Enhancement of the Solubility of Simvastatin by Utilizing Two Distinct Types of Excipient Compositions, L-Isoleucine and Sodium Docusate

Authors

DOI:

https://doi.org/10.24086/cuesj.v9n2y2025.pp26-32

Keywords:

l-isoleucine, solubility, simvastatin, pharmaceutics, sodium docusate

Abstract

Simvastatin is a BCS class II drug, which means it has high absorbability but low solubility. The solubility of a drug plays an important role in determining its bioavailability and the effect that it has on the body as a whole. The study objective was to increase the solubility of simvastatin by using two excipients: sodium docusate and L-isoleucine. These excipients were incorporated in a solid dispersion at different ratios, left to dry, dissolved, and tested for increased solubility against a simvastatin calibration curve (which was prepared using a standard solution of simvastatin). The improvement in solubility for a 4:1:1 ratio was 1.49-fold. A 2:1:1 ratio of simvastatin: docusate: isoleucine was increased 7.18-fold, and a 4:3:3 ratio increased the solubility 4.81-fold. The synergistic effect of docusate and isoleucine showed improvement in the solubility of simvastatin at room temperature when incorporated in relatively low ratios.

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Author Biographies

Maysra A. Al-Jumaili, Department of Pharmaceutics, College of Pharmacy, Hawler Medical University, Erbil, Iraq

Maysra A. Al-Jumaili is a lecturer at the Department of Pharmaceutics, College of Pharmacy, Hawler Medical University, Erbil, Iraq. Her research interest is pharmacy.

Suzan N. Alamdar, Clinical Pharmacy Department, Raparin Teaching Hospital, Erbil, Iraq

Suzan Niyazi Alamdar has been a dedicated pharmacist at Raparin Teaching Hospital since 2004 where she leads the Pharmaceutical Stores Department.  Her research interest focus is on pharmacology and clinical pharmacy, where she aims to develop new therapeutic strategies and improve clinical practices.

Marwa F. Noori, College of Pharmacy, Cihan University-Erbil, Kurdistan Region, Iraq

Marwa F. Noori works as a research assistant at Cihan university, Erbil.  Marwa has developed a keen interest in researching the various effects of medications. Her work focuses on the diverse impact on pharmaceutical substances, contributing valuable insights to the field of pharmacology and medicine. 

Hewa A. Hamad Ameen, Department of Pharmaceutics, College of Pharmacy, Hawler Medical University, Erbil, Iraq

Hewa Abdullah has a M.Sc. degree in Drug Discovery and Development in the UK, and B.Sc. in Pharmacy from Hawler Medical University. He teaches pharmaceutical technology and cosmetics for pharmacy students. Also, he is a member of Global Shapers Community, and different charity organizations.

Muhamed A. Abbas, College of Pharmacy, Cihan University, Erbil, Kurdistan Region, Iraq

Muhamed A. Abbas  holds the position of Dean of the College of Pharmacy at Cihan University, Erbil.  His research interests include pharmacology, clinical pharmacy, molecular pharmacy, and toxicology, aiming to advance knowledge and improve practices in these critical areas.

References

1. E. Rinaki, G. Valsami and P. Macheras. Quantitative biopharmaceutics classification system: The central role of dose/solubility ratio. Pharmaceutical Research, vol. 20, no. 12, pp. 1917-1925, 2003. DOI: https://doi.org/10.1023/B:PHAM.0000008037.57884.11

2. M. Lindenberg, S. Kopp and J. B. Dressman. Classification of orally administered drugs on the world health organization model list of essential medicines according to the biopharmaceutics classification system. European Journal Pharmaceutics Biopharmaceutics, vol. 58, no. 2, pp. 265-278, 2004. DOI: https://doi.org/10.1016/j.ejpb.2004.03.001

3. D. M. Shackleford, C. J. H. Porter and W. N. Charman. Lymphatic absorption of orally administered prodrugs. In: V. J. Stella, R. T. Borchardt, M. J. Hageman, R. Oliyai, H. Maag and J. W. Tilley, editors. Prodrugs: Challenges and Rewards Part 1. In Biotechnology: Pharmaceutical Aspects. Springer, New York, NY, pp. 653-682, 2007. DOI: https://doi.org/10.1007/978-0-387-49785-3_18

4. H. D. Williams, N. L. Trevaskis, S. A. Charman, R. M. Shanker, W. N. Charman, C. W. Pouton and C. J. H. Porter. Strategies to address low drug solubility in discovery and development. Pharmacological Review, vol. 65, no. 1, pp. 315-499, 2013. DOI: https://doi.org/10.1124/pr.112.005660

5. G. L. Amidon, H. Lennernäs, V. P. Shah and J. R. Crison. A theoretical basis for a biopharmaceutic drug classification: The correlation of in vitro drug product dissolution and in vivo bioavailability. Pharmaceutical Research, vol. 12, no. 3, pp. 413- 420, 1995. DOI: https://doi.org/10.1023/A:1016212804288

