Process parameter dependent growth phenomena of naproxen nanosuspension manufactured by wet media milling

• Published in: European journal of pharmaceutics and biopharmaceutics 2015-05, Vol.92, p.171-179
• Main Authors: Bitterlich, A., Laabs, C., Krautstrunk, I., Dengler, M., Juhnke, M., Grandeury, A., Bunjes, H., Kwade, A.
• Format: Article
• Language: English
• Subjects: Chemistry, Pharmaceutical - methods; Crystallization; Drug Compounding - methods; Drug Stability; Excipients - chemistry; Fine grinding; Formulation; Media mill; Morphology; Nanoparticles; Nanosuspension; Naproxen - administration & dosage; Naproxen - chemistry; Particle Size; Particle technology; Poorly water soluble drug; Screening; Solubility; Stabilization; Suspensions
• ISSN: 0939-6411; 1873-3441
• DOI: 10.1016/j.ejpb.2015.02.031

[Display omitted] •Previously unknown growth phenomenon identified during fine grinding of API.•Particle growth depends on process parameters of the mill.•Grinding media material and size influence physical stability of the product. The production of nanosuspensions has proved to be an effective method for overcoming bioavailability challenges of poorly water soluble drugs. Wet milling in stirred media mills and planetary ball mills has become an established top-down-method for producing such drug nanosuspensions. The quality of the resulting nanosuspension is determined by the stability against agglomeration on the one hand, and the process parameters of the mill on the other hand. In order to understand the occurring dependencies, a detailed screening study, not only on adequate stabilizers, but also on their optimum concentration was carried out for the active pharmaceutical ingredient (API) naproxen in a planetary ball mill. The type and concentration of the stabilizer had a pronounced influence on the minimum particle size obtained. With the best formulation the influence of the relevant process parameters on product quality was investigated to determine the grinding limit of naproxen. Besides the well known phenomenon of particle agglomeration, actual naproxen crystal growth and morphology alterations occurred during the process which has not been observed before. It was shown that, by adjusting the process parameters, those effects could be reduced or eliminated. Thus, besides real grinding and agglomeration a process parameter dependent ripening of the naproxen particles was identified to be a concurrent effect during the naproxen fine grinding process.