Powder Flow Characterization PDF

Characterization of powder flow; Determination of bulk and tapped density, Determination of angle of repose Renas Rzgar [email protected]  Introduction Powdered solids are heterogeneous mixture, composed of individual particles of different...

Characterization of powder flow; Determination of bulk and tapped density, Determination of angle of repose Renas Rzgar [email protected]  Introduction Powdered solids are heterogeneous mixture, composed of individual particles of different sizes and shapes, randomly spread with air spaces. Mass-to-volume relationships The mass of a bulk powder sample can be accurately determined, but its volume measurement is complicated. The main problem is the presence of three types of air spaces or voids. Introduction 1. Open intra-particulate voids. 2. Closed intra-particulate voids. 3. Inter-particulate voids.  Powder volume 1. The true volume (Vt) The total volume of the solid particles, which excludes all spaces.Determined using techniques like helium pycnometer 2. The granular volume (Vg) The cumulative volume occupied by particles including all intraparticulate voids. 3. The bulk volume (Vb) The total volume is occupied by the entire powder mass. 4. Tapped Volume (Vtapped) The volume occupied after the powder is mechanically tapped or compressed, reduces void spaces between particles. Tapping increases the packing density. 5. Void Volume The space between particles in the bulk powder. Calculated as: Void Volume = Bulk Volume - True Volume 6. Porosity Porosity is the percentage of space within a material (a substance or a mixture) Porosity is determined by dividing the volume of voids by the total volume of a material to determine a percentage Expressed as a percentage: Porosity (%) = (Volume of Voids / Total Volume) x 100.  Techniques of volume measurement 1. X-ray diffraction method. Techniques of volume measurement 2. Helium pycnometer. This method works on the principle that within a sealed system containing helium (a nonadsorbing gas), the change in pressure caused by a finite change in the system's volume is a function of its volume. 3. Specific gravity bottle method. This method is usually used for granules, in which nonsolvent organic liquids or mercury are used. 4. Cylinder  Determination of density Bulk density The bulk density of a material is the ratio of the mass to the volume (including the inter-particulate void volume) of an untapped powder sample. Bulk density depends on both the density and the arrangement of particles in the powder bed. The bulk density is expressed in (g/mL) The tapped density is an increased bulk density attained after mechanically tapping a container containing the powder sample. The tapped density is obtained by mechanically tapping a graduated measuring cylinder or vessel containing the powder sample. Applications Analysis of Bulk and tapped density of powder give you a possibility: To calculate the compressibility index and Hausner Ratio of your powder Give you an understanding of powder flowability and compressibility Powder flowability Flowability is the ability of a powder to flow. It has an effect on pharmaceutical processes such as mixing, transferring, and compression. Compressibility index and Hausner ratio They are measures of the product’s ability to settle and permit an assessment of the relative importance of inter-particulate interactions. In a free-flowing powder these interactions are less significant and the bulk and tapped densities will be closer in value. For poorly flowing materials, there are greater inter-particulate interactions, and a greater difference between the bulk and tapped densities will be observed. Calculation of flowability Observations Factors affecting powder flow particle size shape Density porosity surface texture Angle of repose Angle of repose: Is the angle between the horizontal and the plane of contact between two bodies when the upper body is just about to slide over the lower; also known as angle of friction. Procedure Put the weight of 2 different powders (lactose vs starch) into the cylinder and measure the bulk volume & density. Turn the density tester on, and let the device complete 500 cycles. Measure the volume and density of the tapped powder and calculate the Compressibility index and Hausner's ratio. Determine angle of repose for both powder Particle Size Analysis Renas Rzgar [email protected] Particle size analysis is a critical process in the pharmaceutical industry, as particle size can significantly influence the physical and chemical properties of drugs, including their ✓efficacy ✓stability ✓dissolution rate ✓bioavailability ✓formulation design, and manufacturing processes ✓drug release  In practice, we may not need to know the exact size of particles intended for a particular purpose, rather a size range may be sufficient. The size or ‘fineness’ of a powder may be expressed by reference to the passage/ non-passage of the powder through sieves of defined mesh size, for instance: Coarse powder Medium powder Fine powder Super fine powder Equivalent Sphere Diameter is a concept used in particle size analysis to describe the size of irregularly shaped particles. It provides a way to express the size of a particle as if it were a perfect sphere. Since most particles in the pharmaceutical industry are not perfectly spherical. The Equivalent Sphere Diameter is a sphere’s diameter with the same specific property as the particle being measured. The particular property used to define the equivalent sphere depends on the measurement technique employed. Feret’s Diameter and Martin’s Diameter are methods used in particle size analysis, particularly in image-based measurements, to describe the size of irregularly shaped particles. These measurements help characterize particle size when the particles are not spherical. Feret’s Diameter Feret’s Diameter (or Feret’s Distance) is the distance between two parallel tangents drawn on opposite sides of a particle’s projection in 2D. It depends on the orientation of the tangents, so rotating the particle may yield different Feret diameters. Common Techniques for Particle Size Analysis 1. Laser Diffraction (LD): Measures particle size distribution in a wide range (0.01 µm to several mm). Works on the principle of light scattering. Advantages: Fast, reproducible, and suitable for wet and dry samples. Common Techniques for Particle Size Analysis 2. Dynamic Light Scattering (DLS): Best for submicron particles (nanometer range). Measures the Brownian motion of particles in a liquid medium. They are commonly used for nanosuspensions and liposomes. Common Techniques for Particle Size Analysis 3. Microscopy (Optical and Electron): Optical microscopy is used for larger particles (>1 µm), while electron microscopy (SEM/TEM) is used for nanosized particles. Provides detailed morphological information. Common Techniques for Particle Size Analysis 4. Sieving: A traditional method for particles larger than 75 µm. Involves passing particles through a series of sieves with decreasing mesh sizes. PDI (Polydispersity Index) is a parameter used to describe the distribution of molecular weight or particle size in a sample. It is a critical quality attribute in pharmaceutical formulations, especially for nanoparticles, liposomes, and polymeric systems. PDI is a dimensionless value that quantifies the uniformity or heterogeneity of particle sizes in a sample. ✓ A low PDI indicates a narrow size distribution (monodisperse system). ✓ A high PDI indicates a broad size distribution (polydisperse system). PDI is calculated from the cumulant analysis of the correlation function, which provides information about particle size variability. PDI (Polydispersity Index) PDI Scale PDI < 0.1: Highly monodisperse system (particles are nearly uniform in size). PDI 0.1–0.5: Moderately polydisperse system (acceptable for many pharmaceutical applications). PDI > 0.5: Highly polydisperse system (not ideal; indicates a need for further optimization or purification). Procedure Weigh about 50 gm of the given granules on analytical balance. Switch on the analytical sieve machine, set the amplitude at 1 and the time of mechanical vibration on 5 minutes. Add the given amount of the powder granules to the coarsest sieve on the top and push start to initiate mechanical vibration. After the vibration has stopped, weigh the granules in each sieve. Calculate the % retained in each sieve. 𝒘𝒆𝒊𝒈𝒉𝒕 𝒊𝒏 𝒕𝒉𝒆 𝒔𝒆𝒊𝒗𝒆 𝒏𝒖𝒎𝒃𝒆𝒓 𝒙 % Retained = × 𝟏𝟎𝟎 𝒕𝒐𝒕𝒂𝒍 𝒘𝒆𝒊𝒈𝒉𝒕  Prepared by Renas Rzgar Jalal M.Sc. in Pharmaceutics  Introductions The term (Parenteral) has its derivation from the Greek words para (beyond, outside) and enteron (intestine) meaning outside of the intestine. The parenteral route is defined as medications placed into the tissues and the circulatory system by injection.  solution Powder Mucoadhesive Parenteral Formulations Introduction preparations Methodology Suspension Gels emulsion 3 Route of parenteral administrations According to the route of administration parenteral are classified into: 1. Intravenous (i.v): injected directly into vein 2. Intramuscular (i.m): injected directly into skeletal muscle 3. Subcutaneous (s.c): this is injected into the alveolar region beneath the layer of the skin. 4. Intra dermal (i.d): injected between layers of the skin. 5. Intra spinal (i.s): injected into the spinal canal. 