In vitro percutaneous transport of sodium diclofenac and diclofenac from oleaginous vehicle

The penetration enhancement of sodium diclofenac and diclofenac by alcohols with various alkyl chains (C8 to C14) was evaluated by the steady state flux of diclofenac through rat abdominal skin. Decanol showed the greatest effect in this series. A more remarkable enhancing effect of the alcohols was observed in sodium diclofenac than in diclofenac. Diclofenac can penetrate through the ethylene-vinyl acetate membrane as a lipoid model membrane, but sodium diclofenac can not. Decanol enhanced the penetration of phenol red being dependent on its concentration in the vehicle. Therefore, decanol may interact with lipoid components of the skin and increase the aqueous pathway in the skin. These results indicate that sodium diclofenac and diclofenac may be penetrated through partially different pathways.     

Transfer of diclofenac sodium across excised guinea pig skin on high-frequency pulse iontophoresis. II. Factors affecting steady-state transport rate

Some of the factors affecting the steady-state transport rate of diclofenac sodium across excised guinea-pig skin during high-frequency pulse iontophoresis were examined. The same mathematical expression was employed for enhancement ratio as a function of applied voltage as the one derived for direct-current iontophoresis. The effective voltage drop across the skin was only 1.1% of the applied voltage. The steady-state flux value increased with increase of the donor concentration.     

In vitro permeation of gold nanoparticles through rat skin and rat intestine: effect of particle size

Purpose of the present work was to study in vitro permeation of gold nanoparticles (NPs) through isolated rat skin and intestine. Another objective was to see the effect of particle size on permeation of the gold NP. Gold NP of 15 nm, 102 nm and 198 nm were synthesized and used for study. Franz diffusion cells were used to evaluate permeation of gold NP from rat skin whereas 'intestinal sac' method was used for assessing intestinal permeation. Number density of gold NP was analyzed by UV-vis spectroscopy whereas amount of gold permeated was measured by ICP mass spectrometry. The absorption and localization of gold NP through rat skin was studied by TEM. Qualitative analysis of gold inside of the rat skin was performed by energy dispersive X-ray spectroscopy (EDS). Gold NP showed negative zeta potential. UV-vis absorption spectra of 15 nm, 102 nm and 198 nm gold NP showed lambda(max) at 520 nm, 535 nm and 577 nm, respectively. SEM study revealed spherical morphology of NP. Gold NP showed size dependent permeation through rat skin and intestine. 15 nm gold NP showed higher permeation compared to 102 nm and 198 nm gold NP. Interestingly, 102 nm and 198 nm gold NP showed lag time of 3h and 6h in case of rat skin only. As the size of the gold NP increased, permeability coefficient and diffusion coefficient was found to be decreased. The permeation of gold NP through intestine was higher than that of skin. TEM study of rat skin revealed accumulation of smaller size gold NP in deeper region of skin whereas larger particles were observed mainly in epidermis and dermis. Presence of gold inside of rat skin was confirmed by EDS. Gold NP would be an interesting carrier for transdermal as well as for oral delivery. The study demonstrated initial proof of concept of percutaneous permeation of smaller size gold particles.     

Penetration of radionuclides across the skin: Rat age dependent promethium permeation through skin in vitro

The composition and the permeation properties of the skin are dependent on age. In the animal models for permation studies, age affects the mechanical as well as the permeation properties significantly. The time dependence of permeation of ¹⁴⁷Pm³⁺ from aqueous solution was established by the animal skin model and the age dependence of promethium permeation through the skin was examined. The aim was to find the optimum rat skin age model for radionuclide permeation studies and to assess the relative importance of the main permeation pathways: transepidermal and transfollicular permeation. The skin from 5-day-old rats (5DR) was found to represent the optimum animal model to study transepidermal permeation of ions. The skin from 9-day-old rats (9DR) was selected to study transfollicular permeation of ions. Comparison of the permeated amounts of promethium through the skin without hairs (3 DR to 6 DR) and with hairs (7DR to 12DR) showed that the additional permation mode via follicles significantly contributed to the permeation rate and extent.     

A combined experimental and theoretical study of the kinetics and mechanism of the addition of alcohols to electronically stabilized silenes: a new mechanism for the addition of alcohols to the Si=C bond

