SPECIAL FEATURE – Improving Bioavailability & Solubility: Each Molecule Is Unique

The virtual 2020 Global Drug Bioavailability Enhancement Summit this past December showcased novel technologies and platforms aimed at addressing bioavailability and solubility challenges. These included techniques like elec­trospinning, mesoporous silica technology, physiochemical optimization, amorphous nanoparticle engineering, and pharmacokinetic modeling. And the end goal is the same: Save time and money while accelerating formulation devel­opment.

“The driver for novel strategies to resolve solubility issues, with a target of improving bioavailability, often stems from a requirement to get more information about the key relationships using less API, in a reduced time frame,” says Andrew Parker, PhD, Director Open Innovation, Small Molecules, Oral and Speciality Drug Delivery, Catalent. “This has led to the implementation of ‘miniaturized’ approaches such as small scale micro-dissolution testing, working with very small amounts of material and establishing accelerated stability predictive modeling that can shave months off a development time­line.”

This annual Drug Development & Delivery report introduces readers to some novel approaches to improving bioavailability and solubility that have one commonality: they treat each molecule as unique.

Adare Pharma Solutions: Proprietary Solutions Enhance Bioavailability

While most of the bioavailability-enhancing technologies are directed toward achieving immediate-release after oral administration, Adare has devoted significant efforts in going be­yond immediate release.

“We realized early on that the magnitude of pH dependency of sol­ubility could be as high as several log orders,” says Jin-Wang Lai, PhD, sen­ior director in R&D, Adare Pharma So­lutions. “Such dramatic change in solubility poses great challenges in the design of an extended-release dosage form using Adare’s Diffucap^®-coated pellet technology.”

Where drug solubility is inade­quate to generate the necessary driv­ing force for drug release, it creates a typical ‘no release, no bioavailability’ situation, explains Dr. Lai. One ap­proach to overcome such a pH-dependent solubility issue in the case of an alkaline drug is to use an organic acid as the drug core or an acid layer prior to using it as the substrate for the drug layer, which is then followed by a rate-controlling membrane. “As water permeates into the organic acid element creating a solution of organic acid, the alkaline drug is dissolved due to the acidity generated by the dissolved acid as it moves through the drug layer and out of the coated pel­lets.” This microenvironment pH approach was granted a US patent.

A second approach to overcome solubility/bioavailability is to enhance solubility by adapting solid dispersion/solid solution technology to the Diffucap concept. For the coated pellet technology, the drug layer typically is sprayed as a solution or a suspension onto the pellet cores. The amount of polymer binder used is usually low rel­ative to that of the active pharmaceu­tical ingredient (API), in about 1/10 weight ratio. The polymer selected serves only as a vehicle for the API to be attached onto the pellet core. When enhanced solubility is neces­sary, the binder polymer is strategically selected based on its ability to form a solid dispersion/solid solution with the drug, usually through a sol­vent system.

“Adare leveraged its solvent-han­dling capability, which is a natural ex­tension of Adare’s Microcap^® technology, using cyclohexane to overcome the solubility challenge through the well-established solid dis­persion/solid solution approach,” says Dr. Lai. A US patent was recently granted for this approach.

Another related technology devel­oped by Adare for the purposes of bioavailability enhancement is “Biorise^®.” The Biorise technology is uniquely characterized as a material state between a solid dispersion/solid solution and nanocrystals. Biorise can be achieved through a media-grind­ing process or a solvent process, and can achieve immediate release.

In addition to Diffucap, Microcap, and Biorise, Adare is equipped with a spray dryer, a hot-melt extruder, and a lipid-based melt congealing tech­nology called Optimμm^®. He says these technologies are designed to be used together for greater flexibility in designing release profiles for cus­tomers.

Adare also announced the launch of a small non-GMP laboratory for the exploration of various technologies that may be suitable for solubility/ bioavailability enhancement. “The new laboratory space brings customizable, flexible systems that will expedite formulation and process development services,” he says.

Ascendia Pharmaceuticals: Tech Platforms for Tough-to-Formulate Compounds

The number-one impediment fac­tor to improve bioavailability and sol­ubility is the intrinsic properties of the compounds, particularly for com­pounds with low permeability through the GI membrane, i.e. BCS IV compounds. “We may improve the solubil­ity of these compounds, however, due to intrinsic low permeability of those compounds to penetrate the intestine membrane before being absorbed into the body, challenges remain to improve the oral bioavailability of those compounds,” says Jim Huang, PhD, CEO, Ascendia Pharmaceuticals.

