The issue of poor solubility of active pharmaceutical ingredients (APIs) is one of the biggest limitations for drug development. It is a matter of concern, as the bioavailability depends on the dissolution of drug in the gastrointestinal fluids. The main determinants of the dissolution kinetics in vivo
are solubility and surface area of the particles. The solubility is a function of the crystal lattice energy and the affinity of solid phase to the solvent. Thus, three groups of strategies that have been implemented to improve the rate of dissolution and solubility rely on: (1) the reduction of the intermolecular forces in solid phase, (2) the enhancement of the solid–solvent interaction, and (3) the increase of the surface area available for solvation (according to the Noyes–Whitney equation) [1
Due to the fact that almost 50% of currently marketed drugs and over 70% of new chemical entities exhibit low solubility in water, numerous techniques have been developed to overcome this problem [2
]. Common strategies include pH adjustment, formation of salts, cosolvency, formation of cocrystals and inclusion complexes, particle size reduction, supercritical fluid technology (SCF), and self-emulsification [3
]. Recently, nanotechnology has emerged as a technique that leads to the formation of robust delivery systems. Numerous attempts have been applied to obtain several types of delivery systems, i.e., micelles [5
], liposomes [6
], capsules [7
], protein nanocontainers [9
], and silica-based nanoparticles [10
]. Poorly water-soluble drugs have been frequently processed with hydrophilic polymers, as the molecular dispersion of drug molecules within the matrix provides better dissolution of the drug. Moreover, when the systems were further formulated into the nanoparticles, the results were more pronounced [12
The main factors affecting the choice of a particular method are the physicochemical characteristics of drugs and carriers. Solid dispersions are commonly formed to enhance the water solubility of APIs; however, the number of marketed products arising from that strategy is rather low. This is a result of the thermal instability of drug and carrier during preparation of systems, a poor in vitro–in vivo
correlation, and instability during storage [15
]. However, the simplicity of preparation, low cost, and great improvements in the dissolution of poorly water-soluble drugs have made the solid dispersions widely investigated. Experimental and theoretical approaches have been involved to determine the thermodynamic properties of APIs dispersed in polymer matrices as well as the mechanisms and factors affecting their stability [16
The concept of solid dispersion—one of the earliest methods of solubility enhancement—was introduced in 1961 by Sekiguchi and Obi, who prepared eutectic mixtures containing microcrystalline drug and a water-soluble carrier [19
]. Although crystalline forms provide high stability and chemical purity, the lattice energy barrier is the major limitation affecting the dissolution rate. Thus, amorphous carriers such as polyvinylpyrrolidone (PVP) [23
] and hydroxypropylmethyl cellulose (HPMC) [25
] have been introduced to prepare amorphous solid dispersions (ASDs). The highly water-soluble amorphous carriers provide stabilization of APIs, increasing the wettability and dispersibility of the drug [27
]. They limit the precipitation of a drug in water; however, the supersaturation may lead to precipitation and recrystallization of APIs, which negatively affects the bioavailability of the drug. To face this problem, surface active agents or self-emulsifiers such as poloxamers (PLXs) [30
], Tween 80 [32
], or sodium lauryl sulfate (SLS) [33
] have been introduced. They improve the dissolution rate as well as physical and chemical stability of the supersaturated system. Surfactants or emulsifiers enhance the miscibility and thus limit the recrystallization rate of the drug. Moreover, they are able to absorb onto the outer layer of drug particles or form micelles encapsulating drug particles, effectively preventing drug precipitation [34
]. On the other hand, many surfactants can absorb moisture, which may result in phase separation during storage, an increase in drug mobility, and conversion from the amorphous or metastable form to the more stable crystalline one. They may change the physical properties of the matrix, increase the water content and cause adverse side effects in vivo
] Thus, their use has to be cautious and their amounts well adjusted.
Among the strategies that allow for obtaining solid dispersions, solvent methods are often used. In these techniques the drug and the carrier are dissolved in a volatile solvent such as ethanol [36
] or methylene chloride–ethanol mixture [37
] that is further evaporated. It requires sufficient solubility of the drug as well as the carrier in the solvent. Moreover, the type of used solvent, the temperature, and rate of its evaporation are of key importance due to the fact that the concentration of residual solvent needs to be below the detection limit after drying. One of the strategies utilized to fulfill that requirement is the use of low-toxicity solvent mixtures, e.g., water with ethanol, which decreases the amount of each solvent in dry formulation. However, this strategy sometimes fails due to insufficient dissolution of components at a given ratio [35
]. Usually, a second drying step is applied to completely removed the solvent as it may lower the glass transition temperature, enhancing the recrystallization tendency.
