Bioavailability Enhancement Techniques for Poorly Aqueous Soluble Drugs and Therapeutics

1The solubility of the drug, the solution, and its gastrointestinal permeability are essential factors that control the amount of absorption and absorption speed, along with the bioavailability of the drug. A necessary factor involved in absorption after a drug’s oral administration is the aqueous solubility of therapeutics. The drug solubility is the dissolution rate at which the drug molecule or the dosage form allows for entering the solution, and it is essential when the time of dissolution is restricted. However, the drug’ bioavailability depends on water solubility, dissolution rate, drug permeability, susceptibility to efflux mechanisms, and first-pass metabolism. “Solubility” has been well-defined as the quantity of solute, which dissolves in a quantity of solvent. Quantity refers as the concentration of the solute in a saturated solution at a definite temperature. The solubility has been represented through multiple concentration expressions—for example, parts, percentage, molality, molarity, volume fraction, and mole fraction. Qualitatively, solubility can be termed as a spontaneous collaboration between two substances to create a homogenous dispersion at the molecular level. The solute can be referred to as at equilibrium with the solvent in a saturated solution.

2In recent years, according to drug detection, the number of poorly soluble drugs has increased, with 70% of novel medications presenting low aqueous solubility. The controlling factors for the in vivo bioavailability of oral formulations of these drugs are the low solubility and low dissolution rate in gastrointestinal solutions. Thus, an essential issue relating to drug development has been recognized as being in vitro dissolution and increasing the speed of dissolving low solvable drugs in addition to improving their bioavailability, representing a major task for pharmaceutical experts..

3For the medicinal product to be immersed, it must exist in a water-soluble state at the place of absorption. The solubility and permeability represent promising factors for in vivo absorption. They can be improved through solubility enhancement techniques.

4Rebamipide belongs to BCS class IV drugs. It exhibits poor bioavailability and has difficulties in formulation preparation for oral administration. Due to its limitations, it is impossible to formulate a self-nano emulsifying drug delivery system (SNEDDS) formulation using this substance. To enhance the solubility of this drug, a SNEDDS formulation was prepared by complexing rebamipide with its counter ion. Tetra-butyl phosphonium hydroxide (TBPOH) and NaOH were used as counter ions to prepare a complex. Okawa et al. reported that the complexes prepared with rebamipide, Reb–TBPOH complex and Reb–NaOH complex, showed enhanced solubility and absorption in in vitro as well as in in vivo studies. Asper recent scenario of pharmaceutical developing market Figure 1 demonstrates the development of different formulations and their ratio as per BCS classification.

5Quercetin is a highly hydrophobic drug, which is a polyphenolic flavonoid. It finds application as an antioxidant. It exhibits anti-proliferative and chemopreventive characteristics. It was found to have potential against colon, lung, ovarian and breast cancer but, due to its poor solubility and low bioavailability, its pharmacological effects are limited. Kakran et al. used bottom-up and top-down approaches as side reduction techniques to prepare nanoparticles. High-pressure homogenization and bead milling approaches were applied top-down and EPN-evaporative precipitation of nanosuspension was applied as a bottom-up technique to prepare quercetin nanoparticles with enhanced solubility and bioavailability.

6Ting et al. drew special attention to specialized polymer design strategies and commercial products, which can enhance the solubility of extremely hydrophobic drugs, and can minimize the probability of drug recrystallization. The specially prepared excipients are molecularly customized polymers which can restructure the APIs into potential oral medication. United States Pharmacopeia (USP) has already approved several such specialized polymers as an excipient for the preparation of solid oral formulations. Natural derivatives and some synthetically prepared polymers were frequently used to enhance the bioavailability of amorphous drugs. At present, several amorphous drugs are available on the market, as listed in Table 1. Hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone), PEG (Polyethylene glycol), HPMCAS (hydroxypropyl methylcellulose acetate succinate (PVP), polyvinylpyrrolidone vinyl acetate (PVP-VA) and several other specialized polymers were approved as excipient by FDA. These were used with drugs such as verapamil (Product trade name: ISOPTIN-SRE, excipient: HPC/HPMC by Abbott Laboratories), Nilvadipine (product trade name: Nivadil, excipient: HPMC by Fujisawa Pharmaceuticals, Tokyo, Japan ), tacrolimus (product trade name: PROGRAF, excipient: HPMC by Astellas Pharma US Inc., Northbrook, IL, USA), nabilone (product trade name: Cesamet, excipient: PVP by Valeant Pharmaceuticals, Bridgewater, NJ, USA ), griseofulvin (product trade name: GRIS-PEG, excipient: PEG by Pedinol Pharmacal Inc. & Novartis, Bridgewater, NJ, USA ), ritonavir (product trade name: NORVIR, excipient: PVA-VA by AbbVie Inc., Chicago, IL, USA) and telaprevir (product trade name: INCIVEK, excipient: HPMCAS by Vertex Pharmaceuticals, Boston, MA, USA)

7Johnson et al. developed seventeen types of poly(N-isopropyl acrylamide) (PNIPAM)-based excipients differing in molar mass and with a variety of end groups. These polymers were studied for their capability to enhance the water solubility of phenytoin. To improve the solubility of phenytoin, Johnson et al. synthesized three polymeric excipients: PNIPAM, poly(N,N-dimethyl acrylamide) (PDMAm) and PHEAmpoly(N-hydroxyethyl acrylamide) (PHEAm). Synthesized polymers were investigated for their solubility enhancement effect on phenytoin. Johnson et al. described a detailed understanding of the critical importance of PNIPAM for the solubility enhancement of phenytoin.

