Unleashing Bioavailability: A Synergistic Approach for the Race Against Disproportionation

Rapid Insights

In our latest joint white paper, we explore a breakthrough strategy to improve the bioavailability of poorly soluble APIs together with Microsize. For those in the pharmaceutical industry, improving the bioavailability of APIs is a critical challenge. We combined two well-established techniques: salt formation and particle size reduction, to tackle this issue synergistically.

Salt formation enhances the solubility of APIs. Meanwhile, reducing particle size boosts the dissolution rate by increasing the surface area exposed to fluids in the digestive system. However, a key obstacle is the phenomenon of salt disproportionation, where the salt form of an API reverts to its less soluble free form, undermining the solubility gains.

Our case study reveals that by strategically measuring, predicting and reducing particle size, we can achieve complete dissolution before disproportionation occurs.

Using our proprietary SPA® technology, which requires only 100 µg of sample, we assessed the solubility, dissolution rate and disproportionation onset of a model API in its HCl salt form. Based on the SPA® measurements the HCl salt disproportionated during the first 80 seconds of dissolution with a consequent 6-fold decrease in the intrinsic dissolution rate (IDR).

Modelling of particle dissolution based on the IDR data predicted that the particle size of the HCl salt should be reduced below 10 µm for the particles to fully dissolve before disproportionation. Using Microsize’s spiral jet milling the Dv90 of the API HCl salt was reduced by 250-fold to 4 µm. The results were clear: by micronizing, we could fully dissolve the API within the critical 80-second window, exploiting the solubility boost of salt formation and significantly enhancing the API’s bioavailability potential.

This key insight underscores the importance of integrating advanced, precise, small-scale measurement tools with particle engineering in early drug development, a strategy that ensures that the best decisions are employed from the outset – talk to our experts.

Download the full whitepaper here:

 

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