INTRODUCTION:

The oral route remains the preferred route of drug administration due to its convenience, good patient compliance and low medicine production costs. In order for a drug to be absorbed into the systemic circulation following oral administration, the drug must be dissolved in the gastric fluids. For hydrophobic drugs, it is this dissolution process which acts as the rate-controlling step and, therefore, determines the rate and degree of absorption. Consequently, many hydrophobic drugs show erratic and incomplete absorption from the gastrointestinal tract of animals and humans. Thus, one of the major challenges to drug development today is poor solubility, as an estimated 40% of all newly developed drugs are poorly soluble or insoluble in water¹. In addition, up to 50% of orally administered drug compounds suffer from formulation problems related to their high lipophilicity². As a result, much research has been conducted into methods of improving drug solubility and dissolution rates to increase the oral bioavailability of hydrophobic drugs. One way of improving dissolution involves the reduction of particle size and/or increasing saturation solubility. One of the most common approaches used to reduce particle size is milling, a mechanical micronization process. Milling is a well-established technique which is relatively cheap, fast and easy to scale-up.

However, milling has several disadvantages, the main one being the limited opportunity to control important characteristics of the final particle such as size, shape, morphology, surface properties and electrostatic charge. In addition, milling is a high energy process which causes disruptions in the drug’s crystal lattice, resulting in the presence of disordered or amorphous regions in the final product³. These amorphous regions are thermodynamically unstable and are therefore susceptible to recrystallization upon storage, particularly in hot and humid conditions⁴. The alteration of the surface properties also changes the milled product’s saturation solubility as well as blending and flow properties, which in turn, have an impact on the formulation process. Furthermore, milled particles often show aggregation and agglomeration which results in poor wettability and thus poor dissolution⁵. An alternative to milling involves growing the particle from a solution to the desired size range under controlled conditions, for example by spray drying, solvent-diffusion⁶ and supercritical fluid technology⁷. One of the advantages of these methods is the possibility of designing in certain beneficial characteristics such as enhancing dissolution rate by inclusion of surfactant or increasing the stability of amorphous material by incorporation of sugars.

In our research work, we have used spray drying in an attempt to enhance the dissolution rate of a model drug (Clarithromycin). As well as being an alternative to milling to reduce particle size, spray drying enabled the designing-in of features, such as improved particle wetting by the incorporation of small amounts of a surfactant (Poloxamer 407). In this paper, we report on the preparation and characterization of these particles and their in vitro dissolution profiles.

MATERIAL AND METHODS:

Materials:

Clarithromycin was a gift sample from Lupin Ltd (Pune). Poloxamer 407 (Pluronic F127) was a gift sample from Glenmark (Nasik). Dichloromethane (analytical grade) were obtained from Loba Chemicals (Mumbai)

Method

Clarithromycin microparticles containing the surfactant, poloxamer 407, were produced by spray drying a solution of dichloromethane containing clarithromycin and poloxamer 407. The solution was spray dried using spray drier (Labultima) at feed rate of 7.5 ml/min, air flow rate of 900 1/h, aspirator level at 80 %, inlet temperature of 50°C and outlet temperature of 29°C. The powder collected was stored in a desiccator until it was ready to be used. Batches are cited in table 1.

Characterization of microparticles:

The two batches of spray-dried particles were characterized in terms of morphology, size and drug release as described below.

Particle morphology:

Scanning electron microscopy (SEM) was used to determine particle shape. The spray-dried particles were fixed on an aluminum stub with conductive double-sided carbon tape, sputter-coated with gold at 30mA for 3 min and observed using a Philips/FEI XL 30 electron microscope.

Particle size analysis:

Particle size of microparticles was measured by photon correlation spectroscopy using Zetasizer (PCS3000, Malvern). The drug particles were suspended in filtered distilled water containing 0.05 % (w/v) 7polyoxyethylene sorbitan monooleate.

Fourier transform-Infra red spectra:

IR is useful tools for investigating structural properties of surfactant and drug. To ensure the compatibility of the drug with surfactant, preformulation studies were done using IR spectrum recorded on FT-IR (Perkin Elmer FT-IR system, spectrum BX) by preparing KBr disk.

