A guide to achieving the optimal solid form
29th Apr 2024
Key solid state processes for API development
In the last several years, solid form investigations have become increasingly important to consider during API development. Solid state chemistry aims to improve an API’s solubility, hygroscopicity, dissolution rate, flow characteristics, compressibility and other key properties. This is especially critical today, with an estimated 90% of newly discovered small molecules displaying poor solubility in water.
Because an API’s physical properties, as well as the crystal lattice packing arrangement, have a significant impact on therapeutic performance, pharmaceutical and biotechnology organisations have made solid state chemistry a key priority during development. In addition, regulatory requirements increasingly insist on a better understanding of API solid forms. Solid state chemistry also presents opportunities for impurity control and intellectual property generation for different API versions, adding to its importance. However, solid state investigations can go on indefinitely, with more and more form versions arising as investigations are carried out, so organisations must find the right balance between timelines, costs and efficacy as they aim to achieve their ideal solid form. An experienced partner can provide the expertise and guidance necessary to strike this crucial balance.
In this guide, we will discuss five key aspects of achieving an API solid form with the desired properties: salt and cocrystal screenings, polymorphism screenings, pre-formulation evaluation, crystallisation development and bulk particle manipulation.
When to use: When the free API demonstrates limited solubility.
An optimal salt version of the free API would ideally have enhanced solubility and, in theory, improved bioavailability. A free API can behave as an acid or base, dependent on the predicted pKa of the ionisable group.
In addition to the counter ion’s pKa units, safety of the counter ion, route of administration, intended dosage form and toxicological and pharmacological implications must also be considered. Due to the large list of considerations and the potential for numerous screenings, generally regarded as safe (GRAS) counter ions and those widely utilised in marketed drugs should be selected as screening candidates.
It is also important to note that in these screenings, a cocrystal may form instead of a salt. While salts are generated through proton transfer, cocrystals are generated through intermolecular attractions between the API and conformer. Salts and co crystsals can be differentiated using solid state NMR, raman or infrared spectroscopy.
Salt screenings should begin with characterisation of the free API, which ultimately makes it easier to identify and eliminate inappropriate salt forms. Then, equilibration of the free API in various solvents should be used to identify suitable dissolution solvents, anti-solvents, and form stability of the input material. Visual solubility, along with the project’s intended length, then informs the number of salt screens that should occur. The free API should then be dissolved in a variety of non-aqueous and aqueous media to then characterise all solid hits, with the most relevant being scaled up for form selection. Ideal salt candidates can be reproducibly isolated without solid form variation and are stable in humid conditions, ultimately improving chemical purity, form stability and solubility.
Look for a partner who:
- Enables the customer to inform the depth of salt screenings
- Utilises robust analytical techniques to differentiate between salts and cocrystals
- Leverages various analytical methods including x-ray powder diffraction, differential scanning calorimetry, and 1H nucler resonance spectroscopy to characterise and select salt hits
- Scales up salt formulations in order to ensure reliability
- Supplements salt screenings with pre-formulation evaluation
Nearly half of all APIs on the market are developed as salt forms.
When to use: After salt screening, to assess the propensity of salt versions towards polymorphism, or on a free API.
The purpose of a polymorph screen is to identify the potential of an API for polymorphism, determine the thermodynamically stable form and establish a form hierarchy. In turn, an organisation can identify an API version with the ideal form and chemical stability ahead of pre-formulation evaluations and crystallisation development.
Like in salt screening, a polymorph screen begins with characterisation of the free API and equilibration in a range of solvent chemotypes and solvent mixtures. If it is determined that the API is crystalline, it is then important to generate anamorphous version, which is highly energetic and able to access other forms. Sometimes, the amorphous version is quite difficult to isolate, but can be used to evaluate visual solubility.
A variety of subsequent investigations may then occur, including further equilibrations with thermal modulation, saturated solution cooling crystallisation and vapour diffusion, as well as scale-up and further assessment of new forms to understand behaviour, form fate and form hierarchy. After performing robust polymorphism investigations, an organisation can summarise the hierarchical relationship with a form diagram to help identify the thermodynamically preferred version for further development.
Look for a partner who:
- Prioritises isolation of the amorphous API version
- Leverages a range of analytical techniques for robust polymorphism investigations
- Can perform a variety of subsequent polymorphism investigations to identify the thermodynamically preferred API version
- Summarises the hierarchical relationship of forms
Around 85% of APIs are polymorphic.
When to use: During salt, cocrystal or polymorph screenings to aid in version selection, or as a separate step.
There are many factors to consider and assess during a pre-formulation evaluation, which can include biorelevant solubility and stability, chemical and form stability under accelerated storage conditions, stability to compression and milling or grinding, bulk density, tap density and flow characteristics.
