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\begin{document}


\def\RunningAuthor{Sureshkumar R and Santhosh Kumar R}
\firstPage{2481}
\articleType{Review Article}
\receivedDate{10 Nov 2019}
\acceptedDate{13 Dec 2019}
\revisedDate{09 Dec 2019}
\journalVolume{2020, 11}
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\journalDoi{ijrps.v11i2.2242}
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\title{A Review on Precipitation inhibitors in supersaturable self emulsifying drug delivery system}
\author{Santhosh~Kumar~R, 
            Sureshkumar~R\textsuperscript{*}~\\[5pt]{Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, Nilgiris, Tamil Nadu, India}}

\begin{abstract}
The super saturable formulation has been widely used as an effective method to improve solubility and oral absorption of poorly aqueous-soluble drugs. When the super saturable formulation comes in contact with gastrointestinal fluids, its drug concentration goes over the equilibrium solubility, but this state does not exist for too long, the drug may precipitate before being absorbed, which minimizes the efficacy and bioavailability of the drug. Therefore, it is necessary to inhibit or retard the precipitation of drugs to achieve the maximum benefits of the super saturable formulation. Polymers (water-soluble and insoluble) are the commonly used excipients to inhibit precipitation. Cyclodextrins and surfactants are the other two excipients used as precipitation inhibitors. In some of the cases, even solid carriers can effectively retard precipitation. The precipitation inhibitors (PI) have the capacity to maintain a super saturable state of the formulation in GI for a particular time period. Therefore, it is important to properly select the precipitation inhibitor; too frequently used methods to select precipitation inhibitor are casting film method and solvent-shift method. Such selected and successfully used precipitation inhibitors are HPMC E5LV, PVP K17, HPMC E5, soluplus, poloxamer 407, HPMCAS, maltodextrin (mal) and microcrystalline cellulose (mcc). Since the super saturable technique has been widely used for delivering poorly water-soluble drugs like ezetimibe, indirubin, feno fibrate, butyl paraben and rosu vastatin calcium. There is a necessity for bio relevant evaluation of supersaturation/precipitation because simple methods like dissolution tests cannot be bio relevant in a supersaturation/precipitation context. Some of the important factors like sink versus non-sink conditions, hydrodynamic, medium selection and temperature play a vital role in the evaluation of in-vitro supersaturation
\end{abstract}\def\keywordstitle{Keywords}

\begin{keywords}Bioavailability,\newline Oral absorption,\newline Poorly water-soluble drugs,\newline precipitation inhibition Supersaturation
\end{keywords}
\twocolumn[ \maketitle {\printKwdAbsBox}]
\makeatletter{\raggedright\textsuperscript{*}Corresponding Author\par Name:\ Sureshkumar~R~\\ Phone:\ 9865064872~\\  Email:\ sureshcoonoor@jssuni.edu.in
        \par}\vspace*{-11pt}\hrulefill\par{\fontsize{12}{14}\selectfont ISSN: 0975-7538}\par% 
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\section{Introduction}
Among the drug delivery system, the oral route of administration is the most standard and selected route for delivering drugs \unskip~\citep{688509:16291481}. The drug delivery through oral administration has certain advantages like \ensuremath{\bf i}) Precision, \ensuremath{\bf ii}) Better patient compliance, \ensuremath{\bf iii}) Effortless administration, \ensuremath{\bf iv}) Avoiding of pain \unskip~\citep{688509:16291471}. The crucial drawback in delivering drugs orally is the drug's low water-solubility. It affects the \ensuremath{\bf i}) Drug's absorption, \ensuremath{\bf ii}) the dissolution rate of drug and \ensuremath{\bf iii}) Drug bioavailability \unskip~\citep{688509:16291484}. Several approaches were developed to overcome this problem (low water-solubility) including cyclo dextrin complex \unskip~\citep{688509:16291455}, particle size reduction \unskip~\citep{688509:16291463}, solid dispersion \unskip~\citep{688509:16291461}, and lipid-based formulations, predominantly self-nano emulsifying drug delivery systems (SNEDDS) have been used \unskip~\citep{688509:16291445}. Among all these different approaches to improve solubility, producing super saturable formulation showed to be an effective approach. In super saturable formulation, drug has the ability to exist in solution state even when its concentration is increased above its saturation solubility, without allowing the drug to precipitate. It is a thermodynamically unstable system, consisting of polymeric precipitation inhibitor (PPI) which is used to inhibit the drug precipitation in the GI tract. Precipitation inhibitors (PI) are significantly used to maintain the drugs in the supersaturated state, their function is to inhibit or retard drug precipitation for a certain period of time, promoting oral absorption for increasing the bioavailability of the drug \unskip~\citep{688509:16291466}.
    