Dr. Huang says Ascendia achieves systemic absorption of For BCS IV compounds in several ways: to utilize permeation-enhancers, including lipid, surfactant, and other GRAS ex­cipients using its technology platforms to open tight junction or enhance ab­sorption through GI membrane or lymphatic routes after oral administra­tion; to explore intranasal route of ad­ministration to overcome the GI barrier and potentially to overcome the blood brain barrier or GI mem­brane barrier; and to develop in­jectable or topical dosage forms that can achieve high drug loading and achieve high systemic bioavailability.

Ascendia routinely utilizes its platform technologies, NanoSol (nanosuspension), AmorSol (amor­phous nanoparticles), and EmuSol (nanoemulsion) to solve over 90% of difficult-to-formulate compounds by enhancing bioavailability and solubil­ity of compounds for different routes of administration.

As an example, Ascendia recently received a request to formulate a compound just out of the discovery labs with no preformulation or animal PK data, with a time window of three months and limited API supply. Dr. Huang explains that Ascendia was able to perform essential preformula­tion studies to understand the compound’s properties related to solubility and in vitro performance; utilize As­cendia’s Technology Trio (EmulSol, NanoSol, and AmorSol) to screen the prototype formulations within the three-month window; and obtain a multiple-fold increase in oral exposure in animal models, utilizing multiple formulation principles that enabled a smooth and rapid transition of the project in the IND-enabling Tox study.

BASF Pharma Solutions: New Module Estimates Oral Bioavailability Based on Computed Molecular Properties

The number-one requirement for improving bioavailability and solubility of a drug is understanding the physiochemical properties of drugs in re­lation to human physiology, says Nitin Swarnakar, PhD, Global Technical Marketing, BASF Pharma Solutions. Drugs categorized as poorly soluble (mainly BCS class II) can show either dissolution rate-limited or solubility-limited absorption, and the final for­mulation considerations and requirements are different, depending on the driving reason for the drug not fully dissolving in GI conditions. Drugs classified as BCS class III and IV ex­hibit permeability-limited absorption, where there is poor absorption due to Pgp efflux, drug first-pass metabolism, the API’s physiochemical properties, and other factors. Here, the final for­mulation strategy must assist in ad­dressing the low permeability.

“Therefore, before a successful and robust formulation can be devel­oped, a mechanistic understanding of the reason for poor bioabsorption is critical to overcome the solubility and bioavailability problem,” says Dr. Swarnakar. “In order to select the right strategy to improve drug delivery, it is first paramount to know the cause for poor solubility of an API. Once you identify the cause, you can best iden­tify your formulation’s dosing, delivery route, dosage form, and processing requirements.”

To help formulators understand their APIs and facilitate the right strat­egy approach, BASF Pharma Solutions recently launched the Developability Classification of Active Ingredients module in its virtual pharma assistant ZoomLabTM platform. This module gives formulators the ability to simply enter a few physical properties about their API, and, in return, the module gives recommendations on develop­ing a formulation for the API, includ­ing additional formulation work or dosing adjustments that might be re­quired to achieve the desired solubility and bioavailability. By combining user-entered information on solubility, permeability, and dose, the module estimates the oral bioavailability based on computed molecular prop­erties and provides formulation op­tions according to the assigned DCS. These recommendations can cover an adjustment on particle size, maximum dose, and more. “In this way, a signif­icant amount of pre-formulation work can be overcome via time- and money-saving digital formulation rec­ommendations,” says Lindsay John­son, PhD, Global Technical Marketing, BASF Pharma Solutions.

In addition to BASF’s virtual pharma assistant like ZoomLab, the technical team supports a wide range of formulation technologies. “Many pharmaceutical companies have col­laborated with BASF to improve drug solubility using functional inactive ex­cipients such as Kolliphor^® ELP, Kol­liphor^® RH 40, Kolliphor^® HS 15, Soluplus^®, and Kollidon^® VA 64,” says Dr. Johnson. “Our experts are trained to help improve efficacy, safety, and patient compliance through a range of technologies, including hot-melt ex­trusion, lipid-based drug delivery for­mulation, spray drying, nanomilling, and drug layering. These technologies can provide drug product develop­ment strategies to innovator compa­nies, and new regulatory application pathways for generic companies, to overcome the solubility and bioavail­ability challenges of the starting API.”

