Scale of Science In Pharmaceutical Development


Published on

Understanding the Pharmaceutical Development

No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide

Scale of Science In Pharmaceutical Development

  1. 1. Scale of Science Understanding of Interactions and Controls in Pharmaceutical Development with reference to solid dosages By Satendra Kumar Vishwakarma, PhDMay 26, 2011 1
  2. 2. Welcome This Presentation is dedicated to inventor of Lipinski’s “Rule-of-Five” in Drug Candidate Screening Methodology Dr Christopher A. Lipinski Exploratory Medicinal Sciences DepartmentLaboratories of Pfizer Global Research & Development, Connecticut, USA. May 26, 2011 2
  3. 3. AnnouncementThe views and graphics in this presentation are collected from various sources and content(s) might have been modified on the basis of scientific justification.Narrator of this slide presentation believes that all the contents are Up-to-Date and isONLY for INFORMATION, NOT for direct APPLICATION without verifying, optimizing, and validating the target. Thank You May 26, 2011 3
  4. 4. Understanding the Scale of Science A Fundamental Tools in Pharmaceutical Development May 26, 2011 4
  5. 5. Early Process Development Activities Expression Lab scale Pilot Develop Scale -up System Process Plant GMP for Mfg Selection Development Scale-up Process Commercial GLP “Tox” Lots GMP Ph1 – 2 Ph 3 Clinical Clinical Supplies SuppliesCell Line Selection Pilot Plant Launch Readiness Process Fermentation Dev Consistency Engineering Modification Process Runs Trials for Tox MBR/SOP’s Validation Process Lots Modification Integration GMP Process Purification Tech Xfer from MBR/SOP’s Production for Develop Optimization Process Dev Development to Finalization Ph1 Commercial Pilot Plant Process Bridging Studies Analytical Method Development Analytical SOP to QC Preformulation Formulation TOX/ADME Transfer to Manufacturing Site Fill/FinishScience based compatibility & Stability Studies Stability Studies May 26, 2011 5 Phillip L. Gomez III, NIH, USA
  6. 6. Lipinskis Rule-of-Five Analysis A significant empirical derivation from the analysis of World Drug Index (32,000) facilitates to make the distinction between Drug-Like and Non-Drug-Like molecule. In order to be adsorbed through the gut and enter the blood stream, orally administered drugs must have certain molecular properties as proposed by Lipinski. The Lipinski "Rule of Five Analysis" states that compounds are likely to have good absorption and permeation in biological systems (ADME) and are more likely to be successful drug candidates if they meet the following criteria:Christopher A. Lipinski Exploratory Medicinal Sciences Department, Connecticut, laboratories of Pfizer Global Research & Development May 26, 2011 6
  7. 7. Lipinskis Rule-of-Five Analysis Five or fewer hydrogen-bond donors (any OH+NH). Ten or fewer hydrogen-bond acceptors (any O+N). Molecular weight less than or equal to 500. Calculated log P less than or equal to 5. Fifth rule includes Number of rotatable bonds LT 15, and other factors – number of aromatic rings, highly reactive and chemically unstable groups. Compound classes that are substrates for biological transporters are exceptions to the rule. If two parameters are out of range, a "poor absorption or permeability is possible" alert is a very visible educational tool for the chemist and serves as a tracking tool for the research organization. May 26, 2011 7
  8. 8. Lipinskis Rule-of-Five Analysis hydrogen-bond donorsMay 26, 2011 8
  9. 9. Lipinskis Rule-of-Five Analysis hydrogen-bond acceptorsMay 26, 2011 9
  10. 10. Lipinskis Rule-of-Five AnalysisThe compounds in Collection of Small Organic Molecules generally obeyLipinskis "rule of five" making them ideal candidates for drug discovery. Molecular weight May 26, 2011 10
  11. 11. Lipinskis Rule-of-Five Analysis Log PMay 26, 2011 11
  12. 12. Lipinskis Rule-of-Five Analysis Number of rotatable bondsMay 26, 2011 12
  13. 13. Drug-Like vs Non Drug-LikeMay 26, 2011 13
  14. 14. Drug-Like vs Non Drug-LikeMay 26, 2011 14
  15. 15. Integrated Workflow Station Accelerate solubility, salt form, polymorphic form and crystallization to minimize potential risk of new polymorphic form Reduce time, resource and material by a factor of 10 Large combinatorial experiment specifications i.e. pre-formulation variables, experiment execution, end-to-end software and database integration, high quality productivity, fast submission May 26, 2011 15
  16. 16. Automated Workflow Station Pharmaceutical Workflows OverviewDesign Synthesis, processing, formulation Sample preparation for screening Properties analysis Data analysis May 26, 2011 16
  17. 17. Automated Workflow Station Solubility Workflows Overview Process Development Optimization: Automated Solubility v pHMeasurements Discovery: Solubility Measurements Formulation, pH, and Stability Testing Accelerating Innovation for Broad Range of Applications May 26, 2011 17
  18. 18. Molecular Pre-Formulation Scale of Science GENERIC HPLC METHODSBenefits of Fast Generic Chromatographic Methods over Traditional or Custom Chromatographic MethodsA knowledge of Molecule Structure and Retention Time is relevant in Early- / Pre- Formulation Development May 26, 2011 18
  19. 19. HPLC in Pre-formulation DevelopmentWith a wide variety of analytical columns, detection systems, mobile phases, andsample pre-treatment techniques, most physicochemical changes in formulation components can be analyzedHPLC Columns: Size-exclusion (or gel filtration), Reversed-phase, Ion-exchange, Hydrophobic interaction, AffinityHPLC Detectors: UV/VIS, Fluorescence, Reflective index, Mass spectrometers, Light scattering, evaporative light scattering, Electrochemical, Chemiluminescence, Circular DichroismHPLC Analysis: Quantitative analysis of physical degradation products Quantitative analysis of chemical degradation products Characterization of product impurities Rapid identification and concentration determination of products May 26, 2011 19
