Impact of Polymorphism and Particle Size on the Bioavailability of Active Pharmaceutical Ingredients

Carlos Lorena^*
*Correspondence: Carlos Lorena, Department of Pharmacy, Brandon University, 270 18th St, Brandon, MB R7A 6A9, Canada, Email:

Keywords

Posterior • Pharmaceutical • Polymorphism • Bioavailability

Introduction

Bioavailability is defined as the proportion of an administered dose of an unaltered drug that reaches the systemic circulation and is thus available for therapeutic action. For orally administered drugs, bioavailability is influenced by factors such as solubility, dissolution rate and intestinal permeability. Polymorphism and particle size play significant roles in these processes.

Literature Review

Polymorphism in pharmaceuticals refers to the ability of a compound to exist in more than one crystalline form. These different forms, or polymorphs, have distinct molecular arrangements and crystal lattice structures. Despite having the same chemical composition, polymorphs can exhibit varied physical and chemical properties, such as melting point, solubility, stability and dissolution rate. These differences can significantly impact the bioavailability and therapeutic effectiveness of the active pharmaceutical ingredient (API). Identifying and characterizing polymorphs is crucial in drug development, as selecting the optimal form can enhance drug performance and stability, ensuring consistent and reliable therapeutic outcomes. Polymorphism can be influenced by factors such as the method of synthesis, solvent used and conditions of crystallization. Techniques such as X-ray diffraction (XRD), differential scanning calorimetry (DSC) and infrared spectroscopy (IR) are commonly used to study and differentiate polymorphic forms. Understanding polymorphism is essential for optimizing drug formulation and manufacturing processes [1].

Polymorphism in pharmaceuticals refers to the phenomenon where a single chemical substance can exist in multiple crystalline forms. Each polymorph has a unique arrangement of molecules in the crystal lattice, leading to different physical and chemical properties, despite having the same molecular formula. This characteristic can have significant implications for the development, manufacturing and performance of pharmaceutical products.

Types of polymorphism

1. Enantiotropic polymorphs: These polymorphs can reversibly transform from one form to another depending on temperature and pressure. The transition between polymorphs is thermodynamically reversible. For example, one form may be stable at lower temperatures, while another becomes stable at higher temperatures.
2. Monotropic polymorphs: In this case, the transition between polymorphs is irreversible. One polymorph is always more stable than the other, regardless of temperature or pressure. The less stable form will eventually convert to the more stable form over time [2].

Impact on drug properties

1. Solubility: Polymorphs can have different solubilities in a given solvent. Typically, the more stable polymorph has lower solubility than the less stable forms. Since solubility directly influences dissolution rate, the bioavailability of a drug can vary significantly between different polymorphs.
2. Dissolution rate: The rate at which a drug dissolves in the gastrointestinal tract is crucial for its absorption. Polymorphs with higher solubility generally dissolve faster, leading to more rapid absorption and higher bioavailability. Conversely, less soluble polymorphs dissolve slowly, potentially reducing the drug's effectiveness.
3. Melting point: Different polymorphs have distinct melting points. The melting point can affect the processing and formulation of the drug. For instance, a polymorph with a higher melting point may be more suitable for manufacturing processes that involve heat, while a lower melting point polymorph might be preferred for formulations requiring lower processing temperatures [3].
4. Stability: The stability of a polymorph affects its shelf life and storage conditions. More stable polymorphs are less likely to undergo physical or chemical changes over time, ensuring consistent therapeutic efficacy. Less stable forms may transform into more stable ones, potentially altering the drug's performance.
5. Mechanical properties: Polymorphs can exhibit different mechanical properties, such as hardness and compressibility. These properties influence the ease of processing and the quality of the final dosage form. For example, a polymorph with better compressibility might be preferred for tablet formation, ensuring uniformity and integrity of the tablets.

Identification and characterization

To ensure the selection of the optimal polymorph for pharmaceutical development, several analytical techniques are employed:

1. XRD is the primary tool for identifying and characterizing polymorphs. It provides detailed information about the crystal structure by measuring the diffraction patterns of X-rays passing through the sample. Each polymorph has a unique diffraction pattern, allowing for precise identification and differentiation.
2. DSC measures the heat flow associated with phase transitions in a sample. By analyzing the endothermic and exothermic peaks in the thermogram, one can determine the melting points and enthalpy changes of different polymorphs. This information is essential for understanding the thermal behavior and stability of polymorphic forms [4].
3. IR spectroscopy identifies molecular vibrations and functional groups within a compound. Each polymorph has a distinct IR spectrum due to differences in molecular arrangement and intermolecular interactions. Comparing the IR spectra of various polymorphs helps in their identification and characterization.
4. ssNMR provides detailed information about the molecular environment and structure of solids. It measures the magnetic properties of atomic nuclei in a sample, offering insights into the arrangement of atoms and their interactions. ssNMR is particularly useful for characterizing complex polymorphic systems and detecting subtle differences in molecular packing and dynamics.
5. TGA measures changes in the weight of a sample as it is heated or cooled. This technique provides information on the thermal stability and decomposition behavior of polymorphs. By analyzing weight loss profiles, TGA can help identify different polymorphs based on their unique thermal degradation patterns.

Polymorphism plays a critical role in drug development and manufacturing. Selecting the optimal polymorph can enhance the bioavailability, stability and manufacturability of a drug. Regulatory agencies, such as the FDA, require detailed characterization of polymorphic forms to ensure the safety and efficacy of pharmaceutical products. Understanding polymorphism also aids in patent protection, as different polymorphs can be patented separately, providing intellectual property advantages [5].

