Excipient Size Research Articles

Facilitating direct compaction tableting of fine cohesive APIs using dry coated fine excipients: Effect of the excipient size and amount of coated silica

The possibility of attaining direct compression (DC) tableting using silica coated fine particle sized excipients was examined for high drug loaded (DL) binary blends of APIs. Three APIs, very-cohesive micronized acetaminophen (mAPAP, 7 μm), cohesive acetaminophen (cAPAP, 23 μm), and easy-flowing ibuprofen (IBU, 53 μm), were selected. High DL (60 wt%) binary blends were prepared with different fine-milled MCC-based excipients (ranging 20- 37 μm) with or without A200 silica coating during milling. The blend flowability (flow function coefficient −FFC) and bulk density (BD) of the blends for all three APIs were significantly improved by 1 wt% A200 dry coated MCCs; reaching FFC of 4.28 from 2.14, 7.82 from 2.96, and > 10 from 5.57, for mAPAP, cAPAP, and IBU blends, respectively, compared to the uncoated MCC blends. No negative impact was observed on the tablet tensile strength (TS) by using dry coated MCCs despite lower surface energy of silica. Instead, the desired tablet TS levels were reached or exceeded, even above that for the blends with uncoated milled MCCs. The novelty here is that milled and silica coated fine MCCs could promote DC tableting for cAPAP and IBU blends at 60 wt% DL through adequate flowability and tensile strength, without having to dry coat the APIs. The effect of the silica amount was investigated, indicating lesser had a positive impact on TS, whereas the higher amount had a positive impact on flowability. Thus, the finer excipient size and silica amounts may be adjusted to potentially attain blend DC processability for high DL blends of fine APIs.

Enhanced blend uniformity and flowability of low drug loaded fine API blends via dry coating: The effect of mixing time and excipient size

Although previous research demonstrated improved flowability, packing, fluidization, etc. of individual powders via nanoparticle dry coating, none considered its impact on very low drug loaded blends. Here, fine ibuprofen at 1, 3, and 5 wt% drug loadings (DL) was used in multi-component blends to examine the impact of the excipients size, dry coating with hydrophilic or hydrophobic silica, and mixing times on the blend uniformity, flowability and drug release rates. For uncoated active pharmaceutical ingredients (API), the blend uniformity (BU) was poor for all blends regardless of the excipient size and mixing time. In contrast, for dry coated API having low agglomerate ratio (AR), BU was dramatically improved, more so for the fine excipient blends, at lesser mixing times. For dry coated API, the fine excipient blends mixed for 30 min had enhanced flowability and lower AR; better for the lowest DL having lesser silica, likely due to mixing induced synergy of silica redistribution. For the fine excipient tablets, dry coating led to fast API release rates even with hydrophobic silica coating. Remarkably, the low AR of the dry coated API even at very low DL and amounts of silica in the blend led to the enhanced blend uniformity, flow, and API release rate.

Development of High Dose Oseltamivir Phosphate Dry Powder for Inhalation Therapy in Viral Pneumonia.

Oseltamivir phosphate (OP) is an antiviral drug available only as oral therapy for the treatment of influenza and as a potential treatment option when in combination with other medication in the fight against the corona virus disease (COVID-19) pneumonia. In this study, OP was formulated as a dry powder for inhalation, which allows drug targeting to the site of action and potentially reduces the dose, aiming a more efficient therapy. Binary formulations were based on micronized excipient particles acting like diluents, which were blended with the drug OP. Different excipient types, excipient ratios, and excipient size distributions were prepared and examined. To investigate the feasibility of delivering high doses of OP in a single dose, 1:1, 1:3, and 3:1 drug/diluent blending ratios have been prepared. Subsequently, the aerosolization performance was evaluated for all prepared formulations by cascade impaction using a novel medium-resistance capsule-based inhaler (UNI-Haler). Formulations with micronized trehalose showed relatively excellent aerosolization performance with highest fine-particle doses in comparison to examined lactose, mannitol, and glucose under similar conditions. Focusing on the trehalose-based dry-powder inhalers’ (DPIs) formulations, a physicochemical characterization of extra micronized grade trehalose in relation to the achieved performance in dispersing OP was performed. Additionally, an early indication of inhaled OP safety on lung cells was noted by the viability MTT assay utilizing Calu-3 cells.

Improved properties of fine active pharmaceutical ingredient powder blends and tablets at high drug loading via dry particle coating

It has been shown that dry coating cohesive active pharmaceutical ingredients (APIs) with nano-silica can improve packing and flow of their blends, facilitating high speed direct compression tableting. This paper examines the broader scope and generality of previous work by examining three fine APIs; micronized Acetaminophen (mAPAP), coarse Acetaminophen (cAPAP) and micronized Ibuprofen (mIBU), and considers dry coating with both hydrophobic or hydrophilic nano-silica to examine the effect not only on packing density and flow of their blends, but also dissolution and tensile strength of their tablets. The impact of the excipient size on blend and tablet properties are also investigated, indicating blend flow is most improved when matching API particle size with excipient particle size. In all cases where the API is dry coated, the blend packing and flow improve, so as to suggest such high drug loaded blends could enable direct compression. Using dry coated API along with finer excipients in blends lead to improved hardness of the corresponding tablets. Interestingly, dissolution profiles show dry coated API tablets generally have faster dissolution rates, regardless of silica hydrophilicity, suggesting API powder deagglomeration via nano-silica coating plays a crucial role. The most significant conclusion is that, although there are differences in properties of blends that depend on the API, hydrophobic or hydrophilic nano-silica coating, as well as large or fine excipients, in all cases, dry coating of APIs significantly improves the possibility of using the specific blend at high drug loading in direct compression tableting.

The role of the drug/excipient particle size ratio in the percolation model for tablets.

In previous papers, a linear relationship between drug particle size and drug percolation threshold was found in inert matrix tablets. The main objectives of the present work are: to study the influence of the excipient particle size on the drug percolation threshold and to investigate if the change in the drug percolation threshold is due either to the absolute or to the relative drug particle size. Matrix tablets have been prepared using KCl (7 different particle size fractions) as a drug model and Eudragit RS-PM (4 granulommetric fractions) as matrix forming material. In vitro release assays were carried out on the 66 lots of tablets. The drug percolation thresholds were estimated following the method of Bonny and Leuenberger. The particle size of the excipient has shown an opposite effect to the drug size on the drug percolation threshold. Nevertheless, the influence of drug and excipient sizes on the drug percolation threshold are of the same magnitude. The drug percolation threshold depends linearly on the relative drug particle size. This finding is in agreement with percolation theory and can facilitate the use of the percolation threshold as a preformulation parameter to improve the pharmaceutical dosage forms design.