Ethyl Acetate Solvate Research Articles

Stability and Mechanical Properties of Darunavir Isostructural Solvates: An Experimental and Computational Study

A search for suitable solid forms was an integral part of pharmaceutical manufacturing. In this study, nine isostructural solvates of darunavir (DLNW), an oral nonpeptidyl HIV-1 protease inhibitor, were prepared in different solvent systems (water [Shen, J. . CrystEngComm 2019, 1102], methanol, ethanol [Shen, J. CrystEngComm 2019, 1102], isopropanol, 1-propanol, ethyl acetate, acetone, N,N-dimethyl formamide, and dimethyl sulfoxide). The phase compositions of prepared samples were confirmed by single-crystal X-ray diffraction studies. The relationship between crystal structure and mechanical properties of each solvate was also investigated through the inspection of crystal structures, with a focus on hydrogen bonding interactions. We further compared the thermal stabilities and mechanical properties of different DLNW solvates, experimentally determined using thermal methods and nanoindentation, in combination with the simulation of topological analysis, energy framework, and core-valence bifurcation, respectively. The results showed that nine solvates were isostructural with varying proportions of solvent and different thermal stabilities because of the differences in solvent molecules. Darunavir dihydrate (DLNW-2H) showed the best compressibility and therefore could be regarded as a sensible choice for active pharmaceutical ingredients. A new solvent-free crystalline DLNW form was also obtained through the transformation of darunavir ethyl acetate solvate (DLNW-EAC), paving a feasible way to develop novel polymorphs, which were worthy of further research and attention in manufacturing.

Dihydrofolate Reductase Inhibitors: The Pharmacophore as a Guide for Co-Crystal Screening.

In this work, co-crystal screening was carried out for two important dihydrofolate reductase (DHFR) inhibitors, trimethoprim (TMP) and pyrimethamine (PMA), and for 2,4-diaminopyrimidine (DAP), which is the pharmacophore of these active pharmaceutical ingredients (API). The isomeric pyridinecarboxamides and two xanthines, theophylline (THEO) and caffeine (CAF), were used as co-formers in the same experimental conditions, in order to evaluate the potential for the pharmacophore to be used as a guide in the screening process. In silico co-crystal screening was carried out using BIOVIA COSMOquick and experimental screening was performed by mechanochemistry and supported by (solid + liquid) binary phase diagrams, infrared spectroscopy (FTIR) and X-ray powder diffraction (XRPD). The in silico prediction of low propensities for DAP, TMP and PMA to co-crystallize with pyridinecarboxamides was confirmed: a successful outcome was only observed for DAP + nicotinamide. Successful synthesis of multicomponent solid forms was achieved for all three target molecules with theophylline, with DAP co-crystals revealing a greater variety of stoichiometries. The crystalline structures of a (1:2) TMP:THEO co-crystal and of a (1:2:1) DAP:THEO:ethyl acetate solvate were solved. This work demonstrated the possible use of the pharmacophore of DHFR inhibitors as a guide for co-crystal screening, recognizing some similar trends in the outcome of association in the solid state and in the molecular aggregation in the co-crystals, characterized by the same supramolecular synthons.

Maleate salts of bedaquiline.

Bedaquiline is one of two important new drugs for the treatment of drug-resistant tuberculosis (TB). It is marketed in the US as its fumarate salt, but only a few salts of bedaquiline have been structurally described so far. We present here five crystal structures of bedaquilinium maleate {systematic name: [4-(6-bromo-2-meth-oxy-quinolin-3-yl)-3-hy-droxy-3-(naphthalen-1-yl)-4-phenyl-but-yl]di-methyl-aza-nium 3-carb-oxy-prop-2-enoate}, C32H32BrN2O2 +·C4H3O4 -, namely, a hemihydrate, a tetra-hydro-furan (THF) solvate, a mixed acetone/hexane solvate, an ethyl acetate solvate, and a solvate-free structure obtained from the acetone/hexane solvate by in situ single-crystal-to-single-crystal desolvation. All salts exhibit a 1:1 cation-to-anion ratio, with the anion present as monoanionic hydro-maleate and a singly protonated bedaquilinium cation. The maleate exhibits the strong intra-molecular hydrogen bond typical for cis-di-carb-oxy-lic acid anions. The conformations of the cations and packing inter-actions in the maleate salts are compared to those of free base bedaquiline and other bedaquilinium salts.

New solvates of the drug naltrexone: protonation, conformation and interplay of synthons.

