INTRODUCTION:

In the today scenario, the most challenging concept of drugs poor solubility is one of the main criteria in formulation development¹. Poor solubility of drug absorption is limited by the extreme achievability of intraluminal concentration². The prime features to achieve the desired concentration in the systemic circulation for their pharmacological effect mostly in the case of oral drug delivery system³. The substandard solubility and dissolution rate of poorly soluble drugs in the GIT fluids often cause in adequate bioavailability and the rate limiting step of BCS class II drugs is release of drug from the dosage form and solubility in the gastric fluid but not the absorption^3-5.

Superfluity is becoming a key parameter of bioavailability enhancement of poorly aqua soluble drugs for the improvement of the drug delivery processes¹. Superfluity drug delivery through oral route is gained at the condition where the concentration of intraluminal part is greater than its thermodynamic equilibrium solubility concentration of the drug². The need for scheming invention in the formulations for the improvement of intestinal absorption and also the therapeutic effect that can gain more attention in concentration of drug in the intestinal region, because this will be achieved due to induction of superfluity condition⁶. The comparison between superfluity strategies and solubilization strategies, the superfluity formulations have high free drug concentration which will be applicable to very poor aqueous soluble drugs and but the solubilization formulations are not applicable ^1,7,8. The formulations prepared under superfluity conditions were do not need the excess amounts of solubilizing excipients such as surfactants (as vehicle), which may be resulting in a reduced pill burden form and/or a lower the toxicity in the system⁹. Therefore, it used the less to less amount of surfactant which will result in low risk of toxicity^10-12. Solubilizing formulations attempt to avoid the creation of supersaturated state by increasing the solubilizing capacity of the GIT environment (Thermodynamic Approach) but it is limited for drugs with very poor water solubility. Superfluity formulations aim at the creation of a metastable supersaturated state, stabilized by temporary inhibiting precipitation (Kinetic Approach) and these formulations can reach to higher intraluminal concentration³. Advantages of superfluity methods includes high free drug concentration, beneficial for very poor aqueous soluble drugs, high dose drugs, less amount of vehicles/surfactants are used (which will avoid from the risk of toxicity), surfeit operation exceeding thermodynamic activity based on the solute through the flux across membrane but in case of solubilization it decreases at equal solution concentration^4,13,14. Disadvantage of SFDDS is Precipitation^10,13.

For superfluity drug delivery system, the degree of super-saturation can be expressed by the super-saturation ratio ‘S’ as shown in equation (1) which will be obtained by using two types of method, the most common methods used for the detection of superfluity assay are the solvent-shift method and pH- shift method ^15-18. In the solvent-shift method, the poorly water-soluble drug is first dissolved in an organic solvent such as dimethyl sulfoxide (DMSO), dimethyl formamide (DMF) and dimethyl acetamide (DMA) are used to evaluate the superfluity condition due to its remarkable water miscibility and drug highly solubilized in this organic solvent compare to aqueous medium^3,8. Next, a fraction of this solution is added to the medium under investigation. Finally, super-saturation and/or precipitation can be evaluated by using equation (1) as result of drug solubility has been changed for precipitation to achieved equilibrium¹⁹. Super-saturation assay can be done both in the presence and absence of precipitation inhibitor used to evaluate the capacity of polymers to inhibit precipitation so that the optimization of nucleation-induction time can also be estimated²⁰. The difference in concentration between the saturation and super-saturation state, where no nucleation occurs^21,22, is known as the metastable zone and the width of this zone is referred to as the metastable zone width (MSZW), above which super-saturation is achieved with spontaneous nucleation⁸ as shown in figure 1. MSZW act for the nucleation-behaviour of drugs and its also shows the solution stability of superfluity system²³, The width is reduced or truant in the case of liquid solution although the system is stabilized in case of polymeric therefore, metastable zone can be attained due to these types of polymers. This is an easy method for the creation of superfluity condition and this method is applicable to any poorly water-soluble drug that can be dissolved at significantly higher concentrations in a water miscible solvent for the determination of superfluity state^24,25. For the Ionizable drugs, pH-shift method is used to evaluate the superfluity potential. Due to ionization process the drug solubility can be increased in polar aqueous solvents; therefore, any shift in the pH indicates that reduction of ionization will be decreasing the drug solubility and inducing the supersaturated state ^26-28.

