ABSTRACT

It’s well understood most drugs emerging from discovery pipelines possess poor aqueous solubility and/or low permeabil­ity, providing barriers to absorption and bioavailability. Enhancing absorption is therefore a cornerstone of formulation science, di­rectly impacting oral bioavailability and therapeutic index.

When choosing a CDMO partner, finding one with experi­ence in the development of enabled formulation systems, such as amorphous solid dispersions and lipidic systems, is critical to advancing molecules that have poor solubility. Additionally, an “end-to-end” integrated service philosophy, in which all elements of drug development can be procured through a single vendor with capabilities and experience to pivot to the respective needs of a drug’s biopharmaceutic properties, can further accelerate development at all stages.

In the preclinical phase, establishing formulations capable of achieving sufficient drug solubility to probe toxicology is key. Here, Quotient Sciences, applies a systematic, data-driven screening platform evaluating solubility-enhancement ap­proaches to direct the toxicology formulation. As a drug ap­proaches a first-in-human (FIH) trial, the Quotient Sciences Translational Pharmaceutics® platform enables development teams to minimize investment in GMP drug product manufactur­ing by making drug products on-demand. This allows the devel­opment team to reduce supply chain complexity and rapidly apply enabled formulations in the trial to ensure drug exposure. Finally, the Translational Pharmaceutics platform can be applied to fur­ther optimize drug product formulations using clinical data fol­lowing Phase 1 studies.

In one case, Quotient Sciences successfully developed an amorphous solid dispersion of a poorly soluble molecule using spray drying. The drug product was used in the first-in-human study of an oral therapy intended for the treatment of amy­otrophic lateral sclerosis (ALS). The randomized, placebo- controlled Phase 1 trial evaluated safety, tolerability, pharmaco­kinetics (PK), pharmacodynamics (PD), and impact of food in healthy volunteers. Among the three formulations tested in this trial, the spray-dried version showed superior performance and was selected for further development. This study highlights how an integrated approach and adaptive design accelerates early phase development and de-risks formulation decisions using real-time clinical data.

INTRODUCTION

The pharmaceutical industry continues to face a critical for­mulation barrier: the intrinsically low aqueous solubility of nu­merous new chemical entities (NCEs), which adversely affect bioavailability and therapeutic performance. It is estimated that approximately 40% of marketed pharmaceuticals and nearly 90% of investigational compounds in the discovery pipeline exhibit poor water solubility, creating significant challenges for oral drug delivery and consistent pharmacokinetic profiles.¹

Retrospective analyses of clinical trial outcomes from 2010 to 2017 indicate a drug development failure rate approaching 90%.² Clinical efficacy has been attributed to upward of 50% of failures, while other factors included dose-limiting toxicities (30%), suboptimal physicochemical and biopharmaceutical properties (10%-15%), and deficiencies in commercial strategy or portfolio alignment (10%).² These trends have continued in re­cent years.

Among the physicochemical limita­tions, poor solubility and membrane per­meability are predominant contributors to clinical attrition, often resulting in inade­quate plasma exposure, high inter-individ­ual variability, and therapeutic failure. These limitations, however, can be miti­gated through formulation strategy and an integrated approach to formulation and clinical testing. Quotient Sciences has es­tablished this through the Translational Pharmaceutics platform, which enables rapid optimization of formulation and clin­ical performance by aligning drug product development with real-time clinical data.

PRECLINICAL SCREENING STRATEGIES LEVERAGING BCS & DCS

A foundational framework published over 20 years ago for understanding de­velopability is Lipinski’s Rule of Five, which outlines molecular properties that influ­ence drug-likeness.³ Compounds that vio­late these rules are more likely to suffer from poor absorption or permeation, making them less viable as oral drugs.

As small molecule therapeutic design has evolved against more challenging tar­gets and binding sites, Lipinski’s rules have needed to be significantly bent — and broken — over the past 2 decades.

As the industry has embraced more innovative and integrated ways to progress drug candidates, developers have seen that early identification of solubility issues is critical to avoid costly delays later in de­velopment. Traditional high-throughput screening (HTS) methods are used to as­sess solubility, permeability, and stability. However, these methods often fall short in predicting human pharmacokinetics, es­pecially for Biopharmaceutics Classifica­tion System (BCS) Class II and IV compounds.