Naltrexone [systematic name: (4R,4aS,7aR,12bS)-3-cyclopropylmethyl-4a,9-dihydroxy-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one] is an important morphine-related drug used for combating alcoholism and opioid dependence. Of the eight crystal forms of naltrexone known thus far, only one exists in the neutral form and it crystallizes as a monohydrate. We have isolated the naltrexone free base as two new solvate forms, i.e. the ethyl acetate 0.33-solvate, C20H23NO4·0.33C4H8O2, (I), and the diethyl ether hemisolvate, C20H23NO4·0.5C4H10O, (II). While just one solvent molecule is present in the asymmetric unit of each solvate, there are three drug molecules (Z' = 3) in ethyl acetate solvate (I) and two (Z' = 2) in diethyl ether solvate (II). In (I), one of the three crystallographically independent drug molecules is present with its cyclopropyl group disordered over two sets of positions, as is the whole diethyl ether solvent molecule in (II). In all known forms, including the title forms, the naltrexone molecule exhibits the same conformation of the fused rings. The only conformational variability of naltrexone is in the cyclopropylmethyl group. Two conformations can be found around the bond connecting this group to the N-heterocycle, which is directly related to drug protonation. We have calculated, at the B3LYP/6-31G** level of theory, the minimum energy conformations of protonated and neutral naltrexone molecules for a chosen torsion angle about this bond. The lowest energy conformers depend on the protonation state and are in agreement with those found in the solid state. Within the cyclopropylmethyl group, the bond joining the methylene C atom to the cyclopropyl fragment also evidences conformational variability. In the literature, there are two well defined conformations around this bond. A third cyclopropyl conformation around this second bond is observed in the title solvates. Concerning the supramolecular features of the previously reported crystal structures, only one classical hydrogen bond between naltrexone molecules and one C(8) homosynthon is known, pointing to the robustness of this synthon and the difficulty in disrupting it. New R22(7) and C22(10) homosynthons are found in both (I) and (II), suggesting that their occurrence derives from crystallization of the neutral drug from nonpolar solvents.

Stable Crystalline Salts of Haloperidol: A Highly Water-Soluble Mesylate Salt

Haloperidol, an antipsychotic drug, was screened for new solid crystalline phases using high throughput crystallization in pursuit of solubility improvement. Due to the highly basic nature of the API, all the solid forms with acids were obtained in the form of salts. Eleven crystalline salts in the form of oxalate (1:1), benzoate (1:1), salicylate (1:1 and 1:2), 4-hydroxybenzoate (1:1), 4-hydroxybenzoate ethyl acetate solvate (1:1:1), 3,4-dihydroxybenzoate (1:1), 3,5-dihydroxybenzoate (1:1), mesylate (1:1), besylate (1:1), and tosylate (1:1) salt were achieved. There is an insertion of carboxylate or sulfonate anion into the hydrogen bonding pattern of haloperidol. The salts with the aliphatic carboxylic acids were found to be more prone to form salt hydrates compared with aromatic carboxylate salts. All the salts were subjected to solubility measurement in water at neutral pH. There was no direct correlation observed between the solubility of the salt and its coformer. All the salts are stable at room te...

Metal complexes of 2-aza-2-benzyloxycarbonylmethyl-5,10,15,20-tetraphenyl-21-carbaporphyrin: M(2-NCH2COOCH2C6H5NCTPP) (M = Ni2+, Pd2+) and Mn(2-NCH2COOCH2C6H5NCTPP)Br (NCTPP = N-confused 5,10,15,20-tetraphenylporphyrinate)

