PHARMACEUTICAL MANUFACTURING TECHNIQUES
, H1. Nanotechnological Formulation 1
1. Introduction on nanotechnology in pharmaceutical industry 1
2. Nanosuspensions 5
3. Downstream processing of nanosuspensions 8
4. Case study: doxil 13
5. Case study: Cripec 14
H2. Process Chemistry & API Manufacturing 17
1. Introduction 17
2. Process chemistry 17
3. Reaction engineering & catalysis 18
4. API separation & puri cation 22
5. Process chemistry 25
6. Click chemistry 25
7. Copper catalysed azide-alkyne cycloaddition 26
8. Biorthogonal chemistry 27
H3. 3D Printing & Electrospinning 29
1. 3D Printing 29
2. Electrospinning 32
H4. Continuous Production, Quality-by Design & PAT 37
1. Introduction 37
2. Pharmaceutical Applications 39
3. Hot melt extrusion 40
4. Continuous wet granulation 43
H5. mRNA, Lipid Nanoparticle & Formulation 45
1. Techniques: mRNA LNP formulation characterisation & activity testing 45
2. Micro uidic Production 50
3. mRNA LNP vaccines 53
fl fi
, H1. NANOTECHNOLOGICAL FORMULATION
1. INTRODUCTION ON NANOTECHNOLOGY IN PHARMACEUTICAL INDUSTRY
- Nanotechnology-based drug products on the market:
- Doxil = a liposomal formulation of the anti-cancer drug doxorubicin
→ solid precipitate inside the hollow void of the liposomes
- Maxitrol = a nanosupension: API = dexamethasone a
- mRNA COVID-19 vaccines = prime example of nanotech drugs:
- Lipid nanoparticles (LNPs) encapsulate mRNA encoding the spike
protein of SARS-CoV-2
- In the lipid-nanoparticle core → concentric rings arise from lipids forming bilayer structures
- De nition of nanotechnology:
- FDA: based on both scale & function: it involves materials of 1 - 1,000 nm
key aspect = the material's physical, chemical, or biological e ects are directly attributable to
its nanoscale dimensions → at this size range, materials can exhibit unique properties—like
increased surface area / biological interactions—that they wouldn't have at a larger scale
- EMA: materials between 0.2 - 100 nm = any materials less than 1,000 nm size
(→ materials up to 1,000 nm can have signi cant e ects)
- Organic nanoparticles: building blocks = quite diverse
- Synthetic compounds: dendrimers, block copolymers, synthetic lipids
- We also utilize naturally produced lipids, protein-based systems (virus-like particles) &
albumin complexes.
- 3 types of nanoparticles: each exhibits di erent PK behaviour due to their size
- Dendrimers = branched macromolecules: < 5 nm → unique structure → can be used in several
ways in drug delivery:
- Covalent conjugation of drug molecules to their end groups
→ this allows us to attach drug molecules directly to the surface of the dendrimer, potentially
improving solubility & o ering the possibility for targeting
- Another important use: solubilization of drugs within their core
- The internal cavities of dendrimers can encapsulate drug molecules, enhancing the solubility
of hydrophobic drugs
- Dendrimers behave like small molecules → they can be ltered through the kidneys
- Block copolymer nanoparticles: a few tens of nanometers → can escape the vasculature
→ they can pass through the walls of blood vessels & in ltrate into tissues + lymphatic system
(similar to proteins) = e ective carriers for drug delivery: they can reach target areas within the
body that might be inaccessible to larger particles
- Liposomes & lipid nanoparticles: lipid bilayer vesicles: few tens - few hundreds of nanometer
- Mainly taken up by phagocytic cells: macrophages & dendritic cells → useful for delivering
drugs to these immune cells = bene cial in treatments targeting immune system / in am.
responses
- More recently, lipid nanoparticles have gained signi cant popularity
- Examples: COVID-19 vaccines produced by Moderna & BioNTech/P zer
- Liposomes = lipid shell with a hollow core lled with water
- Lipid nanoparticles = mostly lled with lipid as well
1
fi ffff fi fi fffifi fffi fi ff fi fl
, - Biopharmaceutical Classi cation System
- 40% of new APIs are hydrophobic→ low bioavailability → molecule fails in clinical trials
- BCS: classi es drug molecules into 4 classes based on their water solubility & intestinal
permeability = crucial: for oral administration & absorption through intestinal lining
- Class I = highly water-soluble + well absorbed in the GI tract.