6. Intra arterial (i.a): injected directly into the artery. 7. Drugs may be injected into almost any organ or area of the body including joints (intra articular), a joint-fluid area (intra synovial), the spinal column (intra spinal), into the spinal fluid(intrathecal), arteries (intra arterial) ad in an emergency, even into the heart (intra cardiac). The Volume of Injections for different types of injections vary Intravenous Volume unlimited (infusion) Subcutaneous Volume (2 ml) Intramuscular Volume (2 -5 ml) Intraspinal Volume (up to 10 ml) Intradermal Volume (0.2 ml)  REQUIREMENTS FOR PARENTERAL PREPARATIONS - Sterile - A pyrogenic - Pure - Stable - Isohydric - Isoviscous - Isotonic  Containers and closures Injectable formulations are packaged into containers made of glass or plastic. Container systems include ampoules vials syringes cartridges bottles and bags.  Ampoules An ampoule is a small sealed container made of glass (glass bottle), that mostly contains liquid drugs.  Ampoule sealing techniques There are two methods to seal the glass ampoule Tip sealing method Pull sealing method In the tip sealing method, heat is evenly applied on all sides of the neck to melt from a bead. In pull sealing method, the neck of the bottle is heated with a burner till the glass becomes soft. With the help of a mechanical device, the top is pulled and twisted.  Procedure 1. Prepare 0.9% Normal saline 2. Place 2 ml of Normal into the ampule glass 3. Seal the top of the glass using manual ampule sealer Mixing and Homogenization Renas Rzgar [email protected] Outline Introduction to mixing 01 Segregation 02 03 Factors affect mixing 04 Procedure 11/1/2024 2 Learning Outcomes Explain the principles and significance of effective powder mixing in ensuring formulation uniformity. Identify factors that contribute to segregation in powder mixtures. Demonstrate techniques to minimize segregation during mixing processes. Assess the impact of particle size, shape, and density on mixing outcomes. Implement quality control measures to evaluate and ensure homogeneity in final products. 11/1/2024 3  It is the process in which two or more components are combined in such a way that the particles of each component are positioned as closely as possible to the particles of the other components. The final product of the mixture contains a uniform distribution of both components.  To ensure a consistent dose. How? To ensure product quality/stability. How?  Positive mixtures: Spontaneously and irreversibly by diffusion and tend to approach a perfect mix. Examples: Gases (like air), alcohol and water, salt in water. Negative mixtures: Components will tend to separate out. Energy must be continuously input to keep the components adequately dispersed. Examples: Oil and water, sand and water, suspensions. Neutral mixtures: The components have no tendency to mix spontaneously or segregate spontaneously once work has been input to mix them. Examples: Powders, ointments, and certain solid mixtures like flour blends. Complete segregation Random mix Perfect mix Segregation  Segregation is the opposite of mixing. Random mix may change to a non-random mix. Particles that differ in size, shape, density and surface properties tend to segregate more easily than monosized mixtures.  Particle size Differences in the particle sizes of components of a formulation are the main cause of segregation. Particle shape Spherical particles segregate more than irregular-shaped particles. Particle Density Flow Characteristics  It’s a neutral type of mixing, one of the most common operations employed in pharmaceutical industries for the preparation of different types of formulations, such as powders, capsules and tablets. Powder mixing is a chance process, so achieving a perfect mix or ideal mix is practically impossible.  Some mixing procedures change size and shape of the particles such as mortar & pestle. Attrition Trituration Agglomeration mixing Spheronization  Instruments: Rotary laboratory mixer Mortar and pestle Balance Oven Chemicals: Insoluble powder NaCl Powder Aim: Examine the efficiency of mixing between two methods.  