Crystallization of Metastable Polymorphs of Phenobarbital by

CRYSTAL GROWTH & DESIGN

Crystallization of Metastable Polymorphs of Phenobarbital by Isomorphic Seeding†

2009 VOL. 9, NO. 8 3444–3456

Neslihan Zencirci,‡ Thomas Gelbrich,‡ Volker Kahlenberg,§ and Ulrich J. Griesser*,‡ Institute of Pharmacy, and Institute of Mineralogy and Petrography, UniVersity of Innsbruck, Innrain 52, 6020 Innsbruck, Austria ReceiVed December 29, 2008; ReVised Manuscript ReceiVed May 21, 2009

ABSTRACT: Six metastable polymorphs (V, VII-XI) of phenobarbital (Pbtl) were produced by melt crystallization via seeding with corresponding isomorphic barbiturate homologues, following the teachings of earlier thermoanalytical studies of isopolymorphic relationships and utilizing the melting phase diagrams of Pbtl admixtures with various 5,5-substituted barbituric acid derivatives. The Pbtl forms and their solid solutions were analyzed with hot-stage microscopy, powder X-ray diffraction, and infrared spectroscopy. The crystal structures of several isomorphic homologues were determined to assess the structural features of the metastable Pbtl polymorphs. In contrast to Pbtl-V, VIII, and IX, which could be isolated as a single component phase, Pbtl-VII, X, and XI could only be stabilized in the presence of one of the isomorphic additives. Form Pbtl-V, the most stable form among the six metastable polymorphs, is structurally similar to Pbtl-IV and was crystallized by seeding with co-crystals of Pbtl/rutonal (3:1). Pbtl-VII was obtained as a stabilized intermediate phase from the system dipropylbarbital/Pbtl. Pbtl-VIII occurs on seeding with alphenal (Alp) form I. The structure analysis of this orthorhombic Alp modification revealed the presence of N-H · · · OdC hydrogen bonded layers. Pbtl-IX and X show isomorphic relationships to a rich variety of different barbiturate structures, all based on the same pair of H-bonded ribbon chains. The packing features of Pbtl-IX were deduced from the isomorphic structures of amytal-II and sonerylI. Pbtl-X is isomorphic to both amytal-I and phanodorm-II. The existence of form XI was confirmed via the solid solutions of Pbtl/Alp and Pbtl/dipropylbarbital. This study conveys some of the basic principles of isomorphic additives on the formation of specific polymorphs or the stabilization of unstable crystal forms, which are not detectable in solvent or melt crystallization experiments of the pure compound. Introduction “Probably every substance is potentially polymorphous. The only question is, whether it is possible to adjust the external conditions in such a way that polymorphism can be realized or not.” This dictum from Maria Kuhnert-Bransta¨tter1 is rather unrecognized compared to the popular statement by Walter McCrone2 that the number of polymorphs is proportional to the time and effort spent in their search, but it addresses more directly what scientists actually do when they discover new crystal forms or stabilize metastable solid-state forms. There are numerous strategies3 that can be employed to find new phases or to control the crystallization of a desired solid-state form. All strategies are based on the “adjustment of proper external conditions” either by varying basic state variables (such as temperature or pressure), composition variables (e.g., solvent, pH, supersaturation), or process variables (agitation, heating/ cooling rates, etc.). The potential impact of additional chemical components (a composition variable) on the nucleation and growth as well as the stability of specific polymorphs is wellknown but is often still far from being well understood. Impurities from the chemical synthesis of a compound are probably the most common additives (or admixtures) that have accidentally caused the formation of new crystalline phases, and many of the stories about “disappearing polymorphs”4 can be traced back to such phenomena. Additives have been deliberately used or designed (tailor-made additives) to crystallize specific polymorphs,5 to stabilize metastable polymorphs,6,7 to control the growth (morphology) of crystals,8 or for chiral † Dedicated to Emer. Prof. Maria Kuhnert-Brandsta¨tter on the occasion of her 90th birthday. * Corresponding author: E-mail:[email protected]. ‡ Institute of Pharmacy. § Institute of Mineralogy and Petrography.

Scheme 1

separations.9 However, the utilization of isomorphic additives as demonstrated recently by He et al.6 for the stabilization of a metastable polymorph of 4-methyl-2-nitroacetanilide is rarely addressed in the newer literature. Studies on the phase behavior of admixtures of compounds that are isomorphic and exhibit polymorphism can be traced back to the late 19th century,10 and cases of “isopolymorphism” have been reported for a series of inorganic compounds (e.g., PbMoO4/PbWO4)11 and many organic substances (e.g., 2-methyl-2-chloropropane and 1,1,1trichloroethane).12 The term isopolymorphism describes phase systems where each polymorphous form of one substance is isomorphous to a respective polymorphic form of another substance.13,14 Isodimorphism is more specifically used for cases where each compound shows two phases. One of the most extensive studies of isopolymorphism has been performed by Kuhnert-Brandsta¨tter and Aepkers15,16 for phenobarbital (Pbtl, Scheme 1) which is a prime example for crystal polymorphism.17 Pbtl is one of the few barbituric acid derivatives that are still therapeutically used and specified in Pharmacopoeias. Though the main indication is reduced to certain forms of epilepsy, this roughly 100-year-old compound actually belongs to the most commonly prescribed drugs and is listed in the WHO Essential

10.1021/cg801416a CCC: $40.75  2009 American Chemical Society Published on Web 06/23/2009

Crystallization of Polymorphs of Phenobarbital

Crystal Growth & Design, Vol. 9, No. 8, 2009 3445 Table 1. List of the Isomorphic Partners of the Form II and of the Six Metastable Forms (V, VII-XI) of Pbtl According to Kuhnert and Aepkers15, a isomorphic partner

Figure 1. Diagram illustrating the main production and transformation pathways of the solid forms of Pbtl (melting point stated below the name symbol of the crystal form). I-XI ) polymorphic forms (unsolvated), H1 ) monohydrate, SACN ) acetonitrile solvate, SDox ) dioxane solvate, SNiMe ) nitromethane solvate. Forms that can be stabilized only in binary mixtures are drawn with dotted lines. Thin arrows mark less common or parallel transformation pathways.

Medicines Library. Kuhnert-Brandsta¨tter and Aepkers15,16 reported the existence of 11 polymorphs, which is an exceptionally high number of nonsolvated forms for a small organic molecule. Moreover, a mono- and a hemihydrate as well as a dioxane solvate have been reported,18,19 and recently we found an acetontrile and a nitromethane solvate.20 An overview illustrating the principal production methods of the different solid-state forms of Pbtl and some transformation pathways between them is shown in Figure 1. Forms I-IV as well as form VI have been the object of many studies,20-26 involving a variety of topics and analytical techniques such as thermal analytical methods,15,16,19,27-29 powder X-ray diffraction (PXRD),30-34 IR-spectroscopy,33,35,36 dissolution,37 solubility,38 bioavailability,39 and formulation studies.19,40 The single crystal structures of form III and the monohydrate have been determined by Williams,31 and Platteau et al.34 reported a structure determination of form I and II from PXRD data. A summary of the solid-state properties and structural features of the five forms that can be produced more easily (I-IV and VI) can be found elsewhere.41 Relatively little is known about the other six modifications of Pbtl (V, VII-XI). These metastable forms have been characterized by hot-stage microscopy,15,16,28 and most of them occur only in the presence of other barbiturates. Their melting points were determined either directly or by extrapolation of the melting curves of isomorphic relationships using temperature/composition phase diagrams. However, the structural background of these isopolymorphic relationships has not been elucidated yet. Our aim was to reproduce these metastable forms and gain insight into their structural features via the crystal structure of the more stable isomorphic partner, using IRspectroscopy and PXRD. An extremely effective and helpful approach in the study of such binary systems is the contactpreparation method,42 which is described in more detail in the experimental section below. This is probably the fastest method to establish whether two components form a molecular compound (co-crystal), a solid solution (mixed crystal), or a eutectic. If the crystal structures of two chemically related compounds are isomorphous and exhibit only minor differences in their unit

