טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentGoldring Dmitry
SubjectSynthesis and Polymorphism of Crystalline Pharmaceutical
Compounds
DepartmentDepartment of Chemistry
Supervisor Professor Emeritus Menahem Kaftory


Abstract

The purpose of this research is synthesis and characterization of new stable polymorphs and solvate forms of two organic API - Torsemide, Zafirlukast - containing sulfonamide-group in their molecular structures.

Zafirlukast is a first anti-asthmatic leukotriene antagonist which are known to be powerful spasmogens (particularly in the lung), to increase vascular permeability and have been implicated in pathogenesis of asthma and inflammation and traumatic shock  The crystal structures of three solvates of zafirlukast [systematic name: cyclopentyl N-{1-methyl-3-[2-methyl-4-(o-tolylsulfonylaminocarbonyl)benzyl]-1H-indol-5-yl}carbamate], viz. the monohydrate, C31H33N3O6S·H2O, (I), the methanol solvate, C31H33N3O6S·CH3OH, (II), and the ethanol solvate, C31H33N3O6S·C2H5OH, (III), have been determined by single crystal

X-ray diffraction analysis, infrared spectroscopy (IR), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and hot-stage microscopy. All three compounds crystallize in the monoclinic crystal system. Zafirlukast adopts a similar Z-shaped conformation in all three solvates. The methanol and ethanol solvates are isostructural. The packing of the zafirlukast molecules in all three crystal structures is similar and is expressed by hydrogen-bonded molecules that are related by translation, along (101) in (I) and along the b axis in (II) and (III). The methanol and ethanol solvent molecules are hydrogen bonded to two molecules of zafirlukast. The water molecule, on the other hand, acts as a connector via hydrogen bonds between three molecules of zafirlukast. The solvent molecules are not released at temperatures below the melting points of the solvates.

Torsemide, 1-isopropyl-3-[(4-m-toluidino-3-pyridyl)sulfonyl] urea is a lipophilic sulphonylurea derivative with pharmacological properties of a high ceiling loop diuretic. Torsemide is used for the treatment of hypertension and edema associated with congestive heart failure, renal disease or hepatic disease. In this thesis we represents our novel process for synthesis of Torsemide via Torsemide Lithium Hydrate. The metal salts of Torsemide, is a stable compound which may be isolated from the reaction mixture by filtration to give, after acidification highly pure Torsemide without further purification steps.

Series of new crystalline solvates of Torsemide Lithium were synthesized: hydrate, ethanolate and iso-butanolate. Torsemide Lithium Hydrate was obtained in highly stable crystalline form.

The purity of Torsemide Lithium determined by reversed-phase HPLC method, which we have developed, was more than 99.9 %. All potential impurities were synthesized and determined by the HPLC method (HPLC impurity profile).

We have found a new group of solid compounds of Torsemide with different acids - Hydrochloric, Formic, Butyric and Hexanoic acids. The crystalline compounds were isolated and characterized by DSC, TGA, XRPD and FT-IR.