Powders and Granules PDF

POWDERS AND GRANULES Sanjay Gayakwad, Ph.D. Associate Professor – Pharmaceutics Email: [email protected] Office # W332 LEARNING OBJECTIVES 1) Discuss the fundamental and derived properties of powders and explain how they affect the powder performance. 2) Di...

POWDERS AND GRANULES Sanjay Gayakwad, Ph.D. Associate Professor – Pharmaceutics Email: [email protected] Office # W332 LEARNING OBJECTIVES 1) Discuss the fundamental and derived properties of powders and explain how they affect the powder performance. 2) Discuss particle size analysis and methods to reduce particle size. 3) Compare and contrast the various types of powders. 4) Differentiate a powder from a granule. 5) Understand the advantages and disadvantages of powders and granules. 6) Discuss preparation methods of powders and granules. 7) Perform calculations involved in the preparation of effervescent granules. POWDERS AND GRANULES ▪ Simple powder A single chemical substance in powder form ▪ Pharmaceutical powder: A mixture of finely divided solids in dry form ▪ Granule: A prepared agglomerate of powdered material http://www.niroinc.com/technologies/spray_ drying_tech.asp ▪ Characteristics ▪ May be very fine, coarse, or of intermediate particle size ▪ Used internally and externally ▪ Dispensed as bulk or divided powders/granules http://www.sz-promo.com/spproduct/ 129825/2b101211c/ modified-pvc-granules-of-injection-401503a.html POWDERS AND GRANULES Advantages ▪ Higher stability – due to dry form ▪ Ease and convenience of administration for larger doses Disadvantages ▪ Problems with bitter tasting and moisture sensitive drugs ▪ Packaging difficulty (especially for divided powders) MICROMERITICS – SCIENCE OF SMALL PARTICLES ▪ Fundamental (primary) properties ▪ Derived (secondary) properties ▪ Relating to basic material properties ▪ Relating to behavioral properties ▪ Particle size ▪ Flow ▪ Particle shape ▪ Density (bulkiness) ▪ Particle surface area ▪ Porosity (compactability or packing ▪ Particle size distribution arrangement etc.) ▪ Lubricity ▪ Study of powder (particle) characteristics e.g. size, size distribution, shape, flow properties, porosity, density and bulkiness FUNDAMENTAL POWDER PROPERTIES PARTICLE SIZE ▪ For spherical particles size can be expressed in diameter ▪ Expressing particle size in diameter becomes complicated when there is little or no symmetry in the particle size i.e. there is no unique diameter for a particle ▪ To describe the size of an asymmetric particle, a parameter called equivalent spherical diameter (ESD) is used ▪ ESD relates size of the particle to the diameter of a sphere having the same surface area, volume etc. EFFECTS OF PARTICLE SIZE ▪ Dissolution rate: ▪ Suspendability: ▪ Content uniformity: ▪ Inhalers: ▪ Grittiness: EFFECTS OF PARTICLE SIZE ▪ Dissolution rate: Micronized drugs have higher dissolution and bioavailability. ▪ Suspendability: Rate of settling can be reduced by using finer particles. ▪ Content uniformity: Dose variation can be reduced by using uniform size of particles. ▪ Inhalers: Only fine particles reach deep in the respiratory tract. ▪ Grittiness: Coarse particles may cause grittiness in dermal ointments, creams and ophthalmic preparations. PARTICLE SIZE AND ANALYSIS Sieve Number Sieve Opening Table 1: Opening of standard sieves (USP31 – NF26) 2.0 9.50 mm 3.5 5.60 mm 4.0 4.75 mm 8.0 2.36 mm 10.0 2.00 mm 20.0 850.0 µm 30.0 600.0 µm 40.0 425.0 µm 50.0 300.0 µm 60.0 250.0 µm 70.0 212.0 µm 80.0 180.0 µm 100.0 150.0 µm 120.0 125.0 µm 200.0 75.0 µm 230.0 63.0 µm 270.0 53.0 µm 325.0 45.0 µm 400.0 38.0 µm PARTICLE SIZE CHARACTERIZATION USP Category Sieve # Definition All pass through sieve #8 Very coarse powder #8 NMT 20% pass through sieve #60 All pass through sieve #20 Coarse powder # 20 NMT 40% pass through sieve #60 Moderately coarse All pass through sieve #40 # 40 powder NMT 40% pass through sieve #80 # 60 All pass through sieve #60 Fine powder NMT 40% pass through sieve #100 Very fine