The online version of this article has been updated from the print version to include additional content.
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High-concentration injectable formulations present unique challenges.
Poor solubility issues are often associated with small-molecule APIs formulated for oral administration. Solubility is also important for parenteral products as well. Injectable products need to be free of particles (foreign substances and active ingredients) and often are high-concentration formulations, and both can be difficult to achieve when drug substances have poor water solubility. Special excipients can help overcome these solubility problems. Top candidates include polymeric micelles and lipid-based formulations.
The online version of this article has been updated from the print version to include additional content.
Solubility is a challenge that most newly discovered drug candidates face, irrespective of the intended route of administration, according to Philip Schäfer, head of process and formulation materials at MilliporeSigma, the Life Science business of Merck KGaA. In fact, approximately 40% of APIs on the market and around 90% of those in development are poorly water soluble (1).
“Today’s approach of target-oriented high throughput screening aimed at identifying more lipophilic compounds combined with the trend towards larger and more complex molecules both contribute to the development of APIs with reduced solubility,” says Schäfer. More specifically, during drug development, explains Shreya Shah, associate director of formulation services at LLS Health, many molecular targets, such as drug/enzyme binding sites, are hydrophobic. “As like attracts like, the main structure of candidate APIs is also often hydrophobic, making them poorly soluble in aqueous media,” she observes.
Molecular weight, chemical structure, and chemical-group lipophilicity are key factors affecting the solubility of small-molecule APIs, adds Philipp Heller, project manager innovation at Evonik Health Care. He notes that some peptide-based drugs can also suffer from poor solubility depending on their amino acid composition, while proteins have solubility challenges as well.
In the case of peptides and proteins, poor solubility generally occurs when the tertiary structure of these molecules includes large hydrophobic portions on the surface and thus exposed to aqueous media, according to Vincenza Pironti, senior staff scientist, research and development, pharma services at Thermo Fisher Scientific. “Often this aspect can be circumvented by conducting pH or ionic strength studies to find the right window where the protein structure contains exposed charged portions,” she comments.
Solubility is important not just for orally administered drugs; it is also essential for parenteral formulations because these product solutions must be particle-free, Schäfer notes. That must be achieved even for high-concentration products—a growing formulation trend, which further increases the need for high solubility.
“There are several strategies used to improve the solubility of hydrophobic compounds and each has its limitations. Safety is always a key concern in the formulation of novel therapeutics, but it is even more crucial for parenteral formulations that bypass the gastrointestinal tract and are delivered directly to receptor sites via the bloodstream. Therefore, not all strategies are practical, especially when formulators are trying to achieve high drug loading, for example, to reduce the frequency of administration,” comments Shah.
Aqueous parenteral formulations must also have the right right tonicity level to avoid the insurgence of pain after administration, Pironti stresses. This requirement has limited the number of excipients currently approved and reported as generally regarded as safe (GRAS) by FDA. Nonstandard formulations leveraging oil-based solutions in lipophilic media present an entirely different set of issues, she adds.
Circumvention of the blood-brain barrier with parenteral formulations also means that excipients used in these formulations must meet high quality requirements with respect to bioburden, endotoxin levels, etc. “Due to this fact,” Schäfer says, “not all types of excipients that may increase solubility are also suitable for parenteral administration.”
In addition, because many parenteral formulations are high-concentration products, there are challenges to increasing solubility with the limited amounts of excipient that can be used, according to Heller. “For each specific API, the hydrophilicity and hydrophobicity of an excipient or excipient mixtures must be balanced to achieve high loading efficiency and formulation stability, while at the same time ensuring efficient release of the API from the formulation,” he remarks. The limited number of excipients available for parenteral use only exacerbates this challenge.
For instance, Shah explains that when surfactants or organic co-solvents are used to increase solubility to enable high drug loadings, toxicity issues and/or immunogenic responses can occur. Cyclodextrins and other excipients that boost API solubility by forming inclusion complexes, a process that is governed by thermodynamics, also must be used at high concentrations that can cause excipient toxicity issues.
Physical modification such as particle-size reduction via nanomilling may in some cases be an effective approach to reducing the concentrations of excipients required to enhance solubility, Shah adds. She also notes that reduced excipient concentrations may enable higher drug loadings because the API remains in a solid-liquid dispersion rather than being solubilized in an aqueous solution.
In general, because poor water solubility is usually driven by the presence of highly hydrophobic regions within APIs, avoiding contact between these hydrophobic areas and the aqueous environment within parenteral formulations has proven to be a potent measure for increasing solubility, Schäfer observes. “Many solubility-increasing excipients consequently share the same mode of action—a shielding effect of the hydrophobic areas,” he says. Examples include silica carriers and polymeric micelles.
