Pressure-temperature state diagram for the phase relationships between benfluorex hydrochloride forms I and II: a case of enantiotropic behavior.

The active pharmaceutical ingredient racemic benfluorex hydrochloride (benfluorex-HCl) has an interesting phase behavior due to an elusive solid-solid phase transition. The stability hierarchy between different phases is often determined based on heat-related experiments only or slurry interconversion. It is shown that if pressure and volume are taken into account, not only the phase equilibria are correctly positioned in the pressure-temperature phase diagram, but the experimental data also improves. Thus, it has been found that the racemic benfluorex-HCl is enantiotropic under "ordinary conditions" with polymorph II and polymorph I, respectively, being the low- and the high-temperature phases. Above ∼ 151 MPa, the system becomes monotropic and polymorph II is the single stable phase.

Structural and energetic aspects of a new bupropion hydrochloride polymorph.

Crystalline bupropion hydrochloride [(±)1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride], recently characterized as form 1, was found to undergo, upon storage at RT within months, a solid-solid conversion to a new polymorphic form, hereafter named form 2, containing a markedly different molecular conformer in the solid state. This new form, available only as a polycrystalline material, has been fully characterized using structural X-ray powder diffraction methods, coupled to thermoanalytical analyses. The relative stability of the two crystalline phases (forms 1 and 2) was compared by quantum mechanics calculations including density functional methods specific for solid state molecular systems. Bupropion hydrochloride form 2 crystallizes in the orthorhombic space group Pbca with Z=8, a=27.2853(5)Å, b=8.7184(3)Å, c=12.0422(3)Å, V=2864.7(1)ų, as centrosymmetric dimers, thanks to the presence of N-H…Cl interactions, and µ2-bridging chloride ions, each connected to two protonated amine moieties.

Calcium acamprosate: a triclinic polymorph.

The title compound, poly[bis-(µ(3)-4-acetamido-propane-sulfon-ato)-calcium], [Ca(C(5)H(10)NO(4)S)(2)](n), is a triclinic polymorph of the previously reported monoclinic structure [Toffoli et al. (1988 ▶). Acta Cryst. C44, 1493-1494]. The triclinic modification was found to have an all-trans configuration of the acetamido-propane chain, in contrast with the monoclinic polymorph which shows an angle of 74.66 (8)° between the S-C-C-C chain plane and that of the amide group. The Ca(2+) cation is situated on an inversion centre and is hexa-coordinated by six O atoms belonging to different anions in a distorted octa-hedral geometry. This arrangement leads to a layered structure parallel to (011). The layers are held together by N-H⋯O hydrogen bonds and by short C-H⋯O inter-actions, both involving the sulfonate O atoms not coordinated to the Ca(2+) cations. The structure was determined from a crystal twinned by non-merohedry [twin law ([Formula: see text]00, 0[Formula: see text]0, -0.335 -0.85 1), with a fractional contribution of the minor twin domain of 46.7 (1)%].

Clostebol acetate.

The title compound, C(21)H(29)ClO(3) [systematic name (8R,9S,10R,13S,14S,17S)-4-chloro-3-oxoandrost-4-en-17ß-yl acetate], is a 4-chloro derivative of testosterone, used as an anabolic androgenic agent or applied topically in ophthalmological and dermatological treatments. The absolute configurations at positions 8, 9, 10, 13, 14 and 17 were established by refinement of the Flack parameter as R, S, R, S, S, and S, respectively. Rings B and C of the steroid ring system adopt chair conformations, ring A has a half-chair conformation, while ring D is in a C(13) envelope conformation. Ring B and C, and C and D are trans fused. In the crystal, molecules are linked by a weak C-H⋯O interaction.

Thermal and X-ray powder diffraction structural characterization of two benfluorex hydrochloride polymorphs.

Two polymorphic forms of benfluorex hydrochloride, phases I and II, were isolated as monophasic polycrystalline samples, and structurally characterized using ab initio X-ray powder diffraction methods and a global optimization strategy (simulated annealing). Form I crystallizes in monoclinic system, space group P2(1)/n, with Z=4, a=21.0719(10)A, b=7.0563(4)A, c=14.8684(7)A, beta=116.998(3) degrees , V=1969.8(2)A(3), while Form II crystallizes in the orthorhombic space group Pbca, with Z=8, a=33.8031(2)A, b=15.1451(8)A, c=7.6138(6)A, V=3897.9(4)A(3). Crystals of Form I and Form II of benfluorex hydrochloride are based upon an ionic packing of protonated benfluorex molecules at the most basic site, the N1 atoms, and chloride anions. Form I shows the presence of mu-Cl ions, generating centrosymmetric dimers with a N(2)Cl(2) moiety, while Form II contains antiparallel chains of C-H...O hydrogen-bonded molecules running along c axis. DSC and thermodiffractometric measurements showed that heating progressively Form II from ambient temperature to 160 degrees C causes a phase transition to the thermodynamically stable Form I, immediately followed by the sample melting, near 165 degrees C. Recrystallization directly to Form I is observed when the melt is cooled back to ambient temperature, with a significant hysteresis (this event being centered near 130 degrees C).

Trihexyphenidyl hydro-chloride: a powder diffraction study.

IN THE CATION OF THE TITLE COMPOUND [SYSTEMATIC NAME: 1-(3-cyclo-hexyl-3-hy-droxy-3-phenyl-prop-yl)piperidinium chloride], C(20)H(32)NO(+)·Cl(-), the cyclo-hexyl and piperidine rings are in chair conformations. In the crystal structure, cations and anions are linked into chains along the c-axis direction via O-H⋯Cl and N-H⋯Cl hydrogen bonds. Weak inter-molecular C-H⋯Cl inter-actions link further these chains into layers parallel to the bc plane. The salt, obtained from a racemic solution, was found to crystallize in the chiral P2(1)2(1)2 space group, indicating that, in the absence of any evident chirality-inducing process, the polycrystalline powders consist of an equivalent mixture of R and S enanti-omers, forming a racemic conglomerate.

