Formulation of Aceclofenac Tablets Using Nanosuspension as Granulating Agent: An Attempt to Enhance Dissolution Rate and Oral Bioavailability
Received 6 July 2020
Accepted for publication 7 October 2020
Published 17 November 2020 Volume 2020:15 Pages 8999—9009
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 4
Editor who approved publication: Prof. Dr. Thomas J. Webster
Haroon Rahim,1 Abdul Sadiq,2 Riaz Ullah,3 Ahmed Bari,4 Fazli Amin,1 Umar Farooq,5 Naeem Ullah Jan,1 Hafiz Majid Mahmood6
1Department of Pharmacy, Sarhad University of Science and Information Technology, Peshawar, Khyber Pakhtunkhwa, Pakistan; 2Department of Pharmacy, University of Malakand, Chakdara, Khyber Pakhtunkhwa, Pakistan; 3Department of Pharmacognosy (MAPPRC), College of Pharmacy, King Saud University Riyadh, Riyadh, Saudi Arabia; 4Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University Riyadh, Riyadh, Saudi Arabia; 5Legacy Pharmaceutical (Pvt.) Ltd., Peshawar, Khyber Pakhtunkhwa, Pakistan; 6Department of Pharmacology, College of Pharmacy, King Saud University Riyadh, Riyadh, Saudi Arabia
Correspondence: Haroon Rahim
Department of Pharmacy, Sarhad University of Science and Information Technology Peshawar, Peshawar 25000, Khyber Pakhtunkhwa, Pakistan
Tel +92 332 946 1642
Email [email protected]
Purpose: The aim of the studies was to fabricate aceclofenac (AC) tablets using nanosuspension as granulating fluid to boost its rate of in vitro dissolution and eventually its oral bioavailability.
Methods: The optimized nanosuspension with particle size of 112± 2.01 nm was fabricated using HPMC 1% (w/v), PVP-K30 1% (w/v) and SLS 0.12% (w/v) at 400 watts of ultrasonication energy for 15 min duration and 3 sec pause. Then, the optimized aceclofenac nanosuspension was used as granulating fluid for aceclofenac tablets formulation. The characterization was performed using Malvern zetasizer, SEM, TEM, DSC and P-XRD. The granules were evaluated for the bulk and tapped densities, Hausner’s ratio, angle of repose and their resulted values were found within limit. The prepared tablets were tested for average weight, hardness, friability, disintegration, dissolution and in vivo bioavailability in rabbits.
Results: The in vitro dissolution data showed the boosted rate of nanosuspension-based tablets compared to the microsuspension-based tablets. The in vivo bioavailability (in rabbits model) of aceclofenac nanosuspension-based tablets (ACN-1, ACN-2) proved an improved absorption as in comparison to the marketed formulation. The Cmax and AUC0→ 24 of ACN-1 and ACN-2 were 1.53-fold, 1.48-fold and 2.23-fold, 2.0-fold greater than that of the marketed drug, and were 1.74-fold, 1.68-fold and 2.3-fold, 2.21-fold greater in comparison to raw drug.
Conclusion: This boosted in vitro and in vivo bioavailability may be attributed to reduced particle size of aceclofenac nanoformulations used in tablets. Finally, this will result in faster absorption of these fabricated tablets.
Keywords: nanosuspension-based tablets, release kinetics, enhanced oral bioavailability
Aceclofenac, [2-[[2-[2- [(2, 6-dichloro phenyl) amino] phenyl] acetyl] oxy] acetic acid], is a well-known non-steroidal anti-inflammatory and analgesic drug compound as shown in Figure 1.1 The main problem in the therapeutic response of aceclofenac in orally taken dosage form is its poor aqueous-solubility as it belongs to Class 2 drug of the BCS (biopharmaceutical classification system).2 Nanosuspension technology has been applicable to improve the poor aqueous solubility and bioavailability issues.3 Anti-solvent precipitation (a bottom-up approach) is an effective way which involved dissolving the drug compound in solvent followed by incorporating into the anti-solvent phase, finally leading to the precipitation of drug.4 But still, this technology is facing some issues including the maintenance of particle size, stability problem after precipitation process and scale-up of batch. In earlier period, precipitation-ultrasonication has gained great focus for controlling both the nucleation and crystallization due to the efficient transfer of mass to hasten molecular diffusion.4–7 HPMC (hydroxypropyl methylcellulose), PVA (polyvinyl alcohol), PVP (polyvinylpyrrolidone) etc., are some polymers used to achieve stability.8,9
Figure 1 Chemical structure of aceclofenac.
