1834
`
`J. Am. Chem. Soc. 2001, 123, 1834-1841
`
`Disappearing and Reappearing Polymorphs. The Benzocaine:Picric
`Acid System
`
`Jan-Olav Henck,*,†,| Joel Bernstein,*,‡ Arkady Ellern,‡ and Roland Boese§
`Contribution from the Institut fu¨r Pharmakognosie der UniVersita¨t Innsbruck Innrain 52,
`Josef-Moeller-Haus, 6020 Innsbruck, Austria, Department of Chemistry, Ben-Gurion UniVersity of the
`NegeV, Beer SheVa, Israel 84105, and FB8/Anorganische Chemie, UniVersita¨t-GH Essen,
`UniVersita¨tstrasse 5, 45117 Essen, Germany
`ReceiVed June 12, 2000
`
`Abstract: The low-melting polymorphic modification of the 1:1 complex of benzocaine (BC) and picric acid
`(PA) had earlier been reported to be an example of a “disappearing polymorph”. The BC:PA system has been
`reinvestigated by thermomicroscopy, calorimetry, solid-state NMR, and X-ray crystallography. The phase
`diagram has been derived, and robust procedures for the crystallization of the two 1:1 complexes, a hydrate
`of the 1:1 complex, and a 2:1 complex have been devised. The structures of all four phases have been determined
`and compared using graph set analysis to characterize the hydrogen-bonding patterns. It is shown that the
`thorough microscopic investigation of the thermal behavior, combined with calorimetric methods, can lead to
`the development of strategies to crystallize metastable polymorphic forms which may be difficult to obtain
`once their stable congeners have been obtained.
`
`Introduction
`
`Polymorphism, the ability of a substance to exist in several
`different crystal forms or modifications, is a frequently observed
`phenomenon in molecular compounds.1 If a solid substance
`includes a solvent during crystallization, this structure is known
`as a pseudopolymorph, and in case of, e.g., water such crystal
`forms are generally called hydrates.2 The polymorphic modi-
`fications of a compound are chemically identical but usually
`differ in their physical and chemical properties, such as density,
`vibrational spectra, and diffraction patterns.
`Since a particular polymorph may have desirable properties,
`it may be useful to develop a robust method to obtain that
`polymorphic modification consistently and reproducibly. There
`are many documented cases of difficulties in obtaining crystals
`of a particular known modification.3,4 Such difficulties may have
`serious practical consequences: a material designed to give a
`particular structure may exhibit an undesired polymorphic one;5
`a plant manufacturing a particular modification may have to
`close because it has been “poisoned” by an undesired poly-
`morph;6 a commercial drug formulation may no longer be
`
`* To whom correspondence should be addressed
`† Universita¨t Innsbruck
`‡ Ben-Gurion University of the Negev
`§ Universita¨t-GH Essen
`| Current address: Bayer AG, PH-PD PQCD1, Building E39, 51368
`Leverkusen, Germany
`(1) The April 1, 1998, release of the Cambridge Structural Database
`contains 181 309 entries, of which 5641 contain the qualifier “form”, 163
`the qualifier “polymorph”, 172 the qualifier “modification”, and 146 the
`qualifier “mod” Not all of these are entries for the structures of all
`polymorphs for a particular substance, but these numbers indicate that
`roughly 3% of the entries in the database are for polymorphic materials
`(2) Byrn, S R Solid State Chemistry of Drugs, 2nd ed ; SSCI, Inc : West
`Lafayette, IN, 1999; pp 513-514
`(3) Dunitz, J D ; Bernstein, J Acc. Chem. Res. 1995, 28, 193-200
`(4) Webb, J ; Anderson, B J. Chem. Educ. 1978, 55, 644
`(5) Aakero¨y, C B ; Nieuwenhuyzen, M ; Price, S L J. Am. Chem. Soc.
`1998, 120, 8986-8993
`(6) Anonymous Ind. Eng. Chem 1953, 11a
`
`available on the market due to the appearance of an undesired
`polymorphic modification.7 We recently documented a number
`of representative cases in which it was difficult to obtain a given
`polymorphic form even though previously it had often been
`obtained routinely over long periods of timesso-called “disap-
`pearing polymorphs”.3 In the conclusion to that review, we
`stated our belief “that once a particular polymorph has been
`obtained, it is always possible to obtain it again; it is only a
`matter of finding the right experimental conditions”. One of
`the challenges to those dealing with the preparation of solids is
`to be able to rationally develop those conditions and to control
`the polymorphic form obtainedsin many instances to recover
`the disappeared polymorph. In this paper we present a case study
`of how such a challenge might be met.
