TOPIC 3.1: Crystallisation (API Isolation)

What is Crystallisation?

• It is the formation of a solid crystalline phase of a chemical compound from a solution in which the compound is dissolved

• Purification method → crystal formed from an impure solution is itself pure

• Polymorphism: A solid may exist in more than one form of crystal structure

  • Each crystal structure is known as a polymorph

  • Different polymorphs have different properties (eg. solubility, dissolution rate, toxicity etc.) → affects their performance

  • Many drugs receive regulatory approval for only a single crystal form → got direct medical implications

    • Difference in solubility will change the rate at which the API crystal dissolves in the body → impacts bioavailability of the drug substance to the body

Factors Affecting Nucleation

• Mechanism of Nucleation

• Quantity & Size of Seeds Added

• Degree of Supersaturation

• Temperature

• Cooling Rate

• Presence of Impurities

• Agitation

Factors Affecting Nucleation — Mechanism of Nucleation

• This is divided into primary and secondary nucleation

• Seeds are added during secondary nucleation and it controls the crystal form → growth will be the main mechanism for crystal mass formation

• During primary nucleation, multiple crystal forms have the potential to simultaneously nucleate, forming fine crystals → BAD!

  • Secondary nucleation is preferred

• Supersaturation must be maintained well within the metastable zone (pink zone) to ensure the main mechanism is growth

• Growth as main mechanism + use of seeds = control of the desired crystal form (as nucleation is minimised)

↓ Mechanism of nucleation = ↓ types of crystal sizes formed

Factors Affecting Nucleation — Quantity & Size of Seeds Added

• The solute contains a fixed amount of API that needs to be crystallised

• Each seed particle acts as a nucleation site that initiates and sustains crystal growth

  • If there were more sites (↑ quantity of seeds), the API will be more widely distributed → each crystal receives less API → forms finer crystals

• Size of seeds controls the crystal growth’s foundation as the growth occurs on the existing surfaces of the seeds

  • If the seeds had a larger surface area (↑ size of seeds), growth on a larger area will form larger crystals

↑ Quantity of seeds = ↓ size of crystals formed

↑ Size of seeds = ↑ size of crystals formed

Factors Affecting Nucleation — Degree of Supersaturation

• Supersaturation is the driving force for crystal nucleation and growth

• High degree of supersaturation will move the system beyond the metastable zone, resulting in spontaneous nucleation → high nucleation → forms fine crystals and multiple crystal forms

• Hence, usually maintain low degree of supersaturation to get the right crystal size distribution and crystal form

  • Low level is dominated by crystal growth with the addition of seeds

↓ Degree of supersaturation = correct crystal size distribution

Factors Affecting Nucleation — Temperature

• Affects yield and purity of drug product

• If not cooled enough, crystallisation may be incomplete → some solute will remain in the solvent and be lost → decreases yield

• If cooled too much, impurities may also crystalise → decreases purity

• Crystallization is an exothermic process → as system temperature increases → process becomes more complex

Factors Affecting Nucleation — Cooling Rate

• Affects crystal size

• Slow cooling rate → decreases spontaneous nucleation → few nuclei formed → larger crystals

• Fast cooling rate → nuclei are formed once supersaturation is achieved → lots of small crystal are produced

↓ Cooling rate = ↑ size of crystals formed

Factors Affecting Nucleation — Presence of Impurities

• Affects rate of nucleation

• Presence of impurities in the system slows down nucleation

  • It gets adsorbed onto the surface of the nucleus or crystal → obstructs the solute molecule from building upon the nuclei

• In certain cases, adsorption occurs preferentially on a particular face of the crystal → modifies the shape of the crystals

Factors Affecting Nucleation — Agitation

• Needed to maintain a uniform solution temperature

• Also used to keep crystals off the vessel bottom

• If not done, there is lesser crystal surface exposed to the supersaturated solution → less crystal growth and mother liquor may retain substantial supersaturation → some solute will remain in the solvent → decrease in actual yield

• If done too much, crystals may break when colliding with each other, the agitator or the walls of the vessel → decrease in crystal size

• Variable speed agitators may be used to allow reducing agitation speed at critical steps

Factors Affecting Crystal Attributes

ATTRIBUTES	FACTORS
Production yield	Temperature Agitation
Purity	Temperature Presence of impurities
Crystal shape / form	Degree of supersaturation Presence of impurities Mechanism of nucleation
Crystal size	Quantity & size of seeds added Degree of supersaturation Cooling rate Agitation