tablets DMS 2012-13

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TABLETS:

TABLETS 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 1 Prof. D. M. Shinkar Assistant Professor, Department of Pharmaceutics, KCT’S R.G.S.College of Pharmacy, Anjaneri, Nashik, Maharashtra.

contents:

contents History and Introduction Advantages and disadvantages of tablets General Properties of tablets Preformulation aspects for designing tablet dosage forms Types of Tablets Tablet Additives / excipients used in tableting Granulation Need of granulation Mechanisms of granulation 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 2

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Granulation methods (Manufacturing Processes for granules formation) Equipments for granulations Advance Granulation Techniques Evaluation and characterization of granules or (Evaluation of Rheological / Pre compressional Characteristics) Physics of tablet Compression Tablet Compression Machines and tooling Evaluation of tablets or IPQC tests for tablets 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 3

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History and Introduction 1843 a patent was granted to - Thomas Brockedon (Englishman) for manufacturing pills and lozenges 1874 both rotary and eccentric presses. 1885 Glyceryl trinitrate tablets was in the BP No other tablet monograph appeared until 1945 1980 nearly 300 monographs for tablets 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 4

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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. Tablet is defined as a compressed unit solid dosage form containing medicaments with or without excipients. According to the Indian Pharmacopoeia, Pharmaceutical tablets are solid, flat or biconvex dishes, unit dosage form, prepared by compressing a drugs or a mixture of drugs, with or without diluents. They vary in shape and differ greatly in size and weight, depending on amount of medicinal substances and the intended mode of administration. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 5

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Continued…. 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 retained in the mouth where drug is liberate dissolved or dispersed in water 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 6

Advantages of tablets:

Advantages of tablets Production aspects 1. Large scale production at lowest cost 2. Easiest and cheapest to package and ship 3. High stability (chemical, mechanical & biological) Formulation aspects 4. Lend themselves to give special release profile products e.g. enteric or delayed release tablets 5. Product identification is easy and rapid requiring no additional steps when employing an embossed and/or monogrammed punch face. 6. Easy to swallowing with least tendency to hang-up over stomach like other dosage forms. User aspect (Doctor, Pharmacist, Patient ) 6. Ease of handling 7. Lightest and most compact 8. Greatest dose precision with least content variability 9. Coating can mask unpleasant tastes & improve patient acceptability. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 7

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Difficult to swallow in case of children and unconscious patients. Some drugs resist compression into dense compacts, owing to amorphous nature, low density character. Drugs with poor wetting, slow dissolution properties, may be difficult to formulate or manufacture as a tablet that will still provide adequate or full drug bioavailability. Bitter testing drugs, drugs with an objectionable odor or drugs that are sensitive to oxygen or moisture may require encapsulation or entrapment prior to compression or the tablets may require coating . In such cases, capsule may offer the best and lowest cost. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 8 Disadvantages of tablets

General Properties of tablet dosage forms:

General Properties of tablet dosage forms 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 9 A tablet should have elegant product identity while free of defects like chips, cracks, discoloration, and contamination. Should have sufficient strength to withstand mechanical shock during its production packaging, shipping and dispensing. Should have the chemical and physical stability to maintain its physical attributes over time. The tablet must be able to release the medicinal agents in a predictable and reproducible manner . Must have a chemical stability over time so as not to follow alteration of the medicinal agents.

Absorption of drug form tablets:

Absorption of drug form tablets 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 10

Factors to be considered during designing of tablet dosage form:

Factors to be considered during designing of tablet dosage form 1. Medical Desired release profile Dissolution is the rate limiting step Targeting drug delivery 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 11 2. Marketing Appearance: color, texture, shape, size, coating and embossing Competitive products in the market

3. Economics :

3. Economics Cost of excipients Selection of granulation method for tableting Type of process (labor, energy and time) 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 12 4 . Experimental approach for developing a prototype tablet formula Analysis of variance (ANOVA) Statistical screening design Plackett Burman (levels) Extreme vertices method 5. Bioavailability studies Stability data Validation data 6. Experimental approach to optimizing a protype tablet formula Commercially available software's like… XSTAT, STATGRAPHICS, PCSAS, ECHIP.

