INTRODUCTION:

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed medication, with approximately 5–10% of all prescriptions written annually ¹. NSAIDs are a group of drugs that act by inhibiting cyclooxygenases (COXs) enzymes which are the rate-limiting enzymes involved in prostaglandins synthesis. Their effects are anti-inflammatory, antipyretic, and analgesic for treating acute and chronic painful conditions ^2,3.

Aceclofenac (ACE), an NSAD, was first approved in Europe in 1990 as a 100mg tablet to be given twice or thrice daily for inflammatory and painful conditions ³.

As shown in its structure (Figure 1), ACE is a phenylacetic acid derivative with potent anti-inflammatory and analgesic actions ^4,5. Its stronger inhibition selectivity on COX 2 than COX 1 explains its safety compared to other NSAIDs and COX 2 selective inhibitors, as well as its improved stomach tolerance and fewer side effects ⁶. ACE belongs to BCS class II, which is practically insoluble in water with high permeability and poor dissolution rate, leading to reduced bioavailability ^6,7.

Figure 1: Aceclofenac chemical structure ⁷.

Poor drug solubility is always a challenge faced by pharmaceutical scientists since solubility and dissolution are interrelated. Poor drug solubility leads to poor drug dissolution with poor absorption in the GI tracts, which causes insufficient bioavailability ⁸. Solid Dispersion (SD) was first studied and proposed in 1961 to improve the solubility and dissolution rate of drugs with poor water solubility. It offered a successful approach for improving the solubility of hydrophobic drugs and the absorption rate and bioavailability ^9,10. In 1971 the definition was expanded to the dispersion of one or more active ingredients in a hydrophilic inert carrier at a solid state which can be manufactured by different methods such as the most common melting (fusion) method, a solvent evaporation method, or melting-solvent method¹¹.

Effervescent assisted fusion solid dispersion (EFSD) is a modified technique of conventional fusion solid dispersion (FSD) that was introduced by Alam et al. which involves using of sodium bicarbonate and organic acids (such as citric acid), which react with each other to produce an effervescent mixture during the melting technique. By combining poorly soluble drugs with the effervescent mixture and a hydrophilic carrier matrix, an effervescent solid dispersion may enhance these drugs' solubility and dissolution rate ^12,13. The present study aimed to prepare ACE-SD by the FSD and EFSD techniques with a different hydrophilic carrier to evaluate their impact on the solubility and dissolution rate of ACE as a comparative study.

MATERIALS AND METHODS:

Aceclofenac (Baoji Guokang bio-technology Co., Ltd, China), Poloxamer 407 (PXM 407) and Poloxamer 188 (PXM 188) (Eastman Chemical Company, USA), Mannitol (Avonchem, UK), Urea (Thomas baker Pvt. Ltd. India), Soluplus^® (BASF pharma, Germany), Sodium bicarbonate (Furat Drug Industry, Iraq) and Citric acid (Jungbunzlauer, Austria). All other reagents were of analytical grade.

Preparation of ACE-solid dispersion by the conventional fusion technique:

In the conventional fusion method (FSD), specific carriers and drugs were prepared at 1:1 and 1:2 (drug: carrier w:w ratio), as shown in Table 1. The required carrier powder (Mannitol, PXM 407, PXM 188, Soluplus^®, and Urea) was first melted in a porcelain petri-dish slightly up to its melting point using a hot plate. The required amount of ACE was added to the molten carrier with continuous stirring of the mixture until homogenous dispersion was obtained, then cooled down at a low temperature (freezer). The resulting mass was then pulverized, sieved through a no.60 sieve, and kept in a desiccator for further characterization ¹⁴.

Table1: Composition of ACE SD prepared by FSD

Formula name	Carrier	Drug: Carrier ratio
FSD1	Mannitol	1:1
FSD2	PXM 407	1:1
FSD3	PXM 188	1:1
FSD4	Soluplus®	1:1
FSD5	Urea	1:1
FSD6	Mannitol	1:2
FSD7	Soluplus®	1:2
FSD8	Urea	1:2

Preparation of ACE-solid dispersion by the effervescent-assisted fusion technique:

In this modified fusion method, the effervescent assisted fusion method (EFSD), the ACE: carriers: effervescent base, was used in different ratios, as listed in Table 2. Different formulas were prepared by melting the carrier (Mannitol, PXM 407, PXM 188, Soluplus^®, and Urea) in a porcelain petri-dish up to the carrier melting point, followed by the addition of citric acid with uniform stirring. Under steady stirring, the powder of ACE was added to the mixture. To the above-molten mixture, sodium bicarbonate was added (according to molar reactivity) with the rapid stirring condition ¹⁵. The addition of sodium bicarbonate in the last step resulted in the generation of effervescence as small bubbles because of the acid-base reaction forming a frothy white mixture, stirring was continued until the effervescence slowed significantly. The product was cooled under low temperatures (freezer) to convert into a solid product. The solidified product was then pulverized and sieved using no. 60 sieve and kept in a desiccator for further investigations ¹⁶.

