Crystal Properties and Polymorphism
Many drug substances can exist in more than one crystalline form with different space lattice arrangements. This property is known as polymorphism, and the different crystal forms are called polymorphs. Occasionally, a solid crystallizes while entrapping solvent molecules in a specific lattice position and in a fixed stoichiometry, resulting in a solvate or pseudopolymorph.
What Is Polymorphism?
Polymorphic forms can be prepared by manipulating crystallization conditions, including solvent nature, temperature, and cooling rate. Sometimes, a solute precipitates from solution in an unordered form, known as the amorphous state, which can result from shock cooling, solvent composition changes, or lyophilization.
Different polymorphs of a given drug vary in properties such as solubility, dissolution, true density, crystal shape, compaction behavior, flow properties, and solid-state stability. Identifying and monitoring a drug’s solid-state form is crucial, and alternative polymorphs may be sought to solve stability, bioavailability, or processing issues.
Crystalline Forms
For a compound to exist as a solid, there must be sufficient internal attraction between molecules to limit the free movement characteristic of liquids and gases. However, the strength of these internal attractions can vary. Pharmaceuticals commonly exist in different solid forms, with two primary classifications: crystalline and amorphous.
Crystalline Solids
A crystalline solid, or crystal, forms when drug molecules arrange themselves in a repeating three-dimensional pattern known as a unit cell. Crystalline solids are typically highly stable, with well-defined solubility and dissolution rates. Due to these predictable properties, most pharmaceutical drugs are developed and used in their crystalline form.
Amorphous Solids
In contrast, the amorphous form is a non-crystalline solid in which molecules are randomly arranged, exhibiting a high degree of disorder. The amorphous state generally dissolves more rapidly than the crystalline form and has a variable but often higher solubility. However, it is usually less stable and tends to absorb moisture from the atmosphere (hygroscopic). In reality, solid-state pharmaceuticals often exist along a continuum between fully crystalline and fully amorphous, with varying degrees of disorder.
Crystal Solvates and Hydrates
Aqueous solubility is a key factor in pharmaceutical development. Some drugs dissolve in water but subsequently incorporate water molecules into their crystal structure, forming hydrates. Depending on the number of water molecules incorporated, these hydrates are classified as monohydrates, dihydrates, trihydrates, etc. Hydrates generally exhibit reduced solubility in water, which can impact bioavailability and manufacturing efficiency. It is essential to identify whether a drug substance can form hydrates, as reduced aqueous solubility can lead to precipitation and formulation challenges. Additionally, some drugs can form solvates, which are similar to hydrates but incorporate solvents such as ethanol or ethyl acetate instead of water. Both hydrates and solvates can be highly stable solid forms with potential benefits for manufacturing
Many drug candidates can exist in multiple polymorphic forms, each with unique structural and physical properties (Table 1).
Effects of Crystal Characteristics
A. Bioavailability
Differences in dissolution rates and solubilities among polymorphic forms significantly impact drug bioavailability. When a drug’s absorption is dissolution rate-limited, using a more soluble polymorph enhances bioavailability. Research on chloramphenicol palmitate and chlortetracycline hydrochloride has demonstrated that the more soluble polymorphic forms show improved bioavailability.
Comparative blood level studies in humans show that the more soluble form B of chloramphenicol palmitate is the most bioavailable, while the less soluble form A has lower bioavailability. The bioavailability of mixtures correlates proportionally with the concentration of form B.
This Figure compares the mean blood serum levels of chloramphenicol obtained from suspensions containing different ratios of polymorphs A and B. A single oral dose equivalent to 1.5 g of chloramphenicol was administered.
- M: 0% polymorph B
- N: 25% polymorph B
- O: 50% polymorph B
- P: 75% polymorph B
- L: 100% polymorph
The results show that polymorph B has higher bioavailability. As the proportion of polymorph B increases, blood serum levels rise accordingly.
Likewise, chlortetracycline hydrochloride’s more soluble form exhibits greater bioavailability, confirming the role of polymorphism in dissolution and drug absorption. This approach is warranted when absorption is dissolution rate-limited, but may not be necessary for highly soluble compounds.
This Figure shows the dissolution curves of the α and β forms of chlortetracycline hydrochloride from compressed disks in water at 37°C.
