Improving the bioavailability and solubility of modern APIs remains one of the most persistent hurdles in drug development. As pipelines continue to shift toward highly lipophilic, poorly water-soluble molecules – particularly BCS Class II and IV compounds – formulators are turning to advanced materials, predictive tools, and mechanistic design approaches to ensure adequate bioavailability and therapeutic performance, explains Gloria Ho, PharmD, RPh, Global Technical Marketing Manager, Pharma Solutions, BASF.

Advances in automation and technology, such as small-scale preparative techniques of solid forms and formulation screening strategies, coupled with evaluation of performance through automated online platforms, is imperative for success in early development, says Craig Grant, Vice President and General Manager, Cambridge, Veranova. “Using these in parallel to one another enables the measurement of critical solubility and dissolution properties, confronting potential developability issues earlier on, saving substantial time and resources.”

Perhaps one of the more contemporary uses of automation and advanced technology is for improving oral GLP-1 bioavailabilty and solubility, protecting these delicate peptides from degradation and facilitating intestinal absorption. “Formulation strategies increasingly rely on permeability enhancers, local pH modulation, and protective excipients to overcome low solubility and permeability, says Sanjay Konagurthu, PhD, Senior Director, Science and Innovation, Thermo Fisher Scientific Pharma Services. “These, combined with model-informed approaches, help quantify expected oral performance and guide rational excipient selection,” he says.

This annual Drug Development & Delivery report highlights other ways formulators are relying on automation, such as Artificial Intelligence and Machine Learning, and how these tools are being combined with experimental confirmation to identify the most promising development strategies.

Ardena: AI-Driven Insights Focus on the Most Promising Development Strategies

At Ardena, improving bioavailability starts with understanding the physico­chemical properties of a drug candidate. Poor aqueous solubility remains one of the most common challenges in drug devel­opment, particularly as modern small mol­ecules tend to be more lipophilic and structurally complex. Ardena, therefore, follows a structured, science-driven roadmap that begins with characterization of key parameters such as solubility, ion­ization behavior, lipophilicity (logP), melt­ing point, and solid-state properties. Laure Descamps, Formulation Scientist, Ardena, says these insights guide the selection of the most appropriate enabling formulation strategy for each compound.

When a molecule is ionizable, Ardena typically evaluates salt formation first. “Salt screening can significantly improve solu­bility and dissolution while maintaining a relatively straightforward development pathway,” says Timothy Pas, PhD, Director, Formulation Development and Production, Ardena. “If salt formation is not viable, al­ternative enabling technologies are con­sidered based on the compound’s limitations.”

Particle size reduction is commonly used for compounds with dissolution-lim­ited absorption. Techniques such as mi­cronization or nanonization increase sur­face area and improve dissolution rates. In particular, nanosuspensions, where the API is reduced to nanometer-scale particles stabilized with surfactants or poly­mers, can significantly enhance dissolution and systemic exposure for poorly soluble molecules, explains Ms. Descamps. “At Ardena, nanosuspensions are also attractive in early development because the stabilized particles can be in­corporated into multiple dosage forms, in­cluding suspensions, capsules, tablets, or parenteral formulations,” she says.

For highly lipophilic molecules, Ardena often explores lipid-based formu­lations such as self-emulsifying drug deliv­ery systems (SEDDS or SMEDDS), which form fine emulsions in the gastrointestinal tract and help maintain the drug in a dis­solved state.

Compounds with strong crystal lattice energy and limited solubility, often referred to as “brick dust” molecules, are fre­quently addressed through amorphous solid dispersions. In these systems, the API is dispersed in a polymeric matrix that in­hibits recrystallization and enhances ap­parent solubility and dissolution kinetics.

Dr. Pas shares that Artificial Intelli­gence is increasingly supporting the pre­diction and optimization of solubility and bioavailability in drug development. Ma­chine Learning models can analyze chem­ical datasets and identify relationships between molecular structure and physico­chemical parameters such as solubility, pKa or lipophilicity. “These insights help scientists identify potential solubility risks earlier and guide formulation strategies more efficiently,” he says.

AI tools can also assist formulation development by predicting how excipients, formulation approaches or processing pa­rameters may influence drug dissolution and absorption. Ms. Descamps says: “By narrowing the experimental design space and prioritizing promising strategies, these tools can reduce the number of laboratory experiments required during early devel­opment. Within a CDMO environment, such as Ardena, the application of AI must be balanced with strict data governance and intellectual property requirements. Client-owned molecular structures cannot easily be shared with external AI platforms, and robust models require large datasets that are often difficult to assemble under confidentiality constraints.”

For this reason, at Ardena, AI is viewed as a complementary tool that sup­ports scientific decision making rather than replacing formulation expertise. Predic­tions generated by computational models still require experimental confirmation, as bioavailability and solubility depend on complex interactions between molecular properties, formulation design, and phys­iological conditions, Dr. Pas explains. “Combining AI-driven insights with formu­lation expertise and targeted laboratory experiments allows Ardena to focus on the most promising development strategies while maintaining scientific rigor.”

Ascendia: Adapting New Technologies & Excipients to Expedite Drug Development

In recent years, drug manufacturers looking for appropriate technologies to bring new chemical entities (NCEs) to clinic faster are adapting novel excipients or technologies to expedite the development. Such strategies, aligned with formulation technologies, do pose some risks, but have led to the advancement of drug candidates across all modalities for oncology, anti-in­flammatory, antiviral, CNS, and rare dis­eases. Soluplus®, for example, a polymer for amorphous dispersions, has helped the advancement of many drug candidates from early-phase screening of molecules to clinical phases, and launch, says Shaukat Ali, PhD, Senior Director Scientific Affairs & Technical Marketing, Ascendia. In addition to novel excipients, there is much interest in co-processed excipients comprised of polymers and solubilizers to address the poor solubility of new drug candidates.

