الفهرس 
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Abstract
The rate limiting step for drug bioavailability after oral administration is dissolution rate of drugs especially those belonging to class II and IV of the biopharmaceutical classification system BCS. The main challenge that most of the newly synthesized compounds are facing is the poor water solubility and therefore slower dissolution rate and poor bioavailability. A high concentration gradient is readily formed by formulating a fast-dissolving drug molecule, which will help in delivering a rapid pharmacological response. Accordingly, extensive research employing many and different approaches in enhancing the drug dissolution rate were done. These techniques include physical (e.g., crystalline structure, particle size, or melting point alterations), chemical (e.g., salt or prodrug production), and miscellaneous approaches (as hydrotropic solubilization). Physical modifications particularly, are widely studied because of how easily they are achieved. The majority of methods for improving poorly water-soluble drug dissolution often include pharmaceutical excipients that are either natural, synthetic, or semi-synthetic to act as a carrier to increase drug bioavailability, hydrophilic excipients such sugars, polymers, or surfactants, etc. To increase the dissolution rate of a drug, it is possible to process it with specific pharmaceutical excipients. These processes include crystallising, spraying, extruding, melting, or grinding the drug and excipient together. In this thesis the dissolution rate of crystalline poorly soluble drugs was enhanced by co-processing of drugs with different pharmaceutical excipients. A summary of the work is illustrated in the following parts. 2 Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. Enhancement of resveratrol dissolution via co-grinding technique: development and evaluation of buccal film. This study was conducted to improve resveratrol (RES) aqueous solubility by liquid assisted co-grinding technique with the aim of preparing fast dissolving buccal films. The urge for more patient compliance to medication, especially for geriatric and paediatric populations, had driven pharmaceutical formulators to focus on the more convenient drug delivery systems. Buccal cavity with its mucus membrane is an attractive site for convenient drug delivery. a- Preparation and characterization of the prepared formulations. To achieve this aim, RES was cogrinded with two different guest molecules. The selected guest molecules were part of our daily food intake that would, in addition to increase RES aqueous solubility, provide additional health benefits. These molecules were the organic acid Ascorbic acid (AA) and the amino acid L-arginine (L-Ar). AA, also known as vitamin C, which is a natural water-soluble vitamin with potent antioxidant activity that plays an important part in many physiological processes within the human body. AA was previously investigated as co-crystals co-former for other API with encouraging results. Therefore, it was selected as a potential modulator to RES crystalline structure, Additionally, the antioxidant activity of RES is expected to be fortified by that of AA due to synergistic effect. L-Ar was used based on the fact that amino acids are one of the highly promising candidates as a guest molecule due to their functional groups that can form hydrogen bonds with different molecules. L-Ar was successively used as co-crystal conformer, with potential antioxidant activity. 3 Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. Liquid assisted technique was adopted to prepare the co-grinded composite. Formulations F1, F2 and F3 were prepared by mixing 228mg of RES with 176.1, 352.2 or 528.4 mg of AA, respectively. Formulations F4, F5 and F6 were prepared by mixing 228 mg of RES with 174.2, 248.4 or 522.6 mg of L-Ar. Both RES and either AA or L-Ar were co-grinded using mortar and pestle with the DROP wise addition of ethanol till obtaining a thin paste. The paste was subjected to continuous grinding till evaporation of the organic solvent and formation of dry powder. The powder was left overnight to ensure complete elimination of residual solvent. RES was manipulated individually and was taken as a positive control. Physical mixture (PM) of selected formulations (F3 and F5) were prepared. This was obtained by geometric dry blending of RES with either AA (PM1) or L-Ar (PM2) according to compositions mentioned before with the aid of a mortar and a pestle. Fourier transform infrared spectroscopy, differential scanning calorimetry, invitro dissolution studies and powder X-ray diffraction was employed to characterize and study the effect of wet co-grinding on the drug and the co-ground products. The diffractogram of the co-grinded RES with AA F1 (1:1) and F2 (1:2) RES: AA, respectively showed a summation of the peaks of the two components of the mixture with reduced intensities. Abolishment