Preformulation Aspects for designing tablet dosage forms:

Preformulation Aspects for designing tablet dosage forms 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 example - 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, increasing 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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 13

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Step 1. Complete Preformulation data regarding the physicochemical characteristics of the drug like Stability (solid state): light, temperature, humidity Stability (solution): drug- excipients stability (DSC or accelerated stability study) 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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 14

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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. Time available. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 15

Preformulation drug characterization in a structured program:

Preformulation drug characterization in a structured program Test Method/ function Characterization Fundamental 1) UV spectroscopy Simple assay 2) Solubility Phase solubility/ purity a) Aqueous Intrinsic & pH effect b) pKa solubility control , salt formation c) Salt Solubility, hygroscopicity & stability d)Solvents Vehicles & Extraction e) k o/ w Lipophillicity , structure activity f) Dissolution Biopharmacy 3) Melting point DSC-polymorphism hydrate & solvent 4) Assay development UV, HPLC, TLC 5) Stability In Solution Thermal, hydrolysis, pH In solid state Oxidation, proteolysis metal ion Derived 6) Microscopy Particle size and morphology 7) Bulk density Tablet and capsule formation 8) Flow properties Tablet and capsule formation 9) Compression properties Acid / excipient choice 10) Excipients compatibility Preliminary screen by DSC, Conformation by TLC Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 16 1/7/2013

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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. 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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 17

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 18

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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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 19

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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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 20

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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 lipophillic/ 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 lipophillic/ 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 lipophillic, 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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 21

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 22

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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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 23

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 24

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 25 Continued…

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 26

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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 1 µm 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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 27

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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 λ m = value of that ratio for monolayer P = partial pressure of the absorbate gas P0 = vapour pressure of the pure absorbate gas C = a constant 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 28 ____1____ λ (P 0 /P – 1) = C - 1 λ m C P P 0 + __ 1__ λ m C

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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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 29

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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 . 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 30

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 31

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 32

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 33

Types of Tablets:

Types of Tablets 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 34 (A) Tablets ingested orally: Compressed tablet, e.g. Paracetamol tablet Multiple compressed tablet Delayed release tablet, e.g. Enteric coated Bisacodyl tablet Repeat action tablet Sugar coated tablet, e.g. Multivitamin tablet Film coated tablet, e.g. Metronidazole tablet Chewable tablet, e.g. Antacid tablet (B) Tablets used in oral cavity: Buccal tablet, e.g. Vitamin-c tablet Sublingual tablet, e.g. Vicks Menthol tablet Troches or lozenges Dental cone

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(c) Tablets administered by other route: Implantation tablet Suppositories or Inserts, e.g. Clotrimazole tablet (D) Tablets used to prepare solution: Effervescent tablet, e.g. Dispirin tablet (Aspirin) Dispensing tablet, e.g. Enzyme tablet (Digiplex) Hypodermic tablet Tablet triturates e.g. Enzyme tablet (Digiplex) 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 35

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1 5 4 3 2 Drug What a tablet contains??? drug excipients (1-7) Excipients : 1 – Diluent 2 – Binder 3 – Disintegrents 4 – Lubricant, Glidants 5 – Colors 6- Sweeteners 7.Flavors 6 7 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 36

Tablet Additives / excipients used in tableting:

Tablet Additives / excipients used in tableting In addition to active ingredients, tablet contains a number of inert materials known as additives or excipients. Different excipients are: Two major classifications of additives by function include those which affect the compressional characteristics of the tablet Diluents Binder and adhesive Lubricants, Antiadherants and glidents And those which affect the Biopharmaceutics, chemical and physical stability and marketing considerations of the tablet Disintegrents and Superdisintigrant Coloring agents Flavoring agents Sweetening agents Miscellaneous component ( example, buffers and adsorbents ) 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 37

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Diluents : Diluents are fillers used to make required bulk of the tablet when the drug dosage itself is inadequate to produce the bulk. Secondary reason is to provide better tablet properties such as improve cohesion , to permit use of direct compression manufacturing or to promote flow . 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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 38

