Optimization of a combined wet milling process in order to produce poly(vinyl alcohol) stabilized nanosuspension

Abstract

PurposeThe article reports a wet milling process, where the planetary ball mill was combined with pearl milling technology to reach nanosize range of meloxicam (Mel; 100–500 nm). The main purpose was to increase the dissolution rate and extent of a poorly water-soluble Mel as nonsteroidal anti-inflammatory drug as well as to study its permeability across cultured intestinal epithelial cell layers.MethodsViscosity of milled dispersion and particle size distribution and zeta potential of Mel were investigated and differential scanning calorimeter and X-ray powder diffractometer were used to analyse the structure of the suspended Mel. Finally in vitro dissolution test and in vitro cell culture studies were made.ResultsIt was found that the ratio of predispersion and pearls 1:1 (w/w) resulted in the most effective grinding system (200-fold particle size reduction in one step) with optimized process parameters, 437 rpm and 43 min. Nanosuspension (1% Mel and 0.5% poly[vinyl alcohol]) as an intermediate product showed a stable system with 2 weeks of holding time. This optimized nanosuspension enhanced the penetration of Mel across cultured intestinal epithelial cell layers without toxic effects.ConclusionThe dissolution rate of Mel from the poly(vinyl alcohol) stabilized nanosuspension justified its applicability in the design of innovative per oral dosage form (capsule) in order to ensure/give a rapid analgesia.

Robustness testing of milling process, analyzing the particle size distribution and crystallinity of the milled samples

“…It should be noted that recently the characterization of the investigated materials (e.g., crystallinity) using DSC as a semiquantitative conventional method has become common in scientific research [7][8][9]. It provides a possibility to predict the crystallinity of the examined materials, but to verify the accuracy of thermoanalytical measurements, the X-ray powder diffraction test is required [10,11]. In our work, it was found that the degree of crystallinity of Mel investigated by DSC and XRPD did not show any significant difference at 95% significance level.…”

“…In this system, the Mel amount was 10% (w/w) and 5% (w/ w) of PVA proved to be an optimal quantity to meet the expected particle size range. During the milling, a high level of amorphization was detected with DSC and XRPD examinations [10]. In this milling system, the ratio of the started pre-suspension and pearls 1:1 (w/w) resulted in about 200-fold particle size reduction in one step.…”

“…Eight samples were prepared from 2.5 to 20.0% of Mel with 2.5% increment per sample. As the stabilizing agent, 5.0% of PVA aqueous solution as initial concentration was added up to 20.0 g to each sample, which was selected on the basis of our previous experiments [10]. Thus, the PVA concentration with 0.14% increment per sample was between 4.44 and 5.42%.…”

“…The samples were ball-milled in a 50-mL steel jar (Retsch PM 100 MA, Retsch GmbH, Haan, Germany) with 0.3-mm ZrO 2 beads as the grinding media. The process parameters optimized in our pervious work were as follows: 437 rpm, 43 min and 20 g of milling media which was used for every process (dispersion to grinding media ratio 1:1) [10]. The temperature of the samples, measured immediately after milling, did not exceed 39°C.…”

A Review Prinsip Dasar Milling Dalam Sintesis Material

“…Ball Mill tersebut terbuat dari logam (36) yang disyaratkan mempunyai karakteristik keras (37) sekaligus tangguh (tidak mudah pecah) dan tahan korosi (38) untuk menanggung beban dan lingkungan selama proses penggilingan materi. Banyak faktor-faktor yang berpengaruh terhadap hasil dari proses milling ini seperti kecepatan (39) , waktu, temperatur (40) , tekanan, ukuran grinding ball, persentasi PCA (Process Control Agent), dan komposisi berat serbuk tersebut.…”