6. M. K. Vadlamudi and S. Dhanaraj. Significance of excipients to enhance the bioavailability of poorly water-soluble drugs in oral solid dosage forms: A review. IOP Conference Series Materials Science Engineering, vol. 263, p. 022023, 2017. DOI: https://doi.org/10.1088/1757-899X/263/2/022023

7. N. Singh, A. P. Singh and A. P. Singh. (PDF) solubility: An overview. International Journal Pharmaceutical Chemistry Analysis, vol. 7, no. 4, pp. 166-171, 2021. DOI: https://doi.org/10.18231/j.ijpca.2020.027

8. V. F. Mauro and J. L. MacDonald. Simvastatin: A review of its pharmacology and clinical use. DICP, vol. 25, no. 3, pp. 257-264, 1991. DOI: https://doi.org/10.1177/106002809102500309

9. D. K. Ellison, W. D. Moore and C. R. Petts. Simvastatin. In: H. G. Brittain, editor. Analytical Profiles of Drug Substances and Excipients. vol. 22. Academic Press, United States, pp. 359-388, 1993. DOI: https://doi.org/10.1016/S0099-5428(08)60246-4

10. A. T. Serajuddin, S. A. Ranadive and E. M. Mahoney. Relative lipophilicities, solubilities, and structure-pharmacological considerations of 3-hydroxy-3-methylglutaryl-coenzyme a (HMGCoA) reductase inhibitors pravastatin, lovastatin, mevastatin, and simvastatin. Journal Pharmaceutical Science, vol. 80, no. 9, pp. 830-834, 1991. DOI: https://doi.org/10.1002/jps.2600800905

11. T. Jiang, N. Han, B. Zhao, Y. Xie and S. Wang. Enhanced dissolution rate and oral bioavailability of simvastatin nanocrystal prepared by sonoprecipitation. Drug Development Industrial Pharmacy, vol. 38, no. 10, pp. 1230-1239, 2012. DOI: https://doi.org/10.3109/03639045.2011.645830

12. M. J. O’Neil. Simvastatin. In: The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biological. Royal Society of Chemistry, UK, p. 1587, 2013.

13. Nikita. Simvastatin SIELC Technologies. Available from: https://sielc.com/simvastatin [Last accessed on 2023 Feb 28].

14. S. Nave, J. Eastoe and J. Penfold. What is so special about aerosol-OT? 1. Aqueous systems. Langmuir, vol. 16, no. 23, pp. 8733-8740, 2000. DOI: https://doi.org/10.1021/la000341q

15. D. K. Kaczmarek, T. Rzemieniecki, K. Marcinkowska and J. Pernak. Synthesis, properties and adjuvant activity of docusatebased ionic liquids in pesticide formulations. Journal Industrial and Engineering Chemistry, vol. 78, pp. 440-447, 2019. DOI: https://doi.org/10.1016/j.jiec.2019.05.023

16. I. Ibrar, S. Yadav, A. Altaee, J. Safaei, A. K. Samal, S. Subbiah, G. Millar, P. Deka and J. Zhou. Sodium docusate as a cleaning agent for forward osmosis membranes fouled by landfill leachate wastewater. Chemosphere, vol. 308, p. 136237, 2022. DOI: https://doi.org/10.1016/j.chemosphere.2022.136237

17. Q. Jia, X. Ni and Z. Li. Physical and chemical characteristics of anionic surfactants. Oilfield Chemistry, vol. 34, pp. 306-311, 2017.

18. P. Held. Rapid Critical Micelle Concentration (CMC) Determination Using Fluorescence Polarization; 2021. Available from: https://www.biotek.com/resources/articles/cmc-determination-usingfluorescence-

polarization.html [Last accessed on 2023 Mar 27].

19. B. Shuang, M. Xiaoqian and Z. Tian. Nano-Engineered Biomaterials for Advanced Drug Delivery. Elsevier Science, Netherlands, pp. 261-278, 2020.

20. Docusate Sodium (Dioctyl Sulfosuccinate Sodium Salt) HSV Inhibitor Med Chem Express. Available from: https://www.medchemexpress.com/docusate-sodium.html [Last accessed on2023 Mar 23].

21. C. Gu, X. Mao, D. Chen, B. Yu and Q. Yang. Isoleucine plays an important role for maintaining immune function. Current Protein Peptide Science, vol. 20, no. 7, pp. 644-651, 2019. DOI: https://doi.org/10.2174/1389203720666190305163135

22. D. A. Bender. The branched-chain amino acids: Leucine, isoleucine and valine. In: Amino Acid Metabolism. John Wiley and Sons, Ltd., United States, pp. 279-303, 2012. DOI: https://doi.org/10.1002/9781118357514.ch7

23. M. J. O’Neil. Isoleucine. In: The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biological. Royal Society of Chemistry, UK, p. 896, 2013.

