Structural Features, Phase Relationships and Transformation

DOI: 10.1021/cg901062n

Structural Features, Phase Relationships and Transformation Behavior of the Polymorphs I-VI of Phenobarbital†

2010, Vol. 10 302–313

Neslihan Zencirci,‡ T. Gelbrich,‡ David C. Apperley,§ Robin K. Harris,§ Volker Kahlenberg,# and Ulrich J. Griesser*,‡ ‡

Institute of Pharmacy, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria, #Institute of Mineralogy and Petrography, University of Innsbruck, Innrain 52c, 6020 Innsbruck, Austria, and § Department of Chemistry, University of Durham, South Road, Durham City, U.K. DH1 3LE Received September 1, 2009; Revised Manuscript Received October 10, 2009

ABSTRACT: Six of the more easily accessible forms of phenobarbital (Pbtl-I, II, III, IV, V, VI) were characterized by a variety of analytical methods (thermal analysis, solution calorimetry, X-ray diffraction methods, infrared, Raman and solid-state NMR spectroscopy), in order to get a clear picture of this complex polymorphic system and to eliminate severe inconsistencies in the existing data. On the basis of the thermochemical data and stability studies, we were able to clarify the thermodynamic relationships of the six forms with the aid of a semi-schematic energy/temperature diagram. The order of the thermodynamic stability at 20 °C was established as I > II > III > IV > V/VI, but forms I and II are energetically almost indistinguishable. This study provides a comprehensive description about the production, identification, and transformation pathways of the six polymorphs and discusses the structural origins for some of the unique solid-state phenomena of this important drug compound.

Introduction Phenobarbital (Pbtl, 5-ethyl-5-phenyl-2,4,6(1H, 3H, 5H)pyrimidinetrione, Scheme 1) is one of the few barbituric acid derivatives that are still therapeutically used. This drug compound has a long history and was first marketed as a hypnotic and a sedative under the trade name Luminal in 1912. Today Pbtl is indicated mainly in the treatment of epilepsy and neonatal seizures (listed in the WHO Essential Medicines Library), as well as in anesthesia. With an annual world production of 250 tons, phenobarbital is one of the most widely traded psychotropic substances and belongs to the most commonly prescribed drugs. The substance can crystallize in at least 11 nonsolvated crystal forms,2,3 which represents one of the highest numbers of polymorphs that have been reported for a small organic molecule. Additionally, a hydrate (H1), a hemihydrate (H0.5), and solvates with dioxane, acetontrile, and nitromethane have been identified so far.4-8 There are numerous reports on Pbtl polymorphs, but some of the data are rather inconsistent and it is still not quite clear how many reproducible forms actually exist. A compiled list of all relevant papers with an assignment to the various forms of Pbtl can be found in the Supporting Information (Table ES1). Forms I, II, III, IV, VI, H1, and H0.5 have been investigated in a number of studies,9-12,14,7 by thermal analytical methods,15,2,3,16,7 powder and single-crystal X-ray diffraction,4,17-21 and IR spectroscopy.18,22-24 Additionally, dissolution,25,5,26 solubility,27-30 and bioavailability31 studies have been carried out. Finally, a number of formulation studies deal with individual forms of Pbtl.32-36,7,37 It should be mentioned that the monohydrate (H1) was originally not recognized as a hydrate and was *Corresponding author. Tel.: (þ43) 512-507-5309. Fax: (þ43) 512-5072939. E-mail:[email protected]. † This article is part 14 of a series of articles with the title “Polymorphic Drug Substances of the European Pharmacopoeia”. pubs.acs.org/crystal

Published on Web 11/25/2009

named “form V” by Cleverley and Williams.18 In another report,4 the monohydrate and hemihydrate (H0.5) were termed forms “XIII” and “XII”, respectively, leaving the implication that these forms are polymorphs. Six additional polymorphs (V, VII, VIII, IX, X, XI) have been reported by Kuhnert-Brandst€ atter and Aepkers.2,3,15 In a preceding 38 study, we have confirmed their existence and upgraded the knowledge about these metastable forms, in particular about their structural characteristics. Except for form V, which can be also obtained from the pure Pbtl melt, all of these polymorphs can only be produced in the presence of other 5,5-substituted barbituric acid derivatives. In that study, forms VIII and IX were isolated as a single component phase, whereas Pbtl-VII, X, and XI could be stabilized only in the presence of some percent of one of the isomorphic additives. In the course of our comprehensive reinvestigation of Pbtl, we also found several new solvates of Pbtl8,39 in addition to the already known7 dioxane solvate. The present paper provides the results we obtained for six of the polymorphs (I, II, III, IV, V, VI). These forms can be obtained from solvent crystallizations and/or melt crystallizations without the use of additives. In spite of the many reports dealing with these forms, there is indeed no agreement concerning the thermodynamic stability order of the most relevant polymorphs (Pbtl-I, II, and III). This fact, and the use of Pbtl as a model compound to demonstrate the nucleation and growth of different polymorphs from the melt in hot-stage microscopy courses, motivated us to reinvestigate the solidstate properties of Pbtl and to elaborate a clearer picture of the phase stabilities and phase relationships of the different forms. Since most of the earlier studies are older than 20 years, it can be expected that the improved technology of analytical instrumentation facilitates a deeper insight into the structural and thermodynamic nature of this highly polymorphic substance. This goal has been achieved with the aid of a variety of analytical methods such as single-crystal and powder X-ray r 2009 American Chemical Society

Article

Crystal Growth & Design, Vol. 10, No. 1, 2010

Scheme 1. Molecular Structure of 5-Ethyl-5-phenylbarbituric acid (C12H12N2O3), Mr: 232.24 g mol-1

Table 1. Crystal Data for the Pbtl Forms Investigated by Single-Crystal X-ray Diffraction form

I

II

III

chemical formula formula weight description

C12H12N2O3 232.24

C12H12N2O3 232.24

C12H12N2O3 232.24

colorless block 0.36 0.29 0.12 298(2) monoclinic P21/n 10.6996(10) 47.259(5) 6.8032(6) 90 94.201(7) 90 3430.8(6) 12/3 1.349 13938/0.0478 5361/488 0.0486 0.1013

colorless thin plate 0.29 0.13 0.03 173(2) triclinic P1 10.736(2) 23.398(5) 6.7194(14) 90.959(17) 94.504(16) 88.358(17) 1681.8(6) 6/3 1.376 25342/25342/464 0.0886 0.2059

colorless prism 0.2 0.18 0.18 298(2) monoclinic P21/c 9.5455(18) 11.852(2) 10.809(2) 90 111.601(14) 90 1136.9(4) 4/1 1.357 7748/0.0452 2229/164 0.0435 0.0975

