Drug delivery and formulation development of hesperidin: a systematic review

The global coenzyme Q10 (CoQ10) market is expanding, driven by the increasing prevalence of chronic diseases, particularly cardiovascular disorders. Forecasts project a compound annual growth rate of 9.68% from 2025 to 2034. Despite its critical role in cellular energy metabolism and antioxidant defense, CoQ10's clinical potential is constrained by poor water solubility and low oral bioavailability. This review delivers a critical and translational comparison of lipid-based and water-based encapsulation strategies, offering novel insights into their mechanistic advantages, formulation challenges, and clinical applicability for enhanced CoQ10 delivery. Lipid-based systems, such as self-emulsifying drug delivery systems (SEDDS), liposomes, and nanoemulsions, improve solubility and gastrointestinal absorption, protect CoQ10 from degradation, and promote lymphatic transport. However, they often require high excipient content and exhibit stability concerns, such as susceptibility to oxidation. Water-based approaches, including β-cyclodextrin complexation, polymeric nanoparticles, solid dispersions, and CoQ10-nicotinamide cocrystals, enhance aqueous solubility and absorption while offering better chemical stability and lower formulation cost. This review highlights the mechanistic differences, benefits, and limitations of each strategy, providing critical insights for the rational design of CoQ10 delivery systems. The findings support formulation optimization to improve therapeutic efficacy and inform manufacturing decisions for clinical and commercial applications. Looking ahead, future directions may include nano-enabled personalized medicine strategies based on individual metabolic profiles and the development of intranasal CoQ10 delivery platforms that leverage nanoscale lipid or water-based carriers for direct nose-to-brain transport in neurological disease therapy.

A major percentage of the new chemical entities are reported to have poor aqueous solubility. Several antihypertensive drugs used clinically have either low solubility or high hepatic metabolism, thereby presenting low bioavailability (BA) and high pharmacokinetic variability. Improving the aqueous solubility of drug molecules would assist in overcoming the variability, and several approaches for improving solubility have been reported. Solid dispersion (SD) is known as a potential technique to conquer the problem of poor aqueous solubility and low BA. Drug solubility is improved by increasing the wetting property of drugs. This review is focused on discussing various approaches to improve solubility, classification, and different approaches used for formulation of SDs, along with special emphasis on the application of the SD approach for improving solubility and eventually enhancing dissolution and increasing the BA of antihypertensive drugs. The review leads to the conclusion that the use of more than one polymeric carrier for formulating SDs might help in overcoming storage and stability issues and in increasing the commercial viability and success of SDs.

: The pharmaceutical sector continues to face difficulties with poorly soluble drug solubility. Insufficiently soluble drugs have low bioavailability, and their effectiveness is frequently affected. Numerous approaches have been developed in response to this challenge, including using various dosage forms, solid dispersions, nano-suspensions, self-emulsifying drug delivery systems, and cyclodextrin complexes. By improving drug dissolving, decreasing drug particle size, and increasing drug dispersion, these dosage forms seek to increase drug solubility. Nanotechnology is one of the latest advances that has the potential to revolutionize the delivery of drugs and significantly improve the solubility of drugs that are now poorly soluble. Since they have a larger surface area and can pass through biological barriers, nanoparticles are particularly well suited for the delivery of drugs. These technologies can potentially enable the development of more effective and efficient drug formulations for the treatment of various diseases. In addition, the review highlights recent advances in the field, including emerging technologies such as nanotechnology, which can revolutionize drug delivery and significantly improve the solubility of poorly soluble drugs with their potential applications.