Amphiphilic excipients with both hydrophilic and hydrophobic moieties that can be fine-tuned work best to enhance the solubility of APIs in parenteral formulations, notes Heller. In addition to polymeric micelles, he points to nanoparticle preparations and liposomal formulations as having been proven useful for the solubilization of hydrophobic, small-molecule APIs. He adds, though, that higher API loadings are typically achievable with polymeric micelles and nanoparticles.
Generally, extensive experimental screening is performed using a variety of excipients to find the right match, according to Shah. Starting from the structural properties of the drug substance, Pironti adds that it is possible to define a strategy for solubility enhancement using in silico models. “Such models enable scientists to start with a limited panel of excipients to increase solubility with a design-of-experiment approach,” she explains.
For instance, if the API is hydrophobic and the excipient is an emulsifier, the API will sequester into the hydrophobic core of the emulsifier. Indeed, she points out that excipients with a hydrophobic group and sufficient hydrophilicity to coexist in an aqueous environment are effective emulsifiers and useful solubilizing agents. Polysorbate 20 and polysorbate 80 are popular excipients in the formulation of parenteral therapeutics. Polyethoxylated surfactants and polyethylene glycols have also been evaluated regarding their ability to improve solubility in these applications.
One overarching consideration for the formulation of poorly soluble APIs for parenteral administration, stresses Shah, is that there is no one-size-fits-all excipient. “Studies are still ongoing that aim to understand which API properties contribute to optimum interactions with different excipients,” she notes. Heller agrees. “Excipients must be carefully chosen and fine-tuned for each API.”
Polymeric micelles work by encapsulating poorly water-soluble APIs within their inner cores, thus shielding the drug substances from the aqueous environment. They are attractive for several reasons, notes Shah, including the fact that polymeric excipients tend to have fewer toxicity issues and are relatively safe at higher concentrations compared to small-chain surfactants. Many are also biocompatible and formed from amino acids or other building blocks that exist within the human body.
According to Schäfer, they can be assembled from a variety of different polymer types, with the most popular choices including polyethylene glycol, polyethylene oxide, stearic acid, and G-chitosan. “All of these polymers have hydrophobic regions that orient towards the cores of the micelles and hydrophilic regions that orient towards the external aqueous medium,” he explains. The polymers exhibit self-assembly behavior triggered by forces such as hydrophobic interactions, electrostatic interactions, and complexation. The resulting micelles are typically smaller than 100 nm in diameter.
Amphiphilic bioabsorbable diblock copolymers such as poly(ethylene glycol)-methyl ether-block poly(DL-lactide) (mPEG-b-poly(DL-lactide) and poly(ethylene glycol)-methyl ether-block poly(DL-lactide-co-glycolide) are commonly used, according to Heller. When formulated with these polymers, hydrophobic APIs associate with the hydrophobic lactide/glycolide polymer segments, while the hydrophilic PEG polymer segments arrange themselves into the surrounding aqueous environment.
“Micelles or nanoparticles are formed based on the molecular weight of the block copolymers,” Heller continues. In the end, extremely small, high-surface area nanomicelles or nanoparticles are generated that are colloidally stabilized by the outer hydrophilic polymer PEG segments. The size and physical properties of polymeric micelles and nanoparticles improve API solubility and enhance API exposure to patients, he comments.
Genexol PM (Samyang Holdings) is an example of a recently introduced commercial paclitaxel product formulated using 20- to 50-nm mPEG-b-poly(DL-lactide polymeric micelles. It offers, according to Heller, sustained release over 48 hours with improved solubility and efficacy and reduced toxicity and hypersensitivity compared to more conventional formulations containing surfactants.
“Polymeric micelles and polymeric nanoparticles are attractive preparations because they combine high loading efficiency, favorable pharmacokinetics properties, and improved clinical efficacy,” Heller concludes. “We see future potential for polymeric micelles and polymer nanoparticles made with biocompatible, bioabsorbable mPEG-b-polylactide diblock copolymers,” he predicts. "These diblock copolymers are part of that class of lactide/glycolide polyester functional excipients that have a proven safety record as evidenced by the number of long-acting injectable products (60) and bioabsorbable medical devices that have been on the market for decades,” Heller explains.
Shah also sees polymeric micelles as an exciting technological advancement for parenteral formulations. In addition to block co-polymers such as PEGylated polylactic acids, PEGylated polyglycolic acids, or even a combination of lactic and glycolic acids, she finds the polaxamers, or pluronics, have also been used for micelle formation and solubility enhancement. “These triblock co-polymers [have] a more hydrophobic central portion of the chain that forms the core, with more polar, hydrophilic ends extending out into the aqueous milieu.”
