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Discovery & Development Small Molecules, Formulation, Ingredients

The Significance of Solid Form Science

sponsored by Johnson Matthey

There are a number of ways to manipulate a molecule’s solid form to achieve the optimal physiochemical properties, including solubility and bioavailability, for the chosen delivery method. Alan Chorlton has spent the best part of 25 years working in solid state science, and in 2003 he cofounded Pharmorphix – a company specializing in solid state pharmaceuticals. In 2015, Pharmorphix was acquired by Johnson Matthey, where Chorlton now works as a Commercial Director. Here, Chorlton gives an overview of the field and how solid form science has progressed in recent years.

Why is solid form optimization so important?

Once a pharmaceutical company has identified a molecule they want to move through to the clinic, understanding and choosing the right solid form is vital to give the product the best chance of future success. Manipulating the solid form can help enhance key properties, such as bioavailability and solubility, and facilitate synthesis and scale up. Different routes of administration all require different physicochemical properties – what works for an oral formulation is often different to what works for a dermal formulation, for example. Adjusting the solid state, by developing co-crystals of a drug molecule, for example, can make a big difference. We managed to transform a drug that caused dermal abrasion into a molecule (using co-crystals) that could permeate the skin, without irritation. It’s also possible to use solid state science to control properties such as solubility and pH, which are important in ocular and intravenous formulations.

How can the solid form be optimized?

The first port of call is usually to manipulate the solid form by choosing the right salt. Around 80 to 90 percent of drugs on the market are ionized, which means researchers can make different salt forms. Choosing the right salt can lead to better stability and solubility, depending on the delivery method, so it’s important to have a good salt selection process. Usually, a molecule is screened against 20-40 different salt types to try and establish the salt that has the best properties for the desired formulation, be that an oral drug or a dermal formulation.

Once you’ve identified one or two salts with the right physiochemical properties, the next step is to consider polymorphism – the ability of a drug to exist as two or more crystalline phases – which can affect stability, solubility, synthesis and scalability. It is critical (and a regulatory requirement) that your polymorph be stable to prevent it from changing during the drug’s shelf life – in extreme cases, some drugs have been withdrawn from the market due to polymorphic changes. At an early stage of drug development, it’s important to review the different polymorphic forms of your molecule to establish which is most suitable. Polymorphic forms can also be patented, offering the potential to extend a drug’s lifecycle.

How is the field of solid state sciences advancing?

Advances in high-throughput screening technologies – as well as analytical systems – have made searching for polymorphs much faster. In the past, it might have taken a PhD chemist an hour to analyze a sample, but now hundreds of polymorphs can be analyzed with x-ray powder diffraction within hours. Another important technique is single crystal x-ray diffraction – which is currently the best way to identify your molecule’s crystalline structure.

There have also been significant advances in the understanding of amorphous materials. Amorphous materials are non-crystalline solids that can help enhance bioavailability and solubility – making them good candidates for pharmaceuticals. Historically, pharma companies have been wary of amorphous forms because, unlike crystalline forms, they lack a specific crystalline order, which means they can destabilize at any time – a ticking time bomb for your approved drug! Over the past decade, advances in solid state science, along with the emergence of hot melt extrusion and spray drying, have allowed amorphous materials to be stabilized. Today, there are around 30 amorphous drugs on the market,  which is a significant increase over the last decade.

What is the most important element of solid state science?

Integrating all the various aspects of solid state science is arguably the most important factor. Understanding a molecule’s physiochemistry and being able to screen for and take forward the right salt forms is one thing, but you must also have the right processes in place to scale up and manufacture the drug to develop stable and effective formulations. You need to develop a crystallization process that allows the molecule to be synthesized and manufactured consistently and repeatedly, and implement control measures to get the right yield and purity.

I derive great satisfaction from the fact that many of the drugs we’ve worked on at Johnson Matthey at the early stage are now on the market. Without the expertise that went into choosing the right solid form, many of these drugs might not have made it.

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