INTRODUCTION:

One of the most challenging problems in pharmaceuticals science is the bioavaibility limitations of drug with poor solubility. About 40% of the drugs currently on the market are struggling with poor aqueous solubility and approximately 90% of drugs in development are classified as poorly soluble drugs based on the definition of the biopharmaceutical classification system (BCS).¹

Figure 1: BCS Classification

Nanocrystals:

Drug NCs are nanoscopic crystals of parent compounds with a dimension of less than 1um. NCs are Nano-range particles composed of 100% drug without any matrix material. Poorly soluble drugs encounter biopharmaceutical delivery problems such as low bioavaibility after oral administration, low penetration of the drug into the skin, large injection volume for intravenous (I.V.) administration and undesired side effects after I.V. injection when using traditional formulations. The unadulterated drug crystals might be physically stabilized by surfactants or polymers. Elan pharma International Ltd. Registered a trademark named NanoCrystal that offers a skill which help in improving the bioavailability of drugs by reducing them as nanosized particles that can be made into powder or suspended in liquid and formed as tablet or can be encapsulated in the same. Above all, physical instability issues inherent with different nanocarriers are to a great extent avoided by the NCs are generally formulated as Aq. Dispersion (nanosuspension), which need further solvent elimination processes to get re-dispersible powders which showed up very quick availability of formulation in market form the year 2000 onwards. Despite one example, all available products in market till now are of oral delivery; they are all solid dosage forms (tablets or capsules), but only one preparation is a suspension called MagaceE.²

Limitation of nanocrystallization are given below

1. High energy required for nanoionisation of drug size.

2. Requirement of stabilizer

3. Not for low therapeutic indices drug

4. Limited over control release.²

Nanocrystallization:

Nanocrystallization is a new carrier free colloidal drug delivery system with particle size ranging from 100-1000nm, and is considered as a viable drug delivery strategy to develop the poorly soluble drugs. Techniques like salt formation, complexation, solubilization, pH alteration, cosolvents, surfactant, microemulsions, self-emulsifying drug delivery system (SEDDS) or self-micro emulsifying drug delivery system (SMEDDS). Nanocrystals have the following features. The surface area of Nanocrystals increase with decreasing particle size. According to the Noyes-Whitney equation, the dissolution rate of nanocrystals increase with improving the surface area³

Solubility:

Solubility is an important determinant in drug liberation andabsorption and hence plays a key role in its bioavailability. For a drugto be absorbed, it must be present in the form of an aqueous solutionat the site of absorption. Solubilization may be defined as thepreparation of a thermodynamically stable solution of a substancethat is normally insoluble or very slightly soluble in a given solvent,by the introduction of one or more amphiphilic components. Themechanism of solubilization involves the property of surface activeagents to form colloidal aggregates known as “micelles”. Whensurfactants are added to a liquid at low concentrations, they tend to orient at the air-liquid interface. As additional surfactant is added, theinterface becomes fully occupied, and the excess molecules are forcedinto the bulk of the liquid. At still higher concentrations, the moleculesof surfactant in the bulk of the liquid begins to form oriented aggregatesor micelles; this change in orientation occurs rather abruptly, and theconcentration of surfactant at which it occurs is known as the “criticalmicelle concentration”. The solubility of a substance is the amount ofit that passes into solution when equilibrium is established betweenthe solute in solution and the excess (undissolved) substance. Thesolution that is obtained under these conditions is said to besaturated. A solution with a concentration less than that at equilibriumis said to be sub-saturated. Solution with a concentration greater than equilibrium can be obtained. These are known as super-saturatedsolutions.The transfer of molecules or ions from a solid state into solution isknown as dissolution. In essence, when a drug dissolves, solidparticles separate and mix molecule by molecule with the liquid andappear to become part of that liquid. Therefore, drug dissolution Isthe process by which drug molecules are liberated from a solid phaseand enter into a solution phase. If particles remain in the solid phaseonce they are introduced into a solution, a pharmaceutical suspensionresults.⁴

In the vast majority of circumstances, only drugs in solutioncan be absorbed, distributed, metabolized, excreted, or even exertpharmacologic action. Thus, dissolution is an important process inthe pharmaceutical science. Fundamentally the process is controlled by the relative affinity between the molecules of the solid substanceand those of the solvent. The extent to which the dissolutionproceeds under a given set of experimental condition is referred to asthe solubility of the solute in the solvent. The extent to which thedissolution proceeds under a given set of experimental condition isreferred to as the solubility of the solute in the solvent. The use ofpoorly soluble drug has a number of drawbacks such as increasingthe dosage, administration frequency and the resultant occurrence ofside effects. Furthermore, the rate-limiting step in the absorptionprocess for poorly water-soluble drugs is the dissolution rate of suchdrugs in the gastro intestinal fluids rather than the rapidity of their diffusion across the gut wall; it is however, important to improve theoral bioavailability of poorly water soluble drugs by improving theirdissolution rate and solubility.Factors affecting Solubility.⁵The solubility of a compound depends upon the physical and chemical properties of the solute and the solvent as well as various otherfactors like:

Temperature

Dielectric constant

Solvent

Particle size

Polymorphism

Salts

Pressure

Techniques⁶

The ability to increase the aqueous solubility and dissolution can be a valuable aid to increasing efficacy or reducing adverse effects forcertain drugs. Following approaches can be employed to enhancethe aqueous solubility and dissolution of a solid drug solute Use of co-solvent: weak electrolytes and nonpolar moleculesfrequently have poor water solubility. Their solubility usually can beincreased by the addition of water miscible solvent in which the drughas good solubility. This process is known as cosolvency, and thesolvents used in combination to increase the solubility of the drugsare known as cosolvents. The cosolvent system works by reducing theinterfacial tension between the predominately aqueous solution andthe hydrophobic solute. Cosolvents are employed not only to enhance solubility of the drug, but also improve the solubility of volatile constituents used to impart a desirable flavour and odour to theproduct The use of mixed solvent system is often necessary in pharmaceuticals when a drug is poorly soluble. Co-solvents such as ethanol, propylene glycol, glycerin, sorbitol and polyoxyethyleneglycolscan be used. Ternary diagrams are used to visualize where maximumsolubility occurs when more than one solvent is usedHydrotropy method:

Hydrotropy is a solubilization process wherebyaddition of large amounts of second solute results in an increase inthe aqueous solubility of another solute. Solute consists of alkalimetal salts of various organic acids. Hydrotropic agents are ionicorganic salts. Additives or salts that increase solubility in given sol-vent are said to “salt in” the solute and those salts that decreasesolubility “salt out” the solute.Several slats with large anions or cat ions that are themselves verysoluble in water result in “salting in” of non-electrolytes called “hydrotrdopic salts” a phenomenon known as “Hydrotropism”. Hydro-tropic solutions do nor show colloidal properties and involve a weakinteraction between the hydrotropic agents and solute. The term “Hydrotropy” has been used to designate the increase in aqueoussolubility of various poorly water soluble compounds due to thepresence of a large amount of additives, concentrated solutions ofsodium benzoate, sodium salicylate; urea, nicotinamide, sodium citrate and sodium acetate have been employed to enhance the aqueous solubility and dissolution of a large number of drugs.⁷

Figure 2: Preparation Techniques of Nanocrystals

Micronization The particle size reduction technique enhance thesolubility and dissolution rate of poorly-water soluble drugs due tothe enormous surface that is generated. The process involves reducing the size of the solid drug particle to 1 to 10 microns commonly byspray drying or by use of air attrition methods (fluid energy or jetmill). The process is also called as “Micro-milling”. Examples of drugwhose bioavailability have been increased by micronization includegriseofulvin and several steroidal and sulpha drugs.^8-9

Nanonisation It is a process whereby the drug powder is converted to nanocrystals of sizes 200-600 nm, e.g. Amphoteric B. Thenanocrystals yield as a product a dispersion of drug nanocrystals ina liquid, typically called “Nanosuspension”. There are three basictechnologies currently in use to prepare nanoparticles:

1. Pearl milling

2. Homogenization in water

3. Homogenization in non aqueous media or in water with water miscible liquid

Drug Release:

Drug release has been an important topic in the field of drug delivery for decades. With advancement in material design and engineering, novel materials with increasing complexity and more functions have been introduced into the development of drug delivery devices and systems. Both naturally derived and synthetic macromolecules are extensively used in controlled drug release to maximize bioefficacy, facilitate clinical applicability and improve the quality of life, just to name a few. “Drug release” refers to the process in which drug solutes migrate from the initial position in the polymeric system to the polymer’s outer surface and then to the release medium. This seemingly simple process is affected by multiple complex factors such as the physicochemical properties of the solutes, the structural characteristics of the material system, release environment, and the possible interactions between these factors^10-12

Methods of Preparation:

Predominantly two essential methodologies are engaged with the preparation of NCs the top-down technologies (Reducing to nano size of the largesize drug powder e.g. by mechanical attrition or wear down) and the bottom-up technologies (controlled precipitation /crystallization). However, the combination techniques, consolidating a pre-treatment with a subsequent size reduction step are additionally being utilized. This review focuses on the various production technologies available till now, also e.g. supercritical fluid.