Pbtl-II (mp 174 °C) Alp-IV Pbtl-V (mp 160 °C) 1:1 cc Pbtl/Phd 3:1 cc Pbtl/Rtl Pbtl-VII (mp 153 °C) 1:1 cc Pbtl/inactin 1:1 cc Pbtl/thiothyr Dpb Pbtl-VIII (mp 148 °C) Alp-I Pbtl-IX (mp 133 °C) Alp-II Amy-II kalypnon I pernocton III Phd-I Snl-I Spt-I 1:1 cc Pbtl/noctal Pbtl-X (mp 126 °C) Amy-I butisol I Mdm-VI Phd-IId 1:1 cc Pbtl/Nbtl-Ie Ipr-I Pbtl-XI (mp 112 °C) 1:2 cc Pbtl/Alp- Alp VI 1:1 cc Pbtl/Cpl S1 Pbtl/Dpb- Dpb VI

type melting temperatureb melting point of cc T1 T3 T1

154 163

T1 T1

164 182

T3

126

T3 T3 T3 T2b T1 T3 T3 T3

123 129 106 130,102c 113 129 130

158

T1 T1 T2 T1 T2a

127

142

T2 T1

127 119

a The column “type” states the assignment to the Roozeboom type of the mixtures and the melting temperatures (°C) of the mixed crystals and of co-crystals (cc) are listed in the right columns. b Minimum in the phase diagram. c Two minima. d Isostructural to Pbtl-X rather than Pbtl-IX according to this work. e The co-crystal is not isostructural to Nbtl-I according to this work.

cell parameters, they may form substitutional solid solutions in which one component of a crystal structure can be randomly replaced by another component. A homogeneous continuous series of solid solutions (mixed crystals) is formed if the mixed isomorphous components crystallize in not more than one phase. The term isomorphism was coined by Mischerlich43 and has a different meaning than “isostructural”, which (according to IUCr online dictionary of crystallography) “...applies to crystals with the same structure, but not necessarily the same cell dimensions nor the same chemical composition, and with a ‘comparable’ variability in the atomic coordinates to that of the cell dimensions and chemical composition.” There are five basic types, T1-T5, of solid solutions according to Roozeboom.44 Type T1 is characterized by two components forming a continuous series of solid solutions over the entire range of the composition. The accompanying temperature-composition diagram shows a melting curve which ascends steadily from the lower-melting to the higher-melting component (Supporting Information, Figure ES1). By contrast, the corresponding diagrams of types T2 and T3 feature a maximum and a minimum, respectively. Types T1 and T2 occur in organic systems less often than T3.45 Kuhnert-Brandsta¨tter and Aepkers16 described two additional subtypes whose temperaturecomposition diagrams feature either a maximum as well as a minimum (type T2a) or two minima in addition to a maximum (T2b).13 Table 1 lists the isomorphic relationships between metastable Pbtl forms and structurally analogous barbiturates (isomorphic partner) as proposed by Kuhnert-Brandsta¨tter and Aepkers.15,16

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Zencirci et al.

Table 2. Composition of Barbiturates with the General Composition of Scheme 1 name

abbreviation

alphenal amylbarbital amytal butisola cyclopal dipropylbarbital 5-ethyl-5-(3′-methylbut2′-enyl)-barbituric acid inactinb ipral kalypnon medomin noctal nembutal pernocton phanodorm phenobarbital rutonal sandoptal soneryl thiothyrb

Alp Amtl Amy

a

Cpl Dpb Embl Ipr Mdm Nbtl Phd Pbtl Rtl Spt Snl

R1

R2

allyl ethyl ethyl ethyl allyl propyl ethyl

phenyl n-pentyl 3-methylbutyl 1-methylpropyl 2-cyclopenten-1-yl propyl 3-methylbut-2-enyl

ethyl ethyl ethyl ethyl 2-bromoallyl ethyl 2-bromoallyl ethyl ethyl methyl allyl ethyl ethyl

1-methylpropyl 2-propyl 2-butenyl 1-cycloheptenyl 2-propyl 1-methylbutyl 1-methylpropyl 1-cyclohexen-1-yl phenyl phenyl 2-methylpropyl n-butyl ethyl

Sodium salt. b The 2-substituted O (see Scheme 1) is replaced by S.

The abbreviations used for different barbiturates in this paper are listed in Table 2. In the present study, we will focus on the six metastable Pbtl forms (V, VII-XI) that occur in binary barbiturate systems and aim to provide conclusive evidence for their existence. The complex isopolymorphic relationships of Pbtl with other barbiturates are studied with hot-stage microscopy, IR-spectroscopy, and PXRD. Furthermore, the single crystal structures of several isomorphic partners (Alp-I, Ipr-I, Phd-II, Spt-I) and other related forms (Cpl-I, Mdm-I, Nbtl-I, Rtl-I) are reported. These data should enable us to derive conclusions about the structural characteristics of the metastable Pbtl forms, which are not accessible to this kind of structural study themselves. It should be stressed that the results presented here are just an extract of a huge number of experiments that had to be performed to assess and understand the complex polymorphic and isopolymorphic behavior of Pbtl and Pbtl-barbiturate mixtures. Experimental Section Contact Preparation Method. A two-component system is usually visualized in a temperature-composition diagram where the melting points associated with different compositions are drawn against the percent ratio or the molar ratio of the components. The contact preparation method is an established technique for the study of such systems. First, a small amount of the higher-melting component is melted on a hot bench (Kofler hot bench, Reichert, Austria), so that the melted substance occupies about one-half of the space between a coverslip and a glass slide, and it is cooled down and allowed to solidify. The lower-melting component is then placed on the other half of the coverslip and melted, so that both melts are eventually in contact with each other. The sample is heated further until both components are completely melted. Crystallization is allowed to proceed from one side of the melt only so that the crystal front of one component grows into the melt of the other. Isomorphous intermingling (the formation of a solid solution) or the formation of co-crystals is observed at the zone of mixing. A reheating experiment will reveal which type of mixed crystal is present in the solidified sample. In a Roozeboom T1 system (see above), the melting begins within the lower-melting pure component. In a T2 system, both components melt completely except for a crystalline strip within a contact zone, since this area corresponds to the maximum in the liquidus curve. The melting process of T3 systems begins within a strip of the contact zone that corresponds to a minimum in the liquidus curve. However, a contact zone containing co-crystals will behave differently from one with solid solutions. Here, melting starts at the first eutectic point which lies between the lower-melting form and the co-crystal. It continues at the

