Solid Dispersion by Fluidized Bed Processing: A Platform for Enhancement of Dissolution Rate of Simvastatin Poorly Water-Soluble Drug

Aim: The aim of this study was to study the solubility and dissolution kinetics of poorly watersoluble drugs simvastatin from its solid dispersion with different carriers by using fluidized bed processing technique. Methods: The effect of different surfactants such as Gelucire® 44/14, PVPK30 and Poloxamer188 on solid dispersion dissolution and solubility of simvastatin was investigated. Solid dispersion is formed using various techniques with polymeric carrier to potentially enhance the solubility and dissolution rate such as fluidized bed processing, it will extend drug absorption, therefore the objectives were to make a comparative evaluation among different solid dispersions. Results: The simvastatin solid dispersion prepared by fluidized bed processing significantly enhanced in vitro dissolution and solubility relative to that of the unprocessed form. The dissolution profiles were correlated using various mathematical models such as Zero order, first order, Higuchi and Hixon Crowell model and the Zero order kinetics model gave better correlation results than the other models. Conclusion: Dissolution profile of simvastatin was significantly improved via complexation with Gelucire 44/14 as compared with the pure drug and other carriers using FBP processing is a highly effective strategy for enhancing the solubility and dissolution of poorly water-soluble drugs. Original Research Article Surawase and Baheti; JPRI, 33(42A): 32-43, 2021; Article no.JPRI.71859 33


INTRODUCTION
After administration of drug, it is usually dissolved and absorbed in the gastrointestinal tract then it reaches the target areas. In this process there are two key points one is the solubility and other is permeability in GIT. Simvastatin (SV) a lipid lowering compound and specific inhibitor of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG COA) reductase. Simvastatin comes under BCS class-II i. e. low soluble and high permeable therefore, poorly absorbed from gastro intestinal tract [1]. Solid dispersions of such drugs in hydrophilic carriers have provided a promising possibility of improving their solubility and dissolution rate [2]. Dissolution of drugs are the most important and crucial phenomenon for all kind of dosage forms. Solid dispersion states to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug [2]. When used, can significantly increase the wettability property of drug, carriers can influence the drug dissolution profile by direct dissolution or cosolvent effects.
In solvent evaporation method consisting of dissolved drug and the polymeric carrier in a common solvent such as ethanol, chloroform, or a mixture of ethanol and dichloromethane. Solvent evaporation methods show some disadvantages such as; expensive and difficult to find common and removable solvents also difficulty in completely removing liquid solvent. In the fluidised bed processing, the carrier and the active ingredient are dissolved or suspend in a suitable solvent [3]. This solvent is evaporated by drying it to apply a stream of fluidized heated air to remove the solvent. Due to the large surface area of the droplets, the solvent rapidly evaporates and solid dispersion is formed quickly [3,4].
In the present study solid dispersion using three carriers in different ratios were prepared by fluidized bed processing technique and solvent evaporation. SD evaluated for its saturation solubility, in vitro dissolution and dissolution kinetics.

Drug Content
The drug content was determined by measuring the absorbance at 239nm (using UV/vis spectrophotometer, Lab India 3000+) after appropriate dilution with methanol. The drug concentration was determined using standard calibration curve [5].

Saturation Solubility Determination
Saturation solubility of Simvastatin, physical mixtures and solid dispersions were determined in distilled water. An excess amount of pure drug, PMs and solid dispersion were added in 10 ml of distilled water [5,6]. The mixture was stirred in shaker for 24 hours, after saturation level mixture was filtered and subjected to determination of concentration of Simvastatin spectrophotometrically at 239 nm.

Preparation of Solid Dispersion
Solid dispersion (SDs) of Simvastatin were prepared by two methods [5,7]

Fluidized Bed Processing
Fluidized bed granulator (FBG), a highly economical and efficient one pot process, is a popular technique in the pharmaceutical industry for achieving particle size enlargement. Fluidized bed granulation technique recently, a method for preparation of solid dispersion using fluid bed granulation process. Solid dispersion using fluidized bed granulation process has been attracting attention as a manufacturing process because it overcomes so many drawbacks and problems arising in other multistep granulation and solid dispersion manufacturing processes. The advantages of FBP is to improve compressibility for tableting & Continuous operation. Applicable for large or small-scale operations & saving labour cost.
PMs containing Simvastatin and carrier (Gelucire, Poloxamer & PVP-K30) was dissolved in methanol (100 ml) to form the solution (Fig. 1). After complete dissolution of PMs in methanol, the solution was sprayed on substrate lactose in fluidized bed processor (Table-2). The flow rate was set at 1.75 rpm, the inlet temperature was kept at 70 ℃, product temperature was kept at 56 ℃, atomization air pressure 2.25 MPa and air flow se at 1.6 Mpa (Table-1).

