HighlightsSimulated use of dapivirine VRs showed no content changes after storage at RT or −20 °C.On average, about 4 mg of dapivirine is released in vivo after 28 days of VR use.Both in vivo and in vitro drug release conform to the Higuchi equation.Residual ring data should be used in conjunction with other PK measures for modeling adherence.
A new approach to the synthesis of 1 (DS003, BMS-599793),
a small-molecule HIV entry inhibitor, is described. The initial medical
chemistry route has been modified by rearranging the sequence of synthetic
steps followed by replacement of the Suzuki coupling step by the Negishi
conditions. Acylation of the resulting azaindole 7 under
the Friedel–Crafts conditions is studied using monoesters of
chlorooxalic acid in the presence of aluminum chloride. Polymorphism
of 1 is also investigated to develop conditions suitable
for preparation of the desired Form 1 of the target compound.
The new route is further optimized and scaled up to establish a new
process that is applied to the synthesis of kilogram quantites of
the target active pharmaceutical ingredient.
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