An ingenious technology for producing stable, amorphus drugs in large scale

Protein kinase inhibitors (PKIs) are remarkably effective in treating various forms of cancer. Unfortunately, many patients experience side effects of the PKI treatment, in some cases with fatal outcome. The problem is that many PKIs have toxic properties and that the oral absorption of the drug is highly variable, which sometimes may lead to treatment failure. The underlying reason is that the solubility of most PKIs is very low in the intestine and that the absorption is dependent on the pH in the stomach. These undesirable properties pose a challenge for the pharmaceutical industry.

Xspray’s patented technology, RightSize™, can modify the absorption of the drug and solve these problems. Other existing methods for manufacturing of amorphous forms have often resulted in formulations with low stability, i.e. the drug substance loses its amorphous form during storage and returns to a more stable crystalline form. RightSize™ technology creates a fully amorphous form that is stable during long-term storage.

The figure illustrates how a crystalline structure differs from the amorphous. While the crystalline structure shows a clear pattern, the amorphous form is disordered, but retains its properties and stability.

Since having a stable amorphous form of the drug is absolutely essential to Xspray’s business model, Xspray uses today’s most sensitive analytical methods to ensure that the product candidates are 100% amorphous. Routine tests are performed with very sensitive X-ray equipment. For example, a sample of HyNap-Dasa stored for 24 months under so-called accelerated stability test (40 degrees and 75% relative humidity) showed no traces of crystallinity and the material sample was considered to be 100% amorphous.

RightSize – stable amorphous forms in commercial scale
supercritical liquid extraction is used to achieve a stable amorphous form. In a supercritical state, the molecules have properties similar to both a liquid and a gas. They move quickly like a gas, while the solubility is good, like in a liquid.

The supercritical fluid makes it possible to control the particle precipitation.

The technology as such is known since the nineties, but despite its many advantages, it has proved difficult to scale up to commercial scale. With Xspray’s basic invention, a special nozzle, the scale up problem has been overcome. In the established manufacturing process, 100 times higher productivity has been obtained compared to previously published results.

With Xspray’s basic invention, a special nozzle, the scale up problem has been overcome

There is currently no other technology in commercial scale that can produce amorphus solid dispersion of PKIs in this way.