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Facteurs affectant la dissolution : polymorphisme, amorphisme et pseudopolymorphisme
Le polymorphisme désigne l'existence d'une substance médicamenteuse sous plusieurs formes cristallines, appelées polymorphes. Récemment, ce terme a ét…
La dissolution du médicament est influencée par le polymorphisme, qui fait référence à l’existence d’une substance médicamenteuse sous plusieurs formes cristallines comme les polymorphes, les solvates et les formes amorphes.
Les polymorphes d'un médicament partagent la même formule chimique mais des structures chimiques différentes, et ils présentent donc des propriétés physiques différentes.
Par exemple, la suspension de chloramphénicol a plusieurs formes cristallines. Cependant, un pourcentage plus élevé de β-polymorphe hautement soluble améliore l’absorption du médicament.
Les polymorphes métastables peuvent se convertir en une forme plus stable pendant la fabrication et peuvent causer des problèmes tels que la fissuration des comprimés ou l’empêchement de la compression par granulation.
Au cours du processus de fabrication, certains médicaments interagissent avec les solvants pour former des solvates. Les différentes formes cristallines de ces solvates sont appelées pseudopolymorphes.
Lorsque le solvant est de l’eau, des hydrates se forment. Dans le cas des hydrates d’érythromycine, le graphique du pourcentage dissous en fonction du temps montre différents modèles de solubilité pour les formes dihydratées, monohydratées et anhydratées.
Enfin, les formes amorphes n’ont pas de structures cristallines et se dissolvent plus rapidement dans les solutions aqueuses que les cristaux.
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Q1: What is polymorphism and how does it affect drug dissolution?
Polymorphism refers to a drug substance existing in multiple crystalline forms with the same chemical formula but different structures and physical properties. Different polymorphs exhibit varying solubility rates; for example, chloramphenicol's highly soluble β-polymorph enhances drug absorption compared to less soluble forms. This variation directly impacts dissolution rates and bioavailability.
Q2: Why do metastable polymorphs cause problems during drug manufacturing?
Metastable polymorphs can convert to more stable forms during manufacturing, causing tablet cracking or preventing granulation compression. These transitions occur because metastable forms possess higher free energy than stable polymorphs. Such changes may require product reformulation to maintain pharmaceutical quality and efficacy.
Q3: What are solvates and pseudopolymorphs in pharmaceutical formulations?
Solvates form when drugs interact with solvents during manufacturing. When water is the solvent, specific crystalline forms called hydrates are produced. These pseudopolymorphs possess different solubility characteristics than their anhydrous counterparts; for instance, erythromycin hydrates show distinct dissolution patterns compared to the anhydrate form.
Q4: How do amorphous drug forms compare to crystalline forms in dissolution?
Amorphous forms lack crystalline structures and dissolve more rapidly in aqueous solutions than crystalline forms. Being less structurally rigid, amorphous drugs often exhibit faster dissolution rates. However, some polymorphic crystals possess lower aqueous solubility than their amorphous counterparts, potentially leading to incomplete absorption.
Q5: Why does anhydrous ampicillin absorb faster than ampicillin trihydrate?
The anhydrous form of ampicillin dissolves more quickly than ampicillin trihydrate, resulting in faster absorption. This difference stems from the distinct solubility characteristics of hydrated versus anhydrous forms. Faster dissolution of the anhydrous form enables more rapid drug availability for mechanisms of drug absorption paracellular transcellular and vesicular transport.
Q6: What determines whether a polymorph is stable or metastable?
The most stable polymorph has the lowest free energy, making it thermodynamically favored. Metastable polymorphs possess higher free energy and may spontaneously transition to more stable forms over time. This energy difference explains why certain crystal forms persist during manufacturing while others convert, potentially causing formulation problems.
Q7: How do hydrate forms of erythromycin differ in their dissolution behavior?
Erythromycin exists in dihydrate, monohydrate, and anhydrate forms, each displaying different solubility patterns. When percent dissolved is plotted against time, these hydrate forms show distinct dissolution curves. The variation in water content directly influences the crystal structure and aqueous solubility of each form.