Solid Dispersions for Oral Administration: An Overview of the Methods for their Preparation

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1 Send Orders for Reprints to REVIEW ARTICLE Current Pharmaceutical Design, 2016, 22, Solid Dispersions for Oral Administration: An Overview of the Methods for their Preparation François Hallouard a,b,d*, Lyes Mehenni c, Malika Lahiani-Skiba a,d, Youssef Anouar d and Mohamed Skiba a,d a Laboratoire de Pharmacie Galénique Biopharmacie, Faculté de Médicine & Pharmacie, Université de Rouen, Rouen, France; b Service de Pharmacie, Centre Hospitalier Asselin Hédelin, Yvetot, France; c COBRA, UMR/CNRS 6014, Université de Rouen, Mont- Saint-Aignan, France; d DC2N Inserm U982, Université de Rouen, Mont-Saint-Aignan, France A R T I C L E H I S T O R Y Received: June 1, 2016 Accepted: July 26, 2016 DOI: / Abstract: Oral drug delivery remains the most physiological and therefore the most preferred, simplest and easiest administration route. Nevertheless, a multitude of potentially clinically important drugs will not reach the market or achieve their full potential unless their oral bioavailability is improved by formulation. The aim of this review is to present an overview of properties, formulation, excipients and characterization of solid dispersions corresponding to one of the different formulation strategies for design and development of poorly soluble drugs. This work will review and compare in detail the evolution of solid dispersions focused on the different methods of formulation and production of solid dispersions, their stability, their release properties, their pharmacokinetics and methods for their physicochemical characterization. Keywords: Bioavailability, carrier, dissolution rate, preparation methods, solid dispersion, solubility enhancement methods. François Hallouard 1. INTRODUCTION Oral drug delivery remains the most physiological and therefore the most preferred, simplest and easiest administration route [1]. Because of the greater stability, smaller bulk, accurate dosage and easy production, solid oral dosages forms have many advantages over other types of oral dosage forms. The development of a successful and effective oral medicine is however often faced with a number of challenges. One of them is the fact that drug s bioavailability influenced by its solubility, dissolution and gastrointestinal permeability [2]. Indeed, bioavailability is becoming very important due to the increase in the number of new chemical entities with medicinal potential that have poor water solubility. Many potentially clinically important drugs will not reach the market or achieve their full potential unless their oral bioavailability is improved by formulation. After a brief description of formulation strategies based on the biopharmaceutics classification system and of the other solubilization methods, this paper will review and compare in detail the evolution of solid dispersions. The discussion will be focused on the different methods of formulation and production, stability properties, release properties, pharmacokinetics and methods for physicochemical characterization of solid dispersions. The aim of this review is to present an overview of the properties, formulation, excipients and characterization of solid dispersions for design and development of poorly water soluble drugs. 2. FORMULATION STRATEGIES BASED ON BIOPHAR- MACEUTICS CLASSIFICATION SYSTEM Understanding the physicochemical and biopharmaceutical properties of drugs is important in the design of pharmaceutical products. To achieve this, Biopharmaceutics Classification System *Address correspondence to this author at Laboratoire de Pharmacie Galénique Biopharmacie, Inserm U982, Faculté de Médecine & Pharmacie, Université de Rouen, F-76183, Rouen, France; Tel: ; francois.hallouard@univ-rouen.fr (BCS) was developed as useful tool for decision-making in formulation development from a biopharmaceutical point of view [3]. The BCS categorize drug substances into one of four categories based on their solubility and intestinal permeability. These four categories are defined as follows: high solubility/high permeability (class I), low solubility/high permeability (class II), high solubility/low permeability (class III), and low solubility/low permeability (class IV). According to the US Food and Drug Administration (FDA), a substance is considered highly permeable when the extent of its absorption in humans is 90% or more of an administered dose [4]. Likewise, a substance is considered highly soluble when its highest dose strength is soluble in 250 ml or less of aqueous media over the ph range of at 37 C. Classification of drug candidates based on the BCS can provide an indication of the difficulty of the development effort. For BCS class I or III drugs, formulations strategies are straightforward. BCS class I drugs presents no bioavailability difficulties. For BCS class III drugs, their bioavailability is rate-limited by the membrane permeability in the gastrointestinal tract. There are a few formulation solutions to enhance their permeability. The first solution is to improve the intrinsic lipophilicity of the drug for an increased transcellular passive transport [5]. The drug s intrinsic lipophilicity is determined by its chemical structure; therefore, it is necessary to design a new chemical entity with potential pharmacological alterations. Another solution is to use permeation enhancers such as fatty acids, bile salts, surfactants, and polysaccharides. These substances can enhance the permeability of hydrophilic drugs via the paracellular pathway. However, some of them are known to induce membrane damage [6,7]. Bioavailability of BCS class II drugs is directly influenced by their solubility and dissolution rate as per the modified Noyes- Whitney equation: /16 $ Bentham Science Publishers

2 2 Current Pharmaceutical Design, 2016, Vol. 22, No. 00 Hallouard et al. This equation provides the relation between dissolution rate (dc/dt) and the surface area available for dissolution (A), the diffusion coefficient of the compound (D), the drug solubility in dissolution medium (C s ), the drug content in the medium at time t (C) and the thickness of the diffusion boundary layer adjacent to the surface of the dissolving compound (h). BCS class IV drugs exhibit challenging molecular properties due to their low solubility and low permeability. Since both solubility and permeability are rate-limiting steps for absorption, physiological factors, for example gastric emptying time and gastrointestinal transit time, highly influence the absorption of BCS class IV drugs. Therefore, drugs categorized in BCS class IV can exhibit large inter- and intra-subject variability in terms of absorption [8]. This variability in absorption is another challenge for drug development as well as their formulation design. There are viable formulation options focusing on improvement of the dissolution behavior that are commonly applied to BCS class II drugs. However, the approaches for enhancing their permeability are still at an early investigational stage. In this context, formulation approaches similar to those for BCS class II drugs could be practically applied to BCS class IV drugs, even though the absorption may be limited by the poor permeability after dissolving in the gastrointestinal tract. 