Amorphous drug formulations – University of Copenhagen


Amorphous drug formulations

Around 90% of the small molecule drugs in the pipeline of pharmaceutical companies show low solubility and belong to the classes 2 and 4 in the biopharmaceutical class systems (BCS). This low solubility often severely reduces the bioavailability of the drug and may lead to pharmacologically effective molecules being abandoned. The transformation of a drug from the crystalline state to a high-energy amorphous form generally leads to an increase in solubility. However, as the amorphous form per definition is a high energy state and therefore metastable, technological approaches are necessary to stabilise amorphous drug formulations.

Recent investigations used several approaches to stabilize the amorphous form:
• surface coverage of amorphous particles
• in situ formation of the amorphous form
• co-amorphous mixtures

Co-amorphous mixtures consist of 2 (or more) types of small molecules which interact on molecular level without detectable crystallisation. The combination of two drug molecules can be beneficial for combination therapy or for the reduction of side effects, in addition to the increased solubility. However, small molecule excipients would be a more generally applicable platform technique.

Based on the fact that drug molecules interact with the active sites of various receptors in the body, and thus interact on a molecular level, our current focus is the use of amino acids as excipients.

Currently, ball milling is used as preferred production process. However, due to the low capacity of ball mills, other production procedures, such as freeze-drying, spray-drying, precipitation and hot-melt processing are under investigation. Further down-stream processing such as the behaviour of co-amorphous mixtures during tableting is also investigated.

Recently, interest also rose towards the development of drug delivery systems wherein the crystalline drug can be transferred into its amorphous counterpart during or directly prior to administration (in situ). With such an approach, the physical stability issues with amorphous drugs can be eliminated as the storage time for the amorphous drug is reduced to seconds or minutes, compared to a shelf life of usually a few years.