Pharmaceutical solids and preformulation importance of particle design Flashcards Preview

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Flashcards in Pharmaceutical solids and preformulation importance of particle design Deck (35)
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1
Q

Multi-particulates

  • Powders: crystals, nanoparticles, microcapsules, microspheres
  • Granules / agglomerates
  • Pellets / spheroids / beads
A

Multi-particulates

  • Powders: crystals, nanoparticles, microcapsules, microspheres
  • Granules / agglomerates
  • Pellets / spheroids / beads
2
Q

Final dosage form
• Capsules: hard, soft
• Tablets / caplets
• Others: films, gums

A

Final dosage form
• Capsules: hard, soft
• Tablets / caplets
• Others: films, gums

3
Q

Why Solid Dosage Form?

A
  • Markedly better chemical stability
  • Dry, does not promote microbial growth
  • Lower bulk volume
  • Ease of handling, added convenience
  • Single chemical component possible
4
Q

Solid state solubility ranking

Ultra-micronization
polymorph
solvate
amorphous

A
LEAST SOLUBLE
1) polymorph
2) solvate
3) amorphous
4) ultra-micronization 
MOST SOLUBLE (Highest Chemical potential)
5
Q

technique to Determine structure of crystaline or amorphous material

A

1) Differential scanning calorimetry (DSC)
2) X-ray diffraction (XRD) by crystals — bragg eqn (nWAVELENGTH = 2dSINE o)
3) single crystal XRD
4) Powder- XRD

6
Q

DSC

A

Differential Scanning Calorimetry (DSC)

A thermoanalytical technique to measure the difference in the amount of heat required to increase the temperature of a sample and reference are measured as a function of temperature

7
Q

Crystal (Single Crystal XRD)

A

Single-crystal XRD is an analytical technique which provides detailed information about a crystal’s interior, including unit cell dimensions, bond-lengths, bond angles, ordering. Single crystal and details of site-XRD data analysis can provide the crystal structure.

8
Q

What are pre-formulation studies?

A

1) involve primary characterization of drugs substances and / or excipients for certain fundamental physical and chemical properties
2) Confirm supplier’s information and ensure quality. especially of raw materials
3) provide information that may dictate many of the subsequent events

9
Q

Applications/uses of preformualtion studies

A

1) to detect batch to batch variations of starting materials
2) enable better specifications to be drawn up for procuring materials, aimed at reducing cost or improving product quality.
3) an excellent database for the assessment of suppliers who can provide materials of consistent quality
4) retrospective study of process or product, improve specifications for raw materials .

10
Q

The physical aspects of raw materials are more likely than chemical properties to exert a greater influence on the granulation process as well as the quality and functionality of finished products.

A

The physical aspects of raw materials are more likely than chemical properties to exert a greater influence on the granulation process as well as the quality and functionality of finished products.

11
Q

Effect of particle shape

A

shape can have significant effects on the bulk properties of a powder.
spherical particles flow better, pack better and have lower surface to volume ratio

12
Q

surface area measurement by

A

1) gas permeability

2) gas adsorption

13
Q

determination of particle shape

A

1) micrometer
2) projected image
3) image analysis

most common is image analysis

  • Sphericity = 4pi (AREA) / (perimeter)^2
    — 1 = spherical
    perimeter UP = less sphere
  • roundness = (perimeter)^2 / 4pi Area
  • — > 1 = less round
  • Aspect ratio
    = Length / breadth
    ~2-3 = needle like
    up = more needle
14
Q

determine particle size

A

1) particle counting
2) particle size

1) size by group
2) get size of every particle and average it.

but only sphere can be described by 1 number.
Use equivalent sphere theory –> possible to gauge if particles become bigger or smaller, according to changes in volume or weight properties.

