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The Concept of Preformulation:Almost all drugs are marketed as tablets, capsules or both. Prior to the development of these major dosage forms, it is essential that pertain fundamental physical and chemical properties of the drug molecule and other divided properties of the drug powder are determined. This information decides many of the subsequent events and approaches in formation development. This first learning phase is known as preformulation.
Definition:Preformulation investigations are designed to deliver all necessary data (especially physicochemical, physicomechanical and biopharmaceutical properties of drug substances, excipients and packaging materials) which may Influence formulation design method of manufacture of API and drug product pharmacokinetic/biopharmaceutic properties of the resulting product packaging of the product (stability) 
It describes the process of optimizing the delivery of drug through determination of physical, chemical properties of new drug molecule that affect drug performance and development of an efficacious, stable and safe dosage form .
Before beginning the formal preformulation programs the preformulation scientist must consider the following factors :- The amount of drug available. - The physicochemical properties of the drug already known. - Therapeutic category and anticipated dose of compound. - The nature of information, a formulation should have or would like to have.
Preformulation drug characterization in a structured program:Test Fundamental 1) UV spectroscopy 2) Purity 3) Solubility a) Aqueous b) pKa c) Salt d)Solvents e) ko/ w f) Dissolution 4) Melting point 5) Assay development 6) Stability In Solution In solid state Derived 7) Microscopy 8) Bulk density 9) Flow properties Particle size and morphology Tablet and capsule formation Tablet and capsule formation Thermal, hydrolysis, pH Oxidation, proteolysis metal ion Simple assay TLC, HPLC, PC, GC & thermal Analysis Phase solubility/ purity Intrinsic & pH effect solubility control , salt formation Solubility, hygroscopicity & stability Vehicles & Extraction Lipophillicity, structure activity Biopharmacy DSC-polymorphism hydrate & solvent UV, HPLC, TLC Method/ function Characterization
UV Spectroscopy :The first requirement of any preformulation study is the development of a simple analytical method for quantitative estimation in subsequent steps. Most of drugs have aromatic rings and/or double bonds as part of their structure and absorb light in UV range, UV spectroscopy being a fairly accurate and simple method is a performed estimation technique at early preformulation stages. It passes a whole series of wavelengths of light through a solution of a substance (the sample cell) and also through an identical container (the reference cell) which only has solvent in it. For each wavelength of light passing through the spectrometer, the intensity of the light passing through the reference cell is measured. This is usually referred to as Io - that's I for Intensity. The intensity of the light passing through the sample cell is also measured for that wavelength given the symbol, I. If I is less than Io, then obviously the sample has absorbed some of the light. A simple bit of maths is then done in the computer to convert this into something called the absorbance of the sample - given the symbol, A. The relationship between A (the absorbance) and the two intensities is given by:
The Beer-Lambert Law:-
The equation for absorbance:-
The Greek letter epsilon in these equations is called the molar absorptivity - or sometimes the molar absorption coefficient. If a white light through a coloured substance, some of the light gets absorbed. Different substances absorb different wavelengths of light, and this can be used to help to identify the substance - the presence of particular metal ions, for example, or of particular functional groups in organic compounds. The amount of absorption is also dependent on the concentration of the substance if it is in solution. Measurement of the amount of absorption can be used to find concentrations of very dilute solutions.
A light source which gives the entire visible spectrum plus the near ultra-violet so that covering the range from about 200 nm to about 800 nm. The light coming from the diffraction grating and slit will hit the rotating disc and one of three things can happen.
1. If it hits the transparent section, it will go straight through and pass through the cell containing the sample. It is then bounced by a mirror onto a second rotating disc. This disc is rotating such that when the light arrives from the first disc, it meets the mirrored section of the second disc. That bounces it onto the detector.
2. If the original beam of light from the slit hits the mirrored section of the first rotating disc, it is bounced down along the green path. After the mirror, it passes through a reference cell (more about that later). Finally the light gets to the second disc which is rotating in such a way that it meets the transparent section. It goes straight through to the detector.
3. If the light meets the first disc at the black section, it is blocked - and for a very short while no light passes through the spectrometer. This just allows the computer to make allowance for any current generated by the detector in the absence of any light.
800 nm).usually very dilute. measuring the absorbance at the wavelength of strongest absorption . The chart recorder Chart recorders usually plot absorbance against wavelength. The solvent is chosen so that it doesn't absorb any significant amount of light in the wavelength range in (200 . Then a graph is plotted of that absorbance against concentration. the greater the intensity of the light. The detector and computer The detector converts the incoming light into a current.using the same container for each one. They are often designed so that the light beam travels a distance of 1 cm through the contents. The output might look like this: Finding concentration by plotting a calibration curve For each solution. The sample cell contains a solution of the substance. 6 . This is a calibration curve. The higher the current. The reference cell just contains the pure solvent.The sample and reference cells These are small rectangular glass or quartz containers.
and so a curve might get under these circumstances. absorbance is proportional to concentration. and so a straight line is expected. That is true as long as the solutions are dilute. 7 .According to the Beer-Lambert Law. The calibration curve will probably look something like- Purity Testing: Thin Layer Chromatography (TLC) High Pressure Liquid Chromatography (HPLC) Paper Chromatography (PC) Gas Chromatography (GC) Thermal Analysis Melting Point Differential Scanning Calorimetry (DSC) Differential Thermal Analysis (DTA) 1. but the Law breaks down for solutions of higher concentration. Thin Layer Chromatography (TLC):Thin layer chromatography (TLC) is very useful to chemists as an analytical technique to separate and identify the compounds in a mixture. Only very small samples of the analyte are needed much less than a milligram.
it is often used to monitor the progress of organic reactions and to check the purity of products. Thin-layer chromatography (TLC) is a chromatographic technique that is useful for separating organic compounds. differential partitioning occurs between the components of the mixture dissolved in the solvent the stationary adsorbent phase. Because of the simplicity and rapidity of TLC. Chromatography works on the principle that different compounds will have different solubilities and adsorption to the two phases between which they are to be partitioned. and inexpensive procedure that gives a quick answer as to how many components are in a mixture. the less time it will spend in the mobile phase and the more slowly it will migrate up the plate. determining their purity and following the progress of a reaction. quick. The more strongly a given component of a mixture is adsorbed onto the stationary phase.Thin-layer chromatography (TLC) is a very commonly used technique in synthetic chemistry for identifying compounds. As the solvent rises by capillary action up through the adsorbent. Principle The principle of TLC is the distribution of a compound between a solid fixed phase (the thinlayer) applied to a glass or plastic plate and a liquid mobile phase (eluting solvent) that is moving 8 . TLC is also used to support the identity of a compound in a mixture when the Rf of a compound is compared with the Rf of a known compound (preferably both run on the same TLC plate). TLC is a simple.
the longer it will stay dissolved in the mobile phase. Whether a compound moves up the plate or stays behind depends on the physical properties of that individual compound and thus depends on its molecular structure. Therefore. the more a sample's components are like the eluting solvent the 9 . especially functional groups. and as the solvent moves over the mixture each compound will either remain with the solid phase or dissolve in the solvent and move up the plate. A small amount of a compound or mixture is applied to a starting point just above the bottom of the TLC plate. The solvent is drawn up through the particles on the plate through capillary action. The Rf is calculated by dividing the distance the compound traveled from the original position by the distance the solvent traveled from the original position (the solvent front). The greater the similarity to the mobile phase. The Rf Values The behavior of an individual compound in TLC is characterized by a quantity known as Rf and is expressed as a decimal fraction. The compounds that are less soluble in the mobile phase and have a higher affinity to the particles on the TLC plate will stay behind. The more similar the physical properties of the compound is to the mobile phase.over the solid phase. the further it will be pulled up through the stationary particles on the TLC plate. The solubility rule "like dissolves like" is followed. The mobile phase will carry the most soluble compounds the furthest up the TLC plate. The plate is then placed in a developing chamber that has a shallow pool of solvent just below the level at which the sample was applied. The distance a compound travels indicates that compound's physical characteristics.
