WO2000078288A2 - Novel process for paroxetine compositions - Google Patents
Novel process for paroxetine compositions Download PDFInfo
- Publication number
- WO2000078288A2 WO2000078288A2 PCT/GB2000/002421 GB0002421W WO0078288A2 WO 2000078288 A2 WO2000078288 A2 WO 2000078288A2 GB 0002421 W GB0002421 W GB 0002421W WO 0078288 A2 WO0078288 A2 WO 0078288A2
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- WO
- WIPO (PCT)
- Prior art keywords
- paroxetine hydrochloride
- spray
- outlet gas
- water
- spray drying
- Prior art date
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Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- 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
-
- 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
- A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
Definitions
- the present invention relates to a process for the preparation of a pharmaceutically active compound in a form suitable for use of the compound in therapy.
- this invention is concerned with the preparation of a free-flowing form of paroxetine hydrochloride by spray-drying.
- EP-810 224-A discloses as its preferred product paroxetine hydrochloride in anhydrous form, which is prepared by "spray drying virtually in the absence of water".
- the specification mentions the use of a wide range of solvents, one of which is water, but makes it clear that anhydrous alcohols, particularly anhydrous ethanol is preferred.
- Spray drying of dilute solutions is said to be necessary to produce a product with "good flowability”. Only Example 5 describes spray drying from water, and it uses a very dilute (1%) solution.
- the product is "hydrous amorphous paroxetine hydrochloride". All the other Examples spray dry from anhydrous ethanol.
- WO 98/31365 discloses the use of aqueous and mixed aqueous organic solvents for spray drying paroxetine hydrochloride. The only example describes spray drying of an aqueous solution at 10% concentration.
- This invention provides procedures by which good quality free-flowing anhydrous amorphous paroxetine hydrochloride can be prepared on a manufacturing scale in excellent yield by an efficient process that uses high concentration feedstock and inexpensive, environmentally acceptable solvents, including 100% water.
- Previous attempts at spray drying paroxetine hydrochloride from water or water solvent mixtures have often resulted in unsatisfactory sticky products, which adhere to the apparatus and result in poor yields and poor flow characteristics.
- This invention is based on the finding that these problems can be solved by inter alia close control of the outlet temperature and outlet gas water content.
- the outlet gas temperature is in the range 40-55°C, preferably in the range 43-50°C, and the water content of the outlet gas is kept below 1.1 kg per 100 kg of outlet gas.
- the feedstock is a water-containing solution at a concentration of 5-50%, preferably 7-30% most preferably 10-25% by wt. paroxetine hydrochloride.
- the non-aqueous component of the solvent mixture may be propan-2-ol, ethanol, or acetone, or other inexpensive commercial grade solvents that are miscible with water without decreasing the solubility of paroxetine hydrochloride.
- the solvent is pure water, in which case the spray drying preferably uses heated feedstock between 60 and 95°C and jacketed heated lines.
- the aqueous solutions typically contain 3-30% paroxetine hydrochloride in the feedstock
- the outlet gas temperature is suitably maintained in the range 40-55°C, preferably in the range 43-50°C.
- the water content of the outlet gas should be kept below 1.1 kg per 100 kg of outlet gas, hence the economics of the operation are improved if pre-dried air or nitrogen is used, particularly when spray drying from 100% aqueous solvent.
- the drying gas inlet temperature is not of primary importance, since a suitable value is determined for a particular apparatus by other parameters, i.e. composition of the feedstock, inlet gas flow rate and humidity, and the critical parameters outlet gas temperature and water content.
- an inlet gas temperature in the range 70-100°C is found to be appropriate, though at less than optimum feed rates a lower inlet temperature may be necessary to keep the outlet temperature within the required range.
- the maximum feed rate for the spray drier is determined by the feedstock composition, drying gas flow rate and humidity, and the acceptable outlet gas water content. Operation significantly below the maximum feed rate is undesirable on economic grounds, and results in an increase in the outlet gas temperature, which must be compensated to bring it within the specified range.
