Impact of Methods of Preparation on Mechanical Properties, Dissolution Behavior, and Tableting Characteristics of Ibuprofen-Loaded Amorphous Solid Dispersions

This study aims to improve the biopharmaceutical, mechanical, and tableting properties of a poorly soluble drug, ibuprofen (IBP), by preparing amorphous solid dispersion (ASD) followed by a sustained-release tablet formulation. A suitable polymer to develop an ASD system was chosen by utilizing the apparent solubility of IBP in various polymer solutions. ASDs containing various ratios of IBP and selected polymer were prepared by the melt fusion (MF) method. ASD containing optimized drug-polymer ratio prepared by freeze-drying (FD) method was characterized and compared physicochemically. The solubility of IBP in water increased 28-fold and 35-fold when formulated as ASD by MF and FD, respectively. Precise formulations showed amorphization of IBP and increased surface area, improving solubility. The dissolution pattern of optimized ASD-IBP in pH 6.8 phosphate buffer after 60 min in MF and FD was enhanced 3-fold. In addition, direct compression tablets comprising optimized ASD granules from MF and FD were made and assessed using compendial and noncompendial methods. ASD-IBP/MF and ASD-IBP/FD formulations showed a similar drug release profile. In addition, 12 h of sustained IBP release from the ASD-IBP-containing tablets was obtained in a phosphate buffer with a pH of 6.8. From the dissolution kinetics analysis, the Weibull model fitted well. The drug release pattern indicated minimal variations between tablets formed using ASD-IBP prepared by both procedures; however, pre- and postcompression assessment parameters differed. From these findings, the application of ASD and sustained-release polymers in matrix formation might be beneficial in improving the solubility and absorption of poorly soluble drugs such as IBP.


Introduction
Ibuprofen (IBP), a classical nonsteroidal anti-infammatory drug, is widely used to treat mild to moderate pain and fever.Due to its poor solubility, IBP is categorized as a BCS class-II drug [1,2] with a pH dependency in the solubility profle [3].In addition, IBP has a short elimination half-life of approximately 1.8-2 h [4].Tus, poor solubility and quick elimination half-life limit in its clinical application, and a multiple-dosage regimen is required to maintain optimum plasma drug concentration.Approximately 25-40% of the current drugs and recently developed active pharmaceutical ingredients (APIs) exhibit limited solubility in water [5].Consequently, it is necessary to administer a substantial dose of the medication to achieve a therapeutically signifcant plasma concentration of drugs with low solubility.Inadequately soluble drugs administered in substantial amounts have reduced systemic bioavailability and heightened local toxicity at sites of aggregate deposition owing to their elevated concentration [6].Such problems may be resolved with a formulation technology that increases the solubility of the drug [7].Several approaches can be employed to enhance the solubility of poorly soluble drugs in water.Tese include using surfactants, pH adjustment, nanosuspension technology, hydrotrophy, solid dispersion, and salt formation [8].Te solid dispersion (SD) approach is commonly employed to enhance the aqueous solubility, dissolution rate, and consequently, the bioavailability of drugs exhibiting limited solubility, among the previously mentioned methods [9].
Generally, SDs involve the incorporation of the drug into a pharmacologically inert hydrophilic carrier.Te physical state of the drugs in SDs can be crystalline or amorphous.When the drug is amorphous, it can be dispersed over the carrier employed at a molecular level or incorporated in the solid dispersion as particles [10,11].On the other hand, when the drug is in its crystalline state, it can be solely incorporated as a particle.Teoretically, the drug and the carrier could form mixed crystals [12].According to various studies, mixed crystals of this kind have never been encountered with SDs.By incorporating the molecular dispersion of one or more APIs in an inert carrier, SD increases the drug's solubility [13].Te chemical and physical stability of SDs, as well as their solubility, dissolution, bioavailability, and manufacturability, are all critical to the development of pharmaceuticals.[14].Terefore, the mechanical properties of SDs may impact the compaction properties of the fnal dosage form formulation and the success of tablet manufacturing.From this perspective, knowledge of the mechanical properties of SDs is crucial for their rapid development into good-quality tablets [15].Along with evaluations of stability and dissolution performance, mechanical property characterization of SD and its associated formulation blend should ideally be a key component of SD formulation design and optimization.However, very little is known about the SD system's potential to improve the biopharmaceutical and mechanical behavior of IBP.
Sustained-release (SR) systems have long been used to keep therapeutically efective plasma drug concentrations of the drug with a short biological half-life over a long period [16].Terefore, SR dosage forms containing SD granules are an appealing formulation strategy for increasing the dissolution rate of poorly soluble drugs having a short biological half-life [17].
Te primary objective of this research is to develop IBPloaded ASD (ASD-IBP) to enhance the physicochemical properties and dissolution behavior of IBP.Furthermore, a sustained-release matrix tablet formulation containing the precised ASD granules was prepared and evaluated physicochemically.

