CN101355942A

CN101355942A - Solid dispersions of opioid antagonists

Info

Publication number: CN101355942A
Application number: CNA2006800459478A
Authority: CN
Inventors: 维伦达·库马尔
Original assignee: Adolor Corp
Current assignee: Adolor Corp
Priority date: 2005-10-07
Filing date: 2006-10-06
Publication date: 2009-01-28

Abstract

Solid dispersions of stable, amorphous opioid antagonists, particularly [[2(S)-[[4(R)- (3 -hydroxyphenyl)-3(R),4-dimethyl-piperidinyl]methyl] - 1 -oxo-3 -phenylpropyl] amino] acetic acid, with improved water solubility and bioavailability are disclosed. Also disclosed are methods of preventing or treating a side effect associated with an opioid. In addition, methods of treating or preventing pain, ileus, and opioid bowel dysfunction are disclosed.

Description

The solid dispersion of opioid antagonists

The cross reference of related application

The application requires the priority of the U. S. application 11/543,619 of submission on October 5th, 2006, and described U. S. application has required the interests of the U. S. application 60/724,819 of submission on October 7th, 2005, and it all openly is merged in this paper as a reference.

Technical field

The present invention relates to the solid dispersion of opioid antagonists.More specifically, the present invention relates to the solid dispersion of the stable amorphous opioid antagonists (particularly Aiweimopan (alvimopan)) that water solublity and bioavailability be improved, and their usage.

Background technology

[[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid dihydrate (the USAN name is called Aiweimopan) is the [mu antagonist that works in periphery, can be used for treating postoperative ileus and opioid causes functional disorder of intestine, and other indication.Aiweimopan is 3 of an amphoteric ion type, 4-is dibasic-and the 4-Arylpiperidine.It has low-down dissolubility in water and many acceptable solvent commonly used.The result is that its oral administration biaavailability is very poor.

[[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid can be used as different crystal form and exists, comprise hydrate forms, solvate form thereof and anhydrous form, and exist as amorphous substance.When the relative humidity that surpasses about 15%, it exists with its crystalline dihydrate form.When the relative humidity that is lower than about 15%, it exists with its anhydrous form.Amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid has hygroscopicity, and be converted into its crystallization dihydrate form stress (stress) time, for example under 54% relative humidity 12 days or about 40 ℃ in about 80 ℃ temperature range under 75% relative humidity three days.Under environmental condition, unbodied [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid was converted into its crystallization dihydrate form fully after 66 days.

[[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] the crystallization dihydrate (Aiweimopan) of acetic acid is than amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid has lower water solubility, so its bioavailability is lower than amorphous form.Therefore, expectation exploitation [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid is with relevant 3, the stable amorphous form of the dibasic 4-Arylpiperidine derivatives of 4-.The present invention relates to these and other important target.

Summary of the invention

In one embodiment, the present invention relates to solid dispersion, comprising:

At least aly be selected from following pharmaceutically acceptable excipient: hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone homopolymer (PVP), polyvinylpyrrolidone copolymer, and composition thereof; With

The chemical compound of at least a formula I:

Wherein said chemical compound is solid amorphous form;

Wherein said amorphous form is stable; And

Wherein:

R ¹Be hydrogen or alkyl;

R ²Be hydrogen, alkyl or thiazolinyl;

R ³Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ⁴Be hydrogen, alkyl or thiazolinyl;

A is OR ⁵Or NR ⁶R ⁷

R ⁵Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ⁶Be hydrogen or alkyl;

R ⁷The B that alkyl, aralkyl, aralkyl or the alkylidene that replaces for the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, aryl, cycloalkyl substituted, cycloalkenyl group, cycloalkenyl group replaces, perhaps, R ⁶And R ⁷The nitrogen-atoms that connects with them forms heterocycle;

B is

Insert the P3 formula

, C (=O) W or NR ⁸R ⁹

R ⁸Be hydrogen or alkyl;

R ⁹The alkyl, the aryl or aralkyl that replace for the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl substituted, cycloalkyl, cycloalkenyl group, cycloalkenyl group, perhaps, R ⁸And R ⁹The nitrogen-atoms that connects with them forms heterocycle;

W is OR ¹⁰, NR ¹¹R ¹², or OE;

R ¹⁰Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹¹Be hydrogen or alkyl;

R ¹²The C that alkyl, aralkyl or the alkylidene that replaces for the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, cycloalkenyl group replaces (=O) Y, perhaps, R ¹¹And R ¹²The nitrogen-atoms that connects with them forms heterocycle;

E is

The C that alkylidene replaces (=O) D or-R ¹³OC (=O) R ¹⁴

R ¹³Alkylidene for the alkyl replacement;

R ¹⁴Be alkyl;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

R ¹⁵Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹⁶Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, aralkyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted or the alkyl of cycloalkenyl group replacement;

R ¹⁷Be hydrogen or alkyl, perhaps, R ¹⁶And R ¹⁷The nitrogen-atoms that connects with them forms heterocycle;

Y is OR ¹⁸Or NR ¹⁹R ²⁰

R ¹⁸Be the alkyl of hydrogen, alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces;

R ¹⁹Be hydrogen or alkyl;

R ²⁰Be the alkyl of hydrogen, alkyl, thiazolinyl, aryl, cycloalkyl, cycloalkenyl group, cycloalkyl substituted, alkyl or the aralkyl that cycloalkenyl group replaces, perhaps, R ¹⁹And R ²⁰The nitrogen-atoms that connects with them forms heterocycle;

R ²¹Be hydrogen or alkyl; With

N is 0 to 4.

In some preferred embodiment, solid dispersion comprises at least a opioid in addition.

In other embodiments, the present invention relates to prevent or treat the method for side effect relevant among the patient with opioid, described side effect comprises that intestinal obstruction, opioid cause functional disorder of intestine, constipation, feel sick, vomit or its combination, said method comprising the steps of:

Described patient is given the above-mentioned solid dispersion of effective dose.

In another embodiment, the present invention relates to treat or prevent the method for patient's pain, said method comprising the steps of:

To the described above-mentioned solid dispersion that has the patient who needs to give effective dose.

In other embodiments, the present invention relates to treat or prevent patient's ileac method, said method comprising the steps of:

In other embodiments, the present invention relates to treat or prevent patient's opioid to cause the method for functional disorder of intestine, said method comprising the steps of:

Can make these and other aspect of the present invention become more apparent from following detailed description.

Detailed Description Of The Invention

Unless otherwise stated, as above-mentioned employed in full with the disclosure, following term is construed as has following implication.

As used in this article, " solid dispersion " is meant the solid system of at least a two-phase, wherein one comprises the finely divided solid particle that is distributed in the whole bulk solids material (bulk solid substance) mutually, and granule is decentralized photo or inner phase, and bulk materials is continuous phase or foreign minister.

As used in this article, " amorphous " is meant noncrystalline; There is not molecular lattice structure.As used in this article, the solid dispersion of the amorphous compound of formula I can comprise more a spot of crystal form, for example comprises the crystal form of the formula I chemical compound that is less than about 25 weight % based on the gross weight of formula I chemical compound.

As being meant that about " amorphous form " employed term " stable " amorphous substance can not be converted into crystal form under specified relative humidity and the temperature conditions at least in a minimum time section herein.For solid dispersion of the present invention, the chemical compound of formula I (with the whole solid dispersion that preferably comprises formula I chemical compound) minimally is to keep amorphous form greater than the following time period:

Relative humidity about 54% and about 10 ℃ under about 30 ℃ temperature about 12 days;

Relative humidity about 75% and about 40 ℃ under about 80 ℃ temperature about 3 days; Or

Be lower than about 30% relative humidity and about 10 ℃ under about 30 ℃ temperature about 66 days.

As used in this article, " bioavailability " is meant speed and the degree that medicine or other material can be utilized by destination organization after administration.In situation of the present invention, bioavailability is meant that opioid antagonists can be by the degree of the utilization of the Opioid Receptors in central nervous system or the peripheral nervous system.

As used in this article, " deliquescence " is meant that salt passes through to melt (melt) or become the process of liquid from the environment moisture absorption.

As used in this article, " alkyl " is meant optional substituted saturated straight chain, side chain or cyclic hydrocarbon, have about 1 to about 20 carbon atoms (and wherein the scope of carbon atom and all combinations and the recombinant of given number), preferred about 1 to about 8 carbon atoms (hereinafter referred to as " low alkyl group ")." side chain " is meant that low alkyl group (for example methyl, ethyl or propyl group) wherein is connected in the alkyl of linear alkyl chain.In some preferred embodiment, alkyl is C ₁-C ₅Alkyl promptly, has 1 branched-chain or straight-chain alkyl to about 5 carbon.In other preferred embodiment, alkyl is C ₁-C ₃Alkyl promptly, has 1 branched-chain or straight-chain alkyl to about 3 carbon.Exemplary alkyl comprises methyl, ethyl, n-pro-pyl, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group, hexyl, heptyl, octyl group, nonyl and decyl." low alkyl group " is meant to have 1 alkyl to about 6 carbon atoms.Preferred alkyl comprises 1 low alkyl group to about 3 carbon.Alkyl includes but not limited to methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, n-pentyl, cyclopenta, isopentyl, neopentyl, n-hexyl, isohesyl, cyclohexyl, ring octyl group, adamantyl, 3-methyl amyl, 2,2-dimethylbutyl and 2, the 3-dimethylbutyl.

As used in this article, " alkylidene " is meant general formula-(CH ₂) _n-shown in divalent alkyl, wherein n is 1 to 10, and scope in all combinations and recombinant.Alkylidene can be straight chain, side chain or cyclic.Limiting examples comprises methene base (methylene), methylene (CH ₂-), ethylidene (CH ₂CH ₂-), propylidene ((CH ₂) ₃-), trimethylene, pentamethylene and hexamethylene.Can randomly insert one or more oxygen, sulfur or optional substituted nitrogen-atoms along alkylidene, wherein the nitrogen substituent group is aforesaid alkyl.Alkylidene can be optional substituted.Term " low-grade alkylidene " in this article refers to has about 1 those alkylidenes to about 6 carbon atoms.Preferred alkylidene has about 1 to about 4 carbon.

As used in this article, " thiazolinyl " is meant and comprises at least one carbon-to-carbon double bond and have 2 monovalent alkyls to about 10 carbon atoms (and all combinations and recombinant in the scope) in chain.Thiazolinyl can be optional substituted.In some preferred embodiment, thiazolinyl is C ₂-C ₁₀Thiazolinyl promptly, has 2 side chain or straight-chain alkenyls to about 10 carbon.In other preferred embodiment, thiazolinyl is C ₂-C ₆Thiazolinyl promptly, has 2 side chain or straight-chain alkenyls to about 6 carbon.In other preferred embodiment, thiazolinyl is C ₃-C ₁₀Thiazolinyl promptly, has 3 side chain or straight-chain alkenyls to about 10 carbon.In other preferred embodiment, thiazolinyl is C ₂-C ₅Thiazolinyl promptly, has 2 side chain or straight-chain alkenyls to about 5 carbon.Exemplary thiazolinyl comprises for example vinyl, acrylic, cyclobutenyl, pentenyl, hexenyl, heptenyl, octenyl, nonene base and decene base.

As used in this article, " aryl " is meant optional substituted monocycle, bicyclo-, three ring or other polycyclic aromatic ring systems, have about 5 to about 50 carbon atoms (and wherein the scope of carbon atom and all combinations and the recombinant of given number), preferred about 6 to about 10 carbon.Limiting examples comprises for example phenyl, naphthyl, anthryl and phenanthryl.

As used in this article, " aralkyl " is meant and has aryl substituent and have about 6 to about 50 carbon atoms (and wherein the scope of carbon atom and all combinations and the recombinant of given number), preferred about 6 alkyl to about 10 carbon atoms.Aralkyl can randomly be substituted at aryl or moieties.Limiting examples comprises for example phenyl methyl (benzyl), diphenyl methyl, trityl group, phenylethyl, diphenyl-ethyl and 3-(4-aminomethyl phenyl) propyl group.

As used in this article, " heteroaryl " is meant optional substituted monocycle, bicyclo-, three ring or other polycyclic aromatic ring systems, and it comprises at least 1, preferred 1 ring hetero atom to about 4 sulfur, oxygen or nitrogen.Heteroaryl can have for example about 3 to about 50 carbon atoms (with the wherein scope of carbon atom and all combinations and the recombinant of given number), and preferred about 4 to about 10 carbon.The limiting examples of heteroaryl comprises for example pyrrole radicals, furyl, pyridine radicals, 1,2,4-thiadiazolyl group, pyrimidine radicals, thienyl, isothiazolyl, imidazole radicals, tetrazole radical, pyrazinyl, pyrimidine radicals, quinolyl, isoquinolyl, thienyl, benzothienyl, isobenzofuran-base, pyrazolyl, indyl, purine radicals, carbazyl, benzimidazolyl, with isoxazolyl.

As used in this article, " cycloalkyl " is meant optional substitutedly to have about 3 to about 20 carbon atoms (and wherein the scope of carbon atom and all combinations and the recombinant of given number), preferred about 3 to about 10 carbon atoms, more preferably preferred about 3 to about 8 carbon atoms, more preferably from about 3 to about 6 carbon atoms, and have the alkyl of one or more rings in its structure.Multiring structure can be bridged ring or condensed ring structure.Cycloalkyl can be randomly by for example alkyl (preferred C ₁-C ₃Alkyl), alkoxyl (preferred C ₁-C ₃Alkoxyl) or halogen replace.Limiting examples comprises for example cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, ring octyl group and adamantyl.

As used in this article, " alkyl of cycloalkyl substituted " is meant the alkyl of straight chain, preferred low alkyl group, its endways on the carbon by cycloalkyl (preferred C ₃-C ₈Cycloalkyl) replaces.Limiting examples comprises for example cyclohexyl methyl, cyclohexyl ethyl, cyclopenta ethyl, cyclopenta propyl group, cyclopropyl methyl etc.

As used in this article, " cycloalkenyl group " is meant and has the about 4 undersaturated cycloalkyl of olefinic to about 10 carbon (and all combinations and recombinant in the scope).In preferred embodiments, cycloalkenyl group is C ₅-C ₈Cycloalkenyl group promptly, has about 5 cycloalkenyl groups to about 8 carbon.

As used in this article, " alkyl-cycloalkyl " is meant optional substituted ring system, and this system comprises the cycloalkyl with one or more alkyl substituents.The limiting examples of alkyl-cycloalkyl for example comprises, 2-methylcyclohexyl, 3,3-dimethylcyclopentyl, trans-2,3-diformazan basic ring octyl group and 4-methyl decahydro naphthyl.

As used in this article, " heteroarylalkyl " is meant to have for example about 2 to about 50 carbon atoms (with the wherein scope of carbon atom and all combinations and the recombinant of given number), preferred about 6 to about 25 carbon atoms, choose alkyl substituted, that replaced by heteroaryl wantonly.Limiting examples comprises 2-(1H-pyrroles-3-yl) ethyl, 3-pyridylmethyl, 5-(2H-tetrazole radical) methyl and 3-(pyrimidine-2-base)-2-methyl cyclopentane base.

As used in this article, " Heterocyclylalkyl " is meant the polycyclic alicyclic ring of optional substituted monocycle, bicyclo-, three rings or other system, and it comprises at least 1, preferred 1 ring hetero atom to about 4 sulfur, oxygen or nitrogen.Heterocyclylalkyl can have for example about 3 to about 20 carbon atoms (with the wherein scope of carbon atom and all combinations and the recombinant of given number), and preferred about 4 to about 10 carbon.Heterocyclylalkyl can be undersaturated, and can condense in aromatic ring.Limiting examples for example comprises also [c] pyranose, 1 of tetrahydrofuran base, tetrahydro-thienyl, piperidyl, pyrrolidinyl, isoxazole alkyl, isothiazole alkyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperazinyl, morpholinyl, piperadinyl, decahydroquinolyl, octahydro benzopyranyl, octahydro Pentamethylene., 2,3,4-tetrahydric quinoline group, octahydro-[2] pyrindinyl, decahydro-cyclooctane be [c] furyl and imidazolidinyl also.

As used in this article, term " spirane base " is meant optional substituted alkylidene double-basis, two end all with the same carbon atom bonding of precursor group, to form the volution group.The spirane base as defined herein, has 3 to 20 annular atomses with its precursor group.Preferably, it has 3 to 10 annular atomses.Limiting examples with the spirane base of its precursor group comprises 1-(1-methyl-cyclopropyl)-propane-2-ketone, 2-(1-phenoxy group-cyclopropyl)-ethylamine and 1-methyl-spiral shell [4.7] dodecane.

As used in this article, term " alkoxyl " is meant optional substituted alkyl-O-group, and wherein alkyl defines as described above.Limiting examples for example comprise methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy and heptan the oxygen base.

As used in this article, term " aryloxy " is meant optional substituted aryl-O-group, and wherein aryl defines as described above.Limiting examples comprises for example phenoxy group and naphthoxy.

As used in this article, term " aralkoxy " is meant optional substituted aralkyl-O-group, and wherein aralkyl defines as described above.Limiting examples comprises for example benzyl oxygen base, 1-phenyl ethoxy, 2-phenyl ethoxy and 3-naphthyl oxygen in heptan base.

As used in this article, term " aryloxy aryl " is meant to have the substituent aryl of aryloxy, and wherein aryloxy and aryl define as described above.The aryloxy aryl can be optional substituted.Limiting examples comprises for example Phenoxyphenyl and naphthoxy phenyl.

As used in this article, term " heteroaryl aryl " is meant to have the substituent aryl of heteroaryl, and wherein heteroaryl and aryl define as described above.The heteroaryl aryl can be optional substituted.Limiting examples comprises for example 3-pyridine radicals phenyl, 2-quinolyl naphthyl and 2-pyrrole radicals phenyl.

As used in this article, term " alkoxy aryl " is meant the aryl that has alkoxy substituent, and wherein alkoxyl and aryl define as described above.Alkoxy aryl can be optional substituted.Limiting examples comprise for example right-anisyl ,-tert-butoxy phenyl and methylenedioxyphenyl.

As used in this article, " carboxyl " is meant-C (=O) OH group.

As used in this article, " alkanoyl " be meant-C (=O)-and alkyl group, wherein alkyl defines as described above.Exemplary alkanoyl comprises acetyl group, positive propiono, positive bytyry, 2-methylpropionyl, positive valeryl, 2-methylbutyryl base, 3-methylbutyryl base, 2,2-dimethyl propylene acyl group, heptanoyl group, capryl and palmityl.

As used in this article, " heterocycle " is meant and comprises about 4 to the monocycle of about 10 annular atomses (and in the scope all combinations and recombinant) or polycyclic ring system carboatomic ring atom group, wherein annular atoms is one or more for being different from the element of carbon, for example is nitrogen, oxygen or sulfur.Heterocyclic group can be aromatic or non-aromatic.Limiting examples comprises for example pyrroles and piperidines group.

As used in this article, " halogen " is meant fluorine, chlorine or bromine.

Typically, substituted chemical part comprises the substituent group of one or more displacement hydrogen.Exemplary substituent group comprises for example halogen (for example, F, Cl, Br, I), alkyl, cycloalkyl, alkyl-cycloalkyl, thiazolinyl, alkynyl, aralkyl, aryl, heteroaryl, heteroarylalkyl, spirane base, Heterocyclylalkyl, hydroxyl (OH), nitro (NO ₂), cyano group (CN), amino (NH ₂) ,-amino that N-replaces (NHR ") ,-N, the dibasic amino of N-(N (R ") R "), carboxyl (COOH) ,-C (=O) R " ,-OR " ,-C (=O) OR " ,-NHC (=O) R ", amino carbonyl (C (=O) NH ₂) ,-amino carbonyl that N-replaces (C (=O) NHR ") ,-N, the dibasic amino carbonyl of N-(C (=O) N (R ") R "), mercaptan, sulfenyl (SR "), sulfonic acid (SO ₃H), phosphonic acids (PO ₃H), S (=O) ₂R ", S (=O) ₂NH ₂, S (=O) ₂NHR ", S (=O) ₂NR " R ", NHS (=O) ₂R ", NR " S (=O) ₂R ", CF ₃, CF ₂CF ₃, NHC (=O) NHR ", NHC (=O) NR " R ", NR " C (=O) NHR ", NR " C (=O) NR " R ", NR " C (=O) R " etc.About above-mentioned substituent group, each radicals R " can be for example following any independently: H, alkyl, cycloalkyl, thiazolinyl, aryl, aralkyl, heteroaryl or Heterocyclylalkyl.

As used in this article, " side effect " be meant and the different consequence of result shown in use medicine or the means, as medicine, particularly tissue or tract produced, and is different from the illeffects that effect is looked in its administration.For example, in opioid situation, term " side effect " may relate to such as for example intestinal obstruction, opioid cause functional disorder of intestine, constipation, feel sick, the situation of vomiting or its combination.

As used in this article, " intestinal obstruction " is the obstruction of duodenum 12 or internal organs (particularly colon).Referring to, for example, Dorland ' s Illustrated Medical Dictionary, p.816,27th ed. (W.B.Saunders Company, Philadelphia 1988).Intestinal obstruction should be different from constipation, and constipation is meant the rare or difficult defecation of defecation.Referring to, for example, Dorland ' s Illustrated MedicalDictionary, p.375,27th ed. (W.B.Saunders Company, Philadelphia 1988).Thereby intestinal obstruction can advance obstacle to be diagnosed by the destroyed intestinal contents that causes of the normal coordination exercise of internal organs.Referring to, for example, Resnick, J.Am.J.of Gastroenterology, 1992,751 and Resnick, J.Am.J.of Gastroenterology, 1997,92,934.In some cases, particularly after the operation that comprises abdominal operation, it is quite serious that functional disorder of intestine can become, and continues to surpass a week and influence the more than part of gastrointestinal.This situation often is called the paralytic ileus of postoperative and (referring to Livingston, E.H. and Passaro, E.D.Jr., Digestive Diseases and Sciences, 1990,35,121) takes place after the laparotomy ventrotomy of being everlasting.Similarly, puerperal, intestinal obstruction was the FAQs of women in minute a period of time in puerperium, and thought that similar fluctuation by natural opioid level that stress the result as childbirth causes.