- An essential requirement for successful spray dying paroxetine hydrochloride from water- containing solutions is that the product should have sufficient time in the drying chamber to satisfy the stated values for outlet gas temperature and water content of the outlet gas; effectively to reach a low enough water and solvent content to bring the glass temperature above that of the outlet gas.
- Various parameters have an effect on these values; the time available is determined by the construction and dimensions of the apparatus and the direction of the spray; the time required is determined by the water and solvent content of the outlet air and the droplet size of the spray.
- the droplet size can be adjusted by selection of a suitable nozzle, or by increasing the amount of nozzle gas. As much as 15 kg nozzle gas per kg feedstock may be necessary at high feedstock concentrations.
- the droplet size is controlled by the choice of wheel and the rotation rate. With either apparatus, a tendency towards stickiness can be corrected by reducing the droplet size.
- the product of spray drying from high concentration aqueous systems is a free-flowing white powder, suitable for formulation into pharmaceutical products, but to maximise throughput it may be desirable to tolerate a residual level of water or solvent.
- This residue may be removed by post drying in conventional drying ovens, but is most conveniently achieved by the use of a combined spray dryer/fluidised bed drier.
- a water or water/solvent solution of paroxetine hydrochloride is slurried with excipient(s) and then spray dried.
- the excipient(s) may be selected so that the product is suitable for direct formulation into tablets, capsules or other dosage forms with little or no further treatment.
- the slurry contains from 20 to 60% by weight of solid excipients, or in some cases excipients in solution.
- Suitable excipients include dibasic calcium phosphate dihydrate, hydroxypropylmethyl cellulose and/or sodium starch glycollate.
- the spray-dried product of this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO 96/24595.
- the free-flowing properties are advantageous for the preparation of solid formulations.
- the easily soluble nature of spray dried paroxetine hydrochloride makes it suitable for the preparation of solutions for parenteral use.
- the present invention also provides:
- paroxetine hydrochloride spray-dried in accordance with this invention to manufacture a medicament in solid or reconstituted liquid form for the treatment or prophylaxis of the disorders
- a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride spray-dried in accordance with this invention as a solid oral composition or as a reconstituted aqueous oral or parenteral composition to a person suffering from one or more of the disorders.
- the product was placed in vacuum oven at 40°C for 16 hours.
- Example 4 A combined solution/slurry of paroxetine hydrochloride hemihydrate (2%) and excipient (23%) in propan-2-ol/water [80:20] was spray dried under the following conditions:
- the product was placed in vacuum oven at 40°C for 16 hours.
- Nozzle Air/Feed Ratio 2.1 Inlet Temperature: 90-1 10°C Outlet Temperature: 42-47°C Drying Nitrogen Flow: 89 kg/hr Duration: 25 minutes
- the product was placed in vacuum oven at 40°C for 16 hours.
Abstract
Difficulties arising when spray drying paroxetine hydrochloride from water-containing solutions are overcome by keeping the outlet gas temperature in the range 40-55 °C, and the water content of the outlet gas below 1.1 kg per 100 kg of outlet gas. The feedstock may be a water-containing solution or suspension of excipient(s) in the range 20-60 % by wt. and paroxetine hydrochloride in the range 1-10 % by wt., in which case the outlet gas temperature is in the range 40-75 °C.
Description
NOVEL PROCESS
The present invention relates to a process for the preparation of a pharmaceutically active compound in a form suitable for use of the compound in therapy. In particular this invention is concerned with the preparation of a free-flowing form of paroxetine hydrochloride by spray-drying.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the (-)trans isomer of 4-(4'-fluorophenyl)-3',4'-methylenedioxy- phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt to treat inter alia depression, obsessive compulsive disorder (OCD) and panic.
In US patent 5,672,612 (Pentech) paroxetine hydrochloride is isolated by spray drying from anhydrous ethanol.
