INTRODUCTION:

A huge number of drugs have been found to possess solubility issues both in aqueous and non-aqueous media. As a result of poor bioavailability due to low solubility, drug effectiveness is also affected. The issue of bioavailability can be attributed to insufficient solubility or permeability. With the advancement of technology, the necessity of advancement of pharmaceutical technologies has also been increasing¹. Development of a new formulation is majorly attributed to parameters such as solubility and stability of the drug at ambient temperature². Therefore, various approaches have been made in developing new formulations to improve the solubility and bioavailability of those drugs. It has been observed that poorly water-soluble drugs pose many problems in formulating it into a conventional dosage form. One of the critical problems associated with those drugs is erratic absorption³.

Many techniques have been developed to improve the dissolution rate of these drugs. Therefore, in the last few decades, the enhancement of bioavailability of poorly water-soluble drugs has become the main target of drug development. A very common way of increasing drug solubility is particle size reduction. The drug particle surface area is also enhanced by micronization, which produces particles in the size range of 2 µm to 5 µm. However, micronization alone sometimes may not be sufficient to increase adequately the drug dissolution rate and absorption in the gastrointestinal tract as in case of poorly soluble drug⁴. Some other techniques have been developed related to the optimization of the dissolution rate of these drugs with solubility issues like particle size reduction, solubilization, salt formation, and preparation of solid dispersion systems. However, there are certain disadvantages related to the production of nanoparticle that limits the use of nanosuspension techniques. Particularly, the particle size reduction technique leads to deterioration of some powder properties, such as their flow properties and wettability, while enhancing the development of electrostatic forces, leading to suspicious formulations. Besides, the dissolution rate of the salt is also very unpredictable as the solubility of salt is highly correlated with the pH value which varies significantly in the gastrointestinal tract. However, these techniques are highly energy consumptive. A number of disadvantages are also associated with this technique such as broad particle size distribution, contamination of medicines, crystal structures variation, uncontrolled particle morphology etc. In the last few years, bottom-up technologies including supercritical fluid (SCF) technique and liquid precipitation which are involved in production of ultrafine drug particles, such as clarithromycin, olanzapine, paclitaxel, etc. have been widely investigated for their efficient performance in the field of nanotechnology. Although advanced technologies like emulsions, microemulsions, liposomes, solid dispersion technology and inclusion complexes employing cyclodextrins are available now days to formulate water-insoluble drugs, but there is no universal approach applicable to all drugs. Therefore, to overcome the formulation-related problems a specific strategy is needed for improvement of its clinical efficacy which will optimize their Pharmacoeconomics concerns.^4,5

This novel technology has been able to show their potential to alter and improve the issues associated with the BCS class II drugs and are unique because of their simplicity and the advantages they confer over other formulation. This novel technology maintains the required crystalline state, which results in improved dissolution rate and improved bioavailability⁶. Thus, it also help to reduce the dose of conventional oral dosage form⁷.

DEFINITION: A pharmaceutical nanosuspension is defined as a very finely colloid, biphasic, dispersed, solid drug particles in an aqueous vehicle, the particle size below 1µm, without any matrix material suitable methods for drug delivery applications, through various routes of administration like oral, topical, parenteral, ocular, and pulmonary routes⁸. Nanoparticles utilized as “ferries” for drug substances of low aqueous solubility and/or undesired pharmacokinetic properties including organ toxicity, bear several advantages in comparison to the use of conventional formulations such as solutions. In the area of parenteral, especially intravenous delivery, the USP Pharmacopoeia prescribes that within injectable lipid emulsions the number of droplets about 5 µm has to be lower than 0.05 vol% (determined by the light obscuration method). Within larger particles, the risk of pulmonary embolism or phlebitis appears. This specification can only be limitedly transferred to the use of solid particles, as the latter are not deformable in comparison to emulsion droplets and the acceptable upper particle size limit might be lower. Therefore, nanoparticles in the submicron size range present a suitable drug delivery system for the parenteral application.