`One of the examples cited in the above-mentioned review
`was the case of benzocaine picrate (BC:PA). This binary system
`has been studied previously at least three separate times.8-10 In
`1972, Nielsen and Borka8 reported the first preparation of the
`complex (now known as Mod. II) with a melting point of 130-
`132 (cid:176)C. At the time, this modification was used as a pharma-
`copoeial standard for the identification of benzocaine (a topical
`anesthetic). Subsequently, the same authors prepared a high-
`melting modification (now known as Mod. I), mp 162-163 (cid:176) C,
`whereupon they encountered severe difficulties in preparing and
`maintaining Mod. II for more than several hours before it
`transformed into Mod. I.11 The low-melting modification is
`thermodynamically unstable at 20 (cid:176)C. 8
`In 1974, Borka and Kuhnert-Brandsta¨tter9 reinvestigated
`the system using thermomicroscopy and found four modifica-
`(7) Chemburkar, S R ; Bauer, J ; Deming, K ; Spiwek, H ; Patel, K ;
`Morris, J ; Henry, R ; Spanton, S ; Dziki, W ; Porter, W ; Quick, J ; Bauer,
`P ; Donaubauer, J ; Narayanan, B A ; Soldani, M ; Riley, D ; McFarland,
`K Org. Process Res. DeV. 2000, 4, 413-417
`(8) Nielsen, T K ; Borka, L Acta Pharm. Suecica 1972, 9, 503-505
`(9) Borka, L ; Kuhnert-Brandsta¨tter, M Arch. Pharmaz. 1974, 307, 377-
`384
`(10) Togashi, A ; Matsunaga, Y Bull. Chem. Soc. Jpn. 1987, 60, 1171-
`1173
`
`10.1021/ja002113o CCC: $20.00 © 2001 American Chemical Society
`Published on Web 02/10/2001
`
`Page 1 of 8
`
`Grunenthal GmbH Exhibit 2010
`Rosellini v. Grunenthal GmbH
`IPR2016-00471
`
`

`
`Disappearing and Reappearing Polymorphs
`
`J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1835
`
`apparently lies in the difficulty of translating the microscopic
`observations to the growth of single crystals that can be used
`for structure determination. In this work, we adopted a strategy
`for crystal growth experiments aimed at obtaining crystals for
`X-ray determination of the various phases of BC:PA based on
`the observations made using optical and thermomicroscopy and
`on the appearance and disappearance of those phases. We
`believe that this approach can be widely utilized and thus can
`provide the means for greatly expanding our understanding of
`the structural basis for polymorphic behavior.
`
`Results
`
`The Phase Diagram. The phase diagram can provide very
`useful information and guidelines for the preparation of a
`particular polymorphic modification. Much of the data for the
`preparation of the phase diagram may be readily obtained from
`thermomicroscopic studies. In fact, for a two-component system,
`such as BC:PA, Kuhnert-Brandsta¨tter pointed out that “Kofler’s
`contact method of thermal analysis offers the possibility of
`investigating organic two component systems qualitatively in
`the shortest possible time in the simplest possible manner.” 16,22
`More quantitative details may be added from DSC measure-
`ments.
`Details on the preparation of the BC:PA contact sample and
`analysis are given in the Experimental Procedures section. Figure
`1a shows the photomicrograph of the recrystallized contact
`preparation of BC and PA at 25 (cid:176)C. The interference colors
`are due to the use of crossed polarizers. The pure compounds
`are at the extremities of the preparation, while in the region
`where the original compounds have merged, a number of
`different areas may be observed, due to the formation of different
`crystalline species combining the two components. Heating this
`preparation on the hot-stage microscope to a temperature of
`about 88 (cid:176)C shows (Figure 1b) the eutectic melt of BC and the
`broad dark yellow crystals of a new compound. Due to the
`crossed polarizers, the isotropic melt appears black. As can be
`seen in Figure 1c, at about 120 (cid:176)C on the left side of the
`preparation BC is melted, and on the right side the eutectic
`between PA and the remaining crystals of the BC:PA 1:1
`complex melts. Figure 1d shows the situation which is observed
`at 122 (cid:176)C. PA is almost melted, and in the middle of the
`preparation a eutectic melt appears. Thus,
`two chemically
`different kinds of complexes between BC and PA have been
`formed. The one on the right side is the 1:1 complex, while the
`small strip on the left side (the BC side) is a complex with
`composition (BC)2:PA.9 The former melts at 129 (cid:176)C, while the
`latter shows a melting point at 124 (cid:176)C.