As used in this article, " opioid causes functional disorder of intestine " or " OBD " is meant that the bowel movement frequency that takes place since beginning opioid treatment back reduces, usually be less than about 3 times spontaneous bowel movement weekly, and merge following one or more: difficult defecation, feces in bulk or hard, anal orifice and rectal intestine blocks sense or defecation is not exclusively felt.Opioid causes that functional disorder of intestine can comprise constipation, abdominal cramps, expansion, feels sick, the trooping of gastroesophageal reflux and combination thereof.

As used in this article, " effective dose " is meant the amount of the chemical compound described herein of the symptom that can suppress, prevent or treat specified disease, disease or side effect on therapeutics effectively.This disease, disease and side effect (for example include but not limited to those pathological conditions relevant with the administration opioid, the situation that relates to treatment of pain and/or prevention), wherein treatment or prevention for example comprise and suppress its activity by making cell, tissue or receptor contact chemical compound of the present invention.Therefore, for example, use opioid to be used for for example treating pain relating to, term " effective dose " is meant and treats and/or prevents pain condition.When relating to the use of peripheral mu opioid substance antagonist, term " effective dose " is meant and treats and/or prevents the usually side effect relevant with opioid, comprises that for example intestinal obstruction, opioid cause functional disorder of intestine, constipation, feels sick, vomits or side effect such as its combination.

As used in this article, in certain embodiments, " with ... combination ", " therapeutic alliance " and " combination product " are meant patient while administration antiemetic and peripheral mu opioid substance antagonist, comprise for example chemical compound of formula I, perhaps be meant patient's administration simultaneously antiemetic, peripheral mu opioid substance antagonist and opioid.When combination medicine-feeding, the administration simultaneously of every kind of component or at different time points with any sequence ground administration.Therefore, but the fully closely administration in time respectively of each component, so that the desired therapeutic effect is provided.

As used in this article, " dosage unit " is meant the unit that is suitable for being used for as dosage unit specific patient's to be treated physics discrete form.Each unit can comprise the bonded reactive compound that produces the scheduled volume of desired therapeutic effect as calculated of pharmaceutical carrier with needs.The specification of dosage unit form of the present invention can have following requirement: (a) specific characteristic of reactive compound and the specific therapeutic effect that will realize and (b) inherent limitations in the field of this reactive compound of preparation.

As used in this article, " pharmaceutically useful " is meant that those chemical compounds, material, compositions and/or dosage form are fit to the tissue of contact humans and animals and do not have too much toxicity, zest, allergy or other to become the complication of problem in rational medical judgment scope, match with rational interests/risk ratio.

Some acidity of the present invention or alkali compounds can be used as zwitterionic form and exist.The form of ownership of chemical compound comprises free acid, free alkali and zwitterionic form, all is considered within the scope of the present invention.Known in this fieldly not only comprised chemical compound amino but also that comprise carboxyl and often existed with the poised state of its zwitterionic form.Therefore, running through as herein described had for example not only comprised any chemical compound amino but also that comprise carboxyl and had also comprised their corresponding zwitterionic form.

As used in this article, " patient " is meant and comprises mammal by animal, preferred people.

As used in this article, " prodrug " is meant the maximized chemical compound of amount that is designed to make the active substance that arrives the response location of expecting especially, prodrug itself for the activity of expectation normally non-activity or have a MIN activity, but be converted into the metabolite of biologic activity by biotransformation.

As used in this article, " stereoisomer " but be meant the different chemical compound of spatial arrangements with identical chemical composition atom or group.

When any variable occurred surpassing one time in any formation or in any chemical formula, its definition when at every turn occurring was independent of at all the definition when other occurs.In addition, the combination of substituent group and/or variable only is only permission when this combination results stable compound.

Suc as formula the I illustrated can be used for the 3-that the piperidine derivative in the solid dispersion of the present invention can be used as at piperidine ring and the 4-position is trans and the form of cis three-dimensional chemical isomer exists.In the chemical compound of most preferred formula I, R ²Substituent group and R ⁴Substituent group is " trans " orientation on piperidines.

R except formula I ²Substituent group and R ⁴Outside substituent " cis " and " trans " orientation, formula I has a R ²Substituent group and R ⁴The absolute stereo chemistry of substituent carbon atom can also use normally used " R " and " S " to define (people such as Orchin, The Vocabulary ofOrganic Chemistry, John Wiley and Sons, Inc., the 126th page, it is merged in this paper as a reference).Preferred compounds of the invention are the R on the piperidine ring of its Chinese style I ²Substituent group and R ⁴Substituent configuration all is those of " R ".

In addition, depend on R ⁴Structure, asymmetric carbon atom can be incorporated in the molecule.Thereby it is that the form of independent " R " or " S " stereoisomer exists that the chemical compound of these classifications can be used as at these chiral centres, and perhaps the racemic mixture form as isomer exists, and all these is considered within the scope of the present invention.Preferably, use the pure in fact stereoisomer of The compounds of this invention, that is, the wherein isomer that is configured as " R " or " S " of chiral centre, that is, wherein the configuration of three chiral centres is preferably 3R, 4R, S or 3R, 4R, those chemical compounds of R.

As used in this article, " periphery " or " working in periphery " is meant the medicine that works outside the central nervous system.

As used in this article, " work " and be meant the medicine that in the central nervous system, works at maincenter.

Solid dispersion of the present invention relates to the opioid antagonists chemical compound of periphery.Term " periphery " is meant the physiological system that mainly acts on beyond the central nervous system and the chemical compound of assembly.In a preferred form, be used for the inventive method periphery the opioid antagonists chemical compound to peripheral tissues for example stomach intestinal tissue show high activity level, it is active and preferably do not have the CNS activity in fact to show low CNS simultaneously.As used in this article, term " does not have the CNS activity in fact " and is meant being lower than of pharmacological activity of the chemical compound that the inventive method uses about 20% performance to be arranged in CNS, preferably be lower than about 15% performance is arranged in CNS, more preferably less than about 10% performance is arranged in CNS, more preferably being lower than of the pharmacological activity of the chemical compound that uses of the inventive method about 5% has performance in CNS, and most preferably 0% pharmacological activity has performance in CNS.

In addition, give therein in certain embodiments of the present invention of the opioid periphery side effect of chemical compound antagonism, preferably this chemical compound does not pass blood brain barrier in fact and does not reduce opioid useful activity thus.As used in this article, about 20 weight % that are lower than that term " does not pass " chemical compound that is meant that the inventive method is used in fact pass blood brain barrier, preferably be lower than about 15 weight %, more preferably less than about 10 weight %, more preferably chemical compound be lower than about 5 weight %, most preferably 0 weight % passes blood brain barrier.The chemical compound of selecting can be estimated the CNS infiltration by being determined at intravenous administration blood plasma level and brain level afterwards.

US-B-6,451,806 and US-B-6,469,030 disclose the method and composition that comprises opioid and opioid antagonists, comprise the [mu antagonist of periphery, and it is open is incorporated into this paper as a reference in full.Solid dispersion can be particularly useful for treating and/or preventing the side effect relevant with opioid, comprise that intestinal obstruction, opioid cause functional disorder of intestine, constipation, feel sick, vomit or its combination, be used for the treatment of and/or prevent irritation, be used for the treatment of and/or prevent intestinal obstruction and be used for the treatment of and/or prevent opioid to cause functional disorder of intestine.

Therefore in one embodiment, the invention provides solid dispersion, comprising:

At least aly be selected from following pharmaceutically acceptable excipient: hydroxypropyl methylcellulose (HPMC), polyvinylpyrrolidone homopolymer (PVP), polyvinylpyrrolidone copolymer (comprising vinylpyrrolidone-vinyl acetate polymer) are (PVP/VAc)), and composition thereof; With

The chemical compound of at least a formula I:

Wherein said chemical compound is solid amorphous form;

Wherein said amorphous form is stable; With

Wherein:

R ¹Be hydrogen or alkyl;

R ²Be hydrogen, alkyl or thiazolinyl;

R ⁴Be hydrogen, alkyl or thiazolinyl;

A is OR ⁵Or NR ⁶R ⁷

R ⁶Be hydrogen or alkyl;

B is

, C (=O) W or NR ⁸R ⁹

R ⁸Be hydrogen or alkyl;

W is OR ¹⁰, NR ¹¹R ¹², or OE;

R ¹¹Be hydrogen or alkyl;

E is

(C=O) D that alkylidene replaces or-R ¹³OC (=O) R ¹⁴

R ¹³Alkylidene for the alkyl replacement;

R ¹⁴Be alkyl;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

Y is OR ¹⁸Or NR ¹⁹R ²⁰

R ¹⁹Be hydrogen or alkyl;

R ²¹Be hydrogen or alkyl; With

N is 0 to 4.

The polyvinylpyrrolidone (PVP) that is fit to is all types of PVP of 10 to 110 for Fei Kenqieer K (Fikentscher K) value, comprise K12 (about 2,000-3,000 dalton), K17 (about 7,000-10,000 dalton), K25 (about 28,000-34,000 dalton), K29/32 (about 44,000-58,000) and K90 (about 1,000,000-1,500,000 dalton).The K value as the abbreviation of Fei Kenqieer K value, is the tolerance of polymer mean molecule quantity.The test method that is used for the calculating K value is by ISO 1628-2 (DIN 53726) (using capillary viscosimeter to measure the polymer viscosity of dilute solution) regulation.The mixture of polyvinylpyrrolidone and polyvinyl acetate also is useful.

In preferred embodiments, the chemical compound of formula I and the weight ratio of pharmaceutically acceptable excipient are about 5: 95 to about 75: 25, are preferably minimum about 10: 90, more preferably minimum about 15: 85, more preferably minimum about 20: 80, more preferably minimum about 25: 75, more preferably minimum about 30: 70.

In some preferred embodiment, compositions of the present invention can comprise opioid, and condition is this bioavailability that can not hinder formula I chemical compound that comprises.The opioid that is fit to comprise alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine(pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, dextropropoxyphene, sufentanil, tramadol, and composition thereof.Preferred opioid comprises morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, dextropropoxyphene, fentanyl and tramadol.

Solid dispersion of the present invention can comprise one or more other active component that is generally used for pain relieving and/or cough-flu-cough-relieving combination product in addition, and condition is this bioavailability that can not hinder formula I chemical compound that comprises.The composition of this routine comprises for example aspirin, acetaminophen, phenylpropanolamine, phenylephrine, chlorphenamine, caffeine and/or guaifenesin.Typical or the conventional composition that can comprise is at for example the Physicians ' DeskReference, describes in 1999, and it is open is incorporated into this paper as a reference in full.

In addition, solid dispersion of the present invention can comprise one or more in addition and can be used for strengthening opioid pain relieving effect and/or reduce the chemical compound that the analgesic toleration forms, and condition is this bioavailability that can not hinder formula I chemical compound that comprises.This chemical compound for example comprise dextromethorphan or other nmda antagonist (Mao, M.J. etc., Pain 1996,67,361), L-364,718 and other CCK antagonist (Dourish, CT. etc., Eur.J.Pharmacol, 1988,147,469), no inhibitor (Bhargava, H.N. etc., Neuropeptides, 1996,30,219), pkc inhibitor (Bilsky, EJ. etc., J.Pharmacol Exp.Ther.1996,277,484) and dynorphin antagonist or antiserum (Nichols, M.L. etc., Pain, 1997,69,317).The open of each all incorporated into this paper as a reference in full in the aforementioned documents.

In case learn instruction of the present disclosure, except above-mentioned illustrational those, can be used for the opioid component of other opioid in the method and composition of the present invention, optional routine and optional being used to and strengthen opioid pain relieving effect and/or reduce the chemical compound that the analgesic toleration forms and it will be apparent to those skilled in the art that.

Solid dispersion of the present invention can be multiple solid dosage forms, comprises tablet, capsule and lozenge.

Preferred 4-aryl-piperidine derivative for example comprises at US-A-5,250,542, US-A-5159,081, US-A-5,270,328 and US-A-5,434,171, US-B-6,451, disclosed chemical compound in 806 and US-B-6,469,030 is describedly openly incorporated into this paper as a reference in full.

In preferred embodiments, the chemical compound of formula I is trans 3, the 4-isomer.

In some embodiment of the chemical compound that uses formula I, preferred:

R ¹Be hydrogen;

R ²Be alkyl;

N is 1 or 2;

R ³Be benzyl, phenyl, cyclohexyl or cyclohexyl methyl; With

R ⁴Be alkyl.

In some embodiment of the chemical compound that uses formula I, preferred:

A is OR ⁵With

R ⁵Be hydrogen or alkyl.

In some embodiment of the chemical compound that uses formula I, preferred:

A is NR ⁶R ⁷

R ⁶Be hydrogen;

R ⁷B for the alkylidene replacement; With

B is C (O) W.

In some embodiment of the chemical compound that uses formula I, preferred:

R ⁷Be (CH ₂) q-B;

Q is about 1 to about 3;

W is OR ¹⁰With

R ¹⁰The alkyl of alkyl, cycloalkyl or the cycloalkyl substituted that replaces for hydrogen, alkyl, phenyl.

In some embodiment of the chemical compound that comprises formula I, preferred:

W is NR ¹¹R ¹²

R ¹¹Be hydrogen or alkyl; With

R ¹²The C that replaces for hydrogen, alkyl or alkylidene (=O) Y.

In some embodiment of the chemical compound that uses formula I, preferred:

R ¹²Be (CH ₂) _mC (O) Y;

M is 1 to 3;

Y is OR ¹⁸Or NR ¹⁹R ²⁰With

R ¹⁸, R ¹⁹And R ²⁰Be hydrogen or alkyl independently.

In some embodiment of the chemical compound that uses formula I, preferred:

W is OE;

E is CH ₂C (=O) D;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

R ¹⁵Be hydrogen or alkyl;

R ¹⁶Be methyl or benzyl; With

R ¹⁷Be hydrogen.

In some embodiment of the chemical compound that uses formula I, preferred:

W is OE;

E is R ¹³OC (=O) R ¹⁴

R ¹³For-CH (CH ₃)-or-CH (CH ₂CH ₃)-; With

R ¹⁴Be alkyl.

In some embodiment of the chemical compound that uses formula I, preferred:

3 of piperidine ring and 4 s' the configuration R type of respectively doing for oneself.

The chemical compound of preferred formula I comprises:

Q-CH ₂CH(CH ₂(C ₆H ₅))C(O)OH，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)OCH ₂CH ₂，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)OH，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)NHCH ₃，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)NHCH ₂CH ₃，

G-NH(CH ₂) ₂C(O)NH ₂，

G-NH(CH ₂) ₂C(O)NHCH ₃，

G-NHCH ₂C(O)NH ₂，

G-NHCH ₂C(O)NHCH ₃，

G-NHCH ₂C(O)NHCH ₂CH ₃，

G-NH(CH ₂) ₃C(O)OCH ₂CH ₃，

G-NH(CH ₂) ₃C(O)NHCH ₃，

G-NH(CH ₂) ₂C(O)OH，

G-NH(CH ₂) ₃C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NHCH ₂C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NH(CH ₂) ₂C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NH(CH ₂) ₂C(O)NH ₂，

Z-NHCH ₂C(O)OCH ₂CH ₃，

Z-NHCH ₂C(O)OH，

Z-NHCH ₂C(O)NH ₂，

Z-NHCH ₂C(O)N(CH ₃) ₂，

Z-NHCH ₂C(O)NHCH(CH ₃) ₂，

Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

Z-NH(CH ₂) ₂C(O)OCH ₂(C ₆H ₅)，

Z-NH(CH ₂) ₂C(O)OH，

Z-NH(CH ₂) ₂C(O)NHCH ₂CH ₃，

Z-NH(CH ₂) ₃C(O)NHCH ₃，

Z-NHCH ₂C(O)NHCH ₂C(O)OH，

Z-NHCH ₂C(O)OCH ₂C(O)OCH ₃，

Z-NHCH ₂C(O)O(CH ₂) ₄CH ₃，

Z-NHCH ₂C(O)OCH ₂C(O)NHCH ₃，

Z-NHCH ₂CC (O) O-(4-methoxyl group cyclohexyl),

Z-NHCH ₂C (O) OCH ₂C (O) NHCH ₂(C ₆H ₅) and

Z-NHCH ₂C(O)OCH(CH ₃)OC(O)CH ₃；

Wherein:

Q represents:

G represents:

Z represents:

The chemical compound of preferred formula I comprises:

(3R，4R，S)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(+)-Z-NHCH ₂C(O)OH，

(-)-Z-NHCH ₂C(O)OH，

(3R，4R，R)-Z-NHCH ₂C(O)-OCH ₂CH(CH ₃) ₂，

(3S，4S，S)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(3S，4S，R)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(3R, 4R)-Z-NHCH ₂C (O) NHCH ₂(C ₆H ₅) and

(3R，4R)-G-NH(CH ₂) ₃C(O)OH，

Wherein Q, Z and G such as above-mentioned definition.

The chemical compound of preferred formula I comprises: (+)-Z-NHCH ₂C (O) OH and (-)-Z-NHCH ₂C (O) OH, wherein Z such as above-mentioned definition.Preferred especially described chemical compound is (+)-Z-NHCH ₂C (O) OH.

The chemical compound of preferred formula I comprises Q-CH ₂CH (CH ₂(C ₆H ₅)) C (O) OH, wherein Q such as above-mentioned definition.Preferred especially described chemical compound be (3R, 4R, S)-Q-CH ₂CH (CH ₂(C ₆H ₅)) C (O) OH.

Most preferably act locally on internal organs, have the chemical compound of the formula I of high effect and Orally active.Particularly preferred embodiment of the present invention are chemical compound (+)-Z-NHCH ₂C (O) OH, that is, and with the chemical compound shown in the following formula (II):

The chemical compound of formula (II) has low water solubility, unless under low or high pH condition.It is inherent that the amphoteric ion type feature can be chemical compound, and can give the character of expectation, for example the system's absorbability difference after oral administration and keeping gastral local action.

In particularly preferred embodiments, the chemical compound of formula I is pure in fact stereoisomer.

In another embodiment, the present invention relates to prevent or treat the method for patient's the side effect relevant with opioid, may further comprise the steps:

To the described above-mentioned composition that has the patient who needs to give effective dose.

This method can be used for prevention and treatment intestinal obstruction, opioid cause functional disorder of intestine, constipation, feel sick, vomit and combination, particularly postoperative ileus, postoperative nausea or postoperative vomiting.

In other embodiments, the present invention relates to prevent or treat the method for patient's pain, may further comprise the steps:

In preferred embodiments, compositions comprises at least a opioid in addition.

In other embodiments, the present invention relates to prevent or treat patient's ileac method, may further comprise the steps:

In preferred embodiments, compositions comprises at least a opioid in addition.

In other embodiments, the present invention relates to prevent or the opioid for the treatment of the patient causes the method for functional disorder of intestine, may further comprise the steps:

In preferred embodiments, compositions comprises at least a opioid in addition.

The present invention relates to comprise the solid dispersion of opioid chemical compound.Just as discussed above, this opioid chemical compound can be used for for example treating and/or preventing pain.Yet, also discuss as above-mentioned, the often side effect do not expected of appearance in the patient who accepts the opioid chemical compound comprises that for example intestinal obstruction, opioid cause functional disorder of intestine, constipation, feels sick, vomiting or its combination (particularly the intestinal obstruction of postoperative, feel sick and/or vomiting) and other side effect.Rely on solid dispersion of the present invention, may advantageously realize inhibition the effective and expectation of the side effect of not expecting relevant with the opioid chemical compound.Therefore, wherein may provide the effect that is better than independent chemical compound and medicine with opioid and peripheral mu opioid substance antagonist chemical compound combination that is fit to or the combined solid dispersion that gives jointly.

In this respect, just as discussed above, the patient often is given opioid and is used for the treatment of for example pain condition.Yet as indicated the opioid administration may cause the side effect of not expecting like that, causes functional disorder of intestine, constipation, feels sick, vomits or its combination such as for example intestinal obstruction, opioid.These side effect of not expecting may conduct and the opioid amount relative restrictions factor that can give the patient.That is to say that owing to do not expect to occur above-mentioned side effect, the opioid amount that can give the patient may be restricted.Can give patient's the limited unfavorable attenuating that causes the pain relief degree subsequently of opioid amount.Combined method of the present invention and compositions can be used for advantageously increasing the opioid amount that gives the patient, obtain enhanced pain relief thus, and make the side effect do not expected relevant with opioid reduce, minimize and/or avoided.The peripheral mu opioid substance antagonist that is used for method and composition of the present invention does not preferably have central nervous system's activity in fact, therefore, can not influence opioid analgesic effect with achieving one's goal.

Although do not want to be bound by any theory or action principle, think the opioid side effect, for example intestinal obstruction, opioid cause functional disorder of intestine, constipation, feel sick, vomiting or its combination may be that the interaction of not expecting by opioid and peripheral mu receptor causes.The [mu antagonist that the method according to this invention gives to work in periphery can be blocked the interaction of opioid chemical compound and μ receptor, prevent thus and/or suppress above-mentioned side effect, comprise that intestinal obstruction, opioid cause functional disorder of intestine, constipation, feel sick, vomit and combination, particularly comprise postoperative or postoperative ileus, feel sick and/or vomiting.

To those skilled in the art, in case known instruction of the present disclosure, except above-mentioned illustrational those, other [mu agonist compounds that can be used for method and composition of the present invention is conspicuous.

The chemical compound that is used for the inventive method can exist by prodrug forms.As used in this article, " prodrug " is intended to comprise the carrier of any covalent bonding, and this prodrug discharges the active parent drug that is used for the inventive method in vivo when giving mammalian subject with this prodrug, for example formula I.Because known prodrug strengthens the character (for example, dissolubility, bioavailability, production etc.) of many expectations of medicine, if expectation, the chemical compound that is used for the inventive method can be sent with prodrug forms.Therefore, the present invention has considered to send the method for prodrug.The prodrug that is used for chemical compound of the present invention (for example chemical compound of formula I) can prepare by the functional group that modification is present in this chemical compound, makes this be modified in routine operation or the body and is cracked into parent compound.

