Solubility, Dissolution and Bioavailability: Three Distinct Concepts in Oral Solid Dosage Form Development

A significant proportion of new drug candidates present limited aqueous solubility. This is a well-documented formulation challenge, particularly for oral solid dosage forms, where the performance of the final product depends not only on the API itself, but also on the way the formulation supports dissolution under physiological conditions.

In this context, excipients play an important role. They do not usually change the intrinsic solubility of an API, but they can influence the physical and functional environment in which the API disperses, wets, disintegrates and dissolves. For formulation teams, a clear distinction between these three concepts can support more targeted and informed development decisions.

Poor aqueous solubility: a growing formulation challenge

Many new chemical entities in development are associated with limited aqueous solubility. This trend is often linked to the nature of modern therapeutic targets, which can favour more lipophilic and structurally complex molecules. As a result, a high proportion of drug candidates fall into Biopharmaceutics Classification System classes where solubility is a key parameter to manage.^1,2

And formulation may therefore represent an important lever to support drug product performance and can help ,  to create more favourable conditions for dissolution, dispersion and exposure of the API to gastrointestinal fluids. This is where excipient selection can become relevant.

Solubility, dissolution and bioavailability: three connected but distinct concepts

Solubility, dissolution and bioavailability are often closely  linked,

• Solubility is a thermodynamic property of the API. It refers to the maximum amount of a substance that can dissolve in a given liquid volume under defined conditions, including pH and temperature. In most cases, excipients do not directly modify intrinsic API solubility.
• Dissolution is a kinetic process. It describes the rate at which the API enters solution. Dissolution is influenced by several formulation-related factors, including particle size, surface area, wettability, disintegration behaviour, local pH and the physical environment created by the excipient system.
• Bioavailability refers to the fraction of the administered dose that reaches systemic circulation. It depends on several parameters, including dissolution, permeability, stability in the gastrointestinal tract and first-pass metabolism.

For oral solid dosage forms, the formulation team often acts most directly on dissolution. By selecting appropriate excipients and controlling critical material attributes, formulators can support the conditions needed for consistent API release and dissolution.

How excipients may influence the solubility-dissolution continuum

Excipients can contribute to dissolution performance through different mechanisms. These mechanisms may be physical, chemical or system-level, depending on the formulation strategy.

Physical mechanisms

Particle size reduction is one of the most established approaches. By increasing the surface area of the API, micronization or nanonization may improve dissolution rate, in line with the Noyes-Whitney .

Dispersion is another approach, where the API is dispersed in a carrier matrix, often in an amorphous state. This can improve apparent dissolution performance, although physical stability and potential recrystallization must be assessed during development and storage.¹

Chemical mechanisms

Some excipients may help adjust the microenvironmental pH around the API. This can be relevant for pH-dependent compounds, where local conditions may influence dissolution behaviour.

Other complexing agents can also increase the apparent concentration of the API in solution by forming inclusion complexes. In such cases, the effect is not a direct change in intrinsic solubility, but rather an increase in apparent solubilization under specific conditions.

System-level mechanisms

In many oral solid dosage forms, dissolution performance depends on how the full excipient system behaves. Hydrophilic matrices, agents, disintegrants, fillers and binders all contribute to the way water enters the tablet, how the matrix opens and how the API becomes exposed to fluids.

This is why excipient selection is generally considered as part of the overall formulation architecture rather than as a list of individual ingredients.

The role of lactose in dissolution performance

Lactose has a long history of use in oral solid dosage forms, but its selection should always be based on the formulation objective and the characteristics of the API.

For APIs containing primary or secondary amines, compatibility with lactose should be assessed because of the potential for Maillard-type reactions under certain conditions. This does not exclude the use of lactose in all cases, but it means that compatibility testing should be part of development.⁵

In complex modified-release systems, lactose may have a more limited role if the release kinetics are mainly driven by polymers, osmotic systems or other controlled-release technologies.

Lactose does not modify the intrinsic solubility of the API. Its contribution is generally indirect and formulation-dependent. In immediate-release oral solid dosage forms, lactose can help create favourable conditions for disintegration, wetting and API dispersion.⁵

Because lactose is water-soluble, it can contribute to the formation of an aqueous phase within the tablet matrix. This may support tablet disintegration and help expose the API surface to gastrointestinal fluids. Its particle characteristics may also influence blend uniformity, compaction behaviour and the reproducibility of the dissolution environment.

Several parameters are particularly relevant:

• Water-soluble filler function. Lactose can dissolve rapidly once water penetrates the tablet, which may support matrix opening and API exposure.
• Wettability contribution. Depending on the formulation, lactose may help distribute water more evenly within the tablet matrix and support contact between the API and the aqueous phase.
• Blend uniformity. For low-dose products, the morphology and particle size distribution of the filler can influence API distribution throughout the blend.
• Batch-to-batch consistency. A well-characterized lactose grade can help reduce variability linked to excipient properties, provided that the formulation and process are also controlled.

These contributions should be validated through formulation trials, dissolution testing and compatibility assessments. Lactose is not a universal solution for all poorly soluble APIs, but it can be a useful and well-understood excipient when selected for a defined technical purpose.

Lactose and MCC: a common combination in tablet formulation

In many oral solid dosage forms, lactose is used in combination with microcrystalline cellulose, or MCC. This association can be relevant because the two excipients bring complementary functionalities.

Lactose is typically valued for its water solubility, good flow properties depending on grade, and its contribution to mouthfeel and tablet matrix behaviour. MCC is widely used for its binding capacity, compressibility and ability to support tablet hardness, particularly in direct compression.⁵

When used together, lactose and MCC may help balance several formulation objectives:

• Compressibility and tablet strength. MCC can contribute to compactibility, while lactose may support flow and soluble filler functionality.
• Disintegration behaviour. MCC can support water uptake and tablet matrix disruption, while lactose dissolution may contribute to the creation of aqueous pathways within the tablet.
• Processing flexibility. The combination may be relevant in direct compression, dry granulation or wet granulation, depending on the API properties and target tablet characteristics.
• Dissolution environment. For some APIs, the lactose-MCC balance may influence porosity, water penetration and exposure of the API surface.

However, the ratio between lactose and MCC should be defined carefully. A formulation with too much binder-like behaviour may reduce useful porosity, while insufficient mechanical strength may affect tablet robustness. As with any excipient combination, the final choice depends on API properties, target dose, process route and dissolution profile requirements.

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Source: Lactalis, website Solubility, Dissolution and Bioavailability: Three Distinct Concepts in Oral Solid Dosage Form Development

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