Conformational Polymorphs Research Articles

Contrasting conformational behaviors of molecules XXXI and XXXII in the seventh blind test of crystal structure prediction.

Accurate modeling of conformational energies is key to the crystal structure prediction of conformational polymorphs. Focusing on molecules XXXI and XXXII from the seventh blind test of crystal structure prediction, this study employs various electronic structure methods up to the level of domain-local pair natural orbital coupled cluster singles and doubles with perturbative triples [DLPNO-CCSD(T1)] to benchmark the conformational energies and to assess their impact on the crystal energy landscapes. Molecule XXXI proves to be a relatively straightforward case, with the conformational energies from generalized gradient approximation (GGA) functional B86bPBE-XDM changing only modestly when using more advanced density functionals such as PBE0-D4, ωB97M-V, and revDSD-PBEP86-D4, dispersion-corrected second-order Møller-Plesset perturbation theory (SCS-MP2D), or DLPNO-CCSD(T1). In contrast, the conformational energies of molecule XXXII prove difficult to determine reliably, and variations in the computed conformational energies appreciably impact the crystal energy landscape. Even high-level methods such as revDSD-PBEP86-D4 and SCS-MP2D exhibit significant disagreements with the DLPNO-CCSD(T1) benchmarks for molecule XXXII, highlighting the difficulty of predicting conformational energies for complex, drug-like molecules. The best-converged predicted crystal energy landscape obtained here for molecule XXXII disagrees significantly with what has been inferred about the solid-form landscape experimentally. The identified limitations of the calculations are probably insufficient to account for the discrepancies between theory and experiment on molecule XXXII, and further investigation of the experimental solid-form landscape would be valuable. Finally, assessment of several semi-empirical methods finds r2SCAN-3c to be the most promising, with conformational energy accuracy intermediate between the GGA and hybrid functionals and a low computational cost.

Study on Several Novel Crystalline Complexes of Sorafenib with Dicarboxylic Acid: Nature Identification and Solubilization Mechanism

The development of solid-state forms of drugs is an effective approach to increase solubility. This study developed three crystalline complexes of sorafenib (SF) with oxalic acid (OA) and malonic acid (MA) using a solvent method, named SF+·OA-·THF, SF+·OA-, and SF-MA. The formation of these complexes was influenced by the crystalline method, solvent polarity, and the carbon chain length of the dicarboxylic acids. Single-crystal X-ray diffraction revealed proton transfer in SF+·OA-·THF, classifying it as a channel-type salt solvate and conformational polymorph due to hydrogen bond formation. 13C solid-state nuclear magnetic resonance and X-ray photoelectron spectroscopy confirmed proton transfer in SF+·OA-·THF and SF+·OA-, but not in SF-MA, indicating that SF+·OA- is a salt while SF-MA is a co-crystal. Fourier Transform Infrared Spectroscopy further supported these findings. Compared with Form Ⅰ, SF+·OA-, SF+·OA-·THF, and SF-MA increased the apparent solubility of SF by 8.3, 7.9, and 6.4 times in pH 1.2 HCl buffer, and by 4.0, 3.1, and 4.5 times in pH 6.8 PBS buffer, respectively. All crystalline complexes exhibited a “spring and parachute” phenomenon due to the solubility difference between the drug and the dicarboxylic acids. Notably, the intermolecular forces between SF and THF in SF+·OA-·THF prolonged the “spring and parachute” process. Additionally, these crystalline complexes demonstrated good stability. This study provides valuable insights into the development and identification of crystalline complexes and their dissolution mechanisms.

