INTRODUCTION:

Numerous drug candidates are developed in the pharmaceutical industry which are faced various challenges in formulation development. Most of the drugs are hydrophobic compounds due to poor solubility and low bioavailability. These type of drugs are problematic when formulated into oral formulations. They can’t deliver the drug at a sufficient amount into the target organ of the biological system.[1]

With the estimated increase number of hydrophobic compounds, various established and popular strategies are already existed to solve their poor solubility and bioavailability problem [2,3]. The incorporation of the hydrophobic compounds into lipid excipients such as oil, surfactant mixture was carried out for improving both solubility and bioavailability.[4] This system act as carrier for drugs by forming microemulsion, when diluted with physiologic media and maintains the drug in very fine dispersion droplets inside the intestinal lumen, providing optimal conditions for absorption.[5,6]. S.

Warke etal. had developed a stable self micro emulsifying drug delivery system (SMEDDS) of herbal extract and investigated that the formulation release completely within 10min [7]. A. Deshmukh etal. had developed Self Microemulsifying Drug Delivery System (SMEDDS) of Darunavir ethanolate (DRE) and found that dissolution profile of DRE from SMEDDS was much improved than API alone [8]. A.S Mohammed etal. had prepared selfemulsifying tablet of Ibuprofen by using various quantity of natural fat obtained from goat. It was found that F2 and F4 formulation showed highest drug release as compared to marketed drug [9]. But some obstracles were arised during development of self microemulsifying drug delivery system i.e. lack of good predictive in vitro models because these formulations potentially are dependent on digestion prior to release of the drug.[10] One of the drawbacks is precipitation tendency of the drug on dilution which may be due to dilution effect of hydrophilic solvents [11,12,13]. Among these well-established approaches, the supersaturated self emulsifying drug delivery system has been proved as great pledge for gaining both solubility and bioavailability [14]. Supersaturated SEDDS formulation contains reduced amount of surfactant and water soluble cellulosic polymeric precipitation inhibitor by which incidence of gastro intestinal (G.I.) side effects is reduced. It is designed to generate and maintain a supersaturated state in vivo before absorption. In g.i. fluid, the above system generates an elevated and sustained level of drug supersaturation by enhancing the drive force for better absorption. So that the bioavailability of poorly water soluble drug is improved. [15]

Various weak acid and weak bases are available as a pharmaceutical ingredient with their corresponding salts. In the fasted state, precipitation is probably expected in the stomach in case of weekly acidic compounds due to its high pka values. So that the solubility of these compounds is achieved in the stomach region to facilitate absorption. But in case of weak bases compounds, the equilibrium solubility will not achieve due to its low pka values (≤7). To achieve increase dissolution rate in the stomach region, formulation containing a free base is used for such weekly basic drug. But there is a tendency for crystallization and tendency for crystallization and precipitation, when it is transit into the small intestine. [16]

Polymeric precipitation inhibitors (PPI) are the concentration enhancing polymers which reduce the rate of precipitation by maintaining the degree of supersaturation. These polymers are not only improved the solubility, solid liquid boundary layer viscosity, molecular mobility and interfacial tension but also they reduce nucleation and growth rate of the particles. So the selection of right PPI for supersaturated SEDDS is very tedious and difficult. [17,18]

The pharmaceutical scientist faced major challenge regarding the use of PPI which describes the rate and maintenance of post administration supersaturation. So design, development of such system and investigation of desired rational selection of PPI with the weight ratio of excipients is not so practical.

So this review will discuss regarding various challenges of supersaturated formulation and their solution to overcome these problem.