→ do not pose signi cant formulation challenges → e ectively formulated using
conventional solid oral dosage forms, such as tablets
→ acetaminophen (paracetamol) = commonly formulated as immediate-release tablets
- Class II = high intestinal permeability but limited water solubility
→ ↑ bioavailability: focus on ↑ dissolution rate:
- ↑ surface-to-volume ratio of crystals: ↓ particle size through milling / nanocrystals
- Transforming the drug into amorphous state (higher solubility)
- Adding solvents / surfactants to improve solubility
- Other formulations: emulsions / suspensions = also suitable to enhance their solubility
→ carbamazepine = anti-epileptic: immediate-and extended-release tablets: some include a
small amount of sodium lauryl sulfate as a surfactant to aid wetting & dissolution
- Class III = well soluble in water but low GI permeability
→ to improve the bioavailability:
- Permeabilization enhancers: bile salts / fatty acids = ↑ permeability of intestinal mucosa
- Muco-adhesive formulations to prolong the residence time of the drug in the intestinal
lumen → enhancing absorption
- Example outside the BCS framework: octreotide
- Macrocyclic peptide to suppress hormone secretion
- Highly water-soluble but very low intestinal permeability + susceptible to enzymatic
degradation → classic BCS (for small molecules) doesn’t strictly apply
- Functionally it behaves like a very low-permeability drug
- Mycapssa = a delayed-release, enteric-coated capsule
- Dry powder formulation that uses a Transient Permeability Enhancer (TPE)system
- Sodium caprylate: transiently loosens tight junctions & facilitates uptake in the small
intestine, improving absorption compared with octreotide without an enhancer
- Class IV = problematic: low solubility & low permeability
- Particularly challenging when it comes to formulation for oral administration
→ don't dissolve well in GI uids & aren't readily absorbed through the intestinal lining
→ extremely di cult to achieve e ective bioavailability with these drugs
- Often require IV administration to ensure they reach systemic circulation & can exert their
therapeutic e ects
- Example: Taxol → API = paclitaxel: very low aqueous solubility
→ supplied as a non-aqueous concentrate in a vehicle of ethanoland Cremophor EL
(polyoxyethylated castor oil) = solubilizing surfactant
2
fi ff ffi fi fi
fl ff ff
, H1. Nanotechnological Formulation 1
1. Introduction on nanotechnology in pharmaceutical industry 1
2. Nanosuspensions 5
3. Downstream processing of nanosuspensions 8
4. Case study: doxil 13
5. Case study: Cripec 14
H2. Process Chemistry & API Manufacturing 17
1. Introduction 17
2. Process chemistry 17
3. Reaction engineering & catalysis 18
4. API separation & puri cation 22
5. Process chemistry 25
6. Click chemistry 25
7. Copper catalysed azide-alkyne cycloaddition 26
8. Biorthogonal chemistry 27
H3. 3D Printing & Electrospinning 29
1. 3D Printing 29
2. Electrospinning 32
H4. Continuous Production, Quality-by Design & PAT 37
1. Introduction 37
2. Pharmaceutical Applications 39
3. Hot melt extrusion 40
4. Continuous wet granulation 43
H5. mRNA, Lipid Nanoparticle & Formulation 45
1. Techniques: mRNA LNP formulation characterisation & activity testing 45
2. Micro uidic Production 50
3. mRNA LNP vaccines 53
fl fi
, H1. NANOTECHNOLOGICAL FORMULATION
1. INTRODUCTION ON NANOTECHNOLOGY IN PHARMACEUTICAL INDUSTRY
- Nanotechnology-based drug products on the market:
- Doxil = a liposomal formulation of the anti-cancer drug doxorubicin
→ solid precipitate inside the hollow void of the liposomes
- Maxitrol = a nanosupension: API = dexamethasone a
- mRNA COVID-19 vaccines = prime example of nanotech drugs:
- Lipid nanoparticles (LNPs) encapsulate mRNA encoding the spike
protein of SARS-CoV-2
- In the lipid-nanoparticle core → concentric rings arise from lipids forming bilayer structures
- De nition of nanotechnology:
- FDA: based on both scale & function: it involves materials of 1 - 1,000 nm
key aspect = the material's physical, chemical, or biological e ects are directly attributable to
its nanoscale dimensions → at this size range, materials can exhibit unique properties—like
increased surface area / biological interactions—that they wouldn't have at a larger scale
- EMA: materials between 0.2 - 100 nm = any materials less than 1,000 nm size
(→ materials up to 1,000 nm can have signi cant e ects)
- Organic nanoparticles: building blocks = quite diverse
- Synthetic compounds: dendrimers, block copolymers, synthetic lipids
- We also utilize naturally produced lipids, protein-based systems (virus-like particles) &
albumin complexes.
