SPECIAL FEATURE - Bioavailability & Solubility: The Promise of Novel Ingredients

There is somewhat of a consensus in life sciences that there have been significant advancements in improving bioavailability. Solubility, however, continues to elude formulators. Excipients are often lauded as a solution to tackling these challenges, but still do fall short. In a 2020 US Pharmacopeia (USP) survey of drug formulators, 84% said that the current roster of excipients present in approved drug products has imposed limitations on drug development, and as many as 28% experienced a discontinuation of drug development as a result of excipient limitations.

Novel excipients may be the answer. In September 2023, the Office of New Drugs and the Center for Drug Evaluation and Research (CDER) launched a voluntary Pilot Program for the Review of Innovation and Modernization of Excipients (PRIME). This program is intended to allow biopharmaceutical manufacturers to obtain FDA review of novel excipients. The development of novel excipients is gaining momentum as pharmaceutical companies seek improved performance and versatility in drug formulations. Novel substances support nanoparticle drug delivery for oncological medications to provide better stability and adoption of medicines.

“The invention of novel excipients bearing the amphiphilic and solubilization characteristics in the recent past has helped excipient and drug manufacturers alike to overcome the regulatory barriers for expediting the new drug candidates to market,” says Shaukat Ali, PhD, Senior Director of Scientific Affairs and Technical Marketing at Ascendia Pharmaceutical Solutions.

According to a May 2024 USP white paper: “While the FDA PRIME program represents a step in a new regulatory direction for excipients, drug developers are currently reluctant to use novel excipients as there is no independent FDA regulatory pathway outside of its drug application and approval process to review and evaluate the safety and toxicity of an excipient for introduction into a new drug, abbreviated new drug, or non-prescription drug. FDA may determine that novel excipients are not fully supported by the submitted safety data such as for the proposed level of exposure, route of administration, duration of exposure, and patient population. An entire drug application using a novel excipient could be rejected due to uncertainty surrounding acceptance of the excipient by FDA. Considering the barriers to using novel excipients that exist in the normal application process for drug products, USP supports the development of a transparent, independent approval pathway for novel excipients.”

This exclusive Drug Development & Delivery annual report explores the use of novel excipients as well as other methods and technologies for tackling bioavailability and solubility once and for all.

Abzena: Formulation Stability Study Increased Concentration

Formulating complex biologics, such as monoclonal antibodies (mAbs), fusion proteins, and bispecifics, require robust development strategies that are flexible and phase-appropriate in order to opti­mize them for solubility, delivery, safety, and sustained stability. Utilizing preformu­lation assessments to establish and char­acterize the physiochemical characteristics of the biologic can dictate which ap­proaches are taken during formulation de­velopment and allow developers to rapidly identify and solve any complex problems earlier on in the process, avoiding costly downstream issues.

In a recent case study, a customer of Abzena’s had acquired a novel mAb that had been formulated by another CDMO. However, there was an issue with the se­lected formulation due to the fundamental properties of the mAb not being assessed during preformulation. During refrigerated storage, the formulation exhibited signs of phase separation and gelation that were resolved by warming to room tempera­ture, without any apparent impact on quality, explains Dr. Gary Watts, Head of Formulation, Abzena.

“This was not ideal from a regulatory perspective or for patient administration,” he says. “A study was designed to evaluate the fundamental factors crucial to formu­lation stability, such as the optimum pH, and stability at high or low ionic strength.”

Dr. Watts says an optimal formulation was identified that showed the desired physical and chemical stability, and was clear, colorless and free of visible particles after >6 months storage at 2-8°C. Fur­thermore, solubility was sufficiently im­proved to allow the concentration to be increased to 100mg/mL from 50mg/mL, in line with the customer’s requirements.

Ardena: Exploring the Dual Role of 2-(Hydroxypropyl)-Beta-Cyclodextrin in Parenterals

Cyclodextrins (CDs) have been widely used in the pharmaceutical industry to im­prove aqueous solubility, bioavailability, and physicochemical stability of active pharmaceutical ingredients. Two CD derivatives are 2-(hydroxypropyl)-beta-cy­clodextrin (HP-β-CD) and Sulfobutylether-Beta-Cyclodextrin (SBE-β-CD) utilized as excipients in marketed drug products. Over the past decade, CDs, especially 2-(hydroxypropyl)-beta cyclodextrin (HP-β-CD), have emerged as increasingly significant therapeutic agents mainly due to their ability to sequester and mobilize cellular lipids. Trappsol®, a proprietary in­travenous formulation of HP-β-CD, is des­ignated an orphan drug in both the US and Europe. It is currently in a Phase III clinical trial for treating Niemann-Pick Dis­ease Type C1 and a Phase 2b study for Alzheimer’s disease. Intravenous HP-β-CD is also being studied for the treatment of diabetic kidney disease. The FDA has ap­proved a modified gamma cyclodextrin (sugammadex®) for the reversal of neuro­muscular blockade induced rocuronium and vecuronium in general anesthesia.

“These emerging applications of cy­clodextrins raise an important question,” says Oluwatomide Adeoye, Formulation Development Scientist, at Ardena. “If these ‘excipients’ exhibit therapeutic activ­ity, is their continued classification as phar­maceutical excipient justifiable, given that they are traditionally expected to be inert? Our experience as a CDMO developing New Chemical Entities (NCEs) for various pharmaceutical and biopharmaceutical companies indicates a growing industry concern regarding the use of cyclodextrins as solubilizers in new parenteral drug products.”

