Formulation optimization during the scale-up process from preclinical through early phase clinical trials is crucial for maintaining control over dissolution rates, which directly impact the bioavailability and therapeutic efficacy of drug products. As drug candidates transition from the research lab to larger-scale production, managing factors such as particle size and formulation composition becomes essential to uphold the integrity and performance of the drug. Inconsistent dissolution rates can lead to variability in drug release profiles, potentially resulting in suboptimal therapeutic outcomes or failure to meet regulatory specifications. 

Therefore, achieving consistent drug release profiles is crucial for maintaining the desired pharmacokinetic properties, such as the targeted therapeutic concentration and the duration of therapeutic exposure. These properties are integral to the effectiveness of the drug and its ability to deliver the intended therapeutic benefits.

To address these challenges, pharmaceutical developers employ various techniques to optimize formulations during scale-up. One such technique is the incorporation of water-soluble polymers, which can modify drug product dissolution kinetics, and, consequently, the overall dissolution rate of the drug. Additionally, optimizing granulation parameters is another critical strategy. Proper granulation ensures uniform particle size and composition, which are fundamental for achieving consistent and predictable drug release profiles.

By meticulously managing these formulation parameters, developers can enhance the reliability and efficacy of drug products. This not only improves patient outcomes but also facilitates the successful advancement of drug candidates through clinical trials. In the subsequent sections of this article, we will explore practical examples of clinical candidates that were optimized during the early development phases, enabling successful scale-up.  

Process optimization for consistent dissolution

Scale-up is a common problem encountered in all forms of development across industries, and oral solid dose manufacturing (OSD) is no exception. Often when transitioning molecules from phase I to II, the drug product design is refined, which can have unintended consequences during scale-up to GMP manufacturing. 

In the following example, scale-up issues were identified and resolved during development of a phase II wet granulation process. The granulation formulation used during phase I manufacturing was modified for phase II with a higher drug loading and increased binder concentration (Table 1).

Pilot manufacturing of the initial Phase II Batch 1 formulation was performed using the same operating parameters as the phase I formulation. The resulting product dissolution was significantly slower than the Phase I batch and can be seen in Figure 1. The particle size of Phase II Batch 1, displayed in Figure 2, was significantly greater than the Phase I batch, indicating the wet granulation process was more efficient than during the previous phase I GMP batches.

Further development at the pilot scale would be required and two additional batches would be made. The Phase II Batch 2 batch reduced the Binder level back to the previous concentration of 3% and maintained the previous batch’s granulation parameters. This batch demonstrated improved release; however, it was still substantially below the target dissolution rate (Figure 1). 

An interesting observation from this second study was that since all formulation and operating parameters were maintained and only the drug loading was adjusted, it was observed that the drug substance itself behaves as a binder. To further combat the unexpected binder effect of the drug substance, the granulation water and wet massing times were further reduced during granulation in Phase II Batch 3 batch. The resulting dissolution (Figure 1) and particle size properties (Figure 2) for Phase II Batch 3 were consistent with the phase I formulation and the process was ready for further GMP manufacturing.

Controlled release for correct exposure time

Maintaining a controlled and consistent drug release profile is crucial in the early-stage development of oral solid-dose (OSD) drug products. If initial pharmacokinetic (PK) data of an instant-release tablet or capsule indicates a maximum concentration (Cmax) above the targeted therapeutic range, development of an extended-release drug product may be necessary. An extended-release tablet or capsule is designed to provide a controlled drug release profile over a specified timeframe, therefore ensuring that Cmax remains within the targeted therapeutic range.

Mechanisms to enable extended drug release can be complex, however simple release mechanisms are generally appropriate for Phase I/II OSD formulations. In a simple extended-release formulation, the drug substance is incorporated into a capsule or tablet alongside a water-soluble polymer. The polymer hydrates upon contact with aqueous media and encapsulates the drug substance into a water-soluble matrix which forms micro channels for diffusion of the drug substance. Additionally, the polymer matrix slowly dissolves as a secondary mechanism for the drug release. Appropriate matrix formation and subsequent dissolution is crucial to enabling a desired extended-release profile. Proper formulation development can ensure appropriate matrix properties and drug release.

A variety of formulation techniques are employed to develop an extended-release capsule formulation. Dry blending drug substance with release-modifying polymers and filler excipients is a simple yet effective technique to extend and control a capsule release profile. Hydroxypropyl methylcellulose (HPMC) polymers of differing molecular weights and viscosities are commonly used to set the release matrix. Fillers with varying degrees of water solubility such as lactose, mannitol or microcrystalline cellulose act to control the initial dispersion of polymer and drug substance, therefore modifying matrix formation and drug release. A disintegrant can be incorporated as needed to further modify release. Additional excipients are required to ensure tabletability of a direct-compression formulation.

