From Plant to Pill: Exploring Phytosome Preparation Techniques and Their Therapeutic Potential

Abstract

Phytosomes are advanced lipid-based vesicular systems designed to enhance the solubility, permeability, and bioavailability of plant-derived phytoconstituents. These nanocarriers overcome the limitations of traditional herbal delivery by forming lipid-compatible complexes, especially suitable for polyphenolic compounds like flavonoids. Various preparation techniques such as solvent evaporation, anti-solvent precipitation, thin film hydration, freeze-drying, and emerging technologies like spray-drying and supercritical fluid methods are employed to formulate phytosomes. Each method significantly influences the physicochemical and biological performance of the final product. This review provides an in-depth exploration of phytosome preparation methods, along with their mechanisms, advantages, and challenges, and includes comparative insights with other nanocarrier systems like liposomes and niosomes. Emphasis is placed on process optimization, clinical relevance, and integration of topical and oral phytosome applications.

Keywords

Introduction

Plant-derived bioactives, particularly polyphenols and flavonoids, are gaining attention due to their diverse therapeutic properties, such as antioxidant, hepatoprotective, anticancer, cardioprotective, and anti-inflammatory activities [1]. However, poor bioavailability and limited solubility hinder their clinical utility [2]. These compounds typically exhibit poor absorption due to large molecular size, poor lipophilicity, or instability in gastrointestinal fluids [3].

Fig.1 Phytosome Structure

Phytosomes, first developed by Indena (Italy) in the late 1980s, revolutionized herbal delivery systems by complexing bioactives with natural phospholipids, usually phosphatidylcholine, to form lipid-compatible molecular complexes [4]. Unlike liposomes, phytosomes are not just physical mixtures but molecular adducts that interact via hydrogen bonding and polar interactions [5]. This improves solubility and membrane permeability, thereby significantly increasing oral and topical bioavailability.

Clinical studies have demonstrated increased absorption and therapeutic efficacy of phytosomal formulations of silymarin, curcumin, green tea catechins, and ginkgo biloba extract [6]. Their applications span nutraceuticals, cosmetics, dermatology, and chronic disease treatment, including diabetes, cancer, and neurodegenerative disorders [7].

2. Advantages and Disadvantages of Phytosomes

2.1 Advantages

Phospholipid complexes offer several significant advantages in drug delivery systems. They enhance bioavailability due to their amphiphilic nature, allowing better interaction with both aqueous and lipid environments [8]. These complexes also improve the stability of labile phytochemicals in biological systems by protecting them from enzymatic and pH-related degradation [9]. Additionally, they facilitate better permeability, enabling easier transdermal and intestinal absorption of active compounds [10]. Their unique structure supports the dual encapsulation of both hydrophilic and lipophilic substances [11], contributing to reduced dose frequency through sustained release and improved pharmacokinetics [12]. In cosmetic applications, they enhance product appeal, particularly in skin and hair care formulations [13]. Furthermore, the synthesis of these complexes is eco-friendly, requiring fewer toxic solvents and lower energy input [14].

2.2 Disadvantages

Despite their advantages, phospholipid complexes also present certain limitations. Their formulation requires precise stoichiometric ratios between the phospholipid and the phytochemical to ensure effective complexation [15]. There is also a risk of thermal or oxidative degradation during the preparation process, which can compromise the integrity of the final product [16]. Inconsistency in raw materials may lead to batch-to-batch variability, affecting the reproducibility and reliability of the formulation [17]. Moreover, high production costs and challenges related to scalability pose significant barriers for industrial applications [18]. Additionally, these complexes often exhibit limited shelf stability, especially under conditions of high humidity or elevated temperatures [19].

3. Methods of Preparation of Phytosomes

3.1 Solvent Evaporation Method

One of the most commonly used methods, this technique involves dissolving both the phytoconstituent and phospholipid in an organic solvent such as ethanol, chloroform, or dichloromethane. The solution is then stirred and refluxed for several hours to allow complexation [20]. The solvent is subsequently evaporated using a rotary evaporator to obtain a thin film or dried mass.

