WO2016198117A1 - New crystal forms of minodronic acid - Google Patents

New crystal forms of minodronic acid Download PDF

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Publication number
WO2016198117A1
WO2016198117A1 PCT/EP2015/063114 EP2015063114W WO2016198117A1 WO 2016198117 A1 WO2016198117 A1 WO 2016198117A1 EP 2015063114 W EP2015063114 W EP 2015063114W WO 2016198117 A1 WO2016198117 A1 WO 2016198117A1
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WIPO (PCT)
Prior art keywords
minodronic acid
solid
crystal form
minodronic
acid
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PCT/EP2015/063114
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French (fr)
Inventor
Stefano Luca Giaffreda
Serena Fabbroni
Marco Curzi
Michael CHIARUCCI
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Polycrystalline S.R.L.
Pharmagenerics Bv
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Application filed by Polycrystalline S.R.L., Pharmagenerics Bv filed Critical Polycrystalline S.R.L.
Priority to JP2018516621A priority Critical patent/JP6705893B2/en
Priority to PCT/EP2015/063114 priority patent/WO2016198117A1/en
Publication of WO2016198117A1 publication Critical patent/WO2016198117A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • Minodronic acid (1 -Hydroxy-2-imidazo[1 ,2-a]pyridin-3-yl-1 -phosphonoethyl) phosphonic acid, is a compound of formula (I)
  • Minodronic acid is known to have excellent bone resorption inhibitory activity, as well as anti-inflammatory, analgesic and antipyretic activities and it is useful in the treatment of diseases in which an increased bone resorption participates (EP 0647649 B1 ; Rizzoli C. et al. Acta Cryst. E71 2015, 51-54).
  • Minodronic acid in pharmaceutical preparations concern its purification and the control of the crystal form.
  • Minodronic acid has limited solubility in many organic solvents and water, therefore purification often relies on the precipitation of its sodium salt, followed by re-acidification.
  • this procedure requires the use of concentrated NaOH to dissolve the Minodronic acid and large amount of alcoholic solvent to precipitate the salt.
  • the product formed exhibits gel- consistency requiring rather tedious steps of filtration and drying of the solid, making the procedure unpractical for the scale-up.
  • Minodronic acid is known to have a rather complex polymorphic behavior.
  • the most preferred forms employed in pharmaceutical preparations are the monohydrate ones.
  • the two known monohydrate forms, labeled as D and E, have the same XRPD pattern but different dehydration temperature. Due to the similar crystal structure, obtaining a single pure monohydrate crystalline form results very challenging, especially in the case of form E.
  • Minodronic acid There is a strong interest in making available new crystalline forms of Minodronic acid easily to obtain and having the required chemical and physical characteristics.
  • the invention is also directed to processes for the preparation of said forms comprising crystallization or re-crystallization from appropriate solvents.
  • the invention is further directed to pharmaceutical compositions comprising Minodronic acid, form X or form Y herein described, and to their use as a medicament.
  • thermogravimetric analysis The main peaks of X-ray powder diffraction, the main bands and characteristic of the FT-IR spectrum, the thermogravimetric analysis are furnished.
  • the X-ray powder diffractogram (XRPD) has been obtained using the instrument X'Pert PRO PANalytical with single scan, using Ka1 radiation.
  • the diffractogram is measured in reflection mode in the range 3-40°2 ⁇ .
  • the FT-IR spectrum (Fourier transform IR spectroscopy) was recorded with the Nicolet iS50 - ATR module appliance equipped with a KBr splitter and DTGS KBr detector. The spectrum was acquired in 32 scans at a resolution of 4 cm "1 .
  • the samples were heated at a heating rate of 10 K/min in the temperature range from - 25 to 200°C.
  • thermograms were obtained using the TGA DSC1 Mettler Toledo thermo-balance.
  • the samples were heated from 25°C to 450°C at 10 K/min.
  • polymorphism is the ability of a compound to crystallize into more than one distinct crystal species. Polymorphs (or crystalline modifications) have an identical chemical structure but quite different physicochemical properties.
  • thermodynamically stable refers to a polymorphic form that, during storage under long-term conditions (25°C, 60% relative humidity), substantially does not convert into another one for a pharmaceutically acceptable period of time (at least 3 months, preferably 6 months, more preferably 1 year).
  • the term "high level of chemical purity” refers to a polymorph wherein the total amount of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC), used by those of skill in the art to assess such purity, is less than 5%, advantageously less than
  • Figure 2 XRPD spectrum of Minodronic acid, form X before and after grinding.
  • Figure 3 XRPD spectrum of Minodronic acid, form X before and after kneading.
  • Figure 6 TGA analysis of Minodronic acid, form X.
  • Figure 7 melting of Minodronic acid, form X.
  • Figure 8 water sorption kinetics for Minodronic acid, form X at 25°C.
  • Figure 10 easy-water analysis for Minodronic acid, form X.
  • Figure 12 HPLC analysis of Minodronic acid, form X.
  • Figure 14 XRPD spectrum of Minodronic acid, form Y before and after grinding.
  • Figure 16 FT-IR spectrum of Minodronic acid, form Y.
  • Figure 17 DSC analysis of Minodronic acid, form Y.
  • Figure 20 water sorption kinetics for Minodronic acid, form Y at 25°C.
  • Figure 21 water sorption and desorption isotherms for Minodronic acid, form Y at 25°C.
  • Figure 22 XRPD of Minodronic acid, form Y after DVS experiment (black line) and the Form F anhydrous patented in EP0647649B1 (grey).
  • Figure 24 XRPD spectrum of Minodronic acid, form Y after 1 day (1 D) at 40°C and 75%RH, reference pattern of Form Y (black line, Form Y), and the Form F anhydrous patented in
  • Figure 25 HPLC analysis of Minodronic acid, form Y.
  • Figure 27 XRPD spectrum of Minodronic acid, Form X (Example 2).
  • Figure 28 HPLC analysis of Minodronic acid, Form X (Example 2).
  • Figure 29 Calibration curve of the Minodronic acid recovered by HPLC.
  • Figure 30 Dissolution comparison of the four different polymorphs at pH 4.5.
  • Figure 32 Dissolution comparison of the four different polymorphs at pH 6.8.
  • Figure 33 Dissolution rate extrapolated for the four different polymorphs at pH 6.8 in the first minutes of the dissolution.
  • Figure 35 Dissolution rate extrapolated for the four different polymorphs at pH 7.4 in the first minutes of the dissolution.
  • Figure 36 Thermodynamic solubility of the different crystalline forms at pH 4.5.
  • Figure 37 Thermodynamic solubility of the different crystalline forms at pH 6.8.
  • Figure 39 XRPD Comparison between Minodronic Acid Form E and Form D and the powder recovered at the end of the thermodynamic study at pH 4.5 of the Form Y, Form D, Form E and Form X.
  • Figure 40 XRPD Comparison between Minodronic Acid Form E and Form D and the powder recovered at the end of the thermodynamic study at pH 6.8 of the Form Y, Form D, Form E and Form X.