Fig 1: various drug delivery systems

Fig 2: Nanocapsule vs Nanospheres

Criteria for selection of Nanosuspension as a dosage form:^8,9

1 Drugs with aqueous insolubility but lipid solubility.

2 Drugs with high melting point and high log P value.

Advantages of nanosuspensions:

1. Presence of stabilizers renders the formulation a long-term physical stability.

2. Drugs with poor aqueous solubility can be easily formulated into nanosuspension.

3. It can be administered through different route of administration.

4. Method of preparation is easy as well as can be produced in large scale.

5. Nanosuspension can be moulded into various dosage forms like suppositories, pellets, hydrogels etc.⁹

Disadvantage of nanosuspension:

1. Dose accuracy and uniformity is difficult to maintain.

2. Sedimentation and Compaction may pose problems.

3. Must be handled carefully during transportation.^9,10

Special features of nanosuspensions:

1 Enhancement in saturation solubility consequently leads to increase in the dissolution rate of the drug.

2 Increased adhesive nature of the formulation results in enhanced bioavailability.

3 Increasing the amorphous fraction in the particles, leading to a potential change in the crystalline structure and higher solubility.

4 Produces long term physical stability as an aqueous suspension due to absence of Ostwald ripening.

5 Nanosuspensions can be formulated for site specific delivery as there is possibility of site modification.¹¹

Benefits of nanosuspensions over conventional formulations in different routes:¹²

1 Oral: Rapid onset of action/ improved solubilities so improved bioavailability

2 Ocular: Higher bioavailability/ dose consistency

3 Intravenous: Rapid dissolution/tissue targeting.

4 Intramuscular: Reduced tissue irritation

5 Inhalations: Rapid dissolution/high bioavailability/dose regulation

Physicochemical properties of drug nanosupension (drug nanocrystal):^13,14,15

1. Internal structure of Nanosuspensions:

Inside the drug particles, the internal structural change can be observed due to high energy input. On exposure to high pressure homogenization the particles from crystalline state are transformed into amorphous powder. The transformation of the state depends upon the hardness of drug, number of homogenization cycles chemical nature of drug, the hardness of drug and power density applied by homogenizer.

2.Saturation solubility:

Saturation solubility (Cs) is a constant that depends upon three parameters

1. The compound,

2. The dissolution medium

3. The temperature and

4. Particle size. The saturation solubility increases with decreasing particle size (below 1000nm).

3. Change of dissolution velocity:

For poorly soluble drugs belonging to BCS class II dissolution velocity is the rate limiting step. Mostly, a low dissolution velocity is correlated with low saturation solubility.

TECHNIQUES FOR PREPARATION OF NANOSUSPENSION:

BOTTOM-UP TECHNOLOGY:

Bottom-Up technology is one of the conventional methods of precipitation (Hydrosols). In this technique, the drug is dissolved in an organic solvent and this solution is mixed with a miscible antisolvent. In the water-solvent mixture and the drug precipitates due to low solubility. Precipitation has also been including high shear processing. The Nano edge process relies on the precipitation of friable materials for subsequent fragmentation under conditions of high shear and/or thermal energy. This is accomplished by combining both rapid precipitation and high-pressure homogenization techniques. Rapid addition of a drug solution to an antisolvent ends up in sudden supersaturation of the mixed solution and generation of fine crystalline or amorphous solids. Precipitation of an amorphous material may be favored at high supersaturation when the solubility of the amorphous state is exceeded This has the advantage of using relatively simple and low-cost equipment. However, this created problems in stirring and mixing when haunted for large-scale production. The major challenge of this technique is to avoid crystal growth that occurs in storage due to Ostwald ripening. ^3,4,5,15

TOP- DOWN TECHNOLOGY:

1.Nanoedge: This technology follows the principle of precipitation and homogenization. This technology helps to achieve smaller particle size and better stability within a short period of time. Nano edge technology also helps to overcome the drawbacks associated with precipitation technique such as crystal growth and long-term stability.

