SPECIAL FEATURE – Solubility & Bioavailability: Difficult Beasts to Tame
By: Contributor Cindy H. Dubin
Solubility remains challenging as new molecules coming out of discovery are poorly soluble. Less soluble means the molecules can’t be absorbed and therefore, can’t be solubilized. Factors responsible for poor solubility stem from high melting (MP) and high partition coefficient (logP) of molecules. Regardless of their structures, the solubility is limited in water because most of them have a tendency to prefer organic phase over aqueous phase. “All these challenges impede drug development, which has resulted in creating the gaps for finding cures for life threatening and rare diseases, and for unmet medical needs,” says Shaukat Ali, PhD, Senior Director, Scientific Affairs & Technical Marketing, Ascendia Pharma, Inc.
These challenges span across all small and large molecules, and with more than 80% of new chemical entities (NCEs) belonging to BCS II and BCS IV, many of them cannot be developed due to lack of understanding of their physicochemical properties and inability to dissolve, says Dr. Ali. Small molecules are equally challenging because of their brick dust or being hydrophobic or lipophilic in nature, as well as their inability to disperse in aqueous solutions.
Driven by the large number of BCS Class II and IV therapies in the current pipeline and growing demand for effective therapeutics, the bioavailability enhancement services market is expected to grow at a steady pace.1 Bioavailability is a key pharmacokinetic property that affects the ability of a drug to reach systemic circulation unaltered after administration. It is dependent on multiple factors, both physiological and drug related, such as solubility, pH, absorption area, permeability, and metabolism, as well as the route of administration. “Consequently, bioavailability can play an influential role in determining whether or not an active pharmaceutical ingredient (API) will be successful or fail during the early stages of drug development,” says Sundeep Sethia, PhD, Head of R&D at Pii.
More than 75 bioavailability enhancement technologies are presently available in the market. Most (55%) support solubility enhancement, and nearly 70% provide bioavailability enhancement services for solids, followed fine particles/powders. Shifting focus of drug developers towards development of lipophilic drug compounds is anticipated to drive the demand for bioavailability enhancement technologies and services in the next 13 years. Consequently, the outsourced commercial demand for bioavailability enhancement is projected to increase.1
This exclusive Drug Development & Delivery annual report highlights the services many of these outsourced providers offer to enhance solubility and bioavailability and get their clients’ projects to market faster and cost effectively – while maintaining critical quality attributes.
Since the advent of High Throughput Screening (HTPS) for lead identification, the volume of new compounds with poor aqueous solubility and/or bioavailability (BA) has been increasing phenomenally. This is because of HTPS’s inherent inclination in identifying leads that are lipophilic in nature in order to favor target binding for efficacy. Even after multiple decades of pharmaceutical technological advancements, addressing solubility and BA issues of these drugs remains a difficult beast to tame for various reasons, says Srinivasan Shanmugam, PhD, Senior Director, Pharmaceutical Sciences, Business Support & New Technologies, Adare Pharma Solutions.
Any formulator trying to address BA issues must primarily understand the underlying reasons for poor bioavailability and design the right formulation strategy to address the BA issue. In general, reasons for poor bioavailability are manifold, and could be one or more of the following: drug-related factors such as poor solubility; poor/slow dissolution/dissolution rate; poor permeability; and physiological barriers such as high first-pass metabolism and high efflux by Pgp. While drug-related factors constituting the Biopharmaceutical Classification System (BCS Class I-IV) determine drug absorption, physiological barriers dictate the ultimate BA of any drug. In other words, a drug with excellent solubility and permeability can achieve excellent absorption via gastrointestinal epithelium, however it could still be poorly bioavailable due to physiological factors like first-pass effect or efflux. Therefore, it is of paramount importance for formulators to understand both drug-related factors and physiological barriers when developing a viable formulation strategy. Additionally, knowledge of physicochemical properties of drugs — such as logP, melting point, and ionization — will be needed to select appropriate formulation strategy.
As far as formulation strategy, the BA of BCS Class II drugs can be enhanced either by improving their dissolution rate (Class IIa) or by enhancing solubility (Class IIb) via various formulation techniques such as particle size reduction, salt formation, surfactants, and amorphous solid dispersions. However, if poor BA is a result of permeability (Class III), then permeation enhancers or lipid formulations — including lipid-based solutions, suspensions, emulsions, lipid particles, and liposomes — can be used to improve the permeability. For drugs with solubility and permeability issues (Class IV), both strategies need to be implemented. Finally, to address poor BA due to physiological barriers, lymphatic delivery and/or metabolic enzyme inhibitors could be a viable option to preclude first-pass metabolism, while the addition of Pgp inhibitor Pgp substrate drug will improve the BA.
