Drug substance solubility and permeability: the importance of solid-state science
For a drug compound crystallinity is a highly desirable solid-state attribute to achieve as this can simplify process development activities, drug product investigations and manufacture. Compound crystallinity does not necessarily guarantee suitability as a drug substance for a drug product.
To aid new chemical entity discovery there are molecular descriptors, ‘Lipinski rule of 5’, which if achieved for a compound would indicate preferred permeability and solubility characteristics. Consequently, the compound would be considered to have ‘drug like’ properties.
In reality the number of oral drug products launched that contain drug substances which breach at least one of the preferred molecular descriptor criteria is common and the incidence of exceeding a ’rule of 5’ criteria is found to be increasing. The two molecular descriptors for which compounds are in excess of the desired criteria are molecular weight and lipophilicity. This increasing trend has and will lead to more drug substances in development which have poor aqueous solubility.
The oral administration of a drug substance as a medical product is the preferred mode and comprises the vast majority of medications that are taken globally.
The aqueous solubility and permeability of a discovery drug compound can reveal what oral absorption might be expected. The Biopharmaceutical Classification System, BCS, and the Developability Classification System, DCS (a refinement of the BCS), divide drug compounds into 4 groups based upon aqueous solubility and permeability.
A large proportion of the drug compounds in development and an even larger number of discovery new chemical entities are poorly soluble and categorised as Class II or IV under DCS. Class IV compounds are the most demanding since they not only have low solubility but also low permeability. With the increasing number of Class II and IV compounds under investigation - which is linked to the increase in the complexity of structure and molecular weight of discovery compounds - increasing the solubility of poorly water soluble compounds for oral administration is necessary to improve bioavailability and for downstream drug product investigations and development.
Salt formation of a new chemical entity or drug substance is a common approach to try and improve the aqueous solubility and bioavailability of the API in the drug product. This has been explored in ‘Salt formation investigations of drug substances: Why should it be considered?’.
Other chemical approaches that might prove beneficial at improving aqueous solubility are cocrystal, solvate formation and modification of the chemical structure of the compound to a prodrug.
There are also physical formulation methods which can improve solubility and include solid dispersion formation, complexation and lipid-based vehicles. Particle size reduction and developing a metastable polymorph to improve drug substance solubility have been delved into in ‘Particle size reduction of drug substances: When should it be considered’ and ‘Polymorphism investigations of drug substances: Why is it important?’ respectively.
The ultimate metastable solid version of a new chemical entity or investigational drug substance is the amorphous state. Historically, the development of amorphous drug substances and subsequent drug products have been avoided as a consequence of physical or chemical instability issues upon storage. Consequently, there are few marketed drug products which contain an amorphous drug substance for oral administration.
This position is evolving with the advance of formulation approaches that can stabilise the amorphous state of a drug compound. The stabilised amorphous drug substance can afford enhanced dissolution properties of a greater dissolution rate and higher apparent solubility.
With the advent of so many investigational and discovery drug compounds that are categorised by DCS as Class II or IV - which is a consequence of increasing molecular weight and complexity for new therapeutic materials - the exploration of the ‘amorphous state’ of these compounds is more prevalent.
Regardless of where your API is, be it investigational early phase or on the development road, MorphCryst Consulting can offer advice upon aspects of solubility, bioavailability and solid-state science to guide and maintain progress.