Therefore, prodrug for example comprises the wherein described chemical compound of hydroxyl, amino or carboxyl and any group bonding herein, and when prodrug during to the mammalian subject administration, its cracking is to form free hydroxyl group, free amine group or carboxylic acid respectively.Example includes but not limited to acetic acid, formic acid and the benzoic acid derivative of alkohol and amine functional group; With the ester of alkyl, carbocyclic ring, aryl and alkylaryl, for example methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl, the tert-butyl group, cyclopropyl, phenyl, benzyl and phenethyl ester etc.

The chemical compound that is used for solid dispersion of the present invention can be by well known to a person skilled in the art many method preparations.Chemical compound can be synthetic by method for example as described below, or synthesize by the change method to method as described below that those skilled in the art understand.Relate to all methods disclosed by the invention and all be considered, comprise milligram, gram, number gram, kilogram, thousands of gram or commercial commercial scale with any scale practice.

Go through as above-mentioned, the chemical compound that is used for the inventive method can comprise the carbon atom of one or more asymmetric replacements, and can be used as optical activity form or racemization isolated in form.Therefore, be intended to consider all chirality forms, diastereomeric form formula, racemization form and all geometrical isomerism forms of structure, unless indicated specific spatial chemistry or isomeric form particularly.Known in this fieldly how to prepare and separate this optical activity form.For example, can be by the mixture of standard technique separation of stereoisomers, include but not limited to fractionation, positive, the anti-phase and chiral chromatography of racemization form, preferential salt formation, recrystallization or the like are perhaps by or deliberately synthesizing by target chiral centre synthetic from chirality initiation material chirality.

As can easily understanding, the functional group of existence can comprise protecting group in building-up process.Itself is known as the chemical functional group protecting group, and it can append to degree of functionality and for example be removed on hydroxyl and the carboxyl or from degree of functionality.These groups are present in the chemical compound, make that this degree of functionality is inert to the chemical reaction condition of this chemical compound contact.The present invention can use any kinds of protect base.Preferred protecting group comprises benzyl oxygen base carbonyl and tert-butyl group oxygen base carbonyl.Can be used for other preferred protecting group of the present invention and can be described in Greene, T.W. and Wuts, P.G.M., Protective Groups in Organic Synthesis 2d.Ed., Wiley﹠amp; Sons is in 1991.

4-aryl-piperidine derivative of formula I of the present invention can use the method for instructing in following document for example synthetic: US-A-5,250,542, US-A-5,434,171, US-A-5,159,081, US-A-5,270,328, US-B-6,451,806, US-B-6,469,030, and Werner, J.A. etc., Journal of Organic Chemistry, 61,587-597 (1996), wherein the open of each all incorporated into this paper as a reference in full.For example; when synthetic The compounds of this invention as the 3-of initiation material replace-4-methyl-4-(3-hydroxyl-or alkanoyl oxygen base phenyl) piperidine derivative can pass through US-A-4; 115; 400 and US-A-4; 891; the conventional method of instruction preparation in 379, the open quilt of described document is incorporated this paper into as a reference in full.Be used for the synthetic parent material (3R of described chemical compound herein, 4R)-4-(3-hydroxy phenyl)-3, the 4-lupetidine can pass through at US-A-4,581,456 and US-A-5,136, the method preparation of describing in 040, it is openly incorporated into this paper as a reference in full, but adjusts as described, makes β-spatial chemistry for preferred.

The first step of this method can comprise by 3-alkoxyl bromobenzene and alkyl lithium reagents reaction formation 3-alkoxyl phenyl lithium reagent.This reaction can be under inert conditions and the non-activity solvent that is fit to for example absolute ether or preferred anhydrous tetrahydro furan in the presence of carry out.The preferred alkyl lithium reagents that is used for this method is a n-BuLi, particularly s-butyl lithium.Usually, can add about equimolar amounts to slight excessive alkyl lithium reagents to reactant mixture.Reaction can be carried out under about-20 ℃ to about-100 ℃ temperature, more preferably about-50 ℃ to-55 ℃ approximately.

In case formed 3-alkoxyl phenyl lithium reagent, can add the 1-alkyl-4-piperidones of equimolar amounts to mixture, keep-20 ℃ to about-100 ℃ temperature approximately simultaneously.Reaction was typically finished after about 1 to 24 hour.At this moment, can make the reactant mixture room temperature of little by little rising again.The separation of product can be carried out with any residual lithium reagent of quencher by add saturated nacl aqueous solution in reactant mixture.Separating organic layer, and if expect suitable 1-alkyl-4-(3-alkoxyl phenyl) piperidines 01 derivatives is provided, can be further purified.

As above the dehydration of Zhi Bei 4-Phenylpiperidine alcohol can use strong acid to finish according to known method.Although dehydration takes place in any of several strong acid (for example hydrochloric acid, hydrobromic acid etc.) with various amounts, preferred dehydration uses phosphoric acid to carry out, and perhaps particularly carries out in toluene that contains p-methyl benzenesulfonic acid or benzene.This reaction is typically under refluxad carried out, and is more typically in about 50 ℃ and carries out to 150 ℃.So acidic aqueous solution alkalization of the salt form that the product that forms can be by making product and with suitable separating with this aqueous solution of solvent extraction of water immiscibility.If expectation can be further purified the residue that obtains after the evaporation then.

1-alkyl-4-methyl-4-(3-alkoxyl phenyl) 5,6-tetrahydropyridine derivative can be by metal enamine (metalloenamine) alkylation preparation.This reaction is preferred uses n-BuLi for example to carry out under nitrogen or the argon at inert atmosphere in oxolane (THF).Usually, can be to being cooled to-50 ℃ to about 0 ℃ approximately, the slightly excessive n-BuLi of adding in the THF solution that contains 1-alkyl-4-(3-alkoxyl phenyl)-tetrahydropyridine of the stirring of-10 ℃ temperature range more preferably from about-20 ℃.With this mixture stir about 10 to 30 minutes, add about 1.0 to 1.5 normal methyl halogenide to solution subsequently, keep the temperature of reactant mixture to be lower than 0 ℃ simultaneously.After about 5 to 60 minutes, can add entry and collect organic facies to reactant mixture.Product can be according to the standard method purification, but preferred crude product by the vacuum distilling purification or by with it at hexane: ethyl acetate (65: 35, v: v) with the mixture of silica gel in making beating came purification in about two hours.According to a kind of method in back, can come separated product by filtering subsequently reduction vaporization filtrate then.

The next procedure of this method can comprise the Mannich reaction of unconjugated endocyclic enamine being carried out amino methylization.This reaction is preferably undertaken by about 1.2 to about 2.0 normal water-containing acetals and about 1.3 to 2.0 normal suitable secondary amine are incorporated in the suitable solvent.Although water may be preferred solvent, in this reaction, can also use other non-nucleophilicity solvent, for example acetone and acetonitrile.Can arrive about 3.0 to 4.0 with the pH regulator that provides the anionic acid of non-nucleophilicity with this solution.The example of this acid comprises sulphuric acid; Sulfonic acid class, for example methanesulfonic acid and p-methyl benzenesulfonic acid; Phosphoric acid; And Tetrafluoroboric acid, preferably sulfuric acid.1-alkyl-4-methyl-4-(3-alkoxyl phenyl) tetrahydropyridine (typically be and be dissolved in the aqueous sulfuric acid) that can add monovalent to this solution, and can adjust the pH of solution again with non-nucleophilicity acid or the secondary amine that is fit to.In course of reaction, preferably keep pH at about 1.0 to about 5.0 scope, more preferably from about 3.0 to about 3.5 pH.When about 50 ℃ to about 80 ℃ temperature range, more preferably when carrying out for about 70 ℃, finish basically after being reflected at about 1 to 4 hour, more typically finished at about 2 hours.Reaction can be cooled to about 30 ℃ then, and join in the sodium hydroxide solution.Then this solution is used and the immiscible organic solvent of water for example hexane or ethyl acetate extraction, and the water thorough washing with after removing any removing residue formaldehyde with the organic facies evaporated under reduced pressure.

The next procedure of this method can comprise that 1-alkyl-4-methyl-4-(3-the alkoxyl phenyl)-3-tetrahydropyridine methylamine catalytic hydrogenation with preparation obtains corresponding anti-form-1-alkyl-3,4-dimethyl-4-(3-alkoxyl phenyl) piperidines.In fact this reaction takes place with two steps.First step is wherein will encircle outer C-N key reductive cleavage to produce the hydrogenolysis of 3-methyl tetrahydropyridine.In second step, with 2 of tetrahydro pyridine ring, the two key reduction of 3-are to provide required piperidine ring.

The reduction of the two keys of enamine is introduced conclusive relative spatial chemistry at 3 of piperidine ring with 4 carbon atoms.Reduction is not carried out with stereo selectivity completely usually.The catalyst that is used for this method can be selected from various palladium catalysts, and preferred platinum catalysts.

The catalytic hydrogenation step of this method is preferably carried out in acid reaction medium.The solvent that is fit to that is used for this method comprises alcohols, for example methanol or ethanol, and ethyl acetate, oxolane, toluene, hexane etc.

Suitable spatial chemistry result can be dependent on the amount of the catalyst of use.The amount of the catalyst that the spatial chemistry result of generation expectation is required can be depending on the purity whether initiation material exists various catalyst poisonings aspect.

Hydrogen Vapor Pressure in the reaction vessel may not be conclusive, but can be at about 5psi in the scope of about 200psi.The concentration of the parent material of by volume is preferably the about 20mL liquid of every gram parent material, although also can use the parent material that improves or reduce concentration.Under the specified in this article condition, the persistent period of catalytic hydrogenation may not be conclusive, because this molecule can not over-reduction.Although reaction can last up to about 24 hours or more of a specified duration, after absorbing two theoretical moles of hydrogen, need not continue this reducing condition.Can come separated product by kieselguhr and with the filtrate decompression evaporate to dryness by reactant mixture is filtered then.Isolating product like this need not be further purified, and preferably, non-enantiomer mixture can be directly used in subsequent reaction.

Can remove alkyl substituent from the 1-position of piperidine ring by the dealkylation method of standard.Preferably, can use chloroformate derivative, particularly vinyl or phenyl derivatives, and remove with acid.Then, the alkoxide compound of preparation can obtain corresponding phenol by dealkylation.This reaction can be undertaken by chemical compound is reacted in 48% hydrobromic acid aqueous solution usually.When about 50 ℃ under about 150 ℃ temperature, when preferably carrying out under the reflux temperature at reactant mixture, this reaction can be finished after about 24 hours basically at about 30 minutes.Then can be by with solution cooling, with neutralize about 8 pH of alkali mixture be carried out post processing subsequently.This aqueous solution can be used and the immiscible organic solvent extraction of water.Residue after the evaporation organic facies can be directly used in step subsequently then.

Chemical compound as the initiation material of The compounds of this invention can also be prepared as follows: with 1-alkyl-4-methyl-4-(3-alkoxyl phenyl)-3-tetrahydropyridine methylamine in 3-position bromination, with the bromo compound lithiumation that so prepares, and make for example MB reaction of the intermediate of lithiumation and methyl halogenide, to provide corresponding 1-alkyl-3,4-dimethyl-4-(3-alkoxyl phenyl) tetrahydropyridine methylamine.Can as mentioned above this chemical compound be reduced and be converted into initiation material then.

As indicated such, the chemical compound that is used for solid dispersion of the present invention can be used as independent stereoisomer and exists.Preferably, to US-A-4,581,456 disclosed or US-A-5,250,542 embodiment, 1 described reaction condition is adjusted into stereospecific basically and provides mainly is the racemic mixture of two kinds of enantiomer.These enantiomer can be split then.The method that can be used for preparing the initiation material of fractionation used in synthetic these chemical compounds comprise usefulness (+)-or (-)-two (toluyl) tartaric acid handle alkyl-3; the racemic mixture of 4-dimethyl-4-(3-alkoxyl phenyl) piperidines is to provide the intermediate of fractionation.Then can be with this chemical compound with the chloro-carbonic acid vinyl esters at 1-position dealkylation and finally be converted into 4-(3-hydroxy phenyl) the piperidines isomer of expectation.

As understood by a person skilled in the art, as required, can also separate independent enantiomer of the present invention from the corresponding racemic mixture of The compounds of this invention with (+) or (-) dibenzoyl tartaric acid.Preferably, obtain (+)-trans enantiomer.

Although (+) trans-3,4 stereoisomers are preferred, all possible stereoisomer of described chemical compound all is considered within the scope of the present invention herein.The racemic mixture of stereoisomer and pure in fact stereoisomer are all within the scope of the present invention.As used in this article, term " pure in fact " is meant with respect to other possible stereoisomer, exists at least about 90 mole percents, more preferably at least about 95 mole percents with most preferably at least about the required stereoisomer of 98 mole percents.

Intermediate can be by making 3,4-alkyl-replacement-4-(3-hydroxy phenyl) piperidines and formula LCH ₂(CH ₂) _N-1CHR ³The chemical compound prepared in reaction of C (O) E, wherein L is for example chlorine, bromine or an iodine of leaving group, E is carboxylic acid, ester or amide, and R ³With n as above-mentioned definition herein.Preferably, L can be chlorine, and is reflected under the existence of alkali and carries out so that the azanylization of piperidines.For example, can make 4-chloro-2-cyclohexyl ethyl n-butyrate. with (3R, 4R)-4-(3-hydroxy phenyl)-3, the contact of 4-lupetidine,, 4R)-4-(3-hydroxy phenyl)-3,4-dimethyl-1-piperidines so that 4-[(3R to be provided] ethyl n-butyrate..Although the ester of carboxylic acid may be preferred, can use the amide of free acid itself or carboxylic acid.

In alternative synthesizing, the piperidines contact methylene Arrcostab that can make replacement is so that the azanylization of piperidines.For example, 2-methylene-3-phenylpropionic acid ethyl ester is contacted with the piperidines of expectation, so that 2-benzyl-3-piperidines ethyl propionate to be provided.

Another synthetic route can comprise piperidines and the reaction of haloalkyl nitrile that makes replacement.The itrile group of the piperidines alkyl nitrile that obtains can be hydrolyzed to corresponding carboxylic acid.

For each synthetic route, ester that obtains or carboxylic acid can react with amine or alcohol, so that the chemical constitution of modification to be provided.In preparation during amide, can make piperidine carboxylic acid or piperidine carboxylic acid ester and amine coupling agent for example dicyclohexylcarbodiimide, boric acid, borine-trimethylamine etc. in the presence of react.The preparation of ester can be by making piperidine carboxylic acid at coupling agent for example p-methyl benzenesulfonic acid, boron trifluoride etherate or N, and the existence of the N '-carbonyl dimidazoles suitable alcohol of contact is down carried out.Perhaps, can use for example preparation piperidines-carboxylic acid chlorides such as thionyl chloride, Phosphorous chloride., phosphorus pentachloride of reagent.Can make alkanoyl chlorine and suitable amine or pure the reaction so that corresponding amide or ester to be provided.

The amorphous form of formula I chemical compound can comprise fusion quenching, lyophilization (lyophilizing), spray drying, grinding, wet granulation, evaporation and the crystalline drying of solvation by conventional method of pharmacy production.Lyophilizing and evaporation are the optimization techniques of the amorphous form of preparation I compound.The existence of the amorphous form of formula I chemical compound can be measured by X-ray powder diffraction or by measuring glass transition temperature, for example by differential scanning calorimetry, modulation differential scanning calorimetry or dynamic mechanical analysis (dynamic mechanical analysis).

For example, the preparation of unbodied Aiweimopan can be by being dissolved in the concentration of medical compounds with about 3mg/mL in the ethanol.Solution can use the nylon filter of 0.2 μ m to filter and rotary evaporation.Perhaps, can also be by Aiweimopan being dissolved in 1,4-dioxane: the tert-butyl alcohol: amorphous solid be produced in lyophilizing subsequently in the solvent mixture of water (1: 1: 1).Can collect solid matter and preferably be placed in the vacuum drying oven that ambient temperature heats under about 100 ℃ of temperature and reach two days, to remove any residual solvent.Can be with solid collection and the storage that obtains.

As another example, the preparation of unbodied Aiweimopan sodium salt can be by with Aiweimopan and the counter ion counterionsl gegenions counter ion counterionsl gegenions with 1: 1 or 2: 1: the ratio of Aiweimopan is dissolved in ethanol or 1,4-dioxane: the tert-butyl alcohol: in the solvent mixture of water (1: 1: 1).Solution can use 0.2 μ m nylon filter filtration and rotary evaporation or lyophilizing.Can collect solid matter and be placed in the vacuum drying oven that heats under the ambient temperature, about 60 ℃, about 100 ℃ of temperature and reach two days, to remove any residual solvent.Can be with solid collection and the storage that obtains.

The solid dispersion of formula I chemical compound can be by conventional method of pharmacy production.For example, the solid dispersion of Aiweimopan and HPMC, mannitol, PVP or PVP/VAc can be prepared as follows: with the medicine of each component with 70: 30: the excipient weight fraction is dissolved in ethanol or 1,4-dioxane: the tert-butyl alcohol: in the solvent mixture of water (1: 1: 1).Solution can use 0.2 μ m nylon filter filtration and rotary evaporation or lyophilizing.Can collect solid matter and preferably be placed in the vacuum drying oven that heats under ambient temperature to the 100 ℃ temperature and reach two days, to remove any residual solvent.Can be with solid collection and the storage that obtains.

The amount of the reactive compound in this compositions with therapeutic use is preferably and makes and will obtain suitable dosage.Preferred compositions of the present invention or preparation can be prepared as and make dosage unit form comprise about 0.1 to about 1000mg reactive compound.

Under common storage and application conditions, these preparations can comprise antiseptic, to prevent growth of microorganism.

Be suitable for most preventing or the dosage of the The compounds of this invention of therapeutic use changes with the specific chemical compound of form of medication, selection and the physiological feature of the particular patient in the treatment.Usually, can adopt low dose at first, if necessary, increase up to producing a desired effect in this case with little increment.Generally speaking, the dosage that parenterai administration need be lower than oral administration.

Combination product of the present invention, for example comprise with peripheral mu opioid substance antagonist chemical compound for example the opioid solid dispersion of formula I chemical compound combination can be any solid dosage forms, example is those dosage forms as described in this article, and can be with variety of way administration described herein.In preferred embodiments, combination product of the present invention is formulated together, is single dosage form (that is to say, be incorporated in the dispersion, or the like).When combination product is not formulated together when the single dosage form, opioid chemical compound and peripheral mu opioid substance antagonist chemical compound can be simultaneously or (be that is to say, together) administration or with any order administration simultaneously.When not being simultaneously or during administration simultaneously, just when the order administration, preferred peripheral mu opioid substance antagonist and opioid dosing interval are lower than about one hour, and preferred interval is lower than about 30 minutes, more preferably be lower than about 15 minutes at interval, and more preferably be lower than about 5 minutes at interval.

Although preferred peripheral mu opioid substance antagonist and opioid administration in an identical manner (that is to say, for example all be oral administration), if but expectation, they can be separately in a different manner administration (that is to say, for example the opioid component of combination product can intravenous administration, and peripheral mu opioid substance antagonist component can oral administration).The dosage of combination product of the present invention can depend on various factors and difference, described factor is pharmacokinetics feature and the administering mode and the approach of for example certain drug, receiver's age, health and body weight, the nature and extent of symptom, and with the treatment type, the frequency of treatment, and desired effects.

Although the suitable dosage of combination product of the present invention can easily be determined after learning of the present invention disclosing by those skilled in the art, but as general guide, for example, with opioid chemical compound and the combination of peripheral mu opioid substance antagonist the time, typically, daily dose can be every kg of patient body weight about 0.01 and arrives about 100 milligrams peripheral mu opioid substance antagonist (with wherein all combinations and the recombinant of scope) to about 100 milligrams of opioids (with wherein all combinations and the recombinant of scope) and about 0.001.Preferably, daily dose can be every kg of patient body weight about 0.1 and arrives about 10 milligrams peripheral mu opioid substance antagonist to about 10 milligrams opioid and about 0.01.More preferably, daily dose can be the about 1.0 milligrams of opioids of every kg of patient body weight and about 0.1 milligram peripheral mu opioid substance antagonist.About the exemplary dosage form of this class combination product, opioid chemical compound (for example, morphine) exists to about 200 milligrams amount with about 15 usually, and the peripheral mu opioid substance antagonist exists to about 4 milligrams amount with about 0.1.

Characterized the chemical compound of the formula I that is used for solid dispersion of the present invention at Opioid Receptors in conjunction with test, it shows with the preferential of [mu and combines.These chemical compounds that studies show that in chorista (Cavia porcellus and mouse vas deferens) can play the effect of antagonist and not have measurable agonist activity.Studies have shown that in animal, with low-down oral dose or parenterai administration the time, chemical compound of the present invention can reverse the constipation of morphine dependency mice, and can not block the analgesic effect of morphine, unless give with Radix Achyranthis Bidentatae or higher dosage.In general, these data show that optionally degree can be very high for the periphery of described chemical compound herein.

Embodiment

Now by the present invention being described with reference to following specific non-limiting example.These embodiment are not intended to and limit the scope of the invention.

Material

Aiweimopan prepares according to following method.Polyvinylpyrrolidone (PVP, mean molecule quantity 1,300,00g/mol), 1-vinylpyrrolidone/vinyl acetate copolymer (PVP/VAc, mean molecule quantity 50,000), HYDROXY PROPYL METHYLCELLULOSE (HPMC, mean molecule quantity 50,000), mannitol, solvent and all other materials are commercially available.PVP/VAc is for comprising the random copolymer of 60: 40 vinyl pyrrolidone of mol ratio and vinyl acetate.

Method

Synthesizing of Aiweimopan

Prepare Aiweimopan according to following synthetic method.

