WO2004007507A1 - Process for controlling the hydrate mix of a compound - Google Patents
Process for controlling the hydrate mix of a compound Download PDFInfo
- Publication number
- WO2004007507A1 WO2004007507A1 PCT/IB2003/003119 IB0303119W WO2004007507A1 WO 2004007507 A1 WO2004007507 A1 WO 2004007507A1 IB 0303119 W IB0303119 W IB 0303119W WO 2004007507 A1 WO2004007507 A1 WO 2004007507A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- process according
- temperature
- pressure
- compound
- water content
- Prior art date
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 46
- 230000008569 process Effects 0.000 title claims abstract description 45
- 239000000203 mixture Substances 0.000 claims abstract description 54
- 230000036571 hydration Effects 0.000 claims abstract description 15
- 238000006703 hydration reaction Methods 0.000 claims abstract description 15
- 230000005496 eutectics Effects 0.000 claims abstract description 11
- 238000004090 dissolution Methods 0.000 claims abstract description 5
- 239000000374 eutectic mixture Substances 0.000 claims abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 57
- 238000001035 drying Methods 0.000 claims description 20
- 238000000859 sublimation Methods 0.000 claims description 16
- 230000008022 sublimation Effects 0.000 claims description 16
- 150000004687 hexahydrates Chemical class 0.000 claims description 15
- 238000007710 freezing Methods 0.000 claims description 11
- 230000008014 freezing Effects 0.000 claims description 11
- 150000004684 trihydrates Chemical class 0.000 claims description 10
- GHJWNRRCRIGGIO-UHFFFAOYSA-N Fosfluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(OP(O)(=O)O)CN1C=NC=N1 GHJWNRRCRIGGIO-UHFFFAOYSA-N 0.000 claims description 9
- 229950008518 fosfluconazole Drugs 0.000 claims description 9
- 238000004108 freeze drying Methods 0.000 claims description 9
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 claims description 3
- 238000007711 solidification Methods 0.000 claims description 3
- 230000008023 solidification Effects 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 2
- 238000012360 testing method Methods 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 27
- 239000012071 phase Substances 0.000 description 19
- 239000000047 product Substances 0.000 description 14
- 230000018044 dehydration Effects 0.000 description 11
- 238000006297 dehydration reaction Methods 0.000 description 11
- 238000000634 powder X-ray diffraction Methods 0.000 description 10
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Natural products OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- 150000004682 monohydrates Chemical class 0.000 description 5
- PXRKCOCTEMYUEG-UHFFFAOYSA-N 5-aminoisoindole-1,3-dione Chemical compound NC1=CC=C2C(=O)NC(=O)C2=C1 PXRKCOCTEMYUEG-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 239000007789 gas Substances 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000002425 crystallisation Methods 0.000 description 3
- 238000009826 distribution Methods 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000011067 equilibration Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000001144 powder X-ray diffraction data Methods 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000003252 repetitive effect Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 208000036366 Sensation of pressure Diseases 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000002144 chemical decomposition reaction Methods 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 229940088679 drug related substance Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000009477 glass transition Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000010587 phase diagram Methods 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000035899 viability Effects 0.000 description 1
Classifications
-
- F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
- F26—DRYING
- F26B—DRYING SOLID MATERIALS OR OBJECTS BY REMOVING LIQUID THEREFROM
- F26B5/00—Drying solid materials or objects by processes not involving the application of heat
- F26B5/04—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum
- F26B5/06—Drying solid materials or objects by processes not involving the application of heat by evaporation or sublimation of moisture under reduced pressure, e.g. in a vacuum the process involving freezing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
- A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having three nitrogen atoms as the only ring hetero atoms
- C07F9/6518—Five-membered rings
Definitions
- This invention relates to a process for controlling the hydrate mix of a compound, or a composition comprising the compound, the compound being capable of forming a plurality of hydration forms of differing stability. More particularly, this invention relates to a process for controlling the hydrate mix of a compound, or a composition comprising the compound, the compound being capable of forming a plurality of hydration forms of differing stability and also of dissolution to give a solution that, when frozen below the eutectic point, is a eutectic mixture.
