Optimization of Tacrolimus Loaded Reconstituted Nanoparticles by QbD Method

 

Prafulla Chaudhari¹*, Snehal Jadhav¹, Priyanka Chaudhari², Sagar Wankhede², Shital Chandewar³

¹Department of Pharmaceutical Quality Assurance, JSPM’s Charak College of Pharmacy and Research, Wagholi, Pune - 412207, Maharashtra, India.

²Department of Pharmaceutical Chemistry, JSPM’s Charak College of Pharmacy and Research,

Wagholi, Pune - 412207, Maharashtra, India.

³Datta Meghe College of Pharmacy, Datta Meghe Institute of Medical Sciences (Deemed to be University), Wardha, Maharashtra, India.

 

ABSTRACT:

The aim of the present study is to implement QbD approach for development and optimization of Tacrolimus Loaded Reconstituted Nanoparticles. Tacrolimus-loaded nanoparticles were prepared by using Kollisolve PEG 300, Kolliphor ELP, Citrate buffer solution and Tween 80. The aqueous medium was added drop by drop into the organic phase at continuous stirring on a magnetic stirrer for half an hour. The solution then homogenized at high pressure that reduced particle size. Drying was done by using Low Endotoxin Lactose Monohydrate as a carrier. The final reconstituted powder stored in a closed container and assessed for zeta potential, drug loading, FT-IR Studies, Particle Size Analysis, SEM, X-Ray Diffraction, DSC etc. Optimization was performed by using Design Expert 8 software, 3 Level Factorial design was selected from Response Surface Design. The drug was found to be 98.65% w/w by assay. The particle size was found to be in the range of 263nm - 500nm. Tacrolimus powder shows O-H stretching vibration at 3374.91^cm−1, C = O stretching vibrations at 1733.38 ^cm−1, and C = C stretching vibration at 1631.55 ^cm−1, C–O (ester) stretching vibration at 1248.11 ^cm−1. Tacrolimus nanoparticles were optimized by QbD method, Methanol: Phosphate Buffer (80:20) solvent phase was used having pH 6. The maximum wavelength of Tacrolimus was found to be 293nm. The desirability value of that optimized method was found to be 1. Tacrolimus Loaded Reconstituted Nanoparticles leads to enhanced solubility and we can conclude that an increase in pH was responsible for increment in absorbance and thus showed the direct relationship between them.

 

 

 

INTRODUCTION: 

Tacrolimus is a macrolide immunosuppressant isolated from Streptomyces tsukubaensis, which has powerful and selective anti-T-lymphocyte activity¹. The 23 member macrolide lactones (molecular weight ¼ 803.5 g/mole) is found to be effective in the prophylaxis of organ rejection following the transplantation of liver, heart, kidney, and small bowel transplantation, as well as in the treatment of various autoimmune diseases such as atopic dermatitis and psoriasis^2–6.

 

Being a neutral and hydrophobic compound, Tacrolimus has low aqueous solubility and higher degradation, causing a problem in formulating it as a liquid preparation⁷. Another problem associated with the use of Tacrolimus is that it has a narrow therapeutic index, and, therefore, it is essential to prevent the possible toxic effects of the drug when the extended-release dosage form is administered^{8, 9}. Liquid crystalline Nanoparticles are bi-continuous cubic phase preparations that can be used as a vehicle for a controlled drug delivery system. The main precursor for liquid crystalline Nanoparticles formation is mono-olein which is a mixture of glycerides of oleic acid and other fatty acids, consisting mainly of the mono-oleate¹⁰. It is a nontoxic biodegradable polar lipid which is insoluble in water^{11– 13}. Surfactant plays a vital role in the formation of liquid crystalline nanoparticles and maintaining the nano-particular dispersion; and Kollisolve PEG 300 is the most commonly used for this purpose¹⁴. Among different Soluplus, Kollisolve PEG 300 has been used most frequently due to its least toxicity and appropriate surfactant action¹⁵. It can be used in a concentration range up to 20% w/w with respect to the lipid phase, that is, mono-olein, for the purpose of liquid crystalline nanoparticles formation¹⁰. ​The emulsifications of the lipid phase in water result in the production of liquid crystalline nanoparticles. These nano-particles can Solubilizes not only hydrophobic but also hydrophilic and amphiphilic drug molecules and can provide controlled release of drug molecules entrapped in the nano-particles^16–18. ICH Q8 (R2) guideline introduces a concept of Quality by Design which is defined as - “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management^19-20. The pharmaceutical industry has focused on product Quality, Safety, and Efficacy. Product quality has been increasing by implementing scientific approaches that will provide clear and sufficient Knowledge from product development to manufacturing. These QbD tools will minimize the risk by increasing productivity and quality. Now a day’s QbD approach has been successfully implemented in generic formulation development. USFDA has released specific QbD guidance for immediate and extended-release drug products. Regulatory authorities are always recommending the implementation of ICH quality guidelines Q8 to Q11. Equivalent to process QbD, the outcome of a QbD is well understood and fit for intended purpose with robustness throughout the life cycle has different tools such as ATP (analytical Target profile), CQA, Risk Assessment, Method optimization and development with DoE, MODR (method operable design region)²¹. Scientific QbD Approach for Synthesis and analysis ICH Q11 has explained the QbD approach for API synthetic process development but there is no specific discussion on A QbD. However, it is recommended to implement Q b D approach in analytical method development termed as A QbD. these two specific approaches (QbD and A QbD) can be progressed in equal time represents the necessary steps in API synthesis and analytical development with QbD implementation. This simultaneous implementation produces high-quality products. It may give better input for the initiation of Process Analytical Technology (PAT)²².

 

MATERIALS AND METHODS:

Materials:

Tacrolimus was supplied as a gift sample by Murli Krishna Pharmaceuticals; Ranjangaon (MIDC), Pune, India. Kollisolve PEG, Kolliphor ELP, Poloxamer 188 and trisodium citrate were purchased from Sigma Aldrich, Mumbai (India).

 

METHOD:

Standardization of Drug:

Solubility:

The solubility studies of the Tacrolimus in various solvents like methanol, ethanol, acetone, ethyl acetate, and ether were studied.

 

Standard Curve:

100mg of Tacrolimus was dissolved in 100ml of methanol. From this stock solution, 10ml was diluted up to 100ml with 0.1 N NaOH of pH 7.4 buffer to make 100mcg/ml solutions. Initial dilutions were made with pH 7.4 buffer solutions to get 10mcg/ml solutions. Further dilutions were made with buffer solution, and estimated spectrophotometrically (Jasco V- 680, UV/ Vis Double beam Spectrophotometer, Japan) at a wavelength of 292nm.

 

FT-IR Studies of Drug:

The infrared spectrums of Tacrolimus drug and Tacrolimus loaded nanoparticles were recorded using IR- spectrophotometer (Bruker)²⁷. The spectrum was scanned over a frequency range of 4000-400cm^-1 with a resolution 4cm^-1.

 

Physical compatibility studies:

Physical Compatibility studies were carried out with potential formulation excipients to determine drug- polymer or excipients interaction/compatibility. The infrared spectrums of Tacrolimus drug and Tacrolimus loaded nanoparticles were recorded using IR- spectrophotometer (Bruker)²⁷. The spectrum was scanned over a frequency range of 4000-400cm^-1 with a resolution 4cm^-1.

 

Preparation of Liquid Crystalline Nanoparticles:

Tacrolimus-loaded liquid crystalline nanoparticles were prepared with a modification of the method reported by previous researchers²³. Kollisolve PEG 300 was melted in the heating condition separately. Kolliphor ELP was added in a previously melted solution of Kollisolve PEG 300 along with a drug sample with continuous stirring for an hour. The aqueous medium was prepared separately using a citrate buffer solution having pH 3.2 and Tween 80 as a surfactant²⁴. The aqueous medium was added drop by drop into the organic phase at continuous stirring on a magnetic stirrer for half a hour²⁵. The solution then homogenized at high pressure that reduced particle size. Tray Drying was done by using Low Endotoxin Lactose Monohydrate as a carrier added into the prepared Tacrolimus Suspension. Drying was then carried out for 8 hours. The final reconstituted powder stored in a closed container²⁶. 

 

Characterization of Nanoparticles:

Scanning Electron Microscopy:

The SEM photograph of Tacrolimus loaded nanoparticle was obtained by using a S-3400 SEM (Hitachi, Japan) at 5.0 KV electron acceleration voltage²⁷.