Timothy Pas, Director, Formulation Development & Production at Ardena, adds that these concerns primarily stem from the risk of ototoxicity associated with high concentrations of HP-β-CD observed in clinical studies for Niemann-Pick Dis­ease Type C1. “While the causative mech­anism of HP-β-CD induced ototoxicity has not been perfectly elucidated, the consen­sus is that it is related to altered lipid traf­ficking in the cochlear structures,” says Mr. Adeoye.

The long history of use in parenteral formulations suggests that the risk of HP-β-CD induced ototoxicity is minimal at typ­ical concentrations and parenteral use cases, Mr. Pas says. However, formulation scientists must carefully assess the clinical requirements of a drug before selecting HP-β-CD as solubilizer. “For instance, it is reasonable to avoid its use in drug formu­lations intended for prolonged administra­tion, where a regular maintenance dose is required, or those that may lead to high cumulative concentrations of HP-β-CD,” says Mr. Adeoye. “Alternatively, SBE-β-CD should be the preferred choice for drug formulations when it can form non-inclu­sion complexes with the same drug, as its reduced interaction with cell membranes minimizes the risk of cholesterol seques­tration.”

Ascendia Pharmaceutical Solutions: Solubilization Technologies Tackle Challenging Molecules

As more molecules coming out of dis­covery possess poor solubility, industry is relying on more innovative approaches to enhance the permeability and bioavailabil­ity of those molecules. Excipients are crucial to help design better and smarter formula­tions to achieve the desired solubility to overcome the bioavailability challenges. Compounded with stability challenges, the industry is looking for the ingredients, sol­ubilizers, and polymers to maximize the drug-polymer intermolecular interactions in the formulation matrices.

“Ascendia’s enabling solubilization technologies, especially EmulSol®, address the challenging molecules for enhancing the solubility and oral bioavailability of drugs formulated in microemulsions and nanoemulsions comprised of lipid-based solubilizers and surfactants, and oils as well,” says Shaukat Ali, PhD, Senior Direc­tor of Scientific Affairs and Technical Mar­keting at Ascendia Pharmaceutical Solutions.

Lipophilic drug molecules (BCS II and IV) require the most advanced technologies to improve their solubility and bring them to the clinic. For instance, the molecules having higher melting and log P due to their inherent high lattice energy and lipophilicity with log P (4-8), require solid amorphous dispersion and/or microemul­sion technologies.

“Ascendia’s enabling solubilization technologies AmorSol® for oral solids and EmulSol and NanoSol® for oral liquids can help engineer better and smarter formula­tions for tablets and liquid capsules using generally regarded safe (GRAS) excipients approved by FDA,” he says. “These tech­nologies are aimed at improving solubility of lipophilic and hydrophobic molecules bearing higher melting and logP. Designed with a carefully selected class of excipients and lipids/surfactants/solubilizer, and cou­pled with our expertise in the enabling technologies, we can expedite the formu­lation and development of molecules and bring them to clinic faster.”

Excipient/surfactant composition and particle size also have a great impact on formulation composition and the desired outcomes. For instance, cyclosporine A available as Sandimmune® (comprised of corn oil, linoleoyl macrogolglycerides) is prone to much greater food effect than Ne­oral® formulation (comprised of corn oil, polyoxyl 40 hydrogenated castor oil) with much smaller particle size. Dr. Ali says that Ascendia’s Emulsol technology can be used for drugs like cyclosporine and peptides to achieve faster absorption and permeation, thus higher oral bioavailability.

BioDuro: Exploring Cutting-Edge Tech for More Reliable Formulations

The development of enhanced drug formulations requires an in-depth, data-driven understanding of Active Phar­maceutical Ingredients’ (APIs) physico­chemical properties and their behavior in vivo. At BioDuro, formulation challenges such as poor solubility, stability, and bioavailability are addressed by systemat­ically analyzing key characteristics of the API and the target patient population, ex­plains Dr. Yuan Yang, Senior Scientist III, Formulation Development, BioDuro. A sci­entific approach that balances the inherent risk of formulation complexity with the practical needs of the drug product is crit­ical for success.

For APIs with poor solubility, several formulation strategies are employed, each with specific advantages and challenges depending on the solubility profile and therapeutic window. Nanoparticles, nanocrystals, lipid-based formulations, cy­clodextrin incorporation, and Amorphous Solid Dispersions (ASD) have proven to be essential tools for solubility enhancement. “BioDuro specializes in employing these strategies, selecting the most suitable for­mulation based on factors such as API sta­bility, solubility, partition coefficient, and the required dose strength,” he says.

By transforming the API into an amor­phous state and dispersing it in a polymer matrix, ASDs improve dissolution rates while maintaining stability. This strategy is particularly beneficial for drugs with poor solubility, as it enhances dissolution rates and improves the drug’s absorption, lead­ing to more consistent and predictable bioavailability. By leveraging precise mod­eling and predictive tools, formulation sci­entists can mitigate risks while maximizing therapeutic performance.

