Application of surfactants in solid dispersion technology for improving solubility of poorly water soluble drugs

Accepted Manuscript Application of surfactants in solid dispersion technology for improving solubility of poorly water soluble drugs Smruti P. Chaudhari, Rohit P. Dugar PII:

S1773-2247(17)30273-3

DOI:

10.1016/j.jddst.2017.06.010

Reference:

JDDST 408

To appear in:

Journal of Drug Delivery Science and Technology

Received Date: 5 April 2017 Revised Date:

10 May 2017

Accepted Date: 9 June 2017

Please cite this article as: S.P. Chaudhari, R.P. Dugar, Application of surfactants in solid dispersion technology for improving solubility of poorly water soluble drugs, Journal of Drug Delivery Science and Technology (2017), doi: 10.1016/j.jddst.2017.06.010. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Application of Surfactants in Solid Dispersion Technology for Improving Solubility of Poorly Water Soluble Drugs

Mayne Pharma Inc, Greenville, NC 27834 USA

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Amway R&D, Buena Park, CA, 96021 USA

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Correspondence Author

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Mayne Pharma Inc 1240 Sugg parkway Greenville NC 27834

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Telephone: +1 252-317-1136;

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Smruti P. Chaudhari Product Development Scientist

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Smruti P. Chaudhari1* and Rohit P Dugar2

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E-mail: [email protected]

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Abstract

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Discovery of several poorly water soluble drugs in the past decade has led to the need of developing a novel dosage form which increases the solubility of the drug and improves oral bioavailability. Solid dispersion is one of the most promising techniques to overcome the challenges faced by poor water solubility. However, there are several limitations associated with the development of solid dispersion, like miscibility of polymer and drug, the stability of the dispersion, etc. The use of surfactant in the solid dispersion can overcome these limitations. The addition of surfactant to solid dispersion not only increases drug-polymer miscibility but also reduces recrystallization. It also improves the wettability of solid dispersion, which leads to increase in dissolution and physical stability. However, caution must be employed in selecting the surfactant. The surfactant can interact with polymer and thereby increase the recrystallization of drugs. This review focuses on the use of surfactant in the solid dispersion. First, the classification of the surfactant is discussed along with its use in the formation of solid dispersion by various techniques. Keywords

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Surfactant, Solid Dispersion, Plasticizers, Stability, Supersaturation, Solubility enhancement.

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Contents 1.

Introduction ............................................................................................................................. 4

2.

Surfactants ............................................................................................................................... 5 Anionic Surfactants .......................................................................................................... 6

2.2.

Cationic surfactants .......................................................................................................... 6

2.3.

Nonionic surfactants ......................................................................................................... 6

2.4.

Amphoteric/Zwitterionic surfactants................................................................................ 6

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2.1.

Use of surfactant in solid dispersion........................................................................................ 7

4.

Selection of Surfactants in Solid dispersion .......................................................................... 11

5.

Use of Surfactants as plasticizer in Hot melt extrusion ......................................................... 11

6.

Mechanism of drug release .................................................................................................... 14

7.

Method of preparation ........................................................................................................... 17

8.

Conclusion ............................................................................................................................. 18

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3.

Conflict of Interest ........................................................................................................................ 19

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References ..................................................................................................................................... 19

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1. Introduction In the recent times, several poorly water soluble drugs are being discovered. The poor solubility of these drugs is a limiting factor for oral bioavailability. Many techniques have been developed

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by the scientific community to overcome the challenges faced due to the poor water solubility of drug molecules, which includes, salt formation [1], micronization [2], prodrug [3], lipid

formulations [4] and solid dispersion [5, 6] and so on. Nevertheless, there are several limitations

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associated with all these techniques [7]. Out of all these methods, the solid dispersion was

demonstrated to be the most promising approach[7]. Solid dispersion is defined as a dispersion

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of one or more active pharmaceutical ingredients (APIs) in the inert carrier matrix. Recently more focus has been given to amorphous solid dispersions. The solid dispersion can be prepared using various techniques like spray drying [5], freeze drying [8], fusion method [9], hot melt extrusion [10] and supercritical fluid precipitation [11]. The solid dispersion of APIs

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demonstrates enhanced dissolution profile and thereby increasing the bioavailability. The dissolution profile of drug with solid dispersion is governed by the properties of the polymer and its concentration used in the formulation. Above a certain concentration of hydrophilic polymer

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in the formulation can retard the solubility of the drug in solid dispersion [12, 13]. Over the last few decades, the surface active agents, including surfactants have been used in solid dispersion

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alone or in combination with a polymeric material. The use of surfactants in solid dispersion not only improves the dissolution rate of the poorlywater solublecompound but also improves the physical stability [14-16]. These surfactants aid in physical miscibility of hydrophobic drugs due to amphiphilic nature and reduce the drug recrystallization. Furthermore, these surfactants improve wettability and prevent drug precipitation in the aqueous medium [15, 17, 18]. Various other reports have also shown improved dissolution profile of drugs with a solid dispersion containing surfactants compared to drugs without using surfactants in the solid dispersion [194

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22]. Surfactants reduce the interfacial energy barrier between the drug and dissolution medium and thereby increase the wettability. Moreover, the concentration of surfactants above the critical micelle concentration (CMC) increases the drug solubility due to solubilization and thereby

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increases the dissolution rate [23, 24]. This review focusses on the use of surfactants in solid dispersions, discusses surfactant classification and commonly used surfactants in solid dispersion

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and the mechanism by which surfactants increase the dissolution rate of drugs.

