Preformulation

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[1].

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) [2]

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 [3].

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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

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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[1]. 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:-

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The equation for absorbance:-

The Greek letter epsilon in these equations is called the molar absorptivity - or sometimes the molar absorption coefficient[4]. 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.
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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.

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800 nm). The chart recorder Chart recorders usually plot absorbance against wavelength[5].The sample and reference cells These are small rectangular glass or quartz containers. Then a graph is plotted of that absorbance against concentration. 6 . This is a calibration curve. the greater the intensity of the light. The higher the current. The reference cell just contains the pure solvent.using the same container for each one.usually very dilute. The output might look like this: Finding concentration by plotting a calibration curve For each solution. The solvent is chosen so that it doesn't absorb any significant amount of light in the wavelength range in (200 . The detector and computer The detector converts the incoming light into a current. They are often designed so that the light beam travels a distance of 1 cm through the contents. measuring the absorbance at the wavelength of strongest absorption . The sample cell contains a solution of the substance.

absorbance is proportional to concentration. Only very small samples of the analyte are needed much less than a milligram. 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. 7 . and so a straight line is expected. but the Law breaks down for solutions of higher concentration. and so a curve might get under these circumstances[6].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. That is true as long as the solutions are dilute.

it is often used to monitor the progress of organic reactions and to check the purity of products. determining their purity and following the progress of a reaction. quick. and inexpensive procedure that gives a quick answer as to how many components are in a mixture. As the solvent rises by capillary action up through the adsorbent.Thin-layer chromatography (TLC) is a very commonly used technique in synthetic chemistry for identifying compounds. differential partitioning occurs between the components of the mixture dissolved in the solvent the stationary adsorbent phase. 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. Because of the simplicity and rapidity of TLC. 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). 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 . The more strongly a given component of a mixture is adsorbed onto the stationary phase. Thin-layer chromatography (TLC) is a chromatographic technique that is useful for separating organic compounds. TLC is a simple. the less time it will spend in the mobile phase and the more slowly it will migrate up the 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 mobile phase will carry the most soluble compounds the furthest up the TLC plate. 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 solvent is drawn up through the particles on the plate through capillary action. A small amount of a compound or mixture is applied to a starting point just above the bottom of the TLC plate. Therefore. 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. 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. the longer it will stay dissolved in the mobile phase. the more a sample's components are like the eluting solvent the 9 . The more similar the physical properties of the compound is to the mobile phase.over the solid phase. The solubility rule "like dissolves like" is followed. the further it will be pulled up through the stationary particles on the TLC plate. 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 distance a compound travels indicates that compound's physical characteristics. 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). especially functional groups. The greater the similarity to the mobile phase.

known Rf values can be compared to those of unknown substances to aid in their identifications. Reproducibility is only possible for given adsorbent of constant particle size and binder. 4. Hence. 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. Thickness of Layer: Standard plates approximately 250 µm is preferable thickness of layer. Rf value is a constant for each component only under identical experimental condition. Because of the difficulties associated with activation procedures it is far better to use plates stored at room temperature and not to activate them. The layers may be of higher or lower thickness in individual compounds. 2. volatile solvents evaporate more quickly. and Rf values generally decrease slightly. Temperature: Although precise control of temperature is not necessary. etc. It depends upon number of factors as: 1. It should made freshly for each run if one of the solvents is very volatile or hygroscopic. sources of heat. 10 . for example acetone. the tank should be kept away from draughts. The Mobile phase: The purity of solvents and quantity of solvent mixed should be strictly controlled. As the temperature is increased.closer to a value of one the Rf will be for that component. Below 200 µm the Rf values vary considerably. direct sunlight. 3. solvents run faster. Nature of Adsorbent: Different adsorbents will give different Rf valve for same solvent.

Mass of Sample: Increasing the mass of sample on the plate will often increase the Rf of a drug. However. the Rf value changes for the same solvent system. descending. horizontal etc. This is best accomplished by using small tanks with filter paper liners and sufficient solvent. either liquid or dissolved in a volatile solvent. 11 .5. 6. A well-fitting lid is essential. Chromatographic Technique: Depending upon the development technique used i. ascending. Developing Tank: It is important that saturated conditions are attained for running TLC plates. Method of Thin Layer Chromatography:Thin-layer chromatography consists of a stationary phase immobilized on a glass or plastic plate. The bottom edge of the plate is placed in a solvent reservoir. 7. 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.e. is deposited as a spot on the stationary phase. The constituents of a sample can be identified by simultaneously running standards with the unknown. and an organic solvent. The separated spots are visualized with ultraviolet light or by placing the plate in iodine vapor. The sample. The two situations are normally easy to distinguish by the intensity of the spot. When the solvent front reaches the other edge of the stationary phase. and the solvent moves up the plate by capillary action. if a plate is grossly overloaded. this too will give a tailing spot and will have the effect of apparently decreasing the Rf value. especially if it normally tails in the system. and by leaving the tank to equilibrate for at least 30 minutes before running the plates. the plate is removed from the solvent reservoir.

