No abstract

Drug solubility screening in solvents and lipids is central for the development of lipid-based formulations (LBFs), and any guidance to reduce the experimental workload would be highly desirable. Solubility parameters are interesting as they can be predicted in silico for a drug but they are hardly predictable for complex lipids. This paper uses a new approach to convert an in silico drug solubility parameter to an estimated relative permittivity, ε r. Diverse solvents and lipid-based excipients were then experimentally tested for ε r and solubility using fenofibrate as model. The typical excipients and solvents used in LBFs showed an ε r range of about 2-24, and good solubility of fenofibrate was indeed evidenced in vicinity of its estimated relative permittivity 13.2 ± 2.7. Mixtures of promising excipients were studied subsequently, and the obtained ε r was predictable based on the known values of the individual components. The novel permittivity approach has demonstrated its usefulness, it has much potential in early development for ranking of suitable excipients, and it gives an initial orientation to design formulations. Future research may clarify further opportunities and limits of the novel approach for LBFs.

The aim of this study was to improve the storage stability by optimizing the L-leucine coating of our previously described isoniazid formulation for pulmonary administration with the TwincerÒ or CyclopsÒ DPI. Time-of-Flight secondary ion mass spectrometry (TOF-SIMS) showed that trileucine results in higher leucine: isoniazid ratios of 29 and 38 at the surface of the particles, compared to the previously described L-leucine formulation, which has surface ratios of 11 and 28. The trileucine coating improves the stability considerably. All L-leucine formulations are stable for less than a day with the exception for the 3% and 5% formulations spray dried at 120°C and stored at 0% relative humidity (RH), which are stable for at least a month. The trileucine formulations are stable longer. The optimum formulation contains 3% trileucine and is spray dried at 40°C. It is stable for at least three months, even when exposed to 75% RH. This formulation is best dispersed with the CyclopsÒ. While the TwincerÒ results in a higher fine particle fraction (FPF), retention is considerably higher. As a result, the CyclopsÒ results in a higher fine particle dose. The CyclopsÒ can disperse 100 mg, which results in a fine particle dose of 61.9 -1.8 mg. However, 100 mg was the maximum that fit in the inhaler. Further research is needed to study whether a higher dose can be dispersed by increasing the size of the dose compartment, and if this increases the fine particle dose further.