S = C /Ceq …………………………………………... (1)

Where, C and Ceq representing the drug concentration at time “t” (Superfluity state) and equilibrium solubility of the drug in the given test medium (saturation)^1-4. An alternative way of expressing super-saturation is the relative super-saturation index σ, deﬁned as σ = S -1 =

C- Ceq/ Ceq

A solution is deﬁned as unsaturated, saturated or supersaturated based on the following relationships: S<1(σ <0), S = 1(σ = 0), or S>1(σ >0), respectively³.

Mechanisms of superfluity:

Superfluity can be achieved by adding more of substance (to a solution) than can normally be dissolved²⁹. This is a thermodynamically unstable state, achieved most often in protein crystallograpy by vapor diffusion or other slow evaporation techniques.^4,5,7 There are two concept on which the mechanisms of superfluity occurs is based as shown in table1.

Table 1: Describing the concept of superfluity mechanism with examples

Superfluity Mechanism	Examples
	Spring and Hang	Parachute and Glider
Spring-Parachute Concept	• Amorphous solid dispersion • Super-SNEDDS • Supersaturated SEDDS Etc…	• Neem Gum, Poly (vinyl pyrrolidone), HPMC E5, HPMC • Tris(hydroxymethyl) aminomethane (tris), maleic acid • Oleic acid, Tween 20, PEG 400, HPMC
Hang-Glider concept

As report in Ref.^31-34

For the improvement of oral bioavailability of poorly aqua soluble drug, the main two steps involved: creating and preserving the metastable supersaturated state based upon the spring and parachute concept, which was proposed by Guzman,¹¹ is widely used to describe the state as shown in the figure 1.

Figure 1: Illustration the Superfluity mechanism based upon Spring-Parachute and Hang-Glider Concept.^16,17,35

Spring-Parachute effect:

Drug absorbed when it is in supersaturated solution form. Superfluity leads to higher absorption¹⁶. Superfluity leads to precipitation (recrystallization) of drug. As superfluity disappears, drug absorption decreased. When the higher energy form of the drug (as compared to the crystalline powder) started then the solution is becoming supersaturated,³⁶therefore unstable this form or state is, the ‘‘spring.’’ This will only generate the superfluity state by means of many types of formulations such as solid dispersion, co-crystals, self-emulsifying drug delivery system^37,38. Precipitation inhibitors are used to delay precipitation. Leads to longer superfluity, thus prolonged absorption of drug⁹. Drug absorption decreases with time but very slowly. This is called Parachute effect which will maintain the state of superfluity^1-5.

Hang-Glider effect:

Some of the techniques which maintained the superfluity state for the enhancement of poorly soluble drugs such as amorphous solid dispersion which achieve the concept of hang-glider effect. The concept of hang effect includes the solubilizing the drug immediately and this phenomenon are known as hang effect²². It also achieves by continues release of drug in free fraction form by avoiding the nucleation and crystal growth and sustained the superfluity condition for an extended time period and sustainability of superfluity state is known as glider effect^22,35.

Precipitation inhibitors (PIs):

The key factors in the development of SFDDS are basically precipitation inhibitors which enhances the oral bioavailability by inhibiting the drug precipitation and due to which the superfluity system is to be maintained or prolonged⁴⁰. The mechanism of precipitation inhibitor is interfering with the theory of drug precipitation³ as shown in the figure 2. However, thermodynamics or kinetics basically thermodynamic process leads to enhance the drug solubility while reducing the degree of super-saturation and also slow the rate of both nucleation and crystal growth⁴¹. The dynamic (kinetic) process involves the inhibition of crystal nuclei formation in the superfluity condition. PIs notion situated on nucleation reticence and amorphous (LLPS) phase stabilization. All this mechanism parameter depends upon the PIs properties⁴² some examples are shown in table 2. Mostly in the case of oral dosage form, it is easy to apply controlled-release technology and consequently, which will give the possibility to increase the drug absorption via sustained release operation. Polymers having high molecular weight were found many applications such as emulsifiers, and solidification excipients in lipid-based formulation designs, in particular self-emulsifing drug delivery system (SEDDS)^40,43. Some polymers shown crystallinity inhibitor or superfluity promoter as well as control release polymer, film former in amorphous solid dispersion⁴¹. Some examples are Poloxamers, hydroxypropylmethylcellulose (HPMC), sodium CMC, Guar Gum and PVP^44,45.

