WO2010141107A1 - Formes solides de pterostilbene - Google Patents

Formes solides de pterostilbene Download PDF

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Publication number
WO2010141107A1
WO2010141107A1 PCT/US2010/022285 US2010022285W WO2010141107A1 WO 2010141107 A1 WO2010141107 A1 WO 2010141107A1 US 2010022285 W US2010022285 W US 2010022285W WO 2010141107 A1 WO2010141107 A1 WO 2010141107A1
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Prior art keywords
pterostilbene
peaks
powder diffraction
ray powder
measured
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PCT/US2010/022285
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English (en)
Inventor
Masna Mahesh
Gottumukkala Venkata Subbaraju
Igor Ivanisevic
Mark Andres
Kyle Stephens
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Aptuit Laurus Private Limited
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Priority claimed from PCT/IN2009/000313 external-priority patent/WO2010010578A2/fr
Application filed by Aptuit Laurus Private Limited filed Critical Aptuit Laurus Private Limited
Publication of WO2010141107A1 publication Critical patent/WO2010141107A1/fr
Priority to US13/011,593 priority Critical patent/US8524782B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/075—Ethers or acetals
    • A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
    • A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/23—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring containing hydroxy or O-metal groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • Pterostilbene trans-3,5-dimethoxy-4'-hydroxystilbene
  • pterostilbene and resveratrol are: [0002]
  • pterostilbene exhibits poor bioavailability and is easily oxidized by various enzymes (Pezet, R., Purification and characterization of a 32- kDa laccase-like stilbene oxidase produced by Botrytis cinerea. FEMS Microbiol. Lett. 1998, 167, 203-208 and Breuil, A. C; Jeandet, P.; Adrian, M.; Chopin, F.; Pirio, N.; Meunier, P.; Bessis, R., Characterization of a pteristilbene dehydrodimer produced by laccase of Botrytis cinerea. Phytopathology 1999, 89, (298-302).).
  • solid form is often used to refer to a class or type of solid-state material.
  • polymorph when used to describe solid-state compounds refers to two or more compounds having the same chemical formula but differing in solid- state structure. When polymorphs are elements, they are termed allotropes. Carbon possesses the well known allotropes of graphite, diamond, and buckminsterfullerene. Polymorphs of molecular compounds, such as active pharmaceutical or nutraceutical ingredients, are often prepared and studied in order to identify compounds meeting scientific or commercial needs including, but not limited to improved solubility, dissolution rate, hygroscopicity, and stability.
  • Other solid forms include solvates and hydrates.
  • a solvate is a compound wherein a solvent molecule is present in the crystal structure together with another compound.
  • the solvent is water, the solvent is termed a hydrate.
  • Solvates and hydrates may be stoichiometric or non-stoichiometric.
  • Five crystalline polymorphs of pterostilbene are disclosed herein and are characterized by various analytical techniques.
  • x-ray amorphous pterostilbene and a t-butanol solvate of pterostilbene are disclosed.
  • the polymorphs, amorphous form, and t-butanol solvate are all solid forms of pterostilbene.
  • the word "characterize” means to identify a collection of data which may be used to identify a solid form.
  • the process by which solid forms are characterized involves analyzing data collected on the forms so as to allow one of ordinary skill in the art to distinguish one solid form from other solid forms containing the same active pharmaceutical or nutraceutical ingredient.
  • Chemical identity of solid forms can often be determined with solution-state techniques such as 13 C NMR or 1 H NMR. While it may help identify the active agent, such as an active pharmaceutical or nutraceutical ingredients, and a solvent molecule for a solvate, such solution-state techniques do not provide information about the solid state.
  • solid-state analytical techniques that can be used to provide information about solid-state structure and differentiate among solid forms such as polymorphs including single crystal x-ray diffraction, powder x-ray diffraction, solid-state 13 C NMR, Raman spectroscopy, and thermal techniques such as Differential Scanning Calorimetry (DSC), melting point, and hot stage microscopy.
  • polymorphs including single crystal x-ray diffraction, powder x-ray diffraction, solid-state 13 C NMR, Raman spectroscopy, and thermal techniques such as Differential Scanning Calorimetry (DSC), melting point, and hot stage microscopy.
  • DSC Differential Scanning Calorimetry
  • peaks which distinguish Form I from the other known forms is a collection of peaks which may be used to characterize Form I. If, for example, two peaks characterize a form then those two peaks can be used to identify the presence of that form.
