DESC:INTRODUCTION
Aspects of the present application relate to polymorphic forms of saxagliptin hydrochloride which are useful in making pharmaceutically acceptable dosage forms, and processes for their preparation.
The drug compound having the adopted name saxagliptin hydrochloride, has a chemical name (1S,3S,5S)-2-[(2S)-2-Amino-2-(3hydroxytricyclo[3.3.1.13,7]dec-1-yl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile hydrochloride, and is represented by structure of formula I.

Formula I
Saxagliptin is a dipeptidyl peptidase-4 inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. U.S. Patent No. 6,395,767 discloses saxagliptin and its pharmaceutically acceptable salts including hydrochloride salt. U.S. Patent No. 7,943,656 specifically discloses several crystalline forms of saxagliptin hydrochloride and process for the preparation thereof. International Application Publication No. WO2010/115974A1 discloses anhydrous crystalline forms of saxagliptin hydrochloride (denoted as I-S, HT-S, HT-IVS and IVS) and process for the preparation thereof.
The occurrence of different polymorphs is possible for some compounds. A single compound may give rise to a variety of solid forms having distinct physical properties. This variation in solid forms may be significant and may result in differences in pharmaceutical products with respect to solubility, bioavailability, stability and other properties. Because polymorphic forms can vary in their physical properties, regulatory authorities require that efforts shall be made to identify all polymorphic forms, e.g., crystalline, amorphous, solvated, etc., of new drug substances.
The existence and possible number of polymorphic forms for a given compound cannot be predicted, and there are no “standard” procedures that can be used to prepare polymorphic forms of a substance. However, new forms of a pharmaceutically useful compound may provide an opportunity to improve the performance characteristics of pharmaceutical products. For example, in some cases, different forms of the same drug can exhibit very different solubility and dissolution rates. The discovery of new polymorphic forms enlarges selection of materials with which formulation scientists can design a pharmaceutically acceptable dosage form of a drug with a targeted release profile or other desired characteristics. Therefore, there remains a need for preparing new and stable polymorphic forms of saxagliptin hydrochloride.
SUMMARY OF THE INVENTION
In an aspect, the present application provides crystalline Form I of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 6.8 ? 0.2, 10.4 ? 0.2, 13.5 ? 0.2, 14.5 ? 0.2, 15.1 ? 0.2, 15.8 ? 0.2, 16.6 ? 0.2, 18.1 ? 0.2 and 20.4 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form I of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising 1-Butanol; and
b) isolating crystalline Form I of saxagliptin hydrochloride.
In an aspect, the application provides crystalline Form II of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 6.9 ? 0.2, 13.8 ? 0.2, 15.0 ? 0.2 and 18.2 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form II of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising
N,N-Dimethylformamide or 1-Butanol; and
b) isolating the crystalline Form II of saxagliptin hydrochloride.
In an aspect, the present application provides crystalline Form III of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 5.7 ? 0.2 and 5.9 ? 0.2 degrees 2-theta.
In an aspect, the present invention provides crystalline Form III of saxagliptin hydrochloride further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 6.6 ? 0.2, 14.2 ? 0.2, 15.0 ? 0.2, 16.4 ? 0.2, 17.0 ? 0.2, 18.0 ? 0.2 and 20.8 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form III of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising N, N-Dimethylacetamide; and
b) isolating the crystalline Form III of saxagliptin hydrochloride.
In an aspect, the present application provides crystalline Form IV of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 3.7 ? 0.2, 6.3 ? 0.2, 14.6 ? 0.2, 15.0 ? 0.2, 16.3 ? 0.2, 17.5 ? 0.2 and 19.2 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form IV of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising dimethylsulphoxide; and
b) isolating the crystalline Form IV of saxagliptin hydrochloride.
In an aspect, the present application provides crystalline Form V of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 4.0 ? 0.2, 6.9 ? 0.2, 13.9 ? 0.2, 15.3 ? 0.2, 16.8 ? 0.2, 17.1 ? 0.2, 18.4 ? 0.2 and 23.2 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form V of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising 2-Butanol and ethanol; and
b) isolating the crystalline Form V of saxagliptin hydrochloride.
