Dispersion: advancing drug delivery

23 March 2018

New developments in the formulation of amorphous solid dispersions are an important facet of advancing new drug delivery systems. World Pharmaceuticals Frontiers explores recent developments in this area, focusing on its four major market offerings.

Drug delivery methods are constantly evolving as new technologies are discovered that can improve patient experience, safety and health. Professor Thomas Rades of the University of Copenhagen is one of the world’s foremost experts on the topic of such systems. The current market of amorphous solid dispersions, he says, can be broken down into four areas: drug solubility in polymers, the alternatives to polymers, the ‘spring and parachute effect’, and the in vitroin vivo correlation (IVIVC).

Amorphous solid dispersions: the low-down

When it comes to drug delivery terminology, a solid dispersion is a drug-polymer two-component system in which the mechanism of drug dispersion is the key to understanding its behaviour.

Amorphous solid dispersion (ASD) is used to describe solid mixtures of polymer and amorphous drugs. Other terms that have been used include amorphous dispersion, amorphous solid solution and molecular dispersion. Solid dispersion has become an established solubilisation technology for drugs that are largely insoluble in water, and the drug-polymer interaction is the determining factor in its design and performance. Current understanding of solid dispersions in their solid state and in dissolution is still expanding, according to Yanbin Huang from the Key Laboratory of Advanced Materials at Beijing’s Tsinghua University, whose paper ‘Fundamental aspects of solid dispersion technology for poorly soluble drugs’ emphasises the core features of this important technology.

Amorphous active pharmaceutical ingredients (APIs) can be produced in a variety of situations, such as vapour condensation; liquid supercooling; precipitation form solution – intentional, such as solvent evaporation, freeze-drying or spray drying, and unintentional, such as wet granulation and dryingpolymer film coating; and disruption of crystalline lattice, which also come in intentional (grinding) and unintentional (grinding, desolvation and compaction) forms.

They have a number of characteristics, including:

  • no long range order
  • a halo in XRPD patterns (versus crystalline peaks)
  • a short range order
  • less physical and chemical stability than crystalline materials
  • a higher apparent solubility and faster dissolution than crystalline materials.

According to papers by Ann Newman from the Seventh Street Development Group, the term ‘solubility’ – unless otherwise specified – refers to the ‘equilibrium solubility’ of the most stable crystal form in equilibrium with the solvent. The solubility of anything other than the most stable form is reported as the ‘apparent solubility’.

Dissolution methodology with an established in vitro-in vivo relationship or correlation may provide the desired in-vivo predictability.
– Gerald Bredead, Merck

Whereas ASDs are an amorphous drug with a polymer, the polymer stabilises amorphous drugs and thus results in better stability, higher apparent solubility and faster dissolution. They are usually prepared on a large scale by spray drying or melt extrusion.

What this all means is that when it comes to amorphous drug delivery systems, they exhibit increased apparent solubility and dissolution rate than crystalline materials, but can result in poor physical and chemical stability. Characterisation can include enthalpy relaxation, fragility and issues around glass transition temperature (Tg). This is the point at which a material alters state – going from a glass-like rigid solid to a more flexible, rubbery compound.

With ASDs however, polymers are added to stabilise amorphous material and can perform screens to find possible dispersions.

When it comes to manufacturing, it’s between spray drying and melt extrusion for larger-scale projects. The most important aspect, though, is performance, and there are three key aspects that must be looked at according to Newman: dissolution, stability and bioavailability.

There may or may not be IVIVC. This means that they can use simple prototype formulations, such as powder in a capsule, for early studies; additional work may be needed for later studies.

Drug solubility in polymers

Synthetic polymers have begun to enable ASDs to emerge as an oral delivery strategy for overcoming poor drug solubility in aqueous environments.

Modern ASD products are designed to non-invasively treat a range of chronic diseases, such as hepatitis C, cystic fibrosis and HIV. In such formulations, polymeric carriers generate and maintain drug super-saturation upon dissolution, increasing the apparent drug solubility to enhance gastrointestinal-barrier absorption and oral bioavailability.

There are several approaches in designing polymeric excipients to drive interactions with APIs in spray-dried ASDs, highlighting polymer-drug formulation guidelines from industrial and academic perspectives.

