INTRODUCTION:

All branches of applied science, manufacturing, and production are embracing nanotechnology. It is a brand-new field of thorough intensive studies that integrates medicine and other life sciences. The high technology and advanced science of nanotechnology precisely defines the molecular structure of matter¹. Colloidal dispersions and biphasic systems called nanosuspensions are composed of particles distributed in an aqueous medium and whose diameter is smaller than 1 um. In nanosuspensions solidified atom typically have a particle size distribution that is smaller than one micron^1,2.

It allows the prospect for fresh and distinctive techniques with several different applications in the treatment of cancer, including diagnostics, therapy, and prognosis. The enhanced chemical characteristics and physical of nanoscale particles are their principal benefit.

Particle size, surface area, hydrophobicity, crystallinity, and surface charge are some of the key factors in drug delivery^2,3.

Nanoparticles and solid nanoparticles of lipid are two different types of nanosuspensions. Solid nanoparticles in lipid are lipid carriers of pharmaceuticals, whereas nanoparticles are often polymeric colloidal transporters of drugs^3.4. These can be utilised to increase the soluble amount of medications that are insufficiently soluble in lipid and aqueous media. The biopharmaceutical categorization system (BCS) classes II and IV are all drug molecules that can use the nanosuspension formulation to make them more soluble⁴.

To increase the solubility of pharmaceuticals that are poorly soluble in water, numerous conventional methods have been developed, including micronization, solubilization employing co-solvents, surfactant dispersions, and precipitation technique. Intravenous fluid, gastrointestinal, ophthalmic, and respiratory routes can all be used to administer nanosuspensions^4,5. At the moment, work is focused on expanding their uses for site-specific medication delivery⁵.

Need of nanosuspension for bioavailability enhancement:

However, pharmacokinetic analyses of BCS class-II medications revealed that they have a low oral bioavailability, which may be caused by the drug's poor water solubility. The problem of drugs with limited bioavailability and reduced water solability was handled using nanosuspension technology^4.5.6.

Drug stability and bioavailability can be increased by the use of nanosuspension technology. With the use of nanosuspension technology, the medicine is kept in the necessary crystalline state with smaller particles, increasing its rate of dissolution and, consequently, its bioavailability⁶. To speed up drug breakdown, a novel method that reduces drug size of molecules has now been developed over the past 20 years. According to the Noyes-Whitney formula that medications with smaller particle sizes have increased surface areas, which increases the rate of disintegration^5,7,8.

The production of ß-cyclodextrin complexes, solid dispersions, and drug salt form are only a few of the traditional pharmaceutical techniques used to increase drug dissolving speed⁷. Because of the impact of humidity, nanosized particles can speed up solutions and improve saturation solubility⁶. Additionally, the drug nanoparticles' surface diffusional distance is reduced, increasing the concentration gradient⁸.

Selection criteria for drugs for nanosuspensions:

For APIs for either of the following attributes, nanosuspension can be created:

· API that is not soluble in water or oils but soluble in the former (high logP)

· medicines that reduce the crystal's propensity to dissolve in any solution

· API with a massive dosage^8,9,10

Advantages of nanosuspension drug delivery system^10,11

· It increases the medicines' solubility and bioavailability.

· It makes pharmaceuticals more physically and chemically stable.

· It offers a passive medication targeting mechanism

· Physical stability superior to liposomes.

· The most economical.

· Decreased tissue irritancy

· More accurate dosage proportionality

Formulation of Nanosuspension^10,11,12

Stabilizer or surfactant, an appropriate solvent system, and other chemicals are essential for the creation of nanosuspension formulation.

Stabilizers:

Provide steric or ionic barriers; thoroughly moisten the drug particles; prevent Ostwald's cultivating and accumulation of nanosuspensions. Poloxamers, Povidones, Cellulosics, Lecithins, and Polysorbate are a few examples.

Surfactant:

Influence phase behaviour when creating nanosuspensions with micro emulsions. Examples include bile salts, dipotassium glycerin, transcutol, glycofurol, ethanol, and isopropanol.

