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WO1993016031A1 - Derive de benzenedimethanol s'adaptant a la desintegration - Google Patents

Derive de benzenedimethanol s'adaptant a la desintegration Download PDF

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Publication number
WO1993016031A1
WO1993016031A1 PCT/GB1992/000245 GB9200245W WO9316031A1 WO 1993016031 A1 WO1993016031 A1 WO 1993016031A1 GB 9200245 W GB9200245 W GB 9200245W WO 9316031 A1 WO9316031 A1 WO 9316031A1
Authority
WO
WIPO (PCT)
Prior art keywords
hydroxynaphthoate
salt
microcrystals
organic
hot
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1992/000245
Other languages
English (en)
Inventor
Steven Frederick Beach
David William Stuart Latham
Tony Gordon Roberts
Colin Brian Sidgwick
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Glaxo Group Ltd
Original Assignee
Glaxo Group Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Glaxo Group Ltd filed Critical Glaxo Group Ltd
Priority to PCT/GB1992/000245 priority Critical patent/WO1993016031A1/fr
Priority to AU12298/92A priority patent/AU1229892A/en
Priority to CN92104115A priority patent/CN1056974C/zh
Priority claimed from CN92104115A external-priority patent/CN1056974C/zh
Priority to UA93003953A priority patent/UA39921C2/uk
Publication of WO1993016031A1 publication Critical patent/WO1993016031A1/fr
Priority to NO933622A priority patent/NO180676C/no
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C07C217/10—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings

Definitions

  • the present invention relates to a drug material suitable for micronisation.
  • the invention relates to a novel readily micronisable form of the 1 - hydroxy-2-naphthalenecarboxylate (hereinafter hydroxy naphthoate) salt of 4- hydroxy- ⁇ -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]- 1 ,3-benzenedimethanol (hereinafter compound A) and to processes for the preparation of this novel form.
  • hydroxy naphthoate 4- hydroxy- ⁇ -[[[6-(4-phenylbutoxy)hexyl]amino]methyl]- 1 ,3-benzenedimethanol
  • United Kingdom Patent Specification No. 2140800A relates to phenethanolamine derivatives having a selective stimulant action at beta-2 adrenoreceptors.
  • the compounds may be used inter alia in the treatment of respiratory diseases associated with reversible airways obstruction, such as asthma and chronic bronchitis.
  • GB2140800A describes compound A and its physiologically acceptable salts, especially (at Example 20) its hydroxy naphthoate salt.
  • Compound A and its hydroxy naphthoate salt have been found to be particularly advantageous in the treatment of such respiratory diseases.
  • the present inventors have found that when the hydroxy naphthoate salt of compound A is prepared as described in GB2140800A, Example 20, crystals are obtained that are extremely difficult to micronise to the required panicle size range. These crystals are seen to adhere to the feed system (in the fluid energy mill) causing accumulation and ultimately blockage. This accumulation and blockage (of crystals) prevents efficient micronisation. It is an object of the present invention to provide a novel, readily micronisable form of the hydroxy naphthoate salt of compound A that overcomes the disadvantage (in terms of micronisation) associated with the specific crystalline form described above.
  • the hydroxy naphthoate salt of compound A in the form of spherical accretions of microcrystals, the spherical accretions being free-flowing, friable and micronisable.
  • the present inventors have surprisingly found that the presently claimed form of the hydroxy naphthoate salt of compound A, a form that combines a novel, spherical shape, and a free-flowing and friable nature, is readily micronisable to a material suitable for use in dosage forms that are administered by inhalation or insufflation.
  • the present invention provides the hydroxy naphthoate salt of compound A in the form of spherical accretions of microcrystals.
  • This form consists of thin crystalline plates arranged radially about a central core or void.
  • the form has an open structure in which the polymorphic form of the compound A hydroxy naphthoate is the same as that obtained from Example 20 of GB2140800 A.
  • the form provided by the present inventors also encompasses two or more spherical accretions (of microcrystals) fused together.
  • the term "spherical” refers both to sphere shaped and spherelike (i.e. spheroidal) shaped forms. Spherelike forms would include elliptical (egg shaped) and distorted elliptical (pear shaped) forms.
  • the present novel form of the compound A hydroxy naphthoate must be free- flowing. This means that the form must flow freely into a powder mill, for example a fluid energy powder mill, to allow its efficient particle size reduction by micronisation on an industrial scale.
  • the physical characteristics of a material that determine its flow characteristics include its bulk density, cohesivity, particle size and shape and uniformity with respect to the particle size.
  • a material in order to be free flowing, will have a high bulk density, a low cohesivity, and a uniform particle size distribution.
  • the individual particles within the material should also be spherical in shape. The present novel form meets these criteria.
  • the present novel form exhibits a high aerated bulk density, preferably from 0.2 to 0.5gml , especially from 0.3 to 0.4gml , a low cohesivity, preferably from 0 to 20%, especially from 0 to 5%, a spherical (or near spherical) particle shape and a uniform particle size distribution, as measured by a uniformity coefficient of from 1 to 20, preferably of from 1 to 5, typically about 3.
  • the present novel form of the compound A hydroxy naphthoate must be friable. This means that the form must be easily broken down to particles of a size suitable for use in a pharmaceutical dosage form to be delivered by inhalation or insufflation.
  • the present novel form of the compound A hydroxy naphthoate must be micronisable. This means that the form must be easily broken down under micronising conditions, for example in a fluid-energy mill, to particles of a size suitable for use in a pharmaceutical dosage form to be delivered by inhalation or insufflation.
  • the present novel form of the compound A hydroxy naphthoate preferably has a mean particle size of from 70 to 300 ⁇ m, most preferably from 100 to 200 ⁇ m, when measured by a laser diffraction method, T. Allen in Particle Size Measurement, 1981, 3rd Edition.
  • the panicle size distribution (measured by sieve analysis) is within the range 10 to 2000 ⁇ m, preferably from 100 to lOOOyrn. For a discussion of sieve analysis, see the above Allen reference.
  • the present novel form of the compound A hydroxy naphthoate preferably has a mean surface area of from 4 to 12m ? ⁇ g 1 , most preferably from 6 to 10m 2 g 1 , when measured by the nitrogen adsorption method of Brunnauer, Emmett and Teller
  • the present novel form of the compound A hydroxy naphthoate is a low compressibility and a relatively low angle of repose. These terms are defined and their means of measurement are described by R.L.Carr in Chemical Engineering, 1965, 163- 168.
  • the present novel form has an angle of repose of from 25-50 , especially from 40-50 , and a compressibility of from 5 to 25%, especially 8 to 20%.
  • a process for the micronisation of the hydroxy naphthoate salt of compound A comprising feeding the hydroxy naphthoate salt of compound A in the form of spherical accretions of microcrystals, the spherical accretions being free-flowing, friable and micronisable into a microniser, micronising the hydroxy naphthoate salt to give a micronised material and collecting the micronised material.
  • the present novel form of the compound A hydroxy naphthoate is micronised until the collected material has a panicle size range that is suitable for pharmaceutical dosage forms to be delivered by inhalation or insufflation.
  • a suitable particle size range for this use is from 1 to 10 ⁇ m, preferably from 1 to 5 ⁇ m.
  • the present novel form of the compound A hydroxy naphthoate may be prepared by any suitable method.
  • a process for the preparation of the hydroxy naphthoate salt of compound A in the form of spherical accretions of microcrystals comprising quenching an organic or aqueous organic solution of the hydroxy naphthoate salt of compound A with an organic or aqueous organic solvent having a lower temperature than the said solution, to give spherical accretions of microcrystals of the hydroxy naphthoate salt of compound A (the product) and collecting the product
  • the organic or aqueous organic solution will hereinafter be described as “hot” and the organic or aqueous organic solvent having a lower temperature will hereinafter be described as “cold”, these are to be understood as relative and not absolute terms.