  • Figure 41 XRPD Comparison between Minodronic Acid Form E and Form D and the powder recovered at the end of the thermodynamic study at pH 7.4 of the Form Y, Form D, Form E and Form X.
  • Minodronic acid synthetized according to procedures known in the state of the art, is dissolved in 6M HCI. After addition of NaOH up to pH 1 , the product precipitate and could be collected by simple filtration, avoiding the necessity to distill a large amount of water, distillation needed in the absence of NaOH.
  • the solid obtained in the step above is re-dissolved in hot 6M HCI and precipitated with methanol, allowing an easier solid filtration and drying with respects to the ones performed on the sodium salt.
  • the Minodronic acid, form X of the present invention is a thermodynamically stable non-hygroscopic crystal form, and it is characterized by high level of chemical purity as well as good handling characteristics for the preparation of pharmaceutical compositions.
  • Minodronic acid, form X is obtained by rapid cooling to 0°C of a boiling solution of Minodronic acid dissolved in HCI 1 M.
  • the concentration of said solution is of about 25 mg/ml.
  • a white precipitate is formed in few minutes and it is slurried for about 12 hrs at 0°C.
  • the product is then recovered under vacuum, washed with water until neutral pH and Methanol.
  • the solid, after drying, at 50 °C for 24 hours, is recovered with a yield -96% and high level of chemical purity (>99.5%).
  • the new crystal form X is characterized by the XRPD spectrum shown in figure 1.
  • Main peaks at 2theta +/- 0.3 degrees are: 9.1 , 10.2, 15.5, 16.5, 18.7, 25.8.
  • Table 1 below shows the significant peaks of the spectrum.
  • the stability of the ground sample was determined comparing its diffraction pattern with that of the standard reference (Minodronic acid, form X before grinding): the sample obtained showed the same diffraction pattern of Minodronic acid, form X, as reported in figure 2 (Form X-grinding line versus Form X line).
  • Form X-kneading line showed the same diffraction pattern of the Minodronic Acid, form X before kneading.
  • FT-IR analysis returns the spectrum shown in figure 4. Said FT-IR spectrum is characterized by the peaks shown in Table 2 below.
  • DSC analysis shown in figure 5, highlights two endothermic events, corresponding to a dehydration step between 80-130 °C (Onset 89.34 °C) and melt and degradation after 210 °C (Onset 233.38 °C).
  • thermogram shown in figure 6 highlights a loss of weight of 9.38% w/w on moving 5 from about 80 to about 140°C.
  • the sample losses water and a dihydrate form can be suggested.
  • the following loss of 3.5% w/w is due to a decomposition event after 220 °C.
  • the melting analysis reported in figure 7 confirms that the weight loss observed between 80-140 °C is not imputable a decomposition event. Melt and decomposition occurred simultaneously after approx. 250 °C, see the pictures taken at 250.4°C and above.
  • the sample analyzed shows a hydrophobic behavior. Under each cycle of sorption/desorption the change weight was maintained under 0.1 %, value typically ascribable to a non-hygroscopic compound.
  • Minodronic acid, form X is stable also when exposed to stress conditions.
  • Minodronic acid, form X has been tested by exposure for 7 days at 40°C and 75%RH.
  • the XRPD patterns of the sample recorded after 1 , 3 and 7 days are reported in figure 25 11 and demonstrate that the crystal form did not change.
  • the here claimed Minodronic acid, form X is thermodynamically stable.
  • HPLC purity profile reported in figure 12, demonstrates that Minodronic acid, form X can be isolated with a high level of chemical purity, > 99.97%.
  • the stability of the ground sample was determined comparing its diffraction pattern with that of the standard reference: the sample obtained showed the same diffraction pattern of the Minodronic acid, form Y, although less crystalline, as reported in figure 14 (Form Y-grinding line versus Form Y line).
  • FT-IR analysis returns the spectrum shown in figure 16. Said FT-IR spectrum is characterised by the peaks shown in Table 4 below.
  • DSC analysis of the Minodronic acid, form Y, shown in figure 17, shows a linear profile with a single event at about 245°C, corresponding to melt and decomposition of the sample (Onset 238.98 °C).
  • thermogram shown in figure 18 for Minodronic acid, form Y highlights a loss of weight on moving from about 140 to about 220°C of 1.65% w/w. The following loss of 4.27% w/w is due to a decomposition event after 220°C.
  • the melting analysis reported in figure 19 confirms that the weight loss observed between 140-220°C is not imputable to a decomposition event. Melt and decomposition occurred simultaneously after approx. 240°C, see the pictures
  • the sample analyzed shows a slightly hygroscopic behavior.
  • the first sorption cycle approx. 1% of water was adsorbed.
  • the following desorption step approx. 1.5% w/w of water was lost and a Minodronic acid form with a smaller quantities of water than the starting material was obtained.
  • the Easy-water analysis confirmed that the weight loss between 140-220°C is imputable to a dehydration step.
  • the amount registered is slightly higher than the quantity registered by gravimetric analysis. Generally, the analysis more confident is the TGA: the Easy- water has been carried out to confirm that the solvent lost was water.
  • Minodronic acid, form Y has been tested by exposure for 7 days at 40°C and 75%RH.
  • the XRPD patterns of the sample recorded after 1 , 3 and 7 days are reported in figure 24 and demonstrate that already after 1 day a total conversion into the anhydrous Form F patented in EP0647649B1 occurs.
  • the here described crystal forms of Minodronic acid can be applied in pharmaceutical compositions.
  • the pharmaceutical composition that comprises said crystal forms may contain additives. Any conventional technique can be used for preparation of pharmaceutical formulations in accordance with this invention.
  • the chlorobenzene was removed using a peristaltic pump and the residue was dissolved in 200 mL of 6 M HCI, heating the solution at 110°C for 2 hours.
  • the orange solution was poured into an Erlenmeyer flask containing 1.2 g of activated carbon (DARCO 100 mesh) and cooled to room temperature under stirring for 40 minutes.
  • the solution was filtered through a paper filter washing the solid residue with 20 ml of 6M HCI.
  • the solution was poured into a jacketed reactor and stirred at 25-30 °C. A 30 % aqueous solution of NaOH was added dropwise until pH 1. In these conditions precipitation of a solid occurred and the mixture was stirred at room temperature for two hours.
  • the solid was transferred into an Erlenmeyer flask and 47.4 mL of HCI 6M were added. The suspension was stirred at 100 °C until complete dissolution of the solid occurred and then 332 mL of methanol were added in one portion. The slurry was cooled at room temperature and then stirred for three hours at this temperature. The precipitate was collected by vacuum filtration and then washed with water, until the pH of the washing solvent was neutral. The white solid was dried at 50 °C for 4 hours affording 10.20 g of product which exhibited HPLC purity of 99.40 % (figure 26).
