Although such biologics as monoclonal antibodies (mAbs), recombinant proteins, and nucleic acid-based therapies have revolutionized disease treatment across therapeutic domains, their utility remains constrained by a near-exclusive reliance on parenteral administration. Intravenous and subcutaneous administrations pose challenges for patient compliance, safety, and accessibility. Because of the limitations on parenteral routes of administration, the development of non-parenteral alternatives, such as oral, inhaled, transdermal, and intranasal formats, represents both a clinical imperative and a formidable scientific challenge. 

An evaluation of the molecular and technical barriers to non-parenteral biologics delivery, as well as reviews of state-of-the-art advancements in formulation technologies and an assessment of current collaborative progress across the biopharmaceutical ecosystem, can shine light on where the biopharma industry stands today in terms of non-parental formulation market readiness. The latest developments led by contract manufacturers, biotechnology innovators, and academic partners will highlight the progress and outlook for emerging delivery systems poised to redefine patient-centric biologics administration (1–3).

How is the biologics delivery landscape evolving?

Despite the promise of mAbs, recombinant proteins, and nucleic acid-based therapies, more than 95% of biologics are still administered via injection or infusion. This dominant reliance on parenteral administration stems from the complex physiochemical properties of biologics, which are of large molecular weights and have structural fragility, as well as susceptibility to enzymatic degradation. These characteristics preclude simple oral dosing. However, reliance on repeated injectable dosing has been shown to result in reduced patient adherence, fear of needles, and added burden on healthcare systems (1–3).

The industry has thus turned its attention to alternative, less-invasive delivery modalities. Oral and inhaled biologics are attracting intensified R&D investment due to their broad patient acceptance, potential for home administration, and alignment with precision medicine initiatives. Market forecasts underscore this momentum. For instance, the oral biologics market is projected to expand at a compound annual growth rate (CAGR) of 35% between 2023 and 2028, while the inhalation contract development and manufacturing organization (CDMO) sector is expected to grow from $1.94 billion in 2023 to $2.7 billion by 2028, a 7.1% CAGR. In specific disease areas, such as asthma, biologic therapies are projected to reach $19.2 billion by 2031, signaling significant demand for innovations in pulmonary delivery (4,5).

What challenges present hurdles to non-parenteral biologics delivery?

Biologics are inherently more complex than small-molecule drugs owing to their large molecular weights, higher structural complexity, and sensitivity to pH, temperature, and proteolytic enzymes. Furthermore, the cost of biologics manufacturing places extreme importance on bioavailability, where even marginal losses during administration render a dosage form economically unviable (1,2,5,6).

Oral delivery of biologics faces route-specific obstacles, such as rapid degradation via enzymes in gastric and intestinal environments; impermeable epithelial and mucosal barriers, which prevent molecules larger than a few hundred Daltons (Da) from passing through (antibodies are typically >150 kDa); reduction of systemic bioavailability upon first-pass metabolism; and intestinal variability across patient populations, which further complicates pharmacokinetics (3). Clinical successes for oral biologics have been scarce, with oral peptide products (e.g., oral semaglutide) demonstrating feasibility but not yet scalability for large proteins or antibodies (7–8).

Although inhalation delivery offers direct access to systemic circulation through pulmonary vasculature, this route of administration suffers from technical and clinical constraints. Historical failures of inhaled insulins (e.g., Pfizer’s Exubera) have highlighted flaws in device ergonomics, interpatient variability, and costs as major barriers to commercialization. In addition, biologics must be formulated to remain stable during aerosolization, storage, and pulmonary transport, which often presents a steep technical challenge (2,9).

Meanwhile, a transdermal delivery option is severely limited by the outermost layer of skin (stratum corneum), which blocks hydrophilic and high-molecular-weight compounds. Advanced approaches, such as microneedle arrays, iontophoresis, and microporation, show promise but are so far limited to peptides or low-dose biologics (10).

What cutting-edge formulation and delivery technologies are in the works?

Particle engineering and inhalation platforms.

 Lonza is advancing particle engineering strategies to modulate pharmacokinetics and bioavailability in spray-dried powders. Collaborations with Iconovo have yielded intranasal biologics targeting obesity, leveraging the ICOone Nasal device to optimize dose delivery (11). Similarly, Lonza’s collaboration with Ethris is aimed at applying spray-drying techniques to stabilize messenger RNA (mRNA)-based vaccines at room temperature, reducing cold chain dependency while maintaining mRNA integrity (12).

