The Influence of Milling on the Dissolution Performance of Simvastatin

Abstract

Particle size reduction is a simple means to enhance the dissolution rate of poorly water soluble BCS-class II and IV drugs. However, the major drawback of this process is the possible introduction of process induced disorder. Drugs with different molecular arrangements may exhibit altered properties such as solubility and dissolution rate and, therefore, process induced solid state modifications need to be monitored. The aim of this study was two-fold: firstly, to investigate the dissolution rates of milled and unmilled simvastatin; and secondly, to screen for the main milling factors, as well as factor interactions in a dry ball milling process using simvastatin as model drug, and to optimize the milling procedure with regard to the opposing responses particle size and process induced disorder by application of a central composite face centered design. Particle size was assessed by scanning electron microscopy (SEM) and image analysis. Process induced disorder was determined by partial least squares (PLS) regression modeling of respective X-ray powder diffractograms (XRPD) and Raman spectra. Valid and significant quadratic models were built. The investigated milling factors were milling frequency, milling time and ball quantity at a set drug load, out of which milling frequency was found to be the most important factor for particle size as well as process induced disorder. Milling frequency and milling time exhibited an interaction effect on the responses. The optimum milling settings using the maximum number of milling balls (60 balls with 4 mm diameter) was determined to be at a milling frequency of 21 Hz and a milling time of 36 min with a resulting primary particle size of 1.4 μm and a process induced disorder of 6.1% (assessed by Raman spectroscopy) and 8.4% (assessed by XRPD), at a set optimization limit of < 2 μm for particle size and < 10% for process induced disorder. This optimum was tested experimentally and the process induced disorder was determined to be 6.9% (± 2.2) by Raman spectroscopy and 7.8% (± 2.3) by XRPD. Subsequent intrinsic dissolution testing revealed that the process induced disorder was negligible with regard to the dissolution rate. The predicted primary particle size of 1.4 μm could be confirmed experimentally, but due to agglomeration of the primary particles a dissolution rate advantage was not shown, highlighting the importance of dissolution testing at an early stage of drug development.

Prediction of Dissolution Data Integrated in Tablet Database Using Four-Layered Artificial Neural Networks

“…4,5), indicating that greater dissolution may be obtained with larger API particle sizes. These results are inconsistent with well-known physicochemical findings, 11,12) suggesting uncertainty with Eqs. 4 and 5.…”

Structure determination of riboflavin by synchrotron high-resolution powder X-ray diffraction

“…Milling the crystal can also strongly improve both the solubility and the dissolution rate of a drug. This is due to the reduction of the size of the crystallite (Zimper et al, 2010a;Chu et al, 2012) and, in some cases, to the formation of some structural disorder that can lead to partial or total amorphization of the sample (Willart & Descamps, 2008;Bordet et al, 2016;Zimper et al, 2010b). For these reasons, it is important to control both the structure and the microstructure of crystalline powders during milling processes (Blagden et al, 2007).…”

Preparation of Fine-Drugs Layered Spherical Particles with Good Micromeritic and Dissolution Properties through Ultra Cryo-Milling and Mechanical Powder Processing

“…Thus, the hydrophobic Phe particles were speculated to form strong secondary aggregates in the aqueous phase despite their primary submicron size, resulting in poor dispersion in the aqueous phase. 13,14) In contrast, M-(Phe + PEG) showed a significant improvement in dissolution profile in both fluids compared to intact Phe and M-Phe. The pulverized Phe particles also formed secondary aggregates with PEG segments after co-milling, as shown in Fig.…”

“…In general, the milled particles of a poorly water-soluble drug with high hydrophobicity tended to flocculate in aqueous medium, resulting in poor improvement of dissolution profiles. 13,14) The strong shear stress by the mechanical powder processor allowed the fine Phe particles to spread a thin layer over the surface of core particles, preventing inter-particle aggregation. The increased effective surface area related to wetting improved dissolution of PEG-free OM particles (CS9 : 1 : 0, NP9 : 1 : 0, CP9 : 1 : 0, closed symbols in Fig.…”