  • Example 1 The solid obtained at the end of example 1 was transferred into a beaker and 204 mL of water were added. The slurry was stirred at room temperature and 6.12 ml of diethyl amine (2 equivalents) were added. The mixture was stirred at room temperature until the solution became clear, then 408 mL of HCI 1 M were added in one portion and the solution was stirred at room temperature for three hours. Minodronic acid precipitated as a white solid, which was collected by vacuum filtration. The solid was washed with water, until the pH of the washing solvent was neutral, and then with methanol (2 x 25 mL).
  • the mixture was heated at 80 °C until complete dissolution of the solid and then 139 mL of HCI (8 % aqueous solution) were added.
  • the solution was cooled to 13 °C in one hour and stirred (120 rpm) at this temperature for 3 hours.
  • the solid was collected by vacuum filtration, washed with water until pH of the washing solvent was neutral, and then with methanol.
  • the white solid was dried at 50 °C for 4 hours affording 35.31 g of Minodronic acid with 99.85 % HPLC purity.
  • the solid (35.31 g) was transferred into a 2 L beaker equipped with a stirring bar and 141 mL of 6M HCI were added. The mixture was heated at 100 °C until complete dissolution of the solid occurred. 988 mL of methanol were added in one portion and the slurry was cooled to room temperature and stirred for three hours at this temperature. The solid was filtered under vacuum and washed with water, until pH of the washing solvent was neutral, and then methanol. The i o white solid was dried at 50 °C for 4 hours affording 30.36 g of Minodronic acid with 99.93 % HPLC purity.
  • the solid (30.36 g) was transferred into a 1 L jacketed reactor equipped with a condenser and a mechanical stirrer. 560 mL of water were added and the mixture was heated at 80 °C for 30 minutes. The hot solution was filtered under vacuum and the solid was washed with methanol 15 and dried under vacuum for 1 hour affording 29.45 g of Minodronic acid with 99.95 % HPLC purity.
  • the solid (29.45 g) was transferred into a 3 L jacketed reactor equipped with a condenser and a mechanical stirrer. 1.09 L of 1 M HCI were added and the mixture was heated at 110 °C until complete dissolution of the solid occurred.
  • the hot solution was filtered through a pad of cotton 20 directly into another jacketed reactor previously cooled at 0°C.
  • the solution was stirred (110 rpm) overnight at 0 °C and then filtered under vacuum.
  • the solid was washed with water, until the pH of the washing solvent was neutral, and then with methanol.
  • the white solid was dried at 50 °C overnight to afford 28.27 g of Minodronic acid, form X (96 % yield) with HPLC purity 99.97 %.
  • the aim of the study was the evaluation of the dissolution capability of the new crystal forms 35 compared to the crystal forms of the API commercially available.
  • Peak width > 0.0031 min (0.63 s resp. Time) (80 Hz)
  • Standard Solution 5 mL was transferred into a 10 mL volumetric flask and diluted to volume with Diluent Solution (SS1 , 0.510 mg/mL of Minodronic Acid).
  • Standard Solution 2.5 mL was transferred into a 10 mL volumetric flask and diluted to volume with Diluent Solution (SS3, 0.2552 mg/mL of Minodronic Acid)
  • Standard Solution 1 mL was transferred into a 10 mL volumetric flask and diluted to volume with Diluent Solution (SS4, 0.10208 mg/mL of Minodronic Acid)
  • the new polymorph form X shows the best dissolution profile: a larger concentration of API was 5 achieved in the first part of the dissolution analysis and this high concentration was maintained during the experiment (figure 30, light grey column)
  • thermodynamic solubility test has been performed on the same crystal form subjected to the kinetic dissolution tests.
  • each crystal form was added as powder in a glass tube, equipped with a magnetic stirring bar, and diluted with 2 ml. of buffer.
  • the mixtures were left under magnetic stirring (100 rpm) at 37 °C for 24 hours.
  • the suspensions were filtered with 0.20 micron filter and analyzed by the HPLC method previously reported and the results were interpolated by the calibration curve reported.
  • thermodynamic solutions were dilutes 20 times to obtain a data comprising in the Calibration Curve.

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Abstract

The present invention provides two stable crystalline forms of (1-Hydroxy-2-imidazo[1,2-a]pyridin-3-yl-1-phosphonoethyl) phosphonic acid, designated crystal form X and form Y, as well as methods for their preparation, by which each crystalline polymorph can be individually obtained as a single crystal form.

Description

DESCRIPTION
New crystal forms of Minodronic acid
State of the art
Minodronic acid, (1 -Hydroxy-2-imidazo[1 ,2-a]pyridin-3-yl-1 -phosphonoethyl) phosphonic acid, is a compound of formula (I)
Figure imgf000002_0001
Minodronic acid is known to have excellent bone resorption inhibitory activity, as well as anti-inflammatory, analgesic and antipyretic activities and it is useful in the treatment of diseases in which an increased bone resorption participates (EP 0647649 B1 ; Rizzoli C. et al. Acta Cryst. E71 2015, 51-54).
The main issues in the utilization of Minodronic acid in pharmaceutical preparations concern its purification and the control of the crystal form.
Minodronic acid has limited solubility in many organic solvents and water, therefore purification often relies on the precipitation of its sodium salt, followed by re-acidification. However, this procedure requires the use of concentrated NaOH to dissolve the Minodronic acid and large amount of alcoholic solvent to precipitate the salt. The product formed exhibits gel- consistency requiring rather tedious steps of filtration and drying of the solid, making the procedure unpractical for the scale-up.
Minodronic acid is known to have a rather complex polymorphic behavior. Usually the most preferred forms employed in pharmaceutical preparations are the monohydrate ones. The two known monohydrate forms, labeled as D and E, have the same XRPD pattern but different dehydration temperature. Due to the similar crystal structure, obtaining a single pure monohydrate crystalline form results very challenging, especially in the case of form E.
There is a strong interest in making available new crystalline forms of Minodronic acid easily to obtain and having the required chemical and physical characteristics.
Detailed description
We report here two new crystal forms of Minodronic acid, referred to as form X and form Y.
Accordingly, the invention is also directed to processes for the preparation of said forms comprising crystallization or re-crystallization from appropriate solvents.
The invention is further directed to pharmaceutical compositions comprising Minodronic acid, form X or form Y herein described, and to their use as a medicament.
More complete understanding of this invention can be obtained referring to the physico-chemical characteristics of Minodronic acid, form X and form Y, provided below.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as it is commonly understood by one of skill in the art to which this subject matter belongs.
The main peaks of X-ray powder diffraction, the main bands and characteristic of the FT-IR spectrum, the thermogravimetric analysis are furnished.
The X-ray powder diffractogram (XRPD) has been obtained using the instrument X'Pert PRO PANalytical with single scan, using Ka1 radiation. The diffractogram is measured in reflection mode in the range 3-40°2θ.
The FT-IR spectrum (Fourier transform IR spectroscopy) was recorded with the Nicolet iS50 - ATR module appliance equipped with a KBr splitter and DTGS KBr detector. The spectrum was acquired in 32 scans at a resolution of 4 cm"1.
