Samarth Institute of Pharmacy Belhe
Only when oral medications exhibit high bioavailability and reasonable solubility in the gastric media can they fully absorb when taken orally. Drug solubility and dissolving characteristics are crucial to the formulation development process. One of the biggest problems facing formulation scientists is the solubility problem, which may be resolved using a variety of technical strategies when developing new pharmaceutical products. Micronization, solvent deposition, and solid dispersion are a few crucial techniques frequently used to improve the solubility of medications that are poorly soluble in water. Every strategy has its benefits and drawbacks. All things considered, the complexation process has been used more specifically to increase the aqueous solubility, dissolution rate, and bioavailability of medications that are not very water soluble. The special cyclic carbohydrates known as cyclodextrins have been effectively employed as possible complexing agents to create inclusion complexes with insoluble pharmaceuticals. A thorough review of the literature was conducted to gather evidence for the appropriate use of cyclodextrins as complexing agents and permeability enhancers. Diverse methodologies have been examined to elucidate the procedures involved in inclusion complex preparation. A survey of several complexation procedures was attempted, along with a brief discussion of their possible uses and related technical and financial limits.
The number of lipophilic medicinal compounds, which are challenging to deliver due to bioavailability issues, is constantly growing as a result of recent high throughput screening linked to combinatorial chemistry and parallel synthesis1. In an attempt to increase their solubility by physical modification, such challenging compounds are being produced. Numerous excipients, including hydro tropes, cyclodextrins, polysaccharides, polyglycolized glycerides, and dendrimers, are used for these kinds of physical changes. Because of preferential pharmacokinetics, half of the medications undergoing clinical trials and about one-third of pharmaceuticals in development are water insoluble2. These weakly water-soluble medications also have a sluggish rate of drug absorption, which can cause gastrointestinal mucosal toxicity as well as insufficient and inconsistent bioavailability. As a result, the majority of newly developed chemicals are meant to be administered orally in solid dosage forms that provide a consistent and efficient in-vivo plasma concentration.
Fig no - The chemical structure of (a) baicalin and (b) b-cyclodextrin.
Discovered little over a century ago, cyclodextrins (also known as CDs) are cyclic oligosaccharides that fall within the carbohydrate group. When A. Villiers originally found them in 1891, they were known as "cellulosine." α, β, and γ are the three naturally occurring cyclodextrins found by F. Schardinger. And they were called "Schardinger Sugars." From 1911 and 1935, a quarter of a century, The pioneer in this field, Pringsheim in Germany, showed that CDs could form stable aqueous complexes with a wide range of different compounds. Enzymatic conversion of starch results in the production of CDs. The industries of food, pharmaceuticals, chemicals, agriculture, and environmental engineering have all seen an increase in the use of CDs in recent years. The ability of CDs to encapsulate lipophilic molecules inside their internal cavity and solubilise in aqueous media can be attributed to their unique structure and hydroxyl group orientation.
History-
Cyclodextrins have been isolated for the first time by Villiers 9 in 1891, thanks to the experience of the starch degradation by microorganisms strain (Bacillus macerans amylase: cyclodextrinase). Villiers highlights two products (probably the α- and β-cyclodextrin) with physicochemical properties similar to those of cellulose. Cyclodextrins have been characterized in 1903 by Schardinger as cyclic oligosaccharides; this is why they are called Schardinger dextrin in the first publications dealing with cyclodextrins. In 1938 Freudenberg et al have demonstrated that cyclodextrins are constructed from D-glucose units linked together by α linkages (1 → 4) glucosidic bond. Freudenberg et al. have found that the cyclodextrins were capable of forming inclusion complexes and entirely determine the structure of the γcyclodextrin. In the 1950, groups of French and that of Cramer have worked on the synthesis and purification of cyclodextrin complexes. The first patent on the application of cyclodextrins for the shaping of a biologically active compound was deposited by Freudenberg 15 in 1953. From that time, the study of cyclodextrins takes considerable growth: industrial production, synthesis of cyclodextrins modified synthesis of inclusion complexes. In the years 1970-80, Szetjli 16, 17 also called 'godfather' of cyclodextrins, contributed importance in the field. Since 1970, there were just over 130,000 documents on cyclodextrins (publications, patents, abstracts). Today, the production of the β-cyclodextrin is greater than 1000 T / year and his ongoing price to drop. Other natural or modified cyclodextrins are produced industrially.
