Tetroxoprim Research Articles

Thermal studies of solvent exchange in isostructural solvates of a tetroxoprim-sulfametrole complex

Isostructural solvates of the 1:1 molecular complex between the antibacterial drugs tetroxoprim (TXP) and sulfametrole (SMTR) with formulae TXP·SMTR·CH3OH (I), TXP·SMTR·C2H5OH (II) and TXP·SMTR·H2O (III), were investigated to establish their propensity for guest exchange. Separate exposure of powdered (I), (II) and (III) to a saturated atmosphere of each solvent of the complementary solvate pair at ambient temperature resulted in reversible solvent exchange in all cases. DSC and TG were the methods of choice for monitoring the exchange processes since (I)-(III) have distinct onset temperatures of desolvation and characteristic mass losses. Interpretation of the results in terms of the known locations of the solvent molecules in crystals of (I)-(III) led to the conclusion that solvent exchange probably proceeds by a co-operative mechanism involving material transport through channels while the common host framework is maintained.

Order‐Disorder Enantiotropy, Monotropy, and Isostructurality in a Tetroxoprim‐Sulfametrole 1:1 Molecular Complex: Crystallographic and Thermal Studies

Two enantiotropic polymorphs of a tetroxoprim (TXP)‐sulfametrole (SMTR) 1:1 molecular complex monohydrate and two isostructural TXP‐SMTR 1:1 molecular complex solvates with methanol and ethanol were grown and studied by X‐ray diffraction and thermal methods (thermogravimetric analysis and differential scanning calorimetry). Interconversion of the polymorphic hydrates is essentially an order/disorder transition involving a substituent on the TXP molecule. These hydrated phases may be described as “nearly isostructural” with the methanol and ethanol solvates. Thermal data for decomposition of the solvates were rationalized on the basis of the location and topologies of solvent crystallographic sites. Solid‐state properties of two monotropic polymorphs of the unsolvated TXP‐SMTR 1:1 molecular complex were also investigated and the theoretical and experimental phase diagrams of the individual components were assessed. The existence of polymorphic and pseudopolymorphic forms is determined by conformational flexibility of the TXP‐SMTR bimolecular complex components, a tendency for molecular disorder in TXP, the ability of the drug complex to form intricate, highly stabilized hydrogen‐bonded frameworks, and the competition between nonspecific van der Waals and specific hydrogen bond interactions. © 2003 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 92:2164–2176, 2003

Structural relationships, thermal properties, and physicochemical characterization of anhydrous and solvated crystalline forms of tetroxoprim

Six distinct phases of the antibacterial tetroxoprim (TXP) have been isolated by recrystallization from various solvents. These comprise two polymorphs, forms I and II, and four solvates with the following solvents and TXP solvent stoichiometric ratios: chloroform (3:2), water (3:2), methanol (2:1), and ethanol (2:1). Thermal and infrared spectral data showed that forms I and II are enantiotropically related with form II being stable below the transition temperature of 118°C and form I melting at 159°C. The crystal structure of form I contains three crystallographically independent TXP molecules arranged in layers formed by extensive base pairing between the 2,4‐diaminopyrimidine rings. This species invariably results upon heating the solvates of TXP. Thermogravimetry and differential scanning calorimetry respectively showed one‐step mass losses and progressively increasing desolvation temperatures for the solvates with chloroform, water, ethanol, and methanol. X‐ray diffraction studies revealed that the latter three solvates are isostructural, belonging to the class of “isolated site” solvates. Extensive base pairing maintains the common TXP crystalline framework. Thermal data for the desolvation of these phases are reconciled with the observed crystal packing features. Experimental and computed powder X‐ray patterns for form I and the solvates with water, methanol, and ethanol are presented.

Diffusion of metioprim, tetroxoprim and sulphadiazine in the cerebrospinal fluid of dogs with healthy meninges and dogs with experimental meningitis.

The diffusion of metioprim (MTP), tetroxoprim (TXP) and sulphadiazine (SDZ) in cerebrospinal fluid (CSF), following single intravenous doses and continuous infusions, was studied in dogs. The drugs penetrated well into the CSF of animals with and without experimental Staphylococcus aureus meningitis. In dogs with healthy meninges, the CSF bioavailability - expressed as the ratio of CSF/plasma area under the curve 0-5-hour values - following continuous infusion was determined to be 86.7% for MTP, 58.2% for TXP and 38.8% for SDZ. In infected animals, CSF availability following continuous infusion increases slightly to ratios of 96% (MTP), 70% (TXP) and 50% (SDZ). For all drugs, the concentrations reached in CSF were above the minimum inhibition concentrations for the majority of Enterobacteriaceae, indicating their potential value in treatment of gram-negative bacillary meningitis.

The pharmacokinetics of tetroxopim in the dog

The pharmacokinetics and metabolism of the newly developed antibacterial tetroxoprim (TXP) were investigated in four male beagle dogs using a 2-(14C)-labelled drug. TXP was administered intravenously and orally at doses of 5 mg/kg bodyweight. Counting of the total 14C-radioactivity shows that the drug was absorbed completely and eliminated almost exclusively by the kidneys. The quantitative absorption of TXP from the canine gastro-intestinal tract was ascertained by comparison of the AUC-values and the renal recoveries of unchanged drug following i.v. and oral dosage. The terminal half-lives of non-metabolized compound in plasma were 4.64 and 4.83 for i.v. and oral dosing respectively. Following either i.v. or oral TXP administration, the major route of excretion was renal elimination of the compound as its major metabolite U-1 (81-82.2% of dose) and as unchanged mother substance (11.4-12.3% of dose).

Biliary excretion of tetroxoprim in man.

The biliary excretion of tetroxoprim (TXP) was studied in 10 patients with T-tube drainage. A mean biliary peak of 32.56 +/- 7.69 micrograms/ml was observed 2-3 h after a single oral dose of 200 mg. The biliary elimination rate constant (kb) of TXP was found to be 0;056 (h-1), indicating a longer elimination from the bile than from the central blood compartment. Taking into account the TXP serum levels, following the same oral dose as reported in the literature, concentration factors of 6-8 can be calculated in the bile.

Determination of 2,4-diamino-5-benzylpyrimidines in combination with sulphadiazine in biological fluids using high-performance liquid chromatography

High-performance liquid chromatographic methods for the simultaneous analysis of tetroxoprim (TXP)/sulphadiazine (SDZ) and metioprim (MTP)/SDZ in serum and prostatic secretion (PS) are described. The detection limits in serum and PS were 50 ng TXP per ml and 100 ng SDZ per ml, and 40 ng MTP per ml and 100 ng SDZ per ml, respectively. The intra-assay coefficients of variation were in the range of 2.7–2.19%. Some preliminary data from a pharmacokinetic study in geriatric patients and a distribution study in dogs are presented. These methods enable the investigator to process a large number of TXP/SDZ and MTP/SDZ samples in one working day.

Pharmacokinetics of tetroxoprim and sulphadiazine in various species.

Pharmacokinetics of tetroxoprim and sulphadiazine in various species.