Prevention of Crystal Agglomeration: Mechanisms, Factors, and Impact of Additives

Abstract

Crystal agglomeration is a common phenomenon for most chemicals and pharmaceuticals. The formation of agglomerates usually lowers product purity and generates a broad particle size distribution. This review focuses on preventing agglomeration in solution crystallization, the storage of crystals, and pharmaceutical preparation processes. The agglomeration mechanisms in these stages are analyzed and the effects of operating parameters are summarized. Furthermore, effective control means related to the crystallization environment are elaborated, including solvents, ultrasound, and additives. Special attention is paid to the influence of additives in preventing the aggregation of both suspensions and dried powders. Besides additives used in solution crystallization, the roles of anti-caking agents, stabilizers of nanosuspensions, and excipients of solid dispersions are also discussed. The additive type and properties like hydrophilicity, hydrophobicity, ionic strength, viscosity, the steric hindrance effect, and intermolecular interactions between additives and crystals can greatly affect the degree of agglomeration.

1. Introduction

Crystal agglomeration refers to the process of adhesion of fine crystals into aggregates [1]. The purity of crystalline products will be contaminated by impurities and solvents entrapped in the agglomerates. An uncontrollable crystal morphology and particle size distribution would be produced. The agglomeration of crystals also brings about a series of problems in the post-treatment process and pharmaceutical preparations. Agglomerated crystals affect their flowability and bulk density, which in turn reduces the filtration and drying efficiency of the product. It may also affect the stability and quality of the crystals. In addition, agglomerated crystals do not facilitate the preservation, transportation, and subsequent use of the product. In pharmaceutical preparations, agglomerated crystals can reduce the homogeneity of the crystal mixture and tablet performance, as well as the effectiveness and safety of drugs. Therefore, it sharply reduces the production efficiency and product quality. Massive efforts have been taken to control the agglomeration process.

Studies have shown that crystal agglomeration often occurs in crystallization processes, post-processing, and pharmaceutical preparation processes [2,3,4]. For the measurement of agglomeration degree, the total number of crystals, the number of large crystals larger than some arbitrary size, and the mass-weighted average size are usually used. Yang et al. [5] proposed the mass ratio of lithium carbonate spherical particles to quantify the degree of agglomeration based on knocking experiments. In addition, image analysis techniques have been used to measure, characterize, and quantify aggregates [6]. Faria et al. [7] used an automated image analysis technique to classify aggregated sucrose crystals based on their shape. Based on the classification results, the degree of aggregation of each crystal was calculated. Studies have shown that aggregation degree (Ag) and aggregation distribution (AgD) are used to quantify aggregation behavior. Within AgD, image analysis tools can be used to quantify the degree of agglomeration of each particle fraction measured by the crystal size distribution (CSD) [8,9].

Crystal agglomeration will directly affect the particle size and particle size distribution of the product. It is critical to prepare crystalline products with stable and uniform particle size distributions. Particle size is an important index to evaluate the quality of crystalline products. A uniform particle size not only improves the powder properties such as bulk density and flowability, but also leads to a stable dissolution rate, good product quality, and efficient storage and transportation. It is also favorable for reducing the production cost, increasing market competitiveness, and expanding application prospects. Current approaches for preventing crystal agglomerations can be summarized as the control of the crystallization/recrystallization environment (e.g., solvent, composition, humidity) and operating conditions (e.g., temperature, pressure, mixing, supersaturation) [10,11,12,13,14,15]. From the perspective of crystal morphology, it also helps to alleviate agglomeration by modifying the crystal shape, for example, from needle-like crystals to cubes or spheres [16,17,18].

In recent years, the application of additives in the crystallization process has become more and more extensive. Yu et al. [19] studied the effect of additives on the morphology of clozapine crystals. The single crystal growth experiment showed that the additive had different effects on the crystal surface, which led to a difference in the facet growth rate. It has been found that the selected additives could prolong the nucleation time. Simone et al. [20] investigated the effect of additive hydroxypropyl methyl cellulose (HPMC) on the crystallization process of anthranilic acid. HPMC can inhibit the nucleation and growth of crystal form I, thereby increasing the transformation time from crystal form II to crystal form I. It can also regulate the shape and size of two crystal forms. Moreover, it has been reported that additives may promote the growth rate of crystals [21]. The additive forms a molecular complex with impurities, eliminating its inhibitory effect and thus accelerating the growth of crystals. With the wide application of additives in various fields, more researchers have also been attracted to exploring the role of additives on crystal agglomeration. Different kinds of additives may have different mechanisms of inhibiting agglomeration, which still needs further exploration.