Candoo Pharmatech Company Inc.: Accelerating Molecules to Medicines

Poorly water-soluble drugs often demonstrate inadequate and/or in­consistent in vivo exposure in nonclin­ical and clinical studies, leading to suboptimal therapeutic performance together with significant food effect. Many promising compounds can be terminated prematurely if their bioavailability results are not inter­preted properly from formulation and biopharmaceutics perspectives.

As a technology-driven contract research organization (CRO) in Canada providing formulation and drug delivery solutions to small and large molecules, Candoo Pharmatech Company Inc. believes the number-one impediment to improving bioavailability and solubility of drug candidates is lack of a clear-cut for­mulation strategy. Each molecule is unique. To accelerate molecules to medicines, Candoo applies a risk-based formulation strategy success­fully to the development of many new chemical entities in nonclinical and clinical stages. This involves three steps: measure and understand the physicochemical and stability profiles, biopharmaceutical properties, and target doses of lead compound; eval­uate and identify the risks for ade­quate oral absorption, figuring out the absorption-limiting factors; and de­sign a compound-specific formulation and manufacturing process to get suf­ficient bioavailability with a control strategy in place.

“Candoo’s risk-based formulation strategy aligns nonclinical and clinical formulations, maximizes bioavailabil­ity right the first time, and expedites first-in-human (FIH) studies,” says Yongqiang Li, PhD, Chief Executive Officer, Candoo.

For a lead compound, having a thorough understanding of three bio­pharmaceutical properties – perme­ability, biorelevant solubility, and target dose – and their interplay, is es­sential to this strategy, he says. If oral absorption is dissolution-limited, mi­cronization or nanosizing of the active compound can achieve optimal therapeutic effect. Otherwise, if oral ab­sorption is solubility limited, enabling and solubilization formulations such as amorphous solid dispersions are necessary to enhance solubility and bioavailability of the compound.

As an example of this strategy, a client wanted to develop a tablet for­mulation using compound CD-8. However, incomplete, variable, and contradicting bioavailability results were reported in the nonclinical studies. CD-8 is a crystalline neutral com­pound with a relatively high permeability in Caco-2 cells (Papp= 1.2 x 10-4 cm/sec) but low solubility (98 μg/mL) in fasted state simulated intestinal fluid (FaSSIF, pH6.5) and high solubility (790 μg/mL) in fed state simulated intestinal fluid (FeSSIF, pH5.0).

Candoo evaluated the factors af­fecting oral absorption of CD-8, re­viewed previous formulations and animal studies, and discovered that target dose, right formulation, and control strategy were critical to ad­dress the observed bioavailability and variability issues, explains Dr. Li. Initial doses were below 50mg/tablet. Can­doo micronized the compound (D90<10μm) and formulated the tablets with good dispersing and wet­ting agents. Control strategy on parti­cle size of CD-8, formulation, and process were developed to ensure re­producible in vivo absorption. Linear and satisfactory absorption profiles were obtained. However, the mi­cronization approach failed when the dose was increased to 100mg/tablet.

Consequently, Candoo developed the HPMCAS-based amorphous solid dispersion formulation and achieved adequate bioavailability for the com­pound. “This demonstrates that Can­doo’s risk-based formulation strategy can ensure sufficient absorption and margins for promising compounds, enable nonclinical studies to be applicable to clinical development, and ac­celerate the transformation of more novel molecules into medicines,” says Dr. Li

Catalent: Identify the Relationship Between Physicochemical & Biopharmaceutical Properties

“It is difficult to completely decon­volute the solubility challenge from the bioavailability challenge as both have mutual and complex interdependen­cies with other factors such as mole­cule permeability, kinetic solubility constraints, pH variation along the gastrointestinal tract, food effects, and first-pass metabolism,” explains An­drew Parker, PhD, Director Open In­novation, Small Molecules, Oral and Speciality Drug Delivery, Catalent. “Generally, the main challenge for any new molecule is understanding the dictating relationships that will dominate final exposure in humans.”

During the course of pre-clinical and early clinical evaluation of a new chemical entity (NCE), the inter-rela­tionships of physicochemical and bio­pharmaceutical properties of the NCE and their impact and dependencies on final bioavailability should be con­sidered, he continues. This is often complex for a NCE, but addressing modeling (both in silico and in vitro); coupled with targeted characterization and analytical testing means that re­lationships can be better understood, and the correct formulation strategy can be identified and implemented based on a working understanding of the critical relationships at play.

