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    Preformulation Preformulation Presentation Transcript

    • Preformulation commences when a newly synthesizeddrug shows sufficient Pharmacological activity inanimal models and warrant evaluation in humanbeings.Prior to the development of major dosage forms it isessential that certain fundamental physical andchemical properties of the drug molecule and otherderived properties of the drug powder aredetermined.This first learning phase is known as preformulation. Rakesh Kumar Sharma 2
    • Before beginning the formal preformulationprogramme the preformulation scientist must covera few factors, which includes•The amount of drug available•The physicochemical properties of the drug alreadyknown•The therapeutic category and anticipated dose ofthe compound•The development schedules•The nature of information a formulator shouldhave or would like to have. Rakesh Kumar Sharma 3
    • Table: A Typical Preformulation design is given below in table Rakesh Kumar Sharma 4
    • SpectroscopyThe first step in preformulation is to establish a simpleanalytical method for quantitative estimation insubsequent steps.Most drugs absorb light in the UV wavelength (190-390nm) as they are generally aromatic and contain doublebonds.The absorption coefficient of the drug can be determinedby the formulaE1= AF/XWhere A= absorbance at λmax , F= dilution factor and X=weight of drug(mg)It is now possible to determine the concentration of drugin any solution by measuring the absorbance.C= AF/E1Once the quantitative analytical method is established thepreformulation parameters are investigated in desireorder. Rakesh Kumar Sharma 5
    • Intrinsic solubility (Cs) and Dissociation constant(pKa)The solubility of drug in purified water, 0.1NHCl and0.1N NaOH is determined.A rise in solubility in acid than water suggests thatthe drug is weak base.Drug is weak acid if its solubility in NaOH is morethan in water. An increase in solubility in both acidand alkali indicates either amphoteric substance ,where as no change in solubility indicates non-ionizable neutral molecule. Rakesh Kumar Sharma 6
    • Intrinsic solubility also known as true solubility[Co] isthe solubility of unionized drug.Phase solubility analysis is an efficient method fordetermination of intrinsic solubility. The drug isadded to the fixed volume of the solvent inincreasing amount.The conc is determined after equilibrium is attained.A typical phase solubility diagram is shown Rakesh Kumar Sharma 7
    • Rakesh Kumar Sharma 8
    • The solubility should ideally be measured at twotemperatures:1. 4°C because the maximum density of water occurs at 4°C.This leads to a minimum aqueous solubility.2. 37°C to support Biopharmaceutical evaluation. Rakesh Kumar Sharma 9
    • However, it is less likely , at early stages that thedrug is pure. As absolute purity is often in doubt it ismore accurate to determine this crucial solubility bythe use of a phase-solubility diagram .Any deviation from the horizontal is indicative ofimpurities, which a higher drug loading and itsinherent impurities either promotes or suppressessolubility. Rakesh Kumar Sharma 10
    • Figure: Effect of Impurities on solubility of Drug Rakesh Kumar Sharma 11
    • Dissociation Constant [pKa]Many drugs are weak acids or weak bases depending onthe pH, they exist as ionized or unionized species or bothin solution. The relative proportion of ionized andunionized species of drug in solution governs itsabsorption, along with pH this proportion depends onpKa. Henderson-Hesselbalch equation establishesfollowing correlation among these factorspH =pKa+log[unionized / ionized] for basespH= pKa + log [ionized/ unionized] for acids Rakesh Kumar Sharma 12
    • Modified Henderson-Hesselbalch equation is moresuitable for quantitative determination of pKapH =pKa+log[Cs-Co / Co] for basespH =pKa+log[Co/Cs-Co] for acids.For example: the intrinsic solubility [Co] of a weak base is2mg/ml. The saturated solubility at pH 4 and pH 6 are14.6 and 2.13 mg/mlpka = 4+ log[14.6-2/2]= 4.799pka = 6+ log[2.13-2/2]= 4.813. Rakesh Kumar Sharma 13
    • SaltsA major improvement in solubility can be achieved byforming a salt.The consequence of changing chlordiazepoxide tovarious salt forms is shown in. Rakesh Kumar Sharma 14