Although the problems of caking have been reported, there is little overview of the approaches dealing with crystal agglomeration in different processes. This review aims to discuss the mechanism of crystal agglomeration during crystallization processes, storage processes, and the preparation of nanosuspensions and solid dispersions. The factors affecting particle coalescence and inhibition methods are summarized. Additives can be applied in all those processes and their effects on the agglomeration of particles are elaborated.

2. Crystal Agglomeration during Crystallization Process

2.1. Agglomeration Mechanism

Crystal agglomeration is a common phenomenon in the crystallization process, where fine crystals adhere together and then grow to create larger and dense particles [22]. The aggregation of crystals in solution crystallization is shown in Figure 1 [23,24]. The solution nucleates spontaneously under supersaturated conditions, and the crystal nuclei grow simultaneously through coagulation and condensation. Coalesced particles are eventually developed. The agglomeration of crystals occurs during the entire crystallization process, including nucleation, crystal growth, phase transition, etc. [25]. The nucleation, growth, fragmentation, and morphological changes of amorphous forms in the process of phase transformation are often accompanied by aggregation.

It has been reported that the agglomeration process of crystals involves three steps: the collision between particles; the adhesion of particles via the weak interaction forces such as van der Waals interactions [26], hydrogen bonding [27], electrostatic interactions [28], and non-covalent intermolecular forces; and the simultaneous growth of the formed aggregates [29]. In the early stage of nucleation, the newly formed nuclei aggregate together due to the collision of fluid, leading to primary agglomeration. When the crystals contact each other, intermolecular interactions might be induced via functional groups on the crystal faces, which results in the agglomeration of crystal particles. This agglomeration is intensified by heterogeneous nucleation and crystal growth. Since there are multiple factors that can cause crystal aggregation, the degree and mechanism of agglomeration may vary in different systems. The occurrence of chemical reactions and polymorph transformation makes the agglomeration process more complicated. The study on nucleation and crystal growth theory as well as phase transformation processes can provide a deeper understanding of the mechanism of crystal agglomeration [24]. External factors such as stirring, temperature, and concentration make the thermochemical processes of the system more complex. da Costa et al. [30] reported that asphaltene aggregation is a process of entropy reduction. It has been found that the aggregation of dodecyl sulfate is driven by entropy contribution [31].

Wang et al. [32] studied the agglomeration mechanism of niacin crystals. They found that enhanced temperature and supersaturation increased the degree of agglomeration. According to molecular dynamics simulations, the intermolecular non-bonding interactions (hydrogen bonding and π-π stacking) between the (011) face and the (11-1) face of niacin dominated the interactions between crystals. These interactions created bridges connecting crystals and reinforced the coalescence, which originated from the effective collision of particles in solution. Wu et al. [33] investigated the agglomeration of azithromycin dihydrate in a mixed system of water and acetone. The results showed that the agglomeration of crystals was attributed to the surface nucleation of monohydrate and the crystal growth of dihydrate during the process of hydrate transformation.

2.2. Control Method

2.2.1. Crystallization Conditions

In solution crystallization, the operating parameters such as temperature, supersaturation, stirring rate, and seeds may affect the agglomeration of crystals. The impact of temperature on agglomeration varies in different systems. The collision of particles increases with the increase in temperature, thereby enhancing the agglomeration of crystals [32]. But in some cases, the increase in crystallization temperature reduces agglomerates and improves the flowability of particles [34]. Based on this phenomenon, the authors proposed strategies of temperature cycling and gassing crystallization to optimize powder properties.

Supersaturation is the driving force for crystal nucleation and growth, and it is also an important factor for crystal aggregation. Under a high driving force, particle collisions become more frequent, resulting in more severe agglomeration [35]. Supersaturation can be modified by controlling the solute concentration, feeding rate, cooling rate, or evaporation rate. Jia et al. [36] investigated the effect of cooling rate on the agglomeration of aspirin crystals. At a slow cooling rate (0.1 °C/min), due to the low slurry density during the precipitation process, crystal collisions and agglomeration were weakened, and aggregates could not be formed. According to Omar [11], faster cooling rates produced aggregates with smaller sizes, since the high supersaturation promoted secondary nucleation. In addition, the crystal morphology can be modified by adjusting the parameters that affect supersaturation, so a crystalline product with good dispersity would be prepared [37,38].

Stirring exerts a complex effect on the agglomeration process. Higher stirring rates increase the probability of collision, but also provide a larger fluid shear stress, leading to particle fragmentation [39,40]. Tang et al. [41] investigated the effect of stirring on the recrystallization of ammonium perrhenate. The crystallization process was accompanied by agglomeration, and an appropriate increase in the stirring rate could reduce the agglomeration. Yu et al. [42] reported the effect of stirring speed on the aggregation behavior of paracetamol crystals in anti-solvent crystallization. It was found that the agglomeration degree of large particles was decreased with the increase in stirring rate.

