NANEX: Process design and optimization.

Previously, we introduced a one-step nano-extrusion (NANEX) process for transferring aqueous nano-suspensions into solid formulations directly in the liquid phase. Nano-suspensions were fed into molten polymers via a side-feeding device and excess water was eliminated via devolatilization. However, the drug content in nano-suspensions is restricted to 30 % (w/w), and obtaining sufficiently high drug loadings in the final formulation requires the processing of high water amounts and thus a fundamental process understanding. To this end, we investigated four polymers with different physicochemical characteristics (Kollidon(®) VA64, Eudragit(®) E PO, HPMCAS and PEG 20000) in terms of their maximum water uptake/removal capacity. Process parameters as throughput and screw speed were adapted and their effect on the mean residence time and filling degree was studied. Additionally, one-dimensional discretization modeling was performed to examine the complex interactions between the screw geometry and the process parameters during water addition/removal. It was established that polymers with a certain water miscibility/solubility can be manufactured via NANEX. Long residence times of the molten polymer in the extruder and low filling degrees in the degassing zone favored the addition/removal of significant amounts of water. The residual moisture content in the final extrudates was comparable to that of extrudates manufactured without water.

Rational Design and Characterization of a Nanosuspension for Intraoral Administration Considering Physiological Conditions.

The oral cavity displays an attractive route in drug administration that is not associated with gastric transit and hepatic first-pass metabolism. However, limiting factors for an efficient transit of drugs through the oral mucosa are poor water solubility and permeability. Hence, various strategies exist to enhance solubility. Specifically, nanotechnology has attracted much research interest in the past decade. This study aimed at developing a stable nanosuspension of the model compound phenytoin via wet media milling. The nanosuspensions were carefully characterized regarding hydrodynamic particle sizes, crystallinity, and dissolution characteristics under nonphysiological or physiological (salivary) conditions. The permeability of bulk phenytoin and nanophenytoin through a buccal in vitro and ex vivo model was investigated, and the apparent permeability coefficients were determined. Moreover, cytotoxicity studies were conducted. The addition of Tween 80 as stabilizer resulted in a stable crystalline nanosuspension (330 nm). The solubility characteristics significantly increased under salivary conditions, which further impacted the permeability, as the steady state appearance rate of nanosized phenytoin was 1.4-fold higher. Cytotoxicity studies demonstrated that bulk-/nano-phenytoin exhibited no harmful effects. It can be concluded that the salivary environment (i.e., ionic strength, pH) strongly impacts the solubility and consequently the permeability of crystalline nanosuspensions across the buccal mucosa.

Continuous low-dose feeding of highly active pharmaceutical ingredients in hot-melt extrusion.

CONTEXT: Manufacturing solid low-dose pharmaceutical products has always the homogeneity challenge. In continuous manufacturing, there is the additional challenge of feeding active pharmaceutical ingredient (API) dry powder at low rates. This paper presents a method for feeding API particles into a continuous extrusion process using a suspension. The challenges for feeding and the product homogeneity are both addressed. OBJECTIVE: The objective of this study is to demonstrate the feasibility of manufacturing low-dose extrudates by feeding the API particles in a diluted anti-solvent suspension. MATERIALS AND METHODS: Extrudates with an Ibuprofen content of 0.021% and 0.043% (w/w) were prepared by feeding a 0.9% w/w suspension of Ibuprofen particles into a Coperion extruder. RESULTS AND DISCUSSION: The homogeneity (RSD) of extrudates was tested during a time span of 30 min and had values between 2% and 7%. CONCLUSION: Feeding particles in an anti-solvent suspension offers a simple feeding option for API and minor components which yield products of desired homogeneity. The liquid feeding approach offers a simplified process with enhanced process control possibilities.

One Polymorph and Various Morphologies of Phenytoin at a Silica Surface Due to Preparation Kinetics.

The preparation of solid crystalline films at surfaces is of great interest in a variety of fields. Within this work the preparation of pharmaceutically relevant thin films containing the active pharmaceutical ingredient phenytoin is demonstrated. The preparation techniques applied include drop casting, spin coating, and vacuum deposition. For the solution processed samples a decisive impact of the solution concentration and the applied film fabrication technique is observed; particular films form for all samples but with their extensions along different crystallographic directions strongly altered. Vacuum deposition of phenytoin reveals amorphous films, which over time crystallize into needle-like or particular-type structures whereby a nominal thickness of 50 nm is required to achieve a fully closed layer. Independent of all preparation techniques, the resulting polymorph is the same for each sample as confirmed by specular X-ray diffraction scans. Thus, morphologies observed via optical and atomic force microscope techniques are therefore a result of the preparation technique. This shows that the different time scales for which crystallization is obtained is the driving force for the various morphologies in phenytoin thin films rather than the presence of another polymorph forming.

