UNIT 1 - PREFORMULATION.pptx

UNIT 1 - PREFORMULATION.pptx

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  INDUSTRIAL PHARMACY It includesdevelopment, manufacturing, marketing and distribution of drug products including quality assurance in every activities
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  UNIT - I Syllabus:Preformulation Studies: Introduction to Preformulation, goals and objectives, Study of physicochemical characteristics of drug substances. a. Physical properties: Physical form (crystal & amorphous), particle size, shape, flow properties, solubility profile (pKa, pH, partition coefficient), polymorphism b. Chemical Properties: Hydrolysis, oxidation, reduction, racemisation, polymerization BCS classification of drugs & its significant Application of preformulation considerations in the development of solid, liquid oral and parenteral dosage forms and its impact on stability of dosage forms.
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  Introduction Preformulation: It is thestudy of the physical and chemical properties of the drug prior to compounding process • Preformulation commences when a new drug shows sufficient pharmacologic actions in animals and assure that it used for evaluation in man and considered safe • This properties may provide a) Rationale for formulation design b) Support the need for molecular modification
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  Goals of preformulation •To establish the physicochemical parameters of a new drug • To determine pharmacokinetic rate profile • To establish its compatibility with common excipients • Providing a scientific data to support the dosage form or design
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  OBJECTIVES OF PREFORMULATION •Will assist in developing a stable, safe effective formulation • strengthen the scientific foundation, provide regulatory relief, and conserve resources in the formulation development and evaluation process. • improve public safety standards, enhance product quality, facilitate the implementation of new technologies, facilitate policy development and regulatory.
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  Physical Properties Physical form & Bulk Characterization Solubility analysis Stability analysis Organoleptic Properties Crystallinity& Polymorphism Ionization constant pka Solution Stability Particle Size & Shape Hygroscopicity pH Solubility profile Solid State Stability Purity Particle Size Characterization Common ion effect ksp Bulk Stability Surface area Bulk density Thermal effects Compatibility Powder flow properties Solubilization Dissolution
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  Physical properties 1. Organolepticproperties
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  2. Physical formof drug: Drug substances may occur as amorphous (higher solubility) or as Crystalline (higher stability) Amorphous form: • Amorphous forms have the atoms or molecules which is placed in random manner. . • These are prepared by precipitation, lyophilization or rapid cooling of liquid melts. Advantages: It have higher solubilities as well as dissolution rates as compared to crystalline forms. So it have high potential energy.
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  Disadvantages: Upon storage,some amorphous solids tend to revert to more stable crystalline forms, this leads to solubility problem during bulk processing Examples: Plastics, Glass, Rubber, Polymers, Gels Novobiocin is inactive when administered in crystalline form but when they are administered in the amorphous form, it is readily absorbed in GIT with good therapeutic response.
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  • Crystalline Solids– The drug substance have the atoms or molecules which are arranged in repetitious spacing in three dimensional array. • These have low potential energy and so it have lesser solubility but higher stability than amorphous form. Examples: Quartz, Calcite, sugar, Diamonds. • The crystalline form of Penicillin G is considerably more stable and result in excellent therapeutic
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  • A Crystallinecompound may contain either stoichiometric or non stoichiometric amount of solvent in its crystal lattice. • Non stoichiometric adducts called inclusions or Clathrates. Stoichiometric adducts referred to as Solvates. • When the incorporated solvent in solvate is water then it is called Hydrates (w.r.t molar equivalent of water present it is described as hemihydrate, monohydrate, dihydrate)
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  Solvates Clathrates
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  2. Polymorphism • Theability of a drug or compound to crystallize in more than one form with different internal lattices. • Chemical stability and solubility changes due to polymorphism which impact on a drug’s bioavailability and its development • Many physicochemical properties vary with the change of polymorphism like melting point, density, hardness, shape, optical parameters and vapor pressure
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  • Eg: Chloramphenicolpalmitate exists in three crystalline polymeric forms (A, B and C) and also amorphous form. B form has increased peak serum levels indicates that it has more absorption than other. • Methods employed to obtain different polymeric forms are Sublimation, Crystallization, Evaporation, Vapor diffusion, Thermal treatment, Changing the pH, Thermal desolvation, Grinding. • Crystalline, amorphous and polymorphic forms are identified by Microscopy, DSC, IR spectroscopy, Xray diffraction, SEM, Thermogravimetric analysis etc
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  3. Particle sizeand shape • Size, Shape and surface area of drug particles affect the flow property, dissolution and biopharmaceutical behavior of the drug • Drugs which are poorly soluble showing less absorption during dissolution, when it is converted into finely divided particle size it will be more readily absorbed Significance of particle size: • It may affect formulation & product efficacy • Physical and chemical properties of the drug is affected by particle size distribution • It influences oral absorption • Affects content uniformity in solid dosage forms
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  Methods to evaluateparticle size and distribution a) Sievieng or Screening – 50-150 μm b)Optical microscopy – 0.2-100 μm c) Sedimentation – 1-200 μm d)Light energy diffraction – 0.5 – 500 μm e)Laser holography – 1.4 – 100 μm a. Sieving or screening: • Sieve analysis is a method of determining the particle size distribution of a material. • During sieving the sample is subjected to vibration with horizontal or vertical movement. • Depending on the size of the particles either it will pass through the sieve mesh or retained above. • This process separates fine particles from coarse particles
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  • Sieve: Adevice with mesh (perforations) through which the finer particles are passed • Sieve number: Mesh number indicates the number of openings in one inch length of the sieve. Eg: 40 mesh means that there are 40 holes in one inch length • Advantages: Simple technique Wide size range Inexpensive • Disadvantages: Wear or damage in use or cleaning Rod like particles are under estimated as fines Requires large sample size
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  b. Optical Microscopy:Range: 0.2 – 100 μm • Microscope can show the exact shape and size of each particle. When coupled with camera the light microscope can take photographs of the particles. Optical microscopy distinguished in three major types a) Manual optical microscopy b) TEM & SEM (Transmission and Scanning Electron Microscopy) c) Automatic and Image analysis microscope Advantages:  Absolute measurement  Most direct method Disadvantages:  Slow and tedious
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  c. Sedimentation method: •Range: 1 – 200 μm • Anderson pipette is used • Particle size is calculated by Stokes law • It is determined by examining a suspension of the powder to settle in a cylinder and taking samples from the settling suspension at a fixed horizontal level at intervals of time • Advantages: Simple and inexpensive • Disadvantages: Time consuming. Particles to be completely insoluble in liquid
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  d. Light energydiffraction: • Range: 0.5 – 500 μm • Particle size is determined by the reduction in light reaching the sensor as the particle, dispersed in a liquid passes through the sensing zone • Quick and fast e. Laser Holography • Range: 1.4 – 100 μm • A pulsed laser is fired through an aerosolized particle spray and photographed in three dimension with holographic camera, allowing the particles to be individually imaged and sized
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  4. Flow properties •Powder flow properties can be affected by change in particle size and density • The flow properties depends upon following, – Frictional force – Cohesion between one particle to another • Fine particle possess poor flow because it will fill the void space • By using glidant, it may be possible to alter the flow properties eg: Starch Talc • It is determined by Angle of repose Compressibility
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  • Angle ofRepose: It is the maximum angle between the surface of a pile of powder and horizontal plane • Where h is height of the pile and r is the radius of the pile • The rougher and more irregular the surface of the particles, the higher will be the angle of repose. Lower values indicate the better flow characteristics
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  • Compressibility: Another measurementof free flowing properties is compressibility calculated from powder density. It is characterized by the following method 1. Carr’s compressibility index 2. Hausner’s ratio Carr’s compressibility index: The carr index explains the compressibility of the powder, which is named after Scientist Ralph J. Carr
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  • Hausners ratio Itis a number that is correlated to the flowability of a powder or granules. It is named after Henry H Hausner
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  5. Solubility profile:(pKa, pH, Partition coeffecient) • It is an important physicochemical property because it affects the rate of drug release into the dissolution medium, the bioavailability of the drug and therapeutic action. • Solubility is defined as When one or more solute is dissolved in solvent, it forms a homogeneous mixture of solution. • It is a saturated solution obtained by stirring an excess of material in the solvent until equilibrium is achieved. This is proposed by Higuchi Connors • Generally polar material dissolve in Polar solvents and non polar materiall dissolve in non polar solvents • Solubility is made by three ways: Dissociation, dispersion and ionization
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  • Common solventsused for solubility determination are water, polyethylene glycol, propylene glycol, Glycerin, sorbitol, Ethanol, Methanol, Benzyl alcohol, Isopropyl alcohol, Tween, polysorbates, castor oil, sesame oil, Various pH buffers
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  pKa (Ionization constant): •Unionized drug – lipophilic – Increased absorption Ionized drug – Hydrophilic – Increased solubility • If the compound containing acidic or basic functional groups, its solubility is influenced by pH of the solvent • Solubility is done by drug acquires a negative or positive charge and gain or lose its electrons to the solvent. So its solubility is greater in the ionized state • Weakly basic drug is fully dissolve in acidic environment (stomach) (ionized) and raise the stomach pH which will lead to decreased solubility. • So, The degree of ionization is depend on pH • Ionization will also impact on stability and permeability.
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  • The Henderson– Hasselbalch equation provides an estimate of ionized & unionized drug concentration at a particular pH. It is used to determine the pKa of the drug, to predict solubility. • For acidic compounds pH = pKa + log (ionized drug/ unionized drug) • For basic compounds pH = pKa + log (unionized drug/ ionized drug) • pKa of a compound is the ionization constant which measure the unionized drug in certain pH • It is determined by potentiometric titration, spectrophotometry, conductometry and solubility method
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  pH profile: • Itis a set of solubility values at specified pH values. • Methods to determine the pH solubility of the drug is Shake flask method, Potentiometric titration, turbidometric • Shake flask method: Determines the solubility of drug at a pH value at equilibrium • Potentiometric titration: acid base titration, a characteristic shift in the middle of the titration while adding acid or base to the solution containing ionizable substance. • Turbidometric method: drug is dissolved in organic solvent (DMSO) and it is added to pH buffer at regular interval. Turbidity is measured. Volume consumed for first detection of turbidity indicates the solubility profile.
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  Partition coeffecient • Partitioncoeffectient is a measure of drug’s liphophilicity and an indication of its ability to cross cell membranes. • It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. P O/W = (Coil / Cwater)equilibrium • Log P – Partition coefficient, which is pH is independent • Log D – Distribution coeffecient , which is pH is dependent • If the log P > 1, the drug is lipophilic • If the log P < 1, the drug is hydrophilic
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  • It isgenerally perfored in Octanol/ water, Chlorform/ Water systems • It is determine by shake flask method. Drug is shaken between octanol and water. Aliquot is taken and analysed for drug content • The partition coeffecient provide an empiric handlle in screening for some biological properties. • It contributes to determine the rate and extent of drug absorption by characterizing the drugs lipophilic and hydrophilic nature.
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  • Dissolution: • Whencombining the solubility, partition coeffecient and pKa results, the dissolution data profile will obtained. This provide the invivo absorption characteristics of the drug. • The dissolution rate of the drug substance and drug absorption is described by Noyes whitney equation • Where dc/dt – Dissolution rate • h – diffusion layer thickness • C – solute concentration in bulk solution • V – Volume of dissolution medium • A – Surface area of dissolving drug • Cs – Solute concentration in diffusion layer.
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  • The dissolutionrate of drug may be affected by • Chemical form – Acid, base and different salt forms • Crystal form – Polymorphic occurrence, Solvates – Which exhibit higher dissolution in aqueous media • Particle size – Reducing particle size which aids in dissolution • Surface properties of the drug – Higher static energy may result in poor wettability and formation of agglomerates
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  6. Stability analysis •Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug and also drug product. • These studies include both solution and solid state experiments. • Solid state: This includes Drug stability, Drug – Drug stability and Drug excipient stability measurement in various temperatures and light. This is severly affected by changes in purity and crystallinity • Solution state: Drug is dissolved or dispersed in various solvents and it is measured for its stability at various pH, ionic strength, cosolvent, light, temperature and oxygen.
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  Storage conditions –4 weaks, 8 weeks and 12 weeks • 5 C – Refrigerator • 22 C – Room temperature • 37 C – Ambient temperature • 37 C/ 75 %RH – Ambient humidity • 50 C • 70 C • 90 C • UV Light – Clear glass container, Amber, yellow-green container • O2 – environment, N2 – environment The decay process may be explained by either zero order or first order kinetics. It is analysed through HPLC analysis, DSC or IR analysis.
