Dissolution rate enhancement of gliclazide by ordered mixing

Abstract

Ordered mixtures consist of adhering fine particles of a hydrophobic drug to the surface of larger particles of a water soluble carrier substance (1). Carrier particles dissolve in the presence of water, whereby adherent particles of the pharmaceutical substance disperse throughout the liquid. This eliminates the inherent tendency of hydrophobic drug particles to collect into not-readily dissolvable and dispersible aggregate. Literature reveals that various water soluble excipients such as lactose, mannitol, sorbitol and sodium chloride have been extensively used in preparation of ordered mixtures (1-3).Gliclazide is 1-(3,3a,4,5,6,6a-hexahydro-1H-cyclopenta[c]pyrrol-2-yl)-3-(4-methylphenyl)sulfonylurea with molecular mass of 323.41 (PubChem Database; http://pubchem. ncbi.nlm.nih.gov). Gliclazide is used for the treatment of type II non-insulin dependent The poorly water soluble antidiabetic drug gliclazide was selected to study the effect of excipients on dissolution rate enhancement. Ordered mixtures of micronized gliclazide with lactose, mannitol, sorbitol, maltitol and sodium chloride were prepared by manual shaking of glass vials containing the drug and excipient(s). Different water soluble excipients, addition of surfactant and superdisintegrant, drug concentration and carrier particle size influenced the dissolution rate of the drug. Dissolution rate studies of the prepared ordered mixtures revealed an increase in drug dissolution with all water soluble excipients. The order of dissolution rate improvement for gliclazide was mannitol > lactose > maltitol > sorbitol > sodium chloride. Composite granules of the particle size range 355-710 mm were superior in increasing the drug dissolution rate from ordered mixtures. Reducing the carrier particle size decreased the dissolution rate of the drug as well as the increase in drug concentration. Kinetic modeling of drug release data fitted best the Hixson--Crowell model, which indicates that all the ordered mixture formulations followed the cube root law fairly well.

Improvement of Dissolution Rate of Gliclazide Through Sodium Salt Formation

“…The log P values of 2.04 and 0.68 were obtained for GLZ and Na-GLZ, respectively (RSD less than 3.1%). These results agree with the previously published data for the partition coefficient of gliclazide (7,30). Accordingly, the salt form is approximately 20 times more hydrophilic than the untreated form.…”

“…Enhanced GLZ dissolution was also achieved via formulation of ordered mixtures of the hydrophobic drug with water-soluble carriers of larger particle size such as mannitol and lactose (7). Cationic and anionic surfactant micelles have also been studied as solubility enhancers for GLZ (5).…”

Solubility of Gliclazide in Transcutol + Water Co-solvent Mixtures at (298.15 to 333.15) K

“…4 Poor solubility and poor dissolution are the main obstacles for formulation development of GLZ. 1,2,4 The aqueous solubility of GLZ at 25 and 37 °C has been reported as < 40 and 55 µg ml -1 , respectively. 3,5 Various approaches such as surfactants, 5 solid dispersions, 1,4,[6][7][8][9][10] micronization, 11,12 ordered mixing, 2 co-grinding 13 and cyclodextrins complexation 14 have been applied to enhance solubility and dissolution rate of GLZ.…”

“…[1][2][3][4] It is very poorly soluble drug according to the biopharmaceutical classification system (BCS) of drugs (BCS class II) due to which its dissolution is poor. 2,4 Poor solubility and dissolution often resulted in poor in vivo absorption of such drugs. 4 Poor solubility and poor dissolution are the main obstacles for formulation development of GLZ.…”

“…1,2 It is a second generation hypoglycemic agent which is prescribed in the treatment of type 2 diabetes mellitus. [1][2][3][4] It is very poorly soluble drug according to the biopharmaceutical classification system (BCS) of drugs (BCS class II) due to which its dissolution is poor. 2,4 Poor solubility and dissolution often resulted in poor in vivo absorption of such drugs.…”