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WO2006023035A2 - Composition de stearate amelioree et procede - Google Patents

Composition de stearate amelioree et procede Download PDF

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Publication number
WO2006023035A2
WO2006023035A2 PCT/US2005/021707 US2005021707W WO2006023035A2 WO 2006023035 A2 WO2006023035 A2 WO 2006023035A2 US 2005021707 W US2005021707 W US 2005021707W WO 2006023035 A2 WO2006023035 A2 WO 2006023035A2
Authority
WO
WIPO (PCT)
Prior art keywords
earth metal
alkaline earth
composition
stearate
dihydrate
Prior art date
Application number
PCT/US2005/021707
Other languages
English (en)
Other versions
WO2006023035A3 (fr
Inventor
Todd P. Heider
Steven M. Wolfgang
Scot R. Randle
Original Assignee
Mallinckrodt Inc.
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
Priority claimed from PCT/US2004/024485 external-priority patent/WO2005011641A2/fr
Application filed by Mallinckrodt Inc. filed Critical Mallinckrodt Inc.
Priority to CA002575497A priority Critical patent/CA2575497A1/fr
Priority to JP2007523564A priority patent/JP2008509092A/ja
Priority to AU2005277992A priority patent/AU2005277992A1/en
Priority to MXPA06014216A priority patent/MXPA06014216A/es
Priority to EP05764429A priority patent/EP1781259A2/fr
Publication of WO2006023035A2 publication Critical patent/WO2006023035A2/fr
Publication of WO2006023035A3 publication Critical patent/WO2006023035A3/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • This invention relates to the industrial manufacture of alkaline earth metal stearate compositions useful as industrial lubricants for uses including metal forming and tablet formulation of pharmaceutical preparations. More particularly, this invention relates to a process for preparing magnesium stearate lubricant exhibiting improved properties in lubrication and dissolution of pharmaceutical preparations in tablet form.
  • magnesium stearate is described as a substance containing at least 40% stearic acid, 90% as the sum of stearic acid and palmitic acid, and not more than 6.0% water.
  • Magnesium stearate commonly used in pharmaceutical applications is a mixture of magnesium stearate and magnesium palmitate, since sources used to derive magnesium stearate include tallow, palm oil, and soybean oil, all of which are glyceryl esters of Ci6 and C] 8 fatty acids.
  • the state of magnesium stearate may be amorphous, or exhibit any of the following crystalline forms - anhydrous, monohydrate, dihydrate, and trihydrate.
  • the USP/NF description of the composition and attributes of magnesium stearate does not account for functionality differences of the various crystalline forms.
  • the water content of up to 6.0% allows for products containing many possible combinations of hydrated forms to meet the requirements in the compendial monograph.
  • magnesium stearate compositions have the potential to adversely affect pharmacological activity by providing a water repellant barrier to dissolution of drugs, and can have a major influence on bioavailability, particularly of sustained release drugs.
  • magnesium stearate is actually a mixture of magnesium stearate and palmitate, and the hydration and degree of crystallinity vary significantly depending upon the manufacturing process, as well as from batch to batch depending on the starting materials. While high-purity forms of magnesium stearate dihydrate or magnesium palmitate dihydrate have been prepared and characterized in the laboratory, there are no commercially viable methods available for the preparation of the preferred dihydrate form.
  • This patent discloses a continuous process for manufacturing alkaline earth metal stearate soaps by the double decomposition method wherein a stream of an alkaline earth metal soap and an inorganic metal salt is dropped on a moving impeller of a mixer thereby instantaneously mixing the reactant together followed by rapid discharge from the reactor of the newly formed stearate salt. This process is purported to provide a product free of unreacted starting materials and unwanted by-products.
  • An improved double decomposition reaction was disclosed in U.S. Patent No. 5,434,277 wherein it is disclosed that such reactions " do not provide high purity products because of the presence of unreacted starting materials present in the product.
  • the solution to this problem according to this disclosure is to provide alternated basification-acidif ⁇ cation of the reaction mixture.
  • the effectiveness of the alternate treatment of the reaction mixture was shown by DSC analysis of the product indicating the disappearance of stearic acid starting material after alternative treatment. None of the prior disclosures mention the relevance of stearic acid/palmitic acid composition impacting hydration nor any means to control hydration of precipitated stearates in aqueous media.
  • An aspect of the present invention is to provide an improved alkaline earth metal stearate composition comprised of the reaction product of at least one fatty acid in a basic solution with at least one alkaline earth metal sulfate.
  • the fatty acid is comprised of at least about 80% by weight stearic acid and at least about 5% by weight palmitic acid.
  • Another aspect of the present invention is to provide a method for preparing the improved alkaline earth metal stearate composition.
  • At least one fatty acid comprised of at least about 80% by weight stearic acid and at least about 5% by weight palmitic acid is added to a basic aqueous solution.
  • At least one alkaline earth metal sulfate is added, and the at least one alkaline earth metal sulfate reacts with the at least one fatty acid to form the improved alkaline earth metal stearate composition.
  • an improved alkaline earth metal stearate composition comprised of at least about 40% alkaline earth metal stearate dihydrate.
  • a method for preparing an alkaline earth metal stearate composition comprises providing a basic aqueous solution and incorporating at least one fatty acid into the basic aqueous solution.
  • the fatty acid is comprised of stearic acid and palmitic acid.
  • At least one alkaline earth metal sulfate is added to form a slurry, and the slurry pH is adjusted to less than about pH 8.
  • the slurry is then subjected to solid-liquid separation via vacuum filtration and resulting wet cake is flash dried to form the improved alkaline earth metal stearate composition.
  • an improved alkaline earth metal stearate composition and related method of preparation wherein a substantial portion of the stearate is in the dihydrate form.
  • Methods of making metallic salts of fatty acids are well known in the art.
  • the "double decomposition" method involves a two-step process. First, the fatty acid is reacted with at least one base in a basic aqueous solution, typically at least one alkali hydroxide to form an alkaline soap. Second, at least one aqueous metallic salt solution is added to the soap to form metallic salts of the corresponding fatty acid.
  • alkaline earth metal stearates for example magnesium stearate and calcium stearate
  • the stearic acid reacts with an alkali hydroxide, for example NaOH, to form the sodium soap, which then reacts with an alkaline earth metal salt, for example magnesium chloride, as shown below:
  • Stearate compositions produced by this method exhibit great variation in quality and properties. It is known that commercially available stearic acid typically contains palmitic acid also. While pure stearic acid does have limited availability, the purification is not feasible on a industrial scale.
  • this impurity can lead to the formation of an improved stearate composition.
  • a significant amount of the dihydrate form of the stearate product can be formed.
  • the dihydrate form of the stearate provides a product which is substantially crystalline, with substantial platelet formation.
  • the dehydrate form is thought to be responsible for the improved lubricating properties and decreased interference with bioavailability observed with the stearate dihydrate when compared with stearates of similar properties excepting for their hydration.
  • a fatty acid component of at least about 80% by weight stearic acid and at least about 5% by weight palmitic acid with 88% by weight stearic acid to about 10% by weight palmitic acid being preferred; 90% by weight stearic acid to 8% by weight palmitic acid being more preferred; and about 93% by weight stearic acid to about 5% by weight palmitic acid being optimal.
  • the water content of the stearic/palmitic acids is defined.
  • the composition disclosed is comprised of magnesium stearate palmitate dihydrate having a stearate/palmitate ratio of at least 10: 1 and a total water content of less than about 6 %. Of that 6% water, preferably 15-100% of the total water content is crystalline water dihydrate, with less than about 10% of the total water content being free water, and the remainder of the water content being mon ⁇ hydrate.
  • the fatty acid stream used in this alternative embodiment contains the sum of stearate and palmitate no less than 98% of the total acid content.
  • the water content and hydration state of the final product vary as the ratio of stearic acid/palmitic acid, pH and conditions of drying are varied.
  • the desired dihydrate is most likely to form in alkaline solution when the ratio of stearic acid/palmitic acid is >10, or at a lesser ratio when the pH is closer to neutral and when the drying temperature does not exceed 60° C.
  • composition disclosed in this alternative embodiment exhibits beneficial functionalities including improving powder flow characteristics, reducing ejection force/compression force ratio, and minimizing any retardation of disintegration and dissolution rates of hydrophobic, or poorly water soluble drugs such as dilantin, modafinil, Zolpidem and alike, which are frequently observed when conventional magnesium stearate was used as the lubricant in making the tablets.
  • the fatty acid component is dispersed into a basic aqueous solution, whereby the fatty acid component reacts with the base to form a soap.
  • the basic aqueous solution may be heated prior to incorporating the fatty acid component to help to prevent the fatty acid component from congealing.
  • the alkaline earth metal salt typically magnesium sulfate or calcium sulfate, is then added and the pH is adjusted to provide an alkaline environment to raise the assay of the product by precipitation of any excess Mg as MgO.