SUPERSATURATED SEDDS:

Supersaturating SEDDS is a mixture of oil, less amount of surfactant, co surfactant and precipitation inhibitor such as HPMC, HPMCAS, PVP etc. Different polymers, surfactants, and cyclodextrin are used as precipitation inhibitor in supersaturable formulation. They generate and maintain a supersaturated state of the drug upon diluted with aqueous fluid. [19,20]

The rate of precipitation is enhanced by the production of nucleation and crystal growth of drug within the supersaturable formulation. The rate of nucleation and crystal growth is gradually reduced by the use of precipitation inhibitor.[21] Reduction of nucleation and crystal growth, it creates stabilization medium within the formulation, which is known as “parachute effect”. However liquid liquid phase separation occurred due to precipitation inhibitor by which the concentration of drug exceeds the amorphous solubility and the kinetic of crystallization became very slow relative to dissolution process. After the formation of LLPS, at certain point the crystallization process is occurred. [22,23] It was illustrated in figure 1. The production of any phase results changes in the appearance and light scattering properties of the solution. Various characterizations are done by using UV/visible spectroscopy, FS (fluorescence spectroscopy) or DLS (dynamic light scattering), differential scanning calorimeter (DSC), Cryo-transmission electron microscopy (Cryo-TEM) etc. [24, 25]

Figure 1 represents fast increase of drug concentration above the equilibrium solubility of the respective crystalline form (spring), and fast production of crystal nuclei, precipitation. In both the cases, use of precipitation inhibitor effectively delays nucleation and reduce crystal growth and allows the supersaturated state to prevail for longer.

SUPERSATURABLE FORMULATION:

Supersaturated formulations are supersaturated drug solution which generate supersaturation and maintain supersaturated state before absorption. The bioavailability can be improved but it may cause precipitation before absorption. The precipitation may cause variability and inaccurate prediction from the in vivo absorption. To determine the degree of supersaturation, supersaturation index has to be estimated from the following equation:[26]

St=Ct/Ceq, where St is supersaturation index.

Ct is concentration of drug at time t.

Ceq is equilibrium concentration within the formulation.

Conceptual Theory for maintanance of Supersaturated State:

“Spring and parachute” are the two theory which describe the concept of generation and maintenance of supersaturated state of the supersaturable formulation. Spring and parachute theory was proposed by Guzman. [27]

spring theory:

Supersaturated form (as compared to crystalline powder) is thermodynamic unstable form which have tendency to produce precipitation and crystallization due to high energy of the system.[1] The above concept describe about the spring theory of supersaturated state. High energy of the system due to change in morphology, particle size or wettability. Generation of supersaturated state from various supersaturable formulations like lipid based formulation, amorphous forms, nanoparticle, and co crystals, crystalline salt form etc. is known as spring. These supersaturable formulations were used to improve oral bioavailability of poorly soluble drug.[28] In recent time, solid dispersion have been extensively applied for improving the bioavailability of poorly soluble drug. In this method, an amorphous form of a drug is prepared and dispersed one or more hydrophilic polymer. These polymers not only improve the wettability and surface areas of particle but also prevent the precipitation of drug in vivo. [29,30]

In supersaturated-SEDDS (s-seed) and S-SMEDDS preparation, the drug is present in amorphous form, which is precipitated due to presence of highly concentrated solution form and high energy of the system. For prevent this precipitation, precipitation inhibitors and cyclodextrin complex are applied to maintain supersaturated state. [31]

Parachute Theory:

When the nucleation and crystal growth is reduced by precipitation inhibitors within the formulation, the formulation is going to be stable and produces stabilizing effect. This stabilization effect occurred by precipitation inhibitor, is known as parachute effect. The above effect describes the parachute theory of a supersaturated formulation.[32] This theory explains that, the precipitation inhibitor maintain high concentration of dug and inhibit the drug precipitation for extended period of time. So for development in designing a supersaturable formulation, the spring and parachute theory has to be clearly understood. Combination of spring theory (development of crystalline form) and parachute theory (mechanism of precipitation inhibitor) provide the benefits of both improved bioavailability and permeability.[28]. Figure 2 represents the formation spring and parachute within the supersaturated solution.

