FROM BRICK-DUST DRUGS TO BREAKTHROUGHS: TRANSFORMING DRUG DELIVERY WITH NOVEL EXCIPIENTS

FORMULATION

Citation: Miinea L, “From Brick-Dust Drugs to Breakthroughs: Transforming Drug Delivery with Novel Excipients”, ONdrugDelivery Online, December 19th, 2025

Dr Liliana Miinea of Lubrizol discusses how next-generation excipients can help formulators realise the potential of promising but poorly soluble drug candidates, including Lubrizol’s Apisolex™ and Apinovex™ polymer excipients for parenteral and oral applications.

“Beyond improving solubility and dissolution rates, excipients should ideally promote stability, scalability and patient-centric drug products, whether for oral solids, injectables or advanced release formulations.”

The pharmaceutical pipeline is becoming increasingly dominated by molecules with extremely poor aqueous solubility. Solubility issues affect up to 90% of new chemical entities1 and around 40% of the top 200 oral drugs on the US market alone.2 Biopharmaceutical classification system (BCS) Class II and IV “brick-dust” APIs present particular problems for drug development. Class II APIs exhibit high gastrointestinal membrane permeability but are poorly soluble, while Class IV APIs have poor permeability and low solubility. This results in limited bioavailability, making many promising drugs highly challenging to formulate.

Selecting the right excipient is key to unlocking the therapeutic potential of brick-dust APIs. Beyond improving solubility and dissolution rates, excipients should ideally promote stability, scalability and patient-centric drug products, whether for oral solids, injectables or advanced release formulations. This need has driven increased attention toward next-generation polymer excipients, which are specially designed to overcome complex formulation challenges.

SOLUBILITY CONSTRAINTS IN DRUG DEVELOPMENT

Solubility-limited bioavailability affects efficacy, dose size, dosing frequency and patient adherence. For injectables, vehicle tolerability and maximum drug concentration often determine the feasibility of a formulation. For oral products, maintaining supersaturation and stability for amorphous solid dispersions (ASDs) is critical.

Many existing excipients can fall short in several ways. For example, polyethylene glycol (PEG)-based solubilisers may trigger hypersensitivity, anaphylactic reactions and neuropathy in parenteral applications, while cellulosic ASD polymers often limit drug loading, which can result in increased tablet weight. This can negatively impact patient compliance, which is an increasingly significant factor in drug development due to regulatory bodies placing more and more focus on the patient experience. As such, novel excipients that are designed to stabilise high API loading and enable simplified processing are gaining strategic importance.

“Among the excipients currently available, many fail to improve the solubility of APIs adequately, and some may cause undesirable side effects for patients.”

INJECTABLE DELIVERY

In parenteral drug development, the range of approved excipients suitable for formulating new APIs is limited. The strict safety requirements and complex chemical challenges associated with excipients for injectable products have made successful commercialisation uncommon over the past three decades. Among the excipients currently available, many fail to improve the solubility of APIs adequately, and some may cause undesirable side effects for patients. In fact, for many oncology drugs, the maximum tolerated dose is restricted not just by the toxicity of the API but also by the toxicity of the excipient itself.

Micellar encapsulation offers a proven alternative for solubilising APIs for parenteral delivery. Polymeric micelles – nano-sized colloidal carriers with a hydrophobic core and hydrophilic shell – sequester poorly soluble APIs within their cores, enabling them to disperse in aqueous environments. Polymeric micelles are formed from amphiphilic block copolymers, which offer a superior safety profile to surfactants.

Lubrizol’s Apisolex™ polymer excipient is a novel polyamino acid-based amphiphilic excipient that is designed to dissolve and stabilise hydrophobic APIs for intravenous (IV) infusion and bolus injection. Based on sarcosine, a non-toxic, non-immunogenic, biocompatible and biodegradable amino acid, Apisolex™ polymer excipient offers a high level of safety for parenteral use. Its safety profile has been confirmed through in vivo studies (Table 1). 

Table 1: Apisolex™ polymer excipient safety test results for parenteral delivery.

For formulators, Apisolex™ polymer excipient offers several key benefits, including:

• Increased solubility by up to 50,000-fold with amorphous and crystalline APIs, with high drug loading of up to 40%, allowing for higher levels of API to be delivered in a smaller volume and enabling a reduction in infusion time or dosage frequency for greater patient-compliance
• Enables formulation as a solution or a lyophilised powder that can reconstitute in saline in under 30 seconds
• Compatibility with straightforward manufacturing processes that have greater than 90% API recovery
• Patent-protected technology.