  • a substantially pure magnesium stearate dihydrate is attained by controlling the pH during the precipitation step.
  • the conventional method for producing magnesium stearate comprises the reaction of stearic acid with an alkali hydroxide to form a metal soap, which then reacts with an alkaline earth metal salt to form the magnesium stearate.
  • the formation of the hydrated magnesium soaps is a consequence of the aqueous precipitation medium.
  • the most common hydrated form obtained when the resulting solution is alkaline is the monohydrate form.
  • the fatty acid starting material can be any combination of stearic and palmitic acid totaling at least 90%. This allows the production of the dihydrate form from any commercially available fatty acid mixtures, which are typically only about 40% stearic acid, with at least about 90% total stearic and palmitic acid.
  • the fatty acid is reacted with sodium hydroxide in water at a temperature of about 75 0 C, forming a soluble sodium stearate/sodium palmitate mixture which is be referred to as "soap solution.”
  • the fatty acid and sodium hydroxide are reacted at an approximately 1 : 1 molar ratio and sodium hydroxide added to produce a soap solution which is slightly alkaline. Any combination of stearic and palmitic acids can be used to form the relatively pure dihydrate form of magnesium stearate.
  • the alkaline earth metal sulfate is added in slight excess to ensure that all sodium stearate reacts to form the alkaline earth metal stearate.
  • the pH after this step is typically about 6.0-6.7. It is noted that the soap solution may be produced by any conventional method, as are well known in the art.
  • the soluble salts are removed from the product by adding water to the slurry, mixing and then separating and draining off the water.
  • the pH after this step is typically about 8.0-8.5.
  • Suitable acids include but are not limited to organic acids such as sulfuric acid, hydrochloric acid, nitric acid and mixtures thereof.
  • the pH is preferably adjusted to below about pH 8; with a pH of below 7 being more preferred; and a pH of about 6.3 to about 6.4 being most preferred, although significant formation of the dihydrate form has been accomplished at lower pH's, for example at pH 5.
  • the pH may be adjusted before or after the precipitation of the stearate. In an illustrative embodiment, the pH adjustment is made immediately before feeding to the flash drying system.
  • wet cakes formed at pH of 6.3-6.4 were substantially pure magnesium stearate dihydrate, at least about 95% or better, with no other hydrated forms present, as analyzed using Thermogravimetric Analysis.
  • the liquid or slurry remaining after wet cake formation is recovered for use as a component in the basic aqueous solution of subsequent dihydrate formation.
  • the magnesium stearate is typically flash dried at about 50 to about 90 0 C with about 60 to about 65 0 C being preferred.
  • the product tends to dehydrate slightly upon drying, but still contains greater than about 80% dihydrate form with the remainder being the anhydrous crystal of the dihydrate.
  • An illustrative drying system consists of a rotary vacuum filter (solid-liquid separation), hammer mill, natural gas-fueled furnace, and a pneumatic conveying system, although the product may be dried and processed by any conventional method.
  • Other suitable types of drying include spray drying, tray drying, and fluid bed drying at the 50-90° C range to retain the dihydrate that was formed during pH adjustment of the magnesium stearate slurry.
  • a magnesium stearate composition containing a variable ratio of discrete monohydrate and dihydrate polymorphs is manufactured from a "soap solution" via precipitation, as is well known in the art.
  • the salt of this illustrative example is formed by mixing of at least one fatty acid and at least one strong base, NaOH and a magnesium salt, MgSO 4 .
  • the soap solution is produced from a fatty acid mixture of suitable stearic/palmitic acid composition to obtain an appreciable amount of the dihydrate form of the resulting stearate. Addition of the alkaline earth metal salt to an alkaline "soap solution" results in the precipitation of magnesium stearate containing the dihydrate phase.
  • the precipitate is separated from the liquor, and dried to a water content of 3.5-6.0%, predominately water of hydration. A f ⁇ ne-particulate solid is obtained.
  • the product is designed for use as a pharmaceutical lubricant/mold release agent, but can be used for other applications, as is known in the art.
  • aqueous solution either water or a heel from a previous batch was heated to a temperature at which the fatty acid did not congeal when introduced to the aqueous solution, as is well known.
  • a 50% sodium hydroxide solution was added in at least a 1 : 1 molar ratio to the fatty acid, so that substantially all the fatty acid constituents were converted to the sodium soap.
  • the fatty acid component was then added until the solution was slightly alkaline to phenolphthalein indicator.
  • a fatty acid composition of about 93% by weight stearic acid to about 5% by weight palmitic acid was used.
  • a solution of magnesium sulfate was then added, without agitation, in an amount to substantially precipitate the sodium soap, thereby forming the magnesium stearate/palmitate.
