BASF辅料应用.pdf

P h arma SolutionsTheyourforChoiceSuccessVolker BhlerFunctions andApplications ofBASF PharmaceuticalExcipientsContentsPageForeword41.Solid dosage forms:tablets,granules and pellets71.1Binders7 Wet granulation7 Dry granulation10 Melt granulation10 Direct compression111.2Fillers141.3Disintegrants141.4 Enhancement of drug release161.5Flow improvers181.6Colorants181.7Matrix formers for sustained-release tablets201.8Soluble tablet coatings23 Subcoating23 Film coating24 Sugar coating251.9Enteric coatings251.10 Coatings for taste-masking271.11 Sustained release agents for pellets281.12 Plasticizers301.13 Polishing agents301.14 Adhesives for buccal tablets312.Soft gelatin capsules352.1Carriers,solvents352.2 Solubilizers352.3Antioxidants352.4Colorants363.Oral and topical suspensions:Ready-to-use suspensions,dry syrups,instant drink granules393.1Sedimentation inhibitors393.2Redispersing agents453.3Crystallization inhibitors,solubilizers463.4Taste masking agents483.5Drug stabilizers493.6Colorants504.Parenteral suspensions554.1Sedimentation inhibitors,redispersing agents554.2Crystallization inhibitors,solvents562Page5.Oral and topical solutions595.1Solubilizers595.2Thickeners625.3Solvents645.4Taste masking agents645.5Drug stabilizers655.6Colorants676.Parenteral solutions,emulsions and lyophilizates716.1Solubilizers 716.2Enhancement of bioavailability736.3Solvents746.4Lyophilization agents756.5Sustained release agents 756.6Drug stabilizers766.7Reduction of toxicity 787.Semisolid dosage forms:gels,creams and suppositories817.1Emulsifiers817.2Gel-forming agents827.3Solubilizers837.4Absorption accelerators857.5Solvents867.6Colorants887.7Carriers for suppositories898.Transdermal systems938.1Bioadhesives,film-forming agents938.2Percutaneous penetration enhancers939.Diagnostic products979.1Stabilizers9710.Alphabetical index of formulations,excipients and technologies993ForewordThis brochure describes the wide range of applications and functions of the excipients manufactured by BASF AG for the pharmaceutical industry.The spectrum of applications is remarkably broad,as can already be seenfrom the list of contents.It covers 14 fields of application in solid dosageforms such as tablets,applications in suspensions and solutions,as well as 7 functions in creams and suppositories.In addition to the applications given here,there are a number of minor speciality areas of lesser importance.Details and descriptions of the BASF excipients can be found in the Technical Information Sheets for the products concerned and the“Kollidon Book”.Almost all the formulations given here have been taken from our GenericDrug Formulations compendium.4561.Solid dosage forms:Tablets Granules(also for hard gelatin capsules)Pellets1.1.BindersAmong the most important binders for the manufacture of tablets,granules and pellets are povidone(e.g.Kollidon30)and copovidone(e.g.Kollidon VA 64).They can be used in practically all the usual granulationand tabletting processes:Wet granulation Dry granulation Direct compressionMacrogol of a certain molecular weight(e.g.LutrolE 6000)is also capable of acting as a binder.Direct compression excipients that contain a binder,such as Ludipressplay an increasingly important role in the production of generic products.The sustained release matrix bases Kollidon SR and KollicoatSR 30Dalso demonstrate strong binding properties in tablets.Wet granulationKollidon 25,Kollidon 30,Kollidon 90 F,Kollidon VA 64The three grades of povidone,Kollidon 25,Kollidon 30 and Kollidon 90 F,as well as copovidone(Kollidon VA 64)are very suitable for wet granulation,whether with a binder solution or with the pure solvent(usually water).Themost widely used methods of wet granulation are the following:Traditional