Skip to main content
Log in

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

AAPS PharmSciTech Aims and scope Submit manuscript

Cite this article


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°C) and refrigerated condition (4°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: dicreatine 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions


  1. Green AL, Simpson EJ, Littlewood JJ, Macdonald IA, Greenhaff PL. Carbohydrate ingestion augments creatine retention during creatine feeding in humans. Acta Physiol Scand. 1996;158:195–202.

    Article  CAS  Google Scholar 

  2. Volek JS, Kraemer WJ. Creatine supplementation: its effect on human muscular performance and body composition. J Strength Cond Res. 1996;10:200–210.

    Article  Google Scholar 

  3. Persky AM, Brazeau GA. Clinical pharmacology of the dietary supplement creatine monohydrate. Pharmacol Rev. 2001;53:161–176.

    CAS  Google Scholar 

  4. Willot CA, Young ME, Leighton B, et al. Creatine uptake in isolated soleus muscle: kinetics and dependence on sodium, but not on insulin. Acta Physiol Scand. 1999;166:99–104.

    Article  Google Scholar 

  5. Dash AK, Miller DW, Huai-Yan H, Camazzo J, Stout Jr.: Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for intestinal absorption. J Pharm Sci. 2001;90:1593–1598.

    Article  CAS  Google Scholar 

  6. Budavari S, O Neil MJ, Smith A, Heckelman PE, eds. The Merck Index. 1 th ed. Rathway, NJ: Merck & Co, Inc; 1989:402–403.

    Google Scholar 

  7. Creatine Edge and Creatine Clear [package insert]. Omaha, NE: FSI Nutrition. US patent 5,925,378. July 20, 1999.

  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.

    Article  CAS  Google Scholar 

  9. Cannan RK, Shore A: The creatine-creatinine equilibrium: the apparent dissociation constants of creatine and creatinine. Biochemistry. 1928;22:920–929.

    CAS  Google Scholar 

  10. Dash AK, Mo Y, Pyne A. Solid-state properties of creatine monohydrate. J Pharm Sci. 2002;91:708–718.

    Article  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  12. Wood J, Syarto J, Letterman H. Improved holder for intrinsic dissolution rate studies. J Pharm Sci. 1965;54:1068.

    Article  CAS  Google Scholar 

  13. Martin A. Physical Pharmacy. 4th ed. Philadelphia, PA: Lea & Febiger. 1993:212–250.

    Google Scholar 

  14. Grant DJW, Brittain HG: Solubility of pharmaceutical solids. In: Brittain HG, ed. Physical Characterization of Pharmaceutical Solids. New York, NY: Marcell Dekker, Inc.; 1995;321–386.

    Google Scholar 

  15. Ganguly S, Carnazzo J, Dash AK. Evaluation of the solution stability of creatine in large volume supplements [abstract]. AAPS PharmSci. 2002;4:R-6248.

    Google Scholar 

Download references

Author information

Authors and Affiliations


Corresponding author

Correspondence to Alekha K. Dash.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Ganguly, S., Jayappa, S. & Dash, A.K. Evaluation of the stability of creatine in solution prepared from effervescent creatine formulations. AAPS PharmSciTech 4, 25 (2003).

Download citation

  • Received:

  • Accepted:

  • DOI: