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Cited by 20Crystallization and Solubility StudiesAnalytical Methods in PharmaceuticalsDrug Solubulity and Delivery Systems

Evaluation of the stability of creatine in solution prepared from effervescent creatine formulations

Open access
Ganguly, Sudipta, Jayappa, Sheela, Dash, Alekha K.·2003·AAPS PharmSciTech
DOI 10.1208/pt040225PMC PMC2750587
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Abstract

The objectives of this study were to determine the cause of the crystallization in a large volume creatine supplement solution made from effervescent powders containing di-creatine citrate, and to characterize these crystals using thermal analyses and x-ray diffractometry. Creatine effervescent powders were dissolved in deionized water (pH 6.2) and stored both at room temperature (RT) (25 degrees C) and refrigerated condition (4 degrees C) over a period of 45 days. Creatine concentration was determined using high-performance liquid chromatography (HPLC). Intrinsic dissolution and saturated solubility of creatine, creatine monohydrate, and di-creatine citrate in water were determined and compared. Crystal growth was detected only in the refrigerated samples on the seventh day of storage. Differential Scanning Calorimetry (DSC) and x-ray diffraction (XRD) studies revealed that the crystals formed were of creatine monohydrate. Ninety percent creatine degradation was observed within 45 days for RT samples. However, at refrigerated condition this degradation was 80% within the same time period. The pH of the RT samples also increased from 3.6 to 4.5 during storage. No such increase was observed in the case of refrigerated samples. The intrinsic dissolution rate constants of the compounds decreased in the following order: di-creatine citrate > creatine > creatine monohydrate. In conclusion, di-creatine citrate used in effervescent formulation dissociates to creatine in aqueous solution and eventually crystallizes out as creatine monohydrate. Significant decrease in solubility and effect of pH contribute to this crystallization process.

AI snapshot

Written from the paper’s full text.

TL;DR

Di-creatine citrate in effervescent creatine formulations dissociates in water to creatine, which can crystallize as creatine monohydrate under refrigeration and degrade substantially over 45 days. The study recommends using lower concentrations for refrigerated solutions and shorter storage times.

Key findings

  • Crystals appeared only in refrigerated (4°C) samples on day 7; DSC and XRD identified them as creatine monohydrate, not di-creatine citrate.
  • Creatine degradation was greater at room temperature: 90% degradation within 45 days at RT versus about 80% under refrigeration over the same period.
  • RT solution pH increased from 3.6 to 4.5 over 45 days, while refrigerated samples showed no such increase.
  • Intrinsic dissolution rate constants decreased as di-creatine citrate (7.61 mg·cm⁻²·min⁻¹) > creatine (6.92 mg·cm⁻²·min⁻¹) > creatine monohydrate (5.18 mg·cm⁻²·min⁻¹).
  • The authors suggest using 2 packets per 960 mL if refrigerated, or 3 packets per 960 mL at RT without crystal formation, and using the solution within 6 days for stability reasons.

Methods

  • Creatine Edge and Creatine Clear effervescent powders (3 packets, 5 g creatine each, in 960 mL water; final 0.0156 g/mL) were stored at 25°C and 4°C for 45 days; samples were collected on days 0, 1, 2, 4, 7, 10, 21, and 45, with creatine concentration measured by HPLC and pH/color monitored.
  • Saturated solubility of creatine, creatine monohydrate, and di-creatine citrate was determined at 4°, 25°, and 37°C; intrinsic dissolution used a modified Wood’s apparatus with compressed discs (0.7 g, 900 psi, 1.54 cm²) in 500 mL deionized water at 37°C, 100 rpm, over 6 hours, analyzed by HPLC in triplicate.
  • Di-creatine citrate degradation was studied at 60°C in sealed ampules over 2 weeks with HPLC; solid-state humidity exposure was tested at RT under 31%, 45%, 79.3%, and 100% RH; degradation data were modeled with SAAM II.

