Podcast
Questions and Answers
What percentage of drugs are weak bases?
What percentage of drugs are weak bases?
Regulatory agencies consider different salt forms of drugs as equivalent.
Regulatory agencies consider different salt forms of drugs as equivalent.
False
What role do salts play in the adjustment of pH in solutions?
What role do salts play in the adjustment of pH in solutions?
They shift the pH of the solution similarly to direct pH adjustment methods.
What is the primary purpose of coformers in drug formulation?
What is the primary purpose of coformers in drug formulation?
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Co-solvents are used to decrease the solubility of poorly water-soluble substances.
Co-solvents are used to decrease the solubility of poorly water-soluble substances.
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The water solubility of Penicillin Potassium is greater than ______ mg/1mL.
The water solubility of Penicillin Potassium is greater than ______ mg/1mL.
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What is the typical log P range for suitable drugs that utilize co-solvents?
What is the typical log P range for suitable drugs that utilize co-solvents?
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Which of the following counterions has the highest oral percentage usage?
Which of the following counterions has the highest oral percentage usage?
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Match the following drugs with their co-solvent formulations and administration routes:
Match the following drugs with their co-solvent formulations and administration routes:
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Weak acids accept protons to hold a formal anionic charge.
Weak acids accept protons to hold a formal anionic charge.
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Name one common acidic counterion used in oral delivery.
Name one common acidic counterion used in oral delivery.
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What is a common problem in pharmaceutical drug development related to solubility?
What is a common problem in pharmaceutical drug development related to solubility?
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Up to 75% of compounds currently under development have high aqueous solubility.
Up to 75% of compounds currently under development have high aqueous solubility.
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What are 'grease balls' in the context of solubility?
What are 'grease balls' in the context of solubility?
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Strategies to enhance solubility include ______, salt formation, and crystal engineering.
Strategies to enhance solubility include ______, salt formation, and crystal engineering.
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Match the following drugs to their solubility characteristics:
Match the following drugs to their solubility characteristics:
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Salt formation is one of the methods used to enhance the solubility of poorly soluble drugs.
Salt formation is one of the methods used to enhance the solubility of poorly soluble drugs.
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Identify a consequence of low drug solubility on drug absorption.
Identify a consequence of low drug solubility on drug absorption.
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Salt formation increases the solubility of a drug in all cases.
Salt formation increases the solubility of a drug in all cases.
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What is the common ion effect?
What is the common ion effect?
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The pKa of the acidic drug that forms a sodium salt is _____ .
The pKa of the acidic drug that forms a sodium salt is _____ .
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Match the following iron oxidation states with their solubility and absorption characteristics:
Match the following iron oxidation states with their solubility and absorption characteristics:
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Erythromycin estolate has a higher solubility than erythromycin stearate.
Erythromycin estolate has a higher solubility than erythromycin stearate.
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Name one additional function of salt formation besides increased solubility.
Name one additional function of salt formation besides increased solubility.
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Which of the following is a disadvantage of salt formation?
Which of the following is a disadvantage of salt formation?
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Van der Waals forces have a higher strength than ionic interactions.
Van der Waals forces have a higher strength than ionic interactions.
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What is crystal engineering?
What is crystal engineering?
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Higher lattice energy results in greater crystal __________ and lower solubility.
Higher lattice energy results in greater crystal __________ and lower solubility.
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Match the crystallization methods with their descriptions:
Match the crystallization methods with their descriptions:
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Which feature can be improved by salt formation?
Which feature can be improved by salt formation?
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Cocrystals are made exclusively of one molecular species.
Cocrystals are made exclusively of one molecular species.
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Name one advantage of using crystalline forms in drug formulation.
Name one advantage of using crystalline forms in drug formulation.
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__________ can lead to issues of hygroscopicity in salt forms.
__________ can lead to issues of hygroscopicity in salt forms.
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What is a significant consequence of preparing a high energy polymorph crystal?
What is a significant consequence of preparing a high energy polymorph crystal?
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Study Notes
Introduction to Solubility Enhancement Strategies
- The course is on Solubility Enhancement Strategies (I, II, III) for Masters in Pharmacy (MPharm) and BSc Advanced Therapeutic Technologies.
- The module is Medicines 1.
- The lecturer is Dr Sam Maher.
Learning Outcomes
- Highlight the pharmaceutical problem posed by poor solubility.
- Describe the strategies used to improve drug solubility.
What is Low Drug Solubility?
- Many receptor-mediated interactions involve hydrophobic interactions.
- High lipophilicity is a common issue in drug development.
- 40% of marketed drugs have low aqueous solubility.
- Up to 75% of compounds in development have low aqueous solubility.
- Risk: low and variable absorption.
Solubility of Top 200 Marketed Oral Drug Products
- Data on the solubility of the top 200 marketed oral drug products is presented in a graph for various regions. This data demonstrates the variability of drug solubility across market regions.
Examples of Dose, Solubility, and Volume Required for Poorly Water-Soluble Drugs
- Provides examples of drugs with different dosages, solubilities, and volumes required for complete solubilisation.
- This table shows cases where the drug may have low or highly variable absorption.
