculated using the CAM SEQ program (Weintraub and Hopfinger, 1 975) which
`employs semiempirical potential and electrostatic functions to calculate the energies of
`each rotamer. These calculations indicate that the conformation of the E-isomer as
`determined by X-ray crystallography is one of the lowest energy conformations,
`although the E- and Z-isomers have nearly the same energy in a vacuum.
`
`C. 4-(N-CHLOROBENZYLIDENE)-4-CHLOROANILINE
`
`Cl~c(~ I \_
`~N~Cl 4-(N -chlorobenzylidene )-4-chloroaniline
`
`The Schiff base 4-(N-chlorobenzylidene)-4-chloroaniline crystallizes in two poly(cid:173)
`morphs (Bernstein and Hagler, 1978). Although the structures of both polymorphs are
`disordered, it can be seen that the conformation of the molecule is strikingly different in
`the two polymorphs. Hence,
`these forms are termed conformational polymorphs.
`Conformational polymorphism of drugs is discussed in more detail later in Section
`10.11. In the stable (triclinic) form, the molecules are planar, whereas in the unstable
`(orthorhombic) form the phenyl rings are rotated by equal but opposite amounts (24.8°)
`with respect to the H-C N least-squares plane of the imine. The crystal packings of
`these two forms is shown in Figures 10.8 and 10.9.
`Molecular orbital and lattice energy calculations were used to analyze the reasons
`for conformational polymorphism of 4-(N-chlorobenzylidene)-4-chloroaniline (Bern(cid:173)
`stein and Hagler, 1978). Quantum-mechanical calculations for a single molecule
`
`Figure 10.8 Stereoview of 4-(N-chlorobenzylidene)-4-chloroaniline triclinic polymorph (Bernstein
`and Hagler, 1978).
`
`1963)
`:hyl {3-
`rm (mp
`has the
`rystalli(cid:173)
`norphic
`
`'(Shieh
`tth a =
`• of this
`·oscopic
`
`re com(cid:173)
`-melting
`ieed the
`he solid
`.tory we
`empera(cid:173)
`.tction at
`
`£-isomer:
`
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`

`
`Chapter 10 Polymorphs
`
`10.
`
`Figure 10.9 Crystal packing stereoview of 4-(N-chlorobenzylidene)-4-chloroaniline orthorhombic
`form. (Bernstein and Hagler, 1978).
`
`showed that the nonplanar conformation was energetically favored by perhaps
`2.09-6.28 kJ/mol but the lattice-energy calculations, using semiempirical potential
`functions, showed that the planar structure (triclinic form) gave a lower lattice energy
`by about 4.19 kJ/mol. These calculations explain why the triclinic polymorph is the
`stable crystalline polymorph even though it contains the less stable (planar) conformer.
`Programs that calculate the packing energy are now available, for example, Ceriui
`(Molecular Simulations, Inc., 1997). These programs alone or in combination with
`structure elucidations based on powder diffraction data will provide new approaches to
`the structure analysis of materials when suitable single crystals are not available.
`
`D. 3-0xo-3H-2,1-BENZOXIODOL-I-YL 3-CHLOROBENZOATE
`
`~(fi-5
`y u
`
`Cl
`
`3-oxo-JH-2,1-benzoxiodol-1-yl
`3-cblorobenzoate
`
`As part of their extensive study of the crystal chemistry of iodoperoxides, Gougoutas
`and Lessinger (1974) determined the crystal structure of two polymorphs of 3-oxo-3H-
`2, 1-benzoxiodol-1-yl 3-chlorobenroate. This compound crystallizes in a- and j3-forms
`that both belong to the monoclinic crystal system (Table 10.4).
`
`Figure 10.10 The crystal p;
`(Gougoutas and
`
`Figure 10.11 The crystal 1
`(Gougoutas anc
`
`Table 10.4 Crystallographic
`2,1-benzoxiodol-1
`
`Parameter
`Space Group
`a(A)
`b(A)
`c(A)
`{3
`z
`Peak (g em-')
`V(A3 )
`
`Gougoutas and Lessinger, 19~
`
`The a-form is essent
`make an angle of aJ
`forms is also quite d
`
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`
`

`
`10.2 Conformational and Configurational Polymorphism
`
`1.53
`
`Figure 10.10 The crystal packing of 3-oxo-3H-2.1-benzoxiodol-l-yl 3-chlorobenzoate a-form
`(Gougoutas and Lessinger, 1974).