`The results obtained by means of thermomicroscopy and DSC
`experiments on different mixtures of benzocaine and picric acid
`led to the phase diagram (Figure 2). These investigations indicate
`the existence of two modifications of the 1:1 complex as well
`as of one modification of the 2:1 complex. The eutectic points
`of Mod. II of the 1:1 complex with benzocaine and picric acid
`are located at mole fractions of 0.07 (88 (cid:176) C) and 0.85 (109 (cid:176) C),
`respectively. The peritectic of Mod. II with the 2:1 complex
`appears at a mole fraction 0.33 and about 120 (cid:176)C, and the
`eutectic between the 2:1 complex and benzocaine is located at
`0.3 and at 110 (cid:176)C.
`Preparation of Single Crystals. The thermodynamic
`phase relationship between the two forms of BC:PA may be
`
`(22) For a summary of the contact method, see also: Emons, H.-H.;
`Keune, H.; Seyfarth, H.-H. In Chemical Microscopy; Svehla, G., Ed.;
`Comprehensive Analytical Chemistry, Vol. XVI; Elsevier: Amsterdam,
`1982; pp 180-184.
`
`tions of BC:PA. They further identified two modifications of a
`(BC)2:PA complex as well as a monohydrate. Apparently
`unaware of both of these earlier works, Togashi and Matsunaga
`also reported a (BC)2:PA complex and an additional charge-
`transfer complex between the two compounds, observed by
`using differential scanning calorimetry (DSC).10 No structural
`studies on any of the complexes were reported.
`The aims of the work we report here were (1) to develop a
`general strategy and specific methods for controllably and
`reproducibly obtaining the “disappearing” modification II of BC:
`PA; (2) to develop methods for obtaining single crystals suitable
`for X-ray structure determination of as many as possible of the
`BC:PA species reported by earlier authors; and (3) to fully
`characterize the BC:PA phases by spectroscopic and structural
`techniques.
`
`Experimental Strategy
`
`Since the discovery of polymorphism in 1822,12 one of the
`principal techniques for investigating the phenomenon has been
`optical microscopy and, in the latter part of the 20th century,
`thermomicroscopy.13-16 These methods are particularly useful
`in detecting the existence of polymorphs and polymorphic
`transitions quickly and easily. In the last few decades, more
`sophisticated analytical techniques have supplanted the two
`classic ones,17 but the net result of years of effort by a number
`of groups is that many polymorphic materials have been
`identified and characterized.16,18-20 Despite the success of these
`methods, very few of these findings have been utilized as the
`starting point for structural studies.21 The general problem
`
`(11) The authors reported the disappearing phenomenon and their
`attempts to overcome it as follows:8 “As a matter of curiosity, it ought to
`be mentioned that once the stable modification was obtained, the metastable
`modification could no longer be isolated. It was first observed by one of us
`(TKN). This observation was later confirmed in a separate laboratory (LB).
`Further,
`it was found that after discarding all samples, washing the
`equipment and laboratory benches and waiting for 8-12 days, the low
`melting modification could be isolated again. This has now been repeated
`several times in our laboratories. Obviously the seeding effect during the
`formation of the primary crystals (or during the very procedure of
`determination of the melting point) is exceptionally strong.”
`(12) Mitscherlich, E. Ann. Chim. Phys. 1822, 19, 350-419.
`(13) Chamot, E. M.; Mason, C. W. Handbook of Chemical Microscopy,
`Volume I, Principles and Use of Microscopes and Accessories Physical
`Methods for the Study of Chemical Problems, 3rd ed.; John Wiley and
`Sons: New York, 1958.
`(14) Kofler, L.; Kofler, A. Thermo-MikroMethoden zur Kennzeichnung
`organischer Stoffe und Stoffgemische; Wagner: Innsbruck, 1954.
`(15) McCrone, W. C. Fusion Methods in Chemical Microscopy; Inter-
`science: New York, 1956.
`(16) (a) Kuhnert-Brandsta¨tter, M. Thermomicroscopy in the Analysis of
`Pharmaceuticals; Pergamon Press: Oxford, 1971 Kuhnert-Brandsta¨tter, M.
`In Thermomicroscopy of Organic Compounds; Svehla, G., Ed.; Compre-
`hensive Analytical Chemistry, Vol. XVI; Elsevier: Amsterdam, 1982; pp
`329-513.
