Keywords

1 Introduction

Nanotechnology is a recent hot topic because of its potential to have an appreciable impact on a number of fields related to biology, chemistry, engineering, as well as medicine.

In the current scenario, approximately 90% of new drug candidates in the development pipeline can have a poor solubility problem that leads to poor dissolution velocity and ultimately variable bioavailability. These new drug candidates belong to biopharmaceutical classification systems (BCS) class II (70%) and class IV (20%). Over the last 10 years, progress in high-throughput screening methods has led to an even higher number of newly discovered drug candidates that have poor water solubility problems (Gigliobianco et al. 2018; Junghanns and Müller 2008; Loftsson and Brewster 2010; Müller and Keck 2012). Given the higher number of poorly bioavailable drug candidates and their non-specific distribution throughout the body may lead to different side effects and may further limit their clinical applications. To overcome the bioavailability issue of drug candidates, appropriate innovative formulation technologies according to the route of administration, e.g., oral and non-oral, need to be adopted (Trapani et al. 2012; Lu et al. 2016a; Keck and Müller 2006).

In the previous era, micronization was used to reduce the particle size and led to an increase in the dissolution velocity of poorly soluble drug candidates. But still, micronization cannot fulfill the needs and satisfy the pharmaceutical requirements to improve the dissolution velocity as well as the bioavailability of drug candidates. The demand for these pharmaceuticals makes the changeover to nanonization. Different and unique innovative nanonization approaches that have emerged to reduce the particle size and improve the dissolution velocity tend to increase the bioavailability of poorly soluble drug candidates for target therapy. These unique innovative technological approaches help to overcome the physicochemical characteristics, including stability issues, that are associated with nanostructures (Jermain et al. 2018).

In this chapter, emerging manufacturing techniques for drug nanoparticles are briefly introduced, followed by a detailed review of the progress of targeted drug delivery. A short introduction with recent advancements in conventional technologies for nanoparticle manufacturing is also included.

2 Definition

The classical definition of “nanocrystals ” is crystals with a nanometer size range, typically between a few nanometers and a thousand nanometers and is crystalline in nature. Another characteristic is that they are made up of 100% drug crystals or with a minimal amount of surface stabilizing agents such as surfactant or polymeric carrier stabilizers. Drug nanocrystals, when suspended in dispersion media, are called “nanosuspension .” Dispersion media can be either aqueous (e.g., water-based dispersion system) or non-aqueous (e.g., different vegetable oils, polyethylene glycol, polypropylene glycol, and solvents). As per the biopharmaceutical classification systems (BCS) , class II drugs are the most prominent candidates for drug nanocrystals, but in some cases class IV drugs may have even more benefits when particle size is decreased.

Nowadays, nanosuspension formulations are used to increase the dissolution velocity and saturation solubility of drug candidates belonging to BCS classes II and IV. Because of the nano-range particles with increased specific surface area, nanosuspensions have unique biological effects. Based on the above-mentioned physicochemical and biological beneficial effects, the US FDA has approved several nanosuspension medications and these are currently marketed well. Owing to the factual information given above, we can say that nanosuspensions are a mature drug delivery system.

“Nanoparticles ” are drug-embedded particles in a nanometer size range, but mainly include polymers or lipids, such as polymeric nanoparticles, liposomes, and solid lipid nanoparticles. Nanoparticles can be in either a crystalline or an amorphous physical state, which depends on the nanoparticle formation technologies. In precipitation techniques, the nanoparticles are generally obtained in an amorphous physical state. Thus, eventually, amorphous drug nanoparticles should not be referred to as nanocrystals (Liu et al. 2012; Peltonen and Hirvonen 2018; Borchard 2015; Gao et al. 2012; Kesisoglou et al. 2007; Liu et al. 2011). Amorphous drug nanoparticles have certain advantages, e.g., it has higher saturation solubility than equally sized nanocrystals. Furthermore, a unique combination of nanometer size range as well as amorphous state is considered ideal for drug candidates to reach the highest saturation solubility. However, to utilize the concept in the pharmaceutical field, it should be equally as important to maintain the amorphous state throughout the shelf-life of product (Hancock and Parks 2000; Gu and Grant 2001).

