Molecular evidence for improved tribological performances of MoDTC induced by methylene-bis(dithiocarbamates) in engine lubricants.

During engine tests, it has been observed that the combined use of molybdenum dithiocarbamates (MoDTC) and methylene-bis(dithiocarbamates) (MBDTC) in formulated engine oils resulted in better fuel efficiency, keeping the friction coefficient stable at low values for a longer period of time as compared to the same oil devoid of MBDTC. Therefore, the interactions between MBDTC and MoDTC have been investigated at the molecular level. The qualitative and quantitative evolution of MoDTC in two engine oils similarly formulated, but with and without MBDTC, were compared during engine tests using a specifically developed high performance liquid chromatography-mass spectrometry (HPLC-MS) analytical method. Parallel to the molecular study, the evolution of the friction coefficients of both lubricants as well as the evolution of the fuel consumption of the engine were determined. The combined use of MoDTC and MBDTC was shown to exhibit better fuel efficiency and to maintain a relatively low friction coefficient for longer periods of time as compared to the oil devoid of MBDTC. It could be determined that the enhanced performances observed were presumably related to an extension of the lifetime of MoDTC in the engine oil containing MBDTC. Since the MoDTC remaining at the end of the engine test in oil containing MBDTC exclusively bear ligands corresponding to the dithiocarbamate moieties of MBDTC, it can be concluded that the prolonged existence of MoDTC was due to the progressive replacement of the degraded dithiocarbamate ligands on MoDTC educts by those released from MBDTC during engine functioning. As a result, the concentrations of MoDTC could be maintained at a useful level for a longer period in the engine oil containing MBDTC, leading to better fuel consumption performances.

Molecular evidence for sulfurization of molybdenum dithiocarbamates (MoDTC) by zinc dithiophosphates: a key process in their synergetic interactions and the enhanced preservation of MoDTC in formulated lubricants?

Molybdenum dithiocarbamates (MoDTC) are widely used in automotive industries as lubricant additives to reduce friction and to enhance fuel economy. Sulfur-containing additives such as zinc dithiophosphates (ZnDTP) are proposed to play a key role in the improvement of friction reducing properties of MoDTC in formulated lubricants by facilitating the formation of MoS2 tribofilm at the rubbing contacts. This study focuses on the interactions between MoDTC and ZnDTP under conditions comparable with those prevailing in operating engines. The capacity of ZnDTP to sulfurize MoDTC in solution in a hydrocarbon base oil could be demonstrated. Sulfurized Mo complexes bearing one or two additional sulfur atoms (1S-MoDTC and 2S-MoDTC, respectively) which have replaced the genuine oxygen atom(s) from the MoDTC core were detected and quantified using a specifically developed HPLC-MS analytical method. A possible sulfurization mechanism relying on the higher affinity of phosphorus from ZnDTP for oxygen could be proposed. In parallel, the evolution and molecular transformation of the prepared 2S-MoDTC in hydrocarbon base oil under thermal and thermo-oxidative conditions were followed using HPLC-MS and compared with the evolution of their friction coefficients. 2S-MoDTC complexes were shown to exhibit a better retention of friction reducing capability under oxidative conditions than the "classical" MoDTC, although they did not seem to significantly reduce the friction coefficients of lubricants as compared to the "classical" MoDTC. Therefore, sulfurization of MoDTC by ZnDTP might contribute to delaying the progressive consumption of MoDTC and the loss of their friction-reducing efficiency in lubricants under thermo-oxidative conditions.

Ligand exchange processes between molybdenum and zinc additives in lubricants: evidence from NMR (1H, 13C, 31P) and HPLC-MS analysis.

The tribological performances of engine oils have been shown to be enhanced by the synergistic interactions between Mo dithiocarbamates (Mo(DTC)2) with other additives, and notably Zn dithiophosphates (Zn(DTP)2). Being two key components in formulated lubricants, a detailed understanding of the mechanisms involved between these two types of additives is needed to develop engine oils with enhanced friction reduction performances, and improved fuel economy. In this context, we report here the investigation at the molecular level of the interactions between Mo and Zn complexes with DTC and DTP ligands using laboratory experiments. Our analytical approach comprised NMR spectroscopy (1H, 13C, 31P) allowing direct investigation of both homoleptic and heteroleptic Mo and Zn complexes as well as a specifically-developed HPLC-MS method for the investigation of the different DTC species formed during lubricant ageing experiments. The results showed that ligand exchange reactions between Mo(DTP)2 and Zn(DTC)2 complexes strongly favor the migration of the DTC ligands from Zn to Mo, illustrating the higher affinity of Mo for DTC ligands. In the case of binary mixtures involving Mo(DTC)2 and Zn(DTP)2 - a combination of additives frequently used in formulated lubricants - the formation of mixed complexes (Mo(DTC)(DTP)) resulting from ligand exchange reactions could be directly evidenced for the first time by the analytical methods used. These species could account, at least to some extent, for the synergistic effect of Mo(DTC)2 and Zn(DTP)2 on the friction reducing properties of engine oils. However, they were formed in significantly lower proportions than those previously reported in the literature using indirect methods.

Preformulation studies of ceftriaxone for pediatric non-parenteral administration as an alternative to existing injectable formulations.