IBP Content Determination.
A 1 : 1 ratio of methanol to phosphate bufer (pH 6.8) solution was used to dissolve 10 mg of IBP in an adequate quantity of solvent to prepare a stock solution of IBP.Te resulting solution had a fnal concentration of 100 µg/mL.Te aforementioned solutions were generated by serial dilution techniques to provide working solutions with concentrations ranging from 4 to 24 μg/mL in methanol and 4 to 20 μg/mL in phosphate bufer.Te absorbance of the working solutions was measured using a UV-visible spectrophotometer (EMC-61PC-UV, EMCLAB, Germany) at a wavelength of 221 nm [18].Te average absorbance value of three runs for each concentration was plotted against respective drug concentrations, and accordingly, a standard curve was generated.Te mean regression equation was y � 0.0455x + 0.2914 (R 2 � 0.9962; p < 0.0001).Te 95% CI estimated for the intercept value was 0.2558 to 0.3271.Te equation derived from the standard curve was used to calculate the amount of IBP.

Phase Solubility Study.
Te apparent solubility of IBP in polymer solutions was assessed in triplicate using a wellestablished method described by Higuchi and Connors [19] to choose an appropriate carrier.At a polymer concentration ranging from 5 to 25 mg/mL, an estimated quantity of 20 mg of IBP was added into 10 mL of aqueous solutions containing Soluplus ® , Kolliphor ® P188, and Kolliphor ® P407, respectively.Te tubes were sealed and subjected to agitation at 75 rpm per minute for 48 h at 37 °C using a shaking water bath (WBS-C1 Water Bath Shaker, China).Following a 48 h period, the samples were subjected to a settling duration of 10 minutes before undergoing centrifugation with a force of 10, 000 × g for 5 min.Te supernatants obtained were subjected to fltration, and the content of IBP was analyzed using the procedure outlined in the preceding section.
Te stability constant (K s ) and complexation efciency (C.E.) were determined by employing the given equations [20]: IBP's equilibrium aqueous solubility, or S 0 can be found by graphing the concentration of IBP against various polymer concentrations.

Preparation of ASD-IBP.
Te amorphous solid dispersion of IBP (i.e., ASD-IBP: ASD1, ASD2, ASD3, and ASD4) with diferent ratios of carrier (2 : 1, 1 : 1, 1 : 2, and 1 : 3) was prepared by the melt fusion (MF) method.Te precise amount of IBP and the amount of the chosen polymer determined based on its apparent solubility were placed in a beaker and heated to about 80 °C using a heating mantle.

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Advances in Pharmacological and Pharmaceutical Sciences Immediately after melt mixing, the beaker was kept in an ice bath and continuously stirred.10% colloidal silicon dioxide (AEROSIL ® 200) was added as an adsorbent.Ten, the mixtures were dried with a vacuum desiccator.Te fnal formulation of ASD-IBP in MF was also produced using the freeze-drying (FD) method to examine the impact of drying on the physicochemical parameters of ASD-IBP.Concisely, the polymer ratio and crystalline IBP in the fnal formulation prepared by MF were accurately measured, mixed with tertbutyl alcohol, and subsequently frozen at −80 °C to produce ASD-IBP using the FD method.Te frozen samples were subjected to lyophilization for 24 h using an Eyela FD-1000 freeze dryer (Tokyo Rikakikai, Tokyo, Japan) at a pressure of 15 Pa.Te solvent trapped in the freeze dryer was maintained at −50 °C.

Equilibrium Solubility Study.
Te equilibrium solubility of IBP samples was determined using a modifed version of a method developed by Higuchi and Connors [21].An excess amount of IBP and ASD-IBP samples (approximately 50 mg) was placed in a test tube containing 10 mL of distilled water and stored at 37 °C for 24 h in an automated water bath shaker.After 24 h, samples of the experimental solutions were obtained, subjected to centrifugation at 10,000 rpm for 5 min, and diluted using methanol.Te IBP content was analyzed using the approach outlined in Section 2.2.
2.6.Surface Morphology.Scanning electron microscopy (SEM) techniques were employed to investigate the surface morphology of crystalline IBP and ASD-IBP samples (FESEM JEOL JSM-7600F, Singapore).Magnetron sputtering apparatus (MSP-1S, Vacuum Device, Ibaraki, Japan) was used to coat the samples with platinum after using double-sided carbon tape to adhere them to an aluminum sample holder.

X-Ray Powder Difraction (XRPD).
Te X-ray difraction patterns of IBP and ASD-IBP samples were recorded using a Rigaku X-ray difractometer (Tokyo, Japan).Te instrument emitted Cu K radiation at a current of 30 mA and a voltage of 40 kV.Te samples underwent scanning at 2 short-range angles ranging from 5 °to 35 °, with a step size of 0.2 °and a scanning speed of 4 °per min.

Diferential Scanning Calorimetry (DSC).
To examine the thermal characteristics of IBP and ASD-IBP samples, 3 mg of each sample was introduced into aluminum pans.Subsequently, the samples were subjected to a heating rate of 5 °C per minute using a diferential scanning calorimeter (DSC) manufactured by Netzsch in Germany.Nitrogen gas (50 mL) was continuously purged throughout the experiment.Te calibration standard for the system consisted of indium, which was 99.999% pure and weighed between 8 and 10 mg.Te onset temperature for this calibration standard was measured to be 156.6 °C.
2.9.Termal Analysis.Termogravimetric analysis (TGA) analysis was accomplished under a 20 mL/min nitrogen constant fow using a thermogravimetric analyzer system model: (STA 449 F1 Jupiter, NETZSCH, Germany).Accurately weighed amount (5 mg) of crystalline IBP, physical mixture, and ASD-IBP samples were placed in a sealed alumina crucible.All test samples were subjected to a constant heating rate of 10 °C/min in the temperature range of 30 °C-300 °C using an empty alumina pan as reference.
2.10.Particle Size Distribution.Te mean hydrodynamic diameter of ASD-IBP samples suspended in water was assessed using a Zetasizer ultra instrument (MALVERN, Worcestershire, UK) equipped with a dynamic light scattering (DLS) technique.Te measurements were conducted at a temperature of 25 °C and an angle of 90 °, employing the correlation of photons from light scattering to ascertain the average diameter.Te experiment was repeated on all three of them.

