Deze samenvatting werd gemaakt o.b.v. de slides en lesinhoud van het vak pharmaceutical manufacturing techniques, gedoceerd in de tweede master geneesmiddelenontwikkeling. Het werd in het Engels opgesteld aangezien de cursus en lessen ook in het Engels waren.
2 Nanotechnological Formulation of Poorly Water-Soluble Drug Molecules............................... 27
2.1 Nanotechnology in Pharmaceutical Industry .........................................................................27
2.1.1 Introduction ................................................................................................................. 27
2.1.2 Poorly Soluble API’s require new techniques… .............................................................. 28
2.1.3 Block Copolymer Micelles ............................................................................................ 30
2.1.4 Nano Emulsions ........................................................................................................... 30
2.2 Nanosuspensions ................................................................................................................32
2.2.1 Introduction ................................................................................................................. 32
2.2.2 Examples of Nanosuspensions ..................................................................................... 33
2.2.3 Producing nanosuspensions ......................................................................................... 34
2.3 Downstream Processing of Nanosuspensions .......................................................................37
2.3.1 Nanosuspensions into solid dosage forms .................................................................... 37
2.4 Case study ..........................................................................................................................42
2.4.1 Doxil ............................................................................................................................ 42
2.4.2 Cripec.......................................................................................................................... 43
3 Continuous Production, QbD, PAT ......................................................................................... 46
3.1 Introduction .........................................................................................................................46
3.1.1 Continuous manufacturing ........................................................................................... 46
3.1.2 PAT .............................................................................................................................. 47
3.1.3 QbD ............................................................................................................................. 48
3.2 Pharmaceutical applications ................................................................................................49
3.3 Hot melt extrusion ...............................................................................................................50
3.3.1 Introduction ................................................................................................................. 50
3.3.2 Solid dispersions .......................................................................................................... 51
3.3.3 CMA’s and CPP’s for hot melt extrusion......................................................................... 52
3.3.4 Downstream processing ............................................................................................... 54
3.3.5 PAT in hot melt extrusion .............................................................................................. 54
3.4 Continuous wet granulation: twin screw granulation ..............................................................54
3.4.1 Introduction ................................................................................................................. 54
3.4.2 Screw based granulation .............................................................................................. 55
3.4.3 PAT during wet granulation............................................................................................ 55
3.4.4 Granule Size Distribution (GSD) as a CQA ...................................................................... 55
3.4.5 Friability as a CQA ........................................................................................................ 57
3.4.6 PAT in wet granulation .................................................................................................. 57
4 Process Chemistry and API Manufacturing ............................................................................ 58
4.1 Need for process chemistry ..................................................................................................58
4.2 Process chemistry ...............................................................................................................58
4.2.1 Process chemistry ¹ medicinal chemistry ...................................................................... 58
4.2.2 API production cost ...................................................................................................... 59
1 Solid Phase Peptide Synthesis
Classical organic synthesis in solution
- Most cases: reagent A + reagent B à product AB
ð Classic method for conventional (simple) compounds
ð Possible through applying specific reactions and conditions: temperature, time, ratio,
solvent, catalyst, base…
- Complexity: chemists could make up to 100 compounds a year, however this was too little
when high throughput screening became a hot topic
ð Therefore, we needed high throughput synthesis!
Principle: synthesis of multiple different compounds at the same time.
ð Simultaneous preparation of a library (a.k.a. different compounds) at once, under
identical conditions.
« classical synthesis provides us with one compound at a time
Classical chemistry Combinatorial chemistry
Starting materials: Starting materials:
Reagent A i reagents A
Reagent B n reagents B
Reaction: A + B ® AB Reactions: A1 + B1 ® A1B1…
…Ai + Bn ® AiBn
Output: 1 product Output: i*n products
1.1.1 Combinatorial libraries
1.1.1.1 types of combinatorial libraries
Scaffold-based: libraries where the scaffold or core structure is always the same, only the “R”-
groups differ.
e.g. Passerini three-component reaction
Scaffold: the core structure or framework of a molecule, around which other chemical groups are
added.
ð This central framework is often responsible for the biological activity
ð Scaffold is like the “skeleton” on which functional groups or side chains “clothing” are
added.
Backbone-based: libraries where the compounds are related by a common backbone, which
always repeats itself.
e.g. Oligopeptides made from 20 different amino acids.
Backbone: the entire structure of a molecule, including both the scaffold and the attached
functional groups.
ð Considers the full molecule as a whole
ð Allows the exploration of different complete molecular structures.
ð Backbone is more like “the entire outfit”
ð Different molecules with varying overall structures are included in the library, not just
variations around a common core.
Key Difference
- Focus: Scaffold-based libraries focus on a shared central framework with varying side
groups, while backbone-based libraries focus on complete, diverse molecular structures.
- Purpose: Scaffold-based libraries are used to systematically explore variations around a
common core, while backbone-based libraries are broader, aiming to maximize chemical
diversity.
1.1.1.2 size of combinatorial libraries
Few 10’s – 100’s – 1000’s of compounds
1.1.1.3 requirements
! Large collection of reactive, small and structurally different building blocks
! Synthesis:
o Fast
o Reproduceable
o Reliable
1.1.1.4 synthesis methods
Parallel synthesis: where multiple compounds are synthesized simultaneously in separate
reactions.
Split synthesis: where a single pool of reactants is split, reacted, and recombined iteratively1 to
generate a diverse library of compounds.
1.1.1.4.1 PARALLEL SYNTHESIS
“The easiest library synthesis.”
ð Each reaction vessel contains an individual reaction/individual compound.
ð Binding and activity screening is possible in solution and on-bead.
ð Automation is possible
Total individual reactions = number of end products * reaction steps
Number of end products = (number of reactions)^(number of building blocks in every step)
Step 1: well with solid support in each reaction vessel.
¢: solid support
¢ ¢ ¢ ¢ ¢ ¢ ¢ ¢ ¢
¢ ¢ ¢ ¢ ¢ ¢ ¢ ¢ ¢
¢ ¢ ¢ ¢ ¢ ¢ ¢ ¢ ¢
Step 2: couple A, B and C to the solid support
¢-A ¢-A ¢-A ¢-A ¢-A ¢-A ¢-A ¢-A ¢-A
1
Repeating cycles of splitting, reacting, and recombining multiple times to systematically build a diverse
library of compounds.
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