Background: Enabling formulations have been implemented by the pharmaceutical industry
as an effective tool for keeping active pharmaceutical ingredient (API) in an amorphous state. Upon
dosing in the amorphous state, many drugs which fail to demonstrate bioactivity due to the limited solubility
and bioavailability of their crystalline form become bioavailable.
Purpose: The analytical techniques use today for crystallinity detection are challenged by the sensitivity
and robustness needed to achieve a 5% quantitation limit in low dose drug products. Our laboratory has
developed a novel procedure capable of meeting this sensitivity and selectivity requirement. This is
achieved by exploiting the differences in kinetic solubility of the formulated amorphous and free crystalline
forms of API currently being used in dosage form platforms.
Method: Representative amorphous drug formulations were prepared and spiked with varying levels of
crystalline drug substances to evaluate the selectivity and recovery of the crystalline drug substance
from the product formulation. Kinetic solubility testing using a (i) particle wetting phase, (ii.) particle
suspending/erosion phase, (iii.) sampling time point and (iv.) a total recovery determination for the drug
Results: The method selectively and quantitatively distinguishes crystalline drug substance from amorphous
drug substance for samples spiked from 2.5% to 10% of the nominal label concentration of the
API in the dosage form matrix.
Conclusion: The kinetic solubility approach reported here achieves sensitive crystallinity quantitation
for low drug level amorphous drug formulations at levels not yet achieved by complimentary analytical
Keywords: Crystallinity determination, amorphous drug, enabling formulation, Meltrex®, Hot-Melt Extrusion (HME), Spray-Dried Dispersions (SDD), amorphous solid dispersion, recrystallization.
Rights & PermissionsPrintExport