Preparation, characterization and antimicrobial assessment of selected ciprofloxacin salts.

The formation of salts is considered a simple strategy to modify the physicochemical properties of active pharmaceutical ingredients. In this study, seven novel binary and ternary organic salts of ciprofloxacin (CP) were prepared with benzoic acid (BA), acetylsalicylic acid (ASA), p-coumaric acid (PCMA) and p-aminosalicylic acid (PASA). They were characterized by spectroscopic techniques and differential scanning calorimetry. Solubility and partition coefficients values were also measured. Evaluation of the antimicrobial activity of the organic salts against Staphylococcus aureus and Staphylococcus epidermidis revealed that most of the new salts had higher antimicrobial activity than CPHCl against both strains. The most active compounds against S. epidermidis and S. aureus were CP-PASA and CPPCMA, resp., which were up to fourteen times more potent than parent CP-HCl. Our findings indicated a strong correlation between the lipophilicity of the formed salts and their antimicrobial activity and showed that an optimum value of lipophilicity (log P = 0.75) seemed to be necessary to maximize the antimicrobial activity. These findings highlighted the improved physical, thermal and antimicrobial properties of the new salts of CP that can aid in providing higher bioavailability than CP-HCl.

Studies on potential interaction between cinacalcet hydrochloride and diclofenac sodium.

Cinacalcet (CT) is an important drug for the treatment hyperparathyroidism. Only few studies havereported thepotential interaction between CT and other potentially coadministered drugs. In this study, the potential of invitro interaction between CT and DF sodium (DF-Na) was investigated. An ion pair salt of CT with DF was obtained by mixing the two compounds in solution; the product was fully characterized by HPLC analysis, UV, FTIR, NMR spectroscopy in addition to DSC. The solubility and partition coefficients were found to significantly decrease and increase, respectively, for the obtained ion pair salt in comparison to the parent compounds. Dissolution studies in phosphate buffer pH 6.8 revealed a significant decrease in the dissolution of an already poorly water soluble drug (decrease to ~20% of the original). Permeation studies, through Caco-2 cells monolayer, revealed a significant decrease in permeation of CT when coexisted with DF (almost to half). Apparent permeability coefficient (Papp) decreased from 3.6 × 10-6 to 1.8 × 10-6 cm/s. Interestingly, a structure for the formed CT-DF salt that could explain the above findings (increase in lipophilicity), could be proposed based on structural modelling, molecular dynamic simulations and NMR proton chemical shifts analysis.

Pancreatic lipase inhibitory activity of selected pharmaceutical agents.

Twenty-five structurally diverse compounds have been tested in vitro for their pancreatic lipase (PL) inhibitory activity. Despite the diversity of tested compounds, the relationship comprising structural attributes of the compounds could be established to correlate with the observed inhibitory activity. Compounds that exerted inhibitory action through surface activity were of different profile from the rest of compounds. When co-incubated with orlistat (OsT), important synergistic effects for some compounds (orphenadrine, gliclazide, cefuroxime and sulfacetamide) were revealed, while antagonistic effects were demonstrated for others (camphor sulfonic acid and dinitro salicylic acid). Docking studies for the most active molecules were performed and molecular interaction forces with the PL active site were identified. The results suggested co-binding of OsT along with the other inhibitor in the binding site in cases of synergistic effect but not in the case of antagonistic effect. These results were additionally supported by affinity capillary electrophoresis. In conclusion, synergistic lipase inhibitory activity between OsT and some other pharmaceutical compounds was demonstrated for the first time, which might help improve the pharmacological effect of OsT.

Interaction of pseudoephedrine and azithromycin with losartan: Spectroscopic, dissolution and permeation studies.

This study aims at investigating the potential effect of selected cationic drugs (azithromycin (AZN) and pseudoephedrine sulfate (PSD) on the dissolution profile and intestinal permeation of losartan potassium (LOS) that might occur due to ion pair salt formation. DSC, FT-IR and 1H NMR indicated the formation of ion pair salts between LOS and each of AZN and PSD. Based on NMR chemical shifts calculations, utilizing specialized software, the most likely structures of the salt were proposed and revealed interesting structural features. The obtained ion pair products were shown to have lower aqueous solubilities (water and phosphate buffer pH 6.8) and higher apparent partition coefficient values compared to the parent compound. Neither of the cations affected the dissolution of LOS tablet (Cozaar® 100 mg) in the studied media (HCl pH 1.2 and phosphate buffer pH 6.8). Interestingly, AZN significantly increased the dissolution of LOS in phosphate buffer pH 4.5 (f2 = 33), and an explanation based on distinguished association pattern between AZN and LOS (CH/π) was offered. Employing permeation test across Caco-2 cells monolayer, the apparent permeability coefficient (Papp) of LOS increased significantly (from 0.9 × 10-5 cm/s to 1.8 × 10-5 cm/s) in the presence of the selected cations. Therefore, while the employed cationic drugs were not shown to form ion pair salts under the in-vitro dissolution conditions, they may still participate in significant in-vivo interaction with LOS.

