NEW SOLID FORMS OF DESVENLAFAXIN (Machine-translation by Google Translate, not legally binding)

专利摘要:
The present invention relates to new amorphous and crystalline solid forms of desvenlafaxine, also called O-desmethylvenlafaxine or desmethylvenlafaxine, and to their salts, solvates, hydrates and polymorphs thereof, as well as to their use in the preparation of a pharmaceutical composition useful for the treatment of depression and/or selective inhibitor of the reuptake of serotonin and norepinephrine as well as the vasomotor disorders associated with menopause. (Machine-translation by Google Translate, not legally binding)
公开号:ES2648369A1
申请号:ES201730859
申请日:2017-06-28
公开日:2018-01-02
发明作者:Jorge Guillermo Domínguez Chávez；Karina Mondragón Vásquez；Hugo Morales Rojas；Dea Herrera Ruiz；Herbert Höpfl；Reyna REYES MARTÍNEZ；Javier HERNÁNDEZ ILLESCAS；Juan Pablo Senosiain Peláez
申请人:Alparis SA De Cv；Alparis SA de CV；
IPC主号:

专利说明:

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DESCRIPTION
NEW SOLID FORMS OF DEVENLAFAXINE FIELD OF THE INVENTION
The present invention relates to new amorphous and crystalline solid forms of desvenlafaxine, also called O-desmethylvenlafaxine or demethylvenlafaxine, and their salts, solvates, hydrates and polymorphs thereof, as well as their use in the preparation of a pharmaceutical composition useful for the treatment of depression and / or selective inhibitor of serotonin and norepinephrine reabsorption as well as vasomotor disorders associated with menopause.
BACKGROUND OF THE INVENTION
Desvenlafaxine is the main active metabolite of venlafaxine, it is called O-desmethylvenlafaxine or desmethylvenlafaxine, it is a selective serotonin and norepinephrine reuptake inhibitor (SSRI), represented by the following structural formula:
image 1
Desvenlafaxine (DSV), chemical name (±) -1- [2- (dimethylamino) -1- (4-hydroxyphenyl) ethyl] cyclohexanol, as well as its pharmaceutically acceptable salts, were first described in US4535186.
Desvenlafaxine free base can also be named as Desvenlafaxine base, pure or neutral. Desvenlafaxine is administered orally, primarily as succinate salt, for
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treatment of depression and for vasomotor disorders associated with menopause. It is preferably administered as modified release preparations.
The dose used ranges from 50mg to 400mg a day, preferably once a day. High doses of 400mg per day may be associated with adverse effects.
Dose between 100mg to 200mg daily is not recommended in patients with moderate to severe hepatic impairment.
There are patent documents that describe the process of obtaining desvenlafaxine and its salts, methods of purification thereof and pharmaceutical compositions, but none of them refers to the NFS of desvenlafaxine described in the present invention.
Patent document WO2000032555 (US6197828) by Sepracor describes desvenlafaxine as a base also known as a free, neutral or pure base.
WO2002064543 (US6673838) by Wyeth, and WO2000059851 (US8269040) by Sepracor refer to the product O-desmethylvenlafaxine succinate.
Lek Pharma documents US2011082213; WO2010060390 and WO2011006455 of Zenti- Va, describe obtaining desvenlafaxine and / or salts such as D-glucuronate monohydrate, orotic acid, among others.
WO2009138234 of KRKA Tovarna and US8481596 of Lupine Ltd, describe processes for obtaining desvenlafaxine using p-toluenesulfonic acid and benzoic acid.
WO2009053840 (US2011046231) of Actavis Group PTC, describes desvenlafaxine salts selected from oxalate, benzoate and lactate salts with addition salts of hydrochloric, sulfuric, toluenesulfonic acid, among others.
US20090246284 Actavis Group describes a co-crystal comprising ortho-desmethylvenlafaxine and succinic acid.
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US20130028937 by Esteve Laboratories refers to a co-crystal of venlafaxine and celecoxib.
In the state of the art, no documents were found that refer to obtaining new solid forms of desvenlafaxine with hydroxybenzoic acid; for example, 3- hydroxybenzoic acid (3-HB), 3,4-dihydroxybenzoic acid (3,4-DHB) or 3,4,5-trihydroxybenzoic acid (3,4,5-THB), among others.
During the process of obtaining new solid forms one can think of a large number of combinations with possible coformers, however only some of these combinations generate a stable solid form, as demonstrated in the description of the present application.
SUMMARY OF THE INVENTION
The present invention relates to new solid forms (NFS) of desvenlafaxine (DSV), which have a constant quality and which can have improved physicochemical properties such as physical and chemical stability, better flow properties and dissolution rate. modified