Brick Dust and Grease Balls
- Hydrophobic substances in the solid state exhibit strong intermolecular forces.
- They are poorly soluble in aqueous and non-aqueous solvents.
- Hydrophobic solutes with solubility not limited by solid state properties are soluble in non-aqueous solvents. They are hydrophobic and lipophilic.
Strategies to Enhance Solubility
- A variety of strategies are listed for enhancing solubility.
- These include manipulation of pH, salt formation, crystal engineering, particle engineering, co-solvency, solid dispersions, surfactant solubilisation, prodrug formation, lipid-based formulations, manipulation of pH, lipid-based drug delivery systems, inclusion complexes, and emerging strategies.
Manipulation of pH
- Adjusting solution pH effectively increases the proportion of weakly acidic and weakly basic drugs present in the more polar ionised form.
- Effectiveness depends on pKa and log D.
- Useful in preparing solution dosage forms (e.g., parenteral).
- 75% of drugs are weak bases, 20% are weakly acidic, and 5% are non-ionic/amphoteric.
Pharmaceutical Salts
- Salts of weak acids and bases are solid-state equivalents of pH adjustment.
- Salts are formed through ionic interactions between weakly acidic/basic drugs and oppositely charged counterions.
- In water, salts dissociate, shifting the solution pH.
- A drug can exist in multiple salt forms with different physicochemical properties.
- Regulatory agencies do not treat different salt forms as equivalent.
Salt Formation (Weak Acids)
- Shows a diagrammatic representation of salt formation in weak acids, highlighting the process, mechanisms and reactions involved.
Salt Formation (Weak Bases)
- Shows a diagrammatic representation of salt formation in weak bases, highlighting the process, mechanisms and reactions involved.
Common Counter Ions in Oral Delivery
- Lists common counter ions categorized by basic and acidic types.
- Includes percentages of oral occurrence for each ion
Salt Formation and Solubility
- Discusses how salt formation can increase or decrease solubility and its relationship with molecular weight and water solubility for both acids and bases.
Salt Formation Can Increase or Decrease Solubility To Tailor Release
- Lists various advantages of using salt formation, including altered solubility and dissolution, controlled release, and improved properties like thermal, photostability, processability, permeability and organoleptic properties, also pain-reduction.
- Also notes disadvantages (only ionisable drugs, reduced % active, formation of other substances like solvates and polymorphs, salt corrosion,additional processing).
Crystal Engineering
- Deliberately designs and controls molecular packing in crystal structures.
- This aims to achieve desired characteristics, and is used for solid state of materials.
- Techniques such as using salts, solvates, polymorph screening, cocrystals are part of this approach.
- Designed to overcome solubility limitations due to the strength of the crystal lattice.
Bonding in a Crystal
- Discusses the strength of forces that help hold a crystal together.
- Van der Waals forces, π-π stacking interactions, electrostatic interactions, hydrogen bonding and ionic interactions, influencing lattice energy, stability and solubility.
- Also mentions the preparation of a high-energy polymorph.
Influence of Polymorph Selection on Dissolution, Solubility and Absorption of Rifaximin
- Illustrates the impact of polymorph selection on drug dissolution, solubility and absorption using data graphs.
Cocrystals
- Mixed crystals formed from two or more molecular species held together by non-covalent forces.
- Similar to salt formation but without proton exchange.
- Stabilizes high-energy crystal forms, preventing unstable polymorphs from reverting.
- Shows a significant increase in dissolution compared to simple crystals.
- Some coformers can intentionally reduce solubility.
Example Cocrystal Coformers
- Gives examples of drug and coformer pairings used in cocrystal formation
Co-solvents
- Water-miscible organic solvents used to increase solubility of poorly water-soluble substances.
- Suitable for drugs lacking ionisable groups.
- Modifies dielectric constant and reduces interfacial tension to match drug polarity.
- Safety and pharmacological action may be affected.
- Solubility in mixed solvents is not easily predictable.
- A drug can have higher solubility in a solvent mixture compared to either neat solvent.
Common Co-solvents in Parenteral Delivery
- Presents examples of commonly used co-solvents and associated drugs in parenteral delivery systems for intravenous and other delivery methods, highlighting common concerns about injection site and systemic side effects.
Co-solvents in Oral Delivery
- Tables of co-solvents and associated drugs in oral delivery are shown.
- Discusses concerns related to oral delivery such as dosage volume and gastrointestinal tract effects.
Common Co-solvents
- Shows chemical structures and properties for common co-solvents, including molecular weight, LogP, and dielectric constant
Problems Pertaining to Dilution of Co-solvent Based Formulations
- Identifies the risk of drug precipitation depending on the rate of administration in co-solvents systems.
- This is problematic for injectables, subcutaneous/intramuscular routes, and intravenous routes, with concerns about possible embolism
Surfactant Solubilisation
- Amphipathic substances with hydrophilic and hydrophobic ends.
- Align at interfaces (e.g., water/air), reducing hydrophobic regions and surface tension.
- Used for solubilisation.
- Examples of surfactant types, such as polysorbate 20, and related information are discussed.
Micelles
- At specific concentrations, soluble surfactants associate into spherical aggregates called micelles.
