Poorly water-soluble molecules account for around 40% of pharmaceuticals with market approval and almost 90% of molecules in pharma companies’ discovery pipelines. An estimated 70 to 90% of drugs currently in development fall in the Biopharmaceutical Classification System’s two low-solubility classes. The development of new technologies to improve solubility are boosting the chances that poorly soluble compounds will advance to the clinic.

The selection of an appropriate solubility enhancement technology can be complex, with each available technology having its own set of requirements and process variables. By understanding both the technologies and the properties of the active pharmaceutical ingredient (API), it is possible to eliminate some options and simplify decision-making. This article examines how formulation scientists can best make an informed and rational decision on which of the many available approaches to solubility enhancement and formulation development to employ.

One approach is to use a technology selection tool early in development, enabling sponsors to narrow their choices to those approaches, leading to the highest chance of success. This can lower costs, optimize success rates, and minimize the product’s time to market. Factors to take into account include: the types of formulation most suitable for the candidate drug; the properties of the drug, which might indicate the suitability of one technology rather than another; and the scalability and cost of the technology.

There are marked variations in the range of compounds to which particular formulations can be applied, and in the complexity of the resulting formulation (see Figure 1 and Table 1). As an example, it is relatively easy to achieve size reduction by micronization, but this approach is not applicable to a large proportion of poorly soluble compounds. Lipid formulation technologies, in contrast, have broader applications, and involve a wider range of options. Spray dried dispersion technologies are widely applicable and relatively straightforward, but require more than simple size reduction.

The most widely used formulation technologies in marketed poorly soluble drugs are spray-dried amorphous dispersions and lipids.

Spray dried amorphous dispersions
Spray drying enables creation of amorphous solid dispersions (ASDs) of poorly soluble drugs using a large array of excipients that can be chosen to optimize performance. This approach to formulation involves co-dissolving the drug and one or more polymeric excipients in an organic solvent such as methanol, ethanol, acetone or dichloromethane. This solution is then sprayed through a nozzle to form droplets and the solvent quickly evaporates, leaving solid particles.

The resulting ASD contains a homogeneous mixture of the drug and polymeric excipients, which can provide sustained levels of dissolved drug in targeted environments. Spray drying is particularly versatile since the wide array of excipient, and solvent choices make this technology applicable to many drug candidates. It is also scalable and can be used from early discovery through to commercialization. Considerations involved with spray drying include the choice of excipient and solvent, capital expenditures on scale-up, and the stability of the resultant amorphous dispersion. 

Lipid-based formulations
Lipid-based formulations take advantage of the body’s lipid digestion and absorption pathways. Here, lipids are used as the primary agent to solubilize and deliver the drug compound. Therefore, a critical early step is to establish the solubility range of the drug in various lipids. In addition to the traditional medium- and long-chain triglycerides such as castor oil, many other excipients can generate lipid-based formulations, such as chemically modified glycerides, and polar and non-polar surfactants and co-solvents. Excipient choice depends on several factors, including the solubility of the API in the excipient, whether the excipient is sensitive to lipid digestion, and its emulsification behavior.

Once created, the drug/lipid mixture can sustain pharmaceutical concentrations in targeted environments. Lipid formulations yield complex structures that deliver the drug, consisting of micelles, micro- and/or nano-structures, and in some cases, liquid crystals. Lipid formulations can be complex due to the number of additives needed to achieve performance objectives, and may contain three or more components. For instance, when a drug compound is both poorly soluble and non-permeable in the intestine, dietary lipids, which are known permeation enhancers, are sometimes combined with other lipids to produce an improved formulation. This adds complexity and must be carefully considered during development.

Selecting a formulation
The strategy for selecting a formulation technology should be based on the specific characteristics of the drug. Table 2 shows a selection strategy chart. The main characteristics are on the vertical axis; these can be measured directly, or estimated by in silico prediction. Based on the results, the drug can be classified into a high, medium or low range for each property, and a shortlist of applicable technologies can be derived—green boxes indicate the technology is an option and red boxes indicate a more challenging option.

For example, if an API has poor lipid solubility, a lipid formulation is excluded. If the same API also has low thermal stability, then hot melt extrusion (HME) can also be eliminated as an option. Size reduction, bead coating and spray drying then remain as possibilities. If the API has acceptable solubility in common organic solvents, then spray drying and bead coating become attractive options. If the API dose is likely to be high, bead coating is unfavorable, and spray drying is the best choice.

Table 2 also illustrates ranges of values, reflecting the fact that multiple factors will influence the decision, including how the API interacts with excipients. If the API has limited solubility in organic solvents, then spray drying can still be a valid choice provided an excipient can provide excellent sustained dissolution profiles in targeted environments. This is particularly true for APIs where the dose is expected to be low.

Other considerations, such as performance, manufacturability and stability, can greatly influence which technology is best suited for a project’s specific requirements. Generally, the properties of the API are the primary drivers of solubilization technology choice. An understanding of the API’s characteristics, as shown in Table 2, leads directly to an intelligent and rational technology choice. Using this toolbox, timelines can be minimized, and additional compounds can potentially be advanced to the clinic using a technology that is well suited for clinical trials and commercialization.

It is vital to understand and consider additional characteristics of a poorly soluble compound, including melting points, potency and dosage levels, to determine the best solubility solution. If all factors are not taken into account, many wasted cycles of effort can be expended on formulation development. When these lead to a formulation dead end, there is no way to recover the costs. It is best to narrow the choices early on, rather than waste time and money by exploring many options, including those that logic dictates are clearly unsuitable.

Market leaders in other sectors have shown that designing for quality and manufacturability from the earliest stages of development can positively impact the success of a product. In addition, predictive modeling and directed product analyses can substantially reduce time-to-market and overall product costs. 

To take advantage of such approaches in pharmaceutical formulation development, in-depth mechanistic understanding is needed to support efficient and robust formulation activities for poorly soluble molecules. Pharmaceutical companies should consider partnering with a contract development and manufacturing organization (CDMO) that takes a comprehensive approach to solubility enhancement and formulation development, incorporating Quality by Design (QbD) principles at the pre-clinical stages of the drug development process through commercial production.

Manufacturability and production costs also play a role in selecting the ideal delivery platform and processing technology. Any robust tool must include these and possibly other factors, such as indication, therapeutic area, chemical stability and thermal stability. Patheon offers Quadrant 2 to meet these needs, presenting viable alternatives to minimize the chance of false negatives, and advising against certain technologies to eliminate false positives. The platform is based on a comprehensive understanding of multiple proven solubilization technologies, coupled with materials science and a targeted application of molecular modeling.

The primary advantage of this approach is that it enables a faster, more informed formulation development process that promises to minimize costly iterations and re-formulations as a drug product moves into the clinic. A promising approach to drug formulation design involves expanding Quadrant 2 to encompass a comprehensive set of in-depth tools combining physical measurements with a variety of calculation modules to fundamentally understand and predict drug and polymer interactions.

This model is not static. As new products come on the market, the model is updated by incorporating data about their characteristics, further improving its ability to predict the best solubility solutions. The latest scientific literature is also incorporated into the model. By using this tool early in the development process, sponsors can narrow their technology choices to the few with the highest potential for success. 

References

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4629443/
2. http://www.pharmtech.com/importance-lipid-screening-development-lipid-based-formulations
3. http://ir.patheon.com/news-releases/2017/02-01-2017-140153886