- DSFF disodium salt of fosfluconazole
- DSFF dodecahydrate
- hexahydrate 20.1% w/w water
- trihydrate 11.2% w/w water
- monohydrate 4.0% w/w water
- the anhydrous form of DSFF is believed to be amorphous. While the tri- and hexahydrate forms of DSFF are both chemically and thermally stable, it has been found that certain hydrate forms, such as the dodecahydrate, exhibit physical and/or chemical instability.
- DSFF eutectic form of DSFF
- DSFF dodecahydrate
- forms of DSFF which have a water content of from 4.0% w/w to 11.2% w/w are also chemically unstable. It is hypothesised that such a hydrate /mix is a combination of tri- and monohydrate forms. Additionally, it has been found/that samples of DSFF having a water content above the hexahydrate stoichiometry (20.1% w/w) collapse in a manner consistent with equilibration to the hexahydrate and water.
- a stable hydration form of DSFF may be obtained by crystallisation from either acetonitrile/water or isopropanol/water mixtures.
- a stable hydration form of DSFF may be obtained by crystallisation from either acetonitrile/water or isopropanol/water mixtures.
- sterile recrystallisation is neither trivial nor economical.
- Lyophilisation is a well known technique for the stabilisation of labile products which would otherwise be susceptible to biological or chemical degradation.
- the process has established itself as the standard method for the stabilization of many drug substances in the solid state to produce products of superior quality and stability.
- thermodynamic equilibrium eutectic freezing is universal. However, it is recognised in the art that it only occurs in the minority of frozen solutions and, actually, in the majority of cases a glass is formed. F. Franks, Cryo-Letters, 11., 93- 110, 1990 teaches that the events taking place in a solution during the freezing process can seldom be predicted from equilibrium phase diagrams. In practice the solutes either incompletely precipitate or do not precipitate at all.
- DSFF DSFF
- a typical freeze-drying process involves reducing the temperature of a compound, or a composition thereof, to below its "collapse" temperature.
- the collapse temperature will be the eutectic temperature.
- the collapse temperature will be the glass transition temperature of the freeze concentrate.
- the shelf temperature must be kept to a level such that the heat coming into the system is balanced by the heat and mass transfer leaving the system, in order that the product never warms above its temperature of collapse.
- the primary drying phase is extended beyond the time at which sublimation of the ice has been completed there is little effect.
- an amorphous compound will still typically contain a substantial amount of water (e.g. about 30% to about 50% by weight). Therefore, a secondary drying phase is undertaken to effect complete dehydration of the compound.
- the secondary drying process involves increasing the temperature of the shelves in the apparatus from below the collapse temperature to from about 25°C to about 30°C.
- the hydrate mix of a compound could, in principle, be controlled by a process which controls the Relative Humidity (RH) to which the compound is exposed.
- RH Relative Humidity
- Such a process would comprise subjecting the compound or composition to a standard drying cycle in a freeze-drying apparatus followed by rehydration by providing a gas having an appropriately selected RH at a controlled temperature.
- RH Relative Humidity
- the rate of rehydration of the intermediate might not be sufficiently high to afford an economically viable process.
- the compound or composition would be dried to the point that an unstable intermediate might be formed, which would mean that the end product of the process would be contaminated and therefore unacceptable for pharmaceutical use.
- the present invention provides a process for the preparation of a stable hydrate mix of a compound, or a composition comprising the compound, the compound being capable of forming a plurality of hydration forms of differing stability and of dissolution to give a solution that, when frozen below the eutectic point, is a eutectic mixture, comprising: a) providing a quantity of an aqueous mixture containing the compound or composition thereof in a suitable vessel in a freeze-drying apparatus; b) reducing the temperature in the apparatus to bring about freezing and eutectic solidification; c) reducing the pressure in the apparatus to below the saturation vapour pressure (SVP) of water over ice at the temperature of the ice; d) maintaining the apparatus at a pressure below the SVP and, optionally, increasing the temperature in the apparatus to facilitate sublimation, until all of the ice has been sublimed; e) maintaining the apparatus at the pressure and temperature conditions according to step d) until the desired water content has been obtained; and f) either: increasing
- the temperature selected in step b) is from about -10°C to about -50°C, more preferably from about -20°C to about -40°C and most preferably the temperature is about -30°C, to ensure that freezing and crystallisation are completed.
