Preparation of Nanocrystal technology for Aqueous Insoluble Drugs

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1		Dandan Han	--	3477	2022-09-09 04:06:29	\|
2	format	Jason Zhu	Meta information modification	3476	2022-09-09 04:39:22	\|

This entry is adapted from the peer-reviewed paper 10.3390/cryst12091200

The low solubility and bioavailability of aqueous insoluble drugs are critical challenges in the field of pharmaceuticals that need to be overcome. Nanocrystal technology, a novel pharmacological route to address the poor aqueous solubility problem of many poorly soluble drugs, has demonstrated great potential for industrial applications and developments.

Preparation nanocrystals top-down bottom-up combinative technology

1. Introduction

One of the most challenging problems in pharmaceutical science is the bioavailability limitations of drugs with poor solubility. About 40% of the drugs currently on the market are struggling with poor aqueous solubility ^[1]^[2] and approximately 90% of drugs in development are classified as poorly soluble drugs ^[3] based on the definition of the biopharmaceutical classification system (BCS). In particular, BCS II drugs with low solubility and high permeability account for approximately 70% ^[4]. The Developability Classification System (DCS) for oral administered drugs was proposed based on the BCS classification system. According to the DCS, DCS II drugs can be divided into two categories, one is dissolving rate limiting DCS IIa, which is insoluble in water and organic phases, and the other is solubility limiting DCS IIb, which is usually soluble in at least some lipids ^[5]^[6]. Until now, several techniques have been proposed to solve the problems of drug insolubility, mainly involving two approaches: (i) modification of morphological properties of raw drug particles, i.e., improving the surface area to volume ratio by preparing a fine powder or promoting the porosity; and (ii) modification of some physicochemical and structural properties of insoluble active pharmaceutical ingredients (APIs), such as preparation of polymorphic forms, cocrystal, solid dispersions, etc. ^[7]^[8]^[9]. However, the second approach usually requires large screening efforts (e.g., the selection of solvents and ligands) when it comes to DCS IIa drugs. Therefore, reducing drug particle size is the best option for DCS IIa drugs ^[10].

Nanocrystal technology brings a new dawn for improving the solubility and bioavailability of insoluble drugs ^[11]. Nanocrystals (usually 1–1000 nm) are pure drug particles stabilized by suitable surfactants/polymers ^[2]^[11]^[12]. Nanocrystals have the following features. (i) The surface area of nanocrystals increase with decreasing particle size. According to the Noyes-Whitney equation ^[13], the dissolution rate of nanocrystals increase with improving the surface area. (ii) According to the Ostwald-Freundlich equation ^[14], downsizing the size to the nanometer range significantly enhances the solubility of a drug ^[15]. (iii) A mucus layer with a porous structure is present on the surface of the gastrointestinal tract. The nanograined size is small, which can rapidly permeate into the pore channels of the mucus layer and tightly adhere to them ^[2]^[16]^[17], so it can prolong the effective range and time of drugs in the gastrointestinal tract. All of these properties contribute to enhancing the absorption and bioavailability of drugs ^[17]. In fact, nanocrystals were originally invented to improve the oral bioavailability of insoluble drugs ^[18]. With advanced research in drug nanocrystals, other advantages have also been explored, such as loading high active pharmaceutical ingredients (APIs) ^[4]^[16], improving the metabolism behavior of drugs ^[19], reducing toxic and side effects, promoting patient compliance ^[20], and so on. Consequently, the superior properties of drug nanocrystals have attracted more and more attention from pharmaceutical enterprises.

2. Top-Down Technology

Top-down technology mainly includes wet bead milling and high pressure homogenization ^[21], which is easily industrialized. Drug particles decrease by mechanically generated shear and collision forces ^[22], accompanied by the fragmentation of crystalline species and the appearance of secondary nucleation nuclei. The formation rate of top-down technology is independent of supersaturation. Most previous reported anticancer drugs have been prepared by this technology because they do not require organic solvents and are relatively easy to scale up production ^[23]. In summary, top-down technology can be used for drugs that are insoluble in both the aqueous and organic phases. It processes quickly and is widely used for marketed drug nanocrystals.

