MXPA97003622A - A new solid form physically stable in unafluoroquinol - Google Patents

Abstract

The present invention relates to a compound comprising the crystal form of acid [S- [R *, S *)] - 1-cyclopropyl-6-fluoro-1,4-dihydro-8-m-ethoxy-7- [3 - [1- (methylamino) ethyl] -1-pyrrolidinyl] -4-oxo-3-quinolonecarboxylic acid, having the formula shown below, and having a range in the presentation of the fusion, as determined by the Calorimetry of Differential Exploration (DSC), between the temperatures of 190§C and 202

Description

A NEW PHYSICALLY STABLE SOLID FORM OF A FLUOROQUINOLONE BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to the field of antibiotic quinolones, in particular, a new crystal form of a fluoroquinolone called, acid (S- (R *, S *)] - l-cyclopropyl- 6-fluoro-4-dihydro-8-methoxy-7- [3- [1- (methylamino) ethyl] -l-pyrrolidinyl] -4-0X0-3-quinolinecarboxylic Description of the information Patent WO93 / 15070 (Chugai), describes a new form of crystalline quinolone.This form is considered to be "stable against moisture." Patent JO 1242582 (Hokuriku), describes a new form of crystalline quinolone, document ES2006099 (Investchemi), The preparation of a dihydrate of the quinolone antibiotic ciprofloxacin In the publication of B. Sustar, N. Bukovec, and P. Bukovec, J. Therm.Anal.40, "Polymorphism and Stability of Norfloxacin, l-Ethyl-6-acid. fluorole, 4-dihydro-4-oxo-7- (l-piperazinyl) -3-quinolonecarboxylic acid, "pages 475 to 481 (1993). discovery of a more stable polymorph of a structural analogy of norfloxacin. In the publication of A.V., Katdare; J.A. Ryan; J.F. Bavitz, Mikrochim and Associates. "Characterization of hydrates of norfloxacin", Acta, (1986) Vol. 3 (1-2), pgs. 1 to 12. Three hydrated forms of norfloxacin are discussed, the dihydrate has the highest stability at room temperature. United States Patent 4,521, 4321, issued June 4, 1985, describes forms 1 and 2 of ranitidine hydrochloride. Background of the Invention Structures of the quinolone type are known for their antibacterial properties, and some quinolone antibiotics (eg, norfloxacin and ciprofoxacin) are found on the market. The physical properties of commercial quinolone are very important. A quinolone with excellent antibiotic properties, but that has a shelf life of just one day, which would be useless. A quinolone with excellent antibiotic properties, but that does not dissolve in a usual solvent, which could be equally useless. Quinolones, when purified, can form crystals or shapes sim to crystals that may have different physical shapes and properties. Solids, including pharmaceuticals, often have more than one form of crystal and this is known as polymorphism. Polymorphism occurs when a compound crystallizes in a multiplicity of solid phases, which differ in its packed crystals. Numerous examples are cited in the standard references of solid state properties of pharmacists, published by S.R. Byrn, in the article "Solid-State Chemistry", by Academic Press of New York, (1982); the publication of M., Kuhnert-Brandstatter, in the article "Thermomiscrocopy In The Analysis of Pharmaceuticals", by Pergamon Press, New York, (1971) and J. Pharm. Sci., 58, 91 1 (1969). Byrn states that, in general, polymorphs exhibit different physical characteristics, including solubility and physical and chemical stability. Due to differences in molecular packaging, polymorphs may differ in the ways they influence drug release, solid-state stability, and pharmaceutical manufacturing. The relative stability and interconversions of polymorphs are particularly important for the selection of a drug that is purchased in the market. A suitable polymorph can depend on the emission of physical stability. For example, the selection of a medicine purchased in the market may depend on the availity and selection of a suitable polymorph, having the desired characteristics, such as excellent physical stability. The efficacy of a dose in solid form, should not be limited by the polymorphic transformations during the life in the warehouse of the product. It is important to note that there are no safe methods to predict the observable crystal structures of a given drug, or to predict the existence of polymorphs with desirable physical properties. The present invention describes a new form of a quinolone having highly desirable physical properties for pharmaceutical development.

SUMMARY OF THE INVENTION The present invention comprises a compound containing the crystal form of [S- (R *, S *)] - l-cyclopropyl-6-fluoro, 4-dihydro-8-methoxy-7- [ 3- [l - (Methylamino) ethyl-l-pyrrolidinyl] -4-oxo-3-quinolicarboxylic acid, which we refer to as "quinolone", which has the following formula, and that has a range of presentation of the fusion, between 190 and 202 ° C, or between 195 and 201 ° C, or of entare 198 and 201 ° C, determined by Differential Scanning Calorimetry (DSC), depending on the purity or as shown in FIGURE 5, or having the X-ray Diffraction pattern, which is described in Table III or having the X-ray Diffraction pattern as shown in FIGURE 4. The present invention, it also comprises a pharmaceutical composition, which includes this same crystal form of the quinolone.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is the powder pattern of lightning diffraction X (XRD), of Form 1. Figure 2 is the absorption of the moisture of the quinolone of Form 1, tested by means of gravimetric measurements in a controlled atmosphere. Figure 3 is the powder pattern of the ray diffraction X (XRD), of Form II.