In addition, CrystecPharma, in partnership with Intertek, is leveraging its modified supercritical anti-solvent (mSAS) technology to precipitate biologics into stable dry particles. Their fast-track dry powder inhaler platform accelerates development from laboratory design to good manufacturing practice and offers a robust approach for inhaled protein and peptide therapies (13).

 Lonza is also pursuing smart capsules, designed for site-specific targeting within the gastrointestinal tract. These smart capsules employ mechanical and electronic components that enable release in the stomach or intestine. Bi-layer capsule technologies further allow compartmentalized release profiles tailored to molecule-specific pharmacology (14).

Meanwhile, Catalent Pharma Solutions is exploring lipid-based formulations (LBFs), building on established small-molecule solubilization methods to enhance macromolecular absorption. One promising line of research focuses on transiently modulating intestinal tight junctions to facilitate the uptake of high molecular weight biologics, a potentially transformative approach for oral mAbs (15–16).

US Specialty Formulations (USSF) has advanced QYNDR, a drinkable, protein-based oral/mucosal vaccine that demonstrated safety in Phase I COVID-19 clinical trials in 2023. Such approaches bypass the gastrointestinal degradation barrier by targeting mucosal tissue for immune activation, representing an alternative strategy for non-parenteral vaccination (17,18).

 Transdermal microneedle patches, jet injectors, and sonophoresis platforms are also under evaluation for delivering smaller biologics, such as peptide vaccines. While dose limitations restrict broader application, such technologies could complement inhaled and oral products in specific contexts, particularly for pediatric or resource-limited populations (1,10).

 The urgency of the COVID-19 pandemic catalyzed progress in non-parenteral biologics, particularly inhaled and intranasal vaccines. Self-administered inhalable or nebulized mRNA/lipid nanoparticle formulations targeting pulmonary diseases are anticipated in the near-term. These formats may be especially impactful for respiratory-targeted therapies, enabling localized lung delivery with systemic immune benefits (19).

 Despite substantial momentum, effective oral or inhaled mAbs remain elusive. Addressing dose limitations, ensuring molecular integrity through complex biological barriers, and establishing reproducible absorption profiles remain key barriers. Moreover, large-scale clinical validation and long-term safety data will be essential before such platforms achieve widespread commercialization (2,3,7,8).

 The diversity of biologics under development suggests that no single non-parenteral strategy will dominate. Instead, modalities will be tailored: oral delivery for chronic, systemic diseases; inhalation or intranasal delivery for respiratory or mucosal immunity; and transdermal approaches for lower-dose applications. The overarching driver will continue to be the pursuit of patient-centric care—convenient, non-invasive, and accessible therapeutics that reduce healthcare burdens while improving treatment adherence (1,2).

1. Mitragotri, S.; Burke, P. A.; Langer, R. Overcoming the Challenges in Administering Biopharmaceuticals: Formulation and Delivery Strategies. 


2. Chauhan, V. M.; Zhang, H.; Dalby, P. A.; Aylott, J. W. Advancements in the Co-Formulation of Biologic Therapeutics. 


3. Muralidhara,B. K.; Wong, M. Critical Considerations in the Formulation Development of Parenteral Biologic Drugs. 

Global Oral Biologics Market Size, Share, Trends & Growth Forecast Report by Drug Class, Disease Indication, Distribution Channel, and Region (North America, Europe, Asia-Pacific, Latin America, Middle East and Africa), Industry Analysis from 2025 to 2033

. Market Research Report. April 2025.
5. The Business Research Company. 

Inhalation CDMO Global Market Report 2025—by Product (Dry Powder Inhaler (DPIs), Metered Dose Inhaler (MDIs), Nebulizer, Soft Mist Inhaler), by Disease Indication (Asthma, Chronic Obstructive Pulmonary Disease (COPD), Pulmonary Arterial Hypertension, Acut

 Market Research Report. January 2025.
6. Synapse by Patsnap. 

What are the Common Challenges in Biologic Drug Development

. March 20, 2025.
7. Andersen, A.; Knop, F. K.; Vilsbøll, T. A Pharmacological and Clinical Overview of Oral Semaglutide for the Treatment of Type 2 Diabetes. 


8. Kalra, S.; Das, S.; Zargar, A. H. A Review of Oral Semaglutide Available Evidence: A New Era of Management of Diabetes with Peptide in a Pill Form. 

 
9. Cefalu, W. T. Concept, Strategies, and Feasibility of Noninvasive Insulin Delivery. 


10. Prausnitz, M. R.; Langer, R. Transdermal Drug Delivery. 

Iconovo and Lonza to Collaborate on the Formulation Development of an Intranasal Biologic

. Press Release. Jan. 13, 2025.
12. Ethris. 