12 . polycyclic compounds in drinking water. diagnosis of metabolic disorders such as PKU (phenylketonuria). 4. Pharmaceuticals and Drugs: Identification. purity testing and determination of the concentration of active ingredients. compliance with limit values (e. Food Analysis: Determination of pesticides and fungicides in drinking water. fatty acids. cystinuria and maple syrup disease in babies. preservatives. Forensic Chemistry and Biochemistry: Determination of active substances and their metabolites in biological matrices. banned additives in Germany (e.g.g. aflatoxins in milk and milk products). vitamins in soft drinks and margarine. surfactants. residues in vegetables. sandalwood extract in fish and meat products). 2. process control in synthetic manufacturing processes. constituents of perfumes. 3. salads and meat. Cosmetology: Dye raw materials and end products. Clinical Chemistry. auxiliary substances and preservatives in drugs and drug preparations.Applications and Importance of Thin Layer Chromatography:1.

5. The column and the solvent Confusingly. This allows a much better separation of the components of the mixture. Other Areas: Electrolytic technology (meta-nitrobenzoic acid in nickel plating baths) [7]. 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. determination of pollutants from abandoned armaments in soils and surface waters. there are two variants in use in HPLC depending on the relative polarity of the solvent and the stationary phase. These methods are highly automated and extremely sensitive. 2. Instead of a solvent being allowed to drip through a column under gravity. That makes it much faster. 7. Environmental Analysis: Groundwater analysis. The other major improvement over column chromatography concerns the detection methods which can be used. it isn't the most commonly used form of HPLC. it is forced through under high pressures of up to 400 atmospheres. 13 . Analysis of Inorganic Substances: Determination of inorganic ions (metals). Normal phase HPLC Although it is described as "normal". High Performance Liquid Chromatography (HPLC):High performance liquid chromatography is basically a highly improved form of column chromatography. 6. decomposition products from azo dyes used in textiles.

Reversed phase HPLC is the most commonly used form of HPLC. the column size is the same.hexane. In this case.for example. The non-polar ones will therefore pass more quickly through the column. 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.The column is filled with tiny silica particles. and the solvent is non-polar . 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. 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. 14 .6 mm (and may be less than that). for example. and a length of 150 to 250 mm. Polar compounds in the mixture being passed through the column will stick longer to the polar silica than non-polar compounds will. Reversed phase HPLC In this case. a mixture of water and an alcohol such as methanol. That means that now it is the polar molecules that will travel through the column more quickly. but the silica is modified to make it non-polar by attaching long hydrocarbon chains to its surface . They therefore spend less time in solution in the solvent and this will slow them down on their way through the column. for example. A polar solvent is used .typically with either 8 or 18 carbon atoms in them. Non-polar compounds in the mixture will tend to form attractions with the hydrocarbon groups because of Van Der Waals dispersion forces. Polar molecules in the mixture will therefore spend most of their time moving with the solvent.

but also particle size)   the exact composition of the solvent the temperature of the column 15 . Because of the pressures involved. 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.Procedure: Injection of the sample Injection of the sample is entirely automated. Retention time The time taken for a particular compound to travel through the column to the detector is known as its retention time. 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. it is not the same as in gas chromatography. For a particular compound. Different compounds have different retention times.

Different compounds absorb most strongly in different parts of the UV spectrum.The detector There are several ways of detecting when a substance has passed through the column. As long as careful to control the conditions on the column. and a UV detector on the opposite side of the stream. absorbs at wavelengths below 205 nm. therefore have to use a wavelength greater than 205 nm to avoid false readings from the solvent.provided. The solvents used don't absorb UV light. If using a methanol-water mixture as the solvent. If a beam of UV light shining through the stream of liquid coming out of the column. and water below 190 nm. 16 .each one representing a compound in the mixture passing through the detector and absorbing UV light. a direct reading of how much of the light is absorbed will get. The amount of light absorbed will depend on the amount of a particular compound that is passing through the beam at the time. Interpreting the output from the detector The output will be recorded as a series of peaks . of course. Methanol. A common method which is easy to explain uses ultra-violet absorption. the retention times can be used to help to identify the compounds present . for example. that had already measured for pure samples of the various compounds under those identical conditions[8]. Many organic compounds absorb UV light of various wavelengths.

This is useful for separating complex mixtures of similar compounds.  Environmental  Biomonitoring of pollutents. for example. Two-way paper chromatography. especially pigments.  Complex molecules separation.  Identification of counterfeit drug products.Applications of HPLC  Pharmaceutical / Biopharmaceutical  Pharmaceutical quality control. 17 .  Water monitoring . involves using two solvents and rotating the paper 90° in between.  Clinical  Analysis of antibiotics and blood substances.Phenol content and toxic componants checking.  Shelf-life determinations of pharmaceutical products. Paper Chromatography (PC):Paper chromatography is an analytical chemistry technique for separating and identifying mixtures that are or can be coloured. This can also be used in secondary or primary colours in ink experiments. amino acids.  Food and Flavor  Sugar analysis in fruit juices.  Detection of endogenous neuropeptides in brain extracellular fluids. This method has been largely replaced by thin layer chromatography. 3. however it is still a powerful teaching tool. also called two-dimensional chromatography.  Ensuring soft drink consistency and quality.

