The top 3 challenges in solid state chemistry and how to overcome them

Solid form selection is an essential step in the API development process, vital to optimising drug substance solubility, bioavailability and efficacy. At the same time, this process is a complex one, marked by several nuanced challenges. It requires a combination of interconnected elements, which must be carefully calibrated to achieve a solid form that not only meets therapeutic objectives, but also performs consistently during manufacturing and throughout the product’s lifecycle.

In this blog, we’ll explore the interconnected steps of solid state chemistry and discuss how these processes collectively influence active pharmaceutical ingredients’ (API) performance. Then, we’ll examine three of the most common challenges in solid state development through the lens of real-world case studies.

Particle size, solubility and process equipment: The interconnected steps of solid state chemistry

Solid state development encompasses a suite of complementary scientific processes, each contributing to the ultimate goal of producing an API with optimal physicochemical properties, including chemical purity, stability, form or version, and particle size and habit. These steps are highly interconnected and must be approached holistically to ensure successful development outcomes.

The journey often begins with salt or co-crystal screening, which aims to improve solubility, efficacy and physical properties. This is followed by an evaluation of the API’s propensity for polymorphism, which identifies the preferred solid form or version to progress into development. Pre-formulation evaluation then helps to further refine this selection by comparing forms with similar characteristics.

Once a form is selected, crystallisation development focuses on being able to reproducibly crystallise that specific form with desired particle characteristics—such as size and, where applicable, habit. Crystallisation is a bottom-up process, where control is achieved from the crystallisation solution. In contrast, bulk particle manipulation techniques like milling and micronisation represent top-down approaches, used to further refine particle size and distribution. These methods, though often more energy-intensive, are essential when precise control over particle dimensions is required for formulation or process compatibility. Together, these steps form a dynamic, iterative process that underpins the successful development of effective drug substances. 

To help illustrate the various processes involved in solid state chemistry in a real-world context, let’s examine some of the many challenges organisations face in achieving a target solid form, including real-life examples of how we have worked to resolve these challenges at Sterling.

• Objective: Produce a defined API salt form with tight particle size control for early-phase development.
• Complication: Process change introduced a new non-solvate form with wide particle size distribution and poor habit.
• Approach:
  • Developed a controlled crystallisation strategy
  • Focused on solvent selection, temperature profiling, and seed regime design
  • Used solvent-mediated ball milling to generate effective seed crystals
• Outcome: Achieved target particle size, form control and uniform habit, meeting all development specifications

In early-phase development, particle size can dramatically influence both formulation behaviour, drug performance, and downstream processing. Due to its importance, the required particle size distribution may have an extremely narrow margin for error, making initial solid form selection critical. 

In one project we encountered at Sterling, our objective was to produce an API salt with a defined particle size. While only one polymorphic form had been isolated during chemical development, our initial investigations confirmed it to be thermodynamically stable and the preferred form for advancement. Polymorphic risk was deemed low, though we identified specific solvent classes to avoid during crystallisation.

However, a subsequent process change, intended to reduce crystallisation time, unexpectedly yielded a new, non-solvate version of the salt with a much broader particle size distribution. The resulting particles were fragile, irregular and prone to agglomeration, rendering the material unsuitable for further development. 

 To regain control, we developed a controlled crystallisation strategy that produced the preferred version of the salt while focusing on controlling particle size and crystal habit. Our approach focused on solvent selection, temperature profiling, and, most importantly, seed regime design. The seed regime was considered to be the key parameter for control since it would not only support solid form version control, but also serve as the most effective approach to particle size control.

Solubility assessments and concentration-temperature studies enabled us to shortlist optimal solvent systems and determine the precise characteristics needed for seeding. The simplest and most common approach is dry API particle size reduction by mechanical means. Unfortunately, several attempts with size fractionation were unsuccessful due to flocculation and poor dispersion.

Ultimately, we turned to solvent-mediated ball milling, which produced seed crystals of appropriate size and morphology that dispersed well in solution. Combined with a carefully engineered temperature hold and controlled cooling profile, this approach yielded API salt with the required chemical purity, polymorphic integrity, particle size distribution and uniform particle habit,meeting all development specifications.

• Objective: Improve poor aqueous solubility of a preferred API form during preclinical development.
• Complication: Salt screening identified soluble candidates, but with poor reproducibility or stability; the API was structurally prone to low solubility.
• Approach:
  • Shifted focus to refining original API form via crystallisation and micronisation
  • Identified optimal solvent systems through in silico modeling
  • Applied seed-assisted crystallisation and jet micronisation
• Outcome: Produced uniform, micronised material with enhanced solubility and permeability, supporting clinical advancement

Improving solubility is an important objective of solid form development, but it can also be quite challenging. When modifying any one characteristic, such as crystal structure, polymorphic form or particle size, it is critical to avoid negatively impacting other properties like stability or bioavailability. 