Poor solubility stems from higher melt­ing and logP, meaning the molecules bear­ing high melting are highly crystalline or have the higher partition coefficient in or­ganic phase. “These attributes create a bottleneck in the industry as more than 80% new molecules coming out of discov­ery possess high melting and logP, yielding poor solubility,” he says.

Fortunately, the pharma industry is open to adapt new technologies and excip­ients to expedite drug development. Con­ventional approaches like micronization, pH modification, salt and/or complex with cyclodextrin, have limited scope for medium- to high-dose drugs. Therefore, the new molecules belonging to BCS Class IIb (solubility limited) and Class IV require non-conventional approaches like amor­phous dispersions or lipid based emulsify­ing systems (SEDDS/SNEDDS) to achieve higher solubility and bioavailability.

Lipophilic molecules with logP <2-4> are most suited for lipid-based liquid dis­persions, while those possessing high melt­ing logP (>4) are ideal candidates for amorphous dispersions, Dr. Ali explains. For example, spray drying (SD) and hot-melt extrusion (HME) are commonly used for preparation of amorphous solid disper­sions (ASDs). For NCEs with a high melting point, Ascendia’s NanoSol® technology for nano-sized API particle engineering and AustinPX’s high shear dispersions (Kineti­sol®) have been used to tackle solubility challenges.

“BCS Class II/IV are most challenging molecules and thus require non-conven­tional approaches to identify the right ex­cipients and formulation technologies,” he says. “Ascendia’s enabling technologies in­cluding AmorSol® for amorphous solid dispersions and EmulSol® for emul­sions/nanoemulsions (SEDDS/SNEDDS) can help expedite development and save time and cost. Our approach includes early molecule screening to find maximum solu­bility and compatibility of APIs in the appro­priate excipients (polymers/solubilizers).”

This is achieved by dissolving API and excipients in varied concentration in polar solvents and casting the aliquot on a glass plate for drying in air or heating in oven at low temperature. The resulting film is ex­amined under light microscopy for any im­miscibility/crystallinity or homogenous mixing. This procedure allows shorter screen time of a number of molecules for AmorSol. For EmulSol, the APIs are screened against a range of compatible and FDA-approved solvents, co-solvents, and solubilizers to identify the maximum solubility, which is taken as the benchmark to design the best SEDDS/SNEDDS formu­lations for an API. “Not one size fits all, so each API is screened individually to identify the appropriate compatible excipients,” says Dr. Ali.

BASF: Science-Driven Suite of Apps Result in Actionable Formulation Decisions

BASF approaches solubility and bioavailability enhancement through a platform-based, excipient-driven strategy. Its excipient portfolio is designed to ad­dress these challenges from multiple an­gles, enabling tailored solutions using advanced polymers (i.e., Soluplus®), lipid and surfactant systems, solid dispersion technologies, and BASF’s digital formula­tion platform ZoomLab®.

“BASF’s multimodal strategy reflects a broader industry shift: formulators increas­ingly combine experimental techniques with computational decision support to rapidly identify the most viable bioavail­ability enhancement pathway,” says Gloria Ho, PharmD RPh, Global Technical Mar­keting Manager, Pharma Solutions, BASF.

For example, a typical oral develop­ment challenge involves the formulation of a poorly soluble API. In such cases, tradi­tional solubilizers may be insufficient to achieve clinically relevant exposure. Here, ASDs – produced via HME or spray drying – offer a route to maintain the API in a high energy amorphous state while ensur­ing improved dissolution, she explains. Before committing to large-scale experi­mental work, formulation scientists are often now relying on virtual predictive models to assess polymer compatibility, miscibility, and long-term stability.

BASF’s open-access virtual formula­tion assistant, ZoomLab is a science-driven suite of applications based on lab data, machine learning, modeling, and simula­tion. ZoomLab accelerates formulation evelopment through data-grounded in­sights, leveraging several AI technologies (excluding GenAI due to current accuracy limitations) by translating the complexity of bioavailability enhancement into a set of mechanistic questions:

• What are the limiting mechanisms?
• What is the most appropriate enabling technology?
• Which excipients are most compatible?
• What polymer classes are most likely to stabilize an amorphous state?
• Would a lipid-based system yield better solubilization?

“Together, these applications form a workflow that converts broad bioavailability challenges into precise, actionable formula­tion decisions that can also be used to pre­dict performance risk,” says Ms. Ho. By enabling data-driven refinement of formu­lation strategies, ZoomLab serves as a meaningful, complementary decision-sup­port for modern drug product development.”

BioDuro: An Optimal Approach Balances Solubilization with Cost and Scalability

Enhancement strategies for improving solubility and bioavailability can be grouped into chemical approaches and physical approaches. Chemical ap­proaches modify the drug molecule to im­prove solubility and absorption through salt formation, whereby, for ionizable drugs, an appropriate counterion is se­lected to form salts that can substantially increase dissolution rates; or through the use of prodrugs, used to covalently attach hydrophilic moieties that enhance solubil­ity. The prodrug is enzymatically converted to the active parent drug in vivo, preserv­ing pharmacological activity while over­coming delivery barriers.

Physical approaches are used to opti­mize a formulation without altering its mo­lecular structure, yet directly driving bioavailability gains. Dr. Hong Li, Vice President of Drug Product, BioDuro, says this can be achieved in several ways:

• Crystal engineering: tailor poly­morphs, cocrystals, or crystal habits or modulate lattice energy to balance sol­ubility and stability and enhance disso­lution and absorption.
• Particle size reduction: use microniza­tion or nanomilling technology to in­crease the surface area, thereby accelerating dissolution and improving the rate and extent of absorption.
• pH modification: adjust formulation or biological pH and maximize the ionized fraction of ionizable drugs, boosting solubility and membrane permeability.
• Solubilizers: surfactants form micelles to encapsulate hydrophobic drugs, in­creasing apparent solubility and facili­tating intestinal absorption.
• Lipid-based formulations: lipid matrices (e.g., self-emulsifying drug delivery sys­tems or SEDDS) exploit lipid solubility, bypassing aqueous dissolution limitations and improving oral bioavail­ability via lymphatic transport.
• Complexation: cyclodextrin inclusion can encapsulate drugs within their hy­drophobic cavity, increasing apparent solubility.
• Amorphous solid dispersions (ASDs): dispersing drugs in polymers as high-energy amorphous forms eliminates crystalline lattice energy, drastically im­proving dissolution rate and bioavail­ability.