In the present invention, the term "new solid forms" (NFS) refers to any solid material (phase) that exhibits intermolecular interactions between at least two independent molecular entities, in any stoichiometric relationship, where at least one of the molecular entities Independent is a pharmaceutical entity.
These new solid forms contain at least one therapeutic molecule also called a drug, in this case desvenlafaxine, and a pharmaceutically acceptable counter-ion or coformor.
In the present invention the new solid forms (NFS) of desvenlafaxine (DSV) are obtained by combining the drug chemically or physically with coformers. The coformers used in the present invention possess one or more hydroxyl and carboxyl groups, which can form new molecules or complexes through ionic interactions, hydrogen bonds and / or
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Van der Waals links with desvenlafaxine or with other active substances that have similar structural characteristics, such as venlafaxine or another cycloalkane ethylamine.
In the present invention the coformers used are:
2-hydroxybenzoic acid or 2-HB or o-HB;
3-hydroxybenzoic acid or 3-HB or m-HB;
4-hydroxybenzoic acid or 4-HB or p-HB, also called salicylic acid.
2,3-dihydroxybenzoic acid or 2,3-DHB or hypogalic acid 2,4-dihydroxybenzoic acid or 2,4-DHB or p-resorcylic acid 2,5-dihydroxybenzoic acid or 2,5-DHB or gentisic acid Acid 2, 6-dihydroxybenzoic or 2,6-DHB or Y-resorcylic acid 3,4-dihydroxybenzoic acid or 3,4-DHB or protocatecholic acid 3,5-dihydroxybenzoic acid or 3,5-DHB or a-resorcyl acid 3,4 , 5-trihydroxybenzoic or 3,4,5-THB or gallic acid.
BRIEF DESCRIPTION OF THE DRAWINGS
The following figures illustrate the characterization of desvenlafaxine NFS by IR spectroscopy, X-ray powder diffraction (DRXP) and DSC-TGA calorimetric analysis.
Figure 1A IR spectrum of: a) Neutral desvenlafaxine, b) New amorphous solid phase Desvenlafaxine-3-hydroxybenzoic acid, and c) 3-hydroxybenzoic acid.
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Figure 1B IR spectrum of: a) Neutral desvenlafaxine, b) 3,4-dihydroxybenzoic acid, and c) New amorphous solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid.
Figure 1C IR spectrum of: a) Neutral desvenlafaxine, b) New amorphous solid phase of Desvenlafaxine-3,4,5-trihydroxybenzoic acid and c) 3,4,5-trihydroxybenzoic acid.
Figure 2A X-ray diffractograms of: a) Neutral desvenlafaxine, b) New amorphous solid phase of Desvenlafaxine-3-Hydroxybenzoic Acid and c) 3-hydroxybenzoic acid.
Figure 2B X-ray diffractograms of: a) Neutral desvenlafaxine, b) New amorphous solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid and c) 3,4-dihydroxybenzoic acid.
Figure 2C X-ray diffractograms of: a) Neutral desvenlafaxine, b) New amorphous solid phase of Desvenlafaxine-3,4,5-trihydroxybenzoic acid and c) 3,4,5-trihydroxybenzoic acid.
Figure 3A DSC-TGA calorimetric analysis of the new amorphous solid phase of Desvenafaxine-3-hydroxybenzoic acid.
Figure 3B DSC-TGA calorimetric analysis of the new amorphous solid phase of Desvenafaxine-3,4-dihydroxybenzoic acid.
Figure 3C DSC-TGA calorimetric analysis of the new amorphous solid phase of Desvenafaxine-3,4,5-trihydroxybenzoic acid.
Figure 4A Comparison of dissolution rate profiles in: a) Phosphate buffer (pH = 6.8), b) Acetate buffer (pH = 4.8) and c) HCl solution pH 1.2, of neutral Desvenlafaxine (line with P-squares)), new solid amorphous phase of Desvenlafaxine-3,4-dihydroxybenzoic acid (line with circles (•)) and the physical mixture of Desvenlafaxine with 3,4-dihydroxybenzoic acid (line with triangles (A)).
Figure 4B Comparison of dissolution rate profiles in: a) Phosphate buffer (pH = 6.8), b) Acetate buffer (pH = 4.8) and c) HCl solution pH 1.2, of neutral Desvenlafaxine (line with P-squares)), the new solid amorphous phase of Desvenlafaxine-Acid 3,4,5-
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trihydroxybenzoic (line with circles (•)) and the physical mixture of Desvenlafaxine with 3,4,5-trihydroxybenzoic acid (line with triangles (A)).
Figure 4C Comparison of dissolution rate profiles in: a) Phosphate buffer (pH = 6.8), b) Acetate buffer (pH = 4.8) and c) HCl solution pH 1.2, of the new amorphous solid phase of Desvenlafaxine-Acid 3 -hydroxybenzoic (line with circles (•)) and the physical mixture of Desvenlafaxine with 3-hydroxybenzoic acid (line with triangles (A)).
Figure 5A Diffractograms of powders obtained from the stability test for: a)
Neutral desvenlafaxine, b) co-formator 3,4,5-trihydroxybenzoic acid, c) the new solid amorphous phase of Desvenlafaxine-3,4,5-trihydroxybenzoic acid, d) amorphous phase subjected to dry 45 ° C and e) amorphous phase subjected to 50 ° C dry.
