1, Dill beeen zero an fit adr rections with table examples 6 Cap eis nd pa ft ot rao wt ae 7 Dan yan emg ce ron tt of 4: Dunc xeon fr ti time ke 9 pret on of oy for a nero order reaction. Hl each question carrie 10 marks 1 We th methods to ascertain he oder of eaction 2 Compare fst and send er acon wih respect 10 the es and Gila heteedson bee eit. 2 Drug Stability ayo! Dagan f Phamaceiten Product ns Seeonpenten of Doe —Prevertve Maa {Rhona of ug on Ong Dnoonposn REE Tmt oe Orn Decorouton emo Sin Tetra Bosoe Forms Seaoe ‘rug decomposition or degradation occurs ding storage because of cherie iteron (reaction) ofthe ative ingredients or aves, The amt of chemin Kins ts elpul to predic the rte of such ‘Rietons and furthermore to evaluate the she ie Stabila is ofall defined asthe time lapse during which the dmg product renin the sime roperis and characteristics that t poser Pa er nmufactre The sabi of product is expressed the sis ied or technically 2s shel/ fe. Expiaion period ia valuable suum fr all pharmaceutical dosage forms. The expiretion Teall be peetiably accompanied by deals of speeifc stores ae aos prided in the parsacopia fr this PuOHs (BSE: ene gingysorage and labeling). Adewne stably dot arqulrg tone anatacarer shouldbe available to support the expraton period en a condlons specified. A manufacture i obliged t0 indicate ee getr sofa drug on the label unless i greater then 3 years: No tive may be sold afer 5 year. Subiity studies are neces fr the following reson 1. Product instability or chemical degradation of ctive drag may leat io undermedicaon due to Towering ofthe concentration of the vin nthe domge frm, Examples are digorin and theopbling ton of rug isnt maintained inthe body (or bood) theo repnoprate dose, te dosage frm bocomes ineffective, ping decomposition of acive dag toxe products may be meal ror example, p-aminasalicyic acid (PAS) is converted into >” [HNTHO0K OF PHYSICAL PHARMACEUTICS uninoponol, which is fois. Infsion of degraded peniclin G cases iron ie eco, eae of seston of bmp foxmation of antipenicitoy! antbioies, 5, Instability may be dv to change in physical appearance Exam ples ot this type are, mottling of tablets, creaming of emulsions oF Coking of solids in 8 suspension. Drug Control Administration has tke steps in the public interest. Ac the sim ime, manufacturers have taken steps to conduct stability Studies, tn this proces, the following advantages are perceived. (@) Assurance to the patient : The manufacturers prescibe the caption period on their product. Tis isan assurance given by the Iinafacturers thatthe patent would receive a uniform dose throughout the sel ie (©) Economie repercussions: Stbilty testing prevents the posse ‘itty of marketing unstable product Heavy expenditure i involved in recalling a product from the market, when found unsable at a later ‘etd, Italo cost the repuation ofthat company. (©) Legal requirement : The Drug Control Administration isis ‘on manures on conducting the stability studies, identity, strength, purity and quality of the drug for an extended period of time in the ondtions of normal storage ‘A more compressive parmacopaia! protocol (USP) prescribes the Following criteria for aeoepable levels of stability Tre of Conitons Mattaned During Ts Salty _Stlf ie of the Prout ‘Chemical Resin ts ceil epi and ble prey Pied’ Apes; abi: uly: sition, ad ‘Sapo be eine Mrbilogal Rete stil; efetvenes of nlcrbil gents ‘Termpewie rug acon renin encanged “oxiolglé_N slelcrt ines in toxiy “Though the principles of Kietics ae sed in predicting the sabiity fof drugs, there are & few differences between kinetics and stability Studies, These area fllows. (a) Chemical kineies are mort ofen stati shrough several halt ives. while stability (ot room temperature atleast) i usually studied oye to 90 (or $594) ofthe inal strength va () Chemial Kneis are mostly carried out in at pure a system a8 1 et with as minimum adjuvans as posible. In stably, he vest under sad rey