Lecture 12- Polymorphism Flashcards
Solid state properties
Most drugs= solid state at room temp
Processing of liquid dosage forms, oral, ophtalmic or parenteral solutions= require drug to be dissolved in a solvent during their manufacture
Power dosage forms= better physiochemical stability and longer shelf-life over the corresponding liquid dosage forms
Solid forms
Polymorphs = different crystal of the same chemical;
Amorphous = disordered state
Solvate= peeudopolymorph; solvent molecules are incorporated in the crystal lattice
Salt= generally have a higher water solubility + bioavailability than the corresponding uncharged molecule
Co-crystal= non=volatile molecules incorporated in the crystal lattice. Additional component= solid at room temp
Solid particles= held together by IMF; hydrogen bonds + Vander Waals Forces
Polymorphism
= when a substance exists in more than one crystalline form, different forms are designated as polymorphs + the phenomenon as polymorphism
Polymorphs= 2 crystals have the same chemical composition but different internal structure
ROY, or 5-methyl-2-thiophene-3-carbonitrile = precursor to the antipsychotic drug olanzapine
Polymorphism; carbon’s polymor
Low temp + pressure= carbon is the mineral graphite
Higher temp + pressure= stable form is diamond
Polymorphism= molecules existing in diff forms
Allotropy= elements existing in different forms
Polymorphs
Differ from each other with respect to their physical properties such as;
-hygroscopicity, solubility+ dissolution, melting point, density, chemical + physical stability, hardness, compression properties + manufacturability
Affects;
-drug product stability, dissolution and bioavailability, quality, safety + efficacy of drug product
Polymorphs
Depending on relative stability- several polymorphic forms will be physically more stable than the others
Stable polymorphic= lowest energy state, has the highest mp + least aqueous solubilites
-higher mp= stronger lattice= hard to remove a molecule= low dissolution rate
Polymorphism
Metastable forms= greater aqueous solubility= show better bioavailability = preferred in formulations
Graph- slide 10+ 11
Paracetamol
Stable monoclinic form I= cannot be compressed into tablet
Metastable form II (orthorhombic) = plastically deforming forms good tablet
-poor thermodynamic stability, aging of dosage forms containing Metastable forms= result in formation of less soluble, stable polymorphs
Polymorphism
Metastable —> stable can be inhibited by dehydrating the molecule environment / adding viscosity building macromolecules such as; PVP, CMC, pectin or gelatin to prevent conversion by adsorbing on to the surface of the crystals
Stable form= slowest dissolution rate, speed up by using Metastable form
Risk using Metastable form= converts back to stable form during products life + gives a consequent change in properties
Appropriate polymorphic form must be used for every product made
Occurrence of polymorphism in pharmaceuticals
Formation of different polymorphs depends on= Solent’s, temp, pressure + rate of cpp;omg
Transitions can occur during crystallisation, milling, granulating, drying + compressing powder to form a tablet
Differ in their physical properties; mp, dissolution, solid state stability + compaction properties
Ritonavir; polymorphism
Slide 15-16
Amorphous state
Atomic arrangements in crystalline silicone + amorphous silicon
Material represent the highest energy state + can be considered as super cooled liquid
Usually prepared by rapid precipitation, rapid cooling of liquid melts, spray drying or freeze drying
Amorphous form of novobiocin= 10x more soluble than crystalline form
Glass transition temp
^when amorphous forms have a characteristic temp at which there is a major change in properties
Sample stored below the Tg= amorphous form will be brittle + known as glassy state
Sample stored above the Tg= becomes rubbery
Tg= molecules in the glass exhibit a major change in mobility
Lack of mobility when sample is glassy= allows the amorphous form to exist for longer, whereas when Tg is below storage temp; increased molecular mobility = rapid conversion to the crystalline form
Amorphous state
Temp of an amorphous material = lowered by adding a small molecule; plasticiser= fits between glassy molecules= greater mobility
More- slide 20
Characterisation
-crystallography; x-ray diffraction pattern
-microscopy
-thermal analysis; DSC + TGA
-infrared absorption + Raman spectroscopy
-solid-state nuclear magnetic resonance
-solubility + dissolution studies
