Cyclodextrins in Formulation Development: Complexation and Stability Enhance

Cyclodextrins (CDs) are cyclic oligosaccharides widely used in pharmaceutical formulations to enhance drug solubility, stability, and bioavailability¹². They form inclusion complexes with poorly water-soluble drugs, improving their physicochemical properties without molecular modifications². While CDs generally increase drug stability, they can sometimes promote degradation, depending on the CD type and complex structure³. Recent research focuses on ternary complexes, incorporating auxiliary agents like water-soluble polymers or amino acids, which offer advantages over binary complexes, including better complexation efficiency and stability constants⁴. Ternary complexes also reduce the required CD concentration for maximum solubility and stability. In silico molecular modeling has emerged as a valuable tool for preliminary evaluation of CD-based complexes⁴.

Poor drug solubility remains a significant challenge in pharmaceutical development, affecting bioavailability and efficacy⁵. Over 60% of marketed drugs and many promising new compounds face solubility issues⁶. Nanotechnology offers potential solutions by increasing surface area and improving drug dissolution⁷. Nanonization techniques, including nanoparticles and lipid-based nanosystems, can enhance solubility and dissolution rates of poorly water-soluble drugs⁸. Various approaches like solid dispersions, nano-suspensions, and cyclodextrin complexes aim to increase drug solubility⁷. Microarray patches (MAPs) have emerged as a promising strategy for delivering poorly soluble drugs through the skin, offering advantages over oral and parenteral routes⁶. 

Cyclodextrins (CDs) are cyclic oligosaccharides with a hydrophobic cavity and hydrophilic exterior, widely used in pharmaceutical formulations to enhance drug properties ⁹³. They form inclusion complexes with poorly water-soluble drugs, improving solubility, bioavailability, and stability¹⁰. CDs can be used in their natural form (α-, β-, γ-CD) or as chemically-modified derivatives for various drug delivery routes⁹. While CDs generally stabilize drugs, they may promote degradation in some cases, depending on the CD type and complex structure³. Multicomponent complexes, formed by adding auxiliary substances like amino acids, organic acids, or water-soluble polymers, can enhance complexation efficiency and therapeutic applicability³. CDs offer numerous advantages in pharmaceutical development, including taste masking, prevention of drug incompatibilities, and extended shelf life¹⁰.

III. Chemistry and Classification of Cyclodextrins

Cyclodextrins (CDs) are cyclic oligosaccharides composed of glucopyranose units linked by α-1,4-glycosidic bonds, featuring a hydrophobic cavity and hydrophilic surface^11,12. This unique structure allows CDs to form inclusion complexes with various compounds, making them valuable in multiple industries, including pharmaceuticals, food, and agriculture¹². CDs are particularly useful in drug delivery systems due to their biocompatibility, safety, and ability to improve drug solubility^9,13. CD-based drug delivery systems include complexes, nanocarriers, hydrogels, and inserts, which can be administered through various routes such as oral, ocular, dermal, nasal, and rectal^9,13. 

Cyclodextrins (CDs) are cyclic oligosaccharides that occur naturally in three main types: α-CD (6 glucose units), β-CD (7 units), and γ-CD (8 units) ^14,15. These CDs have a unique structure with a hydrophilic exterior and a lipophilic cavity, allowing them to form inclusion complexes with various molecules¹⁴. Recent research has shown that CDs and their complexes can self-assemble in aqueous solutions, forming clusters and nanoparticles¹⁶. This property has led to the development of CD-based supramolecular hydrogels for local drug delivery applications¹⁶. Additionally, modified CDs, such as hydroxypropyl-β-CD, sulfobutyl ether-β-CD, and methylated CDs, offer improved properties over native CDs¹⁷. These derivatives can form inclusion complexes with poorly water-soluble drugs, mask unpleasant tastes and odors, and prevent drug degradation¹⁰. Recent developments include CD-based polyrotaxanes, CD-polymer conjugates, and thiolated CDs, which show promise for innovative drug delivery systems¹⁸. The selective modification of CDs at different positions has led to the creation of new derivatives with enhanced properties and applications¹⁹. Clinical trials have demonstrated various new applications of CDs, including the formation of nanoparticles and stabilization of protein drugs¹⁸.