Brunauer, Emmett, and Teller (BET) Surface Area
Analysis.After degassing the IBP and ASD-IBP samples in a fowing nitrogen atmosphere at 40 °C for 14 h, the BET surface area of the samples was evaluated using nitrogen gas adsorption at the ASAP2020 automated adsorption equipment (Micrometric Ltd., USA).Te surface area was determined using the Brunauer, Emmett, and Teller (BET) equation for a relative pressure range of 0.01-1.0.

Fourier-Transform Infrared Spectroscopy (FTIR).
FTIR analysis was conducted to ascertain the probability of hydrophobic interactions between the polymers and the substrate.Te samples were individually placed on the instrument's sample platform (Perkin Elmer, L160000A, USA), and infrared spectra ranging from 4000 (600 cm −1 ) were acquired using spectrum 10 software.During the analysis, the baseline of each sample was adjusted and normalized.Te resulting spectra were smoothed using a nine-point smoothing algorithm.

Formulation of IBP Sustained-Release Matrix Tablets.
Te precise ASD-IBP (ASD3) was selected based on the earlier study to formulate sustained-release matrix tablets.A direct compression method prepared sustained-release matrix tablets containing ASD-IBP equivalent to 100 mg of IBP.ASD granules were mixed with diferent amounts of Kollidon ® SR (10%, 20%, 30%) and Eudragit ® RSPO (10%, 20%, 30%) as a sustained-release polymer.StarTab ® was used as a tableting agent, and talc and magnesium stearate were used as a glidant and lubricant, respectively.After mixing, fowability characterization tests were performed to analyze the powder mixture, which was then directly compressed into tablets in a single rotary tablet press (Emtech, USA) utilizing a 12 mm punch.After selecting the suitable ratio of ingredients in matrix tablets, the ASD3-FD was employed in tablet preparation to compare the impact of drying on the performance of tablet characteristics.
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Precompression Evaluation of Powder Blends.
To evaluate homogenous powder blends, several precompression parameters named loose bulk density, tapped bulk density, Carr's compressibility index, Hausner's ratio, and angle of repose were determined before compression [22].

Postcompression Evaluation of Formulated Tablets.
Postcompression parameters such as weight variation, hardness, and friability were determined.Twenty tablets of each formulation were considered for the weight variation test using an electronic balance (Electrolab India Pvt.Ltd.).Also, the hardness and friability of the formulated tablets (six tablets of each formulation) were evaluated using an automatic tablet hardness tester (YD-1 Tablet Hardness Tester, Wincom China) and a friabilator (Electrolab India Pvt.Ltd.), respectively [23].Tese samples were subsequently subjected to centrifugation at 10,000 rpm for 5 min.Following centrifugation, the samples were diluted using a phosphate bufer with a pH of 6.8.Te spectrophotometric measurement of IBP concentration was conducted at a wavelength of 221 nm.

Dissolution Study of Sustained-Release IBP Matrix
Tablets.Dissolution experiments for sustained-release IBP matrix tablets were conducted at 37 °C for 12 h using the USP paddle method at 50 rpm in 900 mL of pH 6.8 phosphate bufer with the dissolution tester system electrolab dissolution tester, Electrolab India Pvt. Ltd.At predetermined intervals, 5 mL samples were withdrawn from the dissolution vessel followed by quick addition of 5 ml fresh medium to maintain a constant volume.After fltering through a 0.45 μm membrane, the samples were diluted with phosphate bufer at pH 6.8.Spectrophotometry was used to determine the IBP concentration.All experiments were run in triplicate.
Model-independent methods compare the two profles solely at observed time points.Tis method employs both the diference factor (f 1 ) and the similarity factor (f 2 ).Te diference factor (f 1 ) quantifes the percentage diference between the two curves (reference and test samples) at each time point and calculates the relative error between the two curves.Te similarity factor (f 2 ) is a logarithmic reciprocal square root modifcation of the sum of squared error that measures the degree of similarity (%) between two curves.Te diference factor (f 1 ) and similarity factor (f 2 ) were determined using the established equations (24).Mean dissolution time (MDT), as an example of a modelindependent factor, is determined from the cumulative curves of dissolved IBP as a function of time [25].Moreover, the dissolution efciency (DE), which is the area under the dissolution curve within a period, was also calculated [24]: 2.17.2.Model-Dependent Dissolution Kinetics.Numerous model-dependent mathematical models, such as zero-order, frst-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas, and Weibull, were utilized to investigate the in vitro release kinetics.Te following equations describe the modeldependent mathematical kinetics [24].Te best-ftting equation uses the coefcient of determination (R 2 ), adjusted coefcient of determination (R 2 adjusted ), and Akaike information criterion (AIC) [26].According to the previously defned criteria for selecting the best kinetic model, the best and most accurate models should be selected using appropriate metrics such as R 2 , R 2 adjusted , and AIC.Te optimal model may be evaluated with lower AIC and higher R 2 adjusted values.

