OA17146A - Methods of producing anamorelin hydrochloride having controlled chloride content - Google Patents

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

The présent 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 OFTHE INVENTION

Growth hormone is a major participant in the control of several complex physiologie processes including growth and metabolism. Growth hormone is known to hâve a number of 10 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. Defïciencies in growth hormone can resuit in dwarfîsm and other severe medical disorders.

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 15 stimulated by growth hormone releasing hormone (GHRH) and inhibited by somatostatin.

The use of certain compounds to increase Ievels of growth hormone in mammals has prevîously been proposed. Anamorelin Is one such compound. Anamorelin is a synthetic orally active compound originally synthesized in the 1990s as a growth hormone secretagogue for the treatment of cancer related cachexia. The free base of anamorelin is 20 chemically defined os:

• (3R) l-(2-methylalanyl-D-tryptophyl)-3-(phenylmethyl)-3-pÎperidÎnecarboxylic acid

1,2,2tri methyl hydrazide, • 3-{(2R)-3-{(3R)-3-benzyl-3-[(trimethy!hydrazino)carbonyl]piperidin-l-yl}-2-[(2-met hylalanyl)amino|-3-oxopropyl )-IH-indole, or · 2-Amino-N-i(lR)-2-[(3R)-3-benzyl-3-(N,N’,N'-trimethylhydrazinocarbony!)pipcridin-l-yl]-l-(IH-indol-3-ylmethy))-2-oxoethyl]-2-methy!propionamide and has the below chemical structure:

f ^r< r

U.S. Patent No. 6,576,648 to Ankerson reports a process of preparing anamorelin as the fumarate sait, with the hydrochloride sait produced as an intermediate in Step 0) of Example 1. U.S. Patent No. 7,825,138 to Lorimer describes a process for preparing crystal forms of the free base of anamorelin.

There is a need to develop anamorelin monohydrochloride as an active pharmaceutical ingrédient with reduced impurities and improved stability over prior art forms of anamorelin hydrochloride, such as those described in U.S. Patent No. 6,576,648, having good solubility, bioavailability and processability. There is also a need to develop methods of producing pharmaceutically acceptable forms of anamorelin monohydrochloride that hâve improved yield over prior art processes, reduced residual solvents, and controlled distribution of chloride content

SUMMARY OFTHE INVENTION

It has unexpectedly been discovercd that the process of making the hydrochloride sait of anamorelin described in Step (J) of U.S. Patent No. 6,576,648 can resuit in excessive levels of chloride in the final product, and that this excess chloride Ieads to the long-term instability of the final product due ut least partially to an increase in the amount of the less stable dihydrochloridc sait of anamorelin. Conversely, because anamorelin free base is less soluble în water than the hydrochloride sait, déficient chloride content în the final product can lead to decreosed solubility of the molécule. The process described in U.S. Patent No. 6,576,648 also yields a final product that contains more than 5000 ppm (0.5%) of residual solvents, which rentiers the product less désirable from a pharmaceutical standpoint, as described in ICH Harmonized Tripartite Guideline. See Impurities: Guîdelîne for residual solvents Q3C(R3).

In order to overcome these problems, methods hâve been developed which, for the

first time, allow for the efficient and précisé control of the reaction between onamorelin free base and hydrochloric acid in situ, thereby increasing lhe yield of anamorelin monohydrochloride from the reaction and reducing the incidence of unwanted anamorelin dihydrochloride, According to lhe method, lhe free base of anamorelin ls dissolved in an 5 organic solvent and combined wilh water and hydrochloric acid, with the molar ratio of anamorelin and chloride tightly controlled to prevent an excess of chloride in lhe final product. The water and hydrochloric acid can be added either sequentially or at lhe same time as long as two separate phases are formed. Without wishing to be bound by any theory, it is believed that as lhe anamorelin free base in lhe organic phase is protonated by lhe 10 hydrochloric acid it migrâtes into lhe aqueous phase. The controlled ratio of anamorelin free base and hydrochloric acid and homogenous distribution in the aqueous phase allows for the controlled formation of lhe monohydrochloride sait over lhe dihydrochloride, and lhe controlled distribution of the resulting chloride levels within individual batchcs and among multiple batches of anamorelin monohydrochloride.

Thus, in a first embodiment lhe invention provides methods for preparing anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride comprising:

(a) dissolving anamorelin free base in on organic solvent to form a solution; (b) mix in g said solution with water and hydrochloric acid for a time sufficient to: (i) react said anamorelin free base with said hydrochloric acid, and (ii) form an organic phase and on aqueous phase;

(c) separating lhe aqueous phase from the organic phase; and (d) isolating anamorelin monohydrochloride from lhe aqueous phase.

In a particulariy preferred embodiment, lhe molar ratio of anamorelin to hydrochloric acid used in the process is less than or equal to 1:1, so as to reduce the production of anamorelin dihydrochloride and other unwanted chemical species. Thus, for example, 25 hydrochloric acid can be added at a molar ratio of from 0.90 to 1.0 relative to said anamorelin, from 0.90 to 0.99, or from 0.93 to 0.97.

In another particulariy preferred embodiment, the anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride is isolated from lhe aqueous phase via spray drying, preferably preceded by distillation, This technique has proven especially 30 useful in lhe manufacture of anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride because of the excellent réduction in solvent levels observed, and the production of a stable amorphous form of anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride.

In other embodiments, the invention relates to the various forms of anamorelin monohydrochloride and compositions comprising anamorelin monohydrochloride produced by the methods of the présent invention. In a first embodiment, which dérivés from the controlled chloride content among batches accompllshed by the présent methods, lhe invention provides anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having an inter-batch chloride content of from 5.8 to 6.2%, preferably from 5.8 to less than 6.2%. Altematively, the invention provides anamorelin monohydrochloride or a composition comprising anamorelin monohydrodiioride having n molar ratio of chloride to anamorelin less than or equal to 1:1, such as from 0.9 to 1.0 or 0.99. In yet another embodiment the invention provides an amorphous form of anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride. Further descriptions of the anamorelin monohydrochloride and compositions comprising the anamorelin monohydrochloride are given in the detailed description which foliows.

