A differential equation based modelling approach to predict supersaturation and in vivo absorption from in vitro dissolution-absorption system (idas2) data.

In vitro dissolution tests are widely used to monitor the quality and consistency of oral solid dosage forms, but to increase the physiological relevance of in vitro dissolution tests, newer systems combine dissolution and permeation measurements. Some of these use artificial membranes while others (e.g., in the in vitro dissolution absorption system 2; IDAS2), utilize cell monolayers to assess drug permeation. We determined the effect of the precipitation inhibitor Hypromellose Acetate Succinate (HPMCAS) on the supersaturation/permeation of Ketoconazole and Dipyridamole in IDAS2 and its effect on their absorption in rats. Thus the main objectives of this study were to determine: (1) whether dissolution and permeation data from IDAS2 could be used to predict rat plasma concentration using an absorption model and (2) whether the effect of the precipitation inhibitor HPMCAS on supersaturation and permeation in IDAS2 was correlated with its effect on systemic absorption in the rat. Predicted drug concentrations in rat plasma, generated using parameters estimated from IDAS2 dissolution/permeation data and a mathematical absorption model, showed good agreement with measured concentrations. While in IDAS2, the prolongation of Ketoconazole's supersaturation caused by HPMCAS led to higher permeation, which paralleled the higher systemic absorption in rats, Dipyridamole showed no supersaturation and, thus, no effect of HPMCAS in dissolution or permeation in IDAS2 and no effect on Dipyridamole absorption in rats. The ability of IDAS2 to detect supersaturation following a pH-shift supports the potential value of this system for studying approaches to enhance intestinal absorption through supersaturation and the accuracy of plasma concentration predictions in rats suggest the possibility of combining IDAS2 with absorption models to predict plasma concentration in different species.

In vitro dissolution absorption system (IDAS2): Use for the prediction of food viscosity effects on drug dissolution and absorption from oral solid dosage forms.

Existing in vitro dissolution or permeation models to predict food effect are mainly based on Pharmacopeias' compendial media, which specify such variables as pH, bile salts, lipolytic enzymes, and phospholipids content. However, the viscosity of food in the gastrointestinal (GI) tract is not taken into account, although it can affect both the dissolution of the oral solid dosage form and absorption of the released drug. Here, a new in vitro dissolution absorption system (IDAS2) is utilized, which comprises a dissolution apparatus USP2 (DISTEK) equipped with specially constructed permeability chambers containing Caco-2 monolayers, thereby allowing dissolution and transepithelial absorption to be ascertained simultaneously. The IDAS2 was used to evaluate the effect of medium viscosity on both the dissolution of oral solid dosage forms and absorption of released drugs. Such information, which is not ordinarily determined in dissolution and permeation studies, will be helpful to the formulators developing robust oral dosage forms. Commercially available solid dosage forms of ten model drugs from across all BCS classifications were used in this evaluation: metoprolol, minoxidil, and propranolol from BCS class 1; carbamazepine, ketoprofen, and simvastatin from BCS class 2; atenolol and ranitidine from BCS class 3; and acetazolamide and saquinavir from BCS class 4. The study revealed the applicability of IDAS2 as a tool for in vitro screening of dissolution and absorption of intact oral solid products to predict food viscosity effect. The most profound viscosity effect on dissolution and absorption was observed of solid dosage forms for the BCS class 2 compounds carbamazepine and simvastatin. A higher medium viscosity significantly slowed down the dissolution rate of tested BSC class 4 compounds acetazolamide and saquinavir, without significant effect on their absorption. The solid dosage forms least affected by the viscosity of the medium tested were the BCS class 1 compounds minoxidil and propranolol.

1D polymeric platinum cyanoximate: a strategy toward luminescence in the near-infrared region beyond 1000 nm.