Technologies and solvent evaporation. High-pressure homogenization, milling and precipitation are the key strategies utilized to prepare drug NCs. The significance for enhancing bioavailability of the poorly-soluble drugs by the production of drug NCs is generally acknowledged at this point. The top down methods basically include homogenization or milling while the bottom-up methods are primarily based on the principle of precipitation. The combination approaches include both top down method plus bottom down method. The main production technologies currently in use to produce drug NCs yield as a product a dispersion of drug NCs in a liquid, typically water (so called “nanosuspension”).¹³

Top-Down Approaches:

High-energy mechanical forces are associated with the top-down approaches, which can be given by either high- pressure homogenization (HPH) (IDD-P®, Disso Cubes® and Nan pure®) or media milling (MM) (NCs®) to pulverize large crystals.¹⁴

Figure 4: Approaches for Nanocrystals Preparation

Media Milling (NCs):

Nanocrystalline dispersions are formulated by using media milling processes. A milling chamber, recirculating chamber, motor, milling media and coolant are the key components of the media mill. The processing chamber is filled with raw slurry of drug, stabilizers and water. In the process, the milling chamber is fed with crude slurry of drug, water and stabilizers, and this was agitated by the motor. By the end, the slurry occupies 2% - 30% (w/v) space in the milling chamber, while the milling media takes 10%-50% (w/v) of the slurry. The reduction in size is achieved by the mechanical attrition and shear that developed due to the impact between a drug particle and the dividers of the processing chamber or processing media and drug particle or additionally between the two drug particles. The processing media are pearls or little globules made of ceramic (e.g. yttrium stabilized zirconium dioxide) or very cross-connected polystyrene resin or stainless steel or glass having diverse sizes (0.3mm or higher). However, the need is to prevent the formulation from contamination. Media. Range of concentrated drug is from 1 to 400mg/ml. Increased power created shear powers and/or the powers produced during impaction of the processing media with the medication give adequate vitality contribution to break drug crystal into nanometre measured particles. Recirculation is very advantageous to reduce milling time and decrease the particle size. The media milling process readily breaks micron-sized drug crystals into the dispersion of homogeneous nanoparticles. Therefore, the coolant is necessary to control the temperature during the size reduction process.¹⁵

Process Variables in Nanomilling:

Parameters to acquire ideal product through Nanomilling, have been found to incorporate and influenced by different factors like specific amount of drug, number of the processing pearls and size, milling time, processing speed and temperature. Ordinarily, the amount of medication in the chamber is very low, from 2 to 30% (wt.), while the number/volume of the milling pearls/beads is high, 10-50% of the volume of the slurry. Size of the Nanomilling pearls is kept consistent somewhere in the range of 0.5 and 1.0mm. The handling times and speeds required to get NCs of appropriate size range vary significantly. NCs are produced either by low milling velocities (80-90rpm) and longer processing time (1-5days) or high milling speed (1800-4800rpm) and shorter processing times (30-60 min).¹⁶

Figure 5: Media Milling Equipment

High Pressure Homogenization (HPH):

HPH is another top down procedure where the drug particle size is get reduced by shear powers, cavitation powers and drug particle colloid which is supported by high pressure conditions. There are of two types which were known by the micro fluidization and piston gap homogenization. While in HPH processing, drug suspensions are brought into a high-pressure homogenizer and went through a restricted homogenization pathway in an abrupt burst under high pressure: 1. Micro-fluidization is also called jet stream homogenization or air-jet milling wherein the particles are fragmented in a high pressure air jet induced by the collision of two fluid streams under the pressure of 1700 bar. 2. Piston-gap homogenization utilizes high pressure to constrain a fluid suspension through a narrow channel or a little gap inside a pipe. This procedure is commonly made out of three stages: (1) Drug powder dispersed in a pure solution or in a solution containing stabilizer, (2) Molecule size reduction by rapid shearing or low-pressure homogenization and (3) Use of high-pressure homogenization to get the reasonable particle size and size distribution.¹⁷

Bottom-up Techniques:

The bottom-up process forms NCs from solution, which comprises two main steps i.e. consequent crystal growth through nucleation process. In contrast to achieve small and uniform NCs, nucleation pathways are much more adaptive and used. Firstly, the molecules are present in solution phase, and then the molecules are aggregated/ combined to form particles which can be amorphous form or crystalline form. Nucleation can be triggered either by mixing with antisolvent or removal of solvent. This method can be named as ‘a classical precipitation processes. In this method, the drug is totally dissolved in a suitable solvent. Then this solvent solution is added to a non-solvent, causing precipitation of the drug. The mixing of drug solution and nonsolvent can be attained with conventional mixing equipment, i.e. agitator blade and magnetic stirring. To promote nucleation of particles, sonication can be used to provide cavitation effects. This method is called sonoprecipitation or sonocrystallization. However, an essential drawback of these precipitation method is that the utilization of a natural solvent which should be removed, prompting the high cost production. Precipitation has likewise been utilized in combination with homogenization. The significant limitation with precipitation is the uncontrolled development of particles which has resulted in its acceptance for only a few selected molecules. Especially, if there should arise an occurrence of low Aqueous and non-Aqueous dissolvable drug, the high amount of solvent volumes is required. Consequently, in the pharmaceutical business, the bottom up procedures has not been utilized to deliver the marketed drug. One exceptionally effective blending equipment has additionally been utilized to deliver NCs, including the confined impinging jet reactor, static mixer and multiple inlet vortex mixers. With these instruments, exceptional micro mixing scale blending between the two liquids would be possible in milliseconds. Recently, spray- freezing into fluid and controlled crystallization during freezedrying have additionally been developed to prepare NCs by evacuation of the solvent. Process variable of precipitation: The outcome of the process variables, temperature, rate of stirring and infusion rate of solute solution into the antisolvent, was streamlined in terms of how these aspects influence the local super saturation achieved at the initial phases of precipitation. The influence of processing parameters (volume and temperature of the heated aqueous solution; type of nozzle) and formulation aspects (total solid concentrations; stabilizer concentrations) on the size of suspended particles, can be determined by laser light diffraction. But, the size distribution of dispersed nanoparticles was shown to be mostly independent across the different formulation and processing parameters. It was studied that the kind of stabilizer used in the heated aqueous receiving solution is much more important than its actual temperature as an increase in temperature either resulted in an increase or decrease in the mean particle size. Processing also does not require a customized atomizing nozzle to produce submicron or micron-sized particles. Supercritical fluids (SCF) can also be used to make NCs by taking benefit of the exclusive physical characteristics of SCF, with joint diffusivity like gas and solubilization like liquid. Additionally, easy and fast elimination of SCF without too much drying can significantly facilitate the precipitation of nanoparticles. A problem related with this method/technology is that the created nanoparticle is required to be stabilized to avoid growth in micro to metre crystals. Lyophilisation is sometimes suggested to attain the predefined particle size. One more approach is to reserve the size of the precipitated NCs, by using polymeric growth inhibitors, if water phase viscosity increases then it can decrease particle growing.¹⁸

Stabilizing Agents for Ncs and Their Effect on Bioavailability:

Distribution of drug NCs in liquid media leads to so called “nanosuspension” (in contrast to “micro suspensions” or “macro suspensions”). In general, the dispersed particles need to be stabilized, such as by surfactants or polymeric stabilizers. Dispersion media can be water, aqueous solutions or non-aqueous media. For most Nanocrystalline formulations, drug concentration is 400mg/ml or less. The choice and concentration of stabilizer are selected to promote the particle size reduction process and generate physically stable formulations. To be effective, the stabilizer must be able to wet the surface of the drug crystals and providing a steric or ionic barrier. In the absence of the appropriate stabilizer, the high surface energy of nanometre sized particles would tend to agglomerate or aggregate the drug crystals. Physically stable Nanocrystalline formulations are obtained when the weight ratio of drug to stabilizer is 20:1 to 2:1. Too little stabilizer induces agglomeration or aggregation and too much stabilizer promotes Ostwald ripening. The process of identifying an appropriate stabilizer (s) for a drug candidate is empirical and can be accomplished using amount of drug in milligram. Pharmaceutical excipients such as the polysorbates, cellulosic, povidones and platonic are usually used that are acceptable stabilizers for creating physically stable nanoparticle dispersions. NCs are noticeably easy to prepare, but then again the stability and the selection of stabilizer (s) greatest challenging and critical step. The newly created drug NCs are stabilized by the stabilizer, but they also have a vital role in another types of formulations and they even influence bioavailability of drug in body, so before making stabilizer, it should be kept in mind. Choice of stabilizer can dramatically affect the performance of the optimized NCs during the further formulation steps and in vivo. Advancement of nanosized particles makes high energy surfaces, which can spin to aggregate and Ostwald ripening, if stabilization isn't at an efficient level. Stabilizers are surfactants, polymers or amphiphilic. Although greater part of the API materials that are promising candidate for NCs preparation are poorly/inadequately dissolvable and hydrophobic, the amphiphilic stabilizers will likewise enhance the wetting and disintegration properties of these materials. Stabilizers can be non-ionic or ionic in nature and the general steadiness depends on the established DLVO-hypothesis came to either by means of electrostatic powers or steric block.¹⁸