3

size (mm )

diffraction, thermal analysis, solution calorimetry, polarized light microscopy, vibrational spectroscopy (IR and Raman), and solid-state NMR (SSNMR). Experimental Section A phenobarbital sample was available (Mallinckrodt Chemical Works, USP XIII Powder, USA) that consists of a mixture of Pbtl-II and I. This sample was used for solvent crystallization of forms I, II, and III and for the production of the forms IV, V, and VI from the melt. All solvents used in this study were of analytical grade and purchased from either Merck (Darmstadt, Germany) or SigmaAldrich (Munich, Germany). Optical Polarized Light, Hot-Stage Microscopy (HSM). For optical and hot-stage microscopic observations, an Olympus BH2 polarization microscope (Olympus Optical GmbH, Vienna, Austria) equipped with a Kofler hot stage (Reichert Thermovar, Vienna, Austria) was used. Microscope images were recorded with an Olympus ColorView IIIu digital camera in connection with CellD software (Soft Imaging System, Hamburg, Germany). A Kofler hot bench (Reichert, Vienna, Austria) was employed for annealing experiments and the preparation of melt film samples between a glass slide and a coverslip. Differential Scanning Calorimetry (DSC). DSC thermograms were recorded with a DSC 7 instrument (Perkin-Elmer, Norwalk, Ct., USA), operated with the Pyris 2.0 software. Samples of approximately 1-3 mg were accurately weighed ((0.0005 mg) using a UM3 ultramicrobalance (Mettler, Greifensee, Switzerland), into either sealed or pinholed Al-pans (25 μL). Dry nitrogen was used as the purge gas (20 mL/min), and different heating rates, mostly between 2 to 50 K/min, were applied. The temperature was calibrated with pure benzophenone (mp 48.0 °C) and caffeine (mp 236.2 °C), and the energy calibration was performed with pure indium (purity 99.999%, mp 156.6 °C, heat of fusion 28.45 J/g). The errors of the stated temperatures (extrapolated onset temperatures) and enthalpy values are stated as 95% confidence intervals (c.i.) based on at least four measurements. Solution Calorimetry (SolCal). The enthalpies of solution (ΔsolH) of Pbtl-I, II, and III in ethanol (96%, p.a.) were measured with the TAM III Thermal Activity monitor (TA Instruments Inc.) equipped with a precision solution calorimeter. The measurement temperature was 25 ( 10-4 °C the volume of the vessel was 100 mL and the stirrer speed was 500 rpm. Three to six measurements with sample amounts of approximately 300 mg (accuracy ( 0.0005 mg) were performed per polymorph. The calorimeter was calibrated with KCl (analytic grade, >99.5%, Merck) - standard solution enthalpy ΔsolH0 = 17.51 ( 0.0016 kJ 3 mol-1. The TAM Assistant software v 1.2 was used for the data analysis. Solvent-Mediated Transformation (SMT). SMT experiments were carried out by suspending sample mixtures of forms I, II, and III in diisopropylether or ethanol using a glass cylinder, a magnetic stirrer, and a thermostatted water bath. The suspension was stirred (900 rpm) at a constant temperature and at regular intervals. A few milliliters of the suspension were withdrawn, filtered, and the solid residue was investigated with PXRD and IR or Raman spectroscopy. Fourier Transform Infrared (FTIR) Spectroscopy. FTIR spectra were recorded with a Bruker IFS 25 spectrometer (Bruker

303

T (K) crystal system space group a (A˚) b (A˚) c (A˚) R (°) β (°) γ (°) V (A˚3) Z/Z0 dcalc (Mg/m3) coll reflns/Rint data/parameters R1 [I > 2σ(I)] wR2 (all data)

Analytische Messtechnik GmbH, Karlsruhe, Germany). The samples were prepared on ZnSe disks, using a Bruker IR microscope I (15-Cassegrain-objektive, transmission mode, spectral range 4000 and 600 cm-1, resolution of 4 cm-1, 64 interferograms per spectrum). Fourier Transform Raman (FT Raman) Spectroscopy. FT-Raman spectra were recorded with a Bruker RFS 100 Raman spectrometer (Bruker Analytische Messtechnik GmbH, Ettlingen, Germany), equipped with a Nd:YAG Laser (1064 nm) as the excitation source and a liquid-nitrogen-cooled, high-sensitivity Ge-detector. The samples were prepared in aluminum pans and the spectra were recorded with a laser power of 200 mW (64 scans per spectrum) at an instrumental resolution of 4 cm-1. Powder X-ray Diffractometry (PXRD). The X-ray diffraction patterns were obtained with a Siemens D-5000 diffractometer (Siemens AG, Karlsruhe, Germany) equipped with a theta/theta goniometer, a Cu KR radiation source (wavelength 1.5406 A˚), a parallel beam optic (Goebel mirror, Bruker AXS, Karlsruhe, Germany), a 0.15° soller slit collimator and a scintillation counter. The patterns were recorded at a tube voltage of 40 kV and a tube current of 35 mA, by applying a scan rate of 0.005° 2θ/s in the angular range of 2-40° 2θ. As form VI transforms readily to form II upon mechanical treatment, we recorded the pattern with a film preparation of Pbtl-VI (crystallized from the melt using the hotstage microscope) on a coverslip which was mounted on a silicon holder. The diffraction pattern obtained with this design was naturally of rather poor quality and suffered from preferred orientation. The PXRD of forms I and II were additionally obtained with a X’Pert PRO diffractometer (PANalytical, Almelo, NL) equipped with a theta/theta coupled goniometer in transmission geometry, a programmable XYZ stage with a well plate holder, a Cu KR1,2 radiation source (wavelength 1.5419 A˚) with a focusing mirror, a 0.5° divergence slit and a 0.02° soller slit collimator on the incident beam side, a 2 mm antiscattering slit, and a 0.02° soller slit collimator on the diffracted beam side and a solid-state PIXcel detector. The samples were prepared on a 3 μm Mylar foil and recorded at a tube voltage of 40 kV and a tube current of 40 mA, applying a step size of 0.013° 2 θ in the angular range of 2° to 40° 2θ with 40 s per step. Single-Crystal X-ray Diffractometry (SCXRD). Crystallographic data for the Pbtl forms I-III are listed in Table 1. Data sets were recorded with a STOE IPDS-II diffractometer (Stoe & Cie GmbH, Darmstadt, Germany) using Mo KR radiation (0.71069 A˚). Structure solutions and refinements were carried out using the SHELXTL program package.40 For forms I and II, we have maintained the nonconventional unit cell settings of the original

304


report by Platteau et al.21 The structure of form II was refined using the data of two twinned components whose lattices were not superimposed. All non-hydrogen atoms were refined anisotropically. H atoms attached to C were generated by riding models in idealized geometries, and their temperature parameters were set to Uiso(H) = 1.2Ueq(C) for phenyl Uiso(H) = 1.5Ueq(C) for CH3 groups. The H atoms in NH groups were located from difference Fourier maps. Their isotropic temperature parameters were refined freely and N-H distances restrained to 0.88(1) A˚ for forms I and III, while a riding model and Uiso(H) = 1.2Ueq(N) were applied for form II. The crystallographic data have been deposited with the Cambridge Crystallographic Data Centre, CCDC Nos. 750455 (I), 750456 (II), 750457 (III). Solid-state NMR spectroscopy of polymorphs I, II, and III was performed at the University of Durham. Carbon-13 and nitrogen15 cross-polarization magic-angle spinning (CPMAS) spectra at ambient probe temperature were obtained at 100.56 and 40.52 MHz, respectively, using a Varian VNMRS spectrometer based on a 9.4 T Oxford Instruments superconducting magnet. The probe accepts 4.0 mm (outside diameter) zirconia “pencil” rotors, which were fitted with Teflon end-caps. Proton decoupling with the TPPM protocol at power equivalents to frequencies of 97 and 79 kHz was employed during acquisition of 13C and 15N spectra respectively. The MAS rates were 8 kHz and 4 kHz for 13C and 15N, respectively. Contact times for the CP experiments were 1 and 10 ms for 13C and 15 N respectively. A linear ramp on the 1H channel was employed. The numbers of transients (NT) were between 564 and 1500 for 13C. More transients were generally necessary for the 15N spectra of forms I and II (6000 and 5884, respectively), but only 1472 were required for form III because of its simpler spectrum. Recycle delays were 10 s for both nuclei. The 13C spectra were referenced via the high-frequency signal for a replacement sample of adamantane (δC = 38.5 ppm) and are reported relative to the resonance of neat TMS. The 15N spectra were analogously referenced to the resonance of neat nitromethane via the nitrate signal of ammonium nitrate (δN = -5.1 ppm).

