The LF
CS Consortium was established to develop standardized
in vitro tests for lipid-based formulations (LBFs) and to examine the utility of these tests to probe the fundamental me
chanisms that underlie LBF performan
ce. In this publi
cation, the impa
ct of bile salt (sodium taurodeoxy
cholate, NaTDC)
con
centration and drug loading on the ability of a range of representative LBFs to generate and sustain drug solubilization and supersaturation during
in vitro digestion testing has been explored and a
common driver of the potential for drug pre
cipitation identified. Danazol was used as a model poorly water-soluble drug throughout. In general, in
creasing NaTDC
con
centrations in
creased the digestion of the most lipophili
c LBFs and promoted lipid (and drug) traffi
cking from poorly dispersed oil phases to the aqueous
colloidal phase (AP
DIGEST). High NaTDC
con
centrations showed some
capa
city to redu
ce drug pre
cipitation, although, at NaTDC
con
centrations 鈮? mM, NaTDC effe
cts on either digestion or drug solubilization were modest. In
contrast, in
creasing drug load had a marked impa
ct on drug solubilization. For LBFs
containing long-
chain lipids, drug pre
cipitation was limited even at drug loads approa
ching saturation in the formulation and
con
centrations of solubilized drug in AP
DIGEST in
creased with in
creased drug load. For LBFs
containing medium-
chain lipids, however, signifi
cant pre
cipitation was evident, espe
cially at higher drug loads. A
cross all formulations a remarkably
consistent trend emerged su
ch that the likelihood of pre
cipitation was almost entirely dependent on the maximum supersaturation ratio (SR
M) attained on initiation of digestion. SR
M defines the supersaturation 鈥減ressure鈥?in the system and is
cal
culated from the maximum attainable
con
centration in the AP
DIGEST (assuming zero pre
cipitation), divided by the solubility of the drug in the
colloidal phases formed post digestion. For LBFs where phase separation of oil phases did not o
ccur, a threshold value for SR
M was evident, regardless of formulation
composition and drug solubilization redu
ced markedly above SR
M > 2.5. The threshold SR
M may prove to be an effe
ctive tool in dis
criminating between LBFs based on performan
ce.
Keywords:
cs.org/action/doSearch?action=search&searchText=poorly+water%5C-soluble+drug&qsSearchArea=searchText">poorly water-soluble drug; cs.org/action/doSearch?action=search&searchText=LFCS+Consortium&qsSearchArea=searchText">LFCS Consortium; cs.org/action/doSearch?action=search&searchText=lipid%5C-based+drug+delivery+systems&qsSearchArea=searchText">lipid-based drug delivery systems; cs.org/action/doSearch?action=search&searchText=SEDDS&qsSearchArea=searchText">SEDDS; cs.org/action/doSearch?action=search&searchText=drug+solubilization&qsSearchArea=searchText">drug solubilization; cs.org/action/doSearch?action=search&searchText=in+vitro+digestion+testing&qsSearchArea=searchText">in vitro digestion testing; cs.org/action/doSearch?action=search&searchText=solubility&qsSearchArea=searchText">solubility; cs.org/action/doSearch?action=search&searchText=bioavailability&qsSearchArea=searchText">bioavailability; cs.org/action/doSearch?action=search&searchText=in+vitro+models&qsSearchArea=searchText">in vitro models; cs.org/action/doSearch?action=search&searchText=precipitation&qsSearchArea=searchText">precipitation; cs.org/action/doSearch?action=search&searchText=supersaturation&qsSearchArea=searchText">supersaturation