Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C251/72—Hydrazones
  • C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
  • C07C249/16—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of hydrazones
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

• the present disclosure relates to polymorph forms of a pharmaceutical active agent.
• the present disclosure relates to polymorph forms of neuroprotective agent 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide (J147).
• 2,2,2 -trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide (J147) is a potent orally active neurotrophic agent discovered during screening for efficacy in cellular models of age-associated pathologies and has a structure given by Formula I:
• J147 is broadly neuroprotective, and exhibited activity in assays indicating distinct neurotoxicity pathways related to aging and neurodegenerative diseases, with EC50 between 10 and 200 nM. It has been indicated to improve memory in normal rodents, and prevent the loss of synaptic proteins and cognitive decline in a transgenic AD mouse model.
• the present disclosure is directed to a crystalline Form II of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide (J147), and methods of making thereof.
• Certain embodiments of the present disclosure provide a method of making crystalline Form II of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3- methoxyphenyl)methylene] hydrazide (J147), having a powder X-ray diffraction pattern comprising peaks located at 13.37, 18.47, and 23.34 +/- 0.2 degrees 2-theta, the method comprising: providing a slurry comprising saturated amorphous or crystalline Form I of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide (J147) in a solvent/anti-solvent mixture; and mixing the slurry to provide crystalline Form II.
• Certain embodiments of the present disclosure provide an isolated crystalline Form I of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3- methoxyphenyl)methylene]hydrazide (J147), having a powder X-ray diffraction pattern comprising peaks located at 11.85, 17.11, 17.79, and 23.40 +/- 0.2 degrees 2-theta.
• FIG. 1 shows the X-ray Diffraction (XRD) diffractogram of crystalline Form I of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene] hydrazide (J147).
• XRD X-ray Diffraction
• FIG. 2 A shows a differential scanning calorimetry (DSC) thermogram of crystalline Form I of J147.
• FIG. 2B shows a thermogravimetric (TGA) thermogram of crystalline Form I of J147.
• FIG. 3 A shows dynamic vapor sorption isotherms of crystalline Form I of J147 using TGA.
• FIG. 3B shows kinetic plots of crystalline Form I of J147 using TGA.
• FIG. 4 shows the Fourier transform infrared (FTIR) spectrum of crystalline Form I of J147.
• FIG. 5 shows the Raman spectrum of crystalline Form I of J147.
• FIG. 6 shows proton nuclear magnetic resonance (NMR) spectrum of crystalline Form I of J147.
• FIG. 7 shows graphical output using Debye cone integration using a two dimensional detector during XRD analysis of a sample of J147.
• FIG. 8 shows a dendrogram of all XRD results in screening samples of J147.
• FIG. 9 shows a cell plot of all XRD results in screening samples of J147.
• FIG. 10 shows a cluster plot of all XRD results in screening samples of J147.
• FIG. 11A shows a DSC thermogram of crystalline Form I of J147.
• FIG. 11B shows the XRD spectrum of crystalline Form I J147.
• FIG. 12A shows a representative photomicrograph of crystalline Form I J147.
• FIG. 12B shows another representative photomicrograph of crystalline Form I J147.
• FIG. 13 shows the XRD spectrum of crystalline Form II J147.
• FIG. 14A shows a DSC thermogram of crystalline Form II of J147.
• FIG. 14B shows a TGA thermogram of crystalline Form II of J147.
• FIG. 15 shows a representative photomicrograph of crystalline Form II J147.
• FIG. 16A shows the moisture sorption-desorption isotherm of crystalline Form II J 147 using dynamic vapor sorption (DVS) analysis.
• FIG. 16B shows kinetic plots of crystalline Form II J147 using DVS analysis.
• FIG. 17 shows a computer predicted powder XRD pattern of a single crystal of Form II of J147. The predicted pattern matched the pattern of experimental pattern.
• Embodiments herein are directed to various polymorph forms of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide (J147) and methods of preparing such forms.
• Discovery of polymorph forms of active pharmaceutical ingredients is recognized as an important practice in product development.
• Polymorph forms of J 147 disclosed herein may affect various physicochemical properties of J147 including, without limitation, hardness, stability, filterability, solubility, hygroscopicity, melting point, solid density and flowability. Altering one or more physicochemical properties of J147 may lead to downstream improvements in both manufacture as well as having an impact on
• an isolated crystalline Form I of 2,2,2- trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide J147, having a powder X-ray diffraction pattern comprising peaks located at 11.85, 17.11, 17.79, and 23.40 +/- 0.2 degrees 2-theta.
