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.
Lonza Expands Solid Form Screening Services for Accelerated Development of Small Molecule Drugs
Lonza recently announced an expansion of its solid form selection services based at its Bend, OR, site. The increased service capabilities and dedicated team complement…
Artelo Biosciences Announces Positive Pre-Clinical Data Associated With Proprietary CBD Cocrystal
Artelo Biosciences, Inc. recently announced Saoirse O’Sullivan, PhD, Professor of Pharmacology and Scientific Advisor to Artelo, along with Ryan Maguire and Dr. Timothy England of…
Melt Pharmaceuticals Completes Phase 1 Study for Sublingual, Non-Opioid Pain & Sedation Drug Candidate
Melt Pharmaceuticals, Inc. recently announced results from its MELT Phase 1 study, a comparative bioavailability study with the objective of characterizing the pharmacokinetic parameters of…
Molecular Templates Announces FDA Acceptance of IND Application for a PD-L1-Targeted Engineered Toxin Body Enabled With Proprietary Antigen Seeding Technology
Molecular Templates, Inc. recently announced the US FDA has accepted its Investigational New Drug (IND) application for MT-6402, a next-generation ETB targeting PD-L1 that is enabled with….
FORMULATION FORUM - Oral Controlled Delivery of Poorly Water-Soluble Drugs
Jim Huang, PhD, discusses how understanding key biopharmaceutical properties in relationship to drug absorption and elimination plays a critical role in successful design of CR dosage forms from discovery to first-in-human with a shorter timeline and lower development costs.
MULTI-PARTICULATE MANUFACTURING - How Does Experiment Design Affect Multi-Particulates Manufacturing?
Namrata Vora, MS, Danica Cartwright, Karthikeyan Selvaraj, MPharm, and Ryan Larmon, MS, discuss how the careful application of design of experiment studies is an invaluable tool in proving the design space of complex formulations and manufacturing processes.
WuXi STA’s Integrated CMC Platform Supports InnoCare Orelabrutinib Approved by NMPA
STA Pharmaceutical, a WuXi AppTec Company (WuXi STA), recently announced their partner Innocare has received approval by the National Medical Products Administration of China (NMPA)…
Gattefossé Continues International Development & Builds Production Site in Texas
Gattefossé is investing 30 million euros in its industrial operations and announced the construction of a brand new manufacturing plant in Lufkin, TX. This asset will produce lipid-based….
Catalent to Invest $10 Million to Expand High Potency Containment Capabilities for Micronization
Catalent recently announced it is investing $10 million in isolator capabilities at its sites in Malvern, PA, and Dartford, UK, to expand its micronization capabilities…
2021 COMPANY PROFILES & CAPABILITIES
For each participating company, this section presents a detailed summary highlighting their core technologies, capabilities, technologies, and services.
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.
Novo Nordisk to Acquire Emisphere Technologies for $1.35 Billion
Emisphere Technologies, Inc. recently announced it has entered into a definitive agreement with Novo Nordisk, whereby Novo Nordisk will acquire Emisphere, on a cash-free, debt-free basis, for….
Cerevel Therapeutics Announces First Patients Dosed in all Phase 3 Trials for the Treatment of Parkinson’s Disease
Cerevel Therapeutics recently announced that the first participants have been dosed in all three of the clinical trials in their Phase 3 program evaluating tavapadon…
APPLY NOW ! - A Novel Approach for Incentivizing Drug Delivery Innovation
One of the most critical early steps in the development of novel drug delivery systems is to demonstrate convincing proof-of-concept. The dilemma is that while pharma companies can be interested in….
Catalent Launches Delayed/Enteric-Release Softgel for Pharmaceutical & Nutraceutical Applications
Catalent recently announced the launch of OptiGel DR technology for the formulation and manufacture of delayed/enteric-release softgels. The technology allows softgel capsules to be formed…
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.
Lonza Expands Particle Engineering Assets to Advance Complex Molecules
Lonza reecently announced additional investments in its global particle engineering network for expanded capacity and specialized capabilities. Jet milling and spray dry processing for development…
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.