BIOSTATISTICS AND RESEARCH METHODOLOGY Ueto erneratty ceaurautercColleay ALES TENT ERY UNDER THE GUIDANCE OF CGF Toieg ites cei KL tc ype ee Gokara Madhuti eer _ aa eiRESPONSE SURFACE METHODOLOGY Se Sore ecm eS Recerca erry ie Meno eee ee a Ted SOT Oy aPC Se Eee Me eee So COMET RL ECA EaCe COLL ee CURL ca ee Pe COU eee Oe Seen tinieaenrineusl oth) Pesci} Serer tre eccrsa) Se Mace ea ina Rei | PP cece ey nMOS ME ME UT SOS On Rumble) 2. Sequential search stage ( to identify an optimum design region) 3, A final Stage of response surface study ( to obtain an accurate approximation of the response surface) + METHODS OF RSM * There are vo methods of RSM to obtain optimum response. And we move toward our optimum point UL Cc Som NOME LLCOLHTN cuthyns copes oat eRe on Ress ebecscat Come ce rere Cece Tao CT Sere tres amor eee Run he est RS ees ace se ess PSU RU ED os pO + Steepest Descent Method * If minimization is desired then we call this technique the “method of steepest descent”. + APPLICATIONS Sere cee ener deere Neca Te ant err etre * RSM is important in designing formulating and developing and analyzing new specific scientific Rare niceties + Itis also efficient in improvements of existing studies and products. CeCe mera iene ol etm See Tea MEIC TbE TAT Cu ero (erly uth ec ene ance cemeSer ence cnt Pieter crescent By CEU eRe irinotecan CaccsCENTRAL COMPOSITE DESIGN * Central composite designs are two level full factorial (2) or fractional factorial (2) designs Poem Mint mea anit ee in Rul tame noe Wt ean ergs Tn oie eer eeom terete tu trees sth ee eckson es eats ROP thre reg rested Oe ce eo amr Men CMCC ect mmrc LTC Cnt ametaTt Cet ee ec Ca (CCD)(Monigomery,1997). CCD is first-order (2*) designs augmented centre and axial points to allow estimation of the tuning parameters of a second-order model. Figure below shows a CCD for 2 design variables, Parse Meme UR treo oat aN ned fereney eRe Me tase ccia eestor Meee Ree pea ae antec area eens) aati aa o nineteen SC sea eC eM am cae CM OR eCR IR Ios reat il Perr M em Reeser eles Runt Coney + Enter factors ranges in terms of +/-1 to define the limits for the area of interest where the optimum is believed to exist. Axial points will typically be outside this limit. Enter the limits in the low and high ‘eaten:Se Stenger atc er ee CRU Mae ce mom ror fsa reat ec OE interest must be within the area of operability. Enter the limits in the =alpha and + alpha columns TYPES OF CENTRAL COMPOSITE DESIGN Pee ere Mier an eee b Serr Um ie eMC Diet Prone ena een Ee > CCF- Sree ans Pree ma ere keery UCU MUO R ce ue Eate Meee CTA Cae ‘ace centered CCD Teen eR eee cE * Beyond or below that level it is not possible to perform an experiment. Ses ene Bec Eee ae * Itis a sealed down of CCC designtr eee ee TM sar emer U MR TMM os mM ME eco ett ns that support the two-factor interaction model and the axial points in the final block if needed. iets BSc o anaes SR chem ce rete ser mi onern tect on cen Re ena Ree RCTS RCM atecmcn trae oleae SU CR Me Meet cee meee cem Tn) information. See eS Tey nel eos ean My aeons nina PaO Ab) eon Oo) (ey SOUR UCaCM eure th etal can@cley Merce CMe mE eel Bah Serco ine in com esate en ec ema en eros sd depends on the number of factors. If you need blocks in your design and the Pee ene ie tne men ent ss * Centre points: By default there will be some- centre points in a BB design, ‘The number varies somewhat with the number of factors and blocks. Adding Pee cee TRE eam Chuan te rey SRG ETO Coe ts hae cosdi to designs precision capability. Peron rae hacen ei ete toea (rearsHISTORICAL DESIGN + Historical Research Design: This method involves the systematic and objective location, evahiation, PUES edema SoM CONC TR ee Te ee Mee teenie tee amet Maren ome ecco Te research aims to show the importance of past events in the present situation, Mee eum ni een ccna at cornea hearers ere uence are often better understood if we understand the historical perspective. SOU em rts aOR eM Mem CRM cL ML ame MR Le) SMM Ute ML Tra CM aeons Slee cece aCe CoMU Ore LCL Mice Cea Rca LC can AC CLUDES CLC MLM ORC UML CCL TELCO many assumptions are found in this research. > CHARACTERISTICS