INTRODUCTION:

The novel and potential applications of nanotechnology in pharmaceutics are; development of diagnostic tools, formulation of drug carrier systems and gene therapy⁽¹⁾. The advantages of nanotech drugs compared to conventional drugs on the basis of particle size. Drugs/drug products with nano dimension can be used at lower concentration and can lead to early onset of bioactivity.⁽²⁾Nano drug delivery systems are nanoparticles, nanospheres, naosponges, nanoemulsions, solid lipid nanoparticles, nanovesicular system (Liposome, niosomes), molecular system (inclusion complexes) and Nanocrystals^(3).Nanocrystals are crystals having size less than 1μm.As the particle size of crystals is decreased to about 100nm there is a drastic change in the properties of the material.

The decreased size increases the surface area and solubility of drug manifolds and there is proportionate increase in the bioavailability of poorly soluble drug.⁽⁴⁾ Nanocrystals may be able to reduce the dose to be administered, provide a sustained drug release and increase patient compliance.⁽⁵⁾ A particle size reduction down to the nanometres rage can increase the drug solubility.⁽⁶⁾Nanocrystal offer a quick action onset due to faster dissolution and rapid absorption .This is advantageous particularly for drugs were a quick action is desired eg: naproxen for relief of headache. The bio-availability of various drugs has been found to increase significantly when administered in the form of nanocrystals.⁽⁷⁾Limitations of drug Nanocrystaltechnology: Many nanoparticulate delivery systems are under academic investigation. But only few made it to the market. This may be due to missing nanotoxicity and cytotoxicity data. Nanotoxicity may be attributed to the small size (below about 150 nm) of nanocrystals, due to which they can have access to any cell of the body via pinocytosis. This increases the risk of cytotoxicity. ⁽⁸⁾

Figure 1. Images for Nanocrystals

Advantages of nanocrystals:

• Increased rate of absorption,

• Increased oral bioavailability,

• Rapid effect,

• Improved dose proportionality,

• Reduction in required dose,

• Reduction in fed/fasted variability,

• Rapid, simple and cheap formulation development

• Possibility of high amounts (30-40 %) of drug loading,

• Increased reliability. Usually side effects are proportional to drug concentration, so decreasing the concentration of active drug substances leads to an increased reliability for patients ^{(9, 10)}.

• Applicability to all poorly soluble drugs because all these drugs could be directly disintegrated into nanometer-sized particles.

• Sustained crystal structure. Nanocrystal technology leads to an increase in dissolution rate depending on the increase in surface area obtained by reduction of the particle size of the active drug substance down to the nano size range preserving the crystal morphology of the drug ⁽¹¹⁾.

• Improved stability. They are stable systems because of the use of a stabilizer that prevents reaggregation of active drug substances during preparation ⁽¹²⁾. Suspension of drug nanocrystals in liquid can be stabilized by adding surface active substances or polymers.

• Applicability to all routes of administration in any dosage form. Contrary to micronized drugs, nanocrystals can be administered via several routes. Oral administration is possible in the form of tablets, capsules, sachets or powder; preferably in the form of a tablet. Nanosuspensions can also be administered via the intravenous route due to very small size, and in this way, bioavailability can reach 100 %.

Preparation of nanocrystal:

Basically three principles can be used: milling, precipitation methods, homogenization method and their combinations. The industrial relevant methods are:

1. Bottom up technique

Nanoprecipitation

2. Top down technique

 Pearl/ball milling

 High pressure homogenization

 Micro fluidizer technology

 Piston gap homogenization in water

 Piston gap homogenization in non aqueous medium

3. Top down & bottom up

4. Spray drying

Bottom up: (precipitation):

Technology begins with the molecule; active drug substance is dissolved by adding an organic solvent, and then, solvent is removed by precipitation. “Bottom up “technology relies on precipitation .The principle of this method is based on the dissolution of the active drug substance in an organic solvent which is then added in to a non solvent. In the presence of stabilizers, thereafter, the nanocrystals are precipitated.