In an aspect, the present application provides crystalline Form VI of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 7.8 ? 0.2 and 8.9 ? 0.2 degrees 2-theta.
In an aspect, the present invention provides crystalline Form VI of saxagliptin hydrochloride further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 5.1 ? 0.2, 13.5 ? 0.2, 14.4 ? 0.2, 15.3 ? 0.2, 17.9 ? 0.2, 18.5 ? 0.2 and 19.4 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form VI of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent; and
b) isolating the crystalline Form VI of saxagliptin hydrochloride.
In an aspect, the present application provides a process for the preparation of H1.25-2 form of saxagliptin hydrochloride, comprising:
a) providing a solution or slurry of saxagliptin hydrochloride in a solvent; and
b) isolating H1.25-2 form of saxagliptin hydrochloride.
In an aspect, the present application provides pharmaceutical formulations comprising crystalline polymorphic forms of saxagliptin hydrochloride, together with one or more pharmaceutically acceptable excipients.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 depicts a PXRD pattern of saxagliptin hydrochloride, obtained from Example 1.
Fig 2 depicts a PXRD pattern of saxagliptin hydrochloride, obtained fromExample 3.
Fig 3 depicts a PXRD pattern of saxagliptin hydrochloride, obtained from Example 4.
Fig 4 depicts a PXRD pattern of saxagliptin hydrochloride, obtained from Example 5.
Fig 5 depicts a PXRD pattern of saxagliptin hydrochloride, obtained from Example 6.
Fig 6 depicts a PXRD pattern of saxagliptin hydrochloride, obtained from Example 7.
Fig 7 depicts a PXRD pattern of saxagliptin hydrochloride, obtained from Example 8.
DETAILED DESCRIPTION
In an aspect, the present application provides crystalline Form I of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 6.8 ? 0.2, 10.4 ? 0.2, 13.5 ? 0.2, 14.5 ? 0.2, 15.1 ? 0.2, 15.8 ? 0.2, 16.6 ? 0.2, 18.1 ? 0.2 and 20.4 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form I of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising 1-Butanol; and
b) isolating crystalline Form I of saxagliptin hydrochloride.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing saxagliptin hydrochloride
that is obtained in the course of its synthesis that comprises 1-Butanol, or by adding 1-Butanol to a reaction mixture; or
ii) dissolving saxagliptin hydrochloride in a solvent comprising 1-Butanol,
including mixtures of 1-Butanol with other solvents.
Any physical form of saxagliptin hydrochloride may be utilized for providing the solution of saxagliptin hydrochloride in step a).
In embodiments, saxagliptin hydrochloride can be dissolved in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles.
Step b) involves isolating crystalline Form I of saxagliptin hydrochloride from the solution obtained in step a). Isolation of crystalline Form I of saxagliptin hydrochloride in step b) may involve methods including cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; water; or any mixtures thereof.
The crystalline Form I of saxagliptin hydrochloride may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
In an aspect, the application provides crystalline Form II of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 6.9 ? 0.2, 13.8 ? 0.2, 15.0 ? 0.2 and 18.2 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form II of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising
N, N-Dimethylformamide or 1-Butanol; and
b) isolating the crystalline Form II of saxagliptin hydrochloride.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing saxagliptin hydrochloride
that is obtained in the course of its synthesis that comprises N, N-Dimethylformamide or 1-Butanol, or by adding N, N-Dimethylformamide or 1-Butanol to a reaction mixture; or
ii) dissolving saxagliptin hydrochloride in a solvent comprising N, N-
Dimethylformamide or 1-Butanol, including mixtures of N, N-Dimethylformamide or 1-
Butanol with other solvents.
Any physical form of saxagliptin hydrochloride may be utilized for providing the solution of saxagliptin hydrochloride in step a). In embodiments, saxagliptin hydrochloride can be dissolved in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 70°C, less than about 40°C, less than about 30°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
Step b) involves isolating crystalline Form II of saxagliptin hydrochloride from the solution obtained in step a). Isolation of crystalline Form II of saxagliptin hydrochloride in step b) may involve methods including cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; or any suitable solvent or mixtures thereof.
