Dmitrijs Stepanovs

Multicomponent pharmaceutical cocrystals: furosemide and pentoxifylline

The combination of the active pharmaceutical ingredients furosemide [4-chloro-2-(furan-2-ylmethylamino)-5-sulfamoylbenzoic acid] and pentoxifylline [3,7-dimethyl-1-(5-oxohexyl)-3,7-dihydro-1H-purine-2,6-dione] produces a 1:1 cocrystal, C(12)H(11)ClN(2)O(5)S·C(13)H(18)N(4)O(3), (I), a 1:1 cocrystal hydrate, C(12)H(11)ClN(2)O(5)S·C(13)H(18)N(4)O(3)·H(2)O, (II), and a 1:1 cocrystal acetone solvate, C(12)H(11)ClN(2)O(5)S·C(13)H(18)N(4)O(3)·C(2)H(6)O, (III). These structures exhibit the presence of a rarely encountered synthon with the graph set R(2)(2)(7). All potential hydrogen-bond donors of furosemide participate in hydrogen-bond formation in (I)-(III). However, only two hydrogen-bond acceptors of furosemide are active in (I) and (II), and only one is active in (III). Four hydrogen-bond acceptors of pentoxifylline are active in (II), three in (I) and two in (III). These observations are in good agreement with the calculated packing indexes of 69.5, 69.6 and 68.8% for (II), (I) and (III), respectively.

Molecular and Crystal Structure of Sildenafil Base

Sildenafil citrate monohydrate, well known as Viagra®, is a drug for the treatment of erectile dysfunction. Here we present the X-ray crystal structure of the sildenafil base, C22H30N6O4S. The compound crystallizes in the monoclinic system, space group P21/c with the unit cell parameters a = 17:273(1), b=17:0710(8), c=8:3171(4) Å , b =99:326(2), Z = 4, V = 2420:0(3) Å3. A comparison with the known crystal structures of sildenafil citrate monohydrate and sildenafil saccharinate is also presented. Graphical Abstract Molecular and Crystal Structure of Sildenafil Base

Crystal structures and physicochemical properties of diltiazem base and its acetylsalicylate, nicotinate and L-malate salts

Diltiazem is a drug used as a calcium channel blocker in the treatment of cardiovascular disorders. Because of the poor aqueous solubility of the drug, its hydrochloride salt has been marketed. Due to the short elimination half-life of diltiazem, extended-release formulations were developed. In the present work, the crystal engineering approach has been employed to obtain diltiazem forms with lower water solubility by treating with carboxylic acids. Three molecular salts of diltiazem with aspirin, niacin and L-malic acid were synthesized and characterized by single crystal and powder XRD, DTA, solid state CP-MAS, NMR and UV/vis techniques. The single crystal structure determination allowed us to study the supramolecular structures and proton transfer interactions from the carboxylic acids to diltiazem in the solid state, while the NMR studies showed the interactions in solution. In the crystal, the N,N-(dimethyl)ethylamine fragment of the drug molecule interacts with the carboxylic groups of the acids to form heterosynthons. The maximum 40-fold decrease of the aqueous solubility is achieved for diltiazem acetylsalicylate hydrate in comparison with the solubility of diltiazem hydrochloride.

Synthesis and Applications of Silyl 2-Methylprop-2-ene-1-sulfinates in Preparative Silylation and GC-Derivatization Reactions of Polyols and Carbohydrates.

Trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, and triisopropylsilyl 2-methylprop-2-ene-1-sulfinates were prepared through (CuOTf)2⋅C6H6-catalyzed sila-ene reactions of the corresponding methallylsilanes with SO2 at 50 °C. Sterically hindered, epimerizable, and base-sensitive alcohols gave the corresponding silyl ethers in high yields and purities at room temperature and under neutral conditions. As the byproducts of the silylation reaction (SO2 +isobutylene) are volatile, the workup was simplified to solvent evaporation. The developed method can be employed for the chemo- and regioselective semiprotection of polyols and glycosides and for the silylation of unstable aldols. The high reactivity of the developed reagents is shown by the synthesis of sterically hindered per-O-tert-butyldimethylsilyl-α-D-glucopyranose, the X-ray crystallographic analysis of which is the first for a per-O-silylated hexopyranose. The per-O-silylation of polyols, hydroxy carboxylic acids, and carbohydrates with trimethylsilyl 2-methylprop-2-ene-1-sulfinate was coupled with the GC analysis of nonvolatile polyhydroxy compounds both qualitatively and quantitatively.

Molecular salts of propranolol with dicarboxylic acids: diversity of stoichiometry, supramolecular structures and physicochemical properties

Crystallization of the drug propranolol with dicarboxylic acids yielded stable crystalline molecular salts with oxalic and fumaric acids in molar ratios of 1 : 1 and 2 : 1, and with maleic acid in a molar ratio of 1 : 1 only. The melting points of the salts obtained were roughly twice the melting point of pure propranolol, while their aqueous solubility was significantly higher in comparison to that of the propranolol base.

Monoclinic polymorph of 3,7-dimethyl-1-(5-oxohex­yl)-3,7-dihydro-1H-purine-2,6-dione

The structure of the title compound, pentoxifylline, C13H18N4O3, has been previously characterized as a triclinic polymorph [Pavelčík et al. (1989 ▶). Acta Cryst. C45, 836–837]. We have discovered the monoclinic form. There are no strong hydrogen bonds in the crystal structure, rather, moderate C—H⋯O hydrogen bonds are present, which serve to stabilize the three-dimensional architecture.

Structural characterization of cevimeline and its trans-impurity by single crystal XRD.

Cevimeline is muscarinic receptor agonist which increases secretion of exocrine glands. Cevimeline base is a liquid (m.p. 20-25 °C) at ambient conditions, therefore its pharmaceutical formulation as a solid hydrochloride hemihydrate has been developed. The synthesis of cevimeline yields its cis- and trans-isomers and only the cis-isomer is recognized as the API and used in the finished formulation. In this study structural and physicochemical investigations of hydrochloride hemihydrates of cis- and trans-cevimelines have been performed. Single crystal X-ray analyses of both cis- and trans-isomers of cevimeline are reported here for the first time. It was found that the cis-isomer, the API, has less dense crystal packing, lower melting point and higher solubility in comparison to the trans-isomer.

Crystal structures of two (±)-exo-N-isobornyl-acetamides.

The title compounds consist of a 1,7,7-trimethylbicyclo[2.2.1]heptane (bornane or camphane) skeleton which is decorated with acetamide for (±)-(1) and chloroacetamide for (±)-(2), functionalities. In the crystals of both compounds, molecules are linked via N—H⋯O hydrogen bonds, reinforced by C—H⋯O contacts, forming chains propagating along the a axis.

Crystal structure of 3-O-benzyl-4(R)-C-(1-benzyl-1H-1,2,3-triazol-4-yl)-1,2-O-iso­propyl­idene-α-d-erythro­furan­ose

The title compound is a substituted 2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxole. The furanose ring adopts an envelope conformation, close to C 3-exo, as does the fused dioxolane ring. In the crystal, molecules are linked by weak C—H⋯O hydrogen bonds, forming zigzag chains along [010].

Crystal structure of 3-C-(N-benzyl-oxy-carbon-yl)amino-methyl-3-de-oxy-1,2:5,6-di-O-iso-propyl-idene-α-d-allo-furan-ose.

The title compound consists of a substituted 2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxolane skeleton. The furanose ring adopts a conformation close to C 3-exo. Both dioxolane rings adopt envelope conformations with an O atom as the flap in each case. In the crystal, molecules are linked by N—H⋯O hydrogen bonds, forming chains propagating along the b-axis direction.