Despite the progress in this area of research, nanosuspension technologies have an instability problem, produced by the nucleation and particle size growth. In the nonexistence of a stabilizer, the high surface energy of nanosized particles can induce Ostwald’s ripening.10 The solid dosage forms are preferred due to ease of administration, accurate dosing and stability. Nanosuspensions are usually dried to enhance their stability, allowing the conversion into solid dosage forms, either tablets or capsules.11 The literature reports various techniques for transformation of nanosuspension into solid dosage forms (tablets) including: spray drying, layering of nanosuspension onto the pellets or granules, freeze drying or wet granulation, etc.12–14 It is estimated that approximately 33% of all prescribed medications are dispensed in the form of tablets.15,16
Therefore, it is imperative to fabricate stable aceclofenac-tablets to resolve these problems of nanosuspension and ultimately enhanced bioavailability. The WG (Wet granulation) process was selected as it is very simple and fast to execute, which makes it a cost-effective and time saving procedure. Therefore, tablets were produced by using nanosuspension as granulating fluid with other suitable excipients with the objective of increasing the dissolution rate which will ultimately boost bioavailability of the chosen drug candidate.
Materials and Methods
Aceclofenac (AC), sodium lauryl sulphate (SLS), HPMC (Hydroxypropyl methylcellulose) Grade: 6cps, PVP K30 (polyvinylpyrrolidone), ethanol, corn starch (CS), microcrystalline cellulose (MCC) pH 102, Sodium starch glycolate (NaStG), Talcum (Tal), magnesium stearate (Mg) and all the other chemicals used were received as a generous gift from Bryon Pharmaceuticals Private Limited, Peshawar, KPK (Khyber Pakhtunkhwa), Pakistan and Legacy Pharmaceuticals Private Limited, KPK, Pakistan.
All the experiments conducted on animals were approved from Departmental ethical committee, Scientific Procedure Issue-I by Animal Ethics Committee at University of Malakand, KPK and related Bye-Laws 2008 vide approved protocol number UOM/PHARM/EC/01/AC/2017. The 1996 guidelines by National Research Council were followed for the welfare of laboratory animals.17
Formulation of AC Tablets
Optimized AC-N (aceclofenac nanosuspension) was fabricated as per our previously reported work using “precipitation-ultrasonication method”.18 Simply by dissolving aceclofenac (30 mg/mL) in organic solvent i.e. ethanol followed by injecting it to antisolvent phase i.e. water cooled at 4°C. The antisolvent phase containing polymers/stabilizers including HPMC, PVP-K30 and aqueous SLS solution already prepared at speed of 1500 rpm by the magnetic stirrer. Then, the ultrasonication processing of the prepared suspension was carried at different time length and ultrasonic inputs at 3 sec pause. The AC-N (aceclofenac nanosuspension) was added as granulating fluid to other suitable excipients to prepare granules for conversion to the tablets as listed in Table 1. After optimization, two batches (ACN-1, ACN-2) containing nanosuspension as granulating liquid were prepared. Simply, the corn starch, lactose and MCC were mixed and passed through mesh 30. Binder solution was prepared using PVP K30 and IPA (Isopropyl alcohol), then the aceclofenac nanosuspension was added to this (binder) solution. The mixture (binder + nanosuspension) is further incorporated to the already prepared mixture (corn starch, lactose, MCC) and passed through mesh 08. The granules were dried in oven at 60ºC, sifted with extra-granular excipients. The micronized particles batch (AC-M) was prepared by passing the corn starch, lactose, MCC, and micronized drug through the mesh 30 and then blended thoroughly. The binder solution was prepared in the same way as mentioned earlier for fabrication of the ACN-1 and ACN-2 batches, then incorporated it to the first mixture. The blend was passed via mesh 30, dried in oven at 60ºC and sifted with extra-granular excipients. All the prepared and dried granules were evaluated and finally compressed using a compression machine.
