Narrow and wide size distributions: Importance for MCC pellets in sustained-release oral dosage forms

Microcrystalline cellulose (MCC) pellets are widely recognized as an advanced excipient platform in the development of sustained-release oral dosage forms. Produced primarily through extrusion-spheronization, these spherical multi-particulate systems serve as reliable carriers for active pharmaceutical ingredients (APIs), offering a combination of high mechanical strength, excellent compressibility, and compatibility with a broad range of coating and drug layering processes. Pellets are available in different pellet sizes and in narrow and wide size distributions from various manufacturers. Some manufacturers offer explicitly narrow size distributions, while others present more open distributions. This application note will point on differences and shed some light on risks and advantages for variations in this parameter.

Critical parameters for pellets

In sustained-release formulations, consistency and control of drug release are crucial. MCC pellets support this by providing a low-friability, robust matrix that resists mechanical degradation during processing steps such as blending, coating, filling, and packaging. Low friability ensures the structural integrity of pellets throughout manufacturing and storage, which is essential for preserving the uniformity of sustained-release coatings. Pellet breakage can lead to irregular surface areas and unpredictable drug release kinetics, undermining therapeutic consistency. We shed some light on issues arising from high friability levels in this application report.

Another key attribute of MCC pellets is their narrow particle size distribution (PSD) [1]. Uniform size is critical for achieving consistent film coating thickness during fluidized bed or pan coating processes. Variations in pellet size can lead to uneven coating coverage, causing batch-to-batch variability in drug release rates. A tight size distribution also enhances flow properties, which improves dosing accuracy and fill weight consistency during capsule filling or tableting of multiparticulates.

By combining mechanical durability with size uniformity, MCC pellets help formulators design sustained-release products that exhibit predictable pharmacokinetics, minimized dose dumping, and improved patient adherence. These properties are particularly valuable in formulations requiring precise control of release profiles.

In the following, let’s figure out effects, arising from differences pellet size distribution. What could be an issue, when using MCC pellets as starter beads owing a narrow or wide size distribution?

Risks of wide particle size distributions

If the particle size distribution of MCC pellets is too wide, it can negatively affect multiple aspects of a pharmaceutical formulation, especially in oral solid dosage forms like sustained-release capsules or tablets. Here are the key implications:

  • Inconsistent drug release profiles

    • A wide PSD leads to pellets receiving non-uniform coating thickness during functional coating (e.g., enteric, or sustained release).
    • Smaller pellets may be over-coated (slower release), while larger ones may be under-coated (faster release), resulting in unpredictable or even bimodal drug release.

  • Content uniformity problems

    • If the drug is loaded onto pellets of varying sizes, larger pellets may hold more API, while smaller ones hold less.
    • This uneven drug distribution leads to dose variability, especially in capsule formulations.

  • Poor flow and transport behavior

    • A mixture of fine and coarse pellets tends to segregate during handling and filling due to differences in flow dynamics.
    • This can cause inaccurate fill weights during capsule filling or uneven distribution in tablet blends.
    • Rheological behavior need to be considered, such that within production processes, unlike transport phenomena can be identified.

  • Aesthetic and processing challenges

    • Uneven pellet sizes can affect coating process efficiency, tablet surface uniformity, and even the appearance of the final dosage form negatively.
    • Visually, transparent capsules, sachets or stick packs might have a non-professional look, presenting diverse pellet sizes within one dosage unit.
Narrow and wide size distributions

Comparison of narrow and wide size distributions for MCC pellets

Core value Narrow PSD Wide PSD
Drug release uniformity Consistent coating allows a predictable release profile. Uneven coating might risk a variable or bimodal drug release.
Content uniformity Uniform drug loading across pellets. Uneven API distribution might cause dose variability.
Flow properties fair flow behaviour yield to accurate transport processes in production, e.g. filling. Segregation risk can cause inconsistent weights in dosage form, e.g. tablets or capsules.
Coating efficiency Defined surface-volume ratio of pellets allows efficient, uniform coatings. Surface-volume-ration is more undefined and might result in bad coating performance. Thus, poor release control is a risk.
Manufacturing robustness Comparison in performance across batches is high. Higher variability in PSD might cause process challenges.
Final dosage appearance Uniform, professional look, e.g. for transparent capsules, sachets, stick pack applications. Visibly uneven surface or texture.
Regulatory compliance risk Potentially easier to meet quality specs (e.g., dissolution tests). Potentially higher risk of batch rejection.

Take home message

Overall, MCC pellets provide a robust and scalable solution for sustained-release oral dosage forms, enabling pharmaceutical manufacturers to meet stringent quality standards. MCC spheres, such as CELLETS®, provide a reliable base for modified release formulations. Having diverse particle sizes with narrow size distribution function available, these pellets are universal starter beads for modern drug formulations.

Thereby, a narrow particle size distribution supports dose accuracy, process robustness, and release consistency, making it suitable for high-quality pharmaceutical products. As well, narrow PSD is critical for maintaining formulation performance and regulatory compliance and consumer acceptance.