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TABLETS :

TABLETS MAK95

Slide 2:

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. MAK95

ADVANTAGES :

ADVANTAGES Production aspects Large scale production at lowest cost Easiest and cheapest to package and ship High stability (chemical, mechanical & biological) Lightest and most compact Formulation aspects Greatest dose precision with least content variability Lend to give special release profile products e.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 MAK95

DISAVDANTAGES :

DISAVDANTAGES Some drugs resist compression into dense compacts Drugs with poor wetting, slow dissolution, 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, drugs with an objectionable odor, or sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating MAK95

Preformulation Aspects :

Preformulation Aspects Tablets are one of the most challenging of all pharmaceutical products to design and manufacture. Poor wetting or slow dissolution or good cohesive compacts of amorphous or flocculent drugs may result in low bioavailability. The focus is to see that action taken to improve one objective should not cause another objective to degrade For eg. Tablets should have smooth surface, good appearance, surface gloss and also be cohesive and compact so as not to undergo friability, powdering or chipping during handling. Therefore, steps taken to achieve the first set of objectives (using binder or adhesive, ↑ing compression pressure or punch dwell time or using precompression must not have negative impact on other set of objectives (disintegration time, drug dissolution rate & bioavailability) A satisfactory compromise between competing set of objectives may be simple or extremely complex. Statistical optimization can be carried out. MAK95

Slide 6:

Step 1. Complete preformulation data regarding the physicochemical characteristics of the drug like Stability (solid state): light, temperature, humidity Stability (solution): drug-excipient stability (DSC or accelerated ss) Physicomechanical studies: particle size, bulk and tap density, compressibility, MP, taste, color, appearance and odor Physicochemical properties: solubility and pH profile of solution/dispersion (water, solvents) In vitro dissolution: pure drug, pure drug pellet, dialysis of drug, absorbability, effect of excipients and surfactants Step 2. Tablet production design requires 2 major activities. Identifying the excipients most suited for a prototype formulation of drug (checking drug – excipients compatibility) Optimizing the levels of those excipients MAK95

Medical :

Medical Desired release profile Dissolution is the rate limiting step Targeting drug delivery Marketing Appearance: colour, texture, shape, size, coating and embossing MAK95

Economics :

Economics Cost of excipients Type of process (labor, energy and time) Experimental approach Analysis of variance (ANOVA) Statistical screening design Plackett Burman (levels) Extreme vertices MAK95

Bioavailability studies :

Bioavailability studies Stability data Validation data Pg 77- 88; pharmaceutical dosage forms volume 1 MAK95

Slide 10:

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. 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. MAK95

Preformulation drug characterization in a structured program :

Preformulation drug characterization in a structured program MAK95

Slide 12:

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. The absorption Co-efficient of the drug can be determined by the formula:- E = AF / X Where , 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. C = AF / E mg/ ml MAK95

Slide 13:

Characterization of drug molecules is very important step at the preformulation phase of product development. Following studies are conducted as basic preformulation studies, special studies are conducted depending on the type of dosage form and the type of drug molecules. 1) Solubility determination 2) pKa determination 3) Partition co-efficient 4) Crystal properties and polymorphism 5) Practical size, shape and surface area. 6) Chemical stability profile. MAK95

Slide 14:

1. Solubility Determination The solubility of drug is an important physicochemical parameter because it effects the bioavailability of the drug, the rate of drug release into dissolution medium and consequently, 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. Solubility is also determined in variety of commonly used solvents and some oils if the molecules is lipophillic. The solubility of material is usually determined by the equilibrium solubility method, which employs a saturated solution of the material, 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.e when some solute remains undissolved, the total amount added up to that point serves as a good and rapid estimate of solubility. Commonly used solvents include: Water, polyethylene glycols, propylene glycol, glycerin, sorbitol, ethyl alcohol, methanol, benzyl alcohol, isopropyl alcohol, tweens, polysorbates, castor oil, peanut oil, sesame oil, buffer at various pHs MAK95

Slide 15:

2. 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 un-ionized species are more lipid soluble and hence more readily absorbed. The GI absorption of weakly acidic or basic drugs, thus is related to the fraction of drug in solution that is un-ionized. Conditions that suppress ionization favor absorption. The important factors are pH at the site of action, ionization constant and lipid solubility of un-ionized species (pH partition theory). The Henderson – Hasselebalch equation provides an estimate of the ionized and un ionized drug concentration at a particular pH. pH = pKa + log (un-ionized form]) / [ionized form]) for bases pH = pKa + log (ionized form]) / [un-ionized form]) for acids MAK95

Slide 16:

3. Partition Coefficient Partition Coefficient (oil/ water) is a measure of a drug’s lipophilicity and an indication of its ability to cross cell membranes. It is defined as the ratio of unionized drug distributed between the organic and aqueous phases at equilibrium. P o/w = (C oil / C water) equilibrium. For series of compounds, the partition coefficient can provide an empiric knowledge in handling and in screening for some biologic properties. For drug delivery, the lipophilic/ hydrophilic balance has been shown to be a contributing factor for the rate and extent of drug absorption. Although partition coefficient data alone does not provide understanding of in vivo absorption, it does provide a means of characterizing the lipophilic/ hydrophilic nature of the drug. Since biological membranes are lipoidal in nature. The rate of drug transfer for passively absorbed drugs is directly related to the lipophilicity of the molecule. The partition coefficient is commonly determined using an oil phase of octanol or chloroform and water. Drugs having P vales much greater than 1 are classified as lipophilic, whereas those with partition coefficient much less than 1 are indicative of a hydrophilic drug. Although it appears that the partition coefficient may be the best predictor of absorption rate, the effect of dissolution rate, pKa and solubility on absorption must not be neglected. MAK95

