SPECIAL FEATURE - Excipients: Advanced Biologics Require Innovative Excipient Science

The pharmaceutical excipients market was valued at $10 billion in 2023 and is expected to reach almost $14 billion by 2028. Major factors impacting demand are increased R&D investments in novel excipients and growing emphasis on patient-centric formu­lations.¹ Additionally, superior generics and biosimilars are driving demand for novel excipients and drug delivery platforms, which enable differentiated products for chronic diseases, repurposed drugs for new routes of administration.

Novel excipients can play a critical role in achieving challenging technical targets that are not possible with traditional excipients alone, says Nick DiFranco, MEM, Global Market Manager, Novel Pharmaceutical Technologies at Lubrizol. Novel excipients may also provide intellectual property protection — both in the form of excipient licensing and formulation-specific IP tied to a drug product. The combination of technical and commercial benefits provided by novel excipients ensures formulators can meet their target product profile and develop products that have significant market potential, he says.

Additionally, the 505(b)(2) regulatory pathway in the United States (and its European counterpart, the hybrid procedure) has cre­ated an appealing source of innovation in the field of small-molecule drugs. “By leveraging existing safety and toxicity data for ap­proved drugs, pharmaceutical companies can reduce risk and streamline their path to market for drug reformulations for chronic diseases such as cancer and diabetes,” says Mr. DiFranco. “505(b)(2) products can take several forms, such as changes to formulation ingredients or routes of administration. The motivations behind 505(b)(2) product development include improving patient adherence with easier-to-dose products and optimizing properties such as drug delivery efficiency and side-effect profile.

Regarding the latter, industry is work­ing to address issues of adverse reactions, interactions, or contraindications that may result from excipients. A recent case in­volved EG/DEG-contaminated over-the-counter medicines, which alerted worldwide regulatory agencies to create guidelines for determining EG/DEG con­tent in relevant raw materials/excipients.

“Physical and chemical reactions be­tween excipients and APIs are inherent in the drug development process,” says Nitin Swarnakar, M Pharm, PhD, NA Applica­tions Lab Manager Pharma Solution, BASF Corporation. “However, to minimize the potential negative effects of excipients, such as adverse reactions, interactions, or contraindications, several strategies are being employed.” He suggests following ICH M7 and ICH Q3B(R2) guidelines to provide a framework for determining safe limits of mutagenic compounds and impu­rities in pharmaceutical products. “Adher­ing to these guidelines helps establish acceptable thresholds to minimize adverse effects associated with excipient usage.” Additionally, collaborate with excipient manufacturers to address concerns related to drug-excipient interactions, choose reli­able excipient suppliers, and optimize dosage form parameters.

“Quality, high-performance excipients are at the heart of every successful formu­lation,” says Kurt R. Sedo, Vice President Operations, PharmaCircle, which offers an integrated data and analytical enterprise solution. “As the industry continues to de­velop more challenging “traditional” mol­ecules and expand new modalities into advanced biologics, there will be an in­creasing need for innovation in excipient science to enable these products to be successfully developed.”

This exclusive Drug Development & Delivery annual report features the novel and functional excipients being developed, the role they will play in reformulations and new formulations, and their versatility in drug delivery.

 ABITEC Corp.: Formulating Functional Lipids as SEDDS

Most novel active pharmaceutical in­gredients (APIs) currently being developed are low-soluble (BCS Class-II), low-perme­able (BCS Class III), or both (BCS Class IV). For this reason, highly functional excipients capable of addressing these challenges are needed. ABITEC develops and manu­factures highly functional lipids for the pharmaceutical, nutraceutical, and spe­cialty chemicals industries. These excipi­ents include medium chain triglycerides, mono- and diglycerides, pegylated esters, and hydrogenated vegetable oils. ABITEC functional lipids can be formulated as self-emulsifying drug delivery systems (SEDDS) that are of significant utility in improving the bioavailability of various APIs.

Recently, ABITEC launched a novel co-processed excipient system, ABISORB-DC™, designed to allow the direct- compression tableting of liquid lipid pre­concentrates, including SEDDS preconcen­trates. John Tillotson, RPh, PhD, Technical Business Director – ABITEC Corporation, says: “This excipient allows for the bioavailability enhancing features of lipid-based drug delivery to be readily com­bined with the ease of formulation and manufacturing of direct-compression tableting at industry tableting speeds.”

He goes on to explain that excipients can often be employed to allow for dosage form transition from higher cost dosage form manufacturing processes to lower cost dosage form manufacturing costs. For example, transitioning from a liquid-filled hard gelatin capsule or liquid-filled soft gelatin capsule allows for the transition from a lower throughput unit operation to a higher throughput unit operation, which can reduce costs both in the manufacture and formulation of the dosage form.

“While the utility of liquid lipids in the formulation of low-soluble and low-per­meable active pharmaceutical ingredients is well known, these dosage forms, includ­ing SEDDS, have been largely restricted to liquid-filled hard gelatin capsules and liq­uid filled soft gels,” Dr. Tillotson says. “Typ­ically, these dosage forms are less economical, and often, due to ingredient migration between the capsule and fill, are more difficult to formulate and less stable than tablets.”