The core of formulation enhancement often lies in the ability to manipulate the physical form of the API. Spray drying and hot melt extrusion (HME) are widely used, proven techniques that provide effective solutions for API solubility challenges. Conventional spray drying has been the standard for producing amorphous dis­persions and enhancing the bioavailability of poorly soluble drugs. Dr. Yang says: “With a success rate of over 90% in scale-up from lab to commercial manufacturing, spray drying is a reliable method for for­mulating high-quality solid dispersions.” HME, similarly, is recognized for its capac­ity to produce stable, uniform formulations and is integral to the development of im­mediate-release and controlled-release dosage forms, with more than 50% of commercial products utilizing this tech­nique. However, the increasing complexity of drug candidates has led to the explo­ration of newer technologies to address evolving challenges. “Electrospray, a cut­ting-edge technique, has gained signifi­cant attention in producing ASDs,” he says. “Electrospray offers several advan­tages, such as highly repeatable and re­producible processes and the ability to produce fine, uniform particles with a nar­row size distribution. Studies show that electrospray-generated formulations ex­hibit improved stability and dissolution rates compared to conventional methods, making them particularly beneficial for high-potency, low-dose drugs.”

In addition to electrospray, other emerging technologies are being explored to enhance solubility and bioavailability. Techniques, such as formulating with sol­ubility-enhancing excipient, amorphous dispersion granulation and coating fluid bed, co-precipitation, and electrospinning are being evaluated for their potential to improve the solubility of challenging APIs. These approaches, alongside spray dry­ing, HME, and electrospray demonstrate the pharmaceutical industry’s ongoing commitment to innovation. “BioDuro con­tinues to explore and implement these cut­ting-edge techniques to develop more efficient and reliable drug formulations,” says Dr. Yang.

Bend Bioscience: Spray Drying Is Best in Early-Phase Design

As a CDMO specializing in bioavail­ability, particle engineering, and solubility enhancement via spray drying, Bend Bio­science has tackled complex formulations for decades. “We find that the spray drying process is best for early phase design work in terms of material sparing, speed, and efficiency,” says David Vodak, PhD, Chief Scientific Officer, Bend Bioscience, Ore­gon. “We are, however, still observing that amorphous solid dispersion (ASD) technol­ogy is the most applicable to a broad range of solubilization problem state­ments. Certain combinations of ASD tech­nology with other functional architectures, like controlled release, seem to be trend­ing with respect to dialing in specific re­lease and extent profiles for challenging molecules and target product profiles.”

Understanding the relative release rates of functional excipients and active molecule are important features to achieve optimal performance, and designing a particle architecture through spray drying can be enabling, he says. “All molecules are unique and have specific challenges to deliver a successful commercial dosage form. Our science-based approach to de­sign – incorporating a deep understanding of material science, rigorous experimentation and analysis, and emphasis on process optimization and scalability – translates to efficient and effective pro­gressable solutions in drug development.”

Lipophilic (LogP>2) compounds re­main prevalent in Bend’s portfolio. Many compounds in the kinase inhibitor class tend to be more polar with high melting points (i.e., ‘brick dust’). The company is seeing high logP compounds in trends to­ward PROTACs and other TPD programs. Although these compounds are lipophilic, Dr. Vodak says they are often ionic and higher molecular weight moving them into the BCS IV regime.

“At Bend Bioscience, we are still work­ing to discover a ‘magic bullet’ in terms of the technology to delivery these types of molecules,” he says. “In the meantime, we are able to efficiently apply our experience and acumen to design formulations that solve the challenge of delivery in a com­mercializable manner, whether a spray dried amorphous dispersion or lipid-based formulation is optimal.”

Artificial Intelligence (AI) is also help­ing Bend formulate those challenging mol­ecules. AI is helping Bend organize data sets and look for patterns in compound properties and successful formulations. “We have evaluated ‘black box’ modeling and deep learning algorithm techniques, but have not yet found a satisfactory data set with appropriate truth metrics to ensure anything predictable from the data,” says Dr. Vodak. “However, it is early days for AI, and we fully expect to stay on the cutting edge in this area and use the data that we have from a diverse set of pipelines to con­tinue to challenge what AI can do to im­prove our efficiency in formulation and process design.”

Catalent: PBPK Modeling Identifies Root Causes

Developability assessment with phys­iologically-based pharmacokinetic (PBPK) modeling has transformed Catalent’s early development service. “The use of PBPK modelling replaces simplistic tools like BCS/DCS classification, that oversim­plify the challenges in bringing a molecule to the clinic for simple small molecules as well as those in the Beyond Rule-of-5 space,” says Stephen Tindal, Director, Sci­entific Advisory, Oral Small Molecules, Catalent.

As an example, a small biotech faced bioavailability and dose escalation failures with a Beyond Rule-of-5 molecule, leading them to consider shelving the project. In­stead of trial-and-error formulation, Catal­ent applied its Developability Assessment, integrating PBPK modeling and early de­velopment screening to identify the root cause.

“Oral delivery proved unviable, so we recommended a sublingual formulation that significantly improved systemic expo­sure,” he explains. “We also optimized their preclinical study design by identifying species-specific absorption issues and de­veloped a modified-release strategy to manage dose escalation. This structured approach saved the molecule from termi­nation, accelerating its path back to the clinic and reducing development costs.”

He adds that Catalent’s expertise in technology selection, route evaluation, and formulation design empowers biotech teams to make data-driven decisions, sal­vaging high-risk molecules and optimizing early development.

Croda Pharma: Enhancing Drug Formulation with Machine Learning

Drug formulation that exhibits en­hanced solubility, stability, and bioavail­ability is a challenging craftsmanship. In recent years, many have tried resorting to Artificial Intelligence (AI) and Machine Learning (ML) to streamline this process. “Unfortunately, developing digital solu­tions for drug formulation is difficult by it­self, with challenges such as low amounts of (relevant) data points, the need to model complex systems, and frequently changing objectives that require practition­ers to shoot at moving targets,” says Claas Strecker, Lead Technical Data Scientist, Croda Pharma.