Different stirring paddles could change the flow pattern of fluid [43,44]. The effect of impeller type and position on crystallization has been reported. It has been found that the axial flow of the impeller in the crystallizer accelerates the agglomeration of the growing crystals, while the radial flow may inhibit the agglomeration behavior [45,46]. Figure 2 shows the flow patterns generated by several types of impellers [47]. The one-layered pitched blade 45° downflow turbine (1-PBT), the two-layered pitched blade 45° downflow turbine (2-PBT), and maxblend impellers produce different mixing intensities and flow patterns in the vessel. The 1-PBT generates a relatively weak flow circuit along the axial direction. The 2-PBT impeller produces a certain degree of radial mixing on the basis of the axial flow line, and the maxblend impeller interweaves the axial and radial flow lines. The enhanced axial flow of the maxblend impeller promotes mixing and particle collision. Kaćunić et al. [48] studied the influence of the impeller on the crystal growth and agglomeration of disodium tetraborate decahydrate. The agglomeration was not obvious when the radial flow formed by the straight blade turbine in the crystallizer was dominant.

Moreover, some reactor types or wall materials may induce particles to adhere and accumulate on the wall, resulting in blockage [49]. Several studies have investigated the occurrence of particle agglomeration in semi-batch, batch, and continuous reactors, where particle agglomeration was modulated by adjusting the stirring rate, feed concentration, and feed time [50,51]. Li et al. [52] studied the effect of the Taylor vortex on vancomycin crystallization. It is found that vancomycin crystal products prepared by the Couette–Taylor (CT) crystallizer have an octahedral morphology and uniform particle size distribution, which effectively avoided agglomeration problems. Wang et al. [53] reported blockage mechanisms of glycine crystals in continuous tube crystallizers. As shown in Figure 3, there are interactions between the tube and glycine crystals. This interaction energy at the interface of the crystal tubing determines the adhesion and clogging extent. The clogging tendency of the tubing materials is as follows: steel > silicone rubber > polyvinylidene chloride (PVC) > polytetrafluoroethylene (PTEE) > glass. The concentration of diluted glycine solutions passing through the different tubes decreases with increasing interaction energy, which indicates that the interaction between the crystals and the tubing surfaces plays a decisive role in product aggregation.

Seeding is one of the effective means of controlling the crystallization process. The factors like seed number, size, morphology, state of addition, and time of addition also affect crystal agglomeration [54]. Funakoshi et al. [55] pointed out that the larger the number and the smaller the size of the seeds, the more likely that agglomeration would occur. The addition time of seeds is related to the supersaturation of the solution. When the solution is unsaturated, it leads to the dissolution of seeds, while at a high supersaturation, it might induce secondary nucleation and agglomeration [56]. Ulrich et al. [57] suggested that adding seeds at a 30–40% metastable zone width was beneficial in reducing agglomeration. The surface characteristics of seeds will affect the product quality. When the surface of dry-milling seeds is broken or defective, there might be an adhesion of impurities, leading to the agglomeration of particles [58]. When seeds are added in a state of dry powder, they tend to agglomerate due to strong external forces or electrostatic forces. The seeds can be prepared into a wet slurry and then added in a dispersed state. Some studies have predicted optimized seed formulations through the combination of simulation and experiment [59,60].

2.2.2. Solvents

The change of solvent alters the properties of the solution, such as viscosity, surface tension, and solubility. Both the nucleation and crystal growth kinetics would change in different solvent systems [61,62,63,64]. Wang et al. [65] studied the effect of solvent on the crystallization of dirithromycin and found a strong intermolecular interaction between solvent and dirithromycin. The properties of solvent molecules (e.g., Snyder polarity, molecular size, and functional groups) have a great influence on the crystal structure. Du et al. [66] reported that different polymorphs were formed in the reaction crystallization of prasugrel hydrochloride. When the van der Waals force is dominant, form I is easy to form, while when the hydrogen bond is dominant, crystal form II tends to nucleate. Studies have shown that agglomeration is also closely related to solvent properties, and agglomeration is more likely to occur in solvents with lower polarity [67,68]. Solvents with higher polarity have a stronger adsorption force on the crystal surface, thus inhibiting crystal growth and crystal adhesion. Ålander et al. [69] studied the agglomeration of paracetamol crystals and calculated the crystal–crystal adhesion free energy in different solvents. It was pointed out that the degree of agglomeration in solvents is related to the adhesion free energy. Figure 4 shows the formation process of agglomeration and some key parameters [70]. The effect of solvent on agglomeration can be predicted by calculating the free energy of adhesion between particles and solvents according to the Lifshitz–van der Waals acid–base theory. Aggregation occurs when the adhesive force provided by the solvent is greater than the dispersion force.

