Clamp Down on Clumping

First understand what’s really causing the problem.

By Tom Blackwood, Healthsite Associates

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2. Loss on drying (LOD) — for free or surface solvent and a major portion of bound solvent (for moisture, the test usually takes place at 90°C for 6 hours);
3. Infrared — for surface moisture, which is a close approximation to free moisture;
4. Radio frequency — for inherent (sometimes), bound and free moisture;
5. Microwave— for total and interstitial moisture (using different wavelengths);
6. Loss on ignition — for total solvent (can be done following LOD to get solvent of crystallization). Often this test is carried out in temperature steps to observe crystallization solvent as well as other volatile components or decomposition;
7. Thermo-gravimetric analysis — for total solvent loss with time (differential thermal analysis is more precise for solvent flux and can be combined with gas chromatography/mass spectroscopy to identify chemicals in a multi-component solvent system); and
8. DSC — for heat flow with time (which is especially useful in multi-component solvent systems).



1. Simple dissolution followed by drying of solids without any chemical reaction. This is the fundamental problem with a lot of storage systems. Bags aren’t sealed well enough or a solvent gets into the transport line. Several of the following causes also involve this process but in a roundabout way.

2. Chemical reaction between particles and gases in voids in the bulk solid. Most common is formation of hydrates, which changes particle density or creates bridges between particles. Oxidation or reduction of particles is less common but can release gases or yield condensable products that form a sticky film on the solids. Diffusion of soluble gases such as carbon dioxide can soften particles and make them susceptible to shear. In addition, particles can interact with wall material through abrasion, which can act as a catalyst to reduce the potential energy needed for a reaction to occur.

3. Change of phase. This is the most difficult problem to diagnose but often is easiest to prevent. Many people don’t realize that a polymorph could be present. About one-third of all organics have at least one polymorph [1]; lots of pharmaceuticals rely on chemicals that aren’t in their most stable form. While transformation upon storage may take years a small amount of change can result in a big effect on flowability. For crystalline solids the problem usually starts with a very small amount of excess solvent and a temperature change. The unstable form dissolves and then recrystallizes into the stable form with solvent release. The process will repeat as solvent moves from particle to particle. A similar process can occur with amorphous organics because the crystalline form is at a lower potential energy.

4. Recrystallization of solids during storage. Often particles can pick up excess energy prior to storage though handling or milling operations. The latter is a very common culprit because attrition raises the surface potential energy of the solids and creates very fine solids, which have a much higher charge-to-mass ratio. It’s rare for solid-state transformation to occur but it only takes a small amount of solvent to aid the crystallization process, similar to a polymorphic transformation.

5. Viscous films on particles. Interstitial solvent can prompt formation of such films. Heating or cooling solids can cause solvent to migrate and collect in one location. As the solvent partially evaporates, it leaves behind a sticky surface on the particle that can lead to bridging.

6. Impurities in solids. These can induce stresses in the particles, which can hasten chemical reaction, phase changes and recrystallization. Impurities can act as catalysts in a reaction or interact with wall materials to initiate one of the causes previously cited. Localized change in density due to an impurity can prevent normal transfer of shear force from particle to particle and put more stress on an individual particle, resulting in breakage. Location of the impurity — whether on the surface or interior of the particle — may even be critical and cause some batches of solids to behave much differently than others.

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