  • the reaction mixture was then mixed to create a homogeneous mixture and insure reaction with the magnesium sulfate, typically about 20 minutes.
  • the reaction mixture remained heated throughout this and the remaining steps to prevent any solidification of the reaction mixture, thereby providing ease of handling.
  • the pH was then adjusted with sodium hydroxide to precipitate any excess magnesium as MgO.
  • An illustrative pH range is from about 9.0 to about 9.5.
  • a solid- liquid separation was performed, and the resulting solid product was dried, and deagglomerated by suitable conventional methods.
  • the product had a loss on drying of 3.5-6.0% indicating a significant amount of the dihydrate form is present.
  • TGA indicates 2 water loss events, one at about 6O 0 C and one at about 90°C, corresponding to the dihydrate and monohydrate forms respectively.
  • the product had regular or irregular (e.g. fragmented) platelet morphology.
  • a magnesium stearate composition is prepared according to the method of
  • Example 1 utilizing fatty acid having a stearic/palmitic acid ratio of at least about 10: 1 and a total water content of less than about 6 %. Of that 6% water, preferably 15- 100% of the total water content is crystalline water dihydrate, with less than about 10% of the total water content being free water, and the remainder of the water content being monohydrate.
  • the fatty acid stream used in this alternative embodiment contains the sum of stearate and palmitate no less than 98% of the total acid content.
  • the pH adjustment is made to render the reaction mixture substantially neutral.
  • the product is dried at a temperature at or below 60 0 C to remove most of the bulk water resulting in a fine, crystalline powder containing the dihydrate phase as evidenced by TGA/DSC.
  • a magnesium sulfate solution is prepared by dissolving 98 grams of magnesium sulfate heptahydrate in 643 mL of water. The mixture is stirred at 80° C until the salt is dissolved. In a separate vessel add 34 mL of 50% (w/w) NaOH to 1.13 liters of water and heat to 90° C. An alkaline sodium stearate (soap) is made by adding 181 grams of fatty acid containing 93% stearic acid and 5% palmitic acid to the NaOH solution maintaining the temperature at 90° C while stirring. 681 mL of water is added to the soap solution, lowering its temperature to 75° C.
  • the magnesium sulfate solution is added to the soap solution and stirred to assure complete reaction. Once the precipitation is complete the batch is adjusted to a pH of 9.0 using 50% NaOH. The resulting solids are washed with water to remove sodium sulfate byproduct. The solids are dried at 60° C. The product contains a combination of the monohydrate and dihydrate forms of magnesium stearate palmitate.
  • a soap solution was formed by reacting a fatty acid (a mixture of about 65%
  • Palmitic and small percentage of other fatty acids (18Ig) with sodium hydroxide in water (34 ml of 50% wt/wt NaOH added to 1.13 liters of water) at 90 0 C, forming a soluble sodium stearate soap solution.
  • the resulting soap solution is slightly alkaline so that 5 mL of the slurry dissolved in acetone solution, water and phenolphthalein indicator requires 0.1-0.3 mL of 0.1 N HCl to titrate to the endpoint .
  • Aqueous magnesium sulfate solution prepared by dissolving 98 grams of magnesium sulfate heptahydrate in 643 mL of water.
  • the magnesium sulfate solution was added to the soap solution and 191 g insoluble magnesium stearate (weight as the monohydrate) was precipitated.
  • the magnesium sulfate was added in slight excess to ensure that all sodium stearate reacts to form magnesium stearate.
  • the pH after this step was 6.2-6.8.
  • the pH was adjusted to a range of 9.0 to 9.5 by adding 50% wt/wt NaOH in water.
  • the soluble salts were removed by washing the product with city water (3400 ml.)
  • the pH after this step was 8.5.
  • the pH of the slurry was adjusted by adding sulfuric acid until a pH of 6.3 was attained.
  • the resulting wet cakes formed at pH of 6.3 were substantially pure magnesium stearate dihydrate, greater than 90% purity, with no other hydrated forms present when analyzed using thermogravimetric analysis.
  • the magnesium stearate was flash dried at with a target temperature of 71 0 C, resulting in slight dehydration of the product, but greater than 80% dihydrate form with the remainder being the anhydrous crystal of the dihydrate.
  • the drying system consisted of a rotary vacuum filter (solid-liquid separation), hammer mill, natural gas-fueled furnace, and a pneumatic conveying system.
  • the flash drying system has a residence time of less than 30 seconds and a typical inlet temperature of 150 to 260 0 C.
  • the hammer mill contains 12 hammers and rotates at 1800 rpm and acts mainly to deagglomerate the wet cake to facilitate drying.
  • a magnesium stearate composition was made according to Example 4, adjusting the pH to 5.0.
  • the resulting composition was greater than 90% magnesium stearate dihydrate, with no other hydrated forms present when analyzed using thermogravimetric analysis.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Lubricants (AREA)

