• HIRIHATTAYA PHETMUNG Inorganic and Materials Chemistry Research Unit, Faculty of Science, Thaksin University, Amper Muang, Songkhla 90000, Thailand
  • SOMCHAI SAWATDEE Drug and Cosmetics Excellence Center, Walailak University, Thaiburi, Thasala, Nakhon Si Thammarat, 80161, Thailand


Objective: The objective of this present work was to develop the chemical peeling cream containing the synthesized active ingredient pharmaceutical cocrystal of salicylic acid and phenylalanine.

Methods: The salicylic acid and phenylalanine cocrystal (H2Sal·Phe) was synthesized by the solvent evaporation method and characterized by various techniques such as single-crystal X-ray diffraction and Fourier transform infrared spectroscopy. The five formulas of cocrystal cream were prepared. All formulas were then examined and observed for appearance, spreadability, viscosity, pH, homogeneity, SPF test, microbial limit test and stability test.

Results: The (H2Sal·Phe) consists of no zwitterion phenylalanine for the first time. X-ray crystal structure of cocrystal consists of double H2Sal and Phe molecules with stabilized by inter-, intra-molecular and π-π interactions. By using this cocrystal as an active ingredient for cosmetic development, the chemical peeling cream was produced along with the pharmaceutical examinations. The (H2Sal·Phe) formulations were prepared 0-1% and excipients included of jojoba oil, isopropyl myristate, castor oil, glyceryl monostearate cetostearyl alcohol, cyclomethicone (and) dimethicone crosspolymer, vitamin E, white bee's wax, glycerin, PEG 400, xanthan gum, Span 80 and Tween 60. We finally found that the F4 (1% H2Sal·Phe) was the best formulation with suitable physical properties of cream and chemical stable after storage. The results of cell viability show H2Sal·Phe is non-toxic with cell.

Conclusion: The chemical peeling cream containing (H2Sal·Phe) has shown the promising results which are both safe and efficacious peeling agent. Cocrystal (H2Sal·Phe) cream can be used as an alternative choice in whitening skin.

Keywords: Pharmaceutical cocrystal, Salicylic acid, Phenylalanine, Cream, Cosmetics, Formulation development


