You are hereA recent review on enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications

A recent review on enhancement of solubilization and bioavailability of poorly soluble drugs by physical and chemical modifications


(15) Nanocrystallization
The nanocrystallization is defined as a way of diminishing drug particles to the size range of 1-1000 nanometers.  There are two distinct methods used for producing nanocrystals; ’bottom-up’ and ’top-down’ development. The top-down methods (i.e. Milling and High pressure homogenization) start milling down from macroscopic level, e.g. from a powder that is micron sized. In bottom-up methods (i.e. Precipitation and Cryo-vacuum method), nanoscale materials are chemically composed from atomic and molecular components.

 (15.1) Milling
Nanoscale particles can be produced by wet milling process. In ball mills, particle size reduction is achieved by using both impact and attrition forces. The most common models are a tumbling ball mill and a stirred media mill. The degradation of mill surfaces and subsequent suspension contamination are problems of this method.

(15.2) High pressure homogenization
In high pressure homogenization, an aqueous dispersion of the crystalline drug particles is passed with high pressure through a narrow homogenization gap with a very high velocity. Homogenization can be performed in water or alternatively in non-aqueous media or water-reduced media. The particles are disintegrated by cavitations and shear forces. The static pressure exerted on the liquid causes the liquid to boil forming gas bubbles. When exiting from the gap, gas bubbles collapse under normal air pressure. This produces shock waves which make the crystals collide, leading to particle disintegration. A heat exchanger should be used when operating on temperature sensitive materials because high pressure homogenization causes increase in the sample temperature .The particle size obtained during the homogenization process depends primarily on the nature of the drug, the pressure applied and the number of homogenization cycles.

(15.3)Precipitation
In the precipitation method, a dilute solution is first produced by dissolving the substance in a solvent. The solution with the drug is then injected into water, which acts as a bad solvent. At the time of injection, the water has to be stirred efficiently so that the substance will precipitate as nanocrystals. Nanocrystals can be removed from the solution by filtering and then dried in air. 

(15.4) Cryo-vacuum method
In the cryo-vacuum method, the active ingredient is first dissolved in water to attain a quasi-saturated solution. The method is based on sudden cooling of a solvent by immersing the solution in liquid nitrogen (-196 ºC) which causes a very fast rise in the degree of saturation based on the decrease of solubility and development of ice crystals when the temperature drops below 0 ºC. This leads to a fast nucleation of the dissolved substance at the edges of the ice crystals. The solvent must be completely frozen before the vessel is removed from the liquid nitrogen. Next the solvent is removed by sublimation in a lyophilization chamber where the temperature is kept at constant -22 ºC and the pressure is lowered to 10-2 mbar. Cryo-assisted sublimation makes it possible to remove the solvent without changing the size and habit of the particles produced, so they will remain crystalline. The method yields very pure nanocrystals since there is no need to use surfactants or harmful reagents. 

(15.5) Nanomorph
The Nanomorph technology is to convert drug substances with low water-solubility from a coarse crystalline state into amorphous nanoparticles. A suspension of drug substance in solvent is fed into a chamber, where it is rapidly mixed with another solvent. Immediately the drug substance suspension is converted into a true molecular solution. The admixture of an aqueous solution of a polymer induces precipitation of the drug substance. The polymer keeps the drug substance particles in their nanoparticulate state and prevents them from aggregation or growth. Water redispersable dry powders can be obtained from the nanosized dispersion by conventional methods, e.g. spray-drying. Using this technology the coarse crystalline drug substances are transformed into a nanodispersed amorphous state, without any physical milling or grinding procedures. It leads to the preparation of amorphous nanoparticles [86]. Table 5,6 shows that nanotechnology approaches to improve the solubility of hydrophobic drugs.

Table 5. Nanotechnology approaches to improve the solubility of hydrophobic drugs

S.No.

Nanoparticulate  technologies

Description

 1.

 Nanocrystal


Nanocrystal drug particles (<1,000 nm) produced by wet-milling and stabilised against agglomeration through surface adsorption of stabilizers; applied to NMEs eg aprepitant/reformulation of existing drugs eg.  Sirolimus.

 2.

 Biorise

Nanocrystals/amorphous drug produced by physical breakdown of the crystal lattice and  stabilised with biocompatible carriers   (swellable microparticles or cyclodextrins).

 3.

 IDD (Insoluble Drug Delivery)

Micro-nm particulate/droplet water-insoluble drug core stabilized by phospholipids; formulations are produced by high shear, cavitations or impaction.

 4.

 CAP (Calcium   Phosphate-based nanoparticles)

For improved oral bioavailability of hormones /proteins such as insulin; also as vaccine adjuvant.

 5.

 NAB (Nanoparticle Albumin-Bound technology)

Injectable suspension of biocompatible protein with drug improves solubility/removes need for toxic solvents; eg paclitaxel-albumin nanoparticles, injectable suspension of biocompatible protein with drug improves.

 6.

 Nanoedge

Nanoedge technology: drug particle size reduction to nanorange by platforms including direct homogenization, micro precipitation, lipid emulsions and other dispersed-phase technology.

 7.

 BioSilicon

Drug particles are structured within the nano-width pores of biocompatible biosilicon microparticles, membranes or fibres; gives controlled release/improves solubility of hydrophobic drugs.

 8.

 NanoGate

Silicon membrane with nano-width pores (10-100 nm) used as part of an implantable system for drug delivery and biofiltration.

 9.

 NLC8 (Nanostructured Lipid Carriers)

Nanostructured lipid particle dispersions with solid contents produced by high-pressure homogenization; lipid-drug conjugate nanoparticles provide high-loading capacity for hydrophilic drugs for oral delivery.

Table 6. List of poorly soluble drugs along with methods for increasing solubility

S. No.

For  increasing methods solubility

Poorly soluble drugs

1

Nanoparticulation

Dolargin, Loperamide, Tubocurarine, Doxorubicin, Ibuprofen, Diazepam, Naproxen, Carbamazepine, Griseofulvin, Nifedipine, Phytosterol

2

Nanosuspension

Omeprazol, Domperidone, Zidovudine

3

Inulin Glass

Cyclosporin, Diazepam, Amoxacilline, Bacitracin, D9tetra hydro cannabinol                                                                                          

4

Mixed micelle

Adriamycin, Doxorubicin, Paclitaxel

5

RESS

Aspirin, Ibuprofen, Nifedipine, β-Estradiol, Lovastatin, Stigmasterol, Salicylic acid

6

SAS

Lysozyme, Trypsin

7

PCA

Insulin, Hydrocortisone

8

GAS

Dexamethasone

CONCLUSIONS
The solubility of the drug is the factor that controls the formulation of the drug as well as therapeutic efficacy of the drug, hence the most critical factor in the formulation development. Dissolution of drug is the rate determining step for oral absorption of the poorly water soluble drugs and solubility is also the basic requirement for the formulation and development of different dosage form of different drugs. The various techniques described above alone or in combination can be used to enhance the solubility of the drug. Although all techniques mentioned above could enhance the solubility, the choice of the method will be based on its effectiveness as well as safety in terms of biocompatibility of the excipient used. For orally administered drugs solubility is one of the rate limiting parameter to achieve their desired concentration in systemic circulation for pharmacological response. Solubility can be enhanced by many techniques and number of folds increase in solubility. Because of solubility problem of many drugs the bioavailability of them gets affected and hence solubility enhancement becomes necessary. It is now possible that to increase the solubility of poorly soluble drugs with the help of various techniques as mentioned above.

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