Advantages: Simple, effective, and suitable for heat-stable compounds. Allows uniform molecular interaction.

Limitations: Not suitable for thermo-labile phytochemicals. Residual solvent may require complete removal [21].

Example: Silybin-phosphatidylcholine complex was successfully prepared by this method and showed 2.5x increased oral bioavailability [22].

3.2 Anti-Solvent Precipitation

Fig.2 Antisolvent Precipitation Method

In this method, the phospholipid–phytoconstituent mixture (prepared in an organic solvent) is poured into a non-solvent like n-hexane under constant stirring. This leads to precipitation of the complex due to polarity mismatch [23]. The precipitated phytosomes are filtered or centrifuged and dried.

Advantages: Suitable for heat-sensitive phytochemicals. Offers controlled particle formation.

Limitations: Difficult to scale up. Requires careful choice of anti-solvent and stirring rate.

Application: Used in green tea polyphenol phytosomes to enhance their solubility and antioxidant activity [24].

3.3 Thin Film Hydration Technique

The phytoconstituent and phospholipid are dissolved in a volatile solvent (chloroform: methanol), then evaporated under vacuum to form a thin lipid film. This is hydrated with aqueous media (e.g., phosphate-buffered saline), forming multilamellar vesicles [25]. Sonication or extrusion is applied to reduce size.

Advantages: Allows vesicle size control. Mimics liposome production, making it compatible with existing equipment.

Limitations: Time-consuming. Risk of oxidative degradation of bioactives during solvent removal.

Example: Quercetin-loaded phytosomes prepared by this method showed improved topical delivery and antioxidant activity [26].

3.4 Freeze-Drying (Lyophilization)

Involves freezing the phospholipid–phytoconstituent mixture followed by sublimation under vacuum. Cryoprotectants like trehalose or mannitol are often added to stabilize the vesicle structure [27].

Advantages: Results in a dry, stable powder with extended shelf-life. Useful for reconstitution.

Challenges: Requires expensive equipment and multiple process steps.

Application: Applied in curcumin phytosome formulations to enhance solubility and storage stability [28].

3.5 Miscellaneous and Emerging Methods

Spray-Drying: Offers fast, scalable powder production, suitable for capsule or tablet forms [29].

Supercritical Fluid Technology: Uses CO? to form solvent-free phytosomes, offering eco-friendly processing and uniform particle size [30].

Microfluidization: Forces liquids through microchannels to create uniform vesicles with narrow particle distribution [31].

Electrospinning and nanoemulsion-based techniques are also being explored for hybrid phytosome delivery [32].

3.6 Quality Control Parameters

• Particle Size and Distribution: Measured via dynamic light scattering (DLS); important for absorption and release rate [33].
• Zeta Potential: Indicates vesicle stability.
• Entrapment Efficiency: Represents how much drug is retained within the carrier [34].
• Structural Confirmation: Via DSC, FTIR, NMR, and XRD to confirm complexation.
• In Vitro Drug Release: Determines release kinetics; tested in simulated gastrointestinal fluids or skin models.

4. Comparative Evaluation with Other Nanocarrier Systems

Phytosomes differ from liposomes and niosomes in that they involve true complex formation at the molecular level rather than mere encapsulation, resulting in better stability and controlled release [35].

Fig. No.3 Difference between Liposome, Niosome & Phytosome

SUMMARY

Phytosomes serve as a potent nanocarrier platform for overcoming the limitations of herbal actives with poor water solubility and permeability. Among the various preparation methods, solvent evaporation and thin film hydration remain widely adopted, while newer techniques such as microfluidization and supercritical fluid-based methods are advancing towards commercial viability.

Method selection depends on the phytochemical's properties, desired release profile, and final dosage form. Their application in topical delivery, particularly for skin disorders and anti-aging formulations, is expanding rapidly. Comparatively, phytosomes exhibit better stability and bioactive retention than traditional vesicular systems like liposomes or niosomes.

