Category: Formulation and Quality
Purpose: The aim was to study the degradation rate of tacrolimus in cyclodextrin (CD) solutions at various pH values. The ultimate goal is to develop aqueous vehicle for topical administration of the drug. Tacrolimus has several degradation pathways such as dehydration and epimerization, as well as lactone hydrolysis. CD complexation can increase solubility and stability of drugs in aqueous solutions .
Methods: 2-Hydroxylpropyl-β-cyclodextrin (HPβCD) was used as a solubilizer during investigation of tacrolimus degradation in aqueous solutions. Observed first-order rate constants for tacrolimus were determined. All experiments were performed in CD buffer solutions at pH ranging from 2 to 9 containing 2.5%, 5% and 7.5% CD (w/v) equilibrated at 40 ± 0.5°C. Tacrolimus stock solution was prepared in methanol of which 100 µl was added to the aqueous buffer solutions (5ml) resulting in only 2% media dilution. The initial tacrolimus concentration in the reaction media was 2.48 mM. Reversed phase ultra-high performance liquid chromatography (UPLC) was used to determine the tacrolimus degradation rate by quantifying the remaining drug concentration in the aqueous reaction media.
Results: The study indicates that the drug is relatively stable at pH from 3 to 6 but then the degradation rate increased with pH. It also showed that degradation decreases with increasing CD concentration. The degradation pathways of tacrolimus in aqueous solutions will be described as well as formation of various tacrolimus/CD complexes and aggregates.
Table 1. shows that observed first order rate constants (ko) for the drug degradation in aqueous CD solution. The rate constant for free drug (kf) is greater than the first order rate constant for the degradation of the drug CD-complex (kc) in all pH values ranging from 2 to 9.
Conclusion: The effect of CD on the degradation rate of tacrolimus greatly depended upon pH. The drug was more stable at acidic pH than at basic pH where the degradation is relatively fast. Potential degradation pathways are a) dehydration to ketone group, b) epimerization in acidic pH and c) hydrolysis of lactone group to carboxylic acid at basic pH as reported by Skytte et al . CD has stabilizing effect at all pH values tested as observed by comparing the rate constant of the free and drug CD-complex CD% .
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 Skytte, Dorthe M. (2013). Some transformations of tacrolimus, an immunosuppressive drug. European Journal of Pharmaceutical Sciences 48 514-522
 Peterka, T. (2019). Forced degradation of tacrolimus and the development of a UHPLC method for impurities determination. Acta Pharm. 69