Synthesizing of 1-bromo-3-(1-methyl ethoxy) benzene (chemical compound 1)

Reagent	MW	Amount (kg)	Kilomol	Mol ratio
Reagent	MW	Amount (kg)	Kilomol	Mol ratio	The 3-bromophenol	173.01	80.0	0.4624	1.00
The 2-N-Propyl Bromide	123.0	85.6	0.6959	1.51	The 3-bromophenol	173.01	80.0	0.4624	1.00
The 2-N-Propyl Bromide	123.0	85.6	0.6959	1.51	Potassium carbonate, powder	138.2	96.0	0.6946	1.50
Ethanol 1X ^*	46.07	144	--	--	Potassium carbonate, powder	138.2	96.0	0.6946	1.50
Ethanol 1X ^*	46.07	144	--	--	Water	18.02	739	--	--
31% hydrochloric acid	36.46	6.6	--	--	Water	18.02	739	--	--
31% hydrochloric acid	36.46	6.6	--	--	50% sodium hydroxide w/w	40.0	44.4	--	-
Heptane	100.2	185	--	--	50% sodium hydroxide w/w	40.0	44.4	--	-

^*Ethanol 1X is with 0.5% toluene degeneration.

Add potassium carbonate powder (96.0kg) and ethanol 1X (134kg) to reactor.Conditioned reaction mixture to 20 is ℃ to 25 ℃.

Under agitation, keeping temperature simultaneously to reactor adding 3-bromophenol (80.0kg) is 20 ℃ to 35 ℃.Transfer equipment adds in the reaction with ethanol 1X (5kg) rinsing and with rinsing liquid.Attemperation to 20 is ℃ to 25 ℃.Add 2-N-Propyl Bromide (85.6kg) to reactor.Transfer equipment adds in the reaction with ethanol 1X (5kg) rinsing and with rinsing liquid.Add entry (20L) to reactor.

Solution in the reactor is heated to 60 ℃ to 65 ℃ and kept at least 16 hours in this temperature range.Mixture is cooled to 45 ℃ to 50 ℃ and detect 3-bromophenol in the mixture.When waiting for as a result, mixture is warming to 60 ℃ to 65 ℃.Once more mixture is cooled to 45 ℃ to 50 ℃.

Add entry (303L) to reactor.Make reactant mixture reduce to the concentrated volume of 400L by air-distillation.Spissated mixture is cooled to 20 ℃ to 25 ℃.

Add heptane (185kg) to reactor, under 20 ℃ to 25 ℃ temperature, stirred at least 20 minutes then.

With the biphasic solution layering, the solution washing of organic layer water (45L) and 31% hydrochloric acid (6.6kg).The solution washing of organic layer water (56L) and water (49L) and 50% sodium hydroxide (4.4kg).Organic layer water (56L) washing is last.

Organic solution is carried out drying by azeotropic distillation up to no longer collecting water.By air-distillation reactant mixture is reduced to 150 to 170L concentrated volume then, and be cooled to 20 to 25 ℃.Solution sealed be used for next step.From product (chemical compound 1) sampling of sealing, detect: HPLC purity is not less than 98%a/a and HPLC measures 55%w/w at least.

Cis-(±)-1,3-dimethyl-4-[3-(1-methyl ethoxy) phenyl]-4-piperidines alcohol (chemical compound 2) synthetic

Reagent	MW	Amount (kg)	Kilomol	Mol ratio
Reagent	MW	Amount (kg)	Kilomol	Mol ratio	Chemical compound 1	215.1	27.9	0.07514 ^*	1.21
Magnesium chips	24.3	2.1	0.08642	1.39	Chemical compound 1	215.1	27.9	0.07514 ^*	1.21
Magnesium chips	24.3	2.1	0.08642	1.39	1,3-dimethyl-4-piperidine ketone	127.2	7.9	0.06211	1.00
Oxolane	72.01	162	--	--	1,3-dimethyl-4-piperidine ketone	127.2	7.9	0.06211	1.00
Oxolane	72.01	162	--	--	Ammonium chloride	53.5	6.6	--	--
Water	18.02	56	--	--	Ammonium chloride	53.5	6.6	--	--
Water	18.02	56	--	--	Hyflo supercel		4	--	--
Heptane	100.2	86.5	--	--	Hyflo supercel		4	--	--

^*Each mensuration according to reagent is calculated

Before using with batch of material to its water content of oxolane sample analysis.

Add oxolane (18kg) and under not stirring, be heated to backflow to reactor.Make solvent keep refluxing 1 hour and being cooled to 30 ℃ or lower.Carry out the KF analysis and satisfy specification requirement with the amount that guarantees water in the reactor.THF discharged discard and the reactor drying.

Add magnesium (2.1kg) to reactor, add oxolane (80kg) subsequently.Under agitation, make reactant mixture reduce to 40 to 44L concentrated volume by air-distillation.Concentrate is cooled to 40 ℃ to 45 ℃.

Stir stainless cylinder of steel and add oxolane (18kg) and stirred at least 20 minutes to portable.Carry out the KF analysis and satisfy specification requirement with the amount that guarantees water in the reactor.The THF discharge is discarded.

Add 1-bromo-3-(1-methyl ethoxy) benzene (27.9kg) and oxolane (31kg) to jar.Solution was at room temperature stirred 20 minutes at least.

The 2.5kg of the mixture in the jar is partly transferred in the reactor, since 40 ℃ to 45 ℃ temperature.Under agitation, make mixture keep 40 ℃ to 60 ℃ at least 30 minutes.

Second 2.5kg of the mixture in the jar partly transferred in the reactor, since 40 ℃ to 45 ℃ temperature.Under agitation, make mixture keep 40 ℃ to 60 ℃ at least 30 minutes.

The 5kg of the mixture in the jar is partly transferred in the reactor, since 40 ℃ to 45 ℃ temperature.Under agitation, make mixture keep 40 ℃ to 60 ℃ at least 30 minutes.

Add 1 to jar, 3-dimethyl-4-piperidine ketone (7.9kg) also joins transfer equipment in the reaction with oxolane (5kg) rinsing and with rinsing liquid.

The 15kg part of the mixture in the jar was transferred at least 1 hour in the reactor, since 40 ℃ to 45 ℃ temperature.Under agitation, mixture was kept 15 to 30 minutes at 40 ℃ to 60 ℃.Reactant mixture is cooled to 40 ℃ to 45 ℃.

Second 15kg part of the mixture in the jar transferred at least 1 hour in the reactor, since 40 ℃ to 45 ℃ temperature.Under agitation, mixture was kept 15 to 30 minutes at 40 ℃ to 60 ℃.Reactant mixture is cooled to 40 ℃ to 45 ℃.

The 3rd 15kg part of the mixture in the jar transferred in the reactor since 40 to 45 ℃ temperature at least 1 hour.Under agitation, mixture was kept 15 to 30 minutes at 40 ℃ to 60 ℃.Reactant mixture is cooled to 40 ℃ to 45 ℃.

The remainder of the mixture in the jar was transferred at least 1 hour in the reactor, since 40 ℃ to 45 ℃ temperature.Transfer equipment joins in the reaction with THF (5kg) rinsing and with rinsing liquid.Under agitation, mixture was kept 15 to 30 minutes at 40 ℃ to 60 ℃.Reactant mixture is cooled to 40 ℃ to 45 ℃.

After reaction is finished, mixture is cooled to 20 ℃ to 25 ℃.

Add entry (40L) and ammonium chloride (6.6kg) to second reactor.Under the stirring of appropriateness, make mixture 20 ℃ to 25 ℃ maintenances at least 20 minutes.

In case the solid dissolving adds Hyflo supercel (4kg) to second reactor.Aqueous mixture is cooled to 0 ℃ to 5 ℃.

Under agitation, the organic mixture in first reactor is transferred in second reactor.Transfer equipment joins in the reaction with oxolane (5kg) rinsing and with rinsing liquid.Make mixture rise again 20 ℃ to 25 ℃ and kept at least 15 minutes.

Mixture is filled in first reactor, with the heptane rinsing (2 * 6kg) and with rinsing liquid go into to the reaction in, 20 ℃ to 25 ℃ maintenances at least 20 minutes.

With the biphasic solution layering, organic facies water (16L) washing.By air-distillation organic solution is reduced to 30 to 34L concentrated volume, and be cooled to 45 ℃ to 50 ℃.

In reactor, add heptane (54kg) and solution is reduced to 69 to the concentrated volume of 73L by air-distillation.Solution is cooled to 30 ℃ to 35 ℃.With oxolane residual in the measured reaction mixture and water content.Reaction is carried out crystallization with the product crystal as crystal seed and mixture is cooled to 0 ℃ to 5 ℃ and kept 3 hours at least 1 hour.

By the isolated by filtration solid product, with (2 * 10kg) washings and dry of cold heptane.Product sampling is dry and seal.From product (chemical compound 2) sampling of sealing, will survey: HPLC purity is not less than 97%a/a and opened before being used for next step.

Cis-(±)-1,3-dimethyl-4-[3-(1-methyl ethoxy) phenyl]-purification of 4-piperidines alcohol (chemical compound 2)

Reagent	MW	Amount (kg)	Kilomol	Mol ratio
Reagent	MW	Amount (kg)	Kilomol	Mol ratio	Chemical compound 2	263.4	96.1	0.3648	1.00
Heptane	100.2	590	--	--	Chemical compound 2	263.4	96.1	0.3648	1.00

Add chemical compound 2 (96.1kg) and heptane (328L) to reactor.With mixture heated to 55 to 60 ℃ and kept at least 1 hour.Detect mixture to guarantee all solids dissolving.

In at least 1 hour, solution is cooled to 30 to 35 ℃ and kept at least 1 hour.Detecting mixture precipitates with assurance.In at least 2 hours, mixture is cooled to 0 ℃ to 5 ℃ and kept at least 4 hours.

By the solid chemical compound 2 of isolated by filtration purification, with (2 * 131kg) washings and dry of cold heptane.Product sampling is dry and seal.From the sampling of the product sealed, detect HPLC purity: be not less than 97%a/a and before being used for next step, open.

The carbonic acid ethyl ester (3S, 4R)-1,3-dimethyl-4-[3-(1-methyl ethoxy) phenyl]-4-piperidyl ester compounds and (+)-D-2, two [(4-methyl benzoyl) oxygen base] succinic acid (1: 1) (chemical compound 3) of 3-synthetic

Reagent	MW	Amount (kg)	Kilomol	Mol ratio
Reagent	MW	Amount (kg)	Kilomol	Mol ratio	Chemical compound 2	263.4	10.8	0.04100	1.00
Ethyl chloroformate	108.52	5.6	0.05160	1.26	Chemical compound 2	263.4	10.8	0.04100	1.00
Ethyl chloroformate	108.52	5.6	0.05160	1.26	Triethylamine, anhydrous	101.19	0.4	0.003953	0.10
(+)DTTA	386.36	15.8	0.04089	1.00	Triethylamine, anhydrous	101.19	0.4	0.003953	0.10
(+)DTTA	386.36	15.8	0.04089	1.00	Sodium hydroxide, 50%w/w	40.0	47.6	--	--
Ethyl acetate	88.11	52	--	--	Sodium hydroxide, 50%w/w	40.0	47.6	--	--
Ethyl acetate	88.11	52	--	--	Ethanol 1X	46.07	285	--	--

Add chemical compound 2 (10.8kg) and ethyl acetate (48kg) to reactor.Mixture 20 ℃ to 25 ℃ maintenances 30 minutes, is dissolved up to all solids at least.Solution is cooled to 0 ℃ to 5 ℃.

Join in the reaction with ethyl acetate (1kg) rinsing and with rinsing liquid to reactor adding triethylamine (0.4kg) and with transfer equipment.

Add ethyl chloroformate (5.6kg) to reactor, keep 0 ℃ to 15 ℃ temperature simultaneously.Transfer equipment joins in the reaction with ethyl acetate (3kg) rinsing and with rinsing liquid.With mixture 20 ℃ to 25 ℃ maintenances at least 3 hours.

Add sodium hydroxide 50% (7.6kg) to reactor, keep 0 ℃ to 38 ℃ temperature simultaneously.(17L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.With the pH of solution, to guarantee that pH is greater than 10 at 20 ℃ to 25 ℃ maintenances at least 20 minutes and inspection solution.

With the biphasic solution layering, organic facies water (22L) washed twice.Organic solution reduces to 20 to 24L concentrated volume then by azeotropic distillation drying by air-distillation.Solution is cooled to 40 ℃ to 50 ℃.

Add ethanol 1X (60kg) to reactor.By air-distillation solution is reduced to 30 to 34L concentrated volume, and be cooled to 55 ℃ to 60 ℃.

Make to add in the reactor of lining (+)-two toluoyl base-D-tartaric acid (15.8kg) and ethanol 1X (51kg) to glass.Attemperation to 60 is ℃ to 65 ℃ under the stirring of appropriateness.

Reactant mixture is transferred in the acid solution, kept 60 ℃ to 70 ℃ temperature simultaneously.Transfer equipment joins in the reaction with ethanol 1X (17kg) rinsing and with rinsing liquid.Solution was kept 1 to 1.5 hour at 60 ℃ to 65 ℃.Suspension is cooled to 50 ℃ to 55 ℃ and kept 2 to 2.5 hours.In at least 3 hours, suspension is cooled to 20 ℃ to 35 ℃ and kept at least 10 hours.

By the isolated by filtration solid,, dry and seal with ethanol 1X (17kg) washing.Chiral purity from sampling of the crude product sealed and detection compound 3.

Add crude product and ethanol 1X (based on each calculating) to reactor.Mixture is adjusted to 60 ℃ to 65 ℃ and kept 2 to 2.5 hours.In at least 2 hours, suspension is cooled to 20 ℃ to 25 ℃.Suspension is cooled to 0 ℃ to 5 ℃ and kept at least 3 hours.

By isolated by filtration solid chemical compound 3,, dry and seal with cold ethanol 1X (17kg) washing.From the product sampling of sealing, check, HPLC purity is not less than 99.0%a/a; Chirality HPLC is not less than 99.5% and opened before being used for next step.

(3R, 4R)-3-(3,4-dimethyl-4-piperidine base) phenol (chemical compound 4) synthetic

Reagent	MW	Amount (kg)	Kilomol	Mol ratio
Reagent	MW	Amount (kg)	Kilomol	Mol ratio	Chemical compound 3	647.8	18.3	0.02825	1.00.
Toluene	92.14	50	--	--	Chemical compound 3	647.8	18.3	0.02825	1.00.
Toluene	92.14	50	--	--	Water	18.02	434	--	--
Sodium hydroxide, 50%w/w	40.0	110.7	--	--	Water	18.02	434	--	--
Sodium hydroxide, 50%w/w	40.0	110.7	--	--	Phenyl chloroformate	156.57	5.3	0.03385	1.20
31% hydrochloric acid	36.46	2.8	--	--	Phenyl chloroformate	156.57	5.3	0.03385	1.20
31% hydrochloric acid	36.46	2.8	--	--	Glacial acetic acid	60.05	17.6	0.2931	10.38
Hydrobromic acid	80.92	19	0.1127	4.00	Glacial acetic acid	60.05	17.6	0.2931	10.38
Hydrobromic acid	80.92	19	0.1127	4.00	T-butyl methyl ether	88.15	56	--	--
Methanol	32.04	8.7	--	--	T-butyl methyl ether	88.15	56	--	--

Add chemical compound 3 (18.3kg), toluene (48kg) and water (32L) to reactor.Mixture is adjusted to 20 ℃ to 25 ℃.

Add 50% sodium hydroxide (9.2kg) to reactor, keep 20 ℃ to 30 ℃ temperature simultaneously.(4L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.Under agitation, mixture is cooled to 20 ℃ to 25 ℃ and kept 1 hour.The pH that checks water layer is to guarantee that it is greater than 12.

With the biphasic solution layering, the solution washing of organic layer water (14L) and 50% sodium hydroxide (0.7kg).Organic layer water (15L) washed twice and pass through azeotropic distillation drying.Solution is cooled to 80 ℃ to 85 ℃.

In at least 1.5 hours, add phenyl chloroformate (5.3kg) and keep 80 ℃ to 85 ℃ temperature simultaneously to reactor.Transfer equipment joins in the reaction with toluene (2kg) rinsing and with rinsing liquid.Solution is heated to refluxes and kept at least 3 hours, be cooled to 50 ℃ to 55 ℃ then.When waiting for the result, keep mixture to reflux.

Mixture is cooled to 20 ℃ to 25 ℃ and water (14L) joined in the reactor.In at least 1 hour 50% sodium hydroxide (2.3kg) is joined in the reactor, keeping temperature simultaneously is 20 ℃ to 30 ℃.(4L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.With solution remain on 20 ℃ to 25 ℃ at least 1 hour.

With the biphasic solution layering, and with the solution washing of organic layer water (15L) and 31% hydrochloric acid (1.9kg).By air-distillation organic solution is reduced to 23 to 26L concentrated volume, and be cooled to 65 ℃ to 70 ℃.

Water (7L) and acetic acid (13.6kg) are joined in the reactor.(2L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.By air-distillation organic solution is reduced to 26 to 29L concentrated volume, and be cooled to 50 ℃ to 60 ℃.

(19kg) joins in the reactor with hydrobromic acid, adds acetic acid (4kg) subsequently.Solution is heated to refluxes and kept at least 18 hours.Solution is cooled to 55 ℃ to 60 ℃.Solution is cooled to 10 ℃ to 15 ℃.

In at least 1 hour 50% sodium hydroxide (6kg) is joined in the reactor, keeping temperature simultaneously is 10 ℃ to 30 ℃.(5L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.Attemperation to 20 ℃ is to 25 ℃ and check that pH is to guarantee that it is less than 1.7.

Adding t-butyl methyl ether (16kg) in reactor, to keep temperature simultaneously be 20 ℃ to 25 ℃.Water (27L) joined in the reactor and with solution remain on 20 ℃ to 25 ℃ at least 30 minutes.

Separate biphasic solution and aqueous solution is transferred in the reactor.Organic solution is transferred in the 200L glass container.Aqueous solution t-butyl methyl ether (16kg) washed twice.

Organic layer is transferred to the reactor from glass container.(5L) joins in the reactor with water, and adding 31% hydrochloric acid (0.9kg) subsequently, to keep temperature simultaneously be 20 ℃ to 25 ℃.(2L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.Biphasic solution was 20 ℃ to 25 ℃ maintenances at least 20 minutes.

With the biphasic solution layering, aqueous solution t-butyl methyl ether (4kg) washed twice.

The acid solution of new polyethylene bucket is transferred in the 200L reactor.(2L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.

In at least 30 minutes methanol (8.7kg) is joined reactor, keeping temperature simultaneously is 20 ℃ to 25 ℃.

To portable stainless cylinder of steel adding water (41L) and 50% sodium hydroxide (12.5kg) of stirring.(4L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.Solution is transferred in the reactor pH to reach 10.0 to 10.5, and keeping temperature simultaneously is 20 ℃ to 35 ℃.

Suspension is cooled to 0 ℃ to 5 ℃ and kept at least 4 hours.

By isolated by filtration chemical compound 4,, dry and seal with cold water (2 * 9) washing.From the product sampling of sealing, check HPLC purity is not less than 98.5%a/a; Chiral purity is not less than 99.0%; Analyze with HPLC, be not less than 95%w/w and before being used for next step, open.

(α S, 3R, 4R)-4-(3-hydroxy phenyl)-3,4-dimethyl-α-(phenyl methyl)-1-piperidines methyl propionate hydrochlorate (chemical compound 6) synthetic

Reagent	MW	Amount (kg)	Kilomol	Mol ratio
Reagent	MW	Amount (kg)	Kilomol	Mol ratio	Chemical compound 4	205.3	19.2	0.09352	1.00
Acrylic acid methyl ester.	86.09	8.5	0.09875	1.05	Chemical compound 4	205.3	19.2	0.09352	1.00
Acrylic acid methyl ester.	86.09	8.5	0.09875	1.05	Oxolane	72.11	692	--	--
N-BuLi	64.06	87.4	0.2056	2.20	Oxolane	72.11	692	--	--
N-BuLi	64.06	87.4	0.2056	2.20	Diisopropylamine	101.19	21.8	0.2154	2.30
Benzyl bromide a-bromotoluene	171.04	32.0	0.1871	2.00	Diisopropylamine	101.19	21.8	0.2154	2.30
Benzyl bromide a-bromotoluene	171.04	32.0	0.1871	2.00	Heptane	100.21	209	--	--
Methanol	32.04	659	--	--	Heptane	100.21	209	--	--
Methanol	32.04	659	--	--	31% hydrochloric acid	36.46	36.2	0.3078	3.29
50% sodium hydroxide w/w	40.0	4.9	0.06125	0.65	31% hydrochloric acid	36.46	36.2	0.3078	3.29
50% sodium hydroxide w/w	40.0	4.9	0.06125	0.65	Hydrogen chloride gas	36.46	14.4	0.3950	4.23
Hyflo supercel	--	1.9	--	--	Hydrogen chloride gas	36.46	14.4	0.3950	4.23
Hyflo supercel	--	1.9	--	--	Water	18.02	566	--	--

Add chemical compound 4 (19.2kg) and oxolane (222kg) to reactor.50% stir under with mixture heated to 40 ℃ to 45 ℃.

In at least 30 minutes acrylic acid methyl ester. (8.5kg) is joined reactor, keeping temperature simultaneously is 40 ℃ to 45 ℃.Transfer equipment joins in the reaction with THF (17kg) rinsing and with rinsing liquid.Reactant mixture was kept 18 to 19 hours at 40 ℃ to 45 ℃.Reactant mixture is cooled to 20 ℃ to 25 ℃.

To portable stainless cylinder of steel adding hyflo supercel (1.9kg) and the heptane (13kg) of stirring.Mixture was stirred 5 minutes at least.Mixture is transferred to reactor also to join in the reaction with heptane (5kg) rinsing and with rinsing liquid.With mixture 20 ℃ to 25 ℃ maintenances at least 20 minutes.

Mixture is filled in the reactor so that clarificationization joins in the reaction with heptane (26kg) rinsing and with rinsing liquid, is cooled to-5 ℃ to 0 ℃.By vacuum distilling solution is reduced to 29 to 48L concentrated volume, obtain the solution of chemical compound 5.