    • Larger the value of pKa, the smaller the extent ofdissociation, Acid with pKa value less than 2 arestrong acids.In some cases, salts prepared from strong acids orbases are freely soluble but very hygroscopic. Thisdoes lead to instability in tablet or capsuleformulations.A less soluble salt will generally be less hygroscopic. Rakesh Kumar Sharma 15
    • Injections should ideally lie in the pH range 3-9 toprevent vessel or tissue damage and pain at theinjection site.Oral syrups should not be too acidic, to enhancepalatability.Packaging may also be susceptible: undue alkalinitywill attack glass, and hydrochloride salts should notbe used in aerosol as a propellant-acid reaction willcorrode the metal container. Rakesh Kumar Sharma 16
    • SolventsIt is generally necessary to formulate an injection or liquiddosage form, even if there is no intention to market. The firstchoice solvent is obviously water. However, although the drugmay be freely soluble, it may be unstable in aqueous solution.Chlordiazepoxide HCl is such an example.Accordingly, water-miscible solvents are used: In formulations to improve solubility or stability Oils are used in emulsions, Topicals (creams and ointments), intramuscular injections and liquid-fill oral preparations (soft and hard gelatin capsules) Rakesh Kumar Sharma 17
    • Partition coefficientA major criterion in evaluation of the ability of a drug to penetrate thelipid membranes within the body is its apparent oil/ water partitioncoefficient, defined as P = Co/CwWhereCo: equilibrium concentration of the drug in organic phase (n-octanol)Cw: equilibrium concentration of all forms in an aqueous phase (water) It is the measure of lipophilicity of drug(s).There is an optimum partition coefficient for a drug in which it mosteffectively permeates membranes and thus shows greatest activity.Values of the partition coefficient below this optimum result in decreasedlipid solubility and the drug will remain localized in the first aqueous phaseit contacts.Generally for a lipophilic drug, the partition coefficient is (log P >1) Rakesh Kumar Sharma 18
    • Common ion effectAn often overlooked interaction is the common ioneffect. A common ion often significantly reduces thesolubility of a slightly soluble electrolyte.Hydrochloride salts often exhibit suboptimalsolubility in gastric juice owing to the abundance ofCl ions. Rakesh Kumar Sharma 19
    • To identify a common ion interaction, the IDR of thehydrochloride (or inorganic) salt should be comparedbetween:• water and water containing 1.2% w/v NaCl, and• 0.05 M HC1 and 0.9% w/v NaCl in 0.05 M HC1.A common ion effect with Cl- will result in asignificantly reduced IDR in the presence of sodiumchloride. Rakesh Kumar Sharma 20
    • DissolutionThe dissolution rate of a drug is only importantwhere it is the rate-limiting step in the absorptionprocess. Kaplan (1972) suggested that provided thesolubility of a drug exceeded 10 mg/ ml at pH <7, nobioavailability- or dissolution-related problems wereto be expected. Below 1 mg /ml such problems werequite possible, and salt formation could improveabsorption and solubility by controlling the pH of themicroenvironment independently of the drug anddosage forms position within the GI tract. Rakesh Kumar Sharma 21
    • The dissolution of a drug is described by the generalNoyes – whitney equation.dc/dt = KS (Cs-Ct)Where dc/dt= dissolution rateK= dissolution rate constant,Cs= conc. of saturated diffusion layerCt= concentration at time tS= surface areaThe constant K is equal to D/h Where D is the diffusion coefficient of the dissolving solid and h is the thickness of the diffusion layer Rakesh Kumar Sharma 22
    • W/A = ktWhere k = dissolution rate constantAnd W is the weight (mg) of drug dissolve in time tA plot of W versus t gives straight line with slope isequal to k, this is known as intrinsic dissolutionrate (IDR) and is expressed in mg/min/cm2 .Compounds with IDR greater than 1 mg/min/cm2are not likely to present dissolution rate limitedabsorption problems. Rakesh Kumar Sharma 23
    • BULK CHARACTERIZATIONMELTING POINTTechniquesThe melting point of a drug can be measured usingthree techniques:1. Capillary melting2. Hot stage microscopy3. Differential scanning calorimetry or thermalanalysis. Rakesh Kumar Sharma 24
    • Capillary meltingCapillary melting (the observation of melting in acapillary tube in a heated metal block) givesinformation about the melting range but it isdifficult to assign an accurate melting point. Rakesh Kumar Sharma 25