Abstract

L'invention concerne une composition de stéarate de métal alcalino-terreux améliorée, élaborée par réaction entre une composante d'acide gras à acide stéarique et acide palmitique, et un hydoxyde alcalin, pour la formation de savon alcalin. On ajoute ensuite une solution de sel métallique aqueuse au savon, et le pH est réglé à moins d'environ 8 pour la formation du stéarate considéré, lequel offre une quantité sensiblement pure de forme dihydrate du stéarate.
PCT/US2005/021707 2004-07-28 2005-06-16 Composition de stearate amelioree et procede WO2006023035A2 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002575497A CA2575497A1 (fr) 2004-07-28 2005-06-16 Composition de stearate amelioree et procede
JP2007523564A JP2008509092A (ja) 2004-07-28 2005-06-16 改良されたステアリン酸塩組成物およびそれらの産生方法
AU2005277992A AU2005277992A1 (en) 2004-07-28 2005-06-16 Improved stearate composition and method of production thereof
MXPA06014216A MXPA06014216A (es) 2004-07-28 2005-06-16 Composicion de estearato mejorada y metodo de produccion de la misma.
EP05764429A EP1781259A2 (fr) 2004-07-28 2005-06-16 Composition de stearate amelioree et procede

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
USPCT/US2004/024485 2004-07-28
PCT/US2004/024485 WO2005011641A2 (fr) 2003-07-28 2004-07-28 Composition de stearate amelioree et procede

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Publication Number Publication Date
WO2006023035A2 true WO2006023035A2 (fr) 2006-03-02
WO2006023035A3 WO2006023035A3 (fr) 2006-06-15

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PCT/US2005/021707 WO2006023035A2 (fr) 2004-07-28 2005-06-16 Composition de stearate amelioree et procede

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EP (1) EP1781259A2 (fr)
JP (1) JP2008509092A (fr)
CN (1) CN1988890A (fr)
AU (1) AU2005277992A1 (fr)
CA (1) CA2575497A1 (fr)
MX (1) MXPA06014216A (fr)
WO (1) WO2006023035A2 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102372620B (zh) * 2010-08-17 2015-11-25 安徽山河药用辅料股份有限公司 硬脂酸镁提高其比容和白度的制备方法
JP7110756B2 (ja) * 2018-06-22 2022-08-02 日油株式会社 脂肪酸マグネシウム塩組成物

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5277832A (en) * 1991-09-12 1994-01-11 Freiborne Industries, Inc. Recovery of reactive soap lubricants
WO2001005430A1 (fr) * 1999-07-20 2001-01-25 Merck & Co., Inc. Dispositif d'administration d'une dispersion de medicaments a liberation prolongee
WO2003011214A2 (fr) * 2001-07-31 2003-02-13 Royer Biomedical, Inc. Nouvelles methodes et formulations concues pour administrer des agents actifs

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5277832A (en) * 1991-09-12 1994-01-11 Freiborne Industries, Inc. Recovery of reactive soap lubricants
WO2001005430A1 (fr) * 1999-07-20 2001-01-25 Merck & Co., Inc. Dispositif d'administration d'une dispersion de medicaments a liberation prolongee
WO2003011214A2 (fr) * 2001-07-31 2003-02-13 Royer Biomedical, Inc. Nouvelles methodes et formulations concues pour administrer des agents actifs

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
KOIVISTO M ET AL: "Effect of temperature and humidity on vegetable grade magnesium stearate" POWDER TECHNOLOGY, ELSEVIER SEQUOIA, LAUSANNE, CH, vol. 147, no. 1-3, 11 October 2004 (2004-10-11), pages 79-85, XP004657652 ISSN: 0032-5910 *

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CA2575497A1 (fr) 2006-03-02
WO2006023035A3 (fr) 2006-06-15
CN1988890A (zh) 2007-06-27
JP2008509092A (ja) 2008-03-27
EP1781259A2 (fr) 2007-05-09
AU2005277992A1 (en) 2006-03-02
MXPA06014216A (es) 2007-03-12

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