WO2020121326A1 - Amorphous (rac)-tramadol.hcl-celecoxib (1:1) - Google Patents

Amorphous (rac)-tramadol.hcl-celecoxib (1:1) Download PDF

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WO2020121326A1
WO2020121326A1 PCT/IN2019/050904 IN2019050904W WO2020121326A1 WO 2020121326 A1 WO2020121326 A1 WO 2020121326A1 IN 2019050904 W IN2019050904 W IN 2019050904W WO 2020121326 A1 WO2020121326 A1 WO 2020121326A1
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celecoxib
rac
tramadol
hcl
solvent
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PCT/IN2019/050904
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French (fr)
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Ramakoteswara Rao Jetti
Ramamohana Rao Golivi
Sureshbabu JAYACHANDRA
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Mylan Laboratories Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1688—Processes resulting in pure drug agglomerate optionally containing up to 5% of excipient
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention provides amorphous form of (rac) -tramadol HCl-celecoxib (1:1) and its solid dispersion.
  • Celecoxib 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl] benzene sulfonamide, has the following structure.
  • the principal object of the present invention is to provide an amorphous form of (rac)- tramadol.HCl-celecoxib (1:1)
  • the present invention provides an amorphous form of (rac)-tramadol.HCl- celecoxib (1:1)
  • the present invention provides an amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1).
  • the present invention provides a process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving (rac)-tramadol.HCl and celecoxib in an organic solvent or mixtures thereof; b) removing the solvent to isolate amorphous (rac)-tramadol.HCl-celecoxib (1:1).
  • the present invention provides a process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving a 1:1 co-crystal of (rac)-tramadol.HCl-celecoxib in an organic solvent or mixtures thereof;
  • the present invention provides a process for the preparation of an amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib (1: 1) comprising the steps of: a) dissolving (rac)-tramadol.HCl and celecoxib and a pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof, and
  • the present invention provides a process for the preparation of an amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving (rac)-tramadol HC1 and celecoxib in a suitable solvent or mixtures thereof, b) adding a pharmaceutically acceptable excipient, and
  • Figure 1 PXRD pattern of amorphous (rac)-tramadol.HCl-celecoxib (1:1) of Example 1.
  • Figure 2 PXRD pattern of amorphous (rac)- tramadol.HCl-celecoxib (1:1) of Example 2.
  • Figure 3 PXRD pattern of amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1) of Example 3.
  • Figure 4 PXRD pattern of amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1) of Example 4.
  • Figure 5 PXRD pattern of amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1) of Example 5.
  • Figure 6 Modulated DSC thermogram of (rac)- tramadol.HCl-celecoxib amorphous form.
  • Figure 7 Comparison of FTIR spectra of the amorphous form and co-crystal/crystalline form of (rac)- tramadol.HCl-celecoxib (1:1).
  • Figure 8 Comparison of 13 C SSNMR data of an 1:1 admixture of (rac)-tramadol.HCl (A) and celecoxib (B), a 1:1 complex of (rac)- tramadol.HCl-celecoxib amorphous form, a 1:1 co crystal of (rac)- tramadol.HCl-celecoxib crystalline form, (rac)-tramadol.HCl (A) and celecoxib (B).
  • Figure 9 Variable temperature PXRD data of (rac)- tramadol.HCl-celecoxib amorphous form.
  • Figure 10 PXRD overlay of amorphous form storage at 5+3 °C (top) sample after 6 months, (middle) after 2 months, and (bottom) the initial sample.
  • the principal object of the present invention is to provide an amorphous form of (rac)- tramadol.HCl-celecoxib (1:1)
  • the FT-IR data was recorded using Perkin Elmer Spectrum One instrument in the range of 400-4000 cm-1 by using KBr pellets.
  • MDSC Modulated Differential Scanning Calorimetry
  • the glass transition temperature (Tg) of the amorphous of (rac)-tramadol.HCl-celecoxib was measured on TA Q2000 of TA instruments with modulated DSC software. The sample was heated from 30 to 250 °C at a heating rate of 5.0°C/min with modulation amplitude ⁇ 1.0°C, modulation period 60sec and nitrogen purging at a flow rate of 50ml/min. Standard aluminum pans covered by lids with one pin hole were utilized.
  • Solid State NMR The solid-state 13 C cross polarization/ magic angle spinning (CP-MAS) nuclear magnetic resonance spectrum of amorphous form of (rac)-tramadol.HCl-celecoxib was recorded on Bruker 500 MHz Avance III HD NMR spectrometer at 500MHz operated at 125 MHz for carbon 13. The chemical shifts were reported on scale in ppm. Cross polarization technique is used to enhance carbon 13 sensitivity by transferring proton magnetization to carbon.
  • VTPXRD Variable temperature Powder X-ray Diffraction
  • the thermal stability of polymorph of the present disclosure is characterized by variable temperature on Bruker D8 Discover powder X-ray diffractometer equipped with a goniometer of Q/2Q configuration and LynxEye detector with Anton Paar CHC plus Chamber. Primary Optics 0.3° opening; 2.5° Soller slit on the primary and secondary optics; nickel filter in primary optics; secondary optics opening 4mm.
  • the Cu-anode X-ray tube was operated at 40kV and 40mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.03° step size and 0.2 seconds step time.
  • Variable temperature powder X-ray diffraction data was measured in the temperature range of 30°C-180°C and re-cooled to 30°C.
  • present invention provides amorphous form of (rac)-tramadol.HCl- celecoxib (1:1).
  • the present invention provides an amorphous form of (rac)- tramadol.HCl-celecoxib (1:1) characterized by a PXRD pattern substantially as depicted in Figure 1 and Figure 2.
  • the present invention provides a process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving (rac)-tramadol.HCl and celecoxib in an organic solvent or mixtures thereof; and
  • (rac) -tramadol HC1 and celecoxib are dissolved in an organic solvent or mixtures thereof which is capable of dissolving (rac)-tramadol.HCl and celecoxib.
  • the organic solvents of the above embodiment are selected from chlorinated solvents, polar protic solvents, or polar aprotic solvents.