contin many components {The goal of chemical kinetics is to slit reaction mecha: win Watt studies, the objective isto establish an expiry date. v2 DRUG STABIATY s PHYSICAL DEGRADATION OF PHARMACEUTICAL PRODUCTS (4) Loss of Volatile Constiouents van cra agents such ss iodine, campor, mental, ethyl alohol, on tne chloroform ave a tendency 10 evaporate from the eye during stones. Similar iroglyerne tablets may lose i eae ‘ging velaloain of the medicament: ‘The preventive rae clade Keeping the product in wellclsed containers, and Sorin it in coo! place. (@) Loss of Water ato le (water fom the product leads to dereas in weight sch Conseneation of drag and increases potency. Efflorscetsub- ‘ies i nis as borax, caeine and quinidine sulphate, have a ntl tania fp Toe war. Products such as emulsions and semisoids tend) ine. Loss of wafer depends on temperstue and hur Pelbnnive mesures Include preserving the product in a welhclosed Comaine and storing it in cool pace (6 Absorption of Water ‘Aeron of moisture fom the atmosphere Increases the weight of te ea ites the dose, and decreases the poteey., Dellguesent 1 Pen such as casiom chloride and potassam eubonat have & a ericney to absorb wate Gelatin capsle wll sorb mse at nc sot and sticky. Preventive measures include storage of Tack products in wel-eosed containers, (@ Crysal Grow ooo cre the amblenttsmperatue (ay and night or seasonal) cause crystal Solon When temperature is lowered, the stun ecomes ste penmunaed. Henos, precipitation and cra growth of the rug is Fa por example, 10% wh calcium gional in injection is & ee aed solution. Buti ore reduce the iskof erst, supeattgess the use of calm sacharte (more soluble calm” THXTHOOK OF PRYSICAL PHARMACEUTICS uber. A prt of ealeium gluconate (nat more than 56) is by calcium saccharate Sispension—Partiles slowly become bigger in size and finally may fovm a hard ake. These crystals, if present in the injection, may block the hypodermic needle. These pariles produce arity texture when applied es an ophitaeic preparation Preventive measures ince (Select suitable storage conditions to reduce ciation in ambi nt temperature (increase the visosity of the product so that diffi of solute molecules onto the erysal surface willbe hindered. (id) Include surtice active agents in formulations. These agents gt sorbed on the surface ofthe etal and inhibit the farther ‘deposition oF solute molecules. Polymorphiom Polymorph exhibit significant ferences in important physicochemi- cal properties suchas solbilty, dissolution rate and mcitng point Tn ‘genenl, more soluble metastable dr is employed inthe manufrs For example, cortisone estat, Fon Is more soluble (metastable) and formulated an aqueous suspension. During storage, it may be con- verted into Form IV (more sable frm). Such changes ied to aking of the consone acetate suspension. Nomally sispending agents such as methylcellulose re aed to prevent the conversion owing to enhanced ‘scat and limited difsion of molecules. Colour Changes Color changes indicate some kind of chemical or photochemical scomposition ofthe ative ingredients, dyes or other ingredients. Col ‘ourfading of dyes is a filly common ‘ype of insabliy. indigo ‘amine dye tends to fade inthe presence of reducing substances actose sand dextrose). Tartazine tends 1 fade rapidly in the presence of dditives (surface setve agents) or ight. Colourevetopment :Aspiin tablets become pink and ascobie acid tabits turn yellowish browa. Adrenaline om exposure to ir becomes ted Preventive measures: Protet the produt fom light and at. Avoid ing redoing sutstances (dextrose ete) a8 additives, Include ue sorbing substance: sich as 24ihydrobezophenone inthe formulation 38 are used to evaluate the plysia! stability) of spproprite to. discs them in their respective rom, emulsins,semisolids, tablets te, These iy ie fr more important because ae ara cgi cts i ee eae elie ot the emulslon will beak (physia instabii) {EMICAL DECOMPOSITION OF DRUGS