Hans de Waard

Improved dissolution behavior of lipophilic drugs by solid dispersions: the production process as starting point for formulation considerations

Introduction: Many new drug substances have low aqueous solubility which can cause poor bioavailability after oral administration. The application of solid dispersions is a useful method to increase the dissolution rate of these drugs and thereby improve their bioavailability. So far, several methods have been developed to prepare solid dispersions. To obtain a product with the desired attributes, both the formulation and production processes should be considered. Areas covered: The most currently used methods to produce solid dispersions, such as the fusion method, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation, are reviewed in this paper. In addition, the physicochemical characteristics of the obtained solid dispersions are discussed. Expert opinion: Solid dispersions can be successfully prepared by simple fusion, hot melt extrusion, spray drying, freeze drying and supercritical fluid precipitation. Hot melt extrusion, spray drying and freeze drying are processes that can be applied for large scale production. The simple fusion method is not very suitable for large scale production, but is particularly suitable for screening formulations. The most recent method to produce sold dispersions is supercritical fluid precipitation. The process conditions of this method need extensive investigation, in particular in relationship with the selection of the type of carrier and/or solvent. Both processes and formulation aspects strongly affect the characteristics of solid dispersion products. Furthermore, application of crystalline solid dispersions is gaining increasing interest because they are thermodynamically more stable than amorphous solid dispersions.

Molecular dynamics simulation of a polysorbate 80 micelle in water

The structure and dynamics of a single molecule of the nonionic surfactant polysorbate 80 (POE (20) sorbitan monooleate; Tween 80®) as well as a micelle comprising sixty molecules of polysorbate 80 in water have been investigated by molecular dynamics simulation. In its free state in water the polysorbate 80 molecule samples almost its entire conformational space. The micelle structure is compact and exhibits a prolate ellipsoid shape, with the surface being dominated by the polar terminal groups of the POE chains. The radius of gyration of the micelle was 26.2 A. The physical radius, determined from both the radius of gyration and atomic density, was about 35 A. The estimated diffusion constants for the free molecule (1.8 × 10−6 cm2s−1) and the micelle (1.8 × 10−7 cm2s−1) were found to be remarkably close to the respective experimental values. The lateral diffusion of the molecules on the micelle surface was estimated to be 1.7 × 10−7 cm2s−1, which confirms the highly dynamic nature of the micelle structure.

Low temperature extruded implants based on novel hydrophilic multiblock copolymer for long-term protein delivery

Parenteral protein delivery requires preservation of the integrity of proteins and control over the release kinetics. In order to preserve the integrity, parenteral protein delivery formulations typically need to be processed at low temperatures. Therefore, we synthesized a novel low melting biodegradable hydrophilic multiblock copolymer composed of poly (ethylene glycol) and poly (ε-caprolactone) to allow extrusion at relatively low temperatures. We investigated the extrusion characteristics of this polymer and explored a strategy how to control the release of the model protein lysozyme from small diameter extruded implants. It was found that the polymer could be well extruded at temperatures as low as 55 °C. Moreover, lysozyme remained active both during extrusion as well as during release. Lysozyme release kinetics could be tailored by the co-incorporation of an oligosaccharide, inulin, which functions as a pore-forming excipient. It was concluded that this hydrophilic multiblock copolymer has promising characteristics for the preparation by melt extrusion of protein delivery implants with a release profile that is sustained over a period of more than 7 months.

Controlled Crystallization of the Lipophilic Drug Fenofibrate During Freeze-Drying: Elucidation of the Mechanism by In-Line Raman Spectroscopy

We developed a novel process, “controlled crystallization during freeze-drying” to produce drug nanocrystals of poorly water-soluble drugs. This process involves freeze-drying at a relatively high temperature of a drug and a matrix material from a mixture of tertiary butyl alcohol and water, resulting in drug nanocrystals incorporated in a matrix. The aim of this study was to elucidate the mechanisms that determine the size of the drug crystals. Fenofibrate was used as a model lipophilic drug. To monitor the crystallization during freeze-drying, a Raman probe was placed just above the sample in the freeze-dryer. These in-line Raman spectroscopy measurements clearly revealed when the different components crystallized during freeze-drying. The solvents crystallized only during the freezing step, while the solutes only crystallized after the temperature was increased, but before drying started. Although the solutes crystallized only after the freezing step, both the freezing rate and the shelf temperature were critical parameters that determined the final crystal size. At a higher freezing rate, smaller interstitial spaces containing the freeze-concentrated fraction were formed, resulting in smaller drug crystals (based on dissolution data). On the other hand, when the solutes crystallized at a lower shelf temperature, the degree of supersaturation is higher, resulting in a higher nucleation rate and consequently more and therefore smaller crystals. In conclusion, for the model drug fenofibrate, a high freezing rate and a relatively low crystallization temperature resulted in the smallest crystals and therefore the highest dissolution rate.

