Tapping into the potential of vitamins as excipients

Innovations in pharmaceutical formulation don’t necessarily have to come from molecules that are completely new to the world. Well-known chemistries are being used to overcome complex formulation challenges such as poor solubility, oxidative degradation, nitrosamine risk, radiolysis, high viscosity and route-specific manufacturability challenges. A major advantage of this approach is that many of these excipients are already highly characterised, facilitating safety assessments, quality documentation and regulatory compliance.

In practice, antioxidant performance depends on whether the molecule is present in the phase or microenvironment where degradation is taking place. A water-soluble antioxidant will not necessarily protect an oil phase and a lipophilic antioxidant may not efficiently intercept a reaction occurring in an aqueous microenvironment. pH, oxygen exposure, light, transition metals, moisture and packaging can all influence drug performance. Vitamin selection therefore requires a structured degradation pathway assessment, not a generic ‘add antioxidant’ decision.

Nitrosamines can form when nitrosating species react with vulnerable amines or amides in application programming interfaces (APIs), impurities or other formulation components. Nitrite burden, pH, water activity, manufacturing processes, packaging and storage conditions can all increase this risk and regulators expect pharma manufacturers to assess, test and control nitrosamine formation across the product life cycle.1,5 Nitrosamines are difficult to remove from a finished dosage form, so a more robust strategy is to prevent or reduce their formation in the first place. This can be done by controlling nitrite levels in excipients, optimising process and storage conditions, modifying the formulation microenvironment and introducing nitrite scavengers as excipients. Regardless of the approach chosen, the control strategy must be able to show demonstrable improvements to nitrite and nitrosamine analytics, compatibility with the API and other formulation components and good stability, as well as provide a rationale for any bioequivalence bridging approaches.5-8

Ascorbic acid, ascorbate salts and alpha-tocopherol have all been investigated for their ability to intercept reactive nitrosating species before nitrosation occurs.9,10 Recent work with ascorbic acid has highlighted both advantages and limitations of this approach, as distribution of the scavenger in the blend can matter, as can the stability of ascorbic acid during manufacturing.6 This study also highlighted the possibility of the API reacting with ascorbic acid, leading to the formation of new API-related impurities. Several studies of antioxidant addition and oral absorption endpoints also suggest that incorporation does not automatically create a bioequivalence concern, although permeability and

B vitamins are less well established as pharmaceutical excipients than vitamins C and E, but they are increasingly being investigated for a number of potential uses in biologics and advanced formulations. For example, high-concentration monoclonal antibody formulations can become too viscous for convenient subcutaneous administration, so small molecules with balanced ionic, hydrophobic and hydrogen-bonding features – including selected B vitamins and their derivatives – have been explored as viscosity-reducing excipients.13,14 In particular, thiamine-related chemistries (vitamin B1) have been reported as providing large viscosity reductions in concentrated antibody solutions.13 The proposed mechanism is not a simple dilution effect; it is thought to involve disruption or shielding of attractive protein-protein interactions. This makes B vitamins strong candidates for overcoming viscosity, aggregation or injectability limits for biologics.

Niacinamide (a form of vitamin B3) provides another practical example. It is used in fast-acting insulin aspart formulations, where it contributes to earlier insulin appearance and pharmacodynamic onset.15,16 Mechanistic work indicates that niacinamide promotes insulin monomer formation, enhances endothelial permeability and induces local vasorelaxation.17 More generally, niacinamide is a classic hydrotrope, capable of increasing apparent solubility through non-micellar solubilisation.18 Experimental work has also described metal-complexing behaviour for selected B vitamins and vitamin B6 has been studied in the context of free-radical-induced monoclonal antibody aggregation.19,20

The success of a vitamin-based excipient strategy depends as much on material quality and consistency as on functionality. For advanced applications – such as biologics and radiopharmaceuticals – formulators must evaluate not only the excipient’s performance, but also its pharmaceutical-grade quality attributes, including impurity control, microbial quality, elemental impurity limits, particle characteristics, regulatory documentation and supplier change-management processes (see Table 1).

Successful use of vitamin excipients in formulation development is founded on disciplined screening: define the degradation or performance problem; select the vitamin form that matches the microenvironment; verify compatibility in the target product, and build a control strategy that regulators can understand. The future of vitamins in pharmaceutical formulation will likely be shaped by a deeper understanding of their multifunctional properties and how these can be applied to solve emerging development challenges across diverse dosage forms and therapeutic modalities.

Dr Anne-Cécile Bayne leads global science and innovation activities for Pharma & Medical Nutrition at dsm-firmenich, driving the development of novel ingredient and excipient solutions for pharmaceutical and nutritional applications. She holds a PhD in Molecular Pharmacology and Toxicology from the University of Southern California, CA, US, and completed postdoctoral research at the US National Institutes of Health. She specialises in translating scientific insights into patient-centric technologies, based on over 20 years of experience in biotechnology and pharma innovation.