Adare Pharma Solutions has demonstrated solubility enhancements of various drugs with traditional and enabled technologies. “Adare has increased the solubility of pH-dependent and poorly water-soluble drugs by creating acidic or basic micro-environments using organic acid or alkaline buffer with the help of our specialized Diffucaps® technology,” says Dr. Shanmugam. “Additionally, another novel Adare technology platform, Optimum®, can create lipid microspheres and amorphous solid dispersions that enhance solubility and permeability of various BCS class drugs. Overall, Adare’s technology can offer simple, fast, and efficient solutions for difficult-to-solve solubility problems. Most importantly, our expertise in development of easy-to-swallow and palatable patient-centric formulations with solubility/BA enhancement capabilities can deliver great value creation and differentiation for our clients.”
There is continued interest in finding new and innovative technologies for bringing NCEs to lead formulation optimization and further develop as potential drug candidates. The conventional approaches requiring pH adjustment, salt formation, complexation, and micronization all are well understood and used in many approved drugs with poor solubility. However, the continued trend of high melting drug candidates requiring medium to higher doses to meet the clinical end points means conventional formulations are less applicable. Therefore, non-conventional formulation technologies are highly sought to design better and smarter dosages to improve safety and efficacy of drug molecules.
Those approaches entail using polymeric excipients and solubilizers for preparation of amorphous solid dispersions by hot-melt extrusion, spray drying, co-precipitation, and Kinetisol®. On the other hand, some approaches require using lipid-based excipients for preparation of dispersions such as self-emulsifying drug delivery systems (SEDDS/SNEDDS), and SLN and NLC lipid nanoparticles.
To overcome all these challenges, Ascendia has its patented proprietary solubilization technologies for addressing the solubility and bioavailability of new molecules and complex generics. Those include Nanosol®, LipidSol®, EmulSol®, and AmorSol® for tackling liquid/solid orals, parenteral, and topical formulations. “These technologies are aimed at handling small molecules as well as large molecules like peptides and nucleotides,” says Shaukat Ali, PhD, Senior Director, Scientific Affairs & Technical Marketing, Ascendia Pharma, Inc. “Our manufacturing capabilities in sterile aseptic processing and lyophilization for injectable drug products employing one of the proprietary technologies bear the hallmarks of our state-of-the-art cGMP facility equipped with ISO 5 and ISO 7 cleanrooms.”
He says does point out that approaches for oral tablet versus oral liquid formulations differ considerably in terms of excipient selection, compatibility, storage of drug products, and the technologies used. “The molecules highly susceptible to food effects, having short half-life and first-pass metabolism, are difficult to develop by traditional dosage in oral tablets or liquids,” Dr. Ali says. In those cases, different strategies requiring the chemical modification, functional coating or core matrix selection have been used to delay the release.
Of course, for oral tablets, hot-melt extrusion, spray drying, co-precipitation with acceptable polymers and solubilizers are all widely used, but for liquid orals with poorly soluble molecules, solvent, co-solvents, lipids, and surfactants/solubilizers are often used for achieving the desired solubility and bioavailability. In liquid parenteral or injectable, however, the choice of excipients is different and more stringent from liquid orals. It is, therefore, important to select the parenteral excipients free of bioburden and endotoxins to minimize the safety risk and maintain a product’s critical quality attributes.
“Many drugs are unstable in liquid oral or parenteral dosage, thus, monitoring of their degradation and impurities could be important for long-term stability,” says Dr. Ali. “In such cases, if developing a parenteral drug, use of antioxidants, stabilizers, complexing agents, and freeze drying or lyophilization could be better options to stabilize the drugs in powders for transportation, storage, and shelf life over extended periods. In others, sealed coatings of drugs with polymers or waxes are more relevant to minimize the API degradation, reduce the dose variabilities, and improve the performance of formulations.”
Many compounds currently in development have aqueous solubilities as low as 0.001μg/mL, which is close to the solubility of marble, says Firouz Asgarzadeh, Senior Vice President of Pharmaceuticals at BioDuro-Sundia, a CRDMO that provides integrated discovery, DMPK, and finished dose development.
Micronization and nano-milling are commonly used techniques in the preformulation stage to increase the dissolution rate of APIs that are limited by their particle size (DCS IIb). However, these technologies do not address compounds that are limited by their solubility (DCS IIa). To address solubility issues with DCS IIa compounds, lipid-based formulations and Amorphous Solid Dispersion (ASD) technologies are used. With recent advancements in ASD technologies and equipment, most compounds with poor solubility are now screened for ASD first.
ASD technologies have become the primary approach for addressing solubility and bioavailability issues with poorly soluble APIs. The selection of appropriate polymer and lipid combinations is critical for achieving high rates of success in the miscibility of APIs with these materials.
