Pharmaceutical Powders and Granules

Powders vs. Granules

• Powders and granules are common dosage forms in pharmacy
• Powders are solid substances in a finely divided state as amorphous powders or crystals
• Granules consist of aggregated powder particles, typically 2-4 mm in diameter and larger than intermediate tablet granules.

Advantages of Powders

• Powders enable easy alteration of medication quantity by healthcare providers
• Powders are useful in clinical drug studies for readily adjustable doses
• Doses can be individually weighed into powder papers, envelopes or vials
• Powders are suitable for infants/young children because they can be mixed with food
• Powders are suitable for drugs that are too bulky for capsules or tablets
• Powders offer rapid action due to easy dispersion and large surface area, requiring only dissolution for absorption

Use of Powders

• Medicated powders have limited use in therapeutics, but powdered substances are used extensively in preparing other dosage forms
• Powdered drugs can be blended with fillers and other ingredients to fabricate solid dosage forms like tablets and capsules
• Powders can be dissolved or suspended in solvents for liquid dosage forms or incorporated into semisolid bases for ointments and creams

Particle Characteristics

• Characterizing solid materials is important to determine their chemical and physical features
• Pharmaceutical products, require characterization of solid materials to determine:
• Morphology
• Purity
• Solubility
• Flowability
• Stability
• Particle Size
• Uniformity
• Compatibility

Particle Size and USP Standards

• Particle size influences dosage form production and therapeutic effectiveness
• The particle size of pharmaceutical powders and granules ranges from extremely coarse (10 mm) to extremely fine (1 μm or less)
• The United States Pharmacopeia (USP) categorizes powder particle size using descriptive terms
• The descriptive terms include: Very coarse, coarse, moderately coarse, fine, and very fine
• Classifications are based on the proportion of powder passing through standard sieves of varying fineness using a mechanical sieve shaker
• Sieves are classified by aperture size or mesh size (sieve number)
• Mesh size refers to the number of wires per linear inch
• Sieve number indicates the number of holes within a one-inch length of the sieve mesh

Particle Size Influence

• Dissolution rate of particles, drug micronization can increase dissolution rate and bioavailability
• Suspendability of particles, fine dispersions have particles 0.5 to 10 μm
• Uniform distribution of a drug substance in a powder mixture can ensure dose-to-dose content uniformity
• Penetrability of particles intended to be inhaled should be 1 to 5 μm
• Lack of grittiness of solid particles in dermal ointments is achieved with fine powders that are 50 to 100 μm in size

Micromeritics and Angle of Repose

• Micromeritics is the science of small particles, dealing with particles as units of matter

• Micromeritics studies the following characteristics:

  • Particle size
  • Size distribution
  • Shape
  • Angle of repose
  • Porosity
  • True volume
  • Bulk volume
  • Apparent density
  • Bulkiness

• Angle of repose is a technique for estimating powder flow properties

• The angle of repose is determined by allowing powder to flow through a funnel onto a surface and measuring the height and diameter of the cone

• Powders with a low angle of repose flow freely, and powders with a high angle of repose flow poorly.

Powder Flowability Factors

• Number of factors determine flow properties including particle shape and size
• Spherical particles flow better than needle-shaped particles
• Very fine particles do not flow as freely as large particles
• Particles in the size range of 250 to 2,000 μm flow freely if the shape is easily handled
• Particles in the size range of 75 to 250 μm may flow freely or cause problems depending on shape
• Particles smaller than 100 μm usually have flow problems.

Particle Size Reduction

• Comminution reduces the particle size of a solid substance to a finer state to facilitate:
• Crude drug extraction
• Increased dissolution rates
• Improved formulation of dosage forms
• Enhanced drug absorption
• Reducing particle size increases the specific surface area of a substance

Comminution of Drugs

• Comminution reduces chemical substance size through grinding with a mortar and pestle
• A mortar with a rough surface is better for finer grinding than one with a smooth surface
• Grinding a drug in a mortar to reduce its particlesize is termed trituration or comminution
• Mills and pulverizers can be used on a large scale

Manual Methods of Particle Size Reduction

• Trituration is the primary method of comminution achieved by rubbing with a mortar and pestle, using pressure and attrition, and scraping with a spatula
• Levigation involves using a mortar and pestle or ointment tile to reduce particle size and grittiness in ointments/suspensions
• Levigation involves forming a paste by combining the powder with a small amount of insoluble liquid (levigating agent), then triturating
• Levigated paste is added to the ointment base and mixed with a spatula
• Mineral oil and glycerin are commonly used levigating agents
• Pulverization by intervention reduces particle size using a second agent that is readily removed after pulverization
• This is used for substances like camphor which are difficult to triturate otherwise
• Fitz Mill comminuting machine uses rapidly moving blades for grinding within a containment system

Particle Size Reduction: Advantages of Collection and Containment

• Collection and containment systems are advantageous as they:
• Protect the environment from chemical dust
• Reduce product loss
• Prevents product contamination