The issue with tableting the functional lipids is that the oily nature of the lipids in­terferes with the bonding characteristics of the tableting ingredients during com­paction, resulting in non-robust tablets. ABITEC recently launched a co-processed excipient system that allows for the ready compaction of liquid lipids, including the components employed in a SEDDS system. The ABSISORB-DC system allows for the compaction of SEDDS, thereby combining the bioavailability enhancement of SEDDS formulations with the economy and stabil­ity of direct-compression tableting.

As a result of the complexity of opti­mally developing SEDDS, ABITEC devel­oped a formulation and screening tool, the ABISOL™ Emulsion Preconcentrate Kit. This formulation tool is intended to assist in the fast tracking of SEDDs formulation development with new APIs. The kit con­tains five separate emulsion preconcen­trates for use in the creation of API carrying SEDDS preconcentrates, and was devel­oped by varying functional lipids with different HLBs employing a D-Optimal re­sponse surface optimization of solubility and emulsion characteristics to formulate the five emulsion preconcentrates. Recently, a CRO customer was tasked with the solubilization and per-oral deliv­ery of a BCS Class II API to conduct API toxicology and dosing studies. The CRO was experiencing difficulty solubilizing the API. They obtained an ABISOL Kit and screened the active, employing the kit pre­concentrates. The CRO was able to iden­tify preconcentrate V as providing the greatest degree of solubility with the API, as well as providing for the desired emulsion characteristics. “Employing preconcentrate V to dissolve the API al­lowed for the per-oral dosing and con­tinued study with the BCS Class II API,” says Dr. Tillotson.

Actylis: Enhancing the Efficacy of Finished Drugs

The demand for superior generics and innovative drug delivery systems drives the exploration of novel excipients. These excipients enable the development of differentiated products for chronic dis­eases, repurposed drugs for alternative routes of administration, and novel drug delivery platforms. By incorporating the high-quality excipients, customers can en­hance the efficacy of their finished drugs. Through strategic selection and innovative use of excipients, finished drug manufac­turers can overcome development chal­lenges, reduce costs, and drive therapeutic innovation.

As the industry continues to evolve, companies like Actylis continue to play a pivotal role, offering a range of excipients in several grades, suitable for many pharma and biopharma finished drugs.

“Excipients, often overshadowed by the active pharmaceutical ingredients, play a crucial role in the formulation of drugs,” says Kate Buggle, Director of Biopharma Sales, Europe, Actylis. “Understanding the significance of excipients is paramount in optimizing drug formulations and ad­dressing the challenges faced by the phar­maceutical industry.”

Binders, for instance, hold the ingre­dients together in a tablet or capsule, en­suring uniformity and coherence. Fillers add bulk to formulations, facilitating accurate dosing and aiding in the com­pression process. Disintegrants promote the breakup of tablets, enabling efficient dissolution and absorption in the body. Lu­bricants prevent sticking of the formulation to machinery during manufacturing and to the gastrointestinal tract upon ingestion. Solvents assist in dissolving APIs and other excipients, facilitating homogeneity.

Rising development costs pose a chal­lenge to the pharmaceutical sector. Excip­ients offer a cost-effective solution by optimizing formulations, reducing the quantity of expensive APIs required while maintaining efficacy. Moreover, excipients enhance process efficiency, minimizing production expenses.

“We work closely with our customers to custom develop excipients formulations, so they can achieve cost savings without compromising quality,” she says.

While excipients enhance drug per­formance, they may also pose risks such as allergic reactions or interactions with other medications. To mitigate these risks, extensive safety assessments are con­ducted during excipient selection and for­mulation development. Regulatory bodies mandate thorough testing to ensure excip­ient safety and compatibility with APIs. Ms. Buggle says that pharmaceutical manufac­turers need close collaboration with sup­pliers to solve those challenging quality, in­novation or supply chain issues that can delay to-market plans. A deep under­standing of those challenges is critical to minimize those delays.

BASF Pharma Solutions: See How Formulators Choose the Right Excipients

BASF Pharma Solutions specializes in a range of pharmaceutical excipients that offer various functionalities and benefits for drugs. These excipients play a crucial role in ensuring the stability, effectiveness, and ease of administration of APIs, says Nitin Swarnakar, M Pharm, PhD, NA Ap­plications Lab Manager Pharma Solutions, BASF Corporation.

“For drugs with acceptable physio­chemical properties (like particle size, den­sity, flow, and tabletability) belonging to DCS-I and DCS IIa, we recommend co-processed excipients like Ludipress® (Lac­tose, povidone, crospovidone), Ludipress LCE, Ludiflash® (mixture of D-mannitol, crospovidone, polyvinylacetate, povidone), and All-In-One excipients like Kollitab™ DC 87 L (Lactose Monohydrate, Crospovi­done, PEG-PVA-Copolymer, Sodium stearyl fumarate),” he says. “These co-processed excipients combine multiple in­gredients to create a single, optimized excipient with enhanced functionality. They offer significant time-saving benefits in the development, analysis, and blending of pharmaceutical blends, accelerating the rapid development of dosage forms.”

For drugs with poor particle size and tabletability, BASF utilizes binding agents such as wet binder povidone-30, polyvinyl alcohol-polyethylene glycol copolymer (Kollicoat® IR), povidone-90 (Kollidon® 90 evo), and dry binder like copovidones (Kollidon VA 64 fine). These agents help hold the drug particles together, ensuring the tablet remains intact upon compres­sion, says Dr. Swarnakar.

