A comparative evaluation between utilizing SAS supercritical fluid technique and solvent evaporation method in preparation of Azithromycin solid dispersions for dissolution rate enhancement

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Abstract

Azithromycin is a poorly water-soluble drug with a lower dissolution rate which resulted in poor bioavailability after oral administration. The aim of this study was to enhance Azithromycin dissolution by a solid dispersion (SD) using solvent evaporation and supercritical fluid based on solvent-anti-solvent technique. Solid dispersions of Azithromycin were prepared with various concentrations of PEG 6000, Sorbitol and Poloxamer 188, SLS (in ternary systems). All samples were studied for the drug solubility. The formulations were also characterized by IR, DSC, XRD and SEM. The solubility and dissolution rate were remarkably improved in case of most SDs prepared with of PEG 6000 (in binary systems, 1:6 ratio) and both surfactants (ternary systems) compared to the related PMs and pure Azithromycin. But the best result was obtained in the dispersion (Azithromycin:PEG 6000:SLS) with a weight ratio of (1:4:2). SAS–SCF processes were signs of less crystallinity of the drug due to the transformation of its crystalline stat into amorphous state. The analysis of dissolution data indicated that enhanced drug dissolution can be achieved where the SDs obtained in the supercritical fluid process was consisted of PEG 6000 and SLS. The dissolution rate and solubility of Azithromycin improved significantly with PEG 6000 and SLS utilizing SAS-supercritical fluid.

Introduction

Azithromycin with chemical IUPAC name [1]:

[2R-(2R, 3S, 4R, 5R, 8R, 10R, 11R, 12S, 13S, 14R)]-13-[2,6-Dideoxy-3-C-methyl-3O-methyl-α-l-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-d-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one and the following chemical structure (Fig. 1) is an Azalide (nitrogen-containing macrolide) and a subclass of Macrolide antibiotics. Azithromycin is a white crystalline powder with a molecular formula of (C38H72N2O12·2H2O) and a molecular weight of 748.984 g mol−1 [1]. This drug belongs to class II of BCS1 [2], [3]. Azithromycin is derived from Erythromycin, with a methyl-substituted nitrogen atom incorporated into the lactone ring, thus making the lactone ring 15-membered [1]. Azithromycin is one of the best-selling antibiotics in the world [4]. Macrolide antibiotics as Azithromycin are bacteriostatic agents that inhibit protein synthesis by reversible binding to the 50S ribosomal subunits of sensitive organisms. Azithromycin is very active against Moraxella catarrhalis, Pasteurella multocida, Chlamydia spp., Mycoplasma pneumoniae, Legionella pneumophila, Borrelia burgdorferi, Fusobacterium spp., and Neisseria gonorrhoeae. Azithromycin has enhanced activity against Mycobacterium avium-intracellulare, as well as against some protozoa (e.g., Toxoplasma gondii, Cryptosporidium, and Plasmodium spp. [5], [6]. Azithromycin administered orally is absorbed rapidly and distributed widely throughout the body, except to the brain and CSF. Azithromycin with actions and uses similar to those of Erythromycin [6] is given in the treatment of respiratory-tract infections (including otitis media), and in skin and soft-tissue infections. Azithromycin may also be used for the prophylaxis, and as a component of regimens in the treatment of M. avium complex (MAC) infections. It is used in some countries for the prophylaxis of endocarditis in at-risk patients unable to take penicillin. It is also used in the management of trachoma and typhoid [6].

As early as in 1961, Sekiguchi [7], [8] developed the concept of solid dispersion to enhance absorption of poorly water-soluble drugs. Later, Goldberg et al. [9], [10], [11], [12] demonstrated that a certain fraction of the drug may also be molecularly dispersed in the matrix, forming solid solutions, while other investigators [13], [14] reported that the drug may be embedded in the matrix as amorphous materials [15], [16]. On the basis of these considerations, Chiou and Riegelman [17] defined solid dispersion (SD) as “The dispersion of one or more active ingredients in an inert excipient or a matrix, where the active ingredients could exist in finely crystalline, solubilized, or amorphous states”. Particle size reduction often leads to improvement in dissolution rate of poorly soluble drugs through an increase in effective surface area. However, for practical purposes, it is difficult to reduce particle sizes of drug in capsules or Tablets to below the 2–5 μm range, while significantly higher particle size is generally preferred during drug product development for ease of handling, formulating and manufacturing. Solid dispersion, in contrast, could dissolve a portion of the drug immediately in contact with the gastrointestinal (GI) fluid [18], resulting in a saturated or supersaturated solution for rapid absorption, and the excess drug could precipitate in the GI fluid in a very finely divided state. The literatures on the application of solid dispersion in improving the dissolution rate and oral bioavailability of poorly water-soluble drugs have been reviewed by Lunar and Dressman [19]. In addition to the aforementioned formulation options, dissolution rate of poorly water-soluble drug can be enhanced by converting the drug into its amorphous form [20]. Solid dispersion formulations, by stabilizing amorphous drugs, can provide significant advantages. The core steps involved in the formation of solid dispersion between a drug and polymer are:

  • (1)

    Transforming drug and polymer from their solid state to fluid or fluid-like state through processes such as melting, dissolving in solvent or co-solvent, or subliming – a process that is not so commonly used.

  • (2)

    Mixing the components in their fluid state.

  • (3)

    Transforming the fluid mixture into solid phase.

A supercritical fluid (SCF) is a substance whose temperature and pressure are simultaneously above its critical point. CO2-Supercritical is a good solvent for water-insoluble as well as water-soluble compounds (drugs) under suitable conditions of temperature and pressure. Therefore CO2-supercritical has potential as an alternative to conventional organic solvents used in solvent-based processes for forming solid dispersions due to its favorable properties of being non-toxic and inexpensive [21], [22], [23], [24]. The process consists of the following steps:

  • (1)

    Charging the bioactive material and suitable polymer into the autoclave;

  • (2)

    The addition of supercritical CO2 under precise conditions of temperature and pressure, that causes the polymer to swell;

  • (3)

    Mechanical stirring in the autoclave; and

  • (4)

    Rapid depressurization of the autoclave vessel through a computer-controlled orifice to obtain desired particle size;

The temperature conditions used in this process are fairly mild (35–75 °C), which allows the handling of heat sensitive biomolecules, such as enzymes and proteins [24], [25], [26], [27], [28], [29]. Fig. 2 shows representative schematic of the solvent-anti-solvent (SAS) supercritical fluid process. Firstly, the solute dissolves in a liquid organic solvent mixture, and a gas is employed to precipitate the solute. Gas is injected as anti-solvent, into the solution in an adiabatic chamber; in addition, we will obtain a uniform mixture, when it becomes supersaturated with the gas – during which the drug precipitates in the form of the fine particles. The samples are washed with additional anti-solvent to eliminate the remainder of the solvent [26], [29], [30], [31], [32], [33].

Section snippets

Materials

Azithromycin dihydrate (Pharmacopeia grade) and polyethylene glycol 6000 (PEG 6000, Analytical grade) were purchased from Fluka (Fluka, USA). Poloxamer 188 (Pluronic® F-68) was purchased from BASF (BASF, Germany, Analytical grade), SLS, Sorbitol, Potassium dihydrogen orthophosphate, Sodium hydroxide and Ethanol 96% (Analytical grade) were purchased from Merck, USA. Ethanol 99.8% (HPLC grade) was purchased from Fluka, USA. All other chemicals and solvents used were of analytical grades.

Binary systems preparation

Solid

Assay of Azithromycin dihydrate

Outset the Azithromycin solution was prepared (5 mg/ml) in phosphate buffer with pH = 6.0 using a UV spectrophotometer (SHIMADZU UV mini 1240 Spectrophotometer, Japan). Using the Standard calibration curve determined the amount of Azithromycin. Concentration range of required linearity observed in 2–30 μg/ml Azithromycin solution in phosphate buffer pH = 6.0 with the correlation coefficient (R2 = 0.9998) [37].

Drug content

Accurately 100 mg of solid dispersions to the equivalent of Azithromycin were weighed and

Results and discussion

Dissolution and solubility studies were carried out at four levels.

The first level: Includes the study of binary solid dispersion systems and preparation of the binary solid dispersion systems using the solvent evaporation.

The second level: Includes the study of ternary solid dispersion systems and preparation of the ternary solid dispersion using the solvent evaporation.

The third level: At this level, the best formulation of the first and second levels was used for preparation of SAS-SCF. Then

Conclusion

The general conclusions that the hydrophilic polymer as PEG 6000 increased solubility and dissolution rate of Azithromycin. This happened in binary solid dispersion systems using solvent evaporation method (SD4, 1:6 ratios). In other hand, the preparation of the ternary solid dispersion by solvent evaporation using surfactants increased further solubility and dissolution rate of Azithromycin (SD16, 1:4:2 ratios). For the solid dispersions; the decrease of Azithromycin crystallinity and

Acknowledgment

The paper is taken from a part of Pharm.D. Thesis of Ehsan Adeli, The International Branch, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

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