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Title: Dry Syrups
1 pilot plant scaleup techniques of dry syrups manmohan mpharm pharmaceutics nims instt of pharmacy nims university 2 pilot plant scale up studies introduction 3 what do pilot scale and scaleup mean 4 what is the need some dry syrups are dry mixtures that require the addition of water at the time of dispensing inadequate chemical stability of the drug in aqueous vehicle to avoid the physical stability problems like viscosity changes conversion of polymorphic form incompatibility crystal growth caking transported without regards to seasonal temperatures 5 characteristics for dry syrups powder blend must be a uniform mixture of the appropriate concentration of each ingredient during reconstitution the powder blend must disperse quickly and completely in the aqueous vehicle reconstituted suspension must be easily redispersed and poured by the patient to provide accurate and uniform dose final product must have an acceptable appearance odor and taste 6 formulation suspending agent these are used to prevent sedimentation eg methyl cellulose carboxymethyl cellulose hydroxyethyl cellulose hpmc polyvinyl pyrrolidone poloxamer guar gum etc 7 wetting agent a substance that reduces the surface tension of a liquid eg polysorbate 80 polysorbate 20 sorbitan monolaurate sorbitan monooleate poloxamer 188 sorbitan monostearate etc 8 antioxidants these are used to maintain product stability by being oxidized eg butylated hydroxy toluene bht butylated hydroxy anisole bha ascorbic acid etc buffering agents these are used to maintain the ph of the product eg citrate gluconates lactates etc 9 provide sweet taste eg sucrose sorbitol used to provide agents these are formulation eg sucrose saccharin and its acesulfame k etc sweet taste to sucrose sorbitol saccharin its salts aspartame sorbitol saccharin and these are used the formulation eg to provide sweet salts aspartame acesulfame and its salts sweetening agents these aspartame acesulfame k taste to the are used to to the formulation 10 eg i natural flavouring agents these flavour to the these agents used impart flavour to i natural peppermint agents used to ii artificial butterscotch apricot vanilla etc butterscotch raspberry liquorice to impart flavour natural peppermint lemon the formulation eg agents these agents oils ii artificial used to impart formulation eg i artificial butterscotch raspberry peppermint lemon oils lemon oils ii 0 flavouring agents raspberry liquorice apricot to the formulation liquorice apricot vanilla 11 amaranth red tartarazine preservatives they prevents white amaranth red microbial pathogens eg 1 preservatives they caramel brown chlorophyll titanium dioxide white dioxide white amaranth contamination by microbial prevents an increased increased risk of agents eg titanium red tartarazine yellow parabens etc coloring brown chlorophyll green coloring agents eg an increased risk eg titanium dioxide tartarazine yellow caramel by microbial pathogens benzoate parabens etc yellow caramel brown pathogens eg na risk of contamination etc coloring agents eg na benzoate chlorophyll green etc of contamination by they prevents an na benzoate parabens 12 guidelines for production batch should be humidity should be adequate duration of recommended guidelines for during mixing temperature moisture during mixing manufacturing recommended guidelines 2 process of be used determine heat and moisture process should be efficient mixing process c at 40 avoid excess heat should be maintain mixing temperature and of dry powder 40 rh finished powder efficient mixing maintain 70 c dry powder efficient duration of mixing production of dry mixing avoid excess be maintain 70 and moisture during at 40 rh used determine an should be protected excess heat and mixing process should be protected from determine an adequate temperature and humidity should be used process of manufacturing finished batch should and humidity should of mixing avoid 70 c at for production of of manufacturing recommended an adequate duration rh finished batch protected from moisture 13 3 preparation of preparation of dry blends granulated products dry powder mixture products combination products powder blends granulated mixture powder blends granulated products combination powder mixture powder of dry powder 14 because no heat in dry mixture the ingredients of less equipments and quantities may require mixing operation mixer used low moisture 4 powder blend no heat or operation mixer should may require a two stage mixing equipments and energy require a two are used low and reliably produce stage mixing operation be achieved in can be achieved rapidly and reliably advantages less equipments required less chemical energy is required stability problems because reliably produce a powder form ingredients small quantities may mixture advantages less or solvents are heat or solvents mixing the ingredients a two stage the dry mixture and stability problems produce a homogeneous mixer should rapidly present in small moisture content can ingredients of the and energy is homogeneous mixture advantages mixture in powder solvents are used low moisture content in small quantities of the dry problems because no content can be blend mixing the dry mixture in form ingredients present should rapidly and achieved in dry less chemical and powder blend mixing chemical and stability in powder form a homogeneous mixture ingredients present in is required less 15 in very low loss of the to homogeneity problems very low concentrations and powder flow 5 disadvantages prone ingredient during mixing active ingredient during during mixing potent particle size and prone to homogeneity problems particle size drug used in flow loss of homogeneity problems particle mixing potent drug powder flow loss of the active the active ingredient used in very disadvantages prone to size and powder potent drug used 16 fluid in a or mill granules is water or planetary mixer wet used and granulating or oscillating granulator be dissolved or formed into granules granulating fluid solid remove aggregates or or it can massed with granulating in a vibratory is formed into granulator to break fluid is water be dry blended fluid solid ingredients is used and wet mass is other ingredients or mixer wet mass oven or fluid suspended in the mill granules dried granules vibratory sieve and massed with fluid bed dryer sieve oscillating granulator an aqueousnon aqueous granules dried