Organic solvent:

A less toxic solvent that is appropriate for use in medicine is used to prepare the formulation. Examples include Benzyl alcohol, Methanol, Ethanol, Chloroform, Isopropanol, Ethyl Acetate, Ethyl Formate, Butyl Lactate, Triacetin, and Ethyl Acetate.

Other additives:

Depending on the requirements of the administration route or the drug moiety's qualities. For instance, cryoprotectant, buffers, salts, polyols and osmogens.

Preparation methodology of nanosuspension ^{1,2,5,6,12,13,14}

There are primarily two ways to make nanosuspension. The term "Bottom-up technology" refers to the standard method of precipitation. Disintegration technologies, or "Top-down" technologies, are preferred to precipitation technologies.

Media Milling^13,14,15

Using pearl mills or high-shear media mills, nanosuspensions are created. The milling chamber, recirculation chamber, and milling shaft make up this component. Balls or pearls formed of ceramic sintered zirconium oxide or aluminium oxide are used as milling media. Adding water, a medication, and a stabiliser to the milling chamber. The sample is affected by balls rotating at a high shear rate while being kept at a constant temperature. Diminishing particle size as a result of both frictional and impact forces, and nanosized particles are produced.

Homogenization^13,14,17

High pressure homogenization (dissocubes)

This method involves applying strong pressure to a tight valve to drive a suspension through it. The static pressure will drop below the indignation of aqua when the suspension is permitted to proceed through the orifice, causing the water to boil and create gas illusion. Bubbles will implode when the pressure returns to normal after it leaves the orifice. As a result, nearby particles will rush to the surface, resulting in a size reduction. The apvgaulin micron lab 40 homoginizer uses this technique.

Homogenization in non-aqueous media (nano-pure):

In water-free media or a water mixture, it is homogenised. It will be below zero or even at the freezing point. Thus, it is often referred to as deep freeze homoginization. For thermolabile compounds, it is the most effective technique.

Nanoedge:

The homogenization process or the precipitation approach will be comparable to this procedure. The combination of these two approaches is thought to improve stability and bioavailability. The solution created using this technique will be homogenised once more to minimise particle size and stop crystal formation. There is a possibility of crystal development and issues with long-term stability in the precipitation procedure. Such issues will be resolved through nanotechnology. The nano edge technology also incorporates an evaporation method for superior nanosuspension creation, leading to modified starting materials that are solvent-free.

Precipitation technique (solvent antisolvent method):^17,18

Submicron particles have traditionally been prepared using the precipitation process. It is mostly utilised for medications that are poorly soluble. In a suitable solvent, the first medication is dissolved. In the presence of surfactants, this solution is subsequently blended with a miscible anti-solvent system.

The drug abruptly becomes completely saturated in the embedded upon fast adding of the reaction mixture to the dissolvent, resulting in the creation of ultrafine drug rigid. The two phases of the precipitation method are crystal growth and nuclei production. A maximum crystallisation rate but a low growth rate is required when creating a stable suspension with the smallest possible particle size. The temperature affects both rates. For this approach to operate, the medication has to be accessible in at minimum one liquid that is mixable with solvates.

Figure 1: Preparation of nanosuspension

Evaluation Of Nanosuspension:^19-21

Particle size and particle size distribution:

The physical stability, dissolving rate, and biological performance of nanosuspensions are all affected by the molecule size and particle size distribution, which are crucial characterisation characteristics. According to research, dissolving rate and saturation solubility of drugs change significantly as their particle sizes change.

Particle charge (zeta potential):^22-25

The study of the stability of suspensions must take into account the particle charge. Typically, the stabilisation of the dispersions will be deemed to require a particle charge of more than 40mV.

Crystal Structure:

Differential Scanning Calorimetry conjuction with techniques like x-ray diffraction analysis or differential thermal analysis can be used to characterise the polymorphic changes brought on by high-pressure homogenization in the drug's crystalline morphology. Due to high-pressure homogenization, nanosuspensions may alter in crystalline structure, possibly becoming amorphous or taking on other polymorphic forms.