Special Processes for Particle Size Reduction

• Freeze-drying (lyophilization) removes water by sublimation at low temperatures, typically -10 to -40°C
• Freeze-drying is used for biological products like blood serum, plasma, certain antibiotics, and heat-labile substances
• Spray drying converts solutions or suspensions into dry, free-flowing powders in a single step
• Spray drying process involves atomizing the solution/suspension in a chamber with heated air, producing fine, spherical droplets that dry rapidly

Blending Powders

• Reduce particle size of each powder individually before weighing and blending for a uniform mixture
• Depending on the ingredients, amount of powder, and equipment, powders may be blended by various methods
• Various methods for powder blending include: Spatulation, trituration, sifting, and tumbling

Spatulation

• Spatulation involves blending small amounts of powders using a spatula on paper or an ointment tile
• Spatulation is unsuitable for large quantities or potent substances due to uncertain blending
• Spatulation results in very little compression or compacting of the powder making it appropriate for eutectic mixtures
• Eutectic mixtures include: phenol, camphor, menthol, thymol, aspirin, and phenyl salicylate
• To reduce contact, substances that form eutectic mixtures are mixed with an inert diluent like light magnesium oxide or magnesium carbonate

Trituration

• Trituration can be used for both mixing and reducing the particle size of powders.
• A glass mortar is preferred if simple mixing is desired without comminution
• Geometric dilution ensures uniform distribution of a potent drug when mixing a small amount with a large amount of diluent

Geometric Dilution

• When the potent substance and other ingredients are the same color with no sign of mixing
• The potent drug is placed with an approximately equal volume of the diluent in a mortar and is mixed thoroughly by trituration
• Then, a second portion of diluent equal in volume to the mixture is added and the trituration repeated
• This process is continued by adding an equal volume of diluent to the powder mixture and repeating this until all of the diluent is incorporated.
• Some pharmacists add an inert colored powder to the diluent before mixing to permit visual inspection of the mixing process to ensure uniform distribution

Sifting

• Powders are mixed passing them through sifters to produce a light, fluffy product
• This method is not acceptable for incorporating potent drugs into a diluent powder

Tumbling

• Mixing powders can be achieved by tumbling the powder in a rotating chamber
• Special small-scale and large-scale motorized powder blenders mix powders by tumbling them
• Mixing by tumbling is thorough but time consuming
• Motorized blade mixers are widely used in industry, to blend powders in a large vessel

Problems Due to Particle Size Reduction

• Segregation is an undesirable separation of components in a powder mixture (blend) due to differences in density and size
• Segregation typically occurs by: Sifting or percolation
• Fine particles pass through coarse particles, ending up lifting the larger particles
• Air entrapment (fluidization)
• Fine, aerated powders with differences in particle size or density may result in a striation pattern and may occur during powder transfer
• Particle Entrapment (dusting)
• Dusting occurs when the finer, lighter particles remain suspended in air longer and do not settle as quickly as the larger or denser particles

Guidelines for Minimizing Segregation

• Best practices include:
  • Minimum number of transfer steps and drop heights
  • Control of dust generation
  • Control of fluidization of the powder
  • Slow fill and transfer rate
  • Appropriate venting strategies
  • Use of a deflector, vane, or distributor
  • Proper hopper design and operating valves

Medicated Powders

• Some medicated powders are intended for internal and others, external use only

Internal Powders

• Powders for internal use are taken orally or inhaled
• Commercially packaged dry powders are constituted with a liquid for injection, or use as a vaginal douche

Oral Powders

• Medicated powders may be intended for local (e.g., laxatives) or systemic effects (e.g., analgesics)
• Powders can be preferred due to ease of swallowing compared to tablets, capsules
• Powders are suitable to form into tablets in capsules due to being too bulky. They can be mixed with a liquid or soft food for administration
• Powders can result in faster dissolution and absorption compared to solid dosage forms due to immediate contact with gastric fluids, although the actual therapeutic advantage may be negligible
• A disadvantage of oral powders is the undesirable taste of the drug
• Some medications, like antibiotics for children, are more stable as dry powders or granules for constitution with purified water before dispensing
• The product remains stable for the prescribed period (generally up to 2 weeks) under labeled storage conditions
• Oral powders comprise solid, loose, dry particles of varying degrees of fine particle size
• Oral powders contain one or more active substances with/without excipients, colouring matter, and flavoring
• Oral powders are generally administered with water

Aerosol Powders

• Aerosol Powders are medicated powders administered by inhalation with the aid of dry powder inhalers (DPIs), which deliver micronized medication particles in metered quantities
• A DPI is a device used to administer an inhalation powder suitable for inhalation, aerosolizing, and and accurately metered amounts
• Aerosol powders are used in the treatment of asthma
• Aerosol powders have a micronized formulation is in the range of 1 to 6 μm in diameter

Components of Aerosol Powders

• These products contain inert propellants and pharmaceutical diluents, like crystalline alpha-lactose monohydrate
• Additional components support flow properties, metering uniformity, and moisture protection
• Metered-valve containers apply a specific dose through the mouthpiece or powder blowers/insufflators

