Salt Solubility Products of Diprenorphine Hydrochloride, Codeine and Lidocaine Hydrochlorides and Phosphates – Novel Method of Data Analysis Not Dependent on Explicit Solubility Equations

Völgyi, Gergely; Marosi, Attila Csaba; Takács‐Novák, Krisztina; Avdeef, Alex

doi:10.5599/admet.1.4.24

Cited by 39 publications

(86 citation statements)

References 30 publications

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“…The mathematical approach in pDISOL-X has been described by Völgyi et al (2013), and the program has been applied in several other recent studies (Avdeef, 2014a, b;Butcher et al, 2015;Avdeef, 2015a). Briefly, the novel data analysis method uses solubility as a function of pH, log S-pH, as measured input data from any analytical technique (along with standard deviations, SD(log S)).…”

Section: Refinement Of Intrinsic Salt Solubility and Aggregation Conmentioning

confidence: 99%

“…The approach does not assume the validity of the Henderson-Hasselbalch (HH) relationship, nor does it depend on any explicitly derived extensions of the HH equations. The mass action algorithm derives its own implicit equations internally, given any practical number of reactions and estimated constants, which are subsequently refined by weighted nonlinear least-squares regression (Avdeef, 2012;Völgyi et al, 2013). Therefore, in principal, drug-salt precipitates, -aggregates, -complexes, -bile salts, -surfactant can be evaluated.…”

Section: Refinement Of Intrinsic Salt Solubility and Aggregation Conmentioning

confidence: 99%

“…The constants in the solubility calculation are iteratively refined with respect to the fixed value of I ref , but are continuously adjusted in the mass balance calculation to the variable ionic strength, I, for each value of pH. The procedure includes the calculation of the activity coefficients using hydration theory proposed by Stokes and Robinson (1948), and has been detailed elsewhere (Wang et al, 2002;Völgyi et al, 2013).…”

Section: Ionic Strength Dependence Of Constants: Pk a Aggregation mentioning

confidence: 99%

“…Eq. (9) can be modified to reflect this, as described in detail elsewhere (Avdeef, 2012;Völgyi et al, 2013).…”

Section: Promazine Hydrochloridementioning

confidence: 99%

“…There are only a handful of other examples of sub-micellar aggregation (Higuchi et al, 1953;Bogardus and Blackwood, 1979;Serajuddin and Rosoff, 1984;Serajuddin and Jarowski, 1985;Fini et al, 1995;Zhu and Streng, 1996;Ledwidge and Corrigan, 1998;Jinno et al, 2000). In the above examples, the stoichiometries of aggregation were estimated from the re-analysis of published solubility-pH data (Avdeef 2007(Avdeef , 2012; Völgyi et al, 2013;Avdeef, 2014a,b;Butcher et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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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

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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

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Section: Refinement Of Intrinsic Salt Solubility and Aggregation Conmentioning

confidence: 99%

Section: Refinement Of Intrinsic Salt Solubility and Aggregation Conmentioning

confidence: 99%

Section: Ionic Strength Dependence Of Constants: Pk a Aggregation mentioning

confidence: 99%

“…Eq. (9) can be modified to reflect this, as described in detail elsewhere (Avdeef, 2012;Völgyi et al, 2013).…”

Section: Promazine Hydrochloridementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

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Binding studies of promethazine and its metabolites with human serum albumin by high-performance affinity chromatography and molecular docking in the presence of codeine

Coelho,

Lima,

Almeida

et al. 2024

Anal Bioanal Chem

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Abstract“Purple Drank”, a soft drink containing promethazine (PMZ) and codeine (COD), has gained global popularity for its hallucinogenic effects. Consuming large amounts of this combination can lead to potentially fatal events. The binding of these drugs to plasma proteins can exacerbate the issue by increasing the risk of drug interactions, side effects, and/or toxicity. Herein, the binding affinity to human serum albumin (HSA) of PMZ and its primary metabolites [N-desmethyl promethazine (DMPMZ) and promethazine sulphoxide (PMZSO)], along with COD, was investigated by high-performance affinity chromatography (HPAC) though zonal approach. PMZ and its metabolites exhibited a notable binding affinity for HSA (%b values higher than 80%), while COD exhibited a %b value of 65%. To discern the specific sites of HSA to which these compounds were bound, displacement experiments were performed using warfarin and (S)-ibuprofen as probes for sites I and II, respectively, which revealed that all analytes were bound to both sites. Molecular docking studies corroborated the experimental results, reinforcing the insights gained from the empirical data. The in silico data also suggested that competition between PMZ and its metabolites with COD can occur in both sites of HSA, but mainly in site II. As the target compounds are chiral, the enantioselectivity for HSA binding was also explored, showing that the binding for these compounds was not enantioselective.

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Predicting Solubility of Newly-Approved Drugs (2016–2020) with a Simple ABSOLV and GSE(Flexible-Acceptor) Consensus Model Outperforming Random Forest Regression

Avdeef¹,

Kansy²

2022

J Solution Chem

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This study applies the ‘Flexible-Acceptor’ variant of the General Solubility Equation, GSE( Φ,B ), to the prediction of the aqueous intrinsic solubility, log 10 S 0 , of FDA recently-approved (2016–2020) ‘small-molecule’ new molecular entities (NMEs). The novel equation had been shown to predict the solubility of drugs beyond Lipinski’s ‘Rule of 5’ chemical space (bRo5) to a precision nearly matching that of the Random Forest Regression (RFR) machine learning method. Since then, it was found that the GSE( Φ,B ) appears to work well not only for bRo5 NMEs, but also for Ro5 drugs. To put context to GSE( Φ,B ), Yalkowsky’s GSE(classic), Abraham’s ABSOLV, and Breiman’s RFR models were also applied to predict log 10 S 0 of 72 newly-approve NMEs, for which useable reported solubility values could be accessed (nearly 60% from FDA New Drug Application published reports). Except for GSE (classic), the prediction models were retrained with an enlarged version of the Wiki- pS 0 database (nearly 400 added log 10 S 0 entries since our recent previous study). Thus, these four models were further validated by the additional independent solubility measurements which the newly-approved drugs introduced. The prediction methods ranked RFR ~ GSE ( Φ,B ) > ABSOLV > GSE (classic) in performance. It was further demonstrated that the biases generated in the four separate models could be nearly eliminated in a consensus model based on the average of just two of the methods: GSE ( Φ,B ) and ABSOLV. The resulting consensus prediction equation is simple in form and can be easily incorporated into spreadsheet calculations. Even more significant, it slightly outperformed the RFR method.

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Salt Solubility Products of Diprenorphine Hydrochloride, Codeine and Lidocaine Hydrochlorides and Phosphates – Novel Method of Data Analysis Not Dependent on Explicit Solubility Equations

Abstract: Abstract

Cited by 39 publications

References 30 publications

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

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

Binding studies of promethazine and its metabolites with human serum albumin by high-performance affinity chromatography and molecular docking in the presence of codeine

Predicting Solubility of Newly-Approved Drugs (2016–2020) with a Simple ABSOLV and GSE(Flexible-Acceptor) Consensus Model Outperforming Random Forest Regression

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