In formulation, there is a fairly common temptation: to select excellent ingredients individually and assume that, once combined, the result will necessarily be better.

But a formula is not the sum of its ingredients.

It is a chemical and physical system in which each component modifies the environment of the others. Apparently small changes in pH, ionic strength, redox potential, water activity or colloidal structure can completely transform the behaviour of an ingredient.

Two raw materials that are perfectly stable on their own may, when brought into contact, cause loss of viscosity, precipitation, oxidation, reduced enzymatic activity or even decreased bioavailability of a nutrient.

At Admixtio, we believe that understanding these interactions is one of the most interesting—and also one of the most overlooked—parts of formulation.

What does it really mean for two ingredients to be incompatible?

Incompatibility does not necessarily mean that two substances “react” in a spectacular way.

In formulation, it can appear at several levels.

There may be a chemical incompatibility, when one ingredient accelerates the degradation of another. There may also be a physicochemical incompatibility, for example when aggregation, turbidity or precipitation occurs.

In other cases, the product remains apparently perfect, but a functional incompatibility takes place: one ingredient reduces the effectiveness of another.

And there is still a fourth possibility, particularly relevant in food and supplementation: both ingredients may remain stable in the product but later interact during digestion, modifying their bioaccessibility or bioavailability.

That is precisely where the difficulty lies.

An incompatibility is not always visible.

Cosmetics: when the problem is inside an apparently stable formula

Vitamin C: the enemy may be the environment itself

L-ascorbic acid is probably one of the best examples of an active ingredient whose efficacy depends profoundly on its formulation environment.

It is an effective molecule, but chemically labile. Its degradation increases under certain conditions of pH, temperature, oxygen and light exposure. The presence of certain transition metals may also promote oxidative processes.

That is why formulating with vitamin C is not simply a matter of “adding vitamin C”.

Available water, pH, oxygen, excipients, packaging and potential oxidation catalysts all need to be controlled. Current strategies include more stable derivatives, chelating agents, secondary antioxidants, anhydrous systems and encapsulation. Recent research continues to identify stability as one of the main technological limitations of this active.

It is a perfect example of a fundamental concept:

a scientifically excellent active can become a mediocre active inside an unsuitable formula.

Carbomers and electrolytes: when the gel disappears

Another classic example involves acrylic polymers used to control rheology.

Carbomers develop viscosity through expansion of their polymer network after neutralisation. This structure depends largely on electrostatic repulsion between the ionised groups of the polymer.

What happens when a high concentration of electrolytes is introduced?

The ions screen these charges, the network loses expansion and viscosity can decrease significantly. Multivalent cations and certain cationic ingredients can produce even stronger effects, in some systems leading to turbidity or insoluble complexes.

This is why a formula may work perfectly until, for example, a salt-rich extract, certain minerals or a raw material with high conductivity is introduced.

Apparently, the problem lies with “the thickener”.

But in reality, it lies in the interaction between the thickener and the rest of the system.

Cationic + anionic: enemies or allies?

This is one of the most interesting interactions in cosmetic formulation because it shows that compatibility is rarely binary.

Anionic surfactants and cationic polymers display strong electrostatic attraction. Under unsuitable conditions, aggregation, turbidity or precipitation may occur.

However, in a well-designed shampoo, that same interaction can become an extremely useful tool.

When the shampoo is diluted during rinsing, certain cationic polymers and anionic surfactants may form a coacervate that deposits onto the hair fibre. This mechanism can improve conditioning and promote the deposition of silicones, oils or other functional agents.

In other words:

an interaction that can destroy a formulation can also, if properly controlled, become its main functional mechanism.

This is where formulation stops being simply ingredient chemistry and becomes systems engineering.

Detergency: a genuine chemical battlefield

Detergent formulations are particularly demanding because they bring together surfactants, enzymes, sequestrants, polymers, fragrances, bleaching agents and different salts in the same product.

Each ingredient has a function.

But it does not necessarily want to coexist with the others.

Enzymes and oxidising agents: efficacy versus stability

Proteases, amylases, lipases and cellulases have transformed modern detergency because they allow certain stains to be removed at relatively low temperatures.

The problem is that they are still proteins.

And proteins are susceptible to denaturation, proteolysis and oxidation.

Oxidising bleaching agents may damage certain enzymes; some surfactants can also alter their structure and reduce their activity. Proteases present an additional problem: they may degrade themselves—autolysis—or attack other enzymes present in the same formulation.

The industry has responded with highly sophisticated technologies: protein engineering, molecular stabilisation, encapsulation and physical separation of ingredients.

It is no coincidence that powder detergents allow certain combinations that are considerably more difficult in liquid detergents: in the solid state, ingredients can remain physically separated until the moment of washing.

Quaternary ammonium compounds and anionic surfactants: opposite charges, real problems

Quaternary ammonium compounds are cationic surfactants used, among other applications, for their antimicrobial properties.

Anionic surfactants, by contrast, make up one of the major families of cleaning agents.

Combining the two indiscriminately can be problematic.

Electrostatic attraction between opposite charges can produce complexes and aggregates. At certain charge ratios, precipitation and loss of surface activity may even occur. In the case of benzalkonium chloride, incompatibilities with anionic surfactants and soaps have been specifically described.

This is particularly relevant when trying to achieve both cleaning and disinfecting action at the same time.

It is not enough to confirm that the biocide works and that the surfactant cleans.

You also need to confirm that the biocide still works when it is inside that specific formula.

Bleaches, fragrances, enzymes and metals: maintaining the balance

Oxidising systems present another challenge.

