Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-22
2001-07-03
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C544S323000
Reexamination Certificate
active
06255316
ABSTRACT:
The present invention relates to several new, polymorphous crystal forms of dicyclanil, the hydrates and solvates thereof, as well as the preparation thereof.
Dicyclanil is used as a veterinary drug for the control of ectoparasites on domestic and farm animals.
The morphology and polymorphology of organo-chemical active substances is of great importance to the chemical and pharmaceutical development thereof. Substances are known which only appear in a single crystal form; in addition, however, there are also substances which can form two, three or even more polymorphous crystal modifications. It is just as difficult to calculate or predict this possible morphological and structural variety and the respective physico-chemical, especially thermodynamic stability respect thereof on a scientific-mathematical basis, as it is to calculate or predict their different behaviour when they are administered to a living organism. The relevant polymorphism of an organo-chemical substance is always unpredictable in respect of the number of crystal modifications, the stability thereof and their behaviour in a living organism.
If two, three or more crystal modifications of a substance are known, then in general their absolute and relative physico-chemical stabilities may be determined. The unstable crystal modification or unstable crystal modifications normally signify instead a disadvantage through the entire chemical and pharmaceutical preparation process, since in each step of the process or in each intermediate storage, a partial or total conversion to the more stable modification may take place. Due to their meta-stability, many unstable crystal modifications may be maintained for lengthy periods. However, they may also transform spontaneously into a more stable modification at an indeterminate point in time. Such transformation processes cannot be foreseen and each substance behaves in a different way in this respect. The different crystal modifications of one and the same substance may differ considerably from one another in many respects. These differences in morphology and polymorphism may have drastic effects on the development, transport stability and storage stability of individual administration forms, on the ability to produce different administration forms, on their application, on the solubility in polar or non-polar, protic or aprotic solvents, on solubility in blood serum, and finally on bio-availability.
The same also applies in respect of the physical and chemical properties of dicyclanil, a compound of formula
(2-cyclopropylamino-4,6-diaminopyrimidine-5-carbonitrile)
with a published melting point of 249-251°, which is disclosed in European Patent Specification EP-0 244 360 B1 both as a new compound and as an agent for the control of insects pests and ectoparasites on warm-blooded animals. Dicyclanil is effective as a growth regulator for insects and has special activity against Diptera species. Dicyclanil provides long-term protection of sheep against the widespread myasis flies such as
Lucilia sericata, Lucilia cuprina
and the like.
Application is preferably effected by means of the “pour-on” process, whereby the formulation is finely dispersed to the back of the sheep either directly or by a spray appliance. This type of application has considerable advantages, since only the exposed places are sprayed and effects on the environment are thus minimised.
It is precisely with formulations having suspended active substance, such as in the “pour-on” processes, that the different properties of the crystal modifications play a decisive role.
One crystal modification of dicyclanil is already known. Thus, the crystal form described in the above-mentioned publication is referred to hereinafter as modification A. Surprisingly, it has now been found that dicyclanil can occur in at least seven further, differing crystal modifications, hereinafter referred to as modifications B, C, D, E, F, G and H, whereby modification C has proved to be the crystalline dicyclanil hydrate and modification H the dicyclanil-propanediol solvate, which possess unforeseen, advantageous properties over the previously known crystal form. All eight forms are significantly distinct from one another in respect of their physico-chemical properties, their stability and, in part, their biological behaviour. The present invention relates primarily to the crystal modification D of dicyclanil, which is stable in non-polar and in mixtures of non-polar and polar dispersing agents, and is insignificantly soluble in these dispersing agents, and it relates to the production thereof.
In DSC (Differential Scanning Calorimetry), this new crystal modification D of dicyclanil shows a transformation in the temperature range of between 150° C. and 166° C. at a heating rate of 10° C./min. The temperature range and the kinetics of this conversion is dependent both on external measurement conditions and on different properties of the respective sample of dicyclanil. The preferred characterisation of crystal modification D of dicyclanil is effected by means of the interlattice plane distances d of an X-ray diffraction diagram:
d in [Å]: 11.4±0.2, 8.7±0.2, 7.1±0.2, 5.92±0.05, 5.75±0.05, 5.70±0.05, 4.45±0.05, 4.40±0.05, 4.15±0.05, 3.96±0.05, 3.94±0.05, 3.80±0.05, 3.78±0.05, 3.72±0.05, 3.53±0.05, 3.41±0.05, 3.32±0.05, 2.96±0.05, 2.92±0.05, 2.84±0.05 and 2.83±0.05.
The most intensive reflexes in the X-ray diffraction diagram thus give the following interlattice plane distances:
d in [Å]: 11.4±0.2, 8.7±0.2, 5.92±0.05, 5.75±0.05, 5.70±0.05, 4.15±0.05, 3.96±0.05, 3.80±0.05, 3.78±0.05 and 3.53±0.05.
The enthalpy change generally observed in the DSC for dicyclanil between 150° C. and 166° C. can be clearly explained by means of a heatable powder diffractometer using copper-K&agr; X-ray radiation. The crystal modification D, which is characterised by the above-indicated interlattice plane distances, is transformed at between 100° C. and 200° C. into another solid, which is expressed in a different set of interlattice plane distances.
This new specific crystal form D has superior properties over all other known crystal modifications of dicyclanil and its known hydrate. In particular, as a suspension in non-polar, or mixtures of non-polar and polar, dispersing agents, especially in mixtures of non-polar dispersing agents with water, the crystal modification D is physico-chemically and thermodynamically more stable than the other known modifications, including the hydrate, in the usual temperature range. For these reasons, crystal modification D is more suitable both for the development and production of the chemical substance in solid form and for the development and production of insecticide formulations or of preformulations thereof, and also in respect of the application thereof in the field. If all other known modifications of dicyclanil are suspended in non-polar or mixtures of non-polar and polar dispersing agents, a slow transformation of the modification, or of the hydrate or solvate, possibly also a spontaneous transformation, but generally an unpredictable transformation in terms of time and place, may take place, to form a more stable crystal modification. Transformations of solids of this kind are generally associated with a change in the crystal habit and with a change in size of the crystals. These changes lead to various, enormous defects, which, through sedimentation and/or separation of the suspension, end in formulations that can no longer be technically applied. In general, the insecticidal activity of such a formulation will no longer be detectable.
Crystal modification D is thermodynamically stable, but as indicated above, at a heating rate of 10° C./min. in a temperature range between 150° C. and 166° C., transforms into a crystal modification with a melting point range be
Geoffroy André Joseph
Marti Erwin
Oechslein Walter
Balasubramanian Venkataraman
Lee Michael U.
Novartis Animal Health US Inc.
Raymond Richard L.
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