`(17) Threlfall, T. Analyst 1995, 120, 2435-2460.
`(18) Burger, A.; Ramberger, R. Mikrochim. Acta 1979, II, 259-271.
`(19) Haleblian, J. K.; Borka, L. Acta Pharm. Jugosl. 1990, 40, 71-94.
`(20) Borka, L. Pharm. Acta, HelV. 1991, 66, 16-22.
`(21) For a more detailed account of the use and decline of the use of the
`microscope in polymorphism research, see: Bernstein, J.; Henck, J.-O. Cryst.
`Eng. 1998, 1, 119-128.
`
`Page 2 of 8
`
`

`
`1836 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
`
`Henck et al.
`
`Figure 1. Photographs of the microscope slide Kofler preparations showing the various phases of the BC:PA binary system: (a) 25 (cid:176)C, (b) 87 (cid:176)C,
`(c) 120 (cid:176)C, and (d) 123 (cid:176)C (see text for explanation and discussion of details of the phenomena observed here).
`
`enantiotropic or monotropic.16 In the former case, the choice
`of crystallization conditions for one of the two polymorphs
`would be more facile, because thermodynamically controlled
`crystallization conditions could be chosen at temperatures below
`the thermodynamic transition point. To determine the mono-
`tropism/enantiotropism, we crystallized microcrystalline BC:
`PA Mod. II by means of thermomicroscopy and carried out
`DSC measurements on the resulting solid. The DSC trace shows
`an exothermic transition of Mod. II into Mod. I. We could then
`apply the empirical heat-of-transition rule23 to conclude that
`these two crystal forms are monotropically related (Table 1).
`This means that Mod. I is the thermodynamically stable crystal
`form from absolute zero up to its melting point.
`Since the lower melting Mod. II is thermodynamically less
`stable at all temperatures below the melting point, “kinetic”
`conditions must be created to attempt to crystallize this form.
`Therefore, a high-temperature (80 (cid:176)C) crystallization was
`attempted, with water as the solvent, yielding single crystals
`up to 1 mm in maximum dimension. Since the prior work of
`
`(23) According to the “heat-of-transition rule”,18 if the phase transition
`is exothermic, then there is no transition point below the experimentally
`observed transition temperature. This is generally observed if two transitions
`are monotropically related. As can be seen in Table 1, the phase transition
`has been determined by DSC measurements to be exothermic.
`
`Nielson and Borka8 indicated that seeds of the stable form must
`be excluded, we obtained the less stable form prior to carrying
`out crystallization experiments aimed at obtaining the more
`stable one.
`As Mod. I is the thermodynamically preferred form, an
`“equilibrium” crystallization is preferred over a “kinetic” one.
`Nielsen and Borka8 obtained Mod. I by “excessive drying of
`[Mod. II] at 105 (cid:176)C”, conditions which are not particularly
`conducive to an “equilibrium” situation, nor to the growth of
`single crystals. Also, the existence of the hydrate (determined
`in the thermomicroscopic studies) suggests that the presence
`of water might be problematic in attempting to obtain nonhy-
`drated phases. Hence, we resorted to a nonaqueous gel-diffusion
`crystallization,24 using Sephadex as the gel medium, and
`obtained large single crystals (1-2 mm maximum dimension)
`after 3 days at 20 (cid:176)C.
`The rather drastic drying procedure described by Nielsen and
`Borka8 to obtain Mod. I, Borka and Kuhnert-Brandsta¨tter’s
`report,9 and our own observations on the hot-stage microscope
`indicated the existence of a hydrate of BC:PA. To obtain single
`crystals of this material, we attempted a crystallization from a
`
`(24) Desiraju, G. R.; Curtin, D. Y.; Paul, I. C. J. Am. Chem. Soc. 1977,
`99, 6148-6149.
`
`Page 3 of 8
`
`

`
`Disappearing and Reappearing Polymorphs
`
`J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1837
`
`Figure 2. Phase diagram of the BC:PA system.
`
`Table 1. Physicochemical Data of BC:PA Mod. I, BC:PA Mod.
`II, and (BC)2:PA
`
`mp ((cid:176)C), DSConset
`thermomicroscopy
`enthalpy of fusion (kJ mol-1)
`enthalpy of transition (kJ mol-1)
`
`BC:PA
`Mod. I
`161
`161
`63
`
`entropy of fusiona (J mol-1 K-1)
`a Calculated by ¢Sf ) ¢Hf mp-1.