    • Hot stage microscopyThis is the visual observation of melting under amicroscope equipped with a heated and laggedsample stage. The heating rate is controllable andup to three transitions can be registered. It is moreprecise as the phase transitions (first melt, 50% meltand completion) can be registered on a recorder asthe melting proceeds, and because of the highmagnification the values are more accurate. Rakesh Kumar Sharma 26
    • Differential scanning calorimetry and thermalanalysis The sample size require is 2-5 mgDTA measures the temperature difference betweenthe sample and a reference as a function oftemperature or time when heating at a constantrate. DSC is similar to DTA, except that theinstrument measures the amount of energyrequired to keep the sample at the sametemperature as the reference, i.e. it measures theenthalpy of transition. Rakesh Kumar Sharma 27
    • When no physical or chemical change occurs withinthe sample then there is neither a temperaturechange nor input energy to maintain an isotherm.The major concern in preformulation ispolymorphism, and the measurement of meltingpoint and other phase changes is the primarydiagnostic tool.Confirmation by IR spectroscopy and X-raydiffraction is usually required. Rakesh Kumar Sharma 28
    • PolymorphismA polymorph is a solid material with at least twodifferent molecular arrangements that give distinctcrystal species. These differences disappear in theliquid or the vapour state. Of concern are theirrelative stabilities and solubility. The highest-melting species is generally stable; otherpolymorphs are metastable and convert to thestable form. There are also potentially largedifferences in their physical properties so that theybehave as distinct chemical entities. Rakesh Kumar Sharma 29
    • Solubility (particularly important in suspensionsand biopharmaceutically), melting point,density, crystal shape, optical and electricalproperties and vapour pressure are often verydifferent for each polymorph.The steroid progesterone has five polymorphs,whereas the sulphonamide ;sulphabenzamide hasfour polymorphs and three solvates. Rakesh Kumar Sharma 30
    • Pseudopolymorphism (solvates)Prior to this, the presence of solvates or falsepolymorphs, sometimes (incorrectly and confusingly)called pseudopolymorphs, should be identified, asmost polymorphs can be obtained by changing therecrystallizing solvent.Typical solvents inducing polymorphic change arewater, methanol, ethanol, acetone, chloroform, n-propanol, isopropanol alcohol, w-butanol, n-pentanol, toluene and benzene. Rakesh Kumar Sharma 31
    • Trace levels of solvent are usual in early batches ofnew drug candidates (residues from the finalcrystallization). These can become molecularadditions to the crystal and change habit.These hydrates (water) and solvates (e.g.methanolate, ethanolate) have been confused withtrue polymorphism and have led to the termpseudopolymorphism. Rakesh Kumar Sharma 32
    • The distinction between these false forms and truepolymorphs can be ascertained by observing themelting behavior of the compound dispersed in siliconeoil using hot-stage microscopy.Pseudopolymorphs will evolve a gas (steam or solventvapor), causing the oil to bubble. True polymorphsmerely melt, forming a second globular phase. Thetemperature at which the solvent volatilizes will be closeto the boiling point of the solvent. Rakesh Kumar Sharma 33
    • Crystalline solubilityThe most important reason to determine meltingpoint during preformulation is crystalline solubility.Melting point and solubility are related via thelatent heat of fusion, which is the amount of heatgenerated during melting or fusion. Rakesh Kumar Sharma 34
    • A crystal with weak bonds has a low melting pointand low heat of fusion. Conversely, a strong crystallattice leads to a high melting point and a highheat of fusion. Because solubility also requires thedisruption of crystal structure to allow moleculardispersion in the solvent, it is also influenced byintermolecular forces. Rakesh Kumar Sharma 35
    • Polymorphs differ in melting point and solubility.The existence of different crystal arrangements forthe same compound inevitably leads to differences incrystal lattice energy, as intermolecular distances willbe different in the alternative forms. This effect isshown in Figure for riboflavin. Rakesh Kumar Sharma 36
    • Rakesh Kumar Sharma 37