second eutectic point which is located between the higher-melting form and the co-crystal before finally the co-crystal starts to melt. Optical Polarized Light and Hot-Stage Microscopy (HSM). Contact preparations for optical microscopic experiments were crystallized under controlled temperature on a glass slide, and a temperature between 80 and 120 °C was applied according to the desired crystal form. An Olympus BH2 polarization microscope (Olympus Optical GmbH, Vienna, Austria) equipped with a Kofler hot stage (Reichert Thermovar, Vienna, Austria) was used, and the samples were heated to 180 °C at a rate of about 4 °C min-1. Substances Used in Contact Preparation Experiments. Commercial samples of phenobarbital (mixture of forms I and II, Mallinckrodt Chemical Works, USP XIII Powder, USA), alphenal (form I, Heyl Chem.-pharm. GmbH & Co. KG, Berlin, Germany), amytal (form I, Eli Lilly and Company, Indianapolis, USA), cyclopal (mixture of forms I, II and III, Alltech, State College, PA, USA), dipropylbarbital (Heyl & Co Heyl, Chem.-pharm. GmbH & Co. KG, Berlin, Germany), medomin (form I, Ciba-Geigy Pharmaceutical Company Ltd., Basel, Switzerland), nembutal (form III, Pentobarbital Pulver 35, Art No. L984U3T, Knoll-AG, Friedrichshafen, Germany), phanodorm (form II, E. Merck AG, Darmstadt, Germany), rutonal (form II, Dr. Fraenkel & Dr. Landau, Berlin, Germany), sandoptal (form I, Heyl & Co Heyl, Chem.-pharm. GmbH & Co. KG, Berlin, Germany), and soneryl (mixture of forms I-III, Interpharm Kom.-Ges. Vienna, Austria) were available. Single crystals of Alp-I suitable for X-ray single crystal diffraction (XRSD) were obtained by annealing a sample enclosed in a vial for several days on a hot bench at 140 °C. Analogous methods were applied to produce single crystals of Spt-I (130 °C), Cpl-I (110 °C, overnight), Mdm-I (160 °C), Rtl-I (220 °C), and Ipl-I (200 °C). Nbtl-I and Phd-II were crystallized from ethanol of analytical grade (Merck, Darmstadt, Germany). Fourier Transform Infrared (FT-IR) Spectroscopy. FT-IR spectra were recorded with a Bruker IFS 25 spectrometer (Bruker Analytische Messtechnik GmbH, Karlsruhe, Germany) using the Bruker IR microscope I (Bruker Analytische Messtechnik GmbH, Karlsruhe, Germany), with a 15×-Cassegrain-objective (spectral range 4000 to 600 cm-1, resolution 4 cm-1, 64 interferograms per spectrum). Samples were prepared on ZnSe disks. Powder X-ray Diffractometry (PXRD). PXRD patterns were recorded with a Siemens D-5000 diffractometer (Siemens AG, Karlsruhe, Germany) equipped with a theta/theta goniometer, Cu KR radiation source, Goebel mirror (Bruker AXS, Karlsruhe, Germany), 0.15° soller slit collimator and scintillation counter. The patterns were recorded at a tube voltage of 40 kV and a tube current of 35 mA. The scan rate was 0.005° 2θ/s in the 2θ range of 2°-40°. The metastable form Pbtl-V was measured on a glass sample holder. The metastable Pbtl forms VII-X were produced with the contact preparation method, and the coverslip was detached from the glass slide thereafter. Then the site of the coverslip containing a film of the pure PBTL form was separated using a glass cutter, placed on a silicon holder (film of the substance on top) and recorded in reflection mode. It is obvious that the patterns of such preparations are not ideal and exhibit significant preferred orientation. Single Crystal Structure Determination. The crystal data for all structure determinations are listed in Table 3, and hydrogen bond parameters are listed in Table ES1, Supporting Information. Intensity data for Alp-I, Ipl-I, Mdm-I, Phd-II, Rtl-I, and Spt-I were collected on a STOE IPDS-II diffractometer (Stoe & Cie GmbH, Darmstadt, Germany, λ ) 0. 71073 Å). Intensity data for Nbtl-I and Cpl-I were recorded at 120 K on a Bruker-Nonius KappaCCD diffractometer with a Bruker-Nonius FR591 rotating anode using graphite-monochromated Mo KR radiation (λ ) 0.71073 Å), and the data were corrected for absorption using SADABS.46 SIR2002,47 and the SHELXL package48 were used to solve and refine the structures on F2. Non-hydrogen atoms were refined anistropically, and all H positions were generated in idealized geometries using a riding model with Uiso(H) ) 1.2Ueq(C, N) or Uiso(H) ) 1.5Ueq(C) for CH3. Unfortunately, all Nbtl-I and Cpl-I crystals were small and of poor quality. Several data sets were collected for each of these forms, but the best of the data sets used for structure refinement still gave relatively high final R-values. In the structure of Cpl-I, the cyclopentenyl ring in one of the two independent molecules is disordered over two orientations, and the fraction of the major component is 0.56. The Spt-I crystal was found to be nonmerohedrally twinned, and the structure determination was performed with a data set that consisted only of the nonoverlapping reflections of the larger


Crystal Growth & Design, Vol. 9, No. 8, 2009 3447

Table 3. Crystal Data for the Solid Forms Investigated by Single Crystal X-ray Diffraction Form

Alp-I

Cpl-I

Ipl-I

Mdm-I

chemical formula formula weight description size (mm3) T (K) crystal system space group a (Å) b (Å) c (Å) R (°) β (°) γ (°) V (Å3) Z/Z′ dcalc (Mg/m3) reflns collected indep reflns/Rint data/parameters R1 [I > 2σ(I)] wR2 (all data)

C13H12N2O3 244.25 colorless prism 0.30 × 0.15 × 0.10 173 orthorhombic Pbca 13.5468(18) 6.8488(7) 26.458(3) 90 90 90 2454.7(5) 8/1 1.322 11295 2056/0.0554 2056/163 0.0441 0.0867

C12H14N2O3 234.25 colorless needle 0.15 × 0.08 × 0.05 120 triclinic P1j 6.7694(8) 9.8985(12) 17.923(2) 95.837(7) 100.535(6) 91.540(6) 1173.3(2) 4/2 1.326 14288 3994/0.1080 3980/323 0.1316 0.2234

C9H14N2O3 198.22 colorless, isometric fragment 0.32 × 0.32 × 0.32 173 monoclinic C2/c 12.6324(16) 17.373(3) 10.2785(15) 90 118.932(10) 90 1974.2(5) 8/1 1.334 6224 1727/0.0280 1727/130 0.0333 0.0871

C13H18N2O3 250.29 colorless plate 0.20 × 0.10 × 0.10 173 monoclinic P21/c 16.174(2) 6.7704(11) 12.3597(15) 90 109.502(10) 90 1275.8(3) 4/1 1.303 10822 2142/0.0421 2142/164 0.0367 0.0793

Form

Nbtl-I

Phd-II

Rtl-I

Spt-I

chemical formula formula weight description size (mm3) T (K) crystal system space group a (Å) b (Å) c (Å) R (°) β (°) γ (°) V (Å3) Z/Z′ dcalc (Mg/m3) reflns collected indep reflns/Rint data/parameters R1 [I > 2σ(I)] wR2 (all data)

C11H18N2O3 226.27 colorless plate 0.20× 0.10 × 0.05 120 monoclinic P2/c 11.7583(9) 10.9906(9) 10.1713(5) 90 110.394(4) 90 1232.05(15) 4/1 1.220 10559 2127/0.0917 2127/148 0.1237 0.2397

C12H16N2O3 236.27 colorless, isometric fragment 0.32 × 0.32 × 0.28 173 monoclinic C2/c 22.168(3) 10.7160(16) 10.2410(15) 90 91.831(10) 90 2431.5(6) 8/1 1.291 7139 2032/0.0363 2032/155 0.0419 0.1034

C11H10N2O3 218.21 plate 0.40 × 0.24 × 0.18 173 monoclinic P21/c 29.982(3) 6.7382(7) 10.3362(13) 90 99.845(10) 90 2057.4(4) 8/2 1.409 11214 3408/0.0748 3408/292 0.0677 0.1821

C11H16N2O3 224.26 thin lath 0.40 × 0.08 × 0.08 173 triclinic P1j 10.3598(15) 10.4567(19) 11.747(3) 67.656(15) 78.450(14) 88.656(13) 1151.3(4) 4/2 1.294 6529 3044/0.0626 3044/289 0.0658 0.1551

twin component, so that just 74% of the theoretical reflections were available for this structure determination. An alternative refinement using the data sets for both twin components simultaneously was not satisfactory. Rtl-I is pseudomerohedrally twinned, and the fraction of the major twin component is 0.63.