`
`Figure 10.11 The crystal packing of 3-oxo-3H-2, 1-benzoxiodol-1-yl 3-chlorobenzoate ~form
`(Gougouta..;; and Lessinger, 1974).
`
`Table 10.4 Crystallographic Unit Cell Parameters for 3-0xo-3H-
`2, 1-benzoxiodol-1-yl 3-Chlorobenzoate
`
`Parameter
`
`Space Group
`a(A)
`b(Al
`c(A)
`fJ
`z
`Peak (g cm-1
`)
`v <A3l
`Gougoutas and Lessinger. 1974.
`
`a-Form
`P2,1n
`6.376
`10.547
`20.066
`92.0°
`4
`1.984
`1348.6
`
`~Form
`
`Pc
`5.057
`13.035
`10.339
`99.5°
`2
`2.009
`672.2
`
`:>rthorhombic
`
`'Y perhaps
`al potential
`ttice energy
`1orph is the
`:onformer.
`pie, Cerius2
`ination with
`>proaches to
`1ble.
`
`'· Gougoutas
`>f 3-oxo-3H(cid:173)
`and /3-forms
`
`The a-form is essentially planar in the crystal while in the /3-form the two phenyl
`rings make an angle of approximately 55o with each other. The crystal packing of the
`two forms is also quite different as shown in Figures I 0.10 and 1 0.11. These two
`
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`

`
`154
`
`Chapter 10 Polymorphs
`
`forms have different solid-state infrared spectra (see Figure 10.12), as expected since
`the molecule is in different conformation in the two crystal forms.
`
`E. T AUTOMERIZATIONJ
`
`2000
`
`chloroform solution (with baseline)
`
`~ 1600.6cm->
`
`6
`
`10
`9
`8
`Wavelength (microns)
`
`11
`
`12
`
`13
`
`14
`
`15
`
`3000 2500
`
`2000
`
`1500
`
`cm-1
`
`1000
`
`ij 1600.6 em-'
`
`a-form (KBr pellet)
`
`6
`
`7
`
`10
`9
`8
`Wavelength (microns)
`
`11
`
`12
`
`13
`
`14
`
`15
`
`3000 2500
`
`2000
`
`1500
`
`cm-1
`
`1000
`
`/}form {KBr pellet)
`
`6
`
`10
`9
`8
`Wavelength (microns)
`
`11
`
`12
`
`13
`
`14
`
`15
`
`Figure 10.12
`
`Infrared spectra of 3-oxo-3H-2,l-benzoxiodol-l-yl 3-chlorobenzoate {Gougoutas and
`Lessinger, 1974).
`
`keto fon
`3-(4-chlorop
`2-[2-(2-(methoxycal
`amino )phenyl]-3-oxo
`
`Schulenberg (1968) ha:
`pheny l)amino )pheny 1]-3
`form has a melting point
`consistent with
`the
`phenyl)amino)phenyl]-3
`110-122 oc and upon di
`( 4-chlorophenyl)-3-hydr
`acid. Addition of trieth)
`ing 70% of the keto forn
`Although the crysta
`mined, this study illustr<
`containing an individual
`phism (cf. p. 143).
`
`£-conformer of tl
`1,3-diphenylprop:
`
`Several other case~
`enol of 1,3-diphenylprc
`the £-isomer and the ot
`there are numerous exm
`isomer or tautomer out c
`(1972).