  • peaks which may be used to characterize polymorphic forms. For example, one may find that three x-ray powder diffraction peaks characterize a form. Additional peaks could also be used, but are not necessary, to characterize the form up to and including an entire diffraction pattern.
  • An x-ray powder diffraction plot is an x-y graph with °2 ⁇
  • the Applicants identified five polymorphs of pterostilbene. X-ray powder diffraction patterns were collected for each of the polymorphs. The peaks for each of the powder patterns were identified and compared with peaks for the patterns representing the other forms to look for peaks present for each form but not present in the others to within experimental variation. Thus, x-ray powder diffraction data to characterize the different polymorphs were identified. A preference was given for peaks with lower °2 ⁇ on the x-axis of each diffraction pattern due to the greater separation between peaks generally in that region of the diffractograms.
  • Single-crystal x-ray diffraction provides three- dimensional structural information about the positions of atoms and bonds in a crystal. It is not always possible or feasible, however, to obtain such a structure from a crystal, due to, for example, insufficient crystal size or difficulty in preparing crystals of sufficient quality for single-crystal x-ray diffraction.
  • Raman spectroscopy is another technique that may be used to characterize solid forms together with or separately from x-ray powder diffraction.
  • Raman spectroscopy is a scattering technique wherein a light source, often a laser, is used to interact with a sample.
  • Raman scattered light which is light that interacts with the sample, is collected by a detector and the intensity of that light can be plotted versus the "wavenumber" of the light to obtain a spectrum.
  • a wavenumber has the units of inverse centimeters (cm -1 ). Wavenumbers are plotted on the x-axis of a Raman spectrum with intensity on the y-axis.
  • Raman peaks are recorded by reference to their x-axis (wavenumber) position rather than their intensity. Variation in the position of Raman peaks also exists and may be due to sample conditions as well as data collection and processing.
  • the typical variability in Raman spectra reported herein is on the order plus or minus 2.0 cm -1 . Thus, the use of the word "about" when referencing Raman peaks is meant to include this variability and all Raman peaks disclosed herein are intended to be reported with such variability.
  • the Raman peaks used to characterize the polymorphs of pterostilbene are selected so that they distinguish the forms from one another. Peaks present in one form but not present in another are peaks that may be used to distinguish with respect to that form. For peak selection purposes, peak separation between peaks among forms was chosen to be 4 cm '1 , which is the resolution of the Raman instrument used. Therefore, for purposes of the disclosure, when a peak is reported as present in a first form but not in second or more forms, it is intended to mean that there is no peak identified less than 4 cm -1 away from that peak in those second or more forms. [0018] Thermal methods are another typical technique to characterize solid forms.
  • the melting point of a polymorph as measured by methods such as capillary melting point, DSC, and hot stage microscopy, alone or in combination with techniques such as x-ray powder diffraction, Raman spectroscopy, or both, may be used to characterize polymorphs or other solid forms.
  • melting points determinations are also subject to variability. Common sources of variability, in addition to instrumental variability, are due to colligative properties such as the presence of other solid forms or other impurities within a sample whose melting point is being measured. [0020] DRAWINGS
  • FIG. 1 is an x-ray powder diffraction pattern of pterostilbene Form I.
  • FIG. 2 is an x-ray powder diffraction pattern of pterostilbene Form II.
  • FIG. 3 is the crystal structure of Form II of pterostilbene.
  • FIG. 4 is an x-ray powder diffraction pattern of pterostilbene Form 111.
  • FIG. 5 is an x-ray powder diffraction pattern of pterostilbene Form IV.
  • FIG. 6 is an x-ray powder diffraction pattern of pterostilbene Form V.
  • FIG. 7 is an x-ray powder diffraction pattern of the t- butanol solvate of pterostilbene.
  • FIG. 8 is an x-ray powder diffraction pattern of x-ray amorphous pterostilbene.
  • FIG. 9 is a stack plot of x-ray powder diffraction patterns of Forms I-V of pterostilbene.
  • FIG. 10 is a Raman spectrum of pterostilbene Form I.
  • FlG. 1 1 is a Raman spectrum of pterostilbene Form II.
  • FIG. 12 is a Raman spectrum of pterostilbene Form III.
  • FIG. 13 is a Raman spectrum of pterostilbene Form IV.
  • FIG. 14 is a Raman spectrum of pterostilbene Form V.
