MXPA00000133A - POLYMORPHS OF 8-CHLORO-6, 11-DIHYDRO-11- (4-PIPERIDYLIDENE) -5H-BENZO[5,6]CYCLOHEPTA[1, 2-b]PYRIDINE - Google Patents

Abstract

Crystalline polymorphs of 8-chloro-6, 11-dihydro-11- (4-piperidylidene) -5H-benzo[5,6]cyclohepta[1,2-b]pyridine represented by formula (I), pharmaceutical compositions containing such polymorphs, and methods of using such polymorphs to treat allergic reactions in mammals such as man are disclosed.

Description

POLYMORPHOSES OF 8-CHLORINE-6,11-DIHYDRO-11- (4-PIPERIDILIDINE) -5H-BENZ? R5,61CICLOHEPTAH, 2-b1PIRlDlNA BACKGROUND OF THE INVENTION This invention relates to crystalline polymorphs of 8-chloro-6,11-dihydro-11- (4-piperidylidene) -5H-benzo [5,6] cyclohepta [1,2-b] pyridine (hereafter "decarbonylethoxyloratadine") ") represented by the formula pharmaceutical compositions containing said polymorphs, and methods for using said polymorphs to treat allergic reactions in mammals. U.S. Patent No. 4,659,716 discloses decarbonylethoxyioratadine having antihistamine properties, substantially without sedative properties. This U.S. Patent also discloses methods for making descarbonylethoxyloratadine and using it to treat allergic reactions in mammals.

To prepare pharmaceutical compositions containing descarbonylethoxyloratadine for administration to mammals in accordance with the health registration requirement requirements of the international health registration authorities and the United States, for example, the requirements of Good Manufacturing Practices (Good Manufacturing Practices) ("GMP") of the FDA, there is a need to produce descarbonyl-ethoxyloratadine in as pure a form as possible, especially a form that has constant physical properties.

SUMMARY OF THE INVENTION We have discovered that decarbonylethoxyloratadine can exist in the form of two distinct crystalline polymorphs, each having distinctly different physical properties. Accordingly, this invention provides crystalline polymorph of decarbonylethoxyloratadine Form 1 essentially free of polymorph Form 2, and characterized by the following X-ray powder diffraction pattern having characteristic peaks expressed in terms of space "d" and relative intensities ("IR"). ") to approximately: space d (± 0.04) IB 9.04 Weak 6.42 Weak 5.67 Weak 5.02 Weak 3.58 Weak This invention further provides crystalline polymorph of form 1 essentially decarbonyl-ethoxyloratadine-free form 2 polymorph, and characterized by the following X-ray powder diffraction pattern essentially free of charge. polymorph form 2, and having characteristic peaks expressed in terms of spaces "d" and relative intensities ("IR") (f = strong, m = medium, d = weak, mu = very and di = diffuse) to approximately: This invention further provides crystalline polymorph 2-form of decarbonylethoxyloratadine substantially free of polymorph form 1, and characterized by the following x-ray powder diffraction pattern having characteristic peaks expressed in terms of space "d" and relative intensity ("IR)" : space d (± 0.04) IR 8.34 Weak 6.87 Medium 6.20 Medium 4.90 Medium This invention also provides crystalline polymorph of decarbonylethoxyloratadine form 2 substantially free of polymorph form 1, and characterized by the following x-ray powder diffraction having characteristic peaks expressed in terms of of space "d" and relative intensities ("IR") f = strong, m = medium, d = weak, mu = very and di = diffuse) to approximately: fifteen BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 presents the infrared spectrum of crystalline polymorph 1-form of descabonyl-ethoxyloratadine as a mineral oil fertilizer. Figure 2 shows an infrared spectrum of crystalline polymorph form 2 of decarbonylethoxyloratadine as a mineral oil fertilizer.

