Category: Formulation and Quality
Purpose: A significant number of new drug candidates have poor aqueous solubility which can limit absorption and bioperformance. Amorphous solid dispersions, where the amorphous phase of a drug solid is stabilized with a polymer, represent a highly effective formulation approach to help improve the solubility and delivery of these compounds. There are several approaches for preparing amorphous solid dispersions; hot melt extrusion (HME) and spray drying are the most commonly used to manufacture commercial drug products. Small scale spray dryers and associated screening approaches exist but require solubility in a volatile organic solvent. HME does not employ solvents and can be used directly on powder blends. However, HME requires significant amounts of material ( >10 grams) and, as a result, is difficult to implement in the early stages of discovery and preclinical development. This presentation will describe a new method using heated resonant acoustic mixing called acoustic fusion to provide an analogous approach to standard hot melt extrusion, which generates amorphous dispersions on the milligram scale.
Methods: Resonant acoustic mixing has emerged as a powerful method for mixing substances, including highly viscous solids. We envisioned that acoustic mixing a sample of drug and polymer solid, while concurrently heating above their glass transition or melting point temperatures, would sufficiently mix the materials to form a homogenous amorphous solid dispersion. To enable this, we designed and fabricated a 24-well heating block assembly that can be attached to the Resodyn Labram resonant acoustic benchtop mixer. This heating block can be heated up to 200 °C and can contain up to 24 glass vials that can be loaded with drug and polymer solid material. In a process we have termed acoustic fusion, we have demonstrated that when glass vials are loaded with drug and polymer solids in scales from 10 – 2000 mg, they can be subjected to up to 100 G’s of mixing intensity while heated up to 200 °C. The drug and polymer fuse to form amorphous glassy solids after 15 – 30 min of mixing time. The glassy solids containing drug dispersed within the polymer matrix were characterized as homogeneous amorphous materials by DSC and X-ray diffraction.
Results: Several different drug and polymer systems have been successfully evaluated using the acoustic fusion approach suggesting that it is a general process that can be used for drug formulations. We have demonstrated this with amorphous formulations of multiple drug candidates (including Lopinavir, Itraconazole, Torcetrapib, etc.), with different polymer systems, including Soluplus, Vit-E TPGS, PEG-1500, Eudragit, HPMCAS, Cremophor EL, and copovidone. These formulations exhibit substantially enhanced solubility of the amorphous drug compared to its original crystalline form, which is highly desirable for absorption in vivo.
Formulations using the model drug Torcetrapib in either Soluplus, Vit-E TPGS + copovidone, or HPMCAS-L were found to have improved in vitro supersaturation solubility in aqueous media compared to the crystalline free drug material, suggesting that the compound was incorporated as an amorphous material in the formulations. The formulations were also tested in vivo in a rat pharmacokinetic study at a dose of 10 mg/kg. Improved absorption of up to 8-fold greater exposures by AUC0-24 were observed with these formulations compared to a suspension of the crystalline material, validating the capability of these formulations for improving bioperformance.
Conclusion: Amorphous solid dispersions can be prepared by the acoustic fusion process. This enables the preparation of amorphous drug formulations at scales sufficient to support preclinical studies, at a minimum of only a few mg of drug with an appropriate amount of polymer. This approach does not require solvent and can be used for drugs or polymers that are insoluble in volatile organic solvents typically employed in spray drying or solvent casting. In addition, the acoustic fusion process has been developed as a high throughput technique and can accommodate multiple samples in parallel. As a result, this can be used to rapidly screen hot melt extrusion formulations for later stage development.
Zack Guo– Rahway, New Jersey
Zack Guo– Rahway, New Jersey
Christopher Boyce– West Point, Pennsylvania
Dennis Leung– Genentech, Inc., South San Francisco, California
Timothy Rhodes– Rahway, New Jersey
Annette Bak– Head of Advanced Drug Delivery, AstraZeneca, Mölndal, Vastra Gotaland, Sweden
Lina Liu– Senior Scientist, Merck & Co, Inc, Rahway, New Jersey
Keun-joong Lee– Rahway, New Jersey
Gino Salituro– Rahway, New Jersey
Zhiqiang Guo– Associate Principal Scientist, Merck and Co Inc, Rahway, NJ