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The present invention relates to a novel crystalline modification of fipronil, to a process for the preparation of the same, to pesticidal and parasiticidal mixtures and compositions comprising said crystalline modification and to their use for combating pests and parasites.
Fipronil (formula I) is an active compound for controlling certain insect and acarid pests, and parasites.
Various processes for the preparation of fipronil have been described, generally and in detail. Documents which give detailed preparation procedures are e.g. EP 295 117; EP 460 940; EP 484 165; EP 668 269; EP 967 206; EP 1 331 222; EP 1 374 061; U.S. Pat. No. 5,631,381; CN 1374298; or J. of Heibei University of Science and Technology, Vol. 25 (2), Sum 69 (2004), Dok. Serial No. 1008-1542 (2004) 02-0018-03.
Fipronil is an insecticide that has been registered for use by the EPA in the U.S. since 1996. It is used to ward off fleas, ticks and other insects.
Characterization of the fipronil material obtained by the processes described in the prior art is usually done by 1H-NMR analysis and/or measurement of the melting point. The described melting points are in the range of from 187° C. to 203° C., mostly in the range of from 195° C. to 203° C. In the Pesticidal Manual, 13th Edition (2003), British Crop Protection Council, p. 433, fipronil manufacturer is described as a white solid with a melting point of 200 to 201° C., with technical fipronil having a melting point of 195.5° C. to 203° C. Observations of different crystalline forms of fipronil have not been described, let alone any characterization of a certain crystalline modification or a preparation procedure for obtaining a certain crystalline modification.
Fipronil stops regular nerve function by blocking gamma-aminobutyric acid receptors in the central nervous system. This GABA receptor neural system helps prevent over-stimulation of the nerves by blocking some neural activity. When Frontline containing Fipronil is applied topically to your cat, it is stored under your cat's skin in the oil glands. This makes Frontline waterproof as it continuously releases the Fipronil through your cat's hair follicles.
For the large-scale preparation and formulation of a market compound such as fipronil, it is of crucial importance to know whether different crystalline modifications (also frequently referred to as polymorphs) of a compound exist, how they can be obtained, and what their characteristic properties are. Crystalline modifications of one compound may have very different properties, for example with regard to solubility, rate of dissolution, suspension stability, stability during grinding, vapour pressure, optical and mechanical properties, hygroscopicity, crystal size, filtration properties, desiccation, density, melting point, degradation stability, stability against phase transformation into other crystalline modifications, colour, and even chemical reactivity.
Common adverse reactions in cats from Frontline containing Fipronil, are chemical burns to the site where the topical was applied, hair loss, lethargy, behaviors such as running in circles, hiding, agitation, crying and excessive grooming.
For example, different crystalline modifications frequently manifest themselves in different forms of the crystals, such as needles or plates. This is of relevance for e.g a leading to loss of time and being needles can have significantly different bulk densities which has implications for storage and packaging. Another the powder which can produce hazardous dusts, or as dust-free larger crystals. Different modifications of fipronils have different essentially excluding other crystalline modification forms (i.e. in over 80% by weight). This ensures reproducibility and stability in all aspects of the production, transportation, storage and use of the corresponding solid state form.
Accordingly, a novel crystalline modification of fipronil, a process for its preparation, pesticidal and parasiticidal mixtures and compositions comprising it and its use for combating pests and parasites has been found. The novel crystalline modification of fipronil is defined as “novel crystalline modification V” throughout this application.
Also, most surprisingly, 3 other crystalline modifications of fipronil have been found, which are subject to co-pending patent applications. Especially surprising was that the present crystalline modification V of fipronil has a very similar melting point as a second crystalline modification I, both melting points lying in the range of the melting points given in the prior art (i.e. 195 to 203° C.). Moreover, two further crystalline modifications II and IV of fipronil chemical , as described in co-pending applications, undergo phase transformations during heating into the more stable forms I and V, and thus in a typical melting point measurement will give the melting points of these forms I and V. The solid forms of fipronil thus are part of a very complex crystallization scenario. It can be concluded that the melting points given in the literature in no way can indicate which crystalline modification or crystalline modification mixtures were analyzed.
In T 605/02, the Technical Board of Appeal of the European Patent Authority ruled that, in the absence of a respective described preparation procedure, even the XRD pattern of a certain crystalline modification does not constitute prior art for lack of enablement. Thus, melting points given in documents published prior to the filing of this application cannot be regarded as prior art for the present invention as they do not enable the artisan to prepare the novel crystalline modification of fipronil . source:townhallfipronil
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