To address the challenge of poor sol­ubility of drugs in biological fluids, BASF uses various solubilizers options. These include a range of surfactants such as Soluplus®, ethoxylated solubilizers, polox­amers, polysorbates, and sorbitan Esters. “We also utilize solubilizers based on sol­vents like low molecular weight polyethyl­ene glycols (PEGs) and complex forming agents such as povidone and copovi­dones,” he says. “These solubilizers are carefully selected to enhance drug solubil­ity and improve therapeutic outcomes.”

And, for drugs that may not remain stable under storage conditions, formula­tors utilize specific coating polymers like polyvinyl alcohol-polyethylene glycol graft copolymer and polyvinyl alcohol (PVA) (Kollicoat Protect) or Methylmethacrylate–diethylaminoethylmethacrylate copolymer (Kollicoat Smartseal 30 D). These coating polymers offer moisture barrier applica­tions and ensure stability, extending the shelf life of the drug.

In cases where a drug degrades in the harsh gastric environment upon oral ad­ministration, BASF employs enteric coating techniques. This protective coating ensures the drug remains intact until it reaches the desired site of action, enhancing stability and therapeutic effectiveness. For potent drugs with short elimination half-lives, sus­tained-release polymers, like polyvinyl ac­etate (Kollicoat SR 30 D), hydroxy propyl methyl cellulose, ethylcellulose in matrix or reservoir type systems, are used. These systems are designed to release the drug gradually over an extended period, main­taining therapeutic levels in the body and optimizing treatment outcomes.

Celanese: Versatile Platform for Controlled/Sustained Release

Providing continuous long-acting drug release is a growing area of research with the potential to improve treatment for chronic diseases. VitalDose® EVA copoly­mer from Celanese is a biocompatible, biodurable, and adaptable technology de­signed for use in long-acting injectables and drug-eluting implants. It functions as a versatile platform for controlled and sus­tained drug release. It allows for a high drug load in the dose form and enables the design of drug release profiles lasting from months to years – including very water-soluble drugs. Thus, VitalDose EVA can cater to various treatment needs, says Christian Schneider, PhD, Application and Business Development Leader at Celanese.

In addition, the material’s versatility allows it to be compatible with a range of drug types, including complex biologics, RNA, small molecules, and peptides. Monolithic designs highly loaded with a large, very hydrophilic protein, release very fast due to a high degree of porosity inside the EVA matrix. By adding well-de­signed rate control membranes to the highly loaded monolithic designs, the re­tention of the protein is significantly in­creased and the protein release can be adjusted to meet the target rates. Dr. Schneider says: “This compatibility opens doors for the development of new and di­verse therapeutic options in the areas of ophthalmology, oncology, and women’s health.”

Dr. Schneider adds that VitalDose EVA properties hold promise for driving ad­vancements in several areas of drug deliv­ery, particularly when it comes to continuous systemic delivery for chronic dis­eases. Its ability to maintain sustained and controlled drug release profiles over ex­tended periods allows for less frequent dos­ing. This can potentially improve patient adherence and may lead to better out­comes, reducing the healthcare burden for conditions requiring consistent medication.

“Furthermore, the potential for im­proved efficacy and safety using EVA paves the way for repurposing existing drugs with limitations in traditional formu­lations,” says Dr. Schneider. “By enabling alternative routes of administration, such as localized implants, EVA could enhance a drug’s therapeutic effect while minimiz­ing side effects. This can potentially extend drug patent life and offer opportunities for further research and development.”

Croda Inc.: High Purity Excipients for Drug Delivery & Drug Stability

Therapeutic proteins, such as mono­clonal antibodies (mAbs) and other biosimilars, are usually dosed via par­enteral administration to patients. How­ever, due to their inherent instability in the liquid state, many of these products require the use of a surfactant such as a polysorbate. Surfactants are widely used to prevent protein aggregation during man­ufacturing, freeze/thaw stress, shipping agitation, and upon long-term storage.

“Polysorbates and other non-ionic surfactants weakly bind to proteins via in­teraction of the hydrophobic regions of the protein and the hydrophobic chain of the polymers, which results in a tendency to solubilize proteins,” says Andrew Bright, Technology Specialist at Croda. “This weak interaction can slow, reduce, minimize, or prevent hydrophobic regions of the protein molecules interacting and forming aggre­gates, thus preserving their activity. Polysorbates can also coat the container wall and can be present at the air-water interface, which can prevent the protein in­teracting with these interfaces, thereby sta­bilizing the protein.”

He explains that small-scale biopro­cessing manufacture can be expensive. Adding to the small-scale manufacturing expenses are the costs of analytical testing and labor. Many organizations conduct initial screening experiments with multiple excipients when developing new therapeu­tic mAb formulations; surfactants, cryopro­tectants, and pH buffer conditions may also be screened to establish best materi­als and lead formulation conditions to take into further development.

“Several issues can arise during the initial formulation screening, including the use of low-grade or expired excipients (usually used to reduce cost), the use of ex­cipients from different suppliers with wide monographs, and excipients with large batch-to batch-variations,” says Mr. Bright. “Depending on the source, the age, and grade, the same excipient may have dif­ferent properties and impurity profiles, thus leading to a variety of different results, as some degradation may occur at a very slow rate, with some issues being only identified after several months of study.”

