|
With phosphoric acid; In acetonitrile; |
The results are summarized in Table 5. Precipitation took place as soon as the acidic solution was mixed with the anti-solvents. At first, the precipitates were loose floes. The colors were yellow or light-orange in general. The resulting solid was sticky. The microscopic observation of these solids indicated that they were constituted of very small crystallites with good birefringence under polarized light. At least six different PXRD patterns were observed on solids obtained from nine solvent systems. (See Figure 3) The amide side-chain on this molecule is flexible and it undertakes different conformations in free base Form B and in its hydrochloride salt. Therefore, the molecule in the different solid forms may be conformational polymorphs. The PXRD patterns of solids precipitated from ethyl acetate, hexane, and IPA appeared the same. However, a detailed comparison with other PXRD patterns was difficult because of the low diffraction signals of solids from these three solvents. Consequently, they were not assigned as a new form. The precipitate from methanol is the same as the reference lot 35282-CS-51 (assigned as Form I). TGA data of all precipitates indicated residue solvent at a level of 1.7 - 4.7%. Of these solids, the one from CH2Cl2 appeared to be a solid with retained solvent in crystals. The TGA curve showed an abrupt decrease in sample weight at a temperature about 125 0C (see Figure 4). This event is recorded as an endotherm at about the same temperature by DSC. In addition, this powder was constituted of crystals of well-defined morphology and was free-flowing, a very different property from other lots of precipitates. The powder exhibited medium crystallinity by PXRD but good crystallinity when observed by polarized-light microscope. Other lots were constituted of very fine crystallites. On DSC curve of these powders, a broad and shallow endotherm was seen as soon as the sample was loaded to the sample cell. This observation is reflected by TGA as a gradual weight loss from the beginning of heating on TGA. Therefore, for these lots, the residual solvents were probably surface adsorbed solvents and were not solvents in the crystal lattice. |
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With phosphoric acid; In acetonitrile; for 72.0h; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In ethanol; |
The results are summarized in Table 5. Precipitation took place as soon as the acidic solution was mixed with the anti-solvents. At first, the precipitates were loose floes. The colors were yellow or light-orange in general. The resulting solid was sticky. The microscopic observation of these solids indicated that they were constituted of very small crystallites with good birefringence under polarized light. At least six different PXRD patterns were observed on solids obtained from nine solvent systems. (See Figure 3) The amide side-chain on this molecule is flexible and it undertakes different conformations in free base Form B and in its hydrochloride salt. Therefore, the molecule in the different solid forms may be conformational polymorphs. The PXRD patterns of solids precipitated from ethyl acetate, hexane, and IPA appeared the same. However, a detailed comparison with other PXRD patterns was difficult because of the low diffraction signals of solids from these three solvents. Consequently, they were not assigned as a new form. The precipitate from methanol is the same as the reference lot 35282-CS-51 (assigned as Form I). TGA data of all precipitates indicated residue solvent at a level of 1.7 - 4.7%. Of these solids, the one from CH2Cl2 appeared to be a solid with retained solvent in crystals. The TGA curve showed an abrupt decrease in sample weight at a temperature about 125 0C (see Figure 4). This event is recorded as an endotherm at about the same temperature by DSC. In addition, this powder was constituted of crystals of well-defined morphology and was free-flowing, a very different property from other lots of precipitates. The powder exhibited medium crystallinity by PXRD but good crystallinity when observed by polarized-light microscope. Other lots were constituted of very fine crystallites. On DSC curve of these powders, a broad and shallow endotherm was seen as soon as the sample was loaded to the sample cell. This observation is reflected by TGA as a gradual weight loss from the beginning of heating on TGA. Therefore, for these lots, the residual solvents were probably surface adsorbed solvents and were not solvents in the crystal lattice. |
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With phosphoric acid; In tetrahydrofuran; |
The results are summarized in Table 5. Precipitation took place as soon as the acidic solution was mixed with the anti-solvents. At first, the precipitates were loose floes. The colors were yellow or light-orange in general. The resulting solid was sticky. The microscopic observation of these solids indicated that they were constituted of very small crystallites with good birefringence under polarized light. At least six different PXRD patterns were observed on solids obtained from nine solvent systems. (See Figure 3) The amide side-chain on this molecule is flexible and it undertakes different conformations in free base Form B and in its hydrochloride salt. Therefore, the molecule in the different solid forms may be conformational polymorphs. The PXRD patterns of solids precipitated from ethyl acetate, hexane, and IPA appeared the same. However, a detailed comparison with other PXRD patterns was difficult because of the low diffraction signals of solids from these three solvents. Consequently, they were not assigned as a new form. The precipitate from methanol is the same as the reference lot 35282-CS-51 (assigned as Form I). TGA data of all precipitates indicated residue solvent at a level of 1.7 - 4.7%. Of these solids, the one from CH2Cl2 appeared to be a solid with retained solvent in crystals. The TGA curve showed an abrupt decrease in sample weight at a temperature about 125 0C (see Figure 4). This event is recorded as an endotherm at about the same temperature by DSC. In addition, this powder was constituted of crystals of well-defined morphology and was free-flowing, a very different property from other lots of precipitates. The powder exhibited medium crystallinity by PXRD but good crystallinity when observed by polarized-light microscope. Other lots were constituted of very fine crystallites. On DSC curve of these powders, a broad and shallow endotherm was seen as soon as the sample was loaded to the sample cell. This observation is reflected by TGA as a gradual weight loss from the beginning of heating on TGA. Therefore, for these lots, the residual solvents were probably surface adsorbed solvents and were not solvents in the crystal lattice. |
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With phosphoric acid; In acetone; |
The results are summarized in Table 5. Precipitation took place as soon as the acidic solution was mixed with the anti-solvents. At first, the precipitates were loose floes. The colors were yellow or light-orange in general. The resulting solid was sticky. The microscopic observation of these solids indicated that they were constituted of very small crystallites with good birefringence under polarized light. At least six different PXRD patterns were observed on solids obtained from nine solvent systems. (See Figure 3) The amide side-chain on this molecule is flexible and it undertakes different conformations in free base Form B and in its hydrochloride salt. Therefore, the molecule in the different solid forms may be conformational polymorphs. The PXRD patterns of solids precipitated from ethyl acetate, hexane, and IPA appeared the same. However, a detailed comparison with other PXRD patterns was difficult because of the low diffraction signals of solids from these three solvents. Consequently, they were not assigned as a new form. The precipitate from methanol is the same as the reference lot 35282-CS-51 (assigned as Form I). TGA data of all precipitates indicated residue solvent at a level of 1.7 - 4.7%. Of these solids, the one from CH2Cl2 appeared to be a solid with retained solvent in crystals. The TGA curve showed an abrupt decrease in sample weight at a temperature about 125 0C (see Figure 4). This event is recorded as an endotherm at about the same temperature by DSC. In addition, this powder was constituted of crystals of well-defined morphology and was free-flowing, a very different property from other lots of precipitates. The powder exhibited medium crystallinity by PXRD but good crystallinity when observed by polarized-light microscope. Other lots were constituted of very fine crystallites. On DSC curve of these powders, a broad and shallow endotherm was seen as soon as the sample was loaded to the sample cell. This observation is reflected by TGA as a gradual weight loss from the beginning of heating on TGA. Therefore, for these lots, the residual solvents were probably surface adsorbed solvents and were not solvents in the crystal lattice. |
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With phosphoric acid; In dichloromethane;Product distribution / selectivity; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In ethyl acetate;Product distribution / selectivity; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In isopropyl alcohol;Product distribution / selectivity; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In 1,4-dioxane;Product distribution / selectivity; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In butanone;Product distribution / selectivity; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In water; acetonitrile; for 1.0h;Heating;Product distribution / selectivity; |
Compound I free base was used to prepare the phosphate salt. A sample (lot number 35282-CS-51) of Compound I phosphate was prepared as described above. 4 mL of 0.977 M phosphoric acid was added to 1.095 g of free base in a flask immediately followed by adding 4 mL of acetonitrile. A suspension was obtained. EPO <DP n="23"/>The suspension was heated slightly on a hot-plate. Adding 40 mL of water and heating while stirring for about one hour did not completely dissolve the solid. The solid was filtered and washed with 10 mL of acetonitrile. PXRD showed it was the phosphate salt of Compound I.) |
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With phosphoric acid; In water; acetonitrile; for 72.0h;Product distribution / selectivity; |
Characterization Immediately After PrecipitationThe results are summarized in Table 5. Precipitation took place as soon as the acidic solution was mixed with the anti-solvents. At first, the precipitates were loose floes. The colors were yellow or light-orange in general. The resulting solid was sticky. The microscopic observation of these solids indicated that they were constituted of very small crystallites with good birefringence under polarized light. At least six different PXRD patterns were observed on solids obtained from nine solvent systems. (See Figure 3) The amide side-chain on this molecule is flexible and it undertakes different conformations in free base Form B and in its hydrochloride salt. Therefore, the molecule in the different solid forms may be conformational polymorphs. The PXRD patterns of solids precipitated from ethyl acetate, hexane, and IPA appeared the same. However, a detailed comparison with other PXRD patterns was difficult because of the low diffraction signals of solids from these three solvents. Consequently, they were not assigned as a new form. The precipitate from methanol is the same as the reference lot 35282-CS-51 (assigned as Form I). TGA data of all precipitates indicated residue solvent at a level of 1.7 - 4.7%. Of these solids, the one from CH2Cl2 appeared to be a solid with retained solvent in crystals. The TGA curve showed an abrupt decrease in sample weight at a temperature about 125 0C (see Figure 4). This event is recorded as an endotherm at about the same temperature by DSC. In addition, this powder was constituted of crystals of well-defined morphology and was free-flowing, a very different property from other lots of precipitates. The powder exhibited medium crystallinity by PXRD but good crystallinity when observed by polarized-light microscope. Other lots were constituted of very fine crystallites. On DSC curve of these powders, a broad and shallow endotherm was seen as soon as the sample was loaded to the sample cell. This observation is reflected by TGA as a gradual weight loss from the beginning of heating on TGA. Therefore, for these lots, the residual solvents were probably surface adsorbed solvents and were not solvents in the crystal lattice. Example 6C. Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free s... |
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With phosphoric acid; In ethanol; for 72.0h;Product distribution / selectivity; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In tetrahydrofuran; for 72.0h;Product distribution / selectivity; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In acetone; for 72.0h;Product distribution / selectivity; |
Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form I quickly when in contact with solvent. The solid from CH2Cl2 appeared to flow more easily than the solid from hexane. The TGA, morphology, and the flowability indicated that they are two different solids. |
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With phosphoric acid; In methanol;Product distribution / selectivity; |
The results are summarized in Table 5. Precipitation took place as soon as the acidic solution was mixed with the anti-solvents. At first, the precipitates were loose floes. The colors were yellow or light-orange in general. The resulting solid was sticky. The microscopic observation of these solids indicated that they were constituted of very small crystallites with good birefringence under polarized light. At least six different PXRD patterns were observed on solids obtained from nine solvent systems. (See Figure 3) The amide side-chain on this molecule is flexible and it undertakes different conformations in free base Form B and in its hydrochloride salt. Therefore, the molecule in the different solid forms may be conformational polymorphs. The PXRD patterns of solids precipitated from ethyl acetate, hexane, and IPA appeared the same. However, a detailed comparison with other PXRD patterns was difficult because of the low diffraction signals of solids from these three solvents. Consequently, they were not assigned as a new form. The precipitate from methanol is the same as the reference lot 35282-CS-51 (assigned as Form I). TGA data of all precipitates indicated residue solvent at a level of 1.7 - 4.7%. Of these solids, the one from CH2Cl2 appeared to be a solid with retained solvent in crystals. The TGA curve showed an abrupt decrease in sample weight at a temperature about 125 0C (see Figure 4). This event is recorded as an endotherm at about the same temperature by DSC. In addition, this powder was constituted of crystals of well-defined morphology and was free-flowing, a very different property from other lots of precipitates. The powder exhibited medium crystallinity by PXRD but good crystallinity when observed by polarized-light microscope. Other lots were constituted of very fine crystallites. On DSC curve of these powders, a broad and shallow endotherm was seen as soon as the sample was loaded to the sample cell. This observation is reflected by TGA as a gradual weight loss from the beginning of heating on TGA. Therefore, for these lots, the residual solvents were probably surface adsorbed solvents and were not solvents in the crystal lattice. Example 6C. Precipitation After Standing up to Three Days in Solvent.These results are summarized in Table 6. After a standing time of up to three days in the solvent, a new non-fluffy orange-red solid phase appeared. The fluffy precipitates obtained from all organic solvents, except the precipitate from methanol, underwent transformation. Apparently, the solids precipitated immediately after precipitation were metastable in these cases in that they converted to a more stable solid form (Form I) over time. This conversion appeared to be completed in a couple of hours in most of the solvent systems. However, they were allowed to stand for a much longer period of time to ensure the completion of the process in order to avoid reaping a mixture of two solid forms. The TGA curve showed abrupt weight loss at about 124 C and 153 C for the solids obtained from hexane and acetonitrile respectively, coupled by an endotherm at a similar temperature on DSC. Therefore, they also appeared to contain restrained solvent in crystal lattice. The stoichiometrics of the retained solvents are about 0.6 for acetonitrile and about 0.14 for hexane. Needle-shaped crystals were grown from acetonitrile after standing for three days. The PXRD patterns of the acetonitrile-retaining solid were unique while the PXRD pattern of the hexane solvate is similar to the CH2Cl2- retaining solid identified earlier (Figure 3). Both solvent-retaining solids (hexane and acetonitrile) lost weight on a TGA pan. Unique PXRD patterns of both solids were observed after the corresponding retained solvent had been removed by heating (Table 7, Figure 3), indicating that removal of solvent molecules from the solids caused structural changes of the solvate crystals (therefore, the solvent molecules are in crystal lattice not just on crystal surfaces). However, the PXRD pattern of acetonitrile desolvate was low in signal intensity. DSC profile of the acetonitrile desolvate exhibited two additional heat events at 74 C and 174 C, when compared with the DSC profile of the acetonitrile solvate, while the desolvation event at 153 C was absent. Cooling of the sample after desolvation may have changed the solid that undergoes an energetic change at 174 C.When other organic solvents were used, the longer standing period of the precipitates yielded solids of the same PXRD pattern as that of Form I (Lot 35282-CS- 51) although the morphology of the crystals was different (Table 6). The same PXRD pattern indicated that those solids have the same crystal lattice structure. The different morphology must be due to the solvent effects. It is apparent that Form I is the most EPO <DP n="30"/>stable solid phase among all non-solvated polymorphs reported herein. Other solvent-free solid forms were metastable and converted to Form... |