Melting method in the preparation of solid dispersions: Melt agglomeration

The melting method represents a highly promising approach in the development of solid dispersions (SDs), widely utilized to enhance the solubility and bioavailability of poorly water-soluble drugs. This technique involves heating the active pharmaceutical ingredient (API) and/or a carrier to their melting point, ensuring complete liquefaction, and subsequently employing rapid cooling methods to produce a homogenous solid mixture. This process creates an intimate dispersion of the API within the carrier matrix, often resulting in a more thermodynamically favorable amorphous state that enhances solubility.

Building on this principle, several advanced methodologies have been developed, with Melt Agglomeration (MA) and Hot Melt Extrusion (HME) being among the most commonly employed. While HME has gained widespread attention for its continuous processing capabilities, this article delves into the specific features, mechanisms, and practical applications of Melt Agglomeration, highlighting its potential as an efficient and versatile technique in pharmaceutical formulation.

Principle

Melt Agglomeration is a specialized process in which agglomerates are formed by utilizing a binder excipient that is heated to its molten state. During this procedure, the temperature of the system is carefully controlled and maintained above the melting point of the binder. This is achieved either through external heating mechanisms or by generating frictional heat during the mixing process. The molten binder acts as an adhesive, binding the particles of the active pharmaceutical ingredient (API) and other excipients together to create agglomerates.

Once the desired agglomeration is achieved, the system is allowed to cool down to ambient temperature. During this cooling phase, the molten binder transitions back into its solid state, stabilizing the structure of the agglomerates.

Process

1. Heating the mixture: The API, carrier, and binder excipient are heated above the melting point of the binder.
2. Agglomeration: The mixture is stirred to create agglomerates, facilitated by the molten binder or melted polymer.
3. Cooling: After the desired agglomeration is achieved, the mixture is cooled to room temperature, solidifying the binder and stabilizing the agglomerates.
4. Milling and sieving: The agglomerates are milled and sieved to achieve uniform particle size distribution.

Mechanisms for Improving Solubility

The main mechanisms by which Melt Agglomeration enhances solubility include:

• API dispersion: The method evenly disperses the API in the amorphous state within the binder. The amorphous form has higher free energy than the crystalline form, making it more soluble in aqueous environments.
• Particle size reduction: Melt Agglomeration reduces particle size, increasing surface area and improving dissolution rates.
• Water-soluble binders: Binders such as PEG, PVP, and HPMC dissolve rapidly in aqueous environments, releasing finely dispersed API particles that enhance solubility.
• Microenvironment creation: Certain binders create favorable microenvironments for dissolution, reducing interfacial tension or forming complexes with the API to improve solubility

Common Used Binder Excipients

• Liquid Polymer: PEG 300, Caprylocaproyl Macrogol-8 Glycerides (Labrasol)
• Semi-solid polymers: Stearoyl Polyoxyl-32 Glycerides (Gelucire 50/13)
• Solid polymers with low melting points: PEG (3000, 6000) and Poloxamer 188
• Fats and waxes:Fatty acids, fatty alcohols, glycerides

Advantages and Disadvantages

Advantages:

• Solvent-free, reducing risks for APIs sensitive to water or organic solvents.
• Simple, time-saving process.
• Can achieve extended-release formulations by using water-insoluble binders.

Disadvantages:

• Limited applicability for heat-sensitive APIs due to heating requirements.
• Restriction in excipient choice, especially for polymers with high glass transition temperatures (Tg).
• Agglomerates may have larger particle sizes than those produced by techniques like HME or spray drying, affecting uniformity.

References:

[1] R. Censi, M. R. Gigliobianco, C. Casadidio, and P. Di Martino, “Hot melt extrusion: Highlighting physicochemical factors to be investigated while designing and optimizing a hot melt extrusion process,” Pharmaceutics, vol. 10, no. 3, p. 89, 2018.

Explore other solid dispersion techniques like: spray drying, solvent evaporation on SEN Pharma website for further insights.