Table 1 Composition of aceclofenac tablets
Evaluation of Nanosuspensions and Formulated Tablets
Particle Size Determination
The particle size of the diluted sample (nanosuspension) was determined in triplicate using Zetasizer (Malvern, UK), where the Brownian motion of the particles are measured which is converted to size and size distribution by the application of Stokes-Einstein relation.18
Scanning Electron Microscopy (SEM) and Transmission Electron Microscopy (TEM)
Scanning electron microscope was used to evaluate the morphology of freshly prepared raw drug, which was deposited on glass slides followed by evaporating the solvent. Fabricated nanosuspension was evaluated using TEM. Sample (AC liquid nanosuspension) was dropped on a copper 200 mesh formvar/carbon coated grid and allowed to dry.18
For studying compatibility between raw drug and other additives used in formulation, the FTIR analysis was carried out. The drug and formulation blend compatibility were evaluated using Thermoscientific Nicolet, FTIR Instrument, USA. A small quantity of raw drug and blend of formulation were directly placed on germanium piece of the infrared (IR) spectrometer with constantly applied pressure. The IR absorbance scanning range was 4000–500 cm−1.19
Powder X-Ray Diffractometry (P-XRD) and Differential Scanning Calorimetry (DSC)
For crystallinity, the samples were evaluated using P-XRD (Panalytical, X’pert), by scanning detector over 2θ angles at a scan rate of 0.01°. The melting point of aceclofenac raw drug, AC-N and fabricated tablet batch were performed by DSC (TA-60, Shimadzu). All the samples, which were about 3 mg, were placed in pans made of aluminum for heating, under 50 mL per min nitrogen flow rate and the scanning was kept at 10°C per min, from 40–200°C.
Evaluation of the Prepared Granules
The densities (tapped, bulk), HR (Hausner’s ratio), Carr’s index and AOR (angle of repose) were determined for dried granules.
Bulk Density (ρB)
The accurately weighed amount (W) of the granules was placed in a 10 mL graded cylinder, V0 (untapped volume) was recorded and the ρB (bulk density) was obtained (g/mL) by using the following equation:20
Tapped Density (ρT)
The 10 mL graduated cylinder containing the accurately weighed quantity (W) of prepared granules were tapped onto a hard surface till there was no further change in the volume. Then, the VT (tapped volume) was recorded and ρT (tapped density) was determined by using the below formula:19
Carr’s Compressibility Index
Carr’s compressibility index was determined by using the formula:19
Where, ρT is tapped and ρB is the bulk densities.
Hausner’s Ratio (HR)
The HR values were determined by the formula given below:19
Where, “ρT” is the tapped and “ρB” is the bulk densities.
AOR (Angle of Repose)
Compression of Prepared Granules into Tablet Dosage Form
The granules prepared are shown in Table 1. They were compressed to tablet dosage form by a compression machine (ZP19, China) fitted with 11-mm biconcave punches for aceclofenac tablets.
Evaluation of Fabricated Tablets
The post-compression properties (weight variation, % friability, hardness, disintegration time) of the prepared tablets were determined. The hardness of formulated ten tablets was determined using Pharma test hardness test machine. The DT (disintegration time) of prepared tablets was measured in the purified water keeping temperature at 37±2°C, using DT apparatus (Model: DT-0607, Curio) with disks. Drug contents of tablets were evaluated as per HPLC procedure used by Rahim et al.22 Tablets’ friability was calculated for 20 tablets after completion of 100 revolutions in the Friabilator using formula:
Where, W1 is weight of tablets before completing rotations and W2 is final weight after completing revolutions.
Stability Studies of Compressed Tablets
The formulated tablet dosage form was evaluated for the in vitro dissolution by storing at accelerated temperature 40±2°C and RH 75%±5% and at room 30±2°C and keeping the RH 65%±5% for three months.23
In vitro API Release Studies
The in vitro API release studies of both AC-N (aceclofenac nanosuspension) as granulating fluid and microsuspension-based tablets’ batches were performed using dissolution apparatus (USP Type-2). The 0.1N hydrochloric acid containing 2% Tween 80 was used as dissolution medium at speed of 75 rpm keeping the temperature at 37±0.5°C. After 10 minutes, sample of 5 mL, withdrawn up to an hour, were filtered through 0.02 µm syringe filter. The equal volume (5 mL) of the medium was replaced for maintaining sink conditions.22,24 The quantity of active compound (aceclofenac) in the sample was determined by HPLC as method used by Rahim et al.22
To investigate the mechanism of drug release from the formulated tablets, the drug release data were fitted into zero-order, first-order, Higuchi and Korsmeyer’s equation. The Korsmeyer’s equation, Equation (A), describes the drug release behaviour from the polymers.
