Steps in Screening and Selecting the Suitable Amorphous Solid Dispersion System

Amorphous Solid Dispersion (ASD) is an effective solution to improve the solubility and bioavailability of poorly water-soluble Active Pharmaceutical Ingredients (API). However, ASDs are often physically unstable and tend to crystallize to form more stable forms, which can lead to the loss of solubility advantages.

Therefore, screening and selecting the appropriate ASD system is crucial to ensure stability and effectiveness during production, storage, and use. This article outlines the main steps in the process of screening and selecting an amorphous solid dispersion system.

Steps in Screening and Selecting the Amorphous Solid Dispersion System

The process of screening and selecting the suitable ASD system involves several steps, from collecting information about the API to evaluating the properties of the dispersion system. Below are the detailed steps:

1. Initial API Analysis

This is the first and very important step, which includes collecting and analyzing information about the API. This serves as a basis for comparison with the dispersions after formulation. Techniques such as X-Ray Powder Diffraction (XRD), Differential Scanning Calorimetry (DSC) and Thermogravimetric Analysis (TGA), Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM) are used to determine the physicochemical properties of the raw materials:

• Chemical structure, polymorphism, hydrogen bond donor/acceptor groups, solubility parameters, solubility in solvents and biological environments, etc.
• Thermal characteristics of the API, including melting temperature and glass transition temperature (Tg).

2. Experimental Design

The next step involves creating experimental dispersion samples under solvent and non-solvent conditions. This includes selecting excipients (polymers), the API:polymer ratio, and experimental conditions:

• Polymer Selection: Consider the polymer’s characteristics such as molecular weight, glass transition temperature (Tg), hydrophilicity/hydrophobicity, hydrogen bonding ability, solubility parameters, thermal stability, water absorption, and monomer content. Some methods for selecting a polymer include:
• Experience-based: Choosing commonly used polymers.
• Manufacturing method: Choosing polymers based on large-scale manufacturing processes (e.g., hot-melt extrusion or spray drying).
• Compatibility: Selecting polymers that can “mix” with the API.
• Polymer characteristics: Choose polymers with high Tg, low water absorption, and evaluate polymer solubility compared to the pH of the absorption site in the gastrointestinal tract.
• Tm/Tg Ratio: Choose polymers with a high Tg to increase the Tg of the dispersion system compared to the amorphous API. High ratios may lead to easier crystallization.
• Interactions: Consider hydrogen bonds, dipolar interactions, or acid-base interactions between the drug and the polymer.

Start with a two-component mixture of API and polymer, but more polymers or other components (e.g., surfactants) can be added to create three-component systems.

• API-Polymer Ratio: Many studies use a polymer ratio of 50-70%, but even a small amount of polymer (e.g., 5%) can stabilize for up to 6 months, and 30% polymer can remain stable for at least 2 years. It is advisable to test a range of compositions, as miscibility may vary depending on the API:polymer ratio.
• Methods like spray drying or hot melt extrusion can be used to prepare these samples.

3. Sample Analysis

The experimental samples are analyzed using one or more techniques (similar to step 1) to check for the presence of the amorphous structure. The aim of this step is to eliminate samples that do not meet the amorphous and stability criteria.

4. Data Analysis

The data are grouped and evaluated to identify potential solid dispersion forms. This includes comparing solubility, thermal stability, and compatibility between the API and the excipient. Data from different dispersions can be reviewed in several ways. Two common methods are decision trees and form matrix:

• Decision Tree: Narrow down options based on a series of decision points.
• Form Matrix: Summarizes materials and characteristics in a table, highlighting acceptable properties and selecting the dispersions with the best featurest.

5. Preliminary Evaluation

In this step, specific characteristics of the sample (e.g., solvent content, stoichiometric ratio, mechanical strength) are evaluated. The goal is to collect detailed information to support the selection of the best amorphous solid dispersion system.

6. Scale-up

Once promising dispersion systems have been selected, some samples will be scaled up to test production feasibility. This step includes testing large-scale manufacturing technologies such as spray drying on an industrial scale.

7. Comprehensive Evaluation

The samples produced at large scale will undergo comprehensive evaluation. Parameters to be assessed include:

• Solubility
• Long-term stability.
• Moisture uptake
• Mechanical properties and manufacturability.

8. Selection

Finally, the amorphous solid dispersion with the best properties will be chosen. This system meets all criteria for solubility, stability, and manufacturability, ensuring its effectiveness in the final product.

Conclusion

Screening and selecting the suitable amorphous solid dispersion system is a complex process that requires a combination of various analytical techniques and evaluations. These general steps should be followed during the development of solid dispersion systems. The application of modern analytical techniques, combined with a systematic evaluation process, ensures that the final product meets the highest quality standards. At the same time, this process optimizes time and costs, contributing to faster and more efficient market entry.

Reference:

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