Lecture 15: pre-formulation of solid dosage 2

what does the functionality of pharmaceutical products depend on?

• the physical form of the drugs

• their performance depends on understanding the physical properties

what are the phyiscal forms of a drug and what does it affect?

• only applied when a drug is in a solid state

• affects preformance, development, patentability, manufacturing and profitability of a compound

A drug can have many different solid-state forms:

• Crystalline (Polymorphs, Hydrates and Solvates)

• Chiral

• Habits

• Amorphous

crystalline form has ---- solubility, amorphous form has ---- solubility

• low

• high

examples of amorphous and crystalline

what properties are determined by the nature of the crystalline structure?

• Solubility and dissolution rates(amorphous is highly soluble)

• Crystal hardness (compressibility for tablets)

• Chemical stability (enthalpy of solution, enthalpy of transition, hygroscopicity, melting and sublimation temperatures)

• some chemically unstable drugs change forms from active to inactive during storage

• Others include: Colour and refractive index, heat capacity, conductivity, volume, density.

what are crystal habits?

the external shape of a crystal

what are crystal habits associated with?

• the way solute molecules orientate themselves when growing.

• The general shape of a crystal is related to the growth of individual crystal faces.

• The slowest growing face dominates.

• Crystal habit influences flow, compaction, stability and solubility.

what is crystal face identification?

• Each crystal face has a designated index plane

• These are known as Miller indices

what does the miller index do?

• Miller index provides information about the molecular ordering of the surface of a crystal face

pharmaceutical effects of habit:

• Injectables: Plate-like crystals pass through needles better than long needle-like crystals(poor flow, can clog, unstable)

• Tableting: Plate-like tolbutamol crystals do not flow and have poor compressibility.

• Needle-shaped paracetamol crystal powder shows poorest compression properties, showing greater capping and lamination, than the plate- or cube-shaped crystals.

• Dry powder inhaler (DPI) formulations: Needle-like crystals usually have better fine particle fraction.

what is the definition of a crystalline structure?

• A crystal is composed of periodical aligned building blocks called unit cells

• These unit cells reveal the crystal structure and symmetry specific for each substance (Requires X-ray diffraction to elucidate).

• There are a total of 7 types of crystal structures and all can be defined by the lengths and angles between each side of the unit cell.

what are the 7 primitive unit cells

• Cubic

• Tetragonal

• Orthorhombic

• Trigonal

• Monoclinic

• Triclinic

• Hexagonal

  Drug molecules will typically form triclinic, monoclinic and orthorhombic unit cells

molecules can arrange themselves into 14 different configurations and are known as bravais lattices

what forms does paracetamol exist?

• Exists in two polymorphic forms, monoclinic. (Form 1) and orthorhombic (Form 2)

• Form 1 is more thermodynamically stable at room temperature and is the commercially used form.

• Form 1 not suitable for direct compression, has to be mixed with binding agents before tableting.

classes of polymorphs diagram

what does crystal form mean?

ordering of atoms and molecules to form crystal structure

• it does not mean outer appearance (habit) of the crystals/particles.

What are polymorphisms?

When the same chemical compound exists in different crystal forms

what are pseudopolymorphs?

Special cases of polymorphs are pseudopolymorphs like solvates (solvent molecules in crystal lattice) or hydrates (water molecules in crystal lattice

what is enantiomorphism?

Chiral molecules can crystallise as mirror images of each other. This is known as enantiomorphism. A mixture of D (dextro) and L (levo) crystal forms are known as a racemic mixture.

basic overview of solid forms:

what does enantiotropic and montropic mean?

Solid phase transitions which transform reversibly without passing through the liquid or gaseous phases are called enantiotropic.

• If these are not achieved prior to a phase change then they are called monotropic

• any transition from one polymorph to another below melting point will be irreversible

what are the features of form 1 polymorph?

Lower density

Lower lattice energy

Lower melting point

Faster dissolution rate

Possible fracture line

what are the features of form 2 polymorph?

Higher density

Higher lattice energy

Higher melting point

Slower dissolution rate

Lower bioavailability

what are properties that may change with polymorphic forms?

• Melting point

• Dissolution rate

• Compressibility

• Density

• Flowability

• Surface properties (surface energy and morphology)

• Habit and crystal shape

• Hygroscopicity

• Hardness

• Stability

why is polymorphism important?

• It is essential during the preformulation stage that the most thermodynamically stable polymorph is formed, since a more favourable form may be obtained upon scaling-up.

• Moisture-mediated and solid-state phase transformation from one polymorph to another can occur during processing and storage.

• Regulatory: "What assurance can be provided that no other crystalline forms of this compound exist?" -

• Requires the manufacturer to indicate the characterisation of the various forms of the drug

• Patents - Subsidiary patents for desirable forms

e.g. Chloramphenicol-3-palmitate (CAPP)

• CAPP is a broad spectrum antibiotic.

• Can crystallise in at least three polymorphic forms.

• The most thermodynamically stable form A, is marketed.

• Form B, however, has an eightfold higher bioactivity than form A.

• Can create the danger of fatal dosages when the unwanted polymorph is unwittingly administered because of alterations in process or storage conditions (interconversion).