Rajesh L. Dumpala1*, Dr. Akruti Khodakiya1, Dr. Nishant A Oza1, Dr. Nehal J. Shah2,
M. Lakshmi Prasuna3
1Department of Pharmaceutical Science, C.U. Shah University, Research Development and Innovation Centre (RDIC) - Wadhwan, Surendranagar, Gujarat.
2Department of Pharmaceutical Chemistry and Quality Assurance. Indubhai Patel College of Pharmacy and Research Centre, Dharmaj.
3Department of Pharmaceutical Analysis. Sri Sivani College of Pharmacy, Srikakulam - Andhra Pradesh.
*Corresponding Author E-mail: rdumpala64@gmail.com
ABSTRACT:
The study purpose is to further enhanced the rate of dissolution for poorly water soluble drug Nicardipine Hydrochloride (Antihypertensive Drug) which is poorly soluble in nature by using very famous technique called Smedds and liquisolid compact method, The prepared Liquid -SMEDDS were converted into S-SMEDDS by using Neusilin US2 as a Carrier, Aerosil 200 as a Coating agent, Crosscarmellose sodium as a Super disintegrant, Microcrystalline cellulose as a Diluent, Magnesium stearate as a Lubricant, We evaluated our preparation by their micrometric properties, DSC, XRD, SEM, TEM, In vitro dissolution of formulation was studies and compare with marketed formulation, in result liquisolid tablets shows higher % of dissolution, We also evaluated its stability studies at 400C±20C temperature and 75±5% RH for three month (accelerated stability study) which showed no major change in percentage drug content and its release patent.
KEYWORDS: Nicardipine Hydrochloride, Dissolution enhancement, liquisolid compact, Solid-SMEDDS.
INTRODUCTION:
One of the most convincible drug administration route in many diseases is oral route1. Almost 50% of new molecule candidates which undergo low water insoluble problem and dissolution rate, also the delivery from oral route of such molecule is recurrently connected with low bioavailability problem2. As connected to the crucial pressure of solubility and rate of dissolution for bioavailability, In current years, a large amount of awareness has been directed on formulations based on lipids to recover the bioavailability by oral route of low aqueous soluble molecule candidates (drug)3.
Most widely used method for the drug is their conversion into SEDDS and particularly in SMEDDS, Our goal of current study is to Transforming and Characterization of Liquid SMEDDS into Solid SMEDDS Tablets for Nicardipine Hydrochloride (Antihypertensive Drug) by using Liquisolid compact technique in which we use various carrier material and different coating materials with various loading factor and excipients ratio Liquisolid system4.
METHODOLOGY:
Preformulation Studies and Analytical Method Characterization of drug5, Physical appearance, Melting point determination, Flow and compressibility characteristic, UV-visible spectroscopy (Determination of λ max), Equilibrium solubility study, FTIR spectroscopic study, DSC study, Development of calibration curve of Nicardipine Hydrochloride, Preparation of calibration curve of Nicardipine Hydrochloride in Methanol, 0.1N HCl and in water6.
Validation of Analytical Method of Nicardipine HCL:
Validation of analytical method of Nicardipine HCl in Methanol and in 0.1N HCl
Analytical measurement of Nicardipine HCl in Methanol and 0.1N HCl by UV spectrophotometry was validated as per ICH guideline, Q2AR17,8.
1) Linearity and range:
Linearity is expressed in terms of correlation coefficient of linear regression analysis. The linearity response was determined by analyzing 8 independent levels of calibration curve in the range of 5-15μg/ml. Plot the calibration curve of absorbance vs concentration and determine correlation coefficient and regression line equations for Nicardipine HCl.
