Formulation development of a continuously manufactured orodispersible film containing warfarin sodium for individualized dosing.

Continuously manufactured orodispersible films (ODFs) offer a promising approach for individualized therapy with an easy to administer solid dosage form. The aim of this study was to develop a long ODF containing warfarin sodium to enable safe and more flexible dosing. Formulation development was conducted systematically for the continuous film coating process. A continuously working pilot-scale coating bench was used for film manufacturing and the viscosities of the polymer solutions were investigated to obtain processible formulations. The investigation of the mechanical properties of the long film was an integral part of the study, because the handling of the long film during flexible dosing differs distinctly from the handling of a single dosed ODF. The secant modulus and the yield stress were evaluated as parameters with high information value about the deformation behavior of the ODF. A long warfarin ODF was successfully produced using the pilot-scale coating bench equipped with an optical probe for in-line film thickness measurement. It was feasible to use the principle of a tape dispenser for flexible and, therefore, individualized dosing as proof of concept. Combining the long ODF with a dosing device allows individualized therapy with warfarin for all age groups manageable by the patient himself.

Asymmetric synthesis of warfarin and its analogs catalyzed by C2-symmetric squaramide-based primary diamines.

Novel C2-symmetric N,N'-bis(2-amino-1,2-diphenylethyl)squaramides with 1,2-di(pyridin-2-yl)ethane and 1,2-diphenylethane spacer groups were designed and applied as organocatalysts in asymmetric additions of 4-hydroxycoumarin and 4-hydroxy-6-methyl-2H-pyran-2-one to α,ß-unsaturated ketones. Both enantiomers of the anticoagulant warfarin and its analogs were prepared in up to 96% yield and with 96% ee. Recyclability of the developed catalysts and synthetic utility of the prepared Michael adducts for asymmetric synthesis of potential chiral medications via acylation reactions were demonstrated.

An in vivo strategy to counteract post-administration anticoagulant activity of azido-Warfarin.

Drugs, usually long acting and metabolically stable molecules, might be the source of adverse effects triggered by complex drug interactions, anaphylaxis and drug-induced coagulopathy. To circumvent this growing drug safety issue, we herein investigate the opportunity offered by bio-orthogonal chemistry for in vivo drug neutralization. We design a small-molecule anticoagulant drug (Warfarin) containing an azide group that acts as a safety pin. It allows drug deactivation and restoration of physiological coagulation via in vivo click reaction with a suitable cyclooctyne-based neutralizing agent. In this strategy, the new molecule formed by reaction of the drug and the antidote is deprived of biological activity and prone to fast renal clearance. This 'Click &Clear' approach lays ground for new strategies in designing drugs with switchable biophysical properties.

Enzyme-catalyzed Michael addition for the synthesis of warfarin and its determination via fluorescence quenching of l-tryptophan.

A sensitive fluorescence sensor for warfarin was proposed via quenching the fluorescence of l-tryptophan due to the interaction between warfarin and l-tryptophan. Warfarin, as one of the most effective anticoagulants, was designed and synthesized via lipase from porcine pancreas (PPL) as a biocatalyst to catalyze the Michael addition of 4-hydroxycoumarin to α, ß-unsaturated enones in organic medium in the presence of water. Furthermore, the spectrofluorometry was used to detect the concentration of warfarin with a linear range and detection limit (3σ/k) of 0.04-12.0µmolL-1 (R2=0.994) and 0.01µmolL-1, respectively. Herein, this was the first application of bio-catalytic synthesis and fluorescence for the determination of warfarin. The proposed method was applied to determine warfarin of the drug in tablets with satisfactory results.

[Warfarin - its synthesis and properties in a twenty-year retrospective*]. / Warfarín - jeho syntéza a vlastnosti v dvadsatrocnej retrospektíve*

The review paper deals with some aspects of warfarin history and its use, at the beginning as a rodenticide and later as an anticoagulant. It describes its principal physical-chemical properties and it analyzes schematically the possibilities of its preparation by both selective and non-selective synthesis from coumarin derivatives. A survey of syntheses and its results are tabulated, including the literary references, and the paper is concluded with an evaluation of the prospects of this agent in comparison with alternative anticoagulants and its advantages, disadvantages and prospects.

Highly enantioselective synthesis of warfarin and its analogs catalysed by primary amine-phosphinamide bifunctional catalysts.

An efficient enantioselective Michael addition of 4-hydroxycoumarin to α,ß-unsaturated ketones catalysed by primary amine-phosphinamide bifunctional catalysts has been developed. This reaction afforded Warfarin and its analogs in moderate to excellent yields (up to 99%) and good to excellent enantioselectivities (up to 99% ee).

Synthesis and structure-activity relationships of novel warfarin derivatives.

