13-07-2012, 12:12 PM
Improved physicochemical characteristics of artemisinin-nicotinamide solid dispersions by solvent evaporation and freeze dried methods
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INTRODUCTION
Artemisinin (ARMN) like quinine has been originated from herb named Artemisia annua (Qinghaosu) but is structurally a more distinct compound containing endoperoxide group having antimalarial activity (fig. 1). It is useful for treating drug-resistant malaria caused by Plasmodium falciparum. It act faster, has a broad stage-specificity of action and is extremely well tolerated. Evidence of its safety and efficacy comes from large randomised trials in tens of thousands of patients. This artemisinin family is drug of choice for treatment of uncomplicated malaria at the moment (Elizabeth et al, 2005). Being poorly soluble in water, it is not completely absorbed by orally dosage forms and typically exhibits dissolution rate limited absorption. The poor dissolution characteristics of relatively insoluble drugs have been a challenge for formulation development scientists. Numerous solid dispersion systems have been demonstrated in the pharmaceutical literature to improve the dissolution properties of poorly soluble drugs (Aggarwal et al., 2010; Dhirendra et al, 2009; Varma and Pandi, 2005). Solid dispersions of artemisinin with polyvinylpyrrolidone (Nijlen et al., 2003), Eudragit (Hoa and Longl, 1999), Sunderland, 2008), artemether (Ansari et al., 2010). To our knowledge there is no report available about preparation and evaluation of artemisinin-nicotinamide solid dispersions.
MATERIALS AND METHODS
Materials
Artemisinin (Alchem, New Delhi, India), methanol (Sigma-Aldrich, Germany), nicotinamide (BDH chemicals Limited, Germany), sodium hydroxide (Merck Ltd, Germany), potassium bromide (FTIR grade, Fisher chemicals USA), Acetone (Merck, Germany), Starch (Rafhan Maize, Pakistan), Lactose (DMV international Netherlands), Magnesium stearate (Royal Tiger products, Taiwan). Demi water was used for the dilution of various samples.
Dissolution profile
Physical mixtures of artemisinin with nicotinamide at different drug-carrier ratios exhibited enhanced dissolution than artemisinin alone in demi water (Fig 3). Physical mixtures showed enhanced dissolution rate with rise of nicotinamide content up to drug-carrier ratio 1:6 followed by decrease in successive ratios i.e. 1:8 and 1:10. Dissolution was substantially increased compared to pure artemisinin i.e. 3.14 times by 1:1 ratio, 3.29 times (1:4), 3.59 times (1:6), 3.41 times (1:8), 3.48 times (1:10). SLVPs exhibited higher rate of dissolution (47.10-65.88%) than respective PMs. They exhibited higher dissolution rate i.e. 4.62 times by 1:1 ratio, 4.96 times by 1:4 ratio, 5.96 times by 1:6 ratio
DSC thermograms
Artemisinin was melted at 151.03°C and showed immense crystallization behavior at 210.04°C. These melting and crystallization peaks were found in all samples and at all ratios but having altered melting temperatures than artemisinin and nicotinamide. It indicates that artemisinin was not completely soluble in nicotinamide. DSC thermograms of physical mixtures, solid dispersions by solvent evaporation showed substantial decrease in melting and crystallization temperature except 1:6 ratio of PMs and SLVPs than artemisinin alone. All samples at drug-carrier 1:1-1:4 showed melting temperatures below the both partner i.e. artemisinin/nicotinamide. In these samples the physical state of drug has been changed to a high-energy state and high disorder which corresponds to decrease in melting temperature and it resulted in enhanced solubility and faster dissolution (Won et al, 2005). Physical mixtures and its respective SLVPs showed gradual increase in melting temperature with rise of NA up to maximum peak temperature at drug-carrier 1:6 ratio followed by decline.
CONCLUSIONS
XRD patterns of solid dispersions by solvent evaporation method (SLVPs) exhibited more displaced angles, decreased intensity and synergistic effect at higher drug-carrier ratios compared to physical mixtures whereas in freeze dried solid dispersions (FDSDs), some peaks of artemisinin and nicotinamide were masked, showed least number of peaks having low intensity and maximum displaced angles. FTIR spectra revealed stronger interaction among N-H group of nicotinamide and C=O group of artemisinin in SLVPs compared to respective PMs. FDSDs and SLVPs imparted different kinds of bonding i.e. probably FDSDs showed London forces in addition to hydrogen bonding as exhibited by SLVPs. DSC thermograms of PMs and SLVPs showed different thermal behavior compared to FDSDs i.e. gradual increase in melting endotherms were observed up to drug-carrier ratio 1:6 followed by decline in PMs and SLVPs while melting endotherms gradually enhanced up to maximum ratio in FDSDs.