3 Prominent Attributes

3.1 Surface Area Enlargement

The main idea of nanotechnology is the ratio of surface area to volume. Surface area is increased, whereas the volume remains the same. Moreover, it can be explained as follows: an increase in the particle surface area leads to an increased possibility of having a reaction (with atmosphere or gases or liquid/dissolution solvents around the nanoparticles, etc.). Size reduction via micronization to nanonization (Fig. 3.1) leads to a drastic increase in the surface area and thus the possibility of having a reaction with liquid/dissolution solvents is also increased drastically, or what we call increased dissolution velocity, according to the Noyes–Whitney equation (Eq. 3.1) (Noyes and Whitney 1897).

$$ \frac{dC}{dt}=\frac{DS}{Vh}\left( Cs- Cx\right) $$
(3.1)

dC/dt, dissolution rate (concentration change as a function of time); D, diffusion coefficient; S, surface area; V, dissolution volume; h, diffusion layer thickness; Cs, saturation concentration; C, concentration at time t.

Fig. 3.1
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Surface enlargement factor and increase in the number of crystals by size reduction

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Thus, if considering a particle size reduction from 1 mm (typical particle size for conventional drugs) to 100 nm (typical particle size for drug nanocrystals), then the dissolution velocity is increased 100-fold.

This reflects the fact that the particle size has become an important factor for the determination of dissolution velocity. However, when the dissolution parameter tests are performed under specific dissolution sink conditions, the differences are difficult to identify in numbers between different nanocrystal size fractions; thus, it required a more discriminating dissolution test protocol (Liu et al. 2013).

Therefore, surface area enlargement is the correct way to improve the bioavailability of BCS class II and IV drug candidates where the solubility and dissolution velocity is the rate limiting step. It also seems in most the cases that low dissolution velocity correlates directly with low saturation solubility (Owais et al. 2019; Alshora et al. 2016).

3.2 Increase in Saturation Solubility

Ideally, saturation solubility of drug candidates is dependent on the specific dissolution sink conditions, which include dissolution medium, the concentration of the buffers, pH, and temperature. This is valid up to the micrometer range or above the size of the drug candidates. However, saturation solubility also depends on particle sizes of below approximately 1 μm. Saturation solubility increases with decreasing particle size below 1 μm. Also, according to the Noyes–Whitney equation the dissolution rate dC/dt is proportional to the concentration gradient (Cs − Cx)/h (Cs – saturation solubility, Cx – bulk concentration, h – diffusional distance) and therefore the dissolution velocity is further increased. At the same time, increased saturation solubility also increases the concentration gradient between the gut lumen and the blood, which leads to higher absorption by the passive diffusion mechanism (Fig. 3.2).

Fig. 3.2
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Comparison of (a) a microcrystal and (b) a nanocrystal and their surface curvature and concentration gradient over the diffusional distance (h). Cs, drug-saturated water at surface (M, microcrystal; N, nanocrystal); Cx, bulk concentration at diffusional distance; h, diffusional distance. dc/dt ~ (Cs − Cx)/h

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Generally, the diffusion layer starts to get thinner for particle sizes below approximately 50 μm (Sheng et al. 2007), which furthermore become thinner for particle sizes in the nanometer range and hence enhances the dissolution velocity of nanoparticles compared with microparticles.

According to the Ostwald–Freundlich theory , for particle sizes below approximately 1 μm, the saturation concentration starts to increase. The increasing effect on saturation concentration is more pronounced once the particle size is below 100 nm. Drug saturation solubility is theoretically predicted by the Ostwald–Freundlich equation (Eq. 3.2):

$$ {S}_{\mathrm{NP}}={S}_0\exp \left(\frac{2{V}_m\gamma }{RTr}\right) $$
(3.2)

Where S NP is the solubility of nanoparticles with a radius r, S 0 is the solubility of bulk material, V m is the molar volume, γ is the interfacial tension, R is the gas constant and T is the temperature .

In his dissertation of 1885, Robert von Helmholtz (son of the German physicist Hermann von Helmholtz) achieved the Ostwald–Freundlich equation and explained that Kelvin’s equation could be translated into the Ostwald–Freundlich equation (Helmholtz 1886). One aftermath is that small liquid droplets (i.e., particles with more surface curvature or nanoparticles) exhibit a more effective vapor pressure, because the surface is bigger in comparison with the volume. Now, consider that the vapor pressure is equivalent to the dissolution pressure for nanoparticles in liquid; there should be an equilibrium of molecules dissolving and molecules recrystallizing in the state of saturation solubility. This equilibrium can be moved if the dissolution pressure increases, and hence the saturation solubility increases (Fig. 3.3).

Fig. 3.3
figure 3

Dissolution pressure (p) increased over (a) a flat surface, (b) a microparticle, and (c) a nanoparticle with a high surface curvature

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The advantageous effect of nanoparticles, the increased dissolution velocity, and the increased saturation concentration all lead to a supersaturated state and ultimately this increases the drug absorption as well as permeation (Brouwers et al. 2007, 2009; Mellaerts et al. 2008).

The biggest challenge faced by scientists during development is to maintain the supersaturated state in vivo until absorption and permeation have taken place, because there is the highest probability of interference via uncontrolled precipitation or crystallization (Peltonen and Hirvonen 2018).

3.3 Crystalline or Amorphous Particle States

Based on the drug delivery applications of drug candidates, crystalline or amorphous particle states are anticipated to prevent or enhance the solubility, dissolution velocity, and pharmacokinetic profile.

The combination of nanometer size and amorphous state of drug candidate is ideal for higher saturation solubility compared with equally sized nanocrystals, but at the same time it is required to be maintained throughout the shelf-life of the product.

Concurrently, the importance of crystalline nanoparticles to the pharmaceutical field can be evaluated by the fact that more than 20 formulations are already on the market and approximately 15–20 are at different stages of clinical trials (Kumar and Burgess 2012).

To calculate the optimal nanosize and crystalline/amorphous state of the drug candidate, keep in mind the following parameters :

  • Different administration route (oral, intravenous, intramuscular, pulmonary, ocular, dermal, etc.) (Chen et al. 2014; Fu et al. 2013; Ige et al. 2013; Mauludin et al. 2009; Colombo et al. 2017; Zhai et al. 2014; Vidlářová et al. 2016; Mitri et al. 2011; Muller and Keck 2004; Ganta et al. 2009; Patravale et al. 2004; Shegokar and Singh 2011; Gao et al. 2016; Khan et al. 2013; Liu et al. 2010a, 2018; Yang et al. 2010; Zhao et al. 2011).

  • Different pharmaceutical dosage forms (tablets, capsules, suspensions, ointments, etc.) (Baba et al. 2007; Liversidge and Cundy 1995; Merisko-Liversidge et al. 1996; Moschwitzer and Muller 2006; Yang et al. 2017).

  • Preservation of physical and chemical stability (Hancock and Parks 2000; Merisko-Liversidge and Liversidge 2011; Trasi and Byrn 2012; Lee 2003; Van Eerdenbrugh et al. 2008).

    • Different lattice arrangements such as short-, long-range order (Kreuter et al. 1995).

    • Glass transition temperature (Tg), X-ray diffraction, birefringence characteristic, melting event, etc.

    • Presence of stabilizers such as polymers, surfactants, and sugars.

  • Commanded pharmacokinetics profile.

    • Long circulating and favorable biological properties (Wang et al. 2018; Sharma et al. 2016; Lu et al. 2016b).

    • Potential for passive and active targeting (Huang et al. 2010; Pawar et al. 2014).

4 Production Technologies

Previously, physical and chemical methods were only used to produce nanoparticles. Some of the commonly used physical and chemical methods are solvothermal synthesis, reduction, ion sputtering, and sol gel technique. Basically, there are two main approaches to nanoparticle synthesis; namely, bottom-up approaches and top-down approaches.

Top-down approaches involve the reduction of large particles to the nanometer size range, for example, by milling, whereas bottom-up methods generate nanoparticles by fabricating them from drug molecules in solution, such as by precipitation (Fig. 3.4). Some approaches defined as combined technologies involve the application of two technologies in succession.

Fig. 3.4
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Top-down and bottom-up approaches of nanofabrication

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Top-down techniques , particularly media milling and high-pressure homogenization, have become increasingly recognized by the pharmaceutical industry because it was easy to scale up to a commercial level. Top-down processes are universal techniques for preparing crystalline nanoparticles and have also been accepted by the regulatory authorities (Rabinow 2004).

Bottom-up technologies (i.e., starting from a dissolved molecule, precipitation) were difficult to control the process during scale up. One of the reasons was to remove the solvents and to control the process. The reality was that many poorly soluble drugs were poorly soluble not only in aqueous media but also in organic solvent media (Rawat 2015; Muller et al. 2001).

5 Nanocrystallization and Nanoprecipitation Technologies

Research and development (R&D) and the pharmaceutical industry have to focus their efforts on optimizing scalable processes and formulations, and allow for an appropriate physicochemical and biological stability during the shelf life of the drug product.