The stabilized silene 1,1-bis(trimethylsilyl)-2-adamantylidenesilane (4) has been generated by photolysis of a novel trisilacyclobutane derivative in various solvents and studied directly by kinetic UV spectrophotometry. Silene 4 decays with second-order kinetics in degassed hexane solution at 23 degrees C (k/epsilon = 8.6 x 10(-6) cm s(-1)) due to head-to-head dimerization. It reacts rapidly with oxygen [k(25 degrees C) approximately 3 x 10(5) M(-1) s(-1)] but approximately 10 orders of magnitude more slowly with methanol (MeOH) than other silenes that have been studied previously. The data are consistent with a mechanism involving reaction with the hydrogen-bonded dimer of the alcohol, (MeOH)(2) (k = 40 +/- 3 M(-1) s(-1); k(H)/k(D) = 1.7 +/- 0.2). The stable analogue of silene 4, 1-tert-butyldimethylsilyl-1-trimethylsilyl-2-adamantylidenesilane (5), reacts approximately 50 times more slowly, but via the same mechanism. The mechanism for addition of water and methanol (ROH; R = H, Me) to 4, 5, and the model compound 1,1-bis(silyl)-2,2-dimethylsilene (3a) has been studied computationally at the B3LYP/6-31G(d) and MP2/6-31G(d) levels of theory. Hydrogen-bonded complexes with monomeric and dimeric methanol, in which the Si=C bond plays the role of nucleophile, have been located computationally for all three silenes. Reaction pathways have been characterized for reaction of the three silenes with monomeric and dimeric ROH and reveal significantly lower barriers for reaction with the dimeric form of the alcohol in each case. The calculations indicate that 5 should be approximately 40-fold less reactive toward dimeric MeOH than 4, in excellent agreement with the approximately 50-fold difference in the experimental rate constants for reaction in hexane solution.     

Chiral propargyl alcohols via the enantioselective addition of terminal di- and triynes to aldehydes

The enantioselective addition of di- and triynes to aldehydes is presented, including the first examples of an asymmetric triyne addition. Modification of the Carreira alkynylation protocol shows that addition of diynes and triynes to α-branched aldehydes can be complete in as little as 4 h, and these reactions give good yields and enantioselectivities (up to 98% ee) for di- and triynes tested (aryl, alkyl, and silyl). It is shown for two cases (20 and 24) that products of this asymmetric addition reaction can undergo further manipulation (desilylation and triazole formation) without affecting the enantiopurity.     

Principal component analysis for the selection of variables in the application of the H-point and generalised H-point standard addition method

The present paper deals with the selection of variables for the H-point and generalised H-point standard additions methods (HPSAM and GHPSAM, respectively). Both methods are applied for the resolution of spectroscopic interfered signals in the UV-vis range. The HPSAM is a suitable method for the resolution of binary and ternary mixtures when the interferent is known. The GHPSAM is applied for the resolution of samples that contain unknown interferents. In this paper, a method based on the study of a principal components analysis (PCA) for the selection of variables for the HPSAM and GHPSAM is proposed. The PCA results show the isolation of the analyte signal from the sample signal, achieved by the application of the HPSAM and GHPSAM. It is showed that by means of the score and loading plots, it is possible to select the most appropriate variables without a priori establishing any condition.     

Studies on sulfinatodehalogenation: The addition of polyfluoroalkyl iodides to olefins promoted by sodium bisulfite and sodium sulfite

The reaction of polyfluoroalkyl iodides with alkenes or 4-pentenoic acid promoted by sodium bisulfite or sodium sulfite in DMF aqueous solution was realized. The reaction of alkenes gave corresponding adducts, while γ-lactones were obtained in the case of 4-pentenoic acid in good yields.     

Keratinized epithelial transport of beta-blocking agents. I. Relationship between physicochemical properties of drugs and the flux across rat skin and hamster cheek pouch.

The maximum fluxes (Jmax) of beta-blockers through keratinized membranes were determined in vitro and compared with their physiochemical parameters such as lipophilicity (log k'0) and melting point (mp). Rat abdominal skin and hamster cheek pouch mucosa were used as the model membranes. Propranolol, metoprolol, timolol, pindolol, nadolol and agenolol were used as beta-blockers with a variety of physicochemical characters. Linear relations of Jmax with either log k'0 or mp were observed both in intact rat skin and in intact hamster cheek pouch, suggesting that the lipophilicity and thermodynamic activity of a drug in the crystal state primarily affect the drug's permeation through these membranes. However, the slope, dJmax/d(log k'0), for cheek pouch mucosa was greater than that for rat skin, corresponding to the lack of appendigeal shunt pathways in cheek pouch. Penetration studies using the delipidized membranes and the isolated stratum corneum sheet of hamster cheek pouch mucosa clarified that the primary rate-limiting barrier function might exist in the lipid layer of the stratum corneum. Jmax values for the tape-stripped and delipidized skins correlated with both the solubilities of drugs in the vehicle and with the mp, suggesting the polar porous characteristics of both model membranes. However, a theoretical approach confirmed that the contribution of an intracellular or aqueous pore route in the intact membrane to the permeation of drugs with positive lipophilic indexes is negligible.     

