pH-Dependent Stability of Creatine Ethyl Ester: Relevance to Oral Absorption
Open accessAbstract
Creatine ethyl ester hydrochloride (CEE) was synthesized as a prodrug of creatine (CRT) to improve aqueous solubility, gastrointestinal permeability, and ultimately the pharmacodynamics of CRT. We used high-performance liquid chromatography (HPLC) and proton nuclear magnetic resonance (NMR) to characterize the pH-dependent stability of CEE in aqueous solution and compared the permeability of CEE to CRT and creatinine (CRN) across Caco-2 human epithelial cell monolayers and transdermal permeability across porcine skin. CEE was most stable in a strongly acidic condition (half-life = 570 hours at pH 1.0) where it undergoes ester hydrolysis to CRT and ethanol. At pH ≥ 1.0, CEE cyclizes to CRN with the logarithm of the first order rate constant increasing linearly with pH. Above pH 8.0 (half-life = 23 sec) the rate of degradation was too rapid to be determined. The rate of degradation of CEE in cell culture media and simulated intestinal fluid (SIF) was a function of pH and correlated well with the stability in aqueous buffered solutions. The permeability of CEE across Caco-2 monolayers and porcine skin was significantly greater than that of CRT or CRN. The stability of CEE in acidic media together with its improved permeability suggests that CEE has potential for improved oral absorption compared to CRT.
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CEE converts to creatinine in a linear manner as pH levels drop below 8.0 and is mostly stable at a pH of 1.0.
“Gufford et al. [194] reported that CEE converted to creatinine in a linear manner as pH levels dropped below 8.0 and that CEE was mostly stable at a pH of 1.0.”
From Bioavailability, Efficacy, Safety, and Regulatory Status of Creatine and Related Compounds: A Critical Review (2022) · cites this paper as [194]
The Results (pH-Dependent CEE Stability) report a linear relationship between pH and the logarithm of the conversion rate constant only from pH 2.5 to 8.0, not at all pH levels below 8.0. The same section says CEE was most stable at pH 1.0, where it primarily hydrolyzed to creatine rather than cyclizing to creatinine. (LLM, conf=0.88)
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Kreider, R. B., Jäger, R., & Purpura, M. (2022) · Nutrients · doi:10.3390/nu14051035 · Cited by 103 · see citing works
Beyond muscles: The untapped potential of creatine
Riesberg, L. A., Weed, S. A., McDonald, T. L., Eckerson, J. M., & Drescher, K. M. (2016) · International Immunopharmacology · doi:10.1016/j.intimp.2015.12.034 · Cited by 95 · see citing works
- Authors
- Gufford, B. T., Ezell, E. L., Robinson, D. H., Miller, D. W., Miller, N. J., Gu, X., & Vennerstrom, J. L.
- Affiliations
- Nebraska Medical Center (US)
- University of Manitoba (CA)
- Corresponding author
- Vennerstrom, Jonathan L.
- Venue
- Journal of Dietary Supplements
- Publisher
- Informa UK Limited
- Published
- 2013-08-19
- Volume
- 10
- Issue
- 3
- Pages
- 241-251
- ISSN
- 1939-0211 (ISSN-L)
- 1939-022X
- PMC
- PMC4469200
- OpenAlex
- W2100432642
- Cited by
- 17
- References
- 3
- Citations by year
- 2026: 3 · 2024: 1 · 2023: 1 · 2022: 3 · 2021: 1 · 2020: 1 · 2018: 2 · 2017: 1 · 2016: 2 · 2015: 1 · 2013: 1
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Dietary Supplements (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Center for Complementary and Integrative Health (R43AT001145)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Keywords
- pH-dependent stability, ester hydrolysis, creatine, creatinine, oral absorption, gastrointestinal permeability, Caco-2 cell monolayers, simulated intestinal fluid, water solubility, degradation kinetics
- MeSH terms
- Administration, Oral, Animals, Chemistry, Pharmaceutical, Creatine, Creatinine, Drug Stability, Gastric Acid, Humans, Hydrogen-Ion Concentration, Intestinal Mucosa, Prodrugs, Skin, Swine, Caco-2 Cells
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