Table 2: Composition of ACE prepared by EFSD

Formula name	Carrier	Drug:Carrier: Effervescent base ratio
EFSD1	Mannitol	1:1:0.5
EFSD2	PXM 407	1:1:0.5
EFSD3	PXM 188	1:1:0.5
EFSD4	Soluplus^®	1:1:0.5
EFSD5	Urea	1:1:0.5
EFSD6	Mannitol	1:2:1
EFSD7	Soluplus^®	1:2:1
EFSD8	Urea	1:2:1

Preparation of the physical mixture (PM):

By uniformly combining ACE and carrier in the same ratio as the optimum FSD formula and ACE, carrier, and effervescent base as in the optimum EFSD formula, the physical mixture (PM) was prepared. The PM powder was sieved through a no. 60 sieve to get particles of a uniform size.

Evaluation of ACE-solid dispersion:

Determination of percentage yield (PY%) of the prepared ACE-SD:

The percentage yield (PY%) was calculated practically for all the prepared ACE SD formulas to know the efficiency of each technique. The (PY%) was obtained by dividing the SD formula's actual mass by the theoretical SD mass using the equation below ¹⁷.

Practical weight (SD)

PY % = ---------------------------------------------- × 100

Theoretical weight (Drug + Carrier)

Determination of drug content of the prepared ACE-SD:

Using a 100ml volumetric flask, an accurately weighed amount of SD equivalent to 100mg of ACE was dissolved in 50ml of ethanol before being sonicated for 15 minutes. The final drug solution was diluted with ethanol before being tested for drug concentration at 275 nm with a UV spectrophotometer using ethanol as a blank ¹⁸. The drug content % was calculated by applying equation below ¹⁹.

Actual drug amount in SD

Drug content (%) --------------------------------------- × 100

Theoretical drug amount in SD

Determination of saturation solubility:

The solubility study was performed by adding excess amounts of pure ACE and ACE SDs into screw-capped vials containing 10 ml of water. The tightly sealed vials were kept in a water bath shaker at 25°C for 48 hours. Then, the samples were taken out of the water bath, filtered using a 0.45μm filter paper, and dissolved ACE was analyzed using UV-spectrophotometer at 275 λmax. The procedure was carried out three times ^20,21.

In -vitro Dissolution test:

The in-vitro dissolution of pure ACE and the prepared SDs were determined using a USP XXII rotating paddle (apparatus II) by dispersing a quantity equivalent to 100 mg of ACE in phosphate buffer (pH 6.8) as a dissolution medium of 900ml. The temperature was set at 37±0.5°C using a thermostatic water bath with a rotation speed of 50rpm ^21,22. A 5ml sample was taken out at regular intervals and replaced with a fresh dissolution medium. These samples were then filtered and spectrophotometrically measured at 275nm. This test was performed on the SD formulations with the highest solubility. This test was carried out in triplicate.

Using the equation below, a similarity factor (ƒ2) was utilized to analyze the dissolution profile statistically.

At time t, (Rt) is the dissolution value of the reference, (Tt) is the dissolution value of the test, and (n) is the number of dissolution time points. The dissolution profiles are known to be similar when ƒ2 values are >50 (50–100), but if ƒ2 <50, the dissolution profiles are considered not similar ²².

Fourier Transforms Infrared Spectroscopy (FTIR):

FTIR Spectroscopy (IRAffinity-1, Shimadzu, Japan) of pure ACE, selected carrier, the selected SD formula from FSD and EFSD, and their PM was conducted to assess drug-carrier possible interaction. The samples were pressed with KBr and analyzedfrom 4000-400 cm^{-1 23,24}.

Powder X-ray diffraction (PXRD):

Powder x-ray diffraction (XRD-6000, Shimadzu, Japan) was used to evaluate the crystalline state of the pure ACE, selected carrier, the selected SD formula from FSD and EFSD, and their PM. The PXRD study was conducted under the circumstances: the target metals Cu, filter Kα, 40kV, and 30mA. The scan was over a 2θ range of 10-60° at 1.5406 Å wavelength ^24,25.

