PREFORMULATION

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physico-chemical and pharmaceutical factors which is vital to understand during preformulation study.

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PREFORMULATION: 

PREFORMULATION C.U.Shah College of Pharmacy & reseach 1

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2 Definition:- It involves numerous investigation on a new drug candidate in order to produce useful information for physicochemically stable and biopharmaceutically suitable dosage form design. PREFORMULATION Medical chemistry research Preformulation F & D Process research & development Analytical research & development Pharmacological screening

WHERE WE NEED PREFORMULATION?: 

3 WHERE WE NEED PREFORMULATION ? To formulate an elegant, safe, efficacious dosage form with good bioavailability. To formulate new dosage form of already existing drug. Determination of all the properties of drug and the best suitable dosage form for the drug molecule. Produce necessary and useful data for development of analytical methods. Helps in adjustment of Pharmacokinetics and biopharmaceutical properties .

CONTENTS: 

4 CONTENTS 1)Physical & Pharmaceutical factors. a)Organoleptic properties. b)Particle size & surface area. c) Crystallinity . d)Polymorphism. e)Flow property & density. f)Compressibility. g) Hygroscopicity . h)Electrostatic charge. i) Osmolaritty . j)Rheology. k)Wettability. l)Drug excipient compatibility. 2)Solubility analysis. 1)Aqueous solubility. a)Intrinsic solubility (Co). b) Ionisation constant ( Pka ). 2) Solubilization . 3)Partition Coefficient. 4)Thermal effect. 5)Common ion effect. 6)Dissolution.

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5 3)stability analysis. a)solid state stability. b)solution state stability. c)stability assessments. 4)Chemical characteristics. a)Photodecomposition. b)Oxidation. c)Hydrolysis . d)Racemization. e)Polymerization. f)Isomerization. g)Decarboxylation. h)Enzyme decomposition.

Solubility analysis: 

6 AQUEOUS SOLUBILITY:- A drug must possess aqueous solubility for therapeutic efficacy in physiological pH range of 1 to 8 at 37 ºC. Poor solubility (<10mg/ml) may result into bioabsorption problems. If solubility of drug is less than 1 mg/ml it indicates the need for a salt, particularly if the drug will be formulated as a tablet or capsule. In the range 1-10 mg/ml serious consideration should be given to salt formation There are 2 fundamental properties mandatory for a new compound. [a] Intrinsic Solubility (Co). [b] Ionization Constant ( pKa ). Solubility analysis

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7 ( A) INTRINSIC SOLUBILITY (C O ) :- S = So {1 + (K 1 / [H+])} ------ for weak acids. S = So {1 + ([H+] / K 2 )} ------ for weak bases. where, S = Solubility at a given pH. So = Intrinsic solubility of the neutral form. K 1 = Dissociation constant of weak acid. K 2 = Dissociation constant of weak base . The intrinsic solubility should ideally be measured at two temperatures (1) 4 °C To ensure physical and chemical stability. (2) 37°C To support biopharmaceutical evaluation . Solubility analysis

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8 Method to determine solubility (1) Equilibrium solubility method An excess of drug is placed in solvent and shaken at constant temp. over a prolong period of time till eqilibrium is attained. Filtration is done. Analyze the supernent via HPLC to determine degree of solubility. This approach is referred as thermodynamic . Other methods are: (1) Turbidometric solubility method. (2) Nephlometric solubility method. (3) Ultrafiltration LC/MS solubility method. (4) Direct solubility method. (5)modified equilibrium method .

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9 (B) Ionization constant ( pKa ):- Most of the drugs are weak bases, some are weak acids and only few are nonionic amphoteric or alcohol . Henderson- Hasselbalch equation :- pH = pKa + log [ionized form] / [unionized form] --- for acids. pH = pKa + log [unionized form] / [ionized form] --- for bases. Uses of these equations :- To determine pKa . To predict solubility at any pH provided that Co & pKa are known. To facilitate the selection of suitable salt forming compounds. To predict the solubility & pH properties of the salts .

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10 Methods to determine pKa :- Potentiometric method. Conductivity method. Dissolution rate method. Liquid-Liquid partition method. Spectrophotometric method .

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11 SOLUBILIZATION Preformulation study is used to identify the possible mechanism for solubilization for the drug candidates with either poor water solubility or insufficient solubility for projected solution dosage form. Different solubilization techniques: 1)Change in pH :- E.g . Solubility of Nimesulide increases as pH is increased. 2) Micronization :- E.g.. Griseofulvin shows increased solubility by reducing particle size .

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12 3) Cosolvency :- Addition of a water miscible solvent can often improve the solubility of a weak electrolyte or non-polar compound in water by altering the polarity of the solvent. Commonly used cosolvents are ethanol, sorbitol, glycerine, propylene glycol , dimethylacetamide (DMA), DMSO, etc . 4) Solubilization by surfactant :- E.g.. Gelucire 44/14 is a surface active excipient that can solubilize poorly soluble drug. E.g.. Anionic & cationic surfactants exhibited dramatically higher solubilization for gliclazide , while nonionic surfactants showed significantly lower solubilizing ability .

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13 5) Complexation :- E.g. The complexation of iodine with 10-15% PVP can improve aq. solubility of active agent. 6)Formation of Inclusion Compound :- Enhanced solubility of oxicams through inclusion of β- cyclodextrin and its derivatives. E.g. The enhancement of solubilization increased 300 fold for Nimodipine at a polymer conc. 10% by use of water soluble dendrimer based on polyglycer . 7)Use of Metastable polymorphs :- E.g. B form of Chloramphenicol palmitate is more water soluble than A & C forms .

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14 PARTITION COEFFICIENT(P) :- When a solute is added to two immiscible liquids it will distribute itself between the two phases in a fixed ratio, which is referred to as partition or distribution coefficient . In formulation development, the n- octanol /water or CHCl3/water partition coefficient is commonly used . P = (Concentration of drug in octanol ) ---- For unionizable drugs. (Concentration of drug in water) P = (Concentration of drug in octanol ) ---- For ionizable drugs. (1-α)*(Conc. of drug in water) where α = degree of ionization. P > 1  Lipophilic drug. P < 1  Hydrophilic drug.

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15 Methods to determine P :- Shake Flask Method. A solute is shaken with two immiscible solvents, followed by analyzing solute conc. In one or both phase. Before analysis it is vigorously shaken to ensure that equilibrium is reached. M ost commonly used method includes UV-Visible, GLC, Colorimetry (for specific comp.) Chromatographic Method (TLC, HPLC). Counter Current & Filter Probe method. Tomlinson filter probe method . for unstable comp. can be used over wide range of temp. Microelectric titration method.

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16 Applications of P :- Measure of lipophilic character of molecules. Recovery of antibiotics from fermentation broth. Extraction of drug from biological fluid Absorption of drug from dosage forms. Study of distribution of flavoring oil between oil & water in emulsion .

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17 THERMAL EFFECT :- Effect of temperature on the solubility of drug can be determined by measuring heat of solution. (∆ Hs ). ln S = -∆ Hs /R*T + C where , S = Molar solubility at temperature T (ºK). R = Gas constant. Heat of solution represents the heat released or absorbed when a mole of solute is dissolved in a large quantity of solvent. Typical temp. range should include 5ºC, 25ºC, 37ºC & 50ºC . Importance : Determination of temperature effect on solubility helps in predicting storage condition & dosage form designing .

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18 COMMON ION EFFECT :- Addition of common ion reduces the solubility of slightly soluble electrolytes . To identify a common ion interaction the intrinsic dissolution rate of HCl salt should be compared between Water & water containing 1.2% W/V NaCl . 0.05 M HCl & 0.9% NaCl in 0.05 M HCl . Both saline media contains 0.2 M Cl ־ which is typically encountered in fluids in vivo .

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19 DISSOLUTION The absorption of solid drugs administered orally can be understood by following flowchart. K d K a DISSOLUTION ABSORPTION when Kd <<<< Ka , absorption is dissolution rate limited. I n many instances , dissolution rate at the absorption site , is rate limiting steps in absorption process . Dissolution rate can affect:- Onset of action Intensity of action. Duration of response. Control the overall Bioavailability of drug form . DRUG IN GI FLUID SOLUTION OF DRUG DRUG IN BLOOD

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20 Dissolution is to be considered of 2 types : Intrinsic dissolution Noyes-Whitney equation: To predict if absorption would be dissolution rate limited or not . dC / dt = AD(Cs-C) / hv Particulate dissolution Determine the dissolution of solids at different surface area. It is used to study the influence on dissolution of particle size, surface area & mixing with excipients .

STABILITY ANALYSIS : 

21 STABILITY ANALYSIS Development of a drug substance into a suitable dosage form requires the preformulation stability studies as: [1] Solid state stability. [2] Solution state stability. SOLID STATE STABILITY:- Solid state reactions are much slower & more difficult to interpret than solution state reactions because of reduced no. of molecular contacts between drug & excipient molecules & occurrence of multiple reactions .

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22 Techniques for solid state stability studies : Solid State NMR Spectroscopy. (SSNMR) Powder X-ray diffraction. (PXRD) Fourier Transform IR. (FTIR) Raman Spectroscopy. Differential Scanning Calorimetry . (DSC). Thermo gravimetric Analysis. (TGA). Dynamic Vapor Sorption. (DSV). SOLUTION STATE STABILITY:- The primary objective is identification of conditions necessary to form a stable solution. These studies include the effects of pH, Oxygen, Light, Temperature, Ionic Strength, Co-solvent.

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23 Stress condition in stability assessments TEST CONDITION SOLID Heat( (°C) 4,20,30,40,40/75 % RH, 50 & 75. Moisture uptake 30,45,60,75&90% RH at RT. Physical stress Ball milling AQUEOUS SOLUTION pH 1,3,7,9 & 11 at RT & 37ºC. Reflux in 1M HCl & 1M NaOH . Light UV (254 & 366 nm) & Visible at RT. Oxidation Sparing with oxygen at RT, UV may accelerate breakdown.

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24 CHEMICAL CHARACTERISTICS OXIDATION It is a very common pathway for drug degradation in both liquid & solid formulation . Oxidation occurs in two ways:- Auto oxidation. Free radical chain process . OXIDATION SELECTED FUNCTIONAL GROUPS Alkenes. Substituted aromatic groups. (Toluene, phenols, anisole). Ethers. Thioethers . Amines .

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25 FACTORS AFFECTING OXIDATION PROCESS 1)Oxygen concentration. 2)Light. 3)Heavy metals particularly those having two or more valence state.(e.g. copper, iron, nickel, cobalt .) 4)Hydrogen & Hydroxyl ion. 5)Temperature .

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26 PREVENTION OF OXIDATION . Reducing oxygen content. Boiling water & purged with nitrogen gas. Storage in a dark & cool condition. Addition of chelating agent. [ Eg . EDTA, Citric acid, Tartaric acid]. Form complexes with trace amt of heavy metal ions and inactivating their catalyzing activity . Adjustment of pH. Changing solvent. [ Eg . Aldehydes, ethers, ketones may influence free radical reaction]. Additon of antioxidant. Reducing agent. Chain inhibitors of radical induced decomposition .

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27 HYDROLYSIS. it mainly involves nucleophilic attack of labile group. E.g.. Lactam > Ester > Amide > Imide. If attack is by water hydrolysis. If attack is by solvent solvolysis . Generally follows 2 nd order kinetics as there are 2 reacting species, water and API. In aqueous solution, water is in excess, the reaction is 1 st order. Conditions that catalyze the breakdown:- 1.Presence of hydroxyl ion. 5. Presence of hydride ion. 2.Presence of divalent ion. 6.Heat . 3.Light. 7.Ionic hydrolysis. 4.Solution polarity & ionic strength. 8.High drug concentration .

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28 Prevention of hydrolysis :- pH adjustment. Formulate the drug solution close to its pH of optimum stability. Addition of water miscible solvent in formulation. Optimum buffer concentration to suppress ionization . Addition of surfactant: Nonionic, cationic & anionic surfactant stabilizes the drug against base catalysis . Salts & esters: E.g.. Phosphate ester of Clindamycin. The solubility of pharmaceuticals undergoing ester hydrolysis can be reduced by forming less soluble salts. Store with dessicants . By use of complexing agent .

Photolysis: 

29 Photolysis Mechanism of decomposition :- Electronic configuration of drug overlaps with spectrum of sunlight or any artificial light, & thereby energy is absorbed by electron & it goes to the excited state. They are unstable & release the acquired energy & come to the ground state & decompose the drug .

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30 Photosensitization means molecule or excipient which absorbs energy but do not participate themselves directly in the reaction but pass the energy to other that will cause cellular damage by inducing radical formation . Photosensitizer Energy transfer Electron transfer Converts oxygen from its ground state to singlet excited state. Generate superoxide molecule, which is an anion radical & acts as a powerful oxidizing agent.

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31 PHOTODECOMPOSITION PATHWAYS N- Dealkylation : E.g. Diphenhydramine, Chloroquine , Methotrexate . Dehalogenation : E.g. Chlorpropamide , Furosemide . Dehydrogenation of Ca ++ channel blocker. E.g. Solution of Nifedipine → Nitrosophenylpyridine ( with loss of water). Rapidly yellow color Brown.

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32 Decarboxylation in anti-inflammatory agents. E.g.. Naproxen, Flurbiprofen , Benzoxaprofen . Oxidation. E.g.. Chlorpromazine & other phenothiazines give N- & S- oxides in the presence of sunlight. Isomerization & cyclization. E.g.. Noradrenaline, Doxepine . Rearrangement. E.g.. Metronidazole → Oxidiazine → Yellow color .

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33 Prevention of Photodecomposition :- Suitable packing. E.g.. Yellow-green glass gives the best protection in U.V. region while Amber confers considerable protection against U.V. radiation but little from I.R. Use of Anti-oxidant. E.g.. Photodegradation of Sulphacetamide solution may be inhibited by an antioxidant such as sodium thiosulfate or sodium metabisulphate . Protection of drug from light. E.g.. Nifedipine is manufactured under Na light.

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34 Avoiding sunbath. E.g.. Sparfloxacin . Photostabilizer [Light absorber]. Colorant  Curcumine , Azorubine . Pigments  Iron oxide, Titanium dioxide . Coating: E.g. Pigments like TiO2(IN NIFEDIPINE) / ZnO . E.g.. Photostabilization of Sulphasomidine Tab. by film coating containing U.V. absorber ( Oxybenzone ) to protect color & photolytic degradation. presence of TiO 2 noticeably accelerated the degradation of antibiotic in comparison with direct pyrolysis. e.g. with Lincomycin .

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35 RACEMIZATION The inter conversion from one isomer to another can lead to different Pharmacokinetic properties (ADME) as well as different Pharmacological & toxicological effect. E.g.. l -epinephrine is 15 to 20 times more active than d -form, while activity of racemic mixture is just one half of the l - form. It follows first order kinetics. It depends on temperature, solvent, catalyst & presence or absence of light .

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36 POLYMERIZATION It is a continuous reaction between molecules. More than one monomer reacts to form a polymer. E.g.. Darkening of glucose solution is attributed to polymerization of breakdown product [5- (hydroxyl methyl) furfural]. E.g.. Shellac on aging undergoes polymerization & hence prolongs disintegration time &dissolution time .

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37 ISOMERIZATION It is the process involving change of one structure to another having same empirical formula but different properties in one or more respects. Its occurrence is rare . Examples :- Tetracycline & its derivatives can undergo reversible Isomerization at pH range 2-6. Trans- C is Isomerization of Amphotericin B. Isomerization of tetrahydrouridine .

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38 DECARBOXYLATION Evolution of CO 2 gas from –COOH group containing drugs. E.g.. Solid PAS undergoes decarboxylation to m- aminophenol & Carbon dioxide. ENZYME DECOMPOSITION Chemical degradation due to enzymes induced by drug results into decomposition . Remedy : Use of buccal tab. Use of pro-drug. ( Levodopa). Improvement in physicochemical properties has been achieved by structural optimization or pro-drug approach -Enhancement of ocular penetration when given orally.(ORAL DRUG DELIVERY SYSTEM ).

Physical & Pharmaceutical factors.: 

39 Physical & Pharmaceutical factors . 1)Organoleptic properties. A typical preformulation program should begin with the drug substance. IMPORTANCE: When the color attributes are undesirable or variable, incorporation of dye or coating of final product could be recommended. Color Odor Taste Off white Pungent Acidic Cream yellow Sulfurous Bland Tan Fruity Intense Shiny Aromatic Sweet Odorless Tasteless Bitter

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40 CRYSTALLINITY Crystals are characterized by repetition of atoms or molecules in a regular three dimensional structure. There are six crystal systems. Cubic Tetragonal Orthorhombic Monoclinic Triclinic Hexagonal

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41 POLYMORPHISM Many drug substances can exist in more than one crystalline form with different space lattice arrangements, this property is known as polymorphism, the different crystal forms are called polymorphism. Different polymorphic forms of given solid different from each other with respect to many physical properties such as solubility , dissolution, true density , crystal shape , compaction behavior, flow properties and solid state stability . To obtained a good stability . Bioavailability and for solving processing problem , appropriate polymorphic form is identified .

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42 PARTICLE SIZE AND PARTICLE SIZE DISTRIBUTION(PSD) It affects many of factors like flow property, density, mixing, packaging etc… There are mainly two types of powder according to particle size. (1) Monodisperse powder:- All particle are of same size. (2) Polydisperse powder:- particle of different types. Here generally average particle size is considered.

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43 METHODS FOR PARTICLE SIZE ANALYSIS METHOD SIZE RANGE(µm) Microscopy 0.2-100 Sieving >50 Sedimentation 2-200 Elutriation 2-100 Electronic scanning 1-300 Permeability 0.05-150 Centrifugal 5-0.05 Surface Fluid classification Anderson apparatus

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44 Flow property Importance : 1.Weight uniformity 2.Content uniformity 3.Hardness 4.Disintegration 5.Speed of production

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45 Method of determination By Angle of repose By hopper flow rate By bulk density By angle of spatula By vibrational capillary method REPOSOGRAPH : It is a stable instrument which at best can only indicate comparative flow properties. The formation of sharp cone would mean poor flow property while a good spread would indicate a superior flow property . FT (FREEMAN TECHNOLOGY) RHEOMETER: It can discriminate between the samples that differ by 1% Moisture. Important for optimizing granulation because moisture variation have significant impact on final product quality .

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46 VIBRATIONAL CAPILLARY METHOD : Evaluates flowability of micrometer sizes particles The amplitude and frequency of vibration is controlled by computer and mass of powder discharged from vibrating capillary tube is measured by digital balance . Angle of Repose It is a maximum angle between the surface of a pile of powder & horizontal plane . Angle of repose is measured by the equation: tan θ =h /r here , h=height of conical heap & r=radius of horizontal plane of powder

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47 DETERMINATION OF ANGLE OF REPOSE Static angle of repose Fixed height cone, Fixed base cone, Tilting table Dynamic angle of repose Rotating cylinder Rotating Drum Drained angle of repose Ledge type, Crater type

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48 RELATION BETWEEN ANGLE OF REPOSE & TYPE OF FLOW & TYPE OF POWDER Angle of repose Type of flow Type of powder <25 Excellent Non cohesive 25-30 Good Non cohesive 30-40 Passable Cohesive >40 Very poor Very Cohesive

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49 HAUSNER’S RATIO Hausner -ratio= Tapped density Bulk density Hausner ratio Type of Flow <1.25 1.25-1.5 >1.5 Good flow Moderate Poor flow

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50 FACTORS INFLUENCING THE FLOW PROPERTY OF POWDERS :- 1 .Particle size & Size distribution 2.Particle shape 3.Moisture 4.Electrostatic effects 5.Powder cohesion and storage compaction 6.Effect of temperature

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51 IMPROVEMENT OF FLOWABILITY By addition of glidant By addition of fine or by size reduction By wet granulation By removing static charge By densification with the help of slugging Using auger feed equipment By addition of flow activator . Eg . MgO By use silicon treated powder for Hygroscopic & moist powder. e.g. silicon coated talc or Na-bicarbonate By altering process condition like vibration assisted hopper or forced feeder By use of spray drying : Advantose 100 maltose powder has improved flow property than MCC by using this process.

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52 DENSITY The ratio of mass to volume is known as density. Density = Mass ( gms .)/ Volume (ml.) TYPES OF DENSITY : (a) Bulk density (b)Tapped density (c)True density (d)Granule density :- may affect compressibility, tablet porosity , disintegration, dissolution.

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53 Parameter Method 1. Bulk density Measuring cylinder 2. Tapped Density Mechanical Device Mercury Displacement 3. True Density Helium densitometer (Helium Pycnometer ) Mercury Instrution Porosimetry Method of Determination

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54 CORRELATION WITH FLOWABILITY Hausner ratio = Tapped density / Bulk density IMPORTANCE In case of combination therapy or physical mixture, if both drug or drug & excipients have different density then creates problem of segregation ( demixing ). Important in decide size & type of processing equipment. E.g. decide size of capsule formulation, Suppositories.