We report the synthesis and properties of the first representative of a new class of PtL2 complexes with ambidentate mixed-donor cyanoxime ligands [L = 2-cyano-2-oximino-N,N'-diethylaminoacetamide, DECO (1)]. Three differently colored polymorphs of "Pt(DECO)2" (3-5) were isolated, with the first two being crystallographically characterized. The dark-green complex [Pt(DECO)2]n (5) spontaneously forms in aqueous solution via aggregation of yellow monomeric complex 3 into the red dimer [Pt(DECO)2]2 (4), followed by further oligomerization into coordination polymer 5. A spectroscopic and light-scattering study revealed a "poker-chips"-type 1D polymeric structure of 5 in which units are held by noncovalent metallophilic interactions, forming a Pt---Pt wire. The polymer 5 shows a broad absorption at 400-900 nm and emission at unusually long wavelengths in the range of 1000-1100 nm in the solid state. The near-infrared (NIR) emission of polymer 5 is due to the formation of a small amount of nonstoichiometric mixed-valence Pt(II)/Pt(IV) species during synthesis. A featureless electron paramagnetic resonance spectrum of solid sample 5 recorded at +23 and -193 °C evidences the absence of Pt(III) states, and the compound represents a "solid solution" containing mixed-valence Pt(II)/Pt(IV) centers. Exposure of KBr pellets with 5% 5 to Br2 vapors leads to an immediate ∼30% increase in the intensity of photoluminescence at 1024 nm, which confirms the role and importance of mixed-valence species for the NIR emission. Thus, the emission is further enhanced upon additional oxidation of Pt(II) centers, which improves delocalization of electrons along the Pt---Pt vector. Other polymorph of the "Pt(DECO)2" complex--monomer--did not demonstrate luminescent properties in solutions and the solid state. An excitation scan of 5 embedded in KBr tablets revealed an emission only weakly dependent on the wavelength of excitation. The NIR emission of quasi-1D complex 5 was studied in the range of -193 to +67 °C. Data showed a blue shift of λmax and a simultaneous increase in the emission line intensity with a temperature rise, which is explained by analogy with similar behavior of known quasi-1D K2[Pt(CN)4]-based solids, quantum dots, and quantum wells with delocalized carriers. The presented finding opens a route to a new class of platinum cyanoxime based NIR emissive complexes that could be used in the design of novel NIR emitters and imaging agents.

Optimization of PEGylated nanoemulsions for improved pharmacokinetics of BCS class II compounds.

The objective of the study was the optimization of nanoemulsion formulations to prevent their rapid systemic clearance after intravenous administration. An amphiphilic PEG derivative DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(polyethylene glycol) with different chain lengths and concentration was used as a nanoemulsion droplet surface modifier. The danazol loading in all nanoemulsions was kept on the same level of ∼2 mg/mL. In the present investigation, PEGylated and non-PEGylated nanoemulsions were compared in vitro phagocytosis by incubating with lung macrophages and in vivo after intravenous administration in rats. Danazol-containing nanoemulsions (NE) modified with various PEG chain lengths (2000-10 000) and concentrations (3-12 mg/mL) were prepared and characterized. Nanoemulsion droplets were reproducibly obtained in the size range of 213-340 nm. The non-PEGylated NE had the surface charge of -25.4 mV. This absolute charge value decreased with increasing chain length and concentration. With increase in chain length and density the macrophage uptake decreased which could be due to decrease in surface charge and hydrophilicity of droplets. The greatest shielding of the NE droplets was reached with DSPE-PEG5000 at the concentration of 6 mg/mL where the surface charge changed to -1.27 mV. Following intravenous administration a maximum danazol exposure (401 ± 68.2 h ng/mL) was observed with the lowest clearance rate (5.06 ± 0.95 L/h/kg) from 6 mg/mL DSPE-PEG5000 nanoemulsion. PEG5000 and PEG10000 altered the pharmacokinetic of danazol by decreasing clearance and volume of distribution which is likely explained by the presence of hydrophilic shields around the droplets that prevent their rapid systemic clearance and tissue partitioning.

Synthesis and Characterization of Two Cyanoxime Ligands, Their Precursors, and Light Insensitive Antimicrobial Silver(I) Cyanoximates.