- Micelles provide a hydrophobic core, permitting solubilisation of drugs.
Micellar Solubilisation in Parenteral Formulations
- Lists example drugs and surfactants used for micellar solubilisation in parentheral formulations, showing the resultant formulations used.
Safety of Surfactants in Solubilisation
- Surfactants can potentially interfere with cell membranes, requiring safety regulations.
- Various delivery routes, including pain at injection site, and hypersensitivity reactions.
- Types of surfactants used in parenteral and oral formulations and external use are mentioned.
Cyclodextrins
- Macrocyclic oligosaccharides with a hydrophilic exterior and hydrophobic interior cavity.
- Forms non-ionic inclusion complexes that increase apparent drug solubility.
- Described as a "bottomless flower-pot" shape.
- Used in oral and parenteral delivery.
Cyclodextrin Inclusion Complex
- Shows diagrams illustrating the formation of a 1:1 drug-CD complex.
Common Cyclodextrins
- Chemical structure diagrams and cavity volumes are shown for common cyclodextrin types (a, b, g). Also includes data on how the cyclodextrins behave in water.
Example Formulations in Oral & Parenteral Delivery
- Contains examples of drug formulations and associated CDs used in oral and parenteral delivery systems, particularly illustrating high-performance and low-performance examples.
Particle Engineering
- Particle size reduction increases surface area for solvation, increasing dissolution rate and absorption.
- Methods such as bottom-up and top-down approaches to particle size reduction are noted.
Influence of Polymorph Selection on Dissolution, Solubility and Absorption of Rifaximin (Continued).
Particle Size Reduction Can Increase Solubility
- Sub-micron particles are inherently unstable.
- The Ostwald Freundlich equation provides a way to relate solubility, and particle size.
- Pearl milling is a method for producing nanosuspensions containing nanoparticles, which are stabilized by surfactants such as those from Elan.
Marketed Nanosized Drugs
- Presents tables of example drugs, associated formulations, associated technologies used for nanosized drug formulations, and their delivery routes.
Solid Dispersions
- Solid dispersions increase drug dissolution and solubility through reduced particle size, improved wetting, enhanced solubilisation, and decreased lattice energy.
- Solid dispersions use a carrier matrix (e.g., HPMC, PVA) in order to decrease drug recrystallization.
- Marketed solid dispersion examples are shown.
Classification of Solid Dispersions
- Presents different forms of solid dispersions.
- Describes characteristics associated with each form.
Eutectic Mixture
- Eutectic mixtures are crystalline drug suspended in a crystalline carrier
- Crystallization occurs in liquid state
- The mixture yields the lowest melting point
Solubility Dynamics from Solid Dispersions
- Shows graph and illustrates the results obtained from using solid dispersions in a variety of drug forms and mixtures.
Lipid-Based Formulations
- The human body has specialised lipid processing pathways used for the solubilisation and absorption of water-insoluble substances like lipids and vitamins.
- Lipid-based formulations harness these pathways to deliver insoluble drugs in lipids.
- Examples such as griseofulvin illustrate early co-administration with food to solubilize the substance.
- Shows various types of lipid-based formulations (micellar, and microemulsions), with examples.
Sandimune versus Sandimune Neoral
- Shows comparison between two drugs, particularly noting the changes in capsule content and how these formulations create different drug delivery systems.
Lipid Formulation Classification System
- Shows classification of lipid formulations by type, based on increasing hydrophilicity and dispersibility, taking into account the percentage composition of different components in the system
Drug Derivation
- Discusses changes in drug solubility brought about by attaching functional groups via covalent bonding, noting whether this process increases or decreases water solubility.
- Points out that derived molecules are often prodrugs that remain active until the additional functional group has been removed.
Prodrugs
- Prodrugs are inactive compounds that become active after metabolism in the body, with mechanisms such as esterase activity, allowing for modifications to solubility, permeability, stability, taste masking, and toxicity.
Increasing Solubility Through Prodrug Formation (Paracetamol to Propacetmol)
- Illustrates the process of turning a less soluble molecule into an easier to solubilize form via covalent bonding.
Salicylic Acid to Aspirin (Almost a Prodrug)
- Showcases a case study relating to the increased solubility of a drug due to the formation of a prodrug.
Modulating Ionisation Through Prodrug Formation (Enalaprilat to Enalapril)
- Details the effect of converting less ionisable into a more ionisable molecules via functional group modifications.
Functional Groups Involved in Prodrug Formation
- A more detailed and systematic explanation of types of covalent bonds and functional groups involved in the formation of prodrugs.
Example Emerging Strategies
- Includes carrier adsorption using microporous adsorbents (e.g., fumed silica), demonstrating examples of how these strategies are applied to substances.
- Details about the use of solid lipid nanoparticles to stabilize drug solubilisation.
Contact Information
- Includes contact information for the lecturer.
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Description
Test your knowledge on key concepts in pharmaceutical drug formulation, including the role of salts, co-solvents, and counterions in drug solubility. This quiz covers various properties and principles critical to drug development and formulation. Challenge yourself with questions about weak bases and common issues faced in the industry.