Advantages:

· It is simple

· Low cost

· Scale up is simple in this method

Disadvantage:

· The drawbacks of this technique are that the drug needs to be soluble in at least one solvent⁽¹³⁾

Top down: (Homogenization and milling):

“Top –down” technology applies dispersing methods by using different types of milling and homogenization techniques. “top-down” technology is more popular than “Bottom up” technology; it is known as “nanosizing”. In other words, it is a process which breaks down large crystalline particles in to small pieces. ^{(14, 15)}

Pearl/ball milling:

In this technique, the drug along with the milling media, dispersion media and the stabilizer is fed in to the milling chamber .Milling balls or small pearls are used as milling media. The movement of milling media generates high shear forces and forces of impact which leads to particle size reduction. Two basic principle of milling are employed .Either the milling material can be moved by an agitator or the complete container may be moved in a complex movement. ⁽¹⁶⁾

Advantage:

· Low cost

· Simple technology and ability for large scale production

Disadvantage:

· Erosion from the milling material leading to product contamination

· Adherence of the product to the inner surface of the mill and to the surface of the milling pearls⁽¹⁷⁾

High pressure Homogenization Technique:

· This technique is carried out either in water or a non aqueous media.

Micro fluidizer technology:

This technology is based on the jet stream principle. Two stream of liquid with high velocity collide frontally under high pressure⁽¹⁸⁾. The particle size is reduced due to high shear force particle collision and cavitation. ⁽¹⁹⁾ The collision chamber can be either Y-type or Z-type in shape. Surfactants or phospholipids are required to stabilize the desired particle size^(20,21)

Piston gap homogenization in water:

(Dissocubes® technology).In this technique, powdered drug is dispersed. in an aqueous surfactant solution which is then forced by a piston through tiny homogenization gap under high pressure. ⁽²²⁾

Piston-gap homogenisation in water reduced mixtures or non aqueous medium:

(Nanopure ® technology) This technology uses non-aqueous phase or phases with reduced water content as dispersion media. Use of non aqueous media is advantageous for drug, which undergo hydrolysis in water. The different media used for homogenization includes oils water glycerol mixtures, water- alcohol mixtures etc. The forces like collision and shear forces occurring in highly turbulent fluid in the gap is responsible for the size reduction ^(23,24,25).

Top down and bottom up technology:

In “top down and bottom up” (Figure 1) technology, both methods are used together. In which combine a pre-treatment step followed by a high energy homogenization.⁽²⁶⁾NANOEDGE® Technology (Micro precipitation and homogenization) It involves a combination of precipitation followed by annealing process. Smart Crystal® technology in which different combination process are used which depending upon the physical characteristics of the drug.

Advantages:

· Combination technology can overcome crystal growth.

· Better physical stability.

Disadvantage:

· Its cost is high^(27,28)

Figure 2.Top-down and Bottom-up Technology

Spray drying:

Spray drying (Figure 2) is usually used for drying of solutions and suspensions .In a conical or cylindrical cyclone, solution droplets are sprayed from top to bottom, dried in the same direction by hot air and spherical particles are obtained. Spraying is made with an atomizer which rapidly rotates and provides scattering of the solution due to centrifugal effect. The solution is sent to the inner tube with a peristaltic pump, at a certain flow rate, Nitrogen or air at a constant pressure is sent to the outer tube. Spraying is provided by nozzle. Droplets of solution

Figure 3.Spray drying

Become very small due to spraying; therefore, surface area of the drying matter increases leading to fast drying. Concentration, viscosity, temperature, and spray rate of the solution can be adjusted and particle size, fluidity and drying speed can be optimized. ^(29,30)

Application of nanocrystals

Figure 4.Application of nanocrystals

Oral drug delivery:

In oral drug delivery (Figure 5) Due to fast dissolution of nanocrystals, the drug solubility is enhanced, making it bioequivalent in fed and fasting conditions. The bio adhesive nature of nanocrystals offers additional advantage of increased stay in the gastro –intestinal tract which enhances bioavailability ^(31,32).

Figure 5.Application of Nanocrystal in oral drug delivery

Dermal application:

Nanocrystals can increase the penetration of poorly soluble cosmetic and pharmaceutical substances in to skin .This happened because increased saturation solubility increased the concentration gradient ⁽³³⁾.