- the pressure selected in step c) should be below the SVP of water over ice at the temperature of the ice, i.e. at the compound or composition temperature. If a pressure above the SVP is used then there is a significant reduction in the driving force present to encourage the ice to sublime because the gas phase is saturated. As the pressure is lowered the driving force is increased, but if the pressure is too low the drying rate slows. This is because the heat transfer in the drier is mainly through the gas phase, even at reduced pressures. Therefore, at very low pressures the rate of heat input is decreased resulting in the reduction in the drying rate.
- the pressure selected in step c) is from about 1 to about 250Pa, more preferably from about 2 to about 125Pa and most preferably about 4 to about 75Pa (e.g. about 8Pa)
- Subliming water molecules remove energy, which results in a decrease in temperature of the ice within the compound or composition during the primary drying phase of the process. If the rate of sublimation of the ice from the sample is to be increased, the temperature must also be increased, as optionally indicated in step d) of the process. Whether the temperature of step d) represents an increase or not will, necessarily, depend on the temperature selected during step b), but typically the temperature selected in step d) is from about -50°C to about 50°C, such as from about -25°C to about 0°C, preferably about -15°C. A higher temperature than 50°C must not be selected because there is a danger that the ice will not sublime but will pass into the liquid phase.
- the apparatus is maintained at the conditions selected in step d) in order to remove the ice from the compound.
- certain compounds will continue to dehydrate, if maintained under reduced pressure conditions, once all of the ice has sublimed and this can have a deleterious affect on the quality of the resulting product.
- a standard pressure rise test PRT
- the rate at which water leaves the crystal structure may be sufficiently high that the PRT is passed significantly later than would be expected from sublimation of ice alone.
- the drying process is monitored at intervals of about one hour. Once the PRT has been passed the compounds may continue to dehydrate and an additional drying period may be required to give a product of the desired water content. This is the dehydration phase (e), which immediately follows the sublimation phase.
- the duration of dehydration phase (e) depends upon the particular compound or composition, the vial diameter and fill volume and the type of drier used.
- the dehydration phase removes sufficient water from the compound to encourage formation of stable hydration forms and prevent the formation of unstable hydration forms. Should the dehydration phase be allowed to continue for longer than necessary, unstable hydration forms of the compound may be obtained, leading to instability.
- the duration of the dehydration phase will be from 0 to 100 hours, such as 0 to 50 hours, preferably 6 to 30 hours, for example about 8, 12 or 28 hours.
- step f an increase in the pressure in the freeze-drying apparatus slows the dehydration phase sufficiently that the temperature may be increased to facilitate stoppering of the vials, thus allowing a stable hydrate mix to be achieved, although the order of these steps is not critical. Stoppering is conveniently carried out at 5°C and 88% atmospheric pressure (i.e. 89.2kPa).
- This process may be applied to any compound, or composition, thereof, which exhibits multiple hydration forms of differing stability and which is also capable of dissolution to provide a solution which, when frozen, is a eutectic mixture.
- this process may be applied to the production of a stable hydrate mix of DSFF.
- the final water content of the stable hydrate mix of DSFF is from about 11 % to about 20% w/w, more preferably, from about 14% to about 17% w/w, most preferably from about 15% to about 16% w/w, such as about 15 %.
- examples of the process conditions used to prepare a stable hydrate mix of DSFF will now be described. All examples were run in a Virtis Pilot Drier having an eight square foot shelf area and a condenser temperature of -56°C. 7.5 mTorr is equivalent to 1 Pa.
- Vials (1320) having an internal diameter of 21.35 mm and a neck diameter of 20 mm were filled with 1.6 ml of a solution comprising 100.88 mg/ml fosfluconazole in NaOH/citric acid, adjusted to pH 9.05, thereby providing 179.8 mg of DSFF.
- the vials were placed in the drier and frozen at a shelf temperature of -30 °C for 3 hours. The shelf temperature was then increased to -15 °C and the pressure reduced to 8 Pa to facilitate sublimation.
