Int J App Pharm, Vol 13, Issue 3, 2021, 11-17Review Article

FUNDAMENTAL ASPECTS OF A THIRD COMPONENT USED IN TERNARY SOLID DISPERSION: A REVIEW

SREE VARSHINI S1*, VAIYANA RAJESH C1

Department of Pharmaceutics, PSG College of Pharmacy, Coimbatore 641004, Tamilnadu, India
Email: varsha291296@gmail.com

Received: 27 Jan 2021, Revised and Accepted: 13 Mar 2021

ABSTRACT

Ternary solid dispersion (TSD) is one of the promising approaches used in recent studies to address the issues encountered by poorly water-soluble drugs. The binary solid dispersion (BSD) with the drug and the single polymer is not sufficient to satisfy all the criteria such as improved solubility, dissolution, stability, supersaturation, and recrystallization inhibition. Hence, the TSD with the third component/ternary agent aids in overcoming the limitations, thereby enhancing the solubility and bioavailability to a greater extent when compared to the BSD. Excipients that can be used as a third component includes surfactants, pH modulator, polymer and adsorbents. All these excipients have distinct benefits in improving the efficiency of the final dosage form. However, care must be taken in selecting suitable excipients for the research. This review highlights the impact of these excipients in improving the formulation complications and the therapeutic potential of the TSD.

Keywords: Ternary solid dispersion, Ternary agent, Surfactant, pH modulator, Adsorbent, Polymer

© 2021 The Authors. Published by Innovare Academic Sciences Pvt Ltd. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/)
DOI: https://dx.doi.org/10.22159/ijap.2021v13i3.40890. Journal homepage: https://innovareacademics.in/journals/index.php/ijap

INTRODUCTION

Solubility, as well as dissolution, is a fundamental principle across every physicochemical science, including biopharmaceutical and pharmacokinetic aspects of any medicine's therapy [1]. In recent decades, novel drugs with extraordinary medicinal benefits generated by various research activities entering the drug development phase are diminishing, due to their non-optimal biopharmaceutical properties [1, 2]. The foremost obstacle in the drug development phase is limited to the solubility/dissolution of the drugs in aqueous media. Since the drug must be bioavailable for the patient to exert its action, at a certain point of time, the drug must be completely dissolved or solubilized within the body fluid, regardless of the route of administration [3]. These complications significantly affect the pharmacokinetic parameter such as absorption, distribution, metabolism and excretion of the drug [4]. The primary objective of improving the solubility/dissolution is to enhance the bioavailability of the drug. The low solubility and dissolution rate of Active Pharmaceutical Ingredient (API) in G. I. T fluid also lead to inadequate bioavailability, increased dosage, and blood concentration variability [5]. Class II and Class IV drugs with low solubility in the Biopharmaceutical Classification System (BCS) suffer from dissolution-related absorption issues. Specific methods to resolve low solubility include chemical and physical alteration of drug candidates [6]. The Noyes-Whitney equation shows that the rate of dissolution of a drug is proportional to both the concentration gradient and the surface area of particles. Increasing the surface area of the substance will, therefore, increase the dissolution rate [7]. Several methods, such as solid dispersion (SD) [8-11], complexation [12, 13], lipid-based systems [14, 15], micronization [16, 17], nanonization [18, 19] and co-crystals [20, 21] were already suggested to increase the solubility of poorly water-soluble drugs. Among them, SD technology, which involves dispersing drugs in different types of polymers, is commonly used to improve solubility and bioavailability [22]. In 1961, the SD principle was introduced by Sekiguchi K and Obi N [23]. Conventional BSD involves dispersing the drug into a single polymer or surfactant or any other additive, thereby enhancing the solubility of the drug [24]. It is known that the solid-state of the product may be either crystalline or amorphous, which varies with the energetical state of solid-packed molecules [25]. The state at which the drug is dispersed in the crystalline or amorphous carrier has a significant impact on solubility and drug release [26]. Although there have been consistent reports of the utilization of SD's in the pharmaceutical literature, only a few commercial products depend on the SD method [27]. An ideal formulation must be stable, prevent recrystallization, enhance the super saturation and dissolution properties of the drug. BSD may not be adequate for meeting all the criteria listed above [28]. Therefore, TSD can be an efficient technique for combating specific limitations of BSD [29]. TSD was formerly known as a multi-component SD, which involves the addition of a third component other than the drug and a carrier (i.e., API, polymer and an additive) that would further enhance the efficiency of SD [30]. Adding a third component (ternary agent) to produce a TSD system gives improved stability, greater miscibility, stronger intermolecular interactions, significantly higher water-solubility, and synergistic benefit in all of these factors compared to the BSDs [31]. The carrier used in combination with a ternary agent could be a polymer, surfactant or a polymer with surfactant property [32, 33]. Examples of ternary agents comprise surfactant [34], polymer [35], adsorbent [36], pH modulator [37] and hydrotropic agent [38]. Various international publications of the past decade are summarized from the reputed source (Elsevier, Pubmed, NCBI) to emphasize the significance of the key components (ternary agents) particularly, surfactants, polymers, pH modulators, and adsorbents to improve TSD’s reliability in addressing the challenges of formulation associated with the drug solubility and dissolution.