Statistical Analysis.
Te data are presented as the mean and standard deviation (S.D.).Te diagrams were generated utilizing GraphPad, Prism 8.0 software (GraphPad Software, LaJolla, CA).Te mathematical parameters were computed using the DDSolver programme [27].A one-way analysis of variance (ANOVA) was used to compare means with pairwise comparisons using Fisher's least signifcant difference technique, which was employed for statistical comparisons.In all analyses, a p value less than 0.05 was considered signifcant.

Results and Discussion
Scientists continuously struggle with poorly soluble pharmaceuticals in the emerging formulation development and drug delivery feld.Fortunately, SD has emerged as a promising strategy for combating the challenges of drugs with poor solubility [28].SDs usually have two parts: the carrier and the API.Choosing a suitable carrier is essential for the best drug release and therapeutic results [29].Several investigations have shown that the synergistic efect of carriers in SDs may result in head-to-head contacts and electrostatic interactions [30].Tis occurs due to hydrophilic groups bound to the surface by cohesive forces, which reduce surface tension, forming an inner hydrophobic core and increasing solubility [31][32][33].Terefore, the current study aimed to use an amphiphilic carrier to prepare and characterize ASD-IBP to improve biopharmaceutical properties.

Selection of Polymers for ASD System.
Choosing polymers as carriers is critical in improving the biopharmaceutical characteristics of poorly soluble drugs within the self-dispersing 4 Advances in Pharmacological and Pharmaceutical Sciences system.Excipients experiencing increasing popularity are amphiphilic polymers, characterized by hydrophilic and lipophilic groups.Encapsulation facilitates the formation of polymeric micelles by promoting interactions between lipophilic groups of amphiphilic polymers and weakly soluble pharmaceuticals.Tese micelles possess a hydrophobic core and a hydrophilic outside, enhancing the solubility of drugs with low solubility.Tis phenomenon has been observed in previous studies [34].
Te investigation focused on determining the observed solubility of IBP in water when various concentrations of predissolved polymers, such as Soluplus ® , Kolliphor ® P188, and Kolliphor ® P407, ranging from 5 to 25 mg/mL, were present.Te aim was to select appropriate polymers for the IBP amorphous solid dispersion (ASD) system.Soluplus ® , Kolliphor ® P188, and Kolliphor ® P407 are frequently employed as carriers with amphiphilic characteristics to improve the solubility of poorly soluble drugs due to their biocompatibility and widespread availability in the commercial market [35][36][37].As shown in Figure 1, the aqueous solubility of IBP increased as the polymer concentration increased.All analyzed polymers exhibited a linear (A L -type) relationship between increasing IBP solubility and polymer concentration.Soluplus ® and Kolliphor ® P407 enhanced the solubility of IBP signifcantly (p < 0.01) compared to Kolliphor ® P188.Te aqueous solubility of IBP was increased by 13.5-fold and 12.3-fold with the addition of Soluplus ® and Kolliphor ® P407 at a 25 mg/mL concentra- tion.Similarly, Kolliphor ® P188 improved the solubility by 1.5-fold at the same concentration.Te increased dispersibility and miscibility of IBP disseminated in polymers led to an increase in the apparent solubility of IBP in amphiphilic block copolymers [38,39].Furthermore, the stability constants (Ks) were determined by a linear regression analysis of the generated phase solubility diagram.Te obtained data have been compiled and are displayed in Table 1.
Te K s is signifcantly (p � 0.0031) higher for Kolliphor ® P407 than Kolliphor ® P188, justifying the positive efect on solubility enhancement of IBP.Although higher K s for Soluplus ® , due to the lower melting point of Kolliphor ® P407, it was chosen as the suitable polymer for the melt fusion method.Tese fndings implied that IBP might interact with Kolliphor ® P407 more successfully and entangled in the micelle's hydrophobic core, improving its solubility.Tus, Kolliphor ® P407 was chosen as the carrier for developing ASD-IBP to improve the physicochemical behavior of IBP based on its apparent solubility and kinetic data.