Figure 5B Diffractograms of powders obtained from the stability test for: a)
Neutral Desvenlafaxine, b) 3-hydroxybenzoic Acid co-formator, c) the new amorphous solid phase of Desvenlafaxine-Initial 3-hydroxybenzoic Acid, d) amorphous phase subjected to 45 ° C dry and e) amorphous phase subjected to 50 ° C dry.
Figure 5C Diffractograms of powders obtained from the stability test for: a)
Neutral desvenlafaxine, b) coformator 3,4-dihydroxybenzoic acid, c) New amorphous solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid initial, d) amorphous phase subjected to 45 ° C dry, e) amorphous phase subjected to 50 ° C dry and f) amorphous phase subjected to 40 ° C with 75% relative humidity.
Figure 6A X-ray powder diffractogram of the new amorphous solid phase of
Desvenlafaxine-3,4,5-trihydroxybenzoic acid obtained in Methanol.
Figure 6B X-ray powder diffractogram of the new amorphous solid phase of
Desvenlafaxine-3,4,5-trihydroxybenzoic acid obtained in Ethanol.
Figure 7. X-ray diffractogram in crystalline solid phase powder of Desvenlafaxine-3,4-dihydroxybenzoic acid.
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Figure 8. Thermogravimetric analysis of the new crystalline solid phase of Desvenlafaxine-Acid
3.4- dihydroxybenzoic.
Figure 9. Crystal structure obtained by monocrystalline X-ray diffraction for the new crystalline solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid.
Figure 10. X-ray diffractogram of new crystalline solid phase of Desvenlafaxine-Acid
2.4-dihydroxybenzoic.
Figure 11. Thermogravimetric analysis of the new crystalline solid phase of Desvenlafaxine-2,4-dihydroxybenzoic acid.
Figure 12. Crystal structure obtained by monocrystalline X-ray diffraction for the new crystalline solid phase of Desvenlafaxine-2,4-dihydroxybenzoic acid.
Figure 13. Dissolution graph of the new crystalline solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid at pH 1.2, 4.5 and 6.8.
Figure 14. Dissolution profile in HCl solution (pH 1.2, 37 ° C, 50 rpm, n = 3, + SD) of the new crystalline solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid (DSV: 3,4- Crystalline DHB), and comparison with the new amorphous solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid (DSV: 3,4-DHB amorphous), the new crystalline solid phase Desvenlafaxine-2,4-dihydroxybenzoic acid (DSV: 2, 4-crystalline DHB), Desvenlafaxine (DSV) and Desvenlafaxine succinate (DSV Succinate).
Figure 15. Acetate buffer dissolution profile (pH 4.5, 37 ° C, 50 rpm, n = 3, + SD) of the new crystalline solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid (DSV: 3,4- Crystalline DHB), and comparison with the new amorphous solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid (DSV: 3,4-DHB amorphous), the new crystalline solid phase Desvenlafaxine-Acid
2.4- dihydroxybenzoic acid (DSV: crystalline 2,4-DHB), Desvenlafaxine (DSV) and Desvenlafaxine succinate (DSV Succinate).
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Figure 16. Phosphate buffer dissolution profile (pH 6.8, 37 ° C, 50 rpm, n = 3, + SD) of the new crystalline solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid (DSV: 3,4- Crystalline DHB), and comparison with the new amorphous solid phase of Desvenlafaxine-3,4-dihydroxybenzoic acid (DSV: 3,4-DHB amorphous), the new crystalline solid phase Desvenlafaxine-Acid
2,4-dihydroxybenzoic acid (DSV: crystalline 2,4-DHB), Desvenlafaxine (DSV) and Desvenlafaxine succinate (DSV Succinate).
DESCRIPTION OF THE INVENTION
The present invention describes in detail the obtaining of new solid forms of DSV, amorphous and crystalline, starting from neutral DSV and the interaction with the selected coformers. The proposed coform of hydroxybenzoic acids have a pKa ranging from 1.2 to 4.5.
New Amorphous Solid Forms
The present invention shows the formation of new stable amorphous solid phases (NFS) such as Desvenlafaxine-3,4,5-trihydroxybenzoic acid (DSV: 3,4,5-THB), Desvenlavaxine-3,4-dihydroxybenzoic acid ( DSV: 3,4-DHB) and Desvenlafaxine-3- hydroxybenzoic acid (DSV: 3-HB).
In the present invention, amorphous NFS formed from a selective serotonin and norepinephrine reuptake inhibitor (desvenlafaxine or DSV) and a co-former X are exhibited: wherein X has one or more hydroxyl groups and a carboxyl, and can form a new chemical entity through ionic interactions or intermolecular forces such as hydrogen bonds and / or van der Waals bonds; as well as solvates, hydrates and / or polymorphs of DSV: X. The coformer X is selected from: 2-hydroxybenzoic acid (2-HB), 3- hydroxybenzoic acid (3-HB), 4-hydroxybenzoic acid (4-HB), 2,3-dihydroxybenzoic acid (2,3-DHB) , 2,4-dihydroxybenzoic acid (2,4-DHB), 2,5-dihydroxybenzoic acid (2,5-DHB), 2,6-dihydroxybenzoic acid (2,6-DHB), 3,4-dihydroxybenzoic acid ( 3,4-DHB), 3,5-dihydroxybenzoic acid (3,5-DHB) and 3,4,5-trihydroxybenzoic acid (3,4,5-THB).