- The β form dissolves significantly faster than the α form.
B. Chemical Stability
For drugs prone to solid-state degradation, crystal form influences stability. For instance, aztreonam, an antibiotic, has two crystal forms: needle-like α and dense spherical β. Under high humidity (37°C/75% RH), the α form undergoes rapid degradation with a half-life of six months, whereas the β form remains stable for several years.
These cases illustrate the importance of selecting and maintaining the appropriate polymorphic form to enhance stability.
C. Tableting Behavior
During tableting, powder flow and compaction behaviors are critical and depend on crystal morphology, tensile strength, and density. Different polymorphic forms can significantly impact these properties.
Crystal habit refers to the external appearance of a crystal and can change without altering internal structure. Factors like impurities, concentration, crystallization rate, and hydrodynamics influence crystal habit.
Polymorphism affects compaction behavior, as shown in studies on sulfathiazole and aspirin, where different polymorphs exhibited varying compression characteristics. Additionally, crystalline indomethacin produced harder tablets compared to its amorphous counterpart.
D. Physical Stability
Pharmaceutical compounds often exist in multiple polymorphic forms, but only one is thermodynamically stable under specific conditions. Over time, unstable polymorphs transition into the stable form, though the rate of transformation can vary. When the change occurs slowly, the unstable form is referred to as metastable.
The stable polymorph is characterized by a higher melting point, lower solubility, and greater chemical stability. However, a metastable form may still be preferable in certain cases, particularly when it offers better dissolution properties or facilitates tablet production. If a metastable form is selected for formulation, its stability must be thoroughly evaluated under different processing conditions to ensure proper handling and storage.
Various pharmaceutical processes can trigger polymorphic transformations, potentially affecting drug stability and performance. Grinding, granulating, drying, and compressing operations are known to cause such changes. For example, drugs like digoxin, spironolactone, and estradiol undergo polymorphic transformations during grinding, while phenylbutazone changes due to grinding and compression. Granulation, which involves solvents, can lead to solvate formation. Conversely, drying may transform solvates into anhydrous crystalline or amorphous forms.
A comprehensive understanding of polymorphism is essential for predicting the long-term stability of pharmaceutical dosage forms. Without proper control, undesired polymorphic changes can compromise drug efficacy, solubility, and bioavailability. Pharmaceutical scientists can ensure consistent drug performance and extend product shelf life by identifying and stabilizing the optimal polymorphic form.
Techniques for Studying Crystal Properties
Several techniques are available for analyzing solid-state properties:
- Microscopy (including hot-stage microscopy)
- Infrared spectrophotometry
- Single-crystal X-ray diffraction
- (provides detailed structural information, but is time-consuming)
- X-ray powder diffraction
- (rapid and effective for routine analysis; distinguishes polymorphs but not solvates)
- Thermal analysis (Differential Thermal Analysis and Differential Scanning Calorimetry)
- (useful for investigating polymorphism and thermodynamic properties)
- Thermogravimetric analysis
- (detects desolvation by measuring weight loss upon heating)
Polymorphs are analyzed using specialized techniques that provide detailed characterization of pharmaceutical solids at the particulate level. The gold standard for this type of analysis is X-ray diffraction (XRD). When an X-ray beam interacts with atoms in a crystal, it is diffracted at specific angles based on atomic spacing. These diffracted beams are detected and plotted as a graph of intensity versus angle, producing a unique fingerprint for each crystal form of a drug. Since amorphous solids lack a defined crystalline structure, they do not produce characteristic X-ray patterns.
The Case of Acetaminophen
Acetaminophen, a commonly used analgesic and antipyretic, exists in three polymorphic forms: I, II, and III. Forms I and II exhibit packing polymorphism, sharing the same molecular conformation but differing in crystal packing. The commercially available form is form I, while form II has slightly higher solubility and is suitable for direct compression, but is less stable, often converting back to form I during storage and processing.
The figure illustrates X-ray diffraction patterns for two distinct polymorphs of Acetaminophen.
Conclusion
Polymorphism plays a critical role in drug development, influencing bioavailability, stability, tableting behavior, and long-term physical stability. Understanding and controlling polymorphic transformations ensures consistent drug performance, requiring careful selection of solid-state forms during preformulation and manufacturing.
