Anti-solvent Precipitation Method Coupled Electrospinning Process to Produce Poorly Water-Soluble Drug-Loaded Orodispersible Films.

Orodispersible films (ODFs) are more convenient for paediatric and geriatric patients to take as compared to conventional tablets and capsules. Electrospinning has recently been attempted to produce ODFs. This study investigated the feasibility of formulating poorly water-soluble drug into ODFs using electrospinning technology coupled with the anti-solvent precipitation method. Piroxicam (PX), a poorly water-soluble drug, was chosen as a model drug. Polyvinyl alcohol and polyvinylpyrrolidone were used as film forming polymers. PX microcrystals were prepared using poloxamer as the stabilizer with the anti-solvent precipitation method, and then loaded in ODFs through the electrospinning process. The obtained ODFs were characterized using a scanning electron microscope, X-ray powder diffraction and Fourier transform infrared spectroscopy with respect to the morphology, solid state and potential molecular interaction between the model drug and polymers. The mechanical property, disintegration and dissolution rate of the obtained ODF were evaluated using dynamic mechanical analysis, a customized method and USP2 apparatus. The results showed that PX microcrystals suspended in polymeric solutions could be readily electrospun into fibrous films, where the microcrystals scattered between the fibers. The electrospun fibrous film-based ODFs exhibited satisfactory mechanical behaviour, and fast disintegration upon the polymer selection. In the dissolution tests, almost 90% of PX was dissolved within 6 min from the ODFs, whereas 40% of PX dissolved from physical mixtures in 60 min. This study demonstrated that poorly water-soluble drugs could be formulated into ODFs with satisfactory quality attributes by combining micronization and the electrospinning process.

Pectin, beta-cyclodextrin, chitosan and albumin based gastroprotective systems for piroxicam maleate: Synthesis, characterization and biological evaluation.

In order to optimize drug action, new drug formulations have been developed based upon the prodrug approach. This study was inspired by the increasing interest in the field of macromolecular prodrugs and Piroxicam maleate was used as a model drug. A total of five prodrugs were synthesized using beta cyclodextrin, chitosan, pectin, egg albumin, bovine serum albumin. The synthesized conjugates were characterized on the basis of UV, IR and NMR techniques. In-vitro hydrolysis studies were carried out at pH 1.2, pH 7.4, pH 9.0 and in 80% human plasma followed by in-vivo evaluation of analgesic, anti-inflammatory and anti-ulcerogenic potential. The extent of hydrolysis was found to be proportional to increase in pH. Beta cyclodextrin conjugate was found to possess significant analgesic activity whereas chitosan conjugate was found to be the best anti-inflammatory. Pectin conjugate provided maximum protection against ulcers.

Piroxicam: Source for Synthesis of Central Nervous System (CNS) Acting Drugs.

BACKGROUND: The use of central nervous system (CNS) acting drugs in the management of neuro degenerative and psychiatric problems cannot be overemphasized. Therefore, the chemical structure of piroxicam can be modified to yield new CNS stimulants and depressants that can be of great benefit to man and animals. METHODOLOGY: Acetylcholine has Methyl - Oxygen-Oxygen (M-O-O) and Nitrogen (N) functional groups which are structurally related to Sulphur-Oxygen-Oxygen (S-O-O) and Nitrogen (N) of piroxicam that are either methylated or hydrogenated. Each arecoline and nicotine has M-O-O in addition to methylated nitrogen and pyridine ring respectively, making them structurally related to piroxicam. Therefore, when Sulphur of piroxicam is replaced by methyl group, it may likely have muscarinic effects expressed by glandular secretion, gut sedation and vasodepression. Whereas the nitrogen group may be responsible for cholinergic effect in gaglia and striated muscle. Because of the carboxylic functional group (COOH), piroxicam may display depressant effect. Hence C = O, C = N and C = C in piroxicam may change due to biofield treatement. CONCLUSION: The conversion of piroxicam to central nervous system (CNS) acting drugs may be by desulphation, methylation, dehydrogenation, carboxylation and carbonylation. The would-be synthesized CNS drugs from piroxicam, should have low molecular weight, lipid solubility and low PH.

Synthesis of new piroxicam derivatives and their influence on lipid bilayers.