8Chen et al. worked on the drug solubility enhancement of docetaxel (DTX). Docetaxel finds application as a chemotherapeutic agent for cancer treatment. Chen prepared three types of inclusion complex among docetaxel and H1-3 (ethylenediamine modified beta cyclodextrins) with ethylene, propylene and butylene parts. Chen proved that the complexation of DTX with H1-3 is an effective tactic to enhance the solubility and prepare a less toxic and highly active DTX formulation. This approach can maximize its clinical applicability in cancer treatment.

9In recent decades, solid dispersion technology was extensively studied to develop an amorphous carrier to increase the bioavailability, solubility and dissolution rate of drugs with poor water solubility. The solid dispersion preparation methodology and selection of appropriate carriers will play a critical role in its biological behavior. Here are some techniques to prepare amorphous solid dispersions to enhance the bioavailability, solubility and therapeutic efficacy of drugs: (a) cryogenic processing techniques, (b) freeze drying, (c) fluid-bed coating, (d) spray drying, (e) microwave irradiation, (f) co-precipitation method, (g) electrostatic spinning, (h) supercritical anti-solvent (SAS), (i) HME technique, (j) MeltrexTM, (k) melt agglomeration, and the (l) KinetiSolVR dispersing (KSD) technique.

10The drug solubility is mainly influenced by its chemical arrangement and the conditions of its solution. The molecular assembly defines its molecular volume, crystal energy, hydrogen bonding, ionizability, and lipophilicity, which determines the drug solubility. pH, additives, time, temperature, cosolvents, and ionic strength will affect the solution conditions. Pharmaceutical compounds with poor water solubility can intensely decrease output in drug discovery and development.

11A “good compound” must reach the target site’s inactive focuses. Solubility of compound affects their absorption, permeability, and potency. Highly potent and permeable compounds are suitable for low aqueous solubility.

12BCS is one of the most applied scientific classification systems of drug substances based on their permeability and solubility as described in Figure 2. There are two significant factors which regulate the speed and scope of oral drug absorption that is aqueous solubility and intestinal permeability.

13The compounds of drugs can be categorized into four classes, according to BCS.

14When the maximum potency of the drug is soluble in ≤250 mL of the aqueous standard, it means drugs are highly soluble, and their range of pH is 1.0 to 7.5; otherwise, the drug elements are measured as not very soluble. Biopharmaceutical researchers are continuously trying to make a biologically mimicking system that can match conditions such as gut pH, food content, and peristalsis to predict in vivo performance precisely. Several biopharmaceutical research developments were made between 1960 and 1970; numerous studies were carried out and established the relationship between the effect of dissolution and formulation parameters on drug bioavailability. For the proper evaluation of any formulation’s dissolution rate, the first dissolution test apparatus was introduced in 1970, USP apparatus I (basket type), and afterwards, another USP Apparatus II (paddle type) was introduced. Using this apparatus, it has been possible to predict the in vivo performance of the formulation from the in vitro tests. However, because the in vivo performance of every formulation depends on several variables, improvements have been made to the in vivo performance of dosage forms. Figure 3 provides a chronological list of some of the significant studies conducted in this area.

15The main difficulty in the advancement of a new chemical entity is low aqueous solubility. For oral drugs, the most rate-limiting factor is solubility and reaching its concentration aspirated in full circulation for the pharmacological response. To obtain an approved concentration providing the necessary pharmacological reaction, solubility is one of the essential parameters. Hydrophobic drugs usually require high doses and need high dosage regimens to influence therapeutic plasma concentrations after administration.

16The oral administration of drugs is the most accessible and generally applied way of delivering drugs thanks to flexible administration, profitability, high compliance by the patient, flexibility in the dosage design, and fewer sterility restrictions. For this reason, most generics companies prefer to yield bioequivalent oral pharmaceuticals. However, the main problem with oral administration is related to its dosage form design and its low bioavailability.

17The factors affecting oral bioavailability include drug permeability, first-pass metabolism, dissolution rate, aqueous solubility and susceptibility to efflux mechanisms. The most common reasons for low oral bioavailability are associated with low permeability and poor solubility.