Temperature: Although precise control of temperature is not necessary. Nature of Adsorbent: Different adsorbents will give different Rf valve for same solvent. Plates should be the stored over silica gel in a desiccator before use and the sample should be applied quickly so that the water vapor in the atmosphere is not adsorbed by the plate. solvents run faster. Rf value is a constant for each component only under identical experimental condition. known Rf values can be compared to those of unknown substances to aid in their identifications. 2. It should made freshly for each run if one of the solvents is very volatile or hygroscopic. direct sunlight. 4. As the temperature is increased. volatile solvents evaporate more quickly. The layers may be of higher or lower thickness in individual compounds. 3.closer to a value of one the Rf will be for that component. Thickness of Layer: Standard plates approximately 250 µm is preferable thickness of layer. for example acetone. sources of heat. Hence. and Rf values generally decrease slightly. The Mobile phase: The purity of solvents and quantity of solvent mixed should be strictly controlled. Reproducibility is only possible for given adsorbent of constant particle size and binder. Because of the difficulties associated with activation procedures it is far better to use plates stored at room temperature and not to activate them. 10 . etc. Below 200 µm the Rf values vary considerably. the tank should be kept away from draughts. It depends upon number of factors as: 1.
6. Developing Tank: It is important that saturated conditions are attained for running TLC plates. Mass of Sample: Increasing the mass of sample on the plate will often increase the Rf of a drug. the plate is removed from the solvent reservoir. 7. When the solvent front reaches the other edge of the stationary phase. The sample. ascending. either liquid or dissolved in a volatile solvent. A well-fitting lid is essential.e. Method of Thin Layer Chromatography:Thin-layer chromatography consists of a stationary phase immobilized on a glass or plastic plate. 11 . descending. especially if it normally tails in the system. The different components in the mixture move up the plate at different rates due to differences in their partitioning behavior between the mobile liquid phase and the stationary phase. the Rf value changes for the same solvent system. Chromatographic Technique: Depending upon the development technique used i. if a plate is grossly overloaded. The bottom edge of the plate is placed in a solvent reservoir. is deposited as a spot on the stationary phase. this too will give a tailing spot and will have the effect of apparently decreasing the Rf value. and by leaving the tank to equilibrate for at least 30 minutes before running the plates. and the solvent moves up the plate by capillary action. and an organic solvent. horizontal etc. The separated spots are visualized with ultraviolet light or by placing the plate in iodine vapor. This is best accomplished by using small tanks with filter paper liners and sufficient solvent. However. The two situations are normally easy to distinguish by the intensity of the spot. The constituents of a sample can be identified by simultaneously running standards with the unknown.5.
g. 3. Cosmetology: Dye raw materials and end products. purity testing and determination of the concentration of active ingredients. vitamins in soft drinks and margarine. constituents of perfumes. Pharmaceuticals and Drugs: Identification. banned additives in Germany (e. Food Analysis: Determination of pesticides and fungicides in drinking water. Clinical Chemistry. preservatives. Forensic Chemistry and Biochemistry: Determination of active substances and their metabolites in biological matrices. compliance with limit values (e. aflatoxins in milk and milk products). 12 . fatty acids. polycyclic compounds in drinking water.g. process control in synthetic manufacturing processes. sandalwood extract in fish and meat products).Applications and Importance of Thin Layer Chromatography:1. surfactants. residues in vegetables. auxiliary substances and preservatives in drugs and drug preparations. salads and meat. diagnosis of metabolic disorders such as PKU (phenylketonuria). 2. 4. cystinuria and maple syrup disease in babies.
there are two variants in use in HPLC depending on the relative polarity of the solvent and the stationary phase. determination of pollutants from abandoned armaments in soils and surface waters. High Performance Liquid Chromatography (HPLC):High performance liquid chromatography is basically a highly improved form of column chromatography. Other Areas: Electrolytic technology (meta-nitrobenzoic acid in nickel plating baths) . It also allows to use a very much smaller particle size for the column packing material which gives a much greater surface area for interactions between the stationary phase and the molecules flowing past it. That makes it much faster. This allows a much better separation of the components of the mixture. These methods are highly automated and extremely sensitive. decomposition products from azo dyes used in textiles. The other major improvement over column chromatography concerns the detection methods which can be used. 2. 13 . it isn't the most commonly used form of HPLC.5. The column and the solvent Confusingly. 7. Environmental Analysis: Groundwater analysis. Analysis of Inorganic Substances: Determination of inorganic ions (metals). Instead of a solvent being allowed to drip through a column under gravity. 6. Normal phase HPLC Although it is described as "normal". it is forced through under high pressures of up to 400 atmospheres.
and the solvent is non-polar . Polar molecules in the mixture will therefore spend most of their time moving with the solvent. There won't be as much attraction between the hydrocarbon chains attached to the silica (the stationary phase) and the polar molecules in the solution. Reversed phase HPLC In this case. for example.6 mm (and may be less than that). but the silica is modified to make it non-polar by attaching long hydrocarbon chains to its surface . a mixture of water and an alcohol such as methanol. A polar solvent is used . Reversed phase HPLC is the most commonly used form of HPLC. the column size is the same. Polar compounds in the mixture being passed through the column will stick longer to the polar silica than non-polar compounds will.The column is filled with tiny silica particles. They will also be less soluble in the solvent because of the need to break hydrogen bonds as they squeeze in between the water or methanol molecules. They therefore spend less time in solution in the solvent and this will slow them down on their way through the column. 14 . That means that now it is the polar molecules that will travel through the column more quickly. In this case. and a length of 150 to 250 mm. there will be a strong attraction between the polar solvent and polar molecules in the mixture being passed through the column. A typical column has an internal diameter of 4. Non-polar compounds in the mixture will tend to form attractions with the hydrocarbon groups because of Van Der Waals dispersion forces. for example.typically with either 8 or 18 carbon atoms in them.hexane. The non-polar ones will therefore pass more quickly through the column.for example.
but also particle size) the exact composition of the solvent the temperature of the column 15 . Because of the pressures involved. Retention time The time taken for a particular compound to travel through the column to the detector is known as its retention time. the retention time will vary depending on: the pressure used (because that affects the flow rate of the solvent) the nature of the stationary phase (not only what material it is made of. it is not the same as in gas chromatography. This time is measured from the time at which the sample is injected to the point at which the display shows a maximum peak height for that compound. Different compounds have different retention times. For a particular compound.Procedure: Injection of the sample Injection of the sample is entirely automated.
