PART I. SOLID-STATE DESOLVATION STUDIES OF CEFTAZIDIME PENTAHYDRATE AND THE DICHLOROMETHANE AND DICHLOROETHANE SOLVATES OF O-FORMYLMANDELOYL-7-AMINOCEPHALOSPORANIC ACID. PART II. SOLID-STATE DECARBOXYLATION STUDIES OF 2-METHYL-2-PHENYL-PROPANEDIOIC ACID MODEL COMPOUNDS (DEHYDRATION, MALONIC ACID DERIVATIVES)

JOHN JOSEPH CHABER, Purdue University

Abstract

Part I. The crystal structure of ceftazidime pentahydrate was determined and its solid state dehydration behavior was studied. Crystals of ceftazidime pentahydrate obtained from water are orthorhombic and exhibit space group symmetry P2(,1)2(,1)2(,1), with unit cell dimensions: a = 10.422(4), b = 8.993(2), c = 31.62(1)(ANGSTROM). An analysis of the molecular packing revealed that the waters of hydration are arranged differently in the unit cell. Sixteen of the twenty waters per unit cell form two solvent tunnels which are approximately parallel to the crystallographic a axis. The remaining four waters are located in solvent pockets perpendicularly connected to the main solvent tunnels. At 27(DEGREES)C, the pentahydrate form is stable at relative humidity (RH) values greater than 6.5%. Below this RH value the pentahydrate form collapses to a different crystalline form containing less than one mole of water. Equilibrium rehydration of this collapsed form produced only a monohydrate form which by x-ray powder diffraction is crystallographically indistinct from the collapsed pentahydrate. Solid-state carbon-13 NMR substantiated that the greatest change in the pentahydrate's crystal structure upon dehydration is in the vicinity of the main solvent tunnels. Kinetic analysis of the dehydration revealed that the reaction could be described by the contracting area phase boundary model. This model gave an activation energy of 14.4 kcal/mole for the dehydration process. The crystal structures of the dichloromethane and dichloroethane solvates of O-Formylmandeloyl-7-aminocephalosporanic acid were determined. Crystals of both solvates were trigonal and exhibited space group symmetry P3(,1)21. The molecular packing arrangement in both solvates was identical, except the carbon atoms of the solvent molecules in the dichloromethane solvate lie on two three-fold special positions while in the dichloroethane solvate these special positions occur at the midpoint of the carbon-carbon bond. In general, the dichloroethane solvate is less stable than the dichloromethane solvate. These solvates collectively represent the first example of a cephalosporin derivative that crystallizes in a trigonal crystal class. Part II. A number of new 2-Methyl-2-phenylpropanedioic acid derivatives substituted at either the meta or para position on the phenyl ring were synthesized. In general, solid state stability towards decarboxylation decreased when either an alkoxy or alkyl group was substituted on the phenyl ring. Also, within either the meta or para series stability decreased as the size of the substituent group increased.

Degree

Ph.D.

Subject Area

Pharmacology

COinS