Stability of Nanosuspension:²⁶

The aggregation of the drug crystals is caused by the maximum particle energy of nanoscale particles. The stabilizer's primary job is to thoroughly saturate the drug molecules in arrange to prevent Ostwald ripening and Nanosuspension agglomeration and to provide a physical durable formula by acting as a coulombic or ionic obstacle. Stabilizers such cellulosics, polyxamer, polysorbates, lecithin, polyoleate, and povidones are typical examples that are employed in nanosuspensions. If parenteral Nanosuspension is to be developed, lecithin may be preferred.

One drop of the nanosuspension of promising batch was placed on carbon coated grid (3mm) and was allowed to dry. Sample was loaded in TEM using horizontal sample holder. One drop of the nanosuspension of promising batch was placed on carbon coated grid (3mm) and was allowed to dry. Sample was loaded in TEM using horizontal sample holder.

Transmission Electron Microscopy (TEM):^27-31

On a drop of carbon-coated grid measuring 3 millimetres, one drop of the promising batch's nanosuspension was relate. A horizontal sample holder was used to load the material into the TEM. Images were captured with the proper magnification of up to 1600. The Tecani 20 Holland can handle acceleration voltages of up to 200 KV.

Drug Content:

In a 100 ml volumetric flask, a nanosuspension containing 10 mg of the medication was collected and diluted with methanol to a final volume of 100 ml. The final solution's drug content was determined by measuring the absorbance at a specified lambada max in nm.

Table 1: Applications of nanosuspension^32-35

Drug Delivery	Significance of Nanosuspension
Oral Drug Delivery	Boost oral absorption and absulfute bioavailability. Quick start to the action. Increasing bioavailability and enhanced solubility lower ratio of fed / fasted ratio.
Parenteral Drug Delivery	Targeting of tissue and rapid disintegration extended retention duration in the bloodstream. Administration of poorly soluble pharmaceuticals without utilising a greater concentration of hazardous co-solvents, enhancing the therapeutic impact of the substance.
Pulmonary Drug Delivery	It is quite advantageous to start acting quickly and then release the active ingredient gradually. Mechanical or ultrasonic nebulizers can be used to nebulize aqueous nanosuspensions for lung administration. Because of their small dimensions, it is probable that every aerosol drop contains a minimum of one medication particle, causing the medicine to be spread out more evenly throughout the pulmonary.
Ocular Drug Delivery	Greater bioavailability and regularity of dosing Less irritability and longer stays in a cul-de-sac are ideal for treating most ocular disorders effectively and avoiding the high tonicity caused by water-soluble medications. Their real impact is determined by the drug's intrinsic solubility in lachrymal fluids, which controls its release and ocular bioavailability. Due to the continual influx and outflow of lachrymal fluids, the drug's intrinsic dissolving rate will change.
Targeted Drug Delivery	Targeted delivery can be accomplished with nanosuspensions since they are easily adaptable in terms of their surface characteristics and in-vivo behaviour.
Topical Drug Delivery	The drug's saturation solubility increases in the nanocrystalline form when it is administered topically, resulting in improved drug absorption through the skin.

CONCLUSION:

The solubility and dissolving issues have been mostly resolved by nanosuspension formulation to enhance medication absorption. It has therapeutic benefits such a straightforward preparation process, a reduced need for excipients, enhanced drug saturation solubility, and a faster drug dissolving speed. Drug discovery programmes identify numerous drug candidates; however the majority of them are just somewhat soluble. This presents a challenge to pharmaceutical research in terms of coming up with new strategies to increase the solubility, stability, and bioavailability of the drug. An economically viable solution to the drug's low absorption and solvability issues is nanosuspension. High-pressure homogenization technology has been extensively employed for large-scale manufacture of nanosuspension formulation. In addition to addressing the issues of poor solubility, a nanosuspension formulation increases medicinal efficacy.

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

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Received on 14.10.2022 Modified on 16.01.2023

Asian J. Res. Pharm. Sci. 2023; 13(2):106-110.

DOI: 10.52711/2231-5659.2023.00020