http://informahealthcare.com/ddiISSN: 0363-9045 (print), 1520-5762 (electronic)

Drug Dev Ind Pharm, 2015; 41(6): 875–887! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/03639045.2014.971027

REVIEW ARTICLE

Solubility and dissolution enhancement strategies:current understanding and recent trends*

Shashank Jain, Niketkumar Patel, and Senshang Lin

College of Pharmacy and Health Sciences, St. John’s University, Queens, NY, USA

Abstract

Identification of lead compounds with higher molecular weight and lower aqueous solubilityhas become increasingly prevalent with the advent of high throughput screening. Pooraqueous solubility of these lipophilic compounds can drastically affect the dissolution rate andsubsequently the drug absorbed in the systemic circulation, imposing a significant burden oftime and money during drug development process. Various pre-formulation and formulationstrategies have been applied in the past that can improve the aqueous solubility of lipophiliccompounds by manipulating either the crystal lattice properties or the activity coefficient of asolute in solution or both, if possible. However, despite various strategies available in the armorof formulation scientist, solubility issue still remains an overriding problem in the drugdevelopment process. It is perhaps due to the insufficient conceptual understanding ofsolubility and dissolution phenomenon that hinders the judgment in selecting suitable strategyfor improving aqueous solubility and/or dissolution rate. This article, therefore, focuses on(i) revisiting the theoretical and mathematical concepts associated with solubility anddissolution, (ii) their application in making rationale decision for selecting suitable pre-formulation and formulation strategies and (iii) the relevant research performed in this field inpast decade.

Keywords

Amorphous solid dispersion, bioavailability,dissolution rate, formulation strategies,particle size reduction, poor solubility, salts

History

Received 9 August 2013Revised 31 August 2014Accepted 22 September 2014Published online 24 October 2014

Introduction

With the advent of high throughput screening (HTS) tool in drugdiscovery, large number of lipophilic compounds with highmolecular weight are emerging in drug discovery pipeline.Consequently, poor aqueous solubility of the lipophilic com-pounds has become an enduring problem in pharmaceutical drugdevelopment and is becoming increasingly prevalent among newdrug candidates. The preferential selection of more lipophiliccompound by HTS method is attributed to its dependence onkinetic (non-equilibrium) solubility, which represents the max-imum solubility of the fastest precipitating species of a com-pound. It is determined by dissolving the compound in an organicsolvent (typically dimethyl sulfoxide) and then titrating withaqueous medium till the precipitation of the compound1.However, depending upon the degree of super-saturation thatmay occur, kinetic solubility is likely to overestimate the

equilibrium or true solubility, rendering the more lipophiliccompounds to progress through the preliminary screening2,3.

Traditionally, the compounds with aqueous solubility less than10 mg/ml are classified as poorly soluble4. Considering thissolubility bracket, currently more than 49% of the compounds arepoorly soluble in the drug discovery pipeline for oral adminis-tration4. However, according to Biopharmaceutical ClassificationSystem (BCS), the solubility criteria (poor/high solubility) shouldbe decided based on the dose solubility volume, which is thevolume needed to dissolve the highest dose strength of therapeuticcompound. The BCS defines a drug substance as ‘‘highlysoluble’’ when the highest dose strength is soluble in 250 ml orless of aqueous media over the pH range of 1–7.55,6. Therefore,for a drug with the highest dose of 1 mg, aqueous solubility couldbe as low as 4mg/ml (i.e. 1 mg/250 ml) to be considered assoluble. Nonetheless, taking into consideration the dose volume,still almost 44% of the compounds in oral drug discovery pipelinerequire high dose volume4.

The most important impact of poor aqueous solubility of thecompound is on dissolution rate. Low dissolution rate influencedby poor aqueous solubility might render low oral bioavailabilityof such compounds. This is particularly important in oral drugadministration where dissolution should be completed within theintestinal transit time limit to maximize drug absorption. TheBCS defines a drug product as ‘‘rapidly dissolving’’ when over85% of the labeled amount dissolves in 30 min using USP

*This review article was written for and has won first prize in GlobalAcademic Competition for Life Science Leaders of Tomorrow, sponsoredby Catalent Applied Drug Delivery Institute. Visit www.bioavailability.com for more information on this topic.

Address for correspondence: Senshang Lin, College of Pharmacy andHealth Sciences, St. John s University, Queens, NY, USA. Tel: +1 718990 5344. Fax: +1 718 990 1877. E-mail: linse@stjohns.edu

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apparatus I or II in a volume of 900 ml or less buffer solutions5,6.In particular, BCS Class II (low solubility and high permeability)compounds impose a greater challenge to formulation scientists,as dissolution rate is the rate-limiting factor for the drugabsorption. Consequently, various pre-formulation and formula-tion strategies are employed to enhance the aqueous solubilityand/or dissolution rate, though with limited success.

Since the approaches that are traditionally classified assolubility enhancement techniques for BCS Class II drugs maynot necessarily assure to improve the solubility issue for allBCS Class II drugs, the information to increase ideal solubility ordecrease activity co-efficient or both for improving the solubilityof a specific drug molecule in question can be more suitable forthe selection of particular approach. However, despite theimportance of these theoretical and mathematical conceptsassociated with solubility enhancement, these concepts havenot been discussed in conjunction to rationalizing solubilityenhancement technique for a specific drug. Therefore, theobjective of this review article was not to classify the solubilityenhancement approaches in regards to BCS classification, but tounderstand the mechanism by which these approaches can beutilized to manipulate the parameters defining the solubilityof the solute such as its crystal lattice (e.g. melting pointand molar heat of fusion) and the molecular structure (e.g.activity coefficient). Such information is more relevant to aformulation scientist for deciding a suitable strategy appropriatefor particular drug, regardless of BCS classification. Inthis review article, the scientific concepts and techniquesassociated with solubility and dissolution, their application forpoorly soluble drugs in pharmaceutical drug development and therelevant literature reported in past decade are outlined anddiscussed.

Concept of solubility and dissolution rate

Solubility

In order to understand the pre-formulation and formulationstrategies available to enhance solubility, the theoretical andmathematical concepts of solubility need to be reviewed. Thesolubility of a solute in water depends on the properties of crystallattice (e.g. melting point and molar heat of fusion) and themolecular structure (e.g. activity coefficient)7. In the early 1980s,Yalkowsky and Valvani developed the general solubility equation(GSE) to correlate these properties such as activity coefficientand crystal lattice energy to understand and predict aqueoussolubility of the solute8–10. The aqueous solubility, Xa, is generallydefined as:

log Xa ¼ log Xi � log � ð1Þ

where Xi is the ideal solubility and � is the activity coefficient ofthe solute in water. Consequently, to improve aqueous solubility,the approach is to either to increase log Xi or decrease log �, orboth if feasible. The ideal solubility depends on the crystallinestructure of solute without any influence of the nature ofsolubilizing medium. The ideal solubility of a solute can bemathematically expressed as:

� log Xi ¼DHm

2:303 R

T 0m � T

TT 0m

� �ð2Þ

where, Xi is the ideal solubility represented in mole fraction, DHm

is the enthalpy of melting, R is the gas constant (1.98 cal/degmol), T 0m is the melting point of solute in Kelvin and T istemperature of solution in Kelvin.