APPROACHES FOR MAKING OF INCLUSION COMPLEXES-
Physical blending method
Merely by mechanically stirring the medication and CDs together, a solid physical combination is produced. To achieve the required particle size in the finished product, CDs and medication are fully combined by trituration in a mortar and then passed through a suitable sieve in a laboratory setting. On an industrial scale, creating physical combinations involves thoroughly mixing the medication and CDs in a fast mass granulator for around half an hour. Then, the room's temperature and humidity levels are adjusted to preserve these powdered physical combinations.
Kneading method
Using a little quantity of water or hydroalcoholic solutions to impregnate the CDs, this process turns them into a paste. After adding the medication, the paste mentioned above is kneaded for a predetermined amount of time. After kneading, the mixture is dried and, if necessary, sieved16. The complexation approach has been described by Parik et al.17 to increase nimesulide's solubility. A morter and pestle can be used to achieve kneading on a laboratory scale18–20. Extruders and other equipment can be used to knead dough on a huge scale. This is the most popular, straightforward approach for creating inclusion complexes, and it has a very cheap manufacturing cost.
Co-precipitation technique
This method involves the co-precipitation of drug and CDs in a complex. In this method, required amount of drug is added to the solution of CDs. The system is kept under magnetic agitation with controlled process parameters and the content is protected from the light. The formed precipitate is separated by vacuum filtration and dried at room temperature in order to avoid the loss of the structure water from the inclusion complex. The solid-state characterization and dissolution characteristics of gliclazide-bete-cyclodextrin inclusion complexes. This method adds organic solvents and leaves a drug-CD solution in circumstances that are extremely close to saturation and sudden temperature fluctuations. It results from the material constituting inclusion complex precipitating. By spinning the mixture or filtering it with heat and churning it, powders are produced. However, this process is not very popular in the industrial scale due to its low yield, the risk involved in utilising organic solvents, and the lengthier preparation time necessary on a bigger scale.
Solution/solvent evaporation method
In order to generate a solid powdered inclusion compound, this approach entails dissolving the drug and CDs separately in two mutually miscible solvents, combining the two solutions to achieve a molecular dispersion of the drug and complexing agents, and then vacuum-evaporating the solvent. Typically, CDs are only added to the alcoholic drug solution in an aqueous solution. After a 24-hour stirring period, the mixture is vacuum-expelled at 45 oC. After being ground up, the dry material was run through a 60-mesh filter. This approach is thought to be an alternative to the spray drying process since it is quite straightforward and cost-effective for both laboratory and large-scale manufacturing.
Neutralization precipitation method
This procedure involves dissolving the medication in alkaline solutions, such as sodium/ammonium hydroxide, and combining it with an aqueous solution of CDs. It is based on the precipitation of inclusion compounds by neutralisation process. After that, the clear solution is neutralised with agitation using a hydrochloric acid solution until the equivalency point is reached. This is the time when the inclusion compound is forming and a white precipitate is forming. After filtering, this precipitate is dried. Doijad et al. 24 investigated how complexing with beta-cyclodextrin may increase piroxicam's solubility. The drawback of this technique is that medications that are prone to acid and alkaline breakdown may occur during this procedure.