The above-mentioned factors could lead to the formulator being pushed in the wrong direction when exploring excipient options and types for the therapy and rep­etition of testing, thereby increasing the time required to establish a suitable for­mulation for use. “This is why the use of high purity excipients like SR Polysorbates and other high purity excipients in a for­mulation are critical,” he says.

Variations in polysorbates can affect formulation performance, too, as different grades and suppliers of polysorbate have different levels of impurities that can have unwanted interactions, degradation of the proteins, and performance. Croda makes model formulations and evaluates differ­ent excipient grades to determine their im­pact on model API stability. This can usually be used to advise impact of excip­ient grades. Mr. Bright says: “We can eval­uate such performances of different grades of excipients in our formulations and biological applications labs.”

Croda’s Super Refined™ excipients undergo a proprietary purification process, removing excipient impurities and producing a narrow monograph, ensuring consistent performance between different batches, which in turn, ensures that the re­sults obtained for the final clinical or com­mercial formulation are the same as those obtained during initial excipient screening studies.

Curia: Excipients are the Great Problem Solver in Parenteral Development

Since the Covid-19 pandemic, the in­flux of more complex formulation design has emerged to deliver more sensitive pay­loads. Protection of labile therapeutics agents in advanced drug delivery systems, such as liposomal and lipid-nanoparticle (LNPs), are seeing increased numbers of LNP drug products undergoing successful Phase 1 trials (and beyond), year-on-year. “Curia is working with clients to develop LNP formulations where the novel design is in the ionizable lipid, but have found that selection of the right PEG-functional­ized lipid has a multitude of benefits,” ex­plains Jaclyn Raeburn, PhD, Manager, Formulation Development, Glasgow, Curia. “Utilizing a shorter C14 vs C18 chain PEG-functionalized lipid LNP allows for shorter dissociation and, therefore, in­creased efficacy.”

Curia’s capabilities encompass guiding molecules from the lab to first-in-human trials and eventual commercializa­tion. Many of the synthetic small-molecule APIs Curia’s clients are progressing for pre-clinical/Phase I studies show poor aqueous solubility. She says that looking to organic solvents to immediately offer sol­ubility for tox studies, but downstream this can have regulatory issues. She explains that small-molecule APIs frequently de­grade via oxidative pathways, making sta­bilizing excipients crucial to reducing oxidative decomposition in solution. Excip­ients may scavenge oxygen, preventing ox­idative decomposition; or like EDTA, chelate metal ions catalyzing decomposi­tion.²

“We reformulated a drug product for a client where discoloration was a con­cern, using EDTA,” she says. “It was shown to decrease the rate of discoloration on storage, further enhanced by nitrogen headspace to diminish residual oxygen content. The choice of grade of a particu­lar solubilizing/stabilizing excipient is also key to mitigating oxidative decomposition and improving overall drug product per­formance. We use surfactants such as polysorbate 20 and 80 or PEGs to improve solubility, but have seen improved long-term stability with super-refined grades of such excipients.”

In the development of sustained-re­lease formulations, viscosity becomes a fundamental attribute during excipient se­lection. Biocompatible polymers such as carboxymethylcellulose sodium (CMC Na), acacia, sodium hyaluronate, and biodegradable polymers like poly(lactic-co-glycolic acid) (PLGA), are utilized for sustained release due to their tunable properties³ in the polymer-drug matrix. Curia has developed many drug products with common water-soluble polymers, like PEG400 and PEG4000, to increase viscos­ity. Dr. Raeburn says: “Often, a client is tar­geting viscosities >20mPa.s, which requires a substantial concentration of such excipients. This will impact tonicity and bring regulatory concerns. Our clients expect innovative design to solve their for­mulation issues – we look to biocompati­ble polymers to achieve higher viscosities while maintaining a firm regulatory posi­tion.”

Where solution stability is a particular concern, lyophilization is an option; intro­ducing additional excipient classes like cry­oprotectants, lyoprotectants, and bulking agents. Bulking agents, often non-reduc­ing sugars like sucrose or trehalose⁴, en­hance lyophilized solid cake integrity and reconstitution ability. Lyoprotectants ensure stability during the lyophilization process, preventing microstructural collapse and subsequent moisture uptake on storage.⁵

“Mannitol is recognized as ubiquitous in lyophilized products, but itself is crystal­lizable into multiple polymorphic forms, and an amorphous bulking agent/lyopro­tectant would simplify development,” she says. “Replacing with sucrose, for exam­ple, can reduce lyophilization cycle time, but maintain structural and chemical in­tegrity of the lyophilized drug product.”

CycloLab Ltd.: SBECD’s Versatility in Drug Delivery

Today, more than 250 active ingredi­ents or their combinations formulated with cyclodextrins, including 150 with beta- cyclodextrin (betadex), are available throughout the world. There is a growing tendency in the number of approved phar­maceutical formulations containing an an­ionic modified cyclodextrin, referenced in US Pharmacopoeia as betadex sulfobutyl ether sodium or sulfobutylbetadex sodium in European Pharmacopoeia (SBECD, marketed under brand names Captisol or Dexolve).

