Safety and tolerance of Ester-C® compared with regular ascorbic acid
Abstract
The goal of this randomized, double-blind crossover clinical trial in 50 healthy volunteers sensitive to acidic foods was to evaluate whether Ester-C calcium ascorbate causes fewer epigastric adverse effects than are produced by regular ascorbic acid (AA). Volunteers were randomly separated into 2 groups of 25. The study comprised an observation period of 9 days (phase 1 medication for 3 consecutive days, washout phase for 3 consecutive days, phase 2 medication for 3 consecutive days). Participants took 1000 mg vitamin C as Ester-C during phase 1 of the study followed by 1000 mg of vitamin C as AA during phase 2, or vice versa. During the course of the study, 3 examinations for the evaluation of epigastric adverse effects were performed (on days 0, 3, and 9). Participants used a diary to record epigastric adverse effects on a daily basis. In total, 28 (56%) of 50 participants reported 88 epigastric adverse effects of mild to moderate intensity. Of these 88 adverse effects, 33 (37.5%) occurred after intake of Ester-C and 55 (62.5%) were noted after intake of AA. The tolerability of Ester-C was rated "very good" by 72% of participants, whereas AA was rated "very good" by only 54%. This difference is statistically significant (P<.05). Investigators concluded that Ester-C compared with AA caused significantly fewer epigastric adverse effects in participants sensitive to acidic foods and that Ester-C is much better tolerated.
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None of the studies suggested safety or tolerability concerns for any of the alternative supplemental forms, beyond the most common adverse events already known to be experienced due to intake of high doses of ascorbic acid (gastrointestinal adverse events including nausea, heartburn, epigastric pain, abdominal cramps, and diarrhea).
“None of the studies suggested safety or tolerability concerns for any of the alternative supplemental forms, beyond the most common adverse events already known to be experienced due to intake of high doses of ascorbic acid (gastrointestinal adverse events including nausea, heartburn, epigastric pain, abdominal cramps, and diarrhea) [32], attributable to the acidity and osmotic effects of unabsorb”
From Enhanced Vitamin C Delivery: A Systematic Literature Review Assessing the Efficacy and Safety of Alternative Supplement Forms in Healthy Adults (2025) · cites this paper as [32]
From the NICE checklist quality assessment of thirteen RCTs, ten (77%) showed low risk of bias, two (15%) high risk, and one (8%) unclear risk.
“From the assessment of the methodological quality of thirteen RCTs, ten (77%) showed a low risk of bias [12,16,27,28,29,30,31,32,35,37,38], two (15%) showed a high risk of bias [33,36] and one (8%) showed an unclear risk of bias [34].”
From Enhanced Vitamin C Delivery: A Systematic Literature Review Assessing the Efficacy and Safety of Alternative Supplement Forms in Healthy Adults (2025) · cites this paper as [32]
There was a statistically significant difference in the share of participants rating tolerability as "very good" (72% Calcium ascorbate EC vs 54% ascorbic acid).
“There was a statistically significant difference (p < 0.05) in the share of participants rating the tolerability of the supplements as “very good” (72% in the Calcium ascorbate EC group vs. 54% in the ascorbic acid group).”
From Enhanced Vitamin C Delivery: A Systematic Literature Review Assessing the Efficacy and Safety of Alternative Supplement Forms in Healthy Adults (2025) · cites this paper as [32]
In a study of 50 healthy adults sensitive to acidic foods, 28 (56%) reported 88 epigastric adverse effects of mild to moderate intensity; 37.5% were taking Calcium ascorbate EC and 62.5% ascorbic acid.
“Out of 50 participants, 28 (56%) reported 88 epigastric adverse effects of mild to moderate intensity, of whom 37.5% were taking Calcium ascorbate EC and 62.5% ascorbic acid [32].”
From Enhanced Vitamin C Delivery: A Systematic Literature Review Assessing the Efficacy and Safety of Alternative Supplement Forms in Healthy Adults (2025) · cites this paper as [32]
The assessment of the safety and tolerability profile of Calcium ascorbate EC identified significantly fewer incidents of epigastric adverse events compared to regular ascorbic acid.
“The assessment of the safety and tolerability profile of the Calcium ascorbate EC (Ester-C®) form of vitamin C identified significantly fewer incidents of epigastric adverse events, likely due to its neutral pH as compared to regular ascorbic acid [32].”
From Enhanced Vitamin C Delivery: A Systematic Literature Review Assessing the Efficacy and Safety of Alternative Supplement Forms in Healthy Adults (2025) · cites this paper as [32]
The fewer epigastric adverse events with Calcium ascorbate EC are likely due to its neutral pH compared to regular ascorbic acid.
“The assessment of the safety and tolerability profile of the Calcium ascorbate EC (Ester-C®) form of vitamin C identified significantly fewer incidents of epigastric adverse events, likely due to its neutral pH as compared to regular ascorbic acid [32].”
From Enhanced Vitamin C Delivery: A Systematic Literature Review Assessing the Efficacy and Safety of Alternative Supplement Forms in Healthy Adults (2025) · cites this paper as [32]
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- Authors
- Gruenwald, J., Graubaum, H.-J., Busch, R., & Bentley, C.
- Affiliations
- Analyze & Realize (Germany) (DE)
- ORCID
- Bentley, Christine
- Venue
- Advances in Therapy
- Published
- 2006-01
- Volume
- 23
- Issue
- 1
- Pages
- 171-178
- ISSN
- 0741-238X (ISSN-L)
- 1865-8652
- OpenAlex
- W2065976717
- Cited by
- 15
- References
- 12
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2022: 1 · 2017: 2 · 2016: 1 · 2015: 1 · 2013: 1
- FWCI
- 1.17
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Advances in Therapy (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Nursing › Nutrition and Dietetics › Vitamin C and Antioxidants Research
- Health Sciences › Medicine › Biochemistry › Antioxidant Activity and Oxidative Stress
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
- Keywords
- calcium ascorbate, vitamin C, gastrointestinal tolerance, vitamin C supplementation
- MeSH terms
- Adult, Aged, Antioxidants, Ascorbic Acid, Dehydroascorbic Acid, Double-Blind Method, Drug Combinations, Female, Humans, Male, Middle Aged, Threonine, Cross-Over Studies
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