`
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`
`

`
`ected since
`
`700
`
`ine)
`
`14
`
`15
`
`700
`
`14
`
`15
`
`Gougoutas and
`
`10.2 Conformational and Configurational Polymorphism
`
`155
`
`E. TAUTOMERIZATIONAL POLYMORPHISM
`
`Cl
`
`Cl
`
`keto form
`3-( 4-chlorophenyl)-
`2-[2-(2-(methoxycarboxyphenyl)(cid:173)
`amino)phenyl]-3-oxopropanoic acid
`
`enol form
`3-(4-chlorophenyl)-3-hydroxy-
`2-[2-(2-(methoxycarboxyphenyl)(cid:173)
`amino)phenyl]propenoic acid
`
`Schulenberg (1968) has reported that 3-(4-chlorophenyl)-2-[2-(2-(methoxycarboxy(cid:173)
`phenyl)amino)phenyl]-3-oxopropanoic acid crystallizes in two tautomeric forms. One
`form has a melting point of 93-99 oc that upon dissolution in CDC13 gave NMR spectra
`consistent with
`the
`keto
`form,
`3-(4-chlorophenyl-2-[2-(2-(methoxycarboxy(cid:173)
`phenyl)amino)phenyl]-3-oxopropanoic acid. The other form had a melting point of
`110-122 oc and upon dissolution gave NMR spectra consistent with the enol form, 3-
`(4-chlorophenyl)-3-hydroxy-2-[2-(2-(methoxycarboxyphenyl)amino)phenyl]propenoic
`acid. Addition of triethylamine to either solution gave an equilibrium mixture contain(cid:173)
`ing 70% of the keto form and 30% of the enol form.
`Although the crystal structures of the keto and enol forms have not been deter(cid:173)
`mined, this study illustrates a case in which two different crystalline forms exist, each
`containing an individual tautomer. This situation is termed tautomerizational polymor(cid:173)
`phism (cf. p. 143).
`
`£-conformer of the enol ate of
`1,3-diphenylpropane-1 ,3-dione
`
`Z-conformer of the enolate of
`1,3-diphenylpropane-1,3-dione
`
`Several other cases of tautomerizational polymorphism exist. For example, the
`enol of 1,3-diphenylpropane-1 ,3-dione crystallizes in two forms. One form contains
`In addition,
`theE-isomer and the other contains the Z-isomer (Eistert et al., 1952).
`there are numerous examples of the crystallization process freezing one configurational
`isomer or tautomer out of solution. These cases are reviewed by Curtin and Engelmann
`(1972).
`
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`

`
`Chapter 10 Polymorphs
`
`F. POLYCHROMISM
`
`10.
`
`yellow
`
`One of the most striking differences in physical properties among polymorphs is
`polychromism (i.e., different colors). Polychromism has been reported for only a
`limited number of cases. Dimethyl 3,6-dichloro-2,5-dihydroxyterephthalate, for
`example, crystallizes in yellow, light-yellow, and white polymorphs
`(Bym et al.,
`1972; Fletton et al., 1986; Yang et al., 1989; Richardson et al., 1990). The colors of
`these three polymorphs are attributed to differences in orientation of the carboxylate
`group with respect to the aromatic ring (see also Sections 10.7E and 20.\A).
`
`\.
`
`5-methyl-2-[ (2-nitrophenyl)amino 1-
`3-tbiophenecarbonitrile
`(ROY)
`
`Me
`
`5-Methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile is a dramatic example
`of polychromism. Crystallization of this compound from ethanol yields a mixture of
`yellow and red prisms, whereas crystallization from methanol yields orange needles;
`hence the alias ROY for the red, orange, and yellow forms (Borchardt, 1997). Crystals
`of the red form also appear to be pleochroic, displaying both red and orange colors
`under polarized illumination.
`The three polymorphs are free of solvent and stable at room temperature. The red,
`orange, and yellow forms are similar in energy with melting points of 106.2, 114.8,
`and 109.8 oc, respectively (Yu, 1998). The red and orange forms undergo solution(cid:173)
`mediated transformation to the yellow form at room temperature, indicating the latter is
`the most stable at room temperature. The yellow and orange forms are related enantio(cid:173)
`tropically, with yellow being more stable at low temperature. Between room temper(cid:173)
`ature and the melting point, the red form is always less stable than the yellow form.