“SBECD is a versatile excipient that can significantly improve the solubility, bioavailability, and stability of APIs,” says Dr. Éva Fenyvesi, Senior Research Scientist at CycloLab.

The stable solutions are usually in­tended for intravenous or intramuscular use, but other administration routes, such as buccal, vaginal, nasal, ophthalmic, and dermal have also appeared in the litera­ture containing more than 700 scientific papers (Elsevier Scopus database). She ex­plains: “Various nano-formulations con­taining SBECD have been studied to utilize the inclusion complex forming (solubiliz­ing, stabilizing) ability of this CD derivative in synergy with the benefits of the nano­sized particles/droplets.”

For example, nanoparticles formed by self-assembly of chitosan with positive charge and SBECD with negative charge were thoroughly studied for various drugs, such as econazole nitrate, hydrocortisone, famotidine, besifloxacin, and naringenin to get sustained-release formulations with enhanced solubility and bioavailability. The chitosan/SBECD nanoparticles were found effective in targeted and controlled delivery of not only the small molecular drugs, but for protein drugs. Chitosan/tripolyphosphate nanoparticles with drug/SBECD complex were found biocompatible and biodegradable provid­ing increased drug release for Docetaxel. Nanoemulsions (nanodroplets) stabilized by various surfactants (Kolliphor® HS 15, Tween 80, poloxamer 407, and polyethyl­ene glycol 400) have similar advantages for voriconazole and carnosic acid. As a novel drug delivery system, pH-responsive nanoparticles, based on SBECD and cetylbenzyldimethylammonium chloride, showed assembly and disassembly behav­iors with the pH alternating between 10.0 and 2.0, thus enhancing the anticancer ef­ficiency of anticancer drug – celastrol – Dr. Fenyvesi explains.

Additionally, consider the following: Chemically cross-linked SBECD nanopar­ticles using diisocyanate type cross-linking agent can capture and gradually release the active ingredients – such as moxi­floxacin; hydrogels consisting of SBECD and hyaluronic acid have good biocom­patibility and provide prolonged drug re­lease for lidocain as a long-lasting analgesia therapeutic; thermoreversible nasal in-situ gel of drug/SBECD complex in alginate gel was suggested for nasal application of meclizine; and nanovectors useful in enzyme replacement therapy contain enzyme/SBECD complex coated with biomimetic membrane (e.g. albumin) and demonstrate enhanced catalytic activ­ity, prolonged circulation time, and im­proved bioavailability. Fast dissolving oral formulations using electrospinning tech­nique were also developed.

“This non-comprehensive literature may convince the formulators on SBECD’s versatile advantages in various drug deliv­ery systems and its potential for develop­ing state-of-the-art drug formulations,” says Dr. Fenyvesi.

Gattefossé USA: SEDDS Prove Effective for NCEs & Reformulating Molecules

Gattefossé offers innovative lipid ex­cipients and personalized technical sup­port to accelerate customers’ development programs for pharmaceutical and veteri­nary drugs, as well as dietary supple­ments. Extending to oral, (trans)dermal, mucosal, and other routes of administra­tion, its excipients have solubility- permeability- and overall bioavailability-enhancing properties. By type of applica­tion, the product list includes self-emulsifying vehicles, solubilizers, drug release rate modifiers (sustained vs. imme­diate), ready-to-use vehicles for soft gela­tin capsules, and emulsifying bases for topical emulsions. These excipients bring benefits to drugs by improving bioavail­ability, easing manufacturing, and en­hancing patient compliance through taste masking, creating sustained-release ma­trices, and improving the texture of topical products, says Inayet Ellis, PhD, Scientific Affairs Director, Gattefossé USA.

Employing a formulation approach that can be carried from early develop­ment to marketing approval can implicate significant savings in time and costs for the overall development of new chemical en­tities (NCEs) that face solubility and bioavailability issues. A SEDDS formula­tion consisting of well-established self-emulsifying surfactants, cosurfactants, and oily vehicles can carry the development of an NCE from early preclinical to the late-stage phases. Contributing to the speed of development are also the extensive regu­latory, safety, quality, and stability data provided by Gattefossé.

Reformulating drug molecules for chronic diseases is exemplified by the use of SEDDS as an effective strategy for oral delivery in testosterone replacement ther­apy, explains Dr. Ellis. “Traditionally, oral delivery of testosterone was unsuccessful due to extensive first-pass metabolism in the liver,” she says. “However, recent FDA approvals of oral capsules formulated with SEDDS have changed this landscape. Lipids in this formulation enhance intes­tinal permeation and lymphatic uptake, leading to a decrease in first-pass hepatic metabolism of testosterone undecanoate, thereby maintaining its serum levels for optimum pharmacological response. Fur­thermore, the formulation facilitates ab­sorption of testosterone without the necessity of maintaining a high-fat diet.”

Gattefossé collaborates with pharma­ceutical clients to advance their develop­mental programs. Recently, a client with a first-in-class, oral small molecule in oncol­ogy, developed a SEDDS formulation that facilitated the transition of the NCE from preclinical to first-in-human studies. With modified-release excipients such as Compritol® 888 ATO (glyceryl dibehen­ate), a cost-effective formulation has been developed to extend the half-life of an API indicated for Type-2 diabetes, she says.