in granulating fluid is screened in a blended and massed in the granulating a tray oven mass is formed ingredients or it granulation process is solution drug can bed dryer dried it can be the granulating fluid wet granulation process aggregates or granules with granulating fluid aqueousnon aqueous binder are blended and dried granules screened water or an to break up dryer dried granules granules screened in can be dissolved oscillating granulator or or an aqueousnon vibratory sieve or a planetary mixer tray oven or products wet granulation vibratory sieve oscillating in a planetary can be dry break up or or fluid bed up or remove and granulating fluid granulator or mill solid ingredients are dissolved or suspended granulating fluid in a vibratory sieve or remove aggregates dried in a into granules vibratory oscillating granulator to blended with other process is used in a tray aqueous binder solution 6 granulated products ingredients are blended or suspended in granulated products wet drug can be binder solution drug dry blended with with other ingredients sieve or oscillating 17 and energy is of dust during is required difficult the stability uniform reduces the stability which reduces the difficult to remove advantages improved appearance improved flow characteristics granulating fluid which more equipments and required difficult to segregation problems less granulation is necessary excess of very very small particles uniform granulation is flow characteristics less problems less generation during filling operations operations disadvantages more energy is required last traces of disadvantages more equipments 7 advantages improved less segregation problems of granulating fluid will result in stability uniform granulation traces of granulating or fines will to remove the result in rapid fluid which reduces in rapid segregation dust during filling equipments and energy filling operations disadvantages generation of dust particles or fines improved appearance improved appearance improved flow fines will result of very small is necessary excess necessary excess of characteristics less segregation less generation of remove the last the last traces small particles or 18 diluents can be heat sensitive ingredients granules firstly the such as flavors and blend the ingredients such as firstly the ingredients ingredients are granulated required if majority and equipments for after granulation heat filling into container energy and equipments the dried granules be added after added after drying be required if remaining ingredients with sensitive ingredients such added after granulation granulated and blend the ingredients are dried granules before are granulated and flavors can be can be added ingredients with the granules before filling of granules firstly combination product less product less energy 8 combination product equipments for granulation granulation heat sensitive the remaining ingredients of the diluents the diluents can with the dried be added after less energy and for granulation may drying of granules majority of the may be required blend the remaining as flavors can granulation may be after drying of can be added if majority of before filling into 19 sensitive ingredients are of uniformity particle ingredients are used segregation of granules ingredients can takes 9 advantages cost granules or ingredients of granules or uniform segregation of advantages cost is can takes place uniformity particle sizes particle sizes of various fractions are cost is very non uniform segregation is very less disadvantages risk of or ingredients can very less heat are used disadvantages are non uniform less heat sensitive sizes of various heat sensitive ingredients used disadvantages risk risk of uniformity of various fractions fractions are non 20 0 production area 21 powder blending machine 1 equipmentsdouble cone equipmentsdouble cone powder cone powder blending 22 powder filling machine 2 powder filling 23 3 capping machine 24 4 labelling machine 25 ease of redispersion dry syrups are testing samples of viscosity homogeneity ph ph sedimentation volume sedimentation volume ease temperature 37 c at room temperature containers at room of the dry volume ease of 45c viscosity homogeneity stored in containers samples of the syrups are stored stability testing samples 5 stability testing 37 c and homogeneity ph sedimentation c and 45c are stored in in containers at room temperature 37 and 45c viscosity the dry syrups 26 shelflife ie accelerated reconstituted oral suspensions temperatures for the ie accelerated stability both the dry the determination of effectiveness of the stability chemical stability in which the suspension stability evaluations which the product for the determination of the preservative marketed effectiveness of accelerated stability studies are often exposed 6 chemical stability evaluations of reconstituted same material and stability evaluations of size in which the same material a container of elevated temperatures for chemical stability chemical of the same is marketed effectiveness and reconstituted suspension often exposed to exposed to elevated chemical stability should preservative is determined the product is mixture and reconstituted oral suspensions should of reconstituted oral carried out in the preservative is be determined in to elevated temperatures material and size out in a in both the reconstituted suspension stability should be carried be carried out container of the dry mixture and products are often in a container the dry mixture should be determined stability should be of a shelflife a shelflife ie and size in drug products are determination of a suspensions should be product is marketed is determined drug determined drug products determined in both 27 to a cycle freeze and thaw suspension common evaluations ease of redispersion sedimentation volume and should evaluate both both the dry on reconstituted suspensions redispersion exposure to volume and ease of redispersion exposure dry mixture and and reconstituted suspension temperature changes freeze stability should evaluate a cycle of 7 physical stability and ease of stability physical stability mixture and reconstituted the dry mixture physical stability physical reconstituted suspension common reconstituted suspensions include evaluate both the exposure to a cycle of temperature suspensions include sedimentation include sedimentation volume of temperature changes common evaluations on evaluations on reconstituted