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55 COMPRESSIBILITY INTRODUCTION Compressibility is the ability of powder to decrease in volume under pressure. %compressibility = Tapped density – bulk density * 100 Tapped density COMPACTION :- Compaction of powder is term used to describe the situation in which material are subjected to some level of mechanical force . COMPRESSION :- Compression is reduction in the bulk volume of the material as a result of displacement of the gaseous phase .

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56 Relationship between powder flowability and % compressibility SR. NO % COMPRESSIBILTY RANGE FLOW DESCRIPTIONS 1 5-15 Excellent (free flowing granules) 2 12-16 Good ( free flowing powder granules) 3 18-21 Fair to passable ( powder granules 4 23-28 Poor ( very fluid powder) 5 28-35 Poor ( fluid cohesive powder) 6 35-38 Very poor ( fluid cohesive powder) 7 >40 Extremely poor ( cohesive powder)

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57 The characteristics Of material may be :- 1 . PLASTICITY Plastic material are capable of permanent deformation, also exhibit a degree of brittleness (fragment ability) But plastic material will get bonding after Viscoelastic deformation. 2. FRAGMENTABILITY If material is fragment able, neither lubricant mixing time nor dwell time affecting the tablet strength.

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58 3. ELASTICITY E.g. paracetamol , acetyl salicylic acid If material is elastic, it rebound when compression force is released. Elastic material may lead to capping & lamination They require wet massing to induce plasticity or plastic tableting material. 4. PUNCH FILMING [STICKING]: This may lead to chipping of tablet .

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59

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60 METHOD OF IMPROVEMENT If plastic material add fragment able excipient e.g.. Lactose . If Elastic material By plastic tableting material Wet granulation , Pre compression. If sticky material By change in salt form, By using high excipient ratio, By wet massing, By addition of Mg-stearate.

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61 HYGROSCOPICITY INTRODUCTION Hygroscopicity : - It is the tendency of material to absorb moisture from atmosphere & be dynamic equilibrium with water in the atmosphere . Deliquescent : - It is the hygroscopic substance which absorb moisture from air and they can be liquefied by partially or wholly forming solution . Efflorescent : - a substance which loses water to form a lower hydrate or become anhydrous i s term as efflorescent .

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62 METHOD OF DETERMINATION : To carry out study, sample of compound are accurately weighed into container and placed at various humid condition for period of up to 2 weeks. If Weight gain – Deliquescent or Hygroscopic If Weight loss – Efflorescent Also determined by TGA, GC, & KF titration Versaperm has deviced a WVTR meter that can measure the permeability of package to moisture.so that humidity can be accurately controlled .

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63 IMPORTANCE OF HYGROSCOPICITY: It affects the flow property. It affects compression characteristic , granulation & hardness of final tablet. It also affects compaction. Important in aerosol( particle agglomeration ). Affects chemical stability of hydrolysable drug .

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64 METHODS OF IMPROVEMENT For hygroscopic material use non-aqueous solvent . For efflorescent material use anhydrous salt . Add finely powdered adsorbents like MgO or Mg carbonate. Perform the operation under controlled humidity condition . Store hygroscopic compound with desiccants in well closed container. Starch is hygroscopic , but on pregelatinization it exhibits lower propensity for moisture, thus providing excellent stabilization for moisture sensitive materials .

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65 ELECTROSTATIC CHARGE INTRODUCTION : Electrostatic charges are the consequence of classic attraction & repulsion effect between the charges . Particles acquire static charge by : Grinding Attrition Collision Mixing Sieving Moisture

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66 Electro static charge may be positive or negative. + ve charge particles plastic surfaces - ve charge particles metal or glass surfaces IMPORTANCE In preformulation of suspension. Affects flow property of powder. Affects mixing process. For thermal stability of emulsions. It may damage tablet machine. It may affect compression coating

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67 METHOD OF DETERMINATION : INOSTAT , measures negative charge on the surface in volts/cm, when material is flowing from hopper . ELPI(13-stage Electrical Low Pressure Impactor ), gives detailed charge profile of MDI aerosol particles. This has practical application on lung deposition of MDI aerosol . Electrostatic testers which consists of electrostatic voltage sensing probes .