“Our Solution Engine 2.0 platform calculates solubility parameters for the API and compares them to ASD polymers and lipids to identify appropriate combinations with the highest predicted miscibility,” explains Mr. Asgarzadeh. “This approach is based on the principle that ‘like dissolves like.’ By minimizing the number of screening experiments and required API in the early stages of development – where supplies are scarce – we only require 100 to 200mg of API for ASD screening.”
Often, empirical approaches used in screening studies for technologies to address solubility/bioavailability issues require significantly more time, cost more, and also require substantial amounts of API. BioDuro-Sundia recommends using a systematic approach to select formulation ingredients for poorly soluble APIs. This involves identifying existing miscible pairs through solubility parameters, followed by miniaturized screening and animal PK studies using mice or rats.
“We have successfully used this approach on hundreds of APIs, achieving 10 to 100-fold increases in solubility, which are further supported by animal PK data,” he says. We offer this approach to our clients through the Solution Engine 2.0 platform, which requires only 100 to 200mg of API for ASD screening within 8 to 12 weeks, including two rounds of rodent PK studies.”
Candoo Pharmatech Company Inc.: Rational Formulation Design for Poorly Water-Soluble Drugs
As a technology-driven and customer-centric contract research, development and manufacturing organization (CRDMO) in Canada, Candoo Pharmatech specializes in advanced formulation solutions for small and large molecules and provides platform services to pharmaceutical companies.
Each molecule is unique in terms of its physicochemical and biopharmaceutical properties. Candoo integrates formulation expertise and modeling technique to evaluate the developability of compounds, identify the best-fit formulation technique, and allow clients to make informed decisions about their products. “Identification of the best-fit formulation strategy is critical to the successful development of poorly water-soluble compounds,” says Yongqiang Li, PhD, Co-Founder and CEO of Candoo Pharmatech Company Inc. “Moreover, applying readily deployable drug delivery platform technologies will accelerate IND-enabling and clinical studies.”
Candoo’s approach includes five steps: 1) establish a GastroPlus® PBPK model to incorporate physicochemical and biopharmaceutical properties of lead compound together with physiology of animal species; 2) perform a developability assessment for the compound, evaluate rate-limiting factors for oral absorption, and predict food effect; 3) identify the best-fit formulation approach to maximize drug exposure and develop a bio-relevant dissolution method to check potential in vivo precipitation; 4) predict bioavailability profiles for ascending doses in human; 5) develop a practical formulation and scalable manufacturing process with Candoo drug delivery technologies.
“Candoo’s rational formulation design approach addresses the inherit challenges from compounds, shortens formulation development time, and avoids trial-and-error,” says Dr. Li.
Candoo applied its drug delivery technologies to help a pharma company develop four prototype formulations for a large animal study within one month. This was for a BCS II-neutral compound (low solubility, high permeability) with logP = 5.1 and melting point at 139°C. Its solubility was less than 10μg/ml across physiological pH range. A PBPK model showed that the best-fit formulation strategy depended on the dose to be administered. Micronization of API (D90 =10μm) was adequate for drug absorption if the human dose was less than 120mg, indicating that the dissolution rate was the absorption-limiting factor. In contrast, once the dose went beyond 120mg, amorphous solid dispersion or lipid-based self-emulsifying drug delivery system was needed to enhance bioavailability and reduce food effect. In this scenario, solubility became the major barrier for drug absorption. Dr. Li says that, based upon the insights gained from the PBPK model, Candoo developed four prototype formulations for the animal study and established a biorelevant dissolution method for in vitro drug release comparison. The animal study results enabled the client to rank these four prototype formulations and choose the best-fit formulation for a clinical Phase I study.
The portfolio of small molecules coming out of discovery is expanding in terms of accessing new modes of action and targeting the molecular space for high potency. The focus on potency against a biological target has increased the “beyond the Rule of Five” (bRo5) molecules in the pipeline, and the FDA has approved 22 new oral bRo5 drugs, which account for 21% of new oral drug approvals in recent years.2 These molecules often have poor drug-like properties and particularly low permeability, making it challenging to achieve the desired oral absorption profile. Thus, low oral bioavailability represents one of the main sources of inter-subject variability in drug plasma concentration, says William Wei Lim Chin, PhD, Manager, Global Scientific Affairs, Catalent.
Conventional approaches include particle-size reduction, API salt formation or isolating polymorphs, solid dispersion, and cyclodextrin complexation. There is no single technology that has universal applicability to every API displaying bioavailability issues, so each should be considered individually. The Developability Classification System (DCS) can help determine whether the molecule is dissolution-rate limited or solubility-limited for it to become systematically bioavailable, and provides insights into the appropriate formulation technology approach based on a drug’s classification.