A novel series of potentially biologically active 1,2-benzothiazine 1,1-dioxides--analogs of piroxicam (a recognized non-steroidal anti-inflammatory drug) were synthesized from commercially available saccharin. All of the synthesized compounds were subjected to preliminary evaluation for their ability to interact with lipid bilayers. The influence of the new derivatives of piroxicam on liposomes made of EYPC was investigated by fluorescence spectroscopy with two fluorescent probes--Laurdan and Prodan. All the studied compounds showed an interaction with model membranes.

Design, synthesis, antinociceptive and anti-inflammatory activities of novel piroxicam analogues.

In this paper we report the design, synthesis, antinociceptive and anti-inflammatory activities of a series of benzothiazine N-acylhydrazones 14a­h, planned by structural modification of piroxicam (1), a non steroidal anti-inflammatory drug. Among the synthesized analogues, compounds 14f (LASSBio-1637) and 14g (LASSBio-1639) were identified as novel antinociceptive and anti-inflammatory prototypes, active by oral administration, acting by a mechanism of action that seems to be different from that of piroxicam, since they were inactive as an inhibitor of cyclooxygenase (COX-1 and COX-2) at concentrations of 10 mM.

Synthesis and structure analysis of cyclodehydration product of piroxicam: a metabolite detected in dogs and monkeys.

We report here a novel synthesis of 6-methyl-6H-7-oxopyrido[1,2-a]pyrimido[5,4-c]-1,2-benzothiazine-5,5-dioxide or cyclodehydration product of piroxicam, a metabolite detected in dogs and monkeys that was synthesized in 6% yield earlier. The reaction of benzoyl chloride with piroxicam in the presence of triethylamine afforded the piroxicam metabolite in good yield. A comparison of spectral data of the synthesized compound with the reported values remained inconclusive. The structure of the compound was confirmed unambiguously by single-crystal X-ray analysis.

Unusual coordinating behavior by three non-steroidal anti-inflammatory drugs from the oxicam family towards copper(II). Synthesis, X-ray structure for copper(II)-isoxicam, -meloxicam and -cinnoxicam-derivative complexes, and cytotoxic activity for a copper(II)-piroxicam complex.

Cytotoxic tests recently performed at National Cancer Institute, NCI (USA), on [Cu(HPIR)(2)(DMF)(2)], 1, (H(2)PIR=piroxicam, 4-hydroxy-2-methyl-N-pyridin-2-yl-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) a widely used non-steroidal anti-inflammatory drug, NSAID [see R. Cini, G. Giorgi, A. Cinquantini, C. Rossi, M. Sabat, Inorg. Chem. 29 (1990) 5197-5200, for synthesis and structural characterization, DMF=dimethylformamide] (NSC #624662) by using a panel of ca. 50 human cancer cells, showed growth inhibition factor GI(50) values as low as 20microM against several cancer lines, with an average value 54.4microM. The activity of 1 is larger against ovarian cancer cells, non-small lung cancer cells, melanoma cancer cells, and central nervous system cancer cells. The widely used anticancer drug carboplatin (cis-diammine(1,1-cyclobutanedicarboxylato)platinum(II)) (NSC #241240) has average GI(50) value of 102microM. The reactions of copper(II)-acetate with other NSAIDs from the oxicam family were tested and crystalline complexes were obtained and characterized. Isoxicam (H(2)ISO=4-hydroxy-2-methyl-N-(5-methylisoxazol-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) produced [Cu(HISO)(2)].0.5DMF, 2.0.5DMF (DMF=dimethylfomamide). The coordination arrangement is square-planar and the HISO(-) anions behave as ambi-dentate chelators via O(amide),N(isoxazole) and O(enolate),O(amide) donors. Meloxicam (H(2)MEL=4-hydroxy-2-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) produced [Cu(HMEL)(2)(DMF)].0.25H(2)O, 3.0.25H(2)O. The coordination arrangement is square-pyramidal, the equatorial donors being O(amide),N(thiazole) from two HMEL(-) anions and the apical donor being O(DMF). Unexpectedly, cinnoxicam (HCIN=2-methyl-1,1-dioxido-3-[(pyridin-2-ylamino)carbonyl]-2H-1,2-benzothiazin-4-yl-(3-phenylacrylate)) produced [Cu(MBT)(2)(PPA)(2)] (MBT=3-(methoxycarbonyl)-2-methyl-2H-1,2-benzothiazin-4-olate 1,1-dioxide, PPA=3-phenyl-N-pyridin-2-ylacrylamide).