100 gm of NaCl and 250 gm of cellulose are weighed using balance. The mixing technique will performed for 10 mins using mortar & pestle and bottle method. Each group will take samples of 5 gm from their mixture. The samples are examined for the degree of mixing. Sample Preparation: The whole sample is dissolved in a copious amount of water to dissolve all the salt in the sample. After the dissolving has been accomplished. The amount of sample left is filtered through a filter paper. The remaining powder (on the filter paper) is placed in an oven at 80 ºC and left until it is dried (circa 20 minutes). The dried sample is weighed and the percentage of insoluble powder is determined from the following equation: Particle Size Reduction Renas Rzgar [email protected] Learning Outcome Students should be able to: 1. Understand the Principles of Particle Size Reduction 2. Identify Milling Techniques and Mechanisms 3. Select Appropriate Milling Methods for Different Materials 4. Evaluate the Advantages and Limitations of Milling 5. Apply Milling Parameters for Desired Particle Size  Size Reduction Materials are rarely found in the size range required, and it is often necessary either to decrease or to increase the particle size. Milling involves the application of mechanical energy to break down coarse particles into finer ones physically and is regarded as a “top- down” approach to producing fine particles. Why reduce particle size?? ▪ Powder processing ▪ Mixing ▪ Flowability ▪ feeding ▪ Extraction ▪ Dissolution ▪ bioavailability ▪ Penetrability ▪ Physical stability ▪ Product appeal  What about volatile or unstable materials??  Method of Application of Force (a) Impact —particle concussion by a single rigid force. (b) Compression—particle disintegration by two rigid forces. (c) Shear—cutting force produced by a fluid or by particle–particle interaction. (d) Attrition —arising from particles scraping against one another or a rigid surface.  Size reduction equipment Ball Milling: Uses balls in a rotating container to grind materials. It’s commonly used for producing nano-sized particles. Hammer Milling: Involves hammers that rapidly strike materials, which is suitable for coarser reduction and when large quantities are needed. 3. Jet Milling: Uses compressed air or gas to produce very fine particles without generating heat, which is ideal for heat-sensitive substances. 4. Cryogenic Milling: Uses low temperatures (with liquid nitrogen, for instance) to make materials brittle, making it easier to achieve fine powders, especially with tough or elastic materials. Factors affect milling 1. Material properties Hardness of materials Moisture Content Elasticity Heat Sensitivity 2. Milling Technique Ball Miller vs Hammer Miller 3. Milling Parameters Speed and Rotation Temperature Milling Time Feed Rate Procedure: 1. Weigh 30 g of a coarse particle and put it in a mortar and mill it for 15, 30, 45, 60 and 120 sec. 2. Sieve it with 710 mm mesh size. 3. Weigh the passed fine particles on electronic balance. 4. Plot a figure indicating the effect of milling time on the particle size distribution. Preparation of eye drops Renas Rzgar [email protected]  Eye Drops Pharmaceutical preparations are applied topically to the eye to treat surface or intraocular conditions, including bacterial, fungal, and viral infections of the eye or eyelids; allergic or infectious conjunctivitis or inflammation elevated intraocular pressure and glaucoma; and dry eye due to inadequate fluid production bathing the eye.  The normal volume of tear fluid in the cul-de-sac of the human eye is about 7 to 8 μL. An eye that does not blink can accommodate a maximum of about 30 μL of fluid, but, when blinked, can retain only about 10 μL  Excessive liquids, both normally produced and externally delivered, rapidly drain from the eye. A single drop of an ophthalmic solution or suspension measures about 50 μL (based on 20 drops/mL), so much of an administered drop may be lost. The optimal volume to administer, based on eye capacity, is 5 to 10 μL  The preparation of solutions and suspensions for ophthalmic use requires special consideration concerning Sterility Preservation Isotonicity Buffering Viscosity Ocular bioavailability Packaging Sterility and Preservation  Sterility and Preservation Ophthalmic solutions and suspensions must be sterilized for safe use. Although it is preferable to sterilize ophthalmics in their final containers by autoclaving at 121°C (250°F) for 15 minutes, this method sometimes is precluded by the thermal instability of the formulation. As an alternative, bacterial filters (syringe filter) may be used To maintain sterility during use, antimicrobial preservatives generally are included in ophthalmic formulations; an exception