Process for preparing a crystal suspension

Details Process for preparing a crystal suspension Process for preparing a crystal suspension

2000-11-17

2003-02-11

Lovering, Richard D. (Department: 1712)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Biocides; animal or insect repellents or attractants

C504S362000, C514S937000, C516S077000, C516S926000

Reexamination Certificate

active

06517853

ABSTRACT:

This invention relates to a crystallisation process and, in particular, to a process for producing a crystalline suspension of an organic compound in a liquid medium.
In many industries, especially in the agrochemical, pharmaceutical and biocide industries, active ingredients are often supplied in the form of suspension concentrates. These comprise a largely insoluble, particulate active ingredient suspended in a liquid medium, usually an aqueous medium. They are commonly prepared by ball or bead milling a millbase consisting of the active ingredient, liquid medium and one or more dispersing agents, and then formulated with additives and a volume-adjusting amount of the liquid medium. Additives may include, for example, antisettling or suspension agents, preservatives, antifoams, antifreezes and biological adjuvants.
It is important to industry to be able to provide fluid, storage stable concentrates without the need for stirred storage vessels or the use of thickeners to maintain the solid particles in suspension. A key factor in obtaining a physically stable product is the particle size of the suspended solid. Normally, the smaller the particle size, the more stable is the suspension.
Milling is a common technique for reducing the particle size of a suspended solid, but may not always produce the best results, and, because it generates considerable heat, may not always be appropriate, for example, where the active ingredient is a low melting solid.
An alternative technique is to crystallise the solid from an emulsion of the melted solid, or a solution of it, in the liquid medium. For example, it is known from E-P-A-0221465 to prepare suspensions by dispersing a melt above its solidification temperature in an aqueous phase and allowing the melt to solidify by cooling it below its crystallisation temperature. It is also known from DE-A-2551841 and DE-A-2900268 that a melt can be dispersed in an aqueous phase having a temperature below the solidification temperature of the melt. Dispersions of this type are produced using high speed stirrers or rotor-stator machines. The disadvantage of these processes is that they tend to give only coarse dispersions with short shelf lives, although finer dispersions may be obtained if, as described in EP-A-0399266, the initial emulsion is subjected to an additional homogenisation step.
In these emulsions, the melt is suspended in the aqueous phase in the form of droplets. If the droplets crystallise rapidly, the crystal size distribution will be the same as the original droplet size within the emulsion. Therefore, in theory, it should be possible to generate finer and more stable dispersions by reducing the droplet size. However, as the droplet size decreases, crystallisation becomes slower. Furthermore, the solubility of the droplet in the continuous phase increases with decreasing droplet size, due to higher pressures within the droplet. The effect of this is that the continuous phase concentration can rise to a level where it becomes supersaturated relative to the crystalline form, with the result that nucleation and crystal growth occurs in the continuous phase. As nucleation rates tend to be slow in the continuous phase, large crystals are generated which bear no resemblance to the original droplets. This is clearly undesirable if fine dispersions are to be obtained.
The use of ultrasound for crystallising melts and solutions is well known. For example, a process for the crystallisation of adipic acid from aqueous solution is known from U.S. Pat. No. 5,471,001. It is also known to use ultrasonics for preparing emulsions and fine droplet dispersions (see, for example, WO-A-94/20072). It has now been found that ultrasound can be used to generate finer particle size, more stable dispersions from emulsions.
Thus, according to the present invention there is provided a process for preparing a crystalline suspension of an organic compound which has a &Dgr;H/RT value in the range of from 1 to 10, the process comprising dispersing a melt of the organic compound in a liquid dispersion medium to form an emulsion, cooling the emulsion below the melting point of the organic compound and subjecting the emulsion to ultrasonic vibration.
The value &Dgr;H/RT is a well understood expression which means the enthalpy (heat) of fusion of a compound (&Dgr;H in kJmol
−1
) at the normal melting point of the compound divided by the molar gas constant (R, where R is 8.31451 Jmol
−1
K
−1
) and the melting point of the compound measured on the absolute or Kelvin scale (in °K). Thus, for example, the &Dgr;H/RT value of octadecane, which has a melting point of 28.2° C. and a heat of fusion of 61.39 kJmol
−1
(see the
CRC Handbook of Chemistry and Physics,
[1996-1997], 77
th
Edition. 6-138) is calculated as follows:
61.39/8.31451×10
−3
×(28.2+273.16)=24.5
The heat of fusion of a compound (&Dgr;H) may be measured by differential scanning calorimetry. A suitable method is described by McNaughton, J. L. and Mortimer, C. T. in IRS: Physical Chemistry Series 2, Butterworth, London 1975, Vol 10; subsequently reprinted by Perkin-Elmer Corpn. Norwalk, Conn., USA.
In a preferred aspect of the invention process, the organic compound has a &Dgr;H/RT value in the range of from 5 to 10.
The invention is of particular interest in the formulation of low melting agrochemicals, especially pesticides such as fungicides, insecticides and herbicides, and low melting pharmaceutical and biocide products as suspension concentrates. It will be evident, however, that the process is equally applicable to the preparation of a crystalline suspension of any other low melting organic compound.
Where the crystalline suspension is to be stored for long periods at ambient temperature, it is desirable that the organic compound has a mefting point above 20° C. and, preferably, above 30° C. However, the melting point should not be higher than the boiling point of he chosen liquid medium dispersion medium at its operating pressure. This pressure will be as high as it is reasonably practicable or economical to pressurize the apparatus being used. Thus, where the liquid medium is water, as will normally be the case, the organic compound may have a melting point of from 20° C. to 200° C., the upper temperature being possible where the apparatus is pressurized to around 10 bar. Suitably the organic compound will have a melting point of from 20° C. to 120° C. for example, from 30° C. to 100° C. and, typically, from 40° C. to 90° C.
The liquid dispersion medium, which may be any suitable liquid, for example, water or an agriculturally acceptable organic solvent that is benign to living tissue, will ideally have a crystallisation point of at least 10° C., suitably 20° C., below the crystallisation point of the organic compound, and a boiling point of at least the same order as the melting point of the organic compound, and preferably at least 5° C. above the melting point of the organic compound, for example, from 10° C. to 30° C. above. Of most interest, however, are those suspensions where the liquid dispersion medium is an aqueous medium and where the emulsion formed is an oil-in-water emulsion.
Conveniently, the organic compound is melted and heated to a temperature slightly above its melting point, for example 5° C. to 10° C. above, and added to the liquid dispersion medium heated to approximately the same temperature as the melt, ie within 5° C. or so. Alternatively, the organic compound may be added to the liquid medium at a temperature above or below the melting point of the organic compound, for example prior to heating to the melt temperature, and the temperature adjusted until the organic compound has melted.
Depending on the crystallisation properties of the organic compound, it may also be possible to add the melt to the liquid medium at a temperature below the melting point of the organic compound without further heating.
The concentration of the organic compound in the liquid dispersion medium will be up to 60% w/w, normally from

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