mixing and drying on hurdles Mixer granulation with fluidized bed drying Fluidized bed granulation ExtrusionQuantities of 2 5%of the tablet weight are required in the case of Kollidon 25,Kollidon 30 and Kollidon VA 64,but only 1 3%in the case ofKollidon 90 F.This difference is due to the higher molecular weight of Kollidon 90 F which gives it greater binding power.The formulation fornaproxen tablets in Table 1 is a typical example in which an active sub-stance is granulated with a binder solution,but without a filler,and the formulation for gemfibrozil tablets is an example for solvent granulation(Table 2).It would be possible to replace the ethanol in this formulation withwater,though the optimum quantity would have to be determined.78Table 1:Naproxen Tablets(450 mg)1.FormulationI.Naproxen(Syntex)457.5 gII.Kollidon 3025.0 gWater90.0 gIII.Magnesium stearate(Merck)2.5 gKollidon CL10.0 g2.Procedure(binder solution granulation)Granulate mixture I with solution II pass through a 0.8 mm sieve,add III and press to tablets with low compression force.3.Tablet propertiesWeight511 mgDiameter12 mmHardness95 NDisintegration3 minFriability0.3%Dissolution,pH 7.4(10 min)86.9%Particularly with solvent granulation,the quantity of solvent(e.g.water)strongly influences the properties of the tablets obtained.Also,the physicalproperties of the binder,in particular its particle structure and size,have asignificant effect on the hardness of the tablets.This is illustrated in Fig.1for aminophylline tablets,the granules for which contained the same quan-tity of two different binders(6 g Kollidon 30 and 6 g Kollidon VA 64),butwere made with different quantities of water.Kollidon 30 is more sensitiveto the amount of water used in granulation than Kollidon VA 64.With thelatter,adequate tablet hardness is obtained with relatively small quantitiesof liquid.Fig.1:Solvent Granulation:Influence of the Amount of Water on theHardness of Aminophylline TabletsKollidon 30Kollidon VA64Amount of water,ml50556065707580Hardness,NAminophylline 100 g,Starch 100 g,Kollidon 6 g,Mg stearate 1.5 g1214182226303438#?#?#9Table 2:Gemfibrozil Tablets(600 mg)1.FormulationIGemfibrozil600 gCorn starch200 gKollidon CL20 gAerosil20030 gKollidon VA 6440 gIIEthanol 96%(or water)about 72 gIIIKollidon CL20 gPolyethylene glycol 6000,powder10 gTalc40 gMagnesium stearate8 g2.Procedure(solvent granulation)Granulate mixture I with ethanol II,dry,pass through a 0.8 mm sieveand mix with the components III.Press with high compression force(e.g.28 kN)to tablets3.Tablet propertiesWeight950 mgDiameter16 mmHardness151 NDisintegration2 minFriability0.7%Dissolution,USP(paddle),10 min70%20 min84%Solvent granulation with Kollidon VA 64 not only has the economic advan-tage that it is not necessary to dissolve the binder.It is particularly suitableif the capacity of the powder to be granulated is too small for the quantityof solvent that would be necessary to dissolve the binder.Kollidon 25,Kollidon 30,Kollidon 90 F and Kollidon VA 64 can also be usedto produce pellets and granules by wet granulation.The spheronization of averapamil formulation is described in Table 3 as an example.Table 3:Verapamil Spheronized Pellets(48%)1.FormulationIVerapamil HCI(BASF)480 gAvicelPH101300 gKollidon VA 6420 gAerosil 20025 gTalc175 gIIWater400 g2.ProcedureGranulate the mixture(I)in a Diosna granulator with water(II)andpass the moist granules through a sieve of 1.5 mm.Pelletize in aspheronizer at a speed of 300 400 rpm.Dry the pellets in a fluidi-zed bed and pass over a 0.7 mm sieve to remove the fines.10Lutrol E 4000 and Lutrol E 6000These two grades of macrogol are sometimes also used as binders in processes that contain a granulation step.As their binding strength ismuch lower