Improving solubility and accelerating drug development

What’s driving insolubility in drug development?

As the biotech and pharmaceutical industries look for novel, efficacious APIs to meet the needs of the growing, aging population, the industry has shifted towards drug candidates derived from more complex molecular scaffolds. These candidates may meet the need for increased stereoselectivity, target specificity, and higher drug activity. However, their high molecular weights and often increased number of chiral centers present significant solubility challenges.

Understanding the downstream impacts of more complex molecules can be difficult during drug discovery. As drug solubility is a dynamic property, it is dependent on a range of physicochemical factors, such as molecular weight, lipophilicity, solid state, particle size or surface area, and drug concentration.

Furthermore, increasingly complex molecules can bring other unforeseen development and manufacturing challenges. Large synthetic structures are more often difficult to crystallize owing to the number of degrees of freedom associated with them. This presents a problem with the scalable isolation of such molecules.

Drug solubility is also affected by the dosage form and delivery route. To understand the impact of dosage form, let’s examine oral solid dosages. Due to their non-invasive nature and convenience, orally administered drugs are observed to have higher patient compliance rates. However, the solubility of an oral dosage form impacts its dissolution time. Furthermore, APIs exhibit varying permeabilities in the gastrointestinal (GI) tract, which can result in poor bioavailability of the drug. As such, biopharmaceutical classification system (BCS) Class II compounds, which have high permeability in the GI tract but low solubility, present problems for teams in the early stages of drug development.

In a recent article in Pharmaceutical Technology Magazine, Craig Grant, Veranova’s Global Director for Solid Form and Particle Engineering, discussed how novel approaches enable pharmaceutical developers to better understand drug dissolution in the GI tract.

“Oral dosage forms continue to be the most preferable delivery route – due to self-administrative convenience and ease of manufacture. Therefore, advancements in the methods used to monitor their dissolution in the GI tract have been invaluable.

Small-scale in situ dissolution is one such technology that has helped improve understanding of the solubility and bioavailability of BCS Class II compounds. When issues with the dissolution of APIs are highlighted earlier in development, it’s much easier for innovators to identify the potential developability issues and look to understand if the optimal solid form of a drug moiety will solve solubility and bioavailability issues.”

Read the full article to discover Craig’s thoughts on advancing poorly-soluble drugs through the clinical pipeline.

Since solubility issues are set to increase as more complex molecules enter the pipeline, it is important to recognize solubility challenges as an inherent part of the drug development process. As a CDMO that manages complexity with confidence, Veranova is committed to utilizing its solid form and particle engineering expertise to help customers accelerate drug development.

Techniques to enhance solubility

To successfully address solubility issues, it is crucial to understand the solid form landscape of a drug as early as possible. In recent years, the pharmaceutical industry has adapted to increasing complexity of novel APIs and new chemical entities, and a variety of techniques have been developed to characterize, evaluate and optimize the solubility of these compounds. These are typically split into two main groups:

Physical methods

These methods aim to improve solubility by modifying the particle attributes of an API or drug product. Examples include:

• Reduction of particle size: traditional methods include micronization or jet milling, wet milling incorporated into a controlled crystallization; more recently nano-milling, high-pressure homogenization and other methods to achieve sub-micron particles
• Stabilization of amorphous APIs – most commonly within a polymer matrix and scaled via spray drying or hot melt extrusion

Physicochemical modifications

These techniques aim to improve solubility through crystal engineering and other modifications. Examples include:

• Formation of salts or cocrystals
• Solubilization with surfactants
• Formation of complexes or molecular associations, e.g., via cyclodextrins
• Use of prodrugs, e.g., phosphate esters
• The introduction of hydrophilic groups into molecules

In recent years, a range of alternative techniques have been developed to increase solubility. These include hydrotropy, selective adsorption or use of insoluble transporters, use of cosolvents, use of polymeric micelles and nanoparticle formulations.

Crucially, however, there is no single approach to addressing solubility concerns in drug development, and each molecule requires a unique strategy based upon a full understanding of its properties. A wide range of factors must be considered, including absorption site, dosage concentration, drug stability, formulation, administration route, and economic influences. The optimal method for each molecule will therefore require a range of formulation procedures and technologies. Veranova can approach these with confidence, leveraging our integrated solid form and particle engineering services.

Managing complexity with confidence

At Veranova, we understand how solid form and particle engineering solutions can be harnessed to overcome solubility issues in drug development. We’ve been providing customers with leading solid form and particle engineering services for the past 20 years through our Pharmorphix^® offering. Our services include physchem data packages, solid form screening and characterization, and particle engineering solutions.

Employing a holistic approach, we follow a candidate molecule fully through the development process, gathering data at every stage and accelerating its journey to market. By keeping the end product in mind throughout, Veranova works closely with its customers and partners to understand their target product profile (TPP) and ultimate end goal for a novel drug product.

This way, we help our partners to achieve their objectives from the start, including the route of administration, drug target, dosage form, and much more. Leveraging these factors allows Veranova to tailor its solutions to our customer’s needs and provide the expertise, technology, and thorough approach required to advance their projects through to market.

References:

1. S. Kalepu and V. Nekkanti, Acta Pharm. Sin. B., 5 (5) 442–453 (2015)
2. P. Parois, R. I. Cooper and A.L. Thompson, Chem Cent J., 9 (30) doi:10.1186/s13065-015-0105-4 (2015)