Pharmacology Chapter on Dissolution Processes

Physical Pharmacy

• University of Gezira, Faculty of Pharmacy, Department of Pharmaceutics, Wad Medani, Sudan
• Ayman Y. Waddad, Assistant Professor of Pharmaceutics
• Dates: 1975, 1978, 1984, 1994, 1995, 2000, 2023

Drug Solid-State Properties and Dissolution

• Focuses on the properties and dissolution of solid drug forms
• Dissolution of solid dosage forms has five steps: wetting, penetration of medium into dosage form, disintegration, deaggregation, and dissolution.

Basis for Solid Phase Effects on Bioavailability

• Solid phases have different thermodynamic activities, leading to variations in solubility and dissolution rates.
• Metastable solid forms (hydrates, HCl salts) can undergo transformations to stable forms during dissolution, which may impact dissolution and bioavailability.
• Such transformations can lead to reduced or variable dissolution and bioavailability.

Relationship Between Solid Phase and Dissolution

• Solid phases are categorized as crystalline (polymorphs, solvates/hydrates) and amorphous.
• Amorphous phases generally exhibit faster dissolution compared to crystalline.
• Metastable phases can transform to stable phases during dissolution.
• Conversions from metastable to stable phases during dissolution may impact dissolution rates.
• Kinetics of conversion to stable phases are related to solubility and formulation content.

Crystals

• Polymorphs: Example: Acetaminophen
• Crystal Hydrates/Solvates: Example: Thiamine hydrochloride

Factors Affecting Crystal Forms

• Supersaturation of solution
• Formation of crystal nuclei
• Crystal growth around the nuclei

Phase Transitions and their Underlying Mechanisms

• Solid-state phase transitions (polymorphic, hydration/dehydration, amorphous crystallization/vitrification,)
• Melt phase transitions (polymorphic, vitrification, amorphous crystallization/vitrification)
• Solution-mediated phase transitions (polymorphic, hydration/dehydration, amorphous crystallization)

Solution Mediated Mechanism

• Polymorphism: the ability of a substance to exist in multiple crystalline forms with different molecular arrangements/ conformations.
• Monotropic conversion: only one stable phase
• Enantiotropic conversion: two stable phases that interchange reversibly, changing through temperature

Polymorphism Examples

• Choramphenicol palmitate

• Sulphamethoxdiazine

• Mefenamic acid

• Ritonavir

• Chloramphenicol Palmitate is a classical example of polymorphism and its effect on in vivo performance.

Mefenamic Acid

• Free energy difference between polymorphs is ~1/3 that of Chloramphenicol palmitate.
• ~20-30% difference in solubility

Ritonavir

• BCS Class IV compound
• Ritonavir's bioavailability is only observed in a solution state.
• Form II of ritonavir causes precipitation when formulated into capsules and solutions.

Crystal Solvates/Hydrates

• Hydrates: Molecular complexes incorporating water molecules.
• Solvates: Molecular complexes incorporating solvent molecules.
• Anhydrates: Molecular complexes with no water.

Transitions: Hydrates/Solvates

• Examples: Copper sulfate, Quinine

Hydrate Conversion Mechanisms

• Mechanism of transition between hydrate and anhydrous forms.

Hydrates

• Carbamazepine
• Ampicillin
• Theophylline

Carbamazepine

• Crystallization kinetics of hydrate phases occur faster than bulk diffusion.
• Di-hydrate crystals nucleate and grow on the surfaces of anhydrous particals.

Carbamazepine (Continued)

• Solubility dependence on temperature for anhydrous and dihydrate forms

Ampicillin

• Showing the van't Hoff plot for anhydrate and trihydrate phases and mean concentration profiles of ampicillin

Theophylline

• Shows the dissolution rate over time for theophylline

Amorphous

• Disordered arrangement of molecules.
• Short-range intermolecular forces create short-range order

Amorphous Terms

• Glass transition temperature (Tg)
• Crystallization temperature (Tc)
• Kauzmann temperature (Tk)
• Fictive temperature (Tf)
• Relaxation time (Tr)

Why use Amorphous?

• Advantages of amorphous forms over crystalline forms.

Amorphous Example

• 10-fold increase in intrinsic dissolution rate for amorphous forms compared with crystalline forms.

Screening for Amorphous

• High-energy phase has improved dissolution; tools for evaluating amorphous solids, solubility improvement and physical stability.
• Re-crystallization of amorphous should be slow to maintain a reasonable shelf-life

Amorphous: Solubility Improvement

• Solubility improvement can be evaluated from melting point, heat of fusion and change in heat capacity data

Role of Excipient: Amorphous

• Anti-plasticization
• Ritonavir crystallizes rapidly

Definitions

• Salts: Ionic complexes of an active moiety in an ionized state with an appropriate counter ion. Salt formation is used to improve the physicochemical properties of a drug.