DSC analyses were carried out using a differential scanning calorimeter DSC1 Mettler
Toledo. The samples were heated at a heating rate of 10 K/min in the temperature range from - 25 to 200°C.
The thermograms were obtained using the TGA DSC1 Mettler Toledo thermo-balance.
The samples were heated from 25°C to 450°C at 10 K/min.
As used herein, "polymorphism" is the ability of a compound to crystallize into more than one distinct crystal species. Polymorphs (or crystalline modifications) have an identical chemical structure but quite different physicochemical properties.
As used herein, the term "thermodynamically stable" refers to a polymorphic form that, during storage under long-term conditions (25°C, 60% relative humidity), substantially does not convert into another one for a pharmaceutically acceptable period of time (at least 3 months, preferably 6 months, more preferably 1 year).
As used herein, the term "high level of chemical purity" refers to a polymorph wherein the total amount of readily detectable impurities as determined by standard methods of analysis, such as thin layer chromatography (TLC) or high performance liquid chromatography (HPLC), used by those of skill in the art to assess such purity, is less than 5%, advantageously less than
2.5 %, preferably less than 1.0, more preferably less than 0.5%.
Description of the figures
Figure 1 : XRPD spectrum of Minodronic acid, form X
Figure 2: XRPD spectrum of Minodronic acid, form X before and after grinding.
Figure 3: XRPD spectrum of Minodronic acid, form X before and after kneading.
Figure 4: FT-IR spectrum of Minodronic acid, form X.
Figure 5: DSC analysis of Minodronic acid, form X.
Figure 6: TGA analysis of Minodronic acid, form X. Figure 7: melting of Minodronic acid, form X.
Figure 8: water sorption kinetics for Minodronic acid, form X at 25°C.
Figure 9: water sorption and desorption isotherms for Minodronic acid, form X at 25°C.
Figure 10: easy-water analysis for Minodronic acid, form X.
5 Figure 11 : XRPD spectrum of Minodronic acid, form X after 1 (dark grey), 3 (light grey), 7 days (very light grey) at 40°C and 75%RH and the reference pattern of Form X (black line).
Figure 12: HPLC analysis of Minodronic acid, form X.
Figure 13: XRPD spectrum of Minodronic acid, form Y
Figure 14: XRPD spectrum of Minodronic acid, form Y before and after grinding.
i o Figure 15: XRPD spectrum of Minodronic acid, form Y before (Form Y line) and after kneading
(Form-Y-kneading) and of Minodronic acid, form X (Form X).
Figure 16: FT-IR spectrum of Minodronic acid, form Y.
Figure 17: DSC analysis of Minodronic acid, form Y.
Figure 18: TGA analysis of Minodronic acid, form Y.
15 Figure 19: melting of Minodronic acid, form Y.
Figure 20: water sorption kinetics for Minodronic acid, form Y at 25°C.
Figure 21 : water sorption and desorption isotherms for Minodronic acid, form Y at 25°C.
Figure 22: XRPD of Minodronic acid, form Y after DVS experiment (black line) and the Form F anhydrous patented in EP0647649B1 (grey).
20 Figure 23: easy-water analysis for Minodronic acid, form Y.
Figure 24: XRPD spectrum of Minodronic acid, form Y after 1 day (1 D) at 40°C and 75%RH, reference pattern of Form Y (black line, Form Y), and the Form F anhydrous patented in
EP0647649B1 (Form F-Anydrous).
Figure 25: HPLC analysis of Minodronic acid, form Y.
25 Figure 26: HPLC analysis of Minodronic acid after recrystallization.
Figure 27: XRPD spectrum of Minodronic acid, Form X (Example 2).
Figure 28: HPLC analysis of Minodronic acid, Form X (Example 2).
Figure 29: Calibration curve of the Minodronic acid recovered by HPLC.
Figure 30: Dissolution comparison of the four different polymorphs at pH 4.5.
30 Figure 31 : Dissolution rate extrapolated for the four different polymorphs at pH 4.5 in the first minutes of the dissolution.
Figure 32: Dissolution comparison of the four different polymorphs at pH 6.8.
Figure 33: Dissolution rate extrapolated for the four different polymorphs at pH 6.8 in the first minutes of the dissolution.
35 Figure 34: Dissolution comparison of the four different polymorphs at pH 7.4.
Figure 35: Dissolution rate extrapolated for the four different polymorphs at pH 7.4 in the first minutes of the dissolution.
Figure 36: Thermodynamic solubility of the different crystalline forms at pH 4.5. Figure 37: Thermodynamic solubility of the different crystalline forms at pH 6.8.
Figure 38: Thermodynamic solubility of the different crystalline forms at pH 7.4.
Figure 39: XRPD Comparison between Minodronic Acid Form E and Form D and the powder recovered at the end of the thermodynamic study at pH 4.5 of the Form Y, Form D, Form E and Form X.
Figure 40: XRPD Comparison between Minodronic Acid Form E and Form D and the powder recovered at the end of the thermodynamic study at pH 6.8 of the Form Y, Form D, Form E and Form X.
Figure 41 : XRPD Comparison between Minodronic Acid Form E and Form D and the powder recovered at the end of the thermodynamic study at pH 7.4 of the Form Y, Form D, Form E and Form X.
Description of the invention:
A purification procedure surprisingly capable to efficiently produce Minodronic acid at a high level of chemical purity is here described,
At this purpose, Minodronic acid, synthetized according to procedures known in the state of the art, is dissolved in 6M HCI. After addition of NaOH up to pH 1 , the product precipitate and could be collected by simple filtration, avoiding the necessity to distill a large amount of water, distillation needed in the absence of NaOH.
Moreover, the solid obtained in the step above is re-dissolved in hot 6M HCI and precipitated with methanol, allowing an easier solid filtration and drying with respects to the ones performed on the sodium salt.
Finally, it is here demonstrated that the addition of an organic base surprisingly allows an easy dissolution of Minodronic acid in water. In particular, the use of 2 equivalents of diethyl amine enabled the dissolution of Minodronic acid at room-temperature. The product can then be re-precipitated, as free acid, by addition of 1 M HCI, affording the product with HPLC purity higher than 99.5%.
Two novel crystal forms of Minodronic acid, form X and form Y, having surprisingly interesting chemical-physical characteristics, are here described.
The Minodronic acid, form X of the present invention is a thermodynamically stable non-hygroscopic crystal form, and it is characterized by high level of chemical purity as well as good handling characteristics for the preparation of pharmaceutical compositions. Minodronic acid, form X, is obtained by rapid cooling to 0°C of a boiling solution of Minodronic acid dissolved in HCI 1 M. Preferably, the concentration of said solution is of about 25 mg/ml. A white precipitate is formed in few minutes and it is slurried for about 12 hrs at 0°C. The product is then recovered under vacuum, washed with water until neutral pH and Methanol. The solid, after drying, at 50 °C for 24 hours, is recovered with a yield -96% and high level of chemical purity (>99.5%).