2.Nanojet: It is also known as opposite stream technology, where a stream of suspension is divided into two or more parts in a chamber and particle size gets reduced due to high pressure collision produced during the process. M110L and M110S microfluidizers (Microfluidics) are example of few equipment using this technology. Nanosuspension of atovaquone is prepared using the micro fluidization process. However, despite of being an advantageous novel technique it has got few disadvantages. The major One being the higher number of passes through the microfluidizer, and also the final product contains a relatively larger fraction of microparticle^9,16,17.

Media milling (Nanocrystals or Nano systems): Liversidge et.al developed media milling technique for the first time. This technology utilizes high‐shear media mills or pearls Media milling for the production of nanosuspension. Here, the drug is subjected to media milling where a high energy and shear forces are generated as a result of the impaction of the milling media. This whole process provides the necessary energy input to disintegrate the solid drug particles into nanosized particles. In this process, the milling chamber is charged with the milling media, drug, a suitable buffer or water and stabilizer. Then the instrument is rotated at a very high shear rate. The major disadvantage associated with this technique is the residues remaining in the finished product could be problematic for administration^4,9.

Dry co-grinding:

From the various studies on nanosuspensions, it has been found that dry milling technique has also come out as very helpful technique to produce nanosuspension. It has been reported that using dry co-grinding technique, stable nanosuspensions of poorly soluble drugs with soluble polymers and copolymers after dispersing in a liquid media could be prepared successfully. Colloidal suspension of poorly soluble drugs like griseofulvin, glibenclamide, and nifedipine with solvents such as polyvinylpyrrolidone (PVP) and sodium dodecyl sulfate (SDS) are prepared by dry co-grinding method. Many soluble polymers and co-polymers such as PVP, polyethylene glycol (PEG), hydroxypropyl methylcellulose (HPMC), and cyclodextrin derivatives have also been used in this system. Co grinding can also improve the physicochemical properties as well as the dissolution of poorly water-soluble drugs by working on its surface polarity and transformation from a crystalline to amorphous form. Further, dry co-grinding is a easy and economic technique which can be conducted without organic solvents.¹⁸

Lipid emulsion/microemulsion template:

Nanosuspensions can also be produced by conventional method such as emulsion using a partially water-miscible solvent as the dispersed phase. Microemulsions as templates can also produce nanosuspensions. They are thermodynamically stable and isotopically clear dispersions of two immiscible liquids which is stabilized by an interfacial film of surfactant and co-surfactant. The preformed microemulsion can be saturated with the drug by intimate mixing or the drug can also be loaded into the internal phase of the same. A Suitable dilution of the emulsion yields nanosuspension. For example, nanosuspension of griseofulvin with lecithin, butyl lactate, water and the sodium salt of taurodeoxycholate is prepared by the microemulsion technique. The advantages of this technique as templates for nanosuspension formation are that easy production of nanosuspension by controlling the emulsion droplet and easy for scale-up. However, the use of organic solvents affects the environment and large amounts of surfactant or stabilizer are required.¹⁰

Supercritical fluid process:

The supercritical fluid process is another method through which nanosized particles are obtained by solubilization and nanosizing techniques. Through the process drug particles can be micronized to the submicron level. Supercritical fluids (SCF) are noncondensable dense fluids, the temperature and pressure of which is greater than its critical pressure (Tp) and critical temperature (Tc). It has been reported that recent advancement in the SCF technology is to create a nanoparticulate suspension of particle size of 5 to 2000nm in diameter. The low solubility of poorly water-soluble drugs and surfactants in supercritical CO2 and the high pressure required for these processes restrict the utility of this technology in the pharmaceutical industry.^9,19

Table 1: Summary of nanosuspension formation technologies and compounds produced in nanosuspension [4]