EP-810 224-A (Asahi) discloses as its preferred product paroxetine hydrochloride in anhydrous form, which is prepared by "spray drying virtually in the absence of water". The specification mentions the use of a wide range of solvents, one of which is water, but makes it clear that anhydrous alcohols, particularly anhydrous ethanol is preferred. Spray drying of dilute solutions is said to be necessary to produce a product with "good flowability". Only Example 5 describes spray drying from water, and it uses a very dilute (1%) solution. The product is "hydrous amorphous paroxetine hydrochloride". All the other Examples spray dry from anhydrous ethanol.
WO 98/31365 (SmithKline Beecham) discloses the use of aqueous and mixed aqueous organic solvents for spray drying paroxetine hydrochloride. The only example describes spray drying of an aqueous solution at 10% concentration.
Our practical experience of spray-drying paroxetine hydrochloride has brought to light a number of technical problems which must be solved to carry out spray-drying on a manufacturing scale.
Spray drying from dilute solutions is undesirable on economic grounds and tends to give a product with small particles and a large component of "fines".
It is difficult to remove residual solvents from amorphous materials, such as spray dried paroxetine hydrochloride, because of their glass-like supercooled liquid character. Since the process is intended as the final isolation step for the commercial manufacture of the drug substance, control of undesirable impurities, including solvents, is essential.
Totally anhydrous solvents, particularly absolute ethanol, are expensive and therefore undesirable on economic grounds. Cheaper anhydrous products contain undesirable impurities and denaturing agents.
Paroxetine hydrochloride readily forms solvates from alcoholic solvents such as propan-2-ol and ethanol. These solvates crystallise from solution at quite low concentration and prevent the use of concentrated feedstock for spray drying. Low concentration feedstock is undesirable on economic and environmental grounds; during spray drying from a solvent all the solvent is evaporated and mixed with a large volume of nitrogen gas (or other inert gas). This gas must be treated to remove the solvent efficiently and completely for environmental and safety reasons.
This invention provides procedures by which good quality free-flowing anhydrous amorphous paroxetine hydrochloride can be prepared on a manufacturing scale in excellent yield by an efficient process that uses high concentration feedstock and inexpensive, environmentally acceptable solvents, including 100% water. Previous attempts at spray drying paroxetine hydrochloride from water or water solvent mixtures have often resulted in unsatisfactory sticky products, which adhere to the apparatus and result in poor yields and poor flow characteristics. This invention is based on the finding that these problems can be solved by inter alia close control of the outlet temperature and outlet gas water content.
According to the present invention there is provided a process for spray drying paroxetine hydrochloride from water-containing solutions, in which the outlet gas temperature is in the range 40-55°C, preferably in the range 43-50°C, and the water content of the outlet gas is kept below 1.1 kg per 100 kg of outlet gas.
Typically the feedstock is a water-containing solution at a concentration of 5-50%, preferably 7-30% most preferably 10-25% by wt. paroxetine hydrochloride. The non-aqueous component of the solvent mixture may be propan-2-ol, ethanol, or acetone, or other inexpensive commercial grade solvents that are miscible with water without decreasing the solubility of paroxetine hydrochloride.
Preferably the solvent is pure water, in which case the spray drying preferably uses heated feedstock between 60 and 95°C and jacketed heated lines. The aqueous solutions typically contain 3-30% paroxetine hydrochloride in the feedstock
The spray drying may be carried out using pre-dried air, and typically using between 1 and 15 kg nozzle gas per kg feedstock
Spray drying may be followed by post drying in an air or vacuum oven or a fluidised bed drier.
The much greater specific heat of evaporation of water compared to other suitable solvents, means that spray drying conditions are mainly determined by the water component of a solvent mixture. For the purposes of calculation at low levels of water (less than 10%), non- aqueous solvents are treated as equivalent in effect to between one fifth and one tenth of their weight of water, according to their specific heat of evaporation.