  • FIG. 15 is 1 H NMR spectrum of pterostilbene.
  • FIG. 16 is a DSC stack plot for Forms I-V of pterostilbene.
  • FIG. 17 is a Raman peak list for Forms I-V of pterostilbene.
  • Form D in Table I is a solid form of pterostilbene which
  • the invention provides for seven solid forms of pterostilbene: polymorphs of pterostilbene (Forms I, II, III, IV, and V), a t-butanol solvate of pterostilbene, and an x-ray amorphous form of pterostilbene.
  • the invention provides for processes for making each of the solid forms of pterostilbene which are disclosed herein.
  • substantially pure solid forms of pterostilbene forms I, II, III, V and the x-ray amorphous form are herein provided.
  • formulations of solid forms of pterostilbene are provided.
  • FIG. 1 is a powder x-ray diffraction pattern of Form I of pterostilbene and shows the peak locations of many of the peaks within the diffractogram.
  • the peaks were evaluated and compared to the peaks of the other forms described herein. As is apparent from FIG. 1 , the density of peaks increases after about 15-17 °2 ⁇ . Thus, emphasis was placed on peaks less than or equal to about 15- 17 °2 ⁇ .
  • the peak at about 8.3 °2 ⁇ is present in Form I but not in Form III or Form IL
  • the peak at about 16.7 °2 ⁇ is present in Form I but is not present in Form V or Forms II or III.
  • the Form IV prepared in the disclosure is contaminated with some amount of Form 1.
  • Form I and Form IV as prepared can be distinguished based on melting point.
  • a phase pure or substantially phase pure Form IV would likely be distinguishable from a phase pure or substantially phase pure Form 1.
  • the peak found at about 5.7 °2 ⁇ in FIG. 4 is likely due to the presence of Form 1 as evidenced by data from indexing the various forms.
  • Form IV as prepared was measured to have a melting point of about 76oC whereas Form I was measured to have a melting point of about 94- 96°C.
  • Form I can be characterized by peaks at about 8.3 and 16.7 °2 ⁇ as well as a melting point of about 94-96oC.
  • additional peaks present in the diffractogram may also be used to characterize Form I.
  • one or more of the peaks at about 12.5 and 15.8 °2 ⁇ could additionally be used to characterize the form. It is possible, though not necessary, to also use higher angle peaks to further characterize the form.
  • FIG. 2 is the x-ray powder diffraction pattern of pterostilbene Form II and shows the peak locations of many of the peaks within the diffractogram.
  • the peaks were evaluated and compared to the peaks of the other forms described herein.
  • the density of peaks increases after about 15-17 °2 ⁇ .
  • emphasis was placed on peaks less than about 15-17 °2 ⁇ .
  • the peak at about 5.3 °2 ⁇ is not present in Forms I and Form IV.
  • Form II possesses a peak at about 10.5 °2 ⁇ which is not present in Form III, Form 1, or Form IV.
  • FIG.3 illustrates x-ray crystal structure diagrams for
  • Form 11 of pterostilbene The asymmetric unit of pterostilbene Form II, contains one molecule of pterostilbene in space group P2( l)/n.
  • the molecules pack in single-stranded columns through O-H"*O hydrogen bonds from the hydroxyl group to the oxygen of the methoxy group with an O21 —O1 1 distance of 2.8044( 12) A.
  • the individual strands possess a left-handed helical pattern. Additional stabilizing ⁇ - ⁇ interactions exist between slipped-stacked pterostilbene molecules with ring centroidxentroid distances of 4.0 A.
  • Table 3 A summary of the crystallographic data collected on the single crystal data appear in Table 3.
  • FIG. 4 is the x-ray powder diffraction pattern of pterostilbene Form III.
  • the peaks were evaluated and compared to the peaks of the other forms described herein. As is apparent from FIG. 4, the density of peaks increases after about 20-22 °2 ⁇ . Thus, emphasis was placed on peaks less than about 20-22 °2 ⁇ .
  • the peak at about 13.8 °2 ⁇ distinguishes Form III from Form I as well as Forms II, IV, and V of pterostilbene because that peak is not present in those forms. Thus, the peak at 13.8 °2 ⁇ characterizes that form.
  • peaks present in the diffractogram may also be used to characterize Form III.
  • one or more of the peaks at about 1 1.3, 14.1 , 14.9, and 15.5 °2 ⁇ could additionally be used to characterize the form. It is possible, though not necessary, to also use higher angle peaks to further characterize the form.