The detector There are several ways of detecting when a substance has passed through the column. Interpreting the output from the detector The output will be recorded as a series of peaks . If using a methanol-water mixture as the solvent. Many organic compounds absorb UV light of various wavelengths. Methanol. therefore have to use a wavelength greater than 205 nm to avoid false readings from the solvent. and water below 190 nm. The solvents used don't absorb UV light. of course. absorbs at wavelengths below 205 nm. the retention times can be used to help to identify the compounds present . a direct reading of how much of the light is absorbed will get. As long as careful to control the conditions on the column. A common method which is easy to explain uses ultra-violet absorption. 16 . Different compounds absorb most strongly in different parts of the UV spectrum. The amount of light absorbed will depend on the amount of a particular compound that is passing through the beam at the time.each one representing a compound in the mixture passing through the detector and absorbing UV light.provided. that had already measured for pure samples of the various compounds under those identical conditions. and a UV detector on the opposite side of the stream. If a beam of UV light shining through the stream of liquid coming out of the column. for example.
involves using two solvents and rotating the paper 90° in between. Water monitoring . This method has been largely replaced by thin layer chromatography. Clinical Analysis of antibiotics and blood substances. Food and Flavor Sugar analysis in fruit juices.Applications of HPLC Pharmaceutical / Biopharmaceutical Pharmaceutical quality control. This is useful for separating complex mixtures of similar compounds. Paper Chromatography (PC):Paper chromatography is an analytical chemistry technique for separating and identifying mixtures that are or can be coloured. however it is still a powerful teaching tool. Environmental Biomonitoring of pollutents. Complex molecules separation. for example. 3. 17 . Shelf-life determinations of pharmaceutical products. Two-way paper chromatography. Identification of counterfeit drug products.Phenol content and toxic componants checking. Detection of endogenous neuropeptides in brain extracellular fluids. Ensuring soft drink consistency and quality. amino acids. especially pigments. This can also be used in secondary or primary colours in ink experiments. also called two-dimensional chromatography.
which will then travel up the paper with the solvent solute sample. two-way chromatography is used to separate the multiple-pigment spots. 18 . paper chromatography does not separate pigments completely. This sample is absorbed onto the paper and may form interactions with it. As the solvent rises through the paper it meets and dissolves the sample mixture. and placed in a sealed container. Any substance that reacts or bonds with the paper cannot be measured using this technique. Different compounds in the sample mixture travel at different rates due to differences in solubility in the solvent.also this can be explained as differential adsorption of the solute components into the solvent. which occurs as a result of the attraction of the solvent molecules to the paper. The more soluble the component the further it goes. such as ethanol or water.Technique A small concentrated spot of solution that contains the sample of the solute is applied to a strip of chromatography paper about two centimetres away from the base of the plate. In some cases. taking care that the spot is above the surface of the solvent. The paper is then dipped in to a suitable solvent. this occurs when two substances appear to have the same values in a particular solvent. In these cases. and due to differences in their attraction to the fibres in the paper. The solvent moves up the paper by capillary action. usually using a capillary tube for maximum precision. Paper chromatography takes anywhere from several minutes to several hours.
The liquid moves down by capillary action as well as by the gravitational force. It rises up the paper by capillary action against the force of gravity. the solvent is kept in a trough at the top of the chamber and is allowed to flow down the paper. Because of this rapid speed. the flow is more rapid as compared to the ascending method. The major limitation of gas chromatography is the requirement that the solute have a reasonable vapor pressure at a temperature where it is still stable. Gas Chromatography: Gas chromatography (GC) is a method of separation which employs a gas mobile phase and either a solid (GSC) or a liquid (GLC) adsorbed on a solid as a stationary phase. Gas chromatography is capable of separating very complex mixtures and the selectivity can be adjusted to separate almost any given pair of solutes by judicious choice of the stationary phase. Descending Chromatography In this method.Ascending Chromatography In this method. 19 . Substances that cannot be separated by ascending method. The developing solvent is placed in a trough at the top which is usually made up of an inert material. In this case. the chromatography is completed in a comparatively shorter time. the solvent is in pool at the bottom of the vessel in which the paper is supported. can sometimes be separated by the above descending method. The paper is then suspended in the solvent. 4. The apparatus needed for this case is more sophisticated.
It is coiled up so that it will fit into a thermostatically controlled oven. The syringe needle passes through a thick rubber disc (known as a septum) which reseals itself again when the syringe is pulled out. How the column works The packing material There are two main types of column in gas-liquid chromatography. It is hot enough so that all the sample boils and is carried into the column as a gas by the helium (or other carrier gas). the other is even thinner and has the stationary phase bonded to its inner surface. 20 .Injection of the sample Very small quantities of the sample that you are trying to analyse are injected into the machine using a small syringe. The column is typically made of stainless steel and is between 1 and 4 metres long with an internal diameter of up to 4 mm. One of these is a long thin tube packed with the stationary phase. The injector is contained in an oven whose temperature can be controlled.
The chances are that it will then condense again a little further along the column. In some cases. None of these things is necessarily permanent. Some compounds will be more soluble in the liquid than others. It is cooler than the injector oven. the less soluble ones will spend more of their time in the gas. some molecules may dissolve in the liquid stationary phase. It may dissolve in the liquid on the surface of the stationary phase. Similarly. the column starts off at a low temperature and then is made steadily hotter under computer control as the analysis proceeds. A compound with a boiling point higher than the temperature of the column will obviously tend to condense at the start of the column. 21 . as you will see below. However. It may remain in the gas phase. some of it will evaporate again in the same way that water evaporates on a warm day .The column is packed with finely ground diatomaceous earth. The column temperature The temperature of the column can be varied from about 50°C to 250°C.typically a waxy polymer. which is a very porous rock. so that some components of the mixture may condense at the beginning of the column. The more soluble ones will spend more of their time absorbed into the stationary phase. This is coated with a high boiling liquid . How separation works on the column One of three things might happen to a particular molecule in the mixture injected into the column: It may condense on the stationary phase.even though the temperature is well below 100°C.
the better the separation . The answer is to start with the column relatively cool. High solubility in the liquid phase means a high retention time. For a particular compound. This time is measured from the time at which the sample is injected to the point at which the display shows a maximum peak height for that compound. 22 . Different compounds have different retention times. the less time it will spend being carried along by the gas. A high column temperature shortens retention times for everything in the column.either because they evaporate more readily. or because they are so energetic that the attractions of the liquid no longer hold them. the retention time will vary depending on: The boiling point of the compound. Any molecule in the substance spends some of its time dissolved in the liquid and some of its time carried along with the gas. Retention time The time taken for a particular compound to travel through the column to the detector is known as its retention time. there isn't going to be much space between their peaks on the chromatogram. The lower the temperature of the column.The process where a substance divides itself between two immiscible solvents because it is more soluble in one than the other is known as partition.but it could take a very long time to get the compounds through which are condensing at the beginning of the column! On the other hand.but less well separated out. using a high temperature. everything will pass through the column much more quickly . So high boiling point means a long retention time. A higher temperature will tend to excite molecules into the gas phase . If everything passed through in a very short time. and then gradually and very regularly increase the temperature. The temperature of the column. The solubility in the liquid phase. The more soluble a compound is in the liquid phase. A compound which boils at a temperature higher than the column temperature is going to spend nearly all of its time condensed as a liquid at the beginning of the column.