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Each new solid phase is characterized by powder X-ray diffraction, infrared spectroscopy, Raman and thermal analysis by differential scanning calorimetry and thermogravimetric analysis.
The following example is not limiting the process of obtaining new solid amorphous forms.
a) Dissolve a stoichiometric drug-coform composition 1: 1 in polar solvent selected for example from methanol, ethanol, 96 ° ethanol, acetone and mixtures thereof.
b) The mixture is placed in a rotary evaporator in a bath at 70-80 ° C for evaporation assisted by a vacuum pump, until the solvent evaporates completely.
c) The heating is maintained under reduced pressure to ensure complete evaporation of the solvent.
d) The resulting solid is extracted from the container and stored in closed vials for complete characterization.
Results and characterization
A visual analysis of the NFS obtained from desvenlafaxine was performed with the various coformers. In some cases, dry and manageable foamy solids are obtained, and in other cases semi-solids with a smooth and unmanageable appearance are produced, as detailed in Table 1.
Table 1. NFS and its appearance after its synthesis
 New Solid Form  Appearance of amorphous New form Solid Appearance of amorphous
 DSV: 2-HB  Semi-solid DSV: 2,5-DHB Semi-solid
 DSV: 3-HB  DSV foamy solid: 2,6-DHB Semisolid
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 DSV: 4-HB  Semi-solid DSV: 3,4-DHB Foamy solid
 DSV: 2,3-DHB  DSV foamy solid: 3,5-DHB Semisolid
 DSV: 2,4-DHB  Semi-solid DSV: 3,4,5-THB Foamy solid
Amorphous NFS characterization by Infrared Spectroscopy
Infrared spectroscopy is sensitive to the formation of intermolecular forces such as the hydrogen bridge and the formation of ionic pairs, being an important tool in the determination of NFS.
IR spectra were obtained for: a) neutral DSV, b) New solid phase (DSV: coform) and c) coform used. Figures 1A, 1B and 1C show the IR spectra of the NFS (raw materials and product) with 3-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid, respectively. For each of these spectra, item a) corresponds to the neutral desvenlafaxine spectrum, item b) corresponds to the NFS spectrum, and item c) corresponds to the coformer spectrum.
As can be seen in Figures 1A, 1B and 1C, the infrared spectrum of the NFS is different from the overlap of the spectra of the starting materials, but contains bands similar to those of the base DSV and the coformer. In addition, the spectrum corresponding to the NFS contains IR bands markedly wider than the respective crystalline raw materials, which suggests the formation of amorphous solids. In the IR spectra, shifts of the bands are also observed, for example those of the carbonyl group (v C = O) of the coformor that appear in the region of 1621-1705 cm -1, a wavelength shift of 1548-1614 cm-1, which are characteristic displacements of carboxylates, suggesting the formation of amorphous salts.
Characterization of amorphous NFS by X-ray powder diffraction (DRXP)
For the DRXP analyzes the specifications were: copper radiation Ka (A = 1,541 Á) with operating voltage 300KV and 10 mA.
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From the analyzes performed, the loss of crystallinity in the solids obtained is evident, confirming the formation of amorphous NFS. Figures 2A, 2B and 2C show the X-ray diffractograms of the NFS (raw materials and product) obtained with 3- hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid, respectively. For each of these figures, the diffractogram identified with part a) (bottom of the graph) corresponds to neutral desvenlafaxine; the diffractogram of part b) (middle part of the graph) corresponds to the new solid phase; and the diffractogram of part c) (upper part of the graph) corresponds to the coformer.
As can be seen in Figures 2A-2C, the diffractogram of the NFS is different from the superposition of the spectra of the starting materials, DSV and the coform.
Characterization of amorphous NFS by Differential Scanning Calorimetry (DSC) and thermogravimetric analysis (TGA)
Figures 3A, 3B and 3C show the results of the DSC-TGA calorimetric analysis of the NFS with 3-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid, respectively. As can be seen, the DSC analysis shows absence of melting points as reported for amorphous solids. In these vitreous transitions are observed around 50 ° C. The crystallization process and melting points are not observed. In the TGA analysis, a loss of mass at approximately 150 ° C is observed, corresponding to the loss of the drug and the coformer.