Slide 17:

4. 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. When dissolution is the significantly slower of the two processes the absorption is described as dissolution rate-limited. Since dissolution precedes absorption, any change in the process of dissolution would influence the absorption. MAK95

Slide 18:

4a. 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. in the diffusion layer During early phase of disso, Cs >> C and is equal to saturation solubility S and if A and V are constant, at constant temp and agitation above equation reduces to dc = KS (intrinsic dissolution rate) dt where K = AD/hV = constant MAK95

Slide 19:

5. Crystal properties and polymorphism Many drug substance can exit in more than one crystalline from with different space lattice arrangements. This property is known as polymorphism. The different crystal forms are called polymorphs. Occasionally, a solid crystallizes, entrapping solvent molecule in a specific lattice position and fixed stoichiometry, resulting in a solvate or pseudopolymorph. Polymorphs generally have different dissolution, true density, crystal shape, solid state stability, melting points, x-ray diffraction patterns and solubility even though they are chemically identical. Differences in the dissolution rates and solubilities of different polymorphs of a given drug are very commonly observed. When the absorption of a drug is dissolution rate limited, a more soluble and faster-dissolving polymorph may be utilized to improve the rate and extent of bioavailability. For drugs prone to degradation in the solid state, physical form of the drug influences degradation. Therefore, a polymorph that is chemically more stable in a solution is preferred. MAK95

Slide 20:

Different polymorph also lead to different morphology, tensile strength and density of power bed which all contribute of compression characteristics of materials. Some investigation of polymorphism and crystal habit of a drug substance which relates in pharmaceutical processing is desirable during preformulation evaluation especially, when the active ingredient is expected to constitute the bulk of the tablet mass. Although a drug substance may exist in two or more polymorphic forms, only one form is thermodynamically stable at a given temperature and pressure. The other forms would convert to the stable form with time. In general, the stable polymorph exhibits the highest melting point , the solubility, and the maximum chemical stability. Various techniques are available for the investigation of the solid state. These include microscopy (including hot stage microcopy), infrared spectrophotometry, single-crystal x-ray and x-ray power diffraction, differential thermal analysis, differential scanning colorimetry and dilalometry. MAK95

Slide 21:

6. Particle Size, Shape and Surface Area Bulk flow, formulation homogeneity, and surface-area control processes such as dissolution and surface morphology of the drug particles. 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. Chemical, physical properties and biopharmaceutical behavior of drug substances are affected by their particle size distribution and shapes. For e.g. phenacetin & griseofulvin Poorly soluble drugs showing a dissolution- 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. In case of tablets, size and shape influence the flow and the mixing efficiency of powders and granules. Size can also be a factor in stability: fine materials are relatively more open to attack from atmospheric oxygen, humidity, and interacting excipients than coarse materials. MAK95

Slide 22:

6a. Particle size determination Microscopy: is the simplest technique of estimating particle size ranges and shapes. Material is suspended in a non dissolving fluid and polarizing lens is used to observe and determine the particle size. Estimating size range includes particles above 1µm and upwards. But as it requires counting of a large number of particles for quantitative estimation, it is not suited for rapid, quantitative size determination. Sieve analysis: particle size range upwards from above 50 µm. But most pharmaceutical powders range in size from 1 to 120 µm. Therefore instruments based on laser (Malvern), light scattering (Royco), light blockage (HIAC) and blockage of electrical conductivity path (Coulter counter) are used. MAK95

Slide 23:

6b. Surface Area Determination Surface area is most commonly determined based on Brunauer-Emette-Teller (BET) theory of adsorption. Most substances adsorb a monomolecular layer of gas under certain conditions of partial pressure of gas and temperature. Knowing the monolayer capacity of adsorbent and the area of absorbable molecule, the surface area can be calculated The adsorption process is carried out at liquid nitrogen temperatures -195˚C The partial pressure of nitrogen is attainable when it is in a 30% mixture with an inert gas (helium). Then adsorption takes onto most solids by virtue of Vander wall’s forces. The BET equation is Where, λ = gms of absorbate per gram of absorbent λm = value of that ratio for monolayer P = partial pressure of the absorbate gas P0 = vapour pressure of the pure absorbate gas C = a constant ____1____ λ (P0 /P – 1) = C - 1 λmC P P0 + __1__ λmC MAK95

Slide 24:

7. Chemical stability profile Preformulation stability studies are usually the first quantitative assessment of chemical stability of a new drug. These studies include both solution and solid state experiments under condition typical for the handing, formulation, storage, and administration of a drug candidate as well as stability in presence of other excipients. Factors effecting chemical stability which are critical in rational dosage form design include temperature, pH and dosage form diluents. The method of sterilization of potential product will be largely dependent on the temperature stability of the drug. Drugs having decreased stability at elevated temperatures cannot be sterilized by autoclaving but must be sterilized by another means, e.g., filtration. The effect of pH on drug stability is important in the development of both oral and liquid dosage forms. - Solid state stability MAK95

Slide 25:

