As the number of drug candidates with poor solubility profiles increases, several techniques, such as salt or cocrystal formation, the use of lipidic vehicles, micronization (particle-size reduction), and the preparation of amorphous dispersions (spray-dried or hot-melt), have been developed to address this issue. Formulators are thus challenged to select the approach that will most effectively increase the bioavailability of a given active pharmaceutical ingredient (API). Because the choice of method depends significantly on the physical properties of the API, an understanding of the solid-state characteristics of a drug candidate, as well as its stability under various conditions, is important, according to Anil Kane, executive director of global formulation sciences in the pharmaceutical development services business of Patheon. Rapid screening of solid-form APIs is thus critical to efficiently developing formulations with improved bioavailability.
Screening must, in fact, be carried out on a number of different forms of the API, including different possible salts, cocrystals, and polymorphs. “It has been well documented in the literature that different salts of a drug substance can significantly change its solubility and stability profile. Similarly, different polymorphs exhibit varying properties that impact the absorption of drug substances,” Kane notes. Specific properties that must be considered for each of these different versions of the API include the melting point, glass-transition temperature (Tg), aqueous solubility, stability, and lipid solubility, among others. “All of these characteristics are critical considerations when choosing a method for bioavailability improvement,” says Kane.
The first step in the process is to conduct a systematic evaluation to generate data regarding the properties of the drug substance. Information on the physical nature of the API, such as its crystalline structure, particle morphology, density, and its chemical stability profile must be gathered. Determination of the solubility and stability of the drug substance at different pH levels is also important, and the behavior of the compound under forced degradation conditions should be investigated. Permeability data from in-vitro models and exposure data from animal studies are also needed in order to classify the API according to the Biopharmaceutics Classification System (BCS), which will provide a better understanding of the criticality of the bioavailability enhancement issue for that particular drug substance, according to Kane.
Making the right choice
A quick review of the physical property data can then lead to the elimination of some enhancement techniques due to incompatibilities. Micronization, for instance, is not suitable for drug substances with low melting points. “Micronization involves the reduction in size of solid drug particles in order to increase the surface area and is an effective method for enhancing solubility. However, heat may be generated in the process, and thus APIs with low melting points will likely melt and change their form and structure during the process,” Kane explains. Micronization is also often not suitable for nonfriable crystalline drug substances because particle-size reduction of these materials is challenging whether using dry micronization or wet nanomilling techniques.
Meanwhile, the use of lipidic vehicles, along with cosolvents and bioenhancers, will not be effective for drug substances that are insoluble in lipids. Furthermore, the formation of an amorphous form of a drug substance for incorporation into solid dispersions depends on the Tg of the compounds, which must be suitable to enable conversion from the crystalline to the amorphous form. “In addition,” observes Kane, “for spray-dried amorphous dispersions, the API, along with the approved polymer and excipients, must also be soluble in an appropriate solvent, while for hot melt extrusion, the drug substance must have sufficient thermal stability to withstand the solid dispersion manufacturing process.
While the physical properties of a drug substance are of primary importance in selecting a method for improving its solubility and bioavailability, consideration must also be given to the choice of excipients used in possible formulations, such as cosolvents, solubilizers, and permeation- and bioenhancers. “Both the ingredients themselves and the levels at which they are used in the formulation will need to be acceptable from a regulatory standpoint,” says Kane. Such excipients are used, for example, in lipidic vehicles for bioavailability enhancement in two-piece capsules or softgels. The stability of the excipients under manufacturing and formulated conditions must also be evaluated for each type of enhancement technique. “Excipients used in solid dispersions of drugs formulated for spray drying or hot-melt extrusion must be stable throughout the production process and during the shelf-life of the product and retain their forms, structures, and properties. Sufficient supporting stability data is therefore key to gaining regulatory acceptance,” Kane comments.
Griseofulvin, an antifungal active, has a high melting point, a very well-defined packed crystal lattice structure, is chemically stable, and exhibits very low aqueous solubility. Because it has a high melting point and is stable under the slightly elevated temperatures associated with milling/micronizing, particle size reduction is a good candidate technique for improving the solubility of griseofulvin, according to Kane. “It is well known, in fact, that griseofulvin bioavailability is increased using this approach,” he adds.
More generally, according to Kane, compounds that have unstable crystalline forms and show a good glass-transition temperature (Tg) and solubility in organic solvents in which commonly used polymers can be dissolved are good candidates for attempting the formation of solid dispersions by forming amorphous state materials for solubility improvement. On the other hand, the bioavailabilty of drugs that are soluble in lipids can be improved by selecting an appropriate solvent/vehicle system with or without surfactants, solubilizers, and bioenhancers for use in a lipidic formulation.
Rapid screening is key
Patheon’s approach to the selection of appropriate methods for the enhancement of solubility/bioavailability relies on parallel screening of several techniques based on an internal expert assessment of API properties under the “Solupath” program. “This system enables rapid screening of compounds in order to define a path forward and saves time and money. In addition, we have been able to show increases in the solubility/permeability of poorly soluble compounds using Solupath screening that have resulted in many-fold improvements in the bioavailability of these drug substances,” Kane observes.