A variety of potent lipophilic drugs exhibits low oral bioavailability due to poor water solubility of drugs. These drugs are challenging for the formulation scientists with regard to solubility and bioavailability (BA). Extensive efforts are ongoing to enhance oral BA of these types of drugs to increase clinical efficacies. The most common approach is the use of highly developed lipid-based drug delivery systems. This is a strategy to incorporate drug into the safe and biodegradable lipids (natural, semi-synthetic, vegetable oils or hydrolyzed solid lipids) with improved oral bioavailability. Lipid microparticles (LM) are efficient lipid based drug delivery system which might be prudent attempt to increase the oral bioavailability of poor aqueous soluble drugs. Lipid based systems are recognized as a potential approach for the improved oral absorption which ultimately caused to enhanced BA. Wide variety and range of substances have been reported to be entrapped into lipid microparticles including lipophilic and hydrophilic molecules as well as labile proteins and peptides. Moreover, LM can protect drugs from in vitro and in vivo degradation. Several authors reported numerous techniques and methods to enhance drug solubility by exploiting lipids while formulation development. The use of LM is a novel carrier to enhance oral BA of poor aqueous soluble drug. Lipids are well known to deliver a number of drugs with profound systemic availability either through portal vein or lymphatic absorption from gastro-intestinal tract. These lipids are belonging to triglycerides (short chain, medium chain and long chain) with or without double bond in their hydrocarbon chain length. The present chapter discusses the physico-chemical properties, processing techniques necessary to obtain lipid-based microparticles formulations for oral delivery along with a brief discussion of lipid excipients and their characterization. The chapter provided related patents with valuable informations for pharmaceutical research groups which would be very informative and instructive. Keywords: Bioavailability, drug delivery, lipid microparticles, poor soluble drugs.

Phytoconstituents, derived from plants, possess significant therapeutic potential but often face challenges such as poor solubility and low bioavailability, limiting their efficacy. Solid dispersion (SD) is a promising approach to improve the solubility and bioavailability of these poorly water- soluble phytoconstituents. By dispersing the active drug in a hydrophilic carrier, solid dispersion enhances the surface area of the drug, improving its dissolution rate and enhancing absorption. This review provides an overview of the various generations of solid dispersions, highlighting the evolution from crystalline carriers in first-generation solid dispersions to the more advanced amorphous solid solutions in second and third-generation formulations, which offer enhanced solubility and bioavailability. The article also discusses various techniques for preparing solid dispersions, including solvent evaporation, melting, and spray-drying methods, and emphasizes the importance of selecting appropriate carriers, such as hydrophilic polymers, to optimize the dissolution rate of phytoconstituents. The study highlighted the recent case studies on several phytochemicals, like alkaloids, glycosides, Polyphenols, etc., demonstrating the effectiveness of solid dispersion in improving their solubility and therapeutic performance. Additionally, the review addresses the challenges related to the solubility of phytoconstituents and their impact on drug absorption, as well as the role of solid dispersion in overcoming these challenges. Overall, solid dispersion technology emerges as a versatile and effective tool for enhancing the oral bioavailability of phytoconstituents, paving the way for more efficient herbal therapies in modern medicine.

The solubility of a solute is the maximum quantity of solute that can dissolve in a certain quantity of solvent or quantity of solution at a specified temperature. Solubility is one of the important parameter to achieve desired concentration of drug in systemic circulation for pharmacological response to be shown. Solubility is essential for the therapeutic effectiveness of the drug, independent of the route of administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as for the generic development. Poorly soluble drugs are often a challenging task for formulators in the industry Conventional approaches for enhancement of solubility have limited applicability, especially when the drugs are poorly soluble simultaneously in aqueous and in non-aqueous media. Drug with poor water solubility cause slow dissolution rates, generally show erratic and incomplete absorption leading to low bioavailability when administered orally. Solubilization may be affected by cosolvent water interaction, micellar solubilization, reduction in particle size, inclusion complexes, solid dispersion, and change in polymorph. Some new technologies are also available to increase the solubility like micro emulsion, self-emulsifying drug delivery system and supercritical fluid technology. This present review details about the different approaches used for the enhancement of the solubility of poorly water-soluble drugs include particle size reduction, nanonization, pH adjustment, solid dispersion, complexation, co‐solvency, hydrotropy etc. The purpose of this article is to describe the techniques of solubilization for the attainment of effective absorption and improved bioavailability.
 Keywords: Solubility, Solubility Enhancement, bioavailability, solid dispersion, Solid Dispersion, Solubilization.