6 Media Milling

A milling/grinding chamber, milling media, milling shaft, motor, screen, recirculating chamber, and coolant are the major components of the wet media milling process (Fig. 3.5). The milling chamber can be constructed in a horizontal or a vertical position. In the process, the milling chamber is filled to 70–90% with milling beads sized 0.03–30 mm. The milling beads are made of different materials as needed, such as yttrium-stabilized zirconium oxide, stainless steel, glass alumina, titanium, or certain polymers, such as highly cross-linked polystyrene and methacrylate. Milling/grinding beads are generally available in spherical and cylindrical forms. The milling chamber is filled with slurry containing the drug, water, stabilizers, and surfactants agitated by the motor. The slurry occupies approximately 3–30% (w/v) volume of the milling chamber . The activation of the milling beads occurs by use of an agitator shaft with pegs, disks or smooth-shaped agitating elements. The milling media roll over inside the milling chamber during agitation, generating high energy forces by shearing and impacting large drug crystals to reduce the particle size. Separation of the milling media from the product is done with the help of a screen at the outlet by separation (Yadav et al. 2012; Malamatari et al. 2018; Stenger and Peukert 2003; Kwade 1999). The milling operation can be performed, depending on the production scale and other formulation requirements, either in batch mode (discontinuous mode-single pass processing through one or more mills) (Fig. 3.6) or in recirculation mode (continuous mode-circulation processing with a single vessel). Recirculation is advantageous for reducing costs and milling time.

Fig. 3.5
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Schematic diagram describing the continuous wet bead milling process with a single chamber

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Fig. 3.6
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Batch wet bead milling process with (a) one or (b) more milling chambers

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6.1 Mechanism Involved

  • Real comminution: the primary particles are ground during a liquid phase by high shearing, pressure, and impact forces.

  • De-agglomeration and dispersing: agglomerates are dispersed by high shearing, pressure, and impact forces. The surface air is removed and the surface of the particle is easily wetted (Fig. 3.7).

Fig. 3.7
figure 7

Mechanism involved in the bead milling process

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The fracturing of a particle can occur when the force exceeds the elastic limit of the particles. Different theories of size reduction are involved (Table 3.1).

Table 3.1 Different theories of size reduction
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6.2 Selection of Bead Size

The bead diameter is limited by its relationship to the particles. The particles should be smaller than the void volume between the grinding beads. Generally, the selection of bead size depends on the following practical rules, which can form the basis of reference points:

  • Diameter of the grinding media should be approximately 20–50 times larger than the d99 of the particle.

  • 1/1,000 diameter value of the selected grinding media is the d50 of the final particle size.

Selection of the grinding media depends on the grinding characteristics of the particles, which have to be considered (such as hardness, grain shape, agglomerate/primary grain) to determine the best bead size. Different types of grinding media are available on the market (Table 3.2). Selection of the media type is done based on the criticality of milling process and the formulation requirements. The design of the bead separation system must be suitable for the size of the beads and the feed material size. The screen opening should be from one-third to one-half the diameter of the beads. Thus, overall, the bead milling process depends on the different parameters such as formulation, percentage solids, additives, vehicle, viscosity, mixer speed, flow rate, inlet pressure, outlet temperature, shaft speed, screen size, cooling water temperature and flow, motor power, bead density, bead size, and bead filling.

Table 3.2 Different types of grinding media
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Currently, pharmaceutical milling machines are designed and built in accordance with the cGMP (Current Good Manufacturing Practices of the Food and Drug Administration), GAMP (Good Automated Manufacturing Practices), GAMP5, ASME BPE (Bioprocessing Equipment Standard of American Society of Mechanical Engineers). UL or CE Electrical components, 21 CFR Part 11 Compliance, FDA (Food and Drug Administration) guidelines or meeting the specifications of other regulatory bodies.

The major disadvantage of this technology includes high energy leading to stability concerns regarding the drugs, contamination from the milling media, and time consumption, as a long-term operation ranging from hours to days is generally required. The long-term operation is dependent on the properties of the drug, the milling media, and the extent of particle size reduction (Gao et al. 2008; Peltonen and Hirvonen 2010). To overcome the above constraints to a certain extent, coolant is circulated to reduce the thermo-genic effect . For long-term operation, it is also recommended to use special Yttrium Stabilized Zirconia (YSZ) grinding beads, which have the following special features/advantages:

  • Highly cost-effective, low wear, and a long lifetime: YSZ milling/grinding material is the most durable and efficient medium for ball milling of ceramic materials. It reduces operational costs because of its ultra-low wear.

  • Relatively high mechanical strength, beads do not break owing to toughness and impact resistance performance.

  • High specific gravity, high efficiency, which saves processing time.

  • Very smooth and extremely well-polished, even easy to clean, low abrasion to the internal wall of equipment.

  • Highly resistant to acids and solvents.

  • Because it is virtually contamination free it is an ideal solution for a variety of applications that demand minimal contamination, including, but not limited to, nanomaterials, pharmaceuticals, foods, chemicals, batteries, inks, toner, dielectrics, solar cells, semiconductors, aluminum nanoparticles, etc. (Rijesh et al. 2018).

The wet milling approaches of crystalline nanosuspensions in the pharmaceutical industry can also be judged by the fact that more than 20 formulations are already on the market and close to 15 are at different stages of clinical trials (Table 3.3). The modern and sterile wet milling process is a widely adopted processing technology by the pharmaceutical industry for developing different commercial products (Kumar and Burgess 2012; Gulsun et al. 2009; Moschwitzer 2013; Junyaprasert and Morakul 2015). Scaling up with a media mill is possible, but there is a certain limitation in media mill chamber size owing to its weight so that to produce a larger batch size the media mills can be configured in the circulation mode or more milling chambers can be attached. Typically, from a small laboratory scale to a larger production scale can be carried out with different sized chambers from 5 to 15 ml to a few liters, which are commercially available from the Nanomill® system (élan Drug Discovery, King of Prussia, PA, USA), Dynomill (Glen Mills, Clifton, NJ, USA), and Netzsch mills (Netzsch, Exton, PA, USA)).

Table 3.3 Examples of FDA-approved nanocrystal products
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6.3 Particle Surface Modification

Many orally administered nanosuspensions are modified on the surface using mucoadhesive polymers such as chitosan and carbomer, which can increase the adhesion to the gut wall. The residence time can be increased by improving the adhesiveness of nanocrystals to lumen in the gastrointestinal tract with the addition of mucoadhesive polymers (Thanki et al. 2013; Müller et al. 2001).

In other examples of ophthalmic nanosuspensions , polymers such as carbomer, hydroxypropyl methyl cellulose (HPMC), polyvinylpyrrolidone (PVP), and polyvinyl alcohol (PVA) were used as suspension agents (Bartos et al. 2018).

In many examples, the addition of stabilizers on the particle surface works as physical stabilizers and they may have additional properties such as modifying their bioavailability and pharmacological activity. For example, albumin, arginine, lecithin, leucin, vitamin E polyethylene glycol succinate (TPGS), and sodium cholic acid provided nanocrystals with additional favorable biological properties.

Coating the nanocrystals with surfactants was done to allow barrier crossing and access to treating brain diseases by modifying the permeation at the blood–brain barrier (BBB) . For example, atovaquone was safely and effectively used against T. gondii in vitro to treat toxoplasmic encephalitis, but the oral micronized solution showed poor bioavailability. In vivo studies confirmed the capacity of nanosuspensions coated with sodium dodecyl sulfate to cross the blood–brain barrier and permit the treatment of toxoplasmic encephalitis and other cerebral diseases (Shubar et al. 2011).

7 Cryo-Milling

7.1 Definition

Cryo-milling is a technique that involves high-energy ball milling performed in liquid nitrogen at cryogenic temperatures. Because of the intense ball milling at these temperatures, the size of the original powder is reduced to the nanoscale level in a relatively shorter time. Furthermore, the cryo-milling process is capable of producing nanocrystalline materials with enhanced thermal stability of particles. Thus, among the different mechanical processes , such as inert gas condensation, electrode position, rapid solidification, and sputtering, cryo-milling represents a new and effective technique for the production of nano-sized powders (Birringer et al. 1984; Back et al. 2005).

7.2 Ultra Cryo-Milling

An ultra cryo-milling technique uses liquid nitrogen and dry ice as beads. Liquid nitrogen is used as a dispersing solvent instead of water and dry ice was used as a milling medium instead of zirconia beads. The crystals are pulverized by collision with the dry ice beads at cryogenic temperatures. Because dry ice beads and liquid nitrogen spontaneously sublimate and vaporize under ambient conditions, both materials can be easily removed after the milling process, resulting in no residual solvent or bead material remnants in the milled product. Even if beads are broken or eroded during the milling process, there is no concern about contamination. The milled material is easily and efficiently recovered because the separation process from the beads is not necessary. Thus, it is also called a contamination-free cryo-milling technique. It is also advantageous that the dried products are directly available owing to spontaneous vaporization of liquid nitrogen so that a drying process is not required after the process. Thus, this approach encompasses the advantages of both dry and wet milling.

It has been reported that the milling efficiency is much higher than with dry milling using jet milling because dispersing the medium would actively disturb the coaggregation between the milled particles. In contrast, it has also been reported that the milling efficiency is slower compared with the zirconia beads at cryogenic temperatures, suggesting that dry ice is an inferior milling material to zirconia in liquid nitrogen under cryogenic conditions. The mechanism of wet media milling has been reported as the collision between the beads and the vessel wall. The milling efficiency is mainly dependent on collision energy. Heavy zirconia bead density (6.0 g/cm3) would likely provide a higher collision energy to the particles than a light dry ice bead density (1.56 g/cm3). In addition, zirconia beads have a more uniform size, a smoother surface, and a more rigid body than dry ice beads; thus, effective milling power would result from collision between heavier, similar-sized, and smooth-surfaced beads (Uemoto et al. 2018) (Table 3.4).