18In the case of other dosage forms such as parenteral formulations, solubility plays a critical role. Drugs with poor water solubility frequently require a high dosage of the drug to extend therapeutic plasma concentrations following oral administration. The essential criteria include being in an aqueous medium at the absorption site for the absorption of any pharmacological compound. H2O is the preferred solvent for preparing liquefied pharmaceutical preparations. A drug’s slow solubility in aqueous media is the foremost difficulty for formulation scientists. Most drugs are weakly basic or weakly acidic, having less water solubility. Almost 40% of NCEs (new chemical entities) are insoluble in water, as discovered in the pharmaceutical sector.

19Drug solubility enhancement is the most challenging factor in the field of drug discovery. In the literature, several strategies exist and have been described for the solubility improvement of poorly water-soluble drugs. These techniques are preferred based on specific features such as the characteristics of the drug under consideration, intended dosage form types, and chosen excipient characteristics.

20The low dissolution rate and low solubility in the aqueous gastrointestinal fluids lead to inadequate bioavailability. Mainly aimed at group II compounds conferring to the BCS, bioavailability can be improved through enhancing the dissolution rate and solubility of the drug in gastrointestinal fluids. The ratio restrictive factor for the class II BCS is the release of the drug from the dosage form and gastric fluid solubility and not the absorption, and thus enhancing the solubility will improve the bioavailability of BCS class II drug molecules.

21The negative impact of drugs having poor solubility involves less bioavailability and poor absorption for IV dosing, due to that high cost (frequent high-dose administration) are challenges.

22In Table 2, different approaches for solubility enhancement are explained with their advantages and limitations. The major techniques have listed in Table 3.

23The drug solubility depends on its particle size. Large particles provide a low surface area, which results in less interaction of particles with the solvent. One of the methods to increase the drug’s surface area is to reduce its particle size, which improves its dissolution property.

24Micronization: The process of producing drug particles in micron size by using the physical method. The methods widely used for increasing BCS class II drugs’ solubility are freeze-drying, crystallization, spray drying, and milling.

25Size reduction in the conventional time is achieved through mechanical methods, i.e., grinding, milling, and crushing of heavier particles to reduce their size by applying friction, pressure, attrition, shearing or impact. For mechanical micronization, ball mills, jet mills and high-pressure homogenizers are utilized. Dry milling is the most preferred micronization method.

26Micronization raises the dissolution speed rather than the drug’s equilibrium solubility. In various studies, it has been reported these that methods for the reduction in size are used to increase the dissolution and bioavailability through decreasing dimension and increasing the surface area of poorly aqueously soluble drugs.

27Nanosuspension: Nanosuspension is well-defined as a colloidal dispersion of sub-micron drug elements, stabilized by using a surfactant. To produce a nanosuspension, wet milling and homogenization are used. Milling defragments the active compound in the presence of a surfactant. Advantages of nanosuspensionEnhancement of drug solubility and its bioavailabilityHigher drug loadingSuitable for hydrophobic drugsPassive drug targetingReduction in dosageIncrease in drug’s physical and chemical stability.

28Advantages of nanosuspension

29Enhancement of drug solubility and its bioavailability

30Higher drug loading

31Suitable for hydrophobic drugs

32Passive drug targeting

33Reduction in dosage

34Increase in drug’s physical and chemical stability.

35Methods for the Preparation of a Nanosuspension: A nanosuspension is primed via two main methods—“bottom-up” and “top-down” technology.

36Bottom-up technology—This is an assembling technique for the formation of nanoparticles, such as precipitation, melt emulsification, and microemulsion.

37Top-down technology—Includes the decomposition of heavier particles into small particles, such as the high-pressure homogenization method and the grinding techniques.

38Precipitation method—The precipitation technique is employed to produce submicron particles of drugs with poor solubility. Here, drug molecules are solubilized in a solvent, and then that solution is poured into the other solvent in which drug molecules are unsolvable with the occurrence of a surfactant. Quickly mixing the solution with a solvent leads to quick supersaturation of the drug in the solution, which leads to the development of an ultrafine crystalline or amorphous drug. This technique includes two steps: the formation of nuclei and the growth of the crystal. These mainly depend on the temperature. Fundamental necessities for the development of stable suspension are a high nucleation rate and low crystal growth.

39High-pressure homogenization—The high-pressure homogenization method comprises three steps: (i) the dispersion of drug powders in a stabilizing solution to make a presuspension; (ii) the homogenization of the presuspension by the low-pressure, high-pressure homogenizer, sometimes for the previous preparation; and (iii) 10 to 25 cycles of final homogenization at a high pressure until the nanosuspensions attain the desired size.

40Homogenization in aqueous media (Dissocubes).

41Homogenization in nonaqueous media (Nanopure).

42Media milling

43Media milling includes the formation of drug nanoparticles by impaction within drugs and milling media; impaction provides enough energy for particle breakdown. This technique involves a grinding chamber, which is filled with the drug, a stabilizer, grinding means, and water or some other suitable buffer. The grinders rotate at a very high cutting speed to create the suspension. The major drawback of this method is the residues left behind, which are present in the finished product.