Under 30 ℃ or lower temperature, heptane (26kg) is joined reactor.Solution is cooled to-5 ℃ to 0 ℃ and reduce to 29 to the concentrated volume of 48L by vacuum distilling.

(333kg) joins in the reactor with oxolane, adds diisopropylamine (21.8kg) subsequently.Transfer equipment joins in the reaction with oxolane (12kg) rinsing and with rinsing liquid.Solution is cooled to-15 to-10 ℃.

Added the heptane (87.4kg) that contains n-BuLi to reactor at least 1 hour, keeping temperature simultaneously is-15 ℃ to-5 ℃.(2 * 5kg) rinsings also join rinsing liquid in the reaction transfer equipment with THF.Solution was kept 1 to 3 hour at-10 ℃ to-5 ℃, be cooled to-25 ℃ to-20 ℃ then.

Acrylate solution in the reactor is transferred in this reactor, and keeping temperature simultaneously is-25 to-15 ℃.Transfer equipment joins in the reaction with THF (8kg) rinsing and with rinsing liquid.Suspension was kept 30 to 60 minutes at-25 to-20 ℃.

In at least two hours benzyl bromide a-bromotoluene (32.0kg) is joined in the reactor, keeping temperature simultaneously is-25 to-20 ℃.Transfer equipment joins in the reaction with THF (8kg) rinsing and with rinsing liquid.Mixture remain on-25 to-20 ℃ at least 16 hours.

Add entry (61L) and 31% hydrochloric acid (18.1kg) to portable storage tank, stir at least two minutes then to form solution.Add entry (61L) and 31% hydrochloric acid (18.1kg) to second portable storage tank, stir at least two minutes then to form solution.In at least two hours two kinds of acid solutions are all transferred in the reactor, keeping temperature simultaneously is-25 to-15 ℃.In at least 3 hours, solution is warming to 20 to 25 ℃.

Add entry (29L) and 50% sodium hydroxide (4.9kg) to portable storage tank.(15L) rinsing of transfer equipment water also joins rinsing liquid in the reaction, and mixture is stirred at least 2 minutes to form solution.

(29kg) transfers to reactor with alkaline solution, and keeping temperature simultaneously is 20 to 25 ℃, up to the pH that obtains 9.0 to 9.5.Transfer in the 600L reactor with the biphasic solution layering and with aqueous solution.

Aqueous solution washs with heptane (26kg).The organic solution that obtains is transferred to the 1500L reactor and transfer equipment is joined in the reaction with heptane (17kg) rinsing and with rinsing liquid.Solution is cooled to-30 to-20 ℃.

Add methanol (113kg) and be cooled to-30 to-20 ℃ to reactor.Add hydrogen chloride gas (14.4kg) in reactor, keeping temperature simultaneously is-30 to-10 ℃.

Acid solution is joined in the above-mentioned reactor, and keeping temperature simultaneously is-30 to-5 ℃.Transfer equipment joins in the reaction with methanol (19kg) rinsing and with rinsing liquid.Solution temperature is adjusted to-10 to-5 ℃.Make solution reduce to 168 to 216L concentrated volume by vacuum distilling.

Solution is transferred to the 600L reactor also to join in the reaction with methanol (48kg) rinsing and with rinsing liquid.Solution is cooled to-10 to-5 ℃ and reduce to 48 to the concentrated volume of 68L by vacuum distilling.

Join methanol (77kg) in the 1500L reactor and be rinsed in the reactor.Then solution is cooled to-10 to-5 ℃ and reduce to 48 to the concentrated volume of 68L by vacuum distilling.

Under 30 ℃ or lower temperature, methanol (106kg) is joined in the reactor, be heated to 40 to 45 ℃ then.Solution was kept 1 to 2 hour at 40 to 45 ℃.In at least 3 hours, solution is cooled to 20 to 25 ℃ and in this temperature range, kept at least 1 hour.In at least 1 hour, solution is cooled to 2 to 7 ℃ and in this temperature range, kept at least 1 hour.

By isolated by filtration crude product chemical compound 6, with cold methanol (2 * 15kg) washings, and check purity.Keep filtrate and be used for further processing.

Add wet cake and methanol (60kg) to reactor.Mixture heated was refluxed 1 to 2 hour to backflow and maintenance.In at least 4 hours, solution is cooled to 2 to 7 ℃ and in this temperature range keeps at least 1 hour.

By the isolated by filtration crude product, with cold methanol (2 * 15kg) washings, and check purity.Keep filtrate and be used for further processing.

Add wet cake and methanol (60kg) to reactor.Mixture heated was refluxed 1 hour to backflow and maintenance at least.In at least 4 hours, solution is cooled to 2 to 7 ℃ and in this temperature range keeps at least 1 hour.

By the isolated by filtration crude product, with cold methanol (2 * 15kg) washings, and check purity and chirality HPLC.

By isolated by filtration product chemical compound 6, with cold methanol (2 * 15kg) washings, sample analysis HPLC purity, chirality HPLC and isomer, and seal.From the sampling of the product sealed, detect HPLC purity＞99.0%a/a and chirality HPLC, 3.0% and before being used for next step, open.

(α S, 3R, 4R)-4-(3-hydroxy phenyl)-3,4-dimethyl-α-(phenyl methyl)-1-piperidines propanoic acid monohydrate (chemical compound 7) synthetic

Chemical compound 6 chemical compounds 7

Reagent	MW	Amount (kg)	Kilomol	Mol ratio
Reagent	MW	Amount (kg)	Kilomol	Mol ratio	Chemical compound 6	417.97	9.9	0.02369	1.00
Methanol	32.04	107	--	--	Chemical compound 6	417.97	9.9	0.02369	1.00
Methanol	32.04	107	--	--	31% hydrochloric acid	36.46	9.4	0.07992	3.37
50% sodium hydroxide w/w	40.0	7.9	0.09875	4.16	31% hydrochloric acid	36.46	9.4	0.07992	3.37
50% sodium hydroxide w/w	40.0	7.9	0.09875	4.16	Water	18.02	～244	--	--

Add chemical compound 6 (9.9kg) and water (74L) to reactor.Mixture is adjusted to 20 to 25 ℃.

In at least 10 minutes, 50% sodium hydroxide (7.9kg) is joined in the reactor.(10L) rinsing of transfer equipment water also joins rinsing liquid in the reaction.The pH that checks mixture is to guarantee that pH is greater than 12.

Solution remained under 20 to 25 ℃ the temperature and stirred at least 4 hours.Then reactant mixture is filled in the reactor so that clarificationization.Product joins in the reaction with (8L) rinsing and with rinsing liquid.

Methanol (84kg) is joined reactor and be adjusted to 20 to 25 ℃.

31% hydrochloric acid (6.9kg) is joined in the reactor up to the pH that reaches 9.0 to 10.0 in batches.

In new PE bucket, add entry (7.6L) and 31% hydrochloric acid (2.5kg).(4.0L) rinsing of transfer equipment water also joins rinsing liquid in the reaction, with solution stirring at least 2 minutes so that mix.

In beaker, add methanol (0.4kg), water (0.5L) and chemical compound 7 (100g).Mixture joined in the reactor and the solution rinsing of water (0.3L) and methanol (0.2kg) and rinsing liquid joined in the reaction so that be reactant mixture introducing crystal seed.

With the pH of the acid solution for preparing (10.4kg) adjustment reactant mixture, up to the pH that obtains 5.8 to 6.2.With mixture remain on 20 to 25 ℃ at least 1 hour and the check, to guarantee to take place crystallization.Suspension is cooled to 0 to 5 ℃ and reduce to 107 to the concentrated volume of 124L by vacuum distilling.Suspension is adjusted to 20 to 25 ℃ and inspection pH, is 5.8 to 6.2 to guarantee it.

Suspension is cooled to 2 to 7 ℃ and stirred at least 4 hours.

By the isolated by filtration product, with cold water (2 * 30) washing, drying, sample analysis water content and sealing.Product sampling from sealing detects: HPLC purity, 98.%a/a; Chirality HPLC, 98%; Analyze 98.0%w/w with HPLC and before being used for next step, open.

Synthesizing of [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidino] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid dihydrate (Aiweimopan)

Reagent	MW	Amount (kg)	Kilomol	Mol ratio
Reagent	MW	Amount (kg)	Kilomol	Mol ratio	Chemical compound 7	385.5	7.9	2.02049	1.00
Glycine ethyl ester hydrochloride	139.58	3.1	0.02254	1.10	Chemical compound 7	385.5	7.9	2.02049	1.00
Glycine ethyl ester hydrochloride	139.58	3.1	0.02254	1.10	The I-hydroxybenzotriazole hydrate	135.13	3.5	0.02562	1.25
Triethylamine	101.2	2.3	0.02254	1.10	The I-hydroxybenzotriazole hydrate	135.13	3.5	0.02562	1.25
Triethylamine	101.2	2.3	0.02254	1.10	1, the 3-dicyclohexylcarbodiimide	206.33	4.7	0.02254	1.10
Oxolane	72.11	156	--	--	1, the 3-dicyclohexylcarbodiimide	206.33	4.7	0.02254	1.10
Oxolane	72.11	156	--	--	Ethyl acetate	88.11	858	--	--
Soda (sodium carbonate)	105.99	4.8	--	--	Ethyl acetate	88.11	858	--	--
Soda (sodium carbonate)	105.99	4.8	--	--	Sodium bicarbonate	84.00	3.1	--	--
Saline		112	--	--	Sodium bicarbonate	84.00	3.1	--	--
Saline		112	--	--	Ethanol 1X	46.07	743	--	--
Pure water	18.02	1196	--	--	Ethanol 1X	46.07	743	--	--
Pure water	18.02	1196	--	--	50% sodium hydroxide w/w	40.0	16.8	--	--
31% hydrochloric acid	36.46	30.0	--	--	50% sodium hydroxide w/w	40.0	16.8	--	--

Add oxolane (15kg) and 1,3-dicyclohexylcarbodiimide (4.7kg) to the portable stainless cylinder of steel (PAST) that stirs.Transfer equipment joins in the reaction with THF (16kg) rinsing and with rinsing liquid.

Reactor adds chemical compound 7 (7.9kg), glycine ethyl ester hydrochloride (3.1kg), I-hydroxybenzotriazole hydrate (3.5kg), oxolane (99kg) and pure water (3.3kg).Under 60% stirring, mixture is adjusted to 20 to 25 ℃.

(2.3kg) joins reactor with triethylamine.Transfer equipment joins in the reaction with oxolane (3kg) rinsing and with rinsing liquid.Solution was kept 20 to 60 minutes at 20 to 25 ℃.

With 1,3-dicyclohexylcarbodiimide solution is transferred to reactor, and keeping temperature simultaneously is 20 to 25 ℃.Transfer equipment joins in the reaction with oxolane (23kg) rinsing and with rinsing liquid.

Under 100% stirring, reactant mixture was kept 36 to 38 hours at 20 to 25 ℃.

Reactant mixture is cooled to 0 to 5 ℃.Mixture was kept in this temperature range 1 to 2 hour, be filled into then in another reactor.Reactant mixture joins in the reaction with ethyl acetate (20kg) rinsing and with rinsing liquid.Mixture is cooled to 0 to 5 ℃ and reduce to 140 to the concentrated volume of 149L by vacuum distilling.

Ethyl acetate (731kg) is joined reactor and be cooled to 0 to 5 ℃.Make solution reduce to 140 to 149L concentrated volume by vacuum distilling.The remaining oxolane of test mixture.

Stir stainless cylinder of steel and add pure water (94kg), soda (4.8kg) and sodium bicarbonate (3.1kg) to portable.Mixture was stirred 2 minutes at least, dissolve up to solid.

Join alkaline solution in the reactor and attemperation to 20 to 25 ℃.Keep stirring 20 to 60 minutes with 60%.The pH that checks solution to be guaranteeing that pH is 9.5 to 10, and regulates as required.Separate biphasic solution and use saline (112kg) to wash organic solution.

Add ethyl acetate (87kg) and be cooled to 0 to 5 ℃ to reactor.By vacuum distilling solution is reduced to 140 to 149L concentrated volume and is cooled to-25 to-20 ℃.Kept this temperature 10 to 11 hours.

Suspension filtered in reactor, is joined in the reaction with ethyl acetate (20kg) rinsing and with rinsing liquid, and be warming to 0 to 5 ℃.Make filtrate reduce to 39 to 51L concentrated volume by vacuum distilling.

Join ethanol 1X (199kg) in the reactor and be cooled to 0 to 5 ℃.Make solution reduce to 136 to 161L concentrated volume by vacuum distilling.The remaining ethyl acetate that adds ethanol 1X (93kg) and test mixture to reactor.

Add pure water (83kg) and 50% sodium hydroxide (5.6kg) to portable storage tank.Transfer equipment joins in the reaction with pure water (19kg) rinsing and with rinsing liquid.Mixture is stirred at least 2 minutes to form solution.Alkaline solution is transferred to reactor and kept 1.5 to 3.5 hours at 20 to 25 ℃.With suspension filtered to reactor and attemperation to 20 to 25 ℃.With 600L reactor pure water (13kg) rinsing and adding.

Add pure water (15kg) and 50% sodium hydroxide (11.2kg) to portable storage tank.Transfer equipment joins in the reaction with pure water (5kg) rinsing and with rinsing liquid.Mixture is stirred at least 2 minutes to form solution.Acid solution is joined in the reactor in batches, up to the pH that reaches 5.8 to 6.2.

By the isolated by filtration crude product, with pure water (2 * 26kg) washings, with ethanol 1X (13kg) washing, dry and seal.

With pure water (according to calculating) crude product is joined in the reactor.

Add pure water (1.9kg) and 50% sodium hydroxide (5.3kg) to new PE bucket.Transfer equipment joins in the reaction with pure water (1.0kg) rinsing and with rinsing liquid.Mixture is stirred at least 2 minutes to form solution.

Use alkaline solution (7.5kg) with the pH regulator of reactant mixture to minimum be 13.Mixture was kept 20 to 60 minutes at 20 to 25 ℃.

Mixture is filled in the reactor so that clarificationization.Reactor is washed with pure water (10kg) and adding ethanol IX (according to calculating).

Add pure water (14kg) and 31% hydrochloric acid (9.6kg) to portable storage tank.Transfer equipment joins in the reaction with pure water (4kg) rinsing and with rinsing liquid.Mixture is stirred at least 2 minutes to form solution.Acid solution is joined in the reactor in batches, up to the pH that obtains 4.0 to 4.5.

Add pure water (1.9kg) and 50% sodium hydroxide (0.3kg) to new PE bucket.Transfer equipment joins in the reaction with pure water (1.0kg) rinsing and with rinsing liquid.Mixture stirs at least 2 minutes to form solution.Alkaline solution is joined in the reactor in batches, up to the pH that obtains 5.8 to 6.2.

Solid existence in the test mixture, and with suspension 20 to 25 ℃ of maintenances at least 12 hours.

By the isolated by filtration product, at first use pure water (according to calculating) washing, use ethanol 1X (according to calculating) washing then, and use pure water (according to calculating) washing once more.With filtration cakes torrefaction and seal.

Add pure water (1.9kg) and 50% sodium hydroxide (5.3kg) to new PE bucket.Transfer equipment joins in the reaction with pure water (1.0kg) rinsing and with rinsing liquid.Mixture is stirred at least 2 minutes to form solution.Alkaline solution is joined in the reactor in batches, up to pH 13.

Mixture was stirred 20 to 60 minutes at 20 to 25 ℃.Mixture is filled in another reactor so that clarificationization.Reactor adds with pure water (10kg) rinsing and with rinsing liquid.Add ethanol 1X (according to calculating) to reactor.

Add pure water (13.5kg) and hydrochloric acid, 31% (9.2kg) to portable storage tank.Transfer equipment joins in the reaction with pure water (3.9kg) rinsing and with rinsing liquid.Mixture is stirred at least 2 minutes to form solution.Acid solution is joined in the reactor in batches, up to the pH that obtains 4.0 to 4.5.

Add pure water (1.9kg) and 50% sodium hydroxide (0.3kg) to new PE bucket.Transfer equipment joins in the reaction with pure water (1.0kg) rinsing and with rinsing liquid.Mixture is stirred at least 2 minutes to form solution.Alkaline solution is joined in the reactor in batches, up to the pH that obtains 5.8 to 6.2.

By the isolated by filtration product, at first use pure water (according to calculating) washing, use ethanol 1X (according to calculating) washing then, and use pure water (according to calculating) washing once more.With filter cake sample analysis chloride, dry and seal.

Add over-drying product and pure water (2.0kg) to exsiccator, with nitrogen purging and place at room temperature, up to the specified hydration level of realization.

Hydrated product is sealed and joined in the 50L product agitator then.Product was mixed 20 to 30 minutes and the sampling drying.Make product mix other 20 to 30 minutes and resampling.

Then Aiweimopan is sealed, sampling, check: HPLC purity is not less than 99.2%w/w; Chirality HPLC is not less than 99.0%; HPLC analyzes 98.0 to 102.0%w/w; And residual solvent, be not higher than 1.2%w/w altogether and open.

The crystallization technique of preparation amorphous solid

A. lyophilizing

1,4-dioxane: the tert-butyl alcohol: prepare solution in the solvent mixture of water (1: 1: 1) or the water.Solution is stirred under environmental condition, to dissolve described material.In case the dissolving of all solids is filtered solution by 0.2 μ m nylon filter in round-bottomed flask.Be immersed in the liquid nitrogen flask and whirlpool, so that solution is chilled on the flask sidewall.Sample is placed in the freeze dryer that is cooled to-50 ℃ of pacts under the vacuum.In case all solvent evaporations are taken out sample from freeze dryer.

B. rotary evaporation

At ethanol, ethanol: water or 1,4-dioxane: prepare solution in the mixture of water.Solution is carried out sonication to help dissolving.In case the medical compounds dissolving is filtered solution by 0.2 μ m nylon filter in round-bottomed flask.Flask is placed on the rotary evaporator, and be immersed in and be set in about 30 ℃ temperature bath.Solvent is promptly evaporated, and collect the solid that produces.

Prepare unbodied [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid

Be prepared as follows unbodied [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: the concentration of medical compounds with about 3mg/mL is dissolved in the ethanol.Use 0.2 μ m nylon filter that solution is filtered and rotary evaporation.Also by Aiweimopan being dissolved in 1,4-dioxane: the tert-butyl alcohol: lyophilizing subsequently produces amorphous solid in the solvent mixture of water (1: 1: 1).Collect solid matter and be placed at ambient temperature, 60 ℃ or 100 ℃ reach two days in the vacuum drying ovens of heating down, to remove any residual solvent.The solid that collection obtains and before analyzing, being stored in the exsiccator.

Be prepared as follows unbodied [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt: Aiweimopan and counter ion counterionsl gegenions are dissolved in ethanol or 1,4-dioxane: butanols: in the solvent mixture of water (1: 1: 1), counter ion counterionsl gegenions: the ratio of [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid is 1: 1 or 2: 1.Use 0.2 μ m nylon filter with solution filtration and rotary evaporation or lyophilizing.Collect solid matter and be placed at ambient temperature, 60 ℃ or 100 ℃ reach two days in the vacuum drying ovens of heating down, to remove any residual solvent.The solid that collection obtains and before analyzing, being stored in the exsiccator.

The solid dispersion of preparation [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid

Be prepared as follows [[2 (, S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] solid dispersion of acetic acid and HPMC, mannitol, PVP or PVP/VAc: with each components dissolved in ethanol or 1,4-dioxane: the tert-butyl alcohol: in the solvent mixture of water (1: 1: 1), medicine: the weight fraction of excipient is 70: 30.Use 0.2 μ m nylon filter with solution filtration and rotary evaporation or lyophilizing.Collect solid matter and be placed at ambient temperature, 60 ℃ or 100 ℃ reach two days in the vacuum drying ovens of heating down, to remove any residual solvent.The solid that collection obtains and before analyzing, being stored in the exsiccator.

Also with 70: 30 medicine: the excipient weight fraction prepares the solid dispersion of unbodied [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt and above-mentioned excipient.Preparation comprises mannitol: the mol ratio of [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid is some samples of 0.125: 1,0.25: 1 and 0.5: 1.Solid is dissolved in comprises counter ion counterionsl gegenions: [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] mol ratio of acetic acid is 1 of 1: 1 or 2: 1,4-dioxane: butanols: in the solvent mixture of water (1: 1: 1).Use 0.2 μ m nylon filter that solution is filtered and lyophilizing.Collect solid matter and be placed at ambient temperature, 60 ℃ or 100 ℃ reach two days in the vacuum drying ovens of heating down, to remove any residual solvent.The solid that collection obtains and before analyzing, being stored in the exsiccator.

Relative humidity stress be studied

In ambient temperature (about 10 ℃ to about 30 ℃) amorphous samples is exposed under ambient humidity, 53% and 97% the relative humidity.Sample is exposed under 75% relative humidity at 40 ℃.Make sample under stress state, keep reaching 60 days.In research process, regularly obtain sample and the existence by X-ray powder diffraction (XRPD) analyzing crystal (crystallinity).

Instrument

Differential scanning calorimetry

Use TA instrument differential scanning calorimetry (DSC) 2920 to carry out differential scanning calorimetry (DSC).Sample is placed DSC aluminum dish, and accurately write down weight.To coil and cover, and curl then or do not curl with lid.With sample cell 25 ℃ of balances and under nitrogen purging with the final temperature of 10 ℃/minute speed heating up to 350 ℃.Indium metal is used as calibration criterion.

For the glass transition temperature (Tg) of studying amorphous substance, 25 ℃ of balances, the speed with 20 ℃/minute heats up to 130 ℃ under nitrogen then with sample cell.Make sample cell cooling and 30 ℃ of balances.Once more its speed with 20 ℃/minute is heated to 130 ℃, then the cooling and 30 ℃ of balances.Then with 20 ℃/minute speed with the final temperature of sample cell heating up to 350 ℃.Tg is reported as the point that changes beginning.

