Biopharmaceutics and Formulation Development Flashcards

Overview of Biopharmaceutics and Formulation Development

• Course and Institution: University of Pavia, Department of Pharmaceutical Sciences, Medical and Pharmaceutical Biotechnologies (LM).

• Academic Year: $2024-25$.

• Core Focus: This study guide outlines the Biopharmaceutics Classification System (BCS), methodologies for solubility enhancement, particle size reduction, crystal habit modification, and advanced dispersion techniques.

Biopharmaceutical Classification System (BCS) and Drug Disposition

• Metrics for Classification: Oral drug absorption is determined by two primary metrics: drug permeability and aqueous solubility.

• BCS Categories:

  • Class I: High Solubility, High Permeability (indicated as orange).

  • Class II: Low Solubility, High Permeability (indicated as blue).

  • Class III: High Solubility, Low Permeability (indicated as black).

  • Class IV: Low Solubility, Low Permeability (indicated as yellow).

• Marketed vs. Pipeline Drugs: There is a significant challenge in oral drug delivery as a high percentage of pipeline drugs fall into Class II and Class IV, requiring advanced solubility enhancement strategies.

Rationale for Solubility Amelioration

• Lowering Doses: Improved solubility allows for a reduction in the total amount of Active Pharmaceutical Ingredient (API) required in the final dosage form.

• Enhancement of Pharmacological Effect: Better dissolution leads to more effective therapy.

• Ameliorated Bioavailability: Higher solubility directly correlates to better systemic absorption and bioavailability for BCS Class II and IV drugs.

Physical Modification: Particle Size Reduction

• Micronization: Mechanical methods such as grinding, milling, and crushing are used to reduce particle size. This increases the total surface area and improves the rate of dissolution and bioavailability.

• Nanosuspension: A colloidal dispersion of drug particles that are sub-micron in size (< 1000\,nm), stabilized by surfactants.

  • Advantages:

    • Enhancement of drug solubility and bioavailability.

    • Higher drug loading capacity.

    • Suitability for hydrophobic drugs.

    • Passive drug targeting capabilities.

    • Reduction in required dosage.

    • Increase in both physical and chemical stability of the drug.

  • Preparation Methods:

    • Bottom-Up: Precipitation or crystallization from a solution.

    • Top-Down: Mechanical attrition methods such as high-pressure homogenization.

Modification of Crystal Habit

• Importance: The crystal structure of the API is paramount in defining physicochemical properties, specifically solubility.

• Approaches:

  • Crystal engineering.

  • Formation of solvates and hydrates.

  • Polymorphism (utilizing different crystalline forms of the same substance).

• Example - Tibolone: The study of Tibolone Form I and Form II demonstrates how different polymorphs exhibit statistically different solubility values at $25\,^\circ\text{C}$. Form II is noted for possessing different solubility properties compared to Form I at a significance level of $5\%$.

Dispersion in Carriers: Eutectic Mixtures

• Definition: A combination of two or more substances that, when mixed in a specific ratio, melt at a temperature lower than any of the individual components. The temperature and composition are known as the eutectic point and eutectic composition respectively.

• Mechanism for Solubility Enhancement:

  • Lower Melting Point: The mixture may become liquid or soft solid at room or body temperature, improving dissolution.

  • Improved Wettability: Eutectic systems reduce interfacial tension between drug particles and solvents.

  • Increased Surface Area: Fine crystalline or amorphous phases within the mixture expose more surface area for solubilization.

• Common Strategy: Combining a poorly soluble drug with a hydrophilic carrier (e.g., urea, PEG, sugars, organic acids).

• Specific Examples of Eutectic Systems:

  • Ibuprofen + Menthol: Enhances topical absorption by lowering the melting point.

  • Indomethacin + Urea: Oral application, increases melting point depression.

  • Ketoprofen + PEG 4000/6000: Oral application, enhances dissolution.

  • Carbamazepine + Succinic Acid: Oral application, increased solubility via melting point depression.

  • Naproxen + Maleic Acid: Oral application, improves bioavailability.

  • Griseofulvin + Malic Acid: Oral application, enhances solubility.

Therapeutic Deep Eutectic Solvents (THEDES)

• Case Study: Menthol ($ME$) or Thymol ($THY$) mixed with Ibuprofen ($IBU$).

• Preparation: Fusion method involving stirring and heating.

• Findings: Eutectic mixtures of monoterpenoids ($ME$ and $THY$ have antibacterial/antioxidant properties) with $IBU$ significantly increase the solubility of $IBU$ compared to both its powder form and its physical mixture.

• Ratios Used: $3:1$ ratio for $ME:IBU$ and $THY:IBU$.

Dispersion in Carriers: Solid Solutions and Dispersions

• Solid Solutions: A single homogeneous phase where the drug is molecularly dissolved within a solid excipient matrix (e.g., Urea or PEG).

  • Interstitial: Solute atoms occupy spaces in interstitial positions.

  • Substitutional: Solute atoms occupy regular lattice sites of the solvent.

  • Benefits: Improved stability, uniformity, and usefulness in controlled-release formulations.

• Solid Dispersion: Combination of a hydrophilic matrix (polymers like PEG or surfactants) and hydrophobic drugs dispersed in amorphous or crystalline particles.

• Methods for Forming Solid Dispersions:

  • Hot-melt (Fusion) Method: Drug and carrier are melted, rapidly cooled with ice while stirring, then crushed, sieved, and compressed. Limitations include thermal degradation and evaporation of volatile substances.

  • Solvent Evaporation Method: API and carrier are dissolved in an organic solvent, which is then evaporated. This prevents thermal degradation but is costly and the evaporation step is critical to the dissolution rate.