44(b) Dry grinding

45In the early days, nanosuspensions were developed by the wet grinding technique via a pearl ball mill. Now, they are developed via dry milling. In this technique, nanosuspensions are developed using the dry grinding of polymers and soluble copolymers with a poorly soluble drug, after having dispersed it in the liquid medium.

46The nanosuspensions can be prepared simply by the dilution of the emulsion, which is molded through a partly miscible solvent with water according to a dispersed phase. This method is suitable for drugs soluble in volatile organic solvents or partially miscible in water. In addition to that, microemulsion templates can also be used to create nanosuspensions. Physically, a microemulsion comprises a dispersion of oil and water and stabilizer (cosurfactant or surfactant) fluids, which are immiscible. The drug molecules are introduced in the internal phase, consist of a microemulsion, or are saturated through drugs of an informal mixture. Griseofulvin nanosuspensions are developed by the microemulsion process using H2O, taurodeoxycholate sodium salt, butyl lactate, and lecithin.

47This technique is a unification of the high-pressure homogenization and microprecipitation technique. This process involves the precipitation of breakable constituents that succeed through fragmentation.

48This technique is termed the reverse flow technique. Nanojet uses a compartment in which a suspension current is distributed into two or more two parts. Both streams exist as high-pressure colloids. Because of the collision, the high shear force generated throughout the procedure shows particle size reduction. The nano-suspensions of atovaquone are developed using the micro fluidification technique. The main limitation of the method is a high amount of cycles over the microfluidizer, and therefore the resulting output possesses a comparatively greater number of microparticles. The nanoparticle techniques can be useful as a screening protocol for studying the safety and preclinical efficacy of NCEs. Nanoparticle-based drug delivery techniques can be helpful in the preparation of existing NCEs with a higher bioavailability and minimum toxicity. In Table 4, a list of several marketed products using nanotechnology was represented.

49Various approaches based on nanotechnology for the enhancement of oral bioavailability of poorly water-soluble drugs are presented in Table 5.

50Crystal engineering: Crystal engineering is the study of the design, modelling, synthesis, and application of crystalline solids containing a predefined and preferred combination of molecules and ions. Crystal engineering is the exploitation of noncovalent interactions among ionic or molecular components for the rational design of solid-state structures, which show exciting optical, magnetic, and electrical properties.

51Hydrates/solvates: Solvates are molecule adducts that incorporate solvent molecules in their crystal lattice. When the solvent is H2O, then the solvate is called a hydrate.

52Polymorph: Polymorphs are defined as the phenomenon in which a compound has a different crystal structure but similar chemical composition; hence, due to their different network structures/molecular conformations, they have different physicochemical properties. Polymorphism is a common phenomenon by which many drugs can crystallize into dissimilar polymorphic structures to increase solubility.

53When two or more compounds are mixed, generally they do not show phase compatibility with each other to generate a new entity, but, at specific fractions, they prevent the crystallization process of one another, which results in a system having a lower melting point than either of the two starting components.

54When using a hydrophilic matrix and a hydrophobic drug, these two different components become molecularly dispersed in amorphous particles (clusters) or crystalline particles. Solid dispersion techniques are discussed in Table 6, along with their BCS class—for example, drug molecules and trade name, type of formulation and their therapeutic uses.

55Solvent evaporation method: An organic solvent is evaporated after the entire dissolution of both the drug and carrier in solvent evaporation. The dense form is ground, sieved, and dried—e.g., furosemide with eudragits.

56Hot-melt extrusion method: In this method, carriers and active pharmaceutical ingredients are prepared by hot-stage extrusion using a co-rotating twin-screw extruder. The dispersion of drug concentration is 40% (w/w). It is employed for formulating diverse dosage forms—e.g., sustained-release pellets.

57Kneading technique: In this technique, the drug carriers with H2O are converted into a paste, and then the drug compound is mixed into a paste and pressed for a fixed period; after that, the pressed mixture is passed through the sieve after it gets dried.

58Co-precipitation method: A certain quantity of the drug is poured into the carrier solution under continuous magnetic stirring, and the solution must be kept away from sunlight in the co-precipitation method. Then, precipitates are parted via purification through a vacuum, and they should be kept for drying at room temperature to prevent water loss due to the inclusion of complex structures.

59Melting method: In this method, a mortar and pestle are employed for mixing drugs and their carriers. After mixing, the mixture is heated up to the melting temperature of all of the ingredients to achieve a homogenous dispersion; then it is cooled to obtain a congealed mass. The mass is further crushed and sieved—e.g., albendazole and urea.

60Co-grinding method: The combination of the carrier and drug is prepared by a blender (blending for a particular fixed time and speed). Then, the prepared mixture is transferred to the vibration ball mill compartment, in which steel balls are further added. Pulverization is carried out, and the sample is taken out and stored at room temperature—e.g., chlordiazepoxide and mannitol.