Conformational polymorphs of the homoleptic scorpionate sandwich complex [(TpPh,Me)2Ni], TpPh,Me=hydrotris(3-phenyl-5-methylpyrazol-1-yl)borate: Ligand substituent effects include intramolecular non-covalent interactions

The homoleptic scorpionate sandwich complex [(TpPh,Me)2Ni] (1), where TpPh,Me = hydrotris(3-phenyl-5-methylpyrazol-1-yl)borate, crystallizes as a mixture of two polymorphs. A major monoclinic fraction crystallizes as well-formed parallelepipeds and a minor triclinic fraction forms irregularly shaped, anhedral crystals. These exhibit distinct melting points (288 and 294 °C, respectively) as observed by differential scanning calorimetry. We obtained X-ray crystal structures of both polymorphs at 100 K. The complex adopts different conformations between the two lattices. These are supported by distinctive ensembles of intramolecular non-covalent interactions, specifically π-stacking and perpendicular C–H···π contacts between opposing 3-phenylpyrazolyl arms on the co-ligands. The conformation found in the major monoclinic polymorph consists of a counter-rotation of the ligands that reduces the ideal complex symmetry from D3d to D3 and results in three-fold pair-wise association of 3-phenylpyrazolyl arms. In contrast, an alternate conformation of 1 in the minor triclinic polymorph consists of two triads, with an ideal complex symmetry of C2h. Also affected are the tetragonality of the ligand fields and interligand N–Ni–N′ bond angles. A review of sandwich complex structures [(TpR)2M], where R is an aromatic substituent, shows these conformations are adopted broadly. Hence, substituent effects in second-generation scorpionate ligands are not merely steric in origin.

Pushing Technique Boundaries to Probe Conformational Polymorphism.

We present an extensive exploration of the solid-form landscape of chlorpropamide (CPA) using a combined experimental-computational approach at the frontiers of both fields. We have obtained new conformational polymorphs of CPA, placing them into context with known forms using flexible-molecule crystal structure prediction. We highlight the formation of a new polymorph (ζ-CPA) via spray-drying experiments despite its notable metastability (14 kJ/mol) relative to the thermodynamic α-form, and we identify and resolve the ball-milled η-form isolated in 2019. Additionally, we employ impurity- and gel-assisted crystallization to control polymorphism and the formation of novel multicomponent forms. We, thus, demonstrate the power of this collaborative screening approach to observe, rationalize, and control the formation of new metastable forms.

Ab Initio Crystal Structure Prediction of the Energetic Materials LLM-105, RDX, and HMX.

Crystal structure prediction (CSP) is performed for the energetic materials (EMs) LLM-105 and α-RDX, as well as the α and β conformational polymorphs of 1,3,5,7-tetranitro-1,3,5,7-tetraazacyclooctane (HMX), using the genetic algorithm (GA) code, GAtor, and its associated random structure generator, Genarris. Genarris and GAtor successfully generate the experimental structures of all targets. GAtor's symmetric crossover scheme, where the space group symmetries of parent structures are treated as genes inherited by offspring, is found to be particularly effective. However, conducting several GA runs with different settings is still important for achieving diverse samplings of the potential energy surface. For LLM-105 and α-RDX, the experimental structure is ranked as the most stable, with all of the dispersion-inclusive density functional theory (DFT) methods used here. For HMX, the α form was persistently ranked as more stable than the β form, in contrast to experimental observations, even when correcting for vibrational contributions and thermal expansion. This may be attributed to insufficient accuracy of dispersion-inclusive DFT methods or to kinetic effects not considered here. In general, the ranking of some putative structures is found to be sensitive to the choice of the DFT functional and the dispersion method. For LLM-105, GAtor generates a putative structure with a layered packing motif, which is desirable thanks to its correlation with low sensitivity. Our results demonstrate that CSP is a useful tool for studying the ubiquitous polymorphism of EMs and shows promise of becoming an integral part of the EM development pipeline.

Conformational polymorphism of 3-(azidomethyl)benzoic acid

Three conformational polymorphs of 3-(azidomethyl)benzoic acid, C8H7N3O2, are reported. All three structures maintain similar carboxylic acid dimers and π–π stacking. Crystal structure analysis and computational evaluations highlight the azidomethyl group as a source of conformational polymorphism, thus having potential implications in the design of solid-state reactions.