Since the ratio of DHm=T 0m equals to the entropy of melting(DSm) and is approximated to 13.5 cal/deg mol for rigid molecule

(commonly referred as Walden’s rule), the above equation at roomtemperature can be reduced to:

log Xi ¼ �0:01 T 0m � 298� �

ð3Þ

or,

log Xi ¼ �0:01 Tm � 25ð Þ ð4Þ

where Tm represents the melting point of solute in Celsius.According to Equation (4), the ideal solubility is exclusivelydependent on the melting point (representative of crystal latticeenergy) of solute and is the same for every solvent media used. Itcan be observed that a 10-fold solubility enhancement can beachieved for every 100-degree decrease in melting point.

In contrast, activity coefficient term represents the decrease inaqueous solubility due to intermolecular interaction differences ofsolute and solvent molecules. In other words, activity coefficientcan be considered as the measurement of the intermolecularforces of attraction to be overcome, for removing a moleculefrom the solute and placing it in the solvent (Figure 1)8.Mathematically, activity coefficient can be represented as9:

log � ¼ �1 � �2ð Þ2 V2�21

2:303RTð5Þ

where, �1 and �2 are the solubility parameter of solute and solvent,respectively, �1 is the volume fraction of solvent, V2 is the molarvolume of solute, R is the gas constant, T is the absolutetemperature of solution. This equation indicates that activitycoefficient is dependent on both the properties of solute andsolvent (indicated by � term). Also, if the solubility parameter ofsolute and solvent is similar, log � term can be neglected andthe aqueous solubility will become close to ideal solubility.Furthermore, V2 represents the molecular weight of solute,explaining the deviation from ideal solubility seen in highmolecular weight compounds (e.g. polymers)9. Yalkowsky andValvani deduced that the activity coefficient is also directly

Figure 1. Process of solubilization: (a) removal of solute from the crystallattice (cohesive energy of the solute), (b) creation of solvent cavity(cohesive energy of the solvent) and (c) placing of solute molecule in thesolvent cavity (adhesion energy). (Adapted from Ref. [94]).

876 S. Jain et al. Drug Dev Ind Pharm, 2015; 41(6): 875–887

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related to the octanol/water partition coefficient, Ko/w, as repre-sented in the following equation10,11:

log � ¼ log Ko=w þ 0:94 ð6Þ

Combining Equations (1), (4) and (6),

log Xa ¼ �0:01 T 0m � 25� �

� log Ko=w � 0:94 ð7Þ

Even though Equation (7) cannot be used to estimate the aqueoussolubility for all solutes, especially the ionizable molecule, it maystill provide a theoretical understanding of the physicochemicalproperties that may affect the solute solubility. If a solute has a lowor no melting point at room temperature, but possesses a high logKo/w, its molecular structure is limiting the solubility. Therefore,the aqueous medium needs to be modified to improve solubiliza-tion. On the other hand, if the melting point of the solute is veryhigh and the log Ko/w is low, manipulation of its chemical structuremay be necessary. Furthermore, if a solute has a high melting pointand a high log Ko/w, it can be anticipated that solubilization of thesolute molecule will pose a significant challenge.

Dissolution rate

Dissolution is the pre-requisite for the absorption process andconsequently for the bioavailability of orally administered drugs.Process of dissolution is illustrated in Figure 2. The drug particlein aqueous medium is surrounded by diffusion layer, which acts asa barrier for drug equilibration with the bulk solution. For drugparticle to be dissolved in the bulk solution, it has to diffuse outthrough the diffusion layer, which depends on the concentrationgradient of drug in diffusion layer and bulk solution. Thedissolution rate is therefore defined as the rate at which drugdiffuses across the diffusion layer and can be regulated by theNoyes–Whitney equation12:

dx

dt¼ DA

hCs �

Xd

V

� �ð8Þ

where dx/dt is the dissolution rate, A is the surface area availablefor dissolution, D is the diffusion coefficient of the drug particle,h is the thickness of the diffusion layer adjacent to the dissolvingdrug particle surface, Cs is the saturation solubility of the drugparticle in diffusion layer, Xd is the amount of drug particledissolved at time t and V is the volume of dissolution media. Sincedissolution is performed under sink condition, Xd/V term is rathersmall in comparison to Cs. Furthermore, for small drug molecule,the diffusion coefficient in water is relatively high and manipu-lation of drug structure typically do not have significant impact ondissolution rate13. Similarly, the thickness of diffusion layer,though can be altered by stirring the dissolution medium in vitro,

it is particularly difficult to manipulate in vivo. Most pre-formulation and formulation strategies therefore rely on increas-ing saturated solubility or increasing surface area of the drugparticles.

Pre-formulation and formulation strategies to improvesolubility and dissolution

Salts

Salts are obtained by proton transfer from an acid to a base, withthe formation of stable ionic bond. They are held together by freeenergy of crystal lattice. For solubilization, the free energies ofhydration for cationic and anionic species of the salt in the solventmust be greater than the crystal lattice energy of the salt.Thermodynamically, the process of hydration for salts can beillustrated by the following equation14:

DGsol ¼ DGcation þ DGanion � DGlattice ð9Þ

where DGsol, DGcation and DGanion are molar free energies ofhydration of the salt, its cationic and anionic species, respectively,and DGlattice is the crystal lattice energy (i.e. melting point of thesalt). It is important to note that salt formation results in increasedlattice energy due to intra-molecular ionic interactions evidentfrom the increase in melting point15. This can typically hinder thesolubilization process of the salt. However, the hydration processis also hastened due to the ion–dipole interaction betweendissociated ion and the water, which is thermodynamically morefavorable than the hydrogen bond interaction between the waterand the unionized drug. Thus, the solubility of a salt depends notonly on the crystal structure of the salt but also on the solventproperties. For example, the solubility of a weakly basic drugincreases exponentially with decrease in pH of the solution at thepH range between its pKa and the pH of maximum solubility(pHmax) as shown in Figure 316,17. Based on Equation (8), theincreased saturation solubility in the diffusion layer due to saltformation, ultimately contributes to the enhanced dissolution rate.Therefore, salts formation strategy of a poorly soluble drug canimprove both the solubility and dissociation rate.

The utility of salt formation strategy for various drugs toimprove solubility and dissolution rate has been reported18–23. Inthe recent investigation, the aqueous solubility of delveridinemesylate (320 mg/ml) was improved 2000-fold than its free basehaving intrinsic solubility of 143mg/ml (pH 6.0)18. Similarly,potassium salt of chlorothiazide, a poorly water-soluble diuretic,was prepared to improve aqueous solubility, and at the same timesupplement potassium for diuretic induced hypokalemia19. It wasobserved that the chlorothiazide potassium dihydrate showed a400-fold increase in aqueous solubility than chlorothiazide.

