الفهرس 
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Abstract
The dissolution of orally administered drugs is the rate limiting step in achieving the desired concentration at the site of absorption. Moreover, the rate of dissolution is a vital factor for determining the bioavailability of the drug. Recently, pharmaceutical companies have attention on developing orally effective drug products. However, several challenges such as poor aqueous solubility and dissolution rate frequently impair the oral drug delivery. Additionally, about approximately 60% of the drugs coming directly from synthesis and 40% of drugs in the development exhibit poor solubility, hence have limited absorption and bioavailability. Consequently, many approaches were explored to enhance the targeted drugs dissolution and then the bioavailability. These involve chemical approaches as (prodrug or salt formation), physical approaches (e.g., complexation, crystalline structure, particle size reduction or melting point modifications) and miscellaneous approaches (as co-solvency and hydrotropic solubilization). However, physical modification techniques are widely used especially because the molecular structure of the active pharmaceutical ingredients (APIs) is preserved with no chemical change and the wide variety of physical modification approaches. Dissolution rate enhancement usually utilized hydrophilic benign molecules that known as coformers. These molecules could be compounds that are classified as generally recognized as safe (GRAS) or formulation excipients. The co-processing of appropriate benign co-formers with the drug at specific stoichiometric compositions can allow modification in the drug crystalline structure. Modification of the crystalline structure of the drug can weaken the intermolecular forces and cause faster dissolution rate. Abstract. Pharmaceutical Technology department, faculty of Pharmacy, Tanta university, Tanta, Egypt 2 The objective of the work performed in this thesis was investigating the effect of co-processing of different benign co-formers with poorly soluble drug on the physical properties and dissolution rate of the drug. The preceding parts summarize the performed work. 1. Eutectic system formation for enhanced dissolution rate of Eslicarbazepine acetate. Modification of the melting point is a promising strategy for enhancing the drug dissolution rate. Melting point reduction is usually linked with weakening of inter-molecular forces of the crystalline structure. The weaker crystals can release drug molecule faster than the parent crystals. Eslicarbazepine acetate (ESL) is used as antiepileptic agent, but it suffers from poor oral bioavailability and erratic intestinal absorption. This poor oral bioavailability was attributed mainly to its poor solubility and slow dissolution rate thus classified as class II drugs. Tartaric and citric acid were employed in several research articles as eutectic forming agents with several hydrophobic drugs and pH-modifier to enhance dissolution rate of poorly water-soluble drugs. Investigation of the eutectic co-forming potential of either tartaric or citric acid with ESL for enhanced dissolution rate was aimed. a. Ultraviolet spectrophotometer (UV) analysis for drug mixtures A sensitive UV method was utilized for analysis of eslicarbazepine acetate. The method was validated for the range, linearity, accuracy, precision, limit of quantitation and limit of detection. The UV method was able to detect and quantify ESL without interference. The UV method was linear in the range of 15-40 g/ml. The validation results showed both inter- Abstract. Pharmaceutical Technology department, faculty of Pharmacy, Tanta university, Tanta, Egypt 3 day and intra-day precision and accuracy, and acceptable lower limit of quantification and detection according to the international conference of harmonization guidelines (ICH, 1996). b. Preparation and characterization of the co-processed formulations of eslicarbazepine acetate and acids. Eslicarbazepine acetate was mixed with either tartaric acid or citric acid at predetermined molar ratios. These mixtures were subjected to ethanol assisted wet co-grinding. The pure ESL was similarly treated with ethanol and used as a positive control along with the unprocessed drug being anticipated as negative controls. The formulations were characterized by Fourier-transform infrared (FTIR), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and dissolution studies. The characterization techniques confirmed eutectic system formation with tartaric and citric acid. Preparation of wet co-ground mixtures of eslicarbazepine with either tartaric or citric acid presented FTIR spectra, which are the summation of the separate spectra of the components revealing the absence of chemical interaction. The diffractogram of the prepared formulations revealed no changes in the diffraction pattern. Eutectic system was confirmed by DSC with the optimum molar ratio being 1:1 for both (ESL: Tartaric acid) and (ESL: Citric acid). These results exclude the presence of co-crystals in any of the prepared formulation and confirm eutexia formation. That is because formation of a new crystalline species characterizes co-crystallization which has a unique diffraction pattern differs from these of the parent components. Abstract. Pharmaceutical Technology department, faculty of Pharmacy, Tanta university, Tanta, Egypt 4 The dissolution behavior of ESL (processed and unprocessed) and the prepared formulation with either tartaric acid or citric acid were studied. The dissolution behavior of unprocessed eslicarbazepine acetate reflected its very slow dissolution as shown from the recorded % Q5 and % DE values being only 4.4% and 29.12%, respectively. Ethanol assisted wet grinding of eslicarbazepine acetate (positive control) in absence of co-formers did not cause significant change in the pattern of dissolution of unprocessed drug. Co-processing of eslicarbazepine with either tartaric or citric acid significantly enhanced the dissolution pattern of ESL compared with the unprocessed drug. Increasing the ratio of tartaric acid higher than the optimum ratio for eutexia resulted in additional increase in drug dissolution rate. This suggested the impact of pH modification on drug dissolution rate. These explanations were proven from investigating the dissolution rate of the physical mixtures which were inferior in their dissolution rate compared with the prepared formulations. In conclusion, co-processing of ESL with either citric acid or tartaric acid