(MINI WEBINAR) Integrated services for achieving the optimal solid form

In this ten minute webinar, our solid state team discuss the importance of solid state chemistry in API development and manufacturing.

Solid form development has become a core focus for pharmaceutical and biotechnology organisations as they develop novel APIs. An API’s solid form has critical implications for physical properties like solubility and bioavailability, and a given API can have a number of different solid form versions.

Consider these statistics. Around 90% of newly discovered APIs today display poor solubility. Solid state chemistry can be key to enhancing solubility and maximising therapeutic efficacy, and given the complexity and poor solubility of many new APIs, it has become especially important.

In addition, 85% of APIs are polymorphic, meaning that they have multiple different forms, and around half of all commercialised APIs are developed as salt forms, which are identified through solid form investigations.

With that in mind, why is solid state chemistry so important? There are several key reasons. The primary reason is that it enables us to identify a target solid form with the desired physical properties. This is important for ensuring that the API functions as anticipated.

In addition, solid state chemistry can help us to highlight potential challenges different forms may present with absorption in the body. With this in mind, we can investigate other solid forms that may be more desirable, or consider things like bulk particle manipulation to further enhance physical properties.

In addition, solid state chemistry enables us to choose a solid form that will hold up through manufacturing and commercialisation. How will the API behave under different storage conditions? Does it remain stable?

Finally, solid state chemistry enables us to generate intellectual property. Performing various solid form investigations and protecting API versions through IP prevents exploitation.

So, where does solid state fit into the development process? In short, it is relevant throughout the entire project, beginning with early phase research and development and continuing through preparation for commercialisation. Because the solid form is such a key indicator of solubility and bioavailability, it is important to consider at every stage.

When we talk about solid state chemistry, there are several key components. The order of these elements generally remains the same, but not all of them are always necessary. This is dependent upon where the project is in development, as well as the customer’s requirements.

Here, we have salt and cocrystal investigations, polymorphism screenings, pre-formulation evaluation, crystallisation development, and bulk particle manipulation. Now, we’ll take a closer look at each of these.

First, we have salt and cocrystal screening. These investigations aim to identify a target solid form with enhanced solubility, dissolution profile, or physio-chemical properties and manufacturability, as opposed to the free API.

Salt and cocrystal screening start with characterising the free API, looking at crystallographic powder pattern, thermal profile, propensity towards water uptake and purity. Then, we can compare these properties across any salt or cocrystal forms that are generated.

Equilibration of the free API in different solvents is then used to identify visual solubility and understand suitable solvents or anti-solvents. The solubility can then guide the number of possible salt screens, and counter ion are selected based upon pKa. All isolated solids are characterised to identify suitable hits that should be scaled up. When we’re looking for relevant hits, we’re looking for relatively high crystallinity, acceptable thermal profile and composition.

During salt screening, a cocrystal may form instead. While salt generation is determined by proton transfer, cocrystals are generated by intermolecular attractions between the API and conformer. Salts and cocrystals can be differentiated using XRPD, DSC, NMR, Raman, or Infra-red spectroscopy.

Then, we have polymorphism screening, which evaluate the API’s potential for polymorphism. These investigations also help to discover the thermodynamically stable solid form, establish a form hierarchy, and identify the API version that demonstrates the greatest form and chemical stability. This can occur after salt screening, or with a supplied API.

As with salt screening, the free API must first be characterised, and then equilibration in a range of solvents occurs. We can then identify whether any solids formed are solvates, hydrates, or new polymorphic forms. If the API is crystalline, it is important to then isolate the amorphous version, which is highly energetic and can be used to access meta-stable versions.

Additional investigations may then occur to identify suitable new versions to be scaled up and evaluated. In addition to discovering a thermodynamically stable form and helping to control impurities, an understanding of the polymorph landscape is also necessary from a regulatory standpoint.

After these initial investigations, it is likely that multiple potentially-suitable solid forms have been identified. In this case, we perform pre-formulation evaluations, either in conjunction with earlier investigations or as a subsequent step, in order to understand the forms’ behaviour under various conditions.

In these evaluations, we assess API solubility in biorelevant media, chemical and form stability under accelerated storage conditions, under compression or particle size reduction, and powder flow characteristics. This provides an idea of how the form might behave through particle manipulation and manufacture, upon storage, and in the body. We can then eliminate unsuitable versions from further consideration to arrive at an ideal target solid form.

Next, we have crystallisation development, which aims to produce an API version suitable for dosage manufacture. Crystallisation can be challenging, as many competing priorities are at play. These include chemical purity, API version, and particle shape and size. All of these factors can impact operations down the line, like filtration, drying, secondary processing, and formulation, so they are important to control.

Crystallisation development is a broad area, but in general, key things to consider include crystal basics, process variables, material attributes, and economic viability upon scale-up.

The ultimate goal of crystallisation is to reproducibly afford the same quality of material, with the same physio-chemical attributes suitable for the drug product.

Finally, while crystallisation aims to achieve the required API version with a suitable particle size distribution for manufacture, this may not always be the case. In these situations, bulk particle manipulation like milling and micronisation may be required to break down particles in order to improve drug product manufacture or dissolution.

Bulk particle manipulation can be used to modify properties like particle shape, size, size distribution, density and powder flow. All of these properties have important implications for drug product manufacture, and ultimately, efficacy.

Now that we have a strong overview of what goes into solid state chemistry, let’s discuss some of our capabilities here at Sterling. As you can see here, we have capabilities spanning all of the key areas of solid form I’ve just discussed. Our understanding of each of these components and how they connect enables us to pragmatically approach every project based on their unique requirements.

We can offer solid form support at every stage of the project. Our Material Science Centre, located at our Dudley, UK headquarters, houses a wide variety of specialised solid state equipment, enabling us to perform robust investigations and help customers achieve their ideal target solid form.

For bulk particle manipulation, we can achieve a particle size down to 30 microns through milling or 2 microns through micronisation, using a variety of different types of milling. This equipment is housed in ISO Class 8 cleanrooms with containment up to OEB 4, where customers can view project operations live via CCTV.

We do not do high-throughput solid state work at Sterling. Instead, we take the time to understand our customers’ unique requirements and tailor our approach based on their project. Collaboration and partnership are integral across Sterling, and this holds true for our solid state team. It is also important to note that we can offer solid state services both as an integrated offering within a larger project, or as a standalone service.

Thank you for listening, and be sure to take a look below for other useful content.