DETAILED DESCRIPTION OF THE INVENTION The phase "polymorph form 1 essentially free of polymorph form 2" as used herein means that polymorph form 1 of descabonyl ethoxyloratadine prepared according to this invention contains less than about 1% form 2, as measured by infrared spectral analysis in an FTIR spectrometer. The polymorph Form 1 prepared according to Examples 1 and 2 had no detectable amount of Form 2 by FTIR spectrophotometry. The phrase "polymorph form 2 substantially free of polymorph Form 1" as used herein means that the polymorph Form 2 of descabonyl ethoxyloratadine prepared according to this invention contains less than about 15%, preferably less than about 10%, and with more preferably less than about 5-8% of form 1, as measured by infrared spectral analysis on an FTIR spectrometer.

Descabonyl-ethoxylotadine prepared as described in U.S. Patent No. 4,659,716 was isolated as the acetic acid salt (Example III) and as a mixture of polymorphs of the free base from hexane (see examples V + VI) . We have discovered that decarbonylethoxyloratadine exists as a mixture of polymorphs. Such a mixture could lead to the production of a decarbonyl-ethoxyloratadine product which would exist as a variable mixture of variable compositions (ie, varying percentage amounts of polymorphs) having varying physical properties, an unacceptable situation in view of the severe GMP requirements. We have discovered specific solvents and experimental conditions that consistently produce two distinctly different crystalline polymorphs of descarbonylethoxyloratadine, thereby allowing the commercial production of a consistent pharmaceutical product having constant physical properties. In the course of the development of pure crystalline polymorphs of decarbonylethoxyloratadine for a pharmaceutical composition prepared with the demanding requirements of the GMP regulations, we tested many solvent systems, most of which produced only mixtures of polymorphs. Surprisingly we discovered that certain alcohol solvents, eg, hexanol and methanol, produced 100% polymorph Form 1, but others, for example, 3-methyl-1-butanol and cyclohexanol produced significant amounts of form 2. Chlorinated solvents, for example , dichloromethane, produced form 1 substantially free of Form 2, but the compounds were dechlorinated. Ether solvents such as dioxane produced form 2 substantially free form 2, but other alkane ethers, eg, diisopropyl ether, gave form 1 with significant amounts of form 2, and di-n-butyl ether favored formation of form 2. Ketones such as methyl isobutyl ketone produced form-1 crystalline polymorph essentially free form 2, but methyl butyl ketone produced a ratio of 8: 1 form 1 to form 2. The use of methyl isobutyl ketone is preferred to produce crystalline polymorph form 1 essentially Form 2 free. It was found that only ethyl acetate and di-n-butyl ether produced crystalline polymorph form 2 substantially free of form 1. The use of di-n-butyl ether is preferred for the production of substantially free crystalline form 2 of form 1. The infrared spectrum of crystalline polymorph of decarbonylethoxyloratadine form 1, taken as a fertilizer in mineral oil, is characterized by the following three peaks. Acteristic (in reciprocal centimeters) not found in pure polymorph, form 2 to approximately: Frequency (cm "1) 3303 1290 803 780 A more complete infrared spectrum of crystalline polymorph of decarbonylethoxyloratadine form 1, taking as a fertilizer in mineral oil, is characterized by the following characteristic peaks (in reciprocal centimeters) at approximately: Frequency (cm" 1) 3303 3052 3012 1636 1586 1566 1357 1331 1290 1273 1249 1231 1177 1142 1119 1100 1086 1057 1029 1008 987 946 934 906 882 873 847 816 803 780 767 726 703 681 642 572 549 530 520 498 490 449 The crystalline polymorph infrared spectrum of decarbonyl ethoxyloratadine form 2, taking a mineral oil as fertilizer, is characterized by the following five characteristic peaks (in reciprocal centimeters) not found in the polymorph form 1 to approximately: Frequency (cm "1) 3326 Frequency (cm" 1) 1153 1133 795 771 655 A more complete infrared spectrum of crystalline polymorph of decarbonyl ethoxyloratadine form 2, taking as a fertilizer in mineral oil, is characterized by the following characteristic peaks (in reciprocal centimeters) to approximately: Frequency (cm "1) 3326 3304 3052 3015 1635 1586 1569 1558 1479 1456 1437 1420 1398 1383 1328 1301 1282 1250 1199 1174 1153 1133 1118 1089 1010 977 951 915 887 868 846 816 795 781 771 730 707 688 655 623 570 550 528 515 493 467 447 These infrared spectra were obtained in mineral oil fertilizers measured on a Mattson Galaxy 6021 FTIR spectrometer. The mineral oil fertilizers were prepared and placed between NaCI or KBr plates according to the USP < 197M > . See also "Experiments in Techniques of Olnfrared Spectroscopy", R. W. Hannah and J. S. Swinehart, Perkin-Elmer Coporation, September 1974, pages 6-1 to 6-6. The spectral information was presented in absorbance from approximately 3370 to 3250 cm "1. The area of the peaks at 3326 + 1 cm" 1 (form 2) was integrated for the ratio of form 2 to form 1. The powder diffraction patterns X-rays were measured in an APD3720 Philips automated diffractometer system (model PW 1800). The radiation source was copper (K-alpha), and the long thin focus tube connected to a Philips XRG 3100 x-ray