Ligand: Cyclodextrin Addresses Solubility & More

Captisol® is a uniquely derivatized beta cyclodextrin that has been in FDA-ap­proved pharmaceutical products since 2002. The sulfobutyl ether groups of Cap­tisol help to improve the parent beta cy­clodextrin molecule’s solubility, safety, and interaction with hydrophobic drug mole­cules, says Vince Antle, PhD, Senior Vice President, QA & Technical Operations, Lig­and. “These properties, in addition to fun­damental host-guest beta cyclodextrin properties, are key to the ability of Captisol to improve the solubility and stability of many different types of compounds.” There are currently 16 approved products that include Captisol (SBECD) in the drug product formulation.

Because cyclodextrins are eliminated by glomerular filtration, safety questions have arisen for the use of cyclodextrins in renally compromised patients. Recent clin­ical studies with formulations including Captisol have shown that even in renally compromised patients, Captisol is safe to administer, says James Pipkin, PhD, Vice President, New Product Development, at Ligand. These studies have supported broad labelling for two Captisol-enabled formulations – Baxdela® (delafloxacin meglumine) and Veklury® (remdesivir) – that include renally impaired patients. Also noteworthy, the patient population for re­ceiving Veklury has recently been ex­panded to pediatric patients as young as birth and weighing 1.5kg.

A benefit of using Captisol for im­proving solubility and stability is that the resulting formulation is aqueous-based, thereby avoiding co-solvents, surfactants, and other solubilizers that can cause their own set of safety issues, explains Dr. Pip­kin. For example, amiodarone IV formula­tions can contain inactive ingredients benzyl alcohol and polysorbate 80 that have been shown to cause hemodynamic effects, fatal gasping syndrome in neonates, and increased hypotension,^6-8 while the Captisol-enabled formulation, Nexterone®, is available in a ready-to-use or Nexterone Premixed Injection. In addi­tion to removal of excipients that affect blood pressure, added benefits of having an all-aqueous formulation resulted in a consistent droplet size during dose admin­istration that was not regularly achieved with amiodarone formulations containing cosolvents and surfactants and decreased drug adsorption into administration infu­sion sets. Furthermore, the Nexterone for­mulations are ready to use immediately in life-saving emergencies and prevent dose inaccuracies, says Lian Rajewski, PhD, Senior Investigator at Ligand.

While stability and solubility in aque­ous environment are the main reasons for­mulators gravitate toward adding cyclodextrins to their formulations, there are other properties of Captisol that can be exploited. For instance, Captisol is pre­servative-sparing^9,10 and has physical characteristics such as flow and compress­iblity that are amenable to solid oral dosage forms. The Mekinist® (trametinib) oral solution formulation is a good illus­tration of these properties as multiple sol­ubilizers and stabilizers were evaluated during the development of the formula­tion, with Captisol selected for the final product. The inventors of the oral solution composition explain:¹¹ “In pediatric popu­lations, it is often desired that drug be available as a powder for reconstitution to an oral suspension or solution. Such a powder requires an attempt to dry blend various excipients with the active substance in the hope of providing a powder blend with good flow properties and content uni­formity.” Captisol is spray-agglomerated and thus possesses a larger particle size with better flow characteristics than spray-dried material.

Lubrizol Life Science: Polymer Offerings Enhance Mucoadhesion & Bioavailability

Lubrizol’s historic excipient brands are Carbopol®, Pemulen™, and Noveon® polymers, which serve primarily as rheol­ogy modifiers for semisolids and liquids, and extended-release polymers for oral tablets. “These bring a multitude of bene­fits to formulations, ranging from in­creased efficacy to better patient acceptance and easier processing,” says Ashley Rezak, Global Market Manager, Topical Drug Delivery, Lubrizol Life Sci­ence.

Lubrizol also has Apisolex™ and Apinovex™ polymers designed to enhance the solubility of BCS Class II and IV drugs for injectable and oral applications, re­spectively.

Drug product development is an ex­pensive endeavor, and while excipients make up just a portion of that cost, they can still have a critical impact on the bot­tom line. One method for keeping costs down is by using highly efficient excipients, such as Carbopol® polymers, says Ms. Rezak. “Only a small amount is needed to achieve high performance. For example, only 0.6% Carbopol polymer is needed versus 6% xanthan gum to achieve a sim­ilar viscosity, and the Carbopol polymer formulation offers superior clarity and sus­pension at this concentration.”

It is known that even well-established excipients can produce negative side ef­fects in patients, such as with polyethylene glycol (PEG), which is known to induce an immune response in some patients. This highlights the need for safe, non-toxic, and non-immunogenic alternatives to excipi­ents such as PEG, leading to the use of PEG-based alternatives that mimic the technical properties of PEG but carry sig­nificantly lower toxicity and immunogenic­ity potential. Nick DiFranco, MEM, Global Market Manager, Novel Pharmaceutical Technologies, says Lubrizol’s Apisolex™ polymer is being developed by Lubrizol as a polyamino acid-based technology that utilizes natural building blocks of sarcosine and other amino acids to create a safe, ef­fective solubility enhancement option. “By promoting this technology, Lubrizol is en­couraging the pharmaceutical industry to try safer, more patient-friendly options when solubilizing challenging com­pounds,” he says.