Mt = the quantity of drug release at time “t”;
Mf = the quantity of drug release after infinite time;
k = release rate constant incorporating structural and geometric characteristics of the tablet;
n = the diffusional exponent indicating the mechanism of drug release.
To clarify the release exponent for formulated tablets, the log value of % drug release was plotted against log time for each formulation according to Equation (A).19
In vivo Bioavailability Studies
The bioavailability studies were conducted in white albino rabbits (2.5–3.0 kg). Animals were housed in wire cages, offered food and water freely as per protocols earlier mentioned in the Materials and Methods section. Fabricated tablet groups ACN-1 and ACN-2, marketed product and raw drug were administered orally in a dose of 10 mg/kg to animals (n=6 rabbits in each group). Venous blood was collected in the heparinized tubes at different intervals (0, 0.5, 1, 1.5, 2, 4, 6, 8, 12 and 24 hrs) after oral administration. The blood samples were centrifuged at 3000 rpm for 20 min to separate the plasma and stored at −20ºC. The plasma samples were analyzed using the HPLC method by Rahim et al.22 The chromatographic conditions were: mobile phase—methanol: 0.3% TEA pH 7.0 (60:40, v/v), Hypersil BDS C18 (250 cm×4.6 mm), 5μm column was used at 1.0 mL/min flow rate, keeping injection volume 20 μL; at 25°C; Run time: 25 min; 275 nm as detection wavelength; and venlafaxine as internal standard. The pharmacokinetic parameters were determined by PK solutions 2.0 non-compartmental pharmacokinetic analysis.
All the results were given as mean ± standard deviation (SD), mean values were compared using ANOVA and differences were considered significant at the level of P< 0.05 using GraphPad Prism 5.
Results and Discussions
Optimized AC-N (aceclofenac nanosuspension) was fabricated as per previously reported work using “precipitation-ultrasonication method”.18 Then, the optimized batch was used as granulating fluid for conversion to the tablets’ formulations using the AC-N and AC-M (aceclofenac suspension containing unprocessed/raw microparticles) as granulating fluid with other excipients. The optimized batch formulated with particle size found was 112±2.01 nm, keeping the ultrasonic energy input at 200 watts with 15 min duration and 3 a sec pause. The particle size of fabricated optimized batch of nanosuspension is shown in Figures 2 and 3A. All the particles displayed in Figure 3B reveal well-defined morphology related with crystalline material. The nanosuspension was stabilized using polymers/stabilizers, i.e. 1.0% (w/v) of each HPMC and PVP K-30 while 0.12% (w/v) SLS. The formulations of the tablets were shown in the Table 1.
Figure 2 Particle size distribution of aceclofenac nanosuspension.
Figure 3 Scanning electron micrographs of raw drug (A); transmission electron micrographs of drug nanoparticles ().
FTIR Spectra Analysis
The FTIR studies showed that the spectrum of raw drug compound (aceclofenac), aceclofenac nanosuspension and nanoformulation-based tablets are displayed in Figure 4A–D respectively. The raw AC presented distinctive peaks at 3317.3 cm−1 assigned to N–H stretching, 2936.6 cm−1 are due to stretching of O–H, the peak 1770.1 cm −1, 1714.7 cm−1 are assigned to C O stretching, band 1589.2 cm−1 is due to the skeleton vibration of aromatic C C stretching, 1506.3 cm−1 is assigned to in plane bending for N–H, band 1343.6 cm−1 is due to O–H in plane bending, 1291.3 cm−1 (C–N aromatic amine), 964.4 cm−1 (O–H out plane bending) and 750.3 cm−1. The nanosuspension blend exhibited spectra (cm−1) at 3317.9, 2936.8, 2310.7, 1770.1, 1506.4, 1344.1, 1291.0 and 943.0. Whereas the fabricated optimized tablet batch exhibited distinct bands (cm−1) at 3317.9, 2971.7, 2900.8, 1770.7, 1715.8, 1507.3, 1343.5, 1291.2, 766.9. FTIR spectra results showed a lack of any interaction between the aceclofenac and additives employed in the nanoformulation as well as in formulated tablets.
Figure 4 FT-IR of aceclofenac (A), ACN (B), ACN-T (C), and marketed tablets (D).
Powder X-Ray Diffractometry (P-XRD) and Differential Scanning Calorimetry (DSC)
The DSC thermograms as displayed in Figure 5. The raw drug (i.e. aceclofenac), showed an endometrial peak at 154.49°C, conforming the melting point.1 Nanosuspension-based tablets and the prepared nanosuspension of the selected drug candidate indicated a slight change of melting point to 154.12 and 153.67°C respectively. The difference in the particle size among the samples is the leading cause of these alterations. The presence of stabilizers’ traces on the surface of particles of the drug compound may results in the peaks’ broadening.25,26 Hence, no new peak in the DSC thermogram formed, proving the lack of any chemical reaction taking place.
Figure 5 DSC thermogram of raw AC, AC-NT and AC-N.
The results obtained from P-XRD displayed that the prepared nanosuspension of the drug (aceclofenac) were crystalline in nature as shown in Figure 6. However, peaks’ intensities of nanoparticles were comparatively low to the raw drug, this may the effect of nanonization.
Figure 6 PXRD patterns of raw drug, physical mixture and drug nanosuspension.
The smaller PS (particle size) and presence of amorphous stabilizers in trace amounts may be the reason for the peaks’ reduction of AC nanoparticles as displayed in the Figure 6.27–29 Moreover, the X-ray diffractogram of the PM (physical mixture) and nanosuspension-based tablets showed a dominant peak as shown in Figure 6, while the peaks for the small amount of the used stabilizers and other additives in the formulation of tablets were amorphous in nature and did not appear.
Pre-Compression Parameters of Formulation Blends
The granules of ACN-1 and ACN-2 (nanosuspension-based tablets) showed the values of angle of repose ranges from 27.25±1.05 to 28.42±1.25 while the batch ACM-3 (microsuspension-based batch) granules showed the values of 29.45±1.45. All the formulation blends presented excellent to good flow properties.30 The prepared granules exhibited bulk density (mg/mL) value 0.541±0.01 for ACN-1, 0.552±0.01 for ACN-2 and for ACM-3 results 0.574±0.01. The tapped density (mg/mL) recorded for ACN-1 was 0.632±0.01, ACN-2 was 0.662±0.01 and ACM-3 was 0.692±0.01, showing that the prepared granules have good packability. The Carr’s index values of the ACN-1 and ACN-2 batches range from 15.18±0.98 to 16.69±1.28 whereas the microsuspension-based granules (ACM-3) resulted in a value of 16.94±0.58, proving that all batches exhibited good compressibility. The nanosuspension-based granules were found to be Hausner’s ratio values ranging from 1.17±0.01 to 1.19±0.01 and 1.20±0.01 for the micronized/unprocessed batch, these results presented good to fair flow property exhibited by the formulations. All these results are shown in Table 2.
Table 2 Pre-compression parameters of various blends
Compression of Granules into Tablet Dosage Form
The different formulation batches (ACN-1, ACN-2, ACM-3) of tablets resulted in hardness (kg) values from 6.65±0.52 to 9.25±0.25, average weight 199.57±1.42 mg to 200.15±1.75 mg and friability values from 0.46±0.42% to 0.62±0.31%. The DT (disintegration times) recorded were 6.45±1.55 for ACN-1, 7.24±1.36 for ACN-2 and 9.55±1.16 for ACM-3. The compressed batches showed values of performed tests complied with official limits, as shown in Table 3. All the formulated batches had uniformity in weight which complied with USP specifications, i.e. ±7.5% allowed limit.31,32
Table 3 Post-compression evaluation of AC tablets
In vitro Release of Aceclofenac Tablets
The in vitro API release data presented a substantial improvement in dissolution rate of batch ACN-1 in comparison to marketed tablets and unprocessed aceclofenac-based tablet formulation. The graph showed that in the first 30 min, more than 85% of ACN-1 were dissolved compared to 75.89% for ACN-2, 51.06% for unprocessed micronized drug formulation (i.e. ACM-3), 59.56% for the M. Tablets and 29.41% for raw drug. Boosted in vitro release rate of ACN-1 was observed while comparing to ACN-2, unprocessed drug containing formulation i.e. ACM-3, M. Tablets and raw drug, all these results are illustrated in Figure 7. The solubility of drug compound will be enhanced when the particle size of the drug is reduced to nanosized range as described by Xia et al.33 The release data showed the P<0.001 compared with raw drug.
Figure 7 In vitro dissolution of formulations and M. Tablets. Values represent mean±SD, n=3. ***P<0.001 compared with raw drug.
It has evidently been confirmed and support in the development of solid dosage forms BCS Class-II drug compounds i.e. poorly soluble drug candidates.34
Two batches, i.e. ACM-3 and marketed product, obey zero order kinetics with values of r2 0.9939 and 0.9874 respectively. While the formulation batches ACN-1 and ACN-2 follow first order kinetics with values of r2 0.9680 and 0.9615 respectively. Fickian (Case-I) release was obeyed by ACN-1 and marketed product, while ACN-2 and ACM-3 obey the Non-Fickian type release behavior. The value of “n” equal to 0.45 indicates Fickian (Case-I) release; more than 0.45 but less than 0.89 for non-Fickian (anomalous) release and “n” more than 0.89 indicates super case-II type of release. Case-II refers to the erosion of the polymeric chain while non-Fickian (anomalous transport) illustrate a combination of both diffusion and erosion controlled-drug release as shown in Table 4.31
Table 4 In vitro release kinetics of fabricated tablets
The in vivo study of aceclofenac nanosuspension-based tablets (ACN-1, ACN-2) showed an enhanced absorption in comparison to the marketed drug formulation, as displayed in Figure 8. The Cmax and AUC0→24 of ACN-1 and ACN-2 were 1.53-fold, 1.48-fold and 2.23-fold, 2.0-fold greater than that of the marketed drug product (P<0.001), as displayed in Table 5. While, the Cmax and AUC0→24 of ACN-1 and ACN-2 were 1.74-fold, 1.68-fold and 2.3-fold, 2.21-fold greater than that of the raw drug (**P<0.01).
Table 5 Pharmacokinetic parameters from the plasma concentration versus time
Figure 8 Average plasma drug concentration versus time profiles after oral administration of formulations to rabbits (n=6), ***P<0.001 compared with raw drug.
The enhanced bioavailability of aceclofenac nanosuspension-based tablets after oral administration will possibly be owed to the faster absorption of the aceclofenac nanosuspension used in the formulation.22
Stability Studies of Fabricated Tablet Dosage Form
The stability and dissolution of the fabricated tablets of aceclofenac fabricated by utilizing AC nanosuspension in the form of a granulating liquid, was carried out at both accelerated (40°C/75% Relative Humidity) as well as room temperature conditions (25°C/60% Relative Humidity) for three months. The in vitro dissolution rate for fabricated solid dosage form (tablets) was stable at aforementioned storage conditions, as represented in Figure 9.
Figure 9 Stability of ACN-1 batch formulation at different storage conditions.
Hence, it is evidently proved from the results of in vitro dissolution profiles that the optimized nanosuspension-based tablets showed remarkable improved dissolution rate compared to the microsuspension-based (raw drug) tablets. The ACN-1 batch tablets (as depicted in Figure 10) showed stability at two different conditions (30°C/65%RH, 40°C/75%RH).
Figure 10 Visual image of ACN-1 batch tablets.
The conducted research proved that aceclofenac tablets can be prepared using optimized nanosuspension as granulating fluid and micronized drug with other suitable excipients. The stable formulated tablets with improved in vitro dissolution and oral improved bioavailability in rabbits is achieved by using optimized nanosuspension as granulating fluid compared to micronized drug-based and marketed tablets. The Cmax and AUC0→24 of ACN-1 and ACN-2 were 1.53-fold, 1.48-fold and 2.23-fold, 2.0-fold greater than that of the marketed drug product (P<0.001). The studies proposed using similar techniques for other poorly-soluble drug compounds to improve the in vitro rate of dissolution and ultimately their oral in vivo bioavailability.
The authors extend their appreciation to the Deanship of Scientific Research at King Saud University, Saudi Arabia for funding this work through research group no. RG-1440-009. We are thankful to Department of Pharmacy, Sarhad University of Science and Information Technology Peshawar, Khyber Pakhtunkhwa, Pakistan and Department of Pharmacy, University of Malakand, Chakdara, Khyber Pakhtunkhwa, Pakistan for providing facilities.
Umar Farooq is an employee of Legacy Pharmaceutical (Pvt.) Ltd. The authors report no other potential conflicts of interest for this work.
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