High-pressure conformational and crystal polymorphs in 1-hexyl-3-methylimidazolium perfluorobutanesulfonate ionic liquid

An ionic liquid (IL) with conformational polymorphs indicated complicated phase transitions under high pressure (HP). The IL was 1-hexyl-3-methylimidazolium perfluorobutanesulfonate ([C6mim][PFBS]), which has cationic and anionic conformational degrees of freedom. Using HP Raman spectroscopy, a competition between cation and anion conformers corresponded to the HP crystal polymorph. The folding cation appeared at 3.7 GPa due to its flexibility. The rigid [PFBS]− anion also formed the gauche‘ conformer at 7.6 GPa for higher packing efficiency. The conformational flexibility was adjusted depending on pressure. The pressure-variant/invariant conformations were connected with the HP crystal polymorph of [C6mim][PFBS].

Copper(II) halide complexes of aminopyridines: Synthesis, structure, and magnetic behavior of neutral compounds of 5-IAP: (5-IAP)2CuCl2·H2O, [(5-IAP)2CuBr2]2, (5-IAP)2CuBr2 and (5-IAP)3CuCl2·nH2O (5IAP = 2-amino-5-iodopyridine)

Reaction of 2-amino-5-iodopyridine (5IAP) with copper(II) bromide or chloride in alcoholic solution led to four coordination complexes: [(5-IAP)2CuCl2](H2O) (1), (5-IAP)2CuBr2 (2), [(5-IAP)2CuBr2]2 (3) and [(5-IAP)3CuCl2](H2O)n (4). The compounds were characterized by single crystal X-ray diffraction and variable temperature magnetic susceptibility measurements. 1 crystallizes as monomeric units with the 5IAP ligands in the syn-conformation and one lattice water molecule. 2 also exhibits syn-conformation 5IAP ligands, but forms a common bromide bibridged dimer structure. 3 is a conformational polymorph of 2 with anti-oriented 5IAP ligands. Long Cu⋯Br contacts link the molecules into chains. 4 crystallizes with 1.67 lattice water molecules, disordered over three positions. All four compounds exhibit strong halogen bonding. Variable field and temperature magnetic data were obtained on 1–3. 1 is paramagnetic, with no indication of magnetic exchange down to 1.8 K. 2 is well modeled as an antiferromagnetic dimer (J/kB = −22 K) with significant antiferromagnetic interactions between the dimers. 3 is well modeled as a uniform antiferromagnetic chain (J/kB = −6 K) with weak interchain interactions.

Application of the method for visualization of noncovalent interactions in conformational polymorphs of four organic acids.

A method for the visualization of noncovalent interactions using examples of the conformational polymorphs of four organic compounds: 2-(phenylamino)nicotinic, 2-(3-chloro-2-methylphenylamino)nicotinic, N-(3-chloro-2-methylphenyl)anthranilic and 2-(methylphenylamino)nicotinic acids is examined. The changes in noncovalent contacts are plotted against the angle between the planes of aromatic rings allowing a visual representation of conformational adjustment of molecules as well as packing features of crystal structures. According to the k-Φ criterion, the studied structures represent conformational polymorphs. Different types of hydrogen bonding are discussed within the framework of the method of visualization and molecular Voronoi-Dirichlet polyhedra. Good correlations are found between calculated and experimental data for several cases, such as the agreement between π stacking and polymorphic transition temperatures as well as between the area of a contact and the energy of conjugation. Also, an attempt has been made to assess the relative contributions of conformational and packing polymorphism in the formation of polymorphs.

Investigation of the Spatial Structure of Flufenamic Acid in Supercritical Carbon Dioxide Media via 2D NOESY

The search for new forms of already known drug compounds is an urgent problem of high relevance as more potent drugs with fewer side effects are needed. The trifluoromethyl group in flufenamic acid renders its chemical structure differently from other fenamates. This modification is responsible for a large number of conformational polymorphs. Therefore, flufenamic acid is a promising structural modification of well-known drug molecules. An effective approach in this field is micronization, employing "green" supercritical fluid technologies. This research raises some key questions to be answered on how to control polymorphic forms during the micronization of drug compounds. The results presented in this work demonstrate the ability of two-dimensional nuclear Overhauser effect spectroscopy to determine conformational preferences of small molecular weight drug compounds in solutions and fluids, which can be used to predict the polymorphic form during the micronization. Quantitative analysis was carried out to identify the conformational preferences of flufenamic acid molecules in dimethyl sulfoxide-d6 medium at 25 °C and 0.1 MPa, and in mixed solvent medium containing supercritical carbon dioxide at 45 °C and 9 MPa. The data presented allows predictions of the flufenamic acid conformational preferences of poorly soluble drug compounds to obtain new micronized forms.

