Choosing the Right Excipients for the Right Job

The average timelines and costs of bringing a new drug to market vary depending on who you speak with, but are generally in the range of 10 years and over $2 billion, respectively. The broad hurdles of drug development are considered, but a topic that receives far less attention is formulation, including the choice of excipients.

The right excipients can reduce manufacturing costs, improve shelf life and stability, and enhance the patient experience. The competitive contract development and manufacturing landscape has given rise to CDMOs who hold impressive knowledge and know-how in terms of applying good scientific common sense in selecting the most appropriate excipients for the job at hand. Here, we speak with Rob Harris, Chief Technical Officer, Oral Drug Delivery, Catalent, UK, to find out more about the latest trends and drivers in the excipient field.

How have excipients improved over the last decade?

For some of the solvent excipients, such as oils and PEGs, greater purity has been a major improvement. Even low levels of impurities (for example, peroxides and aldehydes) can have a significant detrimental effect on drug stability. Also, reactive impurities can cause cross-linking of gelatin shells, affecting disintegration properties.

Better functionality for excipients has been another improvement. For instance, powder flow is an extremely important property for processes such as tableting and hot melt extrusion, so excipients that can improve powder flow for “difficult” powder blends are of interest to formulators. These can be excipient grades with particular particle size and shape to provide good flow properties or co-processed materials (for example, silicified microcrystalline cellulose), which offer similar advantages.

Indeed, co-processed materials – which combine the properties of two or more separate excipients into one – have become more widely available. These provide formulators with a single, multi-functional excipient option (for example, LudiFlash) that can help reduce development time and cost, certainly during early drug development.

Easy-to-prepare products, such as coating preparations for tablets (for example, Acryl-EZE) are now also available and can cut down on processing time.

What trends are driving innovation in excipients?

The number of poorly water-soluble compounds emerging from drug development pipelines is increasing year-on-year. Thus, there is a constant battle to develop suitable formulations for these poorly soluble drugs to allow administration and good bioavailability. Excipients that can enhance the solubility of otherwise challenging compounds are of great interest to formulation scientists. Non-ionic surfactants (for example, Vitamin E TPGS and Kolliphor RH40) are becoming common ingredients in pharmaceutical formulations. So too are polymer excipients that can be used to produce amorphous solid dispersions through spray drying and hot melt extrusion, such as PVP, HPMC and HPMC-AS and block co-polymers. Mesoporous materials with particles that have extensive internal surface area are also gaining popularity. It is possible to trap poorly soluble drugs in the amorphous state within the narrow passages in these particles and, hence, improve the solubility of the drug in aqueous media.

Regulators are now encouraging and demanding the development of more pediatric versions of medicines, so it has become a key area of focus for the industry – with a subsequent influence on the excipient space. Ease of swallowing and palatability are essential requirements for patient acceptability and, therefore, excipients that can offer benefits in these areas are useful aids for formulation scientists. A number of excipients with attributes well matched to pediatric formulations are now available; for example, fillers and disintegrants that provide good “mouth feel” for orally dispersible tablets and coating materials that prevent premature release of the drug in saliva (for taste-masking).

How can formulators ensure they choose the “right” excipients?

It’s extremely important to consider your choice of excipients – and have clear reason for their use. All formulation scientists should have a thorough understanding of the attributes of excipients used for a given type of formulation, and when certain materials should be used in preference to others. In all regulatory submissions, the reviewers expect a rationale for the selection of excipients, including the amounts used. Different grades of the same excipient can have marked effects on the desired behavior of a formulation.

Formulators should also consider:

• Compatibility with the drug substance to ensure that there is no undesired interaction between the drug and the excipient that could impact the stability and shelf life of the product. A drug-excipient compatibility study is normally one of the first activities undertaken for any formulation development program.
• Moisture content of the excipient – if the drug substance is moisture-sensitive (for example, use of an anhydrous grade versus hydrated).
• The drug substance may be sensitive to trace amounts of reactive impurities. Due care should be taken to use suitable types/low-impurity grades of excipients for such drugs. Low-peroxide-containing excipients are being made available, such as BASF’s Kollidon 30 LP, to help address this issue.
• Particle size of fillers (for example, lactose, microcrystalline cellulose) is important depending on the formulation and manufacturing process.

What about a specific example – cellulose or PVP – how do you choose which is most suitable?

Most formulators favor specific excipients for particular types of formulation. For dry-granulation formulations, Kollidon VA64 has become the go to dry binder of choice for many because its properties are well suited to roller compaction processes (good compressibility and plasticity). However, in general the selection of functional excipients (binders and disintegrants) for a particular formulation should be based on the experimental evaluation of a range of candidates.

In the selection of excipients, it is also important to consider potential interactions with charged drug substances. Such interactions can result in incomplete recovery of the drug from the formulation, which can lead to assay irregularities or, worse, reduce the bioavailability of the drug.  Non-ionic binders and disintegrants (for example, L-HPC, crospovidone) are less likely to interact with these types of drugs.

Where is there further room for improvement in the excipient field?

Solubility enhancement is one of the main issues facing formulators right now, but the tool kit of available, acceptable excipients has grown substantially in recent years; however, there continues to be a need for new excipients that can help overcome the challenges presented by difficult compounds.