OF HISTORICAL RESEARCH DESIGN * Historical research involves the careful study and analysis of data about past events. Seen ice ae ee RS mea MOR TOC CMe Rome cn me Tem TLC GCS Pye meee kon eel tar Seen mene ene rein een ern ce tens Sees erat Om CMCC mae Nm Tale mt eration ete ne mui + It Covers categories stich as historical legal, documentary, bibliographical, biographical institutional PeonSei Waco mua OTe RSL eR COR CCR CURIS Te OL UTR CO OLE ~ DIFFERENT STEPS IN HISTORICAL RESEARCH DESIGN ARE AS FOLLOWS: 1. DATA COLLECTION stir tesl Meculiceec ie) Mee VME Lcoeel RITE in Om eM Ler cose mee EE a eC co Te Rein ees ME eee Re MSC MOL E eLa ec eoe oerceML persons, groups, periods, or events. STAM oc Ta ace SSI Soe SULA LET PCL RD MULTI Cece ty Oe etic aimee tes or to be used as a record. ORs Bere en ecmetl (A Late Rese) neces COTO ARTULULUCOn SAO Teco Ceca ELUCOMOS Car] cece car Ce cM (ca co TS tien ena Eston nage treet ance eM ce CR SE ten on ec na enn gee Meet TT eee ‘event or actual participants in the same. For example most of the history books and encyclopedias. 2. CRITICISM OF THE DATA. * The second step necessitates a comprehensive review of gathered materials. External critieisni is the eee Mae eRe TUL UL aOR ge Sega ict ee Une nce nao o Ute tecture ta LMM ren eee ecm TSPenta Cn meth aire ean meom ener ant + Internal criticism is the determination of reliability by correctly interpreting the contents of the Cetra Vim ome Marne Ts cee Reser ie Tea Soe MTR EA TAS TUTTI Me Meo (erat in question by another collaborating source are a few of the safeguards used to ensure that Dr ecr ue eeee ea ONE MUTI MeM Trace Me cel cia TmteS ea ES cme eu TceMm Loma careC COC EOIN MUR CULM Mec Ras CEU TL CAL Le Cee ie CMe UR Lac oe Scan oe 3. PRESENTATION OF THE FACTS The historical researcher must bring the material together to analyze and test the research hypotheses Pm CUCL RU a La tai ame See Tae Oe Cameo Historical researchers must be careful at this point since the analysis of historical data involves logical Pec MCC MUEM ML Ste OL oom EIA MTree Beat COAL LD topical, thematic, or functional arrangement, ae ee ee Cone eC eet et een tects ROMO Cate eS ersce tem Retna enn traceSc MTOM elec hrc CMT are eStats) oa) CUTIE Tie] accel eo ea TE Sct EC UITU cee Ube * Historical research is a complex process because the topics of research are affected by numerous Rac CLe ReiIC rey + PURPOSE OF HISTORICAL RESEARCH Sree concn sansa See mL eu esa Pa crc tt + To re-evaluate data in relation to selected hypothesis, theories and generalizations, * To understand how and why educational theories and practices developed. Pee UUM ie Leet Se Cites PiU RoC CHO T ear aeCae Pe ey rarten resem oe ence Toten ec eee eect NodADVANTAGES Many current cdlucational practices, theories and issues can be better understood in the light of past eer eeen ec e ee ceieecae eC acc cmcroe em eCn ty enn Poe STANT Ter OsnemmUTPceccc TRUM LIN UO Koes CTI LELomcUe) oot A MOM TU MCere) Nelo Ke HRECTn REST CY AS Fo DISADVANTAGES Tierra om ten cece eM Scere tome mee UENCE Cac el ex RuCl os Oe RCM Ole toe mee emma cee OM Cee ctl ee tec Ree oa LUMO aa aa oe Historical research is In TORO Eom Roca os PS Teter atest ice ones Nao tom ance Te tama Eat ELEOPTIMIZATION TECHNIQUES OPTIMIZATION USING FACTORIAL DESIGNS Seen H MO) ier Les eS Lcoas ogo See haem eC CU ate CN ooo os Tee ec mi ea mC momenta erect are ccmC Tame chen mts See UU MOSCA Traditionally, optimization in pharmaceuticals refer to changing one variable at a time, so to obtain Pantene scouts ees AVOr cn Enero ie Rent Om Rca tm act UOT Se MeO Te ST OTR Loo PMU Me em les Mvorect ce Va Uc mees (UCT Te UCC MOer MI ETECnmUE Ue Teta coimer Mecliielih ra are can Tiare etree mecca eee ints Bae OLN Une eS ORS LESS Oe eo BUMS ce res ee CULO COU RE UROL La oe Catiaecn ec URE Sat Picea eats SN oso TR cc eCL MLR SELL LT oo ROL LoCo eC ae ToT unconfounded by the other experimental factors. Thus, if the effect of increasing stearic acid by Img is to decrease the dissolution by 10%, in the absence of interactions, this effect is independent im iterate murtuicoerrte esWhy is Optimization necessary eee act eo oa ee eth given set