Additional embodiments and advantages of the invention wiii be set forth in part in the description which follows, and tn part wili be obvious from the description, or may be leamed by practice of the invention. The embodiments and advantages of the invention wili be realized and attained by means of the éléments and combinations particularly potnted out in the appended claims. It is to be understood that both the foregoing general description and the following detaiied description are exemplary and explanatory only and arc not restrictive of the invention, as claimed.

That is, the présent invention relates to:

[Par. 1] Anamorelin monohydrochloride having a chloride content ranging from 5.8 to 6.2%.

[Par. 2] Anamorelin monohydrochloride comprising a chloride:anamorclin moiar ratio of from 0.9 to 0.99.

[Par. 3] Anamorelin monohydrochloride in an amorphous state.

[Par. 4J The anamorelin monohydrochloride of Par. 1, 2 or 3, in an isolated state.

[Par. 5j The anamorelin monohydrochloride of Par. 1, 2 or 3, comprising less than 0.5% impurities.

[Par. 6] The anamorelin monohydrochloride of Par. 1,2 or 3, comprising from 1 to 3% water.

[Par. 7] The anamorelin monohydrochloride of Par. 5, wherein the impurities are seiected from by-products, contaminants, dégradation products and residual solvents.

[Par. 8] The anamorelin monohydrochloride of Par. 7, comprising a residual solvent selected from methanol, butyl acetate, propyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl acetate, methylelhyl ketone, methylisobutyl ketone,

2-methyltetrahydrofuran and combinations thereof in an amount less than 1000 ppm.

[Par. 9] The anamorclin monohydrochloride of Par. 8, wherein the residual solvent is isopropyl acetate.

[Par. 10] The anamorelin monohydrochloride of Par. 1, 2 or 3, having a purity greater than 99%.

[Par. 11 ] Anamorelin monohydrochloride having a purity greater than 99% and a chioride content of from 5.8 to 6.2%, comprising less than 0.5% residual solvent.

[Par. 12] A composition comprising anamorelin monohydrochloride, wherein the composition comprises a chioride content of from 5.8 to 6.2%.

[Par. 13] A composition comprising anamorclin monohydrochloride wherein the composition comprises a chloride:anamorelin molar ratio of from 0.9 to 0.99.

[Par. 14] The composition of Par. 12 or 13, in the substantial absence of anamorclin hydrochloride other than anamorelin monohydrochloride.

(Par. 15] The composition of Par. 12,13 or 14, in an amorphous state.

[Par. 16] The composition of Par. 12,13,14 or 15, in an isolated state.

[Par. 17] The composition of Par. 12, 13, 14 or 15, comprising less than 0.5% impurities.

[Par. 18] The composition of Par. 12. 13, 14 or 15. comprising from 1 to 3% water.

[Par. 19] The composition of Par. 17, wherein the impurities are selected from by-products, contaminants, dégradation products and residual solvents.

[Par. 20] The composition of Par. 19, comprising a residual solvent selected from methanol, butyl acetate, propyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl acetate, methylethyl ketone, methylisobutyl ketone, 2-methyltetrahydrofuran and combinations thereof in an amount less than 1000 ppm.

[Par. 21] A composition comprising anamorelin monohydrochloride in the substantial absence of anamorelin hydrochloride other thon anamorelin monohydrochloride, having a chioride content of from 5.8 to 6.2%, less than 0.5% residual solvent, and a purity greater than 99%.

[Par. 22] A process for preparing anamorelin monohydrochloride comprising: a) dissolving anamorelin free base in an organic soivent to form a solution;

b) mixing said solution with water and hydrochloric acid for a time sufficient to:

i) rcact said anamorelin free base with said hydrochloric acid, and n) form an organic phase and an aqueous phase;

c) separating the aqueous phase from the organic phase; and

d) isolating said anamorelin monohydrochloride from said aqueous phase.

[Par. 23] The process of Par. 22, wherein said water and hydrochloric acid in step b are added sequentially or concurrently to said solution.

[Par. 24] The process of Par. 23, wherein said organic solvent is selected from butyl acetate, propyl acetate, ethyl acetate, isopropyl acetate, îsobutyl acetate, methyl acetate, methylethyl ketone, methylîsobutyl ketone, 2-methylietrahydrofuran, and combinations thereof.

[Par. 25] The process of Par. 24, wherein said organic solvent is isopropyl acetate.

[Par. 26] The process of Par. 22, wherein the anamorelin monohydrochloride is [Par. 27] The process of Par. 22, wherein said anamorelin monohydrochloride is combined with from 0.9 to 1.0 molar équivalents of hydrochloric acid, [Par. 28] The process of Par. 22, further comprising processing the anamorelin monohydrochloride Into a finished dosage form.

[Par. 29] Anamorelin monohydrochloride produced by the method of Par. 22.

[Par. 30] A pharmaceutical composition comprising:

a) a therapeutically effective amount of the anamorelin monohydrochloride of Par. 1,2,3 or 29, or the composition of Par. 12; and

b) one or more pharmaceutically acceptable excipients.

[Par. 31J A method of making a pharmaceutical dosage form comprising:

a) combining a therapeutically effective amount of the anamorelin monohydrochloride of Par. 1, 2, 3, or 29, or the composition of Par. 12, with one or more pharmaceutically acceptable excipients to form a mixture: and

b) processing said mixture into a finished dosage form.

Additional embodiments and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be leamed by practice of the invention. The embodiments and advantages of the invention will be realized and attained by means of the éléments and combinations particularly poînted out

in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG.l is an X-ray powder diffraction pattern of amorphous anamorelin monohydrochloride or a composition comprising amorphous anamorelin monohydrochloride prepared according to the methods of the present invention.