Solubility and dissolution rate tests of the new amorphous Solidarity form
The solubility tests could not be determined since the amorphous NFS obtained are very soluble and a very large amount is required to saturate the solution. For example for DSV NFS: 3,4,5-THB 200 mg were added to 200 µl and the solution is not saturated, what is observed is the formation of a dense gel but a precipitate does not form.
Dissolution rate tests were performed in aqueous media, in Wood equipment with 150 mg tablets at 37 ° C at 50 rpm in different dissolution media as shown in Tables 2 and 3.
Table 2. Result of dissolution of the NFS
 Dissolution medium  pH Range, Dissolution rate NFS with respect to DSV
 Phosphate buffer  pH 6.8 11 to 18 times higher
 Acetate buffer  pH 4.5 4 to 5 times higher
 HCl Buffer  pH 1.2 1.2 to 1.5 times lower
Table 3. Dissolution rate constants (mg / cm2-min)
 pH  DSV: 3-HB DSV: 3,4-DHB NFS amorphous / MF * DSV: 3,4,5-THB NFS amorphous / MF * DSV
 1.2  5.8 4.4 / 3.9 5.4 / 3.8 6.9
 4.5  6.1 5.0 /2.8 6.1 / 4.3 1.2
 6.8  5.4 5.7 / 5.0 9.0 / 4.9 0.5
 Water  3.8 2.3 1.6 0.0
MF Physical mixing
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Figures 4A, 4B and 4C show dissolution rate profiles at different pH.
Figure 4A shows the comparison of dissolution rate profiles in a) 10 phosphate buffer (pH = 6.8), b) Acetate buffer (pH = 4.8) and c) Saturated HCl solution (pH = 1.2) for desvenlafaxine base (line with frame «), the new solid amorphous phase of Desvenlafaxine-3,4-dihydroxybenzoic acid (line with circle (•)) and the physical mixture Desvenlafaxine-3,4-dihydroxybenzoic acid (line with triangle (A)) .
15 Figure 4B shows the comparison of dissolution rate profiles in: a) Phosphate buffer (pH = 6.8), b) Acetate buffer (pH = 4.8) and c) Saturated HCl solution (pH = 1.2) for Desvenlafaxine base (line with table P)), the new amorphous solid phase of Desvenlafaxine-3,4,5-trihydroxybenzoic acid (line with circle (•)) and the physical mixture of Desvenlafaxine-3,4,5-Trihydroxybenzoic acid (line with triangle (A)).
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Figure 4C shows the dissolution rate profiles in: a) Phosphate buffer (pH = 6.8), b) Acetate buffer (pH = 4.8) and c) Saturated HCl solution (pH = 1.2) for amorphous NFS of Desvenlafaxine -3-hydroxybenzoic acid (line with circle (•)) and the physical mixture of Desvenlafaxine-3-hydroxybenzoic acid (line with triangle (A)).
From Figures 4A, 4B and 4C it can be noted that amorphous NFS with 2- hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid show a higher dissolution rate with respect to neutral DSV.
During the dissolution rate tests it was observed that DSV has a strong dependence on the pH of the dissolution medium; DSV showed a 14 times higher speed difference in pH 1.2 than in pH 6.8, however the DSV NFS: 3,4-DHB has a smaller or almost no difference in dissolution rates in different dissolution media (Figure 4a ).
Indicative physical stability tests
The amorphous NFS obtained from DSV: 3-HB, DSV: 3,4-DHB and DSV: 3,4,5-THB were subjected to physical stability tests, where the NFS were subjected to temperatures of 45 and 50 ° C dry (no humidity) and at 40 ° C, 75% humidity for 30 days. The NFS were characterized by X-ray powder diffraction and the diffractograms are shown in Figures 5A-5C.
Figure 5A shows the powder diffractograms obtained from the stability test for: a) desvenlafaxine base; b) 3,4,5-THB coform; c) NFS DSV: initial 3,4,5-THB; d) NFS DSV: 3,4,5-THB subjected to 45 ° C dry; and e) NFS DSV: 3,4,5-THB subjected to 50 ° C dry.
Figure 5B shows the powder diffractograms obtained from the stability test for: a) desvenlafaxine base; b) coformer 3-HB; c) NFS DSV: initial 3-HB; d) NFS DSV: 3-HB subjected to 45 ° C dry; and e) NFS DSV: 3-HB subjected to 50 ° C dry.
Figure 5C shows the powder diffractograms obtained from the stability test for: a) desvenlafaxine base; b) 3,4-DHB coformer; c) NFS DSV: initial 3,4-DHB; d) NFS DSV: 3,4-DHB subjected to 45 ° C dry; e) NFS DSV: 3,4-DHB subjected to 50 ° C dry; and f) NFS
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DSV: 3,4-DHB subjected to 40 ° C with 75% relative humidity.
Of the samples subjected to 40 ° C and 75% humidity, only XFS diffraction characterization of the NFS DSV: 3,4-DHB (Figure 5C) was possible, since the other solid forms were hydrated. For this reason, the corresponding spectra are not observed in Figures 5A and 5B.
It was verified that using ethanol as a dissolution medium, as an alternative to methanol, the same phase was obtained. X-ray diffractograms of powders of the new amorphous solid form DSV-3,4,5-THB obtained in methanol and ethanol, respectively, can be seen in Figures 6A and 6B. In these graphs, the reproducibility of the processes to obtain the NFS DSV-3,4,5-THB can be confirmed.