Targeted drug delivery:

Nanocrystals can have deep excess to the human body because of particle size and control of surface properties. So they can also be used for targeted drug delivery ⁽³⁴⁾. (Figure 4)

Parental drug delivery:

carrier –free nanosuspensionsenable potential higher loading capacity compared to other parental application system .using nanosuspensions, the application volume can be reduced compared to solutions ⁽³⁵⁾.(Figure 6)

Figure 6.Parentral drug delivery

Ophthalmic drug delivery:

Nanosuspensions can prove beneficial for drugs that have poor solubility in lachrymal fluids. It have high drug loading which avoids high tonicity created by water soluble drug. Nanosuspension have prolonged retention time in the eye ⁽³⁶⁾.(Figure 7)

Figure 7.Ophthalmic drug delivery in nanocrystals

Pulmonary drug delivery:

Poorly soluble drug can be delivered directly to the lungs by nebulising the aqueous nanosuspensions .Using nanoparticles; drug is more evenly distributed in droplets. Poorly water soluble corticosteroid, has been successfully prepared as a nanosuspensions for pulmonary delivery⁽³⁷⁾.

CONCLUSION:

Besides other approaches (e.g. solid dispersions, the use of co-solvents) particle reduction to the sub micron range is a potent formulation approach to increase the dissolution rate as well as solubility and in turn to increase the oral bioavailability of poorly soluble drugs. The nanosuspension technique has been specifically used to increase the rate and extent of the absorption of drugs, which have poor and erratic dissolution. In the current decade, the concept of nanosuspensions could be commercially exploited by pharmaceutical companies. Therefore, drug nanocrystals represent an alternative technique existing drug delivery technology for poorly soluble drugs.

REFERENCES:

1. Zhang L, Webster TJ. Nanotechnology and Nanomaterials. Promises for Improved Tissue Regeneration. Nano Today 2009; 4:66-80.

2. Chan VSW. Nanomedicine. An unresolved Regulatory issue. Regular Toxicolpharmacol2006; 46:218-224.

3. Keck CM, Muller RH. Drug Nanocrystals of poorly soluble Drug products by High Pressure Homogenisation. Eur J Pharm and Biopharm 2006; 62:3-16.

4. Grant DJW, Brittan HG, In Britton HG(Ed). Physical characterization of pharmaceutical solids. Marcel Dekker, New York 1995.

5. De Waard H, De Beer T, Hinrichs WLJ, Vervaet C, Remon JP, Frijlink HW. Controlled crystallization of the lipophilic drug Fenofibrate during Freeze drying. Elucidation of the mechanism by in – line Raman spectroscopy. The AAPS Journal 2010sss; 12(4):569-575.

6. Brunner E, Reaktionsgeschwindigkeit in heterogenen Systemen. Z Phys Chem. (1904); 47 (1):56-102.

7. Liversidge GG, Conzentino p. Drug particle size reduction for decreasing gastric irritancy and enhancing absorption of naproxen in rats. Int J Pharm 1995; 125: 309-313.

8. Sanjay B, Meena B, Rachna K. Nanocrystals: Current Strategies and Trends International Journal of Research in pharmaceutical and Biomedical sciences ISSN: 2229-3701.

9. Coppola D. Nanocrystal Technology Targets Poorly Water-soluble Drugs. Pharm Tech 27: 20, 2003.

10. Riehemann K, Schneider SW, Luger TA, Godin B, Ferrari MF, Fuchs H. Nanomedicine –challenge and perspectives. Angew ChemInt Ed 48: 872-897, 2009.

11. Waard H, Hinrichs WLJ, Frijlink HW. A Novel Bottom-Up Process to Produce Drug Nanocrystals: Controlled Crystallization During Freeze-Drying. J Control Release128: 179-183, 2008.

12. Technology Focus Helping you bring products to market. Serial online: 23 March2007 Available from: URL:http://www.elan.com/Images/Elan_Technology_07v1_tcm3-17145.pdf

13. Speiser P P, Poorly soluble drugs a challenges in drug delivery;1998.Muller R H, Benita S, Bohm B(eds) Emulsions and Nanosuspension for the Formulation Of Poorly Soluble Drug. Medpharm Stuttgart .Scientific Publishers:15-28

14. Waard H, Hinrichs WLJ, Frijilink HW. A Novel bottom- up Process to produce drug nanocrystals. Controlled crystallization during freeze drying. J control Release 2008; 128:179-183.

15. Geissler M, XiaY. Patterning principles and some new developments.Adv mater.16.1249-1269.

16. Merisko-Liversidge E, Liversidge G G, Copper E R. Nanosizing: a formulation approach for poorly water soluble compounds. Eur J Pharma sci.2003; 18, 113-20.