 

Differential Scanning Calorimetry (DSC):

The physical state of Tacrolimus, drug-loaded nanoparticles was measured with DSC-6 (Mettler-Toledo, Switzerland). Samples (about 5mg) were weighed accurately and sealed in an aluminium pan and the DSC curves were determined at a heating rate of 10°C/min from 25°C to 180°C under N₂ gas purge of 40ml/min, and an empty pan was used as reference²⁹.

 

X-Ray Powder Diffraction (XRPD):

The crystalline characteristics of Tacrolimus loaded nanoparticles were determined by XRD-6000 X-ray Powder Diffractometry²⁹ (Shimadzu, Japan) at 40kV and 40mA using Cu Kα radiation. The samples were measured in the 2θ range between 5° and 60° at a scan rate of 2.8°per second with step of 0.0167°²⁹.

 

Micrometric studies:

Micromeretics studies of Tacrolimus loaded nanoparticles were performed for Bulk Density, Angle of Repose, Tapped Density, Carr’s Index and Hausner’s Ratio²⁹.

 

Particle Size Analysis and Zeta Potential:

The solid content of Nanoparticles dispersion was adjusted to 0.02% by appropriate dilution with distilled water. The particle size analysis and zeta potential were performed with Zeta-sizer Nano ZS (Malvern, UK)²⁹.

 

Entrapment Efficiency:

High Performance Liquid Chromatography (HPLC) method was used for determination entrapment of the drugs in nanoparticles

 

OPTIMIZATION STUDIES:

Solvent Phase and Solution Preparation:

Solvent phase was prepared by mixing Phosphate Buffer (pH7.4) and Methanol (AR grade) in the ratio of 2:8 v/v proportions. The pH of solvent phase was adjusted to 6 with Hydrochloric Acid and the solution was filtered through a 0.45µ membrane filter. A stock solution was prepared by dissolving 10mg of Tacrolimus nanoparticles in solvent phase (2: 8v/v) using a 10ml volumetric flask and final volume was marked with same solvent phase. From stock solution we have withdrawn 0.1ml and were diluted to 10ml with the solvent phase that obtained a concentration of 10µg/ml of Tacrolimus and labelled as a standard stock solution of Tacrolimus²⁹. From the standard stock solution, further dilutions were made using the solvent phase and scanned over the range of 200-400nm. It was observed that the drug showed considerable absorbance at 292 nm.

 

Design of Experiment:

Optimization was performed by using Design Expert 8 software, in that software, there are various factors, among that the 3 Level Factorial design was selected from Response Surface Design³⁰.

 

Table 1: Experiments suggested by Central composite design

 

The various dependent variables (pH, Solvent) and independent variables (absorbance, wavelength) were selected for UV, which is directly or indirectly affect the result of UV. 

 

Table 2: Factorial Design of various mobile phase proportion and pH

 

A selected Factorial design was a miscellaneous Factorial design due to it has the flexibility to change /add/delete any parameter at any time when our experiment is going on and total 9 runs were suggested by software and depicted in the table no. 1. Based on the results obtained from screening of various pH, solvents were selected for the analysis of employing QbD methodology. Miscellaneous Factorial design can pick up one mobile phase. So, we have selected each mobile phase one by one, Buffer: Methanol having pH range: 6-8. We have also changed the mobile phase proportion range: 20-40% (Aqueous Phase) When all above ranges put in miscellaneous Factorial Design³¹, It gave 9 run at different pH, Mobile phase proportion. We have followed same procedure for each mobile phase (Table

 

Table 3: Optimized trials suggested by software based on desirability value

 

2). After completion of all trials software give one optimize best desirability value for validation purpose (Table 3). This methodology is initially based on constructing a desirability function for each individual response.

 

The scale of individual desirability function ranges between i= 0, for completely undesirable response and i =1, for the fully desired response. The selection of the trial was based on maximum desirability value. Therefore, the first trial which was having desirability one (i=1) selected for method optimization.

 

Software was given a three-level Factorial design with 8 runs for every solvent. Then the optimization of accurate method and solvent from are selected by software and their validation was performed. We have selected solvent phase as Methanol: Water, Methanol: Phosphate Buffer, Acetonitrile: Water and Acetonitrile: Phosphate Buffer. We have ranges of dependent factors for aqueous phase Solvent: 20 to 40 and pH: 6 to 8. We have selected independent factor such as Absorbance and Wavelength^32-37.