also this can be explained as differential adsorption of the solute components into the solvent. The more soluble the component the further it goes. The paper is then dipped in to a suitable solvent. Different compounds in the sample mixture travel at different rates due to differences in solubility in the solvent. usually using a capillary tube for maximum precision. which occurs as a result of the attraction of the solvent molecules to the paper. and placed in a sealed container. In some cases. 18 . This sample is absorbed onto the paper and may form interactions with it. paper chromatography does not separate pigments completely.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. and due to differences in their attraction to the fibres in the paper. which will then travel up the paper with the solvent solute sample. Any substance that reacts or bonds with the paper cannot be measured using this technique. two-way chromatography is used to separate the multiple-pigment spots. taking care that the spot is above the surface of the solvent. such as ethanol or water. The solvent moves up the paper by capillary action. In these cases. this occurs when two substances appear to have the same values in a particular solvent. As the solvent rises through the paper it meets and dissolves the sample mixture. Paper chromatography takes anywhere from several minutes to several hours.

It rises up the paper by capillary action against the force of gravity. 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. the flow is more rapid as compared to the ascending method. In this case. Because of this rapid speed. the solvent is in pool at the bottom of the vessel in which the paper is supported. The developing solvent is placed in a trough at the top which is usually made up of an inert material. can sometimes be separated by the above descending method[9]. the chromatography is completed in a comparatively shorter time. The liquid moves down by capillary action as well as by the gravitational force. 19 . 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. 4. 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[10]. the solvent is kept in a trough at the top of the chamber and is allowed to flow down the paper. The paper is then suspended in the solvent. Descending Chromatography In this method.Ascending Chromatography In this method. Substances that cannot be separated by ascending method. The apparatus needed for this case is more sophisticated.

How the column works The packing material There are two main types of column in gas-liquid chromatography. 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. The syringe needle passes through a thick rubber disc (known as a septum) which reseals itself again when the syringe is pulled out. 20 . the other is even thinner and has the stationary phase bonded to its inner surface. The injector is contained in an oven whose temperature can be controlled.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. One of these is a long thin tube packed with the stationary phase. 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). It is coiled up so that it will fit into a thermostatically controlled oven.

the less soluble ones will spend more of their time in the gas. This is coated with a high boiling liquid . Similarly. 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. The more soluble ones will spend more of their time absorbed into the stationary phase. Some compounds will be more soluble in the liquid than others. the column starts off at a low temperature and then is made steadily hotter under computer control as the analysis proceeds. It may dissolve in the liquid on the surface of the stationary phase. 21 . some molecules may dissolve in the liquid stationary phase. A compound with a boiling point higher than the temperature of the column will obviously tend to condense at the start of the column. which is a very porous rock. as you will see below. The chances are that it will then condense again a little further along the column. The column temperature The temperature of the column can be varied from about 50°C to 250°C. It may remain in the gas phase. None of these things is necessarily permanent.The column is packed with finely ground diatomaceous earth. It is cooler than the injector oven. However. In some cases. so that some components of the mixture may condense at the beginning of the column. some of it will evaporate again in the same way that water evaporates on a warm day .even though the temperature is well below 100°C.typically a waxy polymer.

and then gradually and very regularly increase the temperature. The answer is to start with the column relatively cool. A higher temperature will tend to excite molecules into the gas phase . the better the separation . High solubility in the liquid phase means a high retention time.  The temperature of the column. So high boiling point means a long retention time.either because they evaporate more readily. The lower the temperature of the column. A high column temperature shortens retention times for everything in the column. Retention time The time taken for a particular compound to travel through the column to the detector is known as its retention time. or because they are so energetic that the attractions of the liquid no longer hold them.but less well separated out.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. For a particular compound. everything will pass through the column much more quickly . 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. the less time it will spend being carried along by the gas. 22 . there isn't going to be much space between their peaks on the chromatogram. the retention time will vary depending on:  The boiling point of the compound. If everything passed through in a very short time.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. The more soluble a compound is in the liquid phase. using a high temperature. Different compounds have different retention times. Any molecule in the substance spends some of its time dissolved in the liquid and some of its time carried along with the gas.  The solubility 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.

Increasing the temperature a bit will encourage the slightly "stickier" compounds through. 23 . The detector There are several different types of detector in use. A flame ionisation detector In terms of reaction mechanisms. small amounts of ions and electrons are produced in the flame. During the process. compounds which spend most of their time in the gas phase will pass quickly through the column and be detected. The whole detector is enclosed in its own oven which is hotter than the column temperature. The presence of these can be detected. That stops anything condensing in the detector. the burning of an organic compound is very complicated. The flame ionisation detector described below is commonly used and is easier to describe and explain than the alternatives.At the beginning. Increasing the temperature still more will force the very "sticky" molecules off the stationary phase and through the column.