`
`145
`
`(BC)2:PA
`119
`120
`
`BC:PA
`Mod. II
`129
`128
`56
`-9
`f Mod. I
`118
`
`Figure 3. Line drawing representation of the morphologies of the four
`different crystalline materials obtained, as labeled.
`
`saturated water solution in a sealed virgin flask (to prevent the
`unintentional incursion of seeds of any of the other forms) at
`20 (cid:176) C; needle-shaped crystals (up to 4 mm long) appeared after
`48 h.
`Crystals of the 2:1 complex were obtained by slow evapora-
`tion (ca. 4 weeks) of a 1:1 mixture of the components in
`2-propanol at 4 (cid:176) C. Admittedly, this was not an experiment
`designed to obtain the 2:1 complex, but the ample evidence to
`indicate its existence increased our interest in examining all the
`crystals obtained and motivated our attempts to obtain the
`crystals, using conditions different from those used for the other
`three species.
`The crystals of all four complexes were yellow but were easily
`distinguished by their morphology (Figure 3) and, very clearly,
`by their melting points.
`Crystal data for the four structures are given in Table 2; details
`of the structure determination are given in the Experimental
`Procedures section.
`Crystal Structures. (a) General Features. All four structures
`are ionic picrates, the acidic hydrogen of the hydroxyl group
`on picric acid having been transferred to an amino group on
`benzocaine. The atomic numbering, given in a the ORTEP
`diagram (for (BC)2:PA), is identical for all four structures
`
`Figure 4. ORTEP diagram of the molecules in the (BC)2:PA structure, showing the atomic numbering. Hydrogens are numbered according to the
`atoms to which they are attached. Numbering is identical for the other structures; the oxygen of the water molecule in BC:PA(cid:226)H2O is O01.
`
`Page 4 of 8
`
`

`
`1838 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
`
`Henck et al.
`
`Table 2. Summary of Crystallographic Data for the Four Compounds Studied
`BC:PA Mod. I
`BC:PA Mod. II
`C15H14N4O9
`C15H14N4O9
`394.3
`394.3
`monoclinic
`triclinic
`P21/n
`P1
`yellow
`yellow
`4
`2
`7.149(3)
`7.304(3)
`12.240(7)
`8.231(2)
`19.594(9)
`15.361(5)
`90
`99.91(2)
`96.77(3)
`99.53(2)
`90
`106.73(3)
`5.1
`3.3
`0.988
`0.969
`
`formula
`formula weight
`crystal system
`space group
`color of crystal
`Z
`a (Å)
`b (Å)
`c (Å)
`R ((cid:176))
`(cid:226) ((cid:176))
`(cid:231) ((cid:176))
`R-factor (%)
`GOF (on F2)
`
`(BC)2:PA
`C24H25N5O11
`559.5
`triclinic
`P1
`yellow
`2
`8.190(2)
`8.857(3)
`19.747(5)
`78.59(2)
`85.13(2)
`67.93(2)
`4.0
`0.908
`
`BC:PA(cid:226)H2O
`C15H16N4O10
`412.3
`monoclinic
`P21
`yellow
`2
`4.1478(8)
`12.732(3)
`17.518(4)
`90
`93.84(3)
`90
`3.8
`0.980
`
`BC:PA(cid:226)H2O
`-168.5
`8.2
`19.2
`
`(BC)2:PA
`-152.8
`0
`-49.4
`
`Figure 5. Packing diagrams the four crystal structures. For ease of comparison, in all cases the view is chosen on the best plane of the shaded
`picrate anion as a reference, with the C-O vector pointing down. Some slight rotational adjustments of the views have been made to facilitate
`better viewing of the packing and the hydrogen bonds. Carbon atoms are not explicitly drawn. Oxygens are represented by empty circles, and
`nitrogens are represented by filled circles. Hydrogens have been eliminated for clarity except where noted. The unit cell axes are marked as X,Y,Z,
`while hydrogen bonds are identified by lowercase letters (see text). (a) BC:PA Mod. I, (b) BC:PA Mod. II, (c) BC:PA(cid:226)H2O (hydrogens are included
`on the water molecule and on N1 of BC), and (d) (BC)2:PA (hydrogens on N1 and N1¢ are included).
`BC+ and PA- within a stack make an angle of 2.3(cid:176) with each
`other, the distance between centers of rings being 4.04 Å.
