US20040014714A1 - Method for producing a crystalline tableting additive, additive thus obtained and use thereof - Google Patents

Method for producing a crystalline tableting additive, additive thus obtained and use thereof Download PDF

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US20040014714A1
US20040014714A1 US10/333,349 US33334903A US2004014714A1 US 20040014714 A1 US20040014714 A1 US 20040014714A1 US 33334903 A US33334903 A US 33334903A US 2004014714 A1 US2004014714 A1 US 2004014714A1
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additive
lactose
relative humidity
temperature
tableting
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Klaas Kussendrager
Henricus Van Den Biggelaar
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Campina Melkune BV
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Campina Melkune BV
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Assigned to CAMPINA B.V. reassignment CAMPINA B.V. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KUSSENDRAGER, KLAAS DANIEL, VAN DEN BIGGELAAR, HENRICUS ALPHONSUS MARIA
Publication of US20040014714A1 publication Critical patent/US20040014714A1/en
Priority to US13/408,359 priority Critical patent/US8501236B2/en
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    • C—CHEMISTRY; METALLURGY
    • C13—SUGAR INDUSTRY
    • C13B—PRODUCTION OF SUCROSE; APPARATUS SPECIALLY ADAPTED THEREFOR
    • C13B30/00—Crystallisation; Crystallising apparatus; Separating crystals from mother liquors ; Evaporating or boiling sugar juice
    • C13B30/02—Crystallisation; Crystallising apparatus
    • C13B30/028—Crystallisation; Crystallising apparatus obtaining sugar crystals by drying sugar syrup or sugar juice, e.g. spray-crystallisation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • C—CHEMISTRY; METALLURGY
    • C13—SUGAR INDUSTRY
    • C13K—SACCHARIDES OBTAINED FROM NATURAL SOURCES OR BY HYDROLYSIS OF NATURALLY OCCURRING DISACCHARIDES, OLIGOSACCHARIDES OR POLYSACCHARIDES
    • C13K5/00—Lactose
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the invention relates to a method for producing a tableting additive, to the tableting additive thus obtained and to the use of the said additive.
  • the additive is in particular a lactose additive.
  • spray dried materials such as lactose
  • lactose consist of crystalline and amorphous material.
  • spray dried particles comprise monohydrate lactose and amorphous lactose.
  • amorphous lactose is a hygroscopic material. It will readily take up moisture from the surrounding atmosphere. This moisture uptake reduces the glass transition temperature of amorphous lactose drastically: from 104° C. at 0% moisture content in the amorphous material down to 37° C. with 7.2% moisture content for example and even further down to 5° C. at ca. 14% moisture content.
  • the glass transition temperature Tg is lower than the ambient temperature, and the amorphous material changes from a glassy state into a rubbery state. Then molecular rearrangements occur and the amorphous material crystallises.
  • the amorphous form is not stable and may crystallise into the monohydrate form.
  • the active ingredient such as a drug
  • it may become bound in the crystal.
  • the disintegration properties are important.
  • this may affect the disintegration properties and the bioavailability of the active ingredient thus altering the performance of the tablet.
  • the relative humidity (RH) is to be selected in an indirect proportional manner to the temperature. It was found according to the invention that the relative humidity is preferably as defined by the formula:
  • T(° C.) is the temperature to which the particles are subjected during the treatment.
  • the relative humidity should be more than 50%, when the temperature is 40° C., the relative humidity should lie between 50% and 65%, when the temperature is 47° C., the relative humidity should be about 48%, when the temperature is 53° C., the relative humidity preferably lies between 50% and 65%, when the temperature is 60° C., the relative humidity lies between 31 and 44% and when the temperature is 75° C., the relative humidity should be about 25%.
  • a fast crystallisation is required to obtain good or even excellent tableting properties.
  • Such fast crystallisation is obtained by treating the additive material for a short time.
  • the short time is less than 10 minutes, more preferably, it is less than 5 min, most preferably the short time is about 2 min or less.
  • lactose is the only additive material for which the invention may be used.
  • Other materials are monosaccharides, such as glucose, fructose, mannose etc.
  • polyols derived therefrom like sorbitol, mannitol etc., disaccharides, such as maltose, sucrose and their derivatives, such as maltitol, lactitol (from lactose) and oligo- and polysaccharides, such as dextrins, galacto-oligosaccharides and fructo-oligosaccharides and starches.
  • disaccharides such as maltose, sucrose and their derivatives, such as maltitol, lactitol (from lactose)
  • oligo- and polysaccharides such as dextrins, galacto-oligosaccharides and fructo-oligosaccharides and starches.
  • the lactose that is used as the starting product in the method of the invention is spray dried lactose.
  • Such spray dried lactose may for example be obtained by means of the method described in EP-239 172, which is incorporated herein by reference.
  • the method described therein comprises feeding a slurry of crystalline ⁇ -lactose hydrate in a saturated lactose solution to a spray drier and drying the same, wherein the selection of the ratio between the amounts of crystalline material and dissolved lactose in the slurry determines the ratio between the amounts of crystalline and amorphous lactose in the spray dried product.