Croda aims to empower the drug for­mulation process with smart digital ap­proaches that can support drug developers in navigating complex systems, focusing on three key pillars:

1) Automatization: Automating tedious lab experiments is of core importance. “It is not only improving the productivity of our scientists and allowing us to respond to our customers faster, but also opening access to vaster amounts of data that can fuel more complex predictive models downstream,” explains Mr. Strecker.

2) Predictive Modelling: Croda has built a model that predicts if combinations of excipients will form stable self-(micro)emulsifying drug delivery systems (S(M)EEDS). “These systems have emerged as a powerful tool in pharmaceutical for­mulation and enhance the solubility and bioavailability of poorly water-soluble drugs by spontaneously forming fine oil-in-water emulsions in the gastrointestinal tract under mild agitation, thereby improv­ing drug dissolution and absorption,” says Veronica Blanco, Lead Applications Scien­tist, Croda Pharma.

Despite their potential, optimizing S(M)EDDS formulations is a complex, iter­ative, and time-intensive process. Key vari­ables, such as the selection and ratio of excipients, drug characteristics, and system stability, require extensive experimentation. Ms. Blanco says: “Thus, we challenged ourselves to accelerate this experimenta­tion by using ML, but quickly faced a major challenge: How could we inform our model to learn the underlying physics of such complex systems?”

Excipients such as polysorbate 80 are not one well-defined compound, but con­stitute structurally diverse mixtures. More­over, Croda’s series of super-refined (SR) excipients only deviate from their regular counterparts at the trace component level, but exhibit significantly improved formula­tions properties, says Mr. Claas. “During our work, we found that NMR (nuclear magnetic resonance) spectra can serve as a good feature source to inform our pre­dictive model.”

3) Optimization: Drug formulation pre­dictive modelling frequently falls short ei­ther simply due to lack of relevant data to tackle the problem at hand or because, for complex systems, no informative descrip­tors are found that could inform a predic­tive model sufficiently enough, explains Mr. Claas. In such scenarios, optimization techniques such as Bayesian optimization (a method for finding the best solution to a problem without in-depth understanding of how it works internally) can be used. Different options are evaluated, results are presented, and well-calibrated probabili­ties of expected improvements are used to make smarter choices. “This can help us to iterate fast and achieve our objectives without wasting vast amounts of resources and time,” says Mr. Claas.

Ms. Blanco adds: “As formulations continue to become more complex, au­tomation improves efficiency and data col­lection, while predictive models help design stable drug delivery systems.”

Gattefossé: Lipid Excipients Enhance Drug Absorption

Lipophilic drug compounds are a major component of the pre-clinical pipeline, and formulators are increasingly seeking approaches to enhance absorp­tion and drug permeability. A PharmaCir­cle analysis performed by Gattefossé showed that approximately 70% of NCEs in the preclinical pipeline today are poorly soluble. However, only 55% of FDA-ap­proved NCEs from 2019-2023 are con­sidered poorly soluble compounds. “This 15% gap shows that traditional solubility enhancement techniques are not sufficient to bring all these challenging new mole­cules to market,” says Nick DiFranco, Sen­ior Marketing Manager – Pharmaceuticals, Gattefossé USA. “There is significant un­tapped potential for lipid-based drug de­livery systems, which not only address poor solubility but also enhance permeability and absorption of challenging com­pounds.”

An area of growing interest is utilizing combinations of excipients to access new “synergies” and overcome common for­mulation challenges. “For example, an amorphous solid dispersion (ASD) may solubilize a high dose of API, but these for­mulations often face in vivo performance and stability challenges,” says Mr. DiFranco. “In contrast, lipid-based formu­lations (LBFs) improve drug permeation and absorption through mechanisms such as tight junction modulation and lymphatic uptake. LBFs may also reduce dosing vari­ability associated with the food effect.”

Lipid excipients significantly improve drug delivery by enhancing the perme­ation and absorption of drugs. Their simi­larity to dietary lipids allows them to be processed through the digestive system, in­creasing the solubility and supersaturation of lipophilic drugs, especially for BCS Class II and IV compounds. The lipid di­gestion process, involving gastric lipase, bile salts, and pancreatic enzymes, also creates colloidal carriers and mixed mi­celles that prevent drug precipitation. These colloidal structures maintain drug solubility and can penetrate the mucus layer, releasing the drug and creating a supersaturated environment for passive diffusion.

“By combining LBFs and polymeric formulations, scientists can achieve the high drug loading of an ASD with the benefits of lipids, such as improved in vivo permeability and prevention of recrystal­lization, resulting in boosted bioavailabil­ity,” he says. “Utilizing IID-listed polymers and lipids in these ternary systems ensures innovation without additional regulatory risk, and these systems can often be man­ufactured with existing equipment, ensur­ing a clear path to scale-up and commercialization.”

Excipients with high medium-chain fatty acid ester content, such as Gatte­fossé’s Labrasol® ALF, Capryol® 90, and Labrafac™ MC60, are especially good at modulating tight junctions, enhancing paracellular permeation for Class III and IV compounds and helping drugs bypass P-glycoprotein (PgP) inhibition, says Mr. DiFranco.