The outlet gas temperature is suitably maintained in the range 40-55°C, preferably in the range 43-50°C. The water content of the outlet gas should be kept below 1.1 kg per 100 kg of outlet gas, hence the economics of the operation are improved if pre-dried air or nitrogen is used, particularly when spray drying from 100% aqueous solvent.
The drying gas inlet temperature is not of primary importance, since a suitable value is determined for a particular apparatus by other parameters, i.e. composition of the feedstock, inlet gas flow rate and humidity, and the critical parameters outlet gas temperature and water content. In practice, an inlet gas temperature in the range 70-100°C is found to be appropriate, though at less than optimum feed rates a lower inlet temperature may be necessary to keep the outlet temperature within the required range.
The maximum feed rate for the spray drier is determined by the feedstock composition, drying gas flow rate and humidity, and the acceptable outlet gas water content. Operation significantly below the maximum feed rate is undesirable on economic grounds, and results in an increase in the outlet gas temperature, which must be compensated to bring it within the specified range.
An essential requirement for successful spray dying paroxetine hydrochloride from water- containing solutions is that the product should have sufficient time in the drying chamber to satisfy the stated values for outlet gas temperature and water content of the outlet gas; effectively to reach a low enough water and solvent content to bring the glass temperature above that of the outlet gas. Various parameters have an effect on these values; the time available is determined by the construction and dimensions of the apparatus and the direction of the spray; the time required is determined by the water and solvent content of the outlet air and the droplet size of the spray. In the case of a two fluid nozzle, the droplet size can be adjusted by selection of a suitable nozzle, or by increasing the amount of nozzle gas. As much as 15 kg nozzle gas per kg feedstock may be necessary at high feedstock concentrations. In the case of an atomising wheel, the droplet size is controlled by the choice of wheel and the rotation rate. With either apparatus, a tendency towards stickiness can be corrected by reducing the droplet size.
A major economic and environmental disadvantage of previous methods for spray drying paroxetine hydrochloride has been the requirement for low concentration feedstock. We have found that high concentration feedstock may be prepared from water/solvent mixtures which are stable towards crystallisation (and hence blocking of tubes and nozzles) without the need for excessive heating. For example, a 5% solution of paroxetine hydrochloride in anhydrous propan-2-ol crystallises very readily and must be kept near to reflux temperature to ensure freedom from blockages. By contrast, addition of 5% water gives a solution that has no tendency to crystallise as the propan-2-ol solvate and is prevented from crystallising as the hemihydrate by gentle warming. At higher water content, for example between 30 and 60%, feedstock concentrations in excess of 30% can be achieved without excessive heating.
Despite the greater solubility of paroxetine hydrochloride in water/solvent mixtures, there are clear economic advantages to spray drying from water alone. For instance, air can be used in place of nitrogen gas or other inert gas, since there is no requirement for flameproof
operation, but is preferably pre-dried. Furthermore, there is no economic or environmental need to recover solvents or to scrub outlet gases. We have found that, provided the above- mentioned parameters are adhered to, economic spray drying from 100% aqueous solutions is entirely feasible. Optimal concentrations range from 10 to 30% paroxetine hydrochloride in the feedstock, though at the higher concentrations the solution must be maintained above 80°C at all times. This means that the design of the delivery system to the spray dryer desirably incorporates jacketed lines right up to the spray nozzle.
The product of spray drying from high concentration aqueous systems is a free-flowing white powder, suitable for formulation into pharmaceutical products, but to maximise throughput it may be desirable to tolerate a residual level of water or solvent. This residue may be removed by post drying in conventional drying ovens, but is most conveniently achieved by the use of a combined spray dryer/fluidised bed drier.
In another aspect of this invention a water or water/solvent solution of paroxetine hydrochloride is slurried with excipient(s) and then spray dried. The excipient(s) may be selected so that the product is suitable for direct formulation into tablets, capsules or other dosage forms with little or no further treatment. Typically, the slurry contains from 20 to 60% by weight of solid excipients, or in some cases excipients in solution. In the presence of excipients, it may be appropriate to maintain the amount of paroxetine hydrochloride in the range 1-10%. Suitable excipients include dibasic calcium phosphate dihydrate, hydroxypropylmethyl cellulose and/or sodium starch glycollate.
