Physics-based simulations enhance the precision of pharmaceutical drug formulation. This blog presents a proof-of-principle study conducted in collaboration between amofor and Boehringer Ingelheim. This project aimed to evaluate the feasibility of shifting from spray-drying to hot-melt extrusion (HME) in producing amorphous solid dispersions (ASDs), focusing on in vitro and in vivo performance comparisons.
Traditionally, spray-drying has been favored for creating ASDs due to its efficiency in handling various active pharmaceutical ingredients (APIs). However, hot-melt extrusion offers a more economically and ecologically viable alternative, though it is limited by the high melt-viscosity and thermal stability requirements of certain APIs.
From Spray Drying to Hot Melt Extrusion
Spray drying is the preferred method for producing ASDs due to its efficiency at early development stages. However, when it comes to later manufacturing stages, it has significant disadvantages, such as high energy consumption and reliance on large quantities of organic solvents, leading to a high environmental footprint.
HME does not require organic solvents but involves high-temperature processing. While HME can potentially degrade the API or polymer, it is desirable for large-scale production at later stages of drug development. It offers clear economic and ecological benefits.
Using an integrated approach of physical modeling and experimental testing, we compared the dissolution behavior of spray-dried and hot-melt extruded tablets in vitro and in a beagle-dog vivo study. The main results of this approach are described below.
Critical Insights from In Silico Results
In-silico modeling provided key insights through PC-SAFT (perturbed-chain statistical associating fluid theory) calculations, a powerful tool for predicting complex mixtures’ thermodynamic properties.
Our simulations and ASD phase diagrams clearly indicated the optimal temperatures required in an HME process at a desired drug load in the absence and presence of an excipient. This information is pivotal to ensuring full dissolution, stable mixing, and optimizing the drug manufacturing process.
Eduard Trenkenschuh, the lead author, highlighted the importance of this discovery: “Our collaboration with amofor was instrumental. The phase diagrams they provided allowed us to precisely tune the formulations and understand the surfactant role, ensuring optimal performance and stability. We learned already in the beginning about potential crystallization risks and feasible manufacturing windows.”
PC-SAFT calculations also helped to understand which kind of API, polymer, and surfactant solution is better or worse for each manufactured system. The phase diagram showed minimal differences between the two APIcompositions we compared.
Translating Theory into Practice
The practical applications of our in silico predictions were validated through manufacturing the formulations and conducting dissolution and absorption studies:
- Manufacturing outcomes: As predicted by our simulations, the extrudability of a ternary ASD using the API, a polymer, and a surfactant was feasible.
- In vitro results: Amorphization significantly improved the solubility of the API. Spray-dried tablets released seven times, and HME tablets three times, more drug than their crystalline form.
- In vivo findings: The active ingredient was absorbed 1.7 times faster from the tablets prepared from spray-dried material than those prepared from HME material. Thus, the in vitro dissolution profile matched well with the actual absorption rates in the body.
The material’s particle sizes drastically affected dissolution in vitro and in vivo. A decrease in particle size was inversely correlated with an increased drug release. This was expected to be the main reason for the observed release and bioavailability differences, while the ASD material itself turned out to be similar.
Benefits and Strategic Development
The study highlights clear benefits to the pharmaceutical industry:
- Accelerated drug formulation: Physical simulation accelerates the development phase by predicting crucial data for drug formulation design. This reduces the time and cost associated with experimental setups.
- Enhanced precision in drug manufacturing: In silico simulations provide critical insights into the feasibility and limitations of manufacturing processes. They can predict drug release profiles and bioavailability, enabling precise control and tailoring of formulations.
- Risk assessment and technology selection: Simulations are a proactive tool for assessing risks, such as crystallization and shelf-life stability issues, associated with different manufacturing techniques. They guide technology selection based on detailed analysis of phase diagrams and material properties, ensuring that manufacturing decisions are robust and scientifically validated.
Innovation through Collaboration
This work exemplifies how collaboration, openness to innovation, and a predict-first approach can enhance drug formulation and manufacturing.
Engaging in the digital design of drug formulations early offers a strategic advantage. It is not limited to a single development phase but encompasses the entire spectrum, from initial development to final production stages.
As Trenkenschuh aptly put it, “This collaboration showcases the power of combining expertise from different fields. The success of this study opens new avenues for more sustainable and efficient drug manufacturing processes.”
We invite you to contact us to learn how we can assist your drug formulation efforts to produce drug products with a quality-by-design framework.