HPMCAS as an effective precipitation inhibitor in amorphous solid dispersions of the poorly soluble drug candesartan cilexetil


Among the strategies to improve the biopharmaceutic properties of poorly soluble drugs, Supersaturating Drug Delivery Systems like polymer-based amorphous solid dispersions (SD) have been successfully applied. The screening of appropriate polymeric carriers to compose SD is a crucial point on their development. In this study, hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate succinate (HPMCAS) types L, M and H and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (SOL) were evaluated by in vitro supersaturation studies regarding their anti-precipitant ability on the poorly soluble drug candesartan cilexetil (CC) under two different media, including biorelevant conditions. According to the results, HPMCAS M was considered the best carrier to develop SD containing CC among all the polymers tested, due to its good anti-precipitant performance in both media. In addition, the medium used in the in vitro supersaturation studies played an important role on the results, and its selection should be carefully done.



The screening of potential carriers to SDDS formulations is a fundamental step in its development. Polymers can act as precipitation inhibitors and have been extensively applied to compose SD of poorly soluble drugs. In vitro supersaturation studies are used to evaluate their performance in achieving and maintaining drug supersaturation.In this study, different polymers were tested regarding their CC precipitation inhibition performance. Two different media were used in the supersaturation studies conducted by SSM, in presence and absence of PPIs.

HPMCAS M was chosen as the best option of polymeric carrier to compose SD of CC among the polymers tested. This is a cellulose derivative enteric polymer, capable of inhibit CC precipitation, achieving and maintaining supersaturation in both media tested. In contrast, SOL appeared to form a complex with bile salts in FaSSIF, which directly interfered on CC apparent solubility. The polymers ranking regarding their anti-precipitant ability was completely different between the different media, suggesting that the use of a non-biorelevant medium, e.g. PBpH6.8, could either overestimate or reduce the performance of PPIs. FaSSIF also proved to be more discriminative for CC anti-precipitation ability of the polymers tested, regarding their added concentration. Therefore, the use of biorelevant media in supersaturation studies of poorly soluble drugs is highly recommended, in order to guide the polymeric carriers selection by predicting potential interactions between PPIs and gastrointestinal fluid components. As human gastrointestinal fluids availability is considerably limited, the use of commercially available biorelevant media is a good alternative to conduct in vitro supersaturation studies.


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