2.2.3. Ultrasound

Sonocrystallization, the introduction of ultrasound in crystallization process, has become an important method for process intensification. It reduces the induction time and metastable zone and accelerates the nucleation rate [71,72,73]. Yanira et al. [74] proved that a suitable ultrasonic frequency (44 kHz) and ultrasonic power (20 W) could shorten the induction time of lactose and accelerate the formation of lactose nuclei. Ultrasound has also been used for the breakage and re-dispersion of agglomerates, where a high energy of acoustic cavitation is more effective than a mechanical turbulent flow [75]. Therefore, smaller crystals with a narrow size distribution can be generated in the presence of ultrasonic waves. Cheng et al. [76] studied the influence of ultrasound on the crystallization process of ceftezole sodium. The results showed that with the increase in ultrasonic power and time, the aggregate decreased or even disappeared, and the particle size distribution of the product became more uniform (Figure 5). The propagation of ultrasonic waves in solution will produce compression and rarefaction cycles, and cavitation bubbles will be generated [77]. These bubbles are affected by a series of compression and expansion cycles and will violently collapse in the solution. The shock wave released by the collapse of the cavitation bubbles splits the aggregate into small particles by fracture, which significantly reduces the degree of agglomeration. From the study of Guo et al. [78], ultrasound promoted the nucleation of roxithromycin and significantly reduced aggregation. Narducci et al. [79] studied the application of ultrasonic waves in the continuous cooling crystallization of adipic acid. The continuous crystallization assisted by ultrasonic irradiation can reduce agglomerates and improve crystal morphology. In addition, the time of introducing ultrasound is also an important factor affecting agglomeration, which should switch on in the early stage of nucleation [80,81].

2.2.4. Additives

The use of additives in crystallization is a highly efficient method for regulating crystal morphology and solid forms [82,83]. It is known that crystals a with smaller aspect ratio have better dispersibility. A regular crystal shape with tailored physicochemical properties could be obtained by adding a tiny amount of additives [84,85,86]. For example, Han et al. [87] screened out an effective surfactant that can inhibit the crystal growth of thiamine nitrate and modify the crystal shape from rod- to block-like. Block-like crystals filter and blend more readily, which are not easy to aggregate. A low concentration of polyvinylpyrrolidone (PVP) K17 can adjust p-aminobenzoic acid crystals from rod-like to block-like [88]. Furthermore, uniform spherical particles have attracted widespread interest for their excellent properties in bulk density, flowability, and anti-caking performance [89,90,91]. Wang et al. [92] explored the spherulitic growth and morphology control of lithium carbonate. This study showed that sodium hexametaphosphate (SHMP) induced the formation of compact spherulites which were composed of radially arranged needle-like subunits. Xing et al. [93] prepared spherical vanillin particles in the presence of surfactants. Sodium dodecyl sulfate improved the particle size distribution and flowability of the product.

Additives influence the crystallization process in multiple ways. Small molecules with similar structures to the model substance are more likely to affect crystal morphology and polymorphism by doping the lattice or binding to crystal faces [94]. Macromolecules may interact with crystals via their functional moieties or side groups [95]. They can regulate crystallization via classical or nonclassical pathways. Prasad et al. [96] studied the morphological evolution of griseofulvin particles during liquid anti-solvent crystallization in the presence of additives (bovine serum albumin (BSA), PVP, Tween 80, and HPMC). Bipyramidal particles were obtained, which underwent diffusion-limited growth through Ostwald ripening and secondary nucleation on specific crystal faces due to the selective adsorption of additives. Besides additive-crystal interactions like van der Waals forces, electrostatic interactions, and hydrogen bonding, polymeric additives also exert a steric hindrance effect, which contribute to dispersing aggregated crystals. Klapwijk et al. [97] tuned the crystal shape of succinic acid from aggregated plates to individual blocks using a triblock copolymer Pluronic P123. The polymer additive worked in a fully reproducible and scalable manner. Moreover, it is not incorporated in the crystals and can be repeatedly washed away with water. Zhang et al. [98] investigated the effect of PVP on the morphology of ethyl vanillin. The crystals grown in ethanol–water solution at different supersaturations remained aggregated, when PVP greatly improved the aggregation and modified the crystal habit to be block-like (Figure 6). A molecular dynamics simulation demonstrated that PVP could preferentially adsorb on the (011) and (110) faces, which may affect the attraction and association of solvent or solute molecules.