“There is no one-size-fits-all solution,” says Dr. Li. “Success lies in matching the molecule’s properties with the most suit­able manufacturing approach. If the API is ionizable, salt screening is recommended, as stable, highly soluble salts can offer both cost-effectiveness and scalability. For non-ionizable crystalline APIs, ASD or lipid-based formulations are viable. The selection must also align with the develop­ment phase, dose requirements (especially for high-dose candidates), and process simplicity. Ultimately, the optimal ap­proach balances strong solubilization per­formance with cost control and scalability, ensuring a robust and practical path from IND filing and beyond.”

Gattefossé: Lipid Excipients Enable Oral Delivery for New Drug Modalities

For the past several decades, oral drug product development has centered around solubility enhancement, and amor­phous solid dispersions (ASDs) based on spray drying or hot-melt extrusion tech­niques have become a mainstay of oral tablet formulations. While there has been activity around novel polymer development and advanced analytical techniques to bet­ter understand the erosion and dissolution behavior of these systems, the products that advance into clinical studies typically utilize the same processing techniques and polymers as their predecessors.

Just as the industry adopted spray drying and hot-melt extrusion to overcome solubility challenges, it must now evolve to master the next frontier: permeability en­hancement. “New classes of drugs such as novel targeted protein degraders and macrocyclic peptides cannot be served by traditional solubility enhancement tech­niques and excipients,” says Nick DiFranco, Senior Marketing Manager, Pharmaceuticals, Gattefossé USA. “To be successful, these molecules require new approaches that also address drug perme­ation and absorption.”

The need for permeability enhance­ment has brought new focus to the estab­lished field of lipid-based drug delivery. Lipid-based formulations (LBFs) offer an effective, proven strategy for overcoming in vivo barriers and accessing alternative absorption pathways via the oral route, he says. LBFs leverage the body’s natural di­gestive processes to prevent re-precipita­tion, enable supersaturation, and mitigate food effect. But fresh focus is being brought to their other functionalities – tight-junction opening and lymphatic uptake.

“These unique benefits allow formu­lators to safely and reversibly enhance both transcellular and paracellular ab­sorption or bypass first-pass metabolism using the lymphatic system,” explains Mr. DiFranco. “Such features have been used in commercial products, enabling valuable innovation such as the conversion of testosterone from an injectable product to a more convenient oral capsule formula­tion.”

Gattefossé leverages its knowledge of lipid chemistry to identify the best excipi­ents for each API. A broad portfolio and formulation experience allows the entire team – from sales to technical service – to recommend excipients that introduce key problem-solving functionalities. Gatte­fossé’s Technical Centers of Excellence offer free-of-charge screening studies to identify the optimal self-emulsifying drug delivery system (SEDDS) formulation for a particular API, factoring in physicochemi­cal properties and in vivo functionalities, such as tight junction opening and lym­phatic uptake.

“This process accelerates early-stage development and helps to de-risk LBFs,” he says. “We also work closely with CDMOs to ensure successful scale-up and commercialization of soft gel and liquid-filled hard capsule formulations.”

Recently, Gattefossé’s lab in Paramus, NJ, installed a hot-melt extruder and small-scale tableting capability to further explore the use of lipid excipients as sur­factants, plasticizers, and absorption en­hancers in ternary ASDs. With these new capabilities, Gattefossé hopes to apply the unique functionality of lipid excipients to enhance solubility, permeability, and ab­sorption across a wider range of oral dosage forms.

Hovione: Integrated Offering Combines Advanced Formulation Science With Scalable Manufacturing

In Hovione’s view, the most promising technologies are those that address the core challenge of poor solubility, which af­fects over 70% of new drug candidates. Amorphous Solid Dispersions (ASDs), es­pecially those manufactured by spray dry­ing, have become a leading formulation strategy for overcoming poor solubility, with 48 drug products containing ASDs approved by the FDA between 2012 and 2023, demonstrating their clinical and commercial viability. Spray drying contin­ues to be the preferred manufacturing route for ASDs, owing to its scalability, process control, and suitability for a wide range of organic solvents and polymeric excipients including HPMCAS and Copovi­done, says José Luís Santos, PhD, Senior Director, Strategic Business Management – Particle Design, Hovione.

“We are seeing rapid advancement in the platforms used to create these ASDs, supported by better processes and digital solutions,” he says. “This includes the use of in silico formulation models and inte­grated intelligent formulation development tools, such as Hovione’s ASD-HIPROS. “These technologies enable faster, data-driven process and formulation develop­ment with minimal experimental work, rapidly screening for the best combination of drug loads, excipients, and surfactants using advanced formulation models and high-throughput screening methods.”

Furthermore, he adds that the devel­opment of better-performing materials is a key trend. This includes novel excipients, such as protein-based carriers like Disper­some®, which are capable of providing further gains in drug bioavailability, espe­cially when used in the formulation of an ASD-based drug product.

Hovione’s approach to improving bioavailability and solubility is centered on providing a fully integrated offering that combines expertise in advanced formula­tion science with robust, scalable manu­facturing capabilities. “This means going beyond simply offering capacity to provide proven capability in ASD development and integrated manufacturing, ensuring a seamless technology transfer from spray drying to the final dosage form,” says Dr. Santos.