The new crystal form X is characterized by the XRPD spectrum shown in figure 1. Main peaks at 2theta +/- 0.3 degrees are: 9.1 , 10.2, 15.5, 16.5, 18.7, 25.8. Table 1 below shows the significant peaks of the spectrum.
Table 1 :
Pos. [°2Th.] Height [cts] FWHM [°2Th.] d-spacing [A] Rel. Int. [%]
4,8024 90,24 0,2007 18,40092 1,52
9,1040 1231,54 0,0669 9,71400 20,71
9,2871 306,29 0,0669 9,52288 5,15
10,2059 660,34 0,1171 8,66753 11,10
10,3704 158,74 0,0836 8,53037 2,67
12,9183 63,29 0,1004 6,85311 1,06
13,1831 35,20 0,1673 6,71604 0,59
13,8959 81,95 0,1004 6,37308 1,38
15,5476 2899,86 0,1171 5,69957 48,76
16,0969 1686,93 0,1004 5,50629 28,37
16,5513 5947,10 0,1673 5,35613 100,00
17,2468 37,25 0,2676 5,14168 0,63
18,0806 1892,26 0,1338 4,90638 31,82
18,6602 3881,83 0,1171 4,75528 65,27
19,0028 1047,45 0,0669 4,67031 17,61
19,1810 1413,93 0,1171 4,62733 23,78
20,3032 646,09 0,1004 4,37403 10,86
20,6185 640,23 0,1338 4,30785 10,77
21,4588 17,24 0,2007 4,14102 0,29
22,4582 646,84 0,1338 3,95895 10,88
23,0548 77,21 0,1338 3,85784 1,30
23,8588 445,33 0,1171 3,72963 7,49
24,7952 135,15 0,0669 3,59086 2,27
25,4181 124,08 0,1004 3,50425 2,09
25,8497 1194,28 0,1338 3,44672 20,08
26,2645 739,45 0,1004 3,39321 12,43
26,6470 744,62 0,1171 3,34538 12,52
27,0234 675,34 0,1171 3,29962 11,36
27,4362 1553,97 0,1632 3,24822 26,13
27,5681 1662,52 0,0612 3,24101 27,96
28,4985 1612,25 0,1428 3,12951 27,11
28,7283 565,37 0,1020 3,10500 9,51
29,4049 242,27 0,1224 3,03507 4,07
29,6166 413,51 0,1020 3,01385 6,95
30,4426 919,18 0,0612 2,93393 15,46
30,5532 1372,77 0,0816 2,92357 23,08
30,7950 399,44 0,0816 2,90116 6,72
31,3868 815,55 0,2448 2,84779 13,71
31,8613 981,32 0,2040 2,80646 16,50
32,0008 531,85 0,0816 2,80149 8,94
32,3353 124,33 0,1224 2,76640 2,09
32,5339 106,13 0,1632 2,74996 1,78
33,2667 100,23 0,1632 2,69103 1,69
33,6759 100,62 0,0816 2,65927 1,69
34,0280 44,14 0,2040 2,63255 0,74
34,5271 487,49 0,1632 2,59563 8,20
34,8245 62,27 0,0816 2,57414 1,05 35,1481 146,06 0,0816 2,55118 2,46
35,4834 658,10 0,1224 2,52784 11,07
36,0193 103,11 0,1632 2,49145 1,73
36,4438 1185,45 0,1428 2,46340 19,93
36,7350 279,53 0,1020 2,44454 4,70
37,1661 264,91 0,1428 2,41716 4,45
37,9003 125,14 0,1020 2,37201 2,10
38,1775 60,65 0,1224 2,35542 1,02
38,7652 146,60 0,0816 2,32105 2,46
39,0713 202,95 0,1020 2,30357 3,41
39,7679 50,44 0,1020 2,26481 0,85
The stability of the ground sample was determined comparing its diffraction pattern with that of the standard reference (Minodronic acid, form X before grinding): the sample obtained showed the same diffraction pattern of Minodronic acid, form X, as reported in figure 2 (Form X-grinding line versus Form X line).
The stability is confirmed after kneading: the sample obtained after kneading (figure 3,
Form X-kneading line) showed the same diffraction pattern of the Minodronic Acid, form X before kneading.
FT-IR analysis returns the spectrum shown in figure 4. Said FT-IR spectrum is characterized by the peaks shown in Table 2 below.
Table 2:
Figure imgf000007_0001
1434,13 69,929
1461 ,99 68,564
1525,04 61 ,575
1587,37 69,485
1652,73 62,456
2759,40 73,741
3014,03 73,752
3095,12 73,112
3128,18 73,803
3327,25 74,929
DSC analysis, shown in figure 5, highlights two endothermic events, corresponding to a dehydration step between 80-130 °C (Onset 89.34 °C) and melt and degradation after 210 °C (Onset 233.38 °C).
The thermogram shown in figure 6 highlights a loss of weight of 9.38% w/w on moving 5 from about 80 to about 140°C. The sample losses water and a dihydrate form can be suggested. The following loss of 3.5% w/w is due to a decomposition event after 220 °C. The melting analysis reported in figure 7 confirms that the weight loss observed between 80-140 °C is not imputable a decomposition event. Melt and decomposition occurred simultaneously after approx. 250 °C, see the pictures taken at 250.4°C and above.
10 The results of the kinetic moisture sorption are reported in figure 8, where the grey line traces the percentage changes in mass as function of the time, while the black line traces the relative humidity changes as function of the time. In isotherms, reported in figure 9, the diamond line describes the first sorption phase, the black square line describes the first desorption phase, the grey triangle line describes the second sorption phase and the grey square line is describes the second desorption phase.
The sample analyzed shows a hydrophobic behavior. Under each cycle of sorption/desorption the change weight was maintained under 0.1 %, value typically ascribable to a non-hygroscopic compound.
The Easy-water analysis confirmed that the weight loss between 80-140°C is imputable 20 to a dehydration step. The amount registered is confident with that observed by TGA and confirms a dihydrate Minodronic acid form, as reported in figure 10.
The here described Minodronic acid, form X is stable also when exposed to stress conditions. Minodronic acid, form X has been tested by exposure for 7 days at 40°C and 75%RH. The XRPD patterns of the sample recorded after 1 , 3 and 7 days are reported in figure 25 11 and demonstrate that the crystal form did not change. The here claimed Minodronic acid, form X is thermodynamically stable.
The HPLC purity profile, reported in figure 12, demonstrates that Minodronic acid, form X can be isolated with a high level of chemical purity, > 99.97%.
By drying the above described Minodronic acid, form X under vacuum at 80°C for 24 h, 30 surprisingly a new polymorph, Minodronic acid, form Y, has been obtained, showing interesting features. The new crystal form Y is characterized by the XRPD spectrum shown in figure 13. Main peaks at 2theta +/- 0.3 degrees are: 9.5, 10.7, 13.9, 19.1 , 19.78, 19.85. Table 3 below shows the significant peaks of the spectrum.