In vitro dissolution studies:

The two spray dried clarithromycin formulations and pure drug were encapsulated in size 9 (length 8.6 mm, diameter 2.65mm and volume 0.025 ml) capsules such that each capsule contained 0.1gm of active drug. Dissolution studies were carried out using 0.1 N HCl pH 1.2 in a Type II (paddle) dissolution apparatus (Electrolab Model TDT 08L). The stirring speed used was 100 rpm and the temperature of the dissolution medium was maintained at 37±0.5 ◦C. The drug concentration in the dissolution medium was assayed spectrophotometrically (Jasco B530) at 210 nm every 15 min for 2 hrs. The percentage drug dissolved for each formulation was calculated.

Fig.1. SEM of Spray dried microparticles of clarithromycin (Batch B)

Fig. 2: Particle size distribution of clarithromycin microparticles (Batch B)

Fig. 3: IR spectrum of compatibility study of plain clarithromycin (Clari IR), plain poloxamer 407 (Polox IR) and formulation (Batch B)

RESULTS AND DISCUSSION:

Microparticle production and characterization:

Spray drying was found to be a suitable method for producing clarithromycin microparticles. The atomization of the clarithromycin /poloxamer 407 solutions, followed by the evaporation of dichloromethane resulted in the formation of particles. The spray- dried products collected from both formulations were white in color and fairly free-flowing. The yield obtained from both formulations was approximately 30%, which is fairly typical for small scale, bench top spray driers .It has been suggested that the main reasons for this poor yield are the design of the cyclone separator which cannot trap particles smaller than 2 $μ$ m, inadequate process conditions which cause the particles to adhere to the inner walls of the spray dryer and the small amount of materials being processed per batch.

Table 1: Formulation of clarithromycin microparticles

Batch code	Clarithromycin (% w/v)	Poloxamer 407 (% w/v)
A	1.5	0.05
B	1.5	0.1

Fig 4: In vitro drug release studies

Scanning Electron Microscopy:

SEM results of clarithromycin microparticles are shown in Fig. 1 which revealed that, microparticles prepared by spray drying method were spherical in shape with smooth surface.

Particle size analysis:

Particle size analysis of clarithromycin microparticles are shown in Fig. 2 was measured by Malvern zetasizer and found to be about 0.1 µm to 5 µm.

Fourier transform-Infra red spectra:

IR peaks of clarithromycin with the poloxamer 407 i.e. formulation (Batch B) are shown in Fig. 1 resemble almost same structural peaks of pure clarithromycin indicating the compatibility between the clarithromycin and poloxamer407.

In vitro dissolution:

The dissolution profiles of the spray dried clarithromycin particles and the pure drug are illustrated in Fig. 4.

Clarithromycin/Poloxamer 407 particles showed the fastest dissolution rate, with approximately 40 % of the drug being released within 15 min compared to 5% for the pure drug. The fact that the spray dried clarithromycin particles exhibited a faster dissolution rate than the pure drug shows that spray drying process itself was responsible for increased dissolution. Spray drying has been shown to reduce the aggregation tendencies of particles compared to milling⁸, reduced aggregation leads to improved wetting and hereby increased dissolution rate.

Improved wetting ability of the poloxamer 407 containing particles could be observed during the dissolution studies. Once the gelatin capsule had dissolved, the spray dried clarithromycin /poloxamer 407 particles dispersed rapidly within the dissolution medium, in contrast to the pure drug which showed aggregation and floating of a portion of the particles on the surface of the dissolution medium throughout the experiment.

CONCLUSION:

Spray drying was used to produce particles of the model drug clarithromycin in an attempt to improve the drug’s dissolution rate. Small amounts of hydrophilic surfactant, poloxamer 407, were incorporated into the particles in an attempt to enhance particle wetting. Dissolution studies showed the spray- dried particles with Poloxamer 407 had the higher dissolution rate than the pure drug. This indicated that both the spray drying process and the inclusion of the hydrophilic surfactant contributed to enhanced dissolution rates.

REFERENCES:

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Received on 28.08.2009 Modified on 23.10.2009

Research J. Pharm. and Tech. 3(1): Jan.-Mar. 2010; Page 199-201