PRE-FORMULATION studies

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all formulation aspects in m.pharm 1st sem

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Pre formulation aspects of pharmaproducts Ch.mallikarjunayadav M.pharm 2 nd year Vagdevi college of pharmacy nellore 1

Preformulation:

Preformulation Preformulation is branch of Pharmaceutical science that utilizes biopharmaceutical principles in the determination of physicochemical properties of the drug substance. Prior to the development of any dosage form new drug , it is essential that certain fundamental physical & chemical properties of drug powder are determined . This information may dictate many of subsequent event & approaches in formulation development. This first learning phase is called as preformulation. 04/05/2012 2

INTRODUCTION :

INTRODUCTION DEFINITION :- Investigation of physico-chemical properties of the new drug compound that could affect drug performance and development of an efficacious dosage form”. Preformulation commences when a newly synthesized drug shows a sufficient pharmacologic promise in animal model to warrant evaluation in man.

Introduction:

Introduction The preformulation is the first step in the rational development of a dosage form of a drug substance alone and when combined with excipients. Objective : To generate useful information to the formulator to design an optimum drug delivery system.

Introduction:

Introduction Before embarking on a formal programme of preformulation, scientist must consider the following : 1. Available physicochemical data (including chemical structure, different salt available). 2. Anticipated dose. 3. Supply situation and development schedule. 4. Availability of stability – indicating assay.

GOALS OF PREFORMULATION:

GOALS OF PREFORMULATION To establish the necessary physicochemical parameters of new drug substances. To determine kinetic rate profile. To establish physical characteristics. To establish compatibility with common excipients .

Preliminary Evaluation:

Preliminary Evaluation Compound identity. Formula and molecular weight. Structure. Therapeutic indications: - Probable human dose. - Desired dosage form(s) - Bioavailability model - Competitive products 04/05/2012 7 Contd…

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Color is generally a function of a drug’s inherent chemical structure relating to a certain level of unsaturation. Color intensity relates to the extent of conjugated unsaturation as well as the presence of chromophores. Some compound may appear to have color although structurally saturated. 04/05/2012 8

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The substance may exhibit an inherent odor characteristic of major functional groups present. Odor greatly affects the flavor of a preparation or food stuff. Taste:- If taste is considered as unpalatable, consideration is to be given to the use of a less soluble chemical form of the drug. The odour and taste may be suppressed by using appropriate flavors and excipients or by coating the final product. 04/05/2012 9

PURITY:

PURITY Designed to estimate the levels of all known & significant impurities & contaminates in the drug substance under evaluation. Study performed in an analytical research & development group. It is another parameter which allows for comparison with subsequent batches. Occasionally, an impurity can affect stability. e.g. - Metal contamination - Appearance 04/05/2012 10

PURITY:

PURITY The techniques used for characterizing the purity of a drug are the same as those used for other purpose in a preformulation study. Thin layer chromatography is a wide ranging applicability & is an excellent tool for characterizing the purity. HPLC, paper chromatography & gas chromatography are also useful. More quantitative information can be obtained by using quantitative differential scanning colorimetry. 04/05/2012 11

PARTICLE SIZE:

PARTICLE SIZE Particle size is characterized using these terms : Very coarse (#8) Coarse (#20) Moderately coarse (#40) Fine (#60) Very fine (#80) 04/05/2012 12

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Particle size can influence variety of important factors : - Dissolution rate - Suspendability - Uniform distribution - Penetrability - Lack of grittiness 04/05/2012 13

Methods to Determine Particle Size:

Methods to Determine Particle Size Sieving Microscopy Sedimentation rate method Light energy diffraction Laser holography Cascade impaction 04/05/2012 14

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Sieving method : Range : 50 – 150 µm Simple, inexpensive If powder is not dry, the apertures get clogged. Microscopy : Range : 0.2 – 100 µm Particle size can be determined by the use of calibrated grid background. Most direct method. Slow & tedious method. 04/05/2012 15

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Sedimentation method : Range : 1 - 200 µm Andreasen pipette is used. Particle size is calculated by stoke’s law : d st = Where, h = distance of fall in time, t n o = viscosity of the medium ρ s = density of the particles ρ 0 = density of the dispersion medium g = acceleration due to gravity 04/05/2012 16 18 η 0 h ( ρ s - ρ 0 ) gt

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Light energy diffraction : Range : 0.5 – 500 µm Particle size is determined by the reduction in light reaching the sensor as the particle, dispersed in a liquid or gas, passes through the sensing zone. Quick & fast. Laser holography : Range : 1.4 – 100 µm A pulsed laser is fired through an aerosolized particle spray & photographed in three dimensional with holographic camera, allowing the particles to be individually imaged & sized. 04/05/2012 17

POWDER FLOW PROPERTIES:

POWDER FLOW PROPERTIES Powder flow properties can be affected by change in particle size, shape & density. The flow properties depends upon following- Force of friction. Cohesion between one particle to another. Fine particle posses poor flow by filling void spaces between larger particles causing packing & densification of particles.. By using glident we can alter the flow properties. e.g. Starch, Talc. 04/05/2012 18

Determination Of Powder Flow Properties:

Determination Of Powder Flow Properties By determining Angle Of Repose. A greater angle of repose indicate poor flow. It should be less than 30°. & can be determined by following equation. tan θ = h/r. where, θ = angle of repose. h=height of pile. r= radius. Angle Of Repose ( In degree) Type Of Flow <25 Excellent 25-30 Good 30-40 Passable >40 Very poor 04/05/2012 19

Determination Of Powder Flow Properties:

Determination Of Powder Flow Properties Measurement of free flowing powder by compressibility. Also known as Carr's index. CARR’S INDEX(%) =( TAPPED DENSITY – POURED DENSITY) X 100 TAPPED DENSITY It is simple, fast & popular method of predicting powder flow characteristics. 04/05/2012 20

Determination Of Powder Flow Properties:

Determination Of Powder Flow Properties Carr’s Index Type of flow 5-15 Excellent 12-16 Good 18-21 Fair To Passable 23-35 Poor 33-38 Very Poor >40 Extremely Poor 04/05/2012 21

SURFACE AREA:

SURFACE AREA Particle size & surface area are inversely related to each other. Smaller the drug particle, greater the surface area. Specific surface is defined as the surface area per unit weight (Sw) or unit volume (Sv) of the material. 04/05/2012 22

Methods for determining surface area:

Methods for determining surface area Where, V = Volume of gas in cm 3 adsorbed per gram of powder at pressure P. P = Pressure of the adsorbate, in mmHg. P o = Saturation vapor pressure (monolayer) V m = Amount of vapor adsorbed per unit mass adsorbent, when the surface is covered with monomolecular layer b = Constant that express the difference between the heat of adsorption & heat of liquefaction of the adsorbate (nitrogen). 04/05/2012 23 Cont….

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SOLUBILIZATION “ Solubilization is defined as the spontaneous passage of poorly water soluble solute molecules into an aqueous solution of a soap or detergent in which a thermodynamically stable solution is formed ”. 04/05/2012 24

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It is the process by which apparent solubility of an otherwise sparingly soluble substance is increased by the presence of surfactant micelles . MICELLES: - The mechanism involves the property of surface active agents to form colloidal aggregates known as micelles . 04/05/2012 25 SOLUBILIZATION

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When surfactants are added to the liquid at low concentration they tend to orient at the air-liquid interface . On further addition of surfactant the interface becomes completely occupied and excess molecules are forced into the bulk of liquid. At very high concentration surfactant molecules in the bulk of liquid begin to form micelles and this concentration is know as CRITICAL MICELLE CONCENTRATION {CMC} 04/05/2012 26 SOLUBILIZATION

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Solubilization is thought to occur by virtue of the solute dissolving in or being adsorbed onto the micelle. Thus the ability of surfactant solution to dissolved or solubilize water insoluble materials starts at the CMC and increase with increase in the concentration of micelles. Solubilization of any material in any solvent depends on proper selection of solubilising agents. 04/05/2012 27 SOLUBILIZATION

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Process Of Solubilization The process of solubilization involves the breaking of inter-ionic or intermolecular bonds in the solute, the separation of the molecules of the solvent to provide space in the solvent for the solute, interaction between the solvent and the solute molecule or ion. Step 1: Holes opens in the solvent 04/05/2012 28

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Step2: Molecules of the solid breaks away from the bulk Step 3: The free solid molecule is intergraded into the hole in the solvent 04/05/2012 29 Process Of Solubilization

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SOLUBILITY The amount of substance that passes into solution in order to establish equilibrium at constant temperature and pressure to produce a saturated solution. 04/05/2012 30

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If solubility is <1mg/ml indicates need for salt formation to improve solubility. If solubility is <1mg/ml in pH= 1 to 7, preformulation study should be initiated. Solubility should ideally be measured at two temperatures: 4°C and 37°C. 4°C to ensure Physical stability. 37°C to support Biopharmaceutical evaluation. 04/05/2012 31 SOLUBILITY

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DESCRIPTIVE SOLUBILITIES (I.P.) Description Parts of solvent required for one part of solute Very soluble < 1 Freely soluble 1 - 10 Soluble 10 - 30 Sparingly soluble 30 - 100 Slightly soluble 100 - 1000 Very slightly soluble 1000 - 10,000 Insoluble > 10,000 04/05/2012 32

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SOLUBILITY ANALYSIS Preformulation solubility studies focus on drug solvent system that could occur during the delivery of drug candidate. For e.g. A drug for oral administration should be examined for solubility in media having isotonic chloride ion concentration and acidic pH. 04/05/2012 33

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Analytic method that are particularly useful for solubility measurement include HPLC, UV spectroscopy, Fluorescence spectroscopy and Gas chromatography. Reverse phase HPLC offer accurate and efficient mean of collecting solubility data of drug. 04/05/2012 34 SOLUBILITY ANALYSIS

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Ionization constant (pKa) Can be calculated by Henderson Hasselbach equation- For acidic drugs….pH= pKa+ log [ionized drug] [unionized drug] For basic drugs….pH= pKa+ log[unionized drug] [ionized drug] 04/05/2012 35

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pH Solubility Profile The solubility of acidic or basic drug will show difference in solubility with changes in pH. pH solubility profile of a drug can be established by running the equilibrium solubility experiment within pH range of 3-4. 04/05/2012 36

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Partition Coefficient It is the ratio of unionized drug distributed between organic and aqueous phase at equilibrium. P o/w = ( C oil / C water )equilibrium 04/05/2012 37

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Effect Of Temperature The heat of solution Hs, represents the heat released or absorbed when a mole of solute is dissolved in large quantity of solvent. Endothermic reaction Exothermic reaction 04/05/2012 38

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Determination of solubility The following points should be considered The solvent & solute must be pure. A saturated solution must be obtained before any solution is removed for analysis. The method of separating a sample of saturated solution from undissolved solute must be satisfactory. The method of analyzing solution must be reliable Temperature must be adequately controlled . 04/05/2012 39

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Solubility Determination Method Solubility is normally depends on temperature, so temperature is recorded in each solubility measurement. Plot of solubility against temperature is commonly used for solubility determination. Two methods are available for determination are as follow. Analytical method Synthetic method 04/05/2012 40

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Analytical method Temperature of equilibrium is fixed and concentration of the solute in the saturated solution is determined at equilibrium by a suitable analytical procedure. In other words a saturated solution in the presence of an excess of the undissolved solute is prepared at an accurately known temperature. This situation can be achieved by suitable contact b/w solute and solvent. 04/05/2012 41

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In this method a weighed amount of solute is placed in the vessel. While agitating the system at constant temperature known amount of solvent is added gradually until the solubility limit is reached. At equilibrium, temperature and content of the system is recorded. This method is carried out at micro scale level by examining the small amount of the system under hot stage microscope. 04/05/2012 42 Synthetic method

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Addition of co-solvent pH change method Reduction of particle size Temperature change method Hydotrophy Addition of Surfactant Dielectrical Constant Complexation 04/05/2012 43 General Method of Increasing the Solubility

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Weak Electrolyte :- Phenobarbitone Non polar :- Nitro Cellulose These are poorly soluble in given solvent. For such poorly soluble materials, to enhance their solubility, the water miscible solvents are used in which the drug has good solubility. This process of improving solubility is known as co-solvency and the solvent used is known as co-solvents . 04/05/2012 44 Addition Of Co-Solvent

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e.g. Phenobarbitone is insoluble in water. A clear solution is obtained by dissolving in mixture of Alcohol, Glycerin, Propylene glycol. e.g. Of Cosolvents:- PG, glycerin, sorbitol, PEG, Glyceryl formal, glycofurol, ethyl carbamate, ethyl lactate and dimethyl acetamide. 04/05/2012 45 Addition Of Co-Solvent

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pH change Method Weak base:- Alkaloids, Local Anaesthesia Weak acid:- Sulphonamides, Barbiturates In aqueous medium they dissociate poorly and undissociated portion is insoluble. e.g. Benzoic acid, Phenobarbitone So, solubility of the undissociated portion is improved by pH control. For weak acidic drug:- increase pH, solubility is increase. For weak base drug:- decrease pH, increase solubility. 04/05/2012 46

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Reduction in Particle size improve solubility of drug. Basically reduction in particle size increase contact surface area of the particle, there by ultimately it increase rate of solubility of drug. Reduction Of Particle size 04/05/2012 47

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In endothermic reaction by increasing temperature solubility is increase. In exothermic reaction by increasing temperature solubility is decrease. e.g. Methyl Cellulose when mixed with water and temperature is raised, it becomes insoluble. To dissolve it cold water is added. 04/05/2012 48 Temperature Change Method

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The term Hydotrophy has been used to designate the increase in solubility in water of various substances due to the presences of large amount of additives. e.g. Solubilization of Benzoic acid with Sodium benzoate. 04/05/2012 49 Hydotrophy

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Surfactants are molecules with well defined polar and non-polar region that allow them to aggregate in solution to form micelles. Non polar drugs can partition into micelles and be solubilized. e.g. Surfactant based solution of Taxol, that is solubilized in 50% solution of Cremophor. 04/05/2012 50 Addition of Surfactant

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Dielectrical Constant is the effect that substances has, when it acts as a solvent on the case with which it separates oppositely charged atoms. e.g. DEC of Water- 80 Kerosene- 2 Glycerine- 48 Benzene- 2.2 04/05/2012 51 Dielectrical Constant

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Complexation For the Complexation occur both drug and ligand molecule should be able to donate or accept electrons. The solubility of compound is the sum of solubility of the compound and its complex. e.g. HgI 2 (Mercuric Iodide) is sparingly soluble in water. Its solubility in water is increased by forming complex with KI. HgI 2 +2KI K 2 HgI 4 (water soluble) 04/05/2012 52

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Applications of solubilization Drugs with limited aqueous solubility can be solubilized. These include oil-soluble vitamins, steroid hormones and antimicrobial agents etc. Solubilization of orally administered drugs results in an improved appearance and improves unpleasant taste. Both oil-soluble and water-soluble compounds can be combined in a single phase system as in case of multivitamin preparations. 04/05/2012 53

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Solubilization may lead to enhanced absorption and increased biological activity. Improves the intestinal absorption of vitamin A. Drug absorption from ointment bases and suppositories also increased. Liquid preparations with small quantity of preservative can be prepared by solubilization. 04/05/2012 54 Applications of solubilization

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Aqueous concentrates of volatile oils can be prepared by solubilization. Example: soaps used for solubilising phenolic compounds for use as disinfectants- Lysol, Roxenol etc . Barbiturates, anticoagulant, alkloidal drugs are dissolved with polysorbate by solubilization. 04/05/2012 55 Applications of solubilization

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SURFACTANT Surfactants:- are wetting agents that lower the surface tension of a liquid, allowing easier spreading, and lower the interfacial tension between two liquids. Classification Some commonly encountered surfactants of each type include: 1. Ionic 2. Non ionic Cationic Anionic Zwitterionic 04/05/2012 56

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IONIC Cationic Surfactants:- Quaternary ammonium salts are more preferred because they are less affected by pH. e.g. Cetyl Trimethyl Ammonium Bromide (CTAB) Hexadecyl Trimethyl Ammonium Bromide, and other Alkyltrimethyl Ammonium Salts, Cetylpyridinium Chloride (cpc) 04/05/2012 57

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Anionic Surfactants:- They are the most commonly used surfactants, containing Carboxylate, Sulfonate, Sulfate ions. e.g. Sodium Dodecyl Sulphate (SDS), Ammonium Lauryl Sulphate and other alkyl sulfate salts, Sodium Laureth Sulphate, also known as Sodium Lauryl Ether Sulphate (SLES). 04/05/2012 58 IONIC

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Zwitterionic:- When a single surfactant molecule exhibit both anionic and cationic dissociations it is called amphoteric or Zwitterionic. The anion include carboxylates and phosphate group and the cation include quaternary ammonium group. e.g. Dodecly Betamine Dodecly Dimethylamine Oxide 04/05/2012 59 IONIC

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NONIONIC These are most widely used because they are free from non compatability, stability and potential toxicity and classified as water soluble and water insoluble non ionic surfactants. e.g. Long chain fatty acids, fatty alcohols Water solubility of these agents is further increased by addition of polyoxyethylene groups through ether linkage with one of the alcohol group. e.g . spans 04/05/2012 60

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HLB SCALE Griffin in 1947 developed the system of the hydrophilic-lipophilic balance [ HLB ] of surfactant. The higher the HLB of the an agent, the more hydrophilic it is. Tween, polyoxyethylene derivative of the spans are hydrophilic and have high HLB value (9.6-16.7) The lower the HLB of the agent, the more lipophilic it is. The sorbitan ester are lipophilic and have low HLB value (1.8-8.6) 04/05/2012 61

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The HLB of non ionic surfactant whose only hydrophilic portion is polyoxyethylene is calculated using the formula HLB = E/5 Where, E = Percentage weight of ethylene oxide 04/05/2012 62 HLB SCALE

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Importance Of Surfactant Surfactants play an important role in many practical applications and products, including: Detergents Fabric Softener Emulsifier Paints Adhesive Inks Soil remediation Wetting 04/05/2012 63

Temperature, pH, Cosolvancy, Solid dispersion:

Temperature, pH, Cosolvancy, Solid dispersion 04/05/2012 64

Effect of Temperature:

Effect of Temperature The solubility of a solute in a solvent is dependent on temperature, nature of solute and nature of solvent. Heat of solution represents the heat released or absorbed when a mole of solute is dissolved in a large quantity of solvent. Most of the substances are endothermic, absorbing heat in the process of dissolution. 04/05/2012 65

Effect of Temperature:

Effect of Temperature For this substances, an increase in temperature results in an increase in solubility. Exothermic substances give off heat in the process of dissolution. The solubility of such substances would decrease with increase in temperature. Care should be taken as heat may destroy a drug or cause other changes in the solution. e.g. On excess heating the sucrose solution it can get converted in to the invert sugar. 04/05/2012 66

Effect of Temperature:

Effect of Temperature Depending on the type of reactions weather it is exothermic or endothermic heat is either released or absorbed. e.g. Mixture of chloroform and acetone. The heat produced by the solute-solvent interaction is so much greater than the heat necessary to separate the molecules of acetone and chloroform, which can be detected as a rise in temperature of the liquid. 04/05/2012 i . 67

Effect of Temperature:

Effect of Temperature Applications: Pharmaceutical solutions must be administered at or near room temperature. So, it is more important factor for product storage than the formulation. To increase the solubility of sparingly soluble solute. To increase the stability by reducing the moisture content. 04/05/2012 68

Effect of pH:

Effect of pH Weak electrolytes undergo ionization and are more soluble when in ionized form. The degree of ionization depends on dissociation constant (pKa) and the pH of the medium. Solubility is a function of pH, that is related to its pKa which gives ratio of ionized and unionized forms of the substance. This can be shown as: pH = pKa + log [ A - ] [ HA ] 04/05/2012 69

Effect of pH:

Effect of pH If the substance is brought outside its pKa, i.e. the pH value where half the substance is ionized and half is not, than solubility will be changed because we are introducing new intermolecular forces, mainly ionic attraction. e.g. –COOH has pKa value at pH around 4. If pH is increased then –COOH is converted into –COO - . This may interact with the H + of water. 04/05/2012 70

Effect of pH:

Effect of pH It is to be ensured that pH change for one single compound should not affect the other requirements of product. e.g. the chemical stability of drug may depend on pH, and this pH of optimum stability should not coincide with the pH of other ingredients specially colors, preservatives and flavors. 04/05/2012 KLE College of Pharmacy, Nipani. 71

Cosolvancy:

Cosolvancy To enhance the solubility of poorly soluble materials, the water miscible solvents are used in which the drug has good solubility. This process of improving solubility is known as co-solvency. Solvents used to increase the solubility are known as co-solvents. 04/05/2012 72

Cosolvancy:

Cosolvancy The mechanism for solubility enhancement by co-solvency is not clearly understood. But it is proposed that, solubility is increased may be by reducing the interfacial tension between the solvent and hydrophobic solutes and decreasing dielectric constant of solvent. 73

Solid – Dispersion System:

Solid – Dispersion System Definition : Solid dispersion is defined as dispersion of one or more active ingredients in an inert carrier or matrix at solid state prepared by the melting, solvent or melting solvent method. 04/05/2012 74

Classification (Based on Fast Release Mechanism) :

Classification (Based on Fast Release Mechanism) Simple Eutectic Mixtures Solid Solutions Glass Solutions and Glass Suspensions Amorphous precipitation of drug in crystalline carrier Compounds or Complex formation between drug and carrier Any combination among the above 04/05/2012 75

A. Eutectic Mixtures:

A. Eutectic Mixtures The following factors may contribute to faster dissolution rate of drug dispersed in the eutectic mixtures:- 1. Increase in drug solubility. 2. Solubilization effect by the carrier which completely dissolves in a short time in diffusion layer surrounding drug particles. 3. Absence of aggregation and agglomeration between fine crystallites of pure hydrophobic drug. 04/05/2012 76

A. Eutectic Mixtures:

A. Eutectic Mixtures 4. Excellent wettability and dispersibility of a drug as the encircling soluble carrier readily dissolves and causes water to contact as wet drug particles. 5. Crystallization of drug in a metastable form after solidification from fused solution, which has high solubility. 77

A. Eutectic Mixtures:

A. Eutectic Mixtures Eutectics are easy to prepare and economical with no solvents involved. The method however cannot be applied to: - Drugs which fail to crystallize from mixed melt. - Thermolabile drugs. - Carriers such as succinic acid that decompose at melting point. 04/05/2012 78

B. Solid Solutions:

B. Solid Solutions It is made up of a solid solute dissolved in a solid solvent. It is often called a “mixed crystal” because the two components crystallize together in a homogenous phase system. It is prepared by fusion method. A solid solution of poorly soluble drug in a rapidly soluble carrier achieves a faster dissolution because particle size of drug is reduced to molecular size. 04/05/2012 79

Classification:

Classification According to extent of miscibility : Continuous (iso-morphous, unlimited, complete) solid solution. Discontinuous (limited, restricted, incomplete) solid solution. According to crystalline structure of solid solutions : Substitutional solid solutions. Interstitial solid solutions. 04/05/2012 80

D. Amorphous Precipitation of Drug in Crystalline Carrier:

D. Amorphous Precipitation of Drug in Crystalline Carrier Instead of forming a simple eutectic mixture in which both drug and the carrier crystallize simultaneously from a solvent method of preparation, the drug may also precipitate out in an amorphous form in crystalline carrier. It has faster dissolution and absorption rates than crystalline form. e.g. Amorphous novobicin has 10 fold higher solubility than its crystalline form. 81

E. Compound or Complex Formations :

E. Compound or Complex Formations Dissolution and absorption of a drug can occur from a complex or a compound formed between the drug and an inert soluble carrier. Complexation also implies that dissolution could be retarded as observed with PEG 4000 - phenobarbital. However, the formation of a soluble complex with a low association constant results in increased rates of dissolution and absorption. 04/05/2012 82

F. Combinations and Miscellaneous Mechanisms :

F. Combinations and Miscellaneous Mechanisms A solid dispersion entirely belongs to any five groups discussed so far, but it can also be made up of combinations of different groups. These combinations increase the dissolution and absorption rate. The griseofulvin dispersed at high concentrations in PEG may exist as individual molecules and as micro-crystalline particles. 04/05/2012 83

1. Melting Method or Fusion Method :

1. Melting Method or Fusion Method The physical mixture of a drug and water soluble carrier is heated until it melts. The melt is then cooled and solidified rapidly in an ice bath with vigorous stirring . The final solid mass is crushed, pulverized and sieved. To facilitate faster solidification, the homogenous melt is poured in the form of a thin layer onto stainless steel plate and cooled by flowing air or water on the opposite side of the plate. 84

1. Melting Method or Fusion Method :

1. Melting Method or Fusion Method Advantages : Simplicity of method. Supersaturation of a solute or a drug in a system can often be obtained by quenching the melt rapidly from high temperature. Disadvantage : Some drugs or carriers may decompose or evaporate during fusion process at high temperatures . e.g. succinic acid used as a carrier for griseofulvin is quite volatile and may also partially decompose by dehydration near its melting point. 85

2. Solvent Method :

2. Solvent Method They are prepared by dissolving a physical mixture of two solid components in a common solvent, followed by evaporation of the solvent. The method is used to prepare solid dispersions of griseofulvin-polyvinylpyrrolidone, sulphathiazole - pvp. 04/05/2012 86

3. Melting Solvent Method :

3. Melting Solvent Method It is prepared by first dissolving the drug in a suitable solvent and then incorporating this solution in a melt of PEG without removing the solvent. Advantages : Same as above two methods Disadvantage : From practical stand point, it is only limited to drugs with a low therapeutic dose, e.g. below 50mg. 04/05/2012 87

Methods of Determination of Solid Dispersion Systems:

Methods of Determination of Solid Dispersion Systems Thermal analysis a) Cooling curve method b) Thaw-melt method c) Thermoscopic method d) Differential thermal analysis (DTA) e) Zone Melting Method 04/05/2012 88

Methods of Determination of Solid Dispersion Systems:

Methods of Determination of Solid Dispersion Systems X-Ray diffraction Method Microscopic method Spectroscopic method Thin layer chromatography Solubility determinations 89

A. Thermal Analysis:

A. Thermal Analysis It is used to study the physico-chemical interactions of two or more components. Principle : Change in thermal energy as a function of temperature. a) Cooling curve method : - The physical mixtures of various compositions are heated until a homogenous melt is obtained. - The temperature of the mixture is then recorded as function of time. 90

B. X-Ray Diffraction Method :

B. X-Ray Diffraction Method In this method the intensity of x-ray diffraction or reflection from a sample is measured as a function of diffraction angles. Counter and film methods detect diffraction intensity. Counter method provides better resolution of diffraction and relative intensity which can be easily compared. This method is used to characterize physico-chemical properties of Griseofulvin dispersed in PEG 4000 and 6000. 91

C. Microscopic Method :

C. Microscopic Method It has been used to study polymorphism and morphology of solid dispersion. The fine particles of crystallization in glass PVP can be easily detected by polarizing microscope. The resolution of electron microscope was used to study dispersed particle size of iopanic acid in PVP. 92

Pharmaceutical Applications:

Pharmaceutical Applications To obtain a homogenous distribution of small amount of drugs at solid state. To stabilize unstable drugs. To dispense liquid or gaseous compounds. To formulate a faster release priming dose in a sustained release dosage form. To formulate sustained release dosage or prolonged release regimens of soluble drugs by using poorly soluble or insoluble carriers. 93

β-cyclodextrin drug dispersion system, techniques for studies of crystals, polymorphism :

β-cyclodextrin drug dispersion system, techniques for studies of crystals, polymorphism 94

β-cyclodextrin drug dispersion system :

β-cyclodextrin drug dispersion system The poorly dissolution of relatively insoluble drug has for long been a problem in the formulation of oral dosage form. This limits the aspect such as Absorption & Bioavailability 95

β-cyclodextrin drug dispersion system :

β -cyclodextrin drug dispersion system Several approach have been followed in improving the solubility of drug, one of them being complexation using cyclodextrin. Cyclodextrin is cyclic structure oligomers of glucose which are obtained from the starch digests of the bacteria Bacillus macerans. 96

Chemistry of b-cyclodextrin :

Chemistry of b-cyclodextrin Cyclodextrine molecule have cylindrical shape with central axial cavity and resembles with shape of truncated cone. The interior cavity is hydrophobic and the outside of the molecule is hydrophilic. 12 97

Applications :

Applications To increase aq. solubility To increase dissolution rate of drug To improve bioavailability of drug To increase chemical/physical stability To decrease drug irritation 98

Crystallinity:

Crystallinity Crystal habit & internal structure of drug can affect bulk & physicochemical property of molecule. Crystal habit is description of outer appearance of crystal. Internal structure is molecular arrangement within the solid. 99

Crystallinity:

Crystallinity Change with internal structure usually alters crystal habit. Eg. Conversion of sodium salt to its free acid form produce both change in internal structure & crystal habit. 100

Different shapes of crystals:

Different shapes of crystals Solubility & dissolution rate are greater for amorphous form then crystalline, as amorphous form has higher thermodynamic energy. Eg. Amorphous form of Novobiocin is well absorbed whereas crystalline form results in poor absorption.

Polymorphism:

Polymorphism It is the ability of the compound to crystallize as more than one distinct crystalline species with different internal lattice. Different crystalline forms are called polymorphs. Polymorphs are of 2 types 1. Enatiotropic 2. Monotropic

Polymorphism:

Polymorphism The polymorph which can be changed from one form into another by varying temp. or pressure is called as Enantiotropic polymorph . Eg. Sulfur. One polymorph which is unstable at all temp. & pressure is called as Monotropic polymorph . Eg. Glyceryl stearate. 103

Polymorphism:

Polymorphism Polymorph differ from each other with respect to their physical property such as Solubility Melting point Density Hardness Compression characteristic 104

Polymorphism:

Polymorphism During preformulation it is important to identify the polymorph that is stable at room temp. Eg. 1)Chloromphenicol exist in A,B & C forms, of these B form is more stable & most preferable. 2)Riboflavin has I,II & III forms, the III form shows 20 times more water solubility than form I. 105

Techniques for studies of crystals:

Techniques for studies of crystals Microscopy Hot stage microscopy Thermal analysis X-ray diffraction 106

Microscopy :

