Any formulation design and development program for a poorly water-soluble compound should start with a proper assessment of its solubility in biorelevant media as well as in pharmaceutical excipients. The dose-to-solubility ratio is a critical driver of technology selection. In addition, information of a compound’s solubility in pharmaceutical excipients is crucial to establishing its formulate-ability.

During this phase, we also assess the compound’s susceptibility to undergo physical or chemical changes on contact with the vehicle or medium of interest.

In this phase, we map out the formulation options based on the compound’s solubility profile. We construct prototype formulations and assess these for physical and or chemical stability. In addition, prototype formulations are assessed for their ability to enhance dissolution rate and/or apparent solubility via one or more state-of-the-art dissolution tests.

We rarely employ compendial dissolution tests at Harpago, as these fail to incorporate the complex, dynamic conditions of the human gastrointestinal tract. We continuously update our in vitro dissolution tools according to the very rapidly evolving state of the art in this field. We typically use a tiered approach, whereby formulations are subjected to increased levels of ‘stress’ (in terms of pH, mixing conditions or media volume) to identify those prototypes that perform robustly across the broadest range of conditions.

We have embraced the use of physiology-based pharmacokinetic models to guide formulation design. The solubility and dissolution information gathered experimentally gets fed into our in-silico models, which allows us to dramatically reduce the level of lab experiments and to make more informed formulation selection decisions.

Only when we have built enough confidence that a formulation will provide the right level of solubility and bioavailability enhancement, we progress a formulation into development. In this phase, we process our prototype formulations into dosage forms suited for preclinical or early clinical use. These finished dosage forms are then again rigorously assessed for performance (solubility and dissolution enhancement) and physical and chemical stability.

Formulations passing all quality controls are subsequently manufactured to support preclinical or early clinical trials.