Table 3.4 Examples obtained from the scientific literature on the use of cryo-milling for the production of drug nanoparticles
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8 Solvent–Antisolvent Precipitation

Antisolvent precipitation is a bottom-up method, and produces fine particles by starting at the atomic level. This method gives better control over particle properties such as size, morphology, and crystallinity, compared with top-down methods. Antisolvent precipitation is the most attractive method of all the bottom-up methods. Antisolvent precipitation techniques provide a more convenient procedure at room temperatures and atmospheric pressure with no specific requirement of expensive equipment, and is at the same time easily scalable compared with other bottom-up methods (Dua et al. 2015).

8.1 Fundamental Principle of Antisolvent Precipitation Techniques

Antisolvent precipitation techniques proceed in steps of mixing of the solution and antisolvent, the generation of supersaturation, nucleation, and growth by coagulation and condensation, followed by agglomeration in the case of uncontrolled growth (Fig. 3.8).

Fig. 3.8
figure 8

The particle precipitation process

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The precipitation driving force is speedy and eminent supersaturation. The crucial crystal properties, such as size, morphology, and purity are significantly dependent on the rate, magnitude, and uniformity of supersaturation that generated during the process of crystallization (Mullin and Nyvlt 1971; Jones and Mullin 1974).

One component of the crystals’ supersaturation (S) in liquids is defined in Eq. (3.3):

$$ S=\frac{C}{C\ast } $$
(3.3)

where C is the actual drug concentration in the solution (mol/l) and C* is the drug equilibrium solubility (mol/l) in a mixture of organic solvent and antisolvent.

It has been frequently observed that a higher degree of supersaturation typically results in lower Gibbs free energy and leads to higher nucleation rates (Dirksen and Ring 1991; Sugimoto 2003; Cushing et al. 2004).

$$ {B}^0\propto \exp \left(\frac{\Delta Gcr}{kT}\right) $$
(3.4)

where B 0 is the nucleation rate, k is Boltzmann’s constant , ∆Gcr is the critical free energy, and T is the absolute temperature.

There are two mechanisms of “primary” nucleation, homogeneous and heterogeneous nucleation. In homogenous nucleation , the new solid phase generation is in the absence of foreign particles and surrounding surfaces. While in heterogeneous nucleation, the existing foreign particles promote nucleation (Söhnel and Garside 1992). In contrast, “secondary nucleation ” is started by existing native crystals through mechanical abrasion or through thermodynamic effects .

The free energy for homogeneous nucleation is given in Eq. (3.5):

$$ \Delta Gcr=\frac{16\pi {\gamma}_{sl}^3{\upsilon}^2}{3{(kT)}^2{\left(\ln \left(1+s\right)\right)}^2} $$
(3.5)

Thus, after combining Eqs. (3.4) and (3.5), the rate of homogeneous nucleation in the solution is derived by (Eq. 3.6)

$$ {B}^0={A}_{\mathrm{hom}}\exp \left(-\frac{16\pi {\gamma}_{sl}^3{\upsilon}^2}{3{k}^3{T}^3{\left(\ln \left(1+s\right)\right)}^2}\right) $$
(3.6)

where B 0 is the nucleation rate, A hom is the pre-exponential factor, γsl is the interfacial tension at the solid–liquid interface , υ is the molar volume, and T is the temperature. Nucleation rates are primarily dependent on supersaturation and interfacial energy (γ), and the order of magnitude of A hom typically varies from 1032 to 1036. Furthermore, A hom is dependent on the attachment mechanism of the solute on the growing particle surface, i.e., either interface transfer control or volume diffusion control (Johnson 2003; LaMer and Dinegar 1950; Guo et al. 2005; Matteucci et al. 2006; Dalvi and Dave 2010). Table 3.5 summarizes the various examples of drugs obtained from the scientific literature on the use of the antisolvent precipitation technique .