Limitations

  • The paper does not include a formal limitations section. The authors state that further work is necessary to confirm the speculation that ascorbic acid photochemical degradation contributes to the color change seen only in RT samples.
  • Evident from the text: the large-volume stability study used two solutions per storage condition, and findings are limited to two commercial effervescent formulations (Creatine Edge and Creatine Clear) over a 45-day period.
  • The solid-state humidity study tested di-creatine citrate powders, not the complete effervescent formulations.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1208/pt040225

Cites

12 of 12 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

2 of 13 cited sources checked · 1 supported · 0 flagged · accuracy not yet measured

  • Findingreasoning

    No increase in pH was observed in the refrigerated samples.

    “No such increase was observed in the case of refrigerated samples.”
    • Also stated in: § Stability of Creatine in Solutions Prepared from Effervescent Formulations · plain
      “However, no such increase was noted in the case of the refrigerated samples.”
    Quote in the paperSubstantial claim
  • Findingown data

    The pH of the room temperature samples increased from 3.6 to 4.5 during storage.

    “The pH of the RT samples also increased from 3.6 to 4.5 during storage.”
    • Also stated in: § Stability of Creatine in Solutions Prepared from Effervescent Formulations · plain
      “During the stability studies, an increase was observed in the pH of the solutions kept at RT.This increase was at least 1 pH unit over a period of 45 days”
    Quote in the paperNot a substantial claim
  • Findingown data

    DSC and x-ray diffraction studies revealed that the crystals formed were of creatine monohydrate.

    “Differential Scanning Calorimetry (DSC) and x-ray diffraction (XRD) studies revealed that the crystals formed were of creatine monohydrate.”
    Quote in the paperSubstantial claim
  • Findingown data

    Studies using creatine concentration below its solubility limits (2 packets of effervescent powder equivalent to 10 g of creatine in 960 mL water) showed no sign of crystallization over a 45-day period under refrigerated condition.

    “Studies conducted using creatine concentration below its solubility limits (2 packets of effervescent powder equivalent to 10 g of creatine in 960 mL water) showed no sign of crystallization over a 45day period under refrigerated condition.”
    Quote in the paperSubstantial claim
  • Findingreasoning

    A change in color of the solution was noticed in the case of room temperature samples.

    “A change in color of the solution was also noticed in the case of RT samples.”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 11
  • May combine two claims. 10
  • The quote only partly states this claim. 2

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    This process requires an intramolecular cyclization followed by removal of 1 mol of water.

    “This process requires an intramolecular cyclization followed by removal of 1 mol of water.”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [8] Edgar G, Shiver HE. The equilibrium between creatine and creatinine, in aqueous solutions: the effect of hydrogen ion. J Am Chem Soc. 1925;47:1179–1188. source
    • cites [9] Cannan RK, Shore A: The creatine-creatinine equilibrium: the apparent dissociation constants of creatine and creatinine. Biochemistry. 1928;22:920–929. source

      The Creatine-Creatinine Equilibrium section describes conversion of creatine to creatinine as dehydration, supporting the removal-of-water part. Our copy does not specify intramolecular cyclization, the loss of exactly one mole of water, or the claimed sequence of steps. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Creatine is converted to creatinine in water under acidic conditions.

    “Creatine is converted to creatinine in water under acidic conditions.8,9”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [8] Edgar G, Shiver HE. The equilibrium between creatine and creatinine, in aqueous solutions: the effect of hydrogen ion. J Am Chem Soc. 1925;47:1179–1188. source
    • cites [9] Cannan RK, Shore A: The creatine-creatinine equilibrium: the apparent dissociation constants of creatine and creatinine. Biochemistry. 1928;22:920–929. source

  • May combine two claims.

    Findingown data

    The DSC curves of the crystallized samples were different from the curve of the starting material (di-creatine citrate) but identical to creatine monohydrate.

    “However, the DSC curves of these samples were different from the curve of the starting material (di-creatine citrate) but identical to creatine monohydrate.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Citric acid concentrations within the range of 5 to 100 μg/mL were found to be linear.

    “Citric acid concentrations within the range of 5 to 100 µg/mL were found to be linear.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The XRD patterns of both crystallized samples were identical but different from the XRD patterns of di-creatine citrate.

    “Both the XRD patterns of the samples were identical but different from the XRD patterns of di-creatine citrate (patterns not shown).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    There was an increase in both citric acid and creatinine concentration in the solution during di-creatine citrate degradation at 60°C.