3. Caking of Crystalline Products

Highly soluble crystalline products have the tendency to cake and cause large solidification in a compact mass during drying and storage processes. The caking problem of crystalline material not only increases the cost of separation, processing, and transportation, but also affects the quality and performance of the product. Therefore, it is very important to attach great importance to the caking of crystals and explore efficient methods to prevent caking.

3.1. Caking Mechanism

Crystal bridge theory, capillary adsorption theory, chemical action theory, and plastic deformation have been proposed to explain the crystal caking behavior. Capillary adsorption theory refers to the existence of a capillary adsorption force between crystal particles. The saturated vapor pressure above the liquid surface in the capillary is less than the saturated vapor pressure outside, so the external water vapor diffuses into the grains, and the crystals absorb moisture and decompose, finally resulting in caking [99]. During the storage process, various raw materials may react with the release of heat and water, resulting in recrystallization between the surface of the crystal particles to form a crystal bridge and cause crystal caking. When the product is piled up and stored, the crystals are subjected to greater pressure, and the particles will deform under pressure. This leads to an increase in the contact area between the particles, a smaller distance between the grains, and an increase in the gravitational force between the molecules, which makes it easy for agglomeration. This crystal bridge theory is regarded as a relatively general theory. Under the influence of the internal properties of crystal particles and external factors, the crystal surface is prone to adsorb moisture and deliquesce. It is generally believed that crystals tend to form caking during the absorption and desorption of water.

The caking process can be divided into three stages: moisture absorption, liquid bridge, and crystal bridge (Figure 7) [24]. The crystal has deliquescence point RH₀, and when the relative humidity of the environment is less than RH₀, capillary condensation will occur. When the humidity exceeds RH₀, the water is rapidly absorbed and crystals start to deliquescence. Water adsorption leads to the formation of liquid bridges between particles. Then, the liquid bridge recrystallizes and turns into a solidified bridge between crystals [100]. The cycle of this process proceeds, resulting in solid clumps. Overall, crystals experience moisture adsorption, dissolution, and recrystallization. The strength of agglomeration is related to the interaction forces between particles [101]. In the static drying process, since the wet product has more liquid, the particles adhere to each other, and crystal bridges between the particles will form. Chen et al. [102] pointed out that the adhesion free energy plays an important role in the caking process. The adhesion energy influenced by particle size, shape, and liquid bridge composition determines the adhesion behavior of crystals. Crystal bridge growth depends on the solubility and particle shape, of which the premise is that the crystals can be dissolved in the liquid bridge. If crystals cannot be dissolved, an effective crystal bridge cannot be formed, and caking will not occur. Therefore, the caking of crystals can be improved by controlling ambient conditions and crystal properties.

3.2. Factors Affecting Caking

The caking of crystals is greatly affected by the external conditions such as humidity, temperature, pressure, and impurities. It is also related to the physical and chemical properties of materials, as well as the particle size distribution and crystal shape.

The higher the relative humidity of the air, the greater the moisture absorption of the crystal product. It promotes recrystallization and agglomeration. Temperature affects the hygroscopic property and solubility of crystals. When the ambient temperature increases, the hygroscopic point of the substance usually decreases, thus increasing the caking tendency of crystals [103,104]. Therefore, crystals should not be stored in humid and hot environments. As the pressure and storage time of the product increase, the crystals may deform, the contact between the particles becomes tighter, and the crystal particles more easily bond to agglomerates [105]. According to Carpin et al. [106], the presence of impurities greatly enhances the hygroscopic properties of the product, thus weakening their anti-caking properties. Therefore, it is essential to strictly control the washing and purification steps to prevent caking.

Materials with different structures and solid forms have different abilities to absorb moisture in the air. Low hygroscopicity is conducive to preventing agglomeration. Moreover, large crystals with granular or spherical shapes exhibit better performance in inhibiting water adsorption and reducing the contact of particles [107]. These characteristics decrease the caking rate and strength. The effect of particle size distribution on caking has been investigated [108]. It was found that the smaller the particle size, the higher the moisture absorption rate, and the greater the caking tendency. Mathlouthi et al. [109] demonstrated that the presence of fine particles in sucrose crystals enhanced water adsorption. Smaller particles have more contact points and possible liquid bridges, which promotes the adhesion between particles and reduces flow [110]. As a result, larger particles absorb less moisture and flow more easily than smaller particles. Needle-like and flake-like crystals with uneven particle sizes have a high caking ability due to their close adhesion. When crystals undergo polymorph transformation, the density and volume of particles will change. This generates mechanical stress within the particles, resulting in crystal breakage. Therefore, the crystal size distribution becomes large and caking would be aggravated.

3.3. Anti-Caking Agents

In order to prevent the caking of crystals, the measures taken include optimizing process parameters, improving the crystal form and morphology, and preparing crystals with a large size and narrow particle size distribution. Meanwhile, liquid can be screened based on solid–liquid interactions to prevent caking during washing and drying. The crystalline products should be packaged in a low-humidity environment, and the packaging method should be optimized to enhance the sealing of the package. When the powders are stored, ventilation and dehumidification could be used to improve the storage conditions of the warehouse. The products are strictly stacked to reduce the pressure on particles and reduce the storage time.

In addition to the above methods, the rational use of anti-caking agents can effectively inhibit crystal caking. The anti-caking agents can prevent particles from absorbing moisture and forming liquid bridges. This is mainly because some anti-caking agents have a high moisture absorption capacity and can absorb water in the environment. Alternatively, the anti-caking agent is adsorbed on the crystal surface, forming a physical barrier and inhibiting the dissolution and recrystallization of particles. Anti-caking agents can be used as crystal growth inhibitors to suppress the formation of crystal bridges [111,112]. It also decreases the surface tension of the solution and reduces the contact between solid and liquid. Lipasek et al. [113] investigated the effect of various anti-caking agents on vitamins. It was shown that both the type and ratio of anti-caking agents exerted important influences on the hygroscopicity and stability of vitamin C.

The anti-caking agent should have the characteristics of stable physical and chemical properties, no damage to product quality, a strong anti-caking ability, convenient use, and low price. The commonly used anti-caking agents include surfactants, polymers, inert materials, hydrophobic substances, and several types of complexes. Surfactants (lauryl amine and sodium dodecyl sulfonate) have been found to reduce the caking tendency of ammonium perchlorate crystals [114]. Yu et al. [115] studied the effects of calcium stearate, silicon dioxide, and calcium silicate on the hygroscopicity of silkworm pupae peptide powders (SPPPs). The results showed that the additives can effectively decrease the moisture absorption capacity of SPPPs and improve the flowability of particles. Among them, silicon dioxide has the best anti-caking effect, since the hydrophobic characteristics of the additive can prevent particles from contacting and adsorbing water. When a single type of additive cannot prevent crystal caking well, complexes are needed to achieve a better anti-caking effect. Mauriaucourt et al. [116] reported a new anti-caking agent for sodium chloride crystals, a metal–organic complex of iron(III) and meso-tartrate. The Fe-mTA acts as a nucleation promoter and growth inhibitor by inducing roughness on the crystal surface. This roughness reduces the effective contact area between the crystals, which avoids caking and creates anti-adhesion relative to other solid substrates.

4. Crystal Aggregation in Pharmaceutical Preparations

About 40% of active pharmaceutical ingredients are reported to be water-insoluble [117]. The problem of poor solubility decreases the efficacy of medicine and limits drug formulation development. Various formulation strategies have been studied to increase the solubility and dissolution rate of drugs [118,119,120,121,122]. Among them, nanosizing technology and solid dispersion technology as the strategies to improve the bioavailability of insoluble drugs have received wide attention. Nanocrystals improve the dissolution rate of drugs by reducing the particle size [123]. A number of methods have been reported for the preparation of nanocrystals [124,125,126,127,128]. Solid dispersions increase solubility due to the hydrophilic ability of various carriers, which increase the wettability of pharmaceuticals [129]. However, nanoscale crystals are prone to agglomeration and solid dispersions have complex crystallization behavior, further affecting the stability of pharmaceutical preparations.

4.1. Stabilizers in Nanosuspension

A nanosuspension is formed by the dispersion of nanocrystals in a liquid-phase medium. It achieves drug targeting, reduces toxicity, increases drug safety, and enhances absorption and bioavailability [130]. A nanosuspension is a thermodynamically unstable system due to its small particle size, high specific surface area, and high surface energy. Nanoparticles tend to reduce their total energy to achieve a stable state through aggregation and crystal growth. Ostwald ripening also leads to the agglomeration of smaller particles in the nanosuspensions [131]. Therefore, it is necessary to add stabilizers into the nanosuspension. The influence of stabilizers on crystal agglomeration is shown in Figure 8 [132]. In a suitable solvent, the stabilizer is fully adsorbed on the surface of particles to ensure their stability. The incomplete adsorption of stabilizers on the crystal surface or the slow adsorption rate results in the interaction between crystals as well as agglomeration of stabilizers in the form of an auxiliary bridge. In an inappropriate solvent, even if there is a stabilizer adsorbed on the crystal surface, the steric effect is reduced and crystal agglomeration will be triggered. The efficiency of stabilizers in preventing nanocrystals from coalescing depends on the speed and strength of the stabilizer attaching to the particle surface, and whether there is enough stabilizer on the surface to prevent particle-to-particle contact.

Surfactants and polymers are often used to inhibit the aggregation of nanosuspensions [133,134,135]. Surfactants stabilize suspensions by electrostatic repulsion and steric repulsion [136]. The ionic surfactants containing ionic groups form a double electric layer when adsorbed on the particle surface and produce electrostatic repulsion, so particles are stably dispersed in the medium. The large functional groups of nonionic surfactants can form a steric hindrance effect, thus preventing the agglomeration of particles and making the dispersion system more stable. Mauludin et al. [137] prepared rutin nanocrystals by freeze-drying using 0.2% (w/w) sodium dodecyl sulfate (SDS) as a stabilizer. This limits the aggregation of particles by electrostatic repulsion. Liu et al. [138] prepared indomethacin and itraconazole nanosuspensions by wet grinding technology. For indomethacin, poloxamer prevents aggregation by steric hindrance. For itraconazole, the stabilization effect of Tween is better, which is related to the viscosity of suspensions. The mechanism of a polymeric additive as a stabilizer of suspensions is similar to that of the surfactant. The polymers are adsorbed on the surface of particles to prevent agglomeration through the steric hindrance effect [139]. Quan et al. [140] reported that the stability of a chitosan-modified nanosuspension was obviously enhanced. Chitosan worked by electrostatic repulsion and spatial repulsion. The deposition of chitosan on the surface of nanocrystals provides spatial stability. Latham et al. [141] studied the interaction between the drug and stabilizer through molecular simulation calculation. The stabilizer interacted with the drug through the hydrophobic region, and the total interaction was driven by hydrophobicity. Mishra et al. [142] studied the use of HPMC to stabilize naproxen nanosuspensions. The stabilization mechanism can be explained by a large number of hydroxyl hydrogen bonds between drug molecules and stabilizers. Choi et al. [139] studied the interaction between polymer stabilizers and drugs. The stability of polymers is related to surface energy and specific interactions between functional groups.

The stability of a nanosuspension is affected by viscosity, concentration, hydrophilic and lipophilic equilibrium values, and the surface potential of stabilizers. Yue et al. [143] studied the effects of polymers and surfactants on the stability of nanocrystals. The stability of drug nanocrystals prepared with surfactants was better than that of polymers, which is related to its properties of low viscosity and high surface activity. Deng et al. [144] studied the influence of Pluronic F127 with different concentrations on the stability of paclitaxel nanocrystals. This variation brought about different adsorption forces for particles. When the concentration of the stabilizer is greater than the critical micelle concentration, the affinity between the stabilizer and particles decreases, and the stabilization effect decreases. Studies by Dalvi et al. [23] showed that for polymers with long hydrophobic chains and large hydrophilic head groups, a small concentration can achieve stability. Long hydrophobic chains cover a larger particle area, and larger hydrophilic head groups provide greater steric hindrance, thereby preventing the agglomeration of particles. The hydrophobic ends of stabilizers determine their adsorption on the crystal surface, while their hydrophilic ends help nanocrystals become better dispersed in water and remain stable. Hence, an effective stabilizer should have a suitable hydrophilic and lipophilic equilibrium value. Amphiphilic amino acid copolymers have been reported as stabilizers for the preparation of nanocrystalline dispersions [145]. The hydrophobicity of the copolymers seems to be the critical factor during the process of wet comminution. Due to the presence of hydrophobic parts, amphiphilic polymers tend to adsorb on the surface of hydrophobic drugs, and their hydrophilic fragments can be stably dispersed in water. The effect of amino acid copolymers with different proportions of hydrophilic and hydrophobic segments on the preparation of drug nanocrystals has been studied [146]. The results showed that a copolymer with a proportion of hydrophobic segments higher than 15% had a better stable effect. The potential is also an important factor and some repulsion between nanoparticles is conducive to maintaining stability of the nanosuspension. In addition, the temperature [147] and pH value [148] of stabilizers affect the stability of nanocrystals to a certain extent, of which the related mechanisms remain to be further studied.

4.2. Excipients of Solid Dispersions

A solid dispersion is formed by uniformly dispersing a drug in a highly dispersed state, such as molecular, amorphous, or microcrystalline, with another carrier. As an intermediate of drug formulations, solid dispersions have many advantages, including effectively reducing the particle size, increasing the wettability of drugs, and controlling the drug release rate [149,150,151]. The particle size of pharmaceuticals in a solid dispersion is 0.001~0.1 μm [152]. The decrease in particle size increases the specific surface area and accelerates the dissolution rate. The enhancement in drug solubility is closely related to the improvement in drug wettability, which may be attributed to the decrease in particle aggregation in solution [153]. Particles in solid dispersions have a higher porosity, which also accelerates the release of active pharmaceutical ingredients [154].