Mucoadhesion, the adherence of two materials at least one of which is a mu­cosal surface, is a growing area in drug development. However, it can be difficult for a formulator to know how to instill into a formulation. A lesser-known quality of Lubrizol excipients is their ability to offer superior mucoadhesive performance com­pared to other polymers, which has nu­merous advantages such as enhanced bioavailability of a drug and lubrication of mucosal tissues.

Ms. Rezak explains: “Several clients have come to us struggling to retain an ac­tive on a target mucosal surface long enough for the drug to be effective; one example would be an eye drop or a lozenge for a sore throat, both of which struggle to remain at the site of action due to saliva or tear wash off and gravity. How­ever, after formulating with Carbopol or Noveon polymers, their formulations achieved the desired performance and eventually made it to market.”

Pfanstiehl Inc.: Excipient Tools Used in Manufacturing High Concentration Antibody Formulations

The development of High Concentration Antibody Formulations (HCAF) exceeding 100mg/mL is crucial for creating subcutaneously deliverable monoclonal antibody (mAb) therapies. However, inherent variability among molecules presents complex technical challenges that require a diverse range of tools and expertise to overcome.

Viscosity & Solubility Challenges: One of the primary hurdles in HCAF development is the inevitable increase in solution viscosity with rising mAb concentration, explains Dr. Christian Lotz – General Manager EMEA for Pfanstiehl Inc. “High viscosity presents challenges during filtration, filling, and other manufacturing processes,” he says. “Additionally, highly concentrated mAb solutions may encounter solubility limitations, potentially leading to gelation or phase separation, particularly under refrigerated conditions. These occurrences not only jeopardize formulation stability, but also compromise therapeutic efficacy.”

Manufacturing Process Challenges: The formulation process itself poses complex challenges, especially in unit operations like ultrafiltration-diafiltration, sterile filtration, and fill-finish steps, he says. These challenges can impede manufacturing efficiency and increase costs, requiring innovative solutions to streamline processes while maintaining product quality.

Syringeability & Injectability Concerns: High viscosity and mAb aggregation hinder manufacturing processes and compromise syringeability and injectability during patient delivery. These issues reduce patient compliance and treatment effectiveness, emphasizing the importance of formulations optimized for easy administration.

Protein Aggregation & Storage Stability: Protein aggregation presents a significant risk during manufacturing and administration, potentially diminishing therapeutic potency. Dr. Lotz says: “Additionally, aggregate formation increases the risk of triggering anti-drug immune responses, highlighting the importance of maintaining long-term storage stability while preserving formulation integrity.”

Overcoming Manufacturing Challenges With Today’s Excipient Tools: High Purity Low Endotoxin (HPLE) excipients play a crucial role in mitigating viscosity, enhancing solubility, and ensuring stability in HCAF formulations. However, selecting the appropriate excipients while maintaining formulation stability requires a delicate balance of art and science. “Moreover, given that these chemicals are included in the final formulation intended for injection into patients, it is imperative to choose excipients that meet the stringent quality standards mandated by regulatory agencies worldwide,” says Dr. Lotz. “Additionally, selecting excipients from reputable manufacturers with a proven track record of consistently making materials that surpass quality requirements and delivering when needed is equally vital.”

L-Arginine Excipient – High Purity Parenteral Grade: L-Arginine plays a crucial role in mitigating viscosity challenges in high-concentration protein formulations. High protein concentrations often result in increased solution viscosity, hindering manufacturing processes and therapeutic protein administration. L-Arginine reduces viscosity by acting as a solubilizing agent and disrupting protein-protein interactions. The positively charged guanidinium group of L-Arginine interacts with negatively charged protein surfaces, preventing aggregate formation and reducing overall formulation viscosity.

Sucrose Excipient – High Purity Low Endotoxin: Sucrose is instrumental in stabilizing proteins and antibodies. Proteins are sensitive to environmental factors such as temperature, pH, and agitation, which can cause denaturation and loss of biological activity. Dr. Lotz explains that sucrose acts as a stabilizing agent by forming hydrogen bonds with proteins, creating a protective environment that shields them from external stressors. This stabilizing effect preserves the native conformation of proteins and antibodies, maintaining their functionality over time.

In summary, manufacturing high concentration antibody formulations (HCAF) presents complex challenges including viscosity and solubility issues, manufacturing process hurdles, syringeability concerns, and protein aggregation risks. Overcoming these challenges requires innovative solutions and the use of excipients like L-Arginine and sucrose – which are both high purity and low endotoxin parenteral grade – to mitigate viscosity, prevent aggregation, and stabilize therapeutic proteins, ensuring formulation integrity and therapeutic efficacy.

Roquette: The Value of Starch-Based Excipients

At Roquette, everything starts with starch. Native starches can be used on their own, but, when processed, they be­come modified starches. Processing mod­ified starch further produces polyols, like mannitol, sorbitol and xylitol, which can then be processed into cyclodextrins, such as hydroxypropyl beta cyclodextrin (HPβCD), for use in biopharmaceutical drug development.

“The real value of starch-based phar­maceutical excipients is in their versatility as filler/binder solutions,” says Ketaki Pat­wardhan, Global Technical Developer, Roquette.

