ABSTRACT
PURPOSE: To evaluate the role of polymer-surfactant interactions in drug solubilisation/stabilisation during the dissolution of spray-dried solid dispersions and their potential impact on in vivo drug solubilisation and absorption. METHODS: Dissolution/precipitation tests were performed on spray-dried HPMC-Etravirine solid dispersions to demonstrate the impact of different surfactants on the in vitro performance of the solid dispersions. Interactions between HPMC and bio-relevant and model anionic surfactants (bile salts and SDS respectively) were further characterised using surface tension measurements, fluorescence spectroscopy, DLS and SANS. RESULTS: Fast and complete dissolution was observed in media containing anionic surfactants with no drug recrystallisation within 4 h. The CMCs of bile salts and SDS were dramatically reduced to lower CACs in the presence of HPMC and Etravirine. The maximum increases of the apparent solubility of Etravirine were with the presence of HPMC and SDS/bile salts. The SANS and DLS results indicated the formation of HPMC-SDS/bile salts complexes which encapsulated/solubilised the drug. CONCLUSIONS: This study has demonstrated the impact HPMC-anionic surfactant interactions have during the dissolution of non-ionic hydrophilic polymer based solid dispersions and has highlighted the potential relevance of this to a fuller understanding of drug solubilisation/stabilisation in vivo.
Subject(s)
Anti-HIV Agents/administration & dosage , Lactose/analogs & derivatives , Methylcellulose/analogs & derivatives , Pharmaceutical Vehicles/chemistry , Pyridazines/administration & dosage , Surface-Active Agents/chemistry , Anti-HIV Agents/chemistry , Bile Acids and Salts/chemistry , Chemical Precipitation , Drug Stability , Lactose/chemistry , Methylcellulose/chemistry , Micelles , Nitriles , Polysorbates/chemistry , Pyridazines/chemistry , Pyrimidines , Sodium Dodecyl Sulfate/chemistry , SolubilityABSTRACT
Solid dispersion technology represents an enabling approach to formulate poorly water-soluble drugs. While providing for a potentially increased oral bioavailability secondary to an increased drug dissolution rate, amorphous dispersions can be limited by their physical stability. The ability to assess formulation risk in this regard early in development programs can not only help in guiding development strategies but can also point to critical design elements in the configuration of the dosage form. Based on experience with a recently approved solid dispersion-based product, Intelence® (etravirine), a three part strategy is suggested to predict early formulate-ability of these systems. The components include an assessment of the amorphous form, a study of binary drug/carrier cast films and the evaluation of a powder of the drug and polymer processed in a manner relevant to the intended final dosage form. A variety of thermoanalytical, spectroscopic, and spectrophotometric approaches were applied to study the prepared materials. The data suggest a correlation between the glass forming ability and stability of the amorphous drug and the nature of the final formulation. Cast films can provide early information on miscibility and stabilization and assessment of processed powders can help define requirements and identify issues with potential final formulations.
Subject(s)
Pyridazines/chemistry , Reverse Transcriptase Inhibitors/chemistry , Technology, Pharmaceutical , Chemical Phenomena , Chemistry, Pharmaceutical , Drug Carriers/administration & dosage , Drug Carriers/chemistry , Drug Stability , Microchemistry/methods , Nanospheres/chemistry , Nanospheres/ultrastructure , Nitriles , Polymers/chemistry , Powders , Pyridazines/administration & dosage , Pyrimidines , Reverse Transcriptase Inhibitors/administration & dosage , Solubility , SuspensionsABSTRACT
The objective of this case study of the single-droplet drying of two itraconazole/polymer formulations was to determine how the solvent system influences drying rate and dried particle morphology. A clear dual functionality of the two solutes could be identified. The polymeric component (PVP or HPMC) determined drying rate, whereas the drug determined end particle morphology. This could be related to solubilities of the two components in the binary solvent mixtures used. The formulation of a surface skin early on in drying only occurred with HPMC and strongly influenced drying rate but not dried particle morphology.
