Day 3, Wednesday 23 August: Collaborative Drug Development in India
Dr Clare Sansom, Department of Biological Sciences, Birkbeck College, London, UK
For many decades, India has been well-known worldwide for producing cheap, generic versions of essential medicines, in a valuable role that led it to be termed ‘the world’s pharmacy’. The Indian drug discovery industry is much newer, dating only from the 1980s, and if you see success only in terms of drugs registered by the FDA it has had very little. No novel compound discovered in India during the last thirty years has yet reached the market. The challenges currently faced by the Indian pharmaceutical industry, however, are mirrored worldwide and, as in many other countries, increasing collaboration between the various sectors of drug research – academia, government and industry – is seen as key to increasing productivity. This was the theme of an interesting and very well attended session in the IUCr parallel programme. The session focused on an area of research that is equally applicable in innovative drug research and generic drug development, that is a key strength of Indian science, and that has a strong association with crystallography: solid state forms in drug formulations.
With the designated session chair, G. Sahni from CSIR in New Delhi, absent ill, the session was chaired by Gautam Desiraju (IIS, Bangalore). His first task was to introduce himself as the first speaker, and he began by re-stating some of the problems with the Indian pharmaceutical industry in an era in which increased investment is leading to disappointingly few novel drugs on the market. In this context, research into novel drug formulations is a cheaper alternative that plays to India’s strengths in solid state and crystal chemistry. Drug compounds can exist in a variety of forms including salts, co-crystals, solvates and amorphous forms, and each of these can be polymorphic. There are many ways to alter the physical properties of a drug compound; the aim of drug developers is to move their most promising molecules into the so-called ‘golden region’ with high aqueous solubility but high membrane permeability. He ended his talk with an example; the antibacterials norfloxacin and sulfathiazole can be delivered as a mixture, but co-crystallisation will improve the permeability of the mixture without changing the efficacy of either compound.
Regulatory agencies have been involved in solid-state chemistry since the effects of crystal form on drug stability were first noticed in the 1960s. Steve Byrn, who has worked in industry and regulatory affairs and is now at Purdue University in Indiana, USA, explained how regulators approach these issues. He cited the example of the HIV protease inhibitor ritonavir, which was known for a time as the ‘magic Johnson drug’ for the dramatic improvements it offered to patients with AIDS. However, it formed insoluble spherulites in the soft gel capsules in which it was dissolved, reducing its bioavailability and thus its effectiveness. For a while, it was only available in a liquid form that tasted so bad that some patients quipped that they would rather die from AIDS. Some 80% of drugs currently under development have potential problems with solubility. Byrn described the concept of ‘equivalence’ that the FDA uses to determine whether forms of a product will behave in the same way. For two formulations to be equivalent they must have the same microstructure; a new drug polymorphism is not a generic but a novel entity.
With Dr Sahni absent, Professor A. Nangia, the director of the National Chemical Laboratory at Pune, India, gave an unscripted, largely autobiographical talk. He has worked in drug discovery in government and academia and as an entrepreneur, and he described the changes that he has seen in the research funding landscape in India throughout his 30-year career. Before the millennium, funding was low but safe; since then there have been ups and downs but on average there have been more funds available, and students recently graduating from his lab have gained experience with state-of-the-art equipment. Funding is also available for research-based startup companies, but there have been few genuine successes so far. A lively discussion focused on possible reasons for this, with the academic bias of the peer review process and the need for market ‘pull’ as well as technology ‘push’ emerging as likely reasons.
Dr A. Venkateswarlu from Dr Reddy’s Institute of Life Sciences (DRILS) in Hyderabad looked at the role of co-crystals in drug development from a manager’s perspective, starting by stressing the difference between drug substance (the active compound) and drug product (the finished tablet or capsule, in which that compound has been combined with other ingredients). Any molecule that alters the drug’s activity when combined with a drug substance – as co-crystal components may – is also considered a drug substance. He applied the well-established SWOT model (strengths, weaknesses, opportunities and threats) to pharmaceutical co-crystals. A different co-crystal form will sometimes offer a solution to problematic pharmacokinetics and can also add to intellectual property, although not to the same extent as a completely novel compound would. The final talk was entertaining, eclectic and entirely unscripted; the speaker, India Glycols’ R.K. Khandal, abandoned his slides saying that the material he had prepared had all been covered. A.V. Rama Rao, owner of contract research company Avra Laboratories in Hyderabad, summed up the session, stressing again the rewards and challenges of working in industry.