For drug developers working on oral solid dosage drug projects, solubility, and therefore bioavailability, is a significant challenge. At present, poor water solubility impacts around 40% of drugs currently on the market. While in the developmental pipeline, up to 90% of potential active pharmaceutical ingredients (APIs) or new chemical entities (NCEs) are poorly soluble and cannot form viable drug products. [1] In the industry, they are often known as brick-dust APIs.

However, thanks to advancements in technology and formulation techniques, it is becoming easier for drug developers to overcome solubility issues during the early stages of development and formulation. From the emergence of novel excipients to the increasing acceptance of solid dispersion techniques, formulators have new solutions to add to their toolbox.

Current challenges in oral solid dosage formulation

Bioavailability is defined as the fraction of an administered drug that reaches systemic circulation. A key concern when developing an oral solid dosage form comes from generating a therapeutic which can be absorbed into the bloodstream and demonstrate a therapeutic effect.

Solubility is inherently linked to bioavailability, and therefore, must be addressed first. If a drug cannot be dissolved through the gastrointestinal (GI) tract into the bloodstream – due to poor solubility – it will not reach systemic circulation and ultimately lead to low bioavailability.

In recent years, the concept of supersaturation has become increasingly accepted as an effective approach to enhance bioavailability. This is due to the increasing number of poorly water-soluble drugs in the development pipeline. Drug absorption in the GI tract can be enhanced by designing formulations that maximize the intraluminal concentration and go beyond the thermodynamic equilibrium solubility of an API. However, major challenges are faced by scientists adopting supersaturatable formulations. These include controlling the rate and degree of supersaturation – by utilizing polymeric precipitation inhibitors – and maintaining post-administration supersaturation. [2]

Other challenges faced by developers are geared toward developing more patient-friendly dosage forms. Features such as smaller tablet sizes for ease of swallowing and efficient use of API for reduced side effects are common goals in oral tablet formulation.

Solutions on the market to address these challenges

Within the industry, there are a variety of accepted ways to address solubility challenges in APIs; two of these are physical and chemical modifications. Physical modifications encompass techniques such as nanomilling, the formation of co-crystals, and the creation of amorphous solid dispersions (ASD). Meanwhile, techniques like pH modification, drug-salt formation, and PEGylation are known as chemical modifications. Depending on the drug moiety in question, and the required dosage form, the most appropriate solubility- enhancing method will vary. For example, nanomilling can put some APIs under stress, leading to a reduction in stability. In some situations, it is possible to overcome this by leveraging excipients that offer stabilizing qualities. However, no solution is a one size fits all cure, so it’s important to choose the right techniques for the APIs or NCE you’re working with.

In addition to the poor solubility issues already faced by drug developers, new APIs and NCEs are continually discovered and developed, increasing the need for efficient methods to solubilize and deliver life-changing therapeutics. Furthermore, thanks to the introduction of the Food and Drug Association’s (FDA) 505(b)(2) regulatory pathway, formulators can now leverage existing safety and toxicity data to improve or optimize approved drug products. The 505(b)(2) pathway encourages pharmaceutical companies to evaluate new excipients, formulation techniques, dosage forms, and API combinations to bring better treatment options to patients.

Utilizing formulation techniques

Reducing the size of APIs via physical modifications is a popular way to improve solubility. Nanoparticles provide many benefits to formulators looking to improve stability, solubility, and bioavailability, and can be produced from a range of methods like nanomilling. Micronization and jet milling are other techniques that can be used to reduce the particle size to the micron range to improve similar properties.

The creation of ASDs – via spray drying or hot melt extrusion – is also a popular approach to enhance poorly soluble APIs and create viable drug products. These techniques, which rely on thermal- or solvent-based processing to homogeneously disperse API particles into polymers, have been used for decades in the pharmaceutical industry.

Most ASDs are incorporated into tablet or capsule formulations. Products range from single API systems like Sporanox® (Itraconazole) to more advanced, multi-API tablets like Trikafta® (Elexacaftor/Tezacaftor/Ivacaftor).

Leveraging excipients

Polymeric carriers/excipients are crucial in the development of ASDs. Polymer selection impacts key properties including:

Level of solubility improvement
Drug loading capacity
Drug product stability
Drug release profile
Ease of processing
Patient centricity

There are several established classes of excipients that have been used to improve solubility, including, but not limited to: Hypromellose (HPMC), HPMC-AS, povidone, and copovidone. While these polymer families are generally considered “first-choice” options when developing ASDs, the growing pipeline of poorly soluble APIs is creating interest in new materials. Novel excipients can be easily integrated into existing screening programs—such as a film-casting and small-scale spray drying—to increase chances of success when formulating poorly soluble APIs.

In addition to their technical benefits, these new polymer chemistries offer commercial value in the form of product differentiation, product lifecycle management, and potential patent protection.

Apinovex™ Polymer: A New Option for Solubility Enhancement

Excipients and formulation techniques are used in tandem to enhance the solubility of oral solid dosage therapeutics and create viable, effective drug products. Polymeric excipients, such as Lubrizol's Apinovex™ polymers, are valuable tools in the development of ASD-based drug products.

Apinovex [1] polymers are high molecular weight polyacrylic acid excipients that allow drug formulators to improve the solubility of biopharmaceutical classification system (BCS) II and IV APIs to develop efficient, stable, and high drug loading in oral solid dosage forms. With broad solvent and API compatibility, Apinovex polymers can easily be incorporated into existing ASD projects.

In case studies with itraconazole and ritonavir, Apinovex polymers enabled up to 80% drug loading and improved drug dissolution up to 10-fold compared with crystalline APIs. The high drug loading capacity of Apinovex means formulators can develop smaller, easier-to-swallow tablets that improve the patient experience, even for challenging, high dose APIs.

The Apinovex technology is also patented, making it an ideal option for differentiated NCE and 505(b)(2) products. With Apinovex polymers, pharmaceutical companies can rescue poorly soluble APIs in their pipeline or capitalize on high-value reformulations of marketed APIs.

Potential of next-generation oral solid dosage form excipients

The need for novel excipients and formulation techniques to enhance the bioavailability of poorly water-soluble APIs persists. The growing number of BCS Class II and IV APIs, coupled with a rising demand for patient-centricity in pharmaceuticals, will drive demand for new technologies in the coming years.

Much focus is given to novel formulation techniques for solubility enhancement. However, novel polymeric excipients allow formulators to utilize established processing techniques such as spray drying to overcome their technical challenges. New polymer technologies can offer key technical benefits to NCEs and enable pharmaceutical companies to realize the tremendous value of the 505(b)(2) approval pathway.

Apinovex™ polymers are a powerful new tool for creating patient-centric oral solid dosage forms with enhanced solubility. Apinovex polymers allow formulators to achieve their technical goals and develop differentiated products that truly benefit patients.

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References

Kalepu, S., & Nekkanti, V. (2015). Insoluble drug delivery strategies: review of recent advances and business prospects. Acta pharmaceutica Sinica. B, 5(5), 442–453. https://doi.org/10.1016/j.apsb.2015.07.003
Gao, P., & Shi, Y. (2012). Characterization of supersaturatable formulations for improved absorption of poorly soluble drugs. The AAPS journal, 14(4), 703–713. https://doi.org/10.1208/s12248-012-9389-7

Solving Solubilization: Overcoming Challenges in the Formulation Development of Oral Solid Dosage Forms