Topic 2.3 Flashcards
Purpose of crystallization?
- an important operation in drug synthesis
- the formation of solid crystals from a homogeneous solution
- provides crystalline materials in a desired size range
- a method for putification (usually <99% purity desired)
What is nucleation + explain the 2 types
Nucleation refers to the formation of new crystal particles from a super-saturated solution.
Primary nucleation:
- no seeding
- refers to birth of very small bodies of a new phase within a super-saturated phase
- homogeneous nucleation is formation of new particles within the phase that is unifluenced by other solids, including walls of the crystallizer, or foreign substances (never happens irl)
- heterogeneous nucleation occurs when solid particles of a foreign particle catalyze the nucleation process
Secondary nucleation:
- seeding
- refers to formation of nuclei due to existing macroscopic crystals (seeds) in the magma
- fluid shear nucleation happens when super-saturated solution moves past the surfaces of growing crystals at substantial velocity thus sweeping with it embryos or nuclei thus appearing as new crystals
- contact nucleation occurs when breakage of microscopic growth on the surface of growing crystals occurs by collision among crystals, or collision against impellers during mixing ot with walls of crystallizer or pipes and new nuclei are formed which grow into crystals
Importance of crystal shape and flow properties + how to infer flow properties?
- sphere, block or bypyramidal crystals are easy to isolate, dry and handle
- acicular/needle shaped, blade crystals tend to have long isolation time, agglomeration, poor flow and handling properties
Crystal flow characteristics can be inferred from Hausner ratio = tapped density/bulk density
Ratio < 1.2 have acceptable flow properties
Ratio > 1.4 have poor flow properties
Poor flowing crystal powder can:
- affect blending with excipients
- cause funnel flow instead of mass flow in subsequent processing
What is polymorphism?
A solid may exist in more than 1 form of crystal structure.
- such drugs recieve regulatory approval for only a single crystal form
- dissolution rates depend on the exact crystal form of a polymorph resultingn in direct medical implications -> different dissolution speeds gives different medical implications
Importance of crystal size?
Crystals need to have a reasonable size and size uniformity (30 to 100um diameter) for further processing.
Big crystals can be easily damaged in filtration/agitation
Fine crystals can be:
- difficult to dry
- have poor flowability
- difficult to wash effectively during filtration and lead to higher impurity levels
- can retain and entrap mother liquor on crystals surface and in between crystals resulting in higher impurity level
If crystals are final product, individual crystals need to be:
- non-aggregated
- uniform in size
- non-caking in the packaging
What is super-saturation?
How to achieve it?
Supersaturation is the concentration of a solute in excess of solubility. This is the driving force for nucleation and growth.
Neither nucleation nor growth can occur in saturated or unsaturated solutions, must be supersaturated.
To achieve supersaturation,
1. if solute solubility increases with temperature, supersaturation formed by cooling
2. if solute solubility is independent of temperature, supersaturation formed by evaporation of solvent
3. if neither are desirable, supersaturation can be formed by adding a 3rd substance:
- Salting (desired): 3rd substances (anti-solvent) combines physically with the original solvent and reduces solubility of solute sharply
- Precipitation: 3rd substance chemically reacts with original solute and forms insoluble substance
From solubility curve,
- curve is steep; use cooling
- curve is flat; use evaporation
- yield for both processes is low; use anti-solvent
is more supersaturated better?
- high delta C (fast cooling rate) will result in high nucleation
- this forms many fine crystals and multiple crystals forms have the potential to simultaneously nucleate
- delta C is usually maintained at a low level and uses seeding to obtain the right crystal form and distribition
Factors affecting crystallization + describe (4)
- Temperature
- affects crystal size and determies yield and quality of product
- if crystal is product and solution not cooled to proper temp, some material may remain in solvent and be lsot
- if cooled too far, impurities may crystallize and reduce quality - Cooling rate
- slow cooling rate; large crystals obtained as spontaneuous nucleation is reduced and new nuclei formed -> growth can take place (desired)
- fast cooling rate -> many small crystals produced. nuclei formed the moment super-saturation is achieved -> less dissolved solute for growth of nuclei - Presence of impurities
- impurities retard the nucleation due to adsorption of impurity on crystal surface
- in certain cases, adsorption occurs preferentially on a particular face of crystal and shape of crystal is modified
e.g. NaCl crystallized from solution containing uera in small quantity forms octahedral crystals instead of the usual cubic NaCl crystals and these have low packing density -> poor powder flow - Agitation
- needed to maintain a uniform solution temperature
- used to keep crystals off the vessel bottom or it will be lost as heel
- crystals may break as they collide with each other and walls of the vessel
- variable speed agitators can be used to allow reducing agitation speed at critical steps
How to control particle size and crystal form with seeding?
- the amount and sie of seed added controls particle size of product
- growth should be the main mechanism for crystal mass formation instead of nucleation
- supersaturation must be maintained well within metastable zone to ensure main mechanism is growth
- with growth as main mechanism of crystallization and use of seeds, desired crystal form is controlled since nucleation is minimised
GMP requirements for crystallizers?
- Double mechanical seals for agitators
- Baffles (~4 Nos.)
- CIP devices for cleaning in-situ
- Dip pipes for solvent transfer
- On line temperature sensor with fast/accurate temperature control
- Contained charging facility for seed crystals
- jacketed SS with smooth internal finish or glass lined vessels with SS agitators - non shear type to not damage/break crystals
- in line filters (10um) upstream of crystallizers for solvent transfer
- circulation pumps should have SS casing with dry mechanical seals (non-oil type)
Describe batch crystallizer
Batch crystallizer (vacuum):
- employ evaporative cooling often operated under vacuum
- hot feed introduced into vessel
- flash evaporation of solution occurs under vacuum causing rapid cooling, followed by small increase in concentration
- the solution is continuously circulated or agitated in order to prevent stratification