Physiologically-based pharmaco­kinetic (PBPK) modeling of early ani­mal data is pivotal to help understand the overall picture and how difficult the challenge is. Factors such as whether a bioavailability enhance­ment approach is required to improve solubility, what the starting dose should be for first time in-human administration, and what initial formula­tion strategy to use should be considered. “Regarding the latter, con­siderations can include overcoming is­sues such as adverse pH-dependent solubility profiles or better processing of the NCE material to make it more amenable for dosing, such as size re­duction or co-processing with other excipients to prevent aggregation, which is associated with a lack of po­tential exposure,” says Dr. Parker. “From this and the initial clinical test­ing, the relationships can start to be further resolved.”

The most common customer sce­narios that Catalent has observed are requests for creating a development strategy for preclinical toxicology and first-in-human studies for poorly solu­ble drugs, says William Wei Lim Chin, PhD, Manager, Global Scientific Af­fairs, Catalent. Usually, the major challenges revolve around limited budget and limited amounts of API.

“We would typically perform a de­velopability assessment to find out where the compound lies in the devel­opability classification system (DCS) and estimate its solubility-limited ab­sorbable dose (SLAD),” Dr. Chin ex­plains. “If the intended dose is above the SLAD, it suggests that the limited intrinsic solubility of the drug is the limiting factor for absorption, there­fore bioavailability enhancement through formulation would be consid­ered.”

The suitability of each type of for­mulation approach would then be as­sessed, coupled with PBPK modeling based on in vitro and in silico data to rule out first-pass effect and predict human exposure. The result of this as­sessment is a recommendation of a path forward to reach toxicology and pharmacokinetic studies, and ulti­mately, first-in-human clinical studies.

“This recommendation is unique to different drugs, which means the bioavailability-enhancing formulation options depend on biopharmaceutical properties, stability, and processability of the drug,” says Dr. Chin.

Cyclolab Ltd.: Replacing Outdated Inactives with Cyclodextrins in Parenteral Formulations

A major challenge for drug devel­opers is coping with the lipophilicity of active pharmaceutical ingredients. Among the various strategies of for­mulating drug substances in a patient-friendly way (i.e. developing solvent- and surfactant-free compositions), in­troduction of colloidal carriers (typi­cally 30-200nm), such as liposomes, may be a feasible option. However, in­travenous use of such nanostructures is often associated with the potential risk of anaphylaxis.

On the contrary, cyclodextrins (CDs) falling in the size range of the smallest colloids (1nm in diameter) do not typically possess this drawback, explains Dr. Istvan Puskas, Research Chemist, Cyclolab Ltd. CDs may form complex with hydrophilic domains of hard-to-formulate drug molecules. By covering the lipophilic domains of the guest molecules, a non-covalent and reversible physical binding occurs, re­sulting in enhanced water solubility. In practice, water-insoluble drug mole­cules were already successfully incor­porated into hydrophilic CD complexes in various marketed com­positions, enabling the injection of the required dosage quantity in aqueous vehicle without cosolvent.

Hydroxypropyl betadex (HPBCD) and Betadex sulfobutyl ether sodium (SBECD) are types of cyclodextrins that offer the most versatile administration routes. The success of CD complexa­tion strategy may be exemplified by the formulation of different lipophilic drugs with the help of these two CD types. Voriconazole is marketed in var­ious products wherein the solubiliza­tion is achieved in lyophilized amorphous matrices consisting of ei­ther SBECD or HPBCD. Mostly innova­tive drugs and those of weak base character (remdesivir, ziprasidone, amiodarone, aripiprazole and de­lafloxacine) are formulated with SBECD, says Dr. Puskas.

Both types of cyclodextrins are also applied to replace some outdated, toxic, irritative inactive in­gredients. “For example, SBECD-con­taining busulfan formulation does not contain toxic excipient N,N-dimethy­lacetamide and allergizing polyethyl­ene glycol, which are both present in the traditional marketed product,” he says. “SBECD can replace irritating polysorbate 80 in docetaxel prepara­tions. Cyclodextrins may prevent the formation of toxic degradation products compared to classical solubilizing agents, ensuring a higher patient safety profile. Melphalan in SBECD complex shows superior chemical sta­bility over its traditional propylene gly­col-based formulation, and similarly due to the presence of SBECD, fos­phenytoin owns significantly longer shelf life as well.”

Reduction of threats related to therapeutic intervention will remain the utmost focus of developers in the pharmaceutical industry, which re­quires the use of the best tolerable auxiliary materials, says Dr. Puskas. “Selection of cyclodextrins for such a purpose pays off in enhanced safety profile without compromise in solubi­lizing functionality.”

