Nicole Stieger

Co-crystals of the antiretroviral nevirapine: crystal structures, thermal analysis and dissolution behaviour

Synthesis and physicochemical characterization of co-crystals of the antiretroviral drug nevirapine (NV) with the pharmaceutically acceptable co-formers saccharin, rac-tartaric acid, maleic acid, glutaric acid and salicylic acid are reported for the first time. The respective stoichiometric NV : co-former ratios are 2 : 1, 1 : 1, 1 : 1, 1 : 1 and 2 : 1. In the 1 : 1 co-crystals, the predicted R22(8) NV(amide)–carboxylic acid supramolecular synthon occurs, whereas in the 2 : 1 species, the co-former is H-bonded to a centrosymmetric NV dimer formed via the R22(8) amide–amide synthon. Thermal analysis of three co-crystals revealed the unusual phenomenon of precipitation of NV from the melt. Co-crystallization of NV with maleic acid led to the highest (∼fivefold) increase in the aqueous solubility of the drug.

Solution-mediated phase transformation of different roxithromycin solid-state forms: implications on dissolution and solubility

The objective of this study was to describe the solid-state forms in which roxithromycin may exist and the significant influence of solution-mediated phase transformation on the dissolution and solubility behavior of these forms. Roxithromycin may exist as: Form I (monohydrate), Form II (amorphous), Form III (anhydrate) and a mixture of Forms I and III. Form III and Mixture I/III have not been reported previously, probably due to incomplete solid-state characterization or the use of a standard production method which consistently yielded the same solid-state form. Solution-mediated phase transformations of Forms II and III to the stable Form I were proved through dissolution studies and quantification of the phase proportions, as a function of time, utilizing XRPD. This study showed that pharmacopoeial identification methods for roxithromycin do not allow accurate identification of the different solid-state forms. The various forms differed significantly in terms of dissolution profiles, which could have a marked influence on bioavailability and performance of the final dosage form. It was demonstrated that solvent replacement, during dissolution testing, masks the characteristic profile usually obtained with a metastable form undergoing solution-mediated transformation. Finally, we propose that peak dissolution concentrations should be used to give a more exact indication of the aqueous solubility enhancement ratio obtained with metastable forms of APIs.

Recrystallization of Active Pharmaceutical Ingredients

Recrystallization can be described simply as a process whereby a crystalline form of a compound may be obtained from other solid-state forms, being themselves crystalline or amorphous, of the same substance. Recrystallization is the process most often employed for the intermediate separation and last-step purification of solid active pharmaceutical ingredients (APIs) (Shekunov & York, 2000; Tiwary, 2006). Chemical purity is however not the only property of a pharmaceutical active that will affect its performance. Crystal structure (Table 1), crystal habit (Table 2) and particle size all play a part. Polymorphism (different crystal structures of the same substance) affects the physico-chemical properties and stability of an API, whereas crystal habit and particle size mostly affect various indices impacting on dosage form production and performance: particle orientation; flowability; packing and density; surface area; aggregation; compaction; suspension stability; and dissolution (Blagden et al., 2007; Doherty & York, 1988; Tiwary, 2006).