Lipid-based drug delivery systems (LBDDS) offer an alternative method to enhance solubility. Within an LBDDS, an oil solution, self-emulsifying or self-micro emulsifying systems, and co-solvents mixture form part of the formulation with the API. Dr. Chin adds that APIs do not all behave the same way in the gastrointestinal (GI) tract. An API molecule contains different functional groups, which after oral administration, can be ionized or unionized depending on the pH variation along the different parts of the GI tract, in turn affecting drug absorption. For permeation-limited molecules, LBDDS may be beneficial as certain lipid excipients and surfactants can promote permeation of the drug in the GI tract. The digestible lipid excipients in an LBDDS enable the drugs to navigate the GI tract in a natural digestion and lipolysis process.
Dr. Chin recommends specific best practices for formulators dealing with solubility and bioavailability issues. He says to establish whether the bioavailability issue is related to solubility, permeability or both, appropriate modeling tools, both in silico and in vitro, coupled with targeted preformulation and analytical testing, can help determine the issue(s). The correct formulation strategy can then be identified and implemented based on a working understanding of the appropriate critical physicochemical properties.
At Catalent, customers’ issues tend to revolve around the limited amount of available API of a poorly soluble drug. Dr. Chin explains that after a comprehensive developability assessment of the molecule, a formulation approach will be recommended along with essential preformulation characterization, such as small-scale micro-dissolution testing, which works with very small amounts of material. Permeation testing with a Caco-2 cell line may also be recommended to understand transport across the epithelial cells of the gut and any efflux effects, which again requires small amounts of material.
“Together, these data provide powerful leverage into understanding the likely exposure, and support physiologically-based pharmacokinetic modeling to rule out the first-pass effect, and to predict human exposure,” he says. “This assessment recommends a formulation approach with a comprehensive path forward to reach toxicology and pharmacokinetic studies, and ultimately, first-in-human clinical studies.”
Cyclodextrins (CDs) are mostly used in oral and injectable drug delivery for improving solubility or chemical stability of lipophilic drugs, but CDs can solve problems in other routes of administration as well. Ophthalmic drug delivery is one of the most challenging areas for pharmaceutical scientists. The ocular bioavailability via eye drops is very poor, usually lower than 1%, mostly due to the precorneal loss related to drainage, tear turnover, short residence time, and the impermeability of the cornea, explains Dr. Zoltan Fülöp, Senior Formulation Scientist, CycloLab Ltd.
“Furthermore, the administered volume with one drop is somewhere between 25 and 70μl, thus, it is required to maximize the concentration of the drug close to and beyond the physical limits,” he explains.
Currently only a handful of marketed eye drop formulations contain cyclodextrins: hydroxypropyl betadex (HPßCD) is used with indomethacin, levocabastin, and azelastine; hydroxypropyl gamma cyclodextrin (HPßCD) is used with diclofenac and olopatadine; and randomly methylated beta cyclodextrin (RAMEB), is used with chloramphenicol. Other formulations are visible on the horizon, says Dr. Fülöp, such as a reproxalap eye drop with Betadex sulfobutyl ether sodium (SBECD) and a dexamethasone suspension eye drop with Gammadex (GCD). He says: “CDs are utilized as solubilizers in the case of HPßCD, RAMEB, and SBECD, allowing solution eye drop formulations with APIs where only suspension or emulsion formulations were possible before.” He adds that HPGCD is selected due to its compatibility to benzalkonium chloride, and GCD is special due to its ability to form nano- and microparticulate aggregates. CDs also can act as permeation enhancers, providing an elevated drug concentration on the membrane barriers (cornea and conjunctiva). Although CDs cannot cross these barriers (due to toxicity), they can interact a little with the corneal surface, and the complexed drug molecules can permeate into the cornea from the CD cavity. CDs can maximize the permeation of the dissolved drug molecules if the drug concentration on the membranes is close to saturation concentration. The residence time of a CD formulation can be either improved by using viscosity enhancers and gels or CDs can be used in a novel way to form particles that take time to fall apart, as in the case of GCD. Specialized CD-containing formulations can even deliver the drug to the back of the eye, which in the future could replace invasive therapies such as intravitreal injections or implants with a simple eye drop formulation and treat retinal diseases in a patient-friendly manner, says Dr. Fülöp.
“We encourage formulation scientists of pharmaceutical companies to consider CDs in the design of new ophthalmic formulations, as they provide a safe and patient-friendly solution to make new products available of poorly soluble drugs and improve bioavailability up to the point where they can deliver drugs to the back of the eye,” he says. “Based on our experience in early-stage drug product development, we expect to see more SBECD and HPBCD eye drop developments in the future, as these safe excipients have great potential and are already recommended by the EMEA.”
