Pushing the Limits of Molecular Crystal Structure Determination From Powder Diffraction Data in High-Throughput Chemical Environments

Crystal structure determination from powder diffraction data (SDPD) using the DASH software package is evaluated for data recorded using transmission capillary, transmission flat plate, and reflection flat plate geometries on a selection of pharmaceutical compounds. We show that transmission capillary geometry remains the best option when crystal structure determination is the primary consideration and, as expected, reflection flat plate geometry is not recommended for SDPD because of preferred orientation effects. However, the quality of crystal structures obtained from transmission plate instruments can be excellent, and the convenience factor for sample preparation, throughput, and retrieval is higher than that of transmission capillary instruments. Indeed, it is possible to solve crystal structures within an hour of a polycrystalline sample arriving in the laboratory, which has clear implications for making small-molecule crystal structures more routinely available to the practicing laboratory medicinal chemist. With appropriate modifications to crystal structure determination software, it can be imagined that SDPD could become a rapid turn-around walk-up analytical service in high-throughput chemical environments.     

Neotame anhydrate polymorphs. II: Quantitation and relative physical stability

Purpose. To study the relative thermodynamic and kinetic stabilities of neotame anhydrate polymorphs A, D, F, and G, and to develop a quantitative method for analyzing polymorphic mixtures of A and G by powder X-ray diffractometry (PXRD). Methods. Based on the melting points, heats of fusion, and densities of the four polymorphs, thermodynamic rules were applied to study their thermodynamic relationships. The phase transition temperature of Forms A and G was estimated from their heats of solution and intrinsic dissolution rates (J) in 2-propanol. Using PXRD, a method for the quantitative analysis of polymorphic mixtures of Forms A and G was developed. Binary polymorphic mixtures of Forms A, D, F, or G were stored under zero relative humidity at 23 or 70°C, and their compositions were monitored by PXRD. Results. The endothermic enthalpy of solution of A, D, F, and G follows the rank order: G (29.71 ± 0.82 kJ/mol, n = 4) > A (28.48 ± 0.51 kJ/mol, n = 4) > D (20.43 ± 0.45 kJ/mol, n = 4) > F (18.77 ± 0.31 kJ/mol, n = 4). The van't Hoff plots of ln(J) against 1/T for A and G show good linearity between 25°C and 32°C. At 23°C polymorphic mixtures remain unchanged for 4 months. However, at 70°C the phase transition is fast and the relative stability of the four polymorphs follows the rank order: G > D > F and G > A. Conclusions. PXRD provides a reliable and accurate technique for the quantitative analysis of polymorphic mixtures of Forms A and G. Among the four polymorphs, A-G and A-D are enantiotropic pairs, whereas D-F, D-G, F-G are monotropic pairs. The phase transition temperature between A and G lies within the range 35-70°C.     

Crystal structure of L-lysyl-L-glutamic acid dihydrate

L-Lysyl-L-glutamic acid dihydrate, C₁₁N₃O₅H₂₁·2H₂O, crystallizes in the monoclinic space group P2₁ with a = 12.474(2), b = 5.020(1), c = 13.157(2) Å, β= 114.69(1)° and Z = 2. The crystal structure was solved by direct methods and refined to an R value of 0.037 using full matrix least-squares method. The molecule exists as a double zwitterion with both the amino and carboxyl groups ionised. The peptide has a folded conformation with its Lys residue trans and Glu residue gauche^?gauche⁺. The side chains of the Lys and Glu residues correspond to all trans and folded (g^?g^?g^?) conformations respectively. The terminal carboxyl group forms hydrogen bonds with the ξ-amino group of the lysine side chain. The head-to-tail interaction often seen in peptide crystals is absent in the present structure. In the extended crystal structure water molecules form channels along the b direction and are enclosed within helically arranged hydrogen bonds formed by the lysine side chain and the peptide backbone.     