The crystalline Form II of saxagliptin hydrochloride may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
In an aspect, the present invention provides crystalline Form III of saxagliptin hydrochloride further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 6.6 ? 0.2, 14.2 ? 0.2, 15.0 ? 0.2, 16.4 ? 0.2, 17.0 ? 0.2, 18.0 ? 0.2 and 20.8 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form III of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising N,N-Dimethylacetamide; and
b) isolating the crystalline Form III of saxagliptin hydrochloride.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing saxagliptin hydrochloride that is obtained in the course of its synthesis that comprises N,N-Dimethylacetamide, or by adding N,N-Dimethylacetamide to a reaction mixture; or
ii) dissolving saxagliptin hydrochloride in a solvent comprising N,N-Dimethylacetamide, including mixtures of N,N-Dimethylacetamide with other solvents.
Any physical form of saxagliptin hydrochloride may be utilized for providing the solution of saxagliptin hydrochloride in step a). The dissolution temperatures may range from about 0°C to about the reflux temperature, or less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures, depending on the solvent used for dissolution, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
Step b) involves isolating crystalline Form III of saxagliptin hydrochloride from the solution obtained in step a). Isolation of crystalline Form III of saxagliptin hydrochloride in step b) may involve methods including cooling, crash cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. Suitable anti-solvents that may be used include, but are not limited to: aliphatic or alicyclic hydrocarbon solvent; substituted hydrocarbon solvent such as nitromethane; aromatic hydrocarbon solvent; or any mixtures thereof. The crystalline Form III of saxagliptin hydrochloride may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The crystalline polymorphic forms of saxagliptin hydrochloride as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, these crystals may be washed with a solvent or a mixture of solvents to wash out the impurities.
The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
In an aspect, the present application provides crystalline Form IV of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 3.7 ? 0.2, 6.3 ? 0.2, 14.6 ? 0.2, 15.0 ? 0.2, 16.3 ? 0.2, 17.5 ? 0.2 and 19.2 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form IV of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising dimethylsulphoxide; and
b) isolating the crystalline Form IV of saxagliptin hydrochloride.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing saxagliptin hydrochloride
that is obtained in the course of its synthesis that comprises dimethylsulphoxide, or by adding dimethylsulphoxide to a reaction mixture; or
ii) dissolving saxagliptin hydrochloride in a solvent comprising
dimethylsulphoxide, including mixtures of dimethylsulphoxide with other solvents.
Any physical form of saxagliptin hydrochloride may be utilized for providing the solution of saxagliptin hydrochloride in step a). The dissolution temperatures may range from about 0°C to about the reflux temperature, or less than about 120°C, less than about 90°C, less than about 60°C, less than about 40°C, less than about 30°C, less than about 20°C, or any other suitable temperatures, depending on the solvent used for dissolution, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
Step b) involves isolating crystalline Form IV of saxagliptin hydrochloride from the solution obtained in step a). Isolation of crystalline Form IV of saxagliptin hydrochloride in step b) may involve methods including removal of solvent, cooling, crash cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. Suitable anti-solvents that may be used include, but are not limited to: esters, such as ethyl acetate, propyl acetate, isopropyl acetate, or butyl acetate; or any mixtures thereof. The crystalline Form IV of saxagliptin hydrochloride may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The crystalline polymorphic forms of saxagliptin hydrochloride as isolated may carry some amount of occluded mother liquor and may have higher than desired levels of impurities. If desired, these crystals may be washed with a solvent or a mixture of solvents to wash out the impurities.
The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
In an aspect, the present application provides crystalline Form V of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 4.0 ? 0.2, 6.9 ? 0.2, 13.9 ? 0.2, 15.3 ? 0.2, 16.8 ? 0.2, 17.1 ? 0.2, 18.4 ? 0.2 and 23.2 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form V of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent comprising 2-Butanol and ethanol; and
b) isolating the crystalline Form V of saxagliptin hydrochloride.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing saxagliptin hydrochloride
that is obtained in the course of its synthesis that comprises 2-Butanol and ethanol, or by adding 2-Butanol and ethanol to a reaction mixture; or
ii) dissolving saxagliptin hydrochloride in a solvent comprising 2-Butanol
and ethanol, including mixtures of 2-Butanol and ethanol with other solvents.