Cyclodextrins (CDs) are cyclic oligosaccharides widely used in pharmaceutical formulations to enhance drug properties through complexation^3,10. They can improve drug solubility, bioavailability, and stability while reducing irritation¹⁰. CDs form inclusion complexes with appropriately sized molecules, which can stabilize or destabilize drugs depending on the CD type and complex structure³. Multicomponent complexes, incorporating auxiliary substances, can further enhance complexation efficiency and drug properties³. CDs are particularly valuable in parenteral formulations due to their favorable toxicological and pharmacokinetic profiles, often preferred over other solubilizing techniques²⁰. They can temporarily camouflage undesirable physicochemical drug properties without using organic solvents or surface-active agents²⁰. Various CD derivatives, such as captisol and sulfobutyl ether-β-CD, are used in different dosage forms to address specific formulation challenges¹⁰.

Table 1: Cyclodextrin Derivatives and Their Pharmaceutical Properties

Cyclodextrins (CDs) are versatile molecules that form host-guest complexes through noncovalent interactions, enabling various applications in pharmaceuticals, cosmetics, and other industries²¹. Their ability to form inclusion complexes has been extensively studied using techniques like NMR and X-ray crystallography²¹. CDs are biocompatible, biodegradable, and have low toxicity, making them suitable for drug delivery and biomedical applications²². CD-based supramolecular hydrogels exhibit unique properties such as stimuli-responsiveness, self-healing, and shape memory²³. These hydrogels have been explored for local drug delivery through various administration routes, including intra-tumoral, subcutaneous, and ocular²⁴. The shear-thinning nature and stimuli-responsiveness of CD-based hydrogels make them particularly attractive for controlled drug release²⁴. Despite their potential, challenges remain in the clinical translation of CD-based host-guest supramolecular hydrogels²⁴.

Cyclodextrins (CDs) form inclusion complexes with various compounds through non-covalent interactions. The primary driving force for complex formation is van der Waals interactions, followed by hydrophobic interactions and Coulomb forces²⁵²⁶. Hydrogen bonding also plays a role in stabilizing the complexes and influencing their conformation²⁶²⁶. These interactions contribute to the spontaneous formation and stability of inclusion complexes²⁶. The complexation process typically follows a 1:1 stoichiometry, as confirmed by various analytical methods²⁵²⁷. Molecular dynamics simulations and computational approaches have been used to elucidate the mechanisms of complex formation and stability²⁵²⁶²⁶. Inclusion complexes with CDs can improve the solubility, thermal stability, and biological activities of guest molecules ²⁸²⁷.

These complexes, typically in 1:1 stoichiometry, can significantly improve the solubility and stability of poorly soluble compounds like 2R,3R-dihydromyricetin and praziquantel²⁷²⁹. The inclusion mechanism involves non-covalent interactions, with guest molecules partially or fully embedded in the CD cavity²⁷. Different CD derivatives, such as hydroxypropyl-β-cyclodextrin and randomly methylated β-CD, can enhance solubility to varying degrees^27,29.

Phase solubility diagrams are used to characterize these complexes, with AL and AP types indicating increased drug solubility^30–32. Different CDs exhibit varying effects on drug solubility, with some increasing and others decreasing it³². The stability constants and complexation efficiency of drug-CD complexes can be determined through phase solubility studies^30,33. Various analytical techniques, including NMR, IR, XRD, and DSC, are employed to characterize these complexes and confirm their formation^30,31,33. The choice of CD can significantly impact the solubility enhancement of drugs, with some CDs, like HPβ-CD, showing superior performance compared to others³³. These inclusion complexes can lead to improved dissolution rates and potential enhancements in drug bioavailability^31,33.

V. Methods of Preparation of CD Complexes

Cyclodextrin (CD) complexes can be prepared using various methods to enhance drug solubility and dissolution³⁴. Various methods for preparing CD complexes have been investigated, including physical mixing, kneading, co-precipitation, spray drying, freeze drying, and supercritical fluid techniques³⁵³⁶³⁷. These methods can significantly improve drug solubility and dissolution rates. For instance, kneading and co-precipitation methods achieved complete dissolution of pterostilbene within 20-40 minutes when complexed with β-CD and γ-CD³⁷. Spray-freeze drying has been shown to enhance permeation and stability of cannabinoid acids in CD complexes³⁶. The choice of CD derivative and preparation method can greatly impact complex formation and drug solubilization, as demonstrated with lopinavir complexation using HP17-γ-CD and supercritical assisted spray drying³⁵. The effectiveness of these methods in improving drug properties often follows the order: supercritical CO2 processing > spray-drying > freeze-drying > co-evaporation > physical mixing³⁸. Various analytical techniques, such as DSC, SEM, and XRD, are employed to characterize and confirm the formation of CD complexes³⁹. Ultraviolet-visible spectroscopy, Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), and X-ray diffraction (XRD) are used to analyze flavonoid/hydroxypropyl-β-cyclodextrin complexes⁴⁰. Solid-state nuclear magnetic resonance (ssNMR) is valuable for characterizing CD-including systems⁴¹. These techniques, along with scanning electron microscopy (SEM), help confirm complex formation and study their properties⁴². 

Table 2: Preparation Methods for CD Complexes

Cyclodextrins (CDs) are versatile excipients widely used in pharmaceutical formulations to enhance drug solubility, stability, and bioavailability ⁴³¹. They form inclusion complexes with lipophilic drug moieties and can create non-inclusion complexes and self-assembled aggregates⁴⁴. In tablet formulations, CDs serve as complexing agents, fillers, disintegrants, and binders⁴⁵. Their applications extend beyond pharmaceuticals to food, cosmetics, agriculture, and environmental remediation⁴⁶. Various techniques are employed to incorporate CDs into different matrices and enhance their solubilizing effects⁴⁴. Natural CDs and some derivatives ¹have pharmacopeia monographs and are used in food and toiletry products. However, careful consideration of CD concentration is crucial, as both excessive and insufficient amounts can affect drug bioavailability⁴⁴. Overall, CDs play a significant role in addressing poor aqueous solubility and improving drug delivery in various administration routes¹.

1. Solubility Enhancement

Cyclodextrins, particularly β-cyclodextrin (βCD) and its derivatives, have shown significant potential in enhancing the solubility and dissolution rates of poorly soluble drugs. Two recent studies explored novel approaches using cyclodextrins for BCS Class II and IV drugs. El Baraka et al. (2024) demonstrated that combinations of βCD with PEG 6000 and PVP significantly improved solubility and dissolution rates of celecoxib, furosemide, and valsartan. The most effective combinations varied by drug, with improvements ranging from 3.54 to 25.52-fold⁴⁷. Balenzano et al. (2023) introduced cyclodextrin-based supramolecular deep eutectic solvents (CycloDES) using hydroxypropyl-β-cyclodextrin (HPβCD). This approach achieved at least 100-fold solubility improvements for cannabidiol, indomethacin, and dexamethasone. CycloDES also showed superior resistance to dilution compared to standard glucose-choline chloride DES, maintaining high drug solubility (e.g., 93% for indomethacin) upon water addition⁴⁸. These studies highlight the versatility of cyclodextrin-based systems in addressing solubility challenges for poorly soluble drugs.

Cyclodextrins, particularly β-cyclodextrin and its derivatives, have shown significant potential in enhancing the solubility and dissolution rates of poorly soluble drugs like itraconazole and fenofibrate. Binary and ternary complexes of itraconazole with β-cyclodextrin and polyvinylpyrrolidone demonstrated improved solubility and dissolution behavior⁴⁹. Similarly, fenofibrate complexation with hydroxypropyl-β-cyclodextrin resulted in enhanced dissolution rates and decreased mean dissolution time⁵⁰. Itraconazole-β-cyclodextrin complexes incorporated into orally disintegrating tablets exhibited higher dissolution rates compared to pure itraconazole formulations, potentially improving bioavailability and reducing dosage requirements⁵¹. Cyclodextrins form inclusion complexes with guest molecules, enhancing their physicochemical properties such as solubility, stability, and bioavailability. Various methods for complex production and characterization techniques are available, with applications extending beyond pharmaceuticals to other fields⁵².

2. Stability Enhancement

Cyclodextrins (CDs) have been shown to enhance the stability and pharmaceutical properties of various active ingredients. Studies demonstrate that CDs can improve photostability of compounds like trans-polydatin⁵³, roflumilast⁵⁴, and nabumetone⁵⁵. In addition to photostability, CDs can enhance thermal stability and solubility of drugs⁵⁶. They also protect against hydrolysis, oxidation, and thermolysis⁵⁶. Formation of inclusion complexes with CDs can improve drug bioavailability, mask taste and smell, and modify biological properties⁵⁶. Specific CD derivatives like hydroxypropyl-β-cyclodextrin (HP-β-CD) have shown superior performance in some cases, such as increasing water solubility and providing photoprotection in gel formulations⁵⁵. Overall, CDs serve as multifunctional excipients that can significantly enhance drug stability and performance across various applications.

Cyclodextrins (CDs) have shown promise in enhancing drug stability and solubility, particularly for poorly soluble drugs like nimodipine (NIMO) and omeprazole (OME). Inclusion complexes of NIMO with sulfobutylether-β-cyclodextrin significantly improved solubility and stability while maintaining bioequivalence with commercial formulations⁵⁷. Similarly, OME stability was enhanced in mucoadhesive buccal films using β-cyclodextrin and l-arginine⁵⁸. A nano-controlled release agent of NIMO modified with hydroxypropyl-β-cyclodextrin demonstrated improved plasma stability and bioavailability in rats⁵⁹. However, CDs can also promote drug degradation in some cases, highlighting the importance of evaluating the specific CD-drug interaction³.

3. Taste Masking

Cyclodextrins, particularly β-cyclodextrin derivatives, have shown promise in taste-masking applications for pharmaceuticals. They can form inclusion complexes with bitter drugs like ranitidine hydrochloride, effectively reducing their unpleasant taste⁶⁰. The taste-masking efficiency of these complexes can be evaluated using electronic taste sensing systems, providing a rapid and objective assessment method⁶⁰. Cyclodextrins offer a safe and cost-effective approach to taste masking, although their application is not always straightforward and requires careful consideration of factors such as cyclodextrin type and guest-host molar ratio⁶¹. In addition to cyclodextrins, other taste-masking techniques for traditional Chinese medicines include functional masking with sweeteners, physical masking via polymer film-coating, and biochemical masking through intermolecular interactions⁶². These approaches aim to improve patient compliance, particularly among pediatric and elderly populations.

4. Controlled Release Formulations

Cyclodextrins (CDs) are versatile oligosaccharides widely used in pharmaceutical applications for controlled drug delivery⁶³. Their unique structure allows formation of inclusion complexes with various poorly soluble compounds, improving drug solubility, stability, and bioavailability⁶⁴. CDs, particularly β-CD, can form different nanoarchitectures through self-assembly and host-guest interactions, enhancing loading capacity and enabling targeted and controlled release⁶⁵. Various CD-based controlled release systems, including inclusion complexes, coupling, supramolecular hydrogels, and micelles, are employed in practical applications⁶³. CD derivatives, such as hydroxypropyl and sulfobutyl ether CDs, further enhance these properties⁶⁵. CDs have shown promise in non-invasive drug delivery platforms, including ophthalmic and nasal applications⁶⁶. Recent advancements have expanded CD applications to various drug delivery systems, including ocular, osmotic, mucoadhesive, transdermal, nasal, and targeted delivery⁶⁴.

5. Parenteral Formulations

Cyclodextrins (CDs), particularly sulfobutylether-β-cyclodextrin (SBE-β-CD) or Captisol®, have emerged as valuable excipients in parenteral formulations due to their ability to enhance drug solubility and stability⁶⁷⁶⁸. CDs form inclusion complexes with poorly water-soluble drugs, improving their bioavailability and reducing tissue irritation upon injection⁶⁸. Their favorable toxicological and pharmacokinetic profiles often make them preferable to other solubilizing techniques²⁰. Sulfobutyl ether-β-CD (SBE-β-CD, Captisol) and hydroxypropyl-β-CD (HP-β-CD) are particularly useful for injectable formulations, with several FDA-approved products⁶⁸. These modified CDs improve drug solubility, chemical stability, and bioavailability while reducing tissue irritation. CDs can also be used to develop more complex drug delivery systems like nanoparticles and supramolecular hydrogels, which are beneficial for anticancer drugs⁶⁹. Additionally, CDs can prevent drug degradation, extend shelf life, and mask undesirable drug properties¹⁰. Their wide-ranging applications have led to increased acceptance by health authorities, promoting the development of safer and more efficient injectable drug delivery systems⁶⁹.