  20. 20. Generic Gradient HPLC Methods Rapid extraction of Physiochemical Parameters for quality drug development and Generic Screening for Method Development (MD) Characteristics of rapid, generic gradient methods A combination of Methods – eliminate the need for method development. Covers wide range of polarity range (Polar Ionic Mode, Reverse Phase, Polar Organic Mode, Normal Phase for MD). Application of short columns with small particles (Column coupling for multi-column screening for MD). Compromise resolution for speedy results (Quality is not so important for screening of physical parameters and MD). Application of elevated column temp and high flow rate. May 26, 2011 20
  21. 21. Generic Gradient HPLC Methods Configuration of MDS with Isocratic System DETECTOR AUTOSAMPLER PUMPMay 26, 2011 21
  22. 22. Molecular Pre-Formulation Scale of Science UNDERSTANDING OF FUNDAMENTAL PHYSICOCHEMICAL THEORY AND TECHNIQUES IN PREFORMULATION Knowledge of Molecule Structure & Interactions is vital tounderstand manufacturing science through Pre-Formulation / Formulation Development May 26, 2011 22
  23. 23. Introductory Pre-formulation Chapters Interface between formulation development and Early formulation in drug innovation. Data on solubility determinations Physical chemical characterization of solids (thermal methods, XRPD, particle size, moisture sorption). Polymorph screening studies & relative stability determinations of detected solid phases. Characterize API in formulated product to support pharmacology, toxicology, and PK. May 26, 2011 23
  24. 24. Dosage Development Groups Early and Analytical Testing Preformulation Procedures Stability Specifications Evaluation In vitro Vendor Core Formulation Release Testing Qualification Functional Method Activities Validation Reverse Transfer Engineering Reference Method Standard Development Characterization OptimizationMay 26, 2011 24
  25. 25. Influencing Parameters Disintegration of Formulation Drug Drug Characteristics Dissolution PC and Stability Bioequivalence ____________________________________ Bioavailability Drug Drug Absorption Excretion Drug Drug Metabolism DistributionMay 26, 2011 25
  26. 26. Dosage Form Development Chart Active Drug Suspension SolutionSuppositories Topicals Intrinsic Dissolution Dissociation Tonic Constant pKa pH Effect Co-solvents Adjustment Intrinsic pH? Salts Saturated Solubility Solubility IV Injection PEG 400 + 5% Other H2O + GlycerinDelivery Capsule Solution TonicSystem Adjustment Other Excipient Compatibility Dosage Forms Stability Tablets May 26, 2011 26
  27. 27. Formulation ProblemMay 26, 2011 27
  28. 28. Challenges in Development Solid State Properties Crystalline, Amorphous Solvates / Hydrates Excipient Degradation Pathway Prediction & Compatibility Physical and Chemical ? Characterization Particle size, ShapeSolid State Stability Surface Area Physical and Mechanical Characterization Chemical Properties Plastic, Elastic, Brittle May 26, 2011 28
  29. 29. Challenges in Development API Properties NEW CHEMICAL ENTITYChemical Form(s) Physical Form (s) Crystallinity Ionizable Group (s) Salt FormsNeutral compound Polymorphs Hydrates Solvates SOLUTION CHARACTERISTICS SOLID STATE PROPERTIESAqueous and pH Solubility& Stability ABSORPTION Particle Morphology CHARACTERISTICS Mechanical Properties May 26, 2011 29
  30. 30. Excipient Selection in Dosages Physicochemical Physicochemical Properties Manufacturing Properties of Excipient of Drug Process Requirement Physically Stable  Polymorphic / Forms  Direct (Polymorphic / Forms Hydrates compression Hydrates)  Heat & moisture  Wet Granulation Hygroscopic  Fluid Bed sensitive Chemically Stable Coating/ Compatible with drug  Poorly Soluble Granulation Rheology Flow  Poorly absorbable  Spray Drying  Poorly Stable in vivo  Other novel processes Excipients Choice Route of Administration in Solid Dosage Oral Forms Desired Release Pulmonary Characteristics Transdermal  Immediate release Buccal  Sustained Delivered Dose of Rectal/Vaginal Release Drug  Modified Release  High Dose e.g. enteric  Low Dose May 26, 2011 30 Vidya Joshi in
  31. 31. What are Characteristics of an Ideal Drug Candidate? Molecular properties – MW, molecular surface area, size, charge (pKa), H-binding potential Stable and Soluble* - formulatable Low toxicity (ideal > 10 - fold safety margin) Good bioavailability Similar metabolism in humans to a species under investigation Stable or single polymorph for solid oral dosage form * When the solubility of an API is less than 0.1 mg/ml, the optimization of the particle size during preformulation may be critical to efficacy or pharmaceutical equivalence. Other researchers believe that particle size may be critical at a solubility of 1 mg/ml or less. May 26, 2011 31
  32. 32. What is Pre-formulation? Pre-formulation is an exploratory activity and interfacebetween Drug Substance (Solid / Liquid State Organic Chemistry)and Drug Product (Solid / Liquid State Pharmaceutical Chemistry) (i.e. it’s not only about stability and solubility) According to PQRD / USFDA The goal of pre-formulation is to “investigate criticalphysicochemical factors which assure identity, purity of drug substances, formulatability, product performance and quality” May 26, 2011 32 PQRD – Product Quality Research Division
  33. 33. What is Pre-formulation Objective?“The objective of pre-formulation studies is to develop aportfolio of information about the drug substance to serveas a set of parameters against which detailed formulationdesign can be carried out.Pre-formulation investigations designed to identify thosephysicochemical and biopharmaceutical properties of drugsubstances and excipients that may influence theformulation design, method of manufacture, pharmacology,toxicology and PK - biopharmaceutical properties ofresulting product.” May 26, 2011 33
  34. 34. What’s in Preformulation? Pre-formulation involves the application of (bio) pharmaceutical principles to physicochemical parameters of an active drug form. or Pre-formulation (development) provides biophysical characterization of drug – excipients matrix - an insight into physical and chemical stability of Drug Product. The characterization of a drug molecule is a very important part of the pre-formulation phase of product development. Pre-formulation seeks to design an optimum drug delivery system. May 26, 2011 34 Daria Jouraleva, ACD Labs