than that of most of the usual binders,greater quantities mustbe used than is the case with Kollidon 30,for example.Usually,515%(weight,in the tablet)is required.Dry granulationKollidon 25,Kollidon 30,Kollidon VA 64Kollidon 25,Kollidon 30 and Kollidon VA 64 can also be used in compac-tion processes.The latter is particularly suitable for this applicationbecause of its higher plasticity.The quantities required are usually the same as those for wet granulation:2 5%weight,in the tablet.Table 4 shows a typical formulation for thisapplication for a high-dose vitamin C tablet with excellent physical proper-ties in spite of the high active concentration.Table 4:Vitamin C Tablets(500 mg)1.FormulationI.Ascorbic acid powder(BASF)500 mgKollidon 3030 mgII.Sorbitol,crystalline50 mgMacrogol 6000,powder37 mgOrange flavour3 mgCyclamate sodium10 mg2.ProcedurePass mixture I through a roller compactor,mix with the componentsII and press to tablets with low to medium compression force3.Tablet propertiesWeight640 mgDiameter12 mmHardness120 NDisintegration6 7 minFriability0.1%Melt granulationLutrol E 4000,Lutrol E 6000These two macrogol grades with molecular weights of 4000 and 6000 havea relatively low melting point(approx.60 C)and can therefore be used formelt granulation.Here,the binder is used in melted form,rather than in asolution.The concentrations required vary considerably,depending on whether the products are to act as a binder or as a hydrophilic matrix.These twofunctions overlap.Direct compressionKollidon VA 64Kollidon VA 64 is widely used as a binder in direct compression.It has highplasticity,an irregular particle structure,low hygroscopicity,good flow char-acteristics,a low glass transition temperature,and it gives hard tablets,making it the best dry binder available.Kollidon VA64 can be used as a dry binder together with all fillers and prac-tically all active ingredients.A mixture of Kollidon VA 64 with microcrystal-line cellulose has been found to be a particularly effective combination.Theusual concentration of Kollidon VA 64 used in tablets is 2 5%,though thiscan be increased considerably,as,unlike many other binders,its bindingeffect continues to increase with the concentration even beyond 5%,whichis reflected in the tablet hardness.Fig.2 illustrates this effect in ascorbicacid tablets.Fig.2:Influence of the Dry Binder Concentration on the Hardness of Vitamin C Tablets(40%Ascorbic acid pressed with Ludipress+Kollidon)A typical formulation with Kollidon VA 64 for direct compression is that for vitamin C chewable tablets shown in Table 5.It has been taken from the German“Standardzulassungen fr Fertigarzneimittel”published byDeutscher Apothekerverlag.Kollidon VA 64Kollidon 30Hardness,N0%5%10%15%0%5%10%15%5070901101301501701901112Table 5:Vitamin C Chewable Tablets(100 mg,500 mg,1000 mg)1.FormulationAscorbic acid,powder(BASF)42.2%Microcrystalline cellulose(e.g.Avicel PH101)28.3%Sucrose,powder13.0%Sucrose,crystalline8.0%Kollidon VA 642.4%Cyclamate sodium2.4%Macrogol 6000,powder2.0%Orange flavour+strawberry flavour(2+1)1.2%Aerosil 2000.2%Saccharin sodium0.1%2.Procedure(direct compression)Pass all components through a 0.8 mm sieve,mix and press withmedium to high compression force.3.Tablet propertiesVitamin C content/tablet100 mg500 mg1000 mgWeight250 mg1250 mg2500 mgDiameter8 mm15 mm20 mmFormbiplanarbiplanarbiplanarHardness157 N100 N150 NDisintegration(water)15 min15 min14 minFriability93%).Thus,most tabletsmade with these products require no further fillers(for examples,seeTables 6 and 7).However,it is no problem at all to add further quantities offiller in the form of pure lactose monohydrate or another filler such asstarch or sorbitol.This may be desirable for economic or technical reasons.1.3 