European Journal of Pharmaceutical Sciences最新文献

Co-crystals have recently attracted growing interest as enabling formulations for poorly soluble drugs, due to their ability to enhance various physicochemical properties of active pharmaceutical ingredients (APIs). Different co-crystals of the same drug compound are formally regarded as the same active ingredient although they typically have different solubilities. As solubility is one of the key parameters for dissolution profiles, using different co-crystals of the same API can tailor the dissolution behavior. The classical experimental method to determine and compare co-crystal solubility in aqueous media relies on measuring drug and co-former concentrations at the eutectic point. However, these measurements are time- and material- consuming, requiring extensive sampling and sample processing while the eutectic point is being chased. This paper introduces a new and simple approach to predict co-crystal solubility in any medium, including aqueous buffer at physiological pH. The method, based on thermodynamic principles, estimates the solubility product (K_sp) in a target medium by measuring i) the API and coformer concentrations in the solution obtained during cocrystal synthesis and ii) the individual solubilities of the API and coformer in the synthesis solvent and the target medium. From these easily accessible experimental data, K_sp and solubility of the cocrystal in the target medium, such as water, can be derived. The method was validated using two example systems: carbamazepine-benzamide and cilnidipine-p-toluenesulfonamide, which are co-crystals of neutral components. Predicted values aligned well with experimental eutectic point measurements, demonstrating the method's effectiveness even when the two co‑crystals differed in solubility by two orders of magnitude. The approach is advantageous as it minimizes experimental work, and solubility data of the individual components can be collected once and reused for other co-crystals. The prediction method appears suitable for a fast and reasonably accurate estimation of co-crystal solubility during early phase of drug development and solid form selection. The method is currently limited to 1:1 co-crystals of neutral components.

Carrier-free systems are a highly substantial research area due to the side effects of excipients on the lungs and the limited number of excipients suitable for lung-targeted drug delivery systems. The goal of this study is the preparation of a carrier-free dry powder inhaler (DPI) formulation containing clarithromycin for the treatment of pneumonia. Solutions of clarithromycin in methanol:water mixtures were turned into respirable microparticles by the spray-drying process. Ammonium carbonate was added to the formulations at concentrations between 0.05% and 3.00% (w/v), and the effect of the ammonium carbonate concentration on the formulations was investigated in terms of surface characteristics, particle size, and zeta potential. Following these studies, thermal behavior (thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) analysis), chemical interactions (fourier transform infrared (FT-IR) analysis), crystallinity (X-ray diffraction (XRD) analysis), antimicrobial activity, aerodynamic performance with Next Generation Impactor (NGI), surface area, and moisture content were evaluated. It was determined that the formulation F9, containing 0.50% (w/v) ammonium carbonate, had the most convenient features for lung targeting. It exhibited a nearly spherical shape. Its d₅₀ = 4.76 ± 0.05 µm, zeta potential = -21.4 ± 1.5 mV, mass median aerodynamic diameter (MMAD) = 5.08 µm, fine particle fraction (FPF) = 19.65%, surface area = 1.773 m²/g, and moisture content = 3.023%. TGA, DSC, and XRD confirmed the amorphous structure of the formulation. Two considerable outcomes were obtained after this study. First, an effective DPI formulation was obtained without the need for carriers, using the applied production method. Second, a drug candidate was developed that is more efficient than the conventional antibiotic clarithromycin (minimum inhibitory concentrations (MICs) of the optimum formulation and untreated clarithromycin are 0.15 and 0.30 µg/mL, and minimum bactericidal concentrations (MBCs) of the optimum formulation and untreated clarithromycin are 1.22 and 4.88 µg/mL, respectively) by providing local treatment for pneumonia.