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Commonly used tablet diluents 1. Lactose-anhydrous and spray dried lactose 2. Directly compressed starch-Starch Rx 1500 3. Hydrolyzed starch-Emdex and Celutab 4. Microcrystalline cellulose- Avicel (PH 101and PH 102) 5. Dibasic calcium phosphate dehydrate 6. Calcium sulphate dihydrate 7. Mannitol 8. Sorbitol 9. Sucrose- Sugartab, DiPac, Nutab 10. Dextrose 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 39

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2. Binders and Adhesives : Used in tablet formulations to make powders more compressible and to produce tablets that are more resistant to breakage during handling. These materials are added either dry or in wet- form to form granules or to form cohesive compacts for directly compressed tablet. 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. Example : Acacia, tragacanth - Solution for 10-25% Conc. Cellulose derivatives- Methyl cellulose, HPC, HPMC Gelatin- 10-20% solution Glucose- 50% solution Polyvinylpyrrolidone (PVP)- 2% conc. Starch paste-10-20% solution Sodium alginate , Sorbitol 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 40

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 41

3. Disintegrants :

3. 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 water, gastric or intestinal fluid in the GIT and this process of deaggregation 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. Examples Starch USP and various starch derivatives are used as disintegrants in the conc. range of 5-20% of tablet weight and Pregelatinized starch (5 % conc.) Modified starches like Primogel and Explotab , which are low substituted carboxyl methyl starches are used in lower conc. (1 - 8 %) with 4 % as optimum. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 42

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DISINTEGRANTS CONCENTRATION  IN GRANULES (%) SPECIAL COMMENTS Starch USP 5-20 Higher amount is required, poorly compressible Starch 1500 5-15 Avicel®(PH 101, PH 102) 10-20 Lubricant properties and directly compressible Explotab® 2-8 Sodium starch glycolate, superdisintegrant. AC-Di-Sol® 1-3 Direct compression Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 43 1/7/2013 List of disintegrants Sodium carboxy methylcellulose (NaCMC and CARMELLOSE sodium) has highly hydrophilic structure and is soluble in water. (Ac-di-Sol) - It is modified form of Crosscarmellose sodium by internally crosslinking 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. Clays- Veegum HV, Bentonite 10% level in colored tablet only. Alginate PVP (Polyvinylpyrrolidone )- cross-linked.

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Superdisintegrants : Swells up to ten fold within 30 seconds when contact water. Example : Crosscarmellose- cross-linked cellulose, Crosspovidone- cross-linked povidone (polymer), Sodium starch glycolate - cross-linked starch. A portion of disintegrant is added before granulation and a portion before compression, which serve as glidants or lubricant. Evaluation of carbon dioxide in effervescent tablets is also one way of disintegration . 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 44

4. Lubricants, Antiadherants & Glidants:

4. Lubricants, Antiadherants & 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 inter particle 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 antiadherants are added, which prevent sticking to punches and die walls. Talc, magnesium stearate and corn starch have excellent antiadherant properties. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 45

Examples of Lubricants, antiadherants and glidants:

Examples of Lubricants, antiadherants and glidants Lubricants Concentration Comments Stearates (Magnesium Stearate, Calcium Stearate, Sodium stearate) 0.25 -1 Reduce tablet strength; prolong disintegration; widely used. Talc 1 -2 Insoluble but not hydrophobic; moderately effective. Glyceryl behapate (Compritol®888) 1 - 5 Both lubricant and binder; Antiadherants Range Comments Talc 1 – 5 Lubricant with excellent antiadherents properties Cornstarch 3 –10 Lubricant with excellent antiadherents properties Sodium lauryl sulfate <1 Antiadherents with water soluble lubricant Colloidal silica 0.1 – 0.5 Does not give satisfactory results due to small surface area. Cab-O- Sil ® and Syloid® Stearates <1 Antiadherents with water insoluble lubricant Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 46 1/7/2013 Glidants Range Comments Colloidal silica i.e. syloid, pyrogenic silica 0.25% --- Hydrated sodium silio aluminate 0.75% ---