Table 2 outlines the composition of 12 hour extended-release capsule formulations prepared by dry blending drug substance with HPMC polymers of differing viscosities. Mannitol was incorporated as a water-soluble filler. A filler with lower water solubility could have significantly different results on matrix formation and dissolution. Capsules were prepared at a 5mg dosage strength and subjected to dissolution testing. Figure 3 highlights the effect of polymer viscosity on matrix formation and subsequent release. Compared to control capsules filled with neat drug substance, formulations prepared with high-viscosity polymers offered slower release times than formulations prepared with low-viscosity polymers. In this specific formulation, mannitol acted to disperse polymer and drug substance to enable formation of an appropriate matrix upon capsule disintegration. Figure 4 highlights the effect of polymer percent loading on capsule release, with 15% high-viscosity polymer loading resulting in a quicker release profile than 25% high-viscosity polymer loading. 

As shown, formulation composition can be varied to achieve a range of target release profiles. If Cmax issues arise during clinical studies, formulation of a phase appropriate extended-release drug product can aid in progressing a drug candidate through early-stage development. 

Dissolution rate upon scale-up of drug substance

Several drug substance process changes can significantly impact a drug’s dissolution profile, particularly during scale-up, especially those that affect particle size. These can include small changes in crystallization parameters or conditions, changes to the drying process, and changes to milling or grinding parameters. One critical parameter that must be monitored for drug substances with poor solubility is particle size. A larger particle size resulting from uncontrolled drug substance processes can significantly reduce the dissolution rate of the drug product. However, smaller particle sizes generally increase the surface area, enhancing the dissolution rate. Maintaining a consistent particle size distribution during scale-up is crucial to ensure uniform drug release profiles. 

It is important to consider the effects of drug substance process changes on dissolution of drug product during drug substance process scale-up, especially for changes that affect particle size for drug substances with poor solubility. The following provides two examples: 

Project 1

When developing a drug product using drug substance that had been produced in a research lab, the resulting pilot batch met all specifications and was acceptable for scale up. The same drug product manufacturing process was then used for the GMP batch. Unfortunately, the final GMP drug product failed the dissolution specification. 

The only difference was the GMP drug substance that was used, which was manufactured using a scaled-up process. Upon investigation, the particle size of the GMP drug substance had increased significantly from that of the R&D drug substance. The increased particle size was most likely due to a drug substance manufacturing process change, wherein multiple washes were performed to remove an undesired impurity. It is theorized that ostwald ripening could have contributed to the shift in particle size, which was not monitored or tested as part of drug substance release.  Although the drug substance conformed to the release specification, the drug product batch had to be discarded. For subsequent batches, drug substance particle size reduction via micronization was implemented and all subsequent drug product batches had acceptable dissolution profiles. Had particle size been controlled as part of scale-up, the overall timeline and financial impacts could have been avoided.

Project 2

When reformulating an established capsule drug product for manufacturing as a tablet, the GMP drug substance was available for formulation and process development. The R&D batch, which used the GMP drug substance and was placed on informal stability, met all specifications and was acceptable for scale-up. 

However, concurrently, the drug substance manufacturing process was undergoing scale-up and optimization. Drug substance particle size control was not yet implemented. As part of development, a small demo batch of tablets was prepared using the new drug substance. The batch failed the dissolution specification, which ultimately was caused by an increased drug substance particle size. This increase in particle size may be attributed to multiple drug substance manufacturing process changes, including how the final drug substance was dried.

Before proceeding with scale up for the drug product, micronization was implemented to reduce the drug substance particle size and another small demo batch was prepared. Particle size reduction resolved the dissolution issue, and micronization was subsequently implemented prior to manufacture of subsequent batches. By aligning the drug substance and drug product scale-up work and ensuring critical quality attributes are addressed early in the project, the GMP batch was manufactured successfully, passing all release specifications including dissolution. It is critical to control the drug substance particle size to maintain control of drug product dissolution performance (Figures 5a and 5b).

Conclusion

In summary, formulation optimization during the scale-up from early development through phase II of clinical trials is essential for ensuring consistent drug release profiles, which are critical for maintaining the desired pharmacokinetic properties and therapeutic efficacy. By meticulously managing the formulation parameters discussed, pharmaceutical developers can enhance the reliability and efficacy of drug products, ultimately improving patient outcomes and facilitating the successful advancement of drug candidates through clinical trials.

Kyle Rowinski is a scientist in the pharmaceutics group at Cambrex Longmont. His research areas focus on preformulation screening, formulation development, and solid-state optimization of small molecule drug candidates.

Connor Polodna is a process engineer in the drug product manufacturing department at Cambrex Longmont. He focuses on process scale-up, GMP manufacturing, and commissioning/qualification of new equipment.

Kristen Placker is a senior drug product engineer at Cambrex, with experience in both industry and academic research settings. Kristen has over ten years’ experience in pharmaceutical process development and optimization.