消旋棉酚晶态结构的研究

目的:研究消旋棉酚晶形结构。方法:采用红外光谱(IR)、差示扫描量热法(DSC)、测定溶解度和粉末X射线衍射法(XRD)来研究消旋棉酚晶态结构。结果:消旋棉酚[(±)G]、左旋棉酚[(-)G]和右旋棉酚[(+)G]的红外谱图基本相同;DSC图谱及热特征数据不一致;在消旋棉酚的饱和溶液中加入光学活性棉酚,光学活性棉酚可以继续溶解,并且有旋光产生;(±)G与(-)G及(+)G的XRD图完全不同。结论:消旋棉酚晶体属于外消旋化合物。     

Crystal structure of the low‐humidity form of aspartame sweetener

Abstract: The low‐humidity IB crystal form of aspartame (l ‐α‐aspartyl‐l ‐phenylalanine methyl ester) is prepared via humidity‐induced transition from the highly hydrated IA crystal form and is used widely as a sweetener. The crystal structure of the low‐humidity IB form is determined at 1.05 Å resolution (0.476 Å^?1 in maximum sinθ/λ) from an extremely fine fibrous crystal using synchrotron radiation. There are three aspartame molecules and two water molecules in the asymmetric unit of the monoclinic space group P2₁. Each aspartame molecule adopts an almost identical extended conformation which is commonly observed in other crystal forms of aspartame. Three aspartame molecules are assembled into a triangular trimer, and trimer units are stacked along the b‐axis via hydrogen‐bonding and electrostatic interactions in the main chains and also via hydrophobic contacts in the phenyl side‐chains. Six trimer units are related by pseudo 6₁‐screw axis symmetry and form a hydrophilic channel at their center. The hydrophilic channel in the IB form contains only four water molecules in the unit cell, compared with 16 in the IA form. Although the IB form exhibits a trimer structure similar to that of the IA form, one aspartame molecule is rotated by ≈ 20° from the orientation in the IA form. This arrangement of the molecule implies that the humidity‐induced transition is accompanied by a flapping motion of its methyl ester group. These structural differences may imply the stepwise transition from the IA to the IB forms.     

Crystal structure and conformation of l-pyroglutamyl-l-alanine

Crystals of the dipeptide, pyroglutamyl-alanine (C₈H₁₂N₂O₄) grown from aqueous methanol are monoclin-ic, space group P2₁ with the following cell parameters: a = 4.863(2), b = 16.069(1), c = 6.534(2)Å and β= 109.9(2)°, V = 480.0ų, M_r= 200.2, D_c= 1.385 g cm^?3, and Z = 2. The crystal structure was solved by the application of direct methods and refined to an R value of 0.044 for 699 reflections with I > 2σ. The amide of the pyroglutamyl side chain is cis, ω₁= 2.6(7)°; the peptide unit is trans and appreciably non-planar (ω₂= 167.4(5)°). The backbone torsional angles are: Ψ₁= 166.1(5), φ₂=?90.3(6), and Ψ₂=?22.4(6)°. This structure contains a short (2.551(5)Å) intermolecular hydrogen bond between the carboxyl OH and the N-acyl oxygen, a feature common to most acyl amino acids and acyl peptides.     

Crystal and molecular structure of l-valyl-l-lysine hydrochloride

l -Valyl-l -lysine hydrochloride, C₁₁N₃O₃H₂₃ HCl, crystallizes in the monoclinic space group P2, with a = 5.438(5), b = 14.188(5), c = 9.521(5) Å, β= 95.38(2)° and Z = 2. The crystal structure, solved by direct methods, refined to R = 0.036, using full matrix least-squares method. The peptide exists in a zwitterionic form, with the N atom of the lysine side-chain protonated. The two γ-carbons of the valine side-chain have positional disorder, giving rise to two conformations, χ¹¹₁= -67.3 and 65.9°, one of which (65.9°) is sterically less favourable and has been found to be less popular amongst residues branching at β-C. The lysine side-chain has the geometry of g^? tgt, not seen in crystal structures of the dipeptides reported so far. Interestingly, χ³₂ (63.6°) of lysine side-chain has a gauche⁺ conformation unlike in most of the other structures, where it is trans. The neighbouring peptide molecules are hydrogen bonded in a head-to-tail fashion, a rather uncommon interaction in lysine peptide structures. The structure shows considerable similarity with that of l -Lys-l -Val HO in conformational angles and H-bond interactions [4].     

