Introduction

Ascorbic acid, also known as vitamin C, is a type of water-soluble vitamin that acts as an antioxidant [1]. It is present in the form of a white or slightly yellow powder having slightly acidic in taste [2]. It is an antiscorbutic compound that plays various important roles in the body. Vitamin C is used in the body for healthy skin, teeth, cartilage, bone, and blood vessels. Moreover, it also protects the cells of the body from damage. The supplements of Vitamin C are used in the treatment of burns, ulcers, and other injuries as it stimulates the collagen formation [3]. The use of vitamin C is also evident in the treatment of prostate, pancreas, liver, and ovarian cancers as adjuvant where it might act by slowing the growth and proliferation of cancer cells [4,5]. Besides, it reduces the symptoms of nausea, vomiting, pain, tiredness, and anorexia as well as, elevates the mood and improves the physical health. Some studies reported the use of vitamin C supplement in the reduction of cardiovascular risk and heart attack [3]. The other benefits of the use of vitamin C are in the treatment of hypercholesterolemia, hypertension, diabetes mellitus, angina pectoris, coronary heart disease, and congestive cardiac failure. Use of vitamin C as the adjuvant therapy also improves the blood flow by vasodilation to various vital organs [6]. Also, it acts in enhancing the immune functions by improving the cellular motility, resistance to oxidative damage, phagocytosis, and interferon release [7].

In humans, the ascorbic acid acts in the body by reversibly oxidized to dehydroascorbic acid and these two forms play a vital role in the oxidation-reduction reactions [8]. The ascorbic acid is also important for tyrosine metabolism, carbohydrate metabolism, conversion of folic acid to Folinic acid, iron metabolism, and synthesis of proteins and lipids [3]. The deficiency of vitamin C causes scurvy. Moreover, the deficiency also affects the collagenous structures and some lesions started developing in the blood vessels and bones. The other symptoms involve the impaired development of bone and tooth, bleeding gums, gingivitis, and loosened teeth [9]. The supplementation of vitamin C is also needed in some health conditions such as the chronic illness, febrile states, and infection related to pneumonia, tuberculosis, whooping cough, diphtheria, rheumatic fever, hemovascular disorders, sinusitis, delayed fracture and wound healing, burns, etc. [10,11]. The ADME profile of Vitamin C such as its absorption, dissolution, tissue distribution, and other pharmacokinetic properties, etc. depends upon it’s physiochemical properties [8]. Hence, the researchers are using various approaches for improving the physiochemical properties of compounds to achieve the maximum biological activity and efficacy. One among such approaches is the use of Biofield Energy Treatment for altering the properties of various compounds. Putative energy fields (also known as Biofield) are based on the concept that human beings are infused with a subtle form of energy [12]. Therefore, a human has the ability to harness energy from the universe and it could be transmitted to any living organism(s) or non-living object(s) around the globe. Biofield Energy Healing has been used in the treatment against various diseases and it is also considered and accepted as Energy therapy by the National Center for Complementary and Alternative Medicine (NCCAM) [13]. The other similar Energy therapies recommended by NCCAM under the Complementary and Alternative Medicine (CAM) are deep breathing, Tai Chi, yoga, Qi Gong, meditation, chiropractic/osteopathic manipulation, massage, special diets, progressive relaxation, homeopathy, guided imagery, acupressure, acupuncture, hypnotherapy, relaxation techniques, healing touch, movement therapy, pilates, Ayurvedic medicine, naturopathy, traditional Chinese herbs and medicines, etc. [14,15]. The Trivedi Effect^®-Consciousness Energy Healing Treatment is a type of such CAM therapies that have been known worldwide for its impact on the non-living materials and living organisms. It is reported for its significant impact on the physicochemical and thermal properties of various organic, pharmaceutical, and nutraceutical compounds [16-19], changing the characteristics in the field of microbiology [20,21], biotechnology [22], agriculture science [23,24], metals, ceramics, and polymers [25-27], and bone and skin health [28,29]. Thus, in this study, the effect of Biofield Energy Treatment was studied on the physicochemical and thermal properties of ascorbic acid by using various modern analytical techniques.

Materials and Methods

Chemicals and reagents

Ascorbic acid was purchased from Alfa Aesar, USA. Remaining chemicals used during the experiments were of analytical grade purchased from India.