3. SOLUBILIZATION METHODS Different solubilization methods will modify one or more of the modified Noyes-Whitney equation factors to enhance drug solubility by altering either chemical or physical properties of drugs, dissolution medium characteristics or including drug in a carrier (Fig. 1). To obtain an optimal or required drug solubilization, several solubilization methods will be often combined Physical Drug Modifications Drug Size Reduction and Nano-Suspensions The first and simplest method to improve drug dissolution is to increase its surface area by decreasing the particle size [9]. Therefore, the wetting characteristics of drug s surface, the boundary layer thickness and, last but definitely not least, the apparent solubility of the drug under physiologically relevant conditions will be ameliorated. The ultimate goal is to obtain a molecular dispersion combining the benefits of a local increase in the solubility and maximizing the surface area of the compound that is exposed to the dissolution medium. It nevertheless worth to note that drug size reduction brings some disadvantages such as a strong tendency for particle agglomeration and higher risk of drug alteration due to oxidation or hydrolysis. To prevent particle re-agglomeration after drug size reduction, nano-suspensions (also known as nano-crystals) can be made and stabilized using surfactants. Indeed, due to the uniform and narrow particle size range obtained, nano-suspensions eliminate potential concentration gradient factor avoiding therefore Ostwald ripening. However, drugs in crystalline state will have lower solubility compared to the amorphous ones. For example, the solubility difference between amorphous and crystalline forms have been reported to be between 1.1- and 1,000-fold [10,11]. Another solution to avoid particle re-agglomeration is the use of solid dispersions which will be discussed below. Further information about drug size reduction and nano-suspension preparation process, indications and characterization has been given in other reviews [12-14] Polymorphs and Pseudopolymorphs Polymorphism and pseudopolymorphism are approaches to enhance solubility and dissolution rate of solids that involve altering the molecular networks in two main ways: (i) by changes in supramolecular arrays of the same component (crystalline and amorphous states) corresponding to polymorphism and (ii) by changes in molecular components of the network by means of noncovalent forces (co-crystals, solvates, salts) corresponding to pseudopolymorphism [15]. It is worth to note that the incorporated solvent molecules or solvates in pseudopolymorphs are classified in terms of structure as isolated lattice sites, lattice channels, or metalion coordinated solvates. Fig. (1). Summary of the various formulations and chemical approaches usable for enhancing drug solubility.

3 Solid Dispersions for Oral Administration: An Overview of the Methods Current Pharmaceutical Design, 2016, Vol. 22, No The main difference between polymorphs and pseudopolymorphs is that polymorphs have the same chemical composition but different lattice structures and/or different molecular conformations. Therefore, the differences in solubility of polymorphs are solely due to crystal structure changes. On the other hand, solubility of pseudopolymorphs is influenced by both physical and chemical alterations. Due to their less structured layout reducing the molecular interactions between the different drug molecules, amorphous forms have higher solubility than crystalline forms. However, amorphous forms are thermodynamically metastable and have a tendency to evolve and to re-crystallize. Therefore, drug solubility of an amorphous form will depend on it preparation method, storage condition as well as storage time. The different methods used to form polymorphs or pseudopolymorphs are well described in recent reviews [15,16] Chemical Drug Modifications The main chemical drug modification is the preparation of water-soluble produgs by chemical derivatization [17,18]. This strategy utilizes esterification of a drug s hydroxyl, amino or carboxyl group with a moiety (progroup) designed to introduce an ionizable functional group or reduce intermolecular interactions responsible for low solubility. Prodrug strategies may also include the coupling of drug solubilization with membrane barrier targeting. Besides, the use of spacer group could be useful for the introduction of derivatizable functional groups and/or for the position of ionizable progroups in order to allow their in vivo hydrolysis. The main inconvenience of produg strategies is the fact that a prodrug is a new chemical entity that requires a complete toxicological evaluation before commercialization Modifications of Dissolution Medium Characteristics Co-Solvents Weak electrolytes and non-polar molecules frequently have poor water solubility. Their solubility usually can be increased by the addition of a water miscible solvent in which the drug has good solubility. This process is known as co-solvency and the solvents used in combination to increase the solubility of solute are known as co-solvents [19]. The main co-solvents used in pharmaceutical field are ethanol, propylene glycol and polyethylene glycol [20]. The principal disadvantage of the use of co-solvents is that at high concentrations - such as over 5 % (v/v) of ethanol - they may lead to undesirable side effects, especially in neonates [21] Hydrotropes and Surfactants Hydrotropes and surfactants are amphiphilic molecules that can increase aqueous solubility of otherwise insoluble compounds [22]. The main difference between hydrotropes and surfactants is the ability of the latter ones to form well organized structures such as micelles. In addition, strong synergetic effects are often observed when hydrotropes and surfactants are used together [23]. Like for co-solvents, the principal disadvantage of hydrotropes and surfactants is that their high proportion in formulation may lead to undesirable side effects [21] Modification of ph of Dissolution Medium The modification of dissolution medium s ph via buffering is a good option for ionizable drug. Adjustment of ph is frequently combined with co-solvents for further improvement of drug solubility [20]. This approach to formulation strategy development is simple and quick. Nevertheless such formulation strategies have three main limits: (i) the adjusted ph should be compatible with the chosen drug administration route; (ii) the drug could become less soluble and precipitate upon dilution in physiologic fluids after administration; and (iii) drug ionization that improves its solubility could negatively affect its permeability Solubilizing Vehicles Solubilizing vehicles may consist of organic solvents which are water immiscible. Their use in orally administered medications is constrained and complicated by many factors. They may not exert sufficient solubilizing action to be of practical value unless a low drug dosage is used. Otherwise, the required volume of such solvents cannot readily containe a convenient drug dose Solubilization Methods Using Carriers Complexes To enhance solubility