2.1. Wet Bead Milling

Wet bead milling involves crushing the drug itself into nanoparticles by high intensity mechanical force with stabilizers and water ^[24]. The particle size of nanocrystals is mainly relevant to the size of the milling beads ^[25] (usually 0.1–20 nm), the property parameters of the drug, and the setting parameters ^[22]. Since the temperature can be controlled in the preparation process, wet bead milling is especially suitable for preparing thermally unstable drug nanocrystals ^[16]. It operates easily to obtain a uniform product. However, stabilizers and wetting agents still need to be added, and several cycles are required to reach the specific particle size range. Meanwhile, the obtained product has disadvantages in the contamination caused by grinding beads ^[26] and poor physical storage stability due to agglomeration. Funahashi et al. ^[27] found that ice beads melted after the milling process, which could avoid contamination. Most of the drug nanocrystals that have been successfully translated industrially are prepared using milling, including the earliest marketed pentoxifylline capsule VerelanPM, a fenofibrate tablet for the treatment of hypercholesterolemia Tricor, and an anti-inflammatory drug Naprelan ^[28].^®^®^®

2.2. High Pressure Homogenization

High pressure homogenization (HPH) utilizes violent shearing, collision, and cavitation generated in a high pressure homogenization chamber to break down drug particles. Depending on the instrumentation and solution used, it can be divided into microfluidization, IDD-P™, Dissocubes, and Nanopure. Microfluidization has the ‘Z’ or ‘Y’ type chamber based on the jet stream principle. IDD-P™ uses a jet homogenizer for the homogenization of suspensions. Dissocubes uses a piston gap homogenizer for homogenization in aqueous media. Nanopure is suitable for the production of easily hydrolyzed drugs in reduced/non-aqueous media ^[29]. In general, the setting parameters of the homogenization process and the hardness of the drug mainly affect the properties of the product ^[30]. Through these efficient methods, the obtained product has a small particle size with narrow distribution and is not contaminated by the grinding medium. Most importantly, the method can be better combined with other methods to reduce the cycle number of homogenizations and the requirement of homogenization pressure. However, expensive equipment and demanding techniques hinder the transferability to larger scales ^[31]. In addition, high pressure may unintentionally lead to crystal structure changes, increase the content of amorphous states, and affect the stability of some amorphous nanosuspensions ^[30]. The currently marketed paliperidone palmitate intramuscular suspension Invega Sustenna, fenofibrate tablets Triglide, and Luteolin nanocrystals ^[32] are prepared by the HPH technique ^[28].^®^®^®^®^®

2.3. Laser Ablation

Laser ablation is a new technique developed in recent years for nanocrystal preparation. During laser ablation, the solid target is irradiated and the ejected material forms nanoparticles in the surrounding liquid. Then, stirred suspensions of microparticles are broken into nanoparticles by laser-mediated fragmentation ^[33]. According to the laser processing time, it is divided into nanosecond, picosecond, and femtosecond laser irradiation, among which more nanoscale particles can be produced ^[34]. The parameters affecting the particle size include the laser intensity, scanning speed, and the properties of the suspension, etc. In this process, no organic solvent is involved, but a small fraction of the drug may undergo oxidative degradation and crystal state changes due to excessive power. This method has been successfully used to prepare paclitaxel, megestrol acetate, and curcumin nanosuspensions ^[35].

2.4. Ultrasound

Ultrasound is an efficient method to break drug particles into smaller particles through the vibration of acoustic waves. Ultrasound has been shown to enhance nucleation by creating acoustic cavitation in solution and rapidly dispersing the drug solution ^[36]. Because it is easily operated in the laboratory and is highly reproducible, it is also usually combined with other techniques ^[37]. Ultrasound-assisted precipitation of nanoparticles mainly alters the mixing process, nucleation, growth, and agglomeration ^[38]. The size of the nanocrystal depends on the intensity of the ultrasound treatment, the horn length, the horn immersion depth, and the cavitation depth ^[12].

3. Bottom-Up Technology

Bottom-up technology is mainly based on precipitation and evaporation ^[31]. The basic principle is to obtain drug nanocrystals from the supersaturated state of drugs and subsequently control the size distribution of the nanoparticles by appropriate methods ^[39]. Nucleation is especially important for the formation of small and homogeneous nanocrystals. Controlling the crystal growth is the best way to precisely control the particle size of drug particles. Many physical methods have been used to control the crystal growth, such as high gravity controlled precipitation. Compared with top-down methods, these methods provide better control of particle properties ^[40]. In conclusion, bottom-up technology is simple in principle and operation, but difficult to scale up due to poor reproducibility. The process may also use organic solvents.