Milling/Co-grinding technique
Grinding and milling the medication and CDs with the use of mechanical equipment can produce a solid binary inclusion complex. A close combination of drug and CDs is used to fill an oscillatory mill, which grinds the material for the appropriate amount of time. Another option is to prepare the drug-CD binary system via the ballmilling method. A 60-mesh sieve is used to screen the balls that are placed in the ball mill, which is then emptied after operating at a certain speed for a predetermined amount of time. From an economic and environmental perspective, this method is better than others because it doesn't use any hazardous organic solvents, unlike similar techniques. This approach is different from the physical combination method, which just needs basic blending; in contrast, co-grinding necessitates considerable combined attrition and an impact effect on the powder blend.
CYCLODEXTRINS AS PERMEATION ENHANCERS
Despite their utility in solubility augmentation, CDs can also be stabilisers and enhancers of membrane permeability. The presence of cyclodextrins increases the permeability across biological membranes. Masson commented on the ability of CDs to improve the penetration of medications that are not very soluble in water. By allowing the medicine to pass across the water barrier that forms before biological membranes' lipophilic surface, they function as permeation enhancers47. This can also be accomplished via the CDs' dual properties, which give them a highly lipophilic and hydrophilic nature. Additionally, CDs can be employed as nasal permeation enhancers, enhancing the permeability of the membrane by altering the tight junction, lipid, and protein composition of the membrane through contact with the nasal epithelium. Additionally, CDs can be used in pulmonary drug delivery systems as a permeability enhancer. Since ribampicin is a concentration-dependent antibiotic, its ability to kill bacteria depends on reaching a high maximum concentration in comparison to a minimal inhibitory concentration. This determines the rate and degree of bacterial death. When given as an aerosolised solution, the rifampicin-CD inclusion compound can enhance drug transport in the lungs when nebulised with suitable pulmonary deposition and attain the necessary concentration of drug in the broncho-alveolar epithelial lining fluid.
Properties of Cyclodextrins-
There are three different types of cyclodextrins, often known as first generation or parent cyclodextrins: α-, β-, and γ-cyclodextrins. Twelve α-(1, 4)-linked glycosyl units make up six, seven, and eight α-, β-, and γ-cyclodextrins, respectively. Out of all β-cyclodextrins, this one is the easiest to obtain, the cheapest, and typically the most beneficial. The final equilibrium might take significantly longer to attain than the initial equilibrium, which forms the complex extremely quickly (typically in a matter of minutes). After entering the CD cavity, the guest molecule modifies its conformation to optimise the week van der Waals forces present.
Cyclodextrins and Their Inclusion Complexes with Steroids
The core of the structure of cyclodextrins (CDs), a family of cage molecules made of α-D-glucopyranose units, is a hydrophobic cavity that may enclose other materials. Its remarkable encapsulating properties lead to the development of a "host-guest" relationship that modifies or improves the physical, chemical, or biological characteristics of the guest molecule. Large-ring cyclodextrins (LR-CD) with nine to more than several hundred units have also been studied and used; nevertheless, natural α, β, and γ cyclodextrins with six, seven, and eight glucose subunits each are the most commonly used. Furthermore, because of their unique properties, native (non-substituted) CD derivatives have been widely used in a wide range of industries, such as the food, pharmaceutical, cosmetic, and biomedical sectors. Polymer additives and CDs covalently bonded to polymers are now of interest in addition to two-component inclusion complexes made up of a guest molecule and a CD. For example, molecularly imprinted polymers are based on CDs resulting from the noncovalent interactions between the guest molecule (template) and the monomer in the presence of a cross-linking agent during polymerization
CHARACTERIZATION OF COMPLEX:
Determination of Guest Content:
Analytical techniques include Ultraviolet Spectroscopy, Gas Liquid Chromatography (GLC), and High Pressure Liquid Chromatography (HPLC) can be used for quantitative determination. A guest's complexation frequently causes a little adjustment in the molar extinction coefficient and UV absorption maxima.
