Chemistry & Life Sciences

Imagination Over Experience

Exploring new Innovations in High Functionality Excipients

13.08.2010 -

Inventing The Future - The modern tablet development usually includes three basic formulation techniques - direct compression, dry compaction and wet granulation. Depending on the API, characteristics and the desired dosage, one of these formulation approaches is used. Direct compression is the most preferable method due to the low development costs, simple solvent free procedure and a much shorter time-to-market compared to the other methods. Disadvantages of this technique are powder flow difficulties, segregation, poor content uniformity and lubricant sensitivity.

Growing pressure to reduce the production costs and improve the product performance is driving the pharmaceutical companies to look for new solutions. The majority of the tablet formulations include too much and often overdosed conventional excipients: diluents (lactose, powdered cellulose); binders (microcrystalline cellulose, povidones); different disintegrants (croscarmellose, sodium starch glycolate, PVPP); glidants (silicon dioxide); and lubricants (magnesium stearate, sodium stearyl fumarate). The resulted multi-component mixtures of materials with different particle size and shape and bulk density tend to segregation and poor formulation uniformity.

Discussion

Nowadays, the innovation is focused on the development of high functionality excipients (HFE), a synergistic consolidation of two or more conventional excipients that show a synergistic functional performance and overcome the simple blend of its individual components in all technological parameters like flow, compressibility, disintegration, content uniformity and drug dissolution.

Just a co-processing of two or more ingredients is not enough to get high functionality. Every single component of the new formed composite should perform better compared to any other dry mixture or granulated powder with the same excipients content. This requires a precise selection of ingredients and creation of an adequate particle design.

The first generation of co-processed excipients was developed 15-20 years ago. Some of these products have been on the market for a long time: Prosolv SMCC (silicified microcrystalline cellulose); Ludipress (lactose, pvp, pvpp); Cellactose (lactose and powdered cellulose); Starlac (lactose and starch); Emdex (glucose and maltodextrine). What do these co-processed excipients have in common?

  • They all are based on the combination filler+binder, binder+glidant or filler+binder+disintegrant.
  • Their development is focused on achieving good powder flow and compressibility.
  • Not all of them are truly high-functionality excipients.
    They all are mono-particular in nature.
  • They all need an appropriate lubricant to be compressed. 
  • Co-spray drying is the preferable co-processing technology.

The use of these new excipients brought revolutionary advantages in the tablet development. In particular, direct compression formulations were updated and simplified by reducing the number of excipients and improving the formulation efficacy. The development and production benefits of the first generation co-processed excipients include:

  • Simplified tablet development - less excipients and blending steps.
  • Shorter development times, which drastically reduces R&D costs. 
  •  Low segregation risk in direct compression.
  • Better compressibility leads to reduction of the tablet weight and size - better patient compliance and reduced coating costs.
  • Switching from wet granulation to direct compression gives radical production costs reduction.
  • Simplified supply chain management - less excipients, less controlling steps.
  • Getting free manufacturing capacity.

One example for successful HFE application: Diclofenac Sodium. The original wet granulation formulation was re-worked to a direct compression formulation with silicified microctystalline cellulose.

Same tablet size and weight but much elegant direct compression formulation can be achieved with Prosolv SMCC. The high functionality excipient acts as a diluent, binder, glidant and disintegrant , drastically reducing in this case the number of necessary excipients from six to two (see Table 1). The change from the expensive wet granulation to direct compression allows additional cost and time savings.

Still, open formulation issues by using this first generation HFE are lubrication and overmixing, sticking and capping as well as the drug dissolution reproducibility with poorly soluble actives. Next generation high- functionality excipients should be able to solve these problems. But how?

Time For Something New

The old conception diluents+binder+disintegrant is not innovative enough anymore. The blind co-processing of different excipients without a clear vision will lead merely to another "me, too" product.

It's time for something new, maybe something that, up until now, has been considered to be impossible or useless: The incorporation of the only one missing excipient group to make a HFE complete - the lubricant. Limiting factors in the lubricant co-processing were reduced compressibility respective to decreased tablet tensile strength; poor disintegration (disturbed water drainage into the tablet matrix); and drug dissolution. An additional question is what will happen if we affix the lubricant level in the excipient composite? Will the lubrication be enough after adding the API? Is it possible to overcome these at first sight insolvable difficulties?

As Albert Einstein once said, "Experience is more important than knowledge, but imagination is more important than experience."

The breakthrough is has been made. The first lubricant-coated high functionality excipient Prosolv easytab was recently developed and tested successfully in some very problematic direct compression formulations. With innovative particle design and improved functional performance this new product comprising microcrystalline cellulose (diluents and binder), silicon dioxide (glidant), sodium starch glycolate (superdisintegrant) and sodium stearyl fumarate (lubricant) showed a superior all-round functionality. The homogeneous lubricant distribution provides an excellent lubrication, sticking prevention, powder flow improvement, enhanced tablet disintegration and reproducible API dissolution without to disturb the function of the other ingredients.

To demonstrate the benefits of the new lubricant-coated high functionality excipient, a comparison with piroxicam as model API in direct compression was made. This BCS class II active (low solubility, high permeability) is a real challenge for the formulators with its poor blending properties and inconsistent dissolution results. In our study, two direct compression formulations with 5% piroxicam were compared: one with easytab and one with the physical mixture of its individual components. The blending time 20 minutes, and the blends were compressed to 200 mg, 7 mm round-shaped tablets.

The active content uniformity was studied by using the classical analytical procedure and SEM (scanning electron micrograph) pictures of the ready piroxicam blends (figs. 1-2). Dissolution test of six randomly selected 10 mg Piroxicam tablets from the both formulations was preformed: USP Test in simulated gastric fluid (SGF).

The Next Generation

Lubricant co-processed excipients are the next generation high functionality excipients with a completed functional composition - diluent, binder, glidant, superdisintegrant and lubricant. Easy to use, simple application, robust formulation development, no overmixing, time and cost saving switch from wet granulation to direct compression and low production risk are among the advantages of this new HFE group.

How is looking the excipients future? There is no sense in trying to predict the future. As Alan C. Kay said, "The best way to predict the future is to invent it."
The new generation pre-lubricated high functionality excipients will simplify the drug development minimizing the formulation and production risk. The pharmaceutical industry needs reliable, cost effective and low risk production technologies which provide an optimal drug delivery and patient compliance. The creation of the lubricant-containing HFE is a considerable step forward in this direction.

As every new idea this one needs time to be understood and accepted but one is sure - the future belongs to the high functionality excipients. Soon or later they will dominate the formulation development thank their outstanding functional performance.

Dr. Edmont Stoyanov will be speaking at CPhI Worldwide Pre-Show Conference on Exploring new innovations in high functionality excipients and their advantages for the drug delivery.