Wet Milling Technology Research Articles

M- S-H formation in MgO-SiO2slurries via wet milling for magnesia based castables

It is believed that the formation of hydration phase, MgO-SiO2-H2O (M-S-H), contributes to good workability and reliable comprehensive properties for magnesia based castables. In order to stimulate the formation of M-S-H in magnesia based castables and understand the minimum introduction of microslica amount, wet milling process was used to promote the dissolution of MgO and SiO2 in this work. The slurry containing different content of microsilica with wet milling technology and the castables with/without wet milling slurry were prepared. The effects of microsilica content on the formation of hydration phases were analyzed by XRD, FT-IR and TG/DSC and the properties of magnesia based castables were evaluated by explosion resistance, CMOR, HMOR and so on. The results showed that the formation of M-S-H was accelerated because of the dissolution of Mg2+ and HSiO3− in wet milling process. Higher amount of M-S-H led to a tight bonding in the early stage, and a denser structure after firing at high temperature due to the limited formation of brucite and in-situ formation of evenly distributed forsterite phase. In addition, much higher HMOR were obtained when less microsilica was added, attributing to the suppressed formation of low-melting-point liquid. Therefore, 2–3 wt% microsilica addition was recommended in this process.

Efficient design to fabricate smart Lumefantrine nanocrystals using DENA® particle engineering technology: Characterisation, in vitro and in vivo antimalarial evaluation and assessment of acute and sub-acute toxicity

Nanocrystalization technologies have a great potential to substantially increase solubility as well as alleviate the erratic bioavailability behaviour of a range of poorly water soluble drugs. The aim of the current study was to fabricate smart nanocrystals of lumefantrine (LF) using wet milling technology (DENA DM-100) with the subsequent in vitro, in vivo evaluation and toxicity screening. This technology successfully produced nanocrystals with an average particle size (214.1 ± 0.2 nm) and PDI (0.201 ± 0.06) in a period of less than 1 h. DSC and PXRD were used to confirm crystallinity of the processed LF. The dissolution rate and saturation solubility of the processed LF was significantly (P < 0.05) increased compared to the raw and marketed tablets. The IC50 value of LF nanocrystals was significantly (P < 0.05) lower than the IC50 value of the raw drug and marketed tablets. In addition, LF nanocrystals at the same dose (30 mg/kg), showed significantly (P < 0.05) the highest reduction in the percentage of parasitemia compared to its other counterparts against P. vivax. The LD50 value of LF nanocrystals in the acute toxicity was between 1000 and 1500 mg/kg and was devoid of any observable sub-acute toxicity. The histopathological investigations and impact of LF nanocrystals on different internal organs of the chosen animal model were found comparable to the saline treated animal group. The results of current study suggested that wet milling can be effectively used to fabricate nanocrystals of LF both in acidic and aqueous media with enhanced antimalarial activities and a similar safety profile.

Preparation and in vitro-in vivo evaluation of intestinal retention pellets of Berberine chloride to enhance hypoglycemic and lipid-lowing efficacy

Berberine chloride (BBR) is a pharmacokinetic profile of drug with poor bioavailability but good therapeutic efficacy, which is closely related to the discovery of BBR intestinal target. The major aim of this paper is to develop BBR intestinal retention type sustained-release pellets and evaluate their in vivo and in vitro behaviors base on the aspect of local action on intestinal tract. Here, wet milling technology is used to improve dissolution and dissolution rate of BBR by decreasing the particle size and increasing the wettability. The pellets are prepared by liquid layer deposition technology, and then the core pellets are coated with Eudragit® L30D-55 and Eudragit® NE30D aqueous dispersion. The prepared pellets show high drug loading capacity, and the drug loading up to 93%. Meanwhile, it possesses significant sustained drug release effect in purified water which is expected to improve the pharmacokinetic behavior of BBR. The pharmacokinetics results demonstrate that the half-life of BBR was increased significantly from 24 h to 36 h and the inter- and intra-subject variability are decreased compared to commercial BBR tablets. The retention test results indicate that the pellet size and Eudragit® NE30D plays an important role in retention time of the pellet, and it is found that the pellets with small particle size and high Eudragit® NE30D coating content can stay longer in the intestine than the pellets with large particle size. All in all, BBR intestinal retention type pellets are prepared successfully in this study, and the pellets show satisfactory in vivo and in vitro behaviors.

Injectable sustained release PLA microparticles prepared by solvent evaporation-media milling technology

The objective of this study was to develop agomelatine (AGM) intramuscular sustained release PLA microparticles by using solvent evaporation combined with wet milling technology. The final preparation had a regular and homogeneous particle size of approximately 35 µm, as measured by laser diffraction particle size analysis and scanning electron microscopy (SEM). The drug was confirmed to be within the carrier in an amorphous state through differential scanning calorimetry (DSC) and power X-ray diffraction (PXRD) experiments. Additionally, Fourier transform infrared spectroscopy (FT-IR) analysis was applied to confirm that there was hydrogen bonding between the drug and polymer at the molecular level. In vitro release experiments indicated that the drug could achieve long-term sustained release over the period of one month, with only a 3.07% burst release, due to the involvement of the polymer and removal of drug adsorbed on the surface during the wet grinding process. The dominant release mechanism was considered to be diffusion of the drugs in the initial period. Following this, with the hydrolysis of PLA to form a colloidal viscous layer, drug release is due to the combined effect of diffusion and erosion of the polymer matrix. Additionally, drug release behavior is closely related to the degradation mechanism of the polymer carrier. The results suggest that AGM could be developed as a potential delivery system for long-acting intramuscular administration with extensive application prospects.

Techno-economic and ex-ante environmental assessment of C6 sugars production from spruce and corn. Comparison of organosolv and wet milling technologies

This study assesses the techno-economic and environmental performance of C6 sugars production from softwood (spruce) and corn. Two technologies were considered in the assessment: organosolv of spruce woodchips (2nd generation) and corn wet milling (1st generation). Process models were developed to generate relevant data to assess the technical performance and derive inputs for the economic and environmental assessments. The economic assessment was carried out using Net Present Value (NPV) as indicator, while the environmental assessment followed a prospective cradle-to-gate life cycle assessment (LCA) for 5 impact categories. The results indicate that when organosolv is integrated with an anaerobic digestion unit, the net energy requirements are lower than those of the wet milling process to produce an equivalent flowrate of C6 sugars. Assuming equivalent C6 sugar prices for the two technologies (300 €/t), the corn based technology shows positive NPV (178 M€) and lowest fixed capital investment requirements (55 M€). The organosolv technology (coupled to anaerobic digestion) also shows positive NPV (238 M€) at base case lignin prices (630 €/t), but higher fixed capital investment needs (236 M€). The economics of the organosolv process were found to be highly sensitive to sugar and lignin yields and prices as well as biomass feedstock costs. From an environmental perspective, the organosolv based routes show relatively better performance than corn wet milling, with 3 categories including climate change and non-renewable energy use showing lower impacts and 2 showing potentially higher impacts. Overall, the organosolv process (2nd generation) shows better performance from an environmental point of view in addition to a positive NPV. However, the inherent risks of new technologies and high investments associated with the 2nd generation technologies assessed in this work, mean that significant additional development, coupled with appropriate government support, are likely necessary before full-scale implementation.

Smart nanocrystals of artemether: fabrication, characterization, and comparative in vitro and in vivo antimalarial evaluation.

Artemether (ARTM) is a very effective antimalarial drug with poor solubility and consequently low bioavailability. Smart nanocrystals of ARTM with particle size of 161±1.5 nm and polydispersity index of 0.172±0.01 were produced in <1 hour using a wet milling technology, Dena® DM-100. The crystallinity of the processed ARTM was confirmed using differential scanning calorimetry and powder X-ray diffraction. The saturation solubility of the ARTM nanocrystals was substantially increased to 900 µg/mL compared to the raw ARTM in water (145.0±2.3 µg/mL) and stabilizer solution (300.0±2.0 µg/mL). The physical stability studies conducted for 90 days demonstrated that nanocrystals stored at 2°C–8°C and 25°C were very stable compared to the samples stored at 40°C. The nanocrystals were also shown to be stable when processed at acidic pH (2.0). The solubility and dissolution rate of ARTM nanocrystals were significantly increased (P<0.05) compared to those of its bulk powder form. The results of in vitro studies showed significant antimalarial effect (P<0.05) against Plasmodium falciparum and Plasmodium vivax. The IC50 (median lethal oral dose) value of ARTM nanocrystals was 28- and 54-fold lower than the IC50 value of unprocessed drug and 13- and 21-fold lower than the IC50 value of the marketed tablets, respectively. In addition, ARTM nanocrystals at the same dose (2 mg/kg) showed significantly (P<0.05) higher reduction in percent parasitemia (89%) against P. vivax compared to the unprocessed (27%), marketed tablets (45%), and microsuspension (60%). The acute toxicity study demonstrated that the LD50 value of ARTM nanocrystals is between 1,500 mg/kg and 2,000 mg/kg when given orally. This study demonstrated that the wet milling technology (Dena® DM-100) can produce smart nanocrystals of ARTM with enhanced antimalarial activities.

The Effect of an Optimized Wet Milling Technology on the Crystallinity, Morphology and Dissolution Properties of Micro- and Nanonized Meloxicam.

This article reports on the effects of a new combined wet milling technique on the physicochemical properties of meloxicam (MEL). The influence of milling time on the particle size, the crystallinity, the morphology and the dissolution rate of MEL has been studied in the presence and absence of polyvinyl alcohol (PVA) as a stabilizer agent. Micronized MEL particles were produced in aqueous medium which did not contain additive after milling for 10 min. For nanonization an additive and longer milling time were required. After particle size determination the structural and morphological characterization of the wet milled, dried products containing MEL were studied. X-ray powder diffractometry (XRPD) and differential scanning calorimetry (DSC) examinations revealed the change in the crystallinity of MEL. Scanning electron microscopy (SEM) images showed that aggregates of nanosized MEL particles were formed, regardless of the presence of PVA. The nanonized MEL crystals (D50 = 126 nm) exhibited a regular shape and a smooth surface. The increased specific surface area resulted in a high dissolution rate and concentration of free MEL. According to the results, the produced samples could be applied as a basic material (micronized MEL) and intermediate product (micronized and nanonized MEL with PVA) for the design of dosage forms.

Study of sodium hyaluronate-based intranasal formulations containing micro- or nanosized meloxicam particles

This article reports on the micro- and nanonization of meloxicam (MEL) with the aim of developing pre-dispersions as intermediates for the design of intranasal formulations. As a new approach, combined wet milling technology was developed in order to reduce the particle size of the MEL. Different milling times resulted in micro- or nanosized MEL in the pre-dispersions with polyvinyl alcohol as stabilizer agent, which were directly used for preparing intranasal liquid formulations with the addition of sodium hyaluronate as mucoadhesive agent. Reduction of the MEL particle size into the nano range led to increased saturation solubility and dissolution velocities, and increased adhesiveness to surfaces as compared with microsized MEL particles. A linear correlation was demonstrated between the specific surface area of MEL and the AUC. The in vitro and in vivo studies indicated that the longer residence time and the uniform distribution of nano MEL spray throughout an artificial membrane and the nasal mucosa resulted in better diffusion and a higher AUC. Nanosized MEL may be suggested for the development of an innovative dosage form with a different dose of the drug, as a possible administration route for pain management.

Improved dissolution and pharmacokinetic behavior of cyclosporine A using high-energy amorphous solid dispersion approach

The aim of the present investigation is to develop solid dispersion (SD) formulations of cyclosporine A (CsA) for improving the oral bioavailability of CsA. Amorphous SDs of CsA with eight hydrophilic polymers were prepared with wet-mill employing zirconia beads. The physicochemical properties were characterized with a focus on morphology, crystallinity, thermal behavior, dissolution, and interaction of CsA with co-existing polymer. Although CsA molecules were found to be amorphous in all wet-milled formulations, some SD formulations failed to improve the dissolution. Of all CsA formulations, SD using polymer with HPC(SSL) exhibited the largest improvement in dissolution behavior. Pharmacokinetic profiling of orally dosed CsA in rats was carried out using UPLC/ESI-MS. After the oral administration of HPC(SSL)-based SD, enhanced CsA exposure was observed with increases in C max and AUC of ca. 5-fold, and the variation in AUC was ca. 40% less than that of amorphous CsA. Infrared spectroscopic studies suggested an interaction between CsA and HPC(SSL), as evidenced by the conformational transition of CsA. From the improved dissolution and pharmacokinetic data, the amorphous SD approach using wet-milling technology should lead to consistent and enhanced bioavailability, leading to an improved therapeutic potential of CsA.

Safety and Mutagenicity Evaluation of Nanoparticulate Red Mold Rice

Nowadays, people have recognized the importance of Monascus fermented products due to their many health benefits. A previous study demonstrated a novel formulation approach for the preparation of nanoparticulate red mold rice (NRMR). The aim of this study is to determine the useability of stable NRMR dispersion by evaluating its safety and mutagenicity with the Ames test. The crude red mold rice (RMR) was processed using a wet milling technology in the presence of distilled water to form an aqueous-based nanoparticle dispersion with a mean particle size of 259.3 nm. The formulated diepersion was found to be homogeneous and exhibited unimodal particle size distribution when analyzed by dynamic laser scattering techniques. Ames test results indicated that the equivalent of up to 1 mg of ethanol extract of RMR per plate exhibited no genotoxicity toward Salmonella typhimurium strains TA 98, TA 100, and TA 102. In the feeding toxicity test, the no observed adverse effect level (NOAEL) of NRMR was found to be 1000 mg/kg/day for both male and female rats. In conclusion, red mold rice can be formulated as a stable nanoparticulate dispersion using wet milling technology. In vitro and in vivo safety evaluations of NRMR indicated that no mutagenic or toxic responses were observed in this study.