NIR spectroscopy for the in-line monitoring of a multicomponent formulation during the entire freeze-drying process

Freeze drying is a complex, time consuming and thus expensive process, hence creating a need for understanding the material behaviour in the process environment and for process optimization. Near-infrared (NIR) spectroscopy offers the opportunity to monitor physicochemical changes of the formulation during freeze-drying. The aim of this work was to examine whether NIR spectroscopy allows in-line monitoring of all components during the entire freeze-drying process of a multi-component pharmaceutical formulation (a solution of fenofibrate and mannitol in a mixture of tertiary-butyl alcohol, and water). To extract useful information of all components in the formulation from the large multivariate data-sets obtained during in-line spectroscopic monitoring, several spectral pre-processing techniques and spectral data analysis techniques such as the mean of selected wavenumbers (Mws), the correlation coefficient (CorrCoef) and principal component analysis (PCA) have been evaluated and compared. To find out whether these chemometric techniques are also able to differentiate between changes in the process settings influencing the freeze-drying process of the formulation, freeze-drying processes were performed at four different conditions. Results demonstrated that in-line measurements using NIR spectroscopy were possible in an icy environment and that a further process understanding could be obtained. Data-analysis revealed the crystallization behaviour of each of the four components. In addition, using the three pre-processing techniques allowed observe the sublimation of the solvents. Mws and CorrCoef have proven to be adequate methods for monitoring the main physicochemical changes of product during the processes; this affirmation was confirmed by observing the outputs of PCA for entire processes.

A user-friendly model for spray drying to aid pharmaceutical product development

The aim of this study was to develop a user-friendly model for spray drying that can aid in the development of a pharmaceutical product, by shifting from a trial-and-error towards a quality-by-design approach. To achieve this, a spray dryer model was developed in commercial and open source spreadsheet software. The output of the model was first fitted to the experimental output of a Büchi B-290 spray dryer and subsequently validated. The predicted outlet temperatures of the spray dryer model matched the experimental values very well over the entire range of spray dryer settings that were tested. Finally, the model was applied to produce glassy sugars by spray drying, an often used excipient in formulations of biopharmaceuticals. For the production of glassy sugars, the model was extended to predict the relative humidity at the outlet, which is not measured in the spray dryer by default. This extended model was then successfully used to predict whether specific settings were suitable for producing glassy trehalose and inulin by spray drying. In conclusion, a spray dryer model was developed that is able to predict the output parameters of the spray drying process. The model can aid the development of spray dried pharmaceutical products by shifting from a trial-and-error towards a quality-by-design approach.

Protein release from water-swellable poly(d,l-lactide-PEG)-b-poly(ϵ-caprolactone) implants

In this study, water-swellable multiblock copolymers composed of semi-crystalline poly(ϵ-caprolactone) [PCL] blocks and amorphous blocks consisting of poly(D,L-lactide) (PDLLA) and poly(ethylene glycol) (PEG) [PDLLA-PEG] were synthesized. The block ratio of these [PDLLA-PEG]-b-[PCL] multiblock copolymers was varied and the degradation of implants prepared of these polymers by hot melt extrusion (HME) was compared with implants prepared of [PCL-PEG]-b-[PCL], a copolymer which has been described previously (Stanković et al., 2014). It was shown that the initial degradation rate of the [PDLLA-PEG]-b-[PCL] multiblock copolymers increased with increasing the content of amorphous [PDLLA-PEG] block and that the degradation rate of these multiblock copolymers was faster than that of the [PCL-PEG]-b-[PCL] multiblock copolymers due to rapid degradation of the [PDLLA-PEG] block. Furthermore, the release of the model proteins lysozyme and bovine serum albumin from polymer implants prepared by HME was studied. It was found that the protein release from [PDLLA-PEG]-b-[PCL] copolymers was incomplete, which is not acceptable for any application of these polymers. Besides, [PCL-PEG]-b-[PCL] copolymers showed slow and continuous release. We hypothesize that the incomplete release is explained by an irreversible interaction between the proteins and polymer degradation products or by entrapment of the protein in the hydrophobic and non-swellable polymer matrix that was left after degradation and loss of the hydrophilic [PDLLA-PEG] blocks from the degrading polymer.

Nanoparticle Formulation of a Poorly Soluble Cannabinoid Receptor 1 Antagonist Improves Absorption by Rat and Human Intestine

The inclusion of nanoparticles dispersed in a hydrophilic matrix is one of the formulation strategies to improve the bioavailability of orally administered Biopharmaceutics Classification System (BCS) class II and IV drugs by increasing their dissolution rate in the intestine. To confirm that the increased dissolution rate results in increased bioavailability, in vitro and in vivo animal experiments are performed, however, translation to the human situation is hazardous. In this study, we used a range of in vitro and ex vivo methods, including methods applying human tissue, to predict the in vivo oral bioavailability of a model BCS class II CB-1 antagonist, formulated as a nanoparticle solid dispersion. The enhanced dissolution rate from the nanoparticle formulation resulted in an increased metabolite formation in both rat and human precision-cut intestinal slices, suggesting increased uptake and intracellular drug concentration in the enterocytes. In Ussing chamber experiments with human tissue, both the metabolite formation and apical efflux of the metabolite were increased for the nanoparticulate solid dispersion compared with a physical mixture, in line with the results in intestinal slices. The pharmacokinetics of the different formulations was studied in rats in vivo. The nanoparticle formulation indeed improved the absorption of the cannabinoid receptor 1 (CB-1) antagonist and the delivery into the brain compared with the physical mixture. In conclusion, the combined approach provides a valuable set of tools to investigate the effects of formulation on the absorption of poorly soluble compounds in human intestine and may provide relevant information on the oral bioavailability in humans early in the development process.