Thermal Analysis:  Melting Point: The melting point of a solid is the temperature range at which it changes state from solid to liquid. of course.each one representing a compound in the mixture passing through the detector. At the melting point the solid and liquid phase exist in equilibrium[12]. that had already measured them for pure samples of the various compounds under those identical conditions[11]. 5. As long as careful to control the conditions on the column.  Differential Scanning Calorimetry (DSC): 24 .Interpreting the output from the detector The output will be recorded as a series of peaks .provided. could use the retention times to help to identify the compounds present .

melting and sublimation. In DTA. The main application of DSC is in studying phase transitions. or exothermic decompositions. such as glass transitions. glass transitions. The area under a DTA peak is the enthalpy change and is not affected by the heat capacity of the sample[14]. such as melting. can be detected relative to the inert reference. The reference sample should have a well-defined heat capacity over the range of temperatures to be scanned. Changes in the sample. or against temperature (DTA curve or thermogram). the material under study and an inert reference are made to undergo identical thermal cycles. the temperature program for a DSC analysis is designed such that the sample holder temperature increases linearly as a function of time. either exothermic or endothermic.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. Both the sample and reference are maintained at nearly the same temperature throughout the experiment. crystallization. a DTA curve provides data on the transformations that have occurred. while recording any temperature difference between sample and reference.  Differential Thermal Analysis (DTA): Differential thermal analysis (or DTA) is a thermoanalytic technique. These transitions involve energy changes or heat capacity changes that can be detected by DSC with great sensitivity[13]. similar to differential scanning calorimetry. Thus. Generally.[1] This differential temperature is then plotted against time. Solubility Determination:- 25 .

obtained by stirring an excess of material in the solvent for a prolonged until equilibrium achieved.The solubility of drug is an important physicochemical property because it effects the bioavailabilty of the drug. The solubility of the molecules in various solvents is determined as a first step. 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. This information is valuable is developing a formulation. The solubility of material is usually determined by the equilibrium solubility method. 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 rate of drug resale into dissolution medium and consequently. the therapeutic efficiency of the pharmaceutical product. which employs a saturated solution of the material. 26 . Solubility is usually determined in variety of commonly used solvents and some oils if the molecules is lipophillic.

The minimum density of water occurs at 4°C. An increase in acidic and alkaline solubility suggest either impotence or zuitter ion behaviour. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. 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. the fundamental solubility when completely unionized. The Henderson – Hasseslebach equation provides an estimate of the ionized and un ionized durg concentration at a particular pH. In this case there will be two pKa‟s.e. This leads to a minimum aqueous solubility. cab be altered by orders of magnitude with changing pH. 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. The solubility should ideally be measured at two temperature.) i. one acidic & one basic . 1) 4°C to ensure physical stability and entered short term storage and chemical stability unit more definitive data are available.Intensic Solubility (Co) :An increase in solubility in acid compared to aqueous solubility suggests a weak base and an increase in alkali. a weak acid. 2) 37°C to support biopharmaceutral evaluation. 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. 27 . P o/w = (C oil / C water) equilibrium.

the partition coefficient can provide an empiric handle in screening for some biologic properties. Although partition coefficient data alone does not provide understanding of in vivo absorption. The rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. independently of the drug and dosage forms position within the GI ireat. the lipophilic/ hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption. For drug delivery. pKa and solubility on absorption must not be neglected. V is the kinemative viscosity 28 . Since biological membranes are lipoidal in nature. Although it appears that the partition coefficient may be the best predictor of absorption rate. 7 no bioavailability or distinction related problems were to be expected. it does provide a means of characterizing the lipophilic/ hydrophilic nature of the drug. Dissolution :The dissolution rate of the drug is only important where it is the rate limiting step in the absorption process. whereas those with partition coefficient much less than 1 are indicative of a hydrophilic drug. the effect id dissolution rate. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water.For series of compounds. Drugs having values if P much greater than 1 are classified as lipophilic. 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. Kaplan suggested that provided the solubility of a drug exceded to mg/ ml at pH.62 D2/3 v 1/6 w1/2 Where.

29 . 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. In contrast to the volume change that accompanies the vaporization of a liquid. benzoate.W is the anguter velocity of a rotating disc of drug. unlike the boiling point of a liquid. The „selling out‟ results from the removal of water molecules as solvent owing to the completing hydration of other ions. Common Ion Effect :A common ion significantly reduces. 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[1].g. The reverse process „salting in‟ qries with large anions e. the solubility of a slightly soluble electrolyte. Since the melting point of a solid can be easily and accurately determined with small amounts of material. salivate which open the water structure. practically independent of any ordinary pressure change. the change in volume that takes place upon the melting of a solid is very small. These hydro topics increase the solubility of properly water soluble compounds such as diazepam. This makes the melting point of a solid. it is the physical property that has most often been used for the identification and characterization of solids.

