Search

After expiration in 2012 of the patent protection for the blockbuster drug Clopidogrel (Plavix®, Sanofi-Aventis), it has been challenging for drug manufacturers to launch generic forms with improved physicochemical properties and biopharmaceutical performances [1]. Therefore our aim was a cocrystallization screening by crystal engineering approach for new molecular salts of the more active and better tolerated form of clopidogrel, the dextrorotary isomer S(+)clopidogrel, followed by structural determination. Few structures of this drug exist so far in the Cambridge Structural Database (CSD v.5.35): the two polymorphs of S(+)clopidogrel hydrogen sulfate used in pharmaceutical formulations, orthorhombic form II (refcode FUQMOU) and monoclinic form I (FUQMOU01) [2,3], as well as the S(+)clopidogrel camphosulfonate (JASHUG) [4] and S(+)clopidogrel isopropylsulfate (YEXHOZ) [5]. The crystal structures of two new pseudo-polymorphic forms of S(+)clopidogrel-picrate salt obtained by co-crystallization are reported. Compound 1 (CDCC 1448941), prepared by treating clopidogrel hydrogen sulfate with picric acid, crystallizes in the monoclinic space group P21 with a ionic couple S(+)ClopH+•Pic- and a molecule of solvent ethanol in the A.U.. Crystals of Compound 2 (CDCC 1448942), grown dissolving clopidogrel free base and picric acid in a methanol/n-propanol mixture, crystallize in the monoclinic space group C2 with two ionic couples in the A.U.. The configurations and conformations of the ionic couples, held together by quite strong ionized +N─H•••O− hydrogen bonds (H-bonds), are almost identical in both crystals. The two compounds are compared with known structures of clopidogrel salts, including those used in pharmaceutical formulations, and the H-bonds discussed in reference to the general behavior of the N-bases-picrate H-bond and to the coformers acid-base properties. d(N∙∙∙O) contact distances are in the range 2.752-2.815 Å with calculated H-bond energy from 2.68 to 3.45 kcal mol-1 and ΔpKa of -4.26. These medium-strong H-bonds fit well the reported correlations among d(D∙∙∙A), EHB, and pKa [6] aimed to verify the validity of the pKa equalization principle [7-9].

Four different carboxylato bridges have been efficiently utilized for growth of three tetranuclear nickel(II) complexes [Ni4(μ3-H2L)2(μ3-OH)2(μ1,3-CH3CO2)2](ClO4)2 (1), [Ni4(μ3-H2L)2(μ3-OH)2(μ1,3-C2H5CO2)2](ClO4)2·1/2H2O (2), and [Ni4(μ3-H2L)2(μ3-OH)2(μ1,3-O2C-C6H4-pNO2)2](ClO4)(p-NO2-C6H4-CO2)·DMF·5H2O (3) and one dinuclear nickel(II)-based chain complex {[Ni2(μ-H2L)(μ1,3-O2CCH2Ph)2(H2O)](ClO4)·1/2(CH3OH)}n (4). These were obtained via the reaction of Ni(ClO4)2·6H2O with H3L [2,6-bis((2-(2-hydroxyethylamino)ethylimino)methyl)-4-methylphenol] and RCO2Na (R = CH3,C2H5, p-NO2C6H4, and PhCH2). This family of complexes is developed from {Ni2(μ-H2L)}3+ fragments following self-aggregation. The complexes were characterized by X-ray crystallography and magnetic measurements. The changes from acetate, propionate, and p-nitrobenzoate to phenylacetate groups resulted in two different types of coordination aggregation. These compounds are new examples of [Ni4] and [Ni2]n complexes where organization of the building motifs are guided by the type of the carboxylate groups responsible for in-situ generation and utilization of HO– bridges with alteration in the aggregation process within the same ligand environment. Studies on the magnetic behavior of the compounds reveal that the exchange coupling within 1–4 is predominantly antiferromagnetic in nature.