Crystal structure analysis of a β-turn mimic in hydrazino peptides

The crystal structures of four hydrazino peptides (Piv-Pro-h(N^α-Bzl)Gly-NHiPr 1 , Piv-Pro-hAla-NHiPr 2 , Moc-hPro-NHiPr 3 , and Boc-hPro-Gly-N(OH)Me 4 ) deriving from the hydrazino analogues of glycine (hGly), l -alanine (hAla) or l -proline (hPro) have been solved. They reveal a common folded structure of the α-hydrazino acid residue characterized by a bifurcated hydrogen bond closing an eight-membered cycle. This folded structure is topologically similar to the βII′-turn in peptides, and the CO-NH-N hydrazide link can be considered as a good turn-inducer in peptide analogues.     

Synthesis,Characterization, and Crystal Chemistry of Tasimelteon,a Melatonin Agonist,in Its Anhydrous and Hemihydrate Forms

Two crystalline forms of tasimelteon, a drug approved by the U.S. Food and Drug Administration for the treatment of non-24-h sleep-wake disorder, have been studied by single crystal and powder diffraction analyses, thermogravimetric analysis, differential scanning calorimetry, spectroscopic, and optical methods. The synthetic method forming tasimelteon is described in detail, with its full analytical, spectroscopic, and enantiopurity characterization. Solid tasimelteon hemihydrate, C₁₅H₁₉NO₂·0.5H₂O, is tetragonal with a = b = 7.3573(2) Å, c = 52.062(2) Å, V = 2818.1(2) ų; Z = 8. Its crystal structure has been solved and refined in the P4₃2₁2 space group, showing the occurrence of polymeric (H-bonded) slabs, thanks to the presence of water molecule (O_W) tetrahedrally linked to 4 distinct tasimelteon molecules in a N₂(O_W)O₂ fashion. The anhydrous form of tasimelteon, C₁₅H₁₉NO₂, crystallizes in the monoclinic P2₁ space group, with a = 11.130(4), b = 4.907(2), c = 12.230(6) Å, β = 91.03(3)°, V = 667.8(5) ų; Z = 2. Thanks to the availability of good-quality specimens, the structure of the latter phase was solved by conventional single-crystal diffraction analysis, showing short intermolecular C=O^…H–N interactions between (translationally related) tasimelteon molecules, forming, in the crystal, well-defined chains running along the b axis. The morphology of the 2 crystal forms has been analyzed by the means of optical microscopy and particle size distribution analysis. Worthy of note, the newly determined crystal structures enable the successful usage of full-pattern matching X-ray-based quantitative analyses of batches of industrial interest, in search for contamination or phase stability issues.     

Crystal and molecular structure of cyclo(L-prolyl-glycyl)3

The crystal structure of cyclo(L-Pro-Gly)₃ was solved using X-ray crystallographic techniques. The backbone of the peptide is asymmetric and is made up of five trans peptide units and one cis peptide. There is a hydrogen bonded water bridge that links the carbonyl oxygens, O1 and O4. The molecules exist as dimers in the crystal lattice. The two molecules of the dimer are related by crystallographic twofold symmetry and are linked by two N-H O hydrogen bonds. The crystals are trigonal, space group P3₂12 with a = 11.379(3), c = 32.93(1) and z = 6. The structure was solved by multisolution methods and refined by least squares technique to an R of 0.083.     

Crystal and molecular structure of N-α-acetyl-L-arginine-methyl ester hydrochloride

The crystal structure of N-α-acetyl-L-arginine-methyl ester hydrochloride has been determined from X-ray diffraction data. The crystals are orthorhombic, space group P2₁2₁2₁, a = 15.746 (4), b = 11.569 (4), c = 7.158 (3) Å, Z = 4. The structure was solved by direct methods (MULTAN) and refined by fullmatrix least-squares to an R = 0.070 for all observed reflections. The molecule shows a planar peptidic unit, with a distortion of H(N1) due to hydrogen bond interaction. The side chain is in the low energy all-trans conformation. The guanidinium group forms three hydrogen bonds with the carbonyl oxygens of two neighbouring molecules. A direct interaction of the peptidic NH with the chloride ions is observed. The latter ions also interact with the guanidinium groups, neutralizing their charges.     