Axial vs equatorial: Capturing the intramolecular charge transfer state geometry in conformational polymorphic crystals of a donor-bridge-acceptor dyad in nanosecond-time-scale.

Two conformational polymorphs of a donor-bridge-acceptor (D-B-A) dyad, p-(CH3)2N-C6H4-(CH2)2-(1-pyrenyl)/PyCHDMA, were studied, where the electron donor (D) moiety p-(CH3)2N-C6H4/DMA is connected through a bridging group (B), -CH2-CH2-, to the electron acceptor (A) moiety pyrene. Though molecular dyads like PyCHDMA have the potential to change solar energy into electrical current through the process of photoinduced intramolecular charge transfer (ICT), the major challenge is the real-time investigation of the photoinduced ICT process in crystals, necessary to design solid-state optoelectronic materials. The time-correlated single photon counting (TCSPC) measurements with the single crystals showed that the ICT state lifetime of the thermodynamic form, PyCHDMA1 (pyrene and DMA: axial), is ∼3ns, whereas, for the kinetic form, PyCHDMA20 (pyrene and DMA: equatorial), it is ∼7ns, while photoexcited with 375nm radiation. The polymorphic crystals were photo-excited and subsequently probed with a pink Laue x-ray beam in time-resolved x-ray diffraction (TRXRD) measurements. The TRXRD results suggest that in the ICT state, due to electron transfer from the tertiary N-atom in DMA moiety to the bridging group and pyrene moiety, a decreased repulsion between the lone-pair and the bond-pair at N-atom induces planarity in the C-N-(CH3)2 moiety, in both polymorphs. The Natural Bond Orbital calculations and partial atomic charge analysis by Hirshfeld partitioning also corroborated the same. Although the interfragment charge transfer (IFCT) analysis using the TDDFT results showed that for the charge transfer excitation in both conformers, the electrons were transferred from the DMA moiety to mostly the pyrene moiety, the bridging group has little role to play in that.

Collective Variables for Conformational Polymorphism in Molecular Crystals.

Controlling polymorphism in molecular crystals is crucial in the pharmaceutical, dye, and pesticide industries. However, its theoretical description is extremely challenging, due to the associated long time scales (>1 μs). We present an efficient procedure for identifying collective variables that promote transitions between conformational polymorphs in molecular dynamics simulations. It involves applying a simple dimensionality reduction algorithm to data from short (∼ps) simulations of the isolated conformers that correspond to each polymorph. We demonstrate the utility of our method in the challenging case of the important energetic material, CL-20, which has three anhydrous conformational polymorphs at ambient pressure. Using these collective variables in Metadynamics simulations, we observe transitions between all solid polymorphs in the biased trajectories. We reconstruct the free energy surface and identify previously unknown defect and intermediate forms in the transition from one known polymorph to another. Our method provides insights into complex conformational polymorphic transitions of flexible molecular crystals.

A phase variety of fluorinated ionic liquids: Molecular conformational and crystal polymorph

Crystal polymorphs of fluorinated ionic liquids (fILs) were examined at low-temperature (LT) by Raman spectroscopy. The fILs were 1-alkyl-3-methylimidazolium perfluorobutanesulfonate, [Cnmim][PFBS] (n = 4, 6, and 8). The cations and anion possess conformational degrees of freedom. Various LT phases were derived from the conformational polymorphs of the cations and the anion. Conformational flexibility depended on alkyl chain length. The crystal polymorphs in the fILs were sensitive to molecular conformations and flexibility.