New Crystalline Solid phases
In the present invention crystalline NFSs formed from DSV and a coform X are exhibited, wherein X has one or more hydroxyl groups and a carboxyl and can form the new entity through ionic interactions or intermolecular forces such as hydrogen bonds and / or van der Waals links; as well as solvates, hydrates and / or polymorphs of DSV: X. The coformer X is selected from: 2-HB, 3-HB, 4-HB, 2,3-DHB, 2,4-DHB, 2,5-DHB, 2,6-DHB, 3,4-DHB, 3 , 5-DHB, and 3,4,5-THB.
The following is a non-limiting example of the process of obtaining new crystalline solid forms.
a) Dissolve in a stoichiometric ratio 1: 1 DSV with the coform, for example 3,4-DHB, in a polar solvent selected from ethanol, ethanol 96 ° C, acetone and mixtures thereof.
b) The mixture is placed in a flask with stirring means, for example, propels, blades or the like, heated in a water bath at 60 ° C for 20-30 minutes until a homogeneous solution is reached.
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c) After the mixing time has elapsed, the solvent evaporates under vacuum, maintaining constant stirring (140 rpm) and heating between 65 and 70 ° C. The drying time is between 4 and 6 hours.
The mentioned process was used to produce different amounts of the NFS of 3,4-DHB, 2.5 g, 5 g, 10 g and 100 g among other quantities.
Synthesis of the crystalline NFS of DSV by the slurry method
Variations were made to the synthesis method of the new crystalline solid form with 3,4-DHB using the slurry method. For this, it was started from a mixture of DSV and 3,4-DHB (stoichiometric ratio 1: 1) with small amounts of polar solvent (for example 5 mL of 96% ethanol) under stirring (for example 150 rpm) at temperature ambient.
The reaction system was performed with a 3-mouth flask (closed system). After 6 hours of stirring under the above conditions, the remaining solvent was removed in vacuo for a period of 4 hours, maintaining a bath at a temperature of 50 ° C. During the reaction time samples of the solid mixture were taken at the following times: 30 min, 1 h, 2 h, 6 h. It was detected that the NFS was complete 30 minutes after the reaction began. Therefore, a 2 hour reaction time was established.
The development processes developed were reproduced to obtain 2.5 g, 5 g 10 g and larger quantities. The solid obtained in the scaling reactions corresponds to the crystalline phase as the anhydrous desvenlafaxine 3,4-dihydroxybenzoate salt.
Results and characterization of the new crystalline solid forms DSV: 3,4-DHB and DSV: 2,4-DHB
The crystalline NFS of DSV: 3,4-DHB was subjected to recrystallization in 96% ethanol obtaining monocrystals that were useful for study by X-ray diffraction. From this analysis it was possible to elucidate the molecular structure of the solid (Figure 7 ).
A thermogravimetric analysis (TGA / DSC) of the crystalline NFS of DSV: 3,4-DHB is shown in Figure 8. It was observed that the compound is stable up to 190 ° C, at which temperature the decomposition begins to be appreciated.
5 Figure 9 shows the molecular structure of the new crystalline solid phase of Desvenlafaxine: 3,4-dihydroxybenzoic acid obtained by X-ray powder diffraction. The specifications of the diffractometer used are: AcuKal = 15406 Á, germanium monochromator, operated at 40 kV and 40 mA.
10 Table 4 shows the structure parameters obtained by monocrystalline X-ray diffraction of the crystalline NFS Desvenlafaxine-3,4-dihydroxybenzoic acid.
Table 4. Crystalline structure data for Desvenlafaxine-Acid NFS 3,4-
dihydroxybenzoic acid
 Empirical formula  C23H31NO6
 Molecular weight  417.49
 Temperature / K  100.02 (11)
 Crystalline system  monoclinic
 Space group  P21 / c
 a / á  18.9712 (6)
 b / Á  9.4590 (2)
 AC  12.5758 (4)
 at / °  90
 p / °  98,687 (3)
 And / °  90
 Volume / Á3  2230.82 (11)
 Z  4
 p calc, g / cm  1,243
 p / mm-1  0.732
 F (000)  896.0
 Crystal size / mm3  1.0 x 0.8 x 0.15
 Radiation  CuKa (A = 1.54184)
 range of 20 for the collection / °  9,432 to 145.63
 Interval Indices  23 <h <23, -11 <k <11, -12 <l <15
 Reflections collected  15105
 Independent reflections  4391 [Rint = 0.0672, Rsigma = 0.0404]
 Data / restrictions / parameters  4391/0/293
 Goodness of fit over F2  1,067
 Final R Indices [I> = 2nd (I)]  R1 = 0.0982, wR2 = 0.2337
 Final R Indices [all data]  R1 = 0.1023, wR2 = 0.2360
 Major diff. peak / hole / e Á-3  0.79 / -0.48
The crystalline NFS of DSV: 2,4-DHB was also characterized by X-ray powder diffraction (see Figure 10), as well as thermogravimetric analysis (TGA / DSC) (see Figure 11). In the thermogravimetric analysis (TGA / DSC) it was observed that the compound is stable up to approximately 150 ° C, at which temperature the decomposition begins to be appreciated.
