Bioavailability & Solubility
Celanese & Nanoform Demonstrate Enhanced Drug Delivery Through the Power of Smaller Implants
Celanese and Nanoform Finland Plc recently provided an update on their collaboration to evaluate the synergies between their respective technologies in the field of nanoparticle-enabled drug delivery…..
WHITEPAPER - Enhancing the Solubility of Active Pharmaceutical Ingredients Using Hot Melt Extrusion & Polyvinyl Alcohol
This white paper describes how hot melt extrusion (HME) and a specially-engineered grade of polyvinyl alcohol can be used to increase the solubility of DCS IIb molecules.
SPECIAL FEATURE - Outsourcing Formulation Development & Manufacturing: Putting Customers First
Contributor Cindy H. Dubin speaks with several leading CDMOs from around the globe on their unique development and manufacturing capabilities and technologies, and presents real-world examples of how they have put these to use to produce innovative compounds, lower development costs, and shorten time to market.
FORMULATION FORUM - PLGA – A Versatile Copolymer for Design & Development of Nanoparticles for Drug Delivery
Jim Huang, PhD, and Shaukat Ali, PhD, focus on the chemistry, properties, applications, and regulatory aspects of PLGA, and the future trends in the industry, especially those requiring the development of long-acting injectables for the treatment of a variety of rare diseases and for life cycle management.
EXCIPIENT TECHNOLOGY - A Juggling Act: Factors at Play in Your Choice of Solubilizing Parenteral Excipients
Joey Glassco, MBA, says the power of novel excipients such as Apisolex polymer could revolutionize the parenteral drug development landscape, effectively solubilizing a wide range of APIs without compromising on safety or stability.
Minoryx Gains FDA Approval to Initiate Phase 3 Trial in Patients With Cerebral Adrenoleukodystrophy
Minoryx Therapeutics recently announced US FDA approval of its Phase 3 clinical trial (CALYX) of lead candidate leriglitazone, to treat adult male X-linked Adrenoleukodystrophy (X-ALD)…
Evonik Launches Next-Generation Peptide for Biopharma Applications
Evonik now offers cQrex® KC, a performance-boosting peptide for cell culture media used in the manufacture of biological drugs. The new peptide enables cell culture process developers….
Oculis Announces Positive Top Line Results From DIAMOND Stage 1 Phase 3 Trial in Diabetic Macular Edema With OCS-01 Eye Drops
Oculis Holding AG recently announced positive top line results from Stage 1 of its Phase 3 DIAMOND trial of OCS-01 eye drops in Diabetic Macular…
Experic Adds Spray Drying Capabilities to Enhance Pharmaceutical Formulation & Development Services
Experic recently announced the addition of spray drying capabilities to support the formulation and development of biopharmaceuticals. The new spray drying services will be….
FORMULATION FORUM - LIPIDSOL®: Liposomes - Chemistry, Properties & Applications of Lipid Nanoparticles
Jim Huang, PhD, and Shaukat Ali, PhD, describe their LNP platform as well as the latest trends in LNPs as more and more novel therapeutic modalities discovered can’t be handled by traditional microemulsions or nanoemulsions.
ION EXCHANGE EXCIPIENTS - Tackling Patient Compliance With Oral Drug Formulations Using Ion Exchange Resins
Amie Gehris explains how IERs solve various pharmaceutical formulation issues, including decreasing the bitter taste of many pharmaceutical drugs, improving patient outcomes by supporting compliance to treatment regimens, and providing new revenue streams for pharmaceutical companies.
EXECUTIVE INTERVIEW - Ascendia Pharmaceuticals: Innovative Solutions to Challenging Problems
Jim Huang, PhD, CEO and Founder of Ascendia Pharmaceuticals, discusses how his company expanded its people, capabilities, and facilities to meet and exceed customer expectations from early to late-state development and how this investment allows Ascendia to continue be an expert in sophisticated formulations, as well as cGMP sterile and non-sterile clinical trial and commercial manufacturing.
SPECIAL FEATURE - Excipients: Their Future Could Lie in Generics
Contributor Cindy H. Dubin highlights the innovative work being done by several leading companies and exemplifies the importance of excipients to the future of drug development.
FORMULATION FORUM - Tackling Challenging Molecules by Spray Drying: Making the Impossible Possible
Jim Huang, PhD, and Shaukat Ali, PhD, focus on spray drying technology with special reference to polymers and solvents selection, processing conditions, and the challenges with downstream manufacturing, stability, and degradation of APIs in oral dosages.
LIPID-BASED EXCIPIENTS - Misconceptions About Lipid-Based Drug Delivery
Rollie Fuller and Ron Permutt provide formulators confidence in using LBDDS as part of formulation development programs, by demonstrating their benefits and key functional mechanisms when used and addressing commonly misrepresented, misinterpreted, and misunderstood LBDDS topics.
BIOAVAILABILITY ENHANCEMENT - Solving Low Solubility Challenges to Optimize Drug Delivery Platforms
David K. Lyon, PhD, discusses how low aqueous solubility NCEs have come to define the innovative pharmaceutical pipelines and how advanced technologies are often required to overcome this issue.
PLATFORM TECHNOLOGY - An Alternative Solution for Peptide Drug Formulation
Michael Neely introduces a unique technology platform and provides examples of how it has solved difficult formulation problems while adding significant commercial value to the resulting drug products.
Catalent & Grünenthal Announce Successful Collaboration to Facilitate Expedited Clinical Development Timelines
Catalent and Grünenthal recently announced their successful formulation design and clinical-phase manufacturing collaboration for an orally dosed small molecule in Grünenthal's pipeline. Positive preclinical results…
SPECIAL FEATURE - Solubility & Bioavailability: Difficult Beasts to Tame
Contributor Cindy H. Dubin highlights the services many of these outsourced providers offer to enhance solubility and bioavailability and get their clients’ projects to market faster and cost effectively – while maintaining critical quality attributes.
DELIVERY TECHNOLOGY - NeuroDirect™ Ketamine: Novel, Non-Systemic Topical Therapy for PTSD & Associated Intractable Depression
Ronald Aung-Din, MD, and Chantelle G. Martin, MBChB, present scientific data demonstrating how with NeuroDirect technology, the benefits of psychedelic compounds may be achieved without concern for their potential systemic effects.
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.