Process-induced phase transformations in a pharmaceutically relevant salt-free form system
2012
Qu, H. | Savolainen, M. | Christensen, L.P. | Rantanen, J.
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.
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