Solvent Evaporation
To prepare SDs, drug and polymer were mixed in the selected ratio;50 ml or 100 ml methanol was added portion wise with a constant stirring until the mixture completely dissolve [8]. The drug/polymer solution was then evaporated at 35 to 40 ℃ under vacuum (150 mbar) with Vacuum Oven [9]. The thin film was obtained in a flask and dried at 40 ℃ in an oven for 24 h. The resulting SD was ground in mortar and pestle ( Table 2).

Tablet Dosage Form Development
Three type of tablet were prepared using 20 mg simvastatin [10], the FBP-Solid dispersion that showed maximum drug dissolution and saturation solubility SSD3 and SD prepared by solvent evaporation method was further formulated in tablet containing SD equivalent to 20 mg, containing lactose as diluent, magnesium stearate as a lubricant and aerosol as glidant (Table 3) Using a rotary tablet press (Cemech, India), consistent pressure was applied to produce F-1 (simvastatin), F-2 (FBP-SD-3), and F-3 (SE-SD-3) tablets [7,9].

Dissolution Kinetics
The in vitro drug release data obtained from the PMs, SD and marketed formulations were fitted to various dissolution kinetics models included zero order, first order, Higuchi and Hixson Crowell, in order to study the release mechanism [11].

Zero Order Kinetic Model
To study the release kinetics, data obtained from in vitro drug release studies were plotted as the cumulative percent drug released. This relationship can be used to describe the drug dissolution of several types of modified release pharmaceutical dosage forms, as in the case of some transdermal systems, as well as matrix tablets with low soluble drugs in coated forms, osmotic systems, etc. Drug dissolution from dosage forms that do not disaggregate and release the drug slowly can be represented by the equation [4,5]: Where, Q t is the amount remaining to be released in time t, Q 0 is the initial amount of drug in the solution and K 0 is the zero-order release constant expressed in units of concentration/time.

First Order Kinetics Model
This model has been used to describe absorption and/or elimination of a variety of therapeutic agents. First-order release kinetics states that change in concentration with respect to change on time is dependent only on concentration. The data obtained are plotted as log cumulative percentage of drug remaining vs. time, which would yield a straight line with a slope of -K/2.303.
where Ǫ1 is the amount of active agent released on time t, Ǫ1 is the initial amount of drug dissolved, and K1 is the first-order constant [4,6].

Hixson Crowell
Hixson and Crowell (1931) discovered that a group of particles' regular area is proportional to the cube root of its volume. Using this relationship, they proposed an equation: where W o is the initial amount of the drug in the system; W t is the amount remaining in the system on time t; and K HC is the constant of incorporation, which relates surface and volume.
The equation describes the release from systems where there is a change in surface area and diameter of particles or tablets. To study the release kinetics, data obtained from in vitro drug release studies were plotted as the cube root of drug percentage remaining in matrix versus time [4,7].

Higuchi Model
The first example of a mathematical model aimed to describe the drug release from a matrix system was proposed by Higuchi in 1961. The data obtained were plotted as cumulative percentage drug release versus square root of time [4,5,7]. It describes the drug release as a diffusion process based on the Fick's law which is square root of time dependent.
The equation for Higuchi for release of drug is as follows; Where, Q is cumulative amount of drug release at time t, K H is the Higuchi constant and 't' is time.

Saturation Solubility Study
Saturation solubility studies of pure simvastatin and its physical mixture and solid dispersion with Gelucire, poloxamer, and PVP-K30 were performed in distilled water by FBP and solvent evaporation technique. Maximum enhancement of solubility of simvastatin in water was obtained 260.55 μg/ml for solid dispersion with Gelucire 44/14 at 1:3 ratio by fluidized bed processing as shown in Fig. 2. Solubility of SD was enhanced with Gelucire via micellar solubilization at a critical micelle concentration and also the improved wettability of particle surface by Gelucire, Therefore, this batch was selected for further formulation studies [12].

Drug Content
The solid dispersion obtained comparatively maximum solubility in water; these batches were selected for the determination of drug content [13]. The percent drug content of simvastatin in solid dispersion with Gelucire by FBP and SE technique at 1:3 ratio was found to be 98.87% and 97.87% respectively.