  • FIG. 5 is the x-ray powder diffraction pattern of pterostilbene Form IV.
  • the peaks were evaluated and compared to the peaks of the other forms described herein. As is apparent from FIG. 5, the density of peaks increases after about 15- 17 °2 ⁇ . Thus, emphasis was placed on peaks less than about 15- 17 °2 ⁇ .
  • the peak at about 10.0 °2 ⁇ distinguishes Form IV from Form I and from Form V.
  • the peak at about 8.4 °2 ⁇ distinguishes Form IV from Forms II, III, and V of pterostilbene.
  • the peaks at about 8.4 and 10.0 °2 ⁇ characterize Form IV pterostilbene.
  • additional peaks present in the diffractogram may also be used to characterize Form IV.
  • one or more of the peaks at about 12.0 and 15.3 °2 ⁇ could additionally be used to characterize the form. It is possible, though not necessary, to also use higher angle peaks to further characterize the form.
  • FIG. 6 is the x-ray powder diffraction pattern of pterostilbene Form V.
  • the peaks were evaluated and compared to the peaks of the other forms described herein.
  • the peak at about 8.1 °2 ⁇ distinguishes Form V from the other polymorphic forms of pterostilbene.
  • the peak at about 8.1 °2 ⁇ characterize Form V.
  • additional peaks present in the diffractogram may also be used to characterize Form V. For example, one or more of the peaks at about 5.2, 8.9, 10.4. 12.1 and 14.2 °2 ⁇ could additionally be used to characterize the form.
  • FIG. 7 is the x-ray powder diffraction pattern of the t- butanol solvate of pterostilbene.
  • the t-butanol solvate can be distinguished from any one of the polymorphs of pterostilbene due to the presence of t-butanol within the unit cell of the compound.
  • the selection of characteristic peaks of the t-butanol solvate was, therefore, based on using low-angle peaks with sufficient intensity. Thus, one or more of the peaks at about 8, 1 and 16.1 °2 ⁇ can further be used to characterize this form.
  • FlG. 8 is the x-ray diffraction pattern of x-ray amorphous pterostilbene.
  • x-ray amorphous what is meant is a material whose powder x-ray powder diffraction pattern is consistent with an amorphous "halo" as that term is understood in the art.
  • the pattern in FlG. 8 does represents a material without any significant crystallinity. However, the material may be nanocrystalline or some other disordered solid.
  • FIG. 9 a stack plot of the x-ray diffraction patterns of
  • Forms I- V of pterostilbene are presented in one plot to illustrate visually the differences among the forms.
  • FIG. 10 is the Raman spectrum of pterostilbene Form I.
  • Form I of pterostilbene In order to differentiate Form I of pterostilbene from the other polymorphs of pterostilbene, the peaks were evaluated and compared to the peaks of the other forms described herein.
  • the peak at about 865 cm -1 is not present in Forms Il or III.
  • the peak at 195 cm -1 in Form 1 is not present in Form IV.
  • Form I of pterostilbene can be characterized by Raman peaks at about 195, 865 and 1358 cm -1 .
  • Form I can be distinguished by melting point from Form IV.
  • Form IV as prepared was measured to have a melting point of about 76oC whereas Form I was measured to have a melting point of about 94-96oC.
  • Form I of pterostilbene can also be characterized by Raman peaks at about 865 and 1358 cm -1 and by a melting point of about 94-96°C with or without the
  • FIG. 1 1 is the Raman spectrum of Form II of pterostilbene. In order to differentiate Form II of pterostilbene from the other polymorphs of pterostilbene, the peaks were evaluated and compared to the peaks of the other forms described herein. The peak at about 960 cm -1 is not present in Form I. The peak at about 1587 cm- is not present in Forms III or V. The peak at about 1442 cm -1 is not present in Form IV or Form I.
  • Form II of pterostilbene can be characterized by Raman peaks at about 960, 1587, and 1442 cm -1 .
  • Other peaks in the Raman spectrum of Form II such as one or more peaks selected from about 201 , 1 163, and 1 194 cm -1 can further be used to characterize Form II of pterostilbene.
  • FIG. 12 is the Raman spectrum of Form III of pterostilbene. In order to differentiate Form III of pterostilbene from the other polymorphs of pterostilbene, the peaks were evaluated and compared to the peaks of the other forms described herein. The peak at about 958 cm -1 is not present in Form I.
