3 Make, screen & push more compounds into the pipeline! High Failure RateFor every 10,000 NCE’s in Discovery10 enter pre-clinical development5 enter human trials1 is approvedInterestingly…..Winning the lottery 1 in 5,200,000A Royal Flush in Poker 1 in 650,000Struck by lightning 1 in 600,000Appear on the Tonight Show 1 in 490,000Discovery to Market 1 in 10,000A son who will play pro football 1 in 8000Make, screen & push more compounds into the pipeline!
4 Combinatorial Chemistry ‘HITS’ In Silico Screening Lead Compounds High ThroughputScreening‘HITS’In SilicoScreeningLead CompoundsDevelopabilityScreensOptimisationDRUGPRODUCT
5 Combinatorial Chemistry & HTS: Poor Solubility Drug Discovery After 1990advent of HTSuses organic solvents to screen in vitro potencylead optimisation occurs byincreasing mol. weightlipophilicityDrug Discovery Before 1990lead compounds - drug likepotency improved by adding lipophilic moietieslow mol. weights circa.300Brick Dust !40 % of compounds made each year are abandoned due to poor solubility- Giovani Sala, Elan Pharma
6 Preformulation and Developability Screening PotencySelectivityKineticsTissue penetrationCarcinogenicityPhysicochemical PropertiesCombinatorialLibraryDrug candidateIncrease choiceImprove selectionhundreds of compounds evaluated in parallel using rapid, high throughput predictive assays
7 Solubility: Double Edged Sword Relative difficulty in formulation design*poor permeabilityhigh first pass metabolismpoor chemical stabilitylow solubilityinstability in GI fluidshigh dosageMore flexibility in altering physical chemistry then physiologyabsorption rate can vary from min-1 i.e. x 50solubility can vary from 0.1 µg mg/ml i.e. x 1000,000target solubility is 1mg/ml (covers 1 mg to 500 mg oral dose)leastmostTaken from a survey of formulation scientistsfrom 12 companies in Japan
8 GIT Physiology Potential for chemical degradation under different pH’s Changes in mucosal SA, presence of specific absorption windowsInfluence of endogenous secretion along the GI-tractInfluence of gastric emptying, transit time and food dependencyInfluence of hydration state and water availability along GI-tractPre-systemic availability – membrane/faecal binding & metabolism
9 Gastro Intestinal Tract conditions Absorbing surface area of the colon (~0.3m2) very small c.f. rest of GIT ( m2)High viscosity of lumen contents can compromise drug diffusion and therefore absorptionLong residence times (up to 16 hrs)Densely populated with microbial flora
10 Predicting good oral absorption Volume (ml) required to dissolve the doseDose/solubility ratio2505001000500010000100000Increasing permeabilityJejunal solubility (e.g.FaSSIF)Class IClass IIaClass IIbGoodDifficult10(dissolutionrate limited)(solubilitylimited)Good solubility andpermeabilityPoor solubility, good permeabilityParticle size reduction or other bio-enhancement requiredPredicted Permeability in Humans (cm/sec x10-4)1Class IIIClass IVGood solubility,poor permeabilityPoor solubility and permeabilityPoorVery poor0.1Increasing solubilityIncreasing doseButler & Dressman, JPharmSci. Vol 99, Issue 12, pp 4940–4954, Dec 2010
11 Physico-chemical methods for Boosting Oral Absorption* Use a Form with higher solubilitymore soluble polymorphmore soluble saltamorphous c.f. crystalline formFormulate so drug is in solutionIncrease rate of dissolutionparticle size*many principles applicable for parenteral delivery
13 Crystal FormDepending on crystallising conditions, actives may exhibit:different habitsdifferent polymorphssolvates (solubility: organic > non solvate > aqueous solvate)Polymorphs with lowest free energy (lowest solubility) tend to be more thermodynamically stablemetastable (more soluble) form less soluble formsmaller the difference in free energy the smaller the difference in solubilitycould we use metastable form for safety assessment?