resulted in hastened dissolution rate which was accredited to combined effect of eutexia with pH modification. c. Preparation and characterization of oral fast disintegrating tablets The optimum wet co-ground mixtures revealing the fastest dissolution rate (ESL: Tar (1:2) and ESL: Cit (1:1)) were fabricated into fast disintegrating tablets and compared with the marketed tablet and unprocessed ESL. These tablets were characterized with respect to hardness, uniformity of weight and drug content, wetting time, disintegration time and dissolution rate. The tablets showed acceptable hardness. They were uniform Abstract. Pharmaceutical Technology department, faculty of Pharmacy, Tanta university, Tanta, Egypt 5 in drug content and weight and demonstrated fast wetting and disintegrating time as expected from a fast-disintegrating tablets. Finally, the fast-disintegrating tablets of the optimum formulations with promising release pattern (ESL: Cit (1:1), ESL: Tar (1:2)) showed significant enhancement in the dissolution rate compared to the unprocessed drug. 2. Arginine as an adsorbent and hydrotropic agent for enhancing dissolution rate of eslicarbazepine Adsorption is used as approach for enhancing the dissolution rate of drugs with poor solubility. Adsorption involves Adsorbate and Adsorbent, where Adsorbate is the molecules that are adsorbed on the solid surfaces and Adsorbent is the surface to which they are adsorbed. Improved the drug dissolution rate is attributed to reduced drug particle size with a subsequent increase in the surface area. Furthermore, the increase in the drug thermodynamic activity in dispersed state also enhance the drug dissolution. Arginine is utilized as conformer with poorly soluble drugs to enhance their dissolution. Arginine is rich in hydrogen bonding sites, has potential hydrotropic effect and hydrophilic nature, so it can improve the dissolution rate of eslicarbazepine acetate by adsorption of the molecules of one compound on the other. • Preparation and characterization of the co-processed formulations of eslicarbazepine acetate and arginine. Eslicarbazepine and arginine were co-processed by ethanol assisted wet co-grinding method at several molar ratios. The pure drug was similarly treated with ethanol and used as a positive control, and the unprocessed drug was utilized as a negative control. The resulting product was evaluated using scanning electron microscopy, FTIR spectroscopy, X-ray diffraction, thermal Abstract. Pharmaceutical Technology department, faculty of Pharmacy, Tanta university, Tanta, Egypt 6 analysis in addition to monitoring the dissolution behavior and solubility studies. The hydrotropic effect of arginine was confirmed from the solubility study. The equilibrium aqueous solubility of eslicarbazepine was 0.63, 0.73, 0.78, 0.99 and 1.55g/ml in presence of 0, 1, 3, 10 and 30 mg/ml arginine, respectively. These data revealed significant increase in the solubility of eslicarbazepine by increasing the concentration of arginine highlighting the possible hydrotropic effect of arginine. FTIR analysis of wet co-processed mixtures revealed evidence of no interaction between both compounds. This is because the co-processing of eslicarbazepine and arginine at various molar ratios led to an IR spectral pattern that displays the peaks that were allocated for the main functional groups of both substances. The monitoring of pure eslicarbazepine, arginine, and their co-ground products was done using X-ray diffraction. Eslicarbazepine and arginine revealed many diffraction peaks in their diffraction patterns, which is indicative of crystalline material. Wet co-grinding of eslicarbazepine with arginine provided diffractograms with diffraction peaks that, after processing, represented the total of the diffraction peaks of each component individually. Thermal analysis was done for unprocessed eslicarbazepine, arginine and wet co-ground product to detect any potential changes. The simultaneous processing of eslicarbazepine and arginine at various molar ratios led to a thermal pattern with a weak and broad endotherm at Tm of 60oC, which can be attributed to the bound solvent evaporating. In all the studied formulations, the main endothermic peaks of eslicarbazepine and arginine were visible, showing that there was no interaction or change in their crystallinity. Abstract. Pharmaceutical Technology department, faculty of Pharmacy, Tanta university, Tanta, Egypt 7 Nevertheless, the decomposition peak of arginine was broadened and shifted to higher temperature indicating increased stability. Photomicrographs attained by scanning electron microscopy showed large irregular crystals of eslicarbazepine in absence of arginine. However, processed ESL revealed size reduction in drug crystals after being processed. Photomicrographs of arginine showed irregular crystals with variable size range. Wet co-grinding of eslicarbazepine with arginine resulted in size reduction followed by adsorption of eslicarbazepine on the surface of arginine. These results were consistent with the FTIR, X-ray, and DSC data, which showed no interaction between eslicarbazepine and arginine and suggested that the drug was merely physically adsorbing on the arginine’s surface. Dissolution of unprocessed eslicarbazepine (negative control) reflects slow dissolution rate which is clearly shown by (Q5) and (Q60) which were 4.4% and 54.9%, respectively. In the absence of arginine, ethanol assisted wet grinding of ESL (positive control) yielded drug crystals with a comparable dissolution behavior to that of unprocessed ESL. Co-processing of ESL with arginine significantly enhance the dissolution pattern of eslicarbazepine. The dissolution enhancement was observed regardless of the drug’s relative molar ratio to arginine. This dissolution improvement can be attributed to size reduction, followed by the physical adsorption of eslicarbazepine acetate on the surface of arginine, which increased the surface area of drug particles. The potential hydrotropic impact of arginine is the second explanation for the increased dissolution rate with increasing the molar ratio of arginine. Investigating the dissolution rate of physical mixture, which was lower than those of the prepared formulations, led to the validation of these explanations. In conclusion, Eslicarbazepine acetate was wet co-ground with arginine to create a mixture in which it was present as small crystals adsorbed on the surface of arginine crystals. Due to physical adsorption and arginine’s hydrotropic impact, the dissolution is accelerated.