As an example, alendronate sodium, a BCS Class III drug, has very low bioavail­ability due to its polar, hydrophilic nature and susceptibility to pH and enzymatic degradation. In an in vivo rat study using a closed-loop small intestinal administra­tion, vehicles with a high medium-chain fatty acid ester content, namely Capryol 90, Labrasol ALF, and Capryol PGMC, were the most effective permeation en­hancers (Ukai et al. 2020). Capryol 90 generated 9.8-fold increase in AUC, which was attributed to an increase in both tran­scellular and paracellular uptake facili­tated by intestinal membrane fluidization and safe, reversible modulation of tight junction proteins.

Additionally, a human clinical study on enlicitide chloride, a macrocyclic pep­tide developed by Merck & Co., demon­strated the ability of Labrasol ALF to improve solubility and modulate tight junc­tions, generating a 2- to 3-fold increase in plasma concentration (Johns et al. 2023).

“These studies show how lipid excipi­ents with high medium-chain fatty acid ester content, such as Capryol 90 and Labrasol ALF, can greatly enhance drug absorption in vivo, especially for BCS Class III and IV compounds,” says Mr. DiFranco.

Hovione: Early-Stage ASDs by Spray Drying Result in Viable Oral Dosage Form

Amorphous solids dispersions (ASDs) remain the most used enabling platform for solubility enhancement. There are a variety of molecule structures in the pipeline that require tailored bioenhance­ment, including the common greaseballs as well as chameleonic and brick-dust APIs. “ASDs by spray drying are a versatile platform to formulate across the board,” says Inês Ramos, R&D Manager (Formula­tion Development, Oral Drug Product) at Hovione.

For BCS II and IV compounds, bioavailability enhancement is driven by absorption enhancement needs, target product profile, and drug molecular fea­tures. “To maintain a strong focus on man­ufacturability since early-stage, the delivery of a viable ASD oral dosage form follows an integrated approach involving ASD for­mulation screening, particle engineering, drug product formulation and process de­velopment using data-driven tools to ex­pedite development,” says Dr. Ramos.

Hovione’s approach relies on a streamlined workflow supported by com­putational tools that starts with a “technol­ogy fitting” to assess the suitability of using ASDs by spray drying. ASD development includes a comprehensive high-through­put formulation screening (ASD-HIPROS™ proprietary platform that includes com­mon polymers and alternative excipients such as the Dispersome® technology), de­signed to fast-track first-in-human (FiH) formulations that are scalable and provide adequate performance. The ASD-HIPROS platform requires a few grams of API and less than eight weeks to narrow down thousands of possible formulations to the most viable candidates. The drug product intermediate is then formulated into a tablet, capsule, or pellets/granules for oral delivery. “This methodology was designed to expedite the delivery of an enabling for­mulation and an industrially viable manu­facturing process,” says Dr. Ramos. “The goal is to maintain performance and en­sure patience compliance.”

LATITUDE Pharmaceuticals: Formulating the Most Insoluble Compounds

LATITUDE Pharmaceuticals takes a pragmatic approach to identify the most effective solubilization technologies for each client’s individual desired drug pro­file. For more potent compounds with an estimated human dose under 200mg, the company utilizes amorphous solid disper­sions and self-emulsifying formulations, which are free from synthetic lipids, deter­gents, and organic solvents – ensuring im­proved safety profiles and compatibility with capsule shells, says Andrew X. Chen, President and Founder of LATITUDE Phar­maceuticals. For drug substances with an estimated human oral dose exceeding 200mg, the company typically develops nanoparticle suspensions or tablet formu­lations containing API nanoparticles, which significantly enhance the dissolution of in­soluble compounds.

“For injectable formulations, we have successfully formulated even the most in­soluble compounds using one of our three preferred solubilization technologies: nanosuspensions, nanoemulsions, and LATITUDE’s own ClearSol™, all of which are free from toxic or allergenic ingredi­ents, and only contain components ap­proved by the FDA for injection,” he says. “Any of these formulations are readily scal­able and can be manufactured under GLP or GMP conditions for human use.”

Over the past 12-18 months, Dr. Chen says roughly 50% of the projects that LATITUDE developed were for compounds that were lipophilic, insoluble, and re­quired increased bioavailability. LATITUDE often relies on a combination of a bile acid with triglycerides and lecithin (as in its patented ClearSol solubilization platform) for significantly enhanced solubility and safety. “ClearSol is a highly effective, broad-spectrum solubilizer with a systemic and local safety profile that is comparable to, and often better than, cyclodextrins,” he says.

Nanoform: Reduce Pill Regimens with Nanoforming

While numerous biologics have been approved in the last decade, small mole­cules still dominate development pipelines. As the complexity and lipophilicity of new APIs steadily increase, the challenges as­sociated with poor solubility, leading to in­complete absorption and suboptimal pharmacokinetics, persist.

Established technologies such as ASD, nanomilling, cyclodextrins, and lipid for­mulations have been extensively reviewed. Of the emerging technologies, Tamas Solymosi, PhD, Lead Scientist and Techni­cal Sales Manager, Nanoform, says it is worth mentioning deep eutectic solvents capable of solubilizing poorly soluble compounds, drug-drug co-amorphous systems improving both the solubility and stability of APIs even compared to individ­ual amorphous states, and nanoforming, which is a green, ‘bottom-up’ particle en­gineering process to produce nanocrys­talline or nanoamorphous particles.

Nanoforming technology can de­crease the particle size of APIs to the 10nm range. The process works by the controlled precipitation of APIs from supercritical CO2 (scCO2) solution. “As nanoforming is relatively new, it is necessary to establish whether a compound is suitable for the nanoforming process,” says Dr. Solymosi. “Nanoform uses its sparse data AI tool, STARMAP®, to predict the solubility of an API in scCO2. This enables formulators to select the best suited APIs before commit­ting to experimental work.”