If filing does not work. determine a preliminary melting point determination by allowing the temperature of the sample to rise quickly. The transfer of heat energy by conduction takes place rather slowly. The temperature range over which the sample is observed to melt is taken as the melting point. or the iron base of a ring stand. Filling a Capillary Tube Usually. are most often used for the determination of the melting point of a solid. The thermometer and sample must be at the same temperature while the sample melts.Capillary Melting :Capillary melting gives information about the melting range but it is different to assign an accurate melting point. and a thermometer are then suspended so they can be heated slowly and evenly. A few crystals of the compound are placed in a thinwalled capillary tube 10-15 cm long. down a length of glass tubing about 1 cm in diameter (or a long condenser) onto a hard surface such as a porcelain sink. stone desk top. If the approximate temperature at which the sample will melt is not known. 30 . drop the tube. the melting point capillary can be filled by pressing the open end into a small heap of the crystals of the substance. either in an oil bath or a melting-point apparatus. turning the capillary open end up. open end up. about 1 mm in inside diameter. The capillary. The solid should be tightly packed to a depth of 2-3 mm. the temperature of the thermometer bulb and the temperature of the crystals in the capillary may not be the same. Then carry out a more accurate determination. so the rate of heating must be slow as the melting point is approached (about 1 degree per minute). Capillary melting points. Otherwise. with a low rate of heating near the melting point. and closed at one end. which contains the sample. and vibrating it by drawing a file across the side to rattle the crystals down into the bottom.

The simplest use a burner flame and depend upon convection for mixing. 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). It is easy to heat at a low and steady rate with an electric heater. but almost impossible with a flame. the more elaborate and accurate use an electric immersion heater and are stirred. When an oil bath is used. as well as in a boiling point determination. 31 . Hot Stage Microcopy :This the issued observation of melting under a microscope equipped with a heated and lagged sample stage. The heating rate is controllable and upto three transitions can be registered.A variety of oil baths can be used in a melting point determination.

This method requires as little as a single crystal and it is very convenient. the higher the melting point. 32 . Complete thermal equilibrium between the sample. hot stage melting points are inherently too high. block.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. Unfortunately. For this reason. However. and thermometer is not possible. 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. exposed to the cooler atmosphere. observed block melting points often appear to be higher than capillary melting points. the greater the difference. it measures the enthalpy of transition. a melting point quickly determined on a block can serve as an approximate melting point for the determination of a capillary melting point[15]. since the thermometer is inside the block and the sample is on the surface.e.

Some investigation of 33 . For drugs pane to degradation in the solid state. When the absorption of a drug is dissolution rate limited. x-ray diffraction patterns and solubility even though they are chemically identical. Different polymorph also lead to different morphology. Differences in the dissolution rates and solubilities of different polymorphic forms of a given drug are very commonly observed. tensile strength and density of power bed which all contribute of compression characteristics of materials. a more soluble and faster-dissolving from may be utilized to improve the rate and extent of bioavailability. Polymorphs generally have diffrent melting points. This property is known as polymorphism. physical form of the drug influences degradation. Selection of a polymorph that is chemically more stable is a solution in many cases.Crystal Properties and Polymorphism :Many drug substances can exit in more than one crystalline from with different space lattice arrangements.

thermal analysis. the lowest solubility. 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. and the maximum chemical stability. formulation. Although a drug substance may exist in two or more polymorphic forms. and dilalometry. These include microscopy (including hot stage microcopy). only one form is theromdynamically stable at a given temperature and pressure. In general. 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. infrared spectrophotometry. pH and dosage form diluents. Buffer 34 . and administration of a drug candidate as well as stability in presence of other recipients.g. The method of sterilization of potential product will be largely dependent on the temperature stability of the drug. e. Various techniques are available for the investigation of the solid state.. 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 . single-crystal x-ray and x-ray power diffraction. filtration.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. storage. Factor effecting chemical stability critical in rational dosage form design include temperature. These studies include both solution and solid state experiments under condition typical for the handing.

Chemical structure of the drug is the determination of drug to either of these attacks. 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. Esters and lactase and to lesser extent. oxidation. photolysis and pyrolysis. If a substantial change is seen. Elevated temperature studies:The elevated temperatures commonly used are 40. and 60 degree centigrade with ambient humidity. Denser materials are more stable to ambient stress. physical properties of drugs.hydrolysis. 50. The samples stored at highest temperature are observed weekly for physical and chemical changes and compared to an appropriate control . . Amorphous materials are less stable than their crystalline forms. If no changesisseen after 30 days at 60 degree centigrade. samples stored at lower temperature are examined . Instauration or electron rich centre in the structure make the molecule vulnerable for free radical mediated or photo-catalysed oxidation. the stability prognosis is excellent .Typical stability protocol for anew Chemical Entity Solid state stability:Chemical instability normally results from either of the following reaction :. amides are to prone to solvolysis. 35 .Solution phase stability .selection for potential dosage forms will be largely based on the stability characteristic of the drug. 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.Solid state stability .Compatibility studies : stability in the Presence of excipients . The closed desiccators in turn are kept in oven to provide constant temperature.

