Dissolution Profiles of Poorly Soluble Drug Salts in Bicarbonate Buffer

Sakamoto, Aoi; Sugano, Kiyohiko

doi:10.1007/s11095-023-03508-x

Cited by 8 publications

(6 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Furthermore, this method also simplifies pH-shift dissolution tests for investigating the effect of gastrointestinal pH transition on drug dissolution, supersaturation, and precipitation processes . The floating lid BCB method has already been used for evaluating the dissolution profiles of drug salts, ASD, and enteric-coated formulations. ,, A harmonization study of the floating lid BCB method is currently under investigation.…”

Section: Discussionmentioning

confidence: 99%

“…The precipitation of dantrolene in PPB was faster with a floating lid than without a floating lid (Figure 4C and Figure 8A). 28 However, when employing the floating lid for both BCB and PPB, little or no difference was observed (Figure 4C). The floating lid could be a substrate for heterogeneous nucleation for dantrolene.…”

Section: Discrepancy Between the Present Study And The Previous Studymentioning

confidence: 97%

“…24 The floating lid BCB method has already been used for evaluating the dissolution profiles of drug salts, ASD, and enteric-coated formulations. 28,65,66 A harmonization study of the floating lid BCB method is currently under investigation.…”

Section: Practical Use Of Bicarbonate Buffer For Precipitation Tests ...mentioning

confidence: 99%

“…Therefore, it cannot be ruled out that the observed difference in the precipitation profiles between BCB and PPB is attributed to the difference in experimental settings such as CO 2 gas bubbling. In addition, we previously reported that the precipitation of dantrolene was faster in BCB than in PPB . In that study, the floating lid method was used to maintain the pH value of BCB.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, we previously reported that the precipitation of dantrolene was faster in BCB than in PPB. 28 In that study, the floating lid method was used to maintain the pH value of BCB. However, to align the experimental conditions, the floating lid should have been applied to PPB, but was not.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer

Yamamoto,

Sugano

2024

Mol. Pharmaceutics

Self Cite

View full text Add to dashboard Cite

The purpose of the present study was to clarify whether the precipitation profile of a drug in bicarbonate buffer (BCB) may differ from that in phosphate buffer (PPB) by a well-controlled comparative study. The precipitation profiles of structurally diverse poorly soluble drugs in BCB and PPB were evaluated by a pH-shift precipitation test or a solvent-shift precipitation test (seven weak acid drugs (pK a : 4.2 to 7.5), six weak base drugs (pK a : 4.8 to 8.4), one unionizable drug, and one zwitterionic drug). To focus on crystal precipitation processes, each ionizable drug was first completely dissolved in an HCl (pH 3.0) or NaOH (pH 11.0) aqueous solution (450 mL, 50 rpm, 37 °C). A 10-fold concentrated buffer solution (50 mL) was then added to shift the pH value to 6.5 to initiate precipitation (final volume: 500 mL, buffer capacity (β): 4.4 mM/ΔpH (BCB: 10 mM or PPB: 8 mM), ionic strength (I): 0.14 M (adjusted by NaCl)). The pH, β, and I values were set to be relevant to the physiology of the small intestine. For an unionizable drug, a solvent-shift method was used (1/100 dilution). To maintain the pH value of BCB, a floating lid was used to avoid the loss of CO 2 . The floating lid was applied also to PPB to precisely align the experimental conditions between BCB and PPB. The solid form of the precipitants was identified by powder X-ray diffraction and differential scanning microscopy. The precipitation of weak acids (pK a ≤ 5.1) and weak bases (pK a ≥ 7.3) was found to be slower in BCB than in PPB. In contrast, the precipitation profiles in BCB and PPB were similar for less ionizable or nonionizable drugs at pH 6.5. The final pH values of the bulk phase were pH 6.5 ± 0.1 after the precipitation tests in all cases. All precipitates were in their respective free forms. The precipitation of ionizable weak acids and bases was slower in BCB than in PPB. The surface pH of precipitating particles may have differed between BCB and PPB due to the slow hydration process of CO 2 specific to BCB. Since BCB is a physiological buffer in the small intestine, it should be considered as an option for precipitation studies of ionizable weak acids and bases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discrepancy Between the Present Study And The Previous Studymentioning

confidence: 97%

Section: Practical Use Of Bicarbonate Buffer For Precipitation Tests ...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer

Yamamoto,

Sugano

2024

Mol. Pharmaceutics

Self Cite

View full text Add to dashboard Cite

show abstract

Dissolution Profiles of Immediate Release Products of Various Drugs in Biorelevant Bicarbonate Buffer: Comparison with Compendial Phosphate Buffer

Okamoto,

Higashino,

Yamamoto

et al. 2024

Pharm Res

View full text Add to dashboard Cite

Purpose The purpose of this study was to clarify the extent to which the dissolution profiles of immediate release (IR) products of various drugs differ between biorelevant bicarbonate buffer (BCB) and compendial phosphate buffer (PPB). Methods The dissolution profiles of the IR products of fifteen poorly soluble ionizable drugs were measured in BCB and PPB. BCB was set to be relevant to the small intestine (pH 6.8, 10 mM). The pH was maintained using the floating lid method. The Japanese pharmacopeia second fluid (JP2, 25 mM phosphate buffer, nominal pH 6.8) was used as compendial PPB. The compendial paddle apparatus was used for the dissolution tests (500 mL, 50 rpm, 37°C). Results In 11/15 cases, a difference in dissolved% (< 0.8 or > 1.25-fold) was observed at a time point. In 4/15 cases, the ratio of the area under the dissolution curve was not equivalent (< 0.8 or > 1.25-fold). In the cases of free-form drugs, the dissolution rate tended to be slower in BCB than in JP2. In the case of salt-form drugs, a marked difference was observed for the cases that showed supersaturation. However, no trend was observed in the differences. Conclusions Many IR products showed differences in the dissolution profiles between biorelevant BCB and compendial PPB. With the floating lid method, BCB is as simple and easy to use as PPB. Biorelevant BCB is recommended for dissolution testing.

show abstract

Solubility vs Dissolution in Physiological Bicarbonate Buffer

Claussen,

Al-Gousous,

Salehi

et al. 2024

Pharm Res

View full text Add to dashboard Cite

Background Phosphate buffer is often used as a replacement for the physiological bicarbonate buffer in pharmaceutical dissolution testing, although there are some discrepancies in their properties making it complicated to extrapolate dissolution results in phosphate to the in vivo situation. This study aims to characterize these discrepancies regarding solubility and dissolution behavior of ionizable compounds. Methods The dissolution of an ibuprofen powder with a known particle size distribution was simulated in silico and verified experimentally in vitro at two different doses and in two different buffers (5 mM pH 6.8 bicarbonate and phosphate). Results The results showed that there is a solubility vs. dissolution mismatch in the two buffers. This was accurately predicted by the in-house simulations based on the reversible non-equilibrium (RNE) and the Mooney models. Conclusions The results can be explained by the existence of a relatively large gap between the initial surface pH of the drug and the bulk pH at saturation in bicarbonate but not in phosphate, which is caused by not all the interfacial reactions reaching equilibrium in bicarbonate prior to bulk saturation. This means that slurry pH measurements, while providing surface pH estimates for buffers like phosphate, are poor indicators of surface pH in the intestinal bicarbonate buffer. In addition, it showcases the importance of accounting for the H2CO3-CO2 interconversion kinetics to achieve good predictions of intestinal drug dissolution.

show abstract

Dissolution Profiles of Poorly Soluble Drug Salts in Bicarbonate Buffer

Cited by 8 publications

References 50 publications

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer

Drug Crystal Precipitation in Biorelevant Bicarbonate Buffer: A Well-Controlled Comparative Study with Phosphate Buffer

Dissolution Profiles of Immediate Release Products of Various Drugs in Biorelevant Bicarbonate Buffer: Comparison with Compendial Phosphate Buffer

Solubility vs Dissolution in Physiological Bicarbonate Buffer

Contact Info

Product

Resources

About