  • the chlorinated solvents may include but are not limited to dichloromethane, and chloroform.
  • the polar protic solvents may include but not limited to methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3 -methyl- 1 -butanol, 2- methyl-1 -propanol, and 1-pentanol.
  • the polar aprotic solvents may include but are not limited to tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide and N- methyl pyrrolidone.
  • the solvents may be mixtures thereof.
  • the solvent is removed from the resulting clear solution to isolate an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1).
  • the solvent removal can be carried out by processes known in the art such as evaporation, distillation, spray drying, lyophilization, or agitated thin film drying, preferably spray drying.
  • the present invention provides a process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving a 1:1 co-crystal of (rac)-tramadol.HCl-celecoxib in an organic solvent or mixtures thereof; b) removing the solvent to isolate the amorphous (rac)-tramadol.HCl-celecoxib (1:1).
  • the 1:1 co-crystal of (rac)-tramadol HC1 and celecoxib is dissolved in an organic solvent or mixtures thereof which is capable of dissolving 1:1 co-crystal of (rac)-tramadol.HCl-celecoxib.
  • the organic solvents of the above embodiment are selected from chlorinated solvents, polar protic solvents and polar aprotic solvents.
  • the chlorinated solvents may include but are not limited to dichloromethane, and chloroform.
  • the polar protic solvents may include, but are not limited to methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3-methyl- 1- butanol, 2-methyl- 1 -propanol, and 1-pentanol.
  • the polar aprotic solvents may include but are not limited to tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide and N-methyl pyrrolidone.
  • the solvents may be mixtures thereof.
  • the solvent is removed from the resulting clear solution of (rac)-tramadol.HCl and celecoxib to isolate amorphous (rac)-tramadol.HCl-celecoxib (1:1).
  • the removal of solvent can be carried out by processes known in the art such as evaporation, distillation, spray drying, lyophilization, or agitated thin film drying, preferably spray drying.
  • the present invention provides amorphous (rac) -tramadol HCl-celecoxib (1:1) and a pharmaceutical excipient.
  • the present invention provides an amorphous solid dispersion of (rac)- tramadol. HCl-celecoxib (1:1).
  • the pharmaceutical excipient may include diluents, lubricants, binders, glidants, stabilizers, surface active agents, anti-adherents, opacifiers, solvents, colorants, lubricants, pigments, anti-foam agents, and polishing agents.
  • microcrystalline cellulose, polysorbate, mannitol, and hydroxypropyl methylcellulose are found to be particularly useful excipients.
  • the excipient or combinations of excipients may be included in the formulation.
  • Examples of useful pharmaceutical excipients within the context of the present invention include starches, lactose, mannitol (for example, PearlitolTM SD200), cellulose and cellulose derivatives, and confectioner's sugar.
  • lactose may be useful in the context of the present invention, for example, lactose monohydrate, lactose DT (direct tableting), and lactose anhydrous.
  • starches may be used in the context of the present invention, for example, maize starch, potato starch, rice starch, wheat starch, pre-gelatinized starch, starch 1500, starch 1500 LM grade, and fully pre-gelatinized starch.
  • Suitable cellulose compounds for use in the context of the present invention include crystalline celluloses, such as CeolusTM KG-801, and a variety of AvicelTM celluloses (for example, PH- 101, PH-102, PH-301, PH-302, PH-F20, PHI-12, PH-114, and PH-112). Powdered celluloses may be used as well.
  • HPC examples include KlucelTM LF and KlucelTM EXF), low-substituted hydroxypropylcelluloses (L-HPCS examples include LH-11, LH-21, LH-31, LH-22, LH-32, LH-20, LH-30, LH-32 and LH-33), hydroxypropylmethylcellulose (also called hypromellose or HPMC, one example is MethocelTM).
  • Other suitable binders/disintegrants include polyvinylpyrrolidones (also called povidone; examples include PVP-K25, PVP-K29, PVP-K30, and PVP-K90), copovidone (for example, PlasdoneTM S-630).
  • excipients include powdered acacia, gelatin, guar gum, sodium starch glycolate, colloidal silicon dioxide, carbomers (for example, CarbopolTM), methylcelluloses, polymethacrylates, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, and crospovidones (for example, cross-linked povidone, KollidonTM CL PolyplasdoneTM XL, XI- 10, and INF- 10).
  • carbomers for example, CarbopolTM
  • methylcelluloses for example, CarbopolTM
  • polymethacrylates for example, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, and crospovidones (for example, cross-linked povidone, KollidonTM CL PolyplasdoneTM XL, XI- 10, and INF- 10).
  • excipients include sorbitan esters (for example, SpanTM), polyhydroxyethylenically-treated sorbitan esters (for example, TweenTM), aliphatic alcohols and polyethylene glycol (PEG) ethers, phenol and PEG ethers, quaternary ammonium salts (e.g., cetyltrimethylammonium bromide), amine salts (for example, octadecylamine HC1), stearates (for example, glyceryl mono stearates, polyoxyethylene monostearates, ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sodium stearate, potassium stearate, ammonium stearate, calcium stearate, sodium stearate, triethenolamine stearate, zinc stearate, and magnesium stearate), sodium
  • Phospholipids e.g., diacylphosphatidylglycerols, diaceylphosphatidylcholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as soybean lecithin and egg yolk
  • suitable pigments include titanium oxide, silicon dioxide, iron oxides, zinc oxide, and combinations thereof.
  • Suitable plasticizers include, as examples, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate.
  • Suitable basic inorganic salts of sodium, potassium, magnesium, and calcium e.g., sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, potassium hydrogen carbonate, potassium hydroxide, heavy magnesium carbonate, magnesium, [Mg6Al(0H)16 C03-4H20], aluminum hydroxide-magnesium, and [2.5MgO A1203 H20] may be include in the formulation as well.
  • excipients listed above can act in a multitude of functional roles (e.g., starches can act both as a disintegrants and a binder depending on the formulation) to dictate the final properties of the desired product.
  • functional roles e.g., starches can act both as a disintegrants and a binder depending on the formulation
  • One of skill in the art will readily recognize these various functional aspects of each excipient and be able to incorporate, without undue experimentation, an excipient or combinations of excipients to achieve the desired final product.