24. M. M. M. Affandi, M. Tripathy, A. Shah and A. A. B. Majeed. Solubility enhancement of simvastatin by arginine: Thermodynamics, solute-solvent interactions, and spectral analysis. Drug Design Development Therapy, vol. 10, pp. 959-969, 2016. DOI: https://doi.org/10.2147/DDDT.S94701

25. H. A. Hamadameen, H. L. Qader and A. H. Abdullah. Improvement of solubility and dissolution rate of biopharmaceutical class II drug atorvastatin calcium by using an essential amino acid L-leucine. Zanco Journal Medical Science, vol. 26, no. 1, pp. 67-77, 2022. DOI: https://doi.org/10.15218/zjms.2022.008

26. A. M. Helmenstine. Amino Acid Structures. ThoughtCo. Available from: https://www.thoughtco.com/amino-acidstructures-4054180 [Last accessed on 2023 Mar 23].

27. P. Tran, Y. C. Pyo, D. H. Kim, S. E. Lee, J. K. Kim and J. S. Park. Overview of the manufacturing methods of solid dispersion technology for improving the solubility of poorly water-soluble drugs and application to anticancer drugs. Pharmaceutics, vol. 11, no. 3, p. 132, 2019. DOI: https://doi.org/10.3390/pharmaceutics11030132

28. C. L. N. Vo, C. Park and B. J. Lee. Current trends and future perspectives of solid dispersions containing poorly water-soluble drugs. European Journal Pharmaceutics Biopharmaceutics, vol. 85, no. 3 Pt B, pp. 799-813, 2013. DOI: https://doi.org/10.1016/j.ejpb.2013.09.007

29. T. Vasconcelos, B. Sarmento and P. Costa. Solid dispersions as strategy to improve oral bioavailability of poor water soluble drugs. Drug Discovery Today, vol. 12, no. 23-24, pp. 1068-1075, 2007. DOI: https://doi.org/10.1016/j.drudis.2007.09.005

30. K. T. Savjani, A. K. Gajjar and J. K. Savjani. Drug solubility: Importance and enhancement techniques. ISRN Pharmacology, vol. 2012, p. 195727, 2012. DOI: https://doi.org/10.5402/2012/195727

31. R. M. Elkanayati, I. Karnik, P. Uttreja, N. Narala, S. K. Vemula, K. Karry and M. A. Repka. Twin screw melt granulation of simvastatin: drug solubility and dissolution rate enhancement using polymer blends. Pharmaceutics, vol. 16, no. 12, p. 1630, 2024. DOI: https://doi.org/10.3390/pharmaceutics16121630

32. F. M. Khan, M. Ahmad and F. Batool. Enhancement of solubility and release profile of simvastatin by co-crystallization with citric acid. Tropical Journal Pharmaceutical Research, vol. 18, no. 12, pp. 2465-2472, 2019.

33. M. A. Hashem, A. K. Hussein, H. Abdelkader and M. S. Saddik. Solubility enhancement of simvastatin for wound dressing preparation. Journal Advanced Biomedical Pharmaceutical Science, vol. 7, no. 2, pp. 75-79, 2024. DOI: https://doi.org/10.21608/jabps.2024.254472.1211

34. V. Parikh, S. G. Gumaste and S. Phadke. Effect of the interaction between an ionic surfactant and polymer on the dissolution of a poorly soluble drug. AAPS PharmSciTech, vol. 19, no. 7, pp. 3040- 3047, 2018. DOI: https://doi.org/10.1208/s12249-018-1125-x

35. N. S. M. Azmi, N. Anuar, K. J. Roberts, N. F. Abu Bakar and N. F. Kamalul Aripin. Molecular aggregation of L-isoleucine in aqueous solution and its impact on the determination of solubility and nucleation kinetics. Journal Crystal Growth, vol. 519, pp. 91-99, 2019. DOI: https://doi.org/10.1016/j.jcrysgro.2019.04.019

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Published

2025-07-25

How to Cite

1.
Al-Jumaili MA, Alamdar SN, Noori MF, Hamad Ameen HA, Abbas MA. Enhancement of the Solubility of Simvastatin by Utilizing Two Distinct Types of Excipient Compositions, L-Isoleucine and Sodium Docusate. Cihan U Erbil SCI J [Internet]. 2025 Jul. 25 [cited 2026 Jun. 23];9(2):26-32. Available from: https://journals.cihanuniversity.edu.iq/index.php/cuesj/article/view/1234

Issue

Vol. 9 No. 2 (2025)

Section

Research Article

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Copyright (c) 2025 Maysra A. Al-Jumaili, Suzan N. Alamdar, Marwa F. Noori, Hewa A. Hamad Ameen, Muhamed A. Abbas

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