Exploiting Kinetic Solubility Differences for Low Level Detection of Crystallinity in Amorphous Drug Formulations

Abstract

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. Methods: 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 substance. 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 techniques.