Laser synthesis technique could provide better APIs

11-Aug-2015 - Last updated on 12-Aug-2015 at 11:39 GMT

Not that kind of laser... Scientists in Japan are using lasers to synthesise unstable APIs

Related tags Pharmacology Paracetamol

Scientists in Japan have developed a technique for making crystal forms of active pharmaceutical ingredients (APIs) that until now have been hard to synthesise.

Using lasers, the team generated a particular 'polymorphic' form of the anti-inflammatory drug indomethacin that offers increased solubility and bioavailability but is usually too unstable to be used in medicines.

The finding raises the hope that the technique could be used to improve on existing APIs – for example by reducing the dose needed and cutting side effects – and possibly allow them to be repurposed for new therapeutic uses.

Laser irradiation

Kenji Ikeda of Osaka University and co-workers from across Japan developed the technique to create crystals of alpha-form indomethacin which remained stable in air at room temperature for up to eight months. Prior to this, researchers had been unable to make alpha-forms that were stable for more than a day.

The team used femtosecond laser irradiation of a highly-concentrated solution of indomethacin to form crystal nuclei, discovering that when the laser was focused near the side wall of the glass vials, the alpha or 'metastable' form of the drug crystallised rapidly.

The solubility of the metastable form was 1.5 times higher than indomethacin's stable polymorphic form, they found.

One of the members of the research team, Mihoko Maruyama of Osaka University, told in-PharmaTechnlogist.com that "in principle, the laser technique is a very simple physical model [and] applicable to other classes of API," it would be challenging in cases where the API molecules are unstable.

The method is not really suitable for making bulk APIs, although the principle behind it – controlled triggering of crystal nucleation – can be achieved in other ways.

"The application to large-scale may be difficult in the case of laser induced crystallisation as it stands, because nucleation is limited by the laser operation," said Maruyama.

"However, we have another practical technique - selective crystallization of metastable phase by ultrasonic irradiation – that we think […] is more suitable to large scale API manufacture."

Pharma partnership

Maruyama and colleagues in Japan have already used ultrasonic irradiation to control the crystallisation of the non-steroidal anti-inflammatory drug (NSAID) acetaminophen (paracetamol), reporting earlier this year that they had successfully synthesised a metastable form of the drug that is more soluble and easier to compress into tablets.

The new forms would likely require approval as new chemical entities by regulators, but their improved properties could make this a worthwhile endeavour, according to the researchers.

"The next steps are to establish a technique to make the metastable phase with higher stability," said Maruyama, adding the team is hoping to partner with pharmaceutical companies on this research.

"The stability of API is the most important point when we consider practical realisation of the newly crystallized API," she added.

A key objective will be to clarify and suppress the mechanisms behind phase transition - when one polymorphic form switches to another.

Both the laser and ultrasonic radiation studies are published in the journal Applied Physics Express.