\section{Materials and Methods}
\textbf{Mechanism of precipitation inhibition}

When the solubilization ability of the drug's formulation has decreased, it causes the drug to precipitate in the stomach. There are some factors which credit to this process are, \ensuremath{\bf i}) severe change in pH, \ensuremath{\bf ii}) The ability of the body fluid to dilute the formulation (or) the solubilizing agents get digested before the drug is absorbed. Hence the drug bio availability and efficacy are affected due to precipitation. To inhibit the precipitation of drug, polymeric precipitation inhibitors (PPI) incorporated into the actual formulation, the PPI blocks the nucleation process that is required for formation and growth of crystal, this retards the precipitation of drug out of the solution and maintains a metastable supersaturated state for a certain period. Some of the commonly used PPI in the formulation are Methylcellulose, PVP, HPMC, sodium CMC, HPMC phthalate which maintains the supersaturated state by preventing the drug precipitation \unskip~\citep{688509:16291488,688509:16291477}.

Drug Precipitation are also known as crystallization and it involves two phases. First phase, solute particles combine into two or three-dimensional clusters inside the solution, these clusters then proceed to grow if they are greater than the critical size and step on to the second phase. The second phase is the crystal growth, where the particles regularly organize themselves to produce the crystal formation \unskip~\citep{688509:16291452,688509:16291491}. The result of the drug precipitation inhibition highly relies upon the properties of the inhibitor, the medium and the drug \unskip~\citep{688509:16291483}.

The two mechanisms used to achieve the inhibition of drug precipitation are, \ensuremath{\bf i}) thermodynamic inhibition, and \ensuremath{\bf ii}) kinetic inhibition. Thermodynamic inhibition is the process where inhibition of drug precipitation is attained by increasing the solubility of the drug, therefore brings down the amount of super-saturation and also minimize the nucleation and crystal growth (example: inclusion of solubilizing agents like co-solvents, surfactants, and cyclodextrins). Kinetic inhibition is the process where inhibition of drug precipitation is done through retarding or inhibiting the drug in supersaturated form (example: inclusion of polymers which act as PPI) \unskip~\citep{688509:16291485,688509:16291457}.

Moreover, it has been identified that some of the polymers can suppress and restrict the drug nucleation which in turn inhibits the drug precipitation \unskip~\citep{688509:16291489}. Also, some of the solid carriers like maltodextrin and microcrystalline cellulose (MCC) have the ability to inhibit the drug precipitation by adsorbing onto the crystal surface of the drug and blocks the gathering of larger drug particles into the crystal lattice \unskip~\citep{688509:16291449}.

The characterization of the crystallization process and drug-polymer interactions can be studied using different analytical methods. Specific methods like Fourier transform infrared spectroscopy (FTIR), X-ray diffraction, Scanning electron microscope (SEM), Raman spectroscopy, Atomic force microscopy, Differential scanning calorimetry (DSC), X-ray photoelectron spectroscopy, Microfluidic technology, Polarized microscopy. The results obtained from these methods can be useful for promoting promising mechanisms for the inhibition process \unskip~\citep{688509:16291487,688509:16291492,688509:16291446,688509:16291480,688509:16291467,688509:16291482}.

\textbf{Spring and Parachute theory}

To increase the oral absorption and bioavailability of poorly water-soluble drugs, the metastable supersaturated state must be produced and sustained. This concept can be explained by the ``spring and parachute'' theory. The high energy form of the drug produces the supersaturated solution of a drug (known as ``spring''). This supersaturated solution can be induced by two formulation factors: \ensuremath{\bf i}) high-energy or quickly dissolving solid forms and \ensuremath{\bf ii}) extremely concentrated solution \unskip~\citep{688509:16291472,688509:16291474}. The supersaturated should be maintained for a long period of time to get absorbed, but this supersaturated solution has the tendency to precipitate quickly, so it produces no benefits. To inhibit precipitation and attain the benefits of the supersaturated solution certain precipitation inhibitors are used (known as ``parachutes''). Some commonly used excipients as precipitation inhibitors are polymers, cyclodextrins, and surfactants. The effective combinations of ``Spring ``and ``Parachute'' can be identified by designing and developing super saturable formulation. By combining both spring (crystalline salt forms) and parachute (precipitation inhibition), the dissolution and oral bio availability can be improved \unskip~\citep{688509:16291458,688509:16291465}.