  • Form III of pterostilbene can be characterized by Raman peaks at about 958, 1 187, and 1439 cm- .
  • Other peaks in the Raman spectrum of Form III, such as one or more peaks selected from about 1339 and 1596 cm -1 can further be used to characterize Form III of pterostilbene.
  • FIG. 13 is the Raman spectrum of pterostilbene Form IV.
  • Form IV of pterostilbene In order to differentiate Form IV of pterostilbene from the other polymorphs of pterostilbene, the peaks were evaluated and compared to the peaks of the other forms described herein.
  • the peak at about 862 cm -1 is not present in Forms III or Form V.
  • the peak at about 1320 cm -1 is not present in Form II, Form III, or Form V.
  • the peak at about 200 cm -1 is not present in Form I, Form III, or Form V.
  • the peaks at about 200, 862 and 1320 cm '1 characterize Form IV.
  • Form IV as prepared was measured to have a melting point of about 76oC whereas Form I was measured to have a melting point of about 94-96oC.
  • Form IV of pterostilbene can also be characterized by Raman peaks at about 862 and 1320 cm -1 and a melting point of about 76°C with or without a Raman peak at about 200 cm -1 .
  • FIG. 14 is the Raman spectrum of pterostilbene Form V.
  • Form V of pterostilbene In order to differentiate Form V of pterostilbene from the other polymorphs of pterostilbene, the peaks were evaluated and compared to the peaks of the other forms described herein.
  • the peak at about 867 cm -1 is not present in Forms II or IV.
  • the peak at about 962 cm -1 is not present in Form 1.
  • the peak at about 1444 cm -1 is not present in Form III, Form 1, or Form IV.
  • Form V of pterostilbene can be characterized by Raman peaks at about 867, 962, and 1444 cm -1 .
  • Other peaks in the Raman spectrum of Form V such as one or more peaks selected from about 1 160 and 1341 cm -1 can further be used to characterize Form V of pterostilbene.
  • FIG. 15 is the 1 H NMR spectrum of pterostilbene which can be used to verify its chemical structure.
  • the polymorphs of pterostilbene described herein can be characterized by a variety of techniques. Illustrated herein are characterizations done by x-ray powder diffraction, thermal methods such as melting point, and Raman spectroscopy. Those of ordinary skill in the art will recognize that combinations of these techniques can also be used to characterize the polymorphs of pterostilbene. For example, peaks from both the Raman spectrum and from an x-ray diffraction pattern could be used in combination to characterize a particular polymorph of pterostilbene following the general principles of identifying distinguishing peaks as disclosed herein.
  • Form I pterostilbene may be prepared by treating a solution of (2-4-[(E)-2-(3, 5-dimethoxyphenyl)- l -ethenyl] phenoxy tetra hydro-2H-pyran) with pyridinium p -toluenesulfonate in a suitable solvent, followed by removing the solvent by vacuum to obtain a solid, purifying the solid, redissolving it in a suitable solvent, and precipitating it to afford Form I pterostilbene.
  • Embodiments for the preparation of Form I include the preparation of substantially pure Form I.
  • pterostilbene form I may be prepared by dissolving solid pterostilbene of any form in a suitable solvent followed by evaporation of solvent.
  • a suitable solvent is trifluoroethanol.
  • Embodiments for the preparation of Form I include the preparation of substantially pure Form I.
  • Form II may be prepared by dissolving solid pterostilbene of any form in a suitable solvent followed by evaporation of solvent.
  • suitable solvent is acetonitrile.
  • Embodiments for the preparation of Form II include the preparation of substantially pure Form II.
  • Form III pterostilbene may be prepared by dissolving solid pterostilbene of any form in a suitable solvent followed by evaporation of solvent.
  • suitable solvent is methanol.
  • Embodiments for the preparation of Form III include the preparation of substantially pure Form III.
  • Form IV pterostilbene may be prepared by dissolving solid pterostilbene of any form in a suitable solvent followed by slow evaporation of solvent.
  • suitable solvent is methanol.
  • slow evaporation By “slow evaporation” what is meant is evaporation that is limited so that it occurs at a slower rate than by leaving a container open to ambient conditions. Slow evaporation may be accomplished by, for example, covering portions of a container containing the solution to be evaporated. In one embodiment, evaporation conditions are chosen such that for a slow evaporation, evaporation time is greater than about three times the evaporation time than under standard conditions. In a further embodiment, that time is between about three to four times slower than under standard conditions.