Fig-2 represents the spring and parachute theory of supersaturated solution. Regenerated with modification from Brouwers et al. (2009)

Limitation of Supersaturated Formulation:

There are some challenges associated with supersaturated formulation which hampered absorption of drug at a sufficient amount to the target site. So here we will discuss about some limitation by which the oral absorption and bioavailability of drug can be improved. Precipitation, supersaturation, nucleation, crystal growth and appropriate invitro model are the challenges of supersaturated formulation. [26]

supersaturation:

Nucleation and crystallization is developed when supersaturation is created. Supersaturation is performed as the driving force for crystallization.[33] When a supersaturated formulation is administered into g.i. tract, it produces supersaturation of different drug species including free drug, free polymer, polymer colloid, Nano aggregates, drugs and polymer nanostructures etc.[34] Supersaturation is created when the chemical potential of the solute in the solution phase (µDw(s)) is much higher than that of solute at equilibrium (µD(C)) with the most thermodynamically stable crystalline form. The concept of supersaturation(s) can be expressed by the following equation.[35]

(µDw(s)) - (µD(C))

lnS= ––––––––––––––––

The above equation can be expressed in the ratio of the molar concentration in the supersaturated solution(C) and molar concentration in saturated solution is denoted as C*.

Sc = C/C*

The supersaturated system possesses less thermodynamic activity and low bioavailability due to formation of crystallization. But when it is loaded with solubility enhancement generator like precipitation inhibitor, micellular surfactant or cyclodextrin, the free drug concentration is increased and exhibited higher permeation rate.[33]

Presence of free drug concentration in the supersaturated solution can be determined by invitro dissolution test using micro centrifuge. It is very simple and commonly used technique. However small particle can pass through the filter, so that amount of free drug is not accurately estimated.[36] In recent time, Pulsatile Microdialysis method has been developed which provides accurate determination of drug concentration from the collected filtered samples. As it is very sensitive process so that the drug concentration was significantly lower than simple dissolution test.[37]

Supersaturation assay was done by invitro release study or invitro precipitation analysis. HPMC, PVPK17, and PEG 4000 are selected for investigating supersaturation assay. At different concentration, 0.5%, 2% and 5% used in SS-SMEDDS from which 0.5% PVPK17 was achieved highest precipitation inhibiting capacity and drug concentration as compared to SMEDDS.[38]

precipitation:

Precipitation is a non-equilibrium condition by which crystals are generated within supersaturated solution. The difference between precipitation and crystallization is the speed of the process and size of the solid particle. In case of precipitation, the process is rapid and produces small crystal which is not appeared in the eye but some crystalline peaks are observed from the XRD analysis. In case of crystallization process, nucleation and crystal growth is formed. At a very high supersaturation, nucleation is developed which influence the growth of crystals. Crystalline product can usually be redissolved by simple heating and dilution. In both the process, supersaturation, nucleation, and crystal growth has been occurred. [39]

The solid state precipitate may be metastable amorphous precipitate and stable crystal precipitate. Amorphous precipitates improve the absorption and bioavailability but crystal precipitate donot improve the bioavailability.[40] There are so many factors which affect drug precipitation include:

1. Degree of supersaturation which is affected by cooling the solution and use of solvent that lowers the solubility of the drug.[41]

2. Then impurities which stimulate nucleation process then ultimately crystallization proceed.[42]

3. Temperature is also a factor that affects the precipitation of drug. At temperature increases, the intermolecular interaction between drug and excipient is low. So crystal growth and nucleation process is decreased.[43]

lack of good invitro models:

Invitro dissolution performance is desired for understanding the drug release profile of supersaturable system. It is difficult for accurate determination of dissolution profile, rate and degree of supersaturation and precipitation kinetics due to selection of accurate analytical dissolution methodology, selection and application of PPI and the ratio between drug and polymer. [41]

Various USP compendial dissolution tests are used for determination of invitro dissolution kinetic. Such tests are so much valuable for many drug product but they have not ability to address some other measurement. PH change and some dynamic aspects when a formulation is present in G.I. environment.[42] Due to great concern of precipitation and crystallization of a supersaturable formulation, USP compendial dissolution models are not very efficient to determine the invitro dissolution kinetics. This invitro models are necessary for further development and proper validation. For that the correlation between in vitro-in vivo can be developed for supersaturable formulation and a suitable animal models is evaluated for in vivo experiment. [16]

Drug Precipitation Inhibitor:

Precipitation inhibitors have played an important role to maintain supersaturated state of the drug in vivo for extended period of time to get optimum absorption. Especially in supersaturable formulation, three types of precipitation inhibitor such as polymers, surfactants and cyclodextrins are used. [28]

Polymeric Precipitation Inhibitors:

Polymers are called as polymeric precipitation inhibitors which affect the rate of drug nucleation and crystal growth at a low concentration. [43] Various hydrophilic polymer such as HPMC, hydroxy propyl methyl cellulose acetate succinate (HPMCAS), hydroxy propyl cellulose (HPC), polyvinyl pyrrolidone (PVP), polyvinyl acrylic acid (PVA), polyvinyl pyrollidonevinyl acetate (PVPVA) are used in supersaturable formulation. [44]

In various literatures, it has been informed that HPMC has effective drug inhibitory precipitation inhibitory capacity. Gao etal. [45] developed a novel supersaturable SEDDS of AMG517, by using HPMC as precipitation inhibitors. From the invitro study, HPMC loaded S-SEDDS formulation did not show any precipitation but crystalline AMG 517 showed precipitation due to absence of HPMC. From the in vivo analysis, it was seen that ˜30% higher Cmax and short Tmax are attributed to high free drug concentration in vivo as compared to supersaturated formulation without HPMC. From the above study, it was demonstrated that HPMC is an effective precipitation inhibitor by which both in vitro and in vivo profile has been improved.

HPMCAS is also a effective precipitation inhibitor for a different poorly soluble drug. [46] Laine et al. [47] used HPMCAS with mesoporous silicate prepare supersaturable SEDDS of celecoxib (CXB). From the invitro dissolution study, coload of HPMCAS and silica with CXB formulation (CXB-HPMCAS coloaded silica) 1.35fold Cmax increase over crystalline celecoxib. From the above study, HPMCAS is a very effective inhibitor for solubility and bioavailability improvement. Like HPMC and HPMCAS, hydroxy propyl cellulose (HPC) is also a good precipitation inhibitor.

PVP, PVA, PVPVA are categorized into vinyl polymers, which have also very effective precipitation inhibiting capacity. Nan etal. [48] used PVP as precipitation inhibitor for the development of supersaturable selfmicroemulsifying drug delivery system of carbamazepine which is a poorly water soluble drug. They evaluated S-SMEDDS by invitro and invivo analysis. From the invitro dissolution study, the PVP loaded S-SMEDDS formulation shown higher dissolution rate and from the invivo study, the absorption of S-SMEDDS was increased 5fold than commercial tablet of carbamazepine. At 0.5% of PVP K17 has shown very effective precipitation inhibitor and maintain higher indirubin concentration for approximately 2hr. or more.

Surfactants:

In vivo drug precipitation is one of the serious cause for low oral bioavailability of poorly soluble drug. Invivo precipitation reduces the drug concentration in aqueous phase so that release became delayed and efficacy is reduced. For the inhibition of precipitation, surfactants act as solubilizing agent and precipitation inhibiting agent. They inhibit the precipitation by increasing the drug concentration at the blood stream and ultimately bioavailability is increased. Tween 20, sodium dodecyl sulphate (SDS), tocopheryl polyethylene glycol succinate (TPGS), Cremophor RH40, Pluronics, Labrasol are some surfactant which inhibit the precipitation from the supersaturated solution.[58]

Cheryl etal.[59] Investigated the kinetic of precipitation of surfactants. They had used Isperibol calorimetry to investigate the rate of precipitation of several anionic surfactants with calcium and cationic surfactants. The rate of precipitation of both cationic and non-ionic surfactants very slower due to increase supersaturation ratio and below the CMC (critical micelle concentration). But the precipitation rate is more with calcium due to high CMC and decrease in supersaturation ratio.

Dai etal.[60] Investigated precipitation inhibiting effect of combined surfactant of Pluronics/vitamin E TPGS. They had taken nine types of surfactants and investigated the effect of single and combine surfactant effect. Without combination, the single surfactant has no stronger inhibition effect. But when they were combined with vitamin E TPGS showed strong inhibition effect than individual surfactant.

cyclodextrin complexation:

Cyclodextrin have the ability to form inclusion complexes with a variety of hydrophobic drug to increase the solubility and the rate of nucleation and crystal growth. The two well-known cyclodextrins which are used to improve the bioavailability of poorly soluble drug are 2-hydroxypropyl-β-cyclodextrin (HPβCD) and sulphobutylether-β-cyclodextrin (SBEβCD). [61]