generator operated at 45 KV and 40 mA. the exit angle was 6 degrees, and graphite monochromator was used. A scintillation detector was used, and the information was acquired with a tracking index of 0.025 degrees per second, a stage dimension of 0.010 and a stage time of 40 seconds per degree. The diffraction pattern of different x-ray powder for the crystalline polymorph form 1 of decarbonylethoxyloratadine, having characteristic peaks expressed in terms of space "d" and relative intensities ("IR") is given below: space d (+ 0.04) IR 9.04 Weak 6.42 Weak 5.67 Weak 5.02 Weak 3.58 Weak A more complete x-ray powder diffraction pattern for crystalline polymorph of decarbonylethoxyloratadine form 1 having characteristic peaks expressed in terms of "d" spaces and relative intensities ("IR") is given below: fifteen The distinctive X-ray powder diffraction pattern for crystalline polymorph form 2 having characteristic peaks expressed in terms of "d" spaces and relative intensities ("IR") is given below: space d (+ 0,04) JB 8,34 Weak 7,21 Average 6,87 Average 6,30 Average 4,90 Average A more complete x-ray powder diffraction pattern for polymorph of decarbonylethoxyloratadine form 2 having characteristic peaks expressed in terms of space "d" and relative intensities ("IR") is given below: fifteen PHARMACEUTICAL COMPOSITIONS The pharmaceutical compositions of this invention may contain in addition to an antiallergically effective amount of crystalline polymorph Form 1 or Form 2 of decarbonylethoxyloratadine as the active ingredient, inert pharmaceutically acceptable carriers which may be solid or liquid. The solid form compositions include powders, tablets, dispersible granules, capsules and suppositories. A solid carrier can be one or more substances which can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders or tablet disintegrating agents; It can also be an encapsulating material. In powders, the carrier is a finely divided solid that is in admixture with the finely divided active compound. In the tablet the active compound is in mixture with carrier containing the necessary binding properties in suitable proportions, and compacted in the desired shape and size. The powders and tablets preferably contain from about 5 to about 20 percent of the active ingredient. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. The term "compositions is intended to include the formulation of the active compound with encapsulating material as a carrier, provided a capsule in which the active component (with or without other carriers) is surrounded by carrier, which is so in association with it. Also, capsules are included. Tablets, powders, and capsules can be used as solid dosage forms suitable for oral administration. For the preparation of suppositories, a low melting wax is first melted as a mixture of fatty acid glycerides or cocoa butter, and the active ingredient is homogeneously dispensed therein, as by agitation. The molten homogeneous mixture is then poured into molds of suitable size, allowed to cool and thus solidify. Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water-propylene glycol or water solutions for topical administration. Liquid preparations can also be formulated in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use can be prepared by adding the active component in water, and adding suitable colorants, flavors, stabilizers, sweeteners, solubilizers and thickeners as desired. Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water, with viscous material, i.e., natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose and other well-known suspending agents. In addition, the topical formulation useful for nasal or ophthalmic administration is contemplated. Topical formulations suitable for nasal administration may be solutions or suspensions. The ophthalmic formulations can be solutions, suspensions or ointments. Ointments usually contain lipophilic carriers such as mineral oil and / or petrolatum. The solution for ophthalmic administration may contain sodium chloride, acid and / or base to adjust the pH, as well as purified water and preservatives. The antiallergic effective amount of polymorph Form 1 or Form 2 of descarbonylethoxyloratadine for topical administration varies from 0.1 to 5% by weight of the total pharmaceutical composition. The preferred amount ranges from 0.5 to 2% by weight of the total pharmaceutical composition. The effective antiallergic amount of polymorph Form 1 or Form 2 of descarbonyl-ethoxyloratadine for oral administration ranges from about 1 to 50 mg / day, preferably about 2.5 to 20 mg / day, and more preferably, about 5 to 10 mg / day in doses unique or divided. The most preferred amount is 5.0 mg, once a day. Naturally, the precise dosage and dosing regimen can be varied according to the requirements of the patients (eg, sex, age), as well as the severity of the allergic condition being treated. The determination of the appropriate dosage and dosage regimen for a particular patient will be within the ability of the attending physician. The polymorph Form 1 and Form 2 decarbonyl ethoxyloratadine possess antihistamine properties. These antihistamine properties have been demonstrated in standard animal models, such as prevention of histamine-induced lethality in guinea pigs. The antihistamine activity of form 1 and form 2 has also been demonstrated in a monkey model.