- 3 types of nanoparticles: each exhibits di erent PK behaviour due to their size
- Dendrimers = branched macromolecules: < 5 nm → unique structure → can be used in several
ways in drug delivery:
- Covalent conjugation of drug molecules to their end groups
→ this allows us to attach drug molecules directly to the surface of the dendrimer, potentially
improving solubility & o ering the possibility for targeting
- Another important use: solubilization of drugs within their core
- The internal cavities of dendrimers can encapsulate drug molecules, enhancing the solubility
of hydrophobic drugs
- Dendrimers behave like small molecules → they can be ltered through the kidneys
- Block copolymer nanoparticles: a few tens of nanometers → can escape the vasculature
→ they can pass through the walls of blood vessels & in ltrate into tissues + lymphatic system
(similar to proteins) = e ective carriers for drug delivery: they can reach target areas within the
body that might be inaccessible to larger particles
- Liposomes & lipid nanoparticles: lipid bilayer vesicles: few tens - few hundreds of nanometer
- Mainly taken up by phagocytic cells: macrophages & dendritic cells → useful for delivering
drugs to these immune cells = bene cial in treatments targeting immune system / in am.
responses
- More recently, lipid nanoparticles have gained signi cant popularity
- Examples: COVID-19 vaccines produced by Moderna & BioNTech/P zer
- Liposomes = lipid shell with a hollow core lled with water
- Lipid nanoparticles = mostly lled with lipid as well
1
fi ffff fi fi fffifi fffi fi ff fi fl
, - Biopharmaceutical Classi cation System
- 40% of new APIs are hydrophobic→ low bioavailability → molecule fails in clinical trials
- BCS: classi es drug molecules into 4 classes based on their water solubility & intestinal
permeability = crucial: for oral administration & absorption through intestinal lining
- Class I = highly water-soluble + well absorbed in the GI tract.
→ do not pose signi cant formulation challenges → e ectively formulated using
conventional solid oral dosage forms, such as tablets
→ acetaminophen (paracetamol) = commonly formulated as immediate-release tablets
- Class II = high intestinal permeability but limited water solubility
→ ↑ bioavailability: focus on ↑ dissolution rate:
- ↑ surface-to-volume ratio of crystals: ↓ particle size through milling / nanocrystals
- Transforming the drug into amorphous state (higher solubility)
- Adding solvents / surfactants to improve solubility
- Other formulations: emulsions / suspensions = also suitable to enhance their solubility
→ carbamazepine = anti-epileptic: immediate-and extended-release tablets: some include a
small amount of sodium lauryl sulfate as a surfactant to aid wetting & dissolution
- Class III = well soluble in water but low GI permeability
→ to improve the bioavailability:
- Permeabilization enhancers: bile salts / fatty acids = ↑ permeability of intestinal mucosa
- Muco-adhesive formulations to prolong the residence time of the drug in the intestinal
lumen → enhancing absorption
- Example outside the BCS framework: octreotide
- Macrocyclic peptide to suppress hormone secretion
- Highly water-soluble but very low intestinal permeability + susceptible to enzymatic
degradation → classic BCS (for small molecules) doesn’t strictly apply
- Functionally it behaves like a very low-permeability drug
- Mycapssa = a delayed-release, enteric-coated capsule
- Dry powder formulation that uses a Transient Permeability Enhancer (TPE)system
- Sodium caprylate: transiently loosens tight junctions & facilitates uptake in the small
intestine, improving absorption compared with octreotide without an enhancer
- Class IV = problematic: low solubility & low permeability
- Particularly challenging when it comes to formulation for oral administration
→ don't dissolve well in GI uids & aren't readily absorbed through the intestinal lining
→ extremely di cult to achieve e ective bioavailability with these drugs
- Often require IV administration to ensure they reach systemic circulation & can exert their
therapeutic e ects
- Example: Taxol → API = paclitaxel: very low aqueous solubility
→ supplied as a non-aqueous concentrate in a vehicle of ethanoland Cremophor EL
(polyoxyethylated castor oil) = solubilizing surfactant
2
fi ff ffi fi fi
fl ff ff