  • lactose is a pharmaceutical grade of lactose, which means that it meets the European, US and Japanese Pharmacopoeial requirements for lactose monohydrate, in particular regarding purity and water content.
  • the tableting additive obtained according to the method of the invention is substantially free of amorphours material and is preferably completely crystalline, which can be tested by Differential Scanning Calorimetry (DSC) in which a thermogram of the lactose shows no crystallisation peak.
  • DSC Differential Scanning Calorimetry
  • ⁇ - lactose About 5-20% of the total lactose additive prepared with the method of the invention constitutes ⁇ - lactose.
  • This ⁇ -lactose is present in the form of an ⁇ / ⁇ mix crystal which is demonstrated by the comparison of a DSC thermogram of the additive with a DSC thermogram of pure ⁇ / ⁇ mix crystal structure (FIG. 7). This peak is not present on the thermogram of conventional spray dried lactose or naturally crystallised lactose.
  • amorphous lactose is composed of ⁇ - and ⁇ -lactose.
  • the ratio between ⁇ - and ⁇ -lactose depends on the ratio that was originally present in the lactose solution that was spray dried. In principle, there is a permanent mutarotation between the two forms in solution, but this equilibrium may be affected by particular parameters, such as temperature, pH etc. Spray drying temperature may thus have an effect on the ratio between ⁇ - and ⁇ -lactose in the starting product.
  • the tableting profile is defined as the relationship between tablet crushing strength or tensile strength as a function of compaction force or pressure on a tableting press or a compaction simulator.
  • the invention also relates to the additive obtainable by the method.
  • This additive comprises substantially no, preferably no amorphous additive material.
  • the originally present amorphous material is converted at least partially into a mix crystal of ⁇ - and ⁇ -lactose.
  • the advantages of this additive are that it leads to a tabletability that is equivalent or even better than that of conventional spray dried lactose, but in addition the additive is more stable to moisture than the conventional spray dried lactose.
  • the invention furthermore relates to the use of the additive for the preparation of tablets.
  • FIG. 1 Map of crystallisation conditions for stabilising spray dried lactose showing the relationship between temperature and relative humidity.
  • FIG. 2 Map of the relationship between the air temperature and the minimal humidity required for controlled crystallisation into mix crystal.
  • FIG. 3 Scanning Electron Microscope (SEM) images of conventional spray dried lactose and stabilised spray dried lactose of the invention.
  • FIG. 4 Graph showing the effect of the treatment of the invention on a given sample of spray dried lactose.
  • FIG. 5 Graph showing lubricant sensitivity of a given sample of spray dried lactose.
  • FIG. 6 Moisture sorption isotherms of various samples of lactose at 20° C.
  • FIG. 7 DSC thermogram of various samples.
  • Stabilisation of the spray dried additive by means of the method of the invention is obtained by conditioning a spray dried lactose sample to various temperatures between 30° C. and 80° C. at various relative humidity conditions.
  • FIG. 1 shows a map of the conditions tested. Filled symbols show optimal conditions and open symbols show non-optimal conditions.
  • FIG. 2 was used to calculate the formula that can be used to determine the relationship between the treatment conditions temperature and relative humidity.
  • FIG. 3 shows the SEM (scanning electron microscopy) photographs of the various samples.
  • FIGS. 3A and C show different magnifications of conventional spray dried lactose, showing a blurry surface due to the presence of a layer of amorphous lactose embedding the underlying lactose monohydrate crystals. Some tiny spheres (typically ⁇ 10 ⁇ m) amorphous lactose can also be observed on some of the agglomerates.
  • FIGS. 3B and D show different magnifications of stabilised spray dried lactose of the invention, presenting the same agglomerate shape but with a different sub-structure. The amorphous material is no longer present and the picture has gained in sharpness. The crystallised amorphous material has formed a microcrystal structure covering the crystals of lactose monohydrate.
  • FIG. 4 presents the tablet ability of different samples of spray dried lactose treated under different conditions as follows:
  • the tablet ability of the samples treated according to the invention is equivalent to or improved in comparison with the untreated material.
  • Spray dried lactose has the disadvantage of being a bit sensitive to the extent of lubrication.
  • powders are always lubricated to facilitate the compression (reduce the friction between die and punches).
  • the extent of lubrication is determined by the % lubricant used in the mix and the blending time used to lubricate the powders. A longer blending time favors the formation of a continuous film of lubricant on all the external surfaces of the particles.
  • a tableting excipient should be ideally not sensitive to lubrication, meaning that the extent of lubrication would not jeopardise the robustness of the formulation (i.e. a change in lubricant level or mixing intensity would have limited effects on tableting properties).
  • FIG. 5 shows that the additive of the invention, like lactose monohydrate, is practically insensitive to lubrication extent.
  • Stabilised spray dried lactose is not hygroscopic. The moisture uptake of this product is almost null over a wide range of relative humidities. This is not true for standard spray dried lactose, due to the presence of amorphous lactose in the product.