    “However, there was an increase in both citric acid and creatinine concentration in the solution as shown in Figure 4.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The intrinsic dissolution rate was 7.61 mg.cm-2.min-1 for di-creatine citrate, 6.92 mg.cm-2.min-1 for creatine, and 5.18 mg.cm-2.min-1 for creatine monohydrate.

    “In the case of di-creatine citrate, the intrinsic dissolution rate was 7.61 mg.cm -2 .min-1 ; in the case of creatine, 6.92 mg.cm -2 .min-1 ; and in the case of creatine monohydrate, 5.18 mg.cm -2 .min-1 .”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    There was a steady decrease in creatine concentration in solution during di-creatine citrate degradation at 60°C.

    “There was a steady decrease in creatine concentration in solution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Crystallization of creatine monohydrate from such a solution is observed under refrigerated temperature and when the concentration of creatine in solution exceeds 15.6 mg/mL.

    “Crystallization of creatine monohydrate from such a solution is observed under refrigerated temperature and when the concentration of creatine in solution exceeds 15.6 mg/mL, a popular concentration used by athletes (15 g creatine/960 mL water).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation

    The solubility of carbon dioxide in refrigerated samples is much higher compared with room temperature samples.

    “Therefore, one should expect the solubility of carbon dioxide in the refrigerated samples to be much higher as compared with the RT samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The presence of carbon dioxide in water forms carbonic acid, making the pH of the refrigerated samples more acidic.

    “The presence of carbon dioxide in water will form carbonic acid, which, in turn, makes the pH of the solution more acidic as seen in the case of the refrigerated samples.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Of the three possible products (creatine monohydrate, creatinine, and creatine), creatine monohydrate has the lowest solubility and therefore crystallizes out of solution.

    “Of these 3 possible products, creatine monohydrate has the lowest solubility and therefore it crystallizes out of solution.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Creatine monohydrate dehydrates to form anhydrous creatine from 97°C to 125°C with a subsequent phase change.

    “According to this report, creatine monohydrate dehydrates to form anhydrous creatine from 97°C to 125°C with a subsequent phase change.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Dash AK, Mo Y, Pyne A. Solid-state properties of creatine monohydrate. J Pharm Sci. 2002;91:708–718. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). The quote only partly states this claim.

    Interpretationreasoning

    The pH change in room temperature samples is explained by loss of carbon dioxide over time.

    “However, in the case of the room temperature samples, loss of carbon dioxide over time might have contributed to the pH shift.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Anhydrous creatine then undergoes intramolecular cyclization with removal of 1 mol of water to form creatinine.

    “Anhydrous creatine then undergoes intramolecular cyclization with removal of 1 mol of water to form creatinine.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Dash AK, Mo Y, Pyne A. Solid-state properties of creatine monohydrate. J Pharm Sci. 2002;91:708–718. source

  • May combine two claims.

    Interpretationown data

    Creatine in presence of water forms creatine monohydrate, which eventually crystallizes out from solution because of its poor solubility.

    “Creatine in presence of water forms creatine monohydrate, which eventually crystallizes out from solution because of its poor solubility.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    At room temperature, the amount of creatine monohydrate formed may be below its solubility limit at this higher temperature and therefore does not crystallize out from solution.

    “However, at RT, the di-creatine citrate though gets converted to creatine monohydrate, the amount of creatine monohydrate formed may be below its solubility limit at this higher temperature (6 times higher than the refrigerated one) and therefore does not crystallize out from solution.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Significant decrease in solubility and effect of pH contribute to the crystallization of creatine monohydrate from solution.

    “Significant decrease in solubility and effect of pH contribute to this crystallization process.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The creatinine formed finally melts with decomposition.

    “The creatinine formed finally melts with decomposition. 10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Dash AK, Mo Y, Pyne A. Solid-state properties of creatine monohydrate. J Pharm Sci. 2002;91:708–718. source

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationown data

    The underlying hypothesis for the above findings was that di-creatine citrate used in the formulation is converted to creatine in aqueous solutions.

    “Therefore, the underlying hypothesis for the above findings was that di-creatine citrate used in the formulation is converted to creatine in aqueous solutions.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    All studies were carried out in triplicate.