A poor solution stability of drug may 36 . A shallow layer of drug exposed to a sufficient headspace volume ensures that the system is not oxygen limited. It is important ascertain that the drug doesn‟t degrade when exposed to GI fluid. 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 . Samples are kept in desiccators equipped with three-way stop cocks. Solution phase stability: As compared with the dry form. it presentsanaesthetic problem. Mixtures should be examined under nitrogen to ultimate oxidation and paralytic effect at a standard heating rate on DSC.Photolytic stability :Many drugs fade or dorpen on exposure light. the degradation is much rapid in solution form. Usually a 40% oxygen atmosphere allows for rapid evaluation. Though the extent of degradations small and limited to the exposed surface area. using different stimulator GI condition can be designed. 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. Compatibility studies :The knowledge of drug excipients interaction is useful for the formulation to select appropriate excipients. 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 . The pH based stability study. 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. 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. over a temperature range. The process is repeated 3 or 4 times to ensure 100% desired atmosphere. Stability to Oxidation :Drug‟s sensitivity to oxidation can be examined by exposing it to atmosphere of high oxygen tension. which are alternatively evacuated and flooded with desired atmosphere.

pH pH of solution influences the percentage ionization of drug owing to its pKa. thio-halides. Hydrolysis or Solvolysis Hydrolysis is one of the most frequently encountered type of chemical reaction responsible for drug decomposition processes. This can be partially explained by the fact that the redox potential for many reactions depends on pH. halides. Look at the following example 37 . Hydrolytic decomposition can be avoided or slowed down by using an insoluble form of drugs. imines. lactose. Partial in vivo and in vitro test are designed to study pharmacokinetic profile of the drug[1]. On the other hand. Weak acids will be the most soluble in solutions with a pH at least two units above their pKa (>99% ionized form). lactams. pH can also influence the rate of oxidation. ureides. amides. esters. so the buffer system are used to maintain a certain pH in some drug products[16]. usually at different rates. weak bases at two or more pH units below their pKas will be the most soluble. many drugs are stable in a limit pH range. Furthermore. The following types of compounds undergo hydrolytic degradation. Precipitation of drug should be aware according to pH change. In addition.urge the formulator to choose a less soluble salt form. nitriles. 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. stability of drug solution can be increased by the use of suitable buffers. thio-esters.

if a large caffeine molecule is attached to a benzocaine molecule by complexation.through steric hindrance and thus reduces the rate of hydrolysis. 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. So we understand that pH is of extreme importance both in the case of hydrolysis and oxidation. Lachman et. For example. Complexation Complex formation reduces the rate of hydrolysis and oxidation. Complex formation affects decomposition in two ways. Another effect is there for the complexing agent. it will reduce the movement rate as well as ease of movement. Participating in change from oxidation form to reduction form. Since the drugs that are undergoing oxidative decomposition are usually in the reduced stage. (1) steric and (2) polar. This equation helps us to understand that an increase in the concentration of hydrogen ion causes an increase in the value of E.Using the Nernst equation When Eo is the standard potential E is the actual potential 1 is the number of electrons. So complexation reduces the ease of encounter of the ester with various catalytic species such as H+ and OH.06 calculated approximate constant. 0. So the reduced form of the system is less readily oxidized when the pH is low. al have shown that caffeine complexes with local 38 . minimum decomposition or maximum stability is usually found in the pH range of 3 to 4.

Shape and Surface Area:Bulk flow. The hydrolytic groups such as OH cannot penetrate this micelle cover and reach the drug particles. Surfactants Nonionic. 39 . Chelating agents also complex with trace metals that enhance oxidative degradation and apply brakes to that process. iron. Particle Size. with a suitable oxidation – reduction potential between them such as copper. especially those possessing two or more valency states. cationic and anionic surfactants when added to solutions containing drugs form micelle and the drug particles become trapped in the micelle. cobalt and nickel generally catalyze oxidative degradations. and surface-area controlled processes such as dissolution and Surface morphology of the drug particles.1% disodium salt of ethylenediamine tetracetic acid at different buffer concentrations. such as benzocaine. Presence of heavy metals Heavy metals. They found that the solutions not containing any chelating agent decomposed more rapidly as the buffer concentration increased. In general. 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. These metals increase the rate of formation of free radicals and enhance oxidative decomposition[17]. formulation homogeneity. procaine and tetracaime to cause a reduction in their rate of hydrolytic degradation.anesthetics. hence hydrolysis rate is decreased. Scientists studied the oxidative decomposition with and without 0. The buffered solutions containing chelating agent showed that the rate of degradation was independent of the concentration of the buffer.

In case of tablets. Apparatus: 40 . size and its distribution of powdered pharmaceutical drugs and excipients to examine their micromeritic properties. This method can generally be applied to particles in the size range between 0.Various chemical and physical properties of drug substances are affected by their particle size distribution and shapes.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. It is generally recognized that poorly soluble drugs showing a dissolution. on their biopharmaceutical behavior. the humidity.5 and 100µm. The effect is not only on the physical properties of solid drugs but also. size and shape influence the flow and the mixing efficiency of powders and granules. Classical methods for measuring particle size: 1. Size can also be a factor in stability: fine materials are relatively more open to attack from atmospheric oxygen. Microscopy 2. Sieving or screening 3. and interacting axcipients than are coarse materials.Determination of particle size -Determination of surface area[1] Particle size Determination:Powder particle size determination is a method to determine directly or indirectly morphological appearance. in order to measure the particle size. shape. . 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. in some instances.

and microscope base to support all these sections. Preparation of test specimen: After the preprocessing. and this is used as the test specimen. diaphragm and condenser) making the path for the enlarged image of the sample through the objective and ocular. One drop of the suspension is placed on a slide glass and used as the test specimen directly. or used after drying. reflecting mirror. the distance between the scales of the two micrometers is determined. there is usually a built in optical system ( light source. 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. a stage for holding the test specimen. Then. b. In addition. Wet methodThe sample material is suspended in an appropriate liquid which does not dissolve the sample. and a calibrated stage micrometer is placed at the center of the microscope stage and fixed in place. The ocular is attached to the lens barrel and adjusted to the focus point of the stage micrometer scale. Procedure: When the particle size is measured.An optical microscope consists of a lens barrel that houses the optical system consisting of the objective and the ocular. little by little. 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 . the test specimen is prepared with the following methodsa. an ocular micrometer is inserted at the position of the ocular diaphragm. a mirror stand and column to support the illumination system. Dry methodThe sample material is sprinkled on to the slide glass.