The poor solubility and wettability of a non steroidal anti inflammatory drug, celecoxib leads to poor dissolution and hence, low bioavailability after oral administration. The objective of the present study was to formulate solid dispersions of celecoxib, with water soluble polymers poly vinyl pyrrolidine (PVP K30), poly ethylene glycol (PEG 6000), hydroxypropyl methylcellulose 5cps (HPMC) and a super disintegrant namely pregelatinised starch (PGS) by common solvent and solvent evaporation methods. Solid Dispersions prepared were evaluated for dissolution rate and dissolution efficiency in comparison to the corresponding pure drug. Solid dispersions of celecoxib showed a marked enhancement in dissolution rate and dissolution efficiency. The increasing order of dissolution rate of solid dispersions of celecoxib with various polymers was HPMC > PVP > PEG. Solid dispersions at 2:2:6 ratio of C: HPMC: PGS, a 53.57 fold increase in the dissolution rate of celecoxib was observed. Solid dispersions were characterized by infrared spectroscopy (IR), differential scanning calorimetry (DSC) and X-ray diffractogram (XRD). Solid dispersions in combined carriers gave much higher rates of dissolution than super disintegrant PGS alone. Super disintegrant PGS alone or in combination with hydrophilic polymers could be used to enhance the dissolution rate of poorly soluble drug celecoxib. Finally, in-vitro dissolution studies showed that celecoxib release was greatly improved by formation of solid dispersion.

The Poor Solubility of Drugs is a major problem which limits the development of highly potent pharmaceutics. Solubility Enhancement is one of the important parameters which should be considered for those drugs having poor aqueous solubility. Drugs belonging to Biopharmaceutical Classification System (BCS) class II are characterized by low aqueous solubility and high physiological permeability. Solid Dispersion Method Technique and Effervescence Assisted Solid Dispersion Techniques using Modified Fusion Method are the process to enhance the solubility of poorly water soluble drugs. In this work, BCS class-II drugs Clarithromycin was used as a model drugs, having poor solubility but high permeability is individually incorporated with Mannitol, Citric acid, and Sodium bicarbonate (Hydrophilic Carriers used as Excipients) in different ratio respectively. SDMs of Clarithromycin were prepared melting (Fusion) method using Mannitol. EASDs of Clarithromycin were prepared using Modified Fusion Method. Mannitol was melted and in this molten mannitol Citric acid (organic acid) was added and uniformly mixed by continuous stirring. Solubility of Drug Powders, Solid Dispersion, and EASDs was determined at 25 C using shake flask method. The aqueous solubility of Clarithromycin were estimated using a U.V. spectrophotometer at 241nm (?max). Scanning electron Micrographs, FTIR, DSC and PXRD CLN of drug powders, solid dispersion, and EASDs were compared. Scanning electron micrographs of EASDs showed better uniform distribution of drug particles in the carrier matrix. The present technique is better suitable for drugs having a low melting point or melt without charring. Effervescence assisted fusion technique of preparing solid dispersions can be employed for enhancing solubility of poorly soluble drugs.

Poor solubility remains a significant obstacle in drug administration, adversely affecting the bioavailability and therapeutic efficacy of many drugs. It is also recognized as a primary factor contributing to issues with bioavailability, such as poor, inconsistent, limited, and highly variable bioavailability of marketed products. It is estimated that 40% of marketed drugs face bioavailability challenges primarily due to poor water solubility, and about 90% of pharmacological compounds exhibit poor water solubility in their early development stages. Addressing this issue is crucial for improving drug performance, efficacy, and patient outcomes. This review provides an overview of the challenges associated with poorly soluble drugs, including low bioavailability, limited dissolution rates, inconsistent absorption, decreased patient compliance, formulation difficulties, and associated costs and time constraints. Numerous strategies have been now investigated to tackle the issue of poor solubility. This review offers an updated overview of commonly used macro and nano drug delivery systems, including micelles, nanoemulsions, dendrimers, liposomes, lipid-based delivery systems, microemulsions, cosolvents, polymeric micelle preparation, drug nanocrystals, solid dispersion methods, crystal engineering techniques, and microneedle- based systems. Additionally, the review examines advanced techniques like cyclodextrin- based delivery systems, co-solvency and co-crystallization approaches, polymeric micelles, spray drying, co-precipitation, and amorphous solid dispersion. The role of computational modeling and formulation prediction is also addressed. Recent advancements in protein-based approaches, 3D printing, mesoporous silica nanoparticles, supramolecular delivery systems, magnetic nanoparticles, nanostructured lipid carriers, and lipid-based nanoparticles are highlighted as novel solutions for enhancing the solubility of poorly soluble drugs. The review concludes with predictions for the future, emphasizing the potential for further innovation in drug delivery methods to overcome the challenges associated with poorly soluble drugs.