2) Accuracy preparation of sample solution:
The accuracy study was determined by standard addition method. 100mg of Nicardipine HCl was weighed and transferred into a 100ml of volumetric flask, dissolved and diluted up to mark with Methanol and 0.1N HCl. Pipette out 10ml of the above solution in 100ml volumetric flask and diluted to mark with Methanol and 0.1N HCl to get 100μg/ml solution of Nicardipine HCl, from that, Aliquots of 0.5, 0.7, 0.9, 1.1, 1.3 and 1.5ml of working standard solution were pipetted out into 10ml volumetric flasks. The volume was made up to the mark with Methanol and 0.1N HCl. These dilutions gave 5, 7, 9, 11, 13, 15µg/ml. Absorbance of solution was measured at selected wavelength. The amount of Nicardipine HCl was calculated at each level and % recoveries were computed.
3) Precision:
a) Repeatability: The absorbance of same concentration was measured three times and RSD was calculated.
b) Intraday Precision: Solutions containing 5-15 µg/ml of Nicardipine HCl was analyzed three times on the same day and % RSD was calculated.
c) Interday Precision: solutions containing 5-15µg/ml of Nicardipine HCl was analyzed three times on the different 3 days and %RSD was calculated. It is a measure of either the degree of reproducibility or repeatability of the analytical method.
4) LOD: The limit of detection (LOD) is the lowest amount of analyte in a sample that can be detected, but not necessarily quantified, under standard experimental condition. LOD will be calculated using the following formulae:
LOD= 3.3 σ/S Where σ is Standard deviation of the response and S is slope of the calibration curve.
5) LOQ: The limit of quantification (LOQ) is the lowest amount of analyte in a sample that can be determined with acceptable precision and accuracy under standard experimental condition. LOQ were calculated using the following formulae LOQ= 10σ/S Where σ is Standard deviation of the response and S is slope of the calibration curve.
Application of the mathematical model for designing the Liquisolid System10,11:
In current study, we used liquid vehicle like PEG-400, as a carrier Avicel PH 200 and as a coating material (which improves flow properties) we used Aerosil 200. Carrier coating ratio or excipients ratio was calculated by equation
R =Q/q
Where R = Carrier coating ratio, Q = Coating material weight, q = Carrier material weight.
Liquid load factor (Lf) is a ratio of liquid medication weight (W) and carrier powder weight (Q).
Lf = W/Q For calculation of amount of each ingredient we use Flowable liquid retention potentials (Φ -values).
Its relation with R is show in equation. Lf = Φca +Φco (1/R)
Where Φ co and Φ ca are the coating and carrier material’s Φ value. Using Lf values we formulate our formulations.
Calculation for Φ Value for Carrier material (Avicel PH 200)12,13 Carrier is accurately weighed and kept on one of a Glass/metal plate with a refined surface and it is slowly raised till the plate becomes angular to the horizontal so that powder is about to slide. The angle at which powder slips was taken as angle of slide. It was used to measure the flow properties of powder.
Preparation of Liquisolid Compacts14:
Exact quantity of drug was dissolved in Polyethylene glycol 400 (non-volatile solvent), After added an exact amount of coating and carrier material in liquid in mortar by continuously mixing, After that sodium starch glycolate (Disintegrant) and remaining ingredient were added in exact amount and mixed for 10-15minutes in mortar, After became a final mixture compressed into tablets.
Formulation of preliminary trial batches for selection of R (carrier coating ratio)15
Review of literature suggests minimum R (Rmin) to be 20 (To maintain compressibility)
Formulation of preliminary batches for selection of % Cd
Evaluation for preliminary trial batch of Nicardipine Hydrochloride liquisolid compacts.
Powder blend were evaluated for flow properties, Drug content, Angle of slide, In vitro drug release.
RESULT AND DISCUSSION:
Determination of λ max Drug was scanned in uv-visible spectroscopy in methanol and 0.1N HCl and highest peak appeared at λ max 236nm and 239nm.
