Regulating the pH of bicarbonate solutions without purging gases: Application to dissolution testing of enteric coated tablets, pellets and microparticles

Abstract

Dissolution media based on bicarbonate buffers closely mimic the environment of intestinal fluids and thus improve in vitro in vivo correlation compared to phosphate buffers. Purging gases into the medium is used as a method to stabilise bicarbonate buffers; however, this causes issues due to the disturbance of the hydrodynamics in the dissolution vessel. The aim of this study was to develop a novel system to regulate and stabilise the pH of bicarbonate buffers without purging gases for the application of dissolution testing of enteric coated products. A novel enclosure system was applied to the USP II dissolution vessel to supply N2 and CO2 gases above the dissolution medium without purging into the solution. Drug release from enteric coated predinisolone microparticles (216.9 µm), pellets (1.25 mm) and commercially available tablets was determined in 0.1M HCl and subsequently in pH 6.8 phosphate buffer or pH 6.2-6.8 bicarbonate buffers generated by titration of the acidic medium in situ using USP II apparatus. Supplying N2 at 3-4 bar and CO2 at 0.1 bar were able to increase the pH of the bicarbonate buffer from pH 6.2 to 6.8 within 45 min and subsequently stabilise the medium pH at 6.8 ± 0.05 pH units. Enteric coated microparticles showed much faster drug release in the physiological bicarbonate buffers than tablets and pellets. The novel bicarbonate-based dissolution system moves forward the application of the physiological bicarbonate buffers for testing pharmaceutical products to meet compendial requirements.

Effect of Elevated pH on the Commercial Enteric-Coated Omeprazole Pellets Resistance: Patent Review and Multisource Generics Comparison

“…Additionally, after the "gastric phase" at pH 4.5 versus pH 1.2, the release kinetics for 15 min of "intestinal phase" had decreased 1.3, 1.7 and 4.2 times for UQUIFA, Teva and Nosch Labs enteric-coated pellets, respectively (Figure 7, Table IX). In light of recently published information, the aforementioned drug release differences in phosphate buffer solution at pH 7.4 are expected to be even bigger and probably different upon testing in biorelevant bicarbonate solution (57)(58)(59). Apart from that, after the "gastric phase" conditions were changed from pH 1.2, where 85% drug release was observed within 15 min, to pH 4.5, drug release from commercial enteric-coated pellets UQUIFA, Teva and Nosch Labs was observed to be less than 85% in 30 min.…”

In Vitro Methodologies for Evaluating Colon-Targeted Pharmaceutical Products and Industry Perspectives for Their Applications

“…Nonetheless, the lack of correlation against in vivo observations prevents any premature conclusion on the predictivity of this approach. Another sparging-free approach was published by Scott et al, which resulted in a successful pH stabilization of modified Hanks (mHanks) buffer, while still supplementing the media with CO 2(g) [107]. The authors developed an enclosure lid that comprises a plate with two gas inlet holes attached to a ring-shaped bottom chamber with multiple orifices to allow an even gas distribution into the media.…”

“…The authors developed an enclosure lid that comprises a plate with two gas inlet holes attached to a ring-shaped bottom chamber with multiple orifices to allow an even gas distribution into the media. The lack of bubbling with this system allowed the reconciliation of bio-relevant bicarbonate buffer with bile salts, preventing foam formation (See Section 4.2.4) [107]. Carbon dioxide impermeable lids may be a good alternative over the continuous sparging method, as they are easier and faster to assemble [97,106].…”

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“…The T2SS system secretion effectors include CpaA, LipA, and LipH. The LipA and LipH lipases are essential for the use of exogenous lipids, and CpaA is a metalloendopeptidase that degrades fibrinogen and factor V, in a zinc-dependent mechanism, negatively influencing blood clotting pathways [63]. The A. baumannii also harbours the type VI secretion system (T6SS), a multi-component secretion machine capable of injecting protein toxins (like nucleases, peptidoglycan hydrolases, or cell-membrane active toxins) into other bacteria in a contact-dependent manner, without self-intoxication, thus being important in polymicrobial infections [64].…”

“…For example, L. plantarum, Weissela paramesenteroides, Enterococcus faecalis, and L. paraplantarum showed manufacturing way dependent and pH-dependent survivability in a simulated GIT media [62]. There are variable methods to defend stability of dosage form from the stomach environment and deliver it to lower parts of GIT, but the robustness of these methods is different [63][64]. For the vaginal probiotics' delivery could be used different dosage forms such as suppositories, capsules, tablets and others.…”