6. Nasal, Ocular, and Transdermal Delivery

Cyclodextrins (CDs) in ocular drug delivery, thiolated β-CD has shown promising results as a mucoadhesive and permeation-enhancing excipient, improving drug residence time and penetration across ocular tissues⁷⁰. CDs, combined with mucoadhesive polymers, can overcome challenges in ocular drug delivery by enhancing permeability and increasing retention time on the ocular surface⁷¹. Additionally, CDs have been explored for non-invasive drug delivery platforms, including ophthalmic and nasal applications, due to their ability to form water-soluble inclusion complexes with poorly soluble compounds⁶⁶. Recent developments in CD-based nanocarrier systems have further expanded their potential for targeted drug delivery and controlled release, offering improved bioavailability across various administration routes⁶⁴⁶⁶.

CDs are utilized in various formulations, including hydrogels, gel patches, microneedles, and liposome microemulsions for transdermal delivery⁷². These formulations demonstrate improved drug penetration, sustained release, and targeted delivery. CDs also play a role in taste masking and reducing side effects⁷³. Recent advancements have explored CD-based nanocarrier systems for targeted drug delivery⁶⁶ and the potential of CDs to self-assemble into stable nanoaggregates⁶⁴. The versatility of CDs has expanded their applications in drug delivery systems, including ocular, osmotic, mucoadhesive, transdermal, and nasal routes.

V. Cyclodextrin-Based Novel Drug Delivery Systems

A. Nanoparticles and Nanosponges

Cyclodextrin-based nanosponges (CDNS) are emerging as versatile nanocarriers for drug delivery, offering numerous advantages over conventional systems⁷⁴⁷⁵. These three-dimensional, porous structures are formed by cross-linking cyclodextrin molecules, resulting in a large surface area capable of encapsulating various drug molecules⁷⁴⁷⁶. CDNS can enhance drug solubility, bioavailability, and stability while providing controlled release kinetics⁷⁵. Their flexibility allows for targeted drug delivery when coupled with appropriate ligands⁷⁵. CDNS have shown promise in delivering hydrophilic and hydrophobic compounds, proteins, enzymes, and even gaseous substances⁷⁷. The technology's potential extends beyond pharmaceuticals, with applications in nanodiagnostics, nanosensors, and environmental cleanup⁷⁴. As research in this field rapidly expands, CDNS-based products are expected to enter the market soon.

B. Micelles and Liposomes

Cyclodextrins (CDs) are versatile excipients in pharmaceutical applications, enhancing drug solubility, stability, and bioavailability⁴⁴. Their unique structure allows for the formation of inclusion complexes with lipophilic molecules, making them valuable in nanoparticle-based drug delivery systems⁷⁸. Combining CDs with various nanocarriers, such as liposomes, polymeric nanoparticles, and micelles, can overcome limitations of individual carriers and improve drug delivery performance⁷⁹. CD-modified nanomaterials have shown promise in controlled release and increased bioavailability during in vivo studies⁸⁰. These hybrid systems can enhance drug encapsulation efficiency, reduce toxicity to normal cells, and enable targeted delivery to specific locations like cancer cells⁷⁸. However, careful consideration of CD concentration is crucial, as too much or too little can affect drug bioavailability⁴⁴.

C. Hydrogels

Cyclodextrin (CD)-based hydrogels have emerged as promising materials for wound healing and transdermal drug delivery. These hydrogels offer excellent biocompatibility, hydrophilicity, and drug encapsulation capabilities⁸¹. CD's unique structure allows for host-guest interactions, enabling stimulus-responsive and controlled drug release properties²⁴. In transdermal applications, CD-based systems, including hydrogels, gel patches, and microneedles, demonstrate improved drug penetration and sustained release⁸². The versatility of CD-based hydrogels extends to various biomedical fields, such as oncology, bone repair, and myocardial tissue engineering⁸¹. These hydrogels can be designed with different cross-linking methods, allowing for tailored mechanical properties and drug loading capacities⁸¹⁸². Despite their potential, challenges remain in translating CD-based hydrogels from laboratory to clinical applications, necessitating further research to optimize their performance and safety profiles^24,81.

