Overcoming solubility problems –
a convenient way

Poor solubility of drugs is a challenge in drug formulation. This article introduces a simple formulation technology to make poorly soluble drugs intravenously injectable. It uses only accepted excipients and existing large scale production lines in industry.

A commonly known task in pharmaceutical companies is overcoming solubility problems. Especially since a large number of drugs coming directly from synthesis or from high throughput screenings have a very poor solubility. Also quite a number of biotech drugs show poor solubility. Estimates say that in the future an even increased number will be poorly soluble both in aqueous and non aqeuous media and thus may lead to poor bioavailability, and of course challenges in developing the right formulation. There are several ways to overcome the solubility obstacles, for instance the use of organic solvents, encapsulation in liposomes or other “carriers”, or formation of salts or other soluble derivatives. However all these approaches entail several new problems. Often the technology in use is only applicable to a limited number of drugs or, even worse, is a unique solution. Other difficulties are that the organic solvent residue has to be completely removed, carriers are difficult to produce and these ways are just expensive.

Furthermore using a completely new and unique formulation approach might lead to regulatory hurdles and will almost certainly lead to higher costs for reg affairs. An ideal technology would therefore have to be:
-universally applicable to all kinds of drugs or at least to a wide range of drugs,
-easily applicable to the specific situation (e.g. without great technical efforts, realisable in a short time without a vast amount of manpower and easily transferable to the production scale),
-cost effective and
-with little or no regulatory hurdles.
Technology description
The SolEmuls technology recently developed by Mueller et al. provides the benefits stated before with little or without the stated problems [1]. In principal the technology places the poorly soluble drug directly within the interfacial lecithin layer of commercially readily available emulsions by means of high pressure homogenization. The SolEmuls process is very simple. Drug powder is dispersed in a lecithin-stabilized o/w emulsion (e.g. Intralipid, Lipofundin) and this hybrid dispersion is homogenized. The process can be accelerated by using drug nanocrystals. In this case a concentrated aqueous suspension of drug nanocrystals (=nanosuspension) [2] is added to the emulsion and both are subsequently homogenized. The solubility of a drug depends on the size of the individual particles. That means reducing the particle size below approx. 1 mm enhances the solubility (Fig. 1) according to the Noyes-Whitney equation. The high shear and cavitation forces in the homogenization gap of a piston-gap homogenizer lead to radical particle size diminution [3]. Besides the quick stirring provides a very evenly distribution of the drug particles within the emulsion during the process. The finely dispersed drug particles dissolve within the lecithin layer of the emulsion and thus form a stable and injectable drug loaded emulsion.
Succes with “problematic” drugs
The applicability of the SolEmuls technology has already been proven for several very poorly soluble drugs. Among those tested substances are the antifungal agents itraconazole [4, 5], ketoconazole [6] and amphotericin B [6, 7] and the antiepileptic carbamazepine [8, 9]. Tested carrier emulsions included Lipofundin, Lipovenös and Intralipid among others. Amphotericin B was chosen because it is a commercially attractive drug. Its solubility is very poor. The commercially available formulations are either very expensive, for example Ambisome, or are accompanied by severe side effects (nephrotoxicity). Hospital pharmacists have repeatedly tried to directly incorporate the drug Amphotericin B into an emulsion. First trials were made by mixing the raw drug powder directly with the emulsion and then shaking it by hand immediately prior to injection. It was assumed that Amphotericin B would dissolve within the lecithin layer while shaking. However, this assumption proved to be wrong. Even shaking for 18 hours at 1800 rph could not completely dissolve it [10]. There are basically two ways to formulate an amphotericin B loaded emulsion. One way is to incorporate the drug directly into the emulsion by distributing it evenly within the emulsion with a fast stirrer and subsequent high pressure homogenization. However an even better result can be obtained by formulating a nanosuspension from the drug, lecithin and water by means of high pressure homogenization and then mixing the emulsion and the nanosuspension again by means of high pressure homogenization. Figure 2 shows the size distribution of the raw amphotericin B powder before homogenization [A], the emulsion (Lipofundin) [B] and the final formulation of amphotericin B loaded emulsion [C]. After the homogenization process the mean PCS particle size was well below 300 nm (Table 1). Within the emulsion AmphoSol no crystals of amphotericin B were detectable with polarized light microscopy. The AmphoSol was formulated in various drug concentrations to investigate the loading capacity of the system and was stored for over 12 months and regularly investigated by laser diffractometry (LD), photon correlation spectography (PCS), polarized light microscopy, zeta potential and HPLC. The particle size did not significantly change during storage time (Table 1) and even after one year no crystals could be detected. The zeta potential was around -40 mV, which is a good indication for a physically stable emulsion. The chemical stability was monitored using HPLC. Previously sterilized and unsterilized samples were investigated immideatly after production and after one year. The amphotericin B content after production was set to 100% (Fig. 3). After one year it had not significantly changed and was still above 98%. The AmphoSol was further investigated in regard to cytotoxicity and antifungal activity. The test showed, that the AmphoSol was not as cytotoxic as for instance Fungizone but proved to have a comparable antifungal activity. Further studies including itraconazole and other drugs are currently on their way. In regard to Amphotericin B the SolEmuls technology proved to be superior to other technologies. AmphoSol is a cost effective, physically and chemically stable product that may even have fewer side effects. SolEmuls has repeatedly shown that it is applicable to a wide range of poorly soluble drugs and provides a cost effective way to overcome many solubility problems. The whole process can easily be transfered from the lab scale to the industrial scale using the production lines for parenteral emulsions available in pharmaceutical industry.