Excipient expertise

The choice of excipients is crucial in drug formulation, affecting both its quality and its acceptability to the patient. The CPhI conference in October featured a section on formulation and quality. Graham Lampard summarises the key points

Polysaccharides are highly popular carriers for slow release drugs through the oral route. Semi-synthetic polysaccharides, such as cellulose-derived materials, are abundant and widely used in the pharmaceutical industry. Commonly used examples are cellulose ethers and in particular, hydroxypropylmethylcelluloses (HPMC).

The influence of fillers and admix polymers on drug release from HPMC matrices was the subject of a presentation by Ali-Reza Rajabi-Siahboomi, technical director of Colorcon. He compared these properties for three fillers: microcrystalline cellulose (MCC), which is insoluble in water; lactose, which is water soluble; and Starch 1500, a proprietary cold water-soluble product from Colorcon. These were used in formulations with two candidate drugs, diclofenac Na, which is poorly soluble, and highly soluble chlorpheniramine maleate.

All formulations, regardless of the type of filler, resulted in a slow release for both drugs. However, when Starch 1500 was used, drug release was significantly decreased compared with MCC or lactose in HPMC matrices, although it actively contributed to the mechanism of drug release, causing a slowing down in the release rate. For both drugs, increasing the concentration of the Starch 1500 from 20% (w/w) to 49.25% (w/w) in the formulations caused a significant decrease in their release profiles, Rajabi-Siahboomi stated.

The tableting performance and key tablet properties of new spray dried directly compressible (dc) Mannitol against commonly used dc excipients were examined by Julita Pearson, from Merck Speciality Chemicals. The excipients tested were based on Merck's new spray dried mannitol, Parteck M200/300, and compared with various types of Sorbitol DC, MCC, lactose anhydrous DC and lactose monohydrate DC (table 1).

The formulation was standardised as 25% ascorbic acid granulation, 74% excipient, and 1% magnesium stearate. The tests carried out included bulk and tap density, tablet weight uniformity, tablet hardness and disintegration time.

The results suggested the following:

According to Pearson, Merck's new products exhibited excellent compression characteristics and fast disintegration, which 'should make it an excipient of choice for any formulator.'

The advantages of a new functional excipient, erythritol, were highlighted by Jacques Michaud, from Cerestar in Belgium. The chemical, which is a tetraol, has around 60-70% of the sweetness of sucrose as an excipient, but unlike other polyol excipients it has zero calories (figure 1).

It is also easily digested, and has a negative heat of solution – i.e. it has a cool, pleasant effect on the mouth when dissolving (table 2). Michaud said other benefits include better digestive tolerance: three to four times that of sorbitol, and two to three times better than xylitol, lactitol or maltitol. The sensorial profile-modifying capabilities are excellent and provide an 'excellent synergy with intense sweeteners that improves the mouthfeel and taste quality,' said Michaud

From the application point of view, in tablet formation erythritol has very low moisture absorbance (figure 2), which means it can be used as a diluent for moisture sensitive actives. It has excellent stability to heat, is both chemically and metabolically inert, and can also be easily granulated. According to Michaud, the cost of using erythritol is similar to using something like Xylitol.

Natural polymer functional excipients could offer more opportunities to formulators, claimed Fred Heinze, from National Starch, which has developed a range of multi-functional, high purity starch based excipients. 'A unique feature of the Uni-Pure range is that they comply with global specifications, including Ph Eur, NF/USP and JPE,' said Heinze. 'The Uni-Pure range can eliminate the need for starch paste preparation and offers complete functionality for solid dose applications.'

He showed that at around 600s, tablets formulated with Uni-Pure WG were 15% quicker at disintegrating than those with pregelatinised starch as an excipient.

quality issues

The CPhI conference also looked at quality issues surrounding the manufacture of pharmaceutical ingredients and the supply chain.

Dr Frank Milek, chairman of the International Pharmaceutical Excipients Council (IPEC) Europe's good distribution practice committee, highlighted the need for control in the supply chain. He cited examples where lack of control had fatal consequences, including 109 dead in Nigeria when cough syrup was contaminated with solvents and 80 children dead in Haiti when they were given glycerine contaminated with diethylene glycol in a product. According to the WHO, there were 500 unnecessary deaths in the 10 years from 1988-98 caused by contaminated starting materials.

One of the problems, Milek said, is that the supply chain is now worldwide, and control is patchy. Traceability usually occurs only if there is an exclusive contract for distribution agreements, while filling, blending and labelling are mostly carried out on site and could be open to abuse. The main problems in transporting excipients from producer to customer are:

So what is being done? Certificates of analysis (CoA) should be available, Milek said, which show origin and provide traceability, as well as lot numbers and specifications, and dates of production and analysis. There is also a proposal for an EU directive on GMP for starting materials, which would require both excipients APIs to be manufactured according to GMP. The provisions would cover distribution, handling, packaging/repackaging and labelling/relabelling, and would ensure the inspection and certification of distributors and traders.

There are various guidelines that can be followed. These include the IPEC GMP guide for bulk pharmaceutical excipients; the IPEC GMP audit guidelines for bulk pharmaceutical excipients; the IPEC GMP audit guideline for distributors of excipients; as well as an IPEC Europe position paper on good distribution practice.

Milek then outlined the audit guidelines for distributors of bulk pharmaceutical excipients, which cover all aspects of the distribution of excipients. He said it was IPEC's intention to improve the supply chain for excipients by providing the tools for industry to use. He hoped that an independent audit system would be set up for suppliers of excipients, both makers and distributors. He also wanted to see a discussion on GMP supply chain issues with other organisations and authorities.

The implementation of cGMP in the manufacture of excipients was addressed by Hans Hermans, quality assurance manager with DMV International. He said that his company's aim was to improve its GMP from the level suitable for excipients, set by IPEC, to that of active pharmaceutical ingredients (API) by attaining cGMP know-how.

The change, he said, was needed because the company wanted to increase its visibility in the US market, and having cGMP standards for its products would improve the chances of this. It also had to do with customer expectations, and ever-increasing regulatory demands. Finally, it meant that the company would improve on its GBP – good business practice. He said that investment in the project in 2001 was 22,000 man-hours, which equated to investing €1.5m (US$1.3m), with other costs estimated at €1m (US$0.9m).