It has been investigated that the stabilizing effect has been improved by using above cyclodextrin in supersaturated solution. They generated high level of supersaturation and maintained the supersaturated state fir at least two hours in Itraconazole solution. [62] It was also demonstrated that those cyclodextrin performed as both spring and parachute, it means that there is an increase in saturation solubility and the extent of supersaturation is decreased by cyclodextrin. The supersaturated solution is stabilized when the induction time and nucleation time is reduced by increase in cohesive nature of water molecule. [63,64]

Mechanism of Precipitation Inhibition:

Supersaturated system is a thermodynamically unstable formulation due to nucleation and crystal growth. Nucleation and crystal growth are the potent cause of precipitation. Precipitation is occurred due to increased chemical potential. So to delay and avoid precipitation, a precipitation inhibitor is applied to the supersaturated formulation. The rate of drug precipitation is dependent on efficacy of precipitation inhibitor. [65,66] One of the efficient polymer, HPMCAS has been a powerful precipitation inhibitor which maintains the supersaturated state for a longer period of time.[67]

Various analytical methods such as XRD, DSC, FTIR, SEM, Raman spectroscopy, polarized spectroscopy are used to characterize interaction between drug and excipient and crystallization process. Yet the mechanism of drug precipitation inhibition was not well understood but some theories are present, which describe some brief idea of mechanism of precipitation. [68,69,70,71]

A. Hydrogen bonding between drug and polymer:

Hydrogen bonding interaction between drug and polymer could inhibit the growth of crystals aswell as nucleation process. It has been seen that if the drug has hydrogen bond donor sites (hydroxyl, amide group) is always interacted with acceptor site such as PVP, which inhibit the precipitation through formation of hydrogen bond interaction between polymer-drug. When a polymer has hydrogen bond donor site, they are interacted with the drug having hydrogen bond acceptor functional group such as carbonyl, amide, nitro acceptor group etc. [72,38,73] Xie etal. [74] Investigated that drug, salbutamol sulphate rich in donor sites (hydrogen bond) was more interacted with PVPK25 in comparison to HPMC and lecithin. Because, poly vinyl pyrollidone has higher capability to form hydrogen bond donor site of salbutamol sulphate. Hydrogen bond between PVP and salbutamol sulphate have also been studied in other literatures which was stimulated by strong molecular interaction.

B. Hydrophobicity and rigidity:

Hydrophobicity and rigidity of polymer are affecting the precipitation process. In general, excipients with hydrophobicity have more inhibiting capacity than hydrophilic excipients. Because hydrophobic compounds adsorb water and form a protective layer around the crystals. But hydrophilic polymers did not adsorb water to crystal surface, so that they didn’t prevent the crystallization process. It was also seen that moderate hydrophobic polymer are more effective than highly hydrophobic polymer or highly hydrophilic polymer due to weak adsorption of polymer to the drug crystal surface.[75]

The rigidity of polymer also affects the precipitation inhibiting process. On the basis of previous information, due to rigid structures polymers adsorb water to the crystal surface more easily but with flexible and smooth surface; the adsorption capacity is about to very less so that loops like substance is formed. [75,76]

C. Molecular weight and steric hinderance:

Polymer adsorption capacity depends on molecular weight of polymer. It has been investigated that, high molecular weight polymer are the efficient choice for supersaturated solution. They maintain the supersaturated state of a supersaturated solution for a longer period of time. [73, 77] It was seen that PVP 2000 shown less crystal inhibiting capacity than PVP due to low molecular weight. Like the PVPK90 have better inhibiting effect than PVP K12, PVPK29 and PVPK32 [78]

It has been investigated that polymers, having high molecular weight does not always exhibit the strongest inhibition effect.[64] Ma etal. had taken a series of PVP with different molecular weight of PVPK10, PVPK25, PVPK40 and PVPK360 had limited inhibiting capacity on the crystal surface than other grades of PVP due to steric hindrance.[79]

D. viscosity:

A clear aspect of solution viscosity with respect to precipitation inhibition is not well established. As some literatures said that when solution viscosity is increased the crystallization process is inhibed. But some studies found that as in increase of viscosity, the diffusion rate is decreased. [45, 80, 81, 51] So it can be said that viscosity played a negligible role in drug precipitation.

