Solid Particles And Particle Size Flashcards
1
Q
Why is Particle Size Important?
Biopharmaceutics
A
Rate of Dissolution of solids INCREASE
as Surface area INCREASES
Small particles = Large surface area
2
Q
Toxicity
Why is Particle Size Important?
A
Small rod-shaped insoluble particles
~1um x 5um long
CARCINOGENIC if inhaled
- –> attack immune system if they are similar to bacteria
- failed attackks lead to lung tissue damage
3
Q
Inhalation Drug Delivery
Why is Particle Size Important?
A
Particles must be within a critical size of
1-5um
to reach deep recess of lungs (aleovi)
4
Q
Poorly Soluble Drugs
Why is Particle Size Important?
A
Particle Size REDUCTION
–> increase surface area
INCREASES dissolution rate
5
Q
Nanoparticle Technology
Why is Particle Size Important?
A
Extra solubility enhancement can be achieved
W/ colloidal particles
6
Q
Aseptic Processing
Why is Particle Size Important?
A
Filtration is Important
–> REMOvE MICROORGANISMS
laminar air flow hoods
7
Q
Liquid Filtration Process
Why is Particle Size Important?
A
Filter pore size related to Microorganism / drug particle size
8
Q
Compounding
Why is Particle Size Important?
A
Organoleptic Properties
Tase / Smell ENHANCED by particle size
Large particles = gritty and visually unaesthetic
9
Q
Nanometer to Angstrom
A
1nm
= 10 angstroms
1angstrom = 1x10-10m
10
Q
Micrometrics
A
Describes the SCIENCE & TECHNOLOGY
of Small particles
- Range in size from .5um - 3000um (3mm) in size
11
Q
Physical Characteristics of Powder
Molecular Level
A
- Characteristics of individual molecules studied by:
- UV/VIS absorption spectroscopy
- Fluorescence spectroscopy
- Vibrational Spectroscopy
- IR / NMR
12
Q
Particulate Level
Why is Particle Size Important?
A
- Characteristics that pertain to a small group of particles are studied by:
-
Particle Morphology
- SEM
- Sieving / Laser Diffraction
- Crystallography / X-ray diffraction
-
Thermal Methods
- DSC / DTA
-
Particle Morphology
13
Q
Bulk Level
Why is Particle Size Important?
A
- Characteristics pertain to a large group of particles
- Solubility / dissolution rate
- adsorption / flow
- Angle of repose
- Bulk packin / tap density
14
Q
Objective of Size Reduction
Large Particle Size
A
Uniform Particle size/ shape for processing
- Control of raw materials
- Process uniformity
- uniform flow of particles
15
Q
Milling / Comminution
Large Particle Size
A
Comminution = Crush / grind into powder
Hammer Mill / Fitzmill
- Happer = wedge shaped hatchet blade
- Mill speed –> more small particles
- Feed Rate:
- TOO FAST –> choke mill –> BURNING
- too slow –> starve mill –> small particle size
16
Q
Analysis of
Large Particle Size
A
-
SIEVING
- Mesh, GREATER NUMBER = Smaller the size
- screen openings per inch
- Microscopy
- Bulk Density / Tap Density
- Angle of Repose
17
Q
How to measure / characterize Solids
Large Particle Size
A
- Count particles
- Measure longest dimension:
- Surface Area
- Volume
- Mass
18
Q
Equivalent Sphere Method
Large Particle Size
A
Express dimensions in ONE NUMBER
Dimension / Surface Area / Volume
MEAN DIAMETER
19
Q
Number-Length mean
D[1,0]
Large Particle Size
A
Sum of diameter / n
20
Q
Number-Surface mean
D[2,0]
Large Particle Size
A
SURFACE AREA
SQUARE ROOT OF Sum[d2] / n
21
Q
Number Volume or Number-Weight mean
D[3,0]
Large Particle Size
A
Sum of diameters to the 3rd power / n
All to the 1/3 power
22
Q
Particle Characterization
Large Particle Size
A
What matters is
WHAT TYPE OF INSTRUMENT PROVIDES THE DATA
23
Q
Monodisperse Vs Polydisperse
Large Particle Size
A
Mono = all particles are same size and shape
Poly = particles range from small to large
look for an AVERAGE particle size to measure
24
Q
Unimodal vs Bimodal
Large Particle Size
A
Unimodal = Mean size has 1 PEAK
Bimodal = 2 sizes 2 peaks
25
**Bulk Density**
Large Particle Size
* *Not an intrinsic property*
* **Changes depending on how the material is handled**