\textbf{Drug precipitation inhibitor}

As already mentioned, the precipitation inhibitors are capable of maintaining a supersaturable state of the solution for a particular time period \unskip~\citep{688509:16291462}. The screening of precipitation inhibitors can be also done using two methods, \ensuremath{\bf i}) Casting film method, and \ensuremath{\bf ii}) solvent-shift method. The drug's re-crystallization can be quickly observed by casting film method, whereas in the solvent-shift method the degree of supersaturation was used to identify the retarding effect of various polymers on drug precipitation. In this study (super saturable-self nano emulsifying drug delivery system containing silymarin), three polymer groups including non-ionic polymer (hydroxypropyl beta-cyclodextrin), anionic polymers (hydroxypropyl methylcellulose phthalate and Eudragit L100) and co polymer (Poloxamer 407) were tested for the better precipitation inhibiting capacity by casting film method and solvent-shift method. In the casting film method, the films containing different polymers were observed under an optical microscope after 1, 7 and 90days. The appearance of dark spots and clusters on the film after storage interval indicates drug (silymarin) re-crystallization. It was noted that the small amount of Poloxamer 407 was the most effective precipitation inhibitor because it prolonged the appearance of small dark spots on the film after at least 90 days. From the solvent-shift method, it was observed that different polymers produced different degrees of super saturation. This result also matched the casting film method results, as Poloxamer 407 produced a greater degree of supersaturation comparing to other polymers and proved to be the best precipitation inhibitor \unskip~\citep{688509:16291479}. Some of the precipitation inhibitors which are used in improving the solubility of the poorly water-soluble drugs are given in Table~\ref{tw-ab74e2d480a6}.


\begin{table*}[!htbp]
\caption{\boldmath {Examples of precipitation inhibitors used in the formulation and its outcome} }
\label{tw-ab74e2d480a6}
\def\arraystretch{1.1}
\ignorespaces 
\centering 
\begin{tabulary}{\linewidth}{p{\dimexpr.2121\linewidth-2\tabcolsep}p{\dimexpr.17409999999999997\linewidth-2\tabcolsep}p{\dimexpr.6138\linewidth-2\tabcolsep}}
\tbltoprule \rowcolor{kwdboxcolor}Precipitation inhibitor & Drug  & Outcome \\
\tblmidrule 
HPMC E5LV &
  Ezetimibe  &
  The supersaturated state of the formulation increases the drug solubility in the intestine and thereby increases the oral absorption and permeation across the GI membrane \unskip~\citep{688509:16291476}\\
PVP K17 &
  Indirubin  &
  0.5\% PVP K17 can significantly inhibit precipitation and maintain a greater indirubin concentration about 2 hours or more.\\
HPMC E5 &
  AMG 517 &
  Small amount (2-5\%) of water-soluble cellulosic polymer (HPMC E5) efficiently inhibit AMG 517 precipitation. It was also reported that the precipitates collected were in amorphous form \unskip~\citep{688509:16291466}.\\
Soluplus  &
  Fenofibrate  &
  It was reported that by increasing the concentration of the soluplus, the saturation solubility of fenofibrate increases steadily. This shows that fenofibrate was incorporated in the hydrophobic regions of the micelles \unskip~\citep{688509:16291493}.\\
Poloxamer 407 &
  Silymarin  &
  The copolymer (Poloxamer 407) used to retard the silymarin precipitation, this copolymer is miscible with the formulation and maintain the supersaturable state of silymarin formulation \unskip~\citep{688509:16291479}.\\
HPMCAS &
  Butylparaben &
  A particular amount of butylparaben was maintained in the supersaturated state for 72h \unskip~\citep{688509:16291456}.\\
Maltodextrin (mal) and Microcrystalline cellulose (MCC) &
  Rosuvastatin calcium &
  Solid carriers (mal and MCC) possibly inhibit precipitation by interacting with drug molecules by hydrogen bonding \unskip~\citep{688509:16291449}.\\
\tblbottomrule 
\end{tabulary}\par 
\end{table*}

    
\section{Results and Discussion}
HPMC- Hydroxypropyl methylcellulose

HPMC- Hydroxypropyl methylcellulose acetate succinate

PVP- Polyvinylpyrrolidone

\textbf{Hydroxypropyl methylcellulose (HPMC)}

The HPMC polymers of different grades (HPMC E4M, HPMC E5LV, HPMC E15LV, HPMC E50LV) have been widely used as the polymeric precipitation inhibitors that successfully retain supersaturated state of the drug for a particular time period. Among these HPMC polymers, the polymers with more hydrophobic property retarded the precipitation of the drug effectively. This could be due to the ability of the hydrophobic polymer to adsorb onto the hydrophobic nuclear surface and blocks the nucleation process which is essential for the crystallization, this process minimizes or prevents drug precipitation out of the solution to sustain a super saturated state. Further the HPMC polymers are classified into two types based on their hydrophobicity, they are \ensuremath{\bf i}) Hydrophobic E-type (29\% methyl substitution), and \ensuremath{\bf ii}) Hydrophobic K-type (22\% methyl substitution), where the HPMC E-type polymers produce better precipitation inhibition activity than the HPMC K-type polymers due to its ability to adsorb better to the hydrophobic nuclei. HPMC E5 seemed to be an effective polymer to inhibit drug precipitation and maintain a super saturated state of ezetimibe for a minimum 60min. The viscosity of the polymer also plays a major role in inhibiting precipitation, it has been proved that HPMC E5LV (LV denotes `low viscosity') which is less viscous and low molecular weight, effectively sustains the ezetimibe concentration and prevents precipitation than the higher viscosity grade polymers \unskip~\citep{688509:16291477,688509:16291476}. In other cases, the hydrophilic polymer (HPMC K100) effectively inhibited the precipitation of candesartan cilexetil (cc) and helped in increasing the bioavailability of a poorly water-soluble drug (cc) than the marketed form of the drug \unskip~\citep{688509:16291488}. The HPMC polymers are also incorporated in the formulation of poorly water-soluble drugs like AMG 517 and trans-resveratrol as a precipitation inhibitor to enhance the solubility and increase oral absorption \unskip~\citep{688509:16291466,688509:16291469}.

\textbf{Polyvinylpyrrolidone (PVP)}

The hydrophilic polymer (PVP) is one more regularly used polymer as precipitation inhibitor, it was found that the super saturable self-micro emulsifying drug delivery system (S-SMEDDS) holding 0.5\% PVP K17 as PI effectively retarded the precipitation and maintained a greater concentration of indirubin for minimum 2 hours or more than that. In this case, there are two reasons behind the precipitation inhibition activity which are hydrogen bonding and molecular dispersion of the drug into the polymer (PVP K17) matrix. Moreover, only at the small concentration (0.5\%) of PVP K17, the drug release was maximum and when concentration is increased the drug release decreased due to the increase in viscosity. Similarly, PVP-k90 which was incorporated into the self-micro emulsifying drug delivery system (SMEDDS) formulation that consists of the drug (carbamazepine) effectively inhibited the precipitation of the drug and sustained the drug in solubilized state for extended period of time (over 24h), it was also reported that the gradual increase in its effect was noted with the increase in PVP-K90. But when PVP-K90 concentration was above 2\%, it becomes difficult to dissolve 90\% of the carbamazepine within 20 min which was significantly greater than the commercial tablets \unskip~\citep{688509:16291459}.

\textbf{Soluplus}

To develop a successful super saturated formulation, it is important to use a precipitation inhibitor to sustain the drug in a supersaturated state. Soluplus is one of the promising elements for inhibiting precipitation. In the case of feno fibrate (FNB), soluplus an amphiphilic polymer inhibited the precipitation of FNB than the other polymers like HPMC and PVP grades due to its two hydroxyl groups (hydrogen-bond donor). The soluplus: FNB ratio (1:1) showed a better effect on precipitation inhibition, moreover an increase in soluplus concentration showed a similar effect. The soluplus has an ability to act as a surfactant when its concentration goes above critical micelle concentration improves the solubility of the drug and inhibits precipitation (decreases the degree of supersaturation) \unskip~\citep{688509:16291493}. Intake of more amount of surfactant daily causes GI side effects (which is present in SEDDS formulation). To lower the quantity of the surfactant, a little quantity of precipitation inhibitor (soluplus) was incorporated into the SEDDS formulation which usefully maintains the supersaturated state. The in-vivo pharmacokinetic study in rats showed a significant increase in oral absorption of Dutasteride and 3.9 fold higher bioavailability in contrast to drug suspension \unskip~\citep{688509:16291490}.