`BC:PA Mod. II (Figure 5b) also crystallizes in mixed (cid:240)-(cid:240)
`stacks of (cid:226)(cid:226)(cid:226)BC+(cid:226)(cid:226)(cid:226)PA-(cid:226)(cid:226)(cid:226), again essentially along [100]. The
`mode of overlap along the stack is such that the four atom chain
`of the ester group is nearly parallel to the long (O--C(cid:226)(cid:226)(cid:226)p-NO2)
`axis of the molecule, while in Mod. I the chain of the ester
`group is nearly perpendicular to that axis. The angle between
`the phenyl rings (7.6(cid:176) ) is slightly larger, but the distance between
`centers is smaller (3.70 Å), indicating a greater degree of overlap
`between neighboring molecules in Mod. II.
`In contrast to the two anhydrous complexes, in BC:PA(cid:226)H2O
`(Figure 5c) the cations and anions are arranged in segregated
`stacks (cid:226)(cid:226)(cid:226)BC+(cid:226)(cid:226)(cid:226)BC+(cid:226)(cid:226)(cid:226) and (cid:226)(cid:226)(cid:226)PA-(cid:226)(cid:226)(cid:226)PA-(cid:226)(cid:226)(cid:226). The perpendicular
`distance between planes in the BC+ stack is 3.73 Å, while that
`in the PA- stack is 3.45 Å. Sheets of cations or anions are
`generated by the screw operation along the b axis, and in these
`sheets cations and anions alternate along the c axis. The angle
`between the phenyl rings of BC+ and PA- is 35(cid:176). There are
`sheets of cations and sheets of anions, both parallel to the
`stacking direction, so that the structure is built up of parallel
`sheets of cations and anions, in a manner similar to zinc blende.
`Since the structure is polar, this means that, as drawn in Figure
`5c, the (001) and (001h) faces of the crystal should be oppositely
`
`Table 3. Rotation Angles (deg) of Nitro Groups in PA in the Four
`Crystal Structures
`BC:PA
`angle about
`C-N bond
`Mod. I
`C11-N2
`-176.0
`C13-N3
`4.7
`C15-N4
`-37.9
`
`BC:PA
`Mod. II
`-144.4
`11.3
`147.4
`
`(Figure 4). There are no unusual bond lengths or angles. Only
`two of the torsion angle values for the ethyl ester chain of the
`BC moiety suggest some conformational variation, namely that
`for C5-C6-C7-O1 of BC:PA Mod. I (157.6(cid:176)) and that for
`C7-O1-C8-C9 of BC:PA Mod. II (161.0(cid:176)) compared to the
`others, which are all in the range 170-180(cid:176). These conforma-
`tional differences were not investigated further.
`The rotations of the nitro groups in PA are summarized in
`Table 3. That para to the phenolate oxygen is essentially
`coplanar with the benzene ring in all cases. The ortho nitro
`groups are rotated out of the phenyl plane, those about C11-
`N2 all in the same sense but to varying degrees, while those
`about C15-N4 are also rotated to approximately the same
`degree, but the rotation in the hydrate is opposite in sense from
`the other three instances.
`BC:PA Mod. I in (Figure 5a) may be described as mixed
`stacks of (cid:226)(cid:226)(cid:226)BC+(cid:226)(cid:226)(cid:226) PA-(cid:226)(cid:226)(cid:226) with apparently (cid:240)-(cid:240) plane-to-plane
`interactions along the [100] direction. The best planes of the
`
`Page 5 of 8
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`

`
`Disappearing and Reappearing Polymorphs
`
`J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1839
`
`H(cid:226)(cid:226)(cid:226)-O (Å)
`1.772(3)
`1.716(3)
`1.792(4)
`2.182(4)
`1.709(8)
`2.083(7)
`
`BC:PA Mod. I
`BC:PA Mod. II
`(BC)2:PA
`a¢ a
`BC:PA(cid:226)H2O
`a¢
`
`Table 4. Geometric Features of the Hydrogen Bonds Discussed in
`the Text (The Designations a, a¢...d Correspond to the Hydrogen
`Bonds in Figure 4, and Are Defined for Each Section)
`(a) N+sH(cid:226)(cid:226)(cid:226)-OsC
`N+(cid:226)(cid:226)(cid:226)-O (Å)
`2.681(4)
`2.667(3)
`2.762(4)
`3.024(4)
`2.678(7)
`2.791(7))
`(b) N+sH(cid:226)(cid:226)(cid:226)OdC
`H(cid:226)(cid:226)(cid:226)O (Å)
`N+(cid:226)(cid:226)(cid:226)O (Å)
`BC:PA Mod. I
`1.956(3)
`2.834(4)
`BC:PA Mod. II
`2.279(3)
`2.883(3)
`(BC)2:PA
`1.945(4)
`2.860(4)
`b¢ b
`2.163(4)
`2.994(4)
`BC:PA(cid:226)H2O
`-
`-
`(c) N+sH(cid:226)(cid:226)(cid:226)O(w), (d) O(w)sH(cid:226)(cid:226)(cid:226)OdN(nitro)
`D(cid:226)(cid:226)(cid:226)A (Å)
`H(cid:226)(cid:226)(cid:226)A (Å)
`BC:PA(cid:226)H2Oc
`cc
`2.803(8)
`1.983(7)
`d
`2.948(7)
`1.787(7)
`a For this entry, a¢ is the hydrogen bond from the neutral BC to the
`PA- in the 2:1 complex. b For this entry, b¢ is the hydrogen bond from
`the neutral BC to the PA- in the 2:1 complex. c The generic notation
`(DsH(cid:226)(cid:226)(cid:226)A) for the hydrogen bond is used here, since c and d are
`different hydrogen bonds.
