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Published by: Prabha Singh on Feb 28, 2011
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Definition: Tablets are solid preparations consisting of one or more active ingredient obtained by compressing uniform volumes of particles into various shapes and sizes. 
official tablets are defined as circular discs with either flat or convex faces 

intended for oral administration  used mainly for systemic drug delivery but also local action  active ingredients + excipients  some tablets are ----- swallowed whole after being chewed dissolved or dispersed in water retained in the mouth where drug is liberated.

mechanical & biological) Lightest and most compact Formulation aspects Greatest dose precision with least content variability Lend to give special release profile products e. 2. 4.  1.g. enteric or delayed release tablets Product identification is cheap ± embossing or monogrammed punch face Patient aspects Ease of handling Coating can mark unpleasant tastes & improve patient acceptability 3.  1.ADVANTAGES  1. . Production aspects Large scale production at lowest cost Easiest and cheapest to package and ship High stability (chemical. 2. 3. 2.

DISAVDANTAGES  Some drugs resist compression into dense compacts  Drugs with poor wetting. drugs with an objectionable odor. intermediate to large dosages may be difficult or impossible to formulate and manufacture as a tablet that provides adequate or full drug bioavailability Bitter taste drugs. slow dissolution. or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating  .

 Statistical optimization can be carried out.  . ing compression pressure or punch dwell time or using precompression must not have negative impact on other set of objectives (disintegration time.Preformulation Aspects Tablets are one of the most challenging of all pharmaceutical products to design and manufacture. Therefore. drug dissolution rate & bioavailability)  A satisfactory compromise between competing set of objectives may be simple or extremely complex.  The focus is to see that action taken to improve one objective should not cause another objective to degrade For eg. steps taken to achieve the first set of objectives (using binder or adhesive. good appearance. powdering or chipping during handling. surface gloss and also be cohesive and compact so as not to undergo friability.  Poor wetting or slow dissolution or good cohesive compacts of amorphous or flocculent drugs may result in low bioavailability. Tablets should have smooth surface.

appearance and odor Physicochemical properties: solubility and pH profile of solution/dispersion (water. pure drug pellet. effect of excipients and surfactants Step 2. b. dialysis of drug. compressibility. taste. solvents) In vitro dissolution: pure drug. c. e. temperature. Stability (solid state): light. i. humidity Stability (solution): drug-excipient stability (DSC or accelerated ss) Physicomechanical studies: particle size. Identifying the excipients most suited for a prototype formulation of drug (checking drug ± excipients compatibility) ii. Complete preformulation data regarding the physicochemical characteristics of the drug like a. MP. d. Tablet production design requires 2 major activities.Step 1. Optimizing the levels of those excipients . color. absorbability. bulk and tap density.

shape. texture. size.Medical    Desired release profile Dissolution is the rate limiting step Targeting drug delivery Marketing Appearance: colour. coating and embossing .

energy and time) Experimental approach Analysis of variance (ANOVA)  Statistical screening design Plackett Burman (levels) Extreme vertices  .Economics   Cost of excipients Type of process (labor.

pharmaceutical dosage forms volume 1 .88.Bioavailability studies Stability data Validation data Pg 77.

The nature of information. Therapeutic category and anticipated dose of compound.Preformulation involves the application of biopharmaceutical principles to the physicochemical parameters of drug substance are characterized with the goal of designing optimum drug delivery system. . a formulation should have or would like to have. 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.

hygroscopicity & stability Vehicles & Extraction Lipophillicity. pH Oxidation. TLC Method/ function Characterization .Preformulation drug characterization in a structured program Test Fundamental 1) UV spectroscopy 2) Solubility a) Aqueous b) pKa c) Salt d)Solvents e) ko/ w f) Dissolution 3) Melting point 4) Assay development 5) Stability In Solution In solid state Derived 6) Microscopy 7) Bulk density 8) Flow properties 9) Compression properties 10) Excipient compatibility Particle size and morphology Tablet and capsule formation Tablet and capsule formation Acid / excipient choice Preliminary screen by DSC. hydrolysis. salt formation Solubility. structure activity Biopharmacy DSC-polymorphism hydrate & solvent UV. HPLC. proteolysis metal ion Simple assay Phase solubility/ purity Intrinsic & pH effect solubility control . Conformation by TLC Thermal.