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Abstract

A method for producing a tableting additive, which method comprises providing a spray dried tableting additive in particulate form which particles at least partially consist of amorphous additive material and at least partially of crystalline additive material; and crystallising the amorphous additive material by subjecting the particles for a short time and under agitation to a temperature between 30 and 100° C. at a relative humidity between 60 and 25%. More in particular, the relationship between relative humidity and temperature is defined by the formula: % relative humidity =218−47*Ln(T(° C.)), wherein T(° C.) is the temperature to which the particles are subjected.

Description

  • The invention relates to a method for producing a tableting additive, to the tableting additive thus obtained and to the use of the said additive. The additive is in particular a lactose additive. [0001]
  • Usually spray dried materials, such as lactose, consist of crystalline and amorphous material. In the case of lactose, spray dried particles comprise monohydrate lactose and amorphous lactose. Unlike crystalline lactose, amorphous lactose is a hygroscopic material. It will readily take up moisture from the surrounding atmosphere. This moisture uptake reduces the glass transition temperature of amorphous lactose drastically: from 104° C. at 0% moisture content in the amorphous material down to 37° C. with 7.2% moisture content for example and even further down to 5° C. at ca. 14% moisture content. Hence, when the moisture content in the amorphous material has reached a critical value, the glass transition temperature Tg is lower than the ambient temperature, and the amorphous material changes from a glassy state into a rubbery state. Then molecular rearrangements occur and the amorphous material crystallises. [0002]
  • Thus, the amorphous form is not stable and may crystallise into the monohydrate form. When this crystallisation occurs in the presence of the active ingredient, such as a drug, it may become bound in the crystal. For tablets, the disintegration properties are important. When due to the hygroscopic character of the amorphous lactose in the tablets, crystallisation occurs over time, this may affect the disintegration properties and the bioavailability of the active ingredient thus altering the performance of the tablet. [0003]
  • It is therefore desirable to stabilise the tableting additive, such as lactose, in order to avoid changes in bioavailability and disintegration behaviour. [0004]
  • It was found according to the invention that a method which comprises: [0005]
  • a) providing a spray dried tableting additive in particulate form which particles at least partially consist of amorphous additive material and at least partially of crystalline additive material; and [0006]
  • b) crystallising the amorphous additive material by subjecting the particles for a short time and under agitation to a temperature between 30 and 100° C. at a relative humidity between 60 and 25% will lead to a tableting additive that is stable with regard to moisture. [0007]
  • The relative humidity (RH) is to be selected in an indirect proportional manner to the temperature. It was found according to the invention that the relative humidity is preferably as defined by the formula:[0008]
  • % relative humidity=218−47*Ln(T(° C.))
  • wherein T(° C.) is the temperature to which the particles are subjected during the treatment. [0009]
  • More in particular, when the temperature is 36° C., the relative humidity should be more than 50%, when the temperature is 40° C., the relative humidity should lie between 50% and 65%, when the temperature is 47° C., the relative humidity should be about 48%, when the temperature is 53° C., the relative humidity preferably lies between 50% and 65%, when the temperature is 60° C., the relative humidity lies between 31 and 44% and when the temperature is 75° C., the relative humidity should be about 25%. [0010]
  • It was found according to the invention that a fast crystallisation is required to obtain good or even excellent tableting properties. Such fast crystallisation is obtained by treating the additive material for a short time. Preferably, the short time is less than 10 minutes, more preferably, it is less than 5 min, most preferably the short time is about 2 min or less. [0011]
  • During the crystallisation treatment some sort of agitation is required. It was found that good results are obtained when the agitation is provided by a fluid bed device. However, also some sort of mechanical form of agitation, such as stirring can be used. [0012]