is for preparations to be used during surgery or in the treatment of traumatized eyes  Isotonicity In practice, the isotonicity limits of an ophthalmic solution in terms of sodium chloride or its osmotic equivalent may range from 0.6% to 2% without marked discomfort to the eye. Sodium chloride itself does not have to be used to establish a solution's osmotic pressure. Boric acid in a concentration of 1.9% produces the same osmotic pressure as 0.9% sodium chloride. pH of ophthalmic solution Buffering The pH of an ophthalmic preparation may be adjusted and buffered for one or more of the following purposes (a) for greater comfort to the eye, (b) to render the formulation more stable (c) to enhance the aqueous solubility of the drug (d) to enhance the drug's bioavailability (i.e., by favoring unionized molecular species), (e) to maximize preservative efficacy. The pH of normal tears is considered to be about 7.4, but it varies; for example, it is more acidic in contact lens wearers viscosity and thickening agents Viscosity is a property of liquids related to the resistance to flow. The reciprocal of viscosity is fluidity. additional considerations Ophthalmic solutions must be sparkling clear and free of all particulate matter for comfort and safety. The formulation of an ophthalmic suspension may be undertaken when it is desired to prepare a product with extended corneal contact time, or it may be necessary when the medicinal agent is insoluble or unstable in an aqueous vehicle.  Containers for Ophthalmic solutions Although a few commercial ophthalmic solutions and suspensions are packaged in small glass bottles with separate glass or plastic droppers, most are packaged in soft plastic containers with a fixed built-in dropper This packaging type is preferred to facilitate administration and protect the product from external contamination. Procedure 1. Prepare isotonic saline eye drops 2. filter the preparation using a syringe filter 3. test the pH of your preparation and compare it with marketed eye drops of different company Effervescent Granules Renas Rzgar [email protected]  Granules Granules are defined as a dosage form composed of dry aggregates of powder particles that may contain one or more APIs, with or without other ingredients. They may be swallowed as such, dispersed in food, or dissolved in water  Effervescent granules Effervescent granules are a pharmaceutical preparation that release carbon dioxide when added to water due to a chemical reaction between an acid and a base. This creates a fizzy solution (giving up bubbles) Effervescent formulations (composition) At least one acid and at least one base. The base must release carbon dioxide upon reaction with the acid. tartaric acid & citric acid Sodium bicarbonate Why two acids? This combination + The active pharmaceutical ingredient Advantages Better compliance through pleasant taste (Masking bad taste) Quick absorption of API through fast dissolution Easier for people with swallowing difficulties Increased liquid intake by patients marketing aspects (fizzy tablets may have more consumer appeal than traditional dosage forms)  Granules or fine powder ? Using granules or coarse particles of the mixed powders rather than small powder particles? decreases the rate of solution and prevents violent and uncontrollable effervescence. Sudden and rapid effervescence could overflow the glass and leave little residual carbonation in the solution. Methods for preparation ▪ Wet method ▪ Fusion method Dry Method (Fusion Method) Steps: 1. Mix the citric acid and tartaric acid in a ratio of 1:2 to avoid stickiness. Add sodium bicarbonate gradually and mix thoroughly. 2. After mixing, the powder is placed on a suitable dish in an oven at 34-40°C. 3. The citric acid releases moisture, which binds the powders together. 4. Pass the mixture through a sieve to form granules. 5. Dry the granules in an oven at 40–50°C to remove excess moisture. 6. Store in an airtight container to prevent premature reaction. Wet the source of the binding agent is not the water of crystallization from the citric acid but a moisturizing agent (95% ethanol), forming the pliable mass for granulation. Just enough liquid is added (in portions) to prepare a mass of proper consistency; then the granules are prepared and dried. Procedure and calculations You are going to prepare 25 g of effervescent granules The standard ratio for citric acid, tartaric acid, and sodium bicarbonate is (1: 2: 3.44) They are supposed to be taken in 5 divided doses, Each dose contains 200mg API (ferrous sulfate) Calculate the amount of citric acid, tartaric acid, and sodium bicarbonate. Mix all the powder in a suitable container. A binder (e.g., 95% ethanol) is added to form a wet mass of the proper consistency (as bread dough), then rubbed through a sieve to produce granules of the desired size. The granules are dried at a temperature not exceeding 54°C and are immediately placed in containers and tightly sealed.  