Powders

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Powder Dosage forms -- Dr. Jukanti Raju

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When it is not possible to dispense a drug as a solution or a suspension, because of its insolubility or because it is susceptible to microbial contamination if it is wetted, then it is a good idea to dispense it as a powder. Few decades ago, when crude vegetable drugs were the most often prescribed drugs, dispensing them as powders. When the patient has to mix the ingredients before administration, dispensing in separate divided powders is a convenient way. Powders are very good from chemical stability point of view. Bulky drug that has a large dose is to be administered, a powder is a good way of administering it. Small children and old people cannot swallow tablets and capsules. In such situations powders are a good option. Advantages of Powders

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Time consuming to prepare and pack. Bulky to carry. Powders may spill when they are being opened. When a tablet or a capsule is not suitable, a well formulated suspension may be a suitable alternative. When a medicament with an unpleasant taste has to be administered, it may be given as a suspension or in a hard capsule form. Powders are not an ideal way of dispensing substances that are volatile deliquescent, hygroscopic or oxygen-sensitive. Disadvantages of Powders

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One of the following three methods was widely used by the pharmacist, in yester years, for the preparation of powders Trituration Pulverization Levigation Principles involved Drug Content Uniformity Fine size Free flowing Good taste Amount should not be too large or too small.

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Effervescent Powders Acid materials Acids: Citric (monohydrate or anhydrate), tartaric, ascorbic (drug or excipient), fumaric, nicotinic, acetylsalicylic (as drug or excipient), malic, and adipic acids (seldom used). Salts: sodium citrate, sodium acid phosphate, sodium fumarate. Sources of carbon dioxide Salts: sodium bicarbonate (widely used), sodium carbonate, potassium carbonate, calcium carbonate, sodium glycine carbonate. Powders for Oral Administration

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Other Excipients (main characteristic, Solubility in water) Lubricants: PEG 6000 is most frequently used, alone or with sodium stearyl fumarate, sodium benzoate, sodium chloride, sodium acetate, or D,L-leucine. Binders: PVP, Maltodextrins, PEG 6000. Sweeteners, flavors, colors, surfactants, antifoaming agents (polydimethylsiloxane). Manufacturing process Controlled relative humidity (about 20% or less, if necessary). Controlled ambient temperature close to 25°C. Drugs : Aspirin, Acetaminophen, Ibuprofen, NSAIDs, Antibiotics, Mucolytics, Vitamins, and others. Demonstrated many times that drugs are rapidly, and sometimes better, absorbed than conventional dosage forms.

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Solid sterile substances Freeze-dried substances Lyoprotectants - Excipients stabilize during freezing and drying. Cryoprotectants - Stabilize only during freezing. e.g Glycine, mannitol, sucrose, PEG, Trehalose, lactose etc.) A clear solution nearly free of particles or a uniform one is obtained after shaking with the prescribed volume of an appropriate sterile liquid. Powders for Parenteral Use

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Single- or multiple-unit powders free of agglomerated particles. Sterile for application on open wounds or damaged skin. - Multiple-unit powders for local application are preferably packaged in a pressurized container (for skin, teeth, or vaginal douche use). - These preparations consist of a dispersion of a solid phase (drug) in a liquid propellant (liquid phase). Powders for Cutaneous Application

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Dry Powder Inhalers (DPIs) Suppression or reduced use of CFC propellants, DPI are under worldwide development. Metered dose inhalers (MDIs) MDIs were formulated several years ago. Will probably replaced by DPI. A drug in powder form (with a particle size close to 5 µm) was suspended in propellants with a surfactant. Powders for Pulmonary Application

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Spinhaler Rotahaler

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Both the Spinhaler and Rotahaler are rather inconvenient to use because it is necessary to load a gelatin capsule containing the drug powder into the device immediately prior to use. Diskhaler, Turbuhaler [new multidose dry powder inhalers] have been recently introduced.

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Turbuhaler 200 metered doses of the bronchodilator terbutaline in the manner of a pressurized MDI, but without additives of any kind.

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Delivery of drugs to the lung depends on administration by any one of three methods: Nebulizer Metered Dose Inhaler (MDI) Dry Powder Inhaler (DPI) DPIs, the physical properties of the drug substance determine the ease with which processing will yield a stable powder that can be effectively aerosolized in milligram quantities by the inhaler device to deliver the proper drug dosage.

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DPI device presents medication to the patient as a dry powder in a form that can be inhaled orally for delivery to the target lung tissues. Barriers: Oropharynx and for deep lung delivery, the air-conducting bronchi and bronchioles. Delivery system should assist in the generation of very fine particulates of medication in a way that enables them to avoid the impaction barriers that normally operate in the lung to prevent the ingress of potentially harmful particles. Drug containment in DPIs falls into two categories: Unit dose - Dose is pre-metered during manufacture, Reservoir - Dose is metered during dose administration. Multiple unit dose devices for convenience. Dry Powder Inhalers [DPI]

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Characteristics of the Ideal DPI system Simple and comfortable to use Compact and economical to produce Highly reproducible fine-particle dosing Reproducible emitted dose Physically and chemically stable powder Minimal extrapulmonary loss of drug, with low oropharyngeal deposition, low device retention, and low exhaled loss Multidose system Powder protected from external environment and can be used in all climates and protected from moist exhaled air Overdose protection and Indicate number of doses delivered and/or remaining.

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Fine Particles and Solid State Crystalline and Amorphous (Glassy) States Effect of Physical State on Stability of Dry Powder Formulations Moisture uptake by the hydrophilic components of the formulation can lead to surface dissolution and liquid bridging between particles. Leads to crystal growth, particle fusion, and an increase in particle size, which can result in strongly diminished aerosol performance. Because of their greater molecular mobility in the solid state, amorphous systems generally exhibit greater physical and chemical instability at any given temperature compared with their crystalline counterparts. DPI formulations are desirably prepared in a crystalline state

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Freeze-dried and Spray-dried Biologicals for Pulmonary Delivery Excipients that act as protectants such as sugars must also remain amorphous to interact with the protein and/or provide a rigid matrix around the protein molecules to restrict and stabilize their motion. As with any amorphous product, physical change can be minimized by storage at temperatures well below the Tg and protection from moisture during handling and storage. Amorphous materials must be stored well below the glass transition to maintain their physical and chemical stability. Amorphous component likely absorbs greater quantities of water than its crystalline counterpart, leading to reduced Tg, increased molecular mobility and both physical and chemical instability.

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Bulk Powder Properties Primary bulk properties include particle size, particle size distribution, bulk density, and surface area. These properties, along with particle electrostatics, shape, surface morphology, etc., affect secondary bulk powder characteristics such as powder flow, handling, consolidation, and dispersibility. The size, density, and shape of a particle inhalation determine its aerodynamic behavior and therefore its likelihood of depositing in the desired region of the lung. Mass median diameter (MMD) is the most common descriptor of primary particle size and may be determined by sieving or centrifugal sedimentation.

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MMD of a powder, predictor of aerodynamic diameter is given by: MMAD = MMD r true 1/2 where MMAD is the mass median aerodynamic diameter, and r true is the true density of the particle, usually determined by helium pycnometry. Values of MMAD less than 5 µm are considered necessary to facilitate airborne particle transit past the larynx and deposition within the lung. Powders intended for delivery to the deep lung, such as treatments for asthma or for systemic delivery, require aerodynamic behavior reflected by MMAD values between 1 and 3 µm. Particles of MMAD less than approximately 0.5 µm are likely to be exhaled.

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Deposition of the particles in the various regions of respiratory tract

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Surface area Bulk powder characteristic directly dependent on particle size distribution, porosity, and morphology. It is commonly determined by Nitrogen Adsorption. Bulk powder density, porosity, and consolidation rate are used as characteristics of powder structure and ease of flow. Typically more difficult to determine for fine respirable powders than for coarse particles owing to the formation of bridging structures caused by high interparticulate interaction. Forces must be overcome by introducing energy, such as ultrasonic vibration or mechanical agitation, to fluidize micron-sized powders in a controllable manner.

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Carrier-based powder formulations are designed in part to overcome the inherent cohesion of micron-sized particles. In these formulations, the micro fine drug adheres to larger carrier particles, improving powder flow and metering capability. Pelletization is often used to improve the flow properties of micron-sized powders. POWDER PRODUCTION: FORMULATION AND PROCESSING Primary factor influencing the manufacture of DPI powders is the need to produce material that can penetrate into the lung. Formulation of dry powders for inhalation must rely on a very short list of excipients to fulfill the customary roles of diluent, stabilizer, solubilizer, processing aid, and property modifier (e.g., flow, Sustain release agent).

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Controlled Crystallization or Precipitation Micronization Micronization is a high-energy particle-size reduction technique that can convert coarse-diameter particles into particles of less than 5 µm in diameter. Different types of equipment can micronize particles, for example, jet or fluid energy mills and ball mills. Blending The most commonly used method for improving the flowability, fillability, and dispersibility of small cohesive particles is blending the drug with excipient particles, most commonly lactose, of considerably larger particle size. Typically, these large excipient particles are greater than 60 µm, and the small drug particles are less than 5 µm.

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The objective of the mixing process is to produce an ordered powder in which the small particles attach themselves to the surface of larger ‘‘carrier’’ particles. The challenge is to ensure that the force of adhesion between the drug and carrier is strong enough to withstand segregation during blending and product storage and weak enough to allow separation of the drug particles from the carrier surface on aerosolization. During formulation feasibility, the blends are made by mortar and pestle and/or geometric mixing in a tumbling blender. For high-volume production, the process generally involves a high-shear mixer.

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Steps that involve transport or storage of the finished blend should be monitored closely to avoid segregation, which occurs when the drug separates from the carrier or when carriers of different sizes separate. Segregation can be minimized by the careful selection of formulation and process equipment. For example, hopper design can play a significant role in minimizing segregation. Pelletization Pelletization, which often does not require the use of excipients, may offer an alternative to blending for high-dose therapeutics. Process involves deliberate agglomeration of the fine drug material into less cohesive, larger units.

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Spray Drying Spray drying, a process typically used in the production of coarser (up to 500 µm) food, pharmaceutical, and industrial powders, can also be used to prepare microparticulate powders for DPIs. Lyophilization Lyophilization, although a relatively expensive process, can be a good process for relatively unstable compounds. Supercritical Fluid Technology Supercritical fluids are liquids above their critical pressure and temperature. Under these conditions, the molecules exhibit the flow, polarity, and solvency properties common of liquids but have the diffusivities and reactivities characteristic of gases.

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Examples of Excipients Used for Dry Powder Aerosols

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Primary Packaging for DPI Drug Formulation Filling and packaging

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Energy Sources for delivery

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Influence of Powder Behavior on Device Design

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Earliest Dry Powder Inhalation Systems

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More Recent Dry Powder Inhalation Systems

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New DPI technologies in development by Inhale Therapeutic Systems and Alkermes are enabling the delivery of macromolecules to the deep lung. Leading this field is Inhale’s insulin product, currently in the phase 3 trials with Pfizer. In the next years, it is expected that dry powder inhalation will become a broadly accepted and effective means of delivering a wide variety of therapeutics–antibiotics, analgesics, antibodies, hormones, proteins, and perhaps gene therapeutics. Potential of this technology continues to be explored

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Success in life mostly depends on the power of ‘CONCENTRATION’ clear thinking and intellectual understanding are very easy for a concentrated mind. Arjuna could shoot his target with this tremendous concentration.