Therefore:
A) Use graticule (perimeter diameter)
- common

B) use image analysis (projected area diameter)

15
Q

all Sizing methods and their size

A

1) Scales - venier, micrometer
(large particles (>05mm)

2) sieves - popular, robust (>10um)
3) microscopy/image analysis (5um - 5mm)
4) laser diffraction (5um-5mm)
5) laser scattering (0.001um - 5um)

Others:

sedimentation: gravity, sedimentation
(0. 05um - 150um)

SEM/image analysis (nm-um)

AFM/image analysis (nm-um)

16
Q

Microscopy

pros and cons

A

size determination

1) direct examination
2) cheap

3) not for quality or production control
- missing one 10um particles has the same effect as missing one thousand 1um particles
- need 10000 images to be statistically valid.

17
Q

Feret diameter

A

distance between two vertical lines tangent to the ends of the particle, or Feret’s diameter is the greatest distance possible between any two points along the boundary of a region of interest.

18
Q

Martin diameter

A

length of the horizontal line that appears to divide particle into halves.

19
Q

Sieves

pro and cons

A

1) economical
2) readily usable technique for large particles
3) allows separation into some size fractions if required.
4) robust method, for coarse powders.

5) Not possible for sprays and emulsions
6) difficult for very fine dry powders (under 40um)
7) cohesive and agglomerative materials are difficult to impossible to measure (<200um)

  • the longer the measurement times, the smaller is the size as particles orienta themselves to fall through the sieve.
20
Q

Sieves size

A

consists of screens

apertures of different size with a root 2 progression.
divide by root 2

21
Q

techniques for sieving

A

1) wet sieving
2) hand sieving
3) machine sieving
4) air jet sieving

22
Q

Machine sieving procedure

A

1) weighed material on top sieve
2) Sieve shaker vibrated at a known amplitude for a fixed time
3) Each sieve removed from shaker
4) Amount on each sieve weighed = weight oversize.
5) cumulative distribution graph plotted.

23
Q

Air jet sieve

A

1) for sieving fine powders, < 200um
2) can be used with microsieves
3) weighed material placed on sieve of certain aperture size
4) particles smaller than aperture size passed through sieve.
5) material remaining on sieve weighed
6) process repeated with sieves of other aperture size
7) cumulative graph of percent weight oversize plotted.

Parallel methods.
1) weigh different powders

2) placed on sieve of different aperture size on different machine
3) plot graph

Sieve equivalent diameter = at 50% weight frequency

Span = D90 - D10 / D50

24
Q

Electrozone sensing

A

1) Difficult to measure emulsions and impossible to measure sprays.
2) Dry powder required to be in a suspension
3) measurement must take place in an electrolyte, difficult for organic materials
4) Requires calibration standards that are expensive and can change size in distilled water and electrolyte
5) it is slow for materials of relatively wide particle size and it it not easy to size particles below 2um
6) porous particles and dense materials pose additional problems.

7) works based on orifice obscuration
8) size ~ area ~ resistance
9) unaffected by optical properties, densities, colours and shapes of particles.

10) particles need to be insoluble, non-porous, non conductive
11) need reference size calibrator

25
Q

Laser diffraction general uses , note

A
  • Low angle light scattering (LALLS)
  • preferred standard to characterize particle and QC
  • wide dynamic range (5um-5mm)
  • flexible (can measure dry powder, sprays or particles in air/liquid.
  • non destructive and non-intrusive methods and a volume distribution is generated, equal to weight distribution where density is constant.
  • rapid,under a minute, repeatable and high resolution
  • there is no need to calibrate against a standard but equipment performance can be easily verified.
26
Q

Laser diffraction principle

A

The laser diffractin method takes advantage of an optical principle which dictates that small particles in the path of a light beam scatter the light in characteristic, symmetrical pattern, a function of angle to the axis of the incident beam (‘flux pattern’) and the distribution of particle sizes can be deduced.