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5. Coloring agent: The use of colors and dyes in a tablet has three purposes: (1) Masking of off color drugs (2) Product Identification (3) Production of more elegant product Examples - All coloring agents must be approved and certified by FDA. Natural vegetable colors – limited availability & unstable. FD & C and D & C approved dyes and lakes are used. Lake are dyes absorbed on hydrous oxide or alumina or aluminum hydroxide employed as dry powder coloring and are used in dry granulation. FD & C yellow 6-sunset yellow, FD & C yellow 5- Tartrazine, FD & C green 3- Fast Green, FD & C blue 1- Brilliant Blue, FD & C blue 2 - Indigo carmine. D & C red 3- Erythrosine and D & C red 22 – Eosin Yellow . How they added ???? Colors either added in dry granulation mixture or in vehicle used for wet granulation, t hese dyes are applied as solution in the granulating agent or Lake form of these dyes. Wet granulation gives better uniformity of color, but migration of the dye to the top of granules along with solvent during drying should be watched against. Dyes tend to fade on standing and exposure to light leads to mottling. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 47

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6. Flavoring agents: Flavors are usually limited to chewable tablets or other tablets intended to dissolve in the mouth. In general flavors that are water soluble have been found little acceptance in manufacturing of tablets because of there poor stability. Flavoring agents do not affect any physical characteristics of the tablet granulation. Proportion limited to 0.5 % w/w total weight of tablet. Excess quantity will interfere with free flow of granules. How they incorporated into tablet dosage forms???? They 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. Examples - Raspberry, Pineapple, Peppermint, Blackcurrant, Orange, Mango, Strawberry. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 48

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7. Sweetening agents: Use is primarily limited to chewable tablets. For chewable tablets: Sugar, Mannitol. Mannitol – 72% as sweet as sucrose. Earlier saccharin (artificial) was the only artificial sweetener used, it is 500 times sweeter than sucrose. Disadvantage: Bitter after taste and carcinogenic. Aspartame (artificial) is the new sweetener. Disadvantage: Unstable in the presence of moisture. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 49

Granulation :

Granulation 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 50 What are granules? Granules are the multiparticle entities in which primary powder particles are made to adhere to form larger particle and this process is called as granulation. Granule size ranges- between 0.2 to 4 mm. In tablets & capsules granules are the intermediate product & having size of 0.2 to 0.5 mm. Need of granulation To prevent segregation of the constituents of the powder mix. To improve the flow properties of the mix. To improve the compaction characteristics of the mix To densify the materials To facilitate metering or volume dispensing To Control the rate of drug release from tablets, capsules. To decrease dust generation and reduce employee exposure to drug product (toxicity).

Mechanisms of granulation:

Mechanisms of granulation There are five particle bonding mechanisms Adhesion and cohesion forces in the immobile liquid films Adhesion and cohesion forces in immobile liquid films between individual primary powder particles. Interfacial forces in mobile liquid films within the granules 3. Formation of solid bridges after solvent evaporation Partial melting, Binder hardening, crystallization of dissolved sub. 4. Attractive force s between solid particles 5. Mechanical interlocking. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 51

Granulation methods/ techniques :

Granulation methods/ techniques Dry methods 1. Direct Compression 2. Dry granulation (Compression granulation) Wet method 3. Wet granulation 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 52 DRY BLENDING WEIGHING SIZING BLENDING LUBRICATION COMPRESSION COATING 1 DRY GRANULATION WEIGHING SIZING BLENDING COMPACTION MILLING LUBRICATION COMPRESSION WET GRANULATION WEIGHING SIZING GRANULATION DRYING BLENDING LUBRICATION COMPRESSION 3 2

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Granulation technology on large scale by various techniques 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 53

1. Direct Compression :

1. 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. Because of the increased proximity of particle surfaces accomplished during compression, bonds are formed between powder particles which provide coherence to the powder i.e. compact is formed. Additives: Diluents Disintegrating agents Organoleptic additives Glidants, lubricants Need of other component Large dose- not suitable Small dose- impractical Moderate dose- suitable Directly compressible vehicles are needed. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 54

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Powders intended for compression into tablets must possess following essential properties like.. 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 coloring etc Friction and adhesion properties. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 55

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-Pac Ò, 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. Elimination of granulation process Heat (wet granulation) Moisture (wet granulation) High pressure (dry granulation) 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 56

