In the early stage of drug development a vast number of new chemical compounds frequently are synthesized, often using pioneering chemistry at considerable effort and expense in order to supply various preclinical test programs with raw material. It is easy to perceive that these newly synthesized materials may appear in both extremely limited quantities and in forms which are difficult to handle. It is therefore a demand to bring such raw drug candidates into a manageable form more adapted to the models already developed for making the initial necessary steps to study their characteristics. A number of general requirements may already generally be set on such a methodology for improving the manageability. The methodology shall increase the dissolution rate of the compound, preferably in an aqueous system. The methodology shall admit low process losses, it shall preferably be operable at ambient temperature and it shall result in a highly defined form of the compound.
A very desirable preclinical model is represented by systems arranging inhalation exposures both for outlining the suitability of drug candidates for pulmonary delivery and for studying clinical and toxicological effects. A suitable such exposure system employing an aerosolized drug candidate is described in the Swedish Patent application No. 0701569-6, while a target pulmonary model is described in U.S. Patent Application No. 60/934,070 and a useful aerosolizing device is described in U.S. Pat. No. 6,003,512. Together, this technology, hereinafter referred to as the dustgun technology, provides a powerful tool in drug development capable of handling low amounts of powdered compound, i.e. in the mg scale. Yet, this technology, allowing an effective deagglomeration of powders, still require a substrate particle size that is smaller or equal to the desired particle size distribution of the generated aerosols. There are several methods available to provide the dustgun system with powders fine enough to allow generation of respirable aerosols including milling, spray drying and supercritical spray drying. Of these methods, conventional spray drying is the one that has the potential to allow production of very small batches of powder with yields high enough for use with very expensive drug candidates. In milling procedures there are too large losses to the vessel walls and for supercritical spray drying the adjustment of the relatively complicated process tend to consume too much substance before a sufficient quality and quantity of the materials have been obtained.
Even with conventional spray drying systems, commercial as well as custom made ones (Lädhe et al., 2006), the production goal is usually in the scale of grams and upward. This is too much for being optimal for the early synthesis steps in preclinical development. To be optimal for utilizing the dustgun system in early drug development a suitable quantity for powder formulation in a spray dryer system would be in the range of 20-100 mg. With such a small production goal it is possible to reach one important advantage over higher capacity system: to remove most of the solvent vapors from the aerosol stream in the drying column before the particles are separated. Most commercial systems with higher production goals rely on using heated drying gas to quickly evaporate the solvent from the particles before separation of particles from the process stream using filters or cyclones (Lädhe et al., 2006). However, the high volumetric flow rate through the apparatuses is unsuitable for production goals around 100 mg. Already at higher production goals the product yield of cyclones is usually considerably lower than 60% (Prinn et al., 2002; Maury et al., 2005). The removal of solvent vapors before direct use of the resulting aerosol for inhalation exposures has been previously described (Pham and Wiedmann, 1999; Wiedmann and Ravichandran, 2001). These systems have relied on diffusional drying by passing the process aerosol through a column with vapor-absorptive material accessible through the perforated walls of the drying column. The draw backs of this system are the complicated method by which the absorptive pellets of the drying column regularly must be changed, and the fact that the absorptive material will be contaminated with the dried substances. Countercurrent drying is commonly used in the food industry for manufacturing of for example powdered milk. However in these examples the product particles are dried by gravitational settling within the ascending dry air stream (Piatkowski and Zbicinski, 2007). The settling rate of the particles must then be on the order of 10 cm/sec, which limit production to particles >50 μm. This countercurrent method cannot be used for pharmaceutical agents with a desired product particle size of <5 μm, where settling speeds are in the range of mm/min. Accordingly, there is need for a spray drying system and system that is adapted for obtaining small quantities of suitably manageable formulation of drug candidates in the form of dry, near solvent free powder, especially a powder with particle size in the range of 1-5 suitable for generating respirable aerosols with the dustgun technology.
The present invention as it is described in the following section aims at providing a dry, solvent free powder from small amounts of raw, freshly synthesized chemical compounds suitable for aerosol generation, but also potentially useful for a number other applications also outside the context of drug development.