CONCLUSION:

The SS-SEDDS has both surfactants and polymeric precipitation inhibitors in reduced amount. These are used to generate and maintain a supersaturated state, when it is diluted with g.i. fluid. Supersaturable formulation is a very effective formulation for improvement of bioavailability of poorly soluble drug. In this review, we discussed various issues of supersaturable formulation that affect on the absorption and bioavailability. So there are somany approaches are developed to overcome these problems. From various scientific publication, we learned that an appropriate biorelevent dissolution test must be applied to predict accurate drug release profile and selection of an appropriate animal model to predict the accurate invivo data. We can suggest that the advancement of characterization of supersaturated state by appropriate means and establishing their relevance to oral absorption in vivo will greatly facilitate the development and commercialization of supersaturatable formulations.

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Received on 23.05.2019 Modified on 30.06.2019

Research J. Pharm. and Tech. 2019; 12(12): 6165-6173.

DOI: 10.5958/0974-360X.2019.01071.0

Drug	Precipitation inhibitor	purpose	conclusion	reference
piroxicam	HPMC	Investigation of rate of invitro penetration across silicon membrane and full thickness human skin.	HPMC inhibit the formation of pseudo polymorphs and the rate of penetration was increased to 4fold using both silicon membrane and full thickness human skin.	M.A. pellet etal.(1997)[49]
felodipine	HPMC	Evaluating the impact of HPMC on the crystal growth and nucleation kinetic of supersaturated solution.	Crystal growth and crystal nucleation was delayed in presence of HPMC.	David E. etal.(2012)[50]
Indirubin	PVPK17, HPMC, PEG4000	Investigation of crystallization inhibiting capacity of different polymer. Improvement of bioavailability of Indirubin.	PVPK17had more crystallization inhibiting capacity and the relative bioavailability of indirubin was 129.5% which is more than SMEDDS.	Zhi-Qiangchen etal.(2012)[38]
Silybin	HPMC	Enhancement of oral bioavailability of silybin by ss-sedds.	From the invivo study, the SS-SEDDS exhibited higher AUC as compared to SEDDS	Wei,inghui etal.(2012)[51]
Econazole nitrate	HPMC	Improvement of bioavailability by designing ocular supersaturated SNEDDS for improving bioavailability.	The econazole nitrate loaded ss-snedds loaded with HPMC enhanced the bioavailability and non-irritating effect incomparison to S-SNEDDS lacking HPMC 15cp.	Narmeen A.E(2014) [52]
Danazol	PVP, HPMC, HPMCAS	Characterization of phase behaviour aswell as the degree of supersaturation	LLPS occurred prior to crystallization and achievement of sustained supersaturation due to drug loading and use of polymer type.	Jackson MJ etal.(2016)[53]
griseofulvin	Polooxamer and HPMC	Design and investigation of exvivo intestinal permeability study of griseofulvin	All the formulation showed drug permeability through rate intestine 3 folds more than permeability enhancement ratio.	Behzad sharif etal.(2017)[54]
Fenofibrate	Soluplus	Improvement of bioavailability and investigation of precipitation assays of supersaturated formulation.	From the invivo study, the bioavailability was increased to 1.4 fold than solid-SEDDS. From the supersaturation assay, soluplus showed highest precipitation inhibiting capacity.	Guilan quan etal.(2017)[55]
Cyclosporin A	PVP	For improvement of dissolution rate of cyclosporin A by using PVP as precipitation inhibitor.	Upon invitro dialysis test, PVP loaded supersaturated SEDDS had exhibited higher apparent drug concentration time profile than HPMC and kollidone VA64.	Dao Ro Lee etal.(2017)[56]
Pazopanib	HPMC	Investigation of phase behaviour of supersaturated solution from low PH followed by higher PH by phase diagram.	At PH6.5, the phase behaviour was well predicted. The degree of supersaturation was increased and HPMC delayed the time for appearance pazopanib free base crystals.	Hikaru sugihara etal. (2018)[57]