ia PREVENTIVE MEASURES: A sil set ecm ene mtn Soot wert sdergo uifferent nical reactions. Ingredi- ‘se re ay ung ent hema acs, nee a se longe frm al cvionmens Sc (68, AM cintn se) ater pysealand oie sb Se eran aeomponon ects a Ene oda = ‘principles that generally govern hydrol ys reactions may be lised low rag with eter and amide go way and deo Ryalis Sie rou. re ater weak acids or bates. Thee, tte may be * Beis lnc forme or eal olen Hoi Sik terecer Tie specie posts itr than ith moe eet ly eed Pn. 1 and (OH ions ye + Hyérbsreaetons are catlysed by jm. Hy ‘Pow fors ease yrs by about 100 0100 Seuvely than hydrogen os “hese pines help arationaling the eign of frm sb pot of ew es "A fo digs which decompose by hyip ar gten el Taide Cicpic rine ‘iin one copa a Barbituric acids pee rps react with one molecule of ‘ater groups break fst than nins from Fao ‘snaSlcylamie ie ecompesed by both acid and tase catalysts. {onnin ester groups, such as aspirin, procaine, atropine Onsen tee non + acon om a a in pan eae ee Amplelin in sluion undergoes hydrolysis and fliows frst order. Protection Against Hydrolysis: Hydrolysis reactions ae known t0 ccc in preenee of mols, catalytic species Hand (OHY.. Protec tive measures sould aim a eliminating the influence of these factors on the dug (a) Bufers: Drags may te stabilized bythe use of buffer. The pH ‘ot te sltion should Be ajated o that the drag wil ve maxims bi and therapeutic atv. Therefore, by experimentation, the ‘Soe of buffer and the optimum pH should be established. In gener Cimimal pH wil be between 3.5 and 5, since in that range the HT and {OUy catalysed hyareyss are about equal. Pilcarine i highly active (o ahaline fH because it existe inthe unionized (fe base) form. But alkaline pH, it fs Bighly iviatng to the eye and also decomposes Tipily. "Therefore, to prevent hydrolysis, acidic pH has to be selected ‘Stet «ble with low baer pacity stat when administered i he Shor ike pil prdualy rises and releases the fie base for dru. ction Pruhls easan: boric acd bullr of «pl 5.0 with low buffer capacity selected. () Complesation : Hydrolysis of bemzocaine in aqueous solution canbe inhibited by the euiionofeffeine wich forms a complex. AS {rest of complexation, the arack of catalytic speies on benzoeaing foay be redoced. The ion-dipole interactions between [OH or (HI~ Tome and drag molecules wil be reduced. Now the rate of hydrolysis Since prosine undergoes yobs, is nessa 10 cart she tom of io. Normal ct ow ener an lng period of ne (LTLP) or high peste and shor a sine GTS) are employed. for he strlcatn of pone soe oni as sugges tht utlving a 20° son prod ftne ‘is preferred to prolonged heating at 100°C an ‘00 -cH, ae arena enon oO i +$H0-chy-or ae panne : oto Sa t NN'Detn comes” ceeae Ate Eat Atropine is sero i opine ia tropane exter of topic acid, which und ich under i and alkaline hydrolysis. The optimum pH for maximum stability i 4b SeeXC)- corte eens eit fm dn ot pe colnet tenia ret sooo ‘oluton. As the amount of efine creases, more nd more amount of eee, aa ec ths atk cceeel ts sree tea sa ann peng. Ont es Wh ie a oe aes wn ron tate os vd (©) Suppression of solubility : When the solubility of a drug de rots, the concentration of drug insolation phase wil be doors Hance the rate of hydrolyse reduced. AS most ofthe drug is in he Insonble ste ony sal Fncton willbe in sluon Form (it dependssolubility). Nov, the rate depends on the saturation and flows zero order reaction. (0 Addvives : Cirses, dextrose, sorbitol and gluconate, when ‘combined with drug, the solubility of drugs wl be suppressed, probably because of decreased hydration of drug molecules. (i) Salts: The degradation of penis cane prevented by using poorly soluble salt of procaine pencilin in the dosage form. This preparation results a suspension and follows 20 order. ‘Another xample is benzatine penicillin G, (li) Derivatives : Poorly water soluble derivatives such as esters (igher fatty sid) of drugs can be usod o