Ceftriaxone, a third generation cephalosporin, has a wide antibacterial spectrum that has good CNS penetration, which makes it potentially suitable for initial treatment of severe neonatal pediatric infections providing suitable formulation. We evaluated its physicochemical and technical characteristics to assess its potential for development as a non-parenteral dosage form. As ceftriaxone is marked only for injectable use, these data are not available. Using HPLC and Karl Fischer titration, sensitivity of ceftriaxone to water, feasibility and impact of pharmaceutical processes and compatibility with common pharmaceutical excipients were assessed. X-ray diffraction studies gave deeper insight into the mechanisms involved in degradation. Chemometrical analysis of near infrared spectra enabled classification of ceftriaxone powder according to exposure conditions or processes applied. The results showed that ceftriaxone was not highly hygroscopic, could be processed in all climatic zones, but should be packaged protected against humidity. Controlling water presence in formulation was shown critical, as ceftriaxone degraded in the presence of water content above 2.4% w/w. To improve flowability, a critical parameter for dry dosage form development, granulation (wet and dry techniques, providing complete drying and moderate force compaction respectively) was shown feasible. Compression with moderate forces was possible, but grinding and high compression forces significantly affected long term ceftriaxone stability and should be avoided. Based on these results, development of ceftriaxone non-parenteral solid or liquid non-aqueous forms appears feasible.

Pharmaceutical development and optimization of azithromycin suppository for paediatric use.

Pharmaceutical development and manufacturing process optimization work was undertaken in order to propose a potential paediatric rectal formulation of azithromycin as an alternative to existing oral or injectable formulations. The target product profile was to be easy-to-use, cheap and stable in tropical conditions, with bioavailability comparable to oral forms, rapidly achieving and maintaining bactericidal concentrations. PEG solid solution suppositories were characterized in vitro using visual, HPLC, DSC, FTIR and XRD analyses. In vitro drug release and in vivo bioavailability were assessed; a study in rabbits compared the bioavailability of the optimized solid solution suppository to rectal solution and intra-venous product (as reference) and to the previous, non-optimized formulation (suspended azithromycin suppository). The bioavailability of azithromycin administered as solid solution suppositories relative to intra-venous was 43%, which compared well to the target of 38% (oral product in humans). The results of 3-month preliminary stability and feasibility studies were consistent with industrial production scale-up. This product has potential both as a classical antibiotic and as a product for use in severely ill children in rural areas. Industrial partners for further development are being sought.

Development of NIRS method for quality control of drug combination artesunate-azithromycin for the treatment of severe malaria.

Near infrared spectroscopy (NIRS) methods were developed for the determination of analytical content of an antimalarial-antibiotic (artesunate and azithromycin) co-formulation in hard gelatin capsule (HGC). The NIRS consists of pre-processing treatment of spectra (raw spectra and first-derivation of two spectral zones), a unique principal component analysis model to ensure the specificity and then two partial least-squares regression models for the determination content of each active pharmaceutical ingredient. The NIRS methods were developed and validated with no reference method, since the manufacturing process of HGC is basically mixed excipients with active pharmaceutical ingredients. The accuracy profiles showed ß-expectation tolerance limits within the acceptance limits (±5%). The analytical control approach performed by reversed phase (HPLC) required two different methods involving two different preparation and chromatographic methods. NIRS offers advantages in terms of lower costs of equipment and procedures, time saving, environmentally friendly.

In vitro release and stability of an artesunate rectal gel suitable for pediatric use.

The rectal route is indicated to treat patients with rapidly evolving malaria who cannot take oral medication to prevent progression to severe forms of the disease. Improvement can be made in terms of rectal bioavailability and stability of current formulations. We studied a new two-compartment, muco-adhesive gel formulation of artesunate which is adapted for use in children and storage in tropical climates. The formulation contains 50mg of artesunate per gram of gel. Because of its instability in aqueous solutions, artesunate is in the dry component of the gel with Carbopol and separate from the liquid phase until reconstitution. Artesunate is stable in the dry blend for 6 months at 45 degrees C and 60% RH. The gel should be used between 1 and 72 h after being reconstituted. Artesunate release was measured by with a rapid, simple and reliable HPLC-UV which allowed the analysis of artesunate and dihydroartemisinin with an analysis time at 3 min. The amount of artesunate released over 6h was 56 +/- 0.97%. Compared to the reference suspension, total release and dissolution efficiency were lower and rate of release was slower (time to 50% dissolution 271 +/- 21 min), probably because of the higher viscosity of the gel, but the drug release profiles were similar. The calculated in vitro release exponent (n) value suggested that artesunate is released from the gel by non-Fickian transport.

Stability of artesunate in pharmaceutical solvents.

Stability of artesunate (ART) was established in three pharmaceutical solvents. The chromatographic conditions developed for this study were acetonitrile:potassium phosphate buffer 10 mM (40:60, v:v; pH 2.9) at 0.7 mL min(-1) with UV detection at 220 nm using a short X-Terra RP C18 column (50 mm x 3 mm, 3.5 microm). This isocratic condition led to the separation between ART and its main degradation products (i.e. alpha-DHA and beta-DHA) with analysis time of less than 4 min. The retention factors are 1.49, 2.26 and 2.79 min for alpha-DHA, beta-DHA and ART, respectively. This method was proved linear (r(2)=0.9995), accurate (R.S.D.=0.20), precise (R.S.D.=0.74) and robust. The system performance remained unaffected by pH variation from 2.6 to 3.2 and variation of acetonitrile percentage from 38 to 42. Stability of ART was assessed in ethanol, propylene glycol (PG) and polyethylene glycol 400 (PEG 400). Unfortunately none of these solvents prevented ART from degradation longer than 3 months. In ethanol, significant degradation of ART occurred after 3 months at room temperature and this degradation was characterised by numerous degradation products. In PEG 400, significant degradation was observed after only 1 month, however DHA was the unique degradation product, which is also an efficient anti-malarial drug.