An example of a new excipient technology for increasing the solubility of parenteral formulations based on polymeric micelles comes from LLS Health. Its Apisolex excipient is a multiblock co-polymer comprising a polysarcosine block and a D-/L- mixed poly amino acid block, according to Shah. “Sarcosine is an amino acid derivative that is naturally found in human muscles and tissues, making it a biocompatible alternative to existing excipients used in parenteral formulations, especially where high drug loading is desired,” she says. In the polymeric micelles formed by Apisolex polymer, the mixed poly amino acid block forms the hydrophobic cores while the polysarcosine block forms the hydrophilic coronas.
LNPs also encapsulate APIs, but they are structurally different from polymeric micelles. “Solid LNPs house hydrophobic APIs within the lipids in a solid core that remains solid even when the particles are dispersed in the aqueous environment. Nanostructure vesicles, meanwhile, consist of both liquid and solid lipid components/compartments within the solid particles,” says Shah.
LNPs have recently become well known for their use in protecting messenger RNA (mRNA) from degradation and aiding in its cellular uptake, but they can be advantageous for many other drug substances. While nucleic acids such as mRNA and small interfering RNA (siRNA) do not have poor solubility properties, they can enhance the solubility of more conventional small-molecule APIs. “LNPs can provide improved bioavailability and controlled release for poorly soluble small molecules, and there have been many examples in the oncology area reported in the literature,” Pironti observes. “The future for LNPs lies in the development of new functional lipids to navigate the patent landscape and enable targeting of specific organs, tissues, and cells,” contends Heller.
Given that most new drug candidates suffer from poor solubility to some degree, much work has been focused on identifying a wider array of solutions for solubility enhancement. For parenteral drugs, cyclodextrins are an example of a type of excipient that has been re-discovered and used with increasing frequency in recent years.
These cyclic oligosaccharides are derived from natural starch and arranged in the form of a hollow cone with a hydrophilic exterior and hydrophobic interior and thus can shield a broad range of hydrophobic, poorly water-soluble APIs from aqueous media, according to Schäfer. He adds that they exhibit a very good safety profile, which makes them suitable for parenteral administration. In addition, cyclodextrins may also protect APIs from chemical degradation, reduce protein aggregation, and mask odors and tastes. One example highlighted by Schäfer is the use of sulfobutylether-β-CD for the formulation of remdesivir, a parenteral drug used for the treatment of COVID-19.
Heller points to albumin nanoparticles and synthetic polypeptides and other excipients that have attracted attention as solubility enhancers for parenteral formulations.
Using excipients to optimize solubility presents some challenges, because this type of formulation work typically takes place during the latter part of the development cycle. “Often developers will find that formulation optimization alone is not sufficient to enhance API solubility. It is therefore recommended that API solubility issues be tackled sooner in the development process,” states Schäfer.
That entails looking at API processing to improve drug solubility. In addition to particle-size reduction by, for example, nanomilling, salt formation, cocrystal formation, and polymorph screening are also important avenues to pursue, according to Schäfer. “These methods not only offer the possibility to significantly enhance solubility, but can also tackle characteristics like physical and chemical stability, dissolution rate, and processability,” he says. Further optimization by formulation can then be layered on if needed. In fact, Schäfer believes that API processing and tailored formulation should go hand in hand to achieve the optimum probability of success for drug candidates.
Traditionally, there has been limited development in novel excipients for solubility enhancement. Developers tend to focus, Shah observes, on creating new formulation technologies using excipients with a known safety profile rather than developing new excipients for solubility enhancement. “For example, there is significantly more [effort] to develop new technologies using existing polymers with known toxicity profiles, such as amorphous solid dispersion technologies, than [to develop] novel excipients for improving solubility of poorly soluble drugs,” she says.
More recently, however, Shah observes that novel excipients are becoming an attractive route as well. “Novel excipients present a way to leverage existing techniques and achieve the same, if not better, results,” she insists. They also provide increased IP protection and, because the IP is new, longer patent life for drug developers and marketers to leverage. Novel excipient IP may, in particular, be useful for older clinical candidates that have previously been shelved due to solubility issues, she notes.
Polymeric excipients, especially those which enable micelle formulation, are a good example. “These new excipients provide a significant means for achieving better solubility and high drug loading for APIs that previously failed during the drug-development process. Using the FDA’s [US Food and Drug Administration’s] 505(b)(2) regulatory pathway also allows reformulation of previously approved drug substances with novel excipients for enhanced biological performance but lower application risk and expedited time to market,” she concludes.
1. T. Loftsson and M. E. Brewster, J. Pharm. and Pharmacol., 62 (11), pp. 1607–1621 (November 2010).
Cynthia A. Challener, PhD is contributing editor to Pharmaceutical Technology.
Volume 46, Number 11
When referring to this article, please cite it as C.A. Challener, “Excipients for Solubility Enhancement of Parenteral Formulations,” Pharmaceutical Technology 46 (11) 2022.