    “All studies were carried out in triplicate.”
    • Also stated in: § Di-creatine Citrate Degradation Studies · plain
      “All data were collected in triplicate.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The linearity ranges for creatine and creatinine along with all the validation parameters have been published elsewhere.

    “The linearity ranges for creatine and creatinine along with all the validation parameters have been published elsewhere.11”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] Dash AK, Sawhney A. A simple LC method with UV detection for the analysis of creatine and creatinine and its application to several creatine formulations. J Pharm Biomed Anal. 2002;29:939–945. source
22 of 22

  • The paper relies on this without support.

    Creatine Edge and Creatine Clear contain only di-creatine citrate as the creatine source.

    “As per the manufacturer's specification, these formulations contain only di-creatine citrate as the creatine source.”

  • The paper relies on this without support.

    The degradation of di-creatine citrate at 60°C is representative of its degradation at lower temperatures.

    “The stability of di-creatine citrate in solution was monitored at an elevated temperature (60°C).”
    “Degradation of di-creatine citrate in water was performed at elevated temperature to aid in rapid degradation.”

  • The paper relies on this without support.

    The other components in the effervescent formulations do not affect the stability or crystallization of creatine.

    “Besides di-creatine citrate, the other components present in these formulations may include fructose, sodium bicarbonate, potassium bicarbonate, citric acid, ascorbic acid, vitamin B12, artificial/natural orange flavor, FD&C yellow #6, FD&C red #40, and sucralose.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Creatine monohydrate stored at room temperature degraded into creatinine within several days, but refrigerating creatine monohydrate in solution slowed degradation.

    “Similarly, Ganguly et al. (2003) reported that creatine monohydrate stored at room temperature degraded into creatinine within several days but that refrigerating creatine monohydrate in solution slowed degradation.”

    From Analysis of the efficacy, safety, and regulatory status of novel forms of creatine (2011) · cites this paper as Ganguly et al. 2003

    The Stability of Creatine in Solutions Prepared from Effervescent Formulations section reports greater creatine degradation at room temperature than under refrigeration (90% versus about 80% over 45 days). The Conclusion says some creatine converts to creatinine and recommends using the solution within six days. However, the tested solutions were made from formulations containing di-creatine citrate, not creatine monohydrate; creatine monohydrate formed and crystallized from the solution. (LLM, conf=0.89)

    Experimental — accuracy not yet measured

Cites

Flagged first, then by citations

1 of the 13 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Martin A. Physical Pharmacy. 4th ed. Philadelphia, PA: Lea & Febiger. 1993:212–250.
  2. Ganguly S, Carnazzo J, Dash AK. Evaluation of the solution stability of creatine in large volume supplements [abstract]. AAPS PharmSci. 2002;4:R-6248.

Cited by

Sorted by citations

Related

Authors
Ganguly, S., Jayappa, S., & Dash, A. K.
Affiliations
Creighton University (US)
Corresponding author
Dash, Alekha K.
ORCID
Dash, Alekha K.
Venue
AAPS PharmSciTech
Publisher
Springer Science and Business Media LLC
Published
2003-06
Volume
4
Issue
2
Pages
119-128
ISSN
1530-9932 (ISSN-L)
DOI
10.1208/pt040225
PMC
PMC2750587
OpenAlex
W2046821618
Cited by
20
References
13
Citations by year
2026: 1 · 2025: 1 · 2024: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2019: 1 · 2017: 1 · 2016: 1 · 2015: 4 · 2012: 2
FWCI
0.00
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • AAPS PharmSciTech (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
University of Minnesota
Topics
  • Physical Sciences › Materials Science › Materials Chemistry › Crystallization and Solubility Studies
  • Physical Sciences › Chemistry › Analytical Chemistry › Analytical Methods in Pharmaceuticals
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmaceutical Science › Drug Solubulity and Delivery Systems
Keywords
creatine, effervescent powder, crystallization, creatine monohydrate, solubility, intrinsic dissolution rate, pH effect, cold storage, storage stability
MeSH terms
Chemistry, Pharmaceutical, Chemistry, Physical, Creatine, Creatinine, Drug Stability, Solubility, Solutions, Chemical Phenomena

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