  • Plasdone S-630, Povidone-K30, silicon dioxide and mixtures thereof have been found to particularly useful excipients for preparing a premix of (rac)-tramadol.HCl- celecoxib (1: 1).
  • the present invention provides a process for the preparation of amorphous solid dispersion of (rac)-tramadol.HCl - celecoxib (1: 1) comprising the steps of: a) dissolving (rac)-tramadol.HCl, celecoxib and a pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof, and
  • (rac)-tramadol HC1 and celecoxib and a pharmaceutically acceptable excipient are dissolved in a suitable solvent or mixtures thereof which is capable of dissolving (rac)-tramadol.HCl and celecoxib and the pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient is as disclosed in the above embodiments.
  • the suitable solvents of the above embodiment is selected from chlorinated solvents, polar protic solvents and polar aprotic solvents.
  • the chlorinated solvents may include but are not limited to dichloromethane, and chloroform.
  • the polar protic solvents may include, but are not limited to methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3-methyl- 1- butanol, 2-methyl- 1 -propanol, and 1-pentanol.
  • the polar aprotic solvents may include but are not limited to tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide and N-methyl pyrrolidone.
  • the solvents may be mixtures thereof.
  • the solvent is removed from the resulting clear solution to isolate the amorphous solid dispersion of (rac)-tramadol .HCl-celecoxib (1:1) with the pharmaceutically acceptable excipient.
  • the removal solvent can be carried out by processes known in the art such as evaporation, distillation, spray drying, lyophilization, or agitated thin film drying, preferably distillation.
  • the present invention provides a process for the preparation of an amorphous solid dispersion of (rac)-tramadol.HCl - celecoxib (1:1) comprising the steps of: a) dissolving (rac)-tramadol.HCl, celecoxib in a suitable solvent or mixtures thereof, b) adding a pharmaceutically acceptable excipient, and
  • the suitable solvents of the above embodiment is selected from chlorinated solvents, polar protic solvents and polar aprotic solvents.
  • the chlorinated solvents may include but are not limited to dichloromethane, and chloroform.
  • the polar protic solvents may include, but are not limited to methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3-methyl- 1- butanol, 2-methyl- 1 -propanol, and 1-pentanol.
  • the polar aprotic solvents may include but are not limited to tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide and N-methyl pyrrolidone.
  • the solvents may be mixtures thereof.
  • the pharmaceutically acceptable excipient is added to the (rac)- tramadol HC1 and celecoxib mixture.
  • the pharmaceutically acceptable excipient is as disclosed in the above embodiments.
  • the solvent was removed from the resulting clear solution to isolate the amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib (1:1) with the pharmaceutically acceptable excipient.
  • the removal solvent can be carried out by processes known in the art, such as evaporation, distillation, spray drying, lyophilization, or agitated thin film drying, preferably distillation.
  • the MDSC data of amorphous form of (rac)-tramadol.HCl-celecoxib shows a glass transition temperature (Tg) of 59.8 °C above which a recrystallization exothermic event is observed at about 120 °C which converts the material to a crystalline form that finally melts at about 167 °C.
  • Figure 6 shows the modulated DSC thermogram of (rac)-tramadol.HCl-celecoxib amorphous Form.
  • the solid-state NMR spectra of the amorphous complex is similar to the US8598152 co crystal/crystalline form (except the broadening) pointing out that the complex integrity is intact in the amorphous complex ( Figure 8).
  • 13C SSNMR spectra of an 1:1 admixture of (rac)- tramadol. HC1 and celecoxib is comparable to individual spectra of (rac)-tramadol.HCl and celecoxib with no change in chemical shifts corresponding to functional groups such as -CH3, -OCH3, aromatic-carbons and N-methyl groups, etc., further confirming the amorphous form as a molecular complex but not a physical mixture of individual APIs.
  • Figure 8 shows a comparison of 13C SSNMR data of a 1:1 admixture of (rac)-tramdol.HCl (A) and celecoxib (B), 1:1 complex of (rac)-tramdol.HCl-celecoxib amorphous form, 1:1 co-crystal of (rac)- tramdol.HCl-celecoxib crystalline form, (rac)-tramadol.HCl (A) and celecoxib (B).
  • Variable temperature PXRD data of (rac)-tramadol.HCl-celecoxib amorphous form was studied from 30 °C to 180 °C followed by cooling to 30 °C.
  • the amorphous form is stable up to 120°C and above this temperature it converts to crystalline form which melts at about 180 °C and then converts to amorphous which upon re-cooling remains amorphous.
  • Figure 9 shows the variable temperature PXRD data of the (rac)-tramadol.HCl-celecoxib amorphous form.
  • the physical stability of 1 : 1 co-crystal of (rac)-tramadol.HCl-celecoxib amorphous form was determined by storing the samples at 40°C and 75% relative humidity (RH), 25°C and 60% relative humidity (RH) and 5 ⁇ 3°C for six months and the samples were analyzed by PXRD. The results are shown in below Table 1. The 1: 1 co-crystal of (rac)- tramadol.HCl-celecoxib amorphous form was found to be physically stable at 5+3 °C up to six months.
  • the Figure 10 shows the PXRD overlay of amorphous form storage at 5 ⁇ 3°C. (top) sample after 6months, (middle) after 2 months and (bottom) the initial sample.
  • the solubility of a drugs play a major role in in formulating them. Drugs having a low solubility are a major problem encountered with formulation development. Any drug to be absorbed must be present in the form of solution at the site of absorption.
  • the amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib as described herein has enhanced solubility as shown in table 2.
  • Example 1 Five grams of (rac)-tramadol.HCl and 6.36 g of celecoxib were dissolved in 25 mL of methanol at 20-30°C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulate and the solution was subjected to spray-drying in a laboratory spray-dryer (model: Buchi B-290) with a feed rate of solution at 5ml/min and an inlet temperature at 75°C with 100% aspiration to yield an amorphous form of (rac)- tramadol.HCl-celecoxib (1:1).
  • Example 2 Twenty grams of a 1: 1 co-crystal of tramadol.HCl-celecoxib were dissolved in 100 mL of methanol at 20-30 °C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulate and the solution was subjected to spray -drying in a laboratory spray-dryer (model: Buchi B-290) with a feed rate of solution 5ml/min and an inlet temperature at 75°C with 100% aspiration to yield the amorphous form of (rac)-tramadol.HCl- celecoxib (1: 1).
  • Example 3 0.5 gram of (rac)-Tramadol.HCl, 0.636 g of celecoxib and 1.136 g of plasdone S- 630 were dissolved in 6 mL of methanol at 25 ⁇ 5°C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulates, the filter aid washed with methanol, and the solvent was then distilled off under vacuum at 50 °C to yield a 1: 1: 1 amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib with plasdone S-630.
  • Example 4 0.5 gram of (rac)-Tramadol.HCl, 0.636 g of celecoxib and 1.136 g of povidone- K30 were dissolved in 6 mL of methanol at 25+5 °C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulates, the filter aid was washed with methanol, and the solvent was then distilled off under vacuum at 50°C to yield a 1: 1: 1 amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib with povidone K-30.
  • Example 5 0.5 gram of (rac)-Tramadol.HCl and 0.636 g of celecoxib were dissolved in 3 mL of methanol at 25 ⁇ 5°C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulates, and the filter aid was washed with methanol. To the resulting clear solution was added 1.136 g of silicon dioxide (Aeroperl 300) and the solvent was distilled off under vacuum at 50°C to yield 1: 1: 1: 1 amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib with silicon dioxide.

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Abstract

The present invention provides an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) and a solid dispersion and processes for the preparation of the same.

Description

AMORPHOUS (RAC)-TRAMADOL.HCl-CELECOXIB (1:1)
CROSS-REFERENCE TO RELATED APPLICATION(S)
This application claims the priority to and benefit of Indian Patent Application No. IN201841047151 filed on December 13, 2018; the disclosures of which are incorporated herein by reference.
FIELD OF THE INVENTION
The present invention provides amorphous form of (rac) -tramadol HCl-celecoxib (1:1) and its solid dispersion.
BACKGROUND OF THE INVENTION
Tramadol, 2-[(dimethylamino)-methyl]-l-(3-methoxyphenyl) cyclohexanol, is widely used as an analgesic in its physiologically acceptable salt forms. (rac)-Tramadol.HCl of the present invention has the following structure.
Figure imgf000002_0001
(rac)-Tramadol Hydrochloride
Celecoxib, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-lH-pyrazol-l-yl] benzene sulfonamide, has the following structure.
Figure imgf000002_0002
A co-crystal comprising (rac)-tramadol.HCl and celecoxib is reported in US8598152 and US9012440. OBJECT AND SUMMARY OF THE INVENTION
The principal object of the present invention is to provide an amorphous form of (rac)- tramadol.HCl-celecoxib (1:1)
In one aspect, the present invention provides an amorphous form of (rac)-tramadol.HCl- celecoxib (1:1)
In another aspect, the present invention provides an amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1).
In one more aspect, the present invention provides a process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving (rac)-tramadol.HCl and celecoxib in an organic solvent or mixtures thereof; b) removing the solvent to isolate amorphous (rac)-tramadol.HCl-celecoxib (1:1).
In one more aspect, the present invention provides a process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving a 1:1 co-crystal of (rac)-tramadol.HCl-celecoxib in an organic solvent or mixtures thereof;
b) removing the solvent to isolate the amorphous form of (rac)-tramadol.HCl-celecoxib
(1: 1).
In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib (1: 1) comprising the steps of: a) dissolving (rac)-tramadol.HCl and celecoxib and a pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof, and
b) removing the solvent to isolate the amorphous solid dispersion of (rac)-tramadol.HCl- celecoxib (1:1).
In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving (rac)-tramadol HC1 and celecoxib in a suitable solvent or mixtures thereof, b) adding a pharmaceutically acceptable excipient, and
c) removing the solvent to isolate the amorphous solid dispersion of (rac)-tramadol.HCl- celecoxib (1:1). BRIEF DESCRIPTION OF THE DRAWINGS
Further aspects of the present disclosure together with additional features contributing there to and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying figures wherein: Figure 1: PXRD pattern of amorphous (rac)-tramadol.HCl-celecoxib (1:1) of Example 1.
Figure 2: PXRD pattern of amorphous (rac)- tramadol.HCl-celecoxib (1:1) of Example 2.
Figure 3: PXRD pattern of amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1) of Example 3.
Figure 4: PXRD pattern of amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1) of Example 4.
Figure 5: PXRD pattern of amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1) of Example 5.
Figure 6: Modulated DSC thermogram of (rac)- tramadol.HCl-celecoxib amorphous form.
Figure 7: Comparison of FTIR spectra of the amorphous form and co-crystal/crystalline form of (rac)- tramadol.HCl-celecoxib (1:1).
Figure 8: Comparison of 13C SSNMR data of an 1:1 admixture of (rac)-tramadol.HCl (A) and celecoxib (B), a 1:1 complex of (rac)- tramadol.HCl-celecoxib amorphous form, a 1:1 co crystal of (rac)- tramadol.HCl-celecoxib crystalline form, (rac)-tramadol.HCl (A) and celecoxib (B). Figure 9: Variable temperature PXRD data of (rac)- tramadol.HCl-celecoxib amorphous form.
Figure 10: PXRD overlay of amorphous form storage at 5+3 °C (top) sample after 6 months, (middle) after 2 months, and (bottom) the initial sample.
DETAILED DESCRIPTION OF THE INVENTION The principal object of the present invention is to provide an amorphous form of (rac)- tramadol.HCl-celecoxib (1:1)
Instrumentation Details: The PXRD measurements were carried out using PANalytical X'Pert PRO powder diffractometer equipped with goniometer of Q/Q configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.030° step size and 50 seconds step time. FT-IR:
The FT-IR data was recorded using Perkin Elmer Spectrum One instrument in the range of 400-4000 cm-1 by using KBr pellets.
