Bioavailability & Solubility

FORMULATION FORUM – Considerations in Development & Manufacturing of Complex Injectables for Early Phase Studies

Jim Huang, PhD, explains how a niche CDMO, which has specialized  technologies in complex  injectable development and adopts GMP practice with a “laboratory setting,” will have greater flexibility regarding changes, timing, and cost for successful manufacture of complex injectables in early phase development of therapeutic drugs.

FORMULATION FORUM – Age-Appropriate Pediatric Formulation Development

Jim Huang, PhD, reviews how a pediatric formulation should consider the following factors: difference in physiological and pharmacokinetic of patient populations, dosage form selection, route of administration, dose accuracy, dose flexibility, drug and excipient tolerability (safety and toxicity), patient compliance (palatability/swallowability), stability, and drug accessibility.

EXECUTIVE INTERVIEW – Enteris BioPharma: Pioneers in Oral Formulation Development

Dr. Rajiv Khosla, CEO of Enteris BioPharma, discusses how his company’s innovative oral formulation technology is helping the pharmaceutical industry overcome the hurdle of low bioavailability to reshape treatment categories and expand market opportunities with minimal financial and regulatory risks.

OSD FORMULATIONS – Dissolving Bioavailability & Solubility Challenges in Formulation & Development

Vinod Patil, PhD, says many of the innovative and novel formulations introduced throughout the past decade have had to cope with poorly water-soluble APIs. Considering the pace of development, overcoming solubility issues will remain problematic, and this is especially true for important new classes of pharmaceuticals entering the market.

FORMULATION FORUM – Formulation Development Strategy for Early Phase Human Studies

Jim Huang, PhD, says successful translation of discovery compounds into first-in-human and first-in-patient is one of the key challenges facing the pharmaceutical industry, and to achieve this, a rational formulation development strategy will be critical to avoid costly development failures, while speeding up the development timeline in a cost-effective manner.

FORMULATION FORUM – Application of Captisol® Technology to Enable the Formulation of Remdesivir in Treating COVID-19

James Pipkin, PhD, Vince Antle, PhD, and Rebecca Garcia-Fandiño, PhD, explain why more Captisol® than ever is required to meet Gilead’s bold goals of making remdesivir available to COVID-19 patients in the US and to hundreds of countries around the world.

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Bioavailability and Solubility Challenges

Given that a large number of drugs fail to reach the market due to poor solubility and bioavailability, the industry is seeking various methods to mitigate this challenge while many choose to re-formulate existing product candidates. Either way, the demand for novel bioavailability and solubility enhancement methods has grown significantly. To cater to this increasing demand, many contract manufacturers and technology developers have emerged.

What is Solubility?

Solubility is the ability for a drug to be dissolved in an aqueous medium. Drug solubility is defined as the maximum concentration of a substance that can be completely dissolved in a given solvent at a certain temperature and pressure level.

Solubility of drugs is measured by the amount of solvent needed to dissolve one gram of the drug at a specific temperature. For example, a drug that is very soluble needs less than one part solvent to dissolve one gram of the drug. How soluble a drug is varies widely—a drug that is considered soluble needs 10-30 parts, one that is slightly soluble needs 100-1,000 parts and one that is practically insoluble or insoluble needs more than 10,000 parts. How soluble a drug is depends on the solvent, as well as temperature and pressure.

Since 1975, approximately 60 marketed drugs have leveraged solubilization technologies to enhance oral bioavailability. In the preceding 36 years, from the time the FDA required submission of an NDA in 1938, solubilization technology was virtually unused on a regular basis. Apparently, the disease areas focus, drug discovery methodologies, and the lack of mature solubilization platforms restricted the use prior to the 1970s.

In comparison, the past nearly 4 decades have shown robust growth in the reliance on solubilization platforms, accounting on average for around 9% of all NMEs approved from 1975 through 2022, and more than 10% in the past decade. Some years stand out to validate the need and use of solubilization platforms. For example, in 2005, 20% of NMEs approved used technologies including solid dispersion, lipid, and nanocrystal platforms. The data for the most recent 4-year period (2010-2013) seems to represent a slight decline in growth, but it is still early in the decade, and the data set is relatively small. Based on the trends throughout the past 4 decades and the changing chemical space in drug development, we expect the decade will show additional and significant current growth in use of solubilization technologies once we have visibility into the full 10-year period.

Bioavailability & Solubility Impediments

The biggest impediment in addressing bioavailability issues likely lies with a lack of deep familiarity with enabling technologies. Improving drug bioavailability begins with a thorough evaluation of the API’s physical and chemical properties in relation to solubilization in the dose, but more importantly its dissolution in vivo at the site of absorption.

These technologies, such as nanoparticles, cocrystals, computer-aided prodrug design, and electrospinning, represent innovations aimed at enhancing the solubility of a candidate molecule, particularly in the gastrointestinal tract. Technologies such as electrospinning, deep eutectic solvents, and ionic liquids are upcoming formulation approaches to enhance drug solubility, and as the science matures, and the relative strengths and weaknesses are better understood, we expect to see further application of these innovative approaches. They have shown to be successful for some compounds, and have a place alongside other bioavailability enhancement technologies, where each strategy has its benefits and corresponding liabilities. For them to be successful and widely adopted however, they will also have to provide a compelling benefit compared with other well-understood, and commercially precedented technologies, such as amorphous solid dispersions and lipid-based formulations.

Extreme compounds require either significant amounts of stabilizers to maintain the amorphous state or they are not amenable to common manufacturing technologies with reasonable cost of goods due to their low solubility in organic solvents. These include amorphous solid dispersions using polymethacrylate, cellulose, or povidone-based polymeric carriers, she says. In addition, thermostability of new molecular entities becomes an issue as most new molecules have melting points well above 400°F. Alternative production methods for amorphous solid dispersions can address these issues.