The crystal structures of (2-aza-2-benzyloxycarbonylmethyl-5,10,15,20-tetraphenyl-21-carbaporphyrinato-N,N′,N″)nickel(II) [Ni(2-NCH2COOCH2C6H5NCTPP); 5], (2-aza-2-benzyloxycarbonylmethyl-5,10,15,20-tetraphenyl-21-carbaporphyrinato-N,N′,N″)palladium(II) toluene solvate [Pd(2-NCH2COOCH2C6H5NCTPP)·C6H5CH3; 6·C6H5CH3] and bromo(2-aza-2-benzyloxycarbonylmethyl-5,10,15,20-tetraphenyl-21-carbaporphyrinato-N,N′,N″)manganese(III) ethyl acetate solvate [Mn(2-NCH2COOCH2C6H5NCTPP)Br·EtOAc; 7·EtOAc] have been established. The coordination sphere around the Ni2+ ion in 5 (or Pd2+ ion in 6·C6H5CH3) is distorted square planar (DSP), whereas for Mn3+ in 7·EtOAc, it is square-based pyramidal with the Br atom lying in the axial site. The g value of 10.98 measured from the parallel polarization of the X-band ESR spectrum at 4K is consistent with a high spin mononuclear manganese(III) centre (S=2) in 7. The magnitude of the axial (D) zero-field splitting (ZFS) for the mononuclear Mn(III) centre in 7 was determined to be approximately 0.52cm−1 by paramagnetic susceptibility measurements. The 13C [C(19)] and 1H [H(19)] chemical shifts of the N+CH(Ar) fragment at 20°C in CDCl3 are located at δ 152.5±0.5 and 8.21±0.04ppm respectively for the iminium ion of the dipolar form in complexes 5–7. From the X-ray diffraction data, the N(4)–C(19) bond length of 1.312±0.013Å indicates the existence of the dipolar form for 5–7.

Desvenlafaxinium chloranilate ethyl acetate solvate

In the cation of the title compound, C16H26NO2 +·C6HCl2O4 −·C4H8O2, the 1-hy­droxy-cyclo­hexyl ring adopts a slightly distorted chair conformation. The dihedral angle between the mean planes of the 1-hy­droxy­cyclo­hexyl and 4-hy­droxy­phenyl rings is 84.0 (8)°. In the anion, the hydroxyl H atom is twisted slightly out of the ring plane with a C—C—O—H torsion angle of −171.9°. Disorder was modeled for the methyl group of the acetate group in the solvate with an occupancy ratio of 0.583 (15): 0.417 (15). In the crystal, O—H⋯O hydrogen bonds are observed between cations and between cations and anions, while bifuricated N—H⋯(O,O) cation–anion hydrogen bonds are also present, forming chains along [010] and [100]. In addition weak cation–anion and cation–solvate C—H⋯O inter­actions occur.

Pallidol hexaacetate ethyl acetate monosolvate

The entire mol­ecule of pallidol hexa­acetate {systematic name: (±)-(4bR,5R,9bR,10R)-5,10-bis­[4-(acet­yloxy)phen­yl]-4b,5,9b,10-tetra­hydro­indeno­[2,1-a]indene-1,3,6,8-tetrayl tetra­acetate} is completed by the application of twofold rotational symmetry in the title ethyl acetate solvate, C40H34O12·C4H8O2. The ethyl acetate mol­ecule was highly disordered and was treated with the SQUEEZE routine [Spek (2009 ▶). Acta Cryst. D65, 148–155]; the crystallographic data take into account the presence of the solvent. In pallidol hexa­acetate, the dihedral angle between the fused five-membered rings (r.m.s. deviation = 0.100 Å) is 54.73 (6)°, indicating a significant fold in the mol­ecule. Significant twists between residues are also evident as seen in the dihedral angle of 80.70 (5)° between the five-membered ring and the pendent benzene ring to which it is attached. Similarly, the acetate residues are twisted with respect to the benzene ring to which they are attached [C—O(carb­oxy)—C—C torsion angles = −70.24 (14), −114.43 (10) and −72.54 (13)°]. In the crystal, a three-dimensional architecture is sustained by C—H⋯O inter­actions which encompass channels in which the disordered ethyl acetate mol­ecules reside.

Constructing Single-Chain Magnets by Supramolecular π-π Stacking and Spin Canting: A Case Study on Manganese(III) Corroles

