Polymorphism refers to the existence of a drug substance in multiple crystalline forms, known as polymorphs. Recently, this term has been expanded to include solvates (forms containing a solvent), amorphous forms (non-crystalline forms), and desolvated solvates (forms from which the solvent has been removed).
Some polymorphic crystals possess lower aqueous solubility than their amorphous counterparts, leading to incomplete absorption. For instance, the oral suspension of Chloramphenicol, which exists in several crystal forms, demonstrates that drug concentration in the body relies on the proportion of the more soluble and better-absorbed β-polymorph.
Generally, the most stable polymorph has the lowest free energy. An amorphous form of a drug, being less structurally rigid, often dissolves faster than its crystalline form. Some polymorphs are metastable, meaning that they may transition to a more stable form over time.
Changes in crystal form during manufacturing can cause issues such as tablet cracking or obstacles in compressing a granulation into a tablet, requiring product reformulation. During manufacturing, certain drugs can interact with solvents, resulting in the formation of solvate crystals. When water acts as the solvent, it can produce specific crystalline forms known as hydrates, which possess different solubility characteristics than their anhydrous counterparts. For example, erythromycin hydrates differ significantly in solubility from the anhydrous form of the drug. In contrast, the anhydrous form of ampicillin is reportedly more readily absorbed than ampicillin trihydrate due to the former's quicker dissolution.
Drug dissolution is influenced by polymorphism, which refers to the existence of a drug substance in multiple crystalline forms like polymorphs, solvates, and amorphous forms.
A drug's polymorphs share the same chemical formula but different chemical structures, and so they exhibit different physical properties.
For instance, chloramphenicol suspension has multiple crystal forms. However, a higher percentage of highly soluble β-polymorph enhances drug absorption.
Metastable polymorphs can convert to a more stable form during manufacturing and can cause issues like tablet cracking or preventing granulation compression.
During the manufacturing process, some drugs interact with solvents to form solvates. Different crystal forms of these solvates are referred to as pseudopolymorphs.
When the solvent is water, hydrates are formed. In the case of erythromycin hydrates, the plot of percent dissolved versus time displays different solubility patterns for dihydrate, monohydrate and anhydrate forms.
Lastly, amorphous forms lack crystalline structures and dissolve more rapidly in aqueous solutions than crystals.
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