28 research outputs found
Influence of Polymer and Drug Loading on the Release Profile and Membrane Transport of Telaprevir
During the dissolution of amorphous
solid dispersions (ASDs), various
phase transformations can occur, which will ultimately impact the
degree of supersaturation. This study employed dissolution and diffusion
measurements to compare the performance of various ASD formulations
based on the maximum amount of free drug in the solution that was
able to permeate through a cellulose-based membrane. Telaprevir (TPV)
was used as the model drug compound, and ASDs were prepared with different
drug loadings and with four different polymers. Four possible scenarios
that can influence TPV mass flow rates upon ASD dissolution were described
and supported with experimental data: (1) a system dissolves readily
and completely undergoes phase separation via glass–liquid
phase separation (GLPS), forming drug-rich aggregates, and reaches
the maximum anticipated mass flow rate; (2) where the maximum mass
flow rate decreases due to substantial mixing of the polymer into
the drug-rich phase, and/or due to the formation of soluble polymer–drug
complexes; (3) a system does not undergo GLPS due to slow drug release
and/or matrix crystallization; and (4) a system does not undergo GLPS
due to rapid crystallization from the supersaturated solution generated
during dissolution. The results described herein support the importance
of the combined use of the dissolution–diffusion measurements
to determine the maximum level of supersaturation achievable for diverse
drug formulations
A Comparison of the Crystallization Inhibition Properties of Bile Salts
Bile salts are natural surfactants
present in the human gastrointestinal tract. Therefore, it is essential
to consider their effect on the dissolution and crystallization tendency
of oral drug formulations. Although a recent study showed that sodium
taurocholate delayed nucleation for 11 structurally diverse compounds,
there is limited information about the crystallization inhibition
properties of other bile salts and whether they are interchangeable
in this context. In this study, we evaluated the ability of 13 bile
salts to maintain supersaturated aqueous solutions of three compounds:
celecoxib, nevirapine, and fibanserin. Most bile salts extended nucleation
induction times. However, their inhibitory effects varied depending
on the structure and concentration of the bile salt and the drug.
The R5 group and hydrophobicity of the bile salt appeared to be essential.
Molecular dynamics simulations indicated that van der Waals and hydrogen
bonding interactions occurred between nevirapine and bile salts, with
variations in different systems. These results are important to better
understand the crystallization tendency of orally delivered poorly
water-soluble compounds in vivo