  • the simplest flux pattern, a monomodal dispersion of spheres, consists of a central bright spot (AIRY DISK), surrounded by concentric dark and bright rings whose intensity diminishes further from the centre of the pattern, that is at higher scattering angles.
    The scattering angle at which the first dark ring, or diffraction minimum, occurs, depends on the size of the particles; the smaller the particle, the higher the angle of the first dark ring (or alternatively, the larger the size of the Airy disk)
  • As particle size approace wavelength of light ==> some light are scattered FORWARD (BIG PARTICLE)
  • SMALL PARTICLE have more curvature = more diffraction = LIGHT DIFFRACTION SIDE WAY.
27
Q

Light scattering

A

Also known as dynamic light scattering and quasi-elastic light scattering.
- APPLICABLE to particles suspended in liquid, which are in a state of random movement due to brownian motion
( ~2-3um)

  • the pace of the movement is inversely proportional to size (smaller particles, faster movement or diffusion) and the pace can be detected by analyzing the time dependency of light intensity fluctuations scattered from particles when they are illuminated.

BIG particles reflect more light and move slower therefore light decay is slower.

28
Q

Surface area determination

A

1) gas permeability
2) gas adsorption

1) gas passes thru a column of particles.
if SA increase = more resistance = more time needed to pass the column

(packing of column is impt factor)

2) BET theory

29
Q

Brunauer-Emmett-teller (BET) theory

A

1) All air are evacuate out
2) cool to boiling point of nitrogen

3) introduce N2
4) N2 adsorb on surface and form monolayer (At cryogenic temp, weak molecular attractive forces will cause gas molecules to be adsorbed)

specific surface area can be derived from amount of adsorbate required for monolayer absorption, with Avogadro constant (6.022 x 10^23/mol) and the effective cross-sectional area of one adsorbate molecule.

By ideal gas law; measuring pressure, can determin volume of gas adsorbed (adsorption isotherm)

From crosssectional area of adsorbed gas molecule, SA and pore size distribution can be derived.

30
Q
True
particle 
real 
absolute 
skeletal DENSITY  =
A

Weight / true volume of solid (volume without voids)

31
Q

Bulk density:

A

weight / volume occupied.

1) poured: freely settled
2) Tapped: post-tapped
3) Envelope: Bulk density without inter-agglomerate voids.

32
Q

Gas pycnometry

A

to get density

Vs = Vc + Vr / (1-P1/P2)

Vs = sample volume
Vc = Volume of empty sample chamber
(known from a prior calibration step)
Vr = Volume of the reference volume (again known from a prior calibration step)

P1 is the first pressure (ie the sample chamer only)
P2 is the second (lower) pressure after expansion of the gas into the comined volumes of sample chamber and reference chamber.

He an inert small gas is usually used

33
Q

Envelope density

A

Also known as geometric density.

Involves the determination of the geometric space occupied within the envelope of a solid material or aggregate,
including any interior voids, cracks or pores.

The volume of irregularly shaped samples can be determined by dry powder displacement using a free-flowing powder and a measuring cylinder.

PARTICLES SIZE should ideally EXCEED 2mm for best results.

envelope density is the mass of an object divided by its volume where the volume includes that of its internal pore and small cavities.

The unique displacement measurement technique that uses a quasi-fluid composed of small, rigid spheres, freely flowing and referred as free-flow filler.

A test sample of known weight is placed in a bed of the free-flow filler of known volume,
and the filler is agiated to gently blend nd completely embed the sample. The displacement volume is determined; and is considered as the equivalent volume of the sample.

34
Q

Solubility of drugs and excipients affect _____

A

F
Rate of drug release
therefore therapeutic efficacy

35
Q

Factors that affected solubility determination

A

Normally determined from saturated solution.

Factors:

1) Technique/ methodology
2) Temp ctrl
3) Eq point — take long time to establish
4) Supersaturation: crystal form

5) impurities
- LESS pure = more soluble
- MORE pure = less soluble

(MUST be 99.9% pure)