Standard calibration curve of Simvastatin
According to the concentration and absorbance of standard solution, a calibration curve was generated (Fig. 3) and regression coefficient and line equation calculated [14] as follows; = 0.0011 + 0.0255 ( = 0.992)

In Vitro Dissolution Study
In vitro drug release studies have been executed using USP type II dissolution apparatus at rotation speed of 50 rpm. The cumulative drug release in phosphate buffer pH 7.0 of simvastatin pure drug, in physical mixture and in solid dispersion by FBP. PM1 to PM9 and SSD1 to SSD9 batches were shown in Fig. 4  dissolution study were executed. Tablet formulation of PM, SD-FBP and SD-SE containing 20 mg simvastatin after 60 minutes were found to be 67.89%, 98.36%, 80.48% respectively as shown in Fig. 6. However, we focused primarily on the effect of different structural polymers and methods of solid dispersion preparation on the solubility enhancement, dissolution mechanism and release kinetics of simvastatin from solid dispersions. These properties strongly depend upon the nature of all components, but the solubility and dissolution rate of the drug is mainly affected by the polymer carrier [16,17,18]. Therefore, the drug to polymer carrier ratio was fixed at 1:3.

Dissolution Kinetics for Simvastatin Tablet Using Different Equations
The Beer's law standard curves for simvastatin, in the corresponding medium at the maximum absorbance, were determined using three replicates over ten concentrations within the solubility range of drug to achieve sink conditions and had shown no deviation from linearity with regression coefficient of >0.992 as shown in Fig.  3. The dissolution profiles of all formulations were measured and plotted in accordance with the zero-order equation (Fig. 7), the first-order equation (Fig. 8), the Higuchi square root equation (Fig. 9), the Hixson-Crowell (Fig. 10). The release profile from SDs varied depending on the methods of preparation but there is notable improvement in release rate and the quantity of released simvastatin for all SDs over pure SIM. The release rates of SIM were found to be significantly different from each specific method and polymer. Fig. 6 reveals that there was noticeable influence of polymers and preparation methods on SIM dissolution rate. It is also clear that the pure SIM had the lowest dissolution rate. As can be seen in Fig. 6, the presence of Gelucire 44/14 at 1:3 ratio caused faster medium penetration, faster release and faster polymer erosion in comparison to pure SIM. The fastest SIM release, as well as its largest amount released, was observed in SD prepared by FBP this is due to incorporation or encapsulation of drug into the matrices during fluidized bed processing can affect the drug release rate. Therefore, it is clear that polymer dissolution influences the SIM release profile significantly [18,19].
The result using the zero-order equation for simvastatin tablet showed that percent of drug released from F1, F2 and F3 formulation within 60 minutes were 36.78, 98.48 and 79.49 respectively. The result indicated that there is difference in the dissolution profile for the tablet prepared by SD and pure drug. An increase in dissolution by the addition of polymer carrier Gelucire was observed. As there was an increase in dissolution related to the SD prepared by solvent evaporation method. While the dissolution from the SD tablet can be described by the zero-order equation in which the r 2 value was 0.9686, 0.9887 and 0.9994 respectively ( Table  4). Result demonstrated using zero order kinetics from different, dissolution behaviour for the pure drug, SD-FBP and SD-SE. the result showed from the first order kinetics with r 2 value, 0.951, 0.8607 and 0.951 respectively [9,20,19]. Therefore, dissolution data cannot be described by first order equation. The dissolution results were plotted in accordance with the Higuchi square root equation i. e. percent drug dissolved as a fraction of the square root of time ( Fig. 9) A linear relationship was obtained after an initial lag time in all formulations. The linearity of the plots indicated that the drug release process is diffusion controlled. The dissolution data were also plotted in accordance with the Hixon Crowell cube root (Fig. 10) results for all formulation (F1, F2 and F3) indicated that a linear relationship was obtained [20,21].

CONCLUSION
In this study Simvastatin solid dispersion were successfully obtained using the solvent evaporation method and fluidized bed processing. Gelucire 44/14, PVP K-30, Poloxamer were used as a polymeric carrier. Therefore, the use of different techniques for solid dispersion having different properties can provide greater influence on the mechanism of the dissolution. In the case of SDs containing simvastatin prepared by fluidized bed processing, simvastatin was probably encapsulated by Gelucire, poloxamer spray drying. Zero order dissolution kinetic model was suitably used to describe the SIM release at the beginning of the dissolution experiment as well as to assess whether the release corresponds to the Higuchi model. There was noticeable influence of polymers on SIM solubility. All solid dispersions improved the SIM intrinsic dissolution rate, however, the greatest increase in the SIM dissolution rate was obtained from SD containing Gelucire at 1:3 ratio prepared by FBP. It can also be concluded that all SDs of SIM showed considerable enhancement in dissolution rate and solubility compared to both PMs and the dissolution rate of both PMs was higher compared to the pure simvastatin.

CONSENT
It is not applicable.

ETHICAL APPROVAL
It is not applicable. .

DISCLAIMER
The products used for this research are commonly and predominantly use products in our area of research and country. There is absolutely no conflict of interest between the authors and producers of the products because we do not intend to use these products as an avenue for any litigation but for the advancement of knowledge. Also, the research was not funded by the producing company rather it was funded by personal efforts of the authors.