Product, dried physical state

Often the stability of a drug in the solid state depends on its physical state (i.e., crystalline or amorphous [8]). If freeze-drying produces an amorphous solid and the amorphous form is not stable, then freeze-drying will not provide an acceptable product. 

Therefore, freeze-drying should be carried out at the highest allowable product temperature that maintains the appropriate attributes of a freeze-dried product. This temperature depends on the nature of the formulation. Process development and validation requires characterizing the physical state of the solute, or solutes, that result from the freezing process and identifying a maximum allowable product temperature for the primary drying process [20,21]. 

In addition to characterizing frozen systems intended to be freeze dried, it is important to characterize the freeze-dried product. This includes determination of the physical state of the dried product that is, crystalline, partially crystalline, or amorphous. It may also include identification of the polymorph of a crystallizing component which exhibits polymorphism and determination of whether the crystal form observed is affected by changes in formulation and processing conditions. For amorphous systems, the glass transition temperature of the amorphous solid, as well as the extent to which Ts changes with residual moisture, may be a critical attribute of the product with regard to both physical and chemical stability. 

If the crude material is dried at this point, the yield is 60-70 per cent of the theoretical and the product melts at 180-185°. Such drying is not recommended since the physical state of the product changes to a hard form not readily soluble in the recrystalHzing medixim. 

Depending on the physical behaviour and stability of the bioactive component, both amorphous and eutectic systems can be successfully freeze-dried but require different approaches. The most difficult cases are those that exhibit partial crystallisation, which may lead to uncontrollable intrabatch variability. Irrespective of the physical state of the system, maximum temperatures for ice sublimation (7/. or T can be identified. Above these temperatures, ice will melt at an appreciable rate, thus diluting the solution phase. The product may then exhibit mechanical collapse, and most probably it will also become subject to chemical changes (usually deterioration). 

Schliinder [23] has given a classification of dryers that encompasses the physical state of the product as well as the dwell time of the product in the dryer. For very short drying times (<1 min), flash, spray, or drum dryers are used. For very long drying times (>1 h), only tunnel, truck, or conveyor dryers are appropriate. Most dryers operate in the intermediate range, for which a very wide assortment of dryers is available [21]. 

E Shalaev, F Franks. Changes in the physical state of model mixtures during freezing and drying impact on product quality. Cryobiology 33 14—26, 1996. 

Liu, J., Physical characterization of pharmaceutical formulations in frozen and freeze-dried solid states Techniques and applications in freeze-drying development. Pharm. Dev. Technol, 11 3-28 (2006). Whitfield, R.G, Near-infrared reflectance analysis of pharmaceutical products. Pharm. Manuf, 3 31 0 (1986). 

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