7a. Solid state stability Chemical instability normally results from either of the following reactions hydrolysis, oxidation, photolysis and pyrolysis. Chemical structure of the drug is the determination of drug to either of these attacks. Esters and lactase and to lesser extent, amides are prone to solvolysis . In saturation or electron rich centre in the structure make the molecule vulnerable for free radical mediated or photo-catalyzed oxidation. Amorphous materials are less stable than their crystalline forms. Denser materials are more stable to ambient stress. 7b. Elevated temperature studies The elevated temperatures commonly used are 40, 50, and 60 degree centigrade with ambient humidity. The samples stored at highest temperature are observed weekly for physical and chemical changes and compared to an appropriate control. If a substantial change is seen, samples stored at lower temperature are examined. If no change is seen after 30 days at 60 degree centigrade, the stability prognosis is excellent . MAK95

Slide 26:

7c. 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. The closed desiccators in turn are kept in oven to provide constant temperature. 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. 7d. Photolytic stability Many drugs fade or darken on exposure to light. Though the extent of degradations may be small and limited to the exposed surface area, it presents aesthetic problems. Exposure of drug 400 and 900 footcandles (fc) of illumination for 4 and 2 week periods, 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. MAK95

Slide 27:

7e. Stability to Oxidation Drug’s sensitivity to oxidation can be examined by exposing it to atmosphere of high oxygen tension. Usually a 40% oxygen atmosphere allows for rapid evaluation. A shallow layer of drug exposed to a sufficient headspace volume ensures that the system is not oxygen limited. Samples are kept in desiccators equipped with three-way stop cocks, which are alternatively evacuated and flooded with desired atmosphere. The process is repeated 3 or 4 times to ensure 100% 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. Compatibility studies The knowledge of drug excipients interaction is useful for the formulation to select appropriate excipients. 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 . Mixtures should be examined under nitrogen to limit oxidation and paralytic effect at a standard heating rate on DSC, over a temperature range, 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. MAK95

Slide 28:

7g. Solution phase stability As compared with the dry form, the degradation is much rapid in solution form. It is important ascertain that the drug doesn’t degrade when exposed to GI fluid. The pH based stability study, 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, provided the bioavailability is not compromised 7h. Absorption behavior It is essential to test the in vivo behavior of the new drug for successful formulation of a dosage from good bioavailability. Partial in vivo and in vitro test are designed to study pharmacokinetic profile of the drug. MAK95

Tablet- Formulation & Design :

Tablet- Formulation & Design The objective of the design and manufacture of the compressed tablets is to deliver orally the correct amount of the drug in the proper form, at or over the proper time and in the desired location, and to have its chemical integrity protected to that point. A tablet should be elegant product having its own identity while being free from defects such as chips, cracks, discoloration, contamination Shd hv strength to withstand the rigors of mechanical shocks encountered in its production, packing, shipping and dispensing Shd hv chemical and physical stability to maintain its physical attributes over time Must be able to release the medicinal agents in the body in a predictable and reproducible manner Therefore not only the physical but chemical stability of the product is a desired characteristic while designing a tablet formulation. MAK95

Flow chart for production of tablets :

Flow chart for production of tablets MAK95

Tableting methods :

Tableting methods Dry methods Direct compression Compression granulation Wet methods Wet granulation DRY BLENDING WEIGHING SIZING BLENDING LUBRICATION COMPRESSION COATING WET GRANULATION WEIGHING SIZING GRANULATION DRYING BLENDING LUBRICATION COMPRESSION DRY GRANULATION WEIGHING SIZING BLENDING COMPACTION MILLING LUBRICATION COMPRESSION MAK95

Direct compression :

Direct compression Tablets are compressed directly from powder blends of the active ingredient and suitable excipients No pretreatment of the powder blends by wet or dry granulation procedures is necessary Additives: Diluents Disintegrating agents Organoleptic additives Glidants, anti-adhesives,lubricants MAK95

Slide 33:

Powders intended for compression into tablets must possess two essential properties Powder fluidity or flowability The material can be transported through the hopper into the die To produce tablets of a consistent weight Powder flow can be improved mechanically by the use of vibrators, incorporate the glidant Powder compressibility The property of forming a stable, intact compact mass when pressure is applied is called powder compressibility Easily mixed with other particles Homogenous colouring etc Friction and adhesion properties MAK95

Slide 34:

Step I. Weighing – Active ingredient & excipients Step II. Sizing – excipients and API passed through different mesh sizes - For eg. 40#, 60#, 80#, 100#, 200# & 250# Step III. Blending – Powders to be used for encapsulation or to be granulated or directly compressed must be well blended to ensure good drug distribution. Inadequate blending at this stage could result in discrete portion of the batch being either high or low in potency. Steps should also be taken to ensure that all the ingredients are free of lumps and agglomerates. For these reasons, screening and/or milling of the ingredients usually makes the process more reliable and reproducible. Step IV. Lubrication – addition of lubricants, glidants or anti adherents Step V. Compression Step VI. Coating MAK95

Slide 35:

Things to consider at blending stage Homogeneity Risk of over mixing Can lead to demixing Influence by properties of the particles High shear rates Effects the particle size in weak powders Scaling up Not always linear MAK95

Equipments used for Mixing, blending and lubrication :

Equipments used for Mixing, blending and lubrication High share mixers Tumbling mixers Y-cone Rotating cube Double cone Fluidized bed Agitator mixers Ribbon blender MAK95

Equipments used in sieving :

Equipments used in sieving MAK95

Advantages :

Advantages Industry view point: I. Commercial availability of the directly compressible excipients possessing both good compressibility and good flowability. For example, Spray dried lactose, Anhydrous lactose, Starch-1500, microcrystalline cellulose, Di-PacÒ, Sorbitol II. Major advances in tablet compression machinery: i)Improved positive die feeding, ii)Precompression of powder blend. Economy: Fewer manufacturing steps and pieces of equipment, reduce labor costs, Less process validation, Lower consumption of power III. Elimination of heat and moisture, thus increasing not only the stability but also the suitability of the process for thermolabile and moisture sensitive API’s. IV. Particle size uniformity. V. Prime particle dissolution: In case of directly compressed tablets after disintegration, each primary drug particle is liberated. While in the case of tablets prepared by compression of granules, small drug particles with a larger surface area adhere together into larger agglomerates; thus decreasing the surface area available for dissolution. MAK95

Slide 39:

vi) The chances of batch-to-batch variation are negligible, because the unit operations required for manufacturing processes is fewer. vii) Chemical stability problems for API and excipient would be avoided. viii) Provides stability against the effect of aging which affects the dissolution rates. Elimination of granulation process The variables faced in the processing of the granules can lead to significant tableting problems. Properties of granules formed can be affected by viscosity of granulating solution, the rate of addition of granulating solution, type of mixer used and duration of mixing, method and rate of dry and wet blending. The above variables can change the density and the particle size of the resulting granules and may have a major influence on fill weight and compaction qualities. Drying can lead to unblending as soluble API migrates to the surface of the drying granules. MAK95

Disadvantages :

Disadvantages Differences in particle size and bulk density between drug and diluent may lead to stratification with in the granulation leading to poor drug content uniformity in the tablets Large dose of drug may present problems if the drug is not easily compressible. Problems in the uniform distribution of low dose drugs. Diluent may interact with the drug. E.g. amine compound and spray dried lactose which can be seen by a yellow discoloration Direct compression process may lead to static charge buildup during routine screening and mixing which may prevent uniform distribution of drug. MAK95

Compression granulation :

Compression granulation Advantages If the drug dose is too high for DC Drug is sensitive to heat, moisture or both e.g (aspirin & multi vitamin) Dry powder blend that cannot be directly compressed because of poor flow or compression properties. Slugging (dry granulation) : a. It involves the compaction of tablet formulation by means of tablet press followed by milling and screening, prior to final compression of tablets. b. Blend is forced into dies of large capacity tablet press and compacted using flat faced punches. These compacted masses are called slugs and process is called slugging. c. Slugs are then milled or screened to produce good free flowing granules fo compression. The process of Slugging, Screening and Milling can be repeated till desired characteristics of flow are obtained. MAK95

Slugging :

Slugging d. This is done on a tablet press designed for slugging, which operates at pressures of about 15 tons, compared with a normal tablet press, which operates at pressure of 4 tons or less. e. Slugs range in diameter from 1 inch, for the more easily slugged material, to ¾ inch in diameter for materials that are more difficult to compress and require more pressure per unit area to yield satisfactory compacts. f. If an excessive amount of fine powder is generated during the milling operation the material must be screened & fines recycled through the slugging operation. g. The repeat process of compaction pressure causes strengthening of the bonds that holds the tablet together. MAK95

Dry compaction/Roller compaction :

Dry compaction/Roller compaction On a large scale compression granulation can also be performed on a roller compactor. Granulation by dry compaction can also be achieved by passing powders between two rollers that compact the material at pressure of up to 10 tons per linear inch. Materials of very low density require roller compaction to achieve a bulk density sufficient to allow encapsulation or compression. One of the best examples of this process is the densification of aluminum hydroxide. Roller compactor is capable of producing as much as 500 kg/hr of compacted ribbon like materials which can be then screened and milled in to granules for compression. MAK95

Slide 44:

Limitations of dry granulation 1- Dry granulation often produces a higher percentage of fines or non compacted products, which could compromise the quality or create yield problems for the tablet. 2- It requires drugs or excipients with cohesive properties. Compacts Powder to be compacted Size reduction of compacts into granules Roller compactor "Chilsonator" MAK95

Slide 45:

Roller compaction basically consists of three steps, i.e., powder feeding, pre-densification and ribbon formation. During the feeding step, the powder material is fed into two counter-rotating rolls by either gravity or force-feed screws. Once the powder material is drawn into the nip angle area, it rubs against the roll surface and undergoes the pre-densification process. As the material enters the roll gap, particles are deformed or fragmented to form ribbons under hydraulic pressure. The ribbons are then sized through screens to produce granules to be compressed into tablets or filled into capsules. MAK95

Slide 46:

Compaction force is controlled by 3 variables Hydraulic pressure exerted on the compaction rolls Rotational speed of the compaction rolls Rotational speed of the feed screws Std procedure for testing compaction uniformity and machine capacity is to select a hydraulic pressure in the mid ranges, set compaction roll at the slowest speed and feed screw at the highest speed. Roller compactor offers advantage over slugging process of increased production capacity, greater control of compaction pressure and dwell time, and no need for excessive lubrication of the powder. MAK95

Wet granulation :

Wet granulation MAK95

Slide 48:

MAK95

Wet granulation :