The lipophilic compound in solutions of supersaturated condition undergoes liquid-liquid phase separation (LLPS), due to the solubility of the amorphous form of the compound in the aqueous medium is exceeded⁵². The solute thermodynamic activity and the flux across a membrane increases linearly with an increase in solution concentration up to the amorphous solubility; above this value, any further increases in concentration do not lead to an increase in concentration⁵³. Due to that the amorphous solubility marks as the maximum limit of supersaturation that is be sustained for enhanced delivery of the drug. For ionizable drugs, LLPS can also occur as a result of pH change⁵⁴. In pH of acidic environment, the drugs with basic nature with pKa values > 4 will go through ionization state. Still, the drug can convert partially or completely to unionized form, after the transit in basic (intestinal) environment.⁵⁵At that pH, If the amorphous solubility the concentration exceeded leads to LLPS¹³. LLPS is expected to be advantageous in vivo⁵³. Consequently, for a system that has undergone LLPS, the solution phase can provide the maximum possible flux for permeation through the biological membranes (absorption), while the second phase, due to its fast dissolution, can rapidly equilibrate to replenish the absorbed drug thereby serving as a reservoir¹³. Further, the duration of the reservoir effect will increase with an increase in the amount of the drug that is present as the drug-rich phase⁵².

Figure 2: Schematic Illustrating Total Versus Free Drug Concentrations in Suspension, Solubilization and Superfluity Systems (Mechanism of Precipitation Inhibitors in Superfluity system)⁵⁶

Superfluity (supersaturated) formulations:

Amorphous solid dispersions:

In the ASDs method of formulation, drug is to be converted into an amorphous state and, ideally, molecularly dispersed in a pharmaceutical polymer. The drug is in the higher-energy state in which the dissolution and solubility are more favoured due to amorphous state. The polymer acts as stabilizer to the drug in the thermodynamically unfavourable condition by amorphous state as well as to provide in-solution stability through drug-polymer interactions⁵⁷.The advantages of ASDs include, reduction in particle size and unstable drugs are also stabilized, the enhancement of drug wettability and porosity, drug crystallization is decreased by amorphous forms, dissolution rate of a poorly water-soluble drug in a pharmaceutical is also improved as well as bioavailability,⁵⁸ to mask the taste of the drug substance, rapid disintegration of oral tablets can be prepared, homogenous distribution of small amounts of drugs at solid state is obtained. and disadvantages include, reproducibility of physicochemical characteristics^59-61.

The concept of dissolution of ASDs build on the drug uptake from the matrix of polymer where when water is to be entered into the tablet, the initiation of polymer is to be bulge, from the swollen matrix drug dispersed out and polymer started to crumble. They also investigated; the superfluity state of API is stabilized by the gel layer ⁶². Thus, the crystallization of drug will be show at fast polymer erosion. In the case of API dissolution, the diffusion process is managed through the gel layer (carrier-controlled dissolution) and if disintegrant was not used, then the water ingress in the early stage of dissolution ⁶³. They reveal that there is no direct influence on the release kinetics by water ingress rate and polymer mobilization kinetics is correlates by drug release. In precis, there is rack up confirmation in the literature, that mainly three dissolution mechanisms of ASDs take place as shown in figure 3.

Figure 3: ASDs Showing basic hypothesis of drug uptake (dissolution process)^64,65.

Carrier controlled release:

Water get entered into the polymer matrix and the highly viscous gel layer is formed to be persuade, through which the diffusion of API has to be take place. This generally sequel a slower release process, where the API concentration in ASDs is controlled in the dissolution medium and the volume of the release medium. The formation of drug-rich particles can be taking place when their will be the case of exceeding amorphous solubility.

Dissolution controlled release (congruent release):

Into the dissolution medium, simultaneously the release of API and polymer take place quickly which will lead to remarkable supersaturation effect. Here, it is necessary to stabilized the supersaturated state by using polymer in solution. The total drug dose and the volume of the release medium can control the supersaturation concentration.

Drug controlled release:

The polymer is dissolving into the dissolution medium and the remaining amorphous API is to be dissolved at a drug-controlled rate. For this mechanism, already during the process of dissolution, the API crystallization risk has to be taken place. In literature survey, the theoretical concept of view the drug-rich particles could be form if the amorphous drug state is stable enough, but there were no experimental data was to be found for this review.

Apart from feasibility considerations for the three different dissolutions related to a specific API, it remains up to the selection of these concept based upon the formulation choose by the scientist or researcher such as the desired onset of action of the drug can be considered further also⁶⁶.

