Amorphous Drug Substance Solid Dispersions: Solid-State Opportunities and Considerations
When considering oral drug delivery, a major factor for the failure of new chemical entities from entering the market is that they are practically insoluble with reduced bioavailability compromising their pharmacological effects.
The opportunity the amorphous state of a drug substance offers in terms of improved performance which are necessary to be therapeutically beneficial have been delved in Amorphous Drug Substance: Solid-State Opportunities and Considerations, Part 1 and Amorphous Drug Substance: Solid-State Opportunities and Considerations, Part 2. The maintenance of the amorphous state of a drug substance in a drug product is the challenge to the progression of an amorphous API to a drug product.
The preferred approach to produce a stable amorphous drug substance that has come to the forefront of development is the amorphous solid dispersion. This affords an amorphous drug product intermediate which can be formulated into tablets, capsules, or granules.
To identify and develop viable amorphous solid dispersions into drug products, various investigations need to be performed, and the approach to the manufacture of the drug product intermediate should be considered.
An amorphous solid dispersion is a solid solution where the drug substance is dispersed molecularly in a polymer carrier improving apparent aqueous solubility and bioavailability. Polymers are those that have already been employed as formulation excipients. The selection of the polymer carrier requires the assessment of various thermodynamic and kinetic properties which can be influenced by storage conditions and the drug loading in the dispersion. The amorphous solid dispersion properties include compatibility, interactions, miscibility, solubility of the drug in the polymer, glass transition temperature, molecular mobility, the separation of the drug and polymer into domains, nucleus formation and growth kinetics of crystallisation resulting in physical instability leading to compromised therapeutic performance.
Recent modelling and in silico approaches have aided these investigations and the development process by predicting the amorphous properties of the drug substance and suitability of the process to produce the amorphous solid dispersion.
The majority of marketed drug products which use amorphous solid dispersions as drug product intermediates are manufactured by spray-drying (a solvent mediated process) or hot melt extrusion (a heat-based production method). Both manufacturing approaches are complemented by a range of additional mechanical fabrication processes. In addition, there are several laboratory methods which can be employed. Consequently, it is necessary to ensure that the development investigations translate to the manufacturing process in order that the approaches used to identify the drug substance/polymer combination that afford the amorphous solid dispersion drug product intermediate have scalability.
MorphCryst Consulting can offer advice and guidance concerning the solid-state and materials science investigations and progression of your API as an amorphous solid dispersion.