Results and Discussion The scheme in Figure 1 displays the morphologies and most significant transformation pathways of the Pbtl forms that are the matter of the present report. A scheme that includes the relationships between all polymorphs was provided in a previous report.38 Microphotographs showing the characteristic appearance of the forms I-VI as they crystallize from the melt in microscopic film preparations are provided in the Supporting Information (Figure ES1). Moreover, Table 2 summarizes thermochemical properties and other data of the crystal forms of the six Pbtl forms, discussed in more detail below. Preparation and Specification of the Forms. This section describes reproducible preparation procedures for the six polymorphs that were verified in this study. Modification I (mp 176 °C). Pbtl-I is the stable form at high temperatures and can be produced by (a) annealing any other Pbtl form at 160 °C for 2 h or (b) by solvent-mediated transformation of mixtures of Pbtl-III, II, and I in diisopropylether or ethanol at temperatures of 0 °C, 10 °C (isothermal), or at cycling temperature between 10 and 30 °C. The transformation occurred within 7 to 11 days. Pbtl-I is also the thermodynamically stable form at room temperature (see below). Some experiments showed that this form can also be crystallized from solvents such as ethylacetate, ethanol, and diethylether concomitantly with Pbtl-II, particularly when the solution is cooled slowly. Solution-grown Pbtl-I shows rhombohedral to prismatic habits. Moreover, this polymorph crystallizes from the supercooled melt at about 160 °C. Below 160 °C mainly Pbtl-II occurs, indicating higher nucleation and/or growth rates. In melt film

Zencirci et al.

Figure 1. Morphologies, melting points, and transformation pathways of the Pbtl forms I-VI.

preparations, Pbtl-I typically crystallizes as broad rayed spherulites with characteristic, mostly parallel, contraction fissures. Modification II (mp 174 °C). Pbtl-II was present in the available commercial samples and crystallizes preferentially in a prismatic habit. This triclinic polymorph is obtained from organic solvents, such as alcohols (preferred solvents), ether, acetone, 2-butanone, dimethyl sulfoxide (DMSO), dimethyl formamide (DMF), ethylacetate, tetrahydrofuran (THF), chloroform, methylene chloride, and ethylacetate (irrespective of the crystallization method). Crystallization from hot saturated solutions of water also yields Pbtl-II, confirming that this form is more stable than the monohydrate above the reported transition temperature31 of about 50 °C. Furthermore, this form can be obtained by annealing less stable forms for 1 h (Pbtl-III) or less (Pbtl-IV, V, VI, VIII, IX) at 140 °C. Annealing the supercooled melt between 140 and 160 °C yields characteristic, fine rayed spherulites of Pbtl-II (see Figure 2a). At and above 160 °C, Pbtl-II transforms slowly to Pbtl-I within less than an hour. Drying the monohydrate at elevated temperatures results in mainly Pbtl-II, but such products are mostly contaminated with Pbtl-III. Modification III (mp 167 °C). Pbtl-III (monoclinic) crystallizes from saturated solutions (fast cooling rate) of amylalcohol, diisopropylether, chloroform, and methylene chloride, but we always observed small amounts of Pbtl-II in such crystallization batches. Since Pbtl-III grows mostly to polyhedral crystals and Pbtl-II to prisms (see Figure 1), the two forms can be distinguished easily by their appearance. Highly pure Pbtl-III can be obtained by solvent crystallizations from acetonitrile, nitromethane, and dioxane. However, we found that the polymorph does not nucleate directly in these solvents but first appears as the corresponding solvate, which desolvates readily to Pbtl-III on harvesting. Several reports28,13,30 state that this form is also obtained by spray drying. Our experiments showed that annealing Pbtl-IV, V, and VI at 100-120 °C yields Pbtl-III.

Article


305

Table 2. Physicochemical Data for the Phenobarbital Polymorphsa property/form Tfus [°C] HSM2,16 DSC (onset)

I

II

III

IV

V

VI

176 176.2 ( 0.1

174 173.8 ( 0.1

168 167.8 ( 0.3

163 -

160 -

156 -

28.0 ( 0.2

27.9 ( 0.2 II ≈ I

>28 ∼28.3

∼25

∼24

>25 (?)

-

-

-

90-125 (fIII) 133 ( 2 (fII)

116-125 (fII)

HSM

-

160-170 (f I)

150-160 (fII/I)

∼130 (fIII) ∼140 (fII)

116-130 (fIII) 116 ( 2 (fII) ∼130 (fIII) ∼140 (fII) ∼150 (fIV)

ΔtrsH [kJ mol-1] Burger16

-

e0.3 (fI)

e0.3 (fII)

-

-

ca. -3 (fI/II) -3.3 ( 0.4 (fIII) ca. -3 (fI/II)

ΔfusH [kJ mol-1] DSC calc Burger16 Ttrs (exp) [°C] DSC

27.1

This work calc ex solcal ΔsolH [kJ mol-1] EtOH (25 °C)

16.24 ( 0.03

130 °C. Pbtl-III melts at 167 °C, followed by the inhomogeneous melting of Pbtl-II to Pbtl-I, which melts at 176 °C.

PXRD that mainly Pbtl-V nucleates by annealing a melt film preparation at 120-130 °C. Because of a quick transformation on heating between 140 and 150 °C to Pbtl-IV (Figure 2c), the melting point of the latter form is usually observed, which leads2 to the wrong conclusion that Pbtl-IV nucleates preferentially from the melt. The IR spectra of Pbtl-IV and V are similar, but the forms can be readily discriminated by their PXRD patterns. In melt film preparations of the two forms protected by a coverslip, the formation of more stable forms (Pbtl-II and III) was observed after two days (25 °C). Exposing a film of the two forms to the laboratory atmosphere (removing the coverslip from the glass slide) reduces the transformation time to the stable forms to 3-6 h. These forms can also be produced by sublimation, where Pbtl-IV occurs as curved needles with dendritic growth and Pbtl-V as straight needles (see Figure ES2, Supporting Information). Modification VI (mp 156 °C). This polymorph is the most unstable one among the crystal forms described in this study and can only be produced in a microscopic scale from the supercooled melt. In melt film preparations Pbtl-VI grows to aggregates (spherulites) of broad rayed, flat-ended crystals with typical contraction fissures across the long direction of the crystals, and low-order interference colors. A characteristic feature of this polymorph is also the formation of mostly lengthwise-oriented cavities during the crystal growth. It is striking that the nucleation of Pbtl-VI often starts at the surface of Pbtl-II crystals between 90 and 100 °C (see Figure ES1 in Supporting Information), a fact that was stated already in an earlier study.2 Pbtl-VI transforms to Pbtl-III and II within 12 h in film preparations (between glass slide and coverslip) and within a few hours when the glass slide is removed or the substance is scraped off the glass. On heating,

Zencirci et al.