Ethris and Lonza Collaborate to Develop Spray-Dried mRNA Vaccines for Respiratory Disease Prevention

. Press Release. Feb. 11, 2025.
13. Intertek. 

Intertek Partners with CrystecPharma to Advance Formulation Science and Accelerate Development Timelines for Dry Powder Inhaler Products

. Press Release. Dec. 11, 2024.
14. Lonza. 

Lonza Launches Tailored Offering for Smart Capsules Companies Developing Oral Delivery Solutions for Biologic Drugs

. Press Release. Dec. 3, 2024.
15. Mirasol, F. 

The Need for LBFs and Challenges in Oral Biologic Formulation (AAPS PharmSci 360)

Lipid-Based Delivery Systems—New Approaches for Macromolecule Oral Delivery, Abuse Deterrence & Bioavailability Enhancement

US Specialty Formulations Completes Phase I of Clinical Trials for the QYNDR Vaccine

. Press Release. Sept. 7, 2023.
18. Zhang, Z.; Hong, W.; Zhang Y.; et al. Mucosal Immunity and Vaccination Strategies: Current Insights and Future Perspectives. 

How Inhaled mRNA May Help Rare Disease Patients Breathe Easier

When referring to this article, please cite it as Mirasol, F. Challenges, Innovations, and Future Outlook of Biologics Formulations. 

Articles

Biologics, including monoclonal antibodies and nucleic acid-based therapies, face challenges due to their reliance on parenteral administration, impacting patient compliance and accessibility. The industry is exploring non-parenteral delivery methods like oral, inhaled, and transdermal formats, driven by patient-centric care and precision medicine. Despite technical hurdles, advancements in formulation technologies and collaborations are paving the way for innovative delivery systems. The market for oral and inhaled biologics is projected to grow significantly, although challenges in bioavailability and stability remain critical barriers to widespread adoption.

Non-parenteral alternatives for biologics remain a clinical imperative and a formidable challenge.

Challenges, Innovations, and Future Outlook of Biologics Formulations

Radiopharmaceuticals have seen a surge in research and clinical trials as a treatment for cancer due to their ability to target specific cancer cells. Studies suggest that targeted radiation therapy may reduce the risk of side effects, according to the National Cancer Institute at the National Institutes for Health (1).

“Radiopharmaceuticals also work best when the drugs can get inside cells. But that’s not necessary for them to be effective. Once a radiopharmaceutical has stuck to a cancer cell, the radioactive compound naturally breaks down. This decay releases energy that damages the DNA of nearby cells. And when a cell’s DNA is irreparably damaged, that cell dies. Cancer cells are particularly sensitive to radiation-induced DNA damage” (1).

® spoke with Michael Ritchie, chief commercial officer at Champions Oncology, to find out what makes radiopharmaceuticals unique for the treatment of cancer.

Ritchie also talks about FDA’s draft guidance document, 

Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development

, which the agency published on Aug. 18, 2025 (2). The guidance was created to assist drug sponsors with identifying an optimized dosage for radiopharmaceutical therapies for oncology indications during clinical development.

PharmTech: What is unique about the use of radiopharmaceuticals to treat cancer?

 Actually, radio pharmaceuticals have been around for the past 100 years or so. They were used early on to treat more superficial tumors [such as] melanoma and using large machines to direct focused radiation to the tumors. And as that technology evolved, we were able to treat more internal tumors.

So, it’s been around for a very long time, but we’re in the middle of a transformation right now in radiopharmaceuticals, and much of that is owed to a field called antibody-drug conjugates [ADCs]. [ADCs] have been around for quite a while. That’s that magic bullet idea that you can take a chemotherapeutic or something that’s otherwise very toxic to every cell in a patient and direct that to the tumor, specifically, so that you impact only the tumor and nothing else. The first of those drugs was approved in 2000. It’s a drug called Mylotarg, and it really took us 25 years to have a good understanding of what makes a good ADC. Where can they be effective? From a therapeutic point of view, what do we need to do to make this drug long lasting in the patient?

Now we have [seen] really strong, durable responses in patients with ADCs. Now that we have a good understanding of that, we can take these radio ligands, which essentially [are] an element on the periodic table that introduces radiation in a focused way, and we can conjugate that to an antibody in the same way that these ADCs work. And so, with the advent of success in ADCs, we now have radio drug conjugates, and we’re starting to see people employ radio ligands in a similar way to a chemotherapeutic and direct it to a patient administered systemically. It’s really an exciting period, because it’s a new mechanism of action where we can potentially tackle unmet needs.