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Processing without the need for moisture and heat which is inherent in most wet granulation procedures. Avoidance of high compaction pressures involves in producing tablets by slugging or roll compaction Thus increasing not only the stability but also the suitability of the process for thermolabile and moisture sensitive API’s. Elimination of variabilities in wet granulation processing Binders (temp, viscous, age) Viscosity of the granulating solution (depend on its temp), How long it has been prepared ? Rate of binder addition and kneading can affect the properties of the granules formed The granulating solution, the type and length of mixing and the method and rate of wet and dry screening can change the density and particle size of the granules, which can have a major effect on fill weight and compaction qualities. Type and rate of drying Can lead not only to critical changes in equilibrium MC but also to unblending as soluble active ingredients migrate to the surfaces of the drying granules. More unit processes are incorporated in production, the chances of batch-to- batch variation are compounded. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 57

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Particle size uniformity. Prime particle dissolution/dissociation: 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 . Chemical stability problems for API and excipient would be avoided. Provides greatest stability against the effect of aging Dissolution rates . Color Fewer chemical stability problems would be encountered as compared to those made by the wet granulation process. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 58

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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 59

PowerPoint Presentation:

Concerns/ limitatations for selection of direct compression method 1. Excipient available from only one supplier and often cost more than filler used in granulation 2. Procedure conservation 3. Machine investments 4. Lack of material knowledge 5. Physical limitation of drug No compressibility No flowability 6. Physical characteristics of materials (both drug and excipient) Size and size distribution Moisture Shape and surface Flowability Density 7. Lot to lot variability 8. Dusting problem 9. Coloring 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 60

Steps involved in direct compression process (Procedure):

Steps involved in direct compression process (Procedure) 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. Things to consider at blending stage 1. Homogeneity 2 . Risk of over mixing 3.Can lead to demixing 4 . Influence by properties of the particles 4. High shear rates Effects the particle size in weak powders , Scaling up , Not always linear. Step IV. Lubrication – addition of lubricants, glidants or anti adherents Step V. Compression by suitable equipment. Step VI . Coating if necessary. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 61

Directly Compressible vehicles / fillers :

Directly Compressible vehicles / fillers Common materials that have been modified in the chemical manufacturing process to improve fluidity and compressibility. Directly compressible vehicles/additives are generally classified into two categories namely – 1. Soluble fillers Lactose Sucrose Dextrose Mannitol Sorbitol Maltodextrin 2. Insoluble fillers Starch Cellulose Inorganic calcium salts 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 62

1. Soluble fillers:

1. Soluble fillers i. Lactose i. 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. Loss 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 tartrate, citrate and acetate ions. ii. 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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 63

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iii. Tabletose : aggromerate form of lactose More compressible than spray dried but less compressible than Fast Flo lactose. iv. Anhydrous lactose: free flowing crystalline lactose Produced by crystallization above 93C which produces the beta form Pass through steam heated rollers Good flow property, contained high amount of fines, its fluidity is less than optimal Can be reworked At high RH anhydrous lactose will pick up moisture forming the hydrated compound  increase in the size of tablets if the excipient makes up a large portion of the total tablet weight Excellent dissolution property 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 64

ii. Sucrose:

ii. Sucrose Di-Pac- co crystallization 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 aging 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 Concentration of moisture is extremely critical in terms of product compressibility 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 stearate Large particle size distribution and good fluidity Poor color stability 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 65

iii Dextrose:

iii Dextrose Emdex: spray crystallized form of dextrose. 90-92% dextrose, 3-5% maltose and the remainder higher glucose polysaccharides Available both anhydrous and a hydrate product Excellent compressibility Largest particle size, blending problem may occur 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 66 iv. 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 Lubricant requirements increase when the MC of the sorbitol drops below 0.5% or exceeds 2%. Hygroscopic and will clump in the feed frame and stick to the surfaces of the die table when tableted at humidities > 50%

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V. Mannitol Exists in a number of polymorphic forms Not make as hard a tablet as sorbitol 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 Vi. Maltodextrin Maltrin Highly compressible Completely soluble Very low hygroscopic 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 67

2. Insoluble fillers:

2. Insoluble fillers i. Starch Starch 1500: intact starch grains and ruptured starch grains that have been partially hydrolyzed and subsequently aggromerated. Extremely high MC (12-13%) 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 Deforms elastically when a compression force is applied, it imparts little strength to compacts Lubricants tend to dramatically soften tablets containing high concentrations of Starch 1500 Spray dried starch Era-Tab: spray-dried rice starch Good fluidity, MC 10-13%, Compressibility depend on moisture, Rework ability, Low bulk density. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 68

ii. Cellulose:

ii. 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 PH102 more agglomerated , larger particle size, slightly better fluidity but not significant decrease in compressibility. 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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 69

PowerPoint Presentation:

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. Elcema – microfine cellulose form , also in granular grade G-250 , which is the only form that posses all fluidity , self compressible, self disintegrating and antiadherent form of cellulose that can be used to make hard compacts. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 70

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iii. 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 Nonhygroscopic 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. Cel O Cal- 30 parts MCC and 70 % anhydrous calcium sulfate. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 71

EQUIPMENTS USED IN DIRECT COMPRESSION :

EQUIPMENTS USED IN DIRECT COMPRESSION 1. Milling Hammer mill Ball mill Colloid mill Fluid energy mill Cutter mill Roller mill 2. Sieving Different mesh sizes sieves Mechanical sieve shaker 3. Blending/Mixing High share mixers Tumbling mixers Y-cone Rotating cube Double cone Fluidized bed Agitator mixers Ribbon blender 4.Lubrication 5. Compression 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 72

Hammer Mill:

Hammer Mill 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 73 1. Equipments used for Milling

Ball Mill:

Ball Mill 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 74 Bench top Model Industrial Model Working Mechanism

PowerPoint Presentation:

1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 75 Fluid-energy Mill

Cutting Mill :

Cutting Mill 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 76 Roller Mill

Colloid Mill:

Colloid Mill 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 77

2. Equipments used in sieving:

2. Equipments used in sieving 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 78 Mechanical sieve shakers Sieve

3. Equipments used for blending and lubrication:

3. Equipments used for blending and lubrication High shear mixers Tumbling mixers Y-cone blender Rotating cube mixer Double cone blender Fluidized bed mixer/dryer/blender Agitator mixers Ribbon blender 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 79

High shear mixers/granulators:

High shear mixers/granulators 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 80

PowerPoint Presentation:

1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 81 Tumbling mixer Y-cone blender Rotating cube mixer Double cone mixers Fluidized bed granulator

PowerPoint Presentation:

1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 82 Agitator mixers Ribon mixers Planetory mixer Nauta mixer

2. Dry granulation (Compression granulation):

2. Dry granulation (Compression granulation) Advantages If the drug dose is too high for disease condition. 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. There are two methods of dry granulation are as follows 1. Slugging (dry granulation) 2. Roller Compaction 1. 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 for compression. The process of Slugging, Screening and Milling can be repeated till desired characteristics of flow are obtained. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 83

PowerPoint Presentation:

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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 84

2. Dry compaction/Roller compaction:

2. 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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 85

PowerPoint Presentation:

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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 86 Compacts Powder to be compacted Size reduction of compacts into granules Roller compactor "Chilsonator"

PowerPoint Presentation:

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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 87

PowerPoint Presentation:

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 Standard 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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 88

Wet granulation:

Wet granulation 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 89 Dry granulators

PowerPoint Presentation:

1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 90 Dry granulators

3.Wet granulation:

3.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; over wetting will cause the granules to be too hard and under wetting will cause the granules to be too soft and friable. Aqueous solutions have the advantage of being safer to deal with than other solvents. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 91

Advantages of wet granulation method:

Advantages of wet granulation method Cohesiveness and compressibility of powder is improved- increases tooling life and decreases machine wear. Drugs having high dosage , poor flow and compressibility must be compressed. Good distribution and uniform content for soluble, low dosage form drugs and color additives i f these are dissolved in binder solution. A wide variety of powders can be processed together in a single batch. Bulky and dusty powders are handled without great deal of dust and airborne contaminitation. It prevents segregation of powder components- composition of granule is fixed. Dissolution of insoluble drug is may be improved by proper choice of solvent and binder. Controlled release dosage forms can also be accomplished by selection of suitable binder and solvent. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 92

PowerPoint Presentation:

Limitations of wet granulation: The greatest disadvantage of wet method is its Cos t because of large number of space, time, equipments involved . Not suitable for heat and moisture sensitive drugs . It is time consuming especially wetting and drying steps. Possibility of material loss during processing due to transfer from one unit operation to another. Greatest possibility of cross contamination than direct compression method. Presents material transfer problems inducing processing of sticky mass. It can slows dissolution of drugs from inside granules after tablet disintegration if not properly formulated and processed . 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 93

PowerPoint Presentation:

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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 94 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(Compression) Last step in which the tablet is fed into the die cavity and then compressed.