Figure 4 is the dust pattern of X-ray diffraction (XRD), of Form III. Figure 5 is the DSC profile of the quinolone, of Form III. Figure 6 is the quinolone moisture absorption of Form III, tested by means of gravimetric measurements in a controlled atmosphere. Figure 7 is the unique XRD powder pattern of the methanol solvate. Figure 8 are DSC profiles of the quinolone of Form I. Figure 9 (A) shows heat flow profiles for Forms I and III. Figure 9 (B) shows heat flow profiles for Forms I and III. Figure 10 shows DSC profiles of the quinolone, from the Form I.

Additional Description of the Invention Definitions and Methods Several standard methods are described. The following definitions and explanations are for the terms as they are used throughout this document, including both the description and the claims. Optical Microscope The drug is examined with a Stereomicroscope Wild M5, from 6X to 50X magnification. The medical samples are mounted dry, or in a variety of selected liquid medium, such as mineral oil, silicone oil, Cargille MeltMount and water. The usual and crystallized particle size is examined with a Nikon Optihot clear polarized microscope, or in a Olympus BHSP polarized light microscope, from 40X to 600X magnification. Thermal Micoroscope A polarized light microscope, Nikon POH-2, with a 10X magnification objective is used to observe the dry samples mounted between the glass slide of the microscope and a cover of the No. 1 1/2 slide. The samples are heated from room temperature to a temperature of 250 ° C in a Mettler FP-80 micro-oven, controlled by a Mettler Fp-8 microprocessor. The heating ranges can vary from 5 ° C to 20 ° C per minute. The heating stage experiments can be videotaped (Sony T 120-HG tape and PM VHS tape) with a Hitachi VK-C350 Color Video Camera and a Panasonic Ag-6200 Video Recorder. X-Ray Diffraction of the Powder (XRD): The Rigaku DMAX-A X-ray diffractometer is used to acquire the XRD powder pattern. The instrument is operated with copper radiation K-L3 at 1.5406 Á. The main instrument parameters are programmed as follows: 40 KV voltage, 30 mA current, opening of the light beam of 1 ° and opening of the detector (opening reception) of 0.30 °. The patterns are examined in a range of two theta angles from 3 ° to 4 °, with a scanning index of two theta angles of 1.5 ° per minute (step size of 0.05 ° and counting time in 2 seconds per step). ). The samples are ground to obtain fine powders and packed in an aluminum tray. Differential Scanning Calorimetry Differential scanning calorimetry (DSC) is used to monitor enthalpy changes, as a function of temperature during a linear increase in temperature. An integrated DuPont 910 DSC can be used for a TA Instruments TA2100 computer. The scan rate is 5 ° C per minute, and the instrument is operated with dry nitrogen purged at 50-80 ce per minute. The samples are encapsulated in vessels with hermetically sealed aluminum samples, with a pressure in a range of approximately 2 bars. In some experiments, the lids of the vessels are perforated to allow the passage of moisture and other volatile components. Because the calorimetric samples are occasionally affected by the moisture residue, sometimes the samples are studied with different initial water activities. Samples are weighed in DSC tared vessels, and for a few days, open vessels are allowed to equilibrate, in chambers of constant relative humidity of 25 ± 1 ° C. These chambers are prepared from saturated salt solutions at 53% RH and 75% RH. At the end of the calibration period, the chambers are opened, and the caps are placed on the samples to prevent a re-calibration with the ambient atmosphere. The samples are removed from the chambers, and the vessels are closed by folding them quickly.

Dynamic Gravimetry of Moisture Absorption The dynamic humidity taken is studied in a controlled atmosphere microbalance system at 25 ° C.

Approximately ten mg. of the sample are balanced on a scale, for approximately 2 hours at 25% RH. The relative humidity surrounding the sample is increased with increments of 3% RH, up to approximately 92% RH, to such a point that the RH is decreased by 3% of the steps, for a final RH of approximately 2.5% In each of the relative humidities, the sample is allowed to equilibrate until the mass is stable within 0.0005 mg. in a period of ten minutes. It is assumed that the dry mass corresponds to the mass of the sample, before the initial equilibration period. A controlled atmosphere balance is a balance system described by M.S. , Bergren in Int. J. Pharm. (1994), Vol.103, pages. 103 to 1 14. Micro hygrostat ( A small glass container, which has a volume of approximately 0.5 ml, inside which is a saturated salt solution. If the salt is sodium chloride, for example, the relative humidity that is inside the container will be maintained at 75%.