14 Serum Levels: Chloramphenicol Palmitate Effect of Polymorph Type
15 Crystal FormBioavailability of tolbutamide polymorphs in dogs
16 Amorphous formsAmorphous forms afford better solubility & faster dissolution rates c.f. crystalline formse.g. novobiocin, troglitazoneAmorphous forms can transform to a more stable, but less soluble crystalline statetendency to transform is related to Tg & storage tempTg > 80oC for amorphous solids to remain stable at RTfor investigative studies low temperature storage to retain amorphous form is viablecan stabilise by formulating with excipients of higher TgPVP (Tg, 280oC) inhibits crystallisation of Indomethacinmelt-extrusion with PVP to form granules or tablets
17 Schematic view of Melt Extrusion PolymerExcipientDrugShaping DeviceTabletsGranulationGranulatorPellets
19 pH adjustment & Salt Form Any drug moiety with a pKa between 3-11 can potentially be solubilised by pH modificationSalt-Formation is an extension of pH adjustment. Most common forms are as follows:acidic drugs: sodium>potassium>calciumbasic drugs: hydrochloride>sulphate>mesylate>chloride>maleate>tartrate>citrateSalt-form requires agreement from all development partieshighly soluble form might be hygroscopic & unstablechoose the best ‘all-rounder’
20 pH Solubility Profiles Weak BaseSolubility=S0(1+10(pKa-pH) )Intrinsic solubility (S0) region – pH range in which compound is completely unionized and has the lowest solubility.Ionized region – region around pKa of compound. At pKa are equal amounts of ionized and unionized forms of the compound in solution. For every pH unit change either side of the pKa gives a 10-fold change in amount of ionized drug in solution. Implications for lab measurements (pH control), & GI pH/ absorption. Compound precipitating in this region can be as free base or salt (depends upon the strength of solid-state interactions).pHmax – the region where compound has maximum solubility (equilibrium solid state form will be a salt i.e. completely ionized drug associated with oppositely charged counter-ions).Salt plateau – pH range in which the molecule is fully ionized and the salt solubility of the compound predominates. Solubility value is dependent upon strength of solid-state interactions with the counter-ion forming the salt. (Common ion effects & solvent can impact solubility.)SO=0.528mg/mlKsp = [drug ion] [saltcounterion]S = √KspKsp for a compound is a constant value. So, for a saturated solution, drug concentration is a function of counterion concentration. As counterion concentration in solution increases the dissolved drug concentration increases to keep the Ksp constant. Important for HCl salts of poorly soluble compounds – active drug concentration that can be achieved is a function of the chloride concentration in the solvent or GI tract on oral dosing.Increasing pKa, intrinsic solubility or decreasing salt solubility, Ksp, all favour salt formation for a basic drug by increasing pHmax through altering shape of the pH-solubility curve.pKa5.54S0=intrinsic, solubility of free acid/base
21 Classical pH-Solubility profile S0=intrinsic, solubility of free acid/base
22 Salt Form Aqueous solubilities of RPR-127963 salts Sulphate was progressed into developmentCould use a more soluble form for investigative studies?
27 Complexation:Cyclodextrins Enhance the Drug’s Water SolubilityIncrease Drug’s Aqueous Solution StabilityImprove Solubility & Dissolution: Improve Oral BioavailabilityEffective DeliveryLipophilic CavityHydrophilic ExteriorOHCH2OHHOCHLipophilicDrugDrug:CDComplexThe 3-dimensional structure of the cyclodextrin provides a cavity that is hydrophobic relative to an aqueous environment. The sequestration of hydrophobic drugs inside the cavity of the cyclodextrin can improve:1) the drug’s solubility and stability in water,2) the rate and extent of dissolution of the isolated drug:CD complex, and3) the bioavailability of the drug when its dissolution and solubility are limiting delivery.1:1 Complex
33 The NanoCrystal™ Advantage Rapamune (Wyeth)SirolimusImmunosuppressantwas available as a sachet & reconstituted suspensionrequired storage in a fridgeUsing Nanocrystalspossible to supply a solid oral tablet formulationmore stablemore convenient
37 Requirements of a Dosage Form Contains an Accurate Dose.Makes drug available for absorption (oral dosage).Is stable (retains quality).Convenient to take or administer.Is produced economically by an acceptable process.
38 Formulation Development Effect on Drug“Know your Dosage Form”Optimise Levelsof ExcipientsAddition of other materialsEngineering Technologies Physical ModificationsCompensate forDeficiencies“Know your Drug”
39 Functions of Excipients Compensate for deficiencies in the drugAid manufacture of the dosage formQuality assurance and maintenanceIdentity, patient acceptabilitycolourtaste“Target” the drug to site of activityabsorptionsite-specific delivery
40 Standards for Excipients Must not interact (adversely) with the drugMust not compromise safety or toleranceFunction in the manner intended
41 Factors affecting performance of oral dosage forms particle size of activegranulationgranulating agentsmode of granulationlubricanttypedegree of mixingcompression forcefilm coatAll need to be evaluated: CMC section of regulatory submission
42 Ideal that the same formulation is used at all stages Clinical StudiesPhase I absorption, metabolism, tolerance (volunteers)Phase 2A “does the drug work” ? (efficacy)“ B dose/dose regimenPhase III “how good is it”Phase IV post-marketing studiesIdeal that the same formulation is used at all stages
43 Dosage Forms for Clinical Programmes Phase One Flexibility of Dose- powder in bottle- capsule- tabletPhase Two Range of Doses in “look-alike” unitsPhase Three Formulation for MarketingFDA will not consider tablets & capsules as bioequivalent!Tablets more popular than capsules (smaller & more stable)
44 What does a dose look like? Phase 2/3Phase 4 stagesPreclinical stagePhase 1 stagePhase 2 stage
45 Why do Formulations Change ? Technical problemsNeed to incorporate different dosesNature of clinical programmes
46 Formulation and the Stock Market “To Merck’s dismay, Monsanto completed its clinical studies first. Among the reasons was a dosage glitch at Merck. The company found that, instead of 1000mg, the proper dose was mg. The pills that resulted were so tiny that Merck was afraid that Arthritis patients wouldn’t be able to pick them up.It enlarged them with edible filler but that caused another problem. The fiber turned out to slow the drug’s absorption. Three months were lost while researchers worked to fix this”Wall Street Journal January 10th 2001
47 Impact of changing dose! Very difficult to accommodate large changes in dose, as itwill influence processing & manufacturing on scale-up
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