FIG .2 is an infrared spectrum in KBr of amorphous anamorelin monohydrochloride or a composition comprising amorphous anamorelin monohydrochloride prepared according to 10 the methods of the present invention.

DETAILED DESCRIPTION O F THE INVENTION

The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the Examples included therein.

Définitions and Use of Terms “A,” “an and “the” include plural référents unless the context dearly dictâtes otherwise. Thus, for example, reference to “an ingrédient” includes mixtures of ingrédients, reference to “an active pharmaceutical agent” includes more than one active pharmaceutical agent, and the like.

Comprise,” or variations such as “comprises” or comprising.” will be understood to împly the inclusion of a stated élément, înteger or step, or group of éléments, integers or steps, but not the exclusion of any other element, integer or step. or group of éléments, integers or steps.

“Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neilher biologically nor otherwise undesiruble and includes that which is acceptable for veterinary use as well as human pharmaceutical use.

Ail percentages and parts (i.e. ppm) expressed herein are stated on a weight basis unless specifically stated otherwise.

Unless otherwise specified herein, it will be understood that ail numeric values and

ranges could be qualified by the term “about” or “approximately to accommodate the degree of imprécision or variability allowed in the pharmaceutical industry for manufacturing imprécision, dégradation over time, and generic équivalence. Unless otherwise indicated, variability of +/10% is allowed and intended for any numeric figure or range given în this 5 application, and is meant by the term “about or “approximately.” “Impurity refers to any chemical in a pharmaceuticai ingrédient other than anamorelin monohydrochloride as the ingrédient itself and water. Impurities thus indude reaction by-products, contaminants, dégradation products, and residual solvents such as organic volatile impurities.

“Residual solvent refers to any organic solvent which is used in preparing anamorelin monohydrochloride.

“Isolated refers to a state suitabie for use as an active pharmaceutical ingrédient in solid form, prior to admixlng with any pharmaceutically acceptable excipients. Thus, the term generally requires that the recited ingrédient be présent as an isolated solid material to the 15 exclusion of any pharmaceutically ncceptable excipients, and preferably having less than 10, 5,3,1, or 0.5% impurities.

“Anamorelin monohydrochloride” refers to the sait form of anamorelin comprising a précisé !:! stoichiometric ratio of anamorelin and HCi (i.e. 6.08 wt% Cl-). Howcver, the anamorelin monohydrochloride may be présent within a composition that does not hâve a 20 précisé 1:1 ratio of anamorelin and HCi because, for example, the composition may contain small quantifies of anamorelin free base and/or anamorelin hydrochloride (e.g., anamorelin dihydrochloride) other than anamorelin monohydrochloride which do not substantially affect the stability of the composition. Thus, expressed as a weight percentage of chloride content, anamorelin monohydrochloride” or “n composition comprising anamorelin 25 monohydrochloride” may comprise from 5.6 to 6.3 wt%, and preferably from 5.8 to 6.2 wt%, more preferably from 5.9 or 6.0 to 6.1 wt% chloride. The chloride content in the composition is calculated by the formula described in the Example 1. The “hydrochloride sait of anamorelin, in contras t, encompasses any molar ratio of anamorelin to HCl. Anamorelin is used herein to refer to the hydrochloride sait of anamorelin as well as the free base, and 30 should not be taken to mean the free base unless stated so expressly.

A composition comprising anamorelin monohydrochloride” refers to the active pharmaceutical ingrédient which comprises anamorelin monohydrochloride and does not include any pharmaceutically acceptable excipients. More concretely the term refers to the composition having a chloride content rangîng from 5.8 to 6.2%, preferably from 5.8 to 6.1%,

in the substantial absence of anamorelin free base, anamorelin hydrochloride other than anamorelin monohydrochloride, and without any pharmaceutically acceptable excipients.

’Turity refera to the converted value into anamorclin free base within the sample when anamorclin monohydrochloride or a composition comprising anamorclin 5 monohydrochloride prepared by the methods of présent invention is measured via HPLC under the conditions described in Example 3.

Methods of Production

As discussed above, the présent invention provides methods of producing high-quality anamorclin monohydrochloride as an active pharmaceutical ingrédient, as well os the product 10 produced by such methods. The anamorelin hydrochloride of the présent invention îs preferably referred to simply as anamorclin hydrochloride, but could also be considered a composition comprising anamorclin monohydrochloride, due to the presence of ïmpurities and dégradation products.

Thus, in one embodiment the présent invention provides methods for preparing 15 anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having a control led content and distribution of chloride comprising: (a) dissolving anamorelin free base in an organic solvent to form a solution; (b) mixing said solution with water and hydrochloric acid for a time sufficient to: (i) react said anamorclin free base with said hydrochloric acid; and (ii) form an organic phase and an aqueous phase; (c) separating the 20 aqueous phase from the organic phase; and (d) isolating anamorclin monohydrochloride from the aqueous phase.

The organic solvent used to préparé the initial solution ls preferably one in which (i) anamorclin free base is more soluble than it ls in water (ii) anamorelin monohydrochloride is less soluble than it is in water, (iii) the organic solvent has limited miscibility with water, and 25 (iv) the organic solvent forms an azcotropc with water or has a lower boiling point than water. Examples of suitable organic solvents for the anamorelin free base indude but are not limited to butyl acetate, propyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl acetate, methylethyl ketone, methylisobutyl ketone and 2-methyltetrahydrofuran, preferably isopropyl acetate.

The concentration of the hydrochloric acid solution is govemed p ri mari 1 y by the desired molar ratio of anamorelin and chloride in the final composition, which will dictatc the number of moles of hydrochloric acid in the aqueous phase. In a preferred embodiment, the • >o molarity of the hydrochloric acid solution ranges from about 0.1 to about 13 or from about 1.0 to about 10, and the volume of the solution is determined by the molarity of the solution and the quantity of anamorelin to be reacted. ln various embodiments, the molar ratio of chloride to anamorelin free base in the reaction vessel can range from about 0.85 to about 5 1.04, from about 0.92 to about 1.02, from about 0.92 to about 1.00, or from about 0.93 to about 0.97.