A flame ionisation detector In terms of reaction mechanisms. 23 . The whole detector is enclosed in its own oven which is hotter than the column temperature. small amounts of ions and electrons are produced in the flame. The presence of these can be detected. the burning of an organic compound is very complicated. During the process. The flame ionisation detector described below is commonly used and is easier to describe and explain than the alternatives. Increasing the temperature still more will force the very "sticky" molecules off the stationary phase and through the column. That stops anything condensing in the detector.At the beginning. Increasing the temperature a bit will encourage the slightly "stickier" compounds through. The detector There are several different types of detector in use. compounds which spend most of their time in the gas phase will pass quickly through the column and be detected.
As long as careful to control the conditions on the column.Interpreting the output from the detector The output will be recorded as a series of peaks . At the melting point the solid and liquid phase exist in equilibrium. could use the retention times to help to identify the compounds present . 5. that had already measured them for pure samples of the various compounds under those identical conditions.provided. Differential Scanning Calorimetry (DSC): 24 . of course. Thermal Analysis: Melting Point: The melting point of a solid is the temperature range at which it changes state from solid to liquid.each one representing a compound in the mixture passing through the detector.
can be detected relative to the inert reference. These transitions involve energy changes or heat capacity changes that can be detected by DSC with great sensitivity. Generally. glass transitions. The reference sample should have a well-defined heat capacity over the range of temperatures to be scanned. the material under study and an inert reference are made to undergo identical thermal cycles.Differential scanning calorimetry or DSC is a thermoanalytical technique in which the difference in the amount of heat required to increase the temperature of a sample and reference are measured as a function of temperature. Changes in the sample. the temperature program for a DSC analysis is designed such that the sample holder temperature increases linearly as a function of time. similar to differential scanning calorimetry. Thus. Differential Thermal Analysis (DTA): Differential thermal analysis (or DTA) is a thermoanalytic technique. or exothermic decompositions. such as melting. In DTA. melting and sublimation. such as glass transitions. Both the sample and reference are maintained at nearly the same temperature throughout the experiment. Solubility Determination:- 25 . a DTA curve provides data on the transformations that have occurred. The main application of DSC is in studying phase transitions. either exothermic or endothermic. crystallization. while recording any temperature difference between sample and reference. This differential temperature is then plotted against time. The area under a DTA peak is the enthalpy change and is not affected by the heat capacity of the sample. or against temperature (DTA curve or thermogram).
the rate of drug resale into dissolution medium and consequently. Solubility is usually determined in variety of commonly used solvents and some oils if the molecules is lipophillic. which employs a saturated solution of the material.The solubility of drug is an important physicochemical property because it effects the bioavailabilty of the drug. Common solvents used for solubility determination are :·Water ·Polyethylene Glycols ·Propylene Glycol ·Glycerin ·Sorbitol ·Ethyl Alcohol ·Methanol ·Benzyl Alcohol ·Isopropyl Alcohol ·Buffer at various pHs Aqueous Solubility :The availability of a drag is always limited and the preformulation scientist may only have 50 mg. The solubility of the molecules in various solvents is determined as a first step. The solubility of material is usually determined by the equilibrium solubility method. This information is valuable is developing a formulation. 26 . obtained by stirring an excess of material in the solvent for a prolonged until equilibrium achieved. Solubility dictates the ease with which formulation for oral gavages and intravenous injection studies in animals are obtained the pKa allives the informed of pH to maintain solubility and to choose salts required to achieve good bioavailability from the solid state and improve stability and powder properties. the therapeutic efficiency of the pharmaceutical product.
2) 37°C to support biopharmaceutral evaluation. This leads to a minimum aqueous solubility. 1) 4°C to ensure physical stability and entered short term storage and chemical stability unit more definitive data are available. 27 . The minimum density of water occurs at 4°C. cab be altered by orders of magnitude with changing pH.) i. P o/w = (C oil / C water) equilibrium. For acidic compounds pH = pKa + log (un-ionized drug]) / [ionized drug]) Partition Coefficient :Partition Coefficient (oil/ water) is a measure of a drug‟s lipophilicity and an indication of its ability to cross cell membranes.e. The Henderson – Hasseslebach equation provides an estimate of the ionized and un ionized durg concentration at a particular pH. the fundamental solubility when completely unionized. pKa Determination:Determination of the dissociation content for a drug capable of ionization within a ph rang of 1 to 10 is important since solubility and consequently absorption. When the pavrity of the drug sample can be assured the solubility obtained in acid for a weak acid or albali for a weak base can be assured to be the instensic solubility (Co.Intensic Solubility (Co) :An increase in solubility in acid compared to aqueous solubility suggests a weak base and an increase in alkali. one acidic & one basic . a weak acid. The solubility should ideally be measured at two temperature. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. In this case there will be two pKa‟s. An increase in acidic and alkaline solubility suggest either impotence or zuitter ion behaviour.
independently of the drug and dosage forms position within the GI ireat. Although partition coefficient data alone does not provide understanding of in vivo absorption. Kaplan suggested that provided the solubility of a drug exceded to mg/ ml at pH. Intrinsic Dissolution Rate :When dissolution is controlled solely by diffusion the rate of diffusion is directly proportional to the saturated concentration of the drug in solution under these conditions the rate constant K1 is defined by K1 = 0. Below / mg/ ml such problems were quite possible and salt formation could improve absorption and solubility by controlling the pH of the microenvironment. the effect id dissolution rate. pKa and solubility on absorption must not be neglected. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water. The rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. V is the kinemative viscosity 28 . whereas those with partition coefficient much less than 1 are indicative of a hydrophilic drug. Drugs having values if P much greater than 1 are classified as lipophilic. the lipophilic/ hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption. Although it appears that the partition coefficient may be the best predictor of absorption rate. Dissolution :The dissolution rate of the drug is only important where it is the rate limiting step in the absorption process. the partition coefficient can provide an empiric handle in screening for some biologic properties. it does provide a means of characterizing the lipophilic/ hydrophilic nature of the drug. Since biological membranes are lipoidal in nature. For drug delivery. 7 no bioavailability or distinction related problems were to be expected.62 D2/3 v 1/6 w1/2 Where.For series of compounds.
