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.Frontline Top Spot is a flea and tick pesticide containing the active ingredient fipronil, created by drug manufacturer Merial. Frontline products are generally considered safe for healthy pets, but it can have side effects, especially in the very young, sick, or elderly pets. Pet owners who choose Frontline products should be aware of the possible side effects that can occur with the use of fipronil as a topical pesticide.
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.Characterization of the fipronils 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 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 is the active ingredient in all Frontline products, including Frontline Top Spot. It is a pesticide used topically for flea and tick control, effectively killing fleas and ticks on dogs and cats within 18 to 48 hours after the initial application. Fipronil is also used as an ingredient in other pesticides, such as ant bait, roach bait and to kill termites.
Accordingly, a novel crystalline modification of fipronil manufacturer , 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 I??? throughout this application.
While most animals do not have an adverse reaction to Frontline Top Spot, fipronil does have known side effects. The most common side effects are drowsiness and irritation, itching, or hair loss in the area where the Frontline Top Spot was applied. Other more serious side effects include vomiting, increased salivation or excessive drooling, changes in the heart rate, decreased appetite, diarrhea, site irritation, lethargy, muscle tremors, decreased coordination and convulsions.
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 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.
While serious side effects are not considered common, they do occur in a small percentage of animals. The risks are higher in sick or elderly animals, and the risk of side effects is also higher in pets under the age of 8 weeks. The makers of fipronil also caution against using their products on pregnant or lactating animals, or if you plan to breed your animal within 30 days of treatment with any Frontline products.
Also, most suprisingly, 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 I of fipronil has a very similar melting point as a second crystalline modification V, 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, as described in co-pending patent 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 II. 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.
Fipronil has been proven to be systemically absorbed, and according to Virginia Dobozy, a veterinarian at the United States Environmental Protection Agency, fipronil products are classified as carcinogens, as studies showed that laboratory animals treated with pesticides containing the active ingredient fipronil have produced malignant (as well as benign) tumors in laboratory tests.
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