Results and Discussion

Brandsta¨tter et al. stated that Pbtl-V could not be produced as a pure form,15,28 and subsequently these authors determined the melting point of Pbtl-V by extrapolating two melting point curves. Our experiments show that Pbtl-V crystallizes when the melt film is annealed at 120 °C. It was confirmed both by IR spectroscopy and PXRD that the phase that crystallizes in this annealing procedure is indeed identical with the phase of the

Preparation of Metastable Forms. An overview of transformation routes of the metastable Pbtl forms and the isomorphic relationships discussed in this section is given in Figure 1 and Table 1, respectively. Modifications IV and V. Pbtl-V is isomorphic to the cocrystals Pbtl/Phd (1:1, T3) and Pbtl/Rtl (3:1, T1). The corresponding phase diagrams according to Kuhnert-Brandsta¨tter et al.15,28 are displayed in Figure ES2, Supporting Information. Pbtl-V was produced by the contact preparation method using co-crystals of Pbtl/Rtl (3:1) as seed crystals (see Figure 2). PbtlV, the most stable (for one day at 25 °C) of the six metastable Pbtl modifications, is structurally related to Pbtl-IV. Pbtl-IV and Pbtl-V grow spherically from a nucleation center to elongated crystals of mostly blue, purple, and brown interference colors, lacking any transverse cracks when cooled to 20 °C. It is difficult to differentiate between these two forms by their optical appearance with polarized light microscopy. Kuhnert-

Figure 2. Photomicrographs (polarized light) of a contact preparation with Pbtl and Rtl. The co-crystal (cc) Pbtl/Rtl is isomorphous to Pbtl-V (top left photomicrographs). The transformation of form Pbtl-V to PbtlIV occurs at 140-153 °C on heating, followed by the melting process at 163 °C. On cooling, residual crystals of Pbtl-IV grow to larger columnar crystals.

3448


Figure 3. Phase diagram Dpb/Pbtl (reproduced from ref 15) with polarized light photomicrographs of melt film preparations; (a) stabilized intermediate phase S1 (Dpb-XI/Pbtl-VI at 50:50 ratio); (b) growth of Dpb/Pbtl-VII (w/w 80/20) above 120 °C (thin melt film); and (c) Dpb/ Pbtl-VII (thicker melt film) transforming to Pbtl-II (top). The bold lines highlight the parts of the diagram that are relevant for the present study.

contact preparation with Pbtl/Rtl co-crystals. We conclude therefore that the annealed phase was assigned incorrectly as Pbtl-IV (mp 163 °C) in the previous report. Pbtl-V (the phase previously assigned as Pbtl-IV) transforms rapidly to Pbtl-IV upon heating in the temperature range of 140-150 °C (Figure 2). Surprisingly, this transformation is not described in the earlier studies. The best method to obtain PbtlIV is to crystallize Pbtl-V first at 120 °C (hot bench) and then transfer this preparation directly on the hot stage which has been preheated to 140 °C. This procedure results in a rapid transformation of Pbtl-V to Pbtl-IV and does not provide enough time to form Pbtl-II, which would quickly grow on slow heating to 140 °C. The obtained Pbtl-IV crystals melt at 163 °C. The structural difference between this form and other forms (particularly Pbtl-V) was confirmed by IR spectroscopy and PXRD. Form Pbtl-VII. Pbtl-VII cannot be produced as a pure form and was identified via the phase behavior of binary mixtures with inactin and thiothyr15,16,28 and Dpb (see Table 1). Its melting point was determined indirectly by a graphical extrapolation of the melting curves of the solid solutions in the binary phase diagram. As shown in the phase diagram of Figure 3, Dpb/Pbtl-VII forms a so-called “stabilized intermediate phase” (S2), which is stable between 45 and 68% Pbtl and metastable up to a mixture ratio of 90% Pbtl.28 We obtained this form by annealing the supercooled melt of a 20/80 (w/w) mixture between 120 and 125 °C. Such stabilized intermediate phases49 represent cases of isopolymorphism, where a series of unstable mixed crystals becomes stable within a certain composition range. The Dpb/Pbtl system shows a second stabilized intermediate phase Dpb-XI/Pbtl-VI (S1), which below 120 °C grows

Zencirci et al.

Figure 4. Top: phase diagram for Alp/Pbtl (reproduced from ref 15). The bold lines highlight the melting curves of the solid solution that are relevant for the present study: Pbtl-VIII and Alp-I (T3), Pbtl-IX and Alp-II (T3), and Pbtl-XI and Alp-VI (T2). Bottom: polarized light photomicrographs of (a) Alp-I, (b) a contact preparation of Alp-I and Pbtl-VIII, and (c) melting of the contact zone on reheating (minimum of the melting curve: 125 °C).

faster than the S2 phase Dpb/Pbtl-VII. At temperatures above 120 °C also the more stable form Pbtl-II occurs in the 80% Pbtl mixture, and heating to 140 °C results in a fast transformation to this form, as illustrated in Figure 3 (microphotograph, bottom right). The stabilized intermediate Pbtl-VII grows very slowly in the melt to (initially) feathery crystals with low interference colors (Figure 3, microphotograph, bottom middle), and the fully recrystallized melt film shows characteristic transversal cracks when cooled to 20 °C. Pbtl-II grows to aggregates of columnar crystals and shows a higher birefringence than Pbtl-VII. Pbtl-VII is very unstable in the melt film preparation even if the coverslip remains on the glass slide. In contact with environmental moisture (coverslip removed), it transforms within 2 h to Pbtl-II. Form Pbtl-VIII. A continuous miscible solid solution (T3 with a minimum at 126 °C) is formed by Pbtl-VIII and Alp-I, which is also the only barbiturate that has been found to induce the formation of Pbtl-VIII.28 Seeding the Pbtl melt with Alp-I yields pure Pbtl-VIII, as illustrated in Figure 4 (contact preparation of Alp and Pbtl). Initially, Alp-I is obtained by annealing the melt at 130 °C. The growing Alp-I phase reaches the contact zone, where a solid solution with Pbtl is formed. The growth proceeds continuously toward the Pbtl melt until pure Pbtl-VIII is present in the outer zone of the preparation (temperature reduced to 120 °C). The crystals grow very slowly (∼1 mm per hour) in fine-rayed aggregates with mainly orange, red, and violet interference colors. A problem in this preparation procedure is the nucleation and fast growth of Pbtl-V and PbtlVI in the pure Pbtl melt. Pbtl-VI usually nucleates when the supercooled melt of pure Pbtl is annealed at about 120 °C, whereas Pbtl-V preferentially grows in a higher temperature range (120-140 °C). This process had to be monitored carefully in order to prevent the complete crystallization of Pbtl-V (or


Figure 5. Phase diagram (top) of Amy/Pbtl (reproduced from ref 16) and polarized light photomicrographs (bottom) of (a) solid solution of Pbtl-IX/Amy-II (w/w 50/50), (b) the solid solution Pbtl-X/Amy-I (w/w 50/50), and (c) pure Pbtl-IX. The bold lines in the diagram highlight those melting curves that are relevant for the present study, and the arrow indicates the transformation process upon heating.

VI) in the Pbtl melt which would have interrupted the slow growth of Pbtl-VIII. Once the formation of an undesired form had been detected, only the Pbtl site of the contact preparation was heated above the melting point of the form (using a hot bench) which was to be eliminated. The melting point of PbtlVIII can be determined only in the absence of Pbtl-V and PbtlVI. Pbtl-VIII is stable in a melt film preparation for about one day at 25 °C, if no seeds of Pbtl-V are present and the sample is protected from environmental moisture by the coverslip. PbtlVIII shows a higher stability than Pbtl-VII under such conditions. The existence of Pbtl-VIII and its isomorphism to Alp-I were also verified by IR-spectroscopy and PXRD (see below). Form Pbtl-IX. According to Kuhnert-Brandsta¨tter and Aepkers,15,16 Pbtl-IX forms solid solutions with seven other barbiturates (see Table 1). We produced Pbtl-IX by seeding a contact preparation at 100 °C with Amy-II (T3), Alp-II (T3), or Snl-I (T3), whereas the solid solution with amytal turned out to be the most efficient way to produce this form. The Pbtl/ Amy phase diagram is shown in Figure 5. Pbtl-IX grows in the melt as broad rays starting from a few nucleation centers exhibiting mainly gray, blue, and brown interference colors in polarized light. The highest growth rate of this form was observed at 100 °C (note that this growth rate is a multiple of that of Pbtl-VII and Pbtl-VIII). The nucleation and growth rate of Pbtl-V in this temperature range is very low, which is a further advantage and enables a more straightforward production of Pbtl-IX. This form is stable for about 1 day in a melt film preparation (coverslip is not removed from the glass slide), but when the coverslip is removed and the crystal film is scratched off the glass the phase transition occurs within ∼2-3 h. However, this time frame was sufficient to record the PXRD