Characterization of NCS:

NCs are mainly formed as nanosuspension as a product but, the most convenient dosage form for the patient is a dry product, e.g. tablet or capsule. So, formulation of tablet andcapsule homogenization of NCs can be performed in polyethylene glycols being liquid at room temperature. It is a solid dispersion of drug NCs in solid PEG as outer phase. In a subsequent step milling can be performed yielding a flowable powder. The powder can be admixed to a standard mixture used for direct compression. As lined out above, the liquid PEG nanosuspension can be filled into soft gelatine capsules or alternatively into hard gelatin capsule which are subsequently being sealed. In vivo studies of NCs are performed according to the route of administration and thus animal model is designed⁶

Solubility:

Solubility is defined in Quantitative terms as the concentration of the solute in a saturated solution at a certain temperature. In Quantitative terms, solubility may be defined as the spontaneous interaction of two or more substances to form a homogeneous molecular dispersion. A saturated solution is one in which the solute is in equilibrium with the solvent. The solubility of a drug may express as Parts, Percentage, Molarity, Molality, Volume of fraction and Mole fraction. Solubility is an important determinant in drug liberation and absorption and hence plays a key role in its bioavailability⁴

Dissolution:

Dissolution is the process by which a solid solute enters a solution. In the pharmaceutical industry, it may be defined as the amount of drug substance that goes into solution per unit time under standardized conditions of liquid/solid interface, temperature and solvent composition. Drug dissolution testing plays an important role as a routine quality control test, for characterizing the quality of the products and also plays a major role in drug development⁷

Mechanism Over Increasing Solubility:

Decrease in particle size to nano range via nanocrystallization results in improved saturation solubility as well as dissolution velocity. The relation between the saturation solubility of a drug and its particle size is inversely proportional to each other (according) to which decrease in particle size results in increase in Surface area consequently saturation solubility of the drug. NCs offer large surface area which increase the contact area of each particle and solvent system which tremendously increase the passing of drug from bulk to solution hence dissolution velocity is fastened. This relationship can be expressed by simple Noyes Whitney equation, D = diffusion coefficient, A = surface area, Cs = saturation solubility, Cx = bulk concentration, h = Diffusional distance over which the concentration gradient happens The drop of particle size, increased saturation solubility, an enlarged surface area and a thinner diffusion layer can intensely increase the dissolution velocity, which ultimately improves bioavailability of drug in body. Therefore, reduction in particle size is a good approach to successfully improve the drug bioavailability where the drug’s dissolution speed is the rate limiting step Via moving to Nanonisation from micronization, the rate of dissolution increases because of particle shell is further increase. In many cases, a low dissolution speed is related to low saturation solubility but by enhancing the saturation solubility concentration gradient between the blood and gut lumen, then the absorption by passive diffusion. Like other nanoparticles, NCs showed up an increased or improved adhesiveness to tissue which generally lead to an enhancement in oral absorption of poorly soluble drugs apart from the increased dissolution rate and saturation solubility. To establish, the optimal drug NCs size and crystalline state/ amorphous, it all depends on the required blood profile for drug. Administration route and Stability of the amorphous state during shelf life of the product^17-20

Figure 6: Nanoparticle Based Drug & Formulation

CONCLUSION:

Drug nanocrystallization gives Innovative idea about poorly dissolvable drug. These involved in the formulation of medicine. This can be applicable to any route of administration.The enchantment of solubility leads to production of effective dosage form.There are various techniques of nanocrystallization which is effective in drug solubility and administration. Nanocrystallization is a new carrier for free colloidal drug delivery system. By increasing the solubility, drugcan achieve the better pharmacological response. Various method of nanocrystallization are introduced to boost of the drug response. It canbe very useful advanced technique for insoluble drug. Recently another bottom up technique is introduced to prevent the precipitation of drug.This nanocrystallization enhances the formulation of drugs. This can use for the conventional drug which are based on nano particle.

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Received on 17.11.2022 Modified on 12.03.2023

Res. J. Pharma. Dosage Forms and Tech.2023; 15(4):303-310.

DOI: 10.52711/0975-4377.2023.00048