Any physical form of saxagliptin hydrochloride may be utilized for providing the solution of saxagliptin hydrochloride in step a).
In embodiments, saxagliptin hydrochloride can be dissolved in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure.
Step b) involves isolating crystalline Form V of saxagliptin hydrochloride from the solution obtained in step a). Isolation of crystalline Form V of saxagliptin hydrochloride in step b) may involve methods including cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; or any mixtures thereof. The crystalline Form V of saxagliptin hydrochloride may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
In an aspect, the present application provides crystalline Form VI of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 7.8 ? 0.2 and 8.9 ? 0.2 degrees 2-theta.
In an aspect, the present invention provides crystalline Form VI of saxagliptin hydrochloride further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 5.1 ? 0.2, 13.5 ? 0.2, 14.4 ? 0.2, 15.3 ? 0.2, 17.9 ? 0.2, 18.5 ? 0.2 and 19.4 ? 0.2 degrees 2-theta.
In an aspect, the present application provides a process for the preparation of crystalline Form VI of saxagliptin hydrochloride, comprising:
a) providing a solution of saxagliptin hydrochloride in a solvent; and
b) isolating the crystalline Form VI of saxagliptin hydrochloride.
Providing a solution in step a) includes:
i) direct use of a reaction mixture containing saxagliptin hydrochloride that is obtained in the course of its synthesis; or
ii) dissolving saxagliptin hydrochloride in a solvent.
Any physical form of saxagliptin hydrochloride may be utilized for providing the solution of saxagliptin hydrochloride in step a). Optionally, when a hydrate of saxagliptin hydrochloride is used, before or after step a) a water reduction or removal step may be carried out by the techniques known in the art such as distillation, heating, slurrying in a suitable solvent and the like.
In embodiments, saxagliptin hydrochloride can be dissolved in any suitable solvent. Examples of such suitable solvents include, but are not limited to: alcohols, such as methanol, ethanol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, cyclohexanol, glycerol, or C1-C6 alcohols; or any mixtures thereof. The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles.
Step b) involves isolating crystalline Form VI of saxagliptin hydrochloride from the solution obtained in step a). Isolation of crystalline Form VI of saxagliptin hydrochloride in step b) may involve methods including cooling, concentrating the mass, adding an anti-solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation. Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; or any mixtures thereof.
The crystalline Form VI of saxagliptin hydrochloride may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
In an aspect, the present application provides a process for the preparation of H1.25-2 form of saxagliptin hydrochloride, comprising:
a) providing a solution or slurry of saxagliptin hydrochloride in a solvent; and
b) isolating H1.25-2 form of saxagliptin hydrochloride.
Providing a solution or slurry in step a) includes:
i) direct use of a reaction mixture containing saxagliptin hydrochloride that is obtained in the course of its synthesis; or
ii) dissolving or providing slurry of saxagliptin hydrochloride in a solvent.
Any physical form of saxagliptin hydrochloride may be utilized for providing the solution of saxagliptin hydrochloride in step a).
In embodiments, saxagliptin hydrochloride can be dissolved or can be provided slurry in any suitable solvent. Suitable solvents include any solvents that have no adverse effect on the compound and can dissolve the starting material to a useful extent. Examples of such solvents include, but are not limited to: alcohols, such as methanol, 2-nitroethanol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, Isoamyl alcohol, neo-pentyl alcohol, cyclohexanol, or C1-C6 alcohols; or any mixtures thereof.
The dissolution temperatures may range from about 0°C to about the reflux temperature of the solvent, or less than about 100°C, less than about 80°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 10°C, or any other suitable temperatures, as long as a clear solution of saxagliptin hydrochloride is obtained without affecting its quality. The solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material.