Uranyl binary and ternary chelates of tenoxicam Synthesis, spectroscopic and thermal characterization of ternary chelates of tenoxicam and alanine with transition metals.

Ternary Fe(III), Co(II), Ni(II), Cu(II), Zn(II) and UO(2)(II) chelates with tenoxicam (Ten) drug (H(2)L(1)) and dl-alanine (Ala) (HL(2)) and also the binary UO(2)(II) chelate with Ten were studied. The structures of the chelates were elucidated using elemental, molar conductance, magnetic moment, IR, diffused reflectance and thermal analyses. UO(2)(II) binary chelate was isolated in 1:2 ratio with the formula [UO(2)(H(2)L)(2)](NO(3))(2). The ternary chelates were isolated in 1:1:1 (M:H(2)L(1):L(2)) ratios and have the general formulae [M(H(2)L(1))(L(2))(Cl)(n)(H(2)O)(m)].yH(2)O (M=Fe(III) (n=2, m=0, y=2), Co(II) (n=1, m=1, y=2) and Ni(II) (n=1, m=1, y=3)); [M(H(2)L(1))(L(2))](X)(z).yH(2)O (M=Cu(II) (X=AcO, z=1, y=0), Zn(II) (X=AcO, z=1, y=3) and UO(2)(II) (X=NO(3), z=1, y=2)). IR spectra reveal that Ten behaves as a neutral bidentate ligand coordinated to the metal ions via the pyridine-N and carbonyl-O groups, while Ala behaves as a uninegatively bidentate ligand coordinated to the metal ions via the deprotonated carboxylate-O and amino-N. The magnetic and reflectance spectral data confirm that all the chelates have octahedral geometry except Cu(II) and Zn(II) chelates have tetrahedral structures. Thermal decomposition of the chelates was discussed in relation to structure and different thermodynamic parameters of the decomposition stages were evaluated.

Mononuclear metal complexes with piroxicam: synthesis, structure and biological activity.

Piroxicam (=Hpir) is a non-steroidal anti-inflammatory and an anti-arthritic drug. VO(2+), Mn(2+), Fe(3+), MoO(2)(2+) and UO(2)(2+) complexes with deprotonated piroxicam have been prepared and characterized with the use of infrared, UV-Vis, nuclear magnetic resonance and electron paramagnetic resonance spectroscopies. The experimental data suggest that piroxicam acts as a deprotonated bidentate ligand in all complexes and is coordinated to the metal ion through the pyridine nitrogen and the amide oxygen. Molecular mechanics calculations in the gas state have been performed in order to propose a model for the Fe(3+), VO(2+) and MoO(2)(2+) complexes. Potential anticancer cytostatic and cytotoxic effects of piroxicam complexes with VO(2+), Mn(2+) and MoO(2)(2+) on human promyelocytic leukemia HL-60 cells have been investigated. Among all complexes, only VO(pir)(2)(H(2)O) clearly induces apoptosis after 24-h incubation, whereas piroxicam induces apoptosis after 57-h incubation.

Synthesis, investigation and spectroscopic characterization of piroxicam ternary complexes of Fe(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) with glycine and DL-phenylalanine.

The ternary piroxicam (Pir; 4-hydroxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide) complexes of Fe(II), Fe(III), Co(II), Ni(II), Cu(II) and Zn(II) with various amino acids (AA) such as glycine (Gly) or DL-phenylalanine (PhA) were prepared and characterized by elemental analyses, molar conductance, IR, UV-Vis, magnetic moment, diffuse reflectance and X-ray powder diffraction. The UV-Vis spectra of Pir and the effect of metal chelation on the different interligand transitions are discussed in detailed manner. IR and UV-Vis spectra confirm that Pir behaves as a neutral bidentate ligand coordinated to the metal ions via the pyridine-N and carbonyl group of the amide moiety. Gly molecule acted as a uninegatively monodentate ligand and coordinate to the metal ions through its carboxylic group, in addition PhA acted as a uninegatively bidentate ligand and coordinate to the metal ions through its carboxylic and amino groups. All the chelates have octahedral geometrical structures while Cu(II)- and Zn(II)-ternary chelates with PhA have square planar geometrical structures. The molar conductance data reveal that most of these chelates are non electrolytes, while Fe(III)-Pir-Gly, Co(II)-, Ni(II)-, Cu(II)- and Zn(II)-Pir-PhA chelates were 1:1 electrolytes. X-ray powder diffraction is used as a new tool to estimate the crystallinity of chelates as well as to elucidate their geometrical structures.