2. Surfactants Surfactants are also commonly known as surface active agents, wetting agents, emulsifying

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agents or suspending agents based on their use and application. Surfactants exhibit some superficial or interfacial activity [25] and have characteristic structures possessing both hydrophobic(non-polar) and hydrophilic (polar) groups. The polar groups generally contain heteroatoms such as, O, S, P or N, as part of the functional groups such as alcohol, thiol, ester,

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acid, sulfate, sulfonate, phosphate, amides, amines etc. The polar groups of surfactants have a strong affinity for polar solvents, particularly water and are termed hydrophilic whereas the nonpolar part of surfactant is called hydrophobic and the surfactant which has dual affinity are

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termed as amphiphilic.

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The amphiphilic surfactants do not feel “at ease” in any solvent, be it polar or non-polar since there is always one of the groups does not like the solvent environment. As a result, these molecules do have strong tendency to migrate to interfaces or surfaces to orient themselves. Surfactants can be classified into four categories based on their dissociation in water: •

Anionic Surfactants

•

Cationic Surfactants

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•

Amphoteric/Zwitterionic surfactants

•

Nonionic surfactants

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2.1. Anionic Surfactants Anionic Surfactants when added to water dissociate to form an amphiphilic anion and a cation. These are most commonly used surfactants. Examples include sodium lauryl sulfate (SLS),

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alkyl benzene sulfonates, etc.

2.2. Cationic surfactants Cationic surfactants dissociate in water to form an amphiphilic cation and an anion. These are

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commonly used for their disinfectant and preservative properties since they have good bactericidal properties and belong to quaternary ammonium compounds. Examples include cetrimide, benzalkonium chloride, etc.

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2.3. Nonionic surfactants Nonionic surfactants do not dissociate in aqueous solution. These are less irritant than anionic and cationic surfactants. The hydrophilic region contains polyoxypropylene, polyoxyethylene or polyols derivatives and hydrophobic region contains saturated or unsaturated fatty acids or fatty

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alcohols. The most commonly used nonionic surfactants are poloxamers, polysorbates, etc.

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2.4. Amphoteric/Zwitterionic surfactants Amphoteric/Zwitterionic surfactants exhibit both cationic and anionic dissociations. These surfactants are mild in nature and they can be anionic or cationic or nonionic depending on the pH of the water. Alkyl betaine is an example of amphiphilic surfactant. Most commonly used surfactants in the pharmaceutical industry are SLS, Poloxamers, and D-αtocopherol polyethylene glycol 1000 succinate (TPGS), commonly known as Vitamin E TPGS. The structures of SLS, poloxamer and Vitamin E TPGS are given in Figure 1 and the structure of 6

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polysorbate is given in Figure 2. SLS is an anionic surfactant with a hydrophilic-lipophilic balance (HLB) of 40. Poloxamers are non-ionic triblock copolymer of polyoxyethylene– polyoxypropylene–polyoxyethylene with surfactant properties. Various grades of poloxamer are

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available depending on the values of a and b, given in Table 1. Poloxamer 124 has HLB of 12-18 and poloxamer 407 had HLB of 18-23, whereas poloxamer 188, 237 and 338 has HLB of >24. TPGS is a mixture of succinate ester of natural vitamin E and polyethylene glycol 1000. TPGS

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has a hydrophilic head (polyethylene glycol chain) and a lipophilic tail (tocopheryl group). It is non-ionic surfactant with HLB of TPGS is 13. Polysorbates are nonionic surfactants with HLB

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of 14-18.

