Development of Spray-Dried Co-crystals of Piperine and Succinic Acid for Solubility Enhancement

Authors

DOI:

https://doi.org/10.59796/jcst.V15N2.2025.104

Keywords:

co-crystals, piperine, succinic acid, spray drying, solubility, dissolution, stability

Abstract

Piperine (PIP) is an amide alkaloid that belongs to the biopharmaceutical classification system II and shows poor aqueous solubility, which limits its therapeutic efficacy. To counter this issue, the objective of the current research was to screen and prepare co-crystals of piperine using succinic acid as a co-former in different molar ratios. Since spray drying is a well-known scale-up technology for co-crystallization, it has been used in the current research for co-crystal preparation. This study aimed at enhancing solubility and dissolution rate by preparing piperine co-crystals. Equimolar ratios of piperine and succinic acid were used to prepare co-crystals via spray drying. The developed spray-dried co-crystals were characterized by in silico modeling, solubility studies, in vitro dissolution studies, Powder X-ray Diffraction (PXRD), Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FT-IR) and Scanning Electron Microscopy (SEM). PXRD studies of spray-dried co-crystals showed improved crystallinity, SEM studies revealed a distinct morphology compared to parent components, and the DSC thermogram indicated enhanced thermal stability. The solubility of piperine at pH 7.4 (19.2 ± 1.23 µg/mL) and pH 1.2 (35.2 ± 0.16 µg/mL) increased by almost 2-3 times which was 49.5 ± 0.89 µg/mL at pH 7.4 and 96.4 ± 1.62 µg/mL at pH 1.2. Increasing the concentration of succinic acid improves the solubility of PIP. Moreover, compared to pure piperine, the dissolution rate of piperine co-crystals increased by almost threefold. This increase may be due to the strong hydrogen bonding of piperine and succinic acid in co-crystals. The stability of piperine was also improved as the co-crystals remained stable under accelerated temperature and humidity conditions. Our findings conclude that prepared spray-dried co-crystals have the potential to improve the solubility and dissolution profile of piperine. Hence, co-crystals can be a suitable approach for improving the physicochemical properties of BCS Class II drugs.

References

Al-Dulaimi, A. F., Al-Kotaji, M., & Abachi, F. T. (2022). Co-Crystals for Improving Solubility and Bioavailability of Pharmaceutical Products. Egyptian Journal of Chemistry, 65(1), 81-89. https://doi.org/10.21608/ejchem.2021.77694.3793

Ashokkumar, K., Murugan, M., Dhanya, M. K., Pandian, A., & Warkentin, T. D. (2021). Phytochemistry and therapeutic potential of black pepper [Piper nigrum (L.)] essential oil and piperine: A review. Clinical Phytoscience, 7(1), Article 52. https://doi.org/10.1186/s40816-021-00292-2

Bin, L. K., Janakiraman, A. K., Abd Razak, F. S., Uddin, A. H., Sarker, M. Z. I., Ming, L. C., & Goh, B. H. (2020). Supercritical fluid technology and its pharmaceutical applications: A revisit with two decades of progress. Indian Journal of Pharmaceutical Education and Research, 54(2s), s1-s11. https://doi.org/10.5530/ijper.54.2s.56

Burapapadh, K., Warintaksa, P., Ruksapram, S., & Saokham, P. (2024). Development of Enteric Diclofenac Sodium Microparticles Through a Spray-Drying Process Facilitated by Different Aqueous Dispersion Systems. Journal of Current Science and Technology, 14(3), Article 53. https://doi.org/10.59796/jcst.V14N3.2024.53

Choudhary, A., Rana, A. C., Aggarwal, G., Kumar, V., & Zakir, F. (2012). Development and characterization of an atorvastatin solid dispersion formulation using skimmed milk for improved oral bioavailability. Acta Pharmaceutica Sinica B, 2(4), 421-428. https://doi.org/10.1016/j.apsb.2012.05.002

Cousins, K. R. (2011). Computer review of ChemDraw ultra 12.0. Journal of the American Chemical Society, 133(21), 8388. https://doi.org/10.1021/ja204075s

Daina, A., Michielin, O., & Zoete, V. (2017). SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules. Scientific Reports, 7(1), 42717. https://doi.org/10.1038/srep42717

Fitriani, L., Fitriandi, A. D., Hasanah, U., & Zaini, E. (2022). Nano‐co-crystals of piperine‐succinic acid: physicochemical characterization and dissolution rate studies. ChemistrySelect, 7(14), e202104196. https://doi.org/10.1002/slct.202104196

Garbacz, P., & Wesolowski, M. (2018). DSC, FTIR and Raman Spectroscopy coupled with multivariate analysis in a study of co-crystals of pharmaceutical interest. Molecules, 23(9), 2136. https://doi.org/10.3390/molecules23092136

Ganesh, M., Jeon, U. J., Ubaidulla, U., Hemalatha, P., Saravanakumar, A., Peng, M. M., & Jang, H. T. (2015). Chitosan co-crystals embedded alginate beads for enhancing the solubility and bioavailability of aceclofenac. International Journal of Biological Macromolecules, 74, 310-317. https://doi.org/10.1016/j.ijbiomac.2014.12.038

