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Pharmaceutical Manufacturing and Packing Sourcer

Recipe for Success

The application of functional excipients can offer the possibility of creating hard tablets using low compression force, which show fast dissolution and can be used for immediate-release formulations. Particle engineering also offers the ability to create mineral salts, which are directly compressible without additional binder polymers, creating the possibility of enhancing the amount of mineral source or of downsizing the formulation in nutraceuticals.

The pharmaceutical and biopharmaceutical industries are facing challenging times. Historically, the industry has measured itself on the introduction of new molecular entities (NMEs). In 1996, the United States Food and Drug Administration (FDA) approved 53 NMEs.This measure of productivity has fallen from this high point, most recently recording only 21 NMEs in 2010.The pressure on productivity is compounded by the need to reduce costs, streamline operations, and compensate for a large number of blockbuster drugs coming off patent in 2011 and 2012.

So where is additional innovation in the pharmaceutical industry coming from? One source of innovation may be found in drug formulation and the use of functional excipients. Functional excipients can help in controlling dissolution and drug release, and at the same time, display properties that help increase the productivity of the manufacturing process.

The bioavailability of active pharmaceutical ingredients (APIs) is often a limiting factor for therapeutic success. State-of-the-art dosage forms incorporating novel, functional excipients and advanced drug delivery systems can help overcome less than optimal APIs. In parallel, innovative excipients and delivery systems can add to the convenience and ease of administration of new drugs.This in turn can increase patient adherence to a treatment regimen and help target patient groups, such as children or the elderly, who have problems with standard formulations.

To make gaining approval for the final dosage form easier and more costeffective, these improved properties are best created by modifying known chemical entities. Proprietary particle engineering technology leads to advanced functionality, enabling the formulation of drugs without the need for undergoing the complete registration process for novel excipients – a costly pathway typically only used when a specific interaction with a certain API is needed.

Functional excipients offer wideranging benefits to formulators. High compressibility allows for the production of harder tablets using lower compression forces, which thus reduces strain on tableting equipment. In addition, tablets will take effect much faster, as the excipients improve disintegration time and accelerate API release.

Excipients are now available with significantly higher surface areas based on the same chemical structure; these include spray-dried mannitol, sorbitol, and mannitol/Corsscamellose Na formulation. The greater surface area of these excipient particles improve integration and content uniformity, as well as offering an optimised flow behaviour for easier blending and a stable high-throughput process.

Rapid Dissolution, Unmistakable Colour

The specific particle structure can allow additional functionalities to be easily implemented. For example, homogeneous coloured tablets can be achieved without coating or degradation of dissolution properties (1).

The colouration of solid drug forms is a generally accepted and effective way to prevent medication errors and to increase safety.We recently undertook a study of the compatibility of functional excipients (mannitol/Corsscamellose Na formulation) with pigments approved for pharmaceutical use. Based on a natural silicate (mica) combined with titanium dioxide and/or iron oxide, the colours have been widely applied in tablet coatings and in capsules.

Since the coating requires an additional process step, formulators seek opportunities to give tablets an unmistakable appearance by purely dry blending.This is especially important for orally disintegrating tablets (ODT) as the use of coatings would interfere with disintegration requirements.

Figure 1 shows the placebo compression profiles. According to hardness determination results, the colour additive did not lead to a significant change in compressibility, as extreme tablet hardness of more than 300N was still achieved.

In addition, no influence on the in vitro dissolution profile was detected (see Figure 2).The combination of high tablet hardness and fast dissolution results from the large structured surface area of the excipient particles.These surfaces interlock intensively at low compression forces.As the binding is performed by the needles on the surface of the particles, only the needles have to be dissolved to disintegrate the tablet. Especially in ODT applications, it is beneficial to have such a fast dissolution of nearly 100 per cent within five minutes.

Stability and Dissolution

In addition to eliminating the need for coating, the particle structure of excipients should enable the production of tablets that are considerably less sensitive to humidity than dosage forms created with other excipients. Figure 3 shows a comparison of the visual appearance of a placebo tablet formulated with two different excipients; dissolution and release remain the same even after 10 months.

New Directions

Functional excipients offer fast dissolving and orally disintegrating tablets independent of compression force and tablet hardness, giving both the formulation scientist and manufacturing manager new options.

With these functional excipients, it is easier to create small, hard tablets with short dissolution times, which are important features for paediatric formulations (see Figure 5). An additional benefit is that standard tablet hardness can be achieved by using lower compression force in the process, thus resulting in higher productivity. Fast dissolution tablets are frequently used in applications where rapid release is preferred, such as in pain medications or where instantaneous release in US Pharmacopoeia tests is important (see Figure 6).

The value of functional excipients is increasingly recognised in an industry looking for new sources of innovation. Demand for controlled release agents, improved bioavailability and other benefits is growing steadily. Novel functional excipients will continue to address the needs of advanced formulations with products adapted to the challenges of today’s pharmaceutical industry.

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Steffen Denzinger studied chemistry at the Universities of Mainz, UC Santa Barbara and Bayreuth, and obtained his PhD in 1996 in the field of supramolecular chemistry. He then held several positions in R&D, manufacturing, and quality assurance in companies emerging from the former Hoechst AG, working on offset printing plates and thermoplastic polymers. He then moved to Raschig GmbH, a German fine chemicals producer, as Head of R&D, and eventually QC/QA working on formulation solutions for several industries including fuel cell membranes, as well as working with fine chemicals. In 2009 he joined Merck KGaA to head the Global Applied Technology network within its life science solutions business area, which is now part of the new Merck Millipore division of Merck KGaA. In January 2011 he took over a new role as Head of Technical Marketing Pharma Raw Materials in the Pharm Chemicals Solution business of Merck Millipore.
Steffen Denzinger
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