  • The method as described herein is found to be particularly suitable when the additive material is lactose. In the examples, the invention will be illustrated with lactose. This does not mean that lactose is the only additive material for which the invention may be used. Other materials are monosaccharides, such as glucose, fructose, mannose etc. and the polyols derived therefrom, like sorbitol, mannitol etc., disaccharides, such as maltose, sucrose and their derivatives, such as maltitol, lactitol (from lactose) and oligo- and polysaccharides, such as dextrins, galacto-oligosaccharides and fructo-oligosaccharides and starches. [0013]
  • The lactose that is used as the starting product in the method of the invention is spray dried lactose. Such spray dried lactose may for example be obtained by means of the method described in EP-239 172, which is incorporated herein by reference. In summary, the method described therein comprises feeding a slurry of crystalline α-lactose hydrate in a saturated lactose solution to a spray drier and drying the same, wherein the selection of the ratio between the amounts of crystalline material and dissolved lactose in the slurry determines the ratio between the amounts of crystalline and amorphous lactose in the spray dried product. The person skilled in the art of spray drying can modify the process conditions to obtain a suitable spray dried product based on his common general knowledge of spray drying. For tableting purposes for pharmaceutical use the lactose is a pharmaceutical grade of lactose, which means that it meets the European, US and Japanese Pharmacopoeial requirements for lactose monohydrate, in particular regarding purity and water content. [0014]
  • The tableting additive obtained according to the method of the invention is substantially free of amorphours material and is preferably completely crystalline, which can be tested by Differential Scanning Calorimetry (DSC) in which a thermogram of the lactose shows no crystallisation peak. [0015]
  • About 5-20% of the total lactose additive prepared with the method of the invention constitutes β- lactose. This β-lactose is present in the form of an α/β mix crystal which is demonstrated by the comparison of a DSC thermogram of the additive with a DSC thermogram of pure α/β mix crystal structure (FIG. 7). This peak is not present on the thermogram of conventional spray dried lactose or naturally crystallised lactose. [0016]
  • It was found that at temperatures below 35° C. the content of β-lactose decreases. It may still be that some mix crystal is formed but it is not sufficient for obtaining acceptable tableting properties. The tableability of the product seems to follow the change in β-lactose content. If this content falls, the tabletability will also decrease. If after crystallisation, the β-lactose content remains constant, the good tableting properties are retained. [0017]
  • Before crystallisation, amorphous lactose is composed of α- and β-lactose. The ratio between α- and β-lactose depends on the ratio that was originally present in the lactose solution that was spray dried. In principle, there is a permanent mutarotation between the two forms in solution, but this equilibrium may be affected by particular parameters, such as temperature, pH etc. Spray drying temperature may thus have an effect on the ratio between α- and β-lactose in the starting product. [0018]
  • The tableting profile is defined as the relationship between tablet crushing strength or tensile strength as a function of compaction force or pressure on a tableting press or a compaction simulator. [0019]
  • In addition to the method, the invention also relates to the additive obtainable by the method. This additive comprises substantially no, preferably no amorphous additive material. The originally present amorphous material is converted at least partially into a mix crystal of α- and β-lactose. The advantages of this additive are that it leads to a tabletability that is equivalent or even better than that of conventional spray dried lactose, but in addition the additive is more stable to moisture than the conventional spray dried lactose. [0020]
  • The invention furthermore relates to the use of the additive for the preparation of tablets.[0021]
  • The present invention will be further illustrated in the examples that follow. Reference is made herein to the following figures: [0022]
  • FIG. 1: Map of crystallisation conditions for stabilising spray dried lactose showing the relationship between temperature and relative humidity. [0023]