Hasanah, U., Fitriani, L., Putri, V. N., & Zaini, E. (2023). Formulation and evaluation of orally disintegrating film (ODF) containing piperine-succinic acid co-crystal. Pharmaciana, 13(1), 108-118. https://doi.org/10.12928/pharmaciana.v13i1.25286

He, H., Zhang, Q., Wang, J. R., & Mei, X. (2017). Structure, physicochemical properties and pharmacokinetics of resveratrol and piperine co-crystals. Crystal Engineering Communications, 19(41), 6154-6163. https://doi.org/10.1039/C7CE01468F

Hibbard, T., Shankland, K., & Al-Obaidi, H. (2023). Evaluation of two and three fluid nozzle spray drying to prepare co-crystals of salicylic acid and caffeine with improved physicochemical properties. Journal of Drug Delivery Science and Technology, 89, Article 105073. https://doi.org/10.1016/j.jddst.2023.105073

Jain, A., Kaur, J., Bansal, Y., Saini, B., & Bansal, G. (2017). WHO guided real time stability testing on Shankhpushpi Syrup. Journal of Pharmaceutical Technology, Research and Management, 5(1), 1-19. https://doi.org/10.15415/jptrm.2017.51001

Jain, S., Nagaich, U., Singh, I., Sangnim, T., & Huanbutta, K. (2025). Study of MCC, Mannitol and SiO2 Based Co-processed Excipient for Improving the Direct Compression Properties of Paracetamol using SeDeM/SeDeM-ODT Expert System. Journal of Current Science and Technology, 15(1), 81. https://doi.org/10.59796/jcst.V15N1.2025.81

Kawsar, S. M., Kumer, A., Munia, N. S., Hosen, M. A., Chakma, U., & Akash, S. (2022). Chemical descriptors, PASS, molecular docking, molecular dynamics and ADMET predictions of glucopyranoside derivatives as inhibitors to bacteria and fungi growth. Organic Communications, 15(2), Article 203. https://doi.org/10.25135/acg.oc.122.2203.2397

Li, L., Yin, X. H., & Diao, K. S. (2020). Improving the solubility and bioavailability of anti-hepatitis B drug PEC via PEC–fumaric acid co-crystal. RSC Advances, 10(59), 36125-36134. https://doi.org/10.1039/D0RA06608G

Liu, Y., Yang, F., Zhao, X., Wang, S., Yang, Q., & Zhang, X. (2022). Crystal Structure, Solubility, and Pharmacokinetic Study on a Hesperetin Co-crystal with Piperine as Co-former. Pharmaceutics, 14(1), 94. https://doi.org/10.3390/pharmaceutics14010094

Milenković, A. N., & Stanojević, L. P. (2021). Black pepper: chemical composition and biological activities. Advanced Technologies, 10(2), 40-50. https://doi.org/10.5937/savteh2102040M

Mo, P., Hatanaka, Y., Furukawa, S., Takase, M., Yamanaka, S., Doi, M., ..., & Tozuka, Y. (2024). Co-crystal formulation design of 4-Aminosalicylic acid and isoniazid via spray-drying based on a ternary phase diagram toward simultaneous pulmonary delivery. Powder Technology, 445, Article 120126.

Mujwar, S. (2021). Computational Repurposing of Tamibarotene against Triple Mutant Variant of SARS-CoV-2. Computers in Biology and Medicine, 136, 104748. https://doi.org/10.1016/j.compbiomed.2021.104748

Mujwar, S., & Pardasani, K. (2023). Molecular Docking Simulation-based Pharmacophore Modeling to Design Translation Inhibitors Targeting c-di-GMP Riboswitch of Vibrio cholera. Letters in Drug Design & Discovery, 20(6), 745-754. https://doi.org/10.2174/1570180819666220516123249

Mujwar, S., & Pardasani, K. R. (2015). Prediction of riboswitch as a potential drug target and design of its optimal inhibitors for Mycobacterium tuberculosis. International Journal of Computational Biology and Drug Design, 8(4), 326-347. https://doi.org/10.1504/IJCBDD.2015.073671

Ober, C. A., & Gupta, R. B. (2012). Formation of itraconazole–succinic acid co-crystals by gas antisolvent co-crystallization. AAPS PharmSciTech, 13, 1396-1406. https://doi.org/10.1208/s12249-012-9866-4

Octavia, M. D., Hasmiwati, H., Revilla, G., & Zaini, E. (2023). Multicomponent Crystals of Piperine-Nicotinic Acid: The Physicochemical and Dissolution Rate Properties. Tropical Journal of Natural Product Research, 7(8). https://doi.org/10.26538/tjnpr/v7i8.20

Patil, S. P., Modi, S. R., & Bansal, A. K. (2014). Generation of 1: 1 carbamazepine: nicotinamide co-crystals by spray drying. European Journal of Pharmaceutical Sciences, 62, 251-257. https://doi.org/10.1016/j.ejps.2014.06.001