29 . The reverse process „salting in‟ qries with large anions e. the change in volume that takes place upon the melting of a solid is very small. salivate which open the water structure. benzoate. These hydro topics increase the solubility of properly water soluble compounds such as diazepam. Since the melting point of a solid can be easily and accurately determined with small amounts of material. the solubility of a slightly soluble electrolyte. The „selling out‟ results from the removal of water molecules as solvent owing to the completing hydration of other ions. In contrast to the volume change that accompanies the vaporization of a liquid. This makes the melting point of a solid. Melting Point :The normal melting point of a solid is defined as the temperature at which the solid and liquid are in equilibrium at a total pressure of 1 atmosphere.W is the anguter velocity of a rotating disc of drug. Common Ion Effect :A common ion significantly reduces. unlike the boiling point of a liquid. The melting point of a drug can be measured using three techniques :1)Capillary Melting 2)Hot Stage Microcopy 3)Differential scanning calorinetry or thermal Anaylysis.g. it is the physical property that has most often been used for the identification and characterization of solids. practically independent of any ordinary pressure change.
so the rate of heating must be slow as the melting point is approached (about 1 degree per minute). The thermometer and sample must be at the same temperature while the sample melts. turning the capillary open end up. If the approximate temperature at which the sample will melt is not known. and vibrating it by drawing a file across the side to rattle the crystals down into the bottom. down a length of glass tubing about 1 cm in diameter (or a long condenser) onto a hard surface such as a porcelain sink. Filling a Capillary Tube Usually. Capillary melting points. with a low rate of heating near the melting point.Capillary Melting :Capillary melting gives information about the melting range but it is different to assign an accurate melting point. The temperature range over which the sample is observed to melt is taken as the melting point. 30 . The capillary. determine a preliminary melting point determination by allowing the temperature of the sample to rise quickly. or the iron base of a ring stand. the melting point capillary can be filled by pressing the open end into a small heap of the crystals of the substance. the temperature of the thermometer bulb and the temperature of the crystals in the capillary may not be the same. and closed at one end. either in an oil bath or a melting-point apparatus. The transfer of heat energy by conduction takes place rather slowly. If filing does not work. A few crystals of the compound are placed in a thinwalled capillary tube 10-15 cm long. open end up. about 1 mm in inside diameter. The solid should be tightly packed to a depth of 2-3 mm. which contains the sample. and a thermometer are then suspended so they can be heated slowly and evenly. stone desk top. are most often used for the determination of the melting point of a solid. drop the tube. Otherwise. Then carry out a more accurate determination.
The simplest use a burner flame and depend upon convection for mixing. Hot Stage Microcopy :This the issued observation of melting under a microscope equipped with a heated and lagged sample stage. the capillary can be fastened to the thermometer by means of a small slice of rubber tubing used as a rubber band (see Figure below). but almost impossible with a flame. 31 . It is easy to heat at a low and steady rate with an electric heater. the more elaborate and accurate use an electric immersion heater and are stirred. When an oil bath is used. The heating rate is controllable and upto three transitions can be registered. as well as in a boiling point determination.A variety of oil baths can be used in a melting point determination.
However. Differential Scanning Calorimetry and thermal analysis :Differential thermal analysis (DTA) measures the temperature difference between the sample and a reference as a function of temperature or time when heating at a constant rate differential scanning calorimetry (DSC) is similar to DTA except that the instrument measures the amount of energy required to keep the sample at the same temperature as the reference i. For this reason. it measures the enthalpy of transition. block. observed block melting points often appear to be higher than capillary melting points. a melting point quickly determined on a block can serve as an approximate melting point for the determination of a capillary melting point. the higher the melting point.A quick and easy method to determine the melting point of a solid is to heat a few crystals of the sample between a pair of microscope cover glasses on an electrically heated metal block while observing the crystals with the aid of a magnifying glass. This method requires as little as a single crystal and it is very convenient. hot stage melting points are inherently too high. exposed to the cooler atmosphere. Complete thermal equilibrium between the sample. Unfortunately. 32 . since the thermometer is inside the block and the sample is on the surface.e. and thermometer is not possible. the greater the difference.
When the absorption of a drug is dissolution rate limited. x-ray diffraction patterns and solubility even though they are chemically identical. Selection of a polymorph that is chemically more stable is a solution in many cases. Differences in the dissolution rates and solubilities of different polymorphic forms of a given drug are very commonly observed. a more soluble and faster-dissolving from may be utilized to improve the rate and extent of bioavailability. Different polymorph also lead to different morphology. tensile strength and density of power bed which all contribute of compression characteristics of materials. Polymorphs generally have diffrent melting points.Crystal Properties and Polymorphism :Many drug substances can exit in more than one crystalline from with different space lattice arrangements. This property is known as polymorphism. physical form of the drug influences degradation. For drugs pane to degradation in the solid state. Some investigation of 33 .
filtration. formulation. Although a drug substance may exist in two or more polymorphic forms. and administration of a drug candidate as well as stability in presence of other recipients. The other forms would convert to the stable form with time. Drugs having decreased stability at elevated temperatures cannot be sterilized by autoclaving but must be sterilized by another means. These include microscopy (including hot stage microcopy). storage. e.polymorphism and crystal habit of a drug substance as it relates to pharmaceutical processing is desirable during its Preformulation evaluation especially when the active ingredient is expected to constitute the bulk of the tablet mass. infrared spectrophotometry. Assay development : UV Spectroscopy Thin Layer Chromatography (TLC) High Performance Liquid Chromatography (HPLC) Chemical stability profile: Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug. the stable polymorph exhibits the highest melting point . Various techniques are available for the investigation of the solid state. only one form is theromdynamically stable at a given temperature and pressure. These studies include both solution and solid state experiments under condition typical for the handing.g. In general. single-crystal x-ray and x-ray power diffraction. the lowest solubility. and dilalometry. The method of sterilization of potential product will be largely dependent on the temperature stability of the drug. Factor effecting chemical stability critical in rational dosage form design include temperature. thermal analysis. pH and dosage form diluents. Buffer 34 . and the maximum chemical stability. The effect of pH on drug stability is important in the development of both oral administration must be protected from the highly acidic environment of the stomach..
hydrolysis.Compatibility studies : stability in the Presence of excipients . Chemical structure of the drug is the determination of drug to either of these attacks. physical properties of drugs.Solid state stability . amides are to prone to solvolysis. If a substantial change is seen. The preformulation data of this nature are useful in determining if the material should be protected and stored in controlled low humidity environment or if non aqueous solvent be used during formulation. Stability under high humidity conditions :Solid drug samples can be exposed to different relative humidity conditions by keeping them in laboratory desiccators containing saturated solutions of various salts. samples stored at lower temperature are examined . and 60 degree centigrade with ambient humidity.selection for potential dosage forms will be largely based on the stability characteristic of the drug. Esters and lactase and to lesser extent. Amorphous materials are less stable than their crystalline forms. If no changesisseen after 30 days at 60 degree centigrade. The closed desiccators in turn are kept in oven to provide constant temperature.Typical stability protocol for anew Chemical Entity Solid state stability:Chemical instability normally results from either of the following reaction :. 35 . Instauration or electron rich centre in the structure make the molecule vulnerable for free radical mediated or photo-catalysed oxidation.Solution phase stability . Elevated temperature studies:The elevated temperatures commonly used are 40. Denser materials are more stable to ambient stress. 50. . the stability prognosis is excellent . photolysis and pyrolysis. The samples stored at highest temperature are observed weekly for physical and chemical changes and compared to an appropriate control . oxidation.
Resulting data may be useful in determining if an amber colored container is required or if color masking bye should be used in the formulation . Samples are kept in desiccators equipped with three-way stop cocks. over a temperature range. Mixtures should be examined under nitrogen to ultimate oxidation and paralytic effect at a standard heating rate on DSC. Exposure of drug 400 and 900 foot-candles of illumination for 4 and 2 week periods respectively is adequate to provide some idea of photosensitivity. A poor solution stability of drug may 36 . using different stimulator GI condition can be designed. the degradation is much rapid in solution form. which will encompass any thermal changes due to both the drug and appearance or disappearance one or more peaks in themogrames of drug excipient mixtures are considered of indication of interaction. Stability to Oxidation :Drug‟s sensitivity to oxidation can be examined by exposing it to atmosphere of high oxygen tension. The pH based stability study. Usually a 40% oxygen atmosphere allows for rapid evaluation. Results may be useful in predicting if an antioxidant is required in the formulation or if the final product should be packaged under inert atmospheric conditions. A shallow layer of drug exposed to a sufficient headspace volume ensures that the system is not oxygen limited. The process is repeated 3 or 4 times to ensure 100% desired atmosphere. it presentsanaesthetic problem. Though the extent of degradations small and limited to the exposed surface area. Solution phase stability: As compared with the dry form. Compatibility studies :The knowledge of drug excipients interaction is useful for the formulation to select appropriate excipients. which are alternatively evacuated and flooded with desired atmosphere. It is important ascertain that the drug doesn‟t degrade when exposed to GI fluid.Photolytic stability :Many drugs fade or dorpen on exposure light. The described preformulation screening of drug excipients interaction requires only 5mg of drug in a 50% mixture with the excipients to maximize the likelihood of obscuring an interaction .
Hydrolysis or Solvolysis Hydrolysis is one of the most frequently encountered type of chemical reaction responsible for drug decomposition processes. The following types of compounds undergo hydrolytic degradation. pH can also influence the rate of oxidation. weak bases at two or more pH units below their pKas will be the most soluble. provided the bioavailability is not compromised Absorption behavior: It is essential to test the in vivo behavior of the new drug for successful formulation of a dosage from good bioavailability. lactams. esters. ureides. Hydrolytic decomposition can be avoided or slowed down by using an insoluble form of drugs. stability of drug solution can be increased by the use of suitable buffers. In addition.urge the formulator to choose a less soluble salt form. Precipitation of drug should be aware according to pH change. so the buffer system are used to maintain a certain pH in some drug products. This can be partially explained by the fact that the redox potential for many reactions depends on pH. nitriles. Look at the following example 37 . thio-esters. usually at different rates. many drugs are stable in a limit pH range. Partial in vivo and in vitro test are designed to study pharmacokinetic profile of the drug. amides. Weak acids will be the most soluble in solutions with a pH at least two units above their pKa (>99% ionized form). On the other hand. lactose. imines. pH pH of solution influences the percentage ionization of drug owing to its pKa. halides. thio-halides. Furthermore.
minimum decomposition or maximum stability is usually found in the pH range of 3 to 4.Using the Nernst equation When Eo is the standard potential E is the actual potential 1 is the number of electrons.06 calculated approximate constant. This equation helps us to understand that an increase in the concentration of hydrogen ion causes an increase in the value of E. Participating in change from oxidation form to reduction form. So the reduced form of the system is less readily oxidized when the pH is low. Its electronic influence may alter the affinity of the ester carbonyl ion for the catalytic species – this alteration may increase or decrease the rate of hydrolysis.through steric hindrance and thus reduces the rate of hydrolysis. al have shown that caffeine complexes with local 38 . Complexation Complex formation reduces the rate of hydrolysis and oxidation. For example. So complexation reduces the ease of encounter of the ester with various catalytic species such as H+ and OH. 0. it will reduce the movement rate as well as ease of movement. So we understand that pH is of extreme importance both in the case of hydrolysis and oxidation. Lachman et. Another effect is there for the complexing agent. Complex formation affects decomposition in two ways. (1) steric and (2) polar. Since the drugs that are undergoing oxidative decomposition are usually in the reduced stage. if a large caffeine molecule is attached to a benzocaine molecule by complexation.
Chelating agents also complex with trace metals that enhance oxidative degradation and apply brakes to that process. and surface-area controlled processes such as dissolution and Surface morphology of the drug particles. procaine and tetracaime to cause a reduction in their rate of hydrolytic degradation. In general. Presence of heavy metals Heavy metals. cobalt and nickel generally catalyze oxidative degradations. These metals increase the rate of formation of free radicals and enhance oxidative decomposition. with a suitable oxidation – reduction potential between them such as copper. 39 . They found that the solutions not containing any chelating agent decomposed more rapidly as the buffer concentration increased. formulation homogeneity. The hydrolytic groups such as OH cannot penetrate this micelle cover and reach the drug particles. such as benzocaine. iron. hence hydrolysis rate is decreased. Shape and Surface Area:Bulk flow. The buffered solutions containing chelating agent showed that the rate of degradation was independent of the concentration of the buffer. Surfactants Nonionic. cationic and anionic surfactants when added to solutions containing drugs form micelle and the drug particles become trapped in the micelle.anesthetics. each new drug candidate should be tested during Preformulation with the smallest particle size as is practical to facilitate preparation of homogeneous samples and maximize the drug‟ s surface area for interactions. especially those possessing two or more valency states. Scientists studied the oxidative decomposition with and without 0.1% disodium salt of ethylenediamine tetracetic acid at different buffer concentrations. Particle Size.
on their biopharmaceutical behavior. in some instances.Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes. shape. Sieving or screening 3. It is generally recognized that poorly soluble drugs showing a dissolution. Microscopy 2. In case of tablets. This method can generally be applied to particles in the size range between 0. . the humidity. size and its distribution of powdered pharmaceutical drugs and excipients to examine their micromeritic properties. Sedimentation Optical microscopy: The optical microscopy is used to observe the morphological appearance and shape of individual particle either directly with the naked eye or by using a microscopic photograph.rate limiting step in the absorption process will be more readily bio available when administered in a finely subdivided state rather than as a coarse material. Apparatus: 40 . and interacting axcipients than are coarse materials. in order to measure the particle size. Classical methods for measuring particle size: 1. size and shape influence the flow and the mixing efficiency of powders and granules. The effect is not only on the physical properties of solid drugs but also.5 and 100µm. Size can also be a factor in stability: fine materials are relatively more open to attack from atmospheric oxygen.Determination of particle size -Determination of surface area Particle size Determination:Powder particle size determination is a method to determine directly or indirectly morphological appearance.
