Preparation Of Fast-Dissolving Oral Film Of Aripiprazole

Aripiprazole is a serotonin-dopamine system stabilizer.It belongs to the second-generation antipsychotic drug.It is used to treat schizophrenia.It has high permeability and low solubility.Aripiprazole was marketed in 2002.Up to now,aripiprazole preparations marketed at home and abroad include tablets,orally disintegrating tablets,capsules,solutions,long-acting intramuscular injections and other dosage forms.Based on the characteristics of fast dissolution rate and short acting time of fast-dissolving oral films,which is similar to the acting time of liquid preparations,this project aims to design an fast-dissolving oral film for aripiprazole,screen high-quality prescription and preparation process,and establish a reliable quality control method of this product and the stability study,in oader to realize the innovation of the dosage form of the product.Part one: Pre-prescription study of aripiprazoleObjective:Firstly,to conduct a preliminary analysis of the basic physicochemical and pharmacological properties of the drug,so as to select the dosage form,carry out the screening of the prescription and optimize the preparation process,and explore the possibility of making an fast-dissolving oral film.Method:The solubility and oil-water partition coefficient of aripiprazole were determined by HPLC,and the crystal form of aripiprazole was observed by an inverted biological microscope,and the particle size,moisture absorption and fluidity of aripiprazole were investigated.Results:Aripiprazole is a rhombohedral crystal,low solubility,large particle size,poor fluidity,and almost no hygroscopicity.Its oil-water partition coefficient is 2.0828,which is suitable for making an fast-dissolving oral film.Conclusion:The physical and chemical properties and preparation properties of aripiprazole are measured or evaluated,and it is judged that it is suitable for making fast-dissolving oral film.Part two: Preparation and quality evaluation of aripiprazole self-microemulsionObjective:The prescription of aripiprazole self-microemulsion was investigated and evaluated.Method:The solubility of aripiprazole in various excipients was determined by HPLC,the types of oil phase,emulsifier,and co-emulsifier were screened by the pseudo-ternary phase diagram,and central composite design-response surface methodology was used to optimize the prescription,determine the optimal prescription,and evaluated the quality of self-made aripiprazole self-microemulsion.Results:The optimal prescription of aripiprazole fast-dissolving oral film is finally determined as: aripiprazole 0.024 g,oleic acid 0.060 g,triacetin0.110 g,CO-40 0.550 g,PEG 400 0.280 g.Its appearance is a yellow clear liquid,which is clear and transparent after being emulsified with water;the particle size is 16.43 nm,the potential is-5.57 m V,the self-emulsification time is 25 s,and the dissolution rate is greatly improved compared with the bulk drug.There is no significant change in the particle size measured under three conditions of different dilution ratio、 different temperature influence、 and centrifugation,the stability is good.Conclusion:Through the screening and optimization of oil phase,emulsifier,and co-emulsifier,the final aripiprazole self-microemulsion formulation was determined and its quality was evaluated.The results showed that the particle size was small,the dissolution rate was greatly improved compared with the bulk drug,and the stability Great.Part three: Preparation of aripiprazole fast-dissolving oral filmObjective:Screen the optimal prescription and technology of aripiprazole fast-dissolving oral film.Method:The film was prepared by solvent casting method,and the types and dosages of film-forming materials,fillers,and correctives in the prescription were investigated,orthogonal experiments were designed to optimize the prescription,and the preparation process was investigated by single factor.Results:Through the screening of film-forming materials,fillers,flavoring agents and optimization of the prescription,the final prescription is determined as follows: aripiprazole self-microemulsion dosage 0.50 g,HPMC E5 0.40 g,L-HPC 0.20 g,pregelatinized starch 0.30 g,aspartame 0.10 g,PEG400 0.10 g,and distilled water 10 m L.Use static defoaming,the film thickness is 1mm,the drying temperature is 50℃,and the drying time is 60 min.Conclusion:By optimizing the prescription of aripiprazole fast-dissolving oral film,the prepared fast-dissolving oral film has a flat appearance,good folding resistance and short disintegration time,which meets the requirements of the pharmacopoeia.Part four: Study on the quality and stability of aripiprazole fast-dissolving oral filmObjective:Investigate the properties of aripiprazole fast-dissolving oral film,establish a reliable analysis method,conduct influencing factor experiments,and provide reference conditions for the production,packaging,and storage of drugs.Method:The self-made aripiprazole fast-dissolving oral film was evaluated,and the aripiprazole fast-dissolving oral film content determination and dissolution determination method were established,and the stability test was carried out with the appearance,weight,content,and related substances as indicators.Results:The preparation of aripiprazole fast-dissolving oral film has a uniform content,short disintegration time,and good toughness.The content determination method and the dissolution analysis method meet the methodological requirements.The test results of influencing factors show that it is greatly affected by temperature and humidity,and less affected by light.Conclusion:The obtained aripiprazole fast-dissolving oral film has good plasticity and rapid disintegration.The established in vitro analysis method is reliable.The content of the three batches of self-made preparations meets the requirements of the pharmacopoeia.It should be stored in a cool and ventilated manner.