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68 Addition of diluents or lubricant. Surface coating of particle with amphiphilic substance of o/w type. E.g. Aerosol. Use crystallization method using more polar solvent. By granulation. Store under influence of air with sufficient humidity. Super critical fluid technology. METHOD OF REMOVAL OF STATIC CHARGE

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69 OSMOLARITY It is a colligative property and can be measured by following methods. Vapour pressure osmometer : Measures concentration of osmotically active particles that reduce V.P of solution . Membrane osmometer : This invention is directed to a membrane osmometer for direct measurement of osmotic pressures. ( United States Patent 4455864 ) White- vincet method Sprowls method Sodium chloride equivalent method Clifton nanolitre osmometer

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70 IMPORTANCE Normal serum osmolality to be 285 mosmol /kg. Maintain osmolarity by 1%variation. It should be proper maintained in Oral nutrition fluid Peripheral infusion Parenteral product Ophthalmic preparation Administration of Para tonic solution can lead to crenulation or lysis of RBC .

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71 RHEOLOGY It describes flow of liquid and/or deformation of solid under stress. TYPE OF FLOW: Newtonian flow Non Newtonian flow

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72 (1) PLASTIC FLOW It is the Newtonian system at shear stress above yield value. E.g . Flocculated suspension. (2) PSEUDOPLASTIC FLOW Here yield value not associated .As applies shear stress increasing, viscosity decreases and disarranged molecules begin to align their long axes inline of molecules. E.g . Aq. Dispersion of tragacanth , Na-CMC, PVP. (3) DILATANT FLOW Opposite to pseudo plastic flow Increase in the shear rate, increasing in resistance to flow as viscosity increases. E.g. deflocculated suspension of Mg magma

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73 DETERMINATION OF VISCOSITY Capillary viscometer Falling sphere viscometer Cup and bob viscometer Cone and plate viscometer Brook field viscometer Ultrasonic Shear Rheometer :- For analyzing protein solution rheology. Instron Capillary Rheometer :- Measures viscosity as a function of rate of shear & temp at a high rate of shear .

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74 IMPORTANCE OF VISCOSITY [1] FLUID For mixing For particle size reduction of disperse system Passing though orifice, pouring, packaging in bottle, passing though hypodermic needle. Flow though pipe Physical stability of disperse system [2] QUASISOLIDS Spreading and adherence to skin Removal from jar Capacity of solids to mix with liquid Release of drug from base

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75 [3 ] SOLID Flow of powder from hopper and into a die cavity in tableting or in encapsulation Packagability of powder or granules solids. [4] PROCESSING Production capacity of the equipment Processing efficiency THIXOTROPHY : In thixotropy apply shear stress convert gel – sol & remove shear stress convert sol – gel, means gel to sol to gel. Application :- for stability of suspension

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76 WETTABILITY I t is mainly important for solid or suspension type of dosage form. METHOD OF DETERMINATION : By contact angle: The contact angle is the angle between a liquid droplet and the surface over which it spreads. Contact angle – 0 0 – complete wetting. Contact angle – 180 0 – No wetting . By Draves test: IMPORTANCE : Crystal structure can influence the contact angle. Problems associated with Wettability of powder are poor dissolution rate & low adhesion of film coating .

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77 IMPROVEMENT By use of wetting agent (HLB value 6-9 ) Mixing with hydrophilic excipient like Na CMC (water soluble) and bentonite , Al Mg silicate & colloidal silica (water insoluble). Wetting of powder by non aqueous solvent can be enhanced by certain lanolin derivative .

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78 REFERENCES: Pharmaceutics- The science of Dosage Form Design by M. E. Aulton .(2nd edition ) The Science & Practice of Pharmacy by Remington. (19th edition ) The Theory & Practice of Industrial Pharmacy by Leon Lachman , Herbet A. Lieberman, Joseph L. Kaing . (3rd edition ) Pharmaceutical Dosage Forms by Leon Lachman , Herbet A. Lieberman; (Volume 1 ) Indian Journal Of Pharmaceutical Sciences Chemical Absracts www.quantachrome.com

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79 Questions asked 1)Define preformulation . What is the significance of particle size & size distribution in formulation? 2)What is preformulation ? How can it be characterized? Comment: “ preformulation studies are limited to a new drug molecules only”. Suggest different means to arrest hydrolysis of APIs.

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80 THANK YOU Success is a journey not a destination.