The crystalline structure obtained by single crystal X-ray diffraction for the New Crystalline Solid Phase of Desvenlafaxine-2,4-dihydroxybenzoic Acid is shown in Figure 12.
10 Table 5 shows the structure parameters obtained by monocrystalline X-ray diffraction of the crystalline NFS Desvenlafaxine-2,4-dihydroxybenzoic acid.
Table 5. Structure data for crystalline NFS of Desvenlafaxine-Acid 2,4-
dihydroxybenzoic
 Empirical formula  C23H31NO6
 Molecular weight  417.49
 Temperature / K  99.99 (10)
 Crystalline system  orthorhombic
 Space group  Pna21
 a / á  18.0299 (3)
 b / Á  8.69253 (13)
 AC  13,86218 (17)
 at / °  90
 | 3 / °  90
 And / °  90
 Volume / Á3  2172.56 (5)
 Z  4
 p calc, g / cm  3 1,276
 ^ / mm-1  0.752
 F (000)  896.0
 Crystal size / mm3  0.5 x 0.3 x 0.
 Radiation  CuKo (A = 1.54184)
 range of 20 for the collection / °  9,812 to 145,118
 Interval Index  -22 <h <21, -9 <k <10, -9 <l <17
 Reflections collected  7437
 Independent reflections  2936 [Rint = 0.0195, Rsigma = 0.0191]
 Data / restrictions / parameters  2936/1/290
 Goodness of fit over F2  1,050
 Final R indices [I> = 2nd (I)]  R1 = 0.0339, wR2 = 0.0879
 Final R indices [all data]  R1 = 0.0342, wR2 = 0.0882
 Major diff. peak / hole / e Á-3  0.36 / -0.18
Dissolution of the crystalline NFS DSV: 3,4-DHB
The dissolution profiles of the crystalline NFS of DSV: 3,4-DHB were evaluated. The dissolution experiment was carried out at three pH values (1.2, 4.5 and 6.8) and the profiles are presented in Figure 13. The values of the speed constants are grouped in Table 6.
Table 6. Intrinsic dissolution rate constants for crystalline NFS DSV: 3,4-DHB evaluated at pH 1.2, 4.5 and 6.8
 k (mg / cm2min) D.E. R2
 pH 1.2  2.48 0.042 0.9988
 pH 4.5  2.19 0.059 0.9988
 pH 6.8  1.43 0.046 0.9987
A comparative test of the dissolution profiles at pH 1.2, 4.5 and 6.8 of the new crystalline phase DSV: 3,4-DHB with respect to the amorphous NFS with the same coformator, the crystalline NFS with 2.4 -dihydroxybenzoic, as well as desvenlafaxine base and commercial salt (desvenlafaxine succinate). These profiles are shown in Figures 14, 15 and 16. Figure 5 14 shows the dissolution profiles in HCl solution (pH 1.2). Figure 15 shows the
Acetate buffer dissolution profiles (pH 4.5) and Figure 16 shows phosphate buffer dissolution profiles (pH 6.8).
In Figures 14 and 15 it can be seen that the new crystalline phase DSV: 3,4-DHB at pH 1.2 and 4.5 10 has an intrinsic dissolution rate similar to that of the commercial form found as a succinate salt. The solid phase with the highest dissolution rate is the amorphous NFS of DSV: 3,4-DHB.
In the pH evaluated (1.2, 4.5 and 6.8) the crystalline NFS with 2,4-dihydroxybenzoic acid has a dissolution rate less than that of the commercial salt (succinate) and any of the other phases shown.
The values of the intrinsic dissolution rate constants for the five samples are presented in Table 7.
twenty
Table 7. Dissolution rate constants (k)
 pH 1.2 pH 4.5 pH 6.8
 k (mg accum / cm2) Quotient (kNFS / kDSV) k (mg accum / cm2) Quotient (kNFS / kDSV) k (mg accum / cm2) Quotient (kNFS / kDSV)
 DSV  1.35 - 0.37 - 0.32 -
 DSV- Succinate  2.86 2.1 2.57 6.9 3.19 10.0
 DSV: 3,4-DHB Crystalline  2.47 1.8 2.19 5.9 1.54 4.8
 DSV: 3,4-DHB  6.69 5.0 6.81 18.4 5.45 17.0
 Amorphous
 DSV: 2,4-DHB Crystalline  1.07 0.79 0.35 0.94 0.23 0.71
Optionally, the new solid forms obtained by the aforementioned processes can be subjected to an additional purification process to drastically decrease or eliminate residual solvents, which consists of:
5
- Mix the NFS and an alcoholic solvent in a container
- Heat until dissolved and keep at a temperature between 70 ° C and 90 ° C for approximately 10-80 minutes
10
- Concentrate to a quarter of the solvent volume and cool to 10 ° C to 15 ° C
- Filter, wash with alcohol solvent and dry.
The alcoholic solvent can be selected from ethanol, hexane, isopropyl alcohol and methanol.
Table 8 shows the results of two samples of the NFS with 3,4-DHB acid, subjected to a purification process.
twenty
Table 8. Evaluation results of two purified samples of NFS with 3,4-DHB acid
 Sample 1 NFS Sample 2 NFS Specification
 DSV rating  99% 99% Minimum 90%
 Rating 3.4 DHB  99% 98% Minimum 90%
 Acetone residual solvent  0 ppm 0 ppm Maximum 5,000 ppm
 Hexane residual solvent  0 ppm 0 ppm Maximum 390 ppm
 Sol. Residual Ethanol  1965 ppm 3885 ppm Maximum
 5,000 ppm
With the results obtained it can be confirmed that the purification method proposed in the present invention is innovative to obtain a product that meets the specifications.
5

