Amorphous
materials exhibit distinct physicochemical properties
compared to their respective crystalline counterparts. One of these
properties, the increased solubility of amorphous materials, is exploited
in the pharmaceutical industry as a way of increasing bioavailability
of poorly water-soluble drugs. Despite the increasing interest in
drug amorphization, the analytical physicochemical toolbox is lacking
a reliable method for direct amorphous solubility assessment. Here,
we show, for the first time, a direct approach to measure the amorphous
solubility of diverse drugs by combining optics with fluidics, the
single particle analysis (SPA) method. Moreover, a comparison was
made to a theoretical estimation based on thermal analysis and to
a standardized supersaturation and precipitation method. We have found
a good level of agreement between the three methods. Importantly,
the SPA method allowed for the first experimental measurement of the
amorphous solubility for griseofulvin, a fast crystallizing drug,
without the use of a crystallization inhibitor. In conclusion, the
SPA approach enables rapid and straightforward determination of the
supersaturation potential for amorphous materials of less than 0.1
mg, which could prove highly beneficial in the fields of materials
science, analytical chemistry, physical chemistry, food science, pharmaceutical
science, and others.
Solubility is the primary physicochemical property determining the absorption and bioavailability of substances. Here, we present an optofluidic single-particle technique for microscale equilibrium solubility determination, based on on-chip hydrodynamic particle trapping and optical particle size monitoring. The method combines the rapidity, universality, and substance sparing nature of physical analysis, with the accuracy traditionally associated with chemical analysis. Applying the diffusion layer theory, we determined the equilibrium solubility from individual pure substance microparticles of as little as 14 μg in initial mass, in a matter of seconds to minutes. The reduction in time and substance consumption, when compared to the golden standard method, is above 2 orders of magnitude. With a simultaneous improvement above 3-fold in accuracy of the solubility data, the applicability of optofluidics based analytics for small-scale high-throughput quantitative solubility and biological activity screening is demonstrated.
Solubility
is a physicochemical property highly dependent on the
solid-state form of a compound. Thus, alteration of a compound’s
solid-state form can be undertaken to enhance the solubility of poorly
soluble drug compounds. In the Biopharmaceutics Classification System
(BCS), drugs are classified on the basis of their aqueous solubility
and permeability. However, aqueous solubility does not always correlate
best with in vivo solubility and consequently bioavailability. Therefore,
the use of biorelevant media is a more suitable approach for mimicking
in vivo conditions. Here, assessed with a novel image-based single-particle-analysis
(SPA) method, we report a constant ratio of solubility increase of
3.3 ± 0.5 between the α and γ solid-state forms of
indomethacin in biorelevant media. The ratio was independent of pH,
ionic strength, and surfactant concentration, which all change as
the drug passes through the gastrointestinal tract. On the basis of
the solubility ratio, a free-energy difference between the two polymorphic
forms of 2.9 kJ/mol was estimated. Lastly, the use of the SPA approach
to assess solubility has proven to be simple, fast, and both solvent-
and sample-sparing, making it an attractive tool for drug development.
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