Control of 11-Aza:4-X-SalA Cocrystal Polymorphs Using Heteroseeds That Switch On/Off Halogen Bonding

A family of: 1:1 cocrystals 11-Aza:4-X-SalA have been prepared from the potent anti-malarial compound 11-azaartemisinin with 4-halosalicylic acids. When X = 4-Cl, 4-Br and 4-I, two conformational polymorphs can be isolated in each case. Monoclinic type-I was found previously for parent 11-Aza:SalA (1) and 11-Aza:4-Br-SalA (3a) which have polar 21 stacks of molecular pairs with no short halogen bond contacts between stacks. Orthorhombic type-II is found for 4-Cl (3b) and 4-I (4b) from solution growth. This has a translational stack of molecular pairs involving a conformational change of the acid-lactam hetero-synthon and supramolecular association of stacks via halogen bonds. Notably, phase pure polymorph type-I can be formed for 4-Cl (3a) and 4-I (4a) by hetero-seeding with 11-Aza:SalA, whist conversely phase pure type-II for 4-Br (2b) can be formed using homo-seeding from liquid assisted grinding (LAG) product. This work demonstrates both the viability of engineering polymorphic cocrystal forms using hetero-seeds and the involvement of halogen bonds in helping to discriminate quite different polymorphic types.

Examining the Non-Covalent Interactions for Two Polymorphs of a 2,1,3-benzoxadiazole Derivative

Two polymorphs of a benzoxadiazole derivative were examined to determine the interactions leading to the formation of two distinct crystalline forms. Hirshfeld surface analysis was used to establish and contrast the interactions in the two samples. Fingerprints derived from the surface analysis were used to distinguish and lead the analysis in discovering the different interactions in the two crystals. π interactions, specifically, π-hole interactions with a nitro moiety, were found to play an important role in the formation of the crystal structure. Further, carbonyl interactions and π-stacking contribute to the overall relative stability of the different conformational polymorphs. Calculated energy frameworks were used to help visualize the interactions between molecules in the crystal structure, supported by an understanding of the individual interactions. The experimental data were supplemented with theoretical studies to establish a through understanding of these heterocyclic systems.

A Digital Mechanistic Workflow for Predicting Solvent-Mediated Crystal Morphology: The α and β Forms of l-Glutamic Acid

The solvent-mediated crystal morphologies of the α and β polymorphic forms of l-glutamic acid are presented. This work applies a digital mechanistically based workflow that encompasses calculation of the crystal lattice energy and its constituent intermolecular synthons, their interaction energies, and their key role in understanding and predicting crystal morphology as well as assessing the surface chemistry, topology, and solvent binding on crystal habit growth surfaces. Through a comparison between the contrasting morphologies of the conformational polymorphs of l-glutamic acid, this approach highlights how the interfacial chemistry of organic crystalline materials and their inherent anisotropic interactions with their solvation environments direct their crystal habit with potential impact on their further downstream processing behavior.

Conformational polymorphs and solvates of 1-(6-aminopyridin2-yl)-3-phenylthiourea