Table 3.5 Examples of various drug nanoparticles by antisolvent precipitation
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To obtain nanoparticles with a narrow size distribution, the following parameters should be kept in mind:

  • Create a high degree of super saturation

  • Uniform spatial concentration distributions in solutions

  • Negligible growth of all crystals

There are two important parameters. One is the meta stable zone, the range of concentration where no crystallization is observed within a given time. It also called the energy barrier for particle precipitation from saturated solution. In order to achieve higher nucleation rates, a meta stable zone width should be shorter. Another parameter is the induction time. The induction time is the time elapsed between suspension of supersaturation and the appearance of detectable crystals (Granberg et al. 2001; Dixit and Zukoski 2002; Lyczko et al. 2002; Barrett and Glennon 2002; Omar et al. 2006; Schöll et al. 2007; Lindenberg and Mazzotti 2009; Kelly and Rodr’guez-Hornedo 2009; Mahajan and Kirwan 1993; Kim and Mersmann 2001; Chen et al. 2000; Dalvi and Dave 2009).

The nucleation and growth of particles occur simultaneously and both compete for consumption of supersaturation. Once nucleation occurs, the particles grow by condensation (τcond) and by coagulation (τcoag). Condensation competes with nucleation by decreasing supersaturation. Coagulation can reduce the rate of condensation by reducing the total number of particles and the surface area (Thybo et al. 2008; Sun 2002; Jones 2002).

Once the particles grow, they also start to agglomerate because the process depends on the population density. Further agglomeration also depends on the Brownian motion of nanoparticles. It has been reported that at higher temperatures, the Brownian motion increases and results in a further increase in the growth rates of crystals. While at lower temperatures, the smaller crystals and the larger population density with higher surface energy cause agglomeration (Lince et al. 2008).

Particle engineering requires the fine-tuning of different variables such as meta stable zone width, induction time, interfacial surface energy, and supersaturation, to obtain the desired particle characteristics. However, fine tuning and control of these variables require prior observations and in situ measurements. Several methods have been reported for the detection and measurement of nucleation and growth kinetics so far and are summarized in Table 3.6.

Table 3.6 Methods for the detection and measurement of nucleation and growth kinetics
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8.2 Step-Up Antisolvent Precipitation Process

8.2.1 Mixing

Mixing generates supersaturation followed by nucleation and growth in a step-up antisolvent precipitation process. There are two main time scales, mixing time (τmix) and the precipitation or induction time (τprecipitation), both of which are associated with the process of particle formation. Mixing time (τmix) comprises the time required for macro mixing, meso mixing, and micro mixing. Mixing that occurs on a crystallizer scale is called macro mixing . Meso mixing is also known as turbulent mixing and it consists of the large-scale mass transfer of a solution. Molecular diffusion and engulfment of different solvent composition regions below the Kolmogorov micro scale is called micro mixing (Johnson and Prud’homme 2003a, b; Gradl et al. 2006; Shekunov et al. 2001; Baldyga et al. 1997). τprecipitation is composed of nucleation time (τnucleation) and growth time (τgrowth). The Damköhler number (Da), dimensionless is the ratio of τmix to τprecipitation. Thus, when Da is greater than 1, the mixing process is slower than the precipitation process, supersaturation is accomplished at a slower rate, and the metastable zone is crossed very slowly. This leads to particle growth and the formation of large crystals. On the other hand, when Da is less than 1, τmix is reduced compared with τprecipitation, the solution is mixed uniformly at the micro level, where supersaturation is accomplished rapidly and nucleation takes place swiftly. The mixing process is faster than the precipitation step and controls overall particle formation. In a situation where supersaturation is highly accomplished, then the meta stable zone is crossed quickly, and nucleation dominates in the precipitation process. This leads to a large number of nuclei and the precipitation of nanoparticles with a narrower size distribution.

Currently, two approaches have been reportedly used for increasing the mixing rate; namely, the high jet velocity mixing device and ultrasound precipitation (Muntó et al. 2005; Zhao et al. 2007; Beck et al. 2010).

8.2.2 Mixing Devices

There are various mixing device designs reported, such as a static mixer, high gravity precipitation, a confined impinging jet, a multi-inlet vortex mixer (MIVM) , a Y-shaped micro channel reactor, and a T-mixer.

Mixing devices facilitate the process and intensify nanoparticle formation by reducing the diffusion length between drugs containing a solvent and those containing an antisolvent. Mixing devices help to achieve mixing time by milli- to microseconds. In some mixer designs, additional ultrasound as an external energy can help in rapid mixing to achieve higher supersaturation in a very short time.

A static mixer consists of a series of motionless identical elements with a specific structure of mixing elements. The mixing elements are able to redistribute fluid in the radial and tangential directions to realize rapid and homogeneous mixing. Many of the research groups reported the use of static mixing for antisolvent precipitation of drug nanoparticles, as summarized in Table 3.7 (Gassmann et al. 1994; Douroumis and Fahr 2006; Douroumis et al. 2008; Dong et al. 2010; Hu et al. 2011).