 

RESULTS AND DISCUSSION:

Standardization of Drug:

Tacrolimus is soluble in methanol, ethanol, acetone, ethyl acetate, and ether, and it is practically insoluble in water. The UV spectrophotometer showed maximum absorption of Tacrolimus at 292 nm in phosphate buffer pH 7.4.

Standard Curve:

Calibration curve of Tacrolimus in buffer of pH 7.4 (0.1 N NaOH) solution showed a straight line which passes from origin (Figure 1). The calibration curve was found to be linear in the concentration range between 30 - 90 µg/ml having coefficient of correlation value R²=0.996 and slope y = 0.0118x + 0.0533.

 

Figure 1: Calibration curve of Tacrolimus drug at pH 7.4

 

FT-IR studies of Drug:

FT-IR spectrum was carried out and the drug Tacrolimus shows O-H stretching vibration at 3434.77^cm−1, C = O stretching vibrations at 1733.77 ^cm−1 and C = C stretching vibration at 1631.55 ^cm−1, C–O (ester) stretching vibration at 1189.11 ^cm−1. The study confirmed that the test sample was Tacrolimus (Figure 2.)

 

Figure 2: FT-IR Spectrum of Tacrolimus Drug

 

Figure 3: FT-IR Spectrum of Tacrolimus Formulation.

 

 

Figure 4: Scanning Electron Microscopy of Tacrolimus Reconstituted Powder (A) and Stability data for Tacrolimus
(1 Month) (B)

 

 

 

 

Physical Compatibility Studies:

The infrared spectrum of Tacrolimus formulation was recorded using IR- spectrophotometer (Bruker). Tacrolimus formulation shows O-H stretching vibration at 3374.91^cm−1, C = O stretching vibrations at 1733.38 ^cm−1, and C = C stretching vibration at 1631.55 ^cm−1, C–O (ester) stretching vibration at 1248.11 ^cm−1. The study confirmed that the drug sample was compatible with polymers which were used in the formulation of nanoparticles (Figure 3).

 

Characterization of Nanoparticles

Scanning Electron Microscopy:

Particle size of prepared nanoparticles were obtained below range of 700 nm and obtained spherical shaped particles. Stability data of Tacrolimus formulation also shows particles in Nano meter and it proves better stability to nanoparticles (Figure 4).  

 

Differential Scanning Calorimetry (DSC):

The thermograms of tacrolimus loaded nanoparticles were shown in Figure no. 5. Analysis of the thermogram for tacrolimus loaded nanoparticles showed one sharp endothermic peak with an onset temperature at 148°C, indicative of melting and the crystalline nature of the drug loaded nanoparticles.

 

Figure 5: The DSC Spectrum of Tacrolimus loaded nanoparticles.

Table 4: Details of X-Ray Powder Diffraction (XRPD) Studies

 

X-Ray Powder Diffraction (XRPD):

The crystalline characteristics of Tacrolimus, drug-loaded nanoparticles were determined by XRD-6000 X-ray Powder Diffractometry (Shimadzu, Japan) at 40 kV and 40mA using Cu Kα radiation. The samples were measured in the 2θ range between 5° and 60° at a scan rate of 2.8° per second with step of 0.0167°.

 

The XRPD plot shows Sharp peaks which are obtained from crystalline materials, having particle size in ranges of micrometer (Figure 6). The samples were measured in the 2θ range between 5° and 60° at a scan rate of 2.8° per second with step of 0.0167°.The net and gross intensities of X- Ray powder diffraction was shown in table no.4.

 

Micrometric studies of Tacrolimus Nanoparticles:

Micromeretics studies of Tacrolimus loaded nanoparticle were performed²⁸. The result was depicted in Table no. 5.

 

Particle Size Analysis and Zeta Potential:

The particle size analysis was performed with different observations and intensities were found and depicted in table 6.

 

The particle size of prepared nanoparticles was obtained 263 nm which is below 500 nm (figure no. 7). 

 

Figure 6: X-Ray Powder Diffraction Studies (XRPD) of Tacrolimus Nanoparticles.

 

Table 5: Micromeretics of Tacrolimus loaded Nanoparticles.