  • Form V pterostilbene may be prepared by melting pterostilbene of any form to form amorphous pterostilbene and exposing the amorphous pteristilbene to a sufficiently low-humidity environment, such as approximately 10% or less relative humidity, at approximately room temperature to convert the amorphous pterostilbene into Form V pterostilbene.
  • the preparation of Form V includes embodiments for the preparation of substantially pure Form V.
  • x-ray amorphous pterostilbene may be prepared by melting any form of pterostilbene.
  • the t- butanol solvate of pterostilbene may be prepared by making a saturated solutions of pterostilbene in t-butanol, cooling, and lyophi ⁇ zing.
  • suitable solvent is a solvent suitable for the formation of the particular polymorph or solid form of pterostilbene of interest. Such solvents are determined empirically.
  • methanol is a suitable solvent for the preparation of either Form III or Form IV of pterostilbene whereas under certain conditions acetonitrile is a suitable solvent for the preparation of Form II of pterostilbene.
  • compositions containing one or more solid forms of pterostilbene such as pharmaceutical or nutraceutical dosage forms.
  • Such pharmaceutical dosage forms may include one or more excipients, including, without limitation, binders, fillers, lubricants, emulsifiers, suspending agents, sweeteners, flavorings, preservatives, buffers, wetting agents, disintegrants, effervescent agents and other conventional excipients and additives.
  • compositions of the present disclosure can thus include any one or a combination of the following: a pharmaceutically acceptable carrier or excipient; other medicinal agent(s); pharmaceutical agent(s); adjuvants; buffers; preservatives; diluents; and various other pharmaceutical additives and agents known to those skilled in the art.
  • additional formulation additives and agents will often be biologically inactive and can be administered to humans without causing deleterious side effects or interactions.
  • Suitable additives may include, but are not limited to, microcrystalline cellulose, lactose, sucrose, fructose, glucose, dextrose, other sugars, di-basic calcium phosphate, calcium sulfate, cellulose, methylcellulose, cellulose derivatives, kaolin, mannitol, lactitol, maltitol, xylitol, sorbitol, other sugar alcohols, dry starch, dextrin, maltodextrin, other polysaccharides, or mixtures thereof.
  • the solid- form pterostilbene dosage form is an oral dosage form.
  • Exemplary oral dosage forms for use in the present disclosure include tablets, capsules, powders, solutions, syrups, suspensions and lozenges, which may be prepared by any conventional method of preparing pharmaceutical oral dosage forms.
  • Oral dosage forms such as tablets, may contain one or more of the conventional, pharmaceutically acceptable additional formulation ingredients, including but not limited to, release modifying agents, glidants, compression aides, disintegrants, effervescent agents, lubricants, binders, diluents, flavors, flavor enhancers, sweeteners and preservatives. These ingredients are selected from a wide variety of excipients known in the pharmaceutical formulation art. Depending on the desired properties of the oral dosage form, any number of ingredients may be selected alone or in combination for their known use in preparing such dosage forms as tablets.
  • the disclosure also provides methods for delivering the dosage forms to humans.
  • Pterostilbene an anti-oxidant, is known be beneficial for human health.
  • the dosage forms may be administered using any amount, any form of pharmaceutical composition and any route of administration effective for the treatment.
  • the pharmaceutical compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intravenously, intracisternally, intravaginally, intraperitoneal Iy, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the location and severity of the condition being treated.
  • the method of delivery is with an oral dosage form.
  • solid forms of pterostilbene may be administered at dosage levels of about 0.001 mg/kg to about 50 mg/kg , from about 0.01 mg/kg to about 25 mg/kg , or from about 0.1 mg/kg to about 10 mg/kg of subject body weight per day, one or more times a day, to obtain the desired effect. It will also be appreciated that dosages smaller than 0.001 mg/kg or greater than 50 mg/kg (for example 50- 100 mg/kg) can be administered to a subject. [0090] EXAMPLES
  • X-ray powder diffraction (XRPD) patterns on Form IV and the t-butanol solvate were collected using an Inel XRG-3000 diffractometer (Artenay, France) equipped with a curved position sensitive detector with a 2 ⁇ range of 120° and operated in transmission mode.