Technology	Advantage	Disadvantage	Drug
Precipitation	Simple technique equipment cost is low	-The Drug has to be soluble in at least one solvent and this solvent requires to be miscible with a non-solvent. -Growth of drug crystals requires to be controlled by addition of surfactant	Carbamazepine, Cyclosporine, Griseofulvin, Retinoic acid
High pressure homoginisation	applicable to most drugs -Can be Used for formation of very dilute as well as highly concentrated nanosuspension.-Simple technique-Aseptic production possible-Risk of product contamination	-High number of homogenizations cycles -Prerequisite for drug to be in micronized state and suspension formation before homogenization -Possible contamination of product could occur from metal ions coming off from the wall of the homogenizer	Albendazole, Amphotericin Aphidicolin, Atovaquone Azithromycin, Budesonide Bupravaquone, Clofazamine Fenofibrate, Glucocorticoid drugs
Emulsion/ Microemulsion templat	High drug solubilization -Long shelf life -Ease of manufacture	-Use of hazardous solvent -Use of high amount of surfactant and stabilizer	Breviscapine, Griseofulvin Ibuprofen, Mitotane
Media milling	Ease of scale up -Little batch to batch variation -High flexibility in handling large quantities of drugs	-Generation of residue of milling media -Require milling process for hours to days -Prolonged milling may induce the formation of amorphous lead to instability	Cilostazol, Danazol, Naproxen
Dry Co-grinding	Easy process -No organic solvent -Require short grinding time	-Generation of residue of milling media	Clarithromycin, Glibenclamide Glisentide, Griseofulvin, Naproxen, Nifedipine, Phenytoin, Pranlukast

Emulsification-solvent evaporation²⁰

In the solvent evaporation technique, volatile solvents and emulsions area unit accustomed build the chemical compound resolution. within the past, solutions like methylene chloride and chloroform were used that have currently been replaced by ester having a higher pharmacology profile. On evaporation of the solvent from the polymer, the emulsion is then converted into a nanoparticle suspension, which is allowed to diffuse through the continuous phase of the emulsion. In the conventional methods, the two main strategies involved are the preparation of single-emulsions, e.g., oil-in-water (o/w) or double-emulsions, e.g., (water-in-oil)-in water, (w/o)/w. Both the methods require ultrasonication or high-speed homogenization, followed by evaporation of the solvent, either under reduced pressure or by continuous magnetic stirring at room temperature. The ultracentrifugation method makes the solidified nanoparticle which are washed with distilled water to clean it up from the additives like surfactants, and then it is lyophilized. The concentration of polymer, stabilizer, and the speed of homogenizer affected the size of the particle.

Melt emulsification method:

In this technique, the drug is dispersed in the stabilizer which has been prepared in aqueous media. The dispersion is then heated above the melting point of the drug and then it undergoes homogenization to give an emulsion. During this process, the sample holder was enwrapped with a heating tape fitted with a temperature controller. Also the temperature of the emulsion was maintained above the melting point of the drug throughout the process. The emulsion was then allowed to cool down to room temperature either slowly or on an ice‐bath. This technique has got the advantage of total avoidance of organic solvents during the production process. Nanosuspension of ibuprofen was prepared by this method.^7,20

CONCLUSION:

From the whole review study, it may be concluded that the nanosuspension approach has led to the successful formulations of poorly water-soluble drugs and dissolution rate. The reduced particle size of substances enhances solubility as well as the rate of absorption, thus provide better bioavailability and effectiveness of drugs belonging to BCS CLASS II and with high log P-value. Several production techniques such as media milling, high-pressure homogenization made it easy for the large-scale production of nanosuspension. Nanosuspension technology can also be combined with conventional dosage forms such as tablets, capsules, pellets, and can be used for parenteral products. To take advantage of nanosuspension drug delivery, simple formation technologies, and various applications, nanosuspensions will continue to be of interest as oral formulations and non-oral administration develop in the near future.

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Received on 09.07.2020 Modified on 30.12.2020

Research J. Pharm. and Tech 2022; 15(1):489-493.

DOI: 10.52711/0974-360X.2022.00079