Wet granulation The most popular method employed for the production of compressed tablets (over 70% of formulation in tablet manufacture is wet granulation). Rationale for granulating powders (drug and filler mixture) prior to tableting: To prevent segregation of the constituents of the powder blend. To improve flowability of the powder mixture. To improve the compaction characteristics of the powder mixture due to better distribution of the binder within the granules. To improve homogeneity and thus ensure content uniformity of powder blend. Wet granulation is a process of using a solution binder to the powder mixture. The amount of liquid can be properly managed; overwetting will cause the granules to be too hard and underwetting will cause the granules to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than other solvents. MAK95

Slide 50:

Procedure of Wet Granulation Step 1: Weighing and Blending ; the active ingredient and filler (disintegrant may be added in this step) are weighed and mixed. Step 2: The wet granulate is prepared by adding the binder solution to facilitate adhesion of the powder particles forming a damp mass resembling dough. Step 3: Screening the damp mass into pellets or granules: by pressing through a screen (6-8 mesh), by hand or with special equipment that prepare the granules by extrusion through perforations in the apparatus. Step 4: Drying the granulation in the thermostatically controlled ovens after spreading on large pieces of papers in shallow trays. Step 5: Dry screening: After the granules are dried, they are passed through a screen of smaller size than the one used for the wet mass to select granules of uniform size to allow even fill in the die cavity. Step 6: Mixing with other ingredients: A dry lubricant, antiadherent and glidant is added to the granules either by dusting over the spread-out granules or by blending with the granules. Dry binder, colorant or disintegrant may be also added in this step. Step 7: Tableting: Last step in which the tablet is fed into the die cavity and then compressed. MAK95

Slide 51:

Limitations of wet granulation: 1- Multiple separate steps are involved. 2- Not suitable for heat and moisture sensitive drugs. All-In-One Granulation method: Technologic advances now allow the entire process of granulation to be completed in single equipment "the fluid bed granulator". It performs the following steps; - Blending (drug + excipients e.g. filler & disintegrant). - Granulation (fluidized bed powder mix is sprayed by binder solution). - Drying to the desired moisture content. Fluid-bed granulator Binder solution spray Granulation of the powder Warm air flow MAK95

Equipments :

Equipments Traditionally, dry mixing in wet granulation process has been carried out using, Sigma blade mixer, Heavy-duty planetary mixer. Sigma blade mixer Planetary mixer MAK95

Slide 53:

Wet granulation can also be prepared using tumble blenders equipped with high-speed chopper blades. MAK95

List of equipments used in granulation :

List of equipments used in granulation High Shear granulation: i)Little ford Lodgie granulator ii)Little ford MGT granulator iii)Diosna granulator iv)Gral mixer Granulator with drying facility: i) Fluidized bed granulator ii) Day nauta mixer processor iii) Double cone or twin shell processor iv) Topo granulator Special granulator: i) Roto granulator ii) Marumerizer MAK95

High shear power blenders capable of blending and granulating :

High shear power blenders capable of blending and granulating Littleford Lodige mixers MAK95

Diosna mixer :

Diosna mixer MAK95

Gral mixers :

Gral mixers MAK95

Slide 58:

MAK95

Slide 59:

5 4 3 2 1 Drug What a tablet contains drug excipients (1-5) Excipients: 1 – lubricants 2 – disintegrating agents 3 – binding agents 4 – granulating agents 5 - fillers MAK95

EXCIPIENTS :

EXCIPIENTS All non drug components of a formula are termed excipients DILUENTS Diluents are fillers used to increase the bulk volume of a tablet. By combining a diluent with the active pharmaceutical ingredients, the final product is given adequate weight and size to assist in production and handling. Ideal filler should fulfill a series of requirements, such as: Inert so as not to cause pharmacological or chemical activity of its own Biocompatible with the drug substance and other excipients used in the formulation Non-hygroscopic so the formulation does not absorb significant amounts of moisture from its surroundings Compactable and of similar particle size to the active ingredient and should have good dilution capacity Non-conducive to microbiological development Nontoxic, cheap, commercially available in acceptable grades, color-compatible, have no deleterious effect on bioavailability of drugs. If drug product is classified as food (certain vitamin products), excipient must be approved direct food additives MAK95

Lactose :

Lactose Non-reactive in anhydrous or hydrous form Hydrous form undergoes maillard reaction leading to browning and discoloration of certain drugs, hence anhydrous form is preferred But anhydrous form picks up moisture when exposed to humidity. In wet granulation, hydrous lactose of two varieties are used 60-80 mesh (coarse) and 80-100 mesh (regular) grade. Lactose formulation show good release. Low cost diluent But may discolor in presence of amine drug bases or salts of alkaline compounds Spray dried lactose Lactose is placed in aqueous solution, removed impurities and spray dried Mixture of large alpha monohydrate crystals and spherical aggregates of smaller crystals Good flowability but less compressibility Poor dilution potential Less compressibility upon initial compaction Problem of browning due to contamination of 5-hydroxyfurfural which was accelerated in the presence of basic amine drugs and catalyzed by tartarate, citrate and acetate ions MAK95

Slide 62:

Fast-Flo lactose (early 1970s) Spherical aggregates of microcrystals lactose monohydrate Held together by a higher concentration of glass (amorphous lactose) Much more compressible Highly fluid Non hygroscopic Tablets are three to four times harder than regular spray dried Tabletose: aggromerate form of lactose More compressible than spray dried but less compressible than Fast Flo lactose MAK95

Starch :