 

Table 6: Size Distribution Analysis of Nanoparticles

 

Table 7: Zeta Potential of Tacrolimus Nanoparticles

 

Table 8: Summary of assay of Tacrolimus drug formulated Nanoparticles by HPLC Method

Figure 7: Peak of Size Distribution Analysis

 

Zeta Potential:

Particles that possess a zeta potential will migrate toward the opposite-charged electrode and % area of the Tacrolimus nanoparticles was shown in figure no. 8.

 

Figure 8: Peak of Zeta Potential

 

Entrapment Efficiency:

High Performance Liquid Chromatography (HPLC) method was used for determination entrapment of the drugs in nanoparticles and the result was depicted in the table no. 8. The Analytical assay of Standard Tacrolimus Nanoparticles is lies between 90 to 110 % w/w. Our prepared Tacrolimus nanoparticles analytical Assay was obtained 98.65 % w/w which are good enough for the release of the drug and having better Entrapment Efficiency.

 

Assay of Tacrolimus Nanoparticles =

Sample Area/Average of Standard Area × 100

               = 106.7872/108.2478 X 100

               = 98.65% w/w

 

The Analytical assay of Standard Tacrolimus Nanoparticles is lies between 90 to 110% w/w. Our prepared Tacrolimus nanoparticles analytical Assay was obtained 98.65% w/w which are good enough for the release of the drug and having better Entrapment Efficiency.

OPTIMIZATION STUDIES:

The Optimized result of Tacrolimus loaded nanoparticles at pH 6 and Solvent combination of Methanol: Buffer (80:20) at Maximum Wavelength 292.462nm gives 1 Desirability value.

 

Effect of independent variables on absorbance (Y1):

The equation for the response surface quadratic model is as follows

Abs = +0.91- 0.018*A- 0.18*B +0.028 * A* B+0.39* A2 + 0.17 * B2; Where, X1= A, X2 = B 

 

A graphical representation of the amount of pH (A) and Solvent (B), an increase in pH resulted in a decrease in Absorbance (Y1) (as shown in figure 9), while an increase in Solvent resulted in an increase in Absorbance (Y1).

 

Figure 9: Three-dimensional plot for Absorbance as a function of pH and Solvent.

 

A combination of the amount of pH and Solvent showed a decrease in response. Fit Summary: The quadratic model was suggested by the software (figure 9).

 

ANOVA: ANOVA of developed full three-level factorial models for Absorbance (Y1):

Values of "Prob > F" (p-value) less than 0.1000 indicate model terms are significant. In this case, A, B, BC, A2, and C2 are significant model terms (Table 9). For response Y1, factor pH and Solvent were having a synergistic effect with p-value 0.0267. Therefore, we can conclude that an increase in pH was responsible for increment in absorbance and thus showed the direct relationship between them. A combination of the amount of Solvent was responsible for a significant increase in absorbance with a significant p-value of 0.0267. Therefore, a direct relationship between this combination and response is observed. Exponential terms also showed a direct relationship with the response having significant p values 0.0116 and 0.0590 respectively.

 

 

Table 9: Significance of p value on model terms of Absorbance

 

Factor pH and its exponential term differ from zero with a great margin therefore they were having a more significant effect than other factors. Therefore, it is concluded that the pH of the buffer and its exponential term was responsible for significant change in response i.e. Absorbance. Fit Summary: Response Surface Linear Model was suggested by the software.

 

Effect of independent variables on maximum wavelength (Y₂):

ANOVA: ANOVA of developed full three-level factorial models for Wavelength (Y2).

 

After applying experimental design, suggested Response Surface Linear Model (Figure 10) was found to be significant with model F value of 23.79, p value less than 0.005 and R² value of 0.7563.

 

Figure 10: 3D plot for Maximum Wavelength as a function of pH and solvents.

 

There is only a 0.01% chance that a "Model F-Value" this large could occur due to noise. Values of % C.V. and adjusted R² were 3.78 and 0.7245 respectively. The model for response Y₂ is as Y₂ = +292.142 -0.49X₁-0.48X₂.