UV spectroscopy being a fairly accurate and simple method is a performed estimation technique at early preformulation stages. Most of drugs have aromatic rings and/or double bonds as part of their structure and absorb light in UV range. C = AF / E mg/ ml 1. . A = Absorbance F= dilution factor X = weight of drug (mg) It is now possible to determine concentration of drug in any solution by measuring absorbance. The absorption Co-efficient of the drug can be determined by the formula:E = AF / X Where .UV Spectroscopy The first requirement of any preformulation study is the development of a simple analytical method for quantitative estimation in subsequent steps.

1) 2) 3) 4) 5) 6) Solubility determination pKa determination Partition co-efficient Crystal properties and polymorphism Practical size. special studies are conducted depending on the type of dosage form and the type of drug molecules. shape and surface area. Chemical stability profile. Following studies are conducted as basic preformulation studies. .Characterization of drug molecules is very important step at the preformulation phase of product development.

e when some solute remains undissolved. the therapeutic efficiency of the pharmaceutical product is affected by solubility. The solubility of a new drug must be determined as a function of pH over the physiological pH range of 1 to 8. which employs a saturated solution of the material. glycerin. propylene glycol. methanol. Solubility is also determined in variety of commonly used solvents and some oils if the molecule is lipophillic. The solubility of material is usually determined by the equilibrium solubility method. buffer at various pHs     . Solubility Determination  The solubility of drug is an important physicochemical parameter because it effects the bioavailability of the drug. polysorbates. castor oil. ethyl alcohol. obtained by stirring small incremental amounts of solute to a fixed amount of solvent and examining visually for any undissolved solute particles till equilibrium is achieved i. tweens. the rate of drug release into dissolution medium and consequently. polyethylene glycols.1. Commonly used solvents include: Water. the total amount added up to that point serves as a good and rapid estimate of solubility. benzyl alcohol. sesame oil. sorbitol. isopropyl alcohol. peanut oil.

pH = pKa + log (un-ionized form]) / [ionized form]) for bases pH = pKa + log (ionized form]) / [un-ionized form]) for acids . Conditions that suppress ionization favor absorption. The important factors are pH at the site of action. thus is related to the fraction of drug in solution that is un-ionized.2. The un-ionized species are more lipid soluble and hence more readily absorbed. pKa determination       Many drugs are weakly acidic or basic compounds and in solution depending on the pH values exist as ionized or un-ionized species. The Henderson ± Hasselebalch equation provides an estimate of the ionized and un ionized drug concentration at a particular pH. ionization constant and lipid solubility of un-ionized species (pH partition theory). The GI absorption of weakly acidic or basic drugs.

Although it appears that the partition coefficient may be the best predictor of absorption rate. whereas those with partition coefficient much less than 1 are indicative of a hydrophilic drug. the lipophilic/ hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption. Since biological membranes are lipoidal in nature. Partition Coefficient       Partition Coefficient (oil/ water) is a measure of a drug¶s lipophilicity and an indication of its ability to cross cell membranes. Although partition coefficient data alone does not provide understanding of in vivo absorption. Drugs having P vales much greater than 1 are classified as lipophilic. The rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. P o/w = (C oil / C water) equilibrium. it does provide a means of characterizing the lipophilic/ hydrophilic nature of the drug. the partition coefficient can provide an empiric knowledge in handling and in screening for some biologic properties. For drug delivery. . the effect of dissolution rate. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water.3. For series of compounds. pKa and solubility on absorption must not be neglected.

When dissolution is the significantly slower of the two processes the absorption is described as dissolution rate-limited. any change in the process of dissolution would influence the absorption.4. Since dissolution precedes absorption. . Dissolution It is important to realize that usually drugs are absorbed if they are in solution form. Hence a solid dosage form has to undergo dissolution before absorption.