Three conformational polymorphs and two solvates of an asymmetrical N,N'-disubstituted thiourea derivative namely, 1-(6-aminopyridin2-yl)-3-phenylthiourea (PTU) have been reported here. In all the polymorphs and solvates, the PTU molecules self-assemble to dimers in the solid state, via two complementary N-H‧‧‧S bonds resulting in the formation of R22(8)-type of H-bond motif. The two PTU molecules in these dimers interact with each other in a head to tail fashion. Furthermore, the PTU molecule adopts trans, cis- conformation with an intramolecular N-H‧‧‧N interaction in all the crystals. The orientation of the aminophenyl ring with respect to the phenyl ring plays crucial role in the solid state packing of the polymorphs and solvates. Additionally, three polymorphs are distinguishable by C-H‧‧‧π, N-H‧‧‧π and π‧‧‧π interactions. The polymorph PTU-1 crystallizes in P-1 space group with Z'=2, whereas the polymorphs PTU-2 and PTU-3 crystallize in Pbcn and R-3 space group, respectively, with Z'=1. On the other hand, the solvate PTU-DMSO crystallize in P21/c with 1:1 host-guest ratio, and PTU-Morpholine exists in P-1 space group with 2:1 host guest ratio. Hirshfeld surface analysis was carried out to compare the intermolecular interactions in the three polymorphs and two solvates of the title compound. The 2D fingerprint analysis of each of the polymorphs reveals that besides the H‧‧‧H interactions, C‧‧‧H and S‧‧‧H interactions contribute more to the generation of polymorphs. The contribution of C‧‧‧H interactions in both PTU-2 (31.6%) and PTU-3 (32.1%) are much higher than that of any molecule in PTU-1 (19.8% and 23% for Molecule A and B, respectively). Additionally, a tiny amount of π‧‧‧π interaction is observed (C‧‧‧C interaction, 4.5%) in the polymorph PTU-1, which is absent in PTU-2 and PTU-3.

The interplay of intra- and intermolecular errors in modeling conformational polymorphs.

Conformational polymorphs of organic molecular crystals represent a challenging test for quantum chemistry because they require careful balancing of the intra- and intermolecular interactions. This study examines 54 molecular conformations from 20 sets of conformational polymorphs, along with the relative lattice energies and 173 dimer interactions taken from six of the polymorph sets. These systems are studied with a variety of van der Waals-inclusive density functionals theory models; dispersion-corrected spin-component-scaled second-order Møller-Plesset perturbation theory (SCS-MP2D); and domain local pair natural orbital coupled cluster singles, doubles, and perturbative triples [DLPNO-CCSD(T)]. We investigate how delocalization error in conventional density functionals impacts monomer conformational energies, systematic errors in the intermolecular interactions, and the nature of error cancellation that occurs in the overall crystal. The density functionals B86bPBE-XDM, PBE-D4, PBE-MBD, PBE0-D4, and PBE0-MBD are found to exhibit sizable one-body and two-body errors vs DLPNO-CCSD(T) benchmarks, and the level of success in predicting the relative polymorph energies relies heavily on error cancellation between different types of intermolecular interactions or between intra- and intermolecular interactions. The SCS-MP2D and, to a lesser extent, ωB97M-V models exhibit smaller errors and rely less on error cancellation. Implications for crystal structure prediction of flexible compounds are discussed. Finally, the one-body and two-body DLPNO-CCSD(T) energies taken from these conformational polymorphs establish the CP1b and CP2b benchmark datasets that could be useful for testing quantum chemistry models in challenging real-world systems with complex interplay between intra- and intermolecular interactions, a number of which are significantly impacted by delocalization error.

Polymorphism and isomorphism in trans-bis(2,5-diiodopyridine)dihalocopper(ii) complexes: theoretical and crystallographic studies

Two conformational polymorphs of [Cu(25dIpy)2Cl2] have been prepared, the anti-polymorph crystallized from 2-propanol at room temperature (green) and the syn-polymorph crystallized from acetonitrile at 60 °C (brown).

Conformational polymorphs of isotretinoin and their impact on physicochemical and biological properties

Isotretinoin is the first-line drug for treatment of severe acne. Only one polymorph was reported even though it has been launched for nearly 40 years, and its clinic application was however limited by its stability and solubility challenges. In our study, two new polymorphs of isotretinoin were discovered and fully characterized. The transformation relationships between these solid forms were fully discussed, and a visible color change during single-crystal-to-single-crystal phase transition with the conformational change was investigated. Form II is determined to be thermodynamic stable form at room temperature, but metastable form at body temperature. The results show that form II is an ideal solid state possessing both superior thermal stability (60℃, open air) and higher absorption once delivered into body. The thermal stability can be associated with the crystal structure such as torsion angle. The relative bioavailability of form II is higher than form I as expected, and the bioavailability of form II formulation is about 2 times as that of the marketed form I capsule. Therefore, form II formulation could provide an alternative for better performing isotretinoin.