Continuous low-dose feeding of highly active pharmaceutical ingredients in hot-melt extrusion.

CONTEXT: Manufacturing solid low-dose pharmaceutical products has always the homogeneity challenge. In continuous manufacturing, there is the additional challenge of feeding active pharmaceutical ingredient (API) dry powder at low rates. This paper presents a method for feeding API particles into a continuous extrusion process using a suspension. The challenges for feeding and the product homogeneity are both addressed. OBJECTIVE: The objective of this study is to demonstrate the feasibility of manufacturing low-dose extrudates by feeding the API particles in a diluted anti-solvent suspension. MATERIALS AND METHODS: Extrudates with an Ibuprofen content of 0.021% and 0.043% (w/w) were prepared by feeding a 0.9% w/w suspension of Ibuprofen particles into a Coperion extruder. RESULTS AND DISCUSSION: The homogeneity (RSD) of extrudates was tested during a time span of 30 min and had values between 2% and 7%. CONCLUSION: Feeding particles in an anti-solvent suspension offers a simple feeding option for API and minor components which yield products of desired homogeneity. The liquid feeding approach offers a simplified process with enhanced process control possibilities.

Method to study the effect of blend flowability on the homogeneity of acetaminophen.

CONTEXT: Excipient selection is key to product development because it affects their processability and physical properties, which ultimately affect the quality attributes of the pharmaceutical product. OBJECTIVE: To study how the flowability of lubricated formulations affects acetaminophen (APAP) homogeneity. MATERIALS AND METHODS: The formulations studied here contain one of two types of cellulose (Avicel 102 or Ceollus KG-802), one of three grades of Mallinckrodt APAP (fine, semi-fine, or micronized), lactose (Fast-Flo) and magnesium stearate. These components are mixed in a 300-liter bin blender. Blend flowability is assessed with the Gravitational Displacement Rheometer. APAP homogeneity is assessed with off-line NIR. RESULTS: Excluding blends dominated by segregation, there is a trend between APAP homogeneity and blend flow index. Blend flowability is affected by the type of microcrystalline cellulose and by the APAP grade. CONCLUSION: The preliminary results suggest that the methodology used in this paper is adequate to study of the effect of blend flow index on APAP homogeneity.

ADAMTS13 Activity Measurement by ELISA and Fluorescence Resonance Energy Transfer Assay.

Accurate estimation of ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motif, member 13) activity level is crucial in the diagnostic setting of differentiation between thrombotic thrombocytopenic purpura (TTP) and other thrombotic microangiopathies. The original assays were too cumbersome and time-consuming for use in the acute situation, and treatment was often based on clinical findings alone, with confirmatory laboratory assays following days or weeks later. Rapid assays are now available that can generate results fast enough to impact on immediate diagnosis and management. Assays based on fluorescence resonance energy transfer (FRET) or chemiluminescence principles can generate results in less than an hour, although they require specific analytical platforms. Enzyme-linked immunosorbent assays (ELISA) can generate results in about 4 h, but do not require specialized equipment beyond ELISA plate readers that are in regular use in many laboratories. The present chapter describes principles, performance, and practical aspects of an ELISA and a FRET assay, for quantitative measurement of ADAMTS13 activity in plasma.

Shear-induced APAP de-agglomeration.

CONTEXT: Active pharmaceutical ingredient agglomerates can generate many solid product regulatory compliance issues. OBJECTIVE: To study the effects of shear rate, strain, type of excipient, and grade of acetaminophen (APAP) on the process of APAP de-agglomeration. MATERIALS AND METHODS: A shear-controlled environment is used to expose six different blends that consist of one of three APAP grades and one of two possible types of excipient to 10 different combinations of shear rate and strain. APAP agglomerates are sifted and weighed. RESULTS: Finer APAP grades lead to blends with more APAP agglomerates and type of excipient only affects the de-agglomeration process for the finest APAP grade. De-agglomeration proceeds mainly as a function of strain with a minor contribution toward further de-agglomeration when larger shear rates are used. DISCUSSION: When mechanical stress (which us proportional to shear rate) overcomes interparticle forces, de-agglomeration occurs. Higher shear rates (and stress) contribute slightly to further APAP de-agglomeration. Extended exposure to stress (strain) reduces the size and the number of agglomerates. Blends with finer APAP present more agglomerates, particularly after low strain exposure. CONCLUSIONS: This article presents a useful method for formulation and process development. Exposing blends to higher shear rates and especially to strain mitigates APAP agglomeration in blends. Finer APAP presents more agglomerates and the type of excipient used affects the degree of APAP agglomeration.

Influence of shear intensity and total shear on properties of blends and tablets of lactose and cellulose lubricated with magnesium stearate.

