Understanding interactions of oleic acid with basic drugs in solid lipids on different biopharmaceutical levels

Recently, the impact of intestinal supersaturation on absorption of poorly water-soluble drugs has raised much interest among researchers. A focus has been mostly to study excipient effects on maintenance of drug supersaturation. The aim of the present study was to better understand the effects of drug-excipient interactions on the level of the anhydrous formulation, upon dispersion in simple buffer media and, in particular, regarding precipitation kinetics. A solid lipid-based formulation comprising PEG-32 stearate and oleic acid (OA) (8:2 w/w) was developed as a model. Loratadine (pKa = 4.33) and carvedilol (pKa = 8.74) were chosen as basic drugs. UV/FTIR spectroscopy and viscometry were used to characterize drug-OA molecular interactions in solution, while solid formulations were studied using x-ray diffraction, thermal analysis and van’t Hoff solubility-temperature plots. Precipitation kinetics of drug formulations was real-time monitored in phosphate buffer (pH = 6.5) by focused beam reflectance measurements. It was found that the addition of OA in the formulations resulted in substantial drug solubility increase. Although the drug-OA interactions appeared to be partially lost upon formulation dispersion, the extent of precipitation was markedly lowered compared to the formulations without OA. A Precipitation number (Pnc) was introduced as a ratio of a relevant residence time of drug in the gastrointestinal tract (GIT) to the induction time (the onset time of crystalline precipitation). Without OA, Pnc was already taking critical values (>1), while the anhydrous formulation was still below saturation for both model drugs. Interestingly, the addition of OA resulted in amorphous instead of crystalline precipitates, which is advantageous for drug re-dissolution and absorption. In conclusion, this study provides an improved understanding of OA and basic drug interactions on different levels of in vitro performance for more rational oral formulation development

Understanding Biorelevant Drug Release from a Novel Thermoplastic Capsule by Considering Microstructural Formulation Changes During Hydration

Purpose: To study the biorelevant drug release from novel starch-based polyvinyl alcohol capsules (S-PVA-C). The effect of the shell material is studied by considering microstructural formulation changes during hydration. Methods: Two different self-emulsifying systems containing either fenofibrate or probucol were filled in S-PVA-C, as well as capsules of gelatin (SGC) and starch (VegaGels®). Release analysis employed a BioDis® apparatus, while disintegration was studied by texture analysis. For microstructural analysis we used small angle x-ray scattering (SAXS). Results: S-PVA-C opened only partially in biorelevant media compared to completely opened SGC and VegaGels®. In case of the fenofibrate formulation, this opening mechanism caused only a short lag time, while the probucol formulation in S-PVA-C resulted in a sustained release. The latter formulation demonstrated much higher viscosity upon hydration compared to the fenofibrate system. Such a rheological effect on drug release was barely noted for SGC or VegaGels® and SAXS revealed differences in the hydrated microstructure. Conclusions: Even though S-PVA-C are highly attractive for encapsulation of rather hydrophilic formulations, some care is needed regarding an immediate release form. The type of formulation hydration must be considered for adequate selection of the capsule material

Drug-excipient-shell interactions using thermoplastic starch-based capsules for oral lipid-based drug delivery