Slightly higher outlet gas temperatures, for example 5-20°C, may be used if the paroxetine hydrochloride is spray dried in the presence of a large excess of excipients.
Spray-dried paroxetine hydrochloride obtained using this invention has been found to be particularly suitable for applications where uniform particle size and good flow properties are advantageous. Furthermore as a result of the close control of particle size possible by spray- drying, the product may be handled conveniently and safely without the hazards associated with the dust produced when conventionally prepared paroxetine hydrochloride solids are prepared. Examples of applications where uniform particle size are advantageous include controlled release and microencapsulation (coated particle technology). Samples may be
produced with particle sizes for specific applications, for example in the range 10-1000 microns.
Microencapsulation may be incorporated into the spray-drying process or may be carried out in a subsequent step. This technology is useful for taste masking, rapid or controlled release formulations, hence control of pharmacokinetics including the matching of pharmacokinetic properties for combination products.
The spray-dried product of this invention may be formulated for therapy in the dosage forms described in EP-A-0223403 or WO 96/24595. The free-flowing properties are advantageous for the preparation of solid formulations. Also the easily soluble nature of spray dried paroxetine hydrochloride makes it suitable for the preparation of solutions for parenteral use.
Therapeutic uses of the paroxetine product of this invention include treatment of: alcoholism, anxiety, depression, obsessive compulsive disorder, panic disorder, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, pre-menstrual syndrome (PMS), adolescent depression, trichotillomania, dysthymia, and substance abuse, referred to below as "the disorders".
Accordingly, the present invention also provides:
a pharmaceutical composition for treatment or prophylaxis of the disorders comprising paroxetine hydrochloride spray-dried in accordance with this invention and a pharmaceutically acceptable carrier or an aqueous solution of reconstituted paroxetine hydrochloride spray-dried in accordance with this invention;
the use of paroxetine hydrochloride spray-dried in accordance with this invention to manufacture a medicament in solid or reconstituted liquid form for the treatment or prophylaxis of the disorders; and
a method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride spray-dried in accordance with this invention as a solid oral composition or as a reconstituted aqueous oral or parenteral composition to a person suffering from one or more of the disorders.
The invention is illustrated by the following Examples
The compositions of the feed solutions/suspensions for the Examples are given as percentages or ratios by weight. The excipient used in these Examples was a blend of dibasic calcium phosphate dihydrate (89%), hydroxypropylmethyl cellulose (5.5%) and sodium starch glycollate (5.5%).
Example 1
A 5% solution of paroxetine hydrochloride hemihydrate in propan-2-ol/water (95:5) was spray dried under the following conditions:
Apparatus: Niro Mobile Minor
Feed Temperature: 50-73°C
Feed Rate: 3.3 kg/hr
Nozzle diameter 1.5 mm
Nozzle Air/Feed Ratio: 0.9
Inlet Temperature: 90°C
Outlet Temperature: 43-44°C
Drying Nitrogen Flow: 88 kg/hr
Duration: 19 minutes
Product wt: 25.2 g
Appearance: Free moving white powder
The product was placed in a vacuum oven at 40°C for 16 hours.