Nanoforming can also be used to en­able single pill-per-day regimens for nu­merous poorly soluble drugs. Consider that early formulations sometimes sacrifice patient-centric perspectives with large pill burdens and strict food restrictions. He says: “Reformulations and optimized com­positions can help improve patient centric­ity and adherence to therapy.”

Dr. Solymosi adds that initial lipid-based capsules are typically phased out by ASDs. “We have seen that for enzalu­tamide, decreasing pill size and pill bur­den.”

Nanoform successfully nanoformed the prostate cancer drug enzalutamide, al­ready marketed as an ASD. The marketed treatment has a regimen of 4x40mg pills per day. By formulating the treatment in a nanocrystalline form, a single 160mg pill regimen was developed that matched the exposure of the supersaturating ASD for­mulation. Production was scaled up to sev­eral tons/year and the nanoformed tablet showed promising results in clinical eval­uation and is set to enter the market in 2027.

Pharmaceutics International Inc.: Physical Property Evaluations Predict Solubility

In recent years, there has been a lot of focus on biologics and personalized medicine that are mostly delivered via par­enteral routes, but oral medication is still the most convenient route of administra­tion accounting for more than 80% of ap­proved drugs. Use of combinatorial chemistry and high throughput screening in pharmaceutical discovery for the next drug candidate has kept funneling on mol­ecules with poor aqueous solubility. Ninety percent of the new chemical entities and 75% of the compounds under develop­ment have inadequate water solubility. Biopharmaceutical Classification System Class II and IV compounds fall into this category. Bioavailability of an active moi­ety, among other factors, is predominantly affected by its solubility and permeability. Adequate aqueous solubility at absorption site is necessary for sufficient permeation and pharmacological action translating to desired clinical outcome.

To achieve optimal bioavailability, sci­entists have used various physical and chemical approaches to modify the rate of dissolution and solubility. Prodrug, salt for­mation, and cocrystals are the main chem­ical approaches that are used in early development to enhance solubility. Physi­cal approaches to improve solubility have been mainly focused on solid dispersion, lipid-based drug delivery systems using oils, lipids, surfactants and/or cosolvents, particle size reduction and Cyclodextrin in­clusion complex. Primary technologies that were used to improve solubility in FDA-ap­proved products since 2000 are hot melt extrusion and spray drying to form solid dispersion; self-emulsifying -emulsion, -microemulsion, and -nanoemulsion sys­tems (SEDDS, SMEDDS, SNEDDS) for lipid-based delivery; micronization and nanoparticles using dry or wet milling processes; and Cyclodextrin inclusion complexes. Among these, 30% of products were based on a solid dispersion platform.

At Pharmaceutics International Inc., a Jabil Company, initial evaluation of phys­ical properties of insoluble drug molecules is done utilizing Hansen Solubility Param­eters in Practice (HSPiP) software to predict the solubility in various solvent or solvent combinations, explains Sundeep Sethia, Vice President of R&D at Pharmaceutics In­ternational.

“Here, the API and solvent are char­acterized by just three parameters δD for Dispersion (van der Waals), δP for Polarity (related to dipole moment) and δH for hy­drogen bonding and represented as points in three dimensional HSP space,” he says. “API and solvents sharing similar HSP space shows favorable solubility. Solubility is subsequently verified by experimental data. Based on the output, a typical for­mulation approach may be development of a SEDDS or SMEDDS using lipidic ex­cipients and delivered as an oral liquid or soft gelatin capsule dosage form. Softgel capsules mask the oily taste and provide ease of unit dosing.”

For compounds with poor solvent sol­ubility, wet milling to nano size to increase the diffusional surface area is one option. Here, the API is milled along with stabiliz­ers (surfactants/co-surfactants) using mills, such as agitator bead mill (Dyno®Mill), high pressure homogenizer, etc. Mr. Sethia says that increased surface area improves in vivo dissolution, thereby improving bioavailability.

Quotient Sciences: SDD Suspension Enhances Absorption

Dr. Vanessa Zann, Vice President, Sci­entific Consulting, Quotient Sciences, says she has seen positive results with spray dried dispersion (SDD) formulations to help enhance fraction absorbed, which in turn increases exposure. Quotient Sciences uses biorelevant dissolution to rank solu­bility-enhanced technology platforms and then selects the most promising for clinical assessment.

“Note there is often a disconnect be­tween preclinical in vivo data and clinical outcomes,” she says. “We recommend as­sessing the SDD platform initially as a sus­pension formulation, which provides gold standard data for what is likely to be achieved with a good performing SDD tablet.”

For example, Tranquis approached Quotient Sciences in the preclinical stage to help develop clinical formulations for first in human (FIH). The compound in question was a BCS II compound (poor solubility and high solubility) and had shown solubility limited exposure preclini­cally, hence an enhanced formulation was anticipated to be required to achieve effi­cacious clinical exposures, explains Ms. Zann. Quotient Sciences used an inte­grated approach for drug product devel­opment, manufacturing, and clinical testing (this is the Translational Pharma­ceutics® platform) to rapidly identify and overcome solubility and bioavailability challenges for this compound.