Starch Can be corn, wheat or potato source USP grade of starch has poor flow & compression characteristics Also has high moisture content between between 11 & 14 %. Specially dried starches also have standard moisture level of 2-4% Therefore not used in wet granulation Starch 1500: Intact starch grains and ruptured starch grains that have been partially hydrolyzed and subsequently aggromerated Free flowing, self lubricating, containing slightly high MC (10 %) Due to which does not form hard compacts Dilution potential is minimal, not generally used as filler-binder but as filler disintegrant Retains the disintegrant properties of starch without increasing the fluidity and compressibility of the total formulation Flow promoters like colloidal silicon dioxide is needed. Lubricants tend to dramatically soften tablets containing high concentrations of Starch 1500 MAK95

Slide 64:

Two hydrolyzed starches are Emdex and Celutab which are spray crystallized 90-92% dextrose, 3-5% maltose and the remainder higher glucose polysaccharides Available both anhydrous and a hydrate product Excellent compressibility and good flow Contain 8-10% moisture and may increase hardness after compression Largest particle size, therefore blending problem may occur Cerelose is also avilable Dextrose MAK95

Slide 65:

Mannitol Exists in a number of polymorphic forms Not make as hard a tablet as sorbitol Slow solubility Less sensitive to humidity Widely used where rapid and complete solubility is required Use as a filler in chewable tablets Cool mouth feel but expensive MAK95

Slide 66:

Sorbitol Exists in a number of polymorphic crystalline forms and amorphous form Widely used in sugar-free mints and as a vehicle in chewable tablets Cool taste and good mouth feel Forms a hard compact Hygroscopic and will clump in the feed frame and stick to the surfaces of the die table when tableted at humidities > 50% Lubricant requirements increase when the MC of the sorbitol drops below 0.5% or exceeds 2% MAK95

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Maltodextrin Maltrin Highly compressible Completely soluble Very low hygroscopic Sucrose Di-Pac: cocrystallization of 97% sucrose and 3% modified dextrin Small sucrose crystals glued together by dextrin Good flow properties and needs a glidant only when atmospheric moisture levels are high (>50%RH) Excellent color stability on agingConcentration of moisture is extremely critical in terms of product compressibility compressibility increases rapidly in a moisture range of 0.3-0.4%, plateaus at a level of 0.4-0.5% and rises again rapidly up to 0.8% when the product begins to cake and lose fluidity MAK95

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Dilution potential 20-35% Tablets tend to harden slightly during the first hours after compression or when aged at high humidities and then dried (this is typical of most direct compression sucroses or dextroses) Nutab: 95.8% sucrose, 4% convert sugar (equimolecular mixture of levulose and dextrose) and 0.1 to 0.2% each of cornstarch and magnesium strarate Large particle size distribution and good fluidity Poor color stability MAK95

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Cellulose Microcrystalline cellulose (Avicel) The most important tablet excipient developed in modern times Derived from a special grade of purified alpha wood cellulose by severe acid hydrolysis to remove the amorphous cellulose portions, yielding particles consisting of bundles of needlelike microcrystals PH101 powder and PH102 are the two grades available. PH 102 is more agglomerated, larger particle size, slightly better fluidity but not significant decrease in compressibility Both grades are most compressible Highest dilution potential A strong compact is formed due to the extremely large number of clean surfaces brought in contact during the plastic deformation and the strength of the hydrogen bonds formed Extremely low coefficient of friction, no lubricant requirement When >20% of drugs or other excipients are added, lubrication is necessary Not used as the only filler because of its cost and density Usually used in the conc of 10-25% as a filler-binder-disintegrant, rapid passage of water into the compact and the instantaneous rupture of hydrogen bonds Plain MCC Fluidity is poor because of its relatively small particle size, small amount of glidant are recommended in the formulations containing high conc of MCC Tablets are soften on exposure to high humidities This softening is reversible when tablets are removed from the humid environment >80% MCC may slow the dissolution rates of AI having low water solubility Small particles get physically trapped between the deformed MCC particles, which delays wetting and dissolution This phenomenon can be overcome by adding portions of water soluble excipient MAK95

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Inorganic calcium salts Dicalcium phosphate (Emcompress or DiTab) Free flowing aggregates of small microcrystals that shatter upon compaction Inexpensive and possesses a high degree of physical and chemical stability Non hygroscopic at a RH of up to 80% Good fluidity Slightly alkaline with a pH of 7.0 to 7.3 Precludes its use with AI that are sensitive to even minimal amounts of alkalinity Tricalcium phosphate (TriTab) is less compressible and less soluble, higher ratio of calcium ions MAK95

Binders and Adhesives :

Binders and Adhesives Used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling. In some instances the binding agent imparts viscosity to the granulating solution so that transfer of fluid becomes difficult. This problem can be overcome by adding some or all binding agents in the dry powder prior to granulation. For granulation, solutions of adhesive materials like acacia, gelatin, liquid glucose, sucrose syrup, starch paste etc are employed to appropriate extents Solutions of methyl cellulose, CMC and mucilages of naturally occurring gums and colloidal clays are used in most recent times. For water sensitive drugs, solutions of PVP, EC, HPMC etc, in alcohol or other organic solvents are used. A 10% dispersion of partially hydrolyzed starch is commonly applied in industry as it is a good adhesive, has less retardant effect on disintegration and dissolution in comparison to other additives. The heating and cooling of the starch paste can be controlled at precise rate which enables to control degree of hydrolysis of starch causing less batch to batch variation. Some substances possess adhesiveness of their own and hence can be just granulated with ethyl alcohol as binder. Binding agents such as MCC, amylose, colloidal clays, finely powdered acacia are used in dry granulation to afford adhesion in slugging operations. MAK95