Although there have been many advances in terms of solubility enhancement in the past few years, new molecules are more complex, requiring sophisticated approaches. Amorphous solid dispersions (ASD) technologies are often used to enhance small molecule solubility. But this approach is not always feasible if molecules are sensitive to high temperatures, mechanical stress or are poorly soluble in suitable organic solvents, says Kamlesh Oza, Technical Sales and Formulation & Application Services North America, Evonik.
Developers of recently emerging biopharmaceutical therapies are looking for new technologies to address bioavailability challenges. These biopharmaceuticals are normally more effective when delivered in specific target areas of the gastrointestinal tract, which means they need to be protected from gastric juices. However, many are too sensitive for a regular coating process. “These challenges, among others, need to be addressed on ever more restricted timelines, which is why solubility enhancement remains an exciting challenge,” he says.
One of our Evonik’s solutions for small molecules is based on a new technology that allows scientists to obtain an ASD through a gentler, emulsion-based process. This technology processes an API under low temperatures and low mechanical stress and then engineers the final particles to obtain a uniform, free flowing, highly concentrated ASD powder, which can be tableted or filled into capsules. This particle-engineered ASD can also improve pharmacokinetic performance by precisely controlling particle size and shape, which, consequently, also improves scalability. “This latest innovation addresses some tough solubility problems that cannot be solved with conventional technologies and therefore fulfills an unmet need for our pharma partners,” says Dr. Oza.
Another Evonik advancement efficiently improves bioavailability for biologicals or microbiome therapies, for drugs needing protection from an acidic environment. The technology is a gastric-resistant, empty coated capsule based on extensive enteric coating experience. The robust enteric capsules can be tailored to target a specific gastrointestinal site. “They significantly improve the bioavailability of biologics without exposing them to moisture and heat in a regular coating process, thus allowing a wide range of formulations,” he says. Both solutions described are fully adaptable from early pre-clinical to late commercial stage. Dr. Oza concludes: “We are confident that these innovations will enable the use of new molecules that previously could not be formulated as oral drugs.”
Many new compounds being developed sacrifice solubility for potency, leading to an increased need to take a potentially highly efficacious drug and improve its solubility as well as absorption characteristics, says Andrew Schultz, MS, Sales Manager, Pharmaceutical Division at Gattefossé.
“The biggest advances to aid solubility and bioavailability have come from our ability to develop predictive in silico models and biorelevant in vitro methods, which help reduce development lead times and help give us the best chances for success,” he says. “For instance, the historically used in vitro dissolution testing in aqueous media is inadequate for evaluation of lipid formulations. Dissolution testing in the presence of digestive enzymes (lipolysis test), on the other hand, is a more effective way of anticipating the lipid formulation performance.”
Mr. Schultz says that it is extremely important to determine why a compound is not showing good bioavailability. There could be barriers aside from a lack of aqueous solubility that need to be understood and that could help steer formulation development to overcome these hurdles. These may include poor permeability across the enterocytes or pre-systemic elimination. In such cases, the drug may benefit from formulation with long chain fatty acid esters that are known to avoid hepatic elimination, or the addition of short chain fatty acid esters that enhance permeation by transient opening of tight junctions, he says. An equally important consideration is the commonly encountered food effect, requiring lipid-based or other systems to overcome this effect.
“We run into this all the time with clients who have poorly soluble actives and found little success with the commonly available techniques such as amorphous spray dried dispersions, co-crystals, micronization, and pure solvent use to solubilize NCEs,” says Mr. Schultz. “The key is to choose a platform that meets the specific challenges of the drug, not to attempt to force a drug’s characteristics into a technology. In our experience, using lipids in a systematic formulation approach is one of the best ways to improve bioavailability and can help streamline the formulation effort. When the enabling platform matches the true needs of the API, success rates are higher. And, if selected correctly, a single formula may be used for early-stage pK development through commercialization.”
Ligand Pharmaceuticals has seen a steady stream of inquiries for how Captisol® (sulfobutyl ether beta cyclodextrin) can help with solubility/bioavailability and stability of active pharmaceutical ingredients. There are currently at least 60 products in development pipelines around the world using Captisol for formulation enhancement.
“Another indication that APIs continue to need assistance in solubility improvement is the increased demand for Captisol and the number of product approvals containing Captisol expected in 2023-2024,” says Vince Antle, PhD, Senior Vice President of Technical Operations & Quality Assurance at Ligand. “Upcoming product approvals open the door to the use of Captisol in new routes of administration, namely oral, ocular, and subcutaneous. In addition, one of the anticipated product approvals is targeted for a pediatric demographic.”
J.D. Pipkin, PhD, Vice President of New Product Development at Ligand, says that formulators know that best practices for dosage form development of poorly water-soluble compounds depend largely on the physical/chemical characteristics of the API, route of administration, indication, and whether the drug will be given on an acute or chronic regimen. “Keeping the formulation as simple as possible is usually the best strategy from both a product and regulatory standpoint,” says Lian Rajewski, PhD, Senior Research Investigator at Ligand. “Typically, the fastest way to move through the development process, is to use safe, well-established, globally accepted excipients. Captisol is a solubility-enhancing excipient (derivatized cyclodextrin).”