4-Hydroxycoumarins such as warfarin 1 have been the mainstay of oral anticoagulation therapy for over 20 years. Yet little detail is known about the molecular interactions between 4-hydroxycoumarins with vitamin K epoxide reductase (VKER), inhibition of which produces a deficiency of vitamin K and consequently a deficiency of vitamin K-dependent proteins involved in thrombus formation. Using molecular probes, such as 4-sulfhydrylwarfarin 7 and 4-chlorowarfarin 10 it is shown in vitro that inhibition of VKER by warfarin is dependent on deprotonation of the 4-hydroxycoumarin moiety. In addition, the nature of the substituent on carbon 3 of the 4-hydroxycoumarin modulated inhibition. More specifically, a linear isoprenyl side chain increased inhibition of VKER when compared to cyclical substituents as present in warfarin. An example of a 4-hydroxycoumarin with an isoprenyl side chain is the natural product ferulenol 19 derived from Ferula communis. Ferulenol 19 confers approximately 22 times more potent inhibition than warfarin and is approximately 1.5 more potent than the rodenticide brodifacoum in this in vitro assay. Based on these data it is hypothesized that 4-hydroxycoumarins bind to the active site of VKER thereby mimicking the transition state of the elimination of water from substrate 2-hydroxyvitamin K.

A new entry to Pd-H chemistry: catalytic asymmetric conjugate reduction of enones with EtOH and a highly enantioselective synthesis of warfarin.

[reaction: see text] We report here the catalytic asymmetric conjugate reduction of enones using ethanol as a hydride source. The reaction was carried out in the presence of a chiral Pd complex at ambient temperature in ethanol, and the desired products were obtained in high chemical yield and high enantioselectivity. We applied this novel reaction to the catalytic asymmetric synthesis of warfarin (96% ee), and on the basis of d-labeling experiments, the reaction mechanism is proposed.

Improvement of the biological performance of oral anticoagulant drugs. 1. Warfarin.

Coevaporates of warfarin sodium containing different weight fractions of polyvinylpyrrolidone (Kollidon s5 and 30) polymers of different molecular weights were prepared and their characterization, dissolution properties as well as their bioavailability in rabbits were assessed. UV and IR spectrophotometery revealed a sort of binding between the drug and polymers. Optimum binding tendency appears at polymer weight fractions of 0.7 and 0.5 for Kollidon 25 and Kollidon 30, respectively. Incorporation of the drug with PVP enhances its dissolution properties and improves its bioavailability. Of all the investigated warfarin/PVP systems, the coevaporate of warfarin with an equal weight fraction of Kollidon 30 was found to exhibit optimum biological properties beside highest dissolution rate.

[The synthesis, toxicological and comparative cytogenetic characteristics of the anticoagulant warfarin]. / Sintez, toksikologichna i sravnitelna tsitogenetichna kharakteristika na antikoagulanta varfarin.

4-hydroxy-3-(3-oxo-1-phenyl butyl)-2H-1-benzopyran-2-one (warfarin) has been synthesised by an original method. The influence of a phase-transfer catalyst of ammonium type with alkyl substituents containing eight carbon atoms upon the reaction of Michael addition has been investigated. It has been found out that when elongating the hydrocarbon chain of the substituents to the nitrogen atom in the quaternary ammonium salt the yield of the product decreased. The acute (LD50) and subchronic (lasting for 30 days) toxicity was determined when taking warfarin orally. The experimental data show that LD50 is 500 mg/kg for mice and 420 mg/kg body mass for rats. The subchronic toxicity at experiments made with rabbits (each day taking orally respectively 25 and 100 mg/kg) does not reveal any humoral and tissue toxic influence of warfarin. The results from the comparative cytogenetic analysis of warfarin and Niffcumar are the basis of the conclusion cytogenetic analysis of warfarin and Niffcumar are the basis of the conclusion that warfarin damages chromosomes of mice's marrow cells (used as a model) less than Niffcumar. Moreover warfarin has a slight influence on these cells in the first place changing the orientation of chromosomes one towards the other and unlike other drugs it does not damage nuclear chromatin strongly.

Structure of (+-)-6-methyl-6,12-methano-6H,12H,13H-[1]benzopyran[4,3-d] [1,3]benzodioxocin-13-one.

A derivative of warfarin, racemic C19H14O4, Mr = 306.32, monoclinic, Cc, a = 9.594 (2), b = 20.437 (4), c = 7.793 (2) A, beta = 109.94 (3) degree, V = 1436.4 (11) A3, Z = 4, Dx = 1.416 g cm-3, lambda(CuK alpha) = 1.5418 A, mu = 7.742 cm-1, F(000) = 640, T = 293 K, final R = 0.053 for 1224 observations. The title molecule, formed by spontaneous dehydration of 2'-hydroxy-warfarin, is a cyclic ketal in which the side-chain phenyl is disposed pseudoaxially and is linked through a 2'-oxygen to the ketal carbon in a fixed cis 1,3-diaxial configuration. Two dihydropyran rings are formed; one fused with the benzopyran ring adopts an e,f-diplanar conformation, the other is a chroman and is in a similar conformation.

A new warfarin metabolite: structure and function.

The metabolism of the clinically utilized, anticoagulant warfarin [4-hydroxy-3-(3-oxo-1-phenylbutyl)-2H-1-benzopyran-2-one] by rat liver microsomes has been investigated. The structure of a new warfarin metabolite [4-hydroxy-3-(3-oxo-1-phenyl-1-butenyl)-2H-1-benzopyran-2-one] (dehydrowarfarin) has been determined by mass spectral comparison with the chemically synthesized compound. The formation of dehydrowarfarin is catalyzed by cytochrome P-450 and is unusual in that the final product is effectively dehydrogenated warfarin.