Fourth polymorph of [Phe 4 Val 6] antamanide (pentahydrate)

The cyclic decapeptide antamanide and the synthetic, biologically active analog [Phe⁴ Val⁶] antamanide (cyclic[ValProProPhePhe]₂) crystallize in various crystal forms as a function of the solvent. The present crystalline polymorph obtained from acetone/water (also from ethanol/water and DMSO/water) crystallizes in space group P2₁2₁2₁ with a = 20.194 (30) Å, b = 21.118 (31) Å, c = 16.132 (25) Å and four molecules of peptide in the unit cell. There are five cocrystallized water molecules per peptide molecule, of which four water molecules are intrinsic to the peptide molecule. Although the molecular packing is entirely different in each of the polymorphs, the conformation of the peptide molecule, including the intrinsic water molecules, is very similar in all the polymorphs.     

Crystal structure and molecular conformation of achatin-I (H-Gly-d-Phe-Ala-Asp-OH), an endogenous neuropeptide containing a d-amino acid residue

In order to investigate the active conformation of achatin-I (H-Gly-d -Phe-Ala-Asp-OH), an endogenous neuropeptide from the Achatina fulica ganglia, its crystal structure and molecular conformation were analysed by the X-ray diffraction method. Crystals from methanol/dioxane are monoclinic, space group P2₁ with a=5.083(1), b= 9.125(1), c= 20.939(3) Å, β=94.73(1)° The structure was solved by direct methods and refined to R = 0.051 for 1714 independent reflections with Fo > σ(Fo). The molecule exists as a zwitterion with the Gly N-terminal end protonated and Asp β-carboxyl deprotonated; the C-terminal of Asp is in a neutral state. The molecule takes a kind of β turn structure with the d -Phe-Ala residues at the corner of the bend. This turn conformation is primarily formed by the strong intramolecular hydrogen bonds of NH(Gly)—O^δ1 (Asp) and NH(Asp)- O^δ1(Asp) pairs, thus forming a 15-membered ring structure. Judging from the published data concerning the structure-activity relationship, this turn conformation may reflect an important feature related to the neuroexcitatory activity of achatin-I.     

New Polymorph Form of Dexamethasone Acetate

A new monohydrated polymorph of dexamethasone acetate was crystallized and its crystal structure characterized. The different analytical techniques used for describing its structural and vibrational properties were: single crystal and polycrystal X-ray diffraction, solid state nuclear magnetic resonance, infrared spectroscopy. A Hirshfeld surface analysis was carried out through self-arrangement cemented by H-bonds observed in this new polymorph. This new polymorph form appeared because of self-arrangement via classical hydrogen bonds around the water molecule.     

Characteristic molecular packing in the crystal structure of tert-butoxycarbonyl-L-phenylalanyl-L-methionine methyl ester

The molecular conformation and association of the peptide Boc-L-Phe-L-Met-OMe have been studied in the solid state by X-ray diffraction. The peptide crystallizes in the orthorhombic system, space group P2₁2₁2₁, with cell parameters of a= 9.821(2), b= 25.394(6), c= 28.714(8) ų, V= 7161(3) ų. The structure has been solved by direct methods and refined to a final R of 0.079 for 5464 independent reflections with F_o≥σ(F_o). The crystal consists of three independent molecular conformations per asymmetric unit. Respective peptide backbones adopt an extended conformation with the side-chains of Phe and Met residues being arranged below and above the backbone chains. Contrary to the sheet structure most frequently observed in the crystal packing of the extended peptide conformations, three independent molecules lie spirally along the c-axis and form a pin-wheel-like crystal packing. The sheet structures formed by two of three independent molecules are almost at right angles to the backbone of the remaining molecule. This molecular packing mode would provide a possible interaction model between the intersecting β-sheet structure and single-strand structure of polypeptide. © Munksgaard 1994.     