Example 2
A combined solution slurry of paroxetine hydrochloride hemihydrate (2%) and excipient (23%) in propan-2-ol/water [95:5] was spray dried under the following conditions:
Apparatus: Niro Mobile Minor Feed Temperature: 64-68°C Feed Rate: 5.7 kg/hr Nozzle diameter 1.5 mm
Nozzle Air/Feed Ratio: 0.7
Inlet Temperature: 90°C
Outlet Temperature: 43-44°C
Drying Nitrogen Flow: 86 kg/hr
Duration: 11 minutes
Product wt: 208.9 g
Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 3
A combined solution/slurry of paroxetine hydrochloride hemihydrate (2%) and excipient (23%) in ethanol/water [96:4] was spray dried under the following conditions:
Apparatus: Niro Mobile Minor
Feed Temperature: 30-31°C
Feed Rate: 4.3 kg/hr
Nozzle diameter 2.0 mm
Nozzle Air/Feed Ratio: 0.9
Inlet Temperature: 90°C
Outlet Temperature: 42°C
Drying Nitrogen Flow: 89 kg/hr
Duration: 14 minutes
Product wt: 198.0 g
Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 4
A combined solution/slurry of paroxetine hydrochloride hemihydrate (2%) and excipient (23%) in propan-2-ol/water [80:20] was spray dried under the following conditions:
Apparatus: Niro Mobile Minor Feed Temperature: 27-28°C
Feed Rate: 3.5 kg/hr
Nozzle diameter 2.0 mm
Nozzle Air/Feed Ratio: 1.4
Inlet Temperature: 90°C Outlet Temperature: 40-42°C
Drying Nitrogen Flow: 88 kg/hr
Duration: 17 minutes
Product wt: 145.9 g Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 5
A combined solution/slurry of paroxetine hydrochloride hemihydrate (2%) and excipient (23%) in water was spray dried under the following conditions:
Apparatus: Niro Mobile Minor Feed Temperature: 62-70°C Feed Rate: 1.30 kg/hr Nozzle diameter 2.0 mm Nozzle Air/Feed Ratio: 1.9 Inlet Temperature: 90°C Outlet Temperature: 41-45°C Drying Nitrogen Flow: 103 kg/hr Duration: 24 minutes
Product wt: 84.5 g
Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 6
A 5% solution of paroxetine hydrochloride hemihydrate in ethanol/water (96:4) was spray dried under the following conditions:
Apparatus: Niro Mobile Minor
Feed Temperature: 29-32°C Feed Rate: 2.3 kg/hr Nozzle diameter 2.0 mm Nozzle Air/Feed Ratio: 1.4 Inlet Temperature : 90°C Outlet Temperature: 43-44°C Drying Nitrogen Flow: 88 kg/hr Duration: 26 minutes
Product wt: 36.8 g Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 7
A 5% solution of paroxetine hydrochloride hemihydrate in propan-2-ol/water (80:20) was spray dried under the following conditions:
Apparatus: Niro Mobile Minor
Feed Temperature: 26-27°C
Feed Rate: 2.4 kg/hr
Nozzle diameter 2.0 mm
Nozzle Air/Feed Ratio: 2.1
Inlet Temperature: 90-1 10°C Outlet Temperature: 42-47°C Drying Nitrogen Flow: 89 kg/hr Duration: 25 minutes
Product wt: 24.3 g Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 8
A 10% solution of paroxetine hydrochloride in propan-2-ol/water (80:20) was spray dried under the following conditions:
Apparatus: Niro Mobile Minor
Feed Temperature: 26-28°C
Feed Rate: 2.7 kg/hr
Nozzle diameter 2.0 mm
Nozzle Air/Feed Ratio: 2.7
Inlet Temperature: 1 10°C
Outlet Temperature: 42-47°C
Drying Nitrogen Flow: 86 kg/hr
Duration: 22 minutes
Product wt: 27.5 g
Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 9
A 20% solution of paroxetine hydrochloride hemihydrate in propan-2-ol/water (80:20) was spray dried under the following conditions:
Apparatus: Niro Mobile Minor
Feed Temperature: 66-78°C
Feed Rate: 2.7 kg/hr
Nozzle diameter 2.0 mm
Nozzle Air/Feed Ratio: 2.6
Inlet Temperature: 90°C
Outlet Temperature: 46-48°C
Duration: 22 minutes
Drying Nitrogen Flow: 88 kg/hr
Product wt: 159.3 g
Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 10
A 30% solution of paroxetine hydrochloride hemihydrate in propan-2-ol/water (50:50) was spray dried under the following conditions:
Apparatus: Niro Mobile Minor
Feed Temperature: 42-65°C
Feed Rate: 0.9 kg/hr
Nozzle diameter 2.0 mm
Nozzle Air/Feed Ratio: 10.3
Inlet Temperature: 75°C
Outlet Temperature: 46-48°C
Drying Nitrogen Flow: 90 kg/hr
Duration: 34 minutes
Product wt: HO.O g
Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Example 11
A 30% solution of paroxetine hydrochloride hemihydrate in water was spray dried under the following conditions:
Apparatus: Niro Mobile Minor
Feed Temperature: 80-90°C
Feed Rate: 0.7 kg/hr
Nozzle diameter 2.0 mm
Nozzle Air/Feed Ratio: 12.9
Inlet Temperature: 75°C
Outlet Temperature: 44°C
Drying Nitrogen Flow: 90 kg/hr
Duration: 43 minutes
Product wt: 123 g (81%)
Appearance: Free moving white powder
The product was placed in vacuum oven at 40°C for 16 hours.