Differential scanning calorimetry (DSC):

Thermal characteristics were analyzed using an automatic thermal analyzer system (Shimadzu, DSC-60, Japan) of the pure ACE, selected carrier, the selected SD formula from FSD and EFSD, and their PM. Each sample (5mg) was placed in none hermetically aluminum pan and heated at a rate of 10°C/min over temperatures 5°C to 200°C. The analysis was carried out under the atmosphere flow conditions ^26,27.

Statistical analysis:

The results of the experiments were given as a mean for triplicate samples ± standard deviation (std) and were analyzed according to a one-way analysis of variance (ANOVA). The test level of (P<0.05) was considered statistically significant, using SPSS version 25.

RESULTS AND DISCUSSION:

Percentage yield (PY %) of the prepared ACE-SD:

Both FSD and EFSD methods gave acceptable PY% ranging from 93.6-99.92%, as shown in Table 3. This result indicated that both methods were comparable and efficient.

Drug content of the prepared ACE-SD:

The results of drug content % were in the range of (94-102.97%) w/w for all formulas, as shown in Table 3, which is in agreement with the criteria of United States pharmacopeia (90- 105%) ²⁴ indicating negligible loss of ACE upon the preparation and homogenous dispersion of ACE particles in all the produced ACE-SD.

Saturation solubility of pure ACE and ACE-SD:

The results of saturation solubility studies of pure ACE and ACE-SD formulas are shown in Table 4.

Table 4: The Saturation solubility of pure ACE and ACE SDs formulas using different methods with different ratios of the drug: carrier in FSD and drug: carrier: effervescent base in EFSD in distilled water at 25˚C

Formula name (FSD) and (EFSD)	Carrier (drug: carrier) and (drug: carrier: effervescent base) ratio	Saturation solubility mg/ml Mean ±std (n=3)
ACE		0.0735±0.003
FSD1	Mannitol (1:1)	0.1739±0.011
FSD2	PXM 407 (1:1)	0.0899±0.012
FSD3	PXM 188 (1:1)	0.226±0.022
FSD4	Soluplus (1:1)	0.2717±0.078
FSD5	Urea (1:1)	0.9266±0.189
FSD6	Mannitol (1:2)	0.3411±0.002
FSD7	Soluplus (1:2)	1.735±0.1
FSD8	Urea (1:2)	2.86±0.02
EFSD1	Mannitol (1:1:0.5)	2.97±0.22
EFSD2	PXM 407 (1:1:0.5)	1.2633±0.04
EFSD3	PXM 188 (1:1:0.5)	0.4767±0.05
EFSD4	Soluplus (1:1:0.5)	3.693±0.17
EFSD5	Urea (1:1:0.5)	10.32±0.48
EFSD6	Mannitol (1:2:1)	5.5±0.5
EFSD7	Soluplus (1:2:1)	9.97±0.49
EFSD8	Urea (1:2:1)	17.48±1.02

Except for FSD2, a significant difference (P<0.05) in the solubility enhancement of ACE by all SDs formulas was obtained in comparison to the solubility of the pure drug, which is mainly due to the hydrophilic nature of the carriers that enhanced the solubility of the poorly soluble drug ²⁸.

Also, there was a significant difference in solubility enhancement of ACE by the EFSD technique compared with the FSD technique, which indicates that EFSD had a better enhancing effect. This result can be explained to be due to the presence of sodium bicarbonate in EFSD, which increased the pH of the diffusion layer in the micro-environment of the drug, so the solubility of ACE was enhanced as it is a weakly acidic drug with pH-dependent solubility ^29,30.

Furthermore, significant enhancement was obtained (P<0.05) by using a higher ratio of drug:carrier and by increasing the amount of effervescent base within the formula, which confirmed that the hydrophilic property and effervescent base had a pronounced effect on the solubility. As a relatively less solubility enhancing effect was obtained by using PXM 407 and PXM 188 as carriers in a 1:1 ratio in both techniques compared to the other polymers, they were excluded from further study. The solubility improvement impact of carriers was ordered as Urea >Soluplus^®> Mannitol in both FSD and EFSD techniques. The above order can be attributed to the carriers' various characteristics. Urea and mannitol are first-generation SD carriers, and both were used for solubility enhancement³¹. Higher solubility enhancement of ACE resulted from using urea as a carrier due to its higher water solubility than mannitol resulting in higher drug wettability ³². Souplus^® is a third-generation SD carrier³³ with an amphiphilic property that came from its structure containing PEG, which provides the hydrophilic property, and vinyl caprolactam and vinyl acetate, which provide the lipophilic property³⁴. It has many hydroxyl groups, making it a good solubilizer for ACE in aqueous media ^35,36. According to these results, Soluplus^® and mannitol formulas were selected for the in-vitro dissolution study.