Figure 3. Schematic representation of the pH-solubility profile of a basicdrug. (Adapted from Ref. [27]).

Figure 2. Diagrammatic illustration of the dissolution process of drugparticle.

DOI: 10.3109/03639045.2014.971027 Solubility and dissolution enhancement strategies 877

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Similar finding with other drugs has also been reported in recentpast17,20–23.

The application of some novel techniques for salt formationhas also been observed in current decade24. To avoid the use ofsolvents during salt formation, researchers have focused onpreparing salt form of the drug by applying mechano-chemistryconcept24,25. Mechano-chemistry is an alternative for solutionsynthesis, as it initiates chemical reaction into the solids by theinput of mechanical energy25. Vincamine, a poorly soluble base,was synthesized in salt form by solid excipient assisted mechano-chemical salification (SEAMS) using citric acid as the reagent25.It was observed that the solubility kinetic of SEAMS vincaminesalt was significantly higher than the corresponding salt formprepared by solution based method. Interesting, however, bothsalts were bio-equivalent in rats after oral administration reflect-ing the practical difficulties associated with in-vitro–in-vivocorrelations during drug development process. In a recent study,norfloxacin salts were obtained by forming novel charge-assistedhydrogen bonding between drug and various benzenedicarboxylicacids (supramolecular synthons)26. The solubility of the obtainedsalt (I) form was found to be 39 times higher than that ofnorfloxacin in pure water.

The type of counter-ion in the salt greatly affects its solubilityand dissolution rate27,28. To investigate the influence of counter-ions, haloperidol, a weakly basic drug (pKa¼ 8.0, intrinsicsolubility¼ 2.5mg/ml) was studied with two counter-ion,namely, chloride (hydrochloride) and sulfonates (mesylate) ata pH range of 2–7 (pHmax¼ 5.0)29. It was observed thatthe maximum aqueous solubility of haloperidol mesylate(30.4 mg/ml) was significantly improved in comparison tohaloperidol hydrochloride (4.2 mg/ml). The dissolution rateof haloperidol mesylate was also markedly higher than that ofthe haloperidol hydrochloride, suggesting that sulfonate counter-ion was better alternative than their conventional hydrochloridescounterpart. Recently, an extensive review on the utility ofsulfonate counter-ion in the salt formation during drug develop-ment process has been reported30.

Furthermore, properties of counter-ion such as the symmetryand size, its ability to form hydrogen-bonds with the drug (inaddition to ionic interactions), and the capacity to delocalizecharge affect the crystal lattice energy as well as consequently theaqueous solubility of the salt form of the drug27,28. For example,salts of the weakly basic drug candidate (UK-47880) preparedwith planar aromatic acids like sulfonic or hydroxycarboxylicacids were found to have higher melting temperatures comparedto the aliphatic carboxylic acids (citric acid), that can conse-quently affect the drug solubility and dissolution rate27. It is alsoobserved that counter-ions with less hydrophilicity are moresuitable in enhancing drug solubility. For instance, saccharin saltsof lamotrigine were found to be more soluble than those formedwith the more hydrophilic succinic acid and fumaric acid counter-ions31. Similar findings were also observed from other investi-gations15,32. It is considered that hydrophilic counter-ion thoughpossess with higher solvation energy shows lower solubility(compared with a less hydrophilic counter-ion) because of higherlattice energies32. However, recent study on the effect of aminederived counter-ion (2-amino-2-methylpropan-1-ol, 2-amino-2-methylpropan-1,3-diol and tris-hydroxymethyl-aminomethane) onvarious acidic drugs indicates that addition of hydrophilic groupswithin the amine counter-ion increases solubility, reduces meltingpoint and increases the likelihood of surface activity, up to twoOH groups addition (i.e. 2-amino-2-methylpropan-1-ol and2-amino-2-methylpropan-1,3-diol)15. However, with the add-ition of more than two OH groups (i.e. tris-hydroxymethyl-aminomethane) the solubility of salt form of acidic drugsdecreases15. These findings suggest that perhaps the relationship

between hydrophilic counter-ion and solubility might be a morecomplex phenomenon.

During the drug development process, salt formation strategyis a preferred choice because this strategy is easy to synthesizeand can be screened with small quantity of drug in a microplate.Moreover, the availability of large number of GRAS (generallyregarded as safe) approved counter-ion allows this strategy to becost-effective. However, it is subjected to few limitations. First,the aqueous solubility of hydrochloride salt for a basic drug isoften reduced in gastric fluids (containing chloride ion) due tocommon-ion effects33. It is assumed that selecting the counter-ion, other than the endogeneous ions can reduce the common-ioneffect in the stomach. Interestingly, it has been observed that inpresence of high concentration of endogenous chloride ion, themesylate and phosphate (non-endogeneous counter-ion) salts ofhaloperidol are subsequently converted to hydrochloride saltresulting in slower dissolution rate, suggesting that common-ioneffect of non-endogeneous salt form of the drug should not bedisregarded without investigation34. Second, sometime the saltform with high solubility and dissolution rate may have to besacrificed due to stability issue of that particular form. This can beillustrated in the recent study performed on the salt (maleate) andco-crystal (hemifumarate and hemisuccinate) form of micona-zole35. Even though maleate salt showed highest intrinsicdissolution, hemisuccinate co-crystal was selected due to thepoor stability of salt form. Third, sometime even though the saltformation is possible, it might simply not improve the aqueoussolubility desired for therapeutic efficacy. This is evident from thestudy performed for the selection of salt form for RPR127963, apoorly soluble drug being developed for the treatment ofcardiovascular disease36. RPR127963 (pKa of 4.1) forms astable salt with strong acidic counter-ions, forming the hydro-chloride, mesylate and sulfate salts. However, its solubility wasstill low for parenteral as well as oral formulations. Furthermore,a recent investigation on tribo-electrification effect on variousflurbiprofen salts highlights additional concerns on suitability ofsalt selection strategy for certain drugs, especially duringmanufacturing process37. Tribo-electrification is a solid-stateelectrochemical reaction that causes transfer of charge when theparticles come in physical contact with each other. Thisphenomenon is commonly seen during powder handling oper-ations such as sieving, mixing and milling. It is reported thatexcessive tribo-electrification can cause inter-particle cohesion orrepulsion of other charged materials, which can consequentlycontribute to poor flow properties. Another implication, espe-cially from regulatory standpoint, is that salt form of an approveddrug substance is considered as a new chemical entity byregulatory authorities. The salt form of the drug substance isdesignated as ‘‘pharmaceutical alternative’’ rather than ‘‘pharma-ceutical equivalent’’ to the original form since, depending uponthe counter-ion selected, the behavior of the parent drug in thebody can be influenced by alteration in drug solubility, dissolutionand stability.