When a micro-hygrostat is placed inside another container, the salt will dissolve or crystallize in such a way that the moisture inside the larger container will be balanced to the humidity of the micro-hygrostat. HPLC Test Conditions A Hewlett-Packard 1090 liquid chromatograph, equipped with a ChemStation control, is used to determine chemical purity. The separation of the tested compound with the related compounds is carried out, using a pack of 3 microns YMC ODS-AQ 3, in a 4.6 x 100 mm column, at room temperature. The mobile phase consists of 75% (100 mM phosphoric acid, 46 mM tetrabutylammonium hydroxide with pH3): 25% (methanol, tetrahydrofuran, acetonitrile in volumetric proportions of 837/93/70). The mobile phase is pumped at a rate of 0.7 ml per minute. The detection is carried out, by means of monitoring the UV absorbance at 298 nm. The injection volume is 10 μl. Bulk drug samples are prepared by dissolving the material in a mobile phase at a final concentration of approximately 0.25 to 0.5 mg / ml. For the solubility experiments, aliquots of 100 mcl, of ethyl acetate solutions, are melted and placed directly into the HPLC sample vials. A gentle stream of nitrogen gas is used to evaporate the solvent in the vials that contain the sample. Prior to analysis, the solids are reconstituted with 0.05 ml of a mobile HPLC phase. Solubility Solubilities are measured in ethyl acetate. Five to ten milligrams of bulk medication are placed in an amber automatic injection vial, and 3.0 ml of ethyl acetate is added. The vials are capped and shaken at intervals of up to 24 hours at room temperature, using a Burrell manual-shaker model BB. After centrifugation, the aliquots are taken from the surface. The final sample is taken from a solution at rest, which has not been stirred for 24 hours. Isothermal Calorimetry Isothermal calorimetry (ITC) experiments are conducted using a microcalorimeter manufactured by ThermoMetric (see J., Suurkuusk,, Wadso, in Chem. Ser. (1982), Vol 20, pp. 155 to 163) . Software version 2. 1 of The Digitam (R) manufactured by Termometric, is used for the data to appear on the screen and integrate the total heat obtained from the samples. The heat flow is monitored as a function of time in temperatures of 60 ° C and 40 ° C. Both laboratory glassware and stainless steel are used to support solid samples and reference material (quartz sand). Before recording the data, the samples are thermally balanced for a period in the range of 15 minutes (glass laboratory ampules), up to 1 hour (stainless steel plates). The weight of the samples is within the range of 75 to 300 mg. The samples in the glass laboratory ampoules are equilibrated by means of the isopiestic method at 53% and 75% RH, in chambers containing saturated solutions of sodium chloride or calcium nitrate tetrahydrate. The laboratory ampoules are covered immediately after removing the samples. Other samples are balanced, using "microhigrostats" that contain small amounts of saturated salt solutions, which are sealed inside the laboratory ampoules. This arrangement provides an almost constant relative humidity in the form of conversion of the processed crystal.

Enthalpies of the Solution The enthalpies of the solution are determined in 50 mL of 0.1 M HCl at a temperature of 25.0 ± 0.05 ° C. The samples (0.10 -0.1 1 g) are weighed in 2 ml spherical soft glass laboratory ampoules and dried overnight in a desiccator evacuated over P2? 5 > Laboratory ampoules are removed, covered, weighed and sealed by flame. The enthalpies of the solution are measured in a calorimeter of Tronac model 458 isoperibol solution. The accuracy of the calorimetry of this instrument is within 1%, based on calibration with aminomethane tris (hydroxymethyl) (TRIS) at 0. 1 N of HCl. It is understood that in the event that the additional standard terms and definitions are not provided in the present description, these will be considered as those generally accepted by those skilled in the art. All temperatures are in degrees Celsius. HR is Relative Humidity. HPLC is High Liquid Chromatography Resolution. When a pair of solvents is used, the proportions of the solvents used are volume / volume (v / v). When the solubility of a solid in a solvent is used, the ratio of the solid to the solvent is weight / volume (w / v).