List of equipments used in wet granulation/wet granulators :

List of equipments used in wet granulation/wet granulators 1.Shear granulators Planetary mixer Sigma blade mixer Tumbler mixers 2. High speed/shear mixer /granulators Little ford Lodgie granulator Little ford MGT granulator Diosna granulator Collette - Gral mixer/granulator Oscillating granulator 3. Granulators with drying facility Fluidized bed granulator (All in one granulator) Day Nauta mixer processor Double cone or twin shell processor Topo granulator CF granulator Spray dryer/granulator 4. Special granulators Roto granulator Marumerizer (Speronizer) Pelletizer. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 95

1. Shear granulators :

1. Shear granulators Traditionally, dry mixing in wet granulation process has been carried out using, Sigma blade mixer, Heavy-duty planetary mixer. Tumbler mixer. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 96 Sigma blade mixer Planetary mixer Tumbler mixer

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SOP of Shear Mixture Granulators: Mixed powder are fed in to the bowl. Granulating liquid is added. The moist mass has then transferred to a granulator such as oscillating granulator. Advantages Not very sensitive to the material End point can be determined by inspection Disadvantages Long duration Large number of equipment are needed High material loss 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 97

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2. High speed/shear mixer /granulators High shear mixer/granulators are Widely used in pharmaceutical industries. Stainless Steel mixing bowl containing a three blade main impeller, revolves in horizontal plane designed to rotate at 150-300rpm, and A three blade auxiliary chopper – revolves vertical or horizontal plane – 1500-3000 rpm Unmixed powder –in the bowl mixed for few minute with rotating impeller and then granulation. Bowl volumes 1L to 1250 L are available. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 98

High shear power blenders capable of blending and granulating…. :

High shear power blenders capable of blending and granulating…. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 99 1/2. Little ford Lodige mixers / granulators

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 100 Typical Time Sequence Mixing – 2 minutes Granulation – 8 minutes Discharge – 1 minutes Advantage Mixing, Massing, Granulation in a single equipment within few minutes Disadvantage End point monitoring needed Gives more normal Particle Size Distribution with lesser fines . 3. Diosna Mixer / Granulator Rapid Mixer Granulator (RMG) blade chopper

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 101 Rapid Mixing Granulator: (RMG)

3. Diosna mixer/granulator :

3. Diosna mixer/granulator 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 102

4. Collette Gral granulator:

4. Collette Gral granulator Widely used in pharmaceutical industries. Stainless Steel mixing bowl containing a three blade main impeller, revolves in horizontal plane- 10 L t0 200 L – 3 kg to 80 kg batches – blade 450-600rpm and 150-200 rpm respectively and A three blade auxiliary chopper –revolves vertical or horizontal plane- 1500-3000rpm Unmixed powder –in the bowl mixed for few minute with rotating impeller & granulation. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 103

4. Gral mixers:

4. Gral mixers 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 104

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5.Oscillating granulator 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 105 5.Oscillating granulator Oscillating bars rotate at speed 60-100 rpm Sizes available - Wet mass - 300-500 kg/hr And Dry mass – 700- 1200 kg/hr.