Surface active agents (surfactants)

Surfactants are commonly used in the TSD along with the carrier as it provides multiple benefits. In general, the drug should reside in a supersaturated state to reach the optimum rate of dissolution. The addition of surfactants as a ternary agent results in the formation of complex micelles and promotes supersaturation of the drug [39]. Additionally, it provides improved stability and prevents the precipitation of the drug [40]. In TSD, the surfactant along with the carrier act by reducing the surface tension at the interface thereby alters the nature of the drug and enhances dissolution [41]. The Surfactant acts as a wetting agent [42], plasticizer [43], crystallization inhibitor [44], and stabilizer [45] with respect to dissolution properties [46]. Critical micellar concentration (CMC) and hydrophilic-lipophilic balance (HLB) play a key role in the dissolution of the drug [47]. When the concentration of the surfactant is greater than CMC, it aids in the improved dissolution by forming micelles/inhibiting precipitation and while lesser than CMC acts by reducing the interfacial tension [48-50]. Based on the polarity, surfactants are classified into.

The surfactants recently used in combination with carriers in TSD are poloxamer (Pluronic), SLS, and D-α-TPGS/Vitamin E TPGS. It is reported that the combination of poloxamer 188 and Polyvinyl Pyrrolidone (PVP) K30 showed a beneficial impact on solubility, stability, in vitro dissolution, and bioavailability of Febuxostat [51]. The addition of surfactants could be either intra-granular or extra-granular. When mixed intra-granularly with the API and polymer the surfactants have a beneficial effect on the rate of drug release rather than extra-granularly applied [52]. A study documented the effect of surfactant added internally and externally to indomethacin and PVP. Internally incorporated SLS had a dramatic effect on the release of indomethacin as compared with externally added SLS [49]. Past studies on the Surfactant-carrier combination used in TSD are enlisted in table 1.

Table 1: Studies on the surfactant-carrier combination used in TSD

API Surfactant Carrier Impact of surfactant on TSD Ref
Domperidone Poloxamer 188 Gelucire 50/13 Poloxamer 188 was found to be an ideal ternary agent than poloxamer 407 as it exhibited better dissolution of domperidone. [53]
Ezetimibe Poloxamer 188 PVP K30 Melt quenching of Poloxamer 188 with ezetimibe exhibited enhanced solubility as well supersaturation in the bio-relevant media. [54]
Diacerein Pluronic F-68 PEG 4000 Pluronic F-68 in TSD enhanced the solubility of diacerein by micellar solubilization and increased steric hindrance. [55]
Domperidone Pluronic F-127 PVP K30 The interfacial tension between the drug and the dissolution medium was minimized by surfactant in TSD which resulted in increased wettability and thus enhancing domperidone dissolution. [56]
LW6 Poloxamer 407 Povidone K30 The presence of poloxamer 407 in TSD resulted in improved solubility by micelle formation and delivering the drug into the core of micelles. [57]
Manidipine TPGS Copovidone Due to its low CMC, TPGS decreased the interfacial tension and also showed a more porous structure resulting in the improved dissolution of manidipine. [58]
Valsartan TPGS Soluplus The presence of TPGS as a plasticizer in the TSD resulted in reduced glass transition temperature and also enhanced penetration of the valsartan through the mucosal membrane. [59]
Lacidipine SDS Soluplus The Ternary system with SDS not only enhanced the solubility and dissolution but also improved the bioavailability of lacidipine up to 3.7 folds when compared to the binary system. [60]
Felodipine SDS Soluplus By acting as a plasticizer, crystallization inhibitor, a driving force to assist the carrier, SDS offered many advantages and resulted in enhanced dissolution. [61]
Chlorthalidone SLS Soluplus The presence of SLS above the CMC of 2%, significantly enhanced the solubility up to 5.5 times than the pure drug. [62]