of poorly water soluble drugs, several macrocyclic cavity-shaped molecules were used. These are highly hydrophilic substances having a hydrophobic cavity that can form complexes with supramolecular assemblies with drugs. The cavity size correlates with the number of units composing the macrocyclic molecules. In addition, such macrocyclic molecules can prevent molecular aggregation leading to drug precipitation in amorphous or crystal forms. Cyclodextrins and their derivatives are the most notable of such compounds. Cyclodextrins are cyclic oligosaccharides typically having 6 (α-cyclodextrins), 7 (β-cyclodextrins) or 8 (γ-cyclodextrins) α-d-glucopyranoside units [24]. Other structures that were described are: calyxarenes composed of phenolic units linked by methylene or sulfur groups [25], cucurbiturils composed of glycouril units linked by methylene groups [26], porphyrins composed of four modified pyrrole subunits linked by methine bridge, and crown ethers [27].The main limitation of this method is that not all drugs can form inclusion complexes with macrocyclic cavityshaped molecules Nanometer-Scale Carriers Several nanometer-scale carriers were also used to increase the solubility of poorly water soluble drugs. Carriers of lipidic or polymeric nature are liposomes, emulsions, dendrimers, micelles, spheres and capsules. Due to their size, all these carriers are much more unstable than microparticles because of the extra Gibbs free energy contribution related to reducing particle size and being primarily due to surface energy [28]. To prevent particle agglomeration, several approaches are used. These can be categorized in two groups: (i) thermodynamic stabilization which uses surfactant or block co-polymers or (ii) kinetic stabilization which uses energy input to compensate for Gibbs free energy [28]. Frequently, these two types of approaches are combined for maximum effectiveness. It is worth to note that the amount and the nature of stabilizer should be carefully chosen - too little of the stabilizer allows particles to agglomerate and too much of the stabilizer promotes Ostwald ripening [29]. Liposomes consist of amphiphilic phospholipids self-assembled into vesicular structures [30]. The cavities offered by the liposome aqueous cores makes these nano-objects prime candidates for carrying and protecting different hydrophilic or hydrophobic compounds at the same time. Nano-emulsions are nanometer-sized emulsions typically exhibiting diameters ranging from 20 to 200 nm [31,32]. These emulsions are also frequently known as mini-emulsions, finedispersed emulsions or submicron emulsions. They are characterized by a great stability in suspension due to their very small size. Dendrimers are polymeric molecules composed of a series of polymeric branches linked together by an inner core [33,34]. Dendrimer structures are well-controlled and well- defined, potentially exhibiting a high functionality and allowing low polydispersity in spite of their large molecular mass. Poorly water soluble compounds can be encapsulated in the inner structure of dendrimer or bound at dendrimer surface. Micelles are self-assembled, mainly spherically shaped molecular clusters in water [35]. These nanoparticles are formed when the concentration of surfactant rises above the critical micelle concentration (CMC). When the bulk phase is aqueous, micelles have an inner hydrophobic core and an outer

4 4 Current Pharmaceutical Design, 2016, Vol. 22, No. 00 Hallouard et al. hydrophilic shell, a structure which allows them to carry different hydrophobic compounds. Finally, nanometer-scale spheres and capsules are the most common formulations of polymeric molecules. Spheres are solid matrix particles and capsules having a core/shell structure in which the surrounding shell has a solid polymeric structure and the reservoir core can be liquid or semisolid at room temperature [36]. Depending on the hydrophobicity of their core, capsules can solubilize both hydrophilic and lipophilic compounds. 4. SOLID DISPERSIONS 4.1. Definition Solid dispersion was initially defined as a eutectic mixture of a hydrophobic compound with a water-soluble and physiologically inert carrier like urea [1]. Accounting for all the recent innovations, solid dispersion could be now defined as a dispersion of one (or more) active ingredient(s) in an inert carrier or matrix at solid state. The substances can be mixed completely or partially, containing several phases [37,38]. The drug in solid dispersion can be dispersed as molecules, as amorphous particles, or as crystalline particles. The matrix can also be in crystalline or amorphous state. By improving the drug bioavailability through better wettability, enhanced porosity, and polymorphic changes, solid dispersions show many important advantages in comparison with other solubilization techniques. In conventional formulations particles easily agglomerate in the formulation, during dissolution process, or during storage [14,39]. In solid dispersions, the interaction between the drug and the carrier prevents agglomeration of drug particles allowing a particle size reduction up to molecular levels. The lack of agglomeration in solid dispersions allows to avoid the use of long and complex novel nanosizing processes which require stabilizers as well as special equipment [12,14]. The possibility of dramatic particle size reduction to improve drug solubility is complemented by the dissolution or water absorption of carrier molecules surrounding drug particles thus increasing drug wettability, especially when surfactants or emulsifiers are incorporated in solid dispersions. This reduces the risk of agglomeration of drug particles in the dissolution media and the drug is released in supersaturated state which is advantageous for rapid absorption due to the Fick s laws of diffusion. Potential drug precipitation due to supersaturation in the dissolution media will form submicron particle, that are smaller than drug particles produced by other techniques [40,41]. The precipitated drugs may also exist in different amorphous forms which have lower thermodynamic stability than crystalline drug particles, leading to faster dissolution in in vivo situations. Generally, a drug dispersed in a solid dispersion is in a amorphous form even if this compound was in crystalline form before formulation optimization [42]. The polymorphic state of drugs in solid dispersions is mainly determined by the preparation process and the physicochemical interactions between drug and carrier [43]. Solid dispersions produced by solvent methods (see section ) tend to have a highly porous structure induced by the fast solvent removal and leading to increased drug dissolution rate [44]. The choice of the polymer as hydrophilic carrier also influences solid dispersion porosity: linear polymers often lead to higher solid dispersion porosity than reticular ones [45]. From the point of view of the clinical use, solid dispersions were mainly designed for oral administration (Table 1). For this administration route (except for populations having swallowing difficulty such as infants or patients requiring nasogastric tube [32]), solid forms result in better patient compliance than formulation in liquid or gas state. Moreover, solid