The modulation differential scanning calorimetry

On the TA instrument differential scanning calorimetry (DSC) 2920 that is equipped with refrigeration cooling system (RCS), obtain modulation differential scanning calorimetry (MDSC) data.Sample is placed DSC aluminum dish, accurately write down weight.To coil with lid and cover and curl.Use+/-0.8 ℃ modulated amplitude and 60 second cycle be heated to 180 ℃ with 2 ℃/minute the basic rate of heat addition from-20 and obtain the MDSC data.Use indium metal and sapphire to come calibration temperature and thermal capacity respectively as calibration criterion.

Thermogravimetric analysis

Pyrolysis weight (TG) analysis uses TA instrument 2950 thermogravimetric analyzers to carry out.Each sample is placed the aluminum specimen disc and is inserted into the TG stove.Stove speed with 10 ℃/minute under nitrogen is heated, up to 350 ℃ final temperature.With nickel and Alumel ^TMAs calibration criterion.

The thermogravimetric infrared analysis

Be equipped with among the Ever-Glo/Magna of far infrared source, potassium bromide (KBr) spectroscope and deuterate triglycine sulfate (DTGS) detector

Obtain thermogravimetric infrared (TG-IR) analysis on TA instrument thermogravimetric (TG) analyzer 2050 types of Fourier transformation infrared (FT-IR) spectrophotometer (Thermo Nicolet) connection interface.The TG device is operated under the helium flow that is used to purge with equilibrated 90cc/ minute and 10cc/ minute respectively.Each sample is placed the aluminum specimen disc, be inserted in the TG stove, accurately weigh by device, and stove is heated to 150 ℃ from ambient temperature with 20 ℃/minute speed.At first start the TG instrument, immediately start the FT-IR instrument.Each IR spectral representation is with 4.0cm ^-1Spectral resolution 32 co-added scannings of collecting.Collected IR spectrum, carried out 8 minutes in per 15 seconds.Beginning to collect background scans before the experiment.Use polystyrene to carry out wavelength calibration.The TG calibration criterion is nickel and Alumel ^TMVolatile matter is identified in retrieval HighResolution Nicolet TGA Vapor Phase spectrum library.

X-ray powder diffraction (Inel)

The Inel XRG-3000 diffractometer that use is equipped with CPS (curve location sensitivity) detector carries out X-ray powder diffraction (XRPD) analysis, and 2 θ scopes of described detector are 120 °.Begin to use Cu-Ka emission collection real time data from about 4 ° of 2 θ with the resolution of 0.03 ° of 2 θ.Tube voltage and amperage are set to 40kV and 30mA respectively.From 2.5-40 ° of 2 θ display graphics.By being packed in the thin-walled glass capillary tube, sample prepares sample for analysis.Each capillary tube is installed on the clinometer head, and described clinometer head rotates can allow capillary tube in data acquisition through motorization.About 5 minutes of sample analysis.Use the silicon reference standard to carry out instrument calibration.

X-ray powder diffraction (Shimadzu)

Use Shimadzu XRD-6000X ray powder diffraction instrument to carry out X-ray powder diffraction (XRPD) analysis, use Cu Ka ray.Instrument and equipment have long thin burnt X-ray tube.Tube voltage and amperage are set to 40kV and 40mA respectively.Divergent slit and scatter slit are set to 1 °, receive slit and are set to 0.15mm.By the radiation of NaI scintillation detector detection of diffracted.From 2.5 to 40 ° of 2 θ use 3 °/minute (0.4 second/0.020 steps) to carry out 8-26 continuous sweep.Analyzing the silicon standard harmonizes to check instrument.Use XRD-6000v 4.1 to collect and analytical data.Prepare sample for analysis by sample being placed aluminum frame with silicon dummy slider.

Result and discussion

XRPD the analysis showed that initiation material is crystallization, and differentiates to be [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid dihydrate (Aiweimopan).Unbodied [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid prepares by two kinds of major techniques: rotary evaporation and lyophilizing.The amorphous samples that produces is set forth in the table 1.The characteristic of representational amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] the methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sample by rotary evaporation and lyophilizing preparation is set forth in table 2 in table 4.Based on the thermal behavior (table 5) of the excipient of amorphous substance and selection, by the glass transition temperature (Tg) (table 6) that data fitting Gordon-Taylor equation is obtained predicting.For each calculating, use 70: 30 medicine: the ratio of excipient obtains predictive value.Use HPMC, mannitol, PVP and PVP/VAc to prepare the solid dispersion (table 7) of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid as vehicle excipients.The characteristic of representational solid dispersion is set forth in table 8 in table 11.

Table 1

The preparation of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid

The a.t-BuOH=tert-butyl alcohol;

B.Roto evap=rotary evaporation; The vac=vacuum

The c.IS=sample size is not enough to be used for analyze

Table 2:

The characteristic of the amorphous Aiweimopan by rotary evaporation and the preparation of 100 ℃ of vacuum drying oven heat treatments

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	Locate endothermic peak 68 ℃ of maximum temperatures and locate endothermic peak for 138 ℃ at maximum temperature	XRPD	Amorphous
DSC		Circulation DSC	Heating for the first time: the wide endothermic peak of locating 141 ℃ of maximum temperatures heats for the second time: Tg _Beginning=125 ℃, flex point=128 ℃ are offset=129 ℃ of heating: Tg for the third time _Beginning=125 ℃, flex point=128 ℃ are offset=129 ℃
TGA	At 25 ℃ to 200 ℃ 0.5% weight minimizing is arranged	Circulation DSC
TGA	At 25 ℃ to 200 ℃ 0.5% weight minimizing is arranged	Karl Fisher	0.98% water content
Moisture absorption	When the 5%RH balance, have 0.6% to reduce 12.2% weight minimizing is arranged when having 5% to 95%RH the time 13.8% weight to be increased in desorbing	Karl Fisher	0.98% water content
Moisture absorption		XRPD after the moisture absorption	Low-crystallinity; Amorphous, A type, or Type B

The a.endo=heat absorption; The exo=heat release; The max=maximum; The temp=temperature; The Tg=glass transition temperature; The RH=relative humidity

Table 3:

The characteristic of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] the methyl]-1-oxo-3-phenyl propyl] amino] acetic acid by lyophilizing and the preparation of 100 ℃ of vacuum drying oven heat treatments

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	In 72 ℃ of endothermic peaks of locating of maximum temperature in 123 ℃ of endothermic peaks of locating of maximum temperature	XRPD	Amorphous
DSC		Circulation DSC	Heating for the first time: the wide endothermic peak in that 94 ℃ of maximum temperatures are located, heat for the second time in 125 ℃ of heat absorptions of maximum temperature: Tg _Beginning=112 ℃, flex point=117 ℃ are offset=117 ℃ of heating: Tg for the third time _Beginning=112 ℃, flex point=117 ℃ are offset=117 ℃
TGA	There is 0.5% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 0.5% weight to reduce at 25 ℃ to 200 ℃	Moisture absorption	When the 5%RH balance, have 0.2% to reduce 10.8% weight minimizing is arranged when having 5% to 95%RH the time 13.0% weight to be increased in desorbing
XRPD after the moisture absorption	Amorphous	Moisture absorption

Table 4:

The general introduction of hot platform microscopy (the hot stage microscopy) data of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid

The a.t-BuOH=tert-butyl alcohol

Table 5:

Be used for preparing the DSC data of the excipient of [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid solid dispersion

The a.HPMC=hydroxypropyl methylcellulose; The PVP=polyvinylpyrrolidone; The PVP/VAc=1-vinylpyrrolidone/vinyl acetate copolymer

The b.endo=heat absorption, the Tg=glass transition temperature

Table 6:

[[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: the prediction glass transition temperature of the solid dispersion of excipient (70: 30)

Excipient ^a	Mean molecule quantity (g/mol) ^b，c	Density (g/cm ³)	The glass transition temperature of excipient (℃) ^c	Aiweimopan: the experiment glass transition temperature of the solid dispersion of excipient (70: 30) (℃) ^d	The prediction glass transition temperature of solid dispersion (℃) ^e
Excipient ^a	Mean molecule quantity (g/mol) ^b，c	Density (g/cm ³)	The glass transition temperature of excipient (℃) ^c			HPMC	50,000	1.19	155	117	134
Mannitol	182	1.49	L1 ^g	106	85	HPMC	50,000	1.19	155	117	134
Mannitol	182	1.49	L1 ^g	106	85	PVP	1,300,000	1.25	179	123	140
PVP/VAc	50,000	1.18	108	117	119	PVP	1,300,000	1.25	179	123	140

B. molecular weight derives from supplier.Be rounded to nearest integer

C. glass transition temperature is an experiment value, and with the temperature report in when beginning.Temperature is rounded to the immediate number of degrees.

D. numerical value derives from DSC research.Temperature is for the numerical value in when beginning and be rounded to the immediate number of degrees.

E. measure predictive value based on the Gordon-Taylor equation.The experimental mensuration glass transition temperature of amorphous Aiweimopan that uses is used for analyzing.Calculate based on the Aiweimopan of 0.7 weight fraction and the excipient of 0.3 weight fraction.Temperature is rounded to the immediate number of degrees.

Table 7:

The preparation of [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid solid dispersion

B.roto evap=rotary evaporation; The vac=vacuum; The t-BuOH=tert-butyl alcohol

Table 8:

The characteristic of the solid dispersion of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: the HPMC (70: 30) by lyophilizing and the preparation of 100 ℃ of vacuum drying oven heat treatments

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	In 72 ℃ of endothermic peaks of locating of maximum temperature in 126 ℃ of endothermic peaks of locating of maximum temperature	XRPD	Amorphous
DSC		Circulation DSC	Heating for the first time: the wide endothermic peak in that 79 ℃ of maximum temperatures are located, heat for the second time in 127 ℃ of heat absorptions of maximum temperature: Tg _Beginning=115 ℃, flex point=120 ℃ are offset=120 ℃ of heating: Tg for the third time _Beginning=117 ℃, flex point=121 ℃ are offset=121 ℃
TGA	There is 0.5% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 0.5% weight to reduce at 25 ℃ to 200 ℃	Moisture absorption	When the 5%RH balance, have 0.8% to reduce 20.5% weight minimizing is arranged when having 5% to 95%RH the time 22.2% weight to be increased in desorbing
XRPD after the moisture absorption	Amorphous	Moisture absorption

Table 9:

Amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations: the characteristic of the solid dispersion of mannitol (70: 30)

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Degree of crystallinity is poor: the mannitol of II type and III type
DSC	150 ℃ of endothermic peaks of locating of maximum temperature 161 ℃ begin the heat absorption, be to the maximum 165 ℃ 293 ℃ begin the heat absorption, be 294 ℃ to the maximum	XRPD
DSC		Circulation DSC	Heating for the first time: the wide endothermic peak of locating 88 ℃ of maximum temperatures heats for the second time: Tg heats for the second time: Tg _Beginning=106 ℃, flex point=110 ℃ are offset=112 ℃ of heating: Tg for the third time _Beginning=106 ℃, flex point=112 ℃ are offset=112 ℃, in 152 ℃ of heat absorptions of maximum temperature, in 165 ℃ of heat absorptions of maximum temperature
TGA	There is 0.7% weight to reduce at 25 ℃ to 190 ℃	Circulation DSC
TGA	There is 0.7% weight to reduce at 25 ℃ to 190 ℃	Moisture absorption	When the 5%RH balance, have 0.2% to reduce 11.7% weight minimizing is arranged when having 5% to 95%RH the time 13.0% weight to be increased in desorbing
XRPD after the moisture absorption	Degree of crystallinity is poor: the mannitol of II type and III type	Moisture absorption

Table 10:

The characteristic of the solid dispersion of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: the PVP (70: 30) by lyophilizing and the preparation of 100 ℃ of vacuum drying oven heat treatments

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	In 136 ℃ of endothermic peaks of locating of maximum temperature	XRPD	Amorphous
DSC		Circulation DSC	Heating for the first time: heat for the second time in 138 ℃ of endothermic peaks of locating of maximum temperature: Tg _Beginning=123 ℃, flex point=128 ℃ are offset=128 ℃ of heating: Tg for the third time _Beginning=122 ℃, flex point=128 ℃ are offset=128 ℃
TGA	There is 0.5% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 0.5% weight to reduce at 25 ℃ to 200 ℃	Moisture absorption	When the 5%RH balance, have 0.4% to reduce 28.0% weight minimizing is arranged when having 5% to 95%RH the time 30.4% weight to be increased in desorbing
XRPD after the moisture absorption	Amorphous	Moisture absorption

Table 11:

The characteristic of the solid dispersion of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: the PVP/VAc (70: 30) by lyophilizing and the preparation of 100 ℃ of vacuum drying oven heat treatments

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	In 125 ℃ of endothermic peaks of locating of maximum temperature	XRPD	Amorphous
DSC		Circulation DSC	Heating for the first time: heat for the second time in 128 ℃ of endothermic peaks of locating of maximum temperature: Tg _Beginning=112 ℃, flex point=121 ℃ are offset=121 ℃ of heating: Tg for the third time _Beginning=112 ℃, flex point=121 ℃ are offset=121 ℃
TGA	There is 0.2% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 0.2% weight to reduce at 25 ℃ to 200 ℃	Moisture absorption	When the 5%RH balance, have 0.2% to reduce 21.5% weight minimizing is arranged when having 5% to 95%RH the time 23.4% weight to be increased in desorbing
XRPD after the moisture absorption	Amorphous	Moisture absorption

Also prepared [[2 (, S)-and [[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] the amorphous sodium salt (table 12) of acetic acid.Do not obtain crystalline sodium salt.Characteristic shows, prepared 1: 1 and 2: 1 (sodium: [[2 (S)-[[4R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid) amorphous salt (table 13, table 14).Carried out the solid dispersion of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] the methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt of limited research and HPMC, mannitol, PVP and PVP/VAc to prepare.The characteristic of these materials is set forth in table 15 in table 20.

Table 12:

The preparation of [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] sodium acetate

The a.FE=rapid evaporation; AS/S=adds poor solvent in solution; Centrivap=traditional vacuum evaporating solvent; Roto evap=rotary evaporation; The vac=vacuum

The b.IS=sample size is not enough to be used for analyze

Table 13:

Amorphous [the characteristic of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt (1: 1, sodium hydroxide) by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations

Analytical technology	The result ^a
Analytical technology	The result ^a	XKPD	Amorphous
DSC	In 82 ℃ of heat absorptions of maximum temperature, in 130 ℃ of heat absorptions of maximum temperature	XKPD	Amorphous
DSC		Circulation DSC	Heating for the first time: heat for the second time in 131 ℃ of heat absorptions of maximum temperature: Tg _Beginning=118 ℃, flex point=123 ℃ are offset=123 ℃ of heating: Tg for the third time _Beginning=118 ℃, flex point=123 ℃ are offset=123 ℃
TGA	There is 0.7% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 0.7% weight to reduce at 25 ℃ to 200 ℃	Karl Fischer	2.04% water content
¹H NMR	Show the formation of salt	Karl Fischer	2.04% water content
¹H NMR	Show the formation of salt	Elementary analysis	There is 4% sodium; It is 1: 1 stoichiometry
Moisture absorption	When the 5%RH balance, have 2.8% to reduce 58.2% weight minimizing is arranged when having 5% to 95%RH the time 62.2% weight to be increased in desorbing	Elementary analysis	There is 4% sodium; It is 1: 1 stoichiometry
Moisture absorption		XRPD after the moisture absorption	Peak+amorphous

Table 14:

Amorphous [the characteristic of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt (2: 1, sodium carbonate) by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	In 132 ℃ of heat absorptions of maximum temperature, in 149 ℃ of heat absorptions of maximum temperature	XRPD	Amorphous
DSC		Circulation DSC	Heating for the first time:, heat for the second time in 133 ℃ of heat absorptions of maximum temperature: Tg in 70 ℃ of heat absorptions of maximum temperature _Beginning=121 ℃, flex point=125 ℃ are offset=125 ℃ of heating: Tg for the third time _Beginning=12FC, flex point=125 ℃ are offset=126 ℃
TGA	There is 0.8% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 0.8% weight to reduce at 25 ℃ to 200 ℃	Karl Fisher	3.76% water content
¹H NMR	Show the formation of salt	Karl Fisher	3.76% water content
¹H NMR	Show the formation of salt	Elementary analysis	There is 9% sodium; Be 2: 1 stoichiometries
Moisture absorption	When the 5%RH balance, have 0.1% to reduce 112.9% weight minimizing is arranged when having 5% to 95%RH the time 117.4% weight to be increased in desorbing	Elementary analysis	There is 9% sodium; Be 2: 1 stoichiometries
Moisture absorption		XRPD after the moisture absorption	The sample deliquescence

Table 15:

Amorphous [the characteristic of the solid dispersion of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt: HPMC (70: 30) by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	In maximum 69 ℃ and 134 ℃ of heat absorptions	XRPD	Amorphous
DSC	In maximum 69 ℃ and 134 ℃ of heat absorptions	Circulation DSC	Heating for the first time: 67 ℃ of heat absorptions, heating for the second time: do not absorb heat, for the third time heating: 136 ℃ of heat absorptions
TGA	There is 0.5% weight to reduce at 25 ℃ to 150 ℃	Circulation DSC
TGA	There is 0.5% weight to reduce at 25 ℃ to 150 ℃	Moisture absorption	There is 5% to 95%RH the time 96% weight to increase; There is 95% to 5%RH the time 91% weight to reduce
XRPD after the moisture absorption	Amorphous	Moisture absorption
XRPD after the moisture absorption	Amorphous	¹H NMR	Meet 2: 1 sodium salts

The a.endo=heat absorption; The max=maximum; The RH=relative humidity

Table 16:

0.125: 1 mannitol by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations: the amorphous [characteristic of the solid dispersion of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous+peak
DSC	In maximum 78 ℃, 117 ℃ and 156 ℃ of heat absorptions	XRPD	Amorphous+peak
DSC	In maximum 78 ℃, 117 ℃ and 156 ℃ of heat absorptions	Circulation DSC	Heating for the first time: heat for the second time 79 ℃ of heat absorptions: T _gBeginning, 108 ℃; Flex point, 112 ℃; Skew, 114 ℃ are heated for the third time: Tg _Beginning, 107 ℃; Flex point, 112 ℃; Skew, 115 ℃
TGA	There is 2.2% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 2.2% weight to reduce at 25 ℃ to 200 ℃	¹H NMR	Meet 2: 1 sodium salts

The a.endo=heat absorption; The max=maximum

Table 17:

0.25: 1 mannitol by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations: the amorphous [characteristic of the mixture of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous+peak
DSC	In maximum 104 ℃ and 181 ℃ of heat absorptions	XRPD	Amorphous+peak
DSC	In maximum 104 ℃ and 181 ℃ of heat absorptions	Circulation DSC	Heating for the first time: heat for the second time 67 ℃, 99 ℃ heat absorptions: Tg _Beginning, 91 ℃; Flex point, 102 ℃; Skew, 103 ℃ are heated for the third time: Tg _Beginning, 93 ℃; Flex point, 102 ℃; Skew, 104 ℃
TGA	There is 0.6% weight to reduce at 25 ℃ to 150 ℃	Circulation DSC
TGA	There is 0.6% weight to reduce at 25 ℃ to 150 ℃	¹H NMR	Meet 2: 1 sodium salts

The a.endo=heat absorption; The max=maximum

Table 18:

0.5: 1 mannitol by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations: the amorphous [characteristic of the mixture of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous+peak
DSC	At 75 ℃ to 125 ℃ wide, shallow endothermic peak is arranged	XRPD	Amorphous+peak
DSC	At 75 ℃ to 125 ℃ wide, shallow endothermic peak is arranged	Circulation DSC	Heating for the first time: heat for the second time 62 ℃, 87 ℃ heat absorptions: T _gBeginning, 78 ℃; Flex point, 83 ℃; Skew, 87 ℃ are heated for the third time: Tg _Beginning, 78 ℃; Flex point, 84 ℃; Skew, 87 ℃
TGA	There is 0.5% weight to reduce at 25 ℃ to 150 ℃	Circulation DSC
TGA	There is 0.5% weight to reduce at 25 ℃ to 150 ℃	′H NMR	Meet 2: 1 sodium salts

The a.endo=heat absorption; The max=maximum

Table 19:

Amorphous [the characteristic of the solid dispersion of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt: PVP (70: 30) by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	In maximum 69 ℃, 145 ℃ and 170 ℃ of heat absorptions	XRPD	Amorphous
DSC	In maximum 69 ℃, 145 ℃ and 170 ℃ of heat absorptions	Circulation DSC	Heating for the first time: 64 ℃ of heat absorptions; Heating for the second time: no heat absorption incident; Heating for the third time: 142 ℃ of heat absorptions
TGA	There is 2.3% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 2.3% weight to reduce at 25 ℃ to 200 ℃	Moisture absorption	There is 5% to 95%RH the time 90% weight to increase; There is 95% to 5%RH the time 85% weight to reduce
XRPD after the moisture absorption	IS ^b	Moisture absorption
XRPD after the moisture absorption	IS ^b	¹H NMR	Meet 2: 1 sodium salts

The a.endo=heat absorption; The max=maximum; The RH=relative humidity

The b.IS=sample size is not enough to be used for analyze

Table 20:

Amorphous [the characteristic of the solid dispersion (sample ID 1910-06-02) of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt: PVP/VAc (70: 30) by lyophilizing and 100 ℃ of vacuum drying oven heat treatment preparations

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous
DSC	In maximum 72 ℃ and 138 ℃ of heat absorptions	XRPD	Amorphous
DSC	In maximum 72 ℃ and 138 ℃ of heat absorptions	Circulation DSC	Heating for the first time: 93 ℃ of heat absorptions; Heating for the second time: do not have heat absorption; Heating for the third time: 141 ℃ of heat absorptions
TGA	There is 0.9% weight to reduce at 25 ℃ to 200 ℃	Circulation DSC
TGA	There is 0.9% weight to reduce at 25 ℃ to 200 ℃	Moisture absorption	There is 5% to 95%RH the time 90% weight to increase; There is 95% to 5%RH the time 92% weight to reduce
XRPD after the moisture absorption	Amorphous	Moisture absorption
XRPD after the moisture absorption	Amorphous	¹H NMR	Meet 2: 1 sodium salts

The a.endo=heat absorption; The max=maximum; The RH=relative humidity

Amorphous substance is carried out relative humidity stress be studied.The physical mixture of preparation Aiweimopan and mannitol and analyze by XRPD is to determine to detect by XRPD the minimum flow (table 21) of required crystallization Aiweimopan.Stress study at table 22 and in table 28, summarize.