Once the anamorelin with hydrochloric acid reaction is complété, the organic phase can be separated from the aqueous phase by any suitable phase extraction technique, including physical extraction of one phase from the mixture or distillation. Distillation can be 10 performed using various means, such as simple distillation, fractional distillation, vacuum distillation and preferably azeotropîc distillation. The distillation température is determined based upon the boiling point of the particular organic solvent(s) intended to be removed.

Once the aqueous phase has been separated from the organic phase, the anamorelin monohydrochloride or a composition comprising anamorelin monohydrochlorïde can be 15 isolnted from tlie aqueous phase via known techniques, including settling, sédimentation and concentration. Concentration is the preferred method, particulariy concentration via spray drying, optionally in the presence of an inert gas.

Spray drying is a method of producing a dry powder from a liquid or slurry by rapidly drying with a hot gas. Il is well suited for the continuous production of dry solids in either 20 powder, granulate or a ggl orne rate form from liquid feedstocks as solutions, émulsions and pumpable suspensions. Spray drying Is an idéal process where the end-product must comply with précisé quality standards regarding particle size distribution, residual moisture content, bulk density, and/or particle shape.

Spray drying involves the atomîzation of a liquid feedstock into a droplet spray, and contacting the droplets with hot air in a drying chamber. The spray is produced by either a rotary (wheel) or nozzle atomizer. Evaporation of moisture from the droplets and formation of dry particles proceed under controlled température and airflow conditions. Powder is discharged continuously from the drying chamber. Operating conditions and dryer design are selected according to the drying characteristics of the product and powder spécifications.

A spray dryer is a device used in spray drying. It takes a liquid stream and séparâtes the soluté or suspension from a liquid phase by evaporating the solvent. The solid Îs usually collectcd in a drum or cyclone. The liquid input stream is sprayed through a nozzle into a hot vapor stream and vaporized. Solids form as moisture quickly leaves the droplets. A nozzle is usually used to make the droplets as small as possible, maximizing heat transfer and the rate • » of water vaporization. A représentative spray dryer comprises a feed pump, atomizer, air heater, air disperser, drying chamber, and Systems for exhaust air clearing and powder recovery. The sélection of the atomizer, the most suitable airflow pattern, and the drying chamber design are determined by the drying characteristics and quality requirements for the 5 particular product.

The initial contact between spray droplets and drying air controls évaporation rates and product températures in the dryer. There are three modes of contact: l) Co-current: Drying air and particles move through the drying chamber in the same direction; 2) Counler-current: Drying air and particles move through the drying chamber in opposite 10 directions; and 3) Mîxed flow: Particle movement through the drying chamber expériences both co-current and counler-current phases.

Many commercially available spray dryers can be used in the spray drying step according to the présent invention. A représentative example is the Mini-Spray Dryer (Model: Buchi 190, Switzcrland), which opérâtes in a co-current manner, î.c., the sprayed I5 product and the drying gas flow in the same direction. Other suitable spray dryers include the Ntro Mobile Minor (trade mark, GEA Process Engineering Inc.), Niro QSD-3.6 (trade mark, GEA Process Engineering Inc.), L-8i (Ohkawara Kakoki Co., Ltd.) and so forth. The drying gas can be air or inert gases such as nitrogen, argon and carbon dioxide. The spray drying is preferably carried out with the inlet gas température in the range of from about I80 to about 20 200°C and the outlet gas température in the range of from about 80 to about I00°C. Preferred methods of spray drying the anamorelin hydrochloride are given in the examples herelo.

Anamorelin Monohydrochloride

Still other embodiments pertain to the novel forms of anamorelin monohydrochloride or compositions comprising anamorelin monohydrochloridc produced by the présent 25 invention. For example, ïn a first principal embodiment, the invention provides for anamorelin monohydrochloride or compositions comprising anamorelin monohydrochloridc having a uniformly controlled chloride content among batches. In this embodiment the invention provides anamorelin monohydrochloride having an inter-batch (i.c. batch-to-batch) chloride content that varies by no more than 7%, 5%, 3% or even 2%. For example, the 30 invention may provide anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having an inter-batch chloride content that ranges from 5.8 to 6.2%, 5.9 to 6.2%, 5.9 to 6.1%, or 6.0 to 6.1 %.

ln a second principal embodiment, the invention provides anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride having a molar ratio of chloride to anamorelin of from 0.92 to 1.02, or from 0.95 to l.OO. This ratio can exist throughout an entire batch, os an average of samples taken from the batch, or as one 5 or more samples within a batch.

A third principal embodiment provides anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride in an amorphous state. The amorphous state can be represented by an X-ray powder diffraction pattem substantially os depicted in Figure 1 or, altematively or in addition, by the infrared résonance spectrum 10 depicted in Figure 2.

The anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride of each of the foregoing principal embodiments is preferably highly soluble in water. For example, the solubility in water of the anamorelin monohydrochloride or a composition comprising anamorelin monohydrochloride is preferably greater than about 15 lOOmg/ml. The anamorelin monohydrochloride or composition comprising anamorelin monohydrochloride also preferably has a low residual solvent content For example, the total organic volatile impurities such as methanol, isopropanol, isopropyl acetate, ethyl acetate or other organic solvents used in preparing the drug substance are preferably less than 5,000 ppm, 3,000 ppm, or even 1,000 ppm. Altematively or ln addition, the anamorelin 20 monohydrochloride or composition comprising anamorelin monohydrochloride has a residual solvent content less than about 0.5%, 0.3%, or even 0.1% based upon the total weight of the anamorelin monohydrochloride or composition comprising anamorelin monohydrochloride.