pattern and the IR spectrum. The structural relationship of PbtlIX to other Pbtl forms and barbiturate homologues is discussed below. Form Pbtl-X. The highly unstable form Pbtl-X is isomorphic to five other barbiturates or co-crystals (Table 1).15,16 According to ref 15 it should be possible to obtain this form by isomorphic seeding of Pbtl with Amy-I (T1, Figure 5) at 100 °C. However, we could not isolate Pbt-X as a pure form. Annealing the melt of a contact preparation of Amy-I at 100 °C resulted in the immediate growth of the more stable form Pbtl-IX instead of Pbtl-X. Both the solid solution Pbtl/Amy and Amy-I grow as broad-rayed spherulites showing mainly light yellow, orange, blue, green interference colors similar to Pbtl-IX. The melting point of Pbtl-X was determined from mixtures with different barbiturates by Kuhnert-Brandsta¨tter and Aepkers.28 In the present study, the existence of Pbtl-X was confirmed by mutual isomorphic seeding of the three solid solutions Pbtl/Mdm (T2), Pbtl/Amy and Pbtl/Nbtl (T2a). The pathway from point a to b in Figure 5 highlights the transformation of the solid solution Pbtl-IX/Amy-II (w/w 50/50) into the solid solution Pbtl-X/AmyI, which is observed upon heating of such mixtures (>90 °C). The structural features of Pbtl-X could only be verified via its solid solution with three other barbiturates. All these binary mixtures (1:1 ratio) show comparable IR-spectra and PXRD patterns, which confirms the isostructurality of the solid solutions. Form Pbtl-XI. Pbtl-XI has been identified via the phase relationship with three other isostructural barbiturates,15,16,28 namely, Alp-VI (T2, Figure 4), Dpb-VI (T2, Figure 3), and Cpl (T1). The presence of one of these isomorphic additives is essential to stabilize this form. If none of these barbiturates is present or in the low concentration range (85 to 100 Pbtl), the nucleation and growth of Pbtl-V in the melt is much higher than that of Pbtl-XI. It was therefore impossible to isolate PbtlXI as a single component form, and its melting point can be determined only by extrapolating the melting curves of the respective solid solutions in the binary phase diagram.15,16 We evaluated the isomorphic relationship of all three additives (Alp, Cpl, Dpb) by mutual seeding experiments of 50/50 mixtures (w/w) with Pbtl using the contact preparation method. The melt crystallizations were carried out between 90 and 100 °C. An experiment which demonstrates the isomorphous relationship of Pbtl-XI/Alp-VI and Pbtl-XI/Dpb-VI is exemplified in Figure 6. The nucleation of the higher melting solid solution (Pbtl-XI/ Alp-VI, left halve) starts at the left edge of the coverslip and grows toward the center as aggregates of fine-rayed crystals. The crystals grow through the contact zone and the melt of the lower melting solid solution (Pbtl/Dpb) without observable alteration of their habit or birefringence, which is a clear sign for isomorphism. The contact zone becomes visible on reheating, because the ternary mixture melts slightly below the binary mixtures and exhibits obviously a minimum in the melting curve. The IR spectra and PXRD patterns of all three mixed systems (solid solutions) are consistent, which confirms their structural identity and allows us to capture the structure of PbtlXI. Fourier Transform FT-IR Spectroscopy. The Pbtl molecule contains two NH bond donor groups which engage in intermolecular N-H · · · OdC interactions. The number of possible supramolecular synthons is limited, and each connectivity type shows a characteristic IR-spectrum. Thus, the Pbtl polymorphs can be classified, simply based on the features of the bands involved in the strongest interaction (N-H · · · OdC) into five groups: G1 (comprising forms I, II, VII), G2 (III), G3 (IV, V,

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Figure 6. Photomicrographs (polarized light) of a contact preparation of (a) solid solutions of Pbtl-XI/Dpb-VI (right) and Pbtl-XI/Alp-VI (left) crystallized at about 90 °C. On reheating, the melting of (b) the contact zone at 121 °C is observed, followed by (c) the melting of Pbtl-XI/Dpb-VI and (d) the melting of Pbtl-XI/Alp-VI.

Figure 7. FT-IR spectra of Pbtl-forms and corresponding isomorphic phases of other barbiturates (or mixtures), classified into different groups (G1 to G5), representing different connectivity types. Black bold lines highlight the spectra of the pure forms Pbtl-V, VIII, IX, red bold lines those of mixtures with an isomorphic partner representative for Pbtl-VII, X, and XI. Thinner red lines mark spectra of selected isomorphic partners (pure phases) or mixtures of Pbtl with such a partner. To indicate the relationship of all polymorphs of Pbtl, also the spectra of the forms I, II, III, IV, and VI are displayed (thin gray lines) in the corresponding groups. Their structural features are discussed elsewhere.41

VI), G4 (IX, X), G5 (VIII, XI). This assignment becomes obvious from Figure 7. The comparable spectral features of the isomorphic crystal form of the corresponding partners confirm their isomorphic relationships that have been identified via the melting curves of the temperature/composition phase diagrams15,16,28 and finally confirms the existence of these six Pbtl polymorphs. The frequencies of characteristic bands are given in Table ES2, Supporting Information. A detailed discussion of the underlying N-H · · · OdC connectivity modes is given in the section on crystal structures. The spectra of the G1 type (Pbtl-I, Pbtl-II, and the Pbtl-VII) are characterized by four NH vibrations at 3500-3000 cm-1 and four CdO vibrations at 1800-1600 cm-1. Each of these two regions contains two strong and two weaker vibrations. However, in the region of 1200-1300 cm-1 the spectra show stronger differences. The typical G2 spectrum shows three significant NH vibrations in addition to two strong and one weak CdO vibrations. A strong NH doublet at higher wavenumbers and a doublet with weaker adsorption at lower wavenumbers characterize G3 structures. Additionally, the CdO absorption band shows one broad peak with two shoulders in the region around 1700 cm-1. The structures of the G4 type (the most common type in barbiturates) show two strong NH vibrations and a broad CdO vibration band with three maxima. The G5 type is characterized by one very strong and sharp NH vibration

at higher wavenumbers and a weak NH vibration at lower wavenumbers, while the CdO groups are represented by a doublet with a shoulder at higher wavenumbers. This class can be further divided into types G5a and G5b. G5a represents the connectivity type of Pbtl-XI showing a characteristic shoulder of the strong N-H band (∼3220 cm-1). G5b (Pbtl-VIII connectivity) displays an additional very weak NH vibration (at ∼3260 cm-1) between the two characteristic NH vibrations. Powder X-ray Diffraction. Experimental PXRD patterns for the metastable Pbtl forms are displayed in Figure 8 along with patterns calculated from single crystal structures of selected isomorphic partners. In contrast to the IR-spectra, the diffraction patterns of all Pbtl forms can be easily distinguished from one another. For example, forms IV and V exhibit very similar IRspectra, but their PXRD patterns are clearly different. The diffraction patterns also indicate that Pbtl-V is isomorphic to the co-crystal Pbtl/Rtl (3:1). Furthermore, the existence of Pbtl-VII in the solid solution Pbtl/Dpb (w/w 80/20) is confirmed, and it can be seen that this pattern is clearly different from those of Pbtl-I and PbtlII, although the IR-spectra of these three structures are remarkably similar (see Figure 7). This indicates that Pbtl molecules in these three modifications are linked by the same supramolecular N-H · · · O synthon, but the molecular packing arrangements are nevertheless different. The similarity between the patterns of Pbtl-VIII, Alp-I



