Leaching of Lopinavir Amorphous Solid Dispersions in Acidic Media
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Amorphous solid dispersions (ASDs) formulated with acid-insoluble (enteric) polymers form suspensions in acidic media where the polymer is largely insoluble. However, a small amount of drug can dissolve and a supersaturated solution may be generated. The goal of this study was to gain insight into the leaching mechanisms of both drug and polymer from the suspended particles, studying the impact of solution additives such as surfactants.
ASDs were prepared by spray drying lopinavir (LPV) with an enteric polymer, either hydroxypropylmethylcellulose acetate succinate (HPMCAS) or hydroxypropylmethylcellulose phthalate (HPMCP). Four surfactants and a suspending agent were added to the liquid media to evaluate the effect of these excipients on leaching. pH 3 and pH 5 buffers were used to investigate the effect of pH.
The extent of drug leaching from the amorphous formulation was proportional to the crystalline solubility of the drug in the same medium. All surfactants promoted solubilization of LPV with the exception of poloxamer and sodium dodecyl sulfate-HPMCP combinations. A small amount of polymer ionization significantly enhanced LPV leaching in solutions containing an ionic surfactant.
The mechanism of enhanced leaching appeared to be solubilization, with the apparent supersaturation remaining the same for systems containing the same polymer.
KEY WORDSamorphous suspensions leaching solubilization surfactants
Amorphous solid dispersion
Critical aggregation concentration
Critical micelle concentration
High performance liquid chromatography
Hydroxypropylmethylcellulose (hypromellose) acetate succinate
Limit of detection
Limit of quantitation
Sodium dodecyl sulfate
ACKNOWLEDGMENTS AND DISCLOSURES
The authors gratefully thank Merck & Co. for providing financial support for this study. We would like to acknowledge John Higgins, Mike Lowinger, Annette Bak, Nicole Buist and Pete Wuelfing for scientific support and guidance.
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