The solubilisation properties of Apisolex™ polymer excipient were evaluated in comparison with other excipients for a series of poorly water-soluble APIs with the following parameters:

• The experiments were conducted by non-optimised, standard dispersion techniques (mixing or homogenisation), followed by dilution or lyophilisation and reconstitution
• The target API concentration in final product after dilution or reconstitution was 500 μg/mL
• The criteria for solubilisation were turbidity (<100 NTU), particle diameter (<150 nm) and drug recovery after filtration (>80%).

Compared with solubilisers that use a dissolution and dilution technique, only Apisolex™ polymer excipient enabled successful solubilisation of the evaluated APIs, and at a much lower excipient to API ratio (Table 2).

Table 2: Comparison of solubilisers using dissolution and dilution techniques. (*APIs provided by Boehringer Ingelheim)

Similarly, in comparison with solubilisers processed using the same lyophilisation and reconstitution technique, Apisolex™ polymer excipient was the only polymer to enable the successful solubilisation of all evaluated APIs (Table 3).

Table 3: Comparison of solubilisers using a lyophilisation and reconstitution technique. (*APIs provided by Boehringer Ingelheim; TPGS: D-a-tocopheryl polyethylene glycol succinate; PLGA: poly-lactic acid co-glycolic acid)

ORAL BIOAVAILABILITY ENHANCEMENT

For oral solid dosage forms, such as capsules or tablets, brick-dust API solubility can be enhanced via physical modification techniques. For example, ASDs are widely used to disrupt the API’s crystalline structure, increasing the surface area to enhance the gastrointestinal dissolution rate. Excipient choice is critical for formulating ASDs, influencing the degree of solubility enhancement required, drug loading, stability, release kinetics, ease of manufacturing and patient-centricity.

Traditionally, polymers such as hydroxypropyl methylcellulose (HPMC) and its derivatives, povidone and copovidone, have been the main materials used for formulating ASDs. However, these polymers can only typically stabilise drug loadings below 40%, which often leads to larger tablet sizes. Larger tablets can lower patient compliance, especially among the elderly, who are more prone to swallowing difficulties (dysphagia), and among children, up to 40% of whom may struggle to swallow even standard-sized tablets.

Given the growing prevalence of poorly soluble APIs, there is an increasing need for innovative polymer excipients that enhance solubility and drug-loading and are compatible with spray-drying and solvent-based ASD production techniques. Lubrizol’s Apinovex™ is a novel, high molecular weight linear polyacrylic acid excipient. Developed for use with ASDs, it enables more efficient dosage forms with stable drug loading of up to 80%.

Apinovex™ polymer excipient is compatible with a broad range of APIs. Soluble in water and common pharmaceutical solvents such as ethanol and isopropanol, it produces low viscosity solutions for easier processing. It has similar chemistry to Lubrizol’s IID-listed Carbopol® polymers, which have been used in oral drug products for decades. This versatility allows for new drug product development with poorly soluble APIs and reformulation of existing products with the US FDA’s 505(b)(2) reformulation pathway, while also enabling IP protection.

In tests with the BCS Class II drugs itraconazole and ritonavir, Apinovex™ polymer excipient enabled:

• Up to twice as much drug loading as the commonly used solubility-enhancing excipients Soluplus® (BASF, Ludwigshafen, Germany) and AFFINISOL™ (Roquette)
• Up to a 10-fold improvement in API dissolution
• Stable ASDs even after six months under accelerated conditions.

The formulation and processing benefits of Apinovex™ polymer excipient enable the development of more efficient and patient-centric oral dosage forms, including smaller tablets containing the same API dose.

“Lubrizol’s Apisolex™ and Apinovex™ polymer excipients enable formulation of poorly soluble drugs, enhance patient-centric product features, maintain efficient manufacturing processes and support commercial differentiation and lifecycle management.”

SUMMARY

As drug discovery increasingly yields molecules with significant therapeutic potential but challenging physicochemical properties, excipients have evolved from passive formulation aids to active drivers of innovation. Lubrizol’s Apisolex™ and Apinovex™ polymer excipients enable formulation of poorly soluble drugs, enhance patient-centric product features, maintain efficient manufacturing processes and support commercial differentiation and lifecycle management. With the rising demand for formulations that optimise bioavailability, safety and scalable production, these advanced excipients empower formulators to turn difficult APIs into successful medicines, potentially transforming patient outcomes.

REFERENCES

1. Kalepu S, Nakkanti V, “Insoluble drug delivery strategies: review of recent advances and business prospects”. Acta Pharm Sin B, 2015, Vol 5(5), pp 442–453.
2. Rodriguez-Aller M et al, “Strategies for formulating and delivering poorly water-soluble drugs”. J Drug Deliv Sci Technol, Vol 30(Part B), pp 342–351.