the transformation to Pbtl-III occurs at 120 °C, followed by a transition to Pbtl-II at 140 °C. Hot-Stage Microscopy (HSM). On heating Pbtl-I, no particular changes occur in the crystals until they melt at 176 °C, whereas for Pbtl-II a distinct sublimation can be observed above 160 °C. The prismatic sublimates of Pbtl-II (depositing on the coverslip) melt at the same temperature as the original crystals (174 °C) and thus represent the same polymorphic form. The melting process is mostly accompanied by a nucleation and growth process of Pbtl-I. In solution-grown single crystals of Pbtl-II this transformation occurs already below its melting point, between 160 and 170 °C. The same transformation is also observed in melt film preparations of Pbtl-II (Figure 2a). On slowly heating crystals of Pbtl-III (see Figure 2b), two solid-solid transformations can be observed. The first one, occurring at about 150 °C, is the transformation to Pbtl-II, which proceeds without change of the external habit or cleavage of the crystals but with a clear change of the interference colors (polarized light). At about 160 °C, the second transformation to Pbtl-I occurs, yielding agglomerates of small crystals, which melt at 176 °C. On faster heating, the melting of Pbtl-III at 167 °C is observed. The photomicrographs in Figure 2c show the rather diffuse change of Pbtl-V to Pbtl-IV, already discussed above. In preparations containing the crystal forms of V, VI, and II (Figure 3a), Pbtl-II starts to grow quickly between 130 and 140 °C at the expense of other forms. On further heating, the inhomogeneous melting process to Pbtl-I is observed at 174-176 °C. If such crystal film preparations contain PbtlIII along with V and VI, two transformations are observable (see Figure 3b). First (∼117-130 °C) Pbtl-III transforms to the two other forms and then (∼130-167 °C) Pbtl-II nucleates and grows. The transformation rate of Pbtl-V and VI to Pbtl-II is much faster than that of Pbtl-III to II. Differential Scanning Calorimetry. Figures 4 and 5 show the DSC curves of the Pbtl forms. Pbtl-I (Figure 4, top) shows only one clean melting endotherm at 176.2 °C and the enthalpy of fusion could be determined directly. Pbtl-II melts mostly inhomogeneously to form I at 173.8 °C (heating rate 5 K min-1), as indicated by a melting peak with two maxima. At heating rates of 10 K min-1 and higher we were able to record the pure melting peak of Pbtl-II (Figure 4), but we could not establish a statistically significant difference in the heat of fusion (see Table 2) between this form and that of Pbtl-I. At rates of 0.5 to 1 K min-1, a slow transformation of Pbtl-II to Pbtl-I occurs between 150 and 170 °C, which was proven by PXRD. The heat change of this transformation is extremely small and does not cause an observable effect in the DSC curve. An endothermic transformation peak with an enthalpy change of 0.3 kJ mol-1, as reported by Burger and Ramberger,16 was not observed in any of the numerous experiments we performed. We noticed that this information used by these authors relies only on a single DSC experiment41 and is therefore questionable. The melting process of Pbtl-III occurs at 167.8 °C (onset), but simultaneously Pbtl-II and Pbtl-I crystallize in the melt, resulting in an endoexo event (Figure 4). Only at rather high heating rates (50 K min-1) were we able to record the pure melting peak of Pbtl-III. The heat of fusion of such a melting peak is higher than that of Pbtl-II and I. At low heating rates (2 K min-1) of Pbtl-III, an endothermic transformation to these forms occurs over a wide temperature range (110160 °C). According to Burger and Ramberger,16 this

Article


307

Figure 4. DSC curves of Pbtl polymorphs I, II, III. (1) mod. I; (2) Pbtl-II with pure melting endotherm; (3) Pbtl-II melting with recrystallization to Pbtl-I; (4) Pbtl-III with pure melting; and (5, 6) Pbtl-III with melting and recrystallization to forms II and I. Figure 6. ET-diagram of Pbtl forms I, II, III, IV, V, and VI. Tfus: melting point, G: Gibbs free energy, H: enthalpy, ΔfusH: enthalpy of fusion, Ttrs: transition point, ΔtrsH: transition enthalpy, liq: liquid phase (melt). The bold vertical arrows signify experimentally measured enthalpies and the horizontal arrows signify the temperature range where Pbtl-I and III are thermodynamically stable.

Figure 5. DSC curves of Pbtl polymorphs IV (1), V (2), and VI (3). The left graph shows DSC curve with transformations to preferentially Pbtl-II and I (circles mark the melting endotherms of small amounts of Pbtl-III); the melting endotherm at 168 °C in the curves on the right indicate that the transformation resulted in a higher amount of Pbtl-III. The curve starting with Pbtl-V on left site was recorded with 5 K min-1; all other curves with a heating rate of 10 K min-1.

transformation occurs at about 100 °C, with an enthalpy change of ∼0.3 kJ mol-1. Our DSC experiments confirm that the process is endothermic, which means that the relationship to the forms II and I is enantiotropic. However, the weak endotherms are very broad so that their evaluation is not easy, and transition enthalpies between 0.3 and 1.5 kJ mol-1 were obtained. The DSC curves displayed in Figure 5 confirm that Pbtl-IV, V and VI show exothermic transitions which result exclusively in mixtures of Pbtl-III, II, and I. Pbtl-VI

transforms preferentially to Pbtl-II, which is in good agreement with the hot-stage microscopy results. However, it was rather challenging to crystallize phase-pure samples of forms IV, V, and VI directly in aluminum pans, though this is possible between glass slide and coverslip under microscopic control. Thus, we prepared these forms as films on microscope slides. The crystalline material was carefully removed from the glass using a razor blade and then transferred to a DSC pan. After many trials, we were able to record a few thermograms that display rather clean phase transitions to preferentially Pbtl-III or Pbtl-I/II. From these phase transitions, we derived the very rough enthalpies which are listed in Table 2. Since the enthalpy difference between Pbtl-I and -II is extremely small, the transition of the metastable forms to either of these polymorphs is more or less identical. However, we can conclude from the exothermic events that Pbtl-IV, V, and VI are monotropically related to Pbtl-III, II, and I. Thermodynamic and Kinetic Stability. The thermochemical results that we obtained in this study allow us to construct a semi-schematic energy/temperature diagram according to Burger-Ramberger.43 The diagram is shown in Figure 6 and the relevant data are listed in Table 2. On the basis of DSC experiments, Burger and Ramberger16 postulated enantiotropic relationships between Pbtl-I, II, and III and a monotropic relation between each of these forms and Pbtl-IV. The order of thermodynamic stability at 20 °C was established as II > III > I > IV. However, Kato and Watanabe31 as well as Otsuka et al.30 reported that the solubility of Pbtl-I is lower than that of II, which indicates

