INTRODUCTION The dissolution properties of a drug and its release from a solid dosage form have a basic impact on its bioavailability. Solving solubility problems is a major challenge for the pharmaceutical industry with developments of new pharmaceutical products, since nearly half of the active substances are either insoluble or poorly soluble in water and display resistance to being wetted by and dissolved into the fluid in the gastrointestinal tract (Patravale et al., 2004). Since the dissolution rate of a drug is a function of its intrinsic solubility and its particle size, studies with poorly soluble drugs have demonstrated that particle-size reduction to the sub-micron range can lead to an increase in dissolution rate and higher bioavailability. Over the last 10 years, nanoparticle engineering processes have been developed and reported for pharmaceutical applications, such as the nanosuspensions, used to formulate compounds that are insoluble in both water and oils and to reformulate existing drugs to remove toxicologically less favourable excipients (Kesisoglon et al. 2007, Kocbek et al., 2006). In this work we aimed to test the efficiency of the technique of pseudo-emulsion to produce nanoparticles of indomethacin and evaluate how this technique affects the formation of indomethacin polymorphs. Nanoparticles were analyzed by means of size analysis, XRD, DSC, TGA, dissolution test. MATERIALS AND METHODS Indomethacin (Sigma Chemical, USA); Tween 80 (Kock Light Laboratories, LTD, England); Benzalkonium chloride (Carlo Erba, Milano, Italy); Stearic acid (Polichimica, Bologna, Italy); Eudragit® RS PO (Rohm Pharma Gmbh, Weiterstedt, Germany); Acetone; Phosphate buffer pH 7.4 ( Sörensen) Preparation of nanoparticles – Two solutions were prepared separately. An aqueous solution, suitably cooled in an ice bath to prevent temperature increase, contained the surfactant mixture and was stirred using turbo-emulsifier Ultra Turrax T25; the aqueous solution was dropwise added of an organic solution containing indomethacin dissolved in acetone, by means of a peristaltic pump. The emulsion thus formed is left under magnetic and slow stirring for 24 h to allow evaporation of the solvent. Nanoparticles of the drug were recovered by ultra-centrifugation (Alc 4239R-CFC-free). Powder X-ray diffraction (XRD) - To perform X-ray diffractometric analysis a Philips PW3719 diffractometer was used, controlled by a computer. Experimental conditions: Cu K_ radiation (X = 1.78896 A° ); 40 kV and 30 mA. Scanning interval: 5–50◦ 2θ; time per step: l s; graphite monochromator on the diffracted beam. Differential scanning calorimetry - Thermal and thermogravimetric analyses were performed with an automatic thermal analyzer system Mettler FP80 HT Central Processor and FP85 TA Cell and TGA (851/SF/1100). Solubility – Saturated aqueous solutions of the three different physical forms of indomethacin were left to equilibrate at 25° for 72 h. Determination of the solubility was carried out spectrophotometrically. RESULTS AND DISCUSSION An important step in the production of the nanoparticles with the pseudo-emulsion technique is their recovery from the reaction vessel, due to difficulties of filtration as well as evaporation of the solvent that leaves into the particle mass surfactants and inorganic salts used for the nanoparticles preparation. Ultracentrifugation demonstrated suitable to eliminate the solvent, followed by a leaching with water to dissolve foreign substances used for the preparation Thermal analysis revealed that indomethacin, in the gamma form as starting material: following the treatment of pseudo-emulsion, undergoes to a polymorph transition. The drug transforms first into the alpha form and then progressively into an amorphous form: these changes are documented by the position of the melting endotherm peaks in DSC thermogram. In the amorphous form the area surface of the peak dramatically decrea...

STUDY OF THE SOLID STATE OF INDOMETHACIN PARTICLES OBTAINED BY PSEUDO-EMULSION TECHNIQUE

CAVALLARI, CRISTINA;FINI, ADAMO;CORACE, GIUSEPPE;RODRIGUEZ, LORENZO
2010

Abstract

INTRODUCTION The dissolution properties of a drug and its release from a solid dosage form have a basic impact on its bioavailability. Solving solubility problems is a major challenge for the pharmaceutical industry with developments of new pharmaceutical products, since nearly half of the active substances are either insoluble or poorly soluble in water and display resistance to being wetted by and dissolved into the fluid in the gastrointestinal tract (Patravale et al., 2004). Since the dissolution rate of a drug is a function of its intrinsic solubility and its particle size, studies with poorly soluble drugs have demonstrated that particle-size reduction to the sub-micron range can lead to an increase in dissolution rate and higher bioavailability. Over the last 10 years, nanoparticle engineering processes have been developed and reported for pharmaceutical applications, such as the nanosuspensions, used to formulate compounds that are insoluble in both water and oils and to reformulate existing drugs to remove toxicologically less favourable excipients (Kesisoglon et al. 2007, Kocbek et al., 2006). In this work we aimed to test the efficiency of the technique of pseudo-emulsion to produce nanoparticles of indomethacin and evaluate how this technique affects the formation of indomethacin polymorphs. Nanoparticles were analyzed by means of size analysis, XRD, DSC, TGA, dissolution test. MATERIALS AND METHODS Indomethacin (Sigma Chemical, USA); Tween 80 (Kock Light Laboratories, LTD, England); Benzalkonium chloride (Carlo Erba, Milano, Italy); Stearic acid (Polichimica, Bologna, Italy); Eudragit® RS PO (Rohm Pharma Gmbh, Weiterstedt, Germany); Acetone; Phosphate buffer pH 7.4 ( Sörensen) Preparation of nanoparticles – Two solutions were prepared separately. An aqueous solution, suitably cooled in an ice bath to prevent temperature increase, contained the surfactant mixture and was stirred using turbo-emulsifier Ultra Turrax T25; the aqueous solution was dropwise added of an organic solution containing indomethacin dissolved in acetone, by means of a peristaltic pump. The emulsion thus formed is left under magnetic and slow stirring for 24 h to allow evaporation of the solvent. Nanoparticles of the drug were recovered by ultra-centrifugation (Alc 4239R-CFC-free). Powder X-ray diffraction (XRD) - To perform X-ray diffractometric analysis a Philips PW3719 diffractometer was used, controlled by a computer. Experimental conditions: Cu K_ radiation (X = 1.78896 A° ); 40 kV and 30 mA. Scanning interval: 5–50◦ 2θ; time per step: l s; graphite monochromator on the diffracted beam. Differential scanning calorimetry - Thermal and thermogravimetric analyses were performed with an automatic thermal analyzer system Mettler FP80 HT Central Processor and FP85 TA Cell and TGA (851/SF/1100). Solubility – Saturated aqueous solutions of the three different physical forms of indomethacin were left to equilibrate at 25° for 72 h. Determination of the solubility was carried out spectrophotometrically. RESULTS AND DISCUSSION An important step in the production of the nanoparticles with the pseudo-emulsion technique is their recovery from the reaction vessel, due to difficulties of filtration as well as evaporation of the solvent that leaves into the particle mass surfactants and inorganic salts used for the nanoparticles preparation. Ultracentrifugation demonstrated suitable to eliminate the solvent, followed by a leaching with water to dissolve foreign substances used for the preparation Thermal analysis revealed that indomethacin, in the gamma form as starting material: following the treatment of pseudo-emulsion, undergoes to a polymorph transition. The drug transforms first into the alpha form and then progressively into an amorphous form: these changes are documented by the position of the melting endotherm peaks in DSC thermogram. In the amorphous form the area surface of the peak dramatically decrea...
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C. Cavallari; A. Fini; M. Di Cagno; G. Corace; L. Rodriguez
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11585/104055
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