Engineering process and cost model for a conventional corn wet milling facility

Conventional wet milling of corn is a process designed for the recovery and purification of starch and several coproducts (germ, gluten, fiber and steep liquor). The total starch produced by the wet milling industry in the USA in 2004 equaled 21.5 billion kg, including modified starches and starches used for sweeteners and ethanol production. Process engineering and cost models for a corn wet milling process (for steeping and milling facilities) have been developed for a “generic” processing plant with a capacity of 2.54 million kg of corn per day (100,000 bu/day). The process includes grain cleaning, steeping, germ separation and recovery, fiber separation and recovery, gluten separation and recovery and starch separation. Information for the development of the models was obtained from a variety of technical sources including commercial wet milling companies, industry experts and equipment suppliers. The models were developed using process and cost simulation software (SuperPro Designer ®) and include processing information such as composition and flow rates of the various process streams, descriptions of the various unit operations and detailed breakdowns of the operating and capital cost of the facility. Based on the information from the model, we can estimate the cost of production per kilogram of starch using the input prices for corn and other wet milling coproducts. We have also used the model to conduct a variety of sensitivity studies utilizing modifications such as feedstock costs, corn compositional variations, and the sale of wet corn gluten feed. The model is also being used as a base-case for the development of models to test alternative processing technologies and to help in the scale-up and commercialization of new wet milling technologies. This model is available upon request from the authors for educational, non-commercial and research uses.

A Novel Formulation Approach for Preparation of Nanoparticulate Red Mold Rice

Monascus has been used for thousands of years. In China, Monascus has been widely used as a natural food-coloring agent for many kinds of foods. The metabolites of Monascus species, specifically, monacolin K, gamma-aminobutyric acid, and dimerumic acid, have been proven to have cholesterol-lowering, blood pressure-lowering, and antioxidant effects. Nowadays, the public has recognized the importance of Monascus products for its many health benefits. The focus of this study is to explore the effects of nanoparticulate dispersion of red mold rice (RMR) after wet-milling technology treatment. An RMR nanoparticulate formulation was reproducibly obtained after milling in the presence of dispersing agent and water. Furthermore, the physical and chemical properties of these RMR particles were studied using electron microscopy, laser light scattering, pH meter, high-performance liquid chromatography (HPLC), and photometry. The results demonstrate that RMR (mean size = 20.15 microm), processed with wet-milling technology, forms an aqueous-based nanoparticle dispersion (mean particle size of less than 0.41 microm). In addition, HPLC analyses, performed on the secondary metabolites, demonstrated that monacolin K was reduced to 50-92% of its base level and citrinin was reduced to 48-74% of its base level. When testing for the levels of pH, the processed RMR had increased from a pH level of 4.47-4.82 to 5.56-6.4; also, pigment analysis showed that yellow and red pigments were reduced to 36 and 39% of its base level after the wet-milling process. Partial agglomeration has been observed in RMR dispersion when stored in refrigeration after 2 months. RMR can be formulated as a nanoparticulate dispersion without compromising its stability, but its secondary metabolite extraction rate was changed. Further experimentation will be needed to verify safety and functionality evaluations.

Insulin Nanoparticles: A Novel Formulation Approach for Poorly Water Soluble Zn-Insulin

To determine the feasibility of using wet milling technology to formulate poorly water soluble zinc-insulin as a stable, biologically active, nanoparticulate dispersion. The feasibility of formulating zinc-insulin as a nanoparticulate dispersion using wet milling technology was studied. An insulin nanoparticulate formulation was reproducibly obtained after milling zinc-insulin in the presence of F68, sodium deoxycholate and water at neutral pH. The physical and chemical properties of these peptide particles were studied using electron microscopy, laser light scattering, HPLC and SDS-PAGE. To verify efficacy, hyperglycemic rats were dosed subcutaneously and intraduodenally with nanoparticles or solubilized insulin. Glucose and insulin levels were monitored on blood samples collected throughout the study. Zn-insulin (mean size = 16.162 microm) was processed using milling technology to form an aqueous-based nanoparticle dispersion with a mean particle size of less than 0.150 microm. The formulation was homogeneous and exhibited a unimodal particle size distribution profile using laser light diffraction techniques. Insulin, processed as a peptide-particle dispersion, was shown to be comparable to unprocessed powder using HPLC and SDS-PAGE. In addition, HPLC analyses performed on samples, heat-treated at 70 degrees C for 100 minutes, demonstrate that under conditions which effect the solubilized peptide, formulated as a peptide-particle dispersion, insulin was chemically stable. Also, when stored refrigerated, the insulin dispersion was chemically and physically stable. Finally, peptide particles of insulin, dosed subcutaneously and intraduodenally, were effective at lowering blood glucose levels of hyperglycemic rats. Water insoluble Zn-insulin can be formulated as a stable, biologically active nanometer-sized peptide particle dispersion using wet media milling technology.