Figure 8. PXRD patterns of the structural groups of the metastable Pbtl polymorphs; red patterns (bottom of each group): pure phases (Pbtl-V, VIII, IX) and mixtures with an isomorphic partner representative for Pbtl-VII, X and XI); black patterns: selected isomorphic partners and related phases. The mixture ratios are given as w/w or molar ratios. (1) Pbtl-I, (2) Pbtl-II, (3) Pbtl-VII/Dpb S2 (80/20), (4) Pbtl-IV, (5) Pbtl/Rtl, cc (3:1), (6) Pbtl-V, (7) Pbtl/Cpl cc (50/50), (8) Pbtl-XI/Alp-VI (50/50), (9) Pbtl-XI/Dpb-VI S1 (50/50), (10) Alp-I, (11) Pbtl-VIII/Alp-I (20/80), (12) Pbtl-VIII/Alp-I (50/50), (13) Pbtl-VIII, (14) Pbtl/Nbtl cc (50/50), (15) Pbtl-Mdm cc (50/50), (16) Pbtl-X/Amy-I (50/50), (17) Amy-I, (18) Amy-II, (19) Pbtl-IX/Amy-II (50/50), (20) Pbtl-IX. The asterisks mark patterns that show significant preferred orientation (recorded as film preparation on a coverslip or prepared on a silicon-holder).

and the solid solution Pbtl/Alp is a further evidence for this particular isomorphic relationship, and the relationship between Pbtl-IX and Amy-II is also obvious from their PXRD patterns. Because of the fast growth of the kinetically more stable phase Pbtl-IX, a phase pure Pbtl-X could not be obtained. Since Amy-I is isomorphic to Pbtl-X, the PXRD pattern of Amy-I is representative for the pattern of this form. The similarity of the PXRD patterns (Figure 8) obtained for Amy-I, the co-crystals of Pbtl/Mdm and Pbtl/Nbtl to that of the solid solution of Pbtl-X/Amy-I (50/50) clearly confirms that there is an isomorphic relationship between these phases and Pbtl-X. Pbtl-XI could also not be isolated as pure form. However, the existence of this form is confirmed by the phase diagrams stated in the literature,28 and also by the data we obtained from the three isomorphic solid solutions Pbtl/Alp, Pbtl/Cpl, and Pbtl/Dpb using thermomicroscopy, FT-IR spectroscopy (Figure 7) and powder X-ray diffractometry (Figure 8). Crystal Structures. Knowledge of the structures of forms related to the metastable Pbtl polymorphs (V, VII-XI) will enable us, in combination with the thermomicroscopic, IRspectroscopic, and PXRD data, to explore the fundamental structural characteristics of these Pbtl polymorphs, which cannot be accessed via direct crystal structure determination. Pbtl and related barbiturate molecules (Scheme 1) contain two NH groups that can act as H-bond donor sites, while O(2) and the topologically equivalent O(4) and O(6) sites are potential acceptors for H-bonds. Subsequently, the aggregation of barbiturate molecules in the solid state is directed primarily by N-H · · · O interactions. The rigid geometry of the barbiturate ring imposes geometrical restraints which limit the number of connectivity modes (supramolecular synthons)50 that can be observed. The six N-H · · · O connectivity modes relevant for the various forms of Pbtl are illustrated in Figure 9. Figure 9a,b shows two 1D ribbon chains which are both based on N-H · · · O bonded dimers with R22(8) rings.51 All H-bond donor and acceptor functions are employed, except for one O(4,6) function per molecule in the chain of 9a and the O(2) site in 9b. In the 1D tape of Figure 9c three molecules are linked together by

R33(12) rings, and again one O(4,6) function per molecule, which does not participate in H-bonding. The latter is also true for the 1D ladder of Figure 9d, where adjacent R22(8) dimers are doubly linked to form R44(16) rings. Figure 9e shows a 2D structure on the basis of H-bonded R22(8) dimers. Both H-bond donor groups and just one O(4,6) position, but not O(2), are engaged in H-bonding. This acceptor site is employed twice and links to the NH group of another molecule which does not participate in a dimeric interaction. The 2D pattern in Figure 9f is built up by two independent molecules. The ribbon chain of Figure 9b is formed by one molecule type denoted X. Adjacent chains of this kind are additionally bonded, via its O(4,6) sites the second molecule type which acts as a bridge. Both NH functions of the bridging molecule, but neither its O(2) nor O(4,6) participate in the hydrogen bonding. Form Pbtl-V. The powder pattern of Pbtl-V is essentially consistent with that of the isomorphic co-crystal Pbtl/Rtl 3:1 (Figure 8), but they differ both fundamentally from the simulated powder pattern of Rtl-I (not shown). Furthermore, the IR spectrum of Rtl-I is of the G5 type (and more specifically G5a along with Cpl-I and Pbtl-XI, see below) rather than the G3 type of Pbtl-V. This indicates different N-H · · · O bonded synthons. Pbtl-V, Pbtl-IV, and Pbtl-VI are the only known examples of the G3 type among the known IR-spectra of barbiturates. Since we failed to grow single crystals of a Pbtl/ Rtl co-crystal, a clear model of the structure of Pbtl-V cannot be derived from single crystal data. However, the new crystal structure of Rtl-I was determined within the framework of this study, confirming the results obtained by IR-spectroscopy and PXRD. A structure discussion of Rtl-I is available in the electronic Supporting Information. Form Pbtl-VII. The IR spectra of Pbtl-I and Pbtl-II (type G1, Figure 7) imply N-H · · · O connectivity modes similar to that of Pbtl-VII. The crystal structures of forms I and II34 both contain of three independent molecules. One of these molecules forms the ribbon chain of Figure 9a and the other two the structurally related 2D pattern of Figure 9f. Thus, the G1

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Figure 10. Packing diagram of Alp-I, viewed along the b-axis. N and O atoms are shown as balls. H-bonded tapes (see Figure 7c) propagate along the b-axis, and adjacent tapes assemble via allyl-allyl and phenyl-phenyl contacts. An analogous packing scheme is assumed to be present in the isostructural form Pbtl-VIII.

Figure 9. Six fundamental N-H · · · O connectivity modes of barbiturate molecules. The R1 and R2 substituents (Scheme 1) are omitted for clarity, O and H atoms involved in H-bonds are shown as balls, and the unique O(2) position is additionally marked with a white circle. (a) ribbon chain, (b) ribbon chain, (c) tape, (d) ladder, (e) 2D pattern, (f) 2D pattern composed of two independent molecules (one type is marked X).

spectrum results in fact from the combined effects of two N-H · · · O arrangements. Interestingly, our comprehensive study53 of about 70 forms of known barbiturates has revealed that Pbtl-I and Pbtl-II are the only phases that produce a G1type spectrum. Form Pbtl-VIII. Thermomicroscopy, IR and PXRD data indicate that Pbtl-VIII is isostructural to Alp-I which crystallizes in the space group Pbca with one independent molecule (Table 3). Alp-I contains the H-bonded tapes of Figure 9c which are responsible for the G5 (G5b) spectrum (Figure 7), also observed in Snl-II54 and seconal-I,55 and they display glide symmetry and propagate along b. The planes of the phenyl ring moiety and the barbiturate ring are almost perpendicular and form an