PharmTech: What are some of the specific challenges associated with the development of radiopharmaceuticals?

 There [are] real challenges across the board. There are therapeutic development challenges as well as the biology of treating these tumors. From a therapeutic development perspective, we’re still in our infancy as far as what we understand makes a good drug.

There’s so much [put] into pharmaceutical development [to make] something that can be manufactured at scale. It can sit on a shelf for a while. We can administer it to a patient, and it behaves in the way that we want. All of that chemistry, all of that biologics development, we’re just learning how to apply what we learn from ADCs into radio drug conjugates, so the chemistry of how to link this radio ligand to an antibody, [is] something that will continue to evolve, and there’s a real opportunity there to improve the therapeutic activity.

From the biology perspective, again, we’re in our infancy and understanding [of] what are the tumor types or the molecular cohorts within a tumor that are more sensitive to radio ligands. Like any chemotherapy or any therapy, certain tumors will respond. Others will not. They’ll develop resistance. And so really understanding the right cohorts of patients to treat is something that we’re still learning, and I think we’ll continue to learn as the clinical development of these programs evolves.

PharmTech: Can you please explain how clinically annotated patient-derived xenograft (PDX) models are used in radiopharmaceutical testing?

 PDXs are used from a couple different perspectives in radiopharma testing. It really comes back to that second hurdle that we need to overcome in understanding what tumor types or molecular cohorts respond. It’s really important that you do your drug testing and models that represent the tumors that your drugs [are] going to be up against in the clinic. Patients tend to be heavily pretreated. When they take an experimental medicine, their tumor has metastasized to multiple organs, and those are, unfortunately, the lesions that ultimately kill the tumor. Those are the lesions you need your drug to combat effectively. And so, using models that are representative of that biology are key. We simulate clinical trials in animals where we will take our tumor bank, we’ll grow them in animals, and then you’ll test your drug across a broad library of tumor[s] [that] simulate that clinical trial. Then, when you see where you have an effect and where you do not have an effect, we’ll look deeply at the molecular nature of these tumors and try to predict in the clinic which patients should receive the drug because they’re most likely to benefit versus those that are likely to benefit from a different type of therapy.

PharmTech: Why is it important to use real-world data in this type of testing?

 Real-world data are a real important data set, and they’ve been around for a while. And the way I think of real-world data is, is there information on patients? What’s the stage of their tumor, the metastatic nature of it? What were they treated with? How did they respond?

That’s a very important layer. But I think there’s another side to the coin that we really need to think about, and that is, what’s the molecular nature of the tumors associated with that patient? What makes those tumors tick? What are the vulnerabilities and the liabilities within those tumors that you could potentially exploit in therapeutic development? I think Champions is actually one of the unique companies that have both of those sides of the coin. We have a large data set of real-world evidence linked to very deep molecular data of the tumor, whole cell exome sequencing, RNA [sequencing], proteomics, phospholipids, cell surface proteomics. This really allows researchers to dive deep [and] understand molecular characteristics of the tumors that potentially impact survival [and] impacts resistance to the therapeutic. It just gives them real insight early on [about] how to design their clinical trials. As companies come to Champions and they simulate these clinical trials, they utilize these data for prediction purposes and for driving greater insights.

PharmTech: How does FDA’s new draft guidance on identifying dosages for clinical trials of oncology radiopharmaceuticals impact the development and approval of these treatments?

 Classical radiopharma relied on something called EBRT, or external beam radiotherapy, and that is essentially delivering a radio beam to the patient from an external source. But we’re now looking at a new wave of therapies which are injected systemically, and quite frankly, we just don’t know enough about them. And so, FDA has released new guidance that has said, ‘Hey, we want you to come to the table with a better understanding of pharmacodynamics potential liabilities from a toxicity perspective, therapeutic window. But we also want you to design your clinical trials in such a way that we can get an idea on dosimetry. We can get a good idea on toxicity from an acute perspective, but we want you to monitor these patients for a longer period of time to look for more chronic toxicities that could arise. And we want you to try different therapeutic doses, different therapeutic schedules. We really want you to throw quite a lot at this, so that if we consider approving these, we have a better understanding, or the best understanding, of what these patients are receiving’.

What are some of the challenges involved with clinical trials for radiopharmaceuticals to treat cancer?

 I think there’s both scientific and logistic challenges here. From the scientific side, we really just don’t know what we don’t know. These haven’t been around for very long, so we’re really unaware of the tumor types that respond to these types of therapies. We’re unaware of the types of toxicities.