powder # 80 All pass through sieve #80 The larger the sieve # the smaller the particle size PARTICLE SIZE REDUCTION Comminution: Reduction of particle size of a solid substance to a finer state ▪ Trituration: Comminution in dry state. ✓A rough surface (porcelain mortar) is more effective than a smooth surface (glass mortar) ▪ Levigation: Comminution with the aid of a liquid (levigating agent) in which the powder is insoluble. ▪ Pulverization by intervention: The process which uses recrystallization as a method of obtaining fine particles. ✓Useful for rubbery substances such as camphor. PARTICLE SHAPE ▪ Shape affects the flow and packing properties of powder ▪ Sphere has ____________ minimum surface area per unit volume ▪ More asymmetric a particle, the __________is greater the surface area per unit volume ▪ As particle becomes more asymmetric, it is difficult to assign a meaningful diameter to the particle ▪ Hence need for equivalent spherical diameter PARTICLE SIZE DISTRIBUTION ▪ Particle size distribution provides an estimation of size range and the number or weight fraction that falls into each size range % Fraction Particle Size ▪ Two samples may have different distributions even though the average diameter for them is the same ▪ Monodisperse distribution: Only one peak ▪ Polydisperse distribution: Multiple peaks ▪ Particle size distribution can be plotted using either number of particles or weight of particle DERIVED POWDER PROPERTIES FLOW ▪ Angle of repose is used to measure flow properties of a powder ▪ Determined by allowing a powder to flow through a funnel and fall freely onto a surface h tan θ = h/r  r φ = angle of repose h = height of the powder cone r = radius of the powder cone ANGLE OF REPOSE Regular (spherical) Coarse & irregular Angular Smaller angle of repose = Better flow properties POROSITY Interparticle space Intraparticle space Porous particle POROSITY ▪ Bulk/apparent volume: Total volume of an uncompacted powder, Vb ▪ True powder volume: Actual volume of the powder (excludes inter- & intraparticle spaces), Vp ▪ Void volume: Total intra- and inter-particle spaces, v v = Vb − Vp ▪ Granular volume: Total volume of the granules (includes the pores, i.e., intraparticle space), Vg POROSITY ▪ Porosity: The amount of void volume per unit bulk, . v Vb − Vp Vp = = =1− Vb Vb Vb ▪ Expressed as fraction or percentage DENSITY ▪ Bulk density: Density of the bulk powder, b b = Sample weight Vb ▪ Granule density: Density of the granules (includes pores, i.e., Sample weight intraparticle space) g = Vg ▪ True density: Density of the material itself (excludes all voids, Sample weight i.e., inter and intra-particle spaces larger than molecular p = dimensions) Vp identical For nonporous granules: True and granule density are ________. BULKINESS ▪ Bulkiness or bulk or the specific bulk volume is the reciprocal of bulk density ▪ Important consideration in the packaging of powders Vb B= Sample weight T YPES OF POWDERS ▪ Bulk powders ▪ Dispensed in bulk quantities, for non potent drugs. ▪ Internal use: Antacids, laxatives, douche powders ▪ External use: Anti – infectives, antifungals, dental cleaning powders ▪ Generally stored at room temperature, in a clean and dry place ▪ Divided powders ▪ Potent medication powders are available as divided powders or it can also be dispensed by pharmacists. ▪ Divided into individual dosing units based on the amount to be taken or used at a single time MEDICATED POWDERS ▪ External use ▪ Dusted on the affected area from sifters or powder aerosols ▪ Internal use ▪ Local effects: Laxatives, antacids, etc. ▪ Systemic effects: Analgesics, antibiotics etc. ▪ Doses of some drugs are too bulky to be formed into tablets or capsules ▪ Can be mixed with liquids or soft food ▪ Many unstable drugs are dispensed as oral or injectable powders for reconstitution (e.g. antibiotics for children) BLENDING OF POWDERS – 1 Blending: Mixing of two or more powders ▪ Spatulation ▪ Blending small amounts by spatula on sheet