\textbf{Evaluation of drug supersaturation and precipitation}

Some of the commonly used methods to estimate precipitation and supersaturation are spectrophotometric UV/VIS absorbance-time measurements \unskip~\citep{688509:16291486,688509:16291473}, nephelometric turbidity measurements \unskip~\citep{688509:16291447}, and visual inspection and light microscopy \unskip~\citep{688509:16291489}. For the SNEDDS formulation, the main reason for the precipitation of drugs is the secretion of pancreatin in the intestine. When S-SNEDDS is diluted, the drug may exist in three distinct states: free drug molecules (state 1), solubilized globules into nano emulsion (state 2), precipitated form (state 3). Hence the concentration of drugs can be measured by adding the state 1 and 2 excluding the precipitated form of the drug. In-vitro drug supersaturation test is one of the commonly used studies to identify the level of super saturation and response of the drug towards precipitation during the release study of S-SNEDDS formulation \unskip~\citep{688509:16291477,688509:16291449}. As already mentioned, digestion (lipolysis process which is initiated by pancreatic enzymes) is the cause of precipitation in the gastrointestinal tract (GIT). The evaluation of supersaturation and precipitation for lipid-based delivery systems has been done using the in-vitro lipolysis models. During lipolysis, with the use of the pH-stat titration unit which titrates liberated fatty acids to maintain the pH, samples are taken right through the experiment and added with an inhibitor of the lipolysis process to end any advance in digestion. The precipitated substance is separated from the lipid and liquid phases by ultracentrifugation. To estimate the proper drug precipitation behaviour, it is necessary to separate the precipitated drug from the dispersion system. There are two methods that are commonly used to separate the precipitated drug which are, syringe filters method, and centrifugation method. In the syringe filter method, the precipitated drug or substance can be separated from the solution by filtration process. In the centrifugation method, the precipitated drug can be separated from the solution by centrifugation process. When comparing both the methods, the centrifugation method seemed to have greater recovery and repeatability than the filtration method. It is important to understand the interaction between supersaturation, solubilization, and precipitation to effectively estimate the absorption increasing capacity of lipid-based formulations \unskip~\citep{688509:16291451,688509:16291475}. The size is one of the most important factors in determining the role of polymer in the precipitation process of the drug. The drug tends to precipitate fast and form large crystals when there is no precipitation inhibitor added (further, as time increased the size gradually increased), but the precipitation size became smaller with the addition of precipitation inhibitors \unskip~\citep{688509:16291479}.

Some of the critical factors which influence the in-vitro supersaturation evaluation are, \ensuremath{\bf i}) sink versus non-sink conditions, \ensuremath{\bf ii}) hydrodynamics, \ensuremath{\bf iii}) medium selection, \ensuremath{\bf iv}) temperature. All these experimental conditions may remarkably affect the results of supersaturation evaluation. Sink versus non-sink conditions: usually the evaluation test for supersaturation is conducted under sink conditions (large dissolution volumes or high surfactant concentration) to test release kinetics. But to identify the absorption level of the formulation, the dissolution medium requires more bio relevant non-sink conditions. Only these conditions provide sufficient exploration of super saturation and precipitation. Also, the in vitro-in vivo correlation for silica-based formulation and solid dispersions were only attained using non-sink in vitro dissolution approaches \unskip~\citep{688509:16291464}. Hydrodynamics: it plays an important role in the evaluation of super saturation and precipitation. From the studies, it has been noted that the precipitation rate was high in stirring model when compared to the shaking model, so it is important to study the in vivo hydrodynamics and bringing the same into the dissolution/precipitation models may effectively improve the bio relevance of in vitro precipitation evaluation \unskip~\citep{688509:16291460,688509:16291454}. Medium selection: the use of basic aqueous buffer solutions will not efficiently estimate the in vivo performance of drug formulations. Therefore, the dissolution media should be bio relevant with the fasted and fed state conditions in the stomach and the small intestine \unskip~\citep{688509:16291448}. For example; for determining the precipitation kinetics in the intestinal environment, basic aqueous buffer solutions (pH 6.5) should not be used because it has a tendency to overestimate the super saturation stability. Therefore, it is important to select the proper dissolution media for super saturation studies \unskip~\citep{688509:16291453,688509:16291478,688509:16291470}. Temperature: most of the super saturation evaluations are carried at room temperature instead of 37\ensuremath{^\circ}C. A study has been done on the dissolved behaviour of felodipine (amorphous drug) at 37\ensuremath{^\circ}C versus 25\ensuremath{^\circ}C, which resulted in temperature-dependent felodipine crystallization kinetics with exposure with dissolution medium. The dissolution of felodipine influenced supersaturation at 25\ensuremath{^\circ}C but not at 37\ensuremath{^\circ}C \unskip~\citep{688509:16291468}. 
    
\section{Conclusions}
When a supersaturated state exist at the absorption site for a long period of time, it may the enhance drug absorption by generating higher drug concentration. The precipitation inhibitors inhibit drug nucleation or crystal growth by steric stabilization, surface stabilization by adsorption onto colloidal surfaces, and/or specific interactions with a drug. It is important to identify the effective precipitation inhibitor by knowing the precipitation inhibition mechanism to attain the complete benefits of it. The incorporation of the supersaturation technique into the formulation may enhance the oral absorption and bioavailability of poorly water-soluble drugs.
    

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