Chemistry Reference
In-Depth Information
solvent to form an amorphous state and the limited exposure of an API to heat that may
cause degradation. In contrast, spray drying is limited by feed solution viscosity that must
be low enough to be pumped through the spray nozzle. If a high-viscosity polymer is
required to obtain the desired drug release pro
le or supersaturation enhancement, it will
not be viable for spray drying. In addition, the solvent selection should be such that the
vaporization temperature is at least 10
°
C below the
T
g
to ensure the stable formation of
an ASD [87].
The other industrial process for producing amorphous dispersions is HME, a
technique that is covered in detail in Chapter 10 and has been extensively covered in
the literature [86]. Amorphous solid dispersions are created via a process of injecting a
mixture of polymer and drug into one or two rotating screws under elevated tempera-
tures. The con
guration and rotation of the screws combined with the elevated
temperatures create a
fluid state that homogeneously mixes the starting materials and
passes the resulting mixture through a die to create a uniform extrudate. The
nal
extrudate can be molded or cut into precise dosage forms or sized for encapsulation or
pressed into a pellet. HME is advantageous over spray drying in that it is a solvent-free
process and does not require additional processing of the extrudate. However, HME is
limited by the melt viscosity of the polymer used and the high temperatures and sheer
rates that the process utilizes, which can cause degradation of both the polymer and the
drug [86]. Recent advances in the HME technology have resulted in KinetiSol technol-
ogy in which rotating blades produce enough kinetic and thermal energy that additional
heat sources are not utilized [88],
thus mitigating the thermal degradation issues
traditionally associated with HME.
2.4.3 Polymer Selection
Despite the robust understanding of the physical properties of drug compounds and
carrier agents used for amorphous solid dispersions and the processing parameters of the
method used to create amorphous solid dispersions, the choice of carrier agent is
serendipitous. One advantage of using a carrier agent with a drug compound is that
the carrier agent can provide stabilization to a supersaturated solution and prevent
crystallization of the drug upon dissolution of the ASD. Recently, the precipitation
inhibition of polymers as a key performance marker to identify trends in performance
with different classes of drug compounds was reported. In the study, the precipitation
inhibition from supersaturated solutions for 42 different classes of polymers covering a
range of grades and molecular weights for 78 total polymers was tested with nine
different poorly soluble drugs [89]. The drugs were selected to represent three major drug
categories: nonelectrolytes, weak acids, and weak bases. To analyze the vast array of
polymers and drugs tested, principal component analysis was applied to the experimental
results. In general, cellulose-based polymers (particularly HPMC and its derivatives)
provided robust precipitation inhibition across the range of drugs tested [89]. In addition,
it was found that polymers with primary amine functional groups enhanced precipitation
rates and polymer molecular weight has only a minor in
uence on the precipitation
inhibition of the polymer. Furthermore, polymers with the opposite charge of the drug
provided additional stabilization through ionic interactions [89].