  35. 35. Why Pre-formulation? External : End-Use Properties of Drug Product Generic Drug Product should be Pharmaceutical andTherapeutic Equivalents with Same Clinical Effect and Safety Profile.1. Dose and Release – what amount of drug substance is needed in what time?2. Bioavailability and Toxicity – Drug performance level compared with side effects.3. Stability and Shelf-life – To ensure quality and performance during storage. VIA REGULATORY AGENCY May 26, 2011 35
  36. 36. Why & How Pre-formulation? Internal: End-Use Properties of Drug Product Reducing set-backs (risks) during development and maximizing chances of clinical success. The set of process - analytical activities to determine the desired (native) form to an undesirable form (upon storage) of the drug (It is a significant for formulation development). The complete characterization, i.e. Solubility, permeability, stability, and compatibility testing at pre-formulation stage. These are driving force for successful drug development – stable formulation, analytical development & registration application. May 26, 2011 36
  37. 37. Overall Pre-formulation Compartments (Prelim) Patent Literature / literature searches. Physical properties/chemical properties of API. Powder characterization. Chemical reactivity & forced degradation. Excipient compatibility studies. Vehicle selection (factorial techniques - QbD). Package compatibility. May 26, 2011 37
  38. 38. Overall Formulation Compartments (Final) Formulation development for early safety studies. Physical testing of prototype. Preliminary process identification. Preliminary analytical development. Prototype formulations for in-vitro studies (clinical trials). Commercial formulation development.The question based review (QbR) or data on drug developmentand analytical development may required for scrutiny during or after registration of application May 26, 2011 38
  39. 39. Pre-formulation CharacterizationCharacterizations Techniques and Technical Tests Heat, Freezing, pH, Light, Agitation, Accelerated SS Oxidation, Dehydration, Stress, Shear Aggregation, Oxidation, Deamidation, Key DegradationStability Studies Cleavage, Surface adsorption, Surface Products Stress Denaturation Stability-indicating HPLC, Electrophoresis, Spectrometry, assays Particle Count, Turbidity Primary, secondary, tertiary, and quaternary structures, Thermal Physical Denaturation Temperature, Solubility, Viscosity, MW, Extinction Chemical Coefficient, pKa, Solid State Spectroscopy & Analyzers, Salt Selection, Polymorphs, etc. Biological Substrate or Receptor Affinity, in vitro Bioassay Color indicates For Biopharmaceutical Pre-formulation May 26, 2011 39
  40. 40. Why Physicochemical Parameters? Physicochemical data used to understand biological data eg intestinal absorption of drug. Drug solubility for absorption and ability of molecule to permeate barriers for bioavailability are two key properties must meet BCS and ADMET. Parallel attention, not only to Potency, should be given to Biological (selectivity), Toxicological and Pharmacokinetics (Activity) towards target. Attrition during drug development process is often due to inappropriate physicochemical characteristics and related poor pharmacokinetics and poor absorption. May 26, 2011 40 ADMET – Absorption, Distribution, Metabolism, Excretion and Toxicity
  41. 41. Pre-formulation ParametersBulk Properties of Excipients & Drug Substances Fundamental Properties Crystallinity and Polymorphism Particle Size, Shape and Surface Area Secondary Properties Bulk or Tapped Density Powder Flowability Adhesion Compressibility or Compactability Visio / Organoleptic Water Adsorption Lubricity May 26, 2011 41
  42. 42. Pre-formulation Characterizes Solubility pKa Partition coefficient – Log P pH – dependent Log D Chemical stability profile Crystal properties and polymorphism Particle size, shape, surface area Specification for New Drug Substances and Products Dosage Form Development ChartMay 26, 2011 Daria Jouraleva, ACD Labs 42
  43. 43. Pre-formulation ParametersPhysiochemical Properties of Drug Substances Salt selection (salt forms screening, dissociation constant pKa / ionization state determination). Solubility profiles (polar / non - polar i.e. aqueous / buffers / organic solvents) and pH dependence of solubility profile i.e. pH-rate profile. Partition Coefficient (pH partition coefficient i.e. log p or log D), hydrophilicity and lipophilicity. May 26, 2011 43
  44. 44. Pre-formulation ParametersPhysiochemical Properties of Drug Substances  Crystallization studies (impact on amorphous, particle shape, size analysis and brittleness).  Polymorph determination studies (identification, screening, relative stability – enantiotropy / monotropy, process design, and scale up to ensure that robustness of the polymorphic form, dosage method of mixture).  Drug pKa and stability information.  Solution and solid state stability. May 26, 2011 44
  45. 45. Preformulation Parameters Chemical Stability Data Studies Chemical stability, accelerated and stress studies (heat / light / acid / base / oxidizer) Stability profile in aq solutions (pH, buffer, solvent, temperature). Hygroscopicity (RH – moisture sorption isotherm (formation of hydrates / deliquescence) or upon storage conditions). Accelerated stability studies - degradation / degradation kinetics. Thermal properties with and without excipients Solid state stability alone and in combination with excipients. May 26, 2011 45
  46. 46. Pre-formulation Parameters Combinational Data Studies Drug (small molecules) / excipient compatibility studies (depending on dosage route). Aqueous Solubility – solubility / dose ratio? Order of addition and identification spectrometrically for critical process related variables. Osmolarity measurements / aggregation phenomena. Dissolution methodology (design composition and form according to acceptance criteria / specifications, dose and bioavailability). Packaging compatibility studies. Customer’s risk analysis. May 26, 2011 46