One dosage form benefitting from starch-based excipients is mini tablets (multiple unit dosage forms <3.0mm in diameter). These are increasingly popular in pediatric medicine. To formulate mini pills that can replace conventionally sized tablets requires the use of a highly com­pressible excipient, capable of producing smaller, harder tablets with the same API concentration.

“We set out to test the capacity of our PEARLITOL® 200 GT mannitol to produce melatonin mini tablets via direct compres­sion, which could be used as one-to-one substitutes for conventional size tablets, adapted for pediatric patients,” says Dr. Patwardhan.

A series of 15mg mini tablets were produced using a blend of PEARLITOL 200 GT, 3mg of the active melatonin and mag­nesium stearate as a lubricant, with some of the pills also featuring GLYCOLYS® sodium starch glycolate as an additional disintegrant. Each batch was subjected to different compression forces to evaluate the ideal processing parameters for mini pills.

During tablet processing, PEARLITOL 200 GT displayed excellent flowability and compressibility, enabling the production of mini tablets with minimal weight variation and capping risk, she explains. Test batches formulated without an additional disintegrant returned disintegration times of around 2-3 minutes at all compression forces upon testing, with approximately 100% melatonin dissolved in 30 minutes and more than 80% within 10 minutes. The mini tablets formulated with disinte­grant showed a similar dissolution profile as the regular-sized control tablets, releas­ing more than 80% of the active drug within 5 minutes.

In addition to pediatric patients, Roquette services the growing demand for convenient and effective medications for an aging population, leading drug pro­ducers to search for strategies to increase tableting speed and boost output. Faster production lines often come at the expense of more frequent tableting defects and costly active ingredient waste, however. At high speeds, pockets of air can become trapped inside the tablet, leading to cap­ping or breakage. The choice of excipient, therefore, has a significant role to play in mitigating tablet capping and assuring the quality and stability of the final drug.

“Recognizing the need to help manu­facturers reduce tableting defects, we began to consider the features they would look for in a specialized anti-capping ex­cipient,” says Dr. Patwardhan. “We con­cluded that such a solution should be densified to allow for higher compression forces and harder tablets that are more re­sistant to capping, as well as having a more homogenous mass flow for faster, more efficient processing. We put these learnings to practical use in the develop­ment of our mannitol grade PEARLITOL 200 GT, which has been shown to help manufacturers boost production speeds without the typical spike in capped tablets.”

Nanjing Well Pharmaceutical Group: The Versatility of PLGA

Nanjing Well Pharmaceutical Group supplies pharmaceutical excipients for solid, semi-solid, and liquid preparations. Their products are divided into injection grade and non-injection grade, used in various dosage forms (injections, eye drops, microspheres, liposomes, suppositories, ointments, tablets, etc. ), pharmaceutical and health products, personal care, and animal nutrition.

Nanjing Well has long been committed to the R&D and production of poly(lactide-co-glycolide (PLGA) products and has experience in polymerization, quality control, stable supply, and customized services. “PLGA is a biodegradable functional polymer material and is currently the most successful polymer excipient used in microsphere injections and has good applications in a variety of commercial formulations,” says Etham Xu, General Manager, Nanjing Well Pharmaceutical Group Co., Ltd. “PLGA can adjust the drug release and achieve the function of sustained and controlled release.”

In the process of R&D and production of PLGA, Nanjing Well uses high-efficiency catalysts to significantly reduce the amount of isomers and monomer residues; it adopts new polymerization processes and reaction devices to significantly shorten the reaction cycle and ensure the high stability of the product’s molecular weight distribution and intrinsic viscosity, greatly improving the production efficiency. He adds that the company can significantly reduce the production cost of PLGA while ensuring product high-quality products, thereby helping microsphere preparations reduce production costs.

Regarding the PLGA series, the microstructure of the copolymer (such as architecture, sequence structure, etc.) and impurity residues (such as monomer, catalyst, and organic solvent residues) can cause adverse reactions and affect drug release. “Nanjing Well uses high-efficiency catalysts, new polymerization processes,  reaction devices, and sophisticated purified process to maintain the reproducibility of microstructure and reduce the above-mentioned residues, carrying out very strict control of residue limits,” says Mr. Xu.

In the process of developing microsphere preparations, customers often have special requirements for the structure and impurities content of PLGA. Mr. Xu says that sometimes these products cannot be obtained on the market. “Nanjing Well provides customized services to meet the various requirements, such as different monomer polymerization ration, end group, intrinsic viscosity, and microstructure, and we can also offer lower impurity PLGA productions, such as residual monomer lower than 0.2% and tin lower than 1ppm.”

PLGA polymer can be used in multiple modified-release delivery systems, including microspheres, implants, in-situ gel, etc. “Compared to conventional immediate-release dosage forms, above preparations have the advantages of reducing the frequency of dosing, improving patients’ compliance, reducing toxic and side effects, and thus improving treatment safety,” he says. “These advantages are significant in the treatment of chronic diseases.”

References

1. Pharmaceutical Excipients Market Worth $13 Billion, MarketsandMarkets, Jan. 4, 2024, https://www.prnewswire.com/news-releases/pharmaceutical-excipients-mar­ket-worth-13-9-billion–marketsandmarkets-302026034.html.

*All other references are available upon request.