Claims
1. A process for spray drying paroxetine hydrochloride from water-containing solutions, in which the outlet gas temperature is in the range 40-55°C, and the water content of the outlet gas is kept below 1.1 kg per 100 kg of outlet gas.
2. A process according to claim 1, in which the feedstock is a water-containing solution at a concentration of 5-50% by wt. paroxetine hydrochloride.
3. A process according to claim 2, in which the spray drying is carried out using water- containing solutions of paroxetine hydrochloride at concentrations of 10-25% by wt.
4. A process according to any preceding claim, in which the non-aqueous component of the solvent mixture is propan-2-ol, ethanol, or acetone.
5. A process for spray drying paroxetine hydrochloride in which the feedstock is an wholly aqueous solution containing 3-30% paroxetine hydrochloride at 60 to 95°C, the outlet gas temperature is in the range 40-55 °C, and the water content of the outlet gas is kept below 1.1 kg per 100 kg of outlet gas.
6. A process according to any preceding claim, in which the spray drying is carried out using pre-dried air.
7. A process according to any preceding claim, in which the spray drying is carried out using between 1 and 15 kg nozzle gas per kg feedstock
8. A process according to any preceding claim, in which the spray drying followed by post drying in an air or vacuum oven or a fluidised bed drier.
9. A process for spray drying paroxetine hydrochloride in which the feedstock is a water-containing solution or suspension of excipient(s) in the range 20-60% by wt. and paroxetine hydrochloride in the range 1-10% by wt., the outlet gas temperature is in the range 40-75 °C, and the water content of the outlet gas is kept below 1.1 kg per 100 kg of outlet gas.
10. A pharmaceutical composition for treatment or prophylaxis of the Disorders comprising paroxetine hydrochloride spray-dried according to any one of claims 1 to 9 and a pharmaceutically acceptable carrier, or an aqueous solution of reconstituted paroxetine hydrochloride spray-dried according to any one of claims 1 to 9.
11. Use of paroxetine hydrochloride spray-dried according to any one of claims 1 to 9 to manufacture a medicament in solid or reconstituted liquid form for the treatment or prophylaxis of the Disorders.