In order to test biorelevant solubility, organisations should assess a range of dissolution media. Accelerated storage conditions should evaluate the API’s chemical and form stability with regard to temperature alone, and temperature and humidity. It is also critical that an API version is able to withstand manufacturing processes. Utilising compression force through milling and grinding imitates the forces applied in manufacture and particle manipulation. Finally, bulk and tap density help to determine flowability for a powder solid, which has important implications for crystallisation.
It is common for different aspects of pre-formulation evaluation to be employed throughout solid state development, rather than as standalone processes. It has many important use cases, including aiding in salt and cocrystal selection, supporting form version determination, directing crystallisation development and ensuring suitability for manufacture and particle manipulation.
Look for a partner who:
- Assesses the API’s suitability under various conditions
- Ensures that the API version will withstand manufacture and storage
- Provides crystallisation and manufacturing expertise to understand key criteria for pre-formulation evaluation
- Delivers comprehensive solid state chemistry experience to understand what qualifies an ideal target API version
Pre-formulation evaluation considers conditions the API version will be exposed to within the body, in storage and during manufacture.
When to use: After an ideal target API version has been identified.
Crystallisation development can vary significantly, as it depends on a variety of factors. These include the nature of the target API version, solubility data, and whether there is an existing crystallisation process that must be modified, which may require additional screenings.
Assuming a polymorphism screen has been conducted, one or more methods of crystallisation could afford the target API, taking into account recovery, impurity control and residual solvent content. In any crystallisation programme, it is critical to ensure feasibility for scale-up by assessing solubility profiles.
The simplest crystallisations to work with are cooling crystallisations, as the desired salt and/or polymorph is isolated from a solvent or solvent mixture once cooled. Solubility curves largely drive this type of crystallisation, and it evaluates the impact of different cooling profiles. On the other hand, there is anti-solvent driven crystallisation, which is driven by reduced solubility of the API version in the anti-solvent. Lastly, there is salt formation crystallisation, driven by the difference insolubility characteristics between the free API and API salt.
In addition to these types, existing crystallisation optimisation is also common. This can be very simple when key parameters are already defined, or quite difficult when a supplied process is less reliable. Regardless of the type of crystallisation, an optimal process should afford the best balance of improved recovery, impurity control and improved particle habit.
Look for a partner who:
- Aids in API version selection through salt and cocrystal screenings, polymorphism screenings and pre-formulation evaluation prior to crystallisation development
- Delivers expertise across various types of crystallisation
- Has experience optimising existing crystallisation processes
- Maintains an awareness of the potential need for particle size manipulation during crystallisation
Over 90% of APIs are crystalline.
When to use: After crystallisation, if particle properties must be modified to improve dissolution.
If an API version requires additional optimisation to improve manufacture, bulk particle manipulation should be used. Bulk particle manipulation is a ‘topdown’ operation that aims to improve particle properties like shape, size, size distribution, hygroscopicity and flowability through the use of physical force. Milling and mirconisation are most commonly used for bulk particle manipulation, and milling can also be utilised to target an amorphous solid.
Milling and micronisation not only prepare the API for improved formulation, but also aim to enhance bioavailability by reducing particle size and increasing specific surface area. This helps to improve dissolution and absorption within the body. These methods can also afford greater process control by improving particle size uniformity.
As newly discovered small molecule APIs have become more complex, more and more products in the pipeline have been considered poorly water soluble. As a result, because of their ability to improve solubility, milling and micronisation have become increasingly important.
Look for a partner who:
- Ensures proper containment for milling and micronisation equipment
- Provides full visibility to customers through CCTV monitoring
- Offers a variety of milling types to meet different particle size requirements
Milling can reduce particle size to 30 microns, while micronisation can achieve a particle size of 1-5 microns.
Robust solid form solutions to enhance long-term success
Especially in recent years, solid state chemistry has become a key focal point for biotechnology and pharmaceutical organisations as they develop novel APIs. At Sterling, we deliver a full range of solid state capabilities to set our customers up for success. With our expert teams in the UK and US, specialised equipment, a dedicated Material Science Centre at our Dudley facility, and much more, we have the ability to perform full solid form investigations, crystallisation development and bulk particle manipulation.
We offer solid state services as a standalone entity, or as a component of a larger project. With a focus on rich scientific collaboration, we work closely with our customers to understand their specific project requirements and tailor our approach. We are committed to maximising customer success, achieving an ideal target solid form while adhering to time and budget requirements.
An ideal partner for achieving your ideal solid form
At Sterling, we deliver a broad range of solid state services, supported by true scientific partnership. Here are some of the things that set our solid state solutions apart:
- State-of-the-art Material Science Centre with fully equipped analytical laboratory, solid form laboratory and write-up area
- Dedicated team of experienced solid state scientists
- Six ISO class 8 cleanrooms, housing up to four discreet milling and micronisation systems
- Multiple mills offering a range of milling solutions, including hammer, knife, cone, sieve, pin and wet milling
- Standalone services or integrated project work in solid state chemistry
- Wide range of analytical techniques for solid form characterisation
