(T1530-01-03) Feeling the Pressure: Polymorphism, Particle Size and Morphology Control Through Nanoparticle Crystallization Using Controlled Expansion of Supercritical Solutions

Purpose: Poor bioavailability and low efficacy arising from poor solubility are amongst the most common reasons for drug failure. Converting crystalline material to the amorphous form is an alternative means of improving solubility but physical stability of amorphous forms is a drawback in its applicability. An advanced approach is to use crystalline nanoparticles to improve drug solubility and increase the dissolution rate of active pharmaceutical ingredients (APIs).The generation of crystalline nanoparticles can increase the specific surface area of API particles leading to higher dissolution rate whilst maintaining the stability of the crystalline form and avoiding the necessity for additional excipients, as is the case for an amorphous solid dispersion. Controlling crystalline form, morphology and particle size distribution (PSD) is critical for any crystallization process, even more so for nanoparticles.

Methods: The key methodology for this work is Controlled Expansion of Supercritical Solution (CESS®) technology, which is a particle production method based on supercritical carbon dioxide (scCO₂) without the addition of further solvents. Atovaquone (ATO) and Fenofibrate (FEN) were the chosen APIs for the study owing to the presence of multiple polymorphic forms and their predicted high solubility in scCO₂.

Results: Through careful control of the CESS process, it is possible to manipulate the polymorphic form of ATO generated from the crystallization process using scCO₂, between Forms III and I, without the need for additional solvents.  Moreover, the morphology of the nanoparticles of thermodynamically stable Form III can be modified from the lath preference of the larger particles to the more processable cubic shape. In the case of FEN, the PSD of Form I can be controlled merely by varying the temperature at which crystallization occurs. In this way, the PSD can be tailored to the requirement of the desired dosage form without the need for separate processes or solvent systems being developed.

Conclusion: By controlling the CESS process, and without the need for additional solvents, it is possible to not only generate nanoparticles of metastable ATO Form I but also to produce nanoparticles of the thermodynamically stable Form III with a modified, and more processable, morphology. By controlling the temperature of crystallization, it is possible to vary the PSD of crystalline FEN Form I from 0.5 to 1.5 mm in order to tailor the particles for a particular dosage form.

Temperature dependence of the PSD of FEN Form 1 obtained from the CESS crystallization.



ATO Form III micron sized laths (l), ATO Form I nanoparticles (m) and ATO Form III nanoparticles (r).



Micron sized FEM Form 1 (t) and nanoparticles of FEN Form 1 (b).