Modulated Differential Scanning Calorimetry (MDSC)
The glass transition temperature (Tg) of the amorphous of (rac)-tramadol.HCl-celecoxib was measured on TA Q2000 of TA instruments with modulated DSC software. The sample was heated from 30 to 250 °C at a heating rate of 5.0°C/min with modulation amplitude ±1.0°C, modulation period 60sec and nitrogen purging at a flow rate of 50ml/min. Standard aluminum pans covered by lids with one pin hole were utilized.
Solid State NMR: The solid-state 13C cross polarization/ magic angle spinning (CP-MAS) nuclear magnetic resonance spectrum of amorphous form of (rac)-tramadol.HCl-celecoxib was recorded on Bruker 500 MHz Avance III HD NMR spectrometer at 500MHz operated at 125 MHz for carbon 13. The chemical shifts were reported on scale in ppm. Cross polarization technique is used to enhance carbon 13 sensitivity by transferring proton magnetization to carbon. Variable temperature Powder X-ray Diffraction (VTPXRD):
The thermal stability of polymorph of the present disclosure is characterized by variable temperature on Bruker D8 Discover powder X-ray diffractometer equipped with a goniometer of Q/2Q configuration and LynxEye detector with Anton Paar CHC plus Chamber. Primary Optics 0.3° opening; 2.5° Soller slit on the primary and secondary optics; nickel filter in primary optics; secondary optics opening 4mm. The Cu-anode X-ray tube was operated at 40kV and 40mA. The experiments were conducted over the 2Q range of 2.0°-50.0°, 0.03° step size and 0.2 seconds step time. Variable temperature powder X-ray diffraction data was measured in the temperature range of 30°C-180°C and re-cooled to 30°C. In one embodiment, present invention provides amorphous form of (rac)-tramadol.HCl- celecoxib (1:1).
In another embodiment, the present invention provides an amorphous form of (rac)- tramadol.HCl-celecoxib (1:1) characterized by a PXRD pattern substantially as depicted in Figure 1 and Figure 2.
In one more embodiment the present invention provides a process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving (rac)-tramadol.HCl and celecoxib in an organic solvent or mixtures thereof; and
b) removing the solvent to isolate the amorphous form of (rac)-tramadol.HCl-celecoxib
(1: 1)
In one embodiment of the present invention, (rac) -tramadol HC1 and celecoxib are dissolved in an organic solvent or mixtures thereof which is capable of dissolving (rac)-tramadol.HCl and celecoxib. The organic solvents of the above embodiment are selected from chlorinated solvents, polar protic solvents, or polar aprotic solvents. The chlorinated solvents may include but are not limited to dichloromethane, and chloroform. The polar protic solvents may include but not limited to methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3 -methyl- 1 -butanol, 2- methyl-1 -propanol, and 1-pentanol. The polar aprotic solvents may include but are not limited to tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide and N- methyl pyrrolidone. The solvents may be mixtures thereof.
Next, the solvent is removed from the resulting clear solution to isolate an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1). The solvent removal can be carried out by processes known in the art such as evaporation, distillation, spray drying, lyophilization, or agitated thin film drying, preferably spray drying.
In another embodiment, the present invention provides a process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1:1) comprising the steps of: a) dissolving a 1:1 co-crystal of (rac)-tramadol.HCl-celecoxib in an organic solvent or mixtures thereof; b) removing the solvent to isolate the amorphous (rac)-tramadol.HCl-celecoxib (1:1).
In one embodiment of the present invention, the 1:1 co-crystal of (rac)-tramadol HC1 and celecoxib is dissolved in an organic solvent or mixtures thereof which is capable of dissolving 1:1 co-crystal of (rac)-tramadol.HCl-celecoxib. The organic solvents of the above embodiment are selected from chlorinated solvents, polar protic solvents and polar aprotic solvents. The chlorinated solvents may include but are not limited to dichloromethane, and chloroform. The polar protic solvents may include, but are not limited to methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3-methyl- 1- butanol, 2-methyl- 1 -propanol, and 1-pentanol. The polar aprotic solvents may include but are not limited to tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide and N-methyl pyrrolidone. The solvents may be mixtures thereof.
Next, the solvent is removed from the resulting clear solution of (rac)-tramadol.HCl and celecoxib to isolate amorphous (rac)-tramadol.HCl-celecoxib (1:1). The removal of solvent can be carried out by processes known in the art such as evaporation, distillation, spray drying, lyophilization, or agitated thin film drying, preferably spray drying.
The present invention provides amorphous (rac) -tramadol HCl-celecoxib (1:1) and a pharmaceutical excipient.
In an embodiment, the present invention provides an amorphous solid dispersion of (rac)- tramadol. HCl-celecoxib (1:1). In another embodiment, the pharmaceutical excipient may include diluents, lubricants, binders, glidants, stabilizers, surface active agents, anti-adherents, opacifiers, solvents, colorants, lubricants, pigments, anti-foam agents, and polishing agents. In some embodiments, microcrystalline cellulose, polysorbate, mannitol, and hydroxypropyl methylcellulose are found to be particularly useful excipients. Within the context of the present invention, the excipient or combinations of excipients may be included in the formulation.
Examples of useful pharmaceutical excipients within the context of the present invention include starches, lactose, mannitol (for example, Pearlitol™ SD200), cellulose and cellulose derivatives, and confectioner's sugar. Different forms of lactose may be useful in the context of the present invention, for example, lactose monohydrate, lactose DT (direct tableting), and lactose anhydrous. Different forms of starches may be used in the context of the present invention, for example, maize starch, potato starch, rice starch, wheat starch, pre-gelatinized starch, starch 1500, starch 1500 LM grade, and fully pre-gelatinized starch. Examples of suitable cellulose compounds for use in the context of the present invention include crystalline celluloses, such as Ceolus™ KG-801, and a variety of Avicel™ celluloses (for example, PH- 101, PH-102, PH-301, PH-302, PH-F20, PHI-12, PH-114, and PH-112). Powdered celluloses may be used as well. Other useful cellulose derivatives include hydroxypropylcellulose (HPC examples include Klucel™ LF and Klucel™ EXF), low-substituted hydroxypropylcelluloses (L-HPCS examples include LH-11, LH-21, LH-31, LH-22, LH-32, LH-20, LH-30, LH-32 and LH-33), hydroxypropylmethylcellulose (also called hypromellose or HPMC, one example is Methocel™). Other suitable binders/disintegrants include polyvinylpyrrolidones (also called povidone; examples include PVP-K25, PVP-K29, PVP-K30, and PVP-K90), copovidone (for example, Plasdone™ S-630). Other suitable excipients include powdered acacia, gelatin, guar gum, sodium starch glycolate, colloidal silicon dioxide, carbomers (for example, Carbopol™), methylcelluloses, polymethacrylates, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, and crospovidones (for example, cross-linked povidone, Kollidon™ CL Polyplasdone™ XL, XI- 10, and INF- 10). Further examples of suitable excipients include sorbitan esters (for example, Span™), polyhydroxyethylenically-treated sorbitan esters (for example, Tween™), aliphatic alcohols and polyethylene glycol (PEG) ethers, phenol and PEG ethers, quaternary ammonium salts (e.g., cetyltrimethylammonium bromide), amine salts (for example, octadecylamine HC1), stearates (for example, glyceryl mono stearates, polyoxyethylene monostearates, ethylene glycol stearates, propylene glycol stearates, diethylene glycol stearates, glycerol stearates, sodium stearate, potassium stearate, ammonium stearate, calcium stearate, sodium stearate, triethenolamine stearate, zinc stearate, and magnesium stearate), sodium lauryl sulfate, magnesium lauryl sulfate, calcium and sodium soaps, sodium dioctylsulfosuccinate, sodium dodecylbenzenesulfonate, palmitic acid, talc, carnauba wax, silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and combinations thereof. Phospholipids (e.g., diacylphosphatidylglycerols, diaceylphosphatidylcholines, and diaceylphosphatidic acids, the precursors and derivatives thereof, such as soybean lecithin and egg yolk) may also be used. Examples of suitable pigments include titanium oxide, silicon dioxide, iron oxides, zinc oxide, and combinations thereof. Suitable plasticizers include, as examples, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycol, propylene glycol, triacetin, and triethyl citrate. Suitable basic inorganic salts of sodium, potassium, magnesium, and calcium (e.g., sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium carbonate, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, potassium hydrogen carbonate, potassium hydroxide, heavy magnesium carbonate, magnesium, [Mg6Al(0H)16 C03-4H20], aluminum hydroxide-magnesium, and [2.5MgO A1203 H20] may be include in the formulation as well.
Many of the excipients listed above can act in a multitude of functional roles (e.g., starches can act both as a disintegrants and a binder depending on the formulation) to dictate the final properties of the desired product. One of skill in the art will readily recognize these various functional aspects of each excipient and be able to incorporate, without undue experimentation, an excipient or combinations of excipients to achieve the desired final product.
In some embodiments, Plasdone S-630, Povidone-K30, silicon dioxide and mixtures thereof have been found to particularly useful excipients for preparing a premix of (rac)-tramadol.HCl- celecoxib (1: 1).
In another aspect, the present invention provides a process for the preparation of amorphous solid dispersion of (rac)-tramadol.HCl - celecoxib (1: 1) comprising the steps of: a) dissolving (rac)-tramadol.HCl, celecoxib and a pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof, and
b) removing the solvent to isolate the amorphous solid dispersion of (rac)-tramadol.HCl- celecoxib (1: 1).
In one embodiment of the present invention, (rac)-tramadol HC1 and celecoxib and a pharmaceutically acceptable excipient are dissolved in a suitable solvent or mixtures thereof which is capable of dissolving (rac)-tramadol.HCl and celecoxib and the pharmaceutically acceptable excipient.
Within the context of the invention, the pharmaceutically acceptable excipient is as disclosed in the above embodiments.
The suitable solvents of the above embodiment is selected from chlorinated solvents, polar protic solvents and polar aprotic solvents. The chlorinated solvents may include but are not limited to dichloromethane, and chloroform. The polar protic solvents may include, but are not limited to methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3-methyl- 1- butanol, 2-methyl- 1 -propanol, and 1-pentanol. The polar aprotic solvents may include but are not limited to tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide and N-methyl pyrrolidone. The solvents may be mixtures thereof.
Next, the solvent is removed from the resulting clear solution to isolate the amorphous solid dispersion of (rac)-tramadol .HCl-celecoxib (1:1) with the pharmaceutically acceptable excipient. The removal solvent can be carried out by processes known in the art such as evaporation, distillation, spray drying, lyophilization, or agitated thin film drying, preferably distillation.
In another aspect, the present invention provides a process for the preparation of an amorphous solid dispersion of (rac)-tramadol.HCl - celecoxib (1:1) comprising the steps of: a) dissolving (rac)-tramadol.HCl, celecoxib in a suitable solvent or mixtures thereof, b) adding a pharmaceutically acceptable excipient, and
c) removing the solvent to isolate amorphous solid dispersion of (rac)-tramadol.HCl- celecoxib (1:1). In one embodiment of the present invention, (rac) -tramadol HC1 and celecoxib dissolved in a suitable solvent or mixtures thereof which is capable of dissolving (rac)-tramadol.HCl and celecoxib.
The suitable solvents of the above embodiment is selected from chlorinated solvents, polar protic solvents and polar aprotic solvents. The chlorinated solvents may include but are not limited to dichloromethane, and chloroform. The polar protic solvents may include, but are not limited to methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3-methyl- 1- butanol, 2-methyl- 1 -propanol, and 1-pentanol. The polar aprotic solvents may include but are not limited to tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide and N-methyl pyrrolidone. The solvents may be mixtures thereof. In another embodiment, the pharmaceutically acceptable excipient is added to the (rac)- tramadol HC1 and celecoxib mixture.
With in the context of the invention, the pharmaceutically acceptable excipient is as disclosed in the above embodiments. Next, the solvent was removed from the resulting clear solution to isolate the amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib (1:1) with the pharmaceutically acceptable excipient. The removal solvent can be carried out by processes known in the art, such as evaporation, distillation, spray drying, lyophilization, or agitated thin film drying, preferably distillation.
