In Vitro Evaluation of Poly(lactide-co-glycolide) In Situ Forming Gels for Bedaquiline Fumarate Salt and Pharmacokinetics Following Subcutaneous Injection in Rats

This study evaluated in vitro and in vivo drug release of bedaquiline from in situ forming gels (ISGs) containing 200 mg eq./g bedaquiline fumarate salt prepared with four different grades of poly(d,l-lactide) (PDLLA) or poly(d,l-lactide-co-glycolide) (PLGA) with a lactide/glycolide ratio of 50/50 or 75/25 and acid (A) or ester (E) end-capping in N-methyl-2-pyrrolidone at a polymer/solvent ratio of 20/80% (w/w). Mean in vitro drug release in 0.05 M phosphate buffer pH 7.4 with 1% (w/v) sodium lauryl sulphate was 37.3, 47.1, 53.3, and 62.3% within 28 days for ISGs containing PLGA5050A, PDLLA, PLGA7525A, and PLGA7525E, respectively. The data suggested that drug release was primarily controlled by precipitated drug redissolving, rather than polymer erosion. In vivo pharmacokinetic profiles after subcutaneous injections in rats were comparable for all ISGs (mean half-lives (t1/2) ranged from 1411 to 1695 h) and indicated a sustained drug release when compared to a solution of bedaquiline fumarate salt in polyethylene glycol 400/water 50/50% (v/v) (mean t1/2 of 895 h). In conclusion, PLGA or PDLLA-based ISGs have shown potential for parenteral sustained delivery of bedaquiline, suggesting further preclinical and clinical studies. From a formulation point of view, this case example highlights the importance of the interplay between drug solubility in biological media and dissolution of drug precipitates, which, in addition to the incorporation of diffusion controlling polymers, governs the release of the active drug.

5-Methoxy-N,N-di-n-propyltryptamine (5-MeO-DPT): freebase and fumarate

The solid-state structures of the synthetic psychedelic 5-methoxy-N,N-di-n-propyltryptamine (5-MeO-DPT) {systematic name: N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-propylpropan-1-amine}, C17H25N2O, and its fumarate salt, bis(5-methoxy-N,N-di-n-propyltryptammonium) fumarate (systematic name: bis{N-[2-(5-methoxy-1H-indol-3-yl)ethyl]-N-propylpropan-1-aminium} but-2-enedioate), 2C17H25N2O+·C4H2O4 2−, are reported. The freebase has a single tryptamine molecule in the asymmetric unit. The molecules are linked together by N—H...N hydrogen bonds in zigzag chains along the [010] direction. The fumarate salt has a single tryptammonium cation and half of a fumarate dianion in the asymmetric unit. The tryptammonium and fumarate ions are held together in one-dimensional chains by a series of N—H...O hydrogen bonds. These chains are combinations of R 4 4(22) rings, and C 2 2(14) and C 4 4(28) parallel chains along [001].

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-methoxyquinolin-3-yl)-3-hydroxy-3-(naphthalen-1-yl)-4-phenylbutyl]dimethylazanium 3-carboxyprop-2-enoate}, C32H32BrN2O2 +·C4H3O4 −, namely, a hemihydrate, a tetrahydrofuran (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 hydromaleate and a singly protonated bedaquilinium cation. The maleate exhibits the strong intramolecular hydrogen bond typical for cis-dicarboxylic acid anions. The conformations of the cations and packing interactions in the maleate salts are compared to those of free base bedaquiline and other bedaquilinium salts.

Psilacetin derivatives: fumarate salts of the methyl–ethyl, methyl–allyl and diallyl variants of the psilocin prodrug

The solid-state structures of the salts of three psilacetin derivatives, namely, 4-acetoxy-N-ethyl-N-methyltryptammonium (4-AcO-MET) hydrofumarate {systematic name: [2-(4-acetyloxy-1H-indol-3-yl)ethyl](methyl)ethylazanium 3-carboxyprop-2-enoate}, C15H21N2O2 +·C4H3O4 −, 4-acetoxy-N-allyl-N-methyltryptammonium (4-AcO-MALT) hydrofumarate {systematic name: [2-(4-acetyloxy-1H-indol-3-yl)ethyl](methyl)prop-2-enylazanium 3-carboxyprop-2-enoate}, C16H21N2O2 +·C4H3O4 −, and 4-acetoxy-N,N-diallyltryptammonium (4-AcO-DALT) fumarate–fumaric acid (1/1) (systematic name: bis{[2-(4-acetyloxy-1H-indol-3-yl)ethyl]diprop-2-enylazanium} but-2-enedioate–(E)-butenedioic acid (1/1)), 2C18H23N2O2 +·C4H2O4 2−·C4H4O4, are reported. All three salts possess a protonated tryptammonium cation. The 4-AcO-MET and 4-AcO-MALT compounds are charge-balanced by 3-carboxyacrylate (hydrofumarate) anions. The 4-AcO-DALT complex crystallizes as a two-to-one tryptammonium-to-fumarate salt, which co-crystallizes with a fumaric acid molecule. Each structure is consolidated by N—H...O and O—H...O hydrogen bonds.