Nano PharmaSolutions, Inc.: Single Nanoformulation for All Phases with No Chemical Additives
Poor solubility remains one of the greatest challenges in pharmaceutical development. More than 70% of new chemical entity (NCE) candidates have poor solubility and thereby bioavailability, resulting in the leading cause for the failure of Phase 1 First-in-Human (FIH) trials. While the number of methods for enhancing drug solubility continues to increase, trade-offs in cost, development time, and formulation bridging animal and PK studies prove finding an optimal solution elusive.
Chemical modification to create salt forms or co-crystallization requires excipients to enhance solubility, which offer little to no therapeutic benefit; and even pose health hazards at certain levels. Solid dispersion by spray drying or hot-melt extrusion requires lengthy polymer excipient screening steps and has its limitations. Nanoformulation offers an attractive alternative to enhance solubility and bioavailability, says Kay Olmstead, PhD, MBA, CEO, Nano PharmaSolutions. However, nanoformulation is not widely utilized in early drug development of solid oral formulation due to fears of long development time and poor flow characteristics of submicron size drug particles.
NanoTransformer™ is a scalable nanosizing technology that generates drug nanoparticles in the 200-600nm (D50) range. This process uses gentle heat and reduced pressure to evaporate solid API to gas phase, which then gets deposited on commonly used hydrophilic granulation excipient (e.g., mannitol, starch or microcrystalline cellulose) as nano-granules with drug nanoparticles deposited on the drug excipients. Drug loading through this process can be as high as 25-30% in some examples. These nano-granules may be used for animal safety studies as aqueous suspension, for FIH clinical trials as powder-in-capsule or powder-in-bottle, and as compressed tablets for later stage clinical trials, all without changing the base formulation, explains Dr. Olmstead. Using the same nano-granulation as the intermediate of oral dosage form in FIH and Phase II/III clinical trials removes the need for a bridging PK study required by the regulatory agencies for enhanced formulation development after completing a FIH trial. Solvent-free nanoformulation for animal safety studies will lessen the risk of FIH clinical challenges due to formulation changes between the phases.
The NanoTransformer granulator is a retrofitted industrial vacuum nano-coater, which is commonly used in semi-conductor and aerospace industries, enabling the production of drugs under cGMP conditions. “The development time for nanoformulation is rapid and requires very little API, which suits preclinical studies well. Vacuum coaters can generate hundreds of kilograms of nanoparticles, therefore scaling up to production-sized batches is achievable,” she says. GMP manufacturing of clinical supplies for nano-granulation will be available starting late 2023.
She adds that NanoTransformer™ vacuum-generated nano-granules prove to be chemically and physically stable and easy to handle. Surface-area-to-volume can be up to a 1,000-fold increase, thereby improving dissolution according to the Noyes-Whitney equation. The in vitro dissolution itself can see an increase of 4-5x, leading to an increase of up to 500% or more bioavailability for many APIs. In tandem with higher solubility and bioavailability, nano-granulation also enables API to be further formulated into various dosage forms, including liquid or solid oral, ocular, intranasal, dry powder inhaler and injectable, allowing for optimal delivery for various therapeutic applications.
Bioavailability is an important factor to consider when evaluating the efficacy of drug products. The global biopharmaceutical industry is witnessing a rapid increase in difficult-to-develop drugs with low solubility and/or permeability. As this trend persists, there will be a surge in need for technologies that facilitate bioavailability enhancement. Innovation is key in developing better technologies and methods; current approaches may not be adequate to meet the ever-increasing complexity of pharmacological interventions and novel drug classes. These technologies are broadly classified into three main categories: physical, chemical, and biological. Each of these methodologies has its advantages and limitations. But, regardless of the approach taken, technologies must be advanced to ensure that drugs can reach their target sites efficiently. Developing a formulation plan should first include an understanding of the physicochemical properties of the drug, the required dosage form and selection of appropriate excipients/technologies to evaluate in a step by step approach, while keeping in mind the pharmacological properties that may be a factor once dosed.
“Without solubility and bioavailability, desired drug concentrations cannot be attained, leading to failure of drug efficacy,” says Sundeep Sethia, PhD, Head of R&D at Pii.
Knowing this risk, many pharmaceutical companies now prioritize bioavailability enhancement when developing their product candidates, thus allowing for optimal quantities of bioactive compounds at the target site of action. “The influx of the new active molecules that are primarily insoluble in an aqueous environment, and the introduction of relatively few new pharmaceutical excipients providing solubilizing potential, has kept solubility/ bioavailability a major challenge in drug formulation,” he says.