Evonik: Toolbox for Delivering New Modalities

COVID-19 has taught us how fast the world can completely change, and that technological progress is more important than ever before. The same is true for drug discovery. “We need a continuously expanding toolbox that can better address new modalities,” says Dr. Jessica Mueller-Albers, Strate­gic Marketing Director for Oral Drug Delivery Solutions at Evonik.

Small molecules continue to be­come more complex and show re­duced solubility. Increasing demand for mRNA therapeutics, antibody drug conjugates, gene therapies, and other specialized or personalized drug products also requires more sophisti­cated formulation strategies.

She says: “This huge variability in new modalities makes a one-size-fits-all approach to improve bioavailabil­ity and solubility impossible. So, a key market goal must be to create or en­hance transport mechanisms to pre­cise locations in the human intestinal tract or other sites for more efficient and effective delivery.”

Some of the challenges resulting from this paradigm shift are the high molecular weight, the presence of nu­merous hydrogen bond donors and acceptors, and multiple negative charges that can complicate the ability to access the intracellular site of ac­tion, she explains. For example, oligonucleotides have a short half-life and are quickly eliminated. However, physiological functions are not only a barrier to effective delivery but also an opportunity for enhanced nanoparti­cle design. Advanced liposomes, self-nanoemulsifying drug delivery systems, and nanoparticles enabled with targeted delivery in the gastroin­testinal tract are promising emerging technologies with some first-proven success in the market.

Technological progress is also a key element in product development to expedite the formulation of new modalities. Pharmaceutical compa­nies are looking for partnerships dur­ing the early phase of development to get access to the newest and most in­novative solutions and technologies that can optimize targeting and deliv­ery outcomes for their API. “One ex­ample of these new technologies is EUDRATEC^® Fasteric, a formulation technology for enteric protection fol­lowed by rapid release in the proximal region of the small intestine, the duo­denum,” says Dr. Mueller-Albers. “Some drugs, such as cancer drugs or immune-suppressants, must minimize exposure to P-glycoprotein transporter, which increase towards the distal re­gion of the intestine.”

Mesoporous particles are also a promising vehicle for controlled re­lease and targeted delivery due to their unique mesoporous structure that enables stabilization and functionaliz­ing. This remains a highly effective ap­proach for solubility enhancement and drug targeting, she says.

Hovione: Emerging Platforms Address Extreme Compounds

The industry has a wide toolbox to address bioavailability and solubility issues. Promising technologies may require more time and studies, but provide the opportunity to deliver compounds that would be considered unviable in the recent past.

Multiple platforms have emerged in pharmaceutical development to ad­dress bioavailability and solubility challenges. Amorphous solid disper­sions by spray drying have become an industry standard, says João Hen­riques, Scientist, Group Leader, Hov­ione, R&D Drug Product Development. “This growth is generating a wealth of data that not only provides confidence in the platform, but also creates the foundation for empirical-driven for­mulation approaches,” he says. “The use of prior data allows correlating molecular descriptors of low solubility molecules with formulations that have been successfully developed as solid dispersions. The correlations aid in preliminary prototype definition and evaluating of the likelihood of success of such a formulation approach.”

In addition to statistical methods, the use of first-principle models that incorporate thermodynamics of mix­ing, diffusion, and kinetics of solvent evaporation provide valuable infor­mation for in silico screening and ex­cluding non-viable formulations. “Both strategies have their advantages and disadvantages and can be used complementary to each other as a valuable tool for formulators to define the best prototypes to screen and re­duce development time and material consumption while delivering opti­mized formulations that provide the required performance, are stable, and commercially viable,” he explains.

While the formulation of most DCS2b compounds is presently a well-known and understood challenge, there remains a wide space for solu­tions to address some extreme com­pounds that either require significant amounts of stabilizers to maintain the amorphous form or that are not amenable to spray drying with reasonable cost of goods due to low sol­ubility in organic solvents, he states. Alternative production methods of solid dispersions, such as co-precipi­tation, can address the low organic solubility issue. “Emerging platforms, such as impregnation with meso­porous silica, present an opportunity for molecules that cannot be stabilized in the amorphous form with common stabilizers at reasonable ratios,” says Mr. Henriques. “API-loaded silica has been shown to improve amorphous stability of compounds with a high tendency to recrystallize. Additional studies and clinical programs may help establish this technique as a stan­dard alongside lipid formulations and solid dispersions in improving bioavailability and solubility.”

