Blend uniformity measurement

The active pharmaceutical ingredient in a low-dose formulation is typically a small molecule, designed to meet a small particle size requirement for uniformity purposes, and can be susceptible to effects of static charge and segregation. The impact of static charge on the accuracy of blend uniformity measurements (i.e., sampling bias) is discussed in the next section. 

Finally, the off line blend uniformity measurement is typically made once each time the process is optimized, this may only happen a few times during the development of a drug product. Once the blend time is set, it will be blended blindly. This is due to the effort and expense of an offline blend imiformity study. 

The effect on the process of a change in operation of the mixer system (impeller, baffles, etc.) is the final measurement of performance. Thus, operations such as blending, uniform particle suspension, reaction, gas absorption, etc., may be acceptable under one physical system and not so to the same degree under a slightly modified one. The ratio per unit volume on scale-up must be determined experimentally. 

For the blend uniformity application, the primary concern is overall heterogeneity within the sample. This is directly indicated by the width of the distribution and is quantitatively measured as the percent standard deviation relative to the mean (%SD). The %SD value obtained from the PLS scores distribution from each of the six imaged tablets is noted on the histograms in Figure 8.15(A-F). The value of %STD consistently decreases as the blending quality of the sample improves. 

Encapsulation assessment Appearance target (moisture test) and drying cycle Visual-performed measurement of drying cycle Blend uniformity Tools available for online... 

Quantitatively evaluate blend uniformity or homogeneity to determine optimum mixing time. Typically, a measure based on total mixture homogeneity is used as the means to track the evolution of mixture quality in blenders. There are three key factors to consider ... 

The relative signal intensity of the Raman shift was also found to be proportional to HPLC assay results. With the use of confocal Raman spectroscopy, the ibuprofen distribution in the extrudate was mapped therefore, this technique can be used to measure homogeneity (blend uniformity) in a fast and nondestructive manner. 

Without infringing on the other chapters, some of the applications now considered common are on-line blend uniformity testing. This ability to monitor a moving blender was unheard of a few years ago. The same can be said about monitoring the drying of materials in a static or fluidized bed. Not only is the solvent level measured but also any polymorphic or crystalline changes. Coating of tablets may also be followed in real time. 

What is clearly needed is a metric that could monitor the blend uniformity, in real time as the blend occurs. Ideally, such a process would be noninvasive to the blend process, as accurate as the offline measurement, and nonlabor intensive. There are a number of techniques that have been developed to serve as a real-time blend uniformity monitoring. Near infrared (NIR) spectroscopy is probably the most mature technology that has been applied to blend imiformity analysis and will be discussed in detail below. 

It turns out that in low-viscosity blending the acdual result does depend upon the measuring technique used to measure blend time. Two common techniques, wliich do not exhaust the possibilities in reported studies, are to use an acid-base indicator and inject an acid or base into the system that will result in a color change. One can also put a dye into the tank and measure the time for color to arrive at uniformity. Another system is to put in a conductivity probe and injecl a salt or other electrolyte into the system. With any given impeller type at constant power, the circulation time will increase with the D/T ratio of the impeller. Figure 18-18 shows that both circulation time and blend time decrease as D/T increases. The same is true for impeller speed. As impeller speed is increased with any impeller, blend time and circulation time are decreased (Fig. 18-19). 

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