At the earliest stages, Hovione de­ploys in silico and data-driven tools, such as ASD-HIPROS, to rapidly characterize the solubility and bioavailability challenge and select the most appropriate enabling strategy. This process begins with expedi­tious screening for the best combination of drug loads, excipients, and surfactants. The goal is to create a robust, scalable spray drying process from the outset. This scientific foundation is then paired with a focus on scalability and de-risking, apply­ing Quality-by-Design (QbD) principles and standardized tech transfer method­ologies that are consistently applied across Hovione’s network of regulatory-inspected facilities. “Where ASDs are the selected strategy, we offer integration between spray drying and downstream oral solid dose manufacturing, ensuring that what is developed at lab scale is more likely to translate predictably to clinical and commercial supply,” says Dr. Santos.

Artificial Intelligence is accelerating bioavailability enhancement at Hovione through hybrid modeling approaches. “Hybrid mathematical models, combining mechanistic understanding with machine learning methods, are the engines behind these tools, allowing scientists to leverage prior data to predict how a drug and poly­mer will behave together,” explains Dr. Santos. “These models also optimize the formulation composition in a fraction of the time it would take using traditional trial-and-error methods, accelerating the path from a poorly soluble new drug candidate to a robust, bioavailable formulation.”

LATITUDE Pharmaceuticals: Identifying Optimal Strategies for Poorly Soluble APIs

LATITUDE Pharmaceuticals improves bioavailability and solubility through a for­mulation-driven, technology-focused ap­proach tailored for each specific drug candidate. LATITUDE combines detailed preformulation studies – such as pH solu­bility profiling, solvent screening, and ex­cipient compatibility – to identify optimal strategies for poorly soluble APIs. It then applies its expertise in delivery platforms and formulation technologies, including nanosuspensions (a favorite of LATITUDE’s for its simplicity and effectiveness), na­noemulsions (excellent for injectable for­mulations), amorphous solid dispersions, and its Clearsol™ solubilization system (for both injectable and oral formulations) to enhance dissolution, ab­sorption, and stability. By selecting tech­nologies based on dose, route of administration, and API properties, LATITUDE creates scalable formulations that improve drug exposure, safety, and overall therapeutic performance, says Matthew A. Singer, PhD, Vice President, Business Development, LATITUDE Phar­maceuticals Inc.

LATITUDE Pharmaceuticals developed ClearSol, a proprietary drug-solubilization platform designed to address one of the most common challenges in pharmaceu­tical development: the poor aqueous sol­ubility of many active pharmaceutical ingredients (APIs). ClearSol is a sterile aqueous vehicle composed of three FDA-approved, generally recognized as safe (GRAS) excipients that enable poorly solu­ble drugs to form stable, single-phase so­lutions suitable for administration. The system has demonstrated the ability to sol­ubilize roughly 80% of tested insoluble compounds and often achieves higher drug concentrations than traditional solu­bilizers such as cyclodextrins or surfac­tants, while maintaining favorable safety profiles demonstrated in preclinical and Phase 1 clinical stages, explains Dr. Singer.

LATITUDE also uses nanosuspension formulations, which disperse drug particles at nanometer scale in a stabilizing medium. “By dramatically increasing sur­face area, nanosuspensions enhance dis­solution rate and drug absorption, making them especially valuable for lipophilic or poorly soluble compounds,” he says. “To­gether, technologies like ClearSol and nanosuspensions provide innovative ap­proaches to improve drug solubility, bioavailability, and overall therapeutic per­formance.”

Ligand: Combine Mechanistic Clarity, Regulatory Familiarity & Flexibility

Poor aqueous solubility and limited bioavailability continue to be among the most common barriers to successful drug development, particularly as modern discovery efforts yield increasingly lipophilic and structurally complex molecules. In response, recent progress in this area has been characterized less by entirely new concepts and more by the refinemenpansion, and clinical validation of en­abling technologies that can be applied predictably across diverse compounds.

Several strategies currently stand out in this area. Amorphous solid dispersions and lipid-based delivery systems remain widely used for oral small molecules, par­ticularly for BCS Class II compounds, due to their ability to enhance dissolution and maintain supersaturation in the gastroin­testinal tract. “Research has shown that Captisol® helps spray dried amorphous solid dispersions by improving API solubil­ity in feed solution, stabilizing amorphous drug via molecular complexation, enhanc­ing dissolution and maintaining supersat­uration, complementing polymer-based ASD systems, and improving spray drying robustness and particle quality,” says Lian Rajewski, PhD, Senior Director Formulation Development, Ligand.

Nanocrystal technologies and particle engineering approaches continue to ma­ture, offering improvements in dissolution rate without altering chemical structure. In parallel, functional excipients – those that actively influence solubility, stability, and exposure rather than serving as inert for­mulation components – are playing an in­creasingly important role in formulation design.

Within this category, cyclodextrin- based solubilization strategies, particularly those using chemically modified cyclodex­trins, are experiencing renewed attention. While cyclodextrins themselves are not new, advances in their chemical design, safety characterization, and regulatory acceptance have expanded their practical utility.

“Captisol (sulfobutylether β cyclodex­trin) is a notable example of this trend,” says J.D. Pipkin, PhD, Vice President, New Product Development, Ligand. “Designed to address the limited solubility and safety concerns associated with native β cy­clodextrin, Captisol enables reversible in­clusion complexation that can substantially improve aqueous solubility and formula­tion stability without chemically modifying the active pharmaceutical ingredient. What makes Captisol particularly relevant in the current development landscape is its continued appearance in newly approved products and new routes of administra­tion, rather than reliance solely on legacy intravenous formulations.”