A single-chain magnet (SCM) was constructed from manganese(III) 5,10,15-tris(pentafluorophenyl)corrole complex [Mn(III) (tpfc)] through supramolecular π-π stacking without bridging ligands. In the crystal structures, [Mn(tpfc)] molecules crystallized from different solvents, such as methanol, ethyl acetate, and ethanol, exhibit different molecular orientations and intermolecular π-π interaction or weak Mn⋅⋅⋅O interaction to form a supramolecular one-dimensional motif or dimer. These three complexes show very different magnetic behaviors at low temperature. Methanol solvate 1 shows obvious frequency dependence of out-of-phase alternating-current magnetic susceptibility below 2 K and a magnetization hysteresis loop with a coercive field of 400 Oe at 0.5 K. It is the first example of spin-canted supramolecular single-chain magnet due to weak π-π stacking interaction. By fitting the susceptibility data χ(M) T (20-300 K) of 1 with the spin Hamiltonian expression H = -2J Σ(i=1)(n-1) S(Ai) S(Ai+1) + D Σ(i) S((iZ)(2)), the intrachain magnetic coupling parameter transmitted by π-π interaction of -0.31 cm(-1) and zero field splitting parameter D of -2.59 cm(-1) are obtained. Ethyl acetate solvate 2 behaves as an antiferromagnetic chain without ordering or slow magnetic relaxation down to 0.5 K. The magnetic susceptibility data χ(M) T (20-300 K) of 2 was fitted by assuming the spin Hamiltonian H = -2JΣ(i=1)(n-1) S(Ai) S(Ai+1), and the intrachain antiferromagnetic coupling constant of -0.07 cm(-1) is much weaker than that of 1. Ethanol solvate 3 with a dimer motif shows field-induced single-molecule magnet like behavior below 2.5 K. The exchange coupling constant J within the dimer propagated by π-π interaction is -0.14 cm(-1) by fitting the susceptibility data χ(M) T (20-300 K) with the spin Hamiltonian H = -2J S(A) S(B) + β(S((A)g(A)) + S((B)g(B)))H. The present studies open a new way to construct SCMs from anisotropic magnetic single-ion units through weak intermolecular interactions in the absence of bridging ligands.

Stemofoline ethyl acetate solvate

Crystals of the title compound, C22H29NO5·C4H8O2, {[systematic name: (2R,3R,5R,5aS,6R,8aR,9S)-(5Z)-5-[3-butyl­tetra­hydro-6-methyl-2,5-methano-4,3,8a-[1]propan­yl[3]yl­idene­furo[3,2-f][1,4]oxazepin-7(5H)-yl­idene]-4-meth­oxy-3-methyl­furan-2(5H)-one ethyl acetate solvate} were isolated from the root extracts of Stemona aphylla (Stemonaceae). The structure closely resembles those of stemofoline derivatives which have previously been reported. Inter­molecular contacts are observed between some C-bonded H atoms and nearby O atoms, perhaps indicating weak inter­actions which could influence the packing of species within the unit cell.

1,1′-(2-Thienylmethylene)di-2-naphthol ethyl acetate solvate

In the title compound, C25H18O2S·C4H8O2, there are inter­molecular O—H⋯O hydrogen bonds between the main mol­ecule and the solvent molecule. The thio­phene ring is oriented at dihedral angles of 70.87 (7) and 75.36 (4)° with respect to the mean planes of the two naphthyl ring systems.

Structural characterisation of two pharmaceutically important steroids by solid-state NMR

Several crystal modifications of two steroids (androsterone and beclomethasone dipropionate) have been characterised by solid-state NMR methods, and the chemical shifts between the different forms compared. The gradual loss of water from androsterone hemihydrate has been monitored by XRPD. The crystal structures are discussed in relation to the NMR data. That of the beclomethasone dipropionate ethyl acetate solvate has been determined for the first time. It is found that there are clear channels containing the ethyl acetate molecules, which are apparently not incorporated by hydrogen bonding. Carbon-13 CP MAS spectra with long contact times and MAS proton spectra are used to show the mobility of ethyl acetate molecules in the BDP solvate. The second-order effect of chlorine on the 13C spectrum of beclomethasone dipropionate monohydrate has been explored by varying the applied magnetic field.

N-(3-Oxo-2-phenyl-2,3-dihydro-1H-pyrrolo[1,2-c]imidazol-1-yl)-N′-phenyl-N-(2,4,6-trimethylphenyl)urea ethyl acetate solvate

The title compound, C28H26N4O2·C4H8O2, was prepared from (2,4,6-trimethyl­phen­yl)(1H-pyrrol-2-ylmethyl­ene)amine and phenyl isocyanate in the presence of catalytic amounts of [Pd(PPh3)4]. Recrystallization of the crude product from a penta­ne–ethyl acetate mixture (10:1) yielded the title compound as the ethyl acetate solvate. The pyrrolo[1,2-c]imidazole core is essentially planar. In addition, a new stereogenic center at the ring C atom of the biheterocyclic group attached to the urea N atom has been formed during the reaction sequence. The crystal structure is influenced by various N—H⋯O and C—H⋯O hydrogen bonds.