angle of 89.3°. All phenyl moieties (R2) in the same H-bonded tape point in one direction and all allyl (R1) groups in the other. The barbiturate rings of all tapes related by a translation along the a-axis are coplanar. As a consequence, the van der Waals contacts between all adjacent H-bonded tapes in the structure are either phenyl-phenyl or allyl-allyl (see Figure 10). There is a remarkable contrast in phase stability between Alp-I, which is the stable alphenal modification at room temperature, and the isostructural Pbtl form VIII, which is metastable in the same temperature range. So far, the rare H-bonded tape motif of Figure 9c has been found in only three other barbiturate structures, γ-methylamobarbital,56 quinal barbitone (seconal),55 and Snl-II.54 Forms Pbtl-IX and Pbtl-X and Related Structures. PbtlIX and Pbtl-X belong to an extended group of structurally closely related barbiturates together with the following 10 forms (see also Table 2): amobarbital (Amtl),57 two polymorphs of amytal (Amy-I and Amy-II),58 5-ethyl-5-(3′-methylbut-2′-enyl)barbituric acid (Embl, mp 154 °C),59 ipral (Ipr-I), phanodorm (Phd-II),60 nembutal (Nbtl-I), sandoptal (Spt-I), and two polymorphs of soneryl (Snl-I and Snl-LT).61,62 The crystal structures of Ipr-I, Nbtl-I, and Spt-I were determined for the first time in this study, and we also report an improved structure model for Phd-II (see Table 3). We were originally interested in these structures and their relationships since Kuhnert-Brandsta¨tter’s earlier thermomicroscopy study had indicated isomorphous relationships between Pbtl-IX and Amy-II, Spt-I and Snl-I as well as between Pbtl-X and Amy-I, Phd-II and the 1:1 co-crystal Pbtl/Nbtl (Table 1). The 10 structures listed above were compared using the XPac method.52 They were all found to have the H-bonded ribbon motif of Figure 9a in common. This is a frequent supramolecular synthon in 5,5-substituted barbituric acid derivatives and leads typically to an infinite chain with either centers of inversion or 2-fold axes. The latter is the case in the 10 structures investigated here. Moreover, the molecules in the resulting chains always adopt the same geometry, shown in Figure 11a, which is a consequence of the rigid geometry in which the H-bond donor and acceptor atoms are arranged. In Figure 11, R1 (ethyl or allyl) and R2 substituents are colored orange and blue, respectively, and it can be seen that all R1 units of a single chain point in the same direction away from the central strand of chain which consists of joined R22(8) rings, while all R2 fragments are oriented approximately antiparallel with respect



Figure 11. Assembly of closely related barbiturate structures from common building blocks. O and N atoms are shown as balls, each R1 (orange) or R2 (blue) substituent (see Scheme 1) is represented by the three C atoms, regardless of its actual composition. The crystal packing is viewed along the translation of the H-bonded chain. (a) H-bonded ribbon chains of Figure 9a, (b) a pair of ribbon chains related by a center of inversion, (c and d) two 2D packing modes composed of pairs of chains, (e-g) packing diagrams representing three sets of crystal structures. Isomorphic relationships indicate that (e) and (g) represent the structures of Pbtl-IX and Pbtl-X, respectively.

to R1. It is worth noting that the 2-fold symmetry axes passing through the centers of the R22(8) rings represent a pseudosymmetry in the case of the four Z′ ) 2 structures of Amy-I, Embl, Snl-LT, and Spt-I. In all 10 structures, two ribbon chains, related by inversion symmetry, are aligned in such a way that the two sets of R1 substituents interdigitate (Figure 11afb), and these chain pairs again adopt a similar geometry in all structures. Subsequently, the vectors along the translation of this common 1D structure fragment show only a little variation in length (10.17 to 10.37 Å) in this group. The complete crystal structure is then obtained by stacking these 1D chain pair fragments in two directions, namely, approximately parallel and approximately perpendicular to the direction of R1. Amtl, Amy-II, Phd-II, Snl-I, Spt-I, Snl-LT, and Nbtl-I display a common stacking in horizontal direction in the projections of Figure 11, via translational symmetry, so that the 2D column A of Figure 11c is present in each of these structures. Moreover, the first six of these are even isostructural, and their column A

fragments are stacked via 21 axes (Figure 11e). It is worth mentioning however that the ideal C2/c symmetry is present only in Amtl, Amy-II, Phd-II, Snl-I, while Spt-I and Snl-LT contain certain pseudosymmetry elements (see below). On the basis of the earlier mentioned isomorphous relationships indicated by thermomicroscopy, one can also conclude that PbtlIX is very likely to adopt the same structure. The Nbtl-I structure (Figure 11f) is somewhat different from the Pbtl-IX group with regard to the stacking of the column A units in vertical direction, which is here implemented via translational rather than 21 symmetry, so that the resulting space group symmetry is P2/c. Interestingly, the vertical stacking mode of Nbtl-I, represented by column B in Figure 11d, is also found in the three remaining structures investigated here, Ipr-I, Amy-I, and Embl. Moreover, these three forms are isostructural (Figure 11g) despite having different space group symmetries (see below), and the ideal C2/c symmetry is present only in Ipr-I. According to thermomicroscopy studies Amy-I and Pbtl-X are isomorphous so that the latter structure can be regarded as yet another member of this group.

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Figure 12. Projections showing the symmetry elements in the space group C2/c and three maximal nonisomorphic subgroups of index 2 (according to ref 63). (a) C2/c (No. 15), projection along b, (b) C1j (translationengleiche subgroup) shown in the conventional P1j setting, projection along b, (c) P121/n1 (klassengleich), projection along -b with (d) the corresponding P21/c setting, projection along b, (e) P121/c1 (klassengleich), projection along -b. The boundaries of the C2/c supercell are shown as broken lines in (b), (d), and (e). Note that the unit cells of (a) and (c) and those of (d) and (e) have the same outlines, but the directions of a- and c-axes are reversed in each pair.

The common B fragments in the Pbtl-X type structure on the one hand and Nbtl-I on the other are stacked via different types of glide operations. The summary of the structural relationships in Figure 11 illustrates that Nbtl-I is 2D related both to the PbtlIX (bc-plane) and the Pbtl-X group (ac-plane) of structures, while the two sets of isostructures are 1D related through the pair of H-bonded chains. Two isostructural solids typically crystallize in the same space group. However, they may also crystallize in two distinct space groups if these are related by a group/subgroup relationship or if they are both subgroups of a common supergroup. To the best of our knowledge, the Pbtl-IX and Pbtl-X-type isostructures are the first examples of organic solids where all these possible relationships can be demonstrated. For each set, the maximum (Z′ ) 1) space group symmetry is C2/c, and in each case isostructures crystallize also in two subgroups of C2/c with Z′ ) 2 in which certain symmetry elements are broken. The pseudosymmetry is due to slight modifications in the mutual alignment of the barbiturate molecules and there are additional conformational adjustments in the substituents R. For example, in Spt-I (Z′ ) 2) there is a slight shift of adjacent layers of double chains which lie in ab-planes against one another compared to the isostructural C2/c forms. One example for each distinct space group symmetry is shown in Figure 11 (bottom), and crystallographically independent molecules are colored differently in order to highlight their differences. The pathway from a to b in Figure 12 illustrates the transition from C2/c to its translationengleiche subgroup C1j (conventional setting P1j) with Z′ ) 2, or between the settings of Amy-II and Spt-I in the Pbtl-IX group. All glide planes, 2-fold axes, and screw axes of the superstructure become pseudosymmetry elements in the triclinic space setting, whereas all crystallographic translational and inversion operations are maintained. In contrast, the P21/n space group of Snl-LT is a klassengleiche subgroup of C2/c where the c glide, 2-fold axes, and one set of centers of inversion located in 0,0,0 are broken (a f c in Figure 12). The supergroup and subgroup structures have in this case the same unit cell geometry, but their a and c axes are interchanged. In the Pbtl-X group, the maximum C2/c symmetry is adopted only by Ipr-I. Amy-I has been reported in the space group P21/

Figure 13. Isostructural forms Ipr-I and Amy-I, both viewed along the translation of the H-bonded chain, the same color scheme was used as in Figure 11. The unexpectedly large difference in only one unit cell dimension is due to the R2 substituents (isopropyl vs 3-methylbutyl) which are aligned parallel to b.