The common feature of evaporation approaches is the removal of small droplets or thin layers of the solvent from different surfaces. It may lead to the crystal growth of oriented morphology as described for droplet evaporative crystallization or microwave-accelerated evaporative crystallization [38
]. The crystallization of the celocoxib–PVP mixture was found to generate drug crystals of improved dissolution characteristics [41
]. Other approaches such as the evaporative antisolvent method and supercritical carbon dioxide evaporation were applied to the formation of nanoparticles, drug-loaded micelles, and liposomes characterized by improved dissolution of the drug [42
Commonly used solvent methods include vacuum drying using rotary evaporators [44
], spray drying [45
], or freeze-drying [46
], among others. In rotary evaporators, solvents are removed under reduced pressure, limiting thermal decomposition of the components of the mixture as organic solvent evaporation occurs at low temperature. Spray drying combines four processes, i.e., (1) atomization of the liquid containing dissolved or suspended drug, which is transported into the nozzle and then sprayed onto fine droplets, (2) mixing the liquid with the drying gas, (3) evaporation, and finally (4) separation of obtained particles from the gas using cyclone [47
]. Generally, the spray drying process can be applied for the generation of amorphous materials as well as a technique for particle engineering, i.e., particle size reduction [48
In the work reported herein, we study the self-assembly phenomenon of solid dispersions containing either Poloxamer®
188 or Poloxamer®
407 and its effect on dissolution enhancement of the poorly water soluble drug bicalutamide (BCL). Poloxamers are the nonionic surfactants widely used in pharmaceutical formulations as emulsifiers, wetting agents and solubilizers. They have been introduced into solid dispersions to enhance solubility and dissolution profiles of poorly water-soluble APIs from solid dosage forms [49
]. Bicalutamide was used as a model drug. It is a non-steroidal antiandrogenic drug assigned to Biopharmaceutics Classification System (BCS) class II because of poor water solubility (below 3.7 mg/L) and high membrane permeability (logP = 2.92) [51
]. It is known to exhibit polymorphism and undergo mechanical activation upon milling [54
]. Obtained results indicate that the formation of solid dispersions by means of solvent methods led to the changes of particles in solid state, i.e., morphological features, increased wettability, phase transition (in case of ternary solid dispersions containing PVP) and partial disruption of crystal lattice. Moreover, the formation of nanoaggregates in aqueous media led to the 4- to 8-fold increase in the amount of dissolved bicalutamide. Emission spectroscopy allowed for a correlation of the effect of dissolution changes with the solubilization related to the variations of molecular structure of used poloxamers.
The obtained results indicate that co-processing of BCL with PLXs leads to an improvement of bicalutamide dissolution from 4- to 8-times in comparison with the pure drug. That effect was assigned to the formation of nanoaggregates. Surface activity of poloxamers leads to the formation of hydrophobic packets in which bicalutamide was solubilized. Importantly, physical mixtures did not form aggregates with bicalutamide and thus no significant enhancement in drug dissolution was observed. While no variations in dissolution between systems obtained by either spray drying or evaporation processes were noted, some differences in physicochemical characteristics appeared. The most important observation is that the drug partially lost its highly-ordered molecular structure after preparation of solid dispersions. The changes in diffractograms were more pronounced in evaporated systems. The decrease in crystallinity was expressed by the decrease in relative intensity and lack of several peaks. Moreover, the addition of PVP and formation of ternary solid dispersions by spray drying led to the transition of polymorph I into polymorphic form II of bicalutamide. This confirms that the interplay between the process parameters and properties of both drug and carrier is important to obtain solid dispersion of desired characteristics without a great excess of the auxiliary compounds.
The type of polymer was found to affect the size of nanoaggregates formed by solid dispersions in an aqueous medium. The self-assembly of systems containing PLX188 led to the formation of smaller particles, regardless the applied technique of solid dispersion preparation. This may be a result of the composition of the macromolecule, as it contains ca. 15% PPO hydrophobic mers, while PLX407 contains ca. 35%.
Thermal analysis confirmed that poloxamers were partially amorphous in solid dispersions, which indicates that the drug antplasticizes the Tg of the polymer. This would be connected with the dissolution of the drug in a liquid polymer.