The anamorelin monohydrochloride or composition comprising anamorelin monohydrochloride of each of the foregoing embodiments preferably has high purity and low 25 impurities including residual solvents. For example, total impurities such as by-products, contaminants, dégradation products and residual solvents used in preparing the drug substance are preferably less than 3%, 2%, 1%, or 0.5%. In other words, the anamorelin monohydrochloride or composition comprising anamorelin monohydrochloride is in a pharmaceutically acceptable form having greater than 97%, 98%, or even 99% purity.

Altematively or in addition, the anamorelin monohydrochloride or composition comprising anamorelin monohydrochloride of each of the foregoing embodiments can be characterized b y the weight percent of chloride in the composition, or in a sample of the composition, and in various embodiments the anamorelin monohydrochloride or composition comprising anamorelin monohydrochloride is defined by a chloride content ranging from • '3 about 5.8% to about 6.2%, and preferably from about 5.9% to about 6.1% (or 6.08%). The anamoreiin monohydrochloride or composition comprising onamorelin monohydrochloride can also be characterized by its water content, altematively or in addition to the other characteristics of the compound, and in various embodiments the compounds of the présent 5 invention comprise less than 5,4,3 or 2% water.

Medical Uses

Because the anamorelîn monohydrochloride or composition comprising anamoreiin monohydrochloride of the présent invention has growth hormone secretagogue activity, it is useful for preventing and/or treating conditions which require increased plasma growth 10 hormone leveis, ns in growth hormone déficient humons, elderly patients and livestock. The onamorelin monohydrochloride or a composition comprising onamorelin monohydrochioride is found particularly useful in the treatment of cancer related cachexia.

Pharmaceutical Dosage Forms

The anamoreiin monohydrochloride or composition comprising onamorelin monohydrochioride of the présent invention can be présent in on isolated state or, altematively, it can be formulated into a pharmaceutical dosage form (i.e., pharmaceutical composition) that comprises a therapeutically effective amount of the compound and one or more pharmaceuticaily acceptable excipients. As used herein the language “pharmaceuticaliy acceptable excipient*’ includes solvents, dispersion media, coatings, ontibacterial and anlifungal agents, tonicity agents, bufTers, antîoxidants, preservatives, absorption delayîng agents, and the like, compatible with pharmaceutical administration.

The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

A pharmaceutical composition is formulated to be compatible with its intended route 25 of administration. Exampies of routes of administration include parentéral, orai, transmucosal, and rectal administration. The compounds for use in the method of the invention can be formulated for administration by any suitable route, such as for orai or parentéral, for example, transmucosal (e.g., sublingual, lingual, (trans)buccal, nasal, (trans)dermal, and (trans)rectal) administration.

Suitable compositions and dosage forms include tablets, capsules, caplets, piils, gel caps, (roches, dispersions, suspensions, solutions, syrups, granules, beads, gels, powders, φ Ι4 pellets, magmas, lozenges, dises, suppositories, liquid sprays, or dry powders.

It is preferred that the anamorelin monohydrochloride or the composition comprising anamorelin monohydrochloride be orally administered. Suitable oral dosage forms include, for example, tablets, capsules or caplets prepared by conventional means with 5 pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone or hydroxypropylmethylcellulose); Piliers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnésium stéarate, talc or silica); disintegrants (e.g., sodium starch glycolate); and/or wetting agents (e.g., sodium lauiyl sulfate). If desired, the tablets can be coated, e.g., to provide for ease of swallowing or to provide a delayed release of active 10 ingrédients, using suitable methods. Tablets are typically formed by compression methods, whereas capsules are formed by filIîng a dry admixture into a hard outer shcll.

Liquid préparations can be in the form of solutions, syrups or suspensions, and are prepared by mixing the excipients along with the anamorelin hydrochloride in a suitable liquid medium such as water or alcohol. Liquid préparations (e.g., solutions, suspensions and 15 syrups) suitable for oral administration can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehiclcs (e.g., almond oil, oily esters or ethyl alcohol); and preservatîves (e.g., methyl or propyl hydroxy benzoates or sorbic acid).

EXAMPLES

The following examples are put forth so as to provide those of ordinary skill in the art with a complété disdosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be purely exemplary and are not intended to limit the disdosure. Efforts hâve been made to ensure 25 accuracy with respect to numbers (e.g., amounts, température, etc.), but some errors and déviations should be accounted for. Unless indicated otherwise, parts are parts by weight, température is in °C or is at ambient température, and pressure is at or near atmospheric.

EXAMPLE L PREPARATION OF ANAMORELIN HYDROCHLORIDE

Various methods hâve been developed to prépare the hydrochloric acid sait of 30 anamorelin, with differing results.

In a first method, which is the preferred method of the présent invention, anamorelin φ 15 free base was carefully measured and dissolved in isopropyl acetate. Anamorelin free base was prepared according to known method (e.g., U.S. Patent 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, 5 to form n mixture having on 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.

Approximately 150mg of the resulting spray dried sample of anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) was accurately weighed out and dissolved in methanol (50mL). Acetic acid (5mL) and distilled water (5mL) were added to the mixture. The resulting mixture was potentiometrically titrated using 0.01 N sflver nitrate and the endpoint was determined. A blank détermination was also performed and correction was made, if necessary. The chloride content in the sample was calculated by the following formula. This measurement method of chloride content was performed without any cations other than proton (H*).

Chloride content (%) = VxNx35.453xlQOxlOO/|Wx[IOO-(water content (%))-(residual solvent (%))] J

V: volume at the endpoint (mL)

N: actual normality of 0.01 mol/L silver nitrate

35.453 : atomic weight of Chlorine

W: weight of sample (mg)

TABLE IA

HCl (équivalent)	Chloride Content (WL%)
0.80	5.7
0.95	5.9
1.00	6.0
1.05	6.3

This data showed that anamorelin monohydrochloride produced by a fixed volume of

HCl in water containing 0.80 or L05 molar équivalents of HCl relative to anamorelin free base had levels of chloride that were undesirable, and associated with product instability as

shown in Example 3.

