Chemistry Reference
In-Depth Information
consider what is known about the crystallization inhibitory effect of such additives.
Polymers have been shown to decrease the crystallization tendency of amorphous APIs
with explanations for their stabilizing ability including, reduction of molecular mobil-
ity [79,80], disruption of drug
-
drug interactions [81], and formation of speci
c polymer
-
drug interactions [81
83], while others have considered the effectiveness in the context
of the crystallization tendency of the pure amorphous drug [84
-
86]. Each of these
mechanisms will be discussed subsequently; however, it is apparent from the preceding
discussions that crystallization is a complex phenomenon and it is unlikely that the
stabilizing impact of a polymer can be attributed to a single mechanism.
Many polymers, including most of those used in amorphous solid dispersion
formulations, have high glass transition temperatures, typically greater than 100
°
C.
The
T
g
of the drug is on the order of 2/3
T
m
(in Kelvin), and therefore drug
T
g
values
typically range from about
45
-
C (ibuprofen,
T
m
of 77
C) [87] to greater than 100
C
°
°
°
(e.g., telaprevir with a
T
g
of 105
C [88]). Therefore, if a
higher
T
g
polymer is combined with a drug with a lower
T
g
, the addition of a polymer can
act as an antiplasticizer, decreasing the molecular mobility of the amorphous drug and
restricting drug molecules from ordering to form stable nuclei, thus reducing the
crystallization tendency. Thus, it would be anticipated that increasing the polymer
MW, which will both increase
T
g
and decrease free volume, will result in more effective
crystallization inhibition. In an investigation of the ability of various MW grades of PVP
to inhibit the crystallization of a model compound MK-059, it was indeed observed that
the crystallization inhibition (as judged from the size of the crystallization exotherm and
onset of crystallization measured by DSC) increased with polymer MW [82]. From a
theoretical perspective, the higher MW PVP contains fewer chain ends with decreased
motion of the main chains, and thus should decrease the free volume and molecular
mobility. These observations reinforce that decreasing the molecular mobility through
the addition of a polymer can signi
C and a melting point of 246
°
°
cantly decrease the crystallization tendency of the
pure amorphous drug.
Speci
c interactions between the polymer and the drug also appear to be important
in in
uencing the crystallization tendency from the amorphous state. Fourier transform
infrared (FTIR) and Raman spectroscopy were used to show that indomethacin and
PVP interacted through intermolecular hydrogen bonding in solid dispersions prepared
by solvent evaporation [81]. It was postulated that drug-polymer hydrogen bonding
interactions were important for stabilizing amorphous indomethacin by disrupting
the self-association of indomethacin dimers, even at low polymer concentrations where
the antiplasticizing effect of the polymer is minimal. For indomethacin, the dimeric
interactions are critical to achieve the hydrogen bonding patterns present in the prevalent
polymorphic forms. Thus, disruption of dimer
dimer interactions by the polymer
prevents self-association of the drug molecules into the local structure found in the
crystal. In a different study, the ability of two polymers (PVP, MW
-
40,000, and
=
polyacrylic acid (PAA), MW
25,000) to inhibit crystallization of amorphous acet-
aminophen in solid dispersions prepared by melt quenching was investigated [76].
Following observations that PAA
=
drug solid dispersions exhibited much longer crys-
tallization times compared with PVP
-
drug solid dispersions, it was speculated that this
difference was caused by a stronger interaction between the carboxylic acid group on
-
