Lectures 8 & 9 CH 09 - FINAL 2023.pdf

Micromeritics Definition: the science of small particles (J.M. Dalla Valle) – – – – – – – particle size and size distribution, shape, angle of repose, porosity, true volume and apparent density and bulkiness Particles are any unit of matter having defined physical dimensions 3 Micromeritics • Mo...

Micromeritics Definition: the science of small particles (J.M. Dalla Valle) – – – – – – – particle size and size distribution, shape, angle of repose, porosity, true volume and apparent density and bulkiness Particles are any unit of matter having defined physical dimensions 3 Micromeritics • Most pharmaceutical ingredients are in solid state – Amorphous powders or – Crystals of different morphological structures • Powder – Solid compound or solid formulation – May contain additional ingredients along with active drug(s) • Medicated or compounded powders 4 Micromeritics • Properties of powders – – – – – – Particle size shape and distribution Active surface area Porosity Density and packing properties Solubility and Flow This Photo by Unknown author is licensed under CC BY. This Photo by Unknown author is licensed under CC BY. 5 Micromeritics Properties of powders – Determined early in pharmaceutical process – Used in product development – Quality control • To ensure batch-to-batch uniformity 6 Micromeritics • Particle Size – Particle size plays key role in dissolution. – Particle size can be important for therapeutic efficacy. • For example, powders for inhalation must be 1 – 5 µm particle size. 7 This Photo by Unknown author is licensed under CC BY. Micromeritics In solid dosage forms, particle size and distribution influences – – – – powder mixing, compression, wetability, and mechanical flow 8 Micromeritics Size and Size Ranges of Particles in Pharmaceutical Preparations 9 Micromeritics Particle size – Narrow distribution is desired – Wide size distribution • Product separation related to different particle sizes • Leads to inaccurate dosing • Inconsistent performance • Physical change of the solid dosage form – Majority of particles are irregular in shape and size 10 Micromeritics Distribution – Factors deciding particle size distribution • Frequency, mean and standard deviation – Distribution curve is obtained by plotting the frequency against the arithmetic mean of the particle size group – Normal distribution • Curve is symmetrical to the mean • Where the maximum frequency occurs, the mean is identical to the median (50% size) – Pharmaceutical powders often do not process normal particle size distribution This Photo by Unknown author is licensed under CC BY-SA-NC. 11 Micromeritics Distribution • Decided by: – Frequency (f) – Mean (µ) – Standard deviation (σ) • Plot particle size vs. frequency – Normal distribution: curve symmetrical to mean • Mean: maximum value – Identical to median Micromeritics • Determination of Particle Size – Electron microscopy (EM) • Nanoparticles , 1 – 100 nm • Both Scanning and transmission – Optical microscopy • 0.2 – 100 µm • Uses calibrated grid background – Coulter counter • 1 – 500 µm • Apparatus for sizing and counting particles suspended in electrolytes. 13 • Determination of Particle Size Sieving Method: 37 - 9500 µm - Standardized woven-wire sieves defined by National Bureau of Standards (NBS) • Sieve number indicates the number of openings per inch of mesh • Example: “40 mesh” size = 420 µm max • Finest mesh #400 = 38 µm openings 14 This Photo by Unknown author is licensed under CC BY-SA. Determination of Particle Size Sieving method – Set of stacked sieves in a column • Mesh openings decrease in size from top to bottom • Bottom pan catches particles that passes through all sieves – – – – Weighted sample placed in top sieve Joints between sieves taped Sieve column is placed on an automatic shaker “Wet sieving” may be appropriate for fine insoluble particles 15 Sieving Method • Best for particles larger than 50 to 100 µm in diameter • Smaller particles may stick to sieve surface • Sieves arranged in a column • Openings get progressively smaller Sieving Method • Sample of known weight placed at top • Large enough that first sieve retains enough particles to be representative of sample • Smaller samples: more consistent • Smaller particles may be trapped on too-large sieves by other particles Determination of Particle Size • Sieving Method 18 Determination of Particle Size • Sieving Method – Initial sample size is important • Too large