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.

Crystallinity: A Complex Critical Quality Attribute of Amorphous Solid Dispersions

“…In vitro release testing has also been observed to be more sensitive to the presence of crystals or other phase behavior changes in amorphous formulations than most other analytical techniques. − However, typical experimental variability of ±5% indicates that detection of <10% crystallinity might not be possible in a QC environment . This suggests that release testing may be an appropriate challenge test by which to validate solid-state methods which can detect the necessary level of crystallinity which may be considered significant for that specific formulation.…”

“…Another approach that has been investigated to detect crystallinity within a dissolution test relies on differences in dissolution rate associated with each solid-state form . There are several concerns with this approach.…”

Industry White Paper: Contemporary Opportunities and Challenges in Characterizing Crystallinity in Amorphous Solid Dispersions

“…It is uncommon outside of an R&D setting but may be accessible in some development or commercialization QC functions. Evermore sensitive analytical techniques such as SEM, TEM, Secondorder nonlinear optical imaging of chiral crystals (SONNIC) or second-harmonic generation (SHG) microscopy, [31][32][33] μCT 34 and Kinetic Solubility 35 continue to evolve however these newer, noncommercially available and/or niche techniques are constantly evaluated and as they mature may be incorporated into the analytical toolbox.…”

Diagnosis of Agglomeration and Crystallinity of Active Pharmaceutical Ingredients in Over the Counter Headache Medication by Electrospray Laser Desorption Ionization Mass Spectrometry Imaging

“…In the original work, mass spectrometry (MS) imaging was used to detect the crystalline form of an active pharmaceutical ingredient (API) in the presence of its amorphous form used in an enabling tablet formulation [ 4 ]. Crystallinity can be an issue for BCS Class II/IV drugs if the active drug has a significant difference in kinetic solubility between the crystalline and amorphous forms [ 5 , 6 ]. In pharma, many amorphous forms of poorly soluble drugs go into solution faster than their crystalline forms and thus, this kinetic solubility makes the amorphous form more bioavailable.…”

“…For soluble drugs such as acetaminophen, it likely does not matter if the drug is free, agglomerated, or crystalline. Differences in bioavailability for BCS I/III drugs is typically studied by using dissolution studies, not ELDI-MS or other imaging techniques [ 5 ]. The drugs chosen for this investigation are surrogate forms for those expected in enabling formulations.…”