  47. 47. Pre-formulation InstrumentationSolid State Characterization in Drug Development  Powder Analyzers – Optical and Laser light (flow / compaction / density / particle size / surface area).  BET (Moisture Adsorption / desorption phenomena).  Microscopy – Light and Polarized (particle morphology).  Freeze-Drying and Hot-Stage Microscopy (Melting Point)  Isothermal Heat Conduction Micro-calorimetry.  Thermal Analysis (DSC, DTGA, TMA).  Molecular Spectroscopy (FTIR / NIR / Raman / NMR, LC/MS).  X-ray Powder Diffraction (XRPD / EDAX).  Single crystal structure determination. May 26, 2011 47
  48. 48. Why Control Water Activity? Water interactions with Pharmaceutical Solids Water activity (aw) influences solid-state analysis, pre- formulation, formulation, chemical stability, manufacturing process (flow, compaction, hardness, coating), dissolution, product shelf-life properties. Materials that have a high capacity for binding water equilibrate more slowly to higher levels of mobile water and consequently show greater chemical compatibility with a moisture-sensitive drug than materials with lower binding capacities for water. Free water has properties of bulk water and hence critical to chemical and physical stability of DS / DP. Bound water (immobile) is not readily available for chemical interaction with other species. May 26, 2011 48
  49. 49. Why Measure Water Activity? What is Water Activity in Pharmaceutical Dosage Form? Water activity (aw) or Equilibrium relative humidity (ERH) is a measure of free water (or residual or mobile or unbound water). Water activity (aw) is derived thermodynamically as a w = f / fo ≡ p / po = ERH (%) / 100f = fugacity or escaping tendency of a substance,fo = escaping tendency of pure materialp = vapor pressure of water in materialpo = vapor pressure of pure water  Water activity is a better index for microbial growth than water content. May 26, 2011 49
  50. 50. Water Activity Limits: Microbial Growth Water Activity Microorganism <0.60 No microbial proliferation 0.61 Xeromyces bisporus (xerophilic fungi) 0.62 Zygosachharomyces rouxii (osmophilic yeast) 0.78-0.75 Aspergillus niger/flavus, Halobacterium halobium Penicillium chrysogenum/glabrum, Paecilomyces variotti, 0.84-0.81 Aspergillus fumigatus 0.86 Staphylococcus aureus 0.90 Bacillus subtilis, Saccharomyces cerevisiae 0.92 Mucor plumbeus, Rhodotorula mucilaginosa 0.93 Micrococcus lysodekticus, Rhyzopus nigricans 0.94 Enterobacter aerogenes Bacillus cereus, Clostridium botulinum/ perfringens, Escherichia 0.95 coli, Lactobacillus viridescens, Salmonella spp. 0.97 Pseudomonas aeruginosa May 26, 2011 50
  51. 51. Molecular Pre-Formulation Scale of Science POLYMORPHISM ‘When a substance can exist in more than one physical crystalline state it is said to exhibit polymorphism’A Variability Issue in Manufacturing and Stability May 26, 2011 51
  52. 52. What is Active Drug Substance?■ “Same” activeingredient = same active moiety and same salt or ester as the brand product ■ Typically may differ in Polymorphic or other physicalproperties May 26, 2011 52
  53. 53. What are Polymorphs? Chemical Compound ICH Definition on Polymorphism Habit Internal Structure Ordered Disordered Crystalline Amorphousarrangement arrangement Single Entity Molecular Adducts Polymorphs Non - stoichiometric Stoichiometric Inclusion Compounds Solvates (Hydrates) Channel Layer Cage (Clathrate) May 26, 2011 53 Haleblian JK. J. Pharm. Sci. 64:1269-88 (1975)
  54. 54. Definition of Polymorphs“When a solid crystalline substance can exist in more than one physical state, it is said to exhibit polymorphism” or “Polymorphs are drug substances that are the same active ingredient but in different physical forms e.g. A drug substance with different crystalline forms and a drug substance with different waters of hydration” How Different is Different? Melting point Color Sublimation point Morphology Heat capacity Hygroscopicity Conductivity Solubility Volume Dissolution rate Density Chemical stability May 26, 2011 54
  55. 55. Allotropism vs PolymorphismProperty Particles involved Particles combine to formAllotropism Atoms Molecules or crystalsPolymorphism Molecules Crystals Example of Carbon “Allotropism” Diamond Graphite Carbon Nanotube Fullerene 60 May 26, 2011 55
  56. 56. Analytical Methodology Method Data Measured FeaturesDSC, MDSC Heat flow vs Temperature Phase change during cooling + heating Change of Mass vs thermodynamics difference duringTGA / DTGA Temperature dehydration or desolvation Molecular chemical information,FTIR Vibrational IR Spectrum intermolecular interactions about solvent, solvates and quantitation Complementary information to IR, No /Raman Raman Spectrum negligible sample preparation, quantitationSolid State NMR Magnetic Resonance Chemical interactions, quantitationX-RPD Diffractogram Quant/ Qualitative analysis of polymorph Microscopy under light orMicroscopy Morphology, Textural information electron May 26, 2011 56 Source: Giron, D Monitoring of Polymorphism Proceedings ISIC, 13-28, 2002
  57. 57. Polymorph by Raman SpectroscopyThe Principle of Molecular Vibrational Finger Print Raman Spectroscopy Absorbed …Infra Red Laser Light Transmitted What will happen? Scattered …Raman Effect May 26, 2011 57
  58. 58. Raman ScatteringThe Principle of Molecular Vibrational Finger Print Raman Spectroscopy Scattered l0 l 1 > l0 l 2 < l0 Excited state (Virtual)Light l0 Dh1 Energy Dh2 Absorption Initial state Rayleigh Scattering Anti-Stokes Raman Scattering May 26, 2011 Stokes Raman Scattering 58
  59. 59. Raman Spectrum of L-Glutamic Acid 1 [cm] 1 [cm] = - l0 [nm] l [nm]Intensity l0 l2 l1 Some Specific Peaks for α, β form can be seen! In Dry Powder Raman Shift [cm-1] 0 May 26, 2011 59
  60. 60. Raman & X- RPD in Quantification Mixed Glutamic Sample (Pure a-form & Pure b-form)  X-Ray Powder Diffraction & Raman Instrumentation Raman can be used for quantitative analysis (dry powder) directly! May 26, 2011 60