3.1. Liquid Antisolvent Precipitation

Liquid antisolvent (LAS) precipitation is the preparation of nanocrystals by mixing a solution stream (organic phase) dissolved with an insoluble drug with an aqueous antisolvent. The solution–antisolvent method of nanoprecipitation is the most commonly reported. Since this method only contains nucleation and growth steps, it is simple and cost-effective ^[12]. The optimized nanocrystals can be prepared through two steps. However, unstable crystal particles are also recrystallized in the process, leading to the aggregation and precipitation of nanocrystals ^[16]. Additionally, the use of organic solvents in the preparation process leads to the problem of solvent residues, and it is unsuitable for drugs that are neither soluble in aqueous nor insoluble in non-aqueous solvents. Currently, some studies have used this method to obtain suspensions of hydrochlorothiazide ^[37], budesonide ^[41], etc.

3.2. Precipitation Assisted by Acid-Base Method

The carbon dioxide-assisted precipitation method using acid-base reactions usually involves dissolving the drug in a weak acid solution as the acid phase, and weak base in a solution containing stabilizer as the base phase. The acid phase is slowly added to the base phase to produce carbon dioxide, then the drug nanocrystals are precipitated by vapor effervescence ^[42]. This method avoids the addition of organic solvents, which is more friendly to the environment. However, it is only applicable to insoluble drugs whose solubility is related to pH and is stable to acids-bases ^[19]. Wang et al. ^[43] prepared tacrolimus nanocrystal suspensions using this method. In vivo pharmacokinetic results indicated that tacrolimus nanosuspensions significantly increased the oral bioavailability compared with commercial hard capsules.

3.3. High Gravity Controlled Precipitation

High gravity controlled precipitation (HGCP) is ^[44] the improvement of the precipitation method using gravity control to obtain more uniform and smaller drug nanocrystals. Reactant concentration, rotational speed, and volumetric flow rate are effective factors influencing particle size. In this process, the drug suspension in the device can be circulated for long-term mixing and reaction. However, local oversaturation of the feed stream at the turbulent edge during mixing leads to continuous nucleation, thus limiting the industrial application of this method ^[23]. To date, this method has been successfully used on the laboratory scale to prepare salbutamol sulfate ^[45] and sorafenib ^[46].

3.4. Supercritical Fluid Method

The supercritical fluid (SCF) method means drugs dissolve in a supercritical fluid (e.g., CO₂) and precipitate nanocrystals with the rapid vaporization of the supercritical fluid as the fluid is atomized under reduced pressure through a nozzle with a tiny aperture ^[11]. According to the function of supercritical fluid in the crystallization process, supercritical fluid methods include rapid expansion of supercritical solution (RESS) and supercritical antisolvent (SAS). According to the different nozzle positions, the rapid expansion of a supercritical fluid method was improved to yield the rapid expansion of a supercritical solution into a liquid solvent (RESOLV) method, in which the former places the nozzle in the air while the latter places the nozzle in aqueous solution. The state parameters of the supercritical fluid in the process, the morphology of the nozzle, and the concentration of the drug will influence the particle size of the nanocrystals ^[7]. This process does not require organic solvent to produce high purity products. However, the consumption of supercritical fluids is large and it is only suitable for drugs dissolved in supercritical fluids ^[16]. Zhang et al. ^[47] prepared apigenin (AP) nanocrystals using the SAS method. No substantial changes in the crystal structure were observed in the nanocrystals, but decreased particle size and smooth spherical surface were noticed. The AP nanocrystals exhibited faster dissolution profiles than the original AP in dissolution media.

3.5. Emulsion Polymerization Method

API is dissolved in volatile organic solvents or solvents partially mixed with aqueous as the dispersed phase, then the organic solvent is emulsified dropwise into the aqueous phase (usually including stabilizers) to form an O/W emulsion ^[11]. The emulsion droplet size is easy to control. After that, the emulsions are evaporated, stirred, and extracted to obtain drug nanocrystals. Factors such as emulsifier, stirring speed, evaporation rate, temperature gradient, and pH value have significant effects on product quality. Because this emulsion polymerization method requires the assistance of homogenization or ultrasound, it is suitable for laboratory operations but not for large-scale pilot production ^[11]. Chen ^[48] obtained florfenicol nanocrystals with a mean particle size of 226.1 ± 11.3 nm using the emulsification solvent volatilization method. Compared with the original powder, the solubility and dissolution of florfenicol nanocrystals were remarkably improved.

