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Solubilising brick-dust APIs: the challenges and how to resolve them

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Lubrizol Life Science Health (LLS Health)’s Joey Glassco, MBA, senior global market manager for Injectable Drug Delivery, and Nick DiFranco, MEM, global market segment manager for Oral Treatments share the API solubility puzzle that the pharma industry faces and how to solve it.

Key insights:

Solubility continues to challenge the pharma industry. The growth of poorly soluble active pharmaceutical ingredients (APIs) and new chemical entities (NCEs) in the drug pipeline are well known. However, as the sector looks to meet the therapeutic demands of a growing and ageing population, it’s necessary to readdress solubility and investigate new solutions.

Introduction of the FDA’s 505(b)(2) pathway has helped to facilitate faster and more efficient drug development, by offering an expedited route to market for reformulations of previously approved APIs. However, it has also compounded the need to find novel solutions which can improve the solubility and bioavailability of life-changing drugs. This is important for oral solid and parenteral dosage forms that address the needs of specific patient populations.

The solubility puzzle

Fuelled by computational and scientific advancements, combinatorial chemistry and high throughput screening have become crucial to identifying lead compounds in the drug discovery process. These strategies have provided early-stage teams with better tools to investigate previously undruggable targets, which consequently has oriented discovery toward increasingly complex, poorly soluble molecular targets. BCS Class II drug substances are one of the most common examples, with these candidates often containing many chiral centres and larger molecular weights. Solubility impacts many key physicochemical properties in drug release and absorption.

Many of these products rely on finding alternative technologies to solubilise an API, such as new formulation approaches or excipients. The rise of orphan indications has caused additional reliance on complex, poorly soluble drugs which target smaller patient populations. As such, governing agencies have created regulatory pathways and incentives to renew the focus on unmet patient needs in orphan diseases.

The FDA’s 505(b)(2) pathway has been a popular approach to repurpose approved APIs in new formulations or dosage forms to enhance the pharmacokinetic properties, which lowers application risk and expedites time-to-market. Not only does the 505(b)(2) support developers, but it also allows patients to have access to more treatment options. However, formulating drug products for these targets can still present challenges related to poor water solubility and/or bioavailability.

Strategies for solubility

Excipients have always played an important role in the formulation and manufacturing of pharma dosages, aiding product functionality as fillers, binders, or coatings. For oral dosage forms, these include substances such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl methylcellulose acetate succinate (HPMC-AS), and polyvinyl pyrrolidone (PVP). In parenteral formulations, modified cyclodextrins, polyethylene glycol (PEG), polysorbate 20, and polysorbate 80 have been used in many approved drug products over the years.

Alongside the use of excipients, formulators investigating oral solid or parenteral forms for low soluble APIs may also consider utilising formulation techniques, including:

Leveraging the right excipient technology is important for these formulation techniques, as they provide a tool to stabilise APIs and increase solubilisation. But, when it comes to selecting the best method for your drug formulation, factors such as properties of the API, intended final dosage form, and even commercialisation factors such as cost of scale-up and IP protection, need to be considered.

Furthermore, leveraging traditional approaches alone for poorly soluble drugs may not be able to enhance the solubility up to the desired level. As such, finding the right approach for each project requires investigating combinations of various polymers and formulation techniques.

New technologies, collaborative solutions

Novel excipients can open new paths of opportunity for drug developers and are becoming an increasingly attractive option to improve the solubility of hydrophobic APIs.

However, as new, complex, and multifaceted NCEs and 505(b)(2) opportunities continue to move through the pipeline, formulators will need to leverage new tools to ensure more of these drugs make it to market. Polymeric excipients are one of the main areas gaining traction, such as Apinovex and Apisolex, which can support oral solid and parenteral dosage forms, respectively.

Furthermore, novel excipients play a major role in optimising established formulation techniques and efficacy and IP protection are the most prevalent reasons as to why.

The indicative new IP protection from the novel excipient means that there is a long patent life ahead for drug developers and marketers to utilise. New chemical entities can generally rely on their own IP; however, novel excipient IP may be useful for older clinical candidates that had been previously shelved due to solubility issues.

Despite this, there has been hesitancy within the industry to apply them in development programs due to perceived regulatory and scale-up challenges. However, an experienced and reliable excipient supplier can mitigate the risk associated with novel excipients by establishing robust processing under GMP guidelines, providing safety and toxicity data, and creating Drug Master Files (DMFs).

Solutions which support the whole market

Patient centricity is often a concern in the formulation of novel therapeutics. With a growing, ageing population, patients need efficacious therapeutics that can be delivered efficiently and with minimal discomfort. An API that exhibits poor solubility will need a higher dosing or more frequent administration to achieve the desired therapeutic effect, which can increase the incidence of side effects.

The amount of API that can be included in a dose of a drug product is often impacted by the excipients used. In oral solid dosage forms, inefficient drug loading in a tablet means that a patient may need to take a difficult-to-swallow tablet or multiple tablets throughout the day to achieve the desired dose. Similarly, for parenteral therapeutics, patients may need to receive longer IV infusions or multiple injections to achieve the recommended dosage.

Some novel excipients can address these difficult-to-administer challenges, allowing for more efficient drug loading or encapsulation than traditional options.

Formulations that utilise complexing excipients usually require high amounts of polymer to solubilise drugs. This limits the drug loading and increases the potential risk of polymer side effects. Efficient, novel excipients, such as the polyamino acid-based polymers developed by Lubrizol, have been designed for low usage levels, minimising the risk of side effects. And from a compositional perspective, polymers made from naturally occurring amino acids, such as sarcosine, offer an inert replacement to polymers like PEG and polyvinyl alcohol (PVA).

Novel excipient development has helped solubilise BCS Class II and IV APIs, not only easing the pain points for developers, but helping to create better and more effective therapeutics for patients that have a lower risk of adverse side effects.

Solubilising the future, today

As more poorly soluble molecules enter the pipeline and more pharma companies seek ways to utilise the 505(b)(2) regulatory pathway, excipient technologies and manufacturing techniques provide the tools to carry out more efficient and effective drug development.

However, selecting the best excipients requires a balance between time and cost efficiencies as well as anticipated product performance. Looking to the future, collaboration between pharma companies and innovative excipient suppliers continue to play an important role in providing higher quality drug products.

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