Consciousness energy healing treatment strategies

The ascorbic acid sample used in the experiment was equally divided into two parts. The first part of the sample was not given the Biofield Energy Treatment and considered as a control sample. Besides, the second part of the sample was provided the Trivedi Effect^®-Energy of Consciousness Healing Treatment remotely under standard laboratory conditions for 3 minutes and known as the Biofield Energy Treated sample. This Biofield Energy Treatment was provided by a famous Biofield Energy Healer, Gopal Nayak, India, through the unique energy transmission process to the test sample. Further, regarding the comparison, the control sample was treated with a “sham” healer as the “sham” healer did not have any knowledge about the Biofield Energy Treatment. Alter the treatment, the control, and the Biofield Energy Treated samples were kept in sealed conditions and characterized using modern analytical techniques.

Characterization

Powder X-ray Diffraction (PXRD) analysis

The PXRD analysis of control and Biofield Energy Treated ascorbic acid was performed with the help of Rigaku MiniFlex-II Desktop X-ray diffractometer (Japan) [30,31]. The average size of individual crystallites was calculated from XRD data using the Scherrer’s formula 1:

G = kλ/βcosθ                        (1)

Where k is the equipment constant (0.94), G is the crystallite size in nm, λ is the radiation wavelength (0.154056 nm for Kα1 emission), β is the full-width at half maximum (FWHM), and θ is the Bragg angle [32].

The % change in crystallite size (G) of ascorbic acid was calculated using the following equation 2: 

      (2)

Where G_Control and G_Treated are the crystallite size of the control and Biofield Energy Treated samples, respectively.

Particle Size Analysis (PSA)

The particle size analysis of ascorbic acid samples was conducted on Malvern Mastersizer 2000, from the UK with a detection range between 0.01 µm to 3000 µm using the wet method [33,34]. The calculations were done by using software Mastersizer Ver. 5.54.

The % change in particle size (d) for at below 10% level (d₁₀), 50% level (d₅₀), 90% level (d₉₀), and D (4,3) was calculated using the following equation 3:

Where d_Control and d_Treated are the particle size (μm) for at below 10% level (d₁₀), 50% level (d₅₀), and 90% level (d₉₀) of the control and Biofield Energy Treated ascorbic acid samples, respectively.

The % change in surface area (S) was calculated using the following equation 4:

Where S_Control and S_Treated are the surface area of the control and Biofield Energy Treated ascorbic acid samples, respectively.

Thermal Gravimetric Analysis (TGA)/ Differential Thermogravimetric Analysis (DTG)

TGA/DTG thermograms of the control and Biofield Energy Treated ascorbic acid were obtained with the help of TGA Q50TA instruments. A sample of 4-15 mg was loaded to the platinum crucible at a heating rate of 10 °C/min from 25 °C to 1000 °C with the recent literature [35]. The % change in weight loss (W) was calculated using the following equation 5:

Where W_Control and W_Treated are the weight loss of the control and Biofield Energy Treated ascorbic acid, respectively.

The % change in maximum thermal degradation temperature (T_max) (M) was calculated using the following equation 6:

Where M_Control and M_Treated are the T_max values of the control and Biofield Energy Treated ascorbic acid, respectively.

Differential Scanning Calorimetry (DSC)

The DSC analysis of ascorbic acid was performed with the help of DSC Q200, TA instruments. A sample of ~1-5 mg was loaded to the aluminium sample pan at a heating rate of 10 °C/min from 30 °C to 350 °C [35]. The % change in melting point (T) was calculated using the following equation 7:

Where T_Control and T_Treated are the melting point of the control and treated samples, respectively.

The % change in the latent heat of fusion (ΔH) was calculated using the following equation 8:

Where ΔH_Control and ΔH_Treated are the latent heat of fusion of the control and treated ascorbic acid, respectively.

Results and Discussion

Powder X-ray Diffraction (PXRD) analysis

The study showed the PXRD diffractograms of the control and Biofield Energy Treated samples (Figure 1) and their corresponding analysis was done to determine the changes in the relative intensity of the characteristic peaks and the crystallite sizes (Table 1). The diffractograms of both the samples of ascorbic acid showed sharp and intense peaks, thereby showing their crystalline nature; however, the Bragg’s angles corresponding to those peaks of the treated sample were observed to be altered in comparison to the control sample.

