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Related Concept Videos

Factors Affecting Dissolution: Polymorphism, Amorphism and Pseudopolymorphism01:21

Factors Affecting Dissolution: Polymorphism, Amorphism and Pseudopolymorphism

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...
Aryldiazonium Salts to Azo Dyes: Diazo Coupling01:11

Aryldiazonium Salts to Azo Dyes: Diazo Coupling

The reaction of weakly electrophilic aryldiazonium (also called arenediazonium) salts with highly activated aromatic compounds leads to the formation of products with an —N=N— link, called an azo linkage. This reaction, presented in Figure 1, is known as diazo coupling and occurs without the loss of the nitrogen atoms of the aryldiazonium salt. Highly activated aromatic compounds such as phenols or arylamines favor the diazo coupling reaction. The coupling generally occurs at the para position.
Pharmaceutical Alternatives: Polymorphic Form-Related and Particle Size-Related Therapeutic Nonequivalence01:27

Pharmaceutical Alternatives: Polymorphic Form-Related and Particle Size-Related Therapeutic Nonequivalence

Changes in polymorphic forms can significantly influence the bioavailability of poorly soluble drugs. Although the FDA defines pharmaceutical equivalence based on having the same active ingredient, dosage form, and route of administration, it does not automatically disqualify products with different polymorphic forms. This means two products with different polymorphs can still be deemed pharmaceutically equivalent. However, polymorphic differences can affect properties like wettability,...
Diazonium Group Substitution: –OH and –H01:19

Diazonium Group Substitution: –OH and –H

Nitrous acid, a weak acid, is prepared in situ via the reaction of sodium nitrite with a strong acid under cold conditions. This nitrous acid prepared in situ reacts with primary arylamines to form arenediazonium salts. Such reactions are known as diazotization reactions. As shown in Figure 1, the formation of arenediazonium salts begins with the decomposition of nitrous acid in an acidic solution to give nitrosonium ions.
Nucleophilic Aromatic Substitution of Aryldiazonium Salts: Aromatic SN101:14

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Treating arylamines with nitrous acid gives aryldiazonium salts that are effective substrates in nucleophilic aromatic substitution reactions. The diazonio group in these salts can be easily displaced by different nucleophiles, yielding a wide variety of substituted benzenes. The leaving group departs as nitrogen gas, and this easy elimination is the driving force for the substitution reaction.
In the Sandmeyer reaction, for example, the diazonio group is replaced by a chloro, bromo, or cyano...
1° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Mechanism01:37

1° Amines to Diazonium or Aryldiazonium Salts: Diazotization with NaNO2 Mechanism

Nitrous acid is a relatively weak and unstable acid prepared in situ by the reaction of sodium nitrite and cold, dilute hydrochloric acid. In an acidic solution, the nitrous acid undergoes protonation when it loses water to form a nitrosonium ion—an electrophile. Nitrous acid reacts with primary amines to give diazonium salts. The reaction is called diazotization of primary amines.

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Didanosine polymorphism in a supercritical antisolvent process.

R Bettini1, R Menabeni, R Tozzi

  • 1Department of Pharmacy, University of Parma, Parma, Italy. bettini@unipr.it

Journal of Pharmaceutical Sciences
|October 15, 2009
PubMed
Summary

Researchers explored the solid-state properties of didanosine (DDI) using supercritical CO2. A new, metastable polymorph with higher water solubility was identified, differing in crystal packing from the commercial form.

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Area of Science:

  • Pharmaceutical Science
  • Materials Science
  • Chemical Engineering

Background:

  • Solid-state properties of active pharmaceutical ingredients (APIs) critically impact drug development, influencing clinical efficacy and economic viability.
  • Didanosine (DDI) is an important antiretroviral drug, and understanding its solid-state forms is essential for optimizing its pharmaceutical applications.

Purpose of the Study:

  • To investigate the solid-state properties and water solubility of didanosine (DDI) crystallized using a supercritical antisolvent (SAS) process.
  • To characterize a newly obtained polymorph of DDI and compare its properties with the commercially available form.
  • To elucidate structural differences and molecular interactions using advanced solid-state Nuclear Magnetic Resonance (SS NMR) techniques.

Main Methods:

  • Supercritical antisolvent (SAS) process using CO2 to recrystallize didanosine (DDI).
  • Solid-state Nuclear Magnetic Resonance (SS NMR) techniques: 1D and 2D multinuclear NMR ((1)H, (13)C, (15)N), 2D (1)H DQ CRAMPS, and (1)H-(13)C CP FSLG-HETCOR experiments.
  • X-ray diffractometry for structural analysis.
  • Particle size analysis influenced by antisolvent density (pressure).

Main Results:

  • A new polymorph of didanosine was successfully crystallized using the SAS process.
  • Solid-state NMR and X-ray diffractometry confirmed structural differences in crystal packing between the new polymorph and commercial DDI.
  • The new polymorph exhibited higher water solubility and lower stability to mechanical stress compared to the commercial form.
  • Analysis indicated both forms exist in the enol configuration, with similar molecular conformations and hydrogen bond networks but distinct packing arrangements.

Conclusions:

  • The SAS process can yield a new, metastable polymorph of didanosine with altered solid-state properties.
  • Solid-state NMR is a powerful tool for characterizing polymorphism and elucidating intra- and intermolecular interactions in APIs.
  • The identified polymorph's higher solubility suggests potential for improved DDI formulations, while its metastability requires careful consideration for stability during manufacturing and storage.