of some diffraction peaks was also noted. These changes could be due to reduced particle size and/or possible transformation of the drug crystal lattice to the less ordered form. It is worth noting that at the higher molar ratio of AA (F3 (1:3)), new diffraction peaks were noticed. Appearance of these peaks would suggest the development of new crystalline species. Developing of new diffraction peaks were previously taken as indication of co-crystal formation and 1:3 ratio provided the optimum composition for this transformation. For RES co-grinded composite with L- 4 Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. Ar, the diffractograms showed a summation of peaks for both components with reduced intensities. As mentioned earlier, the reduced peak intensities could be due to decreased RES crystalline structure or/and reduced particle size due to grinding. The absence of peaks of excess L-Ar at the higher molar ratio of 1:3 may suppose possible amorphousization of the excess amino acid. FTIR spectrum of co-grinded RES and AA (formula F1 and F2) didn’t reflect significant changes as the recorded spectra and can be considered as the summation of the spectra of both components. The FTIR spectrum for formula F3 (1:3) showed significant alteration where the absorption band of carbonyl group of AA was broadened and shifted to lower wave number. The absorption band of OH group was also broadened. These changes are in consistent with the PXRD and confirm the interaction between RES and AA with the possible formation of new species. This new species could be, to a large extent, co-crystals and the molar ratio of 1:3 RES to AA is the stoichiometric ratio required for co-crystal formation. Co-processing RES with L-Ar didn’t show significant changes in the spectra of formulations having low amino acid molar ratio (F4 and F5). Nevertheless, at the higher ratio of L-Ar (formula F6 1:3) there was a noticeable change. The major alteration was manifested as shift in the vibration band for C=O to a higher wavenumber. This indicates interaction between the two components with possible formation of more strong intermolecular bonds. The variation in the thermograms based on the relative proportion of RES to AA. At 1:1 (F1) and 1:2 (F2) RES:AA ratios, the endothermic peak of the drug disappeared with the appearance of two small broad peaks with decreased enthalpy. Meantime, the endothermic peak of AA was shifted to lower Tm for F1 and F2, respectively. Peak broadening and/or Tm shifting to a lower value were taken by other investigators as indication of reduced 5 Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. crystalline packing of the compound. There is a considerable chance that some RES dissolved in ethanol during the co-grinding steps that later precipitated, after ethanol evaporation, as fine crystals of weaker intermolecular interaction. Increasing AA concentration (F3), its melting transition started to be broader and more shifted to slightly higher Tm compared to the other two formulations. Meantime, the peak of RES disappeared with the appearance of new peak as a fused shoulder following AA peak. This may suggest formation of new species with slightly higher intermolecular force. Co-grinding of RES with L-Ar at different molar ratios produced thermal transitions that differ from those of their individual components. L-Ar melting transition was decreased in F4, F5 and F6, respectively. Meantime, thermal event of RES showed significant peak broadening with reduced Tm compared to the pure RES. The melting transition for F4, F5 and F6 were detected as broad peaks with decreased enthalpies. This may indicate reduced crystalline packing structure of the prepared co-grind mixtures. For RES and AA composites dissolution, there were a significant increase in RES dissolution compared to both processed and unprocessed ones. Formula F1 (1:1) and F2 (1:2) liberated about 32 and 34% of the loaded dose after 5 minutes, respectively (F2 value >50). However, the dissolution efficiency was higher from F2. This improvement in RES dissolution could be due to particle size reduction, with subsequent increment in surface area, as indicated by PXRD. Another possible reason could be the reduced RES crystallinity, due to the co-grinding conditions, as supposed by DSC. Increasing AA content to 1:3 (F3) significantly (P < 0.05) improved dissolution parameters that was superior to F1 and F2. Similarity factor of less than 50 proves such superiority. The obtained high-RES dissolution after processing with AA could be due to many interrelated factors 6 Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. such: possible hydrogen bond formation, as reflected from FTIR data; particle size reduction, reduced drug crystallinity, in addition to possible formation of new species, most properly co-crystals, as indicated by PXRD. Therefore, formula F3 was taken as the optimum formula for RES and AA combination. RES and L-Ar composite