COMPOUNDS OF THE PRESENT INVENTION The acid [S- (R *, S *)] - l-cyclopropyl-6-fluoro, 4-dihydro-8-methoxy-7- [3- [1- (methylamino) ethyl] - l-pyrrolidinyl] -4-oxo-3-quinolonecarboxylic acid, is a member of the quinolone antibiotic family. Its molecular structure, is shown by any of the following formulas, (the stereochemical orientation is indicated) For purposes of this description, the compound represented by the above formulas will be referred to as, "the quinolone compound". Studies on the quinolone compound have revealed three polymorphic forms of anhydrides, Forms I, II and III, as well as a methanol solvate form, the MS Form. Only one form, Form III, is stable for transformation, the other two forms of anhydrides, Forms I and II, and the Methanol Solvate form, MS Form, go through transformation phases under a variety of conditions. Preparation of Form III The material of Form III can be prepared by dissolving the quinolone in hot methanol and slowly distilling it, displacing the methanol with a non-polar solvent, which has a higher boiling point. The quinolone should be sparingly soluble, only in the solvent that is displacing methanol. The different solvents that can be used for this purpose are ethyl acetate, butyl acetate, toluene, heptane, etc. In one example Form III is obtained by dissolving 2.7 g of Form I, in 50 ml of hot methanol, and clarifying it by means of filtration in a glass funnel. The yellow rinsed solution is distilled to remove approximately 25 ml of methanol, and 50 ml of ethyl acetate is slowly added during the continuous distillation of methanol. After distillation of the other 40 ml of solvent, another 50 ml of ethyl acetate is added, and continuously distilled until the vessel reaches a temperature of 74 ° C. The colorless white precipitate is filtered hot in a glass funnel, washed with 2 x 25 ml of ethyl acetate, and dried in a vacuum oven, to obtain 2.0 g of Form III. The Methanol Solvate, is also known, as the MS Form, and as the methanolate. . The most stable form, Form III, can not be directly crystallized from methanol. We came to the conclusion of the existence of a methanol solvate, when we failed to crystallize the more stable form, Form II, from methanol. The methanol solvate form is produced when a quinolone compound is isolated using methanol, in the form of a solvent in the crystallization step. After taking care to avoid desolvation, we isolated the methanol solvate. The methanol solvate is prepared, dissolving the quinolone compound in methanol (200 mg of the quinolone, Form I, in approximately 8 ml of working methanol, and then sealing the suspension in a glass jar, and heating it with a steam bath to achieve The sample is allowed to cool overnight, and the crystals are collected by vacuum filtration the next morning.The form of methanol solvate, Form MS, or metonolate, has a subtle influence on the appearance and characteristics of Form I. The methanolate forms are easily obtained, and this makes the growth of the stable anhydrate, Form III, in methanol impossible.The methanolate desolvates, produce Form I, under such subtle conditions, that the solvate is not normally retained in the crystals produced.The methanolate is discovered, only after it is learned that Form III can not grow from methanol.Thus, Form I is either However, it is the product of a solid state desolvation process that produces a hygroscopic polymorph capable of physical transformation. Another method of isolation is the use of ethyl acetate as a solvent in the crystallization step. The use of ethyl acetate in the final step of the reaction produces Form III, when ethyl acetate is used, no solvate is produced. The solid Form III produced has a unique combination of increased stability and decreased hygroscopicity, thus, a surprising, very useful and unexpected type of quinolone crystal was produced, which it had never before created or described. Forms I. II. v III. If Form I is heated slowly, under the appropriate conditions, Form II is produced, at a temperature in the range of 140 ° C to 151 ° C, which, with additional heating under the appropriate conditions, produces Form III in a melting / recrystallization range from a temperature of 166 ° C to a temperature of 171 ° C. Microscopically, Form II seems to become the sample of Form I, through growth from the present crystal seeds. In Form I samples, where the initial water activity is at least 53% RH, direct conversion from Form I to Form III occurs without the formation of Form II. The conversion is observed at temperatures as low as 40 ° C in the microcalorimeter. The conversion rate increases dramatically, for samples initially balanced at 75% RH at room temperature. These samples are completely converted to Form III in less than a day, at a temperature of 60 ° C. The dried samples of Form I become the Forms II and III, through a sequence of fusions and recrystallizations. It is possible to directly transform the quinolone compound, from Form I into Form III without any occurrence of Form II. The samples of Form I, sealed and humidified, are transformed directly into Form III, through a process of solid state mediated by moisture. Form III is stable for transformation, but the other two forms, Form I and II, go through transformation phases under a variety of conditions. Form III is the preferred form for pharmaceutical preparations. Form III can be isolated directly in the form of a solid by recrystallization from hot ethyl acetate. However, the material produced from Form III is not contaminated with the other solid phases. Form III, is recommended for pharmaceutical preparations, because it is the most stable form of quinolone compound found to date, and it is less hygroscopic than Form I. Form I is an energetic, low fusion, polymorph related with Form III crystal more stable. Form III grows directly from the fact that the solution is lower in Gibbs free energy, by approximately 7.7 kJ / mol, and lower in enthalpy by approximately 8.8 kJ / mol, than Form I. The difference in hygroscopy of the two forms is dramatic. Above 80% RH, Form I absorbs enough moisture to irreversibly transform into an apparent monohydrate, while Form III absorbs less than 0.5% moisture, through the full range of RH. Form III is more stable than Form I, but it is also less soluble than Form I. Form I is approximately 20 times more soluble than Form III in ethyl acetate at room temperature.

