Aim Nanoparticles can be produced by diminution of coarse drug particles down to submicron size by various milling or high pressure homogenization techniques; or starting from solutions where precipitation of the solute was induced by addition of an antisolvent. Particularly this technique has been widely investigated to obtain nanoparticles of various drugs: an organic solution, prepared with a good organic solvent for the solute, is introduced to the antisolvent (frequently water) under rapid mixing, which generates high supersaturation followed by fast nucleation that produces a large number of nuclei. The technique has the advantage of low cost, effective energy consumption and easy scaling up (spironolactone). This technique is usually referred to as ESD (emulsion solvent diffusion): when the organic solution is poured into the aqueous medium, discrete coacervate-like droplets are immediately formed; this quasi-emulsion rapidly experiments counterdiffusion out and into the droplets of the solvent and of the non-solvent respectively. This leads to a decrease of solubility of the solute in the droplet that produces first gelation and then solidification of the solute without any change of size of the droplet formed at initial stage of the process. Indomethacin is known to exist as solvate, polymorph and amorphous forms and the different forms do not exhibit the same stability and solubility and moreover their bioavailabilities are different. These aspects appear common to many drugs, as a consequence it is of a prime importance to develop a method to safely prepare for a given drug each form and to identify them. Methods The present study was carried out with indomethacin employing the ESD technique the analyzed by: TG (thermogravimetric analysis), DSC (different scanning calorimetry), XRD (X-ray diffraction) and HSM (thermomicroscopy). Results Acetone was used as a “good” solvent for the drug; water was used as a “poor” solvent for the drug; dichloromethane was used as “bridge” solvent, soluble in the “good” solvent and immiscible with the “poor” one. The method was tested for the following parameters: concentration of the drug; extent and mode of the stirring; concentration of the surfactant, employing indomethacin, as a model drug, very poorly soluble in water, for its ability to undergo polymorph transition and amorphization, being these processes driven by the ESD technique. The starting sample (gamma form) was dissolved in acetone and dichloromethane and added dropwise into in an aqueous solution containing surfactants, and stirred with ultra-turrax. The solid thus formed was found distributed between the foam, formed by the strong stirring, and the aqueous suspension. The material recovered from the foam displays a thermogram of an almost amorphous substance with a rounded endothermic centered at 148°C: this material is colored bright yellow. From the suspension, stirred overnight, a white material was obtained by filtration that the thermogram revealed to be the pure-alpha form of indomethacin. Gradually changing the ratio indomethacin/surfactants, while maintaining constant all the other parameters, it was observed a progressive increasing yield of the amorphous form in the final mixture. It was thus possible to calculate the optimum ratio necessary to control the polymorph transition to pure alpha-form or the complete amorphisation of the drug, passing through the formation of a solvate. The same technique was used also with diclofenac, ibuprofen and carbamazepine with different results. References Pignatello R, Bucolo C, Ferrara P, Maltese A, Puleo A, Puglisi G. Eudragit RS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofen. Eur J Pharm Sci.16(1-2):53-61; 2002.
EXTENDED ESD TECHNIQUE TO MODIFY THE PHYSICAL STATE OF DRUGS / M. di Cagno; C. Cavallari; E. Aiudi; A. Fini. - STAMPA. - (2012), pp. 64-64. (Intervento presentato al convegno CRS Nordic Chapter - Drug Delivery and Targeting2012 tenutosi a REYJAVIK nel June 3-5, 2012).
EXTENDED ESD TECHNIQUE TO MODIFY THE PHYSICAL STATE OF DRUGS
CAVALLARI, CRISTINA;FINI, ADAMO
2012
Abstract
Aim Nanoparticles can be produced by diminution of coarse drug particles down to submicron size by various milling or high pressure homogenization techniques; or starting from solutions where precipitation of the solute was induced by addition of an antisolvent. Particularly this technique has been widely investigated to obtain nanoparticles of various drugs: an organic solution, prepared with a good organic solvent for the solute, is introduced to the antisolvent (frequently water) under rapid mixing, which generates high supersaturation followed by fast nucleation that produces a large number of nuclei. The technique has the advantage of low cost, effective energy consumption and easy scaling up (spironolactone). This technique is usually referred to as ESD (emulsion solvent diffusion): when the organic solution is poured into the aqueous medium, discrete coacervate-like droplets are immediately formed; this quasi-emulsion rapidly experiments counterdiffusion out and into the droplets of the solvent and of the non-solvent respectively. This leads to a decrease of solubility of the solute in the droplet that produces first gelation and then solidification of the solute without any change of size of the droplet formed at initial stage of the process. Indomethacin is known to exist as solvate, polymorph and amorphous forms and the different forms do not exhibit the same stability and solubility and moreover their bioavailabilities are different. These aspects appear common to many drugs, as a consequence it is of a prime importance to develop a method to safely prepare for a given drug each form and to identify them. Methods The present study was carried out with indomethacin employing the ESD technique the analyzed by: TG (thermogravimetric analysis), DSC (different scanning calorimetry), XRD (X-ray diffraction) and HSM (thermomicroscopy). Results Acetone was used as a “good” solvent for the drug; water was used as a “poor” solvent for the drug; dichloromethane was used as “bridge” solvent, soluble in the “good” solvent and immiscible with the “poor” one. The method was tested for the following parameters: concentration of the drug; extent and mode of the stirring; concentration of the surfactant, employing indomethacin, as a model drug, very poorly soluble in water, for its ability to undergo polymorph transition and amorphization, being these processes driven by the ESD technique. The starting sample (gamma form) was dissolved in acetone and dichloromethane and added dropwise into in an aqueous solution containing surfactants, and stirred with ultra-turrax. The solid thus formed was found distributed between the foam, formed by the strong stirring, and the aqueous suspension. The material recovered from the foam displays a thermogram of an almost amorphous substance with a rounded endothermic centered at 148°C: this material is colored bright yellow. From the suspension, stirred overnight, a white material was obtained by filtration that the thermogram revealed to be the pure-alpha form of indomethacin. Gradually changing the ratio indomethacin/surfactants, while maintaining constant all the other parameters, it was observed a progressive increasing yield of the amorphous form in the final mixture. It was thus possible to calculate the optimum ratio necessary to control the polymorph transition to pure alpha-form or the complete amorphisation of the drug, passing through the formation of a solvate. The same technique was used also with diclofenac, ibuprofen and carbamazepine with different results. References Pignatello R, Bucolo C, Ferrara P, Maltese A, Puleo A, Puglisi G. Eudragit RS100 nanosuspensions for the ophthalmic controlled delivery of ibuprofen. Eur J Pharm Sci.16(1-2):53-61; 2002.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
