Bioavailability & Solubility
THE SECOND QUADRANT – The Birth of Physical Pharma: 1920-1960
Marshall Crew, PhD, observes progress that enabled spray drying for pharmaceutical applications, as well as other progress that has enabled the solubilization technologies and approaches we use today.
LIPID-BASED DELIVERY SYSTEMS – New Approaches for Macromolecule Oral Delivery, Abuse Deterrence & Bioavailability Enhancement
Julien Meissonnier reviews the development of a broad range of advanced oral drug delivery technologies, including a toolkit of technologies based upon the broad application of lipid-based drug delivery systems for optimum solubility enhancement.
THE SECOND QUADRANT – The Birth of Drug Solubilization: 1840 Through 1920
Marshall Crew, PhD, indicates that while it may seem as if today’s technologies for dealing with solubilization challenges have emerged throughout the past 2 decades, their maturation took over a century, and this process itself is an interesting study in innovation diffusion.
FORMULATION DEVELOPMENT – A QbD Approach to Develop Extended Release Softgels
INTRODUCTION Soft gelatin capsules (softgels) continue to be the oral solid dosage form preferred by consumers.1 Understandably, as they are easy to swallow and digest,…
SPECIAL FEATURE – Bioavailability & Solubility: A Demand for Enhanced Technologies & Materials is Spurring Innovation
Contributor Cindy H. Dubin spoke with several contract research/manufacturing organizations on how they are successfully overcoming solubility/bioavailability challenges, such as matching APIs to formulations and choosing the best excipients.
MARKET BRIEF – Miniaturizing Healthcare – From Microelectronics to Nanobiosensing
Cecilia Van Cauwenberghe, MS, Technical Insights Senior Research Analyst, Frost & Sullivan, reports that the proliferation of lower cost microfluidics-based genomics tools offering improved capabilities and allowing more access to end-users is expected to drive this technology for pharmaceutical and biomedical research throughout the next 5 years.
EXECUTIVE INTERVIEW – Ascendia Pharmaceuticals: Sophisticated Formulations for Poorly Soluble Drugs
Jingjun (Jim) Huang, PhD, CEO, and Founder of Ascendia, discusses his company’s unique vision and strategy to provide pharmaceutical companies with a contract research partner that can provide technologies in order to efficiently determine which approach is most suitable for a given molecule.
DISSOLUTION ENHANCEMENT – Dissolution Enhancement Through Factorally Designed Porous Solid Dispersions
Balwan Singh and Harish Dureja, PhD, use mathematical models developed in their present study to predict cumulative percentage of glimepiride from PSDs. These models can then be utilized to formulate PSDs with desired glimepiride release.
THE SECOND QUADRANT – Outsourcing Solubilization: Making Bioavailability More Broadly Available
Marshall Crew, PhD, explores how the contract services and manufacturing market has responded to the opportunity presented by the rising numbers of BCS Type II/IV clinical compounds and solubilized commercial products.
EXCIPIENT UPDATE – Soluplus®: An Understanding of Supersaturation From Amorphous Solid Dispersions
Oksana Tsinman, Konstantin Tsinman, PhD, and Shaukat Ali, PhD, describe the application of a hydrophilic polymeric solubilizer in solid dispersions of a model drug carbamazepine. The scope of this study is limited to understanding of hydrophilic polymers and their behaviors on amorphous dispersions.
EXCLUSIVE ONLINE CONTENT

Celltrion & Rani Therapeutics Partner on Development of Oral Monoclonal Antibody Treatment
Rani Therapeutics Holdings, Inc. recently announced it has partnered with Celltrion for the development of RT-111, an orally administered ustekinumab biosimilar….

Aptose’s New G3 Formulation of Luxeptinib Boosts Bioavailability
Aptose Biosciences Inc. recently announced the G3 formulation of luxeptinib, designed for rapid and efficient absorption, demonstrates approximately an 18-fold improvement in oral bioavailability….

Zerion Pharma & Hovione Extend Partnership to Cover Use of Dispersome Technology Platform in Nutraceuticals
Hovione and Zerion Pharma A/S (Zerion) recently announced an extension of their collaboration on Zerion’s Dispersome technology into the nutraceutical/dietary….

Lonza Strengthens Micronization Portfolio With the Introduction of X-Ray Powder Diffraction Capability
Lonza has expanded the range of particle engineering services offered by its Monteggio (CH) site through the introduction of X-ray powder diffraction (XRPD). This rapid analytical technique provides additional….

Catalent to Acquire Metrics Contract Services for $475 Million
Catalent, Inc. recently announced it has reached an agreement to acquire Metrics Contract Services (Metrics), a full-service specialty Contract Development and Manufacturing Organization (CDMO) with a facility in….
MARKET NEWS & TRENDS
WEBINARS

WEBINAR – Hot-Melt Granulation Technology for Lipid-Based Pharmaceuticals
Join our experts Dr. Mandar Kodgule, Dr. Rahul Aware, and Dr. Agnivesh Shrivastava live as they take you through compelling case studies, current trends and developments, and insights on mastering the design of hot-melt granulation process.

Where Do We Stand on Poorly Soluble Drugs and Peptides in Oral Delivery?
The Rule of 5 suggests that, for oral bioavailability, a better chance for oral absorption is obtained when the molecules are within the parameters of the Rule of 5’. However, the pharmaceutical industry is achieving oral efficacy with drugs that exceed….

Quotient Sciences: Upcoming Solubility Enhancement & Pediatric Development Webinars
Access our webinars on solubility strategies & pediatric drug development….
WHITE PAPERS

WHITEPAPER – Case Study-Improving Bioavailability Using PBPK Modeling & Parallel Formulation Screening
A team of bioavailability experts at Catalent used the in-house bioavailability enhancement platform, OptiForm® Solution Suite, to optimize and develop….

WHITEPAPER – Infographic-Zydis® Orally Disintegrating Tablet (ODT) vs. Standard Tablets (ST)
Catalent’s proprietary Zydis® ODT platform is backed by a large number of clinical studies. This infographic provides a high level summary of studies comparing Zydis ODT against traditional oral tablets…..

WHITE PAPER: Selecting In-Vitro Dissolution Methodologies for Amorphous Solid Dispersions
Read about how achieving good in vivo performance is a key attribute for ensuring safety and efficacy of oral solid dosage (OSD) forms intended for systemic delivery.

WHITE PAPER – Poloxamer: A Simple & Powerful Solution for Accelerating Dissolution
This white paper will introduce the concept of dissolution and discuss how poloxamers are a simple yet powerful formulation approach that can enhance dissolution rate, while minimizing resource requirements.

Outsourcing Drug Development & Production: Technology-Driven Drug Delivery Systems for Small Molecules at Losan Pharma
Due to the increasing demand for drug delivery systems that are able to improve the properties of low soluble, poor permeable, or highly dosed new and existing drug substances, technology-driven CDMOs can offer a wide range of technology platforms to overcome such challenges….
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.