Smoothing the way

Rajeev Karpe, global new product development leader - pharmaceuticals at Huber Engineered Materials, highlights the trends in excipient formulation

As the trend to tabletting of ever more difficult entities continues, the role of excipients will expand apace. Oral solid dosage forms account for 60-70% of drug delivery methods today, and that percentage inches up year after year. Another trend is to package less soluble, higher molecular weight drugs in solid dose form, and these developments increase the formulator's dependence on higher performing excipients.

An excipient is generally defined as an inert or non-active material, and although this is a rather limiting definition, they provide the basic delivery package in many drug formulations. Although termed inert, excipients have functional characteristics that in combination allow the formulator to design new approaches to deliver active pharmaceuticals, with the future for excipients lying in materials that have a specific functionality to open the door to better drug delivery.

better performance

For example, there have been significant developments in recent years with materials that act as 'super disintegrants' and coatings that control the rate of drug dissolution. Huber sees advanced materials science being carried to greater levels of performance to enable formulators to develop delivery systems that take drugs to specific targets in the body. Therefore the need for materials with superior functionalities, such as rapid disintegration, controlled release, taste masking, drug carrying and targeted delivery, will continue to grow over the next few years.

A key to success is not only to develop better functional excipients, but to ensure that these materials are compatible with the drug formulating processes standard in the industry. Such a requirement will reduce the need for added manufacturing equipment or expensive packaging designs.

Although the demands on excipients are higher than ever before, improvements in applications are coming from existing excipient chemical entities rather than by newly designed products, and Huber expects this to continue.

The development of new chemical entities for excipient use is very rare in the current business scenario: the investment in completing safety and toxicity studies to meet regulatory needs simply makes it uneconomical to do so.

As the shift in tabletting processes continues from wet granulation towards a direct compression, process, good flowability and compactibility of the mixture assume greater importance, and these qualities depend on the excipients.

Silicas and silicates as glidants and carriers for difficult to handle drug ingredients have continued to solve production issues, including the accurate flow of the drug/excipient combination to maintain tablet quality and consistency.

The proliferation of excipient grades, however, complicates the selection process for the formulator. A reputable excipient supplier will assume that each application is unique in terms of dosage and bioavailability and will work with the formulator to fine-tune or customise the total excipients package.

A number of key issues link pharmaceutical processing developments and excipients. Drugs are becoming more sophisticated as the molecules are becoming more complex with higher molecular weight and poorer solubility. Enhancing the solubility and bioavailability is a challenge that excipient combinations are resolving.

Improved excipients are also extending the boundaries for timed-release drugs. Properly selected and integrated into the process, the excipients work better in both the plant and the patient. But again, proper selection and application support make all the difference between success and failure.

For example, by combining a special grade of carrier with process optimisation, Huber recently helped a manufacturer of health products to create vitamin pellets that were stubbornly difficult to make with its existing equipment. The company solved a similar problem for an equally difficult AIDS drug in solid dose form.

tabletting trends

There is also good progress in calcium carbonate. A new high-purity grade of ground calcium carbonate (GCC) has lead levels well within current guidelines, which enables formulators to return to the natural GCC from the more expensive precipitated (PCC) form. The new high purity GCC matches PCC for purity, costs 20-40% less and is gentle on tabletting dies. It also offers the marketing cachet of all-natural ingredients.

For Huber, the trend to tabletting is here to stay, with good reason. The tablet is a more convenient dosage form for the patient but, depending on the ingredients, may create processing problems. Compression tooling is expensive, as is production time lost in changeovers.

Last year Huber Engineered Materials added a tabletting laboratory at its Havre de Grace, Maryland, facilities.

In a typical test run, the tabletting line forms the tablets and simultaneously monitors force profile, as well as compaction, ejection and scrape-off forces. All these parameters directly affect tablet integrity and process economics after scale-up.

Although excipients practice has advanced in recent years, much remains to be done as the industry moves to package difficult active ingredients in solid oral dose form.

The outlook is for more speciality excipient grades and greater application knowledge of existing silicas and silicates rather than for any whole new classes of compound.