EXAMPLE 1 Preparation of polymorph Form 1 of decarbonyl-ethoxyloratadine To a solution of 60.0 kg of potassium hydroxide flakes in 200 liters of industrial methylated spirits was added 50.0 kg of loratadine (available from Schering Corporation, Kenilworth, NJ, see also US Patent No. 4,282,233). The mixture thus formed was heated under reflux for 3 hours, and 150 liters of water were added. The mixture thus formed was distilled at atmospheric pressure until the temperature of the mixture reached 108 ° C. The mixture was cooled to 68 ° C, and 150 liters of methyl isobutyl ketone (MIBK) was added and the mixture was stirred until all the solids dissolved. The organic layer was separated and washed with water at 80 ° C, until the separated aqueous layer had a pH of 9. Then fifty (50) liters of MIBK were removed from the organic layer by distillation at atmospheric pressure, and the organic layer formed that way it was cooled to around 0 ° C for 1 hour. The resulting crystalline product was separated by centrifugation, washed with 2 x 12 liters of MIBK at room temperature, and dry stirred in a high speed centrifuge. The product thus formed was dried at 60 ° C for 6 hours, to give 29.05 kg of polymorph Form 1 decarbonylethoxyloratadine as a white crystalline solid, e.g. F. 156.8-157.7. The structure of the compound of the statement was confirmed by comparing its IR and NMR with spectra of a reference standard.

EXAMPLE 2 Preparation of polymorph Form 1 of decarbonyl-ethoxyloratadine Loratadine (45 kg, 117 moles) was refluxed in approximately 180 liters of ethanol containing potassium hydroxide (approximately 40.5 kg, excess) for about 5 hours to complete carbomate hydrolysis (see also example VI of U.S. Pat.