Balance 3. the particle sizes are determined from the number of scale divisions read through the ocular. this method is to evaluate the twodimensional size of the samples. Electromagnet-type sieve shaker 42 .The stage micrometer is removed and the test specimen is placed on the microscope stage. Sieving method : The analytical sieving method is a method to estimate the particle size distribution of powdered pharmaceutical drugs by sieving. which is usually applicable to powdered materials having a particle size of more than about 75 µm. Essentially. Apparatus: 1. Sieve 2. After adjusting the focus.

place the sample on the top sieve.taking into consideration of the physicochemical characteristics such as hygroscopicityor static electricity.select sieves which cover the entire particle size range of the sample to be tasted. 2.then weigh each sieve and the collecting pan.depending on the properties of the sample: 1.and combine it with the sieve fraction retained on each next down sieve.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. the total loss. Drying agglomerated samples owing to their hygroscopicity under a condition which does not change the essential qualities of the sample.Agitate the nest of sieves for the time period previously obtained by the end point determination and then remove each sieve from the nest. and fix the nest of sieves on a mechanical shaker. Unless otherwise specified. Determine the mass of material on each sieve and in the collecting pan by the following equation to obtain the particle size distribution.Pretreatment of sample: The following traetments may be performed. must not exceed 2% of the mass of the original test specimen. 3. take it off by the brush gently. 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. Amount of the material on each sieve (%) = Wi ×100 WT 43 . 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. replace the lid. Procedure: Usually this method is proceeded under the controlled temperature and humidity conditions.

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.Wi: Mass of the material on each sieve (g) WT: Total mass of the material on each sieve and in the collecting pan (g)[18]. Knowing the monolayer capacity of adsorbent and the area of absorbale molecule. Most substances adsorb a mono molecular layer of gas under certain conditions of partial pressure of gas and temperature. Surface Area Determination:Surface area is most commonly determined based on brunaver emette teller (BET) theory of adsorption. From the BET theory of adsorption. Sedimentation method: These are based upon study of the terminal velocity acquired by particles suspended in a viscous liquid. it was possible to calculate the surface area of the adsorbent[20]. The isotherms that display the behavior of N2 upon these compounds are represented as are the pertinent results that can calculated from them. Sedimentation time is longest for the finest particles. then measures the optical density of successive layers using visible light or x-rays[19]. 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). 44 . The adsorption takes place by virtue of vander wall‟s forces[1].  Adsorption method: The process of adsorption and desorption is studied on the compounds of alumina and silica during this experiment. Typical apparatus diperses the sample in liquid.

“BET” consists of the first initials of their family names. which is a theory for monolayer molecular adsorption. In 1938. 45 . c is the BET constant. (b) there is no interaction between each adsorption layer. v is the adsorbed gas quantity (for example. which is expressed by (2): E1 is the heat of adsorption for the first layer. Stephen Brunauer. and (c) the Langmuir theory can be applied to each layer.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. 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. and EL is that for the second and higher layers and is equal to the heat of liquefaction. in volume units). The concept of the theory is an extension of the Langmuir theory. and vm is the monolayer adsorbed gas quantity. to multilayer adsorption with the following hypotheses: (a) gas molecules physically adsorb on a solid in layers infinitely. and Edward Teller published an article about the BET theory in a journal for the first time. Paul Hugh Emmett.

This plot is called a BET plot.05 < P / P0 < 0.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 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. 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[21]. A total surface area Stotal and a specific surface area S are evaluated by the following equations: 46 .35. The linear relationship of this equation is maintained only in the range of 0.

Different values corresponding to this are probably due to the effects previously mentioned. s: adsorption cross section. The path of the desorption isotherm may be different from that of the adsorption isotherm. However. The reason for their adsorbing characteristics are their enormous surface area per unit weight. Method: The measurements were taken from combinations of the ideal gas laws and by variations in calculated values. When the surface of the adsorbent is saturated by the adsorbate. An instrument known as the Omnisorb 360 was used for the experiment. a decrease in adsorbence will be observed. Two of these compounds are used in the experiment. The measurement of adsorption is usually carried out at a constant temperature (77K for this experiment). The opposite process is called desorption. The gas generally used for this is Nitrogen. molecules of the adsorbate are binded to the surface whereas in absorption. Although. This 47 . This may be due to hystersis effects. This is due to the limited number of surface sites available for chemisorption. and activated charcoal. argon and krypton are used in special cases.N: Avogadro's number. The sample must be saturated with the gas before an accurate desorption isotherm can be constructed. 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. Some of the best known and classic adsorbents are silica. This process of binding is generally weak and reversible (as seen in immediate desorption). The area of the adsorbent can be calculated from the isotherms. The process of adsorption should be set apart from the process of absorption. the their just filling the spaces of the pores in the solid. In adsorption. alumina. adsorption could occur beyond the initial monolayer of adsorbate according to BET theory.