The low aqueous solubility of Flufenamic acid (FFA), a Biopharmaceutics Classification System (BCS) II class drug, is a major challenge to overcome its low bioavailability. Poor solubility and low dissolution rate of the poorly aqueous solubility drugs in the aqueous gastrointestinal fluids (6.8 pH) often cause insufficient bioavailability. As for BCS class II drugs, dissolution rate having limiting step, increasing the solubility of drug leads to increases the bioavailability. Therefore, it is important to improve the solubility of flufenamic acid. Several methods such as salt formation, particle size reduction and solid dispersion are available to enhance the solubility of many drugs. In this work, solid dispersion of flufenamic acid with hydrophilic polymer Polyvinylpyrrolidone K 30 (PVP K 30) are produced by solvent evaporation technique. Raw FFA, PVP K-30 and solid dispersion containing FFA and PVP K-30 are characterized by SEM, FTIR. It was observed that morphology of raw FFA was rock like which changed when solid dispersion is formed with PVP K30. The FTIR spectroscopy showed that hydrogen bonding between FFA and PVP occurs in solid dispersion.

The poor solubility and wettability of a non steroidal anti-inflammatory drug, Lornoxicam leads to poor dissolution and hence, low bioavailability after oral administration. The objective of the study was to formulate solid dispersions of Lornoxicam to improve the aqueous solubility and dissolution rate to facilitate faster onset of action. Lornoxicam is a BCS class II drug having low aqueous solubility and therefore low bioavailability. In the present study, solid dispersions of Lornoxicam with three different hydrophilic polymers and one superdisintegrant in 4 drug-carrier ratios were prepared by solvent evaporation and common solvent methods. Solid dispersions were characterized by infrared spectroscopy (IR) and evaluated for drug content, dissolution rate constant, regression coefficient. The dissolution rate and dissolution efficiency of the prepared solid dispersions were evaluated in comparison to the corresponding pure drug. The invitro dissolution studied showed increased drug release rates compared to that of pure API alone. The increasing order of dissolution rate of solid dispersions Lornoxicam with various polymers was HPMC > PVP > PEG. The solid dispersions in combined carriers gave much higher rates of dissolution than superdisintegrants alone. Finally, in-vitro dissolution studies showed that Lornoxicam release was greatly improved by formation of solid dispersion. A 170.2 fold increase in the dissolution rate of Lornoxicam was observed with solid dispersions prepared using combined carriers such as HPMC, MCC whereas only a 15.78 fold increase was observed with solid dispersions prepared using only MCC. Thus, the solid dispersion technique can be successfully used for enhancement of dissolution rate.

Oral route has always been the favorite route of drug administration in many diseases and till today it is the first way investigated in the development of new dosage forms. The major problem in oral drug formulations is low and erratic bioavailability, which mainly results from poor aqueous solubility, thereby pretense problems in their formulation. More than 40% of potential drug products suffer from poor water solubility. For the therapeutic delivery of lipophilic active moieties (BCS class II drugs), lipid based formulations are inviting increasing attention. Currently a number of technologies are available to deal with the poor solubility, dissolution rate and bioavailability of insoluble drugs such as micronization, solid dispersions or cyclodextrin complex formation and different technologies of drug delivery systems. One of the promising techniques is Self‐Micro Emulsifying Drug Delivery Systems (SMEDDS). Self emulsifying drug delivery system has gained more attention due to enhanced oral bio-availability enabling reduction in dose, more consistent temporal profiles of drug absorption, selective targeting of drug(s) toward specific absorption window in GIT, and protection of drug(s) from the unreceptive environment in gut. This article gives a complete overview of SMEDDS as a promising approach to effectively deal with the problem of poorly soluble molecules. Keywords: SMEDDS, surfactant, oil, co-surfactant, bioavailability