If you think about ADCs, which are kind of a second cousin to these therapies, after more than two decades of research, we have a really good understanding of what organ types are. You can easily sustain those types of therapies, and we know how to manage the patient care for different classes. For [radiopharmaceuticals], we just, we just don’t know. And so that creates a challenge. We also really don’t understand, I think, quite yet, what makes the best possible radiotherapy from pharmaceutical sciences perspective.

From the drug development side, the logistics are very, very different. This is a highly regulated space. We’re dealing with nuclear medicine. The nucleotides themselves aren’t so readily available, so that brings challenges. And then obviously not every clinical site that will receive patients for a clinical trial is set up or equipped to offer this type of therapy, so patient enrollment can be a challenge.

And then finally, these nucleotides have a short half-life and a short shelf life. And so, it’s not like drugs can be manufactured and stuck in a refrigerator for months as they’re waiting to be used for a trial. They kind of have to be made and then used within a week, so there’s some logistical hurdles as well.

NCI Staff. Radiopharmaceuticals: Radiation Therapy Enters the Molecular Age. National Cancer Institute. 

https://www.cancer.gov/news-events/cancer-currents-blog/2020/radiopharmaceuticals-cancer-radiation-therapy

Draft Guidance for Industry, Oncology Therapeutic Radiopharmaceuticals: Dosage Optimization During Clinical Development

https://www.fda.gov/regulatory-information/search-fda-guidance-documents/oncology-therapeutic-radiopharmaceuticals-dosage-optimization-during-clinical-development

When referring to this article, please cite it as Haigney, S. Why Radiopharmaceuticals Are Ideal for Treating Cancer. 

Radiopharmaceuticals are gaining traction in cancer treatment due to their ability to target specific cancer cells, minimizing side effects. The integration of antibody-drug conjugates (ADCs) has advanced the field, allowing for precise delivery of radiation to tumors. Challenges remain in optimizing dosage, understanding tumor sensitivity, and overcoming logistical hurdles in clinical trials. The FDA's draft guidance emphasizes the need for comprehensive understanding of pharmacodynamics and toxicity. Real-world data and patient-derived xenograft models are crucial for predicting treatment efficacy and designing effective clinical trials.

Michael Ritchie, chief commercial officer at Champions Oncology, explains what makes radiopharmaceuticals unique in the treatment of cancer.

Why Radiopharmaceuticals Are Ideal for Treating Cancer

Patient-centric drug development is essential to improve patient outcomes, experience, and engagement. By focusing on patients’ needs, experiences, and preferences, drug developers can create treatments that are optimally effective and tolerated. This leads to improved adherence to treatment regimens and better overall health outcomes when compared with not taking these factors into consideration (1). Regulatory bodies like FDA emphasize the importance of patient-focused drug development. They provide guidance on incorporating patient input into drug development and evaluation, which can facilitate smooth regulatory approval processes (2). Ensuring that patients’ needs and preferences are central to drug development acknowledges them as key stakeholders in their own healthcare. It respects their autonomy and dignity. Patient-centric approaches encourage understanding the patient population or sub-groups (through various forms of research) and using the information to inform drug development.

Certain populations, such as pediatric, geriatric, and dysphagic patients and those with chronic conditions, can struggle with taking medicine. Children often have difficulty swallowing tablets and may be sensitive to the taste of medications. Older adults often face such challenges as dysphagia (difficulty swallowing), polypharmacy (taking multiple medications), and cognitive impairments. Patients with dysphagia require medications that are easy to swallow or do not require swallowing at all. Patients with chronic conditions may often require long-term medication and benefit from fixed-dose combinations and extended-release formulations, which can improve adherence (3). These populations demonstrate the breadth of challenges facing drug product formulators, such as swallowing difficulty, poor palatability, dosing accuracy, and complicated or overwhelming medication regimes, all of which can result in poor compliance. Thus, it is important to consider patient-friendly drug delivery formats for these populations.

Patient-centric oral drug design focuses on creating medications that are easier and more pleasant for patients to take, thereby improving compliance and overall treatment outcomes. Approaches that can appeal to individuals that have difficulty swallowing include chewable tablets, fast-dissolving films or tablets, liquids, and particulate or granule sachets. Chewable tablets are designed to be chewed and swallowed, making them easier for children and adults who have difficulty swallowing tablets whole. They often come in pleasant flavors to enhance the experience. Fast-dissolving films and tablets dissolve quickly in the mouth without the need for water. They are convenient for patients who have trouble swallowing or need medication on the go. Sachets contain powdered, granulated, or particulate medication that can be mixed with water or food, offering convenient drug administration. Liquid formulations are ideal for patients who cannot swallow tablets or prefer a liquid form. They allow for flexible dosing and can be flavored to mask the taste of the medication.

