Turning a “Brick Dust” Compound into a Clinically Viable Oral Formulation

Stable, Scalable Nanosuspension Development for a Poorly Soluble, High-Dose Oncology Drug

A clinical-stage pharmaceutical company developing an oral oncology therapy encountered a critical barrier to progress: their active pharmaceutical ingredient (API) exhibited extremely low solubility in both aqueous and organic solvents. Compounding the problem, the drug required a high clinical dose, threatening the feasibility of oral delivery altogether.

Made for complexity, Pii was engaged to design a scalable formulation and process strategy that could transform this challenging molecule into a viable dosage form. Using advanced wet milling technologies and a carefully optimized formulation, the team developed a robust nanosuspension that significantly increased the API surface area, leading to higher systemic exposure.

The resulting formulation exceeded expectations, delivering a stable, scalable, and patient-friendly oral dosage form ready to support clinical programs from first-in-human through late-phase trials.

⬆13x

increase in bioavailability

At equivalent doses, nanomilling the API increased systemic exposure in humans compared with the conventional API, making oral administration clinically viable.

<150nm

median particle size

Wet nanomilling produced uniform, submicron API particles that were incorporated into a formulation meeting all critical quality attributes and demonstrating long-term stability.

⬆100x

increase in API surface area

Increasing the API’s surface area accelerated dissolution and absorption, improving oral bioavailability for a compound previously limited by poor solubility.

CHALLENGE

Managing Low Solubility, High Dose, and Oral Delivery Constraints

The project presented a combination of chemical and physical challenges that threatened both clinical feasibility and process scalability.

Solubility Limitations

A typical “brick dust” API, this compound had very low solubility in both aqueous and organic solvents. Several bioavailability-boosting technologies were incompatible with the API; solubility limitations ruled out spray drying, and hot melt extrusion was impractical due to the drug’s high dosage requirements. Without a viable strategy to increase solubility, achieving therapeutic exposure through oral dosing would remain out of reach, stalling the program’s progress.

Poor Bioavailability

Limited bioavailability threatened the feasibility of oral delivery. Systemic exposure was too low to achieve therapeutic concentrations, so the team needed to identify a strategy that could enhance absorption while maintaining stability and scalable manufacturability. Failure to achieve this balance threatened IND timelines and clinical readiness.

High Dose Requirement

The compound’s high therapeutic dose further complicated formulation design. Delivering gram-level quantities while maintaining acceptable suspension properties and dosage volume required a formulation approach that could maintain uniformity without excessive excipient load. These constraints ruled out several conventional oral dosage options, threatening the feasibility of the preferred route of administration for this oncology drug.

Particle Stability

Reducing the API to the nanoscale introduced new risks to physical stability. At this size range, smaller particles can dissolve and redeposit onto larger ones through Ostwald ripening, reducing uniformity over time. The formulation required carefully balanced levels of surfactant and stabilizer to maintain particle size and suspension stability. Without effective stabilization, particle growth could compromise product consistency and limit the suspension’s shelf life.

SOLUTION

Applying Advanced Enabling Technologies to Deliver a Stable Oral Nanosuspension

Turning a poorly soluble, high-dose compound into a viable oral dosage form required precise formulation science and process control. Pii designed a nanosuspension process that improved exposure, ensured physical stability, and could be scaled reliably for clinical manufacturing.

Improving API Solubility Through Wet Milling

To overcome the compound’s extreme insolubility, Pii selected wet milling as the most practical and effective strategy. Using a DYNO-MILL® MULTI LAB with optimized zirconium bead size, the team reduced the API to a median particle size of <150 nm, increasing surface area by more than 100-fold. The resulting nanoscale dispersion provided a stable foundation for oral suspension and enabled meaningful improvements in clinical performance.

Enhancing Bioavailability with Advanced Particle Engineering

Reducing the particle size to the nanoscale rather than the microscale produced substantial gains in bioavailability. Through process optimization, Pii achieved a uniform submicron distribution with minimal variability, improving dissolution and absorption. The resulting nanosuspension increased systemic exposure by up to 13-fold (AUC and Cmax) compared with the conventional API, enabling clinically viable oral dosing.

Formulating for High-Dose Oral Delivery

Meeting the program’s high-dose requirement demanded a concentrated suspension that maintained uniformity, manageable viscosity, and long-term stability. Pii optimized the ratio of API to excipients to enable gram-level dosing without excessive formulation bulk or phase separation. The resulting nanosuspension retained flowability and homogeneity across scales, supporting reliable manufacturing for early- and late-phase clinical studies and beyond.

Stabilizing the Suspension for Long-Term Consistency

Pii optimized surfactant and stabilizer concentrations to prevent Ostwald ripening and maintain a consistent particle size distribution over time. The final formulation demonstrated excellent chemical and physical stability under both long-term and accelerated conditions and showed consistent performance across manufacturing scales.

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OUTCOMES

A Stable, Bioavailable Oral Nanosuspension Poised for Clinical Success

Pii successfully developed and scaled a nanosuspension formulation that met all CQAs and stability criteria, enabling oral administration. The work delivered clear results across formulation, performance, and scalability:

Stable nanosuspension formulation maintained particle uniformity and integrity
Significant bioavailability improvements made oral dosing possible
Clinical readiness achieved through on-schedule, GMP-compliant manufacturing that met IND timelines
Scalable manufacturing process enabled seamless progression through clinical development to future commercialization

With a validated, stable, and scalable formulation in place, the pharmaceutical company was ready for clinical development, with a clear path toward commercialization.

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John Doe

President and CEO

CONCLUSION

From Formulation Complexity to Clinical Readiness

By uniting advanced enabling technology with practical process design, Pii transformed a poorly soluble, high-dose compound into a stable oral nanosuspension—well-positioned to support early clinical development through late-phase studies and beyond.

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