Analytical Method Development and Validation
Preparation of Standard Curve of Nicardipine Hydrochloride:
Preparation of standard curve of Nicardipine hydrochloride in Methanol and0.1N HCl:
The drug was scanned in wavelength range of 200-400 nm by UV double beam spectrophotometer to determine the absorption maxima. The absorption maxima found to be at wavelength of 236nm in methanol and 239nm in 0.1N HCl Nicardipine hydrochloride in concentration range of 5-15µg/ml in methanol and 0.1N HCl scanned in the UV region of 200-400nm showed absorption maxima of 236nm using methanol as blank and 239nm using 0.1N HCl as blank which is comparable with the value specified in literature. This confirmed the authenticity of the sample and obeyed Beer’s law in the range of 5-15µg/ml.
Validation of Analytical Method of Nicardipine Hydrochloride:
A) Validation of analytical method of Nicardipine hydrochloride in Methanol and
1) Linearity and range Nicardipine hydrochloride exhibits maximum absorbance at 236nm and obeyed Beer’s law in the range of 5-15μg/ml.
2) Accuracy (% recovery) The % recoveries obtained were 99.36% – 102.69%.
3) Precision:
The % RSD found 0.13%-0.58 % for intraday and 0.21%-0.67% for interday. Precision revealed that the proposed method is precise. Results were showed in Table 1
Table 1: Intraday and Interday precision data for Nicardipine hydrochloride in Methanol at λ max 236 nm
|
Sr. No |
Concentration (µg/ml) |
Intraday Precision |
Interday precision |
||||||||
|
Absorbance |
Absorbance (Mean ± SD) (n=3) |
% RSD |
Absorbance |
Absorbance (Mean ± SD) (n=3) |
% RSD |
||||||
|
I |
II |
III |
I |
II |
III |
||||||
|
1 |
5 |
0.261 |
0.262 |
0.264 |
0.262± 0.0015 |
0.580 |
0.262 |
0.264 |
0.263 |
0.263± 0.0010 |
0.380 |
|
2 |
7 |
0.372 |
0.373 |
0.371 |
0.372± 0.0010 |
0.270 |
0.370 |
0.373 |
0.374 |
0.372± 0.0021 |
0.560 |
|
3 |
9 |
0.481 |
0.482 |
0.483 |
0.482± 0.0010 |
0.210 |
0.487 |
0.485 |
0.486 |
0.486± 0.0010 |
0.210 |
|
4 |
11 |
0.591 |
0.595 |
0.592 |
0.593± 0.0021 |
0.350 |
0.588 |
0.594 |
0.587 |
0.590± 0.0038 |
0.640 |
|
5 |
13 |
0.678 |
0.677 |
0.679 |
0.678± 0.0010 |
0.150 |
0.679 |
0.675 |
0.67 |
0.675± 0.0045 |
0.670 |
|
6 |
15 |
0.791 |
0.79 |
0.792 |
0.791± 0.0010 |
0.130 |
0.795 |
0.792 |
0.791 |
0.793± 0.0021 |
0.260 |
4) Detection limit (LOD)The detection limit (DL) was found by following formula:
|
DL = |
3.3 σ |
Where σ = the standard deviation of the response |
|
S |
S = the slope of the calibration curve |
The slope S and standard deviation of the response σ was estimated from the calibration curve of the analyte.
|
DL = |
3.3 σ S |
= |
3.3 × 0.001 0.052 |
= 0.073μg/ml |
5) Quantitation limit (LOQ): The quantitation limit (QL) was found by following formula:
|
QL = |
10 σ |
Where σ = the standard deviation of the response |
|
|
S |
S = the slope of the calibration curve |
The slope S and standard deviation of the response σ was estimated from the calibration curve of the analyte.
|
QL = |
10 σ S |
= |
10 × 0.001 0.052 |
= 0.222 μg/ml |
|
|
Summary of Validation Parameters
Table 2: Summary of validation parameters of Nicardipine hydrochloride in Methanol at λmax 236 nm
|
Sr. No |
Validation parameters |
Results |
|
|
1 |
Linearity range(μg/ml) |
5-15 |
|
|
2 |
Linearity equation |
y=0.052x-0.004 |
|
|
3 |
Linearity (R2, Correlation coefficient) |
0.999 |
|
|
4 |
Precision (% RSD) |
Intraday |
0.13% - 0.58 % |
|
Interday |
0.21%– 0.67 % |
||
|
5 |
Accuracy (% Recovery) |
99.36% – 102.69% |
|
|
6 |
LOD (μg/ml) |
0.073 µg/ml |
|
|
7 |
LOQ (μg/ml) |
0.222 µg/ml |
|
The results of the analysis of Nicardipine hydrochloride by the proposed method were highly reproducible, and reliable which conclude that the proposed method is highly simple, sensitive, reproducible, economic, less time consuming and easy to apply for routine analysis of Nicardipine hydrochloride in Methanol.
B) Validation of analytical method of Nicardipine hydrochloride in0.1N HCl:
1) Linearity and range: Nicardipine hydrochloride exhibits maximum absorbance at 239 nm and obeyed Beer’s law in the range of 5-15 μg/ml.
2) Accuracy (% recovery):
The % recoveries obtained were 100.39- 104.9
3) Precision:
The % RSD found 0.10% - 1.05% for intraday and 0.55%– 1.43% for inter day, Precision revealed that the proposed method is precise. Results were showed in Table 3
Table 3: Intraday and Interday precision data for Nicardipine hydrochloride in 0.1N HCl at λ max 239 nm
|
Sr. No |
Concentration (µg/ml) |
Intraday Precision |
Inter day precision |
||||||||
|
Absorbance |
Absorbance (Mean± SD) (n=3) |
%RSD |
Absorbance |
Absorbance (Mean± SD) (n=3) |
% RSD |
||||||
|
I |
II |
III |
I |
II |
III |
||||||
|
1 |
5 |
0.252 |
0.253 |
0.248 |
0.251±0.0026 |
1.05 |
0.256 |
0.249 |
0.251 |
0.252±0.0036 |
1.43 |
|
2 |
7 |
0.376 |
0.371 |
0.374 |
0.374±0.0025 |
0.67 |
0.377 |
0.379 |
0.371 |
0.376±0.0042 |
1.11 |
|
3 |
9 |
0.482 |
0.483 |
0.481 |
0.482±0.0010 |
0.21 |
0.481 |
0.486 |
0.482 |
0.483±0.0026 |
0.55 |
|
4 |
11 |
0.581 |
0.58 |
0.58 |
0.580±0.0006 |
0.10 |
0.584 |
0.589 |
0.581 |
0.585±0.0040 |
0.69 |
|
5 |
13 |
0.671 |
0.673 |
0.669 |
0.671±0.0020 |
0.30 |
0.67 |
0.679 |
0.668 |
0.672±0.0059 |
0.87 |
|
6 |
15 |
0.781 |
0.788 |
0.789 |
0.786±0.0044 |
0.55 |
0.78 |
0.791 |
0.792 |
0.788±0.0067 |
0.85 |
4) Detection limit (LOD):
The detection limit (DL) was found by following formula:
|
DL = |
3.3 σ |
Where σ = the standard deviation of the response |
|
|
S |
S = the slope of the calibration curve |
The slope S and standard deviation of the response σ was estimated from the calibration curve of the analyte.
|
DL = |
3.3 σ |
= |
3.3 × 0.001 |
= 0.065 μg/ml |
|
|
S |
|
0.051 |
|
5) Quantitation limit (LOQ): The quantitation limit (QL) was found by following formula:
|
QL = |
10 σ |
Where σ = the standard deviation of the response |
|
|
S |
S = the slope of the calibration curve |
The slope S and standard deviation of the response σ was estimated from the calibration curve of the analyte.