  • an "aqueous organic” solution or solvent contains up to about 10%(v/v) water.
  • a hot organic solution and a cold organic solvent are employed in the above process.
  • the organic solvent employed in the hot organic or hot aqueous organic solution has a boiling point (at 760mmHg) from 40 ⁇ to 150°C, especially from 60 to 120 ⁇ C.
  • the compound A hydroxy naphthoate should be sparingly soluble or insoluble in the solvent when cold and soluble in the solvent when hot.
  • Solvents suitable for use in the hot organic or hot aqueous organic solution include lower alkyl (C j _4) alcohols such as methanol, ethanol and isopropanol, lower alkyl (C1.4) ethers, such as methyl t-butylether, and lower alkyl (C j .4) esters, such as ethyl acetate.
  • the organic solvent employed in the hot organic or hot aqueous organic solution is a lower alkyl alcohol, especially methanol, ethanol or isopropanol, most especially methanol.
  • the hot organic or the hot aqueous organic solution may contain a single solvent or a mixture of solvents.
  • the organic solvent employed in the cold organic or cold aqueous organic solvent should be miscible with the organic solvent employed in the hot organic or hot aqueous organic solution. Preferably it has a freezing point from - 150 to -20°C, especially from - 130° to -50°C.
  • Solvents suitable for use in the cold organic or cold aqueous organic solvent include lower alkyl (C j _ ) alcohols, such as methanol, ethanol and isopropanol, lower alkyl (C1 4) ethers, such as methyl t-butyl ether, and lower alkyl (C ⁇ ) esters, such as ethyl acetate.
  • the organic solvent employed in the cold organic or cold aqueous organic solvent is a lower alkyl alcohol, especially methanol, ethanol or isopropanol, most especially isopropanol.
  • the cold organic or the cold aqueous organic solvent may contain a single solvent or a mixture of solvents.
  • the temperature of the "hot” solution and the “cold” solvent are chosen to effect a fast crystallisation of the compound A hydroxy naphthoate, such that spherical accretions of microcrystals are formed.
  • the temperatures employed will depend, in large measure, on the choice of solvent or solvents.
  • the temperature of the hot organic or the hot aqueous organic solution is from 30 ⁇ to 80 ⁇ C, especially from 40 to 70 ⁇ C.
  • the temperature of the cold organic or the cold aqueous organic solvent is form -35 ⁇ to 15 ⁇ C, especially from -25° to 10°C.
  • the hot organic or hot aqueous organic solution may be quenched either by addition to or by the addition of the cold organic or cold aqueous organic solvent.
  • the hot organic or the hot aqueous organic solution is added to the cold organic or the cold aqueous organic solvent.
  • the temperature of the mixture ("hot" solution and "cold” solvent) at a temperature below about 20 ⁇ C, especially from - 10 to 20 ⁇ C, most especially from 0 ⁇ to 20 C.
  • the mixture is maintained at a temperature within this range until all (or most of) the compound A hydroxy naphthoate has crystallised as spherical accretions of microcrystals.
  • This crystallisation process can take, for example, from 10 to 120min, in particular from 20 to 90min.
  • the hydroxy naphthoate salt of compound A may be dissolved as such in the hot organic or the hot aqueous organic solution.
  • the salt may be formed in situ by separately dissolving compound A and l-hydroxy-2-naphthoic acid in the "hot" solution.
  • the starting material (compound A or the hydroxy naphthoate salt of compound A) for use in the above process may be prepared by the methods described in GB2140800A.
  • the spherical accretions of microcrystals may be collected by any suitable process, for example by filtration.
  • Figure 1 is a scanning electron micrograph of the known crystalline form of the hydroxy naphthoate salt of compound A obtained by following the comparative Example set out below, and
  • Figure 2 is a scanning electron micrograph of the claimed form of the hydroxy naphthoate salt of compound A obtained by following Example 8 set out below. This figure also has an inset showing, in close up, the surface of a spherical accretion obtained by the process described in Example 8.
  • Example 5 A solution of the hydroxy naphthoate salt of compound A in hot (ca. 70 ⁇ C) isopropanol (9.5vol) was added over an 8 min. period to cold (5- 10 C) t-butyl methyl ether (25vol.) with stirring under nitrogen. After 30min. (at ca. 5 ⁇ C) the solid material was isolated by filtration, washed with cold isopropanol and dried. The product obtained had a melting point of 121.5-137.5°C.
  • the hydroxy naphthoate salt of compound A was dissolved in hot (75 C) isopropanol (9.5vol.) under nitrogen and the solution was allowed to cool slowly with stirring to 57 ⁇ C.
  • Cold (-30°C) isopropanol (14vol.) was added to give a mixture the temperature of which was ca. 17 ⁇ C.
  • the solid product was filtered, washed with cold isopropanol and dried in vacuo.
  • Micronisation takes place in a fluid energy microniser of known type. Suitable examples are described and illustrated in Remington's Pharmaceutical Sciences, 1985, 17th Edition, at p. 1588, the contents of which disclosure are hereby incorporated by way of reference.
  • raw drug passes through a hopper and is carried through a venturi by a jet of air into a cyclone where the shearing action of air jets and collisions of drug particles break up the crystals.
  • Micronised drug falls from the cyclone into a container; "fines” leave in the exhaust and are trapped in large “vacuum cleaner” bags.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention se rapporte à un sel 1-hydroxy-2-naphtalène carboxylate (hydroxynaphtoate) de 4-hydroxy-α1-[[[6-(4-phénylbutoxy)hexyl]amino]méthyl]-1,3-benzènediméthanol sous la forme d'accroissements sphériques de microcristaux, les accroissements sphériques s'écoulant librement, pouvant être friables et désintégrables, et ayant de préférence une grosseur de particule moyenne de 70 à 300 νm et une aire de surface moyenne de 4 à 12m2g-1. On peut préparer le sel d'hydroxynaphtoate (sous la forme revendiquée) en refroidissant brusquement une solution organique chaude/organique aqueuse contenant le sel avec un solvant organique froid/organique aqueux.
PCT/GB1992/000245 1992-02-11 1992-02-11 Derive de benzenedimethanol s'adaptant a la desintegration Ceased WO1993016031A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
PCT/GB1992/000245 WO1993016031A1 (fr) 1992-02-11 1992-02-11 Derive de benzenedimethanol s'adaptant a la desintegration
AU12298/92A AU1229892A (en) 1992-02-11 1992-02-11 Benzenedimethanol derivative suitable for micronisation
CN92104115A CN1056974C (zh) 1992-02-11 1992-05-29 适宜于微粒化的药物材料的制备方法
UA93003953A UA39921C2 (uk) 1992-02-11 1992-11-02 СПОСІБ ОТРИМАННЯ 1-ГІДРОКСИ-2-НАФТАЛІНКАРБОКСИЛАТНОЇ СОЛІ 4-ГІДРОКСИ-<font face="Symbol">a</font>'-[[[6-(4-ФЕНИЛБУТОКСИ)ГЕКСИЛ]АМІНО]МЕТИЛ]-1,3-БЕНЗОЛДИМЕТАНОЛУ У ФОРМІ СФЕРИЧНИХ ЗРОЩЕНЬ МІКРОКРИСТАЛІВ, ГІДРОКСИНАФТОАТНА СІЛЬ, ОТРИМАНА ЦИМ СПОСОБОМ, СПОСІБ НАДТОНКОГО ПОДРІБНЕННЯ
NO933622A NO180676C (no) 1992-02-11 1993-10-08 1-hydroksy-2-naftalenkarboksylat(hydroksynaftoat)-salt av 4-hydroksy-<alfa>1 £££6-(4-fenylbutoksy)-heksyl|amino|metyl|-1,3-benzendimetanol og fremgangsmåte for fremstilling derav