CHARACTERIZATIONS OF DIFFERENT FORMS Form I Form I is isolated in the form of a faded white fine powder. Microscopically, the material is crystalline, (that is, it exhibits one or more of the following properties: regular interfacial angles, divided planes, or birefringence), but the particles are asymmetric and occur in solid aggregates of compact mass and in layers in the form of needle Larger aggregates appear dark when transmitting light, because scattered light causes misaligned crystals and multiple layers. Normally, an incomplete parallel extinction is observed in polarized cross-light. Two indices of refractories are measured: nmjn = 1.563 and nmax = 1.591. The purity of a sample of the material of Form I is 99.2%, based on the analysis of the minor components, including water, impurities related to drugs (HPLC), and residue in the ignition. The total HPLC impurities are determined by the method described in the paragraph on HPLC Tests above. A value of 0.20% is obtained per area, when a relative response factor of 1.0 is assumed for the individual impurities. A pattern of X-ray diffraction powder (XRD) of Form I is shown in FIGURE I. The narrow and low-background peaks of the diffraction profile indicate that the material is highly crystalline. The diffraction pattern does not change after Form I is exposed to 75% relative humidity at room temperature for 5 days. The profile of moisture absorption of Form I is shown in FIGURE 2. The sample is moderately hygroscopic at ambient relative humidity: the humidity reached is from 1% to 70% RH. Only above 80% RH, moisture absorption increases significantly. The humidity in the sample reached a maximum of approximately 7.5-7.7% w / w from 90% to 92% RH. As the RH decreases, the moisture content drips approximately 4.9% to 80% RH. The moisture content gradually decreased to the intermediate RH, at approximately 4.3% to 10% RH. The maximum stable humidity in the desorption profile, is close to the water content of 4.46% of the ideal monohydrate. Detailed description of FIGURE 2. FIGURE 2 shows the absorption of the quinolone human form I, by means of gravimetric measurements in a controlled atmosphere. The ordinate represents the relative change of mass for the lowest measure of the mass. The abscissa is relative humidity. The circles represent the recorded points, after consecutive increases in relative humidity and the charts were recorded after decreases in relative humidity. The horizontal line in the middle of the line corresponds to the water content in the hypothetical quinolone monohydrate. Form II To obtain Form II for X-ray analysis, we heat a sample of Form I to the temperature of 150 ° C at 5 ° C / minute in a TGA oven. The resulting material is moderately crystalline with a different XRD pattern, shown in FIGURE 3. The XRD profile of the heated material consists of the characteristics of Form II, at 20 angles about 17.4 with minor characteristics, and 10 attributed to the Form I. Form III The material of Form III can be prepared, dissolving the quinolone in hot methanol and slowly distilled, displacing the methanol with a non-polar solvent, having a higher boiling point. The quinolone should be only sparingly soluble in the solvent that displaces methanol. The different solvents that can be used for this purpose are ethyl acetate, butyl acetate, toluene, heptane, etc. In one example, Form III is obtained by dissolving 2.7 g of Form I in 50 ml of hot methanol and clearing it by means of filtration through a glass funnel. The yellow rinsed solution is distilled to remove approximately 25 ml of methanol and 50 ml of ethyl acetate is added slowly during the continuous distillation of methanol. After distillation of the other 40 ml of the solvent, another 50 ml of ethyl acetate is added, and it is distilled continuously until the vessel reaches a temperature of 74 ° C. The precipitate is filtered hot in a glass funnel, washed with 2 x 25 ml of ethyl acetate, and dried over a vacuum oven to yield 2.0 g of Form III. The crystals of Form III grow from the ethyl acetate, as described above, appearing in the form of a faded white powder. The power of the HPLC analysis is 98.2% for this material, in relation to the material of Form I, used as a standard. The TGA, showed that the small volatile matter (including approximately 0.1% of water by means of KF) is present in the samples of Form III; a mass loss of less than 0.3% was observed, up to the melting point (data not shown). Microscopic examination revealed crystalline ribbons and elongated plates of small sizes, generally less than 20 μm. The largest aggregates are also present. The complete parallel extinction is observed in crossed polarized light. Three main refractive indexes are measured, na = 1.527, n? = 1.70 and n? = 1.8. The birefringence is, therefore = 0.27. The XRD and DSC confirmed the distinctive character of this sample and established the absence of measurable quantities in the other phases. The dust pattern shown in FIGURE 4 reflects the highest crystalline nature of the sample. The characteristics of the peaks of Forms I and II are absent. The DSC profile of Form III is shown in FIGURE 5. Due to the instrumental differences and changes in the pure samples, the presentation of the melting point can change values within the range of 190 ° C to 202 ° C. If the compound is reasonably pure, it is expected that the range will be from 195 ° C to 202 ° C. Generally speaking, impurities compress the melting point below the normal melting range. The fusion for this particular sample of Form III was observed at a reported temperature of 198.7 ° C. The enthalpy of the fusion is approximately 150 J / g. The absence of transitions at low temperatures confirmed the absence of Forms I and II and other potential forms. Detailed description of FIGURE 5. The DSC profile of the quinolone, of Form III. The ordinate is heat flow, in units of Watts / gram, and the abscissa is the temperature in units of ° C. The heating rate is 5 ° C per minute. Form III absorbs less moisture than Form I of all relative humidity. The balance of the moisture absorption profile for Form III is shown in FIGURE 6. There is very little hysteresis between the absorption and desorption profiles, and the sample displayed is not evidence of recrystallization and / or hydrate formation. . Detailed description of FIGURE 6. FIGURE 6 shows the absorption of moisture of the quinolone, of Form III, by means of gravimetric measurements in a controlled atmosphere. The ordinate represents the relative change of the mass to the lowest measure of the mass. The abscissa is relative humidity. The circles represent the points recorded after consecutive increases in relative humidity and the squares were recorded after decreases in relative humidity. The horizontal line in the middle of the trace corresponds to the water content in a quinolone monohydrate. The Methanol Solvate The only XRD powder pattern of this sample is shown in the upper part of FIGURE 7. This methanol solvate can be desolvated by heating under vacuum at a temperature of 70 ° C for 5 hours to produce Form I. The Y axis of the FIGURE 7 is intensity, and the X axis is, the two angles theta. Transitions of the Different Forms Thermomicroscopy and DSC, discovered a sequence of thermal transformations, starting from Form I and proceeding through two additional solid phase transitions, prior to the final fusion. The DSC profile of Form I is shown in FIGURE 8. Endothermic and exothermic fusions at a temperature of 140 ° C to 150 ° C and at a temperature of 165 ° C a 180 ° C, represent combined fusion / recrystallization events *.

