Elsevier

Powder Technology

Volume 128, Issues 2–3, 18 December 2002, Pages 188-194
Powder Technology

Spherical agglomeration during crystallization of an active pharmaceutical ingredient

https://doi.org/10.1016/S0032-5910(02)00196-1Get rights and content

Abstract

Lobenzarit disodium (LBD) salt is a drug used in the treatment of rheumatoid arthritis diseases. The objective of this work is to propose and validate a method for selecting the best wetting agent allowing to obtain spherical agglomerates during crystallization. This method is based on the so-called Washburn's test (capillary rise of liquids in a granular medium). Crystallization tests carried out at different conditions showed that the best results were obtained in the presence of n-hexane that was effectively found to be a better wetting liquid of the lobenzarit crystals than the other solvents.

Introduction

The direct compression is a modern method in tablet manufacturing. Many processing steps (granulation, drying, etc.) are limited in direct compression, and additionally, wet technology cannot be used with sensitive agent (e.g., in effervescent tablet-making) [1]. The direct compression of a powder depends on its particle size and size distribution, and in connection with this, on its flowability, consistent with the production rates of modern compression technology and also on its bulk density. Some drug crystals exhibit appropriately such properties, but many materials have very poor flowability and compressibility [2]. For tablet-making from the latter materials, possible solutions may be the use of wet granulation [3] (if this is possible with regard to the drug stability) or the use of direct tablet-making with “good” excipients which promote direct compression (though this might not be favorable in terms of powder flow). Another solution is to generate directly, during the crystallization step, spherical agglomerates of drug crystals with good flowability and compressibility properties. This last possibility recently came into the forefront of interest because the habit of the particles (shape, size, size distribution, specific surface area, etc.) can be changed by crystallization processes.

During the 1970 decade, Kawahima and Capes [4] suggested to obtain the size enlargement of particles during the crystallization step, controlling the crystals agglomeration with the goal to obtain spherical agglomerates with controlled properties. This was possible by two methods:

  • the first one is known as spherical agglomeration (SA) and consists of precipitating fine crystals of drug substance then aggregating them using a nonmiscible liquid (so-called the wetting agent);

  • the second method is referred as emulsion solvent diffusion (ESD). In this method, a quasi emulsion is formed by droplets of solvent containing the drug. The continuous phase is a liquid in which the drug is nonmiscible. Crystallization occurs inside the droplets because of the counter diffusion of the solvents through the droplets.

The two methods, SA and ESD, are both spherical crystallization techniques. By using these techniques, spherical agglomerates with controlled diameters can be produced [5].

SA method proceeds in three steps. The first one is the selection of the crystallization method to precipitate crystals from solution, i.e., thermal methods (temperature decrease or evaporation), physicochemical methods (addition of another solvent, salting out) and chemical reaction. The second step is the choice of the wetting agent that will be nonmiscible with the solvent of crystallization. Finally, the third step is the hardening of the agglomerates. In the literature, there are many papers about the application of this method, and possible mechanisms, but the methodology for selecting wetting agent is not yet clear.

The active ingredient studied in this paper was the lobenzarit disodium (disodium 5-chloro-2,2′-iminodibenzoate, Na2C14H8ClNO4). It is a drug designed for treatment of rheumatoid arthritis. It exerts a prophylactic or therapeutic effect against development of spontaneous arthritis and nephritis. This drug produces an improvement of immunological abnormalities and has a regulatory effect on the antibody-producing system [6], [7], [8].

The aim of this work is to investigate the feasibility of capillary test to select the wetting solvent during spherical agglomeration process. A relative scale of the different solvents possible to carry out the spherical agglomeration was found and the results were tested by SA experiments at the laboratory scale.

Section snippets

Theory

The method used in this work is the capillary rise of liquid in columns of packed powder. This method, following Washburn's equation, is based on Poiseuille's law [9] relative to the liquid flow through capillary. For a Newtonian fluid, the rate of ascension ν of the liquid (covered distance h during a period t) in a cylindrical tube of R in radius and L in length is related to the flowrate of the liquid Q under the Laplace pressure exerted by capillary effect, ΔP=(2γ/R)cos θ, where θ is the

Materials

Lobenzarit disodium (LBD) was used as the raw material (synthesis Laboratory of the Center of Pharmaceutical Chemistry, Cuba) with purity of 99.5%.

The liquids used in this work are bi-distilled water, hexane, octane, acetone, methanol, ethanol, isopropyl alcohol, decane, cyclohexane, chloroform and dichloromethane with purity between 99.5% and 99.7%.

The solubilities of LBD in these different solvents were determined previously by a classical method of dissolution [13]. The results are reported

Contact angles between organic solvents and lobenzarit crystals

The curves m2 versus time were obtained for several organic solvents during their ascension into the bed of lobenzarit disodium (LBD) particles (Fig. 2), and their slopes were determined for the stationary state. The comparative results of wetting of particles of LBD by several solvents were reported in Table 3 (the measurements were carried out at 25 °C).

According to these results, n-hexane was the best wetting agent for LBD particles because when n-hexane is taken as the reference solvent

Conclusion

As expected from the obtained relative wettability scale, n-hexane was a possible wetting agent allowing to obtain spherical agglomerates of lobenzarit disodium salt with an enhanced narrow size distribution. However, two other important parameters must be taken into account to conclude on the feasibility of spherical crystallization: the stirring rate and the temperature.

In fact, the spherical agglomeration process of lobenzarit disodium involves three steps:

  • the dispersion of the wetting

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