Stability is the Key - - BioPharm International


Stability is the Key

BioPharm International

Spray-drying is a dehydration process that uses heat from a hot-air stream to evaporate dispersed droplets created by atomization of a continuous liquid feed. Products dry within a few seconds into fine particles (powders). It is similar to freeze-drying. Important data for formulators working with any type of freezing process will be the glass transition temperature (Tg) of each component and the solution (see box, page 18). At that temperature, ice crystal formation decreases to undetectable levels, and the freeze is an amorphous glass from which water will sublime.

Spray-drying offers some advantages over freeze-drying: shorter process times, lower capital investment in equipment, and lower energy input to the solution, which can lessen the chances for protein denaturation. Disadvantages include the brief but high air-temperature exposure during the rapid-drying step (around 100C) and shear stresses caused by spraying a formulation through a nozzle. The product temperature reaches about 80C but only for a fraction of a second.

The spray-drying technique is used with classical pharmaceuticals. "Spray-drying is a well-developed technique for creating pharmaceutically elegant powders, and it is readily adaptable for protein pharmaceutical applications," said Douglas Nesta, a development scientist at GlaxoSmithKline, at a meeting on formulations and biopharmaceutical drug delivery. However, he cautioned that a range of analytical methods "must be applied to biopharmaceutical powders in the solid state, as well as after reconstitution, to enable an accurate assessment of product quality."

Particle characteristics and size distribution can be closely controlled in spray-drying by changing process variables such as solution composition and feed rate, atomizing gas pressure, air flowrate, and the inlet and outlet gas temperatures. Physical characteristics of the final product (size, morphology, surface area, density of particles) may be manipulated, as well as biochemical characteristics (purity, potency, solubility, stability of the formulation) and process yields. The goal is a dry, free-flowing powder with well-defined particle characteristics, consistent purity and presentation, and an active, stable, and acceptable dissolution profile, all obtained by as simple a process as possible.

PEGylation: An In Vivo Stability Solution
Undercooling. Under certain conditions, a liquid can be cooled to temperatures below its freezing point (supercooling or undercooling). Freezing is usually initiated by particulates, which act as nuclei. The process is similar to the formation of hailstones and how cloud-seeders induce rain out of an apparently dry sky by adding particles around which water condenses. If a solution is separated into droplets, as in a mist or a water-in-oil emulsion, then only those drops with particles in them will freeze if cooled, rather than catalyzing a chain reaction of freezing throughout the solution.

For protein formulations, the product in aqueous solution can be dispersed as microparticles through an oil-phase carrier (liquid at the mixing temperature, solid if stored at -20C), so the drops are locked in as liquid. Reconstitution is easier than with a lyophilized or spray-dried product: Users just warm the final product (sometimes with gentle centrifugation) until those phases separate. This undercooling process may be used for even high-concentration protein formulations, requiring no additives like glycerol, which must be filtered out before the product can be used. Undercooling may be a particularly good choice for products that are susceptible to freeze damage.

Excipients No matter what kind of formulation or stabilization method is chosen, excipients of some kind will be involved. Each has at least one function, and synergistic effects are to be expected. The compound will behave most like its principal constituent. A combination may behave differently than planned, so formulation scientists can spend a lot of time empirically testing the ingredients in combination. Interactions are important: they can make the difference between a formulation that works and one that doesn't. Each ingredient added can change the behavior of the whole mixture.

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