  61. 61. Why Polymorphs so Important? Effects of Polymorphs on Product’s Quality POLYMORPHS Melting Point  Hygroscopicity Melting Point Chemical Hygroscopicity Stability Physical & Chemical Properties Chemical Stability Physical Stability Physical Stability ApparentShape of Crystals Stability Solubility Apparent Solubility Solubility Dissolution Dissolution   Manufacturability Quality of Products Manufacturability Bioequivalence Bioequivalence Bioavailability Fluidity of Dyestuff: Bioequivalence Bioavailability Powders Colors Bioavailability May 26, 2011 61
  62. 62. Polymorph Screening ApproachTier1: Isolate crystals from single solvents. Identify binary systems that offer control of API solubility.Tier2: Performed controlled crystallizations in miscible / immiscible binary systems.Tier3: Perform non-conventional crystallizations (seeding, vapor diffusion, varied temperatures.Tier4: Prepare new polymorphs for solution and solid-state characterization: solubility, stability, hygroscopicity. May 26, 2011 62
  63. 63. What Factors are Important in Polymorphism?  Hydrogen bonding ability  Presence of solvents  Degree of rigidity or floppiness of a molecule  Stabilities of low energy formsIn general, in a series of polymorphs of a compound, thepolymorph with the lowest melting point is the mostthermodynamically stable. May 26, 2011 63
  64. 64. Polymorphic Form Conversion During Manufacturing Interconversion among polymorphs Wet Granulation Inter-conversions between anhydrates and hydrates, or between different hydrates Spray – Drying Amorphous form Milling / Micronization / TablettingQ. Polymorph Appearing and Disappearing?Q. DS polymorph changes throughout a Stability Testing Period?May 26, 2011 64
  65. 65. Decision Tree Development on Polymorphism Process for evaluating when and how polymorphs of drug substances in ANDAs should be monitored and controlled are: ■ Based on the ICH Guidance Q6A decision trees on polymorphism ■ Biopharmaceutics Classification System (BCS) May 26, 2011 65
  66. 66. Must Investigate Polymorphism Application of Decision Trees on Polymorphs ICH Q6A: Decision Tree Criteria for Polymorphism in DS & DP Decision Tree #1. Investigating the need to set acceptance criteria of polymorphs Decision Tree #2. Investigating the need to set acceptance criteria of polymorphs for drug substance Decision Tree #3. Investigating the need to set acceptance criteria of polymorphs for drug product Decision Tree #4. Part 1- Do multiple polymorphic forms exist? Part 2 - Is routine polymorph testing of DS valuable? Part 3 - Is routine polymorph testing of DP valuable? May 26, 2011 66
  67. 67. Screening Decision Tree # 1 Acceptance Criteria of Polymorphs for DS No further test or Are there polymorphic acceptance known polymorphs NO criteria for drug START with different apparent substance and drug solubility? productInitial Elucidationof Structure andother Scientific YES ENDCharacterizationof the Form (s): Are all known YESX-RPD, DSC, TA, polymorphs highlyMicroscopy, and soluble?Spectroscopy Adequate knowledge of drug NO substance polymorphs is available by the time an ANDA is filed Decision Tree # 2 May 26, 2011 67
  68. 68. Screening Decision Tree # 2 Acceptance Criteria of Polymorphs For DS Is there a polymorphic specification NO 1) Different in the USP? (e.g., polymorphic form melting point) 2) Allow to establish tight specificationDecision Tree # 1 YES Is the USP NO Set new polymorphic polymorphic specification acceptance criteria for adequate? drug substance YES Set the same polymorphic acceptance criteria for Decision Tree # 3 drug substance as the USP May 26, 2011 68
  69. 69. Screening Decision Tree # 3 Acceptance Criteria of Polymorphs For DP Is there sufficient No need to set polymorphic concern that polymorphic NO acceptance criteria for acceptance criteria for drug drug product product should be established?Decision Tree # 2 END YES Next Slide In general, there should not be a concern if 1) The most stable polymorphic form is used or Continue… 2) The form is used in a previously commercialized product May 26, 2011 69
  70. 70. Screening Decision Tree # 3 (contd) Acceptance Criteria of Polymorphs For DP FDA BA/BE Guidance: “It is recommended that the Previous Slide sponsor select the agitation speed and medium that provide adequate discriminating ability, taking into account all the available in vitro and in vivo data.” Does drug product YES Set acceptance criteria for the dissolution testing drug product dissolution testing provide adequate controls if polymorphic ratio as a surrogate for polymorph changes? control in the drug product NO Set acceptance criteria for the END drug product using other approaches, such as solid Dissolution testing can frequently detect characterization method potential conversion of polymorphs. In rare cases, solid characterization methods have to END be used. May 26, 2011 70
  71. 71. What is it? and How BCS Works? Allows waiver of requirement for in-vivo bioequivalence studies for IR products The BCS (Biopharmaceutics Classification System) is a scientific framework for classifying drugs based on their aqueous solubility and intestinal permeability. Biopharmaceutics Class Solubility Permeability Compounds Compounds I High* High II ** Low High III High* Low IV Low Low * Highly-soluble substance in a rapidly-dissolving formulation ** If Do Low ~ Highest probability of In vitro / in vivo correlation May 26, 2011 71
  72. 72. Biopharmaceutics Classification System BCS Examples B May 26, 2011 72
  73. 73. Regulatory Issues : Polymorphism1. Pre-clinical Drug Development Identification Early awareness of possible variations in crystalline form2. Early Investigational Phases (IND Phase 1 & 2) Identification Monitoring for possible variations in crystalline form and solvation Increased efforts to find polymorphs and solvates: "polymorph screen" May 26, 2011 73
  74. 74. Regulatory Issues : Polymorphism3. Late Phase Drug Development (IND Phase 3 / NDA Pre- submission) Monitoring the manufacturing process for variations in crystalline form, including solvates Bulk scale-up issues: solvents, temperature, drying, milling Product manufacturing issues: material handling, granulation, compaction Control issues: dissolution, hardness May 26, 2011 74
