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1、ORAL TABLETSDEVELOPMENTCHAPTER 2TABLET D EVELOPMENTWet Gran ulationDevelopme ntH andbook of P PharmaceuticalSect: 22. #Generic DDevelopmentORAL TABLETSDEVELOPMENTCHAPTER 2OverViewmentA :匕 Tablet DevelopDevelop ing low & high stre ngth actives via wet g r a nu lati onhigh shear tech niq ues H andbook
2、 of P PharmaceuticalSect: 22. #Generic DDevelopmentORAL TABLETSDEVELOPMENTCHAPTER 2H andbook of P PharmaceuticalSect: 22. #Generic DDevelopmentORAL TABLETSDEVELOPMENTCHAPTER 2OVERVIEWTablet development of low and high stre ngth drugs may follow two processes, either by traditi onal alcoholic or aque
3、ous wet granu lati on tech niq ues via high shear tech niq ues.Dosage stre ngths with 0.5 to 850 mg or more per tablet are con sidered suitable drug can didates for the high shear developme nt route.Where the tablet stre ngth exists as two stre ngths e.g. Nabumet one 500 & 750 mg tablets, higher str
4、e ngth tablet may be developed from the same granule ble nd using a geometric proporti oned amount of com mon granu late (i.e. x 1.5) for compress ing the higher dosage stre ngth.Low active fill weight are readily processed. Actives vary ing from 0.5 to 50mg of drug substa nces give typical tablet w
5、eights, ra nging betwee n 100 to 200 mg per compressi on. In desig ning geometrically scaled-up formula, the com mon granu late is a simply multiple i.e. 200 to 400 mg per tablet.Table 1.Wet Gran ulationActive Stre ngthTablet Weight0.5 - 50 mg100 - 200 mg100 - 250 mg300 - 550 mg750 - 850 mg850-980 m
6、gW herever possible the use of geometric proporti oned ble nds reduces the nu mber of bioequivale nt studies n ecessary, as a waiver may be obta ined for the lower dosage stre ngths.Common geometric proporti on ratios shown in the formulation tables are 0.75, 1, 1.5, 1.7, 2 and 3. (i.e.tamoxifen coa
7、ted tablets 10, 20, 30 and 40 mg or metform in 500 and 850 mg)DESIGNING THE FORMULATIONKeep ing wet compressi on formulati ons simple cost effective and elega nt require six basic eleme nts - n amely. n Critical choice of either alcoholic (95/99.5%) or aqueous granu lati on procedures (based on un i
8、t stability). n Choice of the overall formulatio n excipie nt mixture (key parts).n Choice of high shear granulator or a fluidized bed tech niq ue.n Choice of the actual wet granulation process ing steps (see flow charts).n Choosing geometrical proportioned mixes for multiple tablet stre ngths.nDesi
9、g ning and optimis ing thetablets physical specifications, for shape, weight, hard ness, thick ness, friability, dis in tegrati on, dissoluti on and film coat ing for light protect ion or taste mask ing.Table 2.Wet Granulation DesignParameterDecisi on RangeWet granu lati on Excipie nt ble ndUse a st
10、a ndardise excipie nts rangeMultiple stre ngthgeometric desig nTablet Weight150 - 980 mgIn dividual weight7.5%Average weight5.0%Tablet Hard ness8-18 SCUThick ness2.5 - 8.0mmFriability 1.0%Disi ntegrati on10 -15 minDissoluti onNLT 80 in 45 minCHOOSING THE FORMULA n Choice of alcoholic (95% or 99.5%)
11、or aqueous granu lati on procedure. The choice of the granu lati ng solve nt whether pure alcohol or a water / alcohol mix is a critical early decisi on.ALCOHOLIC GRANULATIONMany active materials do not produce satisfactory stability profiles whe n granu lated solely with purified water. Active degr
12、adati on and overall impurity growth is ofte n accelerated duri ng wet granu lati on or duri ng the shelf life period due to the prese nee of residual water in the compressed tablet. Hydrous (95%) or an hydrous alcohol (99.5%) is the granu lat ing solve nt of choice in aqueous sen sitive active mate
13、rials.Table 3.Alcoholic GranulationActiveAlcohol %Bupropi on99.5%Carbamazep ine95.0%Diclofe nac Na / K99.5%Glipizide95.0%ISMN 40mg95.0%Mesalami ne95.0%Naproxe n95.0%Omeprazole99.5%Simvastit in95.0%Verapamil HCl99.5%ALCOHOL / WATER GRANULATION Occasi on ally an appropriate ratio of alcohol / water mi
14、xtures from 60 : 40 (Nabumet one) to 95 : 5 (Mesalam ine, ISMN etc.) are appropriate and can produce stable granu lated material.Table 4.Alcoholic GranulationActiveAlcohol/WaterNabumetone 500/75060.0 : 40.0%Mesalam ine95.0 : 5.0%AQUEOUS GRANULATION ACTIVESTable 5.Aqueous GranulationActive% P. WaterC
15、arbidopa /Levodopa100Cion azepam100En alapril Maleate100Famotidi ne100Frusemide100Gemfibrozil100Norfloxac in100Tamoxife n100Trazodo ne HCl100n CHOICE of the wet gra nu latio n excipie nt mixture.The perce ntage of the active ingredient in the overall formula may range from 0.5 mg (Cl on azepam) to 850 mg (metformi n) while excipie nt compositi on may vary from 99.5% to less than 10% ( see tables 15 to 17) Where the active material exceeds 90% with 10% or less of excipients the process o