Thermo Analytical methods:
First, thermal analysis of complexes has been used to distinguish inclusion complexes from adsorbates, and then it has been utilised to characterise the unique thermal effects resulting from molecular entrapment. Techniques like thermo derivatography (TG, DTG) are often utilised. Analysis of Thermal Evolution (TEA) Scanning Calorimetry Differentia Thin layer chromatography (TLC) in pyrolysis Gas Chromatography (GC) in Pyrolysis Mass spectrometry (MS) and vacuum sublimation. DSC measures how quickly heat is released or absorbed by the sample throughout the course of a temperature program, for example. The DSC thermograph of paracetamol reveals that it melts and starts to decompose at 168°C.
The simple mixture's DSC curves are similar to the total cure of two pure drugs. A little exothermic peak is observed upon melting, indicating complex creation. The breakdown of paracetamol only began at around 220°C, and the complex did not exhibit the melting peak of the guest drug. Many visitors exhibit this behaviour, melting or recrystallising before reaching the β-CD breakdown temperature.
Infrared Spectroscopy-
The complex creation little affects the CD distinctive bands, which comprise the majority of the complex. The presence of the guest molecule frequently causes bands to be moved or their intensities to change; however, because the guest molecule's mass is only 5–15% of the complex's mass, these changes are often covered up by the host molecule's spectrum. IR spectroscopy investigations of such CD complexes with a guest containing a carbonyl group are often published in the literature. This is because complexation with CD greatly covers and shifts the carbonyls' sufficient and well-separated bands.
X-ray Powder Diffraction-
Diffraction patterns are not produced by liquid guest molecules. It is necessary to compare the diffractogram of the alleged complex with a mechanical combination of the guest and cyclodextrin when the guest molecule is a solid. Complex development is quite likely when diffractograms change, meaning that new components arise and the distinctive peaks of one or more components disappear as a result of the complex tests.
Scanning Electron Microscopy-
One kind of electron microscope is the scanning electron microscope (SEM), which uses a high-energy electron beam to scan a sample's surface in a raster pattern to create pictures of the surface. A scanning electron microscope was used to study the surface morphology of raw materials such as pharmaceuticals, cyclodextrin, and binary systems. The samples were attached to a brass stub using double-sided tape. A small layer of copper was then vacuum-coated to make the samples electrically conductive, and pictures were taken. Although the SEM method is insufficient to conclude in a true complex development, the acquired microphotographs provide credence to the concept of a novel single component creation.
Mechanism of the Inclusion Complex Formation-
Mechanochemistry is the study of reactions that are triggered by mechanical energy and often take place in the solid state. It is an effective instrument in many domains of application, from nanoscience to material engineering. The most popular method capable of inducing mechanochemical changes is manual grinding with a mortar and pestle or, for more efficient results, mechanical grinding with ball mills, oscillating mills, or vibrating mills. In addition to serving as a fundamental tool for reducing particle size, grinding has evolved into a constantly growing toolset for the synthesis and screening of various supramolecular and covalent materials, completing conventional solvent-based synthesis procedures.
Fig no - Schematic representation of the inclusion complex formation process in the solid state by grinding.
The remarkable success of grinding-based mechanochemical synthesis in creating metal-ligand coordination bonds and non-covalent interactions like hydrogen bonds, halogen bonds, π-π arene stacking, etc., makes it popular. It offers a way to incorporate and systematically study supramolecular structure-templating effects in a solvent-free synthesis, in addition to activating otherwise inactive reactants. This resulted in the use of grinding in the creation of cocrystals, polymeric dispersions, porous meta-organic frameworks, inclusion complexes, and polymorphs of medicinal significance.
We are putting forth a potential scenario, based on the general three-step mechanism described for mechanochemical reactions and taking into account other processes occurring during the mechanochemical drug activation by grinding, even though there are no systematic studies looking into the precise mechanism of the inclusion complex formation occurring during grinding of a drug-cyclodextrin mixture.