  75. 75. Regulatory Issues : Polymorphism4. Pre-Marketing (NDA Submission and Review) Justification of in-process controls on manufacturing Consistent crystalline form in clinical and bioavailability studies Stability studies: monitoring for possible changes in crystalline form5. Post-Approval Influence of manufacturing changes on the product New bulk drug suppliers: do they manufacture the same crystalline form? May 26, 2011 75
  76. 76. Salt Screening in Preformulation Why Salt Screening Converting poorly absorbable free acid/base (API) form to a salt form in order to improve solubility and bioavailability. Saltification improves physical and chemical stability and handleability.of 21 New Molecular Entities approved by FDA in 2003, ten were salt forms. Exceptions are out there. May 26, 2011 76
  77. 77. Salt Screening in Preformulation What to be done Selection of right counterion functionalities with optimum physico-chemical characteristics is crucial during drug development – Physical chemical properties (solubility, crystallinity, solid state stability, hygroscopicity) of New Salt Form, Processability under various manufacturing conditions, and bioavailability is crucial and significant. Analyze by High–Throughput Screening XRPD Instrument. May 26, 2011 Follow Decision Tree 77
  78. 78. Salt Screening Decision TreeGreen borderindicateprocessesthat mayoccur inparallelRed borderindicatecriticalselectioncriteria May 26, 2011 78
  79. 79. Salt Screening Decision Tree CRYSTALLINITY NO Continue crystallization attemptsCan crystalline salt be prepared? YES HYGROSCOPICITY YES Unacceptable Does the salt deliquesce at high humidity? ON Solubility SOLUBILITY enhancement NO If necessary Does the salt Have aqueous solubility? YES May 26, 2011 79 Next Slide
  80. 80. Next Slide Here Salt Screening Decision Tree STABILITY Stability enhancement NO If necessary Is the salt physically stable under accelerated YES conditions? Lead Candidate POLYMORPHISM FINAL SALT Are there multiple NO polymorphs of the salt ? YES SECONDARY CONTROL CANDIDATE NO Can the process be controlled to produce Lead Candidate the desired form? YES FINAL SALT May 26, 2011 80
  81. 81. Potential of Physicochemical Property Process of Drug Dissolution in a Dosage Form Formulated Drug Solubilized Drug Absorbed Drug Kdd Kprecip Kdd = Rate of Disintegration Drug Particles Kid Kprecip = Rate of Precipitation Kid = Rate of Intrinsic DissolutionWhen Kdd > Kid, dissolution is Intrinsic Dissolution Controlled and physicalattributes of the active pharmaceutical ingredients are Important. WhenKdd < Kid, dissolution is disintegration Controlled and the cohesive propertiesof the formulation are important. When Kdd ≈ Kid, dissolution isIntrinsic Dissolution and disintegration Controlled and both cohesive and physical properties may be important. May 26, 2011 81 Source: Cynthia Brown et al Pharma Technology 2004
  82. 82. Potential of Physical Property is the acid-base ionization constant indicating apKa molecule or ion is likely to keep a proton at its ionization centre is the water – octanol / liposome partitionLog P coefficient indicating a molecule will prefer an aqueous or organic phase. Log P is a means to understand relationship between solubility and permeability with respect to pH is used for ionizable drugs. It is the ratio ofLog D concentration of all forms (ionized + unionized) dissolved in the two phases. It is a combination of pKa and Log P. It produces an apparent partition coefficient for any pH value May 26, 2011 82
  83. 83. Why is pKa Important? Information on pKa reflects molecular state of stability over the pH range (e.g. stomach and blood pH ). Neutral molecules are easily absorbed while ionized molecule can affect drug-receptor binding pathway. Ionized molecules remain in plasma and are cleared by renal excretion (Ampholytes have special properties). Most drug molecules (60-70%) contain Ionizable groups that ionize in solution. This group belongs to Lipophilicity, permeability & solubility class are pH dependent – a factor in drug transport & absorption. pKa is required in drug formulation for the choice of counter- ion and excipients. pKa must be recorded for regulatory compliance (either by Gradient Titrator or Spectroscopic Techniques). May 26, 2011 83
  84. 84. Why is pKa Important?Distribution of Ionizable compounds (32,437) in World Drug Index (51,596 compounds) 1999 Combination of ionizable % from above number groups in the molecule1 Base, no Acid 422 Base, no Acid 251 Acid, no Base 121 Acid, 1 Base 82+ Acid, no Base 31 Acid, 2+ Base 42+ Acid, 1 Base 3Others 3 Commercial available drugs are 2/3 ionizable molecules with bases only May 26, 2011 84
  85. 85. Why Log P (Partition) is Important?Biological membranes are lipoidal in nature, rate of drug transfer forpassively absorbed drugs is directly related to lipophilicity ofmolecule. Partition coefficient (water/ octanol or chloroform orliposome) is a measure of a drugs lipophilicity and an indication ofits ability to cross cell membranes.The partition coefficient is the ratios between concentrations ofsubstances in two immiscible phases i.e. organic and aqueousphases at equilibrium. Po/w = (C oil / C water) equilibriumThe lipophilic/hydrophilic balance - a contributing factor for the rateand extent of drug absorption. It is the best predictor of absorptionrate, the effect of dissolution rate, pKa, and solubility on absorptionmust not be neglected. Drugs with Po/w greater than 1 are classified as lipophilic otherwise are indicative of a hydrophilic drug May 26, 2011 85
  86. 86. Polarity and Partition Relation The partition coefficient of a drug depends upon both polarity and size. Drugs with high dipole moment, even though un-ionized, have low lipid solubility and, hence penetrate poorly. Ionization reduces lipid solubility as well as slows down the movement through charged membranes. (Tip: ionized molecules do not penetrate membranes. In such cases, membrane transport carriers that neutralize the charge or shield the molecule are required for absorption). Log P is used in QSAR studies and rational drug design as a measure of molecular hydrophobicity. May 26, 2011 86
