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Fernando J. Muzzio, PhD, is a professor and the director of the pharmaceutical engineering program at the Department of Chemical and Biochemical Engineering, Rutgers University, 98 Brett Road, Piscataway, NJ 08854-8058, tel. 732.445.3357.
C-SOPS, Department of Chemical and Biochemical Engineering at Rutgers, The State University of New Jersey
Shear-sensitive ingredients in a tableting formulation experience different conditions in a batch tumble blender than they would in a continuous paddle blender.
Granular mixing can be generally classified either as macro-mixing or micro-mixing, based on the scale of mixing. Macro-mixing is defined as the macro-scale transport of particles or particle assemblies from one spatial coordinate to the other. Macro-mixing is responsible for most of the reduction in variance in unmixed powder streams. Micro-mixing is defined as mixing at the scale of a single particle. Micro-mixing is always associated with a change in the properties of individual particles (1).
The role of micro-mixing becomes particularly important when it involves shear-sensitive ingredients, such as magnesium stearate or other lubricants, which are added to the formulation to reduce sticking in the tablet press. Magnesium stearate also improves the packing efficiency of coated materials (i.e., increased bulk density) and improves flow properties (2).
Lubricants, however, can also cause problems in the formulation. Magnesium stearate, generally present as thin nanoparticles, is known to coat larger, shear insensitive excipients and active ingredients (3). This coating reduces the bonding ability of particles, and consequently causes a loss in the tabletability of the material (2). Magnesium stearate is also hydrophobic in nature, so coating active ingredient particles with magnesium stearate increases their hydrophobicity, resulting in a lower dissolution rate for the active ingredient (4, 5).
The coating extent of the shear-sensitive material and, consequently, its associated effects, are directly proportional to the total amount of strain experienced by the blend. The greater the strain, the more pronounced the extent of coating and, consequently, the more pronounced the associated effects (2–5).
Close attention is thus paid to the extent of lubricant mixing in traditional batch manufacturing to ensure that the lubricant is not subjected to excessive strain levels during the blending operation. Typically, shear-sensitive ingredients are added in a second stage, after the mixing of other ingredients, to minimize the strain they experience. The bulk ingredients are blended for a few hundred revolutions in the blender before the lubricant is added to the system, and the lubricant is generally mixed for a few tens of revolutions.
The design and operation of a continuous paddle blender differ significantly from that of a batch tumble blender. Moreover, the material is in the continuous blender for a much shorter time. In a continuous blending process, the material spends typically between a few seconds to a few minutes in the blender and experiences anywhere between 50 to a few hundred impeller revolutions (6).
The number of impeller passes or revolutions is defined as follows:
Number of impeller passes = τ (min) * impeller speed (rpm)
where τ is the mean residence time of the material in the blender.
How do strain levels differ in the continuous blender compared to the batch blender? The answer to this question will determine whether or not shear-sensitive ingredients must be added at a second stage.
Razavi et al. (7) performed a study to quantify the amount of strain that the material experiences in a full-scale continuous process, and compared that to the strain resulting from a laboratory-scale batch blending operation. The researchers quantified the difference in the speed of sound in compressed tablets due to density differences between materials subjected to the variable degrees of strain. The authors found that the total amount of strain experienced by the material in a full-scale continuous process was less than that in a laboratory-scale batch operation.
In this experiment, the continuous process was operated at a total mass flow-rate of 20 kg/hr. The continuous blender was run at 200 rpm, while the feed-frame was operated at 25 rpm. The material thus experienced strain in both the continuous blender and the feed-frame (7). The same material was blended in a laboratory-scale V-blender, with magnesium stearate, for 50 revolutions and compressed in a tablet press emulator. The tablet press emulator does not use a feed-frame to feed powder in compression dies. The powder processed by the batch operation is thus only subjected to strain during the batch blending operation. Despite the presence of the additional shear provided by the feed-frame in the continuous process, it was found that, overall, the material experienced less strain in the continuous process than it did in the batch blending operation (7).
These results suggest that the amount of strain experienced by the material while it traverses a full-scale continuous blender is negligible compared to that experienced by the material in a laboratory-scale batch device. There are two reasons for this effect:
Material in the continuous process spends a shorter amount of time in the equipment than it does in the batch process, and thus the total time of exposure to the shearing environment is much lower.
The total mass of material in the continuous process, at any time, is significantly lower than it is in the batch process. A lower net mass results in lower consolidation and frictional stresses, leading to a lower overall degree of strain.
Thus, the typical strain level in industrial-scale horizontal convective blenders is much lower than it is in benchtop batch devices, and most certainly lower than it is in full-scale batch blenders.
Results also suggest that there needn’t be as much concern about potential over-lubrication in continuous blending operations, because they are gentler, so two-staged ingredient addition may not be necessary.
It is also interesting to note that, in a continuous blender, the ratio of free volume in the system (i.e., volume not swept by the rotating blades) to the total blender volume is much smaller than it is in a batch blender (where the entire volume of the blender is considered free).
The authors hypothesize that, in continuous blenders, a small amount of material is more uniformly subjected to the convective action of the blades, resulting in a more uniform nature of strain energy compared to what is found in batch systems.
To quantify the effect of strain rate on blend properties, experiments were performed in which 300 g of material were subjected to 50, 100, 500, and 1000 revolutions with 1% magnesium stearate (w/w), in a modified continuous blender, albeit at different strain rates. The lubricity of the blend was quantified by measuring its contact angle with water, as described by Denesuk et al. (8).
The blend consisted of 65% anhydrous Compap L acetaminophen and 34% Avicel PH-101, by weight. It was added to a Gericke GCM-250 continuous blender whose blades were adjusted such that they do not promote any axial motion of the material. The exit of the blender was sealed so that no material could leave the blender tube. Strain rates of 50, 150, and 250 rpm were investigated.
Figure 1 shows the effect of the strain rate addition on the lubricity or hydrophobicity of the final blend. Blend lubricity is quantified as the cosine of the blend contact angle with water; a smaller cosine value indicates greater hydrophobicity. It can be observed that the blend hydrophobicity is not dependent on the rate at which strain is applied to the material, but only dependent on the total strain it experiences.
The total amount of strain experienced by the in-process material in a batch tumbling blender is greater than that in a continuous paddle blender, under typical operating conditions. The higher strain experienced in batch processing necessitates the addition of shear-sensitive materials, such as magnesium stearate, at a later stage in the blending operation, resulting in two stages of ingredient addition. Two-stage addition may not be necessary in gentler continuous operations. The material experiences a more uniform degree of shear in a continuous blender compared to a batch blender.
Lastly, the rate of strain addition (i.e., rotation speed) does not have an impact on the lubricity of the final blend. Lubricity depends only on the total amount of strain the blend experiences in either batch or continuous processing.
Sarang Oka, Sara Moghtadernejad, Zhanjie Liu, Douglas Hausner and Fernando Muzzio* are all from the Department of Chemical & Biochemical Engineering at Rutgers, The State University of New Jersey, firstname.lastname@example.org.
*To whom all correspondence should be addressed.
Vol. 40, No. 11
When referring to this article, please cite it as S. Oka, et al., "Lubrication in Continuous Tubular Powder Blenders," Pharmaceutical Technology 40 (11) 2016.