Hydrogen bonding in sulfonamides.

The hydrogen-bond connectivity in 39 sulfonamide crystal structures has been deciphered and described using graph set notation. The hydrogen-bond connectivity observed is used to gain information on hydrogen-bond preferences of specific donor and acceptor atoms of related sulfonamide molecules. The amido protons show a greater preference for hydrogen bonding to amidine nitrogens and cocrystal guests, whereas the amino protons show a greater preference for hydrogen bonding to sulfonyl oxygens, forming the only dominant hydrogen-bond pattern, a chain with an eight atom repeat unit. Preferential hydrogen bonding between the amidine group and the guest carboxyl group was observed in five cocrystal structures of sulfamethazine. Sulfamoxole displays a conformation and a hydrogen-bond motif not seen in any other structures. Sulfamerazine and sulfamethazine, differing by a methyl group, show no similarity in hydrogen-bond pattern, whereas sulfamethoxydiazine and sulfamethoxymethazine, which have sterically similar but chemically different heterocycles, show a striking similarity in hydrogen-bond pattern. Sulfamethoxydiazine, sulfamethoxymethazine, and sulfamethoxazole also show a large variation in hydrogen-bond pattern between polymorphs. Studies such as this, by revealing details of hydrogen-bonding patterns in closely related organic crystal structures, can potentially provide predictive capability among the crystal structures of pharmaceutical solids.     

Pharmacokinetics of salsalate and salicylic acid in normal and diabetic rats

The pharmacokinetics (PK) of salsalate (SS) and salicylic acid (SA) was assessed in normal Wistar and diabetic Goto‐Kakizaki rats. Three PK studies were conducted: (1) PK of SA in normal rats after intravenous dosing of SA at 20, 40, 80 mg/kg. (2) PK of SS and SA in normal rats after oral dosing of SS at 28, 56, 112 mg/kg. (3) PK during 4 months feeding of SS‐containing diet in both normal and diabetic rats. The disposition of SS and SA were evaluated simultaneously using a pharmacokinetic model comprising several transit absorption steps and linear and nonlinear dual elimination pathways for SA. The results indicated that the nonlinear elimination pathway of SA only accounted for a small fraction of the total clearance (< 12%) at therapeutic concentrations. A flat profile of SA was observed after oral dosing of SS, particularly at a high dose. The possible reasons for this flat profile were posed. During the SS‐diet feeding, the diabetic rats achieved lower blood concentrations of SA than normal rats with a higher apparent clearance (CL/F), possibly due to incomplete (47%) bioavailability. Such CL/F decreased with age in both diabetic and normal rats. The effect of diabetes on SA pharmacokinetics may necessitate increased dosing in the future usage of SS in diabetes. Copyright © 2012 John Wiley & Sons, Ltd.     

Effects of salsalate (nonacetylated salicylate) and aspirin on serum prostaglandins in humans

Prostaglandin E2 (PGE2), thromboxane B2 (TXB2), and salicylic acid were measured in blood samples from 10 healthy men after administration of antiinflammatory doses of aspirin (3.9 g/day) or salsalate (3.0 g/day). Each medication was given for 3 days, followed by an observation period of 13 days. Plasma salicylate concentrations were slightly, but generally insignificantly, higher during aspirin dosing, although both drugs produced salicylic acid levels in the antiinflammatory range. Serum levels of PGE2 and TXB2, which reflected synthesis of cyclo-oxygenase products by platelets, were minimally affected by salsalate but profoundly suppressed by aspirin. When medication was discontinued, the effects of salsalate on serum PGE2 and TXB2 were readily reversible within 36 h, whereas the recovery from aspirin was still incomplete after 13 days of observation. These results indicate that the two orally administered salicylates have differential effects on prostaglandin synthesis in platelets and may also differ in their therapeutic and adverse effects.     

Fecal blood loss and plasma salicylate study of salicylsalicylic acid and aspirin.

Using a placebo-controlled methodology, 20 healthy volunteers housed in a clinical research facility for 23 days were studied for fecal blood loss and plasma salicylate levels after taking salsalate (salicylsalicylic acid) or aspirin. Daily dosages were 3000 mg salsalate or 3900 mg aspirin. Aspirin produced statistically significant gastrointestinal blood loss over control levels and over that produced by salsalate (P less than 0.01). Blood loss with salsalate was not different than that with placebo. Despite the intentional disparity of dosages between the two drugs, plasma salicylate levels were not statistically different. Side effects occurred at about equal frequency with either drug. Most prominent were headache and nausea. However, concomitant upper respiratory infection in 12 subjects rendered interpretation difficult.     