Cocrystallization became well known bottom-up approach starting from intermolecular interactions among, either selected neutral, ionic or zwitterionic molecules to design and control the properties of the multicomponent crystals. [1] In the scope of interest for drug design and formulation, the main advantage for designing Pharmaceutical Cocrystals (PCCs) is, through their modulating properties, to improve the performance of the native Active Pharmaceutical Ingredients (APIs) such are: biopharmaceutical profile (solubility and dissolution rate), thermodynamical stability (phase transition of polymorphs, solvate/ hydrate formation, decomposition) or bulk powder processability (flowability, compressibility, particle size and shape control). [2,3] Many debates regarding semantic and classification in cocrystals (CCs) based on accomplishments in research of supramolecular chemistry, highlighted the complex reality of multi-component systems, and the wide scope associated between salts and cocrystals in the salt-cocrystal continuum. [4] N,N-dimethylbiguanide is used as oral antidiabetic drug, well known as Metformin (MET). It directlyimproves insulin action and is the only approved hypoglycemic drug of the biguanide class. Because of the biguanide π-conjugated system, MET can exist in three resonance-stabilized forms, i.e. as neutral molecule (MET), monoprotonated (METH+) or diprotonated (METH2+) cation, with dissociation constants in water typical of biguanides (pKa112.40 and pKa2 2.96). A search of the MET fragment in the structural literature, both in the CCDC database and in patents, shows that in crystals it exists as METH+ or METH2+ but never in its neutral form MET. We have undertaken a systematic study of the crystal chemistry of MET with the aim of understanding its properties in the solid state and finding relationships with its biopharmaceutical profile. We have obtained 29 PCCs of quality suitable for crystal structure determination by single crystal X-ray diffraction with the CFs listed below. Inorganic acids: nitric, phosphoric and carbonic acid; Organic NH-type acids: saccharine and acesulfame; Organic OH-type acids: squaric and picric acid; Monocarboxylic acids: fumaric, acetic, trifluoroacetic, trichloroacetic, dichloroacetic, monochloroacetic, glycolic, salicylic, dichlofenac; Dicarboxylic acids: oxalic, malonic, maleic, fumaric, succinic, adipic. In the poster are presented structures analyses for “drug-drug” type of PCCs where both API and CF exhibit pharmacological effect: MET/ Dichloroacetic acid 1:1 and 1:2 molar ratio, MET/ Diclofenac 1:1, MET/ Glycolic 1:1 acid and MET/ Salicylic acid 1:1 molar ratio. Literature: [1] Braga D., Crystal Engineering, Chem Comm, 2003, 2751-2754, [2] Good J. D., et al. N Cryst Growth Des., 2009, 9 (5), pp 2252–2264 [3] Cheney ML, et al. .,J.PharmSci. 2011Jun;100(6):2172-81 [4] Childs, S.L., Stahly, G.P., Park, A., 2007. Mol. Pharm. 4, 323–338

Increased publications and released patents relating to multicomponent crystals of pharmaceutical relevance caused the Food & Drug Administration (USA FDA) to issue the draft guideline for regulatory classification of Pharmaceutical Cocrystals (PCC) of active pharmaceutical ingredients (APIs) as solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds, generally in a stoichiometric ratio [1,2]. The main advantage of PCCs is to improve the performances of the native APIs by modulating their properties, such as: biopharmaceutical profile (solubility and dissolution rate), thermodynamical stability (phase transition of polymorphs, solvate/ hydrate formation, decomposition) or bulk powder processability (flowability, compressibility, particle size and shape control). N,N-dimethylbiguanide is used as oral antidiabetic drug, well known as Metformin (MET). It directly improves insulin action and is the only approved hypoglycemic drug of the biguanide class. It is the drug of first choice for oral therapy of the type 2 diabetes, marketed as hydrochloride, embonat (pamoate) and p-chlorophenoxy acetate salt. Because of the biguanide π-conjugated system, MET can exist in three resonance-stabilized forms, i.e. as neutral molecule (MET), monoprotonated (METH+) or diprotonated (METH2+) cation, with dissociation constants in water typical of biguanides: Metformin = L; [HL]/[L][H] pKa1(N−H+) ~ 12.40; [H2L]/[HL][H] pKa2(N−H+) = 2.96 (NIST database) The high basicity of pKa1 and the difference between the pKa values qualify MET as organosuperbase and determine the stability of its monoprotonated form METH+ within a wide range of pH. A search of the MET fragment in the structural literature, both in the CCDC database and in patents, shows that in crystals it exists as METH+ or METH2+ but never in its neutral form MET. We have undertaken a systematic study of the crystal chemistry of MET with the aim of understanding its properties in the solid state and finding relationships with its biopharmaceutical profile. We have prepared series of PCCs of MET in combination with a variety of organic or inorganic acids as Coformers (CFs) in different experimental conditions of formulation (stoichiometric ratio) and processing (solvent, temperature, crystallization technique). We have obtained PCCs of quality suitable for crystal structure determination by single crystal X-ray diffraction with the CFs listed below. Inorganic acids: nitric, phosphoric and carbonic acid; Organic NH-type acids: saccharine and acesulfame; Organic OH-type acids: squaric and picric acid; Monocarboxylic acids: acetic, trifluoroacetic, trichloroacetic, glycolic, salicylic, dichlofenac; Dicarboxylic acids: oxalic, malonic, maleic, fumaric, succinic, adipic. We have so far determined 26 crystal structures, 22 containing the METH+ and 4 the METH2+ form. In all structures the C-N bond distances of MET are fully delocalized and the fragment is never found to be planar. The crystal packing analysis reveals that MET and CF molecules are linked by extended H-bond networks that, though different, show a number of conserved patterns (dimers, ribbons, rings, sheets, etc). Results of the crystal structure analysis for representative PCCs will be shown in the poster. [1] http//www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm [2] Aitipamula, S., et al., Cryst. Growth Des. 2012, 12, 2147−2152