61Gel entrapment technique: To prepare a clear and transparent gel, an organic solvent is used for dissolving hydroxyl propyl methylcellulose, and then the drug compound is liquefied in the gel by the application of sonication for a certain time. After the organic solvent is detached from the vacuum, the prepared solid dispersions are size reduced by a mortar and pestle and then separated using a sieve.

62Spray-drying method: The essential quantity of a drug solubilized in an appropriate solvent and carrier in water (aqueous media). Sonication or some other appropriate techniques are combined and employed for the preparation of a clear solution, which is further spray-dried in a spray dryer.

63Lyophilization technique: This process was projected as a substitute for the solvent evaporation technique. It is a type of molecular mixing process in which drug compounds and their carriers are combined, solubilized in a universal solvent, frozen and sublimed to obtain a lyophilized molecular dispersion that involves the transfer of mass and heat from the product under preparation.

64Melt agglomeration process: This process is different from other techniques because the binder itself acts as a carrier to prepare solid dispersion. Apart from this, solid dispersions are created by heating the drug compound, binder, drug and their excipient at or above the melting temperature of the binder or by using a high shear mixer. The drug compound is dispersed in the molten binder by spraying it onto the heated excipient. Due to the easy temperature control and high content of the binder, a rotary processor can be combined as a piece of alternative equipment.

65When two components are mixed, they crystallize together in a single homogeneous phase, considered a solid solution.

66They are of two types: substitutional solid solutions (random and ordered), and interstitial solutions.

67Substitutional: The condition where solute atoms occupy some space in the regular lattice sites of the parent metal (solvent)—e.g., random (Cu-Ni) or ordered (Cu-Au).

68Interstitial: The condition where solute atoms occupy the space in interstitial positions—e.g., (steel C solute atoms in Fe).

69Solid solutions can generally attain a quicker dissolution rate than the corresponding eutectic mixture

70Microemulsions are clear, transparent, unstable mixtures of two immiscible liquids—for example, water and oil. Emulsions are alleviated through an interfacial film formed by surfactants.

71Aqueous phase: Water is used as the most common aqueous phase. Because of the phase behavior, the pH of the aqueous phase needs to be adjusted. In the case of microemulsions used for parenteral administration, the aqueous phase should be isosmotic to the blood, which is maintained by sodium chloride, glycerol, dextrose, and sorbitol.

72Oil phase: Built on the method of drug administration and its nature, the selection of oil is performed. The oil should exhibit good solubilization potential for that drug. The oil changes shape and can inflate the surfactant tail assembly. The unsaturated and saturated fatty acids experience an intensification of their penetration. These fatty acids will increase permeability by interrupting the dense lipids and filling the extracellular spaces of the stratum corneum. For the enhancement of skin penetration, oleic acid is employed in unsaturated fatty acids, and the penetration effect is different for each drug. Isopropyl palmitate is a well-known fatty acid ester used for permeability enhancement.

73Recently, the selective tendency is towards the use of semi-synthetic oils, which are highly stable, compared to their natural equivalents. Drugs that have low water solubility must have solubility in the dispersed oil phase to produce an effective oil/water microemulsion arrangement. The size of the drops in the microemulsion will increase if the content of oil increases.

74Surfactant: Surfactants are compounds with a hydrophilic head and a hydrophobic tail. They are present at the interface of systems, and they alter interfacial tension. They are present in deficient concentration. The main aim of the surfactant is to minimize the interfacial tension between the two systems to a negligible value, which promotes the dispersion process during the formation of a microemulsion. It presents the microemulsion with an appropriate lipophilic character to fit the proper shape. A surfactant can unite both nonpolar and polar groups in a single molecule. The selection of a surfactant molecule is performed based on hydrophilic lipophilic balance (HLB) value. This HLB value suggests the kind of emulsion formation (whether it is an o/w or w/o emulsion).

75Co-surfactants: Co-surfactants are amphiphilic, accumulate at the interfacial layer, and increase the fluidity of interfacial film by penetrating the surfactant layer. Single-chain surfactants are unable to decrease the interfacial tension of o/w to form a microemulsion. Chain alcohols are used, utilizing co-surfactants to increase the fluidity of the interface. Ethanol and 1-butanol (medium-chain) are used as permeation enhancers. The relationship between surfactant and co-surfactant is the main factor to consider.

76Depending on the composition, microemulsions are classified into three kinds:Oil-in-water microemulsions (o/w)Water-in-oil microemulsions (w/o)Bi-continuous microemulsions

77Oil-in-water microemulsions (o/w)

78Water-in-oil microemulsions (w/o)

79Bi-continuous microemulsions

80The interface of the components in the three microemulsions must be stabilized with an adequate mixture of surfactants and/or surfactants as a stabilizing agent.

81Methods for the preparation of a microemulsion:Phase titration methodPhase inversion method.

82Phase titration method

83Phase inversion method.