Solid state study of hydrogen bonding in dichlorophen crystals

An X-ray crystallographic study of dichlorophen has been performed. Intramolecular hydrogen bonding is found within the molecule and intermolecular hydrogen bonding is present between molecules. The formation of dimers within the crystal lattice has been established.     

Hydrogen bonding interaction of diphenylhydantoin and 9-ethyladenine

A hydrogen-bonded complex of diphenylhydantoin (DPH) and 9-ethyladenine (EtAd) crystallizes from 2,4-pentanedione with the asymmetrical unit consisting of two DPH molecules, one EtAd molecule, and one solvent molecule. The crystal structure was solved by direct methods and refined to a residual of R = 0.054. Structure determination reveals that one DPH hydrogen-bonds to EtAd in a Watson-Crick scheme while the second DPH N(3)--H bonds to EtAd N(3) to form a 2:1 DPH-EtAd complex. Comparisons are made with barbiturate-adenine complexes and with an earlier postulation of a 1:1 DPH-EtAd complex derived from NMR and IR data. The 2,4-pentanedione molecule adopts the keto-enol configuration with an asymmetrical intramolecular hydrogen bond.     

Isolation of salicylsalicylic acid, acetylsalicylsalicylic acid, and acetylsalicylic anhydride from aspirin tablets by extraction and high-pressure liquid chromatography.

Aspirin and four salicylate impurities of aspirin (salicylic acid, acetylsalicylsalicylic acid, acetylsalicylic anhydride, and salicylsalicylic acid) were resolved by silica gell TLC and by high-pressure liquid chromatography (HPLC) on a reversed-phase C18 column. Care was necessary in the choice of a column because of similar column failed to resolve these five compounds. Salicylsalicylic acid was isolated from aspirin tablets by extraction followed by reversed-phase C18 HPLC. The structure of this compound was confirmed by comparison with an authentic sample of salicylsalicylic acid by HPLC, TLC, IR and UV spectrophotometry, and mass spectrometry. Two other compounds, acetylsalicylic anhydride and acetylsalicylsalicylic acid, which had been previously identified by chromatography as impurities in aspirin, were isolated and further characterized.     

A short-term comparative trial of salsalate and indomethacin in rheumatoid arthritis

Summary

A short-term, double-blind, placebo-controlled crossover study was completed in 15 patients with classical or definite rheumatoid arthritis to compare the antirheumatic activity of salsalate (3?g/day) with placebo and indomethacin (75?mg/day). Subjective and objective assessments showed that both salsalate and indomethacin were significantly superior to placebo. Grip strength was not improved by either of the drugs. Patient preference was in favour of indomethacin, but. the difference between it and salsalate was insignificant.     

Hydrogen bonding with adsorbent during storage governs drug dissolution from solid-dispersion granules

Purpose. To investigate changes in drug dissolution on storage of ternary solid-dispersion granules containing poorly water-soluble drugs. Methods. Hot-melt granulation was used to prepare ternary solid-dispersion granules in which the drug was dispersed in a carrier and coated onto an adsorbent. Seven drugs including four carboxylic acid-containing drugs (BAY 12-9566, naproxen, ketoprofen, and indomethacin), a hydroxyl-containing drug (testosterone), an amide-containing drug (phenacetin), and a drug with no proton-donating group (progesterone) were studied. Gelucire 50/13 and polyethylene glycol (PEG) 8000 were used as dispersion carriers whereas Neusilin US2 (magnesium aluminosilicate) was used as the surface adsorbent. Results. Two competing mechanisms have been proposed to explain the complex changes observed in drug dissolution upon storage of solid dispersion granules. Conversion of the crystalline drug to the amorphous hydrogen bonded (to Neusilin) state seems to increase dissolution, whereas, the phenomenon of Ostwald ripening can be used to explain the decrease in drug dissolution upon storage. The solubility of the drug in Gelucire is a crucial factor in determining the predominant mechanism by governing the flux toward the surface of Neusilin. The mobility for this phenomenon was provided by the existence of the eutectic mixture in the molten liquid state during storage. Conclusions. A competitive balance between hydrogen bonding of the drugs with Neusilin and Ostwald ripening determines drug dissolution from solid-dispersion granules upon storage.     

