Better Data, Better Solid Dose QbD

Newer monitoring technologies can provide real insight into solid-dose forms in process

By Emil W. Ciurczak, Contributing Editor

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Unless direct compression, ribbon compaction, or extrusion techniques are used to make tablets, the most likely method of preparing the powder blend for compression is wet granulation. Despite what some may think, wet granulation is not just a matter of pouring a given amount of liquid into a vat of pre-blended powders. Liquid needs to be added in a specific manner, at a specific rate, and usually from a specific position in the blender. Knowing what the manner, rate and positions are is the trick to a successful granulation. Quite often, “experience of granulations past” has been relied upon for an idea of what to do.


One way of measuring how a liquid disperses through a medium (powdered or another liquid) is Tomography. A series of transducers are placed around a mixing chamber (glass or metal) by measuring such things as dielectric constant changes (varying permittivity) the differences throughout a mix can be visualized, in real time. Figure 4 shows a Process Tomography unit. It is capable of measuring liquids being added into liquids (Figure 5) or dispersal of a liquid into a powder matrix. The multiple transducers allow a 3-D picture to be displayed in real time. Using these data, mixing speeds, fill levels, blade type, addition speeds, and points of addition may be optimized.


Because transducers may be applied to any size container, tablet dissolution may also be optimized. The rates of dissolution are only one piece of information; the shape and extent of the “API cloud” may be seen and sampling points set at the best positions. The effects of tablet/capsule position at the bottom of the vessel may also be seen. This leads to more specific analytical SOPs and more precise testing procedures. The precise dissolution pattern, seen in 3-D, allows for faster and better dissolution formulation.

Tablets have been coated for several decades; first sugar coated, now film coated for cosmetic, identification and protection against moisture, UV and visible light. Since coatings on tablets are more than cosmetic, more attention has been paid to them in recent years. Coatings are now used to protect the API and physical make-up of the core, affect or control dissolution times, and even contain an active outside the core and, thus, need to be accurately measured and controlled.

The industry’s been using NIR in the coating pan for years to measure the amount of coatings and loss of solvents. In recent years, Pharma has seen Raman probes added to the coating control toolbox. The data generated from NIR and Raman probes has been used to determine a number of things, including spray radius, solution addition speed, drying times, pan rotation speeds and exhaust functionality. However, as with any NIR or Raman measurement, the information is about the bulk tablet bed.


For understanding individual coating “goodness,” we now have TeraHertz spectroscopy for coating inspection. Formerly known as “far infrared,” TeraHertz has been on the scene for several years now. It may be used as simple spectroscopy, but, in my opinion, its strength is in measuring interfaces between layers. It basically sends a fast (50 fs) NIR pulse through a transducer (Figure 6) and a 50 fs TeraHertz pulse is generated. This is directed through a solid sample, e.g., a coated tablet, and some of the THz waves are reflected (first, second, etc., surface effects) and recorded (see Figure 7). The time between pulses is measured and gives the thickness of each solid phase. The pulse quality varies when there is a gap in the coating uniformity (not bonded sufficiently to the tablet, for instance).


The technique can even be used for 3-D imaging by varying the wavelengths to account for different chemicals (API and excipients, as well as coatings) within a dosage form. This is superior to NIR or Raman chemical imaging, which only shows the positioning of materials a few microns deep. THz can be manipulated to give a true 3-D picture of the dosage form.

Obviously these are but a few of the available tools for fine-tuning a dosage form as part of a successful QbD program. These and other technologies are maturing and becoming even more competitively priced and are worth careful appraisal in implementing a QbD Design Space. Not your father’s instrument package is it?

Published in the December 2013 edition of Pharmaceutical Manufacturing magazine

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