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