Co-crystals

The Food and Drug Administration (FDA) has recently issued aguideline on pharmaceutical co-crystals that defines co-crystals as‘‘solids that are crystalline materials composed of two or moremolecules in the same crystal lattice’’38. In general, co-crystalinclude drug along with appropriate co-former that can beselected from GRAS list. Co-crystal can be constructed throughseveral non-covalent types of interaction, including hydrogenbonding, pi–pi stacking and van der Waals forces. Co-crystalformation is favored when the non-covalent intermolecularinteractions between the functional groups on the drug and the

878 S. Jain et al. Drug Dev Ind Pharm, 2015; 41(6): 875–887

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co-former are thermodynamically favorable over intra-molecularinteractions between two drug molecules39. The major advantageof this strategy is that, apart from enhancing solubility anddissolution rate, these co-crystals are crystalline in nature withdefinite stoichiometry that improves its solid-state stability.

The preparation of co-crystal can be performed by variousmethods that include solution crystallization, mechanical grind-ing, and melt crystallization40–43. Among them, solution crystal-lization is most common utilized, where the co-crystalcomponents are taken in an appropriate stoichiometric amountand dissolved in a suitable solvent and then the solvent is allowedto evaporate or the solution is allowed to cool. However, there aresome disadvantages associated with this method. Less solublecomponent can instantaneously crystalize out leading to partial orno crystallization44. Furthermore, this technique requires largevolume of organic solvent and can also hinder the co-crystal’sintermolecular interaction leading to formation of solvates orhydrates44. More advance techniques like mechano-chemicalmethod where grinding is performed in the absence of solventor ‘‘liquid assisted grinding’’ (LAG) also referred to assolvent drop grinding (SDG), where small amount of solvent isincorporated, have also gained popularity for preparing co-crystals. Compared to traditional techniques, these advancepreparation techniques are more cost-effective, green, and reliablefor discovery of new co-crystals as well as for preparation ofexisting co-crystals45.

Co-former selection is an important aspect in developingco-crystals. The selection is generally based on the ‘‘synthon’’approach. The synthon approach is based on the fact that there arespecific functional groups within the drug and co-former structurethat play pivotal role in co-crystal formation and therefore involvein creating a ‘‘supramolecular synthons’’ within the co-crystal byutilizing these specific functionalities46. Functional groups thatare typically utilized for pharmaceutical co-crystals formationinclude carboxylic acids, amides, carbohydrates, alcohols andamino acids. More recently conductor-like screening model forreal solvents (COSMO-RS), based on fluid-phase thermo-dynamics was utilized for accurately screening the co-former forco-crystal preparation47. The approach is based on the comparisonof the excess enthalpy between a drug and a co-former mixturerelative to the pure components, which reflects the tendency ofthese compounds to co-crystallize.

As with the interactions of a drug and its counter-ion in asparingly soluble salt, solubility of co-crystals, due to influenceof co-former, can be explained by the following equations:

A�B� �!Ksp

A� þ B� ð10Þ

Ksp ¼ A� � B� ð11Þ

where Ksp represents the solubility of co-crystal, A and Brepresent the drug and its co-former respectively, while � and �represent their corresponding activity coefficients respectively. InEquation (10), for 1:1 ratio of co-crystal of drug (�¼ 1) andco-former (�¼ 1), the co-crystal is in equilibrium with their freeentity (A and B) in the solution. In this case, the activitycoefficients for A and B in solution are assumed to be unity andthe activity of the solid crystal invariant. Both assumptions holdtrue for sparingly soluble systems13,48. It can be concluded fromEquations (10) and (11) that solubility of co-crystals dependson the concentration of co-former in the solution, and similar tothe common ion effect for sparingly soluble salt, increase inco-former concentration decreases the solubility of drug.

Despite the aforementioned similarities with the salt form,co-crystals are uniquely different. In contrast to salts, where theionized components in the crystal lattice are held by the ionic

interaction, co-crystals are in a neutral state and interact via non-ionic interactions. Also co-crystals, unlike salts, can be preparedfor both ionizable and non-ionizable drugs. In fact, even forionizable drugs, co-crystal provides a greater flexibility since thenumber of co-formers available for co-crystal formation exceedsthe number of approved counter-ions for salts49. Furthermore, asdiscussed elsewhere, the salts of strong acid or base are generallymore hygroscopic in nature resulting in stability problems. In acomparative study, despite the intrinsic dissolution of itraconazolesalt (dihydrochloride and trihydrochloride) was higher than that ofthe 2:1 co-crystal of itraconazole and malonic acid, co-crystalstrategy was selected, as salt form was found to be highlyhygroscopic50.

Considering the solubility advantage of co-crystal approach,recently emphasis has shifted to develop strategies to predictpharmaceutical co-crystal solubility during early drug develop-ment phase51–53. In a recent investigation, it was found that co-crystal solubility could be readily characterized by evaluating theeutectic point at the three-phase equilibrium between two solidphases (i.e. co-crystal and drug or co-former) and one solutionphase54. The theoretical relationship between eutectic constants(Keu) and co-crystal solubility for 1:1 stoichiometric ratio of drugand co-former can be expressed by the following equation:

Keu ¼Co-formerð Þeu

Drugð Þeu

¼ Sco-crystal

Sdrug

� �2

ð12Þ

where Keu is eutectic constant, (co-former)eu and (drug)eu areco-former and drug in eutectic phase respectively, whileSco-crystal and Sdrug are solubility of co-crystal and drug, respect-ively. According to Equation (12), a Keu greater than one indicatesthat the 1:1 co-crystal is more soluble than the parent drug.Determination of Keu can therefore provide a valuable predictivetool for estimating solubility advantage of co-crystal approach.

Recent studies on co-crystals have shown promising resultsin enhancing drug solubility and the dissolution rate35,55–59. Theco-crystal of ezetimibe with benzoic acid and salicylic acidrespectively showed a 222- and 480-fold increase in the aqueoussolubility while 1.97- and 2.14-fold increase in dissolution rate incomparison to pure ezetimibe60. The solubility and dissolutionrate of exemestane as well as megestrolacetate were significantlyimproved by forming the novel co-crystals namely exemestane/maleic acid and megestrol acetate/saccharin61. Similarly, incontrast to pure carbamazepine, its co-crystals with nicotinamideco-former showed a 1.5- and 2.5-fold increase in intrinsicdissolution rate at stoichiometric ratio of 1:1 and 1:2 (drug:co-former), respectively62. The increase in intrinsic dissolution ratein comparison to carbamazepine was attributed to decrease inmelting point of the co-crystals formed. In one of the investiga-tion, fluoxetine HCl was co-crystallized with benzoic acid (1:1),succinic acid (2:1) and fumaric acid (2:1) by a chloride-mediatedcarboxylic acid supramolecular synthon approach. Powder dis-solution study indicated that drug dissolution from fluoxetineHCl:benzoic acid co-crystal was significantly lower while thefluoxetine HCl:fumaric acid co-crystal was marginally higherthan fluoxetine HCl. In contrast, fluoxetine HCl:succinic acid co-crystal exhibited a 2-fold increase in aqueous solubility after only5 min compared to fluoxetine HCl. This study highlighted the factthat similar kind of interaction (chloride-mediated carboxylic acidsupramolecular synthon) between co-former and drug can resultin different aqueous drug solubility based on type of co-former63.In one of the interesting studies, co-crystal approach was appliedon a prodrug, adefovir dipivoxil, to improve aqueous solubilitywhile simultaneously provide stability towards its chemicaldegradation64. It was assumed that forming co-crystal by insertinga co-former would separate the original packing of adefovir

