Methods of Producing Anamorelin Hydrochloride Having Controlled Chloride Content

a technology of anamorelin hydrochloride and chloride content, which is applied in the field of anamorelin hydrochloride, can solve the problems of reduced solubility of molecule, high chloride content, and long-term instability of final product, and achieve excellent solvent reduction, stable amorphous form, and reduce the production of anamorelin dihydrochloride

Inactive Publication Date: 2014-01-16
HELSINN HEALTHCARE SA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a method for efficiently and accurately controlling the reaction between anamorelin free base and hydrochloric acid to increase the yield of anamorelin monohydrochloride and reduce the formation of unwanted byproducts. This is achieved by controlling the molar ratio of anamorelin to hydrochloric acid and the distribution of molecules in the reaction mixture. The resulting product is isolated using spray drying and distillation techniques to achieve a stable and solvent-free form of anamorelin monohydrochloride.

Problems solved by technology

It has unexpectedly been discovered that the process of making the hydrochloride salt of anamorelin described in Step (j) of U.S. Pat. No. 6,576,648 can result in excessive levels of chloride in the final product, and that this excess chloride leads to the long-term instability of the final product due at least partially to an increase in the amount of the less stable dihydrochloride salt of anamorelin.
Conversely, because anamorelin free base is less soluble in water than the hydrochloride salt, deficient chloride content in the final product can lead to decreased solubility of the molecule.
The process described in U.S. Pat. No. 6,576,648 also yields a final product that contains more than 5000 ppm (0.5%) of residual solvents, which renders the product less desirable from a pharmaceutical standpoint, as described in ICH Harmonized Tripartite Guideline.

Method used

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  • Methods of Producing Anamorelin Hydrochloride Having Controlled Chloride Content
  • Methods of Producing Anamorelin Hydrochloride Having Controlled Chloride Content

Examples

Experimental program
Comparison scheme
Effect test

example 1

on of Anamorelin Hydrochloride

[0099]Various methods have been developed to prepare the hydrochloric acid salt of anamorelin, with differing results.

[0100]In a first method, which is the preferred method of the present invention, anamorelin free base was carefully measured and dissolved in isopropyl acetate. Anamorelin free base was prepared according to known method (e.g., U.S. Pat. No. 6,576,648). A fixed volume of HCl in water containing various molar ratios (0.80, 0.95, 1.00 or 1.05) of HCl relative to the anamorelin free base was then combined with the anamorelin / isopropyl acetate solution, to form a mixture having an organic and an aqueous phase. The aqueous phase of the mixture was separated from the organic phase and the resulting aqueous phase was concentrated by spray drying to obtain the batches of anamorelin monohydrochloride (or a composition comprising anamorelin monohydrochloride) shown in Table 1A.

[0101]Approximately 150 mg of the resulting spray dried sample of anamo...

example 2

Spray Dry Methods

[0110]Several spray dry methods have been developed by varying the type of nozzle, the conditions at the nozzle, the inlet and outlet temperatures, the temperature of the condenser, and the feed rate. The amount of anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) produced, the yield of each process and representative process parameters according to the present invention using Niro QSD-3.6 (trade mark, GEA process engineering Inc.) are reported in Table 2A.

TABLE 2ACo-current nozzleAmountØFlow [kg / h] / T inletT outletT condenserFeed rateof productBatch[mm]P [bar][° C.][° C.][° C.][kg / h][kg]Yield122519095213.56.1592.5%1.6A2251909522549.8594.6%1.5B22519095225130.498.6%1.6Rotary nozzlePAmountBatch[bar]Flow [kg / h]T inletT outletT condenserFeed rateof productYield23.310.119095213.56.1298.5%34.413.619095213.55.9799.2%45.015.619095213.56.3997.8%

[0111]Various physical properties of the anamorelin monohydrochloride (or composition comprising ...

example 3

Stability Testing

[0114]The stability of anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) prepared according to the foregoing examples was evaluated at 25° C. / 75% relative humidity and 40° C. / 75% relative humidity for one, three and six months. The purity of the anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) was measured using high performance liquid chromatograph (HPLC) (Hewlett-Packard HP 1100 HPLC System, Agilent Technologies Inc.). The concentrated aqueous solution of anamorelin monohydrochloride A of example 1 was concentrated by spray drying using Niro QSD-3.6 (trade mark, GEA process engineering Inc.) to afford anamorelin monohydrochloride referred to as Batch A in Tables 2A and 2B) in an amorphous state. The resulting amorphous product was dissolved in acetonitrile:water (1:1) and measured under the conditions reported in Table 3A. The results are presented below in Table 3B. RRT refers to the relativ...

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Abstract

The present invention relates to particulate forms of anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having controlled chloride content, preferably isolated in an amorphous and / or fine particulate state, processes for making the particulate forms, and pharmaceutical compositions comprising the particulate forms.

Description

FIELD OF THE INVENTION[0001]The present invention relates to anamorelin hydrochloride, improved forms of anamorelin hydrochloride having reduced impurities and controlled chloride content, and improved processes for making and using anamorelin hydrochloride.BACKGROUND OF THE INVENTION[0002]Growth hormone is a major participant in the control of several complex physiologic processes including growth and metabolism. Growth hormone is known to have a number of effects on metabolic processes such as stimulating protein synthesis and mobilizing free fatty acids, and causing a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiencies in growth hormone can result in dwarfism and other severe medical disorders.[0003]The release of growth hormone from the pituitary gland is controlled directly and indirectly by a number of hormones and neurotransmitters. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostati...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12C07D401/06A61P3/04A61K38/05A61K31/454Y02P20/55C07K5/06034A61K9/1682
Inventor KUWABE, SHIN-ITSUYANAGIMACHI, TAKEHIKOYOSHIYAMA, HIDEYUKIPINES, SEEMONDE GROOT, ELEANORGARCIA RUBIO, SILVINAMANINI, PETER
Owner HELSINN HEALTHCARE SA
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