In-vitro Dissolution test:

Figure 2 - A represents in vitro dissolution profile comparison of FSD formulas of different carriers and different ratios in phosphate buffer (pH 6.8) with pure ACE. The results demonstrated that FSD1 showed a similar dissolution rate (f 2=50.60) while FSD4, FSD6, and FSD7 enhanced the dissolution rate (f2=40.10), (f2=28.12), (f2=24.53), respectively as compared with pure ACE. FSD7, which is composed of ACE: Soluplus^® in (a 1:2) ratio, showed the best release profile (85%) after 30 minutes as compared with FSD6 (82%), FSD4 (66%), FSD1 (55%), and pure ACE (45%).

The dissolution rate enhancement of the ACE from FSD can be explained due to several factors, including decreased particle size of the drug in the FSD technique and increased wettability and dispersibility of ACE in a hydrophilic carrier ³⁷.

Figure 2: A - The effect of carrier type and drug: carrier ratio of ACE-FSD on the in-vitro dissolution rate of ACE in phosphate buffer (pH 6.8) at a temperature of 37°C. B -The effect of the type of carrier and drug: carrier: effervescent base ratio of ACE-EFSD on the in-vitro dissolution rate of ACE in phosphate buffer (pH 6.8) at a temperature of 37°C.

Figure 2 - B represents in vitro dissolution profile comparison of EFSD formulas of different carriers and different ratios in phosphate buffer (pH 6.8) with pure ACE. The results showed that all EFSD1, EFSD4, EFSD6, and EFSD7 had enhanced dissolution rates in comparison with pure ACE (f2=34.42), (f2=30.17), (f2=29.36), and (f2=18.73) respectively.

EFSD7, which is composed of ACE: Soluplus^®: Effervescent base in (1:2:1) ratio, showed the best release profile (96%) after 30 minutes as compared with EFSD6 (79%), EFSD4 (73%), EFSD1 (68%), and pure ACE (45%).

To prove the efficiency of each technique, the dissolution profile of FSD7 and EFSD7 were compared with their corresponding physical mixture, as shown in Figure 3. The non-similar faster dissolution obtained from FSD7 (f 2=26.46) and EFSD7 (f2=22.8) indicated that both techniques were efficient.

The further enhancement in dissolution rate (f2=48.14) by EFSD in comparison with FSD can be explained by increased porosity by an effervescent mixture, which resulted in greater surface area in addition to the factors explained in conventional FSD that all led to the fastest dissolution by EFSD technique ^38,39.

The similar release profile (f 2 =65.10) of the physical mixture of both techniques gave additional confirmation about the effect of porosity result in from the effervescence during fusion at high temperatures.

Figure 3: The comparative in-vitro dissolution rate of FSD7 with a physical mixture of the FSD7 (PM FSD) and EFSD7 with a physical mixture of the EFSD7 (PM EFSD7) in phosphate buffer (pH 6.8) at a temperature of 37 °C.

Selection of the optimum formula

The (EFSD7) was selected as the optimum formula composed of ACE: Soluplus^®: effervescent base at a ratio of 1:2:1. It was characterized by the highest solubility and released the highest amount of ACE within a short time. This formula was subjected to further in-vitro evaluation studies. Its results were compared with the best formula obtained by the conventional fusion technique (FSD7) to clarify and explain the reasons behind the superiority of the EFSD technique over the FSD technique ^40,41.

Evaluation of optimum formula:

Fourier transform infrared (FTIR):

The FTIR results of the pure ACE, Soluplus^®, the selected SD formula from FSD and EFSD, and their PM are shown in Figure (4 - A and B), respectively.

The spectrum of pure ACE represents characteristic bands on 3318.8 cm⁻¹of secondary amine N-H stretching, 2935.1 cm⁻¹ of aliphatic stretching vibrations (C-H stretching), two ketone bands are found at 1770.3 and 1714.4 cm−1 (C=O stretching). Multiple bands of the phenyl ring in the fingerprint region, and these results were in line with previous studies ^6,40,42.

Figure 4: A- FTIR spectrum of pure ACE, Solupuls^®, FSD7, and its physical mixture. B- FTIR spectrum of pure ACE, Solupuls^®, EFSD7, and it’s physical mixture.

The spectrum of FSD and EFSD and their PM displayed nearly the same peaks as those for pure ACE (Figure 4 - A and B) but with less intensity may be due to the dilution effect indicating that there was no interaction between the ACE and SDs components.