DOI: 10.3109/03639045.2014.971027 Solubility and dissolution enhancement strategies 879

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dipivoxil molecules in crystal lattices and will therefore improveaqueous solubility as well as chemical stability of the prodrug.The results indicated that adefovir dipivoxil-saccharin co-crystalenhanced the aqueous solubility almost three times than that ofadefovir dipivoxil. This is due to the fact that when weakly acidicco-former (saccharine) component of the co-crystal comes incontact with water, it dissociates and reduces the pH from 6.7 to3.1, which facilitates the dissolving process of the weakly basicadefovir dipivoxil. Furthermore, because of weakly acidic natureand higher aqueous solubility of saccharine, a weakly acidicmicro-environment is created, which might inhibit the hydrolyticdegradation of adefovir dipivoxil. Despite enhanced solubilityadvantage of co-crystals, there are certain considerations thatshould be critically acknowledged. Formulating co-crystals withhigher ratio such as 1:2 or 1:3 stoichiometry, decreases thecontent of active ingredient and results larger dose administra-tion65. Furthermore, the ‘‘supramolecular sython’’ approach forselection of co-former does not take into account for thecompetition among the different functional groups presentedwithin the drug or the co-former, which can prevent formation ofordered crystalline structure. Also, from regulatory standpoint,FDA requires an assurance that complete dissociation of the drugfrom its excipient occurs prior to reaching the site of action forpharmacological activity, which could pose some additionalchallenges during regulatory filing.

Prodrug

Prodrugs, in general, are inactive compound that are chemicallyor enzymatically transformed to biologically active compound. Ithas been widely utilized for improving solubility, metabolicstability, permeability and reducing toxicity66. In particular, theprodrug strategy can be used to improve the aqueous solubility,either by addition of polar moiety (phosphates and esters) or bychange in crystal lattice of the active drug.

In a study performed on hydroxymethyl derivative ofnitrofurazone, the solubility of hydroxymethylnitrofurazone(0.992 mg/ml) was found to improve 1.5-fold than that ofnitrofurazone (0.657 mg/ml) with substantial decrease in meltingpoint. This was attributed to the replacement of a hydrogen atom(bound to a nitrogen) by a hydroxymethyl group that caneventually decreases the intra- or inter-molecular hydrogenbonds, leading to a consequent diminution of the melting pointand an enhancement in water solubility67. Amprenavir is an HIVprotease inhibitor approved by the FDA in 1999 for treating HIVinfection. However, due to limited aqueous solubility, multiplepills for a single dose are given. In order to circumvent thisproblem, fosamprenavir prodrug of amprenavir was introduced inthe market in 200368. Fosamprenavir was synthesized byphosphorylating the secondary alcohol of amprenavir68. Byenhancing the solubility by 10-fold in comparison to the parentdrug, fosamprenavir prodrug reduced the overall pill burden (twotablets replaced eight amprenavir softgels). In another study,prodrug approach was utilized to improve the aqueous solubilityof SNS-314, a selective aurora kinase inhibitor. It was found thephosphonooxymethyl-derived prodrug had significantly enhancedsolubility and was converted to the biologically active parentfollowing intravenous as well as oral administration to rodents69.Similarly, valganciclovir and valacyclovir, valine esters ofacyclovir and ganciclovir, respectively, utilized prodrug approachto improve solubility and hence the bioavailability66,70.

Particle size reduction

Reduction in particle size to improve solubility and/or dissolutionrate is one of the most common strategies used in drugdevelopment process. Mathematically, the relationship between

the solubility and particle size is depicted by the Ostwald–Freunlich equation71:

lnS

S0

¼ 2�V

rRT¼ 2M�

�rRTð13Þ

where, r is the radius of small particles, S is the solubility of smallparticles, S0 is the solubility when r approaches infinity, � is thesurface tension, M is the molecular weight, � is the density ofparticle, V is the molar volume, R is the gas constant and T is theabsolute temperature. For example, a compound with a molecularweight of 500, � of 1 g/ml and a � value of 15–20 mN m�1,Equation (13) would predict an enhanced solubility of 10–15% ata particle size of 100 nm71. The importance of particle size andsurface area in improving solubility can be molecularly under-stood based on Figure 1. During the placement of solute in solventcavity, if the solute size is small, the surface area to volume ratioincreases allowing greater interaction between them. However,for most pharmaceutical powders (large particle size rangingfrom 1 to 10 mm), the estimated solubility enhancement usingEquation (13) is only less than 1%9.

A much greater impact of particle size reduction is ondissolution rate. According to the Noyes–Whitney equation[Equation (8)], reduction of particle size increases the dissolutionrate not only by increasing saturation solubility but also bydirectly affecting the surface area available for dissolution. Inaddition, researchers are also in agreement with the thickness ofdiffusion layer is decreased with decrease in particle size72,73.

Among various techniques available for particle size reduction,micronization techniques like jet milling, ball milling, and pinmilling are the most common. However, the lowest particle sizethat can be achieved by conventional milling is about 2–3 mm16.Various studies have also reported to improve oral bioavailabilityby nano-sizing technique74–78. Nano-sizing can be achieved by theusing bottom-up or top-down approaches. The bottom-upapproach involves the growth of small particles from individualmolecules by controlled precipitation from supersaturated solu-tion. Some of the commercially successful examples of bottom-upapproach are Gris-PEG� (griseofulvin in PEG8000) andCesamet� (nabilone in PVP)79. Techniques involving bottom-upapproach to prepare nano-crystal include solvent evaporation,supercritical fluid and controlled crystallization during freeze-drying (CCFD). Among these techniques, supercritical fluidstechnology (SCT) is the most preferred bottom-up approach.Commonly used SCT technology includes rapid expansion ofsupercritical solutions (RESS), gas antisolvent system (GAS),supercritical antisolvent (SAS) precipitation technique, and aero-sol solvent extraction system (ASES). In a study performed usingthe RESS technology, the dissolution rate of nano-sized griseo-fulvin was found to be about 2-fold higher than the micronizedmaterial80. Vitexin, a poor water solubility, micronized using SAStechnique showed almost 3.5 times improvement in dissolutionrate compared to unprocessed drug81. Similarly, ipratropiumbromide was successfully micronized by ASES technology toimprove the particle shape and size characteristics for pulmonaryuse82. A comprehensive review on the utility of supercritical fluidon particle size reduction was also recently published83.

Another technology that has gained importance as a bottom-upapproach is controlled crystallization during freeze-drying(CCFD). In this technology, non-toxic organic solvent, in whichthe drug is dissolved, along with an aqueous solution of matrixmaterial (e.g. sugar) is freeze-dried at elevated temperature toallow the drug and matrix to crystallize84,85. Recently, fenofibratenano-crystals, prepared using CCFD technique by freeze-dryingthe mixture of organic solution of fenofibrate with aqueoussolution of mannitol, exhibited a significantly higher dissolution

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rate in comparison to physical mixture of fenofibrate andmannitol85.