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/GB1992/000245 WO1993016031A1 (fr) 1992-02-11 1992-02-11 Derive de benzenedimethanol s'adaptant a la desintegration
CN92104115A CN1056974C (zh) 1992-02-11 1992-05-29 适宜于微粒化的药物材料的制备方法

Publications (1)

Publication Number Publication Date
WO1993016031A1 true WO1993016031A1 (fr) 1993-08-19

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PCT/GB1992/000245 Ceased WO1993016031A1 (fr) 1992-02-11 1992-02-11 Derive de benzenedimethanol s'adaptant a la desintegration

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AU (1) AU1229892A (fr)
NO (1) NO180676C (fr)
WO (1) WO1993016031A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2848849A1 (fr) * 2002-12-20 2004-06-25 Boehringer Ingelheim Pharma Poudre pour inhalation, capsule et trousse la contenant et son utilisation pour la preparation d'un medicament

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4329446A1 (de) * 1993-09-01 1995-03-02 Basf Ag Verfahren zur Herstellung von feinteiligen Farb- oder Wirkstoffzubereitungen

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2140800A (en) * 1983-04-18 1984-12-05 Glaxo Group Ltd Phenethanolamine derivatives
WO1992009557A1 (fr) * 1990-11-29 1992-06-11 Glaxo Croup Limited Benzenedimethanol pouvant etre reduit en microns

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2140800A (en) * 1983-04-18 1984-12-05 Glaxo Group Ltd Phenethanolamine derivatives
WO1992009557A1 (fr) * 1990-11-29 1992-06-11 Glaxo Croup Limited Benzenedimethanol pouvant etre reduit en microns

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2848849A1 (fr) * 2002-12-20 2004-06-25 Boehringer Ingelheim Pharma Poudre pour inhalation, capsule et trousse la contenant et son utilisation pour la preparation d'un medicament
WO2004058233A1 (fr) * 2002-12-20 2004-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Medicament pulverulent pour l'inhalation, contenant un sel de tiotropium et du xinafoate de salmeterol
EA010588B1 (ru) * 2002-12-20 2008-10-30 Бёрингер Ингельхайм Фарма Гмбх Унд Ко. Кг Порошковые лекарственные средства, содержащие соль тиотропия и ксинафоат салметерола

Also Published As

Publication number Publication date
NO933622D0 (no) 1993-10-08
NO180676B (no) 1997-02-17
AU1229892A (en) 1993-09-03
NO933622L (no) 1993-10-08
NO180676C (no) 1997-05-28

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