Altematively, a fixed volume of HCl in water containing 0.95 moles of HCl relative to anamorelin free base was used to préparé anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) as follows. Anamorelin free base (I8.8g, 5 34.4mmol) and isopropyl acetate (34l.8g) were mixed În a I000 mL flask. The mixture was heated at 40±5°C to confirm dissolution of the crystals and then cooled at 25±5°C. Distilled water (22.3g) and 3.6% diluted hydrochloric acid (33. Ig. 32.7mmol, 0.95 équivalents) were added into the flask end washed with distilled water. After 30 minutes stirring, the reaction was static for more than 15 minutes and the lower layer (aqueous layer) was transferred into a 10 separate 250mL flask. Distilled water was added to the flask and concentrated under pressure at 5O±5°C. The resulting aqueous solution was then filtered nnd product isolated by spray drying to afford anamorelin monohydrochloride A (the présent invention).

The physical properties of anamorelin monohydrochloride A were compared to anamorelin monohydrochloride produced by a tradition al comparative method (“anamorelin 15 monohydrochloride B”) (comparative example). Anamorelin mono hydrochloride B in the comparative example was produced by bubbling HCl gas into isopropyl acetate to produce a 2M solution of HCl, und reacting 0.95 molar équivalents of the 2M HCl in isopropyl acetate with anamorelin free base. The physical properties of anamorelin monohydrochloride B are reported in Table IB. This data shows that when 0.95 équivalents of HCl is added to 20 anamorelin free base, the chloride content (or amount of anamorelin dihydrochloride) is increased, even when a stoichiometric ratio of hydrochloride to anamorelin of less than 1.0 is used, possibly due to uncontrolled précipitation. In addition, this data shows that the concentration of residual solvents in anamorelin monohydrochloride Π was greater than the concentration in anamorelin monohydrochloride A.

TABLE IB

Anamorelin HCl Salt/Properties	HCI	Chloride Content (wt. %)	Residual Solvent Concentration (Ppm)
A	mono	5.9	< 1.000
B	mono	63	30,000-50,000

A similar decrease in residual solvent concentration was observed when

2-methyltetrahydrofuran was used as the dissolvîng solvent for anamorelin free base instead • π of isopropyl acetate in the process for preparing spray dried anamorelin monohydrochloride A (data not reported).

The résiduel solvent (organic volatile impurities) concentration (specifically isopropyl acetate) of anamorelin monohydrochloride in TABLE IB was measured using gas 5 chromatography (GC-2010, Shimadzu Corporation) according to the conditions shown in TABLE IC.

TABLE IC

GAS CHROMATOGRAM CONDITIONS
Detector	Flame ionization detector
Column	DB624(length30m,i.d.032mm.filmthicknessl .8pm, J&W) or équivalent
Carrier gas	Hélium
Flow rate	39cm/sec( about 2.5 mL/min)
Column température	40 · C(0-6 min) to( 10 · C/min) to 80 ° C to (50 C/min) to 250 ’C (13.425min)
Injection température	150’C
Detector température	260 ’C
Make-up gas	Nitrogen 40mL/min
Run duration	11 min
HEAD SPACE CONDITIONS
Oven température	80°C
Needle température	130C
Transfcr température	140’C
Equilibration time	20 min
Pressurized time	1.0 min
Drawing time	1.0 min
Carrier gas pressure	159 kPa
Injection time	0.08 min

EXAMPLE 2. SPRAY DRY METHODS

Several spray dry methods hâve been developed by varying the type of nozzle, tlie conditions at the nozzle, the inlet and outlet températures, the température of the condenser, and the feed rate. The amount of anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) produced, the yield of each process and représentative process parameters according to the présent invention using Niro QSD-3.6 (trade mark, GEA process engineering Inc.) are reported in Table 2A.

TABLE2A

Batch	Co-ct 0 |mm|	rrent nozzte Flow [kg/h ] /Pfbarl	T Inlet [’C]	T outlet [•ci	T condenser [•ci	Feed rate [kg/hl	Amount of product [kBl	Yield
I	2	23 I.6	I90	95	2	I3J	6.I5	92J%
A	2	25 IJ	I90	95	2	25	49.85	94.6%
B	2	25 I.6	I9O	95	2	25	I3O.4	98.6%
Batch	Rotary nozzle	TInlet	T outlet	T condenser	Feed rate	Amount οΓ product	Yield
P fbarl	Flow [kg/hl
2	3.3	I0.I	I90	95	2	I3J	6.I2	98J%
3	4.4	I3.6	I90	95	2	I3J	5.97	99.2%
4	3.0	I5.6	I90	95	2	I3J	6.39	97.8%

Various physical properties of the anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) prepared according to the foregoing exemples 5 were evaluated and reported below in Table 2B.

TABLE2B

Batch	KF (%]	Part	c[e Size (pm)	Bulk density (g/mL)	Purity %	Cl%	OVI (ppm)
D10	D50	D90
1	2.0	3.0	17.0	43.0	029	99.9	6.0	<1000
A	2.0	4.2	16.0	40.6	029	100.0	6.0	<1000
B	2.1	4.4	17.0	40.4	0.27	100.0	5.9	<1000
2	2.1	1.6	22.3	52.4	0.32	99.9	6.0	<1000
3	2.2	2.9	21.8	47.6	0.31	99.9	6.0	<1000
4	22	4.4	24.7	52.5	0.32	99.9	6.0	<1000

* Purity determined by HPLC, and inciudes only related compounds. ♦*OVI: Organic Volatile Impurities.

Similarly, the amount of anamorelin monohydrochloride (or a composition comprising anamorelin monohydrochloride) produced, the yield of eacli process and représentative process parameters according to the présent invention using Niro Mobile

Minor(trade mark, GEA process engineering Inc.) were reported in Tables 2C and 2D.