reduce the tendeney ‘of hydrolysis. Examples are erythromycin propionate, erythm= ‘nin stent, chloramphenicol palmate et (8) Removal of waer: As the presence of water is responsible for hydrolysis i is beter to avold its contact withthe drug Inthe prepara- ‘ion. This i ahelved bys (@) Storing the deus in dry form. When desired, rconsiut the product. Example i steptomycin dry powder for injection. (©) Using waterimmissible vehicle for the dispersion of drug [Beample is aspirin in silicone fd Solubility tthe ‘Comment 21, The resin rte conto api sluon (10 mg/t0 ‘tater LASe10- ml. 90 water replaed by 30 ml of ei Skool, te rxcton rate coma wil more tha 145°10-* a". Tre fib. Exp ‘Comment 22, Prcsne sluion shoul! e serie by auoclving 120% Tova shor period of ine n eke prolonged hang a 100°C: Tr crfibe Exptun, ‘Comment 23. ‘The si ie of procaine solution can be increased by sing ‘atte Explain, Oxide Oxidation involves the removal of electons from a molecale. The resetion Between the compounds and molecular oxygen is called ‘ooxidation. In fas snd ol, autoxidation of unsaturated fat aids proceeds in the presence of atmospheric oxygen light and traces of avy metals or organic peroxides, For example the rate of oxidation of wicorbic acid is inorsed by a fActor of 108, when copper fons ae fwevent in the concentration of 0.002 M. Simily hydroperoxides aniained in polyethylene glyeol suppository bases have been implicated Ine ovetlon of codeine to codeine N-oxide. 9 ition reaction may be The gener principles that govern an oxi ’ ited a follows. Sree of stamsplrc oxygen alo a) promaes t rae sf otion : «Sree dan feet voles eats chain tons Ses Tear povidesthe nes ee 1 ite ten prose =) «The pseceoftace mls ase he te fox «emi pecsuer pomet the can nation and prom te onda action as Dra ee weak acids baie, Therefore, thee iy ara ae Toms of nual molecules, Oxidation ection a ete proses fer han with eal oes rere eis obi etd phenomenon «Sutton eon ae clad by Han OF” fons, Hodrou Oxia rian se than hyropen ional oe son ect wh step oxygen and Frm xe ‘Drops which decompose by oxidation pathways ae given elo hain ‘Arachis oil “a Ethyl oleate Ribetirvin eve ll Miami Bez ‘anon ol ‘score aid Promethie Morne caeee rele rhe autoonidetion kinetics of ascorbic acid has been extensively studied. “The eral rection may be represented a: ponent secon held sees of Tre atl Te shone fxn aoc ad vy lates ato x ‘Semi On ‘Dehydro ‘Ascorbate on, Ca? auinone “aidexon” ascorbic aid“ xt0OK OF PHYSICAL PHARMACEUTICS When tutions are fee from traces of copper, ascorbis aid it not iden by molecular oxygen to a measurable extent, except i lkaling aM duncver, even tes of copper lead tothe api oxidation of ve acd, Whon CO and KCN are aed to the above reaction mat or complexes with metal ons, and therefore, oxidation ay jd inhib, These reactions demonstrat the influence reaps ion onthe oxidation of ascorbic acid. Infueece ofc on axidation: Thereof decomposition desea sah ihercoocentation of ascorbic acd is wed. tis presumed hat = roi ascorbic aid reacts with oxygen and this depletes fs ra et hen ii bubbled through the reaction mixture the rt of oe Kr eahanced, When dissolved oxygen is mainiained st stra: aon ine reaction rte remains coniat. Therefore, oxygen is ‘Raponsible for the autooxdstion reactions. Tnfluence of ionle species of drags : Ascaic aid can exist 38 8 sing Rarged or doubly charged fn. In he absence of coppe fms, see AE und to rect wth divalent fons at about 10° tines fer OBST tof reaon wth monovalent ascorbate fon. When coPPer compare fed, ontnon ofthe singly charged ascorbate fn alone Is found tobe catalysed Trpuece of acidic amd basic ion species: The ald and bse cate ys Sidon on ascorbic aid proceeds fellows. Dehydonscorbe yt degradation produt) furor degrades to ive Kotoguloic oid ‘Shichi tum gives threone acid and oxalic a ‘Ascorbic _H1,(0H) , Dehydeo ssid ascot acd + Ketoguloni acid “Troon aid + Ona ald tn general, autoxidation proceeds moe