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  CHEMICAL PROPERTIES 1. Hydrolysis: Itis the cleavage of chemical bonds by the addition of water. Example: The catalytic conversion of starch into glucose; Conditions that favor hydrolysis: Presence of OH-, hydride ion, divalent ion, ionic strength, heat, light Prevention of hydrolysis pH adjustment – Formulate the pH of the product which have optimum stability Addition of surfactant – Which stabilize the drug Salts and esters – Convert the drug into its salt or ester form
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  2. Oxidation andReduction • Oxidation – gain of oxygen, loss of hydrogen or loss of electrons • Reduction – Gain of electrons or hydrogen atom • Eg: Iron reacts with oxygen to form rust. Here iron is oxidised and oxygen is reduced. This is called redox reaction ie., transfer of oxygen or hydrogen atoms • Oxidation occur in two ways – Auto oxidation, Free radial oxidation • Functional groups which favor oxidation & reduction are substituted aromatic groups, alkenes, ethers, amines • Factors affecting oxidation & reduction are O2 Concentration, light, heavy metals, H and OH ions, Temperature • Prevention: Reducing O2 content, storage in dark and cool condition, Addition of chelating agent, pH adjustment, addition of antioxidant (BHT, Ascorbic acid) or reducing agent (Zinc, CO)
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  4. Racemization: Itis the process in which one enantiomer of compound converts to the other form and at certain point the drug contains both + and – in equal ratio and becomes optically inactive Eg: + and – Aspartic acid or D and L Ribose sugar, Levo cetirizine, + and – Amphetamine, dextromethorphan This will lead to different pharmacokinetic properties, pharmacological and toxicological effect. Racemizaton depends on temperature, solvent, catalyst, light
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  5. Polymerization: It isa process in which monomer molecules complex together to form polymer chains or three dimensional networks Eg: Darkening of glucose solution is due to polymerization of breakdown product 5 hydroxyl methyl furfural Shellac on aging undergoes polymerization and hence prolonged disintegration time and dissolution time.
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  BCS CLASSIFICATION OFDRUGS • BCS – Biopharmaceutical Classification System • It is a system to differentiate the drugs on the basis of their aqueous solubility and intestinal permeability and dissolution rate • According to BCS, drug substances are classified into 4 classes • Class Solubility Permeability Example I High High Metoprolol, propranolol II Low High Aceclofenac, phenytoin III High Low Ranitidine, metformin IV Low Low Hydrochlorthiazide, Furosemide
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  • BCS isthe guidance provided by the US FDA for predicting the intestinal drug absorption. • The factors affecting oral drug absorption for immediate release dosage form are – Solubility – Intestinal permeability – Dissolution • Solubility – Maximum amount of drug or highest dose of drug should be highly soluble in 250 ml of aqueous media with in the pH range of 1 to 6.8 buffer at 37 °C
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  Permeability • It isdetermined by measuring the rate of mass transfer across the human intestinal membrane. • Also if the drug substance is highly permeable when the systemic bioavailability is determined to be 85% of administered dose based on mass balance determination or comparison with IV reference dose. Dissolution • When the drug product is considered rapidly dissolving if it dissolves within 30 min using USP disso apparatus 1 and 2. It is considered Very rapidly dissolving when it dissolves in 15 min.
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  Applicationof Preformulationconsiderations inthe development of solid, liquidoral and parenteral dosage forms and its impact on stability of dosage forms • Ideal characteristic features to chose a dosage form design are, • Desired therapeutic action • Minimal dose and frequency • Have short onset of action without any side effect • Should completely eliminated from the body • Dosage form should be elegant, physically and chemically stable
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  Biopharmaceutical aspects • Accordingto drug pharmacokinetic profile (ADME), route of administration of drug or dosage form is desired Therapeutic consideration • Incase of emergency, Sublingual or injection form is selected • In case of infants patients, children and geriatric patients and those who are suffering from swallowing problems, chewable tablets or liquid dosage form (Syrups, drops) are preferred
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  Drug factors: Carefulstudy of physical and chemical properties of drug substances is to achieve stable, efficacious product. Physical chemical stability of drug substances: Temperature, pH and excipients will influence the physical chemical stability Sterilization by autoclave cannot be done for Temperature sensitive drug pH of the drug should be most considered during oral administration for stability and absorption Physical stability: • Solid state characteristics are determined in physical stability • Color, odor, identity, Specific gravity and optical rotation are observed according to exposure to temperature and humidity
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  Chemical stability –Liquid state stability is observed • Instability of drug through chemical reaction is easily observed in liquid state mainly; cause reduction in potency Drug excipient compatibility studies: • Depend upon the excipient compatibility with drug which determine the product stability. • Therapeutic or functional change also occur when they are incompatible • The selection of excipient and the ratio added in the formulation is to be justified in regulatory filings.