TABLE 2C

Batch	Rotary nozzle	T Inlet [°C]	Toutlet ra	Feed rate (kg/hj	Amount of product Ikgl	Yield
P (bar)	Flow ikg/hl.
1	2.8	80	188-192	83-87	3.3	26.0	98.6%
2	2.8	80	188-192	83-87	3.3	23.0	98.4%

TABLE2D

Batch	KF [%]	Particle Size fum]	Purity %	Cl%	OV1 (ppm)
D10	D50	D90
1	2.4	6.4	16.8	33.6	99.9	6.1	173
2	2.5	7.3	19.8	38.6	100.0	6.0	not detected

As can be seen, anamorelin monohydrochloride (or a composition comprising anamorelin monohydrochloride) prepared by the method of présent invention had désirable 10 chloride content, reduced residual solvent and high purity when produced under a range of spray drying conditions.

EXAMPLE 3, STABILITY TESTING

The stability of anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) prepared according to the foregoing exemples was evaluated 15 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 II00 HPLC System, Agitent Technologies Inc.). The concentrated aqueous solution of anamorelin monohydrochloride A of exampie I 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 5 an amorphous slate. The resulting amorphous product was dissoived 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 relative rétention time of the impurity versus anamorelin. In addition, the purity was converted into lhe amount of anamorelin free base within a sample without any other organic solvent since anamorelin monohydrochloride (or 10 composition comprising anamorelin monohydrochloride) was dissoived in the solvent to be measured by HPLC condition.

TABLE3A

Detector	UV280nm
Column Column température Mobile phase	Zorbax Bonus RP(4.6mmx250mm.3.5pm, Agi lent) 55°C Mobile phase A : 0.1% Trifluoroacctic acid aqueous solution Mobile phase B : 0.1% Trifluoroacctic acid acetonitrile solution

Gradient
Time (min.)	Phase A (%)	Phase B (%)
0	84	16
12	74	26
26	69.5	30.5
29	69.5	30.5
41	64	36
50	7	93
54	7	93
54.1	84	16
62	84	16

Flow

O.85mL/min (rétention time of anamorelin: 32m in) run duration

62min

Injection volume

IPpL

TABLE SB

month	anamorclin	Impunty 1	Impurity 2	Impunty 3	Impunty 4	Impunty S	Impunty 6	Impunty 7
Initial	100.0%	<0.05	<005	<0 05	<0.05	<005	<0.05	<005
1	100.0%	<0.05	<005	<0.05	<005	<0.05	<0.05	<005
25*C/6O%RH 3	100.0%	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05
6	100.0%	<0.05	<0.05	<0.05	<005	<0.05	<0.05	<005
t	100.0%	<0.05	<0.05	<0.05	<005	<0.05	<005	<0.05
4O*Cf75%RH 3	100.0%	<005	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05
6	100.0%	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05	<0.05

As can be seen. the stabilily of the anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) prepared according lo the présent invention was 5 nearly unchanged, and high purity was maintained for six months under each set of conditions.

The long-term slability of three separate batches of anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) having differing chioride contents were evaluated for stability at 25 °C / 60% relative humidily for one, two and three 10 years, and 40 °C / 75% relative humidïty for one, three and six months. The results are presented below in Table 3C. % Increase in Table 3C was calculated by the foliowing formula.

% Increase = (M - l)/Ixl00

I: initial total impurity (%)

M: measured total impurity (%) at spécifie time (e.g., 3 months, 6 month and so forth)

TABLE_3C

Initial Chioride Content (wt.%)	% increase in Total Impurities From To at 25 °C / 60% RH
1Y	2Y	3Y
6.2%	85%	114%	100%
6.3%	200%	340%	360%
5.6%	10%	48%	29%
5.9%	0%	20%	20%

% Increase in Total Impurities From To at 40 ’C /

75% RH

	IM	3M	6M
6.2%	107%	100%	171%
6.3%	140%	400%	500%
5.9%	0%	21%	17%

As can be seen, the long-term stability of the anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) (from 5.3% to 6.3% chloride content) prepared according to the présent invention was nearly unchanged, and high purîty was maintained for three years under ambient storage conditions (25 ’C / 60% RH).

Stability testing for anamorelin dihydrochloride relative to the monohydrochloride and anamorelin free base at 40 C/ 75% relative humidity is reported below in Table 3D. For the anamorelin dihydrochloride préparation, anamorelin free base was dissolved in ethyl acetate and a molar excess of hydrochloric acid in ethyl acetate was added into the mixture to precipitate anamorelin dihydrochloride. The resuiting anamorelin dihydrochloride was filtered and dried (chloride content approximateiy 12.2%). HPLC Area % in Table 3D refers to the amount of converted value of anamorelin free base in samples.

As can be seen, the long-term stability of anamorelin dihydrochloride was easy to bc changed relative to the monohydrochloride. Thus, when the content of anamorelin dihydrochloride in the composition is increased, the composition results in less stable.

TABLE 3D

	Anamorelin Free Base	Anamorelin Mono-HCI	Anamorelin Di-HCl
I.T.	IM	3M	I.T.	IM	3M	I.T.	IM	3M
HPLC Area %	99.7%	99.9%	99.7%	99.9%	99.3%	99.2%	98.9%	98.2%	97.1%

EXAMPLE 4 SOLUBILITY TEST

A solution of standard curve was prepared to 356 pmol/L by diluting standard substance (anamorelin free base (quantitative value: 93.90%), 86.6mmoI/L, isopropyl acetate solution) with acetonitrile. ln addition, a sample solution was prepared according to the process that test compound (about lOOmg) added into distilled water (10.00g), the solution

Φ ²³ was mixed for 10 minutes at 50 C and then was placed ovemight, obtained suspension was filtered by syringe with filter (0.2 pm) and the filtrate (48.93mg) was diluted with acetonitrile (lOmL). A solution of standard curve and a sample solution (each 5 pL) were determined by injecting into HPLC (GULLIVER 1500 HPLC system, JASCO Corporation). Since 5 anamorelin monohydrochloride was complctely dissolved in the 25% solution of anamorelin monohydrochloride (i.e., anamorelin monohydrochloride (Ig) was dissolved in dîstilled water (3mL)), a solubility of anamorelin monohydrochloride was >333mg/mL.