CONCLUSION

Phytosome technology has emerged as a transformative approach for enhancing the therapeutic efficacy of plant-based compounds. Proper method selection, stoichiometry, and process optimization are essential to achieve desirable pharmacokinetic and therapeutic outcomes. Future research should emphasize process standardization, regulatory alignment, and development of hybrid delivery systems combining phytosomes with polymers or nanoparticles.

The growing interest in green, cost-effective, and patient-compliant formulations makes phytosomes a strategic focus for both research and industry. Integration with modern nanotechnology tools will further expand their pharmaceutical applications in chronic diseases and personalized medicine.

REFERENCES

1. Zhang YJ, Gan RY, Li S, Zhou Y, Li AN, Xu DP, Li HB. Antioxidant phytochemicals for the prevention and treatment of chronic diseases. Molecules. 2015 Dec;20(12):21138-56..
2. Dillard CJ, German JB. Phytochemicals: nutraceuticals and human health. Journal of the Science of Food and Agriculture. 2000 Sep 15;80(12):1744-56.Maiti K, et al. AAPS PharmSciTech. 2006;7(3):E77.
3. Sarika D, Khar RK, Chakraborthy GS, Saurabh M. Phytosomes: a brief overview. J Pharm Res. 2016;15(2):56-62.
4. Semalty A, Semalty M, Singh D, Rawat MS. Preparation and characterization of phospholipid complexes of naringenin for effective drug delivery. Journal of inclusion phenomena and macrocyclic chemistry. 2010 Aug;67(3):253-60.
5. Choudhury A, Verma S, Roy A. Phytosome: a novel dosage form for herbal drug delivery. J. Appl. Pharm. Res. [Internet]. 2014Jun.9 [cited 2025Jul.23];2(2):44-52.
6. Zensi A, Begley D, Pontikis C, Legros C, Mihoreanu L, Wagner S, Büchel C, von Briesen H, Kreuter J. Albumin nanoparticles targeted with Apo E enter the CNS by transcytosis and are delivered to neurones. J Control Release. 2009 Jul 1;137(1):78-86. doi: 10.1016/j.jconrel.2009.03.002. Epub 2009 Mar 11. PMID: 19285109.
7. Kazemi EK, Abedi-Gaballu F, Mohammad Hosseini TF, Mohammadi A, Mansoori B, Dehghan G, Baradaran B, Sheibani N. Glimpse into the cellular internalization and intracellular trafficking of lipid-based nanoparticles in cancer cells. Anti-Cancer Agents in Medicinal Chemistry-Anti-Cancer Agents). 2022 Jun 1;22(10):1897-912.
8. Yanyu X, Yunmei S, Zhipeng C, Qineng P. The preparation of silybin-phospholipid complex and the study on its pharmacokinetics in rats. Int J Pharm. 2006 Jan 3;307(1):77-82. doi: 10.1016/j.ijpharm.2005.10.001. Epub 2005 Nov 18. PMID: 16300915.
9. Tiwari V, Verma V and Verma N: Floating Drug Delivery System: A review. Int J Pharm Sci Res 2014; 5(7): 2596-2605.doi: 10.13040/IJPSR.0975-8232.5(7).2596-2605
10. Tian, S., Wang, J., Li, Y., Li, D., Xu, L., & Hou, T. (2015). The application of in silico drug-likeness predictions in pharmaceutical research. Advanced drug delivery reviews, 86, 2–10. https://doi.org/10.1016/j.addr.2015.01.009
11. Wilar, G., Suhandi, C., Wathoni, N., Fukunaga, K., & Kawahata, I. (2024). Nanoparticle-Based Drug Delivery Systems Enhance Treatment of Cognitive Defects. International journal of nanomedicine, 19, 11357–11378. https://doi.org/10.2147/IJN.S484838
12. Semalty, A., Semalty, M., Rawat, B. S., Singh, D., & Rawat, M. S. (2010). Development and evaluation of pharmacosomes of aceclofenac. Indian journal of pharmaceutical sciences, 72(5), 576–581. https://doi.org/10.4103/0250-474X.78523
13. Kumari, A., Singla, R., Guliani, A., & Yadav, S. K. (2014). Nanoencapsulation for drug delivery. EXCLI journal, 13, 265–286.
14. Shoaib Khan, Kezhen Qi, Iltaf Khan, Aoxue Wang, Jiayin Liu, Muhammad Humayun, Abbas Khan, Ali Bahadur, Amal Faleh Alanazi, Mohamed Bououdina,Eco-friendly graphitic carbon nitride nanomaterials for the development of innovative biomaterials: Preparation, properties, opportunities, current trends, and future outlook,Journal of Saudi Chemical Society, Volume 27, Issue 6,2023,101753,ISSN 1319-6103,https://doi.org/10.1016/j.jscs.2023.101753.
15. Lengyel, M., Kállai-Szabó, N., Antal, V., Laki, A. J., & Antal, I. (2019). Microparticles, Microspheres, and Microcapsules for Advanced Drug Delivery. Scientia Pharmaceutica, 87(3), 20. https://doi.org/10.3390/scipharm87030020
16. Al-Othman ZA, Naushad M. Organic–inorganic type composite cation exchanger poly-o-toluidine Zr (IV) tungstate: preparation, physicochemical characterization and its analytical application in separation of heavy metals. Chemical engineering journal. 2011 Aug 1;172(1):369-75.
17. Neupane NP, Yadav E, Verma A. Cultural, practical, and socio-economic importance of edible medicinal plants native to Central India. InEdible Plants in Health and Diseases: Volume 1: Cultural, Practical and Economic Value 2022 Jan 13 (pp. 181-207). Singapore: Springer Nature Singapore.
18. Unnisa, Vaseem & A, Lakshmana & P, Bhargava & Lakshmi, GNA. (2025). Formulation and Evaluation of Tolterodine Tartrate Sustained Release Pellets by Using Spheronization and Extrusion Technique. Journal of Traditional Medicine and Chinese Medicine. 1-7. 10.47363/JTMCM/2025(3)119.
19. Journal, An & Sharma, Bhavana & Deswal, Renu. (2018). Artificial Cells, Nanomedicine, and Biotechnology Single pot synthesized gold nanoparticles using Hippophae rhamnoides leaf and berry extract showed shape-dependent differential nanobiotechnological applications Single pot synthesized gold nanoparticles using Hippophae rhamnoides leaf and berry extract showed shape-dependent differential nanobiotechnological applications. Artificial cells, nanomedicine, and biotechnology. 46. 10.1080/21691401.2018.1458034.
20. Pradhan, Aditya & Tiwari, Bishal & Poudyal, Abhilash & Subba, Barsha & Bhattarai, Abhishek & Regmi, Dinesh & Bhutia, Sonam. (2022). A Comprehensive Review on Phytosomes: A Novel Drug Delivery System of Phytoconstituents. International Journal of Life Science and Pharma Research. 10.22376/ijpbs/lpr.2022.12.5.p143-161.
21. Khan S, Sharma A, Jain V. An overview of nanostructured lipid carriers and its application in drug delivery through different routes. Advanced pharmaceutical bulletin. 2022 Sep 18;13(3):446.
22. Mitragotri, S., Burke, P. A., & Langer, R. (2014). Overcoming the challenges in administering biopharmaceuticals: formulation and delivery strategies. Nature reviews. Drug discovery, 13(9), 655–672. https://doi.org/10.1038/nrd4363
23. Pradhan, Aditya & Tiwari, Bishalet al. (2022). A Comprehensive Review on Phytosomes: A Novel Drug Delivery System of Phytoconstituents. International Journal of Life Science and Pharma Research. 10.22376/ijpbs/lpr.2022.12.5.p143-161.
24. Vivek, Raju. (2015). COLLOIDS AND SURFACES B: BIOINTERFACES. 10.13140/RG.2.1.3892.5280.
25. Doty, Amber & Schroeder, Jon & Vang, Kou & Sommerville, Mark & Taylor, Mervin & Flynn, Brad & Lechuga, David & Mack, Peter. (2017). Drug Delivery from an Innovative LAMA/LABA Co-suspension Delivery Technology Fixed-Dose Combination MDI: Evidence of Consistency, Robustness, and Reliability. AAPS PharmSciTech. 19. 10.1208/s12249-017-0891-1..
26. Basak, S., Sharma, M., Kaur, H., & Kaur, R. (2019). Volumetric, compressibility, and viscometric properties of L-ascorbic acid and thiamine hydrochloride in aqueous and binary aqueous 1-ethyl-3-methylimidazolium hydrogen sulfate solutions. Journal of Molecular Liquids, 274, 706–716.
27. Bhambere, Deepak & Gaidhani, Kunal & Harwalkar, Mallinath & Nirgude, Pallavi. (2015). LYOPHILIZATION / FREEZE DRYING – A REVIEW. World Journal of Pharmaceutical Research. 4. 516-543.
28. Atoosa Olfati, Naser Karimi, Elham Arkan, Mohsen Zhaleh, M. R. Mozafari, Enhancing Bioavailability and Stability of Plant Secondary Metabolites: Formulation and Characterization of Nanophytosomes Encapsulating Red Bryony and Horned Poppy Extracts, Journal of Functional Biomaterials, 10.3390/jfb16060194, 16, 6, (194), (2025).
29. Li, N. & Tang, D.-D & Wang, L.-W & Xu, X.-Y & Zhang, J.-F. (2014). Preparation of dry powder inhalation based on phytosomes-chitosan microspheres by spray-drying method and study on its characterization. Chinese Traditional and Herbal Drugs. 45. 2475-2481. 10.7501/j.issn.0253-2670.2014.17.010.
30. Parhi, Rabinarayan & Suresh, Padilama. (2013). Supercritical Fluid Technology-A Review. Advanced Pharmaceutical sciences and Technology. 1. 13-36. 10.14302/issn.2328-0182.japst-12-145.
31. Barani, M., Sangiovanni, E., Angarano, M., Rajizadeh, M. A., Mehrabani, M., Piazza, S., Gangadharappa, H. V., Pardakhty, A., Mehrbani, M., Dell'Agli, M., & Nematollahi, M. H. (2021). Phytosomes as Innovative Delivery Systems for Phytochemicals: A Comprehensive Review of Literature. International journal of nanomedicine, 16, 6983–7022. https://doi.org/10.2147/IJN.S318416
32. Nazari, Maryam & Majdi, Hasan & Milani, Morteza & Abbaspour, Soheil & Hamishehkar, Hamed & Lim, Loong-Tak. (2019). Cinnamon nanophytosomes embedded electrospun nanofiber: Its effects on microbial quality and shelf-life of shrimp as a novel packaging. Food Packaging and Shelf Life. 21. 10.1016/j.fpsl.2019.100349.
33. JAIN, ARIHANT & VERMA, RICHA & MEHTA, PARULBEN. (2023). Formulation and Evaluation of Phytosomes Loaded with Pithecellobium Bijeninum Leaf Extract. Current Research in Pharmaceutical Sciences. 13. 151-156. 10.24092/CRPS.2023.130306.
34.  Kumar DS, Deivasigamani K, Roy B. Development and Optimization of Phytosome for Enhancement of Therapeutic Potential of Epiyangambin in Tinospora cordifolia Extract Identified by GC–MS and Docking Analysis. Pharmacognosy Magazine. 2023;19(2):371-384. doi:10.1177/09731296231157192
35. Gaikwad, Sachin & Morade, Yogita & Kothule, Akshada & Kshirsagar, Sanjay & Laddha, Umesh & Salunkhe, Kishor. (2023). Overview of phytosomes in treating cancer: Advancement, challenges, and future outlook. Heliyon. 9. e16561. 10.1016/j.heliyon.2023.e16561.