What's Next In: Solid-Dosage Formulation

Individual Dosing, Process Simulation, and Continuous Processing

Individualized dosing for specific patient needs has been the goal of medical and pharmacotherapy specialists since they first envisioned pharmacogenetic evaluation. With the measurement of individual levels of metabolism, the optimum dose can be calculated for each individual patient. Dosage forms, however, are currently mass produced in defined dosages that may or may not be appropriate for each and every patient. To achieve the goal of individualized dosing, we will need to rethink pharmaceutical processing to produce individualized doses with the same controls that are in place for mass-produced dosage forms. The methods for producing individualized dosage forms are still being explored. Manufacturing of individualized dosages was considered by the National Institute of Pharmaceutical Technology and Education (NIPTE) to be a long-term goal in its Pharmaceutical Technology Roadmap, which was developed in the course of a year by meeting with scientists from industry, the US Food and Drug Administration, and academia.

(IMAGE: PHOTOS.COM/MELISSA MCEVOY)

Other advances that NIPTE envisions in the area of solid-dosage forms include the development of predictive mathematical models of current manufacturing processes including milling, granulation, drying, compaction, and coating. Once mathematical models are developed that can predict the performance of the product or intermediate-product from known material properties, the development process can be significantly shortened. In addition, variation in inputs can be used to predict the impact on product quality, and model predictive feedback control strategies can be implemented to ensure that product-quality specifications are met. The approach of predicting product quality using simulations based on known fundamental physics and engineering as well as knowledge of process and materials is distinctly different from the use of empirical, statistical modeling that one obtains from a factorial or other systematic design of experiments. Process simulation requires a fundamental understanding of the process and materials that, in many cases, is currently beyond our reach. The progress in the area of process simulation is rapid, although we have a long way to go before this becomes reality. Materials characterization of powders, however, is very complex and will require significant concerted effort using a variety of approaches.

Most current pharmaceutical processes are batch processes. The NIPTE Roadmap also includes an exploration of moving from batch to continuous processing. Unlike batch processing, continuous processing is more amenable to process monitoring and control algorithms that allow the process to run without human supervision. Of course, the size of the equipment for continuous processing will be reduced compared to the current batch-sized equipment to allow continuation of the processes for a sufficient time to take advantages of continuous processing. Continuous processing will also allow intermediate materials to be introduced in subsequent processes "just in time." For example, continuous wet-granulation feeds into continuous drying, which feeds directly onto a tablet press without inspection of the intermediate materials.

Robin Bogner, PhD, associate professor of pharmaceutics, Department of Pharmaceutical Sciences, School of Pharmacy at the University of Connecticut

Coatings

A leading British pharmaceutical journal once stated, "Tablets have had their day, and will pass away to make room for something else." This prediction was made in 1895. It's fair to say the prediction was wrong, and tablets, along with capsules, remain the prevailing solid dosage forms. The situation doesn't seem likely to change in the future, even as such innovations as soft gels and oral disintegrating tablets (ODTs) retain niche sectors of the market.

What could have a significant impact on the future of solid dosage forms and formulations is growing attention by the US Food and Drug Administration on the quality and consistency of pharmaceutical manufacturing processes. In line with that, key FDA-driven initiatives will continue to gain prevalence among pharmaceutical manufacturers-and, by necessity, their suppliers-in the years to come. Of these, key is Quality by Design (QbD), which reflects the FDA's belief that quality needs to be built-in or by design. An important aspect of QbD is process analytical technology (PAT), an approach for providing on-line assessment of product quality throughout the manufacturing process. This approach enables the consistent generation of products of predetermined quality, supported by the ability to identify an appropriate design and control space for each manufacturing process.

Coating processes represent one area where the FDA has expressed concern because they involve so many factors that can influence the outcome. A major challenge going forward is to control coating processes more effectively, which can only be done by gaining a full understanding of the key issues taking place in any given coating process. To gain a better understanding of what is a very dynamic process, pharmaceutical companies, in conjunction with academia, are using various modeling techniques, such as computational fluid dynamics (CFD) and discrete element methods (DEM). Additionally, application of thermodynamic principles provides a greater opportunity to understand how best to balance spray application with the drying process.

In keeping with the principles of the QbD initiative, employing statistical design of experiments (DoE) provides an effective means of identifying all critical formulation and process variables essential to designing a quality pharmaceutical dosage form. DoE provides the greatest opportunity for examining the critical interactions between ingredients within a formulation and process variables for effective optimization of pharmaceutical formulations (including coating formulations) and processes.

With respect to coated products, the full implementation of QbD and on-product anti-counterfeiting initiatives for coated products are two issues likely to demand even closer attention in the future.

Stuart C. Porter, PhD, senior science fellow, International Specialty Products

The Future of Drug-Solubility Technology

Greater sophistication in drug discovery is leading to the identification of a growing number of molecules that are proving more potent for disease control. Many of these compounds, however, are also proving very poorly water soluble and in some cases poorly permeable. Indeed, nearly 40% of the drugs on the market today and nearly 60% of drugs in development are poorly soluble. So solubility will be a major challenge for pharmaceutical scientists in the years to come, a situation that could be compounded by the discovery of more and more poorly soluble molecules.

Conventional tablet-forming techniques are not proving adequate to the challenge, and other technologies will gain prominence in the coming years. These may include hot-melt extrusion, nanocrystal technology, and spray-dried solid dispersions technology. Spray-dried solid dispersions technology enables the formation of an amorphous state that is clearly at a high energy level and, for this reason, able to dissolve into the dissolution medium much more effectively than if it were in a highly structured, crystalline form. Amorphous dispersions will enable drugs to be administered in more controlled dosages at lower concentration levels, thus providing the same level of therapeutic benefit with reduced risk of any potential side effects that may be associated with that drug.

However, one challenge that will need to be addressed is the stability of amorphous dispersions over time. The potential exists that new polymers or polymer systems may be needed to help stabilize amorphous solid dispersions. Pharmaceutical scientists will have to work on enabling these materials to have a shelf life of at least three to five years.

Depending on the molecule, one solubility technology may work better than another. One thing is certain: conventional micronizing technology will not be nearly as effective as the newer technologies. For example, spray-dried dispersions have been demonstrated to achieve 10- to 50-fold increases in bioavailability over conventional dosage forms.

To this point, some products of increased solubility have been commercialized using hot-melt extrusion technologies and nanocrystals. With the question still looming as to whether it is possible to make stable amorphous dispersions, spray-dry technology stands on the threshold of the marketplace. The next decade promises to be very promising in the delivery of stable amorphous spray-dried drug products.

Albert W. Brzeczko, PhD, vice-president of global pharmaceutical research and development and pharmaceutical technologies, ISP Pharma Systems LLC

Industry experts give their predictions for the next 30 years.