Cs >> C and is equal to saturation solubility S and if A and V are constant.4a. at constant temp and agitation above equation reduces to dc = KS (intrinsic dissolution rate) dt where K = AD/hV = constant . in the diffusion layer During early phase of disso. Intrinsic dissolution The dissolution rate of a solid in its own solution is described by Noyes-Nernst equation: dc = AD (Cs ± C ) dt hV Where. dc/dt = dissolution rate A = surface area of dissolving solid D = diffusion co-efficient h = diffusion layer thickness V = volume of the dissolution medium Cs = solute conc.

The different crystal forms are called polymorphs. a polymorph that is chemically more stable in a solution is preferred. melting points. For drugs prone to degradation in the solid state.      . x-ray diffraction patterns and solubility even though they are chemically identical. true density. When the absorption of a drug is dissolution rate limited. This property is known as polymorphism. physical form of the drug influences degradation. a more soluble and faster-dissolving polymorph may be utilized to improve the rate and extent of bioavailability. resulting in a solvate or pseudopolymorph. solid state stability. Occasionally. Differences in the dissolution rates and solubilities of different polymorphs of a given drug are very commonly observed. Polymorphs generally have different dissolution. crystal shape. Crystal properties and polymorphism  Many drug substance can exit in more than one crystalline from with different space lattice arrangements. Therefore. a solid crystallizes.5. entrapping solvent molecule in a specific lattice position and fixed stoichiometry.

The other forms would convert to the stable form with time. differential scanning colorimetry and dilalometry. In general.     Different polymorph also lead to different morphology. . Although a drug substance may exist in two or more polymorphic forms. tensile strength and density of power bed which all contribute of compression characteristics of materials. and the maximum chemical stability. These include microscopy (including hot stage microcopy). when the active ingredient is expected to constitute the bulk of the tablet mass. the solubility. single-crystal x-ray and xray power diffraction. infrared spectrophotometry. differential thermal analysis. only one form is thermodynamically stable at a given temperature and pressure. Various techniques are available for the investigation of the solid state. Some investigation of polymorphism and crystal habit of a drug substance which relates in pharmaceutical processing is desirable during preformulation evaluation especially. the stable polymorph exhibits the highest melting point .

Particle Size. size and shape influence the flow and the mixing efficiency of powders and granules. 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. In case of tablets. For e. and interacting excipients than coarse materials. In general.6. humidity. and surface-area control processes such as dissolution and surface morphology of the drug particles. Shape and Surface Area   Bulk flow. phenacetin & griseofulvin Poorly soluble drugs showing a dissolution.g.     . formulation homogeneity. Size can also be a factor in stability: fine materials are relatively more open to attack from atmospheric oxygen. Chemical.rate limiting step in the absorption process will be more readily bioavailable when administered in a finely subdivided state rather than as a coarse material. physical properties and biopharmaceutical behavior of drug substances are affected by their particle size distribution and shapes.

Therefore instruments based on laser (Malvern). quantitative size determination.    . Particle size determination  Microscopy: is the simplest technique of estimating particle size ranges and shapes. light blockage (HIAC) and blockage of electrical conductivity path (Coulter counter) are used. light scattering (Royco). Estimating size range includes particles above 1µm and upwards.6a. But as it requires counting of a large number of particles for quantitative estimation. Material is suspended in a non dissolving fluid and polarizing lens is used to observe and determine the particle size. But most pharmaceutical powders range in size from 1 to 120 µm. Sieve analysis: particle size range upwards from above 50 µm. it is not suited for rapid.