Worldwide, gelatin has been used in the rotary die process as a shell-forming material of soft capsules due to its unique physicochemical properties. The development of soft gelatin capsules (SGCs) is, however, challenging because of their highly dynamic nature. Migrations of components between the shell and the fill, as well as between the shell and the external environment, are very common. These migrations might occur during manufacture, drying and on storage. A major challenge is the large amount of water (up to 35% w/w) that the capsule shell contains immediately after encapsulation. During drying the water migrates from the shell into the environment and the fill until equilibrium moisture content is reached. The water migration pattern greatly depends on the nature of the fill formulation. For lipophilic oily formulations there is no water uptake from the shell. However, a considerably hydrophilic fill might take up a high amount of water (up to 20% w/w). Some water migrates back into the shell with further drying, resulting in capsules containing up to ~ 8% w/w of water in the fill. This water creates a risk of drug precipitation in the fill mass, since the drug solubility in the formulation can be greatly reduced. To overcome the disadvantages of gelatin, a great effort has been directed into finding new materials as a substitute for gelatin in soft capsules. The present thesis comprises two studies that focus on a novel thermoplastic shell material for soft capsules. A particular aim was to gain a better mechanistic understanding of drug-excipient-shell interactions using SGCs and different starch-based thermoplastic capsules. Since thermoplastic capsules allow a filling at rather high temperatures, formulations that are even solid at room temperature can be encapsulated. Therefore, a third study used such solid lipid-based formulations with the aim to investigate drug-excipient-shell interactions on different biopharmaceutical levels in vitro. Recently, a novel starch-based polyvinyl alcohol thermoplastic capsule (S-PVA-C) has been introduced by researchers at Swiss Caps AG, member of the Aenova group (Kirchberg, Switzerland). In the first study, we provided a thorough physical characterization of the new shell material. Additionally, we aimed to determine whether this capsule material is associated with less water exchange between the fill and the capsule shell compared to gelatin, thus preventing precipitation of a poorly water-soluble drug in the fill mass. Both SGCs and S-PVA-Cs were filled with a hydrophilic lipid-based system of fenofibrate and different water migration patterns were observed. SGCs exhibited considerable water migration from the soft gelatin shell to the fill during drying resulting in drug crystallization. In contrast, S-PVA-Cs displayed no substantial water exchange or drug crystallization upon storage. Therefore, S-PVA-Cs provided a more robust drug product following encapsulation of a rather hydrophilic lipid-based formulation compared to SGCs. The second study is focused on the biorelevant drug release from the novel S-PVA-Cs, SGCs, and VegaGels®. We studied the effect of the shell material by considering microstructural formulation changes during hydration. It was found that S-PVA-Cs opened only partially in biorelevant media compared to completely opened SGCs and VegaGels®. This different opening mechanism caused sustained drug release from S-PVA-Cs for formulation that demonstrated high viscosity upon hydration. Such a rheological effect on drug release was barely noted for SGCs or VegaGels®. Additionally, small angle x-ray scattering (SAXS) showed differences in the hydrated microstructure (using a Teubner-Strey model for microemulsions). Our results suggested that even though S-PVA-Cs are highly attractive for encapsulation of rather hydrophilic formulations, some care is needed regarding an immediate release form. In the third study we developed a solid lipid-based system that requires elevated filling temperatures for encapsulation. We aimed at better mechanistic understanding of the effects of drug-excipient interactions at different biopharmaceutical levels (i.e. anhydrous formulation, upon dispersion in simple buffer media and, in particular, regarding precipitation kinetics). Loratadine and carvedilol were chosen as model basic drugs. Drug-OA molecular complexes were formed upon addition of oleic acid (OA) in the formulation, which led to a marked increase in drug solubility. Precipitation kinetics of drug formulations was monitored in phosphate buffer (pH = 6.5) in real-time using focused beam reflectance measurements. The results clearly demonstrated that OA influenced the extent of drug precipitation as well as its kinetics. More importantly, solid-state analysis showed an amorphous precipitate demonstrating that OA acted also as a precipitation modifier. The role of OA as a precipitation inhibitor, and more importantly as a precipitation modifier, can be used in a novel formulation approach. In situ forming amorphous system obtained from OA-containing formulation may be valuable from a biopharmaceutical perspective for the delivery of poorly soluble basic drugs. In summary, the present thesis introduced novel starch-based thermoplastic capsules (S-PVA-Cs) and demonstrated their advantage over SGCs with respect to hydrophilic lipid-based formulations. Release studies in biorelevant media revealed differences in how formulations hydrated and interacted with the shell material. Drug-excipient-shell interactions were observed in various capsule types (SGCs, S-PVA-Cs, and VegaGels®) at different levels of biopharmaceutical in vitro testing. A better mechanistic understanding was attained that may guide future development of soft capsule products

Understanding biorelevant drug release from a novel thermoplastic capsule by considering microstructural formulation changes during hydration

To study the biorelevant drug release from novel starch-based polyvinyl alcohol capsules (S-PVA-C). The effect of the shell material is studied by considering microstructural formulation changes during hydration.; Two different self-emulsifying systems containing either fenofibrate or probucol were filled in S-PVA-C, as well as capsules of gelatin (SGC) and starch (VegaGels®). Release analysis employed a BioDis® apparatus, while disintegration was studied by texture analysis. For microstructural analysis we used small angle x-ray scattering (SAXS).; S-PVA-C opened only partially in biorelevant media compared to completely opened SGC and VegaGels®. In case of the fenofibrate formulation, this opening mechanism caused only a short lag time, while the probucol formulation in S-PVA-C resulted in a sustained release. The latter formulation demonstrated much higher viscosity upon hydration compared to the fenofibrate system. Such a rheological effect on drug release was barely noted for SGC or VegaGels® and SAXS revealed differences in the hydrated microstructure.; Even though S-PVA-C are highly attractive for encapsulation of rather hydrophilic formulations, some care is needed regarding an immediate release form. The type of formulation hydration must be considered for adequate selection of the capsule material

Ten years of the manufacturing classification system: a review of literature applications and an extension of the framework to continuous manufacture

The MCS initiative was first introduced in 2013. Since then, two MCS papers have been published: the first proposing a structured approach to consider the impact of drug substance physical properties on manufacturability and the second outlining real world examples of MCS principles. By 2023, both publications had been extensively cited by over 240 publications. This article firstly reviews this citing work and considers how the MCS concepts have been received and are being applied. Secondly, we will extend the MCS framework to continuous manufacture. The review structure follows the flow of drug product development focussing first on optimisation of API properties. The exploitation of links between API particle properties and manufacturability using large datasets seems particularly promising. Subsequently, applications of the MCS for formulation design include a detailed look at the impact of percolation threshold, the role of excipients and how other classification systems can be of assistance. The final review section focusses on manufacturing process development, covering the impact of strain rate sensitivity and modelling applications. The second part of the paper focuses on continuous processing proposing a parallel MCS framework alongside the existing batch manufacturing guidance. Specifically, we propose that continuous direct compression can accommodate a wider range of API properties compared to its batch equivalent