1. Doaa S Sayed, Amira A Abdel-Motaleb. Salicylic acid versus lactic acid peeling in mild and moderate acne vulgaris. Alpe Adria Microbiol J 2012;10:341-54.
2. Raman K Madan, Jacob Levitt. A review of toxicity from topical salicylic acid preparations. J Am Acad Dermatol 2013;70:788-92.
3. Alex N Manin, Alexander P Voronin, Nikolay G Manin, Mikhail V Vener, Anastasia V Shishkina, Anatoly S Lermontov, et al. Salicylamide cocrystals: screening, crystal structure, sublimation thermodynamics, dissolution, and solid-state DFT calculations. J Phys Chem B 2014;118:6803-14.
4. Tesleem Arif. Salicylic acid as a peeling agent: a comprehensive review. Clin Cosmet Investig Dermatol 2015;8:455-61.
5. Jaishree Sharad. Glycolic acid peel therapy-a current review. Clin Cosmet Investig Dermatol 2013;6:281-8.
6. Franziska Stefanie Ihlefeldt, Fredrik Bjarte Pettersen, Aidan Von Bonin, Malgorzata Zawadzka, Carl Henrik Gorbitz. The polymorphs of l-phenylalanine. Angew Chem Int Ed Engl 2014;53:13600-4.
7. Anaelle Tilborg, Bernadette Norberg, Johan Wouters. Pharmaceutical salts and cocrystals involving amino acids: a brief structural overview of the state-of-art. Eur J Med Chem 2014;74:411-26.
8. Marina Landau. Chemical peels. Clin Dermatol 2008;26:200-8.
9. Marta I Rendon, Diane S Berson, Joel L Cohen, Wendy E Roberts, Isaac Starker, Beatrice Wang. Evidence and considerations in the application of chemical peels in skin disorders and aesthetic resurfacing. J Clin Aesthet Dermatol 2010;3:32-43.
10. William Jones, Samuel Motherwell, Andrew V Trask. Pharmaceutical cocrystals: an emerging approach to physical property enhancement. MRS Bull 2006;31:875-9.
11. Srinivasulu Aitipamula, Annie BH Wong, Pui Shan Chow, Reginald BH Tan. Pharmaceutical cocrystals of ethenzamide: structural, solubility and dissolution studies. Cryst Eng Comm 2012;14:8515-24.
12. MA Elbagerma, HGM Edwards, T Munshi, Ian J Scowen. Identification of a new co-crystal of salicylic acid and benzamide of pharmaceutical relevance. ?Anal Bioanal Chem 2010;397:137-46.
13. Tomislav Friscic, William Jones. Benefits of cocrystallisation in pharmaceutical materials science: an update. J Pharm Pharmacol 2010;62:1547-59.
14. Anna Karagianni, Maria Malamatari, Kyriakos Kachrimanis. Pharmaceutical cocrystals: new solid phase modification approaches for the formulation of APIs. Pharmaceutics 2018;10:18.
15. Sulbha R Fukte, Milind P Wagh, Shilpi Rawat. Conformer selection: an important tool in cocrystal formation. Int J Pharm Pharm Sci 2014;6:9-14.
16. Zhengzheng Zhou, Hok Man Chan, Herman HY Sung, Henry HY Tong, Ying Zheng. Identification of new cocrystal systems with stoichiometric diversity of salicylic acid using thermal methods. Pharm Res 2016;33:1030-9.
17. Pei-Wen Hsieh, Ibrahim A Aljuffali, Chia-Lang Fang, Shu-Hao Chang, Jia-You Fang. Hydroquinone-salicylic acid conjugates as novel anti-melasma actives show superior skin targeting compared to the parent drugs. J Dermatol Sci 2014;76:120–31.
18. Mohamed A Elbagerma, Howell GM Edwards, Tariq Allaudin Munshi, Michael D Hargreaves, Pavel Matousek, Ian J Scowen. Characterization of new cocrystals by raman spectroscopy, powder x-ray diffraction, differential scanning calorimetry, and transmission raman spectroscopy. Cryst Growth Des 2010;10:2360-71.
19. Mohamed Atiega Elbagerma, Howell GM Edwards, Adel Imhemed Alajtal, Ian Ja Scowen. Identification and structural studies of the salicylic acid DL-phenylalanine cocrystal. Am J Chem Mat Sci 2017;4:49-58.
20. Nitha Vincent, Ramya Devi D, BN Vedha Hari. Development and optimization of emollient gel loaded with salicylic acid for the effective treatment of psoriasis. Res J Pharm Biol Chem Sci 2014;5:1299-311.
21. Barkat Ali Khan, Naveed Akhtar, Haji Muhammad Shoaib Khan, Khalid Waseem, Tariq Mahmood, Akhtar Rasul, et al. Basic of pharmaceutical emulsions: a review. Afr J Pharm Pharmacol 2011;5:2715-25.
22. George M Sheldrick. Crystal structure refinement with SHELXL. Acta Cryst 2015:C71:3-8.
23. EE Soje, Jameel Muazu, Shadrack Madu. Formulation and in vitro assessment of cream prepared from Allium cepa L., Bulb. Asian J Pharma Sci Technol 2016;6:1-5.
24. Avish D Maru, Swaroop R Lahoti. Formulation and evaluation of moisturizing cream containing sunflower wax. Int J Pharm Pharm Sci 2018;10:54-9.
25. Ali Heyam Saad, Shehab Naglaa Ahmed, El-ahaj Babiker Mohamed. Formulation and evaluation of herbal cream from Ziziphus Spina leaves extract. Int Res J Pharm 2013;4:44-8.
26. Teelavath Mangilal, KSK Rao Patnaik, R Shyam Sunder, S Anuradha Bai. Preparation and evaluation of poly herbal anti-aging cream by using different synthesis polymers. Int J Herb Med 2017;5:92-5.
27. Shailendra Kumar Sah, Ashutosh Badola, Sayantan Mukhopadhyay. Development and evaluation of tioconazole loaded emulgel. Int J Appl Pharm 2017;9:83-90.
28. Jose Luiz Neves de Aguiar, Katia Christina Leandro, Shirley de Mello Pereira Abrantes, Andre Luis Mazzei Albert. Development of a new analytical method for determination of acetylsalicylic and salicylic acids in tablets by reversed phase liquid chromatography. Braz J Pharm Sci 2009;45:723-7.
29. Mingwiman S, Werawatganone P, Muangsiri W. Correlation of in vitro SPF values from two laboratories. Thai J Pharm Sci 2016;40:65-8.
30. Slim Smaoui, Hajer Ben Hlima, Raoudha Jarraya, Nozha Grati Kamoun, Raoudha Ellouze, Mohamed Damak. Cosmetic emulsion from virgin olive oil: formulation and bio-physical evaluation. Afr J Biotechnol 2012;11:9664-71.
31. Jadhav CM, Kate VK, Payghan SA. Stability study of griseofulvin in non aqueous microemulsion system. Asian J Biomed Pharm Sci 2014;4:79-83.
32. Priyanka R Kapare, Kishan L Jadhav, Divya V Khairmode, Shradha D Sawant, Akash S Mali. Development and evaluation of cosmeceutical cram for acne vulgaris. Int J Adv Community Med 2018;1:50-3.
33. Slim Smaoui, Hajer Ben Hlima, Ines Ben Chobba, Adel Kadri. Development and stability studies of sunscreen cream formulations containing tree photo-protective filters. Arab J Chem 2017;10:S1216-22.
34. Anongtip SA, Somchai Sawatdee, Narubodee Phadoongsombut, Wilaiporn Buatong, Titpawan Nakpeng, Rutthapol Sritharadol, et al. Quantitative analysis of povidone-iodine thin films X-ray photoelectron spectroscopy and their physicochemical properties. Acta Pharm 2017;67:169-86.
35. Yutaka Inoue, Kensuke Suzuki, Rikimaru Maeda, Arisa Shimura, Isumu Murata. Evaluation of formulation properties and skin penetration in the same additive-containing formulation. Results Pharma Sci 2104;4:42-9.
36. Fredrik L Nordstro, Åke C Rasmuson. Solubility and melting properties of salicylic acid. J Chem Eng Data 2006;51:1668-71.
37. Raymond C Rowe, Paul J Sheskey, Marian E Quinn. Handbook of pharmaceutical excipients. 6th edition. Pharmaceutical Press. USA; 2009.
38. Dweck A. Handbook of cosmetic ingredients-their use, safety and toxicology, 3rd edition. Dweck Data; 2011.
39. Ehrhardt Proksch. pH in nature, humans and skin. J Dermatol 2018;45:1044-52.
40. Ravi Shankar, Babita Sarang, Ramesh Gupta, Kamla Pathak. Formulation and characterization of polyherbal cream for skin manifestations. JAASP 2016;1:360-66.
41. Medical Device Division. Notification of the Food and Drug Administration; 2010. p. 1-13.
42. Alireza Firooz, Bardia Sadr, Shahab Babakoohi, Maryam Sarraf-Yazdy, Ferial Fanian, Ali Kazerouni-Timsar, et al. Variation of biophysical parameters of the skin with age, gender, and body region. Sci World J 2012;1-5.
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