Compared to the bottom-up approach, top-down approach ismost widely accepted by the pharmaceutical industry. In thisapproach, mechanical attrition is induced to render large crystal-line particles into nano-sized particles. In a comparative studyusing top-down (wet milling) and bottom-up (microfluidic nano-precipitation) techniques for hydrocortisone nano-suspensions,both techniques were able to achieve a mean diameter ofapproximately 300 nm as well as comparable ocular bioavailabil-ity86. However, top-down wet milling approach showed a higherstorage stability as compared to bottom-up microfluidic nano-precipitation technique. Similar finding was observed in thecomparison of bottom-up (liquid anti-solvent precipitation) andtop-down technique (wet milling) for glipizide nano-suspensions.It was observed that top-down technique is better in terms ofstorage stability, especially at 40 �C/75% RH after 6 months withcomparable particle size87.

Despite various techniques available for top-down approach,high-pressure homogenization and wet milling are most com-monly used. Nano-sized crystals produced by high-pressurehomogenization of UCB-35440-3 (a poorly water-soluble, weakbase) had shown a significant improvement in dissolution rate atpH 3.0, 5.0 and 6.5 compared to its un-milled form88. Recently,nano-suspension of NVS-102, a model drug (free base) ofNovartis Pharma, prepared by wet milling technique showed asignificantly higher dissolution rate (485% in 10 min in 0.01 NHCl with 0.1% sodium lauryl sulfate) and consequently higherAUC (area under the plasma concentration versus time curve) andCmax (maximum drug concentration in plasma) as compared toun-micronized drug suspension89. In an interesting comparison ofRapamune tablets containing sirolimus NanoCrystals prepared bywet milling and Rapamune� solution containing co-solvents andsurfactants, the former showed a 27% increase in oral bioavail-ability attributed to the improved dissolution rate ofNanoCrystals90.

Combination techniques, which utilizes bottom-up and top-down techniques together, have also recently gained popularity. Itis suggested that compared to conventional technique (eitherbottom-up or top-down), combination technique involving bothtechniques together can improve the effectiveness of particle sizereduction91. Baxter is one of the pioneers that have introducedcombination technique approach called Nanoedge� for perform-ing nano-sizing. The technique utilizes bottom-up step (micro-precipitation) followed by a top-down step (high-pressurehomogenization). Briefly, the drug is dissolved in a water-miscible, non-aqueous solvent and then precipitated in form of asuspension consisting of brittle drug particles. This suspension isfurther processed by high-pressure homogenization to a nano-suspension. However, the major limitation of this technology isthat the non-aqueous solvent can act as a co-solvent, which mayincrease the solubility of the drug to an extent that could lead tophysical and chemical instability92. To avoid this limitation,alternative combination techniques like the H 69 technology(cavi-precipitation followed by high pressure homogenization),the H 96 technology (freeze-drying followed by high pressurehomogenization) and the H 42 technology (spray-drying followedby high pressure homogenization) has also been utilized93.

While employing particle size reduction strategy to improvedissolution rate, the effective surface area of drug particlesavailable to the dissolution medium will reduce resulting inslower rate of dissolution, if the drug is hydrophobic and thedissolution medium have poor wetting property9. This is evidentfrom the study where two types of spray-dried particles ofgriseofulvin (i.e. plain griseofulvin and griseofulvin withPoloxamer 407) were produced94. The in vitro dissolution studies

showed that the spray-dried griseofulvin/Poloxamer 407 exhibitedthe highest dissolution rate, followed by spray-dried plaingriseofulvin and the control (raw griseofulvin), respectively.Although spray dried plain griseofulvin increased the in vitrodissolution rate, no significant improvement was observed in theabsolute oral bioavailability as compared to the control. Based onthe contact angle measurement performed later, it was concludedthat spray-dried plain griseofulvin particles have a wettingproblem.

Another common problem associated with the nano-sizedparticles is the agglomeration of the particle7. This phenomenonis commonly referred as Ostwald ripening, which indicates masstransfer from the fine to coarse particles leading to crystal growthand agglomeration due to higher solubility of fine particles in thesolvent compared to coarse particles. This may impact the shelflife of the nano-suspensions as well as dissolution and in vivoperformance95. Therefore, nano-suspension form is preferablytransformed into a solid product, which can pose additionalchallenges. For example, freeze-drying and spray drying are themost commonly used to convert a nano-suspension into a solidform. However, it can result in powders that require furtherprocessing to improve the bulk density and flow properties priorto conversion into a tablet or a capsule dosage form96. Recently, anovel one-step process for converting a liquid stabilized nano-suspension into a solid formulation was introduced which involveshot-melt extrusion combined with an internal de-volatilizationprocess (NANEX)97. In this process, a polymer followed bystabilized aqueous nano-suspension is fed in the extruder and thesolvent (water) is removed by de-volatilization leading toformation of solid extrudates, which contains nano-crystals inthe de-aggregated form.

Amorphous solids and solid dispersion

Converting crystalline drug compounds to their amorphouscounterparts has been widely utilized to improve kinetic solubilityand dissolution rate7,98. In order to recognize the true solubilityadvantage of amorphous substances, it is important to understandthe thermodynamic changes associated with amorphization.Figure 4 represents the schematic plot of the enthalpy (H) andspecific volume (V) of a solid substance, both indicated by bluesolid line, as a function of its temperature. When the melt iscooled slowly, it crystallizes out at melting temperature (Tm) dueto a sudden decrease in H and V. However, upon rapid cooling, Hand V may follow equilibrium line bypassing Tm into the super-cooled liquid region (non-equilibrium state). As the temperaturedecreases and the viscosity increases in this region, marked

Figure 4. Schematic representation of enthalpy (H) or specific volume(V) versus temperature where Tg is glass transition temperature, Tm ismelting temperature while the solid blue line represents both the enthalpyand specific volume.

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reduction in molecular motion occur until the motion is reducedto a limit where rate of molecular rearrangement is less than therate of temperature change. This subsequently results in change ofslope as a function of temperature at a characteristic temperatureknown as glass transition temperature (Tg). The Tg represents theconversion of super-cooled liquid to a glassy state having evenhigher H and V than the super-cooled liquid. As a result, theamorphous state represents enhanced thermodynamic propertieswith greater molecular motion resulting in higher apparent orkinetic solubility and dissolution rate than the crystallinestate99,100.

Although the high-energy amorphous solid exhibits higherkinetic solubility, it can also induce thermodynamic instabilityleading to relaxation, nucleation and crystal growth phenomenaafter achieving the super-saturation in the dissolution media101.The relative super-saturation index (�) depends on the intrinsicsolubility of a drug and can be expressed as:

� ¼ C�Cs

Cs

ð14Þ

where C is the concentration of drug in the solution and Cs is thesaturation drug concentration102. The process of crystallization isinitiated with nucleation followed by crystal growth, where the �is the driving force for crystallization, and a higher magnitudeof � can lead to rapid crashing out of the drug. A very rapidprecipitation from highly supersaturated layer on the formulationcan therefore cause surface crystallization hindering the dissol-ution itself. Thus, to maintain an enhanced flux across the gastro-intestinal membrane, it is important not only to attain a highersuper-saturation state but also to prolong it for a longer durationby inhibiting the crystallization process103.

