Expert Interview : 9 questions to Julien Leroudier

We asked 9 questions to Dr. Julien Leroudier, our technical expert in solid state characterization and scalable crystallization process about solid form.  

1/ What is your background?

I am a chemist with a background in solid state characterization and the development of scalable crystallization process. He graduated his PhD from university of Grenoble, on crystal growth. Julien joined Seqens in 2020 and since then, he has been leading the Solid State department of the Seqen’s Lab, in Porcheville. He has been developing Seqens’ pre-formulation and formulation activities for our SeqensUP! Offer.

2/ How do you correlate poor bioavailability with solid form properties of a Drug candidate?

Most of the pharmaceutical products are solid in nature and could exist in many forms, leading to different physical, chemical, mechanical, and biopharmaceutical properties. Many drug substances can exist as-is (parent compound), a salt or a co-crystal. The latter include in the chemical structure either a counter-ions or co-formers altering the properties of the solid. Furthermore, a drug can exist in more than one crystalline form which is known as polymorphism. Ultimately, polymorphism greatly influences properties such as solubility, flow properties, kinetics of dissolution thus drug efficacy, bioavailability and toxicity.

A broad and comprehensive study of the various solid forms of drugs (salts, co-crystals and polymorphism) is of the utmost importance to maximize the chance of success for a drug and this as early as possible. As a key Figure, around 50% of approved drugs by the FDA are indeed salts . This proves the importance of the solid form selection which drives the efficacy. Furthermore, 40% of drugs candidates are failing during pre-clinical stages due to poor bioavailability and not the most appropriate physical form of the drug. This means that the solid form selection must be taken into account ex vivo and in vivo stability, targeting solubility, dissolution rate, and bioavailability.

Properties that can be altered by choosing different solid forms include:

• Thermodynamic properties, such as melting temperature, free energy, solubility.
• Flow properties, such as particle morphology/habit, density, hardness
• Kinetic properties, such as dissolution rate, physical/chemical stability.
• Surface properties, such as specific surface area, hygroscopicity

3/ How can you improve bioavailability through solid state activities?

The knowledge and understanding of solid-state properties of any active pharmaceutical ingredients (APIs) must be an integral part of drug development. Indeed, solid form screening and selection will drive the chances of success of a drug development

The aim of these screening studies is to evaluate as early as possible the landscape of the active ingredient then select the most suitable one among salts/co-crystals and their respective amorphous/crystalline forms, such as solvates, hydrates. Each form will have its own properties such as solubility thus will have an impact on bioavailability. Crystalline forms are most of the time selected for further development as more stable by nature compared to amorphous phase, however for APIs with very low solubility properties, amorphous solid dispersion (ASD) may be beneficial to improve bioavailability attribute.

Our expertise and capabilities cover:

• Solid forms screening.
• Solid state characterization.
• Crystallization studies and processes.
• Particle size engineering, such as size reduction, morphology control.

Usually, the best compromise is to carry out a tailor-made approach for each API depending on its physico-chemical characteristics.

It should be emphasized again that the understanding of solid form is pivotal to anticipate bioavailability challenges.

4/ What does it mean to assess developability at early-stage Discovery?

Developability is a term that describes the probability of a drug candidate successfully transitioning into a safe, effective, and manufacturable drug. While pharmaceutical companies and regulatory agencies focus on the safety and efficacy of a drug candidate, developability in a narrow sense can be defined as the probability that a drug candidate will go smoothly through the chemistry, manufacturing and control (CMC) process at a reasonable cost and within a reasonable timeframe. To mitigate the risk of advancing a drug candidate with suboptimal developability to the CMC phase, it’s crucial to screen, evaluate, and enhance its developability-related properties as soon as possible. The assessment of developability during the initial discovery phase can save resources and avoid costly late-stage failures.

Furthermore, developability of the Drug substance must be linked to the one of the drug product and how the drug substance properties can affect the manufacturability, stability of the drug product. This would maxims the chances of success of the drug development.

5/ How do you evaluate the solid form properties?