308


that Pbtl-I is the thermodynamically stable form at room temperature. Solution-mediated transformation studies in diisopropylether and in ethanol at 20 °C, starting from mixtures of the three forms, convinced us that the latter is true. In all cases Pbtl-I was obtained, unambiguously confirming that this is the stable form at 20 °C. DSC indicated that the enthalpy difference between Pbtl-I and -II is extremely small (within the error limits of the measurements). This was also confirmed by solution calorimetry (Table 2). Since Pbtl-I is thermodynamically more stable at 20 °C and melts at higher temperature, its free energy must be lower than that of Pbtl-II in this temperature range. Whether there exists a transition point between these forms below room temperature is not evident from the available data. If such a transition point exists, it must be rather close to absolute zero. This is also indicated by the density rule,43 which suggests that the free energies of the two forms at 0 K are almost equal since their densities are virtually identical. However, it should be stressed that the existence of a transition point between Pbtl-I and II at 80.9°, as was extrapolated from the solubility data,42 is impossible if Pbtl-I is truly the less soluble form at room temperature. Since this form is the highest melting form, the free energy curve of Pbtl-I cannot intersect with that of the lower melting Pbtl-II between the melting temperature and room temperature. The observation that the transformation of Pbtl-III to Pbtl-II/I is endothermic, as well as its (though only slightly) higher melting and solution enthalpies, confirms unambiguously that this form is enantiotropically related to Pbtl-I and II. Further evidence for this type of relationship is the fact that Pbtl-III exhibits the highest density, suggesting that its free energy at 0 K is lower than that of Pbtl-I and II (density rule43). The higher solubility of Pbtl-III (see Table 2) at 37 °C is a clear indication that it is less stable at this temperature than Pbtl-I and II and therefore the transition temperatures to these two forms must be distinctly below room temperature. Pbtl-IV, V, and VI are monotropically related to Pbtl-I, II, and III, as they show exothermic transitions to these more stable polymorphs. The exothermic transition enthalpies to more stable forms (III or II/I, see Table 2), estimated from DSC experiments, are higher for Pbtl-V than for Pbtl-IV. Therefore, the enthalpy curve of Pbtl-V must be above that of Pbtl-IV, confirming that this pair is monotropically related. Pbtl-VI shows the lowest exothermic transition enthalpy to form II/I, while the enthalpy curve must be below that of form IV. Considering also a lower melting point, it follows that the free energy curve of Pbtl-VI must intersect with that of Pbtl-IV and V and that the relationship to these forms is thus enantiotropic. However, as the transition enthalpies of Pbtl-VI obtained by DSC are not well reproducible, the thermodynamic relation to Pbtl-IV and V is arguable, which is why the enthalpy and free energy curves in the ET-diagram (Figure 6) are drawn as dotted lines. Finally, we draw the conclusion that the order of thermodynamic stability at 20 °C is as follows: I > II > III > IV > V/VI. Pbtl-II and III represent kinetically highly stable forms. This notion was impressively confirmed when a sample in our possession, originally labeled as Pbtl-II, was found (by PXRD) to still contain this form in a high purity after more than 20 years of storage. Samples of Pbtl-III stored for more than 2 years at ambient conditions already showed a partial transformation to Pbtl-II. In contrast, Pbtl-IV, V, and VI

Zencirci et al.

Figure 7. FTIR spectra of Pbtl forms I-VI.

transform already within a few days to mixtures of Pbtl-II and III. It should also be mentioned that Pbtl-I, II, and III do not transform to the monohydrate at high relative humidities, which was confirmed by the storage of the three forms for 2 years over a saturated solution of potassium sulfate (98% RH). Pbtl-I and II did not show any changes after this storage period, whereas in the sample of Pbtl-III very small traces of the hydrate can be detected. The fact that these three forms are resistant against moisture was also stated by Otsuka.30 Note that computational studies have ranked Pbtl-III as the global minimum structure,44 which it definitely is in the low temperature range. However, at 20 °C form III is metastable. This observation highlights the importance of the entropy term (indicated by the slope of the G-curves in Figure 6) for the assessment of the thermodynamic stability at a given temperature, one of the most important tasks in the characterization of a polymorphic drug substance. Fourier Transform FTIR Spectroscopy. The solid-state FTIR spectra of the six polymorphs are shown in Figure 7, and the frequencies of some characteristic bands are listed in Table ES2 of the Supporting Information. For the sake of completeness, the IR spectra of the forms VII-XI are reproduced38 in Figure ES3. The spectrum of each form shows characteristic features, though the differences between Pbtl-I and II, as well as between Pbtl-IV and V are small. The main differences in the IR spectra can be attributed to distinct NH 3 3 3 OdC interactions and NH out-of-plane vibrations. On the basis of these vibrations, the spectra of 5,5-disubstituted barbiturates have been classified into several groups,45,22 which we extended and already showed in a previous report38 (see also Table ES2 in the Supporting Information). From the fact that Pbtl-I and II have almost identical IR spectra (type G1), except for a missing absorption band at

Article


309

Figure 8. FT Raman spectra of Pbtl forms I-VI.

1323 cm-1 in the Pbtl-I spectrum, we can assume that they show the same H-bond motif and similar packing arrangements. The NH valence vibration of Pbtl-III (type G2 spectrum) is shifted to lower frequencies, indicating a stronger NH 3 3 3 CdO H-bonding than in Pbtl-I and II. The structural differences of Pbtl-IV, V, and VI are more difficult to explain based on the IR spectra. Pbtl-IV and V exhibit only small spectral differences, indicating a high degree of structural similarity. A distinction is possible by the absorption bands at 1200 and 1045 cm-1 in the spectrum of Pbtl-IV and the νNH band, which occurs at lower frequencies in Pbtl-V (3240 cm-1). The NH bands in both forms represent doublets (840 and 790 cm-1) with similar intensity, suggesting two hydrogen bonds of different strength (type G3 spectrum). Pbtl-VI (also type G3) is easily distinguishable from the other forms. The FT Raman spectra (Figure 8) of the forms have not been reported before. The C-H stretching vibrations (around 3000 cm-1), the C-N stretch vibrations (around 1500 cm-1), and the CdO vibrations around 1750 cm-1 show clear differences between all forms, except for Pbtl-I and Pbtl-II. Only one additional small vibration at 1180 cm-1 in the spectrum of Pbtl-II is relevant as a distinguishing feature between these two polymorphs. However, the lattice phonon vibrations in the range between 50 and 200 cm-1 display differences in the spectra of all forms. The Raman spectra of the forms IV and V exhibit clearer differences than do their IR spectra. Powder (PXRD) and Single-Crystal X-ray Diffraction. Figure 9 shows experimental and calculated PXRD patterns for Pbtl forms I-VI. Because of the strong preferred orientation in reflection mode, the patterns of forms I and II were measured in transmission. A comparison of the measurements in reflection and transmission mode of the two forms is shown in Figure ES4 (Supporting Information). All patterns are clearly more distinctive than IR or Raman spectroscopic data, and enable a straightforward identification of each individual form. In particular, forms I and II have very similar IR spectra but produce readily distinguishable XRPD patterns, and the same is also true for the forms IV and V. Such observations indicate the presence of

Figure 9. Experimental and calculated PXRD patterns of Pbtl forms I-VI. The marked PXRD patterns of forms I and II are measured in transmission mode.

topologically equivalent NH 3 3 3 CdO bonds which, however, occur in distinct molecular packing arrangements (see below). The experimental PXRD patterns of forms I-III are consistent with previous reports7,17,33,34,46 and agree also with the single-crystal data discussed below. On the other hand, the PXRD data obtained for the pure Pbtl forms IV and V differ somewhat from the literature data. We conclude that the PXRD patterns of IV and V in the reports by Huang 17,46 and Mesley et al.4 were both contaminated with the forms II and III. Finally, the powder pattern of form VI is in good agreement with that of a form which was labeled “form IV” by Huang. A structure determination of Pbtl-III on the basis of single-crystal X-ray data has been reported by Williams et al.,20 and Platteau et al. determined the crystal structures of Pbtl-I and II from X-ray powder data.21 We have redetermined the structures of all three forms (see Table 1) and obtained significantly improved structure models, particularly with respect to torsion angles and the geometry of the phenyl rings of forms I and II. The geometrical parameters for the hydrogen bonds are available as Supporting Information (Tables ES3-ES5). Since a detailed description of the crystal structures of forms I, II, and III was given elsewhere,21,20 we will focus our discussion on the exact structural relationship between forms I and II and the topology of hydrogen bonding. The molecules of Pbtl and related barbiturates contain two NH groups that can act as donor sites for hydrogen bonds, and O2 and the topologically equivalent O4 and O6 sites are

310


Zencirci et al.

Figure 11. Linkage between molecule types A and B in the Pbtl forms I and II to give a 2D hydrogen bonded network. Top: One ribbon chain formed from molecule type A with four B molecules linking to adjacent chains. Bottom: Three A chains bridged by four molecules of type B. The O4 and O6 atoms are drawn as balls, and the substituents at the C5 position are omitted for clarity. Figure 10. Three NH 3 3 3 O bonded ribbon chains derived from a common motif with R22(8) rings and O4/O6 linkage: (a) centrosymmetric chain (Pbtl-I: molecule C, Pbtl-II: A and C), (b) chain with glide symmetry (Pbtl-I: A), and (c) chain with 21 symmetry (PbtlIII). H and O atoms engaged in hydrogen bonding are drawn as balls. Each chain is viewed parallel (top) and perpendicular (bottom) to the direction of translation.

potential H-bond acceptors (see Scheme 1). The rigid arrangement of these sites drastically reduces the number of possible 1D or 2D topologies and geometries that can ensue as the result of NH 3 3 3 O-bonding interactions. Dimeric units with a central R22(8) ring47 are frequently formed, and they often join together to give a 1D ribbon chain. From this, different chain topologies can arise, depending on the types of O site employed in hydrogen bonding. The most frequent ribbon chain motif, observed in more than 20 barbiturate structures in the current version of the Cambridge Structural Database,48 is a combination of two distinct dimer types, one with a bridge involving two O2 sites and the other with a bridge employing two O4/6 sites, so that one O4/6 position in each molecule is not NH 3 3 3 O bonded. A recent study has shown that this motif is present in at least three of the metastable Pbtl forms, IX-XI.39 By contrast another, lesscommon ribbon chain is present in each of the forms I-III (Figure 10). This particular motif was also identified in forms of barbital49,50 and 6-oxocyclobarbital51 and 5-fluoro5-phenylbarbituric acid.52 Its main characteristic is that all equivalent O4/6 sites of a H-bonded chain are engaged in a NH 3 3 3 O bond, while all O2 sites remain free from any such interactions. Each of the Pbtl forms I and II (both Z0 = 3) contains two independent chains of this kind (labeled here A and C). The third independent molecule (B) forms NH 3 3 3 O bonded bridges between two neighboring A-chains. Thus, a 2D Hbonded pattern A þ B is formed in which both O4/6 sites of each A-molecule accept two H-bonds, whereas neither O site of molecule B participates in any NH 3 3 3 O interaction. This particular 2D topology, illustrated in Figure 11, is unique among barbiturates. Furthermore, we are aware of just one other barbiturate structure with Z0 > 1, a polymorph of butobarbital,53 where independent molecules form two separate and profoundly different NH 3 3 3 O-bonded

structures. Figure 12 illustrates the close structural relationship between forms I and II revealed in an XPac comparison.54 These polymorphs consist both of alternating 2D stacks of C-chains (colored black) and 2D H-bonded A þ B units (blue, orange). However, Figure 12c,d illustrates that the ribbon chain topology is adopted with two fundamentally different geometries characterized by either inversion (form I: chain C; form II: A and C) or glide (form I: A) symmetry. Indeed, the only fundamental difference between forms I and II of Pbtl is the symmetry operation used to generate an A-type ribbon chain. As Figure 12a,b shows, the two structures are composed of the same centrosymmetric 2D ABCCBA fragment which are linked together differently, either by glide (form I) or inversion (form II) symmetry, giving the space group symmetries P21/n and P1, respectively. It follows directly from this 2D similarity that the lattice vectors in the ac-planes of forms I and II correspond to one another, which explains the very close similarity of the associated unit cell parameters in Table 1. Form III of Pbtl displays yet another version of the same ribbon chain motif employing the H-bond acceptor capabilities of O4 and O6. However, in contrast to forms I and II, the ribbon chain of Pbtl-III exhibits a 21 screw axis (Figure 10c) rather than inversion or glide symmetry. Solid-state NMR. The 13C and 15N spectra of polymorphs I, II, and III are shown in Figures 13 and 14, respectively. The spectra of form III are considerably simpler than those of forms I and II. Counting the number of 13C resonances instantly reveals that the asymmetric unit of form III is a single molecule, whereas there are three independent molecules for forms I and II - see especially the triplet signals for C5, C7, and C8. This evidence is in accord with the crystal structures. The 13C spectra of forms I and II are remarkably similar (apart from the signals from the CH2 groups). Again, this agrees with the fact that the crystal structures are nearly identical. However, there are small but reproducible differences, so that the CPMAS spectra can be used to identify the two forms. The most readily distinguishable feature is the set of resonances for C7 - for form I, two of the three expected signals cannot be resolved. The number of signals seen for the CH carbons of the phenyl ring shows that these rings are relatively rigid at ambient probe temperature.

Article


311

Figure 12. Packing diagrams of forms I (a) and II (b) of Pbtl, viewed along the respective a-axis and illustrating their very close structural relationship. 2D structure fragments composed of molecule types A (blue, filled phenyl rings) and B (orange) alternate with stacks of the 1D ribbon chains formed by the third molecule type C (black). Unit cell boundaries are represented by dashed lines. A single ribbon chain is formed by molecule type A as part of a 2D H-bonded A þ B unit. The A ribbon chain of form I exhibits glide symmetry (c), whereas that of form II contains centers of inversion (d). Thus, the two polymorphs represent two modes of connecting the same 2D centrosymmetric ABCCBA structure fragments via a H-bonded ribbon chain with either glide or inversion symmetry.

Figure 13. Carbon-13 CPMAS spectra of phenobarbital forms (a) I, (b) II, and (c) III.

The 13C and 15N chemical shifts are given in Table 3. The small differences between the resonances for forms I and II are revealed by these numbers. The signals for C2 and (to some extent) for C4/C6 are broadened by second-order effects originating in coupling to the quadrupolar 14N nuclei, though the magnitudes of such splittings are small at the magnetic field employed. In general, for 13C the assignments to chemical groups are not in doubt (except for the CH carbons of the phenyl ring). However, there are more difficulties in interpreting the detailed shifts in terms of the crystal structures in the cases of forms I and II (and for all the 15 N spectra). The shift differences between the forms (and

Figure 14. Nitrogen-15 CPMAS spectra of phenobarbital forms (a) I, (b) II, and (c) III.

between different independent molecules of the same form) are affected, in principle, by both intramolecular (geometry) and intermolecular packing variations. The most important of the latter are usually hydrogen bonds, and such considerations sufficed for the understanding of the C4/C6

312


Zencirci et al.

Table 3. Carbon-13 and Nitrogen-15 Chemical Shifts for Phenobarbital in Solution and for Polymorphs I, II, and III form

Z c

0

C4,C6a

C2b

C5

C7

C8

C9

C10-C14

N

71.75 62.3 61.6 61.1 62.4 61.7 61.0 62.3

29.90 31.6d 27.1

9.76 8.8 8.0 7.1 8.9 7.9 6.9 11.4

139.30 137.3d 135.9

129.67d, 126.90d, 129.02 133.7, 132.5, 131.3, 130.2f, 129.8e, f 126.8g, 125.7d, 125.3e

137.2d 136.0

133.7, 132.4, 131.4, 130.8, 130.2g, 129.7, 129.3,127.0g 125.8d, 125.4e

137.6

130.7, 129.9, 129.5, 127.6d

N/A -223.9, -230.0, -226.0, -231.4, -226.7, -233.4 -224.0, -229.7, -226.0, -231.3, -227.2, -232.9 -226.7, -232.6

solution I

N/A 3

173.02 ∼177.1d, ∼175.2, ∼173.2d, ∼169.9

151.06 149.1 147.2d

II

3

∼177.4d, ∼175.0, ∼173.2d, ∼169.9

148.9, 147.2d

III

1

∼174.0h

149.0b

32.2 30.4 27.2 27.1

a The resonances are broadened or split by second-order effects of dipolar coupling to a quadrupolar 14N nucleus. b The resonances are broadened by second-order effects of coupling to two quadrupolar 14N nuclei. c ca. 0.4 molar in methanol.55 d Relative intensity 2. e Shoulder. f The relative intensities of these two signals is difficult to determine. The total must be 6. g Relative intensity 3. h The band is complex since there are two resonances and each is affected to second-order by dipolar coupling to a quadrupolar 14N nucleus.