  87. 87. Why is Lipophilicity Important? The lipophilicity of a drug provides a rough guide to its pharmacokinetic dynamicsLog D at pH 7.4 Implications for drug development Intestinal and CNS permeability problems Below 0 Susceptible to renal clearance May show a good balance between permeability and solubility 0 to 1 At lower values, CNS permeability may suffer Optimum range for CNS and non-CNS orally active drugs 1 to 3 Low metabolic liabilities, generally good CNS penetration 3 to 5 Solubility tends to become lower. Metabolic liabilities increase Low solubility and poor oral bioavailability, although potency may still Above 5 be high May 26, 2011 87 John Comer, Sirius Analytical Instruments Ltd
  88. 88. Why is Permeability Important? Permeability, the rate at which a compound will pass through a membrane Permeability (cm/sec) value depends on the nature of phases and API molecule Permeability of a molecule in vitro study may relate to absorbability in body fluid A relationship between permeability and lipophilicity Ideal drug candidates fall on curve May 26, 2011 88 John Comer, Sirius Analytical Instruments Ltd
  89. 89. Why is Permeability Important? Drug permeability either by passive diffusion (natural) or active / facilitated / ion-pair / pore diffusion or pinocytosis transport High permeability is defined as human absorption of 90% or more of administered dose May 26, 2011 89 *Source:
  90. 90. Why is Solubility Important? Definition of Solubility The amount of a substance (solid) that dissolves in a given (specified) volume (amount) of solvent (liquid) at a specified temperature and pH or to form a saturated solution at any temperature. Significance of Solubility Drug’s physical entity need to be in solution form to interact with biological systems. Active’s solubility is an important parameter for dissolution, bioavailability, and therapeutic efficacy. Poorly soluble molecules rarely constitute successful drug – difficult to absorb / formulate and analyze. It’s difficult to predict accurately - Early screening is vital May 26, 2011 90
  91. 91. Why is Solubility Important? Significance of Solubility Solubility is a property of API and its salt form. Solubility is determined by measuring. concentration of equilibrated saturated solution at 37 ºC for 1 – 24 hrs. Equilibrium time depends on test duration time as well as the physical and chemical stability (conversion of salt form to free base in vitro) of the drug. Low-solubility compounds are compounds whose highest dose is not soluble in 250mL or less aqueous media from pH 1.2 – 7.5 at 37 ºC. May 26, 2011 91
  92. 92. Solubility : Discovery vs Development Solubility in Discovery Solubility in DevelopmentTurbidimetric Solubility Thermodynamic SolubilityNon crystalline CrystallineSolids not Characterized Polymorphs CharacterizedSolubilized in DMSO Solubility measured in term of a solidAdded to stirred gavages medium Equilibrated with an aqueous mediumA time scale measured in tens of A time scale of 24-48 hoursminutesUsed for early in vivo SAR Used to determined the minimum absorbable dose, dissolution rate, and salt selectionCorrelation with in vivo animal Correction with clinical dosage formBetter in early discovery Essential in development May 26, 2011 92
  93. 93. Solubility at EquilibriumSolubility of a molecule in solvents (and some oils if the molecule islipophilic) is determined by the equilibrium solubility method, whichemploys a saturated solution of the material, obtained by stirring an excessof material in the solvent for a prolonged period until equilibrium isachieved. Common solvents used for solubility determination are Water Tweens Ethyl Alcohol Polyethylene Glycols Castor Oil Methanol Propylene Glycol Peanut Oil Benzyl Alcohol Glycerin Sesame Oil Isopropyl Alcohol Polysorbates Sorbitol Buffers at Various pHs May 26, 2011 93
  94. 94. Solubility Assay Methodology Traditional Shake Flask Assay Method Costly, time consuming, polymorphic information required, good for development Kinetic Assay Method Relatively fast (96, 384 well plate) and automated Enhanced solubility and Kinetic due to DMSO Crystal lattice energy disappear and high energy state solution Informative about rank of equilibrium solubility May 26, 2011 94
  95. 95. Solubility Solkin MethodMay 26, 2011 95
  96. 96. Compounds in DMSO Factors Affect Stability / Solubility in DMSO Storage time, Temperature, Concentration, Freeze / Thawing, Water Uptake Once a compound crystallizes from DMSO it will not easily re-dissolve (crystallized compound is in a lower energy less DMSO soluble form) Freeze thaw cycles increase the probability of crystallization Narrow working window (time window) for keeping most compounds dissolved in DMSO (1 to 2 days at room temperature because compounds are active when freshly made but not when stored May 26, 2011 96
  97. 97. Compounds in DMSO Fresh DMSO is highly hygroscopic (5% water in 2hrs) DMSO has a high dielectric constant DMSO doesn’t solvate hydrocarbons e.g. hexane is immiscible in DMSO DMSO solvates compound dipoles - almost all drugs have dipoles Solvation is easier to do in DMSO than in water - no H- bond donor / acceptor networks to disrupt DMSO containing 9% water is unfrozen in the typical lab refrigerator Compounds Differ in DMSO Solubility Based on Crystalline Form - Amorphous is the highest energy form (most soluble in DMSO lowest melting point) May 26, 2011 97
  98. 98. Solubility Kinetic Method  Kinetic Solubility  May 26, 2011 98
  99. 99. Drug Solubilization: Decision Tree May 26, 2011 99
  100. 100. Chemical Stability Profile Solid-State Stability Elevated temperature Studies Stability under High-Humidity Conditions Photolytic Stability Oxidative Stability Solution-Phase Stability Light Stability Oxidation pH-Rate Profile Compatibility Studies: Stability in Presence of Excipients Thin-layer chromatography Differential thermal analysis Diffuse reflectance spectroscopy Typical Stability Protocol for a New Chemical Entity Next Slide….May 26, 2011 100