The final endothermic melting at the temperature of 200 ° C is followed by extensive exothermic decomposition of the melt. These assignments are confirmed by means of thermomicroscopic observations of Form I in heating rates at a temperature of 5 and 10 ° C per minute. The designations of the crystal form are based on the sequence of the thermomicroscopic transformations. The melting / recrystallization at the temperature of 143 ° C to 151 ° C, is assigned to Form I - transformation to Form II, and the second melting / recrystallization at a temperature from 166 ° C to 171 ° C, is assigned to the transformation of the Form II in Form III. The fusion of Form III, occurs at a temperature between 190 ° C and 202 ° C, the fusion of pure samples, between a temperature of 195 ° C and 202 ° C, that of the purest samples is presented in a temperature of between 195 ° C and 201 ° C, and those of the purest samples of all occurs at a temperature between 198 ° C and 201 ° C. Thermomicroscopic observations provided evidence that both Form II and Form III appeared from the crystal seeds present in the fusion of Form I. The growth of Form II is relatively rapid compared to growth of Form III. Detailed description of FIGURE 8. FIGURE 8 shows the DSC profiles of the quinolone, of Form I. The ordinate is the heat flux in units of watts / gram, and the abscissa is the temperature in units of ° C. The heating rate is 5 ° C per minute, (a.) The sample is encapsulated in a standard DSC vessel. (b.) The sample is encapsulated in a hermetically sealed DSC vessel. For comparison, the profiles are neutralized, along with the axis of the ordinate. ITC revealed that Form I converted to Form III at temperatures as low as 40 ° C. Our first ITC results, obtained at the temperature of 60 ° C, suggested that the conversion rate at this temperature is sensitive to water. Therefore, we study the transformation of the samples after equilibration at 51% and at 75% RH. The heat flow profiles for these samples are shown in FIGURE 9 (a). The conversion rates from Form I to Form III, differ significantly between these two samples; The index is lower in HR of 51%, than in a HR of 75%, by approximately two orders of magnitude.

Both the XRD and the DSC confirmed that the high moisture sample has been completely converted to Form III. HPLC analysis of the reaction product confirmed that the ITC profiles at the temperature of 60 ° C contained insignificant contributions from chemical decomposition. The changes in the enthalpy, for the microcalorimetric transformation is obtained by means of the integration of the heat flow, during the time required to convert the sample. The average of the three results obtained at the temperature of 60 ° C, is 18.3 J / g, or 7.4 kJ / mol. The low humidity sample illustrated in FIGURE 9 (a) had a change in the integrated enthalpy of approximately 10 J / g after 80 hours. The XRD results confirmed that the sample is a mixture of Forms I and p. The data at the temperature of 40 ° C, are shown in the FIGURE 9 (b). The initial exothermic characteristic is the same, due to the moisture absorption that the medicine has, diminished by both, the heat of the vaporization of the mixture from the microhygrostat, as well as the crystallization of a small amount of NaCl. The broader exotherm begins in about 6 hours, and ends in about 5 hours, which is the sum of the heat of transition from Form I to Form III, and the heat of desorption of the water from the crystals produced. As the moisture content of the crystals recovered from Form III is 0.61%, and the initial water content of the sample of Form I is 0.54%, there is a small heat exchange in the general profile, because the moisture is taken and released. In this way, we integrate the complete profile, as shown in FIGURE 9 (b), to roughly calculate the heat of the conversion of the Crystal Shape. Our result is expressed as = 20.4 J / g or = 8.2kJ / mol; the inequality is the result of our inability to integrate the initial heat flow profile, in the balanced sample form, and our lack of crystal seed knowledge of the initial concentration of Form II and Form III. A detailed explanation of FIGURE 9 is as follows. The trace "(a)" shows the heat flux on the Y axis, in units of microwatts per gram, in the form of a function of time in hours on the x axis. The trace (a) is registered for a sample of Form I, balanced at 75% relative humidity before sealing the sample container and exposing them to 60 ° C temperature conditions in the calorimeter. The trace (b), is registered for a sample of Form I at a temperature of 60 ° C, but at 75% of relative humidity "microhigrostat", it is placed in the container of the sample, only before the samples are registered. data. The conversion of the trace (a), is delayed due to the fact that the water must be transported from the microhygrostat to the Form I crystals, during the experiment. The trace (c), is registered from the sample of Form I at the temperature of 60 ° C, but the sample is balanced at 53% relative humidity, before the sample container is sealed. The trace "(b)" shows a flow of heat over the y-axis, in units of microwatts per gram in the form of a function of time in hours on the x-axis. This trace results from placing 75% of the relative humidity of the microhygrostat in the sample container just before the data is recorded. The sample is exposed to 40 ° C conditions in the calorimeter; the heat flow results in the shape of the material of Form I that becomes Form III. Interestingly, we never observed Form II in the microcalorimeter, as a product of the transformation of Form II. Apparently, the presence of absorbed moisture provides a direct low temperature route for conversion to Form III, without promoting the growth of Form II. Form I was not converted to Form III, under dry conditions, even after being greater than 7 days at the temperature of 40 ° C / 50% RH, or after 5 days at a temperature of 60 ° C. That humidity that influenced the conversion of the phases is also illustrated by the results of three DSC scans in FIGURE 10. The scan (a) represents the sample balanced at 53% RH, and sealed a perforated DSC vessel. This scan shows a sequence of transitions comparable to those shown in FIGURE 8. In contrast, scans (b) and (c) represent samples encapsulated in hermetically sealed DSC vessels, where moisture is retained through the DSC scanner. . In exploration (b), where the drug is equilibrated at 53% RH, the sample is fused and recrystallized in a temperature range of 140 ° C to 150 ° C, and finally fused as Form III at a temperature of 200 ° C. A very small change in the range from a temperature of 165 ° C to 175 ° C, is observed in the second transformation. Since exploration (a) revealed that the conversion of Form II to Form III is exothermic, we conclude that the transformation to the temperature of 140 ° C to 150 ° C makes a direct transformation of the Form probable. I to Form III: When the drug is equilibrated at 75% RH [Screening (c)], the only visible transformation prior to the fusion of Form III, is a small exotherm at the temperature of approximately 130 ° C. We speculate that sufficient moisture is present in the sample to generate a rapid conversion of Form I into Form III in the pre-fusion region for Form I. The DSC trace does not provide evidence that any Form II, is formed in this sample. Detailed description of FIGURE 10. FIGURE 10 shows the DSC profiles of the quinolone, of Form I. The ordinate is heat flow in units of watts / gram and the abscissa is temperature in units of ° C. The heating rate was 5 ° C per minute, (a.) The sample was balanced at 53% RH, and encapsulated in a standard DSC vessel. (b.) The sample was equilibrated at 53% RH and encapsulated in a hermetically sealed DSC vessel (c.) The sample was equilibrated at 75% RH and encapsulated in a hermetically sealed DSC vessel. For the comparison the profiles were neutralized together with the axis of the ordinate. The solubilities of Form I and III were determined in ethyl acetate at room temperature; The solubility data for each form were simultaneously collected to ensure that each solubility of the form was measured under identical conditions. Ethyl acetate was used in the form of an aprotic solvent, producing the just balanced solubilities of the quinolone; Ethyl acetate was used to evaluate the difference in free energy of the polymorphic forms of an antinociceptive drug, such as described by K. Raghavan and Associates, in J. Pharm. Biomed. Anal. Volume 12 (6), pages. from 777 to 785 (1994). The results are obtained in TABLE S, which is found later. Under the assumption that the solubilities in TABLE S are consistent with the diluted solution limit, we can use the following expression to calculate the difference in free energy Gibbs, between Form I and Form III: AOh -? R in »? F (i) where "sx" is the solubility of Form x, in a sufficiently diluted solution, R is the constant gas, and T is the absolute temperature. Using the data in Table 1, we find that the free-energy Gibbs of Form III are lower than those of the Form I by 7.7 - 0.2 kJ / mole. The difference in solubilities is completely significant, being more of the energy of Form I than 20 times more soluble than the energy of Form III more stable. This difference and the difference noted in the hygroscopic demonstration, point out that the two forms have a total difference of properties. A particular advantage of Form III in this aspect, physical stability in storage for a long time, which can be predicted. Form I has a different risk, that is, shapes can change, possibly causing the suspension to fill or a poor dissolution of the solid dosage forms. These differences demonstrate the obvious advantages of using Form III, in the form of a medically antibiotic.