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2. Granulators with drying facility 1. Fluidized bed granulator /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. Long and product specific process also… .?. . That is optimization of all apparatus, process and product parameters is essential… 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 106 Fluid-bed granulator Binder solution spray Granulation of the powder Warm air flow

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Fluidized Bed Granulator 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 107

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Sizes available – 0.2 & 2L ---few grams to kg granules Also with capacity of 5 kg to 1550 kg. Advantages One unit so saving labour cost, transfer loses and time 2-6 time greater heat transfer than tray dryer , Uniform drying….prevent mottling. Process can be automated once parameters optimized. Disadvantages Expensive, Multiple process variable, Filter clocking, demixing, electrostatic charge, solvent explosion 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 108 Apparatus parameters Process parameters Product parameters Air distribution plate Bed load, fluidizing air temperature Type , quntity of binder, solvent, Shape of granular body Fluidizing air humidity Conc. , temp. of granulating solution, Nozzle height Atomization Starting materials Positive or negative pressure operation Nozzal type, spray angle, spraying regime, liquid flow rate, Fluidization Powder hydrophobicity atomizing air flow rate, air pressure, droplet size

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 109 Fluidized Bed Granulator (Industrial Equipment)

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 110 2. Day Nauta mixer processor/granulators

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 111 3. Double Cone or Twin shell processor Two important standpoint of view to use this granulator … 1.Solvent vapors are not discharged to the atmosphere and 2. Efficient solvent recovery is achievable an economic consideration. But drying time is more than fluidized bed dryer…

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 112 4. Topo granulator

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 113 5. CF granulator

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 114 6. Spray dryer/granulator

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 115 Large surface area for both mass transfer and heat transfer ..by atomizing the liquid to small droplets..into stream of hot air. so each droplet dries as individual particles. Drying chamber is like cyclone –for separation of dried particles from the moving air by centrifugal force action. Three parts of each spray granulator.. Atomizer- initially simple jet was used but they easily blocked due rapid evaporation and deposition of solid on the nozzle. Rotary atomizer- liquid is fed on the disc rotated at speed 10000-30000rpm- has advantage is to used for either solutions, suspensions of solids etc.. Two fluid atomizers – one liquid product and atomizing air. Feed rate 30-80 L/h with two positions for spraying..co-currently - 2 µm and from bottom that is Fountain mode- 100 µm and rotary - 50 µm particle sizes 2. Drying Chamber- air enters tangentially to dry the droplets..spray dryers sizes Laboratory size – 100 - 200 ml - few grams of granules Pilot scale size – chamber diameter 800 mm & height 3 m to evaporate 7 kg/h of water Production scale - chamber diameter 3.5 m& height 6 m to evaporate 50-100 kg/h of water or 4000 kg /h in large industries 3.Product – uniform size of particles or hollow spheres with small hole at the center..

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 116 Advantages of spray drying process Time is less for granule formulation due to high rate of evaporation Droplets not attend high temperature Product with good packing and high bulk density leads to rapid dissolution due to high surface area Provided that suitable atomizer uniform and controllable particle size produced Product is free flowing with good flow and compaction properties Increases dissolution and bioavailability of poorly water soluble drugs Labor cost is low process yields dry free flowing product from solution in a single operation without handling It can be used continuous process Disadvantages The equipment is very bulky and with ancillary equipment is expensive Overall thermal efficiency is low air must be still hot when leaving the dryer and large volume of hot air circulating in the dryer without contributing to the drying process.

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 117 3. Special granulators 1 Rotor granulators

2. Merumizer (Spheronizer):

2. Merumizer (Spheronizer) 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 118 Wet mass containing drug , diluents and binder is pass through extruder to get rod shaped segments. Cylinder Screw-feed Extruder Segments are placed in MERUMIZER where they are shaped into sphere by centrifugal and frictional forces produced by rotating plates/blades and form granules Advantage Granules with regular size, shape with lower friability, so less amount of fines.

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3 Pelletizer 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 119

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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 120

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Upper and Lower Collar Collar locker Single Punch Machine (Tablets) 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 121

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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 powder weight-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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 122

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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 123

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 124

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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 125

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 126

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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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 127

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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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 128

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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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 129

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 130 HIGH SPEED ROTARY MACHINE MULTI ROTARY MACHINE

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 131 DOUBLE ROTARY MACHINE UPPER PUNCH AND LOWER PUNCH

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 132 SINGLE ROTARY MACHINE

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 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 133

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 134

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 135

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 136 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.

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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) 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 137

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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. 1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 138

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1/7/2013 Prof. D. M.Shinkar, KCT'S R.G.S.C.O.P.Nashik 139 Thank You If you salute your duties, No need to salute anybody If you don’t salute your duties, You have to salute everybody . …. [email protected]

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