  • Lyophilization: Projected as a substitute for solvent evaporation to stabilize the dispersion.

  • Co-grinding Method: A simple, eco-friendly mechanical method using a blender and vibration ball mill with steel balls, avoiding organic solvents.

Cryogenic Techniques

• Objective: To enhance drug dissolution speed by transforming the drug into an amorphous nanostructure with high porosity using extremely low temperatures.

• Drying Methods: Following cryogenic treatment, residual moisture is removed via vacuum drying, spray drying, or lyophilization.

• Specific Methods:

  • Spray Freezing onto Cryogenic Fluids.

  • Spray Freezing into Cryogenic Liquids ($SFL$).

  • Spray Freezing into Vapour over Liquid ($SFV/L$).

  • Ultra-Rapid Freezing ($URF$).

Complexation and Cyclodextrins

• Complexation Types:

  • Stanching Complexation: Overlapping planar domains of aromatic compounds.

  • Inclusion Complexation: Guest particles are added to the cavity of host molecules.

  • Peptide Complexation: Enhances solubility for poorly water-soluble therapeutics.

• Cyclodextrins: Natural cyclic oligosaccharides composed of $6, 7,\text{ or } 8$ D-glucopyranose monomers ($\%\alpha, \%\beta, \%\gamma$ units respectively) linked by $\alpha-1,4$ glycosidic bonds.

  • Structure: Truncated cone shape with a lipophilic inner cavity and a hydrophilic outer surface (with hydroxyl groups).

• Cyclodextrin Properties Table:

  • $\alpha$-Cyclodextrin: $6$ units; Molecular weight $972\,g/mol$; Cavity diameter $0.47-0.53\,nm$. Solubility: $14.5\,g/100\,mL$.

  • $\beta$-Cyclodextrin: $7$ units; Molecular weight $1135\,g/mol$; Cavity diameter $0.60-0.65\,nm$. Solubility: $1.85\,g/100\,mL$.

  • $\gamma$-Cyclodextrin: $8$ units; Molecular weight $1297\,g/mol$; Cavity diameter $0.75-0.83\,nm$. Solubility: $23.2\,g/100\,mL$.

  • All Common Properties: Cavity height $\approx 0.78\,nm$; $pK_a \approx 12.2$.

• Drug Interaction: Liposoluble molecules (like Doxorubicin) are encapsulated in the lipophilic cavity to form inclusion complexes.

Chemical Methods for Solubility Enhancement

• pH Adjustment: Altering the charge state of molecules to increase ionization and solubility.

  • Example: Acyclovir is formulated at alkaline pH or as Acyclovir Sodium for intravenous use because deprotonation of its amino group increases solubility.

• Hydrotrophy: Using hydrotropic agents like urea, nicotinamide, or sodium benzoate to form complexes in aqueous solutions.

• Co-solvents: Using liquids like Propylene Glycol (e.g., with Diazepam) to reduce the dielectric constant of water and increase solvation power.

• Co-crystallization: Drug forms crystalline complexes with co-crystal formers via non-covalent interactions (e.g., Ibuprofen-nicotinamide).

• Prodrugs: Introducing hydrophilic or ionizable functional groups.

  • Example: Enalapril Maleate (Enalapril + ester group + maleic acid) increases solubility.

• Derivatization: Chemical modification to increase polarity (e.g., Hydrocortisone Sodium Succinate).

Surfactant-Based and Nanotechnology Systems

• Solubilization by Surfactant: Surfactants reduce surface tension, increasing wettability. Above the Critical Micelle Concentration ($CMC$), micelles form, dramatically increasing solubility.

• Microemulsions: Clear, transparent, thermodynamically unstable (kinetically stable) mixtures of aqueous phase, oil phase, surfactant, and co-surfactant.

• Self-Emulsifying Drug Delivery Systems (SEDDS): Isotropic mixtures of oil, surfactant, and co-surfactant.

  • SNEDDS: Self-nano emulsifying drug delivery system.

  • SMEDDS: Self-micro emulsifying drug delivery system.

  • Advantages (Transcript Note): Enhanced oral bioavailability, selective targeting in the GIT, protection of drugs from the gut environment, reduced variability due to food effects.

  • Disadvantages (Transcript Note): Irritation due to high surfactant quantity ($30-60\%$), potential for volatile co-solvents (Ethanol, Glycerin, PEG) to migrate into capsule shells.

• Solid Lipid Nanoparticles (SLN):

  • Size: $50-1000\,nm$.

  • Structure: Solid lipid matrix core containing API, stabilized by a phospholipidic coating. Used for controlled release of drugs like Ibuprofen, Nimesulide, and Progesterone.

• Polymeric Micellar Carriers: Amphiphilic block co-polymers that self-assemble at lower $CMC$ than low-molecular-weight surfactants.

Miscellaneous Methods

• Supercritical Fluid (SCF) Technology: Using fluids (like $CO_2$) in a supercritical state to dissolve and crystalize drugs, resulting in high-purity, reduced-size particles. It is eco-friendly and cost-effective.

• Selective Adsorption: Using insoluble carriers like Bentonite to form weak bonds with drugs and promote entrapment via hydration and swelling.

• Direct Capsule Filling: Efficient and cost-effective for heat-sensitive drugs; requires good powder flow and content uniformity.

• Electrospinning: Processing a drug-polymer solution into nanofibers.

  • Example: Glibenclamide and PLGA nanofibers. The high surface area of the nanofiber mat significantly increases the dissolution rate and oral bioavailability.

• Dropping Solution Method: Precise manipulation of addition to control crystal formation and bioavailability.