 

ANOVA: ANOVA of developed CCD model for Wavelength (Y2):

Values of "Prob > F" (p-value) less than 0.1000 indicate model terms are significant. In this case A, B is significant model terms. Figure no. 11 shows a graphical representation of the pH of buffer (B) and solvents (A), while absorbance (C) is maintained constant at its optimum of 2.000. An increase in pH of buffer showed an increase in pH (Y1), also increase in the amount of buffer showed a synergistic effect on Y1. A combination of the amount of buffer and pH of buffer showed an antagonistic effect on response.

 

Figure 11: (Desirability Spectra) 3D plot for Absorbance as a function of pH and solvents

 

DISCUSSION AND CONCLUSION:

Nanoparticle delivery methods are a valid route to address the shortcomings of the immunosuppressant drug, Tacrolimus. Tacrolimus powder shows O-H stretching vibration at 3374.91cm⁻¹, C=O stretching vibrations at 1733.38 cm⁻¹, and C=C stretching vibration at 1631.55 cm⁻¹, C–O (ester) stretching vibration at 1248.11 cm⁻¹. The study confirmed that the drug sample was compatible with polymers which were used in the formulation of nanoparticles (Figure 3).  Analysis of the thermogram for tacrolimus showed one sharp endothermic peak with an onset temperature at 148°C, indicative of melting and the crystalline nature of the drug loaded nanoparticles. Differential Scanning Calorimetry (DSC) mainly done for the compatibilty study of drug- excipients when applying heat to the samples (Figure 5). Particle size of prepared nanoparticles were obtained below range of 700nm and obtained spherical shaped particles. The XRPD plot shows Sharp peaks which are obtained from crystalline materials, having particle size in ranges of micrometre (Figure 6). The samples were measured in the 2θ range between 5° and 60° at a scan rate of 2.8° per second with step of 0.0167°. The bulk density of powder should be below 0.7g/ml and our prepared nanoparticles Bulk density was obtained 0.4g/ml which is better and also obtained Angle of Repose was 21⁰C was good for flow property of powder. The particle size of prepared nanoparticles was obtained 263nm which is below 700 nm and useful in higher incorporation rate into the cancerous cell as shown in figure 4. The Analytical assay of Standard Tacrolimus Nanoparticles is lies between 90 to 110% w/w. Our prepared Tacrolimus nanoparticles, the drug was found to be 98.65 % w/w by assay which is good enough for the release of the drug and having better Entrapment Efficiency. A graphical representation of the amount of pH (A) and Solvent (B), an increase in pH resulted in a decrease in Absorbance (Y1) (as shown in figure 9), while an increase in Solvent resulted in an increase in Absorbance (Y1).A combination of the amount of pH and Solvent showed a decrease in response. Fit Summary: The quadratic model was suggested by the software (figure 9). ANOVA: ANOVA of developed full three-level factorial models for Absorbance (Y1). Values of "Prob > F" (p-value) less than 0.1000 indicate model terms are significant. In this case, A, B, BC, A2, and C2 are significant model terms (Table 10).  For response Y1, factor pH and Solvent were having a synergistic effect with p-value 0.0267. Therefore, we can conclude that an increase in pH was responsible for increment in absorbance and thus showed the direct relationship between them. A combination of the amount of Solvent was responsible for a significant increase in absorbance with a significant p-value of 0.0267. Effect of independent variables on maximum wavelength (Y₂): ANOVA: ANOVA of developed full three-level factorial models for Wavelength (Y2). After applying experimental design, suggested Response Surface Linear Model (Figure 10) was found to be significant with model F value of 23.79, p value less than 0.005 and R² value of 0.7563. Values of "Prob > F" (p-value) less than 0.1000 indicate model terms are significant. In this case A, B is significant model terms. Figure no. 11 shows a graphical representation of the pH of buffer (B) and solvents (A), while absorbance (C) is maintained constant at its optimum of 2.000.

 

ACKNOWLEDGEMENTS:

The authors are thankful to Murli Krishna Pharmaceuticals; Ranjangaon (MIDC), Pune, India and Sigma Aldrich Ltd. for providing gift samples of required material for this study.

 

CONFLICT OF INTEREST:

The authors have no conflicts of interest regarding this investigation.

 

ACKNOWLEDGEMENT:

The authors are thankful to Murli Krishna Pharmaceuticals; Ranjangaon (MIDC), Pune, India and Sigma Aldrich Ltd. for providing gift samples of required material for this study.

 

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Accepted on 18.05.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2023; 16(3):1359-1368.