Step b) involves isolating crystalline Form H1.25-2 of saxagliptin hydrochloride from the solution obtained in step a). Isolation of crystalline H1.25-2 of saxagliptin hydrochloride in step b) may involve methods including cooling, concentrating the mass, adding an anti-solvent, extraction with a solvent, adding seed crystals to induce crystallization, or the like. Stirring or other alternate methods such as shaking, agitation, or the like, may also be employed for the isolation.
Optionally, isolation may be effected by combining a suitable anti-solvent with the solution obtained in step a). Anti-solvent as used herein refers to a liquid in which saxagliptin hydrochloride is less soluble or poorly soluble. An inert anti-solvent has no adverse effect on the reaction and it can assist in the solidification or precipitation of the dissolved starting material. Suitable anti-solvents that may be used include, but are not limited to: saturated or unsaturated, linear or branched, cyclic or acyclic, C1 to C10 hydrocarbons, such as heptanes, cyclohexane, or methylcyclohexane; ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, or dimethoxyethane; water; or any mixtures thereof.
The crystalline Form H1.25-2 of saxagliptin hydrochloride may be recovered by methods including decantation, centrifugation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 50°C, less than about 30°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the saxagliptin hydrochloride is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved.
In an aspect, the present application provides pharmaceutical formulations comprising crystalline polymorphic forms of saxagliptin hydrochloride, together with one or more pharmaceutically acceptable excipients. Saxagliptin hydrochloride together with one or more pharmaceutically acceptable excipients of the present application may be formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, but not limited to, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, but not limited to, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated powder coated, enteric coated, and modified release coated. Compositions of the present application may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, or the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pregelatinized starches, or the like; disintegrants such as starches, sodium starch glycolate, pregelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, or the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, or the like; glidants such as colloidal silicon dioxide or the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, or the like. Other pharmaceutically acceptable excipients that are of use include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, or the like.
Crystalline forms are characterized by scattering techniques, e.g., x-ray powder diffraction pattern, by spectroscopic methods, e.g., infra-red, 13C nuclear magnetic resonance spectroscopy, and by thermal techniques, e.g., differential scanning calorimetry or differential thermal analysis. The compound of this application is best characterized by the X-ray powder diffraction pattern determined in accordance with procedures that are known in the art. For a discussion of these techniques see J. Haleblian, J. Pharm. Sci. 1975 64:1269-1288, and J. Haleblian and W. McCrone, J. Pharm. Sci. 1969 58:911-929. Crystal forms of the application can be further processed to modulate particle size. For example, the crystal forms of the application can be milled to reduce average crystal size and/or to prepare a sample suitable for manipulation and formulation.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. As used herein, “consisting essentially of” means that the invention may include ingredients in addition to those recited in the claim, but only if the additional ingredients do not materially alter the basic and novel characteristics of the claimed invention. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Generally, a diffraction angle (2?) in powder X-ray diffractometry may have an error in the range of ±.0.2o. Therefore, the aforementioned diffraction angle values should be understood as including values in the range of about ±.0.2o. Accordingly, the present application includes not only crystals whose peak diffraction angles in powder X-ray diffractometry completely coincide with each other, but also crystals whose peak diffraction angles coincide with each other with an error of about ±.0.2o. Therefore, in the present specification, the phrase "having a diffraction peak at a diffraction angle (2??±.0.2o) of 7.9o" means "having a diffraction peak at a diffraction angle (2?) of 7.7o to 8.1o. Although the intensities of peaks in the x-ray powder diffraction patterns of different batches of a compound may vary slightly, the peaks and the peak locations are characteristic for a specific polymorphic form. Alternatively, the term "about" means within an acceptable standard error of the mean, when considered by one of ordinary skill in the art. The relative intensities of the XRD peaks can vary depending on the sample preparation technique, crystal size distribution, various filters used, the sample mounting procedure, and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-theta values. Therefore, the term "substantially" in the context of XRD is meant to encompass that peak assignments can vary by plus or minus about 0.2.degree. Moreover, new peaks may be observed or existing peaks may disappear, depending on the type of the machine or the settings (for example, whether a Ni filter is used or not. All PXRD data reported herein are obtained using a Bruker AXS D8 Advance Powder X-ray Diffractometer or a PANalytical X-ray Diffractometer, using copper Ka radiation.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise. The term “anti-solvent” refers to a liquid that, when combined with a solution of saxagliptin hydrochloride, reduces solubility of the saxagliptin hydrochloride in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching and/or concentrating. Celite® is flux-calcined diatomaceous earth. Celite® is a registered trademark of World Minerals Inc. Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel™ is a registered trademark of the Manville Corp. Polymorphs are different solids having the same molecular structure, yet having distinct physical properties when compared to other polymorphs of the same structure.