Microscopy Material with more than one refractive index are anisotropic & appear bright with brilliant colors against black polarized background. The color intensity depends upon crystal thickness. Isotropic material have single refractive index and this substance do not transmit light with crossed polarizing filter and appears black. 107

Microscopy :

Microscopy Advantage : By this method, we can study crystal morphology & difference between polymorphic form. Disadvantage : This require a well trained optical crystallographer, as there are many possible crystal habit & their appearance at different orientation. 108

Hot stage microscopy:

Hot stage microscopy The polarizing microscope fitted with hot stage is useful for investigating polymorphism, melting point & transition temp. Disadvantage : In this technique, the molecules can degrade during the melting process. 109

Stability testing….:

Stability testing…. 110

Why Stability?:

Why Stability? Provide a evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as….. temperature, Humidity and light. Establish a re-test period for the drug substance or a shelf life for the drug product and recommended storage conditions. Because physical, chemical or microbiological changes might impact the efficiency and security of the final product 111

Where and Why?:

Where and Why? Stability Studies are preformed on ... Drug Substances (DS)  The unformulated drug substance that may subsequently be formulated with excipients to produce the dosage form. Drug Products (DP)  The dosage form in the final immediate packaging intended for marketing……. controlled and documented determination of acceptable changes of the drug substance or drug product 112

What are changes? :

What are changes? Physical changes • Appearance • Melting point • Clarity and color of solution • moisture • Crystal modification (Polymorphism) • Particle size Chemical changes • Increase in Degradation • Decrease of Assay Microbial changes 113

Forced degradation studies:

Forced degradation studies Acidic & Basic conditions. Dry heat exposure UV radiation exposure Influence of pH Influence of temperature Influence of ionic strength 114

Arrhenius Equation:

Arrhenius Equation Plot of log K v/s 1/T….yields a slope equal to - Δ Ha/2.303 R ….. From which heat of activation ( Δ Ha) can be calculated. Log k2/k1 = Δ Ha/2.303 R . ( T2 – T1 )/ T2.T1 115 Mean Kinetic Temperature

Chemical degradation studies:

Chemical degradation studies Hydrolysis Oxidation Reduction Decarboxylation Photolysis 116

Stability studies at different stages:

Stability studies at different stages Stress- and accelerated Testing with drug substances Stability on pre-formulation batches Stress testing on scale-up Batches Accelerated and long term testing for registration On-going Stability testing Follow-up Stabilities 117

Stability studies at different stages :

Scope • Solubility Profile • Hygroscopicity • Thermal stability (Melting point, Polymorphism) • Chemical stability 􀂄 1 Batch 􀂄 Up to 3 month Stability studies at different stages 118

Testing scope for Solid dosage:

Testing scope for Solid dosage Physical-chemical properties – Appearance – Elasticity – Mean mass – Moisture – Hardness – Disintegration – Dissolution Chemical properties – Assay – Degradation Microbial properties Container closure system properties – Functionality tests (e.g. extraction from blister) 119 Tablet & Capsule

Testing scope for Oral liquid form :

Testing scope for Oral liquid form Physical-chemical properties – pH – Color & clarity of solution – Viscosity – Particle size distribution (for oral suspensions only) Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants Microbial properties Container closure system properties – Functionality tests 120

Testing scope for LIQUID FORMS for inj. and PARENTRAL:

Testing scope for LIQUID FORMS for inj. and PARENTRAL Physical-chemical properties – pH – Loss on weight – Color & clarity of solution Chemical properties – Assay – Degradation products – Degradation preservatives – Content antioxidants Microbial properties Container closure system properties – Functionality tests 121

Testing scope for SEMI LIQUID FORMS:

Testing scope for SEMI LIQUID FORMS Physical-chemical properties – Appearance, odor, homogenesity, consistency – Loss on weight, Viscosity – Content uniformity (within the container) Chemical properties – Assay – Degradation products & preservatives – Content preservatives – Degradation– Content antioxidants Microbial properties Container closure system properties – Functionality tests 122

REFERENCES:

REFERENCES Ansel’s pharmaceutical Dosage forms & Drug delivery systems, 8 th edition by Loyd V. Allen, Nicholas G.popovich, Howard C. Ansel, publised by B.I.Publication pvt. Ltd., page no:- 187-193,42 & 43,126-133. Pharmaceutical preformulation by J.T.Cartensen published by technomic publishing Co., page no:- 1-6, 211-212. Textbook of physical pharmaceutics by C.V.S. Subrahmanyam, published by Vallabh prakashan, page no:- 182-208, 222-226. 123

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