- the PRT was passed at approximately 26 h after the start of ice sublimation and the samples dried for a further 12 hours before terminating the cycle by stoppering at 5 °C and 89.2 kPa pressure.
- the product was a stable hydrate mix with a mean water content of 11.7 % w/w.
- Vials (1173) having an internal diameter of 22.6 mm and a neck diameter of 20 mm were filled with 2.8 ml of a solution comprising 100.88 mg/ml fosfluconazole in
- the shelf temperature was then increased to -15 °C and the pressure reduced to 8
- the PRT was passed at approximately 47 hours after the start of ice sublimation and the samples dried for a further 12 hours before terminating the cycle by stoppering at 5 °C and 89.2 kPa pressure.
- the product was a stable hydrate mix with a mean water content of 14.6 % w/w.
- Vials (1173) having an internal diameter of 22.6 mm and a neck diameter of 20 mm were filled with 5.4 ml of a solution comprising 100.88 mg/ml fosfluconazole in NaOH/citric acid, adjusted to pH 9.05, thereby providing 606.8 mg of DSFF.
- the shelf temperature was then increased to -15 °C and the pressure reduced to 8 Pa to facilitate sublimation.
- the PRT was passed at approximately 96 h after the start of ice sublimation and the samples dried for a further 12 hours before terminating the cycle by stoppering at 5 °C and 89.2 kPa pressure.
- the product was a stable hydrate mix with a mean water content of 16.9 % w/w.
- Vials (582), 10 ml Type 1 Clear glass with a 20 mm neck diameter were filled with 2.9 ml of a solution comprising 100.88 mg/ml fosfluconazole in NaOH/citric acid adjusted to pH 9.0, thereby providing 325.8 mg of DSFF.
- the vials were placed in the drier and frozen at a shelf temperature of -30 °C for 3.5 hours. The shelf temperature was then increase to -15 °C and the pressure reduced to 6 Pa to facilitate sublimation. After 58.3 hours of sublimation the cycle was terminated by stoppering at 5 °C and 96 kPa pressure.
- Fosfluconazole 40g was slurried in water (120 ml) and sodium hydroxide (7-8 ml of a 47% solution, circa 4.9-5.6g NaOH) added stepwise, under nitrogen until a solution formed. The temperature was maintained between ambient and 30°C. The solution was filtered. Sodium hydroxide (42 ml of a 47% solution, circa 29.6g NaOH) was added to the filtrate until precipitation occurred. The mixture was granulated for 4 hours, filtered under vacuum and dried in vacuo at 50°C to afford the title compound (23.79 ⁇ V PXRD:
- Fosfluconazole (26 mmols, 10g) was dissolved in a solution of sodium hydroxide (54 mmols, 2.17g final volume circa 20 ml) and heated to 70°C. Isopropyl alcohol (108ml), was added, in the temperature range 60 - 72°C, and the cloudy solution left to cool to provide the title compound as a slurry of crystals. A single crystal of DSFF hexahydrate was removed therefrom and mounted on a Bruker Diffractometer. The PXRD of Example 6 was consistent with that for Example 5(a).