The broad peaks in both FSD7 and EFSD7 spectrum can be explained by a hydrogen bonding between the carbonyl oxygen in Soluplus^® (Figure 5 A) and the -COOH of ACE (Figure 1). This peak is more pronounced and broader in EFSD7 with the shifting of the N-H stretching peak to a lower frequency of 3440.3 cm^-1, which may be caused by an additional hydrogen bond formed between citric acid (Figure 5 B) and Solupus^{® 37}. The presence of a hydrogen bond is an indication of formulation stability ⁴².

A B

Figure 5: Chemical structure of (A) Soluplus^®, (B) Citric acid ³⁷.

Powder X-ray diffraction (XRD):

The XRD diffractograms of pure ACE, Soluplus^®, the selected SD formula from FSD and EFSD, and their PM are shown in Figure 6.The pure ACE pattern of PXRD shows characteristic intense peaks at a 2θ of 18.8°, 19.8°, 22.6°, 24.8°, and 26.2°, which indicates the presence of ACE in the crystalline state. These values of pure ACE were following previous studies ^43,44.

The physical mixture pattern of PXRD of both FSD7 and EFSD7 represents the distinctive peaks of ACE, although they were less intense, which may be due to the diluting effect of the carrier. While in the selected formulas FSD7 and EFSD7, the distinctive ACE peaks almost disappeared, which can be explainedas ACE beingin amorphous form in the matrix of Soluplus^®, showing that both FSD and EFSD techniques efficiently converted the drug from crystalline to amorphous form ^44,45.

Figure 6: Powder XRD diffractograms of pure ACE, Soluplus^®, physical mixture of FSD7, FSD7, FSD7, and EFSD7.

Differential scanning calorimetry (DSC):

The DSC thermograms for the ACE and Soluplus^® are shown in both Figure 7 - A and B, pure ACE showed an intense melting peak at 154˚C which revealed the crystalline nature of the drug. In contrast, Soluplus^® showed a broad glass transition (Tg) endotherm at 76˚C of the amorphous carrier as previously reported ³⁸.

Figure 7: A- DSC thermogram of pure ACE, Soluplus^®, physical mixture FSD7, and FSD7. B- DSC thermogram of pure ACE, Soluplus^®, physical mixture EFSD7, and EFSD7.

The FSD7 shows an absence of ACE and Soluplus^® peaks which indicates the existence of ACE in an amorphous state, while the drug remains in its crystalline state with the same peak in the physical mixture of FSD7 as shown in Figure 7 - A.

EFSD7 also shows the conversion of ACE into the amorphous state because of the absence of an ACE endothermic peak while it remains in the physical mixture of EFSD7, as shown in figure 7 - B.

Moreover, the DSC thermograms of EFSD7 and the physical mixture of EFSD7 represent peaks at 188º and 190 ºC, respectively, due to the decomposition of citric acid above its melting point ^45,47.

These results followed the PXRD results and explained that the enhancement in solubility and dissolution was due to the amorphous state of ACE, which is one of the most important mechanisms for such enhancement by solid dispersion ^48,51.

In addition, these results confirm that the superior enhancement in the dissolution rate of ACE by the EFSD technique was due to the porosity of the product.

CONCLUSION:

According to the current study's results, ACE's solubility and dissolution rate were efficiently improved using both FSD and EFSD techniques. Soluplus^®was the best carrier utilized in both techniques. Moreover, the EFSD technique was superior to FSD due to the better improvement obtained by all carriers with the used ratios. EFSD can be considered a successful and efficient technique for hydrophobic drug solubility and dissolution rate improvement.

CONFLICT OF INTEREST:

None

ETHICAL REQUIREMENTS:

We received ethical approval to conduct the research from the University of Baghdad College of Pharmacy

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Received on 16.09.2022 Modified on 24.03.2023

Research J. Pharm. and Tech 2023; 16(11):5358-5365.

DOI: 10.52711/0974-360X.2023.00868

Formula name (FSD)	Percentage yield (PY %)	Drug content % (W/W) (Mean±std) (n=3)	Formula name (EFSD)	Percentage yield (PY %)	Drug content % (W/W) (Mean±std) (n=3)
FSD1	93.6	94.9±0.05	EFSD1	96.4	99.54±0.31
FSD2	96.6	101±0.86	EFSD2	98.36	98.12±0.09
FSD3	99.9	102.97±0.52	EFSD3	99	96.18±0.03
FSD4	99.7	96.6±0.48	EFSD4	99.8	99.85±0.02
FSD5	97.8	98±0.02	EFSD5	99.92	97.21±0.01
FSD6	97.53	99.2±0.1	EFSD6	98.4	95.07±0.05
FSD7	99.5	99.4±0.13	EFSD7	99.8	99.92±0.03
FSD8	97.33	100.44±0.45	EFSD8	99	98.87±0.08