or overloading the sieve, fine mesh particle may never have a chance to pass through to the proper sieve • Smaller samples produce more consistent results • Powder with wide particle range (crushed samples) may require a large sample, 500 to 1000 g • Finely ground powder, 25 to 100 g is used • Sieving time, a few minutes to 30 minutes 19 This Photo by Unknown author is licensed under CC BY-NC. Determination of Particle Size • Sieving Method – Each sieve is weighed (g) with a sensitivity of 0.1 g – The total weight of the material retained on various sieves should be very close to the weight of original sample – Weight is expressed as a percentage for the particle size group, of the total sample 20 This Photo by Unknown author is licensed under CC BY-SA. Wet Sieving • For fine, insoluble particles • Top sieve washed with water – Helps move particles to appropriate sieve – Must dry sieves before weighing This Photo by Unknown author is licensed under CC BY-SA-NC. Sieving Method Determination of Particle Size Determination of Particle Size Determination of Particle Size • Sedimentation Method – the tendency for particles in suspension to settle out of the fluid and come to rest against a barrier – Movement through the fluid is due to gravity • centrifugal acceleration, or electromagnetism • Speed of particle moves through medium is used to measure its size 25 This Photo by Unknown author is licensed under CC BY. Determination of Particle Size • Sedimentation method – Fluid is stationary – Separation of particles of various sizes depend solely on particle velocity – Division of particles into size fractions (groups) depends on the time of sedimentation 26 Determination of Particle Size Sedimentation Method - Stoke’s Law applies V = 2r2(ps – pl) g 9η Where v= velocity of sedimentation g = gravitational acceleration ps = density of solid pl = density of liquid r = radius of the particles η = viscosity of the liquid 27 Determination of Particle Size Sedimentation Method – Andreasen pipette • Graduated cylinder (500 mL) • Reservoir for particle suspension • Pipette immersed below the suspensions surface at depth h • Samples (10 mL) removed • Temperature is controlled 28 Determination of Particle Size Sedimentation Method – Andreasen pipette cont’d • Powder sample (C0 = 0.5-1%) is dispersed in the liquid + deflocculating agent • Sample is allowed to settle • At time intervals, samples are removed • Samples are evaporated to dryness and weighed • Ct is determined at the various time intervals • At any time (t), the withdrawn particles terminal settling velocity ≤ h/t – Larger particles settle below the pipette tip – Ratio Ct/C0 gives the weight fraction of particles whose terminal velocity ≤ h/t 29 Determination of Particle Size Sedimentation Method 30 – Andreasen pipette, cont’d • Accurate and costeffective process • Time-consuming process • Points of concern – Poor dispersion – Thermal gradients – Accelerated settling Micromeritics Particle shape and Surface Area – Inverse relationship between particle size and surface area – Particles break into smaller particles with a range of sizes and shapes • Surface area may be greater than calculated – Particle shape can affect particle surface activity 31 Micromeritics Particle Shape – Particles can exist in several different crystalline structures (plates, needles, cubes, aggregates) • If the different structures have different properties and stabilities, this is called polymorphism – May spontaneously convert from a metastable form to a stable form with heat or visa versa – Very important in the development of active pharmaceutical ingredients » Can affect solubility, drug absorption and bioavailability » Metastable forms exhibit higher solubility and dissolution rates » Regulatory approval is given for only the stable crystalline structure for many drugs 32 Micromeritics – Shape of colloids, size and range of particles has direct impact on its behavior in biological system • Particle surface area will be different depending on the shape • Spherical particles may have best permeation through lipid membranes – Penetration of particles across a lipid bilayer is determined by » Contact area between the particle and the lipid bilayer » The local curvature of the particle at the contact point » Spherical particles are taken up 500% more than rod-shaped particles of similar size » Nanoparticle interaction with with cell membranes is important in drug delivery 33 Micromeritics