“One of the recurrent challenges we face is related to accelerated ap­provals from the FDA with Fast Track and Breakthrough designations on low solubility compounds,” says Mr. Henriques. “This is common for oncol­ogy programs that show promising early-stage results and may have re­duced clinical study requirements.”

Accelerated approvals put an in­creased amount of pressure on all Chemistry, Manufacturing, and Con­trol (CMC) activities, which must be compressed and de-risked, he says. The use of enabled formulations fur­ther increases the complexity of this activity. “Adequate risk assessment and management tools are required because reformulations may compro­mise all clinical timelines,” says Mr. Henriques. “Right-first-time formula­tion in this case is a significant advan­tage, and all formulation activities must have a strong sense of the man­ufacturability and scalability early to ensure seamless transition from clini­cal to commercial scales.”

Lubrizol Life Science Health: Proprietary Technologies for Amphiphilic Molecules

Some biologics require high con­centrations to be effective, even though they may be soluble. Formu­lating at these high concentrations can lead to issues with solubility or viscos­ity, requiring advanced delivery tech­nologies such as the formulation of nanoparticles or microparticles. These engineered particles flow well even at high concentrations.

Formulation strategy is deter­mined by looking at the physicochem­ical characteristics of a given active pharmaceutical ingredient (API). For crystalline API compounds with high melting points, a go-to technology for Lubrizol Life Science Health (LLS Health) is nanomilling, which reduces the size and increases the dissolution rate.

“Depending on lipid solubility, nanoemulsions or our proprietary LyoCell^® technology can be useful ap­proaches,” says Dr. Robert Lee, Presi­dent, LLS Health, CDMO Division. “Ly­oCells are better able to accommodate amphiphilic molecules (i.e., those with both a hydrophilic and a hydrophobic region) and are compatible with both small molecules and biologics.”

Assessing the feasibility of nanomilling provides clients with a cost-effective and efficient way to de­termine whether particle size reduction will work for their API, he continues. Nanomilling is well suited for formu­lating APIs with poor aqueous solubil­ity and has been used in a range of dosage forms, including liquids, capsules, tablets, and injectables. “Be­cause this process is in an aqueous vehicle, it bypasses the problems as­sociated with the large volumes and flammability of organic solvents used in other methods; it is also scalable and commercially validated,” he says.

Nanomilled API particles — nanoparticles — can be formulated as liquids, lyophilized powders, or oral solid dosage forms. Solid-lipid nanoparticles (SLNs) are submicron lipid particles that are used as an API delivery vehicle, including for hy­drophobic and high molecular weight APIs. “Their cost and recognized safety make them an attractive alternative,” says Dr. Lee.

Polymeric nanoparticles are a rel­atively new addition to the solubility arsenal and have been used with serum albumin to make such drugs as Abraxane^®. Additionally, other partic­ulate systems comprised of inorganic compounds — silica, magnetite, gold — in a formulation matrix or coating that incorporates chemotherapeutics or other APIs can improve bioavail­ability.

LLS Health has also developed SATx technology, an interpretation of antibody drug conjugates in which the surface of a nanoparticle loaded with a chemotherapeutic agent is deco­rated with biologics or targeting molecules, such as monoclonal anti­bodies. The SATx technology has been successfully applied to vaccines, says Dr. Lee.”

Micropore Technologies Inc: Improved Encapsulation Controls Bioavailability & Solubility

Injectable drug formulations are designed to deliver drugs directly into a cellular environment, bypassing both the acid environment of the stomach and primary metabolism by the liver, to optimize viable therapeutic effects. Formulation of the API within a predictable sustained-release deliv­ery system can optimize bioavailability at the desired therapeutic dose over a defined period with enhanced patient compliance and improved therapeutic outcomes.

Despite their advantages, since the approval of Lupron (1989) as the first sustained-release injectable drug using PLGA, surprisingly few similar drugs have been authorized by the FDA compared to the thousands of oral formulations approved over the same timeframe, says Tom Murphy, Vice President Sales & Business Devel­opment, Micropore Technologies Inc. This, he says, illustrates the scale of the challenge in the development of injectable formulations for clinical use.

There are several issues to con­sider in the development of the de­sired bioavailability characteristics from an injectable formulation. “One of the most important is the control of microsphere size to achieve a balance between predictable drug release over the desired time, a good patient expe­rience, and an optimized manufactur­ing process,” says Mr. Murphy. “Uniform microsphere size in any for­mulation is one of the determinants for controlling bioavailability and sol­ubility of an API.”