An “aliphatic or alicyclic hydrocarbon solvent” refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8aliphatic hydrocarbons, ligroin, petroleum ethers, or mixtures thereof.
“Aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings which has at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of an aromatic hydrocarbon solvent include, but are not limited to, benzene toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10aromatic hydrocarbons, or mixtures thereof.
An “ether solvent” is an organic solvent containing an oxygen atom –O- bonded to two other carbon atoms. “Ether solvents” include but are not limited to diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C2-6ethers, or the like.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention.
EXAMPLES
EXAMPLE 1: Preparation of crystalline Form I of saxagliptin hydrochloride. Saxagliptin hydrochloride (1 g) and 1-Butanol (30 mL) are charged into round bottom flask at 25 °C and stirred at 30 °C for 45 minutes. Tetrahydrofuran (10 mL) was added to the reaction mixture at 30°C, heated to 80°C and stirred at 80°C for 3 hours. The obtained solid is filtered under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Form I of saxagliptin hydrochloride obtained in above example is in accordance with Figure 1.
EXAMPLE 2: Preparation of crystalline Form II of saxagliptin hydrochloride. Saxagliptin hydrochloride (1 g) and N, N-Dimethylformamide (5 mL) are charged into round bottom flask at 30 °C and stirred for 10 minutes. Isopropyl acetate (35 mL) was added to the reaction mixture at 50°C, heated to 80°C and stirred at 80°C for 3 hours. The obtained solid is collected by filtration under reduced pressure to afford title compound.
EXAMPLE 3: Preparation of crystalline Form II of saxagliptin hydrochloride. Saxagliptin hydrochloride (1 g) and 1-Butanol (25 mL) are charged into round bottom flask at 30 °C and stirred for 20 minutes. Isopropyl acetate (150 mL) was added to the reaction mixture at 45°C, heated to 80°C and stirred at 80°C for 3 hours. The obtained solid is collected by filtration under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Form II of saxagliptin hydrochloride obtained in above example is in accordance with Figure 2.
EXAMPLE 4: Preparation of crystalline Form III of saxagliptin hydrochloride. Saxagliptin hydrochloride (2.0 g) and N,N-Dimethylacetamide (4.5 mL) are charged into flask, heated to 80°C and stirred at 80 °C 90 minutes. The obtained solid is collected by filtration under reduced pressure and dried in vacuum tray dryer at 50°C to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Form III of saxagliptin hydrochloride obtained in above example is in accordance with Figure 3.
EXAMPLE 5: Preparation of crystalline Form IV of saxagliptin hydrochloride. Saxagliptin hydrochloride (1 g) and dimethylsulfoxide (10 mL) are charged into round bottom flask at 30 °C and stirred for 15 minutes. Isopropyl acetate (100 mL) was added to the reaction mixture at 45°C, heated to 80°C and stirred at 80°C for 2 hours. The obtained solid is collected by filtration under reduced pressure to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Form IV of saxagliptin hydrochloride obtained in above example is in accordance with Figure 4.
EXAMPLE 6: Preparation of crystalline Form V of saxagliptin hydrochloride. Saxagliptin hydrochloride (1.0 g) and mixture of 2-Butanol (30 mL) & ethanol (30 mL) are charged into round bottom flask at 28 °C, heated to 62 °C and stirred at 62 °C for 5 hours. The resultant reaction mixture was cooled to -5 °C and stirred at -5 °C for 100 minutes. The obtained solid is collected by filtration under reduced pressure, and dried at 60°C to afford 0.7 g of the title compound.