DSC:
The MDSC data of amorphous form of (rac)-tramadol.HCl-celecoxib shows a glass transition temperature (Tg) of 59.8 °C above which a recrystallization exothermic event is observed at about 120 °C which converts the material to a crystalline form that finally melts at about 167 °C. Figure 6 shows the modulated DSC thermogram of (rac)-tramadol.HCl-celecoxib amorphous Form.
IR spectrum:
Comparison of the FTIR spectra of co-crystal/crystalline form of US8598152 and amorphous (rac)-tramadol.HCl-celecoxib (1:1) of present invention. The Figure 7 shows comparative FTIR spectra.
Solid state NMR:
The solid-state NMR spectra of the amorphous complex is similar to the US8598152 co crystal/crystalline form (except the broadening) pointing out that the complex integrity is intact in the amorphous complex (Figure 8). Also, 13C SSNMR spectra of an 1:1 admixture of (rac)- tramadol. HC1 and celecoxib is comparable to individual spectra of (rac)-tramadol.HCl and celecoxib with no change in chemical shifts corresponding to functional groups such as -CH3, -OCH3, aromatic-carbons and N-methyl groups, etc., further confirming the amorphous form as a molecular complex but not a physical mixture of individual APIs. Figure 8 shows a comparison of 13C SSNMR data of a 1:1 admixture of (rac)-tramdol.HCl (A) and celecoxib (B), 1:1 complex of (rac)-tramdol.HCl-celecoxib amorphous form, 1:1 co-crystal of (rac)- tramdol.HCl-celecoxib crystalline form, (rac)-tramadol.HCl (A) and celecoxib (B).
Variable temperature (VT) PXRD data:
Variable temperature PXRD data of (rac)-tramadol.HCl-celecoxib amorphous form was studied from 30 °C to 180 °C followed by cooling to 30 °C. The amorphous form is stable up to 120°C and above this temperature it converts to crystalline form which melts at about 180 °C and then converts to amorphous which upon re-cooling remains amorphous. Figure 9 shows the variable temperature PXRD data of the (rac)-tramadol.HCl-celecoxib amorphous form.
Indicative stability:
In another embodiment, the physical stability of 1 : 1 co-crystal of (rac)-tramadol.HCl-celecoxib amorphous form was determined by storing the samples at 40°C and 75% relative humidity (RH), 25°C and 60% relative humidity (RH) and 5±3°C for six months and the samples were analyzed by PXRD. The results are shown in below Table 1. The 1: 1 co-crystal of (rac)- tramadol.HCl-celecoxib amorphous form was found to be physically stable at 5+3 °C up to six months.
Table 1
Figure imgf000012_0001
The Figure 10 shows the PXRD overlay of amorphous form storage at 5±3°C. (top) sample after 6months, (middle) after 2 months and (bottom) the initial sample.
Solubility:
The solubility of a drugs play a major role in in formulating them. Drugs having a low solubility are a major problem encountered with formulation development. Any drug to be absorbed must be present in the form of solution at the site of absorption. The amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib as described herein has enhanced solubility as shown in table 2.
The solubility of amorphous and crystalline form of 1: 1 co-crystal of (rac)-tramadol.HCl - celecoxib were determined in water and different aqueous buffers of different pH at 37 °C. The results are shown in the following Table 2. The 1:1 co-crystal of (rac)-tramadol.HCl-celecoxib amorphous form shows about a 4-5 fold increase in buffer and aqueous solubility in comparison with the crystalline form. Table 2
Figure imgf000013_0001
In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure. Examples:
Example 1: Five grams of (rac)-tramadol.HCl and 6.36 g of celecoxib were dissolved in 25 mL of methanol at 20-30°C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulate and the solution was subjected to spray-drying in a laboratory spray-dryer (model: Buchi B-290) with a feed rate of solution at 5ml/min and an inlet temperature at 75°C with 100% aspiration to yield an amorphous form of (rac)- tramadol.HCl-celecoxib (1:1).
Yield: 9.1 g Example 2: Twenty grams of a 1: 1 co-crystal of tramadol.HCl-celecoxib were dissolved in 100 mL of methanol at 20-30 °C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulate and the solution was subjected to spray -drying in a laboratory spray-dryer (model: Buchi B-290) with a feed rate of solution 5ml/min and an inlet temperature at 75°C with 100% aspiration to yield the amorphous form of (rac)-tramadol.HCl- celecoxib (1: 1).
Yield: 17.1 g
Example 3: 0.5 gram of (rac)-Tramadol.HCl, 0.636 g of celecoxib and 1.136 g of plasdone S- 630 were dissolved in 6 mL of methanol at 25±5°C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulates, the filter aid washed with methanol, and the solvent was then distilled off under vacuum at 50 °C to yield a 1: 1: 1 amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib with plasdone S-630.
Yield: 1.8 lg
Example 4: 0.5 gram of (rac)-Tramadol.HCl, 0.636 g of celecoxib and 1.136 g of povidone- K30 were dissolved in 6 mL of methanol at 25+5 °C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulates, the filter aid was washed with methanol, and the solvent was then distilled off under vacuum at 50°C to yield a 1: 1: 1 amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib with povidone K-30.
Yield: 1.7g
Example 5: 0.5 gram of (rac)-Tramadol.HCl and 0.636 g of celecoxib were dissolved in 3 mL of methanol at 25±5°C. The resulting clear solution was filtered through Hyflo filter aid to remove any undissolved particulates, and the filter aid was washed with methanol. To the resulting clear solution was added 1.136 g of silicon dioxide (Aeroperl 300) and the solvent was distilled off under vacuum at 50°C to yield 1: 1: 1 amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib with silicon dioxide.
Yield: 1.5g

Claims

We claim:
1. An amorphous form of (rac)-tramadol.HCl-celecoxib (1: 1).
2. An amorphous form of (rac)-tramadol.HCl-celecoxib (1: 1) characterized by a PXRD pattern substantially as depicted in Figure 1 and Figure 2.