Unusual intramolecular hydrogen bonding in cycloamanide A,cyclic (LPro-LVal-LPhe-LPhe-LAla-Gly)

The naturally occurring cyclic hexapeptide, cycloamanide A, has only one intramolecular hydrogen bond. It is a 4 ← 1 type that encompasses the LPhe-LAla sequence in which the experimentally determined ø, ← values are + 54d?, – 118d? and – 88d?, – 4d?, respectively. Even though the chirality is L, L, the ø, ← values are characteristic for a D, L β-bend, Type II°. The conformation of the molecule was established by a crystal structure determination using X-ray diffraction analysis. Cycloamanide A (C₃₃H₄₂N₆O₆←. 4H₂O) crystallizes in space group P2₁2₁2₁ with cell parameters a = 13.307(2) Å, b = 24.820(4) Å and c = 11.231(1) Å.     

A short-term comparative trial of salsalate and indomethacin in rheumatoid arthritis.

A short-term, double-blind, placebo-controlled crossover study was completed in 15 patients with classical or definite rheumatoid arthritis to compare the antirheumatic activity of salsalate (3 g/day) with placebo and indomethacin (75 mg/day). Subjective and objective assessments showed that both salsalate and indomethacin were significantly superior to placebo. Grip strength was not improved by either of the drugs. Patient preference was in favour of indomethacin, but the difference between it and salsalate was insignificant.     

Comparative study of salsalate and aspirin in osteoarthrosis of the hip or knee

Summary

A short-term, double-blind controlled crossover study was carried out in 20 patients with osteoarthrosis of the hip or knee to compare the effectiveness and tolerance of salsalate and aspirin. After a 1-week placebo washout period, patients received either 3 g salsalate per day or 3.6 g soluble aspirin per day for 2 weeks before being crossed over to the alternative treatment. Paracetamol was used as a rescue analgesic. The results of clinical assessments of pain, stiffness and sleep disturbance, using visual analogue scales, showed that salsalate produced a comparable clinical improvement to that with aspirin, and similar serum salicylate levels. Salsalate, however, was significantly superior to aspirin with regard to side-effects and faecal occult blood loss.     

Respirable form of crystals of cromoglycic acid

Respirable crystals of cromoglycic acid (CA) were prepared by precipitation of CA with hydrochloric acid from aqueous solutions of cromolyn sodium and subsequent recrystallization from hot water or mixtures of dimethyl sulphoxide and water. The properties of the materials were established by melting point measurements, UV, IR, and NMR spectroscopy, and X-ray diffraction. Aerosols of CA were generated by nebulization of dilute CA suspensions and drying. The aerodynamic size distribution of CA in the dried aerosols was found by cascade impaction, and could be characterized by a logarithmic normal function with a mass median aerodynamic diameter (MMAD) of 0.7 micron and geometric standard deviation (sigma g) of 1.9. The likely advantages and problems of CA aerosols in the prevention of asthma are discussed.     

Fundamental studies in reversed-phase liquid-solid extraction of basic drugs; II: Hydrogen bonding effects.

Anomalies in the elution order of the beta-blockers atenolol and propranolol on reversed-phase liquid-solid extraction cartridges have been studied. The hydrogen bond acceptor properties of the polar ring substituent in atenolol was found to result in greater retention than would be expected from the reversed-phase or cation-exchange mechanisms alone. This hydrogen bonding interaction could be attenuated by inclusion of a strong hydrogen bond acceptor in the eluent or more successfully by increasing the eluent water content. The conclusions from this work have been used to explain previously reported anomalies in the solid-phase extraction of polar basic drugs.     

Comparative study of salsalate and aspirin in osteoarthrosis of the hip or knee.

A short-term, double-blind controlled crossover study was carried out in 20 patients with osteoarthrosis of the hip or knee to compare the effectiveness and tolerance of salsalate and aspirin. After a 1-week placebo washout period, patients received either 3 g salsalate per day or 3.6 g soluble aspirin per day for 2 weeks before being crossed over to the alternative treatment. Paracetamol was used as a rescue analgesic. The results of clinical assessments of pain, stiffness and sleep disturbance, using visual analogue scales, showed that salsalate produced a comparable clinical improvement to that with aspirin, and similar serum salicylate levels. Salsalate, however, was significantly superior to aspirin with regard to side-effects and faecal occult blood loss.