Figure 15. An overlay of the spectrum for Pbtl-III on that for PbtlI, the latter being in red.

and C2 shifts of barbital.50 However, for the three phenobarbital forms, C2 is not hydrogen bonded at all, although for forms I and II, the C2 signal is split into two resonances with a separation of ca. 1.8 ppm. Moreover, as described above, the C4/C6 atoms in chain B are not hydrogen bonded, whereas the corresponding carbons in the other two chains have intrachain H-bonds with distances between heavy atoms in the range 2.844-2.927 A˚. Chain A has weak additional H-bonding (to chain B), with distances between 3.012 and 3.092 A˚. One would therefore expect to see three signals of equal intensity, with the one for chain B appearing at a lower frequency than the others. However, the observed patterns for forms I and II consist of four signals in intensity ratios (high to low frequency) 2:1:2:1, with total ranges of ca.7.4 ppm. While a detailed understanding of these facts is not apparent, it should be noted that the crucial difference between barbital and phenobarbital is the existence of phenyl rings in the latter, which can affect shifts “through space” via the magnetic properties of the “ring currents”. The orientation of these rings with respect to C4/C6 (and with respect to the two nitrogen nuclei) is presumably of considerable importance. Another fact of significance is that several of the signals for forms I and II are almost coincident with those of form III marked in red in Table 3 (see Figure 15). It is tempting to suggest that these signals arise from chain C for forms I and II, which is analogous to that present in form III. However, the methyl signal for form III is far away from those for the other forms. It is also noteworthy that the range of chemical shifts for phenyl CH carbons of form III is much more limited than those for the other forms, indicating a variety of geometry and/or environmental differences in the chains of the latter. The 15N spectra (Figure 14) neatly confirm the conclusions derived from the 13C results. Thus, the two peaks seen for form III are consistent with a single molecule as the asymmetric unit. Forms I and II give almost identical spectra, with

a doubled 1:1:2 pattern indicating the existence of three molecules in the asymmetric unit. However, the spectra between the two forms are distinguishable, particularly for one of the resonances (see also the chemical shifts listed in Table 3).The range of shifts appears to be too large to be explained solely by differences in hydrogen-bond strength or by ring currents, although it should be noted that the relationships of the two NH groups in each independent molecule to the aromatic ring differ because of the dihedral angle of the latter with respect to the pyrimidinetrione ring. The relationship of the 13C and 15N chemical shifts to the structure is currently being studied by shielding computations and the results will be reported later. Such work is necessary to assign the signals for forms I and II to the independent molecules A, B and C; otherwise, INADEQUATE experiments would be needed, which may not be feasible without isotropic enrichment. Conclusions The polymorphism of phenobarbital shows a series of intriguing phenomena. The existence of 11 polymorphs (of which five are only obtained by seeding with other barbiturates) alone is an impressive demonstration of the diversity of the molecular arrangements in crystal structures of small organic molecules. We experienced in the present study how difficult it can be to manifest the relative thermodynamic differences between polymorphs. Although we believe that polymorphs cannot be truly “isoenergetic”,56 Pbtl-I and II represent another example of a polymorphic pair which are so close in energy that it is very challenging to manifest clear differences even with very modern analytical instrumentation. Such small energetic differences have also been reported from polymorphs of other drug compounds such as ranitidine-HCl,55 cimetidine,57 and diflunisal.58 Pbtl-II and III represent stable kinetic forms that are mostly obtained in crystallization procedures and by transformations of other less-stable polymorphs and solvates, whereas the thermodynamically stable form I can only be obtained in solutionmediated transformations and annealing procedures. Thus, commercial products contain almost exclusively one of these metastable forms or mixtures of these polymorphs. Because of the small energetic difference between Pbtl-I, II, and III it is not surprising that they tend to crystallize concomitantly,59 which enhances the complexity of polymorph studies and is one reason for contradictions or ambiguous results in the literature. Polymorphism which is due to the different stacking of a given 2D structure fragment was identified in several recent studies,60 and forms I and II of Pbtl are yet another example. However, their relationship is an unusual one as the common structure fragment consists of no less than six

Article


consecutive layers of phenobarbital molecules (ABCCBA) along the crystallographic b-axis. The solid-state NMR spectra give considerable information on the crystal structures and provide both supportive and complementary data to the XRD results. The results of this study shed new light on many previous findings regarding the solid-state properties and processing of phenobarbital. We have demonstrated that a deeper understanding of the crystal polymorphism in such a highly complex system can be gained by combining the complementary information obtained from phenomenological, thermodynamic, and structural data. Acknowledgment. The authors would like to thank Ing. E. Gstrein for performing the solution calorimetry measurements. T.G. is supported by the Lise Meitner Program of the Austrian Science Fund (FWF, LM 1135-N17). We are grateful to the U.K. EPSRC for access to the solid-state NMR research service based at the University of Durham. Supporting Information Available: Photomicrographs of melt film preparations and sublimates of Pbtl forms I, II, III, IV, V, and VI; infrared spectra of Pbtl forms VII-XI; comparison of PXRD patterns of Pbtl-I and II recorded in transmission and reflection mode; experimental PXRD patterns of forms VII-XI; table assigning the different Pbtl forms to that referenced in the literature; tables listing characteristic IR bands of Pbtl-I to VI and hydrogen bond parameters of Pbtl-I, II, and III. This material is available free of charge via the Internet at http://pubs.acs.org.

References (1) Part 13: see ref 39; Part 12: Griesser, U. J.; Jetti, R. K. R.; Haddow, M. F.; Brehmer, T.; Apperley, D. C.; King, A.; Harris, R. K. Cryst. Growth Des. 2008, 8, 44–56. (2) Brandst€ atter-Kuhnert, M.; Aepkers, M. Mikrochim. Acta 1962, 6, 1055–1074. (3) Brandst€ atter-Kuhnert, M.; Aepkers, M. Mikrochim. Acta 1963, 2, 360–363. (4) Mesley, R. J.; Clements, R. L.; Flaherty, B.; Goodhead, K. J. Pharm. Pharmacol. 1968, 20, 329–340. (5) Clements, J. A.; Stanski, D. Can. J. Pharm. Sci. 1971, 6, 9–14. (6) Fournival, J. L.; Ceolin, R.; Rouland, J. C. J. Therm. Anal. 1988, 34, 161–175. (7) Otsuka, M.; Onoe, M.; Matsuda, Y. Pharm. Res. 1993, 10 (4), 577–582. (8) Zencirci, N.; Jetti, R. K. R.; Kahlenberg, V.; Griesser, U. J. Sci. Pharm. 2006, 74, 88. (9) Stanley-Wood, N. G.; Riley, G. S. Acta Pharm. Helv. 1972, 47, 58–64. (10) Riley, G. S. J. Pharm. Pharmacol. 1974, 26, 919–920. (11) El-Banna, H. M.; Ebian, A. R.; Ismail, A. A. Pharmazie 1975, 30, 455–460. (12) Traue, J.; Kala, H.; Wenzel, U.; Foerster, B.; Pintyehodi, K.; Szabo, P.; Miseta, M.; Selmeczi, B.; Kedvessy, G. Pharmazie 1986, 41, 291–292. (13) Traue, J.; Kala, H.; Wenzel, U.; Wiegeleben, A.; Pintye-Hodi, K.; Szabo-Revesz, P.; Miseta, M.; Selmeczi, B.; Kedvessy, G. Pharmazie 1987, 42, 86–89. (14) Szabo-Revesz, P.; Pintye-Hodi, K.; Miseta, M.; Selmeczi, B.; Kedvessy, G.; Traue, J.; Kala, H.; Wenzel, U. Pharmazie 1987, 42, 179–181. (15) Brandst€ atter-Kuhnert, M. Mikrochem. Vereinigt Michrochim. Acta 1951, 38, 68–80. (16) Burger, A.; Ramberger, R. Mikrochim. Acta 1979, II, 273–316. (17) (a) Huang, T. Y. Acta Pharm. Intern. 1951, 2, 43–68. (c) Huang, T. Y. Acta Pharm. Intern. 1951, 2, 95-106. (18) Cleverley, B.; Williams, P. P. Tetrahedron 1959, 7, 277–88. (19) Williams, P. P. Acta Crystallogr. 1973, B29, 1572–1579. (20) Williams, P. P. Acta Crystallogr. 1974, B30, 12–17. (21) Platteau, C.; Lefebvre, J.; Hemon, S.; Baehtz, C.; Danede, F.; Prevost, D. Acta Crystallogr. 2005, B61, 80–88.