Structures from powders: bupropion hydrochloride.

The crystal structure of bupropion hydrochloride, 1, was fully characterized from powdered crystalline samples, using the ab-initio XRPD technique and a global optimization strategy (simulated annealing), adopting, as starting model, the already known molecular structure of its ethanol solvate, 2. Bupropion hydrochloride crystallizes as a racemate in monoclinic system, space group P2(1)/c with Z=4, a=14.3406(3)A, b=8.7564(2)A, c=11.8801(2)A, beta=78.025(2) degrees , V=1459.34(5)A(3). In the crystals of 1 the molecules interact via strong NH[...]Cl contacts, generating dimeric entities with mu-Cl ions. Further stabilizing contacts, of the CH[...]O are at work, but differently organized in the 1 and 2 phases. The thermal behaviour of the product was assessed by differential scanning calorimetry.

Structures from powders: diflorasone diacetate.

Diflorasone diacetate, a steroid anti-inflammatory drug (marketed as Diacort or Florone by Pfizer) and used in the treatment of skin disorders, can be prepared as anhydrous form, DD1 (as deposited in the US pharmacopoeia), or as a monohydrated phase, DDW. Heating the DDW form above 90 degrees C, a mixture of DD1 and of a new anhydrous polymorph, DD2 is obtained. Further heating of this mixture, or of pure DD1, up to 230 degrees C (only a few degrees before melting!), generates an elusive anhydrous DD3 polymorph. Their crystal structures, determined uniquely from laboratory powder diffraction data, show the isomorphous character of the DDW and DD1 forms, while the DD2 and DD3 polymorphs crystallize with markedly different unit cells. Crystals of the DD1, DD2 and DDW forms are orthorhombic, P2(1)2(1)2(1), a=29.386(1)A; b=10.4310(9)A, c=8.1422(7)A, V=2495.8(3)A(3) for DD1; a=15.2639(10)A; b=11.7506(7)A, c=13.8931(11)A, V=2491.9(3)A(3) for DD2; a=30.311(2)A; b=10.6150(9)A, c=7.9337(7)A, V=2552.7(4)A(3) for DDW; while the lattice parameters for the monoclinic P2(1)DD3 species are a=11.5276(10)A; b=13.8135(11)A, c=7.8973(7)A, beta=103.053(6) degrees , V=1225.0(2)A(3). These compounds have also been fully characterized by thermo analytical methods, as well by (13)C, (19)F, and (1)H NMR spectroscopy.

Crystal chemistry of sibutramine: thermal, diffractometric and spectroscopic characterization.

Monohydrated sibutramine hydrochloride is a widely used active ingredient for the treatment of obesity. An anhydrous form of sibutramine hydrochloride was prepared starting from its monohydrate form upon heating it at 140 degrees C for 15 min. This dehydration process was monitored using conventional TG/DSC methods. Heated above 190 degrees C, sibutramine hydrochloride sublimes and recrystallizes on the cold walls of the test tube, giving platelet shaped crystals suitable for single crystal X-ray diffraction analysis: monoclinic, P2(1)/n, a = 7.321(2) A, b = 25.456(5) A, c = 9.750(3) A, beta = 101.60(2) degrees , V = 1779.9(8) A(3), Z = 4. At variance, sibutramine free base was typically recovered as a viscous oily material, upon treatment of its hydrochloride salt in ethyl acetate solution. Recrystallization from hexane yielded a white polycrystalline powder, the structure of which was determined by unconventional ab initio X-ray powder diffraction analysis: triclinic, P-1, a = 8.6578(3) A, b = 9.3318(3) A, c = 11.1224(4) A, alpha = 110.434(3) degrees , beta = 100.159(3) degrees , gamma = 89.201(2) degrees , V = 827.76(5) A(3), Z = 2. Sibutramine, in its different crystalline environments, was also fully characterized by solid state (13)C NMR analyses. Additional spectral information was obtained by collecting spectra of a metastable, oily sample, before it slowly recrystallizes (within hours).

Polymorphism of linezolid: a combined single-crystal, powder diffraction and NMR study.

Linezolid (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide is one of the first commercially available (and most widely used) oxazolidinone antibiotics. It was selectively prepared as two anhydrous polymorphic forms, labelled form II and IV in accordance with preliminary reports in the patent literature. Form II has been characterized by single-crystal X-ray diffraction methods (orthorhombic, P2 1 2 1 2 1, a=6.536(1), b=9.949(1), c=24.807(3)A, V=1613.1(3)A3, Z=4, Z'=1), while powders of form IV could be fully characterized by employing ab initio powder diffraction methods (triclinic, P1, a=6.5952(7)A, b=10.9875(10)A, c=12.9189(14)A, alpha=110.683(4) degrees , beta=88.186(6) degrees , gamma=105.826(6) degrees , V=840.5(2)A(3), Z=Z'=2). The interconversion of form II into form IV was studied by TG, DSC and thermodiffractometry, which indicated a quantitative (endothermic and irreversible) transformation (in air) just above 160 degrees C. On cooling from the melt, linezolid gives an oily material, stable at RT, which can be crystallized into form IV by controlled heating near 100 degrees C. These materials were further characterized by high-resolution 1H and 13C NMR studies, as well as by 13C solid-state NMR.