3. Use of surfactant in solid dispersion Surfactants can be added as an extragranular excipient or can be incorporated during the solid dispersion. It was reported in the literature that when surfactants like SLS [26, 27] and

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poloxamer [10], are added extragranularly to the solid dispersion, they did not affect the drug release. However, when the surfactants are intimately mixed with solid dispersion i.e. when surfactant ,drug, and polymer are dissolved in common solvent and dried to yield solid

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dispersion, they have shown a positive effect on drug release [26-28]. It was shown that when surfactants are mixed physically during the solid dispersion, drug released immediately upon the

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disintegration of the tablets, however, when surfactants were incorporated in the solid dispersion, the drug remains in the vicinity of the during dissolution creating micro-environment rich with surfactant increasing the drug solubility [29, 30]. Some researchers believe that SLS is entangled with the drug and polymer leads to increase in dissolution rate [31, 32]. Lang et al observed faster release and supersaturation of poorly water soluble drug itraconazole in aqueous media from solid dispersions in polymeric carriers containing poloxamer 407 and cremophor RH40

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[21]. Pouton et al have shown that surfactants when incorporated in the formulation, may prevent recrystallization of the drugs by forming agglomerates and forming a hydrophobic barrier around the drug particles when dispersed in the dissolution media [33]. A similar study conducted by

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Liu Chen et al found that SLS interacted with PVP-VA to form PVP-VA/SLS complex with lower critical aggregation concentration (CAC) which significantly increased the apparent

solubility of poorly water soluble drug sorafenib [34]. However, incorporation of SLS surfactant,

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negated the crystallization inhibition ability of PVP-VA against the supersaturated sorafenib in solution thus reduced the in vitro dissolution and in vivo bioavailability of the sorafenib

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formulation [34]. The ionic surfactants have shown better results in improving solubility of the poorly water soluble drug griseofulvin with solid dispersion compared to nonionic surfactants [35]. Nonetheless, one must be cautious in selection of surfactants since the use of a surfactant sometimes may expel the drug out from the polymer causing the drug to recrystallize out [36].

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Mosquera-Giraldo et al [18] studied the melting of drug substance on microscope glass slide in the presence of a surfactant such as SLS, TPGS, and sucrose palmitate. It was revealed that surfactant has a detrimental effect on the physical stability of amorphous celecoxib as it

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increased the crystal growth of drugs. However, the authors further conclude that the ternary system was highly complex and the impact of surfactants on the stability of amorphous form of

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the drug should be carefully investigated during the development of solid dispersions. Medarevic et al [37, 38] studied the effect of poloxamer 188 on poorly water soluble drug carbamazepine – soluplus solid dispersion prepared by solvent casting method. Even though the surfactant increased the dissolution rate of formulations, it had a negative impact on the physical stability of amorphous carbamazepine, as the drug crystallized out on storage. Furthermore, DSC analysis of the solid dispersion on storage showed a presence of separate melting endotherm indicating

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poloxamer 188 has phase separated from the solid dispersion. Lang et al studied the melt extrusion of itraconazole-HPMCAS-polyethylene oxide (PEO) and poloxamer 407 mixtures. The phase separation was observed between HPMCAS and PEO or poloxamer 407 immediately after

separation on the miscibility of itraconazole [21].

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preparation, but there was no longer-term stability testing to determine the impact of such phase

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Chen et al [39] studied the impact of SLS on the dissolution behavior and the in vivo

bioavailability of poorly water soluble drug posaconazole. The authors have systematically

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examined several key events occurred in the supersaturated posaconazole solution with or without the addition of SLS, including the kinetics of drug supersaturation or dissolution, oil out or liquid-liquid phase separation (LLPS) induced drug rich amorphous precipitates, the composition and crystallization kinetics of the drug-rich amorphous and so forth. It is hypothesized that the drug-rich amorphous precipitates induced by LLPS are a potential reservoir

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of high energy drug to maintained enhanced and prolonged drug dissolution [40, 41]. Chen et al [39] confirmed that a substantial amount of HPMCAS coprecipitated with posaconazole during LLPS and served as a crystallization inhibitor for the amorphous drug. The molecular

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interactions between the posaconazole, HPMCAS and SLS were revealed by FTIR, 2D-NOESY,

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and CMC/CAC measurements. It was found that the SLS interacts with hydrophobic moieties on HPMCAS competitively with posaconazole, thus preventing HPMCAS from effectively inhibiting posaconazole crystallization of amorphous and subsequently induced the depletion of the amorphous drug reservoir. Furthermore, this phenomenon was proven to be in vivo relevant in a crossover dog PK study where the bioavailability of HPMCAS based posaconazole amorphous solid dispersion with or without SLS was compared. The significant reduction in

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bioavailability of ~30% in systems containing SLS was observed compared to SLS free system. Therefore the appropriate selection appropriate surfactant is important.

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Morris et al [31], Serajuddin et al [32] and Law et al [42] have reported a mixture of PEGpolysorbate 80 as a surface active carrier for poorly soluble drugs. It has improved solubility and dissolution profile of poorly water soluble drugs. However, not much literature is available

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demonstrating bioavailability enhancement of drugs using these mixtures [43]. Joshi et al [14] studied the PEG-polysorbate 80 as a surface active carrier to improve solubility and

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bioavailability of poorly water soluble weakly basic drugs. It was found that bioavailability of a weakly basic drug is improved by use of a surface active carrier. The polysorbate-80 added to the PEG acts as a solubilizer for drugs [28, 44, 45]. Some scientists have also used the mixture of surfactant system like SLS and alkyl polyglucosides (APG) for dissolution rate enhancement of poorly water soluble drug aceclofenac. The physicochemical evaluation of the surfactant blends

enhancement [46].