Table 3:
Pos. [°2Th.] Height [cts] FWHM [°2Th.] d-spacing [A] Rel. Int. [%]
9,5559 1141,37 0,1171 9,25562 46,49
10,7209 832,28 0,1338 8,25226 33,90
13,9299 465,56 0,1673 6,35761 18,96
15,6266 240,45 0,2676 5,67093 9,79
15,8960 334,22 0,2007 5,57540 13,61
17,2369 421,98 0,1840 5,14459 17,19
18,0337 421,60 0,0836 4,91903 17,17
19,1392 1851,67 0,1840 4,63735 75,43
19,7857 2454,92 0,1632 4,48354 100,00
19,8584 2347,89 0,1020 4,47838 95,64
21,4590 50,00 0,2856 4,13756 2,04
24,3293 135,53 0,3264 3,65553 5,52
24,6661 116,47 0,1224 3,60638 4,74
25,6433 40,75 0,2040 3,47111 1,66
26,4873 364,65 0,1836 3,36239 14,85
26,9830 274,39 0,1224 3,30174 11,18
27,5635 113,95 0,2448 3,23351 4,64
28,6277 448,28 0,0816 3,11568 18,26
29,0972 341,50 0,2040 3,06647 13,91
30,7697 83,50 0,2448 2,90349 3,40
31,4108 150,84 0,2040 2,84568 6,14
31,9601 50,51 0,3264 2,79801 2,06
33,1535 39,63 0,3672 2,69997 1,61
34,9243 22,65 0,4896 2,56701 0,92
36,4908 48,45 0,4896 2,46033 1,97
37,7325 42,99 0,4080 2,38217 1,75
38,3974 40,21 0,2040 2,34244 1,64
39,0274 112,88 0,4896 2,30606 4,60
The stability of the ground sample was determined comparing its diffraction pattern with that of the standard reference: the sample obtained showed the same diffraction pattern of the Minodronic acid, form Y, although less crystalline, as reported in figure 14 (Form Y-grinding line versus Form Y line).
Interestingly, after kneading Minodronic acid, form Y of the present invention, a total conversion into crystal form X occurs, as highlighted in figure 15. The sample obtained after kneading (Form-Y-kneading line) showed the same diffraction pattern of the Minodronic acid, form X (Form X line).
FT-IR analysis returns the spectrum shown in figure 16. Said FT-IR spectrum is characterised by the peaks shown in Table 4 below.
Table 4:
Spectrum: FORM-Y
Region: 4000,19 400,16
Absolute threshold: 85,602 Sensitivity: 75
Peak list:
Position Intensity
406,04 27,318
25,466
33,353
46,514
45,304
45,534
43,532
41 ,339
40,738
35,516
29,656
41 ,112
36,965
46,072
52,279
54,604
70,487
66,205
71 ,217
67,810
69,823
1465,80 72,122
1521 ,62 66,297
1654,42 70,456
2775,29 83,284
3048,29 85,157
3095,90 82,368
DSC analysis of the Minodronic acid, form Y, shown in figure 17, shows a linear profile with a single event at about 245°C, corresponding to melt and decomposition of the sample (Onset 238.98 °C).
5 The thermogram shown in figure 18 for Minodronic acid, form Y highlights a loss of weight on moving from about 140 to about 220°C of 1.65% w/w. The following loss of 4.27% w/w is due to a decomposition event after 220°C. The melting analysis reported in figure 19 confirms that the weight loss observed between 140-220°C is not imputable to a decomposition event. Melt and decomposition occurred simultaneously after approx. 240°C, see the pictures
10 taken at 240.0°C and above.
The results of the kinetic moisture sorption are reported in figure 20, where the grey line traces the percentage changes in mass as function of the time, while the black line traces the relative humidity changes as function of the time. In isotherms, reported in figure 21 , the diamond line describes the first sorption phase, the square black line describes the first is desorption phase, the triangle grey line describes the second sorption phase and the square grey line describes the second desorption phase.
The sample analyzed shows a slightly hygroscopic behavior. In the first sorption cycle approx. 1% of water was adsorbed. In the following desorption step approx. 1.5% w/w of water was lost and a Minodronic acid form with a smaller quantities of water than the starting material was obtained.
In the second cycle of sorption/desorption, approx. at 75% of humidity the crystalline structure collapsed to give an anhydrous form.
The sample recovered at the end of the analysis was analyzed by XRPD and a diffractogram similar to the Minodronic acid, form F, patented in EP0647649B1 as anhydrous Form, was registered, see figure 22 where the grey line represents comparative Form F.
The Easy-water analysis confirmed that the weight loss between 140-220°C is imputable to a dehydration step. The amount registered is slightly higher than the quantity registered by gravimetric analysis. Generally, the analysis more confident is the TGA: the Easy- water has been carried out to confirm that the solvent lost was water.
Minodronic acid, form Y has been tested by exposure for 7 days at 40°C and 75%RH. The XRPD patterns of the sample recorded after 1 , 3 and 7 days are reported in figure 24 and demonstrate that already after 1 day a total conversion into the anhydrous Form F patented in EP0647649B1 occurs.
The integrity and high level of chemical purity of the new crystal form Y were confirmed by HPLC analysis, reported in figure 23. Minodronic acid, form Y can be isolated with a high level of chemical purity, > 99.8%.
The solubility of the polymorphs of the present invention has been investigated in kinetic and thermodynamic conditions in three different buffer media (pH 4.5, 6.8, and 7.4). Data are reported in the experimental section below. In all buffers tested, the crystal form X results the more soluble in kinetic conditions and the dissolution rate is two or three times higher of the state of the art Form E and Form D.
The here described crystal forms of Minodronic acid can be applied in pharmaceutical compositions. The pharmaceutical composition that comprises said crystal forms may contain additives. Any conventional technique can be used for preparation of pharmaceutical formulations in accordance with this invention.
EXAMPLES
Example 1 : Synthesis of Minodronic acid.
Figure imgf000011_0001
(I)
12.3 g of imidazo[1 ,2-a]pyridin-3-ylacetic acid hydrochloride, 12.07 g of H3P03 and 82 mL of chlorobenzene were added to a 250 mL jacketed reactor, equipped with a mechanical stirrer and a condenser connected to a NaOH trap. The reaction mixture was heated at 110 °C for 30 minutes and then cooled to 80 °C in 30 minutes. 30.79 g of PCI3 were added and the solution was kept at 80 °C for 15 minutes and then heated to 110 °C in 30 minutes. The reaction mixture was stirred (90-120 rpm) at this temperature for 8 hours and then cooled to 25 °C in 30 minutes and left at this temperature overnight under stirring. The chlorobenzene was removed using a peristaltic pump and the residue was dissolved in 200 mL of 6 M HCI, heating the solution at 110°C for 2 hours. The orange solution was poured into an Erlenmeyer flask containing 1.2 g of activated carbon (DARCO 100 mesh) and cooled to room temperature under stirring for 40 minutes. The solution was filtered through a paper filter washing the solid residue with 20 ml of 6M HCI. The solution was poured into a jacketed reactor and stirred at 25-30 °C. A 30 % aqueous solution of NaOH was added dropwise until pH 1. In these conditions precipitation of a solid occurred and the mixture was stirred at room temperature for two hours. The precipitate was collected by vacuum filtration and then washed with water (2 x 25 mL) and methanol (2 x 25 mL). The pale yellow solid was dried at 50 °C for 4 hours affording 11.85 g of Minodronic acid of formula (I) which exhibited HPLC purity of 98.5 %.