* ****Disturbing a cylinder
* --\> powder particles will move and settle closer together
* --\> **Increased bulk density**
26
**Different ways to compute average/mean particle size**
Large Particle Size
* Average the **longest length**
* **surface area**
* **volume**
* **weighted combination**
* ****arithmetic mean / geometric/ harmonic mean)
**JUST MAKE SURE U COMPARE THE SAME THANG**
27
**Tapped Density**
Large Particle Size
* **Refers to the bulk density of the powder**
* **AFTER a specified compaction process**
* **VIBRATION**
* ****Cylinder is TAPPED
* until the volume reaches a MINIMUM
28
**Angle of Repose**
Large Particle Size
* Bulk materials poored onto a horizontal surface
* --\> form **conical pile**
* Angle of repose
* = **Internal angle between surface of the pile**
* **& the horizontal surface**
* ****Related to:
* **density / surface area / shapes**
* **& STICKINESS (coefficient of friction)**
29
**Product / Process Considerations**
Large Particle Size
* **ENCAPSULATION**
* **VOLUMETRIC FILL INTO CAPSULE**
* **_Dispensed by weight but filled by volume_**
* ****Solid Mixing / blending
* **ORDERED MIXING =** of same size in order
* segregation / volume of material
* SOlids Milling
* **Uniformity of particle size**
* Tablet compressing
* **Product Dissolution performance**
* **Solid granulation proces**
30
**Target Size Reduction**
Small Particle Size
**1 micron = 1mm**
**Uniform size/ shape**
31
**Ball Mill**
Small Particle Size
* **Grinder consisting of cylindrical container**
* **--\> Solids --\> FINE POWDERS**
* ****Rotate around horizontal axis
* **Material to be ground + GRINDING MEDIUM**
* ****ceramic/steel balls
32
**Micronizer (Jet Mill)**
Small Particle Size
**Sturtevant Micronizer = Fluid Energy Mill**
* **Compressed air/gas**
* --\> produce particles **LESS THAN 1 micron (1mm)**
* ****Fine particles move towards center --\> exit through vortex finder
* use centrifugal force
33
**Analysis of**
Small Particle Size
* **Microscopy**
* **Electrozone Sensing**
* **Laser Diffration = LALLS**
* **Photon Correlation Spectroscopy = PCS**
* **Cascade Impactors**
* **BET isotherm analysis**
34
**Microscopy**
Analysis of Small Particle Size
Measurement Slide
**Logarithmic scarle**
**Image analysis software needed**
same technique as w/ larger particles
35
**Electrozone Sensing = Coulter Counter**
Analysis of Small Particle Size
Particle size determined by **VOLTAGE CHARGE**
Must **measure using an electrolyte**
***CAN NOT** MEASURE DRY POWDER / SPRAYS*
requires calibration
lower limit = **2mm**
36
**Laser Diffraction = LALLS**
**Malvern**
Analysis of Small Particle Size
**Low angle laser light scattering**
Range \>.05um
Laser is stable/reliable
NO calibration
_CAN measure dry powders / liquid in suspension / sprays_
37
**Photon Correlation Spectroscopy**
**PCS**
Analysis of Small Particle Size
**For particles BELOW \<1nm**
**Brownian motion to measure particle size**
*CAN NOT use on particles that are sedementing*
**DENSITY** **dependent**
large molecules = slower movement
38
**Cascade Impactors**
Analysis of Small Particle Size
Use to measure particle size in **AEROSOLS**
**Stokes Law**
Particle size serparation is carrried out by **Inertial impaction**
**based on particle mass**
39
**Product / Process Considerations**
of Small Particle Size
* **Product dissolution Performance --\> BIOAVAILABILITY**
* ****Micron particle size --\> Dissolution --\> More Absorption
* **Solid Micronization**
* uniformity of size
* Tablet Coating
* Suspension/cream / ointments
* **Opthalmics**
* ******_AEROSOL DOSAGE FORMS_**
40
**Aerosol Dosage Forms**
of Small Particle Size
**Goal is to get aerosol particles --\> DEEP LUNG ALVEOLI**
*not into upper respiratory*
**_Particle Size is the key to success_**
* **pMDI's or MDI**
* has propellant
* pressurized container with drug --\> actuation