Because there is no viable sterili­zation method after the manufacture of microspheres, he says, the entire process needs to be undertaken in aseptic conditions. The simpler the process, the better the compliance and the fewer the non-conformities. “The manufacture of microspheres using traditional homogenization techniques enable the production of high volumes, but at the cost of a wide particle size distribution requiring sig­nificant downstream processing and significant yield losses,” he says. “Mi­crofluidic techniques offer particle size control, but this precise processing technique is challenging to scale up and suffers from process reliability is­sues.”

Membrane emulsification, at an industrial scale, is a relatively new process offering the high-volume po­tential of homogenization with the particle size control advantages of mi­crofluidics, he explains. “The technol­ogy is available to robustly and reliably delivering a predictably nar­row size distribution (coefficient of variation <20%) at a tunable size be­tween 5-500μm through compact precision engineered, GMP compliant devices. The simplicity and flexibility of this new generation of membrane emulsification devices is such that de­velopments can be transferred seam­lessly from lab bench for pre-clinical formulation development, through pilot scale, and into GMP manufactur­ing, opening rapid development op­portunities to explore the best way to optimize bioavailability for formula­tions.”

He adds that the gentleness of membrane emulsification enables the production of enhanced microspheres using a double emulsion-based processes with microsphere size vari­ability eliminated, high encapsulation efficiencies, and the preservation of the biological activity of sensitive ma­terials, such as proteins, to be maxi­mized.

Mr. Murphy says: “Together, recent advances in biopolymers and membrane-based manufacturing technologies now enable formulation of injectable drug products to be tai­lored at will to achieve a target solu­bility and bioavailability, delivering significantly improved therapeutic out­comes against the target disease.”

Pharmaceutics International Inc: Amorphous API Yields Desired Bioavailability

A client approached Pharmaceu­tics International Inc (Pii) with a mi­cronized poorly soluble drug in combination with excipients that was displaying an incomplete and very slow-release profile. The product needed to be developed as a tablet dosage form. The combination drug and excipient was dissolved in a sol­vent and spray dried to provide amor­phous material. However, the spray dried material was hygroscopic, static, and flowed poorly. Sundeep Sethia, PhD, Senior Director of Research and Development, Pii, explains that for better flow, the material was roller compacted with binder and glidant/lubricant and then milled. The material was then final blended with lubricant and compressed in the tablet dosage form. Precaution was taken to ensure humidity controls during processing and desiccants were used for storage of finished product to ensure stability.

“The amorphous API in the tablets yielded the desired pharmacokinetics profile and much improved bioavail­ability compared to the micronized API tablets,” he says.

Creating an amorphous solid dis­persion of an API, along with excipi­ents, using the spray drying and/or HME process increases surface area, and thereby the rate of dissolution, he says. This approach is easily scaled-up based on the properties of drug molecule characteristics, such as sol­vent solubility and temperature sensi­tivity. He warns, however, that physicochemical characterization of the solid dispersion on stability and its effect on critical quality attributes (CQAs) must be thoroughly under­stood.

Micronization is another ap­proach that speeds rates of dissolu­tion. Nanoparticles via media milling, mesoporous silica technology, and physicochemical optimization can in­crease bioavailability. “Of these, nanoparticles have shown notable success resulting in numerous commercial products,” says Dr. Sethia. Media/wet milling using a grinding mill or high-pressure homogenizer can provide particle size in the 100-200nm range, which can be stabilized by surfactants and delivered as a sus­pension or dried to powder from using spray drying to yield conventional tablets and capsules dosage form.

He concludes: “Each of the above approaches, along with a disciplined system for formulation and process development and robust analytical methods, can achieve improved bioavailability expeditiously.”

Quotient Sciences: Integrated Approach Accelerates Drug Development

Solving bioavailability and solubil­ity challenges to support successful drug delivery is an ever-enduring challenge (and opportunity) for phar­maceutical formulation scientists. Along with well-established ap­proaches to improving each, there are many emerging platform technolo­gies, providing options in the toolbox. In many ways, though, availability of such formulation and process technol­ogy approaches does not present the primary barrier to improving universal solubility and bioavailability chal­lenges. Instead, a key challenge is the continued lack of predictive, clinically relevant models to guide formulation selection early enough in the develop­ment process – such that money and time are not unnecessarily expended, and avoidable risks not taken.

