Poorly water-soluble APIs in fixed-dose combinations: development, challenges, and opportunities in manufacturing techniques
Abstract
The incorporation of poorly soluble active ingredients, which make up the majority of the molecules in development, into fixed-dose combination (FDC) products can be an efficient method to improve the pharmacokinetic properties of these compounds, as well as reduce the side effects and enhance patient compliance by reducing the pill burden. The complexity of formulation development is given by the potential antagonistic interactions present between the components and the specialised equipment or formulation strategies necessary to overcome these limitations, as seen in recent literature in marketed formulations. Although conventional solid dispersions and solid-state alterations appear to be the most common ways of developing FDCs, recent advancements in additive manufacturing, electrospinning, coating, gastroretentive systems and nanomedicine have been successfully applied in formulating FDCs and proven to be promising platforms for novel oral combination systems. Additionally, computational methods and machine learning techniques have potential in accelerating the complex FDC formulation and processing by reducing the number of experiments through simulation of properties providing green, accurate and time-saving alternatives to conventional analytical testing.
Introduction
Modern drug discovery strategies such as phenotypic and target-based approaches have proven to be powerful tools in providing candidate targets and identifying suitable Active Pharmaceutical Ingredients (APIs) to target it 1, 2. However, the effectiveness of these single target chemical entities might not be sufficient, when considering highly complex diseases (such as diabetes, cancer, cardiovascular diseases) due to the multiple molecular pathways and interactions involved 3. This led to the development of combination drug regimens, where multiple active ingredients are administered in parallel, to simultaneously target multiple biological entities. Combination treatments can be beneficial to the patient for a variety of reasons, such as the potential of synergistic effects between active ingredients, the reduction of dosage for individual components or a delay in the development of resistance to drug treatment. However the potential for unwanted adverse effects or reduced patient compliance due to the complexity of treatment delivery are some of the challenges faced by combinational therapy 4.
Combination drug therapy can be administered in several ways with one being each drug being administered separately in given doses, while another approach would be to combine the drugs into a single dosage form. The last option is commonly referred to Fixed-Dose Combinations (FDCs) and are a group of pharmaceuticals that comprise of medicine used to deliver two (or more) active pharmaceutical ingredients within the same formulation. The formulation is produced, optimized and offered to the patient as a single dose 5. The combination of multiple API into one formulation presents some key advantages, particularly in chronic diseases, such as the ability to target multiple receptors at once 6, the possibility of reducing the adverse effects of one API with the other, a lower overall cost for the patient and reducing the amount of pills a patient is required to take 7. From a drug development perspective, by combining API with well-established pharmacokinetic pathways, safety and stability data, the development costs would significantly decrease, compared to the costs of building up a new chemical entity 8.
Oral delivery of drug products is the most common route of administration, due to the numerous advantages that it presents. Tablets, capsules, or lozenges are compact, easy to transport, are normally self-administered, come in flexible dose strengths, present a high level of stability for an increased product shelf life, a low cost of manufacture and relatively rapid rate of production making them appealing for the pharmaceuticals sector 9. This is also largely applicable for FDC products, although the development time and costs associated with oral dosage forms of FDCs are notably longer and higher, due to the complexities in combining 2 or more drugs i.e. compatibility between the drugs, trying to make single dosage forms with all drugs in the solid dosage forms, etc. Combination products that allow for inhalation, transdermal and transmucosal delivery have also been studied in-depth and have allowed for a plethora of products to be released for general use to the public 10, 11.
It is estimated that the vast majority of the drug entities currently in development are poorly water soluble and fall into BCS 12 Group II (60-70%) or BCS Group IV (10-20%), hence there is a constant need for research and innovation in the interest of improving the solubility and permeability properties. 13, 14. Conventionally, to improve the bioavailability of an API, its molecular or crystal structure can be altered, to yield prodrugs, salts, ionic compounds, amorphous or cocrystalline compounds, along with a reduction of particle size. Apart from the molecular and structural adjustments, alterations of dosage from such as mucoadhesive systems, floating systems, orodispersible films or solid dispersions. Novel strategies include the use of nanostructures, such as nanocrystals or nanoemulsions, for a greater adherence to the intestinal epithelium, lipid systems as they present high biocompatibility and improve gastrointestinal absorption when used as carrier, dendrimers and cyclodextrins, for their unique structural properties which help with drug encapsulation and improve the solubility of hydrophobic compounds 15.
The incorporation of these poorly-soluble compounds into FDCs has been regarded as a promising approach for improving their bioavailability, taking into account the combinational therapy advantages mentioned earlier. 16, 17. While previous reviews 18, 19, 20, 21 on the topic of FDCs have looked into historical formulation strategies, characterised products released onto the market or outlined the economic advantages and disadvantages of them, this review manuscript, aims to characterise some general concepts about the early stages of formulating FDC products, with an emphasis on poorly soluble drugs and how conventional and emerging technologies can help deliver these in a more safe and efficient manner, while incorporated in a FDC, focusing on trends and advancements from the last few years.
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Excipients mentioned in the paper: Eudragit, Klucel
Vlad-Nicolae Lesutan, Sune K. Andersen, Dimitrios A. Lamprou, Poorly water-soluble APIs in fixed-dose combinations: development, challenges, and opportunities in manufacturing techniques, Journal of Drug Delivery Science and Technology, 2025, 107212, ISSN 1773-2247, https://doi.org/10.1016/j.jddst.2025.107212.
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