Three suspension formulations were developed for assessment in the FIH: a methylcellulose crystalline (MC) suspen­sion; a spray-dried dispersion (SDD) sus­pension; and a hot melt extrusion (HME) suspension. The regulatory package was filed with 90 days stability for the SDD and HME GMP intermediates and seven days for the powder in bottle (PiB). The suspen­sion had four hours in use stability and a rinsing trial performed on each to allow total dosing volume to be 240mL. She ex­plains that the SDD and HME both showed superior dissolution to the crystalline API in a biorelevant dissolution assessment, demonstrating a spring and parachute ef­fect with reduced precipitation in the intes­tinal phase. A number of SDD suspensions were also assessed in the rat prior to the FIH but didn’t show any improvement over the MC suspension.

The FIH study started dosing SAD co­hort 1 (60mg) and 2 (180mg) with a methylcellulose crystalline suspension, which gave three-fold higher exposure than anticipated from the preclinical species. At SAD cohort 3 (540mg), the subjects were initially dosed with the MC suspension, but then returned to the clinic for dosing with the SDD and HME suspen­sions. The dose of the SDD and HME sus­pension was reduced to 180mg to ensure that the exposure caps were not exceeded due to the already higher exposure in the clinic than originally predicted. The SDD had the highest exposure showing a four-fold increase compared to the MC suspen­sion. This formulation was selected for dosing the remainder SAD and MAD co­horts.

“The Translational Pharmaceutics platform allowed the study not only to de­liver safety, tolerability, and pharmacoki­netic data, but also formulation selection assessment ahead of Phase II patient tri­als,” says Ms. Zann.

Serán Bioscience: A Scientific Approach to Understanding a Molecule’s Barriers

The landscape for oral delivery of novel new chemical entities (NCEs) is rap­idly evolving as we leave the “rule of five” era, says Rod Ketner, PhD, Vice President of Business Operations at Serán Bio­science. Increasingly large and complex “small” molecules with poor solubility and permeability present unique challenges to drug delivery. Successful formulation strategies must meet the target product profile with a robust and scalable manu­facturing process, often on accelerated de­velopment and approval timelines.

Serán’s team takes a hypothesis- driven scientific approach to understand­ing the physical, chemical, and biological barriers to absorption. “Avoiding a shot­gun approach to formulation design, we characterize an NCE and its performance in biorelevant media and dissolution con­ditions,” he says. “An understanding of a molecule’s performance in these media can set the foundation for formulation ap­proaches and dosage form architecture.”

Conventional formulation strategies – such as leveraging the low-pH environ­ment of the stomach to solubilize weak bases – increasingly prove insufficient and more advanced techniques are necessary, he says. Converting crystalline APIs into amorphous solid dispersions (ASDs) can substantially increase solubility, but require excipients that sustain supersaturation through GI transit. “ASDs, manufactured through methods like spray drying, melt extrusion, or precipitation, yield a higher free energy state and, consequently, greater solubility in the small intestine,” says Dr. Ketner. “Amorphous forms have been demonstrated to lead to a tenfold or greater enhancement in solubility.”

Spray dried dispersions (SDDs) stand out as a preferred method for enhancing solubility in the gastrointestinal (GI) tract. These stable, amorphous formulations combine an API and a polymer in an or­ganic solvent, followed by spray drying to create particles ranging from 5-50um. The resulting particles exhibit physical stability and dissolution properties that significantly boost bioavailability compared to crys­talline API alone. “The scalability and well-established nature of spray drying technology are notable, with over 50 ap­proved SDDs on the market currently,” he says. “However, developing and scaling SDDs effectively requires specialized expe­rience, not just an off-the-shelf dryer.”

Beyond solubility, permeability-limited absorption is an increasing obstacle, es­pecially for complex molecules like protein degraders and peptides. Their larger size (800-1500 MW) reduces their passive per­meability across the epithelium in the small intestine, and complex self-assembly can lower the driving force for permeation. Multiple approaches have been screened to address these issues, including lipid sys­tems, and additional permeability en­hancers. Permeation enhancers that modify the lipid bilayer or tight junctions between epithelial cells remain controver­sial and require further research.

“Given these challenges, outside-the-box approaches to addressing permeabil­ity challenges are essential for achieving acceptable pharmacokinetics,” says Dr. Ketner. Nanoparticles, for instance, can maximize drug concentration at the sur­face of the epithelium. For peptides, pro­tecting them from enzymatic degradation in the GI tract and designing dosage forms that transit, protect, and dissolve at the right location is critical. Patient-friendly in­jectable options, such as subcutaneous and intramuscular formulations, also merit consideration for drugs facing significant permeability issues.

Serán applies materials science prin­ciples to develop formulations, including enabled approaches like ASDs, along with scalable processes designed for sustained progress. He says: “This allows Serán’s team to offer flexible formulations and processes that support evolving clinical study needs and ensures R&D resources are effectively focused on the assets most likely to be successful.”

Spokes Sciences: Highlighting the Utility of SNAC with Lipophilic Compounds

In both the development of drug products for new chemical entities (NCEs) and within product life cycle management of existing drug products (such as devel­oping oral dosage forms out of known ac­tives currently administered by injection), major hurdles to the use of new pharma­ceutical excipients are the time, cost, and uncertainty associated with obtaining FDA approval. Despite lipophilic drug com­pounds remaining a driving force behind the development of bioavailability en­hancement technologies, these regulatory approval challenges can hamper or delay the adoption of novel functional excipients for that purpose, explains Kimberly Zubris, PhD, Chief Science Officer, Spokes Sci­ences.