improved dissolution RES, with the improvement depended on the relative proportions of the amino acid to RES. Formulations F4, increased RES dissolution with a prompt release of 60.3 % after 5 minutes with dissolution efficiency of 76.3. Increasing L-Ar concentration to 1:2 (F5) improved further RES release compared to F1 (Similarity factor F1 of <50). The same justifications for the improved RES from AA-containing formulations can be applied here. Unexpectedly, increasing L-Ar concentration to 1:3 (F6) showed dissolution behaviour that is significantly lower than that for F4 and F5 as indicated by similarity factor values more than 50. This finding is against the well accepted conception of increasing co-former stoichiometric concentration should further increase API dissolution. This unexpected reduced dissolution may be also attributed to the generation of supersaturated RES dissolution layer around each particle resulting in its precipitation. Similar finding was obtained by other investigators and was similarly interpreted. For this reason, F5 was selected as the optimum formula showing the highest RES dissolution when co-grinded with L-Ar. b) Preparation and characterization of fast dissolving buccal films The optimized formulations of RES with either AA or L-Ar were formulated into buccal films. For comparison purposes, film containing unprocessed RES was also prepared. Solvent casting was employed in accordance to the previously published method with slight adjustment. PVP 7 Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. and HPMC were used as film-forming polymers. Both polymers were dissolved in 20 ml of ethanol/water (1:1 ratio) mixture under continuous agitation (100 rpm) using hot plate magnetic stirrer at 50οC. After cooling down, the selected formulation or unprocessed RES was added to the polymeric solution while stirring to achieve a uniform distribution. Finally, glycerol was added as a plasticizer at a concentration of 10% of the total film weight. Liquids were sonicated to get rid of entrapped air bubbles. Each liquid was then poured into plastic petri dish having area of 22.1 cm2. The plates were kept in an oven at 50οC until drying. The dried films were carefully scraped off and examined visually for any imperfections or entrapped air bubbles. To retain their integrity, the films were individually wrapped in aluminium foil and stored at room temperature in a desiccator until further use. The prepared films were evaluated for weight, thickness, folding endurance, surface pH value, drug content and the time required for complete dissolution. Films were transparent with weight uniformity and homogenous film thickness. The pH value ranged from 5.7 to 6.4. This indicates the suitability of the films for buccal mucosa with no expected irritation. The drug content ranged from 92 to 102%. reflecting good uniformity of drug within the films. All films underwent rapid disintegration within 45–72 seconds. The longer time taken by Film 1 containing unprocessed API (72 sec) could be due to the hydrophobicity of RES that slightly affected film wettability compared to the other two films. For folding endurances, all films were flexible and showed minor scratches after 300 folding. This indicates that the type and concentration of the plasticizer were suitable for the intended use. Regarding FTIR spectra for the prepared films, bands due to C–O stretching, C–C olefinic stretching and C–C aromatic double bond stretching of RES were broaden indicating hydrogen bond formation. The characteristic C=O band for PVP was slightly broaden with decreased intensity. Additionally, a small shoulder appeared at slightly higher wave number. This could indicate possible hydrogen bonding between PVP and other components. Regarding the in vitro drug dissolution profiles from the prepared films, the incorporation of unprocessed RES in the control film (Film1) resulted in the liberation of 52% of the loaded drug in the first 5 minutes followed by slow drug dissolution pattern. The dissolution efficiency was 40%. Such relatively high initial dissolution compared to the unprocessed drug can be attributed to the presence of RES in a very minute crystals in the thin film. This resulted in a massive increment in the surface area with subsequent increased dissolution. Hydrogen bond formation could be another contributing factor for such enhancement. However, this dissolution still does not fulfil the requirements for buccal dosage forms or even immediate release oral medications. Incorporation of treated RES with either AA (Film 2) or L-Ar (Film3) markedly increased dissolution rate. Both film2 and film3 recorded Q5 of 89.0 and 80.0%, respectively (P< 0.05). The dissolution efficiency was similarly increased. This is because co-processing of RES with either AA or L-Ar enhanced the dissolution rate by co-amorphousization and/or formation of new species with more aqueous solubility compared to the parent compound.