Chemistry Reference
In-Depth Information
microenvironmental pH of the drug to enhance the dissolution rate of the drug. Basic
pH modi
ers (sodium carbonate, sodium hydroxide, magnesium oxide, and calcium
carbonate) were screened with
five polymers to produce ternary dispersions with
improved dissolution properties. A dispersion containing 2:0.5:3 API:PVP K30:sodium
carbonate was chosen for an animal study in rats based on characterization, solubility,
and dissolution data. The dispersion exhibited substantially better performance than
the marketed dosage form with a
C
max
increase of 6.4-fold and an AUC improvement of
2.1-fold.
Cyclodextrins have been used to complex the API to improve solubility and are
being incorporated into amorphous solid dispersions as binary systems with the
API [44,45] or ternary systems with other components such as polymers [46]. It should
be recognized that these types of systems employ complexation with the cyclodextrins,
which is a different method of supersaturation compared with dispersions made with
polymers. Improved performance such as dissolution rate and blood levels has been
shown with these more complex cyclodextrin systems [46], but additional characteriza-
tion data may be needed to understand the mechanism of the enhancement. For early
studies, these more complicated systems may be a second tier of screening if more simple
binary systems have not produced the desired properties.
Lipids have also been added to dispersions to enhance supersaturation by producing
micelles [47,48]. Examples of lipids used in amorphous solid dispersion systems include
Gelucire
, Vitamin E TPGS (
D
-
-tocopheryl polyethylene glycol 1000 succinate), and
phosphatidylcholine. The ability to supersaturate solutions is due to formation of lipid
vesicles that trap a certain amount of drug and enable it to stay in solution. It is also
important to understand the nature of any interactions between the polymer and the lipid
in these ternary dispersions. In one study, it was found that different lipids were
incorporated into the PEG 4000 structure in different ways [49]. Small hydrophilic
lipids were found to increase the folding of PEG, while large nonpolar lipids retarded the
unfolding during secondary crystallization, resulting in different crystalline regions in
the polymer that could ultimately affect the physical stability of an amorphous solid
dispersion.
Small molecules, such as amino acids, have also been used in place of polymers in
binary systems [50,51] or with polymers to form ternary systems [46,52]. Binary co-
amorphous drug
α
amino acid mixtures have been shown to stabilize the
amorphous form and increase the dissolution due to molecular interactions between
the components [50,51]. Further work is needed to determine how this concept will
translate to a wide range of drug molecules, but it does offer another avenue for
dispersion formation.
-
drug or drug
-
The desired composition of a
dispersion is based on (1) miscibility, (2) the extent of antiplasticization needed (
T
g
), and
(3) impact on dissolution rate and supersaturation levels. In early development and
screening, limited information will be available on these aspects. Once the solvents,
polymers, and possible surfactants to be used are determined, other factors need to be
considered when setting up the screening experiments. One important consideration is
the amount of polymer needed to maintain physical stability. It has been shown that
3.2.2.3 Amorphous Dispersion Composition