The solid was transferred into an Erlenmeyer flask and 47.4 mL of HCI 6M were added. The suspension was stirred at 100 °C until complete dissolution of the solid occurred and then 332 mL of methanol were added in one portion. The slurry was cooled at room temperature and then stirred for three hours at this temperature. The precipitate was collected by vacuum filtration and then washed with water, until the pH of the washing solvent was neutral. The white solid was dried at 50 °C for 4 hours affording 10.20 g of product which exhibited HPLC purity of 99.40 % (figure 26).
Example 2: Purification of Minodronic acid
The solid obtained at the end of example 1 was transferred into a beaker and 204 mL of water were added. The slurry was stirred at room temperature and 6.12 ml of diethyl amine (2 equivalents) were added. The mixture was stirred at room temperature until the solution became clear, then 408 mL of HCI 1 M were added in one portion and the solution was stirred at room temperature for three hours. Minodronic acid precipitated as a white solid, which was collected by vacuum filtration. The solid was washed with water, until the pH of the washing solvent was neutral, and then with methanol (2 x 25 mL). The white solid was dried for 4 hours at 50 °C affording 9.73 g of Minodronic acid (95.4 % yield) which exhibited HPLC purity of 99.64 % (figure 28). XRPD analysis showed the presence of a novel crystalline form, which was labeled as form X (figure 27).
Example 3: Preparation of Minodronic acid, form X with high level of chemical purity
35.7 g of Minodronic acid and 121 mL of water were added into a 2 L jacketed reactor equipped with a mechanical stirrer. 30 % aqueous solution of NaOH was added dropwise until pH 7.1-7.2, keeping the temperature between 20 and 30 °C. 929 mL of methanol were added in one portion to the clear solution and the white slurry was stirred at room temperature for 15 minutes. The white solid was collected by vacuum filtration, washed with methanol and dried at 50 °C for 24 hours. The dried solid was added into a 1 L jacketed reactor with 186 mL di H20. The mixture was heated at 80 °C until complete dissolution of the solid and then 139 mL of HCI (8 % aqueous solution) were added. The solution was cooled to 13 °C in one hour and stirred (120 rpm) at this temperature for 3 hours. The solid was collected by vacuum filtration, washed with water until pH of the washing solvent was neutral, and then with methanol. The white solid was dried at 50 °C for 4 hours affording 35.31 g of Minodronic acid with 99.85 % HPLC purity.
5 The solid (35.31 g) was transferred into a 2 L beaker equipped with a stirring bar and 141 mL of 6M HCI were added. The mixture was heated at 100 °C until complete dissolution of the solid occurred. 988 mL of methanol were added in one portion and the slurry was cooled to room temperature and stirred for three hours at this temperature. The solid was filtered under vacuum and washed with water, until pH of the washing solvent was neutral, and then methanol. The i o white solid was dried at 50 °C for 4 hours affording 30.36 g of Minodronic acid with 99.93 % HPLC purity.
The solid (30.36 g) was transferred into a 1 L jacketed reactor equipped with a condenser and a mechanical stirrer. 560 mL of water were added and the mixture was heated at 80 °C for 30 minutes. The hot solution was filtered under vacuum and the solid was washed with methanol 15 and dried under vacuum for 1 hour affording 29.45 g of Minodronic acid with 99.95 % HPLC purity.
The solid (29.45 g) was transferred into a 3 L jacketed reactor equipped with a condenser and a mechanical stirrer. 1.09 L of 1 M HCI were added and the mixture was heated at 110 °C until complete dissolution of the solid occurred. The hot solution was filtered through a pad of cotton 20 directly into another jacketed reactor previously cooled at 0°C. The solution was stirred (110 rpm) overnight at 0 °C and then filtered under vacuum. The solid was washed with water, until the pH of the washing solvent was neutral, and then with methanol. The white solid was dried at 50 °C overnight to afford 28.27 g of Minodronic acid, form X (96 % yield) with HPLC purity 99.97 %.
25 Example 4: Dehydration of Minodronic acid, form X
1 g of crystal form X was dried under vacuum at 80 °C overnight. The solid obtained was analyzed by XRPD and a new crystalline form has been identified. The new form was labeled as crystal form Y.
Example 5: Kinetic and Thermodynamic dissolution
30 The solubility of the new polymorphs of the Minodronic acid (form X and Y) and the known polymorphs, form E and D, were investigated in kinetic and thermodynamic conditions in three different buffer media (pH 4.5, 6.8 and 7.4). A HPLC method was optimized to evaluate the solubility of the new polymorphs synthesized of Minodronic acid.
The aim of the study was the evaluation of the dissolution capability of the new crystal forms 35 compared to the crystal forms of the API commercially available.
Tablets were prepared by mixing 50 mg of Minodronic acid form X, Y and E and D as a reference control with 50 mg of microcellulose. In all buffers tested, the crystal form X results the more soluble in kinetic conditions and the dissolution rate was two or three times higher than the Form E/D, considered as standards. The final concentration of the Minodronic acid after 30 minutes of analysis was comparable for all the polymorphs and values approx. of 700 μς/ηηΙ, 1000 μςΛηΙ and 900 μς/ηηΙ respectively at pH 4.5, 6.8 and 7.4 were extrapolated.
The main difference between the polymorphs is in the first minutes of the analysis, were the 5 crystal form X exhibits an exceptional solubility.
HPLC method:
Instrument: 1200 Infinity Series AGILENT
G4220B - 1290 BinPumpVL
G4226A - 1290 Sampler
10 G1316A - 1260 TCC
G1314F - 1260 VWD
Column: X-bridge C18 (250 mm x 4.6 mm) 5.0 μηη, Waters Corporations
Column Temperature:35 ± 0.3 °C
Mobile Phase:lone-pair solution (26.3 g Disodium hydrogen Phosphate, 3 g EDTA-disodium salt is and 1.9 g Tetrabutyl ammonium bromide were introduced into a suitable container. Dissolve the contents in 800 mL of water. Pipette out 2.0 mL of concentrated Hydrochloric acid into the same container, dissolve and mix well. Adjust the pH of the solution to 7.5, transfer the contents to
1000 mL measuring cylinder and dilute to 960 mL with water. Transfer the contents to a suitable container and mix well. Add 40 mL of methanol into the same container and mix well to obtain 20 said lone-pair solution).