Evaluation of beta-lactose, PVP K12 and PVP K90 as excipients to prepare piroxicam granules using two wet granulation techniques.

The present investigation aimed at evaluating the use of different excipients, beta-lactose and polyvinylpyrrolidone of two molecular weights (PVP K12 and PVP K90), in the production of improved release piroxicam granules, by wet granulation using both water and steam as granulation liquid. The formulations examined were: piroxicam (Px)/beta-lactose; Px/PVP K12 and Px/PVP K90, each one at a 1:9 weight ratio. The most significant difference between beta-lactose and PVP is that, using the first excipient, both steam and water granules were produced while, when PVP were employed, only steam granules were obtained. Image analysis revealed that beta-lactose steam granules had a larger surface area with respect to water granules, whereas lower values of this parameter were observed in PVP-s granules, confirming the Scanning Electron Microscopy micrographs and the fractal analysis results. As regards the enhancement of the dissolution profiles, the best result was obtained using beta-lactose steam granules followed by PVP K12 ones, even if the reactive dimension values indicated that during the dissolution process PVP K12 granules modified the surface more than beta-lactose granules. As regards PVP K90, this excipient was the one less influencing the granule morphology and the dissolution behaviour. Differential Scanning Calorimetry analysis suggested the partial amorphisation of the drug in the granules containing the three excipients. This result was then confirmed by X-ray powder diffraction analysis. Therefore, beta-lactose and PVP K12 could be proposed as useful excipients to enhance the dissolution rate of Px from granules prepared using the steam granulation technique.

Piroxicam benzoate--synthesis, HPLC determination, and hydrolysis.

An improved method of piroxicam benzoate synthesis was described, and an isocratic reversed-phase high-performance liquid chromatography method for its determination was developed and fully validated. The method was found to be specific, precise (relative standard deviation 0.3%), accurate (mean recovery 99.9%), and robust. Limit of detection was estimated at 0.055 microg mL(-1) and limit of quantification at 0.185 microg mL(-1). The kinetics of piroxicam benzoate hydrolysis in aqueous buffer solutions (pH 1.1 and 10), simulated gastric and intestinal fluids was studied. The hydrolysis followed first-order kinetics. The following rate constants were obtained at pH 10: k = 1.8 x 10(-3) hr(-1) at 37 degrees C and k = 3.4 x 10(-2) hr(-1) at 60 degrees C. In acidic media, no significant hydrolysis was observed after 24 hr. During the 24-hr period in simulated intestinal fluid, only 10.9% of the starting ester was hydrolyzed.

Crystal forms of piroxicam pivalate: preparation and characterization of two polymorphs.

This study investigates the polymorphism of piroxicam ester with pivalic acid. Two crystal modifications were prepared by recrystallization from toluene (form 1) and ethyl acetate (form 2). Data regarding preparation conditions, solid state properties, and physicochemical characterization of two polymorphs by means of FT/IR spectroscopy, X-ray diffractometry on powder, and thermal analysis are reported. Heat of fusion rule and thermodynamic formulas consistently indicate an enantiotropic stability relationship of forms 1 and 2 with a calculated transition point (32 degrees C) near the ambient temperature. The phase diagrams of each polymorph with piroxicam were also investigated in order to gain information about the thermal behavior of their solid mixtures. Liquidus curves calculated by the Schröder-Van Laar equation from fusion enthalpies and temperatures were found to agree satisfactorily with experimental results obtained by first heating runs with differential scanning calorimetry.

Analogues and derivatives of tenoxicam. 1. Synthesis and antiinflammatory activity of analogues with different residues on the ring nitrogen and the amide nitrogen.

The synthesis of tenoxicam, 4-hydroxy-2-methyl-N-2-pyridyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxami de 1,1-dioxide (1e), and of the analogues with various residues on the ring nitrogen and the amide nitrogen is described. This new class of "oxicams" has pronounced antiinflammatory and analgesic properties. The very specific structure-activity relationship of isomeric and isosteric groups at the amide nitrogen has been evaluated. The substituent in position 2 also has a great influence on the pharmacological properties. Tenoxicam is presently undergoing clinical trials.