TABLE S. The solubility of quinolone, from Forms I and III, in ethyl acetate at the temperature of 20 ° C.

Concentration in mg / ml Time (hours) Form I Form III 1 2.89, 2.78 0.06, 0.09 2 2. 18, 2.99 0. 1 1, 0. 1 1 4.5 3.01, 3. 1 1 0. 12, 0. 12 18 3.02, 3.08 0. 14, 0. 14 24 3.24, 3.32 0. 15, 0.15 67.5 < * * i! f. 4fc H "0. 14, 0. 14 The following examples are intended to be illustrative, and not to limit in any way, the present invention.

EXAMPLES Preparation of Form I. The quinolone (295 g) is dissolved in 4 liters of methanol under reflux and rinsed by filtration through a glass funnel. The filtrate is allowed to cool to room temperature for 1 hour, and then cooled to the temperature of 0 ° C for 1 hour. The formed solids are collected in a glass funnel, and dried in a vacuum oven at a temperature of 50 ° C at a constant weight, to produce 94 g of crystalline Form I. This material is characterized extensively. Preparation of Form III. Form III is obtained by dissolving 2.7 g of Form I in 50 ml of hot methanol and clearing it through a glass funnel. The yellow rinsed solution is distilled to remove approximately 25 ml of methanol and 50 ml of ethyl acetate are slowly added during the continuous distillation of methanol. After the distillation of another 40 ml of solvent, another 50 ml of ethyl acetate are added, and they are continuously distilled until the temperature of the vessel has reached 74 ° C. The colorless white precipitate is filtered hot in a glass funnel, washed with 2 x 25 ml of ethyl acetate, and dried in a vacuum oven to yield 2.0 g of Form III. Preparation of Methanol Solvate, Form MS. The methanol solvate is prepared by dissolving 200 mg of the quinolone of Form I in approximately 8 ml of methanol. The suspension is sealed in a glass jar and heated in a steam bath to achieve complete dissolution. The sample is allowed to cool overnight and the crystals are collected by vacuum filtration the next morning. To prevent spontaneous desolvation in the absence of methanol vapor, the inlet of the collection funnel is connected to a tube passing air through a bubbler flask containing 50/50 v / v mixture of methanol / butanol. Butanol is added to this mixture, to reduce the activity of methanol vapor. About 100 mg of crystals are collected. The XRD patterns of the quinolone, of Forms I, II, III and MS are provided in tables I, II, III to IV below. For these tables * is the diffraction peak of the aluminum trays of the sample, # indicates the relative intensity for each peak, which is determined by means of the proportionality of its intensity and the strongest peak at an angle of 17.40 degrees as 100 TABLE I. Characteristics of the XRD Diffraction peaks of Form I. Two Angles theta Spacing D- Relative Intensity # (degrees) (Angstrom) (arbitrary) 38.40 * 2,342 19 38.20 2,354 19 24,35 3,652 54 22.75 3,906 16 21.70 4,092 46 21.45 4.139 61 19.45 4.560 27 18.90 4.692 21 18.05 4.911 18 17.40 5.093 100 15.25 5.805 23 12.05 7.339 15 11.95 7.400 15 10.65 8.300 80 10.35 8.540 56 9.65 9.158 68 TABLE II Characteristics of the diffraction peaks of the Form II.