Reasons for Choosing a Salt

• Physical properties (melting point, polymorphism, purity)
• Compressibility, flow, bulk density
• Dissolution to improve oral immediate release formulations or decrease dissolution to achieve controlled release or parenteral depot formulations.

Effect of Salt Form on Intrinsic Dissolution Rate (IDR)

• Properties examined include: crystal lattice energy, diffusion layer, and pH.

Dissolution rate vs pH for salt and base

• Shows how dissolution rate (IDR) changes with respect to pH

Complications with Salts

• Precipitation of very weak bases from strong acid salts
• Precipitation of insoluble HCl salts in stomach

Summary

• Solid state properties influence drug absorption via dissolution rates.
• Metastable solid phases can maximize dissolution but may transition to stable forms.
• Stable phases provide reproducible but slower dissolution behavior.
• Solution-mediated kinetics of transformation to stable phases must be understood for metastable form use for enhanced dissolution.

Solid-state Characterization Methods

• Techniques for characterizing solids and their advantages and disadvantages (Powder X-ray diffraction, Single crystal X-ray diffraction, Differential Scanning Calorimetry, Thermogravimetric analysis, Mid-infrared, Near Infrared, Raman, Solid-state Nuclear Magnetic Resonance, Polarized Microscopy, Hot-stage Microscopy, Solvent Sorption)

Impact of Formulation and Processing on Solid-State Properties and Product Quality

• Impact of various formulation and process steps on solid-state properties and product quality

Transitions: Mechanisms

• Solid-state transitions (occurring without intervening transient liquid or vapor phases)
• Melt transitions (occurring above the melting point)
• Solution-mediated transitions (occurring when drugs are dissolved in liquids)

Solid Phase and Process/Formulation Design

• Influence of solid phase on product quality
• Influence of process-induced phase changes on product quality (e.g. size reduction, granulation, compression, encapsulation, coating)

API Size Reduction

• Importance of API size reduction
• Potential phase transformations during size reduction (shearing, compacting, and impacting)

Wet Granulation

• Improving flowability, compressibility and other properties
• Potential for phase transformations based on the amount of liquid used in granulation.

Dry Granulation

• Method of choice for moisture-sensitive APIs

Melt Granulation

• Method of choice for creating a metastable phase

Spray (or Freeze) Drying

• Useful for generating homogeneous, porous, and uniform particles.

Granulation Milling and Blending

• Less harsh compared to other methods
• Lower risk of transformation

Compression and Encapsulation

• Tableting: Compression force can induce phase transformations
• Encapsulation: Phase transformation during this process is often avoided

Coating

• Non-functional coatings (e.g. aqueous or solvent based) minimize interaction between core and coating liquid and transformation risk.
• Functional coatings may include the drug in the coating layer and may lead to solution or solution-mediated transformation.

Anticipating and Preventing Phase Transformation: Crystal Form

• Starting material selection, particularly for selecting forms that are less sensitive to phase transformations
• Excipient selection to prevent process-induced age hardening
• Monitoring of finished products to detect phase changes

Anticipating and Preventing Phase Transformation: Process

• Managing processing conditions to prevent the formation of unwanted phases like hydrates
• Selection of proper processes to prevent phase transformations
• Avoiding solid-solid transitions

Case Study: ABT-232

• Physicochemical properties (high water solubility, three different phases, chemical stability)
• Formulation (Anhydrous API, immediate release with 0.25-1% drug loading, wet granulation)
• Formulation stability (gradual loss of potency over 6 months related to high amorphous content). Factors investigated to determine the cause for poor stability in the product included PLM, PXRD, and Raman

Case Study: Carbamazepine

• Physicochemical properties (poor water solubility, five different phases, three polymorphic forms).
• Formulation (dose up to 400 mg; poor aqueous solubility; wet granulation)
• Processing (wet granulation)
• During wet granulation, transformation to dihydrate is demonstrated with all three forms; Form I, Form II and Form III.

Carbamazepine: API Selection

• Polymorphs (Form I, Form II, Form III, Dihydrate)
• Solubility differences in various forms
• Thermodynamic stability of different forms

Carbamazepine: Processing

• Wet granulation and observed formation of dihydrate with three forms (Form I, Form II, Form III)
• Granulation conditions can affect the relative amounts of each form during processing.
• The form used for processing affects dissolution

Case Study: Acetaminophen

• Physicochemical properties (three different phases, poor compaction behavior)
• Formulation
• Crystallization (metastable Form II)

Acetaminophen: Compaction

• Crystallization/ formation of Dioxane solvate to Form I
• Properties of Form II, high cohesion index, good for direct compression.
• Phase transformations during tableting processing was minimized or avoided through the use of Form II

Test your knowledge on the dissolution processes of solid dosage forms in this Pharmacology chapter quiz. Explore concepts like the characteristics of various solid phases, factors affecting dissolution, and the significance of the Kauzmann temperature. Perfect for students looking to deepen their understanding of solid-state chemistry.