No. 4,659,716). The warm reaction mixture was diluted with approximately 135 liters and distilled at atmospheric pressure, until a reaction mixture temperature of 105-110 ° C was achieved. The reaction mixture was then cooled to 50-70 ° C, diluted with approximately 135 liters of methyl isobuyl ketone (MIBK), and the mixture thus formed was reheated to 80-90 ° C to redissolve solids. The aqueous layer was separated, and the MIBK layer was washed with additional portions of water until a pH of 6-9 was achieved in the aqueous layer. The MIBK layer was then concentrated under atmospheric pressure, and slowly cooled to -5 -0 ° C as a crude crystallized decarbonylethoxyloratadine. The crude decarbonylethoxyloratadine was filtered, washed with MIBK, and dried at about 60 ° C, to yield approximately 33.5 kg (92% theory) of crude desacarbonyl-ethoxyratadine, which can also be taken to the next step as a wet block. Crude decarbonylethoxyloratadine (33.6 kg, 108 moles) was dissolved in approximately 135 liters of warm MIBK (85-95 ° C), filtered, and approximately 50 liters of the MIBK were distilled from the mixture under atmospheric pressure. The solution thus formed was then slowly cooled to 15-22 ° C, matured for about one hour, and the crystalline pulp resulting from decarbonylethoxyloratadine was filtered, washed with MIBK and dried at about 80 ° C, to produce 31 kg (92% yield ) of polymorph form 1 of decarbonylethoxyloratadine as a white crystalline solid. This white crystalline solid contained 100% of form 1, with no detectable amount of form 2 by FTIR spectrophotometry. The crystalline polymorph Form 1 was micronized using a fluid energy mill, and was packed in double polyethylene bags in a closed fiber drum with a metal ring.

EXAMPLE 3 Alternative preparations of polymorph Form 1 of descarbonyl-ethoxyloratadine A. To a 50 ml Erlenmeyer flask was added 3.3 g of decarbonylethoxyloratadine (prepared according to Example VI of U.S. Patent No. 4,659,716) and methanol (3.5 mL). The mixture formed in this way was heated until complete dissolution was obtained. The clear solution thus formed was allowed to cool slowly to room temperature, and kept at room temperature for 4 hours. The resulting crystalline product was filtered, washed with hexane (10 ml) and dried in a vacuum oven at 40 ° C under nitrogen for 24 hours, to provide 2.77 g of polymorph form 1 of decarbonylethoxyloratadine as a white crystalline solid, (DSC 157.30 ). B. To a 250 ml three-necked round base vessel equipped with overhead stirrer, thermocouple, and nitrogen gas source, 10 g of decarbonylethoxyloratadine (prepared as described in Example VI of USP 4.65) was added. .716) and 60 mi of MIBK. The mixture thus formed was heated to 105 ° C and the temperature was maintained at 105 ° C until complete dissolution was obtained. The solution formed in this way was slowly cooled to room temperature, to allow the crystalline product to precipitate out of the solution. The mixture thus formed was cooled to 5 ° C, and the temperature was maintained at 5 ° C for 1 hour. The solid was filtered under vacuum and washed with 2 volumes of MIBK (cooled to 5 ° C). The solid was dried in an oven at 50 ° C, until the loss in drying was 0-4% or less. Obtained 8.30 g of polymorph form 1 of descarbonylethyloxyratadine (100% by FTIR spectrophotometry) as a white crystalline solid.

EXAMPLE 4 Preparation of Plurorph Form 2 of Decarbonyl-Etoxyloratadine A solution of 366 g of decarbonylethoxyloratadine (prepared as described in Example VI of USP 4.65.716) in 3 liters of ethyl acetate was heated to reflux; 15 g of Darco decolorizing carbon and 25 g of Supercel filter aid were added, and the mixture thus formed was further refluxed for 10 minutes. The mixture was filtered while hot, through a Supercel filter mat. The filtrate was concentrated at an elevated temperature to 650 ml. The concentrated filtrate thus formed was rapidly cooled to 0 ° C. The resulting precipitate was filtered, washed with hexane and dried in an air stream oven at 55-60 ° C, to give 333.2 g of polymorph form 2 of decarbonylethoxyloratadine as a white crystalline solid, having m.p. 154.0-155.5 ° C, and containing 100% form 2 by FTIR spectrophotometry.

