期刊
AAPS PHARMSCITECH
卷 23, 期 6, 页码 -出版社
SPRINGER
DOI: 10.1208/s12249-022-02310-z
关键词
dissolution model; microenvironmental pH modulators; supersaturation; weak acid
资金
- European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie grant [778051]
- Ministry of Science and Higher Education of Poland fund [3899/H2020/2018/2]
- Ministry of Science and Higher Education of Poland [SUB.D190.21.098]
- National Centre for Research and Development of Poland [POIR.04.01.04-00-0142/17-00]
This study examined the effect of a microenvironmental pH modulator on the dissolution of a weak acidic drug under physiologically relevant conditions. The results showed that using a bicarbonate-buffered intestinal fluid can enhance the dissolution of the drug, while using phosphate buffers may have the opposite effect.
Poor water dissolution of active pharmaceutical ingredients (API) limits the rate of absorption from the gastrointestinal tract. Increasing the pH of a solid form microenvironment can enhance the dissolution of weakly acidic drugs, but data on this phenomenon in a physiologically relevant bicarbonate media are lacking. In this paper, we examined the effect of a microenvironmental pH modulator (Na2HPO4) on the dissolution of a Biopharmaceutics Classification System (BCS) class II free weak acid (ibuprofen) at biorelevant conditions, including an automatic bicarbonate buffering system, as well as in compendial (50 mM) and low-concentration (10 mM) phosphate buffers with no external pH control. The tablets of 200 mg ibuprofen with either Na2HPO4 (phosphate formulation, PF) or NaCl (reference formulation, RF) were manufactured using a compression method. In a pH 2 simulated gastric fluid, only PF produced a transient supersaturation of ibuprofen, dissolving a fourfold higher drug amount than RF. In a bicarbonate-buffered simulated intestinal fluid with a dynamically controlled pH (5.7, 7.2, and 5.8 to 7.7 gradient), PF dissolved more drug within 30 min than RF (p <= 0.019). Of note, the use of a 50 mM phosphate buffer pH 7.2 provided opposite results-RF dissolved the API much faster than PF. Moreover, 10 mM phosphate buffers of pH 5.6 and 7.2 could neither maintain a constant pH nor mimic the bicarbonate buffer performance. In conclusion, the use of a bicarbonate-buffered intestinal fluid, instead of phosphate buffers, may be essential in dissolution tests of BCS class II drugs combined with pH modulators.
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