Crystal structure of l-2-oxothiazolidine-4-carboxylic acid

Crystals of the title compound, l -2-oxothiazolidine-4-carboxylic acid, OTC (C₄ H₅ NO₃ S), grown from an aqueous solution are orthorhombic, space group P2₁ 2₁ 2₁ with the following cell parameters at 22 ± 3°; a = 5.381(1), b = 5.961(1), c = 17.929(3)Å V = 575.lų M_r= 146.2, D_c= 1.688 g.cm^?3, μ 43.9cm^?1 and Z = 4. The crystal structure was solved by the application of direct methods and refined to an R value of 0.032 for 596 reflections with I > 3σ(I). The thiazolidine ring adopts a “twist” conformation. This structure contains a short (2.619(3)Å) intermolecular hydrogen bond between the carboxyl OH and the oxygen of the 2-oxo moiety, a feature common to most acyl amino acids and acyl peptides.     

A new polymorph of isoimperatorin

Abstract

Isoimperatorin is a naturally occurring furocoumarin and is being considered as a potential chemoprevention. Only one crystal form of isoimperatorin (Form I) was reported during previous research so that an investigation of polymorphism of isoimperatorin was successfully undertaken. A new polymorph of isoimperatorin was discovered through comprehensive polymorph screening experiments. Their structures were elucidated by single-crystal structure analysis and extensively characterized by XRPD, DSC, FT-IR, and SEM. The results showed that the crystal structure and thermal properties of the new polymorph (Form II) were significantly different from those of Form I. Thermodynamic stability and phase transformation were also discussed in detail.     

Crystal and molecular structure of L-lysyl-L-valine hydrochloride – a new lysine conformation

Thin plates of L-lysyl-L-valine hydrochloride (C₁₁H₂₄N₃O₃Cl) were obtained using the vapour diffusion technique and analysed by X-ray diffraction. The unit cell is orthorhombic, space group P2₁2₁2₁, a = 5.465(6)Å, b = 19.657(4) Å, c = 13.522(2) Å, V = 1452.6(2.1) ų and Z = 4. The structure was solved by direct methods and refined to an agreement factor of 6.7% for 939 reflections with I > 3 σ(I). The lysine side chain conformation (g^- g^- tt) has never been found in peptide crystal structures, although it has been reported to occur in proteins. A network of hydrogen bonds between peptide molecules spreads along the a and c directions while no direct bonds are observed to occur between peptides along the b axis direction. This asymmetric pattern of interactions correlates with the crystal morphology.     

磷霉素钙的晶型稳定性研究

目的 对磷霉素钙晶型稳定性进行研究。方法 将磷霉素钙分别置于对应环境中,制备样品后进行粉末X射线衍射（powder X-ray diffraction,PXRD）、差示扫描量热法分析（differential scanning calorimetry,DSC）、电镜扫描（scanning electron microscopy,SEM）以及热解重量分析（thermogravimetric analysis,TGA）,对磷霉素钙晶型进行表征。结果 磷霉素钙存在结晶型和无定型2种晶型,结晶型磷霉素钙在相对湿度（relative humidity,RH）92.5%放置30 d、150℃以下加热2 h,晶型稳定。结论 结晶型磷霉素钙原料晶型稳定,与参比制剂一致,可以满足湿法制粒、流化床制粒对湿度和温度的要求,在一致性评价中,应当选择结晶型磷霉素钙作为制剂原料。     

Crystal and molecular structure of Destruxin B

The cyclic hexadepsipeptide mycotoxin Destruxin B. produced by Metarrhizium anisopliae. crystallizes in the orthorhombic space group P2₁2₁2₁, with a = 11.010(2)Å, b = 14.679(5)Å, c = 21.273(7)Å and Z = 4. The structure was solved by direct methods and refined by least-squares technique to a final unweighted R value of 0.051, for 3361 reflections with I > 3σ(I). The backbone of the peptide is asymmetric and is made of 5 trans peptide and ester units and 1 cis peptide unit. The backbone conformation of this cyclic depsipeptide is very similar to that of Roseotoxin B, an analogous mycotoxin produced by Trichothecium roseum. The conformation in the crystalline state also correlates well with the solution conformation, as reported from proton n.m.r. studies. The crystal packing is directed by van der Waals contacts.