The gas He was used during volume determinations because it is not adsorbed at this temperature.instrument consists of vacuum pumps and "plumbing" along with the sample containers. the difference from expected values were due to the gas being desorbed[20]. Some of the gas was adsorbed by the sample. The variations upon the gas expansions were due to either adsorption or desorption which ever was relevant. Gas expansions throughout the "plumbing" and sample containers as well as a known flask gave the needed volumes of each necessary component.  Air permeability method: 48 . the gas from the sample container was expanded into the manifold. The manifold of the Omnisorb was filled with a certain pressure of N2 and expanded into the sample container. In the desorption runs. desorption runs could take place. As before. After the sample was saturated with the gas.

The resulting flow-rate of air through the bed yields the specific surface by the Kozeny–Carman equation: where: S is specific surface. Methods Measurement consists of packing the powder into a cylindrical "bed" having a known porosity (i. 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. m3·s-1 49 . m η is the air dynamic viscosity. The SI units are m2·kg-1 ("mass specific surface") or m2·m-3 ("volume specific surface"). kg·m-3 ε is the volume porosity of the bed (dimensionless) δP is the pressure drop across the bed. m ρ is the sample particle density. A pressure drop is set up along the length of the bed cylinder.e. Pa l is the cylinder length. Significance When a powder reacts chemically with a liquid or gas at the surface of its particles. the specific surface is directly related to its rate of reaction. Pa·s Q is the flowrate.The air permeability specific surface of a powder material is a single-parameter measurement of the fineness of the powder. The measurement is therefore important in the manufacture of many processed materials. m2·kg-1 d is the cylinder diameter. The specific surface is derived from the resistance to flow of air (or some other gas) through a porous bed of the powder. volume of air-space between particles divided by total bed volume).

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. 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 . 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. 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.It can be seen that the specific surface is proportional to the square root of the ratio of pressure to flow. and measure the flowrate Allow both to vary. Changes in particles size. Various standard methods have been proposed:    Maintain a constant flowrate. deriving the ratio from the characteristics of the apparatus[22].

In parallel solid-state stability by DSC.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. By comparing the physicochemical properties of each drug candidate with in a therapeutic group. 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. The need for adequate drug solubility can not be overemphasized. Stability studies in solution will indicate the feasibility of parental or other liquid dosage form and can identify methods of stabilization. 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. The most appropriate salt for development. angle of repose. Relationship between flow. 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[1]. 51 .

uk/analysis/uvvisible/analysis.html#top 9.org/wiki/Differential_scanning_calorimetry 14.wikipedia.wikipedia.org/wiki/Paper_chromatography#Technique 10. http://www.pdf 16.chem.pharmtech. http://en. http://en.co.html 11. http://www.html#top 5.chem.chemguide.pharmainfo.org/topics/gas/chromatography.uk/analysis/chromatography/gas.helsinki.org/wiki/Particle_size_distribution#Optical_counting_methods 20.edu. http://www.chromatography-online.net/reviews/preformulation-and-quality-overall-summary- regulatory-insights 4. http://www. http://www.cn/yaodian/jp/14data/General_Test/Powder_Particle_Size_Determ. http://www. http://www.p df 19.com/Stability_Of_Drugs:Factors_Affecting_Rates_Of_Hydrolysi s_And_Oxidation#Stabilization_of_drugs_against_hydrolysis.pharmpedia.wikipedia.njutcm.html#top 6. http://en.co.co. http://en.wikipedia. http://www.wikipedia.ac.co. http://en.Reference: 1.hcu.chemguide.net/pharma-student-magazine/application-and-importance-thin- layer-chromatography-analysis-and-research--0 8.org/wiki/Differential_thermal_analysis 15.uk/analysis/uvvisible/beerlambert.wisc.uk/analysis/uvvisible/spectrometer.ufl.org/wiki/BET_theory 52 . http://www.chemguide.edu/courses/342/Fall2004/Melting_Point.edu/~itl/4411L_f00/ads/sample/knight.html#top 7.wikipedia.pharmainfo.co. http://www.org/wiki/Melting_point 13.pharmainfo. http://www.chemguide.uk/analysis/chromatography/hplc.pdf 3. http://lib.th/default. http://pharmacy.html#top 12.chemguide.net/rajeev-garg/publications/preformulation-a-need-dosage-form- design 2.2C_oxidation_and_photoly sis 18.fi/kurssit/590082/preformulointi_I_tn. http://www. http://www.asp?bigtitle=Wicharn%20Junwitayanuchit&middletitle =Physicochemical%20Factors%20Involving%20Drug%20Incompatibilities&content=pa perwicharn 17.html 21. http://en.

22. http://en.wikipedia.org/wiki/Air_permeability_specific_surface 53 .