EXAMPLE 5 Alternative preparation of polymorph Form 2 of decarbonyl-ethoxyloratadine To a first container with a round base of three necks of 250 ml ("first vessel"), equipped with an overhead stirrer, thermocouple, and nitrogen gas source, were added 10 g of decarbonylethoxyloratadine (prepared as described in Example VI of USP 4.65.716) and 150 ml of di -n-butyl ether. The mixture thus formed was heated to 100 ° C and maintained at this temperature until all the solid material dissolved, and a clear solution was formed. To a second 250 ml three-necked round base vessel ("second vessel") equipped identically to the first vessel, 50 ml of di-n-butyl ether was added. The second vessel was cooled to -50 ° C. A cannula was connected to both vessels and the ends of the cannula were placed below the surface of the solutions in both vessels. Nitrogen pressure was applied to the first container sufficient to completely force the solution in the first container to the second container. The temperature of the second vessel was maintained below -20 ° C, and the very cloudy solution thus formed in the second vessel was stirred for five minutes. The resulting precipitate was filtered under vacuum. The solid was dried in a vacuum oven under a nitrogen atmosphere at room temperature. No heat was applied to avoid discoloration of the product. Seven (7) grams of polymorph Form 2 of descarbonylethoxyloratadine was obtained as a crystalline solid containing 92% (± 5%) of form 2 by FTIR spectrophotometry.

STABILITY EVALUATION FOR CRYSTAL POLYMORPHOST FORM 1 Samples of crystalline polymorph Form 1 prepared in accordance with this invention were subjected to stability evaluation at various temperatures (25, 30 and 40 ° C) and relative humidity of 60%, 60% and 75%, respectively. Tests were performed for Form 1 and related total compounds, including physical appearance, X-ray diffraction, FTIR (identity), FTIR (ratio of polymorphs) and pH. No significant change (< 1%) of% form 1 of initial sample and related compounds was observed.

Claims (18)