Disintegrants :

Disintegrants Disintegrants, an important excipient of the tablet formulation, are always added to tablet to induce breakup or disintegration of tablet when it comes in contact with gastro intestinal fluid and this process of desegregation of constituent particles before the drug dissolution occurs, is known as disintegration process and excipients which induce this process are known as disintegrants. Disintegrants may function by drawing water into the tablet, swelling and causing the tablet to burst apart. This is very critical for drug bioavailability. Starch USP and various starch derivatives are used as disintegrants in the conc range of 5-20% of tablet weight. Modified starches like Primogel and Explotab, which are low substituted carboxylmethyl starches are used in lower conc. (1-8% with 4% as optimum. MAK95

Pregelatinized starch (5 % conc.)Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic structure and is soluble in water. But when it is modified by internally crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium (Ac-di-Sol) which is nearly water insoluble due to cross linking. It rapidly swells to 4-8 times its original volume when it comes in contact with water. :

Pregelatinized starch (5 % conc.)Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic structure and is soluble in water. But when it is modified by internally crosslinking we get modified crosslinked cellulose i.e. Crosscarmellose sodium (Ac-di-Sol) which is nearly water insoluble due to cross linking. It rapidly swells to 4-8 times its original volume when it comes in contact with water. List of disintegrants MAK95

Lubricants, Antiadherents & Glidants :

Lubricants, Antiadherents & Glidants In tablet manufacturing one faces the problem of flow of granules from the hopper into the die cavity, sticking of material to the punches and die walls and release free movement of the compressed tablets from the die cavity. To overcome these difficulties Lubricants are the substance which prevent adhesion of the tablet material to the surface of the dies and punches, reduce interparticle friction, facilitate an easy ejection of tablets from the die cavity and improves rate of flow of tablet granulation. Commonly used lubricants are talc, magnesium stearate, calcium stearate, stearic acid, hydrogenated vegetable oil and PEG. The method of adding lubricant is an important factor for satisfactory results. The quantity of lubricant significantly varies from 0.1 to 5%. A glidant is a substance that improves the flow characteristics of a powder mixture. These materials are always added in the dry state just prior to compression. The most commonly used glidants are colloidal silicon dioxide (Cabosil®, Cabot®) and asbestos free talc. They are used in concentration less than 1%. Talc is also used and may serve the dual purpose of lubricant/glidant. Some material have strong adhesive properties towards the metal of punches and dies or the tablet formulation containing excessive moisture which has tendency to result in picking and sticking problem. Therefore antiadherents are added, which prevent sticking to punches and die walls.Talc, magnesium stearate and corn starch have excellent antiadherent properties. MAK95

List of LAG’s :

List of LAG’s MAK95

Colors, flavours and sweeteners :

Colors, flavours and sweeteners Colors Disguising off-colored drugs Product identification Elegant look Natural vegetable colors – limited availability & unstable FD&C and D&C approved dyes are used. Either added in dry granulation mix or in vehicle used for wet granulation. Wet granulation gives better uniformity of color, but migration of the dye to the top of granules alongwith solvent during drying should be watched against Lake dyes( dyes absorbed on alumina or aluminium hydroxide) are used in dry granulation. Dyes tend to fade on standing and exposure to light leads to mottling. Eg. FD&C approved lakes and dyes – lake sunset yellow, brilliant blue, ferric oxide. MAK95

Flavors :

Flavors Flavours are usually limited to chewable tablets or other tablets intended to dissolve in the mouth. In general flavours that are water soluble have been found little acceptance in manufacturing of tablets because of there poor stability. Flavouring agents do not affect any physical characteristics of the tablet granulation. Flavours can be incorporated by spraying them on to the granules in the form of solutions in some volatile organic solvent. Also can be incorporated with lubricants Proportion limited to 0.5 % Excess quantity will interfere with free flow of granules e.g. Raspberry, Pineapple, Peppermint, Blackcurrant, Orange, Mango, Strawbery MAK95

Sweeteners :

Sweeteners Use is primarily limited to chewable tablets Mannitol – 72% as sweet as sucrose Earlier saccharin was the only artificial sweetener used. Its is 500 times sweeter than sucrose but has a bitter aftertaste and also carcinogenic properties Aspartame is the new sweetener- disadvantage is its instability in the presence of moisture. MAK95

Compression :

Compression Tableting procedure Filling Compression Ejection Tablet compression machines Hopper for holding and feeding granulation to be compressed Dies that define the size and shape of the tablet Punches for compressing the granulation within the dies Cam tracks for guiding the movement of the punches Feeding mechanisms for moving granulation from the hopper into the dies 1. Single punch machine The compression is applied by the upper punch Stamping press MAK95

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Upper andLower Collar Collar locker Single Punch Machine (Tablets) MAK95

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Common stages occurring during compression Stage 1: Top punch is withdrawn from the die by the upper cam. Bottom punch is low in the die so powder falls in through the hole and fills the die Stage 2: Bottom punch moves up to adjust the powderweight-it raises and expels some powder Stage 3: Top punch is driven into the die by upper cam. Bottom punch is raised by lower cam. Both punch heads pass between heavy rollers to compress the powder Stage 4: Top punch is withdraw by the upper cam. Lower punch is pushed up and expels the tablet. Tablet is removed from the die surface by surface plate Stage 5: Return to stage 1 MAK95

