The bioavailability challenge

Between 40-70% of marketed drugs and up to 90% of all new chemical entities (NCEs) registered suffer from poor water solubility, meaning they don’t readily dissolve in an aqueous solution. This can have significant negative consequences for the bioavailability of the active pharmaceutical ingredient (API), with a potential impact on therapeutic effect in turn.

Poor solubility in NCEs is a significant issue because it can hinder innovation, particularly in injectable and oral drug products. To tackle the problem, the market for solubility enhancing excipients and related technologies is growing quickly, expanding at a compound annual growth rate of nearly 13% in the period from 2014 to 2024¹.

The Biopharmaceutical Classification System (BCS) is widely used across the pharmaceutical industry to describe and define the solubility of an API. It divides molecules into four separate classes according to their behavior when interacting with water.

Apinovax - biopharmaceutical classification system
Figure 1

Two classes of molecules, in particular, are challenging when it comes to drug formulation. Class II molecules show high permeability, meaning they can be absorbed by the human body, but have a poor solvation rate, which limits their bioavailability both in vitro and in vivo. Class IV molecules show both low solubility and permeability, which not only means they are difficult to dissolve in a standard water-based formulation, but they are not well absorbed over the intestinal mucosa or other human tissues, impacting on their therapeutic effect.

However, there are techniques that can be harnessed to improve solubility, increase bioavailability, and enable these APIs to be formulated into viable drug products.

Different techniques to overcome solubility challenges

Various techniques can be used to help overcome drug solubility issues, depending on the unique characteristics of the API in question, as well as the specifics of the formulation and the dosage form:

API chemical modification
Examples include pH modification using acidic or basic excipients to enhance the solubility of ionizable APIs. Salt formation, whereby APIs are converted to salts, is another approach; many APIs are more soluble in salt form. PEGylation using polyethylene glycol to form a conjugate with the API is another approach, as is PEGPLUS™ technology, offered by LLS Health.
Encapsulation
Encapsulating APIs within micelles and liposomes, using amphiphilic compounds to enable delivery of hydrophobic APIs or protect large molecules, are possible approaches. LyoCell® technology, solid-lipid nanoparticles, and polymer encapsulation are other possible methods to enhance solubility.
Inclusion complexes
β-cyclodextrins – water-soluble torus-shaped cyclic oligosaccharides with a hydrophilic surface and a hollow hydrophobic core – can be used to entrap APIs and carry them across biological membranes. Serum albumin can also be complexed with APIs to form bioresorbable nanoparticles with improved solubility and dissolution rate.
API physical modification
Physical modification can be used to improve the solubility of APIs. Nanomilling is used to increase the surface-area-to-volume ratio of an API by reducing particle size in a liquid vehicle (typically aqueous) via grinding. Micronization is a similar approach that uses jet milling to reduce particle sizes to the micron scale.

Other physical approaches focus on the molecular structure of APIs:

Co-crystals – engineered materials comprised of API molecules and co-crystal formers (AKA coformers) forming a single crystal lattice – can improve solubility.
Amorphous solutions and dispersions are also used to increase the dissolution rate of APIs. These systems work by disrupting the crystalline structure of an API and maintaining the API in a more soluble amorphous state.

A number of these formulation techniques for poorly soluble drugs are enabled by the use of excipients. Amorphous solid dispersions (ASDs) are one key example.

Excipients in action

When developing drug products, formulating APIs into amorphous solid dispersions (ASD) is becoming increasingly attractive as an approach for improving the solubility and bioavailability of poorly water-soluble oral drugs. The addition of a high-quality excipient that stabilizes the drug in amorphous form is essential to ensuring the success of the final drug product using this approach.

Preparation methods to form non-crystalline API particles include hot-melt extrusion and solvent evaporation processes, such as spray-drying.

Spray drying is a continuous process that entails the transformation of a liquid feed containing, for example, an API and a polymeric excipient by spraying the feed into a hot drying medium, such as air. This approach allows the properties of the resulting particles to be precisely controlled. Spray drying offers particular benefits when it comes to solubility enhancement. It is applicable to a broad range of API and excipients provided they are soluble in volatile organic solvents. One of the main advantages of this process is that it does not expose the API to excessive heat during manufacture of the amorphous dispersion (as opposed to Hot Melt Extrusion).

Some of the most common polymeric excipients used to stabilize drugs as ASD are polyvinylpyrrolidone (PVP), vinylpyrrolidone/vinyl acetate copolymers (PVP/VA), hydroxypropyl methylcellulose (HPMC); hydroxypropyl methylcellulose acetate succinate (HPMC-AS) and Soluplus® (polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer). Selection of polymeric excipients to stabilize drugs as ASD is complex. One of their limitation is the amount of drug they could stabilize, which typically is below 40%. LLS Health recently developed Apinovex™ polymers suitable for stabilizing up to 80% API as ASD. Apinovex™ polymers open the door to produce a wide variety of new-generation solid oral dosage forms.

Apinovax - Fig 2
Figure 2

A need for novel excipients

Excipients have a key role to play in maximizing the bioavailability of poorly soluble NCEs. However, there is no “one-size-fits-all” excipient solution capable of having a positive impact on solubility in all cases. As the number of poorly soluble NCEs increases, the market need for new excipients will grow.

The current lack of a streamlined approval pathway is creating significant challenges. In a 2020 US Pharmacopeia survey of drug formulators, 84% said that the current roster of excipients present in approved drug products has imposed limitations on drug development². As many as 28% experienced a discontinuation of a drug development as a result of excipient limitations. As a result, the US FDA is considering developing a pilot program for the toxicological and quality evaluation of novel excipients.

LLS Health is dedicated to ensuring there are effective and reliable excipients available to address solubility issues, whatever the profile of the NCE. Lubrizol recently developed a range of new polymer excipients to achieve this goal – Apinovex™ polymers for oral usage and Apisolex™ excipients for injectable products. Contact us to learn more.

1. https://klinegroup.com/reports/solubility_enhancement_pharmaceutical_oral_solid_dosage_forms/
2. https://www.pharmtech.com/view/usp-novel-excipients-survey-stakeholders-views-current-state-excipient-innovation

Harnessing Excipients to Solve the Bioavailability Challenge