3.24
Faktoren, die die Auflösung beeinflussen: Polymorphismus, Amorphismus und Pseudopolymorphismus
Polymorphismus bezeichnet die Existenz eines Arzneimittels in mehreren kristallinen Formen, den sogenannten Polymorphen. In jüngster Zeit wurde dieser…
Die Auflösung des Arzneimittels wird durch den Polymorphismus beeinflusst, der sich auf das Vorhandensein eines Wirkstoffs in mehreren kristallinen Formen wie Polymorphen, Solvaten und amorphen Formen bezieht.
Die Polymorphe eines Medikaments haben die gleiche chemische Formel, aber unterschiedliche chemische Strukturen, und weisen daher unterschiedliche physikalische Eigenschaften auf.
Zum Beispiel hat Chloramphenicol-Suspension mehrere Kristallformen. Ein höherer Anteil an hochlöslichem β-Polymorph verbessert jedoch die Wirkstoffabsorption.
Metastabile Polymorphe können sich während der Herstellung in eine stabilere Form umwandeln und Probleme wie Tablettenrisse oder die Verhinderung einer Granulationskompression verursachen.
Während des Herstellungsprozesses interagieren einige Arzneimittel mit Lösungsmitteln zu Solvaten. Verschiedene Kristallformen dieser Solvate werden als Pseudopolymorphe bezeichnet.
Wenn das Lösungsmittel Wasser ist, werden Hydrate gebildet. Im Fall von Erythromycin-Hydraten zeigt das Diagramm des über die Zeit gelösten Prozentsatzes unterschiedliche Löslichkeitsmuster für Dihydrat-, Monohydrat- und Anhydratformen.
Schließlich haben amorphe Formen keine kristallinen Strukturen und lösen sich in wässrigen Lösungen schneller auf als Kristalle.
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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.