To have a comprehensive understanding of the solid forms landscape and their corresponding physical and chemical properties, screening activities such as salt/co-crystals, polymorph must be conducted as early as possible and coupled with state of the art analytical techniques for in-depth characterization (eg. XRPD, DSC/TGA, HPLC, NMR, PLM/SEM, PSD…).

In addition to typical physico-chemical properties, biopharmaceutical properties are also key to assess various formulations of a drug. Detecting formulation challenges early allows to address them before advancing to later stages of drug development, preventing unnecessary investment in unfavorable forms candidates.

Within my team and our capabilities, we provide:

Solid forms screening supported by our HTS platform,

Solid state characterization through state of the art instruments such XRPD analysis, Laser diffraction, flow properties, morphology & specific surface area,

Crystallization studies, including Process Analytical Technologies (Blaze, FBRM, modeling software, DoE approach),

Particle size reduction (from wet mill to nanonization), from Lab to Plant scale equipment.

6/ What is the most common solid form of drug substances approved by FDA?

Between 2015-2019, 50% of the New Molecular Entities (NME) approved by FDA were pharmaceutical salts. Looking at the graph below, you can see the diversity of chemical salts that have been developed.

Please note that the salt form is the first stage of the drug development. Next, comes the polymorph selection which is as critical as the salt form as it will drive the efficacy of the drug.

7/ Tell us, what kind of issues related to drug development do you usually encounter?

Well, the choice of the solid form is usually a compromise among physical, chemical, pharmaceutical and bio-pharmaceutical properties.

During polymorph screening, you need to consider a variety of techniques to maximize the chance of having the most accurate polymorphic landscape. Indeed, it will allow to reduce risks during the drug development:

• For the drug substance: ensure polymorph control, stability, particle size control.
• For the Drug Product: ease of manufacture, dissolution, bioavailability, stability, reduce variability.

The most thermodynamically stable form is usually the solid form selected as provides more confidence especially upon stability testing, manufacturability. 

However, it may be of interest to select a metastable form (crystalline and/or amorphous) for bioavailability and/or Intellectual Properties reason.

8/ How can you accelerate the screening forms activities?

To explore the solid forms landscape and their corresponding physical and chemical properties, solid forms screening methods should be partly supported by HTS (High Throughput Screening) platform.

The use of automated methods will require less material per experiment and will significantly reduce time and resources for a large number of experiments (typically hundreds of experiments).

This approach allows also to assess various formulations of a drug. Detecting formulation challenges early allows to address issues before advancing to later stages of drug development, preventing unnecessary investment in unfavorable forms candidates.

The quality of a polymorph screen is driven by the variety of crystallization techniques used, a full HTS program will be the fastest way, however you may miss the most relevant physical form. At Seqens, we are convinced that a tailor-made approach, by combining adequately manual and HTS tests, will bring the benefit to have a more in-depth understanding of the polymorphism landscape.

I would like to emphasize that even though time is a key attribute during Drug development, it is evenly more important to get it right the first time.

9/ The benefits of solid forms selection at early clinical stage – What’s next?

Solid form selection should also take into consideration the route of administration, dose, dosage form, and release profile that are required to support preclinical and clinical studies and the target commercial formulation. Indeed, different dosage forms may require different physico-chemical properties. For oral solid dosage forms, key considerations include solid-state stability, sufficient solubility and dissolution rate, compatibility with excipients, bulk density and compressibility.

Combining preformulation studies with solid form screening is an excellent way to accelerate the pace of development by integrating drug substance and drug product into a single approach. This will greatly benefit the success rate and save time and resources. As a key Figure, around 40% of drug candidates are falling during that phase of development by not selecting the right solid form.

At Seqens, within our SeqensUP! Offer, we provide scientific agile platforms, including:

• Selection, Isolation & purification: solid forms screening, crystallization, isolation & particle engineering.
• Characterization & analytical science, including solid state, pre-formulation, analytical impurities profiling, toxicological evaluation.
• Early clinical formulation, including bioavailability improvement, controlled release profile, lipids & polymers synthesis, early-phase forms delivery (capsules, sachets, granules…)