c, and the XPac analysis shows that its crystallographic glide plane is equivalent to the .n. rather than the .c. glide in the C2/c structure of Ipr-I. Thus, the associated pathway is a f d in Figure 12, which is completely equivalent to a f c, but it leads to the P21/c rather than the P21/n setting for the subgroup. Furthermore, Embl is also reported in P21/c. In contrast to AmyI, its glide symmetry is equivalent to the .c. glide in the C2/c superstructure of Ipr-I, and subsequently the centers of inversion located at 1/4, 1/4, 0 in Ipr-I survive as crystallographic symmetry elements in the subgroup structure. It is worth noting that the pathways a f d and a f e result in unit cells with the same outline but interchanged a and c axes. A list of all correspondences between lattice vectors identified by XPac and associated parameters are given as Supporting Information in Table ES2. These parameters match generally very well, with one exception. In the Pbtl-X set, the b-axis of Amy-I is no less than 5.23 Å (30%) shorter than the corresponding parameter in Ipr-I. A simple explanation for this unexpectedly large difference despite isostructurality can be derived from Figure 13. The R1 and R2 substituents lie almost parallel along the b-axis in each structure. Thus, the difference in b coincides roughly with the 4-fold difference in lengths between a 3-methylbutyl (Amy) and


an isopropyl (Ipr) residue (R1), whereas all other lattice directions remain largely unaffected by this change in composition. The assertion that Phd-II is isostructural to Pbtl-IX rather than Pbtl-X is consistent with our own thermomicroscopy experiments (see above) and contradicts conclusions drawn from an earlier study (see Table 1). Furthermore, the comparison of the simulated PXRD pattern of Nbtl-I with the experimental pattern recorded for the co-crystal Pbtl/Nbtl confirms that these two phases are not isostructural. The isostructural relationship between Ipr-I and AmyI, which was known to be an isomorphous partner of Pbtl-X, has motivated us to carry out an additional contact preparation experiment. A melt of Pbtl was seeded with Ipr-I, and this unexpectedly resulted in the Pbtl-IX rather than the Pbtl-X polymorph. However, the latter phase may have formed initially as broad-rayed crystals that may have been quickly consumed by the rapid preferential growth of form IX, which is moreover structurally very similar to Pbtl-X. The R1 phenyl substituent of Pbtl occupies considerably more space than the iPr group present in Ipr-I, so that the mismatch between Ipr-I and Pbtl-X along the b-axis would be on a similar scale as that between Amy-I and IprI, illustrated in Figure 13. Thus, seeds of Ipr-I might not be able to induce a replication of their entire 3D structure in Pbtl, but a 1D fragment of Ipr-I, the pair of H-bonded chains of Figure 11b, could serve as a starting point for the growth of the preferred Pbtl-IX phase. We have performed an additional contact preparation experiment with Ipr-I and Amy-I where the behavior of the two forms was consistent with Roozeboom type 3 with a minimum at 134 °C (see Figure ES3, Supporting Information). Hence we conclude that Ipr-I and Amy-I are indeed not just isostructural but also isomorphic (i.e., they form solid solutions). This result is very surprising if the large difference of 30% which they exhibit in one unit cell dimension is taken into account. The comparison of PXRD patterns, usually regarded as a reliable method to determine whether two crystal forms are isostructural, inevitably fails in the present case in this respect. Instead, Figure, ES6, Supporting Information illustrates that the close relationship between the simulated PXRD patterns of Ipr-I and Amy-I can be made visible once the very simple manipulation of setting a common value for both unit cell b parameters has been performed. We have redetermined the structure of Mdm-I (see Table 3), first described some 40 years ago,64 in order to obtain a complete model including H positions. This structure displays the 2D H-bonding pattern of Figure 9e. The simulated PXRD pattern of Mdm-I confirms the assertion that this form is different from the co-crystal Pbtl/Mdm which according to the phase diagram established by Kuhnert-Brandsta¨tter28 is isomorphic to both Pbtl-X and Mdm-VI. It is worth noting that the 2D H-bonding motif of Mdm-I is also found in barbital-V65 and vinbarbital-I66 and that the IR-spectra of these two forms display N-H · · · OdC vibration characteristics similar to those of Mdm-I.64 Form Pbtl-XI. The structure of Cpl-I was determined (Table 3) in order to confirm its relationship to the Pbtl/Cpl co-crystal and implicitly to Pbtl-XI. A comparison of the different PXRD patterns confirms that Cpl-I is indeed not isostructural to the co-crystal. Cpl-I is composed of two independent molecules which are joined together by N-H · · · O bonds to give the ladder motif of Figure 9d which is also present in Rtl-I. The common H-bonded motif of Cpl-I and Rtl-I is associated with IR-spectra of the G5a type, and it is associated with one corresponding vector in the two lattices, Cpl-I: a ) 6.769 Å and Rtl-I: b ) 6.738 Å. The same correlation between H-bond motif and the G5a type was previously established53 for Rtl-II67 and barbitalI.68 Since the IR-type of Pbtl-XI is also G5a, one can conclude


that the ladder of Figure 9d is the predominant structural motif of this polymorph. Conclusions This study confirms the existence of six metastable polymorphs (V, VII, VIII, IX, X, XI) of phenobarbital, reported by Kuhnert-Brandsta¨tter about 50 years ago and explains the structural basis of supramolecular associations in barbiturates. Except for Pbtl-V, which can be also obtained from the pure Pbtl melt, the nucleation of these forms occurs only in the presence of other 5,5-substituted barbituric acid derivatives that exhibit isomorphic relationships and thus form mixed crystals with one of the metastable Pbtl forms. The forms have been obtained only in small amounts by melt crystallizations using hot-stage microscopy and the contact preparation technique as the main experimental tools. The forms Pbtl-V, VIII, and IX (stable for less than one day) could be isolated as a single component phase, whereas Pbtl-VII, X, and XI can be stabilized only in the presence of one of the isomorphic additives. The identity of the forms and their isomorphic relationships to other barbiturates were elucidated with IR-spectroscopy and PXRD. Via the single crystal structures of isomorphic partners, it is possible to assess more detailed structural features of the metastable forms in such isopolymorphic systems. IR-spectroscopy proved to be an ideal complementary technique to X-ray diffraction techniques, allowing a classification of the numerous barbiturates into different H-bonding motif groups. Furthermore, it is demonstrated that the comparison and visualization of their multitudinous crystal packing arrangements (XPac analysis) enables us to gain a better understanding of the complex relationships between the crystal forms. This study exemplifies that a variety of new polymorphic forms that are not detectable in solvent or melt crystallization experiments of the pure compound can be successfully generated in a binary mixture. Moreover, it demonstrates the impact and basic principles of isomorphic additives on the formation of a specific polymorph or for the stabilization of unstable crystal forms. Such additives can be deliberately added or can be present as an impurity in industrial materials. Albeit we did not use solvents in this study and produced the Pbtl forms only by crystallization from the melt, it seems to us that “isomorphic seeding” is the appropriate term to describe the deliberate production of a specific phase by adding isomorphic agents. Because of the abundance of potential isomorphic relationships (isopolymorphism) and its high chemical stability, Pbtl is an ideal model compound for such investigations and also for systematic studies of supramolecular aggregation modes in barbituric acid derivatives in general. However, it should be stressed that this study was only feasible because of the pioneering work performed by Kuhnert-Brandsta¨tter and co-workers and the expertise they developed in the analysis of binary relationships of small organic molecules. This kind of information is a key to the understanding of modern aspects of crystal engineering, particularly the role of additives in the nucleation and growth of specific crystalline phases including polymorphs and co-crystals. Acknowledgment. T.G. acknowledges financial support from the Lise-Meitner Program of the Austrian Science Fund (FWF). Supporting Information Available: Binary temperature/composition phase diagrams of basic types of solid solutions; phase diagrams of Pbtl/ Rtl, Pbtl/Mdm and Pbtl/Phd; photomicrographs of a contact preparation of Ipr-I and Amy-I; diagram illustrating the structural relationship between form IX and X with other barbiturate structures; structure discussions of Rtl-I abd Cpl-I; tables of strong hydrogen bond geometries in the different

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structures; list of lattice parameters identified by XPac as corresponding due to similar packing of barbiturate molecules; List of selected IR bands. This material is available free of charge via the Internet at http:// pubs.acs.org. The crystallographic data of eight different 5,5-substituted barbituric acid derivatives have been deposited with the Cambridge Crystallographic Data Centre CCDC Nos. 714228 (alphenal, form I), 714229 (cyclopal, form I), 714230 (ipral, form I), 714231 (medomin, form I), 714232 (nembutal, form I), 714233 (phanodorm, form II), 714234 (rutonal, form I), 714235 (sandoptal, form I).

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CG801416A

Crystallization of Metastable Polymorphs of Phenobarbital by

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