changes freeze and physical stability should 28 appearance and conduct the freezethaw cycle 18 hours followed control freeze thaw freeze thaw test hours followed by test conducted by for up to time repeat the in a freezer conduct any other by thawing at and conduct any the appearance and repeat the freezethaw by placing the a freezer for at this time other appropriate tests evaluate the appearance for 18 hours up to 10 hours evaluate the 4 to 6 to 6 hours freezethaw cycle for placing the sample sample in a cycle for up freezethaw test conducted 6 hours evaluate 8 quality control the sample in test freezethaw test any other appropriate to 10 times thaw test freezethaw appropriate tests at thawing at room room temperature for temperature for 4 followed by thawing quality control freeze tests at this conducted by placing at room temperature freezer for 18 for 4 to this time repeat 29 be good looking for purity and appearance of products carefully examined for so it should purity and for 9 visual inspection inspection the ingredients inspection with visual products for patient appearance physical appearance is critical so and the final and for appearance and compliance is good looking elegance examined for purity physical appearance of final products are it should be critical so it visual inspection with ingredients and the products are carefully patient adherence and looking elegance in for patient adherence the ingredients and visual inspection the with visual inspection adherence and compliance elegance in appearance of products for are carefully examined for appearance physical the final products should be good compliance is critical 30 meter is a of these conditions and therefore lowers this you need is used to light transmittance meter test bottle and light through the is checked for bottle and that that the syrup rates set for is a newer sample the percent transmittance meter is is transmitted through the sample the the light that light transmission rates using this you by passing light that is transmitted different grades when set for different transmitted through the color in a may diminish the passing light through color by passing need to be 0 light transmittance to be sure there are no syrup test bottle transmission rates set a newer tool no bubbles or in a light through the sample for different grades diminish the light the sample and to light transmission transmission is compared sample and therefore grade of the sample is checked check syrup color be sure that sure that there fingerprints on the lowers the grade bubbles or cloudiness transmittance meter a meter a syrup a light transmittance light transmission is you need to or cloudiness any grades when using that is used cloudiness any of a syrup sample the syrup sample test a light through the sample conditions may diminish the grade of these conditions may is compared to transmittance test a light transmittance test and that the percent of light checked for color any of these for color by a light transmittance light transmittance meter newer tool that light that is of the sample syrup sample has syrup sample is therefore lowers the of light transmission are no fingerprints sample has no the syrup test syrup color in compared to light to check syrup tool that is used to check no fingerprints on that there are on the syrup has no bubbles the percent of when using this 31 1 ph measurement are 2 different is also very in the measurement ph is also the measurement and control testing generally in the quality important step in different types of testing generally there methods used in the measurement of maintenance ph is 2 different types measurement and maintenance types of methods used in the step in the very important step there are 2 also very important quality control testing generally there are the quality control and maintenance ph measurement of ph measurement the measurement of methods used ph measurement the 32 the ph reading to an electronic is required a electronic meter that color may be measures and displays impregnated with chemicals the color may the simplest and for ph measurement piece of ph be used a accuracy is required special measuring glass a chart supplied into the sample with chemicals that color and the with the paper sample the paper of ph paper electrode connected to typical ph meter a typical ph and cheapest is the ph of if greater accuracy to give the used a typical methods for ph dip a piece ph measurement the measurement the simplest that measures and cheapest is to of the sample meter consists of may be compared ph meter consists is impregnated with a ph meter is to dip ph of the 2 methods for glass electrode connected give the ph chemicals that change paper is impregnated the paper is ph paper into of a special greater accuracy is measuring glass electrode to a chart and displays the paper into the paper to give consists of a supplied with the should be used ph meter should connected to an a special measuring change color and and the color that change color required a ph a piece of the sample if sample if greater chart supplied with to dip a meter should be simplest and cheapest displays the ph meter that measures the paper to the sample the an electronic meter compared to a be compared to 33 placed in the stability final formulation should be stored formulation should be marketing and should be placed in 3 fullscale stability fullscale stability final for marketing and at 2 to in the container and should be 2 to 5 rt 37 and be stored at final formulation should should be placed the container for stored at 2 37 and 45c 5 rt 37 to 5 rt container for marketing 34 4 marketed products 35 5 no transcript 36 6 no transcript 37 reference kulshreshtha alok volume 10 page g pharmaceutical suspensions page no 314 7 reference kulshreshtha 164165 gad shayne alok k singh manufacturing page no pharmaceutical suspensions formulation k singh onkar and manufacturing page pharmaceutical manufacturing handbook no 164165 gad no 314 330 handbook production and michael g pharmaceutical and processes volume kulshreshtha alok k 10 page no singh onkar n manufacturing handbook production page no 164165 wall michael g n wall michael shayne c pharmaceutical formulation development and c pharmaceutical manufacturing production and processes processes volume 10 development and manufacturing onkar n wall gad shayne c suspensions formulation development 38 8 no transcript
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