| Objectives:The purpose of the research is to study systematically the prescription of soff gelatin capsule shells and preparation process parameter in order to improve delayed dissolution with prolong of storage time and confirm standard process parameter which fit for pharmaceutical production,promote products quality.Methods:1)Establish and evaluate the indicators such as residual amino acid content(Y),swelling equilibrium quantity(Seq),dissolution rate(k),disintegration time(D),which reflect the degree of gelatin cross-linking and screen the prescription of gelatin shells.Investigate the correlation between them.2)Deduce the cause and mechanism of delayed dissolution and find solution by investigating the soft capsules preserved under different storage time. 3)Establish the methods which prepare gelatin flakes to simulate the soft capsule shells and soak gelatin flakes in content to simulate the soft capsules.4)Establish the methods which simulate gelatin cross-linking①The method treating gelatin flakes with formaldehyde,which simulate aldehyde's cross-linking②The method exposing gelatin flakes to air,which simulate self-oxidation cross-linking③The method soaking gelatin flakes in content,which simulate true cross-linking condition.5)Screen additives such as plasticizer,antioxidant,acidity regulator,disintegrating agent and anything else by means of Seq through single-factor test to confirm the factor's types and levels.Orthogonal experiments were conducted to optimize the prescription of gelatin shells.6)Establish the methods which prepare gelatin liquid in the lab to simulate gelatin melting process and prepare model soft capsules in the plant.Using the viscosity and disintegration time as the indicators,optimal experiments were 'conducted to investigate①swelling time②melting temperature③vacuum pressure④heat preservation condition⑤shell thickness⑥dry condition,to confirm preparation process parameter.(7)Two kinds of improved model soft capsules were produced and investigated through the 10-day period of stress test to verify improved effect.(8) Accelerating and long-term tests were conducted to evaluate the stability of the products.Results:(1) After gelatin cross-linked,a good lineal relativity was found among Y,Seq,k and D(r=0.9953～0.9991).With prolong of time,six kinds of soft capsule products show Y and Seq decreasing,D increasing.(2)Confirm the prescription of gelatin shells which can improve delayed dissolution and preparation process parameter which can fit for pharmaceutical production.(3)Compared with the former,there was obvious statistical significance,all indicators were better.(4)There was no obvious change with all indicators of the improved soft capsules through the 3-month period of accelerating and long-term tests.Conclusions:(1)Cross-linking increased after storage in a longer time.High temperature,humidity,lighting might induce gelatin cross-linking.(2)It can be improved by adding some additives such as glycine,citric acid,lowering storing temperature,humidity and lighting.(3)The prescription of gelatin shells is reasonable,feasible,the preparation process parameter is stable,controllable and suitable for pharmaceutical production.
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