Pentak, D. (2016). In vitro spectroscopic study of piperine-encapsulated nanosize liposomes. European Biophysics Journal, 45, 175-186. https://doi.org/10.1007/s00249-015-1086-x

Rathi, R., Kaur, S., & Singh, I. (2022a). A review on co-crystals of herbal bioactives for solubility enhancement: Preparation methods and characterization techniques. Crystal Growth & Design, 22(3), 2023-2042. https://doi.org/10.1021/acs.cgd.1c01408

Rathi, R., Kaur, S., Chopra, H., Kaur, M., Kumar, S., & Singh, I. (2024) Advancements in microsponges for the management of vaginal and colorectal diseases: A comprehensive review. Applied Chemical Engineering, 7(2), Article 2334. https://doi.org/10.59429/ace.v7i2.2334

Rathi, R., Kushwaha, R., Goyal, A., & Singh, I. (2022b). Oxaliplatin-flavone pharmaceutical co-crystal-CN111205332A: patent spotlight. Pharmaceutical Patent Analyst, 11(5), 147-154. https://doi.org/10.4155/ppa-2022-0011

Rathi, R., & Singh, I. (2022). Multicomponent crystal compromising dasatinib and selected co-crystals formers: a patent evaluation of EP2861589B1. Pharmaceutical Patent Analyst, 11(1), 15-21. https://doi.org/10.4155/ppa-2021-0024

Shah, K., & Mujwar, S. (2022). Delineation of a novel non-steroidal anti-inflammatory drugs derivative using molecular docking and pharmacological assessment. Indian Journal of Pharmaceutical Sciences, 84(3), 642-53. https://doi.org/10.36468/pharmaceutical-sciences.959

Sinha, N., & Ray, S. (2021). Scope of Black Pepper Piper nigrum L. extract in pest control. International Journal of Pharmacognosy, 8(9), 351-360.

Shinu, P., Sharma, M., Gupta, G. L., Mujwar, S., Kandeel, M., Kumar, M., ... & Morsy, M. A. (2022). Computational design, synthesis, and pharmacological evaluation of naproxen-guaiacol chimera for gastro-sparing anti-inflammatory response by selective COX2 inhibition. Molecules, 27(20), 6905. https://doi.org/10.3390/MOLECULES27206905

Thenmozhi, K., & Yoo, Y. J. (2017). Enhanced solubility of piperine using hydrophilic carrier-based potent solid dispersion systems. Drug Development and Industrial Pharmacy, 43(9), 1501-1509. https://doi.org/10.1080/03639045.2017.1321658

Ullah, M., Hussain, I., & Sun, C. C. (2016). The development of carbamazepine-succinic acid co-crystal tablet formulations with improved in vitro and in vivo performance. Drug Development and Industrial Pharmacy, 42(6), 969-976. https://doi.org/10.3109/03639045.2015.1096281

Ullah, M., Ullah, H., Murtaza, G., Mahmood, Q., & Hussain, I. (2015). Evaluation of Influence of Various Polymers on Dissolution and Phase Behavior of Carbamazepine‐Succinic Acid Co-crystal in Matrix Tablets. BioMed Research International, 2015(1), Article 870656. https://doi.org/10.1155/2015/870656

Valdés-Tresanco, M. S., Valdés-Tresanco, M. E., Valiente, P. A., & Moreno, E. (2020). AMDock: a versatile graphical tool for assisting molecular docking with Autodock Vina and Autodock4. Biology Direct, 15, 1-12. https://doi.org/10.1186/s13062-020-00267-2

Wicaksono, Y., Setyawan, D., Siswandono, S., Siswoyo, T.A. (2019). Preparation and characterization of a novel co-crystal of atorvastatin calcium with succinic acid co-former. Indonesian Journal of Chemistry, 19(3), 660-667. https://doi.org/10.22146/ijc.35801

Yu, D., Kan, Z., Shan, F., Zang, J., & Zhou, J. (2020). Triple strategies to improve oral bioavailability by fabricating coamorphous forms of ursolic acid with piperine: Enhancing water-solubility, permeability, and inhibiting cytochrome p450 isozymes. Molecular Pharmaceutics, 17(12), 4443-4462. https://doi.org/10.1021/acs.molpharmaceut.0c00443

Zaini, E., Fitriani, L., Ismed, F., Horikawa, A., & Uekusa, H. (2020). Improved solubility and dissolution rates in novel multicomponent crystals of piperine with succinic acid. Scientia Pharmaceutica, 88(2), Article 21. https://doi.org/10.3390/scipharm88020021

Downloads

Published

2025-03-25

How to Cite

Rathi, R. ., Sharma, A., Mujwar, S. ., Singh, I. ., Sangnim, T. ., & Huanbutta, K. (2025). Development of Spray-Dried Co-crystals of Piperine and Succinic Acid for Solubility Enhancement. Journal of Current Science and Technology, 15(2), 104. https://doi.org/10.59796/jcst.V15N2.2025.104

Issue

Section

Research Article

Categories