Josef Beranek

Investigation of drug-polymer interaction in solid dispersions by vapour sorption methods.

The objective of this study was to investigate the effect of different polymeric carriers in solid dispersions with an active pharmaceutical ingredient (API) on their water vapour sorption equilibria and the influence of the API-polymer interactions on the dissolution rate of the API. X-ray diffraction, scanning electron microscopy (SEM), moisture sorption analysis, infrared (IR) spectroscopy and dissolution tests were performed on various API-polymer systems (Valsartan as API with Soluplus, PVP and Eudragit polymers) after production of amorphous solid dispersions by spray drying. The interactions between the API and polymer molecules caused the water sorption isotherms of solid dispersions to deviate from those of ideal mixtures. The moisture sorption isotherms were lower in comparison with the isotherms of physical mixtures in all combinations with Soluplus and PVP. In contrast, the moisture sorption isotherms of solid dispersions containing Eudragit were significantly higher than the corresponding physical mixtures. The nature of the API-polymer interaction was explained by shifts in the characteristic bands of the IR spectra of the solid dispersions compared to the pure components. A correlation between the dissolution rate and the water sorption properties of the API-polymer systems has been established.

Identifying the mechanisms of drug release from amorphous solid dispersions using MRI and ATR-FTIR spectroscopic imaging

The dissolution mechanism of a poorly aqueous soluble drug from amorphous solid dispersions was investigated using a combination of two imaging methods: attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopic imaging and magnetic resonance imaging (MRI). The rates of elementary processes such as water penetration, polymer swelling, growth and erosion of gel layer, and the diffusion, release and in some cases precipitation of drug were evaluated by image analysis. The results from the imaging methods were compared with drug release profiles obtained by classical dissolution tests. The study was conducted using three polymeric excipients (soluplus, polyvinylpyrrolidone - PVP K30, hydroxypropylmethyl cellulose - HPMC 100M) alone and in combination with a poorly soluble drug, aprepitant. The imaging methods were complementary: ATR-FTIR imaging enabled a qualitative observation of all three components during the dissolution experiments, water, polymer and drug, including identifying structural changes from the amorphous form of drug to the crystalline form. The comparison of quantitative MRI data with drug release profiles enabled the different processes during dissolution to be established and the rate-limiting step to be identified, which - for the drug-polymer combinations investigated in this work - was the drug diffusion through the gel layer rather than water penetration into the tablet.

Non-invasive insight into the release mechanisms of a poorly soluble drug from amorphous solid dispersions by confocal Raman microscopy.

In this study, we investigated the release mechanism of the poorly water soluble drug aprepitant from different amorphous solid dispersions using confocal Raman microscopy (CRM). Solid dispersions were fabricated based on either Soluplus®, as an amphiphilic copolymer and solubilizer, or on polyvinylpyrrolidone, as a hydrophilic polymer, in order to elucidate the influence of the polymer characteristics on the drug form and dissolution mechanisms. Aprepitant exhibited its amorphous form in both solid dispersions. However, the release differed depending on the polymer. The high complexation effect of Soluplus was shown to be a crucial factor for stabilization of the amorphous drug, resulting in continuous release without any recrystallization of aprepitant. In contrast, solid dispersions based on polyvinylpyrrolidone showed a different mechanism of dissolution; due to the good affinity of PVP and water, the polymer is dissolving fast, leading to phase separation and local recrystallization of the drug. The study highlights the complexity of release processes from solid dispersions and elucidates the influence of the polymer on drug release kinetics.

The impact of polymeric excipients on the particle size of poorly soluble drugs after pH-induced precipitation

Active pharmaceutical ingredients (APIs) with strongly pH-dependent aqueous solubility can face the problem of precipitating from solution when the pH changes from acidic in the stomach to neutral in the intestine. The present work investigates the effect of two polymeric excipients - polyvinylpyrrolidone (PVP) and Soluplus - on the ability to either prevent precipitation, or to control the size distribution of precipitated particles when precipitation cannot be prevented. Two different APIs were compared, Dabigatran etexilate mesylate and Rilpivirine hydrochloride. The effect of excipient concentration on the precipitation behaviour during pH titration was systematically investigated and qualitatively different trends were observed: in case of Soluplus, which forms a micellar solution when critical micelle concentration is exceeded, precipitation was inhibited in the case of Dabigatran etexilate, which partitioned into the micelles. On the other hand, Rilpivirine precipitated independently of Soluplus concentration. In the case of PVP, which does not form micelles, precipitation could not be avoided. Increased polymer concentration, however prevented the aggregation of precipitated particles into larger cluster. The observed effect of PVP was especially pronounced for Rilpivirine. The main conclusion of this study is that a suitably chosen polymeric excipient can either prevent precipitation altogether or reduce the size of the resulting particles. The mechanism of action, however, seems-specific to a given molecule. It was also shown that the polymer-stabilised particles have a potential to redissolve.

