Amorphous Drug Substances: Solid-State Opportunities and Considerations, Part 2
The reward in the selection of the amorphous state of a new drug substance has been proposed in Amorphous Drug Substances: Solid-State Opportunities and Considerations, Part 1. Attention moves to the development traits for the compound and subsequent drug product.
The selection and progression of the amorphous version of a new chemical entity have been few with approaches developed to stabilise an API in the amorphous state. Those drug substances which have utilised the amorphous state in marketed products have been low melting materials or characterised by a glass transition, salts, hydrates or solvates, and prodrugs. The approaches to produce the amorphous drug substance have in the most part progressed into relatively simple drug product development as tablet or (in a few instances) capsule formulations. This can be considered a consequence of understanding the specific solid-state characteristics of the amorphous drug substance and utilising these to isolate a suitable solid material for drug product production.
In the main these drug compounds possessed solid-state attributes which would be considered undesirable from a business perspective. In some instance they were low melting and could be isolated with a suitable glass transition allowing drug production whilst maintaining physical stability and consequent efficacy. In other cases, salt versions of the drug substance were found to be amorphous or displayed hygroscopicity. These characteristics were exploited for improving solubility while retaining stability. Although not ideal, these versions of the drug substance were manageable with respect to API isolation and drug product production.
This also places a different emphasis upon API chemical purity control to earlier steps in manufacture. It might not be possible to achieve the desired quality in the final step or steps with certain compound characteristics. During solid-state investigations such as salt identification and propensity to polymorphism of a new drug substance which is affording non-ideal material attributes, these should not be discounted. Further exploration should be considered to establish if they offer suitable opportunity to the drug substance and product.
For new chemical entities which are described as ‘brick dust’ and suffer from poor gastrointestinal absorption and are poorly to practically insoluble, accessing the amorphous state might not be amenable as a drug substance, or physical stability is compromised by conversion to crystalline versions upon storage as the drug substance or in the drug product. Stabilisation of the amorphous state might be achieved via dispersion. This presents a new range of challenges which will be examined.
Regardless of where your API is, investigational early phase or on the development road, MorphCryst Consulting can offer advice upon aspects of solubility, bioavailability, solid-state science and development to guide and maintain progress.