Multi-station rotary presses :

Multi-station rotary presses The head of the tablet machine that holds the upper punches, dies and lower punches in place rotates As the head rotates, the punches are guided up and down by fixed cam tracks, which control the sequence of filling, compression and ejection. The portions of the head that hold the upper and lower punches are called the upper and lower turrets The portion holding the dies is called the die table MAK95

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MAK95

Compression cycle :

Compression cycle Granules from hopper empty in the feed frame (A) containing several interconnected compartments. These compartments spread the granulation over a wide area to provide time for the dies (B) to fill. The pull down cam (C) guides the lower punches to the bottom, allowing the dies to overfill The punches then pass over a weight-control cam (E), which reduces the fill in the dies to the desired amount MAK95

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A swipe off blade (D) at the end of the feed frame removes the excess granulation and directs it around the turret and back into the front of the feed frame The lower punches travel over the lower compression roll (F) while simultaneously the upper punches ride beneath the upper compression roll (G) The upper punches enter a fixed distance into the dies, while the lower punches are raised to squeeze and compact the granulation within the dies After the moment of compression, the upper punches are withdrawn as they follow the upper punch raising cam (H) The lower punches ride up the cam (I) which brings the tablets flush with or slightly above the surface of the dies MAK95

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The tablets strike a sweep off blade affixed to the front of the feed frame (A) and slide down a chute into a receptacle At the same time, the lower punches re-enter the pull down cam (C) and the cycle is repeated MAK95

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Although tablet compressing machinery has undergone numerous mechanical modifications over the years, the compaction of materials between a pair of moving punches within a stationary die has remained unchanged The principle modification from earlier equipment has been an increase in production rate which is regulated by Number of tooling sets Number of compression stations Rotational speed of the press Special adaptations of tablet machines allow for the compression of layered tablets and coated tablets A device that chills the compression components to allow for the compression of low-melting point substances such as waxes i.e. suppositories MAK95

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HIGH SPEED ROTARY MACHINE MULTI ROTARY MACHINE MAK95

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DOUBLE ROTARY MACHINE UPPER PUNCH AND LOWER PUNCH MAK95

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SINGLE ROTARY MACHINE MAK95

Physics of compression :

Physics of compression A tablet is formed by reducing tile volume of a set of autonomous particles until they are consolidated into a solid body Tablet consolidation occurs when the punches and die go between two compression rollers The complete tablet manufacturing cycle occurs in four steps: (I) the die is filled, (ii ) the fill weight is adjusted, (iii) the tablet is compacted. and (iY) the tablet ejected from the die . From a material point of view, a compaction process is normally described by a series of sequential phases MAK95

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Initially as the volume is reduced. the particles rearrange into a closer packing structure. At a certain point, the packing characteristics of the particles and inter particulate friction between particles will prevent any further particle rearrangement. At this point the further reduction in compact volume results in the elastic, viscoelastic and plastic deformation of the particles. Elastic deformation is reversible, whereas the plastic deformation is irreversible. MAK95

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As a consequence of these processes, particle surfaces are brought into close proximity to each other which can lead to the formation of inter particulate bonds. These bonds may later break, which facilitates further compression. To summarize, the following processes are involved in the compaction of a powder: In addition, particle fragmentation or breakage results in smaller particles, which further decreases in compact volume. As the volume is further reduced, the smaller particles formed by fragmentation can undergo deformation. MAK95

Slide 96:

1. Particle rearrangement 2. Elastic, viscoelastic and plastic deformation of particles 3. Fragmentation of particles 4. Formation of interparticulate bonds During tablet formation the following types of bond mechanisms are hypothesized to occur: 1. Mechanical interlocking (between irregularly shaped particles) 2. Inter particulate attraction force s (e.g., intermolecular forces, such as Van der Waal forces, electrostatic forces and hydrogen bonding) 3. Solid bridges (due to melting) MAK95

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In tableting, compact formation occurs due to inter particulate attraction that arises from intermolecular bonding forces that act over very short As the powder bed is consolidated and the particles start to deform around each other this leads to a mechanical interlocking of the particles and this also increases the number of contact points between the particles. The dominant interaction force between solid surfaces is the Van der Waals force of attraction and hydrogen bonding may occur intra and intermolecularly. In addition, the applied load gets transmitted from particle to particle through contact points, the pressure at these points can be very high. This may cause heating with a possibility of localized melting, especially of low-melting point solids. Upon unloading, the reduction of local stress at the point of contact could lead to reso1idification, forming a solid bridge between the particles. Hence solid bridges that contribute to the overall compact strength can be defined as areas of real contact, i.e., contact at an atomic level between adjacent surfaces in the compact. MAK95

Processing problems in tabletting :

Processing problems in tabletting The source of problem can be the formulation or compression equipment or both Capping : capping is partial or complete seperation of the top or bottom crowns of a tablet from main body of the tablet. Lamination : is the separation of a tablet into 2 or more distinct layers. Reason: during compression air is entrapment among the particles and is not able to escape till compression pressure is released. C & L are due to the deformational properties of the formulation during and immediately following compression. Causes and remedies related to formulation: MAK95