In one scenario, our objective was to improve the aqueous solubility of an API during preclinical development. Initial polymorphism investigations revealed that the existing form was thermodynamically preferred, while 10 other identified versions were partial or stoichiometric solvates. 

The propensity of the API to polymorphism was considered low, but solubility was also found to be poor in deionised water. Structural determination and analysis via single crystal X-ray diffraction  attributed the low solubility to strong intermolecular interactions, placing the compound in either Biopharmaceutics Classification System (BCS) Class II or IV, both of which pose significant formulation hurdles. BCS Class II compounds exhibit low solubility but high permeability, often allowing for good absorption with appropriate formulation. In contrast, BCS Class IV compounds suffer from both low solubility and low permeability, making them the most challenging to formulate effectively.

A salt screen investigation followed, where we identified a variety of counter ion salt forming candidates. While several candidates improved water solubility, they introduced other complications: an alkali metal formation salt had poor reproducibility and solubility across batches, while a di-organic counter ion had high molecular weight and showed evidence of disproportionation during pre-formulation evaluation.

Faced with these limitations, we shifted our focus to controlled crystallisation development of the original preferred form in order to produce material of a uniform particle habit for particle size reduction via micronisation. Our objective was to produce material with a DV90 of less than 10 microns to support progression into clinical development. We harnessed jet micronisation in an effort to enhance both solubility and permeability. 

In silico modeling allowed us to identify ideal solvent systems for crystallisation, and including an API seed charge enabled us to achieve precise form control. A trial micronisation allowed us to convert the material to the preferred API form. Navigating this challenge, where there was a structural explanation for the preferred form’s poor solubility, ultimately demonstrated that certain characteristics of the API might limit development opportunities. In such cases, crystallisation of the API from aqueous media may be inevitable.

• Objective: Increase throughput of commercial API production via new filter dryer.
• Complication: Equipment change caused subtle differences in crystal properties, resulting in particle size changes after milling.
• Approach:
  • Investigated form and process behavior with new equipment
  • Modified milling parameters to restore target particle size
• Outcome: Regained alignment with particle specifications, reinforcing the need to assess solid state impacts during scale-up changes

Even once a project reaches commercial manufacturing, solid state chemistry can play an important role. Changes to process equipment can alter key parameters like mixing intensity and drying rates. These shifts can then influence crystal growth or morphology, leading to differences in particle size distribution, surface area, or polymorphic form.

In a final example scenario, a long-standing API was produced by a seeded reactive crystallisation, followed by isolation on a filter dryer and final milling to achieve the required particle size distribution.

To boost throughput, a new filter dryer was introduced.  The new equipment successfully reduced filtration time and accommodated double the batch size, presenting a low risk of change to the API. However, further optimisation was required to achieve the necessary particle size specifications. Investigation revealed subtle but critical differences in the isolated solid form when using the alternate equipment, and existing materials could not process the material in a satisfactory way.

After modifying milling parameters, our team successfully produced milled API that met the required particle size distribution. This example serves as a reminder that even seemingly minor equipment changes can affect the physical properties of an API, and any changes should be evaluated through a solid state lens.

Dedicated solid state expertise at Sterling

Across development stages, from preclinical formulation to commercial manufacturing, solid state challenges can be inevitable. But with the right scientific strategy and technical support, they can be overcome.

At Sterling, solid state chemistry is integral to our comprehensive API development and manufacturing offering. We have the equipment, capabilities, and expertise to support every nuanced element of solid state, including salt and co-crystal screening, polymorph risk assessment, pre-formulation evaluation, crystallisation development and particle manipulation. These services are delivered by specialist teams based across our global network, including our dedicated Material Science Centre located at our Cramlington, UK site?

With over 50 years’ experience handling complex chemistries and a robust infrastructure built for scalability, we help customers optimise their API solid forms to meet stringent development, regulatory and commercial requirements. Whether as part of a fully integrated development programme or as a standalone service, our solid state capabilities are designed to support successful outcomes for every API. 

If you’re interested in learning how we can support your solid state requirements, contact our experts.

Solid state chemistry refers to the study and manipulation of the physical forms of pharmaceutical compounds, particularly APIs. It involves selecting and optimising the solid form — including polymorphs, salts, and co-crystals — to ensure stability, solubility, and manufacturability of the final drug product.

Salt screening helps improve the solubility, stability, and physical properties of APIs by identifying optimal salt forms. It’s a foundational step in solid state chemistry that can impact formulation success and regulatory approval.

Yes — even small changes in process equipment or parameters can alter crystal properties, leading to unexpected changes in particle size or form. Ongoing solid state assessment is essential during tech transfer or scale-up.