`
`charged as in zinc blende.25 The (BC)2:PA complex (Figure
`5d) is composed of BC+ cations, PA- anions, and an additional
`neutral BC molecule, confirming the conclusion of Togashi and
`Matsunaga from IR data.10 The PA- anions are arranged across
`successive inversion centers at 1/2, 1/2, 1/2, forming a stack in
`the b axis direction, with a perpendicular distance between atoms
`of one picrate ring and the plane of its centrosymmetric neighbor
`of 3.48-3.51 Å and a distance between ring centers of 5.90 Å.
`Translation of these stacks along the a crystallographic axis
`generates a sheet of picrate anions. The BC molecules are also
`stacked along the b crystallographic axis, with alternating neutral
`BC and BC+ cations. The angle between the phenyl rings for
`the two species is 13.6(cid:176) , with a center-to-center distance of 3.82
`Å. Sheets of these BC moieties are then generated by the a
`axis translation.
`(b) Hydrogen Bonding. There are clearly a number of
`possibilities for hydrogen bonding in these four structures, and
`a comparison of the hydrogen-bonding patterns facilitates
`recognizing the similarities and differences among them.
`The hydrogen bonds are defined and their metrics are
`compared in Table 4. Hydrogen bond a appears in all structures
`and is remarkably constant, save for the bond to the neutral
`BC in (BC)2:PA and for the second hydrogen bond of the type
`(noted as a¢) in the hydrate. Hydrogen bond b appears in all
`but the hydrate, but the H(cid:226)(cid:226)(cid:226)O distance is longer in BC:PA Mod.
`II and to the neutral BC in (BC)2:PA than in the two other
`cases.
`The two hydrogen bonds involving water (once as donor and
`once as acceptor) in the hydrate are denoted as c and d in Table
`4. It is not clear if the long O-H and concomitantly short
`H(cid:226)(cid:226)(cid:226)O distances for the latter are of significance or merely a
`result of the unconstrained refinement of the hydrogen atom
`position in the crystal structure analysis.
`The most direct way of summarizing the hydrogen-bonding
`
`(25) Mak, T. C. W.; Zhou, G.-D. Crystallography in Modern Chemistry;
`Wiley-Interscience: New York, 1992; pp 77-80.
`
`Figure 6. Graph set assignments for the hydrogen bond patterns in
`the four structures studied. The hydrogen bonds are denoted by
`lowercase letters that correspond to the tabulation in Table 5 and the
`notation in Figure 6. As in ref 27, diagonal elements represent first
`level graph assignments, while off-diagonal ones represent second level
`graph sets composed of the two hydrogen bonds forming that element.
`A hyphen indicates that there is no connectivity between the hydrogen
`bonds at the second level.
`
`patterns and comparing them is through the use of graph sets.26,27
`The graph set assignments are conveniently summarized in
`(symmetric) matrix-type tables,27 in which the diagonal elements
`are the first level graph set assignments and the off-diagonal
`elements are the second level assignments. Consistent ordering
`of the columns and rows with chemically identical hydrogen
`bonds through the four molecules (to the extent that it is
`possible) greatly facilitates comparison of hydrogen-bonding
`patterns among the structures. These graph set assignments are
`summarized in Figure 6.