Fifteen 4-(2-methoxyphenyl)piperazin-1-ium salts containing organic anions: supramolecular assembly in zero, one, two and three dimensions

Fifteen 4-(2-methoxyphenyl)piperazin-1-ium salts containing organic anions have been prepared and structurally characterized. In the isostructural 4-chlorobenzoate and 4-bromobenzoate salts, C11H17N2O+·C7H4ClO2 − (I) and C11H17N2O+·C7H4BrO2 − (II), and the 4-iodobenzoate salt C11H17N2O+·C7H4IO2 − (III), the ions are linked by N—H...O hydrogen bonds, forming centrosymmetric R 4 4(12) four-ion aggregates; a similar aggregate is formed in the 2-chlorobenzoate salt (V), isomeric with (I). In the 2-fluorobenzoate salt C11H17N2O+·C7H4FO2 − (IV), and the isomorphous pair of salts, the 2-bromobenzoate (VI), isomeric with (II) and 2-iodobenzoate (VII), isomeric with (III), N—H...O and C—H...π(arene) interactions link the components into three-dimensional arrays. Four-ion R 4 4(12) aggregates are also found in the 2-methylbenzoate, 4-aminobenzoate and 4-nitrobenzoate salts, C11H17N2O+·C8H7O2 − (VIII), C11H17N2O+·C7H6NO2 − (IX) and C11H17N2O+·C7H4NO4 − (X), but those in (IX) are linked into complex sheets by an additional N—H...O hydrogen bond. In the 3,5-dinitrobenzoate salt, C11H17N2O+·C7H3N2O6 −·2H2O (XI), N—H...O and O—H...O hydrogen bonds link the components into a complex ribbon structure. In the picrate salt, C11H17N2O+·C6H2N3O7 − (XII), the four-ion aggregates are linked into chains of rings by C—H...O hydrogen bonds. In the hydrogen maleate salt, C11H17N2O+·C4H3O4 − (XIII), two- and three-centre hydrogen bonds link the ions into a ribbon structure while both anions contain very short but asymmetric O—H...O hydrogen bonds, having O...O distances of 2.4447 (16) and 2.4707 (17) Å. O—H...O Hydrogen bonds link the anions in the hydrogen fumarate salt (XIV), isomeric with (XIII), into chains that are linked into sheets via N—H...O hydrogen bonds. In the hydrogen (2R,3R)-tartrate salt, C11H17N2O+·C4H5O6 −·1.698H2O (XV), the anions are linked into sheets by O—H...O hydrogen bonds. Comparisons are made with the structures of some related compounds.

Norpsilocin: freebase and fumarate salt

The solid-state structures of the naturally occurring psychoactive tryptamine norpsilocin {4-hydroxy-N-methyltryptamine (4-HO-NMT); systematic name: 3-[2-(methylamino)ethyl]-1H-indol-4-ol}, C11H14N2O, and its fumarate salt (4-hydroxy-N-methyltryptammonium fumarate; systematic name: bis{[2-(4-hydroxy-1H-indol-3-yl)ethyl]methylazanium} but-2-enedioate), C11H15N2O+·0.5C4H2O4 2−, are reported. The freebase of 4-HO-NMT has a single molecule in the asymmetric unit joined together by N—H...O and O—H...O hydrogen bonds in a two-dimensional network parallel to the (100) plane. The ethylamine arm of the tryptamine is modeled as a two-component disorder with a 0.895 (3) to 0.105 (3) occupancy ratio. The fumarate salt of 4-HO-NMT crystallizes with a tryptammonium cation and one half of a fumarate dianion in the asymmetric unit. The ions are joined together by N—H...O and O—H...O hydrogen bonds to form a three-dimensional framework, as well as π–π stacking between the six-membered rings of inversion-related indoles (symmetry operation: 2 − x, 1 − y, 2 – z).