A new mechanism for the addition of alcohols to disilenes revealed by DFT and ONIOM calculations

Density functional and ONIOM calculations of alcohol and phenol additions to two (tetramethyl and tetramesityl) disilenes were carried out. The dimer of MeOH adds to Me₂SiSiMe₂ more readily than the monomer. The trimer does not afford the adduct, but a zwitter-ionic intermediate. In the (CF₃OH)₂ addition to Me₂SiSiMe₂, H?Si bond formation is more advanced than O?Si bond formation in the transition state (TS). Addition of seven phenol derivatives to Me₂SiSiMe₂ was examined, and the dimer reactions were found to be superior to the monomer reaction regardless of the substituents on the benzene rings. (MeOH)₂ reacts also with Mes₂SiSiMes₂ favorably, and an isomer of the reactant-like complex (precursor) may afford an adduct of different stereochemistry via internal rotations. Generally, the dimer of the alcohol or phenol is the reactant toward the disilenes. Exceptionally, a monomer of p-(dimethylamino)phenol reacts with Mes₂SiSiMes₂ owing to steric congestion by the four mesityl groups.     

Organocatalytic asymmetric addition of alcohols and thiols to activated electrophiles: efficient dynamic kinetic resolution and desymmetrization protocols

Bifunctional urea-based cinchona alkaloid derivatives have been shown to promote highly efficient DKR reactions of azalactones using an alcohol nucleophile. The optimum catalyst is remarkably insensitive to the steric bulk of the amino acid residue, allowing alanine-, methionine-, and phenylalanine-derived azalactones to undergo DKR with unprecedented levels of enantioselectivity using a synthetic catalyst. The first DKR of these substrates by thiols and the highly enantioselective desymmetrization of a meso-glutaric anhydride by thiolysis are also reported.     

A method for computing the solubility limit of solids: application to sodium chloride in water and alcohols

We present an adaptable method to compute the solubility limit of solids by molecular simulation, which avoids the difficulty of reference state calculations. In this way, the method is highly adaptable to molecules of complex topology. Results are shown for solubility calculations of sodium chloride in water and light alcohols at atmospheric conditions. The pseudosupercritical path integration method is used to calculate the free energy of the solid and gives results that are in good agreement with previous studies that reference the Einstein crystal. For the solution phase calculations, the self-adaptive Wang-Landau transition-matrix Monte Carlo method is used within the context of an expanded isothermal-isobaric ensemble. The method shows rapid convergence properties and the uncertainty in the calculated chemical potential was 1% or less for all cases. The present study underpredicts the solubility limit of sodium chloride in water, suggesting a shortcoming of the molecular models. Importantly, the proper trend for the chemical potential in various solvents was captured, suggesting that relative solubilities can be computed by the method.     

Reactivity of primary and secondary alcohols in nucleophilic addition to a triple bond: the vinylation of butane-1,3-diol

Acetylene adds to butane-1,3-diol in the presence of KOH to give, along with the corresponding divinyl ether and 2,4-dimethyl-1,3-dioxane, 4-vinyloxybutan-2-ol and its structural isomer 3-vinyloxybutan-1-ol, the ratio between the latter two products, (5–8)∶1, depending on the reaction conditions. Translated fromIzvestiya Akademii Nauk, Seryia Khimicheskaya, No. 12, pp. 2372–2374, December, 1999.     

Synthesis of chiral ferrocenyl aziridino alcohols and use in the catalytic asymmetric addition of diethylzinc to aldehydes

A series of novel chiral ferrocenyl aziridino alcohols 5a–i were conveniently synthesized from L-serine and ferrocenecarboxaldehyde. These compounds have been used as chiral catalysts in the asymmetric addition of diethylzinc to aldehydes and the effects of the ligand structures on the enantioselectivity was studied. Enantioselectivities up to 98.8% have been obtained.     

Asymmetric addition of Grignard reagents to ketones: culmination of the ligand-mediated methodology allows modular construction of chiral tertiary alcohols

A new class of biaryl chiral ligands derived from 1,2-diaminocyclohexane (1,2-DACH) has been designed to enable the asymmetric addition of aliphatic and, for the first time, aromatic Grignard reagents to ketones for the preparation of highly enantioenriched tertiary alcohols (up to 95% ee). The newly developed ligands L12 and L12′ together with the previously reported L0 and L0′ define a set of complementary chiral promoters, which provides access to the modular construction of a broad range of structurally diverse non-racemic tertiary alcohols, bearing challenging quaternary stereocenters. The present advancements bring to completion our asymmetric Grignard methodology by expanding the scope to aromatic organomagnesium reagents, while facilitating its implementation in organic synthesis thanks to improved synthetic routes for the straightforward access to the chiral ligands. The synthetic utility of the method has been demonstrated by the development of a novel and highly enantioselective formal synthesis of the antihistamine API clemastine via intermediate (R)-3a. Exploiting the power of the 3-disconnection approach offered by the Grignard synthesis, (R)-3a is obtained in 94% ee with ligand (R,R)-L12. The work described herein marks the finalization of our ongoing effort towards the establishment of an effective and broadly applicable methodology for the asymmetric Grignard synthesis of chiral tertiary alcohols.

Easily applied enantioselective addition of aliphatic and aromatic Grignard reagents to ketones provides modular and universal access to challenging chiral tertiary alcohols, enabling the straightforward preparation of natural products and APIs.