  • FIG. 2: Map of the relationship between the air temperature and the minimal humidity required for controlled crystallisation into mix crystal. [0024]
  • FIG. 3: Scanning Electron Microscope (SEM) images of conventional spray dried lactose and stabilised spray dried lactose of the invention. [0025]
  • FIG. 4: Graph showing the effect of the treatment of the invention on a given sample of spray dried lactose. [0026]
  • FIG. 5: Graph showing lubricant sensitivity of a given sample of spray dried lactose. [0027]
  • FIG. 6: Moisture sorption isotherms of various samples of lactose at 20° C. [0028]
  • FIG. 7: DSC thermogram of various samples. [0029]
    • EXAMPLES Example 1
  • Crystallisation Conditions [0030]
  • Stabilisation of the spray dried additive by means of the method of the invention is obtained by conditioning a spray dried lactose sample to various temperatures between 30° C. and 80° C. at various relative humidity conditions. FIG. 1 shows a map of the conditions tested. Filled symbols show optimal conditions and open symbols show non-optimal conditions. [0031]
  • FIG. 2 was used to calculate the formula that can be used to determine the relationship between the treatment conditions temperature and relative humidity. [0032]
    • Example 2
  • Scanning Electron Microscopy [0033]
  • FIG. 3 shows the SEM (scanning electron microscopy) photographs of the various samples. FIGS. 3A and C show different magnifications of conventional spray dried lactose, showing a blurry surface due to the presence of a layer of amorphous lactose embedding the underlying lactose monohydrate crystals. Some tiny spheres (typically <10 μm) amorphous lactose can also be observed on some of the agglomerates. FIGS. 3B and D show different magnifications of stabilised spray dried lactose of the invention, presenting the same agglomerate shape but with a different sub-structure. The amorphous material is no longer present and the picture has gained in sharpness. The crystallised amorphous material has formed a microcrystal structure covering the crystals of lactose monohydrate. [0034]
    • Example 3
  • Tableting Properties [0035]
  • Various samples of tablets were prepared on a Kilian [0036] rotary press 15 stations at 30,000 tablets/hour. The tablets are 250 mg tablets made with 9 mm flat punches and lubrication with 0.5% magnesium stearate.
  • FIG. 4 presents the tablet ability of different samples of spray dried lactose treated under different conditions as follows: [0037]
  • untreated spray dried lactose [0038]
  • spray dried lactose left in an open bag to crystallise at ambient conditions (temp. 20-25° C., RH 40-50%, “naturally crystallised”) [0039]
  • spray dried lactose crystallised in a fluid bed with various conditions of air temperature and humidity (25° C./51% RH; 75° C./25% RH; 60° C./35% RH; 40° C./55% RH). [0040]
  • In general the tablet ability of the samples treated according to the invention is equivalent to or improved in comparison with the untreated material. [0041]
  • Spray dried lactose has the disadvantage of being a bit sensitive to the extent of lubrication. Before tableting, powders are always lubricated to facilitate the compression (reduce the friction between die and punches). The extent of lubrication is determined by the % lubricant used in the mix and the blending time used to lubricate the powders. A longer blending time favors the formation of a continuous film of lubricant on all the external surfaces of the particles. A tableting excipient should be ideally not sensitive to lubrication, meaning that the extent of lubrication would not jeopardise the robustness of the formulation (i.e. a change in lubricant level or mixing intensity would have limited effects on tableting properties). FIG. 5 shows that the additive of the invention, like lactose monohydrate, is practically insensitive to lubrication extent. [0042]
    • Example 4
  • Stability [0043]
  • Stabilised spray dried lactose is not hygroscopic. The moisture uptake of this product is almost null over a wide range of relative humidities. This is not true for standard spray dried lactose, due to the presence of amorphous lactose in the product. [0044]
  • The moisture sorption isotherms of different lactoses at 20° C. are presented in FIG. 6. The peak at 40-50% RH for spray dried lactose characterises the moisture uptake in the amorphous part, followed by crystallisation and rejection of moisture from the crystal lattice. The additive of the invention, unlike the conventional spray dried lactose, does not take up any additional moisture. [0045]