A new technique to quantify the effects of shear intensity and total shear on the homogeneity, flowability and bulk density of a lubricated free-flowing pharmaceutical blend and on properties of resulting tablets is presented. A modified Couette cylindrical cell with uniformly spaced pins is used to create a uniform shear environment. The range of lubricant concentrations explored is 0-2% (on a mass basis). Sheared blends are used to produce tablets in the Presster (a simulator of an actual tablet press), allowing us to correlate the shear history of the blend (shear intensity and total shear) with the crushing hardness of tablets. The results show that the larger the total shear, the more homogeneous the blend. Bulk density increases with total shear until reaching a distinctive plateau. Results also indicate that high total shear affects the blend flow properties. For tablets, crushing hardness decreases as concentration of lubricant and total shear increase. Interestingly, and unexpectedly, under constant total shear, shear intensity affects the crushing hardness of tablets only slightly.

The effects of powder compressibility, speed of capsule filling and pre-compression on plug densification.

This paper describes the effect of powder compressibility and two process parameters of a dosator nozzle capsule filling machine on powder densification during plug formation. One process parameter was the ratio between the powder bed's depth and the length of the nozzle dosing chamber, hereinafter referred to as F. The other one was the speed of capsule filling. This paper demonstrates that powder densification during the capsule filling process is a function of the powder compressibility and the above process parameters (increasing them leads to higher plug density). The Walker model was used to characterize the compressibility of powders at low compression forces and the obtained compressibility coefficient W proved to be a good predictor of powder densification during the capsule filling process.

Low-dose capsule filling of inhalation products: critical material attributes and process parameters.

The aim of the present work was to identify the material attributes and process parameters of a dosator-nozzle capsule filling machine that are critical in low-fill weight capsule filling for inhalation therapies via hard-gelatin capsules. Twelve powders, mostly inhalation carriers, some fines and one proprietary active pharmaceutical ingredient (API), were carefully characterized and filled into size 3 capsules. Since different process conditions are required to fill capsules with powders that have very different material attributes, the powders were divided into two groups. A design of experiments (DOE) based exclusively on process parameters was developed for each group, to identify the critical material attributes (CMA) and critical process parameters (CPP). The fill weight (4-45 mg) of the group I powders (larger particles, higher density, better flowability and less cohesion) correlated with the nozzle diameter (1.9-3.4mm), the dosing chamber length (2.5-5mm), the powder layer depth (5-12.5mm) and the powder density (bulk and tapped density). The RSDs were acceptable in most cases, even for very low doses. The fill weight (1.5-21 mg) of group II powders (very fine and low dense particles with a particle size <10 µm, poor flowability and higher cohesion) depended also on the nozzle diameter (1.9-2.8mm), the dosing chamber length (2.5-5mm) and the powder layer depth (5-10mm), albeit in a different way, indicating that for these powders dosator filling was not volumetric. Moreover, frictional (wall friction angle) and powder-flow characteristics (bulk density and basic flowability energy) have an influence on the mass. Thus, in summary, group I and group II powders can be filled successfully via dosator systems at low fill weights. However, the group II powders were more challenging to fill, especially without automated process control. This study is the first scientific qualification of dosator nozzles for low-fill weight (1-45 mg) capsule filling.

The effects of material attributes on capsule fill weight and weight variability in dosator nozzle machines.

The goal of this work is to identify and understand the complex relationship between the material attributes, capsule fill weight and weight variability of capsules filled with a dosator nozzle machine. Six powders were characterized and filled into size-3 capsules in three volumes of dosing chambers and at two filling speeds. Subsequent multivariate data analysis was used to identify the influence of the material attributes on the capsule fill weight and weight variability. We observed a clear correlation between the capsule fill weight and the particle size, the air permeability and the compressibility. As the fill weight decreases, more factors affect capsule fill weight. For example, the wall friction angle, the tapped density, and the particle shape proved to be important factors. Larger fill weights were more affected by density while lower fill weights by flow and friction characteristics. No correlation was found between the material attributes and the weight variability. Rather, we could also see the major effect of process parameters on capsule fill weight and weight variability.

The effect of capsule-filling machine vibrations on average fill weight.

The aim of this paper is to study the effect of the speed of capsule filling and the inherent machine vibrations on fill weight for a dosator-nozzle machine. The results show that increasing speed of capsule filling amplifies the vibration intensity (as measured by Laser Doppler vibrometer) of the machine frame, which leads to powder densification. The mass of the powder (fill weight) collected via the nozzle is significantly larger at a higher capsule filling speed. Therefore, there is a correlation between powder densification under more intense vibrations and larger fill weights. Quality-by Design of powder based products should evaluate the effect of environmental vibrations on material attributes, which in turn may affect product quality.