Selection of an Appropriate Ratio of Polymer.
To identify the ideal ratio for further study, the physicochemical characteristics, including equilibrium solubility and particle size of ASD-IBP, which was prepared by melt fusion using diferent ratios of IBP and Kolliphor ® P407, were in- vestigated to determine the optimal ratio for further study.Considering the limited aqueous solubility of crystalline IBP (50.29 µg/mL), all formulations (ASD1-ASD4) enhanced IBP solubility.Te equilibrium solubility of the ASD-IBP formulations is shown in Table 2. ASD3 and ASD4 demonstrated the greatest solubility enhancement among all formulations.
Kolliphor ® P407 is composed of hydrophobic poly (pro- pylene oxide) (PPO) blocks and hydrophilic poly (ethylene oxide) (PEO) blocks, which serve as surfactants (38).Te critical micelle concentration (CMC) of Kolliphor ® P407 is 34.2 mg/L [40].Tis suggests that combining these two biocompatible polymers may contribute to the enhanced dissolution behavior and oral absorption of IBP.Moreover, it was reported that polymeric micelles dissociate very slowly due to their kinetically stable nature [41].
To investigate the micellization capability of Kolliphor ® P407, the mean particle size of the ASD formulations was also evaluated, and the results are presented in Table 2.According to the micellar size distribution, the size of micelles plays a considerable role in how they enter diferent cells in vivo, regardless of the route of administration [42].According to the results of micellar size distribution, ASD1 and ASD3 showed smaller micelle sizes with better colloidal stability at room temperature.From ASD3 and ASD4, there was no statistically signifcant diference, and it was evident that low polymer concentration is always preferable in the industry for better manufacturability and scalability.Considering the enhanced solubility and particle size distribution, formulation ASD3 was selected for further physicochemical characterization.Moreover, with the same polymer-drug ratio as ASD3, optimized ASD formulation Advances in Pharmacological and Pharmaceutical Sciences prepared by freeze-drying (ASD3-FD) was also characterized to assess the drying method's infuence on the physicochemical characteristics of the formulations.

Physicochemical Characterizations.
Amorphous forms can have more excellent solubility and dissolution rates than crystalline forms due to their higher energy state.Consequently, determining crystallinity becomes crucial for establishing product quality.XRPD and DSC analyses were utilized to investigate the crystalline structure of ASD-IBP (Figure 2).Te XRPD pattern of crystalline IBP revealed several pointed peaks, with the most prominent peak located at approximately 20.18 °(Figure 2 Te elevated level of free energy observed in the amorphous state can potentially confne the drug molecule within an amorphous solid dispersion (ASD), hence impeding drug precipitation or recrystallization in the supersaturated state.Tis characteristic ofers a notable advantage in augmenting lipophilic medicines' solubility [43].According to XRPD and DSC analyses, the amorphization of IBP during the preparation procedure resulted in superior dissolving properties.Using SEM observations, the surface morphology of the IBP samples was evaluated (Figure 3).Te morphology of crystalline IBP consisted primarily of irregularly shaped, disseminated particles (Figure 3(a)).ASD-IBP/MF and ASD-IBP/FD, on the other hand, appeared conventional and faky (Figures 3(c) and 3(d)).Compared to the crystalline IBP, ASD-IBP particles were homogenous, and their size was considerably reduced.Te fndings revealed that integrating IBP into the polymer matrix was successful, suggesting a high degree of assimilation.In contrast to crystalline IBP, the SEM micrographs reveal a notable augmentation in the surface area of ASD-IBP in the freeze-drying process (Figure 3(d)).According to the Noyes-Whitney equation, the increased particle surface area produced by micronization is a significant factor in accelerating dissolution [44].
In addition, the BET study revealed an increase in the BET surface area and total pore volume in ASD-IBP/MF and ASD-IBP/FD compared to crystalline IBP.Besides, the BET study also revealed a reduction in the BET surface area and total pore volume in ASD-IBP/FD compared to ASD-IBP/ MF.ASD-IBP/MF and ASD-IBP/FD manifested a type IV adsorption isotherm.Alternatively, the average pore diameter was slightly reduced from 53.36 (ASD-IBP/MF) to 49.88 (ASD-IBP/FD), as shown in Table 3.
On the other hand, the size distribution of polymeric micelles is believed to be one of the most critical factors in enhancing the biopharmaceutical properties of a drug [38].Tis study evaluated the micellization capabilities of ASD-IBP using the DLS analysis.Te DLS analysis was conducted on water-dispersed samples of ASD-IBP, which resulted in the observation of nanoparticle formation.Te average particle size was 261 nm for ASD-IBP/FD, with a polydispersity index (PDI) of 0.258.Similarly, ASD-IBP/ MF exhibited an average particle size of 305.2 nm, with a PDI of 0.215.Furthermore, the hydrophilic chain on the surface of polymeric micelles contributes to enhanced drug solubility, dispersibility, and difusivity within the mucus layer.Consequently, this phenomenon promotes efcient drug absorption after oral administration [45].
As a result, SEM and DLS data images confrmed the absence of crystalline IBP during the ASD-IBP preparation process.Tese advantages may contribute to the improved dissolution behavior of IBP.

Termal Behavior of IBP Samples.
Termal analyses were used to investigate the efects of thermal stress on the active substances.Tese analyses provided three diferent pieces of information about a particular phase

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Moreover, the DTG analysis showed that the crystalline IBP had deteriorated between 200 °C and 300 °C.Ibuprofen was pure on the thermal analysis diagram, with one endothermic peak around 100 °C corresponding to its melting point [47], and decomposing in one step between 200 °C and 300 °C.It was observed that 99.9% of the mass was lost at temperatures between 250 °C and 300 °C.Te ASD-IBP simultaneously indicates degradation across a wide temperature range.With ASD-IBP, the overall mass loss percentage was estimated to be around 70%. Te mass loss percentage of ASD-IBP/MF and ASD-IBP/FD in the same temperature range is similar, according to DTA/TGA diagrams of the samples.However, the mass loss percentage of IBP/PM is more signifcant than ASD-IBP.Tis distinction can result from the complex formation between IBP and polymer.Te likelihood of a chemical interaction between IBP and the polymer while creating ASD is another signifcant result of heat analysis.Te information suggests that IBP and Kolliphor ® P407 may interact chemically to produce a complex in ASD.