* **DPI (dry powder inhalation)**
* *no propellant no pressure*
* **Admin by ACTUATION**
*
41
**Ideal Respiratory Delivery System**
Small Particle Size
* Respirable particle Delivery:
* Particle Size -**\<2um**
* **Reproducible Plume Pattern**
* Consistant dose UNIFORMITY
* *no electrostatic issues*
* ****Stable & Compatable formulation**
* ****stable particle size
* **free from extractables/microbials**
42
**Biopharmaceutics**
on Particle Size
_**Increasing particle size can delay drug release in suspension**_
* **Rate of Dissolution**
* ****related to **particle size / total surface area**
* **Solubility is INCREASED**
* if particle is extremely smal**l \<100nm**
* **M-Cells** (associated w/ lymph tissue / intestinal wall)
* **absorb nanoparticles**
43
**Griseofulvin**
* Antifungal that was ***POORLY ORALLY ABSORBED***
* ***Reduced particle size***
* ***--\> Decreased the dose***
44
**Fenofibrate**
**Reduction of particle size**
**Allowed for a lower dose needed**
45
**Potassium Chloride / Nitrofurantoin**
**Sustained Release** drug created from
**MICROENCAPSULATING** the product
*reduce the rate of absorption*
individual crystals covered w/ semipermeable coatin
46
**Insulin**
Biopharmaceutics
Insulin is typically RAPIDLY elminated from the body
due to high water solubility
**Formation W/ zinc-insulin suspensions**
**--\> PROLONGS BIOLOGICAL ACTIVITY**
47
**Uses of Nanoparticles**
* **Primarily** used for **Nanotechnology**
* **DRUG DELIVERY SYSTEMS**
* Protective encapsulation
* Target specific tissues
* Act as **water-soluble carriers**
* for poorly soluble drugs
* **Secondary** used to **ENHANCE dissolution rates**
* **--\> to improve Bioavailability**
* ****Ex. _greseofulvin / Fenofibrate_
48
**Top Down Formation of**
**Nanoparticles**
* **Top-Down** comminution
* **Ball Milling / Jet Milling**
* ***REDUCE*** solid particles --\> colloid size
* **200-500nm range******
49
**Bottom-Up Technique**
**Nanoparticles**
* Assemble nanopartcles from **MOLECULAR COMPONENTS**
* **Self-Assembly**
* polymeric surfactants / dendron-substrate complexation
* **Precipitation**
* **Polymerization of Monomers**
50
**Dendrimers**
Nanoparticles
* Highly branched polymers
* --\> **molecular complexing agents that**
* **WRAP AROUND**
* the API
* Similar to chelating agents = **tiny burritos**
* ******Encapsulation of a single drug molecule**
* inside a SINGLE dendrimer shell
* _Size is similar to micelles_
51
**Solvent-Displacement Methods**
Nanoparticles
* **Adding anti-solvent**
* --\> reduces the solubility of the drug-polymer complex
* **Salting Out**
* **Emulsion-Diffusion / SOlvent evaporation**
* **Supercritical fluid vaporizattion**
* **Coacervation reactions**
52
**In-Situ Polymerization**
Nanoparticles
* Sme polymers undergo polymeraztion reactions under special conditions
* --\>**Formation of polymer nanoparticles that**
* **ENTRAP the drug**
53
**Membrane Filtration Requirements**
Air Filtration
**HEPA = High Efficiency Particulate Arrestance**
used to remove bacteria (allergens)
* MUST remove **99.97%**
* **** of all particles **GREATER THAN \>0.3um**
* from the air it passes through
* Pre-filters used before this membrane
* protects the membrane filter
* traps larger molecules
54
**Containment**
**Positive Air Flow**
Air Filtration
* **Airflow INTO** the facility must be filtered to remove any particulate contaminants
* anything **LARGER THAN \> 300nm**
* **Positive Air Pressure**
* ****Air flows **OUT** to reduce contamination
55
**Aseptic Compounding Considerations**
1. **Wash Hands Well**
2. **Wear gloves / cover skin**
3. **Use the right LFH**
4. in a clean facility
5. work within hood / clean & non obstructed
6. FIlter and hood should be properly maintained
56
**Glove Box**
**RABS**
**CAI**
Pharmacy Aseptic Practice
**Glove box = Isolator = RABS = CAI**
* **Similar air flow & fxn of Laminar Flow Hoods**