The improvement in solid dispersion performance is largely due to the action of excipients. They are generally divided into low-molecular carriers, polymer carriers, and surfactant carriers, which are highly water-soluble or hydrophilic in nature [155]. Specific carriers and preparation methods are used to disperse the drug in the carrier. After the carrier with high solubility is dissolved, the drug molecules can be directly dispersed in the dissolution medium. This essentially increases the dissolution rate of drugs [156]. Kim et al. [157] selected d-α-tocopheryl polyethylene glycol-1000 succinate (TPGS) and Neusilin^®US2 to prepare a solid dispersion, which enhanced the oral bioavailability of ticagrelor. Some studies have reported the preparation of Apixaban solid dispersions with hydrophilic carriers, leading to an enhancement in solubility, permeability, and bioavailability [158,159]. Khatri et al. [160] prepared solid dispersions of pyrimethamine using different carriers (PEG 6000, poloxamer 188, and PVP K25). The dissolution rate of pyrimethamine in the presence of poloxamer 188 was substantially increased. Furthermore, a different polymorphic form of pyrimethamine was induced in the presence of carriers due to the disruption of the supramolecular ribbon formation of the original crystal form.

Drugs exist mainly in the form of micronized molecules, an amorphous form, or microcrystals in the carrier of a solid dispersion system, and its dispersion state is extremely unstable. A spontaneous low-energy direction brings about aggregation and recrystallization. The aging problem [161] of solid dispersions limits their application in pharmaceutical preparations. A suitable excipient can provide drugs with a higher dispersibility and stronger inhibition of recrystallization. Kalaiselvan et al. [162] studied the stabilizing effect of PVP on the amorphous albendazole. In the absence of the polymer, albendazole crystallized from the amorphous state. In the presence of the polymer, the onset of crystallization increased with the increase in polymer concentration and molecular weight. It was found that the inhibition effect was related to the hydrogen bond formed between the drug and polymer. The interaction between the drug and carrier is one of the key factors affecting the physical stability of solid dispersions [163]. It makes the free energy of the whole system decrease moderately, so pharmaceutical ingredients can disperse within carriers in a stable amorphous form [164]. Yuan et al. [165] found that indomethacin and PVP formed solid dispersions, and intermolecular hydrogen bonds were formed. Acid–base interaction often improves the stability of solid dispersions significantly. Nie et al. [166] found that the acid–base interaction between clofazimine and hypromellose phthalate (HPMCP) increased the amorphous drug loading capacity of clofazimine/HPMCP solid dispersions, contributing to the excellent stability of the system.

5. Conclusions

Agglomeration frequently occurs in the processes of crystallization, drying/storage, and pharmaceutical preparation. It impedes the preparation of stable and high-quality crystalline products. This work focuses on the prevention of crystal agglomeration for a better control of crystallization/recrystallization processes. Agglomeration occurs simultaneously with nucleation, crystal growth, and polymorph transformation. In solution crystallization, the control methods include optimizing operating parameters and equipment (e.g., agitator and crystallizer), screening solvents, introducing ultrasound, and utilizing additives. Adding an additive becomes an efficient strategy for controlling particle agglomeration, since it modifies the crystal morphology markedly with smaller aspect ratios. Besides additive-crystal interactions like van der Waals forces, electrostatic interactions, and hydrogen bonding, additives also exert a steric hindrance effect, which contribute to dispersing aggregated crystals. Based on the mechanisms of caking in post-processing, we summarize prevention measures and the characteristics of anti-caking agents. Specifically, the caking inhibitor should have a high moisture absorption capacity or be able to adsorb on a crystal surface, forming a physical barrier between particles. In pharmaceutical preparations, nanosizing technology and amorphous solid dispersions greatly enhance the dissolution rate of insoluble drugs. But both nanosuspensions and solid dispersions are unstable, which are prone to agglomeration or recrystallization. This work also analyzes the effects of stabilizers in nanosuspensions and carriers in solid dispersions. The additive type, concentration, and hydrophilic and hydrophobic properties play a vital role in stabilizing the particles. Comprehensive control of the crystallization/recrystallization environment and operating conditions enables a greater modification of agglomeration. Issues such as developing efficient and safe additives, the combined effect of multiple additives, cumulative additive concentration, and scaling up need to be addressed to make it more adaptable in production processes.