According to Dr Jeffrey Ting from the department of chemical engineering and materials science at the University of Minnesota, new commercial and specialised polymer design strategies can solubilise highly hydrophobic APIs and suppress the propensity for rapid drug recrystallisation. These molecularly customised excipients and hierarchical excipient assemblies are promising for informing early-stage drug-discovery development and reformulating existing API candidates into potentially lifesaving oral medicines for the growing global population.

Alternatives to polymers

Rapid advances in medicine and biotechnology have driven the field of drug discovery, leading to the development of many new, highly potent and target-specific drug candidates, and these will need alternatives to polymers.

A major challenge in drug development is ensuring that each new candidate is delivered to the right place, at the right time and in the right amount, according to literature supplied by Sigma Aldrich, the Merck subsidiary. Low drug solubility, drug degradation, drug toxicity or rapid clearance from the body can reduce the effectiveness of an otherwise promising candidate drug, so synthetic and natural polymers become an effective solution for the delivery of small molecules, proteins, genes or peptides.

But what can be done besides polymers? New directions in pharmaceutical amorphous materials and ASDs are not uncommon, but they are complicated.

Many small-molecule APIs exhibit low aqueous solubility and benefit from the generation of amorphous dispersions of the API and polymer to improve their dissolution properties. Spray drying and hot melt extrusion are common methods for producing these dispersions; however, for some systems, these approaches may not be optimal, and it would be beneficial to have an alternative route.

Polymer selection can be optimised by characterising the interactions between the polymer and drug, and by measuring the amorphous solubility in various polymer systems. Quantifying the amorphous solubility provides an understanding of the solubility enhancement provided by an ASD.

The ‘spring and parachute’ effect

A ‘spring and parachute effect’ is a technique such as selfemulsifying systems that allow rapid dissolution of a poorly watersoluble drug at a supersaturated concentration. Basically, polymers can be used to generate a ‘spring and parachute’ for ASDs.

What this means, in detail, is that supersaturating drug delivery systems use two important design elements in their preparation. This includes converting the drug into a high-energy state or another rapidly dissolving form to facilitate the formation of supersaturated drug solutions. This provides a means for stabilising the formed supersaturated solution allowing significant drug absorption to be possible from the gastrointestinal tract.

Drugs with high Tm/Tg (K/K) values tend to be fast crystallisers, while those with lower ratios tend to be slow dissolvers. Therefore, fast crystallisers will require polymers that provide a ‘parachute’ while the slow dissolvers require a ‘spring’, according to Michael Grass, a senior research chemist at Capsugel. The formulation of ASDs typically involves the addition of polymers to raise the Tg, enhance the dissolution and protect the drug from crystallising.

In vitro-in vivo correlation

According to Merck’s Gerald Bredead, the ability to predict the in-vivo response of an oral dosage form based on an in-vitro technique has been a sought-after goal of many pharmaceutical scientists.

In his piece for the Journal of Pharmaceutical Science – ‘In Vitro-In Vivo Correlation Strategy Applied to an Immediate- Release Solid Oral Dosage Form with a Biopharmaceutical Classification System IV Compound Case Study’ – he says, “Dissolution testing that demonstrates discrimination to various critical formulations or process attributes provides a sensitive quality check that may be representative, or may be over predictive of potential in-vivo changes. Dissolution methodology with an established in vitro-in vivo relationship or correlation may provide the desired in vivo predictability.”

The in vitro-in vivo link has many potential outcome scenarios, some of which can be used. The investigation of a Level C IVIVC, which is the most common correlation for immediate-release oral dosage forms, is perhaps the most capable of being worked into drug delivery and commercialisation.

The number of marketed products containing ASDs continues to grow and is an example of successfully transforming academic ideas into marketed products. Current academic research will continue to increase understanding of these materials and will be used to more efficiently develop these systems into marketable products in the future.

What we need to do is find more ways to commercialise drugs quickly, so they don’t languish in development. However, with the current costs of taking a drug to market, this remains untenable.

The question is: how can we make things faster and embrace the new technology on offer, while not losing money? Perhaps, as new avenues are pursued, the answer will become clearer.

Modern ASD products are helping to manage chronic diseases such as hepatitis C, cystic flbrosis and HIV.
Amorphous APIs can be formed in numerous situations, such as liquid supercooling and vapour condensation.

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