| Diphenhydramine citrate [2-(diphenyl-methoxy)-N,N-dimethylethylamine citrate](DC) is an H1antihistamine. But up to now, no one pharmacopoeia includes the drug except the United States Pharmacopoeia, And Diphenhydramine hydrochloride (DH) is recorded in the European Pharmacopoeia and Chinese Pharmacopoeia.In chinese pharmaceutical market, DC cann’t be taken as the active ingredient in any pharmaceut-ical preparation.In pharmaceutical manufacturing, DH was combined with pentoxyverine citrate, ephedrine hydrochloride, paracetamol, Caffeine, dextromethorphan hydrobromide and ibuprofen in compound preparations which were used to relieve allergy symptoms due to the common cold. It also can be applied to treat skin and mucosal allergies singly, such as urticaria, irritability rhinitis, itchy skin, drug eruption and so on. In addition, Allergic reactions caused by blood transfusion or allergen nature can be alleviated effectively, and it is brilliant for getting rid of nausea and vomiting after operation caused by drugs, and it can be combined with other drugs to treat extrapyramidal reactions of Parkinson’s disease, and1%DH can be taken as local anesthesia in dental operation.Compared to DH, with lighter bitterness DC is more suitable for oral preparations. According to the advantages and clinical use, we chose the orally disintegrating tablet of DC as the development object in this experiment. The following two aspects were included in our research, the one is preparation and quality control of diphenhydramine citrate bulk drugs, and the other one is optimization of formulation and evaluation of DC orally disintegrating tablets. The above studies aim to accumulate preclinical study data for declaration of DC and its preparation, with the hope of using in clinical.Synthesis of DC:Two methods of preparation of DC were found in US patents. We improved the synthesis process with the overall considerations of their advantages and disadvantages. In the patent of "Synthetic method of diphenhydramine citrate"(CN102229537A), the degree of processing complex was reduced.Quality control of DC:Based on the the Ch.P2010version, to control the bulk drug quality, we established an RP-HPLC method for the simultaneous detection of DC and its related impurities:Benzhydrol and Benzophenone. The analysis was perfor-med on a Sepax HP-C18column(4.6mm×250mm,5μm). The mobile phase was comp-osed of acetonitrile-water-triethylamine(adjusted pH6.5with phosphoric acid)(5050:0.5). The detection wavelength was at258nm and the flow rate was1.0mL·min-1and the column temperature was30℃. Moreover, these consequences were compared to those obtained from nonaqueous titration method accepted by USP34. the RP-HPLC method was superior to the methods included in Ch.P and USP for the quality control of DC.DC-Ion exchange resin compound preparation:In order to take off the bitterness at utmost when patient take the medicine, we prepared the DC-Ion exchange resin compounds by ion exchange reaction. Compared to the technologies of polyacrylic acid resin solid dispersion and B-cyclodextrin inclusion compound, DC-Ion exchange resin compound has the most significant effect of decreasing bitterness. The preparati-on conditions of compound:Ion exchange resin was added to DC aqueous solution with the concentration of4.0mg-mL"1at room temperature,and it took six hours to stir the solution. The the drug loading of compound was0.895g·g-1.Determination of the drug content of compound:It took four hours to stir the potassium chlorate solution with the concentration of1.0mol·L-1at room temperature. The RP-HPLC method for the detection of DC can be used in determinating the content of subsequent filtrate. The specificity and linearity are good.Orally disintegrating tablets preparation:The main evaluation indexs included angle of repose, disintegration time and taste in the prescription screening. The best prescription of ODTs was obtained by orthogonal experiments as follows:DC-resin compound40%, Lactose20%, Mannitol26.5%, PVPP10%, Gum Acacia2.5%, Magnesium Stearate0.5%, Aas Patan0.5%. ODTs with the weight of100mg were prepared by direct powder compression method in the hardness of25-35N. The ODTs appearance was smooth, and disintegration time was less than15seconds. Volunteers set a high value on taste after administration.Evaluation quality of orally disintegrating tablets:The RP-HPLC method for the detection of DC also can be used in determinating the drug content of ODTs. It took four hours to stir the1.0mol·L-1potassium chlorate solution at room temperature after adding ODTs. In this study, the dissolution of ODTs and conventional tablets in0.1mol·L-1hydrochloric acid and water was determinated respectively. In hydrochloric acid solution, the ODTs and conventional tablets dissolved completely after15min and40min, respectively. However, the ODTs dissolved hardly in the water. This result was in accordance with taste masking function of Ion exchange resin. The drug cann’t be absorded in mouth.The research successfully prepared DC-ODTs with good taste which can disinteg-ate completely in15s. However, the drug release behavior in vivo and bioavailability are worth further study. |
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