Two Angles theta Spacing D- Relative Intensity # (degrees) (Angstrom) (arbitrary) 38. 40 * 2,342 23 38. 15 2,357 4 1 27.55 3,235 22 25.50 3,490 100 23.50 3,783 73 22.35 3.975 28 21.75 4.083 25 21 .35 4. 158 23 20. 15 4.403 4 1 18.70 4.741 24 17.45 5.078 19 16.00 5.535 15 15.50 5.712 17 14.70 6.021 27 14.35 6. 167 16 9.30 9.502 71 8.75 10.098 52 TABLE III. Characteristics of the XRD Diffraction peaks of the Form III.

Two Angles theta Spacing D- Relative Intensity * (degrees) (Angstrom) (arbitrary) 38. 40 * 2,342 7 38,20 2,354 6 35.25 2,544 6 33,65 2,661 7 29.85 2,991 6 28.15 3 167 1 1 26.35 3,380 6 25.90 3,437 7 23.95 3.713 8 23.40 3.799 10 23. 10 3.847 28 22.45 3.957 13 21.50 4. 130 100 19.75 4.492 9 18.65 4.754 12 17.80 4.979 14 14.40 6. 146 8 13.90 6.366 20 9.80 9.0181 61 TABLE IV. Characteristics of the XRD Diffraction peaks of the MS Form.

Two Angles theta Spacing D- Relative Intensity * (degrees) (Angstrom) (arbitrary) 38. 40 2,342 20 38. 10 2,360 37 28.75 3 103 16 27.95 3 190 28 27.45 3,247 15 26.55 3,355 28 26.45 3,367 25 24.70 3,602 15 23.60 3,767 32 22.60 3,931 35 22,45 3,957 31 2 1,05 4,217 13 19.85 4,469 16 19.50 4,549 70 17.85 4.965 30 17.40 5.093 63 14.25 6.2 10 12 12.85 6.884 1 1 8.70 10. 156 100

Claims (8)

1. R E I V I N D I C A C I O N S 1. A compound comprising the acid crystal form
2. (S- (R *, S *)] - l-cyclopropyl-6-fluoro, 4-dihydro-8-methoxy-7- [3- [l- (methylamino) ethyl] -l-pyrrolidinyl] -4 -oxo-3-quinolonecarboxylic, which has the formula shown below, and that it has a range in the presentation of the fusion, as determined by the Differential Scanning Calorimetry (DSC), between the temperatures of 190 ° C and 202 ° C. 2. The compound as described in Claim I, further characterized by having a range in the presentation of the fusion, determined by the Differential Scanning Calorimetry (DSC), between the temperatures of 195 ° C and 201 ° C.
3. 3. The compound as described in Claim 2, further characterized as having a range in the presentation of the fusion, determined by the Differential Scanning Calorimetry (DSC) between the temperatures of 198 ° C and 201 ° C.
4. 4. The compound as described in Claim 2, further characterized in that it has a DSC profile, as shown in FIGURE 5.
5. 5. A compound containing the crystal form of acid [S- (R *, S *)] - l-cyclopropyl-6-fluoro, 4-dihydro-8-methoxy-7- [3- [l- (methylamino ) ethyl] -1-pyrrolidinyl] -4-oxo-3-quinolonecarboxylic acid, which has the formula shown below, and that it has an X-ray Diffraction pattern, which is described in TABLE III.
6. 6. The compound as described in Claim 5, further characterized by having a range in the presentation of the fusion, determined by the Differential Scanning Calorimetry (DSC), between the temperatures of 190 ° C and 202 ° C.
7. 7. The compound as described in Claim 6, further characterized by having a Ray Diffraction pattern X shown in FIGURE 4. A pharmaceutical composition, which contains the quinolone crystal form of Claim 5. EXTRACT OF THE INVENTION The new crystal forms of fluoroquinone, [S- (R *, S *)] - l-cyclopropyl-6-fluoro, 4-dihydro-8-methoxy-7- [3 ~ [l - (Methylamino) ethyl] -l-pyrrolidinyl] -4-oxo-3-quinolonecarboxylic acid. The forms are characterized by means of a methanol solvate form, and three forms of polymorph anhydrides, of which, Form III exhibits the most important stability and decrease in hygroscopicity.