Overview of milling techniques for improving the solubility of poorly water-soluble drugs

AbstractMilling involves the application of mechanical energy to physically break down coarse particles to finer ones and is regarded as a “top–down” approach in the production of fine particles. Fine drug particulates are especially desired in formulations designed for parenteral, respiratory and transdermal use. Most drugs after crystallization may have to be comminuted and this physical transformation is required to various extents, often to enhance processability or solubility especially for drugs with limited aqueous solubility. The mechanisms by which milling enhances drug dissolution and solubility include alterations in the size, specific surface area and shape of the drug particles as well as milling-induced amorphization and/or structural disordering of the drug crystal (mechanochemical activation). Technology advancements in milling now enable the production of drug micro- and nano-particles on a commercial scale with relative ease. This review will provide a background on milling followed by the introduction of common milling techniques employed for the micronization and nanonization of drugs. Salient information contained in the cited examples are further extracted and summarized for ease of reference by researchers keen on employing these techniques for drug solubility and bioavailability enhancement

A Study of 5-aminolevulinic Acid and its Methyl Ester Used in In vitro and In vivo Systems of Human Bladder Cancer

The use of 5-aminolevulinic acid and its esters to induce endogenous porphyrins for the purpose of detection of epithelial cancers is being studied extensively in many centres around the world. The challenge is to prepare an efficacious formulation for the purpose of cancer detection. Photodynamic diagnosis of cancer using 5-aminolevulinic acid (ALA) and its ester derivatives is being actively investigated. In this study, we compared ALA with ALA methyl ester (AME) derivative in terms of PpIX fluorescence intensity in in vitro and in vivo systems of bladder carcinoma. For the in vivo system consisting of RT112 xenografts, the modes of drug administration compared were intravenous administration and topical application. The Karl Storz fluorescence endoscopy system was used to obtain macroscopic fluorescence images. The macroscopic images were further analysed for fluorescence intensity distribution. For the intravenous administration, over all time points studied (1, 3, 6 h), AME-PpIX fluorescence was lower than ALA-PpIX fluorescence and was cleared at a faster rate than the ALA-PpIX when administered intravenously. Topical application with two different polymers, Gantrez and Polyvinyl pyrrolidone (PVP) which are fast releasing polymers was found to be comparable in inducing PpIX fluorescence. Topical AME-PpIX fluorescence was found to be comparable with ALA-PpIX fluorescence. The results of this study suggest that the AME can also be used as a good diagnostic agent

Macro-microscopic Fluorescence Imaging of Human NPC Xenografts in a Murine Model Using Topical vs. Intravenous Administration of 5-Aminolevulinic Acid

The use of 5-aminolevulinic acid to induce endogenous porphyrins for the purpose of detection of epithelial cancers is being studied extensively in many centres around the world. The challenge is to prepare an efficacious formulation of 5-ALA for the purpose of cancer detection. In this study, we compared two formulations of topical 5-ALA applications with intravenous administration in NPC/CNE-2 xenografts on balb/c nude mice. One of the formulations was a gantrez muco-adhesive patch and the other was a polyvinyl-pyrolidone muco-adhesive patch. The Karl Storz fluorescence endoscopy system was used to obtain macroscopic fluorescence images. Microscopic fluorescence imaging was done by laser confocal microscopy. The macroscopic images were further analysed for fluorescence intensity distribution. It was found that between the two formulations of topical application of 5-ALA; there was very little difference in the fluorescence biodistribution. When the topical applications were compared with the intravenous administration, the tumour to normal differential in biodistribution was significantly higher with the topical application compared to the intravenous application

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Alginate-based matrix tablets for drug delivery

10.1080/17425247.2023.2158183Expert Opinion on Drug Delivery201115-13

Tablet Disintegratability: Sensitivity of Superdisintegrants to Temperature and Compaction Pressure

Tablet disintegration is an important pre-requisite for drug dissolution and absorption. The disintegration test is typically conducted at 37 °C, but the intragastric temperature may vary due to meals or fever. This study investigated the effects of temperature and compaction pressure on tablet disintegratability to gain deeper insights into superdisintegrant sensitivity and function. Tablets with either sodium starch glycolate or crospovidone as disintegrant were prepared at various compaction pressures and subjected to the disintegration test using different medium temperatures. Preheating of tablets was also employed to establish instant temperature equilibrium between the tablet and the disintegration medium. Liquid penetration and disintegration were faster as the medium temperature increased or compaction pressure decreased. Swelling or strain recovery disintegrants exhibited similar sensitivity to variations in the medium temperature. Preheating of the tablets resulted in slower disintegration, but this effect was reversible upon cooling, hence the slower disintegration was unlikely to be attributed to changes in the disintegrant physical state. The temperature difference between the tablet and the disintegration medium likely affected the rate of fluid flow into tablets and influenced disintegration. Understanding disintegrant temperature sensitivity would help to avoid unacceptable fluctuations in disintegration due to temperature variations. The temperature difference effect could also be harnessed to boost disintegrant performance

Influence of the porosity of cushioning excipients on the compaction of coated multi-particulates

10.1016/j.ejpb.2020.05.015European Journal of Pharmaceutics and Biopharmaceutics152218-22