Table 21:

In the solid dispersion [XRPD of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid is similar to detectable limit

Theoretical Aiweimopan % ^a	XRPD information
Theoretical Aiweimopan % ^a	XRPD information	6	I type mannitol
11	I type mannitol	6	I type mannitol
11	I type mannitol	16	I type mannitol and a small amount of A type
21	I type mannitol and a small amount of A type	16	I type mannitol and a small amount of A type

A. be rounded to immediate percentage ratio

Table 22:

Amorphous [the stability study of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sample that under environmental condition, stress handle

A.roto evap=rotary evaporation; Wt.=weight; The vac=vacuum; The PVP=polyvinylpyrrolidone; The PVP/VAc=1-vinylpyrrolidone/vinyl acetate copolymer; The HPMC=hydroxypropyl emthylcellulose

B. sample stress be handled under environmental condition.Environmental condition is about 24% relative humidity and 22 ℃.

C.PC=degree of crystallinity is poor; The sample size that SS=is little

Table 23:

Amorphous [the stability study (continuing) of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sample that under environmental condition, stress handle

C.PC=degree of crystallinity is poor; The sample size that SS=is little

Table 24:

Amorphous [the stability study of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sample that under 53% relative humidity and ambient temperature, stress handle

The b.SS=small sample

C.PC=degree of crystallinity is poor

Table 25:

The b.SS=small sample

C.PC=degree of crystallinity is poor

Table 26:

Amorphous [the stability study of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sample that under 97% relative humidity and ambient temperature, stress handle

Explanation ^a	Natural law under the stress state	Observed result	XRPD result ^b
Explanation ^a	Natural law under the stress state	Observed result	XRPD result ^b	Ethanol is at 30 ℃ of rotary evaporations; 100 ℃ of vacuum drying ovens	7	White solid; A little birefringence	The A type
Mannitol (0.3 weight fraction); Lyophilizing; 100 ℃ of vacuum drying ovens	7	White solid; Free of birefringence	PC; A type+mannitol I+II type		7	White solid; A little birefringence	The A type
	7	White solid; Free of birefringence	PC; A type+mannitol I+II type	Lyophilizing; 100 ℃ of vacuum drying ovens	7	Pale solid; A little birefringence	The A type
HPMC (0.3 weight fraction); Lyophilizing; 100 ℃ of vacuum drying ovens	7	White solid; Slight birefringence	The A type	Lyophilizing; 100 ℃ of vacuum drying ovens	7	Pale solid; A little birefringence	The A type
	7	White solid; Slight birefringence	The A type	Sodium carbonate test in 2: 1; Lyophilizing; 100 ℃ of vacuum drying ovens	3	Deliquescence; Free of birefringence
Sodium hydroxide test in 1: 1; Lyophilizing; 100 ℃ of vacuum drying ovens	7	White solid; Slight birefringence	The A type		3	Deliquescence; Free of birefringence
	7	White solid; Slight birefringence	The A type	Sodium carbonate test in 2: 1; Lyophilizing; 100 ℃ of vacuum drying ovens	1	Deliquescence; Free of birefringence
PVP/VAc; (0.3 weight fraction); Ethanol is at 30 ℃ of rotary evaporations; 100 ℃ of vacuum drying ovens	7	White is solid; Birefringence	The A type		1	Deliquescence; Free of birefringence
	7	White is solid; Birefringence	The A type	PVP (0.3 weight fraction); Ethanol is at 30 ℃ of rotary evaporations; 100 ℃ of vacuum drying ovens	7	White is solid; Birefringence	The A type

B.PC=degree of crystallinity is poor

Table 27:

At 75% relative humidity and the 40 ℃ of amorphous [stability studies of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sample that stress handle down

B.PC=degree of crystallinity is poor

Table 28 has been summarized the Aiweimopan freeze-dried drug product of the Aiweimopan load that comprises increase and the characteristic of sample to table 31.

Table 28:

The characteristic of Aiweimopan drug products

The a.endo=heat absorption

Table 29:

Characteristic with Aiweimopan drug products of 10% Aiweimopan drug loading

The a.endo=heat absorption

Table 30:

Characteristic with Aiweimopan drug products of 20% Aiweimopan drug loading

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous+peak
DSC	92 ℃ and 150 ℃ of heat absorptions	XRPD	Amorphous+peak
DSC	92 ℃ and 150 ℃ of heat absorptions	Circulation DSC	Heating for the first time: at 73 ℃ and the 97 ℃ of heat absorption heating second time: Tg _Beginning102.2 ℃, 102.6 ℃ of flex points are offset 102.9 ℃ of heating: Tg for the third time _Beginning101.9 ℃, 102.3 ℃ of flex points are offset 102.6 ℃ at 140 ℃ of acromions, 152 ℃ of heat absorptions
TGA	There is 3.4% weight to reduce at 25 ℃ to 150 ℃	Circulation DSC
TGA	There is 3.4% weight to reduce at 25 ℃ to 150 ℃	¹H NMR	Meet 2: 1 sodium salts

The a.endo=heat absorption

Table 31:

Characteristic with Aiweimopan drug products of 30% Aiweimopan drug loading

Analytical technology	The result ^a
Analytical technology	The result ^a	XRPD	Amorphous+mannitol I and III type
DSC	73 ℃ and 149 ℃ of heat absorptions	XRPD	Amorphous+mannitol I and III type
DSC	73 ℃ and 149 ℃ of heat absorptions	Circulation DSC	Heating for the first time: at 79 ℃ and the 103 ℃ of heat absorption heating second time: T _gBegin 101.5 ℃, 101.9 ℃ of flex points are offset 102.3 ℃ of heating: Tg for the third time _Beginning101.7 ℃, 102.1 ℃ of flex points are offset 102.4 ℃, at 140 ℃ of acromions, 150 ℃ of heat absorptions
TGA	There is 3.5% weight to reduce at 25 ℃ to 150 ℃	Circulation DSC
TGA	There is 3.5% weight to reduce at 25 ℃ to 150 ℃	¹H NMR	Meet 2: 1 sodium salts

The a.endo=heat absorption

Amorphous [the sign of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid and solid dispersion

Prepare amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R) by rotary evaporation and lyophilizing, 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid and [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] solid dispersion (table 1, table 7) of acetic acid.Find that initial amorphous solid has 2% to 5% weight minimizing when TGA analyzes.TG-IR analyzes demonstration, and it is because the solvent of preparation that weight reduces: ethanol during rotary evaporation and residual water, 1 during lyophilizing, 4-dioxane, the tert-butyl alcohol, He Shui.

With all amorphous samples about two days of 100 ℃ of vacuum dryings, to remove residual solvent.The standard of acceptable amorphous substance be sample must be by XRPD analyze for unbodied and by TGA and/or Karl Fisher analysis and observation to comprising＜1% solvent.

Select pharmaceutically acceptable excipient to be used for stable amorphous Aiweimopan: HPMC, mannitol, PVP and PVP/VAc.Also using Gordon-Taylor prediction equation weight fraction is [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid: the Tg value of the solid dispersion of excipient of 70: 30.The thermal behavior of the excipient that uses in this research is summarized in table 5 and is experimentized definite.The glass transition temperature of mannitol derives from literature reference.Prediction glass transition temperature be used for comparing (table 6) with the Tg value of measuring.

1. amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid

Rotary evaporation or 1 by alcoholic solution, 4-dioxane: the tert-butyl alcohol: the lyophilizing of water (1: 1: 1) solution prepares amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid (table 1).Analyze by XRPD, derive from two kinds of preparation methoies [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid all is unbodied.Characteristic is summarized in table 2 and table 3

The dsc analysis of the sample by rotary evaporation preparation shows twice phenomenon of absorbing heat 68 ℃ of maximum temperatures and 138 ℃.The lyophilizing sample has the heat absorption phenomenon 72 ℃ of maximum temperatures and 123 ℃.Freeze dried in the past Aiweimopan sample shows exothermic phenomenon when dsc analysis.Carry out the analysis of hot platform microscopy to study these thermal phenomenons (table 4).Yet, do not observe the thermal behavior that may show exothermic phenomenon.In the freeze dried substance of preparation subsequently, do not observe exothermic phenomenon.The character of uncertain exothermic phenomenon, it may be the illusion of specific sample.

The evaluation of glass transition temperature (Tg) shows that two kinds of materials have different value.Circulation dsc analysis to the rotary evaporation sample has at about 125 ℃ Tg _BeginningTemperature.The lyophilizing sample has about 112 ℃ Tg _BeginningTemperature.The difference of Tg value may be because the result that residual solvent influences amorphous solid.The TGA analytical table of two kinds of samples reveals 25 ℃ to 200 ℃ 0.5% the weight of having an appointment and reduces.

The two moisture absorption analytical table of rotary evaporation sample and lyophilizing sample reveals has 13% approximate weight to increase under 5% to 95% relative humidity, and it loses in desorption process, and hysteresis is arranged.XRPD to remaining solid matter after moisture absorption is analyzed the analysis showed that the crystallization of rotary evaporation sample becomes low crystalline material, and it can comprise the Aiweimopan of amorphous, A type (dihydrate) and/or Type B (anhydrous).As if the lyophilizing sample keep amorphous after moisture absorption is analyzed.

Because two kinds of amorphous samples have different Tg values, two kinds of samples all are used for subsequently stability study.

2.[[2 (S)-and [[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] solid dispersion of acetic acid: HPMC

By with 1,4-dioxane: the tert-butyl alcohol: water (1: 1: 1) lyophilizing prepares Aiweimopan: the solid dispersion of HPMC (70: 30).This solid matter is analyzed to amorphous by XRPD.Characteristic is summarized in table 8.

Dsc analysis shows two heat absorption phenomenons at 72 ℃ and 126 ℃ maximum temperatures.Analyze by TG, observe about 0.5% weight minimizing at 25 ℃ to 200 ℃.The circulation dsc analysis shows that it is about 115 ℃ to 117 ℃ that the Tg of this amorphous substance begins temperature.This value is than low 17 ℃ of Tg predictive value.

The moisture absorption analytical table reveals at 5% to 95% relative humidity has 22% approximate weight to increase.Sample does not satisfy weight standard in analytic process, points out this material to absorb more water in each humidity step.Weight is increased in the desorption process and loses, and some hysteresis are arranged.XRPD analyzes and is presented at after the moisture absorption analysis, and this sample is amorphous.

3.[[2 (S)-and [[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: the heterogeneous body mixture of mannitol (70: 30)

By with 1,4-dioxane: the tert-butyl alcohol: water (1: 1: 1) lyophilizing prepares Aiweimopan: the solid dispersion of mannitol (70: 30).This solid matter shows the diffraction maximum that meets mannitol II and III type.The representative diffraction maximum that does not have known Aiweimopan form.Characteristic is summarized in table 9.

Dsc analysis is presented at three heat absorption phenomenons of 150 ℃ of maximum temperatures, 165 ℃ and 294 ℃.Meet the fusing of mannitol III and II type respectively in the heat absorption phenomenon of 150 ℃ and 165 ℃.294 ℃ heat absorption phenomenon may be owing to decompose.Analyze by TG, observe about 0.7% weight minimizing at 25 ℃ to 190 ℃.

Although this solid dispersion shows some degree of crystallinity by XRPD and dsc analysis, the dsc analysis that circulates shows may form solid dispersion.The circulation dsc analysis shows that it is about 106 ℃ apparent Tg that the pars amorpha of this solid matter has the beginning temperature.This Tg value is than high 21 ℃ (table 6) of predictive value.Because mannitol can be used as plasticizer and works, the amount increase of amorphous mannitol can cause that the mixture glass transition temperature significantly reduces.In order to obtain 106 ℃ glass transition temperature, may need the mannitol of about 0.10 (weight fraction) and amorphous Aiweimopan to interact, to form solid dispersion.

The moisture absorption analytical table reveals 13% approximate weight increase under 5% to 95% relative humidity, it loses in desorption process, and some hysteresis are arranged.XRPD analyzes demonstration, and the diffraction maximum of this sample meets mannitol II and III type, and some amorphous compositions are arranged.In sample, do not detect the crystallization Aiweimopan.

Although [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: the material of mannitol is the heterogeneous body mixture mixture of crystalline material (amorphous and) seemingly, but because measured apparent Tg, this material is used for stability stress be studied.

4.[[2 (, S)-and [[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] solid dispersion of acetic acid: PVP (70: 30)

By solid dispersion with ethanol rotary evaporation preparation [[2 (1S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: PVP (70: 30).Solid matter is analyzed to amorphous by XRPD.Characteristic is summarized in table 10.

Dsc analysis shows a heat absorption phenomenon 136 ℃ of maximum temperatures.Analyze by TG, observe about 0.5% weight minimizing at 25 ℃ to 200 ℃.The circulation dsc analysis shows that it is about 123 ℃ that the Tg of this solid dispersion begins temperature.The measured value of Tg is lower 17 ℃ than predictive value.

The moisture absorption analytical table reveals at 5% to 95% relative humidity has 30% approximate weight to increase.Sample does not satisfy weight standard in analytic process, points out this material to absorb more water in each humidity step.Weight is increased in the desorption process and loses, and some hysteresis are arranged.XRPD analyzes and shows that this sample is amorphous.

5.[[2 ((S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] solid dispersion of acetic acid: PVP/VAc (70: 30)

By the ethanol rotary evaporation is prepared Aiweimopan: the solid dispersion of PVP/VAc (70: 30).Solid matter is analyzed to amorphous by XRPD.Characteristic is summarized in table 11.

Dsc analysis shows a heat absorption phenomenon 125 ℃ of maximum temperatures.Analyze by TG, observe about 0.2% weight minimizing at 25 ℃ to 200 ℃.The circulation dsc analysis shows that it is about 117 ℃ that the Tg of this solid dispersion begins temperature.Tg measured value and Tg prediction have good concordance (table 6).

The moisture absorption analytical table reveals at 5% to 95% relative humidity has 23% approximate weight to increase.Sample does not satisfy weight standard under some relative humiditys, points out this material may absorb more water in those relative humidity steps.Weight is increased in the desorption process and loses, and some hysteresis are arranged.XRPD analyzes and shows that this sample is amorphous.

The sign of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt and solid dispersion

Prepare amorphous Aiweimopan sodium salt (table 12) by rotary evaporation and lyophilizing.Sodium ion with 1: 1 and 2: 1: the mol ratio of Aiweimopan prepares amorphous salt.The characteristic of two kinds of amorphous solids is summarized in table 14 and the table 15.Attempted using HPMC, mannitol, PVP and PVP/VAc to prepare the solid dispersion of amorphous salt as vehicle excipients.The characteristic of these solid materials is summarized in table 15 in table 20.Detailed results provides in the lower part.

1. amorphous [[2 (, S)-and [[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt (1: 1)

By lyophilizing 1,4-dioxane: butanols: water (1: 1: 1) preparation amorphous [[2 ((S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt (1: 1).Use sodium hydroxide to prepare this material as counter ion counterionsl gegenions.Also use sodium carbonate to prepare amorphous salt (table 12) as counter ion counterionsl gegenions.Characteristic is summarized in the table 13.Analyze by XRPD, this solid matter is amorphous.Observe broad peak at about 4.7 ° of 2 θ.

Dsc analysis shows two heat absorption phenomenons 82 ℃ of maximum temperatures and 130 ℃.Analyze by TG, observe about 0.7% weight minimizing at 25 ℃ to 200 ℃.The circulation dsc analysis shows that it is about 118 ℃ that the Tg of this amorphous substance begins temperature.

This amorphous salt ¹The chemical shift of H NMR and Aiweimopan ¹H NMR spectrum difference.Sodium salt shows triplet at about 3.8ppm, and that free acid shows as in this zone is bimodal.Also observe difference between 3.5 to 3.0ppm and 2.9 to 2.5ppm, it may be presented at the change in the molecule that meets sodium salt formation in 1: 1.Elementary analysis shows that amorphous substance comprises about 5% sodium, meets 1: 1 stoichiometry (table 13).

The moisture absorption analysis is presented at 5% to 95% relative humidity 62% approximate weight increase.Sample does not satisfy weight standard in analytic process, points out this material to absorb more water in each humidity step.58% the weight of having an appointment in desorption process reduces.XRPD analyzes and is presented at after the moisture absorption analysis, and this sample is amorphous.

2. amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt (2: 1)

By lyophilizing 1,4-dioxane: butanols: water (1: 1: 1) preparation amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt (2: 1).Use sodium carbonate to prepare this material as counter ion counterionsl gegenions.Also use sodium hydroxide to prepare amorphous salt (table 12) as counter ion counterionsl gegenions.Characteristic is summarized in the table 14.Analyze by XRPD, this solid matter is amorphous.Observe broad peak at about 4.7 ° of 2 θ.

Dsc analysis shows two heat absorption phenomenons 132 ℃ of maximum temperatures and 148 ℃.Analyze by TG, observe about 0.8% weight minimizing at 25 ℃ to 200 ℃.The circulation dsc analysis shows that it is about 121 ℃ that the Tg of this amorphous substance begins temperature.

The solution of 2: 1 amorphous salts ¹H NMR shows the chemical shift relevant with phenol ring, and it may point out the formation of salt.In 2: 1 sodium salts, one bimodal moves to about 6.65ppm from about 6.78ppm.Do not observe this chemical shift in the spectrum of free acid or 1: 1 amorphous sodium salt, it may represent the formation of 2: 1 sodium salts.Elementary analysis shows that this amorphous substance comprises about 9% sodium, meets 2: 1 stoichiometry (table 14).

The moisture absorption analysis is presented at 5% to 95% relative humidity 117% approximate weight increase.Sample does not satisfy weight standard in analytic process, points out this material to absorb more water in each humidity step.About 113% weight minimizing is arranged in desorption process, slight hysteresis is arranged.Because the deliquescence of this material, the XRPD that does not carry out after the moisture absorption analyzes.

3. the mixture of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt/HPMC (70: 30)

Attempted preparing solid dispersion with amorphous Aiweimopan sodium salt and HPMC.By from 1,4-dioxane: the tert-butyl alcohol: water (1: 1: 1) lyophilizing prepares amorphous substance.Characteristic is summarized in the table 15.Analyze by XRPD, this solid matter is amorphous.Dsc analysis shows two heat absorption phenomenons 69 ℃ of maximum temperatures and 134 ℃, and it may be because the release of residual solvent.TG analyzes at 25 ℃ and 150 ℃ and shows about 0.5% weight minimizing.Whether the DSC that circulates has measurable glass transition temperature to measure this material.Observing in the heating process in about 67 ℃ heat absorption phenomenon in the first time, may be because from this material release solvent.Do not observe thermal phenomenon in the second time in the heating process.Observing the heat absorption phenomenon at about 136 ℃ in the heating process for the third time, it may be with to remove residual solvent relevant.In analytic process, do not observe the thermal phenomenon of indication glass transition temperature.This may point out and not form solid dispersion between amorphous salt and HPMC.

Moisture absorption analyze to show that this material increases in have an appointment 96% weight of 5% to 95% relative humidity.91% the weight of having an appointment in desorption process reduces, and slight hysteresis is arranged.This material does not all satisfy the weight requirement in each humidity step, shows that then this material can adsorb more water if in each humidity step there is the longer persistent period.XRPD analyzes and is presented at after the moisture absorption analysis, and this sample is amorphous.

Solution ¹H NMR analytical table reveals the chemical shift that meets 2: 1 amorphous sodium salts.Observe bimodal chemical shift, show in mixture, to form 2: 1 salt from 6.78ppm to about 6.65ppm.Also have the chemical shift relevant with HPMC.

Although this material is amorphous and forms 2: 1 [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt, but dsc analysis does not show measurable glass transition temperature, and prompting does not form solid dispersion.

4. amorphous [[2 (1S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt: the mixture of mannitol

Having prepared mol ratio is 0.125: 1,0.25: 1 and 0.5: 1 (mannitol: [[2 (R)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid) amorphous [[2 (JS)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt and the solid dispersion of mannitol.Do like this is to be used to study the amount that formation does not contain the required mannitol of the homogeneous amorphous solid dispersion of crystallized mannitol.By from 1,4 dioxane: the tert-butyl alcohol: water (1: 1: 1) lyophilizing prepares these materials.

A.0.125: 1 mannitol: amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt

Study with preparation and characterize amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt: the solid dispersion of mannitol.XRPD analyzes and shows that this material is amorphous, at about 4.6 ° of 2 θ broad peak is arranged.Dsc analysis shows three heat absorption phenomenons about 78 ℃, 117 ℃ of maximum temperatures and 156 ℃.TG analyzes and to show about 2.2% weight at 25 ℃ to 200 ℃ and reduce.Circulate DSC with the research glass transition temperature.Observe the about 107 ℃ apparent glass transition temperature of beginning temperature.This glass transition temperature and amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: mannitol mixture conforms to, and may point out the existence of sodium salt can not influence glass transition temperature significantly.The glass transition temperature of measuring also conforms to the predictive value of [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] the acetic acid solid dispersion that comprises 0.10 weight fraction mannitol.

Solution ¹H NMR analytical table reveals the chemical shift that meets 2: 1 amorphous sodium salts.Observe bimodal chemical shift, show in mixture, to form 2: 1 salt from 6.78ppm to about 6.65ppm.Also have the chemical shift relevant with mannitol.

These Notes of Key Datas have formed amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] the methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt by 2: 1: the solid dispersion that mannitol is formed.