Drug Polymer Interactions.
In theory, amorphous molecules can be dispersed at a molecular level within the matrix carrier of a solid dispersion (SD) formulation.Te intermolecular interaction among these molecules has the

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Advances in Pharmacological and Pharmaceutical Sciences potential to lead to an improved amorphization of the medication [48].Te FTIR analysis determined the molecular state of crystalline IBP and processed ASD-IBP. Figure 5 illustrates the FTIR spectrum.Te presence of the asymmetric C-H stretching vibration was identifed by a distinct and well-defned infrared absorption band at 2,954.25 cm −1 and 1,705.31cm −1 (carbonyl-stretching of the isopropionic acid group) (Figure 5).It is believed that the IR spectrum patterns of IBP samples refect diverse chemical environments.Te diagram (Figure 5) depicts the absorption maxima at 2,878.4 cm −1 (C-H stretch aliphatic), 1,341.93cm −1 (in-plane O-H bend), and 1,144.5 cm −1 (C�O stretching) in the IR spectra of Kolliphor ® P407.
In contrast, the lack of a distinct peak in the IR spectra of ASD-IBP/MF and ASD-IBP/FD indicates negligible electrostatic interaction.Te FTIR spectrum analysis demonstrated that the inclusion of Kolliphor ® P407 is associated with a negligible hydrophobic interaction that is unlikely to impact the chemical composition of IBP, as indicated by the fndings of the FTIR spectrum analysis.Teoretically, this phenomenon is desirable because of the potential for drugpolymer interactions to prolong the dissolving process effectively.Te dissolution process will exhibit a greater thermodynamic driving force when there are weak or no interactions between the drug and polymer [49,50].

Dissolution Behavior of ASD-IBP Samples.
Dissolution of IBP in pH 6.8 phosphate bufer was improved with the increment in the ratio of Kolliphor ® P407 in ASDs (Figure 6).
Enhanced dissolution of IBP in ASDs from crystalline IBP may be attributable to the surface activity, hydration efect, and solubilizing efect of Kolliphor ® P407.Tis may result in reduced agglomeration and increased surface area [2].However, the drug release pattern shown in Figure 6 indicates insignifcant diferences between the ASD-IBP prepared by MF and FD.

Precompression Evaluation of Powder Blends.
Te precompression parameters for all seven formulations (the composition of the formulations is presented in Table 4) were performed, and the results are presented in Table 5. Te powder is free-fowing if the Hausner ratio is less than 1.25, whereas a ratio of more than 1.25 indicates poor fowability.Te better the fow properties, the lower the Carr's Index.For example, a range of 5-10 means excellent fow, 11-15 good fow, 16-20 fair fow, and >23 poor fow.However, an angle of repose within 35 degrees suggests good fow properties [22].
Te bulk density and tapped density of the prepared blend ranged from 0.226 ± 0.027 to 0.561 ± 0.033 g/mL and 0.279 ± 0.034 to 0.637 ± 0.017 g/mL, respectively.Te Carr's index was found to range from 7.92 ± 1.331 to 18.87 ± 1.247%, and the Hausner's ratio ranged from 1.09 ± 0.035 to 1.23 ± 0.019.Te angle of repose was found to be ranging from 24.23 ± 0.035 °to 34.99 ± 0.042 °for all formulations.From the results of precompression evaluation tests, the powder blend of all the formulations has good fowing properties and good compressibility, and the results are within the pharmacopeial limit [22].However, based on precompression parameters shown in Table 5, it can be concluded that ASD-IBP prepared by melt fusion (F3) showed better-fowing properties compared to ASD-IBP prepared by freeze-drying (F3-FD).

Postcompression Evaluation of Formulated Tablets.
Te result of the postcompression parameters of all seven formulations is shown in Table 6.Weight variation is used to indicate the uniformity of the tablet content.It is found that from all formulations included in the study, formulation F6 had the most negligible average weight of 592.00 ± 12.31 mg, and formulation F3-FD had the highest average weight of 605.00 ± 19.03 mg.But, all formulations of ASD-IBP tablets showed acceptable uniformity of weight as the weight of the tablets was 600 mg; hence, the excellent weight variation range was between 570 and 630 mg (±5%) as stipulated by the USP [23].
Te mechanical properties of pharmaceutical tablets are measurable by their friability, hardness, or crushing strength [23].Te hardness test determines the ability of tablets to endure stress or pressure during handling, packaging, and transportation [24].Te hardness of all formulations was found to be in the range of 3.50 ± 0.37 (F4)-6.19± 0.58 (F3) kg/cm 2 .Tis study found that hardness was higher for the tablets (F1, F2, F3) containing Kollidon ® SR as release re- tardant compared to the tablets (F4, F5, and F6) containing Eudragit ® RSPO.Besides, hardness was increased with the increment of Kollidon ® SR ratio, that is why formulation F3 (30% Kollidon ® SR) showed the highest hardness in this study.Moreover, tablets formulated using ASD-IBP prepared by MF (F3) showed higher hardness compared to tablets formulated using ASD-IBP prepared by freeze drying (F3-FD).
Te hardness test may not be the fnest indicator of tablet behavior during packaging and handling.Loss due to abrasion or tablet friability measurement may be a more pertinent parameter [24].Tis investigation revealed that all formulations had friability values ranging from 0.21 ± 0.019% to 0.45 ± 0.073%, indicating that all formulations met the pharmacopeial specifcation for friability, which specifes that weight loss of not more than 1% is deemed generally acceptable [23].Te results of friability identifed that the formulated tablets were mechanically stable and had good integrity of the tablet.