The effect of ferrous ions, calcium ions and citric acid on absorption of ciprofloxacin across caco-2 cells: practical and structural approach.

OBJECTIVE: To study the potential influence of selected metal ions on absorption (and hence oral bioavailability of ciprofloxacin (Cipro) in presence and absence of a competing ligand. SIGNIFICANCE: The presence of metal ions together with Cipro results in complexes exhibiting a decreased bioavailability. Attempts were made to better understand the mechanism of decreased Cipro bioavailability in the presence of metals such as calcium and ferrous ions, and a small-sized ligand citric acid (CitA). METHODS: Effect of complex size or other potential factors was studied using diffusion through synthetic membrane, permeation studies across Caco-2 cells and capillary electrophoresis. A molecular dynamics (MD) simulation study was conducted to find the arrangement and the nature of the interactions between Cipro molecules and ferrous ions. RESULTS: Cipro was shown to form complexes with metals and CitA. The presence of CitA improved permeation of Cipro through the synthetic membrane but this was not as obvious in case of Caco-2 cells. Capillary electrophoresis suggested the existence of large molecular aggregates of Cipro: metal complexes. MD simulations offered clear evidence of large size aggregates in line with the experimental findings. CitA alone significantly improved permeation of Cipro through Caco-2 cells. CONCLUSIONS: The size of the formed complexes, rather than the decrease in the solubility of formed complexes, plays a significant role in permeation (absorption) of Cipro. CitA might ameliorate the effect of co-administered metal ions on the bioavailability of Cipro.

Potential interaction between zinc ions and a cyclodextrin-based diclofenac formulation.

Complexes of diclofenac sodium (DF-Na) with hydroxypropyl betacyclodextrin (HPßCD) were prepared by co-evaporation in a 1:1 ratio and characterized in light of previously reported data. Phase solubility diagrams were obtained for DF-Na with HPßCD in the presence and absence of zinc ions. Dissolution profiles were obtained for DF-Na and its HPßCD complex at acidic (pH 1.2) as well as in phosphate buffer (pH 6.8), in the presence and absence of zinc. HPßCD, as expected, was shown to improve the dissolution of DF-Na in acidic medium but not in phosphate buffer (pH 6.8). The presence of zinc ions decreased the in vitro dissolution of DF-HPßCD complex in acidic medium (pH 1.2) but not in phosphate buffer (pH 6.8). It was confirmed that the precipitate that was formed by zinc ions in the presence of HPßCD and DF-Na contained no cyclodextrin and most likely it was a mixture of the complexes: DF2-Zn and DF-Zn with some molecules of water. In vivo experiments on rats have shown that HPßCD has no statistically significant effect on absorption or bioavailability of DF-Na in spite of the observed improvement of its in vitro dissolution by HPßCD. Moreover, zinc ions were shown to decrease the absorption rate of DF-Na in rats model but did neither significantly alter the absorption nor bioavailability of DF-HPßCD complex. The zinc induced precipitates of DF were shown to have significantly different crystalline properties when HPßCD was present. Therefore, the pharmaceutical details of a DF-Na preparation should be considered when designing the formulation and predicting possible interaction between DF-Na (or other potential NSAIDs) and zinc metal.

Potential interaction between zinc ions and a cyclodextrin-based diclofenac formulation.