* **particle filtration is the same as well******
* CAI = Compounding Aseptic Isolator
* RABS = Restricted Access Barrier Systems
57
58
**Macrofiltration**
**10um-100um**
_POLLEN / RBC / Sand_
* **Contain Large Particles**
* wet chemical analysis
* fiberglass/cellulose filters
* Coffee filters
59
****_Micro_**filtration**
**1um - 10um**
Most _bacteria / yeast / some virus (polio)_
_STERILE_
__
60
**Dialysis / Ultrafiltration**
**1nm - 100nm (0.1um)**
_Include most particulates / molecules_
**_VIRUS / Proteins_**
61
**Liquid Filtration Process**
* Membrane FIltration
* **Depth Filters**
* protect mebranes / prolong filter lfife
* **Filter Aids**
* diatomaceous earth / cellulose / perlite
* **Decolorization**
* **activated charcoal adsorption**
62
**Aseptic Filtration**
liquid filtration
**_0.22mm FILTER_**
* **Hydrophilic filters for aqueous solutions**
* **cellulosic**
* ****HydroPHOBIC filters for non-aqueous solutions
* PTFE
63
**Particle Size Considerations**
Non-Aseptic Compounding
* **Mix w/ mortar & pestle**
* Materials might have different particle size
* **mill first** (reduce size before mixing)
* ***different particle sizes will segregate***
* **Moisture Levels**
* affect particle agglomeration
* **Ordered Mixing = Geometric Mixing**
* begin with smallest amount of powder --\> add increasing ammounts
* **Suspension Settling**
* ****Increase particles size --\> increase settling rate
64
**Mixing Powders**
* **NOT possible to produce an ideal mixture of 2 powders**
* there is ALWAYS some content of **nonuniformity**
* ideally = low entropy
* really = high entropy
65
**Demixing**
**Little Particles --\> Bottom**
**Large --\> top**
* Powders have the tendency to **SEPERATE** during processing:
* **Percolation**
* gravity --\> small particles move into voids between large particles
* **Vibration** speeds up demixing
* **Transportation******
66
**Demixing Occurs More Readily if...**
**NOT in uniform SIZE & DENSITY**
* reduce particle size first
* uniformity can not be assumed esp when batch size increases
* always have to MEASURE
67
**Eutectic System**
* Mixture of chemical compounds or elements that have
* **A Single chemical composition that SOLIDIFIES @ lower temp** than the other compositions
* **Liquified**
* **Has a *LOWER* Melting Point**
68
**Desirable Function of**
**a Eutectic**
* **HAVE A LOWER MELTING POINT**
* than either of the individual components
* --\> Eutectics **Dissolve more rapidly as well**
* **HIGHER BIOAVAILABILITY**
* from higher solubility --\> faster dissolution --\> faster absorption
69
***UNDESIREABLE***
**function of Eutectics**
* **Trituration** --\> **Pressure on the mixture**
* low melting point --\> two materials can
* **MELT TOGETHER**
* **Making a blend of the powders is difficult or imposible**
* Can Solve by
* --\> Reduce the particle size **SEPERATELY**
* Mix seperately
* Add dry blend component with **INTERT FILLER**
* **MgO / MgCO3**
* minimize opportunities for contact
70
**Particle Size**
Large
Small
Nano
**1mm**
**1um(1micron)**
**1nm**
71
**Size Reduction**
Large
Small
Nano
**Hammer Mill**
**Micronizer / Fluid Energy Mill / Ball Mill**
**Top-Down/Bottom-Up**
72
**Analysis**
Large
Small
Nano
**Screens / Bulk Density / Mesh Size**
**Laser Diffraction / Equivalent Sphere**
**Same as Small**
73
**Pore Size / Filtration**
Large
Small
Nano
## Footnote
**Wet Chemistry / Coffee Filters**
**Aseptic Processing / Soutions (0.22um) / Air**
**Ultrafiltartion / Semipermeable Membranes**
74
**Applications for Large Particles**
**Manufacturing Processing**
**Capsule Size**
**Mixing Powders**
**Topical dosage forms**
75
**Applications for Small Particles**
**Dissolution**
**Bioavailability**
**Aseptic compounding**
**LFH**
**INHALATION DOSAGE FORMS**
76
**Applications for NANOparticles**
**Hemodialysis**
**Peritoneal Dialysis**
**Bioavailability**