Table 3.7 Summary of mixing devices used for the antisolvent precipitation technique
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High gravity antisolvent precipitation (HGAP), where, under the high gravity, the rotating packed bed disseminates or breaks up the fluids into very fine droplets. The rate of mass transfer is higher in a rotating packed bed than in a conventional reactor. The particle size decreases as the rotating speed is increased. The use of HGAP in the production of fine particles of danazol, cefuroxime axetil, salbutamol sulfate, and cefradine has been reported (Hu et al. 2008; Zhao et al. 2009; Chiou et al. 2007; Zhong et al. 2005; Chen et al. 2006).

A multi-inlet vortex mixer has been reported for many organic and inorganic compounds via flash nanoprecipitation, as summarized in Table 3.7, where the mixing rate is too rapid and requires less time compared with nucleation and drug particle growth time. The flow rate can be adjustable with the entry of solvent and antisolvent into the mixer in such a way that different levels of supersaturation can be achievable. An adjustable facility can help to control the adsorption of the stabilizer, particle growth, and the size of the nanoparticles. Based on the literature, it has been observed that the end fluid phase, which contains mostly antisolvent and a smaller amount of organic solvent in the end solution helps to reduce the extent of Ostwald ripening of particle suspensions (Liu et al. 2007, 2008; Gindy et al. 2008c, d; Kumar et al. 2009b; Zhu et al. 2010a; Cheng et al. 2009).

A confined impinging jet (CIJ) is reported for the nanoparticle production of several drugs via the antisolvent precipitation technique. The high velocity jet of fluid facilitates the rapid mixing, ensuring a shorter mixing time than precipitation. The CIJ reactor chamber’s geometry, size, and ratio of chamber diameter to jet diameter impact the mixing performance. This high mixing efficiency assists in achieving high supersaturation and high nucleation results in uniform fine nanoparticle precipitation. Furthermore, fast stabilizer distribution on the newly formed surfaces of the nanoparticles via adjustment of the precipitation kinetics of the stabilizer and the drug results in very fine and uniformly stabilized drug nanoparticles (Mahajan and Kirwan 1996; Chiou et al. 2008).

Microchannel reactor technology (MRT) provides a high level of velocity and energy dissipation compared with a conventional reactor. Microreactor mixing is mainly operated by molecular diffusion. Moreover, fine control of supersaturation can be achieved by proper selection of stream ratios. MRT is a continuous process and scalable to enable handling of flow rates of a few liters per minute. There are different shaped micro channel reactors reported in the literature. Y-shaped mixers have been used for the precipitation of danazol, hydrocortisone, atorvastatin calcium, and cefuroxime axetil nanoparticles. Similarly, the reported T-mixers remove the issues of proper alignment of nozzles associated with impinging jets. T-mixers are also used in combination with ultrasound in antisolvent precipitations such as fenofibrate, itraconazole, griseofulvin, ascorbyl palmitate, and sulfamethoxazole. Ultrasound used in the mixing zone helps to improve mixing and generates high supersaturation, resulting in controlled growth of fine and uniform nanoparticles (Ehrfeld et al. 1999; Panagiotou et al. 2009; Wang et al. 2010; Zhang et al. 2010; Wong et al. 2004).

Microporous tube-in-tube microchannel reactors (MTMCR) have provided effective micro mixing and high throughput capacities. It has been reported for use in continuous nanoparticle production of amorphous cefuroxime axetil (Wang et al. 2009).

9 Role of Stabilizer in Antisolvent Precipitation Techniques

The role of a stabilizer to make a protective layer on the particle surface during antisolvent precipitation leads to controlled growth and agglomeration. It can be added in either the solvent or the antisolvent phase. There are two main mechanisms of thermodynamic stabilization involved, i.e., steric stabilization and electrostatic repulsion. A list of stabilizers used in the stabilization of nanoparticles during antisolvent precipitation techniques is given in Table 3.8.

Table 3.8 Summary of stabilizers for the stabilization of nanoparticles precipitated by antisolvent precipitation techniques
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10 Future Perspectives

The potential of nanocrystals for different applications needed to be investigated in detail. Nanocrystals will combine with implantable sustained release drug delivery systems to attain a higher local concentration. Future perspective studies on novel unique approaches to manufacturing nanocrystals and related products have a huge market. The use of emerging nanocrystal technology is expected to increase in the future, with exploration of different routes of administrations (i.e., oral, parenteral, pulmonary, ocular, and dermal) to enhance the bioavailability of nutraceuticals or cosmetics products as well as pharmaceutical products.