D. In Situ Gels and Mucoadhesive Systems

Cyclodextrins (CDs) have emerged as versatile pharmaceutical excipients for enhancing drug delivery, particularly in ocular, nasal, and buccal applications. In ocular drug delivery, CDs combined with mucoadhesive polymers increase drug permeability and retention time on the ocular surface⁷¹. Various CD-based systems have been developed, including nanocarriers, hydrogels, and inserts, to overcome the challenges of ocular drug delivery¹³. These systems have shown promise in targeted drug delivery and controlled release, leading to improved bioavailability⁶⁶. The unique properties of CDs, such as their biocompatibility and ability to form stable nanoaggregates, have expanded their applications in drug delivery systems⁶⁴. Ongoing research continues to explore the potential of CD-based formulations in non-invasive drug delivery platforms.

E. Cyclodextrin-Conjugates for Targeted Delivery

Cyclodextrin-based drug delivery systems have gained significant attention in cancer treatment due to their unique properties and versatility. Cyclodextrins (CDs) can form host-guest complexes, enhance drug solubility, and prolong drug half-life⁸³⁸⁴. Various CD-based nanocarriers, including graphenes, carbon nanotubes, nanosponges, hydrogels, dendrimers, and polymers, have been developed to achieve targeted and responsive drug delivery⁸⁴⁸⁵. These systems offer advantages such as enhanced drug solubility, site-specific action, prolonged release, and reduced toxicity to normal cells⁸⁶. CD-based nanoparticles have shown promise in chemotherapy, gene therapy, and protein/peptide drug delivery. Recent advancements include the development of amphiphilic CD nanoparticles and exploration of various administration routes⁸⁷. Despite their potential, challenges remain in optimizing CD-based delivery systems for clinical translation and improving their efficacy in cancer treatment.

VII. Commercial Applications and Approved Products

Cyclodextrins are cyclic oligosaccharides that can form inclusion complexes with drugs, enhancing their solubility and stability⁴⁴. Some notable commercially approved cyclodextrin-based drugs are Vfend® (voriconazole), Geodon® (ziprasidone) and Sporanox® (itraconazole). Voriconazole is a broad-spectrum triazole antifungal approved for treating invasive aspergillosis and other serious fungal infections⁸⁸. A liposomal voriconazole formulation has shown improved pharmacokinetics, tissue distribution, and antifungal activity compared to the commercial product, potentially offering a safer and more effective treatment option⁸⁹. This liposomal formulation demonstrated higher drug accumulation in the liver and kidneys, a 2.5-fold increase in AUC0-24/MIC ratio, and a 30% reduction in the inactive metabolite voriconazole-N-oxide, indicating enhanced antimicrobial activity and reduced metabolism⁸⁹. Ziprasidone formulated with cyclodextrin showed improved dissolution rates and increased absorption in fasted dogs compared to Geodon® capsules⁹⁰. For itraconazole, ternary complexes with cyclodextrins and water-soluble polymers demonstrated enhanced solubility and dissolution compared to Sporanox®⁹¹. Hydroxybutenyl-β-cyclodextrin (HBenBCD) formulations of itraconazole exhibited higher bioavailability and reduced food effects compared to Sporanox® in rats⁹². These studies highlight the potential of cyclodextrin-based formulations to improve the pharmacokinetics of poorly soluble drugs, potentially reducing food effects and enhancing bioavailability.

Captisol® and HP-β-CD, have emerged as important excipients in pharmaceutical formulations. These modified cyclodextrins enhance drug solubility, stability, and bioavailability while demonstrating improved safety profiles compared to parent cyclodextrins⁹³. Captisol®, developed through academic research, is now used in 13 FDA-approved injectable products⁶⁷. Both Captisol® and HP-β-CD have undergone extensive safety studies and are well-tolerated in humans, showing no adverse effects on kidneys or other organs following oral or intravenous administration⁹³. These cyclodextrins rapidly form and dissociate complexes with various drugs, enhancing their solubility and stability⁶⁸. HP-β-CD has been particularly useful in developing brain-targeting chemical delivery systems, providing stable and water-soluble formulations for parenteral administration of drugs such as estradiol, zidovudine, dexamethasone, and enkephalin derivatives⁹⁴.

Table 3: FDA-Approved Drugs Using Cyclodextrins