The lens barrel is moved up and down in the column with handles for course and fine adjustments so that the focus can be adjusted. One drop of the suspension is placed on a slide glass and used as the test specimen directly. a mirror stand and column to support the illumination system. little by little. a stage for holding the test specimen. or used after drying. Preparation of test specimen: After the preprocessing. reflecting mirror. Wet methodThe sample material is suspended in an appropriate liquid which does not dissolve the sample. The ocular is attached to the lens barrel and adjusted to the focus point of the stage micrometer scale. b. and a calibrated stage micrometer is placed at the center of the microscope stage and fixed in place. the distance between the scales of the two micrometers is determined. and the sample size equivalent to 1 division of the ocular scale is calculated using the following formula: The particle size equivalent to 1 division on the ocular scale (µm) = length on the stage micrometer (µm) Number of scale divisions on the ocular micrometer 41 . diaphragm and condenser) making the path for the enlarged image of the sample through the objective and ocular. an ocular micrometer is inserted at the position of the ocular diaphragm. there is usually a built in optical system ( light source. Procedure: When the particle size is measured. Dry methodThe sample material is sprinkled on to the slide glass. Then.An optical microscope consists of a lens barrel that houses the optical system consisting of the objective and the ocular. and microscope base to support all these sections. In addition. and this is used as the test specimen. the test specimen is prepared with the following methodsa.
which is usually applicable to powdered materials having a particle size of more than about 75 µm. Apparatus: 1. After adjusting the focus.The stage micrometer is removed and the test specimen is placed on the microscope stage. Sieve 2. Balance 3. Electromagnet-type sieve shaker 42 . this method is to evaluate the twodimensional size of the samples. the particle sizes are determined from the number of scale divisions read through the ocular. Sieving method : The analytical sieving method is a method to estimate the particle size distribution of powdered pharmaceutical drugs by sieving. Essentially.
taking into consideration of the physicochemical characteristics such as hygroscopicityor static electricity.Place the sieves one upon another on a collecting pan in order from small to large opening.If there is some fine powder on the down surface of each sieve. Procedure: Usually this method is proceeded under the controlled temperature and humidity conditions. the total loss.then weigh each sieve and the collecting pan.depending on the properties of the sample: 1. Determine the mass of material on each sieve and in the collecting pan by the following equation to obtain the particle size distribution. The difference between the mass of the sample taken and the total mass of the sample on each sieve and in the collecting pan. Sieving the agglomerated sample through a coarse mesh sieve previously to deagglomerate it. Drying agglomerated samples owing to their hygroscopicity under a condition which does not change the essential qualities of the sample. and fix the nest of sieves on a mechanical shaker.and combine it with the sieve fraction retained on each next down sieve.place the sample on the top sieve. take it off by the brush gently. Amount of the material on each sieve (%) = Wi ×100 WT 43 .Agitate the nest of sieves for the time period previously obtained by the end point determination and then remove each sieve from the nest.select sieves which cover the entire particle size range of the sample to be tasted.Pretreatment of sample: The following traetments may be performed. Unless otherwise specified. must not exceed 2% of the mass of the original test specimen. replace the lid. 2. 3. Addition of adequate additives to adhesive or agglomerated samples due to their electrostatic charge in an amount which does not affect the results to avoid the generation of electrostatic charge.
Wi: Mass of the material on each sieve (g) WT: Total mass of the material on each sieve and in the collecting pan (g). Adsorption method: The process of adsorption and desorption is studied on the compounds of alumina and silica during this experiment. From the BET theory of adsorption. The adsorption takes place by virtue of vander wall‟s forces. The isotherms that display the behavior of N2 upon these compounds are represented as are the pertinent results that can calculated from them. Knowing the monolayer capacity of adsorbent and the area of absorbale molecule. so this technique is useful for sizes below 10 μm. but sub-micrometer particles cannot be reliably measured due to the effects of Brownian motion. 44 . Sedimentation method: These are based upon study of the terminal velocity acquired by particles suspended in a viscous liquid. Surface Area Determination:Surface area is most commonly determined based on brunaver emette teller (BET) theory of adsorption. then measures the optical density of successive layers using visible light or x-rays. Most substances adsorb a mono molecular layer of gas under certain conditions of partial pressure of gas and temperature. it was possible to calculate the surface area of the adsorbent. Typical apparatus diperses the sample in liquid. the surface area can be calculated the adsorption process is carried out with nitrogen at-195 degree Celsius at a partial pressure attainable when nitrogen is in a 30% temperature with an inert gas (helium). Sedimentation time is longest for the finest particles.
“BET” consists of the first initials of their family names. c is the BET constant. and Edward Teller published an article about the BET theory in a journal for the first time. and (c) the Langmuir theory can be applied to each layer. and vm is the monolayer adsorbed gas quantity. which is expressed by (2): E1 is the heat of adsorption for the first layer. (b) there is no interaction between each adsorption layer. in volume units). and EL is that for the second and higher layers and is equal to the heat of liquefaction.BET theory is a rule for the physical adsorption of gas molecules on a solid surface and serves as the basis for an important analysis technique for the measurement of the specific surface area of a material. Stephen Brunauer. Paul Hugh Emmett. The resulting BET equation is expressed by (1): P and P0 are the equilibrium and the saturation pressure of adsorbates at the temperature of adsorption. to multilayer adsorption with the following hypotheses: (a) gas molecules physically adsorb on a solid in layers infinitely. In 1938. The concept of the theory is an extension of the Langmuir theory. 45 . which is a theory for monolayer molecular adsorption. v is the adsorbed gas quantity (for example.
The linear relationship of this equation is maintained only in the range of 0. The value of the slope A and the y-intercept I of the line are used to calculate the monolayer adsorbed gas quantity vm and the BET constant c.35.BET plot Equation (1) is an adsorption isotherm and can be plotted as a straight line with 1 / v[(P0 / P) − 1] on the y-axis and φ = P / P0 on the x-axis according to experimental results. The following equations can be used: The BET method is widely used in surface science for the calculation of surface areas of solids by physical adsorption of gas molecules.05 < P / P0 < 0. A total surface area Stotal and a specific surface area S are evaluated by the following equations: 46 . This plot is called a BET plot.
and activated charcoal. The reason for their adsorbing characteristics are their enormous surface area per unit weight. The gas generally used for this is Nitrogen. The opposite process is called desorption. The area of the adsorbent can be calculated from the isotherms. Although. Different values corresponding to this are probably due to the effects previously mentioned. alumina. Two of these compounds are used in the experiment. When the surface of the adsorbent is saturated by the adsorbate. argon and krypton are used in special cases. molecules of the adsorbate are binded to the surface whereas in absorption. The path of the desorption isotherm may be different from that of the adsorption isotherm. adsorption could occur beyond the initial monolayer of adsorbate according to BET theory. s: adsorption cross section. V: molar volume of adsorbent gas a: molar weight of adsorbed species The purpose of this laboratory experiment is to study the process of adsorption. This process of binding is generally weak and reversible (as seen in immediate desorption). The measurement of adsorption is usually carried out at a constant temperature (77K for this experiment). This is due to the limited number of surface sites available for chemisorption. The process of adsorption should be set apart from the process of absorption. However. The sample must be saturated with the gas before an accurate desorption isotherm can be constructed. the their just filling the spaces of the pores in the solid.N: Avogadro's number. Some of the best known and classic adsorbents are silica. This 47 . In adsorption. Method: The measurements were taken from combinations of the ideal gas laws and by variations in calculated values. a decrease in adsorbence will be observed. This may be due to hystersis effects. An instrument known as the Omnisorb 360 was used for the experiment.
