Academic Articles

Abstract: Pharmaceutical compounds are subjected to a range of unit operations during manufacture, many of which can lead to hydration and dehydration of the drug material with the potential for phase transformation. The aims of this study were to examine the hydration/dehydration process and its impact on phase purity. Theophylline is widely used for the treatment of asthma and other respiratory conditions. Its solid state chemistry has recently been investigated and four anhydrous forms are discussed. The hydration/dehydration behaviour of this model compound was examined in solvent environments of differing water activity, (a w ) and in the solid state by storage in humidity controlled environments. Analysis by thermal methods and powder x-ray diffraction (XRPD) revealed that certain samples contained a phase impurity, and that this could be “cured” during storage. XRPD analysis was unable to detect this phase impurity generated during the hydration–dehydration process, the nature of which was unclear, but led to the detection of Form I by thermal analysis. The potential for such phase impurities and batch to batch variations in hydrate forming compounds is discussed. [Copyright &y& Elsevier]

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Abstract: Salt formation is the most commonly used technique to improve the aqueous solubility and dissolution rate of active pharmaceutical ingredients. The phase transformation of the salt to the free form of the drug is extremely undesirable, since it will change the solubility and dissolution rate of the active substance and therefore alter the bioavailability of the final product. The mechanism of the salt-to-free form drug transformation was explored in the present work by investigating the pH-solubility profiles of the different solid forms (anhydrate, monohydrate and dihydrate) of the model drug in a salt form (amlodipine besylate), the nucleation of the free base and the transformation of the salt to the free base in aqueous suspensions in the presence of different pharmaceutical excipients. It has been observed that the nucleation of the free base occurred when the pH of the solution reached a certain level pHmetastable, which was related to the free energy penalty associated with the creation of a new interface. The transformation behavior of the salt solid forms to the free base demonstrated that the nucleation of the free base was a decisive step in the phase transformation. The nucleation of the free base happened readily and thus the salt-to-free base transformation occurred rapidly in the excipient–salt suspension with a pH above the pHmetastable. On the other hand, the salt-to-free base transformation was hindered in the excipient suspensions with a pH below the pHmetastable. The results of the present work can support robust formulation design of solid dosage forms containing salts by optimal excipient selection. [Copyright &y& Elsevier]

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