Screening of Fenofibrate-Simvastatin Solid Dispersions in the Development of Fixed-Dose Formulations for the Treatment of Lipid Disorders.

The combination of statins and fibrates in the treatment of lipid abnormalities effectively regulates individual lipid fraction levels. In this study, the screening and assessment of the physicochemical properties of simvastatin-fenofibrate solid dispersions were performed. Fenofibrate and simvastatin were processed using the kneading method in different weight ratios, and the resulting solid dispersions were assessed using differential scanning calorimetry (DSC), X-ray powder diffractometry (XRPD), Fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), contact angle, as well as dissolution tests. The obtained results confirmed the formation of a simple eutectic phase diagram, with a eutectic point containing 79 wt% fenofibrate and 21 wt% simvastatin, lack of chemical interactions between the ingredients, and simvastatin impact on improving fenofibrate dissolution profile, due to the formation of crystalline solid dispersions by the kneading method.

Preformulation Studies of Ezetimibe-Simvastatin Solid Dispersions in the Development of Fixed-Dose Combinations.

Two active pharmaceutical ingredients (APIs) with limited solubility, simvastatin and ezetimibe, prepared as a drug-drug solid dispersion (SD) was evaluated for physicochemical, microstructural, and aqueous dissolution properties. The simvastatin-ezetimibe SD was prepared using the co-grinding method in a wide range of weight fractions and differential scanning calorimetry (DSC) and X-ray powder diffraction (XRPD) were used to perform the phase composition analysis. DSC studies confirmed that simvastatin and ezetimibe form a simple eutectic phase equilibrium diagram. Analysis of Fourier transform infrared spectroscopy (FTIR) studies excluded strong interactions between the APIs. Our investigations have revealed that all studied dispersions are characterized by substantially improved ezetimibe dissolution regardless of simvastatin content, and are best when the composition oscillates near the eutectic point. Data obtained in our studies provide an opportunity for the development of well-formulated, ezetimibe-simvastatin fixed-dose combinations (for hypercholesterolemia treatment) with reduced ezetimibe dosages based on its dissolution improvement.

Binder jetting 3D printing of challenging medicines: From low dose tablets to hydrophobic molecules.

Increasing access to additive manufacturing technologies utilising easily available desktop devices opened novel ways for formulation of personalized medicines. It is, however, challenging to propose a flexible and robust formulation platform which can be used for fabrication of tailored solid dosage forms composed of APIs with different properties (e.g., hydrophobicity) without extensive optimization. This manuscript presents a strategy for formulation of fast dissolving tablets using binder jetting (BJ) technology. The approach is demonstrated using two model APIs: hydrophilic quinapril hydrochloride (QHCl, logP = 1.4) and hydrophobic clotrimazole (CLO, logP = 5.4). The proposed printing method uses inexpensive, well known, and easily available FDA approved pharmaceutical excipients. The obtained model tablets had uniform content of the drug, excellent mechanical properties, and highly porous structure resulting in short disintegration time and fast dissolution rate. The tablets could be scaled and obtained in predesigned shapes and sizes. The proposed method may find its application in the early stages of drug development where high flexibility of the formulation is required and the amount of available API is limited.

The Antimicrobial and Antibiofilm In Vitro Activity of Liquid and Vapour Phases of Selected Essential Oils against Staphylococcus aureus.

The high resistance of staphylococcal biofilm against antibiotics and developing resistance against antiseptics induces a search for novel antimicrobial compounds. Due to acknowledged and/or alleged antimicrobial activity of EOs, their application seems to be a promising direction to follow. Nevertheless, the high complexity of EOs composition and differences in laboratory protocols of the antimicrobial activity assessment hinders the exact estimation of EOs effectiveness. To overcome these disadvantages, in the present work we analysed the effectiveness of volatile and liquid forms of seven EOs (derived from thyme, tea tree, basil, rosemary, eucalyptus, lavender, and menthol mint) against 16 staphylococcal biofilm-forming strains using cohesive set of in vitro techniques, including gas chromatography-mass spectrometry, inverted Petri dish, modified disk-diffusion assay, microdilution techniques, antibiofilm dressing activity measurement, AntiBioVol protocol, fluorescence/confocal microscopy, and dynamic light scattering. Depending on the requirements of the technique, EOs were applied in emulsified or non-emulsified form. The obtained results revealed that application of different in vitro techniques allows us to get a comprehensive set of data and to gain insight into the analysed phenomena. In the course of our investigation, liquid and volatile fractions of thyme EO displayed the highest antibiofilm activity. Liquid fractions of rosemary oil were the second most active against S. aureus. Vapour phases of tea tree and lavender oils exhibited the weakest anti-staphylococcal activity. The size of emulsified droplets was the lowest for T-EO and the highest for L-EO. Bearing in mind the limitations of the in vitro study, results from presented analysis may be of pivotal meaning for the potential application of thymol as a antimicrobial agent used to fight against staphylococcal biofilm-based infections.

