Novel process for the manufacture of pharmaceutical preparations

a technology of solid dispersions and pharmaceutical preparations, which is applied in the direction of biocide, muscular disorder, drug compositions, etc., can solve the problems of poor bioavailability, low dissolution rate, and poor bioavailability of poorly bioavailable compounds, so as to improve stability, reduce the amount of organic solvents, and improve the effect of stability

Inactive Publication Date: 2011-05-12
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0013]In certain aspects and embodiments there are provided methods of preparing solid dispersions comprising HPMCAS and the compound of formula 1. In many embodiments the methods may use a lower amount of organic solvents as compared to other methods and as such may be more environmentally friendly; are safe when used on an industrial scale; and / or show improved properties such as stability against re-crystallization. In many aspects and embodiments the methods involve micro-precipitation of a mixture of HPMCAS and the compound of formula 1 within an aqueous phase using the conditions and process parameters as described herein.

Problems solved by technology

Compounds that have low solubility in water (for example, certain compounds in crystalline form), have a low dissolution rate and as a result can exhibit poor bioavailability.
Poorly bioavailable compounds can present problems for therapeutic administration to a patient, often due to unpredictability in dose / therapy effects caused by erratic absorption of the compound by the patient.
For example, the intake of food may affect the ability of the patient to absorb such poorly bioavailable compounds, thus potentially requiring dosing regimens to take into account the effect of food.
In addition, when dosing, a large safety margin may be required for the dose as a result of the unpredictable dose effects.
Further, due to poor bioavailability, a large dose of the compound may be required to achieve a desired therapeutic effect, thus potentially resulting in undesired side effects.
The amorphous form of Compound 1 has improved solubility in water as compared to the crystalline form, but is unstable as it has a tendency to crystallize.

Method used

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  • Novel process for the manufacture of pharmaceutical preparations
  • Novel process for the manufacture of pharmaceutical preparations
  • Novel process for the manufacture of pharmaceutical preparations

Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of the DMA Phase

[0050]The concentration of the compound of formula 1 and HPMCAS in the organic solvent was 35% (w / w), while the ratio of the compound of formula 1 and HPMCAS is 30 to 70: The temperature of the solution was adjusted to 70° C.

[0051]In a 250 ml double jacked glass flask reactor 21 g of the compound of formula 1 were dissolved in 130 g Dimethylacetamide (DMA) at 20-25° C. Under stirring, 48.9 g of HPMC-AS were added to the solution. The mixture was heated up to 70° C. A clear solution was obtained.

example 2

Preparation of the Aqueous Phase

[0052]In a double jacketed 2.0 liter reactor 1210 g of 0.01 N HCl was tempered to 5° C. Out of the bottom valve of the reactor the water phase was circulated by the high shear mixer or with an auxiliary pump, preferred a rotary lobe pump, and then followed by the high shear mixer, back to the top of the reactor. The inlet of the recirculation into the reactor was under the fluid level in order to prevent foaming (see FIG. 1).

example 3

Precipitation

High Shear Mixer

[0053]The tip speed of the rotor in the high shear mixer was set 25 m / sec. A rotor / stator combination with one teeth row, each for rotor and stator was used.

Dosing of the DMA Solution

[0054]The DMA solution tempered at 70° C. was dosed with a gear pump via an injector nozzle, which was pointing into the mixing chamber of the high shear mixer, into the circulating aqueous phase.

Dosing Rate of the DMA Solution

[0055]The DMA solution was dosed into the aqueous phase resulting in a ratio of HCl / DMA, in the mixing chamber of the high shear mixer of 100 / 1.

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Abstract

The present invention is related to an improved method for the manufacture of Micro-precipitated Bulk Powder (MBP) containing the active pharmaceutical ingredient Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide and Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS). The invention is further directed to pharmaceutical compositions containing said MBP, as well as its use in the manufacture of medicaments for the treatment of cancer.

Description

PRIORITY TO RELATED APPLICATION(S)[0001]This application claims the benefit of European Patent Application No. 09175665.0, filed Nov. 11, 2009, which is hereby incorporated by reference in its entirety.FIELD OF THE INVENTION[0002]The present invention is related to an improved method for the manufacture of solid dispersions, in particular Micro-precipitated Bulk Powder (MBP), containing the compound Propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (formula 1) and Hydroxypropylmethylcellulose Acetate Succinate (HPMCAS).[0003]The compound of formula 1, methods of synthesizing it as well as conventional pharmaceutical formulations containing that compound have been disclosed in WO 2007002433 and WO 2007002325. The compound of formula 1 shows valuable pharmaceutical properties as potential medicament for the inhibition of cancer proliferation, in particular solid tumor growth.BACKGROUND OF THE INVENTION[0004]Compounds that ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/437A61P35/00
CPCC07D471/04A61K9/10A61K9/1635A61K9/0019A61K31/437A61K9/0014A61K9/1652C07B2200/13A61P21/00A61P25/00A61P25/04A61P25/16A61P25/28A61P29/00A61P35/00A61P35/02A61P35/04A61P43/00A61K31/4375
Inventor DIODONE, RALPHLAUPER, STEPHANMAIR, HANS-JUERGENPUDEWELL, JOHANNESWIERSCHEM, FRANK
Owner F HOFFMANN LA ROCHE & CO AG
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