“With many examples of mislead­ing nonclinical and in vitro predictabil­ity out there, robust predictive models would afford the ability to understand and adapt for successful clinical out­comes from the outset,” says Dr. Sarah Stevens, Vice President of Drug Development Sciences at Quotient Sciences. “Quotient Sciences embod­ies science-led decision making, therefore not relying simply on poten­tially unreliable predictive models. A combination of unique development approaches provides the most expedi­tious means to improve potential bioavailability and solubility chal­lenges.”

Quotient, she says, deploys technologies such as particle size reduction, lipid-based formulation mechanisms, HME, SDD, etc., but more pertinently, drives early formula­tion selection by cutting through in­dustry silos and integrating across a range of capabilities to accelerate the drug development process. One ex­ample is Quotient’s Translational Pharmaceutics^® platform, which inte­grates drug product manufacturing and clinical testing and ensures a con­tinuum among lead compound selec­tion, formulation development, and clinical assessments. “This reduces formulation development timelines and money, and mitigates risk in the development pathway by utilizing real-time clinical data to improve bioavailability and solubility,” says Dr. Stevens.

This integrated approach requires finely tuned project management and processes to ensure the most expedi­tious path to evaluate new molecules and formulations in the clinic. Prior to any clinical assessment, Quotient de­ploys a number of approaches based around the Developability Classifica­tion System (DCS) to deeply under­stand molecule properties – physico­chemical characterization, the use of biorelevant methods and physiologi­cally-based modelling/simulation to best position the formulation strategy for success. Quotient uses real-time product manufacturing and clinical testing to make, dose, and test new dosage forms within a 14-day cycle time, using arising clinical PK data to adjust formulation compositions.

As an example, she explains how Quotient rapidly screened a range of formulation types, including a mi­cronized API, spray-dried dispersions, and a lipid-based formulation using both biorelevant media and the inte­grated clinical manufacturing and testing platform.

“Nonclinical data was unable to provide clarity on which formulation strategy would be optimal to address PK issues seen with a simple first-in-human suspension system,” says Dr. Stevens. “Our ability to make decisions based on human PK data al­lowed identification of a powder-in-capsule formulation containing micronized drug, which demonstrated improved exposure, linear PK, and a reduced food effect, saving time and money for our client. This example supports my assertion that the lack of predictive, non-clinical or biorelevant models is the real barrier to success in the development of bioavailability/sol­ubility enhancing formulations.”

Recipharm: Conventional Technologies Are More Time- & Cost-Effective

The most important factor preventing the improvement of solubility issues and advances in bioavailability is low-potency active pharmaceutical ingredients (APIs), says Torkel Gren, Senior Director, Technology Officer & Strategic Investments at Recipharm.

Low potency, he says, works against solubility en­hancement in two ways. First, higher concentrations of API are required, if the dose is high. Secondly, smaller quanti­ties of solubility enhancer can be added to the dosage form, if the dose is high. “All of this means that it is hard to improve the solubility of low-potency formulations, limiting the ability to improve bioavailability and therapeutic ef­fect.”

Recipharm has been exploring solubility improvements in formulations for preclinical and first-in-human studies. “We have found it useful to perform theoretical evaluation before testing prototypes representing different approaches, followed by an optimization phase,” says Mr. Gren. “Usually, time and stocks of drug substance are very limited, so it helps to use experimental design and work in small scale.”

This approach also helps to avoid using more ad­vanced or complex technologies, unless they are necessary. Recipharm’s approach is to use conventional technologies whenever possible, as this will usually be more time- and cost-effective, he says. More importantly, it will make con­tinued development and tech transfer into commercial manufacturing less challenging, maximizing the likelihood of the project succeeding.

In a current project, Recipharm is supporting a cus­tomer with a formulation for safety studies. By applying its own screening platform, Recipharm has been able to rap­idly develop an appropriately optimized formulation solu­tion, combining pH adjustment and complexation by cyclodextrin. Stability was limited, but this was managed by using a frozen solution, which is an appropriate ap­proach for preclinical phase and Phase 1, he explains.

“For clinical Phase 1 and 2, lower doses were required, and we designed a tablet formulation with acceptable bioavailability by controlling drug particle size and adding surface active agents,” says Mr. Gren. “The work with par­ticle size distribution was facilitated by the fact that we were also manufacturing the drug substance on behalf of the customer.”

Mr. Gren admits that this approach may appear low-tech but, in this case, conventional methods were sufficient and significantly reduced the timeline for development. In addition, Recipharm created a drug product that will be easy to scale up for Phase 2 and commercial scale, and can be manufactured at a reasonable cost, he adds.

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