4. Combinative Technology

There are always many limitations to obtain the desired nanocrystals using a single preparation technology due to the properties of various drugs and characteristics of the instruments. When top-down technology is selectively united with bottom-up technology, forming combinative technology, the disadvantages of a single preparation technique can be overcome and the efficiency of particle size reduction can be improved. Combinative technology is divided into the Nanoedge technology developed by Baxter ^[49] and the SmartCrystal technology (Abbott/Soliqs, Ludwigshafen/Germany). Combinative technology combines pre-treatment and a particle size reduction step. It can eliminate the drawbacks of instrument clogging ^[50] and improve the stability of nanocrystals. Combinative technology can take full advantage of various technologies and are also suitable for a wide range of insoluble drugs. However, there are limitations in terms of economics and process complexity.^®^®

4.1. Nanoedge Technology

Nanoedge technology was the first combined method for particle size reduction developed for nanodrug production. It utilizes the HPH method assisted by the precipitation method. Initial crystal particles are obtained by precipitation, reducing the high pressure homogenizer slit blockage and improving the efficiency of reducing particle size during the homogenization process ^[51]. Subsequently, the homogenization process from the HPH method is used to further crush the particles, preventing secondary growth and overcoming the problem of uneven particle size distribution and Oswald ripening in the precipitation method, which increases the physical stability of the nanocrystal particles. Furthermore, other alternative techniques such as ultrasound or microfluidization can be used for the high-energy process ^[31].

4.2. SmartCrystal Technology

SmartCrystal technology mainly combines a pre-treatment step followed by a high pressure homogenization step. The pre-treatment step can be, for example, wet bead milling, spray drying, freeze drying, or precipitation, followed by HPH ^[52]. SmartCrystal technology is recognized as a second-generation nanocrystal preparation method. Specifically, the joint method in this technology takes the form of collection, which is a toolbox of technology optimization for the preparation of drug nanocrystals ^[53]. It includes H69, H42, H96, and combination technology (CT) techniques.^®

H69 is similar to NanoEdge technology, combining nanoprecipitation and HPH methods. The formation of nanocrystals occurs in the high pressure homogeneous cavitation region, which contributes to ultra-small and homogeneous particle size. Li et al. ^[54] tried to prepare ursodeoxycholic acid nanosuspension by homogenization technology and high pressure precipitation tandem homogenization technology. The dissolution rate of ursodeoxycholic acid nanocrystalline powder was quicker than that of the raw and physical mixture powder.

H42 and H96

H42 and H96 are combined with spray drying, freeze drying, and HPH techniques, respectively. The solution of insoluble drug and stabilizer is pretreated by spray/freeze drying, uniformly dispersed in the stabilizer skeleton, then redispersed into the water by HPH to prepare drug nanocrystals. The combination reduces particle aggregation and improves processing efficiency. It is suitable for large-scale production. Möschwitzer et al. ^[55] used poloxamer 188 as a stabilizer to prepare hydrocortisone acetate powder by H42. More uniform nanosuspensions exhibiting good long-term storage stability were obtained. Yu ^[56] prepared meloxicam and naproxen drug nanoamorphous using the H96 technique.

CT is a combination of top-down technology. The two most common types of wet bead milling methods used are rotor-stator and mills ^[57]. Taking the former as an example, artcrystals is a combined rotor-stator high-speed shear and HPH technology. Firstly, the drug suspension is pretreated by shearing in a rotor-stator high-speed shear, then the nanocrystals are homogenized at high pressure to obtain stable and homogeneous suspensions. Wadhawan et al. ^[58] obtained crystalline acyclovir nanocrystals with a mean particle size of 400–500 nm using high pressure homogenizer and hydroxypropyl cellulose-LF as a stabilizer followed by wet bead milling. The saturation solubility of the nanocrystals was 1.6 times higher than that of micronized acyclovir. Martena et al. ^[59] prepared nicergoline nanocrystals in aqueous solutions of polysorbate 80. Four different techniques, HPH, bead milling (BM), and combined techniques (HPH + BM, BM + HPH) were explored in his work. The combined technique was found to be superior, but HPH + BM produced nanocrystals with a smaller mean particle size than BM + HPH. Particle solubility increased for all nanocrystals, especially for HPH and the combination technique, which obtained nanocrystals showing a higher dissolution rate.

4.3. Other New Combinative Technology

Precipitation-lyophilization-homogenization (PLH) method

PLH is a combination of precipitation-lyophilization-homogenization method. Morakul et al. ^[60] obtained clarithromycin nanocrystals by this method, using poloxamer 407 and sodium dodecyl sulfate (SDS) as co-stabilizers. The obtained clarithromycin nanocrystals were cubic particles, about 400 nm, in a crystalline or partially amorphous state. It had high solubility and permeability.

High gravity antisolvent precipitation process (HGAP)

HGCP technology is merged with antisolvent precipitation process to form HGAP. The benefits of the HGCP are retained while the disadvantages of impurities in the product are eliminated ^[12]. Zhao et al. ^[61] prepared danazol nanocrystals with uniform size distribution by the HGAP process. The average particle size was 190 nm. The molecular state and crystalline form of Danazol nanoparticles were maintained. The nanoparticles were highly evaluated by the industry for its high recovery rate and continuous production capacity.