As of March 2026, eighteen ap­proved products incorporate Captisol, says Vince Antle, PhD, Senior Vice President Tech. Operations & QA, Ligand, reflecting sustained regulatory confidence and on­going application across therapeutic areas and dosage forms. “Recent approvals demonstrate its role in enabling formula­tions that were previously difficult to achieve due to solubility or concentration constraints,” he says.

One example is Lasix® ONYU, ap­proved by the FDA in October 2025. This product uses Captisol to enable a high concentration subcutaneous formulation of furosemide suitable for at-home admin­istration via a wearable infusor. In this case, the solubility enabling properties of Captisol supported not only drug delivery but also a shift in care setting – from hos­pital-based intravenous treatment to outpatient self administration – highlight­ing how formulation technology can influ­ence broader therapeutic strategy, says Dr. Pipkin.

Beyond individual products, Capti­sol’s relevance is linked to its compatibility with contemporary development priorities, including simplified formulations, reduced reliance on organic cosolvents, and adapt­ability to multiple routes of administration. “Its safety and regulatory history lowers formulation risk, making it attractive for both new chemical entities and lifecycle management efforts,” says Dr. Rajewski.

Lubrizol: Novel Excipients Are an Effective Alternative to More Common Ingredients

Poor solubility and bioavailability im­pede both therapeutic potential and inno­vation, particularly in oral and injectable dosage forms. Using excipient-based sol­ubilization strategies can enable simplified formulation techniques to streamline man­ufacture and save time during the devel­opment of drug products containing poorly soluble APIs. Yet, many of today’s commonly used excipients were developed decades ago and may not be optimal for transforming insoluble APIs into effective therapeutics.

“Novel excipients specifically de­signed to improve solubility and bioavail­ability offer an effective alternative,” says Dr. Liliana Miinea, Global Technology Manager, Lubrizol.

For example, Lubrizol’s novel excipi­ents, Apisolex™ polymer excipient and Apinovex™ polymer excipient, resolve for­mulation challenges by enhancing the sol­ubility of brick-dust poorly soluble APIs. The polyamino acid-based Apisolex poly­mer increases the solubility of hydrophobic APIs for parenteral applications by up to 50,000-fold, with high drug loading of up to 40:100 API to solubilizer. Being biolog­ically inert, it has no side effects.

“Based on sarcosine – a non-toxic, non-immunogenic, biocompatible, and biodegradable amino acid – Apisolex polymer excipient offers a high level of safety for parenteral use – unlike PEG-based solubilizers, which may trigger neu­ropathy, hypersensitivity, and anaphylactic reactions,” she says.

For its part, Apinovex polymer excipi­ent is a high molecular weight polyacrylic acid that enables homogenous amor­phous dispersion for solid oral dosage forms, with up to 80% drug loading. By comparison, traditional polymer excipients such as hydroxypropyl methylcellulose (HPMC) and povidone typically only sup­port drug loading of up to 40%, she says. Dr. Miinea explains that in case studies with the BCS Class II drug itraconazole and BCS Class IV ritonavir, Apinovex poly­mer excipient-enabled ASDs with twice the drug loading compared to other com­monly used, solubility-enhancing excipi­ents. It also allowed up to tenfold improvements in dissolution for disper­sions compared to crystalline APIs, and maintained stable amorphous solid dis­persions even after six months under ac­celerated conditions.

“Compared to excipients with prece­dence of use, novel excipients can be su­perior solutions for bioavailability and solubility challenges,” says Dr. Miinea. “Yet, the ambiguity surrounding regulatory approval for excipients can lead risk-averse formulators to stick to familiar in­gredients.”

Lubrizol believes that early collabora­tion between drug developers and excipi­ent suppliers is the solution to building formulator confidence in novel excipients. Critically, this strategy can enable early identification of the developer’s specific unmet needs. Lubrizol actively works with partners to co-develop data and regula­tory submissions. Its Drug Master Files (DMFs) in the US, China, and Canada – or data-sharing agreements where DMFs are not used, such as Europe – help streamline the approval process.

“Bridging arguments can also be used to mitigate the regulatory risk of in­cluding a novel excipient in a new drug application,” she says. “The use of an ap­proved excipient’s safety data may support a novel excipient with similar chemistry. For example, Apinovex polymer excipient is chemically similar to our existing, widely used Carbopol® polymers.”

Quotient Sciences: Integrated, Data-Driven Approach Accelerates Development

Quotient Sciences’ approach to bioavailability and solubility integrates De­velopability Classification System (DCS) principles with biopharmaceutic experi­mentation and mechanistic PBPK/PBBM modelling to systematically identify and mitigate solubility and permeability re­lated risks. “Early assessment of intrinsic solubility, pH-dependent solubility, disso­lution behavior, permeability, particle size, and solid state properties enables us to determine whether a compound is solubil­ity or permeability limited and select the most appropriate formulation strategy,” explains Paloma Benito Gallo, Senior Modelling and Simulations Research Fel­low at Quotient Sciences. “Modelling and Simulation (M&S) expertise can be used to review the output and advise on the suit­ability of M&S to inform for further devel­opment and risk assessment.”

Jane McGuffog, Director, Modelling and Simulation, Quotient Sciences, goes on to explain that following non-clinical assessment, Quotient Sciences can com­bine these data with PBPK/PBBM model­ling to quantify the impact of particle size, gastric pH, dose, food effect, and trans­porter interactions on predicted exposure. She says: “This modelling framework guides form/formulation selection, sup­ports dose escalation, and reduces uncer­tainty when transitioning to FIH studies. Where solubility limits performance, we evaluate enabling technologies such as amorphous solid dispersions, lipid-based formulations, and particle size reduction, using rapid small-scale screening to iden­tify the best performing technology. This integrated, data-driven approach im­proves bioavailability, accelerates develop­ment, and reduces experimental burden.”

For Quotient Sciences’ client, Boston Pharmaceuticals, a Phase I Translational Pharmaceutics® study was performed, in­tegrating drug product manufacturing and clinical testing to rapidly screen and select an optimal oral formulation of BOS172767, a first-in-class inverse ago­nist being developed for autoimmune dis­eases. Previous first-in-human studies using an API blend capsule showed low exposure, high variability, non-linear pharmacokinetics and a pronounced food effect, prompting evaluation of solubility-enhanced formulations, explains Dr. An­drew Lewis, Chief Scientific Officer, Quotient Sciences. Three GMP-manufac­tured formulations (micronized capsule, lipid capsule, and spray-dried dispersion tablet) were assessed head-to-head in an integrated adaptive clinical study in healthy volunteers. All prototypes im­proved exposure compared with the IR ref­erence capsule, with the spray-dried dispersion showing the highest Cmax. The micronized capsule was selected as the lead formulation based on comparable AUC and a simpler and cheaper manufac­turing process. This formulation demon­strated approximately dose-proportional exposure up to 800mg, a reduced food ef­fect relative to the FIH formulation, and minimal impact of elevated gastric pH when evaluated within volunteers dosed with a proton-pump inhibitor. A Level C IVIVC was established using biorelevant dissolution testing, supporting future for­mulation development and specification setting.

Quotient Sciences has established a partnership with Intrepid Labs to integrate its proprietary Machine Learning (ML) al­gorithm Andromeda™ with Quotient Sci­ences’ Translational Pharmaceutics™ platform that integrates drug product manufacturing with clinical testing to rapidly identify formulations that meet the Tar­get Product Profile. “When coupled with automation, many hundreds of prototype lipidic and amorphous dispersion formu­lations can be screened to fully map the formulation design space,” says Dr. Lewis. “Not only does this enable the identifica­tion of compositions that achieve the high­est solubility and stability, but it reduces API demands and provides improved knowl­edge of the relationship between compo­sition and performance.”

Samsung Biologics: AI Propels Drug Candidates from “Possible” to “Optimally Bioavailable”

AI is turning bioavailability and solu­bility from experimental bottlenecks into data-driven opportunities early in drug discovery. Jaehoon Jeong, Lead Scientist of AI Technology; Hyunsik Lee, Senior Sci­entist of Antibody Technology Discovery; and Sangyun Park, Senior Scientist of An­tibody Technology Discovery at Samsung Biologics, highlight three key areas where AI is making an impact on solubility and bioavailability.

1. AI-based in silico developability assess­ment: Traditional prescreening of anti­body candidates relies on costly wet lab assays. Recent AI models now ex­tend to antibodies, predicting devel­opability risks such as solubility, thermostability, and aggregation. Inte­grated workflows that enable AI-driven prescreening are being piloted by Big Pharma. “By consolidating multiple predictions into a single pipeline and leveraging internal datasets, these workflows achieve respectable predic­tive accuracy for expression and stabil­ity – attributes that normally require months-long testing,” says Dr. Jeong.

“This approach delivers substantial time and cost savings and enables more efficient selection of candidates.”

2. From accurate structures to physics-based forecasts: AI-driven structure prediction engines such as AlphaFold3, RoseTTAFold, and Boltz-2 provide high resolution antibody structures. When further processed by physics-based simulation platforms, molecular dy­namics and free energy calculations can estimate solubility and aggrega­tion propensity, explains Dr. Lee. Met­rics such as solvent-exposed patches and conformational flexibility guide rational modifications that improve systemic exposure. “Nevertheless, pre­dicting an antibody’s solubility and bioavailability remains challenging,” says Dr. Lee. Antibodies are large, flex­ible proteins that often carry complex glycoforms, can aggregate, and are recycled by the FcRn receptor. “Recent AI advances, especially protein lan­guage models and multimodal net­works that combine sequence, 3D structure, and glycoform data, are be­ginning to address these problems,” says Dr. Lee. “At the same time, gener­ative AI tools are being used to re­design Fc regions and optimize glycosylation patterns, while microflu­idic formulation screens co-optimize excipient blends. Together, these ap­proaches suggest a promising direc­tion, although extensive experimental validation is still required.”
3. Lab in the Loop (LITL) – closing the re­ality gap: Even the best in silico model drifts when confronted with zero-shot prediction lacking internal experimen­tal data. The LITL paradigm turns the laboratory into a self-learning engine: AI proposes candidates, robotic plat­forms perform expression and assay, and the results retrain the predictors. “This loop compresses the design make test analyze cycle from months to weeks, boosting hit to lead conversion and delivering compounds with exper­imentally validated bioavailability and solubility,” says Dr. Park.

Dr. Jeong summarizes: “AI has evolved from a static predictor to a dy­namic partner that continuously integrates structural insight, physicochemical model­ing, and empirical feedbac – propelling drug candidates from “possible” to “opti­mally bioavailable” at unprecedented speed.

Simtra BioPharma Solutions: Improving Solubility With the End in Mind

In the sterile injectables space, inves­tigating an increase in solubility typically begins with fundamental, direct ap­proaches, such as pH modification, tem­perature adjustment, or the addition of organic co-solvents. However, Simtra Bio­Pharma Solutions is seeing significant ad­vancements in parenteral products to improve the bioavailability of molecules that are not naturally water-soluble. Among the most promising technologies are liposomes and lipid nanoparticles (LNPs). Both dosage forms allow poorly water-soluble molecules to be placed within a lipid core, which is then dispersed in aqueous media so they can be effec­tively injected, describes Greg Sacha, PhD, Global Senior Scientist Development and Clinical Services, Simtra BioPharma Solu­tions.

“Our approach to improving solubility is rooted in a product designed with the end in mind philosophy, which ensures that for­mulations are robust, scalable, and facili­tate high-quality manufacturing,” he says. “We have received several requests for de­veloping formulations for molecules that are challenging to dissolve and reconstitute after freeze-drying. Our initial strategies al­ways prioritize simple, proven approaches to maintain efficiency and stability.”

This includes:

• Primary adjustments, such as adjusting the pH of the solution, modulating tem­perature, including an organic co-sol­vent, or adding a small percentage of surfactant;
• If these do not yield the desired results, cyclodextrins are used to improve solu­bility;
• The use of polyethylene glycols (PEGs), propylene glycol, and surfactants is ex­plored to improve the reconstitution process after freeze-drying.

Freeze-drying a formulation can be challenging because many highly potent and chemotherapeutic molecules are poorly soluble in water and often require an organic co-solvent to improve solubility. Simtra BioPharma Solutions dissolves the molecule in a customized organic co-sol­vent solution along with specific excipients. This solution is filled into vials, frozen, and undergoes a specialized freeze-drying process.

“The lyophilization process success­fully removes the organic solvent and sig­nificantly increases the specific surface area of the molecule,” says Dr. Sacha. “This allows the drug to dissolve much more effectively upon reconstitution, en­suring the patient receives the vital in­jectable product in its intended, most bioavailable form.”

In an effort to accelerate the early in­vestigative stages, companies like Simtra BioPharma Solutions are turning to Artifi­cial Intelligence (AI). Dr. Sacha says AI of­fers scientific teams a rapid method of conducting preliminary research, as it can provide quick answers when posing ques­tions about the behavior of certain excipi­ents or the feasibility of specific formulation strategies. These AI-generated insights are then reviewed by onsite ex­perts to determine the best path forward.

“This synergy between digital intelli­gence and our deep technical expertise helps save time and money for our cus­tomers, ultimately accelerating the delivery of life-changing therapies to patients,” says Dr. Sacha. “Our onsite scientific teams support products from initial discov­ery through to commercial launch, solving the scaling challenges that often accom­pany complex formulation development.”

The Solubility Company: Give Every Promising Asset a Chance to Progress to the Clinic

The available toolset of enhancing and enabling formulation technologies broadly covers the bioavailability and sol­ubility challenges of current chemical space. Poor bioavailability and solubility are now inherent in most development programs and the challenge has moved from a lack of technologies to timely selec­tion of the right technology for a particular asset. “Here, miniaturized technologies, such as The Solubility Company’s SPA® platform, work with the material amounts available at the preclinical stage, where decisions lock in development and where actionable insight is most critical and hardest to come by,” says Sami Svanbäck, PhD, CEO, The Solubility Company.

The Solubility Company’s goal is to give every promising asset a chance to progress to the clinic, says Dr. Svanbäck. “Using as little as 2mg of compound, we screen the entire preclinical formulation space. Having this data on hand early on enables us to support our clients with all in vivo PK and toxicology studies before the first scale up of their molecule. The ap­proach is particularly successful for new modalities where the compounds may not behave like traditional small molecules. This paradigm shift ensures that develop­ment is never delayed by material scarcity.”

One of the company’s clients faced a go/no-go decision on a highly lipophilic API with animals booked for toxicology, but no viable vehicle with which to dose. Traditional methods were impossible due to the limited availability of the API. “By applying SPA to map the formulation land­scape, we rapidly identified a specific lipid-based surfactant vehicle,” he explains. “Using only 1mg for the entire screen, we delivered an α-formulation™ that deliv­ered systemic exposure above 50mg/kg, allowing the program to proceed to toxicology without waiting for a secondary synthesis scale-up synthesis and further delays.”

SPA uses standardized, high-preci­sion, automated experimental data to fine-tune Machine Learning models in real time, which Dr. Svanbäck considers to be an active learning loop. “AI is becoming a powerful tool in drug discovery and devel­opment, but it is still limited by the lack of high-fidelity training data. Most historical solubility databases are “noisy” due to in­consistent experimental methods and lack of meta-data on experimental conditions. We see AI’s greatest value in active learn­ing loops. This hybrid approach, where AI predicts and micro-scale experiments rap­idly verify, can significantly cut down on trial-and-error wet-lab experimentation to shorten the path to IND.”

Thermo Fisher Scientific: Combining Predictive In Silico Workflows with Targeted Experimentation

A shift toward model-informed formu­lation design is transforming how bioavail­ability and solubility challenges are addressed. Traditional empirical ap­proaches are increasingly being supple­mented by predictive digital tools that integrate Artificial Intelligence (AI), Ma­chine Learning (ML), Quantum Mechanics (QM), Molecular Dynamics (MD), Quanti­tative Structure–Property Relationship (QSPR), and Quantitative Structure–Activity Relationship (QSAR) models. These ap­proaches enable early prediction of solu­bility, permeability, and absorption-related risks before extensive laboratory screen­ing, says Sanjay Konagurthu, PhD, Senior Director, Science and Innovation, Thermo Fisher Scientific Pharma Services.

“These tools, or digital platforms like OSDPredict™, identify and prioritize for­mulation strategies – including technology selection (e.g., amorphous solid disper­sions, particle size reduction, lipid systems, fluid-bed processing, complexation etc.), drug-excipient combinations, and drug loading – and inform downstream consid­erations such as bio-enhancement, man­ufacturability, and stability,” he says.

Key features include:

• AI/ML-powered predictive modeling, such as Thermo Fisher Scientific propri­etary AI/ML Quadrant 2® platform, which uses molecular structure and key physicochemical properties to identify probable enabling technologies, guide formulation design for solubility and bioavailability enhancement, and esti­mate optimal drug loading.
• Predictive stability modeling for deter­mining product shelf life and packaging extrapolated from short-term acceler­ated data, reducing development time and experimental burden. Both chemi­cal and physical stability aspects are considered for enabling technologies such as amorphous solid dispersions.
• Compaction simulation and process modeling to support scalable and ro­bust oral solid dose manufacturing, scale-up, and technology transfer.
• ADME-PK and PBPK modeling to predict absorption, distribution, metabolism, and excretion, helping align formula­tion decisions with in vivo pharmacoki­netic studies and first-in-human (FIH) predictions.