|
QL = |
10 σ |
= |
10 × 0.001 |
= 0.196 μg/ml |
|
|
S |
|
0.051 |
|
Summary of Validation Parameters
Table 4: Summary of validation parameters of Nicardipine hydrochloride in0.1N HCl at λ max 239 nm
|
Sr. No |
Validation parameters |
Results |
|
|
1 |
Linearity range(μg/ml) |
5-15 |
|
|
2 |
Linearity equation |
y=0.051x-0.005 |
|
|
3 |
Linearity (R2, Correlation coefficient) |
0.998 |
|
|
4 |
Precision (% RSD) |
Intraday |
0.10% - 1.05% |
|
Interday |
0.55%– 1.43% |
||
|
5 |
Accuracy (% Recovery) |
100.39- 104.9 |
|
|
6 |
LOD(μg/ml) |
0.065 µg/ml |
|
|
7 |
LOQ(μg/ml) |
0.196 µg/ml |
|
The results of the analysis of Nicardipine hydrochloride by the proposed method were highly reproducible, and reliable which conclude that the proposed method is highly simple, sensitive, reproducible, economic, less time consuming and easy to apply for routine analysis of Nicardipine hydrochloride in0.1N HCl
|
|
|
|
Figure 1: a) Measurement of angle of slide |
b) Comparison of Ø value of different carriers |
The Ø –value of Aerosil 200 (coating material) was reported to be 3.26 and R=20.
|
a |
|
b |
|
|
Figure 2. DSC thermograms (a) pure Nicardipine Hydrochloride (b) S- SMEDDS |
|||
Where, Φ carrier: liquid retention potential for carrier material (Neusilin US2), Φ coating: liquid retention potential for carrier material (Aerosil 200), R: ratio of carrier to coating material Lf= 0.74+3.26 (1/20)
= Lf= 0.72 + 0.163 = Lf = 0.903, Lf= W/Q Where, W: weight of liquid medication Q: amount of carrier material Q = W/ Lf , = Q = 200/0.903, Q = 221.48mg R = Q/q,q = Q/R, q = 221.48/20 = q = 11.07mg
Differential scanning calorimetry
Figure 2 a shows thermal behavior of the pure drug Nicardipine Hydrochloride and thermal behavior of the solid-SMEDDS of Nicardipine Hydrochloride (b). Pure Nicardipine Hydrochloride shows characteristic sharp endothermic peak at 171.28°C. Sharp peak is primary indication for crystalline nature of pure drug. Now, DSC of solid SMEDDS showed no peak at 171.8°C indicating that the drug was completely converted into amorphous form or present in solubilized form.
Powder X-ray diffraction analysis:
PXRD further verified the physical state of the drug in the Solid SMEDDS. In Figure 3 the presence of sharp peaks is indicative of the presence of Nicardipine Hydrochloride in a highly crystalline form. Neusilin US2 is in amorphous state as demonstrated by the absence of sharp diffraction patterns. The physical mixture (1:1) of Nicardipine Hydrochloride and Neusilin US2 showed some crystalline peaks due to the presence of Nicardipine Hydrochloride in the mixture. In contrast to the physical mixture of Nicardipine Hydrochloride and Neusilin US2, the Solid SMEDDS did not show significant crystalline peaks, which further confirms the molecularly dispersed state of Nicardipine Hydrochloride in the formulation
Scanning electron microscopy:
The scanning electron microscope of Nicardipine Hydrochloride (pure drug), Neusilin US2 (carrier material) and S-SMEDDS were shown in Figure 4. Pure drug powder appeared to crystalline, irregular shaped. The Neusilin US2 appeared with a rough surface with pores. However, the S-SMEDDS appeared as smooth-surfaced, indicating that the liquid SMEDDS is adsorbed or coated inside the pores of Neusilin US2.
Figure 3: Powder X-ray Diffraction (PXRD) of Nicardipine Hychloride, Physical mixture (Nicardipine Hychloride and Neusilin US2), Neusilin US2 and Solid SMEDDS.
|
A |
|
B |
|
C |
|
|
Figure 4: SEM of (a) Nicardipine Hydrochloride (b) Neusilin US2 (c) S-SMEDDS |
|||||
TEM image subsequent to post dilution of NHCl-loaded Solid SMEDDS with distilled water are shown in Figure 5 and are interpreted for size of globule and surface morphology. From the shown figures, it was observed that globules of all composition formula were well dispersed and no aggregation of globule was observed. It was revealed by TEM analysis that most formulas showed homogenous spherical droplets, which satisfies the criteria of Microemulsifying formulae.
Figure 5: TEM Phtonmicrograph for the optimized batches NHCl-loaded Solid SMEDDS
In Table 5, The results revealed that the flow property and compressibility of solid SMEDDS was found to be good and post compression evaluation parameter for Nicardipine Hydrochloride solid-SMEDDS (tablet).
|
Flow characteristic of solid SMEDDS |
Post-compression parameter of solid SMEDD |
||
|
Characteristic |
Result |
Parameter |
Value |
|
Angle of repose |
24.10° ± 0.140° |
Weight variation (mg) |
499.30 ± 0.26 |
|
Bulk density |
0.317 ± 0.004 gm/ml |
Hardness (kg/cm2) |
5.50 ± 0.02 |
|
Tapped density |
0.370 ± 0.014 gm/ml |
Thickness (mm) |
3.17 ± 0.06 |
|
Carr’s index |
14.21 ± 4.12 % |
Disintegration time (sec) |
46.00 ± 2.00 |
|
Hausner’s ratio |
1.16± 0.060 |
Friability (%) |
0.82 |
|
Drug content (%) |
99.45 ± 0.14 |
||
In-vitro drug release study of Nicardipine Hydrochloride S-SMEDDS:
The result found that Nicardipine Hydrochloride loaded solid SMEDDS shows drug release of 90.82% at 15 minutes.
CONCLUSION:
The proposed method was found to be linear over concentration range of 5 - 15μg/ml respectively. The method was found to be accurate and precise as indicated by the results of recovery studies and precision studies whose % RSD is not more than 2%. The proposed method were highly reproducible and reliable which conclude that the proposed method is highly simple, sensitive, reproducible, economic, less time consuming and easy to apply for routine analysis . Previously prepared SMEDDS were transformed into Solid Smedds by a novel technique liquisolid compact to deliver poor water soluble drug with an increase dissolution rate. No incompatibility between drug and excipients proof by FTIR study. The liquid SMEDDS was converted into Solid-SMEDDS tablet by liquid solid compact technique. The carrier materials were screened by angle of slide measurement method and Neusilin US2 was selected as carrier material on basis of Ø value (0.72). The prepared tablet was evaluated for various evaluation parameters and was compared with marketed formulation. The optimized batch formulation shows an increased in % drug release (99.54 ± 0.590 %) when compared with marketed formulation (50.41 ± 0.112%) within 30 min. Superiority of Nicardipine Hydrochloride S-SMEDDS over the commercial formulation w.r.t in vitro dissolution profile was observed. Thus,considering S-SMEDDS as novel and commercially feasible formulation of Nicardipine Hydrochloride with intensified properties for dissolution.
Authors like to acknowledge for their help to Zim Laboratories for providing gift sample of Nicardipine Hydrochloride and Gattefose, lipoids, abitec, Corel Pharma, BASF and Gangwal Chemicals for the excipients. The authors are grateful to IPCPRC- Dharmaj and C.U.SHAH University for providing necessary facilities and support.
DISCLOSURE STATEMENT:
In accordance with the journal policy and my own ethical obligation of being a researcher, I report that Rajesh L Dumpala, Dr. Akruti Khodakiya, Dr. Nishant A Oza, Dr. Nehal J. Shah and M. Lakshmi Prasuna are the named researchers of this work and No conflict of interest is reported by the authors for this work and they are responsible for paper writing and content.
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Received on 07.10.2020 Modified on 15.12.2020
Accepted on 25.05.2021 © RJPT All right reserved
Research J. Pharm. and Tech. 2022; 15(7):2933-2939.
DOI: 10.52711/0974-360X.2022.00489