Superfluity SEDDS:

According to traditional method of self-emulsifying drug delivery systems (SEDDS) will precipitated occasionally after the administration because of the dilution effect into the fluid. The method of solubilization is regularly used to avoid the precipitation process. But still the improvement of bioavailability is limited due to the solubilization because it cannot increase the free drug amount into the system, especially in the case of very poorly soluble hydrophilic drugs. For the preparation of superfluity self-emulsifying drug delivery systems (S-SEDDS) PIs are added to maintained the surfeit condition⁴².The pitfall related to these methods are lack of in vitro models’ good predication for the assessment of the formulations, traditional methods of dissolution do not work, just because of these formulations potentially dependent on the digestion prior to the drug release. The instabilities of drugs chemical and high surfactant concentrations in formulations (approx. 30-60%) which causes the irritation in GIT. High production costs, low drug incompatibility and Drug leakage. So, it may allow less drug loading which leads to the drawbacks of this system⁶⁷.

Superfluity liposomes:

Either passive or active methods used to achieve drug loaded in the liposomal. Active loading is to be driven by a pH or potential gradient, which has to be been proven more effectively for achieving the higher drug-to-lipid ratios as comparing to the passive loading and hence, widely used for some weakly acidic or basic drugs. However, the low solubility which will lead to the low concentration gradient which may cause insufficient driving force, and also limited role in the improvement of drug loading for some poorly water-soluble drugs. A novel method based on supersaturation using cyclodextrin in the small amount as the precipitation inhibitor for active drug loading for the enhancement of drug-lipid ratios for poorly water-soluble drug⁶⁸. The superfluity solution of active drug AR-67 (camptothecin analog) was maintaining the surfeit condition up to 48 h and was used to load the drug. The improvement of drug-loading was done (drug/lipids ratio, 0.17), and the influence of the internal phase by calcium acetate or sodium acetate was small^69,70.

CONCLUSION:

Recently most of the active pharmaceutical ingredients (APIs) in process of development of poorly soluble drug by enhancing the solubility using superfluity drug delivery system (SFDDS). The tremendous possibilities to enhance bioavailability as well as absorption of APIs having poor solubility is achieved by amorphous solid dispersion technique with showing benefit of improved solubility (no impact on permeability) and other technique also their such as self-emulsifying drug delivery system play a role of ‘spring’ and ‘hang’ effect etc. The initial provocation was to attained by enhancing bioavailability by the improvement of APIs solubility. Still in most of the cases, the auxiliary challenge to sustained the solubility for more than 3 hours and this problem is solved by using polymeric precipitation inhibitors in the advancement of drug delivery systems in which these polymers play a role of ‘parachute’ and ‘glider’ effect in the formulation for improving bioavailability, solubility, and drug delivery. Now a days it is possible to enhance the solubility of poorly soluble drugs by using recent technologies with various formulation methods which are discussed in this review article superior than before.

AUTHORS’ CONTRIBUTION:

All authors have equally contributed in this review article. All authors have read and approved the manuscript.

ACKNOWLEDGEMENT:

The authors thanks to their parents and siblings support and encouragement. The authors acknowledge the Department of Pharmaceutical Sciences, Maharishi Markandeshwar (Deemed to be University) Mullana (Ambala), for giving the opportunity to carry out the work under reviews. Also, Department of Pharmacy, Guru Gobind College of Pharmacy, Yamunanagar (Haryana), India is gratefully acknowledged for the support and space.

CONFLICTS OF INTEREST:

The authors declare no conflict of interest.

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Received on 03.05.2021 Modified on 07.09.2021

Research J. Pharm. and Tech. 2022; 15(8):3769-3775.

DOI: 10.52711/0974-360X.2022.00633

S. No.	Technology	Drug	Precipitation inhibitor	Motive
1	Polymeric micelles	Cyclosporine	Soluplus	Increased molecular solubility
2	Amorphous nano-complex	Silibinin	Chitosan	High payload
3	Amorphous solid dispersion	Glipizide	HPMC-AS	Controlled release
4	Ternary solid dispersion	Atorvastatin	HPMC E5	Oral bioavailability increased
5	solid dispersion	Ritonavir	OMS	Enhanced thermodynamic activity
6	SEMDDS	Atorvastatin	Oleic acid Tween 20 PEG 400	Enhanced dissolution rate
7	SNEDDS	Econazole nitrate	HPMC	Enhance ocular bioavailability
8	solid dispersion	Astorvastatin and ezetimide	PVPK30	advantage in the management of hyperlipidemia