84This scheme is employed for solving low bioavailability problems of poorly soluble and extremely porous drug molecules. Hydrophobic drug molecules can be liquefied in this system. When the constituents of the SEDDS are delivered in the lumen of the gastrointestinal tract, they come into contact with the gastrointestinal fluid, which leads to the development of a fine micro/nanoemulsion, due to which this mixture is termed as a self-emulsification in situ emulsion. This additionally leads to drug solubility, which is consequently engaged through lymphatic pathways, bypassing the hepatic first-pass effect. The bioavailability-improving property has been linked to several properties in vivo of the lipid preparations.

85Processes for self-emulsification:Self-nano emulsifying drug delivery system (SNEDDS)Self-micro emulsifying drug delivery system (SMEDDS)

86Self-nano emulsifying drug delivery system (SNEDDS)

87Self-micro emulsifying drug delivery system (SMEDDS)

88Composition of a self-emulsifying drug delivery system:

89Active Pharmaceutical Ingredients (APIs): Generally, a self-emulsifying drug delivery system is employed for the solubility enhancement of drugs with low aqueous solubility; drugs of BCS class II are mostly preferred—e.g., itraconazole, naproxen, vitamin E, mefanimic acid, danazol, nifedipine, simvastatin etc.

90Excipients used in SEDDS: OilsSurfactantsCo-surfactantsViscosity enhancersPolymersAntioxidant agents

91Oils

92Surfactants

93Co-surfactants

94Viscosity enhancers

95Polymers

96Antioxidant agents

97Table 7 represents the details of various marketed parenteral microemulsion products.

98The complex shares a connection between two or more molecules, which develop an entity, unrelated to a definite balancing. This depends on comparatively weak forces, i.e., hydrogen bonds, hydrophobic interactions, and London forces

99Stanching complexes are generally produced as overlapping planar domains of aromatic compounds, and the nonpolar groups lead to the removal of H2O through strong hydrogen bonding connections. These are particular particles which are known to produce stanching complexes, i.e., anthracene, benzoic acid, pyrene, salicylic acid, methylene blue, nicotinamide, ferulic acid, theobromine, gentisic acid, naphthalene, purine, and caffeine.

100Inclusion complexation has been developed using an infusion of a nonpolar particle or a section of the guest particle added to the cavity of different particles or an assembly of molecules (which is termed the host). The main physical prerequisite for complexing the inclusion is a perfect adaptation for guest molecules in the host cavity. The cavity of the host particle should have enough space for accommodating the guest molecule, and it should be small enough that it can eradicate H2O as the association between H2O and the nonpolar domains of the host molecule and the guest molecule decreases. α, β and γ-cyclodextrin are the three types of naturally occurring CDs. Cyclodextrin is used in complexation for solubility enhancement. The embodiment of cyclodextrin is a molecular phenomenon. In the case of cyclodextrin, one guest particle can combine through a cavity and create a stable association. In the cyclodextrin molecule, a shallow external activity is hydrophilic, and an internal activity is hydrophobic; this is because of the organization of the hydroxyl group inside a particle. The inclusion complexation of cyclodextrin involves the examination of positions for either a one-step reaction or a sequential two-step reaction, in which there is the involvement of structural transformation. Cyclodextrins increase the water solubility of drug molecules by inclusion complexation. The complex of cyclodextrin with clofibrate, rofecoxib, melarsoprol, celecoxib, cyclosporin A, taxol, etc., will improve the solubility of the drug.

101Manufacturing techniques for complexation/inclusion complexation:Kneading methodMicrowave irradiation methodCo-precipitate methodLyophilization/freeze-drying techniqueSpray drying

102Kneading method

103Microwave irradiation method

104Co-precipitate method

105Lyophilization/freeze-drying technique

106Spray drying

107The use of protein nanoparticles in the delivery of materials such as genetic materials, poorly water-soluble drugs, peptide hormones, growth factors, DNA, and RNA has many advantages. The advantages of protein nanoparticles over other colloidal carriers include their stability and ease of manufacture. As a result of an easy, cost-effective, and eco-friendly synthesis process, proteins from various sources can be synthesized into nanoparticles, which require fewer chemicals than nanoparticles from other materials and are expected to have a high potential for in vivo use. Moreover, bioactive substances and drugs will absorb more efficiently and be more bioavailable when their water solubility is increased by complexation. This will allow the drug to be administered at a lower dose to achieve the desired effect, and it will reduce the chances of side effects. As a result of the formation of the bioconjugate, the bioactive substances will also be more resistant to digestion. Through this technique, medicine for human health will be improved.

108Chang et al. reported that the improvement of the hydrophobic encapsulation of curcumin in egg white protein nanoparticles and the investigated compound’s encapsulation in egg white protein nanoparticles effectively reduced the degradation ratio as well as protecting the antioxidant activity of encapsulated curcumin. In another study, Prathap et al. reported that a nanoassembly of lysozyme-conjugated curcumin produced a nanoconjugate with enhanced antibacterial, antioxidant, and anticancer activity. The water solubility of a poorly water-soluble nonsteroidal anti-inflammatory drug, indomethacin, was enhanced through complexation with the casein hydrolysate (Figure 4). Similarly, the peptide complexation can enhance the solubility of poorly water-soluble therapeutics.