The pharmaceutical liquid suspensions market is experiencing significant growth, driven by a compound annual growth rate of 6.5%, with projections to reach $5.2 billion by 2033 (4). This growth is driven by the increasing demand for patient-focused formulations for such populations as older adults. Approximately 27–29% of older patients report difficulties with swallowing, which can significantly impact their ability to take medications and lead to issues like aspiration pneumonia, malnutrition, and weight loss (5,6). Liquid suspensions offer ease of administration and flexible dosing, making them a preferred choice for older adults.

Technological advancements have played a crucial role in enhancing the stability, bioavailability, and palatability of liquid suspensions. Such innovations as nanotechnology and taste masking techniques have improved the overall patient experience (4,7). Additionally, the development of extended release formulations has reduced dosing frequency, further improving patient compliance (4). Liquid suspensions can enhance patient compliance due to easier administration and better palatability—particularly important for patients with chronic conditions requiring long-term medication (8).

For patients with dysphagia, or difficulty swallowing, thickened liquid suspensions provide a safer alternative to thin liquids, which can pose a risk of aspiration (4,7). Thickened liquids flow more slowly, allowing for better control during swallowing and reducing the risk of choking (4,7). This makes liquid suspensions a viable option for delivering medications to patients with dysphagia, ensuring treatment without compromising safety (7). While 42.4% of patients generally prefer tablet dosage forms, liquid suspensions are favored by those with swallowing difficulties, allowing for precise and flexible dosing that can improve adherence (1,9).

Three main types of oral liquid drug delivery systems exist: solutions, suspensions, and emulsions. Solutions are homogeneous mixtures in which the drug is completely dissolved in a solvent, which ensures uniform drug distribution, leading to consistent dosing and rapid absorption. Suspensions consist of finely divided drug particles dispersed in a liquid medium, useful for drugs that are insoluble in water. Proper formulation ensures that the particles remain evenly distributed and do not settle quickly. Emulsions are defined as mixtures of two immiscible liquids, typically oil and water. They are stabilized by emulsifying agents and can enhance the bioavailability of drugs that are poorly soluble in water.

Effective oral liquid drug products must have good stability, palatability, and preservation. Ensuring the physical and chemical stability of the formulation is critical. Such factors as pH, temperature, and light exposure can affect the stability of liquid formulations. Proper formulation and packaging can help to maintain stability. Techniques to improve palatability are essential, especially for pediatric and geriatric patients. Flavoring agents, sweeteners, and taste-masking technologies can be used to enhance the taste of liquid medications. Preventing microbial growth is crucial for the safety of liquid formulations; thus, the addition of preservatives ensures that the product inhibits microbial contamination throughout its shelf life.

Excipient selection in oral liquid dosage forms

Choosing appropriate excipients is a vital step for solubility, stability, and taste. Excipients, such as solvents, suspension aids, stabilizers, and flavoring agents, play a significant role in the overall effectiveness and acceptability of the formulation. Their selection is not merely supportive but central to the success of patient-centric drug design, especially in pediatric and geriatric patients and those with swallowing difficulties.

 (e.g., purified water, glycerin, propylene glycol) are essential for dissolving the API in solution-based formulations. They influence the bioavailability and absorption rate of the drug (10). For poorly water-soluble drugs, co-solvents or solubilizers like polyethylene glycol may be used to enhance solubility (11).

, such as xanthan gum and colloidal microcrystalline cellulose—which is a co-processed excipient comprising microcrystalline cellulose (MCC) and sodium carboxymethyl cellulose (NaCMC)—help maintain uniform distribution of insoluble particles in suspensions. These agents prevent sedimentation and also ensure dose uniformity, which is critical for accurate dosing (10). The inclusion of the right amount of suspension aid can be a delicate balancing act between good suspension properties without being overly viscous. One case study involving an oral reconstitutable azithromycin suspension showed that inadequate amount of suspension aid (xanthan gum) led to inhomogeneity (phase separation), while inclusion of too much suspension aid rapidly increased the suspension viscosity (12).

 (e.g., antioxidants like sodium metabisulfite, chelating agents like ethylenediaminetetraacetic acid, preservatives like sorbic acid, and surfactants like polysorbates) protect the formulation from degradation due to oxidation, hydrolysis, or microbial contamination. Without stabilizers, the shelf life and efficacy of the product can be significantly compromised (10). These also need to be included in sufficient quantities to be effective. When sodium benzoate was included at less than 0.05% w/w in a topical formulation, the samples did not pass the 

 (e.g., sucrose, sorbitol, artificial flavors) are crucial for masking unpleasant tastes, especially in pediatric formulations. Palatability, especially poor palatability, directly affects adherence to treatment regimens. Inadequate taste masking can lead to poor compliance and therapeutic failure (10,14).