Claims (20)

1. Method for producing a tableting additive, which method comprises:
a) providing a spray dried tableting additive in particulate form which particles at least partially consist of amorphous additive material and at least partially of crystalline additive material; and
b) crystallising the amorphous additive material by subjecting the particles for a short time and under agitation to a temperature between 30 and 100° C. at a relative humidity between 60 and 25%.
2. Method as claimed in claim 1, wherein the relative humidity is as defined by the formula:
% relative humidity=218−47*Ln(T(° C.))
wherein T(° C.) is the temperature to which the particles are subjected.
3. Method as claimed in claim 1 or 2, wherein the temperature is 36° C. and the relative humidity is more than 50%.
4. Method as claimed in claim 1 or 2, wherein the temperature is 40° C. and the relative humidity lies between 50% and 65%.
5. Method as claimed in claim 1 or 2, wherein the temperature is 47° C. and the relative humidity is about 48%.
6. Method as claimed in claim 1 or 2, wherein the temperature is 53° C. and the relative humidity lies between 50% and 65%.
7. Method as claimed in claim 1 or 2, wherein the temperature is 60° C. and the relative humidity lies 31 and 44%.
8. Method as claimed in claim 1 or 2, wherein the temperature is 75° C. and the relative humidity is 25%.
9. Method as claimed in claims 1-8, wherein the short time is less than 10 minutes.
10. Method as claimed in claim 9, wherein the short time is less than 5 min.
11. Method as claimed in claim 10, wherein the short time is about 2 min.
12. Method as claimed in claims 1-11, wherein the agitation is provided by a fluid bed device.
13. Method as claimed in claims 1-11, wherein the agitation is a mechanical form of agitation.
14. Method as claimed in claims 1-13, wherein the additive material is lactose.
15. Tableting additive being in particulate form, wherein the particles comprise substantially no or no additive material in amorphous form.
16. Tableting additive as claimed in claim 15, obtainable by the method of claims 1-14.
17. Tableting additive as claimed in claim 15 or 16, wherein the additive is lactose.
18. Tableting additive as claimed in claim 17, wherein the additive comprises 5-20% β-lactose based on the total lactose content, the remainder being lactose monohydrate particles and a maximum of 5% water.
19. Tableting additive as claimed in claim 18, wherein the β-lactose is substantially in the form of α/β mix crystal.
20. Use of the tableting additive as claimed in claims 15-19 for the preparation of tablets.
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Cited By (2)

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WO2006068484A2 (en) * 2004-12-22 2006-06-29 Campina Nederland Holding B.V. Anhdyrous lactose agglomerates and the preparation thereof
US10820608B1 (en) 2015-10-26 2020-11-03 The Hershey Company Hard candy confections with low hygroscopicity

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WO2002008470A1 (en) 2000-07-20 2002-01-31 Campina B.V. Method for producing a crystalline tableting additive, additive thus obtained and use thereof
CA2960694C (en) 2014-09-09 2021-05-04 Vectura Limited Formulation comprising glycopyrrolate, method and apparatus

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WO2006068484A2 (en) * 2004-12-22 2006-06-29 Campina Nederland Holding B.V. Anhdyrous lactose agglomerates and the preparation thereof
WO2006068484A3 (en) * 2004-12-22 2006-10-19 Campina Nederland Holding Bv Anhdyrous lactose agglomerates and the preparation thereof
US20090081308A1 (en) * 2004-12-22 2009-03-26 Campina Nederland Holding B.V. Anhdyrous lactose agglomerates and the preparation thereof
US8173173B2 (en) 2004-12-22 2012-05-08 Campina Nederland Holding B.V. Anhdyrous lactose agglomerates and the preparation thereof
US10820608B1 (en) 2015-10-26 2020-11-03 The Hershey Company Hard candy confections with low hygroscopicity

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EP1301638A1 (en) 2003-04-16
ATE374261T1 (en) 2007-10-15
US20120220764A1 (en) 2012-08-30
DE60130657T2 (en) 2008-07-03
HK1057066A1 (en) 2004-03-12
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WO2002008470A1 (en) 2002-01-31

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