Powder Processing - Milling, Mixing, Granulation, Excipients - Dr Hao-Ying Li PDF

Faculty of Life Science & Medicine Dr Hao-Ying Li Formulation & Analysis of Drugs (FAD) MPharm2 Institute of Pharmaceutical Science [email protected] Slides adapted with permission from Dr. Powder Technology To Quality Contro...

Faculty of Life Science & Medicine Dr Hao-Ying Li Formulation & Analysis of Drugs (FAD) MPharm2 Institute of Pharmaceutical Science [email protected] Slides adapted with permission from Dr. Powder Technology To Quality Control Bahijja Raimi-Abraham  Content Overview Role of Pharmaceutics from Lab to the Patient  Particle Size & Methods  Particle Solid State  Powder Milling  Powder Granulation  Powder mixing and flow  Content Overview Role of Pharmaceutics from Lab to the Patient Day Date Title Thu 28-SEPT (Powder Technology) Particle Size Methods (Powder Technology) Summary Particle Size Methods Fri 29-SEPT (Powder Technology) Pharmaceutical Solid State (Powder Technology) Pharmaceutical Solid State (Powder Technology) Powder Processing: Milling, mixing & flow Thu 05-OCT (Powder Technology) Powder Processing: Granulation (Solid Dosage Forms) Excipients (Solid Dosage Forms) Traditional Tablet Manufacturing Methods Fri 06-OCT (Solid Dosage Forms) Tablet Film Coating (Solid Dosage Forms) Capsules Thu 12-OCT (Solid Dosage Forms) New Formulation and Manufacturing Methods (Solid Dosage Forms) Summary of Solid Dosage Forms (Quality control of solid dosage forms) Quality Control & Product Quality Issues Fri 13-OCT (Quality control of solid dosage forms) Quality Control & Product Quality Issues Fri 01-DEC Powder Technology, Solid Dosage Form and Quality Control tutorial Formulation & Analysis of Drugs (FAD) Powder processing: Milling Powder Processing: Milling, Mixing & Flowability Learning Outcomes: Milling After completing this section, you should be able to:  Describe the relevant particle size class for common pharmaceutical products  Explain the impact of material properties / environmental factors on comminution  Elucidate the effect of milling on the particle solid state and the consequence this may cause.  Discuss factors which must be considered when milling a powder with given qualities Particle Size Reduction: Some Definitions Comminution  Mechanical process of reducing the size of particles  Reduction of solid materials from one average particle size to a smaller average particle size. Micronization  The process of reducing particle sizes to the micron or nanometre range. 7  Particle Size Reduction: Some Definitions Pulverization  Reduction of a substance to a powder Trituration  Pharmaceutical process that involves grinding, pulverizing, or rubbing a substance into fine particles or powder using a mortar and pestle. 8  Deformation The physical change or alteration in the size, shape, or configuration of an object or material when subjected to an external force or stress. Elastic and Plastic Deformation Plasticity = material is Elasticity = material stretched or formed into another returns to its original shape shape and then holds that shape, after it has been stretched. without breaking or fracturing. Deformation The physical change or alteration in the shape, size, or configuration of an object or material when subjected to an external force or stress. STRESS Reversible = When external force is removed, material returns to its original shape and size. It occurs when the material's structure is temporarily altered but not permanently changed. Deformation Deformation refers to the physical change or alteration in the shape, size, or configuration of an object or material when subjected to an external force or stress. STRESS Irreversible = Material does not return to its original shape and size after the force is removed. It occurs when the material undergoes permanent changes in its structure. Fragmentation Fragmentation refers to the process of breaking or splitting a larger object, entity, or system into smaller parts or fragments. STRESS What Is the Pharmaceutical Impact of Milling? Milling - to reduce particle size of APIs and excipients Significant impact on the quality, efficacy and safety of pharmaceutical products Particle Size Control Solid-State Changes Directly impacts Affect stability and shelf life Drug dissolution rates of pharmaceutical products. Bioavailability Therapeutic effectiveness Blend Uniformity Micronization Used to achieve dose Can improve the uniformity bioavailability = increasing surface area for dissolution. Pharmaceutically Relevant Particle Size Classes PHARMACEUTICAL PARTICLE SIZE PARTICLE SIZE CLASS FORMULATION RANGE EXAMPLES Tablets, capsules, MACROSCOPIC > 500 µm suppositories Granules for oral and topical GRANULES 500 µm - 2000 µm formulations Dry powder inhalers, COARSE POWDERS 250 µm - 1000 µm effervescent tablets Oral suspensions, wet MEDIUM POWDERS 75 µm - 250 µm granulation intermediates Nasal sprays, topical creams FINE POWDERS 10 µm - 75 µm and ointments Inhalation powders, VERY FINE POWDERS 1 µm - 10 µm submicron emulsions Liposomes, nanoemulsions, NANOPARTICLES < 1 µm targeted drug delivery systems 14 Particle Size Reduction (Milling) Depends… Hardness, Brittleness, Toughness Solid state - crystalline structure MATERIAL Material Density PROPERTIES Chemical Stability Adhesion and Cohesion Moisture Content ENVIRONMENTAL FACTORS 15 Hardness A measure of resistance to permanent deformation, indentation, or scratching when subjected to an external force. Measured using scales like Mohs Hardness Scale Qualitative scale = measure the relative hardness of minerals. Focus on their resistance to scratching. 16 Brittleness The tendency of a material to fracture or break when subjected to stress or an external force without significant deformation. Brittle materials fracture easily with little or no plastic deformation. How to measure brittleness? Assess the material’s ability to fracture or break under stress A brittle material is easily broken or fractured by an or an external force without impact. significant deformation. Impact testing Hardness testing Tensile testing Observational assessment 17 Toughness The ability of a material to absorb energy without fracturing; it combines both strength and ductility. Tough materials can withstand impact and deformation without breaking. They absorb significant energy before failure.  Tough materials require a large Toughness is the ability of a material to impact to fracture or break. withstand impact.  Hardness ≠ toughness. 18  Hardness vs Brittleness vs Toughness Summarised Property Definition Characteristics Examples A measure of resistance to - Hard materials are Tablets, permanent deformation, difficult to scratch or coated Hardness indentation, or scratching dent. pharmaceuti when subjected to an - Measured using scales cal solid external force. like Mohs. dosage forms - Brittle materials The tendency of a material fracture easily with Some to fracture or break when little or no plastic capsules, Brittleness subjected to stress or an deformation. breakable external force without - Often break into sharp gelatin shells significant deformation. fragments. - Tough materials can The ability of a material to Rubber withstand impact and absorb energy without stoppers for deformation without Toughness fracturing; it combines vials, blister breaking. both strength and packaging - They absorb significant ductility. materials energy before failure. 19 Hardness vs Brittleness vs Toughness – Relevance in Milling Pharmaceutical Property Relevance in Milling Application Influences energy and force needed for milling. Tablet manufacturing, Hardness solid dosage form Impacts milling efficiency and milling. equipment selection. Brittleness leads to easy fracturing during milling. Milling of gelatin Brittleness capsules, brittle tablet Contributes to effective size coatings. reduction. Toughness affects energy absorption during milling. Rubber stopper Toughness manufacturing, blister Influences milling efficiency and packaging materials. particle size reduction. 20 Effect of Milling on Solid State Crystalline Amorphous Long range Short range molecular order molecular order Effect of Milling on Solid State Crystalline AMORPHIZATION the act or process of making Amorphous something structurally amorphous or of becoming structurally amorphous POLYMORPH Effect of Milling on Solid State The shear forces arising during milling can cause ~1-10% of the powder (predominately on the surface) to exhibit an amorphous state. This will affect: dissolution profile hygroscopicity chemical stability powder flow properties compressibility 23 How to Deal with Changes in Solid State To avoid the batch-to-batch variability that may arise from amorphous content during milling, careful monitoring of milling time and shear stress is required! Changes to the milling procedure may be necessary: Evaluate milling method Evaluate milling time Switch to dry or wet milling Add stabilising excipients Cryomilling 24 Other Properties of Importance Material Density Affects the force required for milling High-density materials require more energy to reduce particle size. Chemical Stability Milling can introduce mechanical stress that may impact the chemical stability of some substances, especially when dealing with APIs (active pharmaceutical ingredients). 25 Other Properties of Importance Adhesion: Occurs between two unlike surfaces; such as between a particle and equipment. Cohesion: Occurs between like surfaces, such as between particles. Adhesion and Cohesion Adhesive particles - stick to milling equipment. Cohesive particles - may form lumps or agglomerates during milling. 26 Particle Size Reduction (Milling) Depends… Hardness, Brittleness, Toughness Solid state - crystalline structure MATERIAL Material Density PROPERTIES Chemical Stability Adhesion and Cohesion Moisture Content ENVIRONMENTAL FACTORS 27 Environment Factors Moisture content can significantly affect the milling process and final product quality. Impact on Milling Process Agglomeration Excess moisture -> particle agglomeration –> issues in powder mixture. Stickiness High moisture content = sticky materials/particles = Adherence to milling equipment = in poor milling efficiency. Managing Moisture Content  Humidity Control  Control and Monitoring  Drying Techniques 28 Powder Processing: Mixing & Flowability Mixing Powder Processing: Milling, Mixing & Flowability Learning Outcomes: Mixing After completing this section, you should be able to: Describe how powder mixing or segregation can influence a pharmaceutical product. Describe the different causes of powder segregation and ways to prevent segregation. What Is the Pharmaceutical Impact of Mixing? Significant impact on the quality, efficacy and safety of pharmaceutical products Homogeneity Content Uniformity Ensure that the API and Regulatory requirement. excipients are uniformly distributed throughout the formulation. Inconsistent mixing = variations in drug content Blend Time and Equipment Pharmaceutical mixing processes must be optimized for factors like blend time, mixing equipment design, and the order of addition of ingredients to achieve the desired blend uniformity. Why Is Powder Mixing Important?  Content/ dose uniformity (safety)  Uniformity of weight  Uniform dissolution rate  Uniform bioavailability 34  How Would You Like Your Powder Mixed? Random mixture can be obtained  If two different free-flowing powders of approximately the same particle size, density and shape are mixed.  The particles are not cohesive and do not cling to one another.  The mixing time will determine the quality of the random mixture. However, if powders with particles of different size, density or shape are mixed the segregation can occur. 35  Changes to Particle Number and Size, Change the Efficacy of Mixing 75% 48% 200 mg 200 mg 25% 52% Bulk powder Few large = random mix Many smaller particles (Drug/excipient = 1:1) particles Note: Reducing the particle size too much increased cohesion and particle aggregation, resulting in poor mixing and powder flow properties! The Opposite of Mixing: Segregation A separation of powder components can occur dependent upon:  Particle size  Particle density  Particle shape 37  Segregation: Particle Size Effects The process of segregation can occur during handling of completed powder mix It is pronounced with free-flowing powders Powders that are not free flowing or that exhibit high forces of cohesion or adhesion between particles of similar or dissimilar composition are often difficult to mix owing to agglomeration. 38 Segregation: Particle Size Effects Percolation segregation: Smaller particles fall through the voids between larger particles. Trajectory segregation: Larger particles travel faster and further than smaller particles. Elutriation segregation: ‘Dusting out’, small particles are blown into the air during mixing and settle as a layer on top of larger particles. 39 Segregation: Particle Density Effects A separation of powder components can occur if the particles exhibit different densities (even if they are the same size). 40 Strategies to Prevent Segregation If segregation becomes a problem, the following steps may be taken to prevent it:  Select a specific particle size range (sieving) Similar size  Particle size reduction (milling)  Controlled crystallization  Mix with excipients of a similar density Similar density Physically  Increasing particle size (granulation) binding  Reduce vibrations and movement Operation  Reduce powder residence time in processing equipment  Production of an ‘ordered’ mix 41  What Is an ‘Ordered’ Mix? Ordered mix: A mixture of particles where sufficiently small (micronized) particles adsorb to the surface of larger ‘carrier’ particles carrier particles + micronized API  Inhalable powder + carrier particles micronized API (lactose) (salbutamol sulphate) 42  Segregation in Ordered Mixes Ordered unit segregation: Percolation separation of different sized carrier particles resulting in drug-enriched areas. Displacement segregation: Another particle component competes for same adsorption site on the + carrier, e.g. addition of Mg-stearate to tablet formulations. Saturation segregation: + There are insufficient carrier particles. 43 Questions to Guide Further Reading Familiarise yourself with some of the most common mixers. Tumbling mixers/blenders, rotating screw mixers, ribbon mixers, shear mixers, impact mixers. How do they work? Which are better for mixing free-flowing powders, which are better for cohesive powders? Do some mixers have issues with segregation? 44 45 Flowability Powder Processing: Milling, Mixing & Flowability Learning Outcomes: Flowability After completing this section, you should be able to:  Describe the factors that influence powder flow.  Discuss how powder flow affects a pharmaceutical product.  Explain different methods to evaluate powder flow properties.  Predict the powder flow properties when given bulk and tap volume of the powder.  Describe methods to improve powder flow. What Is the Pharmaceutical Impact of Flowability? Significant impact on the quality, efficacy and safety of pharmaceutical products Tablet Compression Blend Uniformity Powders with good flow Powders with consistent properties are essential to flow properties are more ensure consistent tablet likely to achieve blend weight and quality. uniformity. Capsule Filling Storage and Handling Powders with excellent flow Powders with good flow properties can be dosed properties are easier to more accurately and handle and store. uniformly into capsules = improved content uniformity. When Does a Powder Flow? The forces that influence Promotes flow Prevents flow 49 A Closer Look at Drag Forces Adhesion: Occurs between two unlike surfaces; such as between a particle and equipment. Cohesion: Occurs between like surfaces, such as between particles. Co- and ad- hesion both result from particle- particle/surface interactions; primarily van der Waal’s forces. The strength of these forces increases as particle size decreases and varies with humidity. How Does the Particle Size Effect Powder Flow?