The further analysis revealed that the peak intensities of the characteristic peaks and corresponding crystallite sizes of the treated sample were significantly changed ranging from -67.75% to 1059.21% and -29.41% to 271.10%, respectively as compared to the control ascorbic acid sample. The Biofield Energy Treated sample also showed significant alteration in the average crystallite size (561.14 nm) as it shows an increase of 50.67% in comparison to the control sample (372.43 nm). The significant alterations in the crystallite properties such as peak intensities and crystallite size signify the possible alteration in the crystal morphology of ascorbic acid that might indicate the formation of a new polymorphic form [36,37]. Moreover, altering the crystal habit and properties are used as a technique to enhance the solubility, absorption, and bioavailability of the compound [38]. Thus, it could be concluded that the bioavailability of the treated ascorbic acid might increase after the Biofield Energy Treatment in comparison to the untreated sample.

Particle Size Analysis (PSA)

The particle size analysis corresponding to d₁₀, d₅₀, d₉₀, and D (4,3) for the control and the Biofield Energy Treated samples were done and results are presented in Table 2. It showed that the particle size distributions of the treated sample were significantly decreased by 8.23%, 22.07%, 11.64%, and 15.81% at d₁₀, d₅₀, d₉₀, and D (4,3), respectively, compared to the control ascorbic acid sample.

Moreover, the resultant decrease in the particle size affects the surface area of the Biofield Energy Treated sample (0.045 m²/g), as it was increased by 15.38% compared to the control sample (0.039 m²/g). The dissolution, absorption, and bioavailability of a drug are important parameters in terms of its efficacy and these properties are highly influenced by the particle size distribution of the drug [39,40]. Moreover, decreasing the particle size increases the effective surface area of drug, thereby used as an approach to enhance the dissolution and bioavailability of drug [41]. Hence, it could be presumed that the Biofield Energy Treatment of ascorbic acid might improve its efficacy by enhancing the bioavailability in the body compared to the untreated sample.

Thermal Gravimetric Analysis (TGA)/ Differential Thermogravimetric Analysis (DTG)

The thermal degradation and stability profile of the control and treated samples were analysed with the help of the TGA/DTG technique. According to the literature, the heating of ascorbic acid revealed its stability till ~ 200 °C, after which it started degrading and the residual mass contains the non-decomposed ascorbic acid as well as its carbonaceous residues [42]. The TGA thermograms of the control and Biofield Energy Treated sample (Figure 2) also showed the thermal stability of both the samples till 200 °C and thus, observed similarly as reported in the literature. Moreover, the weight loss of the Biofield Energy Treated sample during the thermal heating cycle was found as 76.68%, which is considerably reduced by 20.57% in comparison to the weight loss of the control ascorbic acid sample (96.54%). The residual amount remaining after the thermal degradation of the treated ascorbic acid sample was significantly increased by 573.99% (Table 3) compared to the control sample. Therefore, the TGA analysis revealed improved thermal stability of the treated ascorbic acid sample after the Biofield Energy Treatment compared to the control sample.

On the other hand, the DTG analysis of both the samples showed the presence of two peaks in the DTG thermograms (Figure 3). The further analysis revealed that the maximum degradation temperature (T_max) corresponding to the 1^st and 2^nd peaks of the Biofield Energy Treated sample was increased by 0.58% and 4.93%, respectively, compared to the T_max of the control sample. The T_max of 2^nd peak of the treated sample was significantly increased by ~15 °C as compared to the control sample, which indicated the significant improvement in the thermal stability profile and reduced degradation of the ascorbic acid after the Biofield Energy Treatment.

Differential Scanning Calorimetry (DSC) analysis

The DSC analysis of the drug is used to determine the thermal behaviour of the drug during heating [43]. It was reported in the literature that the heating of ascorbic acid at the rate of 10 °C min^-1 create an endothermic peak in the thermogram at 193 °C, which was considered as the fusion temperature. Besides, there was a second exothermic peak that is reported as the thermal decomposition during heating of the ascorbic acid, which produces a carbonaceous residue after releasing the volatile compounds [42]. The DSC thermograms of the control and the Biofield Energy Treated sample (Figure 4) showed similar peaks as reported in the literature. The endothermic peak was observed at a similar temperature for the control and the treated sample that represents the similar melting point of both the sample (Table 4). However the 2^nd peak of the treated sample i.e., the decomposition temperature was observed to be reduced by 4.17% compared to the control sample. Besides, the Latent heat of fusion (ΔH_fusion) and Latent heat of decomposition (ΔH_{decomposition}) of the treated ascorbic acid sample was observed to be significantly increased by 9.13% and 110.60%, respectively in comparison to the control sample (Table 4).

Therefore, the DSC analysis showed the alterations in the decomposition temperature and ΔH_fusion and ΔH_{decomposition} of the treated sample that might happen as a result of some changes arising in the crystallization structure of the ascorbic acid [43] after the Biofield Energy Treatment. Overall, the melting and thermal decomposition profile of the treated ascorbic acid sample was observed to be altered compared to the control sample.

Conclusions

This study evaluated the impact of the Trivedi Effect^®-Consciousness Energy Healing Treatment on the physicochemical and thermal properties of ascorbic acid such as crystal properties, particle size, surface area, melting temperature, and other thermal properties. The PXRD results revealed the changes in the Bragg’s angles of the peaks present in the diffractograms of the treated sample in comparison to the control sample. Moreover, the Biofield Energy Treated sample showed alterations in the peak intensities and crystallite sizes ranging from -67.75% to 1059.21% and -29.41% to 271.10%, respectively in comparison to the control sample. The average crystallite size of the treated ascorbic acid was increased significantly by 50.67% compared to the control sample. Such changes might appear due to the possible formation of a novel polymorphic form of the ascorbic acid that may show improved bioavailability profile compared to the untreated sample. The particle size distribution of the treated sample was also altered as the particle size values at d₁₀, d₅₀, d₉₀, and D (4,3) were significantly decreased by 8.23%, 22.07%, 11.64%, and 15.81%, respectively in comparison to the control sample. Such changes in the particle size of the treated sample resulted in 15.38% significant increase in the surface area as compared to the untreated sample. Therefore, it is presumed that the Biofield Energy Treatment of the ascorbic acid might help in increasing its solubility and dissolution profile, along with the improved bioavailability parameters compared to the untreated sample. The TGA thermogram of the treated sample revealed a significant decrease in the weight loss by 20.57% during the thermal heating; however, the residual amount was significantly increased by 573.99% in comparison to the control sample. The DTG results revealed two peaks in the thermograms of both the samples. Besides, the T_max corresponding to the 1^st and 2^nd peaks in the thermogram of the treated sample was increased by 0.58% and 4.93%, respectively compared to the T_max of the untreated ascorbic acid sample. Thus, the thermal data showed the improved thermal stability of the treated sample after the Biofield Energy Treatment compared to the untreated sample. The ΔH_fusion and ΔH_{decomposition} of the Biofield Energy Treated sample were significantly increased by 9.13% and 110.60%, respectively compared to the untreated ascorbic acid sample. Thus, it can be concluded that the Trivedi Effect^®-Consciousness Energy Healing Treatment significantly affects the physicochemical and thermal properties of ascorbic acid that might help in producing a new polymorph with improved solubility, dissolution, and bioavailability compared with the untreated sample. Hence, The Biofield Energy Treated ascorbic acid could be used in the formulation for acting more efficiently in the prevention as well as treatment of many diseases such as common cold, diabetes, scurvy, cataracts, heart diseases, glaucoma, cancer, autoimmune diseases, stroke, chronic degenerative diseases, atherosclerosis, anemia, bleeding gums, infections, muscle degeneration, delayed wound healing, capillary haemorrhage, low immunity, and neurotic disturbances, etc.

Acknowledgement

The authors are grateful to Central Leather Research Institute, SIPRA Lab. Ltd., Trivedi Science, Trivedi Global, Inc., Trivedi Testimonials, and Trivedi Master Wellness for their assistance and support during this work.

Figure 1: PXRD diffractograms of the control and Biofield Energy Treated ascorbic acid.

Figure 2: TGA thermograms of the control and Biofield Energy Treated ascorbic acid.

Figure 3: DTG thermograms of the control and Biofield Energy Treated ascorbic acid.

Figure 4: DSC thermograms of the control and Biofield Energy Treated ascorbic acid.

1. Lykkesfeldt J, Michels AJ, Frei B (2014) Vitamin C. Adv Nutr 5: 16-18.
2. Kehinde OS, Christianah OI, Oyetunji OA (2018) Ascorbic acid and sodium benzoate synergistically aggravates testicular dysfunction in adult Wistar rats. Int J Physiol Pathophysiol Pharmacol 10: 39-46.
3. Chambial S, Dwivedi S, Shukla KK, John PJ, Sharma P (2013) Vitamin C in Disease Prevention and Cure: An Overview. Indian J Clin Biochem 28: 314-328.
4. Cameron E, Pauling L (1976) Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A 73: 3685-3689.
5. Block G (1991) Epidemiologic evidence regarding vitamin C and cancer. Am J Clin Nutr 54: 1310S-1314S.
6. Naidu AK (2003) Vitamin C. In human health and disease is still a mystery? An overview. Nutr J 2: 7.
7. Animashaun A, Kelleher J, Heatley RV, Trejdosiewicz LK, Losowsky MS (1990) The effect of zinc and vitamin C supplementation on the immune status of patients with Crohn's disease. Clin Nutr 9: 137-146.
8. Wilson JX (2005) Regulation of vitamin C transport. Ann Rev Nutr 25: 105-125.
9. Delanghe JR, Langlois MR, De Buyzere ML, Na N, Ouyang J, et al. (2011) Vitamin C deficiency: more than just a nutritional disorder. Genes Nutr 6: 341-346.
10. Rowan MP, Cancio LC, Elster EA, Burmeister DM, Rose LF, et al. (2015) Burn wound healing and treatment: review and advancements. Critical Care 19: 243.
11. Figueroa-Méndez R, Rivas-Arancibia S (2015) Vitamin C in Health and Disease: Its Role in the Metabolism of Cells and Redox State in the Brain. Front Physiol 6: 397.
12. Berman JD, Straus SE (2004) Implementing a research agenda for complementary and alternative medicine. Annu Rev Med 55: 239-254.
13. Hintz KJ, Yount GL, Kadar I, Schwartz G, Hammerschlag R, et al. (2003) Bioenergy definitions and research guidelines. Altern Ther Health Med 9: A13-A30.
14. Barnes PM, Bloom B, Nahin RL (2008) Complementary and alternative medicine use among adults and children: United States. Natl Health Stat Report 12: 1-23.
15. Jain S, Hammerschlag R, Mills P, Cohen L, Krieger R, et al. (2015) Clinical Studies of Biofield Therapies: Summary, Methodological Challenges, and Recommendations. Glob Adv Health Med 4: 58-66.
16. Trivedi MK, Branton A, Trivedi D, Nayak G, Bairwa K, et al. (2015) Spectroscopic characterization of disodium hydrogen orthophosphate and sodium nitrate after biofield treatment. J Chromatogr Sep Tech 6: 282.
17. Trivedi MK, Branton A, Trivedi D, Nayak G, Panda P, et al. (2016) Evaluation of the isotopic abundance ratio in biofield energy treated resorcinol using gas chromatography-mass spectrometry technique. Pharm Anal Acta 7: 481.
18. Trivedi MK, Patil S, Shettigar H, Bairwa K, Jana S (2015) Effect of biofield treatment on spectral properties of paracetamol and piroxicam. ChemSci J 6: 98.
19. Smith DM, Trivedi MK, Branton A, Trivedi D, Nayak G, et al. (2017) Skin protective activity of consciousness energy healing treatment based herbomineral formulation. Journal of Food and Nutrition Sciences 5: 86-95.
20. Trivedi MK, Branton A, Trivedi D, Nayak G, Charan S, et al. (2015) Phenotyping and 16S rDNA analysis after biofield treatment on Citrobacter braakii: A urinary pathogen. J Clin Med Genom 3: 129.
21. Trivedi MK, Patil S, Shettigar H, Mondal SC, Jana S (2015) Evaluation of biofield modality on viral load of Hepatitis B and C viruses. J Antivir Antiretrovir 7: 083-088.
22. Trivedi MK, Branton A, Trivedi D, Nayak G, Mondal SC, et al. (2015) Evaluation of biochemical marker - glutathione and DNA fingerprinting of biofield energy treated Oryza sativa. American Journal of BioScience 3: 243-248.
23. Trivedi MK, Branton A, Trivedi D, Nayak G, Mondal SC, et al. (2015) Evaluation of plant growth, yield and yield attributes of biofield energy treated mustard (Brassica juncea) and chick pea (Cicerarietinum) seeds. Agriculture, Forestry and Fisheries. 4: 291-295.
24. Trivedi MK, Branton A, Trivedi D, Nayak G, Gangwar M, et al. (2015) Agronomic characteristics, growth analysis, and yield response of biofield treated mustard, cowpea, horse gram, and groundnuts. International Journal of Genetics and Genomics. 3: 74-80.
25. Trivedi MK, Patil S, Tallapragada RM (2013) Effect of biofield treatment on the physical and thermal characteristics of vanadium pentoxide powders. J Material SciEng S 11: 001.
26. Trivedi MK, Tallapragada RM, Branton A, Trivedi D, Nayak G, et al. (2015) Characterization of physical and structural properties of aluminum carbide powder: Impact of biofield treatment. J Aeronaut Aerospace Eng 4: 142.
27. Trivedi MK, Branton A, Trivedi D, Nayak G, Sethi KK, et al. (2016) Gas chromatography-mass spectrometry based isotopic abundance ratio analysis of biofield energy treated methyl-2-napthylether (Nerolin). American Journal of Physical Chemistry 5: 80-86.
28. Koster DA, Trivedi MK, Branton A, Trivedi D, Nayak G, Mondal S, et al. (2018) Evaluation of biofield energy treated vitamin D₃ on bone health parameters in human bone osteosarcoma cells (MG-63). Biochemistry and Molecular Biology 3: 6-14.
29. Singh J, Trivedi MK, Branton A, Trivedi D, Nayak G, Gangwar M, Jana S (2017) Consciousness energy healing treatment based herbomineral formulation: A safe and effective approach for skin health. American Journal of Pharmacology and Phytotherapy 2: 1-10.
30. Desktop X-ray Diffractometer “MiniFlex+”. The Rigaku Journal 14: 29-36, 1997.
31. Zhang T, Paluch K, Scalabrino G, Frankish N, Healy AM, Sheridan H (2015) Molecular structure studies of (1S,2S)-2-benzyl-2,3-dihydro-2-(1Hinden-2-yl)-1H-inden-1-ol. J Mol Struct 1083: 286-299.
32. Langford JI, Wilson AJC (1978) Scherrer after sixty years: A survey and some new results in the determination of crystallite size. J Appl Cryst 11: 102-113.
33. Trivedi MK, Sethi KK, Panda P, Jana S (2017) Physicochemical, thermal and spectroscopic characterization of sodium selenate using XRD, PSD, DSC, TGA/DTG, UV-vis, and FT-IR. Marmara Pharmaceutical Journal 21/2: 311-318.
34. Trivedi MK, Sethi KK, Panda P, Jana S (2017) A comprehensive physicochemical, thermal, and spectroscopic characterization of zinc (II) chloride using X‑ray diffraction, particle size distribution, differential scanning calorimetry, thermogravimetric analysis/differential thermogravimetric analysis, ultraviolet‑visible, and Fourier transform‑infrared spectroscopy. International Journal of Pharmaceutical Investigation 7: 33-40.
35. Trivedi MK, Branton A, Trivedi D, Nayak G, Plikerd WD, et al. (2017) A systematic study of the biofield energy healing treatment on physicochemical, thermal, structural, and behavioral properties of iron sulphate. International Journal of Bioorganic Chemistry. 2: 135-145.
36. Trivedi MK, Branton A, Trivedi D, Nayak G, Lee AC, et al. (2017) Evaluation of the impact of biofield energy healing treatment (the Trivedi Effect^®) on the physicochemical, thermal, structural, and behavioural properties of magnesium gluconate. International Journal of Nutrition and Food Sciences. 6: 71-82.
37. Trivedi MK, Branton A, Trivedi D, Nayak G, Plikerd WD, et al. (2017) Evaluation of the physicochemical, spectral, thermal and behavioral properties of sodium selenate: influence of the energy of consciousness healing treatment. American Journal of Quantum Chemistry and Molecular Spectroscopy 2: 18-27.
38. Savjani KT, Gajjar AK, Savjani JK (2012) Drug Solubility: Importance and Enhancement Techniques. ISRN Pharmaceutics, 2012: Article ID 195727. 
39. Khadkaa P, Roa J, Kim H, Kim I, Kim JT, et al. (2014) Pharmaceutical particle technologies: An approach to improve drug solubility, dissolution and bioavailability. Asian J Pharm, 9: 304-316.
40. Loh ZH, Samanta AK, Heng PWS (2015) Overview of milling techniques for improving the solubility of poorly water-soluble drugs. Asian J Pharm, 10: 255-274.
41. Hu J, Johnston KP, Williams RO (2004) Nanoparticle engineering processes for enhancing the dissolution rates of poorly water soluble drugs. Drug Dev Ind Pharm, 30: 233-245.
42. Nunes JFL, Melo DMA, de Moura MFV, de Farias RF (2007) TG-DSC study of ascorbic acid pharmaceutical formulations: Sodium croscarmellose, microcrystalline cellulose and lactose as excipients. Revista Química no Brasil 1: 7-14.
43. Zhao Z, Xie M, Li Y, Chen A, Li G, et al. (2015) Formation of curcumin nanoparticles via solution enhanced dispersion by supercritical CO₂. Int J Nanomedicine 10: 3171-3181.