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Particle size reduction is a commonly used process to improve the solubility and the dissolution of drug formulations. The solubility of a drug in the gastrointestinal tract is a crucial parameter, because it can greatly influence the bioavailability. This work provides a comprehensive investigation of the effect of the particle size, pH, biorelevant media and polymers (PVA and PVPK-25) on the solubility and dissolution of drug formulations using three model compounds with different acid-base characteristics (papaverine hydrochloride, furosemide and niflumic acid). It was demonstrated that micronization does not change the equilibrium solubility of a drug, but it results in a faster dissolution. In contrast, nanonization can improve the equilibrium solubility of a drug, but the selection of the appropriate excipient used for nanonization is essential, because out of the two used polymers, only the PVPK-25 had an increasing effect on the solubility. This phenomenon can be explained by the molecular structure of the excipients. Based on laser diffraction measurements, PVPK-25 could also inhibit the aggregation of the particles more effectively than PVA, but none of the polymers could hold the nanonized samples in the submicron range until the end of the measurements. [ABSTRACT FROM AUTHOR]

Solubility and permeability are key parameters for establishing in vitro-in vivo correlation for poorly water-soluble active pharmaceutical ingredients (APIs). Recent studies demonstrate that not only solubility, but also effective permeability of the API may change due to the addition of solubilizing agents, and there is a certain mathematical relation between these physicochemical parameters. The aim of this study was to show the importance of early screening of solubility and permeability in presence of additives in order to achieve the expected bioavailability of the API. In this work, the effect of surfactants and microenvironmental pH modifiers were in focus, and pimobendan was chosen as model drug. In the case of pH modifiers, the equilibrium solubility of the API increased, while the permeability decreased significantly. No negative effect was observed for two surfactants at low additive levels, but these two additives also exhibited a slightly negative effect on permeability when used at higher concentrations. In the simultaneous dissolution-permeation studies the surfactants-containing formulation was found to have slightly higher flux than the pH-modifier-containing one. It can be due to the phenomenon that the dissolution of the active substance can be enhanced by these surfactants without any significant permeability reducing effect. The results obtained from the present study clearly demonstrate the importance of studying drug-additive interactions in every step of formulation development and based on these, the selection of the appropriate quality and quantity of additives. In addition, the results also underline the significance of performing simultaneous dissolution-permeation studies to predict bioavailability. [ABSTRACT FROM AUTHOR]

Creating supersaturating drug delivery systems to overcome the poor aqueous solubility of active ingredients became a frequent choice for formulation scientists. Supersaturation as a solution phenomenon is, however, still challenging to understand, and therefore many recent publications focus on this topic. This work aimed to investigate and better understand the pH dependence of supersaturation of telmisartan (TEL) at a molecular level and find a connection between the physicochemical properties of the active pharmaceutical ingredient (API) and the ability to form supersaturated solutions of the API. Therefore, the main focus of the work was the pH-dependent thermodynamic and kinetic solubility of the model API, TEL. Based on kinetic solubility results, TEL was observed to form a supersaturated solution only in the pH range 3–8. The experimental thermodynamic solubility-pH profile shows a slight deviation from the theoretical Henderson–Hasselbalch curve, which indicates the presence of zwitterionic aggregates in the solution. Based on pKa values and the refined solubility constants and distribution of macrospecies, the pH range where high supersaturation-capacity is observed is the same where the zwitterionic form of TEL is present. The existence of zwitterionic aggregation was confirmed experimentally in the pH range of 3 to 8 by mass spectrometry. [ABSTRACT FROM AUTHOR]

The aim of this study was to draw attention to the challenges of solubility measurement and to present new techniques and detection methods that provide more accurate results. We investigated the effect of crystal structure, pH and buffer composition on thermodynamic equilibrium solubility using two polymorphs of carvedilol (Form I and Form II) as model compounds. Measuring the solubility of carvedilol is challenging, as the literature data show extremely high standard deviation. Therefore standardized measurements were performed in the pH range 3–10, in two solutions at 25 °C: Britton–Robinson (BR) and BR with added KCl. Solid phase analysis was performed by X-ray powder diffraction and Raman spectroscopy. The measured SpH data were compared to the theoretical Henderson–Hasselbalch (HH) curve and a perfect fit was found in the pH range 7–10. The salt formation could be observed in the acidic pH range. The counter-ion and solubility of the salt were found to be different in various buffer solutions. In situ fiber optic UV probes were used to monitor the dissolution of carvedilol polymorphs in real-time. The results showed significantly different dissolution kinetics for the polymorphs depending on the pH and the buffer solution. From the dissolution profile, the time required to reach the equilibrium was determined. In most cases, it was more than 24 hours, therefore using the standard protocol (6 hours agitation, 18 hours sedimentation) would have caused significant inaccuracy in results. In extreme cases the measured concentration after 24 hours was found to be 5 or 6 times higher than the real equilibrium solubility. [ABSTRACT FROM AUTHOR]

Absorption through the skin of topically applied chemicals is relevant for both formulation development and safety assessment, especially in the early stages of development. However, the supply of human skin is limited, and the traditional in vitro methods are of low throughput. As an alternative, an artificial membrane-based Skin Parallel Artificial Membrane Permeability Assay (Skin-PAMPA) has been developed to mimic the permeability through the stratum corneum. In this study, this assay was used to measure the permeability of a model compound, 4-phenylethyl-resorcinol (PER), dissolved in 13 different solvents that are commonly used in cosmetic formulation development. The study was performed at concentrations close to the saturated solution of PER in each solvent to investigate the maximum thermodynamic potential of the solvents. The permeability of PER in selected solvents was also measured on ex vivo pig skin for comparison. Pig ear skin is an accepted alternative model of human skin. The permeability coefficient, which is independent of the concentration of the applied solution, showed a good correlation (R2 = 0.844) between the Skin-PAMPA and the pig skin permeation data. Our results support the use of the Skin-PAMPA to screen the suitability of different solvents for non-polar compounds at an early stage of formulation development. [ABSTRACT FROM AUTHOR]