109Cryogenic techniques are employed to improve the dissolution speed of drugs by formulating an amorphous drug of the nanostructure with a high degree of porosity at minimal temperatures. Afterwards, on completion of cryogenic treatment, the powder is dried via the drying method (vacuum, spray, and lyophilization). Various cryogenic methods are mentioned in Figure 5.

110This plays a critical role in drug solubility. It can influence the aqueous solubility of drugs. By varying the solution pH, one can alter the charge state of the drug molecules. If the pH of the solution is such that a particular molecule carries no net electric charge, the solute often has minimal solubility and precipitates out of the solution. The pH at which the net charge is neutral is called the isoelectric point (sometimes abbreviated to IEP).

111This is a solubility sensation; using it, the water solubility of the solute can be enhanced by the excess addition of a second solute. The term hydrotrophy was used in earlier reports to describe non-micelle-forming materials, either solids or liquids, organic or inorganic, which are proficient in improving solubility of insoluble substances.

112Co-crystals are the complexes of non-ionic supramolecular materials. They can be utilized to address issues regarding physical properties, i.e., drug solubility, bioavailability, and stability, without affecting the chemical structure of APIs. Co-crystals are prepared using two or more different molecular units, in which the weak forces are intermolecular interactions such as π–π stacking and hydrogen bond interactions. The composition and molecular interaction of pharmaceutical compounds will be changed by co-crystallization, and it is accepted as a good option to optimize the drug characteristics. Co-crystals will offer various routes, where any APIs can be crystallized regardless of belonging to acidic, basic or ionizable groups. This can be helpful for compounds with low pharmaceutical profiles due to their nonionizable functional groups.

113When the structural complexity of newly developed entities rises, the H2O solubility of the drug decreases drastically. When the water solubility of a compound is much lower than its therapeutic dose, a blend of solvents is employed to obtain high solubility. Co-solvents are used to enhance the drug’s solubility, providing multiple nonpolar groups, thus increasing its aqueous (water) solubility. Co-solvents are necessary for the pharmaceutical formulation, where, sometimes, it may be required to enhance drug solubility.

114Acidic and basic drugs have low solubility in water as compared to their salts. For the development of parenteral administration, the most favored strategy is solubility enhancement by salt formation.

115Nanotechnology is applicable to promote the solubility of drugs with poor aqueous solubility. Nanotechnology involves extensive investigation and usage of structures and materials at the level of nanoscale, which is up to 100 nm. Micronization is not enough for several NCEs for the enhancement of solubility and oral bioavailability because the micronized material tends to agglomerate, which results in a decline in the effective surface area for dissolution.

116Nanotechnology for nanonization:NanomorphsDrug nanocrystal

117Nanomorphs

118Drug nanocrystal

119Supercritical fluid technology was employed for the first time industrially in the early 1980s in the pharmaceutical sector. During that period, SCF technology was used in pharmaceutical industries for developing pharmaceutical materials through crystallization and precipitation. The SCF. method is safe, eco-friendly, and cost-effective. The low operational parameters (pressure and temperature) make SCFs attractive for pharma research. An SCF survives as a single phase above its critical pressure (Pc) and temperature (Tc).

120Micellar solubilization is a technique in which the component is incorporated into or onto the micelles (the component that undergoes solubilization). The most significant characteristics of micelles are their capability to enhance the solubility of the less soluble compounds in water. In this circumstance, solubilization can be described as the natural dissolution of a compound by reversible interaction with micelles of a surfactant in water to develop a thermodynamically stable isotropic solution with reduced thermodynamic activity of the solubilized substance. If the solubility of a compound with poor water solubility is plotted as a function of the surfactant concentration, generally, it is concluded that the drug solubility is much less until the concentration of surfactant touches the CMC. After the surfactant reaches concentrations beyond the CMC., the solubility rises linearly with the surfactant concentration, intimating that solubilization is relevant to micellization. Gliclazide, glipizide, pioglitazone, glyburide, repaglinide, rosiglitazone, and glimepiride are some of the poorly water-soluble compounds which utilize the micellar solubilization technique for improvement in solubility and bioavailability.

121Other miscellaneous methods are as follows:Direct capsule fillingElectrospinning methodDropping method solution

122Direct capsule filling

123Electrospinning method

124Dropping method solution

125Cyclodextrins are cyclic oligosaccharides with a hydrophilic external surface and a moderately hydrophobic interior cavity. Cyclodextrins create water-soluble inclusion complexes using several hydrophobic drugs with low aqueous solubility. Cyclodextrin host molecules are also recognized as have a significant role in the formation of non-inclusion complexes. Extensive studies have been performed on cyclodextrins and their complexes in the last 2–3 decades. These studies have provided vast data on the physical necessities involved in complex development and the associated forces. Hydrophobic drugs, along with cyclodextrin–drug complexes, are identified for aggregate formation in the aqueous medium. Surface-active preservatives and water-soluble polymers are well-known excipients for the solubility of the drug in an aqueous medium.

126There are several methods for complexation with cyclodextrins, such as spray drying, physical mixing, co-evaporation, melting, freeze-drying, and kneading. By means of these techniques, the drug solubility, dissolution rate, and the bioavailability of poorly water-soluble drugs can be upgraded.

127Solid-lipid nanoparticles are used for organized and specific targeting in drug delivery. They are biocompatible and biodegradable and have an average particle size ranging from 50 nm and 1000 nm. They comprise a solid hydrophobic phospholipid coating. This coating consists of a lipid matrix that must be at room temperature in solid form, which is dispersed in H2O or an aqueous surfactant solution. Solid cores containing the drug are dispersed in the lipid matrix. They are likely to transport both hydrophobic and hydrophilic drugs.. Table 8 represents various examples of drugs developed by using SLN technology. Table 9 lists some examples of the frequently used lipid excipients in lipid-based nanocarriers.

128Incorporating poorly water-soluble molecules in surface-active agents can increase drug solubility and prevent drug precipitation following exposure to the GI environment. Monomeric surfactants, micellar aggregates, and surfactants adsorbed as a film at the interface are the three systems in a surfactant solution where micellar systems occur in dynamic equilibrium. Surfactant concentrations above the critical micellar concentration (CMC) cause the formation of micellar carriers. When dissolved in an aqueous environment, amphiphilic copolymers made up of hydrophobic and hydrophilic building components form micelles. The core and outer shell of the micelles are formed by the hydrophobic domains and hydrophilic tails of the copolymers, respectively. The hydrophobic drug’s contact with the aqueous medium is stabilized by the corona, whilst the lipophilic core acts as a container for loading lipophilic medicines. Lipophilic drugs can have their solubility increased by using micellar carriers incorporated into the micellar core. Table 10 lists the examples of nanocarriers, mainly those utilized for the oral delivery of drugs and therapeutics. Recently, amphiphilic block copolymers were developed as a better alternative for the delivery of hydrophobic drugs and therapeutic molecules with enhanced bioavailability. In the amphiphilic block copolymer, the combination of two or more two types (hydrophilic and hydrophobic) of polymeric segments combines and forms amphiphilic copolymers; moreover, these amphiphilic copolymers can be synthesized precisely by different polymerization techniques such as ATRP, RAFT, and radical polymerization. In these block copolymers, the combination and ratio of the different co-polymeric segments are very important, deciding the efficiency of delivery and bioavailability. In Table 11, the important patents of formulations related to nanoparticles for oral drug delivery are listed.

129This review provides a critical summary of previously reported and some currently developing technologies such as formulation design, solid particle techniques, prodrug strategies, crystal engineering, micronization, solid dispersions, particle size reduction technologies, nanosizing, cyclodextrins, solid lipid nanoparticles, drug conjugates, colloidal drug delivery systems, complexation of drugs, usage of formation of emulsion, micelles, microemulsions, cosolvents, polymeric micelles, pharmaceutical salts, prodrugs, solid state alternation, soft gel technology, drug nanocrystals, and nanomorph technology, with a few appropriate research reports and recent advancements. The solubility improvement technique of poorly water-soluble drugs plays a vital part in the formulation development to fulfil the therapeutic action and drug bioavailability of the pharmaceutically active ingredient (drug) at the target site. The pharmaceutical industry screening programs identified that around 40% of new chemical entities (NCEs) face various difficulties at the formulation and development stage. This is mainly due to poor water solubility and less bioavailability. The bioavailability and drug solubility enhancement are significant challenges in the area of pharmaceutical formulations. According to the biopharmaceutical grouping structure, Class II and IV drugs (APIs) have low water solubility, less bioavailability, and poor dissolution. Solving the above-mentioned problems here is based on molecular properties, but researchers view solid dispersions and lipid delivery as the most highly sought-after techniques to solve these for reasonable compounds. The solid dispersions can be in the form of a spray drawing or hot melt extrusion, and lipid delivery can use lipids for either delivering solubilization or improving permeability, and this is applicable in a variety of dosage forms, including soft shells or liquid-filled hard shells as some examples of lipid delivery. So, there are several trends in solubility enhancement in terms of new processes, including new excipients to help poorly soluble molecules; in particular, one of the areas that is being studied extensively is modelling and understanding the poorly soluble molecules and therefore which formulations will work best. Therefore, the ideal solution would be a technique or a polymer formulation that will overcome 100% of the reported solid molecules. This does not exist, but we are progressing towards being able to model molecules, looking at the properties of the molecule to predict which polymer will work best to perform the technique quickly.

130The graphical abstract of this article is created with Biorender.com (accessed on 7 August 2022).