• isolated refers to the separation of a polymorph form, specifically of J147, to the substantial exclusion of other forms as well as impurities and, if so desired, solvent.
• an isolated polymorph may have a purity of at least about 95%, or about 98%, or about 99%, or about 99.5%, including up to the limits of detection of impurities, or nominally 100% pure.
• isolated crystalline Form I may further comprise X-ray diffraction peaks located at 8.64, 13.36, 19.25, 21.64, and 26.81 +/- 0.2 degrees 2-theta.
• isolated crystalline Form II of 2,2,2- trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide J147
• J147 2,2,2- trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide
• isolated crystalline Form II may further comprise X-ray diffraction peaks located at 17.74, 20.39, 26.25, and 28.74 +/- 0.2 degrees 2-theta.
• crystalline Form I of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide J147
• the method comprising recrystallizing 2,2,2- trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide from an organic solvent selected from the group consisting of nitromethane, methylethylketone, tetrahydrofuran, acetone, acetonitrile, heptane, isopropyl ether, isopropyl acetate, and chloroform.
• J147 may be dissolved in a minimal amount solvent including dissolution at elevated temperatures for a given solvent.
• J147 has been found to be reasonably soluble across an array of solvent types, including polar protic and polar aprotic solvents.
• J147 generally has lower solubility in highly hydrophobic hydrocarbon solvents such as heptane, or at the opposite end, lower solubility in water.
• solvents can serve as co-solvents or anti-solvents during recrystallization.
• Recrystallization may be performed with or without stirring, mixing, agitation, or the like.
• the methods of preparing Form I may further employ water as an anti-solvent.
• a ratio of organic solvent to anti-solvent water is in a range from about 4:1 to about 1:4.
• a yield of Form I is obtainable in some embodiments in a range from about 50% to about 100%, or about 90% to about 100%. In some embodiments, the yield may be at least about 95% based on the amount of J147 being recrystallized, or at least about 98%, or at least about 99%, or quantitative recovery.
• crystalline Form I of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide J147
• a powder X-ray diffraction pattern comprising peaks located at 11.85, 17.11, 17.79, and 23.40 +/- 0.2 degrees 2-theta
• the method comprising recrystallizing 2,2,2- trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide from a solvent-anti-solvent mixture comprising an alcohol as the solvent.
• a ratio of solvent to the anti-solvent is in a range from about 4:1 to about 1:4.
• the solvent alcohol is a C1-C4 alcohol.
• the alcohol may be selected from the group consisting of methanol, ethanol, 1 -propanol, 2-propanol, trifluoroethanol, 1 -butanol and 2-butanol.
• the anti-solvent is water or heptane.
• a yield of Form I is obtainable in some embodiments in a range from about 50% to about 100%.
• the yield may be at least about 95% based on the amount of J147 being recrystallized, or at least about 98%, or at least about 99%, or quantitative recovery.
• crystalline Form II of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3-methoxyphenyl)methylene]hydrazide J147
• the method comprising providing a slurry comprising a saturated crystalline Form I of 2,2,2-trifluoroacetic acid l-(2,4-Dimethylphenyl)-2-[(3- methoxyphenyl)methylene]hydrazide (J147) in a solvent/anti-solvent mixture comprising water as anti-solvent and mixing the slurry at ambient temperature to provide crystalline Form II.
• mixing is broadly intended to include mixing, stirring, agitation and the like.
• Form II can be accessed via amorphous J147.
• the methods to access Form II of J147 may employ a solvent which is selected from the group consisting of an alcohol, dimethylformamide (DMF), and dimethylacetamide (DMA).
• a solvent which is selected from the group consisting of an alcohol, dimethylformamide (DMF), and dimethylacetamide (DMA).
• the methods to access Form II of J147 involve the use of a solvent alcohol which is selected from the group consisting of methanol, ethanol, trifluoroethanol, 1 -propanol, and 2-propanol.
• the methods to access Form II of J147 a ratio of the solvent/anti-solvent mixture is in a range from about 1:2 to about 1: 1.
• the methods to access Form II of J147 includes mixing the slurry of saturated J147 over several days such as about 6 days. In some embodiments, mixing may optionally be accompanied by heating. However, ambient laboratory conditions, i.e., about 25 °C are generally sufficient. In some embodiments, Form II may be accessible in reasonable purity and quantities after about 3 days, or about 4 days, or about 5 days.
• Form II may also be isolated at intervals longer than 6 days if so desired, including about 7 days or about 8 days.
• methods for forming Form II from the slurry includes the use of an apparatus comprising a vessel connected to a re-circulation system.
• the recirculation can be conducted through a homogenization apparatus in which a shear force is applied.
• the homogenization apparatus may comprise a stator and a rotatable rotor, and the high-shear mixing force is applied by rotating the rotor at a speed of more than 250 rpm.
• the rotor can also be rotated as speeds of more than 500 rpm and more than 1,000 rpm.
• Re-circulating the slurry may comprise regulating the flow of slurry through the outlet and the inlet of the vessel.
• the energy for the re-circulation can be provided by a pump.
• Conventional flow regulation mechanisms such as metering pumps, valves, and the like may be used for this purpose.
• the process can also be conducted in a continuous mode.
• Form I or amorphous J147 may be in a supersaturated solution dissolved in a solvent.
• This solution may be mixed with an anti-solvent solution.
• the anti solvent refers to any solvent in which the chemical material has a poor solubility. It may be a mixture of anti-solvents and solvents.
• the anti-solvent may comprise water or heptane. Mixing the solutions reduces the solubility of the material in the solvent mixture, causing it to crystallize out.
• methods may also include the step of introducing seed crystals into the vessel to facilitate crystallization.
• the seed crystals may be placed into the supersaturated solution or into an anti- solvent. These seed crystals are selected to be insoluble in the individual solvents and in the solvent mixture.
• Mixing may comprise regulating the flow of the solution into the vessel. Conventional flow regulation mechanisms such as metering pumps, valves, and the like may be used for this purpose.
• the temperature may be adjusted prior to their introduction into the vessel. This may be achieved by any conventional temperature adjusting equipment, such as a heater or a cooling bath associated with the solution source.
• the re-circulation system may comprise a homogenization apparatus; outlet means for transferring the slurry from the vessel to the homogenization apparatus; and inlet means for receiving the slurry from the homogenization apparatus into the vessel.
• the homogenization apparatus may comprise a stator and a rotatable rotor, and means for applying a high-shear mixing force by rotating the rotor.
• the high-shear mixing force can be applied by rotating the rotor at a speed of more than 250 rpm.
• the rotor can also be rotated as speeds of more than 500 rpm and more than 1,000 rpm.
• the apparatus may include a means for regulating the flow of slurry through the homogenization apparatus. Conventional flow regulation mechanisms such as metering pumps, valves, and the like may be used for this purpose.
• the apparatus may also include a means for adjusting the temperature of the slurry in the vessel. This may be achieved by any conventional temperature adjusting equipment, such as a heater or a cooling bath associated with the solution source or the vessel.
• a yield of Form II is obtainable in a range from about 50% to about 100%, or about 90% to about 100%. In some embodiments, the yield may be at least about 95% based on the amount of J147 being recrystallized, or at least about 98%, or at least about 99%, or quantitative recovery.
• the following Examples are being submitted to illustrate embodiments of the present disclosure. These Examples are intended to be illustrative only and are not intended to limit the scope of the present disclosure. Also, parts and percentages are by weight unless otherwise indicated. As used herein, "room temperature” refers to a temperature of from about 20 ° C to about 25° C.
• This example describes the screening of J 147 for polymorphic behavior.
• the screen was performed using solvent recrystallization, hydration experiments, competitive and non competitive slurry experiments, and grinding to manipulate the solid state form of the test material.
• Samples generated were characterized using differential scanning calorimetry (DSC), polarized light microscopy, thermogravimetric analysis (TGA), Fourier transform nuclear magnetic resonance (NMR) spectroscopy, powder X-ray diffraction (XRD), Fourier Transform Infrared spectroscopy (FTIR), Raman Spectroscopy and dynamic vapor sorption/desorption (DVS).
• DSC differential scanning calorimetry
• TGA thermogravimetric analysis
• NMR Fourier transform nuclear magnetic resonance
• XRD powder X-ray diffraction
• FTIR Fourier Transform Infrared spectroscopy
• Raman Spectroscopy Raman Spectroscopy
• DFS dynamic vapor sorption/desorption
• Microscopy A Zeiss Universal and/or Olympus BX53 microscope configured with a polarized visible light source and polarizable analyzer were used to evaluate the optical properties of the samples. The specimens were typically mounted on a microscope slide with a cover glass. Observations of particle/crystal size and shape and birefringence were recorded.
• Hot S tage Microscopy A 1.ink am hot stage accessory was used in tandem with the microscope. The specimens were mounted on a microscope slide with a cover glass.
• the samples were heated from room temperature through melting using a Linkam TMS 94 temperature control and Linksys 32 data capture software system. Observations of possible phase change, melting, recrystallization, decomposition, etc. were recorded.
• D ifferential S canning C alorimetry (DSC) is a technique used to measure characteristic heat flux of a test article as it is scanned through a temperature gradient under a controlled atmosphere. Thermal phase transitions such as endothermic melting and exothermic decomposition were recorded. The DSC data were collected on a TA Instruments DSC. In general, samples in the mass range of 1 to 10 mg were crimped in aluminum sample pans and scanned from 25 to approximately 150 °C at heating rates of 2, 10, 20, and 50 °C/min using a nitrogen purge of 50 mL/min.
• Thermogravimetric Analysis involves the determination of the mass of a specimen as a function of temperature.
• the TGA data were collected on a TA Instruments Q500 TGA.
• samples in the mass range of 2 to 10 mg were placed in an open, pre-tared platinum sample pan and attached by fine wire to a microbalance.
• the sample was suspended in a furnace, which was heated from 25 to about 250 °C at 10 °C/min using a nitrogen purge at 100 mL/min. The sample weight change as a function of temperature was observed.
• X-Ray P owder D iffraction is an analytical technique used to study the crystalline nature of solid materials. X-rays incident on crystalline material are scattered in all directions. In certain directions, the scattered X-rays are constructively reinforced to form diffracted beams. The conditions for constructive diffraction are described by Bragg’ s Law and depend on the unique composition and spatial arrangements of the crystal structure. As such, each molecular solid diffracts X-rays in different directions and at different intensities resulting in a unique X-ray diffraction pattern. A variable temperature hot stage was used to manipulate sample temperature for some experiments.
• the X-ray powder diffraction patterns were obtained using a Bruker D8 Discovery diffractometer equipped with an XYZ stage, laser video microscope for positioning, and a two dimensional HiStar area Detector or a scintillation detector.
• a Cu K a radiation 1.5406 angstrom source operating at 40 kV and 40 mA was used to irradiate samples.
• the X-ray optics consists of a Gobel mirror coupled with a pinhole collimator of 0.5 mm.
• Theta-theta continuous scans were employed with a sample-detector distance of approximately 30 cm, which gives an effective 2 0 range of 4-40.
• the samples were mounted in low background quartz plates.
• Hygroscopicity-Dynamic V apor Sorption DVS is a gravimetric screening technique that measures how quickly and how much of a solvent (water) is adsorbed by a sample. The relative humidity or vapor concentration surrounding the sample is varied while the change in mass of the sample is measured. A vapor sorption isotherm shows the equilibrium amount of vapor sorbed as a function of relativity humidity. The mass values at each relative humidity step are used to generate the isotherm. Isotherms are divided in two components: sorption for increasing humidity steps and desorption for decreasing humidity steps. A plot of kinetic data is also supplied which shows the change in mass and humidity as a function of time.
• Raman Spectroscopy The Raman spectra were obtained with a Thermo DXR dispersive Raman spectrometer using laser excitation at 780 nm. The spectra were acquired from 3300 to 100 cm 1 . The samples were analyzed as bulk powders.
• Form I The thermal behavior of Form I was determined by DSC and TGA.
• the DSC thermogram exhibited a melting endotherm with an onset of 62.6 °C.
• the endotherm was split with peak maxima at 66.5 °C and 74.7 °C.
• the heat of fusion was 123.8 J/g. This split endotherm proved to be due to a mixture of two polymorphic forms as observed by hot stage microscopy as described further below.
• the scanning TGA thermogram indicated the sample was free of volatiles with a weight loss of less than 0.4 weight % from 25 °C to 104.7 °C.
• Figures 2A and 2B show the DSC and TGA thermograms, respectively.
• This unusual event may be due to differences in the adsorption characteristics of the sample and reference pans and not the J147 sample.
• FTIR Fourier transform infrared
• Solvent Recrystallization To perform the solvent-based portion of the polymorph screen, the test material was recrystallized using various solvents under approximately 150 different crystal growth conditions. The scale of the recrystallization experiments was from approximately 6 mL to 15 ml. The crystal growth conditions were changed by using binary gradient arrays of solvent mixtures. Saturated solutions were prepared by agitating excess (as possible) test material in contact with the various solvent systems at the saturation temperature. If solids did not completely dissolve in the solvent, the mother liquor was separated from the residual solids by filtration. The mother liquor was then heated above the saturation temperature (overheated) to dissolve any remaining solids. The temperature of each solution was then adjusted to the growth temperature and a controlled nitrogen shear flow was introduced to begin solvent evaporation.
• Non-Competitive Slurry Experiments In addition to the solvent recrystallization experiments, non-competitive slurry experiments were performed to search for new solid- state forms. These experiments rely on solubility differences of different polymorphic forms (if the compound exists in different polymorphic forms). As such, only polymorphs having a lower solubility (that is, are more stable) than the original crystalline form can result from a noncompetitive slurry experiment.
• the results of this analysis revealed the material exists as two different polymorphs.
• the polymorphs were designated as Forms I and II.
• the initially supplied material was designated as Form I.
• the resulting form designation for each individual (solvent-based) recrystallization experiment is shown in Tables 3 through 8 above.
• the XRD data collected during the study was evaluated using a full profile chemometric treatment to determine if the crystalline form of the samples had changed during the experiment. To simplify the assessment, X-ray amorphous samples were not included in the chemometric treatment.
• the analysis entailed cluster analysis and multivariate statistics to group together any patterns that were determined to be statistically the same.
• the results of this analysis are summarized in the dendrogram in Figure 8, cell plot in Figure 9, and cluster plot in Figure 10. These figures provide a pictorial cluster analysis of product similarity.
• each group/form was studied to determine if other properties of the forms could be differentiated.
• the characterization of each form began by comparing the diffraction data representative of each form with that from the other forms. This was generally followed by DSC, TGA, DVS analysis and microscopy.
• Form I (Group B): The characteristic diffraction behavior of this form is shown in Figure 1.
• the XRD patterns of the Form I samples were all crystalline and very similar. This form was obtained from a variety of solvents in approximately 50% of the experiments.
• the DSC profile of the Form I samples exhibited a melting endotherm with an onset of approximately 63 °C. In all but one of the Form I samples analyzed, the endotherm was split with peak maximums ranging from approximately 67 °C to 75 °C. This split endotherm is believed to be due to a mixture of two polymorphic forms as observed by hot stage microscopy.
• a representative DSC thermogram is shown in Figure 2A.
• a sample of Form I exhibited a single endotherm in the DSC profile with an onset of melting at approximately 63° C.
• the XRD pattern matched that of the other Form I samples.
• Figures 11 A and 11B show the DSC and XRD profiles, respectively, of this sample.
• the scanning TGA thermogram of Form I ( Figure 2B) showed it to be free from volatiles with a weight loss of less than 0.4 weight % from 25 °C to 104.7 °C.
• Microscopic evaluation of Form I showed a mixture of columnar and needle shaped particles ranging from approximately 10 to 300 microns in length. Upon heating this sample, the larger particles appear to melt at approximately 67 °C, with the smaller needles unmelted.
• Figures 12 A and 12B show representative photomicrographs at room temperature and 67 °C. This along with the multiple endotherms in the DSC profile suggests the majority of the Form I samples may actually be a mixture of Forms I and II.
• Form II (Group A): The Form II polymorph was not obtained from the
• the DSC thermograms of this form exhibit a well-defined melting endotherm with an extrapolated onset of approximately 74 °C, a peak maximum of approximately 75 °C and an enthalpy of fusion of approximately 68 J/g.
• Figure 14A shows the DSC profile of Form II.
• the TGA thermogram for Form II showed it to be free from volatiles with a weight loss less than 0.1% from 25 °C to 75 °C.
• Figure 14B shows the TGA profile. Microscopic evaluation of Form II showed birefringent needle shaped particles ranging from approximately 10 to 50 microns in length.
• Figure 15 shows a representative photomicrograph of Form II crystals at room temperature. Upon heating, one melting event was observed at approximately 75 °C.
• Figures 16A and 16B show the moisture sorption-desorption isotherm and the kinetic plots, respectively, for Form II.
• Form I This form is also very hydrophobic and does not appear to be prone to hydrate formation
• a total weight loss of approximately 0.5 % was observed at 95% RH. This unusual event (weight loss with high humidity) is most likely due to differences in the adsorption characteristics of the sample and reference pans and not the J147 sample.
• the single crystal predicted powder XRD pattern matched the pattern of experimental Form II as shown in Figure 17. A sample of Form II was placed in a 40 °C in oven over weekend. XRD data showed no form conversion. Overall, Form II was attributed to a dry crystalline polymorphic form of the compound.
• a number J147 samples were produced in this Example.
• the polymorph screen recrystallization experiments produced either Form I or an amorphous form of J147 (as shown in Table 11).
• the Form II polymorph was produced by creating a saturated slurry of Form 1 and agitating/stirring for several days at ambient temperature. Many of Form I samples also contained some amount of Form II indicating that the two polymorphs have a tendency to nucleate and grow concomitantly. Form II appears to be the thermodynamically stable form under ambient conditions based on the results of the competitive slurry experiments.
• Form I was ground using a Crescent Wig-L-Bug ball mill for 1 minute at 4800 oscillations per minute (3.2 m/s). XRD analysis showed no transformation under these conditions.
• Thermodynamic Relationship DSC experiments were performed in order to obtain heat of fusion and melting data. This data can often be used to determine if polymorphs exist in an enantiotropic or monotropic relationship.
• the heat of fusion rule states that, if the higher melting polymorph has the lower heat of fusion, the two forms are enantiotropes. Conversely, if the higher melting polymorph has a higher heat of fusion, the two forms are monotropes. For a monotropic system, any transition from one polymorph to another is irreversible. For an enantiotropic system, it may be possible to convert reversibly between the two polymorphs on heating and cooling.
• Static Vapor Sorption Study A dynamic vapor sorption study was done in a sealed humidity chamber with an automatic moisture sorption balance. Data collected during dynamic vapor sorption studies often are not at thermodynamic equilibrium. To determine if the Form I and Form II material form a hydrate over time, samples were monitored in a 75% static humidity chamber.
• samples were stored in open Petri dishes in a chamber containing a saturated salt solution to maintain the relative vapor pressure.
• a solution of saturated sodium chloride (75% RH) salt at ambient temperature was used.
• Table 14 summarizes the different solid state forms of J147 observed during the study.
• the main result is the discovery of two anhydrous polymorphic forms of J147.
• the polymorphic forms isolated in this Example were designated I and II.
• Form II is the thermodynamically form of J147.
• Form I is the metastable form at room temperature and pressure.
• Form I is the metastable form at room temperature and pressure.
• Evidence of a transformation of Form I to Form II was observed after approximately 3 days of storage at 40°C.
• a competitive slurry of a 50/50 mix of Forms I and II in 2 different solvent systems (at ambient temperature) showed conversion of Form I to Form II after 4 and 8 days.
• Non-competitive slurry experiments of Form I in 7 different solvents systems showed conversion to Form II after 6 days.
• the J 147 exhibits two different polymorphic forms designated as Forms I and II in addition to the amorphous form. No solvates or hydrates were uncovered in this Example. Of the two polymorphic forms, the thermodynamically stable polymorph under ambient conditions was Form II.
• Batch Process About 100 kg of crude J147 from its synthetic preparation was evaporated twice from about 80 kg of ethanol. The crude product was taken up in about 48 kg of ethanol and the batch temperature was adjusted to 28 °C. About 37 kg of water was added gradually to the batch. The batch was held at about 30 °C for about 1.7 hours. A sample of the batch was pulled from the reactor and solids precipitated by addition of 45 mL of water. The solids obtained were added back to the batch as seed crystals and the mixture stirred for 40 minutes at 30 °C. An additional about 34 kg of water was added. The batch was held at about 18 °C for about 58 hours and then cooled to about 10 °C for another about 5.5 hours. Analysis of the resultant solids indicated the presence of Form I.
• Form I was converted to Form II by heating the slurry to about 45 °C for about 16 hours and then cooling back to about 10 °C and holding the batch at this temperature for about 3 hours about 17.7 kg of solid Form II of J147 were recovered by filtration after washing and drying.

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