Complexes of diclofenac sodium (DF-Na) with hydroxypropyl betacyclodextrin (HPßCD) were prepared by co-evaporation in a 1:1 ratio and characterized in light of previously reported data. Phase solubility diagrams were obtained for DF-Na with HPßCD in the presence and absence of zinc ions. Dissolution profiles were obtained for DF-Na and its HPßCD complex at acidic (pH 1.2) as well as in phosphate buffer (pH 6.8), in the presence and absence of zinc. HPßCD, as expected, was shown to improve the dissolution of DF-Na in acidic medium but not in phosphate buffer (pH 6.8). The presence of zinc ions decreased the in vitro dissolution of DF-HPßCD complex in acidic medium (pH 1.2) but not in phosphate buffer (pH 6.8). It was confirmed that the precipitate that was formed by zinc ions in the presence of HPßCD and DF-Na contained no cyclodextrin and most likely it was a mixture of the complexes: DF2-Zn and DF-Zn with some molecules of water. In vivo experiments on rats have shown that HPßCD has no statistically significant effect on absorption or bioavailability of DF-Na in spite of the observed improvement of its in vitro dissolution by HPßCD. Moreover, zinc ions were shown to decrease the absorption rate of DF-Na in rats model but did neither significantly alter the absorption nor bioavailability of DF-HPßCD complex. The zinc induced precipitates of DF were shown to have significantly different crystalline properties when HPßCD was present. Therefore, the pharmaceutical details of a DF-Na preparation should be considered when designing the formulation and predicting possible interaction between DF-Na (or other potential NSAIDs) and zinc metal.

Continued investigation into the influence of loaded dose on the performance of dry powder inhalers: surface smoothing effects.

The aerosolization of salbutamol sulfate, measured as fine particle dose (FPD LD) and fine particle fraction (FPF LD) (<6.4 microm mass median aerodynamic diameter), from two sieved (63-90 microm) lactose monohydrate carriers, one as supplied, one smoothed by controlled surface dissolution, was studied. In general, no significant variation in FPD LD was observed at drug loadings between 10 and 63.5 microg and 10 and 135 microg for the surface dissolved and as supplied lactose monohydrates, respectively. Increasing the drug load above these levels resulted in linear increases in FPD LD with increasing drug load with the surface dissolved lactose monohydrate exhibiting higher FPD LD and FPF LD. This suggests that, at lower drug loadings, areas of the carrier exhibiting higher adhesion, so-called active sites, were being preferentially occupied and filled. Since there was no evidence of drug agglomeration using scanning electron microscopy, the observations suggest that the number and range of such higher energy "active sites" can be reduced by modifying the surface roughness, that is, energies, of the carrier.

Novel temperature controlled surface dissolution of excipient particles for carrier based dry powder inhaler formulations.

The surface of lactose monohydrate was modified by solution phase variable temperature dissolution. Lactose monohydrate crystals were added to a known volume of a saturated solution of lactose monohydrate at 25 degrees C. The temperature of the mixture was then ramped to either 30, 35, 40, or 50 degrees C to produce lactose monohydrate batches with reduced levels of fines and lower surface roughness. A dramatic decrease in surface roughness with increasing dissolution temperature was visually observed using scanning electron microscopy. Particle size analysis suggested that the level of lactose fines was reduced after treatment at the lowest dissolution temperature, 30 degrees C. Evaluation of the samples' drug aerosolization using a twin stage impinger, after blending with salbutamol sulphate, suggested that even though there were dramatic changes in roughness and particle size distribution after surface dissolution at 30 degrees C, there was no significant difference in aerosolization as measured by fine particle fraction. However, after surface dissolution at 35 degrees C, there was an increase in fine particle fraction. Surface dissolution at even higher temperatures did not result in any further increase in fine particle fraction. These observations suggest that surface roughness and fines play an important role in the aerosolization of salbutamol sulphate, but the inter-relationships are not straightforward.

The influence of dose on the performance of dry powder inhalation systems.

The relationship between drug/lactose ratio and aerosolisation performance of conventional carrier based formulations was investigated using the twin stage impinger. A dose range of approximately 10-450 microg of drug in a 50 mg lactose carrier formulation was studied. Statistical differences in both the fine particle dose and fine particle fraction were observed across the dosage range (ANOVA, p<0.05). In general, no statistically significant difference (Fishers Pairwise, p<0.05) in fine particle dose was observed between drug levels of approximately 10 microg and 135 microg, whereas a linear decrease in fine particle fraction was observed across the same drug level range (R2=0.977). Increasing the dose from approximately 135 microg to 450 microg resulted in a statistically significant increase in both fine particle dose and fraction (ANOVA p<0.05). Such observations may be attributed to the occupation of 'active' carrier sites by drug particles at low drug concentration, since the quantity of drug particles liberated from the carrier during aerosolisation remains constant at the lower dosing regimes.