1. NOVELTY OF THE INVENTION CLAIMS 1. - Crystalline polymorph Form 1 of decarbonylethoxyloratadine essentially free of polymorph Form 2, and characterized by the following X-ray powder diffraction pattern having characteristic peaks expressed in terms of space "d" and relative intensities ("IR") at about: space d (+ 0.04) JR 9.04 Weak 6.42 Weak 5.67 Weak 5.02 Weak 3.58 Weak 2. - Crystalline polymorph of decarbonylethoxyloratadine Form 1 essentially free of polymorph Form 2, and characterized by the following X-ray powder diffraction pattern having characteristic peaks expressed in terms of "d" spaces and relative intensities ("IR") (f = strong, m = medium, d = weak, mu = very and di = diffuse) to approximately: 10 fifteen twenty 3. - The crystalline polymorph of form 1 of decarbonylethoxyloratadine of claim 1, further characterized by an infrared spectrum generated in a polymorph form 1 fertilizer in mineral oil, which shows the following characteristic peaks in reciprocal centimeters at approximately: frequency (cm "1) 3303 1290 803 780 4. - The crystalline polymorph of form 1 of decarbonylethoxyloratadine of claim 1, further characterized by an infrared spectrum generated in a fertilizer of form 1 polymorph in mineral oil, which shows the following characteristic peaks in reciprocal centimeters at approximately: frequency (cm "1) 3303 3052 3012 1636 1586 1566 1357 1331 1290 1273 1249 1231 1219 1201 1190 1177 1142 1119 1100 1086 1057 1029 1008 987 946 934 906 882 873 847 816 803 780 767 726 703 681 642 572 549 530 520 498 490 449 5. The crystalline polymorph 1 of the decarbonyl ethoxyloratadine of claim 2, further characterized by an infrared spectrum generated in a fertilizer of said polymorph forms 1 in mineral oil, which shows the following characteristic peaks in reciprocal centimeters at approximately: frequency (cm "1) 3303 1290 803 780 6. - The crystalline polymorph of form 1 of decarbonylethoxyloratadine of claim 2, which is further characterized by an infrared spectrum generated in a fertilizer of said polymorph form 1 in a mineral oil, which shows the following characteristic peaks in reciprocal centimeters at approximately: frequency (cm) "1) 3303 3052 3012 1636 1586 1566 1357 1331 1290 1273 1249 1231 1219 1201 1190 1177 1142 1119 1100 1086 1057 1029 1008 987 946 934 10 906 882 873 847 816 15 803 780 767 726 703 20 681 642 572 549 530 520 498 490 449 7. A pharmaceutical composition comprising an antiallergic effective amount of the crystalline polymorph decarbonyl ethoxyloratadine form 1 of claim 1, and a pharmaceutically acceptable carrier. 8.- Crystalline polymorph form 2 of decarbonylethoxyloratadine substantially free of polymorph form 1, and characterized by the following x-ray powder diffraction pattern having characteristic peaks expressed in terms of space "d" and relative intensities ("IR") at approximately: space d (± 0.04) iñ 8.34 Weak 6.87 Average 6.20 Average 4.90 Average 9. - Crystalline polymorph of decarbonylethoxyloratadine form 2 substantially free of polymorph form 1, and characterized by the following x-ray powder diffraction pattern having characteristic peaks expressed in terms of "d" spaces and relative intensities ("IR") (f = strong, m = medium, d = weak, mu = very and di = diffuse) to approximately: 10. The crystalline polymorph of decarbonyl-ethoxyloratadine form 2 of claim 8, further characterized by an infrared spectrum generated in a fertilizer of said polymorph form 2 in mineral oil, which shows the following characteristic peaks in centimeters at approximately: frequency (cm "1) 3326 1153 1133 795 771 655 11.- The crystalline polymorph of decarbonylethoxyloratadine form 2 of claim 8, further characterized by an infrared spectrum generated in a fertilizer of said polymorph form 1 in mineral oil, which shows the following characteristic peaks in reciprocal centimeters at approximately : frequency (cm "1) 3326 3304 3052 3015 1635 1586 1569 1558 10 1479 1456 1437 1420 1398 15 1383 1328 1301 1282 1265 20 1250 1199 1174 1153 1133 1118 1089 1010 977 951 915 887 868 10 846 816 795 781 771 15 730 707 688 655 623 20 570 550 528 515 493 467 447 12. The crystalline polymorph of decarbonyl ethoxyloratadine form 2 of claim 9, further characterized by an infrared spectrum generated in a fertilizer of said polymorph form 2 in mineral oil, which shows the following characteristic peaks in centimeters reciprocal at about: frequency (cm "1) 3326 1153 1133 795 771 655 13.- The crystalline polymorph of decarbonyl ethoxyloratadine form 2 of claim 9, further characterized by an infrared spectrum generated in a fertilizer of said polymorph form 2 in mineral oil, which shows the following characteristic peaks in reciprocal centimeters to approximately: frequency (cm "1) 3326 3304 3052 3015 1635 1586 1569 1558 1479 1456 1437 10 1420 1398 1383 1328 1301 15 1282 1265 1250 1199 1174 20 1133 1118 1089 1010 977 951 915 887 868 846 816 795 781 10 771 730 707 688 655 15 623 570 550 528 515 20 493 467 14. - A pharmaceutical composition comprising an anti-allergic amount of the crystalline polymorph of decarbonyl-ethoxyloratadine form 2 of claim 8 and a pharmaceutically acceptable carrier. 15. A pharmaceutical composition comprising an antiallergic amount of the crystalline polymorph of decarbonyl-ethoxyloratadine form 2 of claim 9 and a pharmaceutically acceptable carrier. 16. A pharmaceutical composition comprising an antiallergic amount of the crystalline polymorph decarbonyl-ethoxyloratadine form 1 of claim 2 and a pharmaceutically acceptable carrier. 17. The use of the crystalline polymorph decarbonyl-ethoxyloratadine form 1 of claim 1 for the manufacture of a medicament for treating allergic reactions in a mammal. 18. The use of the crystalline polymorph decarbonyl-ethoxyloratadine form 2 of claim 8 for the preparation of a medicament for treating allergic reactions in a mammal.