DisintegrantsKollidon CL,Kollidon CL-MThe two crospovidone grades,Kollidon CL and Kollidon CL-M differ mainlyin their particle size.Kollidon CL-M is micronized and has an average par-ticle size of 10 m.It nevertheless flows relatively freely and is thereforesuitable for tablet manufacture.However,Kollidon CL is by far the more important disintegrant,as it deve-lops a much higher swelling pressure than Kollidon CL-M.Crospovidone isreferred to as one of the“super disintegrants”in the literature.Fig.3 shows the influence of the particle size of different fractions of Kollidon CL on the disintegration time of an analgesic tablet that contains5%disintegrant.The particle size clearly affects the disintegration time,but differences of a few minutes in the release of the active substance areusually of minor importance as many trials have shown.Fig.3:Influence of the Particle Size of 5%Crospovidone on the Disintegration Time of Analgesic Tablets(Paracetamol 250 mg,Acetylsalicylic acid 250 mg,Caffeine 50 mg)0246810121-40 m10-100 m100-250 mKollidon CLDisintegration time,minFractions of Kollidon CL1415In the wet granulation process,Kollidon CL can be incorporated after gran-ulation(see Table 1),or before,as its swelling action is completely rever-sible.In difficult cases,it is recommended to add some of the Kollidon CLbefore granulation,and some after.This has been done with the formula-tion of a gemfibrozil tablet in Table 2,as the substance has a relatively lowmelting point and can therefore sinter together on compression.If part ofthe Kollidon CL were not added before granulation,the disintegration timeof the resulting tablets would be much longer.Obviously,Kollidon CL is also very suitable for use in formulations for directcompression.Typical examples are those for a dispersible Piroxicam tabletin Table 8 and an acetylsalicylic acid tablet in Fig.4.The usual concentration of Kollidon CL and Kollidon CL-M used as disintegrants is 2 5%(in the tablet).Table 8:Piroxicam Water-dispersible Tablets(20 mg)1.FormulationPiroxicam20 gCorn starch150 gLudipress50 gKollidon CL8 gMacrogol 6000,powder10 gAerosil 2001 2 g2.Procedure(direct compression)Mix all components,pass through a 0.8 mm sieve and press withlow to medium compression force.3.Tablet propertiesWeight238 mgDiameter8 mmFormbiplanarHardness66 NDisintegration(water)57 secFriability0.1%LudipressAs Ludipress contains 3.5%Kollidon CL,it also acts as a disintegrant.Thedisintegrant effect is adequate,if the content of Ludipress in the tablet ishigh enough(see Table 6).However,if tablets made with Ludipress are found to disintegrate too slowly,it is recommended to add Kollidon CL to the formulation.Such aformulation for acetylsalicylic acid tablets is given in Fig.4.161.4 Enhancement of drug releaseKollidon CL,Kollidon CL-MThe rapid disintegration of a tablet is by no means a guarantee that theactive substance is released and made bioavailable quickly.Thus,the drugrelease rate of a tablet is a much more important criterion than its disinte-gration time.Kollidon CL is often very effective in this respect,as can beseen from Fig.4 which contains data for acetylsalicylic acid tablets madeby direct compression.Although both tablets,with and without KollidonCL,disintegrate within 4 minutes,the difference in drug release remainconsiderable even after 60 minutes.Fig.4:Influence of Kollidon CL on the Dissolution of Acetylsalicylic AcidTablets(Acetylsalicylic acid 400 mg,Ludipress99 mg,Stearic acid 1 mg)Normally,when Kollidon CL and Kollidon CL-M are used to improve drugrelease,quantities of 2 5%(in the tablet)should be added.In difficult cases where drug release still proves inadequate,higher concen-trations of Kollidon CL or Kollidon CL-M can be used.The