  • An incident beam of Cu Ka radiation (40 kV, 30 mA) was used to collect data in real time at a resolution of 0.03° 2 ⁇ .
  • a silicon standard NIST SRJVT 640c
  • Samples were prepared for analysis by packing them into thin-walled glass capillaries. Each capillary was mounted onto a goniometer head and rotated during data acquisition. The monochromator slit was set at 5 mm by 160 ⁇ m, and the samples were analyzed for 5 minutes.
  • PANalytical X'Pert Pro diffractometers (Almelo, The Netherlands) configured in reflection and transmission geometries, respectively.
  • Form V was analyzed using (Bragg-Brentano geometry), an incident beam of Cu Ka radiation (45 kV, 40 mA) was produced using a ceramic tube with a long, fme-focus source and a nickel filter. A reflection stage and a manually operated spinner were used.
  • the specimen was prepared as a thin, circular layer centered on a silicon zero-background substrate. The data were collected from 3.5- 40.0 °2 ⁇ at a resolution of 0.008 °2 ⁇ for approximately 30 min.
  • An Anton Paar (Ashland, VA) TCU 100 Temperature Control Unit and a VTI (Hialeath, FL) RH-200 Relative Humidity Generator were used for temperature and humidity-controlled experiments.
  • Forms I, II, and III and the amorphous form were analyzed using an incident beam of Cu Ka radiation (45 kV, 40 mA) was produced using an Optix long, fine-focus source.
  • An elliptically graded multilayer mirror was used to focus the Cu K ⁇ X-rays of the source through the specimen and onto the detector. The specimen was sandwiched between 3 ⁇ m thick Etnom® films and rotated to optimize orientation statistics.
  • a beam-stop and a helium atmosphere were used to minimize the background generated by air scattering and produce data suitable for indexing.
  • the data were collected from 1.0-40.0 °2 ⁇ at a resolution of 0.017 °2 ⁇ for 12-32 min.
  • anti-scatter slits were used to minimize the background generated by air scattering and soller slits were used for the incident and diffracted beams to minimize axial divergence (1/8° and 1/4°, respectively, for reflection geometry and 1/2° and 1/4°, respectively for transmission geometry).
  • Diffraction patterns were collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen.
  • PANalytical XRPD data were collected and analyzed using X'Pert Pro Data Collector software (v. 2.2b). Prior to the analysis, a silicon specimen (NIST SRM 640c) was analyzed to verify the Si 1 1 1 peak position.
  • Peak positions are dependent upon x-ray wavelength according to Bragg's law. Instruments utilizing different wavelengths of incident x-ray radiation will result in different °2 ⁇ peaks. However given a peak with one wavelength, and by using Bragg's law, one of ordinary skill in the art will readily be able to calculate the appropriate peak in °2 ⁇ for another wavelength. Those of ordinary skill in the art will recognize that diffraction angle may also be calculated in d-space also using Bragg's law. Thus, all diffraction peaks provided herein have equivalent d-spacings which can be used to characterize the forms. D-spacings are not dependent upon the wavelength of the incident x-ray. All diffraction peaks reported herein used Cu-K ⁇ radiation.
  • DSC Differential Scanning Calorimetry
  • TG analyses were performed using a TA Instruments Q5000 IR thermogravimetric analyzer. Temperature calibration was performed using nickel and Alumel. Each sample was placed in an aluminum pan. The pan was hermetically sealed with a lid that was opened using a punching mechanism just before being inserted into the TG furnace. The furnace was heated under nitrogen at a rate of 10 °C/minute. [0099] Raman spectra were acquired on a Thermo Nicolet
  • FT-Raman 960 spectrometer equipped with a germanium (Ge) or indium gallium arsenide (InGaAs) detector. Additional Raman spectra were acquired on a Nexus 670 FT-Raman accessory module interfaced to a Nexus 670 FT-IR spectrophotometer (Thermo Nicolet) equipped with an indium gallium arsenide (InGaAs) detector. Wavelength verification was performed using sulfur and cyclohexane. Each sample was prepared for analysis by placing the sample into a glass tube and positioning the tube in a gold-coated tube holder or placing the sample into a pellet holder.
  • the samples were dissolved in CDCl 3 and each spectrum was acquired with a 1 H pulse width of 7.9 ⁇ s, a 2.500 second acquisition time, a 5.000 second delay between scans, a spectral width of 6400.0 Hz with 32K data points, and 40 co-added scans.