of paper or ointment tile ▪ Not suitable for potent substances or for large quantities of powders ▪ Suitable for eutectic mixtures (as only very little force is needed) ▪ Trituration ▪ Used to comminute as well as blend powders ▪ Geometric dilution is used to ensure uniform distribution, especially in case of potent drugs ▪ Inert colored powder can be added before mixing to permit visual inspection of the mixing process BLENDING OF POWDERS – 2 ▪ Sifting ▪ Powders are passed through sifters ▪ Makes light, fluffy products ▪ Not suitable for mixing potent drugs ▪ Tumbling ▪ Tumbling in rotating chamber ▪ Both small‐scale and large‐scale mixing V - Blender Bin - Blender GRANULES GRANULES Prepared agglomerates of smaller particles of powder ▪ __________ flow properties than powders ▪ ________ resistant to atmospheric humidity (due to ____ surface area, SA) ▪ ____ likely to cake or harden upon standing (due to ____ SA) ▪ _____ to wet compared to powders, which are generally __________ and tend to float on the surface of liquids and therefore, granules are often preferred for dry product http://www.plasticsportal.net/wa/plasticsEU~en_GB/port al/show/common/plasticsportal_news/2007/07_291 intended to be constituted into solutions or suspensions GRANULES Prepared agglomerates of smaller particles of powder Advantages ▪ Better flow properties than powders ▪ More resistant to atmospheric humidity (due to less surface area, SA) ▪ Less likely to cake or harden upon standing (due to less SA) ▪ Easy to wet compared to powders, which are generally light http://www.plasticsportal.net/wa/plasticsEU~en_GB/port and fluffy and tend to float on the surface of liquids. al/show/common/plasticsportal_news/2007/07_291 ✓ Therefore, granules are often preferred for dry product intended to be constituted into solutions or suspensions. GRANULES ▪ Commercial preparations ▪ Antibiotics: Amoxil®, Keflex®, Biaxin® dry suspensions ▪ Lactinex®: Used in uncomplicated diarrhea, including that due to antibiotic therapy http://www.theonlinedrugstore.com/Lactinex-Granules-Probiotic- Dietary-Supplement-p/1292648.htm EFFERVESCENT GRANULES ▪ Effervescent preparations: Sennakot® Granules, Zantac® 25 ▪ EFFER dose Granules ▪ Features ▪ A special form of granules used to provide a pleasant vehicle for selected drug products, especially those with a bitter or salty taste ▪ Contains mixtures of citric acid &/or tartaric acid &/or sodium dihydrogen phosphate combined with sodium bicarbonate EFFERVESCENT GRANULES ▪ In the presence of water, this mixture liberates carbon dioxide resulting in effervescence. ▪ The resulting carbonated solution masks undesirable taste of any medicinal agent. ▪ Granules or coarse particles are better than small powder particles because, in the latter type, rapid dissolution causes violent and uncontrollable effervescence, which may overflow the glass and leave little residual carbonation in the solution. EFFERVESCENT GRANULES ▪ Citric acid ‐ Makes sticky mixture, difficult to granulate ▪ Tartaric acid ‐ Granules readily lose their firmness and crumble ▪ Therefore, a combination of citric and tartaric acids are preferred over a single acid. ▪ The mixture containing citric acid and tartaric acid at a ratio of 1:2 provides desired effervescent effect. Tartaric Acid Citric Acid Sodium Bicarbonate M.W.= 150 M.W.= 210 M.W.= 84 EFFERVESCENT GRANULES 1) Tartaric Acid Sodium Bicarbonate 2) Citric Acid 3) Sodium dihydrogen phosphate EFFERVESCENT GRANULES PROBLEM ▪ Show all calculations on how you are going to prepare the following effervescence prescription: Rx Active drug 10% (w/w) In effervescence granules qs 120 g ▪ Dissolve 1 teaspoonful (5 g) in one‐half glass of cool water and drink. Repeat every 8 hours. EFFERVESCENT GRANULES PROBLEM 10 ▪ Total amount of drug needed = (120)g = 12g 100 ▪ Total amount of effervescence vehicle needed = 120 g – 12 g = 108 g ▪ This 108 g will be composed of citric acid and tartaric acid (1:2 ratio) and sodium bicarbonate ▪ You need to find out the exact amount of the acids and sodium bicarbonate ▪ How much NaHCO3 is needed for 1 g of citric acid? (3 moles of NaHCO3 react with 1 mole of citric acid, see reactions on previous slide) 3(84)g x = = 1.2g 210g 1g EFFERVESCENT GRANULES PROBLEM ▪ For each g of citric acid, 2g of tartaric acid is required. ▪ How much NaHCO3 is needed for 2 g of tartaric acid? (2 moles of NaHCO3 react with 1 mole of tartaric acid) 2(84)g x = = 2.24g Memorize 150g 2g ▪ Therefore, the ratio of citric acid, tartaric acid and NaHCO3= 1:2:(1.2+2.24)=1:2:3.44 ▪ Using the method of proportion (total 108g) ▪ Citric acid needed = 16.77g Tartaric acid needed = 33.54 g ▪ NaHCO3 need = 57.69g DRY OR FUSION METHOD ▪ Citric acid crystals are powdered and then mixed with other powders (including the drug) of the same sieve size. ▪ The mixing of powders should be performed as rapidly as possible in an environment of low humidity to avoid absorption of moisture and a premature chemical reaction. ▪ The powder mixture is placed on a suitable dish in an oven at 34‐40 °C. The heat releases water of crystallization from citric acid molecule. ▪ This water dissolves a portion of the powder mixture and thus acts as the binding agent for the mixture. ▪ This creates a spongy mass, which is removed from the oven and rubbed through sieve #10 (small granules), sieve # 8 (medium granules), sieve #4 (large granules). ▪ The resultant granules are dried in an oven at ≤54 °C and packed. WET METHOD ▪ The binding agent is not the water of crystallization but aqueous alcoholic solution. ▪ This binding agent forms the pliable mass for granulation. ▪ All anhydrous powder can be used in this method. ▪ Only slight amount of moisture is added to prepare a mass with proper consistency. ▪ Then the granules are prepared and dried in the same manner as outlined in the fusion method. REVIEW ▪ Pharmaceutical powder: A mixture of finely divided solids in dry form ▪ Advantages: Stability, ease of administration ▪ Disadvantages: difficult for the bitter taste, moisture sensitive drugs, packaging ▪ Particles size ranges from very fine to very coarse powders ▪ Particle size reduction: ▪ Comminution: reduction of a solid substance to a finer state ▪ Trituration: comminution in dry state ▪ Levigation: comminution with the aid of a liquid ▪ Pulverization by intervention: uses recryatllization REVIEW ▪ Micromeritics: study of small particles ▪ Fundamental (primary) properties: Relating to basic material properties ▪ Particle size, shape, surface area and size distribution ▪ Derived (secondary) properties: Relating to behavioral properties ▪ Flow, density (bulkiness) porosity and lubricity ▪ Inverse relationship between particle size and specific surface area ▪ For spherical particles size can be expressed in diameter, for asymmetrical particles equivalent spherical diameter (ESD) is used to describe the size REVIEW ▪ Sphere has minimum surface area per unit volume ▪ More asymmetric a particle, the greater is the surface area per unit volume ▪ Particle size distribution provides an estimation of size range and the number or weight fraction that falls into each size range ▪ Angle of repose is used to measure flow properties of a powder ▪ Porosity and density (bulkiness): Important consideration in the packaging of powders REVIEW ▪ Blending of powders: ▪ Spatulation: blending small amount by spatula, Trituration : comminute as well as blend ▪ Sifting: pass through sifters, Tumbling: use tumblers to mix ▪ Types of powders: bulk and divided, internal or external ▪ Granules: prepared agglomerates of powdered material ▪ Advantages: better flow, more resistant to humidity, less likely to form hard cake, easy to wet ▪ Effervescent granules: release gas to mask the bitter taste ▪ e.g. citric acid, tartaric acid and/or sodium phosphate and sodium bicarbonate ▪ Preparation methods: ▪ dry method; water comes from water of crystallization of citric acid ▪ Wet method: water is from aqueous alcohol