Isocratic Elution: Yes
Flow: 1 mL/min
Pressure initial: 180 bar
Flow Ramp up:100 mL/min2
25 Flow Ramp down: 100 mL/min2
Jet Weaver:V100 Mixer
Detector Wavelength:280 nm
Peak width:> 0.0031 min (0.63 s resp. Time) (80 Hz)
Injection volume: 10 μΙ
30 Injection with needle wash:3.0 sec.
Stop analysis:30 min
Retention time:4.45 min for Minodronic Acid
Diluent: same of Mobil Phase
Calibration Curve, Standard Solution for Calibration Curve
35 Solution of the Reference Standard: 25.52 mg of Minodronic Acid (99.95% of purity), exactly weighted, were introduced into a 25 mL volumetric flask. The solid was dissolved in 40 mL of Diluent and the mixture was sonicated until a total dissolution was achieved. The solution was maintained at room temperature (using a thermostatic bath) and brought to volume with Diluent (Standard Solution cone. 1.0208 mg/ml_ of Minodronic Acid, Standard Solution SSO).
5 mL of Standard Solution was transferred into a 10 mL volumetric flask and diluted to volume with Diluent Solution (SS1 , 0.510 mg/mL of Minodronic Acid).
4 mL of Standard Solution was transferred into a 10 mL volumetric flask and diluted to volume 5 with Diluent Solution (SS2, 0.40832 mg/mL of Minodronic Acid)
2.5 mL of Standard Solution was transferred into a 10 mL volumetric flask and diluted to volume with Diluent Solution (SS3, 0.2552 mg/mL of Minodronic Acid)
1 mL of Standard Solution was transferred into a 10 mL volumetric flask and diluted to volume with Diluent Solution (SS4, 0.10208 mg/mL of Minodronic Acid)
i o HPLC method for Calibration Curve
Each standard sample was analyzed three times by the optimized chromatography conditions. The peaks of the product were integrated and an average was calculated. The results are reported in table 5.
Table 5:
Figure imgf000015_0001
The calibration curves and the related equation used to interpolate the experimental results is reported in figure 29.
The Kinetic Dissolutions were carried out in three different media: Phosphate Buffer pH 4.5, pH 6.8 and 7.4.
20 The dissolution tests were performed for each Minodronic acid, form D and E, prepared according with the patent EP 0 647 649 B1 and for the new polymorphs synthesized and labeled as form X and form Y formulated into tablets. The values collected are interpolated and plotted in the Figures 31-36 below, where the values extrapolated from the data of dissolution of the polymorphs X and Y were compared with the data of the Minodronic Acid form D or E.
The new polymorph form X shows the best dissolution profile: a larger concentration of API was 5 achieved in the first part of the dissolution analysis and this high concentration was maintained during the experiment (figure 30, light grey column)
The dissolution rate was extrapolated for each form in the first 5 minutes of analysis (figure 31 ). The same experiment has been repeated at pH 6.8 (figure 32, 33) and at pH 7.4 (figure 34, 35) confirming the best results for Form X.
i o A thermodynamic solubility test has been performed on the same crystal form subjected to the kinetic dissolution tests.
50 mg of each crystal form was added as powder in a glass tube, equipped with a magnetic stirring bar, and diluted with 2 ml. of buffer.
The mixtures were left under magnetic stirring (100 rpm) at 37 °C for 24 hours.
15 The experiments were carried out at pH 4.5, pH 6.8 and pH 7.4.
The suspensions were filtered with 0.20 micron filter and analyzed by the HPLC method previously reported and the results were interpolated by the calibration curve reported.
The thermodynamic solutions were dilutes 20 times to obtain a data comprising in the Calibration Curve.
20 It is evident that the solubility of the Minodronic acid is higher at pH 7.4 than pH 4.5 and 6.8 and this is justifiable with the presence of a Phosphoric moiety.
At pH 4.5 the crystalline form X is slightly more soluble than the other forms: in particular D and E showed a comparable solubility while for the Form Y a slight decrease was registered (figure 36).
25 At pH 6.8 all the Forms showed a similar solubility: approx. 7.5 mg/mL, excluding the Form D for which a approx. solubility of 5.5 mg/mL was estimated (figure 37).
At pH 7.4 a trend similar to pH 4.5 was observed: again the form X is the more soluble (approx. >14.3 mg/mL), however for the other polymorphs a good solubility between 13.2 and 14 mg/ml was calculated (figure 38).
30 After the thermodynamic solubility tests the powders were recovered and analyzed by XRPD.
For all the crystalline forms studied, a XRPD of the form D/E was recorded. This result justifies a similar final values of the thermodynamic test for the different polymorph analyzed (figure 39- 41 ).

Claims

1. A crystal form of Minodronic acid characterized by the XRPD spectrum that shows the following main peaks at 2theta +/- 0.3 degrees: 9.1 , 10.2, 15.5, 16.5, 18.7, 25.8, named Minodronic acid, form X.
2. The crystal form of claim 1 , characterized by the XRPD spectrum of figure 1.
3. A crystal form of Minodronic acid, characterized by the IR absorption spectrum shown in figure 4.
4. The crystal form of any of the claims 1-3, which is obtained by rapid cooling to 0°C of a boiling solution of Minodronic acid dissolved in HCI 1 M.
5. A process for purifying Minodronic acid that comprises:
a) Addition of NaOH until pH 1 to an acidic solution of Minodronic acid and precipitation and consequent drying of the solid which is Minodronic acid.
6. A process according to claim 5, further comprising:
b) Re-dissolution of the solid obtained in said step a) in hot HCI 6M, followed by precipitation with methanol, collecting a solid which is Minodronic acid.
7. A process according to claim 5 or 6, further comprising:
c) Addition to the solid obtained in said step a) or b) of an organic base;
d) Acidification and precipitation of a solid which is Minodronic acid.
8. A process according to claim 7, wherein said organic base is diethyl amine, preferably 2 equivalents of diethyl amine are added to said solid.
9. A process for preparing Minodronic acid, form X with high level of chemical purity that comprises:
a) Synthesis of the sodium salt of Minodronic acid and re-acidification;
b) Collection of the solid, which is Minodronic acid, 99.85% HPLC purity;
c) Dissolution of the solid of step b) into HCI 6M and precipitation with methanol;
d) Collection of the solid, which is Minodronic acid, 99.93% HPLC purity;
e) Washing with boiling water and crystallization from 1 M HCI obtaining Minodronic acid, form X with HPLC purity 99.97%.
10. A crystal form of Minodronic acid characterized by the XRPD spectrum that shows the following main peaks at 2theta +/- 0.3 degrees: 9.5, 10.7, 13.9, 19.1 , 19.78, 19.85, named Minodronic acid, form Y.
11. The crystal form of claim 6, characterized by the XRPD spectrum of figure 13.
12. A crystalline form of Minodronic acid, characterized by the IR absorption spectrum shown in figure 16.
13. The crystal form of any of the claims 10-12, which is obtained by drying Minodronic acid, form X under vacuum.
14. A pharmaceutical composition that comprises as active ingredient the crystal form of Minodronic acid of any of the claims 1-3 or 10-12.
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