readily in alaline medium na tai aalton. Alkaline solutions are Known to react with Imospheti oxygen and form oxides. ‘Protection against oxidation : Oxidation reactions are know £0 occur in presence of oxygen, trace metals, Hand (OH). fons. Prots- rae spree sould sim at clminaing the Infloence ofthese ftors ot ‘ena nua STABILITY a “anioidot Toeopstls ae te sary oui ans one, at syed Hyon anisole BHA), vated OS ter em ony pale ee. These a wel ned OE sls CO Pr Tues gets ax by bretng the fe ma! Cost rt ep of ain propagation. Mos of ese co Sounds we citanuble antioxidants cole artodents act by prefreialyendetCn Oe eee cdg it Example is wort ai Comme ton mcr groupe conse racecar cxjeen pre, Sls vere re epson acteyene, tigen aed ce “chtring gens: Aston of heating age 1 2 PUL WN es ot hen me ently ts xian, Subse sel wh fyenedine eto acid) ue and She ptnes oth Rewey meals This, mie ors 9 fo siete cxkaon. For example, aon of TA aval i vents the degradation of vgs uch a prednisone tnd ecorbie oid Another vaialion is that bore eid forms 9 cmt dg. epinepvine. The chad einige Se rk ick tn es enehine: Tis San of epinephrine is inhibited "rhc Ul waters wed a5 aslvent for most padi Ti eo aay ber ve fen RIS role eh vets when ued ie mbna eh sang rm lying eect on ont. Pree of pair our dough hse scents spe in he Sot dor Cohmmealprpenies of solvents sucha mal Pes Shi parameter dielectric constant a sol era rencion. Some enpcal gensalitios ee c= sted below. the eral press (oly) of saves eh es ee trod wi high intern rear“, 08 he oes on te oi ae of ects i ight than us Xe inal pes rad the ref react: Sime rh ‘Rip Served wih oly parameters "ra dike sla, ioe ft renctatpual EUS, see anti is independent ofthe ani sen ay Tou ofstvent inte, which lowes he deste Smet ere ae ot encton Fs olen stan les of 18o TNO OF PHYSICAL PHARMACEUTICS tiny an inerose in the ieee constant results in an incense inthe fate oF the reaction (is) Ifthe solution contains ions of opposite signs, solvents with high Ailectie constant decreases the rate constant. In view of the adverse effects, careful consideration shouldbe given while atempting to use solvents fr stabilizing drugs Micellar solubilisaion : Surfactants suchas polysorbate 80 enhance the tate of oxidation of aecorbie ald at low concentration, but protect tiove its real micelle eonceatation (cme), presumably by entrapping. the drag inte spherical micelles, Sometimes, spherical micelles offer Ati for surface adsorption of citalytc fons and enhance rate of augers : Buffer system imparts sally when oxidation is extalysed by HT" or (OMY tons. Choose a buffer with appropriate pl to maintain ‘maxima stability of the product. Environmental control measures : One oF more of the following preventive matures are employed stabilise the product from oxidation Prevent the exposure fo light: Light i responsible for oxidation. ‘The preparation is protected from light by employing amber coloured bottles or using appropriate packaging mail (cardboard). For exam: is, morphine sulphate ijecon USP is protected from light by using fiber coloured ampoules. Onygen free environmen: Oxygen enhances oxidative depradation ‘Therefore, at is replaced with Inert gaset such as ntogen or carbon Gioxide. "Similarly, use of oxygen foe solvents in manufictue is adviabe, “Low temperature storage : Sine high temperatare enhances the rate ot reaton the prodct store ina cool place. ‘Comment 2-4. The aldion of rdiam EDTA decreases the depradiion of ‘neptine ible solaon. The degradation pater is hays. Trae or fe. Explain ‘Comment 2%, Testability of obi sid a mabiviamin id mires ean Te inpoved by he dition of EDTA the mitre. Truce be. Expl. ous Reactions Preventive Measures Tsomerism : Some drugs often have same stractral forma, but posses diferent stereochemical configurations. Intteonversion of ne Sereochemicl form into another leads inactive o les active drugs. (ona. RUG STABILITY 6 (Optical omerzation: In solutions, te otaly sive form (7 