    • HygroscopicityTablets and capsules must be hydrophilic tofacilitate wetting and the process of de-aggregation and drug dissolution.As a paradox they must have limited hygroscopicityto ensure good chemical and physical stabilityunder all reasonable climatic conditions.Good packaging will accommodate moisturechallenge, e.g. glass bottles, foil blisters anddessicant. Rakesh Kumar Sharma 38
    • Particle size analysisSmall particles are particularly important in low-dose high-potency drug candidates,as large particle populations are necessary toensure adequate blend homogeneity and for anydrug whose aqueous solubility is poor (<1 mgm/Lt), as dissolution rate is directly proportional tosurface area (inversely proportional to particle size). Rakesh Kumar Sharma 39
    • POWDER FLOW PROPERTIESCarr’s Index = tapped density- poured density X 100 Tapped densityHausner’s ratio = Tapped density/ poured densityValues less than 1.25 indicate good flow (= 20%Carr), whereas greater than 1.25 indicates poorflow (= 33% Carr). Between 1.25 and 1.5, addedglidant normally improves flow. Rakesh Kumar Sharma 40
    • Rakesh Kumar Sharma 41
    • Drug degradation occurs by four main processes:• Hydrolysis• Oxidation• Photolysis• Trace metal catalysis.Hydrolysis and oxidation are the most commonpathways, and in general light (c) and metal ionscatalyse a subsequent oxidative process. Rakesh Kumar Sharma 42
    • TemperatureThermal effects are superimposed on all fourchemical processes. Typically a 10°C increase intemperature can produce a 2-5-fold increase indecay. Often the increase in reaction rate withtemperature follows an Arrhenius-type relationship:a plot of the log of the rate of reaction against thereciprocal of absolute temperature yields a straightline. The reaction rate can then be calculated at anytemperature and allows a prediction of shelf-life atroom temperature by extrapolation. Rakesh Kumar Sharma 43
    • HydrolysisThe most likely cause of drug instability is hydrolysis.Water plays a dominant role and in many cases it is implicatedpassively as a solvent vector between two reacting species insolution.Hydrolytic reactions involve nucleophilic attack of labile bonds,e.g. lactam > ester > amide > imide, by water on the drug insolution, and are first order.When this attack is by a solvent other than water it is known assolvolysis.A number of conditions catalyse the breakdown:• The presence of OH-• The presence of H3O+• The presence of divalent metal ions• Ionic hydrolysis (protolysis) is quicker than molecular• Heat• Light• Solution polarity and ionic strength• High drug concentrations. Rakesh Kumar Sharma 44
    • The Influence of pHThe degradation of most drugs is catalysed byextremes of pH, i.e. high [H3O+] and [OH-], andmany drugs are most stable between pH 4 and 8.Where maximum stability dictates wider values, it isimportant for injections that there is low buffercapacity to prevent unnecessary challenge to thehomeostatic pH (7.4) of blood.Weakly acidic and basic drugs are most solublewhen ionized, and it is then that instability is mostlikely as they are charged. This leads to a problem,asmany potent drugs are extremely poorly soluble andpH ionization is the most obvious method to obtaina solution. Rakesh Kumar Sharma 45
    • In some cases, therefore, the inclusion ofa water-miscible solvent in the formulation willincrease stability by:1. Suppressing ionization2. Reducing the extreme of pH required to achievesolubility3. Reducing water activity by reducing the polarity ofthe solvent, e.g. 20% propylene glycol inchlordiazepoxide HC1 injection. Rakesh Kumar Sharma 46
    • Reactions in aqueous solution are usually catalysedby pH, and this is monitored by measuringdegradation rates (usually pseudo first order)against pH, keeping temperature, ionic strengthand solvent concentration constant. Suitablebuffers include acetate, citrate, lactate, phosphateand ascorbate (an intrinsic antioxidant). Rakesh Kumar Sharma 47
    • SolvolysisWhere the reacting solvent is not water, thenbreakdown is termed solvolysis.Phenobarbitone is considerably more stable inpreparations containing water-miscible solvents,whereas aspirin, which undergoes extensivehydrolysis, is degraded further by aqueous solvents.Both effects are directly related to the dielectricconstant (polarity) of the solvent. Rakesh Kumar Sharma 48