Thermo Fisher Scientific’s strategy combines predictive in silico workflows with targeted experimentation. Early in de­velopment, Quadrant 2® predictive mod­eling is used to identify suitable formulation technologies, solubility, and bioavailability enhancement strategies, ex­cipients, and optimal drug loading, ex­plains Dr. Konagurthu. This insight guides formulation selection and prioritizes high-value experimental leads, minimizing API usage and avoiding extensive trial-and-error screening – so developers can focus only on what works best.

Once candidate technologies (e.g., ASDs or lipid systems) are identified, ac­celerated stability models project long-term behavior and inform packaging and storage decisions. Process modeling en­sures that formulations are manufac­turable and scalable with controlled critical quality attributes. Finally, PBPK/ADME-PK models integrate physicochemical and dis­solution data to simulate clinical exposure, supporting dose selection and overall pro­gram de-risking.

In a recent engagement involving a poorly water-soluble BCS Class II candi­date, predictive modeling was applied at the outset. Quadrant 2 evaluated potential drug–polymer interactions and identified polymer systems with favorable miscibility and potential for supersaturation mainte­nance. These in silico predictions were confirmed experimentally using solvent spike assays and biorelevant dissolution testing, he explains.

Spray-dried dispersion (SDD) formu­lations were then developed using process simulation to optimize particle character­istics and manufacturability. Accelerated stability modeling provided early insights into the risk of phase separation or crys­tallization during storage. In vivo pharma­cokinetic studies demonstrated significant enhancement in oral bioavailability com­pared with the crystalline form, and PBPK simulations corroborated the observed in­creases in Cmax and AUC. “This inte­grated workflow enabled rapid refinement and advancement of an enabling formu­lation while reducing development risk,” says Dr. Konagurthu.

Upperton Pharma Solutions: Screening Platform Evaluates Methods for Improving Solubility/Bioavailability

Upperton believes that creating amor­phous solid dispersions (ASDs) by spray drying is the most promising and effective way of improving the bioavailability/solu­bility characteristics of an API. “Not only does this approach work for a wide range of NCEs, but it offers a fast, scalable for­mulation approach,” explains Dr. Richard Johnson, Chief Scientific Officer & Founder, Upperton Pharma Solutions. “The number and range of polymers that can be considered is increasing, giving us more formulation options and the addition of surfactants to help stabilize the API in solution is an added option.”

Dr. Johnson says Upperton will typi­cally screen three enabling technologies; creating ASDs by spray drying, lipid based formulations (semi-solid matrix filled into capsules) and micronisation (to decrease particle size). The pilot formulations are then subjected to a range of tests, includ­ing micro dissolution testing, physical test­ing (thermal properties), and stability. The output of this data is typically a “ranking” order for further testing in a pharmacoki­netic (PK) model. This rapid screening ap­proach is called UpperSolv™.

He describes a recent example where Upperton evaluated the use of its Upper­Solv screening approach to evaluate dif­ferent methods for improving the solubility and bioavailability of Oxfendazole, a poorly soluble API with limited bioavail­ability. “In the study, we evaluated the three main approaches for enhancing sol­ubility/bioavailability using the UpperSolv approach (ASDs lipidic formulations, and micronization). By far the best enabling technology was spray drying; an ASD was created by spray drying enhanced bioavailability sevenfold compared to the API alone.”

Veranova: Improving Dissolution Rates of “Brick Dust” APIs

Key solid form and physicochemical attributes of a molecule, such as crys­tallinity, pKa/LogP, melting point, and un­derstanding particle characteristics help to identify viable development and formula­tion routes early in the screening process. The simplest, low cost, and most robust strategies can be prioritized for evaluation first before moving into increasingly com­plex methods. “As an example, if accessi­ble ionizable centers prevail, tried and tested salt screening and selection is a well understood front line approach for in­creasing aqueous solubility,” explains Craig Grant, Vice President and General Manager, Cambridge, Veranova. “Where salts are not possible, cocrystals, while not as immediately obvious as “simple acid-base” chemistry (sometimes not so sim­ple), are equally valuable for crystal lattice modification that can often result in improving physical properties including solubility. The polymorph landscape of each needs to be understood and control needs to be exerted to link the desired solid form at lab to plant scale to complete the picture.”

Moving beyond crystal engineering, particle engineering encompasses a range of techniques that modify an API’s particle shape, size, and surface area. These in­clude traditional top-down strategies, such as milling and micronization, often with the goal of reducing particle size to in­crease aqueous solubility. On the other end of the spectrum, for molecules where traditional methods have been tried and tested, the production of an ASD is a more costly but effective means of improving solubility; provided the appropriate screening strategies have been applied to stabilize the amorphous material, says Mr. Grant.

A typical example of a challenge faced by many of Veranova’s clients is how to tackle poor aqueous solubility for a non-ionizable compound, which elimi­nates salt formation entirely and therefore requires alternative methods of solubility enhancement. Occasionally, this can be tackled with co-solvents or perhaps via cocrystal formation or the formation of complexes, e.g., cyclodextrins. However, he says, it is often the case that molecule properties do not align with these strate­gies, for example, compounds with a high LogP or the absence of the relevant hydro­gen bond motifs and/or suitable molecu­lar shape and size.

“In these cases, one of the ap­proaches Veranova employs is the devel­opment of a nanosuspension,” says Mr. Grant. “Nanosuspensions vastly improve dissolution rate in “brick dust” APIs by re­ducing particle size to nanometer (sub-mi­cron) levels and dramatically increasing surface area. As a result, saturation solu­bility can be increased and dissolution rate is dramatically enhanced, in turn poten­tially increasing bioavailability.”