Chemistry Reference
In-Depth Information
framework such as QbD, and an adequate attention to every step, the risks become more
than manageable.
11.1.2 Creating an Amorphous Drug Substance
The most common groups of techniques for amorphization (to use an admittedly
awkward term of art) are melting techniques and solvent evaporation techniques.
Each group has its strengths and weaknesses.
For melting techniques such as hot melt extrusion (HME) [12,13], spray congeal-
ing [14,15], and melt agglomeration [16
18], two considerations predominate. First, the
active pharmaceutical ingredient (API) needs to be thermostable enough to survive the
temperatures involved, and second, the API has to be miscible in the polymer matrix with
which it is co-melted. (Choice of polymers is, of course, also limited by the same
consideration for thermostability.) On the up side, melting techniques are less expensive
than solvent evaporation approaches, the instruments involved have a smaller footprint,
and the approach lends itself well to being one stage of a continuous process. As attention
in the pharmaceutical
-
ciency of
continuous over batch processing for drug product manufacture [19,20], the latter
may prove an advantage.
One common melting technique is hot melt extrusion. In this approach, the drug
compound and a polymer are added to the HME device. (A surfactant may be added too,
if needed, to improve the bioavailability downstream. Adding a surfactant also lowers the
melting point, since it acts as an impurity in the crystalline drug; this may be useful for
high-melting APIs.) Heat is applied as the mixture is agitated by twin screws that shear it,
mix it, convey it, and ultimately extrude it from the device. The resulting material is often
quite dense, which may make the later process of compressing it into tablets relatively
more dif
industry increasingly turns to the speed and ef
cult. To reduce the density, two additional steps are often followed: the
extrudate may be milled, mixed with a more compressible substance (e.g., lactose and
methylcellulose), or both.
Vis-à-vis
solvent evaporation methods (see below), HME affords more
flexibility in
choosing a downstream dosage form; on the other hand, the need to add a
filler such as
lactose to increase compressibility represents an extra step of production. With respect to
other melting methods—the most common being melt agglomeration—HME has the
advantage of being the only technique used in formulation development that is also
scalable to clinical and commercial manufacture.
One solvent evaporation method is spray drying [21
23]. In spray drying, the API
is solubilized in organic solvents (also aqueous or a mixture) that have relatively low
boiling temperatures. At a temperature above the solvent
-
'
s (or solvents
'
) boiling point
(or points), the material is sprayed through a high-pressure or two-
uid nozzle and
collected. Because the solvents used are generally organic (particularly to take
advantage of low boiling points), the process is geared toward lipophilic APIs, which
are also, of course, those most in need of being rendered water soluble. The resulting
dispersion not only is soluble, but also can be stabilized
—
that is, made more resistant
to recrystallization
—
by the addition of polymers (e.g., methylcellulose, polyvinyl-
pyrrolidone, etc.).