Nano-extrusion: a promising tool for continuous manufacturing of solid nano-formulations.

Since more than 40% of today's drugs have low stability, poor solubility and/or limited ability to cross certain biological barriers, new platform technologies are required to address these challenges. This paper describes a novel continuous process that converts a stabilized aqueous nano-suspension into a solid oral formulation in a single step (i.e., the NANEX process) in order to improve the solubility of a model drug (phenytoin). Phenytoin nano-suspensions were prepared via media milling using different stabilizers. A stable nano-suspension was obtained using Tween(®) 80 as a stabilizer. The matrix material (Soluplus(®)) was gravimetrically fed into the hot melt extruder. The suspension was introduced through a side feeding device and mixed with the molten polymer to immediately devolatilize the water in the nano-suspension. Phenytoin nano-crystals were dispersed and embedded in the molten polymer. Investigation of the nano-extrudates via transmission electron microscopy and atomic force microscopy showed that the nano-crystals were embedded de-aggregated in the extrudates. Furthermore, no changes in the crystallinity (due to the mechanical and thermal stress) occurred. The dissolution studies confirmed that the prepared nano-extrudates increased the solubility of nano-crystalline phenytoin, regardless of the polymer. Our work demonstrates that NANEX represents a promising new platform technology in the design of novel drug delivery systems to improve drug performance.

Morphologies of Phenytoin Crystals at Silica Model Surfaces: Vapor Annealing versus Drop Casting.

The controlled preparation of different crystal morphologies with varying preferential orientation with respect to the substrate is of crucial importance in many fields of applications. In this work, the controlled preparation of different phenytoin morphologies and the dependency of the preferential orientation of those crystallites is related with the preparation method (solvent annealing vs drop casting), as well as the physical-chemical interaction with the solvents in use. While solvent annealing induces the formation of particular structures that are partially dewetted, the drop casting technique from various solvent results in the formation of needle-like and elongated structures, with each having a distinct morphology. The morphologies are explained via the Hansen solubility parameters and correlated with the solvent vapor pressures. X-ray diffraction experiments reveal preferential orientations with respect to the solid substrate and indicate the surface-mediated stabilization of an unknown polymorph of phenytoin with an elongated unit cell in the b-axis.

Particular film formation of phenytoin at silica surfaces.

Given the increasing number of poorly soluble and thus poorly bioavailable active pharmaceutical materials, there is a demand for innovative formulation platforms for such molecules. Thus a focus on enhancing dissolution properties of poorly soluble drugs exists. Within this study, the spin coating of acetone solutions containing 5,5-diphenyl-2,4-imidazolidinedione (phenytoin) in various concentrations is evaluated. The results reveal strong variations of the morphology of deposited phenytoin crystals at silica surfaces. Individual separated particles are obtained on low phenytoin concentrations, and closely packed particular films form when the concentration is increased. As the material is isomorphic, these various morphologies have the same crystalline structure. Dissolution experiments reveal that both the apparent maximum solubility and as the dissolution rate are strongly enhanced compared to bulk powder, suggesting that formulation based on this preparative technique will allow overcoming the low solubility problematic for a variety of drugs.

Nano-extrusion: a one-step process for manufacturing of solid nanoparticle formulations directly from the liquid phase.

This paper presents a novel one-step process for converting a liquid stabilized nano-suspension into a solid formulation via hot-melt extrusion combined with an internal devolatilization process (nano-extrusion, NANEX). A polymer (Soluplus®) was fed into the extruder and molten, after which a stable nano-suspension was added via side-feeding devices. The solvent (water) was removed by devolatilization and the polymer solidified at the outlet. The solid material can be tableted or filled in a capsule directly. The results showed that the obtained extrudates comprised nanocrystals in the de-aggregated form, confirming that a solid nano-formulation was prepared. This method is capable of overcoming many of the problems associated with other processes involving solid nano-dosage forms and poses a straightforward approach towards manufacturing such products.