Physicochemical and Antifungal Properties of Clotrimazole in Combination with High-Molecular Weight Chitosan as a Multifunctional Excipient.

Chitosans represent a group of multifunctional drug excipients. Here, we aimed to estimate the impact of high-molecular weight chitosan on the physicochemical properties of clotrimazole-chitosan solid mixtures (CL-CH), prepared by grinding and kneading methods. We characterised these formulas by infrared spectroscopy, differential scanning calorimetry, and powder X-ray diffractometry, and performed in vitro clotrimazole dissolution tests. Additionally, we examined the antifungal activity of clotrimazole-chitosan mixtures against clinical Candida isolates under neutral and acid conditions. The synergistic effect of clotrimazole and chitosan S combinations was observed in tests carried out at pH 4 on Candida glabrata strains. The inhibition of C. glabrata growth reached at least 90%, regardless of the drug/excipient weight ratio, and even at half of the minimal inhibitory concentrations of clotrimazole. Our results demonstrate that clotrimazole and high-molecular weight chitosan could be an effective combination in a topical antifungal formulation, as chitosan acts synergistically with clotrimazole against non-albicans candida strains.

Molecular Mobility and Stability Studies of Amorphous Imatinib Mesylate.

The proposed study examined the characterization and stability of solid-state amorphous imatinib mesylate (IM) after 15 months under controlled relative humidity (60 ± 5%) and temperature (25 ± 2 °C) conditions. After 2 weeks, and 1, 3, 6, and 15 months, the samples were characterized using differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), X-ray powder diffractometry (XRPD), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM). Additionally, the amorphous form of imatinib mesylate was obtained via supercooling of the melt in a DSC apparatus, and aged at various temperatures (3, 15, 25 and 30 °C) and time periods (1-16 h). Glass transition and enthalpy relaxation were used to calculate molecular-relaxation-time parameters. The Kohlrausch-Williams-Watts (KWW) equation was applied to fit the experimental enthalpy-relaxation data. The mean molecular-relaxation-time constant (τ) increased with decreasing ageing temperature. The results showed a high stability of amorphous imatinib mesylate adequate to enable its use in solid dosage form.

Thermal stability and decompositions kinetics under non-isothermal conditions of imatinib mesylate α form.

The thermal decomposition and kinetic parameters of synthetized imatinib mesylate α form α form were determined by thermogravimetry (TGA/DTG) under non-isothermal conditions. The experiments were performed at a 25-940°C temperature range at five different heating rates: 2.5Kmin(-1), 5Kmin(-1), 10Kmin(-1), 15Kmin(-1) and 20Kmin(-1) per minute in a nitrogen atmosphere. Imatinib mesylate α form presents one-step mass loss during the degradation process. The thermal stability of the examined material, the melting temperature (Tonset=220.6°C) and ΔH fusion=-95.74Jg(-1) at a heating rate of 10°Cmin(-1) was established. The values of activation energies have been estimated using Kissinger, Flynn-Wall-Ozawa (FWO) and Kissinger-Akahira-Sunose (KAS) methods.

Physicochemical characterization and dissolution studies of acyclovir solid dispersions with Pluronic F127 prepared by the kneading method.

The dissolution rate of anhydrous acyclovir was improved by the preparation of physical mixtures and solid dispersions with the non-ionic polymer Pluronic F127 using the kneading method at different drug-to-polymer ratios. The obtained physical mixtures and solid dispersions were examined in terms of drug content and possible physical and chemical interactions between the drug and polymer using FTIR spectral studies, differential scanning calorimetry and powder X-ray diffraction analysis. The dissolution rate of acyclovir was determined using the rotating disk method. It was found that the minimal content of the polymer within the mixtures needed to increase the dissolution rate of the drug was 50 %.

Solid dispersion in pharmaceutical technology. Part II. The methods of analysis of solid dispersions and examples of their application.

In the first part of the article solid dispersions were classified the properties and methods of their preparation were described. This section presents methods of analysis of solid dispersions i.e.: thermoanalytical methods, XRPD, FTIR, microscopic methods, dissolution studies and examples of drug forms where solid dispersions were used.

Solid dispersions in pharmaceutical technology. Part I. Classification and methods to obtain solid dispersions.

There are many methods to increase solubility of a substance. These include, inter alia, preparation of solid dispersions, i.e. eutectic mixtures, solid solutions, glassy solutions and suspensions. When compared to the individual constituents prior to dispersion formation solid dispersion components are better soluble in water. Therefore, solid solutions became one of the most promising ways to modify solubility, ensuring improved bioavailability and consequently therapeutic efficacy of a substance. In this part of the publication solid dispersions were classified and described in regard to their properties and preparation methods, i.e. melting method, melt evaporation and melt extrusion methods, lyophilisation technique, melt agglomeration process as well as SCF technology and electrospinning.