Nasal Powders

• Nasal Powders are medicated powders that are inhaled into the nasal cavity using a suitable device because they can be rapidly absorbed
• Delivery devices have been developed for nasal powders, for enhanced convenience and uniform dosing
• These devices contain a hard gelatin capsule diluted with an inert, soluble diluent, that is assembled and broken when the device is assembled and inhaled

External Powders

• Medicated powders for external use are applied via a sifter-type container or powder aerosol
• External powders should be labeled for external use only
• Powders for cutaneous application are available in single-dose or multidose forms, free from grittiness
• Powders for large open wounds/severely injured skin must be sterile
• Dusting Powders contain therapeutic, prophylactic, or lubricant ingredients for external use

Dispensing of powders

• Medicated powders provided in bulk or divided into unit-of-use packages

Bulk Powders

• These powders are available in pre-packaged amounts
• Examples include: Antacids (e.g., sodium bicarbonate) and laxatives (e.g., psyllium), Douche powders (e.g., Massengill Powder), or Medicated powders (e.g., bacitracin zinc and polymyxin B sulfate)
• Small measuring scoops are dispensed with powders for measuring the dose
• Dispensing powder medication in bulk quantities is limited to non-potent substances

Patient Education for Powders

• Training for appropriate handling, storage, measurement and preparation is important for both bulk powder prescriptions and nonprescription products
• These products are stored at room temperature in a clean, dry place, and kept out of the reach of children
• Instructions should be given for how to measure powder and diluent with type and volume of delivery liquid consistent with packaging

Divided Powders

• Divided powders are individually blended into dosing units based on amount to be taken
• Divided portions are placed on paper (chartula) and enclosed-Commercially prepared pre measured products are availble in folded papers or packets
• Examples include: (eg Aspegic powders),Powdered (psyllium mucilloid, Fybrogel ), (eg Massengill powder packets

Pharmacist Prepared Divided Powders

• Based on drug potency the pharmacist uses a weighing method versus a block and divide for non-potent versions
• Weighing Method - Used for potent drugs
• Block and divide Method - Used for non-potent drugs: entire amount placed on non-permeable flat surfaces, then the pharmacist cuts a rectangular or block form to delineate the amount of smaller uniform blocks, each representing a dose of medication.

Powder Paper

• Powder papers come in multiple sizes
• Paper can include:
• Simple Bond Paper
• Vegetable Parchment (thin, semi-opaque)
• Glazed transparent paper
• Transparent waterproof paper(waxed)
• Paper selection depends on powder contents whether hydroscopic or deliquescent
• Small cellophane and plastics envelopes can be used for uniformity
• Compounded powder papers are replaced by outpatient community practice, with institutional settings being prefered for use

Granule Dosage Form

• Granules are used to prevent segregation, which can be caused by differences in granule sizes
• Granules are made when smaller particles are robustly handled. Granules are spherically shaped and vary from 4-12-mesh size

Granulation: Advantages

• Flow better than powder making them important for tableting and dust elimination
• Granules offer compressibility
• Granules have smaller surface area
• Granules are easily wetted

Commercial Granules

• Granules offer particle sized and uniformity, specifically for content control
• antibiotic drugs, are prepared as small granules for constitution by the pharmacist with purified water just prior to dispensing
• Examples include: KLACID, Augmentin, or Uricol

Commercial Granules- Composition

• Granules contain colorants and other pharmaceutical components and are mixed into beverages. Granulations for effervescent products are pressed into tablet form

Granules: Preparation

• Prepared by wet and dry methods:
  • Wet method
    • Powder moistened, mix with fluid, then mesh size is passed for size design. The resultant granules are dried over trays
  • Dry Method
    • Dry powder run through roll compactor passing through granulating machine.
    • Alternative dry method, is large tablets, compressed in a machine

Dry Preparation: Effervescent Granulated Salts

• Frequently contain tablets or granules for rapid-release of water soluble ingredients
• Dosage is dissolved and dispersed in water prior to use
• Use a dry mixture of sodium bicarbonate and tartaric and citric acid to liberate dioxide producing fizziness
• Masks any medicinal taste, decreasing uncontrolled reactions and rapid overflow

Acid Types

• Use blends is for best results when granules lose the firmness if only one acid is used
• Effervescent ratio: Citric acid: Tartaric acid: Sodium bicarbonate

Effervescent Granules Preparation: Dry and Wet Methods

• Dry or Fusion Method

• Water is present and acts as the binding agent

• Powdered citric acid + other powders must have the same sieve size to ensure mixture uniformity

• Stainless steep / protected material is required resistant to acids

• Heat in an oven from 34oC -40oC

• Use acid/resistant spatula to move the powder to release water, setting chemicals

• As the softened mass gets spongy, it is set aside to cool and get mixed the sieve granules -Sieve-Large -Sieve 8-Medium -Sieve 10-Small

• Wet Method

• Anhydrous water is used to add more liquid to get a more plied consistency

• Add liquid portions for consistency