B.0.25: 1 mannitol: amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt

The characteristic of this solid matter is summarized in general introduction in table 17.Analyze by XRPD, this material is amorphous, broad peak is arranged and in 2 high θ scopes other peak is arranged at about 4.7 ° of 2 θ, shows that this material has some degree of crystallinity.Dsc analysis shows two heat absorption phenomenons at about 104 ℃ and 181 ℃.TG analyzes and to show about 0.6% weight at 25 ℃ to 150 ℃ and reduce.The circulation dsc analysis shows the about 92 ℃ glassy state of beginning temperature and transforms.

Because XRPD figure shows degree of crystallinity, do not produce the sample of homogenizing.Yet this material shows really in about 92 ℃ apparent glass transition temperature, and this part that can show this material is at amorphous mannitol and formed solid dispersion between the sodium salt in amorphous 2: 1.

C.0.5: 1 mannitol: amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt

The characteristic of this solid matter is summarized in table 18.Analyze by XRPD, this material is amorphous, has at the broad peak of about 4.7 ° of 2 θ with in 2 high θ scopes other peak is arranged, and shows that this material has some degree of crystallinity.Dsc analysis shows wide, the shallow endothermic peak at 75 ℃ to 125 ℃.TG analyzes and to show about 0.5% weight at 25 ℃ to 150 ℃ and reduce.The circulation dsc analysis shows the about 78 ℃ glassy state of beginning temperature and transforms.Seemingly the amount of the amorphous mannitol that exists in the mixture directly influences glass transition temperature.Glass transition temperature reduces along with the increase of the amount of amorphous mannitol in the solid dispersion.Because mannitol can be considered to plasticizer, should be that more substantial amorphous mannitol reduces conversion temperature.Observed mannitol: the glass transition temperature reduction of amorphous sodium salt mixt conforms to theoretical prediction.Predictive value is to use Gordon-Taylor equation (equation 1) to obtain, and wherein uses the glass transition temperature of 2: 1 amorphous sodium salts.Formed 2: 1 amorphous salts in sample, it is being discussed in paragraph subsequently.

Because XRPD figure shows degree of crystallinity, do not produce the sample of homogenizing.Yet this material shows really in about 78 ℃ apparent glass transition temperature, and this part that can show this material is at amorphous mannitol and formed solid dispersion between the sodium salt in amorphous 2: 1.

5. the mixture of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt: PVP (70: 30)

Attempt the solid dispersion of amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt to prepare and PVP.By from 1,4-dioxane: 2-butanols: water (1: 1: 1) lyophilizing prepares amorphous substance.Characteristic is summarized in the table 19.Analyze by XRPD, this solid matter is amorphous.Dsc analysis shows three heat absorption phenomenons 69 ℃ of maximum temperatures, 145 ℃ and 170 ℃.TG analyzes and to show about 2.3% weight at 25 ℃ to 200 ℃ and reduce.Whether the DSC that circulates has measurable glass transition temperature to measure this material.Observing in the heating process in about 64 ℃ heat absorption phenomenon in the first time, may be because from this material release solvent.Do not observe thermal phenomenon in the second time in the heating process.Observing the heat absorption phenomenon at about 142 ℃ in the heating process for the third time, it may be with to remove residual solvent relevant.In analytic process, do not observe the thermal phenomenon of indication glass transition temperature.This may point out and not form solid dispersion between amorphous salt and PVP.

Moisture absorption analyze to show that this material increases in have an appointment 90% weight of 5% to 95% relative humidity.85% the weight of having an appointment in desorption process reduces, and slight hysteresis is arranged.This material does not satisfy the weight requirement in some humidity steps, shows that then this material can adsorb more water if in those humidity steps there is the longer persistent period.Because deliquescence causes the sample size deficiency, do not carry out that the XRPD of sample analyzes after the moisture absorption.

Solution ¹H NMR analytical table reveals the chemical shift that meets 2: 1 amorphous sodium salts.Observe bimodal chemical shift, show in mixture, to form 2: 1 salt from 6.78ppm to about 6.65ppm.Also have the chemical shift relevant with PVP.

Although this material is amorphous and forms 2: 1 Aiweimopan sodium salts that dsc analysis does not show measurable glass transition temperature, points out not form solid dispersion.

6. the mixture of amorphous [[2 (JS)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt: PVP/VAc (70: 30)

Attempted preparing solid dispersion with amorphous Aiweimopan sodium salt and PVP/VAc.By from 1,4-dioxane: the tert-butyl alcohol: water (1: 1: 1) lyophilizing prepares amorphous substance.Characteristic is summarized in the table 20.Analyze by XRPD, this solid matter is amorphous.Dsc analysis shows two heat absorption phenomenons 72 ℃ of maximum temperatures and 138 ℃.TG analyzes and to show about 0.9% weight at 25 ℃ to 200 ℃ and reduce.Whether the DSC that circulates has measurable glass transition temperature to measure this material.Observing in the heating process in about 93 ℃ heat absorption phenomenon in the first time, may be because from this material release solvent.Do not observe thermal phenomenon in the second time in the heating process.Observing the heat absorption phenomenon at about 141 ℃ in the heating process for the third time, it may be with to remove residual solvent relevant.In analytic process, do not observe the thermal phenomenon of indication glass transition temperature.This may point out and not form solid dispersion between amorphous salt and PVP/VAc.

Moisture absorption analyze to show that this material increases in have an appointment 95% weight of 5% to 95% relative humidity.92% the weight of having an appointment in desorption process reduces, and slight hysteresis is arranged.This material does not satisfy the weight requirement in some humidity steps, shows that then this material can adsorb more water if in those humidity steps there is the longer persistent period.The XRPD of sample analyzes and shows that this material is amorphous after the moisture absorption.

Solution ¹H NMR analytical table reveals the chemical shift that meets 2: 1 amorphous sodium salts.Observe bimodal chemical shift, show in mixture, to form 2: 1 salt from 6.78ppm to about 6.65ppm.Also have the chemical shift relevant with PVP/VAc.

Although this material is amorphous and forms 2: 1 [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid sodium salt, dsc analysis does not show measurable glass transition temperature, and prompting does not form solid dispersion.

D. relative humidity stability stress be studied

Carrying out relative humidity stress study to estimate the stability of amorphous Aiweimopan and solid dispersion.Research is carried out under ambient humidity, 53% and 97% relative humidity at ambient temperature.Envionmental humidity and the temperature measured are about 24% and 22 ℃.Also make sample under 75% relative humidity, experience and to handle at 40 ℃.Existence by degree of crystallinity in the XRPD analytic sample.

The physical mixture of preparation Aiweimopan A type (crystallization dihydrate) and mannitol detects the level of approximation of required crystallization Aiweimopan to determine the XRPD in the preparation sample.Having measured about 16% to 21% crystallization Aiweimopan is the detectable minimum flow of XRPD (table 21).Between 16% to 21% Aiweimopan content, be positioned at about 12.1 and become as seen with the diffraction maximum relevant of 13.0 ° of 2 θ with Aiweimopan A type.Therefore, amorphous and solid dispersion sample can comprise about 16% to 21% undetectable crystallization Aiweimopan.

Do not observe [the crystallization (table 22) of [2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid after the exposing to the open air up to 60 days under environmental condition.[[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid: the mannitol sample shows because the diffraction maximum that the partially crystallizable degree of mannitol II and III type produces.Amorphous sodium salt (1: 1 and 2: 1) shows the broad peak at about 4.07 ° of 2 θ place, and it is present in the freshly prepd sample.Under 53% relative humidity, expose the crystallization (table 23) of all not observing Aiweimopan in any sample after handling in 60 days to the open air.In addition, [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] acetic acid: the mannitol sample shows the partially crystallizable degree of mannitol and sodium salt and has wide diffraction maximum at about 4.07 ° of 2 θ place.

After seven days expose to the open air, all the amorphous samples crystallizations that stress handle under 97% relative humidity and ambient temperature form Aiweimopan A types (crystallization dihydrate) (table 24).Because the destruction of salt in stress research process, the easy crystallization of 1: 1 amorphous Aiweimopan sodium salt forms the A type.Amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt of 2: 1 during exposing three days to the open air in deliquescence.

When 75%RH and 40 ℃ stress be handled seven days, amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid crystallization by the rotary evaporation preparation forms Aiweimopan A type (table 25).In amorphous Aiweimopan sample, do not observe crystallization by the lyophilizing preparation.[[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: the mannitol sample shows the degree of crystallinity of Aiweimopan after 30 days expose to the open air.Solid dispersion with HPMC, PVP and PVP/VAc preparation does not show any degree of crystallinity that is produced by Aiweimopan after 60 days expose to the open air.Amorphous sodium salt (1: 1 and 2: 1) deliquescence after exposing three days to the open air.With deliquescence in the amorphous salt solid dispersion of PVP/VAc preparation is during also exposing 18 days to the open air under the stressed condition.In amorphous sodium salt solid mixture, observe slight crystallization, may produce by Aiweimopan with HPMC and PVP preparation.

Amorphous [[2 (, S)-and [[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid is stable under the stressed condition except that 97% relative humidity.By lyophilizing preparation amorphous [[2 (, S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid is stable under 75% relative humidity and 40 ℃ of temperature, and under identical stressed condition, show crystallization by amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid of rotary evaporation preparation.Except [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: outside the mannitol, [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid solid dispersion in the detectability of XRPD for amorphous and to show in exposing at least 60 days under the various stressed conditions (not comprising 97% relative humidity) for crystallization be stable.Amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid sodium salt does not show stability in the time of stress handling under surpassing 53% relative humidity with the solid dispersion that comprises this amorphous sodium salt, and the generation deliquescence.

E. intrinsic stripping research

To containing [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] PVP (70: 30w: w), amorphous [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R) of acetic acid, 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] the amorphous solid dispersion of acetic acid and crystallization [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid dihydrate carries out intrinsic stripping research.

Method

The preparation of the amorphous dispersions of Aiweimopan: PVP (70: 30)

The PVP of about 2.0 grams is dissolved in the ethanol of about 1000mL.The Aiweimopan A types (Lot 204007, SSCI LIMS No 51399) of about 5.0 grams are joined in the PVP solution and stir dissolve up to all substances.Make solution pass through 0.2 μ m nylon filter by vacuum filtration.Solution is rotated evaporation at ambient temperature.Collect solid and about 100 ℃ of vacuum dryings 1 day.Solid matter is analyzed by XRPD and is carried out identification of morphology.

Intrinsic stripping experiment

In being equipped with VK750A heater/circulator's VanKel VK7010 dissolving device, carry out intrinsic stripping experiment.Use intrinsic dissolving device (Woods apparatus) and hydraulic press with the sample of the about 200mg of about 1000psi compression 1 minute, obtain 0.50cm ²Sample surfaces.Experiment is carried out in the medium of pH=1.2HCl solution and pH=4.5 phosphate solution.The medium of 900mL is used in each experiment, and medium is maintained at about 37 ℃.Device rotates with 75rpm.In the whole time-continuing process of this experiment, use Gary 50UV/Vis spectrophotometer to take a sample automatically.

Sample is analyzed with Cary 50UV-VIS double-beam spectrophotometer, analyzes under the wavelength at 271nm in the quartzy Xiao Chi of 1.000-cm.Before sample analysis, detector returns to zero with the Xiao Chi that is full of dissolution medium.Use holmia to carry out wavelength calibration.The photometric precision of x ray intensity monitor x by detector for measuring when the light filter with known optical density places light path.The result is as shown in table 32.

Table 32:

The general introduction of intrinsic stripping research

The sample explanation	XRPD result	Intrinsic dissolution rate, mg/min/cm ²(SD)、pH 1.2HCl
The sample explanation	XRPD result	Intrinsic dissolution rate, mg/min/cm ²(SD)、pH 1.2HCl	The crystallization Aiweimopan	The A type	0.148(0.025)
Amorphous preparation	Amorphous	0.217(0.017)	The crystallization Aiweimopan	The A type	0.148(0.025)
Amorphous preparation	Amorphous	0.217(0.017)	[[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] acetic acid: PVP (70: 30, w: w)	Amorphous	1.48(0.149)

The Aiweimopan sample is carried out intrinsic stripping experiment.Data show, in pH 1.2HCl solution, [[2 (S)-[[4 (R)-(3-hydroxy phenyl)-3 (R), 4-dimethyl-piperidyl] methyl]-1-oxo-3-phenyl propyl] amino] (70: 30, as if w: amorphous solid dispersion w) has better stripping behavior than other Aiweimopan sample to acetic acid: PVP.

In this article for physical property for example molecular weight or chemical property for example during the chemical formula scope of application, be intended to all combinations and recombinant that wherein particular comprises this scope.

The open of each patent, patent application and the publication of quoting in this article or describing all incorporated into this paper as a reference in full.

It should be appreciated by those skilled in the art that and to carry out many changes and modification to the preferred embodiments of the invention, and can carry out this change and modification and do not break away from spirit of the present invention.Therefore, claim is intended to contain all this variants of equal value in spirit of the present invention and scope.

Claims

1. solid dispersion comprises:

The chemical compound of at least a formula I:

Wherein said chemical compound is solid amorphous form;

Wherein said amorphous form is stable; And

Wherein:

R ¹Be hydrogen or alkyl;

R ²Be hydrogen, alkyl or thiazolinyl;

R ⁴Be hydrogen, alkyl or thiazolinyl;

A is OR ⁵Or NR ⁶R ⁷

R ⁶Be hydrogen or alkyl;

B is

C (=O) W or NR ⁸R ⁹

R ⁸Be hydrogen or alkyl;

W is OR ¹⁰, NR ¹¹R ¹², or OE;

R ¹¹Be hydrogen or alkyl;

E is

(C=O) D that alkylidene replaces or-R ¹³OC (=O) R ¹⁴

R ¹³Alkylidene for the alkyl replacement;

R ¹⁴Be alkyl;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

Y is OR ¹⁸Or NR ¹⁹R ²⁰

R ¹⁹Be hydrogen or alkyl;

R ²¹Be hydrogen or alkyl; With

N is 0 to 4.

2. the solid dispersion of claim 1, wherein said polyvinylpyrrolidone copolymer is vinylpyrrolidone/vinyl acetate copolymer (PVP/VAc).

3. the solid dispersion of claim 1, the chemical compound of wherein said formula I is the solid dispersion in the substrate that is formed by described pharmaceutically acceptable excipient.

4. the solid dispersion of claim 1, the chemical compound of wherein said formula I and the weight ratio of described pharmaceutically acceptable excipient are about 5: 95 to about 75: 25.

5. the solid dispersion of claim 4, the chemical compound of wherein said formula I and the weight ratio of described pharmaceutically acceptable excipient are at least about 10: 90.

6. the solid dispersion of claim 5, the chemical compound of wherein said formula I and the weight ratio of described pharmaceutically acceptable excipient are at least about 15: 85.

7. the solid dispersion of claim 6, the chemical compound of wherein said formula I and the weight ratio of described pharmaceutically acceptable excipient are at least about 20: 80.

8. the solid dispersion of claim 7, the chemical compound of wherein said formula I and the weight ratio of described pharmaceutically acceptable excipient are at least about 25: 75.

9. the solid dispersion of claim 8, the chemical compound of wherein said formula I and the weight ratio of described pharmaceutically acceptable excipient are at least about 30: 70.

10. the solid dispersion of claim 1, it comprises at least a opioid in addition.

11. the solid dispersion of claim 10, wherein said opioid is selected from alfentanil, buprenorphine, butorphanol, codeine, dezocine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, meperidine(pethidine), methadone, morphine, nalbuphine, oxycodone, oxymorphone, pentazocine, propiram, dextropropoxyphene, sufentanil and tramadol.

12. the solid dispersion of claim 1, the chemical compound of its Chinese style I are trans 3, the 4-isomer.

13. the solid dispersion of claim 1,

Wherein:

R ¹Be hydrogen;

R ²Be alkyl;

N is 1 or 2;

R ³Be benzyl, phenyl, cyclohexyl or cyclohexyl methyl; With

R ⁴Be alkyl.

14. the solid dispersion of claim 1,

Wherein:

A is OR ⁵With

R ⁵Be hydrogen or alkyl.

15. the solid dispersion of claim 1,

Wherein:

A is NR ⁶R ^7s

R ⁶Be hydrogen;

R ⁷B for the alkylidene replacement; With

B is C (O) W.

16. the solid dispersion of claim 1,

Wherein:

R ⁷Be (CH ₂) q-B;

Q is about 1 to about 3;

W is OR ¹⁰With

17. the solid dispersion of claim 1,

Wherein:

W is NR ¹¹R ¹²

R ¹¹Be hydrogen or alkyl; With

R ¹²The C that replaces for hydrogen, alkyl or alkylidene (=O) Y.

18. the solid dispersion of claim 1,

Wherein:

R ¹²Be (CH ₂) mC (O) Y;

M is 1 to 3;

Y is OR ¹⁸Or NR ¹⁹R ²⁰With

R ¹⁸, R ¹⁹And R ²⁰Be hydrogen or alkyl independently.

19. the solid dispersion of claim 1,

Wherein:

W is OE;

E is CH ₂C (=O) D;

D is OR ¹⁵Or NR ¹⁶R ¹⁷

R ¹⁵Be hydrogen or alkyl;

R ¹⁶Be methyl or benzyl; With

R ¹⁷Be hydrogen.

20. the solid dispersion of claim 1,

Wherein:

W is OE;

E is R ¹³OC (=O) R ¹⁴

R ¹³For-CH (CH ₃)-or-CH (CH ₂CH ₃)-; With

R ¹⁴Be alkyl.

21. the solid dispersion of claim 1, wherein 3 of piperidine ring and 4 s' the configuration R type of respectively doing for oneself.

22. the solid dispersion of claim 1,

Wherein said chemical compound is selected from:

Q-CH ₂CH(CH ₂(C ₆H ₅))C(O)OH，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)OCH ₂CH ₂，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)OH，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)NHCH ₃，

Q-CH ₂CH ₂CH(C ₆H ₅)C(O)NHCH ₂C(O)NHCH ₂CH ₃，

G-NH(CH ₂) ₂C(O)NH ₂，

G-NH(CH ₂) ₂C(O)NHCH ₃，

G-NHCH ₂C(O)NH ₂，

G-NHCH ₂C(O)NHCH ₃，

G-NHCH ₂C(O)NHCH ₂CH ₃，

G-NH(CH ₂) ₃C(O)OCH ₂CH ₃，

G-NH(CH ₂) ₃C(O)NHCH ₃，

G-NH(CH ₂) ₂C(O)OH，

G-NH(CH ₂) ₃C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁)C(O)NHCH ₂C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NH(CH ₂) ₂C(O)OH，

Q-CH ₂CH(CH ₂(C ₆H ₁₁))C(O)NH(CH ₂) ₂C(O)NH ₂，

Z-NHCH ₂C(O)OCH ₂CH ₃，

Z-NHCH ₂C(O)OH，

Z-NHCH ₂C(O)NH ₂，

Z-NHCH ₂C(O)N(CH ₃) ₂，

Z-NHCH ₂C(O)NHCH(CH ₃) ₂，

Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

Z-NH(CH ₂) ₂C(O)OCH ₂(C ₆H ₅)，

Z-NH(CH ₂) ₂C(O)OH，

Z-NH(CH ₂) ₂C(O)NHCH ₂CH ₃，

Z-NH(CH ₂) ₃C(O)NHCH ₃，

Z-NHCH ₂C(O)NHCH ₂C(O)OH，

Z-NHCH ₂C(O)OCH ₂C(O)OCH ₃，

Z-NHCH ₂C(O)O(CH ₂) ₄CH ₃，

Z-NHCH ₂C(O)OCH ₂C(O)NHCH ₃，

Z-NHCH ₂C (O) O-(4-methoxyl group cyclohexyl),

Z-NHCH ₂C (O) OCH ₂C (O) NHCH ₂(C ₆H ₅) and

Z-NHCH ₂C(O)OCH(CH ₃)OC(O)CH ₃；

Wherein:

Q represents:

G represents:

With

Z represents:

23. the solid dispersion of claim 1,

Wherein said chemical compound is selected from:

(3R，4R，S)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(+)-Z-NHCH ₂C(O)OH，

(-)-Z-NHCH ₂C(O)OH，

(3R，4R，R)-Z-NHCH ₂C(O)-OCH ₂CH(CH ₃) ₂，

(3S，4S，S)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(3S，4S，R)-Z-NHCH ₂C(O)OCH ₂CH(CH ₃) ₂，

(3R, 4R)-Z-NHCH ₂C (O) NHCH ₂(C ₆H ₅) and

(3R，4R)-G-NH(CH ₂) ₃C(O)OH。

24. the solid dispersion of claim 1, wherein said chemical compound is selected from (+)-Z-NHCH ₂C (O) OH and (-)-Z-NHCH ₂C (O) OH.

25. the solid dispersion of claim 1, wherein said chemical compound are (+)-Z-NHCH ₂C (O) OH.

26. the solid dispersion of claim 1, wherein said chemical compound are Q-CH ₂CH (CH ₂(C ₆H ₅)) C (O) OH.

27. the solid dispersion of claim 1, wherein said chemical compound be (3R, 4R, S)-Q-CH ₂CH (CH ₂(C ₆H ₅)) C (O) OH.

28. the solid dispersion of claim 1, wherein said chemical compound are pure in fact stereoisomer.

29. dosage form, it comprises the solid dispersion of claim 1.

30. the dosage form of claim 29, wherein said dosage form are tablet, capsule or lozenge.

31. the method for the side effect relevant with opioid comprises the steps: among prevention or the treatment patient

Described patient is given the solid dispersion of the claim 1 of effective dose.

32. the method for claim 31, wherein said side effect are intestinal obstruction, opioid causes functional disorder of intestine, constipation, feel sick, vomiting or its combination.

33. the method for claim 32, wherein said side effect are postoperative ileus, postoperative nausea or postoperative vomiting.

34. the method for treatment or prevention patient's pain comprises the steps:

To the described solid dispersion that has the patient who needs to give the claim 1 of effective dose.

35. the method for claim 34, it comprises in addition: at least a opioid that the described patient that needs are arranged is given effective dose.

36. treatment or prevention patient's ileac method comprises the steps:

37. treatment or prevention patient's opioid causes the method for functional disorder of intestine, comprises the steps: