Cameron Capeletti da Silva

Salts of the anti-HIV drug lamivudine with phthalic and salicylic acids

Salts of the anti-HIV drug lamivudine, with phthalic acid and salicylic acid as counterions, were investigated in this study. Neither the packing of the (lamivudine)+(phthalic acid)− ion pairs nor the conformation of the lamivudine moiety itself were similar to those found in other multicomponent molecular salts of the drug, such as hydrogen maleate and saccharinate ones, even though all three salts crystallize in the same P212121 orthorhombic space group with similar unit cell metrics. Lamivudine salicylate assumes a different crystal structure to those of the hydrogen maleate and saccharinate salts, crystallizing in the P21 monoclinic space group as a monohydrate whose (lamivudine)+(salicylic acid)− ion pair is assembled through two hydrogen bonds with cytosine as a dual donor to both oxygens of the carboxylate, such as in the pairing of lamivudine with a phthalic acid counterion. In lamivudine salicylate monohydrate, the drug conformation is related to the hydrogen maleate and saccharinate salts. However, such a conformational similarity is not related to the intermolecular interaction patterns. Lamivudine and water molecules alternate into helical chains in the salicylate salt monohydrate.

Lamivudine salts with 1,2-dicarboxylic acids: A new and a rare synthon with double pairing motif fine-tuning their solubility

Structures of the anti-HIV drug lamivudine with 1,2-dicarboxylic acids are assembled with in-plane ionic pairs held together by two hydrogen bonds in which the protonated cytosine moiety of the drug acts as donor to both oxygens of the carboxylate motif of the counterion, through a two-point 2-aminopyridinium-carboxylate synthon. Here, we report two lamivudine salts featuring hydrogen bonding donation from cytosine to both carboxylate and carboxyl groups of the 1,2-dicarboxylic acid counterions. Two drug molecules are paired in the plane with the same counterion unit giving rise to a planar trimer and a planar tetramer in the structures of lamivudine hydrogen phthalate hemihydrate and lamivudine hydrogen 4,5-dichlorophthalate, respectively. Furthermore, a new heterosynthon was found in the first salt. This new synthon can be described as a four-point one of two-point 2-aminopyridinium-carboxylate and 2-aminopyridinium-carboxyl synthons fused together. Likewise, the synthon responsible for the assembly of lamivudine hydrogen 4,5-dichlorophthalate is rare in the CSD. It has the 2-aminopyridinium-carboxylate pairing and a bifurcated hydrogen bond involving the hydrogen of the amino group on an opposite side relative to the imine proton and both carboxyl oxygens. In addition, water solubility of both lamivudine salts prepared here and of known ones, namely, lamivudine hydrogen phthalate and lamivudine salicylate monohydrate, were determined in this study. All were less soluble than the lamivudine form II (free base). Such solubility behavior appears to be related to the lipophilicity of the counterions. Moreover, the unexpected heterosynthons play a fine-tuning role in the slightly higher solubility of lamivudine hydrogen phthalate hemihydrate and lamivudine hydrogen 4,5-dichlorophthalate when compared to the antecedent salts.

The enantiopreference in the solid state probed in lamivudine crystal forms with mandelic acid

The separation of enantiomers from a racemic mixture, known as chiral resolution, has been achieved nowadays through the preparation of multicomponent molecular crystals. Here we have investigated the crystallization of lamivudine, an enantiopure anti-HIV/HBV drug, with the enantiomers of mandelic acid. First, chiral resolution has been obtained here through salt formation. Lamivudine R-mandelate was isolated from an isopropyl alcohol solution of the drug and racemic mandelic acid in 1 : 2 stoichiometry. The robust two-point 2-aminopyridinium-carboxylate synthon was identified in this structure. Second, in the course of our investigations to know if diastereomeric salts could be formed from other solvent environment, S-mandelic acid cocrystal of lamivudine R-mandelate trihydrate has grown from a solution of water and ethyl alcohol loading the drug and racemic mandelic acid (lamivudine : racemic mandelic acid 1 : 2 stoichiometry). It is an example of a cocrystal of a salt whose enantiopreference was maintained for ionic pair formation between a lamivudinium cation and R-mandelate anion. Although chiral resolution was not viable in this structure, the robust synthon present in the salt phase was conserved even if both mandelic acid enantiomers are present together in the crystal lattice. Therefore, we here demonstrated the enantiopreference in the solid state even if chiral resolution does not occur.

Salt or cocrystal of salt? Probing the nature of multicomponent crystal forms with infrared spectroscopy.

Abstract The recognition of the nature of a multicomponent crystal form (solvate, salt, cocrystal or cocrystal of salt) is of great importance for pharmaceutical industry because it is directly related to the performance of a pharmaceutical ingredient, since there is interdependence between the structure, its energy and its physical properties. In this context, here we have identified the nature of multicomponent crystal forms of the anti-HIV drug lamivudine with mandelic acid through infrared spectroscopy. These investigated crystal forms were the known S-mandelic acid cocrystal of lamivudine R-mandelate trihydrate (1), a cocrystal of salt, and lamivudine R-mandelate (2), a salt. This approach also supports the identification and distinction of both ionized and unionized forms of mandelic acid in the infrared spectrum of 1. In this way, infrared spectroscopy can be useful to distinguish a cocrystal of salt from either salt or cocrystal forms. In the course of this study, for the first time we have also characterized and determined the crystal structure of R-mandelic acid cocrystal of sodium R-mandelate (3).

Identification and proportion of the enantiomers of the antihypertensive drug chlortalidone in its Form II by high quality single-crystal X-ray diffraction data.

Chlortalidone (CTD) is a diuretic drug largely used as part of antihypertensive therapies. It is marketed as an equimolar mixture of its enantiomers in the racemic crystal phase named Form I, despite of the higher aqueous solubility of another crystal form. The latter, named Form II, was thought to contain both enantiomers as a racemic conglomerate, i.e., in the form of a mixture of crystals, half of which consists solely of the (R)-enantiomer, the other half the (S)-enantiomer. The occurrence of both enantiomers in individual crystals of CTD Form II was demonstrated in this study. Spontaneous resolution does really occur upon crystallization, as presumed previously even without physical evidence of the (S)-enantiomer. Both (R) and (S)-enantiomers were successfully identified as two domains of a twinned by inversion single crystal of CTD Form II. A reliable Flack parameter of 0.14(4) allowed to determine the proportion of the enantiomers in the crystal, which is formed with 86% of the (R)-enantiomer and 14% of the (S)-enantiomer.

Polymorphism and conformerism in chalcones

Herein two solid state phenomena have been observed in two chalcones. Firstly, polymorphism has been found in (E)-1-(2-aminophenyl)-3-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (1). This compound crystallizes with only one conformer rather than three in the known reported structure. In the polymorphs, the conformation of the phenyl ring bonded to carbonyl differs slightly. The intermolecular hydrogen bonding from NH2 is the main interaction responsible for polymorphism. Our polymorph is assembled only with weak N–H⋯π interactions instead of strong N–H⋯O and N–H⋯N ones observed in the known structure. DFT calculations reveal that the three conformers of the known polymorph deviate from the minimum energy conformation which is adopted in our crystal form to compensate for the absence of strong intermolecular contacts. Second, conformerism is reported for (E)-1-(3-hydroxyphenyl)-3-(4-nitrophenyl)prop-2-en-1-one (2). Three crystallographically independent molecules are found in the structure of 2: two of them are similarly planar with an anti conformation around the single bond between the carbonyl and α carbons while the third one is twisted, with its phenyl ring bonded to carbonyl rotated by ca. 60° besides presenting a syn conformation around the corresponding rotatable bond. Both conformational features are related to the crystal packing, allowing accommodation of twisted molecules onto the layers made up of hydrogen bonded planar molecules. Furthermore, our potential energy surface scans indicate that the planar and twisted conformations of the phenyl ring bonded to carbonyl are not compatible with the syn and anti conformations of the chalcone skeleton.

Probing the competition between acetate and 2,2′-bipyridine ligands to bind to d-block group 12 metals

Herein, we were interested in probing the competition between 2,2′-bipyridine (2,2′-bipy) and acetate ligands in binding to Zn2+, Cd2+ and Hg2+. We have obtained eight new supramolecular architectures through tuning the proportion of these two ligands. On doubling the acetate availability compared to 2,2′-bipy, complexes with either Zn2+, Cd2+ or Hg2+ were formed with one 2,2′-bipy and two acetate ligands coordinated to the metal center. One water molecule is also coordinated to Zn2+ and Cd2+ in these two complexes, which are reported here for the first time. One 2,2′-bipy is still coordinated to the three metal ions with an acetate excess of 10-times, but another trinuclear Zn2+ complex is formed with two 2,2′-bipy and six acetate ligands (1 : 3 2,2′-bipy : acetate stoichiometry). Upon setting an equimolar ratio of the ligands, the complex [Zn(CH3CO2)(2,2′-bipy)2]+ is formed, while two 2,2′-bipy and two acetate ligands are coordinated to Cd2+, giving rise to a [Cd(CH3CO2)2(2,2′bipy)2] complex. On doubling the 2,2′-bipy availability compared to acetate, the former does not coordinate to Zn2+ and Cd2+, as observed in the acetate salt form of [Zn(2,2′-bipy)3]2+ and in [Cd(2,2′-bipy)3]2+. This last Cd2+ complex did not crystallize, revealing its unfavorable crystallization as an acetate salt form. However, under this last ligand ratio, the persistence of at least one coordinated acetate was observed in the Hg2+ complex with 2 : 1 2,2′-bipy : acetate stoichiometry. Furthermore, there is a cocrystallized 2,2′-bipy in the acetate salt form of [Hg(CH3CO2)(2,2′-bipy)2]+, which is not able to win the competition with acetate for the third coordination site to Hg2+. Even if the 2,2′-bipy amount is 10-times higher than that of acetate in the reaction batch, one acetate remains coordinated to Hg2+. Our crystal form of [Zn(CH3CO2)(2,2′-bipy)2]+ is strongly photoluminescent, with highly efficient emission centered at 356 nm (external and internal quantum yields of 14.2(1)% and 41.3(1)%), whose optical efficiency was rationalized on the basis of time-dependent DFT calculations.

Experimental and theoretical second harmonic generation and photoluminescence from the pseudo-centrosymmetric dihydrochloride salt dihydrate of trans-1,2-bis(4-pyridyl)ethene

Here we have prepared a dihydrochloride salt dihydrate of the well-known trans-1,2-bis(4-pyridyl)ethene (BPE) featuring both photoluminescent and nonlinear optical properties. In its triclinic lattice (space group P1), BPE cations are stacked face-to-tail through π⋯π interactions between the spacer double-bonded carbons and the protonated pyridyl ring, with a slippage of 3.45 A always towards the same direction, which is common in other NLO crystals. The existence of inversion symmetry was suggested in its crystal structure, which was ruled out by the SHG emission centred at 487 nm upon excitation at 974 nm. While the fully optimized single molecule of the divalent BPE cation in the gas phase had almost null μ, βtot, βCT and βvec values calculated at the CAM-B3LYP/NLO-V//B3LYP/6-31G* level of theory, these values differed from zero in the crystal conformation. More interestingly, a ca. 4-fold increase in βtot, α and μ was observed for the π⋯π stacked four-molecules as found in its crystal structure. Lastly, this BPE material presents high photoluminescence emission centred at 425 nm under excitation at 366 nm, being therefore a multifunctional optical crystal form.

Study of Reactions of Two Mannich Bases Derived of 4'-Hydroxychalcones with Glutathione by RP-TLC, RP-HPLC and RP-HPLC-ESI-MS Analysis

4’-Hydroxychalcones have been reported to possess several beneficial biological effects. Several lines of evidence accumulated to demonstrate increased biological activities of the Mannich base derivatives of the parent 4’-hydroxychalcones. Bioactivities of chalcones and related α,β-unsaturated ketones are frequently associated with their reactivity with cellular thiols, such as GSH. For comparison of GSH reactivity, two bis Mannich bases of two 4’-hydroxychalcones were synthesized and reacted with GSH under non-cellular conditions. Reversed-phase thin layer chromatography (RP-TLC) and reversed-phase high performance liquid chromatography (RP-HPLC) analysis showed formation of two polar products which structures were confirmed by RP-HPLC-ESI-MS (RP-HPLC-electrospray ionization mass spectrometry) as 1:1 chalcone-GSH adducts in each case. At pH values below 8.0, the two bis Mannich bases showed higher GSH reactivity than two 4’-hydroxychalcones. Influence of the nature of the amino groups, the ring-B substituents and pH of the medium on reactivity was also investigated. The findings could serve as useful structure-activity information for subsequent molecular modification of thiol-reactive 4’-hydroxychalcones.

Insights into the opening of DNA-like double-stranded helices in lamivudine duplex IV and the first polymorph of this drug

Here we report an enantiospecific assembly of the drug lamivudine with D-tartaric acid mimicking the opening of a DNA duplex. In this structure, named lamivudine duplex IV, the D-tartrate counterions are in charge of the opening of the two base-paired helically-stacked strands, in analogy to the role of helicase in nature. This multicomponent crystal between lamivudine and D-tartaric acid therefore provides insights into the molecular basis of nucleic acid strand separation. The hydroxyl group from either D-tartrate or a serine residue of helicase is a hydrogen bond donor to the sugar ring from a nucleoside, which suggests a base unpairing role of such an interaction. Furthermore, the enantiospecificity of such a phenomenon can be stated as being the result of the duplex opening through only the D enantiomer. When L-tartaric acid was used to attempt the opening of the lamivudine duplex, only a monohydrate salt without any base-pairing motif was obtained. The first anhydrous polymorph of lamivudine was also obtained in the course of our cocrystallization screening between lamivudine and L-tartaric acid. This new polymorph was named lamivudine form IV and is made up of only the drug, as observed in its commercial polymorphic form II. Lamivudine form IV consists of base-paired dimers held together by uncommon N–H⋯N hydrogen bonds, but they are not helically stacked due to the absence of an enantiospecific strand opener.