`The heats of melting, as measured by DSC, confirmed these stability relationships.
`Solid-state phase transitions from red to yellow and from red to orange have been
`observed between 70-90 oc in a solvent free environment. The transition from red to
`yellow (at temperatures greater than 90 °C) results in a dramatic change in color but no
`apparent change in crystal morphology, whereas the transition from red to orange leads
`to the growth of orange needles from the initial red crystals.
`The crystal structures of red, orange, and yellow forms have been determined by
`single-crystal X-ray diffraction and show that the molecule adopts a dramatically
`different conformation in each of the forms. Subsequent studies show that these
`different conformations are the reasons for the different colors. Hydrogen bonding in
`the polymorphs is exclusively intramolecular--between the adjacent amine and nitro
`substituents. The heteroatom-to-heteroatom distances of the hydrogen bond in red,
`orange, and yellow are 2.636(2), 2.607(3), and 2.625(3) A, respectively. The con(cid:173)
`formations of the molecule in the three polymorphs are significantly different (Figure
`10.13). In the yellow and orange forms, the nitro group is essentially co-planar with
`the phenyl ring, whereas in the red form it is twisted out-of-plane by 18°. The color of
`the polymorphs may be related to the degree of electron de localization, which is related
`to the angle between the planes of the phenyl and the thiophene moieties (red 46°,
`
`Figure 10.13 Conformations
`crystalline fom
`
`orange 54 o, and yellow 1(
`order of the expected w;
`Section 8.1). Studies ha·
`direct result of the differer
`1998; Yu, 1998). The ol
`those calculated from the !
`13C CP/MAS solid-st
`tinguish the polymorphs.
`reported for polymorphic
`shifts of C3 (the carbon in
`97.9, 105.2, and 109.3
`covering a range of 11
`104.41 ppm in solution.)
`red form with respect to tl
`conjugation effect. Smitl
`(total suppression of spir
`shift anisotropy (CSA) o
`increases in magnitude by
`ric as the coplanar angle
`electrons between the tw•
`site.
`This parallels the re~
`quency are 2211, 2223, ~
`tively (see Section 8.1). •
`the red form from a high(
`vations confirm the sigrri
`pronounced color change
`A number of deriva
`nitrile were synthesized
`nitrophenylaminothiophe
`Me) crystallized in three
`the gold form were un
`polymorph" class. How•
`
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`
`

`
`lymorphs is
`d for only a
`1thalate, for
`Byrn et al.,
`lhe colors of
`! carboxylate
`.).
`
`1-
`
`1atic example
`a mixture of
`ange needles;
`t97). Crystals
`orange colors
`
`ure. The red,
`106.2, 114.8,
`ergo solution(cid:173)
`ng the latter is
`elated enantio(cid:173)
`room temper(cid:173)
`yellow form.
`relationships.
`1ge have been
`on from red to
`in color but no
`:o orange leads
`
`determined by
`a dramatically
`ilow that these
`gen bonding in
`mine and nitro
`rr bond in red,
`rely. The con(cid:173)
`ifferent (Figure
`' co-planar with
`o. The color of
`which is related
`1ieties (red 46°,
`
`10.2 Conformational and Configurational Polymorphism
`
`157
`
`red
`
`F"tgure 10.13 Conformations of 5-methyl-2-[(2-nitrophenyl)amino)-3-thiophenecarbonitrile in three
`crystalline forms.
`
`orange 54°, and yellow 106°). The order of these angles appears to correlate with the
`order of the expected wavelengths of absorption by the colored polymorphs (see
`Section 8.1 ). Studies have shown that the different colors of the polymorphs are a
`direct result of the difference in molecular conformation (Borchardt, 1997; Smith et al.,
`1998; Yu, 1998). The observed XRPD patterns of the three polymorphs agree with
`those calculated from the single-crystal structures.