Dissolution Behavior of Sustained-Release Matrix Tablets.
To understand the drug release profle from solid dispersed tablets, IBP in vitro dissolution study was carried out for up to 12 h in phosphate bufer (pH 6.8).Ten, the cumulative percentage of drug release was determined from the standard calibration curve and ftted into many mathematical models to obtain an idea of the drug release profle from the formulations.Te cumulative percentage of drug released vs. time plot is shown in Figure 7 for all formulations and reference samples.Te cumulative percent drug release for all formulations after 12 h of dissolution was found to be Advances in Pharmacological and Pharmaceutical Sciences within the range of 69.43 ± 4.11% (F4)-87.89± 1.11% (F3-FD), and for the reference sample, it was 100.10 ± 2.34% (REF).As evidenced by several studies, tablet hardness can afect the porosity and permeability of the tablet matrix, which in turn infuences the difusion of the drug out of the tablet [51].Terefore, harder tablets may have a denser structure, leading to slower drug release rates.Among the formulations, F3 has the better hardness (6.19 kg/cm 2 ),  which may lead to a slower release of IBP as MDT was found 5.6 h.Tus, based on the dissolution and hardness tests, F3 formulation was chosen as the optimized formulation.With the same ratio of excipients, tablets formulated using ASD-IBP prepared by FD (F3-FD) exhibited dissolution behavior.Tough the formulations containing ASD-IBP prepared by MF and FD methods have identical dissolution behavior, the pre and postcompression characters difer between the drying approaches.Te diference in pre and postcompression parameters between MF and FD might be due to the agglomeration of particles or collapse of the porous structure in the FD process, afecting the fowability and compressibility of the powder [52].Hence, ASD prepared by MF, can produce particles with excellent uniformity and controlled particle size distribution, improving compressibility and tablet uniformity.In addition, Kollidon ® SR showed better release retardant properties than Eudragit ® RSPO.Kollidon ® SR is spray-dried polyvinyl    Advances in Pharmacological and Pharmaceutical Sciences acetate containing soluble polyvinylpyrrolidone in an 8 : 2 ratio.Kollidon ® SR is a suitable polymer for fabricating sustained-release matrix tablets generated through direct compression due to its outstanding fowability and compressibility [53].
On the other hand, Eudragit ® are well-known for their sustained-release and solubilizing capabilities, as they are derivatives of polymethacrylic acid-co-methyl methacrylate.Eudragit ® RSPO is insoluble at physiologi- cal pH due to the existence of low-level quaternary ammonium groups.Still, it can swell and hence could be a suitable carrier for sustained release delivery [54].
3.10.Dissolution Kinetics 3.10.1.Model-Independent Fit Factors.A model-independent approach of diference factor (f 1 ) and similarity factor (f 2 ) was used to demonstrate the equivalence of all the formulated tablets and the reference product.In this study, the diference factor (f 1 ) and similarity factor (f 2 ) were calculated for all seven formulations of ASD-IBP tablets by using a reference sample (Bufen ® SR, 300 mg capsule, Drug International Ltd., Bangladesh).Te f 2 value was found to vary from 17.1 for F3 to 28.35 for F3-FD.Te f 1 value ranged from 31.982 for F3-FD to 56.36 for F3 (Table 7).
When comparing two dissolution profles, f 1 should be between 0 and 15, while f2 should be between 50 and 100 to ensure sameness of the two dissolution profles [24].Tus, the dissolution profles of formulated tablets were signifcantly (p < 0.01) diferent from those of the reference product.Te notable disparity in the dissolution profles of the formed tablets and the reference product raises concerns regarding the sameness of the two formulations, which might afect the product's bioavailability, bioequivalence, safety, efcacy, quality, and consistency.In addition, the release profles were also compared by calculating DE for various formulated tablets included in the study.Te DE value was found to vary from 38.57% for F3 to 60.93% for F3-FD, whereas 86.20 for the REF (Table 7).Terefore, it is revealed that tablets containing ASD granules prepared by melt fusion and freeze-drying difer in the DE value.However, if the diference in their dissolution efciency falls within acceptable ranges (±10%), the reference and test products can be considered equivalent [55].However, all formulated tablets were far from the established limit (±10%).
Te mean dissolution time (MDT) refects the release of the drug from the dosage form and quantifes the efectiveness of the polymer in slowing down this process.A greater MDT suggests a slower rate of drug release from the dosage form [55]. Tis leads to the slow onset of action and higher drug-retaining ability of the polymer and vice versa.Te MDT value ranged from 3.6 h for F3-FD to 5.6 h for F3, whereas it was 1.9 h for the reference product (Table 7).
Tablets prepared with Kollidon ® SR showed higher MDT values than those designed with Eudragit ® RSPO.Moreover, tablets formulated using ASD-IBP prepared by MF (F3) showed higher MDT values than those developed using ASD-IBP prepared by FD (F3-FD).