17. Buchmann S, Fischli W, Thiel F P, Alex R. Aqueous microsuspension, an alternative intravenous formulation for animal studies. In: 42nd annual congress of the International Association for Pharmaceutical Technology (AVP), Mainz .1996.

18. Bruno RP, Mcilwrick R. Microfluidizer processor technology for high performance particle size reduction, mixing and dispersion. Eur J Pharm.1999; Biopharm 56,29-36.

19. Tunick MH, Van Hechen DL, Cook PH, etal. Transmission electron microscopy of mozzarella cheeses made from microfluidized milk. J Agric Food Chem. 2002; 50, 99-103.

20. Sunstrom JE, William R, Marshik-GuertsB. General route to Nanocrystalline Oxides by Hydrodynamic Cavitation. Chem master. 1996; 8(8), 2061-2067.

21. Gruverman IJ, Thum JR. Production of Nanostructures Under Turbulent Collision Reaction Conditions-Application to catalysts, Superconductors, CMP Abrasives, Ceramics and other Nanoparticles. Microfluidics Reserch.

22. Muller RH, Peters K, Becker r, etal. Nanosuspensions-a novel formulation for the IV administration of poorly soluble drugs. I st World Meeting of the International Meeting on Pharmaceutics, Biopharmaceutics and Pharmaceutical Technology; Budapest.1995

23. Muller RH, Mader K, Krause K. Pharmasol GmbH, Dispersions for formulation slightly or poorly soluble active ingredients. Pat: CA000 2388550A1, 2002: feb 7.

24. Radtke M, Nanopure TM. Pure drug nanoparticles for the formulation of poorly soluble drugs.New drugs. 2001; 3, 62-68.

25. Finchera MA, Kerck CM, MullerRH. Nanopure Technology-Drug Nanocrystal for the Delivery of poorly soluble Drugs ,in Particles. Orlando 2004.

26. Keck C M, Muller R H. Drug Nanocrystals of poorly soluble Drugs Produced by High Pressure Homogenisation. Eur J Pharm and Biopharm 2006; 62:3-16.

27. Kipp JE, Wrong JCT, Doty MJ, etal. Micropricipitation method for preparing submicron suspension.2003;US patent 6607784.

28. Frichera MA, Wissing SA Muller RH. Effect of 4000 Bar Homogenisation Pressure on Particle Diminution in Drug Suspension, in APV.Niirnberg2004.

29. Corrigan OI, Crean AM. Comparative physiochemical Properties of Hydrocortisone/PVP Composites prepared Using Supercritical Carbon Dioxide by the GAS Anti-Solvent Recrystallization Process, by Co precipitation and by Spray Drying. Int J Pharm 2002; 245:75-82.

30. Yin SX, Franchini M, Chen J, Hsieh A, Jen S, Lee T, Hussain M, Smith R. Bioavailability Enhancement of a COX-2 inhibitor, BMS-347070, from a Nanocrystaline Dispersion prepared by Spray-Drying. J Pharm sci 2005; 94:1598-1607.

31. Jacobs C, Kayser O, Muller RH. Production and characterization of mucoadhesive nanosuspension for the formulation of Buparvaquone. Int J pharm 2001; 214 :( 1-2), 3-7.

32. Muller RH, Jacobs C. Buparvaquone Mucoadhesive Nanosuspension: preparation Optimization and long term stability. Int J pharm .2002; 237(1-2), 151-161.

33. Peterson R. Nanocrystals for use in topical cosmetic formulation and method of production thereof.US Patent Application No.60/8866, 233.2006.

34. Kayser O. Nanosuspensions for the formulation of aphidicolin to improve drug targeting effects against Leishmania infected macrophages. Int J Pharm. 2000; 196:253-256.

35. Moschwitzer J, Achleitner G, Popmer H, Muller RH. Development of an intravenously injectable chemically stable aqueous omeprazole formulation using nanosuspension technology. Eur J pharm Biopharm 2004; 58(3):615-619.

36. PignatelloR. Eudragit RS 100 nanosuspension for the ophthalmic controlled delivery of ibuprofen. Eur J pharm sci 2002; 16:53-61.

37. Muller RH, Jacob C. Production and characterization of budenosidenanosuspensions for pulmonary administration. Pharma Res 2002; 19:189-94.

Received on 06.01.2016 Modified on 27.01.2016

Res. J. Pharm. Dosage Form. and Tech. 2016; 8(2):122-126.

DOI: 10.5958/0975-4377.2016.00016.1