Formulation as a Development Lever: The Role of immediate-release (IR) and controlled-release (CR) in Preclinical and Early Clinical Programs

In the high-stakes world of drug development, speed and insight are everything. For innovators navigating preclinical and early clinical phases (Phase 1/2), the pressure to generate robust proof-of-concept (POC) data, understand safety margins, and demonstrate therapeutic potential is immense.

While discussions around immediate release (IR) and controlled release (CR) are often reserved for commercial dosage forms, the principles behind these release strategies are profoundly strategic—especially in the earliest stages of development. Choosing the right release profile isn’t just a formulation decision; it’s a development catalyst.

Why Release Profiles Matter Before Commercialization

At the preclinical and early clinical stage, formulation is not about patient convenience—it’s about enabling critical data generation. Strategic release profiles can:

• Enable toxicology studies with consistent, high-dose delivery.
• Generate reliable PK/PD data in humans to understand exposure and effect.
• Demonstrate early POC to justify further investment.
• Mitigate early risks like poor solubility, rapid clearance, or local toxicity.
• Accelerate timelines by enabling faster, more informative studies.

This is where IR and CR become powerful tools—not just dosage forms.

Immediate Release (IR): Fast, Simple, and Strategic

The purpose of the IR formulations is to maximize the speed and extent of drug substance absorption for rapid systemic exposure.

Strategic Role in Early Development

• Simple IR formulations like solutions, suspensions, or capsules can be developed quickly, making them ideal for first-in-human studies with minimal drug substance requirement.
• High and predictable drug exposure from IR formulations supports effective dose-ranging and helps establish safety margins during toxicology studies.
• Immediate release formats offer a clear and unobstructed view of the molecule’s native pharmacokinetic and ADME profile.
• When rapid therapeutic onset is needed and sustained exposure isn’t critical, IR formulations provide a fast and efficient path to proof-of-concept.

IR formulation strategies involve using enabling technologies to improve bioavailability —even for poorly soluble drug substances —using enabling technologies like spray dried amorphous solid dispersions, lipid-based systems, or nanosuspensions.

Controlled Release (CR): Solving Problems, Unlocking Potential

The purpose of CR formulation is to modify the rate, duration, or site of drug release to meet specific therapeutic or developmental goals.

Strategic Role in Early Development:

• CR formulations help extend drug exposure for molecules with short half-lives by using simple, scalable prototypes like matrix mini-tablets or multiparticulates.
• By flattening pharmacokinetic curves, CR strategies can reduce peak concentration-related toxicity, allowing for safer administration of higher doses.
• Sustaining supersaturation or targeting specific regions of the gastrointestinal tract through CR can significantly enhance bioavailability.
• Early use of CR formulations enables differentiation by demonstrating potential clinical advantages such as reduced side effects or improved compliance.
• CR approaches can also minimize variability in pharmacokinetic data caused by differences in fed and fasted states, improving the reliability of early-stage studies.

Early-stage CR isn’t about complex commercial systems—it’s about pragmatic, scalable solutions using right controlled release polymers and technologies.

IR vs. CR: It’s Not Binary—It’s Strategic

The choice between IR and CR isn’t either/or. It’s a programmatic decision based on your molecule’s properties and your development goals:

• Start with IR when speed, simplicity, and baseline PK data are the priority.
• Pivot to CR when early data reveal limitations—short half-life, toxicity, solubility issues, or therapeutic need for sustained exposure.
• Iterate Intelligently: Early IR data often inform the need for CR.

Partnering for Success

In early development, your CDMO must be more than a manufacturer. They must be a strategic partner who understands:

• The urgency of rapid development with minimal API.
• The science of biopharmaceutics and formulation technologies.
• The clinical context of how formulation impacts data quality.
• The supply chain from tox batches to GMP clinical supplies—across both IR and CR.

Formulate Your Strategy, Not Just Your Drug

In preclinical and early clinical development, release profiles are not just formulation attributes—they are strategic levers. The right release strategy can accelerate timelines, de-risk development, and unlock critical data faster.

Partner with Aragen that brings scientific depth, technological agility, and clinical supply expertise to the table. 

Together, we can formulate not just your drug, but your development strategy.