  • the free induction decay (FID) was processed with 13 IK points with an exponential line-broadening factor of 0.2 Hz to improve the signal-to-noise ratio.
  • the spectra were referenced to tetramethylsilane (0 ppm), which was present in the NMR solutions as an internal standard.
  • UV-VIS spectrophotometry samples were analyzed using a SpectraMax M2 Microplate Reader. Wavelength calibration and photometric accuracy was performed using the SpectraMax Pro 5 software as an internal calibration of the instrument. The instrument was blanked with an empty quartz glass plate. Samples were analyzed in the UV range at ambient temperature in the wells of a 96-well quartz plate. The absorbance spectra of water was collected and subtracted from the spectra of the drug solutions to calculate concentrations. Samples were performed in duplicate and absorbance data was averaged. The standard curve was determined based on absorbance at 310 nm.
  • the melted material was determined to be amorphous by x-ray powder diffraction.
  • the sample was immediately placed into a low (-10%) relative humidity environment at 20 oC.
  • the sample was continuously monitored by XRPD until the amorphous material had crystallized (-36 hours).
  • X-ray amorphous material was generated by melting crystalline pterostilbene (Form I) directly into a thin-polymer
  • Single crystals of pterostilbene Form II suitable for single-crystal x-ray diffraction were obtained from crystallizing a 1 :2 stoichiometric ratio of pterostilbene to isonicotinamide by dissolving both components in ethanol and placing the solution in a larger vial containing water (antisolvent) for three days, resulting in crystals of pterostilbene Form II.
  • Data were collected on a Bruker SMART APEX Il using MoKa radiation.
  • Data were collected using APEXII software (APEXII v. 2009.1 1 -0, ⁇ 2005 - 2009, Bruker Analytical X- ray Systems, Madison, WI).
  • Unit cell constants and orientation matrix were improved by least-squares refinement of reflections thresholded from the entire dataset. Integration was performed with SAINT (SAINT v7.68A, ⁇ 1997 - 2009, Bruker Analytical X-ray Systems, Madison, WI) using this improved unit cell as a starting point. Precise unit cell constants were calculated in SAINT from the final merged dataset. Lorenz and polarization corrections were applied. An absorption correction was not applied ( ⁇ *d ⁇ 0.03).

Abstract

L'invention concerne des formes solides de ptérostilbène. L'invention concerne plus particulièrement cinq polymorphes de ptérostilbène. L'invention concerne également un solvate de t-butanol et une forme de ptérostilbène amorphe aux rayons X.
PCT/US2010/022285 2008-07-23 2010-01-27 Formes solides de pterostilbene WO2010141107A1 (fr)

Priority Applications (1)

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US13/011,593 US8524782B2 (en) 2008-07-23 2011-01-21 Key intermediate for the preparation of Stilbenes, solid forms of Pterostilbene, and methods for making the same

Applications Claiming Priority (2)

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PCT/IN2009/000313 WO2010010578A2 (fr) 2008-07-23 2009-06-01 Intermédiaire clé pour la préparation des stilbènes
INPCT/IN2009/000313 2009-06-01

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US8318807B2 (en) 2010-02-03 2012-11-27 Laurus Labs Private Limited Pterostilbene cocrystals
CN104672066A (zh) * 2015-03-09 2015-06-03 大兴安岭林格贝寒带生物科技股份有限公司 从蓝莓中分离纯化紫檀芪的方法
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US8318807B2 (en) 2010-02-03 2012-11-27 Laurus Labs Private Limited Pterostilbene cocrystals
US8399712B2 (en) 2010-02-03 2013-03-19 Laurus Labs Private Limited Pterostilbene cocrystals
US8415507B2 (en) 2010-02-03 2013-04-09 Laurus Labs Private Limited Pterostilbene cocrystals
US8513236B2 (en) 2010-02-03 2013-08-20 Laurus Labs Private Limited Pterostilbene cocrystals
CN104672066A (zh) * 2015-03-09 2015-06-03 大兴安岭林格贝寒带生物科技股份有限公司 从蓝莓中分离纯化紫檀芪的方法
CN104672066B (zh) * 2015-03-09 2017-05-10 大兴安岭林格贝寒带生物科技股份有限公司 从蓝莓中分离纯化紫檀芪的方法
US10610556B2 (en) 2015-09-17 2020-04-07 Therapeutic Solutions LLC Compositions for regulation and control of appetite

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