Surface Area • Expressed in terms of specific surface area • Surface area per unit volume (Sv) or per unit weight (Sw) • Term surface area/volume ratio refers to Sv Surface Activity • Derives from the surface area, surface characteristics and the energy storage capacity of the particles • Large increases in surface area can change properties of drug delivery systems • Surface energy increases as particles are finely divided 34 Surface Area Measurement Adsorption – Governed by the adsorption theory which states that gas molecules will adsorb into a particles surface and surface area can be calculated by the number of gas molecules present – Can be placed into one of two categories, physical or chemical adsorption 35 Surface Area Measurement • Absorption studies may involve measuring amount of gas adsorbed (volume) by a given amount of adsorbent (particles) and the pressure of the gas. – Langmuir isotherm is based on the formation of a monolayer film of gas over the surface of the absorbent • Initially, there is a strong binding of gas molecules to the surface of the absorbent • Subsequently, a leveling off occurs • Limited to mostly chemisorptions – BET Isotherm explains the more complete adsorption process involves multilayer formation • Basis for surface area determinations 36 Particle Porosity – Measurement of pore size can be done using isotherms – Grinding, milling and leaching processes produce pores within the particle’s structure – Particles produced by condensation or crystallization may contain or acquire cracks over time – Fine particles tend to form aggregates or larger secondary particles – Expressed as diameter (cylindrical) or as the width of the pore opening • Micropores: widths < 2 nm (20 Å) • Mesopores: widths 2 to 50 nm • Macropores: widths > 50 nm – Total pore volume 37 Porosity Porosity is the measure of void volume in a powder material. § Expressed as percent or fraction (void) § Bulk volume - total volume measured in cylinder § Void volume is difference between bulk volume and true volume 38 Density • Density is weight per unit volume – Types of density measurements: • True density – determined using a helium densitometer • Envelope density - determined based on the theory of liquid displacement • Bulk density –determined by measuring in a cylinder • Tap density – Bulk density changes with vibration and applied forces due to changes in volume – True and envelope densities of nonporous powders are identical • The two will differ significantly if the particles are of irregular shape 39 Flow Property Important factor for tablet manufacture for consistent die filling Powder flowability defined as the ease with which a powder will flow under a set of conditions. • Pressure on the powder • Humidity • Equipment 40 Flow Properties – Particle size and particle shape – Spherical particles flow better – Small particles do not flow as well as large particles • 250 to 2000 µm flow freely • 75 to 250 µm may or may not flow freely • Less than 100 µm, flow is a problem for most powders – Particle size distribution • Flowability increases as particle size distribution decreases (narrows) • Flowability increases as particle sizes increases 41 Flow Properties • Angle of repose – Powder flows through a funnel and flows freely – Height and radius of the cone are measured, and angle calculated • Tapped density – – – – Tapped density tester Repeated tapping (over 1000 x) until volume is consistent Final volume is used to calculate Hausner ratio H Ratio = 1.25 or below indicates poor flowability • Glidants: mag+ stearate, starch and talc enhance flow, possibly by decreasing the repose and internal friction angles 42 Pharmaceutical Powders Pharmaceutical Techniques of Powder Formulation – Industrial comminution • Coarse crushers – produce powders/particles material between 1.5 to 60 inches • Intermediate grinders – provide powders between 20 and 200 mesh • Fine grinding mills – provide powders smaller than 200 mesh – Methods of comminution in compounding • Trituration • Pulverization by intervention • Levigation 43 Pharmaceutical Powders • Blending • Large techniques – Paddle blenders – Fluidized air mixer – Motionless mixer • Small scale techniques – Spatulation » No particle size reduction » Ideal to blend eutectic formers – Trituration • Geometric dilution 44 Pharmaceutical Powders Medicated Powders – Includes: bulk powders, oral powders, dusting powders, douche powders, insufflations, inhalation powders 45