  101. 101. Chemical Stability Profile Stability Testing of New Drugs and Products General Case for Drug Substances Study Storage Conditions Minimum Time Period at Submission Long Term 25 °C ± 2 °C / 60% RH ± 5% RH 12 monthsIntermediate 30 °C ± 2 °C / 60% RH ± 5% RH 6 monthsAccelerated 40 °C ± 2 °C / 75% RH ± 5% RH 6 months Drug Substances Intended for Storage in a Refrigerator Study Storage Conditions Minimum Time Period at SubmissionLong Term 5 °C ± 3 12 monthsAccelerated 25 °C ± 2 °C / 60% RH ± 5% RH 6 months Drug Substances Intended for Storage in a Refrigerator Study Storage Conditions Minimum Time Period at SubmissionLong Term -20 °C ± 5 °C 12 months May 26, 2011 101
  102. 102. Chemical Stability Profile Stability Testing of New Drugs and Products General Case for Drug Products Study Storage Conditions Min. Time Period at Submission Long Term 25 °C ± 2 °C / 60% RH ± 5% RH 12 monthsIntermediate 30 °C ± 2 °C / 60% RH ± 5% RH 6 monthsAccelerated 40 °C ± 2 °C / 75% RH ± 5% RH 6 months Aqueous Based Products Packaged in Semi-Permeable Containers Study Storage Conditions Min. Time Period at Submission Long Term 25 °C ± 2 °C / 40% RH ± 5% RH 12 monthsIntermediate 30 °C ± 2 °C / 60% RH ± 5% RH 6 monthsAccelerated 40 °C ± 2 °C / NMT 25% RH 6 months (water loss after 3 months) Aqueous Based Drug Products intended for Storage in a Freezer Study Storage Conditions Min. Time Period at SubmissionLong Term -20 °C ± 5 °C 12 months May 26, 2011 102
  103. 103. Chemical Stability Profile Stability Testing of New Drugs and Products Aqueous Based Drug Products intended for Storage in a Refrigerator Study Storage Conditions Min. Time Period at Submission Long Term 5 °C ± 3 °C 12 months Accelerated 25 °C ± 2 °C / 60% RH ± 5% RH 6 months Relative Humidity Ratios CalculationAlternative Humidity Nominated Humidity Ratio 40% RH 25% RH 2.4 60% RH 40% RH 1.5 75% RH 25% RH 3.0 May 26, 2011 103
  104. 104. Permeability Assay Methods    PAMPA - Parallel Artificial Membrane Permeability Assay: Same size chamber separated by filter coated with lipid in organic solvent  Results vary if lipid selection varies.  Easy and results are comparable with Caco-2  Coco-2: Different compartmental volume separated by a monolayer of cells grown on a filter.  Stable monolayer preparation time and cost consuming.  Results agree with human in vivo  jejunal permeability experimentsMay 26, 2011 104
  105. 105. Drug Delivery : Solid Dosage FormsMolecular Transport and Cellular Controlled Diffusion Dosage Form Drug Drug Disintegration In GI Membrane Absorbed Dispersed Granules Dissolution “Solution” into in Dispersion Systemic Primary Drug GI Particles Circulation Media May 26, 2011 105 Modified from Michael J. Hageman, Pfizer Global R&D, NJ, USA
  106. 106. Permeability Assay Methods ≈? K D ≠? ≡? C0 Donor solution Cd C1 h Cr Donor C2 Receptor Do excipients alter or affect permeability / Absorption?May 26, 2011 106
  107. 107. Drug DiffusionMay 26, 2011 Anand Sistla in Mol. Dev. Intern Symp 2003 107
  108. 108. Solubility Decision Trees Solubility? ? 300 low high 200 ? 100 Dose? ? <200 >200 0 High Low ?May 26, 2011 108
  109. 109. Basic Powder PropertiesMay 26, 2011 109
  110. 110. PSD for DS : Decision Tree Is the drug product a solid dosage form NO or liquid containing un-dissolved drug No drug substance substance? particle size acceptance criterion YES required for solution1. Is the particle size critical to dissolution, dosage form solubility or bioavailability?2. Is the particle size critical to drug If NO to All processability? No acceptance3. Is the particle size critical to drug product criterion required stability?4. Is the particle size critical to drug product content uniformity? If YES to All5. Is the particle size critical for maintaining Set Acceptance product appearance? Criterion May 26, 2011 110 ICH Q6A : Particle Size Distribution (DS) Acceptance Criteria
  111. 111. Influence of Particle Size Reduction on Material Characteristics  Homogeneity – Increases  Crystallinity – Decreases  Bulk density – Decreases  Flow characteristics – Worsens  Solubility – Increases  Reactivity – Increases  Taste – Increases  Explosiveness – Increases? May 26, 2011 111 Source: Elizabeth B Vadas Inscitech Inc
  112. 112. Drug Excipient Interactions Effect on Dissolution, Solubility and Stability Processing factors – Micronization, grinding, milling, spray drying, lyophilization, compaction force. Physical factors – Temperature, humidity, and pressure. Chemical factors – Solvation (Formation of agglomerates, inclusion complex and hydrophobic film. Dissolution in vivo will not likely to be rate limiting, if excipients are well characterized under various conditions. High permeability attribute reduces the risk of bio-in- equivalence.The changes in drug structure and dynamics over time needs to be verified by solid-state NMR, FTIR, Raman, X-ray diffraction, and DS calorimetric techniques. May 26, 2011 112
  113. 113. Brodie’s pH Partition Theory Biophysical Significance of Theory in ADMET Solvation – Ionization – Diffusion - Receptor – Interaction The pKa of the drug and pH of the GI tract fluid and the pH of blood stream control the solubility of drug i.e. rate of drug transfer or absorption through membranes Only non-ionized drug get through lipid membrane i.e. unionized drugs have higher lipid solubility Brodie’s distribution is related to Henderson - Hasselbach equation for weak acids and bases  Ci   Cu  pKa  pH  log   for bases pKa  pH  log   for acids  Cu   Ci  Henderson - Hasselbach Equation May 26, 2011 113
  114. 114. Package Compatibility Types of packaging systems – storage, shipping, or marketing. Applicable cGMPs – equipment construction, qualification applies regardless of holding time. Description information – construction material, label information. Suitability information – protection, compatibility, safety, performance. Quality control information – chemical composition, physical characteristics, acceptance criteria. Stability information – shelf life stability, expiration date, CMC documentation. May 26, 2011 114
  115. 115. Thank YouMay 26, 2011 115
  116. 116. “If we can’t describe scientifically and technologically what we are doing as a process, we don’t know what we’re doing” May 26, 2011 116