Microjet reactor technology (MRT)

MRT is similar to HPH. The drug solution is mixed in the high pressure chamber through the micro-hole of the nozzle to form a high-speed fluid sprayed into the reaction chamber, and convective shear in the reaction chamber to form turbulence. At the same time, there is cavitation, impact, and shear effect to reduce the product particle size. The influencing factors of MRT include the mixing ratio of solution and antisolvent, jet strength, stabilizer dosage, temperature, etc. This method can realize continuous large-scale production. However, the energy consumption and path clogging ^[35] cannot be ignored. Chen et al. ^[62] prepared albendazole nanocrystals by MRT with a mean particle size of 367.34 ± 0.68 nm under the optimal preparation process. The nanocrystals can significantly improve the dissolution performance of albendazole and facilitate the improvement of oral absorption of the drug.

Evaporative precipitation into aqueous solution (EPAS)

The EPAS method dissolves the API in the low-boiling-point solvent and heats above its boiling point. Thereafter, the heated solution is sprayed into heated aqueous solutions containing stabilizers ^[12]. Chen et al. ^[63] produced amorphous nanoparticle suspensions of cyclosporine A by EPAS. Due to the low crystallinity, small particle size of nanoparticles, and hydrophilic stabilizers, it has shown a high dissolution rate.

Antisolvent precipitation-high pressure homogenization method

Huang et al. ^[64] combined the antisolvent precipitation method and HPH method to prepare celecoxib nanocrystal suspensions with a particle size of 283.67 ± 20.84 nm, using polyvinylpyrrolidone K30 (PVP K30) and SDS as crystal stabilizers. The solubility of celecoxib nanocrystals was obviously higher than that of the raw celecoxib and the physical mixture. The product remained quite stable under high temperature and high moisture conditions for 10 days of storage.

Ultrasound probe-high pressure homogenization method

Jin et al. ^[65] used an ultrasound probe combined with HPH and fluidized drying process to prepare baicalin nanocrystals with an average particle size of 248 ± 6 nm and PDI 0.181 ± 0.065 by selecting mixed surfactant poloxamer 188 as a steric stabilizer and SDS as an electrostatic stabilizer. The results of pharmacokinetic experiments in rats showed that the drug bioavailability in vivo was significantly improved.

Rotary evaporation method-high pressure homogenization method

Zuo ^[66] prepared curcumin-artemisinin cocrystal nanomedicine by the rotary evaporation-HPH method. The particle size of nanomedicine was 234.6 nm after optimization. Curcumin-artemisinin cocrystal nanomedicine showed obvious solubility advantages and excellent stability compared with that of raw curcumin, curcumin-artemisinin cocrystals, and curcumin nanocrystals. Yu ^[56] also obtained quercetin drug nanoamorphous using the rotary evaporation method assisted by the HPH method.

Melt quench-high pressure homogenization method

Yu ^[56] also used the combined melt quench-high pressure homogenization technique to prepare nanoamorphous indomethacin. The particle size of the prepared suspension was 245 nm. The solubility of the nanosuspensions was significantly enhanced. However, the stability of the nanoamorphous was poor. The particle size started to increase significantly within 7 days and even reached 890 nm after 30 days due to the presence of water and the occurrence of recrystallization.

Antisolvent precipitation-ultrasound method

Zhang et al. ^[67] obtained fenofibrate nanocrystals using the ultrasound probe-precipitation method. However, one of the disadvantages of ultrasonic probes is that they can leave metal particles and thus are not suitable for industrial production. Liu et al. ^[68] used alpha tocopherol succinate as an auxiliary stabilizer in the organic phase to prepare carvedilol nanosuspensions by this method. The mean particle size of the nanoparticles was 212 nm and it was stable at 25 °C for 1 week. The dissolution rate of the nanosuspension was significantly increased. In vivo tests indicated that the nanosuspensions showed approximately two-fold increase in each index compared with commercial tablets. Additionally, the method is fast, inexpensive, and easy to control. Paclitaxel nanocrystals ^[69], zaleplon nanocrystals ^[70], and nintedanib nanocrystals ^[71] are also prepared using this method.

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Qiuyan Ran

Mengwei Wang

Wenjie Kuang

Jinbo Ouyang

Dandan Han

Zhenguo Gao

Junbo Gong

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Update Date: 09 Sep 2022

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