The Powder X-ray diffraction (PXRD) pattern of Form V of saxagliptin hydrochloride obtained in above example is in accordance with Figure 5.
EXAMPLE 7: Preparation of crystalline Form VI of saxagliptin hydrochloride. Saxagliptin hydrochloride (1 g) was added to the iso butanol (15 mL) at 55 °C and stirred for 15 minutes. 1,4-dioxane (25 mL) was added to the reaction mixture at 60 °C and stirred at 80°C for 2 hours 30 minutes. The obtained solid is collected by filtration under reduced pressure, and dried to afford title compound.
The Powder X-ray diffraction (PXRD) pattern of Form VI of saxagliptin hydrochloride obtained in above example is in accordance with Figure 6.
EXAMPLE 8: Preparation of crystalline Form H1.25-2 of saxagliptin hydrochloride. Saxagliptin hydrochloride (1.0 g) and isoamyl alcohol (40 mL) are charged into flask, heated to 62 °C and stirred at 62 °C 6 hours. The resultant reaction mixture was cooled to -5 °C and stirred at -5 °C for 2 hours. The obtained solid is collected by filtration under reduced pressure and dried at 60°C to afford 0.8 g of the title compound.
The Powder X-ray diffraction (PXRD) pattern of Form H1.25-2 of saxagliptin hydrochloride obtained in above example is in accordance with Figure 7.
EXAMPLE 9: Preparation of crystalline Form H1.25-2 of saxagliptin hydrochloride. Saxagliptin hydrochloride (1.0 g) and 1-propanol (20 mL) are charged into flask, heated to 80 °C and stirred at 80 °C 3 hours. The obtained solid is collected by filtration under reduced pressure and dried to afford title compound.
EXAMPLE 10: Preparation of crystalline Form H1.25-2 of saxagliptin hydrochloride. Saxagliptin hydrochloride (1.0 g) and 1-propanol (20 mL) are charged into flask, heated to 60 °C. Saxagliptin hydrochloride H1.25-2 form seed was added to the reaction mixture at 60 °C. The obtained solid is collected by filtration under reduced pressure and dried to afford title compound.
,CLAIMS:WE CLAIM:

1. Crystalline Form I of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 6.8 ? 0.2, 10.4 ? 0.2, 13.5 ? 0.2, 14.5 ? 0.2, 15.1 ? 0.2, 15.8 ? 0.2, 16.6 ? 0.2, 18.1 ? 0.2 and 20.4 ? 0.2 degrees 2-theta.
2. Crystalline Form II of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 6.9 ? 0.2, 13.8 ? 0.2, 15.0 ? 0.2 and 18.2 ? 0.2 degrees 2-theta.
3. Crystalline Form III of saxagliptin hydrochloride further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 6.6 ? 0.2, 14.2 ? 0.2, 15.0 ? 0.2, 16.4 ? 0.2, 17.0 ? 0.2, 18.0 ? 0.2 and 20.8 ? 0.2 degrees 2-theta.
4. Crystalline Form IV of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 3.7 ? 0.2, 6.3 ? 0.2, 14.6 ? 0.2, 15.0 ? 0.2, 16.3 ? 0.2, 17.5 ? 0.2 and 19.2 ? 0.2 degrees 2-theta.
5. Crystalline Form V of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 4.0 ? 0.2, 6.9 ? 0.2, 13.9 ? 0.2, 15.3 ? 0.2, 16.8 ? 0.2, 17.1 ? 0.2, 18.4 ? 0.2 and 23.2 ? 0.2 degrees 2-theta.
6. Crystalline Form VI of saxagliptin hydrochloride characterized by its powder X-ray diffraction (PXRD) pattern having one or more peaks at about 7.8 ? 0.2 and 8.9 ? 0.2 degrees 2-theta.
7. Crystalline Form VI of saxagliptin hydrochloride according to claim 6 further characterized by the powder X-ray diffraction pattern having one or more additional peaks at about 5.1 ? 0.2, 13.5 ? 0.2, 14.4 ? 0.2, 15.3 ? 0.2, 17.9 ? 0.2, 18.5 ? 0.2 and 19.4 ? 0.2 degrees 2-theta.