The Pharmaceutical Journal Vol 267 No 7169 p510-525
13 October 2001

BPC 2001 summary

Disordered drug delivery: destiny, dynamics and the Deborah number

A report published earlier this year by the Royal Pharmaceutical Society, entitled “UK drug delivery research: the way forward in the new millennium”, (PJ, March 10, p324) led Dr Bruno Hancock to think about why he had followed his particular pathway in research. Dr Hancock, senior research investigator, pharmaceutical research and development, Pfizer Inc, said his own dreams for the future of drug delivery covered three areas:

1. Enhancing the activity of low molecular weight pharmaceutical materials
2. Improving physical properties of materials
3. Delivering biotechnology products, such as proteins and peptides, to the human body

Dr Hancock said that these are goals he shares with many other pharmaceutical scientists. A new discipline has emerged in the past 10 years, known as pharmaceutical materials science. This is concerned not only with the characterisation of materials, but also with the manipulation of material properties to bring out the best in the properties of drugs and excipients so that they can be more effectively delivered to the human body. Disordered drug delivery, the subject of his lecture, formed part of this discipline.

Disordered drug delivery

The majority of active pharmaceutical ingredients and excipients exist in the crystalline state because this is the lowest energy state possible for that material. Disordered drug delivery techniques aim to reduce or eliminate this crystalline structure in order to produce a pharmaceutically acceptable high-energy and high-activity form of the drug and/or delivery system. The benefits of this approach to drug delivery are:

• Increased aqueous solubility and therefore improved bioavailability.
• The possibility of forming new and more uniform physical properties that are not available with crystalline forms of drugs. With disordered drug delivery systems, there is no need to comply with certain crystalline features or templates.
• Factors such as particle size, shape and density can be controlled more easily and there is a greater range of properties to choose from.
• An ability to form molecular level mixtures of disordered materials, such as amorphous alloys analogous to metal alloys. This mixing approach can be used to customise the physical and chemical properties of these materials.

For example, in experiments using a disordered drug form of indomethacin, Dr Hancock and colleagues showed that solubility could be improved over that of the crystalline form.

Molecular view

A disordered or amorphous material can be thought of as a solid (ie, a material with a high viscosity) without the three-dimensional long-range molecular order that is normally present in crystals. Generally, with crystals, molecules come out of solution quite slowly and are able to arrange themselves in an ordered fashion. By contrast, with amorphous forms, molecules appear more rapidly and become arranged in a more random fashion relative to each other.

One of the most striking differences between crystalline and amorphous materials is their specific volume (the volume taken up by a unit mass, or 1g, of material). For crystalline materials, the molecules pack efficiently. Thus they generally have a small specific volume. The molecules of amorphous materials do not pack together as efficiently, so these materials have a greater specific volume. The difference in specific volume is typically around 10–15 per cent. The regular molecular packing of crystals means that crystals tend to have regular shapes (eg, needle-shaped), whereas in amorphous material molecules do not form particles with a regular repeating shape. Differences between crystalline and amorphous materials can be detected using a microscope and, in some cases, with the naked eye. For example, crystalline indomethacin is white but amorphous indomethacin is yellow. This is used as a quality control check during the preparation of indomethacin suppositories (where the drug is intended to be in the amorphous state) to detect crystalline contaminants in the amorphous material.

Amorphous products

According to Dr Hancock, amorphous materials are more common in everyday life than perhaps imagined. There are many examples of amorphous pharmaceutical materials, including organic small molecules (such as indomethacin), polymers, sugars and carbohydrates, peptides and proteins, lipids and oils, and inorganic materials (salts, acids or bases). Thus, there are many opportunities for applying disordered drug delivery in common formulation practice.

There are amorphous pharmaceutical materials on the market. In the European Pharmacopoeia, more than 35 materials (both active ingredients and excipients) are described as being amorphous. There are five in the United States Pharmacopeia and over 25 different dosage forms in the Physicians’ Desk Reference contain amorphous drug substances, including antiinfectives, anticoagulants, antiinflammatories, analgesics, hormones and preparations for both internal and external use.

Major challenges

Dr Hancock said that the main challenges for the future of disordered drug delivery research are:

• Characterisation The majority of characterisation tools for drugs and excipients were originally designed for studying crystalline materials
• Predictability How could the performance and stability of amorphous materials be predicted, for example, after they had been on the shelf for two years
• Amorphous engineering Manufacturing custom materials (alloys) with optimal physical properties that are better suited to drug delivery

Characterisation

It is now recognised that amorphous materials should not be simply treated as non-crystalline. They can be characterised in terms of the mobility of molecules within the amorphous material. Dr Hancock explained that all molecules have some degree of molecular mobility at ambient conditions. All solids primarily experience vibrational motions, whether in the crystalline or the amorphous state. Transitional motions (eg, side-to-side movements) are rare in crystals, but more common in amorphous materials. Thus, amorphous systems can be distinguished by this enhanced level of molecular mobility.

“This is a handle that we can grab onto in terms of characterising [amorphous materials],” Dr Hancock said. “I think we have reached a point where we understand these systems well enough, and we can characterise them well enough, that we can start to talk about predictability, especially ... predictability of stability.”

Predicting stability

Materials in the amorphous state are inherently metastable (unstable), compared to materials in the crystalline state. This is one reason why there has been reluctance to study these types of materials. However, there are examples of amorphous materials with good stability, such as glass, certain types of confectionery (eg, seaside rock, which contains sugars in a non-crystalline state), and certain pharmaceutical products. A key question is how stability can be achieved and guaranteed for disordered pharmaceutical materials. In 1995, Dr Hancock and colleagues proposed that a fundamental way of predicting stability was by fully understanding the timescales for molecular motion in non-crystalline materials. To understand timescales, it is important to have a reference point — rates must be considered relative to the timeframe of concern.

In stability, the objective is to reduce the probability of critical molecular motions during the lifetime of a pharmaceutical product to an insignificant level. This is a statistical approach based on probabilities and on relative timescales. It is also important to know exactly what are the critical molecular motions. This approach has led to the development of a parameter known as the Deborah number. This is usually used to describe a material’s viscosity, but can be adapted and used as a molecular mobility index.

Materials that are efficacious, but unstable, present a dilemma with regard to “making them work” in pharmaceutical formulations. Ideally, the properties of these materials should be manipulated, or engineered, so that they have appropriate physical properties.

Engineering amorphous materials

In principle, it should be possible to start with a drug plus excipients, and to apply a process, such as freeze-drying or spray drying, which disorders those materials down to a molecular level. This should result in a single material that is a miscible amorphous alloy of the component materials and which has a set of unique properties.

Amorphous materials can be made in many different ways: from the liquid state by removing energy, for example, by a supercooling process or by a polymerisation-type reaction; from the vapour state by sublimation; from the solution state by rapid solvent removal (eg, by freeze drying, spray drying, precipitation); or from the solid state (ie, directly from a crystalline to an amorphous solid) by processes such as grinding, decompression or dehydration to remove the crystalline order.

Concluding, Dr Hancock said: “The future of this field is wide open ... the opportunities are there for doing an even better job of defining the properties of amorphous materials and developing better tools and techniques for characterising them”

The ability to predict might not be as good as it should be, but steps have been made in the right direction, he continued. It may be possible to predict not only stability, but also biopharmaceutical performance and many other properties of amorphous pharmaceuticals.

This is a new area of pharmaceutical science and one that is likely to learn from other disciplines where custom materials are the norm rather than the exception.

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