pH modulators

In general, water-insoluble drugs are weakly acidic or weakly basic compounds in nature. Hence, they mostly dependent upon the pH for their solubility. An approach to modify the release rate of numerous pH-dependent drugs is to modulate the pH of the formulation known as microenvironmental pH [63]. Weakly acidic drugs show greater solubility at neutral or alkaline pH and weakly basic drugs show improved solubility at acidic pH [64]. The dissolution behavior can be closely associated with the microenvironmental pH at the diffusion layer. pH modifying agents act by altering the pH through intermolecular hydrogen bonding with the drug and thereby decreasing the crystallinity of the drug resulting in an enhanced release rate [65]. Alkalizers [66] or Acidifiers [67] are the agents that can be used for altering the microenvironment pH i.e. either by increasing or lowering the pH at which the drug could dissolve easily. Alkalizers are added to weakly acidic drugs and for weakly basic drugs acidifiers are added. The Conventional BSD technique alone is not sufficient for all pH-dependent drugs as it is restricted to the solubilization capacity [63]. Past studies stated that combining a pH modulator along with a carrier in TSD could effectively enhance the various properties of the drugs [68-70]. A study reported that combining alkalizer with kollidon VA64 and glycyrrhetinic acid (GA), resulted in the enhanced dissolution of GA through the formation of ion complexes by strong electrostatic attraction [71]. Using citric acid (acidifier) along with Amorphous Solid Dispersion (ASD) technology significantly enhanced the absorption of Carvedilol even under elevated gastric pH conditions [72]. Some of the most commonly used alkalizers include Aminoclay, NaOH, Na2CO3, Ca(OH)2, NaHCO3, and Meglumine. Acidifiers generally used in TSD include citric acid, succinic acid, fumaric acid, and tartaric acid. Past studies on the pH modulator-carrier combination used in TSD are enlisted in table 2.

Table 2: Studies on pH modulator-carrier combination used in TSD

API pH modulator Carrier Impact of pH modulator on TSD Ref
Alkalizers
Chrysin Aminoclay Brij L4 Chrysin (pKa 6.72) was found to be more soluble in the basic environment. Adding aminoclay increased the SD's microenvironment pH to the basic state, thus increasing the dissolution. [73]
Telmisartan NaOH Soluplus Among various alkalizer, NaOH (1%) had a beneficial impact on Telmisartan solubility by providing a continuous pH adjustment throughout the dispersion matrix. [74]
Nateglinide Na2CO3 Poloxamer 188 The presence of Na2CO3 deprotonated the nateglinide carbonyl group, resulting in pH-independent solubility in the acid environment, improving the bioavailability of nateglinide by up to four-folds. [75]
Toltrazuril Ca(OH)2 PVP With the increase in the Ca(OH)2 ratio, the rate of dissolution of toltrazuril was found to be enhanced, as it facilitates intermolecular interaction with Toltrazuril which is necessary for the maintenance of supersaturation. [76]
Clarithromycin NaHCO3

HPMC/

PVP

 The Clarithromycin would have been degraded by acidic media after 60 min before leaving the tablet if, NaHCO3 were not added. The alkalizer increased the dissolution and stability of the drug without altering the crystallinity of the drug. [77]
Telmisartan Meglumine

PVP

K-30

 Since meglumine was a strong metal oxide it had a higher pH value than other alkalizers and by forming a salt with telmisartan, it increased dissolution in the intestinal fluid. [78]
Acidifiers
GT0918 Citric Acid

PVP

K-30

 Citric acid aids in preventing the recrystallization of an ASD system and potentially enhances the dissolution by hydrogen bonding between the drug and the pH modifier. [79]
Aripiprazole Succinic acid

Kollidon-12PF

(PVP)

 SD with a concentration of 10% succinic acid enhanced the solubility and drug release compared to the SD without the acidifier by maintaining the optimal pH near the aripiprazole. [80]
Raloxifene HCl Fumaric acid HPMC Raloxifene HCl and fumaric acid in SD resulted in salt formation by hydrogen bonding which significantly increased the solubility and dissolution of raloxifene HCl. [81]
Dipyridamole Tartaric acid Eudragit S100 Though surrounded by enteric polymer, electrostatic interaction between tartaric acid and dipyridamole resulted in a change of microenvironment pH facilitating a rapid dissolution of dipyridamole. [82]

Polymer-polymer TSD

Even though crystalline drugs offer the advantage of high purity and stability, their solubility is limited due to high lattice energy. On the contrary, the amorphous form depicts a disordered texture with high free energy that contributes to greater apparent solubility than its crystalline counterpart [83, 84]. Thus, the Amorphous Ternary Solid Dispersion (ATSD) has gained more attention in enhancing the solubility and dissolution properties of many poorly water-soluble drugs [85]. However, the pharmaceutical benefit of amorphous drugs is impaired by their low thermodynamic stability and their susceptibility to readily recrystallize in the solid-state or else during dissolution [86]. Retaining a drug in the amorphous state in both solid and solution phases is vital. The polymer prevents crystal growth by raising the glass transition temperature and decreasing the molecular mobility of the amorphous drug [87]. The polymer retains the supersaturated state of the drug by forming an intermolecular interaction with them [88]. The BSD with a drug and single polymer may be inadequate to satisfy all the criteria. Hence, the ATSD with polymer as the third component (ternary agent) is used to obtain optimum solubility and dissolution of poorly water-soluble drugs [89]. TSD of Itraconazole with a combination of polymeric carriers such as HPMCP and soluplus prepared by hot-melt extrusion significantly improved solubility and bioavailability and also retained the physical stability of the formulation [90]. PVP K30 was inefficient in preserving the supersaturated state of the drug, whereas Soluplus played an integral part in sustaining its long-term supersaturation. Thus, PVP K30 and Soluplus had a synergistic effect for improving TEL's solubility and dissolution [91]. Some of the most commonly used combinations of polymers include HPMC, PVP (Kollidon), Eudragid, PLGA, and Soluplus. Past research on the combination of polymers used in TSD is shown in table 3.

Table 3: Studies on the polymer-polymer combination used in TSD

API Polymer Carrier Impact of polymers on TSD Ref
Indomethacin Eudragid E100 PVP K90 The SD was stabilized by Eudragid E100 and the supersaturation was retained by PVP K30 and the mixture of both had a synergistic effect on the indomethacin dissolution. [29]
Celecoxib HPMCAS Polyvinyl alcohol Pre-dissolved HPMCAS as a powder extended the supersaturation by inhibiting growth over the dissolution period by maintaining the particle size. [89]
Ibuprofen HPMCP-HP55 Kollidon VA64 By acting as an anti-plasticizer, HPMCP HP55 increased stability and kollidon VA64 improved the dissolution rate by increasing API wettability. [92]
Griseofulvin Soluplus Kollidon VA64 Soluplus as a major component inhibited the crystal growth and a minor component VA64 increased the wettability resulting in a rapid release of griseofulvin. [93]
Dipyridamole HPMC K100 PVP K30 PVP K30 and HPMC K100 had a synergistic impact on the solid-state property and dissolution of both dipyridamole and cinnarizine by maximum supersaturation concentration and crystallization inhibition. [94]
Cinnarizine
API PVP PLGA PLGA sustained the release of the formulation by forming a phase-separated surface layer and PVP enhanced the solubility and dissolution of the API from the SD. [95]
Clopidogrel HPMC PVP The physical stability and oral bioavailability of the drug with low glass transition temperature is improved by a combination of HPMC and PVP. [96]
Celecoxib HPMC E5 PVP K30 The combination of PVP-HPMC prevented recrystallization and considerably improved the dissolution of celecoxib compared to the SD prepared with PVP or HPMC alone. [97]
Griseofulvin

Eudragit

L100

 HPMC As compared to the BSD of individual polymer(s), the TSD substantially increased the supersaturation of griseofulvin. The desired dissolution of griseofulvin is accomplished by the additional benefits of polymer blends. [98]