Applications of cyclodextrins-
alterations to current medication compounds to increase effectiveness The pharmaceutical industries are in need of a novel formulating agent that can be used for both reformulating current medications and enhancing the physical qualities of new active pharmaceutical ingredients. It has been demonstrated that CDs outperform the currently used conventional formulating agents. With relatively few side effects, the complexes that are formed between the active compounds and CDs exhibit enhanced stability, solubility, and bioavailability. CDs are the agents that function as a drug delivery system and have several possible uses for drug delivery characteristics.
These characteristics of CDs result from their propensity to create inclusion complexes, which alter the chemical, physical, and biological characteristics of visiting molecules. Oral, rectal, nasal, ocular, transdermal, and dermal drug delivery channels all see improvements in the undesirable characteristics of therapeutic molecules because to the bioadaptability and multifunctionality of CDs. As a result, CDs are crucial to the pharmaceutical industry.
Safety and efficacy betterment-
Many people use CDs to reduce the irritation that medications might cause. Better medication effectiveness and potency are the outcome of the drug-CD inclusion complex's increased solubility, which also lowers drug toxicity since the drug becomes effective at lower dosages. In the case of parenteral formulations, the soluble CD-drug inclusion complex also aids in reducing the toxicities brought on by the crystallisation of weakly water-soluble medicines. Additionally, drug entrapment in CDc avity at the molecular level shields biological membranes from direct drug interaction, minimising adverse effects and local irritation without compromising the medication's therapeutic effectiveness.
Drug delivery through biological membranes.
The chemical structure, molecular weight, and extremely low octanol/water partition coefficient (logP values) of CD all have an impact on its permeability through biological membranes, which makes it difficult for the substance to pass through them rapidly. The drug's free form, which is unbound from the complex and in balance with drug–CD complexes, has a propensity to permeate lipophilic membranes. The permeability of hydrophilic water-soluble medications across lipophilic biological membranes is not improved by CDs. The physicochemical characteristics of the drug, such as its aqueous solubility, the composition of the drug formulation, such as whether it is aqueous or non-aqueous, and the physiological makeup of the membrane barrier, such as the existence of an aqueous diffusion layer, will determine whether CD increases or decreases the drug delivery across the biological membrane. Using CDs can improve drug delivery across aqueous diffusion-controlled barriers but limit drug delivery through lipophilic membrane-controlled barriers. There is one exception to this rule, nevertheless, in that hydrophobic CDs may pass through mucosa with ease and enhance medication transport across biological membranes—such as the nasal mucosa—by lowering the membranes' barrier properties.
CONCLUSION
The majority of these newly discovered chemical entities have low water solubility, which affects both their bioavailability and therapeutic potential. For medications that dissolve poorly, solubility augmentation strategies are crucial in achieving good dissolving qualities. Effective enhancement of aqueous solubility mostly hinges on the approach selected. To improve the solubility of poorly soluble medicines in water, the most appealing method is to combine inclusion complexes with cyclodextrins. CDs serve as a helpful solubilizer, allowing both parenteral and solid/liquid oral dose forms. Drugs' physicochemical characteristics, such as solubility, particle size, crystal habit, and thermal behaviour, can be changed by a solid binary system of CDs and drug, leading to the formation of highly water soluble amorphous forms. The CDs were able to increase the rate of dissolution and bioavailability of the poorly soluble medicines because of their exceptionally high water solubility. By creating drug-CD inclusion compounds, it is also possible to increase the penetration of insoluble medications through different biological membranes.
ACKNOWLEDGE-
The author would like to thank the Samarth Rural Educational Institute's Samarth Institute of Pharmacy, university library, and all other sources for their help and advice in writing this review.
REFERENCES
Gajare Akshay*, Lamkhade G. J., Dr Bhalekar S. M., Inclusion Complexes Is the Modern & Effective Technique of Encapsulation an Overview, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 6, 952-963. https://doi.org/10.5281/zenodo.15601430
10.5281/zenodo.15601430