2′-[(5-Bromo-1H-indol-3-yl)methylene]-2-(1H-indol-3-yl)acetohydrazide ethyl acetate solvate

The constituent mol­ecules of the title compound, C19H15BrN4O·C4H8O2, are linked by hydrogen bonds into a linear chain, with the acetohydrazide O atom serving as acceptor to the amide group as well as to the amino group of the bromo­indole group. The ethyl acetate solvent mol­ecule is also hydrogen bonded to the chain.

9,9′-Bifluorene-9,9′-diol ethyl acetate solvate

The 9,9′-bifluorene-9,9′-diol mol­ecules in the title compound, C26H18O2·C4H8O2, adopt a gauche conformation stabilized by intra­molecular O—H⋯O hydrogen bonds between hydroxyl groups. There are two formula units per asymmetric unit. The mol­ecules are linked into one-dimensional chains by inter­molecular O—H⋯O hydrogen bonds; ethyl acetate mol­ecules are bound to these chains, also by O—H⋯O hydrogen bonds.

The absolute configuration of a new aminoalkylphenol derived from (R)-(–)-2-phenylglycine

The chiral aminoalkylphenol N-[(S)-1-(5-methyl-2-hydroxyphenyl)ethyl]-N–[(R)-2-hydroxy-1-phenylethyl]amine, C17H21NO2, was synthesized starting from R-(-)-2-phenylglycine. The corresponding hydrochloride salt was prepared and crystallized as an ethyl acetate solvate, affording N-[(R)-2-hydroxy-1-phenylethyl]-N-[(S)-1-(5-methyl-2-hydroxyphenyl)ethyl]aminium chloride ethyl acetate solvate, C17H22NO2 +·Cl−·C4H8O2, and the absolute configuration of the new stereogenic centre determined, from which that of the chiral aminoalkylphenol was inferred. The dihedral angle between the two aromatic rings is 40.74 (11)°.

N-[(S)-1-(5-Chloro-2-hydroxyphenyl)ethyl]-N-[(R)-2-hydroxy-1-phenylethyl]aminium chloride ethyl acetate solvate

The title compound, C16H19ClNO2+·Cl−·C4H8O2, was synthesised and its mol­ecular structure determined. The absolute configuration of a new stereogenic centre is determined to be S. N+—H⋯Cl− and O—H⋯Cl− inter­actions connect structural components, generating a hydrogen-bonded spiral along the twofold screw axis.

Comparison between dehydration and desolvation kinetics of fluconazole monohydrate and fluconazole ethylacetate solvate using three different methods

It was of interest to study the dehydration and the desolvation of fluconazole monohydrate and ethyl acetate solvate respectively and also to determine the kinetics of dehydration and desolvation using thermogravimetry (TGA). Fluconazole monohydrate and ethyl acetate solvate were prepared by crystallization in water and in ethyl acetate solvent respectively. The dehydration and the desolvation processes were characterized by differential scanning calorimetry, thermogravimetry, powder X-ray diffractometry, and Fourier transform infrared spectroscopy. The weight changes of the fluconazole monohydrate and ethyl acetate solvate samples were monitored by isothermal TGA. Kinetic analyses of isothermal TGA data were done using model dependent and model independent methods. Various heating rates were also employed in different TGA samples, in order to apply the Ozawa method to determine the kinetic parameters. Eighteen solid-state reaction models were used to interpret the isothermal TGA experiments. Based on statistics, the three-dimensional phase boundary reaction model provided the best fit of the monohydrate data while the three-dimensional diffusion model provided the best fit for the ethyl acetate solvate data. The activation energy (Ea) values derived from rate constants of the aforementioned models were 90±11 and 153±11 kJ/mol for fluconazole monohydrate and ethyl acetate solvate respectively. Model independent analysis and the Ozawa method were also applied to the experimental results. Based on the results obtained from the model dependent, model independent and the Ozawa method, the mechanisms of the dehydration and the desolvation were determined.

5-Ethoxycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic anhydride ethyl acetate solvate

In the title compound, C34H34N4O11·C4H8O2, the dihydro­pyridine rings display envelope configuration. The solvent mol­ecule links to the anhydride via weak C—H⋯O hydrogen bonding.

Octa-O-acetyl-α,α-trehalose ethanol disolvate

The glycosidic torsion angles φH and φH′ of the title compound, C28H38O19·2C2H5OH, with values of −40.2 and −42.6°, respectively, are closely similar to those in the structure of the same compound crystallized from ethyl acetate. Of particular interest is that the solvent mol­ecules in this structure take up a similar volume to those in the ethyl acetate solvate, thereby highlighting relationships between solvent and solute in these crystal structures.