`13C CP/MAS solid-state NMR, solid-state Ff-IR, and XRPD can be used to dis(cid:173)
`tinguish the polymorphs. The observed spectral differences are among the largest
`reported for polymorphic organic compounds. For example, the 13C NMR chemical
`shifts of C3 (the carbon in the thiophene ring to which the nitrile group is attached) are
`97.9, 105.2, and 109.3 ppm for the red, orange, and yellow forms, respectively,
`(For comparison, the chemical shift of C3 is
`covering a range of 11.4 ppm.
`104.41 ppm in solution.) This indicates an increase in the electron density of C3 in the
`red form with respect to the yellow and orange forms, possibly a result of an increased
`conjugation effect. Smith and coworkers (1998) have used a two-dimensional TOSS
`(total suppression of spinning sidebands) pulse sequence to investigate the chemical(cid:173)
`shift anisotropy (CSA) of C3. These studies show that the extent of the CSA for C3
`increases in magnitude by 30 ppm and the line shape appears to become more asymmet(cid:173)
`ric as the coplanar angle increases. This was taken to reflect a greater transfer of 1r
`electrons between the two ring systems and hence a greater electron density at the C3
`site.
`This parallels the results from IR spectroscopy in which the nitrile stretching fre(cid:173)
`quency are 2211, 2223, and 2231 cm-1
`, for the red, orange, and yellow forms, respec(cid:173)
`tively (see Section 8.1). This shift is indicative of the decreased nitrile bond strength in
`the red form from a higher degree of conjugation with the aromatic ring. These obser(cid:173)
`vations confirm the significant changes in the electronic structure, as demonstrated by
`pronounced color changes among different polymorphs.
`A number of derivatives of 5-methyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbo(cid:173)
`nitrile were synthesized in order to determine the extent of the color polymorphism of
`nitrophenylaminothiophenes. 2-[(2-Nitrophenyl)amino]-3-thiophenecarbonitrile (Nor(cid:173)
`Me) crystallized in three forms: red, orange, and gold. Numerous attempts to obtain
`the gold form were unsuccessful thus placing the gold from in the "disappearing
`polymorph" class. However, crystallization of a newly synthesized lot of NorMe gave
`
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`
`

`
`158
`
`Chapter 10 Polymorphs
`
`the gold form once again only to disappear when the material was subjected to further
`crystallization and handling. As with other disappearing polymorphs, this behavior is
`due to the presence of impurities and the fact that the gold polymorph is unstable in the
`presence of seeds of the other forms (Dunitz and Bernstein, 1995).
`
`are extremely useful
`polymorphs.
`
`2-[ (2-nitrophenyl)amino 1-
`3-thiopbenecarbonitrile
`(NorMe)
`
`The XRPD patterns of the three forms of NorMe are different from the parent
`compound. The crystal structure of the red form NorMe was determined (Borchardt,
`1997). The red form is nearly coplanar further substantiating the concept that the red
`color is associated with planarity. TheIR spectra of the NorMe polymorphs are quite
`similar to ROY. The red form has a nitrile stretching absorption at 2210 em -I, the
`orange is a 2222 cm-1
`, and the yellow at 2230 cm- 1
`•
`
`4-metbyl-
`2-[(2-nitrophenyl)amino 1-
`3-thiophenecarbonitrile
`(4-Me)
`
`4,5-dimethyl-
`2-[(2-nitrophenyl)amino]-
`3-tbiophenecarbonitrile
`(4,5-DiMe)
`
`5-methyl-2-[(4-methyl-
`2-nitropbenyl)amino 1-
`3-thiophenecarbonitrile
`(4'-Me)
`
`The conformation of the red form of 4-methyl-2-[(2-nitrophenyl)amino]-3-thio(cid:173)
`phenecarbonitrile (4-Me) is the most coplanar of the structures determined (see Figure
`10.14).
`4,5-Dimethyl-2-[(2-nitrophenyl)amino]-3-thiophenecarbonitrile (4,5-DiMe)
`crystallized in two polymorphs: red and orange. As with the previous derivatives, the
`conformation of the red form as determined by single-crystal X-ray methods is mther
`coplanar (see Figure 10.14). 5-Methyl-2-[4-methyl-2-nitrophenyl)amino]-3-thiophene(cid:173)
`carbonitrile (4'-Me) w