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Title: Modification of natural hydrophilic polymers for use in pharmaceutical formulations
Author: Daraghmeh, Nedal Hamdan Mahmoud
Awarding Body: University of Greenwich
Current Institution: University of Greenwich
Date of Award: 2012
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The introductory chapter of this doctoral thesis provides an overview of the salient properties of pharmaceutical excipients, chitin, metal silicates and sugar alcohols in order to give a scientific background/context to the research subject matter reported in subsequent chapter of the thesis. When chitin is used in pharmaceutical formulations processing of chitin with metal silicates is advantageous, from both an industrial and pharmaceutical perspective, compared to processing using silicon dioxide. Unlike the use of acidic and basic reagents for the industrial preparation of chitin-silica particles, co-precipitation of metal silicates is dependent upon a simple replacement reaction between sodium silicate and metal chlorides. When co-precipitated onto chitin particles, aluminum, magnesium, or calcium silicates result in non-hygroscopic, highly compactable, and disintegrable compacts. Disintegration and hardness parameters for co-processed chitin compacts were investigated and found to be independent of the particle size. Capillary action appears to be the major contributor to both water uptake and the driving force for disintegration of compacts. The good compaction and compression properties exhibited by the chitin–metal silicates were found to be strongly dependent upon the type of metal silicate co-precipitated onto chitin. In addition, the inherent binding and disintegration abilities of chitin–metal silicates are useful in pharmaceutical applications when poorly compressible and/or highly non-polar drugs need to be formulated. The influence of the lubricant magnesium stearate (MgSt) on the powder and tablet properties of chitin-Mg silicate co-precipitate was examined and compared with lubricated Avicel® 200 and Avicel-Mg silicate co-precipitate. Crushing strength and disintegration-time studies were conducted in order to evaluate tablet properties at different compression pressures. Lubrication of chitin-Mg silicate powder with MgSt was evaluated using a high speed rotary tablet press. The compactability and disintegration time of chitin-Mg silicate are unaffected by the possible deleterious action of up to 2% (w/w) MgSt. The deleterious effect of MgSt on Avicel® 200 compaction was found to be minimized when magnesium silicate was co-precipitated onto Avicel® 200. Lubrication of chitin-Mg silicate with MgSt does not enhance particle agglomeration, whereas the opposite is the case for Avicel® 200; the foregoing was ascertained by measurements of the fixed measured bulk density, constant powder porosity using Kawakita analysis and by the absence of variation in particle size distribution in the presence of up to 5% (w/w) MgSt. In the case of chitin-Mg silicate tablets the ejection force was greatly reduced at a compression speed of 150,000 tablet/h at a MgSt concentration of 0.5% (w/w) when compared with the unlubricated powder. The physical properties and drug dissolution profile of ibuprofen tablets were found to be unaffected when chitin-Mg silicate was lubricated up to 5% (w/w) with MgSt. Optimal drug dissolution was attained for gemfibrozil tablets using 3% (w/w) MgSt when compared to a reference (LOPID® tablets). A co-processed excipient was prepared from commercially available crystalline mannitol and -chitin using direct compression as well as spray, wet and dry granulation. The effect of the ratio of the two components, percentage of lubricant and particle size on the properties of the prepared co-processed excipient has been investigated. -Chitin forms non-hygroscopic, highly compactable, disintegrable compacts when co-processed with crystalline mannitol. The compaction properties of the co-processed mannitol-chitin mixture were found to be dependent upon the quantity of mannitol added to chitin, in addition to the granulation procedure used. Optimal physicochemical properties of the excipient, from a manufacturing perspective, were obtained using a co-processed mannitol-chitin (2:8 w/w) mixture prepared by wet granulation (Cop-MC). Disintegration time, crushing strength and friability of tablets produced by Cop-MC, using magnesium stearate as a lubricant, were found to be independent of the particle size of the prepared granules. The inherent binding and disintegration properties of the compressed Cop-MC are useful for the formulation of poorly compressible, low and high strength active pharmaceutical ingredients. The ability to co-process α-chitin with crystalline mannitol allows chitin to be used as a valuable industrial pharmaceutical excipient. The preparation and characterization of the performance of a novel excipient for use in the development of oro-dispersible tablets (ODT) has also been undertaken. The excipient consists of α-chitin and crystalline mannitol. The physical properties (disintegration and wetting times, crushing force and friability) of the ODTs produced depend on the ratio of chitin and mannitol, in addition to the processing techniques used for excipient preparation. The excipient with optimal physicochemical properties was obtained at a chitin: mannitol ratio of 2:8 (w/w) produced by roll compaction (Cop-CM). Differential scanning calorimetry (DSC), Fourier-transform infrared (FT-IR), X-ray powder diffraction (XRPD) and scanning electron microscope (SEM) techniques were used to characterize the Cop-CM, in addition to characterization of its powder and ODT dosage forms. The effect of particle size distribution of the Cop-CM was investigated and found to have no significant influence on the overall tablet physical properties. The compressibility parameter (a) for Cop-CM was calculated from a Kawakita plot and found to be significantly higher (0.661) than that of mannitol (0.576) due to the presence of the highly compressible chitin (0.818). Montelukast sodium and domperidone ODTs, produced using Cop-CM, displayed the required physicochemical properties. The exceptional binding, fast wetting and super-disintegration properties of Cop-CM, in comparison with commercially available co-processed ODT excipients, results in a unique multi-functional base which can successfully be used in the formulation of oro-dispersible and fast immediate release tablets.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: QD Chemistry