Abstract: Objectives: Artemether (ART), an antimalarial drug, have poor solubility and low bioavailability. Therefore, solid dispersion of the drug was formulated using Soluplus (SOL) and was incorporated in the fast disintegrating tablet. Materials and Methods: The solid dispersion (SD) was prepared using the solvent evaporation method using a rotary evaporator. The optimized SD was evaluated and then incorporated into the tablet. Results: Solubility studies revealed that ART SD A3 of ratio 1:3 (ART: SOP) showed a significantly higher solubility and dissolution rate than plain ART. FTIR results indicated that there was no incompatibility between the drug and hydrophilic carrier. The DSC as well as XRD studies indicated the transformation from crystalline state of drug into the amorphous form. SEM studies revealed the deposition of ART on the surface of the hydrophilic carrier. In-vitro antimalarial activity was improved of the ART due to the SD formulation. Fast disintegrating tablet of ART SD A3 was produced by using directly compressible excipients such as Ludiflash and Ludipress. Ludiflash containing tablet showed fast disintegration with higher drug release. The pharmacokinetic study in mice showed increased Cmax and AUC0–24 by 1.88- and 3.19-fold as compared to those of plain drug. Conclusion: The prepared SDs using SOP provided a platform for increased solubility and also improved the bioavailability of ART with feasibility for tablet formulation. Key words: Artemether, Solid dispersion, Fast disintegrating tablet, Malaria, in-vivo study.

Mefenamic acid (MA), a member of nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), has been widely use to relief pain and inflammation. Its medical uses are limited by poor aqueous solubility resulting in low bioavailability and gastric irritation. The aim of this study was to develop a mefenamic acid delayed-release matrix tablet formulation using solid dispersion (SD). Delayed-release drug delivery systems were designed to retard drug release in upper gastrointestinal tract avoiding gastrointestinal (GI) adverse reactions. SDs of MA were successfully prepared by solvent evaporation method employing methanol as a solvent. SDs incorporated surfactant and super disintegrant gave much higher rates of dissolution than SDs with combined carriers (PEG and surfactant), SD containing PEG and pure drug, respectively. The optimal SD containing MA:PEG4000:poloxamer188:crospovidone in the ratio 1:8:1:3 exhibited higher amount of drug release up to 8-fold compared with pure MA. FTIR and DSC were performed to identify the physicochemical interaction between drug and polymers. The resulting data justified that no change in the chemical structure of MA and the crystalline MA transformed into the amorphous state after preparation. The formulation F4 delayed-release tablet comprising SD of MA dissolved less than 4 % in artificial gastric fluid in the initial 2 h and released more than 95 % at 3 h in the artificial intestinal fluid. Accordingly, formulation F4 containing polyethylene oxide as a time-controlled matrix-forming polymer was a promising delayed-release solid dispersion system of MA. HIGHLIGHTS The present study demonstrated a mefenamic acid delayed-release matrix tablet formulation using solid dispersion (SD) The optimal SD of mefenamic acid exhibited higher amount of drug release (8-fold) compared with that of the pure drug The tablet formulation F4 containing polyethylene oxide is capable of releasing mefenamic acid in a typical delayed-release profile GRAPHICAL ABSTRACT

Approximately 40% of new chemical entities (NCEs), including anticancer drugs, have been reported as poorly water-soluble compounds. Anticancer drugs are classified into biologic drugs (monoclonal antibodies) and small molecule drugs (nonbiologic anticancer drugs) based on effectiveness and safety profile. Biologic drugs are administered by intravenous (IV) injection due to their large molecular weight, while small molecule drugs are preferentially administered by gastrointestinal route. Even though IV injection is the fastest route of administration and ensures complete bioavailability, this route of administration causes patient inconvenience to visit a hospital for anticancer treatments. In addition, IV administration can cause several side effects such as severe hypersensitivity, myelosuppression, neutropenia, and neurotoxicity. Oral administration is the preferred route for drug delivery due to several advantages such as low cost, pain avoidance, and safety. The main problem of NCEs is a limited aqueous solubility, resulting in poor absorption and low bioavailability. Therefore, improving oral bioavailability of poorly water-soluble drugs is a great challenge in the development of pharmaceutical dosage forms. Several methods such as solid dispersion, complexation, lipid-based systems, micronization, nanonization, and co-crystals were developed to improve the solubility of hydrophobic drugs. Recently, solid dispersion is one of the most widely used and successful techniques in formulation development. This review mainly discusses classification, methods for preparation of solid dispersions, and use of solid dispersion for improving solubility of poorly soluble anticancer drugs.