To address this, the Developability Classification System (DCS) emerged as a more nuanced framework (Figure 1).⁴ Un­like the BCS, which focuses on solubility and permeability, the DCS incorporates dose, biorelevant solubility, and perme­ability to better predict in vivo perform­ance. This system also guides formulation strategy by identifying whether a com­pound is dissolution-rate limited or solu­bility-limited.

A preclinical screening platform that integrates DCS principles with advanced formulation technologies, like the one developed by Quotient Sciences, can be used to accelerate preclinical pathways. Quo­tient Sciences’ approach includes nano-milling for particle size reduction, amorphous solid dispersions to enhance dissolution, and lipidic formulation screen­ing for compounds with high lipophilicity (Figure 2).

THE TRANSITION TO FIRST-IN-HUMAN WITH INTEGRATED FORMULATION STRATEGY & CLINICAL TESTING

For first-in-human (FIH) studies, a phase-appropriate clinical formulation, which has scientific justification related to the toxicology-based formulation presen­tation, is prepared for dosing the drug substance of interest. Typically, these are formulations that enable dose titration in response to emerging clinical data. This approach offers flexibility in dosing for healthy volunteers during single and mul­tiple ascending dose (SAD/MAD) phases.

Using the Translational Pharmaceutics platform, dose escalation decisions can be made in real time based upon emerging clinical data. This adaptive approach sup­ports informed decision-making, enabling the selection of the optimal formulation and dosage strength based on actual clin­ical outcomes.

A recent study published in the Amer­ican Society for Clinical Pharmacology and Therapeutics’ Clinical and Transla­tional Science (2024) Journal highlights how the Translational Pharmaceutics plat­form supported a client in conducting a healthy volunteer study for a promising new treatment for ALS.⁵ The study featured a flexible design that enabled the team to develop and test three different formula­tions of the drug within the same clinical trial, saving months of time from the clini­cal program:

• A crystalline methylcellulose (MC) sus­pension
• A spray-dried dispersion (SDD)
• A hot-melt extrusion (HME) suspension

The HME and SDD formulations showed two- and four-fold higher expo­sure than the MC suspension, respectively. The SDD formulation was selected for pro­gression to subsequent SAD and MAD co­horts.

Combining formulation development and clinical testing into one streamlined process, the program saved time, im­proved drug performance, and helped move the treatment forward more effi­ciently.

ADVANCING INTO PHASE 2 WITH A FOCUS ON COMMERCIALLY READY FORMULATIONS

Advancing solubility-enhanced for­mulations (such as nano-milled suspen­sions, lipid-based systems, and amorphous spray-dried dispersions) into solid oral dosage forms requires carefully designed strategies to maintain bioavail­ability and support scalable manufactur­ing.

Nano-milled APIs, typically stabilized in aqueous media, can be converted into solid intermediates through spray drying or lyophilization, followed by granulation and compression or encapsulation. Lipid-based systems, including SEDDS, may be adsorbed onto porous carriers to create free-flowing powders suitable for encap­sulation, or directly filled into hard or soft gelatin capsules to retain their liquid char­acteristics and self-emulsifying behavior. Amorphous solid dispersions produced via spray drying are generally blended with functional excipients to improve flow and compressibility, roller compacted into granules to enable final blending for tableting direct compression or capsule filling.

Each formulation pathway must be optimized to maintain enhanced dissolu­tion performance and desired PK profile while ensuring physical and chemical sta­bility throughout processing and shelf life. Quotient Sciences’ RapidFACT® pro­grams, enabled through the application of the Translational Pharmaceutics platform, approach allows for a more advanced strategy to ensure that a drug product can be a commercially-ready formulation.

PHASE 3 ONWARDS COMMERCIAL FORMULATION LIFECYCLE MANAGEMENT & IP MAXIMIZATION

As drug candidates progress into Phase 3 and approach commercialization, transitioning from immediate-release (IR) solubility-enhanced formulations to modi­fied-release (MR) formats can serve as a strategic lever for lifecycle management and intellectual property (IP) optimization. For example, IR tablets developed using spray-dried dispersion (SDD) technology during Phase 2 can be reformulated into MR dosage forms, offering valuable line extension opportunities.

Leveraging the Translational Pharma­ceutics platform enables rapid prototyping, clinical evaluation, and real-time opti­mization of MR formulations. This inte­grated platform facilitates adaptive formulation development, allowing re­lease profiles to be fine-tuned based on emerging pharmacokinetic (PK) and phar­macodynamic (PD) data. Converting an IR SDD into a once-daily matrix tablet or a sustained-release coated system can help reduce peak plasma concentrations (Cmax), mitigate side effects, and main­tain therapeutic levels over an extended duration. These enhancements not only improve clinical outcomes but also support differentiated product positioning in a competitive market.