or eaten of drug gets converted into it raniiomorph (*¥8 ad eee) his proces contnucs uni the two forms are egal Creecometion, "The optical activity at equirum will be zo, os comet imcve Inger recomiatonretons wnt Gere gre cordance with frst order Kneis. A few examples ae (adrenaline =< ———> Adrenaline peer bilo sc (anki) ‘pom Corvocyamine SHLAA eoriyocamine — leave yar preventive measeres: Th prodact x protected fom Hight and Dest copa hast he malnaind for maxima i J: tn this case, the compound fs woe tan EC erton atoms. While one eye stom ren ea, asa fas to give a pier. At bium, both eines in a mee ck ben eual propor. In oer words ls may ail exhibit optical setivi. For exam: > Brponetinine somtrie tomerhation: Jn this cz, he compounds exis 28 ans sn erat eres on tet lave Spatial coniguation of OS wot ble bond (These changes may being aboot : ge in ts tnlogcal acti. For example: | Uediets ‘Vitamin A palate mono , {aren Scivaive, * derivate toi etymertation : Tse types of rations ae nt of the ret tcompontion Primary decompeston products fy caus eer and polymers. A few examples odin, stydexymetiyt YS» Suay colored fart oe a saAdrenaline 5 Aono. _pobmaie lack brown (cid soliton) ‘ome, “oxdaion lament Absorption of carbon dioxide : Solutions absorb carbon. dioxide hom the amesphare. For example} Sodium rf Acidic pt hesoberitone ee aaa ivinjection = fodrobsis” OSIEBH) “CO, precip Preventive measures: The producti stored in well-fed and well closed containers. Manufoctres supply the product as a iy sterile powder, The isiction should be—todsoive the drug before wei (CO, fee sterile water for injection Decarboxylation : These types of reactions aré normally observed ‘when parenteral soltion contains sodium exrboate, During autoclaving (for sterlisaton), the carboxylic aid groups willbe knocked off Examples: Sodium p-ainoslieyic asl (PAS, at-TB drug) Proctne hydrochloride (Joel anestetic) Procain yan paming COs (Glear solution) > Benvie acid —> Aniline tht Dark coloured fii) > guia Preventive measure : Carbon dioxide ga spaised into the solution far one minate. The container is sealed to as to be aisight prior to sutclaving Eatier discussion highlights various factors which infivence drug scomposiion. Among thes, the influence of temperature has found sppications inthe prediction of shel i INFLUENCE OF LIGHT ON DRUG DECOMPOSITION ight energy ke heat, setvate molecules and enhance the rte of @ reaction. Drugs which undergo light-induced chemical degradation are Called photoabile (photosensitive) drugr. A fw examples se rbofia- in, tetayeline, chlorpromazine. Colour development or color fading ‘Of ublets and liquids ar also afew examples of photochemical degrade tion A few Samir photochemioal reactions are: (a) conversion of ‘ergosterol to vitamin D by uluavolet light, and (b) Photosynbess 6 ‘or2_ AUG STABILITY wherein carbohydrates and oxygen are produced when chlorophyll ab- er vei ra Mei of diation snow the photon a is etal 8 oa Teeny of photon det proporioal Se Ohne maiaon river trope 2 1 Te cbnicaldecmposton of i i pn smh pater te spectro 5 de and evict wavelengs (50010300). Ths vise Hue amloyd in he tesing of eg decomportion we the ah gan lilt as (xe Hato mere VEO rent it enya safle oerey ms be abcd by a ia ate he Terie St son yd canto hese ponmete. i Pa acbomial acon are wally complex and proceed n several ot ts ects aly low 2 ore Kes, Eames Fo ee and ecichce, Howeve, rus Ssh #8 ‘rez ie deen hve sows exhibit i et taka Comment 24, tna poocenio actin. Seay Woy! se light sure Is nt considered INFLUENCE OF TEMPERATURE, "ON DRUG DECOMPOSITION tons increases about two or tree times with bi pesto equation exit of very 108s in temperature. Arron {nperatre on the rate of reaction. io Acton 0 whore = specific rate constant 4A = frsqeney fctor oF Arent stor Ba = energy of activation "R= Weal gas constast (1.987 calino-det) stole temperate Tae ait aa Ink= nd o ‘Converting equation (2) 10 lg base 10 gives Ba ear o eee Sey