He adds that bioavailability and systemic/local absorption and distribution of therapeutic interventions are intertwined, as bioavailability affects the degree to which drug concentration can be maintained in the body. Technologies available today for improving solubility include particle size engineering via dry powder micronization or nanosuspension; crystal structure disruption to provide solid dispersions using various technologies such as melt agglomeration, drug layering onto pellets, and spray drying; use of functional excipients like cyclodextrins to form inclusion complexes with the drug or surfactants/co-surfactants to form SEDDS, SMEDDS or SNEDDS in vivo. All of these have potential for providing higher bioavailability.
The mode of administration is also an important factor that can influence drug bioavailability or the percentage of the drug entering systemic circulation in humans. Intravenous injection offers the highest level of bioavailability with 100% availability of the introduced drug, while other available routes provide lower rates. “Studies have found that physical form also plays a role in the absorption rate of drugs; those released in gas form will be absorbed more quickly than liquids that are more quickly absorbed than solids,” says Dr. Sethia. “Thus, it is essential to consider mode and form when choosing a medication route for effective uptake by the body.”
Pii’s clients bring various compounds to the CDMO that exhibit several reasons for lacking solubility and/or bioavailability. In one case, Pii was a tasked to improve the solubility and bioavailability of a hydrophobic compound. To address these concerns, various approaches were utilized. Solubility and complexation studies were performed to optimize the formulation to increase the solubility. Using the Inclusion Complex formulation approach, a select cyclodextrin provided promising solubility and physical stability, explains Dr. Sethia. Also, a SEDDS approach combination of oil and polymers that included surfactant/co-surfactant and emulsifier was proposed. “Stable formulations using both approaches provided greater than ten-fold increase in drug solubility,” he says. “A bioavailability study comparing the suspension lipidic vehicle in a soft gel dosage form versus neat API resulted in an increase by 100-fold in bioavailability.”
The pharmaceutical industry has a healthy pipeline of promising new chemical entities (NCEs), however development is still constrained by solubility and bioavailability challenges that increase formulation complexity, raise failure rates, and drive-up development costs. This remains a prevalent issue because molecules are progressing too quickly into downstream product development without being properly assessed and understood in the preclinical and candidate selection stages, contends Dr. Dolly Jacob, Director of Integrated Development Services, Quotient Sciences. “Drug developers utilizing the traditional formulation development model aren’t assessing a molecule’s developability before pressing ahead into development or using key biopharmaceutics tools that can greatly aid in ensuring a molecule’s success, thus creating an industry need for a new and innovative way to develop drugs more efficiently.”
For smooth transition of an NCE from candidate selection into First-in-Human (FIH) and onward into Proof-of-Concept (POC) and beyond, Quotient Sciences employs an integrated approach, combining a robust biopharmaceutics, physiochemical, and DMPK package, with appropriate in silico and in vitro modelling tools to aid formulation design and clinical flexibility. “This novel approach, known as Translational Pharmaceutics®, allows us to respond to emerging in vivo clinical performance data that aids in critical formulation decision making and improves the likelihood of both downstream clinical and commercial success,” says Dr. Jacob. “This approach enables formulations to be designed, manufactured, and clinically evaluated under a single organization. Data from the early stages of the clinical evaluation can be fed back into the process, allowing formulations to be adjusted, manufactured, and passed straight into the clinic again. This unique approach means that formulation issues can be detected, corrected, and clinically validated more quickly.”
Some strategies used for clinical predictions include Biopharmaceutics Classification System (BCS) and Developability Classification System (DCS) assessments, biorelevant characterization, precipitation experiments, solid-state characterization, and in silico predictions. “These strategies, in combination with integrated processes and development models, simplify the outsourcing paradigm, enabling reduced timelines, risks, and costs for our customers,” she says.
By understanding the drivers of poor solubility and permeability of a drug, formulation efforts can be focused on the correct development techniques to provide meaningful improvements in in vivo performance. For example, Quotient Sciences utilized its integrated platform, Translational Pharmaceutics, to rapidly identify and overcome solubility and bioavailability challenges for one of its clients. The customer had a BCS II molecule with preclinical data, suggesting that solubility may limit exposure. “Utilizing our integrated platform, we designed a three-part single ascending dose (SAD) and multiple ascending dose (MAD) study for a program that provided formulation flexibility and quickly identified a drug product format that was suitable for Phase II (POC),” explains Dr. Jacob. “Using a unique formulation design space, in addition to the FIH primary objectives of safety and tolerability, we employed exquisite precision in dose escalation, screening multiple formulations and dosage form bridging at a particular SAD dose stage based on real-time emerging data.”
