Chemistry Reference
In-Depth Information
below the
T
g
, it rapidly converted to the crystalline material [44]. The next screening
component for the development of a dispersion was assessing the behavior of cast
films.
Screening experiments suggested that HPMC would be a useful glassy matrix and was
used at various ratios with the API. Data for the API:HPMC (1:3)
films were generated to
assess the effect of temperature (below the
T
g
) on the extent of enthalpic relaxation. At
45
C below
T
g
, the amorphous material relaxes only a few percent over the time course
of the experiment, while the most activated conditions (25
°
C below
T
g
) provide for
°
∼
20% relaxation. The companion data give the occurrence and increase of crystalline
content over time at three conditions: at the
T
g
and at 10 and 25
C above the
T
g
.By
assessing temperatures at or above the
T
g
, crystallization can theoretically be discon-
nected from relaxation. The least aggressive condition shows a signi
°
cant induction time
and a small increase in crystalline content such that 4
5% could be detected by the end of
the experiment. The induction time decreases and the
-
final crystalline content increases
as the temperature increases as would be expected. Importantly, the pure, unformulated
amorphous phase underwent signi
cant crystallization within 4 h at 30
C below the
T
g
°
emphasizing the stabilizing effect of the polymeric dispersion [44].
Clinical trial formulations were generated for etravirine using three concepts, all of
which were predicated on the use of the amorphous phase [43]. The formulations
included a microcrystalline cellulose (MCC) bead onto which was coated a dispersion of
the API and HPMC, a tablet derived from an amorphous granulo-layered powder in
which API:HPMC was processed in a
fluid bed with lactose serving as the carrier and a
tablet based on a spray-dried dispersion containing HMPC, API, and other excipients.
The spray-dried powder was densi
ed by compaction, subjected to postdispersion
drying, blended with other tableting excipients, and compressed into tablets. In all
cases, the API was rendered amorphous and the dispersions were stable on storage.
While the granulo-layered system was slightly better than the bead-based formulation in
terms of oral bioavailability, the spray-dried system was almost ninefold more bio-
available relative to the coated beads (Figure 8.6). This increase in oral bioavailability
meant that the pill burden could be dramatically reduced and was enabling the product
from a compliance and commercial point of view [43]. Intelence was approved as a
100 mg tablet in 2008 with a 200 mg tablet, also based on a spray-dried dispersion, being
introduced to the market in 2010.
New technologies for the configuration of dispersions are emerging and these often
require optimized or improved
in vitro
or
in vivo
testing protocols to assess their possible
usefulness. An important recent example is associated with the marketed solid dispersion
for vemurafenib (Zelboraf
), a useful B-RAF inhibitor used in the treatment of
melanoma [105
107]. Formulation of vemurafenib is complicated by its API properties:
high melting point (272
-
3), and extremely poor water solubil-
ity [108]. In addition, the solvents that provide for useful solubility were high boiling,
including DMA or DMSO. These properties eliminated spray drying and melt-based
approaches for the preparation of a dispersion. The concept that was ultimately selected
was a polymer-stabilized solid amorphous dispersion using solvent-controlled copreci-
pitation [108]. In this approach, the drug and an enteric (ionic) polymer are dissolved in a
common (high-boiling) solvent and then introduced into a cooled acidic or basic aqueous
medium generating a microprecipitated bulk powder (MBP) [109,110]. The solubility
C), moderate log
P
(
∼
°
