Systemic in vitro and in vivo evaluation for determining the feasibility of making an amorphous solid dispersion of a B-Raf (rapidly accelerated fibrosarcoma) inhibitor

• Solubility enhancement predication (about 200 fold) of amorphous form of G–F by using thermal approach.
• Making spray-dried amorphous dispersion (SDD) of G–F based on favorable solubility prediction.
• In vitro dissolution of G–F SDD shows about 20 fold increase compared with crystalline form.
• In vivo, G–F SDD shows about 3.5 fold improvement of AUC and Cmax at 100 mg/kg dose in rat.
• From thermal prediction to in vitro and in vivo tests, this systematic approach provides the success of SDD of G–F to enable efficacy and safety studies.

It is well acknowledged that oral bioavailability of a drug candidate is often influenced by factors such as the permeability, physico-chemical properties, and metabolism of the drug. Among the physico-chemical properties, solubility and dissolution rate are considered the most critical factors affecting the oral bioavailability of a compound G–F is a potent and selective B-Raf inhibitor with poor solubility and adsorption is limited by solubility at high doses. In order to overcome this issue using a spray-dried amorphous dispersion (SDD) formulation was evaluated. A combination of theoretical solubility prediction and in vitro dissolution, were used to predict the in vivo exposure of G–F. The predicted value was found to have good agreement with the in vivo exposure from dosing the crystalline and amorphous form of G–F.In general, this combined approach demonstrated that the amorphous form of G–F offers an advantage over the crystalline form of G–F in terms of solubility; in vitro dissolution and in vivo absorption were predictable and consistent with the literature. This systemic approach provides a great value for compound development.

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