Quotient Sciences developed five formulations: a micronized tablet, a lipid formulation, two spray-dried dispersion intermediates, and a tablet formulation using the spray-dried dispersion. In this three-part study, it was possible to integrate the assessment of solubilization technologies all within a single clinical protocol to enable identification of a drug product suitable for Phase II POC, removing the need to conduct larger scale, cost-prohibitive process development and lengthy stability programs for multiple technologies, she explains.
“Our Translational Pharmaceutics platform allowed us to identify a spray-dried tablet formulation to take into the next phase,” continues Dr. Jacob. “The time taken from development program start to final pK delivery was 18 months, which would typically take an average 46 months using a traditional formulation development model. By employing an integrated approach for this program, we were able to reduce the time and cost of early drug development for our customer, while maximizing the probability of success in getting their molecule to patients faster.”
Roquette: Exploring the Feasibility of a Solubility Enhancer in Lorazepam Formulations
As a provider of excipients, including cyclodextrin, Roquette understands that the solubility of drug formulations – both oral dosage and injectable – can be improved via the application of novel excipients. Cyclodextrins, in particular, are showing significant promise as solubility enhancers in oral as well as parenteral delivery formats, where they have been demonstrated to improve the solubility and bioavailability of small-molecule formulations, in addition to enhancing chemical and physical stability.3 Importantly, they are already approved for oral and parenteral delivery – and thus suitable for vaccine development and oral solids, says Olaf Häusler, Global Technical Application Scientist, Roquette.
“In both delivery systems, the desired outcome is better solubility and higher absorption,” he says. “Cyclodextrin excipients can support both these effects. The hydrophobic interior of the molecule forms a complex with the insoluble drug compound, encapsulating it, while the hydrophilic exterior forms hydrogen bonds with aqueous solvents, forming a solution. This helps to increase the absorption of oral and parenteral formulations containing a hydrophobic compound.”
Roquette’s hydroxypropyl beta-cyclodextrin (HPßCD) solution – KLEPTOSE® – has demonstrated benefits as a solubility enhancer in lorazepam formulations – a BCS Class II drug commercially available as a solid and liquid dosage form. Traditionally, the drug’s parenteral formulations are administered as a solution in polyols, Mr. Häusler explains. However, this can create serious patient compliance issues.
“We explored the feasibility of a parenteral alternative using lorazepam solubilized by cyclodextrin4,” he says. “Our investigation found that HPßCD significantly enhanced the solubility and stability properties of lorazepam, making it a viable manufacturing formulation that addresses patient compliance by eliminating the side effects observed with organic solvents.”
As novel drug delivery tools and technologies keep expanding the boundaries of oral product development beyond the Rule of Five, compounds are increasingly prone to solubility issues, says Sami Svanbäck, PhD, CEO, The Solubility Company.
“Over the past two decades, addressing poor bioavailability has become an interdisciplinary task between stakeholders in drug candidate selection, lead optimization, and drug product development,” says Dr. Svanbäck. “The increase in the number of approved new drug products with molecular properties beyond the Rule of Five is explained by incremental and concurrent advances in analytical technologies, molecular biology, target diversity, drug design, medicinal chemistry, predictive modeling, DMPK, drug metabolism and pharmacokinetics, and drug delivery.”
He adds that lipid-based formulations, in particular amorphous solid dispersions, are leading the trend in novel oral drug delivery technologies reaching the market, with approvals of novel and advanced excipients tailored to specific applications facilitating this trend. The starting point for all development is, however, a broad and deep understanding of the molecular properties such as solubility in conditions relevant to the druggability and developability of the NCE. Novel analytical tools working on the small sample amounts available in discovery and early development phases are driving the advancement in early informed decision making.
The Solubility Company’s proprietary Single Particle Analysis (SPA®) technology, based on machine vision and AI, produces solubility data from microscopic amounts of substance. Services include measurement in aqueous media, biorelevant media, formulation vehicles, lipids, and organic solvents.
- The bioavailability enhancement services market is projected to grow at an annualized rate of 11.12% during the period 2021-2034, claims Roots Analysis, Yahoo!Finance, Feb. 8, 2023.
- DeGoey, Philip B. Cox, Drug Discovery Beyond the Rule of Five Methods in Drug Discovery and Discovering Lead Molecules David A., Burger’s Medicinal Chemistry and Drug Discovery, New 8th Edition, April 2021.
- Cyclodextrins used as excipients (EMA/CHMP/495747/2013). European Medicines Agency, 2017.
- Roquette. Lorazepam Complexation with Hydroxypropyl ß-cyclodextrin (HPßCD) and Sulfobutylether ß-cyclodextrin (SBEßCD): Phase Solubility Parameters Evaluation. Presented at the 27th American Association of Pharmaceutical Scientists annual meeting, 2012, Chicago, IL, USA.
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