High-yield syntheses of N-piperidine-cyanacetamide (1), N-morpholyl-cyanacetamide (4) and their oxime derivatives N-piperidine-2-cyano-2-oximino-acetamide (HPiPCO, 2) and N-morpholyc-2-cyano-2-oximino-acetamide (HMCO, 5) were developed using two-step preparations. At first, the reactions of neat cyanoacetic acid esters and the respective cyclic secondary amines such as piperideine and morpholine afforded pure cyanacetamides, which were converted into cyanoximes at room temperature using the nitrosation reaction with gaseous CH3ONO. The synthesized compounds were investigated by means of IR, 1H, 13C and UV-visible spectroscopy. Crystal structures of two starting substituted cyan-acetamides and two target cyanoximes were determined. Silver(I) complexes of AgL composition (L = PipCO, 3; MCO, 6) were prepared in high yield. Both metal complexes are thermally stable above 100oC, and remarkably stable to high intensity visible light. The stability of dried AgL compounds towards short wavelength UV-radiation (a frequently used germicidal light) was examined using diffusion reflectance spectroscopy. Both complexes demonstrate slow photoreduction within ~3 hrs, observable as a gradual color change and darkening due to the formation of fine (nano-scale) particles of metallic silver. The complex Ag(MCO), 6, is about 2.6 times less stable towards UV-radiation than its more lypophyllic analog Ag(PipCO), 3. Antimicrobial and biofilm growth inhibition properties of the prepared solid acrylate-based polymeric composites containing embedded silver(I) cyanoximates were investigated using three human pathogens: P. aeruginosa PAO1 (wound isolate), S. aureus NRS70 (methicillin resistant respiratory isolate), and S. mutans UA159 (cariogenic dental isolate). Studies showed that both 3 and 6 compounds completely abolished the growth of PAO1 at 0.5 weight % concentration, and the growth of UA159 and NRS70 at 1% concentration. Moreover, data demonstrates that complexes 3 and 6 also inhibit both planktonic and biofilm growth of Gram-positive and Gram-negative bacterial pathogens. The demonstrated thermal stability and pronounced antimicrobial activity of both silver(I) cyanoximates indicates the strong potential for the studied complexes to be used as light insensitive antimicrobial additives to light-curable adhesives that set indwelling devices in place.

Evaluation of a nanoemulsion formulation strategy for oral bioavailability enhancement of danazol in rats and dogs.

The objective of this study was to determine whether nanoemulsion formulations constitute a viable strategy to improve the oral bioavailability of danazol, a compound whose poor aqueous solubility limits its oral bioavailability. Danazol-containing oil-in-water nanoemulsions (NE) with and without cosurfactants stearylamine (SA) and deoxycholic acid (DCA) were prepared and characterized. Nanoemulsion droplets size ranging from 238 to 344 nm and with surface charges of -24.8 mV (NE), -26.5 mV (NE-DCA), and +27.8 mV (NE-SA) were reproducibly obtained. Oral bioavailability of danazol in nanoemulsions was compared with other vehicles such as PEG400, 1% methylcellulose (MC) in water (1% MC), Labrafil, and a Labrafil/Tween 80 (9:1) mixture, after intragastric administration to rats and after oral administration of NE-SA, a Labrafil solution, or a Danocrine® tablet to dogs. The absolute bioavailability of danazol was 0.6% (PEG400), 1.2% (1% MC), 6.0% (Labrafil), 7.5% (Labrafil/Tween80), 8.1% (NE-DCA), 14.8% (NE), and 17.4% (NE-SA) in rats, and 0.24% (Danocrine), 6.2% (Labrafil), and 58.7% (NE-SA) in dogs. Overall, danazol bioavailability in any nanoemulsion was higher than any other formulation. Danazol bioavailability from NE and NE-SA was 1.8- to 2.2-fold higher than NE-DCA nanoemulsion and could be due to significant difference in droplet size.

The first bis-cyanoxime: synthesis and properties of a new versatile and accessible polydentate bifunctional building block for coordination and supramolecular chemistry.