3. A process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1: 1) comprising the steps of:
a) dissolving (rac)-tramadol.HCl and celecoxib in an organic solvent or mixtures thereof; and
b) removing the solvent to isolate the amorphous form of (rac)-tramadol.HCl- celecoxib (1: 1)
4. A process for the preparation of an amorphous form of (rac)-tramadol.HCl-celecoxib (1: 1) comprising the steps of:
a) dissolving a 1: 1 co-crystal of (rac)-tramadol.HCl-celecoxib in an organic solvent or mixtures thereof;
b) removing the solvent to isolate amorphous (rac)-tramadol.HCl-celecoxib (1: 1).
5. The process as claimed in claim 3 and 4, wherein the organic solvent or mixtures thereof is selected from the solvent which is capable of dissolving (rac)-tramadol HC1 and celecoxib.
6. The process as claimed in claim 5, wherein the organic solvent is selected from dichloromethane, chloroform, methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3 -methyl- 1 -butanol, 2-methyl- 1 -propanol, 1-pentanol, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide, N-methyl pyrrolidone, and mixtures thereof.
7. The process as claimed in claim 3 and 4, wherein the solvent is removed by evaporation, distillation, spray drying, lyophilization, or agitated thin film drying.
8. An amorphous solid dispersion of (rac)-tramadol.HCl-celecoxib (1:1) with at least one pharmaceutically acceptable excipient.
9. The amorphous solid dispersion as claimed in claim 8, wherein the pharmaceutically acceptable excipient is selected from diluents, lubricants, binders, glidants, stabilizers, surface active agents, anti- adherents, opacifiers, solvents, colorants, pigments, anti foam agents, polishing agents, starches, lactose, mannitol, cellulose derivatives, confectioner's sugar, binders, powdered acacia, gelatin, guar gum, sodium starch glycolate, colloidal silicon dioxide, carbomers, methylcelluloses, polymethacrylates, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidones, stearates, phospholipids, sorbitan esters, aliphatic alcohols, and polyethylene glycol ethers.
10. The pharmaceutical excipient as claimed in claim 8, wherein the pharmaceutically acceptable excipient is selected from a 60:40 linear random copolymer of N-vinyl-2- pyrrolidone, polyvinylpyrrolidone, and silicon dioxide.
11. A process for the preparation of an amorphous solid dispersion of (rac)-tramadol.HCl and celecoxib (1:1) comprising the steps of:
a) dissolving (rac)-tramadol.HCl, celecoxib and a pharmaceutically acceptable excipient in a suitable solvent or mixtures thereof, and
b) removing the solvent to isolate the amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1).
12. A process for the preparation of an amorphous solid dispersion of (rac)-tramadol.HCl and celecoxib (1:1) comprising the steps of:
a) dissolving (rac)-tramadol.HCl, celecoxib in a suitable solvent or mixtures thereof,
b) adding a pharmaceutically acceptable excipient, and
c) removing the solvent to isolate the amorphous solid dispersion of (rac)- tramadol.HCl-celecoxib (1:1).
13. The process as claimed in claim 11 and 12, wherein the pharmaceutically acceptable excipient is selected from diluents, lubricants, binders, glidants, stabilizers, surface active agents, anti- adherents, opacifiers, solvents, colorants, pigments, anti-foam agents, polishing agents, starches, lactose, mannitol, cellulose derivatives, confectioner's sugar, binders, powdered acacia, gelatin, guar gum, sodium starch glycolate, colloidal silicon dioxide, carbomers, methylcelluloses, polymethacrylates, carmellose calcium, carboxymethyl starch sodium, croscarmellose sodium, crospovidones, stearates, phospholipids, sorbitan esters, aliphatic alcohols, and polyethylene glycol ethers.
14. The process as claimed in claim 11 and 12, wherein the pharmaceutically acceptable excipient is selected from a 60:40 linear random copolymer of N-vinyl-2-pyrrolidone, polyvinylpyrrolidone, and silicon dioxide.
15. The process as claimed in claim 11 and 12, wherein the suitable solvent or mixture thereof is selected from a solvent capable of dissolving (rac)-tramadol.HCl; celecoxib.
16. The process as claimed in claim 15, wherein the suitable solvent is selected from chlorinated solvents selected from dichloromethane, chloroform, methanol, ethanol, propanol, butanol, 2-butanol, isopropanol, 3 -methyl- 1 -butanol, 2-methyl- 1 -propanol, 1-pentanol, tetrahydrofuran, dioxane, dimethyl sulfoxide, acetonitrile, dimethyl formamide, N-methyl pyrrolidone, and mixtures thereof.
17. The process as claimed in claim 11 and 12, wherein the solvent is removed by evaporation, distillation, spray drying, lyophilization, or agitated thin film drying.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11672761B2 (en) 2020-11-16 2023-06-13 Orcosa Inc. Rapidly infusing platform and compositions for therapeutic treatment in humans

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8598152B2 (en) 2008-10-17 2013-12-03 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8598152B2 (en) 2008-10-17 2013-12-03 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibs
US9012440B2 (en) 2008-10-17 2015-04-21 Laboratorios Del Dr. Esteve, S.A. Co-crystals of tramadol and coxibs

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CARMEN ALMANSA ET AL: "A Novel API-API Co-crystal for the Treatment of Pain", CRYSTAL GROWTH & DESIGN., vol. 17, no. 4, 20 March 2017 (2017-03-20), US, pages 1884 - 1892, XP055636403, ISSN: 1528-7483, DOI: 10.1021/acs.cgd.6b01848 *
YU L ED - KWON ICK CHAN ET AL: "AMORPHOUS PHARMACEUTICAL SOLIDS: PREPARATION, CHARACTERIZATION AND STABILIZATION", ADVANCED DRUG DELIVERY REVIEWS, ELSEVIER, AMSTERDAM, NL, vol. 48, no. 1, 16 May 2001 (2001-05-16), pages 27 - 42, XP009065056, ISSN: 0169-409X, DOI: 10.1016/S0169-409X(01)00098-9 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11672761B2 (en) 2020-11-16 2023-06-13 Orcosa Inc. Rapidly infusing platform and compositions for therapeutic treatment in humans

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