Originally developed to improve the oral bioavailability of water-soluble active ingredients, salcaprozate sodium or SNAC, is an absorption-enhancing excip­ient already approved by the FDA and used in a blockbuster diabetes drug with the active ingredient semaglutide (Rybel­sus®). SNAC’s generally recognized as safe (GRAS) status means it could imme­diately be used in over-the-counter supple­ments, says Dr. Zubris.

Spoke Sciences creates innovative proprietary technologies through the delivery of highly lipophilic/poorly water-soluble active pharmaceutical and plant-derived functional ingredients. Previously, Spoke and its predecessor discovered that SNAC could be combined with some lipophilic functional ingredients to make new proprietary oral dosage forms with significantly improved bioavailability. Strik­ing among these data are a human clini­cal study showing that SNAC increases cannabidiol (CBD) oral bioavailability by 6-fold compared to standard solid-filled capsules without SNAC, and another clin­ical study showing that SNAC increases oral tetrahydrocannabinol (THC) exposure by 2.3-fold compared to THC in ethanol.

Highlighting the utility of SNAC as a blockbuster absorption enhancing ingre­dient, Dr. Zubris says that Spoke has recently undertaken studies to show that a broad range of hydrophobic actives can be combined with SNAC to significantly improve both their aqueous solubility and their rate of dissolution. This SNAC-driven solubility enhancing effect applies to mol­ecules that span the range of the lipophilic spectrum, including: melatonin (Log P ≅ 1.6), resveratrol (Log P ≅ 3.09), pterostil­bene (Log P ≅ 3.54), ibuprofen (Log P ≅ 3.8), curcumin (Log P ≅ 4.28) and coen­zyme Q10 (Log P ≅ 10). With a stoichio­metric optimum ratio of SNAC:active, solubility was seen to increase by up to 350 times in the presence of SNAC relative to that of water alone.

“SNAC enhances the oral bioavail­ability of lipophilic drugs, not just hy­drophilic drug substances as previously assumed,” she says.

Ongoing studies at Spoke continue to develop data validating SNAC’s mecha­nism of action with these lipophilic active ingredients. But given these results, Dr. Zubris says that SNAC is well poised to be­come a key tool for the use in formulating poorly absorbed drugs.

Thermo Fisher Scientific: Molecule-Centric Approach to Amorphous Drug Development

When asked how Thermo Fisher Sci­entific solved a bioavailability issue for a client, Sanjay Konagurthu, PhD, Senior Di­rector, Science and Innovation, Pharma Services, at Thermo Fisher Scientific, shares the design of a solubilized amor­phous spray dried dispersion (SDD) that enhanced oral bioavailability of a poorly water-soluble drug. To support this partner, Thermo Fisher used a molecule-centric ap­proach to amorphous drug development that, instead of empirical or ‘shotgun’ ap­proaches to accelerate formulation screen­ing, is routinely performed leveraging Thermo Fisher’s Quadrant 2® approach. Quadrant 2 is an artificial intelligence (AI) and machine learning (ML)-based predic­tive modeling platform, designed for sol­ubility and bioavailability enhancement.

“Lead formulations were identified with a combination of in silico modeling and in vitro solubility-supersaturation measurements to predict drug-excipient in­teractions,” he explains. “The combination of computational and experimental tools provides a cost- and time-efficient strategy to select drug-excipient combinations, prior to embarking on more time-consum­ing formulation and process develop­ment.”

Thermo Fisher performed molecular modelling to characterize interactions of pure drug, excipients, and drug-excipient systems via molecular dynamic (MD) and quantum mechanical (QM) simulations using a suite of programs assembled by the team. The goal of this work was to ex­amine the drug-drug and drug-excipient molecular level interactions between a BCS Class II molecule and compen­dial/GRAS polymers, in order to provide a rational basis for the selection of appro­priate polymers for inclusion in a solubi­lized drug product intermediate.

“This rationale is based on molecular descriptors and specific drug-polymer in­teraction energies. In silico modelling re­sults were corroborated by an in vitro solvent spike assay,” Dr. Konagurthu says.

Lead drug loading and polymer sys­tems were characterized by in vitro tests and confirmed by in vivo animal studies. In agreement with the in silico predictions, SDDs demonstrated substantial improve­ment of bioavailability in both in vitro and animal pharmacokinetic studies compared to the crystalline drug. Solvent spike assay analysis demonstrated that the addition of polymer excipients improved the sustain­ment of supersaturation in FaSSIF (Fasted State Simulated Intestinal Fluid). Non-sink dissolution results agreed with predictive in silico modelling and solvent spike analysis that HPMCP HP-55, Eudragit L-100 and CAP provided the greatest synergistic ef­fects and provided improved sustainment of supersaturation.

He says: “The in vivo data demon­strated that the SDDs resulted in significant enhancement of oral bioavailability. SDDs with a ranging polymer composition and drug loading provided up to an approxi­mately three-fold increase in maximum drug plasma concentration and an ap­proximately seven-fold increase in total AUC (Area Under the Curve). In silico modeling accurately predicted that HPMCP HP-55, CAP and Eudragit L-100 based SDDs would provide miscible drug-polymer systems with significantly en­hanced performance.”

In summary, Dr. Konagurthu says that a combination of experimental and com­putational modeling approaches allows for predictive drug-polymer miscibility and supersaturation sustainment. “Utilization of Quadrant 2 modeling allows for rapid screening with zero Active Pharmaceutical Ingredient (API) usage and a significant re­duction in benchtop manufacturing/analy­sis,” he says. “This led to the successful development of an enabling formulation for a BCS Class II drug that demonstrated superior oral bioavailability by leveraging our Quadrant 2 platform.”