Drying Renas Rzgar [email protected] Drying Drying is the process of removing the presence of solvents (i.e. water or other liquids) in a formulation with the presence of heat. The final product of this unit operation is a dry solid mass or powders. This process is widely used in the pharmaceutical field, from the research and development phase, until large-scale manufacture. It is important to have a good understanding of this process, because it impacts on the quality attributes of the active pharmaceutical ingredient (API) in order to guarantee it will not have any adverse impact on the drug’s safety and efficiency, thus, providing high quality final products. All drying processes of relevance to pharmaceutical manufacturing involve evaporation or sublimation of the liquid phase and the removal of the subsequent vapor. Purpose of drying 1. Preventing microbial growth 2. Improving shelf life 3. Enhancing flow property 4. testing Quality Moisture content determination 1. Loss on drying 2. Karl Fischer Titration 3. Infrared moisture analysis 4. Thermogravimetric Analysis 5. Dielectric moisture meter 6. Microwave Drying 7. Distillation Method (toluene distillation) Moisture Content Total moisture content is the total amount of liquid associated with a wet solid. Some of this water can be easily removed by the simple evaporative processes used by most pharmaceutical dryers and some cannot. The amount of easily removable water (unbound water) is known as the free moisture content, and the moisture content of the water that is more difficult to remove in practice (bound water) is the equilibrium moisture content. Thus the total moisture content of a solid is equal to its bound and unbound moisture content. Equilibrium moisture content Equilibrium Moisture Content (EMC) refers to the moisture content of a material when it has reached a state of balance with the surrounding environment, meaning it no longer gains or loses moisture. The material is in equilibrium with the air’s relative humidity and temperature, and any further drying or moisture absorption would not occur unless environmental conditions change. In pharmaceutical manufacturing, determining the EMC is essential for ensuring the stability of products, especially in formulations like tablets, powders, and granules, which can be sensitive to moisture.  Equilibrium moisture content The equilibrium moisture content of a solid exposed to moist air varies with the relative humidity and with the nature of the solid powder. Typical equilibrium moisture contents at 20 °C for starch-based materials (1), fibrous materials (2) and inorganic substances (3). H.W Critical moisture content Vs Equilibrium moisture content moisture content Its value changes with 1. Temperature 2. Humidity 3. The nature of the solid.  How to choose drying method?? The choice of drying method depends on factors like: Moisture Content: High moisture materials might benefit from fluidized bed or spray drying, while low moisture content is ideal for freeze or vacuum drying. Material Sensitivity: Heat-sensitive materials like pharmaceuticals require freeze or vacuum drying to prevent degradation. Particle Size and Structure: Fine powders work well in fluidized bed drying, while larger particles may be better suited for rotary drying. Production Scale: Batch processes may use tray or vacuum drying, while continuous operations can benefit from fluidized bed or rotary drying Solute migration during drying Solute migration is the phenomenon that can occur during drying which results from the movement of a solution within a wet system. The solvent moves towards the surface of a solid, taking any dissolved solute with it. Many drugs and binding agents are soluble in granulating fluid, and during the drying of granulates these solutes can move towards the surface of the drying bed or granule and be deposited there when the solvent evaporates.  Procedure Weigh 5 g of MCC or Lactose and wet it with water and weigh it again Put the wet sample in an oven. Weigh the samples at 2, 5, 8, 10, 12, …. Min. until you reach an equilibrium. Measure % LOD and % MC. Draw a figure between % MC and time.