Anomalous Solubility Behavior of Several Acidic Drugs

Avdeef, Alex

doi:10.5599/admet.2.1.30

Cited by 35 publications

(45 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Figures 4 and 5 ratchet up the complexity of logS-pH profiles of surface-active molecules which precipitate both as salts and as uncharged species. The examples were selected to show that care needs to be exercised in interpreting the shapes of the solubility-pH profiles [21][22][23][24][25] and that assays need to be optimized to enhance the confidence in the interpretations of the data. The following logS-pH curve notations are used (except Figures 4b and 5b):…”

Section: Case Studiesmentioning

confidence: 99%

“…Figure 4 shows a very complex solubility-pH profile of a surface-active weak acid, N-[4-(1,4-benzodioxan-6-yl)-2-thiazolyl]oxamic acid, which has two pK a s: 1.32 and 10.31, both determined spectrophotometrically [6]. It is an example of a molecule, when added as a salt, that becomes more soluble as more of it is added to solution, somewhat like the case of amiodarone [24]. The prominent "bump" in the logS-pH profile is consistent with the formation of a hexameric anionic aggregate, (HA -) 6 .…”

Section: Figure 3ementioning

confidence: 99%

“…Several excellent books and reviews serve as background material for the commentary covering the solubility of druglike molecules: general coverage of solubility [7][8][9][10]; salt formation/selection [11][12][13][14][15][16]; polymorphism [17][18][19][20]; analysis of saturated solution speciation [21][22][23][24][25][26][27]; dissolution/solubility of cocrystals [28][29][30][31][32][33][34][35][36][37]; anhydrous forms versus hydrates [16,38,39].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Case Studiesmentioning

confidence: 99%

Section: Figure 3ementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Under such conditions, drugs, especially those with surface-active properties, can form micelles or selfassociated aggregates in the form of dimers, trimers, or higher-order oligomers (62). Many non-steroidal antiinflammatory drugs, such as indomethacin, diclofenac, ibuprofen, ketoprofen, and naproxen, tend to selfassociate by forming mixed-charged micelles or micellelike structures (63).…”

Section: Buffer Solutionsmentioning

confidence: 99%

Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System

Bou‐Chacra

Melo

Morales

et al. 2017

AAPS J

View full text Add to dashboard Cite

Abstract.The introduction of the biopharmaceutics drug classification system (Biopharmaceutics Classification System (BCS)), in 1995, provided a simple way to describe the biopharmaceutics behavior of a drug. Solubility and permeability are among the major parameters, which determine the fraction dose absorbed of a drug substance and consequently its chances to be bioavailable. The purpose of this review is to summarize the evolution of the media used for determining solubility and dissolution and how this can be used in modern drug development. Over the years, physiologically adapted media and buffers were introduced with the intention to better predict the in vivo solubility and dissolution of drug substances. Water, buffer solutions, compendial media, micellar solubilization media, and biorelevant media are reviewed. At this time point, there is no universal medium available which can be used to predict every drug substance's solubility or a drug product's in vivo dissolution behavior. However, there have been many improvements and additions made to media to optimize their in vivo predictability; for example, the current phosphate concentrations in buffers seem to be too high to correlate with the carbonate buffer concentrations in vivo. Biorelevant media were updated to correlate them better with the composition of human intestinal fluids. The BCS was introduced into regulatory sciences as a scientific risk management tool to waive bioequivalence studies under certain conditions. Today's different guidance documents define the dose-solubility ratio differently. As shown for amoxicillin, this can cause more confusion than certainty for globally operating companies. Harmonization of BCS guidelines is highly desirable.

show abstract

“…A step-by-step solubility model construction (for a case similar to that of fluphenazine, Figure 3g) was described recently (Avdeef, 2014a). Each of the log S-pH profile shapes in Figure 3 was compared against a series of templates (Avdeef, 2007(Avdeef, , 2012.…”

Section: Solution Chemistry Model Construction -"Shape Templates"mentioning

confidence: 99%

Phenothiazines solution complexity – Determination of pKa and solubility-pH profiles exhibiting sub-micellar aggregation at 25 and 37°C

Pobudkowska

Ràfols

Subirats

et al. 2016

European Journal of Pharmaceutical Sciences

Self Cite

View full text Add to dashboard Cite

The ionization constants (pK a ) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride, triflupromazine hydrochloride, fluphenazine dihydrochloride, perphenazine free base, and trifluoperazine dihydrochloride) were determined at 25 and 37 o C. The pK a values of these low-soluble surface active molecules were determined by the cosolvent method (n-propanol/water at 37 o C and methanol/water at 25 o C). The log S-pH profiles were measured at 24 h incubation time in 0.15 M phosphate buffers. The log S-pH "shape-template" method, which critically depends on accurate pK a values (determined independently of solubility data), was used to propose speciation models, which were subsequently refined by rigorous mass-action weighted regression procedure described recently. Differential scanning calorimetry (DSC), UV-visible spectrophotometry, potentiometric, and high performance liquid chromatography (HPLC) measurements were used to characterize the compounds. The intrinsic solubility (S 0 ) values of the three least-soluble drugs (chlorpromazine·HCl, triflupromazine·HCl, and trifluoperazine·2HCl) at 25 o C were 0.5, 1.1, and 2.7 μg/mL (resp.). These values increased to 5.5, 9.2, and 8.7 μg/mL (resp.) at the physiological temperature. The enthalpies of solution for the latter compounds were exceptionally high positive (endothermic) values (99-152 kJ·mol -1 ).Cationic sub-micellar aggregates were evident (from the distortions in the log S-pH profiles) for chlorpromazine, fluphenazine, perphenazine, and trifluoperazine at 25 o C. The effects persisted at 37 o C for chlorpromazine and trifluoperazine. The solids in suspension were apparently amorphous in cases where the drugs were introduced as the chloride salts.3

show abstract

Anomalous Solubility Behavior of Several Acidic Drugs

Abstract: The "anomalous solubility behavior at higher pH values" of several acidic drugs originally studied by Higuchi et al. in 1953 [1]

Cited by 35 publications

References 6 publications

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

Equilibrium solubility measurement of ionizable drugs – consensus recommendations for improving data quality

Evolution of Choice of Solubility and Dissolution Media After Two Decades of Biopharmaceutical Classification System

Phenothiazines solution complexity – Determination of pKa and solubility-pH profiles exhibiting sub-micellar aggregation at 25 and 37°C

Contact Info

Product

Resources

About