Molecular-level insight into hot-melt loading and drug release from mesoporous silica carriers

ABSTRACT Drug amorphisation by loading to inorganic mesoporous carriers represents an emerging area of improving the dissolution rate and bioavailability of poorly water‐soluble active pharmaceutical ingredients (APIs). In this work, for the first time, a molecular‐level insight into the process of API loading to mesoporous SiO2 (silica) carriers by the hot‐melt impregnation method and its subsequent release during dissolution was obtained using ATR‐FTIR spectroscopic imaging. A physical mixture of ibuprofen crystals and mesoporous silica particles was heated and the dynamics of melt loading into the silica pore structure was directly observed in situ by ATR‐FTIR spectroscopic imaging. The loss of crystallinity, the redistribution of the API in the silica pore network and the subsequent stabilisation of the amorphous form upon cooling were proven. The API was involved in two different kinds of molecular‐level interactions: API dimers in the amorphous bulk, and individual API molecules adsorbed on the silica surface. The melt‐loaded silica carriers were comprehensively characterised by DSC, SEM and dissolution tests, which proved dissolution rate enhancement due to amorphisation of the API. Drug release form the hot‐melt loaded mesoporous silica carriers was observed in real time and the conditions leading to local re‐crystallisation of super‐saturated solution of the API were identified.

The effect of the composition of a fixed dose combination on bioequivalence results

Graphical abstract Figure. No Caption available. &NA; The purpose of this work was to develop a new supergeneric product Meloxicam/Omeprazole. Such a combination brings a benefit in terms of decreasing side effects for the patients using meloxicam. The new combination is composed of a meloxicam powder blend (MPB) and omeprazole gastro‐resistant pellets (OAP) in hard gelatin capsules. The main tasks were to select the excipients to keep the functional layer of OAP active and to prove the bioequivalence to the original products of meloxicam tablets together with omeprazole capsules. Although dissolution profiles similar to the original product were obtained, the unexpected results of omeprazole low bioavailability in the fed bioequivalence study (BES I) showed the necessity to investigate the formulation in greater depth. A modified more complex dissolution method was developed in order to understand the release of omeprazole under gastric conditions. This method revealed the degradation of omeprazole in the formulation when exposed to the fed conditions because of the increase in microenvironmental pH in the capsule caused by trisodium citrate, commonly used for improving solubility of meloxicam. This pH increase dissolved the gastro‐resistant layer of OAP and caused the chemical degradation. To prevent this effect, a trisodium citrate‐free formulation was developed. Reformulated capsules passed the repeated fed bioequivalence study (BES II).

Probing the early stages of tablet disintegration by stress relaxation measurement

ABSTRACT Rapid tablet disintegration is a requirement for the efficient dissolution of the active pharmaceutical ingredient (API) from immediate release tablets. From the mechanistic viewpoint, tablet disintegration begins by the wetting of the tablet surface and the ingress of dissolution medium into the tablet pore structure, followed by the loosening of inter‐particle bonds. The present work introduces a new methodology for probing and quantifying the early stages of tablet disintegration by stress relaxation measurements using texture analysis (TA). The method is based on applying a pre‐defined load on the tablet by means of a needle‐shaped probe and measuring the tablet resistance in time after the addition of the dissolution medium. This measurement provides information about the extent and rate of stress relaxation within the tablet upon hydration. Using a tablet formulation containing ibuprofen as the API and lactose as excipient, the effect of the API content, compaction pressure, and pH of the dissolution medium on the stress relaxation rate was systematically investigated. It is shown that using a dissolution medium pre‐saturated by the formulation components has only a minor effect on the tablet disintegration rate compared to a pure phosphate buffer, meaning that the surface dissolution of particles within the tablet is not the main pre‐requisite of disintegration in this case. On the other hand, pH of the dissolution medium was found to have a very strong effect on the stress relaxation rate in the tablet after wetting, suggesting that van der Waals interactions rather than solid bridges are the predominant particle bonding mechanism in the investigated formulations.

Virtual Prototyping and Parametric Design of 3D-Printed Tablets Based on the Solution of Inverse Problem

The problem of designing tablet geometry and its internal structure that results into a specified release profile of the drug during dissolution was considered. A solution method based on parametric programming, inspired by CAD (computer-aided design) approaches currently used in other fields of engineering, was proposed and demonstrated. The solution of the forward problem using a parametric series of structural motifs was first carried out in order to generate a library of drug release profiles associated with each structural motif. The inverse problem was then solved in three steps: first, the combination of basic structural motifs whose superposition provides the closest approximation of the required drug release profile was found by a linear combination of pre-calculated release profiles. In the next step, the final tablet design was constructed and its dissolution curve found computationally. Finally, the proposed design was 3D printed and its dissolution profile was confirmed experimentally. The computational method was based on the numerical solution of drug diffusion in a boundary layer surrounding the tablet, coupled with erosion of the tablet structure encoded by the phase volume function. The tablets were 3D printed by fused deposition modelling (FDM) from filaments produced by hot-melt extrusion. It was found that the drug release profile could be effectively controlled by modifying the tablet porosity. Custom release profiles were obtained by combining multiple porosity regions in the same tablet. The computational method yielded accurate predictions of the drug release rate for both single- and multi-porosity tablets.