Physical Form (Crystal & Amorphous)
– Crystalline Form:
– Crystal Lattice Structure: Crystalline substances have a defined and repetitive arrangement of molecules. This structure is characterized by unit cells that repeat in three dimensions.
– Types of Crystals: Includes polymorphs (different crystal forms of the same compound), hydrates/solvates (crystals containing solvent molecules), and co-crystals (crystals composed of two or more components).
– Analysis Techniques: X-ray diffraction (XRD) is used to identify and characterize the crystalline structure. Other techniques include differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA).
– Amorphous Form:
– Disordered Structure: Amorphous substances lack a defined crystalline structure, leading to higher energy states and increased solubility.
– Preparation Methods: Techniques like spray drying, melt quenching, and freeze-drying are used to produce amorphous forms.
– Stability Concerns: Amorphous forms may crystallize over time, leading to changes in solubility and stability. Stability can be enhanced by using polymers to inhibit crystallization.
Particle Size and Shape
– Particle Size:
– Impact on Dissolution and Absorption: Smaller particles dissolve more rapidly due to a larger surface area. However, very fine particles may agglomerate, reducing effective surface area.
– Techniques for Size Reduction: Milling (ball milling, jet milling), micronization, and nanonization.
– Size Measurement Techniques:
– Laser Diffraction: Measures particle size distribution by detecting the scattering of light.
– Dynamic Light Scattering (DLS): Suitable for nanoparticles, measures the size based on Brownian motion.
– Microscopy: Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) provide detailed images of particle shape and size.
– Particle Shape:
– Impact on Flow and Packing: Spherical particles generally have better flow properties and pack more densely than irregularly shaped particles.
– Shape Measurement: Image analysis using microscopy can quantify particle shape parameters such as aspect ratio, roundness, and sphericity.
Flow Properties
– Factors Affecting Flow:
– Particle Size and Distribution: Narrow particle size distribution enhances flow, while a wide distribution can lead to segregation.
– Shape and Surface Texture: Smooth, spherical particles flow better than rough, irregular ones.
– Moisture Content: Excess moisture can cause particles to stick together, reducing flowability.
– Electrostatic Charges: Particles with electrostatic charges can adhere to each other, hindering flow.
– Measurement Techniques:
– Angle of Repose: Measures the maximum angle at which a pile of powder remains stable. Lower angles indicate better flow.
– Compressibility Index (Carr’s Index): Calculated from the bulk and tapped densities of the powder. Lower values indicate better flow.
– Hausner Ratio: The ratio of tapped density to bulk density. Lower ratios indicate better flow.
– Flow Rate Through an Orifice: Measures the time taken for a powder to flow through a standardized orifice under gravity.
Solubility Profile
– Intrinsic Solubility: The concentration of a drug in a saturated solution in the presence of excess solid at a given temperature and pressure.
– Measurement: Prepare a saturated solution of the drug in the solvent, equilibrate, filter, and analyze the concentration.
– pKa (Acid Dissociation Constant):
– Determination Methods:
– Potentiometric Titration: Measures the pH change during the titration of the drug with a strong acid or base.
– Spectrophotometric Method: Involves measuring the absorbance of the drug at different pH values.
– pH Solubility Profile:
– Relevance: Helps predict the drug’s solubility in different parts of the gastrointestinal tract.
– Measurement: Dissolve the drug in buffer solutions of varying pH (usually ranging from 1 to 8) and measure the solubility at each pH.
– Partition Coefficient (log P):
– Relevance: Indicates the drug’s ability to cross biological membranes.
– Determination Methods:
– Shake Flask Method: Involves shaking a mixture of water and octanol with the drug and measuring the concentration in each phase.
– HPLC Method: Uses a chromatographic column with a biphasic solvent system to determine the partition coefficient.
– Interpretation: Drugs with very high log P values (>3) are highly lipophilic and may accumulate in fatty tissues, while those with very low log P values (<1) are too hydrophilic to pass through cell membranes easily.
Polymorphism
– Definition: The ability of a drug substance to exist in more than one crystalline form, each with distinct physical and chemical properties.
– Polymorph Screening: Involves the systematic study of crystallization conditions to identify all possible polymorphic forms.
– Techniques for Screening: Solvent evaporation, cooling crystallization, melt crystallization, and vapor diffusion.
– Characterization Techniques:
– X-Ray Diffraction (XRD): Provides a fingerprint of the crystal structure. Polymorphs have distinct XRD patterns.
– Differential Scanning Calorimetry (DSC): Measures heat flow associated with phase transitions. Different polymorphs show distinct melting points and heat of fusion.
– Thermogravimetric Analysis (TGA): Measures weight changes under controlled heating. Can distinguish between polymorphs based on their thermal stability.
– Infrared (IR) and Raman Spectroscopy: Detect differences in molecular vibrations that correspond to different crystal forms.
– Solid-State NMR: Provides information on the local chemical environment of nuclei, sensitive to different polymorphic forms.
– Impact on Drug Development:
– Solubility and Dissolution Rate: Polymorphs with higher energy states typically have higher solubility and faster dissolution rates.
– Stability: Some polymorphs may be more stable than others under certain storage conditions.
– Bioavailability: Different polymorphs can result in varying levels of bioavailability.
– Manufacturing and Processing: Polymorphs can have different mechanical properties, affecting processing parameters like compression and milling.
Conclusion
A comprehensive understanding of the physicochemical properties of drug substances, including their physical form, particle size and shape, flow properties, solubility profile, and polymorphism, is essential in pharmaceutical development. These properties influence the drug’s formulation, manufacturability, stability, and bioavailability, ultimately affecting the efficacy and safety of the final pharmaceutical product. Detailed characterization and optimization of these properties enable the development of high-quality, effective, and stable medications.