From a commercial and regulatory standpoint, MR formulations derived from SDDs can underpin new patent filings based on novel composition, process, or therapeutic use claims. This approach of­fers a strategic pathway to extend market exclusivity beyond the original compound patent, particularly when aligned with the expiration of the primary patent. Addition­ally, such line extensions can be tailored to address new patient populations, enhance adherence in chronic conditions, or intro­duce alternative dosing regimens — each contributing to sustained product value and long-term competitive advantage.

SUMMARY

The development of poorly soluble drugs remains a significant challenge in pharmaceutical R&D. However, by adopt­ing an adaptive approach that integrates services from preclinical screening to clin­ical optimization, developers can achieve significant time- and cost-saving benefits.

The Quotient Sciences Translational Pharmaceutics platform can be applied to optimize drug product formulations using clinical data following Phase 1 studies, a RapidFACT program. This enables real-time formulation adjustments and seam­less transitions between development phases to reduce timelines, lower costs, and improve clinical outcomes.

REFERENCES

1. Kalepu, S., & Nekkanti, V. (2015). In­soluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B, 5(5), 442–453.
2. Sun, D., Gao, W., Hu, H., & Zhou, S. (2023). Why 90% of clinical drug development fails and how to improve it? Therapeutic Innovation & Regula­tory Science.
3. Lipinski, C. A. (2006). Lead- and drug-like compounds: the rule-of-five revo­lution. Drug Discovery Today: Technologies, 1(4), 337–341. [DOI: 10.1016/j.ddtec.2004.11.007].
4. Butler, J. M., & Dressman, J. B. (2010). The developability classifica­tion system: application of biopharma­ceutics concepts to formulation development. Journal of Pharmaceuti­cal Sciences, 99(12), 4940–4954.
5. Hannestad, et al. (2024). A random­ized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, toler­ability, pharmacokinetics, pharmaco­dynamics, and food effect. Clinical and Translational Science, 17, e70064.

Dr. Andrew Parker has over two decades of experience in the pharmaceutical industry, spanning from preclinical development, through early clinical formulation development into late-stage development, scale-up, and commercialization. At Quotient Sciences, his focus is on Translational Pharmaceutics® and the acceleration of drug candidate progression provided through the integration of formulation development, clinical drug product manufacture, and clinical dosing activities. He has an interest in enabling technologies for bioavailability enhancement, characterization of all delivery formats, innovative technologies, and understanding drug product structure and function relationships. Additionally, he has advised clients in all types of clinical pharmacology study objectives, including first-in-human, drug-drug interaction studies, relative bioavailability, bioequivalence, TQT, and studies where various types of PD biomarkers and PD bio-responses (such as EEG) are part of exploratory endpoints in healthy volunteer studies. Before joining Quotient Sciences, he worked at Cooper Surgical and Healthcare as a Program Director and at Catalent as an Open Innovation Director covering two business units. He also spent 15 years at Juniper Pharma Services and Molecular Profiles CDMOs in a variety of roles combining technical and commercial knowledge, sitting at the operational and business interfaces with external clients.

John McDermott has over 25 years of experience in pharmaceutical sciences with prior roles at companies including Rhone Poulenc Rorer and Covance (later acquired by LabCorp). He joined Pharmaceutical Profiles in 2001, which, following a series of M&A and organic growth, was rebranded as Quotient Sciences in 2017. He has been central to the development of Quotient Sciences Translational Pharmaceutics®, the company’s flagship drug development platform. This platform integrates formulation development, on-demand GMP drug product manufacturing, and healthy volunteer clinical testing to deliver time and cost efficiencies in small molecule and oral peptide drug programs and applications. He has significant experience in scintigraphy imaging studies for oral and inhaled dosage forms, including the development and validation of radiolabeling methods.

Dr. Sandeep Kumar is a Drug Development Consultant at Quotient Sciences, with a PhD in Pharmacy and experience across the CDMO and excipient industries. He specializes in formulation development and early phase clinical strategy, supporting programs from candidate nomination through first-in-human trials. He is passionate about working closely with clients to shape scientifically grounded study designs that reflect the unique needs of each molecule. He uses a practical and strategic approach to help teams solve development challenges clearly and effectively. Prior to joining Quotient, he held roles in formulation and technical consulting, contributing to preclinical service innovation and client engagement.