of restrictions & thereby produce the best formulation under a Safety & Reducing Roproducib tyCO NeAO ee niaon Cocoa UNO eC No) an _ Pao NaA) Problem typ Menke See te mhy ane Ut Re eS tc MeL sti limitatic simply practical based. This can best explained by taking hardness: of tablet and its d ene Penna Senet Tete ent ace roth eretureitorg sre Om Teron teem Neste Tee eg perhaps by simply practical based. Raa ote Pee OR) * But in pharmaceuticals, there is always-a limitation of a means of a physical limitation or perhaps by SR ean eins SOOT etn rtect feta tertiresntgtetn Res mate ttm eres nee Tmo eel ta oem Se cca me tran rete re ears nner ert ath MGR ones tera els mre ro Seen eon ni a ean ene Tne Rte cy Eye Teed Sere A ur ee watts ire Manto ieh ieee con ece tect eden CPese ume) nine vat came Grid Die rater rt ic9 ERO ene eT co + These are the variables which are directly under the control of the formulator. These might include the ro mC RUM oat oe UTM a SS mgDOR e ec oes UC eT ES cE MS RE ER ae) CO Pe en aT a St CAMS SME T eT ea cc Ce aca eT eT eC ree CAS UR USRU SEL nao These are the variables which are not directly under the control of the formulator, these variables:are the cee ee ee ee OR Ly cca Cdr Remco (eae toc Coe mt ice Ue a Ceri eee cian ie ccrer tem ‘XU Diduentrati XZ compressional fre XY Disimegrantlevel X$ Binder vet ‘XS Lubricant levelOptimization Process; SUR te neice resent ar oinec tee PRU UTR or eeu tcuiy SER Ue ies etki ee SOAR RIE ROTe ce ue ROR aCe eked ecm area es 2. Based on previous Knowledge and data, a preliminary choice can be made such as which process is to Peter hiteieci ee rence Be aE Ree UUM ec a eon cer rarer reece ce 5. The responses are analyzed for statistics by ANOVA. Test on lack of fit is done to get an empirical DUS mS Cems LT Nee nooner COC ie Corea SIRI Ue ee nom AC eee ene lce acu Rr lh (cag example restriction of hardness to 6-8 kg/cm2 and disintegration time < 5 min for a tablet formulation to Rau ecm cna MORO aU eeu ar Ter ty mee Tuam Mate Teme mee acc Ce Ooh eae near ee oeRea ht Bee ee Seen ce rn cre Ceara Recs eRe rea Mea Be ee a eet pecrnares + Depending on the number of factors, their levels, possible interactions and order of the model, various experimental See ace ah ks see ALU aC CULL a od defined by its co-ordinate (ihe Value given to variables) in the space. Oe renee att Sea * Factorial designs were used in the 19th century by John Bennet Lawes and Joseph Henry Gilbert Ronald Fisher argued in 1926 that “complex” designs (such as factorial designs) were more efficient than STNG Trae Cem eee a RT Com + A factorial design allows the effect of several factors and even interactions between them to be eae RT SLT Sh a ee RO Le eee Sit wei cm er acces erect Mm Mnin | fe ee cuneate Sa RUST aI omer e i MS te ee Rela Cuenca Tete SSR Mec Ne pou e eelnUc Nati iocah Ue bee uelt Coker le) Reuben aio into one. Finally, factorial designs are the only effective way to examine interaction effecis Pa eer ee Se eo ogee esa eR een Um CCS eo Ue eM Coa Cora os Ceo Factorial designs are used in experiments where the effects of different factors or conditions on choice for simultaneous determination of the effect of several factors and their interactions.* The simplest factorial design is the 2 factorial designs, where two factors are-considered each at two HTSCRSa Cerri SN CoB COU a SULLA DCL LIL Les bees TST EI Cac eee ann Sa eens ee ear eee nee ett ta eters CT Rua Laat Le UES RS er Coco MUS CGD OS EUS pas eR aa CTU ae a ane e COEUR ogee tee mre Mae eec sorter aitec tnt eun tare) factorial design is large. irae eat ema emir een ar eon iC csta kena menue rom erostct nuniber of experiments with full factorial design). The fitting of an empirical polynomial equation to the exy Pace ener manatee tener ey les Y =BO+BIX1 + B2 X2 + B3.X3+ + B12 X1X2+ BI3X1X3 + B23X2X3 — Where Y is the response, X1, X2, X3 are the levels (concentration) of the 1, 2, 3 factors and B1, B2, B3, B12, B13, B23, are the polynomial coefficients,B0 is the intercept (which represents the response when veer stom b. Plackett-Burman Design + Itis.a fractional factorial design with K = m*4 experiment, for seteening of (K-i) variables. Whete K is etn ceeRe Tr eur ene en rn caer rimental result facilitates the optimizationROC a + Star design is simply a 22 factorial design rotated over 45° angle in the space, A center point is usually ee RL LR reas ie eRe UL re Sn UO USAR Coa Ce ee eC eM eee Re ee MTR orth ee ee oe cee eer ou the full factorial design. In star design, 2k factorial designs are rotated over 45° in (k-i) direction in k- dimensional space with a replicated center point. k is the number of factors in the design. This results in Pe tee Ree ee aie eon teenage 4. Ceinsrat Composite Design. + A better désign that encompasses the advantages of factorial design or fractional factorial design or the Sear ecu iren ete Mts nectito ecru COD) Uitte Mea eatole cen NE voee Tm a hea aang ee Rade eae ent sae torments Osean See ae ea eon ar eae Conant et ce sg Lee each ee ial reac TAP aacUe aa Snes ec creer Emm loca MSc On cuca ee experiments may become too high. The Box designs for three or more factors are economical alternative fe etme tom etncm tsa ravo ee Se emt ctr er CURT Caen Mee ect MmLDSenany Cece Kee (SSL sce CLS SL incomplete blocks. which means thai every effect is not estimated in every block, but every factor effect is measured as equal number of times with a balanced partition over the different blocks. Seas ert ea Te Te aa + Doehiert proposed uniform shell designs, starting with an equilateral triangle, mirrored in one side to a hexagon. The hexagon is expandable in 2- dimensional space by mirroring the center point in the rs mM el heme ere Rear nM ULL CMU COU Meta Mes Cee taco cea ee) PTTL PLCS ULC OOM OL US eT el Se eee Co eC USS Me UCe i Raice SCs Re cata nce MRR reenact eT ae aa ce eC eer mute Cormac with one side of the hexagon parallel to the most important axis. va ete rare * For mixtures of components (such as drugs and excipients in the formulation), special models have been RRR eCea SAL* A fraction cannot be negative, and sum of the fractions of the components should be equal to one. An Tere a ER mee ORR Lem cmos i tA RMU Cmte een eee eee etna etc eee wee eee nce neo tae Mm me aT Pon ken em erence eC and so on. ‘The remaining fraction completes the sum to one, which implies a dimension reduction. For k variable, the factor space can be represented geometrically by a (k-I} dimensional regular simplex, for ROU nL eM CLC Me To eS COL ALE V) Simplex Lattice design Be men emt ed eons c Cen oR MUR RU ee at Te hem Pecan cae Linn tcrim cam omen emir crc mtr atin rcs eGR se CM rma emer co Mme Cm CoM aM cocci aT oot ae tes distributed orderly over the factor space, forming a lattice. The factors can be controlled accurately and cere ta ireterctet eamerone Metter teres et tere rhs VI) Extreme-Vertices design CO Cees Chase ism im Luai Ut ComyUTe BUM ema He) (ame Ce Comer asta eee lacics sem elo out ety vet teeter eae ceo tu Marit cmtere arc ncemn Tar crete ion enter setae observations are made at the corners of the bounded design space, at the middle of the edges and Fah Peace comm Uireate esta Nes item Mires MCR OU MTG CU Cen cecal Oe eS Sa Recenter Tare MmLULene ceCelarl ccna reinLe oe nu ee ee RE ce RR OR RCO LEC ceo MLM Ce} CU MRE Re ce CS eam eee CR totes MCA od EU RU Re eMC UNA ee ee COCR CETL Co ee ee eas eee rR eRe ERO Cece ene Re ee OR ee UL Co De aoe elon ema CO neo ssc ese) i) because of the necessarily smail changes utilized, it is not particularly suitable for lab. ee + “D-Optiiial” means that these’designs maximize the information in the selected set of experimental Rca eres oe Burr cc Tue a Sireeee nme entice lets Rereuts en es yee OR TTL) AD-Optimal design is suggested when: SU Ree cmc i Rem cL RU eng oeTComc nCORTmUcac Tg PON ett There are no classi¢al designs that can well investigate an irregular region. A D-Optimal design is then the preferred choice as it makes efficient tse of the entire experimental space. Tir Oe ee cer eee aes MUTA NOC CRORE RUSE utMeee UC Eee RU Coe Tene umn CRC UTUR ecole MACUL RCM Sie SRL Lait ee eeen ence aby ssn Cee net nn es ete Soren ce eet ae ata Pee seer tea henna nents ts Bl) eae ase arom CLM SPER ecme Eek emE Loe Pee RsaI UC E Ce Cm CMU Rm ORR nme EL eke code cera