Therefore, pure amorphous drugs are typically not developedas such to a commercial dosage form, but are combined with otherexcipients (generally amorphous) that can maintain and prolongsuper-saturated state of the amorphous drug. One such approach isamorphous solid dispersion (ASD). In this approach, the hydro-phobic drug is molecularly dispersed within the polymer matrixto form a single-phase amorphous mixture of the drug and thepolymer. The effect of polymer on drug super-saturation state canbe explained by ‘‘spring’’ and ‘‘parachute’’ model102. ASD canessentially be described as a compressed mechanical spring thatcontains stored potential energy. When ASD is placed in thedissolution media, the potential energy is released and thedispersion ‘‘springs’’ the drug into a supersaturated state. Sincesuper-saturation is thermodynamically unstable, the formulationmust provide a ‘‘parachute’’ to keep the solubility from rapidlyreturning to the crystalline drug equilibrium solubility. In general,solubility enhancing polymers are considered to function as aparachute or stabilizer by interfering with nucleation and/orcrystal growth. It is speculated that the polymer in ASD increasesthe overall phase transition temperature (Tg) of the amorphousmixture that lowers the mobility of the drug molecules in thepolymer matrix and consequently reduces the formation of crystalnuclei104–106.

Polymer selection is therefore an important variable that needsto be considered for ASD approach. Effect of polymer type onsolubility and dissolution rate has been widely studied in recentpast107–109. In the study on solid dispersion of tacrolimus withthree different polymers [polyethylene glycol 6000 (PEG 6000),polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose(HPMC)], the maximum supersaturated concentrations of tacro-limus from these three formulations were almost similar and wereabout 25-fold higher (about 50mg/ml) than the solubility oftacrolimus in the dissolution media110. The dissolution profile oftacrolimus in PEG 6000 and PVP showed that the supersaturated

level of tacrolimus rapidly decreased and was only about 6 and30 mg/ml after 24 h respectively, which was attributed to therecrystallization of the drug. Similarly, in recent study, thesolubility and dissolution of ASD formulation of ellagic acid withPVP, carboxymethyl cellulose acetate butyrate (CMCAB), andhydroxypropylmethyl cellulose acetate succinate (HPMCAS)were studied. At pH 6.8, relative solubility of ellagic acid inthese polymers was PVP4HPMCAS4CMCAB. However, only35% of ellagic acid was released using HPMCAS at pH 6.8 while,the ellagic acid crystallized out in acidic medium using PVP111.

Since screening of the polymer is crucial and time consumingprocess, researches have been focused on developing effectivescreening tools for polymer selection. In this regards, a newapproach called miniaturized screening of polymers for amorph-ous drug stabilization (SPADS) with small amounts of materialshas been recently developed112. Basically, it comprises of twosteps. First, drug dissolution is performed in 96-well plates todetect systems that can generate and maintain super-saturation.Promising drug–polymer combinations are then subjected SPADSinteraction (by Fourier transform infrared spectroscopy) andSPADS imaging assays (by atomic force microscopy). Similarly,Hansen solubility parameter approach, which is well knownpredictive tool for miscibility of liquids, was tailored and appliedfor evaluating polymers for ASD formulation113. However,more focused research is required to explore improved predictivetools for this purpose.

Once an appropriate drug-polymer combination is selected, thenext crucial variable is the preparation technique for ASDformation. ASD formulations are commonly prepared by hotmelt extrusion (HME) and spray drying technologies. HME is acontinuous process that involves conveying of drug and the carrierpolymer through rotary screw extruder, under controlled condi-tions of temperature and shears, to obtain melt extrudes. HMEis advantageous for commercial manufacturing because it is acontinuous and scalable technique. Furthermore, it does notrequire the use of organic solvents that can consequently reducethe cost and alleviates safety and/or environmental concerns.Another commonly used technique to prepare ASD is spraydrying. In spray drying, a drug solution (aqueous or organic)along with formulation components (polymers) is atomized;whereby the solvent is evaporated and spray dried dispersionparticles are obtained. The method is readily scalable from gram-sized batches during discovery and early development to kilogramand metric ton quantities during later stage manufacturing andcommercialization. However, like HME, spray drying is notsuitable for thermo-labile material. To overcome such impedi-ment, novel electrospray drying has been introduced. In electro-spray drying, solvent evaporation from the atomized droplets takeplace using ambient temperature and pressure. For drugs, whichare thermo-labile and have poor solubility in the solvent, HME,spray drying as well as electrospray drying might not be suitable.For such drugs, KinetiSol� dispersing technique, a novel fusion-based process for preparing ASD has recently been introduced114.In this technique, drug–polymer blend is rapidly converted to themolten state by applying a combination of frictional and shearwithout utilizing external heat. During the conversion to themolten state, drug along with its polymeric carrier is rapidlymixed on a molecular level to achieve a single-phase ASDsystem115. The advantage of this technique is that it is a rapid,non-solvent process where the drug is typically exposed toelevated temperature for less than 5 s.

Several researches have shown the solubility advantage ofASD using the aforementioned technologies. In the recent inves-tigation, ASD of ABT-102 (solubility in buffer, 0.05 mg/ml)prepared by hot melt extrusion improved the apparent solubilityand molecular solubility up to 200 times and 2 times respectively,

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in comparison to crystalline ABT-102116. ASD formulationsof tranilast (a weakly acidic drug) with Eudragit EPO demon-strated a 3000-fold increase in dissolution rate at pH 1.2 ascompared to crystalline drug117. Solid dispersion of fenofibratewith Eudragit E100, prepared by HME, showed higher dissolutionrate as compared to physical mixture of drug and polymers118.ASD formulation of curcumin and polyvinylpyrrolidone (PVP)prepared by spray drying showed complete dissolution within30 min as compared to their physical mixture, which exhibitednegligible dissolution even after 90 min in 0.1 N HCl119.Amorphous form of the salt has also been utilized as a noveltechnique to improve the aqueous solubility of drug by combiningthe solubility enhancing potential of amorphous and saltform23,120. For example, amorphous furosemide sodium, preparedvia spray drying, showed a significantly higher apparent solubilityand dissolution rate as compared to amorphous and crystallinefree acid120. In a recent investigation, solid dispersion ofketoprofen with PVP obtained via electrospray drying showedalmost complete release in 1 min in comparison to pure drug andits physical mixture121. Furthermore, in a study performed toevaluate the feasibility of KinetiSol� technique for itraconazolesolid dispersion, it was observed that KinetiSol� techniqueproduced a single-phase solid dispersion and higher dissolutionwhile reducing the processing time by factor of 20 as compared toHME114. ASD approach for improving the solubility and dissol-ution rate has also been reported by other researchers104,122–125.Despite promising results, commercial success of ASD approachis rather limited. Since the drug is in supersaturated state in ASD(one phase system), the variation in processing and storageconditions may cause phase separation106. Also, ASD isassociated with poor scale up of the manufacturing processalong with laborious and expensive method of preparation.Furthermore, as discussed earlier, effective and less timeconsuming techniques are required to screen appropriate polymerfor ASD formulations.

Co-solvents

As shown in Figure 1, the network in the process of removingsolute and placing it in the solvent cavity can be mathematicallyrelated to activity co-efficient as7:

log � ¼ W11 þW22 � 2W12 ð15Þ

where W11 represents the cohesive energy of solvent, W22 is thecohesive energy of solute and W12 is the adhesive energy betweensolvent and solute. In case of poorly soluble solutes in water, W11

is very large, because of which activity co-efficient is high andconsequently solubility is low. Upon addition of co-solvent, W11

becomes closer in value to W22, which results in both factorsbecoming more similar to W11. This leads to decrease in activityco-efficient and improvement in solubility.

In general, the solubility of drug in a co-solvent system can bedescribed as follows126:

log Smix ¼ log Sw þ �f c ð16Þ

where Smix and Sw are the solubility of non-polar solute in co-solvent mixture and water, respectively, fc is the co-solventfraction and � is the solubilizing power of the co-solvent. The �term in this equation is solely a function of activity co-efficient.Equation (16) indicates that on a linear scale, solubility willincrease exponentially with the increase in co-solvent fraction.

Drug candidates to be considered for co-solvent approach arethe ones that lack ionizable groups rendering them unsuitable forpH adjustment strategies and those with moderate lipophilicity(log P between 1 and 3) that show relatively low affinity forsolubilization by surfactants or lipids127. The solubility advantage

using co-solvents approach has been studied with variety ofdrugs128–130. Aqueous solubility of toxaphene in various solvents(methanol, ethanol, isopropanol and propanol) was found toincrease as a function of co-solvent fraction increase in water131.The aqueous solubility of various drugs was improved with2-pyrrolidone as co-solvent compared to glycerin, propyleneglycol, polyethylene glycol 400 or ethanol132. In particular,N-methyl pyrrolidone (NMP), a derivative of 2-pyrrolidone, hasbeen widely studied for its solubilization efficiency133,134. In astudy with 13 poorly soluble drugs, up to 800-fold solubilityenhancement was obtained in 20% v/v NMP solution as comparedto that in water. The solubility enhancement was attributed to thenon-polar carbon of NMP that weakens the hydrogen bonding ofwater enabling the co-solvent effect of NMP134. In past decade,combination of co-solvent with other formulation strategies hasalso been successfully studied. The addition of Poloxamer-188 tothe PEG-400/water systems containing cyclodextrin showedsignificant increase in the solubility of valdecoxib135.

Although co-solvent approach can enhance solubility anddissolution rate of the drug to several magnitudes, its success ismainly limited due to toxicity effects, especially at high concen-trations. Furthermore, due to the exponential dependence of co-solvent fraction on the solubility of the drug, dilution can lead tothe precipitation of the drug.

Selection of suitable solubility enhancement technique

The decision of selecting suitable solubility enhancement tech-nique depends on various parameters. The formulator need to firstestablish the core reason that is causing solubility issues in theparticular drug, especially during early drug discovery ordevelopmental phase. This could be achieved by physio-chemicalprofiling, quantitative structure–property relationship (QSAR)study or available historic literature. Fragment-based models (e.g.E-state indices, group contribution approach, molecular topology,etc.) that are based on the summation of individual contributionsof atoms, molecules or larger structure motif are widely utilized topredict molecular properties especially aqueous solubility andpartition co-efficient136. Although this approach is useful forestimation of partition co-efficient, it is not particularly suitablefor estimation of solubility, where intramolecular hydrogenbonding along with electron donating or accepting contributionsof substituents can play a complex role in defining aqueoussolubility. However, fragment contributions approach can facili-tate to understand the effect of crystal packing in the drugmolecule on aqueous solubility137. Furthermore, software likeSparc Performs Automated Reasoning in Chemistry (SPARC) canalso provide useful information regarding solute–solventinteraction.

After establishing the reason for poor aqueous solubility of thedrug molecule, formulator can prudently select the solubilityenhancement technique for the particular drug molecule. Asdiscussed elsewhere, if a drug molecule has a high log Ko/w, butpossess low melting point at room temperature, then its molecularstructure is rate-limiting factor for the drug solubility. In suchinstances, modifying the aqueous medium can be more beneficialfor drug solubilization. On the other hand, if the drug moleculehas low the log Ko/w but possess high the melting point,manipulation of its chemical structure may be necessary. Alsoin some cases, modification of aqueous medium as well aschemical structure may be required to achieve desired drugsolubility and dissolution rate enhancement. Once the reason ofpoor aqueous solubility is identified and possible solubilityenhancement techniques are narrowed down, various rapid miniscreening tools (SPADS, COSMO-RS, 96 well-plate in vitrodissolution) can be utilized to analyze the feasibility of these

DOI: 10.3109/03639045.2014.971027 Solubility and dissolution enhancement strategies 883

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selected techniques for the improvement of solubility or/anddissolution enhancement of specified drug.

Furthermore, other relevant factors like processing conditions,stability, toxicity, and permeability of the drug or formulationmust also be considered. For example, ASD approach is generallynot suitable for thermo-labile drugs due to extreme temperaturesencountered during processing. Similarly, European regulatoryauthorities have recently shown some serious concerns for the useof sulfonate counter-ion due to potential formation of genotoxicsulfonate esters, emphasizing the caution required for selection ofcounter-ion during salt formation approach30. It is thereforeprudent to avoid one-size-fit-all approach when selecting anappropriate pre-formulation and formulation strategies for enhan-cing drug solubility and dissolution rate. The decision of selectinga suitable strategy should not only be based on the effectiveness ofsolubility and dissolution rate enhancement but also on the gamutof other formulation, process and bio-pharmaceutical relatedfactors.

Conclusion

Despite various pre-formulation and formulation strategies avail-able in the armor of formulation scientist, poor aqueous solubilityof compounds still is an overriding problem in the pharmaceuticaldrug development process. Compounds with low aqueous solu-bility and dissolution rate can significantly affect the in vitro andin vivo performance and subsequently imposes significant burdenswith respect to time and money during drug development.Partially, the problem can be attributed to our obliviousness tounderstand and apply the theoretical concept of solubility anddissolution rate in selecting suitable pre-formulation and formu-lation strategies. It is important to acknowledge the physico-chemical property of the drug and its limitations before decidingthe suitable pre-formulation and formulation strategies.Furthermore, other formulation, process and bio-pharmaceuticalfactors must also be considered.

Acknowledgements

The authors acknowledge St. John’s University for providing financialassistance and research facilities.

Declaration of interest

The authors report no conflicts of interest. The authors alone areresponsible for the content and writing of this paper.

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