WO2020121326A1 - (rac)-tramadol.hcl-célécoxib (1 : 1) amorphe - Google Patents

(rac)-tramadol.hcl-célécoxib (1 : 1) amorphe Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
celecoxib
rac
tramadol
hcl
solvent
Prior art date
Application number
PCT/IN2019/050904
Other languages
English (en)
Inventor
Ramakoteswara Rao Jetti
Ramamohana Rao Golivi
Sureshbabu JAYACHANDRA
Original Assignee
Mylan Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mylan Laboratories Limited filed Critical Mylan Laboratories Limited
Publication of WO2020121326A1 publication Critical patent/WO2020121326A1/fr

Links

Classifications

    • 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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une forme amorphe de (rac)-tramadol.HCl-celecoxib (1 : 1) ainsi qu'une dispersion solide et des procédés de préparation de celle-ci.
PCT/IN2019/050904 2018-12-13 2019-12-11 (rac)-tramadol.hcl-célécoxib (1 : 1) amorphe WO2020121326A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201841047151 2018-12-13
IN201841047151 2018-12-13

Publications (1)

Publication Number Publication Date
WO2020121326A1 true WO2020121326A1 (fr) 2020-06-18

Family

ID=69159881

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2019/050904 WO2020121326A1 (fr) 2018-12-13 2019-12-11 (rac)-tramadol.hcl-célécoxib (1 : 1) amorphe

Country Status (1)

Country Link
WO (1) WO2020121326A1 (fr)

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

Similar Documents

Publication Publication Date Title
JP6906308B2 (ja) ４環性化合物の非晶質体
US11117875B2 (en) Crystalline forms, preparation methods and pharmaceutical compositions of ozanimod
IL259493A (en) Solid dispersions containing sgc actuator
US11286259B2 (en) Co-crystals of ribociclib and co-crystals of ribociclib monosuccinate, preparation method therefor, compositions thereof, and uses thereof
JPWO2011122620A1 (ja) フェニルアラニン誘導体を含有する医薬製剤
US10660963B2 (en) Pharmaceutical composition containing tacrolimus and preparation methods thereof
WO2016125190A2 (fr) Nouvelles formes cristallines de vortioxétine, prémélanges, et procédés pour la préparation de ceux-ci
US20100297241A1 (en) Amorphous Fesoterodine Fumarate
CA2677649A1 (fr) Formulations biodisponibles de composes heterocycliques
US10479782B2 (en) Forms of lumacaftor and processes for the preparation thereof
US20190300483A1 (en) POLYMORPHS OF BETRlXABAN & ITS MALEATE SALT
JP2024517431A (ja) （ｓ）－ｎ－（３－（２－（（（ｒ）－１－ヒドロキシプロパン－２－イル）アミノ）－６－モルホリノピリジン－４－イル）－４－メチルフェニル）－３－（２，２，２－トリフルオロエチル）ピロリジン－１－カルボキサミドおよびその塩の固体状態での形態
WO2020121326A1 (fr) (rac)-tramadol.hcl-célécoxib (1 : 1) amorphe
US11466031B2 (en) Polymorphic forms of bictegravir and its sodium salt
US8598183B2 (en) Solid state forms of a potent HCV inhibitor
US20150328215A1 (en) Stable amorphous raltegravir potassium premix and process for the preparation thereof
KR20210125994A (ko) 비정질 스파르센탄 조성물
US20090030057A1 (en) Pharmaceutical composition of telmisartan
JP7489370B2 (ja) ピラゾール－アミド化合物の非晶質固体分散体
US20180064714A1 (en) Process for the Preparation of Amorphous Idelalisib and its Premix
WO2022224274A1 (fr) Formes polymorphes de sacubitril-telmisartan (1 : 1)
US10487059B2 (en) Crystalline form of Eluxadoline
US20200392084A1 (en) Sulfasalazine salt compositions and methods of using the same
US10391178B2 (en) Premix of crystalline raltegravir potassium salt and a process for the preparation thereof
US11795180B2 (en) Formulation of a pan-JAK inhibitor

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19835833

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19835833

Country of ref document: EP

Kind code of ref document: A1