If key excipients are omitted or improperly selected, consequences can occur. For example, the API may precipitate, leading to inconsistent dosing. The formulation may degrade faster, reducing efficacy (and possibly unintended side effects). Microbial growth may occur in liquids without preservatives. Omitting taste modifiers could result in non-compliance. Ultimately, excipients are not just inert ingredients—they are functional components that ensure the drug product is safe, effective, and acceptable to the patient (10).

Rheological performances of suspension aids or agents, such as gel-like structure, thixotropic property, viscosity profile, and stability, are crucial to the successful development of a suspension formulation. Colloidal MCC is a great example of a suspension aid with ideal rheological performance. When activated in water, colloidal MCC forms a thixotropic gel-like structure that can be stable for months. The thixotropic behavior means it can flow easily under shear stresses, like pouring out of a bottle, and slowly regains its structure or viscosity upon removal of the stress (i.e., storage). The colloidal MCC can be used for both pre-made liquid suspensions (like Avicel RC-591) or reconstitutable suspensions (like Avicel CL-611).

Other common excipients used as suspending aids are xanthan gum and NaCMC. Xanthan gum is a high molecular weight polysaccharide produced by the fermentation of glucose or sucrose by various strains of the bacterium 

. Its ability to make highly viscous solutions at low concentrations makes it amenable to suspensions. NaCMC is an anionic polysaccharide produced by chemically modifying cellulose to make it soluble in water. The functional properties of NaCMC are able to be modulated by changing the substitution on the cellulose backbone and the molecular weight. Both xanthan gum and NaCMC can be used to increase the viscosity of a solution, thus helping to keep insoluble particles suspended.

The following case studies highlight colloidal MCC, xanthan gum, and NaCMC when used as suspension aids. Colloidal MCC often demonstrates better suspension performance than xanthan gum and NaCMC, including shelf stability (case study 1). However, such conditions as low pH and high salt content are shown to stress colloidal MCC suspensions, leading to flocculation. Combinations of suspending aids are able to overcome some of these challenges, as highlighted in case studies 2 and 3.

Suspension case study 1: impact of suspension aid selection

In case study 1, the suspension capability of colloidal MCC, in both pre-made liquid and reconstitutable suspensions, was compared with that of xanthan gum and NaCMC in a paracetamol (2.4 wt%) model suspension. Paracetamol (acetaminophen) is a common active ingredient used in suspension formulations. Each of the suspension aids was added at recommended levels to achieve good suspension properties: 1.2 wt% for the pre-made liquid suspension, 2.4 wt% for the reconstitutable suspension, 0.5 wt% for xanthan gum (GRINDSTED 80 PRM Plus or Clear 80 PRM) and 0.5 wt% for NaCMC (TEXTURECEL 20,000 PA 07). The remainder of the formulation components (paracetamol, polysorbate 80, Lycasin 80/55, sodium benzoate, phenoxyethanol) were kept at constant concentrations (quantum satis water). The suspension formulations were evaluated for pH, rheological properties, sedimentation, and stability (up to four weeks at room temperature).

The pre-made liquid and reconstitutable suspensions exhibited thixotropic behavior (

) with a strong gel-like structure, while the suspensions with xanthan gum showed only some thixotropic behavior and moderate gel-like structure. The suspension that contained NaCMC did not have any thixotropic and gel-like characteristics. These different rheologic properties led to different suspending capabilities. As displayed in 

, the premade liquid and reconstitutable paracetamol suspensions were the most stable formulations after four weeks of storage, as measured by the TURBISCAN stability index (TSI). The TSI corresponds to the cumulative sum of all backscattering or transmission variations of the entire sample due to destabilization over time—and accordingly, the higher the value, the more unstable the sample (15,16). They possessed the lowest TSI, resulting in stability rankings of “A+” and “A,” respectively. TSI of suspensions with xanthan gum were ranked “C.” The formulation with NaCMC was not stable and ranked “D.”

Colloidal MCC, in pre-made liquid form, makes a strong and stable suspension, but has its limitations. Two conditions can destabilize the colloidal MCC structure: low pH and high salts. Adding a protective colloid to the formulation can often overcome these issues, as highlighted in the next two case studies.