313

(22) Mesley, R. J.; Clements, R. L. J. Pharm. Pharmacol. 1968, 20, 341– 347. (23) Mesley, R. J. Spectrochim. Acta 1970, 26A, 1427–1448. (24) Kuhnert-Brandstaetter, M.; Bachleitner-Hofmann, F. Arch. Pharm. 1971, 304, 580–590. (25) Nogami, H.; Nagai, T.; Yotsuyanagi, T. Chem. Pharm. Bull. 1969, 17, 499–509. (26) Sekiguchi, K.; Kanke, M.; Nakamamura, N.; Tsuda, Y. Chem. Pharm. Bull. 1975, 26, 1347–1352. (27) Chopra, S. K.; Tawashi, R. Pharm. Ind. 1969, 31, 489–491. (28) Corrigan, O. I.; Sabra, K.; Holohan, E. M. Drug. Dev. Ind. Pharm. 1983, 9, 1–20. (29) Prankerd, R. J.; McKeown, R. H. Int. J. Pharm. 1990, 62, 37–52. (30) Otsuka, K.; Onoe, M.; Matsuda, Y. Drug. Dev. Ind. Pharm. 1994, 20, 1453–1470. (31) Kato, Y.; Watanabe, F. Yakugaki Zasshi 1978, 98, 639–648. (32) Chan, H. K.; Doelker, E. Dev. Ind. Pharm. 1985, 11, 315–332. (33) Kopp, S.; Beyer, C.; Engelbert, G.; Kubel, F.; Doelker, E. J. Pharm. Pharmacol. 1989, 41, 79–82. (34) Kopp, S.; Beyer, C.; Engelbert, G.; Kubel, F.; Doelker, E. Acta Pharm. Technol. 1989, 34, 213–217. (35) Kopp-Kubel, S.; Beyer, S.; Graf, E.; Kubel, F.; Doelker, E. Eur. J. Pharm. Biopharm. 1992, 38, 17–25. (36) Malamataris, S.; Dimitriou, A. J. Pharm. Pharmacol. 1990, 42, 158–163. (37) Otsuka, M.; Nakanishi, M.; Matsuda, Y. Drug. Dev. Ind. Pharm. 1999, 25, 205–215. (38) Zencirci, N.; Gelbrich, T.; Kahlenberg, V.; Griesser, U. J. Cryst Growth Des. 2009, 9, 3444–3456. (39) Zencirci, N.; Griesser, U. J., Gelbrich, T.; Jetti, R. K. R.; Kahlenberg, V.; Apperley, D. C.; Harris, R. K., in preparation. (40) Sheldrick, G. M. Acta Crystallogr. 2008, A64, 112–122. (41) Schulte, K. F. Thesis, Univerity of Innsbruck, 1980, pp 118-123. (42) Kato, Y.; Okamoto, Y.; Nagasawa, S.; Ueki, T. Chem. Pharm. Bull. 1981, 29, 3410–3413. (43) Burger, A.; Ramberger, R. Mikrochim. Acta 1979, II, 259–271. (44) Day, G. M.; Motherwell, W. D. S.; Jones, W. Phys. Chem. Chem. Phys. 2007, 9, 1693–1704. (45) Goenechea, S. Fresenius Z. Anal. Chem. 1966, 218, 416–26. (46) Huang, T. Y. Acta Pharm. Intern. 1951, 2, 317–342. (47) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.-L. Angew. Chem., Int. Ed. 1995, 34, 1555–1573. (48) Allen, F. H. Acta Crystallogr. 2002, B58, 380-388. (49) Craven, B. M.; Vizzini, E. A.; Rodrigues, M. M. Acta Crystallogr. 1969, B25, 1978–1993. (50) Zencirci, N; Griesser, U. J.; Gelbrich, T.; Kahlenberg, V.; Apperley, D. C.; Harris, R. K. J. Pharm. Sci., submitted. (51) Chentli-Benchikha, F.; Declercq, J. P.; Germain, G.; van Meerssche, M.; Bouche, R.; Draguet-Brughmans, M. Acta Crystallogr. 1977, B77, 2739–2743. (52) DesMarteau, D. D.; Pennington, W. T.; Resnati, G. Acta Crystallogr. 1994, C50, 1305. (53) Gelbrich, T.; Zencirci, N.; Griesser, U. J. Acta Crystallogr. 2007, C63, o751–o753. (54) Gelbrich, T.; Hursthouse, M. B. CrystEngComm 2005, 7, 324–336. (55) Long, R. C.; Goldstein, J. H. J. Magn. Reson. 1974, 16, 228–234. (56) Carstensen, J. T.; Franchini, M. K. Drug. Dev. Ind. Pharm. 1995, 21, 523–536. (57) Bauer-Brandl, A.; Marti, E.; Geoffroy, A.; Poso, A.; Suurkuusk, J.; Wappler, E.; Bauer, K. H. J. Therm. Anal. 1999, 57, 7–22. (58) Perlovich, G. L.; Hansen, L. Kr.; Bauer-Brandl, A. J. Pharm. Sci. 2002, 91, 1036–1045. (59) Bernstein, J.; Davey, R. J.; Henck, J. O. Angew. Chem. 1999, 111, 3646–3699. (60) (a) Gelbrich, T.; Hughes, D. S.; Hursthouse, M. B.; Threlfall, T. L. CrystEngComm 2008, 10, 1328–1334. (b) Braun, D. E.; Gelbrich, T.; Kahlenberg, V.; Laus, G.; Wieser, J.; Griesser, U. J. New J. Chem. 2008, 32, 1677–1685. (c) Gelbrich, T.; Hursthouse, M. B. CrystEngComm 2006, 8, 448–460. (d) Florence, A. J.; Bedford, C. T.; Fabbiani, F. P. A; Shankland, K; Gelbrich, T.; Hursthouse, M. B.; Shankland, N.; Johnston, A.; Fernandes, P. CrystEngComm 2008, 10, 811–813. (e) Bond, A. D.; Boese, R.; Desiraju, G. R. Angew. Chem., Int. Ed. 2007, 46, 618–622. (f) Vrcelj, R. M.; Sherwood, J. N.; Kennedy, A. R.; Gallagher, H. G.; Gelbrich, T. Cryst. Growth Des. 2003, 3, 1027–1032.

Structural Features, Phase Relationships and Transformation

Recommend Documents