12. A method of treating the disorders which comprises administering an effective or prophylactic amount of paroxetine hydrochloride spray-dried according to any one of claims 1 to 9 as a solid oral composition or as a reconstituted aqueous oral or parenteral composition to a person suffering from one or more of the Disorders.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU55507/00A AU5550700A (en) | 1999-06-22 | 2000-06-22 | Novel process |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9914600.3 | 1999-06-22 | ||
| GBGB9914600.3A GB9914600D0 (en) | 1999-06-22 | 1999-06-22 | Novel,process |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| WO2000078288A2 true WO2000078288A2 (en) | 2000-12-28 |
| WO2000078288A3 WO2000078288A3 (en) | 2001-02-15 |
Family
ID=10855850
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/GB2000/002421 WO2000078288A2 (en) | 1999-06-22 | 2000-06-22 | Novel process for paroxetine compositions |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU5550700A (en) |
| GB (1) | GB9914600D0 (en) |
| WO (1) | WO2000078288A2 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002009710A2 (en) * | 2000-07-27 | 2002-02-07 | Pentech Pharmaceuticals, Inc. | Paroxetine tablets and capsules |
| WO2002017921A2 (en) * | 2000-08-28 | 2002-03-07 | Synthon B.V. | Paroxetine compositions and processes for making the same |
| DK200100341A (en) * | 2001-03-02 | 2002-09-03 | Gea Farmaceutisk Fabrik As | Process for the preparation of pharmaceutical tablets containing paroxetine hydrochloride anhydrate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0810224A1 (en) * | 1996-05-30 | 1997-12-03 | Asahi Glass Company Ltd. | Method of producing amorphous paroxetine hydrochloride |
| WO1998031365A1 (en) * | 1997-01-15 | 1998-07-23 | Smithkline Beecham Plc | Paroxetine compositions |
| WO1999016440A1 (en) * | 1997-09-30 | 1999-04-08 | Pentech Pharmaceuticals, Inc. | Amorphous paroxetine composition |
| WO1999048499A1 (en) * | 1998-03-24 | 1999-09-30 | Smithkline Beecham Plc | Paroxetine compositions |
-
1999
- 1999-06-22 GB GBGB9914600.3A patent/GB9914600D0/en not_active Ceased
-
2000
- 2000-06-22 WO PCT/GB2000/002421 patent/WO2000078288A2/en active Application Filing
- 2000-06-22 AU AU55507/00A patent/AU5550700A/en not_active Abandoned
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0810224A1 (en) * | 1996-05-30 | 1997-12-03 | Asahi Glass Company Ltd. | Method of producing amorphous paroxetine hydrochloride |
| WO1998031365A1 (en) * | 1997-01-15 | 1998-07-23 | Smithkline Beecham Plc | Paroxetine compositions |
| WO1999016440A1 (en) * | 1997-09-30 | 1999-04-08 | Pentech Pharmaceuticals, Inc. | Amorphous paroxetine composition |
| WO1999048499A1 (en) * | 1998-03-24 | 1999-09-30 | Smithkline Beecham Plc | Paroxetine compositions |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002009710A2 (en) * | 2000-07-27 | 2002-02-07 | Pentech Pharmaceuticals, Inc. | Paroxetine tablets and capsules |
| WO2002009710A3 (en) * | 2000-07-27 | 2002-06-13 | Pentech Pharmaceuticals Inc | Paroxetine tablets and capsules |
| US6660298B1 (en) | 2000-07-27 | 2003-12-09 | Pentech Pharmaceuticals, Inc. | Paroxetine tablets and capsules |
| WO2002017921A2 (en) * | 2000-08-28 | 2002-03-07 | Synthon B.V. | Paroxetine compositions and processes for making the same |
| WO2002017921A3 (en) * | 2000-08-28 | 2002-10-03 | Synthon Bv | Paroxetine compositions and processes for making the same |
| DK200100341A (en) * | 2001-03-02 | 2002-09-03 | Gea Farmaceutisk Fabrik As | Process for the preparation of pharmaceutical tablets containing paroxetine hydrochloride anhydrate |
| WO2002069969A1 (en) * | 2001-03-02 | 2002-09-12 | A/S Gea Farmaceutisk Fabrik | A process for the manufacture of pharmaceutical tablets containing paroxetine hydrochloride anhydrate |
| AU2002233182B2 (en) * | 2001-03-02 | 2004-10-14 | A/S Gea Farmaceutisk Fabrik | A process for the manufacture of pharmaceutical tablets containing paroxetine hydrochloride anhydrate |
Also Published As
| Publication number | Publication date |
|---|---|
| AU5550700A (en) | 2001-01-09 |
| GB9914600D0 (en) | 1999-08-25 |
| WO2000078288A3 (en) | 2001-02-15 |
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