`The same two indiVidual hydrogen bonds are present in
`BC:PA Mod. I and BC:PA Mod. II. The monotropic transfor-
`mation from mod. II to mod. I is not accompanied by any overall
`pattern change. Also, the fact that the (cid:24)7 Å axis is maintained
`suggests that the transformation takes place within the sheets
`nearly perpendicular to this axis. The transformation, observed
`by microscope, is seen to be a solid-solid transformation but
`involves extensive shattering of the crystalline material, indicat-
`ing that quite drastic structural changes are, indeed, taking place.
`However, a careful visual examination and comparison of the
`two structures with all of these considerations did not reveal a
`simple geometric mechanism for the phase change.
`Thermal Studies and Thermodynamic Relationships among
`the Structures Studied. The structural properties of Mod. I
`
`(26) Etter, M. C. Acc. Chem. Res. 1990, 23, 120-127.
`(27) Bernstein, J.; Davis, R. E ; Chang, N.-L.; Shimoni, L. Angew. Chem.,
`Int. Ed. Engl. 1995, 35, 1555-1567.
`
`Page 6 of 8
`
`

`
`1840 J. Am. Chem. Soc., Vol. 123, No. 9, 2001
`
`Henck et al.
`
`Figure 7. CP-MAS solid-state NMR spectra: (a) benzocaine, (b) BC:PA Mod. I, (c) BC:PA Mod. II, (d) BC:PA(cid:226)H2O, and (e) (BC)2:PA.
`
`and Mod. II are quite similar. Lacking the structural data, one
`might be tempted to suggest the 30 K difference in melting
`point as being due to extraordinary differences in the packing
`properties of the two modifications. The system studied here
`shows that it is questionable whether differences in melting can
`be used to try to relate thermodynamic properties of crystalline
`
`systems to structural features. It is the difference in entropy of
`fusion between the two forms which is the thermodynamic
`quantity for comparison here. The thermoanalytical results on
`BC:PA (Table 1) indicate that the entropy of fusion of the two
`crystal forms is also close. Since melting point, enthalpy of
`fusion, transition temperature, or enthalpy of transition can be
`
`Page 7 of 8
`
`

`
`Disappearing and Reappearing Polymorphs
`
`J. Am. Chem. Soc., Vol. 123, No. 9, 2001 1841
`
`measured by “power compensation” DSC, the entropy of fusion
`is usually more readily available than the enthalpy of sublima-
`tion, which is a direct measure of the lattice energy.
`Solid-State NMR Studies. The four crystalline complexes
`studied here (Figure 7) show different 13C solid-state NMR
`spectra, which can be used as fingerprint identifiers. One of
`the most distinguishing signals is that for the methylene carbon
`atom of the ethyl group of benzocaine. For Mod. I, Mod. II,
`and the hydrate, this chemical shift appears at approximately
`64 ppm, whereas the 2:1 complex shows two signals at 64 and
`61 ppm, respectively, clearly reflecting two different kinds of
`benzocaine species. The chemical shift for this carbon atom in
`pure solid benzocaine is 61 ppm. Another observation reflecting
`the ionic and neutral nature of the two benzocaine molecules
`in the 2:1 complex is the fact that the chemical shift for the
`carbon atom which is connected to the amino group is at 152
`ppm for pure solid benzocaine and 156 ppm in the 2:1 complex.
`This peak is not observed in the other crystal forms, in which
`all benzocaines are cationic.
`
`Experimental Procedures
`Kofler’s Contact Method for Determination of the Binary Phase
`Diagram.14,16 A few crystals of the lower melting substance picric acid
`(mp 122 (cid:176)C) were placed on a microscope slide at the edge of a cover
`glass. The amount of substance is chosen in such a way that the melt,
`which is pulled by capillary forces between the microscope slide and
`cover glass, occupies about half of the space between them. The
`preparation is solidified by cooling, and benzocaine (mp 90 (cid:176)C) is
`treated in the same manner. In the zone where the melts come into
`contact, the two compounds merge. The thermal behavior observed on
`the Kofler hot-stage microscope during heating of the resulting
`preparation was used to construct and confirm the phase diagram. DSC
`experiments were also performed to construct the isobar phase diagram
`(Figure 2) using the melting points and enthalpies of fusion of mixtures
`of benzocaine and picric acid, determined from DSC studies.
`Production of Single Crystals of the Crystal Forms. Crystal
`growth experiments were carried out using commercially available
`benzocaine and picric acid (Sigma), and the solvents were of analytical
`grade. Note: Picric acid is potentially explosiVe!
`The crystallization of Mod. II as described by Nielsen and Borka8
`leads to a microcrystalline precipitate, which is not suitable for single-
`crystal X-ray structure determi