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Abstract Amiodarone is one of the world’s most common antiarrhythmic medicines. It is a derivative of benzofuran, used for the treatment of both supraventricular and ventricular arrhythmias. The bioavailability of Amiodarone is low due to its poor water solubility because it is classified as a compound of class II drugs, which are low water soluble and highly permeable by biopharmaceutical classification system. Various technological techniques for improving solubility and dissolution rate of low water-soluble drugs have been recorded. Coprocessing with hydrophilic carriers increases the dissolution rate due to reduced particle size and the micro-level interaction between drug and carrier. Co-grinding affects physical characteristics of drugs such as the surface area, crystal structure and shape. It is an environmentally friendly solvent-free method that may be employed in large doses of APIs with variable levels of solubility. It is simple, cost-effective and quick, with simple equipment that can be readily expanded for business use. The objective of this research was to create a single step, solvent-free method to improve the dissolution of low water-soluble drugs. The objective of this work was to prepare and assess rapidly disintegrating amiodarone tablets after increasing the dissolution rate of Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. XIII the drug. For this purpose, mechanochemical technique was applied by co-grinding the drug with sugar excipients (mannitol and xylitol) that impart good taste to the tablets in addition to its potential for forming cocrystal with the drug with the aim to improve its dissolution. Possible cocrystal formation will be evaluated by solid state characterization. Additionally, co-grinding with salt forming excipient (benzoic acid) will also be investigated. The selection of these excipients based on the reported ability to modify the crystalline structure of many drugs after coprocessing. Preparation of amiodarone co-processed formulations Solid state grinding, or also called dry co-grinding, was used for the preparation of amiodarone formulations. Amiodarone and the selected excipient, at Different molar ratios were dry grinded for 30 minutes using mortar and pestle. The obtained powder samples were stored in air-tight containers till use. To evaluate the effect of grinding technique, Pure Amiodarone and excipients were similarly treated, with the former taken as positive control. Physical characterization of the prepared formulations FTIR spectroscopy was conducted to amiodarone, pure excipients and selected formulations. Regarding the co-processed mixtures of the Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. XIV drug with either xylitol or mannitol, the main characteristic peaks of both materials and the drug can be detected. This suggested no interaction between the drug and the used sugar excipients. Co-processed mixture of benzoic acid and amiodarone showed a compromised spectrum. The peak for carbonyl group of the drug was reduced in intensity and slightly shifted to a lower wave length. Meantime, the broad peak for the carboxylic OH group was reduced and became more broader. This suggested interaction between the basic amiodarone and the acidic excipient. The thermal behavior of Amiodarone, pure excipients and their cogrinded formulations were also monitored. The thermogram of coprocessed drug with either xylitol or mannitol revealed peaks broadening and shifting to lower temperatures. The main peak of amiodarone in the binary mixtures reduced to lower Tm values. This indicates partial amorphousization of the drug. This was accompanied by broadening of the decomposition peak of the sugar and shifting to lower Tm value. For benzoic acid co-processed mixtures both the endothermic peaks of amiodarone and the co-former disappeared and new peaks were detected. This may suggest formation of new species, most probably salt form. The crystalline nature of unprocessed amiodarone, pure excipients and different formulations were investigated using PXRD. The X-ray Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. XV spectra of co-grinded drug with either xylitol or mannitol showed the sum of the diffraction peaks for sugars as well as the drug. This indicated no interaction between the drug and the excipients and confirms the results of the DSC. This support the results of FTIR and DSC. For co-processed drug with benzoic acid produced crystalline materials having slight compromised X-ray diffraction pattern compared with that of the individual components of the co-ground mixture. The appearance of new diffraction peaks would indicate formation of new species. This result coincides with the DSC data that suggested salt formation between the drug and the additive. Dissolution studies of the prepared formulations The dissolution profiles of pure unprocessed amiodarone reflected its poor dissolution behavior as indicated from the Q5 and DE (percentage dissolved after 5 minutes and dissolution efficiency). However, there was a slight improvement in dissolution for the positive control (grinded drug alone) most probably due to particle size reduction. As our aim was to formulate rapidly dissolving tablets of amiodarone, a prompt initial release was important. Therefore, amiodarone was coground with inert materials expected to produce co-crystal with the drug while maintaining their function as excipients used in formulating fast disintegrating tablets (i.e. sweetening agents). Xylitol and mannitol were Abstract Pharmaceutical Technology department, College of Pharmacy, University of Tanta, Tanta, Egypt. XVI used for this purpose. Additionally, benzoic acid was also used as potential salt forming excipients. For drug:xylitol co-processed mixtures the enhancement in dissolution parameters increased by increasing xylitol content in the formula. The improved dissolution of drug after neat grinding with xylitol could be due to the reduced particle size, as shown by X-ray data. Partial amorphousization, as reflected by DSC results, and possible adsorption of drug over the excipient surface should be taken into account. Mechanochemical treatment of the drug with mannitol markedly increased drug dissolution compared to either negative or positive control. The reason for the obtained results can be explained as for xylitol. For Benzoic acid-amiodarone co-grinded mixtures, the dissolution profiles indicated improved dissolution of amiodarone relative to unprocessed drug, as well as positive control. In addition to the above mentioned reasons for the enhancement of drug dissolution after neat cogrinding with xylitol and mannitol, such improvement could be due to salt formation. This salt was a result of possible interaction between the amine group of amiodarone and the carboxylic group of benzoic acid. |