Nathan Boersen

Evaluation of different screening methods to understand the dissolution behaviors of amorphous solid dispersions.

Abstract Objective: The objectives of the current study were to understand the dissolution behaviors of amorphous solid dispersions (ASD) using different screening methods and their correlation to the dissolution of formulated products. Materials and methods: A poorly soluble compound, compound E, was used as a model compound. ASDs were prepared with HPMC, Kollidon VA64 and Eudragit EPO using hot-melt extrusion. Different techniques including precipitation, powder, capsule and compact dissolution and the dissolution of formulated products were conducted in USP simulated gastric fluid using a USP II dissolution apparatus. Results and discussions: It was found that a precipitation study could generally predict powder, capsule and compact dissolution. Yet, it was recommended to run the dissolution at a higher paddle speed or for a longer duration to improve the predictability. It was also recommended to run powder, capsule and compact dissolution at both slow and high speeds to gain insights into wetting, dispersion and the dissolution of a system. Sometimes, capsule or compact dissolution could not be predicted by precipitation or powder dissolution due to plug formation. In this case, properly designed dosage forms were needed to break up this plug to optimize the dissolution profiles. On the contrary, formulations and dissolution conditions would have minimal effects on the dissolution profiles of a fast-dissolving solid dispersion. Conclusions: Different techniques are available to select the right polymers to optimize dissolution behaviors. However, it is important to understand the merits and limitations of each technique in order to optimize the formulations for amorphous solid dispersions.

Delivery of Poorly Soluble Compounds by Amorphous Solid Dispersions

Solid state manipulation by amorphous solid dispersion has been the subject of intensive research for decades due to their excellent potential for dissolution and bioavailability enhancement. The present review aims to highlight the latest advancement in this area, with focus on the fundamentals, characterization, formulation development and manufacturing of amorphous solid dispersions as well as the new generation amorphization technologies. Additionally, specific applications of amorphous solid dispersion in the formulation of herbal drugs or bioactive natural products are reviewed to reflect the growing interest in this relatively neglected area.

Development of Preclinical Formulations for Toxicology Studies

Toxicological formulations for new chemical entities that have poor physico-chemical properties are very challenging to develop, especially within the short timelines established by many project teams. This chapter presents details of many of the difficult aspects of toxicological formulations, such as the requirement to formulate doses that can be 50–100 times more concentrated than the efficacious human dose. It requires in-depth knowledge of the animal species, sampling volumes, sampling sites and dosing routes as well as the physico-chemical properties of the active ingredient, such as solubility and stability. These properties require a combination of solubility enhancing techniques in order to obtain the required concentrations needed for the dosing study. Since toxicological studies are a critical component of pharmaceutical development, the development of effective formulations aids candidate selection and optimization that will ensure safety in subsequent human trials.

A preliminary assessment of the impact of hot-melt extrusion on the physico-mechanical properties of a tablet

Abstract Objectives: This research aimed at investigating the difference between the powders prior to and after hot melt extrusion. A preliminary assessment was also conducted to gain a better mechanistic understanding of the impact of hot melt extrusion on tabletability. Materials and methods: Kollidon® VA 64 and mannitol were sieved into different particles sizes and used as is or after drying for 24 h. Hot melt extrusion was used to manufacture an amorphous solid dispersion of Kollidon® VA 64 and mannitol. The extrudates were milled and sieved into different particles sizes. Tablets were manufactured from the different powders and their tabletability, compressibility and compactibility determined. Results and discussions: It was shown that the as received tablets gave higher tabletability compared with the tablets manufactured from the dried or hot melt extruded (HME) powder. Differences in the tabletability between the as received. dried and HME material could be related back to changes in the bonding area and bonding strength as a result of the hot melt extrusion process and/or a loss of moisture because of the high processing temperature. Conclusions: The reduced tabletability of the HME tablets appeared to be a function of multiple factors. Both the hot melt extrusion process and the moisture content may play significant roles in determining this phenomenon.

Hot-Melt Extrusion: The Process-Product-Performance Interplay

Hot-melt extrusion is commonly used to manufacture amorphous solid dispersions. This chapter focuses on the process-formulation-performance interplay of a hot-melt-extruded product within the framework of a hypothetical phase diagram. Special attention is paid to the liquidous curve and melt mixing, the mixed-phase glass transition temperature, and hypothetical lower and upper critical solution temperatures. With a complete understanding of the liquidous curve, rheological properties, and the thermal liabilities, a workable processing temperature range for hot-melt extrusion can be defined. Strategies and processing solutions are given to minimize or avoid thermal degradation. Finally, the heat, mass, and momentum balances are outlined and can be leveraged to model the extrusion process when appropriate material properties are understood. The fundamental concepts provided herein will facilitate successful manufacture and scale-up of the extrusion process.