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.

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 pK_a 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.

Most novel active pharmaceutical ingredients have low water solubility; therefore, solubility-enhancing methods are applied. The aim of the present investigation is to study the impact of nine commonly used pharmaceutical excipients (fillers, surfactants, cyclodextrins, polymers) on solubility, permeability and their relationship. This is crucial for ensuring optimal bioavailability. Carbamazepine, naproxen and pimobendan were chosen as model compounds due to their different acid–base properties. Equilibrium solubility was measured by the traditional shake flask method. Effective permeability was determined by the PAMPA model. Measurements of ionizable compounds were carried out at three pH values. The pH-dependent change in the investigated parameters is maintained even in the presence of excipients. Fillers resulted in a slight or no effect, while the impact of other excipients showed a significant concentration dependence. The impact of excipients was influenced by the structure and ionization state of the molecules. The dominance of the ionized form moderates the impact of excipients. The changes in solubility were more pronounced than in the case of permeability. By examining the effect of the ionization state and interactions with excipients, this work supports the development of formulations that enhance solubility with minimal impacts on permeability. Additionally, it can serve as good basis for preformulation studies and design optimization.

Background and purpose: The effective transport of an active pharmaceutical ingredient across various membrane systems is critical for enhancing its bioavailability, especially in formulations involving solubilizing agents. This study aims to investigate the permeability differences of carvedilol (CAR) between lipophilic and size-exclusion membranes in the presence of hydroxypropyl-beta-cyclodextrin (HP-β-CD) using in vitro side-by-side diffusion cell assays. Experimental approach: Solubility and permeability assays confirmed that HP-β-CD significantly enhanced the solubility of CAR, while simultaneously decreasing its permeability, indicating an interplay between the two parameters. Key results: A mathematical model based on Fick’s first law of diffusion was developed to describe drug transport across the UWL, and generally through the UWL-membrane system, with a particular focus on the role of solubilizing agents. Conclusion: Results from both the UWL and membrane limited transport conditions demonstrated that the supersaturation ratio (SSR, defined as the ratio of the drug concentration present in solution to its thermodynamic solubility measured in exactly the same media) between donor and acceptor compartments is the real driving force of the transport, when the complexing agent and the drug- HP-β-CD complex does not penetrate the membrane or the permeation of the solubilizing additive through the membrane is relatively slow, so it does not affect the transport of the API substantially.

Background and purpose: The effective transport of an active pharmaceutical ingredient across various membrane systems is critical for enhancing its bioavailability, especially in formulations involving solubilizing agents. This study aims to investigate the permeability differences of carvedilol between lipophilic (organic solvent) and size-exclusion membranes in the presence of 2-hydroxypropyl-beta-cyclodextrin in just the acceptor compartment or both sides of the membrane using in vitro side-by-side diffusion cell assays. Experimental approach: Cyclodextrins (CDs) on the acceptor side significantly improved flux and permeability for the lipophilic membrane. In contrast, with size-exclusion membranes that allow the permeation of CDs and their complexes, the benefits of sink conditions were completely diminished. When the same amount of CD was introduced on both sides, the negative effect of CD on the donor side surpassed the positive sink effects on the acceptor side, resulting in reduced flux and permeability across all membrane types. Key results: A novel aspect of this work is the assessment of the applicability of a previously described general mathematical equation for sink conditions. Findings indicated that the supersaturation ratio between donor and acceptor compartments serves as the primary driving force of the membrane transport. For the lipophilic membrane, CDs on the acceptor side not only influenced the driving force of the transport by enhancing the solubility of carvedilol in the acceptor compartment but also altered the proportionality coefficient, hence modifying the apparent thickness of the unstirred water layer. The impact was not observed with size-exclusion membranes. The applicability of the mathematical model was additionally evaluated for CD placed on both sides of the membrane. Conclusion: The model effectively describes the impact of CD placed on the donor side when the solid membrane permits only the drug’s permeation, as in the case of a lipophilic membrane, where the solubilizing additive cannot pass through. It is also applicable when the solubilizing additive permeates slowly and has minimal influence on transport, such as with a size-exclusion membrane with a 1 kDa molecular weight cut-off. The model remains suitable if the additive is small enough in hydrodynamic size to permeate the membrane, but no concentration gradient exists to drive its transport, for example, with a 6 kDa size-exclusion membrane containing the same CD concentration on both sides of the membrane.