Suspension case study 2: overcoming low pH

Acidic components, like citric acid, may be added to suspensions for many reasons:

to improve stability and/or solubility of an API or other components

to attempt to mask bitter flavor with more pleasant flavor

to reduce pH and aid in the prevention of microbial growth in the formulation

to buffer the formulation to resist changes to pH.

Low pH formulations are particularly challenging to suspensions using colloidal MCC, as it flocculates out. The suspension images below contain ibuprofen (2 wt%) formulations with citric acid anhydrous added to the formulation to modify the pH of the suspensions to approximately 2.7, below the recommended pH levels for colloidal MCC. After four weeks at room temperature, the pre-made liquid colloidal MCC sample was observed to have a visible aqueous layer on top (

). The TSI was higher for that suspension (5, “C”) than the reconstitutable one (1.3, “B”), all indicating the pre-made liquid suspension was flocculating. The reconstitutable suspension showed moderately good stability (grade “B”) over the four weeks and could be an option for low pH suspensions.

To overcome flocculation challenges of the pre-made liquid colloidal MCC suspension at low pH, a protective colloid can be added to the formulation. Xanthan gum (Clear 80 PRM) was added at 0.2 wt% to the pre-made liquid colloidal MCC formulated suspensions and showed stability improvements over those without xanthan gum (

). With xanthan gum, the suspension was stable for the full four-week test period at room temperature. One potential downside of adding xanthan gum is the significant increase in suspension viscosity: Without xanthan gum, the set-up viscosity of the suspension was about 250 cP (Brookfield at room temperature, spindle #3, 20 rpm) and increased to 700 cP with the addition of 0.2 wt% xanthan gum.

Suspension case study 3: overcoming high salt content

Salts may be added to suspension formulations for many reasons. They can be used as buffers to maintain a pH that is amenable to the API, and they can enhance absorption through mucosa (for nasal administration). Too much salt can cause the pre-made liquid colloidal MCC to flocculate and lose stability over time. Addition of a protective colloid, like xanthan gum, can restore the suspending powers of the formulation and maintain them throughout storage. The example here shows how incorporating calcium chloride (CaCl2) at concentrations from 0.5 to 1.5 wt% causes flocculation of the pre-made liquid paracetamol formulation after four weeks of room temperature storage (

). Adding 0.2 wt% xanthan gum (Clear 80 PRM) to the formulation with the highest salt content stabilized the suspension (TSI of “A”), even monitored out to four weeks (

The above case studies highlight the importance of excipient selection on the stability of a suspension formulation. It is equally important to both identify and understand how to overcome any limitations of those excipients. Advancements in formulation technologies are paving the way for more effective and patient-friendly liquid medications. Such techniques as nanotechnology, microencapsulation, and lipid-based delivery systems are being explored to enhance drug solubility, stability, and bioavailability (17).

The role of liquid medicines is poised to expand significantly as accessibility and personalization become even larger drivers. The number of patients who need more accessible dosage forms is increasing. The proportion of the world’s population older than 60 will nearly double between 2015 and 2050, from 12% to 22% (18). In populations with swallowing difficulties, dosage form and flexibility are paramount. Stability, taste, and reliable and accurate dosing are also important for pediatric populations, as they often have difficulties taking medicine. A 2021 survey of 1172 children in several European countries identified liquid as the most favored dosage form overall, especially for kids aged 12 and younger (19).

Liquid oral drug delivery systems offer significant benefits in patient-centric development, addressing such challenges as ease of administration, flexible dosing, improved compliance, and faster onset of action. With ongoing innovations and a focus on personalized medicine, liquid medicines are positioned to not only be more effective, but also ensure vulnerable populations receive the right treatment in the right form at the right time. Timing is everything.

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 is Global Strategic Marketing Manager, and 

, is Application and Innovation Technical Service Manager, Roquette.

When referring to this article, please cite it as Owens, L. and Zhang, Y. Selecting the Right Drug Delivery Formulations to Enhance Patient-Centric Care. 

Patient-centric drug development prioritizes patient needs, experiences, and preferences, enhancing treatment adherence and outcomes. Regulatory bodies like the FDA support this approach, emphasizing patient input in drug development. Special populations, such as pediatric, geriatric, and dysphagic patients, face unique challenges with medication intake, necessitating patient-friendly drug delivery formats. Liquid suspensions are gaining popularity due to their ease of administration and flexible dosing. Technological advancements, including nanotechnology and taste masking, improve liquid formulations' stability and palatability, enhancing patient compliance and treatment efficacy.

The growing demand for liquid medicines is increasingly driven by the unique needs of several distinct patient groups, improving compliance in these demographics through flexible, palatable dosing options.

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