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Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002492266A CA2492266A1 (en) | 2002-07-16 | 2003-07-07 | Process for controlling the hydrate mix of a compound |
EP03764062A EP1534721B1 (en) | 2002-07-16 | 2003-07-07 | Process for controlling the hydrate mix of the disodium salt of fosfluconazole |
DE60307110T DE60307110T2 (en) | 2002-07-16 | 2003-07-07 | Method of controlling the hydrate mixture of the disodium salt of fosfluconazole |
BR0312684-6A BR0312684A (en) | 2002-07-16 | 2003-07-07 | Process for controlling the hydrate mixture of a compound |
MXPA05000721A MXPA05000721A (en) | 2002-07-16 | 2003-07-07 | Process for controlling the hydrate mix of a compound. |
JP2004521009A JP2005533099A (en) | 2002-07-16 | 2003-07-07 | Method for controlling a hydrate mixture of compounds |
AU2003247026A AU2003247026A1 (en) | 2002-07-16 | 2003-07-07 | Process for controlling the hydrate mix of a compound |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0216515.7 | 2002-07-16 | ||
GBGB0216515.7A GB0216515D0 (en) | 2002-07-16 | 2002-07-16 | Process |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2004007507A1 true WO2004007507A1 (en) | 2004-01-22 |
Family
ID=9940569
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IB2003/003119 WO2004007507A1 (en) | 2002-07-16 | 2003-07-07 | Process for controlling the hydrate mix of a compound |
Country Status (11)
Country | Link |
---|---|
EP (1) | EP1534721B1 (en) |
JP (1) | JP2005533099A (en) |
AT (1) | ATE334133T1 (en) |
AU (1) | AU2003247026A1 (en) |
BR (1) | BR0312684A (en) |
CA (1) | CA2492266A1 (en) |
DE (1) | DE60307110T2 (en) |
ES (1) | ES2266863T3 (en) |
GB (1) | GB0216515D0 (en) |
MX (1) | MXPA05000721A (en) |
WO (1) | WO2004007507A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008063933A2 (en) | 2006-11-10 | 2008-05-29 | Massachusetts Institute Of Technology | Pak modulators |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3178829A (en) * | 1962-05-25 | 1965-04-20 | J P Devine Mfg Company | Process and apparatus for freeze dehydrating of food material |
US3487554A (en) * | 1965-09-23 | 1970-01-06 | George Tooby | Method and apparatus for dehydrating materials |
EP0327081A2 (en) * | 1988-02-05 | 1989-08-09 | Fujisawa Pharmaceutical Co., Ltd. | Alpha-crystals of cefazolin sodium |
-
2002
- 2002-07-16 GB GBGB0216515.7A patent/GB0216515D0/en not_active Ceased
-
2003
- 2003-07-07 AU AU2003247026A patent/AU2003247026A1/en not_active Abandoned
- 2003-07-07 AT AT03764062T patent/ATE334133T1/en not_active IP Right Cessation
- 2003-07-07 JP JP2004521009A patent/JP2005533099A/en not_active Withdrawn
- 2003-07-07 ES ES03764062T patent/ES2266863T3/en not_active Expired - Lifetime
- 2003-07-07 WO PCT/IB2003/003119 patent/WO2004007507A1/en active IP Right Grant
- 2003-07-07 MX MXPA05000721A patent/MXPA05000721A/en unknown
- 2003-07-07 DE DE60307110T patent/DE60307110T2/en not_active Expired - Fee Related
- 2003-07-07 BR BR0312684-6A patent/BR0312684A/en not_active IP Right Cessation
- 2003-07-07 CA CA002492266A patent/CA2492266A1/en not_active Abandoned
- 2003-07-07 EP EP03764062A patent/EP1534721B1/en not_active Expired - Lifetime
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3178829A (en) * | 1962-05-25 | 1965-04-20 | J P Devine Mfg Company | Process and apparatus for freeze dehydrating of food material |
US3487554A (en) * | 1965-09-23 | 1970-01-06 | George Tooby | Method and apparatus for dehydrating materials |
EP0327081A2 (en) * | 1988-02-05 | 1989-08-09 | Fujisawa Pharmaceutical Co., Ltd. | Alpha-crystals of cefazolin sodium |
Non-Patent Citations (1)
Title |
---|
G. ZOGRAFI ET AL.: "Stimuli to the revision process", PHARM. FORUM, 1991, pages 1459 - 1474, XP009020377 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2008063933A2 (en) | 2006-11-10 | 2008-05-29 | Massachusetts Institute Of Technology | Pak modulators |
Also Published As
Publication number | Publication date |
---|---|
EP1534721A1 (en) | 2005-06-01 |
JP2005533099A (en) | 2005-11-04 |
DE60307110D1 (en) | 2006-09-07 |
CA2492266A1 (en) | 2004-01-22 |
DE60307110T2 (en) | 2006-12-21 |
EP1534721B1 (en) | 2006-07-26 |
GB0216515D0 (en) | 2002-08-28 |
ES2266863T3 (en) | 2007-03-01 |
BR0312684A (en) | 2005-04-26 |
ATE334133T1 (en) | 2006-08-15 |
AU2003247026A1 (en) | 2004-02-02 |
MXPA05000721A (en) | 2005-04-08 |
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