The BET equation is __1__ ____1____ = C-1 P + P0 mC mC (P0 /P ± 1) = gms of absorbate per gram of absorbent m= Where. Knowing the monolayer capacity of adsorbent and the area of absorbable molecule. Most substances adsorb a monomolecular layer of gas under certain conditions of partial pressure of gas and temperature. Surface Area Determination        Surface area is most commonly determined based on Brunauer-Emette-Teller (BET) theory of adsorption. Then adsorption takes onto most solids by virtue of Vander wall¶s forces. the surface area can be calculated The adsorption process is carried out at liquid nitrogen temperatures -195ÛC The partial pressure of nitrogen is attainable when it is in a 30% mixture with an inert gas (helium). value of that ratio for monolayer P = partial pressure of the absorbate gas P0 = vapour pressure of the pure absorbate gas C = a constant .6b.

These studies include both solution and solid state experiments under condition typical for the handing.  The effect of pH on drug stability is important in the development of both oral and liquid dosage forms. Chemical stability profile  Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug.  Factors effecting chemical stability which are critical in rational dosage form design include temperature. pH and dosage form diluents. storage. and administration of a drug candidate as well as stability in presence of other excipients.g. .  The method of sterilization of potential product will be largely dependent on the temperature stability of the drug. filtration.Solid state stability .7..  Drugs having decreased stability at elevated temperatures cannot be sterilized by autoclaving but must be sterilized by another means. formulation. e.

 The samples stored at highest temperature are observed weekly for physical and chemical changes and compared to an appropriate control.  In saturation or electron rich centre in the structure make the molecule vulnerable for free radical mediated or photo-catalyzed oxidation.  If a substantial change is seen.7a. .  Denser materials are more stable to ambient stress. samples stored at lower temperature are examined.  Amorphous materials are less stable than their crystalline forms. 7b. and 60 degree centigrade with ambient humidity. Elevated temperature studies  The elevated temperatures commonly used are 40. 50.  If no change is seen after 30 days at 60 degree centigrade.  Chemical structure of the drug is the determination of drug to either of these attacks. oxidation. the stability prognosis is excellent . photolysis and pyrolysis. amides are prone to solvolysis .  Esters and lactase and to lesser extent. Solid state stability  Chemical instability normally results from either of the following reactions hydrolysis.

7c. Photolytic stability  Many drugs fade or darken on exposure to light. respectively is adequate to provide some idea of photosensitivity.  Resulting data may be useful in determining if amber glass or opaque containers can be used or if dye can be incorporated in the product to mask the discoloration. it presents aesthetic problems.  Exposure of drug 400 and 900 footcandles (fc) of illumination for 4 and 2 week periods. .  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.  The closed desiccators in turn are kept in oven to provide constant temperature. 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.  Though the extent of degradations may be small and limited to the exposed surface area. 7d.

Stability to Oxidation       Drug¶s sensitivity to oxidation can be examined by exposing it to atmosphere of high oxygen tension. over a temperature range. The knowledge of drug excipients interaction is useful for the formulation to select appropriate excipients. The process is repeated 3 or 4 times to ensure 100% desired atmosphere. A shallow layer of drug exposed to a sufficient headspace volume ensures that the system is not oxygen limited. which will encompass any thermal changes due to both the drug and excipient Appearance or disappearance of one or more peaks in themograms of drug excipient mixtures are considered as indication of interaction.7e. which are alternatively evacuated and flooded with desired atmosphere. 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. 7f. Samples are kept in desiccators equipped with three-way stop cocks. Compatibility studies     . Usually a 40% oxygen atmosphere allows for rapid evaluation. Mixtures should be examined under nitrogen to limit oxidation and paralytic effect at a standard heating rate on DSC. 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 .

Absorption behavior  It is essential to test the in vivo behavior of the new drug for successful formulation of a dosage from good bioavailability. provided the bioavailability is not compromised 7h. using different stimulator GI condition can be designed.  A poor solution stability of drug may urge the formulator to choose a less soluble salt form. .  The pH based stability study.  It is important ascertain that the drug doesn¶t degrade when exposed to GI fluid.7g. the degradation is much rapid in solution form. Solution phase stability  As compared with the dry form.  Partial in vivo and in vitro test are designed to study pharmacokinetic profile of the drug.

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