US FD’s released draft guidelines for regulatory classification of pharmaceutical cocrystals (PCC) of active pharmaceutical ingredients (APIs) enforced by the increased interest for research on multicomponent crystal with pharmaceutical relevance brought an attention to scientiffic community broadly to spread the deffinition of PCC as solids that are crystalline single phase materials composed of two or more different molecular and/or ionic compounds generally in a stoichiometric ratio [1,2]. Well know antidiabetic drug metformin (MET) was chosen as drug model (DM) with basic property for cocrystallization with range of coformers (CF) from the classes of carboxylic and inorganic acids in order to prepare PCC. Following twelve PCC with metfomin were obtained: MET/ Acetic Acid1/1 (molar ratio) M/M; MET/ Maleic Acid 1/1 M/M; MET/Fumaric Acid 1/0.5 M/M; MET/Oxalic Acid Hydrate 1/1/1/ M/M/M; MET/Malonic Acid 1/1 M/M; MET/Succinic Acid 1/0.5 M/M; MET/Salicylic Acid 1/1 M/M; (7) MET/Picric Acid 1/1 M/M, (8) MET / Picric Acid 1/2 M/M and MET/Saccharine 1/1 M/M (obtained two polymorphic forms); MET/Phosphoric Acid/Dihydrate 2/1/2 M/M/M and MET/Nitric Acid 1/1 M/M. All these PCCs form a complex network of H-bonds and other intermolecular interactions. The systematic analysis of the molecular geometries and crystal packing indicate correlations between the intermolecular H-bonds with the ∆pKa values in the PCCs obtained.

11 pages; International audience; A new family of distorted pentacoordinate [Co2] complexes was prepared and structurally characterized. In [CoIIA- (bip)]2·S (1–3) [A = NCS–, N3 –, NCO–; S = dmf, MeOH, dcm; Hbip = 2,6-bis(phenylmethyliminomethyl)-4-methylphenol], the nonbonded Co···Co separations are in the 3.243 to 3.254 Å range, and the pseudohalide-coordinated CoII ions are asymmetrically doubly bridged by the phenolate oxygen atoms of the ligand. The complementary basal–apical (b–a) and apical–basal (a–b) coordination modes of the phenolate bridges of bip– offer one O and two N donors for metal-ion coordination. In the three dinuclear complexes, the h.s. CoII ions are coupled antiferromagnetically to yield a singlet ground state. The solid-state variable-temperature magnetic susceptibility measurement data on the complexes were fitted to an isotropic Heisenberg dimer model that allowed estimation of the antiferromagnetic interactions for 1–3.

We have experimentally studied and theoretically interpreted the addition under stoichiometric conditions of halogens or interhalogens to σ-butadienyl palladium complexes bearing the heteroditopic thioquinolines as spectator ligands. The observed reactions do not involve the expected extrusion of the butadienyl fragment but rather the unpredictable substitution of the halide coordinated to palladium and in some cases also of that bound to the terminal butadienyl carbon. We have explained this peculiar reactivity with a mechanistic hypothesis based on a sequence of selective processes of oxidative addition and reductive elimination involving Pd(iv) intermediates.

We have studied the oxidative addition of some organic halides on palladium(0) dimethylfumarate complexes bearing heteroditopic (N–P or N–S) quinoline-based spectator ligands from the experimental and theoretical point of view. We have measured the half-life of some oxidative addition reactions carried out in two different solvents (CD2Cl2 and CD3CN). The reactions were studied under mild conditions by NMR and the reactivities of different oxidants towards the complexes under study were compared. The rates of reaction were influenced by the nature of the spectator ligands and the solvent. The thioquinoline derivatives display a higher reactivity than that of the phosphoquinoline complexes and in general the reaction rates are higher in CD3CN than in CD2Cl2, although such a behavior is not always observed. We propose a plausible mechanism for the oxidative reaction in different solvents based on the experimental results and an adequate computational approach. Finally, the solid state structures of two reaction products were resolved and reported.

We have synthesized two palladacyclopentadienyl derivatives bearing bidentate ligands heteroditopic 8-(diphenylphosphino)quinoline or 8-(diphenylphosphino)-2-methylquinoline. We have reacted the palladacyclopentadienyl complexes with Br2 and I2 to gain clues on the formation mechanism of the corresponding σ-butadienyl derivatives. We were able to obtain the pure σ-butadienyl derivative only in the case of Br2 reacting with the palladacyclopentadienyl complex bearing the unsubstituted quinoline. However, an equilibrium mixture of the σ-butadienyl and a novel zwitterionic species was obtained when the same complex reacts with I2. Furthermore, we have obtained exclusively an unprecedented zwitterionic complex when I2 reacts with the palladacyclopentadienyl complex bearing the substituted quinoline and a different ratio of an equilibrium mixture of σ-butadienyl and the zwitterionic species when the latter derivative reacts with Br2. The solid state structures of one σ-butadienyl complex and of the two novel zwitterionic derivatives were determined and an interpretation of the observed reactivity based on kinetic data and a computational study has been suggested.