dispersions can be formulated in oral dosage forms which are more acceptable for patients than liquid products produced by solubilization method [46]. Indeed, solid forms prevent most of dosing errors because they are ready to use and are easier to transport and store Drug release Mechanisms The purpose of making hydrophobic drugs into solid dispersion formulation is to disperse the drug into the hydrophilic matrix so that the hydrophilic matrix can dissolve prior to the drug in the gastrointestinal fluid. The drug dispersed in the matrix can then be saturated in the gastrointestinal fluid increasing drug bioavailability when the solid dispersion drug is taken orally. Drug release from solid dispersions involves two main types of mechanisms which often exist simultaneously at different proportions: drug diffusion and carrier-controlled release (Fig. 2) [48,49]. Considering drug diffusion, this mechanism will occur in two steps. The first step is the water absorption at the surface of the formulation inducing either a carrier layer or gel layer around the solid dispersion. These layers can be designed in order to control Table 1. Examples of current solid dispersion-based pharmaceutical formulations [42,47]. Formulation Drug Carrier Process Form FDA approval a Cesamet Nabilone PVP Solvent evaporation Tablet 1985 Sporanox Itraconazole HPMC Fluid bed bead layering Capsule 1992 Prograf Tacrolimus HPMC Spray drying Capsule 1994 Kaletra Lopinavir/ritonavir PVPVA Melt extrusion Tablet 2007 Intelence Etravirin HPMC Spray drying Tablet 2008 Zortress Everolimus HPMC Spray drying Tablet 2010 Norvir Ritonavir PVP Melt extrusion Tablet 2010 Onmel Itraconazole HPMC/PVP Melt extrusion Tablet 2010 Incivek Teleprevir HPMCAS-M Spray drying Tablet 2011 Zelboraf Vemurafenib HPMCAS Solvent/anti-solvent precipitation Tablet 2011 a Data taken from the US FDA website

5 Solid Dispersions for Oral Administration: An Overview of the Methods Current Pharmaceutical Design, 2016, Vol. 22, No drug release. Indeed, the viscosity and the thickness of the layer influence drug diffusion through the layer and therefore drug diffusion in the bulk phase. The second step corresponds to drug diffusion through solid dispersion layer that is influenced by properties, such as drug solubility, particle size and polymorphic state. The carrier-controlled release mechanism is the quick dissolution of this matrix in water leading to a massive drug release. The hydrophilic carrier is generally not dissolved immediately, thus inducing the two other carrier-release mechanisms: slow carrier dissolution and carrier erosion. It is worth to note that during slow carrier-dissolution, drug diffusion will occur. If drugs and carriers are well dispersed in internal structure of solid dispersions, carrier-controlled release via the diffusion of drugs through the matrix will be the main mechanism. If drugs and carriers exist in separate particles, the solid dispersion erosion may become the predominant mechanism for drug release. All these release mechanisms can explain and predict the different drug-release behaviors of solid dispersions. It was described in several works that the improvement of drug dissolution profile was correlated to the ratio of carrier(s) to drug in solid dispersions. This observation revealed that in some situations the drug-diffusion is the predominant release mechanism. This release behavior could be explained by both a better dispersion of drug in the formulation and a prevention of crystal formation [50]. Other publications demonstrated, on the contrary, a decrease of drug dissolution rate when the proportion of carrier in solid dispersions increased [51]. In these cases, the mechanism will depend on the dissolution rate of the hydrophilic carrier. If the dissolution rate is very rapid, the predominant release mechanism is the carrier-controlled release. The gel or concentrated carrier layer formed at the beginning of the solubilization of solid dispersions, acts as a diffusion barrier delaying drug release. Another possibility is the crystallization of the amorphous carrier above a critical proportion in the solid dispersion slowing its dissolution and therefore reducing the importance of drug-controlled release mechanisms versus the other three main release mechanisms [44]. The last explanation for such a decrease in dissolution rates is the ratio of drug to carrier in solid dispersions [52]. The proportion of the drug in solid dispersions determines the main mechanism of drug release - it is drug diffusion at low drug content and erosion at high drug content. These results showed the importance of studies on the carrier properties such as solubility, polymorphic state, viscosity and gel forming ability at different ratios of drug to carrier in order to improve dissolution profiles of solid dispersions Classification of Solid Dispersions Solid dispersions can be classified based on different aspects such as their release profile, their preparation processes or their composition. When we talk about solid dispersion generations, it is very common to classify solid dispersions according to their composition (Fig. 3) First Generation The first generation solid dispersions correspond to crystalline solid dispersions. In such solid dispersions, drug is dispersed within a crystalline carrier forming a crystalline mixture [53]. For example, the first crystalline solid dispersions described for a pharmaceutical application was an eutectic mixture of sulphathiazole (drug) with urea (hydrophilic carrier) [1]. Simple eutectic mixture is usually prepared by rapid solidification of the fused liquid of two components which show complete liquid miscibility and negligible solid-solid solubility [54]. The melting point of such mixtures is lower than the melting point of the drug and carrier whereas in the monotectic mixture, the melting points of the carrier and drug are constant. In addition, eutectic mixtures release a fine crystalline form of drug enhancing the dissolution rate. This is due to the simultaneous crystallization in solid dispersion of both drug and carrier resulting in a well-dispersed state of the drug in carrier [37,55]. However, if the mixture of the drug and carrier is not exactly at the eutectic composition, there will be a partial separation of the two components leading to superfine dispersion of drug in the carrier. This is the consequence of the crystallization of one component until the eutectic composition is reached. As a result, only few of studied solid dispersions had exact eutectic composition [48]. Solid solutions are made up of a solid solute dissolved in a solid solvent [53]. Such solids are also called mixed crystals because the two components together in a homogeneous one-phase system [54]. Solid solutions improve drug dissolution rate compared to eutectic mixture, because the drug particle size in formulation is reduced to its molecular size [37]. Solid solutions can also be classified according to the extent of miscibility between drug and the carrier into two groups: continuous (or isomorphous, unlimited, complete) solid solutions and discontinuous (or limited, restricted, Fig. (2). Mechanisms of drug release from a solid dispersion and drug bioavaibility.

6 6 Current Pharmaceutical Design, 2016, Vol. 22, No. 00 Hallouard et al. Fig. (3). Generations of solid dispersions. partial, incomplete) solid solutions. Continuous solid solutions in which the two components are miscible in every proportion, have not been applied to pharmaceutical products [56]. In contrast, in a discontinuous solid solution, the solubility of each component is limited. Each component is capable of dissolving the other component to a certain degree above the eutectic temperature. In reality, some solid-state solubility can be expected for all two-component systems nevertheless it is typically small enough to be considered negligible [55]. Goldberg et al. suggested that from a practical standpoint a solid solution can be considered as discontinuous when the solubility of one component in the other is greater than 5% [37]. Solid solutions could also be classified based on the obtained crystal structure. In substitutional solid solutions, the solute molecules substitute for the solvent ones in the crystal lattice of the solid solvent. The size of solute and solvent molecules should be as close as possible. According to the Hue-Ruthery rule, the size difference should be less than 15% [57]. In interstitial solid solutions, the solute (or guest) molecule occupies the interstitial space of the solvent (or host) lattice. Unlike substitutional solid solutions, interstitial ones are mainly discontinuous solid solutions. In additions, the apparent diameter of the solute molecules in interstitial solid solutions should not exceed 0.59 of the solvent [57]. Drug entrapped in crystalline solid dispersion could also precipitate in amorphous form rather than in crystalline one. In such cases, drug has a higher Gibbs free energy leading to a faster drug dissolution and absorption rates. For example, amorphous form of novobiocin has 10-fold higher dissolution rate than its crystalline form [58]. For the preparation of crystalline solid dispersions, carriers that exhibit promising properties are sugars like sorbitol and mannitol [59], polymers like poly(ethylene glycol) (PEG) over 4,000 Da and poloxamers [41,60] or urea [1]. The main advantage all the crystalline solid dispersion types have in common is the high thermodynamic stability of the carriers that prevents drug particle aggregation (thus allowing for a large surface area and better wettability of drug) and the conversion of amorphous drug to crystalline forms by minimizing the molecular mobility in formulation [61]. The crystallinity of such solid dispersions is however also a significant drawback. Indeed, crystalline compounds have lower Gibbs free energy (and, correspondingly, a lower dissolution rate) than amorphous ones Second Generation The second generation of solid dispersions corresponds to drug dispersion within an amorphous carrier (typically a polymer) [62]. This carrier type came into use at the end of 1960s, its better efficiency in drug release compared to the crystalline ones explained by the lower thermodynamic stability of amorphous solid dispersions [63,64]. Therefore, as solid dispersion techniques developed, materials used as carriers have been changed from crystalline ones such as urea or sugar to amorphous ones (including polymers). The first solid dispersion of this generation was developed for itraconazole, a water insoluble antifungal drug (aqueous solubility ~ 4 ng/ml) [47]. According to the solid state of a drug, amorphous solid dispersions can be classified into glass solutions (amorphous solid solutions), amorphous solid suspensions and a mixture of both. In glass solution, drug and amorphous carrier are completely miscible to form molecularly homogenous mixture while amorphous solid suspension consists of two separate phases [42]. If the drug has limited carrier solubility or an extremely high melting point, an amorphous solid suspension may form [65]. Such systems induce a dispersion of amorphous drug particles in amorphous carriers. An important point is that when an amorphous component is present in formulation, it could exist in different amorphous states and also be present in crystalline state. This has an impact on in vivo behavior of this component. The interaction between the drug and carrier is also important for carrier selection. Some drugs have plasticizing effect on polymers or form hydrogen bonds with carriers. It is therefore possible to control the particle size or crystalline or amorphous drug form as a function of the amorphous carrier [52,66]. These interactions can affect the formulation process, physical properties and stability of the solid dispersions and/or the drug dissolution rate. Solid dispersions can be classified by the nature of their amorphous carriers in two classes: those employing synthetic polymers, and those employing natural polymers. All these amorphous carriers are soluble in multiple solvents and thus well designed for solid dispersion formulation. In addition, these polymers improve drug's wettability due to their high water solubility. Only crospovidone does not have this last property due to its ability to quickly swell in contact to water and enhance the drug release rate [67]. The examples of synthetic polymers are PEG and povidone (PVP), and natural polymers are hydroxypropylmethyl cellulose (HPMC) and sugar glass (trehalose, sucrose, inulin). It is worth to note that the molecular weight of polymers is a very important factor. The polymer viscosity of polymer solutions has a negative influence on their aqueous solubility. Thus, a too high viscosity can hinder the drug dispersion in carrier during the preparation process and thus decrease the drug dissolution rate when solid dispersions are dispersed in water. However a high polymer viscosity also prsents some advantages like the prevention of drug s recrystallization during the preparation process, the storage and the dissolution process. Sugar carriers such as trehalose, sucrose and inulin can induce a drug precipitation via formation of large drug crystals during the dissolution of solid dispersion in aqueous medium [68]. Indeed, these carriers exhibit an extremely fast dissolution rate inducing an

7 Solid Dispersions for Oral Administration: An Overview of the Methods Current Pharmaceutical Design, 2016, Vol. 22, No important burst release of drugs in the near vicinity of the dissolving solid dispersions. Among the different sugars, inulin exhibits the slowest aqueous dissolution rate and therefore the lowest crystallization risk [69]. One can also achieve a release control, for example, by using HPMCP or HPMCAS as carrier to avoid drug release in the stomach [70]. Similarly to the first generation solid dispersions, a drug in amorphous solid dispersions is dispersed in very small size particles (molecules, amorphous particles or small crystals). At the same time, a drug exists in supersaturated state in amorphous carriers because of forced solubilization [62,71,72]. Generally, a dispersed drug is supersaturated in amorphous solid dispersions carrier [73]. These properties increase the wettability and dispersibility of drugs associated with the faster dissolution rate of amorphous carriers due to the low thermodynamic stability of amorphous state carriers enhancing the drug solubility and release rate [74,75]. The high dissolution rate of the amorphous carriers leading to drug surpersaturation in dissolution medium can be, however, an important drawback. Indeed, if drug s diffusion through physiological membrane is not fast enough, it could precipitate in amorphous or even crystalline form, thus limiting its absorption. In addition, the amorphous nature of carrier allows, in absence of drug-carrier interactions, progressive drug crystallization in solid dispersion which leads to compromised physicochemical characteristics (such as solubility, particle size, uniformity and dissolution) and thus to an altered pharmacokinetic profile of solid dispersion. This phenomenon is due to the difference in aqueous solubility between the amorphous carrier and drug [76]. The multiple factors influencing carrier crystallization (such as molecule s mobility, preparation methods or preparation conditions) are still poorly understood. An interesting and exhaustive review of our knowledge on this solid dispersion aspect was made by Laitinen et al. [77] Third Generation The third-generation solid dispersions are, like the previous generation, amorphous dispersions. However, in the third generation, an additive is used in order to improve the biopharmaceutical performance of the supersaturation systems. Such additives are mainly surfactants, self-emulsifiers or inclusion/complexation agents that prevent the drawbacks of the second generation: drug crystallization in dispersion during storage or in vivo drug precipitation by supersaturation in dissolution medium [13,73]. The surface activity which prevents drug nucleation and agglomeration in carrier may improve physical and chemical in vitro stabilities [56]. In addition, surfactants reduce the drug recrystallization rate in dissolution medium by absorbing to the outer layer of drug particles or forming micelles to encapsulate drugs. Surfactants mentioned in the literature for their utility as additives are: glyceryl behenate (Compritol 888 ATO ) [78], Inutec SP1 [79], Neulisin [80], polyoxyl castor oil (Kolliphor EL ) [81], polysorbate (Tween 80 ) [82,83], poloxamer [84], d-αtocopheryl poly(ethylene glycol) succinate (TPGS 1000 ) [85], sodium lauryl sulfate [86], sucrose laurate [87], lauroyl macrogol- 32 glycerides (Gelucire 44/14 ) [88] and polyvinyl caprolactam - polyvinyl acetate - polyethylene glycol copolymer (Soluplus ) [89]. Inutec SP1 is a derivative of inulin prepared by the reaction between isocyanates and the polyfructose backbone. As seen before (in section ), inclusion/complexation agents, by separating the drug molecules, prevent drug agglomeration in formulation and drug precipitation in dissolution medium after in vivo release. Indeed, inclusion/complexation agents avoid a supersaturation of the free form of drug and therefore precipitation risks [44,90-92]. At the end, the presence of these additives in solid dispersion increases drug dissolution profile [42]. The main potential drawback of the third generation of solid dispersions is the potential heterogeneity of drug and/or additive in the amorphous carrier. This risk is greater in the third generation than in the first or second generation of solid dispersions due to the use of at least three required substances (carrier, drug and additive Fourth Generation The fourth generation of solid dispersions adds one or both of the two innovative aspects to the previous generations of amorphous dispersions. The first aspect consists of prevention of drug or additive heterogeneity in solid dispersion by the development of amorphous polymeric carriers having surfactant properties or incorporating complexing/inclusion agents [93-97]. Therefore, due to the fact that polymer plays simultaneously the role of carrier and additive, the heterogeneity risk will be comparable to the first or second generation of solid dispersions with the advantages coming from the third generation of such formulations. The second aspect corresponds to the design of solid dispersions having a controlled drug release. Indeed, the aim of the previous generations of solid dispersions was to increase as much as possible drug bioavailability producing a profound but short-lived increase in drug concentration in the blood. However, such drug release profile could have negative clinical consequences with poorly water soluble drugs having short biological half-life (e.g. adenosine) and/or narrow therapeutic range (e.g. theophylline). The design principle of solid dispersions having a controlled drug release is that molecular dispersion of poorly water soluble drugs in carriers will improve the drug solubility while the solid dispersion carriers (e.g. water insoluble, swelling or ph sensitive) are used to control or retard the drug release in the dissolution medium [98]. The main drug release mechanisms in this generation are thus diffusion and erosion. Therefore, such solid dispersion are able to deliver an adequate amount of drug for an extended period of time improving patient compliance due to less frequent administration, fewer side effects and more constant or prolonged drug effect [99,100]. The water insoluble or slowly-soluble polymers used as carriers in the design solid dispersions having a controlled drug release include: acrylic polymers [98,100], carboxyvinylpolymer [101], ethyl cellulose [99], hydroxypropylcellulose [71], and poly(ethylene oxide) (PEO) [42]. For ph sensitive effect, PEO + ph modifier (Na 2 CO 3 ) [102] or simply hypromellose can be used [49] Preparation of Solid Dispersions The different methods of solid dispersion preparations could be classified in 4 categories: co-milling methods, melting methods; solvent methods; and melting solvent methods (Fig. 4) Co-Milling Methods Co-milling method is a simple and easily scalable process for solid dispersion formulation. Briefly, drug and carrier are mixed for hours without solvent or heating to obtain a homogeneous solid [103]. This method can also reduce the size of drug particles and convert the drug from crystalline to amorphous form [104,105]. It is hypothesized that milling at low temperature favors the amorphization tendency, whereas milling above T g may generate crystalline forms [106,107]. Nevertheless, it is worth to note that this method is not regarded as promising because solid dispersions prepared by co-milling method were found to be more heterogeneous, formed weakest drug-polymer interactions and showed lowest physical stability [103,106] Melting Methods The melting methods are suitable for heat stable materials with low melting points. The basic principle of such methods consists of melting together drug and carrier at a temperature slightly above their eutectic point, mixing the liquefied components and then cooling this mix in order to obtain a homogeneous solid dispersion. The resulting dispersion can be crushed, sieved or pulverized to reduce the particle size. Alternatively, before the cooling, the mix could be

8 8 Current Pharmaceutical Design, 2016, Vol. 22, No. 00 Hallouard et al. injected into dosage forms and then cooled without undergoing milling step [42]. The main advantages of melting methods are their simplicity, their relatively low cost and the absence of solvent (that limits formulation-induced toxicities and hazards). However, melting methods also exhibit some disadvantages that can have significant impact on in vivo behavior of poorly water soluble drugs: insufficient drug stability in the carrier at high temperature, drug solubility in the carrier at heating temperature leading to drug heterogeneity in solid dispersion, and, in some cases, lower porosity of the final product (compared to other methods, especially solventbased ones). To limit these disadvantages, several adaptations on the basic melting method were proposed. Concerning the risk of drug or carrier alteration at elevated temperatures, a modified technique reduces the heating duration of by dispersing the drug in molten carrier instead of heating both of the components at the same time to obtain molten mixture [108]. Two processes that employ this adaptation were patented - MeltDose (Lifecycle Pharma A/S) and Lidose (SMB laboratory). In MeltDose process a drug incorporated in molted carrier is sprayed onto inert carrier particles by using fluid bed equipment which is the originality of this process [109]. The obtained particles can be formed into tablets or capsules. This patented process was used, for example, to manufacture an FDA approved formulation Fenoglide TM (fenofibrate tablet). Concerning Lidose technology, a drug, after mixing with melted carrier, is filled into hard capsules and cooled under specific and constant conditions. (http: // formulation/lidose). The risk of drug heterogeneity in solid dispersions can be prevented by using the Hansen solubility parameter predicting the drug-carrier miscibility [110,111]. In some cases, the use of surfactants by increasing drug miscibility in carrier at high temperature is required. It is however important to note that a large amount of surfactant in solid dispersion can induce the formation of a gel layer during product dissolution in water; this layer acts like a diffusion barrier and in consequence delays drug release [51]. In addition, the tensio-active properties of surfactants (such as PEGylated castor oil) may change as a function of temperature. Therefore, with or without surfactant, it is important to perform a rapid cooling to prevent any demixing phenomenon. A rapid mix cooling also prevents drug recrystalization in solid dispersion during the formulation process allowing a faster dissolution rate of drug in in vivo dissolution medium. The main cooling methods for solid dispersions are: ice bath agitation [53], incubating Petri dishes inside a dessicator [112], immersion in liquid nitrogen [113], spreading on a thin sheet of stainless steel cooled by air or water [63], and spray congealing technique. The latter technique consists of spraying a hot molten mixture into an environment maintained at temperatures below the carrier melting point [114,115]. Recently, hot melt extrusion was developed to obtain a homogeneous drug/carrier mix and therefore limit the risk of drug heterogeneity in solid dispersions. This method consists of simultaneously mixing, heating, melting, homogenizing and extruding drug and carrier in a form of tablets, pellets or other pharmaceutical forms [116]. The rotating screw induces an intense mixing leading to the disaggregation of drug particles in carrier. Thus, a homogeneous solid dispersion is obtained [74]. The main advantages of this process are its efficiency, simplicity of scaling-up and the possibility of continuous production [117]. In addition, hot melt extrusion has the advantage of limiting the residence time of drug and carrier at elevated temperature in the extruder reducing also the risk of component alterations due to the temperature [41]. That is why this technology has been used to design many drug delivery systems such as immediate and controlled release tablets, granules, pellets, implants, transdermal drug delivery systems, and ophthalmic ocular inserts [118]. Meltrex TM, a patented and modified process of hot melt extrusion, uses a special twin screw extruder with two independent hoppers. This equipment reduces the residence time of drug at high Fig. (4). Proposed classification for solid dispersion preparation processes.

9 Solid Dispersions for Oral Administration: An Overview of the Methods Current Pharmaceutical Design, 2016, Vol. 22, No temperature to approximately 2 minutes and therefore limits the risk of its alteration [73]. Concerning an amorphous solid dispersions prepared by melting method, the final products are often soft, sticky and have poor flow properties and poor compressibility which hinder their applications in a large-scale pharmaceutical tableting [119]. To limit these drawbacks, melt agglomeration method can be used where the chosen carrier acts as a meltable binder. In this method, also using a high shear mixer or rotary processor, the mixture can be prepared using one of three processes: addition of molten carrier containing the drug to the heated excipients [109,120], addition of molten carrier to a heated mixture of the drug and excipients [84], or heating a mixture of the drug, carrier and excipients to a temperature within or above the melting range of the carrier [120]. It is worth to note that the rotary processor may be preferable to the high shear mixer in melt agglomeration technique because the temperature can be more easily controlled and higher binder content can be incorporated in the agglomerates [62] Solvent Evaporation Methods The solvent evaporation methods were developed mainly for heat unstable components because drug/carrier mixing will be performed by a solvent instead of heat. Therefore, these methods also allow the use of carriers having a melting point which is too high for melting methods. The basic principle of such methods consists of dissolving drug and carrier in a volatile solvent in order to mix them homogeneously [53]. Then, a solid dispersion is obtained by evaporating the solvent under constant agitation. Similarly to the melting methods, the precipitated solid dispersion can be crushed, sieved or pulverized to reduce the particle size. The main advantage of solvent evaporation methods is, as we stated above, the absence of heat that limits alteration risks during the formulation process of heat unstable components. Such methods also produce a more porous final product than do the melting methods, thus resulting in a favorable dissolution rate of the solid dispersion. Nevertheless, when the stability and bioavailability enhancement of solid dispersions prepared by melting methods are ensured, melting methods are actually preferred over the solvent evaporation ones in preparation of solid dispersions [42]. Indeed, solvent evaporation methods present several drawbacks reducing their scalability due to the use of volatile solvent, such as higher costs due to the equipment for solvent extraction step and additional protection needed to mitigate the explosion risks due to the solvent. In addition, solvent evaporation methods may result in a residual solvent remaining in the final product, which is a potential source of toxicity and also may alter the solid dispersion s properties. For example, concerning the alteration of these properties, traces of water in solid dispersion can lower the T g and act to plasticize the system leading to phase separation due to the increased mobility of components [121]. Also, rapid solidification rates are required in solvent extraction methods to prevent drug heterogeneity in solid dispersion and drug crystallization during the formulation process. To limit these drawbacks, the design of solvent evaporation methods is centered on several adaptations concerning the choice of volatile solvent or co-solvent and the solvent extraction method. Concerning the choice of the solvent or co-solvent, such methods require a sufficient solubility of all components constituting the solid dispersions: drug, carrier and potential additives [41]. This could already be difficult because carriers are hydrophilic whereas drugs are hydrophobic [122]. In addition, this solvent or co-solvent should be non-toxic and non-hazardous to respectively allow a pharmaceutical use of the final product and scale up the designed process. The choice is thus limited mainly to methanol, ethanol, ethyl acetate, methylene chloride, acetone, water and mixtures thereof [123]. To enhance the solubility of the components, surfactant can be used the same way as in melting methods. However, due to the concentration effect induced by solvent evaporation, solvent evaporation methods are particularly sensitive to a surfactant excess, with the latter resulting in a gel layer acting like a diffusion barrier and in consequence delaying drug release. An alternative modification concerning the volatile solvent choice is the co-precipitation which consists of dissolving completely drug and carrier in an organic solvent before being added to an anti-solvent which causes simultaneous precipitation of the drug and carrier [124]. The resulting suspension is then filtered and washed to remove residual solvents. To better control the simultaneous precipitation of drug and carrier, the polymers used in coprecipitation method often are ionic polymers because they have ph dependent solubility. Therefore these polymers are mainly cellulose acetate phthalate, poly(methylacrylate), poly(methylmethacrylate), poly(vinyl phthalate), hypromellose phthalate (HPMCP), and hypromellose acetate succinate (HPMCAS). Concerning the solvents, the ones preferred in this method due to their excellent dissolving power (particularly for high molecular weight polymers) are dimethylacetamide, dimethylformamide and N-methylpyrrolidone [125]. The main advantage of this method compared to the other evaporation solvent methods is the possibility to extract the solvent used for the drug/carrier mixing by washing with water or another volatile solvent. Solvent evaporation requires lower temperature than melting methods, thus being better in preventing drug alteration induced by elevated temperature [126]. In addition, this washing may allow the use of less volatile solvent during the drug/carrier co-precipitation. However, it is worth to note that the solvent/anti-solvent mixture during the precipitation step of this method could have an plasticizer effect showing, as for the other solvent evaporation methods, the critical importance of solvent choice [126]. More recently, supercritical fluids like carbon dioxide (CO 2 ) were described in the literature as replacements for conventional solvents. Supercritical fluids are interesting because they present favorable properties of gases (such as high diffusivity) and at the same time low surface tension and low viscosity imparted to liquids. Manipulation of the pressure of supercritical fluids allows for a precise control of the solubilization of many drugs. Thus, the extraction of supercritical fluids is particularly easy and fast and does not require elevated temperature. The extraction is performed simply by reducing the pressure. The extraction rate could also control particle size and dispersity of formulated solid dispersions. For example, two patented processes (RightSize TM from XSpray Microparticles and Formuldisp TM from Pierre Fabre) were developed [76]. In addition, supercritical CO 2 extraction is considered as an environmentally and pharmaceutically friendly technique [42]. Besides, supercritical fluids can also be used as anti-solvent for coprecipitation method limiting the solvent residue drawbacks [81]. However, the use of such fluids required expensive and specialized equipment designed for industrial scale. Concerning the choice of the process use for solvent extraction step, many methods were developed for a fast solvent removal leading to a rapid solidification of the drug/carrier mix and therefore guaranteeing the amorphous state and the homogeneity of drug in solid dispersion. These rapid solvent extraction methods are spray drying [127], freeze drying [128], spray freeze drying [129] and ultra rapid freezing [130]. Other methods such as heating on a hot plate [99], vacuum drying [131] and rotary evaporation [132] seem to be too slow to obtain acceptable results leading to a risk of phase separation and drug alteration and crystallization in solid dispersion Spray-Drying Spray-drying is a quick, economical and one of the most commonly used methods for volatile solvent extraction resulting in fast transformation of an drug/carrier solution to solid dispersion particles [133]. This process consists of atomizing liquid solution or