权利要求:
Claims (13)
[1]
5
10
fifteen
twenty
25
30
1. An amorphous or crystalline solid compound formed by the selective serotonin and noradrenaline recapture inhibitor desvenlafaxine (or DSV) and a co-former X, wherein X has one or more hydroxyl groups and a carboxyl group, which form the new entity through ionic interactions or non-covalent intermolecular forces, such as hydrogen bonds and / or van der Waals bonds; as well as solvates, hydrates and / or polymorphs of DSV: X.
[2]
2. An amorphous or crystalline solid compound formed by desvenlafaxine and a coform X, wherein X is selected from the group consisting of 2-hydroxybenzoic acid, 3- hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2 , 4- dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid; as well as solvates, hydrates and / or polymorphs of said new solid form.
[3]
3. An amorphous compound formed by desvenlafaxine and a coform X, where X is selected
of: 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4-hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-
dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-dihydroxybenzoic acid, 3,4,5-trihydroxybenzoic acid; as well as the solvates, hydrates and / or polymorphs of said amorphous compound.
[4]
4. The amorphous compound according to claim 2, wherein the coform X is selected from the group consisting of: 3-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid.
[5]
5. A crystalline compound formed by desvenlafaxine and a coform X, where X is
selected from the group consisting of: 2-hydroxybenzoic acid, 3-hydroxybenzoic acid, 4- hydroxybenzoic acid, 2,3-dihydroxybenzoic acid, 2,4-dihydroxybenzoic acid, 2,5-dihydroxybenzoic acid, 2,6-dihydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3,5-
dihydroxybenzoic acid and 3,4,5-trihydroxybenzoic acid; as well as the solvates, hydrates and / or polymorphs of said crystalline compound.
5
10
fifteen
twenty
25
30
[6]
6. The crystalline compound according to claim 5, wherein the coform X is selected from: 2,4-dihydroxybenzoic acid and 3,4-dihydroxybenzoic acid.
[7]
7. The crystalline compound according to claim 5, wherein the coform X is 3,4-dihydroxybenzoic acid, as well as the solvates, hydrates and / or polymorphs thereof.
[8]
8. The use of the amorphous or crystalline solid compound formed by desvenlafaxine or DSV and a coform X: wherein X possesses one or more hydroxyl groups and a carboxyl of claim 1 for the preparation of a pharmaceutical composition useful for the selective inhibition of the recapture of serotonin and norepinephrine.
[9]
9. A pharmaceutical composition containing the compound according to claim 1 in combination with pharmaceutically acceptable excipients.
[10]
10. A process for obtaining amorphous or crystalline solid compound formed by the selective serotonin and noradrenaline recapture inhibitor desvenlafaxine or DSV and a co-former X: wherein "X" has one or more hydroxyl groups and a carboxyl, which they form the new entity through ionic interactions or intermolecular forces.
[11]
11. A process for obtaining the amorphous solid compound of claim 3 characterized in that it consists of the following steps:
a) Dissolve a 1: 1 stoichiometric drug-coform composition in polar solvent;
b) Place the mixture in a rotary evaporator in a bath at 70-80 ° C under reduced pressure, until the solvent evaporates completely.
[12]
12. A process for obtaining the crystalline compound of claim 5, characterized in that it consists of the following steps:
a) Dissolve a 1: 1 stoichiometric drug-coform composition in polar polar solvent selected from ethanol, 96 ° C ethanol, acetone and mixtures thereof.
b) Place the mixture in a flask with stirring in a water bath at 60-70 ° C under reduced pressure, until reaching a homogeneous solution, then evaporate.
[13]
13. A process of purification of new solid forms characterized in that it consists of the following 5 stages:
a) Heat a mixture of NFS and polar solvent to dissolution
b) Concentrate to a quarter of the volume of the solvent and cool to 10 ° C a
10 15 ° C
c) Filter, wash with polar solvent and dry, the polar solvent can be selected from methanol, ethanol, isopropyl alcohol, hexane, acetone.
fifteen
DRAWINGS
image 1
image2
FIG. 1 B
% R
image3
FIG. 1 C
image4
image5
FIG. 2B
image6
Heat Flow (W / g)
tn o ó »or
image7
100
150 170 190 210 230 250 270 290
Temperature ° C
FIG. 3A
Heat Flow (W / g)
i ». J ro o
image8
image9
130 150 170 190 210 230 250 270 290
Temperature ° C
FIG. 3C
OR OR> -Ú hJ O
image10

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同族专利:

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公开号 | 公开日

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SV2017005474A|2017-10-12|

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ES2648369B2|2018-06-08|

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MX2016008646A|2017-12-28|

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CO2017006492A1|2018-01-05|

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PE20180025A1|2018-01-09|

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CA2972156A1|2017-12-29|

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MX367362B|2019-08-16|

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US10207982B2|2019-02-19|

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US20180002273A1|2018-01-04|

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