Issue:October 2025
PRECLINICAL SCREENING PLATFORM - From Preclinical Screening to Clinical Optimization: Accelerating Poorly Soluble Drug Development
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
- Kalepu, S., & Nekkanti, V. (2015). Insoluble drug delivery strategies: review of recent advances and business prospects. Acta Pharmaceutica Sinica B, 5(5), 442–453.
- 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.
- 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].
- 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.
- 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.
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