TABLE4

run		solvent	mg/mL
1	anamorelin monohydrochloride	dis lilled water ( initial pH 7)	>333
2	Anamorelin free base	dîstilled water (initial pH 7)	0.04

As can be seen, the solubility of the anamorelin monohydrochloride is superior to that of anamorelin free base in dîstilled water, illustrating that a réduction of chloride content in anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) can lead to decreased solubility.

EXAMPLE 5, PHYSIC AL CHARACTERIZATION

The amorphous form of the anamorelin monohydrochloride (or composition comprising anamorelin monohydrochloride) produced by spray drying was evaluated using X-Ray powder diffraction and infrared résonance under the following measurement conditions. The XRPD spectra and IR spectra observed are depicted in Figures 1 and 2.

X-ray powder diffraction spectra Apparatus: BRUKER D8 DÏSCO VER with GADDS monufactured by BRUKER axs

Target: Cu, Fil ter. Nonc Voltage: 40 kV, Current: 40 mA, Light exposure: 5 min.

Infrared résonance spectrum

Apparatus: FTIR-660 Plus produced by JASCO Corporation DURASCOPE produced by SENSIR Measuring method: Potassium bromide added into the tablet forming machine and it was pressured by hand-press to préparé the thin film. This sample was measured as background. Subsequently, the amorphous sample (1 mg) and potassium bromide (lOOmg) was combined and the mixture added into the tablet forming machine to préparé the thin film and then measured.

•i

Dissolution performance: 2 cm Scanning number of time: 16 times

Throughout this application, various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. It will be apparent to those skilled in the art that various modifications and variations can be made in the présent invention without departing from the scope or spirit of the invention. Other embodiments of lhe invention will be apparent to those skilled in the art from considération of the spécification and practice of the invention disclosed herein. It is intended that the spécification and cxamples be considered as exemplary only, wîlh a true scope and spirit of tlie invention being indicated by the following claims.

Claims (23)

1. REPLACEMENT CLAIM SET(CLEAN)

   1. Anamorelin monohydrochloride having a chloride content ranging from 5.8 to 6.2 wt%.
2. 2. Anamorelin monohydrochloride comprising a chloride:anamorclin molar ratio of from 0.9 to 0.99.
3. 3. The anamorelin monohydrochloride of claim 1 or 2 in an amorphous state.
4. 4. The anamorelin monohydrochloride of claims 1-3, in an isolated state.
5. 5. The anamorelin monohydrochloride of claims 1-3, comprising less than 0.5 wt% impurilics.
6. 6. The anamorelin monohydrochloride of claims 1-3, comprising from 1 to 3 wt% water.
7. 7. The anamorelin monohydrochloride of claim 5, wherein the impurities are selected from by-products, contaminants, dégradation products and residual solvents.
8. 8. The anamorelin monohydrochloride of claim 7, comprising a residual solvent selected from methanol, butyl acetate, propyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate. methyl acetate, methyl ethyl ketone, mcthylîsobutyl ketone, 2methyltetrahydrofuran and combinations thereof in an amount less than 1000 ppm.
9. 9. The anamorelin monohydrochloride of claim 8, wherein the residual solvent is isopropyl acetate.
10. 10. The anamorelin monohydrochloride of claims 1-3, having a purity greater than 99%.
11. 11. A composition comprising anamorelin monohydrochloride, wherein the composition comprises a chloride content ranging from 5.8 to 6.2 wt%.
12. 12. A composition comprising anamorelin monohydrochloride, wherein the composition has a chiorideianamorelin molar ratio of from 0.9 to 0.99.
13. 13. The composition of claim II or 12, in the substantial absence of anamorelin hydrochloride other than anamorelin monohydrochloride.
14. 14. A process for preparing anamorelin monohydrochloride comprising:

    a) dissolving anamorelin free base in an organic solvent to form a solution;

    b) mixing said solution with water and hydrochloric acid for a lime suffïcient to:

    i) react said anamoreiin free base with said hydrochloric acid, and

    I ii) form an organic phase and an aqueous phase;

    c) separating the aqueous phase from the organic phase; and

    d) isolating said anamorelin monohydrochloride from said aqueous phase, wherein said hydrochloric acid is added in a molar ratio of 0.90 to 1.0 relative to said

    5 anamorelin.
15. 15. The process of claim 14, wherein said water and hydrochloric acid in step b) are added sequentially or concurrently to said solution.
16. 16. The process of claim 14, wherein said organic solvent is selected from butyl acetate, propyl acetate, ethyl acetate, isopropyl acetate, isobutyl acetate, methyl acetate, methyl

    10 ethyl ketone, methylisobutyl ketone and 2-methyltetrahydrofuran.
17. 17. The process of claim 16, wherein said organic solvent is isopropyl acetate.
18. 18. The process of claim 14 wherein the anamorelin monohydrochloride is isolated from said aqueous phase by spray drying.
19. 19. The process of claim 14, further comprising processing the anamorelin

    15 monohydrochloride into a finished dosage form.
20. 20. Anamorelin monohydrochloride produced by the method of claim 14.
21. 21. A pharmaceutical composition comprising:

    a) a therapeutically effective amount of the anamorelin monohydrochloride of claims 1,2 or 20; and

    20 b) one or more pharmaceutically acceptable excipients.
22. 22. A method of making a pharmaceutical dosage form comprising:

    a) combining a therapeutically effective amount of the anamorelin monohydrochloride of claims 1, 2, 3 or 20 with one or more pharmaceutically acceptable excipients to form a mixture; and

    25 b) processing said mixture into a finished dosage form.
23. 23. An oral pharmaceutical dosage form comprising anamorelin monohydrochloride of claims 1,2 or 20 and one or more pharmaceutically acceptable excipients.