The gas He was used during volume determinations because it is not adsorbed at this temperature. Gas expansions throughout the "plumbing" and sample containers as well as a known flask gave the needed volumes of each necessary component. In the desorption runs.instrument consists of vacuum pumps and "plumbing" along with the sample containers. the difference from expected values were due to the gas being desorbed. The variations upon the gas expansions were due to either adsorption or desorption which ever was relevant. Some of the gas was adsorbed by the sample. the gas from the sample container was expanded into the manifold. After the sample was saturated with the gas. The manifold of the Omnisorb was filled with a certain pressure of N2 and expanded into the sample container. Air permeability method: 48 . desorption runs could take place. As before.
The measurement is therefore important in the manufacture of many processed materials. m3·s-1 49 .e. Methods Measurement consists of packing the powder into a cylindrical "bed" having a known porosity (i. Significance When a powder reacts chemically with a liquid or gas at the surface of its particles. The resulting flow-rate of air through the bed yields the specific surface by the Kozeny–Carman equation: where: S is specific surface. m ρ is the sample particle density. A pressure drop is set up along the length of the bed cylinder.The air permeability specific surface of a powder material is a single-parameter measurement of the fineness of the powder. It is universally used in the cement industry as a gauge of product fineness which is directly related to such properties as speed of setting and rate of strength development. volume of air-space between particles divided by total bed volume). the specific surface is directly related to its rate of reaction. kg·m-3 ε is the volume porosity of the bed (dimensionless) δP is the pressure drop across the bed. Pa·s Q is the flowrate. Pa l is the cylinder length. The specific surface is derived from the resistance to flow of air (or some other gas) through a porous bed of the powder. The SI units are m2·kg-1 ("mass specific surface") or m2·m-3 ("volume specific surface"). m2·kg-1 d is the cylinder diameter. m η is the air dynamic viscosity.
and shape are generally very important an increase in crystal size or a more uniform shape will lead to a small angle or repose and a smaller Carr‟s index. Changes in particles size. Powder Flow Properties:When limited amounts of drugs are available Power flow properties can be evaluated by measurements of bulk density and angle of repose. Various standard methods have been proposed: Maintain a constant flowrate. Bulk Density :Knowledge of absolute and bulk density of the drug substance is Very useful in Having some idea as to the size of final dosage form the density of solids also of affects their flow Properties Carr‟s compressibility index can be used to predict the flow properties based on density measurement. and measure the pressure drop Maintain a constant pressure drop. deriving the ratio from the characteristics of the apparatus.It can be seen that the specific surface is proportional to the square root of the ratio of pressure to flow. Carr‟s index (%) = Tapped density – Pored density *100 Tapped density A similar index has been defined by Hausner : Hausner ratio = Tapped density Pored density 50 . and measure the flowrate Allow both to vary.
Carr’s index fee power flow Flow Excellent Good Fair to passable Poor Very Poor Extremely Poor <25 25-30 30-40 > 40 Angle of repose 5-15 Carr’s index ( % ) 12-16 18-21 23-35 33-38 >40 Conclusion: Preformulation studies have a significant part to play in anticipating formulation problems and identifying logical path in both liquid and solid dosage form technology. Stability studies in solution will indicate the feasibility of parental or other liquid dosage form and can identify methods of stabilization. The most appropriate salt for development. In parallel solid-state stability by DSC. TLC and HPLC in the presence of tablet and capsule excipient will indicate the most acceptable vehicles for solid dosage form. the preformulation scientist can assist the synthetic chemist to identify the optimum molecule. angle of repose. 51 . By comparing the physicochemical properties of each drug candidate with in a therapeutic group. provide the biologist with suitable vehicles to elicit pharmacological response and advise the bulk chemist about the selection and production of the best salt with appropriate particle size and morphology for subsequent processing. The need for adequate drug solubility can not be overemphasized. Relationship between flow.Angle of repose:The maximum angle which is formed b/w the surface of a pile of powder and horizontal surface is called the angle of repose.
html#top 12.uk/analysis/uvvisible/analysis.html#top 7.com/Stability_Of_Drugs:Factors_Affecting_Rates_Of_Hydrolysi s_And_Oxidation#Stabilization_of_drugs_against_hydrolysis.chem.p df 19.chemguide. http://en.org/wiki/BET_theory 52 .co. http://www.pharmpedia.cn/yaodian/jp/14data/General_Test/Powder_Particle_Size_Determ.njutcm. http://lib.ufl.org/topics/gas/chromatography.org/wiki/Differential_scanning_calorimetry 14.chemguide.pharmtech.fi/kurssit/590082/preformulointi_I_tn. http://www. http://pharmacy.asp?bigtitle=Wicharn%20Junwitayanuchit&middletitle =Physicochemical%20Factors%20Involving%20Drug%20Incompatibilities&content=pa perwicharn 17. http://en. http://www.uk/analysis/uvvisible/spectrometer.net/pharma-student-magazine/application-and-importance-thin- layer-chromatography-analysis-and-research--0 8.org/wiki/Paper_chromatography#Technique 10.pdf 3.wikipedia.hcu.html 21.pdf 16.uk/analysis/chromatography/gas.uk/analysis/chromatography/hplc.pharmainfo.edu/~itl/4411L_f00/ads/sample/knight.net/rajeev-garg/publications/preformulation-a-need-dosage-form- design 2.wisc.uk/analysis/uvvisible/beerlambert.ac. http://en.org/wiki/Particle_size_distribution#Optical_counting_methods 20. http://www.co.co.html#top 6.html#top 5.Reference: 1.co.wikipedia.edu/courses/342/Fall2004/Melting_Point.wikipedia.pharmainfo.html 11. http://www.html#top 9.helsinki.chemguide. http://en.chemguide.chromatography-online.wikipedia. http://www. http://www. http://www. http://www.pharmainfo.wikipedia.chem.wikipedia. http://www. http://en. http://www.th/default.org/wiki/Melting_point 13.chemguide.2C_oxidation_and_photoly sis 18. http://en.org/wiki/Differential_thermal_analysis 15.edu.net/reviews/preformulation-and-quality-overall-summary- regulatory-insights 4.co. http://www. http://www.
22.wikipedia.org/wiki/Air_permeability_specific_surface 53 . http://en.
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