Design Space and QbD Approach for Production of Drug Nanocrystals by Wet Media Milling Techniques

Abstract

Drug nanocrystals are nanosized solid drug particles, the most important application of which is the improvement of solubility properties of poorly soluble drug materials. Drug nanocrystals can be produced by many different techniques, but the mostly used are different kinds of media milling techniques; in milling, particle size of bulk sized drug material is decreased, with the aid of milling beads, to nanometer scale. Utilization of Quality by Design, QbD, approach in nanomilling improves the process-understanding of the system, and recently, the number of studies using the QbD approach in nanomilling has increased. In the QbD approach, the quality is built into the products and processes throughout the whole production chain. Definition of Critical Quality Attributes, CQAs, determines the targeted final product properties. CQAs are confirmed by setting Critical Process Parameters, CPPs, which include both process parameters but also input variables, like stabilizer amount or the solid state form of the drug. Finally, Design Space determines the limits in which CPPs should be in order to reach CQAs. This review discusses the milling process and process variables, CPPs, their impact on product properties, CQAs and challenges of the QbD approach in nanomilling studies.

Overcoming the Solubility Barrier of Ibuprofen by the Rational Process Design of a Nanocrystal Formulation

“…Therefore, Pharmacoat 603 was selected as the stabilizing agent of choice. This finding is also in line with bibliographic data [ 43 ], suggesting that cellulose-type polymers are proven to be suitable for the stabilization of nano-suspensions. In the cases of Soluplus and PVP K12, size measurements by dynamic light scattering after 30 and 60 min did not produce credible results, probably due to extensive API dissolution.…”

Study on Optimization of Wet Milling Process for the Development of Albendazole Containing Nanosuspension with Improved Dissolution

“…During a milling process, selection of stabilizer(s) is the crucial step for successful accelerated breakdown of raw materials (Rehbinder effect) [63,64] and stabilization of newly formed nanocrystals, reported as the first step in the Quality by Design concept of nanosuspension development [56]. In order to compare surface-active agents, that were the most ideal for wet planetary bead milling of ABZ, two non-ionic (Tween 20 and 80), one anionic (SLS) emulsifiers, four triblock copolymers (poloxamer 407 and 188, macrogolglicerol-hidroxystearate, macrogolglicerol-ricinoleate) and two water soluble polymers (PVP K30, HPMC) with low molecular weight values in concentrations of 0.40 % (w/w) have been tested.…”

“…Determination of the preliminary composition of presuspension regarding to drug loading (albendazole concentration) and surfactants is one of the utmost importance during nanosuspension formulation development [56]. Then critical process parameter optimization of the wet planetary bead milling process was applied.…”

Using a Material Library to Understand the Impacts of Raw Material Properties on Ribbon Quality in Roll Compaction

“…In future studies, the representative materials will be selected under the guidance of the roll compaction behavior classification system (RCBCS) established in this paper, as well as considering the similarities or Euclidean distance between different materials with the help of material properties data or scores from the multivariate calibration model. Then, the interactions between critical raw materials attributes and more critical process parameters will be adequately investigated through design of experiment methodologies under the guidance of QbD and quality risk management (QRM) principles [97]. The freedom of design space built in this paper will be improved to provide more flexibility on adjusting CPPs of the roll compaction process.…”