Polymorphic forms can exhibit substantial differences in solubility and dissolution rates. For example, a metastable polymorph may have higher solubility than its stable counterpart, leading to enhanced bioavailability. However, the metastable form may convert to the stable form over time or under certain conditions, potentially reducing its bioavailability.

Ritonavir, an antiretroviral drug, experienced a dramatic decrease in bioavailability due to the appearance of a less soluble polymorph, which led to its withdrawal and reformulation [6].

Discussion

Analytical techniques used to study polymorphism and particle size include X-ray diffraction (XRD), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared spectroscopy (IR) and solid-state nuclear magnetic resonance (ssNMR). XRD is essential for identifying and characterizing different polymorphic forms by analyzing their unique diffraction patterns. DSC measures the heat flow associated with phase transitions, providing information on melting points and thermal stability, which helps distinguish polymorphs. TGA assesses changes in weight as a function of temperature, offering insights into the thermal stability and decomposition of polymorphic forms. IR spectroscopy identifies molecular vibrations and functional groups, helping to distinguish different polymorphs based on their unique spectral signatures. ssNMR provides detailed information about the molecular environment and structure of solids, making it useful for characterizing complex polymorphic systems. For particle size analysis, techniques such as laser diffraction, dynamic light scattering (DLS) and scanning electron microscopy (SEM) are employed. Laser diffraction measures particle size distribution by analyzing light scattering patterns. DLS evaluates particle size based on the Brownian motion of particles in suspension. SEM provides high-resolution images of particles, allowing for detailed morphological analysis. Each technique contributes to a comprehensive understanding of the physical properties that influence the bioavailability of APIs.

Analytical techniques used to study polymorphism and particle size are essential for understanding the physical properties of APIs, as these properties directly impact bioavailability. The following are the primary analytical techniques employed:

1. X-ray diffraction (XRD): XRD is a powerful tool for identifying and characterizing different polymorphic forms of a compound. This technique involves directing X-rays at a sample and measuring the intensity and angles of the diffracted beams. Each polymorph produces a unique diffraction pattern, known as a fingerprint, which allows for the identification and differentiation of various crystalline forms. XRD is particularly useful in determining the crystalline structure and detecting the presence of multiple polymorphs in a sample.
2. Differential scanning calorimetry (DSC): DSC measures the heat flow associated with phase transitions in a material as a function of temperature. This technique is used to determine melting points, crystallization temperatures and other thermal events. By comparing the DSC thermograms of different polymorphs, one can identify and distinguish them based on their unique thermal behavior. DSC is also useful for assessing the purity and stability of polymorphic forms.
3. Thermogravimetric analysis (TGA): TGA measures changes in the weight of a sample as it is heated or cooled. This technique provides information on the thermal stability and decomposition behavior of polymorphic forms. By analyzing the weight loss profiles, TGA can help identify different polymorphs based on their unique thermal degradation patterns. TGA is also useful for detecting the presence of solvents or hydrates in the crystal lattice.
4. Infrared spectroscopy (IR): IR spectroscopy identifies molecular vibrations and functional groups within a compound by measuring the absorption of infrared light. Each polymorph has a distinct IR spectrum due to differences in molecular arrangement and intermolecular interactions. By comparing the IR spectra of different polymorphs, one can distinguish between them and identify specific functional groups associated with each form. IR spectroscopy is a valuable tool for studying the structural differences and chemical environment of polymorphic forms.
5. Solid-state nuclear magnetic resonance (ssNMR): ssNMR provides detailed information about the molecular environment and structure of solid materials. This technique measures the magnetic properties of atomic nuclei in a sample, offering insights into the arrangement of atoms and the interactions between them. ssNMR is particularly useful for characterizing complex polymorphic systems, as it can detect subtle differences in molecular packing and dynamics. This technique complements other methods by providing a deeper understanding of the solid-state structure of polymorphs.
6. Laser diffraction: Laser diffraction is a widely used technique for particle size analysis. It measures the size distribution of particles in a sample by analyzing the scattering pattern of a laser beam passing through the sample. The intensity and angle of the scattered light are related to the size of the particles. Laser diffraction is suitable for a wide range of particle sizes and provides rapid and accurate measurements. This technique is essential for optimizing particle size to enhance the dissolution rate and bioavailability of APIs.
7. Dynamic light scattering (DLS): DLS, also known as photon correlation spectroscopy, measures the size of particles in suspension by analyzing the fluctuations in scattered light caused by the Brownian motion of the particles. DLS provides information on the hydrodynamic diameter and size distribution of particles in a sample. This technique is particularly useful for characterizing nanoparticles and submicron-sized particles. DLS is essential for ensuring consistent particle size distribution, which directly impacts the dissolution rate and bioavailability of APIs.
8. Scanning electron microscopy (SEM): SEM provides high-resolution images of the surface morphology and structure of particles. This technique uses a focused beam of electrons to scan the surface of a sample, producing detailed images with high magnification. SEM allows for the examination of particle shape, surface texture and aggregation state. This information is crucial for understanding how particle morphology influences dissolution behavior and bioavailability. SEM is often used in conjunction with other particle size analysis techniques to provide a comprehensive characterization of particle properties.

These analytical techniques are integral to the study of polymorphism and particle size in pharmaceuticals. They provide the necessary data to optimize the physical properties of APIs, ultimately enhancing their bioavailability and therapeutic efficacy. By understanding and controlling polymorphism and particle size, pharmaceutical scientists can improve drug formulation and delivery, ensuring better patient outcomes.

Conclusion

Polymorphism and particle size are crucial factors in the bioavailability of APIs. Understanding and controlling these properties can lead to more effective drug formulations, improved therapeutic outcomes and reduced risk of drug failure. Future research should continue to explore the interplay between these factors and develop strategies to optimize bioavailability.

Acknowledgement

None.

Conflict of Interest

None.

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