A new multidentate bifunctional organic ligand ­ di-N,N'-(2-cyano-2-oximinoacetyl)piperazine ­ was synthesized in high yield using a two-step procedure carried out under ambient conditions. At first, the reaction of piperazine and neat methylcyanoacetate led to the di-N,N'-(cyanoacetyl)piperazine (1), which then was converted into bis-cyanoxime, di-N,N'-(2-cyano-2-oximinoacetyl)piperazine (HL, 2) using a room temperature nitrosation reaction with gaseous methylnitrite. Synthesized bis-cyanoxime was characterized by 1H, 13C NMR, UV-visible, IR spectroscopy and the X-ray analysis. The ligand 2 exists as a mixture of three diastereomers arising from the syn- and anti-geometry of the cyanoxime group. The prolonged crystallization of 2 from an ethanol­water mixture leads to the formation of: (a) colorless crystals that according to the X-ray analysis contain a 51.2:48.8% co-crystallized mixture of both isomers that have the same H-bonding motif (minority), and (b) a white amorphous material that represents an almost pure anti-isomer (majority). The deprotonation of 2 leads to the formation of a yellow dianion that demonstrated pronounced solvatochromism of its n → π* transition in the nitroso-chromophore. The disodium salt Na2L·4H2O (3) was obtained from 2 using NaOC2H5 in ethanol. The new bis-cyanoxime 2 reacts with Tl2CO3 and AgNO3 in aqueous solutions with the formation of light-stable, sparingly soluble yellow precipitates of M'2L·xH2O composition (M' = Tl, Ag; Tl = 4, x = 0; Ag = 5, x = 2). The reaction of 3 with Ni2+ or K2M''Cl4 (M'' = Pd, Pt) in aqueous solutions leads to NiL·4H2O (6), PdL·4H2O (7) and PtL·5H2O (8). The crystal structure of 4 was determined and revealed the formation of a 3D-coordination polymeric complex in which the bis-cyanoxime acts as a dianionic, bridging, formally decadentate ligand. Each Tl(I) center has two bonds (2.655, 2.769 Å), shorter than the sum of ionic radii Tl­O (oxime group), and three longer, >2.89 Å, mostly electrostatic Tl···O contacts, involving oxygen atoms of the amide-group and the oxime-group of neighboring units. Among several possible binding modes, the coordination of the bis-cyanoxime dianion of 2 adopted in complex 4 is unusual, and evidenced its great potential as a versatile building block for coordination and supramolecular chemistry.

Benz(2-heteroaryl)cyanoximes and their Tl(i) complexes: new room temperature blue emitters.

A series of five 2-heteroarylcyanoximes such as: alpha-oximino-(2-benzimidazolyl)acetonitrile (HBIHCO), alpha-oximino-(N-methy-l-2-benzimidazolyl)acetonitrile (HBIMCO), alpha-oximino-(2-benzoxazolyl)acetonitrile (HBOCO), alpha-oximino-(2-benzothiazolyl)acetonitrile (HBTCO) and alpha-oximino-(2-quinolyl)acetonitrile (HQCO) and their monovalent thallium(i) complexes were synthesized and characterized using spectroscopic methods ((1)H, (13)C NMR, IR, UV-visible, mass-spectrometry) and X-ray analysis. The HBIMCO (as monohydrate) adopts planar trans-anti configuration in the solid state. The crystal structure of "HBOCO" revealed the presence of nitroso anion a, BOCO(-), and protonated oxime cation b, H(2)BOCO(+), that form a H-bonded dimer in the unit cell. Both molecules adopt planar structures, but different configurations: cis-anti in the molecule a, and trans-anti for b. This is the first reported case of a zwitterionic pair in oximes and the coexistence of the two geometrical cis/trans isomers in the same crystal. All 2-heteroarylcyanoximes form yellow anions upon deprotonation, which exhibit significant negative solvatochromism in solution. Heterogeneous reactions between hot aqueous solutions of Tl(2)CO(3) and solid protonated 2-heteroarylcyanoximes HL afford yellow TlL. The crystal structure of Tl(BTCO) shows the formation of centrosymmetrical dimers, which connect with each other to form a double-stranded one-dimensional coordination polymer. The oxygen atom of the oxime group acts as a bridge between the three different Tl(i) centers. The anion is non-planar and adopts a trans-anti configuration in the complex. The polymeric motif in the complex represents a ladder-type structure. Staggered pi-pi interactions between benzothiazolyl groups provide additional stabilization of the structure. Both organic ligands and their Tl(i) complexes exhibit strong room temperature blue emission in the solid state.