A bleaching agent must remain sufficiently stable during storage, but become effectively activated during washing. At the same time, it must coexist with enzymes, fragrances, polymers and other oxidation-sensitive components.

Trace metals can accelerate oxidative decomposition, which is why sequestrants and raw-material quality become so important.

This explains why the stable incorporation of certain bleaching systems into liquid detergents remains significantly more difficult than in granular formulations or tablets.

Food and supplements: ingredients that are compatible in the jar, but not necessarily in the body

Here another, even more interesting concept appears.

In nutrition, two ingredients may coexist perfectly throughout the entire shelf life of a product and yet interfere with one another after ingestion.

Iron, phytates and polyphenols: when “more healthy ingredients” does not necessarily mean better nutrition

Non-haem iron is particularly sensitive to the composition of the food matrix.

Phytates present in cereals, legumes and seeds can form complexes with minerals. Certain polyphenols may also reduce iron absorption.

Ascorbic acid, by contrast, can enhance it.

This is why the bioavailability of a mineral does not depend solely on how many milligrams are present in a supplement or functional food. It also depends on what it is formulated with and the matrix in which it is consumed.

It is also important not to oversimplify this interaction: effects observed in isolated meals may be greater than those detected in complete diets, where multiple inhibitors and enhancers coexist simultaneously.

This distinction matters because it shows that functional nutrition cannot be designed by looking at ingredients individually either.

Proteins and polyphenols: a two-sided interaction

Polyphenols can associate with proteins through hydrogen bonding, hydrophobic interactions, electrostatic forces and even covalent interactions following certain oxidative processes.

The result can vary greatly depending on the protein, the polyphenol, pH, temperature and processing conditions.

In some systems, these associations can cause turbidity, sedimentation, changes in solubility or astringency. They may also modify protein digestibility and the bioaccessibility of the phenolic compound.

But once again, we encounter a paradox:

those same interactions can be deliberately used to improve emulsion stability, build encapsulation systems or protect certain bioactives.

The 2026 review on plant protein–polyphenol systems summarises this duality very well: a stronger molecular interaction does not necessarily mean better nutritional functionality.

Omega-3: when a healthy ingredient meets a pro-oxidant environment

EPA and DHA have a high degree of unsaturation.

That structure is precisely responsible for many of their properties, but it also makes them highly susceptible to lipid oxidation.

When incorporated into foods or supplements, the formulation environment becomes critical. Oxygen, temperature, interfaces, antioxidants, emulsification and the presence of certain metals can significantly affect their stability.

The consequence is not only a loss of nutritional value. Oxidation also generates characteristic aromas and flavours that can completely undermine the sensory acceptance of the product.

For this reason, the incorporation of omega-3 into functional foods has driven technologies such as microencapsulation, protective emulsions and specific antioxidant systems.

The key lesson: incompatibility belongs to the system, not to the ingredient

This is probably the most important point.

Saying that two ingredients “are incompatible” is usually an oversimplification.

Compatibility depends on variables such as concentration, pH, temperature, ionic strength, water activity, order of addition, presence of oxygen, chemical form, packaging and storage time.

Even manufacturing scale can alter the outcome.

The relationship between an anionic surfactant and a cationic polymer is an excellent example: it may produce unwanted precipitation or become the conditioning mechanism of a modern shampoo.

That is why the popular internet lists of “ingredients you should never mix” have little value from the point of view of formulation science.

The right question is not:

Can I mix A with B?

But rather:

What happens when A and B coexist in this matrix, at these concentrations, at this pH and throughout the entire shelf life of the product?

How are these incompatibilities detected?

This is where the real development work begins.

Compatibility should be studied before and during formulation through preformulation and stability testing.

Depending on the product, parameters such as pH, conductivity, viscosity, rheological behaviour, particle-size distribution, zeta potential, turbidity, colour, enzymatic activity, active concentration using chromatographic techniques, or the evolution of oxidation products may be evaluated.

And above all, checking physical stability is not enough.

A cream can remain white and homogeneous while its vitamin C degrades.

A detergent can maintain exactly the same viscosity while its enzyme loses activity.

A supplement can remain perfectly stable while the combination of ingredients later reduces the bioavailability of one of them.

Visual stability does not mean functional stability.

Formulating also means separating

Sometimes the best solution is not to make two ingredients coexist.

It is to prevent them from coming into contact until the right moment.

This is the principle behind many technologies currently being used: microencapsulation, multi-chamber capsules, biphasic products, anhydrous systems, multilayer tablets and dual-compartment packaging.

Innovation does not always mean discovering a new ingredient.

Sometimes it simply means making sure that two excellent ingredients do not meet too soon.

Conclusions

Ingredients do not work in isolation.

Every addition modifies a chemical, physical and functional balance that can affect the formulation as a whole.

That is why selecting good ingredients is only the beginning.

True formulation is about understanding how they interact with one another.

In cosmetics, this can determine the stability of an active or the texture of a cream.

In detergency, it can determine whether an enzyme retains its activity or whether a biocide remains effective.

In food, it can even modify the actual bioavailability of a nutrient.

At Admixtio, we help analyse these interactions from a cross-disciplinary perspective: ingredient selection, compatibility, stability, efficacy and behaviour within the real matrix.

Because an excellent formula is not the one that contains the largest number of interesting ingredients.

It is the one in which all of them know how to coexist.

Bibliography and webography

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8. Milman, N.T. (2020). A Review of Nutrients and Compounds Which Promote or Inhibit Intestinal Iron Absorption.
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