Adsorbents

Despite several advantages, TSD has certain drawbacks due to its handling and stability issues. TSD formulation often results in a waxy yield, and this is due to the carrier’s nature. As a result, they tend to have a poor flow, poor compressibility, and hard to pulverize [99, 100]. To resolve these problems, inert material with good flow and compressibility should be used to absorb the dispersion on its surface [101]. Moreover, adsorption carriers not only prevent the crystal growth due to confined space within the pores of carriers but also stabilize the drug in the TSD by various chemical interactions [102]. Previous research has suggested that the adsorption carriers (sylysia 350) can be used as a ternary agent in addition to their anti-plasticizing effect in the ATSD of itraconazole [103]. Another study stated that using neusilin US2, as an adsorbent effectively turned viscous semisolid substance into a free-flowing powder so that it can be compressed into a tablet or filled into the capsule as powders [104]. The presence of neusilin US2 not only resolved the issue of TPGS's stickiness but also enhanced the ticagrelor flow property and the study revealed that the use of neusilin US2 in TSD preparation would improve industrial processes [105]. Some of the adsorbent widely used are sylysia 350 [106, 107], neusilin [108, 109], Aerosil [110, 111], Lactose [112, 113], Florite [114]. Past studies on the adsorbent-carrier combination used in TSD are enlisted in table 4.

Table 4: Studies on adsorbent-carrier combination used in TSD

API Adsorbent Carrier Impact of adsorbents on TSD Ref
Valsartan Lactose Gelucire 50/13 Increased quantity of lactose addition resulted in free-flowing powder with reproducible dissolution characteristics. [100]
Bosentan Sylysia 350 Poloxamer 188 The inclusion of Sylysia 350 turned the waxy SD into a free-flowing powder with adequate compressibility and also expanded the surface area, resulting in rapid drug desorption. [101]
Cefuroxime axetil Sylysia 350 Gelucire 50/13 The benefits of adding sylysia 350 are better yield, inhibition of recrystallization, flowability, an increase in the effective surface area, and amorphous state preservation. [106]
Celecoxib Neusilin US2 Phosphatidylcholine (PC) As the PC-based SD exhibited a lipidic consistency, it was challenging to formulate it into an oral dosage form. The flowability of the SD was improved by adding an adsorbent. [107]
Carbamazepine Neusilin UFL2 Kollidon VA64 Together with the carrier, Neusilin UFL2 improved the dissolution by increasing the surface area and carbamazepine flowability. [108]
Curcumin Aerosil Gelucire 50/13 Due to the hydrogen bonding between the drug and the carrier and its surface adsorption onto the aerosil, the TSD was found to be stable for around 9 mo. [109]
Nifedipine Aerosil 200 Eudragit E The absence of adsorbent resulted in a gelatinous mass, while free-flowing powder was observed along with a significant increase in dissolution in the presence of Aerosil 200. [110]
Gliclazide Lactose

Poloxamer/

PEG

 Complete desorption of gliclazide resulted in rapid dissolution by the combined effect of adsorption and reduction in size. [111]
Lurasidone hydrochloride Florite Poloxamer 188 Florite prevented the transformation of an amorphous form to a crystalline and increased the stability of the amorphous state. [112]

CONCLUSION

Various additives are used as a third component to overcome the limitations associated with BSD. These additives improve the efficiency of TSD as a formulation through several strategies. For example, surfactants along with the carrier act by distinct mechanisms such as reducing the surface tension, preventing recrystallization, maintenance of supersaturation and also improves the physical stability of the drug. CMC and HLB are the important variables to be considered when selecting a surfactant for the study. Therefore, care must be taken in choosing suitable surfactants. For drugs that depend on the pH for their solubility, pH modulators are the appropriate choice of excipients. Alkalizers/acidifiers aids in solubility and dissolution of weakly acidic/weakly basic drugs by modulating the microenvironment pH at which the drug dissolves easily.

They also assist in supersaturation by establishing an intermolecular interaction with the drug. Additionally, pH modulators improved stability without altering the nature of the formulation. The amorphous form of the drug offers improved apparent solubility than its crystalline counterpart owing to its high free energy. Since the ATSDs are thermodynamically unstable and more liable to recrystallization, it is vital to maintain them in the amorphous state. The polymer-polymer combination aids in maintaining the super saturation, inhibiting the crystal growth, and improved the stability of the ATSD. Despite enormous benefits, the commercial use of SD is limited due to the complexity of handling and scale-up. To overcome these obstacles, adsorbents are added to the TSD as a third component. These adsorbents convert the waxy SD into a free-flowing powder so that it can be compressed into a tablet or powder that can be filled into the capsule. Every excipient has both benefits and drawbacks, so caution should be given to selecting the appropriate excipient for the research. It is therefore concluded that the addition of different additives as a third component improves TSD's efficacy in enhancing the solubility, dissolution, and bioavailability of poorly water-soluble drugs.

FUNDINGS

Nil

AUTHORS CONTRIBUTIONS

All the authors contributed equally.

CONFLICTS OF INTERESTS

Declared none

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