    • In general, if a compound produces degradationproducts which are more polar then the addition ofa less polar solvent will stabilize the formulation.If the degradation products are less polar, then thevehicle should be more polar to improve stability.With the hydrolysis of neutral non-polar drugs, e.g.steroids, the transition state will be non-polar withno net charge. In this case solvents will not affectthe rate of decomposition and can be used withimpunity to increase solubility. Rakesh Kumar Sharma 49
    • OxidationOxidation is controlled by the environment, i.e. light,trace metals, oxygen and oxidizing agents. Reduction isa complimentary reaction (redox) and there is amutual exchange of electrons. Oxidation is a loss ofelectrons and an oxidizing agent must be able to takeelectrons. Most antioxidants function by providingelectrons or labile H+, which will be accepted by anyfree radical to terminate the chain reaction. Aprerequisite for effective antioxidant activity in anyparticular preparation is that the antioxidant is morereadily oxidized than the drug. Rakesh Kumar Sharma 50
    • Chelating agentsChelating agents are capable of forming more thanone bond. For example, ethylene diamine isbidentate (two links), tripyridyl is tridentate(three) and ethylene diamine tetra-acetic acid(EDTA) is hexadentate (six), which makes itparticularly effective as a pharmaceutical chelatingagent. Rakesh Kumar Sharma 51
    • PhotolysisWhen molecules are exposed to electromagneticradiation they absorb light (photons) atcharacteristic wavelengths which causes an increasein energy,which can:• cause decomposition• be retained or transferred• be converted to heat• result in light emission at a new wavelength(fluorescence, phosphorescence).photolysis is prevented by suitable packaging: lowactinic amber glass bottles, cardboard outers andaluminium foil overwraps and blisters. Rakesh Kumar Sharma 52
    • Solid-State stabilityIn all solid dose formulations there will be some freemoisture (contributed by excipients as well as thedrug), and certainly in tablets a significant percentage,typically 2% w/w, is required to facilitate goodcompression.This free water acts as a vector for chemical reactionsbetween drug and excipients, and the adsorbedmoisture films are saturated with drug compared to thedilute solutions encountered in injectables. Rakesh Kumar Sharma 53
    • ASSAY DEVELOPMENTThe assumption that the drug is stable may not bevalid as drugs are notoriously unstable, particularlyas hydrolysis is often the predominant cause. Inorder to follow drug stability, in both solution andsolid phase, it is mandatory to have suitablestability- indicating assays. In some cases UVspectroscopycan be used, but in general chromatography isrequired to separate the drug from its degradationproducts and any excipients. Rakesh Kumar Sharma 54
    • EXCIPIENT COMPATIBILITYThe successful formulation of a stable andeffective solid dosage form depends on the carefulselection of the excipients that are added tofacilitate administration, promote the consistentrelease and bioavailability of the drug and protectit from degradation. Rakesh Kumar Sharma 55
    • Thermal analysis can be used to investigate andpredict any physicochemical interactions betweencomponents in a formulation and can therefore beapplied to the selection of suitable chemicallycompatible excipients.Primary excipients recommended for initialscreening for tablet and capsule formulations areshown in Table Rakesh Kumar Sharma 56
    • Rakesh Kumar Sharma 57
    • Rakesh Kumar Sharma 58
    • Basically, The thermal properties of a physicalmixture are the sum of the individual components,and this thermogram can be compared with thoseof the drug and the excipients alone.An interaction on DSC will show as changes inmelting point, peak shape and area and/or theappearance of a transition. Rakesh Kumar Sharma 59
    • CONCLUSIONSPreformulation studies have a significant part to playin anticipating formulation problems and identifyinglogical paths in both liquid and solid dosage formtechnology (Figure).The availability of good solubility data should allowthe selection of the most appropriate salt fordevelopment. Rakesh Kumar Sharma 60
    • Stability studies in solution will indicate thefeasibility of parenteral or other liquid dosageforms, and can identify methods of stabilization.In parallel, solid-state stability by DSC, TLC andHPLC, and in the presence of tablet and capsuleexcipients, will indicate the most acceptablevehicles for solid dosage forms. Rakesh Kumar Sharma 61
    • Rakesh Kumar Sharma 62