Model-Dependent Dissolution Kinetics.
Te dissolution profles of all formulated tablets and the reference product were determined by ftting experimental data to model-dependent mathematical models, such as zero-order, frst-order, Higuchi, Hixson-Crowell, Korsmeyer-Peppas, and Weibull.As indicated in Table 8, the regression parameters of all the samples, such as correlation coefcients and rate constants, were calculated and compared.Te model with the highest adjusted determination coefcient (R 2 adjusted ) and the lowest Akaike information criterion (AIC) best ft the release data [25,56].
As shown in Table 8, based on the highest value of R 2 adjusted and the smallest AIC values for all dissolution data of all the formulated tablets and reference products, among the six models ftted to each dissolution profle, the Weibull model was best ftted to the dissolution data of the formulations (F2, F5, F3-FD, and REF) and the formulations (F4 and F6) and was best ftted to the Korsmeyer-Peppas model.On the other hand, for formulations F1 and F3, the best-ftted model was the zero-order kinetics based on the highest value of R 2 adjusted and the Weibull model based on the lowest value of AIC value.However, there is no statistically signifcant diference in the R 2 adjusted value of the formulations (F1 and F3) in terms of zero-order kinetics and Weibull model.For this reason, it can be declared that the Weibull model is predominant among all the formulated tablets and reference product under investigation.
Te dissolution data were ftted into the Korsmeyer-Peppas model to confrm the difusional mechanism.As indicated in Table 8, the difusion coefcient (n) found for all the formulated tablets were more than 0.5, whereas for the reference product, it was less than 0.5.A difusion coefcient value (n) of less than 0.5 is consistent with a difusioncontrolled release or Fickian difusion.In contrast, values of n between 0.5 and 1 indicate non-Fickian (anomalous) release mechanisms [57].Moreover, in this study, the difusion coefcient (n) was within the range of 0.52-0.74for all the formulated tablets, indicating a non-Fickian difusion mechanism.Difusion and matrix erosion were, therefore, responsible for controlling drug release.Tus, the drug 12 Advances in Pharmacological and Pharmaceutical Sciences release was regulated by multiple procedures for all formulated matrix tablets.On the other hand, the difusion coefcient (n) was 0.24377 for the reference product, indicating a Fickian difusion.

Conclusion
Te therapeutic applicability of IBP is limited due to its poor solubility with dependency, low oral bioavailability, and short elimination half-life.In this study, IBP was prepared as an ASD utilizing two commercially viable techniques: solvent evaporation by rotary vacuum drying (RVD) and freeze-drying.Te solubility and dissolution characteristics of IBP were signifcantly improved in all of the formulated solutions.In addition, a sustained-release matrix tablet formulation with the precise amount of ASD-IBP was prepared.Te results indicate that the formulated product demonstrated dissolution profles appropriate for prolonged-release properties.Terefore, the combination of the ASD approach and the sustained-release idea ofers considerable promise in improving the biopharmaceutical performance of IBP.Advances in Pharmacological and Pharmaceutical Sciences analysis of the samples.Te authors also thank BASF, Bangladesh, and Colorcon, Bangladesh, for their generous gift of polymers.Tis work was partly supported by a research grant from the Ministry of Science and Technology, Bangladesh (special allocation/Grant/ID-533/2021-2022).
(a)), indicating the crystalline nature of IBP.In contrast, ASD-IBP/MF and ASD-IBP/FD exhibited a difractive halo pattern.Minimal peaks were detected in the difractogram for ASD-IBP, indicating that IBP was in an amorphous state.In DSC analysis, although crystalline IBP had an endothermic peak around 100 °C (Figure2(b)), the endothermic peak at the melting point of crystalline IBP was absent in ASD-IBP/MF and ASD-IBP/FD.

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Advances in Pharmacological and Pharmaceutical Sciences transition: (1) the identity of the involved phase (structural information), (2) the temperature of the phase transition, and (3) the heat capacity of the system[46].Te temperature rise could cause thermal stress, which could occasionally cause the API's structural changes.To investigate the thermal behavior of IBP samples, TGA/DTG tests were carried out.Figure4shows the TGA and DTG curves of the IBP samples.Te TGA curves demonstrated that the crystalline IBP thermally degraded between 200 °C and 300 °C.Te samples showed thermal stability up to 150 °C, indicating less moisture content in the sample, then melting and peaking at 240 °C.Te TG/DTG curves show that the thermal decomposition takes place in one step for all samples.

Figure 7 :
Figure 7: In vitro cumulative (%) drug release profle of various formulations of ASD-IBP/SR tablets.Data represent the mean ± S.D. of 3 experiments.

Table 2 :
Te efect of diferent drugs: polymer ratios on the solubility and particle size distribution.

Table 1 :
Apparent solubility data of complexes of IBP with diferent polymers.

Table 4 :
Formulation of IBP sustained-release matrix tablets.
All values are mean ± S.D.