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revealed the existence of synergism between the surfactant blends leads to dissolution rate

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Recently, a new class of surfactant, gelucire, has been used in the pharmaceutical industry to improve the solubility of poorly water soluble drugs. Gelucire is a mixture of saturated

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polyglycolized glycerides consisting of mono, di and tri glycerides and mono, di-fatty acids esters of polyethylene glycols. They are solid waxy materials with nonionic in nature. Some scientists have used gelucire in combination with PEG and PVP K30 to improve the solubility of antiviral agent UC-781. Incorporation of gelucire improved the solubility, dissolution, and stability of the solid dispersion [47, 48]. Apart from gelucire, the other surfactants reported recently is labrasol. This is chemically similar to gelucire and liquid in nature. There is literature,

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showing that use of surfactants like labrasol and gelucire on poorly water soluble drug piroxicam improved dissolution and subsequent increase in bioavailability [49, 50].

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4. Selection of Surfactants in Solid dispersion As discussed above the selection of appropriate surfactant is crucial since it affects the solubility and stability of the drug in solid dispersion. There are a few miniaturized testing methods

available in the literature. Chaudhari et al used the solvent casting for the screening of polymers

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for solid dispersions [5, 6]. The screening was conducted in 96 well plates and hence it requires very little amount of drug. The solvent casts are prepared in 96 well plates in varying

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concentration of polymer by dissolving the drug and polymer in common solvents and solvent evaporation is carried by vacuum drying. The solvent cast prepared by this method cannot be considered as formulation. However, the manufacturing procedure of solvent cast mimics solvent evaporation method of preparation of solid dispersion and is a good tool for polymer selection.

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This method can be used for selection surfactant for solid dispersion by use of ternary mixture in preparing solvent cast in 96 well plates. Figure 3 describe the method of surfactant selection in solid dispersion formulation. The ternary mixture of drug, polymer, and surfactant is added to the

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96 well plate with varying concentration of polymer and surfactant. After the solvent casts are prepared, they are subjected to solubility, DSC, and FTIR testing. The result will determine the

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selection of the surfactant for the drug studied. 5. Use of Surfactants as plasticizer in Hot melt extrusion Hot melt extrusion (HME) has been widely used in pharmaceutical industry [51-54]. The manufacturing process involves melting of the polymer and API followed by cooling to form a composite material in which the drug is embedded in polymer matrices. The extrudates obtained can be milled and mixed with an extragranular excipient for capsule or tableting purposes. One

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of the advantages of hot melt extrudates over other technologies is that the milled extrudates obtained are dense free flowing [55] in nature which is a critical attribute for commercialization of the dosage forms. Since the manufacturing process involves heating, often plasticizer is

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incorporated to facilitate the thermal processing and to modify the drug release from the

polymeric system and to enhance the mechanical properties and surface appearance of the

dosage forms [56-60]. Ghebremeskel et al have studied in depth the use of surfactants like

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Tween-80, Docusate sodium, Myrj-52, Pluronic-F68 and SLS as a plasticizer in preparing a solid dispersion of poorly soluble APIs using hot melt extrusion technique [19]. It was shown that

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surfactant based plasticization serves the dual purpose of aiding polymer processing, as well as subsequent API solubilization/bioavailability enhancement. Solubility parameters of the surfactants, APIs, and polymers, as well as the blends, were studied. It is said that compounds with similar values for solubility parameters are likely to be miscible because the energy of

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mixing within the component is balanced by the energy released by interactions between the components [61]. It was demonstrated that the compounds with ∆δ<7.0 MPa½ are likely to be miscible while the compounds with ∆δ>7.0 MPa½ are likely to be immiscible [61].

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Ghebremeskel et al demonstrated that surfactant caused plasticization of the solid dispersion, which was shown by a reduction in Tm of the API and Tg of the polymer and the combined Tg of

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the solid dispersion formed from quench cooling [19]. Additionally, the level of the plasticization observed correlated to the solubility parameter differences between the various components. It was demonstrated that surfactants decreased the glass transition temperature of the polymer, which further decreases the melt viscosity of the polymers due to plasticization of the polymers. However, the processing temperature used in HME will affect the performance of the solid dispersion [62]. It was observed that for API/PVP-K30 system containing surfactant is

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seen no change in dissolution profile compared to API/PVP-K30 system without surfactant. The possible reason being, PVP-K30 system is extruded at a higher temperature such as 1600C to 1800C. At this high temperature denaturation of surfactants results in compromising its

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effectiveness to enhance dissolution rate [62]. Fule et al performed a similar study in which PEG 400, Poloxamer 188 and Poloxamer 407 were used as plasticizing agents with the polymer

Soluplus® [63, 64]. In addition to plasticizing effect, the surfactants like Poloxamer 188 and

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Poloxamer 407 have surface activity with increased dissolution rate. However, in these studies, low levels of surfactants, 0.6% w/w [64] in one study and in another study 5% to 10% w/w [63]

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of surfactants were used. The drug appeared to be miscible with the polymer at a low level of surfactant. However, the miscibility of the drug in a polymer with a higher concentration of surfactant is unknown.

When hot melt extrusion is used for the preparation of solid dispersion, as often the drug and

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polymer carrier are incompatible in a molten state [61, 65], surfactants are often added to drug and polymer carrier in order to aid in the preparation of homogenous solid dispersions [47, 66]. Some scientists have used an alternate way to make solid dispersion using melt extrusion

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technology. In this method, the drug is converted into anamorphous state and then melt extruded

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with suitable polymer and surfactant [10]. In this case, melt extrusion could be performed much below the melting temperature of the drug. The addition of surfactant to the solid dispersion resulted in enhanced dissolution and oral bioavailability. Lang et al [21] have investigated the effect of hot melt extrusion process on the properties of itraconazole amorphous solid dispersion made by thin film freezing technology (TFF) using HPMCAS. TFF yields an amorphous solid dispersion, which is highly porous with matrix like structures. Since both itraconazole and

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HPMCAS are hydrophobic, melt extrusion of TFF with a poloxamer and polyethylene oxide resulted in a granular material with enhanced dissolution properties.

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Ghebremeskel et al studied the stability of the extruded solid dispersion in presence of the surfactants and found out that extruded solid dispersion stored at 300C & 60% RH at open

condition was stable for 6 months whereas dispersion stored 600C & 85% RH at open condition

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is stable for the duration of 1250 hours [62].

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6. Mechanism of drug release Surfactants can act as precipitation inhibitors to increase the extent of supersaturation in vivo. Overhoff et al studied the effect of ionic surfactant like SLS on the solid dispersion of tacrolimus prepared by ultrarapid freezing technique and observed that SLS act as a good precipitation inhibitor below its CMC [67]. However, nonionic surfactants like, poloxamers, have been shown to inhibit the precipitation of celecoxib at a concentration above its CMC through drug

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partitioning into micelles [68]. Poloxamers have shown precipitation inhibition of nifedipine through increased aqueous solubility or hydrogen bonding [69]. Mitra et al studied the commonly used surfactants like SLS, poloxamers and polysorbate 80 and compared the

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precipitation inhibition tendency of surfactants below their CMC [70]. These surfactants were

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added to simulate stomach duodenum compartment and measured solubility of dipyridamole after administration of 100 mg dose of dipyridamole, figure 4. All the surfactants studied by Mitra et al have successfully stabilized the supersaturated dipyridamolesupersaturation to different extents. Supersaturation ratio of up to 11-fold has been observed to maintain supersaturation up to 120 min. In the duodenal compartment, the AUC60min for the dipyridamole concentration profile is significantly different for all the surfactants explored (Table 2). The AUC60min and AUC120min in the simulated gastric fluid with SLS was found to be over 2 fold of 14

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that observed in the other surfactant systems, despite the predicated solubilities as extrapolated from pH-solubility profiles are similar. Dipyridamole concentration in the duodenum compartment decline much faster in the case of poloxamer 188 and degree of supersaturation

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decline from 15 mins onwards is much lower than for the SLS system. Supersaturation is

maintained for 115 and 75 min in the SLS and poloxamer -188 systems respectively. In the case of polysorbate 80, the maximum supersaturation ratio is 20% lower and supersaturation was

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maintained for the similar duration for the poloxamer-188 system.

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Drug crystallization/precipitation from supersaturated solution generally occurs in two steps i.e. nucleation and crystal growth. For nucleation to occur the activation energy for the nucleation must be overcome. This activation energy can be mainly attributed to interfacial tension between the medium and the small particles with the high curvature. In other words, until a certain degree of supersaturation is reached; the activation energy will not be overcome and, therefore, no new

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nuclei will be formed for a certain time span. This state is known as a metastable state in which no nucleation is formed. Certain excipients can expand this region. The rate of homogenous

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nucleation of the spherical cluster is given by Equation 1. =

(−

∆ ∗

)…………………Eq 1

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Where J is the number of nuclei formed per unit of time and volume, N is the number of molecules of crystallizing phase in a unit volume, ν is the frequency of molecular transport at the solid–liquid interface, ∆G* is the maximum change in Gibbs free energy for the formation of nuclei with a critical radius, kb is the Boltzman constant and T is the absolute temperature. ∆G* is given by Equation 2

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∆

∗

= 16

( ))! ………Eq 2

/3(

Ν is the frequency of atomic or molecular transport at the nucleus–liquid interface and γ are the

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interfacial energy per unit area between the medium and the nucleating cluster. The transport frequency, υ, depends on the fluidity, 1/η of the solution. The combination of Equations 1 and 2

exp %−

=

3(

16

) ( ( )!

& … … … … … … . . )* 3

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renders Equation 3.

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This equation shows that the nucleation rate depends on the degree of supersaturation S and the interfacial energy γns between the solvent and the nucleus [71-74]. Accordingto this equation, nucleation rate will increase with increasing degree of supersaturation and with a decrease in the interfacial energy. Hence, the degree of supersaturation will be influenced by formulation

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compounds and the interfacial tension will decrease in the presence of surfactants. Therefore, non-surface-active compounds that increase solubility could explicitly reduce the nucleation rate. The addition of surfactants, however, might, on one hand, reduce the degree of supersaturation

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by solubilizing the drug and hence decrease the free drug concentration; while on the other hand, they will decrease the interfacial tension between the nuclei and the solvent. Hence, their

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influence on the nucleation rate will depend on their relative contribution to both S and γns. Therefore, if some particles of drugescape the dissolution in the stomach, they will end up in the duodenum and act as nuclei for precipitation in the small intestine and thus make the precipitation more pronounced [75]. Some researchers have shown that if the nucleation is slow, a supersaturated drug solution will be maintained for a long period of time [76]. However, Mitra et al showed that the presence of nuclei does not accelerate the precipitation in case of

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dipyridamole. The rate limiting step in the precipitation of dipyridamole in the surfactant system studied was found to be crystal growth rather than nucleation when concentration below CMC is studied. This was supported by optical microscopy, as it was observed that crystal growth over

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time and the rate of growth was shown to be faster in the polysorbate 80 and the poloxamer188systems in which drug particles were initially absent when compared to the SLS [70]. It is also shown that surfactant contributes to precipitation inhibition by an alteration in the bulk

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properties such as surface tension or saturation solubility [77-79]. Drug partitioning into micelles is also one of the plausible mechanisms for precipitation inhibition. One of the mechanisms

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through which surfactant can inhibit precipitation is through improved solvation of the drug. Hydrophobic interaction can improve the solvation of the drug, which in turn increases the activation energy necessary for desolvation during nucleation and the crystal growth [80]. Scientists have shown that adsorption of the excipient onto the surface of small embryo drug

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particle will inhibit precipitation by retarding the crystal growth through blocking of the active surface and steric stabilization [67].

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7. Method of preparation Solid dispersion using surfactant can be prepared by using several methods like spray drying, vacuum drying, hot melt extrusion, freeze drying, etc. Table 3 gives the examples of solid

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dispersion prepared using different methods. Out of all these methods, spray drying and hot melt extrusions are commonly used. In solvent evaporation technique, drug and polymer are dissolved in common solvent. The solvent can be evaporated using various techniques like spray drying, vacuum drying, freeze drying. Hot melt extrusion, on the other hand, is the fusion method, in which drug and carrier are melted together and subsequently cooled to form a solid dispersion. For the development of solid dispersion enabling the highest level of solubility and dissolution

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with consequent improvement of bioavailability, both fusion method, and solvent method must be used and compared. However, there is very little literature available for comparison of methods of preparation of solid dispersion with surfactants, as most of the methods depend on

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the carrier and the drug characteristics [81-85]. Eloy et al [86] prepared the solid dispersion of poorly water soluble drug ursolic acid containing poloxamer 407 using the fusion method and solvent evaporation method. It was found that solid dispersion prepared by both the methods was

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homogenous in nature. However, a solid dispersion prepared by solvent evaporation method shows the higher solubility of the drug. This was attributed to the smaller particle size and

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conversion of the ursolic acid to an amorphous state when a solvent evaporation method is used, whereas fusion method of preparation of solid dispersion causes the polymorphic changes in the drug. Hence, the method of preparation also plays a very important role in the preparation of solid dispersion containing surfactants.

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8. Conclusion Incorporation of surfactants in the solid dispersion will lead to increasing in dissolution rate as well as physical stability. However, one must use caution in selecting the surfactant for solid

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dispersion. Although several in vitro studies show enhanced dissolution behavior by use of surfactants there are relatively few in vivo studies reported on this topic. Hence, all the features

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of surfactants as a carrier for solid dispersion have not been thoroughly explored. Surfactants maintain drugs in supersaturated state i.e. increased dissolution rate by partitioning into micelle or by hydrophobic interactions which in turn improves solubility of drugs. Below CMC, surfactants inhibit crystal growth of the drugs and thereby preventing precipitation. However, more work is needed to understand the detailed mechanism of interactions of drugs in surfactant. There is very little information available about the molecular arrangements and vibrational

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spectroscopy, which is used to gain information on molecular interactions such as hydrogen bonding, which will eventually lead to commercialization of the surfactants, based on solid

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dispersions. Declaration of Interest The authors report no declaration of interests.

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[75] D. Psachoulias, M. Vertzoni, K. Goumas, V. Kalioras, S. Beato, J. Butler, C. Reppas, Precipitation in and Supersaturation of Contents of the Upper Small Intestine After Administration of Two Weak Bases to Fasted Adults, Pharmaceutical Research, 28 (2011) 31453158. [76] P.G. Vekilov, The two-step mechanism of nucleation of crystals in solution, Nanoscale, 2 (2010) 2346-2357. [77] W.-G. Dai, L.C. Dong, X. Shi, J. Nguyen, J. Evans, Y. Xu, A.A. Creasey, Evaluation of drug precipitation of solubility-enhancing liquid formulations using milligram quantities of a new molecular entity (NME), Journal of Pharmaceutical Sciences, 96 (2007) 2957-2969. [78] M.E. Brewster, R. Vandecruys, J. Peeters, P. Neeskens, G. Verreck, T. Loftsson, Comparative interaction of 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin with itraconazole: phase-solubility behavior and stabilization of supersaturated drug solutions, European Journal of Pharmaceutical Sciences, 34 (2008) 94-103. [79] H. Terayama, K. Inada, H. Nakayama, S. Yasueda, K. Esumi, Preparation of stable aqueous suspension of a hydrophobic drug with polymers, Colloids and Surfaces B: Biointerfaces, 39 (2004) 159-164. [80] J. Brouwers, M.E. Brewster, P. Augustijns, Supersaturating drug delivery systems: The answer to solubility-limited oral bioavailability?, Journal of Pharmaceutical Sciences, 98 (2009) 2549-2572. [81] M. Dehghan, M. Saifee, R. Hanwate, Comparative dissolution study of glipizide by solid dispersion technique, Journal of Pharmaceutical Science and Technology, 2 (2010) 293-297. [82] D.-H. Won, M.-S. Kim, S. Lee, J.-S. Park, S.-J. Hwang, Improved physicochemical characteristics of felodipine solid dispersion particles by supercritical anti-solvent precipitation process, International Journal of Pharmaceutics, 301 (2005) 199-208. [83] G. Poovi, M. Umamaheswari, S. Sharmila, S. Kumar, A. Rajalakshmi, Development of domperidone solid dispersion powders using sodium alginate as carrier, European Journal of Applied Sciences, 5 (2013) 36-42. [84] T. Patel, L. Patel, T. Patel, S. Makwana, T. Patel, Enhancement of dissolution of Fenofibrate by Solid dispersion Technique, Int. J. Res. Pharm. Sci, 1 (2010) 127-132. [85] S. Verheyen, N. Blaton, R. Kinget, G. Van den Mooter, Mechanism of increased dissolution of diazepam and temazepam from polyethylene glycol 6000 solid dispersions, International Journal of Pharmaceutics, 249 (2002) 45-58. [86] J.O. Eloy, J.M. Marchetti, Solid dispersions containing ursolic acid in Poloxamer 407 and PEG 6000: A comparative study of fusion and solvent methods, Powder Technology, 253 (2014) 98-106.

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Table captions Table 1: Different types of Poloxamer depending on a and b

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Table 2: AUC60min for the dipyridamole concentration profile for all the surfactant studied; reprinted from reference (70) with permission from ACS publication

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Table 3: Use of surfactant in solid dispersion prepared using different methods

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Figure captions Figure 1: Chemical structure of SLS, poloxamer and vitamin E TPGS. Figure 2: Chemical structure of polysorbate.

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Figure 3: Schematic representation for selection of surfactants in solid dispersions. Figure 4: Overview of HME

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Figure 5: Comparison of the effect of different surfactants on dipyridamole concentrations in the stomach (a) and duodenal compartments (b) of the SSD (mean ± SD). mFaSSGF in the gastric compartment, dipyridamole dose 100 mg, and monoexponential gastric emptying T1/215min; reprinted from reference (70) with permission from ACS publication.

a 12 80 64 141 101

b 20 27 37 44 56

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Poloxamer 124 188 237 338 407

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Surfactant

AUC60min (µg min/mL) (mean ± SD)

Sodium lauryl sulfate (SLS)

5170.5 ± 506

117

10.1

Poloxamer188

2603.8 ± 282

115.3

11.2

Polysorbate1975.4 ± 118 80

75.9

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Method of Preparation

Polysorbate 80

Solvent evaporation

Indomethacin

SLS

Solvent evaporation

Sulfathiazole

SLS

Solvent evaporation

Posaconazole

SLS

Spray drying

Itraconazole

Cremophor RH 40 Poloxamer 407

Hot Melt extrusion

LAB687

Polysorbate 80

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Hot Melt extrusion

Ezetimibe

Tween 80

Spray Drying,

Daidzein

Tween 80

Solvent

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Reference

Permeability of solid dispersion prepared (He et al., with PVP-Tween 80 2014) combination was increased I Caco-2 cells Incorporation of SLS in the solid dispersion (Dave et al., increases the dissolution 2012) rate. Incorporation of SLS in the solid dispersion (Dave et al., increases the dissolution 2013) rate. Bioavailability of the amorphous solid dispersion is highly (Chen et al., dependent on the 2016) interaction of drug, polymer, and surfactant Incorporation of (Lang et al., surfactant increased the 2014) dissolution rate Bioavailability of the drug was greatly enhanced by a solid (Dannenfelser dispersion containing et al., 2004) surface, active agent. The solid dispersion was stable for 6 months The addition of surfactant increased the dissolution rate. However, analysis of (Sotthivirat et stability samples al., 2013) revealed that solid dispersion containing surfactants needs to be protected from moisture The addition of surfactant did not have (Rashid et al., profound effect on 2015) dissolution and bioavailability in rats Incorporation of Tween (Hu et al.,

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Melting method

Ursolic acid

Gelucire 50/13

Solvent evaporation

Diclofenac Salt II

Gelucire 50/13

Melting method

Indomethacin

Gelucire 50/13

Melting method

Ezetimibe

Gelucire 44/14

Mesalamine

SLS

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Kneading method

Spray drying

Sorafenib

SLS

Meloxicam

Poloxamer 188

Kneading method

Poloxamer 188

Melting method

Rofecoxib

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Ritonavir

in the solid dispersion 2011) increases the dissolution rate. Solvent evaporation Incorporation of surfactant increased dissolution rate and (Sinha et al., bioavailability. The 2010) solid dispersion prepared by solvent method were promising Incorporation of Gelucire in the solid (de Oliveira dispersion increases the Eloy et al., dissolution rate and in 2012) vitro trypanocidal activity Incorporation of Gelucire in the solid (Fini et al., dispersion increases the 2005) dissolution rate Incorporation of Gelucire in the solid (El-Badry et dispersion increases the al., 2009) dissolution rate Incorporation of Gelucire in the solid (Parmar et al., dispersion increases the 2011) dissolution rate Incorporation of SLS in the solid dispersion (Jejurkar and increases the dissolution Tapar, 2011) rate Incorporation of SLS in the solid dispersion (Truong et al., increases the dissolution 2015) rate Dissolution enhancement of drugX was obtained by (Ghareeb et preparing its solid al., 2009) dispersion with poloxamer 188 Dissolution (Shah et al., enhancement of drug 2007) was obtained by

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Diazepam

Polysorbate 80

Solvent evaporation

Carbamazepi ne

Poloxamer 188 Poloxamer 407

Cetrimonium bromide SLS Poloxamer 80

AC C

Gliclazide, Glyburide, Glimepiride, Glipizide, Repaglinide, Pioglitazone, Rosiglitazone Phenylbutazo ne

Docetaxel

Ibuprofen Ketoprofen

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Solvent evaporation

Solvent evaporation

EP

Oxazepam

Cetrimonium bromide SLS Myrj 52 Dodecyltrimeth ylammonium bromide SLS Brij-35

Melting method

Poloxamer F127

Poloxamer 188 (Lutrol F68) Poloxamer 235 (Pluronic P85) Poloxamer 407 Poloxamer 188

Melting method-

Freeze drying

Melting method

(Newa et al., 2008)

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Poloxamer 407

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Ibuprofen

Melting method

preparing its solid dispersion with poloxamer 188 Incorporation of Poloxamer 407 in the solid dispersion increases the dissolution rate Inclusion of polysorbate 80 in solid dispersion increased the dissolution rate but does not protect against aging Poloxamer 188 exhibits higher efficacy in increasing dissolution rate of carbamazepine

(Fernandez et al., 1989)

(Medarević et al., 2016a)

All the surfactant increase the solubility of oxazepam

(Shokri et al., 2006)

Anionic surfactant enhanced dissolution rate of Griseofulvin

(Akin et al., 1998)

Non-ionic surfactant was better solvent as compared to ionic surfactant

(Seedher and Kanojia, 2008)

Incorporation of Poloxamer in the solid dispersion increases the dissolution rate

(Rouchotas et al., 2000)

Incorporation of Poloxamer in the solid dispersion increases the dissolution rate

(Song et al., 2016)

Incorporation of Poloxamer in the solid dispersion increases the

(Ali et al., 2010)

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ABT-963

Poloxamer 188

Solvent evaporation

Itraconazole

Poloxamer 188

Solvent evaporation

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Poloxamer 407 Poloxamer 188

(Kolašinac et al., 2012)

(Chen et al., 2004)

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Melting method

Desloratadin e

dissolution rate Incorporation of Poloxamer in the solid dispersion increases the dissolution rate Incorporation of Poloxamer in the solid dispersion increases the dissolution rate Incorporation of Poloxamer in the solid dispersion increases the dissolution rate

(Parikh et al., 2016)

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